1. Adipocyte. 2012 Apr 1;1(2):96-100. Galectin-12: A protein associated with lipid droplets that regulates lipid metabolism and energy balance. Yang RY(1), Havel PJ, Liu FT. Author information: (1)Department of Dermatology; University of California Davis School of Medicine; Sacramento, CA USA. Galectin-12, a member of the galectin family of animal lectins, is preferentially expressed in adipocytes. We recently reported that this galectin is localized on lipid droplets, specialized organelles for fat storage. Galectin-12 regulates lipid degradation (lipolysis) by modulating lipolytic protein kinase A (PKA) signaling. Mice deficient in galectin-12 exhibit enhanced adipocyte lipolysis, increased mitochondria respiration, reduced adiposity and ameliorated insulin resistance associated with weight gain. The results suggest that galectin-12 may be a useful target for treatment of obesity-related metabolic conditions, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Most previously described galectins largely reside in the cytosol, although they can also be induced to become associated with membrane-containing structures. Along with an in-depth characterization of galectin-12, this mini-review comments on this first report of a galectin normally localized specifically in an organelle that performs an important intracellular function. Further studies will help shed light on how this protein regulates cellular homeostasis, especially energy homeostasis, and provide additional insight into the intracellular functions of galectins. PMCID: PMC3609087 PMID: 23700518 [PubMed] 2. Monaldi Arch Chest Dis. 2012 Sep;78(3):120-8. [Adipokines and coronary artery disease]. [Article in Italian] Strisciuglio T(1), Galasso G, Leosco D, De Rosa R, Di Gioia G, Parisi V, De Luca S, Niglio T, De Biase C, Luciano R, Rengo G, Trimarco B, Piscione F. Author information: (1)Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Italy. Adipose tissue, besides being an important energetic storage, is also a source of cytokines and hormones which act in a paracrine, autocrine and especially endocrine manner, influencing the cardiometabolic axis. Adipokines are a group of mediators with pleiotropic function, that are involved in many physiological processes, so that a disregulation in their secretion can lead to multiple pathological conditions. In this review our aim was to clarify the role of adipokines in the pathogenesis of atherosclerosis, especially in coronary artery disease, and based on current scientific evidence, to analyze the therapeutic and behavioral strategies that are so far available. PMID: 23614326 [PubMed - indexed for MEDLINE] 3. Lik Sprava. 2012 Jul-Sep;(5):27-34. [The effects of hypoxia on initiation and progression of cardiovascular disease in patients with chronic obstructive pulmonary disease]. [Article in Ukrainian] Lyzogub VH, Savchenko OV, Zaval's'ka TV, Dykukha IS, Tyravs'ka IuV. Hypoxia accompanied chronic obstructive pulmonary disease leads to hypercoagulation, vessels' inflammation, imbalance of oxidative and antioxidative systems. These pathological changes cause arterial hypertension, corpulmonale, metabolism disturbance of the whole organism. PMID: 23534269 [PubMed - indexed for MEDLINE] 4. Nutr Hosp. 2012 Sep-Oct;27(5):1408-14. doi: 10.3305/nh.2012.27.5.5887. Gut microbiota and the development of obesity. Boroni Moreira AP(1), Fiche Salles Teixeira T, do C Gouveia Peluzio M, de Cássia Gonçalves Alfenas R. Author information: (1)Federal University of Viçosa, Minas Gerais, Brazil. apboroni@yahoo.com.br INTRODUCTION: Advances in tools for molecular investigations have allowed deeper understanding of how microbes can influence host physiology. A very interesting field of research that has gained attention recently is the possible role of gut microbiota in the development of obesity and metabolic disorders. OBJECTIVE: The aim of this review is to discuss mechanisms that explain the influence of gut microbiota on host metabolism. RESULTS AND DISCUSSION: The gut microbiota is important for normal physiology of the host. However, differences in their composition may have different impacts on host metabolism. It has been shown that obese and lean subjects present different microbiota composition profile. These differences in microbiota composition may contribute to weight imbalance and impaired metabolism. The evidences from animal models suggest that it is possible that the microbiota of obese subjects has higher capacity to harvest energy from the diet providing substrates that can activate lipogenic pathways. In addition, microorganisms can also influence the activity of lipoprotein lipase interfering in the accumulation of triglycerides in the adipose tissue. The interaction of gut microbiota with the endocannabinoid system provides a route through which intestinal permeability can be altered. Increased intestinal permeability allows the entrance of endotoxins to the circulation, which are related to the induction of inflammation and insulin resistance in mice. The impact of the proposed mechanisms for humans still needs further investigations. However, the fact that gut microbiota can be modulated through dietary components highlights the importance to study how fatty acids, carbohydrates, micronutrients, prebiotics, and probiotics can influence gut microbiota composition and the management of obesity. Gut microbiota seems to be an important and promising target in the prevention and treatment of obesity and its related metabolic disturbances in future studies and in clinical practice. PMID: 23478685 [PubMed - indexed for MEDLINE] 5. Int J Dev Biol. 2012;56(10-12):959-67. doi: 10.1387/ijdb.120134jd. Involvement of adipokines, AMPK, PI3K and the PPAR signaling pathways in ovarian follicle development and cancer. Dupont J(1), Reverchon M, Cloix L, Froment P, Ramé C. Author information: (1)Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, UMR85, Nouzilly, France. jdupont@tours.inra.fr The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Adipose tissue plays an important role in this regulation. Indeed, it releases a variety of factors, termed adipokines that regulate energy metabolism, but also reproductive functions. This article summarizes the function and regulation of some better-characterized adipokines (leptin, adiponectin, resistin, visfatin, chemerin and apelin) involved in ovarian follicle development. The follicle appears to use various "nutrient sensing" mechanisms that may form the link between nutrient status and folliculogenesis. This review examines evidence for the presence of pathways that may sense nutrient flux from within the follicle including the PI3K/Akt pathway, adenosine monophosphate-activated kinase (AMPK), and peroxisome proliferator-activated receptors (PPARs). It also reviews current information on the role of these adipokines and signalling pathways in ovarian cancers. PMID: 23417417 [PubMed - indexed for MEDLINE] 6. Adv Exp Med Biol. 2012;771:240-51. Molecular mechanisms of insulin resistance in diabetes. Soumaya K(1). Author information: (1)Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Manar I, Tunis, Tunisia. soumaya15@yahoo.fr Molecular components of impaired insulin signaling pathway have emerged with growing interest to understand how the environment and genetic susceptibility combine to cause defects in this fundamental pathway that lead to insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or Type 2 diabetes can result. The most common underlying cause is obesity, although primary insulin resistance in normal-weight individuals is also possible. The adipose tissue releases free fatty acids that contribute to insulin resistance and also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. This chapter deals with the core elements promoting, insulin resistance, associated with impaired insulin signalling pathway and adipocyte dysfunction. A detailed understanding of these basic pathophysiological mechanisms is critical for the development of novel therapeutic strategies to treat diabetes. PMID: 23393683 [PubMed - indexed for MEDLINE] 7. Curr Genomics. 2012 Aug;13(5):379-94. doi: 10.2174/138920212801619269. Application of Top-Down and Bottom-up Systems Approaches in Ruminant Physiology and Metabolism. Shahzad K(1), Loor JJ. Author information: (1)Department of Animal Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois, 61801, USA. Systems biology is a computational field that has been used for several years across different scientific areas of biological research to uncover the complex interactions occurring in living organisms. Applications of systems concepts at the mammalian genome level are quite challenging, and new complimentary computational/experimental techniques are being introduced. Most recent work applying modern systems biology techniques has been conducted on bacteria, yeast, mouse, and human genomes. However, these concepts and tools are equally applicable to other species including ruminants (e.g., livestock). In systems biology, both bottom-up and top-down approaches are central to assemble information from all levels of biological pathways that must coordinate physiological processes. A bottom-up approach encompasses draft reconstruction, manual curation, network reconstruction through mathematical methods, and validation of these models through literature analysis (i.e., bibliomics). Whereas top-down approach encompasses metabolic network reconstructions using 'omics' data (e.g., transcriptomics, proteomics) generated through DNA microarrays, RNA-Seq or other modern high-throughput genomic techniques using appropriate statistical and bioinformatics methodologies. In this review we focus on top-down approach as a means to improve our knowledge of underlying metabolic processes in ruminants in the context of nutrition. We also explore the usefulness of tissue specific reconstructions (e.g., liver and adipose tissue) in cattle as a means to enhance productive efficiency. PMCID: PMC3401895 PMID: 23372424 [PubMed] 8. Ann Pharm Fr. 2013 Jan;71(1):13-26. doi: 10.1016/j.pharma.2012.07.008. Epub 2012 Aug 28. [Fat mass expansion, fatty acids and adipokines: metabolic markers and risk factors for cardiovascular pathologies]. [Article in French] Lafontan M(1). Author information: (1)Inserm/UPS UMR 1048 - I2MC, institut des maladies métaboliques et cardiovasculaires, 1, avenue Jean-Poulhès, BP 84225, 31432 Toulouse cedex 4, France. max.lafontan@inserm.fr Obesity is described as an independent risk factor for cardiovascular disease. Fat mass expansion is often associated with occurrence of a pro-inflammatory state, which will interfere with cell metabolism in various tissues and alter noticeably insulin-signaling processes. This low-grade, systemic inflammatory response that characterizes obesity will develop towards dysfunctions which will include insulin-resistance, type 2 diabetes, dyslipidemia, hypertension and coronary and vascular pathologies and even toward some cancers. Metabolic and endocrine functions will be briefly considered as well as events related to fat mass expansion such as hypertrophy-related disturbances in adipocyte function and adipose tissue infiltration by immune cells (i.e., macrophages and lymphocytes which could secrete cytokines and chemokines). In addition to the well known function of storage and release on non esterified fatty acids (NEFAs), the adipocytes synthesize and secrete circulating hormones (called adipokines such as leptin, adiponectin and apelin) which are acting as signaling molecules and which are mediators/modulators of the inflammatory processes. The interest of adipose tissue productions as plasma metabolic markers and the dialogue and interactions between adipose tissue productions (i.e., NEFAs, adipokines and cytokines) and other target tissues will be considered. The objective of this paper is to describe adipose tissue dysfunctions observed in obesity and to delineate putative relationships, which could exist between adipose tissue dysfunctions and other tissues. The idea is to describe how adipose tissue dysfunction is involved in the development of type 2 diabetes and cardiovascular diseases. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 23348852 [PubMed - indexed for MEDLINE] 9. Mediators Inflamm. 2012;2012:815953. doi: 10.1155/2012/815953. Epub 2012 Dec 27. Alternatively activated macrophages in types 1 and 2 diabetes. Espinoza-Jiménez A(1), Peón AN, Terrazas LI. Author information: (1)Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Iztacala, 54090 Tlalnepantla, MEX, Mexico. Macrophages are innate immune cells derived from monocytes, which, in turn, arise from myeloid precursor cells in the bone marrow. Macrophages have many important roles in the innate and adaptive immune response, as well as in tissue homeostasis. Two major populations have been defined: The classically activated macrophages that respond to intracellular pathogens by secreting proinflammatory cytokines and reactive oxygen species and alternatively activated macrophages which are induced during Th2 responses displaying anti-inflammatory activities. Both macrophage populations are central players in diabetes, the first one triggering inflammatory responses which initiates insulitis and pancreatic β cell death during type 1 diabetes, whereas the second population decreases hyperglycemia, insulitis, and inflammation in the pancreas, thereby negatively regulate type 1 diabetes. Obesity is an important factor in the development of type 2 diabetes; classically activated macrophages are a dominant cell population involved in the establishment of the inflammatory profile, insulin resistance, and activation of inflammatory signals during the development and progression of this disease. In contrast, alternatively activated macrophages regulate the release of proinflammatory cytokines, attenuating adipose tissue inflammation. Here, we review the advantages and disadvantages of these two macrophage populations with regard to their roles in types 1 and 2 diabetes. PMCID: PMC3543813 PMID: 23326021 [PubMed - indexed for MEDLINE] 10. Rev Fac Cien Med Univ Nac Cordoba. 2012;69(2):102-10. [Obesity and male fertility]. [Article in Spanish] Martini AC(1), Molina RI, Ruiz RD, Fiol de Cuneo M. Author information: (1)Investigadores del Consejo Nacional de Investigaciones Científicas y Tecnológicas, Cátedra de Fisiología Humana, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina. acmartini2000@yahoo.com Obesity and male infertility have increased in the last decades; therefore, a possible association between these pathologies has been explored. Studies inform that obesity may affect fertility through different mechanisms, which alltogether could exert erectile dysfunction and/or sperm quality impairment. These include: 1) hypothalamic-pituitary-testicular (HPG) axis malfunction: obese hormonal profile is characterized by reduction of testosterone, gonadotrophins, SHBG and/or inhibin B concentrations (marker of Sertoli cells function) and hyperestrogenemy (consequence of aromatase overactivity ascribed to adipose tissue increase); 2) increased release of adipose-derived hormones: leptin increase could be responsible for some of the alterations on the HPG axis and could also exert direct deleterious effects on Leydig cells physiology, spermatogenesis and sperm function; 3) proinflammatory adipokines augmentation, higher scrotal temperature (due to fat accumulation in areas surrounding testes) and endocrine disruptors accumulation in adiposites, all of these responsible for the increase in testes oxidative stress and 4) sleep apnea, frequent in obese patients, suppresses the nocturnal testosterone rise needed for normal spermatogenesis. Finally, although controversial, all the above mentioned factors could comprise gametes quality; i.e. decrease sperm density and motility and increase DNA fragmentation, probably disturbing spermatogenesis and/or epididymal function. In summary, although obesity may impair male fertility by some/all of the described mechanisms, the fact is that only a small proportion of obese men are infertile, probably those genetically predisposed or morbidly obese. Nevertheless, it is likely that because the incidence of obesity is growing, the number of men with reduced fertility will increase as well. PMID: 23286540 [PubMed - indexed for MEDLINE] 11. Biol Res. 2012;45(3):279-87. doi: 10.4067/S0716-97602012000300009. In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Pino AM(1), Rosen CJ, Rodríguez JP. Author information: (1)Laboratorio de Biología Celular y Molecular, INTA, Universidad de Chile, Santiago, Chile. The formation, maintenance, and repair of bone tissue involve close interlinks between two stem cell types housed in the bone marrow: the hematologic stem cell originating osteoclasts and mesenchymal stromal cells (MSCs) generating osteoblasts. In this review, we consider malfunctioning of MSCs as essential for osteoporosis. In osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis and insufficient osteoblastogenesis. MSCs are the common precursors for both osteoblasts and adipocytes, among other cell types. MSCs' commitment towards either the osteoblast or adipocyte lineages depends on suitable regulatory factors activating lineage-specific transcriptional regulators. In osteoporosis, the reciprocal balance between the two differentiation pathways is altered, facilitating adipose accretion in bone marrow at the expense of osteoblast formation; suggesting that under this condition MSCs activity and their microenvironment may be disturbed. We summarize research on the properties of MSCs isolated from the bone marrow of control and osteoporotic post-menopausal women. Our observations indicate that intrinsic properties of MSCs are disturbed in osteoporosis. Moreover, we found that the regulatory conditions in the bone marrow fluid of control and osteoporotic patients are significantly different. These conclusions should be relevant for the use of MSCs in therapeutic applications. PMID: 23283437 [PubMed - indexed for MEDLINE] 12. J Pregnancy. 2012;2012:134758. doi: 10.1155/2012/134758. Epub 2012 Nov 1. In utero programming of later adiposity: the role of fetal growth restriction. Sarr O(1), Yang K, Regnault TR. Author information: (1)Department of Obstetrics and Gynaecology, Children's Health Research Institute and Lawson Research Institute, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5C1. osarr@uwo.ca Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation. PMCID: PMC3518064 PMID: 23251802 [PubMed - indexed for MEDLINE] 13. Reprod Fertil Dev. 2012;25(1):48-61. doi: 10.1071/RD12272. Associations between lipid metabolism and fertility in the dairy cow. Wathes DC(1), Clempson AM, Pollott GE. Author information: (1)Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK. dcwathes@rvc.ac.uk Dairy cows mobilise body tissues to support milk production and, because glucose supplies are limited, lipids are used preferentially for energy production. Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue increase through changes in the expression of several key enzymes. This results in a loss of body condition, together with high circulating concentrations of non-esterified fatty acids. Changes in the synthesis, secretion and signalling pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth factor 1) and adipokines (e.g. leptin) are central to the regulation of these processes. A high reliance on fatty acids as an energy source in the peripartum period causes oxidative damage to mitochondria in metabolically active tissues, including the liver and reproductive tract. The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway. Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been associated with longevity in dairy cows. Polymorphisms in many other genes that affect lipid metabolism also show some associations with fertility traits. These include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid accumulation in oocytes and the regenerating endometrium reduces fertility via reductions in embryo survival and increased inflammatory changes, respectively. PMID: 23244828 [PubMed - indexed for MEDLINE] 14. Pharmacol Rep. 2012;64(5):1055-65. 11β-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome. Joharapurkar A(1), Dhanesha N, Shah G, Kharul R, Jain M. Author information: (1)Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India. amitjoharapurkar@zyduscadila.com Obesity and associated metabolic syndrome is one of the greatest health threat to the modern society. Cortisol excess and the glucocorticoid receptor signaling pathway in the metabolically active tissues have been implicated in the development of diabetes and obesity. The key enzyme in the regeneration of intracellular cortisol is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 increases local cortisol production in metabolically active tissue types such as adipose and liver. Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. Clinical and preclinical studies indicate that 11β-HSD1 inhibitors are likely to exert major pharmacological actions in metabolically active tissues. These effects suggest that inhibition of 11β-HSD1 in vivo may be a novel therapeutic target for obesity, diabetes, and metabolic syndrome. The advancement of numerous structural classes of selective 11β-HSD1 inhibitors further indicates that more refined design and screening for isoform and tissue selectivity would yield potential therapeutics in this area. PMID: 23238463 [PubMed - indexed for MEDLINE] 15. Postepy Biochem. 2012;58(2):195-203. [Prodiabetic effect of statins--do we know the mechanisms of this phenomenon?]. [Article in Polish] Otocka-Kmiecik A(1), Rysz J, Banach M. Author information: (1)Zakład Nadciśnienia Tetniczego, Katedra Nefrologii i Nadciśnienia Tetniczego, Uniwersytet Medyczny w Łodzi. Statins are drugs with the unquestionable effectiveness in the reduction of low density lipoprotein cholesterol (LDL-C) and the cardiovascular risk with the acceptable safety profile. On the basis of the above statins are the most common used drugs worldwide. The present review is aimed to discuss the potential mechanisms of statins leading to occurrence of glucose metabolism disturbances through the influence on insulin secretion by the beta-cells of pancreatic islets and the cells' sensitivity on insulin. It might be a results of disadvantageous statin properties connected to the intensification of inflammation and oxidation within the pancreatic islets, and the influence on adipokines secretion by the fat tissue cells. However, it should be emphasized that despite the recommendations of US Food and Drug Administration suggesting to keep caution in connection to potentially prodiabetic statins' properties, this data need to be confirmed in large multicenter clinical trials with properly designed main endpoints. PMID: 23214143 [PubMed - indexed for MEDLINE] 16. Postepy Biochem. 2012;58(2):186-94. [Endothelial dysfunction related to oxidative stress and inflammation in perivascular adipose tissue]. [Article in Polish] Filip M(1), Maciag J, Nosalski R, Korbut R, Guzik T. Author information: (1)Laboratorium Medycyny Translacyjnej, Katedra i Klinika Chorób Wewnetrznych i Medycyny Wsi UJ, CM, Katedra Farmakologii UJ CM, Kraków. Endothelial dysfunction plays an important role in the pathogenesis of many common diseases, like atherosclerosis and hypertension. The key role of the interaction between oxidative stress and inflammation in causal mechanisms of these diseases is widely accepted. Until recently, perivascular adipose tissue was not taken into account while looking at mechanisms of these disorders. However, it has recently been demonstrated that most processes involved in endothelial dysfunction development are taking place in this tissue. Adipocytes are an important source of free radicals and pro-inflammatory cytokines. These molecules lead to further enhancement of oxidative stress, through uncoupling of endothelial nitric oxide synthase (eNOS) and production of peroxynitrite radical instead of nitric oxide which further disrupts eNOS function. In addition, macrophages and T lymphocytes infiltrate adipose tissue as a result of chemotactic proteins release, upon oxidative stress activation, which further enhances inflammation. Thus, the chronic inflammation, which develops in this compartment of adipose tissue in patients with obesity, is the first step in the development of atherosclerotic plaque or hypertension. That is why comprehensive understanding of ongoing processes within perivascular adipocytes is so important. PMID: 23214142 [PubMed - indexed for MEDLINE] 17. Postepy Biochem. 2012;58(2):175-85. [Metabolic and regulatory function of fatty acid synthase]. [Article in Polish] Swierczyński J(1), Sledziński T. Author information: (1)Katedra i Zakład Biochemii, Gdański Uniwersytet Medyczny, Gdańsk. juls@gumed.edu.pl Fatty acid synthase (FAS)--enzyme present in many tissues, catalyses synthesis of palmitate from malonyl-CoA, acetyl-CoA and NADPH. The highest activity of FAS was found in lipogenic tissues (liver, adipose tissue) and in mammary gland during lactation. Palmitate serves as a substrate for synthesis of saturated and unsaturated long chain fatty acids. In turn, fatty acids (including palmitate) are substrates for the synthesis of triacylglycerols (mainly in liver and adipose tissue), membrane lipids and lipids which play a regulatory role. In this review we discuss the structure, regulation and role of FAS in lipogenic tissues. Moreover, this review presents the recently postulated role of FAS in: a) synthesis of natural ligands of PPARalpha; b) feeding behavior; c) endothelial NO production; d) protection of cardiomiocytes from pathological calcium influx; and e) diet induced atherosclerosis. Finally, the role of FAS in the growth of malignant cells is discussed. PMID: 23214141 [PubMed - indexed for MEDLINE] 18. Postepy Biochem. 2012;58(2):127-34. [The endocannabinoid system and its role in regulation of metabolism in peripheral tissues]. [Article in Polish] Rumińska A(1), Dobrzyń A. Author information: (1)Pracownia Sygnałów Komórkowych i Zaburzeń Metabolicznych, Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN, Warszawa. The endocannabinoid system (ECS) comprises cannabinoid receptors (CB1R and CB2R), endogenous lipid ligands (endocannabinoids) and enzymes that synthesize and degrade these compounds. ECS is involved in the regulation of lipogenesis and fatty acids utilization in liver, skeletal muscle and adipose tissue. Activation of CB1 receptor leads to: (i) increase in the activity of transcription factors which regulate gene expression involved in lipid synthesis (SREBP-1c, PPARgamma), (ii) inhibition of AMP-activated protein kinase and (iii) decrease in fatty acid oxidation. Furthermore, increased level of endocannabinoids is associated with reduced insulin sensitivity in skeletal muscle. ECS is also involved in regulation of adipocyte differentiation. This review summarizes the current knowledge on the regulatory function of endocannabinoids and addresses the role of ECS in the pathogenesis of metabolic disorders. PMID: 23214136 [PubMed - indexed for MEDLINE] 19. Horm Res Paediatr. 2012;78(5-6):269-78. doi: 10.1159/000345310. Epub 2012 Nov 28. Development of obesity and polycystic ovary syndrome in adolescents. Vilmann LS(1), Thisted E, Baker JL, Holm JC. Author information: (1)The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital, Holbaek, Denmark. Obesity in adolescents is prevalent worldwide. Polycystic ovary syndrome (PCOS) is often associated with obesity in women, and it has serious metabolic and reproductive health implications. Although PCOS does not become clinically visible until early adolescence, its origins are likely much earlier. Therefore, we reviewed the recent literature regarding the mechanisms linking the development of PCOS and obesity in adolescent girls. We found that excess abdominal adipose tissue (AT) initiates metabolic and endocrine aberrations that are central in the progression of PCOS. As an example, abdominal AT impairs insulin action, which interacts with the progression of hyperandrogenism. In addition, excessive androgen levels lead to impaired glucose uptake, which also contributes to insulin resistance, which again increases the deposition of visceral fat. The body composition is influenced by testosterone, which decreases subcutaneous fat lipolysis and influences adipocyte distribution. These mechanisms may explain why PCOS girls have an increased visceral adipose mass independent of body mass index. Therefore, first-line treatment in adolescent PCOS is often lifestyle intervention to prevent the damaging effects of obesity. Pharmacological treatment of adolescent PCOS is not standardized because the long-term effects in adolescents have not yet been evaluated; therefore, drugs should be prescribed cautiously. Although the complex metabolic interrelationships between obesity and PCOS have yet to be fully understood, the co-occurrence of these conditions in adolescent girls tends to increase the severity of the negative health consequences of each condition. Copyright © 2012 S. Karger AG, Basel. PMID: 23208318 [PubMed - indexed for MEDLINE] 20. Stem Cells Transl Med. 2012 Sep;1(9):658-67. doi: 10.5966/sctm.2012-0069. Epub 2012 Sep 7. Concise review: therapeutic potential of adipose tissue-derived angiogenic cells. Szöke K(1), Brinchmann JE. Author information: (1)University of Oslo, Oslo, Norway. krisztina.szoke@rr-research.no Inadequate blood supply to tissues is a leading cause of morbidity and mortality today. Ischemic symptoms caused by obstruction of arterioles and capillaries are currently not treatable by vessel replacement or dilatation procedures. Therapeutic angiogenesis, the treatment of tissue ischemia by promoting the proliferation of new blood vessels, has recently emerged as one of the most promising therapies. Neovascularization is most often attempted by introduction of angiogenic cells from different sources. Emerging evidence suggests that adipose tissue (AT) is an excellent reservoir of autologous cells with angiogenic potential. AT yields two cell populations of importance for neovascularization: AT-derived mesenchymal stromal cells, which likely act predominantly as pericytes, and AT-derived endothelial cells (ECs). In this concise review we discuss different physiological aspects of neovascularization, briefly present cells isolated from the blood and bone marrow with EC properties, and then discuss isolation and cell culture strategies, phenotype, functional capabilities, and possible therapeutic applications of angiogenic cells obtained from AT. PMCID: PMC3659736 PMID: 23197872 [PubMed - indexed for MEDLINE] 21. Stem Cells Transl Med. 2012 Mar;1(3):230-6. doi: 10.5966/sctm.2011-0054. Epub 2012 Feb 22. Concise review: adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical implications for tissue engineering therapies in regenerative surgery. Gentile P(1), Orlandi A, Scioli MG, Di Pasquali C, Bocchini I, Cervelli V. Author information: (1)Plastic and Reconstructive Surgery Department Tor Vergata University, Rome, Italy. pietrogentile2004@libero.it Cell-based therapy and regenerative medicine offer a paradigm shift in regard to various diseases causing loss of substance or volume and tissue or organ damage. Recently, many authors have focused their attention on mesenchymal stem cells for their capacity to differentiate into many cell lineages. The most widely studied types are bone marrow mesenchymal stem cells and adipose-derived stem cells (ADSCs), which display similar results. Based on the literature, we believe that the ADSCs offer advantages because of lower morbidity during the harvesting procedure. Additionally, platelet-rich plasma can be used in this field for its ability to stimulate tissue regeneration. The aims of this article are to describe ADSC preparation and isolation procedures, preparation of platelet-rich plasma, and the application of ADSCs in regenerative plastic surgery. We also discuss the mechanisms and future role of ADSCs in cell-based therapy and tissue engineering. PMCID: PMC3659840 PMID: 23197782 [PubMed - indexed for MEDLINE] 22. J Biomed Biotechnol. 2012;2012:462543. doi: 10.1155/2012/462543. Epub 2012 Oct 3. Adipose tissue regeneration: a state of the art. Casadei A(1), Epis R, Ferroni L, Tocco I, Gardin C, Bressan E, Sivolella S, Vindigni V, Pinton P, Mucci G, Zavan B. Author information: (1)Casadei Clinic, Via Olimpia 9, Mestre, 30174 Venezia, Italy. Adipose tissue pathologies and defects have always represented a reconstructive challenge for plastic surgeons. In more recent years, several allogenic and alloplastic materials have been developed and used as fillers for soft tissue defects. However, their clinical use has been limited by further documented complications, such as foreign-body reactions potentially affecting function, degradation over time, and the risk for immunogenicity. Tissue-engineering strategies are thus being investigated to develop methods for generating adipose tissue. This paper will discuss the current state of the art in adipose tissue engineering techniques, exploring the biomaterials used, stem cells application, culture strategies, and current regulatory framework that are in use are here described and discussed. PMCID: PMC3488420 PMID: 23193362 [PubMed - indexed for MEDLINE] 23. Prog Brain Res. 2012;201:119-67. doi: 10.1016/B978-0-444-59544-7.00007-X. Prospects for stem cell-derived therapy in stroke. Sinden JD(1), Vishnubhatla I, Muir KW. Author information: (1)ReNeuron Limited, Surrey Research Park, Guildford, Surrey, UK. john-sinden@reneuron.com The prospects for stem cell-derived therapy in stroke look promising, with a myriad of cell therapy products developed from brain, blood, bone marrow, and adipose tissue in early clinical development. Eight clinical trials have now reported final results, and several are currently registered recruiting patients or pending to start. Products passing the safety hurdle are recruiting patients for large efficacy studies. Besides identifying the most appropriate cell type, other issues to resolve include optimal timing for intervention, optimal delivery route, cell dose, patient selection, relevant clinical endpoints, and monitoring for effectiveness, to advance cell therapy through the hurdles of clinical research. In this chapter, we present the products and strategies used in the current cell therapy trials in ischemic stroke, provide an update on relevant preclinical research, and discuss the vital developments still needed to advance their clinical application as a future therapeutic option. Copyright © 2012 Elsevier B.V. All rights reserved. PMID: 23186713 [PubMed - indexed for MEDLINE] 24. Front Physiol. 2012 Nov 19;3:437. doi: 10.3389/fphys.2012.00437. eCollection 2012. Obesity and endocrine dysfunction programmed by maternal smoking in pregnancy and lactation. Lisboa PC(1), de Oliveira E, de Moura EG. Author information: (1)Laboratory of Endocrine Physiology, Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro Rio de Janeiro, Brazil. Obesity is a global epidemic, and maternal smoking has been shown to be associated with the development of childhood obesity. Overall, approximately 40% of children worldwide are exposed to tobacco smoke at home. It is well known that environmental changes within a critical window of development, such as gestation or lactation, can initiate permanent alterations in metabolism that lead to diseases in adulthood, a phenomenon called programming. It is known that programming is based on epigenetic alterations (changes in DNA methylation, histone acetylation, or small interfering RNA expression) that change the expression pattern of several genes. However, little is known concerning the mechanisms by which smoke exposure in neonatal life programs the adipose tissue and endocrine function. Here, we review several epidemiological and experimental studies that confirm the association between maternal nicotine or tobacco exposure during gestation or lactation and the development of obesity and endocrine dysfunction. For example, a positive correlation was demonstrated in rodents between increased serum leptin in the neonatal period and exposure of the mothers to nicotine during lactation, and the further development of leptin and insulin resistance, and thyroid and adrenal dysfunction, in adulthood in the same offspring. Thus, a smoke-free environment during the lactation period is essential to improving health outcomes in adulthood and reducing the risk for future diseases. An understanding of the pathophysiological mechanisms underlying the effects of smoking on programming can provide new insights into therapeutic strategies for obesity. PMCID: PMC3500832 PMID: 23181022 [PubMed] 25. J AOAC Int. 2012 Sep-Oct;95(5):1235-55. Determination and confirmation of parent and total ractopamine in bovine, swine, and turkey tissues by liquid chromatography with tandem mass spectrometry: First Action 2011.23. Burnett TJ(1), Rodewald JM, Brunelle SL, Neeley M, Wallace M, Connolly P, Coleman MR. Author information: (1)Elanco Animal Health, 2500 Innovation Way, Greenfield, IN 46140, USA. tjburnett@elanco.com A candidate method selected by the AOAC Expert Review Panel (ERP) for Ractopamine for determination and confirmation of parent and total ractopamine by LC/MS/MS was validated in a single laboratory for bovine, swine, and turkey tissues. The candidate method utilizes methanol extraction of the tissues, followed by an optional enzymatic hydrolysis for determination of total (parent plus conjugate) ractopamine. A mixed-mode cation exchange SPE cartridge is used to purify the initial extract before LC/MS/MS. Matrix-matched standards and a ractopamine-d6 internal standard are used for quantification of parent and total ractopamine in unknown samples. Validation data demonstrated that mean intertrial recoveries for ractopamine across all concentrations tested ranged from 79.7 to 102.2% for parent ractopamine and from 79.0 to 100.0% when a hydrolysis step was included. Intertrial repeatability precision ranged from 2.44 to 11.1% for parent ractopamine and 4.97 to 15.0% with hydrolysis. Estimated LOD values were below 0.1 ng/g and LOQ values were validated at 0.25x the maximum residue limits. The data satisfy the requirements of the AOAC Stakeholder Panel for Veterinary Drug Residue Methods for single laboratory validation studies. The method was awarded Official Methods of Analysis First Action 2011.23 by the AOAC ERP on Veterinary Drug Residues. PMID: 23175955 [PubMed - indexed for MEDLINE] 26. Best Pract Res Clin Endocrinol Metab. 2012 Dec;26(6):791-804. doi: 10.1016/j.beem.2012.06.002. Epub 2012 Jul 26. Mitochondria and endocrine function of adipose tissue. Medina-Gómez G(1). Author information: (1)Dpto. de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Facultad de Ciencias de la Salud, Avda. de Atenas s/n, 28922 Alcorcón, Madrid, Spain. gema.medina@urjc.es Excess of adipose tissue is accompanied by an increase in the risk of developing insulin resistance, type 2 diabetes (T2D) and other complications. Nevertheless, total or partial absence of fat or its accumulation in other tissues (lipotoxicity) is also associated to these complications. White adipose tissue (WAT) was traditionally considered a metabolically active storage tissue for lipids while brown adipose tissue (BAT) was considered as a thermogenic adipose tissue with higher oxidative capacity. Nowadays, WAT is also considered an endocrine organ that contributes to energy homeostasis. Experimental evidence tends to link the malfunction of adipose mitochondria with the development of obesity and T2D. This review discusses the importance of mitochondrial function in adipocyte biology and the increased evidences of mitochondria dysfunction in these epidemics. New strategies targeting adipocyte mitochondria from WAT and BAT are also discussed as therapies against obesity and its complications in the near future. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 23168280 [PubMed - indexed for MEDLINE] 27. Duodecim. 2012;128(20):2074-84. [Free fat transfer--a versatile tool in reconstructive surgery]. [Article in Finnish] Kauhanen S(1), Peltoniemi H. Author information: (1)HYKS, Jorvin Sairaala, plastiikkakirurgian klinikka. Free fat transfer or lipofilling is a procedure quickly increasing in popularity. Free fat transfer offers treatment for soft tissue defects caused by trauma or cancer, congenital anomalies, painful scars, irradiation injuries and aesthetic indications. The advantages compared to, e.g., traditional flap reconstructions includes surgical easiness, minor donor-site morbidity, easy access, hardly no scars, quick recovery and avoidance of foreign bodies such as implants. The regenerative potential of free fat transfer is due to abundant adipose derived mesenchymal stem cells (ADSC). These cells are under extremely active investigation and have rapidly led to clinical trials and treatment modalities in combination with tissue engineering. Free fat transfer nowadays offers hope to patients that formerly could not be helped with surgical intervention. PMID: 23167166 [PubMed - indexed for MEDLINE] 28. Nutr Hosp. 2012 Jul-Aug;27(4):991-8. doi: 10.3305/nh.2012.27.4.5833. Possible molecular mechanisms soy-mediated in preventing and treating nonalcoholic fatty liver disease. Oliveira LP(1), de Jesús RP, Freire TO, Oliveira CP, Castro Lyra A, Lyra LG. Author information: (1)Nutrition Science Department, Bahía Federal University, Salvador, Bahia, Brazil. lucipmo@ufba.br The aim of this review is to describe the molecular mechanisms of nonalcoholic fatty liver disease (NAFLD) and to present evidence regarding the mechanisms of soy-mediated therapeutic activity in preventing and treating NAFLD. NAFLD is induced by multiple metabolic pathways, including an increase in the release of fatty acids from the adipose tissue (lipolysis), insulin resistance (IR), and an increase in "de novo" fatty acid synthesis. Furthermore, NAFLD is correlated with a decrease in liver β-oxidation, an increase in oxygen free radical production, and an increase in pro-inflammatory cytokine production, which leads to an increase in liver fat and, subsequently, to tissue damage. The bioactive compounds in soy can prevent and treat NAFLD by modulating lipid metabolism and regulating the expression of related transcription factors. Soy intake decreases the expression of sterol regulatory-element binding protein-lc (SREBP-1) and increases the expression of SREBP-2, which are transcription factors associated with the regulation of hepatic lipogenesis and reduction of cholesterol synthesis and absorption in the liver, respectively. Besides, interactions between soy components, such as standard amino acids, polyunsaturated fat, and the isoflavonoid-enriched fraction, are believed to improve fatty acid oxidation in the liver parenchyma by increasing the expression of peroxisome proliferator-activated receptor α (PPARα)-regulated genes, thus decreasing lipid accumulation in the liver. Therefore, including soy-derived foods in the diet as a therapeutic tool for patients with NAFLD might improve their clinical evolution. PMID: 23165534 [PubMed - indexed for MEDLINE] 29. Nutr Hosp. 2012 Jul-Aug;27(4):971-7. doi: 10.3305/nh.2012.27.4.5792. [Relation of serum levels of C-reactive protein to anthropometric meaurements; a sustematic review of studies in South America]. [Article in Spanish] Ramírez Alvarado MM(1), Sánchez Roitz C. Author information: (1)Departamento de Bioquímica, Escuela de Ciencias Biomédicas y Tecnología, Facultad de Ciencias de Salud, Universidad de Carabobo, Estado Carabobo, Venezuela. mmramirez@uc.edu.ve In many studies the Body Mass Index (BMI) is associated with serum markers of inflammation such as CRP. In obesity there is an increase of adipose tissue resulting in an increase in BMI. It has been reported that adipose tissue has a high production and secretion of a variety of proinflammatory molecules such as tumor necrosis factor-α, interleukin-6, interleukin-8 and C-reactive protein, which may have local effects on the physiology of fat cell and systemic effects on other organs.OBJECTIVE: To conduct a systematic review of studies conducted in South America where they relate serum levels of CRP and anthropometric measurements, BMI and waist circumference (CC) in the healthy adult population. METHODS: We searched the PubMed database for articles published until January 2012, in English, Spanish and Portuguese, which relates serum levels of CRP and anthropometric measurements, BMI and WC. Search for words used PCR, BMI and WC and the names of each of the South American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay and Venezuela). RESULTS: We identified 141 potential studies, of which 8 met the inclusion criteria. In studies serum levels of CRP were positively correlated with BMI (r 0.08 to 0.84) and CC (r 0.27 to 1.03), being highly relevant correlation between BMI and CC with CRP serum levels observed in obese people in South America. CONCLUSION: Serum levels of CRP, and therefore subclinical inflammation seems to be related to increased rates of anthropometric measures in the South American population. A better understanding of the mechanisms and molecular components of the inflammatory response induced by an increase in BMI may lead to identifying new therapeutic targets that can prevent the complications associated with obesity. PMID: 23165532 [PubMed - indexed for MEDLINE] 30. Diabetes Metab Syndr. 2012 Apr-Jun;6(2):120-4. doi: 10.1016/j.dsx.2012.08.011. Epub 2012 Aug 30. Visfatin and its role in obesity development. Stastny J(1), Bienertova-Vasku J, Vasku A. Author information: (1)Department of Pathological Physiology, Masaryk University, Czech Republic. opravdu.stastny@seznam.cz Visfatin, a product of PBEF gene, is an adipocytokine that harbours strong insulin-mimetic activity and it has been reported previously to associate with obesity. Recent reports also provide evidence that Visfatin has also important intracellular effects as it is homologous with nicotinamide phosphoribosyltransferase (NAMPT). In this review, we summarize the main documented effects of Visfatin on metabolism in humans, with special emphasis put on the pathways associated with obesity. Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved. PMID: 23153983 [PubMed - indexed for MEDLINE] 31. Pediatr Endocrinol Diabetes Metab. 2012;18(3):116-9. Thyroid axis alterations in childhood obesity. Gertig AM(1), Niechciał E, Skowrońska B. Author information: (1)Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poland. anna.gertig@interia.pl In recent years researchers have become increasingly interested in the particular relation between the function of the thyroid gland and the body mass in the population of obese children. Numerous studies have been conducted and the literature on the related issues has been abounding. Several thereof have strived at pinpointing a significant link between the function of the thyroid axis and the body mass. Yet, it still remains to be clarified whether these subtle changes in the level of thyroid hormones and TSH observed in childhood obesity are responsible for the increased body mass or rather they represent a secondary phenomenon. The mechanism most often put forward by the researchers that links obesity to thyroid function is the increased level of leptin, which affects neurones in the hypothalamus and the thyroid axis causing TRH and TSH secretion. The body mass is positively correlated with serum leptin and elevated level of leptin is connected with an increase in TSH level. However, there is still controversy whether these inconspicuous differences observed in thyroid axis merit the treatment with thyroxine since these changes seem to constitute a consequence rather than a cause of obesity. Therefore, as most authors postulate, primary importance should be placed on lifestyle changes and body weight reduction leaving substitutive treatment as a supplementary option. The purpose of this review is to present the most current issues on child obesity and the related malfunction of the thyroid axis through an overview of international publications from the years 1996-2011. PMID: 23146791 [PubMed - indexed for MEDLINE] 32. Nestle Nutr Inst Workshop Ser. 2012;73:49-60; discussion p61-6. doi: 10.1159/000341287. Epub 2012 Oct 29. Targeting adipose tissue inflammation to treat the underlying basis of the metabolic complications of obesity. Goran MI(1), Alderete TL. Author information: (1)Department of Preventive Medicine and Childhood Obesity Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. goran@usc.edu The prevalence of obesity has increased throughout the last three decades due to genetic, metabolic, behavioral, and environmental factors [1]. Obesity in turn increases risk for a number of metabolic diseases including type 2 diabetes, cardiovascular disease, fatty liver disease and some forms of cancer [1]. Despite the well-known link between obesity and increased morbidity, the mechanism of this remains elusive. Thus, the question 'why does increased body fat cause increased metabolic comorbidities' remains unanswered. By understanding the underlying basis of obesity-associated metabolic diseases, different therapies could be designed to target relevant pathways. Although we lack a full understanding of the underlying mechanisms that result in disease, several putative explanations exist for why fat affects metabolic health. One such theory is based on the anatomic location of fat deposition and ectopic fat accumulation [2]. Specifically, current literature suggests that visceral, liver and skeletal fat accumulation affects organ function and contributes to the development of insulin resistance, fatty liver, and the metabolic syndrome [3]. However, even in individuals matched for body fat and fat distribution, significant differences can exist in metabolic outcomes, and the phenomenon of metabolically healthy obese has been well described [4]. More recent data suggest the alternative hypothesis relating excess adipose tissue to disease risk based on the metabolic function and morphological properties of adipose tissue. In this scenario, excess adipose tissue is hypothesized to contribute to a state of chronic inflammation which promotes development of insulin resistance as well as other metabolic complications by stimulating nuclear factor-ĸB and Jun N-terminal kinase pathways in adipocytes and the liver [5]. In this paper, we will review the hypothesis linking excess adipose tissue to increased disease risk through adipose tissue inflammation. Copyright © 2012 Nestec Ltd., Vevey/S. Karger AG, Basel. PMCID: PMC4439096 PMID: 23128765 [PubMed - indexed for MEDLINE] 33. Med Sport Sci. 2012;59:94-103. doi: 10.1159/000341968. Epub 2012 Oct 15. Impact of milk consumption and resistance training on body composition of female athletes. Josse AR(1), Phillips SM. Author information: (1)Department of Kinesiology, Faculty of Science, McMaster University, Hamilton, Ont., Canada. Resistance exercise (RE) preceding the provision of high-quality dairy protein supports muscle anabolism. Milk contains bioactive components, including two high-quality protein fractions, calcium and vitamin D, each of which has been shown modulate body composition (increasing lean mass and decreasing fat mass) under energy balance and hypoenergetic conditions. These dairy nutrients are also essential for skeletal health. Acutely, no study of RE and milk/whey consumption has been undertaken exclusively in female athletes, let alone women, nevertheless, studies with both men and women show increased lean mass accretion following milk/whey compared to soy/placebo. Currently, no longer-term RE studies with milk supplementation have been done in female athletes. However, trials in young recreationally active women demonstrated augmented increases in lean mass and decreases in fat mass with RE and milk or whey protein consumption. The amount of protein consumed post-exercise is also important; two trials using yogurt (5 g protein/6 oz) failed to demonstrate a positive change in body composition compared to placebo. For bone health, RE plus dairy improved bone mineral density at clinically important sites and reduced bone resorption. With energy restriction, in one study, higher dairy plus higher protein resulted in greater fat loss, lean mass gain and improved bone health in overweight women. In another study, milk and calcium supplementation showed no greater benefit. Neither trial exclusively utilized RE. Overall, RE and milk/dairy consumption positively impact body composition in women by promoting losses in fat, gains or maintenance of lean mass and preservation of bone. Future studies in female athletes and under energy restriction with RE alone are warranted. Copyright © 2012 S. Karger AG, Basel. PMID: 23075559 [PubMed - indexed for MEDLINE] 34. Endocr Pract. 2012 Sep-Oct;18(5):763-71. doi: 10.4158/EP12139.RA. Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance. Gorden P(1), Zadeh ES, Cochran E, Brown RJ. Author information: (1)Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. phillipg@intra.niddk.nih.gov OBJECTIVE: To investigate the link between insulin resistance and the metabolic syndrome how to develop treatment approaches. METHODS: We present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment. RESULTS: In lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin "receptoropathies," including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed. CONCLUSIONS: We present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes. PMCID: PMC3875336 PMID: 23047930 [PubMed - indexed for MEDLINE] 35. Curr Med Chem. 2012;19(34):5837-53. Obesity-driven inflammation and colorectal cancer. Vazzana N(1), Riondino S, Toto V, Guadagni F, Roselli M, Davi G, Ferroni P. Author information: (1)Internal Medicine, G. D'Annunzio University Foundation, Chieti, Italy. Visceral obesity is characterized by increased risk of cardiovascular disease as well as higher incidence of malignancies, including colorectal cancer (CRC), although the mechanisms linking excess adiposity with cancer are only partly characterized. Visceral obesity is currently acknowledged as a chronic inflammatory disorder and a growing body of evidence demonstrates the interconnections between obesity-related secretion pattern of adipo/cytokines and CRC. Specific molecules derived from the visceral adipose tissue (VAT), including adiponectin, leptin and resistin, are able to establish a positive feedback loop, thus increasing the proinflammatory and insulin resistant state and promoting tumorigenesis. Interestingly, these molecules have emerged as novel prognostic factors and therapeutic targets. This review will focus on current molecular and clinical evidence linking VAT-related inflammation to CRC initiation and progression, and summarize the role of dietary factors and lifestyle interventions aimed at promoting weight control and physical activity on CRC prevention and prognosis. PMID: 23033947 [PubMed - indexed for MEDLINE] 36. Indian J Pathol Microbiol. 2012 Jul-Sep;55(3):389-91. doi: 10.4103/0377-4929.101755. Left-sided giant adrenal myelolipoma secreting catecholamine. Udupa S(1), Usha M, Visweswara RN, Desai MG. Author information: (1)Department of Pathology, MSU-GEF International Medical School, Bangalore, Karnataka, India. Adrenal myelolipoma (AML) is a rare benign tumor composed of mature adipose and hematopoietic tissue. Most of these patients are asymptomatic and the tumors are non-secreting. We present a case with a large functional adrenal myelolipoma, wherein the patient was hypertensive and biochemistry revealed increase in 24 hours urinary Vanillylmandelic Acid (VMA), a metabolite of catecholamine. The mass was removed surgically and diagnosed as adrenal myelolipoma on histopathological examination. Both his blood pressure and urinary VMA returned to normal following surgery, which suggested that the mass was functioning and was secreting catecholamine. To the best of our knowledge, a catecholamine secreting adrenal myelolipoma has been reported in the literature only once previously. The association of hypertension and adrenal myelolipoma may not be entirely coincidental, as it may be associated with secreting catecholamine, as seen in our case. We also review the literature on functioning adrenal myelolipoma. PMID: 23032842 [PubMed - indexed for MEDLINE] 37. Przegl Lek. 2012;69(4):149-56. [Lipodystrophy: a new insight into an old disease]. [Article in Polish] Krysiak R(1), Rudzki H, Okopień B. Author information: (1)Klinika Chorób Wewnetrznych i Farmakologii Klinicznej Katedry Farmakologii Slaskiego Uniwersytetu Medycznego w Katowicach. r.krysiak@interia.pl Adipose tissue is now recognized as a highly active metabolic and endocrine organ secreting a range of bioactive peptides with both local and distant action, known as adipokines. Some of these factors are specific fat-related hormones that are involved in regulating energy homeostasis, carbohydrate and lipid metabolism. Adipose tissue disorders may have potential repercussions in the pathophysiology of obesity, insulin resistance, and dyslipidemia. Lipodystrophies are characterized by a selective loss of body fat although the extent of fat loss is different. They may be either inherited or acquired, as well as either generalized or limited to some parts of the body. Females are affected more often than men. If the fat loss is marked, patients develop insulin resistance and its complications, such as diabetes, atherogenic dyslipidemia, hepatic steatosis, and indices of hyperandrogenism. The aim of this article is to discuss the aetiology, clinical manifestations, diagnosis and treatment of different lipodystrophy syndromes with a special emphasis on the most recent literature. PMID: 23029709 [PubMed - indexed for MEDLINE] 38. Circ Res. 2012 Sep 28;111(8):1079-90. Novel biological functions of high-density lipoprotein cholesterol. Mineo C(1), Shaul PW. Author information: (1)Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. In addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger receptor class B, type I, and plasma membrane receptor activation by HDL cargo molecules. In endothelial cells and their progenitors, HDL attenuates apoptosis and stimulates proliferation and migration. HDL also has diverse anti-inflammatory actions in both endothelial cells and leukocytes. In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. There are additional actions of HDL of potential cardiovascular consequence that are indirect, including the capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties. Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health. PMCID: PMC3500606 PMID: 23023510 [PubMed - indexed for MEDLINE] 39. Cytokine. 2013 Jan;61(1):1-14. doi: 10.1016/j.cyto.2012.08.036. Epub 2012 Sep 27. Functional and structural features of adipokine family. Raucci R(1), Rusolo F, Sharma A, Colonna G, Castello G, Costantini S. Author information: (1)Biochemistry and Biophysic Department, CRISCEB, Second University of Naples, Naples, Italy. In the mid-1990s, the interest in adipose tissue was revived by the discovery of leptin. Since then numerous other hormones have been isolated from white adipose tissue that has no longer considered an inert tissue mainly devoted to energy storage but emerged as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines, as well as cytokines and chemokines. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified. In this paper we want to review: (i) the role of adipose tissue in different biological processes, (ii) the functional and structural description of all the known adipokines subdivided in different subfamilies, (iii) the adipokine involvement in obesity and cancers, and (iv) the adipokine interactome. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 23022179 [PubMed - indexed for MEDLINE] 40. Metabolism. 2012 Dec;61(12):1659-65. doi: 10.1016/j.metabol.2012.09.001. Epub 2012 Sep 26. Advances in adipokines. Sahin-Efe A, Katsikeris F, Mantzoros CS. PMID: 23021039 [PubMed - indexed for MEDLINE] 41. Vitam Horm. 2012;90:397-417. doi: 10.1016/B978-0-12-398313-8.00015-4. New insights into anticarcinogenic properties of adiponectin: a potential therapeutic approach in breast cancer? Delort L(1), Jardé T, Dubois V, Vasson MP, Caldefie-Chézet F. Author information: (1)Clermont Université, Université d'Auvergne, UFR Pharmacie, Laboratoire SVFp, 28 Place Henri Dunant, F-63000 Clermont-Ferrand, France. laetitia.delort@udamail.fr Obesity is a recognized breast cancer risk factor in postmenopausal women. A recent hypothesis suggests a major role for adipose tissue in carcinogenesis. During many years, the adipose tissue was only considered as a fat storage of energy. This tissue is now described as an endocrine organ secreting a large range of molecules called adipokines. Among these adipokines, adiponectin may play a major role in breast cancer. Plasma adiponectin levels were found to be decreased in cases of breast cancer and in obese patients. Adiponectin may act directly on breast cancer cells by inhibiting proliferation and angiogenesis or by stimulating apoptosis. Increasing adiponectin levels may be of major importance in the prevention and/or the treatment of breast cancer. This therapeutic approach may be of particular significance for obese patients. The beneficial effects of adiponectin and its possible therapeutic applications will be discussed in this review. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017724 [PubMed - indexed for MEDLINE] 42. Vitam Horm. 2012;90:375-95. doi: 10.1016/B978-0-12-398313-8.00014-2. Adiponectin and interleukin-6 in inflammation-associated disease. Li L(1), Wu LL. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. Numerous lines of evidence implicate a role for adipose tissue in the development of a systemic inflammatory state that contributes to metabolic, cardiovascular, and autoimmune disorders. Serum levels of adiponectin, a cytokine that is mainly produced by adipocytes, are paradoxically decreased in individuals with obesity, type 2 diabetes, and cardiovascular disease compared with healthy individuals. Mounting experimental data have revealed that adiponectin exhibits beneficial effects on energy homeostasis and cardiovascular functions that are attributed to its direct modulation of a proinflammatory factor, interleukin-6. However, some recent studies indicate that adiponectin appears to function as an inducer of proinflammatory factors and the elevated adiponectin level aggravates inflammation response in autoimmune disease. In this review, we focus on the action of adiponectin in chronic inflammation-associated metabolic, cardiovascular, and autoimmune disorders. In particular, we discuss the interaction between adiponectin and interleukin-6 in adipocytes and cardiovascular cells. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017723 [PubMed - indexed for MEDLINE] 43. Vitam Horm. 2012;90:341-74. doi: 10.1016/B978-0-12-398313-8.00013-0. Lipid-lowering drugs and circulating adiponectin. Wanders D(1), Plaisance EP, Judd RL. Author information: (1)Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA. Pharmacological agents used to treat primary and combined hyperlipidemia reduce cardiovascular disease morbidity and mortality. Risk reduction has been attributed to improvements in blood lipid and lipoprotein characteristics. However, each class of available lipid-lowering drugs has been shown to exhibit pleiotropic effects that broaden their anticipated actions. Indeed, the results of a growing number of available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and circulating concentrations of the adipose tissue derived protein, adiponectin. Adiponectin is the most abundantly secreted protein from adipose tissue and has been shown to decrease hepatic glucose production, increase fatty acid oxidation in liver and skeletal muscle, and decrease vascular inflammation. In this chapter, we present a comprehensive analysis of the effects of the available classes of lipid-lowering drugs (statins, fibrates, niacin, and omega-3-fatty acids) on circulating adiponectin and the known mechanisms which produce these important events. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017722 [PubMed - indexed for MEDLINE] 44. Vitam Horm. 2012;90:289-319. doi: 10.1016/B978-0-12-398313-8.00011-7. Adiponectin in the heart and vascular system. Ding M(1), Rzucidlo EM, Davey JC, Xie Y, Liu R, Jin Y, Stavola L, Martin KA. Author information: (1)Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA. Adipose tissue is not only a storage depot for energy, but also an active endocrine tissue. Adipokines, hormones and cytokines secreted from adipocytes, relay information about energy stores to peripheral tissues throughout the body. Most adipokines are produced in direct proportion to fat mass, and many have proinflammatory or otherwise adverse effects on the cardiovascular system. The notable exception is the cardioprotective adipokine adiponectin, which is secreted in inverse proportion to fat mass. Circulating adiponectin levels are highest in lean individuals and inversely correlate with fat mass. Low levels of serum adiponectin are now appreciated as a risk factor in a variety of cardiovascular diseases including coronary artery disease and restenosis, type 2 diabetes mellitus, and hypertension. In this chapter, we provide an introduction to adiponectin and review the extensive evidence in humans and in mouse and in vitro models for adiponectin's cardioprotective effects. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017720 [PubMed - indexed for MEDLINE] 45. Vitam Horm. 2012;90:239-87. doi: 10.1016/B978-0-12-398313-8.00010-5. Adiponectin and the control of female reproductive functions. Palin MF(1), Bordignon VV, Murphy BD. Author information: (1)Agriculture and Agri-Food Canada, Sherbrooke, Quebec, Canada. mariefrance.palin@agr.gc.ca Adiponectin is the most abundant protein secreted by the white adipose tissue. It circulates at high levels in the bloodstream and its serum concentration is inversely correlated with body fat mass. The wide distribution of adiponectin receptors (AdipoR1, AdipoR2, and T-cadherin) in peripheral tissues and organs allows adiponectin to exert pleiotropic effects on whole-body metabolism. Besides its well-known antidiabetic, antiatherogenic, and anti-inflammatory properties, accumulating evidence suggests a direct role for adiponectin in reproductive tissues. The mammalian ovary and the ovarian follicle express AdipoR1 and AdipoR2, and treating pig granulosa cells with adiponectin induces changes characteristic of the periovulatory period. Moreover, additive effects are observed between adiponectin and insulin in induction of granulosa cell gene expression, thus suggesting that adiponectin actions on the ovary may be mediated through its insulin-sensitizing effects. Adiponectin receptors are also detected in the uterus. In women, higher AdipoR1 and AdipoR2 gene expression was observed during the mid-secretory phase of the menstrual cycle, suggesting that adiponectin is implicated in the endometrial changes in preparation for embryo implantation. Adiponectin receptors are found in oocytes and early developing pig, rabbit, and mice embryos, and it has been demonstrated that adiponectin can increase the success of porcine embryo development to the blastocyst stage in vitro. Moreover, adiponectin concentration is two to three times greater in human fetal circulation and in umbilical cord blood, compared to adult plasma. This further indicates a role for adiponectin in fetal growth. It has been further suggested that adipose-derived and locally produced adiponectin may act as a key neuromodulator of reproductive functions. For example, the inhibition of LH and GnRH release from rat pituitary and hypothalamic cells following treatment with adiponectin provides evidence that adiponectin may also act on the release of gonadotropins. Adipose tissue is now recognized as an important factor in the complex equation by which the nutritional status regulates female reproductive functions. For example, underweight women have delayed puberty and higher risk of premature delivery, whereas overweight and obese women have early puberty and are prone to develop polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and preeclampsia. Because hypoadiponectinemia is often associated with the abovementioned disorders, it has been suggested that this adipokine might play a role in the development of these pregnancy-related complications. Moreover, as these reproductive disorders often come with metabolic complications such as insulin and glucose resistance, the insulin-sensitizing effects of adiponectin may explain the observed association of this adipokine with PCOS, GDM, and preeclampsia. This review summarizes current knowledge on the role of adiponectin in female reproductive tissues and highlights mechanisms where information is available. We also discuss about the known and potential roles of adiponectin in the development of reproductive disorders. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017719 [PubMed - indexed for MEDLINE] 46. Vitam Horm. 2012;90:211-38. doi: 10.1016/B978-0-12-398313-8.00009-9. Adiponectin and its receptors in preimplantation embryo development. Cikoš S(1). Author information: (1)Institute of Animal Physiology, Slovak Academy of Sciences, Šoltésovej 4, Košice, Slovak Republic. cikos@saske.sk Adiponectin can play an important role in regulating the female reproductive function and embryo development and can affect the embryo at very early stages of pregnancy--during the preimplantation period. Disturbances in the maternal adiponectin system are associated with several diseases, including diabetes type 2, obesity, and some female reproductive disorders. Adiponectin receptors are expressed in oocytes and preimplantation embryos and can be activated by adiponectin produced by maternal adipose tissue or organs of the female reproductive tract. Adiponectin can affect proliferation and survival of cells in preimplantation embryos, and these effects are isoform dependent. Experimental results suggest involvement of various protein kinases, including mitogen-activated protein kinases, in the regulation of these processes by adiponectin. Actions of adiponectin on lipid and glucose metabolism can increase the energy supply to the embryo, and final targets of adiponectin signaling are metabolic enzymes, glucose transporters, and fatty acid transporters. The involvement of several signaling molecules, such as AMPK/PRKA, PI3K, or AKT/PKB, in the regulation of metabolic processes by adiponectin has been demonstrated in preimplantation embryos. In summary, adiponectin produced in an endocrine/paracrine/autocrine manner can significantly influence preimplantation embryo development, uterine receptivity, and embryo implantation. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017718 [PubMed - indexed for MEDLINE] 47. Vitam Horm. 2012;90:163-86. doi: 10.1016/B978-0-12-398313-8.00007-5. Glucocorticoid effects on adiponectin expression. Sukumaran S(1), Dubois DC, Jusko WJ, Almon RR. Author information: (1)Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA. Maintenance of energy metabolism and glucose homeostasis is achieved by the regulatory effects of many hormones and their interactions. Glucocorticoids produced from adrenal cortex and adiponectin produced by adipose tissue play important roles in the production, distribution, storage, and utilization of energy substrates. Glucocorticoids are involved in the activation of a number of catabolic processes by affecting the expression of a plethora of genes, while adiponectin acts primarily as an insulin sensitizer. Both are regulated by a number of physiological and pharmacological factors. Although the effects of glucocorticoids on adiponectin expression have been extensively studied in different in vitro, animal and clinical study settings, no consensus has been reached. This report reviews the primary literature concerning the effects of glucocorticoids on adiponectin expression and identifies potential reasons for the contradictory results between different studies. In addition, methods to gain better insights pertaining to the regulation of adiponectin expression are discussed. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3693220 PMID: 23017716 [PubMed - indexed for MEDLINE] 48. Vitam Horm. 2012;90:143-62. doi: 10.1016/B978-0-12-398313-8.00006-3. Adiponectin and PPARγ: cooperative and interdependent actions of two key regulators of metabolism. Astapova O(1), Leff T. Author information: (1)Department of Pathology, The Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, Michigan, USA. The recent advances in the understanding of adiponectin and other adipokines have highlighted the role of adipose tissue as an active endocrine organ. One of the central regulators of adipocyte biology is peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that induces the adipogenic gene expression program during development, promotes adipose remodeling, and regulates the functions of adipocytes in lipid storage, adipokine secretion, and energy homeostasis. Activation of PPARγ results in increased insulin sensitivity in skeletal muscle and liver and improves the secretory profile of adipose tissue, favoring release of insulin-sensitizing adipokines, such as adiponectin, and reducing inflammatory cytokines. Increased adiponectin production is likely a significant mediator of the systemic effects of PPARγ activation. This chapter will review the interplay between PPARγ and adiponectin in regulating metabolism, presenting evidence that PPARγ regulates adiponectin gene expression, processing, and secretion and that the two proteins have overlapping effects on downstream metabolic pathways. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017715 [PubMed - indexed for MEDLINE] 49. Vitam Horm. 2012;90:57-94. doi: 10.1016/B978-0-12-398313-8.00003-8. Nutritional and hormonal modulation of adiponectin and its receptors adipoR1 and adipoR2. de Oliveira C(1), de Mattos AB, Silva CB, Mota JF, Zemdegs JC. Author information: (1)Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, USA. crioliva@uol.com.br Adiponectin is the most abundant plasma protein synthesized mostly by adipose tissue and is an insulin-sensitive hormone, playing a central role in glucose and lipid metabolism. Adiponectin effects are mediated via two receptors, adipoR1 and adipoR2. Several hormones and diet components that are involved in insulin resistance may impair insulin sensitivity at least in part by decreasing adiponectin and adiponectin receptors. Adiponectin expression and serum levels are associated with the amount and type of fatty acids and carbohydrate consumed. Other food items, such as vitamins, alcohol, sodium, green tea, and coffee, have been reported to modify adiponectin levels. Several hormones, including testosterone, estrogen, prolactin, glucocorticoids, catecholamines, and growth hormone, have been shown to inhibit adiponectin production, but the studies are still controversial. Even so, adiponectin is a potential therapeutic target in the treatment of diabetes mellitus and other diseases associated with hypoadiponectinemia. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017712 [PubMed - indexed for MEDLINE] 50. Vitam Horm. 2012;90:31-56. doi: 10.1016/B978-0-12-398313-8.00002-6. Molecular tools to characterize adiponectin activity. Juhl C(1), Beck-Sickinger AG. Author information: (1)Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Leipzig, Germany. Within the past years, numerous hormones were found to be secreted by adipose tissue. As these adipokines exert different physiological effects with great importance in obesity, they provide new strategies for the treatment of obesity associated disorders. Adiponectin is one of the most promising targets due to its protective properties in glucose and lipid metabolism, which are mediated by the adiponectin receptor 1 and 2. Within the past decades, substantial progress in understanding the molecular function of this unique ligand-receptor system could be achieved. This review summarizes the most important approaches for the investigation of adiponectin activity. Even though many insights into adipokine function could be achieved, clarification of the detailed mode of action is still challenging. For this reason, this review gives an overview of frequently used methods, which led to the molecular characterization of adiponectin and might help to get more detailed insights into the broad aspects of obesity. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017711 [PubMed - indexed for MEDLINE] 51. Vitam Horm. 2012;90:1-30. doi: 10.1016/B978-0-12-398313-8.00001-4. Lifestyle factors increasing adiponectin synthesis and secretion. Tishinsky JM(1), Dyck DJ, Robinson LE. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. Adiponectin is an anti-inflammatory adipokine released from adipose tissue that is known to exert insulin-sensitizing effects in skeletal muscle and liver. Given that the secretion of adiponectin is impaired in obesity and related pathologies, strategies to enhance its synthesis and secretion are of interest. There is evidence that several lifestyle factors, including consumption of dietary long-chain n-3 PUFA, TZD administration, and weight loss can increase adiponectin synthesis and secretion. The effect of chronic exercise, independent of weight loss, is variable and less convincing. Potential mechanisms by which such lifestyle factors exert their favorable effects on adiponectin include activation of PPARγ and AMPK, regulation of posttranslational modifications, and changes in adipose tissue morphology and macrophage infiltration. As a clear role for adiponectin in mitigating obesity-related impairments in lipid metabolism and insulin sensitivity is evident, further research investigating factors that enhance adiponectin synthesis and secretion is distinctly warranted. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23017710 [PubMed - indexed for MEDLINE] 52. Pharmacol Res. 2012 Dec;66(6):505-12. doi: 10.1016/j.phrs.2012.09.004. Epub 2012 Sep 24. Autophagy in adipose tissue biology. Zhang Y(1), Zeng X, Jin S. Author information: (1)Department of Pharmacology and the Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Obesity, which predisposes individuals to type II diabetes and cardiovascular diseases, results from accumulation of white adipose tissue (WAT). WAT comprises mainly white adipocytes that have a unique cellular structure in which almost the entire intracellular space is occupied by one single lipid droplet. The cytoplasm envelopes this lipid droplet and occupies negligible space. Differentiation of WAT, or adipogenesis, requires dramatic cytoplasmic reorganization, including a dynamic change in mitochondrial mass. Autophagy is a major cytoplasmic degradation pathway and a primary pathway for mitochondrial degradation. Recent studies indicate that autophagy is implicated in adipogenesis. In this review, we summarize our current knowledge on autophagy in adipose tissue biology, with the emphasis on its role in mitochondrial degradation. Adipose tissue is a central component for whole-body energy homeostasis regulation. Advancement in this research area may provide novel venues for the intervention of obesity and obesity related diseases. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 23017672 [PubMed - indexed for MEDLINE] 53. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012 Aug;26(8):1007-11. [Differentiation potential and application of stem cells from adipose tissue]. [Article in Chinese] Shi L(1), Yang X. Author information: (1)No.2 Clinical Company, Graduate Management Team, Institute of Biomedical Engineering, Second Military Medical University, Shanghai 200433, PR China. OBJECTIVE: To introduce types and differentiation potentials of stem cells from adipose tissue, and its applications on regenerative medicine and advantages. METHODS: The literature of original experimental study and clinical research about bone marrow mesenchymal stem cells (BMSCs), adipose-derived stem cells (ADSCs), and dedifferentiated fat (DFAT) cells was extensively reviewed and analyzed. RESULTS: ADSCs can be isolated from stromal vascular fraction. As ADSCs have multi-lineage potentials, such as adipogenesis, osteogenesis, chondrogenesis, angiogenesis, myogenesis, and neurogenesis, they have already been successfully used in regenerative medicine areas. Dramatically, mature fat cells can be dedifferentiated and changed into fibroblast-like cells, named DFAT cells, via ceiling culture method. DFAT cells also had the same multi-lineage potentials as ADSCs, differentiating into adipocytes, osteocytes, chondrocytes, endothelial cells, muscle cells, and nerve cells. Compared with BMSCs which are commonly used as adult stem cells, ADSCs and DFAT cells have extensive sources and can be easily acquired. While compared with ADSCs, DFAT cells have good homogeneity and strong proliferation capacity. CONCLUSION: As a potential source of stem cells, adipose tissue will provide a new promising for regenerative medicine. PMID: 23012940 [PubMed - indexed for MEDLINE] 54. Yale J Biol Med. 2012 Sep;85(3):387-401. Epub 2012 Sep 25. The role of circadian clocks in metabolic disease. Li MD(1), Li CM, Wang Z. Author information: (1)Department of Cellular and Molecular Physiology, Section of Comparative Medicine, and Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale School of Medicine, New Haven, CT 06520, USA. mindian.li@yale.edu The circadian clock is a highly conserved timing system, resonating physiological processes to 24-hour environmental cycles. Circadian misalignment is emerging as a risk factor of metabolic disease. The molecular clock resides in all metabolic tissues, the dysfunction of which is associated with perturbed energy metabolism. In this article, we will review current knowledge about molecular mechanisms of the circadian clock and the role of clocks in the physiology and pathophysiology of metabolic tissues. PMCID: PMC3447202 PMID: 23012586 [PubMed - indexed for MEDLINE] 55. Pediatr Obes. 2012 Dec;7(6):e75-80. doi: 10.1111/j.2047-6310.2012.00089.x. Epub 2012 Sep 21. The potential role of fatty liver in paediatric metabolic syndrome: a distinct phenotype with high metabolic risk? Nobili V(1), Bedogni G, Berni Canani R, Brambilla P, Cianfarani S, Pietrobelli A, Agostoni C. Author information: (1)Metabolic and Autoimmune Liver Disease Unit, Bambino Gesù Children's Hospital, Rome, Italy. nobili66@yahoo.it BACKGROUND: The prevalence of obesity and its metabolic consequences has dramatically increased in the last two decades urging physicians to find a reliable definition for early detection, treatment and possibly prevention of metabolic syndrome (MS). MS could be diagnosed in adult patients in the presence of a large waist circumference and ≥2 of the following features: high serum triglycerides, low serum high-density lipoprotein cholesterol, high blood pressure and high fasting glucose. The definition of MS in children is more problematic, and the potential role of its single components on metabolic risk remains largely undefined. Recent evidence strongly suggests not only a relationship between non-alcoholic fatty liver disease (NAFLD) and MS in obese children, adolescents and adults, but also the key role exerted by liver fat deposition in the pathogenesis of MS. CONCLUSION: We propose that NAFLD should be routinely checked in obese subjects because early lifestyle changes may be effective in reducing the overall risk of MS. © 2012 The Authors. Pediatric Obesity © 2012 International Association for the Study of Obesity. PMID: 23001964 [PubMed - indexed for MEDLINE] 56. Prog Lipid Res. 2013 Jan;52(1):15-42. doi: 10.1016/j.plipres.2012.08.002. Epub 2012 Sep 21. Stearoyl-CoA desaturase: rogue or innocent bystander? Hodson L(1), Fielding BA. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LE, UK. leanne.hodson@ocdem.ox.ac.uk Different lipid fractions in humans have characteristic fatty acid profiles and these are maintained partly through diet and to a lesser extent through endogenous synthesis. The enzyme stearoyl-CoA desaturase (SCD; EC 1.14.99.5) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids such as palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9). These are the two most abundant monounsaturated fatty acids in human plasma lipids, membranes and adipose tissue. Although in quantitative terms, the endogenous synthesis of fatty acids in humans is not great in most circumstances, it is becoming increasingly evident that SCD plays important structural and metabolic roles. In addition, 16:1 n-7 has been purported to act as a beneficial 'lipokine' in an animal model. Research in humans has relied on indirect measurements of SCD1 activity and therefore, much of our understanding has come from work on animal models. However, results have been somewhat counterintuitive and confusing, so the purpose of this review is to try to summarise our current understanding of this fascinating enzyme. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 23000367 [PubMed - indexed for MEDLINE] 57. Metabolism. 2013 Apr;62(4):457-78. doi: 10.1016/j.metabol.2012.08.012. Epub 2012 Sep 20. The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. Michalakis K(1), Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. Author information: (1)First Department of Internal Medicine, Laikon University Hospital, Athens University Medical School, Greece. The aim of this narrative review is to provide current evidence for the interaction between obesity, metabolic syndrome (MS) and reproductive axis. Gonadotropin-releasing hormone (GnRH) pulses and, consequently, normal function of reproductive (hypothalamus-pituitary-gonadal) axis depend on normal energy balance, which presupposes sufficient food intake, reasonable energy consumption and average thermoregulatory costs. In case of an energy imbalance, reproductive dysfunction may occur. In young women, excessive leanness is accompanied by puberty delay, whereas premature puberty might be a manifestation of obesity. In a similar way, obesity in men affects fertility. Excess adipose tissue results in increased conversion of testosterone to estradiol, which may lead to secondary hypogonadism through reproductive axis suppression. Moreover, oxidative stress at the level of the testicular micro-environment may result in decreased spermatogenesis and sperm damage. Products of the adipocyte, such as leptin, adiponectin and resistin, and gut peptides, such as ghrelin, are considered to be crucial in the interaction between energy balance and reproduction. Finally, an indirect evidence for the interplay between MS and reproductive axis is the fact that when treating components of one, parameters of the other can be improved as well. These therapeutic interventions include lifestyle modifications, pharmacological agents, such as sex hormone replacement therapy, and surgical procedures. Although many issues remain unclear, the elucidation of the complex interaction between MS and reproductive axis will have obvious clinical implications in the therapeutic approach of both entities. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 22999785 [PubMed - indexed for MEDLINE] 58. Heart Fail Clin. 2012 Oct;8(4):671-8. doi: 10.1016/j.hfc.2012.06.013. Epub 2012 Aug 9. Epicardial steatosis, insulin resistance, and coronary artery disease. Toth PP(1). Author information: (1)CGH Medical Center, 101 East Miller Road, Sterling, IL 61081, USA. peter.toth@cghmc.com Insulin resistance (IR) is the accepted primary cause of the metabolic syndrome. Visceral obesity is inversely correlated with insulin sensitivity. Hyperinsulinemia (a surrogate for IR) is highly prevalent in patients with coronary artery disease (CAD). Abnormalities in lipid metabolism give rise to steatosis in multiple organs. Evidence is rapidly accumulating to show that epicardial steatosis and expansion of coronary fat pad volume are highly deleterious and associated with increased risk for CAD. This article explores such associations from biochemical and structural standpoints, focusing on changes in epicardial adiposity. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22999248 [PubMed - indexed for MEDLINE] 59. Lakartidningen. 2012 Aug 22-Sep 4;109(34-35):1467-70. [Prolonged bouts of sitting is a metabolic risk factor]. [Article in Swedish] Ekblom-Bak E(1), Ekblom B. Author information: (1)Institutionen for medicin, Karolinska universitetssjukhuset. eline@gih.se PMID: 22993895 [PubMed - indexed for MEDLINE] 60. Arq Bras Endocrinol Metabol. 2012 Aug;56(6):341-50. [Hypothalamic dysfunction in obesity]. [Article in Portuguese] van de Sande-Lee S(1), Velloso LA. Author information: (1)Laboratório de Sinalização Celular, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (FCM-Unicamp), Campinas, SP, Brasil. simonevslee@yahoo.com.br Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans. PMID: 22990637 [PubMed - indexed for MEDLINE] 61. Nicotine Tob Res. 2012 Nov;14(11):1270-90. doi: 10.1093/ntr/nts159. Epub 2012 Sep 18. Nicotinic regulation of energy homeostasis. Zoli M(1), Picciotto MR. Author information: (1)Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125, Modena, Italy. michele.zoli@unimore.it INTRODUCTION: The ability of nicotine, the primary psychoactive substance in tobacco smoke, to regulate appetite and body weight is one of the factors cited by smokers that prevents them from quitting and is the primary reason for smoking initiation in teenage girls. The regulation of feeding and metabolism by nicotine is complex, and recent studies have begun to identify nicotinic acetylcholine receptor (nAChR) subtypes and circuits or cell types involved in this regulation. DISCUSSION: We will briefly describe the primary anatomical and functional features of the input, output, and central integration structures of the neuroendocrine systems that regulate energy homeostasis. Then, we will describe the nAChR subtypes expressed in these structures in mammals to identify the possible molecular targets for nicotine. Finally, we will review the effects of nicotine and its withdrawal on feeding and energy metabolism and attribute them to potential central and peripheral cellular targets. PMCID: PMC3611985 PMID: 22990212 [PubMed - indexed for MEDLINE] 62. Anadolu Kardiyol Derg. 2012 Dec;12(8):684-8. doi: 10.5152/akd.2012.221. Epub 2012 Sep 18. Brain derived neurotrophic factor (BDNF) in cardiometabolic physiology and diseases. Taşçı İ(1), Kabul HK, Aydoğdu A. Author information: (1)Department of Internal Medicine, Gülhane School of Medicine, Ankara-Turkey. itasci@gata.edu.tr Important advances in our understanding of the relationships between adipose tissue derived peptides, namely adipokines, and their effects on cardiovascular functions have been achieved in recent years. Growing knowledge of adipokine biology is revealing the complexity of these proteins. Adipose tissue releases some other proteins called neurotrophins that are mainly active in central and peripheral nervous system. However, secretion and activity of these hormones are not only limited to neuronal cells and tissues, but they also take part in adipose tissue development, energy metabolism, glucose utilization, insulin sensitivity, inflammation, lipoprotein synthesis, and atherosclerosis. In this review, we describe the most recent advances in the functions of brain derived nerve growth factor (BDNF), a major type of neurotrophins, focusing primarily on cardiovascular and metabolic diseases. PMID: 22989797 [PubMed - indexed for MEDLINE] 63. Obes Facts. 2012;5(4):611-24. doi: 10.1159/000342776. Epub 2012 Sep 5. The renin-angiotensin system in the pathophysiology of type 2 diabetes. Goossens GH(1). Author information: (1)Department of Human Biology, NUTRIM School for Nutrition, Toxicology & Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. G.Goossens@maastrichtuniversity.nl Increased activation of the renin-angiotensin system (RAS) has been related to cardiovascular disease and type 2 diabetes mellitus. Most randomized clinical trials have demonstrated that RAS blockade reduces the incidence of type 2 diabetes, which has been explained by improved insulin secretion and insulin sensitivity. In this review, an overview of the mechanisms that may underlie the association between the RAS and type 2 diabetes will be provided, with focus on skeletal muscle and adipose tissue function. This will include discussion of several human studies performed in our laboratory to investigate the metabolic and hemodynamic effects of the RAS, combining in vivo measurements of whole-body and tissue metabolism with molecular and immunohistochemical approaches. Available data suggest that the detrimental effects of the RAS on insulin secretion are mediated by a reduction in pancreatic blood flow and induction of islet fibrosis, oxidative stress as well as inflammation, whereas both impaired skeletal muscle function and adipose tissue dysfunction may underlie RAS-induced insulin resistance. Thus, although future studies in humans are warranted, current evidence supports that targeting the RAS in intervention studies may improve metabolic and cardiovascular function in conditions of insulin resistance like obesity and type 2 diabetes. PMID: 22986649 [PubMed - indexed for MEDLINE] 64. Pharmacol Res. 2012 Dec;66(6):513-25. doi: 10.1016/j.phrs.2012.09.003. Epub 2012 Sep 13. Autophagy, signaling and obesity. Lavallard VJ(1), Meijer AJ, Codogno P, Gual P. Author information: (1)INSERM, U1065, Equipe 8 «Complications hépatiques de l'obésité», Nice, France. Autophagy is a cellular pathway crucial for development, differentiation, survival and homeostasis. Autophagy can provide protection against aging and a number of pathologies such as cancer, neurodegeneration, cardiac disease and infection. Recent studies have reported new functions of autophagy in the regulation of cellular processes such as lipid metabolism and insulin sensitivity. Important links between the regulation of autophagy and obesity including food intake, adipose tissue development, β cell function, insulin sensitivity and hepatic steatosis exist. This review will provide insight into the current understanding of autophagy, its regulation, and its role in the complications associated with obesity. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22982482 [PubMed - indexed for MEDLINE] 65. Vascul Pharmacol. 2013 Jan;58(1-2):3-20. doi: 10.1016/j.vph.2012.09.002. Epub 2012 Sep 12. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Leiherer A(1), Mündlein A, Drexel H. Author information: (1)Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria. Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too. In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22982056 [PubMed - indexed for MEDLINE] 66. Biochimie. 2012 Oct;94(10):2150-6. doi: 10.1016/j.biochi.2012.02.024. Epub 2012 Mar 2. The complex role of adiponectin in chronic kidney disease. Jia T(1), Carrero JJ, Lindholm B, Stenvinkel P. Author information: (1)Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. Although adiponectin, an adipocytokine released from adipose tissue, is thought to have anti-atherogenic, anti-inflammatory, and insulin-sensitizing effects, it appears that high, rather than low, circulating levels of adiponectin predict increased mortality in chronic kidney disease (CKD) patients in whom the circulating levels may rise to about three times higher than the levels in healthy subjects. As it could be hypothesized that in the uremic milieu high adiponectin levels reflect protein-energy wasting, lower residual renal function and/or volume overload, this may explain, at least in part, the observed paradoxical link between hyperadiponectinemia and poor outcome in CKD. To determine the biological consequences of high circulating adiponectin levels on carbohydrate and insulin metabolism as well as relations with cardiovascular function and mortality in the uremic milieu, further studies need to take into account both high-, and low-molecular weight adiponectin moieties as well as the role of adiponectin receptors. This brief review summarizes some of the recent advances in our understanding of the complex and context-sensitive role of this elusive and intriguing adipokine in the uremic milieu. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22980197 [PubMed - indexed for MEDLINE] 67. Biochimie. 2012 Oct;94(10):2075-81. doi: 10.1016/j.biochi.2012.02.022. Epub 2012 Mar 2. Leptin and reproductive function. Hausman GJ(1), Barb CR, Lents CA. Author information: (1)USDA, ARS, Richard B. Russell Research Center, RRC, 950 College Station Rd, Athens, GA 30605, USA. ghausman@saa.ars.usda.gov Adipose tissue plays a dynamic role in whole-body energy homeostasis by acting as an endocrine organ. Collective evidence indicates a strong link between neural influences and adipocyte expression and secretion of leptin. Developmental changes in these relationships are considered important for pubertal transition in reproductive function. Leptin augments secretion of gonadotropin hormones, which are essential for initiation and maintenance of normal reproductive function, by acting centrally at the hypothalamus to regulate gonadotropin-releasing hormone (GnRH) neuronal activity and secretion. The effects of leptin on GnRH are mediated through interneuronal pathways involving neuropeptide-Y, proopiomelanocortin and kisspeptin. Increased infertility associated with diet induced obesity or central leptin resistance are likely mediated through the kisspeptin-GnRH pathway. Furthermore, Leptin regulates reproductive function by altering the sensitivity of the pituitary gland to GnRH and acting at the ovary to regulate follicular and luteal steroidogenesis. Thus leptin serves as a putative signal that links metabolic status with the reproductive axis. The intent of this review is to examine the biological role of leptin with energy metabolism, and reproduction. Published by Elsevier Masson SAS. PMID: 22980196 [PubMed - indexed for MEDLINE] 68. Xenotransplantation. 2012 Sep-Oct;19(5):273-85. doi: 10.1111/xen.12000. Do mesenchymal stem cells function across species barriers? Relevance for xenotransplantation. Li J(1), Ezzelarab MB, Cooper DK. Author information: (1)Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA. BACKGROUND: Allogeneic mesenchymal stem (stromal) cells (MSC) are a promising therapy for various pathological conditions. Genetically modified pig MSC have been demonstrated to downregulate the human T-cell response to pig antigens in vitro. Before genetically modified pig MSC can be used clinically, however, evidence needs to be provided to indicate whether they will survive in a human (xenogeneic) host. LITERATURE SEARCH AND RESULTS: A literature search through the end of 2011 identified 94 reports of the in vivo cross-species administration of MSC in a variety of experimental models. The majority (n = 89) involved the use of human MSC in various other species, with an occasional study using pig, rat, or guinea-pig MSC. When human MSC were used, they were largely derived from the bone marrow, adipose tissue, or umbilical cord blood. The routes of administration were varied, although almost half of the studies utilized the intravenous route. In 88 experiments (93.6%), there was evidence that the MSC engrafted and functioned across the species barrier, and in only six cases (6.4%) was there evidence of failure to function. Importantly, MSC function was confirmed in several different cross-species models. For example, human MSC functioned in no fewer than seven different recipient species. CONCLUSIONS: The data provided by this literature search strengthen the hypothesis that pig MSC will function satisfactorily in a different species, for example, humans. The data also suggest that our own in vitro observations on the efficacy of pig MSC in downregulating the strength of the human T-cell response to pig antigens will likely be reproduced in vivo in pre-clinical large animal models and in clinical trials. © 2012 John Wiley & Sons A/S. PMCID: PMC3445044 PMID: 22978461 [PubMed - indexed for MEDLINE] 69. Gac Med Mex. 2012 Jul-Aug;148(4):381-9. [Cells of innate and adaptive immunity in type 2 diabetes and obesity]. [Article in Spanish] Guzmán-Flores JM(1), López-Briones S. Author information: (1)Departamento de Ciencias Médicas, Universidad de Guanajuato, México. Both type 2 diabetes mellitus (T2DM) and obesity are a major public health problem in Mexico and around the world for increased incidence. In T2DM, insulin secretion, insulin action or both are altered. Also, in T2DM as well as in obesity a low grade chronic inflammation has been associated. In both conditions there is an important increase of visceral adipose tissue, which induces to an up-regulation of synthesis in proinflammatory molecules. This process involves different subsets of the immune system. The macrophages and monocytes are the best studied, but recently has been reported the involvement of other type of cells; such as neutrophils, mast cells, eosinophils, dendritic cells, NKs, NKT. Also, some T cells subsets, such as Th1, Th2, T regulatory, Th17 and B cells seems to be involved in the low grade chronic inflammation. This review focuses on recent evidences of the role of innate and adaptative immune system cells in the pathology of T2DM and obesity. We concluded with the general proposal of a theoretical model, how the immune cells may participate in inflammation of fat tissue, insulin resistance and T2DM. PMID: 22976756 [PubMed - indexed for MEDLINE] 70. Angiology. 2013 Apr;64(3):181-7. doi: 10.1177/0003319712459212. Epub 2012 Sep 11. Renalase, hypertension, and kidney - the discussion continues. Malyszko J(1), Malyszko JS, Rysz J, Mysliwiec M, Tesar V, Levin-Iaina N, Banach M. Author information: (1)Department of Nephrology and Transplantology, Medical University in Bialystok, Bialystok, Poland. jolmal@poczta.onet.pl Hypertension and cardiovascular complications are very common in chronic kidney disease (CKD). Overactivation of sympathetic nervous system is also widely recognized in CKD. Renalase may play an important role in the control of blood pressure (BP) by its regulatory function of catecholamine metabolism. Renalase could be synthesized not only by the kidney but also by cardiomyocytes, liver, and adipose tissue. It probably exerts a hypotensive action, at least in animal models. Whether it metabolizes catecholamines remains to be proved. Another issue that remains to be resolved is the relationship between renalase and renal natriuresis and phosphaturia. In this review, the updated experimental and clinical data on renalase are presented and possible interactions with the endothelium are discussed. Renalase is "a new postulated therapeutic target." Proof of concept studies are needed to define the pathophysiological link between the kidney, sympathetic tone, BP, and cardiovascular complications. PMID: 22969162 [PubMed - indexed for MEDLINE] 71. Benef Microbes. 2012 Sep;3(3):171-4. doi: 10.3920/BM2012.0041. Lactobacillus species causing obesity in humans: where is the evidence? Lahtinen SJ(1), Davis E, Ouwehand AC. Author information: (1)Active Nutrition, DuPont Nutrition & Health, Sokeritehtaantie 20, 02460 Kantvik, Finland. By definition, probiotics are to provide health benefits and are expected not to cause any adverse effects in the general population. Recently, it has been suggested that probiotics and in particular lactobacilli are contributing to human obesity. Here, we critically review the data available on this topic. The main misconception in this hypothesis is that growth in livestock and children equals with obesity in adults. The former two are expected to grow and probiotics may, by reducing disease risk, contribute to an improved growth. It is not correct to extrapolate this growth (of all tissues) to body weight gain (growth of adipose tissue) in adults. Furthermore, when looking at animal models of obesity, it even appears the lactobacilli may potentially contribute to a reduction in body weight. Epidemiological studies lend strength to this. We therefore conclude that there is no evidence that consumption of lactobacilli or probiotics in general would contribute to obesity in humans. PMID: 22968407 [PubMed - indexed for MEDLINE] 72. Biochim Biophys Acta. 2013 Jul;1830(7):3956-64. doi: 10.1016/j.bbagen.2012.08.019. Epub 2012 Aug 29. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Arrojo E Drigo R(1), Fonseca TL, Werneck-de-Castro JP, Bianco AC. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, FL, USA. BACKGROUND: Thyroid hormone signaling is critical for development, growth and metabolic control in vertebrates. Although serum concentration of thyroid hormone is remarkable stable, deiodinases modulate thyroid hormone signaling on a time- and cell-specific fashion by controlling the activation and inactivation of thyroid hormone. SCOPE OF THE REVIEW: This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold-containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner. MAJOR CONCLUSIONS: D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic- and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis. GENERAL SIGNIFICANCE: Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling. Copyright © 2012 Elsevier B.V. All rights reserved. PMID: 22967761 [PubMed - indexed for MEDLINE] 73. Diab Vasc Dis Res. 2013 Mar;10(2):115-22. doi: 10.1177/1479164112455817. Epub 2012 Sep 10. CD40-CD40L: linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications. Seijkens T(1), Kusters P, Engel D, Lutgens E. Author information: (1)Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. t.t.seijkens@amc.uva.nl Numerous epidemiological studies have consistently demonstrated the strong association between type 2 diabetes mellitus (T2DM) and an increased risk to develop cardiovascular disease. The pathogenesis of T2DM and its complications are characterized by pancreatic, adipose tissue and vascular inflammation. CD40 and CD40L, members of the tumour necrosis factor (receptor) TNF(R) family, are well known for their role in immunity and inflammation. Here we give an overview on the role of CD40-CD40L interactions in the pathogenesis of T2DM with a special focus on pancreatic, adipose tissue and vascular inflammation. In addition, we explore the role of soluble CD40L (sCD40L) as a potential biomarker for the development of cardiovascular disease in T2DM subjects. Finally, the therapeutic potential of CD40-CD40L inhibition in T2DM is highlighted. PMID: 22965071 [PubMed - indexed for MEDLINE] 74. Prog Lipid Res. 2013 Jan;52(1):51-61. doi: 10.1016/j.plipres.2012.08.001. Epub 2012 Aug 30. Manipulating molecular switches in brown adipocytes and their precursors: a therapeutic potential. Birerdinc A(1), Jarrar M, Stotish T, Randhawa M, Baranova A. Author information: (1)Center for the Study of Chronic Metabolic Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA. Brown adipocytes constitute a metabolically active tissue responsible for non-shivering thermogenesis and the depletion of excess calories. Differentiation of brown fat adipocytes de novo or stimulation of pre-existing brown adipocytes within white adipose depots could provide a novel method for reducing the obesity and alleviating the consequences of type II diabetes worldwide. In this review, we addressed several molecular mechanisms involved in the control of brown fat activity, namely, the β₃-adrenergic stimulation of thermogenesis during exposure to cold or by catecholamines; the augmentation of thyroid function; the modulation of peroxisome proliferator-activated receptor gamma (PPARγ), transcription factors of the C/EBP family, and the PPARγ co-activator PRDM16; the COX-2-driven expression of UCP1; the stimulation of the vanilloid subfamily receptor TRPV1 by capsaicin and monoacylglycerols; the effects of BMP7 or its analogs; the cannabinoid receptor antagonists and melanogenesis modulating agents. Manipulating one or more of these pathways may provide a solution to the problem of harnessing brown fat's thermogenic potential. However, a better understanding of their interplay and other homeostatic mechanisms is required for the development of novel therapies for millions of obese and/or diabetic individuals. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22960032 [PubMed - indexed for MEDLINE] 75. Surg Obes Relat Dis. 2013 Sep-Oct;9(5):609-16. doi: 10.1016/j.soard.2012.07.010. Epub 2012 Aug 2. Inflammation, obesity, and the promise of immunotherapy for metabolic disease. O'Rourke RW(1). Author information: (1)Department of Surgery, Oregon Health and Science University, Portland, Oregon. Electronic address: orourkro@ohsu.edu. PMCID: PMC3530006 PMID: 22959472 [PubMed - indexed for MEDLINE] 76. Crit Rev Toxicol. 2012 Oct;42(9):751-67. doi: 10.3109/10408444.2012.709225. Epub 2012 Sep 7. An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry. Bosgra S(1), van Eijkeren J, Bos P, Zeilmaker M, Slob W. Author information: (1)Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, NL 3508, Utrecht, The Netherlands. We developed a population physiology model, physB, which provides a statistical description of the physiological characteristics in the human population, in terms of the physiological parameters that are needed in physiologically based pharmacokinetic modelling. The model predicts individual organ weights, blood flows and some respiratory parameters from anthropometric properties (body height and weight, age and gender). It draws on two existing models, PK-Pop and P(3)M, but various changes and improvements were made. The conceptual differences among the three models are discussed and they are quantitatively compared by running all three models for various specific combinations of anthropometric properties. PMID: 22954170 [PubMed - indexed for MEDLINE] 77. Expert Opin Biol Ther. 2012 Dec;12(12):1575-88. doi: 10.1517/14712598.2012.721763. Epub 2012 Sep 6. Mimicking the functional niche of adipose-derived stem cells for regenerative medicine. Kaewsuwan S(1), Song SY, Kim JH, Sung JH. Author information: (1)CHA University, Department of Applied Bioscience, Seoul, Korea. brian99@empal.com INTRODUCTION: A stem cell (SC) niche is defined as the microenvironment in which the adult SC resides and includes surrounding cells, low oxygen content and growth factor gradients. Crosstalk between SCs and their niche provides signals that keep SCs quiescent, or modulates their activation. AREAS COVERED: This review discusses the characterization of niche conditions in the adipose-derived stem cell (ASC) in vivo environment, and introduces key signalling pathways and autocrine/paracrine regulators of ASCs. EXPERT OPINION: Control of in vivo niche factors (such as low oxygen content, generation of reactive oxygen species and activation of platelet-derived growth factor receptor signalling) should increase ASC yields synergistically and reduce production costs. Additionally, the preconditioning of ASCs with these niche factors prior to transplantation might enhance their regenerative potential. ASC niche is complex, and there are components of the niche that we may not yet understand. Therefore, future research needs to focus on identifying the key regulatory factors of the ASC niche in vivo, and developing a novel method to mimic these niche factors for in vitro manipulation. PMID: 22953993 [PubMed - indexed for MEDLINE] 78. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a008417. doi: 10.1101/cshperspect.a008417. Adipogenesis. Sarjeant K(1), Stephens JM. Author information: (1)Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA. Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered. PMCID: PMC3428766 PMID: 22952395 [PubMed - indexed for MEDLINE] 79. Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:84-92. doi: 10.1016/j.prostaglandins.2012.07.004. Epub 2012 Aug 20. 12- and 15-lipoxygenases in adipose tissue inflammation. Cole BK(1), Lieb DC, Dobrian AD, Nadler JL. Author information: (1)Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA. The lipoxygenases (LOs) are principal enzymes involved in the oxidative metabolism of polyunsaturated fatty acids, including arachidonic acid. 12- and 15-LO and their lipid metabolites have been implicated in the development of insulin resistance and diabetes. Adipose tissue, and in particular visceral adipose tissue, plays a primary role in the development of the inflammation seen in these conditions. 12- and 15-LO and their lipid metabolites act as upstream regulators of many of the cytokines involved in the inflammatory response in adipose tissue. While the role that 12- and 15-LO play in chronically inflamed adipose tissue is becoming clearer, there are still many questions that remain unanswered regarding their activation, signaling pathways, and roles in healthy fat. 12- and 15-LO also generate products with anti-inflammatory properties that are under investigation. Therefore, 12- and 15-LO have the potential to be very important targets for therapeutics aimed at reducing insulin resistance and the comorbid conditions associated with obesity. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3526691 PMID: 22951339 [PubMed - indexed for MEDLINE] 80. Nucleic Acid Ther. 2012 Oct;22(5):289-94. doi: 10.1089/nat.2012.0381. Epub 2012 Sep 5. Role of regulatory micro RNAs in type 2 diabetes mellitus-related inflammation. Hamar P(1). Author information: (1)Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. hampet@net.sote.hu Micro RNAs (miRNAs) are small, non-coding RNAs with the function of post-transcriptional gene expression regulation. Micro RNAs may function in networks, forming a complex relationship with diseases. Alterations of specific miRNA levels have significant correlation with diseases of divergent origin, such as diabetes. Type 2 diabetes mellitus (T2DM) has an increasing worldwide epidemic with serious complications. However, T2DM is a chronic process, and from early metabolic alterations to manifest complications decades may pass, during which our diagnostic arsenal is limited. Micro RNAs may thus serve as novel diagnostic tools as well as therapeutic targets in pre-diabetes. Recent Fundings: Micro RNAs (miRNAs) involved in inflammatory processes contributing to the development of type 2 diabetes mellitus (T2DM) published mostly in the past 2 years. MiRNAs are involved in such early diabetic processes as non-alcoholic steatohepatitis (NASH) and inflammation of the visceral adipose tissue. Evidence is emerging regarding the continuous spectrum between type 1 diabetes (T1DM) and T2DM being just 2 endpoints of the same disease with different genetic background. Thus, miRNA regulation of autoimmune components in T2DM may shed new light on pathogenesis. Finally, the involvement of miRNAs in inflammation as a key driving force of diabetic complications is also summarized.CONCLUSION: Inflammation is emerging as a central pathophysiological process in the development of T2DM. Visceral adipose tissue inflammation and non-alcoholic steatohepatitis together with insulitis are probably the first events leading to a complex metabolic disorder. These early events may be diagnosed or even influenced through our increasing knowledge about the involvement of post-transcriptional gene regulation by miRNAs. PMCID: PMC3464406 PMID: 22950794 [PubMed - indexed for MEDLINE] 81. Ther Deliv. 2012 Aug;3(8):997-1004. Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. Greco SJ(1), Rameshwar P. Author information: (1)University of Medicine & Dentistry of New Jersey-New Jersey Medical School, MSB, Room E-579, 185 South Orange Ave, Newark, NJ 07103, USA. greco@umdnj.edu Stem cells have been therapeutically utilized in replacement of hematopoetic cells for decades. This is in contrast to the recent emergence of adult stem cells as, perhaps, safe and beneficial therapeutics for multiple diseases and disorders. In particular, mesenchymal stem cells (MSCs) are currently used in multiple human clinical trials. Although MSCs are ubiquitous, bone marrow, umbilical cord and adipose tissue are the sources where MSCs are isolated for research and clinical application. MSCs were thought to be mesodermal due to the initial reports showing their differentiation into specialized mesodermal cells such as chondrocytes. However, it now appears that MSCs might be neuroectodermal in origin. Thus far, there is no evidence of in vivo transformation of MSCs. However, it is too early to prove or disprove that MSCs can be transformed in vivo in clinical trials. MSCs display immunosuppressive properties when placed in a milieu of inflammatory mediators. This phenotype makes MSCs easily available for therapies as 'off-the-shelf cells. Additionally, MSCs express chemotactic receptors, thereby allowing them to migrate to sites of tissue injury. This latter property has proven useful in the embodiment of MSCs as cellular vehicles to deliver targeted therapeutics to precise regions. The MSCs would typically harbor a prodrug or ectopically express a therapeutic gene to be delivered at a targeted site. This approach has been utilized in a number of different indications requiring precise therapeutic delivery, specifically cancer, cardiovascular disorders and neurodegenerative diseases. Combined with their immune-privileged status, safe clinical profile and low tumorigenicity, MSCs offer vast potential to benefit patients with serious diseases, for which limited treatment options exist. PMID: 22946432 [PubMed - indexed for MEDLINE] 82. J Clin Invest. 2012 Sep;122(9):3035-43. doi: 10.1172/JCI60047. Epub 2012 Sep 4. Mechanisms of thyroid hormone action. Brent GA(1). Author information: (1)Department of Medicine, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA. gbrent@ucla.edu Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function. PMCID: PMC3433956 PMID: 22945636 [PubMed - indexed for MEDLINE] 83. Semin Immunopathol. 2013 Mar;35(2):191-202. doi: 10.1007/s00281-012-0336-6. Epub 2012 Sep 4. Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. Shimizu M(1), Tanaka T, Moriwaki H. Author information: (1)Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. shimim-gif@umin.ac.jp Obesity and related metabolic abnormalities, including a state of chronic inflammation, increase the risk of hepatocellular carcinoma (HCC). Adipose tissue constitutively expresses the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are important tumor promoters in inflammation-related carcinogenesis. Dysregulation of TNF-α and IL-6 is associated with the development of steatosis and inflammation within the liver. These cytokines also lie at the core of the association between obesity and insulin resistance, which is a key factor in the development of obesity-related HCC. Here we present a detailed review of the relationship between metabolic abnormalities and the development of HCC, focusing on the role played by inflammation. Drawing from our basic and clinical research, the present report also reviews evidence that targeting metabolic abnormalities, such as attenuation of chronic inflammation and improvement of insulin resistance by either pharmaceutical or nutritional intervention, may be an effective strategy in preventing the development of HCC in obese individuals. PMID: 22945457 [PubMed - indexed for MEDLINE] 84. Biol Chem. 2012 Sep;393(9):1005-11. doi: 10.1515/hsz-2012-0192. Adipose triglyceride lipase in immune response, inflammation, and atherosclerosis. Radovic B(1), Aflaki E, Kratky D. Author information: (1)Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria. Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, including macrophages. The hydrolytic cleavage of triacylglycerol by adipose triglyceride lipase (ATGL) generates non-esterified fatty acids, which are subsequently used as essential precursors for lipid and membrane synthesis, mediators in cell signaling processes or as energy substrate in mitochondria. This review summarizes the current knowledge concerning the consequences of ATGL deficiency in macrophages with particular emphasis on macrophage (dys)-function, apoptosis, and atherosclerosis. PMCID: PMC3520003 PMID: 22944699 [PubMed - indexed for MEDLINE] 85. Obes Rev. 2012 Dec;13(12):1083-95. doi: 10.1111/j.1467-789X.2012.01024.x. Epub 2012 Sep 3. Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis. Yehuda-Shnaidman E(1), Schwartz B. Author information: (1)Institute of Biochemistry, Food Science and Nutrition, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel. Due to its prevalence, obesity is now considered a global epidemic. It is linked to increased risk of colorectal cancer, the third most common cancer and the second leading cause of death among adults in Western countries. Obese adipose tissue differs from lean adipose tissue in its immunogenic profile, body fat distribution and metabolic profile. Obese adipose tissue releases free fatty acids, adipokines and many pro-inflammatory chemokines. These factors are known to play a key role in regulating malignant transformation and cancer progression. Obese adipose tissue is infiltrated by macrophages that participate in inflammatory pathways activated within the tissue. Adipose tissue macrophages consist of two different phenotypes. M1 macrophages reside in obese adipose tissue and produce pro-inflammatory cytokines, and M2 macrophages reside in lean adipose tissue and produce anti-inflammatory cytokines, such as interleukin-10 (IL-10). The metabolic networks that confer tumour cells with their oncogenic properties, such as increased proliferation and the ability to avoid apoptosis are still not well understood. We review the interactions between adipocytes and immune cells that may alter the metabolism towards promotion of colorectal cancer. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22937964 [PubMed - indexed for MEDLINE] 86. Aging (Albany NY). 2012 Aug;4(8):535-46. Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Lutz CT(1), Quinn LS. Author information: (1)Department of Pathology and Laboratory Medicine, Department of Microbiology, Immunology, and Molecular Genetics, and the Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. ctlutz2@uky.edu Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence. PMCID: PMC3461341 PMID: 22935594 [PubMed - indexed for MEDLINE] 87. Clin Calcium. 2012 Sep;22(9):1383-90. doi: CliCa120913831390. [Diabetes mellitus and osteoporosis. Effect of antidiabetic medicine on osteoporotic fracture]. [Article in Japanese] Hayakawa N(1), Suzuki A. Author information: (1)Clinical Pharmacotherapeutics I, Faculty of Pharmacy, Meijo University, Nagoya, Aichi, Japan. Type 2 diabetes is closely associated with fragility fracture risk. Metabolic control of diabetes may improve bone status, but several anti-diabetic medicines could directly affect bone metabolism. Thiazolidinediones (TZD) may have a negative effect by switching mesenchymal progenitor cells to adipose rather than bone tissue. Clinical trials and meta-analyses showed that elderly women taking TZD could be at increased risk of fractures. On the contrary, in vitro studies suggest that incretin mimetics and incretin enhancers could positively regulate bone metabolism. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which enhance serum incretin concentration, have been reported to reduce clinical fractures. However, further studies would be required for their long term-efficacy and safety on bone metabolism. PMID: 22932293 [PubMed - indexed for MEDLINE] 88. Pneumonol Alergol Pol. 2012;80(5):454-62. [Bronchial asthma in obesity--a distinct phenotype of asthma?]. [Article in Polish] Ziora D(1), Sitek P, Machura E, Ziora K. Author information: (1)Klinika Chorób Płuc i Gruźlicy, ul. ks. Koziołka 1, 41–803 Zabrze. zioradar@wp.pl Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous large cross-sectional and prospective studies performed in adults, adolescents, and children throughout the world supports the hypothesis that obesity is an independent risk factor for asthma. The pathogenetic basis for asthma and obesity associations in humans is not well established. Obesity is capable of reducing pulmonary compliance, lung volumes, and the diameter of peripheral respiratory airways, and may influence on airway hyperresponsiveness. The increase of adipose tissue in obese subjects leads to a systemic inflammatory state, which produces a rise in the serum concentrations of several pro-inflammatory cytokines, chemokines and adipokines. The proinflammatory adipokines (leptin, resistin) and antiinflammatory (adiponectin) may be causally associated with asthma, however human studies are inconclusive. Obese asthma patients very often demonstrate increased asthma severity and relative corticosteroid resistance. Some studies suggest improvements in the disease with weight loss in obese asthma patients. Recently published data suggest that obese asthma patients may represent a distinct phenotype of asthma. PMID: 22926907 [PubMed - indexed for MEDLINE] 89. Brain Res Bull. 2012 Nov 1;89(3-4):144-9. doi: 10.1016/j.brainresbull.2012.08.003. Epub 2012 Aug 18. Metabolic syndrome, mild cognitive impairment and Alzheimer's disease--the emerging role of systemic low-grade inflammation and adiposity. Misiak B(1), Leszek J, Kiejna A. Author information: (1)Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland. mblazej@interia.eu The past decade has shed new light on the etiology of Alzheimer's disease (AD), which is the consequence of interactions between numerous lesions. There is a growing body of evidence that the most beneficial effects of treatment might only be achieved in the preclinical stage of dementia, prior to the immense hallmarks of neurodegeneration. In view of this, several studies have focused on mild cognitive impairment (MCI) as a state, which represents a less severe form of the neuropathological process. However, early treatment interventions initiated in MCI have failed to slow down progression of the disease. Thus, great effort has been made to indicate modifiable risk factors for MCI. Consistent with the role of vascular malfunction in AD, this approach has shown the predictive value of the metabolic syndrome (MetS), which is a multidimensional entity and includes visceral obesity, dyslipidemia, hyperglycemia and hypertension. Despite the positive results of several epidemiological studies, the exact mechanisms underlying the connection between MetS and AD remain uncertain and various theories are being assessed. MetS, similarly to AD, has been attributed to a low-grade chronic inflammation. There is a general consensus that the aberrant inflammatory response underlying MetS may arise from a deregulation of the endocrine homeostasis of adipose tissue. Hence, it might be assumed that the subclinical inflammation of adipose tissue may interact with the impaired central inflammatory response, leading to neurodegeneration. This article reviews the role of low-grade inflammation of adipose tissue in the pathophysiology of cognitive impairment and translates several considerable and unexplored findings from studies focused on subjects with MetS and animal models mimicking the phenotype of MetS into the etiology of AD. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22921944 [PubMed - indexed for MEDLINE] 90. Br J Nutr. 2012 Aug;108 Suppl 1:S46-51. doi: 10.1017/S0007114512000773. Pulse grain consumption and obesity: effects on energy expenditure, substrate oxidation, body composition, fat deposition and satiety. Marinangeli CP(1), Jones PJ. Author information: (1)Kellogg Canada Inc. 5350 Creekbank Rd. Mississauga, ON, Canada L4W 5S1. Pulses have been identified as important components of a healthy diet. Assessment of pulse grains' nutritional composition alongside data from available preclinical and clinical trials suggests that pulses can modulate biological processes that lead to obesity. Components of pulse grains, including pulse-derived fibre and resistant starch, have been shown to alter energy expenditure, substrate trafficking and fat oxidation as well as visceral adipose deposition. Although mechanistic studies are scarce, studies have indicated that fibres found in pulses can have an impact on the expression of genes that modulate metabolism. Arginine and glutamine may produce thermogenic effects as major components of pulse grain proteins. Finally, evidence suggests that pulse-derived fibres, trypsin inhibitors and lectins may reduce food intake by inducing satiety via facilitating and prolonging cholecystokinin secretion. Nonetheless, the aforementioned data remain controversial and associations between dietary pulse grains and energy intake require further study. Given the available evidence, it can be concluded that pulses could be useful as functional foods and food ingredients that combat obesity. PMID: 22916815 [PubMed - indexed for MEDLINE] 91. Adipocyte. 2012;1(1):4-12. Adipose tissue signaling by nuclear receptors in metabolic complications of obesity. Jacobi D(1), Stanya KJ, Lee CH. Author information: (1)Department of Genetics and Complex Diseases; Department of Nutrition; Division of Biological Sciences; Harvard School of Public Health; Boston, MA USA. In recent years white adipose tissue inflammation has been recognized to be associated with obesity. Adipocytes and adipose tissue associated macrophages (ATMs) secrete bioactive molecules, including adipokines, chemokines/cytokines and free fatty acids that modulate the development of low-grade inflammation and insulin resistance responsible for obesity-related metabolic and cardiovascular diseases. Nuclear receptors, notably peroxisome-proliferator-activated receptors, are sensors of dietary lipids and control transcriptional programs of key metabolic and inflammatory pathways in adipocytes and macrophages. This review focuses on mechanisms by which nuclear receptors maintain white adipose tissue homeostasis. The identification of ATMs as active players in the initiation of chronic inflammation and the links between inflammatory signaling and metabolic dysfunction will be presented, followed by discussion of recent evidence for nuclear receptors in ATM function, with an emphasis on the paracrine interaction between adipocytes and ATMs. PMCID: PMC3423221 PMID: 22916336 [PubMed] 92. Dis Model Mech. 2012 Sep;5(5):595-607. doi: 10.1242/dmm.009613. The evolution of human adiposity and obesity: where did it all go wrong? Wells JC(1). Author information: (1)Childhood Nutrition Research Centre, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. Jonathan.Wells@ucl.ac.uk Because obesity is associated with diverse chronic diseases, little attention has been directed to the multiple beneficial functions of adipose tissue. Adipose tissue not only provides energy for growth, reproduction and immune function, but also secretes and receives diverse signaling molecules that coordinate energy allocation between these functions in response to ecological conditions. Importantly, many relevant ecological cues act on growth and physique, with adiposity responding as a counterbalancing risk management strategy. The large number of individual alleles associated with adipose tissue illustrates its integration with diverse metabolic pathways. However, phenotypic variation in age, sex, ethnicity and social status is further associated with different strategies for storing and using energy. Adiposity therefore represents a key means of phenotypic flexibility within and across generations, enabling a coherent life-history strategy in the face of ecological stochasticity. The sensitivity of numerous metabolic pathways to ecological cues makes our species vulnerable to manipulative globalized economic forces. The aim of this article is to understand how human adipose tissue biology interacts with modern environmental pressures to generate excess weight gain and obesity. The disease component of obesity might lie not in adipose tissue itself, but in its perturbation by our modern industrialized niche. Efforts to combat obesity could be more effective if they prioritized 'external' environmental change rather than attempting to manipulate 'internal' biology through pharmaceutical or behavioral means. PMCID: PMC3424456 PMID: 22915021 [PubMed - indexed for MEDLINE] 93. Dis Model Mech. 2012 Sep;5(5):588-94. doi: 10.1242/dmm.009662. The adipose organ at a glance. Cinti S(1). Author information: (1)Department of Experimental and Clinical Medicine, Azienda Ospedali Riuniti-University of Ancona (Politecnica delle Marche), 60020 Ancona, Italy. cinti@univpm.it The main parenchymal cells of the adipose organ are adipocytes. White adipocytes store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions can both originate from endothelial cells, and co-exist in the multiple fat depots of the adipose organ - a feature that I propose is crucial for this organ's plasticity. This poster review provides an overview of the adipose organ, describing its anatomy, cytology, physiological function and histopathology in obesity. It also highlights the remarkable plasticity of the adipose organ, explaining theories of adipocyte transdifferentiation during chronic cold exposure, physical exercise or lactation, as well as in obesity. White-to-brown adipocyte transdifferentiation is of particular medical relevance, because animal data indicate that higher amounts of brown adipose tissue are positively associated with resistance to obesity and its co-morbidities, and that 'browning' of the adipose organ curbs these disorders. PMCID: PMC3424455 PMID: 22915020 [PubMed - indexed for MEDLINE] 94. Dis Model Mech. 2012 Sep;5(5):583-7. doi: 10.1242/dmm.009902. Brain-gut-adipose-tissue communication pathways at a glance. Yi CX(1), Tschöp MH. Author information: (1)Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Technical University Munich, Munich, Germany. One of the 'side effects' of our modern lifestyle is a range of metabolic diseases: the incidence of obesity, type 2 diabetes and associated cardiovascular diseases has grown to pandemic proportions. This increase, which shows no sign of reversing course, has occurred despite education and new treatment options, and is largely due to a lack of knowledge about the precise pathology and etiology of metabolic disorders. Accumulating evidence suggests that the communication pathways linking the brain, gut and adipose tissue might be promising intervention points for metabolic disorders. To maintain energy homeostasis, the brain must tightly monitor the peripheral energy state. This monitoring is also extremely important for the brain's survival, because the brain does not store energy but depends solely on a continuous supply of nutrients from the general circulation. Two major groups of metabolic inputs inform the brain about the peripheral energy state: short-term signals produced by the gut system and long-term signals produced by adipose tissue. After central integration of these inputs, the brain generates neuronal and hormonal outputs to balance energy intake with expenditure. Miscommunication between the gut, brain and adipose tissue, or the degradation of input signals once inside the brain, lead to the brain misunderstanding the peripheral energy state. Under certain circumstances, the brain responds to this miscommunication by increasing energy intake and production, eventually causing metabolic disorders. This poster article overviews current knowledge about communication pathways between the brain, gut and adipose tissue, and discusses potential research directions that might lead to a better understanding of the mechanisms underlying metabolic disorders. PMCID: PMC3424454 PMID: 22915019 [PubMed - indexed for MEDLINE] 95. Proc Nutr Soc. 2012 Nov;71(4):622-33. doi: 10.1017/S0029665112000730. Epub 2012 Aug 22. Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance. Finucane OM(1), Reynolds CM, McGillicuddy FC, Roche HM. Author information: (1)Insitiute of Molecular Medicine, School of Medicine, Trinity Centre for Health Sciences, St James Hospital, Dublin 8, Republic of Ireland. High-fat diet (HFD)-induced obesity has emerged as a state of chronic low-grade inflammation characterised by a progressive infiltration of immune cells, particularly macrophages, into obese adipose tissue. Adipose tissue macrophages (ATM) present immense plasticity. In early obesity, M2 anti-inflammatory macrophages acquire an M1 pro-inflammatory phenotype. Pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β produced by M1 ATM exacerbate local inflammation promoting insulin resistance (IR), which consequently, can lead to type-2 diabetes mellitus (T2DM). However, the triggers responsible for ATM recruitment and activation are not fully understood. Adipose tissue-derived chemokines are significant players in driving ATM recruitment during obesity. Macrophage migration inhibitory factor (MIF), a chemokine-like inflammatory regulator, is enhanced during obesity and is directly associated with the degree of peripheral IR. This review focuses on the functional role of macrophages in obesity-induced IR and highlights the importance of the unique inflammatory cytokine MIF in propagating obesity-induced inflammation and IR. Given MIF chemotactic properties, MIF may be a primary candidate promoting ATM recruitment during obesity. Manipulating MIF inflammatory activities in obesity, using pharmacological agents or functional foods, may be therapeutically beneficial for the treatment and prevention of obesity-related metabolic diseases. PMID: 22914223 [PubMed - indexed for MEDLINE] 96. Am J Physiol Endocrinol Metab. 2012 Nov 1;303(9):E1085-93. doi: 10.1152/ajpendo.00338.2012. Epub 2012 Aug 21. Secondary muscle pathology and metabolic dysregulation in adults with cerebral palsy. Peterson MD(1), Gordon PM, Hurvitz EA, Burant CF. Author information: (1)Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA. mdpeterz@med.umich.edu Cerebral palsy (CP) is caused by an insult to or malformation of the developing brain which affects motor control centers and causes alterations in growth, development, and overall health throughout the life span. In addition to the disruption in development caused by the primary neurological insult, CP is associated with exaggerated sedentary behaviors and a hallmark accelerated progression of muscle pathology compared with typically developing children and adults. Factors such as excess adipose tissue deposition and altered partitioning, insulin resistance, and chronic inflammation may increase the severity of muscle pathology throughout adulthood and lead to cardiometabolic disease risk and/or early mortality. We describe a model of exaggerated health risk represented in adults with CP and discuss the mechanisms and secondary consequences associated with chronic sedentary behavior, obesity, aging, and muscle spasticity. Moreover, we highlight novel evidence that implicates aberrant inflammation in CP as a potential mechanism linking both metabolic and cognitive dysregulation in a cyclical pattern. PMCID: PMC3492860 PMID: 22912367 [PubMed - indexed for MEDLINE] 97. Pediatr Obes. 2012 Oct;7(5):e42-61. doi: 10.1111/j.2047-6310.2012.00073.x. Epub 2012 Aug 21. Adiposity in children and adolescents: correlates and clinical consequences of fat stored in specific body depots. Katzmarzyk PT(1), Shen W, Baxter-Jones A, Bell JD, Butte NF, Demerath EW, Gilsanz V, Goran MI, Hirschler V, Hu HH, Maffeis C, Malina RM, Müller MJ, Pietrobelli A, Wells JC. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808-4124, USA. peter.katzmarzyk@pbrc.edu The 2011 Pennington Biomedical Research Center's Scientific Symposium focused on adiposity in children and adolescents. The symposium was attended by 15 speakers and other invited experts. The specific objectives of the symposium were to (i) integrate the latest published and unpublished findings on the laboratory and clinical assessment of depot-specific adiposity in children and adolescents, (ii) understand the variation in depot-specific adiposity and related health outcomes associated with age, sex, maturation, ethnicity and other factors and (iii) identify opportunities for incorporating new markers of abdominal obesity into clinical practice guidelines for obesity in children and adolescents. This symposium provided an overview of important new advances in the field and identified directions for future research. The long-term goal of the symposium is to aid in the early identification of children and adolescents who are at increased health risk because of obesity and obesity-related conditions. © 2012 The Authors. Pediatric Obesity © 2012 International Association for the Study of Obesity. PMID: 22911903 [PubMed - indexed for MEDLINE] 98. Cytokine Growth Factor Rev. 2013 Feb;24(1):83-9. doi: 10.1016/j.cytogfr.2012.07.004. Epub 2012 Aug 19. Adiponectin: a biomarker for rheumatoid arthritis? Chen X(1), Lu J, Bao J, Guo J, Shi J, Wang Y. Author information: (1)State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. xpchen@umac.mo Recent achievements in the biology and the function of adipose tissue have regarded white adipose tissue (WAT) as an important endocrine and secretory organ. Releasing a series of multiple-function mediators, WAT is involved in a wide spectrum of diseases, including not only cardiovascular and metabolic complications, such as atherosclerosis and type 2 diabetes, but also inflammatory- and immune-related disorders, such as rheumatoid arthritis (RA) and osteoarthritis (OA). A large number of these mediators, called adipokines, such as tumor necrosis factor alpha (TNF-α), leptin, adiponectin, resistin, chemerin, interleukin-6 (IL-6), visfatin, and so on have been identified and studied widely. Important advances related to these proteins shed new insights into the pathophysiological mechanisms of many complicated diseases, although details of which remain unclear. Adiponectin, one of the most widely investigated adipokine, has been shown to possess both anti- and pro-inflammatory effects. RA is a chronic systemic inflammatory-related autoimmune disease. Accumulated evidence has demonstrated that cytokines and adipokines play an important role in the pathogenesis of RA. In this review, we have summarized the most recent advances in adiponectin research in the context of RA, focusing primarily on its effect on RA-related cells, its regulation on pro-inflammatory cytokines, as well as its validation as a biomarker for RA. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22910140 [PubMed - indexed for MEDLINE] 99. Expert Rev Cardiovasc Ther. 2012 Jul;10(7):933-9. doi: 10.1586/erc.12.74. Obesity and metabolic syndrome as related to cardiovascular disease. Nikolopoulou A(1), Kadoglou NP. Author information: (1)Attikon Hospital, University of Athens, Athens, Greece. The metabolic syndrome (MetS) constitutes a multifaceted disorder, including obesity, dyslipidemia, hyperglycemia and hypertension, associated with an increased propensity towards cardiovascular disease (CVD). Besides this, accumulating data suggest the involvement of nontraditional, novel, cardiovascular risk factors in MetS. Among them, insulin resistance seems to possess a predominant role in MetS-related CVD in obese patients. Furthermore, adipose tissue fatty acid metabolism, increased incidence of oxidative stress and endothelial dysfunction, and excessive production of adipocyte derivatives, known as adipokines, have all been proposed to contribute to the pathogenesis of CVD in obese patients with MetS. Lifestyle interventions, such as weight loss and increased physical activity, have long been the cornerstone for the treatment of obesity-related disorders. With the exception of obesity, pharmaceutical interventions targeting each disorder of MetS have yielded considerable improvement in cardiovascular morbidity and mortality. The long-term management of obesity and its complications seems promising but requires further investigation. PMID: 22908926 [PubMed - indexed for MEDLINE] 100. Hormones (Athens). 2012 Jul-Sep;11(3):272-89. Steroid hormones interrelationships in the metabolic syndrome: an introduction to the ponderostat hypothesis. Alemany M(1). Author information: (1)Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, Barcelona, Spain. malemany@ub.edu PMID: 22908060 [PubMed - indexed for MEDLINE] 101. Circ Res. 2012 Aug 17;111(5):642-56. doi: 10.1161/CIRCRESAHA.111.246546. Sirtuins and pyridine nucleotides. Abdellatif M(1). Author information: (1)Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. abdellma@umdnj.edu The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent role in metabolic homeostasis in mammals. The Sir1-4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism- and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body's metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3-5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of the functionality of sirtuin involves their regulation by the circadian rhythm, which affects their function via cyclically regulating systemic NAD(+) availability, further establishing the link of these proteins to metabolism. In this review, we will discuss the relation of sirtuins to NAD(+) metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems. PMCID: PMC3496429 PMID: 22904043 [PubMed - indexed for MEDLINE] 102. Am J Physiol Endocrinol Metab. 2012 Oct 15;303(8):E937-49. doi: 10.1152/ajpendo.00061.2012. Epub 2012 Aug 14. Cellular cross-talk between epicardial adipose tissue and myocardium in relation to the pathogenesis of cardiovascular disease. Cherian S(1), Lopaschuk GD, Carvalho E. Author information: (1)Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. Epicardial and perivascular fat depot size is considered an index of cardiac and visceral obesity. The functional and anatomic proximity of epicardial adipose tissue (EAT) to myocardium has drawn increasing attention in recent years among researchers attempting to elucidate its putative role as an endocrine organ. This includes the role of EAT as a lipid storing depot and as an inflammatory tissue secreting cytokines and chemokines under pathogenic conditions such as cardiovascular diseases. In this review, we discuss the current state of knowledge regarding the potential EAT mediators of inflammation and the paracrine cross-talk between EAT and the underlying myocardium. We also highlight the most recent findings on the causes and correlates of myocardial steatosis/cardiac lipotoxicity and its association with cardiac dysfunction. PMID: 22895783 [PubMed - indexed for MEDLINE] 103. Expert Rev Cardiovasc Ther. 2012 Jun;10(6):797-803. doi: 10.1586/erc.12.47. Adiposopathy and thyroid disease: tracing the pathway to cardiovascular risk. Duntas L(1), Micic D. Author information: (1)Endocrine Unit, Evgenidion Hospital, University of Athens Medical School, Athens, Greece. ledunt@otenet.gr Adiposopathy, defined as functionally disturbed adipose tissue mainly composed of large adipocytes and induced by chronic excess of food intake, has been associated with immune, metabolic and endocrine derangements promoting inflammation and, eventually, cardiovascular disease. Adiposopathy may positively influence thyrotropin-stimulating hormone, by raising leptin levels, and triggering autoimmunity. In this regard, it is hypothesized that the increased thyrotropin-stimulating hormone is independent of the negative regulation of the thyroid hormone, thereby constituting a secondary phenomenon and not a causal effect. Replacement therapy with thyroid hormones should therefore be applied following strict individualized consideration. Leptin is involved in the immune response and neuroendocrine appetite regulation, while leptin resistance may further promote autoimmune disease. The lipid derangement in adiposopathy may be aggravated in the presence of hypothyroidism and thus considerably augment cardiovascular risk. Lifestyle-modification counselling, including low-fat dietary intake and regular physical exercise, is today the cornerstone of adiposopathy treatment. Meanwhile, new drug formulations, such as leptin and leptin analogs, 5-HT2C-receptor agonist, and potent thyromimetics, currently comprise a promising armamentarium against adiposity and adiposopathy. PMID: 22894634 [PubMed - indexed for MEDLINE] 104. Methods Mol Biol. 2012;904:243-52. doi: 10.1007/978-1-61779-943-3_20. Progenitor cell mobilization from extramedullary organs. Kolonin MG(1). Author information: (1)Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA. Mikhail.G.Kolonin@uth.tmc.edu The course of various pathological conditions relies on the mobilization of stem cells and partially differentiated progenitor cells. Bone marrow transplantation studies have demonstrated that medullary hematopoietic and endothelial progenitors can undergo mobilization and trafficking. While the ability of the bone marrow to boost its resources in fighting disease or repairing injury declines with age, other organs have surfaced as reservoirs of various progenitor cell populations. This chapter discusses our current understanding of non-bone marrow-derived progenitor pools, focusing on mesenchymal stem cells. The evidence for the extramedullary progenitor mobilization, with a specific emphasis on white adipose tissue, is presented. PMID: 22890937 [PubMed - indexed for MEDLINE] 105. Appetite. 2013 Feb;61(1):111-8. doi: 10.1016/j.appet.2012.08.006. Epub 2012 Aug 10. Is leptin the parabiotic "satiety" factor? Past and present interpretations. Harris RB(1). Author information: (1)Department of Physiology, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912, USA. ruharris@georgiahealth.edu In 1959 Hervey hypothesized that a circulating feedback signal informed the hypothalamus of the size of fat stores and initiated appropriate corrections to energy balance. The hypothesis resulted from a parabiosis study in which one animal became obese following lesioning of the ventromedial hypothalamus. The partner of the lesioned rat was hypophagic and lost a large amount of body fat. Similar results came from parabiosis studies with obese Zucker rats and rats that overate due to stimulation of the lateral hypothalamus. In studies in which one parabiont was made obese by overfeeding the non-overfed partners lost substantial amounts of fat with a minimal reduction in food intake and no loss of lean tissue. The loss of fat was due to inhibition of adipose lipogenesis and other metabolic adjustments typical of food restriction. Parabiosis with genetically obese mice implied that ob/ob mice did not produce the feedback signal and subsequently the mutant ob protein, leptin, was identified. This paper provides a review and interpretation of parabiosis work that preceded the discovery of leptin, an evaluation of leptin in relation to its function as the circulating feedback signal and evidence for additional circulating factors involved in the control of adipose tissue mass. Copyright © 2012 Elsevier Ltd. All rights reserved. PMCID: PMC3749919 PMID: 22889986 [PubMed - indexed for MEDLINE] 106. Can J Cardiol. 2012 Nov-Dec;28(6):642-52. doi: 10.1016/j.cjca.2012.06.004. Epub 2012 Aug 11. Abdominal obesity and cardiovascular disease: is inflammation the missing link? Després JP(1). Author information: (1)Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Ste-Foy, Québec, QC, Canada. jean-pierre.despres@criucpq.ulaval.ca It is well established that cardiovascular disease has an inflammatory component. The present narrative review explores the role of adipose tissue distribution, morphology, and function as potential mediators of the link between inflammation and cardiovascular disease. Evidence that abdominal obesity is a key driving force behind a constellation of atherothrombotic inflammatory abnormalities linked to insulin resistance and often referred to as the metabolic syndrome is also reviewed. It is also proposed that the amount of visceral adipose tissue and the liver fat content are important factors responsible for the link between abdominal obesity and features of the metabolic syndrome. It is suggested that the inflammatory profile associated with excess visceral adipose tissue/liver fat may be a consequence of the relative inability of subcutaneous adipose tissue to expand through hyperplasia and to act as a protective metabolic sink storing the chronic energy surplus resulting from a positive energy balance (overnutrition or lack of physical activity or both). In this model, the inflammatory profile often observed among sedentary overweight/obese individuals with an excess of visceral adipose tissue/liver fat may be a consequence of a more primary defect in subcutaneous adipose tissue. On that basis, it is proposed that therapeutic strategies relieving the stress for storage of a chronic energy surplus in the subcutaneous adipose tissue (reduced caloric intake, increase in energy expenditure, pharmacotherapy) should induce a substantial loss of visceral adipose tissue and of ectopic fat depots such as the liver, thereby substantially reducing inflammation. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. PMID: 22889821 [PubMed - indexed for MEDLINE] 107. Immunol Rev. 2012 Sep;249(1):253-75. doi: 10.1111/j.1600-065X.2012.01142.x. The outliers become a stampede as immunometabolism reaches a tipping point. Nikolajczyk BS(1), Jagannathan-Bogdan M, Denis GV. Author information: (1)Department of Microbiology, Boston University, Boston, MA 02118, USA. bnikol@bu.edu Obesity and Type 2 diabetes mellitus (T2D) are characterized by pro-inflammatory alterations in the immune system including shifts in leukocyte subset differentiation and in cytokine/chemokine balance. The chronic, low-grade inflammation resulting largely from changes in T-cell, B-cell, and myeloid compartments promotes and/or exacerbates insulin resistance (IR) that, together with pancreatic islet failure, defines T2D. Animal model studies show that interruption of immune cell-mediated inflammation by any one of several methods almost invariably results in the prevention or delay of obesity and/or IR. However, anti-inflammatory therapies have had a modest impact on established T2D in clinical trials. These seemingly contradictory results indicate that a more comprehensive understanding of human IR/T2D-associated immune cell function is needed to leverage animal studies into clinical treatments. Important outstanding analyses include identifying potential immunological checkpoints in disease etiology, detailing immune cell/adipose tissue cross-talk, and defining strengths/weaknesses of model organism studies to determine whether we can harness the promising new field of immunometabolism to curb the global obesity and T2D epidemics. © 2012 John Wiley & Sons A/S. PMCID: PMC3419483 PMID: 22889227 [PubMed - indexed for MEDLINE] 108. Immunol Rev. 2012 Sep;249(1):239-52. doi: 10.1111/j.1600-065X.2012.01145.x. Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Tack CJ(1), Stienstra R, Joosten LA, Netea MG. Author information: (1)Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. c.tack@aig.umcn.nl A growing body of evidence suggests that cytokines of the interleukin-1 (IL-1) family, particularly IL-1β but also IL-1Ra and IL-18, are involved in obesity-associated inflammation. IL-1β is produced via cleavage of pro-IL-1β by caspase-1, which in turn is activated by a multiprotein complex called the inflammasome. The components of the NLRP3 inflammasome are involved in sensing obesity-associated danger signals, both in mice and in human (obese) subjects, with caspase-1 seemingly the most crucial regulator. Autophagy is upregulated in obesity and may function as a mechanism to control IL-1β gene expression in adipose tissue to mitigate chronic inflammation. All these mechanisms are operative in human adipose tissue and appear to be more pronounced in human visceral compared to subcutaneous tissue. In animal studies, blocking caspase-1 activity results in decreased weight gain, decreased inflammation, and improved insulin sensitivity. Human intervention studies with IL-1Ra (anakinra) have reported beneficial effects in patients with diabetes, yet without significant changes in insulin sensitivity. Clearly, the IL-1 family of cytokines, especially IL-1β, plays an important role in obesity-associated inflammation and insulin resistance and may represent a therapeutic target to reverse the detrimental metabolic consequences of obesity. © 2012 John Wiley & Sons A/S. PMID: 22889226 [PubMed - indexed for MEDLINE] 109. Immunol Rev. 2012 Sep;249(1):218-38. doi: 10.1111/j.1600-065X.2012.01151.x. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Johnson AR(1), Milner JJ, Makowski L. Author information: (1)Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. As humans evolved, perhaps the two strongest selection determinants of survival were a robust immune response able to clear bacterial, viral, and parasitic infection and an ability to efficiently store nutrients to survive times when food sources were scarce. These traits are not mutually exclusive. It is now apparent that critical proteins necessary for regulating energy metabolism, such as peroxisome proliferator-activated receptors, Toll-like receptors, and fatty acid-binding proteins, also act as links between nutrient metabolism and inflammatory pathway activation in immune cells. Obesity in humans is a symptom of energy imbalance: the scale has been tipped such that energy intake exceeds energy output and may be a result, in part, of evolutionary selection toward a phenotype characterized by efficient energy storage. As discussed in this review, obesity is a state of low-grade, chronic inflammation that promotes the development of insulin resistance and diabetes. Ironically, the formation of systemic and/or local, tissue-specific insulin resistance upon inflammatory cell activation may actually be a protective mechanism that co-evolved to repartition energy sources within the body during times of stress during infection. However, the point has been reached where a once beneficial adaptive trait has become detrimental to the health of the individual and an immense public health and economic burden. This article reviews the complex relationship between obesity, insulin resistance/diabetes, and inflammation, and although the liver, brain, pancreas, muscle, and other tissues are relevant, we focus specifically on how the obese adipose microenvironment can promote immune cell influx and sustain damaging inflammation that can lead to the onset of insulin resistance and diabetes. Finally, we address how substrate metabolism may regulate the immune response and discuss how fuel uptake and metabolism may be a targetable approach to limit or abrogate obesity-induced inflammation. © 2012 John Wiley & Sons A/S. PMCID: PMC3422768 PMID: 22889225 [PubMed - indexed for MEDLINE] 110. Immunol Rev. 2012 Sep;249(1):116-34. doi: 10.1111/j.1600-065X.2012.01154.x. At the crossroad of T cells, adipose tissue, and diabetes. Matarese G(1), Procaccini C, De Rosa V. Author information: (1)Dipartimento di Medicina, Facoltà di Medicina, Università di Salerno, Baronissi, Salerno, Italy. gmatarese@unisa.it The study of how different intracellular metabolic signaling pathways impact the control of self-immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self-immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self-immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the 'metabolic pressure' induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self-tolerance. We hypothesize that the leptin-induced metabolic pressure sets the basis for an exaggerated immuno-inflammatory response to altered self or non-self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans-disciplinary expertise in metabolism, self-tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility. © 2012 John Wiley & Sons A/S. PMID: 22889219 [PubMed - indexed for MEDLINE] 111. Vopr Pitan. 2012;81(3):58-65. [Characteristics of cytokine and hormone status in patients with diabetes mellitus type 2 during alimentary exposure]. [Article in Russian] Semenchenko IIu, Sharafetdinov KhKh, Plotnikova OA, Sentsova TB, Meshcheriakova VA. Diabetes mellitus (DM) is a main noninfectious disease, making significant influence on patients quality of life and life time. The medico-social role of diabetes is defined by wide prevalence of a disease in population and high risk of development of incapacitating complications. Therefore, considerable efforts of modern medicine focused on the study of etio-pathogenetic mechanism and the possibility of dietetic correction in this disease. In this review discusses efficacy of dietary therapy in type 2 diabetes, the role of insulin-like growth 1 (IGF-1)/insulin of pathogenesis microvascular complications. The role of inflammation in the development of microvascular complications, in the first place cytokines, act on the insulin signal pathway and affect the intracellular inflammatory kinase cascade was shown. Also, it is shown that adipose tissue inflammation modulates B-cell function and promotes progressive reduction of insulin secretion. When blood glucose levels are elevated, Glucagon-like peptide--1 stimulates insulin secretion, decrease glucagon secretion, improve B-cell function, and slows gastric emptying. It determines the necessity of fulfillment of further researches of cellular and humoral immunity in diabetes mellitus and the development of personal methods in prevention and treatment of this disease. PMID: 22888673 [PubMed - indexed for MEDLINE] 112. Endocr J. 2012;59(10):849-57. Epub 2012 Aug 9. Adipose tissue inflammation and ectopic lipid accumulation. Suganami T(1), Tanaka M, Ogawa Y. Author information: (1)Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Indeed, unbalanced production of pro- and anti-inflammatory adipocytokines critically contributes to the obesity-induced insulin resistance. In addition to lipid-laden mature adipocytes, adipose tissue is composed of various stromal cells such as preadipocytes, endothelial cells, fibroblasts, and immune cells that may be involved in adipose tissue functions. Accumulating evidence has suggested that adipocytes and stromal cells in adipose tissue change dramatically in number and cell type during the course of obesity, which is referred to as "adipose tissue remodeling." Among stromal cells, infiltration of macrophages in obese adipose tissue precedes the development of insulin resistance in animal models, suggesting that they are crucial for adipose tissue inflammation. We have provided evidence suggesting that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. On the other hand, storing excessive energy as triglyceride is also a fundamental function of adipose tissue. Recent evidence suggests that reduced lipid storage in obese adipose tissue contributes to ectopic lipid accumulation in non-adipose tissues such as the liver, skeletal muscle, and pancreas, where lipotoxicity impairs their metabolic functions. Notably, chronic inflammation is capable of inducing insulin resistance, lipolysis, and interstitial fibrosis in adipose tissue, all of which may reduce the lipid-storing function. Understanding the molecular mechanism underlying adipose tissue remodeling may lead to the identification of novel therapeutic strategies to prevent or treat obesity-induced adipose tissue inflammation. PMID: 22878669 [PubMed - indexed for MEDLINE] 113. Prog Brain Res. 2012;199:183-201. doi: 10.1016/B978-0-444-59427-3.00011-3. Circadian rhythms in white adipose tissue. van der Spek R(1), Kreier F, Fliers E, Kalsbeek A. Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands. r.d.vanderspek@amc.uva.nl Adipose tissue is an important endocrine organ. It is involved in the regulation of energy metabolism by secreting factors (adipokines) that regulate appetite, food intake, glucose disposal, and energy expenditure. Many of these adipokines display profound day/night rhythms, and accumulating evidence links disruption of these rhythms to metabolic diseases such as obesity and type 2 diabetes. Here, we briefly present the circadian system, describe the development of white adipose tissue (WAT) and its depot-specific characteristics and innervation, we discuss energy storage in WAT and, lastly, review recent findings that link circadian rhythmicity to adipose tissue biology and obesity. Copyright © 2012 Elsevier B.V. All rights reserved. PMID: 22877666 [PubMed - indexed for MEDLINE] 114. Curr Med Chem. 2012;19(32):5501-12. Adiponectin, an anti-carcinogenic hormone? A systematic review on breast, colorectal, liver and prostate cancer. Perrier S(1), Jardé T. Author information: (1)AGM Communication, Clermont-Ferrand, France. Adiponectin is an adipose tissue-derived hormone, expressed almost exclusively in adipose tissue, with significant antidiabetic, anti-atherosclerotic, anti-inflammatory and anti-proliferative properties. The anti-carcinogenic effects of adiponectin result from two main mechanisms: a modulation in the signaling pathways involved in proliferation process and a subtle regulation of the apoptotic response. In this review, we present recent findings on the association of adiponectin with the risk of several malignancies (breast, colorectal, liver and prostate cancers), as well as data on underlying molecular mechanisms by which adiponectin plays a substantial role in cancer pathogenesis. PMID: 22876928 [PubMed - indexed for MEDLINE] 115. Curr Med Chem. 2012;19(32):5493-500. Adiponectin in pulmonary disease and critically ill patients. Garcia P(1), Sood A. Author information: (1)University of New Mexico Health Sciences Center School of Medicine, Department of Medicine, 1 University of New Mexico, MSC 10 5550, Albuquerque, NM 87131, USA. asood@salud.unm.edu Adiponectin is a predominantly anti-inflammatory protein produced by adipose tissue with possible signalling activity in the lung. It is increasingly associated with inflammatory pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and in critical illness. Although mouse studies indicate causative associations between adiponectin and asthma and COPD, the human literature in this regard is inconclusive. Some, but not all, studies demonstrate that serum adiponectin concentrations are inversely associated with asthma prevalence among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are associated with lower asthma severity among boys but greater severity among men. Further, case-control studies demonstrate higher systemic and airway adiponectin concentrations in primarily male COPD patients than controls. Systemic adiponectin is positively associated with lung function in healthy adults but inversely associated in studies of male subjects with COPD. Murine and human studies further show contradictory associations of systemic adiponectin with critical illness. Higher premorbid systemic adiponectin concentrations are associated with improved survival from sepsis in mice. On the other hand, higher systemic adiponectin concentrations on day 1 of critical illness are associated with lower survival in critically ill patients with respiratory failure. In the absence of adequate longitudinal data, it is not possible to determine whether the adiponectin derangements are the consequence or the cause of the disease studied. Future research will determine whether modulation of adiponectin, independent of BMI, may be helpful in the prevention or treatment of asthma, COPD or critical illness. PMCID: PMC3607498 PMID: 22876927 [PubMed - indexed for MEDLINE] 116. Curr Med Chem. 2012;19(32):5481-92. Adiponectin in metabolic bone disease. Kanazawa I(1). Author information: (1)Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan. ippei.k@med.shimane-u.ac.jp Adiponectin has attracted widespread attention because of its pivotal role in glucose metabolism and energy homeostasis. Adiponectin and its receptor are shown to be expressed in osteoblasts, suggesting that adiponectin might affect bone metabolism. A number of clinical studies have shown that serum adiponectin is negatively associated with bone mineral density (BMD) and positively with biochemical markers of bone turnover, suggesting that adiponectin may be a negative regulator of bone mass. However, most in vitro studies demonstrate that adiponectin stimulates the differentiation and mineralization of osteoblasts as well as the expression of osteocalcin. Adiponectin indirectly stimulates osteoclast differentiation via receptor activator for nuclear factor κB ligand and osteoprotegerin expression in osteoblasts, while adiponectin directly inhibits osteoclast activity and bone resorption. These in vitro findings suggest that adiponectin stimulates bone formation and remodeling as well as inhibits bone resorption. In contrast, previous in vivo studies using overexpression and knockout mice of adiponectin have produced controversial results. On the other hand, recent studies have shown that osteocalcin derived form osteoblasts acts as a hormone regulating glucose metabolism and fat mass. Osteocalcin could decrease fat pads and stimulate the expression of adiponectin in adipocytes, suggesting that bone metabolism is associated with fat metabolism through adiponectin and osteocalcin. In this review, I summarize the effect of adiponectin on osteoblasts and osteoclasts in vitro and in vivo, the association of adiponectin with BMD and bone markers in humans, and the role of adiponectin in the endocrine loop between bone and fat metabolism. PMID: 22876926 [PubMed - indexed for MEDLINE] 117. Curr Med Chem. 2012;19(32):5467-73. Adiponectin: key player in the adipose tissue-liver crosstalk. Moschen AR(1), Wieser V, Tilg H. Author information: (1)Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria. The adipose tissue has recently emerged as an important endocrine organ releasing numerous mediators including adipocytokines, classical cytokines and others. Adiponectin, one of the major products of adipocytes, is a prototypic anti-diabetic adipocytokine, the actions of which are mainly exerted by the activation of AMP-activated kinase and peroxisome proliferator-activated receptor alpha. This adipocytokine is one of the most abundant circulating (adipo)cytokines in health. Non-alcoholic fatty liver disease (NAFLD), the major reason for abnormal liver functions in the western world, is commonly associated with obesity, insulin resistance and decreased adiponectin serum levels. Adiponectin has many anti-inflammatory activities and suppresses tumour necrosis factor-alpha (TNFα), a cytokine of key importance in NAFLD. The anti-inflammatory effects of adiponectin are also exerted by induction of the anti-inflammatory cytokines interleukin-10 (IL-10) or IL-1 receptor antagonist and up-regulation of heme-oxygenase-1. Whereas the liver probably is not a relevant source of circulating adiponectin, it is a major target organ for many adiponectin effects. Adiponectin is able to regulate steatosis, insulin resistance, inflammation and fibrosis. NAFLD is also associated with decreased liver expression of the two adiponectin receptors (AdipoR1 and 2) thereby contributing to a state of hepatic adiponectin resistance. In contrast, most other liver diseases especially in advanced disease states exhibit increased adiponectin serum levels with highest levels observed in cirrhosis. Targeting adiponectin could evolve as a major treatment concept especially for fatty liver diseases in the future. PMID: 22876924 [PubMed - indexed for MEDLINE] 118. Curr Med Chem. 2012;19(32):5459-66. Protective role of adiponectin in cardiovascular disease. Shibata R(1), Murohara T, Ouchi N. Author information: (1)Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. This review focuses on the recent findings that adiponectin plays a significant role of in cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting adipocytokines that can directly affect nearby or remote organs. Adiponectin is an adipocytokine whose concentration is down-regulated in subjects with obesity-related disorders. Low levels of circulating adiponectin appear to associate with the increased prevalence of obesity-linked diseases including atherosclerosis and ischemic heart disease. A number of experimental studies have shown that adiponectin exerts beneficial effects on the cardiovascular system by directly acting on the component cells in the heart and blood vessels. The cardiovascular protection by adiponectin is mediated through its ability to attenuate inflammatory responses and apoptotic activities in the target organs. Thus, adiponectin could represent a therapeutic target molecule for prevention or treatment of cardiovascular diseases. PMID: 22876923 [PubMed - indexed for MEDLINE] 119. Curr Med Chem. 2012;19(32):5513-23. Therapeutic perspectives for adiponectin: an update. Li FY(1), Lam KS, Xu A. Author information: (1)Department of Medicine, University of Hong Kong, Hong Kong. In obesity, the expansion of dysfunctional adipose tissue leads to augmented production of pro-inflammatory adipokines that mediate metabolic changes through their paracrine and/or endocrine actions. By contrast, the secretion and plasma concentration of adiponectin, an adipokine with cardiovascular protective, anti-diabetic and anti-inflammatory properties, are markedly decreased in obesity and its related pathologies. Epidemiological studies on different ethnic groups have identified hypoadiponectinemia as an independent risk factor for type 2 diabetes, hypertension, coronary heart disease and several types of cancers. In animals, replenishment of recombinant adiponectin or transgenic expression of adiponectin can reverse these obesity-related pathological conditions. Although there is currently no direct clinical evidence demonstrating that adiponectin is effective in treating obesity-related cardiometabolic diseases, therapeutic benefits of several anti-diabetic and cardiovascular drugs, such as the agonists of peroxisome proliferator-activated receptor (PPAR) γ and PPAR α and statins, are associated with increased plasma adiponectin in humans. In addition, a number of medicinal herbs and natural compounds with beneficial effects on cardiometabolic diseases, have been shown to increase adiponectin secretion in adipocytes. This review highlights recent advances on multiple beneficial effects of adiponectin and discusses the potential therapeutic interventions for obesity-related cardiometabolic syndromes by targeting adiponectin. PMID: 22876919 [PubMed - indexed for MEDLINE] 120. Am J Psychother. 2012;66(2):111-28. Of mind and matter: psychological dimensions in obesity. Karasu SR(1). Author information: (1)Weill Cornell Medical College, New York, NY, USA. sylkar@aol.com Obesity is a physiological energy imbalance, a chronic disorder that results from an increase in caloric intake and/or a decrease in caloric expenditure. Other than the accumulation of excess adipose tissue, there are no signs or symptoms characteristic of all obese people. Obesity rates have increased exponentially worldwide in the past thirty years for reasons that we do not entirely understand. Multiple environmental, genetic, neuro-endocrinological, and psychosocial factors contribute to the development of obesity. Though there are many different, and even controversial, frameworks for obesity, most researchers acknowledge that it can lead to serious medical and psychological morbidity. This paper focuses on psychological dimensions in the study of obesity: the intricate human "minded brain" that promotes self-regulation, motivation, and self-efficacy; the complexities involved in considering obesity a psychiatric disorder, with the possibility of a so-called "obese personality"; the role of stigma, prejudice, and discrimination; and psychiatric symptomatology among the obese. PMID: 22876525 [PubMed - indexed for MEDLINE] 121. Front Pharmacol. 2012 Aug 2;3:148. doi: 10.3389/fphar.2012.00148. eCollection 2012. Aldo-Keto Reductases 1B in Endocrinology and Metabolism. Pastel E(1), Pointud JC, Volat F, Martinez A, Lefrançois-Martinez AM. Author information: (1)CNRS, UMR6293/INSERM U1103, Génétique, Reproduction et Développement, Clermont Université Aubière, France. The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers. PMCID: PMC3410611 PMID: 22876234 [PubMed] 122. Thromb Haemost. 2012 Nov;108(5):840-8. doi: 10.1160/TH12-05-0337. Epub 2012 Aug 7. Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Antonopoulos AS(1), Margaritis M, Shirodaria C, Antoniades C. Author information: (1)Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom. Vascular oxidative stress is a key feature of atherogenesis, and targeting vascular redox signalling is a rational therapeutic goal in vascular disease pathogenesis. 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins are potent lipid-lowering drugs that improve cardiovascular outcomes. It is now widely accepted that cardiovascular disease prevention by statins is dependent not only on their lipid lowering effects, but also on their beneficial effects on vascular redox signalling. Cell culture and animal models have provided important findings on the effects of statins on vascular redox and nitric oxide bioavailability. Recent evidence from studies on human vessels has further enhanced our understanding of the "pleiotropic" effects of statins on vascular wall. Reversal of endothelial dysfunction in human vessels by statins is dependent on the mevalonate pathway and Rac1 inhibition. These critical steps are responsible for reducing NADPH-oxidase activity and improving tetrahydrobiopterin bioavailability and nitric oxide synthase (NOS) coupling in human vessels. However, mevalonate pathway inhibition has been also held responsible for some of the side effects observed after statin treatment. In this review we summarise the existing knowledge on the effects of statins on vascular biology by discussing key findings from basic science as well as recent evidence from translational studies in humans. Finally, we discuss emerging aspects of statin pleiotropy, such as their effects on adipose tissue biology and adipokine synthesis that may light additional mechanistic links between statin treatment and improvement of clinical outcome in primary and secondary prevention. PMID: 22872079 [PubMed - indexed for MEDLINE] 123. J Appl Biomater Funct Mater. 2012 Sep 27;10(2):67-81. doi: 10.5301/JABFM.2012.9418. New perspectives in cell delivery systems for tissue regeneration: natural-derived injectable hydrogels. Munarin F(1), Petrini P, Bozzini S, Tanzi MC. Author information: (1)Laboratorio di Biomateriali, Bioengineering Department and UdR INSTM Milano Politecnico, Politecnico di Milano, Milano - Italy

. Erratum in J Appl Biomater Funct Mater. 2013;11(1):e71. Natural polymers, because of their biocompatibility, availability, and physico-chemical properties have been the materials of choice for the fabrication of injectable hydrogels for regenerative medicine. In particular, they are appealing materials for delivery systems and provide sustained and controlled release of drugs, proteins, gene, cells, and other active biomolecules immobilized.In this work, the use of hydrogels obtained from natural source polymers as cell delivery systems is discussed. These materials were investigated for the repair of cartilage, bone, adipose tissue, intervertebral disc, neural, and cardiac tissue. Papers from the last ten years were considered, with a particular focus on the advances of the last five years. A critical discussion is centered on new perspectives and challenges in the regeneration of specific tissues, with the aim of highlighting the limits of current systems and possible future advancements. PMID: 22865572 [PubMed - indexed for MEDLINE] 124. Obes Facts. 2012;5(4):546-60. doi: 10.1159/000341560. Epub 2012 Jul 27. Influence of exclusive resistance training on body composition and cardiovascular risk factors in overweight or obese children: a systematic review. Dietz P(1), Hoffmann S, Lachtermann E, Simon P. Author information: (1)Department of Sports Medicine, Rehabilitation and Disease Prevention, Faculty of Social Science, Media and Sports, Johannes Gutenberg-University Mainz, Germany. pdietz@uni-mainz.de OBJECTIVE: Since the last decade, a significant increase in the prevalence of overweight and obesity among children has been reported. Low aerobic fitness and a low compliance with endurance sports in such children are theoretical reasons to favor the use of resistance training in intervention studies, even though positive effects of resistance training on morbidity without accompanying dietary modifications are a matter of debate. In this review we summarize the studies that have shown the isolated effect of resistance training on body composition and cardiovascular risk factors in overweight and obese children. METHOD: We systematically reviewed interventional studies that exclusively applied resistance training to overweight and obese 3- to 18-year-old children. Outcome measurements were body composition or cardiovascular risk factors. RESULTS: Only six studies passed the inclusion criteria. All studies preferred an individually planned and supervised whole-body resistance training of moderate to submaximal intensity during treatment. The mean compliance was 84%. Four studies reported significant changes in body composition, with an increase in fat free mass and BMI, along with a decrease in fat mass. Three studies analyzed the effect of resistance training on cardiovascular risk factors, and only one study reported a significant decrease in systolic blood pressure. CONCLUSION: An individually planned and supervised whole-body resistance training of moderate to submaximal intensity in children seems to be safe and tends to show positive effects on body composition. Similar to interventions based on endurance exercise alone or in combination with dietary modifications, the effects on cardiovascular risk factors cannot be substantiated. In consequence, we suggest to substantiate the effect of resistance training on cardiovascular risk factors in overweight and obese children in upcoming randomized controlled trials with high case numbers, applying both resistance training only and resistance training in combination with dietary intervention to get knowledge about whether resistance training alone is effectual in the treatment of overweight and obesity in youth or if a combination of resistance training and dietary interventions is actually needed. PMID: 22854678 [PubMed - indexed for MEDLINE] 125. Exp Diabetes Res. 2012;2012:484696. doi: 10.1155/2012/484696. Epub 2012 Jul 18. MicroRNAs in insulin resistance and obesity. Williams MD(1), Mitchell GM. Author information: (1)O'Brien Institute, Melbourne, VIC 3065, Australia. mwilliams.student@gmail.com MicroRNAs (miRNAs) are a class of short, single-stranded non-protein coding gene products which can regulate the gene expression through post-transcriptional inhibition of messenger RNA (mRNA) translation. They are known to be involved in many essential biological processes including development, insulin secretion, and adipocyte differentiation. miRNAs are involved in complex metabolic processes, such as energy and lipid metabolism, which have been studied in the context of diabetes and obesity. Obesity, hyperlipidemia (elevated levels of blood lipids), and insulin resistance are strongly associated with the onset of type 2 diabetes. These conditions are also associated with aberrant expression of multiple essential miRNAs in pancreatic islets of Langerhans and peripheral tissues, including adipose tissue. A thorough understanding of the physiological role these miRNAs play in these tissues, and changes to their expression under pathological conditions, will allow researchers to develop new therapeutics with the potential to correct the aberrant expression of miRNAs in type 2 diabetes and obesity. PMCID: PMC3407629 PMID: 22851965 [PubMed - indexed for MEDLINE] 126. J Bras Nefrol. 2012 Jun;34(2):184-8. [Crosstalk between bone and adipose tissue in chronic kidney disease]. [Article in Portuguese] Marinho SM(1), Moraes C, Mafra D. Author information: (1)Universidade Federal Fluminense, Niterói, RJ, Brazil. sandramaramarinho@ hotmail.com Within the concept that hormones are regulated by a cycle of reciprocity, the fact that osteoblasts and adipocytes are developed from mesenchymal stem cells and that bone remodeling is regulated by leptin brings up the idea of possible bone participation in energy metabolism and vice-versa. Recent studies have shown that the differentiation and function of these bone cells are regulated by leptin, which seems to trigger a bimodal response, via sympathetic nervous system, and a local response, in which leptin acts on the bone. In fact, studies have shown complex interactions between bone, adipose tissue and brain. However, there are few studies on crosstalk in patients with chronic kidney disease (CKD). These patients have a tendency to decreased bone mineral density and high levels of leptin. Then, this article presented a review of potential involvement of adipose tissue and bone mass in patients with CKD. PMID: 22850921 [PubMed - indexed for MEDLINE] 127. Nat Rev Endocrinol. 2012 Dec;8(12):709-16. doi: 10.1038/nrendo.2012.114. Epub 2012 Jul 31. Adaptive immunity in obesity and insulin resistance. Sell H(1), Habich C, Eckel J. Author information: (1)Paul-Langerhans Group, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. Obesity is the hallmark of the metabolic syndrome and predisposes patients to the development of major chronic metabolic diseases including type 2 diabetes mellitus. Adipose tissue expansion in obesity is characterized by increasing infiltration of proinflammatory immune cells into adipose tissue causing chronic, low-grade inflammation. Phenotypic switching of macrophages is an important mechanism of adipose tissue inflammation, and there is involvement of cells from the adaptive immune system in this process. T-cell phenotype changes and recruitment of B cells and T cells precedes macrophage infiltration. Cytokines and chemokines produced by immune cells influence localized and systemic inflammation, which is a pathogenic link between obesity and insulin resistance. Antigens absorbed from the gut might contribute to T-cell activation and recruitment into visceral adipose tissue in obesity. This Review summarizes, in the context of obesity, the evidence for infiltration of adipose tissue by cells of the adaptive immune system, how adaptive system cells affect innate cell populations and the influence of adaptive immune cells on the development of insulin resistance. PMID: 22847239 [PubMed - indexed for MEDLINE] 128. Int J Obes (Lond). 2013 Jun;37(6):759-64. doi: 10.1038/ijo.2012.124. Epub 2012 Jul 31. Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight. Tremblay A(1), Royer MM, Chaput JP, Doucet E. Author information: (1)Department of Kinesiology, PEPS, Laval University, Quebec City, Quebec, Canada. angelo.tremblay@kin.msp.ulaval.ca The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals, such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously lose body fat. PMID: 22846776 [PubMed - indexed for MEDLINE] 129. Exp Gerontol. 2013 Jul;48(7):608-11. doi: 10.1016/j.exger.2012.07.009. Epub 2012 Jul 27. Expression and function of APP and its metabolites outside the central nervous system. Puig KL(1), Combs CK. Author information: (1)Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA. Amyloid precursor protein (APP) derived amyloid beta (Aβ) peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the function of this ubiquitously expressed protein and its metabolites outside of the central nervous system. This review summarizes key aspects of the current understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3505247 PMID: 22846461 [PubMed - indexed for MEDLINE] 130. Br J Nutr. 2011 Jul;106(2):196-202. The efficacy of Phaseolus vulgaris as a weight-loss supplement: a systematic review and meta-analysis of randomised clinical trials. Onakpoya I(1), Aldaas S, Terry R, Ernst E. Author information: (1)Complementary Medicine, Peninsula Medical School, University of Exeter, Exeter, UK. igho.onakpoya@pcmd.ac.uk A variety of dietary supplements are presently available as slimming aids, but their efficacy has not been proven. One such slimming aid is the bean extract, Phaseolus vulgaris. The aim of the present systematic review is to evaluate the evidence for or against the efficacy of P. vulgaris. Electronic and non-electronic searches were conducted to identify relevant human randomised clinical trials (RCT). Hand searches of bibliographies were also conducted. No age, time or language restrictions were imposed. The eligibility of studies was determined by two reviewers independently, and the methodological quality of the included studies was assessed. We identified eleven eligible trials, and six were included. All the included RCT had serious methodological flaws. A meta-analysis revealed a statistically non-significant difference in weight loss between P. vulgaris and placebo groups (mean difference (MD) − 1.77 kg, 95 % CI − 3.33, 0.33). A further meta-analysis revealed a statistically significant reduction in body fat favouring P. vulgaris over placebo (MD − 1.86 kg, 95 % CI − 3.39, − 0.32). Heterogeneity was evident in both analyses. The poor quality of the included RCT prevents us from drawing any firm conclusions about the effects of P. vulgaris supplementation on body weight. Larger and more rigorous trials are needed to objectively assess the effects of this herbal supplement. PMID: 22844674 [PubMed - indexed for MEDLINE] 131. Kardiologiia. 2012;52(7):78-83. [The problem of bone marrow fatty transformation]. [Article in Russian] Shishkova VN. PMID: 22839719 [PubMed - indexed for MEDLINE] 132. Clin Rheumatol. 2012 Sep;31(9):1401-2. doi: 10.1007/s10067-012-2034-0. Epub 2012 Jul 27. Improvement in insulin resistance after short-term treatment with abatacept: case report and short review. Ursini F(1), Mauro D, Naty S, Gagliardi D, Grembiale RD. Author information: (1)Program in Molecular Oncology, Experimental Immunology and Development of Innovative Therapies, University of Catanzaro Magna Graecia campus Salvatore Venuta, viale Europa, 88100 Catanzaro, Italy. francesco.ursini@yahoo.it Insulin resistance, a key feature of type 2 diabetes, is an independent risk factor for developing cardiovascular diseases (CVD), and represents the core of metabolic syndrome (MetS). Actually, an intriguing correlation between MetS and inflammation associated with rheumatoid arthritis (RA) is largely accepted but not yet completely clarified in detail. Recently, the therapeutic arsenal against RA has been enriched of abatacept, a fusion protein (CTLA4 immunoglobulin) designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. Here, we report a case of dramatic improvement in insulin resistance, estimated with the surrogate measure HOMA-IR, after treatment with abatacept. Lastly, we shortly review the preclinical evidences supporting a possible role of T lymphocytes in rheumatoid arthritis-associated insulin resistance and how abatacept could improve glucose metabolism by suppressing adipose tissue infiltrating cells. PMID: 22837017 [PubMed - indexed for MEDLINE] 133. Dent Clin North Am. 2012 Jul;56(3):549-61. doi: 10.1016/j.cden.2012.05.004. Epub 2012 Jun 23. Dental stem cells and their sources. Sedgley CM(1), Botero TM. Author information: (1)Department of Endodontology, School of Dentistry, Oregon Health and Science University, 611 Southwest Campus Drive, Portland, OR 97239, USA. sedgley@ohsu.edu The search for more accessible mesenchymal stem cells than those found in bone marrow has propelled interest in dental tissues. Human dental stem/progenitor cells (collectively termed dental stem cells [DSCs]) that have been isolated and characterized include dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. Common characteristics of these cell populations are the capacity for self-renewal and the ability to differentiate into multiple lineages. In vitro and animal studies have shown that DSCs can differentiate into osseous, odontogenic, adipose, endothelial, and neural-like tissues. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22835537 [PubMed - indexed for MEDLINE] 134. Ann Med. 2013 May;45(3):242-53. doi: 10.3109/07853890.2012.705015. Epub 2012 Jul 26. Metabolic inflammation: connecting obesity and insulin resistance. Dali-Youcef N(1), Mecili M, Ricci R, Andrès E. Author information: (1)Laboratoire de Biochimie et de Biologie Moléculaire, Hôpitaux universitaires de Strasbourg, 1 place de l'hôpital 67091 Strasbourg Cedex, France. n.daliyoucef@unistra.fr Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID: 22834949 [PubMed - indexed for MEDLINE] 135. Crit Rev Oncog. 2012;17(3):263-76. Is tissue cross-talk important in cancer cachexia? Johns N(1), Greig C, Fearon KC. Author information: (1)Department of Clinical Surgery and Geriatrics, School of Clinical Sciences and Community Health, University of Edinburgh, Edinburgh, EH16 4SB, UK. Recent work suggests molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines. These molecules act in an endocrine fashion to play an intricate role in regulating body composition in both health and disease. Studies in exercise physiology have focused on the molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines and on the role these molecules may play in chronic diseases. Similarly, integrative physiology in obesity and diabetes has long emphasised the importance of chronic inflammation, increased adipocyte lipolysis, and increased levels of circulating free fatty acids in the adipose-muscle cross-talk that contributes to lipotoxicity and insulin resistance in muscle. Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, quality of life, and duration of survival. Although cachexia in patients with cancer is characterized by systemic inflammation, increased lipolysis, insulin resistance, and reduced physical activity, there has been little effort to manipulate the integrative physiology of adipose tissue and muscle tissue for therapeutic gain. PMID: 22831157 [PubMed - indexed for MEDLINE] 136. Crit Rev Oncog. 2012;17(3):247-51. Neuroinflammation: a contributing factor to the pathogenesis of cancer cachexia. Laviano A(1), Seelaender M, Rianda S, Silverio R, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University, Rome, Italy. alessandro.laviano@uniroma1.it The clinical journey of cancer patients is frequently complicated by the development of a complex and multifaceted syndrome, the main features of which are reduced appetite, decreased food intake, progressive weight loss, and wasting of muscle mass and adipose tissue, which is not prevented by the provision of calories and proteins. This syndrome, termed Cachexia, is responsible for increased morbidity, reduced survival, and impinged quality of life of cancer patients. The pathogenesis is complex and involves deranged metabolism of peripheral tissues and profound alterations of brain neurochemistry. Recent studies indicate that brain neurochemistry is perturbed during tumor growth by cancer-induced increased intrahypothalamic expression of proinflammatory cytokines. The attending neurochemical chaos mediates the anorexigenic behavioral responses associated to cancer cachexia, but recent data seem to suggest that neuronal output also may be involved in the metabolic changes occurring at the peripheral level. PMID: 22831155 [PubMed - indexed for MEDLINE] 137. Oxid Med Cell Longev. 2012;2012:349710. doi: 10.1155/2012/349710. Epub 2012 Jul 5. Exercise in the metabolic syndrome. Golbidi S(1), Mesdaghinia A, Laher I. Author information: (1)Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada. The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism. PMCID: PMC3399489 PMID: 22829955 [PubMed - indexed for MEDLINE] 138. J Mol Endocrinol. 2012 Aug 30;49(2):R79-87. doi: 10.1530/JME-12-0080. Print 2012 Oct. Searching for ways to switch on brown fat: are we getting warmer? Whittle A(1). Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. ajw232@medschl.cam.ac.uk Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states. PMID: 22829654 [PubMed - indexed for MEDLINE] 139. Endocr Rev. 2012 Oct;33(5):812-41. doi: 10.1210/er.2012-1003. Epub 2012 Jul 24. Cardiometabolic aspects of the polycystic ovary syndrome. Randeva HS(1), Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Author information: (1)Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom. Harpal.Randeva@warwick.ac.uk Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic perturbations, in addition to chronic anovulation and factors related to androgen excess. In general, women live longer than men and develop cardiovascular disease at an older age. However, women with PCOS, as compared with age- and body mass index-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality. Further alterations in PCOS include an increased prevalence of sleep apnea, as well as various changes in the secretion and/or function of adipokines, adipose tissue-derived proinflammatory factors and gut hormones, all of them with direct or indirect influences on the complex signaling network that regulates metabolism, insulin sensitivity, and energy homeostasis. Reviews on the cardiometabolic aspects of PCOS are rare, and our knowledge from recent studies is expanding rapidly. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge, focusing on the alterations of cardiometabolic factors in women with PCOS. Further insight into this network of factors may facilitate finding therapeutic targets that should ameliorate not only ovarian dysfunction but also the various cardiometabolic alterations related to the syndrome. PMCID: PMC3461136 PMID: 22829562 [PubMed - indexed for MEDLINE] 140. Pathol Int. 2012 Aug;62(8):538-42. doi: 10.1111/j.1440-1827.2012.02831.x. Epub 2012 Jun 12. Mixed angiosarcoma, clear cell adenocarcinoma and mature teratoma elements in an ovarian tumor: a case report and literature review. Takahashi H(1), Chaopotong P, Kajita S, Hashimura M, Yamazaki H, Saegusa M. Author information: (1)Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. hiroyuki.takahashi36@gmail.com Malignant transformation of a mature teratoma in the ovary is a rare event, with an approximate rate of only 1-2%. Here, we report an ovarian tumor with a unique combination of epithelial and non-epithelial malignant components, including mature teratoma elements. A 59 year-old postmenopusal woman underwent total hysterectomy and bilateral salpingo-oophorectomy to remove a huge solid mass of the right ovary. The ovarian tumor was 16 × 12 × 4.5 cm in dimensions, composed of red-brown and greyish-white tissue with several cystic areas. Microscopically, atypical cells immunopositive for both CD31 and CD34 formed irregular ectatic vascular patterns with a high MIB-1 labeling index in red-brown areas. In contrast, tubule-cystic and papillary structures were lined by HNF-1β-immunopositive atypical cuboidal and hobnail cells with clear cytoplasm in greyish-white areas. In addition, normal-looking epithelial and stromal components, including mature squamous, cuboidal and ciliated epithelial cells, and adipose tissues, were observed in red-brown areas, suggesting an ovarian tumor combining angiosarcoma, clear cell adenocarcinoma, and mature teratoma features. We could demonstrate identical X-chromosome inactivation patterns among all three components by human androgen receptor gene (HUMARA) assays, pointing to complex inter-relationships regarding their pathogenesis. These observations suggest that a malignant tumor composed of two characteristic phenotypes arose in mature teratoma. © 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd. PMID: 22827762 [PubMed - indexed for MEDLINE] 141. Clin Liver Dis. 2012 Aug;16(3):505-24. doi: 10.1016/j.cld.2012.05.005. Mechanisms of simple hepatic steatosis: not so simple after all. Matherly SC(1), Puri P. Author information: (1)Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, 23298, USA. Nonalcoholic fatty liver disease is becoming an epidemic. Fat is typically stored in adipose tissue in the form of triglycerides (TGs). The deposition of TGs in the liver is the result of an imbalance between the amount of energy taken in and the amount used. This balance is maintained by a complex interplay between the dietary intake of nutrients, the hormonal response to the nutrients, and their effect on both the liver and adipose tissue. Disruption of this system is what leads to the development of steatosis and is the focus of this article. Copyright © 2012. Published by Elsevier Inc. PMID: 22824478 [PubMed - indexed for MEDLINE] 142. Endocrine. 2012 Dec;42(3):496-505. doi: 10.1007/s12020-012-9754-4. Epub 2012 Jul 21. Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus. Rasul S(1), Wagner L, Kautzky-Willer A. Author information: (1)Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Although type 2 diabetes mellitus (DM) is a chronic metabolic disorder with multiple etiologies, obesity has been constantly linked with insulin resistance and manifestation of type 2 DM. In addition, obesity is associated with hypertension, dyslipidemia, and fatty liver disease and is regarded as a subclinical inflammatory condition characterized by release of pro-inflammatory mediators such as cytokines from adipose tissue. Both, type 2 DM and obesity are considered as major risks for developing micro- and macrovascular diseases. Recent studies showed that impaired circulating levels of fetuin-A, which is involved in propagating insulin resistance as well as circulating levels of angiopoietins, which are growth factors promoting angiogenesis, were observed in patients with obesity, metabolic syndrome, and type 2 DM. However, independent of type 2 DM and obesity, defective regulation of fetuin-A and angiopoietin are playing a critical role in predisposing to coronary and peripheral vascular diseases. Therefore, mechanisms linking type 2 DM and obesity with fetuin-A and angiopoietins seem to be complex and are in need of further exploration. In this review, we aimed to present a summary concerning associations of type 2 diabetes, obesity, and vascular diseases with circulating levels of angiopoietins and fetuin-A. Furthermore, we aimed to focus on roles of fetuin-A and angiopoietins and to highlight the most plausible mechanisms that might explain their associations with type 2 DM and obesity. PMID: 22820893 [PubMed - indexed for MEDLINE] 143. Exp Gerontol. 2013 Jul;48(7):654-60. doi: 10.1016/j.exger.2012.07.005. Epub 2012 Jul 20. Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents. Perrone CE(1), Malloy VL, Orentreich DS, Orentreich N. Author information: (1)Orentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, NY 10516, USA. perrone@orentreich.org Restriction of dietary methionine by 80% slows the progression of aged-related diseases and prolongs lifespan in rodents. A salient feature of the methionine restriction phenotype is the significant reduction of adipose tissue mass, which is associated with improvement of insulin sensitivity. These beneficial effects of MR involve a host of metabolic adaptations leading to increased mitochondrial biogenesis and function, elevated energy expenditure, changes of lipid and carbohydrate homeostasis, and decreased oxidative damage and inflammation. This review summarizes observations from MR studies and provides insight about potential mediators of tissue-specific responses associated with MR's favorable metabolic effects that contribute to health and lifespan extension. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22819757 [PubMed - indexed for MEDLINE] 144. Metab Syndr Relat Disord. 2012 Oct;10(5):319-20. Epub 2012 Jul 20. Role of subcutaneous adipose tissue in metabolic complications of obesity. Abate N, Chandalia M. PMID: 22816652 [PubMed - indexed for MEDLINE] 145. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1771-6. doi: 10.1161/ATVBAHA.111.241869. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Romeo GR(1), Lee J, Shoelson SE. Author information: (1)Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation. Recent studies have also begun to unravel the heterogeneity of adipose tissue macrophages, and their physical and functional interactions with adipocytes, endothelial cells, and other immune cells within the adipose tissue microenvironment. Translating the information gathered from experimental models of insulin resistance and diabetes into meaningful therapeutic interventions is a tantalizing goal with long-term global health implications. In this context, ongoing clinical studies are testing the effects of targeting inflammation systemically on metabolic and cardiovascular outcomes. PMID: 22815343 [PubMed - indexed for MEDLINE] 146. Curr Opin Clin Nutr Metab Care. 2012 Sep;15(5):424-9. doi: 10.1097/MCO.0b013e328356b944. Segmental bioelectrical impedance analysis: an update. Ward LC(1). Author information: (1)School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, Australia. l.ward@uq.edu.au PURPOSE OF REVIEW: Bioelectrical impedance analysis is a popular, noninvasive and practical method for assessment of body composition. The last decade has seen the development of impedance analyzers designed to assess the composition of body segments as well as the whole body. This review outlines the theoretical basis for segmental impedance analysis, validity and use in practice. RECENT FINDINGS: Segmental impedance analysis tends to underestimate fat-free mass and overestimate fat mass when compared to reference techniques, although the magnitude of these differences can be small. Performance is improved with population-specific prediction equations; algorithms in-built into instrument firmware should not be relied upon. Prediction of whole-body composition from the sum of the individual segments, although theoretically preferable, shows little advantage over whole body wrist to ankle impedance approaches. Prediction of appendicular skeletal muscle mass, although promising, requires further research. The use of measured impedance data directly as indices of composition, rather than for prediction, has not found extensive application in nutritional research despite its success in other fields. SUMMARY: Segmental bioimpedance techniques have advanced substantially in recent years due to availability of simple-to-use analyzers and simplified measurement protocols. The method has been well validated and increasingly adopted in nutritional and clinical practice. Segmental impedance, like conventional whole body impedance approaches, provides indirect prediction of body composition whose accuracy is yet to achieve that of reference techniques such as magnetic reference imaging. This lack of accuracy, however, is outweighed by the method's practicality of use in many settings. PMID: 22814626 [PubMed - indexed for MEDLINE] 147. Annu Rev Nutr. 2012 Aug 21;32:17-33. doi: 10.1146/annurev-nutr-071811-150644. Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Pagliassotti MJ(1). Author information: (1)Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA. pagliasm@cahs.colostate.edu The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease. PMID: 22809102 [PubMed - indexed for MEDLINE] 148. Swiss Med Wkly. 2012 Jul 16;142:w13622. doi: 10.4414/smw.2012.13622. Stem cells for heart valve regeneration. Weber B(1), Emmert MY, Hoerstrup SP. Author information: (1)Swiss Centre for Regenerative Medicine, University of Zurich, Switzerland. benedikt.weber@access.uzh.ch Heart valve tissue engineering holds the potential to overcome limitations of currently used heart valve prostheses. It involves the isolation and expansion of autologous patient cells, the subsequent seeding of these cells onto an appropriate scaffold material, the in vitro incubation and the in vivo implantation of the derived tissue-engineered construct into the patient from whom the cells were taken. While vascular-derived cells require harvest of intact donor tissue and show limited expansion capacities, the use of stem or progenitor cells may overcome these limitations and expand the versatility of the concept of heart valve tissue engineering. Possible sources include cells isolated from blood, bone marrow, adipose tissue, amniotic fluid, chorionic villi, umbilical cord and induced pluripotent stem cells. Here we review different stem cell sources with particular regard to cellular phenotypes and their suitability for application in heart valve tissue engineering. PMID: 22802212 [PubMed - indexed for MEDLINE] 149. Steroids. 2012 Sep;77(11):1107-12. doi: 10.1016/j.steroids.2012.06.005. Epub 2012 Jul 16. The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer. Krishnan AV(1), Swami S, Feldman D. Author information: (1)Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States. Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3429709 PMID: 22801352 [PubMed - indexed for MEDLINE] 150. Biochimie. 2012 Oct;94(10):2143-9. doi: 10.1016/j.biochi.2012.06.030. Epub 2012 Jul 13. Adiponectin: anti-inflammatory and cardioprotective effects. Villarreal-Molina MT(1), Antuna-Puente B. Author information: (1)Instituto Nacional de Medicina Genómica, Mexico City, Mexico. Adipose tissue is an endocrine organ that plays an essential role in regulating several metabolic functions through the secretion of biological mediators called "adipokines". Dysregulation of adipokines plays a crucial role in obesity-related diseases. Adiponectin (APN) is the most abundant adipokine accounting for the 0.01% of total serum protein, and is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology. APN plasma levels are reduced in individuals with obesity, type 2 diabetes and coronary artery disease, all traits with low-grade chronic inflammation. It is has been suggested that the absence of APN anti-inflammatory effects may be a contributing factor to this inflammation. APN inhibits the expression of tumor necrosis factor-α-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-α expression in macrophages and adipose tissue, and smooth muscle cell proliferation. It also has anti-apoptotic and anti-oxidant effects, which play a role in its cardioprotective action. This review will focus on APN as an anti-inflammatory, anti-atherogenic and cardioprotective plasma protein. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22796520 [PubMed - indexed for MEDLINE] 151. Trends Endocrinol Metab. 2012 Aug;23(8):407-15. doi: 10.1016/j.tem.2012.05.011. Epub 2012 Jul 12. Adipose tissue-resident immune cells: key players in immunometabolism. Schipper HS(1), Prakken B, Kalkhoven E, Boes M. Author information: (1)Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Adipose tissue (AT) plays a pivotal role in whole-body lipid and glucose homeostasis. AT exerts metabolic control through various immunological mechanisms that instigated a new research field termed immunometabolism. Here, we review AT-resident immune cells and their role as key players in immunometabolism. In lean subjects, AT-resident immune cells have housekeeping functions ranging from apoptotic cell clearance to extracellular matrix remodeling and angiogenesis. However, obesity provides bacterial and metabolic danger signals that mimic bacterial infection, and drives a shift in immune-cell phenotypes and numbers, classified as a prototypic T helper 1 (Th1) inflammatory response. The resulting AT inflammation and insulin resistance link obesity to its metabolic sequel, and suggests that targeted immunomodulatory interventions may be beneficial for obese patients. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22795937 [PubMed - indexed for MEDLINE] 152. Cell Metab. 2012 Aug 8;16(2):153-66. doi: 10.1016/j.cmet.2012.06.011. Epub 2012 Jul 12. Cancer cachexia: mediators, signaling, and metabolic pathways. Fearon KC(1), Glass DJ, Guttridge DC. Author information: (1)Clinical Surgery, School of Clinical Sciences and Community Health, University of Edinburgh, Royal Infirmary, Edinburgh EH16 4SA, UK. k.fearon@ed.ac.uk Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22795476 [PubMed - indexed for MEDLINE] 153. Cell Transplant. 2012;21(2-3):387-99. doi: 10.3727/096368911X605286. Regenerative cells for transplantation in hepatic failure. Ishikawa T(1), Banas A, Teratani T, Iwaguro H, Ochiya T. Author information: (1)Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have an enormous potential; however, their potential clinical application is being arrested due to various limitations such as teratoma formation followed by tumorigenesis, emergent usage, and the quality control of cells, as well as safety issues regarding long-term culture are also delaying their clinical application. In addition, human ES cells have two crucial issues: immunogenicity and ethical issues associated with their clinical application. The efficient generation of human iPS cells requires gene transfer, yet the mechanism underlying pluripotent stem cell induction has not yet been fully elucidated. Otherwise, although human adult regenerative cells including mesenchymal stem cells have a limited capacity for differentiation, they are nevertheless promising candidates for tissue regeneration in a clinical setting. This review highlights the use of regenerative cells for transplantation in hepatic failure. PMID: 22793046 [PubMed - indexed for MEDLINE] 154. Arq Bras Endocrinol Metabol. 2012 Jun;56(4):215-25. The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus. Brondani LA(1), Assmann TS, Duarte GC, Gross JL, Canani LH, Crispim D. Author information: (1)Endocrinology Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, RS, Brazil. It is well established that genetic factors play an important role in the development of both type 2 diabetes mellitus (DM2) and obesity, and that genetically susceptible subjects can develop these metabolic diseases after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2 and/or obesity. Uncoupling protein 1 (UCP1) is mainly expressed in brown adipose tissue, and acts in thermogenesis, regulation of energy expenditure, and protection against oxidative stress. All these mechanisms are associated with the pathogenesis of DM2 and obesity. Hence, UCP1 is a candidate gene for the development of these disorders. Indeed, several studies have reported that polymorphisms -3826A/G, -1766A/G and -112A/C in the promoter region, Ala64Thr in exon 2 and Met299Leu in exon 5 of UCP1 gene are possibly associated with obesity and/or DM2. However, results are still controversial in different populations. Thus, the aim of this study was to review the role of UCP1 in the development of these metabolic diseases. PMID: 22790465 [PubMed - indexed for MEDLINE] 155. Adv Biol Regul. 2012 May;52(2):340-50. doi: 10.1016/j.jbior.2012.03.001. Epub 2012 Mar 30. Secretomics for skeletal muscle cells: a discovery of novel regulators? Yoon JH(1), Kim J, Song P, Lee TG, Suh PG, Ryu SH. Author information: (1)Division of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk 790-784, Republic of Korea. Metabolic tissues, including skeletal muscle, adipose tissue and the digestive system, dynamically secrete various factors depending on the metabolic state, communicate with each other and orchestrate functions to maintain body homeostasis. Skeletal muscle secretes cytokines such as interleukin-6 (IL-6), IL-15, fibroblast growth factor-21 (FGF21) and IL-8. These compounds, myokines, play important roles in biological homeostasis such as energy metabolism, angiogenesis and myogenesis. New technological advances have allowed secretomics - analysis of the secretome - to be performed. The application of highly sensitive mass spectrometry makes qualitative and quantitative analysis of the secretome of skeletal muscle possible. Secretory proteins derived from skeletal muscle cells under various conditions were analyzed, and many important factors were suggested. In-depth studies of the secretome from metabolic cells in various conditions are strongly recommended. This study will provide information on methods of novel communication between metabolic tissues. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22781747 [PubMed - indexed for MEDLINE] 156. Nihon Eiseigaku Zasshi. 2012 May;67(3):363-74. [Associations of exposure to dioxins and polychlorinated biphenyls with diabetes: based on epidemiological findings]. [Article in Japanese] Uemura H(1). Author information: (1)Department of Preventive Medicine, the University of Tokushima Graduate School, Japan. uemura@basic.med.tokushima-u.ac.jp Persistent organic pollutants (POPs) are a group of chemical substances that have the common properties of resistance to biodegradation, wide-range transportation, high lipophilicity, bioaccumulation in fat, and biomagnification in the food chain. POPs are persistent in the environment worldwide and have potential adverse impacts on human health and the environment. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are well known chemicals that are considered as POPs. The association between high-level exposure to dioxins and type 2 diabetes among U.S. Air Force veterans who had been exposed to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the Vietnam War was reported in the late 1990s. This association has been supported by similar epidemiologic studies, whose subjects were exposed to high doses of dioxins in their places of work involving phenoxyacid herbicide production and spraying, and in the industrial accident in Seveso, Italy. Recently, low-level exposure to dioxins and PCBs has been reported to be linked to type 2 diabetes. Cross-sectional studies in the U.S. general population and Japanese general population showed that body burden levels of some dioxins and PCBs were strongly associated with the prevalence of type 2 diabetes. Very recently, following these cross-sectional studies, several prospective studies have suggested that low-level exposure to some PCBs predicted the future risk of type 2 diabetes in the general population. Environmental exposure to some dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes. PMID: 22781010 [PubMed - indexed for MEDLINE] 157. J Biol Chem. 2012 Sep 14;287(38):31658-65. doi: 10.1074/jbc.R112.356485. Epub 2012 Jul 9. Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology. Racioppi L(1), Means AR. Author information: (1)Department of Pharmacology and Cancer Biology, Duke University Medical Center, Duke University, Durham, North Carolina 27710, USA. luigi.racioppi@duke.edu Many cellular Ca(2+)-dependent signaling cascades utilize calmodulin (CaM) as the intracellular Ca(2+) receptor. Ca(2+)/CaM binds and activates a plethora of enzymes, including CaM kinases (CaMKs). CaMKK2 is one of the most versatile of the CaMKs and will phosphorylate and activate CaMKI, CaMKIV, and AMP-activated protein kinase. Cell expression of CaMKK2 is limited, yet CaMKK2 is involved in regulating many important physiological and pathophysiological processes, including energy balance, adiposity, glucose homeostasis, hematopoiesis, inflammation, and cancer. Here, we explore known functions of CaMKK2 and discuss its potential as a target for therapeutic intervention. PMCID: PMC3442500 PMID: 22778263 [PubMed - indexed for MEDLINE] 158. Curr Opin Lipidol. 2012 Aug;23(4):290-302. doi: 10.1097/MOL.0b013e328354fcf4. Lysophospholipid acyltransferases: 1-acylglycerol-3-phosphate O-acyltransferases. From discovery to disease. Agarwal AK(1). Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Anil.Agarwal@UTSouthwestern.edu PURPOSE OF REVIEW: Over the past several years, many more isoforms for the same enzymes, specifically for 1-acylglycerol-3-phosphate O-acyltransferases (AGPATs), have been cloned and studied. In this review, we summarize their biochemical features and discuss their functional role. RECENT FINDINGS: The most significant role of these AGPATs appeared from our observation of AGPAT2 in the biology of adipose tissue (adipocytes) in humans and mice. Other isoforms are shown to be implicated in lung, reproductive and cardiac muscle function and in the cause of cancer. In-vitro substrate specificities of these AGPATs also suggest the in-vivo role of these AGPATs in remodeling of several of the glycerophospholipids. SUMMARY: Despite significant progress in understanding the role of these AGPATs, much is still to be discovered in terms of how each of these AGPATs function in the presence or absence of other AGPATs and what their functional role might be. PMID: 22777291 [PubMed - indexed for MEDLINE] 159. Trends Endocrinol Metab. 2012 Aug;23(8):381-90. doi: 10.1016/j.tem.2012.06.003. Epub 2012 Jul 4. New insights into ER stress-induced insulin resistance. Flamment M(1), Hajduch E, Ferré P, Foufelle F. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Unité Mixte de Recherche en Santé (UMR-S) 872, Paris, F-75006 France. Insulin resistance is a major characteristic of obesity and type 2 diabetes (T2DM). During the last decade, endoplasmic reticulum (ER) stress has emerged as a new player in this field and a considerable number of recent studies have pointed out its role in the onset of insulin resistance (IR). ER stress appears to act directly as a negative modulator of the insulin signaling pathway but also indirectly by promoting lipid accumulation. This review aims to summarize and decipher the abundant new literature concerning the emerging and multifaceted involvement of ER stress in the development of metabolic dysfunctions in insulin target tissues. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22770719 [PubMed - indexed for MEDLINE] 160. Rev Med Inst Mex Seguro Soc. 2012 Jan-Feb;50(1):39-45. [New trends in macrophages, inflammation and adipose tissue]. [Article in Spanish] Rico-Rosillo MG(1), Vega-Robledo GB. Author information: (1)Universidad Nacional Autónoma de México, Distrito Federal, México, Mexico. gricor12@yahoo.com.mx Obesity is considered a low-inflammatory condition. An increasing number of reports suggest that the adipose tissue itself might be a source of proinflammatory factors and a target of inflammatory processes. Accumulating evidence suggest the involvement of adipose tissue derived proteins, collectively known as adipokines as well as other factors produced in this tissue by cells besides to adipocytes, like fibroblasts, lymphocytes and macrophages. The burden of obesity on health extends across multiple organs systems and diseases (atherosclerosis, coronary heart diseases, osteoarthritis, diabetes, hypertension, dyslipidemia). The high incidence and its chronic inflammatory condition have had a wide impact. The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. In this review we highlight the macrophage participation in the generation of obesity-induced inflammation. PMID: 22768816 [PubMed - indexed for MEDLINE] 161. J Pediatr Endocrinol Metab. 2012;25(3-4):233-7. Brown adipose tissue: distribution and influencing factors on FDG PET/CT scan. Hao R(1), Yuan L, Zhang N, Li C, Yang J. Author information: (1)Healthcare Center of Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, 100050 Beijing, China. Brown adipose tissue (BAT) functions as a thermogenic organ by producing heat to maintain body temperature in many mammals, especially in the young. BAT is generally found in deep cervical, supraclavicular, interscapular, and paravertebral regions, as well as areas near large vessels. If not recognized, BAT activity can considerably interfere with 18F-fluorodeoxyglucose position emission tomography (PET)/computed tomography (CT) image interpretation. BAT activation can be influenced by several factors and reduced by different methods. In this paper, we review BAT distribution and factors influencing BAT activity on FDG PET/CT scan. The purpose of this review is to enhance the recognition of pediatric-related physician of BAT on FDG PET/CT scan. PMID: 22768649 [PubMed - indexed for MEDLINE] 162. Biomed Mater Eng. 2012;22(1-3):105-11. doi: 10.3233/BME-2012-0695. Research on stem cells as candidates to be differentiated into hepatocytes. Zhang L(1), Ye JS, Decot V, Stoltz JF, de Isla N. Author information: (1)BRC, First Hospital of Kun Ming (affiliated Calmette Hospital of Kun Ming Medical College), Kun Ming, China. zlei01@hotmail.com Liver diseases have become one of the most important causes of morbidity and mortality in the world. Cell therapy and liver transplantation are though to be two treatment options well accepted. However, the shortage of cells sources in cytotherapy and the lack of liver donor in liver transplantation are the major obstacles for the performance of these treatment methods. It urged us to find new origins of extra-hepatic cells. A number of recent studies show that extra-hepatic mesenchymal stem cells (MSC) from different tissues can be differentiated into hepatocytes like cells (HLC). Several hepatic differentiation protocols of MSC have been published in recent years, based on cellular stimulation with exogenous cytokines/growth factors, co-culture with fetal or adult hepatocytes, 2- or 3-dimensional (2D, 3D) matrices to favor differentiation. Independently from the starting stem cells population used, some minimal criteria must be fulfilled to ensure therapeutic success: in vitro expandability, expression of hepatic like surface markers, with hepatic cell functions, and minimal or absent immunogenicity in the recipient host. In this review, we focused on stem cells originated from bone marrow, umbilical cord and adipose tissue which are widely investigated in recent years and have been proved to have liver regenerative potential, the factors used to differentiate stem cells to hepatocyte-like cells and the methods used to investigate these cells. PMID: 22766708 [PubMed - indexed for MEDLINE] 163. Trends Endocrinol Metab. 2012 Aug;23(8):372-80. doi: 10.1016/j.tem.2012.05.003. Epub 2012 Jul 4. Novel links between HIFs, type 2 diabetes, and metabolic syndrome. Girgis CM(1), Cheng K, Scott CH, Gunton JE. Author information: (1)Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Hypoxia inducible factors (HIFs) are master-regulators of cellular responses to hypoxia, and thus are crucial for survival. HIFs also play a role in regulating cellular processes in β-cells, liver, muscle, and adipose tissue, have effects on the regulation of weight, and play a role in type 2 diabetes (T2D). Indeed, in people with T2D the HIF pathway is dyregulated in major metabolic tissues involved in the pathogenesis of diabetes. This review covers the contrasting, complementary and conflicting effects of decreasing and increasing HIFs in various tissues, and shows that a delicate balance exists between HIF levels and optimal metabolic function. We propose that increasing the activity of HIFs might be a potential therapeutic strategy for treating T2D. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22766319 [PubMed - indexed for MEDLINE] 164. Expert Opin Ther Targets. 2012 Aug;16(8):819-32. doi: 10.1517/14728222.2012.703656. Epub 2012 Jul 5. Can targeting SIRT-1 to treat type 2 diabetes be a good strategy? A review. Pulla VK(1), Battu MB, Alvala M, Sriram D, Yogeeswari P. Author information: (1)Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Department of Pharmacy, Drug Discovery Research Laboratory, R.R. District-500078, Andhra Pradesh, India. INTRODUCTION: Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to type 2 diabetes characterized by high glucose concentration in the blood due to insulin resistance which is a major disorder in developed countries. AREAS COVERED: One of the recent treatment strategies is using activators of SIRT1, which has been in clinical trials. Many of the cellular processes including insulin secretion, cell cycle, and apoptosis are imperatively regulated by a family of mediators called sirtuins. First known mammalian sirtuin, SIRT1 is a positive regulator of insulin secretion, which triggers glucose uptake and utilization. Since the past decade, a major outstanding question is whether SIRT1 activation is a safe therapy for human diseases such as type 2 diabetes? This review summarizes and discusses the advances of the past decade and the challenges that will brazen out perplexity about homeostasis and metabolic pathways linked to SIRT1 and type 2 diabetes. Furthermore, we described the interlink between SIRT1 metabolic pathways of various tissues such as pancreas, skeletal muscle, adipose tissue and liver. EXPERT OPINION: However be the complexity of the pathways involved, T2DM regulated by SIRT1 affected metabolism is dropping down progressively due to profound research. In the context of interlinking all the SIRT1 pathways in T2DM we found various crucial intermediaries in metabolic tissues, which can also be targeted for future prospects. PMID: 22762724 [PubMed - indexed for MEDLINE] 165. Mol Nutr Food Res. 2012 Jul;56(7):1173-84. doi: 10.1002/mnfr.201100785. Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis. McGillicuddy FC(1), Roche HM. Author information: (1)UCD Conway Institute, School of Public Health & Population Science, University College Dublin, Dublin, Ireland. Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22760984 [PubMed - indexed for MEDLINE] 166. Sleep Breath. 2013 May;17(2):505-10. doi: 10.1007/s11325-012-0729-8. Epub 2012 Jun 20. Does physical exercise reduce excessive daytime sleepiness by improving inflammatory profiles in obstructive sleep apnea patients? Alves Eda S(1), Ackel-D'Elia C, Luz GP, Cunha TC, Carneiro G, Tufik S, Bittencourt LR, de Mello MT. Author information: (1)Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo, CEP: 04020-050, Brazil. INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is associated with a variety of long-term consequences such as high rates of morbidity and mortality, due to excessive diurnal somnolence as well as cardiovascular and metabolic diseases. Obesity, recurrent episodes of upper airway obstruction, progressive hypoxemia, and sleep fragmentation during sleep cause neural, cardiovascular, and metabolic changes. These changes include activation of peripheral sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, insulin sensitivity, and inflammatory cytokines alterations, which predispose an individual to vascular damage. DISCUSSION: Previous studies proposed that OSAS modulated the expression and secretion of inflammatory cytokines from fat and other tissues. Independent of obesity, patients with OSAS exhibited elevated levels of C-reactive protein, tumor necrosis factor-α and interleukin-6, which are associated with sleepiness, fatigue, and the development of a variety of metabolic and cardiovascular diseases. OSAS and obesity are strongly associated with each other and share many common pathways that induce chronic inflammation. Previous studies suggested that the protective effect of exercise may be partially attributed to the anti-inflammatory effect of regular exercise, and this effect was observed in obese patients. Although some studies assessed the effects of physical exercise on objective and subjective sleep parameters, the quality of life, and mood in patients with OSAS, no study has evaluated the effects of this treatment on inflammatory profiles. In this review, we cited some studies that directed our opinion to believe that since OSAS causes increased inflammation and has excessive daytime sleepiness as a symptom and being that physical exercise improves inflammatory profiles and possibly OSAS symptoms, it must be that physical exercise improves excessive daytime sleepiness due to its improvement in inflammatory profiles. PMID: 22760814 [PubMed - indexed for MEDLINE] 167. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):273-8. doi: 10.1111/j.1468-3083.2012.04622.x. Epub 2012 Jul 3. Cellulite's aetiology: a review. de la Casa Almeida M(1), Suarez Serrano C, Rebollo Roldán J, Jiménez Rejano JJ. Author information: (1)Physiotherapy, University of Seville, Seville, Spain. Cellulite, highly prevalent among women, represents a serious problem for many of them, and one of their main aesthetic concerns. It is difficult to pinpoint its aetiology and physiology/pathophysiology, as there are many factors that are involved in it, affect it, and many processes that are taking place simultaneously and sequentially. Our objective is therefore, to review the scientific scholarship on cellulite to explore the causes of its origin. We carried out a preliminary search of the Medline, Cochrane, and Web of Knowledge databases covering the period from 1978 to April 2011. As there is no specific key word for the phenomenon at hand, we used the following descriptors: adipose tissue, subcutaneous fat, subcutaneous tissue, connective tissue, skin, skin disease and dermis. This resulted in a retrieval of 26 articles contributing to relevant information on the aetiology of cellulite. As a result of our first research, we concluded that cellulite is a physiological phenomenon or at least, that it has a physiological origin, which is characteristic of women, and multi-causal, with the coexistence of a number of factors that trigger, perpetuate, or exacerbate it. The outstanding factors include, among others, connective tissue architecture, oestrogen action, microvascular alterations and certain genetic and hormonal characteristics. All of them provide us with future and novel clues to cellulite treatment, and is necessary to take some or all of these factors into account in developing an effective therapy. However, we are aware of the necessity of further investigation in this field. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology. PMID: 22758934 [PubMed - indexed for MEDLINE] 168. Anticancer Res. 2012 Jul;32(7):2585-90. A significant role of lipogenic enzymes in colorectal cancer. Notarnicola M(1), Messa C, Caruso MG. Author information: (1)Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases, Via Turi, 27, 70013 Castellana Grotte (Bari), Italy. In this review, we summarize recent progress regarding the study of the main enzymes of lipid metabolism involved in colorectal cancer development, namely of a) farnesyltransferase (Ftase), a cytosolic enzyme that catalyzes the first step in the protein farnesylation; b) farnesyl diphosphate synthase (FPPS, which yields FPP, a substrate for Ftase; c) fatty acid synthase (FAS), an enzyme required for the conversion of acetyl-CoA and malonyl-CoA to palmitate; and d) lipoprotein lipase (LPL), the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Alterations in the levels of these enzymes may contribute to a cell growth advantage acquired during the carcinogenic process and to the development of malignancy. We have demonstrated an elevated Ftase activity in human colorectal cancer (CRC), with differences in Ftase activity related to histological grading, tumor location and KRAS mutation status. Moreover, the first evidence of FPPS activity in human CRC was demonstrated by our study, where a higher FPPS activity and mRNA expression was present in cancer rather than in normal mucosa. We also detected a hyperactivation of FAS in colon cancer, related to tumor location, sex and, p53 mutation status. Our data reinforce the role of lipid metabolism in the regulation of cellular metabolic processes and in carcinogenesis. Moreover, our findings suggest that biological factors including sex, gene mutation status, as well as the stratification of patients with colorectal cancer into right- and left-sided subsets may be important in patient selection for targeted therapies. Our studies in vitro demonstrated that FAS might also be a molecular target for the antiproliferative activity of olive oil polyphenols in a metabolically defined subset of patients with colon cancer. Moreover, we detected that the serum levels of FAS in patients with colorectal cancer are associated with tumor stage. Recently, we found a significant reduction in the levels of FAS and another lipogenic enzyme, LPL, in adipose tissue adjacent to tumor lesions, compared to the levels of FAS detected in paired tissue distant from neoplasia in patients with colorectal cancer. The study of metabolic changes in lipogenic enzyme pathways, as well as the determination of the distribution of individual roles within each biochemical pathway provide a rationale for selecting a particular reaction step suitable for therapeutic intervention. PMID: 22753716 [PubMed - indexed for MEDLINE] 169. Mol Cell Endocrinol. 2013 Sep 25;378(1-2):1-14. doi: 10.1016/j.mce.2012.06.021. Epub 2012 Jun 29. Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance. Marcus Y(1), Shefer G, Stern N. Author information: (1)Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. This review focuses on the expression of the key components of the renin-angiotensin-aldosterone axis in fat tissue. At the center of this report is the role of RAAS in normal and excessive fat mass enlargement, the leading etiology of insulin resistance. Understanding the expression and regulation of RAAS components in various fat depots allows insight not only into the processes by which these complex patterns are modified by the enlargement of adipose tissue, but also into their impact on local and systemic response to insulin. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22750719 [PubMed - indexed for MEDLINE] 170. Biochimie. 2012 Oct;94(10):2104-10. doi: 10.1016/j.biochi.2012.06.017. Epub 2012 Jun 29. Is there NO help for leptin? Joffin N(1), Niang F, Forest C, Jaubert AM. Author information: (1)Institut National de la Santé et de la Recherche Médicale UMR-S 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France. Since the initial identification of leptin as the product of the ob gene in 1994, the signaling pathways by which this hormone alters cell physiology have been the subject of extensive investigations. The fact that leptin can induce nitric oxide (NO) production was first demonstrated in studies of the pituitary gland and pancreatic islets. A large number of additional studies further showed that this adipokine stimulates NO synthesis in multiple tissues. This review article discusses the role of leptin in NO production and its pathophysiological consequences. The role of this gaseous messenger in cell physiology depends on the cell type, the concentration of NO and the duration of exposure. It can be either a potent oxidant or a protector of cell integrity against the formation of reactive oxygen species. Leptin plays two opposing roles on arterial pressure. It exerts a hypertensive effect due to sympathetic activation and a vasorelaxant effect due to NO production. This adipokine acts via NO to produce pro-inflammatory factors in cartilage pathology, potentially contributing to an increased risk for osteoarthritis. Another well-documented role of leptin-induced NO, acting either directly or via the hypothalamus, concerns lipid metabolism in muscle and adipose tissue. In adipocytes, the direct and rapid action of leptin is to activate the nitric oxide synthase III, which favors lipolysis. In contrast, in the long-term, leptin reduces lipolysis. However, both in the short-term and in the long-term, glyceroneogenesis and its key enzyme, the cytosolic phosphoenolpyruvatecarboxykinase (PEPCK-C), are down-regulated by the adipokine, thus favoring fatty acid release. Hence, leptin-induced NO production plays a crucial role in fatty acid metabolism in adipose tissue. The resulting effects are to prevent lipid storage and to improve energy expenditure, with possible improvements of the obese state and its associated diseases. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22750650 [PubMed - indexed for MEDLINE] 171. Pulm Pharmacol Ther. 2013 Aug;26(4):420-6. doi: 10.1016/j.pupt.2012.06.006. Epub 2012 Jun 26. Fat, fire and muscle--the role of adiponectin in pulmonary vascular inflammation and remodeling. Medoff BD(1). Author information: (1)Pulmonary and Critical Care Unit and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. bmedoff@partners.org Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and anti-proliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in peri-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22750271 [PubMed - indexed for MEDLINE] 172. Biochimie. 2012 Oct;94(10):2082-8. doi: 10.1016/j.biochi.2012.05.018. Epub 2012 Jun 26. Immunological functions of leptin and adiponectin. Carbone F(1), La Rocca C, Matarese G. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Napoli 80131, Italy. Recent years have seen several advances in our understanding of the functions of adipose tissue regarding not only the energy storage, but also the regulation of complex metabolic and endocrine functions. In this context, leptin and adiponectin, the two most abundant adipocyte products, represent one of the best example of adipocytokines involved in the control of energy expenditure, lipid and carbohydrate metabolism as well as in the regulation of immune responses. Leptin and adiponectin secretion is counter-regulated in vivo, in relation to degree of adiposity, since plasma leptin concentrations are significantly elevated in obese subjects in proportion to body mass index while adiponectin secretion decreases in relation to the amount of adipose tissue. In this review we focus on the main biological activities of leptin and adiponectin on the lipid and carbohydrate metabolism and on their contribute in regulation of innate and adaptive immune responses. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22750129 [PubMed - indexed for MEDLINE] 173. Mol Cell Endocrinol. 2013 Feb 25;366(2):194-203. doi: 10.1016/j.mce.2012.06.014. Epub 2012 Jun 28. The role of AMP-activated protein kinase in regulating white adipose tissue metabolism. Ceddia RB(1). Author information: (1)School of Kinesiology and Health Science, York University, Toronto, ON, Canada. roceddia@yorku.ca AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that plays a major role in the maintenance of energy homeostasis in various organs and tissues. When activated, AMPK can induce substrate catabolism and shut down energy-consuming anabolic pathways to increase intracellular ATP availability. Even though most of these effects have been described in muscle and liver, several studies have provided compelling evidence that AMPK also plays an important role in the regulation of white adipose tissue (WAT) glucose and lipid metabolism. In fact, the effects of acute and chronic AMPK activation in the WAT induce profound changes in adiposity with important implications for the treatment of obesity and its related metabolic disorders. This review discusses the role of AMPK in the regulation of white adipocyte metabolism with respect to energy storage and release, gene expression, mitochondrial biogenesis, oxidative capacity, cell differentiation, and the potential impact on whole-body adiposity and energy homeostasis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22750051 [PubMed - indexed for MEDLINE] 174. J Nutr Biochem. 2012 Sep;23(9):1027-40. doi: 10.1016/j.jnutbio.2012.03.004. Epub 2012 Jun 27. The role of dietary fatty acids in the pathology of metabolic syndrome. Lottenberg AM(1), Afonso Mda S, Lavrador MS, Machado RM, Nakandakare ER. Author information: (1)Faculty of Medical Sciences of the University of Sao Paulo, Sao Paulo, Brazil. amlottenberg@uol.com.br Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22749135 [PubMed - indexed for MEDLINE] 175. Ann Endocrinol (Paris). 2012 Jun;73(3):170-89. doi: 10.1016/j.ando.2012.04.010. Epub 2012 Jun 28. How to diagnose a lipodystrophy syndrome. Vantyghem MC(1), Balavoine AS, Douillard C, Defrance F, Dieudonne L, Mouton F, Lemaire C, Bertrand-Escouflaire N, Bourdelle-Hego MF, Devemy F, Evrard A, Gheerbrand D, Girardot C, Gumuche S, Hober C, Topolinski H, Lamblin B, Mycinski B, Ryndak A, Karrouz W, Duvivier E, Merlen E, Cortet C, Weill J, Lacroix D, Wémeau JL. Author information: (1)Inserm U859, service d'endocrinologie et maladies métaboliques, hôpital Huriez, CHRU de Lille, 1, rue Polonovski, 59000 Lille, France. mc-vantyghem@chru-lille.fr The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders. Copyright © 2012. Published by Elsevier Masson SAS. PMID: 22748602 [PubMed - indexed for MEDLINE] 176. BMC Physiol. 2012 Jun 27;12:8. doi: 10.1186/1472-6793-12-8. Interleukin-1 beta: a potential link between stress and the development of visceral obesity. Speaker KJ(1), Fleshner M. Author information: (1)Department of Integrative Physiology, University of Colorado at Boulder, 80309, USA. BACKGROUND: A disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT) and their possible role in modulating stress-induced shifts in body fat distribution. HYPOTHESIS: The current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β) signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity. CONCLUSIONS: This review establishes the following key points: 1) body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2) repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight; 3) because of the heterogeneity of WAT composition and function, an accurate understanding of WAT responses requires sampling multiple WAT depots; 4) acute, non-pathogenic stressor exposure increases WAT IL-1β concentrations in a depot specific manner suggesting an adaptive, metabolic role for this cytokine; however, when repeated, stress-induced IL-1β in non-visceral WAT may result in functional impairments that drive the development of stress-induced visceral obesity. PMCID: PMC3404929 PMID: 22738239 [PubMed - indexed for MEDLINE] 177. Diabetologia. 2012 Oct;55(10):2583-92. doi: 10.1007/s00125-012-2607-0. Epub 2012 Jun 26. Lymphocytes in obesity-related adipose tissue inflammation. Chatzigeorgiou A(1), Karalis KP, Bornstein SR, Chavakis T. Author information: (1)Department of Internal Medicine III, Division of Vascular Inflammation, Diabetes and Kidney, University Clinic Carl-Gustav-Carus, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. Antonios.Chatzigeorgiou@uniklinikum-dresden.de Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8(+) T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4(+) Th1 and CD4(+) Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies. PMID: 22733483 [PubMed - indexed for MEDLINE] 178. Curr Opin Pediatr. 2012 Aug;24(4):523-9. doi: 10.1097/MOP.0b013e3283557d22. Metabolic actions of fibroblast growth factor 21. Cuevas-Ramos D(1), Aguilar-Salinas CA, Gómez-Pérez FJ. Author information: (1)Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. PURPOSE OF REVIEW: FGF21 has emerged as a hormone involved in energy homeostasis. A large number of recent reports have expanded the role of FGF21 from a response factor to prolonged fasting to a key hormone that regulates free fatty acid (FFAs) levels. The therapeutic role of recombinant human FGF21 for type 2 diabetes and dyslipidemia is under study. RECENT FINDINGS: Recent evidence suggests that supraphysiological concentrations of FFAs induce FGF21 secretion (i.e., starvation and intense physical activity) through the peroxisome proliferator-activated receptor alpha (PPARα) pathway. The rise in FGF21 levels is aimed at improving energy production (ketogenesis) and utilization (oxidation) of FFAs. FGF21 increment may protect against chronic exposure to high concentrations of FFAs, which causes lipotoxicity in muscle, pancreas, and liver. In addition, FGF21 induces appetite and inhibits growth, probably as part of the adaptive starvation response. The autocrine function of FGF21 in adipose tissue increases PPARγ activity and glucose uptake. Increased plasma FGF21 levels have been found in insulin resistance states in humans. However, the reason for this rise in FGF21 values is still under study. SUMMARY: We propose that FGF21 serves as a defense mechanism against supraphysiological concentrations of FFAs. In addition, FGF21 might have a therapeutic indication in humans. PMID: 22732636 [PubMed - indexed for MEDLINE] 179. Clin Plast Surg. 2012 Jul;39(3):281-92. doi: 10.1016/j.cps.2012.04.005. Epub 2012 May 22. Early experiences with stem cells in treating chronic wounds. Akita S(1), Yoshimoto H, Akino K, Ohtsuru A, Hayashida K, Hirano A, Suzuki K, Yamashita S. Author information: (1)Department of Plastic and Reconstructive Surgery, Nagasaki University Hospital, Japan. akitas@hf.rim.or.jp This review provides a thorough and clear discussion on the outcomes of stem cells in treating chronic wounds. With recent technological developments that now allow isolation and culture of stem cells, researchers are able to perform vigorous studies on somatic or adult stem cells. Human and animal stem cell studies are discussed with a focus on the basic process of stem cells in wound healing and the authors' first-hand clinical experience with stem cells used for chronic wound healing. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22732376 [PubMed - indexed for MEDLINE] 180. Rev Prat. 2012 May;62(5):621-4. [Osteoarthritis and obesity]. [Article in French] Sellam J(1), Berenbaum F. Author information: (1)Service de rhumatologie, hôpital Saint-Antoine, AP-HP, 75012 Paris. jeremie.sellam@sat.aphp.fr Obesity is one of the risk factors for hip or knee osteoarthritis (OA), since mechanical overload on weight-bearing joints activates chondrocytes and accelerates cartilage degeneration. Surprisingly, obesity and overweight also contribute to hand OA due to a systemic effect involving the pro-inflammatory and -degenerative role of some adipokines, secreted by adipose tissue, as well as some joint cells. Obesity-induced OA is now included in a larger phenotype termed "metabolic GA", since OA is associated with various parameters of the metabolic Ssyndrome (including type-2 diabetes) and excess cardiovascular mortality related to this disease. Early-onset OA should lead to suspect a potential metabolic syndrome. Weight loss strategies remain a valuable therapeutic approach to prevent OA and reduce its symptoms, and must be associated with physical activity to allow for optimal outcomes. PMID: 22730785 [PubMed - indexed for MEDLINE] 181. Protein Cell. 2012 Sep;3(9):648-60. doi: 10.1007/s13238-012-2043-4. Epub 2012 Jun 22. Mitochondria in the pathogenesis of diabetes: a proteomic view. Chen X(1), Wei S, Yang F. Author information: (1)Key Laboratory of Protein and Peptide Pharmaceuticals and Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes. PMID: 22729395 [PubMed - indexed for MEDLINE] 182. Dig Dis. 2012;30(2):154-7. doi: 10.1159/000336668. Epub 2012 Jun 20. The role of obesity in gastroesophageal reflux disease and Barrett's esophagus. Eusebi LH(1), Fuccio L, Bazzoli F. Author information: (1)Department of Internal Medicine and Gastroenterology, University of Bologna, Italy. The prevalence of gastroesophageal reflux disease (GERD) and related disorders has been increasing worldwide, particularly in Western populations where a parallel rise in obesity prevalence has been reported. As weight gain often overlaps with the GERD-related symptoms, several recent studies investigated the significance of this correlation, mainly using meta-analyses. Here, we discuss the large amount of evidence linking obesity and GERD-related symptoms, providing potential mechanisms for their co-occurrence. Particular attention is given also to the association between obesity, Barrett's esophagus and esophageal adenocarcinoma development. Copyright © 2012 S. Karger AG, Basel. PMID: 22722430 [PubMed - indexed for MEDLINE] 183. Dig Dis. 2012;30(2):148-53. doi: 10.1159/000336664. Epub 2012 Jun 20. Obesity and metabolic syndrome: an inflammatory condition. Scarpellini E(1), Tack J. Author information: (1)Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Belgium. Obesity causes chronic low-grade inflammation that contributes to systemic metabolic dysfunction associated with obesity-linked disorders that fall under the definition of metabolic syndrome. Adipose tissue is a key endocrine organ as it releases multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have proinflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this emerging context, the gut microbiota-metabolism interactions play an increasingly important role in the understanding and hopefully future treatment of complex metabolic unbalances responsible for insulin resistance and cardiovascular high-risk diseases. Copyright © 2012 S. Karger AG, Basel. PMID: 22722429 [PubMed - indexed for MEDLINE] 184. Crit Rev Biochem Mol Biol. 2012 Jul-Aug;47(4):379-90. doi: 10.3109/10409238.2012.694843. The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. Kalupahana NS(1), Moustaid-Moussa N. Author information: (1)Obesity Research Center, The University of Tennessee (UT), Knoxville, TN, USA. The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements. PMID: 22720713 [PubMed - indexed for MEDLINE] 185. J Gastrointestin Liver Dis. 2012 Jun;21(2):205-8. Is visceral fat reduction necessary to favour metabolic changes in the liver? Finelli C(1), Tarantino G. Author information: (1)Center of Obesity and Eating Disorder, Stella Maris Mediterraneo Foundation Chiaromonte, Potenza, Italy. As excess body weight constitutes a major health problem, it is now important for hepatologists to weigh risk factors that lead to insulin resistance and hepatic steatosis. This mini-review focuses on the type of bodily fat distribution that determines the ectopic fat storage into the liver in overweight or obese people. Although obesity is closely associated with non-alcoholic fatty liver disease, the excess of visceral fat storage is reckoned to be just as or even more important. PMID: 22720311 [PubMed - indexed for MEDLINE] 186. Ann Med. 2012 Jun;44 Suppl 1:S74-84. doi: 10.3109/07853890.2012.663928. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. Aghamohammadzadeh R(1), Heagerty AM. Author information: (1)Cardiovascular Research Group, University of Manchester, UK. The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension. PMID: 22713152 [PubMed - indexed for MEDLINE] 187. Adv Exp Med Biol. 2012;984:287-98. doi: 10.1007/978-94-007-4315-1_15. Immune response and Coxiella burnetii invasion. Amara AB(1), Bechah Y, Mege JL. Author information: (1)Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, CNRS-IRD UMR 6236, Institut Fédératif de Recherche 48, Faculté de Médecine, Université de la Méditerranée, Marseille, France. Coxiella burnetii, the causative agent of Q fever, has evolved a wealth of mechanisms in order to persist within hosts. Two tissues, namely adipose tissue and placenta, are candidates to house C. burnetii, but the mechanisms governing C. burnetii survival in these tissues are still unknown. In contrast, monocytes and macrophages are well-known targets of C. burnetii. First, C. burnetii has developed a specific strategy of phagocytosis subversion that consists of the inhibition of integrin interplay. Second, C. burnetii persistence is associated with macrophage activation profiles. Indeed, monocytes (in which C. burnetii survives without replication) exhibit a proinflammatory M1-type response, whereas macrophages (in which C. burnetii slowly replicates) are polarized towards an M2-type. Third, interleukin-10 produced by monocytes is a main factor of the chronic development of Q fever, and murine models confirm the key role of interleukin-10 in C. burnetii persistence. Fourth, apoptotic cells may play a key role in chronic Q fever. The uptake of apoptotic cells by circulating monocytes increases C. burnetii replication by redirecting monocytes toward a non-protective M2 profile. In the presence of interferon-γ, apoptotic cell engulfment is inhibited and monocytes polarized toward an M1 program are able to kill C. burnetii; this is the situation observed in patients with uncomplicated acute Q fever. Finally, we cannot exclude that regulatory T cells may play a role in C. burnetii persistence because their number is increased in patients with chronic Q fever. PMID: 22711638 [PubMed - indexed for MEDLINE] 188. Int J Obes (Lond). 2012 Oct;36(10):1261-9. doi: 10.1038/ijo.2012.95. Epub 2012 Jun 19. Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents. Staiano AE(1), Katzmarzyk PT. Author information: (1)Population Science, Pennington Biomedical Research Center, Baton Rouge, LA, USA. Body fat and the specific depot where adipose tissue (AT) is stored can contribute to cardiometabolic health risks in children and adolescents. Imaging procedures including magnetic resonance imaging and computed tomography allow for the exploration of individual and group differences in pediatric adiposity. This review examines the variation in pediatric total body fat (TBF), visceral AT (VAT) and subcutaneous AT (SAT) due to age, sex, maturational status and ethnicity. TBF, VAT and SAT typically increase as a child ages, though different trends emerge. Girls tend to accumulate more TBF and SAT during and after puberty, depositing fat preferentially in the gynoid and extremity regions. In contrast, pubertal and postpubertal boys tend to deposit more fat in the abdominal region, particularly in the VAT depot. Sexual maturation significantly influences TBF, VAT and SAT. Ethnic differences in TBF are mixed. VAT tends to be higher in white and Hispanic youth, whereas SAT is typically higher in African American youth. Asian youth typically have less gynoid fat but more VAT than whites. Obesity per se may attenuate sex and ethnic differences. Particular health risks are associated with high amounts of TBF, VAT and SAT, including insulin resistance, hepatic steatosis, metabolic syndrome and hypertension. These risks are affected by genetic, biological and lifestyle factors including physical activity, nutrition and stress. Synthesizing evidence is difficult as there is no consistent methodology or definition to estimate and define depot-specific adiposity, and many analyses compare SAT and VAT without controlling for TBF. Future research should include longitudinal examinations of adiposity changes over time in representative samples of youth to make generalizations to the entire pediatric population and examine variation in organ-specific body fat. PMCID: PMC4129655 PMID: 22710928 [PubMed - indexed for MEDLINE] 189. Int J Cardiol. 2013 Jul 15;167(1):22-5. doi: 10.1016/j.ijcard.2012.05.082. Epub 2012 Jun 17. Cardiac adipose tissue: a new frontier for cardiac regeneration? Bayes-Genis A(1), Gálvez-Montón C, Prat-Vidal C, Soler-Botija C. Author information: (1)ICREC, Heart Failure and Cardiac Regeneration, Research Program, Health Sciences Research Institute Germans Trias i Pujol, Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. abayes.germanstrias@gencat.cat The human heart has limited regenerative capacity. We focused on cardiac adipose tissue as a source of progenitor cells and biological matrix material for salvaging injured myocardium. First, a population of human adult mesenchymal-like progenitors derived from cardiac adipose tissue, with inherent cardiac and endothelial cell potential, was identified and characterized. Next, a salvage strategy was tested, where a pericardial-derived, vascularized, adipose flap was used to cover oxygen-deprived myocardium in a porcine model. The fat flap reduced the myocardial scar size, in both acute and chronic infarcts. A human clinical trial to examine this novel intervention is currently underway. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22709728 [PubMed - indexed for MEDLINE] 190. Obes Rev. 2012 Oct;13(10):848-57. doi: 10.1111/j.1467-789X.2012.01013.x. Epub 2012 Jun 19. Effect of calcium intake on fat oxidation in adults: a meta-analysis of randomized, controlled trials. Gonzalez JT(1), Rumbold PL, Stevenson EJ. Author information: (1)Brain, Performance and Nutrition Research Centre, School of Life Sciences, Northumbria University, Newcastle upon Tyne, UK. janvier.gonzalex@northumbria.ac.uk Calcium intake is likely to increase body fat loss during energy restriction. Part of this effect may be explained by increased fat oxidation in the presence of a similar energy balance, yet studies have not provided a conclusive answer. Therefore a meta-analysis was performed to determine whether chronic or acute high calcium intake increases fat oxidation. Randomized controlled trials of high calcium intake in human adults where measures of fat oxidation were taken were included. A random-effects meta-analysis was performed on outcomes expressed as standardized mean differences. Chronic high calcium intake increased fat oxidation by a standardized mean difference of 0.42 (95% confidence intervals: 0.14, 0.69; P= 0.003; estimated to correspond to an 11% increase), displaying low heterogeneity (I(2) = 18%), which was more prominent when habitual calcium intake was low (<700 mg d(-1) ). Acute high calcium intake increased fat oxidation by a standardized mean difference of 0.41 (0.04, 0.77; P = 0.03), with low heterogeneity (I(2) = 19%), yet sensitivity analysis revealed that this effect was relatively weak. In conclusion, chronic high calcium intake is likely to increase rates of fat oxidation. The effects of acute high calcium intake appear to point in the same direction, but further work is needed to permit a greater degree of certainty. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22708505 [PubMed - indexed for MEDLINE] 191. Postepy Hig Med Dosw (Online). 2012 May 23;66:267-74. [Leptin as a mediator between obesity and cardiac dysfunction]. [Article in Polish] Karbowska J(1), Kochan Z. Author information: (1)Katedra Biochemii, Gdański Uniwersytet Medyczny, Gdańsk. Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients. PMID: 22706112 [PubMed - indexed for MEDLINE] 192. Trends Endocrinol Metab. 2012 Jul;23(7):351-63. doi: 10.1016/j.tem.2012.05.001. Epub 2012 Jun 14. PPARs at the crossroads of lipid signaling and inflammation. Wahli W(1), Michalik L. Author information: (1)Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland. walter.wahli@unil.ch Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivatives, many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metabolism is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22704720 [PubMed - indexed for MEDLINE] 193. Proc Nutr Soc. 2012 Aug;71(3):363-70. doi: 10.1017/S0029665112000584. Epub 2012 Jun 18. Adipose tissue development during early life: novel insights into energy balance from small and large mammals. Symonds ME(1), Pope M, Budge H. Author information: (1)The Early Life Nutrition Research Unit, Academic Child Health, School of Clinical Sciences, University Hospital, Nottingham NG7 2UH, UK. michael.symonds@nottingham.ac.uk Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle. PMID: 22704581 [PubMed - indexed for MEDLINE] 194. J Intern Med. 2012 Oct;272(4):317-29. doi: 10.1111/j.1365-2796.2012.02564.x. Epub 2012 Jul 29. New insights into osteoporosis: the bone-fat connection. Kawai M(1), de Paula FJ, Rosen CJ. Author information: (1)Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan. Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis. © 2012 The Association for the Publication of the Journal of Internal Medicine. PMCID: PMC3634716 PMID: 22702419 [PubMed - indexed for MEDLINE] 195. Exp Diabetes Res. 2012;2012:789174. doi: 10.1155/2012/789174. Epub 2012 Jun 4. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Arcidiacono B(1), Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, Foti D, Chiefari E, Brunetti A. Author information: (1)Department of Health Sciences, Magna Græcia University of Catanzaro, Viale Europa (Località Germaneto), 88100 Catanzaro, Italy. Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression. PMCID: PMC3372318 PMID: 22701472 [PubMed - indexed for MEDLINE] 196. Ann Hepatol. 2012 Jul-Aug;11(4):440-9.  Gut microbiota and nonalcoholic fatty liver disease. Machado MV(1), Cortez-Pinto H. Author information: (1)Departamento de Gastrenterologia, Hospital Santa Maria, CHLN, Lisbon, Portugal. Comment in Ann Hepatol. 2013 Jan-Feb;12(1):161-3.  Recent evidence has linked obesity and the metabolic syndrome with gut dysbiota. The precise mechanisms underlying that association are not entirely understood; however, microbiota can enhance the extraction of energy from diet and regulate whole-body metabolism towards increased fatty acids uptake from adipose tissue and shift lipids metabolism from oxidation to de novo production. Obesity and high fat diet relate to a specific gut microbiota, which is enriched in Firmicutes and with less Bacterioidetes. Microbiota can also play a role in the development of hepatic steatosis, necroinflammation and fibrosis. In fact, some studies have shown an association between small intestinal bacterial overgrowth, increased intestinal permeability and nonalcoholic steatohepatitis (NASH). That association is, in part, due to increased endotoxinaemia and activation of the Toll-like receptor-4 signaling cascade. Preliminary data on probiotics suggest a potential role in NASH treatment, however randomized controlled clinical trials are still lacking. PMID: 22700625 [PubMed - indexed for MEDLINE] 197. J Mal Vasc. 2012 Jul;37(4):213-8. doi: 10.1016/j.jmv.2012.05.002. Epub 2012 Jun 13. [Lipedema: a misdiagnosed entity]. [Article in French] Vignes S(1). Author information: (1)Unité de lymphologie, centre national de référence des maladies vasculaires rares (lymphœdèmes primaires), hôpital Cognacq-Jay, 15, rue Eugène-Millon, 75015 Paris, France. stephane.vignes@cognacq-jay.fr Lipedema is a clinical entity frequently misdiagnosed or confound with primary lymphedema. Lipedema is a disorder of adipose tissue that occurs almost exclusively in obese women. It is characterized by bilateral enlargement from hip to ankle due to abnormal depositions of subcutaneous fat associated with often mild edema, usually sparing the feet. Disease onset is usually at or soon after puberty. Lipedema results in considerable frustration and distress resulting from the cosmetic appearance. Patients may complain of pain, tenderness, easy bruising of the affected areas with moderate to severe sensitivity to digital pressure or pinching. Imaging studies using computed tomography, magnetic resonance imaging, ultrasound, lymphoscintigraphy are not indicated, except if the diagnosis is atypic or doubtful. Long-term evolution may alter lymphatic system and lead to a lipo-lymphedema with specific complications such as cellulitis. Lipedema management is not codified and included weight loss (poorly improving leg appearance or discomfort), psychological counselling and compression therapy. Liposuction, especially using tumescent local anaesthesia, may reduce edema, spontaneous pain, sensitivity to pressure, bruising and improve appearance resulting in a important increase in quality of life. Copyright © 2012. Published by Elsevier Masson SAS. PMID: 22698628 [PubMed - indexed for MEDLINE] 198. J Laryngol Otol. 2012 Jul;126(7):725-8. doi: 10.1017/S0022215112000783. Case of progressive facial hemiatrophy with cervical sympathetic hyperactivity as underlying aetiology. Monobe H(1), Miyano K, Kagoya R, Tojima H. Author information: (1)Department of Otolaryngology, Hitachi General Hospital, Ibaraki, Japan. h-monobe@chime.ocn.ne.jp OBJECTIVE: We report a case of progressive facial hemiatrophy with cervical sympathetic hyperactivity as a possible underlying aetiology, based on clinical findings, three-dimensional computed tomography and thermographic imaging. METHODS: We present a case report in which we describe the investigation and clinical course of progressive facial hemiatrophy, and we also review the world literature on this condition. RESULTS: To our knowledge, this is the first report in the world literature of progressive facial hemiatrophy with cervical sympathetic hyperactivity indicated as a possible underlying aetiology, based on clinical findings, three-dimensional computed tomography and thermographic imaging. CONCLUSION: This syndrome may lead to atrophy of the subcutaneous adipose tissue with hyperfunction of the vegetative system. Although this is a rare syndrome, otolaryngologists should be aware of its symptoms, aetiology and treatment. PMID: 22697810 [PubMed - indexed for MEDLINE] 199. Stomatologiia (Mosk). 2012;91(1):71-5. [Stem cells and possibilities of their application in parodontology]. [Article in Russian] Grudianov AI, Sysoeva VIu, Ternovoĭ IuV. PMID: 22696797 [PubMed - indexed for MEDLINE] 200. Am J Physiol Regul Integr Comp Physiol. 2012 Aug 1;303(3):R247-58. doi: 10.1152/ajpregu.00167.2012. Epub 2012 Jun 13. Potential clinical translation of juvenile rodent inactivity models to study the onset of childhood obesity. Roberts MD(1), Company JM, Brown JD, Toedebusch RG, Padilla J, Jenkins NT, Laughlin MH, Booth FW. Author information: (1)Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, 65211, USA. According to the latest data from the Center for Disease Control and Prevention 17%, or 12.5 million, of children and adolescents aged 2-19 years in the United States are obese. Physical inactivity is designated as one of the actual causes of US deaths and undoubtedly contributes to the obesity epidemic in children and adults. Examining the effects of inactivity on physiological homeostasis during youth is crucial given that 58% of children between the ages 6-11 yr old fail to obtain the recommended 60 min/day of physical activity and 92% of adolescents fail to achieve this goal [Troiano et al. Med Sci Sports Exerc. 40, 2008]. Nonetheless, invasive mechanistic studies in children linking diminished physical activity with metabolic maladies are lacking for obvious ethical reasons. The rodent wheel lock (WL) model was adopted by our laboratory and others to study how different organ systems of juvenile rats respond to a cessation of daily physical activity. Our WL model houses rats in cages equipped with voluntary running wheels starting at 28 days of age. After a certain period of voluntary running (3 to 6 wk), the wheels are locked, thus preventing the rats' primary source of physical activity. The studies discussed herein suggest that obesity-associated maladies including skeletal muscle insulin resistance, hypothalamic leptin resistance, fatty acid oxidation impairments in skeletal muscle and adipose tissue, nonalcoholic fatty liver disease, and endothelial dysfunction are initiated in juvenile animals that are restrained from voluntary exercise via WL. The use of the juvenile rodent WL or other inactivity models will continue to provide a powerful clinical translational tool that can be used for primordial prevention of human childhood obesity. PMCID: PMC3423989 PMID: 22696577 [PubMed - indexed for MEDLINE] 201. Magn Reson Med. 2012 Aug;68(2):378-88. doi: 10.1002/mrm.24369. Epub 2012 Jun 12. ISMRM workshop on fat-water separation: insights, applications and progress in MRI. Hu HH(1), Börnert P, Hernando D, Kellman P, Ma J, Reeder S, Sirlin C. Author information: (1)Departments of Radiology and Electrical Engineering, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027, USA. houchunh@usc.edu Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding opportunities from the National Institutes of Health. Copyright © 2012 Wiley Periodicals, Inc. PMCID: PMC3575097 PMID: 22693111 [PubMed - indexed for MEDLINE] 202. Physiology (Bethesda). 2012 Jun;27(3):156-66. doi: 10.1152/physiol.00007.2012. Orphan nuclear receptors and the regulation of nutrient metabolism: understanding obesity. Pearen MA(1), Muscat GE. Author information: (1)Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia. m.pearen@uq.edu.au Nuclear hormone receptors (NRs) are a superfamily of eukaryotic ligand-dependent transcription factors that translate endocrine, metabolic, nutritional, developmental, and pathophysiological signals into gene regulation. Members of the NR superfamily (on the basis of sequence homology) that lack identified natural and/or synthetic ligands are/were classified as "orphan" NRs. These members of the NR superfamily are abundantly expressed in tissues associated with major metabolic activity, such as skeletal muscle, adipose, and liver. Subsequently, in vivo genetic studies on these orphan NRs and exploitation of novel natural and synthetic agonists has revealed that orphan NRs regulate 1) carbohydrate, lipid, and energy homeostasis in a tissue-specific manner, and 2) the pathophysiology of dyslipidemia, obesity, Type 2 diabetes, and cardiovascular disease. This review discusses key studies that have implicated the orphan NRs as organ-specific regulators of metabolism and mediators of adverse pathophysiological effects. The emerging discovery of novel endogenous orphan NR ligands and synthetic agonists has provided the foundation for therapeutic exploitation of the orphans in the treatment of metabolic disease. PMID: 22689791 [PubMed - indexed for MEDLINE] 203. Diabetologia. 2012 Sep;55(9):2319-26. doi: 10.1007/s00125-012-2598-x. Epub 2012 Jun 12. Adiponectin: mechanistic insights and clinical implications. Turer AT(1), Scherer PE. Author information: (1)Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8521, USA. Aslan.Turer@UTSouthwestern.edu Adiponectin is an adipocyte-derived secretory protein that has been very widely studied over the past 15 years. A multitude of different functions have been attributed to this adipokine. It has been characterised in vitro at the level of tissue culture systems and in vivo through genetic manipulation of rodent models. It is also widely accepted as a biomarker in clinical studies. Originating in adipose tissue, generally positive metabolic effects have been attributed to adiponectin. In this review, we briefly discuss the key characteristics of this interesting but very complex molecule, highlight recent results in the context of its mechanism of action and summarise some of the key epidemiological data that helped establish adiponectin as a robust biomarker for insulin sensitivity, cardiovascular disease and many additional disease phenomena. PMID: 22688349 [PubMed - indexed for MEDLINE] 204. Yakugaku Zasshi. 2012;132(6):721-5. [Pivotal role of skeletal tissues in the regulation mechanisms for physiological functions mediated by multiple organ networks]. Hinoi E(1). Author information: (1)Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan. hinoi@p.kanazawa-u.ac.jp Bone formation and maintenance are sophisticatedly orchestrated through a well-organized and highly regulated mechanism by two distinct cell types; bone-forming osteoblast and bone-resorbing osteoclast. It has been previously established that the adipocyte-derived hormone leptin regulates bone metabolism through the central nervous system and the sympathetic nervous system. We recently identified the osteoblast as the principal cell type in which the sympathetic tone could signal to regulate bone mass by generating and analyzing the cell specific adrenergic receptor deletion mice. The fact that adipocyte-derived hormone regulates bone metabolism implies that the skeleton might exert a feedback control of glucose metabolism. We then revealed that the skeleton acts as an endocrine regulator of energy metabolism through the osteoblast-specific secreted molecule osteocalcin that activates insulin secretion by pancreatic β-cells, insulin sensitivity in fat, liver, and muscle. Moreover, we have recently reported that the sympathetic tone into osteoblast is a pivotal mediator of leptin regulation of insulin secretion by regulating osteocalcin bioactivity. This unexpected functional cross talk between fat, nervous systems, and skeleton illustrates the importance of the skeleton for the regulation of major physiological functions such as glucose homeostasis in vertebrates. PMID: 22687731 [PubMed - indexed for MEDLINE] 205. Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):406-14. doi: 10.1016/j.ijrobp.2012.04.044. Epub 2012 Jun 9. Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies. Liang Y(1), Bydder M, Yashar CM, Rose BS, Cornell M, Hoh CK, Lawson JD, Einck J, Saenz C, Fanta P, Mundt AJ, Bydder GM, Mell LK. Author information: (1)Department of Radiation Oncology, and Center for Advanced Radiotherapy Technologies, University of California, San Diego, La Jolla, California 92093, USA. PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). METHODS AND MATERIALS: We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. RESULTS: In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. CONCLUSIONS: IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 22687195 [PubMed - indexed for MEDLINE] 206. J Biomed Biotechnol. 2012;2012:871272. doi: 10.1155/2012/871272. Epub 2012 May 22. Role of pigment epithelium-derived factor in stem/progenitor cell-associated neovascularization. Liu JT(1), Chen YL, Chen WC, Chen HY, Lin YW, Wang SH, Man KM, Wan HM, Yin WH, Liu PL, Chen YH. Author information: (1)Department of Neurosurgery, School of Medicine, Chung-Shan Medical University and Hospital, Taichung 402, Taiwan. Pigment epithelium-derived factor (PEDF) was first identified in retinal pigment epithelium cells. It is an endogenously produced protein that is widely expressed throughout the human body such as in the eyes, liver, heart, and adipose tissue; it exhibits multiple and varied biological activities. PEDF is a multifunctional protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic, and neuroprotective properties. More recently, PEDF has been shown to be the most potent inhibitor of stem/progenitor cell-associated neovascularization. Neovascularization is a complex process regulated by a large, interacting network of molecules from stem/progenitor cells. PEDF is also involved in the pathogenesis of angiogenic eye disease, tumor growth, and cardiovascular disease. Novel antiangiogenic agents with tolerable side effects are desired for the treatment of patients with various diseases. Here, we review the value of PEDF as an important endogenous antiangiogenic molecule; we focus on the recently identified role of PEDF as a possible new target molecule to influence stem/progenitor cell-related neovascularization. PMCID: PMC3364713 PMID: 22685380 [PubMed - indexed for MEDLINE] 207. J Lipid Res. 2012 Sep;53(9):1738-54. doi: 10.1194/jlr.R024505. Epub 2012 Jun 8. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. Huang JV(1), Greyson CR, Schwartz GG. Author information: (1)Cardiology Section, Denver VA Medical Center, US Department of Veterans Affairs, Denver, CO, USA. Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease. PMCID: PMC3413217 PMID: 22685322 [PubMed - indexed for MEDLINE] 208. J Burn Care Res. 2012 Jul-Aug;33(4):463-70. doi: 10.1097/BCR.0b013e31825af547. Heterotopic ossification following burn injury: the role of stem cells. Nelson ER(1), Wong VW, Krebsbach PH, Wang SC, Levi B. Author information: (1)Department of Surgery, Plastic and Reconstructive Surgery Division, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA. Heterotopic ossification (HO), or the abnormal development of bone tissue in soft-tissue locations, can be physically debilitating and clinically devastating. For unclear reasons, HO is highly associated with burn injury. The objective of this review is to summarize 1) cells that are responsible for HO, 2) in vitro and in vivo models of HO and how they have contributed to our current knowledge of the disease process, 3) the effects of the adipose compartment on HO, 4) the effects of inflammation on HO, and 5) the effects of mesenchymal stem cells (MSCs) on HO. Preclinical models of HO suggest several possible mechanisms for the development of this pathologic process, including progenitor cell differentiation and paracrine modulation of local inflammatory responses. Further studies are needed to elucidate the molecular mechanisms driving HO so that targeted therapies can be developed. Current literature supports a role for MSCs in modulating heterotopic bone formation, and direct manipulation of MSCs might one day be used to prevent and treat HO. PMID: 22683987 [PubMed - indexed for MEDLINE] 209. Endocrinol Metab Clin North Am. 2012 Jun;41(2):283-95, v-vi. doi: 10.1016/j.ecl.2012.04.011. The insulin-like growth factors in adipogenesis and obesity. Garten A(1), Schuster S, Kiess W. Author information: (1)Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig, University Hospitals, Liebigstraße 20a, 04103 Leipzig, Germany. Adipose tissue has been recognized as a major target of growth hormone (GH) action. GH was shown to inhibit adipocyte differentiation but stimulated preadipocyte proliferation in vitro. GH acts directly via its receptor or via upregulating insulin-like growth factor (IGF)-I, which is a critical mediator of preadipocyte proliferation, differentiation, and survival. Results from clinical studies on GH treatment in patients with GH deficiency or GH insensitivity syndrome can be used to dissect GH and IGF as well as IGF-binding protein (IGFBP) actions in vivo. In this article, changes of the GH/IGF system during adipocyte differentiation in vitro as well as related signaling pathways and their impact on adipose tissue growth and function are discussed. Clinical considerations include the effects of GH and IGF-I on adipose tissue during treatment of GH deficiency, differences in the IGF system between visceral and subcutaneous adipose tissue depots as well as the recently emerging role for adipose tissue in the regulation of glucose homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22682631 [PubMed - indexed for MEDLINE] 210. Cell Mol Life Sci. 2012 Jun 8. [Epub ahead of print] Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology. Schlegel A(1). Author information: (1)University of Utah Molecular Medicine (U2M2) Program, University of Utah School of Medicine, 15 North 2030 East, Building 533, Room 3240B, Salt Lake City, UT, 84124, USA, amnons@u2m2.utah.edu. Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states. PMCID: PMC3492697 PMID: 22678663 [PubMed - as supplied by publisher] 211. Bioessays. 2012 Aug;34(8):681-91. doi: 10.1002/bies.201200031. Epub 2012 Jun 5. New vistas for treatment of obesity and diabetes? Endocannabinoid signalling and metabolism in the modulation of energy balance. Lipina C(1), Rastedt W, Irving AJ, Hundal HS. Author information: (1)Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, Scotland. Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22674489 [PubMed - indexed for MEDLINE] 212. Acta Physiol (Oxf). 2012 Aug;205(4):456-71. doi: 10.1111/j.1748-1716.2012.02455.x. Exercise training, genetics and type 2 diabetes-related phenotypes. Hagberg JM(1), Jenkins NT, Spangenburg E. Author information: (1)Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA. hagberg@umd.edu Type 2 diabetes mellitus (T2DM) is at virtually pandemic levels world-wide. Diabetes has been referred to as 'a geneticist's nightmare'. However, dramatic advances in our understanding of the genetics of T2DM have occurred in the past 5 years. While endurance exercise training and increased habitual physical activity levels have consistently been shown to improve or be associated with improved T2DM-related phenotypes, there is substantial interindividual variation in these responses. There is some evidence that T2DM-related phenotype responses to exercise training are heritable, indicating that they might have a genetic basis. Genome-wide linkage studies have not identified specific chromosomal loci that could account for these differences, and no genome-wide association studies have been performed relative to T2DM-related phenotype responses to exercise training. From candidate gene studies, there are relatively strong and replicated data supporting a role for the PPARγ Pro12Ala variant in the interindividual differences in T2DM-related phenotype responses to training. This is a potentially important candidate locus because it affects T2DM susceptibility, has high biological plausibility and is the target for the primary pharmaceutical method for treating T2DM. Is it time to conduct a hypothesis-driven large-scale exercise training intervention trial based on PPARγ Pro12Ala genotype with T2DM-related phenotypes as the primary outcome measures, while also assessing potential mechanistic changes in skeletal muscle and adipose tissue? Or would it be more appropriate to propose a smaller trial to address the specific skeletal muscle and adipose tissue mechanisms affected by the interaction between the PPARγ Pro12Ala genotype and exercise training? © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society. PMID: 22672138 [PubMed - indexed for MEDLINE] 213. Clin Microbiol Infect. 2012 Jul;18 Suppl 4:50-3. doi: 10.1111/j.1469-0691.2012.03866.x. Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue. Cani PD(1). Author information: (1)Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Université Catholique de Louvain, Brussels, Belgium. patrice.cani@uclouvain.be Obesity is associated with type 2 diabetes, insulin resistance and low grade inflammation. The gut microbiota is now considered as one of the most important environmental factors impacting on host physiology and metabolism. We have recently pointed out the role of this 'organ' on the onset of insulin resistance and the low grade inflammatory tone characterizing obesity. Among the mechanisms, we have introduced the novel concept of metabolic endotoxaemia as factor triggering low grade inflammation and associated disorders. More recently, two novel mechanisms involved in the development of gut permeability and adipose tissue plasticity have been identified. Specific attention has been paid to the role of the glucagon-like peptide 2 and the endocannabinoid system. This review briefly discusses the role of prebiotics as a key tool to modulate the gut microbiota, the gut barrier function, inflammation and the insulin resistance associated with obesity. © 2012 The Author. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases. PMID: 22647050 [PubMed - indexed for MEDLINE] 214. J Pregnancy. 2012;2012:681306. doi: 10.1155/2012/681306. Epub 2012 May 14. Adrenocortical and adipose responses to high-altitude-induced, long-term hypoxia in the ovine fetus. Myers DA(1), Ducsay CA. Author information: (1)Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. dean-myers@ouhsc.edu By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress. PMCID: PMC3361245 PMID: 22666594 [PubMed - indexed for MEDLINE] 215. Circulation. 2012 Jun 5;125(22):2782-91. doi: 10.1161/CIRCULATIONAHA.111.042929. Brown adipose tissue: mechanisms and potential therapeutic targets. Tam CS(1), Lecoultre V, Ravussin E. Author information: (1)Human Physiology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. PMID: 22665886 [PubMed - indexed for MEDLINE] 216. Front Endocrinol (Lausanne). 2012 Feb 6;3:14. doi: 10.3389/fendo.2012.00014. eCollection 2012. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases. Boss O(1), Farmer SR. Author information: (1)Energesis Pharmaceuticals, Inc. Cambridge, MA, USA. Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obese individuals is therapeutically powerful. We also propose that enhancement of brown adipocyte functions in white adipose tissue (WAT) will also regulate energy balance as well as reduce insulin resistance in obesity-associated inflammation in WAT. PMCID: PMC3356088 PMID: 22654854 [PubMed] 217. Minerva Cardioangiol. 2012 Jun;60(3):299-304. Epicardial and pericardial adipose tissue: physiological importance and role of imaging techniques. Arepalli CD(1), Vrettoy RA, Lamanna JJ, Ebert EL, Kremastinos DT, Lerakis S. Author information: (1)Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA. Epicardial adipose tissue (EAT) is becoming a cardiovascular risk factor. Multiple imaging techniques are used to measure it, each one with its prons and cons. We will review the literature realizing that there is still a lot of work that needs to be done. PMID: 22653044 [PubMed - indexed for MEDLINE] 218. Front Biosci (Schol Ed). 2012 Jun 1;4:1275-94. Cell sources for cartilage repair; contribution of the mesenchymal perivascular niche. Diaz-Flores L Jr(1), Gutierrez R, Madrid JF, Acosta E, Avila J, Diaz-Flores L, Martin-Vasallo P. Author information: (1)Department of Pathology, Histology and Radiology, School of Medicine, La Laguna University, Canary Islands, Spain. Tissue and cell sources for cartilage repair are revised, including: 1) cartilage and subchondral bone (auto and allografts; single or multiple/mosaicplasty grafts), 2) cultured chondrocytes (autologous/ACI, characterized/CCI, matrix assisted/MAC, or allogenic), 3) adult mesenchymal stem cells (MSCs), 4) progenitor cells from perichondrium and periosteum, 5) embryonic and prenatal stem cells, 6) induced pluripotent stem cells, and 7) genetically modified cells. We consider the biological mechanisms that explain usage and possible complications, advantages and limitations, emerging technologies and possible modulations on extracellular matrix properties and on migration, proliferation, de-differentiation, re-differentiation, morphology, function and integration of the cells. The study of MSC role involve: a) identification, b) location (perivascular niche hypothesis, pericytes as progenitor cells), c) lineage (myoadipofibrogenic system: transit amplifying cells, fibroblast/myofibroblasts, chondrocytes, osteoblasts, odontoblasts, vascular smooth muscle cells and adipocytes), and d) use in cartilage repair, comprising: 1) MSCs recruited from neighbouring tissues (bone marrow stimulation, MSCs based "in situ" cartilage repair, microfracture) and 2) MSCs cultured and expanded from bone marrow, adipose tissue, synovial membrane or granulation tissue. PMID: 22652871 [PubMed - indexed for MEDLINE] 219. Front Biosci (Landmark Ed). 2012 Jun 1;17:2550-8. Association between obesity and gallbladder cancer. Wang F(1), Wang B, Qiao L. Author information: (1)Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China. wangby@medmail.com.cn Obesity has become a global health issue because of its increased morbidity and mortality, and a close association with at least 20 different cancers. Clinical and epidemiological studies have suggested that obesity and overweight are positively related with the risk of GBC. Gallbladder cancer (GBC) is a relatively infrequent but highly lethal neoplasm. Obesity may disturb lipid and endogenous hormones metabolism, affect gallbladder motility, increase the risk of gallstones, and thus plays a role in GBC. Control of obesity through measures such as lifestyle modification, healthy diet, and regular exercise may prove useful in the prevention of GBC. PMID: 22652797 [PubMed - indexed for MEDLINE] 220. Front Biosci (Landmark Ed). 2012 Jun 1;17:2356-70. Obesity-related hepatocellular carcinoma: roles of risk factors altered in obesity. Shen C(1), Zhao CY, Zhang R, Qiao L. Author information: (1)Department of Infectious Disease, the Third Hospital of Hebei Medical University, Shijiazhuang, China. Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulin-like growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesity-related HCC. PMID: 22652784 [PubMed - indexed for MEDLINE] 221. Front Biosci (Landmark Ed). 2012 Jun 1;17:2237-46. Regulatory roles for L-arginine in reducing white adipose tissue. Tan B(1), Li X, Yin Y, Wu Z, Liu C, Tekwe CD, Wu G. Author information: (1)Research Center of Healthy Breeding of Livestock and Poultry and Key Laboratory for Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, the Chinese Academy of Sciences, Changsha, Hunan, China. As the nitrogenous precursor of nitric oxide, L-arginine regulates multiple metabolic pathways involved in the metabolism of fatty acids, glucose, amino acids, and proteins through cell signaling and gene expression. Specifically, arginine stimulates lipolysis and the expression of key genes responsible for activation of fatty acid oxidation to CO2 and water. The underlying mechanisms involve increases in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), mitochondrial biogenesis, and the growth of brown adipose tissue growth. Furthermore, arginine regulates adipocyte-muscle crosstalk and energy partitioning via the secretion of cytokines and hormones. In addition, arginine enhances AMP-activated protein kinase (AMPK) expression and activity, thereby modulating lipid metabolism and energy balance toward the loss of triacylglycerols. Growing evidence shows that dietary supplementation with arginine effectively reduces white adipose tissue in Zucker diabetic fatty rats, diet-induced obese rats, growing-finishing pigs, and obese patients with type II diabetes. Thus, arginine can be used to prevent and treat adiposity and the associated metabolic syndrome. PMCID: PMC3422877 PMID: 22652774 [PubMed - indexed for MEDLINE] 222. Metabolism. 2013 Jan;62(1):21-33. doi: 10.1016/j.metabol.2012.05.002. Epub 2012 May 30. 11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders? Anagnostis P(1), Katsiki N, Adamidou F, Athyros VG, Karagiannis A, Kita M, Mikhailidis DP. Author information: (1)Department of Endocrinology, Hippokration Hospital, 49 Konstantinoupoleos Str, Thessaloniki, 54 642, Greece. anagnwstis.pan@yahoo.gr OBJECTIVE: Metabolic syndrome (MetS) and Cushing's syndrome share common features. It has been proposed that increased glucocorticoid activity at peripheral tissues may play a role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue. Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the opposite direction inactivating cortisol to cortisone in the kidney. This review considers the significance of the 11β-HSD1 inhibition in the treatment of several features of MetS and provides current data about the development of 11β-HSD1 inhibitors, as new agents for this purpose. MATERIALS/METHODS: Using PubMed, we searched for publications during the last 20years regarding the development of 11β-HSD1 inhibitors. RESULTS: Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed, natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile. In view of this concept, novel compounds, such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under investigation and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels. CONCLUSIONS: Many compounds inhibiting 11β-ΗSD1 are under development and preliminary data about their impact on glucose metabolism and obesity-related disorders are encouraging. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 22652056 [PubMed - indexed for MEDLINE] 223. Acta Naturae. 2011 Oct;3(4):30-7. Mesenchymal stem cells in tissue growth and repair. Kalinina NI(1), Sysoeva VY, Rubina KA, Parfenova YV, Tkachuk VA. Author information: (1)Department of Fundamental Medicine, Lomonosov Moscow State University. It has been established in the recent several decades that stem cells play a crucial role in tissue renewal and regeneration. Mesenchymal stem cells (MSCs) are part of the most important population of adult stem cells. These cells have hereby been identified for the very first time and subsequently isolated from bone marrow stroma. Bone marrow-derived MSCs have been believed to play the role of a source of cells for the renewal and repair of connective tissues, including bone, cartilage and adipose tissues. Cells similar to bone marrow-derived MSCs have now been identified in all postnatal tissues. Data on the distribution and function of MSCsin vivocollected using novel approaches pertaining to the identification of MSCsin situ, to their isolation from tissues, and finally to the determination of their biological properties have enabled successful revision of the role of MSCs in various organs and tissues. This review summarizes our own, as well as others', data concerning the role of MSCs in the regulation processes of tissue repair and regeneration. In our opinion, MSCs provide the connection between the blood-vascular, immune, endocrine, and nervous systems and tissue-specific stem cells in the body. PMCID: PMC3347612 PMID: 22649702 [PubMed] 224. Can J Physiol Pharmacol. 2012 Aug;90(8):1029-59. doi: 10.1139/y2012-053. Epub 2012 May 30. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Northcott JM(1), Yeganeh A, Taylor CG, Zahradka P, Wigle JT. Author information: (1)Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada. This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells. PMID: 22646022 [PubMed - indexed for MEDLINE] 225. Int Arch Allergy Immunol. 2012;158 Suppl 1:87-91. doi: 10.1159/000337799. Epub 2012 May 15. Obesity and eosinophilic inflammation: does leptin play a role. Takeda M(1), Ueki S, Kato H, Konno Y, Chihara M, Itoga M, Kobayashi Y, Moritoki Y, Ito W, Kayaba H, Chihara J. Author information: (1)Department of Infection, Allergy, Clinical Immunology and Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan. It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases. Copyright © 2012 S. Karger AG, Basel. PMID: 22627373 [PubMed - indexed for MEDLINE] 226. Curr Osteoporos Rep. 2012 Sep;10(3):208-16. doi: 10.1007/s11914-012-0106-3. Body composition and skeletal health: too heavy? Too thin? Faje A(1), Klibanski A. Author information: (1)BUL 457, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. afaje@partners.org The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity. PMCID: PMC3583521 PMID: 22644889 [PubMed - indexed for MEDLINE] 227. Cancer Lett. 2012 Nov 28;324(2):142-51. doi: 10.1016/j.canlet.2012.05.019. Epub 2012 May 27. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Wang YY(1), Lehuédé C, Laurent V, Dirat B, Dauvillier S, Bochet L, Le Gonidec S, Escourrou G, Valet P, Muller C. Author information: (1)Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France. Among the many different cell types surrounding breast cancer cells, the most abundant are those that compose mammary adipose tissue, mainly mature adipocytes and progenitors. New accumulating recent evidences bring the tumor-surrounding adipose tissue into the light as a key component of breast cancer progression. The purpose of this review is to emphasize the role that adipose tissue might play by locally affecting breast cancer cell behavior and subsequent clinical consequences arising from this dialog. Two particular clinical aspects are addressed: obesity that was identified as an independent negative prognostic factor in breast cancer and the oncological safety of autologous fat transfer used in reconstructive surgery for breast cancer patients. This is preceded by the overall description of adipose tissue composition and function with special emphasis on the specificity of adipose depots and the species differences, key experimental aspects that need to be taken in account when cancer is considered. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22643115 [PubMed - indexed for MEDLINE] 228. Int J Obes (Lond). 2013 May;37(5):640-50. doi: 10.1038/ijo.2012.80. Epub 2012 May 29. Adaptation of human adipose tissue to hypocaloric diet. Rossmeislová L(1), Mališová L, Kračmerová J, Štich V. Author information: (1)Department of Sport Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. Hypocaloric diet is a key component of the weight-reducing treatment of obesity and obesity-related disorders. Hypocaloric diets and the associated weight reduction promote improvement of metabolic profile of obese individuals. Among the mechanisms that underlie this beneficial metabolic outcome, the diet-induced modifications of morphological and functional characteristics of human adipose tissue (AT) are believed to have an important role. Prospective studies of hypocaloric weight-reducing dietary intervention demonstrate effects on adipocyte metabolism, namely lipolysis and lipogenesis, and associated changes of the adipocyte size. The endocrine function of AT, which involves cytokine and adipokine production by adipocytes, as well as by cells of stromavascular fraction, is also regulated by dietary intervention. Related inflammatory status of AT is modulated also as a consequence of the changes in recruitment of immune cells, mainly macrophages, in AT. Here, we give an overview of metabolic and endocrine modifications in human AT induced by a variety of hypocaloric diets. PMID: 22641066 [PubMed - indexed for MEDLINE] 229. Nat Rev Endocrinol. 2012 Oct;8(10):579-87. doi: 10.1038/nrendo.2012.75. Epub 2012 May 29. The role of Klotho in energy metabolism. Razzaque MS(1). Author information: (1)Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Research and Education Building, Room 304, 190 Longwood Avenue, Boston, MA 02115, USA. mrazzaque@hms.harvard.edu A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism. PMCID: PMC3704949 PMID: 22641000 [PubMed - indexed for MEDLINE] 230. Curr Pharm Des. 2012;18(31):4749-54. The growth hormone secretagogue receptor (Ghs-R). Laviano A(1), Molfino A, Rianda S, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University, viale dell'Università 37, 00185 Rome, Italy. alessandro.laviano@uniroma1.it The growth hormone secretagogue receptor (GHS-R) is a component of the ghrelin signaling pathway and is involved in mediating the pleiotropic effects of ghrelin. Two isoforms have been identified, but only GHS-R1a binds with acyl ghrelin and transduces its message. However, the inactive variant of GHS-R, GHS-R1b, appears to play a critical role in modulating the activity of GHS-R1a by forming heterodimeric complexes which attenuates trafficking of the active variant to the cell surface. The molecular mechanisms of signal transduction are complex and are specific of the tissues where GHS-R1a is expressed. The potent induction of GH secretion and the stimulation of appetite are the most intensively studied functions of GHS-R1a. However, the tissue distribution of GHS-R1a extends beyond the pituitary and the hypothalamus, and reflects the different biological functions of the ghrelin/GHS-R system. GHS-R1a is also expressed in other brain areas, in the pancreas, adipose tissue, immune cells and cardiovascular system, and modulates learning and memory, glucose and lipid metabolism, inflammatory response and cardiac performance. The pleiotropic effects of the ghrelin/GHS-R system suggest their exploitation to prevent and treat a number of clinical conditions. Among many other syndromes and diseases, cancer cachexia, aging related cognitive decline, obesity and diabetes may significantly benefit from the use of GHS-R1a agonists or antagonists. PMID: 22632856 [PubMed - indexed for MEDLINE] 231. Drug Discov Today. 2013 Jun;18(11-12):567-73. doi: 10.1016/j.drudis.2012.05.008. Epub 2012 May 22. Treatment of obesity as a potential complementary approach to cancer therapy. Sirin O(1), Kolonin MG. Author information: (1)Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA. Obesity has long been recognized as a risk factor for diabetes and cardiovascular disease. Recent epidemiological data also associate obesity with cancer risk and progression. For this reason, a combination treatment of obesity along with treatment of the cancer itself may improve patient survival and well-being. As the molecular pathways linking obesity and cancer become better understood, new potential therapy targets are surfacing. In this article, we summarize the mechanisms proposed to account for the obesity-cancer association and discuss approaches to manipulation of adipose tissue as potential interventions aimed at cancer prevention or supplemental therapy. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22627005 [PubMed - indexed for MEDLINE] 232. Nutr Res Rev. 2012 Jun;25(1):150-61. doi: 10.1017/S0954422412000054. Epub 2012 May 25. Excess body fat in obese and normal-weight subjects. Thomas EL(1), Frost G, Taylor-Robinson SD, Bell JD. Author information: (1)Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. louise.thomas@csc.mrc.ac.uk Excess body adiposity, especially abdominal obesity and ectopic fat accumulation, are key risk factors in the development of a number of chronic diseases. The advent of in vivo imaging methodologies that allow direct assessment of total body fat and its distribution have been pivotal in this process. They have helped to identify a number of sub-phenotypes in the general population whose metabolic risk factors are not commensurate with their BMI. At least two such sub-phenotypes have been identified: subjects with normal BMI, but excess intra-abdominal (visceral) fat (with or without increased ectopic fat) and subjects with elevated BMI (> 25 kg/m(2)) but low visceral and ectopic fat. The former sub-phenotype is associated with adverse metabolic profiles, while the latter is associated with a metabolically normal phenotype, despite a high BMI. Here, examples of these phenotypes are presented and the value of carrying out enhanced phenotypical characterisation of subjects in interventional studies discussed. PMID: 22625426 [PubMed - indexed for MEDLINE] 233. Radiology. 2012 Jun;263(3):836-42. doi: 10.1148/radiol.12100683. Brown fat at PET/CT: correlation with patient characteristics. Cronin CG(1), Prakash P, Daniels GH, Boland GW, Kalra MK, Halpern EF, Palmer EL, Blake MA. Author information: (1)Department of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, 55 Fruit St, White 270, Boston, MA 02114, USA. cgcronin@partners.org PURPOSES: To assess the prevalence of brown fat in patients with cancer, compare demographic characteristics of those with and those without brown fat, and correlate these characteristics with the mean and maximum standardized uptake values of brown fat. MATERIALS AND METHODS: This case-control study was institutional review board approved and HIPAA compliant. Informed consent was waived. Reports of 12 195 consecutive positron emission tomography/computed tomography examinations performed in 6867 patients between January 2004 and November 2008 were reviewed for documented fluorodeoxyglucose (FDG) uptake in brown fat (n = 298). Control patients (n = 298) without brown fat were chosen and matched for age, sex, and month and year of examination. Age, sex, weight, body mass index, ethnicity, and examination stage (initial vs restaging) were compared between groups. Paired Student t test, χ(2) test, Pearson correlation coefficient, and analysis of variance were used for statistical analysis. RESULTS: Uptake of FDG in brown fat was demonstrated in 298 of 6867 (4.33%) patients. Prevalence of brown fat was significantly higher in female (5.9% [211 of 3587]) than in male patients (2.65% [87 of 3280]; P < .001). Those with brown fat had significantly lower body weight (147.5 lb ± 3.8 vs 168.61 lb ± 5.0; P < .001) and body mass index (24.3 ± 0.54 vs 27.6 ± 0.77; P < .001) than control patients. There was no significant difference in the prevalence of brown fat among ethnic groups. The maximum standardized uptake value of brown fat had a significant inverse correlation with age (r = -0.3, P < .001). CONCLUSION: Patients with brown fat were more likely to be female and thinner than those without brown fat. Younger patients were more likely to have higher maximum standardized uptake values of brown fat. PMID: 22623697 [PubMed - indexed for MEDLINE] 234. Br J Nutr. 2012 Jun;107 Suppl 2:S64-76. doi: 10.1017/S000711451200147X. Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Serra-Majem L(1), Nissensohn M, Øverby NC, Fekete K. Author information: (1)Department of Clinical Sciences, University of Las Palmas de Gran Canaria, PO Box 550 35080, Las Palmas de Gran Canaria, Spain. lserra@dcc.ulpgc.es The aims of the present study were to review the validity of dietary methods used to measure the usual long chain (LC) omega-3 polyunsaturated fatty acid (n-3 PUFA) intake of a population and to assess the usefulness of different biomarkers of n-3 PUFA in healthy humans. Two systematic literature searches were conducted until May 2011 to update previous systematic reviews. The first literature search aimed to find studies validating the methodology used for measuring the dietary intake of n-3 PUFA. The second search aimed to find human intervention studies in which n-3 PUFA status changed after 2 weeks of n-3 PUFA supplementation. Sixteen studies were identified for inclusion in the first review. Correlation coefficients between fatty acids in subcutaneous fat or blood lipids and dietary intake of n-3 PUFA from different questionnaires were similar. Subcutaneous fat has been reported as the best reference method for some authors, and these studies showed moderate correlation coefficients with no dietary intake method being superior to any other. As for the evaluation of biomarkers of docosahexaenoic acid (DHA, 22 : 6 n-3) and eicosapentaenoic acid (EPA, 20 : 5n-3) status in response to supplementation, the new search reaffirmed and reinforced the evidence supporting that plasma phospholipid DHA, erythrocyte DHA, and platelet DHA were all effective and robust biomarkers of DHA status. Our findings only confirmed earlier studies and did not provide evidence for reaching new conclusions. PMID: 22591904 [PubMed - indexed for MEDLINE] 235. Br J Nutr. 2012 Jun;107 Suppl 2:S53-63. doi: 10.1017/S0007114512001468. Novel methodologies for assessing omega-3 fatty acid status - a systematic review. Klingler M(1), Koletzko B. Author information: (1)University of Munich Medical Center, Dr. von Hauner Children's Hospital, Div. Metabolic and Nutritional Medicine, München, Germany. Over the last few decades n-3 long chain polyunsaturated fatty acid status became of special interest for scientists. Biochemical measures on the n-3 fatty acid status vary depending on body compartment assessed and measures chosen. Plasma phospholipids and red blood cell membrane phospholipids are mainly used as n-3 fatty acid status marker. The conventional analysis of phospholipid fatty acids involves lipid extraction and consecutive chromatographic separation of phospholipids from other lipid fractions, which is time-consuming and costly. In recent years, different investigators have tried to overcome these limitations by using other biological markers or by modifying the analytical procedures used to assess n-3 fatty acid status. The aim of this systematic review was to provide an overview on these novel analytical methods developed for the fatty acid quantification by gas chromatography, highlights the methodological limitations, and discusses advantages or disadvantages of the biological markers used. Seventeen papers were identified that fulfilled the inclusion criteria. New opportunities arise from sensitive and precise high-throughput methodologies for assessment of plasma total lipid and plasma glycerophospholipid fatty acids, as well as cheek cell fatty acid composition. PMID: 22591903 [PubMed - indexed for MEDLINE] 236. Mar Drugs. 2012 Mar;10(3):604-16. doi: 10.3390/md10030604. Epub 2012 Mar 7. Fucoxantin: a treasure from the sea. D'Orazio N(1), Gemello E, Gammone MA, de Girolamo M, Ficoneri C, Riccioni G. Author information: (1)Human and Clinical Nutrition Unit, Department of Biomedical Science, Via Dei Vestini, University G. D'Annunzio, Chieti, 66013, Italy. ndorazio@unich.it The World Health Organization (WHO) estimates that 2.3 billion people will be overweight and 700 million obese in 2015. The reasons for this disastrous trend are attributed to the global tendency toward the reduced magnitude of exercise and physical activity and the increased dietary intake of fats, sugars and calories with reduced amount of vitamins and minerals. To prevent life-style-related diseases, like Metabolic Syndrome (MS), researchers' attention is increasingly focusing on some of the so called "functional foods" which may be useful for their prevention and treatment. One of these functional ingredients is fucoxanthin (FX), a characteristic carotenoid present in edible brown seaweeds, such as Undaria pinnatifida (Wakame), Hijikia fusiformis (Hijiki), Laminaria japonica (Ma-Kombu) and Sargassum fulvellum. The increasing popularity of this molecule is certainly due to its anti-obesity effect, primarily detected by murine studies. These works revealed FX mediated induction of uncoupling protein-1 (UCP-1) in abdominal white adipose tissue (WAT) mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Beyond this important role, in recent studies FX has shown a great antioxidant activity, anti-cancer, anti-diabetic and anti-photoaging properties. The aim of this review is to highlight the main effects of FX on human health. PMCID: PMC3347018 PMID: 22611357 [PubMed - indexed for MEDLINE] 237. Mol Nutr Food Res. 2012 Jul;56(7):1160-72. doi: 10.1002/mnfr.201100685. Epub 2012 May 18. Gene expression of peripheral blood mononuclear cells as a tool in dietary intervention studies: What do we know so far? de Mello VD(1), Kolehmanien M, Schwab U, Pulkkinen L, Uusitupa M. Author information: (1)Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. Vanessa.Laaksonen@uef.fi Peripheral blood mononuclear cells (PBMCs) generally refer to monocytes and lymphocytes, representing cells of the innate and adaptive immune systems. PBMCs are a promising target tissue in the field of nutrigenomics because they seem to reflect the effects of dietary modifications at the level of gene expression. In this review, we describe and discuss the scientific literature concerning the use of gene expression at the mRNA level measured from PBMCs in dietary interventions studies conducted in humans. A search of literature was undertaken using PubMed (last assessed November 24, 2011) and 20 articles were selected for discussion. Currently, results from these studies showed that PBMCs seem to reflect liver environment and complement adipose tissue findings in transcriptomics. PBMC gene expression after dietary intervention studies can be used for studying the response of certain genes related to fatty acid and cholesterol metabolism, and to explore the response of dietary interventions in relation to inflammation. However, PBMC transcriptomics from dietary intervention studies have not resulted yet in clear confirmation of candidate genes related to disease risk. Use of microarray technology in larger well-designed dietary intervention studies is still needed for exploring PBMC potential in the field of nutrigenomics. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22610960 [PubMed - indexed for MEDLINE] 238. Rev Environ Contam Toxicol. 2012;219:1-114. doi: 10.1007/978-1-4614-3281-4_1. Parameters for pyrethroid insecticide QSAR and PBPK/PD models for human risk assessment. Knaak JB(1), Dary CC, Zhang X, Gerlach RW, Tornero-Velez R, Chang DT, Goldsmith R, Blancato JN. Author information: (1)Department of Pharmacology and Toxicology, SUNY at Buffalo, Buffalo, NY 14214, USA. jbknaak@aol.com In this review we have examined the status of parameters required by pyrethroid QSAR-PBPK/PD models for assessing health risks. In lieu of the chemical,biological, biochemical, and toxicological information developed on the pyrethroids since 1968, the finding of suitable parameters for QSAR and PBPK/PD model development was a monumental task. The most useful information obtained came from rat toxicokinetic studies (i.e., absorption, distribution, and excretion), metabolism studies with 14C-cyclopropane- and alcohol-labeled pyrethroids, the use of known chiral isomers in the metabolism studies and their relation to commercial products. In this review we identify the individual chiralisomers that have been used in published studies and the chiral HPLC columns available for separating them. Chiral HPLC columns are necessary for isomer identification and for developing kinetic values (Vm,, and Kin) for pyrethroid hydroxylation. Early investigators synthesized analytical standards for key pyrethroid metabolites, and these were used to confirm the identity of urinary etabolites, by using TLC. These analytical standards no longer exist, and muste resynthesized if further studies on the kinetics of the metabolism of pyrethroids are to be undertaken.In an attempt to circumvent the availability of analytical standards, several CYP450 studies were carried out using the substrate depletion method. This approach does not provide information on the products formed downstream, and may be of limited use in developing human environmental exposure PBPK/PD models that require extensive urinary metabolite data. Hydrolytic standards (i.e., alcohols and acids) were available to investigators who studied the carboxylesterase-catalyzed hydrolysis of several pyrethroid insecticides. The data generated in these studies are suitable for use in developing human exposure PBPK/PD models.Tissue:blood partition coefficients were developed for the parent pyrethroids and their metabolites, by using a published mechanistic model introduced by Poulin and Thiele (2002a; b) and log DpH 7.4 values. The estimated coefficients, especially those of adipose tissue, were too high and had to be corrected by using a procedure in which the proportion of parent or metabolite residues that are unbound to plasma albumin is considered, as described in the GastroPlus model (Simulations Plus, Inc.,Lancaster, CA). The literature suggested that Km values be adjusted by multiplying Km by the substrate (decimal amount) that is unbound to microsomal or CYPprotein. Mirfazaelian et al. (2006) used flow- and diffusion-limited compartments in their deltamethrin model. The addition of permeability areas (PA) having diffusion limits, such as the fat and slowly perfused compartments, enabled the investigators to bring model predictions in line with in vivo data.There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmental transit models (ACAT) need to be included in PBPK models. This is especially true of the absorption of an oral dose of tefluthrin in male rats, in which 3.0-6.9%,41.3-46.3%, and 5.2-15.5% of the dose is eliminated in urine, feces, and bile,respectively (0-48 h after administration). Several percutaneous studies with the pyrethroids strongly support the belief that these insecticides are not readily absorbed, but remain on the surface of the skin until they are washed off. In one articular study (Sidon et al. 1988) the high levels of permethrin absorption through the forehead skin (24-28%) of the monkey was reported over a 7- to 14-days period.Wester et al. (1994) reported an absorption of 1.9% of pyrethrin that had been applied to the forearm of human volunteers over a 7-days period.SAR models capable of predicting the binding of the pyrethroids to plasma and hepatic proteins were developed by Yamazaki and Kanaoka (2004), Saiakhov et al. (2000), Colmenarejo et al. (2001), and Colmenarejo (2003). QikProp(Schrodinger, LLC) was used to obtain Fu values for calculating partition coefficients and for calculating permeation constants (Caco-2, MDCK, and logBBB). ADMET Predictor (Simulations Plus Inc.) provided Vm~,x and Km values for the hydroxylation of drugs/pyrethroids by human liver recombinant cytochrome P450 enzymes making the values available for possible use in PBPK/PD models.The Caco-2 permeability constants and CYP3A4 Vmax and Km values are needed in PBPK/PD models with GI ACAT sub models. Modeling work by Chang et al.(2009) produced rate constants (kcat) for the hydrolysis of pyrethroids by rat serumcarboxylesterases. The skin permeation model of Potts and Guy (1992) was used topredict K, values for the dermal absorption of the 15 pyrethroids.The electrophysiological studies by Narahashi (1971) and others (Breckenridgeet al. 2009; Shafer et al. 2005; Soderlund et al. 2002; Wolansky and Harrill 2008)demonstrated that the mode of action of pyrethroids on nerves is to interfere with the changes in sodium and potassium ion currents. The pyrethroids, being highly lipid soluble, are bound or distributed in lipid bilayers of the nerve cell membrane and exert their action on sodium channel proteins. The rising phase of the action potential is caused by sodium influx (sodium activation), while the falling phase is caused by sodium activation being turned off, and an increase in potassium efflux(potassium activation). The action of allethrin and other pyrethroids is caused by an inhibition or block of the normal currents. An equation by Tatebayashi and Narahashi (1994) that describes the action of pyrethroids on sodium channels was found in the literature. This equation, or some variation of it, may be suitable for use in the PD portion of pyrethroid PBPK models. PMID: 22610175 [PubMed - indexed for MEDLINE] 239. Vascul Pharmacol. 2012 Sep-Oct;57(2-4):91-7. doi: 10.1016/j.vph.2012.05.003. Epub 2012 May 15. From excess adiposity to insulin resistance: the role of free fatty acids. Capurso C(1), Capurso A. Author information: (1)University of Foggia, Department of Internal Medicine and Geriatrics, Foggia, Italy. a.capurso@alice.it With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22609131 [PubMed - indexed for MEDLINE] 240. Int J Stroke. 2012 Aug;7(6):491-8. doi: 10.1111/j.1747-4949.2012.00824.x. Epub 2012 May 18. Changes in fat mass in stroke survivors: a systematic review. English C(1), Thoirs K, Coates A, Ryan A, Bernhardt J. Author information: (1)International Centre for Allied Health Evidence, School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia. coralie.english@unisa.edu.au BACKGROUND: Stroke survivors have less muscle mass in their paretic limbs compared with nonparetic limbs, which may or may not be accompanied by changes in regional and/or whole body fat mass. AIM: To examine the current evidence regarding differences in regional fat mass between paretic and nonparetic limbs and changes in whole body fat mass over time in stroke survivors. METHODS: A systematic search of relevant databases. Studies measuring whole body or regional fat mass using dual-energy X-ray absorpiometry, computed tomography, or magnetic resonance imaging were included. RESULTS: Eleven trials were identified. Fat mass differences between paretic and nonparetic limbs and change in fat mass over time were not consistent. Meta-analyses were conducted using dual-energy X-ray absorpiometry-derived data from 10 trials (n = 324). There were no differences in fat mass between paretic and nonparetic legs (pooled mean difference 31·4 g, 95% confidence interval -33·9 to 96·6, P = 0·35), and slightly greater fat mass in the paretic arms compared with nonparetic arms (pooled mean difference 84·0 g, 95% confidence interval 30·7 to 137·3, P = 0·002). Whole body fat mass did not increase significantly between one-month and six-months poststroke (pooled mean difference 282·3 g, 95% confidence interval -824·4 to 1389, P = 0·62), but there was an increase between six- and 12 months poststroke (pooled mean difference 1935 g, 95% confidence interval 1031 to 2839, P < 0·001). CONCLUSIONS: There were inconsistent findings regarding changes in fat mass after stroke. Large, well-designed studies are required to further investigate the impact of body composition changes on the health of stroke survivors. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization. PMCID: PMC3399979 PMID: 22594664 [PubMed - indexed for MEDLINE] 241. ScientificWorldJournal. 2012;2012:793039. doi: 10.1100/2012/793039. Epub 2012 Apr 19. Review analysis of the association between the prevalence of activated brown adipose tissue and outdoor temperature. Huang YC(1), Hsu CC, Wang PW, Chang YH, Chen TB, Lee BF, Chiu NT. Author information: (1)Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Brown adipose tissue (BAT) is important for regulating body weight. Environmental temperature influences BAT activation. Activated BAT is identifiable using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). (18)F-FDG PET/CT scans done between June 2005 and May 2009 in our institution in tropical southern Taiwan and BAT studies from PubMed (2002-2011) were reviewed, and the average outdoor temperatures during the study periods were obtained. A simple linear regression was used to analyze the association between the prevalence of activated BAT (P) and the average outdoor temperature (T). The review analysis for 9 BAT studies (n = 16, 765) showed a significant negative correlation (r = -0.741, P = 0.022) between the prevalence of activated BAT and the average outdoor temperature. The equation of the regression line is P(%) = 6.99 - 0.20 × T (°C). The prevalence of activated BAT decreased by 1% for each 5°C increase in average outdoor temperature. In a neutral ambient temperature, the prevalence of activated BAT is low and especially rare in the tropics. There is a significant linear negative correlation between the prevalence of activated BAT and the average outdoor temperature. PMCID: PMC3349155 PMID: 22593707 [PubMed - indexed for MEDLINE] 242. Pol Merkur Lekarski. 2012 Feb;32(188):143-6. [Resveratrol--phytophenol with wide activity]. [Article in Polish] Fraczek M(1), Szumiło J, Podlodowska J, Burdan F. Author information: (1)Department of Ophthalmology, Medical University of Lublin, Poland. Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytophenol. It is found in many plants, but the highest concentration was detected in different grape-derived products, especially in red wine. The substance is also an active ingredient of some over-the-counter diet supplements. High resveratrol popularity is a consequence of wide biological properties. Numbers of epidemiological and experimental studies have proved a complex chemiopreventive activity of resveratrol against various cardio-vascular disorders and cancer. Furthermore, the compound possesses anti-inflammatory activity and positively regulates glucose level and metabolism of adipose tissue. Diet rich in resveratrol promotes longevity and attenuates neurodegenerative diseases. PMID: 22590921 [PubMed - indexed for MEDLINE] 243. J Infect Dis. 2012 Jun;205 Suppl 3:S383-90. doi: 10.1093/infdis/jis205. Body composition and metabolic changes in HIV-infected patients. Stanley TL(1), Grinspoon SK. Author information: (1)Program in Nutritional Metabolism, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA. As antiretroviral therapy has decreased human immunodeficiency virus (HIV)-associated mortality, cardiometabolic abnormalities have become increasingly apparent in HIV-infected individuals. Many patients treated for HIV infection exhibit body composition changes, including peripheral fat atrophy and visceral lipohypertrophy. In addition, HIV-infected individuals demonstrate a higher prevalence of dyslipidemia, insulin resistance and diabetes, and cardiovascular risk, compared with the general population. Although antiretroviral therapy appears to contribute to some of the cardiometabolic abnormalities in HIV infection, HIV itself, immunologic factors, and lifestyle factors are also important mediators of cardiovascular risk. Treatment strategies for body composition changes and cardiometabolic abnormalities in HIV infection include lifestyle modification, lipid-lowering agents, insulin sensitizers, and treatments to reverse endocrine abnormalities in HIV, including growth hormone-releasing hormone. None of these strategies has comprehensively addressed the abnormalities experienced by this population, however, and further research is needed into combined strategies to improve body composition and ameliorate cardiovascular risk. PMCID: PMC3349298 PMID: 22577212 [PubMed - indexed for MEDLINE] 244. Am J Manag Care. 2012 Jan;18(1 Suppl):S4-10. Examining the mechanisms of glucose regulation. Triplitt CL(1). Author information: (1)Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, TX, USA. Curtis.Triplitt@uhs-sa.com The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic α-cells (glucagon), and associated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resistance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis. PMID: 22559855 [PubMed - indexed for MEDLINE] 245. Nutr Res Rev. 2012 Jun;25(1):130-41. doi: 10.1017/S0954422412000029. Epub 2012 May 16. Calcium and vitamin D in obesity. Song Q(1), Sergeev IN. Author information: (1)Department of Health and Nutritional Sciences, South Dakota State University, Brookings, SD 57007, USA. New and more effective nutritional measures are urgently needed for the prevention of obesity. The role of Ca and vitamin D in obesity has been recently implicated. Low Ca intake and low vitamin D status have been linked with an increased risk of obesity in epidemiological studies; however, clinical intervention trials designed to test this association have produced controversial results. The suggested anti-obesity mechanisms of Ca and vitamin D include the regulation of adipocyte death (apoptosis), adipogenesis and lipid metabolism. Dietary Ca has been also shown to increase faecal fat excretion. The potential role of Ca and vitamin D in shifting energy balance towards a more negative state is an area of considerable interest. Ultimately, a review of recent research findings does not allow the reaching of a definitive conclusion that increasing Ca intake and rising vitamin D status will influence fat mass and body weight or decrease the risk of obesity and overweight. PMID: 22588363 [PubMed - indexed for MEDLINE] 246. Curr Diabetes Rev. 2012 Sep;8(5):362-81. Glucagon and cyclic AMP: time to turn the page? Rodgers RL(1). Author information: (1)Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. rrodgers@uri.edu It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca(2+) (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes. PMID: 22587514 [PubMed - indexed for MEDLINE] 247. Eur J Nutr. 2012 Aug;51(5):513-28. doi: 10.1007/s00394-012-0370-0. Epub 2012 May 15. The role of adipokines in connective tissue diseases. Krysiak R(1), Handzlik-Orlik G, Okopien B. Author information: (1)Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland. OBJECTIVE: To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings. METHODS: PubMed literature search complemented by review of bibliographies listed in identified articles. RESULTS: Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adipokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented. CONCLUSIONS: Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors. PMCID: PMC3397228 PMID: 22584415 [PubMed - indexed for MEDLINE] 248. J Mol Neurosci. 2012 Nov;48(3):654-9. Epub 2012 May 13. Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis. Fargali S(1), Sadahiro M, Jiang C, Frick AL, Indall T, Cogliani V, Welagen J, Lin WJ, Salton SR. Author information: (1)Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis. PMCID: PMC3480664 PMID: 22581449 [PubMed - indexed for MEDLINE] 249. Endocrine. 2012 Dec;42(3):514-20. doi: 10.1007/s12020-012-9692-1. Epub 2012 May 12. Androgens for postmenopausal women's health? Montalcini T(1), Migliaccio V, Ferro Y, Gazzaruso C, Pujia A. Author information: (1)Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy. tmontalcini@unicz.it Obesity, metabolic syndrome, and diabetes are becoming a leading health concern in the developed Countries, due to their link to cardiovascular disease. These conditions are common in women in the post-menopausal period. Unfortunately, actual lifestyle change strategy fail to prevent cardiovascular events for several reasons, thus specific medications are needed. In addition, it was showed an increased cardiovascular diseases and breast cancer risk in postmenopausal women taking estrogens alone or with progestin, thus the optimal therapy for the prevention of chronic disease in women is still lacking. Androgens exert different actions on organs like adipose tissue, brain, bone, and on cardiovascular system. However, a debate still exists on the positive role of androgens on human health, especially in women. Furthermore, the vascular effects of androgens remain poorly understood and have been controversial for a long time. Sex hormones are important determinants of body composition. Aging is, often, accompanied by a decrease in free testosterone levels, a concomitant reduction in muscle mass and an increase in fat mass. Furthermore, numerous studies showed that total serum testosterone levels were inversely related to the atherosclerosis disease incidence in postmenopausal women. New therapeutic targets may, therefore, arise understanding how androgen could influence the fat distribution, the metabolic disease onset, the vascular reactivity and cardiovascular risk, in both sex. PMID: 22581204 [PubMed - indexed for MEDLINE] 250. Exp Diabetes Res. 2012;2012:635472. doi: 10.1155/2012/635472. Epub 2012 Apr 17. Cardiovascular benefits of GLP-1-based herapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control. Forst T(1), Weber MM, Pfützner A. Author information: (1)Institute for Clinical Research and Development, 55116 Mainz, Germany. thomasf@ikfe.de Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors. PMCID: PMC3345223 PMID: 22577369 [PubMed - indexed for MEDLINE] 251. Endocr Rev. 2012 Aug;33(4):526-46. doi: 10.1210/er.2011-1042. Epub 2012 May 10. The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases. Prudente S(1), Sesti G, Pandolfi A, Andreozzi F, Consoli A, Trischitta V. Author information: (1)Instituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, Mendel Laboratory, Italy. Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations. PMCID: PMC3410226 PMID: 22577090 [PubMed - indexed for MEDLINE] 252. Dig Dis. 2012;30(1):70-4. doi: 10.1159/000335722. Epub 2012 May 3. The role of visceral fat. Batra A(1), Siegmund B. Author information: (1)Charité-Universitätsmedizin Berlin, Medizinische Klinik I, Berlin, Germany. Until a decade ago, fat tissue had been exclusively considered as an endocrine organ. The emerging functional characterization of adipokines as well as adipocytes and preadipocytes suggested for the first time a close link between the endocrine and the immune system. This is emphasized by the changes of the expression pattern of adipokines when the fat tissue is adjacent to inflamed sites. In addition, adipokines are capable of regulating adaptive and acquired immune responses. Remarkably, adipocytes express functional pattern recognition receptors and can consequently respond to bacterial and viral antigens. This seems to be highly relevant for intestinal inflammation and here in particular transmural inflammation where bacteria or bacterial antigens translocalize into the mesenteric fat tissue. Besides phagocytosis of these antigens, adipocytes as well as preadipocytes can be activated resulting in a release of adipokines and chemokines mediating the infiltration of immune cells thus allowing for an immune response. Recent data suggest that the adipokine milieu of the fat tissue closely regulates the polarization of infiltrating immune cells. This is of increasing interest since the pattern of infiltrating cells allows for a characterization of the underlying disease. Thus, in obesity pro-inflammatory M1 macrophages dominate this site. Remarkably, in colorectal carcinoma the presence of M1 and M2 macrophages represents a prognostic marker for the disease course. In conclusion, the visceral fat tissue represents a complex organ with multifaceted function linking the endocrine and the immune system. Copyright © 2012 S. Karger AG, Basel. PMID: 22572689 [PubMed - indexed for MEDLINE] 253. Nutr Hosp. 2012 Jan-Feb;27(1):138-45. doi: 10.1590/S0212-16112012000100016. [Asthma, obesity and diet]. [Article in Spanish] Barranco P(1), Delgado J, Gallego LT, Bobolea I, Pedrosa M, García de Lorenzo A, Quirce S. Author information: (1)Servicio Alergología, Hospital La Paz, IdiPAZ, Madrid, España. pbarranco.hulp@salud.madrid.org Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous studies have linked both disorders. Most prospective studies show that obesity is a risk factor for asthma and have found a positive correlation between baseline body mass index (BMI) and the subsequent development of asthma, although these results are not conclusive when studying the association between airway hyperresponsiveness with BMI. Furthermore, several studies suggest that whereas weight gain increases the risk of asthma, weight loss improves the course of the illness. Different factors could explain this association. Obesity is capable of reducing pulmonary compliance, lung volumes and the diameter of peripheral respiratory airways as well as affecting the volume of blood in the lungs and the ventilation-perfusion relationship. Furthermore, the increase in the normal functioning of adipose tissue in obese subjects leads to a systemic proinflammatory state, which produces a rise in the serum concentrations of several cytokines, the soluble fractions of their receptors and chemokines. Many of these mediators are synthesized and secreted by cells from adipose tissue and receive the generic name of adipokines, including IL-6, IL-10, eotaxin, TNF-α, TGF- 1, PCR, leptin y adiponectin. Finally, specific regions of the human genome which are related to both asthma and obesity have been identified. Most studies point out that obesity is capable of increasing the prevalence and incidence of asthma, although this effect appears to be modest. The treatment of obese asthmatics must include a weight control program. PMID: 22566313 [PubMed - indexed for MEDLINE] 254. Nutr Hosp. 2012 Jan-Feb;27(1):103-8. doi: 10.1590/S0212-16112012000100011. Influence of the dietary intake of medium chain triglycerides on body composition, energy expenditure and satiety: a systematic review. Rego Costa AC(1), Rosado EL, Soares-Mota M. Author information: (1)Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil. Increased prevalence of obesity is associated with the growth of chronic degenerative diseases. One of the main factors associated with this increase is the change in nutritional status of individuals. Medium chain triglycerides (MCT) are rapidly metabolized and less stored in the adipose tissue, being a possible tool for weight control. In order to analyze the influence of consumption of this lipid on satiety, body composition and energy expenditure (EE), a literature review was performed of controlled clinical studies reported in PUBMED and ELSEVIER between the years 2000 and 2010. Fourteen articles were selected presenting short and long-term intervention. Among these, six showed a decrease in body mass of individuals, with consequent loss of weight. Only one showed a positive effect on satiation and four showed an increase in EE. Thus the results are inconclusive and there is a need for further controlled studies with standardized amounts of MCT, so that its use can become an alternative for obesity nutritional treatment. PMID: 22566308 [PubMed - indexed for MEDLINE] 255. Drug Discov Today. 2012 Aug;17(15-16):880-9. doi: 10.1016/j.drudis.2012.04.007. Epub 2012 Apr 25. Physiological, pathological and potential therapeutic roles of adipokines. Falcão-Pires I(1), Castro-Chaves P, Miranda-Silva D, Lourenço AP, Leite-Moreira AF. Author information: (1)Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Universidade do Porto, Porto, Portugal. Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases. In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1). Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22561894 [PubMed - indexed for MEDLINE] 256. Cell Metab. 2012 May 2;15(5):635-45. doi: 10.1016/j.cmet.2012.04.001. Inflammation and lipid signaling in the etiology of insulin resistance. Glass CK(1), Olefsky JM. Author information: (1)Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0673, USA. ckg@ucsd.edu Inflammation and lipid signaling are intertwined modulators of homeostasis and immunity. In addition to the extensively studied eicosanoids and inositol phospholipids, emerging studies indicate that many other lipid species act to positively and negatively regulate inflammatory responses. Conversely, inflammatory signaling can significantly alter lipid metabolism in the liver, adipose tissue, skeletal muscle, and macrophage in the context of infection, diabetes, and atherosclerosis. Here, we review recent findings related to this interconnected network from the perspective of immunity and metabolic disease. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC4156155 PMID: 22560216 [PubMed - indexed for MEDLINE] 257. Gynecol Endocrinol. 2012 Dec;28(12):974-8. doi: 10.3109/09513590.2012.683082. Epub 2012 May 4. Mediators of chronic inflammation in polycystic ovarian syndrome. Deligeoroglou E(1), Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C, Creatsas G. Author information: (1)2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens Medical School, Athens, Greece. Polycystic ovarian syndrome (PCOS) is an endocrine disorder affecting 5-10% of reproductive-age women. Hyperandrogenemia, which characterizes the syndrome, stimulates the maturation of adipocytes and favors central obesity. The linking hub between obesity and other metabolic manifestations of the syndrome seems to be chronic low-grade inflammation. We discuss the most reliable current data regarding the role of inflammatory mediators in PCOS, with particular focus on the genetic mechanisms implicated. C-reactive protein levels are 96% higher in PCOS patients than in healthy controls. Patients with the -308A polymorphism of the tumor necrosis factor-α gene have elevated androgens in comparison with carriers of the -308G. Interleukin 18 (IL-18) is elevated in lean patients, with a further rise in the presence of obesity and insulin resistance. Polymorphisms of the IL-1a, IL-1b and IL-6 genes have also been associated with PCOS. Plasminogen activator inhibitor-1 levels are positively associated with the syndrome, and carriers of the 4G allele of the 4G/5G polymorphism are at risk of developing PCOS. Other mediators discussed include adhesion molecules, osteoprotegerin, asymmetric dimethylarginine, homocysteine and advanced glycation end-products. The elucidation of the pathogenetic mechanisms implicated in PCOS and their connection with low-grade inflammation may in the future offer the opportunity for the formulation of novel therapeutic strategies and individualized therapy for these patients. PMID: 22553983 [PubMed - indexed for MEDLINE] 258. Ann N Y Acad Sci. 2012 Apr;1254:57-65. doi: 10.1111/j.1749-6632.2012.06519.x. A bird's-eye view of cell therapy and tissue engineering for cardiac regeneration. Soler-Botija C(1), Bagó JR, Bayes-Genis A. Author information: (1)Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Research Institute Germans Trias i Pujol (IGTP), Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Erratum in Ann N Y Acad Sci. 2012 Oct;1270:121. Complete recovery of ischemic cardiac muscle after myocardial infarction is still an unresolved concern. In recent years, intensive research efforts have focused on mimicking the physical and biological properties of myocardium for cardiac repair. Here we show how heart regeneration approaches have evolved from cell therapy to refined tissue engineering. Despite progressive improvements, the best cell type and delivery strategy are not well established. Our group has identified a new population of cardiac adipose tissue-derived progenitor cells with inherent cardiac and angiogenic potential that is a promising candidate for cell therapy to restore ischemic myocardium. We also describe results from three strategies for cell delivery into a murine model of myocardial infarction: intramyocardial injection, implantation of a fibrin patch loaded with cells, and an engineered bioimplant (a combination of chemically designed scaffold, peptide hydrogel, and cells); dual-labeling noninvasive bioluminescence imaging enables in vivo monitoring of cardiac-specific markers and cell survival. © 2012 New York Academy of Sciences. PMID: 22548570 [PubMed - indexed for MEDLINE] 259. Endocr Rev. 2012 Aug;33(4):547-94. doi: 10.1210/er.2011-1015. Epub 2012 Apr 30. The role of adiponectin in cancer: a review of current evidence. Dalamaga M(1), Diakopoulos KN, Mantzoros CS. Author information: (1)Laboratory of Clinical Biochemistry, Attikon General University Hospital, University of Athens, School of Medicine, 12462 Athens, Greece. Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies. PMCID: PMC3410224 PMID: 22547160 [PubMed - indexed for MEDLINE] 260. Orphanet J Rare Dis. 2012 Apr 30;7:23. doi: 10.1186/1750-1172-7-23. Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Hansson E(1), Svensson H, Brorson H. Author information: (1)Department of Clinical Sciences in Malmö, Lund University, Plastic and Reconstructive Surgery, Skåne University Hospital, Malmö, Sweden. emma.hansson@med.lu.se DEFINITION AND CLINICAL PICTURE: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint aches.CLASSIFICATION: We suggest that Dercum's disease is classified into: I. Generalised diffuse form A form with diffusely widespread painful adipose tissue without clear lipomas, II. Generalised nodular form - a form with general pain in adipose tissue and intense pain in and around multiple lipomas, and III. Localised nodular form - a form with pain in and around multiple lipomas IV. Juxtaarticular form - a form with solitary deposits of excess fat for example at the medial aspect of the knee. EPIDEMIOLOGY: Dercum's disease most commonly appears between the ages of 35 and 50 years and is five to thirty times more common in women than in men. The prevalence of Dercum's disease has not yet been exactly established. AETIOLOGY: Proposed, but unconfirmed aetiologies include: nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction and trauma. DIAGNOSIS AND DIAGNOSTIC METHODS: Diagnosis is based on clinical criteria and should be made by systematic physical examination and thorough exclusion of differential diagnoses. Advisably, the diagnosis should be made by a physician with a broad experience of patients with painful conditions and knowledge of family medicine, internal medicine or pain management. The diagnosis should only be made when the differential diagnoses have been excluded. DIFFERENTIAL DIAGNOSIS: Differential diagnoses include: fibromyalgia, lipoedema, panniculitis, endocrine disorders, primary psychiatric disorders, multiple symmetric lipomatosis, familial multiple lipomatosis, and adipose tissue tumours. GENETIC COUNSELLING: The majority of the cases of Dercum's disease occur sporadically. A to G mutation at position A8344 of mitochondrial DNA cannot be detected in patients with Dercum's disease. HLA (human leukocyte antigen) typing has not revealed any correlation between typical antigens and the presence of the condition. MANAGEMENT AND TREATMENT: The following treatments have lead to some pain reduction in patients with Dercum's disease: Liposuction, analgesics, lidocaine, methotrexate and infliximab, interferon α-2b, corticosteroids, calcium-channel modulators and rapid cycling hypobaric pressure. As none of the treatments have led to long lasting complete pain reduction and revolutionary results, we propose that Dercum's disease should be treated in multidisciplinary teams specialised in chronic pain. PROGNOSIS: The pain in Dercum's disease seems to be relatively constant over time. PMCID: PMC3444313 PMID: 22546240 [PubMed - indexed for MEDLINE] 261. Invest Radiol. 2012 Jun;47(6):368-75. doi: 10.1097/RLI.0b013e31824baff3. Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard. Kang BK(1), Yu ES, Lee SS, Lee Y, Kim N, Sirlin CB, Cho EY, Yeom SK, Byun JH, Park SH, Lee MG. Author information: (1)Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. OBJECTIVE: The aims of this study were to assess the confounding effects of hepatic iron deposition, inflammation, and fibrosis on hepatic steatosis (HS) evaluation by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to assess the accuracies of MRI and MRS for HS evaluation, using histology as the reference standard. MATERIALS AND METHODS: In this institutional review board-approved prospective study, 56 patients gave informed consents and underwent chemical-shift MRI and MRS of the liver on a 1.5-T magnetic resonance scanner. To estimate MRI fat fraction (FF), 4 analysis methods were used (dual-echo, triple-echo, multiecho, and multi-interference), and MRS FF was calculated with T2 correction. Degrees of HS, iron deposition, inflammation, and fibrosis were analyzed in liver resection (n = 37) and biopsy (n = 19) specimens. The confounding effects of histology on fat quantification were assessed by multiple linear regression analysis. Using the histologic degree of HS as the reference standard, the accuracies of each method in estimating HS and diagnosing an HS of 5% or greater were determined by linear regression and receiver operating characteristic analyses. RESULTS: Iron deposition significantly confounded estimations of FF by the dual-echo (P < 0.001) and triple-echo (P = 0.033) methods, whereas no histologic feature confounded the multiecho and multi-interference methods or MRS. The MRS (r = 0.95) showed the strongest correlation with histologic degree of HS, followed by the multiecho (r = 0.92), multi-interference (r = 0.91), triple-echo (r = 0.90), and dual-echo (r = 0.85) methods. For diagnosing HS, the areas under the curve tended to be higher for MRS (0.96) and the multiecho (0.95), multi-interference (0.95), and triple-echo (0.95) methods than for the dual-echo method (0.88) (P ≥ 0.13). CONCLUSION: The multiecho and multi-interference MRI methods and MRS can accurately quantify hepatic fat, with coexisting histologic abnormalities having no confounding effects. PMID: 22543969 [PubMed - indexed for MEDLINE] 262. J Alzheimers Dis. 2012;30 Suppl 2:S97-112. doi: 10.3233/JAD-2012-120487. Adiposity and cognitive decline: underlying mechanisms. Gustafson DR(1). Author information: (1)Section for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. deborah.gustafson@neuro.gu.se Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body. PMID: 22543853 [PubMed - indexed for MEDLINE] 263. Meat Sci. 2012 Nov;92(3):297-301. doi: 10.1016/j.meatsci.2012.04.008. Epub 2012 Apr 11. Cultured meat from stem cells: challenges and prospects. Post MJ(1). Author information: (1)Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. m.post@maastrichtuniversity.nl As one of the alternatives for livestock meat production, in vitro culturing of meat is currently studied. The generation of bio-artificial muscles from satellite cells has been ongoing for about 15 years, but has never been used for generation of meat, while it already is a great source of animal protein. In order to serve as a credible alternative to livestock meat, lab or factory grown meat should be efficiently produced and should mimic meat in all of its physical sensations, such as visual appearance, smell, texture and of course, taste. This is a formidable challenge even though all the technologies to create skeletal muscle and fat tissue have been developed and tested. The efficient culture of meat will primarily depend on culture conditions such as the source of medium and its composition. Protein synthesis by cultured skeletal muscle cells should further be maximized by finding the optimal combination of biochemical and physical conditions for the cells. Many of these variables are known, but their interactions are numerous and need to be mapped. This involves a systematic, if not systems, approach. Given the urgency of the problems that the meat industry is facing, this endeavor is worth undertaking. As an additional benefit, culturing meat may provide opportunities for production of novel and healthier products. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22543115 [PubMed - indexed for MEDLINE] 264. Free Radic Biol Med. 2012 May 15;52(10):2108-19. doi: 10.1016/j.freeradbiomed.2012.03.003. Epub 2012 Apr 18. Regulation of adipose tissue energy availability through blood flow control in the metabolic syndrome. Alemany M(1). Author information: (1)Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain. malemany@ub.edu Maintenance of blood flow rate is a critical factor for tissue oxygen and substrate supply. The potentially large mass of adipose tissue deeply influences the body distribution of blood flow. This is due to increased peripheral resistance in obesity and the role of this tissue as the ultimate destination of unused excess of dietary energy. However, adipose tissue cannot grow indefinitely, and the tissue must defend itself against the avalanche of nutrients provoking inordinate growth and inflammation. In the obese, large adipose tissue masses show lower blood flow, limiting the access of excess circulating substrates. Blood flow restriction is achieved by vasoconstriction, despite increased production of nitric oxide, the vasodilatation effects of which are overridden by catecholamines (and probably also by angiotensin II and endothelin). Decreased blood flow reduces the availability of oxygen, provoking massive glycolysis (hyperglycemic conditions), which results in the production of lactate, exported to the liver for processing. However, this produces local acidosis, which elicits the rapid dissociation of oxyhemoglobin, freeing bursts of oxygen in localized zones of the tissue. The excess of oxygen (and of nitric oxide) induces the production of reactive oxygen species, which deeply affect the endothelial, blood, and adipose cells, inducing oxidative and nitrosative damage and eliciting an increased immune response, which translates into inflammation. The result of the defense mechanism for adipose tissue, localized vasoconstriction, may thus help develop a more generalized pathologic response within the metabolic syndrome parameters, extending its effects to the whole body. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22542444 [PubMed - indexed for MEDLINE] 265. Eur J Immunol. 2012 May;42(5):1073-9. doi: 10.1002/eji.201142305. Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. Dooley J(1), Liston A. Author information: (1)Autoimmune Genetics Laboratory, VIB and University of Leuven, Belgium. james.dooley@vib-kuleuven.be The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22539280 [PubMed - indexed for MEDLINE] 266. J Physiol Biochem. 2013 Mar;69(1):155-63. doi: 10.1007/s13105-012-0170-2. Epub 2012 Apr 26. Impact of leucine on energy balance. McAllan L(1), Cotter PD, Roche HM, Korpela R, Nilaweera KN. Author information: (1)Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland. Body weight is determined by the balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the surplus energy is stored as fat in the adipose tissue, which causes its expansion and may even lead to the development of obesity. Thus, there is a growing interest to develop dietary interventions that could reduce the current obesity epidemic. In this regard, data from a number of in vivo and in vitro studies suggest that the branched-chain amino acid leucine influences energy balance. However, this has not been consistently reported. Here, we review the literature related to the effects of leucine on energy intake, energy expenditure and lipid metabolism as well as its effects on the cellular activity in the brain (hypothalamus) and in peripheral tissues (gastro-intestinal tract, adipose tissue, liver and muscle) regulating the above physiological processes. Moreover, we discuss how obesity may influence the actions of this amino acid. PMID: 22535285 [PubMed - indexed for MEDLINE] 267. Biochimie. 2012 Oct;94(10):2089-96. doi: 10.1016/j.biochi.2012.04.015. Epub 2012 Apr 19. Understanding leptin-dependent regulation of skeletal homeostasis. Motyl KJ(1), Rosen CJ. Author information: (1)Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, USA. motylk@mmc.org Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro-apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMCID: PMC3512082 PMID: 22534195 [PubMed - indexed for MEDLINE] 268. J Pediatr. 2012 Oct;161(4):735-41.e1. doi: 10.1016/j.jpeds.2012.03.023. Epub 2012 Apr 24. Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages. Stokes TA(1), Holston A, Olsen C, Choi Y, Curtis J, Higginson J, Enright L, Adimora C, Hunt CE. Author information: (1)Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20814-4799, USA. Theophil.Stokes@usuhs.edu OBJECTIVE: To assess anthropometric changes from birth to hospital discharge in infants born preterm and compare with a reference birth cohort of infants born full-term. STUDY DESIGN: Retrospective chart review was conducted of 501 preterm and 1423 full-term infants. We evaluated birth and hospital discharge weight, length, and waist circumference (WC). WC/length ratio (WLR), ponderal index, and body mass index (BMI) were calculated. Preterm infants were categorized into quartiles (Q1-4) based on birth weight (BW). RESULTS: At birth mean length, WC, WLR, BMI, and ponderal index were all significantly less for preterm infants in the lowest BW quartile (Q1) than preterm infants in higher BW quartiles or full-term infants. Although their weight, length, and BMI remained significantly less at discharge, preterm infants in Q1 had a disproportionate increase in WLR and ponderal index such that at discharge their WLR and ponderal index were greater than infants in Q2-3 and comparable with infants in Q4 and full-term infants. Discharge WLR and ponderal index in Q1 were significantly higher with decreasing postmenstrual age at birth. CONCLUSIONS: Preterm infants of a lower birth postmenstrual age have disproportionate increases in WLR and ponderal index that are suggestive of increased visceral and total adiposity. Published by Mosby, Inc. PMID: 22534153 [PubMed - indexed for MEDLINE] 269. Biochem J. 2012 May 15;444(1):1-10. doi: 10.1042/BJ20120030. SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. Giralt A(1), Villarroya F. Author information: (1)Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, University of Barcelona, Spain. SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration. PMID: 22533670 [PubMed - indexed for MEDLINE] 270. Int J Obes (Lond). 2013 Mar;37(3):325-32. doi: 10.1038/ijo.2012.59. Epub 2012 Apr 24. MicroRNAs in adipose tissue: their role in adipogenesis and obesity. Hilton C(1), Neville MJ, Karpe F. Author information: (1)OXLIP group, OCDEM, University of Oxford, Churchill Hospital, Oxford, UK. catriona.hilton@ocdem.ox.ac.uk MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets. PMID: 22531086 [PubMed - indexed for MEDLINE] 271. Stem Cells Dev. 2012 Sep 1;21(13):2355-63. doi: 10.1089/scd.2012.0060. Epub 2012 Jun 26. Mesenchymal stem cell-based tumor-targeted gene therapy in gastrointestinal cancer. Bao Q(1), Zhao Y, Niess H, Conrad C, Schwarz B, Jauch KW, Huss R, Nelson PJ, Bruns CJ. Author information: (1)Department of Surgery, University of Munich, Campus Großhadern, Munich, Germany. Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMCID: PMC3424981 PMID: 22530882 [PubMed - indexed for MEDLINE] 272. Molecules. 2012 Apr 23;17(4):4755-69. doi: 10.3390/molecules17044755. Dynamic action of carotenoids in cardioprotection and maintenance of cardiac health. Agarwal M(1), Parameswari RP, Vasanthi HR, Das DK. Author information: (1)Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry-605014, India. mhsh.agarwal@gmail.com Retraction in McPhee D. Molecules. 2014;19(3):3850. Oxidative stress has been considered universally and undeniably implicated in the pathogenesis of all major diseases, including those of the cardiovascular system. Oxidative stress activate transcriptional messengers, such as nuclear factor-κB, tangibly contributing to endothelial dysfunction, the initiation and progression of atherosclerosis, irreversible damage after ischemic reperfusion, and even arrhythmia, such as atrial fibrillation. Evidence is rapidly accumulating to support the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as intracellular signaling molecules. Despite this connection between oxidative stress and cardiovascular disease (CVD), there are currently no recognized therapeutic interventions to address this important unmet need. Antioxidants that provide a broad, "upstream" approach via ROS/RNS quenching or free radical chain breaking seem an appropriate therapeutic option based on epidemiologic, dietary, and in vivo animal model data. Short-term dietary intervention trials suggest that diets rich in fruit and vegetable intake lead to improvements in coronary risk factors and reduce cardiovascular mortality. Carotenoids are such abundant, plant-derived, fat-soluble pigments that functions as antioxidants. They are stored in the liver or adipose tissue, and are lipid soluble by becoming incorporated into plasma lipoprotein particles during transport. For these reasons, carotenoids may represent one plausible mechanism by which fruits and vegetables reduce the risk of chronic diseases as cardiovascular disease (CVD). This review paper outlines the role of carotenoids in maintaining cardiac health and cardioprotection mediated by several mechanisms including redox signaling. PMID: 22525440 [PubMed - indexed for MEDLINE] 273. Presse Med. 2013 Jan;42(1):13-8. doi: 10.1016/j.lpm.2012.02.041. Epub 2012 Apr 21. [Adipokines: some players of inflammation in inflammatory rheumatic diseases and systemic autoimmune diseases?]. [Article in French] Toussirot E(1). Author information: (1)CHU hôpital Saint-Jacques, pôle recherche, centre investigation clinique - biothérapie 506, 25000 Besançon, France. etoussirot@chu-besancon.fr Adipocytokines or adipokines are a group of molecules (such as leptin, adiponectin, visfatine and resistine) mainly produced by adipose tissue. The adipokines are involved in different physiological processes but their participation to inflammatory and immune responses have been recently described. Their contribution to inflammatory diseases such as chronic inflammatory joint diseases and autoimmune diseases, and osteoarthritis as well, is currently growing, suggesting new pathophysiological schema and treatments. Leptin, visfatin and resistin have pro-inflammatory properties while adiponectin is anti-inflammatory, especially for the vascular wall. Adiponectin is considered to be protective for cardiovascular risk. The influence of the treatments given in inflammatory rheumatic diseases and autoimmune diseases (traditional drugs and biologics) on adipokines requires to be studied. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22521967 [PubMed - indexed for MEDLINE] 274. Clin Res Hepatol Gastroenterol. 2012 Oct;36(5):412-9. doi: 10.1016/j.clinre.2012.03.008. Epub 2012 Apr 18. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Keitel V(1), Häussinger D. Author information: (1)Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany. verena.keitel@med.uni-duesseldorf.de Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti-inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22521118 [PubMed - indexed for MEDLINE] 275. Arterioscler Thromb Vasc Biol. 2012 May;32(5):1094-8. doi: 10.1161/ATVBAHA.111.241489. CIDE proteins and lipid metabolism. Xu L(1), Zhou L, Li P. Author information: (1)Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. Lipid homeostasis is maintained through the coordination of lipid metabolism in various tissues, including adipose tissue and the liver. The disruption of lipid homeostasis often results in the development of metabolic disorders such as obesity, diabetes mellitus, liver steatosis, and cardiovascular diseases. Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including Cidea, Cideb, and Fsp27 (Cidec), are emerging as important regulators of various lipid metabolic pathways and play pivotal roles in the development of metabolic disorders. This review summarizes the latest cell death-inducing DNA fragmentation factor 45-like effector protein discoveries related to the control of lipid metabolism, with emphasis on the role of these proteins in lipid droplet growth in adipocytes and in the regulation of very low-density lipoprotein lipidation and maturation in hepatocytes. PMID: 22517368 [PubMed - indexed for MEDLINE] 276. Curr Mol Med. 2012 Jun;12(5):574-91. Immunosuppressive properties of mesenchymal stem cells: advances and applications. De Miguel MP(1), Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F. Author information: (1)Cell Engineering Laboratory, IdiPaz, La Paz Hospital Research Institute, Madrid, Spain. mariapdemiguel@gmail.com Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory. PMID: 22515979 [PubMed - indexed for MEDLINE] 277. Nagoya J Med Sci. 2012 Feb;74(1-2):19-30. Adipocytokines and obesity-linked disorders. Ouchi N(1), Ohashi K, Shibata R, Murohara T. Author information: (1)Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, 466-8550, Japan. nouchi@med.nagoya-u.ac.jp Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit antiinflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases. PMID: 22515108 [PubMed - indexed for MEDLINE] 278. Biochim Biophys Acta. 2012 Jul;1822(7):1090-5. doi: 10.1016/j.bbadis.2012.03.014. Epub 2012 Apr 4. Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Floyd ZE(1), Stephens JM. Author information: (1)Ubiquitin Biology Laboratory, Pennington Biomedical Research Resaerch Center, Louisiana Sate University Systems, Baton Rouge, LA 70808, USA. Adipocytes are highly specialized cells that play a central role in lipid homeostasis and the maintenance of energy balance. Obesity, an excessive accumulation of adipose tissue, is a major risk factor for the development of Type 2 diabetes mellitus (T2DM), cardiovascular disease, and hypertension. A variety of studies suggest that obesity and T2DM can be linked to a breakdown in the regulatory mechanisms that control the expression and transcriptional activity of PPARγ. PPARγ is a nuclear hormone receptor that functions as a master switch in controlling adipocyte differentiation and development. Also important in controlling glucose homeostasis and insulin sensitivity, PPARγ is a ligand-dependent transcription factor that is the functional receptor for the anti-diabetic thiazolidinediones (TZDs). In the last fifteen years, a variety of covalent modifications of PPARγ activity have been identified and studied. These covalent modifications include phosphorylation, ubiquitylation, O-GlcNAcylation and SUMOylation. Covalent modifications of PPARγ represent key regulatory mechanisms that control both PPARγ protein stability and transcriptional activity. A variety of PPARγ transgenic models, including mice heterozygous for PPARγ, have demonstrated the importance of PPARγ expression in glucose homeostasis and insulin resistance. In the following review, we have highlighted the regulation of PPARγ by covalent modifications, the interplay between these interactions and how these post-translational modifications impact metabolic disease states. © 2012 Elsevier B.V. All rights reserved. PMCID: PMC3355475 PMID: 22504298 [PubMed - indexed for MEDLINE] 279. Expert Opin Biol Ther. 2012 Jun;12(6):713-29. doi: 10.1517/14712598.2012.679652. Epub 2012 Apr 14. Stem cells combined with bone graft substitutes in skeletal tissue engineering. Gamie Z(1), Tran GT, Vyzas G, Korres N, Heliotis M, Mantalaris A, Tsiridis E. Author information: (1)Newcastle University, Institute of Cellular Medicine, Musculoskeletal Research group, Newcastle upon Tyne, Tyne and Wear NE17RU, UK. INTRODUCTION: Bone grafting is used to repair large bone defects and autograft is recognised as producing the best clinical outcome, which is partly due to its cellular component. When autograft is unavailable, allograft and bone graft substitutes can be used; however, they rely on the host bed to provide cellular osteogenic activity. AREAS COVERED: Bone graft substitutes have the potential to benefit from the addition of stem cells aimed at enhancing the rate and quality of defect repair. Mesenchymal stem cells (MSCs) can be isolated from bone marrow or periosteum and culture expanded. Other sources of primary cells include muscle, adipose tissue, human umbilical cord and the pluripotent embryonic stem cells (ESCs). EXPERT OPINION: MSCs isolated from bone marrow have been the best characterised approach for osteogenic differentiation. Their use with synthetic scaffolds such as hydroxyapatite and tricalcium phosphate has produced promising clinical results. MSCs derived from adipose tissue, muscle or human umbilical cord cells combined with various scaffolds are an attractive option. Further in vivo and clinical investigation of their potential is required. Pluripotent ESCs have a theoretical advantage over MSCs; however, purification, cell-specific differentiation, effective delivery vehicles-scaffolds and teratogenesis control are still under in vitro and in vivo evaluation. PMID: 22500826 [PubMed - indexed for MEDLINE] 280. Obes Rev. 2012 Aug;13(8):733-43. doi: 10.1111/j.1467-789X.2012.00997.x. Epub 2012 Apr 12. Leptin as a link between the immune system and kidney-related diseases: leading actor or just a coadjuvant? Moraes-Vieira PM(1), Bassi EJ, Araujo RC, Câmara NO. Author information: (1)Immunology Department, Institute of Biomedical Science, University of São Paulo, SP, Brazil. Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune-related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue-derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney-related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune- and metabolic-related kidney diseases. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22498577 [PubMed - indexed for MEDLINE] 281. Acta Orthop Traumatol Turc. 2012;46(2):139-43. doi: 10.3944/AOTT.2012.2542. Large para-articular osteochondroma of the knee joint: a case report. Singh R(1), Jain M, Siwach R, Rohilla S, Sen R, Kaur K. Author information: (1)Department of Orthopaedic Surgery, Paraplegia & Rehabilitation, Pt. B.D. Sharma University of Health Sciences, Rohtak, India. Comment in Acta Orthop Traumatol Turc. 2012;46(4):320-1; author reply 321-2. A unique case of large intra-articular osteochondroma of the knee of a 15-year duration is presented along with a review of the literature. The tumor may have remained asymptomatic for such a long period because of its slow growth and stretch elongation of the quadriceps mechanism. PMID: 22491430 [PubMed - indexed for MEDLINE] 282. Biol Rev Camb Philos Soc. 2012 Nov;87(4):838-55. doi: 10.1111/j.1469-185X.2012.00227.x. Epub 2012 Apr 5. Genetic explorations of recent human metabolic adaptations: hypotheses and evidence. Brown EA(1). Author information: (1)Harvard University, Department of Human Evolutionary Biology, Peabody Museum, Cambridge, MA 02138-2019, USA. eabrown@fas.harvard.edu Since humans and chimpanzees split from a common ancestor over 6 million years ago, human metabolism has changed dramatically. This change includes adaptations to a high-quality diet, the evolution of an energetically expensive brain, dramatic increases in endurance abilities, and capacity for energy storage in white adipose tissue. Human metabolism continues to evolve in modern human populations in response to local environmental and cultural selective forces. Understanding the nature of these selective forces and the physiological responses during human evolution is a compelling challenge for evolutionary biologists. The complex genetic architecture surrounding metabolic phenotypes indicates that selection probably altered allelic frequencies across many loci in populations experiencing adaptive metabolic change to fit their environment. A recent analysis supports this hypothesis, finding that classic selective sweeps at single loci were rare during the past 250,000 years of human evolution. Detection of selective signatures at multiple loci, as well as exploration of physiological adaptation to environment in humans, will require cross-disciplinary collaboration, including the incorporation of biological pathway analysis. This review explores the Thrifty Genotype Hypothesis, high-altitude adaptation, cold-resistance adaptation, and genetic evidence surrounding these proposed metabolic adaptations in an attempt to clarify current challenges and avenues for future progress. © 2012 The Author. Biological Reviews © 2012 Cambridge Philosophical Society. PMID: 22487590 [PubMed - indexed for MEDLINE] 283. Clin Endocrinol (Oxf). 2012 Aug;77(2):159-68. doi: 10.1111/j.1365-2265.2012.04406.x. Is there sufficient evidence to consider the use of 11β-hydroxysteroid dehydrogenase type 1 inhibition in children? Fürst-Recktenwald S(1), Dörr HG, Quinkler M, Dötsch J, Stewart PM. Author information: (1)F. Hoffmann-La Roche Ltd, Basel, Switzerland. sabine.fuerst-recktenwald@roche.com Manifestations of the metabolic syndrome [obesity, dyslipidaemia, hypertension, blood glucose derangements including prediabetes or type 2 diabetes mellitus (T2DM)] in juvenile populations are becoming increasingly prevalent throughout the world and are at the point of being a global public health concern. Derangements in cortisol regeneration seem to be involved in the pathophysiology. Treatment with selective 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors could be a therapeutic strategy in paediatric patients with manifestations of the metabolic syndrome. Based on preclinical and clinical data regarding development of the 11β-HSD1 enzyme, it appears that maturation occurs within the first year of life. Different changes in biomarkers for assessing the efficacy and safety of 11β-HSD1 inhibitors are to be expected in paediatric patients compared to adults, reflecting differences in metabolism. The effect of 11β-HSD1 treatment in children on bone differentiation and development as well as adrenocorticotropic hormone (ACTH), circulating and local cortisol tissue concentrations, androgens and respective stress response is not yet known. Based on current literature, the concept of inhibition of 11β-HSD1 is considered a potentially effective mean to regulate local cortisol levels in the paediatric population, and 11β-HSD1 inhibitors may provide a valuable target and treatment option for the metabolic syndrome in paediatric patients. However, the uncertainty over effects on the developing skeleton combined with mild increases in adrenal androgen levels raises potential concerns regarding growth as well as onset of puberty as to their future use in children. Future clinical studies are needed to thoroughly assess the risks and benefits of this new class of drugs in the paediatric population. © 2012 Blackwell Publishing Ltd. PMID: 22486586 [PubMed - indexed for MEDLINE] 284. Clin Biochem. 2012 Jun;45(9):610-8. doi: 10.1016/j.clinbiochem.2012.03.024. Epub 2012 Mar 28. Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. Grattagliano I(1), de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, Portincasa P. Author information: (1)Department of Interdisciplinary Medicine, Clinica Medica A. Murri, University of Bari Medical School, Bari, Italy. i.grattagliano@semeiotica.uniba.it OBJECTIVES: Mitochondria play a major role in cell energy-generating processes and integrate several signalling pathways to control cellular life and death. DESIGN AND METHODS: Several liver diseases are characterized by mitochondrial alterations which are directly or indirectly dependent on the activation of intracellular stress cascades or receptor-mediated pathways. This article examines the role of mitochondrial dysfunction in critical initiating or propagating events in fatty liver infiltration and nonalcoholic fatty liver disease (NAFLD). Genetic variants and the role of drug-induced toxicity have been considered. RESULTS: Key alterations of mitochondrial physiology associated with hepatocyte fatty changes are described. The value of novel non-invasive diagnostic methods to detect mitochondrial metabolic alterations is also discussed. CONCLUSIONS: Mitochondrial metabolic remodeling is a predominant factor in the appearance and perpetuation of hepatocyte fat accumulation. Non-invasive techniques to identify mitochondrial dysfunction and proper mitochondria protection are two necessary clinical steps for an efficient management of NAFLD. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. PMID: 22484459 [PubMed - indexed for MEDLINE] 285. Nat Rev Endocrinol. 2012 Apr 3;8(8):457-65. doi: 10.1038/nrendo.2012.49. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Pedersen BK(1), Febbraio MA. Author information: (1)The Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet, Section 7641, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. bkp@rh.dk During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. PMID: 22473333 [PubMed - indexed for MEDLINE] 286. Cardiovasc Hematol Agents Med Chem. 2012 Jun;10(2):124-34. PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations. Abbas A(1), Blandon J, Rude J, Elfar A, Mukherjee D. Author information: (1)Department of Internal Medicine, Texas Tech University, El Paso, Texas 79905, USA. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed. PMID: 22471957 [PubMed - indexed for MEDLINE] 287. Indian J Physiol Pharmacol. 2011 Jul-Sep;55(3):197-206. Recent advances in human brown fat physiology. Muralidhara DV(1), Muralidhara KD. Author information: (1)Department of Physiology, Faculty of Medicine and Health Sciences, University Sultan Zainal Abidin, Kuala Terengganu, Malaysia. diviem@yahoo.com Of the two variants of adipose tissue, white fat is traditionally known as a lipid rich tissue which undergoes pathological expansion in obese conditions. To counter the excess accumulation of white fat in states of energy imbalance, the second and unique type of brown fat plays a key role by burning extra energy into heat through a special metabolic pathway. In addition brown fat also plays a vital role in thermoregulation in animals and newborn humans and infants. Recent progress in research areas of these two types of fat tissue has provided compelling evidence to show that they secrete a large number of chemicals that play an important role in body weight control that involves several mechanisms. Brown fat was considered absent in the adult humans until recently. But new techniques have provided ample support for its active existence. Based on the very recent data it has been suggested that brown fat can be a target organ in the treatment of obesity which can lead to exciting and informative outcomes in the future. PMID: 22471225 [PubMed - indexed for MEDLINE] 288. Nutr Hosp. 2011 Jul-Aug;26(4):685-91. doi: 10.1590/S0212-16112011000400004. [Positive effects of physical exercise on reducing the relationship between subcutaneous abdominal fat and morbility risk]. [Article in Spanish] González Calvo G(1), Hernández Sánchez S, Pozo Rosado P, García López D. Author information: (1)Departamento de Didáctica de la Expresión Musical, Plástica y Corporal, Universidad de Valladolid, Valladolid, España. gustavogonzalezcalvo@gmail.com INTRODUCTION: The consequences related to the accumulation of abdominal fat above healthy levels create a considerable organic damage. Among the physiological consequences we can highlight heart diseases, hypertension, type-2 diabetes, obesity and metabolic syndrome, which drastically reduce life expectancy and quality. Evidence shows that health improvement is correlated to greater levels of physical activity. However, physical exercise can create oxidative damage on organs and muscular tissue, more relevant in subjects with a high percentage of abdominal fat. This piece of work determines which are the fundamental variables of the exercise program in order to optimize its advantages while minimizing oxidative stress. MAIN PURPOSE: To know the key variables in the accumulation of abdominal fat above healthy levels, and the role of exercise in prevention and improvement of such issue. SPECIFIC PURPOSES: 1) to identify the key variables in an exercise program aimed at reducing abdominal fat; 2) to understand the relationship between abdominal fat, health and exercise; 3) to review the latest research related to physical exercise and its effect on abdominal adipose tissue. METHODOLOGY: A search and identification of original and reviewed articles will be carried out in indexed impact journals within the main databases. DISCUSSION: Regular physical exercise, most notably aerobic one, reduces body adipose tissue deposits in general, and abdominal ones in particular, both in obese and overweight subjects. PMID: 22470011 [PubMed - indexed for MEDLINE] 289. J Clin Gastroenterol. 2012 Jul;46(6):457-67. doi: 10.1097/MCG.0b013e31824cf51e. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. Mouzaki M(1), Allard JP. Author information: (1)Department of Gastroenterology, Hepatology & Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in adults and children and is currently the third most common indication for liver transplantation in North America. Its pathogenesis is thought to be secondary to multiple "hits" derived from the dietary components, adipose tissue, immune system, and intestinal microbiota. Lack of physical activity may contribute as well. Nutrients may exert their effect directly or through alteration of the intestinal microbiota. Research focusing on specific dietary components predisposing to NAFLD has shown conflicting results. Total energy intake, and macronutrients, has been linked to the development of NAFLD. Fructose not only contributes to hepatic steatosis but may trigger inflammatory signals as well. Polyunsaturated fatty acids are thought to exert anti-inflammatory effects. The role of vitamins as well as minerals in this field is actively being investigated. In this review, we discuss the evidence-linking macronutrients (such as carbohydrates and fat in general and fructose, fiber, short chain fatty acids, polyunsaturated fatty, and choline specifically) and micronutrients (such as vitamin E and C and minerals) with the development and treatment of NAFLD. We also discuss the literature on physical activity and NAFLD. PMID: 22469640 [PubMed - indexed for MEDLINE] 290. Stem Cells Dev. 2012 Sep 20;21(14):2724-52. doi: 10.1089/scd.2011.0722. Epub 2012 May 9. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Strioga M(1), Viswanathan S, Darinskas A, Slaby O, Michalek J. Author information: (1)Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania. marius.strioga@vuoi.lt Mesenchymal stem/stromal cells (MSCs) comprise a heterogeneous population of cells with multilineage differentiation potential, the ability to modulate oxidative stress, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. Recent data indicate that these paracrine factors may play a key role in MSC-mediated effects in modulating various acute and chronic pathological conditions. MSCs are found in virtually all organs of the body. Bone marrow-derived MSCs (BM-MSCs) were discovered first, and the bone marrow was considered the main source of MSCs for clinical application. Subsequently, MSCs have been isolated from various other sources with the adipose tissue, serving as one of the alternatives to bone marrow. Adipose tissue-derived MSCs (ASCs) can be more easily isolated; this approach is safer, and also, considerably larger amounts of ASCs can be obtained compared with the bone marrow. ASCs and BM-MSCs share many biological characteristics; however, there are some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity. Some of these differences may represent specific features of BM-MSCs and ASCs, while others are suggestive of the inherent heterogeneity of both BM-MSC and ASC populations. Still other differences may simply be related to different isolation and culture protocols. Most importantly, despite the minor differences between these MSC populations, ASCs seem to be as effective as BM-MSCs in clinical application, and, in some cases, may be better suited than BM-MSCs. In this review, we will examine in detail the ontology, biology, preclinical, and clinical application of BM-MSCs versus ASCs. PMID: 22468918 [PubMed - indexed for MEDLINE] 291. Endocrinology. 2012 May;153(5):2070-5. doi: 10.1210/en.2012-1022. Epub 2012 Mar 30. Minireview: The link between fat and bone: does mass beget mass? Zaidi M(1), Buettner C, Sun L, Iqbal J. Author information: (1)Mount Sinai Bone Program and Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. mone.zaidi@mountsinai.org Osteoporosis is less common in individuals with high fat mass. This putative osteoprotection is likely an adaptive mechanism that allows obese individuals to better carry their increased body mass. Recent studies have focused on hormones that link fat to bone. Adipokines, such as leptin, modulate bone cells through both direct and indirect actions, whereas molecules activating peroxisome proliferator-activated receptor γ drive mesenchymal stem cell differentiation towards adipocytes away from the osteoblastic lineage. There is emerging evidence that bone-derived osteocalcin regulates insulin release and insulin sensitivity and, hence, might indirectly affect fat mass. Despite these molecular connections between fat and bone, animal and human studies call into question a primary role for body fat in determining bone mass. Mice devoid of fat do not have a skeletal phenotype, and in humans, the observed correlations between bone and body mass are not just due to adipose tissue. An improved understanding of the integrative physiology at the fat-bone interface should allow us develop therapies for both osteoporosis and obesity. PMCID: PMC3339646 PMID: 22467495 [PubMed - indexed for MEDLINE] 292. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):652-60. doi: 10.1093/gerona/gls086. Epub 2012 Mar 30. GH and IGF1: roles in energy metabolism of long-living GH mutant mice. Brown-Borg HM(1), Bartke A. Author information: (1)Department of Pharmacology, Physiology & Therapeutics, School of Medicine & Health Sciences, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58202-9037, USA. holly.brown.borg@med.und.edu Of the multiple theories to explain exceptional longevity, the most robust of these has centered on the reduction of three anabolic protein hormones, growth hormone (GH), insulin-like growth factor, and insulin. GH mutant mice live 50% longer and exhibit significant differences in several aspects of energy metabolism as compared with wild-type mice. Mitochondrial metabolism is upregulated in the absence of GH, whereas in GH transgenic mice and dwarf mice treated with GH, multiple aspects of these pathways are suppressed. Core body temperature is markedly lower in dwarf mice, yet whole-body metabolism, as measured by indirect calorimetry, is surprisingly higher in Ames dwarf and Ghr-/- mice compared with normal controls. Elevated adiponectin, a key antiinflammatory cytokine, is also very likely to contribute to longevity in these mice. Thus, several important components related to energy metabolism are altered in GH mutant mice, and these differences are likely critical in aging processes and life-span extension. PMCID: PMC3348496 PMID: 22466316 [PubMed - indexed for MEDLINE] 293. Yakugaku Zasshi. 2012;132(4):425-31. [In vivo imaging reveals adipose tissue inflammation in obesity and multi-cellular processes of developing thrombus]. [Article in Japanese] Nishimura S(1). Author information: (1)Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan. snishi-tky@umin.ac.jp The metabolic syndrome is a major risk factor of cardiovascular events, and obese visceral adipose tissue remodeling based on chronic inflammation plays a central role. To assess dynamic interplay between multiple cell types in obese adipose tissue, a visualization technique in vivo was developed. By this technique we identified inflammatory cell clusters associated with angiogenesis and adipogenesis in obese adipose tissue. We also found increased leukocyte-platelet-endothelial cell interactions in obese adipose tissue microcirculation, which were indicative of local chronic inflammation. Moreover, we found that large numbers of CD8(+) effector T cells infiltrated into obese adipose tissue. Immunological and genetic depletion of CD8(+) T cells reduced inflammatory (M1) macrophage infiltration and adipose tissue inflammation, and ameliorated systemic insulin resistance. Infiltration of CD8(+) T cells is essential for inflammatory macrophage recruitment into obese adipose tissue, and the initiation and development of inflammation therein. Our results clearly demonstrate the power of our imaging technique to analyze complex cellular interplay in vivo, especially parenchymal and stromal cell crosstalk, and to evaluate new therapeutic interventions against conditions arising from these interactions. PMID: 22465917 [PubMed - indexed for MEDLINE] 294. Mol Cell Endocrinol. 2013 Sep 25;378(1-2):23-8. doi: 10.1016/j.mce.2012.03.005. Epub 2012 Mar 23. Role of renin-angiotensin-aldosterone system in adipose tissue dysfunction. Jing F(1), Mogi M, Horiuchi M. Author information: (1)Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. The renin-angiotensin-aldosterone system (RAAS) is known to be closely linked to the pathogenesis of insulin resistance. The angiotensin (Ang) II type 1 (AT₁) receptor mediates the major effects of Ang II in adipose tissue, and blockade of the AT₁ receptor improves insulin sensitivity, with enhanced adipocyte differentiation. In contrast, the role of angiotensin type 2 (AT₂) receptor activation in insulin sensitivity is still controversial, although AT₂ receptor functions are thought to be mutually antagonistic against those of the AT₁ receptor in the cardiovascular system. Aldosterone exerts its biological roles via the mineralocorticoid receptor (MR), and inhibition of MR signaling in adipose tissue ameliorates inflammation, with upregulation of insulin-mediated glucose transport and adipocyte differentiation. Clinical studies indicate that blockade of RAAS prevents the new onset of type 2 diabetes and improves the metabolic syndrome in diabetic patients. We here review the recent concepts of the roles of RAAS in adipose tissue. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22465098 [PubMed - indexed for MEDLINE] 295. Public Health Nutr. 2013 Jan;16(1):27-35. doi: 10.1017/S1368980012000894. Epub 2012 Apr 2. Aetiological factors behind adipose tissue inflammation: an unexplored research area. von Scholten BJ(1), Andresen EN, Sørensen TI, Jess T. Author information: (1)Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark. OBJECTIVE: Despite extensive research into the biological mechanisms behind obesity-related inflammation, knowledge of environmental and genetic factors triggering such mechanisms is limited. In the present narrative review we present potential determinants of adipose tissue inflammation and suggest ways ahead for future research in the field. DESIGN: We searched the literature for potential determinants of obesity with inflammation through MEDLINE by applying the MeSH headings 'obesity' and 'inflammation' in combination with specific terms for a series of environmental and genetic factors. RESULTS: Numerous articles reported on the association between environmental or genetic factors and respectively obesity and inflammation, whereas only a few studies assessed obesity and inflammation as a combined outcome. Among suggested determinants for obesity with inflammation were Adenovirus-36, the gut microbiota, trans-fatty acids, and the four genes FTO, MC4R, TNF-α and LEPR. CONCLUSIONS: We present a limited number of factors potentially contributing to the development of obesity with inflammation, while concluding that overall the area is indeed sparsely investigated. We present ideas for future studies that can identify relevant aetiological factors. This identification is essential for targeted prevention of obesity with inflammation and the clinical consequences thereof. PMID: 22464010 [PubMed - indexed for MEDLINE] 296. Annu Rev Biochem. 2012;81:715-36. doi: 10.1146/annurev-biochem-052110-115718. Epub 2012 Mar 29. Adipogenesis: from stem cell to adipocyte. Tang QQ(1), Lane MD. Author information: (1)Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Excessive caloric intake without a rise in energy expenditure promotes adipocyte hyperplasia and adiposity. The rise in adipocyte number is triggered by signaling factors that induce conversion of mesenchymal stem cells (MSCs) to preadipocytes that differentiate into adipocytes. MSCs, which are recruited from the vascular stroma of adipose tissue, provide an unlimited supply of adipocyte precursors. Members of the BMP and Wnt families are key mediators of stem cell commitment to produce preadipocytes. Following commitment, exposure of growth-arrested preadipocytes to differentiation inducers [insulin-like growth factor 1 (IGF1), glucocorticoid, and cyclic AMP (cAMP)] triggers DNA replication and reentry into the cell cycle (mitotic clonal expansion). Mitotic clonal expansion involves a transcription factor cascade, followed by the expression of adipocyte genes. Critical to these events are phosphorylations of the transcription factor CCATT enhancer-binding protein β (C/EBPβ) by MAP kinase and GSK3β to produce a conformational change that gives rise to DNA-binding activity. "Activated" C/EBPβ then triggers transcription of peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα, which in turn coordinately activate genes whose expression produces the adipocyte phenotype. PMID: 22463691 [PubMed - indexed for MEDLINE] 297. Vnitr Lek. 2012 Feb;58(2):135-9. [Soft tissues, hormones and the skeleton]. [Article in Czech] Zofková I(1). Author information: (1)Endokrinologický ústav Praha, Reditelka RNDr. Bĕla Bendlová, CSc. izofkova@endo.cz Mechanical load activates bone modeling and increases bone strength. Thus physical activity is extremely important for overall bone health. Muscle volume and muscle contraction are closely related to bone mineral density in men and women, although these relationships are more significat in men. The muscle-bone unit has been defined as a functional system, in which both components are under control of the somatotropin-IGF-I system, androgens and D hormone. These endocrine systems play, via the muscle-bone unit, an important role in development of the skeleton and its stability in adulthood. That is why deficiency of any of these hormonal systems, or reduced physical activity (mainly in childhood) could seriously affect bone density and quality. Bone is also under control of adipose tissue, which modulates its metabolism via mechanical load and more importantly via adipocytokines (leptin, adiponectin and rezistin). Leptin increases bone formation by activation of osteoblasts. This direct effect of leptin is amplified by stimulation of the β-1 adrenergic system, which inhibits the negative osteotropic effects of neuropeptide Y. On the other hand, leptin also activates β-2 adrenergic receptors, which increase bone resorption. In humans, the overall osteo-anabolic effect of leptin tends to be dominant. Furthermore, leptin has a principal role in the start of puberty in girls and maturation, remodeling and development of the female skeleton. Adiponectin (and probably rezistin) has an unambiguous deteriorating effect on the skeleton. Further studies are needed to confirm the clinical importance of soft tissues relative to the integrity of the skeleton. PMID: 22463094 [PubMed - indexed for MEDLINE] 298. Expert Rev Proteomics. 2012 Apr;9(2):181-99. doi: 10.1586/epr.12.12. Angiopoietin-like protein 4: health effects, modulating agents and structure-function relationships. Grootaert C(1), Van de Wiele T, Verstraete W, Bracke M, Vanhoecke B. Author information: (1)Laboratory of Microbial Ecology & Technology (LabMET), Ghent University, Ghent, Belgium. charlotte.grootaert@ugent.be Angiopoietin-like protein 4 (ANGPTL4) has been identified as a multifunctional signal protein. It is produced by a variety of tissues, and is secreted into the bloodstream in glycosylated, oligomerized, native and cleaved isoforms to modulate physiological events such as angiogenesis, cell differentiation and the crosstalk between liver, brain, adipose and muscle tissue in lipid and glucose metabolism. In addition, the expression and isoform appearance of ANGPTL4 are modified by the intestinal microbiota. With an eye on an effective strategy to improve health using ANGPTL4, we will focus on: health issues associated with ANGPTL4 expression, including obesity, Type 2 diabetes, cardiovascular diseases and cancer; several modulators of ANGPTL4 of chemical, microbiological, food and host origin; and the correlation of the specific ANGPTL4 isoforms with these modulators and their health effects. PMID: 22462789 [PubMed - indexed for MEDLINE] 299. J Clin Pharm Ther. 2012 Oct;37(5):525-35. doi: 10.1111/j.1365-2710.2012.01347.x. Epub 2012 Mar 30. Recent advances in the pathophysiology and pharmacological treatment of obesity. Chugh PK(1), Sharma S. Author information: (1)Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, New Delhi, India. docpreeta@yahoo.com WHAT IS KNOWN AND OBJECTIVE: The increasing prevalence of obesity and associated morbidity present unmet medical needs for safe and effective new drug therapies. Our aim is to review the diverse targets and compounds that are in clinical development. METHODS: Literature searches were conducted using the PUBMED database for studies published in English from January 1985 to December 2011 using combinations of key words, including obesity, overweight, weight loss and treatment in addition to the clinical trials website. Bibliographies of selected references were also evaluated for relevant articles. Press/news releases were also utilized. The collection of information for this review was limited to the most recently available human and animal data. RESULTS AND DISCUSSION: Weight loss drugs in development include compounds that act centrally (neuropeptide Y, AgRP and MCH1 receptors) to limit food intake or reduce the absorption of fat from the gastrointestinal tract (lipase inhibitors) or increase energy expenditure or reduce adipose tissue formation. Among the existing therapy, new combinations (topiramate plus phentermine, bupropion plus naltrexone) offer greater efficacy with reduced adverse effects. WHAT IS NEW AND CONCLUSION: Despite recent setbacks in the pharmacotherapy of obesity (withdrawal of rimonabant and sibutramine), many compounds are in phase II/III trials. The future holds promise for a new drug that alone or in combination with an existing agent could target the initial pathophysiology and morbidities associated with obesity. © 2012 Blackwell Publishing Ltd. PMID: 22462645 [PubMed - indexed for MEDLINE] 300. Annu Rev Nutr. 2012 Aug 21;32:229-43. doi: 10.1146/annurev-nutr-071811-150746. Epub 2012 Mar 29. Visfatin/NAMPT: a multifaceted molecule with diverse roles in physiology and pathophysiology. Dahl TB(1), Holm S, Aukrust P, Halvorsen B. Author information: (1)Research Institute for Internal Medicine, Faculty of Medicine, University of Oslo, Oslo University Hospital Rikshospitalet, Oslo, Norway. tuvad@rr-research.no Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is a protein with several suggested functions. Although the first discovery of this molecule as a pre-B-cell colony-enhancing factor suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide generation has considerably widened its potential biological activities. Although originally thought to be produced in adipose tissue (i.e., adipocytes and infiltrating macrophages), its production seems to involve other cells and tissues such as skeletal muscle, liver, immune cells, cardiomyocytes, and the brain. Visfatin/NAMPT has both intracellular and extracellular effects influencing several signaling pathways. Its broad spectrum of effects is mirrored by its potential involvement in a wide range of disorders including human immunodeficiency virus infection, septicemia, myocardial failure, atherosclerosis, metabolic disorders, inflammatory diseases, malignancies, and neurodegenerative disorders and aging. Moreover, studies on visfatin/NAMPT in atherosclerotic disorders suggest a rather complex role of this molecule in pathophysiology, potentially mediating both adaptive and maladaptive responses. PMID: 22462624 [PubMed - indexed for MEDLINE] 301. Rev Bras Reumatol. 2012 Mar-Apr;52(2):278-87. Possible role of adipokines in systemic lupus erythematosus and rheumatoid arthritis. [Article in English, Portuguese] Barbosa Vde S(1), Rêgo J, Antônio da Silva N. Author information: (1)Serviço de Reumatologia, Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Goiás. vitalina.barbosa@gmail.com In recent years, mediators synthesized in the adipose tissue, the so-called adipokines, have been described. They have a hormonal action, regulating appetite and glucose metabolism, but also act as cytokines with effects on the immune system, including effects on autoimmunity. The most important adipokines are leptin, adiponectin, resistin and visfatin, and some of them have been assessed in autoimmune rheumatic diseases, especially systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Studies have shown high levels of leptin and adiponectin in SLE, but correlation with disease activity is questionable. In RA, studies have also reported increased levels of leptin and adiponectin, and correlation with disease activity and joint erosion, but the results are conflicting. This review describes the role of leptin and adiponectin on the immune system, as well as on SLE and RA. PMID: 22460416 [PubMed - indexed for MEDLINE] 302. J Mol Endocrinol. 2012 May 29;49(1):R1-7. doi: 10.1530/JME-12-0043. Print 2012 Aug. Role of sex hormones in modulation of brown adipose tissue activity. Quarta C(1), Mazza R, Pasquali R, Pagotto U. Author information: (1)Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of Clinical Medicine, University of Bologna, Bologna, Italy. The recent demonstration that metabolically active brown adipose tissue (BAT) is present with a high prevalence in humans undoubtedly represents one of the major advancements in the field of metabolic research in the last few years. The increasing interest in BAT is justified by preclinical observations highlighting an important role of this tissue in energy dissipation and metabolic clearance of substrates from the blood. These findings imply that stimulation of BAT activity may represent a new therapeutic approach for obesity and associated comorbidities. However, before proposing BAT as a target organ for therapeutics in a clinical setting, many further notions about BAT function and modulation need to be explored. Keeping in mind the importance of sex dimorphism in energy metabolism control under physiological and pathological conditions, sex hormones may play a relevant role in the regulation of BAT activity in both males and females. Much of the evidence acquired in the past supports the concept of an important role for different sex hormones in BAT thermogenesis and indicates that this tissue mediates the ability of sex hormones to modulate energy balance. These findings make it plausible that a modified interaction between BAT and sex hormones may contribute to the development and the maintenance of obesity and associated metabolic complications. PMID: 22460126 [PubMed - indexed for MEDLINE] 303. Nutr Rev. 2012 Apr;70(4):218-33. doi: 10.1111/j.1753-4887.2012.00454.x. Relationship between bread consumption, body weight, and abdominal fat distribution: evidence from epidemiological studies. Bautista-Castaño I(1), Serra-Majem L. Author information: (1)Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. A long-standing belief held by the general public is that bread fattens. This encourages many people to restrict, or even eliminate, bread from their diet. The present review was conducted to assess whether or not eating patterns that include bread are associated with overall obesity or excess abdominal adiposity, whether in the general population or in subjects undergoing obesity management. The literature search included articles published over the past 30 years that focused on dietary patterns that included bread (refined or whole-grain) and their association with ponderal status and abdominal fat distribution. A total of 38 epidemiological studies fulfilled the inclusion criteria (22 cross-sectional, 11 prospective cohort, and five intervention). The results indicate that dietary patterns that include whole-grain bread do not positively influence weight gain and may be beneficial to ponderal status. With respect to dietary patterns that include refined bread, the majority of cross-sectional studies indicate beneficial effects, while most of the well-designed cohort studies demonstrate a possible relationship with excess abdominal fat. Because differences in the study designs make it difficult to form definitive conclusions, more studies are needed that focus specifically on bread consumption, within different dietary patterns, and its influence on ponderal status. © 2012 International Life Sciences Institute. PMID: 22458695 [PubMed - indexed for MEDLINE] 304. Birth Defects Res C Embryo Today. 2012 Mar;96(1):1-29. doi: 10.1002/bdrc.21006. Organ repair and regeneration: an overview. Baddour JA(1), Sousounis K, Tsonis PA. Author information: (1)Department of Biology and Center for Tissue Regeneration and Engineering, University of Dayton, Dayton, Ohio 45469-2320, USA. A number of organs have the intrinsic ability to regenerate, a distinctive feature that varies among organisms. Organ regeneration is a process not fully yet understood. However, when its underlying mechanisms are unraveled, it holds tremendous therapeutic potential for humans. In this review, we chose to summarize the repair and regenerative potential of the following organs and organ systems: thymus, adrenal gland, thyroid gland, intestine, lungs, heart, liver, blood vessels, germ cells, nervous system, eye tissues, hair cells, kidney and bladder, skin, hair follicles, pancreas, bone, and cartilage. For each organ, a review of the following is presented: (a) factors, pathways, and cells that are involved in the organ's intrinsic regenerative ability, (b) contribution of exogenous cells - such as progenitor cells, embryonic stem cells, induced pluripotent stem cells, and bone marrow-, adipose- and umbilical cord blood-derived stem cells - in repairing and regenerating organs in the absence of an innate intrinsic regenerative capability, (c) and the progress made in engineering bio-artificial scaffolds, tissues, and organs. Organ regeneration is a promising therapy that can alleviate humans from diseases that have not been yet cured. It is also superior to already existing treatments that utilize exogenous sources to substitute for the organ's lost structure and/or function(s). Copyright © 2012 Wiley Periodicals, Inc. PMID: 22457174 [PubMed - indexed for MEDLINE] 305. Sports Med. 2012 May 1;42(5):415-31. doi: 10.2165/11599590-000000000-00000. Effect of acute endurance and resistance exercise on endocrine hormones directly related to lipolysis and skeletal muscle protein synthesis in adult individuals with obesity. Hansen D(1), Meeusen R, Mullens A, Dendale P. Author information: (1)Heart Centre Hasselt, Cardiovascular Medicine and Rehabilitation, Jessa Hospital, Hasselt, Belgium. Hansen_dominique@yahoo.com In subjects with obesity, the implementation of long-term exercise intervention increases lean tissue mass and lowers adipose tissue mass. However, data indicate a blunted lipolytic response, and/or skeletal muscle protein synthesis, when subjects with obesity are exposed to acute endurance or resistance exercise, respectively. Therefore, subjects with obesity seem to display a suboptimal physiological response to acute exercise stimuli. It might be hypothesized that hormonal disturbances contribute, at least in part, to these abnormal physiological reactions in the obese. This review discusses the impact of acute endurance and resistance exercise on endocrine hormones directly related to lipolysis and/or skeletal muscle protein synthesis (insulin, [nor]epinephrine, cortisol, growth hormone, testosterone, triiodothyronine, atrial natriuretic peptide, insulin-like growth factor-1), as well as the impact of long-term endurance and resistance exercise intervention on these hormonal responses to acute endurance and resistance exercise. In the obese, some endocrinological disturbances during acute endurance and resistance exercise have been identified: a blunted blood growth hormone, atrial natriuretic peptide and epinephrine release, and greater cortisol and insulin release. These hormonal disturbances might contribute to a suppressed lipolytic response, and/or suppressed skeletal muscle protein synthesis, as a result of acute endurance or resistance exercise, respectively. In subjects with obesity, the impact of acute endurance and resistance exercise on other endocrine hormones (norepinephrine, testosterone, triiodothyronine, insulin-like growth factor-1) remains elusive. Furthermore, whether long-term endurance and resistance exercise intervention might reverse these hormonal disturbances during acute endurance and resistance exercise in these individuals remains unknown. PMID: 22455310 [PubMed - indexed for MEDLINE] 306. Hormones (Athens). 2012 Jan-Mar;11(1):8-20. Adiponectin: regulation of its production and its role in human diseases. Shehzad A(1), Iqbal W, Shehzad O, Lee YS. Author information: (1)School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, Korea. Adiponectin is a white and brown adipose tissue hormone, also known as gelatin-binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin. AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review we present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARα pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies. PMID: 22450341 [PubMed - indexed for MEDLINE] 307. Curr Opin Lipidol. 2012 Jun;23(3):190-5. doi: 10.1097/MOL.0b013e328352dcef. The holy grail of metabolic disease: brown adipose tissue. Bartelt A(1), Heeren J. Author information: (1)Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D - 20246 Hamburg, Germany. abartelt@uke.uni-hamburg.de PURPOSE OF REVIEW: The finding that brown adipose tissue (BAT) is present in adults brought BAT physiology into the focus of many researchers interested in energy metabolism. Here, we review recent insight into how BAT develops, functions and might help to treat metabolic disorders in humans. RECENT FINDINGS: BAT is under control of the nervous system, and several pathways have been identified that allow direct manipulation of BAT biology. In addition, some brown adipocytes arise from a distinct subset of white adipocyte precursors and studies were performed that characterize the development of these 'brite' adipocytes. Importantly, progress has been made in understanding how BAT takes up and dissipates nutrients that in metabolic disorders are present in excess. Finally, as it seems that BAT activity declines with age and obesity, we review findings that might shed light on how humans could sustain or increase BAT activity, thus preventing or treating obesity, hyperlipidemia and type 2 diabetes. SUMMARY: BAT is a powerful organ that controls the development of metabolic disease. These powers are boosted by mechanisms that turn white into brown fat and enhance lipid flux into BAT. However, in humans, it remains unclear what was the first: metabolic disease or decreased BAT activity. PMID: 22449813 [PubMed - indexed for MEDLINE] 308. Pulm Pharmacol Ther. 2013 Aug;26(4):427-9. doi: 10.1016/j.pupt.2012.03.003. Epub 2012 Mar 17. Obesity: "priming" the lung for injury. Konter J(1), Baez E, Summer RS. Author information: (1)The Pulmonary Center, Boston University School of Medicine, 80 East Concord St, R-304, Boston, MA 02118, USA. Acute lung injury (ALI) is a severe inflammatory condition that develops in response to local and systemic lung challenges. To date, specific risk factors for development of ALI remain poorly defined. Recent epidemiological studies have reported obesity as an important predisposing factor in the development of this condition. Although the pathogenic mechanisms linking obesity and ALI have not been well-elucidated, emerging scientific evidence has described factors secreted by adipose tissue that have important biological activities in lung and has suggested that altered secretion of these factors during obesity contributes to increased ALI susceptibility. The objective of this manuscript is to highlight recent clinical evidence supporting the association between obesity and ALI and to discuss the posited role for adipose tissue-derived factors in the pathogenesis of this condition. Copyright © 2012 Elsevier Ltd. All rights reserved. PMCID: PMC3387298 PMID: 22449512 [PubMed - indexed for MEDLINE] 309. Am J Physiol Heart Circ Physiol. 2012 Jun 1;302(11):H2148-65. doi: 10.1152/ajpheart.00907.2011. Epub 2012 Mar 23. Inflammation and metabolic dysfunction: links to cardiovascular diseases. Taube A(1), Schlich R, Sell H, Eckardt K, Eckel J. Author information: (1)Paul Langerhans Group, German Diabetes Center, Duesseldorf, Germany. Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets. PMID: 22447947 [PubMed - indexed for MEDLINE] 310. Biochimie. 2012 Oct;94(10):2180-9. doi: 10.1016/j.biochi.2012.03.006. Epub 2012 Mar 14. Leptin, adiponectin and pulmonary diseases. Ali Assad N(1), Sood A. Author information: (1)University of New Mexico Health Sciences Center School of Medicine, Department of Medicine, 1 University of New Mexico, MSC 10 5550, Albuquerque, NM 87131, USA. Adipose tissue produces leptin and adiponectin - energy-regulating adipokines that may also play a role in inflammatory pulmonary conditions, as suggested by some murine studies. Leptin and adiponectin and their respective receptors are expressed in the human lung. The association between systemic or airway leptin and asthma in humans is currently controversial, particularly among adults. The majority of the evidence among children however suggests that systemic leptin may be associated with greater asthma prevalence and severity, particularly among prepubertal boys and peripubertal/postpubertal girls. Systemic and airway leptin concentrations may also be disproportionately higher in chronic obstructive pulmonary disease (COPD) patients, particularly among women, and reflect greater airway inflammation and disease severity. Quite like leptin, the association between systemic and airway adiponectin and asthma in humans is also controversial. Some but not all studies, demonstrate that serum adiponectin concentrations are protective against asthma among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are inversely associated with asthma severity among boys but positively associated among men. Further, systemic and airway adiponectin concentrations are higher in COPD patients than controls, as demonstrated by case-control studies of men. Systemic adiponectin is also positively associated with lung function in healthy adults but inversely associated with lung function in subjects with COPD. It is therefore possible that pro-inflammatory effects of adiponectin dominate under certain physiologic conditions and anti-inflammatory effects under others. The adipokine-lung disease literature has critical gaps that include a lack of adequately powered longitudinal or weight-intervention studies; inadequate adjustment for confounding effect of obesity; and unclear understanding of potential sex interactions. It is also uncertain whether adipokine derangements precede pulmonary disease or are a consequence of it. Future research will determine whether modulation of adipokines, independent of BMI, may allow novel ways to prevent or treat inflammatory pulmonary conditions. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMCID: PMC3399062 PMID: 22445899 [PubMed - indexed for MEDLINE] 311. Trends Endocrinol Metab. 2012 May;23(5):234-41. doi: 10.1016/j.tem.2012.02.005. Epub 2012 Mar 22. Apelin, a promising target for type 2 diabetes treatment? Castan-Laurell I(1), Dray C, Knauf C, Kunduzova O, Valet P. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France. Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22445464 [PubMed - indexed for MEDLINE] 312. Nucl Recept Signal. 2012;10:e001. doi: 10.1621/nrs.10001. Epub 2012 Feb 27. Post-translational modifications of nuclear receptors and human disease. Anbalagan M(1), Huderson B, Murphy L, Rowan BG. Author information: (1)Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA. Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments. PMCID: PMC3309075 PMID: 22438791 [PubMed - indexed for MEDLINE] 313. Eur J Endocrinol. 2012 Jun;166(6):959-67. doi: 10.1530/EJE-12-0030. Epub 2012 Mar 21. The endocrine role of the skeleton: background and clinical evidence. Schwetz V(1), Pieber T, Obermayer-Pietsch B. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, Austria. Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, β-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated. PMID: 22436399 [PubMed - indexed for MEDLINE] 314. Animal. 2012 Feb;6(2):327-38. doi: 10.1017/S1751731111001625. Factors in pig production that impact the quality of dry-cured ham: a review. Candek-Potokar M(1), Skrlep M. Author information: (1)Agricultural Institute of Slovenia, Hacquetova ulica 17, 1000 Ljubljana, Slovenia. meta.candek-potokar@kis.si This study reviews the factors of pig production that impact the quality of dry-cured ham. When processing is standardized, the quality of the final dry-cured product is primarily determined by the quality of the meat before curing (green ham). This has been defined as the aptitude for seasoning and is determined by the green ham weight, adipose tissue quantity and quality, meat physico-chemical properties and the absence of visual defects. Various ante-mortem factors including pig age and weight, genetic type, diet, feeding strategy and slaughter conditions determine green ham properties such as the dynamics of water loss, salt intake and, as a consequence, proteolysis and lipolysis. Muscle conditions (pH, salt concentration, water content and availability, temperature) influence enzymatic activity and development of characteristic texture and flavor. Generally, hams of older and heavier pigs present better seasoning aptitude because of higher adiposity. Adiposity is also positively correlated with fat saturation, which is desired to avoid rancidity and oiliness. The fatty acid profile of tissue lipids can be manipulated by diet composition. Feeding strategy affects tissue accretion and protein turnover, thus directly impacting proteolysis. With respect to the impact of pig genotype on dry-cured ham quality, local breeds are generally considered more suitable for producing quality dry hams; however, the majority of dry-cured hams on the market today are from modern pig breeds raised in conventional systems, providing lean hams. The importance of all these factors of pig production is discussed and synthesized, with an emphasis on the main difficulties encountered in dry-cured ham production. PMID: 22436192 [PubMed - indexed for MEDLINE] 315. Endocrine. 2012 Jun;41(3):374-83. doi: 10.1007/s12020-012-9617-z. Epub 2012 Mar 21. Obesidomics: contribution of adipose tissue secretome analysis to obesity research. Pardo M(1), Roca-Rivada A, Seoane LM, Casanueva FF. Author information: (1)Grupo Obesidómica, Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain. maruxapardo@hotmail.com Obesity is presently reaching pandemic proportions and it is becoming a major health concern in developed and developing countries due to its comorbidities like type II diabetes, cardiovascular pathologies, and some cancers. The discovery of the adipose tissue role as an endocrine gland able to secrete adipokines that affects whole-body energy homeostasis has become a key break-through toward a better molecular understanding of obesity. Among the known adipokines involved in the regulation of energy metabolism very few have been clearly seen as central regulators of insulin sensitivity, metabolism, and energy homeostasis. Thus, the discovery and characterization of new adipocyte-derived factors is still in progress. Proteomics technology has emerged as a useful tool to analyze adipose tissue secretion (secretome) dynamics giving a wider picture into the molecular events that control body weight. Besides the identification of new secreted proteins, the advantage of using this approach is the possibility to detect post-translational modifications and protein interactions that generally cannot be predicted by genome studies. In this review, we summarize the recent efforts to identify new bioactive adipokines by proteomics especially in pathological situations such as obesity. PMID: 22434412 [PubMed - indexed for MEDLINE] 316. Proc Nutr Soc. 2012 May;71(2):332-8. doi: 10.1017/S0029665112000092. Epub 2012 Mar 20. Obesity, inflammation and the immune system. de Heredia FP(1), Gómez-Martínez S, Marcos A. Author information: (1)Immunonutrition Research Group, Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition of the Spanish National Research Council (ICTAN-CSIC), Madrid, Spain. fatima.perezdeheredia@ictan.csic.es Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications. PMID: 22429824 [PubMed - indexed for MEDLINE] 317. Clin Biochem. 2012 Aug;45(12):874-9. doi: 10.1016/j.clinbiochem.2012.03.006. Epub 2012 Mar 10. The relationship between adipose tissue and bone metabolism. Gimble JM(1), Nuttall ME. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu OBJECTIVES: The authors have set out to evaluate the literature relevant to the dynamic regulation of adipogenesis and osteogenesis. DESIGN AND METHODS: A detailed search of the past and recent literature was conducted on Pubmed using a combination of keywords including: adipogenesis, bone marrow, hematopoiesis, mesenchymal stromal/stem cell, and osteogenesis. RESULTS: Throughout one's lifespan, the bone marrow microenvironment provides a unique niche for mesenchymal stromal/stem cells (BMSCs) and hematopoietic stem cells (HSCs). The marrow changes as a function of biological age and pathophysiology. Historically, clinical biochemistry has observed these changes from an HSC and hematological perspective. Nevertheless, these changes also reflect the balance between BMSC adipogenic and osteogenic processes which can display an inverse or reciprocal relationship. Multiple hormonal factors and nuclear hormone receptor ligands and drugs are responsible for BMSC lineage selection. Data from a number of laboratories now implicates endocrine feedback loops between extramedullary adipose depots and the central nervous system. CONCLUSIONS: This concise review provides a perspective on the mechanisms regulating BMSC differentiation in the context of biological aging, obesity, and osteoporosis. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. PMID: 22429519 [PubMed - indexed for MEDLINE] 318. Circ Res. 2012 Mar 16;110(6):889-900. doi: 10.1161/CIRCRESAHA.111.263186. Lymphocytes and the adventitial immune response in atherosclerosis. Campbell KA(1), Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Author information: (1)Cardiovascular Research Center, University of Virginia, Charlottesville, USA. Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature. PMCID: PMC3373006 PMID: 22427326 [PubMed - indexed for MEDLINE] 319. Mol Aspects Med. 2012 Oct-Dec;33(5-6):665-75. doi: 10.1016/j.mam.2012.02.004. Epub 2012 Mar 8. Implications of aquaglyceroporins 7 and 9 in glycerol metabolism and metabolic syndrome. Maeda N(1). Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan. norikazu_maeda@endmet.med.osaka-u.ac.jp The discovery of water channel protein (aquaporin [AQP]) has made a great impact on life sciences. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in the maintenance of water homeostasis, but the physiological significance of some AQPs as glycerol channels remains elusive. Adipocyte is a major source of glycerol, which is one of the substrates for hepatic gluconeogenesis. This review focuses on recent studies on glycerol metabolism through AQP7 and AQP9, and briefly discusses the importance of glycerol channel in adipocytes, liver, and heart. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22425521 [PubMed - indexed for MEDLINE] 320. J Craniomaxillofac Surg. 2012 Dec;40(8):750-6. doi: 10.1016/j.jcms.2012.01.025. Epub 2012 Mar 16. Congenital infiltrating lipomatosis of the face with associated involvement of the TMJ structures. Case report and review of the literature. Keramidas T(1), Lagogiannis G, Vlachou V, Katsikeris N. Author information: (1)Department of Oral and Maxillofacial Surgery, "G. Gennimatas" General Hospital of Athens, Athens, Greece. filkeramidas@gmail.com We report a case of congenital infiltrating lipomatosis of the face (CILF) with right TMJ ankylosis causing asymmetry and reduced mouth opening. The management involved soft tissue debulking combined with a right TMJ arthroplasty and is explained in detail. A review of the relevant literature revealed the rarity of this condition. The diagnosis of CILF remains challenging. The currently accepted treatment strategy is less aggressive as facial asymmetry tends to recur. Infiltration of the facial structures from adipose tissue requires several surgical procedures in most cases. Bony hypertrophy on the affected side has been a common finding in reported cases. There have been no previous reports of TMJ ankylosis associated with this condition. CILF is a benign condition with a good long term prognosis. After 2 years of follow up our patient, has maintained full function despite facial asymmetry. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. PMID: 22425497 [PubMed - indexed for MEDLINE] 321. J Neurol Neurosurg Psychiatry. 2012 May;83(5):488-94. doi: 10.1136/jnnp-2011-302029. Epub 2012 Mar 15. Update on the pathophysiology and management of idiopathic intracranial hypertension. Biousse V(1), Bruce BB, Newman NJ. Author information: (1)Department of Ophthalmology, Emory University, Atlanta, GA, USA. vbiouss@emory.edu Idiopathic intracranial hypertension is a disease of unknown aetiology, typically affecting young obese women, producing a syndrome of increased intracranial pressure without identifiable cause. Despite a large number of hypotheses and publications over the past decade, the aetiology is still unknown. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. There continues to be no evidence based consensus or formal guidelines regarding management and treatment of the disease. Treatment studies show that the diagnostic lumbar puncture is a valuable intervention beyond its diagnostic importance, and that weight management is critical. However, many questions remain regarding the efficacy of acetazolamide, CSF shunting procedures and cerebral transverse venous sinus stenting. PMCID: PMC3544160 PMID: 22423118 [PubMed - indexed for MEDLINE] 322. Semin Liver Dis. 2012 Feb;32(1):49-64. doi: 10.1055/s-0032-1306426. Epub 2012 Mar 13. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Musso G(1), Olivetti C, Cassader M, Gambino R. Author information: (1)Gradenigo Hospital, Turin, Italy. giovanni_musso@yahoo.it Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common conditions, frequently encountered in patients with metabolic disorders. OSAS has been associated with an increased risk of cardiovascular and metabolic complications. It has been recently suggested that the chronic intermittent hypoxia of OSAS may also affect the presence and severity of NAFLD. We will critically review experimental and human evidence connecting OSAS to NAFLD pathogenesis, trying to dissect the effect of intermittent hypoxia from that of obesity and associated comorbidities, and examine molecular mechanisms connecting OSAS to liver and metabolic disease in NAFLD, including hypoxia inducible factor (HIF), nuclear factor-kappa B, unfolded protein response, hypoxic adipose tissue inflammation, and their therapeutic potential for NAFLD and its complications, including cirrhosis and hepatocellular carcinoma. Finally, we will provide suggestions for the management of NAFLD patients with suspected OSAS and recommendations for future research. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PMID: 22418888 [PubMed - indexed for MEDLINE] 323. Trends Endocrinol Metab. 2012 Jun;23(6):270-7. doi: 10.1016/j.tem.2012.01.003. Epub 2012 Mar 12. Adipose tissue stem cells: the great WAT hope. Cawthorn WP(1), Scheller EL, MacDougald OA. Author information: (1)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. The past decade has witnessed an explosion in research into adipose tissue stem cells (ASCs), facilitated by their ease of isolation from white adipose tissue (WAT) and fueled by their therapeutic potential. Recent developments have extended ASC multipotency to include endodermal and ectodermal cell types, as well as the generation of induced pluripotent stem cells. This expanding multipotency has been paralleled by burgeoning translational applications, ranging from tissue engineering to anti-cancer therapy, that are currently subject to clinical trials. However, this promise is tempered by potential pitfalls, such as tumorigenicity, and is further undermined by lingering uncertainties regarding the precise identity of ASCs. Confronting these issues will be essential if we are to bypass the pitfalls and develop the promises of ASCs. Published by Elsevier Ltd. PMCID: PMC3367055 PMID: 22417866 [PubMed - indexed for MEDLINE] 324. Stem Cells. 2012 May;30(5):804-10. doi: 10.1002/stem.1076. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Mizuno H(1), Tobita M, Uysal AC. Author information: (1)Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan. hmizuno@juntendo.ac.jp The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. The use of either embryonic stem cells (ESCs) or induced pluripotent stem cells in clinical situations is limited due to cell regulations and to technical and ethical considerations involved in the genetic manipulation of human ESCs, even though these cells are, theoretically, highly beneficial. Mesenchymal stem cells seem to be an ideal population of stem cells for practical regenerative medicine, because they are not subjected to the same restrictions. In particular, large number of adipose-derived stem cells (ASCs) can be easily harvested from adipose tissue. Furthermore, recent basic research and preclinical studies have revealed that the use of ASCs in regenerative medicine is not limited to mesodermal tissue but extends to both ectodermal and endodermal tissues and organs, although ASCs originate from mesodermal lineages. Based on this background knowledge, the primary purpose of this concise review is to summarize and describe the underlying biology of ASCs and their proliferation and differentiation capacities, together with current preclinical and clinical data from a variety of medical fields regarding the use of ASCs in regenerative medicine. In addition, future directions for ASCs in terms of cell-based therapies and regenerative medicine are discussed. Copyright © 2012 AlphaMed Press. PMID: 22415904 [PubMed - indexed for MEDLINE] 325. Rev Endocr Metab Disord. 2012 Jun;13(2):129-40. doi: 10.1007/s11154-012-9212-x. Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Roth CL(1), Sathyanarayana S. Author information: (1)Division of Endocrinology, Seattle Children's Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA. christian.roth@seattlechildrens.org Signaling peptides produced in peripheral tissues such as gut, adipose tissue, and pancreas communicate with brain centers, such as hypothalamus and hindbrain to manage energy homeostasis. These regulatory mechanisms of energy intake and storage have evolved during long periods of hunger in the evolution of man to protect the species from extinction. It is now clear that these circuitries are influenced by prenatal and postnatal environmental factors including endocrine disruptive chemicals. Hypothalamic appetite regulatory systems develop and mature in utero and early infancy, and involve signaling pathways that are important also for the regulation of puberty onset. Recent studies in humans and animals have shown that metabolic pathways involved in regulation of growth, body weight gain and sexual maturation are largely affected by epigenetic programming that can impact both current and future generations. In particular, intrauterine and early infantile developmental phases of high plasticity are susceptible to factors that affect metabolic programming that therefore, affect metabolic function throughout life. In children born small for gestational age, poor nutritional conditions during gestation can modify metabolic systems to adapt to expectations of chronic undernutrition. These children are potentially poorly equipped to cope with energy-dense diets and are possibly programmed to store as much energy as possible, leading to later obesity, metabolic syndrome, disturbed regulation of normal puberty and early onset of cardiovascular disease. Most cases of disturbed energy balance are likely a result of a combination of genetics, epigenetics and environment. This review will discuss potential mechanisms linking intrauterine growth retardation with changes in growth, energy homeostasis and sexual maturation. PMID: 22415297 [PubMed - indexed for MEDLINE] 326. Proc Nutr Soc. 2012 May;71(2):263-75. doi: 10.1017/S0029665112000195. Epub 2012 Mar 14. Energy restriction and the prevention of breast cancer. Harvie M(1), Howell A. Author information: (1)Nightingale Centre, University Hospital of South Manchester, Manchester M23 9LT, UK. michelle.harvie@manchester.ac.uk Erratum in Proc Nutr Soc. 2012 Aug;71(3):433. Energy restriction (ER) to control weight is a potential strategy for breast cancer prevention. The protective effects of habitual continuous energy restriction (CER) and weight loss on breast tumour formation have been conclusively demonstrated in animal studies over the past 100 years, and more recently in women using data from observational studies and bariatric surgery. Intermittent energy restriction (IER) and intermittent fasting (IF) are possible alternative preventative approaches which may be easier for individuals to undertake and possibly more effective than standard CER. Here, we summarise the available data on CER, IER and IF with special emphasis on their potential for breast cancer prevention. In animals, IER is superior or equivalent to CER with the exception of carcinogen-induced tumour models when initiated soon after carcinogen exposure. There are no human data on IER and breast cancer risk, but three studies demonstrated IER and CER to be equivalent for weight loss. IF regimens also reduce mammary tumour formation in animal models and also led to weight loss in human subjects, but have not been directly compared with CER. Animal and some human data suggest that both IER and IF may differ mechanistically compared with CER and may bring about greater reduction in hepatic and visceral fat stores, insulin-like growth factor 1 (IGF-1) levels and cell proliferation, and increased insulin sensitivity and adiponectin levels. Although IER and IF were first studied 65 years ago, we conclude that further studies are required to assess their values compared with CER. PMID: 22414375 [PubMed - indexed for MEDLINE] 327. Eur Heart J. 2012 May;33(10):1190-200. doi: 10.1093/eurheartj/ehr453. Epub 2012 Mar 8. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Bhatia LS(1), Curzen NP, Calder PC, Byrne CD. Author information: (1)National Institute of Health Research Biomedical Research Unit, Southampton University Hospitals NHS Trust, Southampton General Hospital, Tremona Road, Southampton, UK. loke.bhatia@soton.ac.uk Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease. PMID: 22408036 [PubMed - indexed for MEDLINE] 328. Inflamm Bowel Dis. 2012 Aug;18(8):1550-7. doi: 10.1002/ibd.22893. Epub 2012 Mar 8. Adipose tissue and inflammatory bowel disease pathogenesis. Fink C(1), Karagiannides I, Bakirtzi K, Pothoulakis C. Author information: (1)Inflammatory Bowel Disease Center, Division of Digestive Diseases, University of California at Los Angeles, Los Angeles, California 90095, USA. Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc. PMCID: PMC3374883 PMID: 22407798 [PubMed - indexed for MEDLINE] 329. Annu Rev Nutr. 2012 Aug 21;32:261-86. doi: 10.1146/annurev-nutr-071811-150623. Epub 2012 Mar 9. Mechanisms of inflammatory responses in obese adipose tissue. Sun S(1), Ji Y, Kersten S, Qi L. Author information: (1)Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA. The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome. PMCID: PMC4041712 PMID: 22404118 [PubMed - indexed for MEDLINE] 330. Diabetologia. 2012 Jun;55(6):1597-606. doi: 10.1007/s00125-012-2505-5. Epub 2012 Mar 9. Adipose tissue and fetal programming. Symonds ME(1), Pope M, Sharkey D, Budge H. Author information: (1)The Early Life Nutrition Research Unit, Academic Division of Child Health, School of Clinical Sciences, University Hospital, Nottingham, NG7 2UH, UK. michael.symonds@nottingham.ac.uk Adipose tissue function changes with development. In the newborn, brown adipose tissue (BAT) is essential for ensuring effective adaptation to the extrauterine environment, and its growth during gestation is largely dependent on glucose supply from the mother to the fetus. The amount, location and type of adipose tissue deposited can also determine fetal glucose homeostasis. Adipose tissue first appears at around mid-gestation. Total adipose mass then increases through late gestation, when it comprises a mixture of white and brown adipocytes. BAT possesses a unique uncoupling protein, UCP1, which is responsible for the rapid generation of large amounts of heat at birth. Then, during postnatal life some, but not all, depots are replaced by white fat. This process can be utilised to investigate the physiological conversion of brown to white fat, and how it is re-programmed by nutritional changes in pre- and postnatal environments. A reduction in early BAT deposition may perpetuate through the life cycle, thereby suppressing energy expenditure and ultimately promoting obesity. Normal fat development profiles in the offspring are modified by changes in maternal diet at defined stages of pregnancy, ultimately leading to adverse long-term outcomes. For example, excess macrophage accumulation and the onset of insulin resistance occur in an adipose tissue depot-specific manner in offspring born to mothers fed a suboptimal diet from early to mid-gestation. In conclusion, the growth of the different fetal adipose tissue depots varies according to maternal diet and, if challenged in later life, this can contribute to insulin resistance and impaired glucose homeostasis. PMID: 22402988 [PubMed - indexed for MEDLINE] 331. Radiat Res. 2012 Apr;177(4):398-435. Epub 2012 Mar 8. Magnetic resonance spectroscopy of cancer metabolism and response to therapy. McIntyre DJ(1), Madhu B, Lee SH, Griffiths JR. Author information: (1)Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Dominick.McIntyre@cancer.org.uk Magnetic resonance spectroscopy allows noninvasive in vivo measurements of biochemical information from living systems, ranging from cultured cells through experimental animals to humans. Studies of biopsies or extracts offer deeper insights by detecting more metabolites and resolving metabolites that cannot be distinguished in vivo. The pharmacokinetics of certain drugs, especially fluorinated drugs, can be directly measured in vivo. This review briefly describes these methods and their applications to cancer metabolism, including glycolysis, hypoxia, bioenergetics, tumor pH, and tumor responses to radiotherapy and chemotherapy. PMID: 22401303 [PubMed - indexed for MEDLINE] 332. Adv Exp Med Biol. 2012;728:25-40. doi: 10.1007/978-1-4614-0887-1_2. Klotho and βKlotho. Kuro-o M(1). Author information: (1)Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. makoto.kuro-o@utsouthwestern.edu Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. FGF21 is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. FGF23 is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases. PMID: 22396160 [PubMed - indexed for MEDLINE] 333. Nat Med. 2012 Mar 6;18(3):363-74. doi: 10.1038/nm.2627. The cellular and signaling networks linking the immune system and metabolism in disease. Osborn O(1), Olefsky JM. Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, University of California-San Diego, La Jolla, California, USA. It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries. Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation. Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver. PMID: 22395709 [PubMed - indexed for MEDLINE] 334. Gynecol Endocrinol. 2012 Mar;28 Suppl 1:27-32. doi: 10.3109/09513590.2012.651930. Neuroendocrine control of metabolism. Kuliczkowska-Plaksej J(1), Milewicz A, Jakubowska J. Author information: (1)Department of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland. kuliczk@interia.pl Metabolism is controlled through homeostatic system consisting of central centers, gut hormones, hormones from adipose tissue and the other hormonal axes. This cooperation is based on cross-talk between central and peripheral signals. Among them the hypothalamus plays a crucial role, with interconnected nuclei forming neuronal circuits. Other regions in the brain, such as the brain stem, the endocannabinoid system, the vagal afferents, are also involved in energy balance. The second component is peripheral source of signals--the gastrointestinal tract hormones. Additionally, adipokines from adipose tissue, thyrotropic, gonadotropic and somatotropic axes play a role in energy homeostasis. Knowledge about all components of this neuroendocrine circuit will be helpful in developing novel therapeutic approaches against the metabolic syndrome and its components. PMID: 22394301 [PubMed - indexed for MEDLINE] 335. Cold Spring Harb Perspect Med. 2012 Mar;2(3):a007724. doi: 10.1101/cshperspect.a007724. Connecting type 1 and type 2 diabetes through innate immunity. Odegaard JI(1), Chawla A. Author information: (1)Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. The escalating epidemic of obesity has driven the prevalence of both type 1 and 2 diabetes mellitus to historically high levels. Chronic low-grade inflammation, which is present in both type 1 and type 2 diabetics, contributes to the pathogenesis of insulin resistance. The accumulation of activated innate immune cells in metabolic tissues results in release of inflammatory mediators, in particular, IL-1β and TNFα, which promote systemic insulin resistance and β-cell damage. In this article, we discuss the central role of innate immunity and, in particular, the macrophage in insulin sensitivity and resistance, β-cell damage, and autoimmune insulitis. We conclude with a discussion of the therapeutic implications of this integrated understanding of diabetic pathology. PMCID: PMC3282495 PMID: 22393536 [PubMed - indexed for MEDLINE] 336. J Dermatol Sci. 2012 Apr;66(1):3-11. doi: 10.1016/j.jdermsci.2012.02.007. Epub 2012 Feb 24. Multi-layered environmental regulation on the homeostasis of stem cells: the saga of hair growth and alopecia. Chen CC(1), Chuong CM. Author information: (1)Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University and Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan. docs1.tw@yahoo.com.tw Stem cells are fascinating because of their potential in regenerative medicine. Stem cell homeostasis has been thought to be mainly regulated by signals from their adjacent micro-environment named the "stem cell niche". However, recent studies reveal that there can be multiple layers of environmental controls. Here we review these environmental controls using the paradigm of hair stem cells, because to observe and analyze the growth of hair is easier due to their characteristic cyclic regeneration pattern. The length of hair fibers is regulated by the duration of the growth period. In the hair follicles, hair stem cells located in the follicle bulge interact with signals from the dermal papilla. Outside of the follicle, activation of hair stem cells has been shown to be modulated by molecules released from the intra-dermal adipose tissue as well as body hormone status, immune function, neural activities, and aging. The general physiological status of an individual is further influenced by circadian rhythms and changing seasons. The interactive networks of these environmental factors provide new understanding on how stem cell homeostasis is regulated, inspiring new insights for regenerative medicine. Therapies do not necessarily have to be achieved by using stem cells themselves which may constitute a higher risk but by modulating stem cell activity through targeting one or multiple layers of their micro- and macro-environments. Copyright © 2012. Published by Elsevier Ireland Ltd. PMCID: PMC3684257 PMID: 22391240 [PubMed - indexed for MEDLINE] 337. Chronobiol Int. 2012 Apr;29(3):227-51. doi: 10.3109/07420528.2012.658127. Clock genes and clock-controlled genes in the regulation of metabolic rhythms. Mazzoccoli G(1), Pazienza V, Vinciguerra M. Author information: (1)Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy. g.mazzoccoli@operapadrepio.it Daily rotation of the Earth on its axis and yearly revolution around the Sun impose to living organisms adaptation to nyctohemeral and seasonal periodicity. Terrestrial life forms have developed endogenous molecular circadian clocks to synchronize their behavioral, biological, and metabolic rhythms to environmental cues, with the aim to perform at their best over a 24-h span. The coordinated circadian regulation of sleep/wake, rest/activity, fasting/feeding, and catabolic/anabolic cycles is crucial for optimal health. Circadian rhythms in gene expression synchronize biochemical processes and metabolic fluxes with the external environment, allowing the organism to function effectively in response to predictable physiological challenges. In mammals, this daily timekeeping is driven by the biological clocks of the circadian timing system, composed of master molecular oscillators within the suprachiasmatic nuclei of the hypothalamus, pacing self-sustained and cell-autonomous molecular oscillators in peripheral tissues through neural and humoral signals. Nutritional status is sensed by nuclear receptors and coreceptors, transcriptional regulatory proteins, and protein kinases, which synchronize metabolic gene expression and epigenetic modification, as well as energy production and expenditure, with behavioral and light-dark alternance. Physiological rhythmicity characterizes these biological processes and body functions, and multiple rhythms coexist presenting different phases, which may determine different ways of coordination among the circadian patterns, at both the cellular and whole-body levels. A complete loss of rhythmicity or a change of phase may alter the physiological array of rhythms, with the onset of chronodisruption or internal desynchronization, leading to metabolic derangement and disease, i.e., chronopathology. PMID: 22390237 [PubMed - indexed for MEDLINE] 338. Obes Rev. 2012 Jul;13(7):578-91. doi: 10.1111/j.1467-789X.2012.00988.x. Epub 2012 Mar 2. Resistance training, visceral obesity and inflammatory response: a review of the evidence. Strasser B(1), Arvandi M, Siebert U. Author information: (1)Institute for Nutritional Sciences and Physiology, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria. barbara.strasser@umit.at Intra-abdominal obesity is an important risk factor for low-grade inflammation, which is associated with increased risk for diabetes mellitus and cardiovascular disease. For the most part, recommendations to treat or prevent overweight and obesity via physical activity have focused on aerobic endurance training as it is clear that aerobic training is associated with much greater energy expenditure during the exercise session than resistance training. However, due to the metabolic consequences of reduced muscle mass, it is understood that normal ageing and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. Whether resistance training alters visceral fat and the levels of several pro-inflammatory cytokines produced in adipose tissue has not been addressed in earlier reviews. Because evidence suggests that resistance training may promote a negative energy balance and may change body fat distribution, it is possible that an increase in muscle mass after resistance training may be a key mediator leading to a better metabolic control. Considering the benefits of resistance training on visceral fat and inflammatory response, an important question is: how much resistance training is needed to confer such benefits? Therefore, the purpose of this review was to address the importance of resistance training on abdominal obesity, visceral fat and inflammatory response. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22385646 [PubMed - indexed for MEDLINE] 339. Adv Ther. 2012 Mar;29(3):249-66. doi: 10.1007/s12325-012-0004-1. Epub 2012 Feb 29. Exploring channeling optimized radiofrequency energy: a review of radiofrequency history and applications in esthetic fields. Belenky I(1), Margulis A, Elman M, Bar-Yosef U, Paun SD. Author information: (1)Clinical Department, Viora, Inc., Jersey City, NJ 07306, USA. inna@vioramed.com INTRODUCTION: Because of its high efficiency and safety, radiofrequency (RF) energy is widely used in the dermatological field for heating biological tissue in various esthetic applications, including skin tightening, skin lifting, body contouring, and cellulite reduction. This paper reviews the literature on the use of nonablative RF energy in the esthetic field and its scientific background. The purpose of this article is to describe in detail the extensive use of medical devices based on RF technology, the development of these medical devices over the years, and recent developments and trends in RF technology. METHODS: The authors conducted a systematic search of publications that address safety and efficacy issues, technical system specifications, and clinical techniques. Finally, the authors focused on their own clinical experiences with the use of patented Channeling Optimized RF Energy technique and mechanical massage. An in-vivo study was conducted in domestic pigs, with a thermal video camera. Twenty-seven female patients participated in a cellulite and body shaping study. The treatments were conducted according to a three-phase protocol. An additional 16 females participated in a skin tightening case study. All of the patients underwent three treatment sessions at 3-week intervals, each according to a protocol specific to the area being treated. RESULTS: The review of the literature on RF-based systems revealed that these systems are safe, with low risks for potential side effects, and effective for cellulite, body contouring, and skin tightening procedures. The in-vivo measurements confirmed the theory that the penetration depth of RF is an inverse function of its frequency, and using a vacuum mechanism makes an additional contribution to the RF energy penetration. The heating effect of RF was also found to increase blood circulation and to induce collagen remodeling. The results from the cellulite and body shaping treatments showed an overall average improvement of 55% in the appearance of cellulite, with an average circumferential reduction of 3.31 cm in the buttocks, 2.94 cm in the thighs, and 2.14 cm in the abdomen. The results from the skin tightening procedure showed moderate improvement of skin appearance in 50% and significant improvement in 31%. At the follow-up visits the results were found to be sustained without any significant side effects. CONCLUSION: Of all tissue heating techniques, RF-based technologies appear to be the most established and clinically proven. The design and specifications of the described vacuumassisted bipolar RF device fall within the range of the specifications currently prescribed for esthetic, nonablative RF systems. PMID: 22382873 [PubMed - indexed for MEDLINE] 340. Minerva Endocrinol. 2012 Mar;37(1):25-40. Neuroendocrine and endocrine dysfunction in the hyperinsulinemic PCOS patient: the role of metformin. Weickert MO(1), Hodges P, Tan BK, Randeva HS. Author information: (1)Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK. m.weickert@warwick.ac.uk Metformin is a widely used and extensively studied insulin sensitising drug for the treatment of women with polycystic ovary syndrome (PCOS), with various actions in tissues responding to insulin that include the liver, skeletal muscle, adipose tissue, the endothelium of blood vessels, and the ovaries. Treatment of PCOS women with metformin has been shown to reduce fasting glucose levels, blood pressure, and serum androgens; further effects of metformin in women with PCOS may include direct effects on the central nervous system; and indirect effects via the modification of gut hormone and adipokine synthesis and/or secretion. A number of "novel" adipokines and metabolic factors have been recently identified which may play a role both in the pathogenesis and the treatment of women with PCOS. We here discuss recent advances in the area, with a focus on neuroendocrine and endocrine dysfunctions in women with PCOS and the potential role of metformin in this context. PMID: 22382613 [PubMed - indexed for MEDLINE] 341. J Antimicrob Chemother. 2012 Jun;67(6):1305-10. doi: 10.1093/jac/dks066. Epub 2012 Mar 1. Altered vancomycin pharmacokinetics in obese and morbidly obese patients: what we have learned over the past 30 years. Grace E(1). Author information: (1)Presbyterian College School of Pharmacy, 307 North Broad Street, Clinton, SC 29325, USA. eegrace@presby.edu Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. Despite the numerous benefits of vancomycin, clinicians have struggled to dose vancomycin successfully in obese patients to achieve a therapeutic concentration for optimal bacterial killing. Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution of vancomycin in obese patients is likely to be altered compared with non-obese patients. In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins, which results in altered free serum vancomycin concentration. Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume, resulting in increased vancomycin clearance in obese patients. Vancomycin pharmacokinetics in the obese population remain an area of much debate, one that requires continued research given the rising number of obese patients in both the USA and worldwide. PMID: 22382471 [PubMed - indexed for MEDLINE] 342. Bratisl Lek Listy. 2012;113(1):52-6. Brown fat tissue - a potential target to combat obesity. Ginter E(1), Simko V. Author information: (1)Institute of Preventive and Clinical Medicine, Brtislava, Slovakia. ginter.emil@mail.t-com.sk From the global population perspective, the epidemic of "globesity" (more than one billion adults being overweight) represents one of the largest public health problems (1). Traditional reasoning related to the dysbalance between caloric intake and energy expenditure does not provide a satisfying explanation for a complexfailure to combat obesity. The brown adipose tisue (BAT) has a unique chemical structure and a specific metabolic role. A potential preventive co-factor is thermogenesis. BAT has the ability to dissipate energy byproducing heat, rather than storing energy as triglycerides. The cells of the white adipose tissue (WAT) contain one large globule of triglycerides which displaces the cell nucleus and other cell organelles excentrically, to the cell periphery. BAT contains numerous smaller droplets of triglycerides, much higher number of mitochondria and a specific uncoupling protein 1 or thermogenin. This specialized protein uncouples ATP production from mitochondrial respiration and converts energy into heat. Using sophisticated diagnostic techniques (e.g. imaging combination of positron-emisson tomography and computed tomography), scientists confirmed the importance of BAT not only in the newborn but also in adults who were found to possess considerable body stores of BAT.The highest proportion of BAT has been detected in lean individuals. As the body mass increases, BAT proportionately drops. Data both from animal and human studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity. Melatonin and arginine have been proposed as possible interventional tools. The scientific world eagerly awaits further advanced studies to document possible metabolic and pharmacologic interventions, using BAT as a primary target to prevent and manage obesity (Fig. 5, Ref. 41). PMID: 22380505 [PubMed - indexed for MEDLINE] 343. Int J Obes (Lond). 2013 Feb;37(2):163-6. doi: 10.1038/ijo.2012.28. Epub 2012 Feb 28. Activins in adipogenesis and obesity. Dani C(1). Author information: (1)Institute Biology of Valrose (iBV), CNRS/Inserm, Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, Cedex, France. dani@unice.fr Activins are secreted proteins members of the transforming growth factor-β family. They are involved in many biological responses including regulation of apoptosis, proliferation and differentiation of different cell types. Activins A, B and AB are highly expressed in adipose tissue, and in this review we will illustrate that activins have a role in several steps of physiological and pathological development of adipose tissue. Activin A has been shown to be a critical regulator of human adipocyte progenitor proliferation and a potent inhibitor of their differentiation. Activin A could also be a mediator of fibrosis observed in obese adipose tissue. Activin B/AB is proposed as a new adipokine having a role in energy balance and insulin insensitivity associated with obesity. Therefore, activin pathway could represent a potential therapeutic target both for controlling the size and the phenotype of the adipose precursor pool and for obesity-associated metabolic complications. PMID: 22370854 [PubMed - indexed for MEDLINE] 344. Int J Obes (Lond). 2012 Dec;36(12):1494-502. doi: 10.1038/ijo.2012.21. Epub 2012 Feb 28. Liver X receptors and fat cell metabolism. Laurencikiene J(1), Rydén M. Author information: (1)Karolinska Institutet, Department of Medicine (H7), Karolinska University Hospital, Huddinge, Sweden. Jurga.Laurencikiene@ki.se Liver X receptors (LXRs) are members of the nuclear receptor family and are present in two isoforms, α and β, encoded by two separate genes. Originally described in the liver, LXRs have in the last 15 years been implicated in central metabolic pathways, including bile acid synthesis, lipid and glucose homeostasis. Although the vast majority of studies have been performed in non-adipose cells/tissues, results in recent years suggest that LXRs may have important modulatory roles in adipose tissue and adipocytes. Although several authors have published reviews on LXR, there have been no attempts to summarize the effects reported specifically in adipose systems. This overview gives a brief introduction to LXR and describes the sometimes-contradictory results obtained in murine cell systems and in rodent adipose tissue. The so far very limited number of studies performed in human adipocytes and adipose tissue are also presented. It should be apparent that although LXR may impact on several different pathways in metabolism, the clinical role of LXR modulation in adipose tissue is still not clear. PMCID: PMC3520012 PMID: 22370853 [PubMed - indexed for MEDLINE] 345. Arch Pharm Res. 2012 Feb;35(2):213-21. doi: 10.1007/s12272-012-0202-z. Epub 2012 Feb 28. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Yi T(1), Song SU. Author information: (1)Clinical Research Center, Inha Research Institute, Inha University School of Medicine, Incheon 400-712, Korea. Mesenchymal stem cells (MSCs) are adult stem cells that can be isolated from most adult tissues, including bone marrow, adipose, liver, amniotic fluid, lung, skeletal muscle and kidney. The term MSC is currently being used to represent both mesenchymal stem cells and multipotent mesenchymal stromal cells. Numerous reports on systemic administration of MSCs leading to functional improvements based on the paradigm of engraftment and differentiation have been published. However, it is not only difficult to demonstrate extensive engraftment of cells, but also no convincing clinical results have been generated from phase 3 trials as of yet and prolonged responses to therapy have been noted after identification of MSCs had discontinued. It is now clear that there is another mechanism by which MSCs exert their reparative benefits. Recently, MSCs have been shown to possess immunomodulatory properties. These include suppression of T cell proliferation, influencing dendritic cell maturation and function, suppression of B cell proliferation and terminal differentiation, and immune modulation of other immune cells such as NK cells and macrophages. In terms of the clinical applications of MSCs, they are being tested in four main areas: tissue regeneration for cartilage, bone, muscle, tendon and neuronal cells; as cell vehicles for gene therapy; enhancement of hematopoietic stem cell engraftment; and treatment of immune diseases such as graft-versus-host disease, rheumatoid arthritis, experimental autoimmune encephalomyelitis, sepsis, acute pancreatitis and multiple sclerosis. In this review, the mechanisms of immunomodulatory effects of MSCs and examples of animal and clinical uses of their immunomodulatory effects are described. PMID: 22370776 [PubMed - indexed for MEDLINE] 346. Proc Nutr Soc. 2012 May;71(2):290-7. doi: 10.1017/S0029665112000079. Epub 2012 Feb 28. Effect of vitamin A deficiency on the immune response in obesity. García OP(1). Author information: (1)School of Natural Sciences, Universidad Autónoma de Querétaro, Av de la Ciencia S/N, Juriquilla, Querétaro 76230, Mexico. olga.garcia@uaq.mx Obesity has been associated with low-grade systemic inflammation and with micronutrient deficiencies. Obese individuals have been found to have lower vitamin A levels and lower vitamin A intake compared with normal-weight individuals. Vitamin A plays a major role in the immune function, including innate immunity, cell-mediated immunity and humoral antibody immunity. It has also been recognised recently that vitamin A has important regulatory functions. Vitamin A status has an important effect on the chronic inflammatory response. Vitamin A deficiency increases a T-helper type 1 (Th1) response, elevates levels of pro-inflammatory cytokines, increases the expression of leptin, resistin and uncoupling proteins (UCP) and promotes adipogenesis. The effect of vitamin A deficiency on obesity might be increasing the risk of fat deposition and also the risk of chronic inflammation associated with obesity. Supplementation with vitamin A in vitro and in animal models has been found to reduce concentrations of adipocytokines, such as leptin and resistin. In conclusion, vitamin A deficiency increases a Th1 response in the presence of obesity and thus, increases the inflammatory process involved in chronic inflammation and fat deposition. The metabolism of leptin and other adipocytokines may play a critical role in the effect of vitamin A deficiency in the inflammatory response observed in obesity. PMID: 22369848 [PubMed - indexed for MEDLINE] 347. Arch Toxicol. 2012 Sep;86(9):1337-48. doi: 10.1007/s00204-012-0814-6. Epub 2012 Feb 25. Cytokines in alcoholic liver disease. An L(1), Wang X, Cederbaum AI. Author information: (1)Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. Comment in Arch Toxicol. 2012 Sep;86(9):1331-2. Alcoholic liver disease (ALD) is associated with a spectrum of liver injury ranging from steatosis and steatohepatitis to fibrosis and cirrhosis. While multifactorial pathogenesis plays a role in the disease progression, enhanced inflammation in the liver during ethanol exposure is a major feature of ALD. Dysregulated cytokine metabolism and activity are crucial to the initiation of alcohol-induced liver injury. The pro-inflammatory cytokine tumor necrosis factor (TNF-α) has been demonstrated to be one of the key factors in the various aspects of pathophysiology of ALD. The immunomodulatory cytokines such as interleukin 10 and interleukin 6 play roles in exerting hepatic protective effects. Adiponectin is an adipose tissue-derived hormone, which displays protective actions on ethanol-induced liver injury. Treatment for mice with adiponectin decreases TNF-α expression, steatosis and prevents alcohol-induced liver injury. Adiponectin exerts its anti-inflammatory effects via suppression of TNF-α expression and induction of anti-inflammatory cytokines such as IL-10. Adiponectin attenuates alcoholic liver injury by the complex network of multiple signaling pathways in the liver, leading to enhanced fatty acid oxidation and reduced steatosis. Interactions between pro- and anti-inflammatory cytokines such as TNFα and adiponectin and other cytokines are likely to play important roles in the development and progression of alcoholic liver disease. PMID: 22367091 [PubMed - indexed for MEDLINE] 348. Vascul Pharmacol. 2012 May-Jun;56(5-6):204-9. doi: 10.1016/j.vph.2012.02.003. Epub 2012 Feb 15. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Eringa EC(1), Bakker W, van Hinsbergh VW. Author information: (1)Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. A small amount of adipose tissue associated with small arteries and arterioles is encountered both in mice and man. This perivascular adipose tissue (PVAT) has a paracrine effect on the vascular tone regulation. PVAT is expanded in obesity and in diabetes. This expansion not only involves enlargement of fat cells, but also the accumulation of inflammatory cells and a shift in the production of adipokines and cytokines. This effect is illustrated in this review by the effect of PVAT-derived factors of insulin-mediated vasoregulation in mouse resistance arteries. Insulin sensitivity of endothelial cells is also involved in the insulin-mediated regulation of muscle glucose uptake. Insulin affects vasoregulation by acting on different signaling pathways regulating NO and endothelin-1 release. This process is influenced by various adipokines and inflammatory mediators released from PVAT, and is affected by the degree of expansion and content of inflammatory cells. It is modulated by adiponectin (via 5' adenosine monophosphate-activated protein kinase, AMPK), TNFα (via c-jun N-terminal kinase) and free fatty acids (via protein kinase C-θ). PVAT thus provides an important site of control of vascular (dys)function in obesity and type 2 diabetes. An altered profile of adipokine and cytokine production by PVAT of resistance arteries may also contribute to or modulate hypertension, but a causal role in hypertension has still to be established. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22366250 [PubMed - indexed for MEDLINE] 349. Sheng Li Ke Xue Jin Zhan. 2011 Dec;42(6):467-71. [Research on MSTN coordination body fat and skeletal muscle cell proliferation and differentiation and energy metabolization balance]. [Article in Chinese] Ji YT, Qu CQ. PMID: 22363990 [PubMed - indexed for MEDLINE] 350. Environ Health Prev Med. 2012 Sep;17(5):348-56. doi: 10.1007/s12199-012-0271-0. Epub 2012 Feb 24. Preventive and improvement effects of exercise training and supplement intake in white adipose tissues on obesity and lifestyle-related diseases. Sakurai T(1), Ogasawara J, Kizaki T, Ishibashi Y, Sumitani Y, Takahashi K, Ishida H, Miyazaki H, Saitoh D, Haga S, Izawa T, Ohno H. Author information: (1)Department of Molecular Predictive Medicine and Sport Science, School of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan. sakutaku@ks.kyorin-u.ac.jp Recent increases in the number of obese individuals and individuals suffering from lifestyle-related diseases, such as type 2 diabetes, that accompany obesity have become a serious social problem. White adipose tissue (WAT) is more than a mere organ for storage of energy; it is also a highly active metabolic and endocrine organ that secretes physiologically active substances collectively known as adipokines, including tumor necrosis factor-α and adiponectin. Dysregulated expression of adipokines in WAT that is hypertrophied by obesity has been closely associated with the phenomenon of insulin resistance. Therefore, WAT is currently considered to be one of the tissues that promote lifestyle-related diseases. Reduction of excess WAT that results from obesity is seen as an important strategy in preventing and improving lifestyle-related diseases. This review shows that exercise training as well as intake of supplements, such as polyphenols, is one strategy for this, because this regimen can result in reduction of WAT mass, which affects the expression and secretory response of adipokines. PMCID: PMC3437364 PMID: 22362099 [PubMed - indexed for MEDLINE] 351. Curr Pharm Des. 2012;18(13):1821-45. Clinical applications and biosafety of human adult mesenchymal stem cells. Mariani E(1), Facchini A. Author information: (1)Laboratorio di Immunoreumatologia e Rigenerazione Tissutale and Laboratorio RAMSES, Rizzoli Orthopedic Institute, Bologna, Dipartimento di Medicina Clinica, University of Bologna, Italy. erminia.mariani@unibo.it Mesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases. PMID: 22352750 [PubMed - indexed for MEDLINE] 352. J Physiol. 2012 Apr 15;590(Pt 8):1787-801. doi: 10.1113/jphysiol.2011.221036. Epub 2012 Feb 20. Obesity and adipokines: effects on sympathetic overactivity. Smith MM(1), Minson CT. Author information: (1)Department of Human Physiology, University of Oregon, Eugene, OR 97403-1240, USA. Excess body weight is a major risk factor for cardiovascular disease, increasing the risk of hypertension, hyperglycaemia and dyslipidaemia, recognized as the metabolic syndrome. Adipose tissue acts as an endocrine organ by producing various signalling cytokines called adipokines (including leptin, free fatty acids, tumour necrosis factor-α, interleukin-6, C-reactive protein, angiotensinogen and adiponectin). A chronic dysregulation of certain adipokines can have deleterious effects on insulin signalling. Chronic sympathetic overactivity is also known to be present in central obesity, and recent findings demonstrate the consequence of an elevated sympathetic outflow to organs such as the heart, kidneys and blood vessels. Chronic sympathetic nervous system overactivity can also contribute to a further decline of insulin sensitivity, creating a vicious cycle that may contribute to the development of the metabolic syndrome and hypertension. The cause of this overactivity is not clear, but may be driven by certain adipokines. The purpose of this review is to summarize how obesity, notably central or visceral as observed in the metabolic syndrome, leads to adipokine expression contributing to changes in insulin sensitivity and overactivity of the sympathetic nervous system. PMCID: PMC3573303 PMID: 22351630 [PubMed - indexed for MEDLINE] 353. J Physiol Biochem. 2012 Dec;68(4):701-11. doi: 10.1007/s13105-012-0154-2. Epub 2012 Feb 17. Oxidative stress and inflammation interactions in human obesity. Bondia-Pons I(1), Ryan L, Martinez JA. Author information: (1)Department of Nutrition, Food Science, Physiology and Toxicology Research Building, University of Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain. Obesity is often characterized by increased oxidative stress and exacerbated inflammatory outcomes accompanying infiltration of immune cells in adipocytes. The oxidative stress machinery and inflammatory signaling are not only interrelated, but their impairment can lead to an inhibition of insulin responses as well as a higher risk of cardiovascular diseases and associated features. Mitochondria, in addition to energy transformation, play a role in apoptosis, cellular proliferation, as well as in the cellular redox state control. Under certain circumstances, protons are able to re-enter the mitochondrial matrix via different uncoupling proteins, disturbing free radical production by mitochondria. Disorders of the mitochondrial electron transport chain, over-generation of reactive oxygen species, and lipoperoxides or alterations in antioxidant defenses have been reported in situations of obesity and type-2 diabetes. On the other hand, obesity has been linked to a low grade pro-inflammatory state, in which impairments in the oxidative stress and antioxidant mechanism could be involved. The current scientific evidence highlights the need of investigating the interplay between oxidative stress and inflammation with obesity/diabetes onset as well as the interactions of such factors either as a cause or consequence of obesity. The signaling mediated by the activation of inflammatory markers or nuclear factor kappa β and other transcription factors as central regulators of inflammation are key issues to understanding oxidative stress responses in obesity. This review aims at summarizing the main mechanisms and interplay factors between oxidative stress and inflammation in human obesity according to the last 10 years of research in the field. PMID: 22351038 [PubMed - indexed for MEDLINE] 354. Sheng Li Xue Bao. 2012 Feb 25;64(1):96-100. [Effects of visfatin gene polymorphisms on glycolipid metabolism and exercise-induced weight reduction in obesity]. [Article in Chinese] Lai AP(1), Chen WH. Author information: (1)Physical Education Department of Zhejiang College of Sports, Hangzhou 311231, China. lap810@163.com Visfatin, also named nicotinamide phosphoribosyl transferase (NAMPT), is a cytokine secreted from adipose tissue. Visfatin can regulate immune action and is involved in the NAD+ salvage pathway. In addition, recent researches have shown that visfatin helps the regulation of glucose and lipid metabolism, especially in exercise-induced weight reduction for obesity. The aim of this review is to provide an overview of the contribution of visfatin gene polymorphisms to glucose and lipid metabolism and exercise-induced weight reduction in obesity. PMID: 22348967 [PubMed - indexed for MEDLINE] 355. World J Gastroenterol. 2012 Feb 7;18(5):393-400. doi: 10.3748/wjg.v18.i5.393. Estrogen, male dominance and esophageal adenocarcinoma: is there a link? Yang H, Sukocheva OA, Hussey DJ, Watson DI. Esophageal adenocarcinoma is a cancer with poor prognosis, and its incidence has risen sharply over recent decades. Obesity is a major risk factor for developing this cancer and there is a clear male gender bias in the incidence that cannot be fully explained by known risk factors. It is possible that a difference in the expression of estrogen, or its signaling axes, may contribute to this gender bias. We undertook a comprehensive literature search and analyzed the available data regarding estrogen and estrogen receptor expression, and the possible sex-specific links with esophageal adenocarcinoma development. Potentially relevant associations between visceral vs subcutaneous fat deposition and estrogen expression, and the effect of crosstalk between estrogen and leptin signaling were identified. We also found limited studies suggesting a role for estrogen receptor β expression in esophageal adenocarcinoma development. The current literature supports speculation on an etiological role for estrogen in the male gender bias in esophageal adenocarcinoma, but further studies are required. PMCID: PMC3270506 PMID: 22346245 [PubMed - indexed for MEDLINE] 356. Drug Discov Today. 2012 Jul;17(13-14):702-9. doi: 10.1016/j.drudis.2012.02.001. Epub 2012 Feb 10. Myostatin: more than just a regulator of muscle mass. Argilés JM(1), Orpí M, Busquets S, López-Soriano FJ. Author information: (1)Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. The presence of sufficient skeletal muscle mass is of paramount importance for body function and the myostatin cascade is known to inhibit muscle growth in mammals. In addition, myostatin seems to have an important role in the cross-talk between skeletal muscle and adipose tissue and is involved in insulin sensitivity. In this article we highlight the latest developments related to the myostatin system, emphasizing therapeutic implications for wasting diseases and also the involvement of the system in other organs, in addition to skeletal muscle, such as heart or adipose tissue. Moreover, we highlight the possible role of the myostatin system in the cross-talk between skeletal muscle and adipose tissue, an important aspect that deserves consideration in wasting diseases. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22342983 [PubMed - indexed for MEDLINE] 357. Biochimie. 2012 Oct;94(10):2172-9. doi: 10.1016/j.biochi.2012.01.021. Epub 2012 Feb 4. Adiponectin and leptin in human severe insulin resistance - diagnostic utility and biological insights. Groeneveld MP(1), Huang-Doran I, Semple RK. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. Further investigation of the cellular basis of insulin receptoropathy-related hyperadiponectinaemia may shine further light on the human pathobiology of this most abundant and enigmatic product of adipose tissue. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22342226 [PubMed - indexed for MEDLINE] 358. Rev Med Suisse. 2012 Jan 25;8(325):220-1. [The optimum weight...and how can it be reached and sustained ]. [Article in German] Imoberdorf R(1). Author information: (1)CA Klinik für Innere Medizin, Winterthur Kantonsspital, 8400 Winterthur. reinhard.imoberdorf@ksw.ch PMID: 22338524 [PubMed - indexed for MEDLINE] 359. Adv Nutr. 2011 Jul;2(4):304-16. doi: 10.3945/​an.111.000505. Epub 2011 Jun 28. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: mechanistic insights. Kalupahana NS(1), Claycombe KJ, Moustaid-Moussa N. Author information: (1)The University of Tennessee (UT) Obesity Research Center, Knoxville, TN 37996, USA. Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. PMCID: PMC3125680 PMID: 22332072 [PubMed - indexed for MEDLINE] 360. Adv Nutr. 2011 May;2(3):261-74. doi: 10.3945/an.111.000422. Epub 2011 Apr 30. Effects of adiposity on plasma lipid response to reductions in dietary saturated fatty acids and cholesterol. Flock MR(1), Green MH, Kris-Etherton PM. Author information: (1)Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Dietary SFA and cholesterol are major targets for reducing plasma total and LDL cholesterol as a strategy to decrease cardiovascular disease risk. However, many studies show that excess adiposity attenuates the expected lipid and lipoprotein response to a plasma cholesterol-lowering diet. Diets low in SFA and cholesterol are less effective in improving the lipid profile in obese individuals and in patients with metabolic syndrome. In contrast, lean persons are more responsive to reductions in dietary SFA and cholesterol. Multiple mechanisms likely contribute to the altered plasma lipid responses to dietary changes in individuals with excess adiposity. The greater rate of hepatic cholesterol synthesis in obese individuals suppresses the expression of hepatic LDL receptors (LDLR), thereby reducing hepatic LDL uptake. Insulin resistance develops as a result of adipose-tissue induced inflammation, causing significant changes in enzymes necessary for normal lipid metabolism. In addition, the LDLR-mediated uptake in obesity is attenuated by alterations in neuroendocrine regulation of hormonal secretions (e.g. growth hormone, thyroid hormone, and cortisol) as well as the unique gut microbiota, the latter of which appears to affect lipid absorption. Reducing adipose tissue mass, especially from the abdominal region, is an effective strategy to improve the lipid response to dietary interventions by reducing inflammation, enhancing insulin sensitivity, and improving LDLR binding. Thus, normalizing adipose tissue mass is an important goal for maximizing the diet response to a plasma cholesterol-lowering diet. PMCID: PMC3090171 PMID: 22332058 [PubMed - indexed for MEDLINE] 361. Nat Rev Endocrinol. 2012 Feb 14;8(6):352-62. doi: 10.1038/nrendo.2012.15. The genetics of familial combined hyperlipidaemia. Brouwers MC(1), van Greevenbroek MM, Stehouwer CD, de Graaf J, Stalenhoef AF. Author information: (1)Department of Internal Medicine and Endocrinology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands. Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes. PMID: 22330738 [PubMed - indexed for MEDLINE] 362. Curr Opin Endocrinol Diabetes Obes. 2012 Apr;19(2):81-7. doi: 10.1097/MED.0b013e3283514e13. What causes the insulin resistance underlying obesity? Hardy OT(1), Czech MP, Corvera S. Author information: (1)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. PURPOSE OF REVIEW: The association between obesity and insulin resistance is an area of much interest and enormous public health impact, with hundreds of articles being published in the last year focused on the possible mechanisms that underlie this association. The purpose to this review is to highlight some of the key recent literature with emphasis on emerging concepts. RECENT FINDINGS: The specific link between visceral adipose tissue accumulation and insulin resistance continues to be discerned. Visceral adiposity is correlated with accumulation of excess lipid in liver, and results in cell autonomous impairment in insulin signaling. Visceral adipose tissue is also prone to inflammation and inflammatory cytokine production, which also contribute to impairment in insulin signaling. The expansion of visceral adipose tissue and excess lipid accumulation in liver and muscle may result from limited expandability of subcutaneous adipose tissue, due to the properties of its extracellular matrix and capacity for capillary growth. SUMMARY: Recent studies underscore the need to better understand the mechanisms linking visceral adiposity with liver fat accumulation, the mechanisms by which ectopic fat accumulation cause insulin resistance, and the mechanisms by which the size of adipose tissue depots is determined. PMCID: PMC4038351 PMID: 22327367 [PubMed - indexed for MEDLINE] 363. Mol Med Rep. 2012 May;5(5):1135-40. doi: 10.3892/mmr.2012.785. Epub 2012 Feb 10. Gene expression of adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome (Review). Pérez PM(1), Moore-Carrasco R, González DR, Fuentes EQ, Palomo IG. Author information: (1)Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile. Metabolic syndrome is a combination of medical disorders including hypertension, dyslipidemia, hyperglycemia, insulin resistance and increased waist circumference, and is associated with a higher risk of cardiovascular disease. An increase in adipose tissue mass is associated with the augmented secretion of certain adipokines, such as interleukin-6, tumor necrosis factor-α and resistin, which cause endothelial dysfunction (an increase in vasoconstrictor molecules and in the expression of adhesion molecules as well as a decrease of vasodilator molecules, amongst other features) and hemostasis alterations that also favor a prothrombotic state (increased fibrinogen and plasminogen activator inhibitor-1 concentrations and platelet activation/aggregation). This interaction between adipose tissue, endothelial cells and platelets is associated with an increase or decrease in the expression of several transcription factors (peroxisome proliferator-activated receptors, CCAAT-enhancer-binding proteins, carbohydrate responsive element-binding proteins and sterol regulatory element-binding proteins) that play a crucial role in the regulation of distinct metabolic pathways related to the metabolic syndrome. In the present review, we present the primary changes in adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome and their possible target sites at the gene expression level. PMID: 22327350 [PubMed - indexed for MEDLINE] 364. Gastroenterology. 2012 Apr;142(4):711-725.e6. doi: 10.1053/j.gastro.2012.02.003. Epub 2012 Feb 8. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Cusi K(1). Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida 32610-0226, USA. kenneth.cusi@medicine.ufl.edu As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved. PMID: 22326434 [PubMed - indexed for MEDLINE] 365. J Androl. 2012 Sep-Oct;33(5):763-76. Epub 2012 Feb 9. Diet, obesity, and prostate health: are we missing the link? Tewari R(1), Rajender S, Natu SM, Dalela D, Goel A, Goel MM, Tandon P. Author information: (1)Department of Pathology, Chatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India. Prostate problems, such as benign prostatic hyperplasia, prostatic intra-epithelial neoplasia, prostatitis, and prostate cancer have been recognized as problems largely related to androgens and genetic factors. They affect a large fraction of the elderly population, contributing significantly to morbidity and mortality. Estrogen has also now been recognized as one of the important regulators of prostate growth. Diet, general health, and obesity were disregarded as the causative or complicating factors until very recently. Increasing episodes of prostate problems, complications in overweight/obese individuals, or both have attracted attention toward these contemporary risk factors. Prostate problems are reportedly less frequent or less severe in areas in which a plant-based diet is predominant. Consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. As adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems. Adipose tissue is now known to affect circulating levels of several bioactive messengers and therefore could affect the risk of developing prostate problems in addition to several other well-recognized health problems. Nevertheless, increased plasma volume, excess tissue growth, and fat deposition could affect resection and number of biopsies required, thus adding further complications because of a delayed diagnosis. In short, evidence is gathering to support the influence of diet and obesity on prostate health. In this review article, we have tried to make this connection more apparent using supporting published data. PMID: 22323623 [PubMed - indexed for MEDLINE] 366. Diabetes Obes Metab. 2012 Oct;14(10):869-81. doi: 10.1111/j.1463-1326.2012.01582.x. Epub 2012 Mar 8. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Pereira CD(1), Azevedo I, Monteiro R, Martins MJ. Author information: (1)Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, Portugal. Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases. © 2012 Blackwell Publishing Ltd. PMID: 22321826 [PubMed - indexed for MEDLINE] 367. Clin Liver Dis. 2012 Feb;16(1):95-131. doi: 10.1016/j.cld.2011.12.009. Epub 2012 Jan 23. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses. Periyalwar P(1), Dasarathy S. Author information: (1)Department of Gastroenterology, Metrohealth Medical Center, 2500 Metrohealth Drive, Cleveland, OH 44109, USA. Malnutrition is the most common, reversible complication of cirrhosis that adversely affects survival, response to other complications, and quality of life. Sarcopenia, or loss of skeletal muscle mass, and loss of adipose tissue and altered substrate use as a source of energy are the 2 major components of malnutrition in cirrhosis. Current therapies include high protein supplementation especially as a late evening snack. Exercise protocols have the potential of aggravating hyperammonemia and portal hypertension. Recent advances in understanding the molecular regulation of muscle mass has helped identify potential novel therapeutic targets including myostatin antagonists, and mTOR resistance. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC4383161 PMID: 22321468 [PubMed - indexed for MEDLINE] 368. Am J Physiol Endocrinol Metab. 2012 May 1;302(10):E1157-70. doi: 10.1152/ajpendo.00351.2011. Epub 2012 Feb 7. Update on adipose tissue blood flow regulation. Sotornik R(1), Brassard P, Martin E, Yale P, Carpentier AC, Ardilouze JL. Author information: (1)Diabetes and Metabolism Research Group, Division of Endocrinology, Department of Medicine, Centre Hospitalier, Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, Canada. According to Fick's principle, any metabolic or hormonal exchange through a given tissue depends on the product of the blood flow to that tissue and the arteriovenous difference. The proper function of adipose tissue relies on adequate adipose tissue blood flow (ATBF), which determines the influx and efflux of metabolites as well as regulatory endocrine signals. Adequate functioning of adipose tissue in intermediary metabolism requires finely tuned perfusion. Because metabolic and vascular processes are so tightly interconnected, any disruption in one will necessarily impact the other. Although altered ATBF is one consequence of expanding fat tissue, it may also aggravate the negative impacts of obesity on the body's metabolic milieu. This review attempts to summarize the current state of knowledge on adipose tissue vascular bed behavior under physiological conditions and the various factors that contribute to its regulation as well as the possible participation of altered ATBF in the pathophysiology of metabolic syndrome. PMID: 22318953 [PubMed - indexed for MEDLINE] 369. J Gastroenterol. 2012 Mar;47(3):215-25. doi: 10.1007/s00535-012-0527-x. Epub 2012 Feb 7. Inflammation and fibrogenesis in steatohepatitis. Fujii H(1), Kawada N. Author information: (1)Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan. Nonalcoholic fatty liver disease consists of a range of disorders characterized by excess accumulation of triglyceride within the liver. Whereas simple steatosis is clinically benign, nonalcoholic steatohepatitis (NASH) often progresses to cirrhosis. Inflammation and fibrogenesis are closely inter-related and are major targets of NASH research. Experimental data have shown that inflammation in NASH is caused by insulin resistance, systemic lipotoxicity due to overnutrition, lipid metabolites, the production of proinflammatory cytokines and adipokines by visceral adipose tissue, gut-derived bacteria, and oxidative stress. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is recognized as the hepatic stellate cell. Although the fibrotic mechanisms underlying NASH are largely similar to those observed in other chronic liver diseases, the altered patterns of circulating adipokines, the generation of oxidative stress, and the hormonal profile associated with the metabolic syndrome might play unique roles in the fibrogenesis associated with the disease. Information on the basic pathogenesis of NASH with a focus on the generation of inflammation and fibrosis will be discussed. PMID: 22310735 [PubMed - indexed for MEDLINE] 370. Lipids Health Dis. 2012 Feb 6;11:20. doi: 10.1186/1476-511X-11-20. Effects of sterol regulatory element-binding protein (SREBP) in chickens. Khesht FA(1), Hassanabadi A. Author information: (1)Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran. Alipour_387@yahoo.com Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2) are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens. PMCID: PMC3305589 PMID: 22309629 [PubMed - indexed for MEDLINE] 371. Cell Microbiol. 2012 May;14(5):634-43. doi: 10.1111/j.1462-5822.2012.01764.x. Epub 2012 Feb 24. Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Nagajyothi F(1), Machado FS, Burleigh BA, Jelicks LA, Scherer PE, Mukherjee S, Lisanti MP, Weiss LM, Garg NJ, Tanowitz HB. Author information: (1)Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. Trypanosoma cruzi infection leads to development of chronic Chagas disease. In this article, we provide an update on the current knowledge of the mechanisms employed by the parasite to gain entry into the host cells and establish persistent infection despite activation of a potent immune response by the host. Recent studies point to a number of T. cruzi molecules that interact with host cell receptors to promote parasite invasion of the diverse host cells. T. cruzi expresses an antioxidant system and thromboxane A(2) to evade phagosomal oxidative assault and suppress the host's ability to clear parasites. Additional studies suggest that besides cardiac and smooth muscle cells that are the major target of T. cruzi infection, adipocytes and adipose tissue serve as reservoirs from where T. cruzi can recrudesce and cause disease decades later. Further, T. cruzi employs at least four strategies to maintain a symbiotic-like relationship with the host, and ensure consistent supply of nutrients for its own survival and long-term persistence. Ongoing and future research will continue to help refining the models of T. cruzi invasion and persistence in diverse tissues and organs in the host. © 2012 Blackwell Publishing Ltd. PMCID: PMC3556388 PMID: 22309180 [PubMed - indexed for MEDLINE] 372. Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1539-45. doi: 10.1152/ajpheart.00626.2011. Epub 2012 Feb 3. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Algahim MF(1), Sen S, Taegtmeyer H. Author information: (1)Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA. Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology. PMCID: PMC3330804 PMID: 22307676 [PubMed - indexed for MEDLINE] 373. Physiol Rev. 2012 Jan;92(1):157-91. doi: 10.1152/physrev.00012.2011. Physical activity and exercise in the regulation of human adipose tissue physiology. Thompson D(1), Karpe F, Lafontan M, Frayn K. Author information: (1)Department for Health, University of Bath, Bath, UK. d.thompson@bath.ac.uk Physical activity and exercise are key components of energy expenditure and therefore of energy balance. Changes in energy balance alter fat mass. It is therefore reasonable to ask: What are the links between physical activity and adipose tissue function? There are many complexities. Physical activity is a multifaceted behavior of which exercise is just one component. Physical activity influences adipose tissue both acutely and in the longer term. A single bout of exercise stimulates adipose tissue blood flow and fat mobilization, resulting in delivery of fatty acids to skeletal muscles at a rate well-matched to metabolic requirements, except perhaps in vigorous intensity exercise. The stimuli include adrenergic and other circulating factors. There is a period following an exercise bout when fatty acids are directed away from adipose tissue to other tissues such as skeletal muscle, reducing dietary fat storage in adipose. With chronic exercise (training), there are changes in adipose tissue physiology, particularly an enhanced fat mobilization during acute exercise. It is difficult, however, to distinguish chronic "structural" changes from those associated with the last exercise bout. In addition, it is difficult to distinguish between the effects of training per se and negative energy balance. Epidemiological observations support the idea that physically active people have relatively low fat mass, and intervention studies tend to show that exercise training reduces fat mass. A much-discussed effect of exercise versus calorie restriction in preferentially reducing visceral fat is not borne out by meta-analyses. We conclude that, in addition to the regulation of fat mass, physical activity may contribute to metabolic health through beneficial dynamic changes within adipose tissue in response to each activity bout. PMID: 22298655 [PubMed - indexed for MEDLINE] 374. Ann Pharmacother. 2012 Feb;46(2):240-7. doi: 10.1345/aph.1Q629. Epub 2012 Jan 31. Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. Spooner LM(1), Olin JL. Author information: (1)School of Pharmacy-Worcester/Manchester, Massachusetts College of Pharmacy and Health Sciences, USA. linda.spooner@mcphs.edu OBJECTIVE: To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. DATA SOURCES: Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. DATA SYNTHESIS: In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. CONCLUSIONS: Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection. PMID: 22298602 [PubMed - indexed for MEDLINE] 375. Nutr Res Rev. 2011 Dec;24(2):206-27. doi: 10.1017/S0954422411000114. Human health effects of conjugated linoleic acid from milk and supplements. McCrorie TA(1), Keaveney EM, Wallace JM, Binns N, Livingstone MB. Author information: (1)Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Cromore Road, Coleraine, County Londonderry BT52 1SA, UK. t.mccrorie@ulster.ac.uk The primary purpose of the present review was to determine if the scientific evidence available for potential human health benefits of conjugated linoleic acid (CLA) is sufficient to support health claims on foods based on milk naturally enriched with cis-9, trans-11-CLA (c9, t11-CLA). A search of the scientific literature was conducted and showed that almost all the promising research results that have emerged in relation to cancer, heart health, obesity, diabetes and bone health have been in animal models or in vitro. Most human intervention studies have utilised synthetic CLA supplements, usually a 50:50 blend of c9, t11-CLA and trans-10, cis-12-CLA (t10, c12-CLA). Of these studies, the only evidence that is broadly consistent is an effect on body fat and weight reduction. A previous review of the relevant studies found that 3.2 g CLA/d resulted in a modest body fat loss in human subjects of about 0.09 kg/week, but this effect was attributed to the t10, c12-CLA isomer. There is no evidence of a consistent benefit of c9, t11-CLA on any health conditions; and in fact both synthetic isomers, particularly t10, c12-CLA, have been suspected of having pro-diabetic effects in individuals who are already at risk of developing diabetes. Four published intervention studies using naturally enriched CLA products were identified; however, the results were inconclusive. This may be partly due to the differences in the concentration of CLA administered in animal and human studies. In conclusion, further substantiation of the scientific evidence relating to CLA and human health benefits are required before health claims can be confirmed. PMID: 22296934 [PubMed - indexed for MEDLINE] 376. World J Gastroenterol. 2012 Jan 21;18(3):212-24. doi: 10.3748/wjg.v18.i3.212. Hepatitis C virus induced insulin resistance impairs response to anti viral therapy. El-Zayadi AR(1), Anis M. Author information: (1)Tropical Medicine Department, Faculty of Medicine, Ain-Shams University and Cairo liver center, Dokki, Giza 12311, Egypt. clcz@tedata.net.eg Hepatitis C virus (HCV) infection is an important risk factor for insulin resistance (IR). The latter is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhosis, and possibly hepatocellular carcinoma (HCC). The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of insulin receptor substrates 1 and 2, blocking intracellular insulin signaling. The latter is mediated by increased levels of both tumour necrosis factor-α (TNF-α) and suppressor of cytokine signaling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis and even HCC. In addition, IR has a role in impairing TNF signaling cascade, which in turn blocks STAT-1 translocation and interferon stimulated genes production avoiding the antiviral effect of interferon. PMCID: PMC3261538 PMID: 22294824 [PubMed - indexed for MEDLINE] 377. Cell Mol Life Sci. 2012 Jul;69(13):2135-46. doi: 10.1007/s00018-012-0917-5. A role for sphingolipids in the pathophysiology of obesity-induced inflammation. Bikman BT(1). Author information: (1)Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. benjamin_bikman@byu.edu Following the initial discovery that adipose tissue actively synthesizes and secretes cytokines, obesity-induced inflammation has been implicated in the etiology of a host of disease states related to obesity, including cardiovascular disease and type II diabetes. Interestingly, a growing body of evidence similarly implicates sphingolipids as prime instigators in these same diseases. From the recent discovery that obesity-related inflammatory pathways modulate sphingolipid metabolism comes a novel perspective—sphingolipids may act as the dominant mediators of deleterious events stemming from obesity-induced inflammation. This paradigm may identify sphingolipids as an effective target for future therapeutics aimed at ameliorating diseases associated with chronic inflammation. PMID: 22294100 [PubMed - indexed for MEDLINE] 378. Pathologe. 2012 Feb;33(1):61-4. doi: 10.1007/s00292-011-1547-7. [Granular cell tumor of the stomach]. [Article in German] Gilg MM(1), Mrak K, Vieth M, Langner C. Author information: (1)Institut für Pathologie, Medizinische Universität Graz, Auenbruggerplatz 25, 8036, Graz, Österreich. Granular cell tumors are peripheral neuroectodermal tumors. Within the gastrointestinal tract, they have to be differentiated from gastrointestinal stromal tumors (GIST). We present the case of a 61-year-old patient who was diagnosed with a granular cell tumor of the stomach. The tumor cells showed transmural infiltration form the mucosa into the adipose tissue of the lesser curvature. The tumor cells were diffusely positive for S100-protein and negative for KIT, CD34 und SMA. The MIB1-proliferation index was below 2%. Granular cell tumors rarely occur within the gastrointestinal tract. Oesophagus and colon are most commonly affected. Diagnostic criteria and differential diagnosis of this peculiar lesion are thoroughly discussed. PMID: 22293791 [PubMed - indexed for MEDLINE] 379. Gen Comp Endocrinol. 2012 May 15;177(1):28-36. doi: 10.1016/j.ygcen.2012.01.009. Epub 2012 Jan 28. Leptin and the hypothalamo-pituitary-adrenal stress axis. Roubos EW(1), Dahmen M, Kozicz T, Xu L. Author information: (1)Department of Cellular Animal Physiology, Faculty of Science, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, PO Box 9010, 6500 GL Nijmegen, The Netherlands. roubos@science.ru.nl Leptin is a 16-kDa protein mainly produced and secreted by white adipose tissue and informing various brain centers via leptin receptor long and short forms about the amount of fat stored in the body. In this way leptin exerts a plethora of regulatory functions especially related to energy intake and metabolism, one of which is controlling the activity of the hypothalamo-pituitary-adrenal (HPA) stress axis. First, this review deals with the basic properties of leptin's structure and signaling at the organ, cell and molecule level, from lower vertebrates to humans but with emphasis on rodents because these have been investigated in most detail. Then, attention is given to the various interactions of adipose leptin with the HPA-axis, at the levels of the hypothalamus (especially the paraventricular nucleus), the anterior lobe of the pituitary gland (action on corticotropes) and the adrenal gland, where it releases corticosteroids needed for adequate stress adaptation. Also, possible local production and autocrine and paracrine actions of leptin at the hypothalamic and pituitary levels of the HPA-axis are being considered. Finally, a schematic model is presented showing the ways peripherally and centrally produced leptin may modulate, via the HPA-axis, stress adaptation in conjunction with the control of energy homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22293575 [PubMed - indexed for MEDLINE] 380. Biochem Cell Biol. 2012 Apr;90(2):142-52. doi: 10.1139/o11-079. Epub 2012 Jan 31. Roles of vitamin A status and retinoids in glucose and fatty acid metabolism. Zhao S(1), Li R, Li Y, Chen W, Zhang Y, Chen G. Author information: (1)The Diabetes Center, Wuhan Central Hospital, Wuhan, Hubei 430014, China. The rising prevalence of metabolic diseases, such as obesity and diabetes, has become a public health concern. Vitamin A (VA, retinol) is an essential micronutrient for a variety of physiological processes, such as tissue differentiation, immunity, and vision. However, its role in glucose and lipid metabolism has not been clearly defined. VA activities are mediated by the metabolite of retinol catabolism, retinoic acid, which activates the retinoic acid receptor and retinoid X receptor (RXR). Since RXR is an obligate heterodimeric partner for many nuclear receptors involved in metabolism, it is reasonable to assume that VA status and retinoids contribute to glucose and lipid homeostasis. To date, the impacts of VA and retinoids on energy metabolism in animals and humans have been demonstrated in some basic and clinical investigations. This review summarizes the effects of VA status and retinoid treatments on metabolism of the liver, adipocytes, pancreatic β-cells, and skeletal muscle. It proposes a mechanism by which the dietary and hormonal signals converge on the promoter of sterol regulatory element-binding protein 1c gene to induce its expression, and in turn, the expression of lipogenic genes in hepatocytes. Future research projects relevant to the VA's roles in metabolic diseases are also discussed. PMID: 22292422 [PubMed - indexed for MEDLINE] 381. Korean J Gastroenterol. 2012 Jan;59(1):16-26. [Obesity and colorectal cancer]. [Article in Korean] Na SY(1), Myung SJ. Author information: (1)Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer. PMID: 22289950 [PubMed - indexed for MEDLINE] 382. Korean J Gastroenterol. 2012 Jan;59(1):8-15. [Obesity and gastrointestinal cancer-related factor]. [Article in Korean] Kim DJ(1). Author information: (1)Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Seoul, Korea. djkim@paik.ac.kr Despite a higher incidence and less favorable outcome of malignant tumors in obese patients, much less recognized is the link between obesity and cancer. The mechanism of the association of obesity with carcinogenesis remains incompletely understood. Postulated mechanisms include insulin resistance, insulin-like growth factor signaling, chronic inflammation, immunomodulation, hyperglycemia-induced oxidative stress, and changes of intestinal microbiome. Insulin resistance leads to direct mitogenic and antiapoptotic signaling by insulin and the insulin-like growth factor axis. Obesity can be considered to be a state of chronic low-grade inflammation. In obesity, numerous proinflammatory cytokines are released from adipose tissue which may involve in carcinogenesis. Hyperglycemia in susceptible cells results in the overproduction of superoxide and this process is the key to initiating all damaging pathways related to diabetes. This hyperglycemia-induced oxidative stress could be one possible link among obesity, diabetes, and cancer development. The role of obesity-related changes in the intestinal microbiome in gastrointestinal carcinogenesis deserves further attention. PMID: 22289949 [PubMed - indexed for MEDLINE] 383. Biochim Biophys Acta. 2012 Apr;1825(2):207-22. doi: 10.1016/j.bbcan.2012.01.002. Epub 2012 Jan 24. Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. Guo S(1), Liu M, Wang G, Torroella-Kouri M, Gonzalez-Perez RR. Author information: (1)Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA. Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e., canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts. Copyright © 2012 Elsevier B.V. All rights reserved. PMCID: PMC3307887 PMID: 22289780 [PubMed - indexed for MEDLINE] 384. Biofactors. 2012 Jan-Feb;38(1):14-23. doi: 10.1002/biof.201. Epub 2012 Jan 30. Adipokines, an adipose tissue and placental product with biological functions during pregnancy. D'Ippolito S(1), Tersigni C, Scambia G, Di Simone N. Author information: (1)Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. Latter half of pregnancy is characterized by a "physiological diabetogenic state" since changes in insulin-sensitivity have been well documented. These changes ensure continuous supply of nutrients to the growing fetus. In the last years the role of adipocyte-derived signaling molecules, collectively known as adipokines has been object of different in vitro and in vivo studies. Of interest, adipokines and/or their receptors are expressed in the placental tissue which, therefore, can contribute to development of maternal insulin-resistance and, as a consequence, fetal growth. Leptin, adiponectin, and resistin represent the most well studied adipokines and, with the exception of adiponectin, their serum and placental levels increase as pregnancy progresses. High levels of adipokines have also been detected in umbilical plasma hence suggesting a possible role on fetal development and metabolism; however, it remains still unclear if such adipokines can directly stimulate fetal tissues development acting as growth factors. In addition to their well known metabolic effects, we also reported studies describing the role of adipokines in promoting proliferation and invasiveness of trophoblast cells and affecting local angiogenic processes. These observations strongly suggest that adipokines, by alternatively interfering with placental development, may affect pregnancy outcome and fetal growth. However, further studies are needed to better understand the local regulation of their expression. © 2012 International Union of Biochemistry and Molecular Biology, Inc. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc. PMID: 22287297 [PubMed - indexed for MEDLINE] 385. Obesity (Silver Spring). 2012 May;20(5):923-31. doi: 10.1038/oby.2011.398. Epub 2012 Jan 26. Adipose tissue as a potential source of hematopoietic stem/progenitor cells. Błogowski W(1), Ratajczak MZ, Zyżniewska-Banaszak E, Dołęgowska B, Starzyńska T. Author information: (1)Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland. drannab@wp.pl It has been more than 30 years since adipose tissue (AT) has been recognized as a central modulator orchestrating sophisticated process termed "immunometabolism". Nonetheless, despite its unique involvement in the regulation of immune and endocrine homeostasis, recent studies demonstrated that AT also contains significant number of hematopoietic stem/progenitor cells (HSPCs) that may be there "settling down" throughout life. In this article we will focus on presenting the current concepts regarding endocrine, immunological, and molecular mechanisms that may contribute to and regulate bone marrow (BM)-derived HSPCs homing into AT environment, as well as, highlight various structural and morphological similarities between BM and AT that might be involved in creating appropriate tissue niches for BM-derived HSPCs in AT. Finally, we will discuss how development of obesity or type 2 diabetes may influence balance of homing signals for HSPCs in AT environment. PMID: 22282043 [PubMed - indexed for MEDLINE] 386. Curr Opin Lipidol. 2012 Apr;23(2):111-21. doi: 10.1097/MOL.0b013e3283508c4f. Bone marrow transplantation as an established approach for understanding the role of macrophages in atherosclerosis and the metabolic syndrome. Aparicio-Vergara M(1), Shiri-Sverdlov R, Koonen DP, Hofker MH. Author information: (1)Molecular Genetics, Medical Biology Section, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. PURPOSE OF REVIEW: Bone marrow transplantation (BMT) technology is a firmly established tool for studying atherosclerosis. Only recently it is helping us to understand the inflammatory mechanisms leading to the development of obesity, insulin resistance and type 2 diabetes. Here we review the use of BMT as a tool for studying the metabolic syndrome. RECENT FINDINGS: Bone marrow-derived cells, and particularly monocytes and macrophages, have been a major subject in the study of atherogenesis, and they are highly amenable for research purposes because of their application in bone marrow transplantations. For example, the many pathways studied using BMT have helped unmask ABC transporters as the genes controlling reverse cholesterol transport and foam cell formation, as well as other genes like CCR2 and IκBα controlling leukocyte development, migration and activation. The invasion of leukocytes, not only in the vessel wall, but also in adipose tissue and liver, shares many common mechanisms relevant to atherosclerosis and metabolic diseases. SUMMARY: BMT is an efficient and versatile tool for assessing the roles of specific genes that are restricted to hematopoietic cells, and especially the monocytes and macrophages in metabolic syndrome and its related pathologies. PMID: 22274753 [PubMed - indexed for MEDLINE] 387. J Burn Care Res. 2012 Jul-Aug;33(4):471-82. doi: 10.1097/BCR.0b013e318247959b. Obesity and burns. Goutos I(1), Sadideen H, Pandya AA, Ghosh SJ. Author information: (1)Department of Plastic and Reconstructive Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom. The population of overweight patients presenting to burn facilities is expected to increase significantly over the next decades due to the global epidemic of obesity. Excess adiposity mediates alterations to key physiological responses and poses challenges to the optimal management of burns. The purpose of this study is to document the general epidemiological aspects of thermal injuries in the obese population, outline relevant physiological aspects associated with obesity, and draw attention to topics relating to the management, rehabilitation, and prognosis of burns in this emerging subpopulation of patients. PMID: 22274633 [PubMed - indexed for MEDLINE] 388. J Physiol. 2012 Mar 1;590(Pt 5):1059-68. doi: 10.1113/jphysiol.2011.225011. Epub 2012 Jan 23. Regulation and limitations to fatty acid oxidation during exercise. Jeppesen J(1), Kiens B. Author information: (1)Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Denmark. Fatty acids (FAs) as fuel for energy utilization during exercise originate from different sources: FAs transported in the circulation either bound to albumin or as triacylglycerol (TG) carried by very low density lipoproteins and FAs from lipolysis of muscle TG stores. Despite a high rate of energy expenditure during high intensity exercise the total FA oxidation is suppressed to below that observed during moderate intensity exercise. Although this has been known for many years, the mechanisms behind this phenomenon are still not fully elucidated. A failure of adipose tissue to deliver sufficient FAs to exercising muscle has been proposed, but evidence is emerging that factors within the muscle might be of more importance. The high rate of glycolysis during high intensity exercise might be the 'driving force' via the increased production of acetyl-CoA, which in turn is trapped by carnitine. This will lead to decreased availability of free carnitine for long chain FA transport into mitochondria. This review summarizes our present view on how FA metabolism is regulated during exercise with a special focus on the limitations in FA oxidation in the transition from moderate to high intensity exercise in humans. PMCID: PMC3381814 PMID: 22271865 [PubMed - indexed for MEDLINE] 389. Semin Reprod Med. 2012 Jan;30(1):14-22. doi: 10.1055/s-0031-1299593. Epub 2012 Jan 23. Tissue-specific regulation of genes by estrogen receptors. Leitman DC(1), Paruthiyil S, Yuan C, Herber CB, Olshansky M, Tagliaferri M, Cohen I, Speed TP. Author information: (1)Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA. dale@leitmanlab.com Estrogens are frequently used in reproductive medicine. The Women's Health Initiative trial found that the risks of menopausal hormone therapy (MHT) exceed the benefits. The estrogens in MHT, however, were introduced prior to our understanding of the mechanism of action of estrogens. Estrogen signaling is highly complex, involving various DNA regulatory elements to which estrogen receptors bind. Numerous transcription factors and co-regulatory proteins modify chromatin structure to further regulate gene transcription. With a greater understanding of estrogen action, the major problem with the current estrogens in MHT appears to be that they are nonselective. This produces beneficial effects in bone, brain, and adipose tissue but increases the risk of breast and endometrial cancer and thromboembolism. Resurrecting MHT for long-term therapy will require the development of more selective estrogens, such as estrogen receptor (ER)β-selective estrogens and tissue-selective ERα agonists. These compounds will offer the best prospects to expand the indications of MHT and thus prevent the chronic conditions associated with menopause. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PMID: 22271290 [PubMed - indexed for MEDLINE] 390. Cell Mol Neurobiol. 2012 Jul;32(5):645-59. doi: 10.1007/s10571-011-9793-z. Epub 2012 Jan 24. NPY and stress 30 years later: the peripheral view. Hirsch D(1), Zukowska Z. Author information: (1)Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA. dalay.hirsch@gmail.com Almost 30 years ago, neuropeptide Y (NPY) was discovered as a sympathetic co-transmitter and one of the most evolutionarily conserved peptides abundantly present all over the body. Soon afterward, NPY's multiple receptors were characterized and cloned, and the peptide's role in stress was first documented. NPY has proven to be pivotal for maintaining many stress responses. Most notably, NPY is known for activating long-lasting vasoconstriction in many vascular beds, including coronary arteries. More recently, NPY was found to play a role in stress-induced accretion of adipose tissue which many times can lead to detrimental metabolic changes. It is however due to its prominent actions in the brain, one of which is its powerful ability to stimulate appetite as well as its anxiolytic activities that NPY became a peptide of importance in neuroscience. In contrast, its actions in the rest of the body, including its role as a stress mediator, remained, surprisingly underappreciated and not well understood. Our research has focused on that other, "peripheral" side of NPY. In this review, we will discuss those actions of NPY on the cardiovascular system and metabolism, as they relate to adaptation to stress, and attempt to both distinguish NPY's effects from and integrate them with the effects of the classical stress mediators, glucocorticoids, and catecholamines. To limit the bias of someone (ZZ) who has viewed the world of stress through the eyes of NPY for over 20 years, fresh insight (DH) has been solicited to more objectively assess NPY's contributions to stress-related diseases and the body's ability to adapt to stress. PMCID: PMC3492947 PMID: 22271177 [PubMed - indexed for MEDLINE] 391. J Mol Med (Berl). 2012 May;90(5):523-34. doi: 10.1007/s00109-012-0861-8. Epub 2012 Jan 22. Evolutionary medicine and chronic inflammatory state--known and new concepts in pathophysiology. Straub RH(1). Author information: (1)Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de During the last 10 years, a series of exciting observations has led to a new theory of pathophysiology using insights from evolutionary biology and neuroendocrine immunology to understand the sequelae of chronic inflammatory disease. According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system. These disease sequelae are highly diverse and include the following: sickness behavior, anorexia, malnutrition, muscle wasting-cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue near inflamed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, hypertension, inflammation-related anemia, and osteopenia. Since these disease sequelae can be found in many animal models of chronic inflammatory diseases with mammals (e.g., monkeys, mice, rats, rabbits, etc.), the evolutionary time line goes back at least 70 million years. While the initial version of this theory could explain prominent sequelae of chronic inflammatory disease, it did not however address two features important in the pathogenesis of immune-mediated diseases: the time point when an acute inflammatory disease becomes chronic, and the appearance of hypertension in chronic inflammation. To address these aspects more specifically, a new version of the theory has been developed. This version defines more precisely the moment of transition from acute inflammatory disease to chronic inflammatory disease as a time in which energy stores become empty (complete energy consumption). Depending on the amount of stored energy, this time point can be calculated to be 19-43 days. Second, the revised theory addresses the mechanisms of essential hypertension since, on the basis of water loss, acute inflammatory diseases can stimulate water retention using a positively selected water retention system (identical to the energy provision system). In chronic smoldering inflammation, however, there is no increased water loss. In contrast, there is increased water generation in inflamed tissue and inflammatory cells, and the activation of the water retention system persists. This combination leads to a net increase of the systemic fluid volume, which is hypothesized to be the basis of essential hypertension (prevalence in adults 22-32%). PMCID: PMC3354326 PMID: 22271169 [PubMed - indexed for MEDLINE] 392. J Burn Care Res. 2012 May-Jun;33(3):e101-7. doi: 10.1097/BCR.0b013e318239c5d7. Spontaneous human combustion in the light of the 21st century. Koljonen V(1), Kluger N. Author information: (1)Department of Plastic Surgery, Töölö Hospital, University of Helsinki, Helsinki, Finland. The term "spontaneous human combustion" refers to a situation when a human body is found with significant portions of the middle parts of the body reduced to ashes, much less damage to the head and extremities, and minimal damage to the direct surroundings of the body. Typically, no observable source of ignition is found in the vicinity of the victim and a bad smelling oily substance is noted. In the past, such a situation was erroneously attributed to supernatural powers, as such phenomenon occurs in the absence of any witness. The purpose of this review article was to analyze articles published from January 1, 2000, on this unique type of burn injury. Further aims were to gather and present data on the causes and events leading to this situation. The literature was reviewed with PubMed interface using the key words spontaneous human combustion and preternatural combustion. Specific inclusion criteria resulted in 12 patients. A unique sequence of events takes place for the human body to incinerate to ashes. The flame burn victim has to die for the body fat to start melting. A tear in the skin has to occur for the melted fat to impregnate the charred clothes, igniting a wick effect that produces localized heat for extended period. A phenomenon called spontaneous human combustion is reality. The term "spontaneous human combustion" has nuances which are not applicable to this situation or to these modern times, therefore we suggest a new term "fat wick burns." PMID: 22269823 [PubMed - indexed for MEDLINE] 393. Brain Behav Immun. 2012 Jul;26(5):691-8. doi: 10.1016/j.bbi.2012.01.004. Epub 2012 Jan 17. Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis. Cluny NL(1), Reimer RA, Sharkey KA. Author information: (1)Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22269477 [PubMed - indexed for MEDLINE] 394. Dermatol Surg. 2012 Jul;38(7 Pt 2):1112-27. doi: 10.1111/j.1524-4725.2011.02291.x. Epub 2012 Jan 23. Hand rejuvenation: a review and our experience. Fabi SG(1), Goldman MP. Author information: (1)Goldman, Butterwick, Fitzpatrick, and Groff Cosmetic Laser Dermatology, San Diego, CA 92121, USA. sgfabi@gmail.com BACKGROUND: The aged hand is characterized by cutaneous and dermal atrophy, with deep intermetacarpal spaces, prominent bones and tendons, and bulging reticular veins. Epidermal changes include solar lentigines, seborrheic keratoses, actinic keratoses, skin laxity, rhytides, tactile roughness, and telangiectasia. STUDY DESIGN: A Medline search was performed on hand rejuvenation from 1989 to 2011, and results are summarized. Practical applications of these procedures are also discussed. RESULTS: Reports of injectable hyaluronic acid, calcium hydroxylapatite, poly-L-lactic acid, autologous fat transfer, vein treatment, and chemical peels, along with lasers and light sources such as Q-switched laser, intense pulsed light, photodynamic therapy, nonablative resurfacing lasers, and ablative resurfacing lasers, in the rejuvenation of hands were found. CONCLUSION: Review of the literature revealed options for minimally invasive treatment for rejuvenation of the skin and volume restoration of the dorsal hand. These treatments include injectables and fat transfer for volume restoration; sclerotherapy or vein ablation for dorsal hand vein treatment; and chemical peels, lasers, light, and energies for the treatment of epidermal and dermal changes. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. PMID: 22268976 [PubMed - indexed for MEDLINE] 395. Curr Diabetes Rev. 2012 Mar;8(2):131-43. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F(1), Aversa A, Isidori AM, Gooren LJ. Author information: (1)Bayer Pharma, Scientific Affairs Men’s Healthcare, Berlin, Germany. Farid.Saad@bayer.com OBJECTIVE: Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity. METHODS: EVIDENCE ACQUISITION AND SYNTHESIS: A literature search in PubMed on the role of T in counteracting obesity and its complications. RESULTS: Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights. CONCLUSION: While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity. © 2012 Bentham Science Publishers PMCID: PMC3296126 PMID: 22268394 [PubMed - indexed for MEDLINE] 396. Prog Lipid Res. 2012 Jul;51(3):267-71. doi: 10.1016/j.plipres.2011.12.004. Epub 2012 Jan 13. Novel qualitative aspects of tissue fatty acids related to metabolic regulation: lessons from Elovl6 knockout. Shimano H(1). Author information: (1)Department of Internal Medicine-Endocrinology and Metabolism, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. hshimano@md.tsukuba.ac.jp Insulin resistance, often associated with obesity, precipitates metabolic syndrome, type 2 diabetes, and finally, atherosclerosis. Sources of excess energy cause abnormal accumulation of tissue lipids leading to cellular dysfunction through cellular stress and inflammation. This process is often referred to as lipotoxicity. Until date, effective approaches that aim to overcome insulin resistance involve amelioration of obesity by caloric restriction and/or exercise. Quantitative control of lipids, especially triglycerides and fatty acids in adipose and other tissues, and plasma can be addressed using these measures. However, altering tissue lipid composition may provide another strategy to prevent or control lipotoxicity. Endogenous fatty acid synthesis plays a crucial role in determining tissue energy states. As a target gene of SREBP-1 that controls lipogenesis we identified a unique enzyme, Elovl6, which is responsible for the final step in endogenous saturated fatty acid synthesis, thereby controlling tissue fatty acid composition. Elovl6-deficient mice become obese and develop hepatosteatosis when fed a high-fat diet or when mated to leptin-deficient ob/ob mice. However, the mice exhibited marked protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia. Hepatic fatty acid composition is a novel determinant of insulin sensitivity independent of cellular energy balance. Inhibiting Elovl6 activity may provide a novel therapeutic approach for treating insulin resistance, diabetes, metabolic syndrome, and cardiovascular risks by circumventing obesity problems. In this review, we consider fatty acid metabolism and lipotoxicity, and discuss the role of Elovl6 in newly recognized aspects of metabolic regulation. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22266797 [PubMed - indexed for MEDLINE] 397. Nutr Metab Cardiovasc Dis. 2012 Feb;22(2):81-7. doi: 10.1016/j.numecd.2011.11.001. Epub 2012 Jan 21. Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives. Muscogiuri G(1), Sorice GP, Ajjan R, Mezza T, Pilz S, Prioletta A, Scragg R, Volpe SL, Witham MD, Giaccari A. Author information: (1)Endocrinologia e Malattie del Metabolismo, Università Cattolica, Rome, Italy. giovanna.muscogiuri@edu.rm.unicatt.it Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22265795 [PubMed - indexed for MEDLINE] 398. Best Pract Res Clin Rheumatol. 2011 Dec;25(6):779-84. doi: 10.1016/j.berh.2011.11.009. Joint appendages: the structures which have historically been overlooked in arthritis research and therapy development. Ash Z(1), McGonagle D. Author information: (1)Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, UK. Z.Ash@leeds.ac.uk Rheumatologists have largely conceptualised joint disease in inflammatory and degenerative arthritis in terms of bone, cartilage and the synovial lining, but have tended to overlook other integral components of the joints which are attached close to joint margins. We discuss these structures under the umbrella term of 'appendages'. These structures include ligaments, tendons, entheses or joint insertions, regional fibrocartilages, bursae and other peri-articular joint structures including fat pads and nails. In this review, we highlight how these structures play key pathophysiological roles in inflammatory arthritis and we emphasise how an understanding of these structures is collectively important for both clinical practice and future rheumatological research. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22265260 [PubMed - indexed for MEDLINE] 399. Semin Immunol. 2012 Feb;24(1):67-74. doi: 10.1016/j.smim.2011.11.011. Epub 2012 Jan 20. Immuno-microbiota cross and talk: the new paradigm of metabolic diseases. Burcelin R(1), Garidou L, Pomié C. Author information: (1)Institut National de la Santé et de la Recherche Médicale, U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), BP 84225, 31432 Toulouse, France. remy.burcelin@inserm.fr Over the last decades the rising occurrence of metabolic diseases throughout the world points to the failure of preventive and therapeutic strategies and of the corresponding molecular and physiological concepts. Therefore, a new paradigm needs to be elucidated. Very recently the intimate cross talk of the intestinal microbiota with the host immune system has opened new avenues. The large diversity of the intestinal microbes' genome, i.e. the metagenome, and the extreme plasticity of the immune system provide a unique balance which, when finely tuned, maintains a steady homeostasis. The discovery that a new microbiota repertoire is one of the causes responsible for the onset of metabolic disease suggests that the relationship with the immune system is impaired. Therefore, we here review the recent arguments that support the view that an alteration in the microbiota to host immune system balance leads to an increased translocation of bacterial antigens towards metabolically active tissues, and could result in a chronic inflammatory state and consequently impaired metabolic functions such as insulin resistance, hepatic fat deposition, insulin unresponsiveness, and excessive adipose tissue development. This imbalance could be at the onset of metabolic disease, and therefore the early treatment of the microbiota dysbiosis or immunomodulatory strategies should prevent and slow down the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences. Copyright © 2011. Published by Elsevier Ltd. PMID: 22265028 [PubMed - indexed for MEDLINE] 400. Cesk Fysiol. 2011;60(2):40-7. [Insulin resistance and nitric oxide: molecular mechanisms and pathophysiological associations]. [Article in Czech] Tousková V(1), Haluzík M. Author information: (1)Univerzita Karlova, 1. lékarská fakulta a VFN v Praze, III. interní klinika, Praha. Vera.Touskova@vfn.cz Subclinical inflammation that primarily arises in adipose tissue as a result of its excessive infiltration by immunocompetent cells represents one of the typical etiopathogenetic mechanisms underlying the development of insulin resistance and type 2 diabetes. Immunocompetent cells together with adipocytes are a major source of proinflammatory cytokines triggering proinflammatory cascades that in turn interfere with postreceptor insulin signalling cascade. Recent studies have suggested that inducible nitric oxide synthase plays a key role in this process. Obesity is associated with increased inducible nitric oxide synthase mRNA expression, with subsequent overproduction of nitric oxide and reactive nitrogen species leading to S-nitrosylation of proteins involved in insulin signalling cascade. These post-translational modifications decrease their activity and eventually lead to insulin resistance. Number of experimental studies demonstrated that inhibition of inducible nitric oxide synthase attenuates insulin resistance. The aim of this review is to summarize the current knowledge about the physiology and patophysiology of nitric oxide and inducible nitric oxide synthase with respect to its relationship to insulin resistance and to discuss the possibility of improvement of insulin resistance and type 2 diabetes mellitus by modulating inducible nitric oxide synthase activity. PMID: 22263324 [PubMed - indexed for MEDLINE] 401. Gerontology. 2012;58(4):337-43. doi: 10.1159/000335166. Epub 2012 Jan 18. Healthy aging: is smaller better? - a mini-review. Bartke A(1). Author information: (1)Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, 62794-9628, USA. abartke@siumed.edu A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth. Copyright © 2012 S. Karger AG, Basel. PMCID: PMC3893695 PMID: 22261798 [PubMed - indexed for MEDLINE] 402. Orv Hetil. 2012 Jan 29;153(4):125-36. doi: 10.1556/OH.2012.29287. [Interactions of insulin and estrogen in the regulation of cell proliferation and carcinogenesis]. [Article in Hungarian] Suba Z(1), Kásler M. Author information: (1)Országos Onkológiai Intézet Sebészeti és Molekuláris Tumorpatológiai Osztály Budapest Ráth György u. subazdr@gmail.com Equilibrium of sexual steroids and metabolic processes has close correlations. Insulin is a potent regulator of human sexual steroid hormone production and modulates their signals at receptor level. Insulin resistance and excessive insulin production provoke hyperandrogenism and estrogen deficiency in women resulting not only in anovulatory dysfunction but also a high risk for cardiovascular diseases and cancer. Physiologic functions of all female organs have higher estrogen demand as compared with men. In healthy women estrogen predominance against androgens is a favor in their reproductive period, which means a strong defense against insulin resistance and its complications. However, in postmenopausal cases the increasing prevalence of insulin resistance and type-2 diabetes associated with estrogen deficiency and androgen excess, result in a gender specific higher risk for precancerous lesions and cancer as compared with men. Estrogen has beneficial effect on the energy metabolism, glucose homeostasis and on the lipid metabolism of liver and of peripheral tissues as well. A moderate or severe decrease in serum estrogen level enhances the prevalence of insulin resistant states. In premenopausal women long or irregular menstrual cycles are predictors for the risk of insulin resistance and type-2 diabetes. Moreover, in postmenopausal estrogen deficient cases elevated fasting glucose, increased body weight and abdominal fat deposition are often observed progressively with age in correlation with an impaired glucose tolerance. In the rare cases of estrogen deficient men severe type-2 diabetes seems to be a characteristic complication. Upon becoming familiar with the cancer risk of insulin resistance and estrogen deficiency, there would be plenty of possibilities for primary cancer prevention. In patients with cancer the treatment of hormonal and metabolic disturbances may become effective adjuvant therapy. PMID: 22257509 [PubMed - indexed for MEDLINE] 403. Nutrients. 2011 Jan;3(1):27-39. doi: 10.3390/nu3010027. Epub 2011 Jan 6. Vitamin A metabolism and adipose tissue biology. Frey SK(1), Vogel S. Author information: (1)Department of Medicine and the Institute of Human Nutrition, Columbia University, New York, NY 10032, USA. mail@simonefrey.de In recent years, the importance of vitamin A in adipose tissue biology, obesity and type II diabetes has become apparent. This review focuses on recent developments within the area of vitamin A and adipose tissue biology. Adipose tissue has an active vitamin A metabolism as it not only stores vitamin A but retinol is also converted to its active metabolite retinoic acid. Several mouse models point to a relationship between vitamin A metabolism and the development of adiposity. Similarly, in vitro studies provide new molecular mechanisms for the function of different forms of vitamin A and retinol- or retinoic acid-binding proteins in adipose tissue. PMCID: PMC3257733 PMID: 22254074 [PubMed - indexed for MEDLINE] 404. Nutrients. 2010 Dec;2(12):1212-30. doi: 10.3390/nu2121212. Epub 2010 Dec 9. Long-chain omega-3 polyunsaturated fatty acids may be beneficial for reducing obesity-a review. Buckley JD(1), Howe PR. Author information: (1)Nutritional Physiology Research Centre, University of South Australia Adelaide, South Australia, 5000, Australia. jon.buckley@unisa.edu.au Current recommendations for counteracting obesity advocate the consumption of a healthy diet and participation in regular physical activity, but many individuals have difficulty complying with these recommendations. Studies in rodents and humans have indicated that long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation which might facilitate nutrient delivery to skeletal muscle and changes in gene expression which shift metabolism toward increased accretion of lean tissue, enhanced fat oxidation and energy expenditure and reduced fat deposition. While LC n-3 PUFA supplementation has been shown to reduce obesity in rodents, evidence in humans is limited. Epidemiological associations between LC n-3 PUFA intakes and obesity are inconclusive but small cross-sectional studies have demonstrated inverse relationships between markers of LC n-3 PUFA status and markers of obesity. Human intervention trials indicate potential benefits of LC n-3 PUFA supplementation, especially when combined with energy-restricted diets or exercise, but more well-controlled and long-term trials are needed to confirm these effects and identify mechanisms of action. PMCID: PMC3257626 PMID: 22254005 [PubMed - indexed for MEDLINE] 405. Diabetes Metab. 2012 Jun;38(3):183-91. doi: 10.1016/j.diabet.2011.11.006. Epub 2012 Jan 16. Inflammation and type 2 diabetes. Calle MC(1), Fernandez ML. Author information: (1)Department of Nutritional Sciences, University of Connecticut, 3624 Horsebarn Road, ext. U-4017, Storrs, CR 06269, USA. Low-grade inflammation is a common feature in subjects with type 2 diabetes (T2D). Heart disease, the metabolic syndrome and T2D all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral actions. This review focuses on C-reactive protein (CRP), a well-established marker of the development of inflammation, on tumour necrosis factor (TNF)-α, an inflammatory marker strongly associated with diabetes, and on adiponectin, a cytokine produced by adipose tissue and associated with insulin sensitivity. While it is clear from the literature that these cytokines play a major role in the development of T2D or, in the case of adiponectin, its prevention, the best strategy for favourably altering the inflammatory response is still a matter of debate. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22252015 [PubMed - indexed for MEDLINE] 406. Handb Exp Pharmacol. 2012;(209):111-29. doi: 10.1007/978-3-642-24716-3_5. The central insulin system and energy balance. Begg DP(1), Woods SC. Author information: (1)Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, OH 45237, USA. Insulin acts throughout the body to reduce circulating energy and to increase energy storage. Within the brain, insulin produces a net catabolic effect by reducing food intake and increasing energy expenditure; this is evidenced by the hypophagia and increased brown adipose tissue sympathetic nerve activity induced by central insulin infusion. Reducing the activity of the brain insulin system via administration of insulin antibodies, receptor antisense treatment, or receptor knockdown results in hyperphagia and increased adiposity. However, despite decades of research into the role of central insulin in food intake, many questions remain to be answered, including the underlying mechanism of action. PMID: 22249812 [PubMed - indexed for MEDLINE] 407. Handb Exp Pharmacol. 2012;(209):3-21. doi: 10.1007/978-3-642-24716-3_1. Leptin receptors. Cottrell EC(1), Mercer JG. Author information: (1)Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, EH16 4TH, UK. The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry-the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy. PMID: 22249808 [PubMed - indexed for MEDLINE] 408. Int J Obes (Lond). 2012 Dec;36(12):1485-93. doi: 10.1038/ijo.2011.269. Epub 2012 Jan 17. Effect of dairy consumption on weight and body composition in adults: a systematic review and meta-analysis of randomized controlled clinical trials. Abargouei AS(1), Janghorbani M, Salehi-Marzijarani M, Esmaillzadeh A. Author information: (1)Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. BACKGROUND: Although several observational and experimental studies have investigated the effect of dairy consumption on weight and body composition, results are inconsistent. OBJECTIVE: This systematic review and meta-analysis was conducted to summarize the published evidence from randomized controlled clinical trials (RCTs) regarding the effect of dairy consumption on weight, body fat mass, lean mass and waist circumference (WC) in adults. DESIGN: PubMed, ISI Web of Science, SCOPUS, Science Direct and EMBASE were searched from January 1960 to October 2011 for relevant English and non-English publications. Sixteen studies were selected for the systematic review and fourteen studies were included in meta-analysis. RESULTS: Our search led to 14, 12, 6 and 8 eligible RCTs that had data on weight, body fat mass, lean mass and WC, respectively. Overall, mean difference for the effect of dairy on body weight was -0.61 kg (95% confidence interval (CI): -1.29, 0.07, P=0.08). Increased dairy intake resulted in 0.72 kg (95% CI: -1.29, -0.14, P=0.01) greater reduction in fat mass, 0.58 kg (95% CI: 0.18, 0.99, P<0.01) gain in lean mass and 2.19 cm (95% CI: -3.42, -0.96, P-value <0.001) further reduction in WC than that in controls. Subgroup analysis revealed that increasing dairy intake without energy restriction in both intervention and control groups does not significantly affect weight, body fat mass, lean mass and WC; consumption of high-dairy weight loss diets led to 1.29 kg (95% CI: -1.98, -0.6, P<0.001) greater weight loss, 1.11 kg (95% CI: -1.75, -0.47, P=0.001) greater reduction in body fat mass, 0.72 kg (95% CI: 0.12, 1.32, P=0.02) gain in body lean mass and 2.43 cm (95% CI: -3.42, -1.44, P<0.001) additional reduction in WC compared with controls. CONCLUSION: Increased dairy consumption without energy restriction might not lead to a significant change in weight or body composition; whereas inclusion of dairy products in energy-restricted weight loss diets significantly affects weight, body fat mass, lean mass and WC compared with that in the usual weight loss diets. PMID: 22249225 [PubMed - indexed for MEDLINE] 409. Pediatr Endocrinol Diabetes Metab. 2011;17(4):206-13. [Insulin resistance in children]. [Article in Polish] Witek J(1), Witek P, Pańkowska E. Author information: (1)Instytut Matki i Dziecka w Warszawie. joanna.witek@imid.med.pl Insulin resistance is characterized by decreased tissue sensitivity to insulin. The hallmark of insulin resistance is decreased tissue glucose uptake despite normal or elevated insulin concentration. There has been an upward trend in the incidence of insulin resistance in developed countries, although in pediatric population it is difficult to assess. Both genetic and environmental factors play an important role in the etiology of insulin resistance, namely increased diet caloricity and decreased physical activity. Gradually, this leads to adipose tissue build-up. The role of visceral adipose tissue is of particular importance, mainly due to its significant endocrine activity, leading to adverse metabolic effects. The most important consequences of insulin resistance in children include increased incidence of type 2 diabetes, atherogenic dyslipidemia and arterial hypertension, which lead to increased cardiovascular risk. Children with insulin resistance can develop nonalcoholic steatohepatitis and sleep apnea syndrome. In case of female pediatric patients a higher incidence of polycystic ovary syndrome (PCOS) is observed. Furthermore, the authors reviewed opinions on risk factors for insulin resistance, as well as direct and indirect insulin resistance assessment methods. The article presents the principles of primary and secondary prevention of insulin resistance in children, with particular allowance for dietary recommendations and recommendations to increase physical activity, and, in selected cases, current guidelines on pharmacological treatment. PMID: 22248781 [PubMed - indexed for MEDLINE] 410. Int J Food Sci Nutr. 2012 Sep;63(6):749-65. doi: 10.3109/09637486.2011.649250. Epub 2012 Jan 17. Bioactive compounds with effects on inflammation markers in humans. Rosa FT(1), Zulet MÁ, Marchini JS, Martínez JA. Author information: (1)Division of Clinical Nutrition, Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Calle Irunlarrea 1, São Paulo, Brazil. Obesity and other chronic diseases are accompanied by adipose tissue, liver, pancreas, muscle and brain low-grade chronic inflammation. Indeed, the obese condition and metabolic syndrome are characterized by an increased expression of inflammatory cytokines and infiltration of immune cells in adipocytes. The inflammatory response promotes the activation of transcriptional factors and pro-inflammatory cytokines, which can lead to an unresolved inflammatory response associated with an inhibition of insulin signalling and high risk for cardiovascular events. Epidemiological and intervention studies have been carried out to find out dietary patterns, foods and bioactive compounds with protective anti-inflammatory actions. The most studied compounds are polyphenols, especially isoflavone and anthocyanin, but quercertin, catechin and resveratrol have also been investigated. Furthermore, some studies have reported the effects of milk peptides, plant sterol and stanol, l-carnitine and α-lipoic acid on inflammatory processes. This review aimed to collect and discuss those relevant studies reported in the scientific literature following a systematic scientific search about the effect of such bioactive compounds on inflammation in humans. PMID: 22248031 [PubMed - indexed for MEDLINE] 411. Curr Cardiovasc Risk Rep. 2012 Feb;6(1):80-90. Epub 2011 Nov 22. Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease. Houben AJ, Eringa EC, Jonk AM, Serne EH, Smulders YM, Stehouwer CD. Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease. PMCID: PMC3251783 PMID: 22247785 [PubMed] 412. Proteomics. 2012 Feb;12(4-5):607-20. doi: 10.1002/pmic.201100355. Epub 2012 Jan 23. Proteomic characterization of adipose tissue constituents, a necessary step for understanding adipose tissue complexity. Peinado JR(1), Pardo M, de la Rosa O, Malagón MM. Author information: (1)Faculty of Medicine, Departament of Medical Sciences, Ciudad Real, Spain. juanramon.peinado@uclm.es The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22246603 [PubMed - indexed for MEDLINE] 413. Trends Endocrinol Metab. 2012 Mar;23(3):133-41. doi: 10.1016/j.tem.2011.12.004. Epub 2012 Jan 13. Insulin resistance in the nervous system. Kim B(1), Feldman EL. Author information: (1)University of Michigan, Department of Neurology, Ann Arbor, MI 48109, USA. bhumsoo@med.umich.edu Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer's disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3392648 PMID: 22245457 [PubMed - indexed for MEDLINE] 414. J Shoulder Elbow Surg. 2012 Feb;21(2):175-80. doi: 10.1016/j.jse.2011.11.017. Mechanisms of fatty degeneration in massive rotator cuff tears. Kang JR(1), Gupta R. Author information: (1)Department of Orthopaedic Surgery, University of California, Irvine, CA, USA. Fatty degeneration of chronically injured muscle is a commonly recognized consequence of massive rotator cuff tears. Current surgical treatments are unable to alter or reverse the progression of fatty degeneration and are associated with poor functional outcomes in these patients. Therefore, a better understanding of the pathophysiology of fatty degeneration is required. As such, recent discoveries in stem cell biology and new animal models have significantly advanced our understanding of the cellular and molecular basis of fatty degeneration. Future studies will facilitate development of novel treatments to prevent the progression of fatty degeneration and improve muscle regeneration in patients with massive rotator cuff tears. Copyright © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved. PMID: 22244060 [PubMed - indexed for MEDLINE] 415. J Shoulder Elbow Surg. 2012 Feb;21(2):164-74. doi: 10.1016/j.jse.2011.09.027. Muscle degeneration in rotator cuff tears. Laron D(1), Samagh SP, Liu X, Kim HT, Feeley BT. Author information: (1)Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- and medium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown to develop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologic changes have been found to be independent predictors of failed surgical repair with poor functional outcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an understanding of the changes that occur within the cuff muscles themselves. The purpose of this review is to summarize the molecular pathways behind muscular degeneration and emphasize new findings related to the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understanding these molecular pathways will help guide further research and treatment options that can aim to alter expression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears. Copyright © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved. PMID: 22244059 [PubMed - indexed for MEDLINE] 416. Biopolymers. 2012 Jun;97(6):455-67. doi: 10.1002/bip.22024. Epub 2012 Jan 12. Invited review nonmulberry silk biopolymers. Kundu SC(1), Kundu B, Talukdar S, Bano S, Nayak S, Kundu J, Mandal BB, Bhardwaj N, Botlagunta M, Dash BC, Acharya C, Ghosh AK. Author information: (1)Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India. kundu@hijli.iitkgp.ernet.in The silk produced by silkworms are biopolymers and can be classified into two types--mulberry and nonmulberry. Mulberry silk of silkworm Bombyx mori has been extensively explored and used for century old textiles and sutures. But for the last few decades it is being extensively exploited for biomedical applications. However, the transformation of nonmulberry silk from being a textile commodity to biomaterials is relatively new. Within a very short period of time, the combination of load bearing capability and tensile strength of nonmulberry silk has been equally envisioned for bone, cartilage, adipose, and other tissue regeneration. Adding to its advantage is its diverse morphology, including macro to nano architectures with controllable degradation and biocompatibility yields novel natural material systems in vitro. Its follow on applications involve sustained release of model compounds and anticancer drugs. Its 3D cancer models provide compatible microenvironment systems for better understanding of the cancer progression mechanism and screening of anticancer compounds. Diversely designed nonmulberry matrices thus provide an array of new cutting age technologies, which is unattainable with the current synthetic materials that lack biodegradability and biocompatibility. Scientific exploration of nonmulberry silk in tissue engineering, regenerative medicine, and biotechnological applications promises advancement of sericulture industries in India and China, largest nonmulberry silk producers of the world. This review discusses the prospective biomedical applications of nonmulberry silk proteins as natural biomaterials. Copyright © 2012 Wiley Periodicals, Inc. PMID: 22241173 [PubMed - indexed for MEDLINE] 417. Curr Opin Nephrol Hypertens. 2012 Mar;21(2):147-56. doi: 10.1097/MNH.0b013e32834fb25b. Extrarenal effects of aldosterone. Nguyen Dinh Cat A(1), Jaisser F. Author information: (1)Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada. cattuong.ndc@gmail.com PURPOSE OF REVIEW: The renal distal tubule has been considered for a long time as the main cellular target of aldosterone, where the hormone enhances sodium reabsorption and potassium secretion. However, other cell types in nonepithelial tissues, such as the heart, the vessels, adipose tissue, and macrophages, are now also recognized as targets for aldosterone. The functions that aldosterone exerts in these nonclassical target tissues are still a matter of debate. This review will highlight the recent findings on the extrarenal effects of aldosterone. RECENT FINDINGS: Numerous studies showed that aldosterone exerts profibrotic and proinflammatory effects, but one or more cofactors such as salt, angiotensin II, and oxidative stress are required. Moreover, inflammation and macrophage infiltration are a prerequisite to aldosterone-induced cardiac fibrosis. This underlines a key role for aldosterone and the mineralocorticoid receptor in macrophages. Inflammatory effects of aldosterone in vascular smooth muscle cells involve trafficking to lipid rafts/caveolae through receptor tyrosine kinases. Finally, a growing body of evidence indicates a prominent role of aldosterone/mineralocorticoid receptor in the metabolic syndrome, in insulin resistance, and in adipocyte biology. SUMMARY: The idiom from Socrates, 'the more we learn, the less we know', can be applied to aldosterone with its different facets and its pleiotropic effects. There is clear evidence for rapid nongenomic effects of aldosterone, mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent signaling, in the heart, the vessels, and other nonepithelial tissues, leading to inflammation, fibrosis, and progression of cardiovascular diseases including hypertension and metabolic syndrome. PMID: 22240440 [PubMed - indexed for MEDLINE] 418. Phys Med Rehabil Clin N Am. 2012 Feb;23(1):67-73, x. doi: 10.1016/j.pmr.2011.11.007. Epub 2011 Dec 11. Regional and whole-body dual-energy X-ray absorptiometry to guide treatment and monitor disease progression in neuromuscular disease. Skalsky AJ(1), Han JJ, Abresch RT, McDonald CM. Author information: (1)Department of Pediatrics, University of California San Diego, Rady Children's Hospital and Health Center, San Diego, CA 92123, USA. askalsky@rchsd.org Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22239875 [PubMed - indexed for MEDLINE] 419. Obes Rev. 2012 Apr;13(4):381-7. doi: 10.1111/j.1467-789X.2011.00978.x. Epub 2012 Jan 12. Oestradiol is a protective factor for non-alcoholic fatty liver disease in healthy men. Tian GX(1), Sun Y, Pang CJ, Tan AH, Gao Y, Zhang HY, Yang XB, Li ZX, Mo ZN. Author information: (1)Department of Ultrasound, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China. Visceral fat is a risk factor for non-alcoholic fatty liver disease (NAFLD). A reduction in sex hormones is associated with increased abdominal fat. Thus, we investigated whether reduced testosterone (T) or oestradiol (E2) levels in men are associated with NAFLD and central obesity. The study involved a survey of 1,882 men between 20 and 60 years of age. We detected hepatic fat infiltration by ultrasound. Early morning serum was analyzed for total testosterone (TT), E2, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Free testosterone (FT) was calculated using the Vermeulen method. In the studied population, the prevalence of NAFLD, FSH, LH and SHBG increased with age, TT and FT declined with age, and E2 remained stable. However, in the NAFLD group, TT remained stable, FT and E2 declined, and hepatic fat infiltration increased (P < 0.001 for both). Using multivariate analysis, a correlation was found between E2 and NAFLD, with an odds ratio of 0.954 (95% confidence interval: 0.946-0.967). E2 is one of the protective factors against NAFLD in healthy men. T has no significant correlation with NAFLD. Further investigation would be required to assess the clinical consequences of reduced E2 in men with NAFLD, particularly for men whose TT remained stable. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22239319 [PubMed - indexed for MEDLINE] 420. J Clin Endocrinol Metab. 2012 Mar;97(3):745-55. doi: 10.1210/jc.2011-2525. Epub 2012 Jan 11. Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. Guyenet SJ(1), Schwartz MW. Author information: (1)Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington School of Medicine, South Lake Union, 815 Mercer Street, N334, Box 358055, Seattle, Washington 98109, USA. CONTEXT: Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment. EVIDENCE ACQUISITION: We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited. EVIDENCE SYNTHESIS: The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass. CONCLUSIONS: Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies. PMCID: PMC3319208 PMID: 22238401 [PubMed - indexed for MEDLINE] 421. Anat Sci Int. 2012 Mar;87(1):24-44. doi: 10.1007/s12565-011-0128-4. Epub 2012 Jan 12. Mesenchymal cell populations: development of the induction systems for Schwann cells and neuronal cells and finding the unique stem cell population. Kitada M(1). Author information: (1)Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi, 980-8575, Japan. Masaaki.Kitada@gmail.com Mesenchymal cell populations, referred to as mesenchymal stem cells or multipotent stromal cells (MSCs), which include bone marrow stromal cells (BMSCs), umbilical cord stromal cells and adipose stromal cells (ASCs), participate in tissue repair when transplanted into damaged or degenerating tissues. The trophic support and immunomodulation provided by MSCs can protect against tissue damage, and the differentiation potential of these cells may help to replace lost cells. MSCs are easily accessible and can be expanded on a large scale. In addition, BMSCs and ASCs can be harvested from the patient himself. Thus, MSCs are considered promising candidates for cell therapy. In this review, I will discuss recently discovered high-efficiency induction systems for deriving Schwann cells and neurons from MSCs. Other features of MSCs that are important for tissue repair include the self-renewing property of stem cells and their potential for differentiation. Thus, I will also discuss the stemness of MSCs and describe the discovery of a certain stem cell type among adult MSCs that can self-renew and differentiate into cells of all three germ layers. Furthermore, I will explore the prospects of using this cell population for cell therapy. PMID: 22237924 [PubMed - indexed for MEDLINE] 422. Curr Pharm Des. 2012;18(6):789-98. Apelin in the control of body fluid homeostasis and cardiovascular functions. Galanth C(1), Hus-Citharel A, Li B, Llorens-Cortès C. Author information: (1)Center for Interdisciplinary Research in Biology, College de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France. The discovery of apelin, an endogenous ligand of the orphan APJ receptor is an important advance for fundamental research and clinical medicine. Apelin and its receptor have a wide tissue distribution not only in the brain but also in peripheral organs including kidney, heart, vessels, and adipose tissue. Apelin is implicated in many physiological and pathophysiological processes such as the regulation of body fluid homeostasis, cardiovascular functions, glucose homeostasis, cell proliferation, and angiogenesis. This review focuses on, i) the various signaling cascades evoked upon stimulation of the apelin receptor by the different molecular forms of apelin found in vivo, ii) the distribution of apelin and its receptor in the brain and the cardiovascular system, iii) the opposing actions of vasopressin and apelin in the regulation of water balance at the central and kidney levels, and on the cardiovascular system regarding regulation of arterial blood pressure, vascular tone, and cardiac function. PMID: 22236125 [PubMed - indexed for MEDLINE] 423. ScientificWorldJournal. 2011;11:2509-29. doi: 10.1100/2011/397971. Epub 2011 Dec 28. Macrophages, meta-inflammation, and immuno-metabolism. Shapiro H(1), Lutaty A, Ariel A. Author information: (1)Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel. Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes. PMCID: PMC3253544 PMID: 22235182 [PubMed - indexed for MEDLINE] 424. Pharmacol Ther. 2012 May;134(2):127-38. doi: 10.1016/j.pharmthera.2011.12.009. Epub 2011 Dec 30. Targeting ASIC3 for pain, anxiety, and insulin resistance. Wu WL(1), Cheng CF, Sun WH, Wong CW, Chen CC. Author information: (1)Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan. The acid-sensing ion channel 3 (ASIC3) is a pH sensor that responds to mild extracellular acidification and is predominantly expressed in nociceptors. There is much interest in targeting ASIC3 to relieve pain associated with tissue acidosis, and selective drugs targeting ASIC3 have been used to relieve acid-evoked pain in animal models and human studies. There is accumulating evidence that ASIC3 is widely expressed in many neuronal and non-neuronal cells, such as neurons in the brain and adipose cells, albeit to a lesser extent than in nociceptors. Asic3-knockout mice have reduced anxiety levels and enhanced insulin sensitivity, suggesting that antagonizing ASIC3 has additional benefits. This view is tempered by recent studies suggesting that Asic3-knockout mice may experience cardiovascular disturbances. Due to the development of ASIC3 antagonists as analgesics, we review here the additional benefits, safety, risks, and strategy associated with antagonizing ASIC3 function. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22233754 [PubMed - indexed for MEDLINE] 425. J Mol Med (Berl). 2012 Aug;90(8):887-93. doi: 10.1007/s00109-012-0858-3. Epub 2012 Jan 10. A new, powerful player in lipoprotein metabolism: brown adipose tissue. Bartelt A(1), Merkel M, Heeren J. Author information: (1)Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Important causes for modern epidemics such as obesity, diabetes, and cardiovascular disease are over- and malnutrition. Dietary as well as endogenous lipids are transported through the bloodstream in lipoproteins, and disturbances in lipoprotein metabolism are associated with atherosclerosis, heart disease, and diabetes. Recent findings reveal biological principles-how lipoproteins, in particular triglyceride-rich lipoproteins, are metabolized and what factors regulate their processing. The fate of triglycerides delivered by lipoproteins is quite simple: either they can be stored or they can be utilized for combustion or biosynthetic pathways. In the healthy state, fatty acids derived from triglycerides can be burned in the heart, muscle, and other organs for actual work load, or they can be stored in white adipose tissue. The combination of storage and combustion is realized in brown adipose tissue (BAT), a peripheral organ that was long thought to be only of relevance in small mammals: Recent data however prove that BAT plays an important role in human adults. Here, we will review recent insights on how BAT controls triglyceride clearance and the possible implications for the treatment of chronic diseases caused by lipid mishandling. PMID: 22231746 [PubMed - indexed for MEDLINE] 426. Immunol Cell Biol. 2012 Sep;90(8):755-62. doi: 10.1038/icb.2011.110. Epub 2012 Jan 10. The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. Winer S(1), Winer DA. Author information: (1)Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis. PMID: 22231651 [PubMed - indexed for MEDLINE] 427. Nat Rev Neurol. 2012 Jan 10;8(2):70-1. doi: 10.1038/nrneurol.2011.223. Epilepsy in 2011: Insights into epilepsy treatments and biomarkers. Cendes F(1). Author information: (1)Department of Neurology, FCM, University of Campinas, Rua Vital Brasil, 251 Cidade Universitária, Campinas, SP13.083-888, Brazil. fcendes@unicamp.br PMID: 22231197 [PubMed - indexed for MEDLINE] 428. Kardiol Pol. 2011;69 Suppl 3:89-93. [The role of apelin in pathogenesis of cardiovascular diseases and metabolic disorders]. [Article in Polish] Cudnoch Jędrzejewska A(1), Czarzasta K, Gomółka R, Szczepańska Sadowska E. Author information: (1)Katedra i Zakład Fizjologii Doświadczalnej i Klinicznej, Warszawski Uniwersytet Medyczny, Warszawa. agnieszka.cudnoch@wum.edu.pl Apelin is a recently discovered biologically active peptide present in several isoforms that are agonists for orphan receptor APJ. Apelin and APJ receptor were found in the central nervous system and in different peripheral tissues. In the cardiovascular system the peptide is present both in the heart and in the endothelium and smooth muscles cells of the vascular wall. Acting on cardiomyocytes apelin exerts positive inotropic effect, in the endothelium it releases nitric oxide, which mediates its vasodilatory action, while acting directly on smooth muscles cells it causes vasoconstriction. Apelin interacts with other compounds regulating blood pressure; for instance with angiotensin II, vasopressin, and with the sympathetic nervous system. Special attention is focused on the possibility of positive role of apelin in hypertension, initial stages of heart failure and ischaemic heart disease. Synthesis of apelin in adipocytes permits to include this peptide among adipokines. In the adipose tissue its production is increased in obesity and by insulin. It appears that apelin may play essential role in pathogenesis of insulin-resistant obesity. In patients with type 2 diabetes apelin improves glucose tolerance in initial stages of the illness. However, further experimental and clinical studies are required for full evaluation of significance of positive and negative aspects of the role of apelin in the cardiovascular and metabolic diseases. PMID: 22125210 [PubMed - indexed for MEDLINE] 429. Maturitas. 2012 Mar;71(3):227-39. doi: 10.1016/j.maturitas.2011.12.009. Epub 2012 Jan 9. Anti-inflammatory properties of culinary herbs and spices that ameliorate the effects of metabolic syndrome. Jungbauer A(1), Medjakovic S. Author information: (1)Department of Biotechnology and Christian Doppler Laboratory of Receptor Biotechnology, University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria. alois.jungbauer@boku.ac.at Obesity and metabolic syndrome are increasing global health problems. In addition to the malnutrition of a sedentary lifestyle, high calorie intake leads to obesity with many negative health consequences. Macrophages infiltrate adipose tissue and induce chronic inflammation by secreting pro-inflammatory cytokines, including COX-2 and iNOS, among other mediators of inflammation. Free fatty acids mediate adipose tissue signalling through toll-like receptor 4 and the expression of these pro-inflammatory mediators via NF-κB or JNK. PPAR γ activators can inhibit the activation of NF-κB, down-regulating the expression of pro-inflammatory cytokines. Here we provide an overview of how different culinary herbs and spices exert anti-inflammatory activities and the extent to which they activate PPAR α and PPAR γ, inhibit the activation of NF-κB, and enhance expression of anti-inflammatory cytokines. Spices can play essential roles as anti-inflammatory agents in our diet, acting as pan PPAR activators and improving insulin sensitivity, counteracting dyslipidaemia and weight gain. The effects of chronic inflammation caused by obesity are counteracted and, consequently, the progression of diseases associated with chronic inflammation slowed. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 22226987 [PubMed - indexed for MEDLINE] 430. Int J Biochem Cell Biol. 2012 Mar;44(3):475-9. doi: 10.1016/j.biocel.2011.12.014. Epub 2011 Dec 31. The transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipogenesis. Margoni A(1), Fotis L, Papavassiliou AG. Author information: (1)Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece. Rising obesity epidemic makes the better understanding of transcription factor networks regulating adipogenesis very challenging. Adipogenesis begins with the commitment of pluripotent mesenchymal stem cells to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. Among the molecules that influence the decision of progenitor cells to become adipocytes are members of transforming growth factor-beta superfamily and particularly bone morphogenetic proteins. Transforming growth factor-beta and bone morphogenetic proteins exert their biological functions mainly through their downstream molecules, the Smads. Here, we review the role(s) of transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipocyte differentiation. Unravelling the precise mechanism of each molecule/pathway is necessary for developing suitable inhibitors or mimetic agents in order to treat obesity and improve insulin resistance. Current research efforts aim at discovering drugs that reduce fat mass or change the phenotype of adipose tissue into a more thermogenic one. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22226816 [PubMed - indexed for MEDLINE] 431. Acta Physiol (Oxf). 2012 Jun;205(2):194-208. doi: 10.1111/j.1748-1716.2012.02409.x. Epub 2012 Feb 1. Structural and biochemical characteristics of various white adipose tissue depots. Wronska A(1), Kmiec Z. Author information: (1)Department of Histology, Medical University of Gdansk, Gdansk, Poland. It is now widely accepted that white adipose tissue (WAT) is not merely a fuel storage organ, but also a key component of metabolic homoeostatic mechanisms. Apart from its major role in lipid and glucose metabolism, adipose tissue is also involved in a wide array of other biological processes. The hormones and adipokines, as well as other biologically active agents released from fat cells, affect many physiological and pathological processes. WAT is neither uniform nor inflexible because it undergoes constant remodelling, adapting the size and number of adipocytes to changes in nutrients' availability and hormonal milieu. Fat depots from different areas of the body display distinct structural and functional properties and have disparate roles in pathology. The two major types of WAT are visceral fat, localized within the abdominal cavity and mediastinum, and subcutaneous fat in the hypodermis. Visceral obesity correlates with increased risk of insulin resistance and cardiovascular diseases, while increase of subcutaneous fat is associated with favourable plasma lipid profiles. Visceral adipocytes show higher lipogenic and lipolytic activities and produce more pro-inflammatory cytokines, while subcutaneous adipocytes are the main source of leptin and adiponectin. Moreover, adipose tissue associated with skeletal muscles (intramyocellular and intermuscular fat) and with the epicardium is believed to provide fuels for skeletal and cardiac muscle contraction. However, increased mass of either epicardial or intermuscular adipose tissue correlates with cardiovascular risk, while the presence of the intramyocellular fat is a risk factor for the development of insulin resistance. This review summarizes results of mainly human studies related to the differential characteristics of various WAT depots. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society. PMID: 22226221 [PubMed - indexed for MEDLINE] 432. Cell Metab. 2012 Jan 4;15(1):10-8. doi: 10.1016/j.cmet.2011.10.011. The inflammasome puts obesity in the danger zone. Stienstra R(1), Tack CJ, Kanneganti TD, Joosten LA, Netea MG. Author information: (1)Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands. Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the cytokine interleukin-1β (IL-1β) has emerged as a prominent instigator of the proinflammatory response in obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms responsible for IL-1β activation in adipose tissue, liver, and macrophages and demonstrated a central role of the processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome. These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to insulin resistance and type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22225872 [PubMed - indexed for MEDLINE] 433. Annu Rev Immunol. 2012;30:677-706. doi: 10.1146/annurev-immunol-020711-075008. Epub 2012 Jan 6. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Trinchieri G(1). Author information: (1)Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, USA. trinchig@mail.nih.gov Recent scientific advances have contributed much to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The evidence for this connection in humans is based on the association between infection or chronic sterile inflammation and cancer. The decreased incidence of tumors in individuals who have used nonsteroidal anti-inflammatory drugs is supportive of a role for inflammation in cancer susceptibility. The increased incidence of tumors in overweight patients points to a role for adipose tissue inflammation and energy metabolism in cancer. Energy metabolism, obesity, and genetic instability are regulated in part by the relationship of the organism with commensal bacteria that affect inflammation with both local and systemic effects. Different aspects of inflammation appear to regulate all phases of malignant disease, including susceptibility, initiation, progression, dissemination, morbidity, and mortality. PMID: 22224761 [PubMed - indexed for MEDLINE] 434. Tissue Eng Part B Rev. 2012 Aug;18(4):258-69. doi: 10.1089/ten.TEB.2011.0440. Epub 2012 Mar 23. Bone tissue engineering: current strategies and techniques--part II: Cell types. Szpalski C(1), Barbaro M, Sagebin F, Warren SM. Author information: (1)Department of Plastic Surgery, New York University Langone Medical Center, New York, New York 10016, USA. Bone repair and regeneration is a dynamic process that involves a complex interplay between the (1) ground substance; (2) cells; and (3) milieu. Each constituent is integral to the final product, but it is often helpful to consider each component individually. While bone tissue engineering has capitalized on a number of breakthrough technologies, one of the most valued advancements is the incorporation of mesenchymal stem cells (SCs) into bone tissue engineering applications. With this new idea, however, came new found problems of guiding SC differentiation. Moreover, investigators are still working to understand which SCs source produces optimal bone formation in vitro and in vivo. Bone marrow-derived mesenchymal SCs and adipose-derived SCs have been researched most extensively, but other SC sources, including dental pulp, blood, umbilical cord blood, epithelial cells reprogrammed to become induced pluripotent SCs, among others, are being investigated. In Part II of this review series, we discuss the variety of cell types (e.g., osteocytes, osteoblasts, osteoclasts, chondrocytes, mesenchymal SCs, and vasculogenic cells) important in bone tissue engineering. PMID: 22224439 [PubMed - indexed for MEDLINE] 435. ScientificWorldJournal. 2011;11:1568-81. doi: 10.1100/tsw.2011.146.. Epub 2011 Aug 16. Current status of human adipose-derived stem cells: differentiation into hepatocyte-like cells. Al Battah F(1), De Kock J, Vanhaecke T, Rogiers V. Author information: (1)Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), Brussels, Belgium. falbatta@vub.ac.be The shortage of human organ donors and the low cell quality of available liver tissues represent major obstacles for the clinical application of orthotropic liver transplantation and hepatocyte transplantation, respectively. Therefore, worldwide research groups are investigating alternative extrahepatic cell sources. Recent in vitro studies have demonstrated that mesenchymal stem cells (MSCs) from various sources, including human bone marrow, adipose tissue, and umbilical cord, can be differentiated into hepatocyte-like cells when appropriate conditions are used. In particular, interest exists for human adipose-derived stems cells (hASCs) as an attractive cell source for generating hepatocyte-like cells. The hASCs are multipotent MSCs that reside in adipose tissue, with the ability to self-renew and differentiate into multiple cell lineages. Moreover, these cells can secrete multiple growth factors and cytokines that exert beneficial effects on organ or tissue injury. In this review, we will not only present recent data regarding hASC biology, their isolation, and differentiation capability towards hepatocytes, but also the potential application of hASC-derived hepatocytes to study drug toxicity. Additionally, this review will discuss the therapeutic potential of hASCs as undifferentiated cells in liver regeneration. PMCID: PMC3201629 PMID: 22224071 [PubMed - indexed for MEDLINE] 436. Int J Biochem Cell Biol. 2012 Mar;44(3):435-40. doi: 10.1016/j.biocel.2011.12.011. Epub 2011 Dec 28. White adipocytes: more than just fat depots. Henry SL(1), Bensley JG, Wood-Bradley RJ, Cullen-McEwen LA, Bertram JF, Armitage JA. Author information: (1)Department of Anatomy and Developmental Biology, Monash University, Australia. Globally 30% of adults are overweight or obese. The white adipocyte is a major component of adipose tissue, and as the obesity epidemic increases it is critically important to understand the factors determining adipocyte development and function. Adipogenesis has two distinct phases; determination of the adipocyte from a multipotent stem cell, and terminal differentiation of a pre-adipocyte into a mature adipocyte. The environment encountered in early life can alter adipocyte number and size and potentially impact upon adipocyte endocrine function in adulthood. These alterations may contribute to the pathophysiology of chronic diseases and thus targeted therapy of the adipocyte has great potential for treating the current obesity epidemic. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22222895 [PubMed - indexed for MEDLINE] 437. J Pharm Pharmacol. 2012 Feb;64(2):161-71. doi: 10.1111/j.2042-7158.2011.01366.x. Epub 2011 Oct 13. Role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. Saraf N(1), Sharma PK, Mondal SC, Garg VK, Singh AK. Author information: (1)Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut (UP), India. saraf.140588@gmail.com OBJECTIVES: Adipose tissue is the key regulator of energy balance, playing an active role in lipid storage and metabolism and may be a dynamic buffer to control fatty acid flux. Peroxisome proliferator-activated receptor gamma isoform-2 (PPARg2), an isoform of the nuclear hormone receptor superfamily, has been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance, type-2 diabetes and dyslipidaemia. The PPARg2 isoform is highly present in adipose tissue where it functions as a thrifty phenotype, which promotes adipocyte differentiation and triglyceride storage. Thiazolidinediones, antidiabetic drugs, induce insulin sensitivity by controlling adipokines. The thiazolidinediones bind with PPARg2 in adipocytes and exert an agonist effect by enhancing adipogenesis and fatty acid uptake. Thiazolidinediones stimulate PPARg2, by which they down-regulate tumour necrosis factor-α, leptin, interleukin-6 and plasminogen and also enhance insulin sensitivity. The aim of this work is to define role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. KEY FINDINGS: The PPARg2 alters the transcription of the target gene. This altered gene transcription results in the up-regulation of insulin-sensitizing factors and down-regulation of insulin-resistant factors. The variant Pro12Ala of the PPARg2 gene is an important modulator in metabolic control in the body. Thiazolidinediones stimulate PPARg2 transcription factor by which PPARg2 binds to responsive elements located in the promoter regions of many genes and modulates their transcriptive activity. There is a strong mutual relationship between receptor binding and agonism, which is evidence of the insulin-sensitizing target of thiazolidinediones in PPARg2. This evidently increases the biological potency of the glucose-lowering effect of thiazolidinediones in vivo as well as their antidiabetic activity. CONCLUSIONS: PPARg2 transcription factor plays an important role in treatment of type-2 diabetes with thiazolidindiones. The variant Pro12Ala of the PPARg2 gene promotes the activity of thiazolidinediones in minimizing insulin resistance. Transcriptional activity of Pro12Ala variant improves the activity of insulin. Thus thiazolidinediones promote the phosphorylation of PPARg2 to induce insulin sensitivity. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society. PMID: 22221092 [PubMed - indexed for MEDLINE] 438. Nihon Rinsho Meneki Gakkai Kaishi. 2011;34(6):464-75. [Topics of glucocorticoids--centered on therapy for rheumatoid arthritis]. [Article in Japanese] Akama H(1). Author information: (1)Japan/Asia Clinical Research Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd, Japan. Glucocorticoids (steroids) have been widely used for the treatment of patients with rheumatoid arthritis (RA) since Hench had attempted to administer cortisone (Kendall's compound E) to an active RA patient in 1948. Rheumatologists even in the 21st century can learn a lot from the history of steroid. In this feature article on steroid, a brief outline of 11β-hydroxysteroid dehydrogenase type 1, a tissue-specific regulator of steroid response, is presented. The isozyme re-activates inactive cortisone (compound E) to active cortisol (compound F), and seems to play an important role particularly in adipose tissue. In addition, I give an account of non-genomic mechanisms of steroid, which might be relevant to early and rapid effects during methylprednisolone pulse therapy. As for the field of practical rheumatology, rates and dosages of steroid administration for RA in Japan are shown, by looking into 3 large observational cohort researches and post-marketing surveillance programs for several biologics. The definition or an appropriate interpretation of medical/technical terms such as 'effectiveness' in the clinical setting and 'low-dose' steroid is also described. PMID: 22214807 [PubMed - indexed for MEDLINE] 439. Proteomics Clin Appl. 2012 Jan;6(1-2):91-101. doi: 10.1002/prca.201100052. Epub 2011 Dec 27. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Lehr S(1), Hartwig S, Sell H. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany. stefan.lehr@ddz.uni-duesseldorf.de Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion which may contribute to the development of metabolic diseases. Consequently, this correlation has emphasized the importance to further characterize the adipocyte secretion profile, and several attempts have been made to characterize the complex nature of the adipose tissue secretome by utilizing diverse proteomic profiling approaches. Although the entirety of human adipokines is still incompletely characterized, to date more than 600 potentially secretory proteins were identified providing a rich source to identify putative novel biomarkers associated with metabolic diseases. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22213627 [PubMed - indexed for MEDLINE] 440. Ann N Y Acad Sci. 2011 Dec;1243:30-46. doi: 10.1111/j.1749-6632.2011.06246.x. Interactions between metabolism and circadian clocks: reciprocal disturbances. Delezie J(1), Challet E. Author information: (1)Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique, UPR3212, University of Strasbourg, Strasbourg, France. Obesity is a medical condition of excess body fat, recognized as a global epidemic. Besides genetic factors, overconsumption of high-energy food and a sedentary lifestyle are major obesogenic causes. A newly identified determinant is altered circadian rhythmicity. To anticipate and adapt to daily changes in the environment, organisms have developed an endogenous circadian timing system, comprising a main circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, principally synchronized to the light-dark cycle. Secondary peripheral clocks are found in various tissues, such as the liver, pancreas, and adipose tissue. These clocks control the rhythmic patterns of myriad metabolic processes. We will review the evidence that metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, conversely, that disruption of circadian clock functioning can lead to obesity. The roots of these reciprocal interactions will be illustrated by transcriptional crosstalk between metabolic and circadian systems. Chronotherapeutic approaches of dieting to maintain or restore a proper circadian alignment could be useful to limit the magnitude of metabolic risks. © 2011 New York Academy of Sciences. PMID: 22211891 [PubMed - indexed for MEDLINE] 441. Am J Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1231-40. doi: 10.1152/ajpheart.00765.2011. Epub 2011 Dec 30. Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Xu A(1), Vanhoutte PM. Author information: (1)Department of Pharmacology and Pharmacy, the University of Hong Kong, Hong Kong. The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-α, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment. PMID: 22210749 [PubMed - indexed for MEDLINE] 442. Expert Opin Biol Ther. 2012 Feb;12(2):155-63. doi: 10.1517/14712598.2012.644533. Epub 2011 Dec 31. Adipose stem cell-based soft tissue regeneration. Philips BJ(1), Marra KG, Rubin JP. Author information: (1)University of Pittsburgh, Division of Plastic Surgery, Department of Surgery, Pittsburgh, PA 15261, USA. INTRODUCTION: Since their isolation and characterization nearly a decade ago, adipose-derived stem cells (ASCs) have become one of the most popular adult stem cell populations for research in soft tissue engineering and regenerative medicine applications. Compared with other stem cell sources, ASCs offer several advantages including an abundant autologous source, minor invasive harvesting (liposuction), significant proliferative capacity in culture and multi-lineage potential. Numerous preclinical studies have been pursued, with early clinical data appearing in the literature. AREAS COVERED: Autologous fat grafting has gained tremendous momentum in clinical practice over the past several years due to its potential applications in trauma and reconstructive surgery. This review focuses on the published clinical and pre-clinical (i.e., animal) data to date using ASCs for soft tissue reconstruction, with particular attention to experimental models and methodologies. Future directions for rendering soft tissue reconstructive therapies more effective are discussed. EXPERT OPINION: Although standardization of ASC harvesting and processing techniques, as well as long-term results of existing clinical studies, remains to be addressed, the known biological properties of ASCs suggest a potential role in enhancing fat graft retention and facilitating minimally invasive reconstructive treatments. While clinical applications are being reported, well controlled clinical studies are needed to demonstrate safety and efficacy. PMID: 22208874 [PubMed - indexed for MEDLINE] 443. Nutrition. 2012 Feb;28(2):113-7. doi: 10.1016/j.nut.2011.09.009. Visceral fat and gut inflammation. Drouet M(1), Dubuquoy L, Desreumaux P, Bertin B. Author information: (1)Université Lille Nord de France, Lille, France. The etiology of inflammatory bowel disease and, in particular, Crohn's disease involves a deregulated mucosal immune system under the influence of intestinal flora and environmental factors in genetically susceptible individuals. A new hypothesis has focused on mesenteric fat hypertrophy and the presence of ectopic fat surrounding inflamed bowel, the so-called creeping fat, which are hallmarks of Crohn's disease. Mesenteric adipose tissue is currently recognized as an active actor in immunity with a capacity for mediator secretion. These mediators include classic pro- and anti-inflammatory cytokines or chemokines and hormone-like adipokines with multiple effects. Mesenteric fat participates in the course of Crohn's disease and may play an active role in the regulation of intestinal inflammation. However, little is known about the origin and role of mesenteric fat in Crohn's disease, essentially because of a lack of experimental models that develop creeping fat. The purpose of this review is to present the recent data describing the immune properties of mesenteric fat and the recent advances in animal models, which have suggested a new hypothesis about the role of creeping fat in Crohn's disease. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22208553 [PubMed - indexed for MEDLINE] 444. Scientifica (Cairo). 2012;2012:525374. doi: 10.6064/2012/525374. Epub 2012 Aug 30. The prothrombotic tendency in metabolic syndrome: focus on the potential mechanisms involved in impaired haemostasis and fibrinolytic balance. Russo I(1). Author information: (1)Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences of the Turin University, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy. The metabolic syndrome is a clinical disorder characterized by impairment of glucose metabolism, increased arterial blood pressure, and abdominal obesity. The presence of these clinical features exposes patients to a high risk of atherothrombotic cardiovascular events. The pathogenesis of atherothrombosis in the metabolic syndrome is multifactorial, requiring a close relationship among the main components of the metabolic syndrome, including insulin resistance, alterations of glycaemic and lipid pattern, haemodynamic impairment, and early appearance of endothelial dysfunction. Furthermore, haemostatic alterations involving coagulation balance, fibrinolysis, and platelet function play a relevant role both in the progression of the arterial wall damage and in acute vascular events. The mechanisms linking abdominal obesity with prothrombotic changes in the metabolic syndrome have been identified and partially elucidated on the basis of alterations of each haemostatic variable and defined through the evidence of peculiar dysfunctions in the endocrine activity of adipose tissue responsible of vascular impairment, prothrombotic tendency, and low-grade chronic inflammation. This paper will focus on the direct role of adipose tissue on prothrombotic tendency in patients affected by metabolic syndrome, with adipocytes being able to produce and/or release cytokines and adipokines which deeply influence haemostatic/fibrinolytic balance, platelet function, and proinflammatory state. PMCID: PMC3820496 PMID: 24278711 [PubMed] 445. Adipocyte. 2012 Jan 1;1(1):13-24. Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Townsend K(1), Tseng YH. Author information: (1)Joslin Diabetes Center and Harvard Medical School; Boston, MA USA. Obesity is currently a global pandemic, and is associated with increased mortality and co-morbidities including many metabolic diseases. Obesity is characterized by an increase in adipose mass due to increased energy intake, decreased energy expenditure, or both. While white adipose tissue is specialized for energy storage, brown adipose tissue has a high concentration of mitochondria and uniquely expresses uncoupling protein 1, enabling it to be specialized for energy expenditure and thermogenesis. Although brown fat was once considered only necessary in babies, recent morphological and imaging studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. In recent years, the topic of brown adipose tissue has been reinvigorated with many new studies regarding brown adipose tissue differentiation, function and therapeutic promise. This review summarizes the recent advances, discusses the emerging questions and offers perspective on the potential therapeutic applications targeting this tissue. PMCID: PMC3661118 PMID: 23700507 [PubMed] 446. Vopr Onkol. 2012;58(4):464-72. [Heterogeneity of obesity and cancer: the potential role of brown adipose tissue]. [Article in Russian] Bershteĭn LM. PMID: 23607199 [PubMed - indexed for MEDLINE] 447. Vopr Onkol. 2012;58(6):744-7. [Ursolic acid as antitumor agent and inductor of PTEN and brown fat]. [Article in Russian] Bershteĭn LM. In this mini-review the basic evidence about anticancer properties of ursolic acid (UA), the compound belonging to the class of triterpenoids, is given. Beside inhibiting tumor cell growth in vitro and in vivo and activating of apoptosis, UA (as well as some other related and not related compounds) is capable to induce PTEN (a tumor suppressor mutation of which is rather often discovered in human tumors including endometrial cancer type I) and amount/activity of brown fat. The latter action may explain obesity-preventing capacity of UA that also may lead to an additional antiblastomogenic effect. PMID: 23600297 [PubMed - indexed for MEDLINE] 448. J Long Term Eff Med Implants. 2012;22(3):181-93. Factors influencing the long-term behavior of extracellular matrix-derived scaffolds for musculoskeletal soft tissue repair. Rowland CR(1), Little D, Guilak F. Author information: (1)Department of Orthopaedic Surgery and Biomedical Engineering, Duke University Medical Center, Durham, NC 27710, USA. Musculoskeletal connective tissues such as tendon, ligament, and cartilage possess a limited ability for self-repair. Tissue engineering seeks to use combinations of cells, bioactive molecules, and biomaterials to develop new treatment options for the repair or replacement of damaged tissues. The use of native extracellular matrix as scaffold material for tissue engineering has become increasingly attractive because such tissues can not only provide structural support, but also regulate cell behavior. Although demineralized bone matrix has long been recognized for its osteoinductive abilities, recent studies have identified the ability of cartilage and tendon extracellular matrices to stimulate the differentiation of mesenchymal or adipose-derived adult stem cells toward chondrogenic or tenogenic lineages, respectively. This review discusses the motivation for fabricating scaffolds from musculoskeletal tissues, the in vitro and in vivo efficacy of these tissue-derived scaffolds, and various processing techniques such as decellularization or cross-linking that can mitigate immunogenic responses, moderate the degradation profile, and enhance the mechanical properties of these constructs following long-term implantation in vivo. PMCID: PMC3633148 PMID: 23582110 [PubMed - indexed for MEDLINE] 449. J Stem Cells. 2012;7(2):87-95. The characterisation of mesenchymal stem cells: a stem cell is not a stem cell is not a stem cell. Khan WS(1), Hardingham TE. Author information: (1)University College London Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, London HA7 4LP, UK. wasimkhan@doctors.org.uk There has been an increasing interest in stem cell applications and tissue engineering approaches in surgical practice to deal with damaged or lost tissue. Although there have been developments in almost all surgical disciplines, the greatest advances are being made in orthopaedics. This is due to many factors including the familiarity with bone marrow derived mesenchymal stem cells. Unfortunately significant hurdles remain to be overcome in many areas before tissue engineering becomes more routinely used in clinical practice. Stem cells have been identified in a number of adult tissues, albeit in small numbers. In addition to bone marrow, mesenchymal stem cells have been identified in a number of tissues including adipose tissue and fat pad. The mesenchymal stem cells are generally isolated from the tissue and expanded in culture. These cells are characterised or defined using a set of cell surface markers; mesenchymal stem cells are generally positive for CD44, CD90 and CD105, and are negative for haematopoetic markers CD34 and CD45, and the neurogenic marker CD56. In this paper the characterisation of stem cells is discussed followed by preliminary evidence suggesting that pericytes may be a candidate stem cell. PMID: 23550347 [PubMed - indexed for MEDLINE] 450. Nutr Diabetes. 2012 Mar 5;2:e29. doi: 10.1038/nutd.2012.1. Getting 'Smad' about obesity and diabetes. Tan CK(1), Chong HC, Tan EH, Tan NS. Author information: (1)School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. Recent findings on the role of transforming growth factor (TGF)-β/Smad3 signaling in the pathogenesis of obesity and type 2 diabetes have underscored its importance in metabolism and adiposity. Indeed, elevated TGF-β has been previously reported in human adipose tissue during morbid obesity and diabetic neuropathy. In this review, we discuss the pleiotropic effects of TGF-β/Smad3 signaling on metabolism and energy homeostasis, all of which has an important part in the etiology and progression of obesity-linked diabetes; these include adipocyte differentiation, white to brown fat phenotypic transition, glucose and lipid metabolism, pancreatic function, insulin signaling, adipocytokine secretion, inflammation and reactive oxygen species production. We summarize the recent in vivo findings on the role of TGF-β/Smad3 signaling in metabolism based on the studies using Smad3(-/-) mice. Based on the presence of a dual regulatory effect of Smad3 on peroxisome proliferator-activated receptor (PPAR)β/δ and PPARγ2 promoters, we propose a unifying mechanism by which this signaling pathway contributes to obesity and its associated diabetes. We also discuss how the inhibition of this signaling pathway has been implicated in the amelioration of many facets of metabolic syndromes, thereby offering novel therapeutic avenues for these metabolic conditions. PMCID: PMC3341711 PMID: 23449528 [PubMed] 451. Horm Metab Res. 2012 Jan;44(1):6-14. doi: 10.1055/s-0031-1295491. Epub 2011 Dec 28. The metabolic role of retinol binding protein 4: an update. Christou GA(1), Tselepis AD, Kiortsis DN. Author information: (1)Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece. Retinol binding protein 4 (RBP(4)) is regarded as a novel cardiometabolic risk factor, which is secreted mainly by the hepatocytes and also by the adipose tissue. RBP(4) has been shown to induce insulin resistance, and plasma RBP(4) values are increased in type 2 diabetes mellitus, obesity, metabolic syndrome, and cardiovascular disease. Moreover, it has been found that circulating RBP(4) decreases during medical interventions that result in amelioration of the metabolic profile, such as diet, exercise, oral antidiabetic drugs, and hypolipidemic agents. However, only few of the RBP(4)-related studies have investigated whether RBP(4) constitutes a causal factor of the above-mentioned metabolic conditions. Importantly, circulating RBP(4) is influenced by some nonmetabolic conditions, such as renal failure, acute illness, injury, and liver failure. Thus, further studies investigating the metabolic roles of RBP(4) should be carefully planned, taking into account the effects of nonmetabolic conditions on circulating RBP(4). © Georg Thieme Verlag KG Stuttgart · New York. PMID: 22205567 [PubMed - indexed for MEDLINE] 452. Curr Pharm Des. 2011 Dec;17(37):4121-31. Inflammation in hypertension: current therapeutic approaches. Androulakis E(1), Tousoulis D, Papageorgiou N, Latsios G, Siasos G, Tsioufis C, Giolis A, Stefanadis C. Author information: (1)1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, Greece. The role of inflammation as crucial underlying process contributing to the initiation and the progression of atherosclerosis as well as its clinical manifestations is well established. Recent data have demonstrated also a strong association between essential hypertension and inflammatory process. In addition, several studies have shown that tissue expression and plasma concentrations of several inflammatory biomarkers/mediators are related to increased risk of hypertension. The determination of markers such as acute phase proteins (C-reactive protein), adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and chemokines is crucial in determining therapeutic responses and clinical outcomes of hypertensive patients. In addition, several therapeutic approaches targeting blood pressure may have also beneficial effects in terms of inflammation and thus further clinical benefits. Although the available data are encouraging, further large scale studies are required to evaluate the reported anti-inflammatory effects in management and treatment of arterial hypertension. PMID: 22204373 [PubMed - indexed for MEDLINE] 453. Exp Diabetes Res. 2012;2012:103063. doi: 10.1155/2012/103063. Epub 2011 Dec 8. The pathophysiology of HIV-/HAART-related metabolic syndrome leading to cardiovascular disorders: the emerging role of adipokines. Palios J(1), Kadoglou NP, Lampropoulos S. Author information: (1)2nd Department of Cardiology, Attikon University Hospital of Athens, Haidari 12462, Greece. Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate metabolic syndrome (MS) associated with increased incidence of cardiovascular disorders. Characteristics of HIV infection, such as immunodeficiency, viral load, and duration of the disease, in addition to the highly active antiretroviral therapy (HAART) have been suggested to induce MS in these patients. It is well documented that MS involves a number of traditional cardiovascular risk factors, like glucose, lipids, and arterial blood pressure abnormalities, leading to extensive atherogenic arterial wall changes. Nevertheless, the above traditional cardiovascular risk factors merely explain the exacerbated cardiovascular risk in MS. Nowadays, the adipose-tissue derivatives, known as adipokines, have been suggested to contribute to chronic inflammation and the MS-related cardiovascular disease. In view of a novel understanding on how adipokines affect the pathogenesis of HIV/HAART-related MS and cardiovascular complications, this paper focuses on the interaction of the metabolic pathways and the potential cardiovascular consequences. Based on the current literature, we suggest adipokines to have a role in the pathogenesis of the HIV/HAART-related MS. It is crucial to understand the pathophysiology of the HIV/HAART-related MS and apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients. PMCID: PMC3235775 PMID: 22203832 [PubMed - indexed for MEDLINE] 454. Front Biosci (Schol Ed). 2012 Jan 1;4:916-31. Insulin resistance, metabolic stress, and atherosclerosis. Pansuria M(1), Xi H, Li L, Yang XF, Wang H. Author information: (1)Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMCID: PMC3319745 PMID: 22202099 [PubMed - indexed for MEDLINE] 455. Front Biosci (Elite Ed). 2012 Jan 1;4:768-78. Role of sirtuins, calorie restriction and physical activity in aging. Corbi G(1), Conti V, Scapagnini G, Filippelli A, Ferrara N. Author information: (1)Department of Health Sciences, Faculty of Medicine and Surgery, University of Molise, via Giovanni Paolo II -Localita Tappino, 86100 Campobasso, Italy. graziamaria.corbi@unimol.it Recently it has been discovered that Sirtuins represent pivotal regulators of lifespan. Caloric restriction (CR) enhances longevity from yeast to mammals. Whereas the relationship between Sirt-1 and CR is clear, the molecular mechanisms by which Sir2 increases longevity are still unknown. In mammals, CR induces physiological and behavioral changes, and many studies have shown that CR decreases production of reactive oxygen species production thus minimizing oxidative damage, leading to the hypothesis that CR by reducing oxidative stress extends the lifespan by counteraction of aging. In fact, the pathophysiology of aging and age-related diseases involves oxidative stress as an early stage in its development. Recently we found that in aged rats the SIRT1 activity was decreased in heart and adipose tissue, showing as aging is characterized in vivo by a reduced efficiency of this key-regulator of longevity. Whereas several studies have reported that increased physical activity can improve mean life span presumably by reducing mortality risk from many age-related diseases, exercise and longevity studies have failed to document an exercise effect on maximum life span. However, in aged rats a moderate prolonged exercise training is able to induce increase in SIRT1 activity, suggesting that this tool could counteract age-related dysfunctions. PMID: 22201912 [PubMed - indexed for MEDLINE] 456. Front Biosci (Landmark Ed). 2012 Jan 1;17:892-908. The biology of equine mesenchymal stem cells: phenotypic characterization, cell surface markers and multilineage differentiation. Penny J(1), Harris P, Shakesheff KM, Mobasheri A. Author information: (1)Musculoskeletal Research Group, Division of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, College Road, Sutton Bonington, Leicestershire, LE12 5RD, United Kingdom. Mesenchymal stem cells (MSCs) are multipotent stem cells that can give rise to a range of connective tissue cells including osteoblasts, chondrocytes and adipocytes. MSCs have been isolated from humans and a variety of animal species including rodents, dogs, horses and rabbits. There is currently no consensus on how these cells are identified and characterized. This is partly due to the lack of standardized specific cell surface markers for MSCs. The aim of this review is to examine the literature on equine MSCs and establish whether there is a well-defined phenotype for these cells. Equine MSCs have been obtained from four main sources, bone marrow, adipose tissue, umbilical cord (blood and matrix) and peripheral blood. MSCs from these tissue sources have been shown to undergo chondrogenic, adipogenic and osteogenic differentiation. However the markers used to identify these cells vary significantly in the literature. Despite this, CD90 and CD34 seem to be reliable positive and negative markers respectively. Our understanding of the biology of equine MSCs will benefit from better reagents for their phenotypic characterization. The antibodies and molecular probes needed for the reliable identification of equine MSCs are not standardized and this is a high priority for future research. PMID: 22201780 [PubMed - indexed for MEDLINE] 457. Neuropharmacology. 2012 Jul;63(1):57-75. doi: 10.1016/j.neuropharm.2011.12.010. Epub 2011 Dec 17. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Harwood HJ Jr(1). Author information: (1)Delphi BioMedical Consultants, LLC, 10 Eska Drive, Ledyard, CT 06339, USA. h.james.harwood@gmail.com Over the past decade and a half it has become increasingly clear that adipose tissue is a much more complex organ than was initially considered and that its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. In fact, it is now well established that adipose tissue plays a critical role in maintenance of energy homeostasis through secretion of a large number of adipokines that interact with central as well as peripheral organs such as the brain, liver, pancreas, and skeletal muscle to control diverse processes, such as food intake, energy expenditure, carbohydrate and lipid metabolism, blood pressure, blood coagulation, and inflammation. While many of these adipokines are adipocyte-derived and have a variety of endocrine functions, others are produced by resident macrophages and interact in a paracrine fashion to control adipocyte metabolism. It is also abundantly clear that the dysregulation of adipokine secretion and action that occurs in obesity plays a fundamental role in the development of a variety of cardiometabolic disorders, including the metabolic syndrome, type 2 diabetes, inflammatory disorders, and vascular disorders, that ultimately lead to coronary heart disease. Described herein are the traditional as well as endocrine roles of adipose tissue in controlling energy metabolism and their dysregulation in obesity that leads to development of cardiometabolic disorders, with a focus on what is currently known regarding the characteristics and roles in both health and disease of the adipocyte-derived adipokines, adiponectin, leptin, resistin, and retinol binding protein 4, and the resident macrophage-derived adipokines, tumor necrosis factor-α and interleukin-6. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22200617 [PubMed - indexed for MEDLINE] 458. J Ren Nutr. 2012 Jan;22(1):81-5. doi: 10.1053/j.jrn.2011.10.029. Adipokines as uremic toxins. Teta D(1). Author information: (1)Service of Nephrology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. daniel.teta@chuv.ch The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 22200420 [PubMed - indexed for MEDLINE] 459. ScientificWorldJournal. 2011;11:1932-47. doi: 10.1100/2011/290142. Epub 2011 Oct 25. Beyond fat mass: exploring the role of adipokines in rheumatic diseases. Scotece M(1), Conde J, Gómez R, López V, Lago F, Gómez-Reino JJ, Gualillo O. Author information: (1)Laboratory of Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, SERGAS, Institute of Medical Research IDIS, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain. The cloning of leptin in 1994 by Zhang et al. introduced a novel concept about white adipose tissue (WAT) as a very dynamic organ that releases a plethora of immune and inflammatory mediators, such as adipokines and cytokines, which are involved in multiple diseases. Actually, adipokines exert potent modulatory actions on target tissues involved in rheumatic diseases including cartilage, synovial, bone and immune cells. The goal of this paper is to elucidate the recent findings concerning the involvement of adipokines in rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). PMCID: PMC3236382 PMID: 22194660 [PubMed - indexed for MEDLINE] 460. Ageing Res Rev. 2012 Apr;11(2):220-9. doi: 10.1016/j.arr.2011.12.003. Epub 2011 Dec 13. "Is obesity linked to aging?": adipose tissue and the role of telomeres. Tzanetakou IP(1), Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN. Author information: (1)Laboratory for Experimental Surgery and Surgical Research "N. S. Christeas", University of Athens Medical School, Greece. itzanetakoy@yahoo.gr Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22186032 [PubMed - indexed for MEDLINE] 461. Am J Physiol Endocrinol Metab. 2012 Jun 1;302(11):E1315-28. doi: 10.1152/ajpendo.00561.2011. Epub 2011 Dec 20. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Watt MJ(1), Hoy AJ. Author information: (1)Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. matthew.watt@monash.edu Fatty acids derived from adipose tissue lipolysis, intramyocellular triacylglycerol lipolysis, or de novo lipogenesis serve a variety of functions in skeletal muscle. The two major fates of fatty acids are mitochondrial oxidation to provide energy for the myocyte and storage within a variety of lipids, where they are stored primarily in discrete lipid droplets or serve as important structural components of membranes. In this review, we provide a brief overview of skeletal muscle fatty acid metabolism and highlight recent notable advances in the field. We then 1) discuss how lipids are stored in and mobilized from various subcellular locations to provide adaptive or maladaptive signals in the myocyte and 2) outline how lipid metabolites or metabolic byproducts derived from the actions of triacylglycerol metabolism or β-oxidation act as positive and negative regulators of insulin action. We have placed an emphasis on recent developments in the lipid biology field with respect to understanding skeletal muscle physiology and discuss unanswered questions and technical limitations for assessing lipid signaling in skeletal muscle. PMID: 22185843 [PubMed - indexed for MEDLINE] 462. Crit Rev Eukaryot Gene Expr. 2011;21(4):363-77. Mesenchymal stem cells in the aging and osteoporotic population. Veronesi F(1), Torricelli P, Borsari V, Tschon M, Rimondini L, Fini M. Author information: (1)Preclinical and Surgical Studies Laboratory, Codivilla-Putti Research Institute--Rizzoli Orthopedica Institute, Bologna-Italy. Because of their ability to self-renew and differentiate, mesenchymal stem cells (MSCs) are the in vivo source for replacing lost cells in high-turnover tissues during the life of an organism. MSCs have osteogenic potential and can be eligible for the repair and maintenance of the skeleton, thus they are very attractive for tissue engineering and regenerative medicine approaches. However, many changes in their behavior, caused by aging and bone disease, have been reported in the literature. These changes, which affect MSC self-renewal ability and differentiation potentiality, are related to cell proliferation, differentiation, cell cycle phases (depending on gene modification), and cytokine and growth factor production. This review summarizes the literature related to intrinsic and extrinsic characteristics of human bone marrow or adipose tissue MSCs during aging and osteoporosis. Although some studies reveal contrasting results, the results of this review suggest that the cellular modifications due to aging and osteoporosis should be carefully considered in relation to the use of MSCs for therapeutic application. PMID: 22181705 [PubMed - indexed for MEDLINE] 463. J Med Food. 2012 Mar;15(3):223-30. doi: 10.1089/jmf.2011.0072. Epub 2011 Dec 19. Dietary fiber, gut peptides, and adipocytokines. Sánchez D(1), Miguel M, Aleixandre A. Author information: (1)Department of Pharmacology, Faculty of Medicine, Complutense University, Madrid, Spain. The consumption of dietary fiber (DF) has increased since it was related to the prevention of a range of illnesses and pathological conditions. DF can modify some gut hormones that regulate satiety and energy intake, thus also affecting lipid metabolism and energy expenditure. Among these gut hormones are ghrelin, glucagon-like peptide 1, peptide YY, and cholecystokinin. Adipose tissue is known to express and secrete a variety of products known as "adipocytokines," which are also affected by DF. Some of the most relevant adipocytokines include adiponectin, leptin, tumor necrosis factor-α, and interleukin-6. The release of adipocytokines, by either adipocytes or macrophage-infiltrated adipose tissue, leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, therefore increasing the risk of cardiovascular disease associated with obesity. DF modulation of these molecules could also have positive effects on obesity, insulin resistance, and hyperlipidemia. This review is focused on the effects of DF on the above-mentioned gut peptides and adipocytokines. PMID: 22181071 [PubMed - indexed for MEDLINE] 464. Steroids. 2012 Mar 10;77(4):300-5. doi: 10.1016/j.steroids.2011.12.003. Epub 2011 Dec 8. Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction. González F(1). Author information: (1)Indiana University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Indianapolis, IN 46202, USA. gonzalef@iupui.edu Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3309040 PMID: 22178787 [PubMed - indexed for MEDLINE] 465. Cytotherapy. 2012 May;14(5):555-62. doi: 10.3109/14653249.2011.638914. Epub 2011 Dec 16. Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine. Wu X(1), Ren J, Li J. Author information: (1)Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. The use of tissue-engineering techniques such as stem-cell therapy to renew injured tissues is a promising strategy in regenerative medicine. As a cell-delivery vehicle, fibrin glues (FG) facilitate cell attachment, growth and differentiation and, ultimately, tissue formation and organization by its three-dimensional structure. Numerous studies have provided evidence that stromal cells derived from bone marrow (bone marrow stromal cells; BMSC) and adipose tissue (adipose-derived stromal cells; ADSC) contain a population of adult multipotent mesenchymal stromal cells (MSC) and endothelial progenitor cells that can differentiate into several lineages. By combining MSC with FG, the implantation could take advantage of the mutual benefits. Researchers and physicians have pinned their hopes on stem cells for developing novel approaches in regenerative medicine. This review focuses on the therapeutic potential of MSC with FG in bone defect reconstruction, cartilage and tendon injury repair, ligament, heart and nerve regeneration, and, furthermore, wound healing. PMID: 22175911 [PubMed - indexed for MEDLINE] 466. Ann N Y Acad Sci. 2011 Dec;1240:70-6. doi: 10.1111/j.1749-6632.2011.06309.x. Pathogenesis of diabetic neuropathy: bad to the bone. Chan L(1), Terashima T, Urabe H, Lin F, Kojima H. Author information: (1)Diabetes and Endocrinology Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA. lchan@bcm.edu Insulin and proinsulin are normally produced only by the pancreas and thymus. We detected in diabetic rodents the presence of extra pancreatic proinsulin-producing bone marrow-derived cells (PI-BMDCs) in the BM, liver, and fat. In mice and rats with diabetic neuropathy, we also found proinsulin-producing cells in the sciatic nerve and neurons of the dorsal root ganglion (DRG). BM transplantation experiments using genetically marked donor and recipient mice showed that the proinsulin-producing cells in the DRG, which morphologically resemble neurons, are actually polyploid proinsulin-producing fusion cells formed between neurons and PI-BMDCs. Additional experiments indicate that diabetic neuropathy is not simply the result of nerve cells being damaged directly by hyperglycemia. Rather, hyperglycemia induces fusogenic PI-BMDCs that travel to the peripheral nervous system, where they fuse with Schwann cells and DRG neurons, causing neuronal dysfunction and death, the sine qua non for diabetic neuropathy. Poorly controlled diabetes is indeed bad to the bone. © 2011 New York Academy of Sciences. PMCID: PMC3636709 PMID: 22172042 [PubMed - indexed for MEDLINE] 467. Int J Surg Pathol. 2012 Aug;20(4):390-5. doi: 10.1177/1066896911428735. Epub 2011 Dec 14. Neuroendocrine tumor of the pancreas in a patient with tuberous sclerosis: a case report and review of the literature. Díaz Díaz D(1), Ibarrola C, Goméz Sanz R, Pérez Hurtado B, Salazar Tabares J, Colina Ruizdelgado F. Author information: (1)Pathology Service, Hospital Universitario 12 de Octubre, Madrid, Spain. delissadiaz@gmail.com A rare case of pancreatic neuroendocrine neoplasm in a patient with tuberous sclerosis complex is described. The patient was a 31-year-old man who had multiple congenital subependymal nodules, bilateral cortical tubers, and seizures of difficult control. A 2.3 cm × 2 cm well-delimitated solid tumor in the tail of the pancreas was discovered during a monitoring abdominal computed tomography. A distal pancreatectomy was performed. Histologically, the tumor was formed by uniform cells with moderated cytoplasm arranged in a combined trabecular and nested pattern. The nuclear features were bland, and mitosis was infrequent. There was no vascular invasion. Immunoreactivity for cytokeratine AE1/AE3, chromogranin A, and synaptophysin confirmed the neuroendocrine nature of this neoplasia. Pancreatic hormones were negatives. One of the 5 lymph nodes isolated from the peripancreatic adipose tissue was positive for metastases. Small series and case reports have documented that in tuberous sclerosis many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid, and other neuroendocrine tissue, including islet cells of the pancreas. However, the true association of these pathological conditions remains uncertain. As far as we know, there are 10 cases reported of pancreatic neuroendocrine tumors in a setting of tuberous sclerosis complex, in which 2 cases resulted in malignant, nonfunctioning pancreatic neuroendocrine tumors. PMID: 22169969 [PubMed - indexed for MEDLINE] 468. Trends Endocrinol Metab. 2012 Feb;23(2):83-9. doi: 10.1016/j.tem.2011.10.003. Epub 2011 Dec 12. Aromatase, breast cancer and obesity: a complex interaction. Bulun SE(1), Chen D, Moy I, Brooks DC, Zhao H. Author information: (1)Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE(2) production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3428377 PMID: 22169755 [PubMed - indexed for MEDLINE] 469. Zhonghua Xin Xue Guan Bing Za Zhi. 2011 Aug;39(8):772-5. [Adipose tissue-derived stem cells-a novel option for cardiac regenerative]. [Article in Chinese] Yin QX, Zhao YS. PMID: 22169431 [PubMed - indexed for MEDLINE] 470. Gen Comp Endocrinol. 2012 Jul 1;177(3):296-304. doi: 10.1016/j.ygcen.2011.11.039. Epub 2011 Dec 7. Peptidergic Edinger-Westphal neurons and the energy-dependent stress response. Xu L(1), Scheenen WJ, Roubos EW, Kozicz T. Author information: (1)Department of Cellular Animal Physiology, Faculty of Science, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands. The continuously changing environment demands for adequate stress responses to maintain the internal dynamic equilibrium of body and mind. A successful stress response requires energy, in an amount matching the severity of the stressor and the type of response ('fight, flight or freeze'). The stress response is generated by the central nervous system, which needs to be informed about both the threatening stressor and the availability of energy. In this review, evidence is considered for a role of the midbrain Edinger-Westphal centrally projecting neuron population (EWcp; synonym: non-preganglionic Edinger-Westphal nucleus) in the energy-dependent stress adaptation response. It deals with studies on the neurochemical organization of the EWcp with particular reference to the neuropeptides urocortin-1 and cocaine- and amphetamine-regulated transcript peptide, on the EWcp responses to different types of stressor (e.g., acute and chronic) and a changed energy state (e.g., fasting and leptin change), and on the sex-specificity of these responses. Finally, a model is presented for the way the EWcp might contribute to the coordination of the energy-dependent stress adaptation response. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22166814 [PubMed - indexed for MEDLINE] 471. Immunol Res. 2012 Jun;52(3):182-99. doi: 10.1007/s12026-011-8261-7. Immunomodulation at epithelial sites by obesity and metabolic disease. Cheung KP(1), Taylor KR, Jameson JM. Author information: (1)The Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, Imm-25, La Jolla, CA, 92037, USA. Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options. PMID: 22160809 [PubMed - indexed for MEDLINE] 472. Mol Biol Rep. 2012 May;39(5):5367-71. doi: 10.1007/s11033-011-1336-7. Epub 2011 Dec 13. Role of NYGGF4 in insulin resistance. Chen X(1), Huang Z, Chen D, Jia G, Mao X, Wu X. Author information: (1)Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, 625014, Sichuan, People's Republic of China. chenxlh@hotmail.com Insulin resistance is a clinical condition that is characterized by reducing glucose uptake in response to insulin. A major factor in the development of insulin resistance syndrome is obesity. NYGGF4 is a novel gene that is abundantly expressed in the adipose tissue of obese subjects. NYGGF4 induced the secretion of FFAs and TNF-α and caused mitochondrial dysfunction, which may cause insulin resistance. This review will summarize the effect of NYGGF4 on the adipogenesis, glucose uptake and mitochondrial dysfunction in vitro, and the possible mechanism and signal pathway of NYGGF4 for insulin resistance. PMID: 22160469 [PubMed - indexed for MEDLINE] 473. Pediatr Emerg Care. 2011 Dec;27(12):1167-9. doi: 10.1097/PEC.0b013e31823b0186. Traumatic pediatric olecranon injury: a report of suture fixation and review of the literature. Rath NK(1), Carpenter EC, Thomas DP. Author information: (1)Department of Paediatric Orthopaedics and Trauma, University Hospital of Wales, Cardiff, UK. rath.narendra@gmail.com Elbow injuries make up to 3% to 4% of all emergency department presentations and are often difficult to diagnose. These injuries are often missed on radiographs because of the large cartilaginous component of the pediatric elbow resulting in malunion. Fractures around the elbow joint are one of the leading causes of litigation claim, and awareness of the pitfalls in diagnosis of these subtle injuries is necessary for a prompt diagnosis. Fracture of the olecranon epiphysis is rare and often being described around puberty and in association with osteogenesis imperfecta. Management using K-wire tension band fixation has been described in the past, which can lead to growth arrest in younger patients.We hereby present a missed rare sleeve-type open olecranon epiphyseal fracture in a young child, highlighting the pitfalls in the diagnosis of these injuries. This article also reviews various options to manage such a rare fracture and also suggests an alternative method of transosseous suture fixation with an excellent result. PMID: 22158276 [PubMed - indexed for MEDLINE] 474. Ann Saudi Med. 2012 Jan-Feb;32(1):68-77. Human stromal (mesenchymal) stem cells: basic biology and current clinical use for tissue regeneration. Aldahmash A(1), Zaher W, Al-Nbaheen M, Kassem M. Author information: (1)Stem Cell Unit, King Saud University, Riyadh, Saudi Arabia. mkassem@health.sdu.dk Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy. PMID: 22156642 [PubMed - indexed for MEDLINE] 475. Circulation. 2011 Dec 13;124(24):e837-41. doi: 10.1161/CIRCULATIONAHA.111.077602. Ectopic fat depots and cardiovascular disease. Britton KA(1), Fox CS. Author information: (1)Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. PMID: 22156000 [PubMed - indexed for MEDLINE] 476. Georgian Med News. 2011 Oct;(199):81-5. [Role of the adipose derived adult stem cell in cartilage regeneration, features and brief history (review)]. [Article in Russian] Salmanov A. Regeneration of the cartilage is one of the difficult and uncertain solved problems of reconstructive surgery. Lot of successfully experiments was done about regeneration of cartilage defects with ADAS cells. Use of stem cells promise new decisons in this direction at the near future. Little information about ADAS cells and their use in regeneration of cartilage defects was revealed. PMID: 22155811 [PubMed - indexed for MEDLINE] 477. Sports Med. 2012 Jan 1;42(1):51-67. doi: 10.2165/11595680-000000000-00000. Evaluation and treatment of disorders of the infrapatellar fat pad. Dragoo JL(1), Johnson C, McConnell J. Author information: (1)Department of Orthopaedic Surgery, Stanford University, Palo Alto, CA, USA. jdragoo@stanford.edu The infrapatellar fat pad (IFP), also known as Hoffa's fat pad, is an intracapsular, extrasynovial structure that fills the anterior knee compartment, and is richly vascularized and innervated. Its degree of innervation, the proportion of substance-P-containing fibres and close relationship to its posterior synovial lining implicates IFP pathologies as a source of infrapatellar knee pain. Though the precise function of the IFP is unknown, studies have shown that it may play a role in the biomechanics of the knee or act as a store for reparative cells after injury. Inflammation and fibrosis within the IFP, caused by trauma and/or surgery can lead to a variety of arthrofibrotic lesions including Hoffa's disease, anterior interval scarring and infrapatellar contracture syndrome. Lesions or mass-like abnormalities rarely occur within the IFP, but their classification can be narrowed down by radiographical appearance. Clinically, patients with IFP pathology present with burning or aching infrapatellar anterior knee pain that can often be reproduced on physical exam with manoeuvres designed to produce impingement. Sagittal MRI is the most common imaging technique used to assess IFP pathology including fibrosis, inflammation, oedema, and mass-like lesions. IFP pathology is often successfully managed with physical therapy. Passive taping is used to unload or shorten an inflamed IFP, and closed chain quadriceps exercises can improve lower limb control and patellar congruence. Training of the gluteus medius and stretching the anterior hip may help to decrease internal rotation of the hip and valgus force at the knee. Gait training and avoiding hyperextension can also be used for long-term management. Injections within the IFP of local anaesthetic plus corticosteroids and IFP ablation with ultrasound guided alcohol injections have been successfully explored as treatments for IFP pain. IFP pathology refractory to physical therapy can be approached through a variety of operative treatments. Arthroscopic partial resection for IFP impingement and Hoffa's disease has showed favourable results; however, total excision of the IFP performed concomitantly with total knee arthroplasty (TKA) resulted in worse results when compared with TKA alone. Arthroscopic debridement of IFP fibrosis has been successfully used to treat extension block following anterior cruciate ligament reconstruction, and arthroscopic anterior interval release has been an effective treatment for pain associated with anterior interval scarring. Arthroscopic resection of infrapatellar plicae and denervation of the inferior pole of the patella have also been shown to be effective treatments for refractory infrapatellar pain. PMID: 22149697 [PubMed - indexed for MEDLINE] 478. Benef Microbes. 2011 Dec 1;2(4):305-18. doi: 10.3920/BM2011.0020. Prebiotics to manage the microbial control of energy homeostasis. Grootaert C(1), Marzorati M, Van den Abbeele P, Van de Wiele T, Possemiers S. Author information: (1)Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Coupure Links 653, 9000 Ghent, Belgium. The prevalence of obesity is continuously growing and has reached epidemic proportions. It is clear that current methods to combat obesity are not effective enough to reduce the problem. Therefore, further investigation is needed to develop new strategies. Recent research pointed out a potential role of the microbial community associated to the human host in controlling and influencing the energy homeostasis. According to the concept of Gastrointestinal Resource Management, this microbiota and its metabolic potential can be steered with the aim of improving host health. This review therefore focuses on the modulation of the intestinal microbiota through prebiotics with the aim to control several aspects of metabolic homeostasis. In a first part, the importance of host-microbe cross-talk at the intestinal epithelium is discussed. Yet, energy metabolism, which includes both lipid and glucose metabolism, is also regulated by several key organs including the adipose tissue, brain, liver, muscles, pancreas and gut. Therefore, in a second part, we will discuss the microbial factors that are involved in the communication between these different tissues, and their potential management. Finally, we will give some future prospects of the use of prebiotics in an individualised treatment of metabolic disorders. PMID: 22146690 [PubMed - indexed for MEDLINE] 479. Metabolism. 2012 May;61(5):611-9. doi: 10.1016/j.metabol.2011.10.005. Epub 2011 Dec 5. Metabolic consequences of stress during childhood and adolescence. Pervanidou P(1), Chrousos GP. Author information: (1)First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, 11527 Athens, Greece. ppervanid@med.uoa.gr Comment in Metabolism. 2012 May;61(5):e1; author reply e3-4. Stress, that is, the state of threatened or perceived as threatened homeostasis, is associated with activation of the stress system, mainly comprised by the hypothalamic-pituitary-adrenal axis and the arousal/sympathetic nervous systems. The stress system normally functions in a circadian manner and interacts with other systems to regulate a variety of behavioral, endocrine, metabolic, immune, and cardiovascular functions. However, the experience of acute intense physical or emotional stress, as well as of chronic stress, may lead to the development of or may exacerbate several psychologic and somatic conditions, including anxiety disorders, depression, obesity, and the metabolic syndrome. In chronically stressed individuals, both behavioral and neuroendocrine mechanisms promote obesity and metabolic abnormalities: unhealthy lifestyles in conjunction with dysregulation of the stress system and increased secretion of cortisol, catecholamines, and interleukin-6, with concurrently elevated insulin concentrations, lead to development of central obesity, insulin resistance, and the metabolic syndrome. Fetal life, childhood, and adolescence are particularly vulnerable periods of life to the effects of intense acute or chronic stress. Similarly, these life stages are crucial for the later development of behavioral, metabolic, and immune abnormalities. Developing brain structures and functions related to stress regulation, such as the amygdala, the hippocampus, and the mesocorticolimbic system, are more vulnerable to the effects of stress compared with mature structures in adults. Moreover, chronic alterations in cortisol secretion in children may affect the timing of puberty, final stature, and body composition, as well as cause early-onset obesity, metabolic syndrome, and type 2 diabetes mellitus. The understanding of stress mechanisms leading to metabolic abnormalities in early life may lead to more effective prevention and intervention strategies of obesity-related health problems. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22146091 [PubMed - indexed for MEDLINE] 480. J Sex Med. 2012 Feb;9(2):385-403. doi: 10.1111/j.1743-6109.2011.02556.x. Epub 2011 Dec 6. Multipotent stromal cell therapy for cavernous nerve injury-induced erectile dysfunction. Albersen M(1), Kendirci M, Van der Aa F, Hellstrom WJ, Lue TF, Spees JL. Author information: (1)Laboratory of Experimental Urology, University Hospitals Leuven, Leuven, Belgium. INTRODUCTION: Erectile dysfunction (ED) following radical prostatectomy (RP) is a result of inadvertent damage to the cavernous nerves that run close to the prostate capsula. The mechanisms behind the development of post-RP ED are increasingly recognized and include cavernosal fibrosis and cavernosal smooth muscle apoptosis, resulting from cavernous nerve degeneration due to neuropraxia. In recent years, cell-based therapies have received increasing attention regarding their potential for recovery of erectile function following cavernous nerve injury (CNI). Multipotent stromal cells (MSCs) are an attractive cell source for this application based on their regenerative potential and their clinical applicability. AIM: To review available evidence on the efficacy and mechanisms of action of MSC application for the treatment of ED, with an emphasis on ED following CNI. METHODS: A nonsystematic review was conducted on the available English literature between 1966 and 2011 on the search engines SciVerse-sciencedirect, SciVerse-scopus, Google Scholar, and PubMed. RESULTS: MSCs from both bone marrow and adipose tissue have shown beneficial effects in a variety of animal models for ED. While MSC application in chronic disease models such as diabetes, aging, and hyperlipidemia may result in cell engraftment and possibly MSC differentiation, this observation has not been made in the acute CNI rat model. In the latter setting, MSC effects seem to be established by cell recruitment toward the major pelvic ganglion and local paracrine interaction with the host neural tissue. CONCLUSIONS: While the type of model may influence the mechanisms of action of this MSC-based therapy, MSCs generally display efficacy in various animal models for ED. Before translation to the clinic is established, various hurdles need to be overcome. © 2011 International Society for Sexual Medicine. PMID: 22145667 [PubMed - indexed for MEDLINE] 481. Ann Nutr Metab. 2011;59(2-4):176-86. doi: 10.1159/000334071. Epub 2011 Dec 2. Effects of monounsaturated fatty acids on cardiovascular risk factors: a systematic review and meta-analysis. Schwingshackl L(1), Strasser B, Hoffmann G. Author information: (1)University for Health Sciences, Medical Informatics and Technology, Institute for Nutritional Sciences and Physiology, Hall in Tirol, Austria. lukas.schwingshackl@umit.at The appropriate pattern of macronutrient distribution for dietary protocols aimed at treating or preventing obesity and its associated cardiovascular diseases is still a controversial topic of discussion. Recommendations considering a specific percentage or range for monounsaturated fatty acids (MUFA) are rare. It was the aim of this study to analyze long-term, randomized, controlled dietary intervention trials and to investigate the effects of MUFA on the biomarkers of obesity and cardiovascular risk factors. Dietary regimens with a high amount of MUFA (>12%) were compared to those with ≤12%. The biomarkers taken into account were weight, waist circumference, fat mass, total cholesterol, LDL cholesterol, HDL cholesterol, triacylglycerols, systolic and diastolic blood pressure, as well as C-reactive protein. A total of 12 studies met the inclusion criteria. Data analysis was performed using the Review Manager 5.0.25 software. Significant differences between high- and low-MUFA protocols could be observed with respect to fat mass [-1.94 kg (confidence interval -3.72, -0.17), p = 0.03], systolic blood pressure [-2.26 mm Hg (confidence interval -4.28, -0.25), p = 0.03] and diastolic blood pressure [-1.15 mm Hg (confidence interval -1.96, -0.34), p = 0.005] favoring the dietary protocols with >12% MUFA. Therefore, MUFA might represent a useful tool in the design of dietary regimens for obesity and cardiovascular disease. Copyright © 2011 S. Karger AG, Basel. PMID: 22142965 [PubMed - indexed for MEDLINE] 482. Dan Med Bull. 2011 Dec;58(12):B4368. Glucose-dependent Insulinotropic Polypeptide (GIP): From prohormone to actions in endocrine pancreas and adipose tissue. Ugleholdt R(1). Author information: (1)Department of Biomedical Sciences, Cellular and Metabolic Research Section, University of Copenhagen, Faculty of Health Sciences, Blegdamsvej 3B build. 12.2, 2200 Copenhagen N, Denmark. randi@ugleholdt.com The present thesis consists of one published article and one draft manuscript. Interest in the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) was reignited by the discovery that GIP receptor deficient mice were unable to gain weight in response to high fat feeding. However, the path from processing of the prohormone to regulation of secretion and establishment of its role in the complicated network of mediators involved in energy mobilization is not fully understood. The biologically active GIP1-42 was found in vivo to be dependent on processing from the immature prohormone by proprotein convertase 1/3 (PC1/3) in the intestinal K-cell. Even so, ~50% of GIP immunoreactive cells do not express PC1/3 raising the possibility that subsets of K-cells exist in which the precursor may be cleaved at alternative sites. Cell line studies did demonstrate that another convertase in endocrine cell types, PC2, mediated cleavage at alternative sites liberating larger and smaller GIP fragments. It was possible to detect fragments of similar size in gel filtration extracts of murine upper jejunum, but the identity, mechanism of processing and function of these immunoreactivities remains uncertain. Once correctly processed GIP1-42 is secreted in response to food intake. The K-cell is believed to directly sense and respond to nutrients in the intestine, but as the molecular profiling of this cell type has just begun, the nutrient sensing machinery and possible feedback regulation are still poorly characterized. When secreted to the blood stream, GIP acts as a mediator of energy mobilization in a complex network with other hormones. An acute and established function of GIP is to exert its incretin function thereby enhancing glucose stimulated insulin secretion necessary for prompt disposal of nutrients, yet GIP also stimulates glucagon secretion to increase blood glucose. In the diabetic state the insulinotropic effect of GIP is impaired and an early inexpedient glucagon stimulation in response to a meal further counteracts effects of insulin and worsens glycaemic control. A demonstration that GIP receptor deficient mice were resistant to diet induced obesity let to the categorization of GIP as a fat promoting hormone and direct insulin-mimetic effects in adipose tissue has been proposed. We were able to demonstrate a redundancy for the GIP receptor in incorporation of lipids into adipocytes. We also observed that GIP receptor deficient mice could respond normally to high fat feeding with increased fat mass, but failed to increase lean mass. Mice with rescue of the GIP receptor in adipose tissue normalized the body composition in response to high fat diet, but the mice had a lower total body weight. In contrast, the GIP receptor expressed in the pancreatic beta-cell was able to promote lean mass gain on a low fat diet, but not on a high fat diet. Overall, we have established principal requirements for GIP maturation. Furthermore, we have demonstrated that neither beta-cell nor adipocyte GIP receptor expression can replace the endogenous GIP receptor in regulation of body weight and body composition. PMID: 22142579 [PubMed - indexed for MEDLINE] 483. J Lipid Res. 2012 Feb;53(2):227-46. doi: 10.1194/jlr.R021089. Epub 2011 Dec 2. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. Cawthorn WP(1), Scheller EL, MacDougald OA. Author information: (1)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. White adipose tissue (WAT) is perhaps the most plastic organ in the body, capable of regeneration following surgical removal and massive expansion or contraction in response to altered energy balance. Research conducted for over 70 years has investigated adipose tissue plasticity on a cellular level, spurred on by the increasing burden that obesity and associated diseases are placing on public health globally. This work has identified committed preadipocytes in the stromal vascular fraction of adipose tissue and led to our current understanding that adipogenesis is important not only for WAT expansion, but also for maintenance of adipocyte numbers under normal metabolic states. At the turn of the millenium, studies investigating preadipocyte differentiation collided with developments in stem cell research, leading to the discovery of multipotent stem cells within WAT. Such adipose tissue-derived stem cells (ASCs) are capable of differentiating into numerous cell types of both mesodermal and nonmesodermal origin, leading to their extensive investigation from a therapeutic and tissue engineering perspective. However, the insights gained through studying ASCs have also contributed to more-recent progress in attempts to better characterize committed preadipocytes in adipose tissue. Thus, ASC research has gone back to its roots, thereby expanding our knowledge of preadipocyte commitment and adipose tissue biology. PMCID: PMC3269153 PMID: 22140268 [PubMed - indexed for MEDLINE] 484. Endocrine. 2012 Apr;41(2):176-82. doi: 10.1007/s12020-011-9572-0. Epub 2011 Dec 3. Vaspin in obesity and diabetes: pathophysiological and clinical significance. Blüher M(1). Author information: (1)Department of Medicine, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany. bluma@medizin.uni-leipzig.de Vaspin (visceral adipose tissue-derived serpin; serpinA12) was originally identified as an adipokine, which is predominantly secreted from visceral adipose tissue in Otsuka Long-Evans Tokushima fatty (OLETF), an animal model of obesity and type 2 diabetes. Consistent with that higher vaspin serum concentrations and increased vaspin mRNA expression in human adipose tissue were found to be associated with obesity, insulin resistance, and type 2 diabetes in humans. However, the mechanisms how vaspin secretion may be linked to deterioration of glucose metabolism and insulin sensitivity are not entirely understood. Vaspin serum concentrations show a food intake-related diurnal variation. Vaspin is also expressed in the skin, hypothalamus, pancreatic islets, and stomach. Administration of vaspin to obese mice improves glucose tolerance, insulin sensitivity, and reduces food intake. Until now molecular target(s) of vaspin and its mode of action are unknown. Thus, identification of the proteases, which are inhibited by vaspin may lead to the development of novel strategies in the treatment of obesity, diabetes and insulin resistance. This review discusses the clinical relevance of vaspin in the pathophysiology of obesity and type 2 diabetes. PMID: 22139797 [PubMed - indexed for MEDLINE] 485. Proc Nutr Soc. 2012 Feb;71(1):27-37. doi: 10.1017/S0029665111003375. Epub 2011 Dec 5. Musculoskeletal phenotype through the life course: the role of nutrition. Ward K(1). Author information: (1)MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK. kate.ward@mrc-hnr.cam.ac.uk This review considers the definition of a healthy bone phenotype through the life course and the modulating effects of muscle function and nutrition. In particular, it will emphasise that optimal bone strength (and how that is regulated) is more important than simple measures of bone mass. The forces imposed on bone by muscle loading are the primary determinants of musculoskeletal health. Any factor that changes muscle loading on the bone, or the response of bone to loading results in alterations of bone strength. Advances in technology have enhanced the understanding of a healthy bone phenotype in different skeletal compartments. Multiple components of muscle strength can also be quantified. The critical evaluation of emerging technologies for assessment of bone and muscle phenotype is vital. Populations with low and moderate/high daily Ca intakes and/or different vitamin D status illustrate the importance of nutrition in determining musculoskeletal phenotype. Changes in mass and architecture maintain strength despite low Ca intake or vitamin D status. There is a complex interaction between body fat and bone which, in addition to protein intake, is emerging as a key area of research. Muscle and bone should be considered as an integrative unit; the role of body fat requires definition. There remains a lack of longitudinal evidence to understand how nutrition and lifestyle define musculoskeletal health. In conclusion, a life-course approach is required to understand the definition of healthy skeletal phenotype in different populations and at different stages of life. PMID: 22137032 [PubMed - indexed for MEDLINE] 486. Br J Nutr. 2011 Dec;106 Suppl 3:S5-78. doi: 10.1017/S0007114511005460. Dietary factors and low-grade inflammation in relation to overweight and obesity. Calder PC(1), Ahluwalia N, Brouns F, Buetler T, Clement K, Cunningham K, Esposito K, Jönsson LS, Kolb H, Lansink M, Marcos A, Margioris A, Matusheski N, Nordmann H, O'Brien J, Pugliese G, Rizkalla S, Schalkwijk C, Tuomilehto J, Wärnberg J, Watzl B, Winklhofer-Roob BM. Author information: (1)School of Medicine, University of Southampton, Southampton, UK. Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified. PMID: 22133051 [PubMed - indexed for MEDLINE] 487. Obes Rev. 2012 Apr;13(4):368-80. doi: 10.1111/j.1467-789X.2011.00957.x. Epub 2011 Dec 1. Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms. Gadéa E(1), Thivat E, Planchat E, Morio B, Durando X. Author information: (1)Clinical Research Medical Oncology, Centre Jean Perrin INRA/UdA, Clermont-Ferrand, France.emilie.gadea@hotmail.fr Weight variation has been reported as a side effect of chemotherapy treatment in early breast cancer patients and has been identified as a factor of poor prognosis. Causes of weight variation during chemotherapy and mechanisms involved in the poor prognosis have been little studied. Here is reviewed the current knowledge about the main causes and mechanisms involved in body weight change. Special emphasis is placed on factors associated with weight variation which could potentially be involved in the risk of relapse in breast cancer survivors. In recent decades, some studies have investigated the causes of weight variation by studying energy balance of breast cancer patients during chemotherapy. Weight gain or loss may be the consequence of energy imbalance through different factors linked with chemotherapy, such as poor treatment tolerance, decreased muscle mass and function, or hormonal alterations. This results in body composition modifications in favour of fat gain and/or lean body mass loss. Increased adipose tissue, especially in the abdominal region, could induce metabolic disturbances such as insulin resistance, through various pathways involving adipokines. These molecules have growth properties and could therefore play a role in cancer relapse. Understanding such mechanisms is key to developing preventive strategies for improving the prognosis of early-stage breast cancer patients. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22133030 [PubMed - indexed for MEDLINE] 488. Clin Exp Immunol. 2012 Jan;167(1):40-6. doi: 10.1111/j.1365-2249.2011.04501.x. Immunology in the Clinic Review Series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Brooks-Worrell B(1), Palmer JP. Author information: (1)Department of Medicine, University of Washington, Seattle, WA, USA. bbrooks@u.washington.edu Historically, the development of type 2 diabetes has been considered not to have an autoimmune component, in contrast to the autoimmune pathogenesis of type 1 diabetes. In this review we will discuss the accumulating data supporting the concept that islet autoreactivity and inflammation is present in type 2 diabetes pathogenesis, and the islet autoimmunity appears to be one of the factors associated with the progressive nature of the type 2 diabetes disease process. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. PMCID: PMC3248085 PMID: 22132883 [PubMed - indexed for MEDLINE] 489. Am J Kidney Dis. 2012 Feb;59(2):276-83. doi: 10.1053/j.ajkd.2011.10.013. Epub 2011 Nov 29. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Budde K(1), Gaedeke J. Author information: (1)Department of Nephrology, Charité Universitätsmedizin Berlin, Germany. klemens.budde@charite.de Tuberous sclerosis complex (TSC) is an autosomal dominant disorder promoting the development of benign tumors in multiple organ systems, including the skin, brain, and kidneys. In contrast to asymptomatic spontaneous angiomyolipomas, angiomyolipomas in patients with TSC are mostly bilateral and are accompanied by other typical clinical features of TSC. Kidney angiomyolipomas are benign tumors composed of blood vessels, adipose tissue, and smooth muscle and are associated with spontaneous bleeding and potential life-threatening hemorrhage if >4 cm. Current treatment options for angiomyolipoma are focused on conserving kidney function and limiting potentially fatal hemorrhage. TSC is caused by mutations in either TSC1 or TSC2 suppressor genes, resulting in increased mammalian target of rapamycin (mTOR) activity. Preclinical studies have shown the efficacy of mTOR inhibitors in inhibiting the growth of patient-derived cell lines and suppressing tumors in animal models of TSC. In the clinical setting, mTOR inhibitors have shown promising efficacy in patients with TSC-associated angiomyolipomas and subependymal giant cell astrocytomas. This review explores the diagnosis and current management of TSC-associated angiomyolipomas, the relevance of the mTOR pathway in the pathogenesis of TSC, and the potential promise of mTOR-inhibitor therapy as a systemic therapeutic approach to treat the underlying cause of TSC. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 22130643 [PubMed - indexed for MEDLINE] 490. Med Sci (Paris). 2011 Nov;27(11):993-9. doi: 10.1051/medsci/20112711016. Epub 2011 Nov 30. [Adipose tissue, a new playground for immune cells]. [Article in French] Dalmas E(1), Tordjman J, Guerre-Millo M, Clément K. Author information: (1)Université Pierre et Marie Curie-Paris 6, Centre de recherche des Cordeliers, F-75006 Paris, France. Adipose tissue has been under focus in the last decade and pivotal concepts have emerged from the studies of its complex biology. Low-grade inflammation both at the systemic level and in adipose tissue itself characterizes obesity. Among the different cell types contributing to inflammation, this review focuses on the mechanisms and consequences of macrophage accumulation in obese adipose tissue. Mechanisms for monocyte recruitment to adipose tissue, and how macrophages' phenotypes are modified in this environment in response to increasing fat mass, are considered. We review recent studies addressing the complex and versatile phenotype of adipose tissue macrophages that contribute to inflammatory and metabolic alterations, but could also help to maintain adipose tissue homeostasis in the setting of obesity both in mouse and human situations. A newly discovered consequence of adipose tissue inflammation is fibrosis. Whether macrophages and/or other immune cells exert a pro-fibrotic effect in adipose tissue is still unclear. This wealth of new information will hopefully help to design new ways to control adipose tissue inflammation and its deleterious sequels. © 2011 médecine/sciences – Inserm / SRMS. PMID: 22130027 [PubMed - indexed for MEDLINE] 491. Annu Rev Food Sci Technol. 2011;2:237-57. doi: 10.1146/annurev-food-022510-133656. Food components with anti-obesity effect. Kim KH(1), Park Y. Author information: (1)Department of Food Science, Purdue University, West Lafayette, Indiana 47907, USA. keehong@purdue.edu Although many food components are reportedly beneficial to body-weight management, lack of understanding of molecular mechanisms and their function in overall adiposity under physiological conditions hinders successful and safe development of antiobesity functional foods. A positive energy balance resulting from an increase in food intake, a reduced energy expenditure, and/or dysfunction of adipose biology is associated with the development of obesity. This article provides an overview of the components involved in energy balance and adipose development and function. There is evidence that numerous ingredients found in foods can modulate energy balance and adipose biology, thereby potentially lowering adiposity. PMID: 22129382 [PubMed - indexed for MEDLINE] 492. Adv Clin Chem. 2011;55:61-79. Adipokine actions on cartilage homeostasis. Dozio E(1), Corsi MM, Ruscica M, Passafaro L, Steffani L, Banfi G, Magni P. Author information: (1)Department of Human Morphology and Biomedical Sciences "Città Studi," Chair of Clinical Pathology, School of Medicine, Università degli Studi di Milano, Milan, Italy. Epidemiological studies have shown an intriguing correlation between obesity and articular cartilage disease. An increase in mechanical forces across weight-bearing joints has long been considered the primary factor leading to joint degeneration. However, emerging data suggest that additional soluble factors such as the adipocyte-derived molecules "adipokines" may also play an important role in the onset and progression of weight-associated cartilage degradative process. Adipokines are pleiotropic secretory molecules mainly produced by white adipose tissue. Adipokines exert their actions through endocrine, paracrine, autocrine, or juxtacrine cross talk in a wide variety of physiological or pathophysiological processes. In particular, they are mainly involved in the regulation of food intake and energy metabolism, in both health and disease states, and in the inflammatory response. Recent observations have shown that, among adipokines, leptin, adiponectin, resistin, visfatin, and apelin may also participate to the complex mechanisms that regulate skeleton biology, both at bone and cartilage level. Herein, we review the present knowledge about the role of these adipokines in cartilage function as well as in inflammatory and degenerative joint diseases. Moreover, we describe some methodological approaches which can be utilized in the measurement of these adipokines in different biological matrices, like plasma and synovial fluid (SF), and may be helpful to better clarify the involvement of these molecules in cartilage disease. PMID: 22126024 [PubMed - indexed for MEDLINE] 493. Curr Mol Pharmacol. 2012 Jun;5(2):272-81. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists on glycemic control, lipid profile and cardiovascular risk. Derosa G(1), Maffioli P. Author information: (1)Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuseppe.derosa@unipv.it Peroxisome proliferator-activated receptor (PPAR) is involved in the pathology of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can be demonstrated through several alterations in carbohydrates, lipids, and protein metabolism. For that reason a class of compounds, called thiazolidinediones, has been developed for the management of type 2 diabetes mellitus. Thiazolidinediones are PPAR-γ agonists regulating the expression of several genes involved in the regulation of glucose, lipid and protein metabolism, enhancing the action of insulin in insulin-sensitive tissue by increasing glucose uptake in skeletal muscle and adipose tissue, and decreasing hepatic glucose production. Pioglitazone is the only available PPAR-γ agonist for the treatment of type 2 diabetes after rosiglitazone withdrawal from several countries. This review discusses the safety and effectiveness of pioglitazone in the clinical practice for the treatment of type 2 diabetes mellitus. PMID: 22122457 [PubMed - indexed for MEDLINE] 494. Curr Mol Pharmacol. 2012 Jun;5(2):224-40. The involvement of PPARs in the causes, consequences and mechanisms for correction of cardiac lipotoxicity and oxidative stress. Sugden MC(1), Warlow MP, Holness MJ. Author information: (1)Centre for Diabetes, Blizard Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK. m.c.sugden@qmul.ac.uk Chronically-elevated plasma lipid concentrations, particularly when combined with high glucose, elicit a plethora of effects that cause the progressive deterioration of insulin sensitivity and ultimately cellular malfunction or death. This review addresses how metabolic abnormalities in white adipose tissue leading to excessive lipid or abnormal adipokine release can be modified by PPARγ activation. It also discusses the etiology of cardiac lipotoxicity and oxidative stress, in relation to imbalanced lipid delivery and clearance and how PPARα activation can be used to correct some of these effects. PMID: 22122452 [PubMed - indexed for MEDLINE] 495. Zentralbl Chir. 2011 Oct;136(5):399-403. [Stem cell therapy in vascular medicine]. [Article in German] Nikol S(1). Author information: (1)Chefärztin Klinische und Interventionelle Angiologie, Asklepios Klinik St. Georg, Lohmühlenstr. 5, 20099 Hamburg. s.nikol@asklepios.com PMID: 22121537 [PubMed - indexed for MEDLINE] 496. J Innate Immun. 2012;4(3):260-72. doi: 10.1159/000332435. Epub 2011 Nov 22. The role of complement in the development and manifestation of murine atherogenic inflammation: novel avenues. Francescut L(1), Steiner T, Byrne S, Cianflone K, Francis S, Stover C. Author information: (1)Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK. Atherosclerosis is a chronic progressive inflammatory disease which manifests in the arterial vascular tree. It is a major cause of cardiovascular morbidity and contributes significantly to mortality in the developed world. Triggers for this inflammatory process are elevated levels of cholesterol, bacterial infection and obesity. The immune response in atherosclerosis is essentially pro-atherogenic, leading to lipid accumulation and cellular changes within the arterial wall. Small-animal models of atherosclerosis are used to study the relevance of candidate factors (cells, genes, diets) in the development and progression of lesions. From a multidisciplinary viewpoint, there are challenges and limitations to this approach. Activation of complement determines or modifies the outcome of acute and chronic inflammation. This review dissects the role of complement in the early development as well as the progressive manifestation of murine atherosclerosis and the advances in knowledge provided by the use of specific mouse models. It gives a critical overview of existing models, analyses seemingly conflicting results obtained with complement-deficient mouse models, highlights the importance of interrelationships between pro-coagulpant activity, adipose tissue, macrophages and complement, and uncovers exciting avenues of topical research. Copyright © 2011 S. Karger AG, Basel. PMID: 22116497 [PubMed - indexed for MEDLINE] 497. J Biomech. 2012 Jan 3;45(1):1-8. doi: 10.1016/j.jbiomech.2011.10.023. Epub 2011 Nov 21. Mechanotransduction in adipocytes. Shoham N(1), Gefen A. Author information: (1)Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 69978, Israel. Obesity is widely recognized as a major public health problem due to its strong association with a number of serious chronic diseases including hyperlipidemia, hypertension, type II diabetes and coronary atherosclerotic heart disease. During the development of obesity, the positive energy balance involves recruitment of new adipocytes from preadipocytes in adipose tissue, which have proliferated and differentiated. Given that cells in adipose tissues are physiologically exposed to compound mechanical loading: tensile, compressive and shear strains/stresses, which are caused by bodyweight loads as well as by weight-bearing, it is important to determine whether the adipose conversion process is influenced by mechanical stimulations. In this article we provide a comprehensive review of the experimental studies addressing mechanotransduction in adipocytes, as well as of mathematical and computational models that are useful for studying mechanotransduction in adipocytes or for quantifying the responsiveness of adipocytes to different types of mechanical loading. The new understanding that adipogenesis is influenced by mechanical stimulations has the potential to open new and important research paths, driven by mechanotransduction, to explore mechanisms as well as treatment approaches in obesity and related conditions. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22112919 [PubMed - indexed for MEDLINE] 498. Exp Diabetes Res. 2012;2012:716425. doi: 10.1155/2012/716425. Epub 2011 Oct 26. Role of transcription factor modifications in the pathogenesis of insulin resistance. Kim MY(1), Bae JS, Kim TH, Park JM, Ahn YH. Author information: (1)Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver not due to alcohol abuse. NAFLD is accompanied by variety of symptoms related to metabolic syndrome. Although the metabolic link between NAFLD and insulin resistance is not fully understood, it is clear that NAFLD is one of the main cause of insulin resistance. NAFLD is shown to affect the functions of other organs, including pancreas, adipose tissue, muscle and inflammatory systems. Currently efforts are being made to understand molecular mechanism of interrelationship between NAFLD and insulin resistance at the transcriptional level with specific focus on post-translational modification (PTM) of transcription factors. PTM of transcription factors plays a key role in controlling numerous biological events, including cellular energy metabolism, cell-cycle progression, and organ development. Cell type- and tissue-specific reversible modifications include lysine acetylation, methylation, ubiquitination, and SUMOylation. Moreover, phosphorylation and O-GlcNAcylation on serine and threonine residues have been shown to affect protein stability, subcellular distribution, DNA-binding affinity, and transcriptional activity. PTMs of transcription factors involved in insulin-sensitive tissues confer specific adaptive mechanisms in response to internal or external stimuli. Our understanding of the interplay between these modifications and their effects on transcriptional regulation is growing. Here, we summarize the diverse roles of PTMs in insulin-sensitive tissues and their involvement in the pathogenesis of insulin resistance. PMCID: PMC3205681 PMID: 22110478 [PubMed - indexed for MEDLINE] 499. Steroids. 2012 Jan;77(1-2):27-35. doi: 10.1016/j.steroids.2011.10.013. Epub 2011 Nov 13. Tissue physiology and pathology of aromatase. Stocco C(1). Author information: (1)Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States. costocco@uic.edu Aromatase is expressed in multiple tissues, indicating a crucial role for locally produced oestrogens in the differentiation, regulation and normal function of several organs and processes. This review is an overview of the role of aromatase in different tissues under normal physiological conditions and its contribution to the development of some oestrogen-related pathologies. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3286233 PMID: 22108547 [PubMed - indexed for MEDLINE] 500. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):12-22. doi: 10.1097/MCO.0b013e32834dd297. Chronic low-grade inflammation and age-related sarcopenia. Beyer I(1), Mets T, Bautmans I. Author information: (1)Geriatrics Department, Universitair Ziekenhuis Brussel, Brussels, Belgium. PURPOSE OF REVIEW: Age-related chronic low-grade inflammatory profile (CLIP) has been recognized as an important causative factor for sarcopenia. Here, we report the recent evidence concerning CLIP and sarcopenia. RECENT FINDINGS: Twenty-one studies were included (12 observational, five interventional studies and four randomized controlled trials). Observational studies strengthen the association between CLIP and sarcopenia in cross-sectional and longitudinal designs. Interleukin (IL)-6 and tumour necrosis factor-α are the most reported inflammatory parameters. Biopsy studies confirm the role of oxidative mechanisms, protein kinase B and nuclear factor kappa-light-chain-enhancer of activated B cells pathways and implicate stress response mechanisms and heat shock protein. Adipose tissue as source of inflammatory cytokines remains unclear and correction for fat mass is advisable in new research. Exercise interventions (both aerobic and resistance training) demonstrate beneficial effects on CLIP even in the absence of decreases in weight, BMI or fat mass. IL-6 is also released during exercise, in hormone-like fashion unrelated to inflammation, and exercise-induced IL-6 changes require careful interpretation. Soy supplementation in one study showed no influence on CLIP and no recent pharmacological trials were retrieved. SUMMARY: Associations between CLIP and sarcopenia are observed quite consistently and underlying mechanisms become apparent. Exercise remains the mainstay intervention to lower CLIP and counter sarcopenia. More research is warranted to unravel the exact dose-response relationship. PMID: 22108098 [PubMed - indexed for MEDLINE] 501. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):49-57. doi: 10.1097/MCO.0b013e32834d199f. Cysteine and obesity: consistency of the evidence across epidemiologic, animal and cellular studies. Elshorbagy AK(1), Kozich V, Smith AD, Refsum H. Author information: (1)Department of Pharmacology, University of Oxford, Oxford, UK. amany.elshorbagy@pharm.ox.ac.uk PURPOSE OF REVIEW: The concentrations of several plasma amino acids increase in obesity. Notably, plasma total concentrations of the sulphur amino acid cysteine (tCys) are linearly associated with fat mass in large population studies. Animal and cellular experiments support the concept that cysteine may be obesogenic. Here we review experimental and epidemiologic findings linking cysteine and related compounds with fat regulation and obesity. RECENT FINDINGS: tCys, and to a lesser extent cystathionine, are the only plasma sulphur amino acids consistently associated with human obesity, whereas glutathione is inversely associated with BMI. Supplementing cyste(i)ne in rodents decreases energy expenditure and promotes adiposity, whereas defects of cysteine-synthesizing enzymes decrease body weight. In adipocytes, cysteine inhibits lipolysis and promotes lipogenesis via H2O2 production. Unlike most plasma amino acids, tCys levels do not decrease with gastric bypass-induced weight loss, further supporting the concept that elevated cysteine may be a cause, not a consequence of obesity. Although cysteine products (glutathione, taurine and H2S) are altered in obesity, they do not appear to explain cysteine's effects on body weight. SUMMARY: Cellular, animal and epidemiologic data are consistent with the view that cysteine is obesogenic. Targeted research linking in-vitro and in-vivo findings is needed to elucidate mechanisms involved. PMID: 22108094 [PubMed - indexed for MEDLINE] 502. J Tissue Eng Regen Med. 2012 Nov;6(10):e1-e11. doi: 10.1002/term.502. Epub 2011 Nov 21. Can one generate stable hyaline cartilage from adult mesenchymal stem cells? A developmental approach. Hellingman CA(1), Koevoet W, van Osch GJ. Author information: (1)Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Centre Rotterdam, PO Box 2040, 3000, CA, Rotterdam, The Netherlands. Chondrogenically differentiating bone marrow-derived mesenchymal stem cells (BMSCs) display signs of chondrocyte hypertrophy, such as production of collagen type X, MMP13 and alkaline phosphatase (ALPL). For cartilage reconstructions this is undesirable, as terminally differentiated cartilage produced by BMSCs mineralizes when implanted in vivo. Terminal differentiation is not restricted to BMSCs but is also encountered in chondrogenic differentiation of adipose-derived mesenchymal stem cells (MSCs) as well as embryonic stem cells, which by definition should be able to generate all types of tissues, including stable cartilage. Therefore, we propose that the currently used culture conditions may drive the cells towards terminal differentiation. In this manuscript we aim to review the literature, supplemented by our own data to answer the question, is it possible to generate stable hyaline cartilage from adult MSCs? We demonstrate that recently published methods for inhibiting terminal differentiation (through PTHrP, MMP13 or blocking phosphorylation of Smad1/5/8) result in cartilage formation with reduction of hypertrophic markers, although this does not reach the low level of stable chondrocytes. A set of hypertrophy markers should be included in future studies to characterize the phenotype more precisely. Finally, we used what is currently known in developmental biology about the differential development of hyaline and terminally differentiated cartilage to provide thought and insights to change current culture models for creating hyaline cartilage. Inhibiting terminal differentiation may not result in stable hyaline cartilage if the right balance of signals has not been created from the start of culture onwards. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 22106029 [PubMed - indexed for MEDLINE] 503. J Endocrinol Invest. 2011 Dec;34(11):869-75. doi: 10.3275/8108. Epub 2011 Nov 21. Application of proteomics to the study of polycystic ovary syndrome. Insenser M(1), Escobar-Morreale HF. Author information: (1)Diabetes, Obesity and Human Reproduction Research Group, Hospital Universitario Ramon y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain. BACKGROUND: Clinical proteomics consists of qualitative and quantitative profiling of proteins present in clinical specimens such as body fluids or tissues, with the aim of discovering novel proteins and cellular pathways associated with the disease of interest. AIM: To review the proteomic studies conducted to date that addressed different aspects of the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Descriptive review of studies that applied proteomic techniques to the study of PCOS. Published articles were identified using the Entrez-PubMed online search facilities. RESULTS: Most studies conducted to date focused on protein variations in plasma and different target tissues. Plasma proteomics analysis revealed that PCOS associates changes in protein expression in several acute-phase response proteins. Moreover, some of these molecules play major roles in iron metabolism and low-grade chronic inflammation. Studies using omental adipose tissue from morbidly obese women with or without PCOS revealed differences in abundance of proteins that may be involved in lipid and glucose metabolism, oxidative stress processes, and adipocyte differentiation. Moreover, identification of differentially expressed proteins in ovarian tissue, granulosa cells or T lymphocites may help to characterize more clearly some aspects of this disorder. CONCLUSIONS: Although the application of proteomic techniques to the study of PCOS is in its early infancy, studies conducted to date highlight its heterogeneous nature. Aside from androgen excess, several pathways related to intermediate metabolism, oxidative stress processes, inflammation and iron metabolism appear to be involved in the pathophysiology of PCOS. PMID: 22104628 [PubMed - indexed for MEDLINE] 504. Expert Rev Cardiovasc Ther. 2011 Dec;9(12):1557-64. doi: 10.1586/erc.11.167. Adiposity assessment: explaining the association between obesity, hypertension and stroke. Rhéaume C(1), Leblanc MÈ, Poirier P. Author information: (1)Institut Universitaire de Cardiologie et de pneumologie de Québec, 2725 ch Sainte-Foy, Québec, QC, G1V 4G5, Canada. Obesity is associated with a greater prevalence of cardiovascular risk factors and a higher risk of cardiovascular events, and contributes to the rise in cardiovascular morbidity and mortality worldwide. Increased BMI is established as an independent risk factor for cardiovascular disease (CVD). Attention has recently been drawn to alternate measures of adiposity/obesity, such as waist circumference, waist-to-hip ratio and waist-to-height ratio, that provide information regarding body fat distribution. Although BMI is the established clinical measurement to estimate CVD risk associated with excess bodyweight, there is evidence suggesting that abdominal obesity could represent a better marker of CVD risk than BMI. It is now recognized that abdominally obese individuals tend to have higher blood pressure. A major cardiovascular risk factor associated with stroke is systemic hypertension followed closely by obesity. Clinical adiposity indices used to describe obesity linked with systemic hypertension and stroke incidence are reviewed in this article. In summary, BMI, waist circumference, waist-to-hip ratio and waist-to-height ratio measurements are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated with other cardiometabolic risk factors to refine cardiovascular risk stratification. PMID: 22103875 [PubMed - indexed for MEDLINE] 505. Biochem Soc Trans. 2011 Dec;39(6):1752-7. doi: 10.1042/BST20110675. LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations. Bidault G(1), Vatier C, Capeau J, Vigouroux C, Béréziat V. Author information: (1)UMPC Université Paris 6, UMR S938, F-75005 Paris, France. Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A-type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases. PMID: 22103520 [PubMed - indexed for MEDLINE] 506. Biochem Soc Trans. 2011 Dec;39(6):1698-704. doi: 10.1042/BST20110657. Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells. Lattanzi G(1). Author information: (1)National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR, Via di Barbiano 1/10, I-40136 Bologna, Italy. giovanna.lattanzi@cnr.it Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor. PMID: 22103510 [PubMed - indexed for MEDLINE] 507. Biochem Soc Trans. 2011 Dec;39(6):1687-92. doi: 10.1042/BST20110670. Clinical and genetic heterogeneity in laminopathies. Bertrand AT(1), Chikhaoui K, Yaou RB, Bonne G. Author information: (1)Inserm, U974, Paris, France. Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability. PMID: 22103508 [PubMed - indexed for MEDLINE] 508. Endocrinol Nutr. 2012 Jan;59(1):50-61. doi: 10.1016/j.endonu.2011.08.002. Epub 2011 Nov 18. [Chronobiological aspects of obesity and metabolic syndrome]. [Article in Spanish] Gómez-Abellán P(1), Madrid JA, Ordovás JM, Garaulet M. Author information: (1)Departamento de Fisiología, Facultad de Biología, Universidad de Murcia, Murcia, España. Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved. PMID: 22100640 [PubMed - indexed for MEDLINE] 509. Cytokine. 2012 Jan;57(1):9-16. doi: 10.1016/j.cyto.2011.10.008. Epub 2011 Nov 17. Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors. Batista ML Jr(1), Peres SB, McDonald ME, Alcantara PS, Olivan M, Otoch JP, Farmer SR, Seelaender M. Author information: (1)Laboratory of Adipose Tissue Biology, Center for Integrated Biotechnology, University of Mogi das Cruzes, Mogi das Cruzes, Sao Paulo, Brazil. miguelj@umc.br Cancer cachexia is a multifaceted syndrome whose aetiology is extremely complex and is directly related to poor patient prognosis and survival. Changes in lipid metabolism in cancer cachexia result in marked reduction of total fat mass, increased lipolysis, total oxidation of fatty acids, hyperlipidaemia, hypertriglyceridaemia, and hypercholesterolaemia. These changes are believed to be induced by inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and other factors. Attention has recently been drawn to the current theory that cachexia is a chronic inflammatory state, mainly caused by the host's reaction to the tumour. Changes in expression of numerous inflammatory mediators, notably in white adipose tissue (WAT), may trigger several changes in WAT homeostasis. The inhibition of adipocyte differentiation by PPARγ is paralleled by the appearance of smaller adipocytes, which may partially account for the inhibitory effect of PPARγ on inflammatory gene expression. Furthermore, inflammatory modulation and/or inhibition seems to be dependent on the IKK/NF-κB pathway, suggesting that a possible interaction between NF-κB and PPARγ is required to modulate WAT inflammation induced by cancer cachexia. In this article, current literature on the possible mechanisms of NF-κB and PPARγ regulation of WAT cells during cancer cachexia are discussed. This review aims to assess the role of a possible interaction between NF-κB and PPARγ in the setting of cancer cachexia as well as its significant role as a potential modulator of chronic inflammation that could be explored therapeutically. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved. PMID: 22099872 [PubMed - indexed for MEDLINE] 510. Plast Reconstr Surg. 2011 Dec;128(6):1236-40. doi: 10.1097/PRS.0b013e318230c7b8. Panniculectomy in preparation for renal transplantation: a new indication for an old procedure to reduce renal transplantation-associated wound complications. Kuo JH(1), Troppmann C, Perez RV, Wong MS. Author information: (1)University of California, Davis, CA, USA. End-stage renal disease patients who have lost a significant amount of weight are increasingly being evaluated for kidney transplantation. An abdominal panniculus, almost uniformly observed, creates an area predisposed to wound complications. Consequently, a panniculus may limit a patient's candidacy for transplantation. The authors describe their preliminary experience utilizing panniculectomy as a prophylactic procedure to reduce wound complications following kidney transplantation in patients whose panniculus would exclude them from renal transplantion. A single-institution chart review was conducted of nine patients with end-stage renal disease who underwent a panniculectomy in preparation for transplantation. Clinical outcomes and complications were reviewed. The nine patients included three men and six women with a mean age of 54.5 years and a mean body mass index of 28.3 kg/m. Four patients had diabetes. All patients underwent an uncomplicated panniculectomy, with a mean resected weight of 3.0 kg, and a mean length of hospital stay of 1.75 days. No one required blood transfusions. All patients were followed postoperatively for 3 months. Complications included an abscess and a skin dehiscence treated with local wound care. After recovery, patients were referred to the transplant center for re-evaluation for kidney transplantation. Thus far, four of these nine patients have undergone transplantation. This case series suggests that panniculectomy can be performed safely in patients with end-stage renal disease. Furthermore, panniculectomy gives these otherwise unsuitable kidney transplant candidates access to a life-saving operation. PMID: 22094742 [PubMed - indexed for MEDLINE] 511. Diabetes Obes Metab. 2012 Jun;14(6):493-9. doi: 10.1111/j.1463-1326.2011.01538.x. Epub 2011 Dec 27. Controversies surrounding the clinical potential of cinnamon for the management of diabetes. Rafehi H(1), Ververis K, Karagiannis TC. Author information: (1)Epigenomic Medicine Laboratory, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia. Obesity levels have increased significantly in the past five decades and are predicted to continue rising, resulting in important health implications. In particular, this has translated to an increase in the occurrence of type II diabetes mellitus (T2D). To alleviate associated problems, certain nutraceuticals have been considered as potential adjuncts or alternatives to conventional prescription drugs. Cinnamon, a commonly consumed spice originating from South East Asia, is currently being investigated as a potential preventative supplement and treatment for insulin resistance, metabolic syndrome and T2D. Extensive in vitro evidence has shown that cinnamon may improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle. In adipose tissue, it has been shown that cinnamon increases the expression of peroxisome proliferator-activated receptors including, PPARγ. This is comparable to the action of commonly used thiazolinediones, which are PPAR agonists. Studies have also shown that cinnamon has potent anti-inflammatory properties. However, numerous human clinical trials with cinnamon have been conducted with varying findings. While some studies have showed no beneficial effect, others have indicated improvements in cholesterol levels, systolic blood pressure, insulin sensitivity and postprandial glucose levels with cinnamon. However, the only measurement consistently improved by cinnamon consumption is fasting glucose levels. While it is still premature to suggest the use of cinnamon supplementation based on the evidence, further investigation into mechanisms of action is warranted. Apart from further characterization of genetic and epigenetic changes in model systems, systematic large-scale clinical trials are required. In this study, we discuss the mechanisms of action of cinnamon in the context of T2D and we highlight some of the associated controversies. © 2011 Blackwell Publishing Ltd. PMID: 22093965 [PubMed - indexed for MEDLINE] 512. Am J Clin Nutr. 2011 Dec;94(6 Suppl):2036S-2043S. doi: 10.3945/ajcn.111.018903. Epub 2011 Nov 16. Programming research: where are we and where do we go from here? Koletzko B(1), Symonds ME, Olsen SF; Early Nutrition Programming Project; Early Nutrition Academy. Author information: (1)Division of Metabolic and Nutritional Medicine, Department of Pediatrics, Dr von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany. office.koletzko@med.uni-muenchen.de Convincing evidence has accumulated to show that both pre- and postnatal nutrition preprogram long-term health, well-being, and performance until adulthood and old age. There is a very large potential in the application of this knowledge to promote public health. One of the prerequisites for translational application is to strengthen the scientific evidence. More extensive knowledge is needed (eg, on effect sizes of early life programming in contemporary populations, on specific nutritional exposures, on sensitive time periods in early life, on precise underlying mechanisms, and on potential effect differences in subgroups characterized by, eg, genetic predisposition or sex). Future programming research should aim at filling the existing gaps in scientific knowledge, consider the entire lifespan, address socioeconomic issues, and foster innovation. Research should aim at results suitable for translational application (eg, by leading to health-promoting policies and evidence-based dietary recommendations in the perinatal period). International collaboration and a close research partnership of academia, industry, and small and medium enterprises may strengthen research and innovative potential enhancing the likelihood of translational application. The scientific know-how and methodology available today allow us to take major steps forward in the near future; hence, research on nutritional programming deserves high priority. PMID: 22089444 [PubMed - indexed for MEDLINE] 513. Curr Med Chem. 2011;18(34):5267-80. Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Vazzana N(1), Santilli F, Sestili S, Cuccurullo C, Davi G. Author information: (1)Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy. Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue is recognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying this evidence is still unravelled. The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in body weight homeostasis, but also in coagulation, fibrinolysis, endothelial dysfunction, insulin resistance (IR) and atherosclerosis. Moreover, there is evidence that oxidative stress may be a mechanistic link between several components of MS and CVD, through its role in inflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathways enhances both metabolic IR and endothelial dysfunction, which synergize to predispose to CVD. Persistent platelet hyperreactivity/activation emerges as the final pathway driven by intertwined interactions among IR, adipokine release, inflammation, dyslipidemia and oxidative stress and provides a pathophysiological explanation for the excess risk of atherothrombosis in this setting. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesity drugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of these therapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach for cardiovascular prevention. PMID: 22087824 [PubMed - indexed for MEDLINE] 514. Rev Bras Cir Cardiovasc. 2011 Jul-Sep;26(3):440-6. Absence of arteriosclerosis in intramyocardial coronary arteries: a mystery to be solved? Ramalli EL Jr(1), Braga LH, Evora PM, Albuquerque AA, Celotto AC, Mota AL, Evora PR. Author information: (1)Surgery and Anatomy Department, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Several studies show that portions of intramyocardial coronary arteries are spared of arteriosclerosis, involving morphological, embryological, biochemical and pathophysiological aspects. Endothelial function is significantly affected in the segment of transition, as estimated by the vasoactive response to Ach. These findings suggest that myocardial bridge can provide protection against arteriosclerosis by counteracting the negative effects of endothelial dysfunction. The intramyocardial portion's protection phenomenon deserves further scientific research on all research fronts. Improved morphological, biomechanical and especially physiological and embryological knowledge may be the key to a future window of opportunity for chronic arterial disease therapy and prevention. In addition, this review discusses possible therapeutic approaches for symptomatic coronary ischemia caused by myocardial bridges. PMID: 22086582 [PubMed - indexed for MEDLINE] 515. Nat Rev Endocrinol. 2011 Nov 15;8(5):263-75. doi: 10.1038/nrendo.2011.184. The multifactorial role of leptin in driving the breast cancer microenvironment. Andò S(1), Catalano S. Author information: (1)Department of Cell Biology and Centro Sanitario, University of Calabria, via Pietro Bucci, 87036 Arcavacata di Rende, Italy. sebastiano.ando@ unical.it Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed. PMID: 22083089 [PubMed - indexed for MEDLINE] 516. Amyloid. 2011 Dec;18(4):177-82. doi: 10.3109/13506129.2011.630762. Proteomic typing of amyloid deposits in systemic amyloidoses. Lavatelli F(1), Vrana JA. Author information: (1)Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy. francesca.lavatelli@unipv.it Comment in Amyloid. 2011 Dec;18(4):175-6. Amyloidoses are characterized by the presence of extracellular amyloid deposits, constituted by fibrillar aggregates of misfolded proteins. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been detected as causative agents of human amyloidoses, 14 of which associated with systemic forms. Unequivocal typing of the amyloid deposits is a key step in the management of these diseases. Existing drawbacks of traditional, immunohistochemistry-based techniques have driven the search for alternative solutions for direct amyloid typing. Proteomics indicates the comprehensive study of the proteins in a biological sample, centered on analysis by mass spectrometry. The great potential of this approach in describing the composition of amyloid deposits and in studying the molecular features of the amyloidogenic precursors has become immediately clear and the introduction of proteomics in the clinical practice has revolutionized the field of amyloid typing. This review provides a critical overview of the various approaches that have been proposed in this specific context, along with a brief description of the proteomic methods for assessment of the circulating amyloidogenic proteins. PMID: 22080761 [PubMed - indexed for MEDLINE] 517. Joint Bone Spine. 2012 Mar;79(2):129-33. doi: 10.1016/j.jbspin.2011.08.004. Epub 2011 Nov 12. Bone tissue and muscle dystrophin deficiency in mdx mice. Nakagaki WR(1), Camilli JA. Author information: (1)Department of Anatomy, Cell Biology and Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Erratum in Joint Bone Spine. 2013 Oct;80(5):557-8. Duchenne muscular dystrophy is a neuromuscular disease caused by the lack of dystrophin that affects skeletal muscles, causing degeneration of muscle fibers and replacing them with fibrous and adipose tissue, events that gradually lead to functional loss. Patients with Duchenne muscular dystrophy have shown that bones become more fragile with age and with advancement of the disease. Muscle weakness and reduced mobility have been suggested to be the factors that promote bone deterioration. However, it seems that this does not occur in mdx mice. It has been identified in mdx mice the existence of a factor related or not to the lack of dystrophin that also participates in the impairment of bone quality. Mdx mice also exhibit muscle degeneration, but unlike human, it is compensated by muscle regeneration. In consequence, there is an increase in the muscle mass, but not necessarily of muscle contractile strength. The accommodation of this increased muscle mass promotes bone formation at specific sites, such as at tendo-osseous junctions. In addition, the inflammatory response to muscle injury may be responsible for the increase in angiogenesis and regeneration observed in mdx mice, inducing the release of cytokines and chemokines that play an important role in the recruitment of leukocytes and macrophages. Then, mdx mice may possess compensatory mechanisms in bone in response to a genetic defect. Copyright © 2011 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved. PMID: 22079415 [PubMed - indexed for MEDLINE] 518. Thromb Res. 2012 Mar;129(3):285-9. doi: 10.1016/j.thromres.2011.10.021. Epub 2011 Nov 9. Thrombosis and obesity: cellular bases. Lorenzet R(1), Napoleone E, Cutrone A, Donati MB. Author information: (1)Laboratori di Ricerca, Fondazione di Ricerca e Cura Giovanni Paolo II, Largo Gemelli, 1, 86100 Campobasso, Italy. roberto.lorenzet@rm.unicatt.it The prevalence of obesity has dramatically increased during the past two decades. Epidemiological studies suggest that obesity is an independent, modifiable risk factor for coronary heart disease, possibly due, at least in part, to the development of a pro-inflammatory and a pro-thrombotic state in obese subjects. In addition, numerous cohort studies have shown a link between obesity and different types of cancer. Accordingly, the regulation of body weight is becoming a serious concern for public health experts and scientists. Although the mechanisms responsible for these associations are still to be fully elucidated, a key role has been assigned to adipokines, a family of hormones which act as modulators of metabolism or inflammation, secreted by adipocytes. Tissue factor, the major physiological trigger of the blood coagulation cascade in vivo, which plays a central role in atherothrombosis and tumor biology, has also been proposed as one of the key molecules responsible for these associations. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22078462 [PubMed - indexed for MEDLINE] 519. Crit Rev Eukaryot Gene Expr. 2011;21(2):131-42. Inflammatory mediators: tracing links between obesity and osteoarthritis. Rai MF(1), Sandell LJ. Author information: (1)Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA. PMID: 22077152 [PubMed - indexed for MEDLINE] 520. Nihon Yakurigaku Zasshi. 2011 Nov;138(5):182-6. [Role of chronic inflammation in the pathogenesis of atherosclerosis]. [Article in Japanese] Sata M(1). Author information: (1)sata@clin.med.tokushima-u.ac.jp PMID: 22075459 [PubMed - indexed for MEDLINE] 521. Nihon Yakurigaku Zasshi. 2011 Nov;138(5):178-81. [Obesity and homeostatic inflammation]. [Article in Japanese] Ogawa Y(1). Author information: (1)ogawa.mmm@mri.tmd.ac.jp PMID: 22075458 [PubMed - indexed for MEDLINE] 522. Obes Rev. 2012 Mar;13(3):234-57. doi: 10.1111/j.1467-789X.2011.00948.x. Epub 2011 Nov 10. Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit. Sainsbury A(1), Zhang L. Author information: (1)Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia. a.sainsbury-salis@garvan.org.au Energy deficit in lean or obese animals or humans stimulates appetite, reduces energy expenditure and possibly also decreases physical activity, thereby contributing to weight regain. Often overlooked in weight loss trials for obesity, however, is the effect of energy restriction on neuroendocrine status. Negative energy balance in lean animals and humans consistently inhibits activity of the hypothalamo-pituitary-thyroid, -gonadotropic and -somatotropic axes (or reduces circulating insulin-like growth factor-1 levels), while concomitantly activating the hypothalamo-pituitary-adrenal axis, with emerging evidence of similar changes in overweight and obese people during lifestyle interventions for weight loss. These neuroendocrine changes, which animal studies show may result in part from hypothalamic actions of orexigenic (e.g. neuropeptide Y, agouti-related peptide) and anorexigenic peptides (e.g. alpha-melanocyte-stimulating hormone, and cocaine and amphetamine-related transcript), can adversely affect body composition by promoting the accumulation of adipose tissue (particularly central adiposity) and stimulating the loss of lean body mass and bone. As such, current efforts to maximize loss of excess body fat in obese people may inadvertently be promoting long-term complications such as central obesity and associated health risks, as well as sarcopenia and osteoporosis. Future weight loss trials would benefit from assessment of the effects on body composition and key hormonal regulators of body composition using sensitive techniques. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22070225 [PubMed - indexed for MEDLINE] 523. Diabetes Metab Res Rev. 2011 Nov;27(8):913-8. doi: 10.1002/dmrr.1279. 'Sensing' the link between type 1 and type 2 diabetes. Tsui H(1), Paltser G, Chan Y, Dorfman R, Dosch HM. Author information: (1)The Research Institute, Hospital For Sick Children, University of Toronto, Neuroscience and Mental Health Program, Toronto, ON M5G 1X8, Canada. hubert.tsui@utoronto.ca Obesity-associated insulin resistance is a core element of metabolic syndrome and type 2 diabetes (T2D). Notably, insulin resistance is also a feature of type 1 diabetes (T1D), where findings in the non-obese diabetic mouse model have implicated transient receptor potential vanilloid-1 (TRPV1+) sensory neurons in local islet inflammation and glucose metabolism. Here, we briefly review the role of TRPV1 in non-obese diabetic (NOD) T1D pathogenesis, highlighting commonalities that suggest TRPV1 may contribute to obesity and T2D as well. With the recently discovered importance of adipose infiltrating lymphocytes in the metabolic disturbances of obesity and T2D, sensory innervation of fat may thus play an analogous role to sensory neurons in the islet--modulating neuroendocrine homeostasis and inflammation. In such a scenario, TRPV1+ sensory nerves would provide the pathoaetiological link connecting the shared metabolic and immunologic features of type 1 diabetes and T2D. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 22069284 [PubMed - indexed for MEDLINE] 524. Circ J. 2011;75(12):2739-48. Epub 2011 Nov 8. Chronic inflammation links cardiovascular, metabolic and renal diseases. Manabe I(1). Author information: (1)Department of Cardiovascular Medicine and Global COE, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. manabe-tky@umin.ac.jp Chronic inflammation appears to underlie most, if not all, the chronic diseases of today, including cardiovascular disease, type 2 diabetes, chronic kidney disease, Alzheimer's disease and cancer. We have demonstrated that obesity induces chronic local inflammation in adipose tissue. We also found that chronic inflammation is crucially involved in the development of heart failure and chronic kidney disease. In this article, I review recent findings reported by my group and others regarding the mechanisms underlying the chronic inflammatory processes commonly observed in adipose tissue, heart and kidney. I then discuss the key features of the chronic inflammation seen in chronic diseases. PMID: 22067929 [PubMed - indexed for MEDLINE] 525. Int J Immunopathol Pharmacol. 2011 Oct;24(4 Suppl):13-6. Adipokines and their role in allergies. Ciprandi G(1), Caimmi D, Raschetti R, Miraglia Del Giudice M, Salpietro C, Caimmi S, Castellazzi AM. Author information: (1)Department of Internal Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, Genoa, Italy. gio.cip@libero.it Both allergic disorders and obesity keep increasing in industrialized countries. Even though a strong association between obesity and allergy- related diseases has been reported in several studies, no published data show a scientific and firm link in-between the two conditions. In general, obesity and weight gain have been associated with an increased risk of asthma and allergic rhinitis. Asthma, allergic rhinitis and obesity have a common inflammatory pattern that could therefore justify their association. In fact, the chronic inflammation that characterizes the increase in white adipose tissue typically pushes the immune system toward a Th2 pattern. Such a polarization might, consequentially, worsen a pre-existing allergic disease or even stimulate the evolution from a sensitization to a respiratory form of allergy. Several studies have been published on the role of different adipokines on allergic diseases. We focus our review on the role of adipokines on asthma and allergic rhinitis. PMID: 22032780 [PubMed - indexed for MEDLINE] 526. Dis Model Mech. 2011 Nov;4(6):733-45. doi: 10.1242/dmm.008698. Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity. Speakman JR(1), Levitsky DA, Allison DB, Bray MS, de Castro JM, Clegg DJ, Clapham JC, Dulloo AG, Gruer L, Haw S, Hebebrand J, Hetherington MM, Higgs S, Jebb SA, Loos RJ, Luckman S, Luke A, Mohammed-Ali V, O'Rahilly S, Pereira M, Perusse L, Robinson TN, Rolls B, Symonds ME, Westerterp-Plantenga MS. Author information: (1)Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, AB39 2PN, UK. J.Speakman@abdn.ac.uk The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the 'obesity epidemic'--the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models--the general intake model and the dual intervention point model--that address this issue and might offer better ways to understand how body fatness is controlled. PMCID: PMC3209643 PMID: 22065844 [PubMed - indexed for MEDLINE] 527. Prog Neurobiol. 2012 May;97(2):152-72. doi: 10.1016/j.pneurobio.2011.10.003. Epub 2011 Nov 2. Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases. Sambataro F(1), Pennuto M. Author information: (1)Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova 16163, Italy. Polyglutamine diseases are neurodegenerative disorders caused by expansion of polyglutamine tracts in the coding regions of specific genes. One of the most important features of polyglutamine diseases is that, despite the widespread and in some cases ubiquitous expression of the polyglutamine proteins, specific populations of neurons degenerate in each disease. This finding has led to the idea that polyglutamine diseases are cell-autonomous diseases, in which selective neuronal dysfunction and death result from damage caused by the mutant protein within the targeted neuronal population itself. Development of animal models for conditional expression of polyglutamine proteins, along with new pharmacologic manipulation of polyglutamine protein expression and toxicity, has led to a remarkable change of the current view of polyglutamine diseases as cell-autonomous disorders. It is becoming evident that toxicity in the neighboring non-neuronal cells contributes to selective neuronal damage. This observation implies non-cell-autonomous mechanisms of neurodegeneration in polyglutamine diseases. Here, we describe cell-autonomous and non-cell-autonomous mechanisms of polyglutamine disease pathogenesis, including toxicity in neurons, skeletal muscle, glia, germinal cells, and other cell types. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22061202 [PubMed - indexed for MEDLINE] 528. Clin Chim Acta. 2012 Jan 18;413(1-2):81-7. doi: 10.1016/j.cca.2011.10.028. Epub 2011 Oct 26. ESR1 in myocardial infarction. Puzianowska-Kuźnicka M(1). Author information: (1)Department of Human Epigenetics, Mossakowski Medical Research Centre, Warsaw, Poland. mpuzianowska@wum.edu.pl Women live longer than men; this can be attributed in part to the function of estrogens. In premenopausal women 17β-estradiol (E2) is produced mainly by the ovaries. Extra-ovarian sources of this hormone comprise adipose tissue, breast tissue, bone, leukocytes, heart, testes, prostate, adrenal tissues, and some brain structures. E2 exerts the majority of its biological functions by interacting with the nuclear receptors ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively. The genomic mechanism of ER action is the regulation of the activity of target genes. In addition, E2 induces rapid cellular effects in transcription-independent, non-genomic mechanisms, acting via receptors localized in the plasma membrane, in the cytoplasm, and in the mitochondria. Notably, ERα commonly serves as an extra-nuclear receptor of E2. In wild type animal models of cardiac ischemia ERα activation reduces infarct size, apoptosis of cardiomyocytes, inflammation, and oxidative stress, induces vasodilatation and increases neovascularization. The cardioprotective role of ERα in human is not fully elucidated. An individual with disruptive ESR1 mutation had dysfunctional epithelium and suffered from early cardiovascular disease. An association of the common ESR1 -397T>C and -351A>G polymorphisms and of other polymorphisms with cardiovascular disease and with myocardial infarction is still not firmly established. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22061094 [PubMed - indexed for MEDLINE] 529. Transl Res. 2011 Dec;158(6):369-84. doi: 10.1016/j.trsl.2011.08.004. Epub 2011 Sep 3. Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress. Codoñer-Franch P(1), Valls-Bellés V, Arilla-Codoñer A, Alonso-Iglesias E. Author information: (1)Department of Pediatrics, Dr. Peset University Hospital, Valencia, Spain. pilar.codoner@uv.es Evidence of obesity-induced oxidative stress in adults has emerged in the past several years, and similar evidence has been demonstrated in children more recently. The reactive species of oxygen or nitrogen can chemically alter all major classes of biomolecules by modifying their structure and function. Organisms have developed mechanisms to protect biomolecules from the deleterious effects of free radicals. These include the enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as water and lipid-soluble antioxidants, such as glutathione, ascorbate (vitamin C), α-tocopherol (vitamin E), and β-carotene. Obesity creates oxidant conditions that favor the development of comorbid diseases. Energy imbalances lead to the storage of excess energy in adipocytes, resulting in both hypertrophy and hyperplasia. These processes are associated with abnormalities of adipocyte function, particularly mitochondrial stress and disrupted endoplasmic reticulum function. In this sense, oxidative stress can also be induced by adipocyte associated inflammatory macrophages. There is a close link among obesity, a state of chronic low-level inflammation, and oxidative stress. In addition, the dysregulation of adipocytokines, which are secreted by adipose tissue and promoted by oxidative stress, act synergistically in obesity-related metabolic abnormalities. Adipocytokines link the local and systemic inflammation responses in the context of obesity. It is thought that the evaluation of oxidative status may allow for the identification of patients at an increased risk of complications. Decreasing the levels of chronic inflammation and oxidative stress in childhood may decrease cardiovascular morbidity and mortality in adulthood. Copyright © 2011 Mosby, Inc. All rights reserved. PMID: 22061044 [PubMed - indexed for MEDLINE] 530. Scand J Clin Lab Invest. 2012 Feb;72(1):1-13. doi: 10.3109/00365513.2011.626868. Epub 2011 Nov 7. Soluble CD163. Møller HJ(1). Author information: (1)Department of Clinical Biochemistry, Aarhus University Hospital, Nørrebrogade 44, Aarhus C, Denmark. holgmoel@rm.dk CD163 is an endocytic receptor for haptoglobin-hemoglobin complexes and is expressed solely on macrophages and monocytes. As a result of ectodomain shedding, the extracellular portion of CD163 circulates in blood as a soluble protein (sCD163) at 0.7-3.9 mg/l in healthy individuals. The function of sCD163 is unknown, but during inflammation and macrophage activation, sCD163 levels increase acutely due to metalloproteinase-mediated cleavage near the cell membrane. It is now evident that sCD163 is very useful as a biomarker of macrophage activation in various inflammatory diseases, such as macrophage activation syndrome, sepsis, and liver disease. Moreover, sCD163 is a general risk marker of comorbidity and mortality in several chronic inflammatory disease states. Recently, sCD163 has been shown to be strongly associated with later development of type 2 diabetes in both lean and obese subjects, likely due to macrophage infiltration of adipose tissue and the liver. This review summarizes the current knowledge on the regulation of sCD163 in normal and pathological states and also deals with analytical aspects of sCD163 measurements in biological samples. PMID: 22060747 [PubMed - indexed for MEDLINE] 531. Regen Med. 2011 Nov;6(6):757-65. doi: 10.2217/rme.11.91. Urologic applications of engineered tissue. Kollhoff DM(1), Cheng EY, Sharma AK. Author information: (1)Loyola University Medical Center, Maywood, IL 60153, USA. Many congenital and acquired anomalies affect the genitourinary tract, necessitating surgical intervention. Among these are bladder exstrophy, hypospadias, epispadias, posterior urethral valves, myelomeningocele, bladder carcinoma, urethral stricture disease, stress urinary incontinence, pelvic organ prolapse, vesicoureteral reflux and traumatic injuries of the urinary tract. Surgical repair of these conditions often utilizes skin, oral mucosa or bowel autograft or xenograft material to replace missing tissue or to augment inadequate tissues. These materials are often sufficient to restore the basic anatomy of the organ to which they are being grafted, but they usually do not completely restore normal function. In addition, postoperative complications are common, especially in the case of bladder augmentation or neobladder creation with autologous bowel. The complications and inherent limitations of these procedures may be mitigated by the availability of alternative tissue sources. Therefore, there has been a great deal of interest in developing tissues engineered from autologous materials, such as mature bladder cells, bone marrow-derived stem cells and adipose tissue. Ideally, an engineered tissue would restore or preserve the normal function of the organ it is augmenting or replacing. In addition, the engineered tissue should be nonimmunogenic to minimize rejection or foreign-body reactions. For the purposes of this article, we will focus on selection of scaffolding materials, selection of cell sources, and the current applications and potential future roles of tissue engineering in urology. PMID: 22050527 [PubMed - indexed for MEDLINE] 532. BioDrugs. 2011 Dec 1;25(6):405-8. doi: 10.2165/11208290-000000000-00000. Spotlight on tesamorelin in HIV-associated lipodystrophy. Dhillon S(1). Author information: (1)Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz Tesamorelin (Egrifta™) is a synthetic analog of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral edema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image. PMID: 22050344 [PubMed - indexed for MEDLINE] 533. Arthritis. 2011;2011:203901. doi: 10.1155/2011/203901. Epub 2011 Aug 18. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Conde J(1), Scotece M, Gómez R, Lopez V, Gómez-Reino JJ, Gualillo O. Author information: (1)SERGAS, NEIRID Lab (Laboratory of NeuroEndocrine Interaction in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital Building C, Level-2, 15706 Santiago de Compostela, Spain. Obesity has been considered a risk factor for osteoarthritis and it is usually accepted that obesity contributes to the development and progression of osteoarthritis by increasing mechanical load of the joints. Nevertheless, recent advances in the physiology of white adipose tissue evidenced that fat cells produce a plethora of factors, called adipokines, which have a critical role in the development of ostearthritis, besides to mechanical effects. In this paper, we review the role of adipokines and highlight the cellular and molecular mechanisms at play in osteoarthritis elicited by adipokines. We also emphasize how defining the role of adipokines has broadned our understanding of the diversity of factors involved in the genesis and progression of osteoarthritis in the hope of modifying it to prevent and treat diseases. PMCID: PMC3200120 PMID: 22046513 [PubMed] 534. Clin Ter. 2011;162(5):e145-53. [The ketogenic diet: an underappreciated therapeutic option?]. [Article in Italian] Paoli A(1), Canato M, Toniolo L, Bargossi AM, Neri M, Mediati M, Alesso D, Sanna G, Grimaldi KA, Fazzari AL, Bianco A. Author information: (1)Dipartimento di Anatomia e Fisiologia Umana, Università di Padova, Italy. antonio.paoli@unipd.it Obesity is reaching epidemic proportions in Western countries and is a strong risk factor for cardiovascular disease. Despite the constant recommendations of health care organizations regarding the importance of weight control, this goal often fails. Although there is a common agreement about the concept that exercise and diet are two key factors for the control of body weight, the ideal amount and type of exercise and also the ideal diet for weight control are still under debate. A widely accepted nutritional regime is the Mediterranean diet that has evident health benefits although less attention has been paid to see if the effects are due to other lifestyle factors which may contribute to the health benefits perhaps as much as specific food choices. There are several other options available to the physician that may produce good weight loss results in the short/medium term and also for maintenance of the goal achieved. One of these strategies is the ketogenic diet or VLCKD (very low carbohydrate ketogenic diet) that has been widely studied in recent years. Most studies show that this diet has a solid physiological and biochemical basis which is able to induce effective weight loss and improvement of several parameters of cardiovascular risk. This review discusses the physiological basis of VLCKD and the main applications together with its strengths and weaknesses compared to common dietary recommendations. PMID: 22041813 [PubMed - indexed for MEDLINE] 535. Yakugaku Zasshi. 2011;131(11):1557-62. [Novel therapeutic approach based on recent understanding of the development of metabolic syndrome]. [Article in Japanese] Hosoi T(1). Author information: (1)Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toruh@hiroshima-u.ac.jp Obesity is associated with metabolic syndrome, a cluster of symptoms including diabetes, hyperlipidemia, hypertension and arteriosclerosis, which can cause serious health problems. Accumulating evidence suggests that endoplasmic reticulum stress (ER stress) is associated with metabolic syndrome. Leptin is an anti-obesity hormone, which is secreted from adipose tissue. Circulating leptin acts at the brain hypothalamus and reduces food intake. As most forms of obesity indicate a state of leptin resistance, elucidation of the mechanisms of leptin resistance would be an important subject. We and other groups have recently suggested that leptin resistance may be derived from ER stress. These results raised the possibility that attenuating ER stress would be effective treatment for the disease. In the present review article, recent understanding of the mechanisms of the development of obesity and the potential novel therapeutic approaches targeting ER stress are discussed. PMID: 22041693 [PubMed - indexed for MEDLINE] 536. Peptides. 2011 Nov;32(11):2340-7. doi: 10.1016/j.peptides.2011.10.006. Epub 2011 Oct 29. Ghrelin in neuroendocrine tumors. Vu JP(1), Wang HS, Germano PM, Pisegna JR. Author information: (1)Department of Gastroenterology and Hepatology, Veterans Administration GLAHS, Los Angeles, CA 90073, USA. Ghrelin is a 28 amino acid peptide, primarily produced by the oxyntic mucosa X/A like neuroendocrine cells in the stomach. It is also found in the small intestine, hypothalamus, pituitary gland, pancreas, heart, adipose tissue, and immune system. In gastrointestinal neuroendocrine tumors (NETs) ghrelin release has been well documented. Ghrelin is a brain-gut circuit peptide with an important role in the physiological regulation of appetite, response to hunger and starvation, metabolic and endocrine functions as energy expenditure, gastric motility and acid secretion, insulin secretion and glucose homeostasis, as well as in the potential connection to the central nervous system. Recently, there has been a significant interest in the biological effects of ghrelin in NETs. In this article, we present a comprehensive review of ghrelin's expression and a brief summary of ghrelin's physiological role in NETs patients with carcinoids, type A chronic atrophic gastritis (CAG), with or without MEN-1, and with and without liver metastases. We hope, with the research reviewed here, to offer compelling evidence of the potential significance of ghrelin in NETs, as well as to provide a useful guide to the future work in this area. Published by Elsevier Inc. PMID: 22041110 [PubMed - indexed for MEDLINE] 537. Mol Aspects Med. 2012 Feb;33(1):26-34. doi: 10.1016/j.mam.2011.10.011. Epub 2011 Oct 21. Immunity as a link between obesity and insulin resistance. Kalupahana NS(1), Moustaid-Moussa N, Claycombe KJ. Author information: (1)Obesity Research Center, The University of Tennessee, United States. Obesity is a major public health problem in the United States and worldwide. Further, obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and type-2 diabetes (T2D). A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesity-induced insulin resistance. This adipose tissue inflammation is characterized by changes in immune cell populations giving rise to altered adipo/cytokine profiles, which in turn induces skeletal muscle and hepatic insulin resistance. Detailed molecular mechanisms of insulin resistance, adipose tissue inflammation and the implications of these findings on therapeutic strategies are discussed in this review. Published by Elsevier Ltd. PMID: 22040698 [PubMed - indexed for MEDLINE] 538. Biofactors. 2011 Nov-Dec;37(6):413-20. doi: 10.1002/biof.185. Epub 2011 Oct 28. Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Conde J(1), Scotece M, Gómez R, López V, Gómez-Reino JJ, Lago F, Gualillo O. Author information: (1)NEIRID Lab (NeuroEndocrine Interaction in Rheumatology and Inflammatory Diseases), SERGAS, Santiago University Clinical Hospital, Institute of Medical Research (IDIS), Building C, Level-2, Santiago de Compostela, Spain. Until the identification of leptin, the first adipokine discovered in 1994, adipose tissue was considered only as an energy storage tissue. However, it is now clear that adipose tissue is an endocrine/paracrine/autocrine organ, which plays a relevant role in physiopathology of several inflammatory diseases. Actually, it is mainly involved not only in the low-grade inflammatory status in obesity but also in other relevant inflammatory conditions and autoimmune disorders. In this review article, we discuss the main biological activities of leptin, adiponectin, lipocalin-2, resistin, and visfatin, as well as their contributions to certain inflammatory conditions. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc. PMID: 22038756 [PubMed - indexed for MEDLINE] 539. Acta Pharmacol Sin. 2012 Feb;33(2):182-8. doi: 10.1038/aps.2011.131. Epub 2011 Oct 31. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Gao ZG(1), Ye JP. Author information: (1)Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. Chronic inflammation occurs in obese conditions in both humans and animals. It also contributes to the pathogenesis of type 2 diabetes (T2D) through insulin resistance, a status in which the body loses its ability to respond to insulin. Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. Insulin sensitizers (such as rosiglitazone and pioglitazone) inhibit inflammation while improving insulin sensitivity. Therefore, anti-inflammatory agents have been suggested as a treatment strategy for insulin resistance. This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however, no significant progress has been made in any of the model systems. This status has led us to re-evaluate the biological significance of chronic inflammation in obesity. Recent studies have consistently asserted that obesity-associated inflammation helps to maintain insulin sensitivity. Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure. We propose that these beneficial activities of inflammation provide an underlying mechanism for the failure of anti-inflammatory therapy in the treatment of insulin resistance. Current literature will be reviewed in this article to present evidence that supports this viewpoint. PMCID: PMC3270211 PMID: 22036866 [PubMed - indexed for MEDLINE] 540. Cell Biosci. 2011 Oct 28;1:35. doi: 10.1186/2045-3701-1-35. Recent progress in the study of brown adipose tissue. Yao X(1), Shan S, Zhang Y, Ying H. Author information: (1)Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. yinghao@sibs.ac.cn. Brown adipose tissue in mammals plays a critical role in maintaining energy balance by thermogenesis, which means dissipating energy in the form of heat. It is held that in mammals, long-term surplus food intake results in energy storage in the form of triglyceride and may eventually lead to obesity. Stimulating energy-dissipating function of brown adipose tissue in human body may counteract fat accumulation. In order to utilize brown adipose tissue as a therapeutic target, the mechanisms underlying brown adipocyte differentiation and function should be better elucidated. Here we review the molecular mechanisms involved in brown adipose tissue development and thermogenesis, and share our thoughts on current challenges and possible future therapeutic approaches. PMCID: PMC3219668 PMID: 22035495 [PubMed] 541. Diabetol Metab Syndr. 2011 Oct 28;3(1):29. doi: 10.1186/1758-5996-3-29. The macrophage at the intersection of immunity and metabolism in obesity. Samaan MC(1). Author information: (1)Division of Pediatric Endocrinology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada. samaanc@mcmaster.ca. Obesity is a worldwide pandemic representing one of the major challenges that societies face around the globe. Identifying the mechanisms involved in its development and propagation will help the development of preventative and therapeutic strategies that may help control its rising rates.Obesity is associated with chronic low-grade inflammation, and this is believed to be one of the major contributors to the development of insulin resistance, which is an early event in obesity and leads to type 2 diabetes when the pancreas fails to keep up with increased demand for insulin. In this review, we discuss the role of macrophages in mediation of inflammation in obesity in metabolic organs including adipose tissue, skeletal muscle and liver. The presence of immune cells at the interface with metabolic organs modulates both metabolic function and inflammatory responses in these organs, and may provide a potential therapeutic target to modulate metabolic function in obesity. PMCID: PMC3223491 PMID: 22035457 [PubMed] 542. Antioxid Redox Signal. 2012 Jul 1;17(1):81-94. doi: 10.1089/ars.2011.4358. Epub 2011 Dec 19. Modulation of h(2)s metabolism by statins: a new aspect of cardiovascular pharmacology. Bełtowski J(1), Jamroz-Wiśniewska A. Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@umlub.pl SIGNIFICANCE: Statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors) are commonly used in the treatment of cardiovascular diseases. Statins reduce plasma low-density lipoproteins, inhibit inflammatory reaction, improve endothelial function, ameliorate oxidative stress, and reduce platelet activity. Consequently, statins markedly decrease the risk of acute cardiovascular events. H(2)S is synthesized in all layers of the vascular wall, including the endothelium, smooth muscle cells, and perivascular adipose tissue (PVAT). RECENT ADVANCES: Recent studies demonstrate that PVAT-derived H(2)S decreases vascular tone by activating K(ATP) and/or KCNQ potassium channels in smooth muscle cells. Lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H(2)S production in PVAT by inhibiting its mitochondrial oxidation, and augments the anticontractile effect of PVAT. Inhibition of H(2)S metabolism results from atorvastatin-induced decrease in coenzyme Q, which is a cofactor of H(2)S oxidation by sulfide:quinone oxidoreductase. In contrast to H(2)S, statins do not impair mitochondrial oxidation of organic substrates. CRITICAL ISSUES: Taking into account antiatherosclerotic and anti-inflammatory effect of H(2)S, the gas may mediate some of the beneficial effects of statins on the cardiovascular system. In addition, specific statins differ in their ability to enhance H(2)S signaling. FUTURE DIRECTIONS: Since both statins and H(2)S reduce ischemia-reperfusion injury, the possible effect of statins on H(2)S oxidation in other tissues such as the heart and the kidney needs to be examined. Inhibition of H(2)S metabolism may be a new therapeutic strategy to improve H(2)S signaling, especially in the mitochondrial compartment. PMCID: PMC3342564 PMID: 22034938 [PubMed - indexed for MEDLINE] 543. Annu Rev Med. 2012;63:329-43. doi: 10.1146/annurev-med-042010-113026. Epub 2011 Oct 27. Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. Stanhope KL(1). Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California, USA. klstanhope@ucdavis.edu There is controversy concerning the role of sugar in the epidemics of obesity and metabolic syndrome. There is less controversy concerning the effects of fructose on components of metabolic syndrome; consumption of fructose has been shown to increase visceral adipose deposition and de novo lipogenesis (DNL), produce dyslipidemia, and decrease insulin sensitivity in older, overweight/obese subjects. This review examines the potential mechanisms of these effects of fructose and considers whether these mechanisms are relevant to the effects of consuming sucrose or high-fructose corn syrup. Evidence demonstrating that the commonly consumed sugars increase visceral adipose deposition, DNL, and insulin insensitivity is limited or inconclusive. Evidence that sugar consumption promotes development of an unfavorable lipid profile is strong and suggests that the upper added sugar consumption limit of 25% of energy or less, suggested in the Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans 2010, may merit re-evaluation. PMID: 22034869 [PubMed - indexed for MEDLINE] 544. Obes Rev. 2012 Feb;13(2):136-49. doi: 10.1111/j.1467-789X.2011.00942.x. Epub 2011 Oct 31. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Kalupahana NS(1), Moustaid-Moussa N. Author information: (1)Obesity Research Center, The University of Tennessee, Knoxville, TN 37996-4588, USA. The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22034852 [PubMed - indexed for MEDLINE] 545. Plast Reconstr Surg. 2011 Nov;128(5):411e-418e. doi: 10.1097/PRS.0b013e31822b669f. Evaluation of clinical outcomes and aesthetic results after autologous fat grafting for contour deformities of the reconstructed breast. de Blacam C(1), Momoh AO, Colakoglu S, Tobias AM, Lee BT. Author information: (1)Department of Surgery, Division of Plastic and Reconstructive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Comment in Plast Reconstr Surg. 2012 Sep;130(3):500e-1e. BACKGROUND: Autologous fat grafting is gaining widespread acceptance for the management of soft-tissue deformities of the reconstructed breast. However, published data on long-term outcomes and aesthetic results of fat grafting to the breast are lacking. The purpose of this study was to review the authors' early experience of fat grafting in the correction of acquired contour deformities after postmastectomy breast reconstruction. METHODS: A detailed retrospective review of 49 patients who underwent fat grafting to 68 reconstructed breasts was carried out. Clinical outcomes were analyzed and aesthetic results were assessed with objective grading of preoperative and postoperative photographs by two independent, blinded plastic surgeons. RESULTS: On average, 67 cc of fat was injected into each breast per session. There were 111 fat injection procedures, as more than one injection was required in 51.5 percent of cases. Average follow-up time was 2.4 years. Complications occurred in 6.3 percent of procedures, including fat necrosis (3.6 percent), oil cysts (1.8 percent), and infection (0.9 percent). Aesthetic outcome was significantly improved across all measurements, including volume, contour, placement, and superomedial fullness (p<0.001 for all). CONCLUSION: Although further studies are required to provide surgeons with definitive guidelines for the implementation of this technique, fat injection is a safe intervention and significantly improves the aesthetic results in patients with contour deformities of the reconstructed breast. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID: 22030501 [PubMed - indexed for MEDLINE] 546. Plast Reconstr Surg. 2011 Nov;128(5):382e-394e. doi: 10.1097/PRS.0b013e31822b7a3b. The low transverse extended latissimus dorsi flap based on fat compartments of the back for breast reconstruction: anatomical study and clinical results. Bailey SH(1), Saint-Cyr M, Oni G, Wong C, Maia M, Nguyen V, Pessa JE, Colohan S, Rohrich RJ, Mojallal A. Author information: (1)Department of Plastic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9132, USA. BACKGROUND: Despite many modifications to the extended latissimus dorsi flap, its use in autologous breast reconstruction remains limited because of insufficient volume and donor-site morbidity. Through a detailed analysis of the deposition of back fat, this study describes a low transverse extended latissimus dorsi flap harvest technique that increases flap volumes and improves donor-site aesthetics. METHODS: Eight fresh cadaver hemibacks were used to identify the anatomical location of the fat compartments. Correlation between the fat compartments and the fat folds was made using photographic analysis of 216 patients. Retrospective case note review was conducted of all patients who had a low transverse extended latissimus dorsi flap performed by the senior author (M.S.-C.). RESULTS: Cadaveric dissection and photographic analysis confirmed the presence of the four distinct fat compartments in the back. The lower compartments 3 and 4 were the most frequently identified and the largest, with mean values of 367 cm and 271 cm, respectively. The clinical series comprised eight high-body mass index patients who underwent 12 pure autologous breast reconstructions using the low transverse skin paddle harvest technique. Donor-site complications included partial dehiscence (n=2) and minor infection (n=3). There were no instances of seroma, and fat necrosis (<5 percent) occurred in one breast. CONCLUSIONS: The low transverse skin paddle extended latissimus dorsi flap is reliable and provides sufficient volume for purely autologous breast reconstruction with low donor-site morbidity and improved body contouring for a select group of patients. The authors' initial experience with high-body mass index patients shows promising results with this flap in a challenging group. PMID: 22030499 [PubMed - indexed for MEDLINE] 547. Bioessays. 2012 Jan;34(1):50-60. doi: 10.1002/bies.201100107. Epub 2011 Oct 26. PRDM proteins: important players in differentiation and disease. Fog CK(1), Galli GG, Lund AH. Author information: (1)Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Denmark. The PRDM family has recently spawned considerable interest as it has been implicated in fundamental aspects of cellular differentiation and exhibits expanding ties to human diseases. The PRDMs belong to the SET domain family of histone methyltransferases, however, enzymatic activity has been determined for only few PRDMs suggesting that they act by recruiting co-factors or, more speculatively, confer methylation of non-histone targets. Several PRDM family members are deregulated in human diseases, most prominently in hematological malignancies and solid cancers, where they can act as both tumor suppressors or drivers of oncogenic processes. The molecular mechanisms have been delineated for only few PRDMs and little is known about functional redundancy within the family. Future studies should identify target genes of PRDM proteins and the protein complexes in which PRDM proteins reside to provide a more comprehensive understanding of the biological and biochemical functions of this important protein family. Copyright © 2012 WILEY Periodicals, Inc. PMID: 22028065 [PubMed - indexed for MEDLINE] 548. Nat Rev Endocrinol. 2011 Oct 25;8(3):183-92. doi: 10.1038/nrendo.2011.158. Resistance to type 2 diabetes mellitus: a matter of hormesis? Kolb H(1), Eizirik DL. Author information: (1)Immunobiology Research Group, Institute of Molecular Medicine, University of Düsseldorf, D-40001 Düsseldorf, Germany. hubert.kolb@uni-duesseldorf.de Type 2 diabetes mellitus is characterized by subclinical systemic inflammation and impaired regulation of blood glucose levels. Interestingly, impairment of glycemic control occurs despite substantial insulin secretion early in the course of this disease. Dysfunction of several organs (including pancreatic islets, liver, skeletal muscle, adipose tissue, gut, hypothalamus and the immune system) has been implicated in the pathogenesis of type 2 diabetes mellitus. However, diabetes-promoting lifestyle factors do not inevitably cause disease in all persons exposed. Hence, defense mechanisms must exist that can keep the detrimental influence of these risk factors at bay. Hormesis describes the phenomenon that exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This Review discusses the emerging concept that the effectiveness of an adaptive (hormetic) response to detrimental lifestyle factors determines the extent of protection from progression to type 2 diabetes mellitus. Further analysis of these protective hormetic responses at the molecular level should help to identify novel targets for preventive or therapeutic intervention in patients at risk of developing type 2 diabetes mellitus or those with overt disease. PMID: 22024974 [PubMed - indexed for MEDLINE] 549. Curr Drug Targets. 2011 Dec;12(14):2103-28. Molecular players at the intersection of obesity and osteoarthritis. Bonet ML(1), Granados N, Palou A. Author information: (1)Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Crta. Valldemossa Km 7.5, Palma de Mallorca, Spain. luisabonet@uib.es Obesity and degenerative joint disease (osteoarthritis, OA) are two multifactorial pathologies that are becoming major medical issues with the aging of the world population. The relationship of OA with obesity is complex, involving both biomechanical and metabolic links. Dysregulated production of adipose tissue-derived inflammatory mediators, hyperlipidemia, and increased systemic oxidative stress are conditions frequently associated with obesity that may favor joint degeneration. In addition, it is remarkable that many regulatory factors have been implicated in the development, maintenance and function of both adipose tissues and cartilage and other articular joint tissues. Disturbances in these factors may underlie additional links between obesity and OA. In this review, molecular players at the intersection of adipose tissue and joint cell biology - including differentiation signals and transcription factors, extracellular matrix components and remodelers, joint cell- and adipose tissue cell-derived mediators (cytokines, adipokines), hypoxia inducible transcription factors, lipids, advanced glycation end products and miRNAs - are reviewed, with emphasis on their dysregulation in obesity and OA. Knowledge of these factors may illuminate a novel, adipocentric avenue for the pathogenesis and therapy of OA and other joint diseases. PMID: 22023406 [PubMed - indexed for MEDLINE] 550. Curr Drug Deliv. 2012 Jul;9(4):326-32. "Metabolic aspects" in inflammatory bowel diseases. Kaser A(1), Tilg H. Author information: (1)Department of Medicine II (Gastroenterology and Hepatology), Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. arthur.kaser@i-med.ac.at Mesenteric fat hypertrophy is a common feature of inflammatory bowel diseases (IBD), especially Crohn's disease. Although this "creeping fat" has been observed in the early days of this disease, its biological relevance is not understood. This adipose tissue has been recognized to release large amounts of various cytokines such as TNFa and adipocytokines such as adiponectin or leptin. Whereas leptin is definitely a pro-inflammatory adipocytokine, the role of the prototypic anti-inflammatory adipocytokine, namely adiponectin, in intestinal inflammation is less clear. Some experimental studies suggest that it could exert also pro-inflammatory activities in the gut. An important role for metabolic aspects and potentially adipocytokines has also come from recent studies demonstrating that ATG16L1- deficient mice show a strikingly enhanced expression of both adiponectin and leptin in epithelial cells. Autophagy not only plays a key role in intestinal inflammation, but is also involved in the regulation of lipid metabolism. Another recently identified pathway in IBD, namely endoplasmic stress/XBP1, regulates fatty acid synthesis and facilitates adipogenesis and adipocyte differentiataion. Therefore, XBP1 could possibly link intestinal inflammation with the development of "creeping fat" in Crohn's disease. Metabolic aspects have evolved as of key importance in experimental colitis and human IBD, and certain adipocytokines, autophagy, and ER stress might reflect the central players. PMID: 22023201 [PubMed - indexed for MEDLINE] 551. Curr Vasc Pharmacol. 2012 Mar;10(2):238-46. Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists. Ronconi V(1), Turchi F, Appolloni G, di Tizio V, Boscaro M, Giacchetti G. Author information: (1)Division of Endocrinology, Ospedali Riuniti, Universita Politecnica delle Marche, Ancona, Italy. Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae. PMID: 22022770 [PubMed - indexed for MEDLINE] 552. Regen Med. 2011 Nov;6(6 Suppl):33-41. doi: 10.2217/rme.11.62. In vivo manipulation of stem cells for adipose tissue repair/reconstruction. Yoshimura K(1), Eto H, Kato H, Doi K, Aoi N. Author information: (1)Department of Plastic Surgery, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan. kotaro-yoshimura@umin.ac.jp Many features of adipose stem/progenitor cells, including their physiological functions and localization, have been clarified in the past decade. Adipose tissue turns over very slowly, with perivascular progenitor cells differentiating into new adipocytes to replace dead adipocytes. A number of clinical trials using freshly isolated or cultured adipose-derived stromal cells containing adipose progenitor/stem cells are ongoing. Therapeutic use of adipose stem/progenitor cells has been shown to promote angiogenesis and adipose tissue regeneration. Identification of adipocyte-releasing factors upon apoptosis/necrosis would be a breakthrough and could lead to the next stage for adipose tissue regeneration. Activation of precursors in perichondrium and periosteum shows a dramatic neogenesis by simple injection and is an ideal example of in situ tissue engineering. The 'hit and catch' strategy using a mobilizer of bone-marrow stem/progenitor cells (hit) and attractants to lead the cells to proper homing into the target tissue (catch) may be the future of stem cell manipulation. Careful design of the microenvironment, cell delivery protocol to avoid unexpected behavior and induce maximal potential, and selection of target diseases, will be critical to the success of clinical applications of adipose-derived stromal cells. PMID: 21999260 [PubMed - indexed for MEDLINE] 553. Microb Cell Fact. 2011 Aug 30;10 Suppl 1:S10. doi: 10.1186/1475-2859-10-S1-S10. Epub 2011 Aug 30. Modulation of the gut microbiota by nutrients with prebiotic properties: consequences for host health in the context of obesity and metabolic syndrome. Delzenne NM(1), Neyrinck AM, Cani PD. Author information: (1)Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Brussels, Belgium. nathalie.delzenne@uclouvain.be The gut microbiota is increasingly considered as a symbiotic partner for the maintenance of health. The homeostasis of the gut microbiota is dependent on host characteristics (age, gender, genetic background...), environmental conditions (stress, drugs, gastrointestinal surgery, infectious and toxic agents...). Moreover, it is dependent on the day-to-day dietary changes. Experimental data in animals, but also observational studies in obese patients, suggest that the composition of the gut microbiota is a factor characterizing obese versus lean individuals, diabetic versus non diabetic patients, or patients presenting hepatic diseases such as non alcoholic steatohepatitis. Interestingly, the changes in the gut microbes can be reversed by dieting and related weight loss. The qualitative and quantitative changes in the intake of specific food components (fatty acids, carbohydrates, micronutrients, prebiotics, probiotics), have not only consequences on the gut microbiota composition, but may modulate the expression of genes in host tissues such as the liver, adipose tissue, intestine, muscle. This in turn may drive or lessen the development of fat mass and metabolic disturbances associated with the gut barrier function and the systemic immunity. The relevance of the prebiotic or probiotic approaches in the management of obesity in humans is supported by few intervention studies in humans up to now, but the experimental data obtained with those compounds help to elucidate novel potential molecular targets relating diet with gut microbes. The metagenomic and integrative metabolomic approaches could help elucidate which bacteria, among the trillions in human gut, or more specifically which activities/genes, could participate to the control of host energy metabolism, and could be relevant for future therapeutic developments. PMCID: PMC3231917 PMID: 21995448 [PubMed - indexed for MEDLINE] 554. J Korean Med Sci. 2011 Oct;26(10):1339-43. doi: 10.3346/jkms.2011.26.10.1339. Epub 2011 Oct 1. Correlation between complicated diverticulitis and visceral fat. Jeong JH(1), Lee HL, Kim JO, Tae HJ, Jung SH, Lee KN, Jun DW, Lee OY, Yoon BC, Choi HS, Hahm JS, Song SY. Author information: (1)Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea. The aim of this study was to examine the relationship of complications related to diverticulitis and visceral obesity. The study was based on a retrospective case note review conducted at the Hanyang University Hospital. Patients were diagnosed with diverticulitis based on clinical symptoms and abdominal computed tomography (CT) findings and divided into two groups: those admitted with complicated diverticulitis and those with a simple diverticulitis episode. We compared the body mass index (BMI) and degree of visceral obesity, measured by abdominal CT. The study included 140 patients, 87 (62.1%) were simple diverticulitis and 53 (37.9%) were complicated diverticulitis. In the complicated diverticulitis group, 9 (6.4%) cases were recurrent, 29 (20.7%) were perforation or abscess patients, and 28 (20%) were patients with systemic inflammatory response syndrome (SIRS). Of the SIRS patients, 13 were involved in other complication groups. When comparing in the two groups, the complicated diverticulitis group had a significantly higher visceral fat area (128.57 cm(2) vs 102.80 cm(2), P = 0.032) and a higher ratio of visceral fat area/subcutaneous fat area (0.997 vs 0.799, P = 0.014). Visceral obesity is significantly associated with complications of diverticulitis. PMCID: PMC3192347 PMID: 22022188 [PubMed - indexed for MEDLINE] 555. Proc Nutr Soc. 2012 Feb;71(1):175-80. doi: 10.1017/S0029665111003259. Epub 2011 Oct 21. Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin. Drew JE(1). Author information: (1)Metabolic Health, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, UK. j.drew@abdn.ac.uk Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer. PMID: 22014041 [PubMed - indexed for MEDLINE] 556. Bone. 2012 Feb;50(2):430-6. doi: 10.1016/j.bone.2011.10.001. Epub 2011 Oct 11. Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue. Shi YC(1), Baldock PA. Author information: (1)Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia. Skeletal research is currently undergoing a period of marked expansion. The boundaries of "bone" research are being re-evaluated and with this, a growing recognition of a more complex and interconnected biology than previously considered. One aspect that has become the focus of particular attention is the relationship between bone and fat homeostasis. Evidence from a number of avenues indicates that bone and adipose regulation are both related and interdependent. This review examines the neuropeptide Y (NPY) system, known to exert powerful control over both bone and fat tissue. The actions of this system are characterized by signaling both within specific nuclei of the hypothalamus and also the target tissues, mediated predominantly through two G-protein coupled receptors (Y1 and Y2). In bone tissue, elevated NPY levels act consistently to repress osteoblast activity. Moreover, both central Y2 receptor and osteoblastic Y1 receptor signaling act similarly to repress bone formation. Conversely, loss of NPY expression or receptor signaling induces increased osteoblast activity and bone mass in both cortical and cancellous envelopes. In fat tissue, NPY action is more complex. Energy homeostasis is powerfully altered by elevations in hypothalamic NPY, resulting in increases in fat accretion and body-wide energy conservation, through the action of locally expressed Y1 receptors, while local Y2 receptors act to inhibit NPY-ergic tone. Loss of central NPY expression has a markedly reduced effect, consistent with a physiological drive to promote fat accretion. In fat tissue, NPY and Y1 receptors act to promote lipogenesis, consistent with their roles in the brain. Y2 receptors expressed in adipocytes also act in this manner, showing an opposing action to their role in the hypothalamus. While direct investigation of these processes has yet to be completed, these responses appear to be interrelated to some degree. The starvation-based signal of elevated central NPY inducing marked inhibition of osteoblast activity, whilst promoting fat accretion, indicating skeletal tissue is a component of the energy conservation system. Moreover, when NPY expression is reduced, consistent with high calorie intake and weight gain, bone formation is stimulated, strengthening the skeleton. In conclusion, NPY acts to regulate both bone and fat tissue in a coordinated manner, and remains a strong candidate for mediating interactions between these two tissues. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22008645 [PubMed - indexed for MEDLINE] 557. Histopathology. 2012 Jun;60(7):1034-44. doi: 10.1111/j.1365-2559.2011.03911.x. Epub 2011 Oct 18. The connective tissue changes of Crohn's disease. Shelley-Fraser G(1), Borley NR, Warren BF, Shepherd NA. Author information: (1)Gloucestershire Cellular Pathology Laboratory Department of Colorectal Surgery, Cheltenham General Hospital, Cheltenham, Gloucestershire, UK. Although the inflammatory pathology of Crohn's disease is manifestly its most important attribute, the connective tissue changes are important in the genesis of the more chronic features of the disease, and yet these have received little attention from clinicians, pathologists, and scientists. Fat-wrapping appears to be pathognomonic of Crohn's disease, and is an important marker of disease for surgeons. There is evidence of a complex interplay between the effector inflammatory cells of Crohn's disease and adipocytes, hyperplasia of which results in fat-wrapping. Pathologically, this is exhibited in the close relationship between the transmural inflammation that is so characteristic of Crohn's disease and fat-wrapping. Fibrosis and muscularization are also important components of the chronic changes of intestinal Crohn's disease. Neuronal and vascular changes make up the remaining connective tissue changes: these constitute a distinctive feature, and are even specific for Crohn's disease. For pathologists, the combination of these connective changes will allow a diagnosis of chronic 'burnt-out' Crohn's disease, even in the absence of its highly characteristic inflammatory features. The connective tissue changes of Crohn's disease form an important part of its long-term pathology. They deserve more attention from clinicians, diagnostic pathologists and researchers alike. © 2011 Blackwell Publishing Limited. PMID: 22008086 [PubMed - indexed for MEDLINE] 558. J Pathol. 2012 Jan;226(2):185-99. doi: 10.1002/path.3031. Interstitial guidance of cancer invasion. Gritsenko PG(1), Ilina O, Friedl P. Author information: (1)Microscopical Imaging of the Cell, Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In the brain, the guidance is provided by myelinated axons, astrocyte processes, and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen-rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if not all, tissues include (i) guidance by integrins towards fibrillar interstitial collagen and/or laminins and type IV collagen in basement membranes decorating vessels and adipocytes, and, likely, CD44 engaging with hyaluronan; (ii) haptotactic guidance by chemokines and growth factors; and likely (iii) physical pushing mechanisms. Tissue-specific, resticted guidance cues include ECM proteins with restricted expression (tenascins, lecticans), cell-cell interfaces, and newly secreted matrix molecules decorating ECM fibres (laminin-332, thrombospondin-1, osteopontin, periostin). We here review physical and molecular guidance mechanisms in interstitial tissue and brain parenchyma and explore shared principles and organ-specific differences, and their implications for experimental model design and therapeutic targeting of tumour cell invasion. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID: 22006671 [PubMed - indexed for MEDLINE] 559. J Sep Sci. 2011 Dec;34(24):3470-83. doi: 10.1002/jssc.201100556. Epub 2011 Oct 17. Determination of acylglycerols from biological samples with chromatography-based methods. Hellmuth C(1), Uhl O, Segura-Moreno M, Demmelmair H, Koletzko B. Author information: (1)Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Centre, München, Germany. christian.hellmuth@med.uni-muenchen.de Lipids are the most diverse class of metabolites in mammalian physiology and dysregulation of lipid metabolism is linked to various diseases. Alterations in acylglycerols, a major class of lipids in plasma and adipose tissue, are involved in the pathogenesis of obesity and type 2 diabetes. Therefore, determination of acylglycerols is important to depict and unravel cellular mechanisms related to pathological outcomes, and specific molecular species of acylglycerols might be promising biomarker candidates. The variety of acylglycerols can be characterized in different ways. Enzymatic assays enable the determination of total tri- or diacylglycerols showing a possible relation to diseases, but they do not allow clarification of molecular mechanism. While gas chromatography can provide an overview of the fatty acid composition of total or separated lipids, a very detailed description of the individual molecular acylglycerol species is possible via liquid chromatography, particularly when combined with mass spectrometry. This review describes the determination of acylglycerols considering recent developments, with a focus on mammalian serum/plasma and tissue. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22002927 [PubMed - indexed for MEDLINE] 560. Curr Opin Lipidol. 2011 Dec;22(6):479-88. doi: 10.1097/MOL.0b013e32834c7cfc. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Schattenberg JM(1), Schuppan D. Author information: (1)Department of Medicine I bCenter for Molecular and Translational Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, Mainz, Germany. PURPOSE OF REVIEW: Nonalcoholic fatty liver (NAFL) and especially its inflammatory variant nonalcoholic steatohepatitis (NASH) have become a major challenge to healthcare systems worldwide because of the increasing prevalence of its major risk factors obesity and type 2 diabetes, which are closely linked to overeating, physical inactivity, and the metabolic syndrome. RECENT FINDINGS: Between 10 and 20% of patients with NAFL develop NASH, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The overall mortality in these patients is significantly increased because of both cardiovascular and liver-related complications. Sustained weight loss by diet and exercise, which is the most effective therapeutic measure, is only achieved by a minority of patients, having led to a great yet unmet need for medical therapies of NASH. SUMMARY: Pharmacological therapies should target the underlying pathophysiology that involves insulin resistance, enhanced peripheral lipolysis and release of free fatty acids, oxidative stress, accumulation of toxic lipids, adipose tissue inflammation, sensitization of hepatocytes toward apoptotic cell death, and fibrogenesis. However, pharmacological therapy that is well tolerated, cost-effective, and poses an acceptable risk-to-benefit ratio has still to be identified. This review summarizes the current and promising treatment options and their implications for future research and clinical practice. PMID: 22002020 [PubMed - indexed for MEDLINE] 561. Cell Mol Life Sci. 2012 Mar;69(5):741-62. doi: 10.1007/s00018-011-0840-1. Epub 2011 Oct 15. Metabolic syndrome as a risk factor for neurological disorders. Farooqui AA(1), Farooqui T, Panza F, Frisardi V. Author information: (1)Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43221, USA. farooqui.1@osu.edu The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders. © Springer Basel AG 2011 PMID: 21997383 [PubMed - indexed for MEDLINE] 562. Expert Opin Biol Ther. 2011 Dec;11(12):1591-7. doi: 10.1517/14712598.2011.628933. Epub 2011 Oct 13. Stem cells treatment for sciatic nerve injury. Dadon-Nachum M(1), Melamed E, Offen D. Author information: (1)Felsenstein Medical Reasearch Center, Tel Aviv University, Petah Tikva, 49100, Israel. INTRODUCTION: Sciatic nerve injury is common and usually results in degeneration of the distal axons and muscle denervation. Chronic muscle atrophy and fibrosis limit the recovery of muscle function and severely compromises efforts to restore muscle function. Despite early diagnosis and modern surgical techniques there is still poor functional recovery. AREAS COVERED: Stem cell transplantation has been investigated as a promising treatment strategy for peripheral nerve injury, and has demonstrated utility in limiting neuronal damage. The focus has been on the isolation of stem cells from bone-marrow and adipose tissue in addition to embryonic and neuronal stem cells. Transplantation of these cells into transected sciatic nerve in animal models demonstrates clinical improvement, inducing vigorous nerve regeneration accompanied by myelin synthesis. Cell replacement, trophic factor production, extracellular matrix molecule synthesis, guidance, remyelination, microenvironmental stabilization and immune modulation have been postulated as possible mechanisms for stem cell implantation. EXPERT OPINION: Although further research is still needed, this therapeutic approach will probably become a routine treatment technique in the coming years, especially with bone marrow mesenchymal stem cells. We believe that the most promising results were noted for the use of stem cells of this origin in the treatment of sciatic nerve injury. PMID: 21995439 [PubMed - indexed for MEDLINE] 563. Diabet Med. 2011 Dec;28(12):1476-86. doi: 10.1111/j.1464-5491.2011.03463.x. Mechanistic insights into insulin resistance in the genetic era. Parker VE(1), Savage DB, O'Rahilly S, Semple RK. Author information: (1)University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Sir Harold Himsworth first observed and articulated the phenomenon of insulin resistance in the late 1930s. Although a long delay followed before his observations were acknowledged and enshrined in formal diagnostic classifications of diabetes mellitus, insulin resistance-related pathology in the early 21st century poses one of the major global healthcare challenges for contemporary physicians. Whilst insulin resistance is closely related to obesity and decreased physical fitness, despite intensive investigation it has proved extremely challenging to discriminate key events in its causation from epiphenomena, many related to compensation for the primary defect. Thus, a complete account of the molecular pathogenesis of insulin resistance-related diseases remains elusive. One approach circumventing such problems is the study of patients with single gene defects causing severe insulin resistance. In such patients the primary defect is known, and thus lessons may be learned about human physiology from detailed physiological study allied to knowledge of the function of the mutated protein. This review discusses developments in understanding of monogenic severe insulin resistance since discovery of the first insulin receptor mutations in 1988 and reviews the physiological lessons learnt, including the critical role of adipose tissue in human metabolic health and the meaning and importance of 'partial' insulin resistance for major human disease. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK. PMID: 21992440 [PubMed - indexed for MEDLINE] 564. World J Gastroenterol. 2011 Sep 7;17(33):3785-94. doi: 10.3748/wjg.v17.i33.3785. JNKs, insulin resistance and inflammation: A possible link between NAFLD and coronary artery disease. Tarantino G(1), Caputi A. Author information: (1)Department of Clinical and Experimental Medicine, Federico II University Medical School of Naples, Via Sergio Pansini 580131 Naples, Italy. tarantin@unina.it The incidence of obesity has dramatically increased in recent years. Consequently, obesity and associated disorders such as nonalcoholic fatty liver disease constitute a serious problem. Therefore, the contribution of adipose tissue to metabolic homeostasis has become a focus of interest. In this review, we discuss the latest discoveries that support the role of lipids in nonalcoholic fatty liver disease. We describe the common mechanisms (c-Jun amino-terminal kinases, endoplasmic reticulum stress, unfolded protein response, ceramide, low-grade chronic inflammation) by which lipids and their derivatives impair insulin responsiveness and contribute to inflammatory liver and promote plaque instability in the arterial wall. Presenting the molecular mechanism of lipid activation of pro-inflammatory pathways, we attempt to find a link between nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular diseases. Describing the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver and discussing the molecular mechanism of lipid activation of pro-inflammatory pathways, the key roles played by the proliferator-activated receptor and liver X receptor α, nuclear receptors-lipid sensors that link lipid metabolism and inflammation, should be emphasized. Further studies are warranted of anti-inflammatory drugs such as aspirin, anti-interleukin-6 receptors, immune-modulators (calcineurin inhibitors), substances enhancing the expression of heat shock proteins (which protect cells from endoplasmic reticulum stress-induced apoptosis), and anti- c-Jun amino-terminal kinases in well-designed trials to try to minimize the high impact of these illnesses, and the different expressions of the diseases, on the whole population. PMCID: PMC3181439 PMID: 21987620 [PubMed - indexed for MEDLINE] 565. Curr Opin Support Palliat Care. 2011 Dec;5(4):342-9. doi: 10.1097/SPC.0b013e32834c49eb. The advantages and limitations of cross-sectional body composition analysis. MacDonald AJ(1), Greig CA, Baracos V. Author information: (1)Department of Clinical and Surgical Sciences (Surgery), University of Edinburgh, Edinburgh, UK. PURPOSE OF REVIEW: Cross-sectional (C-S) imaging is now commonly used to measure body composition in clinical studies. This review highlights the advantages, limitations and suggested future directions for this technique. RECENT FINDINGS: Current understanding of C-S imaging reproducibility, tissue identification and segmentation methods, comparison between imaging techniques and estimates of whole body composition using a single image are described. SUMMARY: C-S imaging can reliably measure muscle and fat distribution and uniquely discriminate between intra-abdominal organ and muscle component of fat-free mass. It precisely tracks changes within an individual, but is less able to distinguish true differences in whole body estimates between individuals. PMID: 21986910 [PubMed - indexed for MEDLINE] 566. Int J Obes (Lond). 2012 Aug;36(8):1017-24. doi: 10.1038/ijo.2011.192. Epub 2011 Oct 11. Causes and consequences of obesity: the contribution of recent twin studies. Naukkarinen J(1), Rissanen A, Kaprio J, Pietiläinen KH. Author information: (1)Obesity Research Unit, Division of Internal Medicine and Department of Psychiatry, Helsinki University Central Hospital, Department of Medicine, Helsinki, Finland. Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution. PMID: 21986704 [PubMed - indexed for MEDLINE] 567. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):554-61. doi: 10.1097/MCO.0b013e32834ad94b. Circadian rhythms in adipose tissue: an update. Gimble JM(1), Sutton GM, Ptitsyn AA, Floyd ZE, Bunnell BA. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu PURPOSE OF REVIEW: Over the past decade, evidence has accumulated from basic science, clinical and epidemiological studies linking circadian mechanisms to adipose tissue biology and its related comorbidities, diabetes, metabolic syndrome and obesity. This review highlights recent in-vitro and in-vivo findings from murine, human and model organism studies. RECENT FINDINGS: High-fat diets attenuate circadian mechanisms in murine adipose depots and these effects appear to be due to obesity rather than hyperglycemia. Deletion of circadian regulatory genes such as AMPK1 and nocturnin alter the circadian biology of adipose tissue. Unlike the mouse, circadian gene oscillation in human adipose tissue appears to be independent of BMI and diabetes status, suggesting that circadian mechanistic variation occurs across species. Clues for future directions in this emerging field come from studies of the hibernation and torpor state in mammals and infection models involving the Drosophila metabolic organ or 'fat body'. SUMMARY: There is a growing consensus that circadian rhythms and metabolism are tightly regulated in adipose tissue and peripheral metabolic organs. Although central mechanisms are critical, autonomous clocks exist within the adipocytes themselves. Future circadian advances are likely to result from the studies of adipose tissue-specific gene deletions. PMID: 21986477 [PubMed - indexed for MEDLINE] 568. Int J Cardiol. 2013 Jan 10;162(2):77-85. doi: 10.1016/j.ijcard.2011.09.079. Epub 2011 Oct 7. Metabolism and the heart: an overview of muscle, fat, and bone metabolism in heart failure. Loncar G(1), Fülster S, von Haehling S, Popovic V. Author information: (1)Cardiology Department, Clinical Medical Center Zvezdara, Belgrade, Serbia. loncar_goran@yahoo.com PURPOSE OF REVIEW: To review original research studies and reviews that present data on changes of body compartments and its mutual cross-talk with respect to the failing heart predominantly in non-cachectic patients with chronic heart failure (HF). RECENT FINDINGS: Thanks to the integrative approach considering the whole organism, several recent studies suggested a complex network of communication between body compartments in respect to failing heart during the natural course of body wasting in non-cachectic patients with HF. Interestingly, recent studies suggest that failing heart trough secretion of natriuretic peptides acts on fat metabolism by inducing adiponectin secretion and lipolytic actions. Soluble myostatin released from the failing heart may induce skeletal muscle wasting in HF through an endocrine-like mechanism, as well. The likelihood that adipocyte-derived hormones influence bone status has been recently proven. Increased serum adiponectin was independently associated with reduced bone mass in elderly patients with non-cachectic HF. SUMMARY: The concept of body compartments cross-talk in respect to failing heart provides a very interesting paradigm of integrative physiology. Better understanding of body compartments changes and its complex biochemical interplay may provide more efficacious and forehand treatment to prevent and/or postpone disability and improve quality of life in patients with chronic HF. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21982619 [PubMed - indexed for MEDLINE] 569. Biol Aujourdhui. 2011;205(3):147-62. doi: 10.1051/jbio/2011017. Epub 2011 Oct 11. [Laminopathies: one gene, several diseases]. [Article in French] Bertrand AT(1), Chikhaoui K, Ben Yaou R, Bonne G. Author information: (1)UPMC Université Paris VI, IFR14, 75013 Paris, France. a.bertrand@institut-myologie.org Lamins A and C, encoded by the LMNA gene, are nuclear proteins expressed in all post-mitotic cells. Together with B-type lamins, they form a meshwork of proteins beneath the inner nuclear membrane, the lamina, in connection with the cytoskeleton. Lamins A/C also interact with chromatin and numerous proteins, including transcription factors. Mutations in LMNA are responsible for more than ten different disorders, commonly called "laminopathies". These diseases affect tissues in a specific (striated muscle, adipose tissue, peripheral nerve) or in a systemic manner (premature ageing syndromes). This wide spectrum of phenotypes is associated to a wide variety of mutations. This large clinical and genetic heterogeneity, unique to the LMNA gene, makes genotype-phenotype relations particularly difficult to establish. However, correlations have been obtained in several cases. Hence, LMNA mutations identified in premature ageing syndromes lead to the accumulation of immature proteins with a toxic effect for cells. Mutations in laminopathies of the adipose tissue mainly localize in the Ig-like domain of the proteins, potentially affecting the interaction with the SREBP-1 transcription factor. In laminopathies of the striated muscles, the mutations are spread throughout the gene. These mutations are thought to induce structural modifications of the proteins, thereby affecting their polymerization into nuclear lamina. Such defect would lead to a mechanical weakness of the nuclear lamina and of the cells, particularly in striated muscles continuously stretching. The exploration of pathophysiological mechanisms of LMNA mutations largely benefits from the numerous mouse models created, which have been widely used to analyze affected molecular pathways and to test putative therapeutic treatments. Société de Biologie, 2011. PMID: 21982404 [PubMed - indexed for MEDLINE] 570. Expert Opin Ther Targets. 2011 Nov;15(11):1297-306. doi: 10.1517/14728222.2011.628315. Epub 2011 Oct 10. Generation of reactive oxygen species in adipose-derived stem cells: friend or foe? Park SG(1), Kim JH, Xia Y, Sung JH. Author information: (1)CHA University, Department of Biomedical Science, Seoul, Korea. INTRODUCTION: Reactive oxygen species (ROS) participate in cellular apoptosis and are involved in pathophysiological etiology of degenerative diseases. However, recent studies suggest that ROS at low levels may play a pivotal role as second messengers and activate normal cellular processes. Intracellular ROS increase the proliferation, migration, and regenerative potential of adipose-derived stem cells (ASCs). In contrast, manipulations that diminish intracellular ROS levels interfere with normal ASC function. ROS generation therefore acts like a double-edged sword. AREAS COVERED: This review discusses the following research questions: i) Do ROS stimulate or suppress ASCs? ii) How are ROS generated from ASCs? iii) Which function(s) is/are regulated by intracellular ROS generation? In addition, the antioxidant/antiapoptotic effect of ASCs is briefly introduced. EXPERT OPINION: Whether ROS is harmful or beneficial is primarily a question of dosage. Low or moderate ROS generation increases the proliferation, migration and regenerative potential of ASCs. Therefore, it is beneficial to expose ASCs to moderate oxidative stress during manipulation. The addition of a ROS donor in culture can reduce the cost for the expansion of ASCs and a ROS preconditioning can enhance the regenerative potential of ASCs. PMCID: PMC3371372 PMID: 21981031 [PubMed - indexed for MEDLINE] 571. Biochim Biophys Acta. 2012 May;1821(5):852-7. doi: 10.1016/j.bbalip.2011.09.010. Epub 2011 Sep 25. Fatty acid transport proteins, implications in physiology and disease. Kazantzis M(1), Stahl A. Author information: (1)Metabolic Biology, NST, UC Berkeley, Berkeley, CA 94720, USA. Uptake of long-chain fatty acids plays pivotal roles in metabolic homeostasis and human physiology. Uptake rates must be controlled in an organ-specific fashion to balance storage with metabolic needs during transitions between fasted and fed states. Many obesity-associated diseases, such as insulin resistance in skeletal muscle, cardiac lipotoxicity, and hepatic steatosis, are thought to be driven by the overflow of fatty acids from adipose stores and the subsequent ectopic accumulation of lipids resulting in apoptosis, ER stress, and inactivation of the insulin receptor signaling cascade. Thus, it is of critical importance to understand the components that regulate the flux of fatty acid between the different organ systems. Cellular uptake of fatty acids by key metabolic organs, including the intestine, adipose tissue, muscle, heart, and liver, has been shown to be protein mediated and various unique combinations of fatty acid transport proteins (FATPs/SLC27A1-6) are expressed by all of these tissues. Here we review our current understanding of how FATPs can contribute to normal physiology and how FATP mutations as well as hypo- and hypermorphic changes contribute to disorders ranging from cardiac lipotoxicity to hepatosteatosis and ichthyosis. Ultimately, our increasing knowledge of FATP biology has the potential to lead to the development of new diagnostic tools and treatment options for some of the most pervasive chronic human disorders. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. Copyright © 2011 Elsevier B.V. All rights reserved. PMCID: PMC3274620 PMID: 21979150 [PubMed - indexed for MEDLINE] 572. Atherosclerosis. 2012 Mar;221(1):2-11. doi: 10.1016/j.atherosclerosis.2011.09.003. Epub 2011 Sep 9. The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Qin Z(1). Author information: (1)Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. qinz@uthscsa.edu Since their establishment thirty years ago, THP-1 cells have become one of most widely used cell lines to investigate the function and regulation of monocytes and macrophages in the cardiovascular system. However, because this cell line was derived from the blood of a patient with acute monocytic leukemia, the extent to which THP-1 cells mimic monocytes and macrophages in the vasculature is not entirely known. This article serves as a meaningful attempt to address this question by reviewing the recent publications. The interactions between THP-1 cells and various vascular cells (such as endothelial cells, smooth muscle cells, adipocytes, and T cells) provide insight into the roles of the interconnection of monocytes-macrophages with other vascular cells during vascular inflammation, particularly atherogenesis and obesity. Transcriptome, microRNA profile, and histone modifications of THP-1 cells shed new light on the regulatory mechanism of the monocytes-macrophages in response to various inflammatory mediators, such as oxidized low density lipoprotein, lipopolysaccharide, and glucose. These studies hint that under certain defined conditions, THP-1 cells not only resemble primary monocytes-macrophages isolated from healthy donors or donors with disease, such as diabetes mellitus, but also mimic the in situ alteration of macrophages in the adipose tissue of obese subjects and in atherosclerotic lesions. A potential trajectory is to use this cell line to study the novel molecular mechanisms in monocytes and macrophages in relation to the physiology and pathophysiology of the cardiovascular system, however, the conclusion of studies employing THP-1 cells requires further verification using primary cells and/or in vivo models to be generalized to monocytes and macrophages. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21978918 [PubMed - indexed for MEDLINE] 573. Clin Exp Pharmacol Physiol. 2012 Feb;39(2):168-78. doi: 10.1111/j.1440-1681.2011.05623.x. Leptin and the regulation of endothelial function in physiological and pathological conditions. Bełtowski J(1). Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@umlub.pl Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser(1177) , increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone. © 2011 The Author. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21973116 [PubMed - indexed for MEDLINE] 574. J Diabetes Investig. 2011 Oct 7;2(5):333-40. doi: 10.1111/j.2040-1124.2011.00133.x. Adipocytes as a vehicle for ex vivo gene therapy: Novel replacement therapy for diabetes and other metabolic diseases. Kuroda M(1), Bujo H(2), Aso M(3), Saito Y(4). Author information: (1)Center for Advanced Medicine, Chiba University Hospital. (2)Department of Genome Research and Clinical Application, Graduate School of Medicine. (3)CellGenTech, Inc., Chiba, Japan. (4)Chiba University. Because of its availability and recent advances in cell biology, adipose tissue is now considered an ideal target site for the preparation of recipient cells and for the transplantation of gene-transduced cells for supplementation of therapeutic proteins. Inherited or acquired serum protein deficiencies are the ideal targets for gene therapy. However, to develop an effective ex vivo gene therapy-based protein replacement treatment, the requirements for the recipient cells are different from those for standard gene therapy that is intended to correct the function of the recipient cells themselves. To meet the requirements for such a therapeutic strategy, recent in vitro and animal model studies have developed new methods for the preparation, culture, expansion and manipulation of adipose cells using advanced gene transduction methods and transplantation scaffolds. In this short review, we introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies by our group and other investigators, and describe their future applications for diabetes and other metabolic diseases. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00133.x, 2011). PMCID: PMC4019298 PMID: 24843509 [PubMed] 575. Circ J. 2011;75(11):2522-31. Epub 2011 Oct 5. AIMing at metabolic syndrome. -Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM).-. Miyazaki T(1), Kurokawa J, Arai S. Author information: (1)Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. tm@m.u-tokyo.ac.jp Metabolic syndrome (MetS) is a cascade of metabolic diseases, starting with obesity and progressing to atherosclerosis, and is often fatal because of serious cardiovascular problems such as heart/brain infarction and hemorrhage. Accumulating evidence has revealed a critical involvement of inflammatory responses triggered by lesional macrophages in the pathogenesis of MetS. Importantly, we found that macrophages are associated with disease progression, not only in the induction of inflammation but also in the production of apoptosis inhibitor of macrophages (AIM), which we initially identified as a soluble factor expressed by macrophages. In atherosclerotic plaques, AIM is highly expressed by foam macrophages and inhibits apoptosis of these cells, which results in the accumulation of macrophages, causing inflammatory responses within the lesion, and ultimately disease progression. In adipose tissue, macrophage-derived AIM is incorporated into adipocytes through CD36-mediated endocytosis, thereby reducing the activity of cytosolic fatty acid synthase. This unique response stimulates lipolysis, resulting in a decrease in adipocyte size, which is physiologically relevant to the prevention of obesity. The lipolytic response also stimulates inflammation of adipocytes in association with the induction of metabolic disorders subsequent to obesity. Thus, AIM is involved in the progression of MetS in both an advancing and inhibitory fashion. Regulation of AIM could therefore be therapeutically applicable for MetS. PMID: 21970839 [PubMed - indexed for MEDLINE] 576. J Mammary Gland Biol Neoplasia. 2011 Dec;16(4):305-22. doi: 10.1007/s10911-011-9232-2. Epub 2011 Oct 4. Functional adaptations of the transcriptome to mastitis-causing pathogens: the mammary gland and beyond. Loor JJ(1), Moyes KM, Bionaz M. Author information: (1)Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. jloor@illinois.edu Application of microarrays to the study of intramammary infections in recent years has provided a wealth of fundamental information on the transcriptomics adaptation of tissue/cells to the disease. Due to its heavy toll on productivity and health of the animal, in vivo and in vitro transcriptomics works involving different mastitis-causing pathogens have been conducted on the mammary gland, primarily on livestock species such as cow and sheep, with few studies in non-ruminants. However, the response to an infectious challenge originating in the mammary gland elicits systemic responses in the animal and encompasses tissues such as liver and immune cells in the circulation, with also potential effects on other tissues such as adipose. The susceptibility of the animal to develop mastitis likely is affected by factors beyond the mammary gland, e.g. negative energy balance as it occurs around parturition. Objectives of this review are to discuss the use of systems biology concepts for the holistic study of animal responses to intramammary infection; providing an update of recent work using transcriptomics to study mammary and peripheral tissue (i.e. liver) as well as neutrophils and macrophage responses to mastitis-causing pathogens; discuss the effect of negative energy balance on mastitis predisposition; and analyze the bovine and murine mammary innate-immune responses during lactation and involution using a novel functional analysis approach to uncover potential predisposing factors to mastitis throughout an animal's productive life. PMID: 21968536 [PubMed - indexed for MEDLINE] 577. Int J Biochem Cell Biol. 2011 Dec;43(12):1651-4. doi: 10.1016/j.biocel.2011.09.006. Epub 2011 Sep 28. Epicardial fat: from the biomolecular aspects to the clinical practice. Iacobellis G(1), Malavazos AE, Corsi MM. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, 1400 NW 10th Ave, Dominion Tower Suite 805-807, Miami, FL 33136, USA. giacobellis@med.miami.edu Epicardial fat is the visceral fat depot of heart. It is a metabolically active organ with anatomical and functional contiguity to the myocardium. A dichotomous role has been attributed to the epicardial fat. Under physiological conditions, epicardial fat displays biochemical and thermogenic cardio-protective properties. Under pathological circumstances epicardial fat can locally affect the heart and coronary arteries through vasocrine or paracrine secretion of pro-inflammatory cytokines. Epicardial fat can be measured with imaging techniques. Epicardial fat thickness reflects intra-abdominal and myocardial fat and correlates with metabolic syndrome and coronary artery disease. Epicardial fat measurement may play a role in the stratification of the cardio-metabolic risk and serve as therapeutic target. Weight loss and anti-inflammatory drugs targeting the fat may modulate epicardial fat. Because epicardial and myocardial tissues share the same coronary arterial supply it is reasonable to hypothesize that improved local vascularisation may resume epicardial fat to its physiological role. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21967993 [PubMed - indexed for MEDLINE] 578. Nutr Rev. 2011 Oct;69(10):599-612. doi: 10.1111/j.1753-4887.2011.00414.x. Effect of diet on adiponectin levels in blood. Silva FM(1), de Almeida JC, Feoli AM. Author information: (1)Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. Dietary management has been considered an alternative means of modulating adiponectin levels. The purpose of this review is to examine the scientific evidence regarding the effect of diet on adiponectin levels in blood. Clinical trials were selected from Medline until April 2010 using the following MeSH terms: adipokines OR adiponectin AND diet OR lifestyle. A total of 220 articles were identified in the initial search, and 52 studies utilizing three different methods of dietary management were included in the present review: low-calorie diets (n = 9 studies), modification of diet composition (n = 33), and diet plus exercise (n = 10). Daily intake of fish or omega-3 supplementation increased adiponectin levels by 14-60%. Weight loss achieved with a low-calorie diet plus exercise increased adiponectin levels in the range of 18-48%. A 60-115% increase in adiponectin levels was obtained with fiber supplementation. In conclusion, dietary management can be an effective therapeutic means of increasing adiponectin levels. Studies investigating different forms of adiponectin and changes in the types of adipose tissue are necessary in order to elucidate the mechanisms involved in the modulation of adiponectin levels. © 2011 International Life Sciences Institute. PMID: 21967160 [PubMed - indexed for MEDLINE] 579. J Anim Sci. 2012 Mar;90(3):942-9. doi: 10.2527/jas.2011-4616. Epub 2011 Sep 30. Meat Science and Muscle Biology Symposium: the influence of extracellular matrix on intramuscular and extramuscular adipogenesis. Hausman GJ(1). Author information: (1)Poultry Processing and Swine Physiology Research, ARS, Richard B. Russell Research Center, USDA, Athens, GA 30605, USA. Gary.Hausman@ars.usda.gov The extracellular matrix (ECM) and specific ECM components can have a major influence on cell growth, development, and phenotype. The influence of the ECM and ECM components on adipogenesis in vivo and in vitro will be reviewed in this paper. Engelbreth-Holm-Swarm substratum and laminin per se markedly increased attachment, spreading, and hypertrophy of preadipocytes in serum-free primary cultures of porcine adipose tissue stromal-vascular cells. Furthermore, primary cultures of stromal-vascular cells showed that preadipocytes express ECM components after preadipocyte recruitment. Staining for plant lectins, type IV collagen, and laminin in fetal pig adipose tissue demonstrates that adipocyte reactivity for laminin was strong throughout fetal development and was similar for developing adipocytes and vasculature. However, lectin binding and type IV collagen reactivity of blood vessels preceded that for adipocytes. Therefore, these studies indicated that the ECM and in particular laminin may play a critical role in morphological aspects of preadipocyte development. Specific inhibitors and modulators of collagen synthesis have been used to evaluate the role of collagens in the differentiation of bovine intramuscular preadipocytes (BIP) and other preadipocyte cell lines. Triglyceride accretion of BIP cells was inhibited by a general inhibitor of collagen biosynthesis, whereas specific inhibitors or modulators of type IV collagen inhibited 3T3-L1 cell differentiation. Further study revealed that compared with collagens types I to IV, type V and VI collagens have an important and active role in BIP adipogenesis. The growth of intramuscular bovine adipose tissue may be dependent on collagen newly synthesized and organized by the adipocytes per se. The role of extracellular or ECM proteolysis in regulating adipogenesis also will be reviewed in this paper. Many members of the matrix metalloproteinase (MMP) family are expressed by adipocytes, and specific inhibition of MMP-9 greatly reduces adipogenesis in vitro. Possibly, MMP and other proteases regulate turnover of key adipocyte ECM proteins that are involved in the regulation of preadipocyte proliferation and differentiation. PMID: 21965449 [PubMed - indexed for MEDLINE] 580. Acta Diabetol. 2011 Dec;48(4):257-73. doi: 10.1007/s00592-011-0333-6. Epub 2011 Oct 2. Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Burcelin R(1), Serino M, Chabo C, Blasco-Baque V, Amar J. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France. remy.burcelin@inserm.fr More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10-20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain. PMCID: PMC3224226 PMID: 21964884 [PubMed - indexed for MEDLINE] 581. Intern Emerg Med. 2013 Jun;8(4):283-9. doi: 10.1007/s11739-011-0700-x. Epub 2011 Oct 2. COPD and the metabolic syndrome: an intriguing association. Clini E(1), Crisafulli E, Radaeli A, Malerba M. Author information: (1)Department of Oncology, Haematology and Pneumology, University of Modena, Modena, Italy. enrico.clini@unimore.it Chronic Obstructive Pulmonary Disease (COPD) has been recently recognized as a condition involving more than the lungs. The presence of common factors in COPD and in other chronic extra-pulmonary diseases, as well as the co-existence of these conditions in the same adult individual, supports the hypothesis of a shared pathogenetic pathway. We will here review the interplay between coexisting COPD and the metabolic syndrome (MS), based on the most updated knowledge. We will discuss this clinical condition from the definition, to the pathophysiology and to the clinical implications. Basically, MS is more likely to be present in a COPD patients, and increased levels of circulatory pro-inflammatory proteins from both the lung and adipose tissue coincide in these patients. The relative impact of the coexisting COPD and MS may depend on several factors: the presence of physical inactivity and of systemic inflammation related to a smoking habit, sedentary lifestyle, airway inflammation and obstruction, adipose tissue and inflammatory marker activation. More studies will be required to elucidate the association between COPD and MS and to formulate individualized management approaches for this specific disease phenotype. PMID: 21964838 [PubMed - indexed for MEDLINE] 582. Mol Genet Metab. 2011 Dec;104(4):666-9. doi: 10.1016/j.ymgme.2011.08.035. Epub 2011 Sep 8. Shared genetic variance between the features of the metabolic syndrome: heritability studies. Povel CM(1), Boer JM, Feskens EJ. Author information: (1)Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Cecile.Povel@rivm.nl Heritability estimates of MetS range from approximately 10%-30%. The genetic variation that is shared among MetS features can be calculated by genetic correlation coefficients. The objective of this paper is to identify MetS feature as well as MetS related features which have much genetic variation in common, by reviewing the literature regarding genetic correlation coefficients. Identification of features, that have much genetic variation in common, may eventually facilitate the search for pleitropic genetic variants that may explain the clustering of MetS features. A PubMed search with the search terms "(metabolic syndrome OR insulin resistance syndrome) and (heritability OR genetic correlation OR pleiotropy)" was performed. Studies published before 7th July 2011, which presented genetic correlation coefficients between the different MetS features and genetic correlation coefficients of MetS and its features with adipose tissue-, pro-inflammatory and pro-thrombotic biomarkers were included. Nine twin and 19 family studies were included in the review. Genetic correlations varied, but were strongest between waist circumference and HOMA-IR (r(2): 0.36 to 0.79, median: 0.50), HDL cholesterol and triglycerides (r(2): -0.05 to -0.59, median -0.45), adiponectin and MetS (r(2): -0.32 to -0.43; median -0.38), adiponectin and insulin (r(2): -0.10 to -0.60; median -0.30) and between adiponectin and HDL-cholesterol (r(2): -0.22 to -0.51, median -0.29). In conclusion, heritability studies suggest that genetic pleiotropy exist especially between certain MetS features, as well as between MetS and adiponectin. Further research on actual genetic variants responsible for the genetic pleiotropy of these combinations will provide more insight into the etiology of MetS. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21963081 [PubMed - indexed for MEDLINE] 583. Clin Calcium. 2011 Oct;21(10):1489-95. doi: CliCa111014891495. [Relationship between metabolic syndrome and urinary stone disease]. [Article in Japanese] Yamaguchi S(1). Author information: (1)Department of Urology, Hokkaido Social Welfare Association Furano Hospital, Japan. Epidemiologically, there are many same characteristics among patients with urolithiasis, life-style related diseases and metabolic syndrome. In a comparison with the major urological diseases, the patients with stone disease have the largest amount of visceral fat on computerized tomography. The patients who finally had a diagnosis of metabolic syndrome in urolithiasis were 43% of men and female 31%. The clinical features of the patients include increased urinary oxalate excretion, abnormal uric acid metabolism, and acidic urine. The basic studies by the animal experiments suggest that there is a close relationship between urolithiasis and metabolic syndrome. After the treatment of the urinary stone, it is very important to make a long-term follow-up by not only the prevention of recurrent stone episode but also life style management and medical treatment for metabolic syndrome. PMID: 21960234 [PubMed - indexed for MEDLINE] 584. Korean J Gastroenterol. 2011 Sep 25;58(3):125-32. doi: 10.4166/kjg.2011.58.3.125. [Stem cell properties of therapeutic potential]. [Article in Korean] Seo GS(1). Author information: (1)Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea. Stem cell research is a innovative technology that focuses on using undifferentiated cells able to self-renew through the asymmetrical or symmetrical divisions. Three types of stem cells have been studied in laboratory including embryonic stem cell, adult stem cells and induced pluripotent stem cells. Embryonic stem cells are pluripotent stem cells derived from the inner cell mass and it can give rise to any fetal or adult cell type. Adult stem cells are multipotent, have the ability to differentiate into a limited number of specialized cell types, and have been obtained from the bone marrow, umbilical cord blood, placenta and adipose tissue. Stem cell therapy is the most promising therapy for several degenerative and devastating diseases including digestive tract disease such as liver failure, inflammatory bowel disease, Celiac sprue, and pancreatitis. Further understanding of biological properties of stem cells will lead to safe and successful stem cell therapies. (Korean J Gastroenterol 2011;58: 125-132). PMID: 21960099 [PubMed - indexed for MEDLINE] 585. Maturitas. 2011 Dec;70(4):322-7. doi: 10.1016/j.maturitas.2011.09.002. Epub 2011 Sep 29. Adipokines and stroke: a review of the literature. Savopoulos C(1), Michalakis K, Apostolopoulou M, Miras A, Hatzitolios A. Author information: (1)International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College, London, United Kingdom. c.savopoulos@imperial.ac.uk Stroke represents one of the most important menaces to public health. A number of modifiable and non-modifiable risk factors have been identified and studied in detail; among those, obesity, the new world epidemic, seems to be one of the most important in terms of prevention. The discovery of the secretory role of the adipose tissue and of adipokines has opened new fields of research. A number of studies have been published on their relation to cardiovascular risk and the potential of using them as prevention markers. In the present review the physiology of leptin, adiponectin and resistin is described and their role in the pathogenesis of stroke is examined. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21958940 [PubMed - indexed for MEDLINE] 586. Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1 Suppl 2):45-50. Tendinopathy and inflammation: some truths. Del Buono A(1), Battery L, Denaro V, Maccauro G, Maffulli N. Author information: (1)Department of Orthopaedic and Trauma Surgery, Campus Biomedico University of Rome, Via Alvaro del Portillo, Rome, Italy. Overuse tendinopathies are a common cause of pain and disability in athletes. According to histological findings, it is a failed healing response to overuse tendon injury. In obesity, macrophages and mast cells migrate to adipose tissue, and the resulting decreased availability of immune circulating cells should be responsible for less effective immune responses to acute tendon injury. In diabetic patients, free glucose molecules attach to collagen, alter collagen solubility, increase resistance to enzymatic degradation, and impair cross linking, contributing to the subsequent development of chronic tendinopathy secondary to a failed healing response to a tendon insult. Prolonged systemic, low-grade inflammation and impaired insulin sensitivity act as a risk factor for a failed healing response after an acute tendon insult, and predispose to the development of chronic overuse tendinopathies. Further studies may reveal novel therapeutic treatment approaches. PMID: 21669137 [PubMed - indexed for MEDLINE] 587. Nat Rev Mol Cell Biol. 2011 Sep 28;12(11):722-34. doi: 10.1038/nrm3198. Forming functional fat: a growing understanding of adipocyte differentiation. Cristancho AG(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally. PMID: 21952300 [PubMed - indexed for MEDLINE] 588. Am J Reprod Immunol. 2012 Jan;67(1):1-8. doi: 10.1111/j.1600-0897.2011.01069.x. Epub 2011 Sep 23. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Soleymaninejadian E(1), Pramanik K, Samadian E. Author information: (1)Center for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, India. ehsan.soleymaninejadian@gmail.com Mesenchymal stem cells (MSCs) are defined as undifferentiated cells that are capable of self renewal and differentiation into several cell types such as chondrocyte, adipocyte, osteocyte, myocyte, hepatocyte, and neuron-like cells. MSC can be isolated from bone marrow, umbilical cord blood, adipose tissue, placenta, periosteum, trabecular bone, synovium, skeletal muscle, and deciduous teeth. Immunomodulatory of MSCs is one of the important issues nowadays, because this aspect can be clinically applied for graft-versus-host and autoimmune diseases. In this review, we tried to discuss in detail about cytokines and factors such as members of the transforming growth factor superfamily (transforming growth factor-β), hepatic growth factors (HGF), prostaglandin E2 (PGE2), IL-10, indolamine 2,3-dioxygenase (IDO), nitric oxide (NO), heme oxygenase-1 (HO-1), and human leukocyte antigen-G (HLA-G) that are involved in immunomodulatory of MSCs. © 2011 John Wiley & Sons A/S. PMID: 21951555 [PubMed - indexed for MEDLINE] 589. Obes Rev. 2012 Jan;13(1):68-91. doi: 10.1111/j.1467-789X.2011.00931.x. Epub 2011 Sep 26. A systematic review and meta-analysis of the effect of aerobic vs. resistance exercise training on visceral fat. Ismail I(1), Keating SE, Baker MK, Johnson NA. Author information: (1)Discipline of Exercise and Sport Science, University of Sydney, Sydney, New South Wales, Australia. It is increasingly recognized that the location of excess adiposity, particularly increased deposition of visceral adipose tissue (VAT), is important when determining the adverse health effects of overweight and obesity. Exercise therapy is an integral component of obesity management, but the most potent exercise prescription for VAT benefit is unclear. We aimed to evaluate the independent and synergistic effects of aerobic exercise (AEx) and progressive resistance training (PRT) and to directly compare the efficacy of AEx and PRT for beneficial VAT modulation. A systematic review and meta-analysis was performed to assess the efficacy of exercise interventions on VAT content/volume in overweight and obese adults. Relevant databases were searched to November 2010. Included studies were randomized controlled designs in which AEx or PRT in isolation or combination were employed for 4 weeks or more in adult humans, where computed tomography (CT) or magnetic resonance imaging (MRI) was used for quantification of VAT pre- and post-intervention. Of the 12196 studies from the initial search, 35 were included. After removal of outliers, there was a significant pooled effect size (ES) for the comparison between AEx therapy and control (-0.33, 95% CI: -0.52 to -0.14; P < 0.01) but not for the comparison between PRT therapy and control (0.09, 95% CI: -0.17 to -0.36; P = 0.49). Of the available nine studies which directly compared AEx with PRT, the pooled ES did not reach statistical significance (ES = 0.23, 95% CI: -0.02 to 0.50; P = 0.07 favouring AEx). The pooled ES did not reach statistical significance for interventions that combined AEx and PRT therapy vs. control (-0.28, 95% CI: -0.69 to 0.14; P = 0.19), for which only seven studies were available. These data suggest that aerobic exercise is central for exercise programmes aimed at reducing VAT, and that aerobic exercise below current recommendations for overweight/obesity management may be sufficient for beneficial VAT modification. Further investigation is needed regarding the efficacy and feasibility of multi-modal training as a means of reducing VAT. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21951360 [PubMed - indexed for MEDLINE] 590. Obes Rev. 2011 Oct;12(10):866-83. doi: 10.1111/j.1467-789X.2011.00909.x. The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients. Dulloo AG(1). Author information: (1)Department of Medicine/Physiology, University of Fribourg, Fribourg, Switzerland. abdul.dulloo@unifr.ch The concept of managing obesity through the stimulation of thermogenesis is currently a focus of considerable attention by the pharmaceutical, nutraceutical and functional food industries. This paper first reviews the landmark discoveries that have fuelled the search for thermogenic anti-obesity products that range from single-target drugs to multi-target functional foods. It subsequently analyses the thermogenic and fat-oxidizing potentials of a wide array of bioactive food ingredients which are categorized under methylxanthines, polyphenols, capsaicinoids/capsinoids, minerals, proteins/amino acids, carbohydrates/sugars and fats/fatty acids. The main outcome of this analysis is that the compounds or combination of compounds with thermogenic and fat-oxidizing potentials are those that possess both sympathomimetic stimulatory activity and acetyl-coA carboxylase inhibitory property, and are capable of targeting both skeletal muscle and brown adipose tissue. The thermogenic potentials of products so far tested in humans range from marginal to modest, i.e. 2-5% above daily energy expenditure. With an increasing number of bioactive food ingredients awaiting screening in humans, there is hope that this thermogenic potential could be safely increased to 10-15% above daily energy expenditure - which would have clinically significant impact on weight management, particularly in the prevention of obesity and in improving the long-term prognosis of post-slimming weight maintenance. © 2011 The Author. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21951333 [PubMed - indexed for MEDLINE] 591. Diabet Med. 2011 Dec;28(12):1445-54. doi: 10.1111/j.1464-5491.2011.03460.x. Current perspectives of insulin resistance and polycystic ovary syndrome. Pauli JM(1), Raja-Khan N, Wu X, Legro RS. Author information: (1)Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA 17033, USA. AIMS: To review the relationship between insulin resistance and polycystic ovary syndrome. METHODS: A literature review. RESULTS: Insulin resistance likely plays a central pathogenic role in polycystic ovary syndrome and may explain the pleiotropic presentation and involvement of multiple organ systems. Insulin resistance in the skeletal muscle of women with polycystic ovary syndrome involves both intrinsic and acquired defects in insulin signalling. The cellular insulin resistance in polycystic ovary syndrome has been further shown to involve a novel post-binding defect in insulin signal transduction. Treatment of insulin resistance through lifestyle therapy or with a diabetes drug has become mainstream therapy in women with polycystic ovary syndrome. However, effects with current pharmacologic treatment with metformin tend to be modest, with limited benefit as an agent to treat infertility. Insulin resistance contributes to increased risk for pregnancy complications, diabetes and cardiovascular disease risk profile in polycystic ovary syndrome, which is further exacerbated by obesity. While numerous studies demonstrate increased prevalence of cardiovascular disease risk factors in women with polycystic ovary syndrome, there are limited data showing that women with polycystic ovary syndrome are at increased risk for cardiovascular disease events. CONCLUSIONS: Insulin resistance is linked to polycystic ovary syndrome. Further study of lifestyle and pharmacologic interventions that reduce insulin resistance, such as metformin, are needed to demonstrate that they are effective in reducing the risk of diabetes, endometrial abnormalities and cardiovascular disease events in women with polycystic ovary syndrome. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK. PMID: 21950959 [PubMed - indexed for MEDLINE] 592. Diabetes. 2011 Oct;60(10):2441-9. doi: 10.2337/db11-0425. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Karpe F(1), Dickmann JR, Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K. fredrik.karpe@ocdem.ox.ac.uk PMCID: PMC3178283 PMID: 21948998 [PubMed - indexed for MEDLINE] 593. Peptides. 2011 Oct;32(10):2141-50. doi: 10.1016/j.peptides.2011.09.010. Epub 2011 Sep 16. A new look at the renin-angiotensin system--focusing on the vascular system. Nguyen Dinh Cat A(1), Touyz RM. Author information: (1)Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. The renin-angiotensin system (RAS), critically involved in the control of blood pressure and volume homeostasis, is a dual system comprising a circulating component and a local tissue component. The rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II, which in turn regulates cardiovascular function by binding to AT(1) and AT(2) receptors on cardiac, renal and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identified in brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II are synthesized within these tissues, there is still controversy as to whether renin is produced locally or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS remains elusive, but may contribute to fine-tuning of vascular tone and arterial structure and may amplify vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension, atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution to vascular RAS of Ang II derived from immune and inflammatory cells within the vascular wall. The present review highlights recent progress in the RAS field, focusing on the tissue system and particularly on the vascular RAS. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21945916 [PubMed - indexed for MEDLINE] 594. Mol Cell Endocrinol. 2012 Mar 24;350(2):281-8. doi: 10.1016/j.mce.2011.09.011. Epub 2011 Sep 10. The role of the mineralocorticoid receptor in adipocyte biology and fat metabolism. Marzolla V(1), Armani A, Zennaro MC, Cinti F, Mammi C, Fabbri A, Rosano GM, Caprio M. Author information: (1)San Raffaele Sulmona, Sulmona (AQ), Italy. Aldosterone controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor which regulates critical genes controlling salt and water homeostasis in the kidney. In recent years, inappropriate MR activation has been shown to trigger deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction, and oxidative stress. Moreover, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. In particular, recent work has revealed functional MRs in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity. This recent evidence finally moved MR out of the shadow of the glucocorticoid receptor (GR), which had previously been considered the only player mediating corticosteroid action in adipose tissue. This has opened a new era of research focusing on the complexity and selectivity of MR function in adipocyte biology. The aim of this review is to summarize the latest concepts on the role of MR in white and brown adipocytes, and to discuss the potential benefits of tissue-selective MR blockade in the treatment of obesity and metabolic syndrome. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21945603 [PubMed - indexed for MEDLINE] 595. Integr Comp Biol. 2011 Oct;51(4):505-13. doi: 10.1093/icb/icr019. Epub 2011 May 5. Leptin as a physiological mediator of energetic trade-offs in ecoimmunology: implications for disease. French SS(1), Dearing MD, Demas GE. Author information: (1)Department of Biology, Utah State University, Logan, UT 84322-5305, USA. sfrench@biology.usu.edu Organisms must distribute sufficient energy among different and often competing physiological systems. This task can become challenging, however, as resources are often limiting, resulting in energetic trade-offs. For example, energetically based trade-offs between the reproductive and immune systems are common across taxa, yet the regulatory mechanisms underlying these trade-offs remain unclear. The adipose tissue hormone leptin is an ideal candidate for the modulation of energetic trade-offs between different physiological systems as this hormone serves as a gage of fat reserves and also modulates a range of physiological activities including the reproductive and immune processes. This article presents a review of the evidence for the role of leptin as a modulator of energetic trade-offs with the immune system and suggests its importance in disease ecology. In addition, we provide a case study of the ornate tree lizard (Urosaurus ornatus), testing whether leptin is involved in mediating a well-documented influence of energy state on the trade-off between reproductive activity and immune function. Overall, the combined results suggest that leptin serves as a proximate endocrine signal of available energy to the immune system, and therefore likely to affect susceptibility to diseases. PMID: 21940777 [PubMed - indexed for MEDLINE] 596. Physiol Behav. 2012 Apr 12;106(1):22-8. doi: 10.1016/j.physbeh.2011.09.011. Epub 2011 Sep 14. Maternal obesity, metabolic disease, and allostatic load. Power ML(1), Schulkin J. Author information: (1)Department of Research, American College of Obstetricians and Gynecologists, 409 12th St SW, Washington, DC 20024, United States. mpower@acog.org Maternal obesity is a risk factor for many metabolic diseases for the mother, both during gestation and post partum, and for the child in later life. Obesity and pregnancy both result in altered physiological states, significantly different from the state of the non-obese, non-reproductive adult female. The concept of allostasis may be more appropriate for understanding the physiology of both pregnancy and obesity. In pregnancy these altered physiological states are adaptive, in both the evolutionary and physiological senses of the word. Obesity, however, represents a state outside of the adaptive evolutionary experience of our species. In both cases the altered physiological state derives at least in part from signals from an active endocrine organ. In obesity this is adipose tissue, and in pregnancy it is the placenta. The signaling molecules from adipose tissue and placenta all have multiple functions and can affect multiple organ systems. Placenta acts as a central regulator of metabolism for both the maternal and fetal compartments, in essence acting as a "third brain" during pregnancy. Both adipose tissue and placenta express many proinflammatory cytokines; obesity and pregnancy are states of low-grade inflammation. Both obesity and pregnancy are also states of insulin resistance, and maternal obesity is associated with fetal insulin resistance. We argue that obesity during pregnancy leads to sustained and inappropriate activation of normally adaptive regulatory circuits due in part to competing and conflicting signaling from adipose tissue and placenta. This results in allostatic load, leading to the eventual break down of regulatory mechanisms. The result is impaired metabolic function of the mother, and altered development of metabolic systems and potentially altered neural appetite circuits for the offspring. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21939681 [PubMed - indexed for MEDLINE] 597. Pol Merkur Lekarski. 2011 Aug;31(182):118-21. [Metabolic obesity in normal weight individuals and cardiovascular disease]. [Article in Polish] Nowak M(1), Grzywa M. Author information: (1)Szpital Wojewódzki Nr 2 im. św. Jadwigi Królowej w Rzeszowie, Oddział Kardiologii z Pododdzialem Ostrych Zespołów Wierńcowych i z Ośrodkiem Implantacji Rozruszników Serca. nmarys@poczta.onet.pl Since thirty years there is growing interest in normal weight individuals who have metabolic disorders. These individuals are identified as metabolically obese but normal weight (MONW). Insulin resistance, elevated arterial blood pressure, abnormal lipid profile and sedentary style of live are known risk factors of atherosclerosis in general population. On the other hand, increased amount of visceral and subcutaneous abdominal adipose tissue is associated with increased risk of metabolic abnormalities. These abnormalities existing in MONW individuals exert an effect on increased risk of cardiovascular diseases and non insulin dependent diabetes mellitus. Identification of individuals at risk is difficult not only because no clear definition of MONW is established but also due to common belief that the cardiovascular risk in nonobese is low. The awareness of association of metabolic abnormalities in MONW with atherosclerosis should argue physicians into early screening and modification of cardiovascular risk factors in nonobese individuals. PMID: 21936351 [PubMed - indexed for MEDLINE] 598. Int J Obes (Lond). 2011 Sep;35 Suppl 3:S7-15. doi: 10.1038/ijo.2011.141. Bariatric surgery, adipose tissue and gut microbiota. Clément K(1). Author information: (1)Cardiometabolism Division, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. karine.clement@psl.aphp.fr Human obesity can be viewed as a set of phenotypes that evolve over time in a sequence of stages that need to be precisely measured. Environmental, behavioral, genetic and biological factors interact to cause obesity. This presentation provides a clinical viewpoint on some biological processes that may explain some of the stages in the development of human obesity, its chronic maintenance and occurrence of complications, with a focus on brain structures, genetics, the profound alterations in adipose tissue biology and gut microbiota components. Roux-en-Y gastric bypass surgery is an increasingly effective model to study in this context because it leads to major improvements in glucose and lipid homeostasis and to the amelioration of some systemic inflammatory markers. PMID: 21912389 [PubMed - indexed for MEDLINE] 599. Horm Res Paediatr. 2011;76 Suppl 3:56-8. doi: 10.1159/000330165. Epub 2011 Sep 7. Metabolic benefits of growth hormone therapy in idiopathic short stature. Dahlgren J(1). Author information: (1)Göteborg Paediatric Growth Research Centre, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes. Copyright © 2011 S. Karger AG, Basel. PMID: 21912170 [PubMed - indexed for MEDLINE] 600. Curr Opin Support Palliat Care. 2011 Dec;5(4):356-60. doi: 10.1097/SPC.0b013e32834bde0e. Lipid mobilization in cachexia: mechanisms and mediators. Bing C(1). Author information: (1)Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. bing@liverpool.ac.uk PURPOSE OF REVIEW: Extensive loss of body fat is considered as a hallmark of cancer cachexia which affects the quality of life and shortens survival. Evidence suggests that increased lipid mobilization has a central role in adipose tissue wasting. This review summarizes recent progress, with a particular focus on the mechanisms and the potential mediators of lipid mobilization in cachexia. RECENT FINDINGS: Accelerated fat loss begins at around 7 months before death and predicts survival in advance cancer patients. Adipose tissue remodelling with reduced lipid storage is evident in cancer patients with cachexia. Enhanced lipolysis regulated by adipose triglyceride lipase and hormone-sensitive lipase could be essential for triacylglycerol degradation. In addition to cytokines, other factors such as zinc-α2-glycoprotein (ZAG) are implicated in adipose atrophy. ZAG expression and release by adipose tissue is upregulated in weight-losing cancer patients, and serum ZAG has been shown as a marker for pancreatic cancer-associated cachexia, suggesting that ZAG may function locally and systemically to stimulate lipid mobilization. SUMMARY: Recent progress in clinical and mechanistic studies provides some new insights into the pathogenesis of adipose atrophy in cachexia. Further studies to unravel the mechanisms and mediators may lead to novel pharmacological targets to ameliorate cachexia syndrome. PMID: 21934502 [PubMed - indexed for MEDLINE] 601. Hellenic J Cardiol. 2011 Jul-Aug;52(4):327-36. Update on the cardiovascular risk in obesity: endocrine and paracrine role of the adipose tissue. Schäfer K(1), Konstantinides SV. Author information: (1)Department of Cardiology and Pulmonary Medicine, Georg August University, Göttingen, Germany. katrin.schaefer@med.uni-goettingen.de PMID: 21933764 [PubMed - indexed for MEDLINE] 602. Sheng Li Ke Xue Jin Zhan. 2011 Jun;42(3):169-74. [Research progress in regulation of adiponectin receptors expression]. [Article in Chinese] Cui XB(1), Han Y, Li L, Wu LL. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Adiponectin is an adipokine mainly secreted by adipose tissue, which exerts insulin-sensitivity, anti-inflammation, anti-atherosclerosis and cardio-protective effects. These biological effects are mediated by adiponectin receptor 1 and adiponectin receptor 2. Expression levels of adiponectin receptor affect activation of downstream signaling pathway and biological effects. Research about regulation factors of adiponectin receptor expression contributes discovering the molecular mechanism and provides new ideas for the prevention and treatment of the metabolism disorder and cardiovascular diseases. PMID: 21932513 [PubMed - indexed for MEDLINE] 603. Nat Rev Endocrinol. 2011 Sep 20;8(1):11-21. doi: 10.1038/nrendo.2011.151. Management of the metabolic effects of HIV and HIV drugs. Brown TT(1), Glesby MJ. Author information: (1)Division of Endocrinology and Metabolism, Johns Hopkins University, 1830 East Monument Street, Baltimore, MD 21287, USA. tbrown27@jhmi.edu Morphologic and metabolic abnormalities, including subcutaneous adipose tissue wasting, central adipose tissue accumulation, dyslipidemia and disorders of glucose metabolism are common among HIV-infected patients receiving highly active antiretroviral therapy (HAART) and contribute to the risk of cardiovascular disease in this population. The pathogenesis of these disorders is due to complicated interactions between effects of chronic HIV infection, HAART medications and patient factors, including genetic susceptibility. HAART has transformed HIV into a chronic condition for many patients and as a result the majority of HIV-infected patients in many areas of the developed world will soon be aged ≥50 years. Given that metabolic and cardiovascular diseases increase with aging, knowledge of the optimal management of these conditions is essential for practitioners caring for HIV-infected patients, including endocrine subspecialists. This Review highlights the clinical management of these disorders, focusing on the latest evidence regarding the efficacy of treatment strategies, newly available medications and potential interactions between HAART medications and medications used to treat metabolic disorders. PMCID: PMC3371609 PMID: 21931374 [PubMed - indexed for MEDLINE] 604. Acta Pol Pharm. 2011 Sep-Oct;68(5):803-4. Insights into the antihypertensive effects of conjugated linoleic acid (CLA) in different rodent models. Khan SA(1). Author information: (1)LECOM School of Pharmacy, 1858, West Grandview Blvd., Erie, PA 16509 USA. seherkhan@lecom.edu PMID: 21928728 [PubMed - indexed for MEDLINE] 605. J Anim Sci. 2012 Jun;90(6):1835-45. doi: 10.2527/jas.2011-4516. Epub 2011 Sep 16. Ruminant Nutrition Symposium: Optimizing Performance of the Offspring: nourishing and managing the dam and postnatal calf for optimal lactation, reproduction, and immunity. Bach A(1). Author information: (1)Department of Ruminant Production, Institute for Research and Technology in Agrifood, Barcelona, Spain. alex.bach@irta.es For several mammalian species, it has been shown that fetal and early postnatal nutrition has a role in long-term lipid and glucose metabolism of the offspring, and it thus also may have consequences on milk yield in the dairy cow. For instance, high-energy diets during the last weeks of pregnancy may result in increased glycemia, which in turn, may alter fetal adipose tissue development. However, most research efforts on management and nutrition of dry cows have focused on minimizing metabolic disorders of the postpartum cow without devoting much attention to potential consequences for the offspring. Similarly, nutritional needs for proper placental development and early fetal growth have received little attention, despite the fact that alterations in placental and fetal development may alter expression of genes participating in homeorhesis of the offspring. Therefore, nutrition of the pregnant cow, both while lactating and dry, should also consider aspects of placental and fetal development that may affect health and performance of the progeny. Similarly, newborn calves and young heifers are fed to ensure a particular growth target without compromising mammary development, although data linking postnatal growth targets with future milk yield are scarce. However, milk yield not only depends on mammary development, but also on nutrient partitioning, which is regulated by the endocrine milieu. There are some periods of time during development where nutrition may have long-lasting effects on metabolic function and milk production. For instance, the first months of postnatal life seem to be critical because recent data from both retrospective and controlled studies indicate that increased growth rate or plane of nutrition during this phase is positively associated with future milk production. Postnatal growth rate depends on nutrition (a necessary but not sufficient condition) and management (i.e., grouping strategies and housing systems), and thus optimal rearing programs should be designed considering long-term consequences on milk yield. PMID: 21926322 [PubMed - indexed for MEDLINE] 606. Cytokine Growth Factor Rev. 2011 Aug;22(4):221-9. doi: 10.1016/j.cytogfr.2011.08.001. Epub 2011 Sep 15. Bone morphogenetic protein 7: a broad-spectrum growth factor with multiple target therapeutic potency. Boon MR(1), van der Horst G, van der Pluijm G, Tamsma JT, Smit JW, Rensen PC. Author information: (1)Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. m.r.boon@lumc.nl Bone morphogenetic protein 7 (BMP7) is a member of the transforming growth factor-β (TGF-β) superfamily of growth factors. In recent years, it has become clear that BMP7 is a very pleiotropic growth factor. As described in this review, it plays a pivotal role in the development of bone and kidney, and has only recently been demonstrated to also be crucially involved in differentiation of brown adipose tissue. Because BMP7 thus controls the development and maintenance of many physiological processes in the human body, aberrant expression of BMP7 is associated with a variety of diseases. This review gives a broad overview on the involvement of BMP7 in several pathological conditions, such as incomplete fracture healing, osteoarthritis, the development of bone metastases, renal fibrosis and obesity. Furthermore, the therapeutic potential of BMP7 in these disease states is discussed. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21924665 [PubMed - indexed for MEDLINE] 607. Eur Respir J. 2012 Mar;39(3):746-67. doi: 10.1183/09031936.00047010. Epub 2011 Sep 15. Adipose tissue in obesity and obstructive sleep apnoea. Bonsignore MR(1), McNicholas WT, Montserrat JM, Eckel J. Author information: (1)Biomedical Dept of Internal and Specialistic Medicine, Section of Pneumology, University of Palermo, Palermo, Italy. marisa@ibim.cnr.it A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk. PMID: 21920888 [PubMed - indexed for MEDLINE] 608. Exerc Sport Sci Rev. 2012 Jan;40(1):43-9. doi: 10.1097/JES.0b013e3182355e8c. Endoplasmic reticulum stress in skeletal muscle: origin and metabolic consequences. Deldicque L(1), Hespel P, Francaux M. Author information: (1)Research Centre for Exercise and Health, Department of Biomedical Kinesiology, K.U. Leuven, Belgium. louise.deldicque@faber.kuleuven.be In secretory organs, such as the liver, the pancreas, and the adipose tissue, endoplasmic reticulum (ER) stress plays a key role in the etiology of cell disturbances implicated in many diseases. Although much less studied, ER stress also is present in skeletal muscle. In the present review, we hypothesize that ER stress may have important metabolic consequences in skeletal muscle. This review presents the situations in which ER stress is activated in skeletal muscle and its metabolic consequences. PMID: 21918459 [PubMed - indexed for MEDLINE] 609. Postepy Hig Med Dosw (Online). 2011 Aug 10;65:515-23. [Natural compounds involved in adipose tissue mass control in in vitro studies]. [Article in Polish] Kowalska K(1). Author information: (1)Katedra Biotechnologii i Mikrobiologii Żywności, Wydział Nauk o Żywności i Żywieniu, Uniwersytet Przyrodniczy w Poznaniu. kaskakow@up.poznan.pl The World Health Organization (WHO) has recognized obesity as an epidemic of the 21st century. Obesity is pathological fat accumulation in the body influenced by many factors: metabolic, endocrine, genetic, environmental, psychological and behavioral. The quality and quantity of food intake to a considerable degree determine excessive fat accumulation in the body. The strategy in obesity prevention includes, among other things, a proper diet. It is widely known that a diet rich in fruits and vegetables reduces body weight. Adipocytes are not only cells serving as storage depots for "energy", but are also specialized cells influenced by various hormones, cytokines and nutrients, which have pleiotropic effects on the body. Knowledge of adipocyte biology is crucial for our understanding of the pathophysiological basis of obesity and metabolic diseases, such as type 2 diabetes. Furthermore, rational manipulation of adipose physiology is a promising avenue for therapy of these conditions. Adipose tissue mass can be reduced through elimination of adipocytes by apoptosis, inhibition of adipogenesis and increased lipolysis in adipocytes. Natural products have a potential to induce apoptosis, inhibit adipogenesis and stimulate lipolysis in adipocytes. Various dietary bioactive compounds target different stages of the adipocyte life cycle and may be useful as natural therapeutic agents in obesity prevention. PMID: 21918254 [PubMed - indexed for MEDLINE] 610. Endocrinol Nutr. 2011 Nov;58(9):492-6. doi: 10.1016/j.endonu.2011.06.004. Epub 2011 Sep 13. [Genes and obesity: a cause and effect relationship]. [Article in Spanish] González Jiménez E(1). Author information: (1)Departamento de Enfermería, Facultad de Ciencias de la Salud, Universidad de Granada, Granada, España. emigoji@ugr.es The International Task Force on Obesity (IOTF) and the World Health Organization (WHO) have defined obesity as a 21st century epidemic. In countries with economies in transition and even in some urban areas in developing countries, progressive increase in obesity has been reported to be an emerging problem in recent years. Its causes include lifestyle changing, particularly consumption of high-calorie food, as well as an increasingly sedentary lifestyle. However, the genetic origin of obesity is well known and currently proven. Obesity usually results from interaction of certain gene polymorphisms with environment. Moreover, only a small number of cases of obesity (5%) result from mutations in specific genes (monogenic obesity), causing in some cases Mendelian syndromes with a very low incidence in the population. One hundred and thirty genes related to obesity have been reported, some of which are involved in coding of peptide transmitting hunger and satiety signals, while others are involved in adipocyte growth and differentiation processes, and still others are involved in regulation of energy expenditure. In addition, obesity is a chronic inflammatory state. In this regard, altered expression of genes related to insulin metabolism and adipose tissue inflammation is a basic process which may explain the etiology of obesity. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved. PMID: 21917535 [PubMed - indexed for MEDLINE] 611. Obes Rev. 2012 Jan;13(1):27-42. doi: 10.1111/j.1467-789X.2011.00930.x. Epub 2011 Sep 15. Platelet activation in obesity and metabolic syndrome. Santilli F(1), Vazzana N, Liani R, Guagnano MT, Davì G. Author information: (1)Internal Medicine and Center of Excellence on Aging, G. D'Annunzio University of Chieti, Chieti, Italy. Obesity is associated with increased cardiovascular disease. Metabolic syndrome (MS) identifies substantial additional cardiovascular risk beyond the individual risk factors, and is a powerful predictor of cardiovascular events even regardless of body mass index, thus suggesting a common downstream pathway conferring increased cardiovascular risk. Platelet hyper-reactivity/activation plays a central role to accelerate atherothrombosis and is the result of the interaction among the features clustering in obesity and MS: insulin resistance, inflammation, oxidative stress, endothelial dysfunction. Interestingly, the same pathogenic events largely account for the less-than-expected response to antiplatelet agents, namely low-dose aspirin. The proposed explanations for this phenomenon, besides underdosing of drug and/or reduced bioavailability, subsequent to excess of adipose tissue, include enhanced platelet turnover, leading to unacetylated COX-1 and COX-2 in newly formed platelets as a source of aspirin-escaping thromboxane formation; extraplatelet sources of thromboxane, driven by inflammatory triggers; and enhanced lipid peroxidation, activating platelets with a mechanism bypassing COX-1 acetylation or limiting COX-isozyme acetylation by aspirin. This review will address the complex interactions between platelets and the pathogenic events occurring in obesity and MS, trying to translate this body of mechanistic information into a clinically relevant read-out, in order to establish novel strategies in the prevention/treatment of atherothrombosis. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21917110 [PubMed - indexed for MEDLINE] 612. Int J Pediatr Obes. 2011 Sep;6 Suppl 1:13-20. doi: 10.3109/17477166.2011.604326. Is adipose tissue metabolically different at different sites? Gil A(1), Olza J, Gil-Campos M, Gomez-Llorente C, Aguilera CM. Author information: (1)Department of Biochemistry and Molecular Biology, Institute of Nutrition and Food Technology, Centre for Biomedical Research, University of Granada, Granada, Spain. This review focuses on metabolic differences of adipose tissue at different sites of the body, with emphasis in pediatrics. Adipose tissue is composed of various cell types, which include adipocytes and other cells of the stromal vascular fraction such as preadipocytes, blood cells, endothelial cells and macrophages. Mammals have two main types of adipose tissue: white adipose tissue (WAT), and brown adipose tissue (BAT), each of which possesses unique cell autonomous properties. WAT and BAT differ at the functional, as well as the morphological and molecular levels. WAT accumulates surplus energy mainly in the form of triacylglycerols and BAT dissipates energy directly as heat. Recently, functional BAT in humans has been located in the neck, supraclavicular, mediastinal and interscapular areas. WAT is distributed throughout the body in the form of two major types: subcutaneous adipose tissue (SWAT) and the intra-abdominal visceral adipose tissue (VWAT). VWAT tissue is associated with insulin resistance, diabetes mellitus, dyslipidaemia, hypertension, atherosclerosis, hepatic steatosis, and overall mortality whereas SWAT and BAT have intrinsic beneficial metabolic properties. Subcutaneous and visceral adipocytes derive from different progenitor cells that exhibit a different gene expression pattern. SWAT responds better to the antilipolytic effects of insulin and other hormones, secrets more adiponectin and less inflammatory cytokines, and is differentially affected by molecules involved in signal transduction as well as drugs compared with VWAT. Current research is investigating various approaches of BAT and SWAT transplantation, including new sources of adipocyte progenitors. This may be important for the potential treatment of childhood obesity. PMID: 21905811 [PubMed - indexed for MEDLINE] 613. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):527-34. doi: 10.1097/MCO.0b013e32834bbac9. CD36 genetics and the metabolic complications of obesity. Love-Gregory L(1), Abumrad NA. Author information: (1)Washington University School of Medicine, St Louis, Missouri, USA. lgregory@wustl.edu PURPOSE OF REVIEW: The review summarizes our current understanding of the function of the fatty acid translocase, CD36, in lipid metabolism with an emphasis on the influence of CD36 genetic variants and their potential contribution to obesity-related complications. RECENT FINDINGS: Studies in rodents implicate CD36 in a number of metabolic pathways with relevance to obesity and its associated complications. These include pathways related to fat utilization such as taste perception, intake, intestinal processing, and storage in adipose tissue. Dysfunction in these pathways, coupled with the ability of CD36 to transduce intracellular signals that initiate inflammation in response to excess fat supply, promotes metabolic pathology. In the last few years, the relevance of discoveries in rodents to humans has been highlighted by genetic studies, which identified common CD36 variants that influence circulating lipid levels and cardiometabolic phenotypes. SUMMARY: Recent genetic studies suggest that CD36 plays an important role in lipid metabolism in humans and may be involved in obesity-related complications. These findings may accelerate the translation of CD36 metabolic functions determined in rodents to humans. Importantly, these studies highlight the potential utility of assessing CD36 expression and common single-nucleotide polymorphism genotypes. PMCID: PMC3295590 PMID: 21912245 [PubMed - indexed for MEDLINE] 614. Clin Exp Pharmacol Physiol. 2011 Dec;38(12):888-96. doi: 10.1111/j.1440-1681.2011.05602.x. Adipokines in inflammation, insulin resistance and cardiovascular disease. Li ZY(1), Wang P, Miao CY. Author information: (1)Department of Pharmacology, Second Military Medical University, Shanghai, China. 1. Obesity is a major determinant of cardiovascular disease (CVD). Studies in the past two decades have shown that adipose tissue is not merely an inert energy reserve of triglycerides, but also an active endocrine organ. 2. Adipose tissue can produce and secrete numerous bioactive peptides and/or proteins termed adipokines. These secretory factors are involved in the regulation of local and systemic inflammation and insulin sensitivity in a paracrine and/or endocrine manner. Inflammation and insulin resistance (IR) play critical roles in the obesity-linked development of CVD, such as atherosclerosis, hypertension and restenosis. 3. In the present minireview, we summarize the relationship between inflammation and IR, as well as their contribution to the development of CVD during adipose tissue dysfunction. In particular, we focus on the effects of various adipokines in pathological processes, which may provide an insight into obesity-linked CVD and facilitate the development of new therapeutic strategies. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21910745 [PubMed - indexed for MEDLINE] 615. Clin Sci (Lond). 2012 Jan;122(1):1-12. doi: 10.1042/CS20110151. Perivascular adipose tissue: more than just structural support. Szasz T(1), Webb RC. Author information: (1)Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA. iszasz@georgiahealth.edu PVAT (perivascular adipose tissue) has recently been recognized as a novel factor in vascular biology, with implications in the pathophysiology of cardiovascular disease. Composed mainly of adipocytes, PVAT releases a wide range of biologically active molecules that modulate vascular smooth muscle cell contraction, proliferation and migration. PVAT exerts an anti-contractile effect in various vascular beds which seems to be mediated by an as yet elusive PVRF [PVAT-derived relaxing factor(s)]. Considerable progress has been made on deciphering the nature and mechanisms of action of PVRF, and the PVRFs proposed until now are reviewed here. However, complex pathways seem to regulate PVAT function and more than one mechanism is probably responsible for PVAT actions in vascular biology. The present review describes our current knowledge on the structure and function of PVAT, with a focus on its role in modulating vascular tone. Potential involvements of PVAT dysfunction in obesity, hypertension and atherosclerosis will be highlighted. PMCID: PMC3966487 PMID: 21910690 [PubMed - indexed for MEDLINE] 616. Adv Exp Med Biol. 2011;721:67-86. doi: 10.1007/978-1-4614-0650-1_5. Adipose tissue and ceramide biosynthesis in the pathogenesis of obesity. Samad F(1), Badeanlou L, Shah C, Yang G. Author information: (1)Torrey Pines Institute for Molecular Studies, San Diego, California, USA. fsamad@tpims.org Although obesity is a complex metabolic disorder often associated with insulin resistance, hyperinsulinemia and Type 2 diabetes, as well as with accelerated atherosclerosis, the molecular changes in obesity that promote these disorders are not completely understood. Several mechanisms have been proposed to explain how increased adipose tissue mass affects whole body insulin resistance and cardiovascular risk. One theory is that increased adipose derived inflammatory cytokines induces a chronic inflammatory state that not only increases cardiovascular risk, but also antagonizes insulin signaling and mitochondrial function and thereby impair glucose hemostasis. Another suggests that lipid accumulation in nonadipose tissues not suited for fat storage leads to the buildup of bioactive lipids that inhibit insulin signaling and metabolism. Recent evidence demonstrates that sphingolipid metabolism is dysregulated in obesity and specific sphingolipids may provide a common pathway that link excess nutrients and inflammation to increased metabolic and cardiovascular risk. This chapter will focus primarily on the expression and regulation of adipose and plasma ceramide biosynthesis in obesity and, its potential contribution to the pathogenesis of obesity and the metabolic syndrome. PMID: 21910083 [PubMed - indexed for MEDLINE] 617. Int J Cardiol. 2012 Mar 8;155(2):188-93. doi: 10.1016/j.ijcard.2011.07.047. Epub 2011 Sep 9. The role of adiponectin in human vascular physiology. Vaiopoulos AG(1), Marinou K, Christodoulides C, Koutsilieris M. Author information: (1)Department of Experimental Physiology, Athens University School of Medicine, Greece. Comment in Int J Cardiol. 2012 Mar 8;155(2):285-6; author reply 286-7. Int J Cardiol. 2013 Oct 12;168(5):4796-8. Adiponectin (ApN) is an adipose tissue-derived hormone which is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology via actions on a broad spectrum of target organs including liver, skeletal muscle, and vascular endothelium. Besides possessing insulin sensitizing and anti-inflammatory properties ApN also exerts a pivotal role in vascular protection through activation of multiple intracellular signaling cascades. Enhancement of nitric oxide generation and attenuation of reactive oxygen species production in endothelial cells along with reduced vascular smooth muscle cell proliferation and migration constitute some of ApN's vasoprotective actions. Additionally, recent data indicate that ApN has direct myocardio-protective effects. Decreased plasma ApN levels are implicated in the pathogenesis of the metabolic syndrome and atherosclerosis and may serve as a diagnostic and prognostic biomarker as well as a rational pharmaco-therapeutic target to treat these disorders. This review article summarizes recent work on the cardiovascular actions of ApN. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21907426 [PubMed - indexed for MEDLINE] 618. Cell Metab. 2011 Sep 7;14(3):289-99. doi: 10.1016/j.cmet.2011.08.005. Estrogen receptors and the metabolic network. Barros RP(1), Gustafsson JÅ. Author information: (1)Center for Nuclear Receptors and Cell Signaling, Department of Cell Biology and Biochemistry, University of Houston, Houston, TX 77004, USA. rbarros@central.uh.edu The metabolic syndrome has reached pandemic level worldwide, and evidence is that estradiol plays a key role in its development. The discovery of the second estrogen receptor, ERβ, in tissues previously not considered targets of estradiol was a breakthrough in endocrinology. In the present review, we discuss how the presence of ERβ and the previously described ERα in tissues involved in glucose and lipid homeostasis (brain, skeletal muscle, adipose tissue, pancreas, liver, and heart) may have important implications to risk factors associated with the metabolic syndrome. Imbalance of ERα/ERβ ratio in this "metabolic network" may lead to the metabolic syndrome. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21907136 [PubMed - indexed for MEDLINE] 619. Chirurg. 2011 Sep;82(9):767-74. doi: 10.1007/s00104-011-2107-7. [Modern face lift surgery]. [Article in German] von Gregory HF(1), Gubisch W. Author information: (1)Klinik für Plastische Gesichtschirurgie, Marienhospital Stuttgart, Deutschland. Face lift surgery is generally considered the classical surgical procedure of plastic surgery. This is an extensive operation which has undergone a huge development since its first implementation more than 100 years ago. What began as a simple skin tightening procedure is today a sophisticated and complex technique which ideally combines different treatment methods planned with surgical precision. This article provides an overview of the history of the procedure to the present state of the art concept of pairing biplanar and bivectorial face-neck lifts with autologous fat transfer and dermabrasion. PMID: 21904971 [PubMed - indexed for MEDLINE] 620. Am J Physiol Cell Physiol. 2012 Jan 15;302(2):C327-59. doi: 10.1152/ajpcell.00168.2011. Epub 2011 Sep 7. Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways. Lafontan M(1). Author information: (1)Institut National de la Santé et de la Recherche Médicale, UMR, Hôpital Rangueil, Toulouse, France. max.lafontan@inserm.fr For many years, there was little interest in the biochemistry or physiology of adipose tissue. It is now well recognized that adipocytes play an important dynamic role in metabolic regulation. They are able to sense metabolic states via their ability to perceive a large number of nervous and hormonal signals. They are also able to produce hormones, called adipokines, that affect nutrient intake, metabolism and energy expenditure. The report by Rodbell in 1964 that intact fat cells can be obtained by collagenase digestion of adipose tissue revolutionized studies on the hormonal regulation and metabolism of the fat cell. In the context of the advent of systems biology in the field of cell biology, the present seems an appropriate time to look back at the global contribution of the fat cell to cell biology knowledge. This review focuses on the very early approaches that used the fat cell as a tool to discover and understand various cellular mechanisms. Attention essentially focuses on the early investigations revealing the major contribution of mature fat cells and also fat cells originating from adipose cell lines to the discovery of major events related to hormone action (hormone receptors and transduction pathways involved in hormonal signaling) and mechanisms involved in metabolite processing (hexose uptake and uptake, storage, and efflux of fatty acids). Dormant preadipocytes exist in the stroma-vascular fraction of the adipose tissue of rodents and humans; cell culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells. Finally, more recent insights into adipocyte secretion, a completely new role with major metabolic impact, are also briefly summarized. PMID: 21900692 [PubMed - indexed for MEDLINE] 621. Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1207-28. doi: 10.1152/ajpregu.00109.2011. Epub 2011 Sep 7. Central circuitries for body temperature regulation and fever. Nakamura K(1). Author information: (1)Career-Path Promotion Unit for Young Life Scientists, Kyoto Univ., School of Medicine Bldg. E, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. kazu@cp.kyoto-u.ac.jp Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E(2) produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia. PMID: 21900642 [PubMed - indexed for MEDLINE] 622. J R Soc Interface. 2012 Jan 7;9(66):1-19. doi: 10.1098/rsif.2011.0301. Epub 2011 Sep 7. Biomaterial strategies for alleviation of myocardial infarction. Venugopal JR(1), Prabhakaran MP, Mukherjee S, Ravichandran R, Dan K, Ramakrishna S. Author information: (1)Healthcare and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, Singapore. nnijrv@nus.edu.sg World Health Organization estimated that heart failure initiated by coronary artery disease and myocardial infarction (MI) leads to 29 per cent of deaths worldwide. Heart failure is one of the leading causes of death in industrialized countries and is expected to become a global epidemic within the twenty-first century. MI, the main cause of heart failure, leads to a loss of cardiac tissue impairment of left ventricular function. The damaged left ventricle undergoes progressive 'remodelling' and chamber dilation, with myocyte slippage and fibroblast proliferation. Repair of diseased myocardium with in vitro-engineered cardiac muscle patch/injectable biopolymers with cells may become a viable option for heart failure patients. These events reflect an apparent lack of effective intrinsic mechanism for myocardial repair and regeneration. Motivated by the desire to develop minimally invasive procedures, the last 10 years observed growing efforts to develop injectable biomaterials with and without cells to treat cardiac failure. Biomaterials evaluated include alginate, fibrin, collagen, chitosan, self-assembling peptides, biopolymers and a range of synthetic hydrogels. The ultimate goal in therapeutic cardiac tissue engineering is to generate biocompatible, non-immunogenic heart muscle with morphological and functional properties similar to natural myocardium to repair MI. This review summarizes the properties of biomaterial substrates having sufficient mechanical stability, which stimulates the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering. PMCID: PMC3223634 PMID: 21900319 [PubMed - indexed for MEDLINE] 623. Tijdschr Psychiatr. 2011;53(9):613-20. [Depressive symptoms, cortisol, visceral fat and metabolic syndrome]. [Article in Dutch] Vogelzangs N(1), Penninx BW. Author information: (1)VU Medisch Centrum, Amsterdam. n.vogelzangs@ggzingeest.nl Comment in Tijdschr Psychiatr. 2011;53(9):621-3. BACKGROUND: Metabolic syndrome might explain the relationship between depression and cardiovascular disease. AIM: To examine the (longitudinal) relationship between depressive symptoms, cortisol and metabolic syndrome, especially visceral fat. METHODS: Our study derives data on depressive symptoms, cortisol, visceral fat and metabolic syndrome obtained from three different cohorts of older persons (Inchianti, lasa, Health abc). RESULTS: Metabolic dysregulation, especially in relation to fat occurs mainly in depressed persons with hypercortisolemia. There seems to be a vicious cycle between depressive symptoms and visceral fat. CONCLUSION: Early detection of metabolic disturbances in depressed patients might prevent cardiovascular outcomes. Future research should investigate whether the treatment of depression could positively influence metabolic syndrome, and whether, conversely, the treatment of metabolic syndrome could relieve depression. PMID: 21898316 [PubMed - indexed for MEDLINE] 624. Clin Exp Pharmacol Physiol. 2011 Dec;38(12):879-87. doi: 10.1111/j.1440-1681.2011.05601.x. Human epicardial fat: what is new and what is missing? Sacks HS(1), Fain JN. Author information: (1)Endocrinology and Diabetes Division 111D, VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA. hsacks@hotmail.com 1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21895738 [PubMed - indexed for MEDLINE] 625. Br J Pharmacol. 2012 Feb;165(3):561-73. doi: 10.1111/j.1476-5381.2011.01661.x. Human obesity and endothelium-dependent responsiveness. Campia U(1), Tesauro M, Cardillo C. Author information: (1)Department of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Obesity is an ongoing worldwide epidemic. Besides being a medical condition in itself, obesity dramatically increases the risk of development of metabolic and cardiovascular disease. This risk appears to stem from multiple abnormalities in adipose tissue function leading to a chronic inflammatory state and to dysregulation of the endocrine and paracrine actions of adipocyte-derived factors. These, in turn, disrupt vascular homeostasis by causing an imbalance between the NO pathway and the endothelin 1 system, with impaired insulin-stimulated endothelium-dependent vasodilation. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not just limited to the endothelium, but also involves the other layers of the vessel wall. In particular, obesity-related changes in medial smooth muscle cells seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and perivascular fat appear to be a source of pro-inflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction, and to the pathogenesis of vascular disease. While obesity-induced vascular dysfunction appears to be reversible, at least in part, with weight control strategies, these have not proved sufficient to prevent the metabolic and cardiovascular complication of obesity on a large scale. While a number of currently available drugs have shown potentially beneficial vascular effects in patients with obesity and the metabolic syndrome, elucidation of the pathophysiological mechanisms underlying vascular damage in obese patients is necessary to identify additional pharmacologic targets to prevent the cardiovascular complications of obesity, and their human and economic costs.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315031 PMID: 21895631 [PubMed - indexed for MEDLINE] 626. Dig Dis. 2011;29(4):371-6. doi: 10.1159/000329799. Epub 2011 Aug 30. Modulation of liver fibrosis by adipokines. Marra F(1), Navari N, Vivoli E, Galastri S, Provenzano A. Author information: (1)Dipartimento di Medicina Interna, University of Florence, Italy. f.marra @ dmi.unifi.it Hepatic fibrosis is an integrated process triggered by chronic liver damage, leading to the accumulation of extracellular matrix. In patients with chronic liver disease, this process is favored by the presence of obesity or overweight, which are also relevant risk factors for the progression of nonalcoholic steatohepatitis. In this paper, we review the available evidence indicating the modulation of the fibrogenic process by adipokines, a group of cytokines secreted primarily by adipose tissue. In particular, we discuss in detail the role of leptin and adiponectin, which favor and limit the fibrogenic process, respectively. The possible involvement of other recently identified adipokines is also briefly outlined. Copyright © 2011 S. Karger AG, Basel. PMID: 21894007 [PubMed - indexed for MEDLINE] 627. Clin Chem Lab Med. 2011 Sep 6;49(12):1925-35. doi: 10.1515/CCLM.2011.697. New insights into adipose tissue dysfunction in insulin resistance. Mlinar B(1), Marc J. Author information: (1)Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. barbi.mlinar@gmail.com In a state of caloric excess, adipose tissue plays an essential role by storing lipids. Its expandability determines the onset of metabolic syndrome (central obesity, dyslipidemia, glucose intolerance and hypertension). When the adipocyte endoplasmic reticulum is no longer capable of processing the excess nutrients, the so-called "endoplasmic reticulum stress" develops. This triggers efflux of free fatty acids from adipocytes into the circulation and causes triglyceride overload in skeletal muscle, liver and pancreas. Adipose tissue hypoxia then develops, due to the failure of vasculature to expand with adipocyte hypertrophy. Increased catabolism in mitochondria leads there to oxidative stress. Both phenomena cause deranged adipokine secretion and low-grade inflammation. Inflammatory cytokines, reactive oxygen species and ectopic lipid deposition are the main mediators of insulin resistance and vascular impairment, which both lead finally to diabetes type 2 and cardiovascular disease. Recently, fibrosis of adipose tissue was also demonstrated in obesity, contributing to the interplay of deleterious factors forcing inflammation. The present paper reviews recent evidence for adipose tissue dysfunction, trying to define causes and consequences. In conclusion, insulin resistance and associated complications originate from excess lipids, which cannot be stored without limit in adipose tissue, thus affecting its integrity and adipokine secretion. PMID: 21892913 [PubMed - indexed for MEDLINE] 628. Stem Cell Rev. 2012 Jun;8(2):375-92. doi: 10.1007/s12015-011-9312-0. Immunosuppressive properties of mesenchymal stem cells. Abumaree M(1), Al Jumah M, Pace RA, Kalionis B. Author information: (1)King Saud Bin Abdulaziz University for Health Sciences/King Abdullah International Medical Research Center, King Abdulaziz Medical City, National Guard Health Affairs, PO Box 22490, Riyadh, 11426, Mail Code 1515, Saudi Arabia. Mesenchymal stem cells (MSC) can be isolated from different adult tissues including bone marrow, adipose tissue, cord blood and placenta. MSCs modulate the immune function of the major immune cell populations involved in alloantigen recognition and elimination, including antigen presenting cells, T cells, B cells and natural killer cells. Many clinical trials are currently underway that employ MSCs to treat human immunological diseases. However, the molecular mechanism that mediates the immunosuppressive effect of MSCs is still unclear and the safety of using MSC in patient needs further confirmation. Here, we review the cytokines that activate MSCs and the soluble factors produced by MSCs, which allow them to exert their immunosuppressive effects. We review the mechanism responsible, at least in part, for the immune suppressive effects of MSCs and highlight areas of research required for a better understanding of MSC immune modulation. PMID: 21892603 [PubMed - indexed for MEDLINE] 629. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):542-7. doi: 10.1097/MCO.0b013e32834b6e5e. The thin-fat phenotype and global metabolic disease risk. Kurpad AV(1), Varadharajan KS, Aeberli I. Author information: (1)St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, Karnataka, India. a.kurpad@sjri.res.in PURPOSE OF REVIEW: There has been a great deal of interest in the thin-fat phenotype evident in Asian Indians and its risk associations in the epidemic of noncommunicable chronic disease associated with it. The cause of this phenotype is probably related to lifestyle and environment; however, genotypic and epigenetic modifications in utero also have been considered. RECENT FINDINGS: The thin-fat phenotype occurs when fat is added to an already thin frame. This may occur with rural-urban migration, when positive energy balance occurs in a migrating population who were predominantly thin and physically active to begin with. The role of the pre-existing skeletal muscle mass and its interaction with newly deposited fat must be considered. The thin-fat phenotype may be programmed during fetal growth, but the evidence for this phenomenon is still not completely clear. Finally, although there is increased chronic disease morbidity at lower BMI and younger age in south Asian populations, BMI-related mortality does not appear to follow this trend. SUMMARY: At present, the weight of evidence appears to link the thin-fat phenotype to an environmental and lifestyle phenomenon occurring in previously thin people. This is particularly relevant in India, given the pace of transition over the last two decades. PMID: 21892076 [PubMed - indexed for MEDLINE] 630. Appl Physiol Nutr Metab. 2011 Oct;36(5):598-607. doi: 10.1139/h11-076. Epub 2011 Sep 2. Skeletal muscle and beyond: the role of exercise as a mediator of systemic mitochondrial biogenesis. Little JP(1), Safdar A, Benton CR, Wright DC. Author information: (1)Department of Biology, I K Barber School of Arts and Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada. It has been known for more than 4 decades that exercise causes increases in skeletal muscle mitochondrial enzyme content and activity (i.e., mitochondrial biogenesis). Increasing evidence now suggests that exercise can induce mitochondrial biogenesis in a wide range of tissues not normally associated with the metabolic demands of exercise. Perturbations in mitochondrial content and (or) function have been linked to a wide variety of diseases, in multiple tissues, and exercise may serve as a potent approach by which to prevent and (or) treat these pathologies. In this context, the purpose of this review is to highlight the effects of exercise, and the underlying mechanisms therein, on the induction of mitochondrial biogenesis in skeletal muscle, adipose tissue, liver, brain, and kidney. PMID: 21888528 [PubMed - indexed for MEDLINE] 631. Adv Parasitol. 2011;76:235-50. doi: 10.1016/B978-0-12-385895-5.00010-4. Adipose tissue, diabetes and Chagas disease. Tanowitz HB(1), Jelicks LA, Machado FS, Esper L, Qi X, Desruisseaux MS, Chua SC, Scherer PE, Nagajyothi F. Author information: (1)Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA. Adipose tissue is the largest endocrine organ in the body and is composed primarily of adipocytes (fat cells) but also contains fibroblasts, endothelial cells, smooth muscle cells, macrophages and lymphocytes. Adipose tissue and the adipocyte are important in the regulation of energy metabolism and of the immune response. Adipocytes also synthesize adipokines such as adiponectin which is important in the regulation of insulin sensitivity and inflammation. Infection of mice with Trypanosoma cruzi results in an upregulation of inflammation in adipose tissue that begins during the acute phase of infection and persists into the chronic phase. The adipocyte is both a target of infection and a reservoir for the parasite during the chronic phase from which recrudescence of the infection may occur during periods of immunosuppression. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3552250 PMID: 21884894 [PubMed - indexed for MEDLINE] 632. Microcirculation. 2012 Jan;19(1):5-18. doi: 10.1111/j.1549-8719.2011.00130.x. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. De Boer MP(1), Meijer RI, Wijnstok NJ, Jonk AM, Houben AJ, Stehouwer CD, Smulders YM, Eringa EC, Serné EH. Author information: (1)Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. The intertwined epidemics of obesity and related disorders such as hypertension, insulin resistance, type 2 diabetes, and subsequent cardiovascular disease pose a major public health challenge. To meet this challenge, we must understand the interplay between adipose tissue and the vasculature. Microvascular dysfunction is important not only in the development of obesity-related target-organ damage but also in the development of cardiovascular risk factors such as hypertension and insulin resistance. The present review examines the role of microvascular dysfunction as an explanation for the associations among obesity, hypertension, and impaired insulin-mediated glucose disposal. We also discuss communicative pathways from adipose tissue to the microcirculation. © 2011 John Wiley & Sons Ltd. PMID: 21883642 [PubMed - indexed for MEDLINE] 633. Clin Exp Pharmacol Physiol. 2011 Dec;38(12):872-8. doi: 10.1111/j.1440-1681.2011.05596.x. Regulation of stem cell differentiation in adipose tissue by chronic inflammation. Ye J(1), Gimble JM. Author information: (1)Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. yej@pbrc.edu 1. Recent studies suggest that a local hypoxic response leads to chronic inflammation in the adipose tissue of obese individuals. The adipose tissue hypoxia may reflect a compensatory failure in the local vasculature system in response to obesity. 2. Studies suggest that inflammation stimulates angiogenesis and inhibits adipocyte activities in a feedback manner within the obese adipose tissue. Adipose-derived stem cells (ASC) are able to differentiate into multiple lineages of progenitor cells for adipocytes, endothelial cells, fibroblasts and pericytes. Differentiation of ASC into those progenitors is regulated by the adipose tissue microenvironment. 3. As a major factor in the microenvironment, inflammation may favour ASC differentiation into endothelial cells through the induction of angiogenic factors. At the same time, inflammation inhibits ASC differentiation into adipocytes by suppressing peroxisome proliferator-activated receptor γ activity and the insulin signalling pathway. In this context, inflammation may serve as a signal mediating the competition between adipocytes and endothelial cells for the limited source of ASC. 4. It is a new concept that inflammation mediates signals in the competition between adipocytes and endothelial cells for the limited ASC in obesity. There is a lot of evidence that inflammation promotes endothelial cell differentiation. However, this activity of inflammation remains to be established in adipose tissue. The present article reviews the literature in support of this conclusion. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMCID: PMC3225698 PMID: 21883381 [PubMed - indexed for MEDLINE] 634. Obesity (Silver Spring). 2011 Nov;19(11):2113-20. doi: 10.1038/oby.2011.68. Epub 2011 Sep 1. Role of the gut in visceral fat inflammation and metabolic disorders. Lam YY(1), Mitchell AJ, Holmes AJ, Denyer GS, Gummesson A, Caterson ID, Hunt NH, Storlien LH. Author information: (1)Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Sydney, New South Wales, Australia. yan.lam@sydney.edu.au PMID: 21881620 [PubMed - indexed for MEDLINE] 635. Rev Med Chil. 2011 Apr;139(4):505-15. doi: /S0034-98872011000400014. Epub 2011 Aug 25. [The role of uric acid in heart failure]. [Article in Spanish] Alcaíno H(1), Greig D, Castro P, Verdejo H, Mellado R, García L, Díaz-Araya G, Quiroga C, Chiong M, Lavandero S. Author information: (1)Escuela de Medicina, Campus San Felipe, Universidad de Valparaíso, San Felipe, Chile. Complications and mortality of heart failure are high, despite the availability of several forms of treatment. Uric acid, the end product of purine metabolism would actively participate in the pathophysiology of heart failure. However, there is no consensus about its action in cardiovascular disease. Serum uric acid would have a protective antioxidant activity. This action could help to reduce or counteract the processes that cause or appear as a result of heart failure. However, these protective properties would vanish in the intracellular environment or in highly hydrophobic areas such as atherosclerotic plaques and adipose tissue. This review discusses the paradoxical action of uric acid in the pathophysiology of heart failure. PMID: 21879191 [PubMed - indexed for MEDLINE] 636. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9. doi: 10.1016/S0168-8227(11)70014-6. Insulin effects in muscle and adipose tissue. Dimitriadis G(1), Mitrou P, Lambadiari V, Maratou E, Raptis SA. Author information: (1)2nd Department of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, Attikon University Hospital, Haidari, Greece. gdimi@ath.forthnet.gr The major effects of insulin on muscle and adipose tissue are: (1) Carbohydrate metabolism: (a) it increases the rate of glucose transport across the cell membrane, (b) it increases the rate of glycolysis by increasing hexokinase and 6-phosphofructokinase activity, (c) it stimulates the rate of glycogen synthesis and decreases the rate of glycogen breakdown. (2) Lipid metabolism: (a) it decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level, (b) it stimulates fatty acid and triacylglycerol synthesis in tissues, (c) it increases the uptake of triglycerides from the blood into adipose tissue and muscle, (d) it decreases the rate of fatty acid oxidation in muscle and liver. (3) Protein metabolism: (a) it increases the rate of transport of some amino acids into tissues, (b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other tissues, (c) it decreases the rate of protein degradation in muscle (and perhaps other tissues). These insulin effects serve to encourage the synthesis of carbohydrate, fat and protein, therefore, insulin can be considered to be an anabolic hormone. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21864752 [PubMed - indexed for MEDLINE] 637. Braz J Med Biol Res. 2011 Oct;44(10):966-72. Epub 2011 Aug 26. Effect of high-fat diets on body composition, lipid metabolism and insulin sensitivity, and the role of exercise on these parameters. Coelho DF(1), Pereira-Lancha LO, Chaves DS, Diwan D, Ferraz R, Campos-Ferraz PL, Poortmans JR, Lancha Junior AH. Author information: (1)Departamento de Biologia Celular e Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil. decoelho@usp.br Dietary fat composition can interfere in the development of obesity due to the specific roles of some fatty acids that have different metabolic activities, which can alter both fat oxidation and deposition rates, resulting in changes in body weight and/or composition. High-fat diets in general are associated with hyperphagia, but the type of dietary fat seems to be more important since saturated fats are linked to a positive fat balance and omental adipose tissue accumulation when compared to other types of fat, while polyunsaturated fats, omega-3 and omega-6, seem to increase energy expenditure and decrease energy intake by specific mechanisms involving hormone-sensitive lipase, activation of peroxisome proliferator-activated receptor α (PPARα) and others. Saturated fat intake can also impair insulin sensitivity compared to omega-3 fat, which has the opposite effect due to alterations in cell membranes. Obesity is also associated with impaired mitochondrial function. Fat excess favors the production of malonyl-CoA, which reduces GLUT4 efficiency. The tricarboxylic acid cycle and beta-oxidation are temporarily uncoupled, forming metabolite byproducts that augment reactive oxygen species production. Exercise can restore mitochondrial function and insulin sensitivity, which may be crucial for a better prognosis in treating or preventing obesity. PMID: 21876873 [PubMed - indexed for MEDLINE] 638. Adv Clin Chem. 2011;54:129-64. Aromatase activity and bone loss. Gennari L(1), Merlotti D, Nuti R. Author information: (1)Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy. gennari@unisi.it Aromatase is a specific component of the cytochrome P450 enzyme system that is responsible for the transformation of C19 androgen precursors into C18 estrogenic compounds. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is expressed in ovary and testis not only but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen not only in men (since only 15% of circulating estradiol is released directly by the testis) but also in women after the menopause. Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity and thus in estrogen levels may significantly affect bone loss and fracture risk in both genders. PMID: 21874760 [PubMed - indexed for MEDLINE] 639. Anticancer Res. 2011 Jul;31(7):2413-7. KRAS-induced actin-interacting protein: a potent target for obesity, diabetes and cancer. Fujimoto T(1), Shirasawa S. Author information: (1)Department of Cell Biology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. KRAS-induced actin-interacting protein (KRAP) was originally identified as one of the genes deregulated in colorectal cancer. KRAP encodes a cytoplasmic protein associated with filamentous-actin (F-actin), and the amino acid sequences are highly conserved among KRAP orthologues from fish to mammalian species. We demonstrated that KRAP-deficient mice show altered whole-body energy metabolism and resistance to diet-induced obesity and diabetes. Although the precise mechanisms underlying the metabolic phenotypes in the KRAP-deficient mice remain unclear, KRAP is considered to be a target for metabolism-related diseases. Furthermore, several groups have reported that KRAP is a cancer-associated gene. Further studies on the molecular functions of KRAP in physiological tissues could provide a better understanding of various diseases, and opportunities for intervention in various human diseases. In this review, we summarize the current understanding of KRAP and the roles that it plays in a variety of diseases. PMID: 21873152 [PubMed - indexed for MEDLINE] 640. Biometals. 2012 Feb;25(1):1-8. doi: 10.1007/s10534-011-9490-x. Epub 2011 Aug 25. ZnT3: a zinc transporter active in several organs. Smidt K(1), Rungby J. Author information: (1)Department of Pharmacology, University of Aarhus, Aarhus, Denmark. kcjs@farm.au.dk The review collects the emerging information about zinc transporter 3 (ZnT3). ZnT3 has been associated with Alzheimer's disease, airway diseases and diabetes. ZnT3 was discovered and cloned in 1996. Since then, the major interest in the protein has been in its ability to transport zinc into pre-synaptic vesicles of glutamatergic neurones and its role during the development of amyloid β plaques in Alzheimer's disease. Increasing evidence suggests that ZnT3 is present in various cell types like different cell types in the brain, cells from adipose tissue, beta-cells from pancreatic islets, epithelial cells, cells from testis, prostate cancer cells and cells from retina. The expression of ZnT3 is regulated by age, hormones, fatty acids, zinc chelation, and glucose. PMID: 21866305 [PubMed - indexed for MEDLINE] 641. J Clin Endocrinol Metab. 2011 Nov;96(11):3313-25. doi: 10.1210/jc.2011-1159. Epub 2011 Aug 24. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. Garg A(1). Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8537, USA. abhimanyu.garg@utsouthwestern.edu CONTEXT: Lipodystrophies are heterogeneous, genetic or acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. EVIDENCE ACQUISITION AND SYNTHESIS: Both original and review articles were found via PubMed search reporting on clinical features and management of various types of lipodystrophies and were integrated with the author's knowledge of the field. CONCLUSION: The autosomal recessive congenital generalized lipodystrophy and autosomal dominant familial partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophies. Mutations in AGPAT2, BSCL2, CAV1, and PTRF have been reported in congenital generalized lipodystrophy and in LMNA, PPARG, AKT2, and PLIN1 in FPL. CIDEC is the disease gene for autosomal recessive, FPL and LMNA and ZMPSTE24 for autosomal recessive, mandibuloacral dysplasia-associated lipodystrophy. Recently, an autosomal recessive autoinflammatory lipodystrophy syndrome was reported to be due to PSMB8 mutation. Molecular genetic bases of many rare forms of genetic lipodystrophies remain to be elucidated. The most prevalent subtype of acquired lipodystrophy currently occurs with prolonged duration of protease inhibitor-containing, highly-active antiretroviral therapy in HIV-infected patients. The acquired generalized and partial lipodystrophies are mainly autoimmune in origin and display complement abnormalities. Localized lipodystrophies occur due to drug or vaccine injections, pressure, panniculitis, and other unknown reasons. The current management includes cosmetic surgery and early identification and treatment of metabolic and other complications with diet, exercise, hypoglycemic drugs, and lipid-lowering agents. PMID: 21865368 [PubMed - indexed for MEDLINE] 642. Metabolism. 2011 Nov;60(11):1500-10. doi: 10.1016/j.metabol.2011.06.012. Epub 2011 Aug 23. The effects of glucocorticoids on adipose tissue lipid metabolism. Peckett AJ(1), Wright DC, Riddell MC. Author information: (1)School of Kinesiology and Health Science Muscle Health Research Centre, York University, Toronto, Ontario, Canada. apeckett@yorku.ca Glucocorticoids (GCs) have long been accepted as being catabolic in nature, liberating energy substrates during times of stress to supply the increased metabolic demand of the body. The effects of GCs on adipose tissue metabolism are conflicting, however, because patients with elevated GCs present with central adiposity. We performed an extensive literature review of the effects of GCs on adipose tissue metabolism. The contradictory effects of GCs on lipid metabolism occur through a number of different mechanisms, some of which are well defined and others remain to be elucidated. Firstly, through increases in caloric and dietary fat intake, along with increased hydrolysis of circulating triglycerides (chylomicrons, very low-density lipoproteins) by lipoprotein lipase activity, GCs increase the amount of fatty acids in circulation, which are then available for ectopic fat distribution (liver, muscle, and central adipocytes). Glucocorticoids also increase de novo lipid production in hepatocytes through increased expression of fatty acid synthase. There is some controversy as to whether these same mechanisms occur in adipocytes, thereby contributing to adipose hypertrophy. Glucocorticoids promote preadipocyte conversion to mature adipocytes, causing hyperplasia of the adipose tissue. Glucocorticoids also have acute antilipolytic effect on adipocytes, whereas their genomic actions facilitate increased lipolysis after about 48 hours of exposure. The acute and long-term effects of GCs on adipose tissue lipolysis remain unclear. Although considerable evidence supports the notion that GCs increase lipolysis through glucocorticoid-induced increases of lipase expression, they clearly have antilipolytic effects within these same tissues and cell line models. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21864867 [PubMed - indexed for MEDLINE] 643. Expert Rev Neurother. 2011 Sep;11(9):1295-303. doi: 10.1586/ern.11.113. Harnessing the therapeutic potential of mesenchymal stem cells in multiple sclerosis. Darlington PJ(1), Boivin MN, Bar-Or A. Author information: (1)Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montréal, QC, Canada. Phase I clinical trials exploring the use of autologous mesenchymal stem cell (MSC) therapy for the treatment of multiple sclerosis (MS) have begun in a number of centers across the world. MS is a complex and chronic immune-mediated and neurodegenerative disease influenced by genetic susceptibility and environmental risk factors. The ideal treatment for MS would involve both attenuation of detrimental inflammatory responses, and induction of a degree of tissue protection/regeneration within the CNS. Preclinical studies have demonstrated that both human-derived and murine-derived MSCs are able to improve outcomes in the animal model of MS, experimental autoimmune encephalomyelitis. How MSCs ameliorate experimental autoimmune encephalomyelitis is being intensely investigated. One of the major mechanisms of action of MSC therapy is to inhibit various components of the immune system that contribute to tissue destruction. Emerging evidence now supports the idea that MSCs can access the CNS where they can provide protection against tissue damage, and may facilitate tissue regeneration through the production of growth factors. The prospect of cell-based therapy using MSCs has several advantages, including the relative ease with which they can be extracted from autologous bone marrow or adipose tissue and expanded in vitro to reach the purity and numbers required for transplantation, and the fact that MSC therapy has already been used in other human disease settings, such as graft-versus-host and cardiac disease, with initial reports indicating a good safety profile. This article will focus on the theoretical and practical issues relevant to considerations of MSC therapy in the context of MS. PMCID: PMC3234364 PMID: 21864075 [PubMed - indexed for MEDLINE] 644. Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E749-55. doi: 10.1152/ajpendo.00363.2011. Epub 2011 Aug 23. Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria. Coletta DK(1), Mandarino LJ. Author information: (1)Center for Metabolic and Vascular Biology, Arizona State University, Tempe, Arizona 85287-3704, USA. Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in "naturally" occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance. PMCID: PMC3214002 PMID: 21862724 [PubMed - indexed for MEDLINE] 645. Trends Endocrinol Metab. 2011 Nov;22(11):458-66. doi: 10.1016/j.tem.2011.07.002. Epub 2011 Aug 19. Hepatic FXR: key regulator of whole-body energy metabolism. Teodoro JS(1), Rolo AP, Palmeira CM. Author information: (1)Center for Neurosciences and Cell Biology, MitoLab, Department of Life Sciences, University of Coimbra, Coimbra, Portugal. The farnesoid X receptor (FXR) is a nuclear receptor whose activation leads to alterations in pathways involved in energy metabolism. For example, it serves as a bile acid receptor in tissues such as the liver, and as an energy metabolism regulator in liver, muscle and adipose tissue. However, the effects of FXR activation are not exclusive to the tissue where it is present, because receptor crosstalk affects tissues throughout the body. It has been demonstrated that FXR regulates the metabolism of not just bile acids, but also of fats and hydrocarbon metabolites. FXR is currently under study as a therapeutic target for the treatment of diseases of excess, such as diabetes. Here we review the effects of FXR activation in the response of an organism to excess energy. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21862343 [PubMed - indexed for MEDLINE] 646. Proc Nutr Soc. 2011 Nov;70(4):418-25. doi: 10.1017/S0029665111001674. Epub 2011 Aug 24. Endothelial dysfunction associated with obesity and the effect of weight loss interventions. Kerr SM(1), Livingstone MB, McCrorie TA, Wallace JM. Author information: (1)Northern Ireland Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, UK. Endothelial damage is central to the initiation and progression of atherosclerosis, while in addition vascular endothelial cells secrete several anti-atherogenic substances including the potent vasodilator nitric oxide. Increased adhesion molecule expression, in response to pathophysiological stimuli is perhaps the earliest indicator of compromised endothelial integrity. Obesity and adiposity are associated with an increased risk of CVD, influencing disease progression via a number of mechanisms, including enhanced endothelial activation. This review discusses possible mechanisms linking adiposity and more specifically regional fat depots with endothelial function and evaluates studies investigating the effect of weight loss on endothelial function, assessed by biochemical and physiological measurements. Overall, the research to date suggests that visceral adiposity is a stronger predictor of endothelial activation than overall adiposity, possibly mediated via the action of NEFA in circulation. While in general there is a suggestion that weight loss is associated with significant improvements in endothelial function, this is not apparent in all interventions and published literature to date provides less than convincing evidence for the effects of weight loss on endothelial activation. PMID: 21861950 [PubMed - indexed for MEDLINE] 647. Curr Pharm Des. 2011;17(28):3074-80. Ectopic fat storage, insulin resistance, and hypertension. Sironi AM(1), Sicari R, Folli F, Gastaldelli A. Author information: (1)Institute of Clinical Physiology, National Research Council, Pisa Italy. Obesity, insulin resistance, glucose intolerance/type 2 diabetes and hypertension are clustered in the metabolic syndrome representing critical risk factors for increased incidence cardio-cerebro-vascular diseases, kidney failure and cancer. Ectopic fat accumulation, i.e., accumulation in the mediastinum, liver and the abdomen, as well as generalized fat accumulation are associated with arterial hypertension, either systolic or diastolic. Several mechanisms including insulin resistance, sub-inflammatory state, increased Renin- Angiotensin-Aldosterone System (RAAS) system activity, oxidative stress, autonomic dysregulation as well as mechanical compression on the kidneys are all activated by obesity. Interestingly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers, while correcting arterial hypertension, also have a positive effect on glucose metabolism and diabetes prevention, in high risk patients. The implementation of dietary, medical and surgical strategies to prevent and treat obesity, are cornerstones for the primary prevention as well as treatment of arterial hypertension. PMID: 21861830 [PubMed - indexed for MEDLINE] 648. Med Clin North Am. 2011 Sep;95(5):893-902. doi: 10.1016/j.mcna.2011.06.003. Obesity and dyslipidemia. Franssen R(1), Monajemi H, Stroes ES, Kastelein JJ. Author information: (1)Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-159.2, 1105 AZ, Amsterdam, The Netherlands. Dyslipidemia associated with obesity and the metabolic syndrome is one of the central features contributing to the increased CV risk in these patients. In view of the pandemic of the metabolic syndrome, it is imperative to fully understand the mechanisms leading to the metabolic lipid phenotype before embarking upon optimal treatment strategies. The traditional concept that insulin resistance causes increased FFA flux via increased TG hydrolysis in adipose tissue is still of a central theme in the general hypothesis. The combination of increased hepatic VLDL secretion with impaired LPL-mediated TG clearance explains the hypertriglyceridemia phenotype of the metabolic syndrome. Hence, central IR may be an important factor contributing to peripheral hypertriglyceridemia. Recently recognized regulatory systems include the profound impact of the hypothalamus on TG secretion and glucose control. In addition, dysfunctional (or inflamed) intra abdominal adipose tissue has emerged as a potent regulator of dyslipidemia and IR. It will be a challenge to design novel treatment modalities that target “dysfunctional” fat or central IR to attempt to prevent the epidemic of CV disease secondary to the metabolic syndrome. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21855698 [PubMed - indexed for MEDLINE] 649. Proc Nutr Soc. 2011 Nov;70(4):426-38. doi: 10.1017/S0029665111001662. Epub 2011 Aug 22. Pathogenic obesity and nutraceuticals. Conroy KP(1), Davidson IM, Warnock M. Author information: (1)Department of Dietetics, Nutrition and Biological Sciences, Queen Margaret University, Edinburgh, Queen Margaret Drive, Musselburgh EH21 6UU, UK. kconroy@qmu.ac.uk Over a decade of intense research in the field of obesity has led to the knowledge that chronic, excessive adipose tissue expansion leads to an increase in the risk for CVD, type 2 diabetes mellitus and cancer. This is primarily thought to stem from the low-grade, systemic inflammatory response syndrome that characterises adipose tissue in obesity, and this itself is thought to arise from the complex interplay of factors including metabolic endotoxaemia, increased plasma NEFA, hypertrophic adipocytes and localised hypoxia. Plasma concentrations of vitamins and antioxidants are lower in obese individuals than in the non-obese, which is hypothesised to negatively affect the development of inflammation and disease in obesity. This paper provides a review of the current literature investigating the potential of nutraceuticals to ameliorate the development of oxidative stress and inflammation in obesity, thereby limiting the onset of obesity complications. Research has found nutraceuticals able to positively modulate the activity of adipocyte cell lines and further positive effects have been found in other aspects of pathogenic obesity. While their ability to affect weight loss is still controversial, it is clear that they have a great potential to reverse the development of overweight and obesity-related comorbidities; this, however, still requires much research especially that utilising well-structured randomised controlled trials. PMID: 21854698 [PubMed - indexed for MEDLINE] 650. Trends Endocrinol Metab. 2011 Nov;22(11):450-7. doi: 10.1016/j.tem.2011.07.003. Epub 2011 Aug 16. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Iacobellis G(1), Bianco AC. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA. giacobellis@med.miami.edu Epicardial adipose tissue is an unusual visceral fat depot with anatomical and functional contiguity to the myocardium and coronary arteries. Under physiological conditions, epicardial adipose tissue displays biochemical, mechanical and thermogenic cardioprotective properties. Under pathological circumstances, epicardial fat can locally affect the heart and coronary arteries through vasocrine or paracrine secretion of proinflammatory cytokines. What influences this equilibrium remains unclear. Improved local vascularization, weight loss, and targeted pharmaceutical interventions could help to return epicardial fat to its physiological role. This review focuses on the emerging physiological and pathophysiological aspects of the epicardial fat and its numerous and innovative clinical applications. Particular emphasis is placed on the paracrine/endocrine properties of epicardial fat and its role in the development and progression of atherosclerosis. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21852149 [PubMed - indexed for MEDLINE] 651. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):535-41. doi: 10.1097/MCO.0b013e32834ad8b6. Origins of metabolic complications in obesity: adipose tissue and free fatty acid trafficking. Mittendorfer B(1). Author information: (1)Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. mittendb@wustl.edu PURPOSE OF REVIEW: Obesity is associated with a number of serious medical complications that are risk factors for cardiovascular disease (e.g., insulin resistance, dyslipidemia, and liver fat accumulation). Alterations in fatty acid trafficking, both between tissues and within cells, represent a key feature in the pathophysiology of the metabolic complications in obese patients. The ways by which fatty acid 're-routing' may affect metabolic function are summarized in this article. RECENT FINDINGS: Ectopic fat accumulation (i.e., fat accumulation in nonadipose tissues) appears to be a key feature distinguishing metabolically healthy from metabolically abnormal patients. This observation has led to the belief that an imbalance in fatty acid trafficking away from adipose tissue toward nonadipose tissues is a primary cause for the development of metabolic alterations in obese patients. More recently, however, it has become apparent that fatty acid trafficking within nonadipose tissues cells (i.e., toward storage - in the form of triglycerides - and oxidation) may be equally important in determining a person's risk for development of metabolic disease. SUMMARY: The pathophysiology of the metabolic alterations associated with obesity is probably multifactorial within a complex network of coordinated physiological responses. Only through the integration of multiple concepts, will it be possible to further our understanding in this area and to help prevent the metabolic alterations associated with obesity. PMCID: PMC3711689 PMID: 21849896 [PubMed - indexed for MEDLINE] 652. Clin Exp Pharmacol Physiol. 2011 Dec;38(12):864-71. doi: 10.1111/j.1440-1681.2011.05589.x. Adipokines and thrombosis. Schäfer K(1), Konstantinides S. Author information: (1)Department of Cardiology and Pulmonary Medicine, University Medical Center Goettingen, Goettingen, Germany. 1. Obesity is a major risk factor for cardiovascular disease. An increased body mass index (BMI) is associated with venous thromboembolism, myocardial infarction, stroke and stent thrombosis after percutaneous interventions. Studies in mouse models of obesity and induced arterial or venous thrombosis have provided insights into the mechanisms involved. 2. In addition to elevated circulating levels of fibrinogen, factor VII and plasminogen activator inhibitor (PAI)-1, changes in platelet biology and function may underlie the increased (athero) thrombotic risk in obesity. These include elevated platelet counts, an increase in mean platelet volume, an increased platelet aggregatory response to agonists and a reversible resistance to the anti-aggregatory effects of nitric oxide and prostacyclin I(2) . 3. Specific adipokines mediate the prothrombotic state in obesity. Of these, leptin enhances both arterial and venous thrombosis by promoting platelet adhesion, activation and aggregation. Leptin also induces tissue factor expression by human neutrophils and other cells. C-Reactive protein enhances the formation of monocyte-platelet aggregates and also promotes P-selectin expression and platelet adhesion to endothelial cells. Further, the adipose tissue is a significant source of tissue factor and PAI-1. Conversely, the circulating levels of adiponectin, a hormone that exerts vasculoprotective, anti-atherosclerotic and antithrombotic effects, are reduced in obese individuals. 4. A better understanding of the interactions of the adipose tissue with circulating and vascular cells and the dissection of the mechanisms linking adipokines to arterial and venous thrombosis may identify obese individuals at particularly high cardiovascular risk and indicate promising vasculoprotective and therapeutic targets. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21848866 [PubMed - indexed for MEDLINE] 653. Mol Aspects Med. 2011 Jun;32(3):159-221. doi: 10.1016/j.mam.2011.07.001. Epub 2011 Aug 10. Caloric restriction. Speakman JR(1), Mitchell SE. Author information: (1)Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, UK. J.Speakman@abdn.ac.uk Restricting the intake of calories has been practiced as a method for increasing both the length and quality of life for over 500 years. Experimental work confirming the success of this approach in animals has accumulated over the last 100 years. Lifelong caloric restriction (CR) may extend life by up to 50% in rodents, with progressively less impact the later in life it is started. This effect is matched by profound impacts on age related diseases including reduced risk of cancer, neurodegenerative disorders, autoimmune disease, cardiovascular disease and type II diabetes mellitus. The disposable soma theory of ageing suggests that CR evolved as a somatic protection response to enable animals to survive periods of food shortage. The shutdown of reproductive function during CR is consistent with this suggestion, but other features of the phenomenon are less consistent with this theory, and some have suggested that in rodents it may be mostly an artifact of domestication. CR induces profound effects on animals at all levels from the transcriptome to whole animal physiology and behavior. Animals under CR lose weight which is disproportionately contributed to by white adipose tissue. Generally animals on CR change their activity patterns so that they are more active prior to food delivery each day but total activity may be unchanged or reduced. Considerable debate has occurred over the effects of CR on resting metabolic rate (RMR). Total RMR declines, but as body mass and body composition also change it is unclear whether metabolism at the tissue level also declines, is unchanged or even increases. Body temperature universally decreases. Hunger is increased and does not seem to abate even with very long term restriction. Circulating adipokines are reduced reflecting the reduction in white adipose tissue (WAT) mass under restriction and there is a large reduction in circulating insulin and glucose levels. There are profound tissue level changes in metabolism with a generalized shift from carbohydrate to fat metabolism. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. These different pathways may interact and may all play important roles mediating different aspects of the response. Exactly how they generate the health benefits remains open for debate, however CR results in reduced oxidative stress and enhanced autophagy, both of which could be essential components of the beneficial effects. Most data about the effects of CR in mammals comes from work on rodents. There is limited work on non-human primates that shows promising effects and one randomized controlled trial in humans where physiological markers of the CR response are consistent with the responses in mice and rats. There are also populations of humans voluntarily restricting themselves. Humans on long term restriction report similar negative side effects to those observed in animals - perpetual hunger, reduced body temperature leading to a feeling of being cold, and diminished libido. Considerable effort has been directed in recent years to find drugs that mimic the CR response. Promising candidates are those that intersect with the critical signaling pathways identified above and include biguanides such as metformin that target the insulin signaling pathway, stilbenes (e.g. resveratrol) that affect sirtuin activity and drugs such as rapamycin that interact with mTOR signaling. Whether it will ever be possible to find drugs that capture the health benefits of CR without the negative side-effects remains unclear. Moreover, even if such drugs are developed how the current licensing system for drug use in western societies would cope with them may be a further obstacle to their use. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21840335 [PubMed - indexed for MEDLINE] 654. Eur J Endocrinol. 2011 Nov;165(5):703-11. doi: 10.1530/EJE-11-0431. Epub 2011 Aug 10. RBP4: a controversial adipokine. Kotnik P(1), Fischer-Posovszky P, Wabitsch M. Author information: (1)Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany. Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine. PMID: 21835764 [PubMed - indexed for MEDLINE] 655. Peptides. 2011 Nov;32(11):2290-4. doi: 10.1016/j.peptides.2011.07.021. Epub 2011 Jul 30. Ghrelin and appetite control in humans--potential application in the treatment of obesity. Patterson M(1), Bloom SR, Gardiner JV. Author information: (1)Department of Investigative Medicine, Hammersmith Hospital, Imperial College London, 6th Floor Commonwealth Building, Du Cane Road, London W12 0NN, UK. Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21835215 [PubMed - indexed for MEDLINE] 656. Proc Nutr Soc. 2011 Nov;70(4):408-17. doi: 10.1017/S0029665111000565. Epub 2011 Aug 12. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue. Harford KA(1), Reynolds CM, McGillicuddy FC, Roche HM. Author information: (1)Nutrigenomics Research Group, UCD Conway Institute, Belfield, University College Dublin, Republic of Ireland. High-fat diet-induced obesity is associated with a chronic state of low-grade inflammation, which pre-disposes to insulin resistance (IR), which can subsequently lead to type 2 diabetes mellitus. Macrophages represent a heterogeneous population of cells that are instrumental in initiating the innate immune response. Recent studies have shown that macrophages are key mediators of obesity-induced IR, with a progressive infiltration of macrophages into obese adipose tissue. These adipose tissue macrophages are referred to as classically activated (M1) macrophages. They release cytokines such as IL-1β, IL-6 and TNFα creating a pro-inflammatory environment that blocks adipocyte insulin action, contributing to the development of IR and type 2 diabetes mellitus. In lean individuals macrophages are in an alternatively activated (M2) state. M2 macrophages are involved in wound healing and immunoregulation. Wound-healing macrophages play a major role in tissue repair and homoeostasis, while immunoregulatory macrophages produce IL-10, an anti-inflammatory cytokine, which may protect against inflammation. The functional role of T-cell accumulation has recently been characterised in adipose tissue. Cytotoxic T-cells are effector T-cells and have been implicated in macrophage differentiation, activation and migration. Infiltration of cytotoxic T-cells into obese adipose tissue is thought to precede macrophage accumulation. T-cell-derived cytokines such as interferon γ promote the recruitment and activation of M1 macrophages augmenting adipose tissue inflammation and IR. Manipulating adipose tissue macrophages/T-cell activity and accumulation in vivo through dietary fat modification may attenuate adipose tissue inflammation, representing a therapeutic target for ameliorating obesity-induced IR. PMID: 21835098 [PubMed - indexed for MEDLINE] 657. Benef Microbes. 2010 Nov;1(4):433-7. doi: 10.3920/BM2010.0028. The interaction of short-chain fatty acids with adipose tissue: relevance for prevention of type 2 diabetes. Roelofsen H(1), Priebe MG, Vonk RJ. Author information: (1)Centre for Medical Biomics, University Medical Centre of Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. j.roelofsen@med.umcg.nl Short chain fatty acids (SCFA) are the main bacterial metabolites of colonic fermentation processes. The physiological relevance of the SCFA for the host outside the gastrointestinal tract is getting increased attention. In this review we will focus on the effect of SCFA on inflammation processes in the host in relation to insulin resistance. Obesity has been associated with a pro-inflammatory state of the adipose tissue that is associated with whole body insulin resistance leading to type 2 diabetes. Recently, two G protein-coupled receptors (GPCR) for SCFA, GPCR 41 and GPCR43, were described that are mainly expressed by immune cells but also by adipose tissue. Propionate can induce the satiety hormone leptin and reduce expression of inflammatory cytokines and chemokines indicating that SCFA have anti-inflammatory effects in human adipose tissue. In addition, in human nutritional experiments we observed that whole grain products could counteract a glucose-induced tumour necrosis factor α and interleukin-6 increase which was associated with increased plasma butyrate concentrations. This suggests that dietary fibre can produce a SCFA profile that could have anti-inflammatory effects in the body. The physiological relevance of these observations especially in relation to obesity-associated inflammation and insulin resistance is discussed. PMID: 21831781 [PubMed - indexed for MEDLINE] 658. Benef Microbes. 2010 Nov;1(4):407-21. doi: 10.3920/BM2010.0030. Intestinal microbiota and overweight. Lyra A(1), Lahtinen S, Tiihonen K, Ouwehand AC. Author information: (1)Danisco Sweeteners, Health and Nutrition, Sokeritehtaantie 20, 02460 Kantvik, Finland. anna.lyra@danisco.com The microbes in our gut can influence our weight by providing us with energy through the degradation of nondigestable carbohydrates and by affecting the cellular energy status of liver and muscle cells and the accumulation of lipids in adipose tissue. Thus, it is not surprising that in several studies the gastrointestinal microbiota of overweight and obese subjects has been found to differ from that of lean subjects. The initial findings linked obesity with proportionally decreased levels of the phylum Bacteroidetes and increased levels of the phylum Firmicutes. Later, several studies have assessed the association between overweight or obesity and the gastrointestinal microbiota, applying an array of molecular methods targeting the microbiota as a whole or specific bacterial groups or species within. However, at present it is difficult to draw conclusions on which of the observed microbiota alterations are relevant; essentially all of the bacterial groups that have been studied in more than one trial have given contradictory results in regard to their association with weight. Some of these discrepancies can result from methodological issues and some from the nature of the gastrointestinal microbiota, which is an extremely complex and dynamic microbial ecosystem with high subject specificity. In addition, selecting subjects purely based on weight may result in a largely heterogeneous group with several potentially confounding factors. While it may be premature to conclude which specific groups of bacteria are prominent in the intestinal tract of overweight and obese subjects, it appears clear that microbes contribute to weight gain and related health issues, such as the metabolic syndrome and type II diabetes. Therefore, it is important to continue to search for common microbial markers and predictors of obesity, and to study how these may be modulated with probiotics and prebiotics to promote health. PMID: 21831779 [PubMed - indexed for MEDLINE] 659. Obes Rev. 2012 Jan;13(1):17-26. doi: 10.1111/j.1467-789X.2011.00914.x. Epub 2011 Aug 10. Mechanisms linking obesity to hypertension. Dorresteijn JA(1), Visseren FL, Spiering W. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Obesity-related hypertension is increasingly recognized as a distinct hypertensive phenotype requiring a modified approach to diagnosis and management. In this review rapidly evolving insights into the complex and interdependent mechanisms linking obesity to hypertension are discussed. Overweight and obesity are associated with adipose tissue dysfunction, characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in secretion of adipokines and free fatty acids. This results in chronic vascular inflammation, oxidative stress, activation of the renin-angiotensin-aldosterone system and sympathetic overdrive, eventually leading to hypertension. These mechanisms may provide novel targets for anti-hypertensive drug treatment. Recognition of obesity-related hypertension as a distinct diagnosis enables tailored therapy in clinical practice. This includes lifestyle modification and accommodated choice of blood pressure-lowering drugs. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21831233 [PubMed - indexed for MEDLINE] 660. Endocr Metab Immune Disord Drug Targets. 2011 Sep 1;11(3):198-205. The role of angiotensin in obesity and metabolic disease. Mathai ML(1), Chen N, Cornall L, Weisinger RS. Author information: (1)School of Biomedical and Health Sciences, Victoria University, Melbourne, Australia. michael.mathai@vu.edu.au Obesity is associated with increased body fat composition and elevated risk of metabolic and cardiovascular disease. The activity of the renin-angiotensin system is generally increased in obesity and experimental evidence has shown that angiotensin influences appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. This review summarises some of the key evidence from animal and human experiments that links the renin-angiotensin system to obesity and metabolic disease. This research has been greatly aided by the continuing development of new pharmaceuticals that inhibit the renin-angiotensin system. While their primary use is in the treatment of hypertension and heart failure, a range of experimental and clinical evidence indicates their potential use in the treatment of obesity and metabolic disease. PMID: 21831033 [PubMed - indexed for MEDLINE] 661. Chirurg. 2011 Sep;82(9):759-60, 762-4, 766. doi: 10.1007/s00104-011-2106-8. [Liposuction]. [Article in German] Pallua N(1), Wolter T. Author information: (1)Klinik für Plastische Chirurgie, Hand- und Verbrennungschirurgie, Universitätsklinikum der RWTH Aachen, Deutschland. npallua@ukaachen.de Liposuction is one of the most commonly performed procedures in aesthetic surgery. The primary aim is body contouring and not weight reduction. The vast amount of available methods for suctioning subcutaneous fat allows an optimal individual treatment plan, keeping in mind the correct indications. Although liposuction is often offered as a minor and harmless surgery, it is a complex procedure. A thorough training of the surgeon and in-depth knowledge about possible complications is essential. In addition to aesthetic indications liposuction is also a valuable tool in reconstructive surgery. For optimal patient selection the skin elasticity has to be considered during the preoperative assessment. Besides pure volume reduction through liposuction, the regenerative possibilities of adipose tissue are of great interest for basic research and clinical applications. Lipofilling or autologous fat transfer is used for a wide variety of aesthetic and reconstructive procedures. Of special interest is the regenerative and reconstructive potential of adipose-derived stem cells (ADSC). PMID: 21826569 [PubMed - indexed for MEDLINE] 662. Nat Rev Endocrinol. 2011 Aug 9;7(11):639-46. doi: 10.1038/nrendo.2011.126. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Delzenne NM(1), Neyrinck AM, Bäckhed F, Cani PD. Author information: (1)Université catholique de Louvain, Brussels, Belgium. nathalie.delzenne@ uclouvain.be At birth, the human colon is rapidly colonized by gut microbes. Owing to their vast number and their capacity to ferment nutrients and secrete bioactive compounds, these gastrointestinal microbes act as an environmental factor that affects the host's physiology and metabolism, particularly in the context of obesity and its related metabolic disorders. Experiments that compared germ-free and colonized mice or analyzed the influence of nutrients that qualitatively change the composition of the gut microbiota (namely prebiotics) showed that gut microbes induce a wide variety of host responses within the intestinal mucosa and thereby control the gut's barrier and endocrine functions. Gut microbes also influence the metabolism of cells in tissues outside of the intestines (in the liver and adipose tissue) and thereby modulate lipid and glucose homeostasis, as well as systemic inflammation, in the host. A number of studies describe characteristic differences between the composition and/or activity of the gut microbiota of lean individuals and those with obesity. Although these data are controversial, they suggest that specific phyla, classes or species of bacteria, or bacterial metabolic activities could be beneficial or detrimental to patients with obesity. The gut microbiota is, therefore, a potential nutritional and pharmacological target in the management of obesity and obesity-related disorders. PMID: 21826100 [PubMed - indexed for MEDLINE] 663. Curr Opin Lipidol. 2011 Oct;22(5):365-72. doi: 10.1097/MOL.0b013e32834a77b4. Macrophage polarization in metabolic disorders: functions and regulation. Chinetti-Gbaguidi G(1), Staels B. Author information: (1)Univ Lille Nord de France, Inserm, U1011, Lille, France. PURPOSE OF REVIEW: To discuss recent findings on the role and regulation of macrophage polarization in obesity and atherosclerosis. RECENT FINDINGS: Macrophages infiltrate the vascular wall during atherosclerosis and adipose tissue during obesity. At least two distinct subpopulations with different functions, the classically (M1) and the alternatively (M2) activated macrophages, have been found in these tissues. Reciprocal skewing of macrophage polarization between the M1 and M2 states is a process modulated by diet, humoral and transcription factors, such as the nuclear receptor peroxisome proliferator-activated receptor gamma. SUMMARY: Recent literature highlights the importance not only of the number of infiltrated macrophages, but also their activation in the maintenance of the inflammation state. Identifying mechanisms and molecules able to modify the balance between M1 and M2 represents a promising field of research. PMCID: PMC3565956 PMID: 21825981 [PubMed - indexed for MEDLINE] 664. Endocrinol Nutr. 2011 Oct;58(8):422-32. doi: 10.1016/j.endonu.2011.05.015. Epub 2011 Aug 6. [Endocrine function in obesity]. [Article in Spanish] Álvarez-Castro P(1), Sangiao-Alvarellos S, Brandón-Sandá I, Cordido F. Author information: (1)Servicio de Endocrinología, Hospital Lucus Augusti, Lugo, España. Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved. PMID: 21824829 [PubMed - indexed for MEDLINE] 665. Trends Pharmacol Sci. 2011 Oct;32(10):607-16. doi: 10.1016/j.tips.2011.06.006. Epub 2011 Aug 6. The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact. Phielix E(1), Szendroedi J, Roden M. Author information: (1)Institute for Clinical Diabetology, German Diabetes Center, D-40225, Düsseldorf, Germany. Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21824668 [PubMed - indexed for MEDLINE] 666. Clin Plast Surg. 2011 Jul;38(3):463-74, vii. doi: 10.1016/j.cps.2011.02.003. Laser, light, and energy devices for cellulite and lipodystrophy. Peterson JD(1), Goldman MP. Author information: (1)Goldman, Butterwick, and Associates Cosmetic Laser Dermatology, 9339 Genesee Avenue, Suite 300, San Diego, CA 92121, USA. Jdd4920@hotmail.com Cellulite affects all races, and it is estimated that 85% of women older than 20 years have some degree of cellulite. Many currently accepted cellulite therapies target deficiencies in lymphatic drainage and microvascular circulation. Devices using radiofrequency, laser, and light-based energies, alone or in combination and coupled frequently with tissue manipulation, are available for improving cellulite. Laser assisted liposuction may improve cellulite appearance. Although improvement using these devices is temporary, it may last several months. Patients who want smoother skin with less visible cellulite can undergo a series of treatments and then return for additional treatments as necessary. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21824543 [PubMed - indexed for MEDLINE] 667. Am Heart Hosp J. 2011 Summer;9(1):E28-32. Biomarkers associated with cardiometabolic risk in obesity. Younus S(1), Rodgers G. Author information: (1)University Medical Center Brackenridge, USA. BACKGROUND: The US is facing an obesity epidemic. Recognizing the biomarkers associated with adipose tissue may impact physicians' management of cardiometabolic disease greatly. EVIDENCE OF ACQUISITION: We searched PubMed for keywords 'obesity', 'leptin', and 'adiponectin', reviewed national surveys, and searched reference articles used in review articles retrieved via the PubMed search. We included articles with multiple relevant citations. Observational data acquired from two sources, not previously published, were also used to support our conclusion. RESULTS: Literature review and analysis of observational data showed that the level of leptin increases with the increase in weight gain, while adiponectin decreases. The roles of these adipokines in the body have been defined. With the increase in leptin levels, the incidence and prevalence of the components of the metabolic syndrome were seen to be higher, resulting in higher cardiovascular disease, while adiponectin was seen to play a more protective role in the body against developing such disease. CONCLUSIONS: Measuring circulating levels of leptin and adiponectin as a screening tool may help recognize those individuals who do not only have obesity as a major risk factor toward developing cardiometabolic disease but also may have an unfavorable 'biomarker profile', putting them at highest risk. This may encourage the mobilization of resources to help these individuals lose weight rapidly with possibly aggressive measures such as bariatric surgery. PMID: 21823073 [PubMed - indexed for MEDLINE] 668. Bone. 2012 Feb;50(2):437-43. doi: 10.1016/j.bone.2011.06.034. Epub 2011 Jul 28. FoxO1, the transcriptional chief of staff of energy metabolism. Kousteni S(1). Author information: (1)Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. sk2836@columbia.edu FoxO1, one of the four FoxO isoforms of Forkhead transcription factors, is highly expressed in insulin-responsive tissues, including pancreas, liver, skeletal muscle and adipose tissue, as well as in the skeleton. In all these tissues FoxO1 orchestrates the transcriptional cascades regulating glucose metabolism. Indeed, FoxO1 is a major target of insulin which inhibits its transcriptional activity via nuclear exclusion. In the pancreas, FoxO1 regulates β-cell formation and function by a balanced dual mode of action that suppresses β-cell proliferation but promotes survival. Hepatic glucose production is promoted and lipid metabolism is regulated by FoxO1 such that under insulin resistance they lead to hyperglycemia and dyslipidemia, two features of type 2 diabetes. In skeletal muscle FoxO1 maintains energy homeostasis during fasting and provides energy supply through breakdown of carbohydrates, a process that leads to atrophy and underlies glycemic control in insulin resistance. In a dual function, FoxO1 regulates energy and nutrient homeostasis through energy storage in white adipose tissue, but promotes energy expenditure in brown adipose tissue. In its most recently discovered novel role, FoxO1 acts as a transcriptional link between the skeleton and pancreas as well as other insulin target tissues to regulate energy homeostasis. Through its expression in osteoblasts it controls glucose metabolism, insulin sensitivity and energy expenditure. In a feedback mode of regulation, FoxO1 is also a target of insulin signaling in osteoblasts. Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism. The multiple actions of FoxO1 in all glucose-regulating organs, along with clinical studies suggesting that its glycemic properties are conserved in humans, establish this transcription factor as a master regulator of energy metabolism across species. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3228887 PMID: 21816244 [PubMed - indexed for MEDLINE] 669. Obes Rev. 2011 Oct;12(10):813-28. doi: 10.1111/j.1467-789X.2011.00897.x. Epub 2011 Aug 5. Glucose-dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity-associated disorders. Paschetta E(1), Hvalryg M, Musso G. Author information: (1)Department of Internal Medicine, University of Turin, Turin, Italy Helgelandssykehu set, Mosjøen, Norway Gradenigo Hospital, Turin, Italy. Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secreted from the intestinal K-cells with established insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the adipose tissue, gut, bone and brain, where GIP modulates energy intake, cell metabolism and proliferation, and lipid and glucose metabolism, eventually promoting lipid and glucose storage. In diabetes and obesity, the incretin effect of GIP is blunted, while the extrapancreatic tissues keep a normal sensitivity to this hormone. As GIP levels are normal or elevated in obesity and diabetes, mounting evidence from chemical or genetic GIP deletion in animal models of obesity-related diabetes suggests that GIP may have a pro-obesogenic action and that a strategy antagonizing GIP action may be beneficial in these conditions, clearing triglyceride deposits from adipose tissue, liver and muscle, and restoring normal insulin sensitivity. Emerging evidence also suggests that the metabolic benefits of bypass surgery are mediated, at least in part, by surgical removal of GIP-secreting K-cells in the upper small intestine. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21815989 [PubMed - indexed for MEDLINE] 670. Br J Nutr. 2011 Nov;106(9):1297-309. doi: 10.1017/S0007114511003849. Epub 2011 Aug 3. The putative effects of green tea on body fat: an evaluation of the evidence and a review of the potential mechanisms. Thavanesan N(1). Author information: (1)University of Oxford, Oxford, UK. navamayooran.thavanesan@seh.ox.ac.uk The increase in the prevalence of obesity in recent years has prompted research into alternative methods of modulating body weight and body fat. The last decade has reflected this with a surge in studies investigating the potential of green tea as a natural agent of weight loss, with a view to confirming and elucidating the mechanisms underlying its effect on the body. Currently, it is widely believed that the polyphenolic components present in green tea have an anti-obesogenic effect on fat homeostasis, by increasing thermogenesis or reducing fat absorption among other ways. The data published to date, however, are inconsistent, with numerous putative modes of action suggested therein. While several unimodal mechanisms have been postulated, a more plausible explanation of the observed results might involve a multimodal approach. Such a mechanism is suggested here, involving simultaneous inhibition of the enzymes catechol-O-methyltransferase, acetyl-CoA carboxylase, fatty acid synthase and impeding absorption of fat via the gut. An evaluation of the available evidence supports a role of green tea in weight loss; however the extent of the effects obtained is still subject to debate, and requires more objective quantification in future research. PMID: 21810286 [PubMed - indexed for MEDLINE] 671. J Transl Med. 2011 Aug 2;9:129. doi: 10.1186/1479-5876-9-129. Anti-inflammatory effects of nicotine in obesity and ulcerative colitis. Lakhan SE(1), Kirchgessner A. Author information: (1)Global Neuroscience Initiative Foundation, Los Angeles, CA, USA. slakhan@gnif.org Cigarette smoke is a major risk factor for a number of diseases including lung cancer and respiratory infections. Paradoxically, it also contains nicotine, an anti-inflammatory alkaloid. There is increasing evidence that smokers have a lower incidence of some inflammatory diseases, including ulcerative colitis, and the protective effect involves the activation of a cholinergic anti-inflammatory pathway that requires the α7 nicotinic acetylcholine receptor (α7nAChR) on immune cells. Obesity is characterized by chronic low-grade inflammation, which contributes to insulin resistance. Nicotine significantly improves glucose homeostasis and insulin sensitivity in genetically obese and diet-induced obese mice, which is associated with suppressed adipose tissue inflammation. Inflammation that results in disruption of the epithelial barrier is a hallmark of inflammatory bowel disease, and nicotine is protective in ulcerative colitis. This article summarizes current evidence for the anti-inflammatory effects of nicotine in obesity and ulcerative colitis. Selective agonists for the α7nAChR could represent a promising pharmacological strategy for the treatment of inflammation in obesity and ulcerative colitis. Nevertheless, we should keep in mind that the anti-inflammatory effects of nicotine could be mediated via the expression of several nAChRs on a particular target cell. PMCID: PMC3163205 PMID: 21810260 [PubMed - indexed for MEDLINE] 672. Nat Rev Rheumatol. 2011 Aug 2;7(9):528-36. doi: 10.1038/nrrheum.2011.107. What's new in our understanding of the role of adipokines in rheumatic diseases? Gómez R(1), Conde J, Scotece M, Gómez-Reino JJ, Lago F, Gualillo O. Author information: (1)SERGAS, Santiago University Clinical Hospital, Research Laboratory, Institute of Medical Research, Travesía de la Choupana, Santiago de Compostela, Spain. Important advances in our understanding of the relationships between adipokines, inflammation and the immune response have been achieved in the past 10 years. White adipose tissue has emerged as a highly dynamic organ that releases a plethora of immune and inflammatory mediators that are involved in numerous diseases, including not only rheumatic diseases such as rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus, but also cardiovascular and metabolic complications that are frequently observed in rheumatic diseases. Our rapidly growing knowledge of adipokine biology is revealing the complexity of these amazing proteins, thereby redefining white adipose tissue as a key element of the inflammatory and immune response in rheumatic diseases. Adipokines exert potent modulatory actions on target tissues and cells involved in rheumatic disease, including cartilage, synovium, bone and various immune cells. In this Review, we describe the most recent advances in adipokine research in the context of rheumatic diseases, focusing primarily on leptin, adiponectin, visfatin and resistin, and also the potential role of newly identified adipokines such as chemerin, lipocalin 2 and serum amyloid A3. PMID: 21808287 [PubMed - indexed for MEDLINE] 673. Yakugaku Zasshi. 2011;131(8):1189-94. [Lipin 1 in lipid metabolism]. [Article in Japanese] Ishimoto K(1). Author information: (1)Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. kenji@phs.osaka-u.ac.jp The gene encoding lipin 1 was identified with a positional cloning approach that localized the causative mutation in fatty liver dystrophic (fld) mice, a mouse model of lipodystrophy. The fld mouse lacks normal adipose tissue in the body, and displays metabolic dysregulation such as obesity, insulin resistance, and hypertriglyceridemia. Lipin 1 is abundantly expressed in key metabolic tissues, including adipose tissue, skeletal muscle, and liver. In the cytosol, lipin 1 acts as an Mg²⁺-dependent phosphatidate phosphatase type-1 (PAP1), catalyzing a key step in the synthesis of glycerolipids. In the nucleus, lipin 1 acts as a transcriptional coactivator through its direct interaction with peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and PPARα. Through two distinct functions in the nucleus and cytosol, lipin 1 modulates lipid metabolism and glucose homeostasis. Here we will discuss recent developments in our understanding of the role of lipin 1 in lipid metabolism. PMID: 21804322 [PubMed - indexed for MEDLINE] 674. J Am Soc Nephrol. 2011 Aug;22(8):1416-22. doi: 10.1681/ASN.2010050481. Succinate receptors in the kidney. Deen PM(1), Robben JH. Author information: (1)Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands. The G protein-coupled succinate and α-ketoglutarate receptors are closely related to the family of P2Y purinoreceptors. Although the α-ketoglutarate receptor is almost exclusively expressed in the kidney, its function is unknown. In contrast, the succinate receptor, SUCRN1, is expressed in a variety of tissues, including blood cells, adipose tissue, liver, retina, and the kidney. Recent evidence suggests SUCRN1 and its succinate ligand are novel detectors of local stress, including ischemia, hypoxia, toxicity, and hyperglycemia. Local levels of succinate in the kidney also activate the renin-angiotensin system and together with SUCRN1 may play a key role in the development of hypertension and the complications of diabetes mellitus, metabolic disease, and liver damage. This makes the succinate receptor a promising drug target to counteract an expanding number of interrelated disorders. PMID: 21803970 [PubMed - indexed for MEDLINE] 675. Am J Obstet Gynecol. 2011 Dec;205(6):518-25. doi: 10.1016/j.ajog.2011.05.042. Epub 2011 Jun 7. Understanding obesity and endometrial cancer risk: opportunities for prevention. Schmandt RE(1), Iglesias DA, Co NN, Lu KH. Author information: (1)Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease. Copyright © 2011. Published by Mosby, Inc. PMCID: PMC4264838 PMID: 21802066 [PubMed - indexed for MEDLINE] 676. Pharmacol Res. 2011 Nov;64(5):438-55. doi: 10.1016/j.phrs.2011.07.004. Epub 2011 Jul 21. Dietary phytochemicals and their potential effects on obesity: a review. González-Castejón M(1), Rodriguez-Casado A. Author information: (1)IMDEA Food Institute, CLAID-PCM Building C/Faraday 7, Campus de Cantoblanco, Madrid 28049, Spain. The incidence of obesity is rising at an alarming rate and is becoming a major public health concern with incalculable social costs. Indeed, obesity facilitates the development of metabolic disorders such as diabetes, hypertension, and cardiovascular diseases in addition to chronic diseases such as stroke, osteoarthritis, sleep apnea, some cancers, and inflammation-bases pathologies. In this review we summarize the progresses made in our understanding of obesity, including the role of inflammation process, the recently understood endocrine function of adipose tissue, as well as passive roles of processes of energy storage and adipogenesis related to fat cell lifecycle: differentiation, maturation, and apoptosis. In addition, the article discusses the anti-obesity potential of dietary phytochemicals and analyzes their mechanisms of action, e.g. induction of apoptosis and lipolysis and inhibition of inflammation. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21798349 [PubMed - indexed for MEDLINE] 677. Br J Pharmacol. 2012 Feb;165(3):544-60. doi: 10.1111/j.1476-5381.2011.01606.x. Microvascular responsiveness in obesity: implications for therapeutic intervention. Bagi Z(1), Feher A, Cassuto J. Author information: (1)Department of Pharmacology, University of Oxford, UK Department of Physiology, New York Medical College, Valhalla, New York, USA. zsolt.bagi@pharm.ox.ac.uk Obesity has detrimental effects on the microcirculation. Functional changes in microvascular responsiveness may increase the risk of developing cardiovascular complications in obese patients. Emerging evidence indicates that selective therapeutic targeting of the microvessels may prevent life-threatening obesity-related vascular complications, such as ischaemic heart disease, heart failure and hypertension. It is also plausible that alterations in adipose tissue microcirculation contribute to the development of obesity. Therefore, targeting adipose tissue arterioles could represent a novel approach to reducing obesity. This review aims to examine recent studies that have been focused on vasomotor dysfunction of resistance arteries in obese humans and animal models of obesity. Particularly, findings in coronary resistance arteries are contrasted to those obtained in other vascular beds. We provide examples of therapeutic attempts, such as use of statins, ACE inhibitors and insulin sensitizers to prevent obesity-related microvascular complications. We further identify some of the important challenges and opportunities going forward.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315030 PMID: 21797844 [PubMed - indexed for MEDLINE] 678. Stem Cells Dev. 2012 Feb 10;21(3):343-51. doi: 10.1089/scd.2011.0303. Epub 2011 Sep 7. Stem cell therapy for erectile dysfunction: a critical review. Lin CS(1), Xin ZC, Wang Z, Deng C, Huang YC, Lin G, Lue TF. Author information: (1)Department of Urology, School of Medicine, University of California, San Francisco, California 94143-0738, USA. clin@urology.ucsf.edu Erectile dysfunction (ED) is a prevailing health problem that seriously impacts quality of life. Current treatment options are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED. These 2 types of ED are thus the main focus of past and current stem cell (SC) therapy studies. In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle. For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2-phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation. SC transplantation was done exclusively by intracavernous (IC) injection, which has been recently shown to have systemic effects. Functional assessment was done exclusively by measuring increases of IC pressure during electrostimulation of CN. Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis. In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial. Recent studies have shown that intracavernously injected SCs rapidly escaped the penis and homed into bone marrow. This could perhaps explain why intracavernously injected SCs had systemic antidiabetic effects and prolonged anti-ED effects. These hypotheses and the differentiation-versus-paracrine debate require further investigation. PMCID: PMC3272247 PMID: 21793654 [PubMed - indexed for MEDLINE] 679. Am J Hum Biol. 2011 Sep-Oct;23(5):577-85. doi: 10.1002/ajhb.21202. Epub 2011 Jul 25. Why does starvation make bones fat? Devlin MJ(1). Author information: (1)Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. mdevlin1@bidmc.harvard.edu Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. Copyright © 2011 Wiley-Liss, Inc. PMCID: PMC3169094 PMID: 21793093 [PubMed - indexed for MEDLINE] 680. Am J Physiol Endocrinol Metab. 2011 Oct;301(4):E567-84. doi: 10.1152/ajpendo.00315.2011. Epub 2011 Jul 26. Leptin in human physiology and pathophysiology. Mantzoros CS(1), Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. cmantzor@bidmc.harvard.edu Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics. PMCID: PMC3191548 PMID: 21791620 [PubMed - indexed for MEDLINE] 681. Endocr Rev. 2011 Oct;32(5):670-93. doi: 10.1210/er.2011-0007. Epub 2011 Jul 26. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Boelen A(1), Kwakkel J, Fliers E. Author information: (1)Department of Endocrinology and Metabolism, F5-165, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. a.boelen@amc.uva.nl Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression. PMID: 21791567 [PubMed - indexed for MEDLINE] 682. J Toxicol Environ Health B Crit Rev. 2011;14(5-7):423-48. doi: 10.1080/10937404.2011.578561. The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. Decherf S(1), Demeneix BA. Author information: (1)CNRS UMR 7221 «Evolution of Endocrine Regulations», Department Regulations, Development and Molecular Diversity, Muséum National d'Histoire Naturelle, Paris, France. sdecherf@mnhn.fr The obesogen concept proposes that environmental contaminants may be contributing to the epidemic of obesity and its related pathology, metabolic disorder. The first references to such a notion appeared at the beginning of the current decade, with the hypothesis that the correlation between increasing incidence of obesity and enhanced industrial chemical production was not simply coincidental, but potentially causally related. The next event was the introduction of the term "obesogen" as representing an environmental pollutant that adversely affects various aspects of adipose tissue functions. More recently, the concept was extended to include substances that may modify metabolic balance at the central, hypothalamic level. The actions of two prime candidate obesogens, tributyltin (TBT) and tetrabromobisphenol A (TBBPA), acting at the central level are the main focus of this review. Having discussed the evidence for contaminant accumulation in the environment and in human tissues and the potential mechanisms of action, data are provided showing that these two widespread pollutants modify hypothalamic gene regulations. Our studies are based on maternal exposure and measurement of effects in the progeny, mainly based on in vivo gene reporter assays. Such models are obviously pertinent to testing current hypotheses that propose that early exposure might exert effects on later development and physiological functions. The potential molecular mechanisms involved are discussed, as are the broader physiological consequences of these hypothalamic dysregulations. PMID: 21790320 [PubMed - indexed for MEDLINE] 683. Int J Oral Sci. 2011 Jul;3(3):117-24. doi: 10.4248/IJOS11044. Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues. Shen JF(1), Sugawara A, Yamashita J, Ogura H, Sato S. Author information: (1)Department of Periodontology, School of Life Dentistry at Niigata, Nippon Dental University, Niigata 951-1500, Japan. When adipose-derived stem cells (ASCs) are retrieved from the stromal vascular portion of adipose tissue, a large amount of mature adipocytes are often discarded. However, by modified ceiling culture technique based on their buoyancy, mature adipocytes can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and undertake multipotent capacities. Compared with ASCs and other adult stem cells, DFAT cells showed unique advantages in their abundance, isolation and homogeneity. In this concise review, the establishment and culture methods of DFAT cells are introduced and the current profiles of their cellular nature are summarized. Under proper induction culture in vitro or environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic and myogenic potentials. In angiogenic conditions, DFAT cells could exhibit perivascular characteristics and elicit neovascularization. Our preliminary findings also suggested the pericyte phenotype underlying such cell lineage, which supported a novel interpretation about the common origin of mesenchymal stem cells and tissue-specific stem cells within blood vessel walls. Current research on DFAT cells indicated that this alternative source of adult multipotent cells has great potential in tissue engineering and regenerative medicine. PMCID: PMC3470092 PMID: 21789960 [PubMed - indexed for MEDLINE] 684. Cold Spring Harb Symp Quant Biol. 2011;76:121-7. doi: 10.1101/sqb.2011.76.010447. Epub 2011 Jul 22. Surviving starvation: essential role of the ghrelin-growth hormone axis. Goldstein JL(1), Zhao TJ, Li RL, Sherbet DP, Liang G, Brown MS. Author information: (1)Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA. joe.goldstein@utsouthwestern.edu After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation. PMID: 21785007 [PubMed - indexed for MEDLINE] 685. Mol Cell Endocrinol. 2012 Mar 24;350(2):196-205. doi: 10.1016/j.mce.2011.07.001. Epub 2011 Jul 18. Interactions of the mineralocorticoid receptor--within and without. Yang J(1), Fuller PJ. Author information: (1)Department of Medicine, Prince Henry's Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia. The mineralocortoid receptor (MR) regulates salt homeostasis in the kidneys and plays a range of other roles in the heart, vasculature, brain and adipose tissue. It interacts with both mineralocorticoids and glucocorticoids to mediate transcription of target genes. The ability of the MR to exert tissue- and ligand-specific effects relies on its interactions with a range of binding partners, including the chaperone proteins, coregulators, other transcription factors, DNA and modifying proteins. Interactions within the domains of the MR also modulate the overall transcriptional complex. This review will discuss the current understanding of interactions involving the MR and highlight their relevance to ligand- or tissue-specificity as well as their suitability as therapeutic targets. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21784126 [PubMed - indexed for MEDLINE] 686. Gen Comp Endocrinol. 2011 Oct 1;174(1):1-4. doi: 10.1016/j.ygcen.2011.06.018. Epub 2011 Jul 14. The evolution of the adipose tissue: a neglected enigma. Ottaviani E(1), Malagoli D, Franceschi C. Author information: (1)Department of Biology, University of Modena and Reggio Emilia, Modena, Italy. enzo.ottaviani@unimore.it The complexity of the anatomical distribution and functions of adipose tissue (AT) has been rarely analyzed in an evolutionary perspective. From yeast to man lipid droplets are stored mainly in the form of triglycerides in order to provide energy during periods when energy demands exceed caloric intake. This simple scenario is in agreement with the recent discovery of a highly conserved family of proteins for fat storage in both unicellular and multicellular organisms. However, the evolutionary history of organs such as the fat body in insects, playing a role in immunity and other functions besides energy storage and thermal insulation, and of differently distributed subtypes of AT in vertebrates is much less clear. These topics still await a systematic investigation using up-to-date technologies and approaches that would provide information useful for understanding the role of different AT subtypes in normal/physiological conditions or in metabolic pathologies of humans. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21781968 [PubMed - indexed for MEDLINE] 687. J Cutan Med Surg. 2011 Jul-Aug;15(4):230-5. Multiple symmetric lipomatosis. Gomes da Silva R(1), Detoffol Bragança R, Ribeiro Costa C, Torres de Melo L, Weiss Telles R, Costa Silva L. Author information: (1)Federal University of Minas Gerais, Belo Horizonte/MG, Brazil. rodrigogsilva@uol.com BACKGROUND: Multiple symmetric lipomatosis (MSL) is a relatively uncommon entity of unknown etiology characterized by symmetrically subcutaneous accumulation of nonencapsulated adipose tissue. Approximately 200 to 300 cases have been published. OBJECTIVES: The aims of this article are to report the case of a 58-year-old Brazilian patient with MSL and provide a comprehensive overview of the current concepts concerning this disease. METHODS: Our search yielded 28 articles on MSL, including case reports and reviews of the literature. RESULTS: MSL predominantly affects Mediterranean males with a history of chronic alcohol abuse. It is usually asymptomatic and may be associated with diabetes mellitus, hyperlipidemia, hyperuricemia, macrocytic anemia, and oral cancer. Surgical resection is the best treatment option. CONCLUSION: The case reported is a classic presentation of MSL; however, it is particularly uncommon owing to the association with immune thrombocytopenic purpura. This association has been described only once in the medical literature. PMID: 21781630 [PubMed - indexed for MEDLINE] 688. Proc Nutr Soc. 2011 Aug;70(3):342-50. doi: 10.1017/S002966511100084X. Tracing the fate of dietary fatty acids: metabolic studies of postprandial lipaemia in human subjects. Fielding B(1). Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK and Postgraduate Medical School, University of Surrey, Guildford, UK. barbara.fielding@ocdem.ox.ac.uk Most postprandial studies have investigated the response of a single meal, yet the ingestion of sequential meals is more typical in a Western society. The aim of this review is to explain how natural and stable isotope tracers of fatty acids have been used to investigate the metabolism of dietary fat after single and multiple meals, with a focus on in vivo measurements of adipose tissue metabolism. When stable isotope tracers are combined with arteriovenous difference measurements, very specific measurements of metabolic flux across tissues can be made. We have found that adipose tissue is a net importer of dietary fat for 5 h following a single test meal and for most of the day during a typical three-meal eating pattern. When dietary fat is cleared from plasma, some fatty acids 'spillover' into the plasma and contribute up to 50% of postprandial plasma NEFA concentrations. Therefore, plasma NEFA concentrations after a meal reflect the balance between intracellular and extracellular lipolysis in adipose tissue. This balance is altered after the acute ingestion of fructose. The enzyme lipoprotein lipase is a key modulator of fatty acid flux in adipose tissue and its rate of action is severely diminished in obese men. In conclusion, in vivo studies of human metabolism can quantify the way that adipose tissue fatty acid trafficking modulates plasma lipid concentrations. This has implications for the flux of fatty acids to tissues that are susceptible to ectopic fat deposition such as the liver and muscle. PMID: 21781361 [PubMed - indexed for MEDLINE] 689. Vasa. 2011 Jul;40(4):271-9. doi: 10.1024/0301-1526/a000115. Lymphedema and lipedema - an overview of conservative treatment. Wagner S(1). Author information: (1)RehaClinic Bad Zurzach, Switzerland. s.wagner@rehaclinic.ch Lymphedema and lipedema are chronic progressive disorders for which no causal therapy exists so far. Many general practitioners will rarely see these disorders with the consequence that diagnosis is often delayed. The pathophysiological basis is edematization of the tissues. Lymphedema involves an impairment of lymph drainage with resultant fluid build-up. Lipedema arises from an orthostatic predisposition to edema in pathologically increased subcutaneous tissue. Treatment includes complex physical decongestion by manual lymph drainage and absolutely uncompromising compression therapy whether it is by bandage in the intensive phase to reduce edema or with a flat knit compression stocking to maintain volume. PMID: 21780050 [PubMed - indexed for MEDLINE] 690. Endocrinol Nutr. 2011 Aug-Sep;58(7):360-9. doi: 10.1016/j.endonu.2011.05.008. Epub 2011 Jul 22. [Obesity, adipogenesis and insulin resistance]. [Article in Spanish] Ros Pérez M(1), Medina-Gómez G. Author information: (1)Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Facultad de Ciencias de la Salud, Alcorcón, Madrid, España. Insulin resistance precedes the development of type 2 diabetes mellitus and is also a common denominator in the so-called metabolic syndrome. Although the cause of insulin resistance has not been fully elucidated, it seems clear that lifestyle changes, including little physical exercise and constant access to food, particularly in developed and economically emergent countries, as well as genetic factors, appear to have triggered the escalating incidence of diseases related to insulin resistance, including type 2 diabetes and metabolic syndrome. Obesity is considered as a risk factor for developing insulin resistance. Increased adipose tissue has been related to an increased production of pro-inflammatory cytokines which, together with fatty acids, appear to be responsible for the development of insulin resistance. Thus, a greater or lesser expansibility or ability of adipose tissue to store lipids also appears to play a significant role in the development of insulin resistance because overcoming of this capacity, which is variable in each case, would result in leaking of lipids to other tissues where they could interfere with insulin signaling. This article reviews various molecular mechanisms related to the development of insulin resistance and its relationship to expansibility of adipose tissue and obesity. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved. PMID: 21778123 [PubMed - indexed for MEDLINE] 691. Amino Acids. 2011 Nov;41(5):1185-93. doi: 10.1007/s00726-011-0983-2. Epub 2011 Jul 20. Leucine nutrition in animals and humans: mTOR signaling and beyond. Li F(1), Yin Y, Tan B, Kong X, Wu G. Author information: (1)Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan, China. Macronutrients, such as protein or amino acid, not only supply calories but some components may also play as signaling molecules to affect feeding behavior, energy balance, and fuel efficiency. Leucine, a branched-chain amino acid is a good example. After structural roles are satisfied, the ability of leucine to function as signal and oxidative substrate is based on a sufficient intracellular concentration. Therefore, leucine level must be sufficiently high to play the signaling and metabolic roles. Leucine is not only a substrate for protein synthesis of skeletal muscle, but also plays more roles beyond that. Leucine activates signaling factor of mammalian target of rapamycin (mTOR) to promote protein synthesis in skeletal muscle and in adipose tissue. It is also a major regulator of the mTOR sensitive response of food intake to high protein diet. Meanwhile, leucine regulates blood glucose level by promoting gluconeogenesis and aids in the retention of lean mass in a hypocaloric state. It is beneficial to animal nutrition and clinical application and extrapolation to humans. PMID: 21773813 [PubMed - indexed for MEDLINE] 692. Eur J Clin Nutr. 2011 Nov;65(11):1173-89. doi: 10.1038/ejcn.2011.132. Epub 2011 Jul 20. Obesity and energy balance: is the tail wagging the dog? Wells JC(1), Siervo M. Author information: (1)Childhood Nutrition Research Centre, UCL Institute of Child Health, London, UK. j.wells@ich.ucl.ac.uk The scientific study of obesity has been dominated throughout the twentieth century by the concept of energy balance. This conceptual approach, based on fundamental thermodynamic principles, states that energy cannot be destroyed, and can only be gained, lost or stored by an organism. Its application in obesity research has emphasised excessive appetite (gluttony), or insufficient physical activity (sloth), as the primary determinants of excess weight gain, reflected in current guidelines for obesity prevention and treatment. This model cannot explain why weight accumulates persistently rather than reaching a plateau, and underplays the effect of variability in dietary constituents on energy and intermediary metabolism. An alternative model emphasises the capacity of fructose and fructose-derived sweeteners (sucrose, high-fructose corn syrup) to perturb cellular metabolism via modification of the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio, activation of AMP kinase and compensatory mechanisms, which favour adipose tissue accretion and increased appetite while depressing physical activity. This conceptual model implicates chronic hyperinsulinaemia in the presence of a paradoxical state of 'cellular starvation' as a key driver of the metabolic modifications inducing chronic weight gain. We combine evidence from in vitro and in vivo experiments to formulate a perspective on obesity aetiology that emphasises metabolic flexibility and dietary composition rather than energy balance. Using this model, we question the direction of causation of reported associations between obesity and sleep duration or childhood growth. Our perspective generates new hypotheses, which can be tested to improve our understanding of the current obesity epidemic, and to identify novel strategies for prevention or treatment. PMID: 21772313 [PubMed - indexed for MEDLINE] 693. Sheng Li Ke Xue Jin Zhan. 2011 Apr;42(2):100-3. [Brown adipose tissue in human and its potential physiological significance]. [Article in Chinese] Li YG(1), Yan ZC, Wang DH. Author information: (1)State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Brown adipose tissue (BAT) plays an important role in nonshiverthing thermogenesis, thermoregulation and body mass regulation in small mammals. However, in human, the presence of brown adipose tissue was thought to be relevant only in infants, with negligible physiologic relevance in adult. Recently, using 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans showed that adults retain metabolically active BAT depots that can be induced in response to cold and sympathetic nervous system activation. These findings highlight BAT as a potential relevant target for pharmacological and gene expression manipulation to combat human obesity. We reviewed the recent research progresses of BAT in human and its potential functional significance. PMID: 21770256 [PubMed - indexed for MEDLINE] 694. Mol Cell Endocrinol. 2012 Mar 24;350(2):163-7. doi: 10.1016/j.mce.2011.06.026. Epub 2011 Jul 13. Non-adrenal synthesis of aldosterone: a reality check. MacKenzie SM(1), Connell JM, Davies E. Author information: (1)Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. smmk1w@clinmed.gla.ac.uk Advances in the sensitivity of molecular techniques during the 1990s led to a flurry of studies that supported the existence of extra-adrenal sites of aldosterone production in various tissues including the brain and the heart. Subsequent work was often conflicting or ambiguous, leading many to question whether extra-adrenal aldosterone was of any physiological importance, or whether it even existed. In this article, we review these studies and, in light of this evidence, discuss whether the current lack of interest in extra-adrenal aldosterone biosynthesis is justified. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21767599 [PubMed - indexed for MEDLINE] 695. Nihon Rinsho. 2011 Jan;69 Suppl 1:566-70. [Basic concept for the treatment of metabolic syndrome]. [Article in Japanese] Katayama S(1). Author information: (1)Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University. PMID: 21766661 [PubMed - indexed for MEDLINE] 696. Nihon Rinsho. 2011 Jan;69 Suppl 1:285-9. [Roles of Angptl2 in obesity-related chronic inflammation/adipose tissue]. [Article in Japanese] Kadomatsu T(1), Oike Y. Author information: (1)Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University. PMID: 21766611 [PubMed - indexed for MEDLINE] 697. Nihon Rinsho. 2011 Jan;69 Suppl 1:279-84. [Molecular mechanism of adipose tissue remodeling]. [Article in Japanese] Tsuda N(1), Suganami T, Ogawa Y. Author information: (1)Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University. PMID: 21766610 [PubMed - indexed for MEDLINE] 698. Nihon Rinsho. 2011 Jan;69 Suppl 1:269-74. [Role of TFAP2B and WntSB in adipose tissue]. [Article in Japanese] Ugi S(1), Maegawa H, Maeda S. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science. PMID: 21766608 [PubMed - indexed for MEDLINE] 699. Nihon Rinsho. 2011 Jan;69 Suppl 1:165-70. [Lipotoxicity]. [Article in Japanese] Ebihara K(1), Nakao K. Author information: (1)Translational Research Center, Kyoto University Hospital. PMID: 21766590 [PubMed - indexed for MEDLINE] 700. Mol Pharm. 2011 Oct 3;8(5):1480-7. doi: 10.1021/mp200151a. Epub 2011 Jul 25. Stem cell based cancer gene therapy. Cihova M(1), Altanerova V, Altaner C. Author information: (1)Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia. The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Suicide gene therapy using genetically engineered mesenchymal stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. This review provides an explanation of the stem cell-targeted prodrug cancer gene therapy principle, with focus on the choice of prodrug, properties of bone marrow and adipose tissue-derived mesenchymal stem and neural stem cells as well as the mechanisms of their tumor homing ability. Therapeutic achievements of the cytosine deaminase/5-fluorocytosine prodrug system and Herpes simplex virus thymidine kinase/ganciclovir are discussed. In addition, delivery of immunostimulatory cytokines, apoptosis inducing genes, nanoparticles and antiangiogenic proteins by stem cells to tumors and metastases is discussed as a promising approach for antitumor therapy. Combinations of traditional, targeted and stem cell-directed gene therapy could significantly advance the treatment of cancer. PMID: 21755953 [PubMed - indexed for MEDLINE] 701. Can J Physiol Pharmacol. 2011 Jun;89(6):383-91. doi: 10.1139/y11-039. Epub 2011 Jul 13. Subcutaneous adipose tissue metabolism and pharmacology: a new investigative technique. Martin E(1), Brassard P, Gagnon-Auger M, Yale P, Carpentier AC, Ardilouze JL. Author information: (1)Diabetes and Metabolism Research Group, Division of Endocrinology, Department of Medicine, Sherbrooke University Hospital Centre, Sherbrooke, QC J1H 5N4, Canada. According to the Fick principle, any metabolic or hormonal exchange through a given tissue depends on the product of blood flow by arteriovenous difference. Because adipose tissue plays dual storage and endocrine roles, regulation of adipose tissue blood flow (ATBF) is of pivotal importance. Monitoring ATBF in humans can be achieved through different methodologies, such as the (133)Xe washout technique, considered to be the "gold standard", as well as microdialysis and other methods that are not well validated as of yet. This report describes a new method, called "adipose tissue microinfusion" or "ATM", which simultaneously quantifies ATBF by combining the (133)Xe washout technique together with variations of ATBF induced by local infusion of vasoactive agents. The most appropriate site for ATM investigation is the subcutaneous adipose tissue of the anterior abdominal wall. This innovative method conveniently enables the direct comparison of the effects on ATBF of any vasoactive compound, drug, or hormone against a contralateral saline control. The ATM method improves the accuracy and feasibility of physiological and pharmacological studies on the regulation of ATBF in vivo in humans. PMID: 21751894 [PubMed - indexed for MEDLINE] 702. Monaldi Arch Chest Dis. 2011 Mar;76(1):13-21. [Obesity and ischemic heart disease. Is there a link between wellness' diseases?]. [Article in Italian] Maresca F(1), D'Ascoli GL, Ziviello F, Petrillo G, Di Palma V, Russo A, Grieco A, Cirillo P. Author information: (1)Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università degli Studi di Napoli "Federico II", Italy. Obesity, the most common nutritional disorder in Western countries, is usually associated to cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Nowadays, the adipose tissue is considered as an endocrine organ able to produce substances called adipo(cyto)kines that have different effects on lipid metabolism, closely involved in metabolic syndrome, and cardiovascular risk. The increased cardiovascular risk can be related also to peculiar dysfunction in the endocrine activity of adipose tissue observed in obesity responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. The present review aims at providing an up-dated overview on the adipocyte-derived molecules potentially involved in cardiovascular pathophysiology. PMID: 21751733 [PubMed - indexed for MEDLINE] 703. Obes Rev. 2011 Oct;12(10):829-40. doi: 10.1111/j.1467-789X.2011.00900.x. Epub 2011 Jul 12. Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management. van de Woestijne AP(1), Monajemi H, Kalkhoven E, Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center, Utrecht, the Netherlands Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, the Netherlands. Elevated plasma triglyceride levels, as often seen in obese subjects, are independently associated with an increased risk of cardiovascular diseases. By secreting adipokines (such as adiponectin and leptin) and other proteins (such as lipoprotein lipase and cholesteryl ester transferase protein), adipose tissue affects triglyceride metabolism. In obesity, adipocyte hypertrophy leads to many changes in adipocyte function and production of anti- and pro-inflammatory cytokines. Furthermore, free fatty acids are released into the circulation contributing to insulin resistance. Adipose tissue dysfunction will eventually lead to abnormalities in lipid metabolism, such as hypertriglyceridemia (due to increased hepatic very-low-density lipoprotein production and decreased triglyceride hydrolysis), small dense low-density lipoprotein particles, remnant lipoproteins and low high-density lipoprotein cholesterol levels, all associated with a higher risk for the development of cardiovascular diseases. The clinical implications of elevated plasma triglycerides are still a matter of debate. Understanding the pathophysiology of adipose tissue dysfunction in obesity, which is becoming a pandemic condition, is essential for designing appropriate therapeutic interventions. Lifestyle changes are important to improve adipose tissue function in obese patients. Pharmacological interventions to improve adipose tissue function need further evaluation. Although statins are not very potent in reducing plasma triglycerides, they remain the mainstay of therapy for cardiovascular risk reduction in high-risk patients. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21749607 [PubMed - indexed for MEDLINE] 704. Aging Clin Exp Res. 2011 Apr;23(2):84-90. Osteoporosis and risk of fracture in patients with diabetes: an update. Montagnani A(1), Gonnelli S, Alessandri M, Nuti R. Author information: (1)Metabolic Bone Diseases and Osteoporosis Unit, Department of Internal Medicine, Misericordia Hospital, Via Senese, Grosseto, Italy. montagnaniand@gmail.com Diabetes mellitus (DM) and osteoporotic fractures are two of the most important causes of mortality and morbidity in older subjects. Recent data report a close association between fragility fracture risk and DM of both type 1 (DM1) and type 2 (DM2). However, DM1 is associated with reduced bone mineral density (BMD), whereas patients with DM2 generally have normal or increased BMD. This apparent paradox may be explained by the fact that, at a given level of BMD, diabetic patients present lower bone quality with respect to non-diabetics, as shown by several studies reporting that diabetes may affect bone tissue by means of various mechanisms, including hyperinsulinemia, deposition of advanced glycosylation endproducts (AGEs) in collagen, reduced serum levels of IGF-1, hypercalciuria, renal failure, microangiopathy and inflammation. In addition, the propensity to fall and several comorbidities may further explain the higher fracture incidence in DM patients with respect to the general population. It is reasonable to expect that close metabolic control of diabetes may improve bone status, although its effect on reduction of fracture risk has not yet been demonstrated. However, metformin has a direct effect on bone tissue by reducing AGE accumulation, whereas insulin acts directly on osteoclast activity, and thiazolidinediones (TZD) may have a negative effect by switching mesenchymal progenitor cells to adipose rather than bone tissue. New prospects include the incretins, a class of antidiabetic drugs which may play a role linking nutrition and bone metabolism. Better knowledge on how diabetes and its treatments influence bone tissue may lie at the basis of effective prevention of bone fracture in diabetic patients. Thus, close glycemic control, adequate intake of calcium and vitamin D, screening for low BMD, and prevention and treatment of diabetic complications are key elements in the management of osteoporosis in both DM1 and DM2. Attention should be paid to treating diabetes with TZD in women with DM2, particularly if elderly. Lastly, patients with osteoporosis and diabetes should be offered the same pharmacological treatments as non-diabetics, although specific trials on the effects of anti-osteoporotic drugs in the diabetic population are lacking. PMID: 21743287 [PubMed - indexed for MEDLINE] 705. Trends Cardiovasc Med. 2010 Jul;20(5):143-8. doi: 10.1016/j.tcm.2010.12.002. Omentin: a novel link between inflammation, diabesity, and cardiovascular disease. Tan BK(1), Adya R, Randeva HS. Author information: (1)Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, CV4 7AL Coventry, UK. b.k.tan.1@warwick.ac.uk Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae including insulin resistance, diabetes, dyslipidemia, hypertension, and cardiovascular disease, where adipose tissue-secreted cytokines, that is, adipokines, have been implicated in these processes. Omentin is a novel adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects, where circulating levels are decreased in insulin-resistant states, for example, obesity and diabetes. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis potentially via the nuclear factor B signaling pathway, a potent proinflammatory signaling pathway. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent in this respect. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21742269 [PubMed - indexed for MEDLINE] 706. Trends Endocrinol Metab. 2011 Oct;22(10):404-11. doi: 10.1016/j.tem.2011.05.004. Epub 2011 Jul 7. Phosphodiesterase type 5 (PDE5) in the adipocyte: a novel player in fat metabolism? Armani A(1), Marzolla V, Rosano GM, Fabbri A, Caprio M. Author information: (1)Center for Clinical and Basic Research, Scientific Institute for Research, Hospitalization and Health Care (IRCCS) San Raffaele Pisana, Rome, Italy. Phosphodiesterase type 5 (PDE5) is expressed in many tissues (e.g. heart, lung, pancreas, penis) and plays a specific role in hydrolyzing cyclic guanosine monophosphate (cGMP). In adipocytes, cGMP regulates crucial functions by activating cGMP-dependent protein kinase (PKG). Interestingly, PDE5 was recently identified in adipose tissue, although its role remains unclear. Its inhibition, however, was recently shown to affect adipose differentiation and aromatase function. This review summarizes evidence supporting a role for the PDE5-regulated cGMP/PKG system in adipose tissue and its effects on adipocyte function. A better elucidation of the role of PDE5 in the adipocyte could reveal new therapeutic strategies for fighting obesity and metabolic syndrome. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21741267 [PubMed - indexed for MEDLINE] 707. Curr HIV/AIDS Rep. 2011 Sep;8(3):200-8. doi: 10.1007/s11904-011-0087-3. Management of fat accumulation in patients with HIV infection. Falutz J(1). Author information: (1)Immunodeficiency Treatment Center, McGill University Health Center, Montreal, Quebec, Canada. julian.falutz@muhc.mcgill.ca Erratum in Curr HIV/AIDS Rep. 2011 Dec;8(4):297-9. The use of antiretroviral therapies has improved survival in people living with HIV to nearly normal rates. However, ongoing low-level HIV replication and incomplete immune recovery are associated with a chronic inflammatory stimulus. This increases several non-typically AIDS-related complications, including fat mass changes and metabolic conditions. Abdominal adiposity occurs as a result of complex interactions involving HIV itself, antiretroviral drug-associated factors, and several intermediary metabolic alterations and abnormal hormone levels. Abdominal adiposity in turn can further the metabolic derangements, and increase the risk of diabetes and cardiovascular disease. Abnormal growth hormone secretion plays a role in development of the fat depot changes. Effective long-term interventions to decrease central adiposity are limited but studies using growth hormone and especially growth hormone-releasing factor have shown encouraging results. Other emerging therapeutic options have been variably successful in the short term and the continuing clinical and therapeutic challenges will require ongoing investigation. PMID: 21739217 [PubMed - indexed for MEDLINE] 708. Mol Med. 2011;17(11-12):1397-410. doi: 10.2119/molmed.2010.00105. Epub 2011 Jul 5. Potential role of leptin, adiponectin and three novel adipokines--visfatin, chemerin and vaspin--in chronic hepatitis. Kukla M(1), Mazur W, Bułdak RJ, Zwirska-Korczala K. Author information: (1)Department of Physiology in Zabrze, Medical University of Silesia, Katowice, Poland. kuklamich@poczta.onet.pl Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Steatosis, independently of its metabolic or viral origin, leads to liver injury and fibrosis. It is suggested that hepatitis C virus may contribute to a wide spectrum of metabolic disturbances-namely, steatosis, insulin resistance, increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and lipid metabolism abnormalities. Adipokines, which are produced mainly by adipose tissue, may influence the inflammatory response and insulin sensitivity and contribute to the development of metabolic abnormalities in CHC and also regulate fibrogenesis and angiogenesis. Visfatin was described as an adipokine with immunomodulating and proinflammatory properties that promotes B-cell maturation and enhances activation of leukocytes, synthesis of adhesion molecules and production of proinflammatory cytokines. Visfatin exerts insulin-mimetic effects, decreases plasma glucose levels and regulates cell energy balance. Chemerin stimulates chemotaxis of dendritic cells, macrophages and natural killer (NK) cells toward the site of inflammation. On the other hand, it inhibits synthesis of proinflammatory mediators and enhances adiponectin production, influences adipocyte differentiation and maturation and regulates glucose uptake in adipocytes. Vaspin expression in human adipose tissue seems to be a compensatory mechanism associated with obesity and insulin resistance. Vaspin suppresses leptin, tumor necrosis factor (TNF)-α and resistin expression. Leptin protects against liver steatosis but accelerates fibrosis progression and exacerbates the inflammatory process. In contrast, adiponectin exerts a hepatoprotective effect. In this report, data indicating a possible role of these adipokines in the pathogenesis of chronic hepatitis are summarized. PMCID: PMC3321801 PMID: 21738955 [PubMed - indexed for MEDLINE] 709. J Atheroscler Thromb. 2011;18(8):629-39. Epub 2011 Jul 8. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. Matsuzawa Y(1), Funahashi T, Nakamura T. Author information: (1)Sumitomo Hospital, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Although abdominal obesity or visceral obesity is considered to be one of the components of metabolic syndrome and to have an important role in a cluster of cardiovascular risks, there is no consensus about the definition and diagnostic criteria for this syndrome, probably because there is considerable disagreement about the location and definition of abdominal obesity or visceral obesity.In this review article, the important role of visceral fat accumulation in the development of a variety of lifestyle-related diseases is shown, including cardiovascular disease based on our clinical studies using CT scans, and the mechanism of these disorders is discussed, focusing on adipocytokines, especially adiponectin.The importance of diagnosing metabolic syndrome, in which visceral fat accumulation plays an essential role in the development of multiple risk factors, should be emphasized because lifestyle modification for the reduction of visceral fat may be very effective for the reduction of risks of this type, namely metabolic syndrome in the narrow sense. PMID: 21737960 [PubMed - indexed for MEDLINE] 710. Biochim Biophys Acta. 2012 Mar;1821(3):345-57. doi: 10.1016/j.bbalip.2011.06.013. Epub 2011 Jun 28. Role of plasma phospholipid transfer protein in lipid and lipoprotein metabolism. Albers JJ(1), Vuletic S, Cheung MC. Author information: (1)Northwest Lipid Metabolism and Diabetes Research Laboratories, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, 401 Queen Anne Ave N, Seattle, WA 98109, USA. jja@uw.edu The understanding of the physiological and pathophysiological role of PLTP has greatly increased since the discovery of PLTP more than a quarter of century ago. A comprehensive review of PLTP is presented on the following topics: PLTP gene organization and structure; PLTP transfer properties; different forms of PLTP; characteristics of plasma PLTP complexes; relationship of plasma PLTP activity, mass and specific activity with lipoprotein and metabolic factors; role of PLTP in lipoprotein metabolism; PLTP and reverse cholesterol transport; insights from studies of PLTP variants; insights of PLTP from animal studies; PLTP and atherosclerosis; PLTP and signal transduction; PLTP in the brain; and PLTP in human disease. PLTP's central role in lipoprotein metabolism and lipid transport in the vascular compartment has been firmly established. However, more studies are needed to further delineate PLTP's functions in specific tissues, such as the lung, brain and adipose tissue. Furthermore, the specific role that PLTP plays in human diseases, such as atherosclerosis, cancer, or neurodegenerative disease, remains to be clarified. Exciting directions for future research include evaluation of PLTP's physiological relevance in intracellular lipid metabolism and signal transduction, which undoubtedly will advance our knowledge of PLTP functions in health and disease. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). Copyright © 2011 Elsevier B.V. All rights reserved. PMCID: PMC3192936 PMID: 21736953 [PubMed - indexed for MEDLINE] 711. World J Gastroenterol. 2011 Jun 21;17(23):2801-11. doi: 10.3748/wjg.v17.i23.2801. Adiponectin, a key adipokine in obesity related liver diseases. Buechler C(1), Wanninger J, Neumeier M. Author information: (1)Department of Internal Medicine I, University Hospital of Regensburg, D-93042 Regensburg, Germany. christa.buechler@klinik.uni-regensburg.de Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), and progressive liver fibrosis is considered the most common liver disease in western countries. Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance. Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients. Besides liver biopsy no diagnostic tools to identify patients with NASH are available, and no effective treatment has been established. Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage, insulin resistance, and progressive liver damage. Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage. Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH. Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis. This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin. PMCID: PMC3120939 PMID: 21734787 [PubMed - indexed for MEDLINE] 712. Curr Opin Lipidol. 2011 Aug;22(4):302-7. doi: 10.1097/MOL.0b013e3283488c39. Serum amyloid A in atherosclerosis. King VL(1), Thompson J, Tannock LR. Author information: (1)Division of Cardiovascular Medicine, Lexington, Kentucky, USA. Lisa.Tannock@uky.edu PURPOSE OF REVIEW: Serum amyloid A (SAA) is a family of acute-phase proteins which are shown to correlate with cardiovascular disease, but whether this SAA contributes causally to atherosclerosis development or reflects underlying disease or risk factors remains unclear. RECENT FINDINGS: SAA has been detected within atherosclerotic lesions and within adipose tissue where it is hypothesized that it may play a contributory role in disease development. In the acute-phase response SAA is synthesized by the liver and transported primarily in association with HDL. However, there is a growing literature suggesting that localized synthesis of SAA within the vasculature, or adipose tissue, may play a distinct role in disease development. Furthermore, SAA can be found in association with apoB-containing lipoproteins, in which its biological activity may be different. SUMMARY: This review will discuss recent experimental evidence supporting a causal role of SAA with atherosclerosis. PMID: 21734573 [PubMed - indexed for MEDLINE] 713. Curr Opin Urol. 2011 Sep;21(5):356-61. doi: 10.1097/MOU.0b013e32834962d5. BMI and the risk of renal cell carcinoma. McGuire BB(1), Fitzpatrick JM. Author information: (1)The Mater Misericordiae University Hospital, Dublin, Ireland. PURPOSE OF REVIEW: Incidence of obesity and renal cell carcinoma (RCC) are increasing, and RCC remains a lethal disease if not identified at an early stage. There is an increasing body of evidence linking obesity to the risk of developing RCC. RECENT FINDINGS: There is a wealth of epidemiological evidence supporting a higher risk of developing RCC in obese individuals, and in a dose-response manner. This is particularly pertinent in the development of the clear cell subtype (ccRCC), in which there appears to be a special interplay between ccRCC, obesity and von Hippel-Lindau (VHL) gene defects, driving the proangiogenic/proliferative pathway as a result of metabolites produced by adipose tissue, the epigenetic silencing of a tumour suppressor in close proximity to the VHL gene, hypoxia, obesity-related hypertension, lipid peroxidation and increased insulin-like growth factor-1. SUMMARY: Obesity-related diseases, including cancers, are increasing. There are many complex biomolecular pathways interacting in obesity, especially in ccRCC in which there appears to be a specific interplay in VHL mutations. PMID: 21730854 [PubMed - indexed for MEDLINE] 714. Clin Sci (Lond). 2011 Aug;121(3):91-106. doi: 10.1042/CS20100520. The forgotten face of regular physical exercise: a 'natural' anti-atherogenic activity. Szostak J(1), Laurant P. Author information: (1)Service de Médecine Vasculaire, Département de Médecine Interne, Centre hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland. Humans are not programmed to be inactive. The combination of both accelerated sedentary lifestyle and constant food availability disturbs ancient metabolic processes leading to excessive storage of energy in tissue, dyslipidaemia and insulin resistance. As a consequence, the prevalence of Type 2 diabetes, obesity and the metabolic syndrome has increased significantly over the last 30 years. A low level of physical activity and decreased daily energy expenditure contribute to the increased risk of cardiovascular morbidity and mortality following atherosclerotic vascular damage. Physical inactivity leads to the accumulation of visceral fat and consequently the activation of the oxidative stress/inflammation cascade, which promotes the development of atherosclerosis. Considering physical activity as a 'natural' programmed state, it is assumed that it possesses atheroprotective properties. Exercise prevents plaque development and induces the regression of coronary stenosis. Furthermore, experimental studies have revealed that exercise prevents the conversion of plaques into a vulnerable phenotype, thus preventing the appearance of fatal lesions. Exercise promotes atheroprotection possibly by reducing or preventing oxidative stress and inflammation through at least two distinct pathways. Exercise, through laminar shear stress activation, down-regulates endothelial AT1R (angiotensin II type 1 receptor) expression, leading to decreases in NADPH oxidase activity and superoxide anion production, which in turn decreases ROS (reactive oxygen species) generation, and preserves endothelial NO bioavailability and its protective anti-atherogenic effects. Contracting skeletal muscle now emerges as a new organ that releases anti-inflammatory cytokines, such as IL-6 (interleukin-6). IL-6 inhibits TNF-α (tumour necrosis factor-α) production in adipose tissue and macrophages. The down-regulation of TNF-α induced by skeletal-muscle-derived IL-6 may also participate in mediating the atheroprotective effect of physical activity. PMID: 21729002 [PubMed - indexed for MEDLINE] 715. Gen Comp Endocrinol. 2011 Sep 1;173(2):227-47. doi: 10.1016/j.ygcen.2011.06.014. Epub 2011 Jun 25. New insights into the signaling system and function of insulin in fish. Caruso MA(1), Sheridan MA. Author information: (1)Department of Biological Sciences, North Dakota State University, Fargo, ND 58108, USA. Fish have provided essential information about the structure, biosynthesis, evolution, and function of insulin (INS) as well as about the structure, evolution, and mechanism of action of insulin receptors (IR). INS, insulin-like growth factor (IGF)-1, and IGF-2 share a common ancestor; INS and a single IGF occur in Agnathans, whereas INS and distinct IGF-1 and IGF-2s appear in Chondrichthyes. Some but not all teleost fish possess multiple INS genes, but it is not clear if they arose from a common gene duplication event or from multiple separate gene duplications. INS is produced by the endocrine pancreas of fish as well as by several other tissues, including brain, pituitary, gastrointestinal tract, and adipose tissue. INS regulates various aspects of feeding, growth, development, and intermediary metabolism in fish. The actions of INS are mediated through the insulin receptor (IR), a member of the receptor tyrosine kinase family. IRs are widely distributed in peripheral tissues of fish, and multiple IR subtypes that derive from distinct mRNAs have been described. The IRs of fish link to several cellular effector systems, including the ERK and IRS-PI3k-Akt pathways. The diverse effects of INS can be modulated by altering the production and release of INS as well as by adjusting the production/surface expression of IR. The diverse actions of INS in fish as well as the diverse nature of the neural, hormonal, and environmental factors known to affect the INS signaling system reflects the various life history patterns that have evolved to enable fish to occupy a wide range of aquatic habitats. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21726560 [PubMed - indexed for MEDLINE] 716. Hormones (Athens). 2011 Apr-Jun;10(2):104-16. Menstrual function in sports. Roupas ND(1), Georgopoulos NA. Author information: (1)Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Patras University Medical School, Patras, Greece. OBJECTIVE: To highlight the recent developments in the field of menstrual function in sports and to provide an overview of our current understanding in regard to the pathophysiology, evaluation and management strategies of exercise-related reproductive dysfunction. DESIGN: A PUBMED search was carried out and all articles published from 1980 to 2010 with title words related to exercise, athletes, menstrual function and primary and secondary amenorrhea were reviewed. The review structure includes a pathophysiology overview, menstrual dysfunction among different athletic disciplines, clinical manifestations, evaluation and management strategies, with particular emphasis on recent data regarding the use of oral contraceptives and hormone replacement therapy. RESULTS AND CONCLUSION: Exercise-related reproductive dysfunction appears to be multifactorial in origin and remains a diagnosis of exclusion. Recent findings underscore the endocrine role of adipose tissue in the regulation of metabolism and reproduction, providing further data on our understanding of the pathophysiology of exercise-related reproductive dysfunction. Clinical manifestations range from primary amenorrhea or delayed menarche to luteal phase deficiency, oligomenorrhea, anovulation and secondary amenorrhea. Amenorrhea constitutes the most serious clinical consequence and is associated with bone pathology. Early diagnosis, thorough evaluation and individualized management (ranging from diet and exercise, or behavior adjustments to pharmacologic treatment) should be achieved in order to preserve bone mass. PMID: 21724535 [PubMed - indexed for MEDLINE] 717. Semin Immunol. 2011 Dec;23(6):431-7. doi: 10.1016/j.smim.2011.06.002. Epub 2011 Jul 2. Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Cipolletta D(1), Kolodin D, Benoist C, Mathis D. Author information: (1)Department of Pathology, Harvard Medical School, Boston, MA 02115, United States. Foxp3+CD4+ regulatory T (T(reg)) cells are a key population in controlling the immune response. Recently, their roles have been expanded to broader, non-immune, contexts, in particular the metabolic consequences downstream of obesity-induced inflammation, e.g. type-2 diabetes and cardiovascular disease. This review highlights the major innate and adaptive immune cell subsets contributing to adipose-tissue inflammation, the key role played by fat-resident T(regs), and the potential of T(reg)-based therapies for treatment of the metabolic syndrome. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21724410 [PubMed - indexed for MEDLINE] 718. J Steroid Biochem Mol Biol. 2012 Jul;130(3-5):159-68. doi: 10.1016/j.jsbmb.2011.06.009. Epub 2011 Jun 23. Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis. Fitzsimmons RL(1), Lau P, Muscat GE. Author information: (1)Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, Services Rd St. Lucia, Queensland, 4072 Australia. Many nuclear hormone receptors (NRs) control lipid, glucose and energy homeostasis in an organ specific manner. Concordantly, dysfunctional NR signalling results in metabolic disease. The Retinoic acid receptor-related orphan receptor alpha (RORα), a member of the NR1F subgroup, is expressed in metabolic tissues. Previous studies identified the role of this NR in dyslipidemia, apo-lipoprotein metabolism and atherosclerosis. Recent data is underscoring the significant role of this orphan NR in the regulation of phase I/II metabolism (bile acids, xenobiotics, steroids etc.), adiposity, insulin signalling, and glucose tolerance. Moreover, oxygenated sterols, have been demonstrated to function as native ligands and inverse agonists. This review focuses on the rapidly emerging and evolving role of RORα in the control of lipid and glucose homeostasis in major mass metabolic tissues. Article from the special issue orphan receptors. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21723946 [PubMed - indexed for MEDLINE] 719. Acta Diabetol. 2012 Apr;49(2):89-95. doi: 10.1007/s00592-011-0309-6. Epub 2011 Jul 1. Metabolic syndrome: its history, mechanisms, and limitations. Oda E(1). Author information: (1)Medical Check-up Center, Tachikawa Medical Center, Nagachou, Nagaoka, Niigata, Japan. ijie@venus.sannet.ne.jp In late twentieth century, Ruderman and Reaven showed that insulin resistance might be fundamental to metabolic syndrome (MetS) which means a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 2001, user-friendly National Cholesterol Education Program (NCEP) criteria of MetS were proposed. In 2005, the International Diabetes Federation (IDF) and the Examination Committee for Criteria of Metabolic Syndrome in Japan issued different criteria of MetS where abdominal obesity is a necessary component. In 2009, IDF, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity jointly adopted the revised NCEP criteria, where abdominal obesity is not a necessary component, as worldwide criteria of MetS. In 2010, WHO Expert Consultation warned that MetS is a concept that focuses attention on complex multifactorial health problems but has limited practical utility as a management tool. In animal studies, adipose tissue inflammation characterized by an increased number of crown-like structures in adipose tissue, rather than obesity per se, was shown to be a fundamental mechanism of metabolic derangements. PMID: 21720880 [PubMed - indexed for MEDLINE] 720. J Endocrinol Invest. 2011 Nov;34(10):793-800. doi: 10.3275/7808. Epub 2011 Jun 27. Chronic sleep deprivation and seasonality: implications for the obesity epidemic. Cizza G(1), Requena M, Galli G, de Jonge L. Author information: (1)Section on Neuroendocrinology of Obesity, NIDDK, Bethesda, MD, USA. cizzag@intra.niddk.nih.gov Sleep duration has progressively fallen over the last 100 years while obesity has increased in the past 30 years. Several studies have reported an association between chronic sleep deprivation and long-term weight gain. Increased energy intake due to sleep loss has been listed as the main mechanism. The consequences of chronic sleep deprivation on energy expenditure have not been fully explored. Sleep, body weight, mood and behavior are subjected to circannual changes. However, in our modern environment seasonal changes in light and ambient temperature are attenuated. Seasonality, defined as cyclic changes in mood and behavior, is a stable personality trait with a strong genetic component. We hypothesize that the attenuation in seasonal changes in the environment may produce negative consequences, especially in individuals more predisposed to seasonality, such as women. Seasonal affective disorder, a condition more common in women and characterized by depressed mood, hypersomnia, weight gain, and carbohydrate craving during the winter, represents an extreme example of seasonality. One of the postulated functions of sleep is energy preservation. Hibernation, a phenomenon characterized by decreased energy expenditure and changes in the state of arousal, may offer useful insight into the mechanisms behind energy preservation during sleep. The goals of this article are to: a) consider the contribution of changes in energy expenditure to the weight gain due to sleep loss; b) review the phenomena of seasonality, hibernation, and their neuroendocrine mechanisms as they relate to sleep, energy expenditure, and body weight regulation. PMCID: PMC3297412 PMID: 21720205 [PubMed - indexed for MEDLINE] 721. J Hepatol. 2011 Oct;55(4):920-32. doi: 10.1016/j.jhep.2011.05.008. Epub 2011 Jun 28. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. Dongiovanni P(1), Fracanzani AL, Fargion S, Valenti L. Author information: (1)Department of Internal Medicine, Centro Malattie Metaboliche del Fegato, Università degli Studi di Milano, and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage. Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. PMID: 21718726 [PubMed - indexed for MEDLINE] 722. S D Med. 2011;Spec No:18-21. Dysfunctional hormonal regulation of metabolism in obesity. Eyster KM(1). Author information: (1)Sanford School of Medicine, University of South Dakota, USA. A complex network of hormones from the pancreas, adipose tissue, stomach, intestines and the central nervous system coordinates regulation of metabolism and energy balance. Obesity disrupts this regulatory network. This paper reviews the anorexigenic and orexigenic hormones and their dysfunctional regulation in obesity. PMID: 21717812 [PubMed - indexed for MEDLINE] 723. Endokrynol Pol. 2011;62(3):258-62. The role of leptin in the regulation of carbohydrate metabolism. Tucholski K(1), Otto-Buczkowska E. Author information: (1)Diabetes Clinic, Child and Mother’s Health Centre, Katowice, Poland. The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described as acting on the satiety centre in the hypothalamus through specific receptors (ob-R) to restrict food intake and enhance energy expenditure. Leptin plays a crucial role in the maintenance of body weight and glucose homeostasis hrough central and peripheral pathways, including regulation of insulin secretion by pancreatic b cells. Leptin may also directly affect the metabolism and function of peripheral tissues. Leptin has been implicated in causing peripheral insulin resistance by attenuating insulin action, and perhaps insulin signalling, in various insulin-responsive cell types. Research has demonstrated a significant relationship between leptin and insulin, but the mechanisms underlying the changes of leptin induced by insulin, and vice versa, remain to be studied in more detail. Recent data provides convincing evidence that leptin has beneficial effects on glucose homeostasis in mouse models of insulin-deficient type 1 diabetes mellitus. Our study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic properties of leptin as an anti-diabetic agent. Safety evaluation should include a careful assessment of the effects of this combination therapy on the counterregulatory response to hypoglycaemia. The role of leptin in alpha-cell function has not been studied in detail. Extensive studies will be needed to determine the long-term safety and efficacy of this therapy. PMID: 21717410 [PubMed - indexed for MEDLINE] 724. Rev Endocr Metab Disord. 2011 Sep;12(3):235-43. doi: 10.1007/s11154-011-9190-4. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Scherer T(1), Buettner C. Author information: (1)Department of Medicine and Department of Neuroscience, Mount Sinai School of Medicine, NY, 10029-6574, USA. Fatty acids released from white adipose tissue (WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes. PMCID: PMC3253350 PMID: 21713385 [PubMed - indexed for MEDLINE] 725. Cardiovasc J Afr. 2011 May-Jun;22(3):147-54. Once fat was fat and that was that: our changing perspectives on adipose tissue. Ferris WF(1), Crowther NJ. Author information: (1)Division of Endocrinology, Department of Medicine, Faculty of Health Sciences, University of Stellenbosch, Stellenbosch, South Africa. wferris@sun.ac.za Past civilisations saw excess body fat as a symbol of wealth and prosperity as the general population struggled with food shortages and famine. Nowadays it is recognised that obesity is associated with co-morbidities such as cardiovascular disease and diabetes. Our views on the roll of adipose tissue have also changed, from being solely a passive energy store, to an important endocrine organ that modulates metabolism, immunity and satiety. The relationship between increased visceral adiposity and obesity-related co-morbidities has lead to the recognition that variation in fat distribution contributes to ethnic differences in the prevalence of obesity-related diseases. Our current negative view of adipose tissue may change with the use of pluripotent adipose-derived stromal cells, which may lead to future autologous stem cell therapies for bone, muscle, cardiac and cartilage disorders. Here, we briefly review the concepts that adipose tissue is an endocrine organ, that differences in body fat distribution underline the aetiology of obesity-related co-morbidities, and the use of adipose-derived stem cells for future therapies. PMCID: PMC3721932 PMID: 21713306 [PubMed - indexed for MEDLINE] 726. Endocrinology. 2011 Sep;152(9):3306-11. doi: 10.1210/en.2011-1104. Epub 2011 Jun 28. Minireview: cracking the metabolic code for thyroid hormone signaling. Bianco AC(1). Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, 1400 North West 10th Avenue, Suite 816, Miami, Florida 33136, USA. abianco@deiodinase.org Cells are not passive bystanders in the process of hormonal signaling and instead can actively customize hormonal action. Thyroid hormone gains access to the intracellular environment via membrane transporters, and while diffusing from the plasma membrane to the nucleus, thyroid hormone signaling is modified via the action of the deiodinases. Although the type 2 deiodinase (D2) converts the prohormone T(4) to the biologically active T(3), the type 3 deiodinase (D3) converts it to reverse T(3), an inactive metabolite. D3 also inactivates T(3) to T(2), terminating thyroid hormone action. Therefore, D2 confers cells with the capacity to produce extra amounts of T(3) and thus enhances thyroid hormone signaling. In contrast expression of D3 results in the opposite action. The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development, childhood, and adult life. In addition, the D2 protein is unique in that it can be switched off and on via an ubiquitin regulated mechanism, triggered by catalysis of T(4). Induction of D2 enhances local thyroid hormone signaling and energy expenditure during activation of brown adipose tissue by cold exposure or high-fat diet. On the other hand, induction of D3 in myocardium and brain during ischemia and hypoxia decreases energy expenditure as part of a homeostatic mechanism to slow down cell metabolism in the face of limited O(2) supply. PMCID: PMC3159779 PMID: 21712363 [PubMed - indexed for MEDLINE] 727. Orv Hetil. 2011 Jul 17;152(29):1156-60. doi: 10.1556/OH.2011.29147. [Diabetes and bone metabolism]. [Article in Hungarian] Ruzicska E(1), Poór G. Author information: (1)Országos Reumatológiai és Fizioterápiás Intézet Budapest Frankel Leó út 38-40. 1023. evaruzicska@gmail.com In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic β-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures. PMID: 21712180 [PubMed - indexed for MEDLINE] 728. Lege Artis Med. 2011 Feb;21(2):105-11. [Anti-atherosclerotic effect of pioglitazone--the first evidence of the role of triglyceride/HDL ratio]. [Article in Hungarian] Császár A(1). Author information: (1)Honvédkórház-Allami Egészségügyi Központ, II. Belgyógyászati Osztály, Budapest/Military Hospital, State Health Centre, 2nd Department of Medicine. The presence of multiple risk factors can multiply exponentially the risk of cardiovascular events, thus cardiovascular diseases are more severe in diabetes mellitus. One of the challenges we face today is the application of drugs that, besides improving glucose homeostasis, also have antiatherosclerotic effect. Such candidates are glitazones, which have pleiotropic efficiency beyond their main effect: they improve distribution of adipose tissue, blood pressure and endothelial function and also have anti-inflammatory and anti-coagulation capacity. Regarding the effects on lipid metabolism, there are differences between various glitazones: improvements are mainly achieved by pioglitazone, which markedly reduces triglyceride levels, and also elevates HDL levels and decreases the ratio of small, dense LDL-particles. Studies on clinical outcomes also show the superiority of pioglitazone. Imaging of blood vessels (carotis-IMT, intracoronary ultrasound technique) also suggest a greater efficiency of pioglitazone. According to the latest analysis of the PERISCOPE study, the stability of the coronary plaque was associated only with the triglyceride/ HDL ratio in case of pioglitazone. The newest data also revealed that pioglitazone uniquely increases the cholesterol-efflux attributed to HDL-related macrophages. On the basis of the latest results, pioglitazone not only improves glucose homeostasis, but also has a remarkable anti-atherosclerotic effect, which is primarily due to its favourable lipid metabolism profile. PMID: 21710708 [PubMed - indexed for MEDLINE] 729. Semin Reprod Med. 2011 May;29(3):237-45. doi: 10.1055/s-0031-1275517. Epub 2011 Jun 27. Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet. Desai M(1), Ross MG. Author information: (1)Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. mdesai@obgyn.humc.edu A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target-specific modalities that depend on the primary etiology. © Thieme Medical Publishers. PMCID: PMC4010300 PMID: 21710399 [PubMed - indexed for MEDLINE] 730. Diabetes. 2011 Jul;60(7):1825-31. doi: 10.2337/db11-0171. MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Fernandez-Valverde SL(1), Taft RJ, Mattick JS. Author information: (1)Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia. Comment on Diabetes. 2011 Jul;60(7):1832-7. PMCID: PMC3121441 PMID: 21709277 [PubMed - indexed for MEDLINE] 731. Lancet. 2011 Jul 9;378(9786):169-81. doi: 10.1016/S0140-6736(11)60614-4. Epub 2011 Jun 24. Type 2 diabetes across generations: from pathophysiology to prevention and management. Nolan CJ(1), Damm P, Prentki M. Author information: (1)Department of Endocrinology, Canberra Hospital and Australian National University Medical School, Canberra, ACT, Australia. christopher.nolan@anu.edu.au Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21705072 [PubMed - indexed for MEDLINE] 732. World Neurosurg. 2011 May-Jun;75(5-6):692-5. doi: 10.1016/j.wneu.2011.01.023. Sequelae of autologous fat graft used for reconstruction in skull base surgery. Taha AN(1), Almefty R, Pravdenkova S, Al-Mefty O. Author information: (1)Department of Neurosurgery, Mansoura University Hospital, Mansoura-Dakhlia, Egypt. BACKGROUND: The use of an autologous free fat graft is a widely applied technique to obliterate dead space and reinforce dural closure during skull base reconstructions. The associated complications and outcomes of this practice have not been studied. Dissemination of fat in the subarachnoid space resulting in lipoid meningitis has been reported after translabyrinthine approaches, and leakage of liquefied fat is seldom reported in the literature. This study aims to evaluate the morbidity associated with the usage of autologous fat graft in reconstruction of skull base defects based on an extensive experience. METHODS: This study is a retrospective review of 1581 cases in which the senior author (O.A.) used a skull base approach for the resection of tumor. Autologous fat grafts were used for reconstruction in 974 cases and 10 cases (male to female ratio, 4:6) in which there were associated complications were analyzed. RESULTS: Complications included leakage of sterile liquefied fat from fistula (patients 1, 2, 3), delayed cerebrospinal fluid leak after radiation (Patients 5, 6, 9), and postoperative lipoid meningitis (Patients 4, 7, 8, 10). The onset ranged from 11 days to 10 years. Four patients were managed conservatively, and the other six required surgical intervention. All patients had good outcomes after treatment. CONCLUSIONS: The use of autologous fat is associated with a 1% complication rate and should be considered a safe and effective method for skull base reconstruction. However, neurosurgeons should be aware of early and late complications of fat necrosis, including sterile liquefied fat fistula, cerebrospinal fluid leakage, and lipoid meningitis. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21704937 [PubMed - indexed for MEDLINE] 733. Biochim Biophys Acta. 2012 Jan;1821(1):190-7. doi: 10.1016/j.bbalip.2011.06.004. Epub 2011 Jun 13. The contribution of vitamin A to autocrine regulation of fat depots. Yasmeen R(1), Jeyakumar SM, Reichert B, Yang F, Ziouzenkova O. Author information: (1)Department of Human Nutrition, Ohio State University, Columbus, OH 43210, USA. Morbidity and mortality associated with increased white fat accumulation in visceral fat depots have focused attention on the pathways regulating the development of this tissue during embryogenesis, in adulthood, and while under the influence of obesogenic diets. Adipocytes undergo clonal expansion, differentiation (adipogenesis) and maturation through a complex network of transcriptional factors, most of which are expressed at similar levels in visceral and subcutaneous fat. Rigorous research attempts to unfold the pathways regulating expression and activity of adipogenic transcription factors that act in a fat-depot-specific manner. Peroxisome proliferator-activated receptor-γ (PPARγ) is the master regulator of adipogenesis, and is expressed at higher levels in subcutaneous than in visceral depots. PPARγ expression in adipogenesis is mediated by CCAAT/enhancer binding proteins (C/EBPs) and several transcription factors acting in conjunction with C/EBPs, although alternative pathways through zinc-finger protein-423 (ZFP423) transcription factor are sufficient to induce PPARγ expression and adipogenesis. Vitamin A and its metabolites, retinaldehyde and retinoic acid, are transcriptionally-active molecules. Retinoic acid is generated from retinaldehyde in adipose tissue by the aldehyde dehydrogenase-1 family of enzymes (Aldh1). In this review, we discuss the role of Aldh1 enzymes in the generation of retinoic acid during adipogenesis, in the regulation of the transcriptional network of PPARγ in a fat-depot-specific manner, and the important contribution of this autocrine pathway in the development of visceral obesity. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. Published by Elsevier B.V. PMCID: PMC3196743 PMID: 21704731 [PubMed - indexed for MEDLINE] 734. Obes Facts. 2011;4(3):229-37. doi: 10.1159/000329450. Epub 2011 Jun 6. The correlates and treatment of obesity in military populations: a systematic review. Sanderson PW(1), Clemes SA, Biddle SJ. Author information: (1)School of Sport, Exercise and Health Sciences, Loughborough University, UK. P.W.Sanderson@lboro.ac.uk OBJECTIVE: The emergence of obesity as a distinct disease could have far reaching consequences for an organisation where optimum health and physical fitness are required for personnel to perform their occupational roles effectively. The objectives of this paper are to systematically review the literature concerning correlates and treatment of obesity in military populations. METHODS: Through computerised searches of English language studies, 17 papers were identified (treatment (13), correlates (4)). RESULTS: Successful treatment interventions incorporated exercise, healthy eating information, behavioural modification, self-monitoring, relapse prevention, and structured follow-up and were supported by trained personnel. Efficacy due to physical activity was underreported. Reduction in body fat rather than body weight was the most significant outcome. The major significant correlates of obesity were being enlisted personnel, male, ≥35 years of age, African-American/Hispanic ethnicity, and married (with spouse present). CONCLUSION: This systematic review highlights the deficit in knowledge concerning treatment and the lack of engagement in relation to the specific correlates of obesity in military populations. Copyright © 2011 S. Karger AG, Basel. PMID: 21701240 [PubMed - indexed for MEDLINE] 735. Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S43-52. doi: 10.1089/dia.2011.0039. Optimizing the replacement of basal insulin in type 1 diabetes mellitus: no longer an elusive goal in the post-NPH era. Bolli GB(1), Andreoli AM, Lucidi P. Author information: (1)Section of Internal Medicine, Endocrinology and Metabolism, Department of Internal Medicine, University of Perugia, Perugia, Italy. bolli@unipg.it In physiology, insulin is released continuously by the pancreas at a nearly constant rate between meals and in the fasting state (basal insulin secretion). The pivotal role of basal insulin is to restrain release of glucose from the liver and free fatty acids from adipose tissue, thus preventing hyperglycemia and ketosis. In type 1 diabetes mellitus (T1DM) (absolute insulin deficiency), the replacement of basal insulin is challenging because the currently available pharmacological preparations of long-acting insulin do not exactly reproduce the fine physiology of flat action profile of basal insulin of subjects without diabetes. NPH and NPH-based insulin mixtures no longer have a place in the treatment of T1DM because of their early peak effects and relatively short duration of action, which result into risk of nocturnal hypoglycemia and fasting hyperglycemia, respectively, after the evening injection. Only continuous subcutaneous (s.c.) insulin infusion (CSII) or long-acting analogs such as glargine (>24 h in duration, once a day) and detemir (<24 h in duration, once or more often twice a day) should be used as basal insulin in T1DM in combination with mealtime rapid-acting analogs. CSII and the long-acting analogs are nearly peakless and therefore reduce the risk for hypoglycemia (especially at night), blood glucose (BG) variability, and lower A1C with similar or less hypoglycemia. CSII is the "gold standard" of replacement of basal insulin because of better reproducibility of subcutaneous absorption of soluble insulin. Although CSII is not superior to multiple daily insulin injections in the general T1DM population, CSII might be indicated in subsets of T1DM (long-term T1DM with insulin "supersensitivity" and needs for low-dose insulin, some individuals with variable subcutaneous absorption of long-acting analogs) to minimize BG variability, reduce hypoglycemia, and benefit A1C. PMID: 21668336 [PubMed - indexed for MEDLINE] 736. Exerc Sport Sci Rev. 2011 Oct;39(4):187-90. doi: 10.1097/JES.0b013e31822673f0. Pigment epithelium-derived factor: a not so sympathetic regulator of insulin resistance? Bell C(1). Author information: (1)Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA. christopher.bell@colostate.edu Pigment epithelium-derived factor (PEDF), an adipokine, is a regulator of oxidative stress, inflammation, angiogenesis, and insulin sensitivity. Contrary to animal and cell culture data, inhibition of the sympathoadrenal system does not affect serum PEDF in humans. However, during acute beta-adrenergic receptor stimulation serum PEDF concentration is decreased. PEDF may be involved in cross talk between adipose tissue and skeletal muscle. PMID: 21697716 [PubMed - indexed for MEDLINE] 737. Int J Obes (Lond). 2012 Mar;36(3):387-96. doi: 10.1038/ijo.2011.119. Epub 2011 Jun 21. The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Earthman CP(1), Beckman LM, Masodkar K, Sibley SD. Author information: (1)Department of Food Science and Nutrition, University of Minnesota, Saint Paul, MN 55108, USA. cearthma@umn.edu Obesity and vitamin D deficiency have both been recognized as major public health issues worldwide, and there is growing evidence that they are related, although the cause-effect relationship remains unclear. Could obesity be contributing to low circulating 25-hydroxyvitamin D concentrations? Alternatively, could low vitamin D status predispose to obesity? In this review, the relationship between low circulating 25-hydroxyvitamin D and obesity, and possible underlying reasons from both perspectives, is presented. One potential mechanism by which obesity could contribute to low serum 25-hydroxyvitamin D is adipose sequestration of vitamin D. On the other hand, adipose tissue has both the vitamin D receptor and the ability to synthesize 1,25-dihydroxyvitamin D, and there is evidence that vitamin D may regulate adipose tissue mass, differentiation and metabolism in ways that might contribute to obesity. Of particular interest, vitamin D deficiency is common both before and after bariatric surgery, and is often difficult to treat, particularly with the more malabsorptive procedures. Additional research is needed to elucidate the complex and multifaceted factors underlying the association between low circulating 25-hydroxyvitamin D and obesity, and to identify optimal treatment approaches in obese individuals and in bariatric surgical patients both before and after surgery. PMID: 21694701 [PubMed - indexed for MEDLINE] 738. Reprod Biol Endocrinol. 2011 Jun 21;9:91. doi: 10.1186/1477-7827-9-91. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters. Khan SI(1), Zhao J, Khan IA, Walker LA, Dasmahapatra AK. Author information: (1)National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone-dependent breast cancer. PMCID: PMC3142499 PMID: 21693041 [PubMed - indexed for MEDLINE] 739. Acta Med Croatica. 2010 Oct;64(4):253-62. [Adipocytokines as mediators of metabolic role of adipose tissue]. [Article in Croatian] Pandzić Jaksić V(1). Author information: (1)Odjel za endokrinologiju, Klinicka bolnica Dubrava, Zagreb, Hrvatska. vpandzic@kbd.hr The discovery of adipocytokines, products of adipose tissue, has been a turning point in the understanding of metabolic disorders. Historically considered as a passive depot of energy, adipose tissue has become an important active participant and adipocytokines crucial mediators of its metabolic role. Among a number of adipose tissue products, leptin and adiponectin are exclusively secreted by adipocytes. Leptin regulates energy homeostasis and interferes with several neuroendocrine and immune functions. Adiponectin is an intriguing adipocytokine with its serum level inversely correlated with fatness. It has been related to enhanced insulin sensitivity, anti-inflammatory and anti-atherogenic actions. Recent investigations have also emphasized the important role of resistin, visfatin, retinol binding protein 4, and of a whole list of cytokines like interleukin-6, tumor necrosis factor a, plasminogen activator inhibitor-1, or a chemokine, monocyte chemoattractant protein-1. The fact that secretory balance of adipose tissue in obesity is shifted towards the proinflammatory spectrum has supported the hypothesis on the development of dysfunctional adipose tissue in these circumstances. It contributes to the state of chronic inflammation and insulin resistance, and it seems to be a fundamental link between obesity and atherosclerosis. PMID: 21688608 [PubMed - indexed for MEDLINE] 740. Int J Mol Sci. 2011;12(5):3117-32. doi: 10.3390/ijms12053117. Epub 2011 May 13. Inflammation, oxidative stress, and obesity. Fernández-Sánchez A(1), Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA. Author information: (1)Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Ex-Hacienda de la Concepción, Tilcuautla, 42080 Pachuca de Soto, Hgo, Mexico; E-Mails: alba_mfs@hotmail.com (A.F.-S.); eomsmx@yahoo.com.mx (E.M.-S.); mirandeli@hotmail.com (M.B.); m.valadezvega@lycos.com (C.V.-V.). Obesity is a chronic disease of multifactorial origin and can be defined as an increase in the accumulation of body fat. Adipose tissue is not only a triglyceride storage organ, but studies have shown the role of white adipose tissue as a producer of certain bioactive substances called adipokines. Among adipokines, we find some inflammatory functions, such as Interleukin-6 (IL-6); other adipokines entail the functions of regulating food intake, therefore exerting a direct effect on weight control. This is the case of leptin, which acts on the limbic system by stimulating dopamine uptake, creating a feeling of fullness. However, these adipokines induce the production of reactive oxygen species (ROS), generating a process known as oxidative stress (OS). Because adipose tissue is the organ that secretes adipokines and these in turn generate ROS, adipose tissue is considered an independent factor for the generation of systemic OS. There are several mechanisms by which obesity produces OS. The first of these is the mitochondrial and peroxisomal oxidation of fatty acids, which can produce ROS in oxidation reactions, while another mechanism is over-consumption of oxygen, which generates free radicals in the mitochondrial respiratory chain that is found coupled with oxidative phosphorylation in mitochondria. Lipid-rich diets are also capable of generating ROS because they can alter oxygen metabolism. Upon the increase of adipose tissue, the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), was found to be significantly diminished. Finally, high ROS production and the decrease in antioxidant capacity leads to various abnormalities, among which we find endothelial dysfunction, which is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in endothelium-derived contractile factors, favoring atherosclerotic disease. PMCID: PMC3116179 PMID: 21686173 [PubMed - indexed for MEDLINE] 741. Postgrad Med. 2011 Jul;123(4):27-37. doi: 10.3810/pgm.2011.07.2301. Basal insulin: beyond glycemia. Niswender KD(1). Author information: (1)Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, TN 37232-0475, USA. Kevin.niswender@vanderbilt.edu Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome. PMID: 21680986 [PubMed - indexed for MEDLINE] 742. Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R581-600. doi: 10.1152/ajpregu.00755.2010. Epub 2011 Jun 15. Biology's response to dieting: the impetus for weight regain. Maclean PS(1), Bergouignan A, Cornier MA, Jackman MR. Author information: (1)University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, Center for Human Nutrition, Denver, Colorado, USA. paul.maclean@ucdenver.edu Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults. In this review, we summarize the evidence of biology's role in the problem of weight regain. Biology's impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented. Finally, a novel model is proposed to explain the persistence of the "energy depletion" signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter. PMCID: PMC3174765 PMID: 21677272 [PubMed - indexed for MEDLINE] 743. Curr Drug Targets. 2011 Sep;12(10):1498-512. Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit. Papaetis GS(1), Orphanidou D, Panagiotou TN. Author information: (1)Diabetes Clinic, Paphos, Cyprus. gpapaetis@yahoo.gr The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population. PMID: 21675944 [PubMed - indexed for MEDLINE] 744. Int J Obes (Lond). 2012 Apr;36(4):581-94. doi: 10.1038/ijo.2011.113. Epub 2011 Jun 14. Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models. Girousse A(1), Langin D. Author information: (1)Laboratoire de Recherche sur les Obésités, INSERM U1048-I2MC, Equipe 4, Toulouse, France. Adipose tissue lipolysis is the catabolic process whereby stored triacylglycerol (TAG) is broken down by lipases into fatty acids and glycerol. Here, we review recent insights from transgenic mouse models. Genetic manipulations affecting lipases are considered first, followed by transgenic models of lipase co-factors and lastly non-lipase lipid droplet (LD)-associated proteins. The central role of hormone-sensitive lipase (HSL), long considered to be the sole rate-limiting enzyme of TAG hydrolysis, has been revised since the discovery of adipose triglyceride lipase (ATGL). It is now accepted that ATGL initiates TAG breakdown producing diacylglycerol, which is subsequently hydrolyzed by HSL. Furthermore, lipase activities are modulated by co-factors whose deletion causes severe metabolic disturbances. Another major advance has come from the description of the involvement of non-lipase proteins in the regulation of lipolysis. The role of perilipins has been extensively investigated. Other newly discovered LD-associated proteins have also been shown to regulate lipolysis. PMID: 21673652 [PubMed - indexed for MEDLINE] 745. Phys Sportsmed. 2011 May;39(2):98-106. doi: 10.3810/psm.2011.05.1899. Exercise in the management of type 2 diabetes mellitus: what are the benefits and how does it work? Duclos M(1), Virally ML, Dejager S. Author information: (1)Department of Sports Medicine and Functional Explorations, University-Hospital, Hopital Gabriel Montpied, Clermont-Ferrand, France. In this article, we examine the results from meta-analyses of studies that have focused on the effects of supervised exercise in patients with established type 2 diabetes mellitus. Exercise has been clearly demonstrated to have benefits on blood glucose control (average reduction of glycated hemoglobin, 0.6%) and cardiovascular risk factors. These benefits are observed independently of any change in body mass index and fat mass, and are also seen in older populations. Multiple mechanisms are involved, and the improved insulin-sensitizing effect of exercise training is not restricted to muscle but extends to hepatic and adipose tissue. However, while the benefits of exercise in type 2 diabetes management are undisputable, it is not as easy to draw correlations between clinical benefit and the amount of physical activity included in daily life. Recent studies have shown encouraging results with moderate increases in physical activity, which are feasible for most patients and are sufficient to induce sustained positive changes for 2 years. Thus, the benefits of structured and supervised exercise in patients with type 2 diabetes have been consistently demonstrated. Currently, the primary challenge is to determine how long-term increased physical activity can be durably implemented in a patient's daily life. PMID: 21673489 [PubMed - indexed for MEDLINE] 746. Arch Physiol Biochem. 2011 Jul;117(3):177-87. doi: 10.3109/13813455.2011.584538. Mitochondrial pathophysiology and type 2 diabetes mellitus. Garcia-Roves PM(1). Author information: (1)Diabetes and Obesity Laboratory, Institute for Biomedical Research August Pi i Sunyer (IDIBAPS) and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain. pgarciar@clinic.ub.es Retraction in Arch Physiol Biochem. 2011 Dec;117(5):283. Over the last decades, substantial progress has been made in defining the molecular events and relevant tissues controlling insulin action and the potential defects that lead to insulin resistance and later on Type 2 diabetes mellitus (T2DM). Mitochondrial dysfunction has been postulated as a common mechanism implicated in the development of insulin resistance and T2DM aetiology. Since then there has been growing interest in this area of research and many studies have addressed whether mitochondrial function/dysfunction is implicated in the progression of T2DM or if it is just a consequence. Mitochondria are adjusted to the specific needs of the tissue and to the environmental interactions or pathophysiological state that it encounters. This review offers a current state of the subject in a tissue specific approach. We will focus our attention on skeletal muscle, liver, and white adipose tissue as the main insulin sensitive organs. Hypothalamic mitochondrial function will be also discussed. PMID: 21671709 [PubMed - indexed for MEDLINE] 747. Liver Transpl. 2011 Sep;17(9):993-1004. doi: 10.1002/lt.22358. Does adiponectin benefit steatotic liver transplantation? Elias-Miro M(1), Massip-Salcedo M, Jimenez-Castro M, Peralta C. Author information: (1)Esther Koplowitz Center, August Pi i Sunyer Institute for Biomedical Research, Barcelona, Spain. Strategies for improving the viability of steatotic donor livers could increase the number of organs suitable for transplantation. There is evidence that adiponectin, the most abundant adipose-specific adipokine, acts as an anti-obesity and anti-inflammatory hormone. Here we review the signaling pathways of adiponectin and the possible therapies based on adiponectin regulation that have been examined or applied clinically. Recent studies on the role of adiponectin in steatotic livers subjected to ischemia/reperfusion are discussed. The data suggest that further investigations are required to determine whether adiponectin is a potential therapeutic target in liver transplantation. Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21671349 [PubMed - indexed for MEDLINE] 748. Biochim Biophys Acta. 2012 Jan;1821(1):177-89. doi: 10.1016/j.bbalip.2011.06.001. Epub 2011 Jun 12. Lipid metabolism in mammalian tissues and its control by retinoic acid. Bonet ML(1), Ribot J, Palou A. Author information: (1)Molecular Biology, Nutrition and Biotechnology (Nutrigenomics), Universitat de les Illes Balears, Palma de Mallorca, Spain. Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved. PMID: 21669299 [PubMed - indexed for MEDLINE] 749. Drugs. 2011 May 28;71(8):1071-91. doi: 10.2165/11202240-000000000-00000. Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy. Dhillon S(1). Author information: (1)Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz Tesamorelin (Egrifta™) is a synthetic analogue of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral oedema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image. PMID: 21668043 [PubMed - indexed for MEDLINE] 750. Mol Cell Endocrinol. 2012 Feb 5;349(1):45-50. doi: 10.1016/j.mce.2011.05.008. Epub 2011 Jun 1. Adipose circadian rhythms: translating cellular and animal studies to human physiology. Johnston JD(1). Author information: (1)University of Surrey, Guildford, Surrey GU2 7XH, UK. j.johnston@surrey.ac.uk Emerging links between circadian rhythms and metabolism promise much for the understanding of metabolic physiology and pathophysiology, in which white adipose tissue (WAT) plays a prominent role. Many WAT endocrine molecules, termed adipokines, display rhythmic plasma concentration. Moreover, similar to most other tissues, WAT exhibits widespread 24-h variation in gene expression, with approximately 20% of the murine adipose transcriptome estimated to undergo daily variation. A major limitation to human chronobiology research is the availability of physiologically defined peripheral tissues. To date most analyses of in vivo human peripheral clocks has been limited to blood leucocytes. However, subcutaneous adipose tissue represents a novel opportunity to study peripheral molecular rhythms that are of clearly defined metabolic relevance. This review summarises basic concepts of circadian and metabolic physiology before then comparing alternative protocols used to analyse the rhythmic properties of human adipose tissue. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21664232 [PubMed - indexed for MEDLINE] 751. Best Pract Res Clin Endocrinol Metab. 2011 Jun;25(3):487-99. doi: 10.1016/j.beem.2010.12.001. Adipose tissue biology and HIV-infection. Giralt M(1), Domingo P, Villarroya F. Author information: (1)Department of Biochemistry and Molecular Biology and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Catalonia, Spain. mgiralt@ub.edu HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is an adipose tissue redistribution disorder characterized by subcutaneous adipose tissue lipoatrophy, sometimes including visceral adipose tissue hypertrophy and accumulation of dorsocervical fat ('buffalo hump'). The pathophysiology of HALS appears to be multifactorial and several key pathophysiological factors associated with HALS have been identified. These include mitochondrial dysfunction, adipocyte differentiation disturbances, high adipocyte lipolysis, and adipocyte apoptosis. These alterations in adipose tissue biology expand to involve systemic metabolism through alterations in endocrine functions of adipose tissue (via disturbed adipokine release), enhanced production of pro-inflammatory cytokines and excessive free fatty-acid release due to lipolysis. The deleterious action of some antiretroviral drugs is an important factor in eliciting these alterations in adipose tissue. However, HIV-1 infection-related events and HIV-1-encoded proteins also contribute directly to the complex development of HALS through effects on adipocyte biology, or indirectly through the promotion of local inflammation in adipose tissue. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 21663842 [PubMed - indexed for MEDLINE] 752. Best Pract Res Clin Endocrinol Metab. 2011 Jun;25(3):459-68. doi: 10.1016/j.beem.2010.10.017. Molecular mechanisms for insulin resistance in treated HIV-infection. Hruz PW(1). Author information: (1)Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA. hruz_p@kids.wustl.edu Identification and characterization of the molecular mechanisms contributing to the high incidence of insulin resistance in HIV infected patients treated with combined antiretroviral therapy remains a critically important goal in the quest to improve the safety of antiretroviral treatment regimens. The use of in vitro model systems together with the investigation of drug-mediated effects on glucose homeostasis in animals and healthy human volunteers has provided important insight into the contribution of individual drugs to insulin resistance and affected cellular pathways. HIV protease inhibitor mediated blockade of glucose transport and nucleoside reverse transcriptase inhibitor mediated mitochondrial toxicity have been well characterized. Together with growing understanding of mediators of insulin resistance in non-HIV metabolic syndrome, additional cellular effects including the induction of endoplasmic reticulum and oxidative stress, altered adipocytokine secretion, and lipotoxicity have been integrated into this developing picture. Further elucidation of these mechanisms provides potential for the continued development of safer antiviral drugs and targeted treatment of insulin resistance in affected patients. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3115529 PMID: 21663839 [PubMed - indexed for MEDLINE] 753. Curr Opin Otolaryngol Head Neck Surg. 2011 Aug;19(4):289-94. doi: 10.1097/MOO.0b013e32834896a0. Lipotransfer in the upper third of the face. Chen HH(1), Williams EF. Author information: (1)Department of Facial Plastic and Reconstructive Surgery, Williams Center Plastic Surgery Specialists, Latham, New York 12110, USA. PURPOSE OF REVIEW: The purpose of this article is to review the latest developments and techniques in lipotransfer to the upper third of the face. RECENT FINDINGS: Volume loss is becoming increasingly recognized as a significant contributor to upper facial aging. Lipotransfer has been used more extensively because fat exhibits many qualities of an ideal filler, able to restore volume to deflated tissues. Whereas certain nuances and differences in techniques exist, all authors agree that transfer of conservative volumes of fat in key regions of the upper face restores a natural youthful look. SUMMARY: Volume loss in the upper third of the face contributes significantly to aging. The use of lipotransfer in this area is an important adjunct to traditional surgical techniques. It can also be used as a primary rejuvenation procedure in select patients. More studies are needed to elucidate the optimal method of fat harvest, processing, and injection as well as longevity of transplanted grafts. PMID: 21659877 [PubMed - indexed for MEDLINE] 754. Biochimie. 2011 Oct;93(10):1631-40. doi: 10.1016/j.biochi.2011.05.018. Epub 2011 May 30. Several agents and pathways regulate lipolysis in adipocytes. Chaves VE(1), Frasson D, Kawashita NH. Author information: (1)Department of Basic Sciences in Health, Federal University of Mato Grosso, Cuiabá, Mato Grosso, Brazil. Adipose tissue is the only tissue capable of hydrolyzing its stores of triacylglycerol (TAG) and of mobilizing fatty acids and glycerol in the bloodstream so that they can be used by other tissues. The full hydrolysis of TAG depends on the activity of three enzymes, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase, each of which possesses a distinct regulatory mechanism. Although more is known about HSL than about the other two enzymes, it has recently been shown that HLS and ATGL can be activated simultaneously, such that the mechanism that enables HSL to access the surface of lipid droplets also permits the stimulation of ATGL. The classical pathway of lipolysis activation in adipocytes is cAMP-dependent. The production of cAMP is modulated by G-protein-coupled receptors of the Gs/Gi family and cAMP degradation is regulated by phosphodiesterase. However, other pathways that activate TAG hydrolysis are currently under investigation. Lipolysis can also be started by G-protein-coupled receptors of the Gq family, through molecular mechanisms that involve phospholipase C, calmodulin and protein kinase C. There is also evidence that increased lipolytic activity in adipocytes occurs after stimulation of the mitogen-activated protein kinase pathway or after cGMP accumulation and activation of protein kinase G. Several agents contribute to the control of lipolysis in adipocytes by modulating the activity of HSL and ATGL. In this review, we have summarized the signalling pathways activated by several agents involved in the regulation of TAG hydrolysis in adipocytes. Copyright © 2011 Elsevier Masson SAS. All rights reserved. PMID: 21658426 [PubMed - indexed for MEDLINE] 755. Br J Pharmacol. 2012 Feb;165(3):603-21. doi: 10.1111/j.1476-5381.2011.01528.x. Small lipid-binding proteins in regulating endothelial and vascular functions: focusing on adipocyte fatty acid binding protein and lipocalin-2. Wang Y(1). Author information: (1)Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong. yuwanghk@hku.hk Dysregulated production of adipokines from adipose tissue plays a critical role in the development of obesity-associated cardiovascular abnormalities. A group of adipokines, including adipocyte fatty acid binding protein (A-FABP) and lipocalin-2, possess specific lipid-binding activity and are up-regulated in obese human subjects and animal models. They act as lipid chaperones to promote lipotoxicity in endothelial cells and cause endothelial dysfunction under obese conditions. However, different small lipid-binding proteins modulate the development of vascular complications in distinctive manners, which are partly attributed to their specialized structural features and functionalities. By focusing on A-FABP and lipocalin-2, this review summarizes recent advances demonstrating the causative roles of these newly identified adipose tissue-derived lipid chaperones in obesity-related endothelial dysfunction and cardiovascular complications. The specific lipid-signalling mechanisms mediated by these two proteins are highlighted to support their specialized functions. In summary, A-FABP and lipocalin-2 represent potential therapeutic targets to design drugs for preventing vascular diseases associated with obesity.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315034 PMID: 21658023 [PubMed - indexed for MEDLINE] 756. Cell Cycle. 2011 Jul 15;10(14):2281-6. Epub 2011 Jul 15. Stem cell induced cardiac regeneration: fusion/mitochondrial exchange and/or transdifferentiation? Song YH(1), Pinkernell K, Alt E. Author information: (1)Department of Molecular Pathology, Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Potentially, adult stem cell-based therapy provides a new therapeutic option for myocardial regeneration. However, to date, with regard to the benefits seen, the mechanisms involved in stem cell-based therapy are not well understood. Suggested pathways proposed so far include fusion of stem cells with cardiomyocytes, transdifferentiation into cardiac and vascular cells and secretion of paracrine factors. In a recent study, our group examined the fate of human adipose tissue-derived stem cells (hASCs) fused with rat cardiomyocytes after treatment with fusion-inducing hemagglutinating virus of Japan (HVJ). In this study, we demonstrated that cells of fused hASC cardiomyocytes display a cardiomyocyte phenotype and spontaneous rhythmic contraction and generate an action potential in vitro. As part of the work underlying this paper, we co-cultured rat neonatal cardiomyocytes with hASCs or pig bone marrow-derived mesenchymal stem cells (MSCs), where ASCs or MSCs had previously been transduced with a lentivirus encoding eGFP. Our data evidence early cardiac contractile proteins, such as Titin and MF20, identified in eGFP-positive cells, suggesting a cardiomyogenic phenotype. Recent work by others has shown that the myogenic conversion increased when BMSCs were cultured with apoptotic cells. In this Extra View article, we review the current understanding of stem cell-derived factors, fusion/partial fusion and the manner in which the exchange of cellular contents between stem cells and cardiomyocytes might contribute to the reprogramming of fully differentiated cardiomyocytes based on recently published literature. PMID: 21654195 [PubMed - indexed for MEDLINE] 757. Adv Physiol Educ. 2011 Jun;35(2):219-26. doi: 10.1152/advan.00135.2010. The case of thyroid hormones: how to learn physiology by solving a detective case. Lellis-Santos C(1), Giannocco G, Nunes MT. Author information: (1)Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil. Thyroid diseases are prevalent among endocrine disorders, and careful evaluation of patients' symptoms is a very important part in their diagnosis. Developing new pedagogical strategies, such as problem-based learning (PBL), is extremely important to stimulate and encourage medical and biomedical students to learn thyroid physiology and identify the signs and symptoms of thyroid dysfunction. The present study aimed to create a new pedagogical approach to build deep knowledge about hypo-/hyperthyroidism by proposing a hands-on activity based on a detective case, using alternative materials in place of laboratory animals. After receiving a description of a criminal story involving changes in thyroid hormone economy, students collected data from clues, such as body weight, mesenteric vascularization, visceral fat, heart and thyroid size, heart rate, and thyroid-stimulating hormone serum concentration to solve the case. Nevertheless, there was one missing clue for each panel of data. Four different materials were proposed to perform the same practical lesson. Animals, pictures, small stuffed toy rats, and illustrations were all effective to promote learning, and the detective case context was considered by students as inviting and stimulating. The activity can be easily performed independently of the institution's purchasing power. The practical lesson stimulated the scientific method of data collection and organization, discussion, and review of thyroid hormone actions to solve the case. Hence, this activity provides a new strategy and alternative materials to teach without animal euthanization. PMID: 21652508 [PubMed - indexed for MEDLINE] 758. Trends Endocrinol Metab. 2011 Aug;22(8):333-43. doi: 10.1016/j.tem.2011.04.004. Epub 2011 Jun 7. Metabolic nuclear receptor signaling and the inflammatory acute phase response. Venteclef N(1), Jakobsson T, Steffensen KR, Treuter E. Author information: (1)Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, S-14183 Stockholm, Sweden. The acute phase response (APR) classically refers to the rapid reprogramming of gene expression and metabolism in response to inflammatory cytokine signaling. As components of the innate immune system, hepatocyte-derived acute phase proteins (APPs) play a central role in restoring tissue homeostasis. Recently, an intriguing 'metaflammatory' facet of the APR became evident with chronically elevated APP levels being connected to metabolic syndrome disorders. The causality of these connections is unclear but could relate to adverse metabolic and inflammatory disturbances, particularly those affecting lipoprotein properties, cholesterol metabolism and atherogenesis. Here we review these aspects with an emphasis on the emerging importance of lipid-sensing nuclear receptors (LXRs, LRH-1, PPARs), in conjunction with anti-inflammatory transrepression pathways, as physiological and pharmacological relevant modulators of the APR. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21646028 [PubMed - indexed for MEDLINE] 759. Curr Diabetes Rev. 2011 Jul;7(4):270-7. Adipose triglyceride lipase: a new target in the regulation of lipolysis by insulin. Chakrabarti P(1), Kandror KV. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. partha@bu.edu In adipose tissue, the primary physiological function of insulin is the suppression of lipolysis, the hydrolysis of stored fat. Mechanistically, insulin suppresses lipolysis both in transcriptional and post-transcriptional levels. Insulin signaling acutely inhibits beta-adrenergic signaling by decreasing intracellular cyclic AMP levels and the rate of lipolysis. Insulin also suppresses lipolysis by down-regulating the expression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase or ATGL. In insulin resistance and type 2 diabetes, insulin mediated attenuation of lipolysis is impaired leading to an increased rate of lipolysis and increased release of free fatty acids (FFA) in the circulation. This is one of the potential mechanisms behind the development of hyperlipidemia and subsequent metabolic abnormalities in type 2 diabetes. In this article, we focus on the recent findings that highlight distinct molecular mechanisms by which insulin action is mediated and possible implications of the deregulation of these pathways in the pathophysiological context. PMID: 21644917 [PubMed - indexed for MEDLINE] 760. Endocr Rev. 2011 Aug;32(4):550-70. doi: 10.1210/er.2010-0030. Epub 2011 Jun 2. Paracrine and endocrine effects of adipose tissue on cancer development and progression. Park J(1), Euhus DM, Scherer PE. Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA. The past few years have provided substantial evidence for the vital role of the local tumor microenvironment for various aspects of tumor progression. With obesity and its pathophysiological sequelae still on the rise, the adipocyte is increasingly moving center stage in the context of tumor stroma-related studies. To date, we have limited insight into how the systemic metabolic changes associated with obesity and the concomitant modification of the paracrine and endocrine panel of stromal adipocyte-derived secretory products ("adipokines") influence the incidence and progression of obesity-related cancers. Here, we discuss the role of adipocyte dysfunction associated with obesity and its potential impact on cancer biology. PMCID: PMC3369575 PMID: 21642230 [PubMed - indexed for MEDLINE] 761. Clin Exp Rheumatol. 2011 Jul-Aug;29(4):712-27. Epub 2011 Sep 1. Obesity, adipose tissue and rheumatoid arthritis: coincidence or more complex relationship? Derdemezis CS(1), Voulgari PV, Drosos AA, Kiortsis DN. Author information: (1)Laboratory of Physiology, Medical School, University of Ioannina, Greece. In the last two decades we have witnessed a boost in scientific interest and knowledge of adipose tissue biology to such an extent that it was promoted to an active endocrine organ. Adipose tissue is not just related to body weight and appetite regulation. It is also implicated in obesity, a low-grade inflammatory state, as well as inflammatory conditions including rheumatoid arthritis (RA), an autoimmune disease where anti- and pro-inflammatory cytokine balance is critical. All major adipose derived products, simply termed adipokines, like leptin, adiponectin, visfatin and resistin, reportedly participate in inflammation and immunity. In this review we explore in depth the relationship between adipose tissue and RA, with focus on possible mechanisms, beyond observations about circulating or synovial levels, and special reference to future perspectives and clinical implications. PMID: 21640051 [PubMed - indexed for MEDLINE] 762. J Clin Invest. 2011 Jun;121(6):2111-7. doi: 10.1172/JCI57132. Epub 2011 Jun 1. Inflammatory links between obesity and metabolic disease. Lumeng CN(1), Saltiel AR. Author information: (1)Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109-5652, USA. clumeng@umich.edu The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses. PMCID: PMC3104776 PMID: 21633179 [PubMed - indexed for MEDLINE] 763. J Clin Invest. 2011 Jun;121(6):2102-10. doi: 10.1172/JCI46069. Epub 2011 Jun 1. The role of lipid droplets in metabolic disease in rodents and humans. Greenberg AS(1), Coleman RA, Kraemer FB, McManaman JL, Obin MS, Puri V, Yan QW, Miyoshi H, Mashek DG. Author information: (1)Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. Andrew.greenberg@tufts.edu Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease. PMCID: PMC3104768 PMID: 21633178 [PubMed - indexed for MEDLINE] 764. J Clin Invest. 2011 Jun;121(6):2094-101. doi: 10.1172/JCI45887. Epub 2011 Jun 1. Adipose tissue remodeling and obesity. Sun K(1), Kusminski CM, Scherer PE. Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549, USA. To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth. PMCID: PMC3104761 PMID: 21633177 [PubMed - indexed for MEDLINE] 765. J Clin Invest. 2011 Jun;121(6):2087-93. doi: 10.1172/JCI45888. Epub 2011 Jun 1. Sixteen years and counting: an update on leptin in energy balance. Gautron L(1), Elmquist JK. Author information: (1)Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. PMCID: PMC3104762 PMID: 21633176 [PubMed - indexed for MEDLINE] 766. Med Clin (Barc). 2012 Mar 3;138(5):208-14. doi: 10.1016/j.medcli.2011.03.032. Epub 2011 May 31. [Laminopathies. Nuclear lamina diseases]. [Article in Spanish] Méndez-López I(1). Author information: (1)Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA. ivan.mendez.lopez@cfnavarra.es Laminopathies are a group of diseases that share wrong codification of lamins, building proteins of the nuclear lamina. Different tissues are affected in those disorders: striated muscle, adipose tissue, central or peripheral nervous system and aging process. Emery-Dreifuss muscular dystrophy and Hutchinson-Gildford Progery Syndrome are two examples of laminopathies. Other diseases, due to mutations in different genes, impair lamins function by a direct or an indirect way and they are frequently considered together. The last decade has seen an increasing interest and scientific advances on laminopathies that will allow us to answer key questions regarding metabolism, insulin resistance, sudden death and aging. Laminopathies are reviewed in this article from a molecular, pathogenic and clinical point of view. Copyright © 2011 Elsevier España, S.L. All rights reserved. PMID: 21632068 [PubMed - indexed for MEDLINE] 767. Cir Cir. 2011 Mar-Apr;79(2):209-16. Pathophysiological implications between chronic inflammation and the development of diabetes and obesity. González-Chávez A(1), Elizondo-Argueta S, Gutiérrez-Reyes G, León-Pedroza JI. Author information: (1)Unidad 308, Servicio de Medicina Interna, Hospital General de México, Secretaría de Salud, México, D. F., Mexico. antglez51@yahoo.com.mx The different theories about the mechanisms involved in the development of metabolic disease and its complications converge in the presence of an etiologic chronic proinflammatory state. Chronic inflammation is, at present, the central pathophysiological mechanism involved in the genesis of metabolic diseases. The multiple interactions between the immune system, adipose tissue, the vascular wall and the pancreas are the issues addressed in this review, focusing on specific intracellular and molecular aspects that may become new therapeutic targets. These lead to a proinflammatory, prothrombotic state as well as to proapoptotic endothelial damage that allows the development of atherosclerosis and, consequently, cardiovascular disease. The multiple immunopathological processes associated with the etiology and pathophysiology of different chronic diseases is still in the process of being fully elucidated, allowing the development of new therapeutic targets. PMID: 21631985 [PubMed - indexed for MEDLINE] 768. J Diabetes. 2011 Sep;3(3):225-31. doi: 10.1111/j.1753-0407.2011.00132.x. Apelin and insulin resistance: another arrow for the quiver? Xu S(1), Tsao PS, Yue P. Author information: (1)Department of Medicine/Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. Apelin is a newly discovered peptide hormone that has recently been linked to insulin resistance and obesity. Data collected from both the clinical and basic research settings show that apelin: (i) is correlated with the states of insulin resistance and obesity; (ii) stimulates glucose utilization; (iii) decreases insulin secretion; and (iv) negatively regulates catecholamine-mediated lipolysis. These and other lines of evidence demonstrate that apelin may be a potentially viable candidate in the search for treatments for Type 2 diabetes and the insulin resistance (metabolic syndrome). The present review summarizes the literature on the regulation by apelin of glucose and lipid metabolism and the signaling pathways involved. © 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd. PMCID: PMC3156858 PMID: 21631898 [PubMed - indexed for MEDLINE] 769. J Pediatr Gastroenterol Nutr. 2011 Aug;53(2):131-40. doi: 10.1097/MPG.0b013e31822578db. Mechanisms of lipotoxicity in NAFLD and clinical implications. Ibrahim SH(1), Kohli R, Gores GJ. Author information: (1)Division of Pediatric Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA. With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways. PMCID: PMC3145329 PMID: 21629127 [PubMed - indexed for MEDLINE] 770. Nihon Naika Gakkai Zasshi. 2011 Apr 10;100(4):989-95. [Obesity: Progress in diagnosis and treatment; Topics, IV. Recent topics; 2. Obesity and inflammation]. [Article in Japanese] Suganami T(1), Ogawa Y. Author information: (1)Department of Molecular Medicine and Metabolism, Tokyo Medical and Dental University, Japan. PMID: 21626836 [PubMed - indexed for MEDLINE] 771. J Physiol Biochem. 2011 Sep;67(3):487-96. doi: 10.1007/s13105-011-0101-7. Epub 2011 May 31. Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes. Sauvant P(1), Cansell M, Atgié C. Author information: (1)UMR 5248 CBMN Chimie et Biologie des Membranes et des Nanoobjets, CNRS, Université de Bordeaux, Institut Polytechnique de Bordeaux, Allée Geoffroy de St Hilaire, Pessac, Bordeaux, France. p.sauvant@cbmn.u-bordeaux.fr Vitamin A or retinol plays a major role in the regulation of cellular homeostasis. Retinyl palmitate remains the main chemical form of vitamin A storage and is mainly located in hepatic stellate cells (HSCs) in lipid droplets resembling those found in adipose cells. White adipose tissue (WAT), is essentially involved in the regulation of lipid metabolism, through its role in lipid storage, and might also be considered as a vitamin A storage and metabolism site. WAT contains all the intracellular equipment for vitamin A metabolism and signaling pathways which allows retinol to be metabolized into retinoic acid, known to control genomic expression in WAT. The description of molecular mechanisms involved in the activation of HSCs and the differentiation of preadipocytes reveal similar cellular and molecular mechanisms. Indeed HSCs and adipocytes share a common expression of key transcription factors like PPAR-γ and RXR known to influence perilipin expression, which play fundamental roles in lipid droplet metabolism. Both cells are also sources of important endocrine signaling secretions influencing the expression of these transcription factors. The morphological and functional characteristics of HSCs and adipocytes, including the metabolism of vitamin A and other lipids and their related signaling pathways, are summarized and compared in this review. We highlight the complexity of the interrelationship between lipids and vitamin A metabolism and the role of the complex communication existing between HSCs and WAT in diseases such as non-alcoholic fatty liver disease which is the hepatic manifestation of the metabolic syndrome. PMID: 21626400 [PubMed - indexed for MEDLINE] 772. Contrib Nephrol. 2011;171:120-6. doi: 10.1159/000327228. Epub 2011 May 23. Recent insights in inflammation-associated wasting in patients with chronic kidney disease. Meuwese CL(1), Carrero JJ, Stenvinkel P. Author information: (1)Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands. In patients with end-stage renal disease (ESRD), inflammation, and protein energy wasting (PEW) are two highly prevalent and interconnected entities, jointly exerting a deleterious effect on multiple other ESRD-specific pathological processes and eventually on patient outcome. With respect to the pathophysiology underlying this strong association, knowledge has been actively expanded over the past few years. As such, it is nowadays recognized that inflammation acts via direct, as well as indirect, pathways in its contribution to PEW. Directly, inflammation causes alterations in amino acid utilization, translating into increased catabolism and decreased anabolism of muscle tissue. Indirectly, inflammation may act via altered ghrelin and adipokine metabolism, adipose tissue distribution, and pathological neuroendocrine signaling, as well as coexistent depression in inducing anorexia and PEW. In addition, two relatively new inflammatory markers (pentraxin-3 and TNF-like weak inducer of apoptosis) have gained attention with respect to their roles in this specific context. The current review deals with recent updates in the literature on the aforementioned pathways connecting inflammation to PEW and subsequent mortality. Copyright © 2011 S. Karger AG, Basel. PMID: 21625100 [PubMed - indexed for MEDLINE] 773. Clin Endocrinol (Oxf). 2011 Aug;75(2):147-55. doi: 10.1111/j.1365-2265.2011.04133.x. Regulation of glucose metabolism and the skeleton. Ng KW(1). Author information: (1)Department of Endocrinology and Diabetes, St. Vincent's Hospital, Fitzroy, Vic., Australia. kongwn@unimelb.edu.au Complex interactions occur among adipose tissue, the central nervous system, bone and pancreas to integrate bone remodelling, glucose, lipid and energy metabolism. Data obtained largely from the judicious use of gain-of-function and loss-of-function genetic mouse models show that leptin, an adipocyte-secreted product, indirectly inhibits bone accrual through a central pathway comprising the hypothalamus and central nervous system. Increased sympathetic output acting via β2-adrenergic receptors present in osteoblasts decreases bone formation and causes increased bone resorption. Insulin is a key molecular link between bone remodelling and energy metabolism. Insulin signalling in the osteoblasts increases bone formation and resorption as well as the release of undercarboxylated osteocalcin. An increase in the release of bone-derived undercarboxylated osteocalcin into the systemic circulation enables it to act as a circulating hormone to stimulate insulin production and secretion by pancreatic β-cells and adiponectin by adipocytes. Insulin sensitivity increases, lipolysis and fat accumulation decreases while energy expenditure increases. Whether this model of integrative physiology involving the skeleton, pancreas and adipose tissue, so elegantly demonstrated in rodents, is applicable to humans is controversial. The mouse Esp gene, encoding an intracellular tyrosine phosphatase that negatively regulates insulin signalling in osteoblasts, is a pseudogene in humans, and a homolog for the Esp gene has so far not been identified in humans. A close homologue of Esp, PTP1B, is expressed in human osteoblasts and could take the role of Esp in humans. Data available from the limited number of clinical studies do not provide a sufficient body of evidence to determine whether osteocalcin or undercarboxylated osteocalcin affects glucose metabolism in humans. © 2011 Blackwell Publishing Ltd. PMID: 21623861 [PubMed - indexed for MEDLINE] 774. Front Biosci (Schol Ed). 2011 Jun 1;3:1478-85. Possible involvement of the (pro)renin receptor-dependent system in the development of insulin resistance. Rafiq K(1), Hitomi H, Nakano D, Ichihara A, Nishiyama A. Author information: (1)Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita, Kagawa, Japan. It is widely acknowledged that activation of the renin-angiotensin system impairs insulin sensitivity. Pharmacological inhibition of the (pro)renin receptor-dependent system has shown beneficial effects in diabetic nephropathy, retinopathy and hypertensive cardiac damage in animal models. Previously, we showed that fructose feeding stimulated nonproteolytic activation of prorenin and subsequent production of angiotensin II in skeletal muscle in rats, and that inhibition of the (pro)renin receptor-dependent system improved the development of fructose feeding-induced insulin resistance. In addition, our current preliminary study suggests that local angiotensin II generation in skeletal muscle and adipose tissues induced by nonproteolytic activation of prorenin is involved in the development of spontaneous insulin resistance in type 2 diabetic rats. In this review, we will briefly summarize the possible contribution of the (pro)renin receptor-dependent system to the pathogenesis of insulin resistance, with a focus on how the nonproteolytic activation of prorenin contributes to the development of insulin resistance. PMID: 21622283 [PubMed - indexed for MEDLINE] 775. Front Biosci (Schol Ed). 2011 Jun 1;3:1180-95. Nitric oxide and thermogenesis--challenge in molecular cell physiology. Otasevic V(1), Korac A, Buzadzic B, Stancic A, Jankovic A, Korac B. Author information: (1)Department of Physiology, Institute for Biological Research, Sinisa Stankovic, University of Belgrade, Belgrade, Serbia. Only recently we can link thermogenesis, mitochondria, nitric oxide, and redox regulation in biochemical terms. Currently, we are discussing these processes from the aspect of fundamental principles of molecular physiology. Thus, the present article highlights both cell physiology and the principles of the maintenance of energy homeostasis in organisms. Energy homeostasis means much more than simple combustion; adipose tissues at this point of evolution development are related to a broad spectrum of metabolic disturbances and all aspects of cellular remodeling (i.e. structural, metabolic and endocrine changes). Therefore, this paper addresses not only thermogenesis but also energy homeostasis, oxidative phosphorylation and ATP production, proliferation and differentiation of brown adipocytes, their life and death, mitochondriogenesis and angiogenesis. These processes will be united by molecular players of oxidation/reduction reactions, thus creating the principles based on the redox regulation. PMID: 21622264 [PubMed - indexed for MEDLINE] 776. Trends Immunol. 2011 Jul;32(7):307-14. doi: 10.1016/j.it.2011.04.008. Epub 2011 May 26. Defining macrophage phenotype and function in adipose tissue. Dalmas E(1), Clément K, Guerre-Millo M. Author information: (1)INSERM, U872, Paris, F-75006 France. In obesity, chronic low-grade inflammation is thought to mediate the effects of increased adipose tissue mass on metabolic comorbidity. Of the different cell types that contribute to obesity-induced inflammation in adipose tissue, this review focuses on macrophages and their monocytes precursors. Mechanisms for monocyte recruitment to adipose tissue, and how both monocytes and macrophages are phenotypically modified in this environment in response to increasing fat mass, are considered. The versatile phenotype of adipose tissue macrophages might contribute not only to inflammatory and metabolic alterations, but could also help to maintain adipose tissue homeostasis in the setting of obesity. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21616718 [PubMed - indexed for MEDLINE] 777. J Am Diet Assoc. 2011 Jun;111(6):864-73. doi: 10.1016/j.jada.2011.03.011. Signaling proteins that influence energy intake may affect unintentional weight loss in elderly persons. Wernette CM(1), White BD, Zizza CA. Author information: (1)Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL, USA. werneca@auburn.edu After age 70 to 75 years, average body weight decreases both in ailing and healthy people because of a loss of appetite that results in reduced energy intake and the loss of body fat and lean muscle tissue. This so-called anorexia of aging predisposes elderly people to continued pathologic weight loss and malnutrition-major causes of morbidity and mortality. Health care professionals must understand the many factors involved in the anorexia of aging to help older adults prevent unintentional weight loss. Psychological, social, and cultural factors are important effectors; however, physiological factors are emphasized here because they are not thoroughly understood and they make it inherently difficult for most people to alter their body weight. Monoamines, steroid hormones (glucocorticoids and mineralocorticoids), endocannabinoids, and proteins all influence body weight. This review is an analysis of proteins from the brain, pancreas, adipose tissue, and gastrointestinal tract that are known to affect energy intake and energy balance, with an attempt to identify those factors that may change with aging. The articles included in this review were obtained by a PubMed database search using the keywords mouse OR rat OR human AND aged OR aging OR older OR elderly AND adult AND anorexia OR "unintentional weight loss," and each of the individual proteins discussed, as well as from the reference lists of those articles. The results reveal that some proteins may be important in the development of unintentional weight loss in elderly persons, whereas others may not have a significant role. However, many of the proteins that could conceivably have a role in unintentional weight loss have not yet been studied with that question in mind. Preventing unintentional weight loss in older adults is an important goal and further research on the role of proteins important for the maintenance of energy balance and the development of unintentional weight loss in elderly persons is warranted. Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved. PMID: 21616199 [PubMed - indexed for MEDLINE] 778. Ann Med. 2012 May;44(3):233-41. doi: 10.3109/07853890.2011.564202. Epub 2011 May 25. Visceral adiposity as a target for the management of the metabolic syndrome. Kishida K(1), Funahashi T, Matsuzawa Y, Shimomura I. Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Japan. kkishida@imed2.med.osaka-u.ac.jp Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome. PMID: 21612331 [PubMed - indexed for MEDLINE] 779. South Med J. 2011 May;104(5):331-4. doi: 10.1097/SMJ.0b013e318213d0f9. Protean manifestations of vitamin D deficiency, part 1: the epidemic of deficiency. Bell DS(1). Author information: (1)Southside Endocrinology, University of Alabama Medical School, Birmingham, AL, USA. dshbell@yahoo.com Just when vitamin deficiencies were thought to be a "thing of the past" a new vitamin deficiency-that of vitamin D has developed over the past 20 years. Vitamin D works like a hormone being produced primarily in one organ (the kidney) before circulating through the bloodstream to multiple organs where it has multiple effects. The increased prevalence of vitamin D deficiency is due to changes in modern lifestyle-mainly lack of exposure to sunlight and the increased prevalence of obesity that, results in sequestration of this fat-soluble vitamin in adipose tissue. Distance from the Equator and increasing age and skin pigmentation are additional risk factors. In pregnancy vitamin D deficiency can result in low birth weight, pre-term labor, pre-term birth, infections, and pre-eclamptic toxemia. While vitamin D deficiency is classically associated with rickets and osteomalacia, its effects are much more protean. PMID: 21606711 [PubMed - indexed for MEDLINE] 780. J Endocrinol Invest. 2011 Sep;34(8):630-44. doi: 10.3275/7746. Epub 2011 May 23. Understanding polycystic ovarian syndrome pathogenesis: an updated of its genetic aspects. Calogero AE(1), Calabrò V, Catanuso M, Condorelli RA, La Vignera S. Author information: (1)Section of Endocrinology, Andrology and Internal Medicine, Department of Internal Medicine and Systemic Diseases, and Master in Andrological, Human Reproduction and Biotechnology Sciences, University of Catania, Catania, Italy. acaloger@unict.it Polycystic ovary syndrome (PCOS) is the most frequent cause of female infertility. It is also characterized by metabolic defects that raise the risk for cardiovascular disease. Despite the progress in the definition of the clinical aspects of the syndrome, only very few definite data are available about the ethiopathogenetic mechanisms that subtend PCOS. It is likely that the PCOS phenotype derives from the interaction between environmental and genetic factors. While environmental factors have easily been investigated, the individuation of the genetic factors seem to be more complex. Indeed, PCOS appears to be inherited as a complex, polygenic trait. Several family studies have been conducted with the aim to clarify the genetic aspects of PCOS, but their findings are often conflicting and not conclusive.Moreover, it is difficult to establish with certainty which genes are involved and their effective role in the development of the syndrome because in PCOS, genetic analysis is hampered by low fecundity, lack of a male phenotype, absence of an animal model, and dissimilarity of the diagnostic criteria used to select the patients. Since multiple biochemical pathways are implicated in PCOS pathogenesis, genes of steroid hormone metabolism, gonadotropin release and action, insulin secretion and action, adipose tissue metabolism and others have been investigated. Nevertheless, none of them seems to play a key role in the ethiopathogenesis of PCOS. This article reviews the large body of literature generated to support the presence of genetic abnormalities in PCOS women by taking in consideration the most important studies regarding PCOS candidate genes. PMID: 21606667 [PubMed - indexed for MEDLINE] 781. Trends Mol Med. 2011 Aug;17(8):405-11. doi: 10.1016/j.molmed.2011.04.001. Epub 2011 May 24. Using brown adipose tissue to treat obesity - the central issue. Whittle AJ(1), López M, Vidal-Puig A. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. ajw232@medschl.cam.ac.uk Current therapeutic strategies are proving inadequate to deal with growing obesity rates because of the inherent resistance of the human body to weight loss. The activation of human brown adipose tissue (BAT) represents an opportunity to increase energy expenditure and weight loss alongside improved lipid and glucose homeostasis. Research into the regulation of BAT has made increasing the thermogenic capacity of an individual to treat metabolic disease a plausible strategy, despite thermogenesis being under tight central nervous system control. Previous therapies targeted at the sympathetic nervous system have had deleterious effects because of a lack of organ specificity, but advances in our understanding of central BAT regulatory systems might open up better strategies to specifically stimulate BAT in obese individuals to aid weight reduction. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21602104 [PubMed - indexed for MEDLINE] 782. Prostaglandins Leukot Essent Fatty Acids. 2011 Aug;85(2):83-8. doi: 10.1016/j.plefa.2011.04.027. Epub 2011 May 23. The effect of maternal omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during pregnancy and/or lactation on body fat mass in the offspring: a systematic review of animal studies. Muhlhausler BS(1), Gibson RA, Makrides M. Author information: (1)FOODplus Research Centre, School of Agriculture Food and Wine, The University of Adelaide, Adelaide, Australia. beverly.muhlhausler@adelaide.edu.au Dietary n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) reduce adipogenesis and lipogenesis in adult rodents, but it is not clear whether an increased n-3 LCPUFA supply during the perinatal period influences body fat mass in the offspring. This systematic review aimed to evaluate the existing evidence from animal studies, which have addressed this question. Medline was searched for relevant articles. Studies were included if they involved maternal n-3 PUFA or LCPUFA supplementation and measured fat mass in the offspring. The design and quality of each study was assessed. Only four animal studies met our inclusion criteria. Three studies reported a lower fat mass in offspring of n-3 LCPUFA supplemented dams, however only one of these studies confined the intervention to the perinatal period. The dose of n-3 PUFA, the nature of the control treatment, the approaches used and outcomes assessed differed between studies. This review highlights the paucity of robust animal data as to the effect of increased n-3 LCPUFA exposure during the perinatal period alone, on body fat mass in the offspring and calls for further studies. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21601438 [PubMed - indexed for MEDLINE] 783. Arch Physiol Biochem. 2011 Jul;117(3):151-64. doi: 10.3109/13813455.2011.562514. Epub 2011 May 23. Toll-like receptors, inflammation, metabolism and obesity. Fresno M(1), Alvarez R, Cuesta N. Author information: (1)Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. mfresno@cbm.uam.es Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance. PMID: 21599616 [PubMed - indexed for MEDLINE] 784. Zh Evol Biokhim Fiziol. 2011 Mar-Apr;47(2):105-12. [Neuropeptide Y and autonomic nervous system]. [Article in Russian] Nozdrachev AD, Masliukov PM. Neuropeptide Y (NPY) containing 36 amino acid residues belongs to peptides widely spread in the central and peripheral nervous system. NPY and its receptors play an extremely diverse role in the nervous system, including regulation of satiety, of emotional state, of vascular tone, and of gastrointestinal secretion. In mammals, NPY has been revealed in the majority of sympathetic ganglion neurons, in a high number of neurons of parasympathetic cranial ganglia as well as of intramural ganglia of the metasympathetic nervous system. At present, six types of receptors to NPY (Y1-Y6) have been identified. All receptors to NPY belong to the family of G-bound proteins. Action of NPY on peripheral organs-targets is predominantly realized through postsynaptic receptors Y1, Y3-Y5, and presynaptic receptors of the Y2 type. NPY is present in large electron-dense vesicles and is released at high-frequency stimulation. NPY affects not only vascular tone, frequency and strength of heart contractions, motorics and secretion of the gastrointestinal tract, but also has trophic effect and produces proliferation of cells of organs-targets, specifically of vessels, myocardium, and adipose tissue. In early postnatal ontogenesis the percent of the NPY-containing neurons in ganglia of the autonomic nervous system increases. In adult organisms, this parameter decreases. This seems to be connected with the trophic NPY effect on cells-targets as well as with regulation of their functional state. PMID: 21598694 [PubMed - indexed for MEDLINE] 785. J Androl. 2012 Mar-Apr;33(2):154-61. doi: 10.2164/jandrol.111.013649. Epub 2011 May 19. Physical activity and erectile dysfunction in middle-aged men. La Vignera S(1), Condorelli R, Vicari E, D'Agata R, Calogero AE. Author information: (1)Section of Endocrinology, Andrology, and Internal Medicine, Department of Internal Medicine and Systemic Diseases, Catania University, Policlinico G. Rodolico, S Sofia 78th St, Bldg 4, Rm 2C82, 95123 Catania, Italy. sandrolavignera@email.it The prevalence of erectile dysfunction is high in men of all ages and increases greatly in the elderly. In particular, severity and prevalence both increase with aging. Because erectile dysfunction is a symptom, physicians should diagnose underlying pathologies that might lead to it instead of focusing only on finding a viable treatment. Physical inactivity negatively impacts on erectile function; experimental and clinical exercise interventions have been shown to improve sexual responses and overall cardiovascular health. Several studies have confirmed that combining 2 interventions (Mediterranean diet and physical activity) provides additional benefit to erectile function, likely via reduced metabolic disturbances (eg, inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (eg, increased endothelial function). This brief review shows the main clinical evidence of benefits induced by physical activity on erectile and endothelial dysfunction. The literature shows that erectile dysfunction in middle-aged men is often an early event in endothelial damage, and physical activity is able to improve both erectile and endothelial dysfunction. There are conflicting data regarding the effects of exercise on androgen status. In clinical practice it would be recommended to add regular physical activity to balanced diet and drugs to achieve better therapeutic results. PMID: 21597089 [PubMed - indexed for MEDLINE] 786. Expert Rev Clin Immunol. 2011 May;7(3):287-94. doi: 10.1586/eci.11.18. Obesity and susceptibility to autoimmune diseases. Procaccini C(1), Carbone F, Galgani M, La Rocca C, De Rosa V, Cassano S, Matarese G. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy. For decades, obesity has been considered to be the result of the complex interaction between genes and the environment and its pathogenesis is still unresolved. The discovery of hormones and neural mediators responsible for the control of food intake and metabolism at the hypothalamic level has provided fundamental insights into the complicated pathways that control food intake. However, the molecular basis for the association between obesity and low-degree chronic inflammation is still unknown. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones, has suggested that nutritional status, through leptin secretion, can control immune self-tolerance modulating Treg suppressive function and responsiveness. Furthermore, recent experimental evidence has shown the presence of an abundant adipose tissue-resident Treg population responsible for the control of metabolic parameters and glucose homeostasis. Better knowledge of the intricate network of interactions among leptin-related energy regulation, Treg activities and obesity could lead to valuable strategies for therapeutic intervention in obesity and obesity-associated insulin resistance. PMID: 21595595 [PubMed - indexed for MEDLINE] 787. Nihon Rinsho. 2011 May;69(5):813-20. [Structure and function of incretin receptor]. [Article in Japanese] Harada N(1). Author information: (1)Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University. G protein-coupled receptor (GPCR) is integral membrane protein with seven alfa-helices and most diverse families of protein in mammals. It is located on cell membrane and activated by binding neurotransmit proteins and hormones. It has critical role of functional regulation in central nerve system and peripheral organs. Recently, many orphan GPCRs have been identified from the data of genomic sequence in human genomic project. GIP receptor and GLP-1 receptor belong to glucagon receptor subfamily of class B and are widely expressed in many organs. GIP receptor is expressed in intestine, adipose tissue, brain, adrenal gland, and bone, while GLP-1 receptor is expressed in intestine, CNS, lung, kidney and heart. GIP and GLP-1 have not only pancreatic effect, such as potentiation of insulin secretion but also many extrapancreatic effects. PMID: 21595264 [PubMed - indexed for MEDLINE] 788. Vet J. 2012 Mar;191(3):292-8. doi: 10.1016/j.tvjl.2011.04.009. Epub 2011 May 17. The potential role of leptin and adiponectin in obesity: a comparative review. Ricci R(1), Bevilacqua F. Author information: (1)Department of Animal Science, University of Padua, Viale dell'Università 12 and 16, 35020 Legnaro (PD), Italy. rebecca.ricci@unipd.it Comment in Vet J. 2012 Jul;193(1):4-5. Leptin and adiponectin are adipokines produced by the white adipose tissue. The adipokines have been shown to be valuable quantitative markers of adiposity in dogs. Leptin positively correlates with body condition score (BCS) in dogs, regardless of age, sex and breed, and is influenced by feeding state, pharmacological treatment and thyroid gland activity. Conversely, adiponectin negatively correlates with body fat mass and is therefore more abundant in lean animals. The implication of leptin and adiponectin in the pathogenesis of metabolic syndrome is well established in humans, but currently lacking in dogs. Additional studies are necessary to demonstrate their potential usefulness for monitoring the progression of obesity-related diseases and response to treatment. To date, measurement of canine leptin and adiponectin has been used in experimental studies only, whereas bodyweight and BCS are considered the first-approach parameters for the routine assessment of body fat content in obese dogs. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21592831 [PubMed - indexed for MEDLINE] 789. Wien Klin Wochenschr. 2011 May;123(9-10):259-67. doi: 10.1007/s00508-011-1574-7. Epub 2011 May 18. [Growth hormone therapy in adult patients: a review]. [Article in German] Kann PH(1). Author information: (1)Fachbereich Medizin, Endokrinologie & Diabetologie, Universitätsklinikum Gießen und Marburg, Philipps-Universität Marburg, Marburg, Germany. kannp@med.uni-marburg.de Growth hormone deficiency (GHD) can frequently be expected in hypopituitarism of adult patients. If GHD is proven by dynamic testing of the somatotrophic axis, growth hormone substitution is useful for improving quality of life, body composition, bone and lipid metabolism, and myocardial function according to the criteria of evidence-based medicine and is admitted by most national health authorities. There are no other reasonable indications for growth hormone treatment in adulthood. PMID: 21590321 [PubMed - indexed for MEDLINE] 790. Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):347-53. doi: 10.1097/MCO.0b013e32834777fa. The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease. Martínez-Clemente M(1), Clària J, Titos E. Author information: (1)Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centre Esther Koplowitz, IDIBAPS, CIBERehd, and Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain. PURPOSE OF REVIEW: Obesity is a major risk factor for metabolic syndrome-related comorbidities such as insulin resistance, type-II diabetes, and nonalcoholic fatty liver disease (NAFLD). A wealth of evidence indicates that the associated pathologies of the metabolic syndrome are aggravated by the presence of a chronic state of 'low-grade' inflammation in the adipose tissue. This article discusses recent data implicating lipoxygenases and especially 5-lipoxygenase and its derived products, the leukotrienes, in mounting adipose tissue inflammation and related pathologies in obesity. RECENT FINDINGS: Overexpression of selected members of the 5-lipoxygenase pathway and increased leukotriene production are common findings in excessive visceral fat depots. In these conditions, 5-lipoxygenase products exert potent proinflammatory actions including induction of nuclear factor-κB and secretion of proinflammatory and insulin resistant adipokines (i.e., monocyte chemotactic protein-1, tumor necrosis factor-α, macrophage inflammatory protein-1γ, and interleukin-6) by adipose tissue. The 5-lipoxygenase pathway also plays a major role in mounting inflammation in hepatic tissue and has emerged as a pathogenic factor in obesity-induced NAFLD. Similar role in NAFLD has been proposed for the 12/15-lipoxygenase pathway. SUMMARY: Modulation of lipoxygenases represents a novel target in the prevention of adipose tissue and hepatic dysfunction related to the metabolic syndrome. PMID: 21587068 [PubMed - indexed for MEDLINE] 791. Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):328-33. doi: 10.1097/MCO.0b013e3283478727. Role of intestinal inflammation as an early event in obesity and insulin resistance. Ding S(1), Lund PK. Author information: (1)Department of Cell and Molecular Physiology, Center for Gastrointestinal Biology and Disease University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7574, USA. PURPOSE OF REVIEW: To highlight recent evidence supporting a concept that intestinal inflammation is a mediator or contributor to development of obesity and insulin resistance. RECENT FINDINGS: Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity. Recent findings support a concept that high-fat diet and bacteria interact to promote early inflammatory changes in the small intestine that contribute to development of or susceptibility to obesity and insulin resistance. This review summarizes the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms. SUMMARY: The role of diet-induced intestinal inflammation as an early biomarker and mediator of obesity, and insulin resistance warrants further study. PMCID: PMC3650896 PMID: 21587067 [PubMed - indexed for MEDLINE] 792. Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):341-6. doi: 10.1097/MCO.0b013e328347970b. Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Morris DL(1), Singer K, Lumeng CN. Author information: (1)Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan 48109-5652, USA. PURPOSE OF REVIEW: Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans. RECENT FINDINGS: The phenotypic diversity of ATMs is now known to include more than two types requiring an expansion of the simple concept of an M2 to M1 shift with obesity. Potential functions for ATMs now include the regulation of fibrosis and response to acute lipolysis in states of caloric restriction. Novel pathways that can potentiate ATM action have been identified, which include inflammasome activation and the response to lipodystrophic adipose tissue. Studies provide a new appreciation for the ability of ATMs to respond dynamically to the adipose tissue microenvironment. SUMMARY: ATMs play a key role in shaping the inflammatory milieu within adipose tissue, and it is now apparent that ATM heterogeneity is acutely shaped by the adipose tissue environment. To account for the new findings, we propose a new nomenclature for ATM subtypes that takes into account their diversity. PMID: 21587064 [PubMed - indexed for MEDLINE] 793. Biochim Biophys Acta. 2012 Jan;1821(1):113-23. doi: 10.1016/j.bbalip.2011.05.001. Epub 2011 May 8. Retinyl ester hydrolases and their roles in vitamin A homeostasis. Schreiber R(1), Taschler U, Preiss-Landl K, Wongsiriroj N, Zimmermann R, Lass A. Author information: (1)Institute of Biosciences, University of Graz, Austria. achim.lass@uni-graz.at In mammals, dietary vitamin A intake is essential for the maintenance of adequate retinoid (vitamin A and metabolites) supply of tissues and organs. Retinoids are taken up from animal or plant sources and subsequently stored in form of hydrophobic, biologically inactive retinyl esters (REs). Accessibility of these REs in the intestine, the circulation, and their mobilization from intracellular lipid droplets depends on the hydrolytic action of RE hydrolases (REHs). In particular, the mobilization of hepatic RE stores requires REHs to maintain steady plasma retinol levels thereby assuring constant vitamin A supply in times of food deprivation or inadequate vitamin A intake. In this review, we focus on the roles of extracellular and intracellular REHs in vitamin A metabolism. Furthermore, we will discuss the tissue-specific function of REHs and highlight major gaps in the understanding of RE catabolism. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved. PMCID: PMC3242165 PMID: 21586336 [PubMed - indexed for MEDLINE] 794. Curr Protein Pept Sci. 2011 Jun;12(4):316-24. Alterations in the peptidergic regulation of energy balance in the course of aging. Pétervári E(1), Soós S, Székely M, Balaskó M. Author information: (1)Department of Pathophysiology and Gerontology, Medical School, University of Pécs, Hungary. With advancing age most aspects of the peptidergic regulation of energy balance are altered. The alteration involves both the peripheral peptides derived from the adipose tissue or the gastrointestinal tract and the peptides of the central nervous system (brainstem and hypothalamus). In general, the expression of orexigenic peptides and their receptors decreases with age, while that of the anorexic ones rather increases, but not simultaneously and not in a linear fashion. Apart from such quantitative changes, the efficacy of the related peptides may also change with age. These changes are not necessarily linear, either: instead of continuous decline or increase of its effects, the effects of a peptide may become less pronounced in some phases of aging and much enhanced in other ones. Comparing the individual peptides, the phasic alterations in their anabolic or catabolic roles in the regulation of energy balance may exhibit dissimilar time-patterns. In addition, within the overall anabolic or catabolic effects, the feeding and metabolic actions of certain peptides may not change simultaneously. Altogether, as compared with young adults, in middle-aged animals or individuals the anabolic processes (increased food intake with decreased energy expenditure) seem to prevail, which processes may contribute to the explanation of age-related obesity, while in the old ones the catabolic processes (anorexia with enhanced metabolic rate) dominate, which possibly explain the aging anorexia, frailty and sarcopenia. PMID: 21574955 [PubMed - indexed for MEDLINE] 795. Curr Protein Pept Sci. 2011 Jun;12(4):305-15. Development of insulin resistance during aging: involvement of central processes and role of adipokines. Carrascosa JM(1), Andrés A, Ros M, Bogónez E, Arribas C, Fernández-Agulló T, De Solís AJ, Gallardo N, Martínez C. Author information: (1)Centro de Biología Molecular, Severo Ochoa (UAM-CSIC), Universidad Autónoma, 28049 Madrid, Spain. jmcarrascosa@cbm.uam.es Aging in mammals associates with the development of peripheral insulin resistance. Additionally, adiposity usually increases with aging and this could play a relevant role in the gradual impairment of insulin action. In fact, fat accretion leads to changes in the expression and circulating concentrations of factors originated in adipose tissue like leptin, resistin and inflammatory cytokines which have been shown to modulate insulin signaling in insulin target tissues acting both, directly or through the central nervous system. Even insulin action on peripheral target tissues has been recently demonstrated to be partially mediated by its central action, suggesting that a decrease in central insulin action could be involved in the development of peripheral insulin resistance. In the present review we analyze the available research data on aging-associated insulin resistance making emphasis in the following aspects: 1) The time-course of development of overall insulin resistance and the evolution of changes in circulating adipokines; 2) The effect of caloric restriction and the decrease of adiposity in insulin action; 3) The influence of changes in the central action of factors like leptin or insulin in the development and maintenance of insulin resistance during aging. PMID: 21574953 [PubMed - indexed for MEDLINE] 796. Vasc Endovascular Surg. 2011 Jul;45(5):381-90. doi: 10.1177/1538574411407698. Epub 2011 May 13. The vascular adventitia: its role in the arterial injury response. Havelka GE(1), Kibbe MR. Author information: (1)Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. The belief that the adventitia serves only a structural purpose has changed over the last decade. Studies have begun to elucidate the role the adventitia plays in the arterial response to injury. The adventitial fibroblast plays an integral part in the development of neointimal hyperplasia. Adiponectin, an adipokine produced from periadventitial adipose tissue, exhibits numerous vasoprotective properties. Stem cells arise, in part, from the adventitia, and stem cell recruitment into the adventitia from the vasa vasorum has been shown to be important in the development of neointimal hyperplasia. The exact role the vasa vasorum plays in neointimal growth is poorly understood and different studies endorse conflicting viewpoints. Thus, understanding the nuances of adventitial pathophysiology will allow us to better appreciate the mechanisms behind the pathology of neointimal hyperplasia. This review will summarize recent findings on the active role the adventitia plays toward the development of neointimal hyperplasia. © The Author(s) 2011 PMID: 21571779 [PubMed - indexed for MEDLINE] 797. Cell Commun Signal. 2011 May 14;9:12. doi: 10.1186/1478-811X-9-12. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Hass R(1), Kasper C, Böhm S, Jacobs R. Author information: (1)Laboratory of Biochemistry and Tumor Biology, Gynecology Research Unit, Department of Obstetrics and Gynecology, Medical University, Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. hass.ralf@mh-hannover.de. The mesenchymal stroma harbors an important population of cells that possess stem cell-like characteristics including self renewal and differentiation capacities and can be derived from a variety of different sources. These multipotent mesenchymal stem cells (MSC) can be found in nearly all tissues and are mostly located in perivascular niches. MSC have migratory abilities and can secrete protective factors and act as a primary matrix for tissue regeneration during inflammation, tissue injuries and certain cancers.These functions underlie the important physiological roles of MSC and underscore a significant potential for the clinical use of distinct populations from the various tissues. MSC derived from different adult (adipose tissue, peripheral blood, bone marrow) and neonatal tissues (particular parts of the placenta and umbilical cord) are therefore compared in this mini-review with respect to their cell biological properties, surface marker expression and proliferative capacities. In addition, several MSC functions including in vitro and in vivo differentiation capacities within a variety of lineages and immune-modulatory properties are highlighted. Differences in the extracellular milieu such as the presence of interacting neighbouring cell populations, exposure to proteases or a hypoxic microenvironment contribute to functional developments within MSC populations originating from different tissues, and intracellular conditions such as the expression levels of certain micro RNAs can additionally balance MSC function and fate. PMCID: PMC3117820 PMID: 21569606 [PubMed] 798. Br J Pharmacol. 2012 Feb;165(3):670-82. doi: 10.1111/j.1476-5381.2011.01479.x. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Aghamohammadzadeh R(1), Withers S, Lynch F, Greenstein A, Malik R, Heagerty A. Author information: (1)Cardiovascular Research Group, University of Manchester, Manchester, UK. Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315039 PMID: 21564083 [PubMed - indexed for MEDLINE] 799. Br J Dermatol. 2011 Oct;165(4):743-50. doi: 10.1111/j.1365-2133.2011.10393.x. Obesity and the skin. Shipman AR(1), Millington GW. Author information: (1)Department of Dermatology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich NR4 7UY, UK. Comment in Br J Dermatol. 2012 Jun;166(6):1357-8; author reply 1358-9. Obesity is a serious global health problem, perhaps the biggest public health issue of our times. Excess body weight may be a factor in carcinogenesis in general, as well as contributing to the pathogenesis of metabolic, cardiovascular and musculoskeletal disorders. Obesity also has many cutaneous features, which form the basis for this review article. Many of these clinical entities are common to the majority of obese patients, e.g. striae distensae, plantar hyperkeratosis and an increased risk of skin infections. However, it may also be associated with poor wound healing, malignant melanoma and an increased risk of inflammatory dermatoses, such as psoriasis, as well as some rarer disorders. Therapeutic interventions for obesity, whether over-the-counter, prescription medicines or surgical interventions, are increasingly commonplace. All of these treatment modalities potentially have dermatological side-effects too. © 2011 The Authors. BJD © 2011 British Association of Dermatologists. PMID: 21564065 [PubMed - indexed for MEDLINE] 800. Trends Endocrinol Metab. 2011 Aug;22(8):325-32. doi: 10.1016/j.tem.2011.03.007. Epub 2011 May 10. Emerging roles of JAK-STAT signaling pathways in adipocytes. Richard AJ(1), Stephens JM. Author information: (1)Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA. Twenty years ago, adipocytes were largely considered to be inert energy-storage depots. We now know that fat cells are highly insulin-sensitive with significant endocrine functions. Alterations in adipocyte development or function can contribute to metabolic disease, in particular type 2 diabetes. The current obesity epidemic that plagues many nations provides a strong rationale for understanding basic adipocyte biology. The JAK-STAT signaling pathway mediates the action of a variety of hormones that have profound effects on adipocyte development and function. In addition, adipocytes secrete hormones that utilize this signaling pathway. This review summarizes research on the expression and function of JAKs and STATs in adipocytes and highlights the roles of JAK-STAT-activating cytokines in adipose tissue. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3149764 PMID: 21561789 [PubMed - indexed for MEDLINE] 801. Curr Pharm Biotechnol. 2011 Dec;12(12):1996-2001. The relevance of drug volume of distribution in antibiotic dosing. Ulldemolins M(1), Rello J. Author information: (1)Critical Care Department, University Hospital Vall d’Hebron, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona Spain. Despite the importance of early an appropriate therapy for the outcomes of severe infections in critically ill patients, there is still little understanding of dose optimization during the most important phase of the treatment, the initial phase. Disease-driven variations in pharmacokinetics and pharmacokinetics/ pharmacodynamics may compromise the therapeutic success of antibiotic therapy. Therefore, dose adjustments that account for these variations are paramount for improving antibiotic use in critically ill patients. Compelling evidence shows significant increases in the Vd of both hydrophilic and lipophilic drugs in critically ill patients as a consequence of patient pathology and from clinical interventions. These increases in the Vd can lead to lower than expected plasma concentrations during the first day of therapy, which may result in sub-optimal achievement of antibiotic pharmacokinetics/pharmacodynamic targets, resulting in inappropriate treatment. Therefore, loading doses of antibiotic during the first day of therapy that account for the predicted increase in the Vd are required. Further research towards the establishment of new dosing regimens that use loading doses to satisfy such increased volumes of distribution is recommended. PMID: 21554218 [PubMed - indexed for MEDLINE] 802. J Atheroscler Thromb. 2011;18(7):545-50. Epub 2011 May 7. Adipokines and aging. Arai Y(1), Takayama M, Abe Y, Hirose N. Author information: (1)Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. yasumich@sc.itc.keio.ac.jp Dysregulation of adipose tissue-derived bioactive molecules, termed adipokines, is recognized as common ground for insulin resistance and metabolic syndrome associated with obesity. However, adipokine dysregulation is paradoxically associated with lipodystrophy and lipoatrophy with aging. In familial partial lipodystrophic syndromes and Hutchinson-Gilford progeria syndrome, both of which are caused by mutations in the LMNA gene, loss of adipose tissue is associated with adipokine dysregulation, insulin resistance, and atherosclerosis, suggesting a critical role of adipose tissue function in controlling whole body energy metabolism, age-related pathologies, and longevity. Centenarians, a model of healthy aging and longevity, are reported to exhibit preserved insulin sensitivity as well as favorable adipokine profiles, particularly high levels of circulating adiponectin. Furthermore, adipose tissue dysfunction indicated by dysregulation of leptin, tumor necrosis factor-α, and adiponectin is associated with poor prognosis in centenarians. In contrast to results obtained for obesity, adipokine dysregulation in centenarians is associated with very low leptin levels, suggesting that age-related lipoatrophy is the major factor for adipose tissue dysfunction at an advanced age. These observations suggest that adipose tissue excess as well as its aging is implicated in the regulation of adipokines, insulin sensitivity, and lifespan in humans. PMID: 21551960 [PubMed - indexed for MEDLINE] 803. Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H12-20. doi: 10.1152/ajpheart.00226.2011. Epub 2011 May 6. Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. Clerico A(1), Giannoni A, Vittorini S, Passino C. Author information: (1)Laboratory of Cardiovascular Endocrinology and Cell Biology, Fondazione CNR-Regione Toscana G. Monasterio, Scuola Superiore Sant'Anna, Via Trieste 41, 56126 Pisa, Italy. clerico@ifc.cnr.it Thirty years ago, De Bold et al. (20) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction. PMID: 21551272 [PubMed - indexed for MEDLINE] 804. Physiol Behav. 2011 Jul 25;104(1):8-14. doi: 10.1016/j.physbeh.2011.04.058. Epub 2011 May 6. Metabolic and humoral mechanisms of feeding and genesis of the ATP/ADP/AMP concept. Nicolaidis S(1). Author information: (1)Ex Neurobiologie des Regulations, College de France, Adr. 84 Bd du Marechal Joffre, 92340 Bourg La Reine, France. snicolaidis@laposte.net The organization of the regulatory system of feeding and of the parallel metabolic changes is schematized by a cyclical cartoon depicting the 8 phases of regulation. As I proposed in 1974, the cycle starts with the detection by hypothalamic sensors of decrease of the ATP/ADP/AMP turnover that reflects the post-prandial slow decline of general metabolic rate. That detection is translated into a signal of hunger. Experimental evidence is provided. Once initiated, this 'basic' signal follows the 7 remaining steps of the cycle, particularly the steps 2 and 4, where it receives multiple 'modulating' positive and negative signals (particularly peptides) that inform the central regulator, on the state of peripheral organs such as the adipocytes, stomach, intestine, and liver, on the outside world like day/light and on the available foods. Particular attention is given to the homeostatic and "homeoreutic" (see definition in the text) regulation of adipose reserves that are announced to brain specialized glio-neuronal "lipo-counters". The role of insulin alongside leptin is shown. The conception of a part of the above mechanisms postulates and shows that some specialized glio-neuronal populations in the antero-ventral hypothalamus share metabolic properties along with somatic cells. Finally, the signal resulting from the algebraic sum of the main (the metabolic) signal and of the modulating pluses and minuses (peptides) leaves the integrative units and reaches the efferent phases (steps 5 and 6) that finish by inducing both metabolic adjustments and consequently food intake. The last steps (4 to 8) are only shortly commented. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21550354 [PubMed - indexed for MEDLINE] 805. Regul Pept. 2011 Oct 10;170(1-3):7-17. doi: 10.1016/j.regpep.2011.04.005. Epub 2011 May 4. Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function. Kalafatakis K(1), Triantafyllou K. Author information: (1)Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, “Attikon” University General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece. Among various hormones, which are synthesized by intestinal cells and influence enteric function, neurotensin (NT) has gained scientific attention the last three decades. This neuropeptide, mainly located in neuronal synaptic vesicles of hypothalamus and in neuroendocrine cells of the small bowel, participates in enteric digestive processes, gut motility and intestinal inflammatory mechanisms by cooperating with other regulators such as histamine, substance P and somatostatin. NT plays an important role mainly in intestinal lipid metabolism by cooperating with cholecystokinin and establishes a hormonal brain-gut-adipose tissue connection, which could adjust appetite, weight status and generally eating behavior with the amount and the content (particularly fat) of food intake. Moreover, NT achieves a multi-level control of intestinal motility by cooperating with the enteric- and central nervous system, and other enteric hormones (such as somatostatin). NT regulates motility patterns related to the efficiency of the digestive process, stool emptying, transition from the fasted to the postprandial state and reestablishment of the fasted status. In addition, NT possesses a long-term enteroprotective role towards the intestinal tract, despite the fact that under certain circumstances NT may participate in short-term subcellular pathways promoting an acute inflammatory response. The aim of this review is two-fold. First, is to provide an up-to-date synopsis of the available knowledge regarding the involvement of neurotensin in enteric functional status, and highlight its significance in physiological and pathological conditions. Second, is to propose new research directions concerning the role of neurotensin and other intestinal regulatory peptides in the establishment of the brain-gut axis and in the development of functional disorders of the abdominal tract. Conclusively, to clarify the areas, in which an experimental therapeutic intervention, based on NT analogs, may lead to encouraging results. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 21549161 [PubMed - indexed for MEDLINE] 806. Curr Pharm Des. 2011;17(16):1576-82. Neuropeptide - adipose tissue communication and intestinal pathophysiology. Karagiannides I(1), Bakirtzi K, Pothoulakis C. Author information: (1)Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA. cpothoulakis@mednet.ucla.edu Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. During this time adipose tissue has been shown to produce a number of hormones and inflammatory mediators collectively termed as adipokines. These molecules have been shown to be involved in the etiology of a number of inflammation-associated pathological conditions ranging from atherosclerosis and hypertension to diabetes and cancer. Despite the close physical association of abdominal fat and the intestine in the visceral cavity and the significant paracrine functions now attributed to adipose tissue, very little is known on the potential interactions between these tissues as they may relate to intestinal homeostasis. Considering the dramatic alterations in mesenteric fat depot size and placement during at least one intestinal disease, Crohn's disease, the potential involvement of fat tissue in the development as well as the progression of this and other pathological conditions should be considered. In this review we discuss the latest knowledge on neuropeptide-adipose tissue communication and the potential changes such interaction may induce in intra-abdominal fat tissue physiology. Finally we will discuss evidence on the potential pathways by which such changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease. PMID: 21548874 [PubMed - indexed for MEDLINE] 807. Annu Rev Nutr. 2011 Aug 21;31:155-76. doi: 10.1146/annurev-nutr-072610-145149. Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. Chuang CC(1), McIntosh MK. Author information: (1)Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402, USA. c_chuan2@uncg.edu Obesity and metabolic disease-related health problems (e.g., type 2 diabetes, atherosclerosis, and hypertension) are the most prevalent nutrition-related issues in the United States. An emerging feature of obesity and type 2 diabetes is their linkage with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential strategy to reduce inflammation and insulin resistance is consumption of polyphenol-rich foods like grapes or their by-products, which have anti-inflammatory properties. Polyphenols commonly found in grape products have been reported to reduce inflammation by (a) acting as an antioxidant or increasing antioxidant gene or protein expression, (b) attenuating endoplasmic reticulum stress signaling, (c) blocking proinflammatory cytokines or endotoxin-mediated kinases and transcription factors involved in metabolic disease, (d) suppressing inflammatory- or inducing metabolic-gene expression via increasing histone deacetylase activity, or (e) activating transcription factors that antagonize chronic inflammation. Thus, polyphenol-rich grape products may reduce obesity-mediated chronic inflammation by multiple mechanisms, thereby preventing metabolic diseases. PMID: 21548775 [PubMed - indexed for MEDLINE] 808. Annu Rev Nutr. 2011 Aug 21;31:33-47. doi: 10.1146/annurev-nutr-072610-145209. The implication of brown adipose tissue for humans. Ravussin E(1), Galgani JE. Author information: (1)Human Physiology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. eric.ravussin@pbrc.edu We here discuss the role of brown adipose tissue on energy homeostasis and assess its potential as a target for body weight management. Because of their high number of mitochondria and the presence of uncoupling protein 1, brown fat adipocytes can be termed as energy inefficient for adenosine-5'-triphosphate (ATP) production but energy efficient for heat production. Thus, the energy inefficiency of ATP production, despite high energy substrate oxidation, allows brown adipose tissue to generate heat for body temperature regulation. Whether such thermogenic property also plays a role in body weight regulation is still debated. The recent (re)discovery of brown adipose tissue in human adults and a better understanding of brown adipose tissue development have encouraged the quest for new alternatives to treat obesity since obese individuals seem to have less brown adipose tissue mass/activity than do their lean counterparts. In this review, we discuss the physiological relevance of brown adipose tissue on thermogenesis and its potential usefulness on body weight control in humans. PMCID: PMC4404503 PMID: 21548774 [PubMed - indexed for MEDLINE] 809. Br J Pharmacol. 2012 Feb;165(3):659-69. doi: 10.1111/j.1476-5381.2011.01370.x. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Payne GA(1), Kohr MC, Tune JD. Author information: (1)Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Adipose tissue is an active endocrine and paracrine organ that may influence the development of atherosclerosis and vascular disease. In the setting of obesity, adipose tissue produces a variety of inflammatory cytokines (or adipokines) that are known to modulate key mechanisms of atherogenesis. In particular, adipose tissue located on the surface of the heart surrounding large coronary arteries (i.e. epicardial perivascular adipose tissue) has been implicated in the pathogenesis of coronary artery disease. The present review outlines our current understanding of the cellular and molecular links between perivascular adipose tissue and atherosclerosis with a focus on potential mechanisms by which epicardial perivascular adipose tissue contributes to obesity-related coronary disease. The pathophysiology of perivascular adipose tissue in obesity and its influence on oxidative stress, inflammation, endothelial dysfunction and vascular reactivity is addressed. In addition, the contribution of specific epicardial perivascular adipose-derived adipokines (e.g. leptin, adiponectin) to the initiation and expansion of coronary disease is also highlighted. Finally, future investigative goals are discussed with an emphasis on indentifying novel therapeutic targets and disease markers within perivascular adipose tissue.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315038 PMID: 21545577 [PubMed - indexed for MEDLINE] 810. Arch Physiol Biochem. 2011 Jul;117(3):188-94. doi: 10.3109/13813455.2011.571700. Epub 2011 May 6. A new paradigm for the understanding of obesity: the role of stem cells. San Martín N(1), Gálvez BG. Author information: (1)Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Obesity is a pandemic disorder that can be defined as a chronic excess of adipose tissue that increases the risk of suffering chronic diseases such as, diabetes, arterial hypertension, stroke and some forms of cancer. We now know that adipose tissue, aside from being an energy store, is also an important endocrine and metabolic organ. Recently, new mechanisms that control obesity have been identified, such as the equilibrium between white and brown adipose tissue, the localization of adipose mass (visceral or ventral), and the presence of adipose and mesenchymal stem cells. In this review, we describe the implication of these stem cell types in the normal physiology and dysfunction of adipose tissue. These stem cells provide a potential target for modulating the response of the body to obesity and diabetes, as well as a potential tool for regenerative medicine. PMID: 21545335 [PubMed - indexed for MEDLINE] 811. Stem Cells. 2011 Jul;29(7):1034-40. doi: 10.1002/stem.653. Concise review: adipocyte origins: weighing the possibilities. Majka SM(1), Barak Y, Klemm DJ. Author information: (1)Gates Center for Stem Cell Biology and Regenerative Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA. Adipose tissue is the primary energy reservoir in the body and an important endocrine organ that plays roles in energy homeostasis, feeding, insulin sensitivity, and inflammation. While it was tacitly assumed that fat in different anatomical locations had a common origin and homogenous function, it is now clear that regional differences exist in adipose tissue characteristics and function. This is exemplified by the link between increased deep abdominal or visceral fat, but not peripheral adipose tissue and the metabolic disturbances associated with obesity. Regional differences in fat function are due in large part to distinct adipocyte populations that comprise the different fat depots. Evidence accrued primarily in the last decade indicates that the distinct adipocyte populations are generated by a number of processes during and after development. These include the production of adipocytes from different germ cell layers, the formation of distinct preadipocyte populations from mesenchymal progenitors of mesodermal origin, and the production of adipocytes from hematopoietic stem cells from the bone marrow. This review will examine each of these process and their relevance to normal adipose tissue formation and contribution to obesity-related diseases. Copyright © 2011 AlphaMed Press. PMCID: PMC3428116 PMID: 21544899 [PubMed - indexed for MEDLINE] 812. Int Urol Nephrol. 2011 Sep;43(3):771-84. doi: 10.1007/s11255-011-9974-1. Epub 2011 May 5. The role of obesity in kidney disease: recent findings and potential mechanisms. Kalaitzidis RG(1), Siamopoulos KC. Author information: (1)Department of Internal Medicine, Medical School, University of Ioannina, 451 10 Ioannina, Greece. Obesity epidemic is in rise in almost every industrialized country and continues to be a growing problem worldwide. In fact, obesity per se has been recognized as a chronic disease. Consequently, there has been a cascade of metabolic changes initiated by the markedly risen prevalence that contributes to the increased incidence of diabetes, hypertension, and cardiovascular disease. Moreover, obesity is also associated with an increased risk of chronic kidney disease (CKD). The majority of the studies indicate a direct relationship between body mass index (BMI) and CKD risk. Moreover, current evidence emphasized the fact that central obesity measurements, such as waist circumference, could be a better predictor of CKD progression and mortality than BMI. The detrimental effects of obesity on kidney outcome have been recognized in nondialysis-dependent (NDD)-CKD patients. However, survival in overweight or obese CKD patients undergoing maintenance hemodialysis is paradoxically opposed compared with the general population. This "reverse epidemiology," however, is valid mainly for the inflammated end-stage renal disease (ESRD) patients. In fact, renal transplant recipients with higher BMI have inferior patient and graft survival compared to patients with lower BMI. This review also provides perspectives concerning the mechanisms associated with obesity, such as the renin-angiotensin-aldosterone system (RAAS) activation, and the role of leptin, adiponectin, fetuin-A, and adipose tissue, as factors that contribute to the development of CKD. Prevention strategies for CKD patients are also discussed and should be considered by clinicians. PMID: 21544651 [PubMed - indexed for MEDLINE] 813. Vestn Ross Akad Med Nauk. 2011;(3):37-42. [Markers of endocrine system and inflammation as prognostic risk factors of vascular complications of type 2 diabetes mellitus]. [Article in Russian] Verbovoĭ AF, Morkovskikh NV. The high risk of cardiovascular complications in patients with type 2 diabetes mellitus is a key problem in modern medicine. In this review, the basic risk factors of vascular complications in diabetes mellitus are described and their prognostic value analysed. Special attention is paid to the evaluation of the role of adipose tissue hormone adiponectin. The anti-inflammatory properties of adiponectin suggest its protective action against atherosclerosis and cardiovascular complications. In this article, we review a number of studies on the relationship between adiponectin and the main cardiovascular risk factors in patients with type 2 diabetes mellitus. PMID: 21542374 [PubMed - indexed for MEDLINE] 814. Diabetes Care. 2011 May;34 Suppl 2:S371-9. doi: 10.2337/dc11-s250. Myocardial, perivascular, and epicardial fat. Iozzo P(1). Author information: (1)Institute of Clinical Physiology, National Research Council, Pisa, Italy. patricia.iozzo@ifc.cnr.it Myocardial fat content refers to the storage of triglyceride droplets within cardiomyocytes. In addition, the heart and arteries are surrounded by layers of adipose tissue, exerting vasocrine and paracrine control of the subtending tissues. The rapid development of the field of noninvasive imaging has made it possible to quantify ectopic fat masses and contents with an increasing degree of accuracy. Myocardial triglyceride stores are increased in obesity, impaired glucose tolerance, and type 2 diabetes. The role of intramyocardial triglyceride accumulation in the pathogenesis of left ventricular (LV) dysfunction remains unclear. Increased triglyceride content is associated with states of fatty acid overload to the heart, saturating the oxidative capacity. It may initially serve as a fatty acid sink to circumscribe the formation of toxic lipid species and subsequently foster cardiac damage. Epicardial and perivascular fat depots may exert a protective modulation of vascular function and energy partition in a healthy situation, but their expansion turns them into an adverse lipotoxic, prothrombotic, and proinflammatory organ. They are augmented in patients with metabolic disorders and coronary artery disease (CAD). However, the progressive association between the quantity of fat and disease severity in terms of extent of plaque calcification or noncalcified areas, markers of plaque vulnerability, and number of vessels involved is less confirmed. Functional or hybrid imaging may contribute to a better definition of disease severity and unveil the direct myocardial and vascular targets of adipose tissue action. PMCID: PMC3632210 PMID: 21525485 [PubMed - indexed for MEDLINE] 815. Diabetes Care. 2011 May;34 Suppl 2:S367-70. doi: 10.2337/dc11-s249. Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. Perseghin G(1). Author information: (1)Department of Sport, Nutrition and Health, Università degli Studi di Milano, Milan, Italy. perseghin.gianluca@hsr.it PMCID: PMC3632209 PMID: 21525484 [PubMed - indexed for MEDLINE] 816. Autoimmun Rev. 2011 Aug;10(10):582-9. doi: 10.1016/j.autrev.2011.04.018. Epub 2011 Apr 22. The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular risk. Gremese E(1), Ferraccioli G. Author information: (1)Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy. elisa.gremese@rm.unicatt.it Rheumatoid arthritis (RA) patients have an incidence of cardiovascular (CV) diseases at least two times higher than the general population. Atherosclerosis, the main determinant of CV morbidity and mortality, and carotid intima-media thickness, an early preclinical marker of atherosclerosis, also occur early on in RA. Traditional CV risk factors seem to have the same prevalence in RA and non-RA patients, and thus do not fully explain the increased CV burden, suggesting that RA inflammation and therapies play a role in increasing CV risk in these patients. The metabolic syndrome and fat tissue are likely to be the major players in this complex network. The metabolic syndrome (MetS) represents a cluster of cardiovascular risk factors that have in common insulin resistance and increased visceral adiposity. This entity has received great attention in the last few years due to its contribution to the burden of cardiovascular morbidity and mortality. Moreover, recently the adipose tissue has emerged as a dynamic organ that releases several inflammatory and immune mediators (adipokines). The association of MetS and atherosclerosis is thought to be partly mediated by altered secretion of adipokines by the adipose tissue and, on the other hand, there are evidence that adipokines may play some role in inflammatory arthritides. Obesity is now regarded as a systemic, low-grade inflammatory state, and inflammation as a link between obesity, metabolic syndrome, and cardiovascular diseases. To obtain a full control of the CV risk, data suggest that it is therefore mandatory a "tight control" of both RA and MetS inflammations. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 21539940 [PubMed - indexed for MEDLINE] 817. World J Diabetes. 2010 Sep 15;1(4):116-28. doi: 10.4239/wjd.v1.i4.116. Pharmacological effects of lipid-lowering drugs on circulating adipokines. Wanders D(1), Plaisance EP, Judd RL. Author information: (1)Desiree Wanders, Robert L Judd, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States. The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism. However, emerging evidence indicates that lipid-lowering drugs also modulate the synthesis and secretion of adipose tissue-secreted proteins referred to as adipokines. Adipokines influence energy homeostasis and metabolism and have also been shown to modulate the vascular inflammatory cascade. The purpose of this review will be to examine the reported effects of commonly used lipid-lowering drugs (statins, fibrates, niacin and omega-3-fatty acids) on the circulating concentrations of leptin, adiponectin, tumor necrosis-factor-α (TNF-α), Retinol binding protein 4 (RBP4) and resistin. Overall, the lipid-lowering drugs reviewed have minimal effects on leptin and resistin concentrations.Conversely, circulating adiponectin concentrations are consistently increased by each lipid-lowering drug reviewed with the greatest effects produced by niacin. Studies that have examined the effects of statins, niacin and omega-3-fatty acids on TNF-α demonstrate that these agents have little effect on circulating TNF-α concentrations. Niacin and fibrates appear to lower RBP4 but not resistin concentrations. The results of the available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and adiponectin that is not obvious for other adipokines reviewed. PMCID: PMC3083894 PMID: 21537437 [PubMed] 818. Endocr Rev. 2011 Aug;32(4):498-514. doi: 10.1210/er.2010-0020. Epub 2011 May 2. Genetic syndromes of severe insulin resistance. Semple RK(1), Savage DB, Cochran EK, Gorden P, O'Rahilly S. Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. rks16@cam.ac.uk Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology. PMID: 21536711 [PubMed - indexed for MEDLINE] 819. Tijdschr Diergeneeskd. 2011 Apr 1;136(4):244-55. [Postnatal changes in the ductus arteriosus and brown adipose tissue: a review and an exploratory post-mortem study of lambs]. [Article in Dutch] Egberts J(1). Author information: (1)Afd. Algemene Ziektekunde, Pathologie, Faculteit der Diergeneeskunde, Utrecht. hansegberts@gmail.com After a short review of the literature, postnatal changes in the ductus arteriosus Botalli are described in 52 lambs sampled in 1970 and 1971. Five groups of animals were formed on the basis of findings. (I) All lambs (n = 18) that died of asphyxia or prematurity had open ducti and, in most cases, severe adventitial bleeding (2). Completely anatomically closed ducti were found in I-week-old lambs (n = 9). Lambs that died within about 4 days of birth were grouped as (3) low-birth weight (dysmaturity) (n = 2), (4) normal weight and died after bacterial infection (n = 7), or (5) normal birth weight and died of other causes (n = 6). The dysmature lambs died because of cold and poor suckling. Compared with the lambs with a normal body weight, the dysmature lambs had almost completely closed ducti. Extensive, often circular, haemorrhages at the periphery of the necrotic muscular tissue of the ductal media were found in the dysmature and infected lambs. In these lambs, the brown adipose tissue surrounding the ductus was red-brownish and often depleted of its fat. This fat depletion and haemorrhages were less severe in lambs that died of other causes. The haemorrhages in the media of the ductus arteriosus, which were not found in older lambs, have not been described previously in other species, including humans. These haemorrhages are most likely the result of a short period of ductal relaxation, resulting in the passage of blood through the vasa vasorum and leakage of blood cells from degenerated capillaries at the border of the necrotic muscular tissue. It is hypothesized that the relaxation results from one or a combination of the following: (i) direct heat from heat-producing brown adipose tissue surrounding the ductus (because of cold or infection), (2) infection or inflammatory mediators, and (3) adipose tissue-derived relaxing factors. PMID: 21534277 [PubMed - indexed for MEDLINE] 820. Clin Calcium. 2011 May;21(5):703-8. doi: CliCa1105703708. [Adipocytes and bone metabolism]. [Article in Japanese] Waki H(1), Yamauchi T, Kadowaki T. Author information: (1)Department of Diabetes and Metabolic Diseases, the University of Tokyo. Adipocytes, osteoblasts and chondrocytes derive from common mesenchymal stem cells. A number of factors were reported to regulate differentiation of multiple cell types among adipocytes, osteoblasts and chondrocytes. Thiazolidinediones are prescribed to treat diabetes in obese subjects, but recent clinical data suggested that it increases a risk of bone fracture especially in postmenopausal women. Here, we will review recent advances in the researches of mutual connection between adipocytes and bone metabolism. PMID: 21532120 [PubMed - indexed for MEDLINE] 821. Clin Calcium. 2011 May;21(5):677-82. doi: CliCa1105677682. [Bone metabolism in dyslipidemia and metabolic syndrome]. [Article in Japanese] Yamaguchi T(1). Author information: (1)Internal Medicine 1, Shimane University Faculty of Medicine. Dyslipidemia and osteoporosis are etiologically related to each other. Experiments show that oxidized LDL suppresses the differentiation of bone marrow stromal cells to osteoblasts, while it promotes that to adipocytes, which may result in fatty marrow and bone mass reduction. Inactivation of LRP5÷6 is linked to hypercholesterolemia as well as bone mass reduction, indicating the involvement of Wnt signaling in both disorders. A few clinical studies suggest that high serum triglyceride levels may lower the risk of vertebral fractures. Metabolic syndrome, especially visceral fat accumulation, may have a beneficial effect on bone possibly through mechanical stress from gravity, as long as patients are devoid of advanced type 2 diabetes and are less affected by hyperglycemia or oxidative stress. PMID: 21532116 [PubMed - indexed for MEDLINE] 822. Curr Aging Sci. 2011 Dec;4(3):221-33. Age-related changes in adult muscle morphology. Kostek MC(1), Delmonico MJ. Author information: (1)mkostek@mailbox.sc.edu Skeletal muscle undergoes numerous morphological changes from early adulthood to old age including muscle size, configuration, and structure. This review discusses these changes, considers the limitations in interpreting studies, addresses the potential health implications, and describes some mechanisms and interventions to ameliorate aging-related changes in skeletal muscle. Discussion in each section focuses on measurement and analysis techniques of muscle morphology, limitations of human research, and the discussion uses animal work to support findings in humans. We examine the discrepancies in the study of fiber type distribution with age, and special emphasis is given to two topics: fiber-type distribution and intra- and intercellular fat. Finally, training adaptations and health implications are briefly discussed. The focus of the current review is the morphological changes that occur in skeletal muscle during the normal aging process, with emphasis on human studies. PMID: 21529325 [PubMed - indexed for MEDLINE] 823. Physiol Rev. 2011 Apr;91(2):389-411. doi: 10.1152/physrev.00007.2010. Leptin and the central nervous system control of glucose metabolism. Morton GJ(1), Schwartz MW. Author information: (1)Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. gjmorton@u.washington.edu The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMCID: PMC3379883 PMID: 21527729 [PubMed - indexed for MEDLINE] 824. Stem Cells Dev. 2011 Oct;20(10):1793-804. doi: 10.1089/scd.2011.0040. Epub 2011 Jun 20. Current methods of adipogenic differentiation of mesenchymal stem cells. Scott MA(1), Nguyen VT, Levi B, James AW. Author information: (1)Orthodontics and Dentofacial Orthopedics, College of Dental Medicine, University of Southern Nevada, Henderson, Nevada, USA. There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator-activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques--however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted. PMCID: PMC3182038 PMID: 21526925 [PubMed - indexed for MEDLINE] 825. Pediatr Endocrinol Rev. 2011 Mar;8(3):190-9. Congenital syndromes of severe insulin resistance. Huang-Doran I(1), Savage DB. Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, UK. Rare syndromes of severe insulin resistance (IR), caused by genetic defects in canonical insulin signalling or adipose tissue development, place patients at high, early risk of adverse clinical complications but are clinically challenging to manage. Prompt evaluation and diagnosis of these individuals not only facilitates more appropriate intervention but, together with identification of the underlying genetic defects, may provide valuable mechanistic insights into the pathogenesis of rare as well as common, obesity-associated IR. Although diagnosis of these syndromes is complicated by the variability of their natural history, several presenting features are common to all severe IR syndromes including disturbed glucose metabolism (either hypoglycaemia or hyperglycaemia), acanthosis nigricans and severe ovarian dysfunction in lean individuals. These features may be evident at birth, or appear during childhood or adolescence, so their recognition by paediatricians is essential. Here we review the general and specific features of syndromes of severe IR, summarise their classification, and recommend strategies for their subsequent investigation. PMID: 21525795 [PubMed - indexed for MEDLINE] 826. Clin Endocrinol (Oxf). 2011 Jun;74(6):661-70. doi: 10.1111/j.1365-2265.2011.04018.x. Brown fat and obesity: the next big thing? Stephens M(1), Ludgate M, Rees DA. Author information: (1)Centre for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, UK. Brown adipose tissue (BAT) is well recognised to have an important role in the maintenance of body temperature in animals and human neonates, its thermogenic action affected by a tissue-specific uncoupling protein; fatty acid oxidation within the numerous brown adipocyte mitochondria is rendered inefficient leading to heat, rather than adenosine triphosphate (ATP), production. BAT was believed to show rapid involution in early childhood, leaving only vestigial amounts in adults. However, recent evidence suggests that its expression in adults is far more common than previously appreciated, with a higher likelihood of detection in women and leaner individuals. It is conceivable that BAT activity might reduce the risk of developing obesity since fat stores are used for thermogenesis, and a directed enhancement of adipocyte metabolism might have value in weight reduction. However, it is as yet unclear how such manipulation of BAT might be achieved; even in animal models, the control of thermogenic activity is incompletely understood. Even so, there is still much to interest the endocrinologist in BAT, with a range of hormones affecting adipocyte activity. This may either contribute to normal physiological function, or the phenotypical presentation of states of pathological hormone excess or deficiency. Thus, the gender differences in BAT distribution may be attributable to the differential effects of male and female sex hormones, whilst BAT expansion may drive the weight loss associated with catecholamine-producing phaeochromocytomas. These observations support an important influence of the endocrine system on BAT activity and offer new potential targets in the treatment of obesity. © 2011 Blackwell Publishing Ltd. PMID: 21521287 [PubMed - indexed for MEDLINE] 827. Curr Pharm Des. 2011;17(15):1500-11. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Giagulli VA(1), Triggiani V, Corona G, Carbone D, Licchelli B, Tafaro E, Resta F, Sabbà C, Maggi M, Guastamacchia E. Author information: (1)Endocrinology and Metabolic Diseases, University of Bari Aldo Moro, Foggia, Italy. vitogiagulli@alice.it Until the 2000s Testosterone (T) Replacement Therapy (TRT) wasn't very satisfactory for male hypogonadic patients because the available T formulations weren't able to reproduce the physiological pattern of T secretion in man. In fact, oral formulations (oral undecanoate T) showed very short half-life (<24 hours), requiring the administration of several daily doses, whereas the old injection products (T esters) were characterized by very long half-life (>7 days) because of their adipose tissue storage, requiring to be administered every 2-3 weeks but determining remarkable and quick fluctuations (in 2-3 weeks) of the testosteronemia with variations in a few days from over-physiological levels (> 2000 ng/dl) to very low levels (< 200 ng/dl). Nowadays, several compounds can attain the standards of suitability and effectiveness of TRT in hypogonadal men. Both transcutaneous (gel) T and long-acting injectable formulations are the most modern preparations that can satisfy the criteria of an ideal chronic replacement therapy. In fact, they keep the serum T levels in the physiological range imitating its circadian rhythm, leading to the development and/or the preservation of male sexual characteristics and, finally, positively influencing bone mass, skeletal muscle and adipose tissue distribution. In particular, the availability and use of long-acting injectable undecanoate T can really improve the patients' compliance as requested for a life-long treatment. However, definitive and conclusive evidence regarding the main end-points, such as the diminished recurrence of falls in elderly men, the decrease in fractures in osteoporotic subjects, the reduction in disabling conditions and the extension of life, have not been reached so far. Therefore, the aim of this review is to sum up the most important evidence that has been collected regarding TRT, highlighting in particular those concerning both transcutaneous and long-acting injectable T compounds. PMID: 21521164 [PubMed - indexed for MEDLINE] 828. Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):360-6. doi: 10.1097/MCO.0b013e328346df4e. Osteocalcin: a new link between bone and energy metabolism. Some evolutionary clues. Fernández-Real JM(1), Ricart W. Author information: (1)Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona (IdIBGi) CIBER Fisiopatología de la Obesidad y Nutrición CB06/03/010, Girona, Catalonia, Spain. jmfernandezreal.girona.ics@gencat.cat PURPOSE OF REVIEW: Recent findings suggest that the bone is an active regulator of energy and glucose metabolism. The purpose of this review is to summarize current evidence in humans. RECENT FINDINGS: Both cross-sectional and longitudinal studies support osteocalcin as an active regulator of carbohydrate metabolism in humans, being the muscular load of physical activity one of the possible links between the osteoblast and the insulin axis. This axis could also have been involved in the modulation of nonalcoholic steatohepatitis. The osteoblast-to-insulin axis seems to act paradoxically in patients with increased growth hormone (acromegaly) and during bone repair. Some possible evolutionary implications are suggested. SUMMARY: Osteocalcin may have a role in the regulation of systemic energy metabolism, given the common origin of the osteoblast with the two other cells implicated (adipocytes and muscle cells). Bioactivity of circulating human carboxylated and uncarboxylated osteocalcin should be characterized in depth, especially in those patients with increased concentrations (renal failure). Osteocalcin is one of the clues in the interaction between calcium and glucose metabolism, and the discovery of the osteocalcin receptor will aid in the study of these relationships. PMID: 21519236 [PubMed - indexed for MEDLINE] 829. J Endocrinol. 2012 Jan;212(1):3-12. doi: 10.1530/JOE-11-0044. Epub 2011 Apr 21. The diversity of sex steroid action: regulation of metabolism by estrogen signaling. Faulds MH(1), Zhao C, Dahlman-Wright K, Gustafsson JÅ. Author information: (1)Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden. malhed@ki.se Comment in J Endocrinol. 2012 Jan;212(1):1-2. The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic β cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed. PMID: 21511884 [PubMed - indexed for MEDLINE] 830. Obstet Gynecol Surv. 2011 Jan;66(1):47-63. doi: 10.1097/OGX.0b013e318217b0a4. Adipokines: new emerging roles in fertility and reproduction. Tersigni C(1), Di Nicuolo F, D'Ippolito S, Veglia M, Castellucci M, Di Simone N. Author information: (1)Department of Obstetrics and Gynecology, Catholic University School of Medicine, Rome, Italy. Adipose tissue is a specialized endocrine and paracrine organ producing specific factors called adipokines. It is well known that adipokines balance is fundamental to prevent obesity, metabolic syndrome, and cardiovascular diseases. During the last years, new roles of adipokines have been emerging in the field of fertility and reproduction. Although the literature is still quite controversial, this review serves to resume current knowledge on this topic. Alterations in adipokine levels or in their mechanism of action are associated with fertility impairment and pregnancy diseases, as well as with obesity, metabolic syndrome, and cardiovascular diseases. Normal levels of adipokines are fundamental to maintain integrity of hypothalamus-pituitary-gonadal axis, regular ovulatory processes, successful embryo implantation, and physiologic pregnancy. More efforts are needed to understand the mechanisms and to the extent to which adipokine changes are involved in the impairment of fertility and pregnancy outcome, to find possible medical treatments.TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this educational activity, the obstetrician/gynecologist should be better able to demonstrate current knowledge in the research field of adipokines in fertility and reproduction; evaluate the central role of metabolism balance in good pregnancy outcome; and apply new perspectives of studies. PMID: 21510912 [PubMed - indexed for MEDLINE] 831. Expert Opin Drug Metab Toxicol. 2011 Aug;7(8):949-65. doi: 10.1517/17425255.2011.577740. Epub 2011 Apr 21. The mechanistic basis for the induction of hepatic steatosis by xenobiotics. Amacher DE(1). Author information: (1)Sciadvisor Toxicology Consultant, Hadlyme, CT 06439, USA. Toxadvisor-hadlyme@yahoo.com INTRODUCTION: Hepatic steatosis is the histological observation of numerous lipid inclusions due to an excess accumulation of triacylglycerols. They are a concern with new therapeutic candidates because they signify altered lipid metabolism that can progress to more serious liver toxicity. AREAS COVERED: This article is based on an article search using the PubMed database from 1987 to 2011 and confirms associations for several previously marketed drugs with four basic hepatocellular mechanisms. The article also describes how these mechanisms are controlled by master regulators of lipid metabolism, which include gene transcription factors, nuclear receptors, hormonal signaling, energy sensing proteins, endoplasmic reticulum stress signaling and certain key metabolic intermediates. EXPERT OPINION: Drug-induced hepatic steatosis is typically not detectable by conventional means other than invasive histological examinations. By understanding the basic mechanisms, key regulators and energy signaling systems of the liver, the investigator is better equipped to avoid xenobiotics with steatogenic potential in the drug discovery or early development process. There are now a number of methods for detecting this potential, specifically gene expression or metabolomic profiling and pathway analysis or mechanism-based in vitro systems. PMID: 21510823 [PubMed - indexed for MEDLINE] 832. Trop Anim Health Prod. 2011 Oct;43(7):1371-8. doi: 10.1007/s11250-011-9865-6. Epub 2011 Apr 21. The effects of diet, slaughter weight and docking on growth, carcass composition and meat quality of fat-tailed Barbarine lambs. A review. Atti N(1), Mahouachi M. Author information: (1)Laboratoire de Productions Animales et Fourragères, INRA-Tunisie, rue Hédi Karray, 2080 Ariana, Tunisia. belhaj.naziha@iresa.agrinet.tn This review summarises the main factors that influence meat production and quality in fat-tailed Barbarine (FTB) lambs. As a general feature, FTB lamb's growth is moderate, and the average daily gain ranges between 100 and 350 g. The carcass being relatively fatty, carcass fat content varies from 10% to 32%; white fat and rose meat are often dominant in these carcasses. The meat fatty acid profile of this fat-tailed breed is similar to that of thin-tailed ones, with a prevalence of palmitic, stearic and oleic acids. The order of dissected adipose tissues accumulation, estimated by allometry coefficients, is in agreement with observations in thin-tailed sheep. However, tail fat allometry coefficient is closer to kidney fat values rather than to the subcutaneous one. Concerning effects of feed level, growth of FTB lambs fed silage is higher than those fed oat hay. With moderate concentrate supply, FTB lambs' growth is more pronounced on pasture diet than on the feedlot (FL) diet. Furthermore, at similar slaughter weights, carcasses of lambs fed pasture diet have less tail and carcass fat than those from lambs fed FL diet (5% and 18% vs. 9% and 24% for grazing and FL lambs, respectively). No difference in fat colour, fat firmness or cooked meat flavour is observed between carcasses obtained at different slaughtering weight (i.e. from 25 to 35 kg). The tail docking of FTB improved lambs' growth particularly before weaning. Its effect on carcass composition and fat proportion depends on stage of slaughtering and type of fattening diet. For suckled lambs (4 months), the docking resulted in the lower carcass fat weight (and proportion), while for fattened lambs, carcass composition was similar for all types of lambs. Overall, FTB lambs always grow slower than Noire de Thibar lambs. This is particularly pronounced during the fattening phase. Then, for FTB breed, the possibilities to obtain heavy carcasses are at risks of fat accumulation, 22.8% vs. 14.4% for FTB and Noire de Thibar thin-tailed lambs, respectively. However, the main advantage of FTB breed is that adults are well adapted to food scarcity and may produce lambs even under harsh conditions. PMID: 21509453 [PubMed - indexed for MEDLINE] 833. Curr Opin Pediatr. 2011 Jun;23(3):269-74. doi: 10.1097/MOP.0b013e3283464b3e. Insulin resistance in critical illness. Dhar A(1), Castillo L. Author information: (1)Division of Critical Care, Department of Pediatrics, Children's Medical Center, University of Texas Southwestern, Dallas, USA. PURPOSE OF REVIEW: The purpose of this review is to describe current concepts on inflammation, immunity and insulin resistance. Metabolic and immune systems are closely involved in inflammation and significantly contribute to the pathology seen in the pediatric intensive care unit. The ability of insulin to decrease hepatic glucose production, suppress adipose tissue lipolytic rate, stimulate skeletal muscle glucose uptake, suppress protein breakdown and increase protein synthesis is critical to maintain metabolic function. Hence, a better understanding of these regulatory mechanisms and the alterations leading to dysfunction will set the basis for a better metabolic and immune support of critically ill patients. RECENT FINDINGS: Inflammation can be elicited by infection (sepsis) through pathogen associated molecular patterns (PAMPs) or through danger associated molecular patterns (DAMPs) as a response to an insult (systemic inflammatory response syndrome; SIRS) in the absence of infection. Mitochondrial DAMPs and PAMPs share the same pattern recognition receptors. These receptors act also as nutrient sensors, and in the presence of fatty acids will induce an inflammatory cascade that affects insulin signaling with development of insulin resistance. Lipotoxicity is emerging as a significant contributor to the development of insulin resistance. SUMMARY: Insulin resistance is an adaptive mechanism that prioritizes utilization of energy for immune response in the presence of infection or injury. A better understanding of the complex interactions between metabolism, inflammation and immunity in critically ill children will lead to appropriate metabolic and immune support of these patients. PMID: 21508840 [PubMed - indexed for MEDLINE] 834. Diabetes Metab. 2011 Sep;37(4):283-90. doi: 10.1016/j.diabet.2011.03.002. Epub 2011 Apr 19. Immune cells in adipose tissue: key players in metabolic disorders. Lolmède K(1), Duffaut C, Zakaroff-Girard A, Bouloumié A. Author information: (1)Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, équipe 1, Université Paul-Sabatier, 1, avenue Jean-Poulhès, BP 84225, 31432 Toulouse cedex 04, France. karine.lolmede@inserm.fr Obesity, defined as the excess development of adipose tissue, is an important risk factor for metabolic and cardiovascular diseases such as type 2 diabetes, hypertension and atherosclerosis. Over the past few years, metabolic inflammation has emerged as a major process underlying the link between obesity and its associated pathologies. Adipose tissue appears to play a primary and crucial role as a source and site of inflammation. Accumulation of immune cells within adipose tissue occurs in obese conditions. The present review focuses on the relationship between adipose tissue and immune cells, including macrophages, dendritic cells, T and B lymphocytes, and natural killer cells, in both the physiological state and under obese conditions. The factors involved in the accumulation of both myeloid and lymphoid cells in adipose tissue are also described. In addition, the role of adipose-tissue immune cells on adipocyte metabolism and cells of the adipose tissue stromal-vascular fraction are discussed, with particular emphasis on the cross-talk between macrophages and adipocytes, together with recent reports of T lymphocytes in adipose tissue. Copyright © 2011 Elsevier Masson SAS. All rights reserved. PMID: 21507694 [PubMed - indexed for MEDLINE] 835. Curr Mol Med. 2011 Jun;11(4):304-16. microRNAs in the regulation of adipogenesis and obesity. McGregor RA(1), Choi MS. Author information: (1)Center for Food & Nutritional Genomics Research, Department of Food Science and Nutrition, Kyungpook National University, Daegu, Republic of Korea. Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity. PMCID: PMC3267163 PMID: 21506921 [PubMed - indexed for MEDLINE] 836. Arch Physiol Biochem. 2011 Jul;117(3):96-104. doi: 10.3109/13813455.2011.563748. Epub 2011 Apr 20. Tissue-specificity of insulin action and resistance. Benito M(1). Author information: (1)Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. benito@farm.ucm.es Insulin resistance is the most important pathophysiological feature in many pre-diabetic states. Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion by pancreatic beta cells. The creation of monogenic or polygenic genetically manipulated mice models in a tissue-specific manner was of great help to elucidate the tissue-specificity of insulin action and its contribution to the overall insulin resistance. However, complete understanding of the molecular bases of the insulin action and resistance requires the identification of the intracellular pathways that regulate insulin-stimulated proliferation, differentiation and metabolism. Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin receptors or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B were developed. Indeed, these cell lines have been also very useful to understand the tissue-specificity of insulin action and inaction. PMID: 21506723 [PubMed - indexed for MEDLINE] 837. Int Urogynecol J. 2011 Sep;22(9):1075-83. doi: 10.1007/s00192-011-1432-1. Epub 2011 Apr 20. Development of cellular therapy for the treatment of stress urinary incontinence. Wang HJ(1), Chuang YC, Chancellor MB. Author information: (1)Department of Urology, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Stress urinary incontinence (SUI) is highly prevalent and associated with a reduced quality of life. An intact rhabdosphincter at the mid-urethra is mandatory to maintain urinary continence. Adult stem cell injection therapy for the regenerative repair of an impaired sphincter is currently at the forefront of incontinence research. The implanted cells will fuse with muscle and release trophic factors promoting nerve and muscle integration. Hereby, we review the use of mesenchymal stem cell therapy for SUI and the experience with the development of muscle-derived stem cells. PMID: 21505907 [PubMed - indexed for MEDLINE] 838. Diabetologia. 2011 Jun;54(6):1291-7. doi: 10.1007/s00125-011-2155-z. Epub 2011 Apr 19. The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism. Ducy P(1). Author information: (1)Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. pd2193@columbia.edu Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. This, together with the observation that the adipocyte-derived hormone leptin is a major inhibitor of bone remodelling, led to the hypothesis that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. In contrast, leptin is a potent inhibitor of osteocalcin function through its effect on the sympathetic tone. Hence, osteocalcin is part of a complex signalling network between bone and the organs more classically associated with the regulation of energy homeostasis, such as the pancreas and adipose tissue. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology. PMID: 21503740 [PubMed - indexed for MEDLINE] 839. Nat Rev Endocrinol. 2011 Apr 19;7(8):473-84. doi: 10.1038/nrendo.2011.57. RNAi-based therapeutic strategies for metabolic disease. Czech MP(1), Aouadi M, Tesz GJ. Author information: (1)University of Massachusetts Medical School, Worcester, MA 01605, USA. michael.czech@umassmed.edu RNA interference (RNAi) is a robust gene silencing mechanism that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). As a therapeutic strategy, RNAi has an advantage over small-molecule drugs, as virtually all genes are susceptible to targeting by siRNA molecules. This advantage is, however, counterbalanced by the daunting challenge of achieving safe, effective delivery of oligonucleotides to specific tissues in vivo. Lipid-based carriers of siRNA therapeutics can now target the liver in metabolic diseases and are being assessed in clinical trials for the treatment of hypercholesterolemia. For this indication, a chemically modified oligonucleotide that targets endogenous small RNA modulators of gene expression (microRNAs) is also under investigation in clinical trials. Emerging 'self-delivery' siRNAs that are covalently linked to lipophilic moieties show promise for the future development of therapies. Besides the liver, inflammation of the adipose tissue in patients with obesity and type 2 diabetes mellitus may be an attractive target for siRNA therapeutics. Administration of siRNAs encapsulated within glucan microspheres can silence genes in inflammatory phagocytic cells, as can certain lipid-based carriers of siRNA. New technologies that combine siRNA molecules with antibodies or other targeting molecules also appear encouraging. Although still at an early stage, the emergence of RNAi-based therapeutics has the potential to markedly influence our clinical future. PMID: 21502982 [PubMed - indexed for MEDLINE] 840. Curr Opin Clin Nutr Metab Care. 2011 May;14(3):237-42. doi: 10.1097/MCO.0b013e328345bbcd. Hypothalamic regulation of muscle metabolism. Braun TP(1), Marks DL. Author information: (1)Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA. marksd@ohsu.edu PURPOSE OF REVIEW: The interest in obesity research has produced a large body of data describing the impact of neuronal signaling in the hypothalamus and brainstem on metabolic regulation in the periphery. Studies have historically focused on central regulation of metabolism in adipose and hepatic tissue. Recent studies highlight an important role for these same central regulatory centers in the control of muscle metabolism. This review will focus on these new studies, and will highlight the implications of these new data for the study of muscle catabolism in disease states. RECENT FINDINGS: The balance of anabolism and catabolism in muscle requires activation of the hypothalamic-pituitary-adrenal axis as well as changes in energy-dependent signaling pathways in the muscle. It is now apparent that the sympathetic nervous system conveys much of this information between key metabolism-regulating nuclei in the hypothalamus and skeletal muscle. SUMMARY: Peripheral signals conveying information regarding the metabolic status of the animal appear to alter the function of metabolic centers in the brain that in turn regulate energy partitioning in muscle via a sympathetic relay. Our understanding of how this system is regulated in normal physiological states and in obesity is providing important clues for understanding muscle catabolism in disease. PMID: 21502918 [PubMed - indexed for MEDLINE] 841. Can J Gastroenterol. 2011 Mar;25(3):157-60. Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review. Yellapu RK(1), Mittal V, Grewal P, Fiel M, Schiano T. Author information: (1)Division of Liver Diseases, Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY 10029, USA. Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful. PMCID: PMC3076034 PMID: 21499580 [PubMed - indexed for MEDLINE] 842. Curr Opin Lipidol. 2011 Jun;22(3):216-24. doi: 10.1097/MOL.0b013e3283462e16. Hepatic fatty acid partitioning. Hodson L(1), Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. leanne.hodson@oxlip.ox.ac.uk PURPOSE OF REVIEW: A net retention of triacylglycerol within the liver is a prerequisite for the development of nonalcoholic fatty liver disease. The accumulation of liver fat reflects an imbalance between fatty acid input and disposal. Here we summarize recent research into understanding the fate of fatty acids within the hepatocyte. RECENT FINDINGS: Several recent studies have elucidated the contribution of different sources of fatty acids to liver fat and to plasma triacylglycerol. Some recent studies have suggested that, contrary to expectations, hepatic fatty acid oxidation is upregulated in insulin-resistant individuals. A recent observation shows the potential importance of fatty acid transformation, especially desaturation, to determination of metabolic fate. These studies highlight our lack of understanding of the regulation of metabolic partitioning of fatty acids within the human liver. SUMMARY: The regulation of hepatic fatty acid partitioning involves many factors; not least insulin. Insulin undoubtedly regulates the supply of fatty acids to the liver from adipose tissue; however, whether insulin has a direct intrahepatic effect on hepatic fatty acid partitioning, in humans, remains unclear. The transformation of fatty acids, by desaturases, may have an important role in aiding the disposal of saturated fatty acids via oxidative pathways. Factors that upregulate hepatic fatty acid oxidation need to be elucidated. PMID: 21494141 [PubMed - indexed for MEDLINE] 843. Maturitas. 2011 Jun;69(2):137-40. doi: 10.1016/j.maturitas.2011.03.020. Epub 2011 Apr 14. The impact of obesity on diabetes mellitus and the role of bariatric surgery. Gill RS(1), Sharma AM, Gill SS, Birch DW, Karmali S. Author information: (1)Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. Over 1.5 billion adults worldwide are classified as either overweight or obese, with rates continuing to increase. Obese individuals are at an increased risk for multiple disease processes, particularly type-2 diabetes mellitus (T2DM). Obesity has a strong association with insulin resistance, hyperinsulinemia and glucose intolerance. Adiposity, both subcutaneous and visceral, has been proposed to contribute to insulin resistance, eventually leading to T2DM. Strong evidence exists, in both genders, for the increased glucose intolerance and incidence of T2DM with increasing weight gain. Conversely, weight loss is associated with improvement of glycemic control, insulin resistance and T2DM. Bariatric surgery has risen as a therapeutic option that provides exceptional reduction in overall weight and resolution of T2DM. However, bariatric surgery serves as one component of a multifaceted weight management strategy that is required for long-term success. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21493021 [PubMed - indexed for MEDLINE] 844. Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R285-96. doi: 10.1152/ajpregu.00652.2010. Epub 2011 Apr 13. Implications of nonshivering thermogenesis for energy balance regulation in humans. van Marken Lichtenbelt WD(1), Schrauwen P. Author information: (1)Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. markenlichtenbelt@maastrichtUniversity.nl The incidence of the metabolic syndrome has reached epidemic levels in the Western world. With respect to the energy balance, most attention has been given to reducing energy (food) intake. Increasing energy expenditure is an important alternative strategy. Facultative thermogenesis, which is the increase in energy expenditure in response to cold or diet, may be an effective way to affect the energy balance. The recent identification of functional brown adipose tissue (BAT) in adult humans promoted a renewed interest in nonshivering thermogenesis (NST). The purpose of this review is to highlight the recent insight in NST, general aspects of its regulation, the major tissues involved, and its metabolic consequences. Sustainable NST in adult humans amounts to 15% of the average daily energy expenditure. Calculations based on the limited available literature show that BAT thermogenesis can amount to 5% of the basal metabolic rate. It is likely that at least a substantial part of NST can be attributed to BAT, but it is possible that other tissues contribute to NST. Several studies on mitochondrial uncoupling indicate that skeletal muscle is another potential contributor to facultative thermogenesis in humans. The general and synergistic role of the sympathetic nervous system and the thyroid axis in relation to NST is discussed. Finally, perspectives on BAT and skeletal muscle NST are given. PMID: 21490370 [PubMed - indexed for MEDLINE] 845. Lik Sprava. 2010 Jul-Sep;(5-6):39-55. [Hormones of adipose tissue in diabetes mellitus and its complications (review of literature and the authors'own data)]. [Article in Russian] Zak KP, Kondratskaia IN, Popova VV. The contemporary ideas on endocrine function of the adipose tissue and its role in pathogenesis of diabetes mellitus and insulin resistance associated with it and the metabolic syndrome are shown in the review. A change in the life style (excessive and irrational nutrition, insufficient physical loading, psychological disorders) and also the reduction of genetic and immunologic controlling mechanisms contribute to the development of obesity, that is now considered as low-grade inflammation. An increased number of small size adipocytes and macrophages of the adipose tissue begin to secrete an increase number of proinflammatory adipocytokines and chemokines that result in the inflammatory and metabolic stress accompanied by the stimulation of signal pathways, leading to increased insulin requirement, on the one hand, and promoting to the beta-cell death, on the other hand. The role of some adipocytokines such as IL-6, TNF-alpha, leptin, adiponectin, visfatin and resistin was demonstrated in these processes. PMID: 21488367 [PubMed - indexed for MEDLINE] 846. Br J Pharmacol. 2012 Feb;165(3):633-42. doi: 10.1111/j.1476-5381.2011.01430.x. Vasodilator signals from perivascular adipose tissue. Gollasch M(1). Author information: (1)Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Experimental and Clinical Research Center (ECRC) and Max-Delbrück Center for Molecular Medicine, Berlin, Germany. maik.gollasch@charite.de Visceral fat has been linked to metabolic disturbances and increased risk for cardiovascular disease and type 2 diabetes. Recent studies propose a paracrine role for periadventitial adipose tissue in the control of arterial vascular tone. This regulation depends on the anatomical integrity of the vessels and involves a transferable mediator(s) (adipokine) released from either periadventitial adipocytes or perivascular adipose tissue. Although a number of adipokines with vasoactive properties have been identified, a still unidentified adipocyte-derived relaxing factor (ADRF) plays a major role in the periadventitial vasoregulation of visceral arteries, such as the aorta and mesenteric arteries. ADRF is released by visceral periadventitial adipocytes and primarily produces endothelium-independent vasorelaxation by opening voltage-dependent (K(v) ) K(+) channels in the plasma membrane of smooth muscle cells. At least in part, KCNQ (K(v) 7) channels could represent the subtype of K(v) channels involved. Glibenclamide-sensitive K(ATP) channels are not involved or play a minor role. The 'third gas', namely H(2) S, could represent ADRF. Alterations in the paracrine control of arterial tone by visceral periadventitial adipose tissue have been found in animal models of hypertension and metabolic disease. ADRF, or perhaps its putative targets, might represent exciting new targets for the development of drugs for treatment of cardiovascular and metabolic disorders.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315036 PMID: 21486288 [PubMed - indexed for MEDLINE] 847. Handb Exp Pharmacol. 2011;(203):127-46. doi: 10.1007/978-3-642-17214-4_6. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 in antidiabetic therapy. Wang M(1). Author information: (1)Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA. mwang@amgen.com Glucocorticoid action is mediated by glucocorticoid receptor (GR), which upon cortisol binding is activated and regulates the transcriptional expression of target genes and downstream physiological functions. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol. Since cortisol is also produced through biosynthesis in the adrenal glands, the total cortisol level in a given tissue is determined by both the circulating cortisol concentration and the local 11β-HSD1 activity. 11β-HSD1 is expressed in liver, adipose, brain, and placenta. Since it contributes to the local cortisol levels in these tissues, 11β-HSD1 plays a critical role in glucocorticoid action. The metabolic symptoms caused by glucocorticoid excess in Cushing's syndrome overlap with the characteristics of the metabolic syndrome, suggesting that increased glucocorticoid activity may play a role in the etiology of the metabolic syndrome. Consistent with this notion, elevated adipose expression of 11β-HSD1 induced metabolic syndrome-like phenotypes in mice. Thus, 11β-HSD1 is a proposed therapeutic target to normalize glucocorticoid excess in a tissue-specific manner and mitigate obesity and insulin resistance. Selective inhibitors of 11β-HSD1 are under development for the treatment of type 2 diabetes and other components of the metabolic syndrome. PMID: 21484570 [PubMed - indexed for MEDLINE] 848. Handb Exp Pharmacol. 2011;(203):75-104. doi: 10.1007/978-3-642-17214-4_4. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Di Marzo V(1), Piscitelli F, Mechoulam R. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34 Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy. The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes. PMID: 21484568 [PubMed - indexed for MEDLINE] 849. Handb Exp Pharmacol. 2011;(203):35-51. doi: 10.1007/978-3-642-17214-4_2. Dual acting and pan-PPAR activators as potential anti-diabetic therapies. Heald M(1), Cawthorne MA. Author information: (1)Clore Laboratory, University of Buckingham, Buckingham, Buckinghamshire, UK. The thiazolidinedione PPAR-γ activator drugs rosiglitazone and pioglitazone suppress insulin resistance in type 2 diabetic patients. They lock lipids into adipose tissue triglyceride stores, thereby preventing lipid metabolites from causing insulin resistance in liver and skeletal muscle and β-cell failure. They also reduce the secretion of inflammatory cytokines such as TNFα and increase the plasma level of adiponectin, which increases insulin sensitivity in liver and skeletal muscle. However, they have only a modest effect on dyslipidaemia, and they increase fat mass and plasma volume. Fibrate PPAR-α activator drugs decrease plasma triglycerides and increase HDL-cholesterol levels. PPAR-δ activators increase the capacity for fat oxidation in skeletal muscle.Clinical experience with bezafibrate, which activates PPAR-δ and -α, and studies on the PPAR-α/δ activator tetradecylthioacetic acid, the PPAR-δ activator GW501516, and combinations of the PPAR-α activator fenofibrate with rosiglitazone or pioglitazone have encouraged attempts to develop single molecules that activate two or all three PPARs. Most effort has focussed on dual PPAR-α/γ activators. These reduce both hyperglycaemia and dyslipidaemia, but their development has been terminated by issues such as increased weight gain, oedema, plasma creatinine and myocardial infarction or stroke. In addition, the FDA has stated that many PPAR ligands submitted to it have caused increased numbers of tumours in carcinogenicity studies.Rather than aiming for full potent agonists, it may be best to identify subtype-selective partial agonists or compounds that selectively activate PPAR signalling pathways and use these in combination. Nutrients or modified lipids that are low-affinity agonists may also have potential. PMID: 21484566 [PubMed - indexed for MEDLINE] 850. Handb Exp Pharmacol. 2011;(203):1-33. doi: 10.1007/978-3-642-17214-4_1. Targeting type 2 diabetes. Schwanstecher C(1), Schwanstecher M. Author information: (1)Molekulare Pharmakologie und Toxikologie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany. M.Schwanstecher@tu-braunschweig.de The evolving concept of how nutrient excess and inflammation modulate metabolism provides new opportunities for strategies to correct the detrimental health consequences of obesity. In this review, we focus on the complex interplay among lipid overload, immune response, proinflammatory pathways and organelle dysfunction through which excess adiposity might lead to type 2 diabetes. We then consider evidence linking dysregulated CNS circuits to insulin resistance and results on nutrient-sensing pathways emerging from studies with calorie restriction. Subsequently, recent recommendations for the management of type 2 diabetes are discussed with emphasis on prevailing current therapeutic classes of biguanides, thiazolidinediones and incretin-based approaches. PMID: 21484565 [PubMed - indexed for MEDLINE] 851. Curr Opin Cardiol. 2011 Jul;26(4):348-55. doi: 10.1097/HCO.0b013e32834659d4. Ideal lipid profile and genes for an extended life span. Kolovou G(1), Kolovou V, Vasiliadis I, Wierzbicki AS, Mikhailidis DP. Author information: (1)1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. genovefa@kolovou.com PURPOSE OF REVIEW: The world population is aging and a rapid increase is being seen in the very elderly (aged >80 years). Cholesterol levels in general rise with age and high cholesterol has been associated with extreme longevity. The relationship between lipids and cardiovascular events in the extreme elderly is unclear. RECENT FINDINGS: A number of genetic factors associated with lipid metabolism have also been described as having potential antiaging roles, including the genes encoding lipoprotein-associated factors - apolipoprotein E and cholesterol ester transfer protein; adipose tissue metabolism - adiponectin, leptin, glycaemia; and blood pressure - angiotensinogen. Clinical trials of lipid-lowering therapies have recruited subgroups of moderately elderly patients, but only the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial specifically recruited an elderly population. There is no direct equivalent of the Hypertension in the Very Elderly trial (HYVET) study of antihypertensive patients in the extreme elderly. No heterogeneity has been seen with the effects of statin therapy in the elderly compared with younger age groups on classical cardiovascular endpoints of coronary heart disease and stroke. SUMMARY: The optimal cholesterol target, long-term tolerability and the specific effects of statins on other vascular-associated diseases of aging, for example arterial aneurysms, microvascular renal and cerebral disease (dementias), remain to be determined. PMID: 21478743 [PubMed - indexed for MEDLINE] 852. Expert Rev Gastroenterol Hepatol. 2011 Apr;5(2):201-12. doi: 10.1586/egh.11.6. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Alkhouri N(1), Carter-Kent C, Feldstein AE. Author information: (1)Department of Pediatric Gastroenterology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. alkhoun@ccf.org Pathological increases in cell death in the liver as well as in peripheral tissues has emerged as an important mechanism involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). An increase in hepatocyte cell death by apoptosis is typically present in patients with NAFLD and in experimental models of steatohepatitis, while an increase in adipocyte cell death in visceral adipose tissue may be an important mechanism triggering insulin resistance and hepatic steatosis. The two fundamental pathways of apoptosis, the extrinsic (death receptor-mediated) and intrinsic (organelle-initiated) pathways, are both involved. This article summarizes the current knowledge related to the distinct molecular and biochemical pathways of cell death involved in NAFLD pathogenesis. In particular, it will highlight the efforts for the development of both novel diagnostic and therapeutic strategies based on this knowledge. PMCID: PMC3119461 PMID: 21476915 [PubMed - indexed for MEDLINE] 853. Expert Rev Gastroenterol Hepatol. 2011 Apr;5(2):189-200. doi: 10.1586/egh.11.21. Inflammation in nonalcoholic steatohepatitis. Harmon RC(1), Tiniakos DG, Argo CK. Author information: (1)Division of Gastroenterology and Hepatology, University of Virginia Health System, Box 800708, Charlottesville, VA 22908, USA. rh5am@virginia.edu Nonalcoholic fatty liver disease (NAFLD) describes a range of disorders characterized by excess accumulation of triglyceride within the liver. While simple steatosis may be clinically stable, nonalcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. This article will review and interpret the current literature in an attempt to expand our understanding of the environmental and genetic causes of inflammation and its effects in NAFLD. PMID: 21476914 [PubMed - indexed for MEDLINE] 854. Am J Chin Med. 2011;39(2):215-31. Physiological and therapeutical roles of ginger and turmeric on endocrine functions. Al-Suhaimi EA(1), Al-Riziza NA, Al-Essa RA. Author information: (1)Department of Biology, Sciences College, Dammam University, Dammam, Saudi Arabia. dr_suhaimi2008@windowslive.com The natural product ginger (Zingiber officinale) has active constituents gingerol, Shogaol and Zerumbone, while turmeric (Curcuma longa) contains three active major curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. They have the same scientific classification and are reported to have anti-inflammatory and many therapeutic effects. This article reviews the physiological and therapeutic effects of ginger and turmeric on some endocrine gland functions, and signal pathways involved to mediate their actions. With some systems and adipose tissue, ginger and turmeric exert their actions through some/all of the following signals or molecular mechanisms: (1) through reduction of high levels of some hormones (as: T4, leptin) or interaction with hormone receptors; (2) by inhibition of cytokines/adipokine expression; (3) acting as a potent inhibitor of reactive oxygen species (ROS)-generating enzymes, which play an essential role between inflammation and progression of diseases; (4) mediation of their effects through the inhibition of signaling transcription factors; and/or (5) decrease the proliferative potent by down-regulation of antiapoptotic genes, which may suppress tumor promotion by blocking signal transduction pathways in the target cells. These multiple mechanisms of protection against inflammation and oxidative damage make ginger and curcumin particularly promising natural agents in fighting the ravages of aging and degenerative diseases, and need to be paid more attention by studies. PMID: 21476200 [PubMed - indexed for MEDLINE] 855. Growth Horm IGF Res. 2011 Jun;21(3):113-23. doi: 10.1016/j.ghir.2011.03.002. Epub 2011 Apr 5. Growth hormone and adipose tissue: beyond the adipocyte. Berryman DE(1), List EO, Sackmann-Sala L, Lubbers E, Munn R, Kopchick JJ. Author information: (1)School of Applied Health Sciences and Wellness College of Health Sciences and Human Performance, Ohio University, Athens, OH 45701, United States. berrymad@ohio.edu The last two decades have seen resurgence in research focused on adipose tissue. In part, the enhanced interest stems from an alarming increase in obesity rates worldwide. However, an understanding that this once simple tissue is significantly more intricate and interactive than previously realized has fostered additional attention. While few would argue that growth hormone (GH) radically alters fat mass, newer findings revealing the complexity of adipose tissue requires that GH's influence on this tissue be reexamined. Therefore, the objective of this review is to describe the more recent understanding of adipose tissue and to summarize our current knowledge of how GH may influence and contribute to these newer complexities of this tissue with special focus on the available data from mice with altered GH action. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3112270 PMID: 21470887 [PubMed - indexed for MEDLINE] 856. Nutrition. 2011 Jun;27(6):624-32. doi: 10.1016/j.nut.2010.11.003. Epub 2011 Apr 6. Endocannabinoid signaling and energy metabolism: a target for dietary intervention. Kim J(1), Li Y, Watkins BA. Author information: (1)Lipid Chemistry and Molecular Biology Laboratory, Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA. The endocannabinoid (EC) signaling (ECS) system involves the activation of receptors targeted by endogenously produced ligands called endocannabinoids that trigger specific physiologic events in various organs and tissues throughout the body. ECs are lipid mediators that bind to specific receptors and elicit cell signaling. The focus of this review is to discuss the responses that direct pathways of systemic energy metabolism. Recent findings have indicated that an imbalance of the ECS contributes to visceral fat accumulation and disrupts energy homeostasis, which are characteristics of the metabolic syndrome. Constant activation of ECS has been linked to metabolic processes that are associated with the hypothalamus and peripheral tissues of obese patients. In contrast, inhibition of ECS results in weight loss in animal and human subjects. Despite these findings, the mechanism involved in the dysregulation of ECS is unclear. Interestingly, the level of endogenous ligands, derived from arachidonic acid, can be directly manipulated by nutrient intervention, in that a diet rich in long-chain ω-3 polyunsaturated fatty acids will decrease the production of ligands to modulate the activation of target receptors. In contrast, a diet that is high in ω-6 polyunsaturated fatty acids will cause an increase in ECS activation and stimulate tissue specific activities that decrease insulin sensitivity in muscle and promote fat accumulation in the adipose tissue. The purpose of this review is to explain the components of ECS, its role in adipose and muscle energy metabolism, and how nutritional approaches with dietary ω-3 polyunsaturated fatty acids may reverse the dysregulation of this system to improve insulin sensitivity and control body fat. Copyright © 2011. Published by Elsevier Inc. PMID: 21470818 [PubMed - indexed for MEDLINE] 857. Br J Pharmacol. 2012 Feb;165(3):643-58. doi: 10.1111/j.1476-5381.2011.01404.x. The role of perivascular adipose tissue in vascular smooth muscle cell growth. Miao CY(1), Li ZY. Author information: (1)Department of Pharmacology, Second Military Medical University, Shanghai, China. cymiao@smmu.edu.cn Adipose tissue is the largest endocrine organ, producing various adipokines and many other substances. Almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which has not received research attention until recently. This review will discuss the paracrine actions of PVAT on the growth of underlying vascular smooth muscle cells (VSMCs). PVAT can release growth factors and inhibitors. Visfatin is the first identified growth factor derived from PVAT. Decreased adiponectin and increased tumour necrosis factor-α in PVAT play a pathological role for neointimal hyperplasia after endovascular injury. PVAT-derived angiotensin II, angiotensin 1-7, reactive oxygen species, complement component 3, NO and H(2) S have a paracrine action on VSMC contraction, endothelial or fibroblast function; however, their paracrine actions on VSMC growth remain to be directly verified. Factors such as monocyte chemoattractant protein-1, interleukin-6, interleukin-8, leptin, resistin, plasminogen activator inhibitor type-1, adrenomedullin, free fatty acids, glucocorticoids and sex hormones can be released from adipose tissue and can regulate VSMC growth. Most of them have been verified for their secretion by PVAT; however, their paracrine functions are unknown. Obesity, vascular injury, aging and infection may affect PVAT, causing adipocyte abnormality and inflammatory cell infiltration, inducing imbalance of PVAT-derived growth factors and inhibitors, leading to VSMC growth and finally resulting in development of proliferative vascular disease, including atherosclerosis, restenosis and hypertension. In the future, using cell-specific gene interventions and local treatments may provide definitive evidence for identification of key factor(s) involved in PVAT dysfunction-induced vascular disease and thus may help to develop new therapies.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315037 PMID: 21470202 [PubMed - indexed for MEDLINE] 858. Diabetologia. 2011 Jul;54(7):1596-607. doi: 10.1007/s00125-011-2127-3. Epub 2011 Apr 6. Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance. Lipina C(1), Hundal HS. Author information: (1)Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK. Erratum in Diabetologia. 2011 Nov;54(11):2969. Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders. PMID: 21468641 [PubMed - indexed for MEDLINE] 859. Dan Med Bull. 2011 Apr;58(4):B4269. Investigations of the endocannabinoid system in adipose tissue: effects of obesity/ weight loss and treatment options. Bennetzen MF(1). Author information: (1)Department of Internal Medicine and Endocrinology, MEA, Aarhus University Hospital, Denmark. Bennetzen@ki.au.dk Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy - it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds. PMID: 21466769 [PubMed - indexed for MEDLINE] 860. J Clin Hypertens (Greenwich). 2011 Apr;13(4):224-37. doi: 10.1111/j.1751-7176.2011.00449.x. Renin-Angiotensin-aldosterone system in diabetes and hypertension. Hsueh WA(1), Wyne K. Author information: (1)Diabetes Research Center, The Methodist Hospital Research Institute, Diabetes Research Center, Weill Cornell Medical College, Houston, TX 77030, USA. wahsueh@tmhs.org Activation of the renin-angiotensin-aldosterone system (RAAS) is the primary etiologic event in the development of hypertension in people with diabetes mellitus. Modulation of the RAAS has been shown to slow the progression and even cause regression of the microvascular and macrovascular complications associated with diabetes mellitus. Early pharmacotherapy with agents that decrease RAAS activation in the adipose tissue have had a dramatic impact on the prevalence of diabetes related complications. Recent data show that preventing the development of "angry fat" can prevent not just hypertension but also type 2 diabetes mellitus and its associated complications. This review updates what is known about angry fat and the role of RAAS inhibition in preventing the metabolic sequelae of local RAAS activation. © 2011 Wiley Periodicals, Inc. PMID: 21466617 [PubMed - indexed for MEDLINE] 861. Expert Opin Investig Drugs. 2011 Jun;20(6):745-56. doi: 10.1517/13543784.2011.575359. Epub 2011 Apr 6. Novel C-C chemokine receptor 2 antagonists in metabolic disease: a review of recent developments. Kang YS(1), Cha JJ, Hyun YY, Cha DR. Author information: (1)Medical College of Korea University, Ansan Hospital, Division of Nephrology, Department of Internal Medicine, Ansan City, Korea. INTRODUCTION: C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, and its receptor, C-C chemokine receptor 2 (CCR2), play important roles in various inflammatory diseases. Recently, it has been reported that the CCL2/CCR2 pathway also has an important role in the pathogenesis of metabolic syndrome through its association with obesity and related systemic complications. AREAS COVERED: This review focuses on the roles of CCR2 in the pathogenesis of adipose tissue inflammation and other organ damage associated with metabolic syndrome, which is still a matter of debate in many studies. It also covers the use of novel CCR2 antagonists as therapies in such conditions. EXPERT OPINION: There is abundant experimental evidence that the CCL2/CCR2 pathway may be involved in chronic low-grade inflammation of adipose tissue in obesity and related metabolic diseases. Although animal models of diabetes and obesity, as well as human trials, have produced controversial results, there is continued interest in the roles of CCR2 inhibition in metabolic disease. Further identification of the mechanisms for recruitment and activation of phagocytes and determination of the roles of other chemokines are needed. Future study of these fundamental questions will provide a clearer understanding of adipose tissue biology and potential therapeutic targets for treatment of obesity-related metabolic disease, including diabetic nephropathy. PMID: 21466412 [PubMed - indexed for MEDLINE] 862. Aging (Albany NY). 2011 Mar;3(3):325-8. Does hypothalamic SIRT1 regulate aging? Ramadori G(1), Coppari R. Author information: (1)Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, 75390, USA. In virtually all organisms, life expectancy is profoundly affected by caloric intake. For example, dietary restriction (DR; a feeding regimen of fewer calories compared to the ad libitum level without causing malnutrition) has been shown to lengthen, whereas hypercaloric (HC) diet feeding to shorten, lifespan. Recent findings in invertebrates indicate that specialized groups of cells (e.g.: metabolic-sensing neurons) detect changes in caloric intake and convey energy-status-variation signals to other cells in the body to regulate lifespan. In mammals, whether metabolic-sensing neurons govern aging in a cell-non-autonomous fashion is unknown. Yet, this is a captivating and testable hypothesis. PMCID: PMC3091526 PMID: 21464518 [PubMed - indexed for MEDLINE] 863. Curr Diab Rep. 2011 Jun;11(3):211-7. doi: 10.1007/s11892-011-0186-y. Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease. Meijer RI(1), Serne EH, Smulders YM, van Hinsbergh VW, Yudkin JS, Eringa EC. Author information: (1)Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands. Obesity is associated with insulin resistance, hypertension, and cardiovascular disease, but the mechanisms underlying these associations are incompletely understood. Microvascular dysfunction may play an important role in the pathogenesis of both insulin resistance and hypertension in obesity. Adipose tissue-derived substances (adipokines) and especially inflammatory products of adipose tissue control insulin sensitivity and vascular function. In the past years, adipose tissue associated with the vasculature, or perivascular adipose tissue (PAT), has been shown to produce a variety of adipokines that contribute to regulation of vascular tone and local inflammation. This review describes our current understanding of the mechanisms linking perivascular adipose tissue to vascular function, inflammation, and insulin resistance. Furthermore, we will discuss mechanisms controlling the quantity and adipokines secretion by PAT. PMCID: PMC3085790 PMID: 21461998 [PubMed - indexed for MEDLINE] 864. Curr Opin Clin Nutr Metab Care. 2011 May;14(3):255-60. doi: 10.1097/MCO.0b013e3283457a8f. HIV infection, body composition changes and related metabolic complications: contributing factors and evolving management strategies. Falutz J(1). Author information: (1)McGill University Health Center, Immunodeficiency Treatment Center, Montreal, Quebec, Canada. PURPOSE OF REVIEW: Metabolic toxicities in HIV patients are common and contribute to clinical status and long-term sequelae. Body fat mass alterations, of multifactorial causes, continue to occur, despite use of antiretroviral drugs associated with fewer metabolic side-effects. The role of HIV itself in the development of these changes is being better defined and a deeper understanding of perturbations in intermediary metabolic processes is emerging. Treatment options are also being identified. RECENT FINDINGS: HIV itself may be a direct causal factor in the accelerated atherosclerosis and decreased levels of high-density lipoprotein that occur and contribute to increased cardiovascular complications. Antiretroviral drug-related and inflammation-related effects can cause mitochondrial toxicity and are an emerging area of research. The association of increased visceral adipose tissue with both drug-related and chronic inflammation-related factors is now better understood. The role of accelerated aging as a paradigm is useful to understand long-term outcome risks for patients. The use of growth hormone-releasing factor as a viable treatment option for increased visceral abdominal tissue has recently been confirmed for selected patients. SUMMARY: Metabolic issues persist in HIV patients who are otherwise stable. Understanding the various inter-related contributing factors has allowed for rapid improvement in patients' clinical status, but long-term consequences are of concern and require ongoing investigation in order to prevent limiting the otherwise important clinical achievements that have recently occurred. PMID: 21460720 [PubMed - indexed for MEDLINE] 865. J Mol Cell Biol. 2011 Apr;3(2):81-90. doi: 10.1093/jmcb/mjr003. Take-over: multiple mechanisms of inter-adipocyte communication. Müller G(1). Author information: (1)Department Biology I, Genetics Martinsried, Biocenter, Ludwig-Maximilians-University Munich, Munich, Germany. guenter.mueller@sanofi-aventis.com Retraction in J Mol Cell Biol. 2011 Dec;3(6):382. Adipose tissue mass in mammals is thought to expand with an increase in both volume and total number of the adipocytes. Recent findings suggest that in normal-weight as well as obese individuals, the adipocyte number is set during adolescence prior to adulthood, whereas the subsequent increase in size predominantly drives obesity. The simultaneous existence of large and small adipocytes and their unsynchronized growth, even within the same adipose tissue depot, argues against simple filling-up of emerging adipocytes with lipids and lipid droplets (LDs). Consequently, it is tempting to speculate about signals sent by large adipocytes to order small adipocytes the take-over of the burden of lipid loading. Currently there is experimental evidence for three distinct types of inter-adipocyte signals, i.e. cell-to-cell contacts, adipokines, and other soluble factors and microvesicles. Very recently, microvesicles have been shown (i) to harbour the glycosylphosphatidylinositol-anchored (c)AMP-degrading phosphodiesterase Gce1 and 5'-nucleotidase CD73, (ii) to be released from large adipocytes, (iii) to interact with small adipocytes, and (iv) to transfer Gce1 and CD73 to plasma membranes and LDs of small adipocytes where they degrade (c)AMP. This sequence of events leads to the up-regulation of lipid storage in small adipocytes in response to the microvesicle-encoded 'take-over' signal from large adipocytes. A model is proposed for the maturation of small adipocytes driven by large ones along a gradient of those inter-adipocyte signals. Pharmacological modulation of inter-adipocyte communication and thereby adipocyte maturation may be useful for the therapy of metabolic diseases. PMID: 21459887 [PubMed - indexed for MEDLINE] 866. Br J Pharmacol. 2012 Feb;165(3):574-90. doi: 10.1111/j.1476-5381.2011.01395.x. Adiponectin and cardiovascular health: an update. Hui X(1), Lam KS, Vanhoutte PM, Xu A. Author information: (1)Department of Medicine, the University of Hong Kong, Hong Kong. The global epidemic of obesity is accompanied by an increased prevalence of cardiovascular disease (CVD), in particular stroke and heart attack. Dysfunctional adipose tissue links obesity to CVD by secreting a multitude of bioactive lipids and pro-inflammatory factors (adipokines) with detrimental effects on the cardiovascular system. Adiponectin is one of the few adipokines that possesses multiple salutary effects on insulin sensitivity and cardiovascular health. Clinical investigations have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for CVD. In animals, elevation of plasma adiponectin by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction and diabetic cardiomyopathy. Furthermore, many therapeutic benefits of the peroxisome-proliferator activated receptor gamma agonists, the thiazolidinediones, are mediated by induction of adiponectin. Adiponectin protects cardiovascular health through its vasodilator, anti-apoptotic, anti-inflammatory and anti-oxidative activities in both cardiac and vascular cells. This review summarizes recent findings in the understanding of the physiological role and clinical relevance of adiponectin in cardiovascular health, and in the identification of the receptor and postreceptor signalling events that mediate the cardiovascular actions of adiponectin. It also discusses adiponectin-targeted drug discovery strategies for treating obesity, diabetes and CVD.LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. PMCID: PMC3315032 PMID: 21457225 [PubMed - indexed for MEDLINE] 867. Aesthetic Plast Surg. 2011 Oct;35(5):882-90. doi: 10.1007/s00266-011-9691-2. Epub 2011 Apr 1. Autologous fat grafting for primary breast augmentation: a systematic review. Rosing JH(1), Wong G, Wong MS, Sahar D, Stevenson TR, Pu LL. Author information: (1)Division of Plastic Surgery, University of California at Davis, 2221 Stockton Boulevard, Suite 2123, Sacramento, CA 95817, USA. jamesrosing@gmail.com As the technique of autologous fat grafting is being refined and perfected, its clinical applications are expanding. The use of autologous fat grafting for primary breast augmentation is controversial due to a lack of clarity regarding its safety and efficacy. Most notably, concerns about interference with the detection of breast cancer have been raised, but these have not been clearly addressed in the literature. To help surgeons gain further insight, the authors conducted a systematic review of the literature, carefully comparing technique, clinical outcome, radiologic impact, and complications in all available data on this subject. Although an optimal method of autologous fat grafting for primary breast augmentation is yet to be standardized, further strong evidence-based studies are necessary to confirm the findings of this approach. PMID: 21455825 [PubMed - indexed for MEDLINE] 868. Endocr Pract. 2011 May-Jun;17(3):430-40. doi: 10.4158/EP10106.RA. Mechanistic and clinical aspects of renin-angiotensin-aldosterone system blockade in the prevention of diabetes mellitus and cardiovascular disease. Hershon KS(1). Author information: (1)North Shore Diabetes and Endocrine Associates, New Hyde Park, NY, USA. khershon@nsdea.com OBJECTIVE: To review the rationale for the use of renin-angiotensin-aldosterone system (RAAS) inhibition to prevent type 2 diabetes mellitus and cardiovascular events and to discuss clinical data evaluating the relationship between RAAS blockade and diabetes prevention. METHODS: PubMed was searched to identify preclinical and clinical data addressing this aim. RESULTS: Potential mechanisms of angiotensin II-mediated insulin resistance and type 2 diabetes may include impaired blood flow and sympathetic activity, increased oxidative stress, alterations in insulin signaling, and effects on adipose tissue. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated reduced incidences of new-onset diabetes in patients with prediabetes or hypertension and in other cardiovascular populations; however, insight into the corresponding impact on cardiovascular-related morbidity and mortality has been lacking. A recent trial (NAVIGATOR) was designed to evaluate incident diabetes and cardiovascular outcomes as part of its primary endpoint. In this trial, valsartan-based therapy reduced the incidence of new-onset diabetes by 14% relative to placebo over the 5-year follow-up period (P<.001). Cardiovascular outcomes, however, were not significantly affected by active treatment, which may be attributed to a number of potential confounding factors including the low rate of cardiovascular disease at baseline, concurrent implementation of lifestyle modification in all patients, and the substantial use of other risk-reducing agents. CONCLUSIONS: Angiotensin II has been implicated in a number of pathophysiologic processes with the potential to indirectly or directly influence the pathogenesis of insulin resistance and type 2 diabetes. Most clinical trials show a reduced risk of new-onset diabetes with RAAS blockade; however, recent results of the NAVIGATOR trial show that the addition of valsartan to lifestyle modification reduces the risk of diabetes, but does not improve cardiovascular outcomes. PMID: 21454245 [PubMed - indexed for MEDLINE] 869. Recent Pat Cardiovasc Drug Discov. 2011 May;6(2):78-88. Adiponectin as a regulator of vascular redox state: therapeutic implications. Antonopoulos AS(1), Lee R, Margaritis M, Antoniades C. Author information: (1)Department of Cardiovascular Medicine, University of Oxford, UK. antonopoulosal@yahoo.gr Recently, adipose tissue has been implicated in the regulation of vascular function in humans. This regulatory function is mediated via the release of vasoactive cytokines called adipokines. Adiponectin is an adipokine with powerful anti-inflammatory and antioxidant properties being dysregulated in obesity and in insulin resistance states. In both in vitro and in vivo models adiponectin has been shown to increase nitric oxide bioavailability, improve endothelial function, and exert beneficial effects on vascular smooth muscle cell function. Strategies to upregulate adiponectin expression or to potentiate adiponectin signalling may favourably modulate vascular redox state and therefore reduce cardiovascular risk. Various drug classes such as glitazones, newer sulfonylureas, angiotensin receptor blockers, ACE inhibitors and nicotinic acid exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels. Others such as tetrahydrobiopterin or certain antioxidants are also promising in normalizing plasma adiponectin levels. Given the central role of adiponectin in vascular disease states and obesity-related metabolic disorders, improving adiponectin vascular or systemic bioavailability via existing drugs or novel therapeutic strategies may be valuable in the prevention of cardiovascular disease in humans. The discussion of recent patents for the adiponectin as a regulator of vascular redox state also included in this review article. PMID: 21453253 [PubMed - indexed for MEDLINE] 870. Ann Plast Surg. 2011 May;66(5):518-22. doi: 10.1097/SAP.0b013e3181fe9334. Autologous fat grafting in secondary breast reconstruction. Losken A(1), Pinell XA, Sikoro K, Yezhelyev MV, Anderson E, Carlson GW. Author information: (1)Emory Division of Plastic and Reconstructive Surgery, Atlanta, GA, USA. alosken@emory.edu Comment in Ann Plast Surg. 2013 Jan;70(1):119. Autologous fat grafting has become a common technique for revisional breast surgery. The purpose of this series is to review our experience with fat grafting for the correction of acquired breast deformities. A retrospective review was performed on 107 patients with a history of breast cancer between 1996 and 2010, who had autologous fat grafting at the time of secondary breast reconstruction. The indications were for improvement in contour, shape, and volume of the breast following transverse rectus abdominis myocutaneous (TRAM) flap reconstruction (n = 55), latissimus dorsi with or without implant (n = 20), implant reconstruction (n = 20), and breast conservation therapy deformity (n = 12). The average volume of injection was 40 mL (range, 5-150 mL), the most common location being upper and medial quadrants. Fat was harvested mainly from the abdomen, thighs, and flanks. Complications occurred in 11% of the patients, and included fat necrosis, erythema, keloid scarring, and pain. Complications were higher when performed with implant reconstructions. Repeat fat injection was performed in 25% (n = 27/107), which increased with the length of follow-up. Patients with a history of radiation therapy had an increased incidence of repeat injections (36% vs. 18%). Patients with >6 months follow-up reported an improvement of about 83%. Autologous fat grafting is a safe and effective tool for secondary breast reconstruction. It is helpful in all types of reconstructions to improve contour, volume, and overall breast shape and symmetry. Repeat injections are often required and this is more common in patients with longer follow-up and in those with a history of radiation therapy. The popularity of this approach in reconstructive breast surgery will likely continue to increase. PMID: 21451387 [PubMed - indexed for MEDLINE] 871. Int J Med Sci. 2011 Mar 2;8(3):180-91. A comparative effectiveness study of bone density changes in women over 40 following three bone health plans containing variations of the same novel plant-sourced calcium. Kaats GR(1), Preuss HG, Croft HA, Keith SC, Keith PL. Author information: (1)Integrative Health Technologies, Inc, 4940 Broadway, San Antonio, Texas 78209, USA. grk@ihtglobal.com Erratum in Int J Med Sci. 2013;10(9):1135. BACKGROUND: The US Surgeon General's Report on Bone Health suggests America's bone-health is in jeopardy and issued a "call to action" to develop bone-health plans incorporating components of (1) improved nutrition, (2) increased health literacy, and (3) increased physical activity. OBJECTIVE: To conduct a Comparative Effectiveness Research (CER) study comparing changes in bone mineral density in healthy women over-40 with above-average compliance when following one of three bone health Plans incorporating the SG's three components. METHODS: Using an open-label sequential design, 414 females over 40 years of age were tested, 176 of whom agreed to participate and follow one of three different bone-health programs. One Plan contained a bone-health supplement with 1,000 IUs of vitamin D(3 )and 750 mg of a plant-sourced form of calcium for one year. The other two Plans contained the same plant form of calcium, but with differing amounts of vitamin D(3) and other added bone health ingredients along with components designed to increase physical activity and health literacy. Each group completed the same baseline and ending DXA bone density scans, 43-chemistry blood test panels, and 84-item Quality of Life Inventory (QOL). Changes for all subjects were annualized as percent change in BMD from baseline. Using self-reports of adherence, subjects were rank-ordered and dichotomized as "compliant" or "partially compliant" based on the median rating. Comparisons were also made between the treatment groups and two theoretical age-adjusted expected groups: a non-intervention group and a group derived from a review of previously published studies on non-plant sources of calcium. RESULTS: There were no significant differences in baseline BMD between those who volunteered versus those who did not and between those who completed per protocol (PP) and those who were lost to attrition. Among subjects completing per protocol, there were no significant differences between the three groups on baseline measurements of BMD, weight, age, body fat and fat-free mass suggesting that the treatment groups were statistically similar at baseline. In all three treatment groups subjects with above average compliance had significantly greater increases in BMD as compared to the two expected-change reference groups. The group following the most nutritionally comprehensive Plan outperformed the other two groups. For all three groups, there were no statistically significant differences between baseline and ending blood chemistry tests or the QOL self-reports. CONCLUSIONS: The increases in BMD found in all three treatment groups in this CER stand in marked contrast to previous studies reporting that interventions with calcium and vitamin D(3) reduce age-related losses of BMD, but do not increase BMD. Increased compliance resulted in increased BMD levels. No adverse effects were found in the blood chemistry tests, self-reported quality of life and daily tracking reports. The Plans tested suggest a significant improvement over the traditional calcium and vitamin D(3) standard of care. PMCID: PMC3053489 PMID: 21448303 [PubMed - indexed for MEDLINE] 872. Med Sci (Paris). 2011 Mar;27(3):289-96. doi: 10.1051/medsci/2011273289. Epub 2011 Mar 30. [Stem cells for osteoarticular and vascular tissue engineering]. [Article in French] Vinatier C(1), Bordenave L, Guicheux J, Amédée J. Author information: (1)Inserm U791, LIOAD, groupe STEP, Université de Nantes; Graftys SA, Aix-en-Provence, France. Tissue damages or loss of organs often result in structural and metabolic changes that can cause serious complications. The therapeutic objective of tissue engineering (TE) is to recreate, regenerate or restore function of damaged tissue. TE is based on the coalescence of three components: a scaffold or matrix from natural or synthetic origin biodegradable or not, reparative cells and signals (hypoxia, mechanical stress, morphogens…). Articular cartilage, bone and blood vessels are tissues for which TE has progressed significantly, from basic research to clinical trials. If biomaterials must exhibit different properties depending on the tissue to regenerate, the cellular component of TE is mostly represented by stem cells notably adult mesenchymal stem cells harvested from bone marrow or adipose tissue. In recent years, progress has been made in our understanding of the biological mechanisms that govern stem cell differentiation and in the development of materials with controlled physicochemical and biological properties. However, many technological barriers and regulations concerns have to be overcome before tissue engineering enters into the therapeutic arsenal of regenerative medicine. This review aims at highlighting the progress in the use of stem cells for engineering osteoarticular and vascular tissues. © 2011 médecine/sciences - Inserm / SRMS. PMID: 21447302 [PubMed - indexed for MEDLINE] 873. Discov Med. 2011 Mar;11(58):179-85. Temperatures rising: brown fat and bone. Motyl KJ(1), Rosen CJ. Author information: (1)Center for Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Portland, Maine 04074, USA. Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in adipocytes within the bone marrow. The nature of these adipocytes is uncertain, although there is emerging evidence of a direct relationship between bone remodeling and brown adipocytes. For example, in heterotrophic ossification, brown adipocytes set up a hypoxic gradient that leads to vascular invasion, chondrocyte differentiation, and subsequent bone formation. Additionally, deletion of retinoblastoma protein in an osteosarcoma model leads to increased hibernoma (brown fat tumor). Brown adipose tissue (BAT) becomes senescent with age at a time when thermoregulation is altered, bone loss becomes apparent, and sympathetic activity increases. Interestingly, heart rate is an unexpected but good predictor of fracture risk in elderly individuals, pointing to a key role for the sympathetic nervous system in senile osteoporosis. Hence the possibility exists that BAT could play an indirect role in age-related bone loss. However, evidence of an indirect effect from thermogenic dysfunction on bone loss is currently limited. Here, we present current evidence for a relationship between brown adipose tissue and bone as well as provide novel insights into the effects of thermoregulation on bone mineral density. PMCID: PMC3629549 PMID: 21447277 [PubMed - indexed for MEDLINE] 874. Acta Physiol (Oxf). 2012 Jan;204(1):34-51. doi: 10.1111/j.1748-1716.2011.02296.x. Epub 2011 May 7. The role of WNT10B in physiology and disease. Wend P(1), Wend K, Krum SA, Miranda-Carboni GA. Author information: (1)Department of Obstetrics and Gynecology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, USA. Wnt10b is a member of the Wnt ligand gene family that encodes for secreted proteins, which activate the ancient and highly conserved Wnt signalling cascade. The Wnt pathway has been shown to be essential for embryonic development, tissue integrity, and stem cell activity, but if deregulated, also causes disease such as cancer. Although the 19 different Wnt ligands found in both human and mouse can activate several branches of the Wnt pathway, WNT10B specifically activates canonical Wnt/β-catenin signalling and thus triggers β-catenin/LEF/TCF-mediated transcriptional programs. In this review, we highlight the unique functions of WNT10B and mechanisms of how WNT10B acts in the immune system, mammary gland, adipose tissue, bone and skin. In these organs, WNT10B has been well established to be involved in signalling networks controlling stemness, pluripotency and cell fate decisions. Deregulation of these processes causes diseases such as breast cancer, obesity and osteoporosis. Compelling evidence suggests that WNT10B is a valuable candidate for the development of therapeutic regimens for human diseases. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society. PMID: 21447090 [PubMed - indexed for MEDLINE] 875. Braz J Med Biol Res. 2011 May;44(5):381-7. Epub 2011 Mar 29. Leptin and adiponectin in the female life course. Lecke SB(1), Morsch DM, Spritzer PM. Author information: (1)Unidade de Endocrinologia Ginecológica, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Laboratório de Endocrinologia Molecular, Departamento de Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. Adipose tissue secretes a variety of adipokines, including leptin and adiponectin, which are involved in endocrine processes regulating glucose and fatty metabolism, energy expenditure, inflammatory response, immunity, cardiovascular function, and reproduction. The present article describes the fluctuations in circulating leptin and adiponectin as well as their patterns of secretion in women from birth to menopause. During pregnancy, leptin and adiponectin seem to act in an autocrine/paracrine fashion in the placenta and adipose tissue, playing a role in the maternal-fetal interface and contributing to glucose metabolism and fetal development. In newborns, adiponectin levels are two to three times higher than in adults. Full-term newborns have significantly higher leptin and adiponectin levels than preterms, whereas small-for-gestational-age infants have lower levels of these adipokines than adequate-for-gestational-age newborns. However, with weight gain, leptin concentrations increase significantly. Children between 5 and 8 years of age experience an increase in leptin and a decrease in adiponectin regardless of body mass index, with a reversal of the newborn pattern for adiponectin: plasma adiponectin levels at age five are inversely correlated with percentage of body fat. In puberty, leptin plays a role in the regulation of menstrual cycles. In adults, it has been suggested that obese individuals exhibit both leptin resistance and decreased serum adiponectin levels. In conclusion, a progressive increase in adiposity throughout life seems to influence the relationship between leptin and adiponectin in women. PMID: 21445529 [PubMed - indexed for MEDLINE] 876. Circ J. 2011;75(5):1019-27. Epub 2011 Mar 25. Prevention of atherosclerosis in overweight/obese patients. - In need of novel multi-targeted approaches-. Lim S(1), Despres JP, Koh KK. Author information: (1)Division of Endocrinology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea. Obesity has reached epidemic proportions and complications related to obesity contribute substantially to both healthcare costs and mortality. Obesity, particularly when accompanied by an excess of visceral/ectopic fat, is a major risk factor for diseases ranging from insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The epidemic proportions reached by obesity has made these conditions a global problem in human health. Accordingly, preventive and/or therapeutic interventions should be considered in obese patients. Regular physical activity/exercise has numerous beneficial effects on the cardiometabolic risk profile and on the cardiovascular system. However, our current clinical environment is not designed to provide the regular support needed by patients to help them maintain over the long term their improved physical activity/nutritional habits. Because hypertension, dyslipidemia, hyperinsulinemia, and excess visceral adipose tissue are linked by complex reciprocal molecular interactions, it is logical to expect that targeting an interconnected pathway may provide multiple benefits. At this stage, combined therapy of statins or PPAR agonists and renin-angiotensin-aldosterone system blockers to target multiple therapeutic pathways may optimally improve the cardiometabolic risk profile through both distinct and interrelated mechanisms. In the present article, we will discuss updated novel approaches, including potential multi-targeted intervention strategies, based on underlying pathophysiological processes. PMID: 21441697 [PubMed - indexed for MEDLINE] 877. J Vasc Surg. 2011 Sep;54(3):819-31. doi: 10.1016/j.jvs.2011.01.003. Epub 2011 Mar 24. Vascular biology of metabolic syndrome. Vykoukal D(1), Davies MG. Author information: (1)Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, The Methodist Hospital, Houston, TX77030, USA. The metabolic syndrome is a constellation of clinical risk factors comprising atherogenic dyslipidemia (low high-density lipoprotein and high triglycerides levels), elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state accompanied by an increased risk for cardiovascular disease and type 2 diabetes mellitus. The adipose tissue of obese humans contains increased numbers of macrophages, and once activated, these macrophages are responsible for the expression of most of the tissue's tumor necrosis factor (TNF)-α and interleukin (IL)-6. Chronic inflammation associated with visceral obesity induces altered lipoprotein metabolism and insulin resistance in the liver. Adipocytes secrete a variety of hormones, cytokines, growth factors, and other bioactive substances, conceptualized as adipocytokines, including plasminogen activator inhibitor 1 (PAI-1), TNF-α, leptin, and adiponectin. The dysregulation of these adipokines contributes to the pathogenesis of obesity. Adipose tissue-resident macrophages and adipocytes in the adipose tissue combined with the consequences of hyperglycemia, altered lipoproteins, and hyperinsulinemia in the vasculature and within organ microcirculation lead to dysfunctional endothelia and a proinflammatory state. Metabolic syndrome thus represents a combination of synergistic vascular pathologies that lead to an accelerated atherogenic state that compromises the ability of the patient to satisfactorily respond to humoral, cellular, and mechanical stresses. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved. PMCID: PMC3136643 PMID: 21439758 [PubMed - indexed for MEDLINE] 878. Acta Physiol (Oxf). 2011 Sep;203(1):279-86. doi: 10.1111/j.1748-1716.2011.02290.x. Epub 2011 Apr 22. Obesity, blood vessels and metabolic syndrome. Tesauro M(1), Cardillo C. Author information: (1)Department of Internal Medicine, Università di Tor Vergata, Rome, Italy. Obesity is rising worldwide at an alarming rate and so is the incidence of obesity-related disorders, such as the metabolic syndrome, type 2 diabetes and cardiovascular diseases. The obesity-dependent vascular damage appears to be derived from a variety of changes in the adipose tissue, leading to a chronic inflammatory state and dysregulation of adipocyte-derived factors. This, in turn, impairs vascular homeostasis by determining an unbalance between the protective effect of the nitric oxide pathway and the unfavourable action of the endothelin-1 system. In addition, hyperinsulinemia and insulin resistance contribute to vascular dysfunction because the opposing endothelium-dependent vasodilating and vasoconstrictor effects of insulin are shifted towards a predominant vasoconstriction in patients with obesity. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not only limited to the endothelium but also involves the other layers of the vessel wall. In particular, obesity-related changes in vascular smooth muscle seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and the perivascular fat appear to be a source of proinflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction and to the pathogenesis of vascular disease. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society. PMID: 21439028 [PubMed - indexed for MEDLINE] 879. Stem Cells. 2011 May;29(5):749-54. doi: 10.1002/stem.629. Concise review: Adipose-derived stromal vascular fraction cells and stem cells: let's not get lost in translation. Gimble JM(1), Bunnell BA, Chiu ES, Guilak F. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. gimblejm@pbrc.edu Subcutaneous fat has emerged as an alternative tissue source for stromal/stem cells in regenerative medicine. Over the past decade, international research efforts have established a wealth of basic science and preclinical evidence regarding the differentiation potential and regenerative properties of both freshly processed, heterogeneous stromal vascular fraction cells and culture expanded, relatively homogeneous adipose-derived stromal/stem cells. The stage has been set for clinicians to translate adipose-derived cells from the bench to the bedside; however, this process will involve "development" steps that fall outside of traditional "hypothesis-driven, mechanism-based" paradigm. This concise review examines the next stages of the development process for therapeutic applications of adipose-derived cells and highlights the current state of the art regarding clinical trials. It is recommended that the experiments addressing these issues be reported comprehensively in the peer-review literature. This transparency will accelerate the standardization and reproducibility of adipose-derived cell therapies with respect to their efficacy and safety. Copyright © 2011 AlphaMed Press. PMID: 21433220 [PubMed - indexed for MEDLINE] 880. J Sci Food Agric. 2011 May;91(7):1166-74. doi: 10.1002/jsfa.4353. Epub 2011 Mar 23. The allenic carotenoid fucoxanthin, a novel marine nutraceutical from brown seaweeds. Miyashita K(1), Nishikawa S, Beppu F, Tsukui T, Abe M, Hosokawa M. Author information: (1)Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido 041-8611, Japan. kmiya@fish.hokudai.ac.jp Obesity and type 2 diabetes are pathologies with rapidly growing prevalence throughout the world. A few molecular targets offer the most hope for anti-obesity and anti-diabetic therapeutics. One of the keys to success will be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity and anti-diabetic effects of fucoxanthin, a characteristic carotenoid found in brown seaweeds, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of carotenoids for the expression of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups. Copyright © 2011 Society of Chemical Industry. PMID: 21433011 [PubMed - indexed for MEDLINE] 881. Curr Diab Rep. 2011 Jun;11(3):167-72. doi: 10.1007/s11892-011-0190-2. Why does NAFLD predict type 2 diabetes? Lattuada G(1), Ragogna F, Perseghin G. Author information: (1)Department of Sport, Nutrition and Health, Università degli Studi di Milano, via Kramer 4/A, 20129 Milan, Italy. Based on the "lipotoxic" hypothesis, the free fatty acid flux from the excessive amount of adipose tissue toward the peripheral tissues would induce the development of insulin resistance especially when the triglyceride storage or the concentration of intermediate fat metabolites (diacylglycerides, ceramides) within the cytoplasm of these cells become excessive. Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis and advanced fibrosis. NAFLD is associated with general and intra-abdominal obesity and with a reduced ability of insulin to stimulate metabolic pathways in the liver itself and in other tissues. There are animal models and models in human diseases sustaining the hypothesis that a primary hepatic disease may determine the development of type 2 diabetes (T2DM). Epidemiologic data generated on surrogate markers of NAFLD (transaminases and γ-glutamyltransferase), semiquantitative assessment of fatty liver (ultrasound), and surrogate algorithms of NAFLD also support a causative effect of NAFLD on the risk to develop T2DM. In spite of the presence of these indirect associations, a clear-cut link between NAFLD and abnormal β-cell function is yet to be reported. Therefore, more data are warranted to prove what is considered a likely causative relationship between NAFLD and T2DM. PMID: 21431854 [PubMed - indexed for MEDLINE] 882. Methods Mol Biol. 2011;698:201-14. doi: 10.1007/978-1-60761-999-4_16. Osteogenic differentiation of human multipotent mesenchymal stromal cells. Gupta DM(1), Panetta NJ, Longaker MT. Author information: (1)Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. A comprehensive knowledge of the molecular biology underlying osteogenic differentiation in a controlled, laboratory setting may promise optimization of future cell-based tissue engineering strategies for clinical problems. The scope of this review encompasses a discussion of the methodology utilized to perform such studies. Our laboratory routinely performs both in vitro and in vivo assays underlying osteogenic differentiation, and the widespread use of singular methodology across multiple investigators and institutions promises great advancements for the skeletal tissue engineering community. PMID: 21431521 [PubMed - indexed for MEDLINE] 883. J Mol Med (Berl). 2011 Jul;89(7):667-76. doi: 10.1007/s00109-011-0748-0. Epub 2011 Mar 23. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. Salminen A(1), Hyttinen JM, Kaarniranta K. Author information: (1)Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. antero.salminen@uef.fi Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy metabolic homeostasis and thus a major survival factor in a variety of metabolic stresses and also in the aging process. Metabolic syndrome is associated with a low-grade, chronic inflammation, primarily in adipose tissue. A low-level of inflammation is also present in the aging process. There are emerging results indicating that AMPK signaling can inhibit the inflammatory responses induced by the nuclear factor-κB (NF-κB) system. The NF-κB subunits are not direct phosphorylation targets of AMPK, but the inhibition of NF-κB signaling is mediated by several downstream targets of AMPK, e.g., SIRT1, PGC-1α, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance energy metabolism while it can repress inflammatory responses linked to chronic stress, e.g., in nutritional overload and during the aging process. AMPK can inhibit endoplasmic reticulum and oxidative stresses which are involved in metabolic disorders and the aging process. Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. The activation capacity of AMPK declines in metabolic stress and with aging which could augment the metabolic diseases and accelerate the aging process. We will review the AMPK pathways involved in the inhibition of NF-κB signaling and suppression of inflammation. We also emphasize that the capacity of AMPK to repress inflammatory responses can have a significant impact on both healthspan and lifespan. PMCID: PMC3111671 PMID: 21431325 [PubMed - indexed for MEDLINE] 884. Metab Syndr Relat Disord. 2011 Aug;9(4):239-45. doi: 10.1089/met.2011.0003. Epub 2011 Mar 23. Pathogenic role of scavenger receptor CD36 in the metabolic syndrome and diabetes. Kennedy DJ(1), Kashyap SR. Author information: (1)Department of Cell Biology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Ohio 44195, USA. Obesity is increasing at epidemic proportions in the United States and is a major contributor to the development of both metabolic syndrome (glucose intolerance, dyslipidemia, hypertension) and atherosclerotic cardiovascular disease. A wide body of evidence has linked systemic low-grade inflammation as underlying obesity and insulin-resistant states via monocyte/macrophage activation. Transgenic deletion of scavenger receptor type B CD36 in rodents has suggested a pivotal role for CD36 in mediating inflammation, insulin resistance, and atherogenesis through transport of fatty acids and uptake of oxidized lipids, respectively. CD36 signaling pathways involving c-Jun N-terminal kinase (JNK) activation and Toll-like receptors have been implicated in the induction of insulin resistance. This review will focus on the pathogenic role of CD36 receptors in metabolic syndrome and type 2 diabetes. PMID: 21428745 [PubMed - indexed for MEDLINE] 885. Arch Physiol Biochem. 2011 Jul;117(3):195-208. doi: 10.3109/13813455.2011.560951. Epub 2011 Mar 23. A new era for brown adipose tissue: New insights into brown adipocyte function and differentiation. Vila-Bedmar R(1), Fernández-Veledo S. Author information: (1)Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain. Until quite recently, brown adipose tissue was considered of metabolic significance only in small mammals and human newborns, since it was thought to disappear rapidly after birth in humans. However, nowadays this tissue is known to play a role in the regulation of energy balance not only in rodents, but also in humans. In this review we highlight new features regarding brown adipose tissue origin and function and revise old paradigms about brown adipocyte differentiation. PMID: 21428723 [PubMed - indexed for MEDLINE] 886. Stem Cells. 2011 Mar;29(3):404-11. doi: 10.1002/stem.593. Concise review: human adipose-derived stem cells: separating promise from clinical need. Locke M(1), Feisst V, Dunbar PR. Author information: (1)Department of Surgery and University of Auckland, Auckland, New Zealand. michellebjoyce@yahoo.co.nz Human adipose-derived stem cells (ASCs) have become an increasing interest to both stem cell biologists and clinicians because of their potential to differentiate into adipogenic, osteogenic, chondrogenic, and other mesenchymal lineages, as well as other clinically useful properties attributed to them, such as stimulation of angiogenesis and suppression of inflammation. ASCs have already been used in a number of clinical trials, and some successful outcomes have been reported, especially in tissue reconstruction. However, a critical review of the literature reveals considerable uncertainty about the true clinical potential of human ASC. First, the surgical needs that ASC might answer remain relatively few, given the current difficulties in scaling up ASC-based tissue engineering to a clinically useful volume. Second, the differentiation of ASC into cell lineages apart from adipocytes has not been conclusively demonstrated in many studies due to the use of rather simplistic approaches to the confirmation of differentiation, such as the use of nonspecific histological dyes, or a small number of molecular markers of uncertain significance. Third, the ASC prepared from human lipoaspirate for different studies differ in purity and molecular phenotype, with many studies using cell preparations that are likely to contain heterogeneous populations of cells, making it uncertain whether ASC themselves are responsible for effects observed. Hence, while one clinical application already looks convincing, the full clinical potential of ASC awaits much deeper investigation of their fundamental biology. Copyright © 2011 AlphaMed Press. PMID: 21425404 [PubMed - indexed for MEDLINE] 887. Curr Diab Rep. 2011 Jun;11(3):179-84. doi: 10.1007/s11892-011-0189-8. Adipose tissue dysfunction in polycystic ovary syndrome. Villa J(1), Pratley RE. Author information: (1)Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine, Colchester Research Facility, 110C, 208 South Park Street, Colchester, VT 05446, USA. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among premenopausal women. In addition to infertility, PCOS is associated with insulin resistance, features of the metabolic syndrome, and an increased risk for diabetes. Similar to individuals with metabolic syndrome, many women with PCOS manifest abdominal obesity, suggesting adipose tissue dysfunction. The adipose tissue of women with PCOS is characterized by hypertrophic adipocytes and impairments in lipolysis and insulin action. The expression and secretion of a wide variety of adipokines implicated in insulin resistance, including adiponectin and others, are also altered in PCOS. Collectively, the available data indicate that adipose tissue dysfunction plays a central role in the metabolic abnormalities observed in PCOS. Whether these abnormalities are primary or secondary to hyperandrogenism or other abnormalities in PCOS is not yet known. PMID: 21424395 [PubMed - indexed for MEDLINE] 888. Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H1973-82. doi: 10.1152/ajpheart.00200.2011. Epub 2011 Mar 18. Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting. Breitbart A(1), Auger-Messier M, Molkentin JD, Heineke J. Author information: (1)Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Rebirth-Cluster of Excellence, Carl-Neuberg-Str.1, 30625 Hannover, Germany. A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future. PMCID: PMC3119101 PMID: 21421824 [PubMed - indexed for MEDLINE] 889. Transl Res. 2011 Apr;157(4):253-64. doi: 10.1016/j.trsl.2011.01.009. Epub 2011 Feb 4. Diabetes mellitus, a microRNA-related disease? Guay C(1), Roggli E, Nesca V, Jacovetti C, Regazzi R. Author information: (1)Department of Cell Biology and Morphology, University of Lausanne, Lausanne, Switzerland. Diabetes mellitus is a complex disease resulting in altered glucose homeostasis. In both type 1 and type 2 diabetes mellitus, pancreatic β cells cannot secrete appropriate amounts of insulin to regulate blood glucose level. Moreover, in type 2 diabetes mellitus, altered insulin secretion is combined with a resistance of insulin-target tissues, mainly liver, adipose tissue, and skeletal muscle. Both environmental and genetic factors are known to contribute to the development of the disease. Growing evidence indicates that microRNAs (miRNAs), a class of small noncoding RNA molecules, are involved in the pathogenesis of diabetes. miRNAs function as translational repressors and are emerging as important regulators of key biological processes. Here, we review recent studies reporting changes in miRNA expression in tissues isolated from different diabetic animal models. We also describe the role of several miRNAs in pancreatic β cells and insulin-target tissues. Finally, we discuss the possible use of miRNAs as blood biomarkers to prevent diabetes development and as tools for gene-based therapy to treat both type 1 and type 2 diabetes mellitus. Copyright © 2011 Mosby, Inc. All rights reserved. PMID: 21420036 [PubMed - indexed for MEDLINE] 890. Nutr Res Rev. 2011 Jun;24(1):132-54. doi: 10.1017/S0954422411000035. Epub 2011 Mar 22. Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin. Somogyi V(1), Gyorffy A(1), Scalise TJ(1), Kiss DS(1), Goszleth G(1), Bartha T(1), Frenyo VL(1), Zsarnovszky A(1). Author information: (1)Department of Physiology and Biochemistry, Szent Istvan University Faculty of Veterinary Sciences, 1078 Istvan u. 2, Budapest, Hungary. Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake. PMID: 21418732 [PubMed - indexed for MEDLINE] 891. Sheng Li Ke Xue Jin Zhan. 2010 Oct;41(5):341-6. [Directional differentiation of adipose-derived stem cell]. [Article in Chinese] Xiang XX(1), Zhao J, Li Y, Zhang WZ. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Science Center, Beijing, China. Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) derived from adipose tissue, which have the ability to self-renew and differentiate into many types of tissues. Here we summarize the recent advances in the research of ADSCs, introduce the methods of ADSCs isolation and culture, and discusse the factors regulating the adipo-differentiation and osteo-differentiation of ADSCs. The present review will yield novel insight relevant to the therapeutic intervention of obesity and osteo-tissue engineering. PMID: 21416923 [PubMed - indexed for MEDLINE] 892. G Ital Cardiol (Rome). 2010 Oct;11(10 Suppl 1):93S-97S. [Insulin-resistance and cardiovascular risk]. [Article in Italian] Dei Cas A(1), Spigoni V, Metra M, Dei Cas L. Author information: (1)Dipartimento di Medicina Interna e Scienze Biomediche, Università degli Studi, Parma. alessandra.deicas@unipr.it Insulin resistance is associated with a cluster of metabolic and hemodynamic abnormalities that lead to increased cardiovascular morbidity and mortality. In this review the main pathophysiological mechanisms and metabolic consequences of insulin resistance are summarized. The correlation between insulin resistance and cardiovascular disease and the practical utility of the concept of metabolic syndrome as a diagnostic tool are also discussed. PMID: 21416835 [PubMed - indexed for MEDLINE] 893. Rev Invest Clin. 2010 Sep-Oct;62(5):480-90. [The metabolic and molecular bases of Cockayne syndrome]. [Article in Spanish] Flores-Alvarado LJ(1), Ramirez-Garcia SA, Núñez-Reveles NY. Author information: (1)Departamento de Biología Molecular y Genómica CUCS, Universidad de Guadlajara. Cockayne is a segmental progeroid syndrome that has autosomal recessive inheritance pattern. It is mainly characterized by Intrauterine growth retardation, severe postnatal growth deficiency, cachectic dwarfism, microcephaly, wizened face, sensorineural hearing loss, cataracts, dental caries, cardiac arrhythmias, hypertension, atherosclerosis, proteinuria, micropenis, renal failure, skeletal abnormalities, skin photosensitivity, decreased subcutaneous adipose tissue, cerebral atrophy, dementia, basal ganglia calcifications, ataxia and apraxia. It has a complex phenotype given by genetic heterogeneity. There are five gene responsible for this syndrome: CSA, CSB, XPB, XPD and XPG, in which various mutations have been found. The biochemical effect of these mutations includes dysfunctional protein of the repair system for oxidative damage to DNA, the complex coupled to transcription and the nucleotide excision repair system. Considering the role played for these proteins and its effects on clinical phenotype when they are deficient, we suggest that these genes might be candidates for analyzing susceptibility to common chronic degenerative diseases related to oxidative stress and aging. PMID: 21416736 [PubMed - indexed for MEDLINE] 894. Curr Opin Clin Nutr Metab Care. 2011 May;14(3):243-9. doi: 10.1097/MCO.0b013e3283455d7a. Skeletal muscle mitochondrial uncoupling, adaptive thermogenesis and energy expenditure. van den Berg SA(1), van Marken Lichtenbelt W, Willems van Dijk K, Schrauwen P. Author information: (1)Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. PURPOSE OF REVIEW: The prevalence of obesity is still increasing, despite obesity treatment strategies that aim at reducing energy intake. In addition to this, exercise programmes designed to increase energy expenditure have only a low efficiency and have generated mixed results. Therefore, strategies based on increasing energy expenditure via nonexercise means are currently under investigation. One novel strategy is the modulation of adaptive thermogenesis. RECENT FINDINGS: Among others, adaptive thermogenesis can be modulated by changing dietary composition, treatment with hormone mimetics as well as by cold exposure. In humans, a large part of the adaptive thermogenic response is, in addition to a putative role of brown adipose tissue, determined by the skeletal muscle mass via the process of mitochondrial uncoupling. Here, we describe the molecular processes involved in mitochondrial uncoupling, state-of-the-art techniques to measure mitochondrial uncoupling in vitro and in vivo, as well as the current strategies to mitochondrial uncoupling. SUMMARY: Data generated in rodents and humans implicate that increasing adaptive thermogenesis by increasing skeletal muscle mitochondrial uncoupling indeed elevates total energy expenditure and thus may provide a promising target for the treatment of obesity. PMID: 21415733 [PubMed - indexed for MEDLINE] 895. FEBS Lett. 2011 May 20;585(10):1412-26. doi: 10.1016/j.febslet.2011.03.021. Epub 2011 Mar 21. Circadian disruption and SCN control of energy metabolism. Kalsbeek A(1), Scheer FA, Perreau-Lenz S, La Fleur SE, Yi CX, Fliers E, Buijs RM. Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands. a.kalsbeek@amc.uva.nl In this review we first present the anatomical pathways used by the suprachiasmatic nuclei to enforce its rhythmicity onto the body, especially its energy homeostatic system. The experimental data show that by activating the orexin system at the start of the active phase, the biological clock not only ensures that we wake up on time, but also that our glucose metabolism and cardiovascular system are prepared for increased activity. The drawback of such a highly integrated system, however, becomes visible when our daily lives are not fully synchronized with the environment. Thus, in addition to increased physical activity and decreased intake of high-energy food, also a well-lighted and fully resonating biological clock may help to withstand the increasing "diabetogenic" pressure of today's 24/7 society. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. PMCID: PMC3095769 PMID: 21414317 [PubMed - indexed for MEDLINE] 896. Expert Opin Biol Ther. 2011 Jun;11(6):775-86. doi: 10.1517/14712598.2011.570258. Epub 2011 Mar 18. Hypoxia and adipose-derived stem cell-based tissue regeneration and engineering. Zachar V(1), Duroux M, Emmersen J, Rasmussen JG, Pennisi CP, Yang S, Fink T. Author information: (1)Aalborg University, Laboratory for Stem Cell Research, Fredrik Bajers Vej 3B, 9220 Aalborg, Denmark. vlaz@hst.aau.dk INTRODUCTION: Realization that oxygen is one of the key regulators of development and differentiation has a profound significance on how current cell-based and tissue engineering applications using adipose-derived stem cells (ASCs) can be further improved. AREAS COVERED: The article provides an overview of mechanisms of hypoxic responses during physiological adaptations and development. Furthermore, a synopsis of the hypoxic responses of ASCs is provided, and this information is presented in context of their utility as a major source of stem cells across the regenerative applications explored to date. EXPERT OPINION: The reader will obtain insight into a highly specific area of stem cell research focusing on ASCs and hypoxia. In order to enhance the level of comprehension, a broader context with other stem cell and experimental systems is provided. It is emphasized that the pericellular oxygen tension is a critical regulatory factor that should be taken into account when devising novel stem cell-based therapeutic applications along with other parameters, such as biochemical soluble factors and the growth substrates. PMID: 21413910 [PubMed - indexed for MEDLINE] 897. J Tissue Eng Regen Med. 2011 Apr;5(4):e36-51. doi: 10.1002/term.386. Epub 2011 Jan 10. State of the art and future perspectives of articular cartilage regeneration: a focus on adipose-derived stem cells and platelet-derived products. Hildner F(1), Albrecht C, Gabriel C, Redl H, van Griensven M. Author information: (1)Red Cross Blood Transfusion Service of Upper Austria, Linz, Austria. florian.hildner@o.roteskreuz.at Trauma, malposition and age-related degeneration of articular cartilage often result in severe lesions that do not heal spontaneously. Many efforts over the last centuries have been undertaken to support cartilage healing, with approaches ranging from symptomatic treatment to structural cartilage regeneration. Microfracture and matrix-associated autologous chondrocyte transplantation (MACT) can be regarded as one of the most effective techniques available today to treat traumatic cartilage defects. Research is focused on the development of new biomaterials, which are intended to provide optimized physical and biochemical conditions for cell proliferation and cartilage synthesis. New attempts have also been undertaken to replace chondrocytes with cells that are more easily available and cause less donor site morbidity, e.g. adipose derived stem cells (ASC). The number of in vitro studies on adult stem cells has rapidly increased during the last decade, indicating that many variables have yet to be optimized to direct stem cells towards the desired lineage. The present review gives an overview of the difficulties of cartilage repair and current cartilage repair techniques. Moreover, it reviews new fields of cartilage tissue engineering, including stem cells, co-cultures and platelet-rich plasma (PRP). Copyright © 2011 John Wiley & Sons, Ltd. PMID: 21413156 [PubMed - indexed for MEDLINE] 898. Planta Med. 2011 May;77(8):773-85. doi: 10.1055/s-0030-1270924. Epub 2011 Mar 16. Natural inhibitors of pancreatic lipase as new players in obesity treatment. de la Garza AL(1), Milagro FI, Boque N, Campión J, Martínez JA. Author information: (1)Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain. Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity. The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion. In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic. © Georg Thieme Verlag KG Stuttgart · New York. PMID: 21412692 [PubMed - indexed for MEDLINE] 899. BMC Med. 2011 Mar 16;9:25. doi: 10.1186/1741-7015-9-25. Regulation of vascular tone by adipocytes. Maenhaut N(1), Van de Voorde J. Author information: (1)Department of Pharmacology, Ghent University, Belgium. Recent studies have shown that adipose tissue is an active endocrine and paracrine organ secreting several mediators called adipokines. Adipokines include hormones, inflammatory cytokines and other proteins. In obesity, adipose tissue becomes dysfunctional, resulting in an overproduction of proinflammatory adipokines and a lower production of anti-inflammatory adipokines. The pathological accumulation of dysfunctional adipose tissue that characterizes obesity is a major risk factor for many other diseases, including type 2 diabetes, cardiovascular disease and hypertension. Multiple physiological roles have been assigned to adipokines, including the regulation of vascular tone. For example, the unidentified adipocyte-derived relaxing factor (ADRF) released from adipose tissue has been shown to relax arteries. Besides ADRF, other adipokines such as adiponectin, omentin and visfatin are vasorelaxants. On the other hand, angiotensin II and resistin are vasoconstrictors released by adipocytes. Reactive oxygen species, leptin, tumour necrosis factor α, interleukin-6 and apelin share both vasorelaxing and constricting properties. Dysregulated synthesis of the vasoactive and proinflammatory adipokines may underlie the compromised vascular reactivity in obesity and obesity-related disorders. PMCID: PMC3069942 PMID: 21410966 [PubMed - indexed for MEDLINE] 900. Obes Rev. 2011 Jul;12(7):e593-601. doi: 10.1111/j.1467-789X.2011.00873.x. Epub 2011 Mar 17. Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss? Varady KA(1). Author information: (1)Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA. varady@uic.edu Dietary restriction is an effective strategy for weight loss in obese individuals. The most common form of dietary restriction implemented is daily calorie restriction (CR), which involves reducing energy by 15-60% of usual caloric intake every day. Another form of dietary restriction employed is intermittent CR, which involves 24 h of ad libitum food consumption alternated with 24 h of complete or partial food restriction. Although both diets are effective for weight loss, it remains unknown whether one of these interventions produces superior changes in body weight and body composition when compared to the other. Accordingly, this review examines the effects of daily CR versus intermittent CR on weight loss, fat mass loss and lean mass retention in overweight and obese adults. Results reveal similar weight loss and fat mass loss with 3 to 12 weeks' intermittent CR (4-8%, 11-16%, respectively) and daily CR (5-8%, 10-20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR. These findings suggest that these diets are equally as effective in decreasing body weight and fat mass, although intermittent CR may be more effective for the retention of lean mass. © 2011 The Author. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21410865 [PubMed - indexed for MEDLINE] 901. Traffic. 2011 Jun;12(6):672-81. doi: 10.1111/j.1600-0854.2011.01178.x. Epub 2011 Mar 15. Mapping insulin/GLUT4 circuitry. Rowland AF(1), Fazakerley DJ, James DE. Author information: (1)Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. One of the most important metabolic actions of insulin is catalysing glucose uptake into skeletal muscle and adipose tissue. This is accomplished via activation of the phosphatidylinositol-3-kinase/Akt signalling pathway and subsequent translocation of GLUT4 from intracellular storage vesicles to the plasma membrane. As such, this represents an ideal system for studying the convergence of signal transduction and protein trafficking. The GLUT4 translocation process is complex, but can be dissected into at least four discrete trafficking steps. This raises the question as to which of these is the major regulated step in insulin-stimulated GLUT4 translocation. Numerous molecules have been reported to regulate GLUT4 trafficking. However, with the exception of TBC1D4, the molecular details of these distal signalling arms of the insulin signalling network and how they modify distinct steps of GLUT4 trafficking have not been established. We discuss the need to adopt a more global approach to expand and deepen our understanding of the molecular processes underpinning this system. Strategies that facilitate the generation of detailed models of the entire insulin signalling network will enable us to identify the critical nodes that control GLUT4 traffic and decipher emergent properties of the system that are not currently apparent. © 2011 John Wiley & Sons A/S. PMID: 21401839 [PubMed - indexed for MEDLINE] 902. Cell Transplant. 2011;20(1):5-14. doi: 10.3727/096368910X. Mesenchymal stem cells. Ding DC(1), Shyu WC, Lin SZ. Author information: (1)Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC. Stem cells have two features: the ability to differentiate along different lineages and the ability of self-renewal. Two major types of stem cells have been described, namely, embryonic stem cells and adult stem cells. Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis, and the use of human ESCs involves ethical and legal considerations. The use of adult mesenchymal stem cells is less problematic with regard to these issues. Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as umbilical cord, endometrial polyps, menses blood, bone marrow, adipose tissue, etc. This is because the ease of harvest and quantity obtained make these sources most practical for experimental and possible clinical applications. Recently, MSCs have been found in new sources, such as menstrual blood and endometrium. There are likely more sources of MSCs waiting to be discovered, and MSCs may be a good candidate for future experimental or clinical applications. One of the major challenges is to elucidate the mechanisms of differentiation, mobilization, and homing of MSCs, which are highly complex. The multipotent properties of MSCs make them an attractive choice for possible development of clinical applications. Future studies should explore the role of MSCs in differentiation, transplantation, and immune response in various diseases. PMID: 21396235 [PubMed - indexed for MEDLINE] 903. Arch Physiol Biochem. 2011 Jul;117(3):131-9. doi: 10.3109/13813455.2011.557387. Epub 2011 Mar 11. Lipid peroxidation of poly-unsaturated fatty acids in normal and obese adipose tissues. Cohen G(1), Riahi Y, Sasson S. Author information: (1)Institute for Drug Research, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel. Adipose tissues function as the primary storage compartment of fatty acids and as an endocrine organ that affects peripheral tissues. Many of adipose tissue-derived factors, often termed adipokines, have been discovered in recent years. The synthesis and secretion of these factors vary in different depots of adipose tissues. Excessive lipid accumulation in adipocytes induces inflammatory processes by up-regulating the expression and release of pro-inflammatory cytokines. In addition, activated macrophages in the obese adipose tissue release inflammatory cytokines. Adipose tissue inflammation has also been linked to an enhanced metabolism of polyunsaturated fatty acids (PUFAs). The non-enzymatic peroxidation of PUFAs and of their 12/15-lipoxygenase-derived hydroperoxy metabolites leads to the generation of the reactive aldehyde species 4-hydroxyalkenals. This review shows that 4-hydroxyalkenals, in particular 4-hydroxynonenal, play a key role in lipid storage homeostasis in normal adipocytes. Nonetheless, in the obese adipose tissue an increased production of 4-hydroxyalkenals contributes to the inflamed phenotype. PMID: 21395403 [PubMed - indexed for MEDLINE] 904. Cell Mol Biol Lett. 2011 Jun;16(2):236-57. doi: 10.2478/s11658-011-0005-0. Epub 2011 Mar 9. Stem cells from adipose tissue. Witkowska-Zimny M(1), Walenko K. Author information: (1)Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego 5, 02-004, Warsaw, Poland. mwitkowska@wum.edu.pl This is a review of the growing scientific interest in the developmental plasticity and therapeutic potential of stromal cells isolated from adipose tissue. Adipose-derived stem/stromal cells (ASCs) are multipotent somatic stem cells that are abundant in fat tissue. It has been shown that ASCs can differentiate into several lineages, including adipose cells, chondrocytes, osteoblasts, neuronal cells, endothelial cells, and cardiomyocytes. At the same time, adipose tissue can be harvested by a minimally invasive procedure, which makes it a promising source of adult stem cells. Therefore, it is believed that ASCs may become an alternative to the currently available adult stem cells (e.g. bone marrow stromal cells) for potential use in regenerative medicine. In this review, we present the basic information about the field of adipose-derived stem cells and their potential use in various applications. PMID: 21394447 [PubMed - indexed for MEDLINE] 905. Int J Biochem Cell Biol. 2011 Jun;43(6):862-76. doi: 10.1016/j.biocel.2011.03.002. Epub 2011 Mar 8. Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Vigouroux C(1), Caron-Debarle M, Le Dour C, Magré J, Capeau J. Author information: (1)INSERM UMR_S938, Centre de Recherche Saint-Antoine, Paris, France. Adipose tissue is now recognized for its major role in the control of energy metabolism and insulin sensitivity. We review here the human lipodystrophies, that are rare conditions in which total or partial fat loss is associated with severe lipid and glucose abnormalities leading to diabetes with early cardiovascular and hepatic complications. The genetic origin of a number of human lipodystrophies has been recently unraveled, emphasizing the importance of proteins of previously unknown or unexpected functions. Major adipose functions were also illuminated when studying acquired forms of lipodystrophies linked to human immunodeficiency virus-antiretrovirals. Overall, most of the proteins or functions affected by mutations or antiretrovirals result in altered adipogenesis and insulin sensitivity, triglyceride storage and formation of the unique adipocyte lipid droplet, oxidative stress and fat remodeling. Some mutations or antiretrovirals could affect directly (peroxisome proliferator-activated receptor-γ, Akt2) or indirectly (lamin A/C, human immunodeficiency virus-protease inhibitors) adipogenesis, through the transcription factors peroxisome proliferator-activated receptor gamma-γ or sterol regulatory element binding protein 1c, and insulin signaling through Akt2 that controls adipocyte lipolysis. A number of proteins mutated in genetic lipodystrophies are involved in the control of triglyceride synthesis towards the lipid droplet (1-acylglycerol-3-phosphate-O-acyltransferase 2), or its functions (seipin, cell death-inducing DFF45-like effector C, perilipin, caveolin-1, cavin-1). Decreased triglyceride storage leads to adipocyte lipotoxicity, mitochondrial dysfunction and increased oxidative stress, which could also be induced by some thymidine analogue antiretrovirals. This results in production of inflammatory mediators and deregulated release of free fatty acids. Thus, the impaired ability of adipose tissue to safely store triglycerides inside the lipid droplet results in impaired insulin sensitivity and adverted liver, muscles and heart functions leading to early complications. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21392585 [PubMed - indexed for MEDLINE] 906. Genes Immun. 2011 Jun;12(4):239-50. doi: 10.1038/gene.2011.14. Epub 2011 Mar 10. State of the union between metabolism and the immune system in type 2 diabetes. Nikolajczyk BS(1), Jagannathan-Bogdan M, Shin H, Gyurko R. Author information: (1)Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, MA 02118, USA. bnikol@bu.edu Lymphocytes and myeloid cells (monocyte/macrophages) have important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity, insulin resistance and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role of immune cells in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies hyper-nutrition, thus are critical players in metabolic homeostasis. More recently, multiple studies have indicated a role for T cells in obesity-associated inflammation and insulin resistance in model organisms, with parallel work indicating that pro-inflammatory changes in T cells also associate with human T2D. Furthermore, the expansion of T cells with similar antigen-binding sites in obesity and T2D indicates these diseases share characteristics previously attributed to inflammatory autoimmune disorders. Parallel pro-inflammatory changes in the B-cell compartment of T2D patients have also been identified. Taken together, these studies indicate that in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets has an important role in T2D disease pathogenesis. Basic immunological principles suggest that alterations in lymphocyte function in obesity and T2D patients are an integral part of a feed-forward pro-inflammatory loop involving additional cell types. Importantly, the pro-inflammatory loop almost inevitably includes adipocytes, known to respond to pro-inflammatory, pro-diabetogenic cytokines originating from the myeloid and lymphoid compartments. We propose a model for inflammation in T2D that functionally links lymphocyte, myeloid and adipocyte contributions, and importantly proposes that tools for B-cell ablation or regulation of T-cell subset balance may have a place in the endocrinologist's limited arsenal. PMID: 21390053 [PubMed - indexed for MEDLINE] 907. Aesthet Surg J. 2011 Mar;31(3):328-41. doi: 10.1177/1090820X11398353. Treatment of cellulite using a 1440-nm pulsed laser with one-year follow-up. DiBernardo BE(1). Author information: (1)Department of Surgery, Division of Plastic Surgery, University of Medicine and Dentistry of New Jersey, Newark, USA. DrD@NJPS1.com Comment in Aesthet Surg J. 2011 Mar;31(3):342-3. BACKGROUND: Cellulite is characterized by a thickened hypodermal fat layer, along with hypodermal fat lobules that extend upward into the dermis, expanding and stretching the fibrous septae that separate the fat lobules. Eventually, the septae sclerose, contract, and harden, holding the skin at an inflexible length while the surrounding tissue continues to expand. OBJECTIVES: The author evaluates the efficacy, safety, and duration of clinical benefit associated with a pulsed laser that delivers 1440-nm energy to the dermal-hypodermal interface for the treatment of cellulite. The changes in the dermal structure that affect the appearance of cellulite are also examined. METHODS: Ten healthy women with cellulite on their thighs enrolled in a prospective Institutional Review Board-approved study conducted in the author's private plastic surgery clinic. Patients received a single treatment with a 1440-nm pulsed laser. Energy was delivered to the subdermal tissue through a fiber that was designed for side firing and enclosed in a cannula. Treatment addressed the thickened hypodermal fat layer, hypodermal fat lobules that extended upward into the dermis, and fibrous septae by thermal subcision. RESULTS: The mean age of the patients was 47 years ± 5.4 years. Mean skin thickness (as shown by ultrasound) and skin elasticity were shown by objective measurements to increase significantly at one, three, six, and 12 months. Subjective physician and subject evaluations indicated improvement, high subject satisfaction, and minimal adverse effects. CONCLUSIONS: In this study, a single treatment with the 1440-nm pulsed laser improved the appearance of cellulite, an improvement that persisted through at least one year of follow-up with minimal adverse effects. PMID: 21385743 [PubMed - indexed for MEDLINE] 908. PLoS One. 2011 Feb 23;6(2):e17205. doi: 10.1371/journal.pone.0017205. Objectively measured physical activity and fat mass in children: a bias-adjusted meta-analysis of prospective studies. Wilks DC(1), Sharp SJ, Ekelund U, Thompson SG, Mander AP, Turner RM, Jebb SA, Lindroos AK. Author information: (1)Medical Research Council Collaborative Centre for Human Nutrition Research, Cambridge, United Kingdom. BACKGROUND: Studies investigating the prevention of weight gain differ considerably in design and quality, which impedes pooling them in conventional meta-analyses, the basis for evidence-based policy making. This study is aimed at quantifying the prospective association between measured physical activity and fat mass in children, using a meta-analysis method that allows inclusion of heterogeneous studies by adjusting for differences through eliciting and incorporating expert opinion. METHODS: Studies on prevention of weight gain using objectively measured exposure and outcome were eligible; they were adopted from a recently published systematic review. Differences in study quality and design were considered as internal and external biases and captured in checklists. Study results were converted to correlation coefficients and biases were considered either additive or proportional on this scale. The extent and uncertainty of biases in each study were elicited in a formal process by six quantitatively-trained assessors and five subject-matter specialists. Biases for each study were combined across assessors using median pooling. Results were combined across studies by random-effects meta-analysis. RESULTS: The combined correlation of the unadjusted results from the six studies was -0.04 (95%CI: -0.22, 0.14) with considerable heterogeneity (I² = 78%), which makes it difficult to interpret the result. After bias-adjustment the pooled correlation was -0.01 (95%CI: -0.18, 0.16) with apparent study compatibility (I² = 0%). CONCLUSION: By using this method the prospective association between physical activity and fat mass could be quantitatively synthesized; the result suggests no association. Objectively measured physical activity may not be the key determinant of unhealthy weight gain in children. PMCID: PMC3044163 PMID: 21383837 [PubMed - indexed for MEDLINE] 909. Acta Physiol (Oxf). 2011 Aug;202(4):605-16. doi: 10.1111/j.1748-1716.2011.02272.x. Epub 2011 Apr 6. Glucose intolerance in the West African Diaspora: a skeletal muscle fibre type distribution hypothesis. Nielsen J(1), Christensen DL. Author information: (1)Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. In the United States, Black Americans are largely descendants of West African slaves; they have a higher relative proportion of obesity and experience a higher prevalence of diabetes than White Americans. However, obesity rates alone cannot explain the higher prevalence of type 2 diabetes. Type 2 diabetes is characterized by insulin resistance and beta-cell dysfunction. We hypothesize that the higher prevalence of type 2 diabetes in African Americans (as compared to White Americans) is facilitated by an inherited higher percentage of skeletal muscle fibre type II and a lower percentage of skeletal muscle fibre type I. Skeletal muscle fibre type II is less oxidative and more glycolytic than skeletal muscle fibre type I. Lower oxidative capacity is associated with lower fat oxidation and a higher disposal of lipids, which are stored as muscular adipose tissue in higher amounts in Black compared to White Americans. In physically active individuals, the influence of muscle fibre composition will not be as detrimental as in physically inactive individuals. This discrepancy is caused by the plasticity in the skeletal muscle fibre characteristics towards a higher activity of oxidative enzymes as a consequence of physical activity. We suggest that a higher percentage of skeletal muscle fibre type II combined with physical inactivity has an impact on insulin sensitivity and high prevalence of type 2 diabetes in Blacks of West African ancestry. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society. PMID: 21382179 [PubMed - indexed for MEDLINE] 910. Eur Rev Med Pharmacol Sci. 2011 Jan;15(1):9-14. Visfatin--a review. Sonoli SS(1), Shivprasad S, Prasad CV, Patil AB, Desai PB, Somannavar MS. Author information: (1)Department of Biochemistry, J. N. Medical College, Nehru nagar, Belgaum - Karnataka, India. drsmitasonoli@yahoo.co.in Expedited research on Obesity has confirmed that, adipose tissue is highly active in secreting a variety of proteins, one among them is visfatin. It was originally identified as Pre B cell Colony Enhancing Factor (PBEF), to be secreted by the lymphocytes and can act as a cytokine with immune regulatory action. Besides, it acts as Nicotinamide phosphoribosyl transferase (Nampt), an enzyme involved in the NAD+ salvage pathway. It has been shown to help in the regulation of glucose homeostasis, but whether it binds to insulin receptor and exerts insulin mimetic activity is still a controversy. Visfatin has antiapoptotic activity and has a regulatory role in inflammation. Several studies have identified changes in the circulatory levels of visfatin in diseases. Notable among them are obesity, diabetes mellitus, kidney diseases and bone disorders. It is a molecule of clinical relevance and could be a promising biomarker with diagnostic and prognostic significance. PMID: 21381495 [PubMed - indexed for MEDLINE] 911. Curr Pharm Des. 2011;17(4):320-4. A role for rev-erbα ligands in regulation of adipogenesis. Kojetin DJ(1), Burris TP. Author information: (1)Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, 33458, USA. Rev-erbs are members of the nuclear receptor (NR) transcription factor superfamily and are widely expressed, but are most prevalent in liver, adipose tissue, skeletal muscle and brain. Rev-erbs are key regulators of the circadian rhythm and are expressed in a circadian manner. The discovery that Rev-erbs are ligand-regulated receptors, whose repressive activity is regulated by the endogenous porphyrin ligand, heme, as well as the recent report of the first synthetic Rev-erb ligand, GSK4112/SR6452, suggests that pharmacological modulation through Rev-erb may provide new routes to treat metabolic diseases. Here, we review the work leading to the discovery that Rev-erbs are indeed ligand-regulated and the role that both natural and synthetic Rev-erb ligands have on adipogenesis. PMID: 21375499 [PubMed - indexed for MEDLINE] 912. Curr Pharm Des. 2011;17(4):325-31. Lipogenic enzymes as therapeutic targets for obesity and diabetes. Lenhard JM(1). Author information: (1)Cardiovascular and Metabolic Research, Johnson and Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Springhouse, PA 19477, USA. Jlenhar1@its.jnj.com Since storage of excess fat in peripheral tissues is a contributing factor leading to obesity and type II diabetes, many investigators are studying the key lipid metabolizing enzymes found in adipose tissue as drug targets to reduce excess fat. The availability of cultured cell lines and primary stem cells, preadipocyetes, and adipocytes has facilitated therapeutic approaches aimed at targeting fat storage. This includes developing inhibitors for enzymes regulating lipogenesis in these cells, such as acetyl-CoA carboxylase, fatty acid synthase, diacylgycerol acyl transferase, and stearoyl CoA desaturase. High level expression of each protein is often used to confirm stem cells have undergone adipogenesis. Inhibition of these enzymes often leads to reduced fat cell fat differentiation and lipid synthesis and may also contribute to increased fat oxidation and energy expenditure. This article reviews developments in pharmaceutical research on these enzymes, with particular emphasis on the role of the enzymes in adipose tissue metabolism. PMID: 21375498 [PubMed - indexed for MEDLINE] 913. Curr Pharm Des. 2011;17(4):332-9. Adipose-derived stromal/stem cells (ASC) in regenerative medicine: pharmaceutical applications. Gimble JM(1), Nuttall ME. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Information relating to the biology, culture expansion, and mechanisms relating to adipose-derived cells has advanced significantly in the past decade. Both the heterogeneous stromal vascular fraction (SVF) and more homogeneous adipose-derived stem cells (ASC) offer unique opportunities as novel cell-based therapeutics and as traditional pharmaceutical discovery tools. This review highlights the cytokine secretory functions of ASC and SVF cells as well as their potential use as immunomodulators and gene delivery vehicles. These functions make it feasible to exploit adipose-derived cells in the treatment of ischemic, musculoskeletal, and oncological disorders. With appropriate commercial development and in vivo validation, ASC and SVF cells will have a significant therapeutic impact in the future. PMID: 21375497 [PubMed - indexed for MEDLINE] 914. Curr Osteoporos Rep. 2011 Jun;9(2):67-75. doi: 10.1007/s11914-011-0051-6. The role of bone marrow and visceral fat on bone metabolism. Sheu Y(1), Cauley JA. Author information: (1)Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 North Bellefield Avenue, Room 467, Pittsburgh, PA 15213, USA. sheuy@edc.pitt.edu The protective effect of total fat mass on bone mineral density (BMD) has been challenged with studies showing no or negative association after adjusting for weight. Subsequently, more studies have evaluated the relationship of regional adiposity with BMD, and findings were inconsistent for central obesity. Advancements in imaging techniques enable us to directly and noninvasively study the role of adiposity on skeletal health. Visceral adiposity measured by computed tomography (CT) has consistently been shown to have negative effects on bone. Availability of magnetic resonance spectroscopy (MRS) also allows us to noninvasively quantify bone marrow fat (BMF), which has been known to be associated with osteoporosis from histomorphometric studies. Using MRS along with dual energy x-ray absorptiometry, studies have reported a detrimental role of BMF on BMD. With the increase in aging and obesity of the population, it is important to continue this effort in identifying the contribution of adipose tissues to bone quality and fracture. PMCID: PMC4188476 PMID: 21374105 [PubMed - indexed for MEDLINE] 915. Horm Res Paediatr. 2011;75(4):231-9. doi: 10.1159/000324806. Epub 2011 Mar 2. Renaissance of brown adipose tissue. Tews D(1), Wabitsch M. Author information: (1)Division of Pediatric Endocrinology and Diabetes, Endocrine Research Laboratory, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany. The recent discovery of functional brown adipose tissue in human adults raised this tissue again into the focus of current investigations concerning human energy homeostasis. Brown fat is a key thermogenic tissue and is essential for non-shivering thermogenesis in the human newborn and hibernating mammals. This review highlights the biological and molecular aspects of brown adipose tissue development and function from the embryonic state to childhood and adolescence. Copyright © 2011 S. Karger AG, Basel. PMID: 21372557 [PubMed - indexed for MEDLINE] 916. Biol Pharm Bull. 2011;34(3):307-10. Vascular effects of novel adipocytokines: focus on vascular contractility and inflammatory responses. Yamawaki H(1). Author information: (1)Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034–8628, Japan. yamawaki@vmas.kitasato-u.ac.jp Adipose tissue is now regarded as an active endocrine organ which can secrete various cytokines. Adipocyte-derived cytokines are termed adipocytokines (adipocytes+cytokine). Adipocytokines can affect vascular systems to prevent or exacerbate obesity-related vascular complications, including diabetes-related vascular dysfunction, hypertension, and atherosclerosis. However, their basic vascular functions remain to be fully determined. In this manuscript, I summarize our recent findings on the vascular effects of 5 newly identified adipocytokines (omentin, visfatin, nesfatin, vaspin, and chemerin), with a special focus on 1) vascular contractile reactivity, and 2) vascular inflammatory response/injury. These novel adipocytokines may be important future targets for the development of drugs and therapy for treating metabolic vascular disorders. PMID: 21372376 [PubMed - indexed for MEDLINE] 917. Obes Rev. 2011 Jul;12(7):e573-81. doi: 10.1111/j.1467-789X.2011.00862.x. Epub 2011 Mar 2. The effects of catechin rich teas and caffeine on energy expenditure and fat oxidation: a meta-analysis. Hursel R(1), Viechtbauer W, Dulloo AG, Tremblay A, Tappy L, Rumpler W, Westerterp-Plantenga MS. Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. rick.hursel@hb.unimaas.nl Different outcomes of the effect of catechin-caffeine mixtures and caffeine-only supplementation on energy expenditure and fat oxidation have been reported in short-term studies. Therefore, a meta-analysis was conducted to elucidate whether catechin-caffeine mixtures and caffeine-only supplementation indeed increase thermogenesis and fat oxidation. First, English-language studies measuring daily energy expenditure and fat oxidation by means of respiration chambers after catechin-caffeine mixtures and caffeine-only supplementation were identified through PubMed. Six articles encompassing a total of 18 different conditions fitted the inclusion criteria. Second, results were aggregated using random/mixed-effects models and expressed in terms of the mean difference in 24 h energy expenditure and fat oxidation between the treatment and placebo conditions. Finally, the influence of moderators such as BMI and dosage on the results was examined as well. The catechin-caffeine mixtures and caffeine-only supplementation increased energy expenditure significantly over 24 h (428.0 kJ (4.7%); P < 0.001 and 429.1 kJ (4.8%); P < 0.001, respectively). However, 24 h fat oxidation was only increased by catechin-caffeine mixtures (12.2 g (16.0%); P < 0.02 and 9.5 g (12.4%); P = 0.11, respectively). A dose-response effect on 24 h energy expenditure and fat oxidation occurred with a mean increase of 0.53 kJ mg(-1) (P < 0.01) and 0.02 g mg(-1) (P < 0.05) for catechin-caffeine mixtures and 0.44 kJ mg(-1) (P < 0.001) and 0.01 g mg(-1) (P < 0.05) for caffeine-only. In conclusion, catechin-caffeine mixtures or a caffeine-only supplementation stimulates daily energy expenditure dose-dependently by 0.4-0.5 kJ mg(-1) administered. Compared with placebo, daily fat-oxidation was only significantly increased after catechin-caffeine mixtures ingestion. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21366839 [PubMed - indexed for MEDLINE] 918. Obes Rev. 2011 May;12(5):e494-503. doi: 10.1111/j.1467-789X.2010.00811.x. Epub 2011 Mar 2. Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue. Divoux A(1), Clément K. Author information: (1)INSERM, U872, Nutriomique (Team 7), Paris, France. adeline.divoux@crc.jussieu.fr Fibrosis is usually characterized by the modification of both the amount and composition of a wide panel of extracellular matrix (ECM) proteins. In the liver, pancreas, kidney and lung the accumulation of fibrosis disrupts cellular processes and appears detrimental for organ function. This review highlights the available evidence supporting an important ECM remodelling in adipose tissue (AT) and, in particular, during the development of obesity. The modifications and occurrence of new adipose ECM components leads to an abnormal accumulation of fibrosis in this tissue. This phenomenon was well described in rodent models and evidence is beginning to emerge in humans; however, the origin and potential impact of these depots in AT biology are unclear. Two animal models with disruptions in ECM components (secreted proteins acidic in nature rich in cysteine null mice and ob/ob collagen VI null mice) suggest that fibrosis limits adipocyte hypertrophy and may cause the metabolic disorders associated with obesity. Over-expression of Hypoxia-inducible factor 1 leading to an increase in collagen expression suggests a role for hypoxia in fibrosis development. We conclude this review with possible hypotheses regarding the cellular and molecular contributors of fibrosis initiation. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21366833 [PubMed - indexed for MEDLINE] 919. Stem Cell Rev. 2012 Mar;8(1):55-66. doi: 10.1007/s12015-011-9242-x. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Billon N(1), Dani C. Author information: (1)Institut Biologie du Développement et Cancer, CNRS UMR 6543, Faculté de Médecine Pasteur, Université de Nice Sophia-Antipolis, 28 avenue de Valombrose, 06108, Nice Cedex 2, France. billon@unice.fr The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of adipocyte progenitors into mature adipocytes. However, the early steps of adipocyte development and the embryonic origin of this lineage have been largely disregarded until recently. In mammals, two functionally different types of adipose tissues coexist, which are both involved in energy balance but assume opposite functions. White adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) is specialized in energy expenditure. WAT and BAT can be found as several depots located in various sites of the body. Individual fat depots exhibit different timing of appearance during development, as well as distinct functional properties, suggesting possible differences in their developmental origin. This hypothesis has recently been revisited through large-scale genomics studies and in vivo lineage tracing approaches, which are reviewed in this report. These studies have provided novel fundamental insights into adipocyte biology, pointing out distinct developmental origins for WAT and BAT, as well as for individual WAT depots. They suggest that the adipose tissue is composed of distinct mini-organs, exhibiting developmental and functional differences, as well as variable contribution to obesity-related metabolic diseases. PMID: 21365256 [PubMed - indexed for MEDLINE] 920. Med Sci Sports Exerc. 2011 Oct;43(10):1828-35. doi: 10.1249/MSS.0b013e3182178bb4. Expression and function of myostatin in obesity, diabetes, and exercise adaptation. Allen DL(1), Hittel DS, McPherron AC. Author information: (1)Department of Integrative Physiology, University of Colorado, Boulder, CO 80309-0354, USA. allendl@colorado.edu Myostatin is a member of the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) superfamily of secreted factors that functions as a potent inhibitor of skeletal muscle growth. Moreover, considerable evidence has accumulated that myostatin also regulates metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. Although at least part of these effects on metabolism can be attributable to myostatin's influence over skeletal muscle growth and therefore on the total volume of metabolically active lean body mass, there is mounting evidence that myostatin affects the growth and metabolic state of other tissues, including the adipose and the liver. In addition, recent work has explored the role of myostatin in substrate mobilization, uptake, and/or utilization of muscle independent of its effects on body composition. Finally, the effects of both endurance and resistance exercise on myostatin expression, as well as the potential role of myostatin in the beneficial metabolic adaptations occurring in response to exercise, have also begun to be delineated in greater detail. The purpose of this review was to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation. PMCID: PMC3192366 PMID: 21364474 [PubMed - indexed for MEDLINE] 921. Clin Res Cardiol. 2011 May;100(5):383-94. doi: 10.1007/s00392-011-0295-2. Epub 2011 Mar 1. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update. Azaouagh A(1), Churzidse S, Konorza T, Erbel R. Author information: (1)Department of Medicine, Westgerman Cancer Center, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany. Abdelouahid.Azaouagh@uk-essen.de Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a predominantly genetically determined and heritable form of cardiomyopathy that is characterized pathologically by the replacement of myocytes by adipose and fibrous tissue and leads to right ventricular failure, arrhythmias, and sudden cardiac death. The estimated prevalence of ARVC/D in the general population ranges from 1 in 2,000 to 1 in 5,000, men are more frequently affected than women, with an approximate ratio of 3:1. ARVC/D can be inherited as an autosomal dominant disease with reduced penetrance and variable expression, autosomal recessive inheritance is also described. There have been 12 genes identified which are linked to ARVC/D, encoding several components of the cardiac desmosome. Dysfunctional desmosomes resulting in defective cell adhesion proteins, such as plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP-2), and desmoglein-2 (DSG-2) consequently cause loss of electrical coupling between cardiac myocytes, leading to myocyte cell death, fibrofatty replacement and arrhythmias. Diagnosis is based on the finding a combination of characteristic abnormalities in family history, electrocardiography, cardiac imaging as well as endomyocardial biopsy (original task force criteria). Therapeutic options remain limited because of the progressive nature of ARVC/D. Competitive athletics should be avoided. Patients with ARVC/D with a history of having been resuscitated from sudden cardiac death, patients with syncope, very young patients, and those who have marked right ventricular involvement are at the highest risk for arrhythmic death and also, the presence of left ventricular involvement is a risk factor. Several authors concluded that patients who meet the Task Force criteria for ARVC/D are at high risk for sudden cardiac death and should undergo ICD placement for primary and secondary prevention, regardless of electrophysiologic testing results. The role of electrophysiologic study and VT catheter ablation in ARVC/D remains poorly defined, and is frequently used as a palliative measure for patients with refractory VT. The progressive nature of ARVC/D suggests that catheter ablation would not be a long-term curative procedure. Sotalol proved to be highly effective in patients with ARVC/D and inducible as well as non-inducible ventricular tachycardia; if it is ineffective in inducible ventricular tachycardia response to other antiarrhythmic drugs is unlikely and therefore non-pharmacological therapy without further drug testing should be considered. Orthotopic heart transplantation is considered in patients with progressive heart failure and intractable recurrent ventricular arrhythmias. PMID: 21360243 [PubMed - indexed for MEDLINE] 922. Postepy Hig Med Dosw (Online). 2011 Jan 3;65:1-7. [The role of ghrelin in the organism]. [Article in Polish] Polińska B(1), Matowicka-Karna J, Kemona H. Author information: (1)Zakład Laboratoryjnej Diagnostyki Klinicznej Uniwersytet Medyczny w Białymstoku. Ghrelin was discovered in 1999 as an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). About 60-70% of ghrelin in the blood is released from oxyntic cells (X/A-like cells) of the stomach body and fundus. Ghrelin acts via interactions with specific receptors located, for example, in the hypothalamus, pituitary gland, pancreas, kidneys, myocardium, blood vessels, adipose tissue, ovaries and placenta. Ghrelin is directly related to the control of energy balance through appetite stimulation, food intake increase and meal initiation as well as reduction of adipose tissue utilization. Moreover, ghrelin increases hydrochloric acid secretion and gastrin release, controls gastric motility, and also protects the mucous membrane of the stomach and intestine. Besides its effects on the gastrointestinal tract, ghrelin influences the cardiovascular system, bone metabolism, insulin secretion, gonad function and the immune system. It exerts anti-inflammatory effects and inhibits apoptosis of cardiomyocytes and endothelium. The plasma ghrelin level depends on the nutrition level and lifestyle factors. This article describes the most important functions of ghrelin in the organism. PMID: 21357989 [PubMed - indexed for MEDLINE] 923. Expert Opin Drug Metab Toxicol. 2011 May;7(5):533-42. doi: 10.1517/17425255.2011.562193. Epub 2011 Feb 28. Studies on the metabolism and toxicology of emerging capsinoids. Watanabe T(1), Ohnuki K, Kobata K. Author information: (1)University of Shizuoka, School of Food and Nutritional Sciences, Shizuoka, Japan. watanbt@u-shizuoka-ken.ac.jp INTRODUCTION: Capsinoids are nonpungent compounds that are found in almost all pungent peppers and are abundant in the sweet pepper cultivar CH-19 Sweet. Since the discovery of capsinoids 13 years ago, various physiological effects of these compounds - especially reduction of visceral fat - have been observed both in rodents and humans. Recently, capsules containing capsinoids have become commercially available and comprehensive studies have been performed on the metabolism and toxicity of capsinoids. AREAS COVERED: This article reviews all the literature from 1998 to date providing details on the nature and physiological effects of capsinoids. In addition to this, the article also looks at their metabolism as well as their acute and chronic toxicity including their genotoxicity and teratology. EXPERT OPINION: Capsinoids are the most promising compounds among all known transient receptor potential vanilloid 1 agonists. The physiological activities of capsinoids are similar to those of capsaicin, the most pungent food component of red pepper, but appear to be much safer to use as a therapeutic compound. That said, there is still a need for further research into the capsinoid mechanism of action before it can be 'green-lighted' for therapeutic use. PMID: 21355789 [PubMed - indexed for MEDLINE] 924. Expert Opin Ther Targets. 2011 May;15(5):623-36. doi: 10.1517/14728222.2011.561317. Epub 2011 Feb 28. MicroRNAs in adipogenesis and as therapeutic targets for obesity. Alexander R(1), Lodish H, Sun L. Author information: (1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. INTRODUCTION: Obesity and obesity-related disease have reached pandemic proportions and are prevalent even in developing countries. Adipose tissue is increasingly being recognized as a key regulator of whole-body energy homeostasis and consequently as a prime therapeutic target for metabolic syndrome. This review discusses the roles of miRNAs, small endogenously expressed RNAs that regulate gene expression at a post-transcriptional level, in the development and function of adipose tissue and other relevant metabolic tissues impacted by obesity. Several high-throughput studies have identified hundreds of miRNAs that are differentially expressed during the development of metabolic tissues or as an indication of pathophysiology. Further investigation has functionalized the regulatory capacity of individual miRNAs and revealed putative targets for these miRNAs. Therefore, as with several other pathologies, miRNAs are emerging as feasible therapeutic targets for metabolic syndrome. AREAS COVERED: This review provides a comprehensive view of miRNAs involved in adipogenesis, from mesenchymal stem cell lineage determination through terminal adipocyte differentiation. We also discuss the differential expression of miRNAs among adipose depots and the dysregulation of miRNAs in other metabolic tissues during metabolic pathophysiology. Finally, we discuss the therapeutic potential of targeting miRNAs in obesity and give a perspective on the challenges and advantages of miRNA-based drugs. EXPERT OPINION: miRNAs are extensive regulators of adipocyte development and function and are viable therapeutic targets for obesity. Despite the broad-spectrum and redundancy of miRNA-target interactions, sophisticated bioinformatic approaches are making it possible to determine the most physiologically relevant miRNAs to target in disease. In vivo delivery of miRNAs for therapeutic purposes is rapidly developing and has been successful in other contexts. Additionally, miRNAs can be used as prognosis markers for disease onset and progression. Ultimately, miRNAs are prime therapeutic targets for obesity and its consequent pathologies in other metabolic tissues. PMCID: PMC3188954 PMID: 21355787 [PubMed - indexed for MEDLINE] 925. Theriogenology. 2011 May;75(8):1381-99. doi: 10.1016/j.theriogenology.2010.11.020. Epub 2011 Feb 26. Strategies for regeneration of the bone using porcine adult adipose-derived mesenchymal stem cells. Monaco E(1), Bionaz M, Hollister SJ, Wheeler MB. Author information: (1)Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. Comment in Theriogenology. 2012 Jan 1;77(1):229-30; author reply 230-1. Bone is a plastic tissue with a large healing capability. However, extensive bone loss due to disease or trauma requires tissue-engineering applications. Presently, bone grafting is the gold standard for bone repair, but presents serious limitations including donor site morbidity, rejection, and limited tissue regeneration. The use of stem cells appears to be a means to overcome such limitations. Bone marrow mesenchymal stem cells (BMSC) have been the choice, thus far, for stem cell therapy for bone regeneration. However, it has been shown that adipose-derived stem cells (ASC) have similar immunophenotype, morphology, multilineage potential, and transcriptome compared to BMSC. Moreover, ASC are much more abundant, more accessible and have lower donor morbidity, which combined may make ASC a better alternative to BMSC. ASC are also able to migrate to the site of injury and have immunosuppressive abilities similar to BMSC. Further, ASC have demonstrated extensive osteogenic capacity both in vitro and in vivo in several species, greatly enhancing the healing of critical size defects. The use of scaffolds in combination with ASC and growth factors provides a valuable tool for guided bone regeneration, especially for complex anatomic defects. Some critical elements include ASC-scaffold interactions and appropriate three-dimensional design of the porous osteoinductive structures. This review examines data that provides strong support for the clinical translation of ASC for bone regeneration. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21354606 [PubMed - indexed for MEDLINE] 926. Brain Behav Immun. 2011 Jul;25(5):811-6. doi: 10.1016/j.bbi.2011.02.010. Epub 2011 Feb 25. Exercise-induced myokines and their role in chronic diseases. Pedersen BK(1). Author information: (1)Department of Infectious Diseases,University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. bkp@rh.dk Physical inactivity has recently been identified as a major and independent risk factor for the development of dementia and cognitive decline. In addition to the effect of exercise with regard to protection against neurodegenerative diseases, it is well-established that physical inactivity increases the risk of type 2 diabetes, cardiovascular diseases (CVD), colon cancer and postmenopausal breast cancer. These diseases constitute a network of related diseases, also called "the diseasome of physical inactivity". In this review, physical inactivity is given the central role as an independent and strong risk factor for accumulation of visceral fat and consequently the activation of a network of systemic inflammatory pathways, which promote development of neurodegeneration as well as insulin resistance, atherosclerosis, and tumour growth. The recent finding that muscles produce and release myokines provides a conceptual basis for understanding some of the molecular mechanisms underlying organ cross talk, including muscle-fat cross talk. Accumulating data suggest that contracting skeletal muscles release myokines, which may work in a hormone-like fashion, exerting specific endocrine effects on visceral fat or mediating direct anti-inflammatory effects. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21354469 [PubMed - indexed for MEDLINE] 927. Vitam Horm. 2011;85:217-34. doi: 10.1016/B978-0-12-385961-7.00011-1. Activin in glucose metabolism. Hashimoto O(1), Funaba M. Author information: (1)Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine, Towada, Aomori, Japan. Activins, members of the TGF-β family, are multifunctional growth and differentiation factors. Activins regulate glucose/energy metabolism by promoting the differentiation of insulin-producing and -responsive cells, and regulating function of the differentiated cells. In the pancreas, activins stimulate the differentiation of β cells and secretion of insulin, which enables the cells to respond to glucose uptake efficiently. By contrast, in the liver, skeletal muscle and white adipose tissue, activins exert negative regulation on organogenesis, which leads to impaired insulin sensitivity. Activins induce the phenotypic switch of macrophages from the M1 to M2 phenotypes, which reduces inflammation. Since adipose inflammation is closely associated with insulin resistance and the onset of type 2 diabetes, activins may improve insulin resistance through their anti-inflammatory activity. Because activins modulate events involved in insulin sensitivity in a tissue-dependent manner, the activities of activins should be locally regulated to improve whole-body insulin responsiveness. Thus, activins or activin inhibitors may be effective as therapeutic agents for metabolic syndrome. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21353883 [PubMed - indexed for MEDLINE] 928. J Craniomaxillofac Surg. 2012 Jan;40(1):11-6. doi: 10.1016/j.jcms.2010.12.006. Epub 2011 Feb 25. Management of maxillofacial hard and soft tissue discrepancy in Möbius sequence: clinical report and review of the literature. Guijarro-Martínez R(1), Hernández-Alfaro F. Author information: (1)Institute of Maxillofacial Surgery and Implantology, Teknon Medical Center, Vilana, 12, D-185, 08022 Barcelona, Spain. raquelguijarro@comv.es BACKGROUND: Möbius sequence implies significant maxillofacial hard and soft tissue anomalies which nevertheless have not been addressed thoroughly in the scientific literature. OBJECTIVES: To report a case of complete Möbius sequence and discuss the management of maxillofacial hard and soft tissue anomalies. PATIENTS AND METHODS: A 15-year-old girl with complete Möbius underwent bimaxillary orthognathic surgery, horizontal sliding genioplasty and mentalis muscles reinsertion. Vestibuloplasty and bilateral canthopexy were performed to address lip deficiency and attenuate hypotonic depression of the lower eyelids, respectively. Cheekbone augmentation was achieved with an autologous fat transfer. The authors review the scientific literature and discuss surgical planning for the correction of maxillofacial discrepancy. RESULTS: The patient exhibits significant functional and aesthetic improvement, with excellent integration of the transferred fat and adequate bone healing. CONCLUSIONS: Orthognathic bimaxillary surgery combined to soft tissue management can improve aesthetics and orofacial function in Möbius patients, thereby contributing to facilitate social interaction and increase patients' self-esteem. Copyright © 2011 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. PMID: 21353788 [PubMed - indexed for MEDLINE] 929. World J Gastroenterol. 2011 Feb 7;17(5):572-7. doi: 10.3748/wjg.v17.i5.572. Extraluminal factors contributing to inflammatory bowel disease. Batra A(1), Stroh T, Siegmund B. Author information: (1)Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Department I, Gastroenterology/Rheumatology/Infectious Diseases, Hindenburgdamm 30, 12200 Berlin, Germany. Many identified and yet unknown factors contribute to the pathogenesis of inflammatory bowel disease (IBD). The genome-wide association studies clearly support the earlier developed concept that IBD occurs in genetically predisposed individuals who are exposed to distinct environmental factors, which together result in dysregulation of the mucosal immune system. Thus, the majority of previous studies have focused on the immune response within the intestinal wall. The present review aims to emphasize the contribution of three extraluminal structures to this inflammatory process, namely the mesenteric fat tissue, the lymphatics and the microvasculature. Broadening our view across the intestinal wall will not only facilitate our understanding of the disease, but will also us to identify future therapeutic targets. PMCID: PMC3040329 PMID: 21350706 [PubMed - indexed for MEDLINE] 930. Nutrients. 2011 Jan;3(1):63-103. doi: 10.3390/nu3010063. Vitamin A metabolism: an update. D'Ambrosio DN(1), Clugston RD, Blaner WS. Author information: (1)Department of Medicine and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. dd2244@columbia.edu Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years. PMCID: PMC3042718 PMID: 21350678 [PubMed - indexed for MEDLINE] 931. J Tissue Eng. 2010 Nov 7;2010:218142. doi: 10.4061/2010/218142. Fibroblast growth factors: biology, function, and application for tissue regeneration. Yun YR(1), Won JE, Jeon E, Lee S, Kang W, Jo H, Jang JH, Shin US, Kim HW. Author information: (1)Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, Republic of Korea. Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues. PMCID: PMC3042641 PMID: 21350642 [PubMed] 932. Trends Pharmacol Sci. 2011 May;32(5):300-7. doi: 10.1016/j.tips.2011.01.004. Epub 2011 Feb 23. Vascular targeting of adipose tissue as an anti-obesity approach. Daquinag AC(1), Zhang Y, Kolonin MG. Author information: (1)The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, UTHealth, 1825 Pressler St., Rm. 630-F, Houston, TX 77030, USA. Development of obesity is characterized by hypertrophy and hyperplasia of adipocytes in white adipose tissue (WAT). This process relies on concomitant angiogenesis. Results from experimental inhibition or depletion of cells comprising the vasculature in animal models have contributed to the understanding of the mechanisms governing expansion of WAT. Disruption of neovascularization might be potentially useful for obesity prevention. In addition, approaches in which the mature WAT vasculature is disrupted have been sought with the aim of combating obesity after its onset. Other cell types in WAT, including adipose stromal cells, which support angiogenesis, could represent alternative targets for combinatorial WAT treatment. This review discusses recent advances in WAT vascular targeting and implications for the development of new anti-obesity therapeutics. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21349592 [PubMed - indexed for MEDLINE] 933. Obes Rev. 2011 Jun;12(6):440-8. doi: 10.1111/j.1467-789X.2010.00832.x. Epub 2011 Feb 23. Acylation stimulating protein: a female lipogenic factor? Saleh J(1), Al-Wardy N, Farhan H, Al-Khanbashi M, Cianflone K. Author information: (1)Biochemistry Department, Faculty of Medicine, Sultan Qaboos University, P.O. Box 35, 123 Muscat, Oman. jumana@squ.edu.om Acylation stimulating protein (ASP) is a potent lipogenic factor produced from adipocytes. Plasma ASP levels were shown to increase in obesity, diabetes mellitus type II and dyslipidemia, and decrease after weight loss and fasting. Growing evidence suggests that ASP may significantly contribute to subcutaneous fat storage in females. In vitro, ASP stimulated triglyceride synthesis to a larger extent in subcutaneous compared with omental adipocytes. The ASP receptor binding affinity to plasma membranes prepared from adipose tissue showed higher binding affinity to plasma membranes from female adipose tissue compared with male adipose tissue, and was more pronounced to subcutaneous compared with omental plasma membranes. Human studies demonstrated that postprandial triglyceride clearance predicted by ASP levels was more efficient in women than in men. In mice, postprandial triglyceride clearance, with intraperitoneal ASP administration, was faster in females compared with males. The ASP deficient mice were resistant to weight gain and had reduced fat mass that was more pronounced in females. Recent findings in humans and mice point to a significant association between progesterone and ASP variations in females. In this review, we highlight findings, to date, linking ASP to physiological and hormonal alterations that may contribute to subcutaneous fat distribution typical to females. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21348923 [PubMed - indexed for MEDLINE] 934. Nutr Rev. 2011 Mar;69(3):123-31. doi: 10.1111/j.1753-4887.2011.00376.x. Epub 2011 Feb 14. Impact of conjugated linoleic acid on bone physiology: proposed mechanism involving inhibition of adipogenesis. Ing SW(1), Belury MA. Author information: (1)Division of Endocrinology, Diabetes, & Metabolism, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210-1296, USA. steven.ing@osumc.edu Conjugated linoleic acid (CLA) supplementation decreases adipose mass and increases bone mass in mice. Recent clinical studies demonstrate a beneficial effect of CLA on reducing weight and adipose mass in humans. This article reviews possible biological mechanisms of action of CLA on bone metabolism, focusing on modulation of nuclear receptor peroxisome proliferator-activated receptor gamma activity to steer mesenchymal stem cell differentiation toward an adipose and away from an osteoblast lineage. Clinical studies of the effects of CLA on bone mass and clinical implications of the effects of CLA on bone health in humans are summarized and discussed. © 2011 International Life Sciences Institute. PMCID: PMC3814018 PMID: 21348876 [PubMed - indexed for MEDLINE] 935. Endocr Metab Immune Disord Drug Targets. 2011 Mar;11(1):23-31. The evil axis of obesity, inflammation and type-2 diabetes. Das A(1), Mukhopadhyay S. Author information: (1)Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Bldg. 7, Gruhakalpa, 5-4-399/B, Nampally, Hyderabad - 500001, India. Obesity and type 2 diabetes (T2D) are global problems affecting all age groups and have been characterized as lifestyle disorders. Though no study has clearly proved a direct correlation between obesity and T2D, a number of factors are associated with obesity causing insulin resistance and T2D. The factors such as adipokines and various transcription factors help to maintain a proper metabolic state in the body. Deregulation in any of these signalling balances due to obesity may trigger an inflammatory cascade which could lead to the aforesaid problems of insulin resistance and T2D. In this review, we have discussed the factors that probably link inflammation to obesity-induced insulin resistance and subsequently T2D and the possible therapeutic opportunities to decrease health risk of T2D in future. PMID: 21348821 [PubMed - indexed for MEDLINE] 936. Nat Rev Mol Cell Biol. 2011 Mar;12(3):141-51. doi: 10.1038/nrm3072. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Altarejos JY(1), Montminy M. Author information: (1)Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, Florida 32827, USA. The cyclic AMP-responsive element-binding protein (CREB) is phosphorylated in response to a wide variety of signals, yet target gene transcription is only increased in a subset of cases. Recent studies indicate that CREB functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation. A dual requirement for CREB phosphorylation and CRTC dephosphorylation is likely to explain how these activator-co-activator cognates discriminate between different stimuli. Following their activation, CREB and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues. PMCID: PMC4324555 PMID: 21346730 [PubMed - indexed for MEDLINE] 937. Mol Cell Endocrinol. 2011 Jun 20;340(1):15-25. doi: 10.1016/j.mce.2011.02.011. Epub 2011 Feb 21. Ghrelin in obesity and endocrine diseases. Scerif M(1), Goldstone AP, Korbonits M. Author information: (1)Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Ghrelin shows orexigenic effect through its action on the hypothalamic appetite-regulating pathways, while in the periphery ghrelin increases adipose tissue accumulation and has a diabetogenic effect on the liver and pancreas. Adenosine monophosphate-activated protein kinase (AMPK) has been suggested as one of the mediators of ghrelin's effects. Plasma ghrelin levels are dependent on body mass index as well as food intake patterns. Ghrelin levels are in general reduced in obese individuals and in subjects with insulin resistance. In contrast to other forms of obesity, patients with Prader-Willi syndrome (PWS) display high levels of ghrelin, reduced visceral adiposity and relative hypoinsulinemia. Relationships between obesity and common genomic variants of GHRL and GHS-R genes have been studied. Ghrelin may have a role in the weight-reducing effect of bariatric surgery; however, this is a much debated issue. Altered ghrelin levels have also been observed in Cushing's syndrome and thyroid disease probably due to the secondary insulin resistance in these subjects. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21345363 [PubMed - indexed for MEDLINE] 938. Ann Med. 2011 May;43(3):198-211. doi: 10.3109/07853890.2010.547211. Epub 2011 Feb 24. Sirtuin 1 in lipid metabolism and obesity. Schug TT(1), Li X. Author information: (1)Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NC 27709, USA. Sirtuin 1 (SIRT1), the mammalian ortholog of yeast Sir2, is a highly conserved NAD(+)-dependent protein deacetylase that has emerged as a key metabolic sensor that directly links environmental nutrient signals to animal metabolic homeostasis. SIRT1 is known to be involved in gluconeogenesis in the liver, fat mobilization in white adipose tissue, and insulin secretion in the pancreas. Recent studies have shown SIRT1 to regulate fatty acid oxidation in the liver, sense nutrient availability in the hypothalamus, influence obesity-induced inflammation in macrophages, and modulate the activity of the circadian clock in metabolic tissues. The activity of SIRT1 also appears to be under the control of AMPK and adiponectin. This review focuses on the involvement of SIRT1 in regulating metabolic diseases associated with obesity. It includes brief overviews of sirtuin signaling, with emphasis on SIRT1's role in the liver, macrophage, brain, and adipose tissue as it relates to obesity. PMCID: PMC3173813 PMID: 21345154 [PubMed - indexed for MEDLINE] 939. Tissue Eng Part B Rev. 2011 Jun;17(3):195-211. doi: 10.1089/ten.TEB.2010.0738. Epub 2011 Apr 8. Adipose-derived stem cells in functional bone tissue engineering: lessons from bone mechanobiology. Bodle JC(1), Hanson AD, Loboa EG. Author information: (1)Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695-7115, USA. This review aims to highlight the current and significant work in the use of adipose-derived stem cells (ASC) in functional bone tissue engineering framed through the bone mechanobiology perspective. Over a century of work on the principles of bone mechanosensitivity is now being applied to our understanding of bone development. We are just beginning to harness that potential using stem cells in bone tissue engineering. ASC are the primary focus of this review due to their abundance and relative ease of accessibility for autologous procedures. This article outlines the current knowledge base in bone mechanobiology to investigate how the knowledge from this area has been applied to the various stem cell-based approaches to engineering bone tissue constructs. Specific emphasis is placed on the use of human ASC for this application. PMCID: PMC3098956 PMID: 21338267 [PubMed - indexed for MEDLINE] 940. Rev Endocr Metab Disord. 2011 Sep;12(3):153-62. doi: 10.1007/s11154-011-9167-3. Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle. Silvestri C(1), Ligresti A, Di Marzo V. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry-CNR, Italy. The endocannabinoid system (ECS) is composed of lipid signalling ligands, their G-protein coupled receptors and the enzymes involved in ligand generation and metabolism. Increasingly, the ECS is emerging as a critical agent of energy metabolism regulation through its ability to modulate caloric intake centrally as well as nutrient transport, cellular metabolism and energy storage peripherally. Visceral obesity has been associated with an upregulation of ECS activity in several systems and inhibition of the ECS, either pharmacologically or genetically, results in decreased energy intake and increased metabolic output. This review aims to summarize the recent advances that have been made regarding our understanding of the role the ECS plays in crucial peripheral systems pertaining to energy homeostasis: adipose tissues, the liver and skeletal muscle. PMID: 21336842 [PubMed - indexed for MEDLINE] 941. J Reprod Immunol. 2011 Mar;88(2):142-8. doi: 10.1016/j.jri.2011.01.008. Epub 2011 Feb 17. Inflammatory pathways linking obesity and ovarian dysfunction. Robker RL(1), Wu LL, Yang X. Author information: (1)School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia 5005, Australia. rebecca.robker@adelaide.edu.au This review summarizes some of the recent advances in obesity research and describes how we and others have built upon these findings to better understand the impact of obesity on granulosa cells, cumulus cells and oocytes within the ovaries of obese females. Obesity is associated with lipid accumulation in non-adipose tissue cells and the induction of oxidative stress and endoplasmic reticulum stress responses that are tightly linked with systemic inflammation. Analysis of ovarian cells and fluid of obese women indicates that these same mechanisms are activated in the ovary in response to obesity. Studies in mice support this and allow further dissection of the pathways by which diet-induced obesity contributes to changes in mitochondria and the endoplasmic reticulum. These studies are in their infancy but cumulatively provide basic information about the cellular mechanisms that may lead to the impaired ovulation and reduced oocyte developmental potential that is observed in obese females. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21333359 [PubMed - indexed for MEDLINE] 942. J Clin Pathol. 2011 Jul;64(7):553-60. doi: 10.1136/jcp.2010.085951. Epub 2011 Feb 17. The pathogenesis of endometrial carcinomas at menopause: facts and figures. Sivridis E(1), Giatromanolaki A. Author information: (1)Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Alexandroupolis, Greece. esivrid@med.duth.gr Almost a third of the life of a woman is now postmenopausal, and during this period over 80% of endometrial carcinomas develop. This is by far the most common gynaecological malignancy in the industrialised world and, probably, the less completely understood with regard to its pathogenesis after the menopause. For while it is generally thought that these neoplasms are non-oestrogen-induced, we are, at the same time, informed that oestrogenic stimulation is continuous during menopause through increases to oestrone formation in the adipose tissue from androgens of adrenal and ovarian origin. Furthermore, the postmenopausal endometrium has been typified as atrophic, which is indeed true, but is also implied as being inactive, which in fact it is not; in most cases, the postmenopausal endometrium appears to be weakly proliferative with potential to give rise to an endometrial carcinoma. It is also assumed that postmenopausal endometrial tumours are predominantly of serous papillary and clear cell type, and, in general, they are not well-differentiated endometrioid carcinomas; in reality, no more than 15% are serous papillary and clear cell carcinomas, and no less than 55% are well-differentiated endometrioid neoplasms. The overall prognosis is presumed to be poor, yet postmenopausal patients harbouring well-differentiated endometrioid carcinomas have the same excellent prognosis as those premenopausal women having endometrioid tumours of similar grade and stage. This brief account of endometrial carcinogenesis at menopause re-evaluates these issues and, in the light of new and old evidence, proposes the separation of G1 endometrioid adenocarcinomas (low-grade tumours) from all others (high-grade tumours). PMID: 21330315 [PubMed - indexed for MEDLINE] 943. J Cardiovasc Transl Res. 2011 Apr;4(2):200-10. doi: 10.1007/s12265-011-9257-3. Epub 2011 Feb 15. Adult human adipose tissue contains several types of multipotent cells. Tallone T(1), Realini C, Böhmler A, Kornfeld C, Vassalli G, Moccetti T, Bardelli S, Soldati G. Author information: (1)Swiss Stem Cell Foundation, Via Tesserete 48, Lugano, Switzerland. tiziano.tallone@cardiocentro.org Multipotent mesenchymal stromal cells (MSCs) are a type of adult stem cells that can be easily isolated from various tissues and expanded in vitro. Many reports on their pluripotency and possible clinical applications have raised hopes and interest in MSCs. In an attempt to unify the terminology and the criteria to label a cell as MSC, in 2006 the International Society for Cellular Therapy (ISCT) proposed a standard set of rules to define the identity of these cells. However, MSCs are still extracted from different tissues, by diverse isolation protocols, are cultured and expanded in different media and conditions. All these variables may have profound effects on the selection of cell types and the composition of heterogeneous subpopulations, on the selective expansion of specific cell populations with totally different potentials and ergo, on the long-term fate of the cells upon in vitro culture. Therefore, specific molecular and cellular markers that identify MSCs subsets as well as standardization of expansion protocols for these cells are urgently needed. Here, we briefly discuss new useful markers and recent data supporting the rapidly emerging concept that many different types of progenitor cells are found in close association with blood vessels. This knowledge may promote the necessary technical improvements required to reduce variability and promote higher efficacy and safety when isolating and expanding these cells for therapeutic use. In the light of the discussed data, particularly the identification of new markers, and advances in the understanding of fundamental MSC biology, we also suggest a revision of the 2006 ISCT criteria. PMID: 21327755 [PubMed - indexed for MEDLINE] 944. Curr Diab Rep. 2011 Jun;11(3):203-10. doi: 10.1007/s11892-011-0183-1. Adipose tissue vascularization: its role in chronic inflammation. Ye J(1). Author information: (1)Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA. yej@pbrc.edu In obesity, the vascular complication is a result of insulin resistance, such as decreased capillary recruitment in skeletal muscle from endothelial insulin resistance. Recent progress in the study of obesity-associated inflammation suggests that vasculature dysfunction occurs in adipose tissue before insulin resistance. In obesity, capillary density and function fail to meet the demand of adipose tissue growth. The failure leads to microcirculation dysfunction from an impaired blood perfusion, which results in a local hypoxia response in adipose tissue. The hypoxia response in adipocytes and macrophages is a new cellular basis for the chronic inflammation. The obesity-associated inflammation has both positive and negative effects in the body. At the early stage, it amplifies the hypoxia signal to stimulate vasculature remodeling locally, and promotes systemic energy expenditure against obesity. At the late stage, it causes adipose tissue dysfunction for insulin resistance. These points suggest that in obesity, adipose tissue vascularization controls chronic inflammation and influences systemic insulin sensitivity. PMCID: PMC3119578 PMID: 21327583 [PubMed - indexed for MEDLINE] 945. Annu Rev Physiol. 2011;73:183-211. doi: 10.1146/annurev-physiol-012110-142320. Zebrafish in endocrine systems: recent advances and implications for human disease. Löhr H(1), Hammerschmidt M. Author information: (1)Institute for Developmental Biology, University of Cologne, Germany. Since its introduction as a genetic vertebrate model system approximately 30 years ago, the focus of zebrafish research has increasingly shifted to questions that are also relevant for human development and disease. Here, we review the potential of the zebrafish as a model for human endocrine systems. A recent review compared the functions of the different endocrine systems and glands in zebrafish with those in other vertebrates, including humans, coming to the conclusion that major aspects are conserved. Here, we present an updated overview of this rapidly growing field of zebrafish research, focusing on the hypothalamo-pituitary axis, which links the central nervous system with the endocrine systems, and on major processes that are under (neuro)endocrine control and are the subject of intensive current research in other endocrine model organisms, such as feeding circuits and energy homeostasis, sleep, stress, reproduction, osmoregulation, and calcium homeostasis. Finally, we summarize the strengths and weaknesses of zebrafish as a model for studying endocrine systems. PMID: 21314433 [PubMed - indexed for MEDLINE] 946. Stem Cells. 2011 Apr;29(4):576-82. doi: 10.1002/stem.612. Concise review: adipose-derived stromal cells for skeletal regenerative medicine. Levi B(1), Longaker MT. Author information: (1)Hagey Pediatric Regenerative Medicine Research Laboratory, Department of Surgery, Plastic and Reconstructive Surgery Division, Stanford University School of Medicine, Stanford, California 94305-5148, USA. As the average age of the population grows, the incidence of osteoporosis and skeletal diseases continues to rise. Current treatment options for skeletal repair include immobilization, rigid fixation, alloplastic materials, and bone grafts, all which have significant limitations, especially in the elderly. Adipose-derived stromal cells (ASCs) represent a readily available abundant supply of mesenchymal stem cells, which demonstrate the ability to undergo osteogenesis in vitro and in vivo, making ASCs a promising source of skeletal progenitor cells. Current protocols allow for the harvest of over one million cells from only 15 ml of lipoaspirate. Despite the clinical use of ASCs to treat systemic inflammatory diseases, no large human clinical trials exist using ASCs for skeletal tissue engineering. The aim of this review is to define ASCs, to describe the isolation procedure of ASCs, to review the basic biology of their osteogenic differentiation, discuss cell types and scaffolds available for bone tissue engineering, and finally, to explore imaging of ASCs and their potential future role in human skeletal tissue engineering efforts. Copyright © 2011 AlphaMed Press. PMCID: PMC3323288 PMID: 21305671 [PubMed - indexed for MEDLINE] 947. Ann Nutr Metab. 2011;58(1):42-8. doi: 10.1159/000323748. Epub 2011 Feb 8. Caloric restriction and antiaging effects. Xiang L(1), He G. Author information: (1)School of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China. Caloric restriction (CR) is widely used to study aging processes. It is a simple and highly reproducible method for delaying the aging process, preventing the onset of aging-related diseases and extending average or maximum lifespan. However, the mechanism underlying these effects of CR is still not clear. CR can inhibit growth, reduce body size and maintain a low body temperature. At the same time, there is a measurable decrease in the volume of adipose tissue, hyperglycemia and hyperinsulinemia, accompanied by modifications of lipid and energy metabolism and increased resistance to endogenous and extraneous stress. The metabolic changes induced by dietary restriction, the inhibition of fat deposition in nonadipose tissue and the effects on signal transduction are considered the most likely candidates for mechanisms underlying the effects of CR. Copyright © 2011 S. Karger AG, Basel. PMID: 21304246 [PubMed - indexed for MEDLINE] 948. Ann Nutr Metab. 2011;58(1):25-36. doi: 10.1159/000323395. Epub 2011 Feb 8. Insulin resistance: pathophysiology and rationale for treatment. Muntoni S(1), Muntoni S. Author information: (1)Centre for Metabolic Diseases and Atherosclerosis, The ME.DI.CO. Association, Unit of Oncology and Molecular Pathology, University Medical School, Cagliari, Italy. sergiomuntoni@hotmail.com After binding to its receptor and activating the β-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting 'compensatory hyperinsulinemia' is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human β cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation. Copyright © 2011 S. Karger AG, Basel. PMID: 21304221 [PubMed - indexed for MEDLINE] 949. Meat Sci. 2011 Jun;88(2):213-20. doi: 10.1016/j.meatsci.2011.01.003. Epub 2011 Jan 16. A review of the factors influencing the development of intermuscular adipose tissue in the growing pig. Kouba M(1), Sellier P. Author information: (1)INRA, UMR 1079 Systèmes d'Elevage, Nutrition Animale et Humaine, 35590 Saint-Gilles, France. Maryline.Kouba@agrocampus-ouest.fr Compared with subcutaneous or abdominal fat depots of pig carcasses, intermuscular fat displays a number of original properties. It cannot be easily removed from fresh or processed meat delivered to consumers and has therefore an influence on consumer acceptability of pork. Particular compositional characteristics of intermuscular fat include low lipid content and small size of adipocytes. How age (or body weight), gender, castration, environmental temperature, feeding restriction, diet composition, as well as genetic factors affect intermuscular fat development and composition are surveyed in this review paper. Up to now, few studies have specifically dealt with the intermuscular compartment of body fat while very abundant information is available on the subcutaneous one. As a general rule, any factor, either genetic or non-genetic, which causes a decrease of whole carcass fat deposition generates a higher relative importance of the intermuscular fraction of total fat as well as an increased degree of unsaturation of constituent fatty acids. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21303725 [PubMed - indexed for MEDLINE] 950. Ann Plast Surg. 2011 May;66(5):523-7. doi: 10.1097/SAP.0b013e3182012580. Abdominal contouring in super obese patients: a single-surgeon review of 22 cases. Mericli AF(1), Drake DB. Author information: (1)Department of Plastic Surgery, University of Virginia, Charlottesville, VA, USA. BACKGROUND: It is generally believed that increasing obesity is a predictor of postoperative complications after abdominal contouring procedures such as abdominoplasty and panniculectomy. The purpose of this study is to review the complication rate for abdominal contouring in the level 3 obesity category (body mass index [BMI], >40 kg/m2) and to examine the safety of this procedure when performed in this select patient population. METHODS: Between 2003 and 2008, an institutional review board-approved, single-surgeon, single-institution retrospective review was conducted for all patients presenting for abdominal contouring. In all, 100 patients with precontouring BMI <40 kg/m2 were excluded, resulting in 22 patients who met the criteria for Level 3 obesity category, which are also referred as "super obese." To date, this is the largest series that has reported pertaining to this category and procedures. RESULTS: In this series, 77% (17/22) had prior bariatric surgery. The mean hospitalization was 2.8 days and mean length of follow-up was 202 days. The major complication rate was 4.5% (1/22). CONCLUSIONS: Abdominal contouring can be performed safely, effectively, and with minimal morbidity in the super obese. Only one patient required readmission after developing an infected seroma and all patients progressed to a well-healed wound. BMI >40 kg/m2 should not preclude patients from undergoing this functional and beneficial surgical procedure. PMID: 21301300 [PubMed - indexed for MEDLINE] 951. Dan Med Bull. 2011 Feb;58(2):B4248. New physiological effects of the incretin hormones GLP-1 and GIP. Asmar M(1). Author information: (1)Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Denmark. masmar@mfi.ku.dk With approximately 400 million people worldwide today being obese, we are facing a major public health problem due to the increasing prevalence of the related comorbidities such as type 2 diabetes, hypertension and coronary heart disease. To date, pharmacological treatment of obesity has been largely unsuccessful, only achieving modest and short-lasting reductions in body weight and with adverse effects. Scientific interest in recent years has concentrated on both the secretion and function of the incretin hormones, GLP-1 and GIP, and their suitability as new target drugs. The potential of GLP-1 to reduce gastric emptying, appetite and food intake makes it an attractive tool in the fight against obesity and several companies are developing weight lowering drugs based on GLP-1. Currently, it is not known whether the inhibiting effects of GLP-1 on gastric emptying, appetite and food intake are directly mediated by GLP-1, or if the effects are secondary to the robust insulin responses, and thereby amylin responses, elicited by GLP-1. The first study aimed to further elucidate the mechanisms of these effects in order to strengthen the development of anti-diabetic drugs with potential weight lowering capabilities. We found that GLP-1 mediates its effect on gastrointestinal motility, appetite, food intake and glucagon secretion directly and thereby in an amylin-independent fashion. In vitro and animal studies indicate that GIP exerts direct effects on adipose tissue and lipid metabolism, promoting fat deposition. Due to its therapeutic potential in obesity treatment, a rapidly increasing number of functional studies are investigating effects of acute and chronic loss of GIP signaling in glucose and lipid homeostasis. However, the physiological significance of GIP as a regulator of lipid metabolism in humans remains unclear. In the second study, we investigated the effects of GIP on the removal rate of plasma TAG and FFA concentrations, which were increased after either a mixed meal or infusion of Intralipid and insulin. Under these experimental conditions, we were not able to demonstrate any effects of GIP on the removal rate of either chylomicron-TAG or Intralipid-derived TAG concentrations. However, we found evidence for enhanced FFA re-esterification under conditions with combined high GIP and insulin concentrations. Based on findings from this study, the third study was designed to evaluate the direct effects of GIP on regional adipose tissue and splanchnic metabolism. Regional net substrate fluxes across the subcutaneous, abdominal adipose tissue and the splanchnic tissues were examined by direct measurements of arterio-venous concentration differences of various metabolites in combination with regional blood flow measurements (Fick's principle). GIP in combination with hyperinsulinemia and hyperglycemia increased blood flow, glucose uptake, and FFA re-esterification, resulting in increased TAG deposition in abdominal, subcutaneous adipose tissue. Finally, it was not possible to demonstrate any effect of GIP per se on net lipid metabolism in the splanchnic area either during fasting conditions or in combination with hyperinsulinemia and hyperglycemia. PMID: 21299928 [PubMed - indexed for MEDLINE] 952. Eur J Pharmacol. 2011 Apr 10;656(1-3):1-4. doi: 10.1016/j.ejphar.2011.01.035. Epub 2011 Feb 2. Let's shift lipid burden--from large to small adipocytes. Müller G(1). Author information: (1)Ludwig-Maximilians-University Munich, Biocenter, Department Biology I, Genetics, Martinsried, Germany. Guenter.Mueller@sanofi-aventis.com Adipose tissue mass in mammals expands by increasing both volume and total number of the adipocytes. The simultaneous existence of large and small adipocytes and their unsynchronized growth, even within the same adipose tissue depot, argues against simple filling-up of nascent small adipocytes with lipids and lipid droplets. Consequently, it is tempting to speculate about signals provoking shift of lipid loading from mature large to small adipocytes. Very recently, microvesicles have been shown (i) to harbor the glycosylphosphatidylinositol-anchored (c)AMP-degrading phosphodiesterase Gce1 and the 5'-nuceotidase CD73, (ii) to be released (preferably) from large adipocytes, (iii) to interact (preferably) with small adipocytes and (iv) to transfer Gce1 and CD73 to plasma membranes and lipid droplets of the small adipocytes where they degrade (c)AMP. This sequence of events leads to upregulation of lipid storage in small adipocytes in response to the microvesicle-encoded "take-over" signal from large adipocytes. A model is proposed for the maturation of small adipocytes driven by large cells along a gradient of microvesicle-derived inter-adipocyte signals. Pharmacological modulation of the communication between adipocytes for their maturation may be useful for the therapy of metabolic diseases. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 21295025 [PubMed - indexed for MEDLINE] 953. Stress. 2011 May;14(3):233-46. doi: 10.3109/10253890.2010.534831. Epub 2011 Feb 6. The glucocorticoid contribution to obesity. Spencer SJ(1), Tilbrook A. Author information: (1)Department of Physiology, Faculty of Medicine, Monash UniversityMelbourne, Vic., Australia. sarah.spencer@monash.edu Obesity is fast becoming the scourge of our time. It is one of the biggest causes of death and disease in the industrialized world, and affects as many as 32% of adults and 17% of children in the USA, considered one of the world's fattest nations. It can also cost countries billions of dollars per annum in direct and indirect care, latest estimates putting the USA bill for obesity-related costs at $147 billion in 2008. It is becoming clear that the pathophysiology of obesity is vastly more complicated than the simple equation of energy in minus energy out. A combination of genetics, sex, perinatal environment and life-style factors can influence diet and energy metabolism. In this regard, psychological stress can have significant long-term impact upon the propensity to gain and maintain weight. In this review, we will discuss the ability of psychological stress and ultimately glucocorticoids (GCs) to alter appetite regulation and metabolism. We will specifically focus on (i) GC regulation of appetite and adiposity, (ii) the apparent sexual dimorphism in stress effects on obesity and (iii) the ability of early life stress to programme obesity in the long term. PMID: 21294656 [PubMed - indexed for MEDLINE] 954. Diabetes Metab Res Rev. 2011 Feb;27(2):104-12. doi: 10.1002/dmrr.1154. Peptide hormones regulating appetite--focus on neuroimaging studies in humans. Schloegl H(1), Percik R, Horstmann A, Villringer A, Stumvoll M. Author information: (1)Department of Medicine, University of Leipzig, Leipzig, Germany. In recent years, knowledge about hormonal feedback from the gastrointestinal tract and adipose tissue has increased tremendously. Peptide hormones modulating hunger have been intensively studied, mostly in animals but increasingly also in humans. The first therapeutic agents, such as GLP-1 analogues, are in successful clinical use for T2D and may beneficially affect hunger and reduce weight. Data from in vitro studies and animals provide detailed insight into regulatory mechanisms leading to peptide secretion and receptor bindings, as well as to the distribution of receptors involved in different parts of the body. With neuroimaging techniques human brain structures have been identified that play a role in hunger, satiety and eating behaviour. These include the primary gustatory (insular) and olfactory (pyriform) cortex and regions with a highly permeable blood-brain barrier (hypothalamus, brain stem), which facilitates humoral input via gut peptides and leptin. In addition, cerebral networks involved in higher cognitive functions, especially those relevant to reward, pleasure and also addiction (ventral and dorsal striatum, amygdala, orbitofrontal cortex (OFC), prefrontal cortex (PFC)) were shown to be involved. First indications of direct influences of peptide hormones on these networks have become available from neuroimaging studies administrating synthetic PYY, ghrelin and leptin. Insulin also appears to play an important role as a central satiety hormone, and evidence indicating the possibility of central insulin resistance in obesity is available. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 21294236 [PubMed - indexed for MEDLINE] 955. J Nutr Biochem. 2011 Jul;22(7):605-11. doi: 10.1016/j.jnutbio.2010.09.008. Epub 2011 Feb 2. Bidirectional signaling of mammary epithelium and stroma: implications for breast cancer--preventive actions of dietary factors. Su Y(1), Shankar K, Rahal O, Simmen RC. Author information: (1)Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. The mammary gland is composed of two major cellular compartments: a highly dynamic epithelium that undergoes cycles of proliferation, differentiation and apoptosis in response to local and endocrine signals and the underlying stroma comprised of fibroblasts, endothelial cells and adipocytes, which collectively form the mammary fat pad. Breast cancer originates from subversions of normal growth regulatory pathways in mammary epithelial cells due to genetic mutations and epigenetic modifications in tumor suppressors, oncogenes and DNA repair genes. Diet is considered a highly modifiable determinant of breast cancer risk; thus, considerable efforts are focused on understanding how certain dietary factors may promote resistance of mammary epithelial cells to growth dysregulation. The recent indications that stromal cells contribute to the maintenance of the mammary epithelial 'niche' and the increasing appreciation for adipose tissue as an endocrine organ with a complex secretome have led to the novel paradigm that the mammary stromal compartment is itself a relevant target of bioactive dietary factors. In this review, we address the potential influence of dietary factors on mammary epithelial-stromal bidirectional signaling to provide mechanistic insights into how dietary factors may promote early mammary epithelial differentiation to decrease adult breast cancer risk. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21292471 [PubMed - indexed for MEDLINE] 956. Am J Clin Nutr. 2011 Apr;93(4):875S-83. doi: 10.3945/ajcn.110.001909. Epub 2011 Feb 2. Energy, evolution, and human diseases: an overview. Roth J(1), Szulc AL, Danoff A. Author information: (1)Feinstein Institute for Medical Research, Elmezzi Graduate School of Molecular Medicine, North Shore-Long Island Jewish Health System, Manhasset, NY, USA. jesserothmd@hotmail.com In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications. PMID: 21289219 [PubMed - indexed for MEDLINE] 957. Med Res Rev. 2012 Nov;32(6):1263-91. doi: 10.1002/med.20240. Epub 2011 Feb 1. Oleoyl-estrone. Remesar X(1), Fernández-López JA, Alemany M. Author information: (1)Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, Barcelona, Spain. Oleoyl-estrone (OE) is a powerful slimming agent that is also present in plasma and adipose tissue, where it is synthesized. It acts through the formation of a derivative W. OE effects (and W levels) are proportional to the dose. OE reduces food intake but maintains energy expenditure (thermogenesis). The energy gap is fulfilled with adipose tissue fat, sparing body protein and maintaining glycemia (and glycogen) with lower insulin and leptin levels. OE (in fact W) acts through specific receptors, different from those of estrogen. OE increases cholesterol catabolism, reducing hypercholesterolemia in obese rats. The main metabolic effect on adipose tissue is lowering of lipid synthesis, maintaining unchanged the intracellular lipolytic processes; the imbalance favors the progressive loss of fat, which is largely used by the muscle. OE administration induces additive effects with other antiobesity agents, such as β(3)-adrenergic agonists, forcing a massive loss of lipid. Corticosteroids markedly limit OE action by altering the liver control of lipogenesis. OE also inhibits the action of 17β-hydroxysteroid dehydrogenase, decreasing the synthesis of β-estradiol and testosterone. Discontinuous treatment allows for maximal efficacy both in rats and humans. OE has the advantage that the loss of fat is maintained and does not require additional dietary limitations. © 2011 Wiley Periodicals, Inc. PMID: 21287573 [PubMed - indexed for MEDLINE] 958. Head Neck Pathol. 2011 Jun;5(2):184-7. doi: 10.1007/s12105-011-0241-7. Epub 2011 Feb 1. Angiomyxolipoma (vascular myxolipoma) of the oral cavity. Report of a case and review of the literature. Martínez-Mata G(1), Rocío MF, Juan LE, Paes AO, Adalberto MT. Author information: (1)Faculty of Dentistry, Universidad Autónoma de Chihuahua, Chihuahua, México. gmmata2001@yahoo.com.mx Angiomyxolipoma is a rare tumor characterized by a proliferation of adipose tissue associated with a myxoid stroma and multiple vascular channels. To date, ten cases of angiomyxolipoma located in subcutaneous tissue, spermatic cord and subungual area have been reported in the literature. We describe the clinical and histopathologic findings of the first case of intraoral angiomyxolipoma in a 12 year-old male, as well as the utility of immunohistochemistry as a useful tool in differential diagnosis of this particular lesion with respect to other benign and malignant lesions derived from adipose tissue. PMCID: PMC3098340 PMID: 21286875 [PubMed - indexed for MEDLINE] 959. Sleep. 2011 Feb 1;34(2):131-2. Short sleep and circulating adipokine concentrations: does the fat hit the fire? Penev PD(1). Author information: (1)Department of Medicine, University of Chicago, Chicago, IL. Comment on Sleep. 2011 Feb;34(2):147-52. PMCID: PMC3022929 PMID: 21286248 [PubMed - indexed for MEDLINE] 960. Med Clin North Am. 2011 Mar;95(2):309-25, vii. doi: 10.1016/j.mcna.2010.11.004. Mechanisms of vascular complications in prediabetes. Milman S(1), Crandall JP. Author information: (1)Division of Endocrinology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street, Bronx, NY 10467, USA. Although the state of prediabetes is defined by its role as a diabetes risk factor, it also carries a significant risk of cardiovascular disease, independent of progression to diabetes. Typical diabetic microvascular complications also occur, albeit at low rates, in prediabetes. There is evidence that both glucose-related and glucose-independent mechanisms contribute to these vascular complications. Effective preventive strategies will likely require control of glycemia, as well as other metabolic risk factors. This article reviews some of the proposed mechanisms for the vascular complications of the prediabetic state. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21281835 [PubMed - indexed for MEDLINE] 961. Int J Biochem Cell Biol. 2011 May;43(5):693-6. doi: 10.1016/j.biocel.2011.01.017. Epub 2011 Jan 28. C-terminal binding protein: A metabolic sensor implicated in regulating adipogenesis. Jack BH(1), Pearson RC, Crossley M. Author information: (1)School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. The development of mature adipocytes from preadipocyte precursor cells requires coordinated changes in gene expression. Management of these expression changes relies on the actions of both DNA-binding transcription factors and their coregulators. Recent studies have identified the corepressor C-terminal binding protein (CtBP) as a key transcriptional coregulator in adipose tissue. CtBP proteins work with several different partner proteins to regulate the development of both white and brown adipocytes. CtBP is of particular interest as it binds to NAD(+)/NADH and may respond to the metabolic state of the cell, thereby linking changes in nutrient levels to transcriptional outcomes. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21281737 [PubMed - indexed for MEDLINE] 962. Prev Med. 2011 Jun;52 Suppl 1:S36-42. doi: 10.1016/j.ypmed.2011.01.021. Epub 2011 Jan 31. Classroom-based physical activity, cognition, and academic achievement. Donnelly JE(1), Lambourne K. Author information: (1)Energy Balance Laboratory & Center for Physical Activity & Weight Management, University of Kansas, Lawrence, KS 66045, USA. BACKGROUND: There is increasing evidence for the association between physical activity, cardiovascular fitness, fatness, and cognitive function during childhood and adolescence. Evidence also suggests that these variables are linked to academic achievement. Classroom-based physical activity provides a viable approach to improve fitness, body mass index (BMI), cognitive function, and ultimately academic achievement. METHODS: Studies examining the relation between physical activity, fitness, fatness, cognitive function, and academic achievement are described. The results of a large-scale, longitudinal, cluster randomized trial to examine the impact of classroom based physical activity on body mass index and academic achievement will be presented. RESULTS: Overall, the data support the link between physical activity, cognitive function, and academic achievement. The role of physical activity in the classroom was also supported by the Physical Activity Across the Curriculum (PAAC) project. Physically active academic lessons of moderate intensity improved overall performance on a standardized test of academic achievement by 6% compared to a decrease of 1% for controls (p<0.02). Body mass index increased less from baseline to 3 years in students with greater than 75 minutes of PAAC lessons per week (1.8 BMI) compared to students with less than 75 minutes of PAAC per week (2.4 BMI), p<0.00. CONCLUSIONS: Future research examining the effects of physically active academic instruction is warranted. The impact of physically active academic lessons of greater intensity may provide larger benefits for body mass index and academic achievement. Copyright © 2011. Published by Elsevier Inc. PMID: 21281666 [PubMed - indexed for MEDLINE] 963. Rev Med Chil. 2010 Oct;138(10):1294-301. doi: /S0034-98872010001100015. Epub 2011 Jan 10. [Adipose tissue as an endocrine modulator: hormonal changes associated with obesity]. [Article in Spanish] Baudrand B R(1), Arteaga U E, Moreno G M. Author information: (1)Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Chile. rbaudrand@med.puc.cl Adipose tissue not only stores fat, but secretes factors and hormones, which modify the regulation, metabolism and secretion of several other hormones. The objective of this review is to describe the hormonal disorders associated with increased adipose tissue, which acts as a modulator or disruptor of the endocrine physiology, with special reference to cortisol, androgens, growth hormone and thyroid axis, and discuss the implications for the management and treatment of these patients. PMID: 21279279 [PubMed - indexed for MEDLINE] 964. J Anim Sci. 2011 Jul;89(7):1965-80. doi: 10.2527/jas.2010-3602. Epub 2011 Jan 28. Triennial Growth Symposium: effects of polymeric carbohydrates on growth and development in pigs. Bach Knudsen KE(1). Author information: (1)Aarhus University, Faculty of Agricultural Sciences, Department of Animal Health and Bioscience, Research Centre Foulum, BlichersAllé 20, DK-8830 Tjele, Denmark. knuderik.bachknudsen@agrsci.dk Polymeric carbohydrates, starch and nonstarch polysaccharides (NSP), quantitatively represent the largest portion of the diets for pigs and are, therefore, the largest energy contributor. The 2 types of polysaccharides, however, have different fates and functions in the gastrointestinal tract and lead to different metabolites upon digestion. Pancreatic and mucosal enzymes in the small intestine break down the majority of starch, whereas NSP primarily are degraded by the microflora in the large intestine. Starch degradation leads to the release of glucose, which is absorbed by an active absorption process that triggers the release of insulin from the pancreas, whereas the fermentation of NSP to short-chain fatty acids (SCFA; i.e., acetate, propionate, and butyrate) occurs at a slower and more constant rate and with SCFA being absorbed by passive diffusion. Type and amounts of polymeric carbohydrates influence growth and development through different mechanisms. First, the proportion of starch to NSP plays an important role for the content of available energy (i.e., DE, ME, and NE); available energy relative to protein is crucial for performance and carcass quality. Second, the proportion of starch to NSP will influence rate and type of metabolites (i.e., glucose vs. SCFA) deriving from carbohydrate assimilation. Third and finally, the type of starch (i.e., types A, B, and C) and soluble NSP will influence the release of insulin, the hormone that facilitates nutrient uptake by tissues, organs, and cells, and thus plays a critically essential role in protein synthesis and muscle growth, as well as lipid synthesis and adipose tissue growth. In conclusion, polymeric carbohydrates influence growth and development through events in the gut and direct and indirect effects of different metabolites deriving from carbohydrate assimilation. © 2011 American Society of Animal Science. All rights reserved. PMID: 21278117 [PubMed - indexed for MEDLINE] 965. J Steroid Biochem Mol Biol. 2011 Apr;124(3-5):65-76. doi: 10.1016/j.jsbmb.2011.01.011. Epub 2011 Jan 26. Fatty acid esters of steroids: synthesis and metabolism in lipoproteins and adipose tissue. Vihma V(1), Tikkanen MJ. Author information: (1)Institute of Clinical Medicine, Department of Medicine, University of Helsinki, 00290 Helsinki, Finland. At the end of the last century ideas concerning the physiological role of the steroid fatty acid ester family were emerging. Estrogens, fatty acylated at C-17 hydroxyl group and incorporated in lipoproteins were proposed to provide antioxidative protection to these particles. A large number of studies involving non-estrogenic adrenal steroids, and their fatty acylated forms, demonstrated their lipoprotein-mediated transport into cells and subsequent intracellular activation, suggesting a novel transport mechanism for lipophilic steroid derivatives. After these important advances the main focus of interest has shifted away from C-19 and C-21 steroids to fatty acylated estrogens. However, interest in their lipoprotein-mediated transport has decreased because only minute amounts of these derivatives were detected in circulating lipoproteins, and their antioxidative activity remained unconfirmed under physiological circumstances. It now appears that the overwhelming majority of estradiol in postmenopausal women resides in adipose tissue, most of it in esterified form. This is poorly reflected in plasma levels which are very low. Recent data suggest that estrogen fatty acid esters probably represent a storage form. The future focus of investigation is likely to be on firstly, the enzymatic mechanisms regulating the esterification and de-esterification of estradiol and other steroids residing in adipose tissue and secondly, on the role of insulin and other hormones in the regulation of these enzymatic mechanisms. Thirdly, as a large proportion of fatty acid esterified C-19 and C-21 non-estrogenic steroids is transported in lipoproteins and as they are important precursors of androgens and estrogens, this field should be investigated further. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21277977 [PubMed - indexed for MEDLINE] 966. Nutr Metab Cardiovasc Dis. 2011 Mar;21(3):222-30. doi: 10.1016/j.numecd.2010.10.012. Epub 2011 Feb 1. From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation. Mollica MP(1), Lionetti L, Putti R, Cavaliere G, Gaita M, Barletta A. Author information: (1)Dipartimento delle Scienze Biologiche, Sezione Fisiologia ed Igiene, Università degli Studi di Napoli Federico II, Via Mezzocannone 8, 80134 Napoli, Italy. mariapia.mollica@unina.it We analyse how chronic overfeeding, by increasing circulating fatty acids, might lead to inflammation, insulin resistance (IR) and injury in the liver. Chronic overfeeding causes an increase in adipose tissue depots and is characterised by an increased presence of hypertrophic adipocytes when adipose tissue expandability is inadequate. Adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER), which will activate inflammatory and apoptotic pathways and cause IR in adipose tissue. Insulin-resistant adipocytes, being more lipolytic and less liposynthetic, induce an increase in circulating free fatty acids. Moreover, the strongly compromised secretion/function of the adipocyte hormones, adiponectin and leptin, decreases lipid oxidation, particularly in the liver, causing lipid accumulation, ER stress and IR in hepatocytes. ER stress may lead to reduced very-low-density lipoprotein (VLDL) secretion and increased lipogenic gene expression despite the presence of IR. These events and reduced lipid oxidation may lead to further hepatic lipid accumulation. When the triglyceride storage capacity of hepatocytes is exceeded, hepatic injury may occur. ER-stressed steatotic hepatocytes activate apoptotic and inflammatory pathways, which trigger IR and the release of chemokines and cytokines, and these, in turn, elicit an increased influx of Kupffer cells (KCs) and hepatic stellate cells (HSCs) around dying hepatocytes. Soluble mediators, secreted mainly by ER-stressed steatotic hepatocytes and activated KCs, induce the transdifferentiation of HSCs to myofibroblasts, which secrete fibrogenic cytokines and matrix components that trigger fibrosis. In conclusion, chronic lipid overloading due to inadequate fat-storing capacity of adipose tissue can induce hepatic injury when triglyceride storage capacity of hepatocytes is exceeded. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 21277757 [PubMed - indexed for MEDLINE] 967. Cardiovasc Diabetol. 2011 Jan 28;10:13. doi: 10.1186/1475-2840-10-13. Pharmacological and non-pharmacological interventions to influence adipose tissue function. Westerink J(1), Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, the Netherlands. Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-γ agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes. PMCID: PMC3039566 PMID: 21276223 [PubMed - indexed for MEDLINE] 968. Ann N Y Acad Sci. 2010 Nov;1212:E1-E19. doi: 10.1111/j.1749-6632.2010.05875.x. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Deng Y(1), Scherer PE. Author information: (1)Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA. Erratum in Ann N Y Acad Sci. 2011 May;1226(1):50. Over the past two decades our view of adipose tissue has undergone a dramatic change from an inert energy storage tissue to an active endocrine organ. Adipose tissue communicates with other central and peripheral organs by synthesis and secretion of a host of molecules that we generally refer to as adipokines. The levels of some adipokines correlate with specific metabolic states and have the potential to impact directly upon the metabolic homeostasis of the system. A dysregulation of adipokines has been implicated in obesity, type 2 diabetes, hypertension, cardiovascular disease, and an ever-growing larger list of pathological changes in a number of organs. Here, we review the recent progress regarding the synthesis, secretion, and physiological function of adipokines with perspectives on future directions and potential therapeutic goals. © 2010 New York Academy of Sciences. PMCID: PMC3075414 PMID: 21276002 [PubMed - indexed for MEDLINE] 969. J Biomed Biotechnol. 2011;2011:524067. doi: 10.1155/2011/524067. Epub 2011 Jan 11. Contributions of cytogenetics and molecular cytogenetics to the diagnosis of adipocytic tumors. Nishio J(1). Author information: (1)Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. jnishio@cis.fukuoka-u.ac.jp Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13-15 involving the MDM2, CDK4, and CPM genes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors. PMCID: PMC3025394 PMID: 21274402 [PubMed - indexed for MEDLINE] 970. Oral Maxillofac Surg Clin North Am. 2011 Feb;23(1):63-71, vi. doi: 10.1016/j.coms.2010.10.002. Reoperative soft tissue trauma. Fattahi T(1). Author information: (1)Division of Oral and Maxillofacial Surgery, University of Florida Health Science Center, Jacksonville, FL 32209, USA. Tirbod.Fattahi@Jax.Ufl.Edu Trauma remains the leading cause of death in the first 4 decades of life and is surpassed only by cancer and atherosclerotic disease as the overall leading causes of death in the United States. Many of the injuries involve the facial region, including soft tissue trauma. This article highlights the current available modalities used in the management of unsightly scars or those scars whose location and appearance compromise function. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21272767 [PubMed - indexed for MEDLINE] 971. J Bioenerg Biomembr. 2011 Feb;43(1):53-8. doi: 10.1007/s10863-011-9325-z. Hypothalamic inflammation and thermogenesis: the brown adipose tissue connection. Arruda AP(1), Milanski M, Velloso LA. Author information: (1)Laboratory of Cell Signaling, University of Campinas, Campinas, Brazil. aarruda@hsph.harvard.edu Hypothalamic inflammation and dysfunction are common features of experimental obesity. An imbalance between caloric intake and energy expenditure is generated as a consequence of this inflammation, leading to the progressive increase of body adiposity. Thermogenesis, is one of the main functions affected by obesity-linked hypothalamic dysfunction and the complete characterization of the mechanisms involved in this process may offer new therapeutic perspectives for obesity. The brown adipose tissue is an important target for hypothalamic action in thermogenesis. This tissue has been thoroughly studied in rodents and hibernating mammals; however, until recently, its advocated role in human thermogenesis was neglected due to the lack of substantial evidence of its presence in adult humans. The recent demonstration of the presence of functional brown adipose tissue in adult humans has renovated the interest in this tissue. Here, we review some of the work that shows how inflammation and dysfunction of the hypothalamus can control brown adipose tissue activity and how this can impact on whole body thermogenesis and energy expenditure. PMID: 21271281 [PubMed - indexed for MEDLINE] 972. J Appl Physiol (1985). 2011 May;110(5):1137-49. doi: 10.1152/japplphysiol.01227.2010. Epub 2011 Jan 26. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. Morrison SF(1). Author information: (1)Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon 97239, USA. morrisos@ohsu.edu Central neural circuits orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific core efferent pathways within the central nervous system (CNS) that share a common peripheral thermal sensory input. The thermal afferent circuit from cutaneous thermal receptors includes neurons in the spinal dorsal horn projecting to lateral parabrachial nucleus neurons that project to the medial aspect of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output neurons control heat production by reducing the discharge of thermogenesis-promoting neurons in the dorsomedial hypothalamus. The rostral ventromedial medulla, including the raphe pallidus, receives projections form the dorsomedial hypothalamus and contains spinally projecting premotor neurons that provide the excitatory drive to spinal circuits controlling the activity of thermogenic effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a platform for further understanding of the functional organization of central thermoregulation. PMCID: PMC3098654 PMID: 21270352 [PubMed - indexed for MEDLINE] 973. Trends Endocrinol Metab. 2011 Mar;22(3):94-102. doi: 10.1016/j.tem.2010.12.003. Epub 2011 Jan 25. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Howell JJ(1), Manning BD. Author information: (1)Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA. The mammalian target of rapamycin complex 1 (mTORC1) has the ability to sense a variety of essential nutrients and respond by altering cellular metabolic processes. Hence, this protein kinase complex is poised to influence adaptive changes to nutrient fluctuations toward the maintenance of whole-body metabolic homeostasis. Defects in mTORC1 regulation, arising from either physiological or genetic conditions, are believed to contribute to the metabolic dysfunction underlying a variety of human diseases, including type 2 diabetes. We are just now beginning to gain insights into the complex tissue-specific functions of mTORC1. In this review, we detail the current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3744367 PMID: 21269838 [PubMed - indexed for MEDLINE] 974. Anim Sci J. 2011 Feb;82(1):17-25. doi: 10.1111/j.1740-0929.2010.00844.x. Promotion of intramuscular fat accumulation in porcine muscle by nutritional regulation. Katsumata M(1). Author information: (1)National Institute of Livestock and Grassland Science, Ikenodai, Tsukuba, Ibaraki, Japan. masaya@affrc.go.jp Recently, pork with marbling has received attention as good quality pork and scientists are required to develop methods to produce pork with reasonable amounts of intramuscular fat (IMF). The aim of this review is to describe studies relevant to promotion of IMF accumulation in porcine muscle by nutritional regulation. The main focus is on effect of dietary lysine levels. First, we found dietary low lysine up-regulated glucose transporter protein 4 messenger (m)RNA expression in Longissimus dorsi (L. dorsi) and Rhomboideus muscles. In addition, the proportion of oxidative fiber of both muscles was also enhanced by dietary low lysine. Because it has been observed that higher oxidative capacity is associated with higher IMF content, we hypothesized that dietary low lysine would promote IMF accumulation. Further, higher mRNA abundance of peroxisome proliferator-activated receptor γ, a master regulator of adipogenesis, in both muscles induced by dietary low lysine, supported this hypothesis. Indeed, IMF content of L. dorsi muscle of finishing pigs given a low lysine diet for 2 months until reaching the market weight was twice that of pigs given a control diet. Possible underlying mechanisms of IMF accumulation in porcine muscle and future perspectives are also discussed in this review. © 2011 The Author. Journal compilation © 2011 Japanese Society of Animal Science. PMID: 21269355 [PubMed - indexed for MEDLINE] 975. Anim Sci J. 2011 Feb;82(1):1-7. doi: 10.1111/j.1740-0929.2010.00845.x. Identification and utilization of genes associated with beef qualities. Mannen H(1). Author information: (1)Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Nada, Kobe, Japan. mannen@kobe-u.ac.jp The fatty acid composition of adipose tissue in beef has been recognized as an important trait because of its relationship with beef quality, including favorable beef flavor and tenderness. Over the last decade, we have tried to identify the genes responsible for the fatty acid composition in cattle, and have found the following. (i) Genetic polymorphism of stearoyl-CoA desaturase (SCD) is one of the responsible genes associated with fatty acid composition. The average effects of gene substitution of the SCD type A gene on the monounsaturated fatty acid (MUFA) percentage and the melting point of intramuscular fat were approximately +1.0% and -1.0°C, respectively. (ii) Intron polymorphism of sterol regulatory element binding protein-1 (SREBP-1) also affected MUFA. (iii) No effect of SCD or SREBP-1 genotypes on any representative carcass traits of Japanese Black in the field population was observed. (iv) Additional genetic markers adipocytes fatty acid binding protein 4 (FABP4) and liver X receptor α also affected the fatty acid composition. (v) SCD and FABP4 significantly affected fatty acid composition in Holstein steers. These findings will bring new insight into the fat-related carcass traits of beef cattle and will thus contribute to the beef industry. © 2011 The Author. Journal compilation © 2011 Japanese Society of Animal Science. PMID: 21269353 [PubMed - indexed for MEDLINE] 976. J Cardiovasc Pharmacol. 2012 Jan;59(1):1-9. doi: 10.1097/FJC.0b013e31820eb8f6. Visfatin and cardio-cerebro-vascular disease. Wang P(1), Vanhoutte PM, Miao CY. Author information: (1)Department of Pharmacology, Second Military Medical University, Shanghai, China. Nicotinamide phosphoribosyltransferase is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide from nicotinamide. This protein was originally cloned as a putative pre-B cell colony-enhancing factor and also found to be a visceral fat-derived adipokine (visfatin). As a multifunctional protein, visfatin plays an important role in immunity, metabolism, aging, inflammation, and responses to stress. Visfatin also participates in several pathophysiological processes contributing to cardio-cerebro-vascular diseases, including hypertension, atherosclerosis, ischemic heart disease, and ischemic stroke. However, whether visfatin is a friend or a foe in these diseases remains uncertain. This brief review focuses on the current understanding of the complex role of visfatin in the cardio-cerebro-vascular system under normal and pathophysiological conditions. PMID: 21266913 [PubMed - indexed for MEDLINE] 977. Digestion. 2011;83(3):142-5. doi: 10.1159/000321810. Epub 2011 Jan 21. Visceral obesity and the risk of Barrett's esophagus. Akiyama T(1), Yoneda M, Maeda S, Nakajima A, Koyama S, Inamori M. Author information: (1)Department of Gastroenterology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan. It still remains controversial whether simple obesity, as measured by the body mass index (BMI), is an independent risk factor for Barrett's esophagus (BE). Recent studies have shown abdominal obesity, as defined by the waist circumference (WC) and the waist-to-hip ratio (WHR), to be a risk factor for BE, independent of the BMI, with the association between BMI and BE being no longer observed after adjustment for the WC and WHR. Moreover, visceral obesity, as directly measured by the surface area of the visceral adipose tissue (VAT) on abdominal CT images, has also been reported to have an association with the risk of BE. In addition to the mechanical effects of abdominal obesity, that is, increase of the intra- abdominal pressure by the large amount of adipose tissue, circulating factors secreted from the VAT, such as tumor necrosis factor-α, interleukin-6, leptin, and adiponectin, have also been proposed to be pathogenetically linked to BE and esophageal adenocarcinoma. Obesity is associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal obesity, especially visceral obesity. This raises several questions regarding the pathogenesis of obesity-related BE. Larger studies with prospective enrollment of patients are required for further examination of this issue. Copyright © 2011 S. Karger AG, Basel. PMID: 21266807 [PubMed - indexed for MEDLINE] 978. HIV Med. 2011 Sep;12(8):453-62. doi: 10.1111/j.1468-1293.2010.00906.x. Epub 2011 Jan 25. Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials. Sivakumar T(1), Mechanic O, Fehmie DA, Paul B. Author information: (1)Endocrinology Department, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. doctor_sivakumar@hotmail.com BACKGROUND: HIV-associated lipodystrophy is a disorder of fat metabolism that occurs in patients with HIV infection. It can cause metabolic derangements and negative self-perceptions of body image, and result in noncompliance with highly active antiretroviral therapy (HAART). Growth hormone (GH) axis drugs have been evaluated for treatment of this disorder, but no systematic review has been conducted previously. OBJECTIVES: The aim of the review was to compare the effects of GH axis drugs vs. placebo in changing visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and lean body mass (LBM) in patients with HIV-associated lipodystrophy. SEARCH METHODS: We searched MEDLINE (1996-2009), CENTRAL (Issue 4, 2009), Web of Science, Summons, Google Scholar, the Food and Drug Administration (FDA) website, and Clinicaltrials.gov from 13 October 2009 to 7 June 2010. We excluded newspaper articles and book reviews from the Summons search; this was the only search limitation applied. We also manually reviewed references of included articles. SELECTION CRITERIA: Inclusion criteria were as follows: randomized placebo-controlled trial (RCT); study participants with HIV-associated lipodystrophy; intervention consisting of GH, growth hormone releasing hormone (GHRH), tesamorelin or insulin-like growth factor-1 (IGF-1); study including at least one primary outcome of interest: change in VAT, SAT or LBM. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and assessed study quality using a standardized form. The authors of one study were contacted for missing information. The main effect was calculated as a summary of the mean differences in VAT, SAT and LBM between the intervention and placebo groups in the included studies. Subgroup analyses were performed to assess different GH axis drug classes. RESULTS: Ten RCTs including 1511 patients were included in the review. All had a low risk of bias and passed the test of heterogeneity for each primary outcome. Compared with placebo, GH axis treatments decreased VAT [weighted mean difference (WMD) -25.20 cm(2) ; 95% confidence interval (CI) -32.18 to -18.22 cm(2) ; P<0.001] and increased LBM (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; P<0.001], but had no significant effect on SAT mass (WMD -3.94 cm(2) ; 95% CI -10.88 to 3.00 cm(2) ; P=0.27]. Subgroup analyses showed that GH had the most significant effects on VAT and SAT, but none on LBM. The drugs were well tolerated but statistically significant side effects included arthralgias and oedema. CONCLUSIONS: Our review indicates that, based on the findings of the 10 included studies, GH axis treatments are effective in reducing VAT and increasing LBM in patients with HIV-associated lipodystrophy. However, clinicians must decide whether the attributed benefits are clinically significant, considering the costs and potential risks of GH axis treatments. A limitation of this study is the small number of studies available of each GH axis drug class. © 2011 British HIV Association. PMID: 21265979 [PubMed - indexed for MEDLINE] 979. Nat Rev Cardiol. 2011 Apr;8(4):233-7. doi: 10.1038/nrcardio.2010.209. Epub 2011 Jan 25. Impact of obesity on total and cardiovascular mortality--fat or fiction? Cepeda-Valery B(1), Pressman GS, Figueredo VM, Romero-Corral A. Author information: (1)Department of Internal Medicine, Albert Einstein Medical Center, 5401 Old York Road, Klein Professional Building, Suite 300, Philadelphia, PA 19141, USA. Obesity is an excessive accumulation of fat that can impair health. Because the direct measurement of body fat is difficult to perform, a number of anthropometric measures have been employed as surrogates, of which BMI is the most commonly used. However, its usefulness has been questioned as a BMI in the overweight and mildly obese range is associated with improved survival and fewer cardiovascular events than a BMI in the normal range, a phenomenon known as the 'obesity paradox'. Waist circumference, waist-to-hip ratio, and waist-to-height ratio take into consideration body-fat distribution, especially abdominal obesity, and seem to predict cardiovascular risk better than does BMI. © 2011 Macmillan Publishers Limited. All rights reserved PMID: 21263454 [PubMed - indexed for MEDLINE] 980. Nat Rev Endocrinol. 2011 Apr;7(4):219-31. doi: 10.1038/nrendo.2010.217. Epub 2011 Jan 25. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Goodarzi MO(1), Dumesic DA, Chazenbalk G, Azziz R. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of up to 10%. Various diagnostic criteria have been proposed, generally centered around the features of hyperandrogenism and/or hyperandrogenemia, oligo-ovulation and polycystic ovarian morphology. Insulin resistance is present in a majority of cases, with compensatory hyperinsulinemia contributing to hyperandrogenism via stimulation of ovarian androgen secretion and inhibition of hepatic sex hormone-binding globulin production. Adipose tissue dysfunction has been implicated as a contributor to the insulin resistance observed in PCOS. Environmental and genetic factors also have a role in the development of PCOS. The syndrome is associated with numerous morbidities, including infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders. Despite these morbidities, PCOS may be common in our society owing to evolutionary advantages of the syndrome in ancient times, including smaller family sizes, reduced exposure to childbirth-related mortality, increased muscle mass and greater capacity to store energy. The diagnosis of PCOS hinges on establishing key features while ruling out other hyperandrogenic or oligo-ovulatory disorders. Treatment is focused on the goals of ameliorating hyperandrogenic symptoms, inducing ovulation and preventing cardiometabolic complications. © 2011 Macmillan Publishers Limited. All rights reserved PMID: 21263450 [PubMed - indexed for MEDLINE] 981. Thromb Res. 2011 Feb;127 Suppl 3:S17-20. doi: 10.1016/S0049-3848(11)70006-8. Murine models of obesity and hormonal therapy. Lijnen HR(1). Author information: (1)Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium. roger.lijnen@med.kuleuven.be Obesity is a common disorder, and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Westerntype societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. Adipogenesis is tightly associated with angiogenesis, as shown by the findings that adipose tissue expiants trigger blood vessel formation, whereas in turn adipose tissue endothelial cells promote preadipocyte differentiation. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems and of angiogenesis in the development of obesity. Most studies support a role of these systems in adipogenesis and obesity, and suggest that their modulation may affect development of adipose tissue. Such models have also shown that treatment of obese female mice with estrogens has the potential to improve obesity, insulin resistance and glucose intolerance, via decreased expression of lipogenic genes. Thus, murine models of obesity have been very useful tools to study mechanisms of adipose tissue development, as well as effects of hormonal therapy. © 2011 Elsevier Ltd. All rights reserved. PMID: 21262432 [PubMed - indexed for MEDLINE] 982. Obes Rev. 2011 Jul;12(7):543-51. doi: 10.1111/j.1467-789X.2010.00851.x. Epub 2011 Jan 24. Could increased time spent in a thermal comfort zone contribute to population increases in obesity? Johnson F(1), Mavrogianni A, Ucci M, Vidal-Puig A, Wardle J. Author information: (1)Cancer Research UK Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College London, London, UK. f.johnson@public-health.ucl.ac.uk Domestic winter indoor temperatures in the USA, UK and other developed countries appear to be following an upwards trend. This review examines evidence of a causal link between thermal exposures and increases in obesity prevalence, focusing on acute and longer-term biological effects of time spent in thermal comfort compared with mild cold. Reduced exposure to seasonal cold may have a dual effect on energy expenditure, both minimizing the need for physiological thermogenesis and reducing thermogenic capacity. Experimental studies show a graded association between acute mild cold and human energy expenditure over the range of temperatures relevant to indoor heating trends. Meanwhile, recent studies of the role of brown adipose tissue (BAT) in human thermogenesis suggest that increased time spent in conditions of thermal comfort can lead to a loss of BAT and reduced thermogenic capacity. Pathways linking cold exposure and adiposity have not been directly tested in humans. Research in naturalistic and experimental settings is needed to establish effects of changes in thermal exposures on weight, which may raise possibilities for novel public health strategies to address obesity. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21261804 [PubMed - indexed for MEDLINE] 983. Ann N Y Acad Sci. 2011 Jan;1215:40-7. doi: 10.1111/j.1749-6632.2010.05845.x. Effect of resveratrol on fat mobilization. Baile CA(1), Yang JY, Rayalam S, Hartzell DL, Lai CY, Andersen C, Della-Fera MA. Author information: (1)University of Georgia, Athens, 30602, USA. cbaile@uga.edu Higher levels of body fat are associated with increased risk for development of numerous adverse health conditions. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing adipose tissue mass. Resveratrol decreased adipogenesis and viability in maturing preadipocytes; these effects were mediated not only through down-regulating adipocyte specific transcription factors and enzymes but also by genes that modulate mitochondrial function. Additionally, resveratrol increased lipolysis and reduced lipogenesis in mature adipocytes. In addition, combining resveratrol with other natural products produced synergistic activities from actions on multiple molecular targets in the adipocyte life cycle. Treatment of mice with resveratrol alone was shown to improve resistance to weight gain caused by a high-fat diet. Moreover, dietary supplementation of aged ovariectomized rats with a combination of resveratrol and vitamin D, quercetin, and genistein not only decreased weight gain but also inhibited bone loss. Combining several phytochemicals, including resveratrol, or using them as templates for synthesizing new drugs, provides a large potential for using phytochemicals to target adipocyte adipogenesis, apoptosis, and lipolysis. © 2011 New York Academy of Sciences. PMID: 21261640 [PubMed - indexed for MEDLINE] 984. Exp Dermatol. 2011 Feb;20(2):81-7. doi: 10.1111/j.1600-0625.2010.01210.x. Adipokines and psoriasis. Gerdes S(1), Rostami-Yazdi M, Mrowietz U. Author information: (1)Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. sgerdes@dermatology.uni-kiel.de Adipose tissue is an active endocrine organ contributing to the regulation of multiple metabolic pathways via self-produced bioactive products called adipokines. These adipokines are key players in the pathogenesis of metabolic syndrome and cardiovascular diseases. Co-occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis. Until today numerous adipokines have been identified of which the most important ones are discussed in the following within the context of obesity, chronic inflammation and their possible role in the pathogenesis of psoriasis. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success. © 2011 John Wiley & Sons A/S. PMID: 21255085 [PubMed - indexed for MEDLINE] 985. Ann Med. 2011 Mar;43(2):104-15. doi: 10.3109/07853890.2010.535557. Epub 2011 Jan 24. Between brown and white: novel aspects of adipocyte differentiation. Cinti S(1). Author information: (1)Department of Molecular Pathology and Innovative Therapies, Faculty of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy. cinti@univpm.it In all mammals including humans, most white and brown adipocytes are found together in visceral and subcutaneous depots (adipose organ) despite the well known difference in their function, respectively of storing energy and producing heat. A growing body of evidence suggests that the reason for such anatomical arrangement is their plasticity, which under appropriate stimulation allows direct conversion of one cell type into the other. In conditions of chronic cold exposure white-to-brown conversion meets the need for thermogenesis, whereas an obesogenic diet induces brown-to-white conversion to meet the need for storing energy. White-to-brown transdifferentiation is of medical interest, because the brown phenotype of the adipose organ is associated to obesity resistance, and drugs inducing this phenotype curb murine obesity and related disorders. Type 2 diabetes is the most common disorder associated to visceral obesity. Macrophages infiltrating the adipose organ are responsible for the low-grade chronic inflammation related to the removal of dead adipocytes, which leads to insulin resistance and T2 diabetes. Adipocyte death is closely related to their growth up to the critical death size. The critical death size of visceral adipocytes is smaller than that of subcutaneous adipocytes, likely accounting for the greater morbidity related to visceral fat. PMID: 21254898 [PubMed - indexed for MEDLINE] 986. Nat Rev Immunol. 2011 Feb;11(2):85-97. doi: 10.1038/nri2921. Epub 2011 Jan 21. Adipokines in inflammation and metabolic disease. Ouchi N(1), Parker JL, Lugus JJ, Walsh K. Author information: (1)Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, 466-8550 Japan. The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function. PMCID: PMC3518031 PMID: 21252989 [PubMed - indexed for MEDLINE] 987. Aliment Pharmacol Ther. 2011 Apr;33(7):801-14. doi: 10.1111/j.1365-2036.2011.04579.x. Epub 2011 Jan 20. Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. Baranova A(1), Tran TP, Birerdinc A, Younossi ZM. Author information: (1)Betty and Guy Beatty Center for Integrated Research, Inova Health System, 3300 Gallows Road, Falls Church, VA 22042, USA. BACKGROUND: Polycystic ovary syndrome (PCOS) is a common disorder for women of child-bearing age and is associated with metabolic syndrome (MS). AIM: To assess the literature for associations between polycystic ovary syndrome and non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a systematic review using PubMed-search for peer-reviewed articles related to polycystic ovary syndrome and NAFLD. Articles were summarised and grouped according to different sections defining interactions of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease as well as risk factors, pathogenic pathways and treatment options. RESULTS: Obesity is a common factor involved in both polycystic ovary syndrome and non-alcoholic fatty liver disease. Obesity causes non-alcoholic fatty liver disease and aggravates hirsutism and menstrual disorders in polycystic ovary syndrome. Insulin resistance, a hallmark of metabolic syndrome is observed in 50-80% of women with polycystic ovary syndrome and patients with non-alcoholic fatty liver disease. Recent findings suggest that women with polycystic ovary syndrome may be at risk for developing non-alcoholic fatty liver disease and conversely, non-alcoholic fatty liver disease may be a risk for polycystic ovary syndrome. Based on the association of polycystic ovary syndrome and other metabolic abnormalities, such as insulin resistance, hyperandrogenism, obesity and non-alcoholic fatty liver disease, the candidate genes have been speculated for polycystic ovary syndrome. Closer scrutiny of these genes placed most of their proteins at the crossroads of three highly inter-related conditions: metabolic syndrome, obesity and non-alcoholic fatty liver disease. In most studies, the prevalence of both polycystic ovary syndrome and non-alcoholic fatty liver disease rises proportionally to the degree of insulin resistance and increases in the mass of adipose tissue. CONCLUSIONS: Non-alcoholic fatty liver disease is considered as the hepatic manifestation of metabolic syndrome. Similarly, it seems appropriate to consider polycystic ovary syndrome as the ovarian manifestation of metabolic syndrome. Both these conditions can co-exist and may respond to similar therapeutic strategies. © 2011 Blackwell Publishing Ltd. PMID: 21251033 [PubMed - indexed for MEDLINE] 988. Eur Cell Mater. 2010 Sep 1;20:121-33. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. Augello A(1), Kurth TB, De Bari C. Author information: (1)Regenerative Medicine Unit, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK. Mesenchymal Stromal Progenitor/Stem Cells (MSCs) are a rare population of non-hematopoietic stromal cells, present in the bone marrow and most connective tissues of the body. They are capable of differentiation into mesenchymal tissues such as bone, cartilage, adipose tissue and muscle. In the absence of specific markers, MSCs have been defined following isolation and culture expansion, by their expression of various molecules including CD90, CD105 and CD73 and absence of markers like CD34, CD45, and CD14. MSCs have extensive proliferative ability in culture in an uncommitted state while retaining their multilineage differentiation potential, which make them attractive candidates for biological cell-based tissue repair approaches. However, their identity in their tissues of origin is not clear and the niches in which they reside are not defined. This review addresses the current state of MSC research including the differentiation potency of culture expanded MSCs, expression of chemokines and their receptors in MSCs--both relevant issues for the advocated use of MSCs for tissue repair and their systemic delivery to the affected tissues. It also reviews current knowledge of MSC niches in their native tissues, addressing the relationship with pericytes. Finally, it provides a scientific basis for the requirement of a thorough characterisation of the endogenous MSC niches within their native tissues in vivo. The knowledge of MSC niches will instruct development of innovative therapeutic measures such as producing pharmacological substances that target endogenous MSCs and their niches in order to activate and guide intrinsic repair and to improve disease outcomes. PMID: 21249629 [PubMed - indexed for MEDLINE] 989. J Mol Endocrinol. 2011 Mar 7;46(2):R65-72. doi: 10.1530/JME-10-0169. Print 2011 Apr. Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes. Laudes M(1). Author information: (1)Department of Internal Medicine II, University of Cologne, Kerpener Strasse 62, 50924 Cologne, Germany. matthias.laudes@uk-sh.de The development of obesity is characterised not only by increased storage of lipids in existing fat cells but also by the generation of new adipocytes from progenitor cells. This process, called adipogenesis, can be divided into two related steps. First, during determination, multipotent mesenchymal stem cells commit to preadipocytes. These cells exhibit similar morphology compared with stem cells; however, they are committed to the adipogenic lineage and are not longer able to transform into osteoblasts, myocytes or chondrocytes. Secondly, during differentiation, preadipocytes become mature fat cells. As in other developmental processes, adipogenesis is tightly regulated at a molecular level by several transcription factors. Within the last decade, it has also become clear how the activity of these transcription factors is coordinated by extracellular signals. In this respect, secreted WNT signalling molecules are particularly important. Several members of the WNT family have been shown to inhibit early steps of adipogenesis. Conversely, endogenous inhibitors of WNT signalling were found to promote generation of adipocytes, indicating a fundamental role of these bioactive peptides in adipogenesis. From a pathophysiological point of view, it is of interest that polymorphisms in genes of the WNT signalling system have been associated with the development of obesity and type 2 diabetes in humans. Moreover, recent findings indicate that certain WNT molecules are involved in the so-called low-grade inflammation of adipose tissue, which is crucial in the development of obesity-associated insulin resistance. These important findings in nutritional and metabolic medicine will be summarised in the present review. PMID: 21247979 [PubMed - indexed for MEDLINE] 990. Gene. 2011 May 15;477(1-2):1-11. doi: 10.1016/j.gene.2011.01.007. Epub 2011 Jan 15. The resurgence of Hormone-Sensitive Lipase (HSL) in mammalian lipolysis. Lampidonis AD(1), Rogdakis E, Voutsinas GE, Stravopodis DJ. Author information: (1)Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Zografou, 157 84 Athens, Greece. The ability to store energy in the form of energy-dense triacylglycerol and to mobilize these stores rapidly during periods of low carbohydrate availability or throughout the strong metabolic demand is a highly conserved process, absolutely essential for survival. In the industrialized world the regulation of this pathway is viewed as an important therapeutic target for disease prevention. Adipose tissue lipolysis is a catabolic process leading to the breakdown of triacylglycerols stored in fat cells, and release of fatty acids and glycerol. Mobilization of adipose tissue fat is mediated by the MGL, HSL and ATGL, similarly functioning enzymes. ATGL initiates lipolysis followed by the actions of HSL on diacylglycerol, and MGL on monoacylglycerol. HSL is regulated by reversible phosphorylation on five critical residues. Phosphorylation alone, however, is not enough to activate HSL. Probably, conformational alterations and a translocation from the cytoplasm to lipid droplets are also involved. In accordance, Perilipin functions as a master regulator of lipolysis, protecting or exposing the triacylglycerol core of a lipid droplet to lipases. The prototype processes of hormonal lipolytic control are the β-adrenergic stimulation and suppression by insulin, both of which affect cytoplasmic cyclic AMP levels. Lipolysis in adipocytes is an important process in the management of body energy reserves. Its deregulation may contribute to the symptoms of type 2 diabetes mellitus and other pathological situations. We, herein, discuss the metabolic regulation and function of lipases mediating mammalian lipolysis with a focus on HSL, quoting newly identified members of the lipolytic proteome. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 21241784 [PubMed - indexed for MEDLINE] 991. Aesthet Surg J. 2011 Jan;31(1):68-75. doi: 10.1177/1090820X10390922. Oncologic risks of autologous fat grafting to the breast. Fraser JK(1), Hedrick MH, Cohen SR. Author information: (1)Cytori Therapeutics Inc., San Diego, CA, USA. As the frequency of fat grafting to the breast has increased, some investigators have raised the possibility that this procedure may potentially increase the risks associated with breast cancer. Their concerns included not only interference with cancer detection, but also promotion of tumor formation or recurrence mediated by mechanisms such as aromatase expression, angiogenesis, and tumor stromal cells. However, published clinical studies describing outcomes of fat grafting to the breast in more than 2000 patients have not reported any increase in new or recurrent cancers. The reason for this apparent disconnect may lie in the small sample sizes and relatively short follow-up, but it may also reside in the considerable gap between laboratory studies or theoretical considerations suggesting potential risks and the actual clinical practice. This review discusses potential risks of current and novel approaches to autologous fat grafting to the breast within the context of both the underlying science and clinical practice. PMID: 21239674 [PubMed - indexed for MEDLINE] 992. Nat Rev Immunol. 2011 Feb;11(2):98-107. doi: 10.1038/nri2925. Epub 2011 Jan 14. Type 2 diabetes as an inflammatory disease. Donath MY(1), Shoelson SE. Author information: (1)Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland. MDonath@uhbs.ch Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease. PMID: 21233852 [PubMed - indexed for MEDLINE] 993. Proc Nutr Soc. 2011 May;70(2):268-75. doi: 10.1017/S0029665110004921. Epub 2011 Jan 14. The conflicting effects of maternal nutrient restriction and early-life obesity on renal health. Fainberg HP(1), Budge H, Symonds ME. Author information: (1)School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK. Pablo.Fainberg@nottingham.ac.uk Epidemiological and animal studies have demonstrated that early-life nutrition alters the metabolic responses and generates structural changes in complex tissues, such as the kidneys, which may lead to a reduction in the offspring lifespan. Independently, obesity induces a spontaneous low-grade chronic inflammatory response by modulating several of the major metabolic pathways that ultimately compromise long-term renal health. However, the combined effects of maternal nutrition and early-life obesity in the development of renal diseases are far from conclusive. Previous results, using the ovine model, demonstrated that the combination of a reduction in fetal nutrition and juvenile obesity induced a series of adaptations associated with severe metabolic syndrome in the heart and adipose tissue. Surprisingly, exposure to an obesogenic environment in the kidney of those offspring produced an apparent reduction in glomerulosclerosis in relation to age- and weight-matched controls. However, this reduction in cellular apoptosis was accompanied by a rise in glomerular filtration rate and blood pressure of equal intensity when compared with obese controls. The intention of this review is to explain the adaptive responses observed in this model, based on insights into the mechanism of renal fetal programming, and their potential interactions with some of the metabolic changes produced by obesity. PMID: 21232171 [PubMed - indexed for MEDLINE] 994. Blood Purif. 2011;31(1-3):189-96. doi: 10.1159/000321845. Epub 2011 Jan 10. Lipid disorders and their relevance to outcomes in chronic kidney disease. Vaziri ND(1), Norris K. Author information: (1)Division of Nephrology and Hypertension, Irvine Medical Center, University of California-Irvine, Orange, CA 92868, USA. ndvaziri@uci.edu Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Cardiovascular disease and many other complications of CKD are mediated by oxidative stress, inflammation, and dyslipidemia. This review provides a concise overview of the nature and mechanisms of CKD-induced lipid disorders and their adverse consequences. Lipid abnormalities in end-stage renal disease are characterized by: (a) reduced serum apoA-1 and high-density lipoprotein (HDL) concentrations, impaired HDL maturation and defective HDL antioxidant, anti-inflammatory and reverse cholesterol transport properties; (b) impaired clearance of very low-density lipoprotein and chylomicrons by the muscle and adipose tissue and of their remnants by the liver leading to hypertriglyceridemia, accumulation of intermediate-density lipoprotein and chylomicron remnants, and (c) oxidative modification of LDL and lipoprotein remnants favored by their structural abnormalities, oxidative stress, and impaired HDL antioxidant activity. Together these abnormalities result in: (a) uptake of oxidized LDL and remnant particles by macrophages and resident cells in the artery wall which along with impaired HDL-mediated reverse cholesterol transport causes foam cell formation and atherosclerosis, (b) production of inflammatory mediators and reactive oxygen species by leukocytes and macrophages in response to stimulation by oxidized LDL and phospholipids leading to intensification of oxidative stress and inflammation, (c) dissemination of oxidative stress by circulating oxidized lipids and lipoproteins via lipid peroxidation chain reaction, (d) heightened injurious effects of oxidative stress and inflammation due to diminished antioxidant, anti-inflammatory and antithrombotic activities of HDL, and finally (e) impaired ability of very low-density lipoprotein and chylomicron to deliver lipid fuel to muscle and adipose tissue contributing to muscle weakness and cachexia which commonly occur in end-stage renal disease patients. Copyright © 2011 S. Karger AG, Basel. PMID: 21228589 [PubMed - indexed for MEDLINE] 995. Eur J Clin Nutr. 2011 Mar;65(3):285-97. doi: 10.1038/ejcn.2010.277. Epub 2011 Jan 12. Fatty acid-gene interactions, adipokines and obesity. Stryjecki C(1), Mutch DM. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. It is now recognized that the low-grade inflammation observed with obesity is associated with the development of a wide range of downstream complications. As such, there is considerable interest in elucidating the regulatory mechanisms underlying the production of inflammatory molecules to improve the prevention and treatment of obesity and its co-morbidities. White adipose tissue is no longer considered a passive reservoir for storing lipids, but rather an important organ influencing energy metabolism, insulin sensitivity and inflammation by the secretion of proteins, commonly referred to as adipokines. Dysregulation of several adipokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and adiponectin, contributes to the low-grade inflammation that is a hallmark of obesity. Evidence now suggests that fatty acids represent a class of molecules that can modulate adipokine production, thereby influencing inflammatory status. Although the precise molecular mechanisms by which dietary fats regulate adipokine production remain unclear, recent findings indicate that diet-gene interactions may have an important role in the transcriptional and secretory regulation of adipokines. Single-nucleotide polymorphisms in the genes encoding TNF-α, IL-6 and adiponectin can modify circulating levels of these adipokines and, subsequently, obesity-related phenotypes. This genetic variation can also alter the influence of dietary fatty acids on adipokine production. Therefore, the current review will show that it is paramount to consider both genetic information and dietary fat intake to unravel the inter-individual variability in inflammatory response observed in intervention protocols targeting obesity. PMID: 21224869 [PubMed - indexed for MEDLINE] 996. Pathol Oncol Res. 2011 Dec;17(4):785-90. doi: 10.1007/s12253-010-9352-9. Epub 2011 Jan 9. Roles of hormones and signaling molecules in describing the relationship between obesity and colon cancer. Sikalidis AK(1), Varamini B. Author information: (1)Division of Nutritional Sciences, Cornell University, 214 Savage Hall, Ithaca, NY 14853, USA. as545@cornell.edu Colon cancer represents a highly prevalent disease in the Western world. While dietary and lifestyle recommendations remain important factors in disease prevention and treatment, epidemiological data have made it clear that obesity and excess body weight remain significant risk factors for the disease. A number of potential direct and indirect relationships exist between obesity and increased risk of colon cancer. Several mechanisms which appear promising and warrant further investigation are discussed here, specifically the modifying role of insulin and insulin-like growth factors, leptin, adipose-tissue induced changes in estrogens and androgens, and inflammatory molecules. A brief review of these hormones and signaling molecules and their action in colon cancer development is described. A thorough integration and understanding of the mechanisms of action these systems exert on colonic epithelia will be important in designing studies and experiments aimed at elucidating disease etiology for prevention and treatment. PMID: 21221874 [PubMed - indexed for MEDLINE] 997. Trends Endocrinol Metab. 2011 Mar;22(3):110-6. doi: 10.1016/j.tem.2010.12.001. Epub 2011 Jan 7. Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis. Hoffman NJ(1), Elmendorf JS. Author information: (1)Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Centers for Diabetes Research, Membrane Biosciences, and Vascular Biology and Medicine, VanNuys Medical Science Building Room 308A, Indianapolis, IN 46202, USA. Solving how insulin regulates glucose transport into skeletal muscle and adipose tissue remains a fundamental challenge in biology and a significant issue in medicine. A central feature of this process is the coordinated accumulation of the glucose transporter GLUT4 into the plasma membrane. New signaling and cytoskeletal mechanisms of insulin-stimulated GLUT4 exocytosis are of emerging interest, particularly those at or just beneath the plasma membrane. This review examines signals that functionally engage GLUT4 exocytosis, considers cytoskeletal regulation of the stimulated GLUT4 itinerary, and appraises the involvement of plasma membrane parameters in GLUT4 control. We also explore how these newly-defined signaling, cytoskeletal and membrane mechanisms could be of therapeutic interest in the treatment and/or prevention of GLUT4 dysregulation in disease. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3049829 PMID: 21216617 [PubMed - indexed for MEDLINE] 998. Diabetes Metab. 2010 Oct;36 Suppl 3:S39-44. doi: 10.1016/S1262-3636(10)70465-1. Relationships between adipose tissues and brain: what do we learn from animal studies? Pénicaud L(1). Author information: (1)Centre des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS, 1324 INRA-Université de Bourgogne, Dijon, France. Luc.Pénicaud@u-bourgogne.fr Over the last decades, more and more data supporting the importance of the relationships between the brain and adipose tissues (white and brown) in regards of body weight regulation and energy homeostasis have been published. Indeed the brain via the autonomic nervous system participates to the regulation of different parameters such as the metabolic (lipolysis, lipogenesis and thermogeneis), and secretory (leptin and other adipokines) activities but also plasticity (proliferation differentiation and apoptosis) of adipose tissues. In turn the various fat pads will send information via sensory innervation of white adipose tissue as well as metabolic and hormonal signals acting directly on some brain areas. Altogether these results showed the presence of a neural feedback loop between adipose tissues and the brain which plays a major role in the regulation of energy homeostasis and as been shown to vary according to physiological and pathological states. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 21211734 [PubMed - indexed for MEDLINE] 999. Nephrol Ther. 2011 Apr;7(2):80-5. doi: 10.1016/j.nephro.2010.11.007. Epub 2011 Jan 3. [Renal consequences of obesity]. [Article in French] Laville M(1). Author information: (1)Inserm U 886, service de néphrologie, hôpital Édouard-Herriot, université de Lyon, 69437 Lyon cedex 03, France. laville@univ-lyon1.fr The steady increase in the prevalence of obesity contributes to the increase in the prevalence of chronic kidney disease, through renal damages associated with type-2 diabetes and hypertension. Obesity is also an independent risk factor for the kidney, since it is associated with an increased risk of albuminuria and glomerulosclerosis, and worsens the course of chronic kidney disease regardless of the primary renal disease. The existence of a metabolic syndrome, constant in type-2 diabetes, and associated with abdominal obesity, is not the only requirement for renal anomalies of which the translation is a functional hyperfiltration, a clinical microalbuminuria and histologically a glomerulomegaly and glomerulosclerosis. The estimated glomerular filtration rate (GFR) in obese patients is strongly influenced by the weight or indexation to body surface area, and it is logical to take into account the value of non-indexed GFR to assess renal risk and treatment effects, especially if they lead to weight loss. Hypertension is promoted by salt sensitivity, potentially reversible, and overactivity of the renin-angiotensin system (RAS) in part due to adipose tissue. The cytokines secreted by adipose tissue (adipokines), induce sympathetic hyperactivity through leptin, and low-grade inflammatory state that contributes to the development of glomerular sclerosis lesions, especially because a resistance to adiponectin. The treatment relies on weight loss, possibly through bariatric surgery, and antagonists of the RAS. Copyright © 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved. PMID: 21208837 [PubMed - indexed for MEDLINE] 1000. Curr Opin Lipidol. 2010 Dec;21(6):507-17. doi: 10.1097/MOL.0b013e32833ea912. Exercise and fat accumulation in the human liver. Magkos F(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. fmagkos@bidmc.harvard.edu PURPOSE OF REVIEW: Fat accumulation in the liver is strongly associated with metabolic dysfunction. Regular exercise improves many cardiometabolic risks factors; however, its effect on intrahepatic triglyceride (IHTG) content remains elusive. This article summarizes available data regarding the effects of exercise on IHTG. RECENT FINDINGS: Several but not all observational studies report negative associations of habitual physical activity and cardiorespiratory fitness with IHTG and the prevalence of fatty liver. Aerobic exercise training in combination with hypocaloric diet reduces IHTG by a considerable amount (20-60%), even when weight loss is mild (<5%); hence weight loss per se may not be a critical factor. Longitudinal studies involving exercise training without dietary restriction and no weight loss demonstrate that increased cardiorespiratory fitness and reduced intra-abdominal adiposity are not invariably associated with liver fat depletion, whereas relatively large exercise-induced reductions in IHTG content (20-40%) can occur even in the absence of changes in body weight, body composition, or visceral adipose tissue. Although the majority of studies have examined aerobic training, resistance exercise has also been shown to be inversely associated with the prevalence of fatty liver in humans and effectively reduces IHTG content in animals. SUMMARY: Exercise does hold promise as an effective treatment for hepatic steatosis; this field of research is still in its infancy, and there is much more to be learned. PMID: 21206340 [PubMed - indexed for MEDLINE] 1001. Exerc Sport Sci Rev. 2011 Apr;39(2):102-8. doi: 10.1097/JES.0b013e31820ac03e. The role of adenosine monophosphate kinase in remodeling white adipose tissue metabolism. Gaidhu MP(1), Ceddia RB. Author information: (1)School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. Recent evidence indicates that the enzyme adenosine monophosphate (AMP) kinase exerts important fat-reducing effects in the adipose tissue, which has created great interest in this enzyme as a potential target for obesity treatment. This review summarizes our findings that chronic AMP kinase activation remodels adipocyte glucose and lipid metabolism and enhances the ability of adipose tissue to dissipate energy within itself and reduce adiposity. PMID: 21206283 [PubMed - indexed for MEDLINE] 1002. Ann Plast Surg. 2011 Feb;66(2):210-5. doi: 10.1097/SAP.0b013e3181e6d06c. Adipose-derived stem cells for wound healing applications. Cherubino M(1), Rubin JP, Miljkovic N, Kelmendi-Doko A, Marra KG. Author information: (1)Division of Plastic Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Nonhealing wounds remain a significant challenge for plastic surgeons. More than 600,000 people suffer from venous ulcers and 1.5 to 3 million people are being treated for pressure sores every year in the United States. The use of tissue engineering techniques such as stem-cell therapy and gene therapy to improve wound healing is a promising strategy. Adipose tissue represents a source of cells that may be able to enhance wound healing. Adipose-derived stem cells (ASCs) are adult stem cells that are easily harvested and of great interest for plastic surgeons. Specifically, ASCs secrete angiogenic growth factors that can induce tissue regeneration. This review describes innovative research strategies using ASCs therapies for treatment of chronic, nonhealing wounds. PMID: 21200308 [PubMed - indexed for MEDLINE] 1003. Cell Prolif. 2011 Feb;44(1):86-98. doi: 10.1111/j.1365-2184.2010.00736.x. Adipose-derived stem cells for clinical applications: a review. Wilson A(1), Butler PE, Seifalian AM. Author information: (1)Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, UK. The use of stem cells derived from adipose tissue as an autologous and self-replenishing source for a variety of differentiated cell phenotypes, provides a great deal of promise for reconstructive surgery. In this article, we review available literature encompassing methods of extraction of pluripotent adipose stem cells (ASCs) from lipoaspirate locations, their storage, options for culture, growth and differentiation, cryopreservation and its effect on stem cell survival and proliferation, and new technologies involving biomaterials and scaffolds. We will conclude by assessing potential avenues for developing this incredibly promising field. © 2010 Blackwell Publishing Ltd. PMID: 21199013 [PubMed - indexed for MEDLINE] 1004. Wiley Interdiscip Rev Syst Biol Med. 2011 Nov-Dec;3(6):666-80. doi: 10.1002/wsbm.141. Epub 2010 Dec 31. Human cardiomyogenesis and the need for systems biology analysis. Young DA(1), DeQuach JA, Christman KL. Author information: (1)Department of Bioengineering, University of California, San Diego, CA, USA. Cardiovascular disease remains the leading cause of death in the Western world and myocardial infarction is one of the primary facets of this disease. The limited natural self-renewal of cardiac muscle following injury and restricted supply of heart transplants has encouraged researchers to investigate other means to stimulate regeneration of damaged myocardium. The plasticity of stem cells toward multiple lineages offers the potential to repair the heart following injury. Embryonic stem cells have been extensively studied for their ability to differentiate into early cardiomyocytes, however, the pathway has only been partially defined and inadequate efficiency limits their clinical applicability. Some studies have shown cardiomyogenesis from adult mesenchymal stem cells, from both bone marrow and adipose tissue, but their differentiation pathway remains poorly detailed and these results remain controversial. Despite promising results using stem cells in animal models of cardiac injury, the driving mechanisms behind their differentiation down a cardiomyogenic pathway have yet to be determined. Currently, there is a paucity of information regarding cardiomyogenesis on the systemic level. Stem cell differentiation results from multiple signaling parameters operating in a tightly regulated spatiotemporal pattern. Investigating this phenomenon from a systems biology perspective could unveil the abstruse mechanisms controlling cardiomyogenesis that would otherwise require extensive in vitro testing. Copyright © 2010 John Wiley & Sons, Inc. PMCID: PMC3282989 PMID: 21197666 [PubMed - indexed for MEDLINE] 1005. Front Biosci (Schol Ed). 2011 Jan 1;3:352-71. Physiological importance and control of non-shivering facultative thermogenesis. Silva JE(1). Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baystate Medical Center and Pioneer Valley Life Sciences Institute, Western Campus Tufts University School of Medicine, Springfield, Massachusetts 01199, USA. j.enrique.silva@baystatehealth.org This review examines general and evolutionary aspects of temperature homeostasis, focusing on mammalian facultative or adaptive thermogenesis and its control by the sympathetic nervous system and hormones. Thyroid hormone acquired a new role with the advent of homeothermy enhancing facultative thermogenesis by interacting synergistically with the sympathetic nervous system, and directly increasing basal metabolic rate (obligatory thermogenesis). Facultative thermogenesis is triggered by cold. The major site of facultative thermogenesis in mammals is brown adipose tissue, endowed with abundant mitochondria rich in a protein called uncoupling protein-1. This protein can uncouple phosphorylation in a controlled manner, releasing the energy of the proton-motive force as heat. Its synthesis and function are regulated synergistically by the sympathetic nervous system and thyroid hormone and modulated by other hormones directly, or indirectly, modulating sympathetic activity as well as thyroid hormone secretion and activation in brown adipose tissue. Alternate, evolutionary older forms of facultative thermogenesis activated in transgenic mice with disabled brown adipose tissue thermogenesis reveal this latter as the culmination of energy-efficient facultative thermogenesis. PMID: 21196381 [PubMed - indexed for MEDLINE] 1006. Front Biosci (Schol Ed). 2011 Jan 1;3:69-81. Adipose tissue as a stem cell source for musculoskeletal regeneration. Gimble JM(1), Grayson W, Guilak F, Lopez MJ, Vunjak-Novakovic G. Author information: (1)Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA. gimblejm@pbrc.edu Adipose tissue is an abundant, easily accessible, and reproducible cell source for musculo-skeletal regenerative medicine applications. Initial derivation steps yield a heterogeneous population of cells of stromal vascular fraction (SVF) cells. Subsequent adherent selection of the SVF results in a relatively homogeneous population of adipose-derived stromal/stem cells (ASCs) capable of adipogenic, chondrogenic, myogenic, and osteogenic differentiation in vitro on scaffolds in bioreactors and in vivo in pre-clinical animal models. Unlike hematopoietic cells, ASCs do not elicit a robust lymphocyte reaction and instead release immunosuppressive factors, such as prostaglandin E2. These immunomodulatory features suggest that allogeneic and autologous ASCs will engraft successfully for tissue regeneration purposes. The differentiation and expansion potential of ASCs can be modified by growth factors, bio-inductive scaffolds, and bioreactors providing environmental control and biophysical stimulation. Gene therapy approaches using lentiviral transduction can be used to direct differentiation of ASCs to particular lineages. We discuss the utility of ASCs for musculo-skeletal tissue repair and some of the technologies that can be implemented to unlock the full regenerative potential of these highly valuable cells. PMCID: PMC3636575 PMID: 21196358 [PubMed - indexed for MEDLINE] 1007. Front Biosci (Landmark Ed). 2011 Jan 1;16:1663-74. Inflammatory markers and cardiovascular risk in the metabolic syndrome. Espinola-Klein C(1), Gori T, Blankenberg S, Munzel T. Author information: (1)2nd Department of Internal Medicine, University Medical Center of the Johannes, Gutenberg-University Mainz, Germany. espinola@uni-mainz.de Elevated blood glucose, obesity, high blood pressure, elevated triglycerides and low high density lipoprotein (HDL) cholesterol are well accepted risk factors in the development of coronary artery disease. Clustering of at least three of these factors in an individual is defined as metabolic syndrome (MetS). Obesity is a central pathological mechanism in the disease and it is expected that the incidence of this condition will increase dramatically within the next years. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules, the so called adipokines. In the setting of obesity, the over-production of proinflammatory and pro-thrombotic adipokines is associated with insulin resistance. This mechanism represents the pathophysiological basis for the development of MetS. Inflammation has a central role in the pathogenesis of MetS and in mediating its impact on the development of cardiovascular disease. Knowledge of these mechanisms has relevance in the context of preventive and therapeutic strategies. PMID: 21196255 [PubMed - indexed for MEDLINE] 1008. Front Biosci (Landmark Ed). 2011 Jan 1;16:1634-50. Associations between adipokines and obesity-related cancer. Paz-Filho G(1), Lim EL, Wong ML, Licinio J. Author information: (1)Department of Translational Medicine, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Canberra, Australia. There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies. PMID: 21196253 [PubMed - indexed for MEDLINE] 1009. Front Biosci (Landmark Ed). 2011 Jan 1;16:1589-608. Brown adipose tissue growth and development: significance and nutritional regulation. Satterfield MC(1), Wu G. Author information: (1)Department of Animal Science, Texas A and M University, College Station, TX 77843-2471, USA. csatterfield@tamu.edu The last decade has witnessed a profound resurgence in brown adipose tissue (BAT) research. The need for such a dramatic increase stems from the ever-growing trend toward global obesity. Indeed, it is currently estimated that rates of obesity in developed countries such as the United States exceed 35% of the population (1). The higher incidence of obesity is associated with increased prevalence of the metabolic syndrome including diabetes, hypertension, and coronary heart disease, among others (1, 2). BAT holds great promise in combating obesity given its unprecedented metabolic capacity. Leading the way has been recent studies, which conclusively demonstrate significant quantities of functional BAT in adult humans (3-7). These findings have been complimented by elegant studies elucidating the developmental origin of the brown adipocyte and the transcriptional regulation involved in its differentiation. This review will attempt to meld the wealth of new information regarding BAT development with established literature to provide an up to date synopsis of what is known and thus a framework for future research directions. PMID: 21196250 [PubMed - indexed for MEDLINE] 1010. Front Biosci (Landmark Ed). 2011 Jan 1;16:1233-60. Brown fat biology and thermogenesis. Richard D(1), Picard F. Author information: (1)Quebec Heart And Lung Institute Research Center and Laval University Interdisciplinary Group In Obesity Research, 2725 Chemin Sainte-Foy, Quebec G1V 4G5, Canada. denis.richard@criucpq.ulaval.ca Brown fat (brown adipose tissue, BAT) primary function is to produce heat. There is now compelling evidence to indicate that brown fat cells in some BAT depots share their predecessor cells with myocytes. Brown adipocyte (trans)differentiation depends on various receptors / transcription factors that include peroxisome proliferator-activated receptor g (PPARgamma), PPARgamma-coactivator-1alpha (PGC1alpha), PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16), CCAAT/enhancer-binding protein beta (C/EBP-beta) and bone morphogenetic protein 7 (BMP7). Such mediators also help BAT to acquire its thermogenic phenotype, which is essentially conferred by uncoupling protein 1 (UCP1). UCP1 uncouples adenosine-5'-triphosphate (ATP) synthesis from substrate oxidation in brown adipocytes. Its activity depends on the availability of fatty acids delivered upon BAT's beta)-adrenergic activation, which, physiologically, ensues from the sympathetic nervous system (SNS) activation of the tissue. SNS-mediated thermogenesis is largely controlled by the hypothalamus and brainstem. Recently, positron emission tomography / computed tomography (PET/CT) scanning investigations have revealed the presence in adult humans of important neck and shoulder BAT depots. That finding has contributed to reinstate a strong interest for brown adipocyte biology and thermogenesis. This review aims at the unique biology of BAT with the emphasis put on the recent discoveries regarding the brown adipocyte development and function. PMID: 21196229 [PubMed - indexed for MEDLINE] 1011. Front Biosci (Landmark Ed). 2011 Jan 1;16:74-104. Central neural pathways for thermoregulation. Morrison SF(1), Nakamura K. Author information: (1)Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. morrisos@ohsu.edu Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction. PMCID: PMC3051412 PMID: 21196160 [PubMed - indexed for MEDLINE] 1012. J Ren Nutr. 2011 Jan;21(1):87-91. doi: 10.1053/j.jrn.2010.10.014. Adiponectin and leptin in chronic kidney disease: causal factors or mere risk markers? Zoccali C(1), Mallamaci F. Author information: (1)Unità Operativa di Nefrologia, Dialisi e Trapianto Renale Ospedali Riuniti and IBIM-CNR, Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell'Ipertensione Arteriosa, Reggio Calabria, Italy. carmine.zoccali@tin.it Experimental and clinical evidence implicates the 2 major adipose tissue cytokines, adiponectin (ADPN) and leptin (LEP), in renal damage. The interpretation of the link between these cytokines and renal outcomes is strictly context-sensitive. Albuminuria is a feature of renal disease in the ADPN null mouse and this alteration can be reversed by supplementing ADPN. Accordingly, in young normoalbuminuric obese individuals low ADPN is associated with higher albumin excretion rate. Conversely, high ADPN is associated with more severe proteinuria in chronic kidney disease patients, possibly underlying a protective response aimed at countering the high renal and cardiovascular risk of high proteinuria. LEP administration ameliorates insulin resistance in insulin-resistant patients with hereditary lipodystrophy--a disease characterized by severe LEP deficiency and renal disease--and the same intervention reverses both, insulin resistance and renal damage in a mouse model of LEP deficiency. However, LEP may exert noxious effects on the kidney (particularly renal fibrosis) if administered in conditions of LEP sufficiency or excess. Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 21195927 [PubMed - indexed for MEDLINE] 1013. J Ren Nutr. 2011 Jan;21(1):2-6. doi: 10.1053/j.jrn.2010.10.008. Fighting protein-energy wasting in chronic kidney disease: a challenge of complexity. Guarnieri G(1), Barazzoni R. Author information: (1)Department of Medical, Technological and Translational Sciences, Clinica Medica, University of Trieste, Ospedale Cattinara, Strada di Fiume 447, Trieste, Italy. guarnier@units.it Chronic uremia is often characterized by wasting of muscle and fat mass, which has been defined as protein-energy wasting (PEW), and is responsible for substantial worsening of patient outcome in terms of morbidity and mortality, mostly from cardiovascular events. Despite major advances in patient treatment, nutritional outcome in patients with end-stage renal disease has not improved substantially in recent years. Extensive research in this field has provided plausible explanations for this limitation by indicating that the pathogenesis of PEW in kidney disease is complex and multifactorial. Complexity involves underlying metabolic alterations, including inflammation, oxidative stress, and insulin resistance. In addition, patient heterogeneity is increasing with large numbers of obese individuals as a result of the ongoing obesity epidemics. Several tissues are involved in cross-talk and contribute to metabolic derangements, including adipose tissue, the gut, and the central nervous system, with novel mediators including the gastric hormone ghrelin. Acknowledging its complex pathogenesis may favor the development of novel and more effective therapeutic tools for PEW. These should ideally be effective in treating the underlying common mechanisms of wasting, which appear to include oxidative stress, inflammation, and insulin resistance. Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 21195908 [PubMed - indexed for MEDLINE] 1014. Antioxid Redox Signal. 2011 Jul 15;15(2):461-83. doi: 10.1089/ars.2010.3848. Epub 2011 May 5. Adipokines and redox signaling: impact on fatty liver disease. Parola M(1), Marra F. Author information: (1)Dipartimento di Medicina e Oncologia Sperimentale and Centro Interuniversitario di Fisiopatologia Epatica Università degli Studi di Torino, Turin, Italy. Comment in Antioxid Redox Signal. 2011 Jul 15;15(2):421-4. Adipokines (adipose tissue cytokines) are polypeptide factors secreted by adipose tissue in a highly regulated manner. The 'classical' adipokines (leptin, adiponectin, and resistin) are expressed only by adipocytes, but other adipokines have been shown to be released by resident and infiltrating macrophages, as well as by components of the vascular stroma. Indeed, adipose tissue inflammation is known to be associated with a modification in the pattern of adipokine secretion. Several studies indicate that adipokines can interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Moreover, plasma levels of adipokines have been investigated in patients with nonalcoholic fatty liver disease in order to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. In this Forum article, we provide a review of recent data that suggest a significant role for oxidative stress, reactive oxygen species, and redox signaling in mediating actions of adipokines that are relevant in the pathogenesis of nonalcoholic fatty liver disease, including hepatic insulin resistance, inflammation, and fibrosis. PMID: 21194387 [PubMed - indexed for MEDLINE] 1015. Biochim Biophys Acta. 2011 Aug;1812(8):919-28. doi: 10.1016/j.bbadis.2010.12.016. Epub 2010 Dec 28. Role of nuclear receptor corepressor RIP140 in metabolic syndrome. Rosell M(1), Jones MC, Parker MG. Author information: (1)Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of Medicine, Hammersmith Campus 158 Du Cane Road, W12 0NN, UK. m.parker@imperial.ac.uk Obesity and its associated complications, which can lead to the development of metabolic syndrome, are a worldwide major public health concern especially in developed countries where they have a very high prevalence. RIP140 is a nuclear coregulator with a pivotal role in controlling lipid and glucose metabolism. Genetically manipulated mice devoid of RIP140 are lean with increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Moreover, white adipocytes with targeted disruption of RIP140 express genes characteristic of brown fat including CIDEA and UCP1 while skeletal muscles show a shift in fibre type composition enriched in more oxidative fibres. Thus, RIP140 is a potential therapeutic target in metabolic disorders. In this article we will review the role of RIP140 in tissues relevant to the appearance and progression of the metabolic syndrome and discuss how the manipulation of RIP140 levels or activity might represent a therapeutic approach to combat obesity and associated metabolic disorders. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. Copyright © 2010 Elsevier B.V. All rights reserved. PMCID: PMC3117993 PMID: 21193034 [PubMed - indexed for MEDLINE] 1016. Compr Physiol. 2011 Jan;1(1):263-82. doi: 10.1002/cphy.c100017. Environmental perturbations: Obesity. Shore SA(1). Author information: (1)Dept. of Env. Health, Harvard School of Public Health, USA. sshore@hsph.harvard.edu Obesity currently affects about one-third of the U.S. population, while another one-third is overweight. The importance of obesity for certain conditions such as heart disease and type 2 diabetes is well appreciated. The effects of obesity on the respiratory system have received less attention and are the subject of this article. Obesity alters the static mechanical properties of the respiratory system leading to a reduction in the functional residual capacity (FRC) and the expiratory reserve volume (ERV). There is substantial variability in the effects of obesity on FRC and ERV, at least some of which is related to the location rather than the total mass of adipose tissue. Obesity also results in airflow obstruction, which is only partially attributable to breathing at low lung volume, and can also promote airway hyperresponsiveness and asthma. Hypoxemia is common is obesity and correlates well with FRC, as well as with measures of abdominal obesity. However, obese subjects are usually eucapnic, indicating that hypoventilation is not a common cause of their hypoxemia. Instead, hypoxemia results from ventilation-perfusion mismatch caused by closure of dependent airways at FRC. Many obese subjects complain of dyspnea either at rest or during exertion, and the dyspnea score also correlates with reductions in FRC and ERV. Weight reduction should be encouraged in any symptomatic obese individual, since virtually all of the respiratory complications of obesity improve with even moderate weight loss. © 2011 American Physiological Society. PMCID: PMC4061695 PMID: 23737172 [PubMed - indexed for MEDLINE] 1017. Ital J Anat Embryol. 2011;116(3):127-38. The fascia: the forgotten structure. Stecco C(1), Macchi V, Porzionato A, Duparc F, De Caro R. Author information: (1)Section of Anatomy, Department of Human Anatomy and Physiology, University of Padova, Padova, Italy. This paper examines the main characteristics of the human fascial system, considered in its three-dimensional continuity. To better understand the anatomy of the human fascial system, a simple diagram of the subcutaneous tissue must be borne in mind. From the skin to the deepest plane, we find the superficial fascia, dividing the subcutaneous tissue into two fibroadipose layers, superficial and deep, and the deep fascia, which envelops all the muscles of the body, showing different characteristics according to region. Under the deep fascia is the epimysium, occurring in the limbs and some regions of the trunk. Skin ligaments connect the superficial fascia to the skin and to the deep fascia, forming a three-dimensional network among the fat lobules. The typical features of the superficial and deep fasciae and their relationships to nerves, vessels and muscles are reported here, highlighting the possible role of the deep fascia in proprioception and peripheral motor coordination. The main features of the fasciae with imaging techniques are also discussed. This knowledge may contribute to clinicians' understanding of the myofascial system and the role which the deep fasciae may play in musculoskeletal dysfunctions. PMID: 22852442 [PubMed - indexed for MEDLINE] 1018. Front Endocrinol (Lausanne). 2011 Dec 21;2:84. doi: 10.3389/fendo.2011.00084. eCollection 2011. Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ. Festuccia WT(1), Blanchard PG, Deshaies Y. Author information: (1)Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo, Brazil. Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed. PMCID: PMC3356105 PMID: 22654830 [PubMed] 1019. Front Endocrinol (Lausanne). 2011 Oct 17;2:52. doi: 10.3389/fendo.2011.00052. eCollection 2011. Human brown fat and obesity: methodological aspects. van Marken Lichtenbelt W(1). Author information: (1)Department of Human Biology, School for Nutrition and Toxicology and Metabolism, Maastricht University Medical Center Maastricht, Netherlands. Much is known about brown adipose tissue (BAT) in rodents. Its function is to generate heat in response to low environmental temperatures and to diet or overfeeding. The knowledge about BAT in humans is still rather limited despite the recent rediscovery of its functionality in adults. This review highlights the information available on the contribution of BAT in increasing human energy expenditure in relation to obesity. Besides that methodological aspects will be discussed that need special attention in order to unravel the heat producing capacity of human BAT, the recruitment of the tissue, and its functionality. PMCID: PMC3356108 PMID: 22654813 [PubMed] 1020. Rev Diabet Stud. 2011 Winter;8(4):446-53. doi: 10.1900/RDS.2011.8.446. Epub 2012 Feb 10. Beta-cell preservation…Is weight loss the answer? Mazza AD(1), Pratley RE, Smith SR. Author information: (1)Florida Hospital Diabetes Institute, Winter Park, Orlando, Florida 32789, USA. angela.mazza.do@flhosp.org Obesity is associated with an increased risk of type 2 diabetes (T2D). Pancreatic beta-cell failure is an early event in the development of glucose dysregulation and diabetes. Interventions to halt beta-cell failure in T2D include diet modification, exercise, and use of pharmacologic agents. There is evidence that abdominal obesity may contribute to diabetes through insulin resistance and beta-cell impairment. Pivotal long-term studies into the prevention of T2D have shown the importance of weight loss beside diet, lifestyle, and medication. The Finnish Diabetes Prevention Program (DPP) showed that weight loss gradually reduces the risk of diabetes, and that even modest weight loss can significantly reduce the incidence of T2D. Similarly, in the US DPP, weight loss as part of intensive lifestyle modification was the major factor in reducing the incidence of T2D in high-risk subjects, being more effective than drug intervention. While understanding the relationship between obesity and diabetes is complex, we know that weight loss has positive effects on adipose tissue. It causes an increase in the beneficial fat cell hormone adiponectin, and a decrease in adipose tissue inflammation. Also, it is associated with reduced insulin resistance and a consequential reduction in glucolipotoxicity, which can improve beta-cell function. In summary, weight loss improves glycemic control and thereby mitigates diabetes symptoms and complications, possibly through the preservation of beta-cell function. Therefore, efforts to prevent diabetes and preserve beta-cell function in patients with T2D should more consequently emphasize and target weight loss. PMCID: PMC3359689 PMID: 22580726 [PubMed - indexed for MEDLINE] 1021. J Nutr Sci Vitaminol (Tokyo). 2011;57(6):383-93. The optimal dietary fat to carbohydrate ratio to prevent obesity in the Japanese population: a review of the epidemiological, physiological and molecular evidence. Ezaki O(1). Author information: (1)Department of Nutritional Science, National Institute of Health and Nutrition, Tokyo, Japan. ezaki@nih.go.jp The prevention of obesity, which leads to diabetes and other diseases, is a major concern for public health. There might be an optimal dietary fat to carbohydrate ratio for prevention and treatment of obesity. According to the Japanese Dietary Reference Intakes (RDA) for 2010, the optimal fat intake is 20-30% of energy for ages 1-29 y and 20-25% for ages 30 y and over. Upper boundary values of this recommendation were the median of the percentage of energy from dietary fat in Japanese. In a systematic review to estimate the optimal dietary fat to carbohydrate ratio, it was found that obese subjects with hyperinsulinemia (or insulin resistance) lost more weight on a mild low-carbohydrate (LC) (or low-glycemic load diet; 40% carbohydrate, 30-35% fat) than on a low-fat (LF) diet (55-60% carbohydrate, 20% fat), whereas those without hyperinsulinemia showed the opposite. In non-obese primarily insulin-sensitive subjects, decreasing fat rather than carbohydrate intake is generally more effective to prevent obesity. Physiological and molecular evidence supports this conclusion. Increased carbohydrate intake, especially in high-glycemic food, leads to postprandial hyperglycemia and hyperinsulinemia, which are exaggerated in obese insulin-resistant subjects. Even in an insulin-resistant state, insulin is able to stimulate fatty acid synthesis in liver, activate lipoprotein lipase, and prevent lipolysis in adipose tissues, which all facilitate adipose tissue enlargement. Optimal dietary fat to carbohydrate ratio may differ in populations depending on their prevalence for obesity. Because the prevalence of overweight/obesity in Japanese is low, a LF diet is recommended in the general population. PMID: 22472280 [PubMed - indexed for MEDLINE] 1022. Surg Today. 2011 Jan;41(1):18-23. doi: 10.1007/s00595-010-4415-9. Epub 2010 Dec 30. Human adipose-derived stem cells: potential clinical applications in surgery. Utsunomiya T(1), Shimada M, Imura S, Morine Y, Ikemoto T, Mori H, Hanaoka J, Iwahashi S, Saito Y, Iwaguro H. Author information: (1)Cancer Clinical Cooperation Center, Tokushima University Hospital, 3-18-15 kuramoto-cho, Tokushima 770-8503, Japan. Regenerative medicine is emerging as a rapidly evolving field of research and therapeutics. Stem cells hold great promise for future translational research and clinical applications in many fields. Much research has focused on mesenchymal stem cells isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells. By contrast, adipose tissue represents an abundant and easily accessible source of adult stem cells, termed adipose-derived stem cells (ADSCs), with the ability to equally differentiate along multiple lineage pathways. These stem cells have angiogenic properties, possibly because of their secretion of cytokines. They may also play a role in healing acute and chronic tissue damage. Subsequently, they have a wide range of potential clinical implications. This article reviews the potential preclinical and clinical applications of mesenchymal stem cells, especially ADSCs, in surgery. PMID: 21191687 [PubMed - indexed for MEDLINE] 1023. Discov Med. 2010 Dec;10(55):543-52. Hormonal interactions between gut and brain. Zac-Varghese S(1), Tan T, Bloom SR. Author information: (1)Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom. No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment. PMID: 21189225 [PubMed - indexed for MEDLINE] 1024. Biochim Biophys Acta. 2012 Jan;1822(1):14-20. doi: 10.1016/j.bbadis.2010.12.012. Epub 2010 Dec 23. Mast cells and metabolic syndrome. Zhang J(1), Shi GP. Author information: (1)Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Mast cells are critical effectors in the development of allergic diseases and in many immunoglobulin E-mediated immune responses. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymase and tryptase. Like macrophages and T lymphocytes, mast cells are inflammatory cells, and they participate in the pathogenesis of inflammatory diseases such as cardiovascular complications and metabolic disorders. Recent observations suggested that mast cells are involved in insulin resistance and type 2 diabetes. Data from animal models proved the direct participation of mast cells in diet-induced obesity and diabetes. Although the mechanisms by which mast cells participate in these metabolic diseases are not fully understood, established mast cell pathobiology in cardiovascular diseases and effective mast cell inhibitor medications used in pre-formed obesity and diabetes in experimental models offer hope to patients with these common chronic inflammatory diseases. This article is part of a Special Issue entitled: Mast cells in inflammation. Copyright © 2010 Elsevier B.V. All rights reserved. PMCID: PMC3136576 PMID: 21185370 [PubMed - indexed for MEDLINE] 1025. Adv Drug Deliv Rev. 2011 Apr 30;63(4-5):342-51. doi: 10.1016/j.addr.2010.12.004. Epub 2010 Dec 22. Regeneration of cartilage and bone by defined subsets of mesenchymal stromal cells--potential and pitfalls. Aicher WK(1), Bühring HJ, Hart M, Rolauffs B, Badke A, Klein G. Author information: (1)Center for Regenerative Medicine, University of Tübingen Hospital, Eberhard-Karls-University, Tübingen, Germany. aicher@uni-tuebingen.de Mesenchymal stromal cells, also referred to as mesenchymal stem cells, can be obtained from various tissues. Today the main source for isolation of mesenchymal stromal cells in mammals is the bone marrow. Mesenchymal stromal cells play an important role in tissue formation and organogenesis during embryonic development. Moreover, they provide the cellular and humoral basis for many processes of tissue regeneration and wound healing in infancy, adolescence and adulthood as well. There is increasing evidence that mesenchymal stromal cells from bone marrow and other sources including term placenta or adipose tissue are not a homogenous cell population. Only a restricted number of appropriate stem cells markers have been explored so far. But routine preparations of mesenchymal stromal cells contain phenotypically and functionally distinct subsets of stromal cells. Knowledge on the phenotypical characteristics and the functional consequences of such subsets will not only extend our understanding of stem cell biology, but might allow to develop improved regimen for regenerative medicine and wound healing and novel protocols for tissue engineering as well. In this review we will discuss novel strategies for regenerative medicine by specific selection or separation of subsets of mesenchymal stromal cells in the context of osteogenesis and bone regeneration. Mesenchymal stromal cells, which express the specific cell adhesion molecule CD146, also known as MCAM or MUC18, are prone for bone repair. Other cell surface proteins may allow the selection of chondrogenic, myogenic, adipogenic or other pre-determined subsets of mesenchymal stromal cells for improved regenerative applications as well. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 21184789 [PubMed - indexed for MEDLINE] 1026. FEBS Lett. 2011 Apr 6;585(7):967-72. doi: 10.1016/j.febslet.2010.12.015. Epub 2010 Dec 21. Re-evaluating the general(ized) roles of AMPK in cellular metabolism. Mantovani J(1), Roy R. Author information: (1)Department of Biology-DBRI, McGill University, Montreal, QC, Canada. AMPK is a protein kinase activated by various cellular stresses such as glucose deprivation, hypoxia or exercise. Despite having been studied for decades only a limited number of targets have been well described in tissues as varied as liver, muscle, and adipose tissue. Recent studies have shown that AMPK does not function in a similar manner, or through identical targets, in all cellular situations, posing challenges to some accepted paradigms describing AMPK function. A combination of genetic models and cell biological analysis of AMPK function in specific cell/developmental/environmental contexts will be required to accurately complement our understanding of the role(s) of AMPK in cancer, diabetes and other diseases. Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved. PMID: 21182839 [PubMed - indexed for MEDLINE] 1027. Curr Med Chem. 2011;18(5):725-32. Toward a biochemical diagnosis of NASH: insights from pathophysiology for distinguishing simple steatosis from steatohepatitis. Yilmaz Y(1), Ulukaya E. Author information: (1)Department of Gastroenterology, Marmara University, School of Medicine, 34662 Altunizade, Istanbul, Turkey. yusufyilmaz@uludag.edu.tr With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development. PMID: 21182485 [PubMed - indexed for MEDLINE] 1028. World J Cardiol. 2010 Nov 26;2(11):370-6. doi: 10.4330/wjc.v2.i11.370. Emerging role of adipokines as mediators in atherosclerosis. Zhang H(1), Cui J, Zhang C. Author information: (1)Hanrui Zhang, Jian Cui, Cuihua Zhang, Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, United States. Atherosclerotic cardiovascular disease is a major health problem around the world. Obesity is a primary risk factor for atherosclerosis and is associated with increased morbidity and mortality of cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Adipokines are cytokines, chemokines and hormones secreted by adipose tissue that couple the regulation of lipid accumulation, inflammation, and atherogenesis, and therefore serve to link obesity with cardiovascular disorders. Obesity-related disorders including metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with dysregulated adipokine(s) expression. Recent studies demonstrate the proinflammatory effects as well as atherogenic properties of adipokines. Adipokines also participate in the regulation of endothelial function, which is an early event in atherosclerosis. By contrast, adiponectin, an adipocyte-derived hormone, exerts anti-inflammatory, anti-atherogenic and vascular protective effects. Furthermore, there is an interactive association among adipokines, by which adipokines reciprocally regulate each other's expression. Understanding this interplay may reveal plausible mechanisms for treating atherosclerosis and coronary heart disease by modulating adipokine(s) expression. In this review, we discuss insights into the role and the therapeutic potential of adipokines as mediators of atherosclerosis. PMCID: PMC3006473 PMID: 21179304 [PubMed] 1029. Nat Rev Endocrinol. 2011 Feb;7(2):98-107. doi: 10.1038/nrendo.2010.214. Epub 2010 Dec 21. Prospective influences of circadian clocks in adipose tissue and metabolism. Gimble JM(1), Sutton GM, Bunnell BA, Ptitsyn AA, Floyd ZE. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu Circadian rhythms make a critical contribution to endocrine functions that involve adipose tissue. These contributions are made at the systemic, organ and stem cell levels. The transcription factors and enzymes responsible for the maintenance of circadian rhythms in adipose depots and other peripheral tissues that are metabolically active have now been identified. Furthermore, the circadian regulation of glucose and lipid metabolism is well-established. Animal and human models provide strong evidence that disturbances in circadian pathways are associated with an increased risk of type 2 diabetes mellitus, obesity and their comorbidities. Thus, circadian mechanisms represent a novel putative target for therapy in patients with metabolic diseases. PMID: 21178997 [PubMed - indexed for MEDLINE] 1030. J Exp Biol. 2011 Jan 15;214(Pt 2):242-53. doi: 10.1242/jeb.050989. Nonshivering thermogenesis and its adequate measurement in metabolic studies. Cannon B(1), Nedergaard J. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm SE-106 91, Sweden. barbara.cannon@wgi.su.se Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance. PMID: 21177944 [PubMed - indexed for MEDLINE] 1031. Clin Nephrol. 2011 Jan;75(1):26-33. The role of adiponectin in metabolic and vascular disease: a review. Cui J(1), Panse S, Falkner B. Author information: (1)Department of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA. Adiponectin is a protein secreted by adipose tissue. Unlike other adipocytokines produced by adipose tissue, adiponectin appears to have anti-inflammatory, anti-diabetic, and anti-atherogenic properties. Although secreted solely by adipose tissue, plasma levels of adiponectin are generally negatively related to total adipose mass; with higher plasma adiponectin levels in lean individuals and lower adiponectin levels in obese individuals. Plasma concentrations of adiponectin are lower in patients with insulin resistance compared to insulin sensitive patients; and lower in patients with diabetes compared to non-diabetics. A similar inverse relationship of plasma adiponectin level has been reported with hypertension (HTN), blood pressure level, and albuminuria. However, in chronic kidney disease (CKD) marked elevations in plasma adiponectin concentrations have been described. Plasma adiponectin levels are markedly elevated among patients with end-stage renal disease and are lower following kidney transplantation. Considering the inverse relationship of plasma adiponectin with renal function, the cardiovascular protective role of adiponectin in patients with CKD remains controversial. Further research on the distribution and function of different circulating fractions of adiponectin in patients with CKD will be needed in order to determine if adiponectin is a useful biomarker in patients with CKD. PMID: 21176748 [PubMed - indexed for MEDLINE] 1032. Eur J Med Res. 2010 Nov 4;15 Suppl 2:147-51. Adiponectin as a biomarker of the metabolic syndrome in children and adolescents. Pyrzak B(1), Ruminska M, Popko K, Demkow U. Author information: (1)Department of Pediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland. beata.pyrzak@wum.edu.pl The prevalence of obesity in children and adolescents has been increasing worldwide. As in adults, childhood obesity is closely related to hypertension, dyslipidemia, type 2 diabetes, and insulin resistance (IR) syndrome. Moreover, obese children have been found to be at increased risk of becoming obese adults. Obese children and adolescents tend to develop serious medical and psychosocial complications and also are at greater risk morbidity and mortality in adulthood. The molecular basis of the pathogenesis of obesity-linked disorders has not been fully elucidated. Adipose tissue serves not only as an energy storage organ, but also as an endocrine organ. It releases many factors with autocrine, paracrine and endocrine functions. Adipokines such as leptin, resistin, tumor necrosis factor-α, interleukin-6, adipsin, visfatin, and adiponectin are biologically active molecules produced by adipose tissue. They play a role in energy homeostasis, and in glucose and lipid metabolism. Adiponectin level, unlike that of other adipocytokines, is decreased in obesity and increased after weight reduction. Adiponectin has been associated with both central obesity and increased visceral adipose tissue and it has anti-inflammatory, anti-atherogenic, and potent insulin-sensitizing (anti-diabetic) effects. PMCID: PMC4360280 PMID: 21147643 [PubMed - indexed for MEDLINE] 1033. Prog Biophys Mol Biol. 2011 Jul;106(1):307-14. doi: 10.1016/j.pbiomolbio.2010.12.004. Epub 2010 Dec 17. Periconceptional nutrition and the early programming of a life of obesity or adversity. Zhang S(1), Rattanatray L, McMillen IC, Suter CM, Morrison JL. Author information: (1)The Sansom Institute of Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 50000, Australia. Women entering pregnancy with a high body weight and fat mass have babies at increased risk of becoming overweight or obese in childhood and later life. It is not known, whether exposure to a high level of maternal nutrition before pregnancy and exposure to a high transplacental nutrient supply in later pregnancy act through similar mechanisms to program later obesity. Using the pregnant sheep we have shown that maternal overnutrition in late pregnancy results in an upregulation of PPARγ activated genes in fetal visceral fat and a subsequent increase in the mass of subcutaneous fat in the postnatal lamb. Exposure to maternal overnutrition during the periconceptional period alone, however, results in an increase in total body fat mass in female lambs only with a dominant effect on visceral fat depots. Thus the early programming of later obesity may result from 'two hits', the first occurring as a result of maternal overnutrition during the periconceptional period and the second occurring as a result of increased fetal nutrition in late pregnancy. Whilst a short period of dietary restriction during the periconceptional period reverses the impact of periconceptional overnutrition on the programming of obesity, it also results in an increased lamb adrenal weight and cortisol stress response, together with changes in the epigenetic state of the insulin like growth factor 2 (IGF2) gene in the adrenal. Thus, not all of the effects of dietary restriction in overweight or obese mother in the periconceptional period may be beneficial in the longer term. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 21168433 [PubMed - indexed for MEDLINE] 1034. J Plast Reconstr Aesthet Surg. 2011 Aug;64(8):985-92. doi: 10.1016/j.bjps.2010.11.018. Epub 2010 Dec 17. Liposuction: a review of principles and techniques. Berry MG(1), Davies D. Author information: (1)The Institute of Cosmetic & Reconstructive Surgery, London W1G 8EN, United Kingdom. enquiries@aestheticus.co.uk For one of the most commonly performed aesthetic procedures, liposuction has a somewhat mixed reputation. This may result from suboptimal technical comprehension and/or poor patient selection. It has also attracted strong commercial pressure from manufacturers of new, sometimes less assiduously-evaluated, technologies. Liposuction is not a panacea for obesity and patients are not always cognisant of this. On the other hand, it can produce highly satisfactory outcomes for well-selected patients and anatomical areas when performed by appropriately-trained operators using properly selected technologies. Although introduced by the Europeans, liposuction was enthusiastically adopted by the North Americans, yet seems to have excited little scientific interest in the UK, despite widespread use. Given the numerous techniques and recent advances, a review may be timely. Copyright © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. PMID: 21168378 [PubMed - indexed for MEDLINE] 1035. Adv Drug Deliv Rev. 2011 Apr 30;63(4-5):375-8. doi: 10.1016/j.addr.2010.12.003. Epub 2010 Dec 15. From tissue engineering to regenerative medicine in urology--the potential and the pitfalls. Feil G(1), Daum L, Amend B, Maurer S, Renninger M, Vaegler M, Seibold J, Stenzl A, Sievert KD. Author information: (1)Dept. of Urology, University of Tuebingen, Hoppe-Seyler-Strasse 3, Tuebingen, Germany. Tissue engineering is a promising technique for the development of biological substitutes that can restore, maintain, or improve tissue function. The creation of human tissue-engineered products, generated of autologous somatic cells or adult stem cells with or without seeding of biocompatible matrices is a vision to resolve the lack of tissues and organs for transplantation and to offer new options for reconstructive surgery. Tissue engineering in urology aims at the reconstruction of the urinary tract by creating anatomically and functionally equal tissue. It is a rapidly evolving field in basic research and the transfer into the clinic has yet to be realized. Necessary steps from bench to bed are the proof of principle in animal models and the proof of concept in clinical trials following good manufacturing practice and ethical and legal requirements for human tissue-engineered products. Up to now, obstacles still occur in the neovascularization of implants and ingrowth of nerves in vivo. Moreover the harvesting of mesenchymal stem cells out of bone marrow as well as the explant of urothelial cells yet demands rather invasive surgery to achieve a successful outcome. Thus, other cell sources and harvesting techniques like placenta and adipose tissue for mesenchymal stem cells and bladder irrigation for urothelial cells require closer investigation. Copyright © 2010. Published by Elsevier B.V. PMID: 21167237 [PubMed - indexed for MEDLINE] 1036. Prog Biophys Mol Biol. 2011 Jul;106(1):300-6. doi: 10.1016/j.pbiomolbio.2010.11.008. Epub 2010 Dec 14. Adipose tissue development--impact of the early life environment. Symonds ME(1), Budge H, Perkins AC, Lomax MA. Author information: (1)Early Life Nutrition Research Unit, Academic Child Health, School of Clinical Sciences, University Hospital, Nottingham NG72UH, United Kingdom. michael.symonds@nottingham.ac.uk Increasing experimental and observational evidence in both animals and humans suggests that early life events are important in setting later fat mass. This includes both the number of adipocytes and the relative distribution of both brown and white adipose tissue. Brown adipose tissue is characterised as possessing a unique uncoupling protein (UCP)1 which enables the rapid generation of large amounts of heat and is most abundant in the newborn. In large mammals such as sheep and humans, brown fat that is located around the major internal organs, is largely lost during the postnatal period. However, it is retained in small and discrete areas into adulthood when it is sensitive to environmental cues such as changes in ambient temperature or day length. The extent to which brown adipose tissue is lost or replaced by white adipose tissue and/or undergoes a process of transdifferentiation remains controversial. Small amounts of UCP1 can also be present in skeletal muscle which now appears to share the same common precursor cell as brown adipose tissue. The functional consequences of UCP1 in muscle remain to be confirmed but it could contribute to dietary induced thermogenesis. Challenges in elucidating the primary mechanisms regulating adipose tissue development include changes in methylation status of key genes during development in different species, strains and adipose depots. A greater understanding of the mechanisms by which early life events regulate adipose tissue distribution in young offspring are likely to provide important insights for novel interventions that may prevent excess adiposity in later life. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved. PMID: 21163289 [PubMed - indexed for MEDLINE] 1037. Lipids. 2011 Feb;46(2):105-19. doi: 10.1007/s11745-010-3501-5. Epub 2010 Dec 15. The health promoting properties of the conjugated isomers of α-linolenic acid. Hennessy AA(1), Ross RP, Devery R, Stanton C. Author information: (1)TEAGASC, Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland. The bioactive properties of the conjugated linoleic acid (CLA) isomers have long been recognised and are the subject of a number of excellent reviews. However, despite this prominence the CLA isomers are not the only group of naturally occurring dietary conjugated fatty acids which have shown potent bioactivity. In a large number of in vitro and in vivo studies, conjugated α-linolenic acid (CLNA) isomers have displayed potent anti-inflammatory, immunomodulatory, anti-obese and anti-carcinogenic activity, along with the ability to improve biomarkers of cardio-vascular health. CLNA isomers are naturally present in high concentrations in a large variety of seed oils but can also be produced in vitro by strains of lactobacilli and bifidobactena through the activity of the enzyme linoleic acid isomerase on α-linolenic acid. In this review, we will address the possible therapeutic roles that CLNA may play in a number of conditions afflicting Western society and the mechanisms through which this activity is mediated. PMID: 21161605 [PubMed - indexed for MEDLINE] 1038. Pediatr Radiol. 2011 Jun;41(6):759-68. doi: 10.1007/s00247-010-1925-y. Epub 2010 Dec 16. Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging. Hong TS(1), Shammas A, Charron M, Zukotynski KA, Drubach LA, Lim R. Author information: (1)Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada. Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET. PMID: 21161205 [PubMed - indexed for MEDLINE] 1039. J Clin Endocrinol Metab. 2011 Feb;96(2):333-43. doi: 10.1210/jc.2009-2304. Epub 2010 Dec 15. Endocrine manifestations of eating disorders. Warren MP(1). Author information: (1)Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. mpw1@columbia.edu CONTEXT: The endocrinopathies associated with eating disorders involve multiple systems and mechanisms designed to preserve energy and protect essential organs. Those systems that are most affected are in need of significant energy, such as the reproductive and skeletal systems. The changes in neuropeptides and in the hypothalamic axis that mediate these changes also receive input from neuroendocrine signals sensitive to satiety and food intake and in turn may be poised to provide significant energy conservation. These adaptive changes are described, including the thyroid, GH, and cortisol axes, as well as the gastrointestinal tract. EVIDENCE ACQUISITION: Articles were found via PubMed search for both original articles and reviews summarizing current understanding of the endocrine changes of eating disorders based on peer review publications on the topic between 1974 and 2009. CONCLUSION: The signals that control weight and food intake are complex and probably involve multiple pathways that appear to have as a central control the hypothalamus, in particular the medial central area. The hypothalamic dysfunction of eating disorders provides a reversible experiment of nature that gives insight into understanding the role of various neuropeptides signaling nutritional status, feeding behavior, skeletal repair, and reproductive function. PMID: 21159848 [PubMed - indexed for MEDLINE] 1040. Arch Physiol Biochem. 2011 May;117(2):47-56. doi: 10.3109/13813455.2010.535835. Epub 2010 Dec 15. Secreted proteins from adipose tissue and skeletal muscle - adipokines, myokines and adipose/muscle cross-talk. Trayhurn P(1), Drevon CA, Eckel J. Author information: (1)Obesity Biology Unit, Institute of Ageing and Chronic Diseases, University of Liverpool, UK. p.trayhurn@liverpool.ac.uk White adipose tissue and skeletal muscle are the largest organs in the body and both are composed of distinct cell types. The signature cell of adipose tissue is the adipocyte while myocytes are the defining cell of skeletal muscle. White adipocytes are major secretory cells and this is increasingly apparent also for myocytes. Both cells secrete a range of bioactive proteins, generally termed adipokines in the case of adipocytes and myokines for muscle cells. There has, however, been some confusion over nomenclature and we suggest that the name myokine is restricted to a protein that is secreted from myocytes, while the term adipokine should be used to describe all proteins secreted from any type of adipocyte (white, brown or brite). These definitions specifically exclude proteins secreted from other cells within adipose tissue and muscle, including macrophages. There is some commonality between the myokines and adipokines in that both groups include inflammation-related proteins - for example, IL-6, Il-8 and MCP-1. Adipokines and myokines appear to be involved in local autocrine/paracrine interactions within adipose tissue and muscle, respectively. They are also involved in an endocrine cross-talk with other tissues, including between adipose tissue and skeletal muscle, and this may be bi-directional. For example, IL-6, secreted from myocytes may stimulate lipolysis in adipose tissue, while adipocyte-derived IL-6 may induce insulin resistance in muscle. PMID: 21158485 [PubMed - indexed for MEDLINE] 1041. Curr Opin Lipidol. 2011 Feb;22(1):49-54. doi: 10.1097/MOL.0b013e3283425243. Brown adipose tissue in humans. Virtanen KA(1), Nuutila P. Author information: (1)Turku PET Centre, University of Turku, Finland. PURPOSE OF REVIEW: Human brown adipose tissue (BAT) has recently found to be functionally active in adults. The purpose of this review is to chart the importance of BAT in the light of recent publications in humans. RECENT FINDINGS: After publication of the direct evidence of functional BAT in human adults the original findings in human studies have been sparse. This indicates that intensive human data collection is ongoing. SUMMARY: Brown adipocytes and myocytes share the same origin. Regardless of different origin, brown and white adipocytes transdifferentiate into each other's under specific exposure but in addition, another cell type is suggested to exist, 'brite' adipocyte, holding the capacity of transdifferentiation. This indicates the plasticity of adipose organ.Human BAT can be detected using PET. Cold exposure increases the probability to detect brown fat due to increased metabolic activity by induced thermogenesis.BAT glucose uptake rate is 10-15-fold higher in cold than in normal room temperature. Other factors that may increase the activity of sympathetic nervous system and uncoupling protein 1 are several including the complex network of hormonal and neuronal signals. Preliminary results suggest that BAT resembles skeletal muscle not only by origin but also by the effect of insulin on the tissue. PMID: 21157334 [PubMed - indexed for MEDLINE] 1042. Nephrol Ther. 2011 Apr;7(2):69-79. doi: 10.1016/j.nephro.2010.11.004. Epub 2010 Dec 14. [Kidney, adipose tissue, adipocytes--what's new?]. [Article in French] Lafontan M(1). Author information: (1)Équipe 1, unité Inserm 1048, institut des maladies cardiovasculaires et métaboliques, BP 84225, 31432 Toulouse cedex 4, France. max.lafontan@inserm.fr Increased evidence suggests that obesity-related glomerulopathy and chronic kidney diseases should be identified as isolated complications of obesity. It is questioned if the numerous adipose tissue productions could play a role in the initiation/maintenance of such kidney diseases. This review will provide a sum-up of recent advances on fat cell metabolism and adipose tissue physiology. The adipose tissue behaves as an endocrine organ with multiple activities. It is secreting hormones (leptin, adiponectin, apelin) and numerous factors with autocrine, paracrine and systemic effects. These secretions are coming from adipocytes themselves or from cells present in the stroma-vascular fraction of the adipose tissue. When expanding, the adipose tissue of the obese is infiltrated by immune cells such as macrophages and lymphocytes; the role of which is not fully clarified. An attempt will be done to delineate if alterations of lipid storage/fatty acid release or of the secretion potencies of adipose tissue could contribute to kidney lipotoxicity and other chronic kidney diseases described in the obese. Copyright © 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved. PMID: 21156355 [PubMed - indexed for MEDLINE] 1043. World J Gastroenterol. 2010 Dec 14;16(46):5801-9. Leptin in hepatocellular carcinoma. Wang SN(1), Lee KT, Ker CG. Author information: (1)Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, San-Ming District, Kaohsiung 807, Taiwan, China. snwang@kmu.edu.tw The risk factors for hepatocellular carcinoma (HCC) development have been established, and include chronic hepatitis B and C, heavy alcohol consumption, and aflatoxins. In fact, 5%-30% of patients with HCC still lack a readily identifiable risk factor. It has been reported that the majority of ''cryptogenic'' HCC may be attributed to nonalcoholic fatty liver disease, the hepatic presentation of the metabolic syndrome (MS). Obesity is associated with the development of the MS. Recently, adipose tissue has been considered as an endocrine organ because of its capacity to secrete a variety of cytokines, which are collectively known as the adipokines. Leptin, the product of the obese gene, is mainly produced by adipose tissue. Since leptin was first characterized in 1994, accumulated literature has demonstrated the involvement of this adipokine in several areas of human physiology. After binding to its receptor, leptin initiates a cascade of signaling events and subsequent cellular effects. In addition to being the regulatory mediator of energy homeostasis, several in vitro studies have demonstrated the fibrogenic role of leptin in the liver. Furthermore, the deregulated expression of leptin and its receptor have been demonstrated to be associated with a variety of metabolic disorders as well as human cancers. Most importantly, direct evidence supporting the inhibitory and/or activating role of leptin in the process of carcinogenesis and progression of human HCC has been accumulating rapidly. This review aims to provide important insights into the potential mechanisms of leptin in the development of HCC. Hopefully, further investigations will shed light on a new therapeutic target in HCC. PMCID: PMC3001970 PMID: 21155000 [PubMed - indexed for MEDLINE] 1044. An Bras Dermatol. 2010 Sep-Oct;85(5):647-56. Human adipose-derived stem cells: current challenges and clinical perspectives. Yarak S(1), Okamoto OK. Author information: (1)Universidade Federal do Vale do São Francisco, Brazil. sa.la@terra.com.br Adult or somatic stem cells hold great promise for tissue regeneration. Currently, one major scientific interest is focused on the basic biology and clinical application of mesenchymal stem cells. Adipose tissue-derived stem cells share similar characteristics with bone marrow mesenchymal stem cells, but have some advantages including harvesting through a less invasive surgical procedure. Moreover, adipose tissue-derived stem cells have the potential to differentiate into cells of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle, as well as cells of non-mesodermal lineage, such as hepatocytes, pancreatic endocrine cells, neurons, cardiomyocytes, and vascular endothelial cells. There are, however, inconsistencies in the scientific literature regarding methods for harvesting adipose tissue and for isolating, characterizing and handling adipose tissue-derived stem cells. Future clinical applications of adipose tissue-derived stem cells rely on more defined and widespread methods for obtaining cells of clinical grade quality. In this review, current methods in adipose tissue-derived stem cell research are discussed with emphasis on strategies designed for future applications in regenerative medicine and possible challenges along the way. PMID: 21152789 [PubMed - indexed for MEDLINE] 1045. Int J Obes (Lond). 2010 Dec;34 Suppl 2:S59-66. doi: 10.1038/ijo.2010.241. Determinants of brown adipocyte development and thermogenesis. Richard D(1), Carpentier AC, Doré G, Ouellet V, Picard F. Author information: (1)Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, et Groupe interdisciplinaire de Recherche sur l'Obésité de l'Université Laval, Québec, Canada. denis.richard@criucpq.ulaval.ca The brown adipocyte is a thermogenic cell. Its thermogenic potential is conferred by uncoupling protein-1, which 'uncouples' adenosine triphosphate synthesis from energy substrate oxidation. Brown fat cells in so-called classical brown adipose tissue (BAT) share their origin with myogenic factor-5-expressing myoblasts. The development of myocyte/brown adipocyte progenitor cells into a brown adipocyte lineage is apparently triggered by bone morphogenetic protein-7, which stimulates inducers of brown fat cell differentiation, such as PRD1-BF1-RIZ1 homologous domain-containing-16 and peroxisome proliferator-activated receptor-γ co-activator-1-α. The control of brown fat cell development and activity is physiologically ensured by the sympathetic nervous system (SNS), which densely innervates BAT. SNS-mediated thermogenesis is largely governed by hypothalamic and brainstem neurons. With regard to energy balance, the leptin-melanocortin pathway appears to be a major factor in controlling brown adipocyte thermogenesis. The involvement of this homeostatic pathway further supports the role of the brown adipocyte in energy balance regulation. The interest for the brown fat cell and its potential role in energy balance has been further rejuvenated recently by the demonstration that BAT can be present in substantial amounts in humans, in contrast to what has always been thought. Positron emission tomography/computed tomography scanning investigations have indeed revealed the presence in humans of important neck and shoulder cold-activable BAT depots, in particular, in young, lean and female subjects. This short review summarizes recent progress made in the biology of the brown fat cell and focuses on the determinants of the brown adipocyte development and activity. PMID: 21151149 [PubMed - indexed for MEDLINE] 1046. Int J Obes (Lond). 2010 Dec;34 Suppl 2:S4-17. doi: 10.1038/ijo.2010.234. Body composition phenotypes in pathways to obesity and the metabolic syndrome. Dulloo AG(1), Jacquet J, Solinas G, Montani JP, Schutz Y. Author information: (1)Department of Medicine/Physiology, University of Fribourg, Fribourg, Switzerland. abdul.dulloo@unifr.ch Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height(2) (H(2)), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H(2)) and an FFM index (FFM/H(2)), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome. PMID: 21151146 [PubMed - indexed for MEDLINE] 1047. Int J Obes (Lond). 2010 Dec;34 Suppl 2:S18-23. doi: 10.1038/ijo.2010.235. Open questions about metabolically normal obesity. Pataky Z(1), Bobbioni-Harsch E, Golay A. Author information: (1)Department of Community Medicine, WHO Collaborating Centre, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland. Comment in Int J Obes (Lond). 2012 Jan;36(1):164; author reply 165. Subsets of obese subjects without any cardiometabolic risk factors have been repeatedly described. This raises questions whether obesity 'per se' enhances the risk for cardiovascular or metabolic diseases and whether healthy obese subjects would benefit from a medical treatment. In order to answer these questions, as a first step, an expert consensus should be reached for the definition of metabolic normality. In fact, up to now, different parameters related to the metabolic syndrome and/or to insulin sensitivity have been utilized across studies. Once an agreement is reached, population-based studies should be undertaken to establish the incidence of metabolic normality among obese subjects. Furthermore, many other parameters such as age, sex, race, fat distribution and physical activity should be monitored to obtain results representative of a general population. Longitudinal studies aimed at investigating the evolution of the cardiometabolic profile of healthy obese subjects are also needed. In conclusion, data from the literature strongly suggest that a regular surveillance of the cardiometabolic parameters and a prevention of any further weight gain should be applied to healthy obese individuals, whereas possible benefits of a weight loss treatment are still a matter of debate. PMID: 21151142 [PubMed - indexed for MEDLINE] 1048. Curr Opin Organ Transplant. 2011 Feb;16(1):83-9. doi: 10.1097/MOT.0b013e32834254f1. Stem cells of the skin and cornea: their clinical applications in regenerative medicine. Proulx S(1), Fradette J, Gauvin R, Larouche D, Germain L. Author information: (1)Centre LOEX de l'Université Laval, Génie tissulaire et régénération: LOEX-Centre de recherche FRSQ du Centre hospitalier affilié universitaire de Québec, Canada. PURPOSE OF REVIEW: The use of stem cells is of great interest for the treatment of various pathologies and ultimately for the restoration of organ function. Progress pointing towards future treatments of skin and corneal epithelial stem cell defects are reviewed, including the transplantation of living tissue-engineered substitutes. RECENT FINDINGS: This article focuses on substitutes optimized for permanent replacement of skin and cornea. New skin substitutes for burn care are currently under development. More complex tissue-engineered skin substitutes in which stroma, adipose tissue, capillaries, and neurons are combined with the epithelium are being developed. Some dermal/epidermal substitutes have been applied to the treatment of patients. Cultured corneal epithelial cells have been characterized and more complete corneal substitutes are being designed. Long-term clinical results on the transplantation of cultured corneal stem cells for the treatment of limbal stem cell deficiency have been reported. SUMMARY: Advances in tissue engineering for the development of substitutes that will benefit patients suffering from skin or corneal stem cell deficiencies are reviewed. These products are often a combination of cells, scaffolds and other factors. Key considerations in the development of corneal and skin substitutes for clinical applications are discussed. PMID: 21150608 [PubMed - indexed for MEDLINE] 1049. J Hepatol. 2011 Apr;54(4):773-94. doi: 10.1016/j.jhep.2010.11.006. Epub 2010 Nov 17. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. Begriche K(1), Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. Author information: (1)Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA. Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis). Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. PMID: 21145849 [PubMed - indexed for MEDLINE] 1050. J Nutr Biochem. 2011 Feb;22(2):101-8. doi: 10.1016/j.jnutbio.2010.07.003. Epub 2010 Dec 9. The role of adipose tissue in mediating the beneficial effects of dietary fish oil. Puglisi MJ(1), Hasty AH, Saraswathi V. Author information: (1)Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615, USA. Fish oil improves several features of metabolic syndrome (MetS), such as dyslipidemia, insulin resistance and hepatic steatosis. Fish oil may mediate some of its beneficial effects by modulating the storage and/or secretory functions of adipose tissue (AT). The storage of triglycerides in AT is regulated by the availability of free fatty acids and the degree of lipolysis in AT. Fish oil has been shown to reduce lipolysis in several studies, indicating improved triglyceride storage. Importantly, AT secretes a variety of adipokines and fish oil feeding is associated with remarkable changes in the plasma levels of two key adipokines, adiponectin and leptin. Much attention has been focused on the contribution of adiponectin in fish oil-mediated improvements in MetS. However, emerging evidence also indicates a role of leptin in modulating the components of the MetS upon fish oil feeding. In addition to improving the storage and secretory functions of AT, fish oil, and the n-3 fatty acids found in fish oil, has been shown to reduce inflammation in AT. These effects may be in part a result of activation of peroxisome proliferator-activated receptor γ or inhibition of Toll-like receptor 4. Thus, there is compelling evidence that fish oil mediates its beneficial effects on MetS by improving AT storage and secretory functions and by reducing inflammation. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3038466 PMID: 21145721 [PubMed - indexed for MEDLINE] 1051. Comp Biochem Physiol A Mol Integr Physiol. 2011 Mar;158(3):329-36. doi: 10.1016/j.cbpa.2010.11.028. Epub 2010 Dec 7. The use of body mass loss to estimate metabolic rate in birds. Portugal SJ(1), Guillemette M. Author information: (1)Centre for Ornithology, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. S.Portugal.1@bham.ac.uk During starvation, energy production occurs at the expense of body reserve utilisation which results in body mass loss. Knowing the role of the fuels involved in this body mass loss, along with their energy density, can allow an energy equivalent of mass loss to be calculated. Therefore, it is possible to determine daily energy expenditure (DEE) if two body mass loss measurements at an interval of a few days are obtained. The technique can be cheap, minimally stressful for the animals involved, and the data relatively simple to gather. Here we review the use of body mass loss to estimate DEE in birds through critiquing the strengths and weaknesses of the technique, and detail the methodology and considerations that must be adhered to for accurate measures of DEE to be obtained. Owing to the biology of the species, the use of the technique has been used predominantly in Antarctic seabirds, particularly penguins and albatrosses. We demonstrate how reliable the technique can be in predicting DEE in a non-Antarctic species, common eiders (Somateria mollissima), the female of which undergoes a fasting period during incubation. We conclude that using daily body mass loss to estimate DEE can be a useful and effective approach provided that (1) the substrate being consumed during mass loss is known, (2) the kinetics of body mass loss are understood for the species in question and (3) only species that enter a full phase II of a fast (where substrate catabolism reaches a steady state) and are not feeding for a period of time are appropriate for this method. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21144908 [PubMed - indexed for MEDLINE] 1052. Proc Nutr Soc. 2011 Feb;70(1):57-63. doi: 10.1017/S0029665110004015. Epub 2010 Dec 14. DNA methylation of genes in adipose tissue. Pinnick KE(1), Karpe F. Author information: (1)Oxford Centre for Diabetes, Endocrinology, University of Oxford, Churchill Hospital, Oxford, UK. katherine.pinnick@ocdem.ox.ac.uk Body fat distribution plays an important role in determining metabolic health. Whereas central obesity is closely associated with the development of CVD and type 2 diabetes, lower body fat appears to be protective and is paradoxically associated with improved metabolic and cardiovascular profiles. Physiological studies have demonstrated that fatty acid handling differs between white adipose tissue depots, with lower body white adipose tissue acting as a more efficient site for long-term lipid storage. The regulatory mechanisms governing these regional differences in function remain to be elucidated. Although the local microenvironment is likely to be a contributing factor, recent findings point towards the tissues being intrinsically distinct at the level of the adipocyte precursor cells (pre-adipocytes). The multi-potent pre-adipocytes are capable of generating cells of the mesenchymal lineage, including adipocytes. Regional differences in the adipogenic and replicative potential of these cells, as well as metabolic and biochemical activity, have been reported. Intriguingly, the genetic and metabolic characteristics of these cells can be retained through multiple generations when the cells are cultured in vitro. The rapidly emerging field of epigenetics may hold the key for explaining regional differences in white adipose tissue gene expression and function. Epigenetics describes the regulation of gene expression that occurs independently of changes in DNA sequence, for instance, DNA methylation or histone protein modification. In this review, we will discuss the contribution of DNA methylation to the determination of cells of adipogenic fate as well as the role DNA methylation may play during adipocyte terminal differentiation. PMID: 21144123 [PubMed - indexed for MEDLINE] 1053. Curr Vasc Pharmacol. 2011 Mar;9(2):162-6. Obesity and gastrointestinal hormones-dual effect of angiotensin II receptor blockade and a partial agonist of PPAR-γ. Nakagami H(1), Morishita R. Author information: (1)Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Japan. nakagami@gts.med.osaka-u.ac.jp Obesity is strongly associated with type 2 diabetes, hypertension, and hyperlipidemia, which is one of the leading causes of mortality and morbidity worldwide. It is now clear that gut hormones play a role in the regulation of body weight and represent therapeutic targets for the future treatment of obesity. Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, but also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Importantly, blockade of the RAS attenuates weight gain and adiposity by enhanced energy expenditure. The favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. Treatment with telmisartan or losartan significantly reduced the development of lipid-rich plaque. However, treatment with telmisartan significantly improved endothelial dysfunction and inhibited lipid accumulation in the liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPAR-γ, beyond its blood pressure-lowering effect, through Ang II blockade, which may be called "metabosartan". PMID: 21143167 [PubMed - indexed for MEDLINE] 1054. Gerontology. 2012;58(1):15-23. doi: 10.1159/000321319. Epub 2010 Dec 7. Brown versus white adipose tissue: a mini-review. Saely CH(1), Geiger K, Drexel H. Author information: (1)Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria. vivit@lkhf.at Comment in Gerontology. 2012;58(2):120-2; discussion 123-5. BACKGROUND: Brown adipose tissue (BAT) is abundant in small mammals and in newborns and helps them to survive cold temperatures. In adults, it had long been considered to be absent or at least of no relevance. Recent investigations, however, have fuelled interest in adult BAT. OBJECTIVE: We aimed at (1) summarizing structural and physiological characteristics of BAT versus white adipose tissue (WAT); (2) discussing the development of the two adipose tissue types; (3) reviewing the data available from human studies on BAT, and (4) discussing the impact of aging. METHODS: We summarize recent descriptions of BAT and WAT based on the original literature and reviews in the field, with emphasis on human BAT. RESULTS: WAT and BAT have essentially antagonistic functions: WAT stores excess energy as triglycerides and BAT is specialized in the dissipation of energy through the production of heat. Considerable amounts of BAT are present in a substantial proportion of adult humans and relatively high quantities of BAT are associated with lower body weight. With increasing age, BAT decreases and body weight increases. CONCLUSIONS: Although the available cross-sectional data do not allow definite conclusions to be drawn concerning a causal relationship between loss of BAT and increasing body weight with advancing age or obesity-related metabolic disorders of older age, stimulation of BAT appears to be an attractive novel candidate target for the treatment of age-related obesity. Copyright © 2010 S. Karger AG, Basel. PMID: 21135534 [PubMed - indexed for MEDLINE] 1055. G Ital Nefrol. 2010 Nov-Dec;27(6):629-38. [Obesity in dialysis and reverse epidemiology: true or false?]. [Article in Italian] Panzetta G(1), Abaterusso C. Author information: (1)S.C. di Nefrologia e Dialisi, Azienda Ospedaliero-Universitaria, Trieste, Italy. giovanni.panzetta@aots.sanita.fvg.it About 50% of patients who undergo dialysis are overweight or obese. Rather than being a disadvantage, the extra weight is associated with improved survival in this patient group. However, the relationship between weight and outcome is complex among dialysis patients. In the general population obesity constitutes a clear cardiovascular risk factor. By contrast, in obese dialysis patients the nutritional status may be better, and obesity thus provides, at least in the short term, some protection against malnutrition and the associated morbidity. On the other hand, some studies suggest that mortality in the long term is directly correlated with excess weight and obesity, which indicates that fat represents a risk factor also in uremia. In the elderly, particularly those affected by end-stage renal disease, endocrine and metabolic effects on the nitrogen balance cause the loss of muscle mass despite an excess of adipose tissue, which is a condition known as sarcopenic obesity. While a good nutritional state is found in some obese dialysis patients, which probably accounts for the improved survival of the obese group as a whole, there is a sizable proportion of sarcopenic obese, which is probably increasing. Sarcopenic obesity is not only characterized by the reduction of muscle mass but also by the accumulation of fat surrounding the abdominal viscera (visceral fat syndrome), which may be associated with a greater degree of metabolic and atherosclerotic disease. Several studies have shown that malnutrition associated with obesity, including sarcopenic obesity, is the risk factor most closely correlated with morbidity and mortality both in dialysis patients and the general population. The timely identification of this condition has therefore become necessary in the dialysis population now dominated by the elderly and very elderly. Body mass index is inadequate as a measure of sarcopenic obesity since it cannot define muscle mass nor indicate the localization of the fat in the visceral compartment. Other indices must be developed and validated in well performed clinical trials to identify fat localization and the presence of sarcopenia. PMID: 21132645 [PubMed - indexed for MEDLINE] 1056. Aesthet Surg J. 2010 Nov-Dec;30(6):838-42. doi: 10.1177/1090820X10386364. Clinical applications of mesenchymal stem cells in soft tissue augmentation. Hanson SE(1), Gutowski KA, Hematti P. Author information: (1)Division of Plastic and Reconstructive Surgery, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA. shanson2@uwhealth.org Comment in Aesthet Surg J. 2010 Nov-Dec;30(6):843-4. Based on a variety of preclinical studies showing that mesenchymal stem cells (MSC) play a significant role in tissue repair and homeostasis, MSC have rapidly moved into a phase of clinical trials investigating their efficacy as a cell-based therapeutic modality for a diverse group of applications. An emerging body of evidence shows that in addition to being a progenitor cell population with self-renewing and multipotent differentiation capabilities, MSC have unique immunomodulatory properties, making them even more attractive for regenerative medicine. Emerging discoveries in stem cell biology have revealed a multitude of mechanisms through which MSC could potentially augment the current techniques in aesthetic surgery. In this article, the authors review the clinical advances in cell-based therapies relevant to aesthetic surgery, including tissue augmentation, rejuvenation, and regeneration. PMCID: PMC4074905 PMID: 21131458 [PubMed - indexed for MEDLINE] 1057. Gen Comp Endocrinol. 2011 Feb 1;170(3):416-23. doi: 10.1016/j.ygcen.2010.11.025. Epub 2010 Dec 3. Perspectives on endocrine disruptor effects on metabolic sensors. Migliarini B(1), Piccinetti CC, Martella A, Maradonna F, Gioacchini G, Carnevali O. Author information: (1)Dipartimento di Scienze del Mare, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy. Erratum in Gen Comp Endocrinol. 2012 Jan 1;175(1):214. Endocrine disrupting (EDs) chemicals can increase or block the metabolism of endogenous peptidergic or steroid hormones by activating or antagonizing nuclear receptors in the hypothalamus, besides adipose tissue, liver and gonads. Toxicological and epidemiological studies have suggested the involvement of different EDs in an increasing number of metabolic disorders such as obesity and diabetes. The aim of this review is to summarize the literature from experimental animal studies demonstrating the impairment of body weight raised by the deregulation of peptidergic signals as well as by the activation of key metabolic molecular targets. Regarding the modification of gene transcription levels induced by EDs, new data on DEHP effect on food intake and lipid metabolism in the experimental model zebrafish (Danio rerio) have also been included in this review providing evidences about the dangerousness of DEHP low doses. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21130769 [PubMed - indexed for MEDLINE] 1058. Antioxid Redox Signal. 2011 Jul 15;15(2):505-21. doi: 10.1089/ars.2010.3790. Epub 2011 Apr 26. Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease. Gentile CL(1), Frye M, Pagliassotti MJ. Author information: (1)Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, Colorado 80523-1571, USA. Comment in Antioxid Redox Signal. 2011 Jul 15;15(2):421-4. The underlying causes of nonalcoholic fatty liver disease (NAFLD) are unclear, although recent evidence has implicated the endoplasmic reticulum (ER) in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of ER homeostasis, often termed "ER stress," has been observed in liver and adipose tissue of humans with NAFLD and/or obesity. Importantly, the signaling pathway activated by disruption of ER homeostasis, the unfolded protein response, has been linked to lipid biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt ER homeostasis in NAFLD and the role of ER-mediated signaling have become topics of intense investigation. The present review will examine the ER and the unfolded protein response in the context of NAFLD. PMCID: PMC3118611 PMID: 21128705 [PubMed - indexed for MEDLINE] 1059. Antioxid Redox Signal. 2011 May 15;14(10):1971-8. doi: 10.1089/ars.2010.3777. Epub 2011 Mar 16. Autophagic degradation of mitochondria in white adipose tissue differentiation. Goldman SJ(1), Zhang Y, Jin S. Author information: (1)Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA. Recent work has revealed that autophagy plays a significant role in the process of white adipocyte differentiation. In both in vitro and in vivo model systems, autophagy inactivation by targeted deletion of essential autophagy genes results in alterations in white adipocyte structure. In both models, postdifferentiation cells exhibit atypical morphology, with many small lipid droplets and large numbers of mitochondria, rather than the single large lipid droplet and relatively few mitochondria observed in normal white adipocytes. The role of autophagy as the primary means of the degradation of mitochondria has long been studied, and it is likely that a deficiency in the degradation of mitochondria contributes to the unusual phenotypes observed in mice with autophagy-deficient adipose tissue, including reduced adiposity, resistance to diet-induced obesity, and increased insulin sensitivity. What is not yet known is whether the process of mitochondria-specific autophagy, often referred to as "mitophagy," is specifically induced during adipogenesis or if a general increase in the nonspecific autophagic degradation of mitochondria plays a role in normal adipose differentiation. Despite remaining questions, these findings not only establish the critical role of autophagy in white adipose tissue development, but also suggest that the manipulation of autophagy in adipose tissue may provide novel therapeutic opportunities for metabolic diseases. PMCID: PMC3078505 PMID: 21126221 [PubMed - indexed for MEDLINE] 1060. Antioxid Redox Signal. 2011 Oct 1;15(7):1911-26. doi: 10.1089/ars.2010.3739. Epub 2011 May 6. Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome. Otani H(1). Author information: (1)Second Department of Internal Medicine, Kansai Medical University, 10-15-Fumizono-cho, Moriguchi City, Japan. otanih@takii.kmu.ac.jp Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering of metabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, and hypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensable component of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is central to the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysregulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associated vasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present review is to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulin resistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench to bedside will be provided to develop novel strategies to cardiovascular risk factors in MetS. PMID: 21126197 [PubMed - indexed for MEDLINE] 1061. J Cardiovasc Transl Res. 2011 Apr;4(2):154-60. doi: 10.1007/s12265-010-9245-z. Epub 2010 Dec 2. Adult stem cells: from new cell sources to changes in methodology. Pelacho B(1), Mazo M, Gavira JJ, Prósper F. Author information: (1)Hematology and Cell Therapy and Foundation for Applied Medical Research, Division of Cancer, Clínica Universidad de Navarra, University of Navarra, Av. Pío XII 36, Pamplona, Navarre, Spain. Cardiovascular diseases constitute the first cause of mortality and morbidity worldwide. Alternative treatments like transplantation of (stem) cell populations derived from several adult tissue sources, like the bone marrow, skeletal muscle, or even adipose tissue, have been already employed in diverse clinical trials. Results from these studies and previous animal studies have reached to the conclusion that stem cells induce a benefit in the treated hearts, which is exerted mainly through paracrine mechanisms and not through direct differentiation as it was initially expected. However, a strong technical limitation for the stem cell therapy, which is the low level of cell survival and engraftment, diminishes their potential. Thus, new strategies like combination of the cells with bioengineering techniques have been developed and are being subject of intense research, suggesting that new strategies may improve the efficacy of these therapies. In this review, we will discuss the different therapeutic approaches, drawbacks, and future expectations of new regenerative therapies for cardiovascular diseases. PMID: 21125433 [PubMed - indexed for MEDLINE] 1062. Plast Reconstr Surg. 2010 Dec;126(6):1936-46. doi: 10.1097/PRS.0b013e3181f44790. Basic science review on adipose tissue for clinicians. Brown SA(1), Levi B, Lequeux C, Wong VW, Mojallal A, Longaker MT. Author information: (1)Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8560, USA. Erratum in Plast Reconstr Surg. 2011 Feb;127(2):1025. Lequex, Charlotte [corrected to Lequeux, Charlotte]. Comment in Plast Reconstr Surg. 2011 Sep;128(3):829-30. The recognition that fat contains stem cells has driven further examination into the potential uses of fat and adipose-derived stem cells in a wide number of clinical situations. New information about the harvesting, isolation, and subsequent differentiation properties of isolated adipose-derived stem cells has led to new research into novel tissue-engineered constructs and the transformation of adipose-derived stem cells to induced pluripotent stem cells. Clinically, use of fat grafts and adipose-derived stem cells worldwide and in the United States has dramatically increased in parallel to questions concerning the safety and efficacy of adipose-derived stem cell-based treatments. Currently, the U.S. Food and Drug Administration has not approved the use of isolated adipose-derived stem cells for medical indications. PMID: 21124133 [PubMed - indexed for MEDLINE] 1063. Sci Transl Med. 2010 Dec 1;2(60):60rv5. doi: 10.1126/scitranslmed.3001007. The role of JNK proteins in metabolism. Vallerie SN(1), Hotamisligil GS. Author information: (1)Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. The stress-activated c-Jun amino-terminal kinase (JNK) plays a pivotal role in metabolic conditions such as obesity, insulin resistance, and type 2 diabetes. Intricate tissue-specific tweaking of JNK activity in preclinical models of metabolic diseases reveals a complex interplay among local and systemic effects on carbohydrate and lipid metabolism. Synthesis of these entangled effects illustrates that for JNK inhibitors to have therapeutic impact, they must function in multiple cell types to modulate JNK activity. PMID: 21123811 [PubMed - indexed for MEDLINE] 1064. Biochem Soc Trans. 2010 Dec;38(6):1565-70. doi: 10.1042/BST0381565. The involvement of microRNAs in Type 2 diabetes. Ferland-McCollough D(1), Ozanne SE, Siddle K, Willis AE, Bushell M. Author information: (1)Medical Research Council Toxicology Unit, Hodgkin Building, University Leicester of Leicester, Leicester LE1 9HN, UK. dfm3@le.ac.uk T2D (Type 2 diabetes mellitus) is a major health issue that has reached epidemic status worldwide. T2D is a progressive metabolic disorder characterized by reduced insulin sensitivity, insulin resistance and pancreatic β-cell dysfunction. Improper treatment of TD2 can lead to severe complications such as heart disease, stroke, kidney failure, blindness and nerve damage. The aetiology and molecular mechanisms of T2D are not fully understood, but compelling evidence points to a link between T2D, obesity, dyslipidaemia and insulin resistance. Although T2D seems to be strongly linked to environmental factors such as nutrition and lifestyle, studies have shown that genetic factors, such as polymorphisms associated with metabolic genes, imprinting, fetal programming and miRNA (microRNA) expression, could also contribute to the development of this disease. miRNAs are small 22-25-nt-long untranslated RNAs that negatively regulate the translation of mRNAs. miRNAs are involved in a large number of biological functions such as development, metabolism, immunity and diseases such as cancer, cardiovascular diseases and diabetes. The present review examines the various miRNAs that have been identified as being potentially involved in T2D, focusing on the insulin-sensitive organs: white adipose tissue, liver, skeletal muscle and the insulin-producing pancreatic β-cells. PMID: 21118127 [PubMed - indexed for MEDLINE] 1065. J Cardiovasc Transl Res. 2011 Apr;4(2):145-53. doi: 10.1007/s12265-010-9246-y. Epub 2010 Nov 30. Adipose-derived stem cells for myocardial infarction. Mazo M(1), Gavira JJ, Pelacho B, Prosper F. Author information: (1)Hematology and Cell Therapy and Foundation for Applied Medical Research, Division of Cancer, University of Navarra, Av. Pío XII 36, Pamplona, Spain. In recent years, stem cell treatment of myocardial infarction has elicited great enthusiasm upon scientists and physicians alike, thus making the finding of a suitable cell a compulsory subject for modern medicine. Due to its potential, accessibility and efficiency of harvesting, adipose tissue has become one of the most attractive sources of stem cells for regenerative therapies. The differentiation capacity and the paracrine activity of these cells has made them an optimal candidate for the treatment of a diverse range of diseases from immunological disorders as graft versus host disease to cardiovascular pathologies like peripheral ischemia. In this review, we will focus on the use of stem cells derived from adipose tissue for treatment of myocardial infarction, with special attention to their putative in vivo mechanisms of action. PMID: 21116883 [PubMed - indexed for MEDLINE] 1066. Int J Gen Med. 2010 Oct 20;3:335-43. doi: 10.2147/IJGM.S11926. Obesity and respiratory diseases. Zammit C(1), Liddicoat H, Moonsie I, Makker H. Author information: (1)Sleep and Ventilation Unit, Department of Respiratory Medicine, North Middlesex University Hospital, London, UK. The obesity epidemic is a global problem, which is set to increase over time. However, the effects of obesity on the respiratory system are often underappreciated. In this review, we will discuss the mechanical effects of obesity on lung physiology and the function of adipose tissue as an endocrine organ producing systemic inflammation and effecting central respiratory control. Obesity plays a key role in the development of obstructive sleep apnea and obesity hypoventilation syndrome. Asthma is more common and often harder to treat in the obese population, and in this study, we review the effects of obesity on airway inflammation and respiratory mechanics. We also discuss the compounding effects of obesity on chronic obstructive pulmonary disease (COPD) and the paradoxical interaction of body mass index and COPD severity. Many practical challenges exist in caring for obese patients, and we highlight the complications faced by patients undergoing surgical procedures, especially given the increased use of bariatric surgery. Ultimately, a greater understanding of the effects of obesity on the respiratory disease and the provision of adequate health care resources is vital in order to care for this increasingly important patient population. PMCID: PMC2990395 PMID: 21116339 [PubMed] 1067. Diabetes Obes Metab. 2011 Jan;13(1):1-6. doi: 10.1111/j.1463-1326.2010.01305.x. 11β-Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus. Hollis G(1), Huber R. Author information: (1)Incyte Corporation, Wilmington, DE 19880, USA. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inert cortisone to physiologically active cortisol, functioning to enhance local cortisol action beyond what would be predicted based on simple plasma exposures. Adipose tissue overexpression of 11β-HSD1 in rodents to levels observed in human obesity can lead to a near complete metabolic syndrome phenotype, and inhibition of 11β-HSD1 has been proposed to be of potential therapeutic benefit to patients with type 2 diabetes mellitus (T2DM). Recently published clinical results with the selective 11β-HSD1 inhibitor, INCB13739, have, for the first time, provided evidence substantiating this hypothesis, and suggest that 11β-HSD1 activity may be important in regulating glycaemia and cardiometabolic risk. In patients with T2DM failing metformin monotherapy, INCB13739 treatment achieves significant reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), and when present improves hyperlipidaemia and hypertriglyceridaemia. Interestingly, these positive effects are observed primarily in subjects categorized as obese (body mass index, BMI > 30 kg/m²) and not in subjects categorized as overweight (BMI ≤ 30 kg/m²), underscoring the likely importance of adipose tissue 11β-HSD1 activity to the cardiometabolic sequelae of obesity. This review summarizes the therapeutic rationale for 11β-HSD1 inhibition, and describes in detail the metabolic and endocrinologic changes observed in patients with T2DM treated with INCB13739. © 2010 Blackwell Publishing Ltd. PMID: 21114597 [PubMed - indexed for MEDLINE] 1068. Physiol Res. 2011;60(2):253-61. Epub 2010 Nov 29. The role of non-aromatizable testosterone metabolite in metabolic pathways. Dušková M(1), Pospíšilová H. Author information: (1)Institute of Endocrinology, Prague, Czech Republic. mduskova@endo.cz Dihydrotestosterone (DHT) originates via irreversible reduction of testosterone by catalytic activity of 5alpha-reductase enzyme and it is demonstratively the most effective androgen. Androgens influence adipose tissue in men either directly by stimulation of the androgen receptor or indirectly, after aromatization, by acting at the estrogen receptor. DHT as a non-aromatizable androgen could be responsible for a male type fat distribution. The theory of non-aromatizable androgens as a potential cause of a male type obesity development has been studied intensively. However, physiological levels of DHT inhibit growth of mature adipocytes. In animal models, substitution of DHT in males after gonadectomy has a positive effect on body composition as a testosterone therapy. Thus, DHT within physiological range positively influences body composition. However, there are pathological conditions with an abundance of DHT, e.g. androgenic alopecia and benign prostatic hyperplasia. These diseases are considered as risk factors for development of metabolic syndrome or atherosclerosis. In obese people, DHT metabolism in adipose tissue is altered. Local abundance of non-aromatizable androgen has a negative effect on adipose tissue and it could be involved in pathogenesis of metabolic and cardiovascular diseases. Increased DHT levels, compared to physiological levels, have negative effect on development of cardiovascular diseases. Difference between the effect of physiological and increased level brings about certain paradox. PMID: 21114370 [PubMed - indexed for MEDLINE] 1069. Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):843-51. doi: 10.1016/j.beem.2010.08.011. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Drager LF(1), Jun JC, Polotsky VY. Author information: (1)Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human OSA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human OSA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of OSA have improved our understanding of the metabolic impact of OSA, but further studies are needed before we can translate recent basic research findings to clinical practice. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3011976 PMID: 21112030 [PubMed - indexed for MEDLINE] 1070. Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):763-73. doi: 10.1016/j.beem.2010.08.007. The impact of sleep disturbances on adipocyte function and lipid metabolism. Broussard J(1), Brady MJ. Author information: (1)Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, MMR 626, Los Angeles, CA 90089, USA. josiane.broussard@usc.edu Classically, sleep has been considered to serve an essential restorative function for the brain. However, there are an increasing number of studies linking decreased sleep quantity and/or quality in humans to an increased obesity and diabetes risk. Reductions in sleep quantity or quality lead to an increase in hunger and appetite, which chronically could predispose an individual to obesity. Carefully controlled studies have shown that two nights of insufficient sleep is causally linked to a decrease in disposition index, the most commonly used predictor of an individual's diabetes risk, and impairments in glucose tolerance and insulin sensitivity. Thus, sleep appears to play a critical role in modulating energy metabolism in peripheral tissues. Here we will discuss recent work implicating adipose tissue as a potential direct target of disruption of sleep quality, and explore the potential mechanistic links between sleep, adipose tissue and the global control of energy metabolism in humans. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3031100 PMID: 21112024 [PubMed - indexed for MEDLINE] 1071. Biochim Biophys Acta. 2011 Jun;1807(6):664-78. doi: 10.1016/j.bbabio.2010.11.004. Epub 2010 Nov 24. Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach. Prieto-Hontoria PL(1), Pérez-Matute P, Fernández-Galilea M, Bustos M, Martínez JA, Moreno-Aliaga MJ. Author information: (1)Department of Nutrition, Food Science, Physiology and Toxicology, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain. Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 21111705 [PubMed - indexed for MEDLINE] 1072. Trends Endocrinol Metab. 2011 Jan;22(1):24-33. doi: 10.1016/j.tem.2010.10.002. Epub 2010 Nov 5. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Mauvais-Jarvis F(1). Author information: (1)Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. f-mauvais-jarvis@northwestern.edu Because of increasing life expectancy, the contribution of age-related estrogen or androgen deficiency to obesity and type 2 diabetes will become a new therapeutic challenge. This review integrates current concepts on the mechanisms through which estrogen receptors (ERs) and androgen receptor (AR) regulate energy homeostasis in rodents and humans. In females, estrogen maintains energy homeostasis via ERα and ERβ, by suppressing energy intake and lipogenesis, enhancing energy expenditure, and ameliorating insulin secretion and sensitivity. In males, testosterone is converted to estrogen and maintains fuel homeostasis via ERs and AR, which share related functions to suppress adipose tissue accumulation and improve insulin sensitivity. We suggest that ERs and AR could be potential targets in the prevention of age-related metabolic disorders. PMCID: PMC3011051 PMID: 21109497 [PubMed - indexed for MEDLINE] 1073. Klin Med (Mosk). 2010;88(2):4-8. [Arterial hypertension and metabolic disorders]. [Article in Russian] Dzherieva IS, Volkova NI. Combination of arterial hypertension (AH) and metabolic disorders accelerates development of organic lesions in target organs. As shown in recent prospective studies, myocardial hypertrophy rate closely correlated with severity of metabolic disturbance. The thickness of interventricular septum and posterior wall show stronger dependence of severity of metabolic disorders than left ventricular density while left atrial enlargement is correlates with fasting glycemia and excess body mass. There is close relationship between microalbuminurea and hyperinsulinemia and the number of metabolic syndrome components is linearly correlated with glomerular filtration rate below 60 ml/min. It is shown that rigidity of arteries is a new independent risk factor of cardiovascular complications in obese patients. Moreover, metabolic disturbances cause affective disorders that impair quality of life and therapy motivation. Combination of AH, metabolic disturbances, and borderline psychic disorders dictated consideration of abnormal melatonin secretion as a condition developing as a consequence of disturbed adaptive circadian rhythms. This hypothesis was prompted by the discovery of the so-called "clock genes" in the central nervous system and practically all peripheral organs including heart, vessels, and adipose tissue. PMID: 21105463 [PubMed - indexed for MEDLINE] 1074. Vnitr Lek. 2010 Oct;56(10):1028-34. [Adipose tissue hormones]. [Article in Czech] Haluzík M(1), Trachta P, Haluzíková D. Author information: (1)III. Interní klinika 1. lékarské fakulty UKa VFN Praha. mhalu@lf1.cuni.cz Adipose tissue had been traditionally considered a passive energy storage site without direct influence on energy homeostasis regulation. This view has been principally changed during early nineties by the discovery of hormonal production of adipose tissue. At present, the list of hormonally active substances of adipose tissue includes more than one hundred factors with paracrine or endocrine activity that play an important role in metabolic, food intake a inflammatory regulations and many other processes. Only minority of adipose tissue-derived hormones is produced exclusively in fat. Most of these factors is primarily put out by other tissues and organs. Adipose tissue-derived hormones are produced not only by adipocytes but also by preadipocytes, immunocompetent and endothelial cells and other cell types residing in fat. This paper summarizes current knowledge about endocrine function of adipose tissue with special respect to its changes in obesity. It also describes its possible role in the ethiopathogenesis of insulin resistance, atherosclerosis and other obesity-related pathologies. PMID: 21105447 [PubMed - indexed for MEDLINE] 1075. Cell Biochem Funct. 2010 Dec 2;28(8):623-31. doi: 10.1002/cbf.1706. The role of inflamed adipose tissue in the insulin resistance. Torres-Leal FL(1), Fonseca-Alaniz MH, Rogero MM, Tirapegui J. Author information: (1)Department of Food Science and Experimental Nutrition, University of São Paulo, São Paulo, Brazil. torresleal@usp.br In this article, we discuss inflammation associated with adipose tissue dysfunction as a potential link with obesity-related insulin resistance, and how obesity-related inflammatory components, such as immune cells, cytokines/chemokines and adipocytokines, induce obesity-related pathologies. Copyright © 2010 John Wiley & Sons, Ltd. PMID: 21104928 [PubMed - indexed for MEDLINE] 1076. Clin Chem. 2011 Feb;57(2):162-7. doi: 10.1373/clinchem.2010.148833. Epub 2010 Nov 22. Therapeutic approaches to target inflammation in type 2 diabetes. Goldfine AB(1), Fonseca V, Shoelson SE. Author information: (1)Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA. allison.goldfine@joslin.harvard.edu BACKGROUND: Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states. CONTENT: Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates. SUMMARY: The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity. PMCID: PMC3227024 PMID: 21098138 [PubMed - indexed for MEDLINE] 1077. Endocrinol Metab Clin North Am. 2010 Dec;39(4):729-43. doi: 10.1016/j.ecl.2010.08.001. Appetite and hedonism: gut hormones and the brain. Simpson KA(1), Bloom SR. Author information: (1)Section of Investigative Medicine, Imperial College London, Commonwealth Building, Du Cane Road, London, W12 0NN, UK. Precise automatic control of food intake and energy expenditure maintains a steady weight and is fundamental to survival. The brainstem and hypothalamus are key areas within the brain that integrate peripheral signals from the gut and adipose tissue to control feeding behavior according to energy need. Gut hormones are released after a meal and signal to the brain to initiate meal termination and feelings of satiation. However, reward pathways are able to override this mechanism so that when palatable food is presented, food is consumed irrespective of energy requirements. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21095541 [PubMed - indexed for MEDLINE] 1078. Vitam Horm. 2010;84:151-84. doi: 10.1016/B978-0-12-381517-0.00005-9. The emerging role of promiscuous 7TM receptors as chemosensors for food intake. Wellendorph P(1), Johansen LD, Bräuner-Osborne H. Author information: (1)Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. In recent years, several highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized of which many are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids (FFAs) and are expressed in taste tissue, the gastrointestinal (GI) tract, endocrine glands, adipose tissue, and/or kidney. This has led to the hypothesis that these receptors may act as sensors of food intake modulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. In the present review, we describe the molecular mechanisms of nutrient-sensing of the calcium-sensing receptor (CaR), the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3-sensing L-α-amino acids; the carbohydrate-sensing T1R2/T1R3 receptor; the proteolytic degradation product sensor GPR93 (also termed GPR92); and the FFA sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. Due to their omnipresent nature, the natural ligands have had limited usability in pharmacological/physiological studies which has hampered the elucidation of the physiological function and therapeutic prospect of their receptors. However, an increasing number of subtype-selective ligands and/or receptor knockout mice are being developed which at least for some of the receptors have validated them as promising drug targets in, for example, type II diabetes. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21094899 [PubMed - indexed for MEDLINE] 1079. Vitam Horm. 2010;84:21-79. doi: 10.1016/B978-0-12-381517-0.00002-3. Pleiotropic actions of the incretin hormones. McIntosh CH(1), Widenmaier S, Kim SJ. Author information: (1)Department of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. The insulin secretory response to a meal results largely from glucose stimulation of the pancreatic islets and both direct and indirect (autonomic) glucose-dependent stimulation by incretin hormones released from the gastrointestinal tract. Two incretins, Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have so far been identified. Localization of the cognate G protein-coupled receptors for GIP and GLP-1 revealed that they are present in numerous tissues in addition to the endocrine pancreas, including the gastrointestinal, cardiovascular, central nervous and autonomic nervous systems (ANSs), adipose tissue, and bone. At these sites, the incretin hormones exert a range of pleiotropic effects, many of which contribute to the integration of processes involved in the regulation of food intake, and nutrient and mineral processing and storage. From detailed studies at the cellular and molecular level, it is also evident that both incretin hormones act via multiple signal transduction pathways that regulate both acute and long-term cell function. Here, we provide an overview of current knowledge relating to the physiological roles of GIP and GLP-1, with specific emphasis on their modes of action on islet hormone secretion, β-cell proliferation and survival, central and autonomic neuronal function, gastrointestinal motility, and glucose and lipid metabolism. However, it is emphasized that despite intensive research on the various body systems, in many cases there is uncertainty as to the pathways by which the incretins mediate their pleiotropic effects and only a rudimentary understanding of the underlying cellular mechanisms involved, and these are challenges for the future. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21094896 [PubMed - indexed for MEDLINE] 1080. Antioxid Redox Signal. 2011 Oct 1;15(7):1863-73. doi: 10.1089/ars.2010.3743. Epub 2011 Apr 20. Systemic adiponectin malfunction as a risk factor for cardiovascular disease. Lau WB(1), Tao L, Wang Y, Li R, Ma XL. Author information: (1)Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA. Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and anti-ischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits. PMCID: PMC3159112 PMID: 21091079 [PubMed - indexed for MEDLINE] 1081. Annu Rev Med. 2011;62:141-55. doi: 10.1146/annurev-med-042909-093756. HIV infection, inflammation, immunosenescence, and aging. Deeks SG(1). Author information: (1)Department of Medicine, San Francisco General Hospital, University of California San Francisco, CA, USA. sdeeks@php.ucsf.edu Although antiretroviral therapy for HIV infection prevents AIDS-related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at higher than expected risk for a number of complications typically associated with aging, including cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly exhibited by a number of immunologic abnormalities that persist despite effective suppression of HIV replication. These changes are consistent with some of the changes to the adaptive immune system that are seen in the very old ("immunosenescence") and that are likely related in part to persistent inflammation. HIV-associated inflammation and immunosenescence have been implicated as causally related to the premature onset of other end-organ diseases. Novel therapeutic strategies aimed at preventing or reversing these immunologic defects may be necessary if HIV-infected patients are to achieve normal life span. PMCID: PMC3759035 PMID: 21090961 [PubMed - indexed for MEDLINE] 1082. Methodist Debakey Cardiovasc J. 2010 Nov-2011 Jan;6(4):33-6. Management of obesity in the prevention of cardiovascular disease. Jones PH(1). Author information: (1)Methodist DeBakey Heart & Vascular Center, Methodist Weight Management Center, Houston, Texas, USA. The prevalence of obesity is increasing in the United States and many other countries, and has now passed smoking as the most preventable cause of morbidity and mortality. Obesity is an excess of adipose tissue that results from a mixture of genetic predisposition, environmental influences (e.g., sedentary lifestyle), and behavioural components (e.g., food as a reward), and it is a chronic, relapsing condition. The rapid increase in obesity prevalence is, however, not due to genetic changes but rather is a societal mismatch between physiology and environment, where food is abundant and exercise is unnecessary. The definition of excess adipose tissue, for the purpose of correlating this to disease outcomes, is through body mass index (BMI), which is calculated as weight (kg)/height (m²). Overweight is a BMI of 25-29.9 kg/m², and obesity is a BMI equal to or greater than 30 kg/m². There is evidence that all-cause mortality is higher in obese people, primarily due to increased cardiovascular disease (CVD) mortality and increased obesity related cancer (colon, breast, uterine, ovarian, renal, and pancreatic) mortality. PMID: 21088657 [PubMed - indexed for MEDLINE] 1083. Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):1-6. doi: 10.1097/MCO.0b013e328341221e. Brown adipose tissue and aging. Lecoultre V(1), Ravussin E. Author information: (1)Human Physiology, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA. PURPOSE OF REVIEW: Brown adipose tissue (BAT) was thought to be a tissue with physiological importance early in life (maintenance of body temperature) and to disappear after birth. Recent studies using functional imaging have identified the presence of BAT activity throughout life. This review focuses on the effect of age on BAT function as well as BAT as a potential therapeutic target against age-related metabolic diseases. RECENT FINDINGS: The PET/computed tomography method likely underestimates the prevalence of BAT because it measures only active BAT. The factors underlying the decline of BAT activity with age are currently unknown, but likely associated with changes in the activity of the sympathetic nervous system and the thyroid axis. Apart from age, the presence of active BAT is decreased in males and overweight. The developmental origins of brown adipose depots as well as transcription factors involved in their differentiation have recently been described. Data suggest that BAT may be recruited throughout life. SUMMARY: New imaging techniques may provide more accurate estimations of BAT mass in adults. Given its high metabolic rate, it is suggested that BAT mass and activity could be activated and thus represent a potential target for the management of body weight. PMID: 21088572 [PubMed - indexed for MEDLINE] 1084. Prog Lipid Res. 2011 Jan;50(1):14-27. doi: 10.1016/j.plipres.2010.10.004. Epub 2010 Nov 16. Lipolysis - a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Lass A(1), Zimmermann R, Oberer M, Zechner R. Author information: (1)Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria. Lipolysis is the biochemical pathway responsible for the catabolism of triacylglycerol (TAG) stored in cellular lipid droplets. The hydrolytic cleavage of TAG generates non-esterified fatty acids, which are subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, it is most abundant, however, in white and brown adipose tissue. Over the last 5years, important enzymes and regulatory protein factors involved in lipolysis have been identified. These include an essential TAG hydrolase named adipose triglyceride lipase (ATGL) [annotated as patatin-like phospholipase domain-containing protein A2], the ATGL activator comparative gene identification-58 [annotated as α/β hydrolase containing protein 5], and the ATGL inhibitor G0/G1 switch gene 2. Together with the established hormone-sensitive lipase [annotated as lipase E] and monoglyceride lipase, these proteins constitute the basic "lipolytic machinery". Additionally, a large number of hormonal signaling pathways and lipid droplet-associated protein factors regulate substrate access and the activity of the "lipolysome". This review summarizes the current knowledge concerning the enzymes and regulatory processes governing lipolysis of fat stores in adipose and non-adipose tissues. Special emphasis will be given to ATGL, its regulation, and physiological function. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3031774 PMID: 21087632 [PubMed - indexed for MEDLINE] 1085. Cytokine Growth Factor Rev. 2010 Dec;21(6):449-53. doi: 10.1016/j.cytogfr.2010.10.005. Epub 2010 Nov 16. IL-17 in obesity and adipogenesis. Ahmed M(1), Gaffen SL. Author information: (1)University of Pittsburgh, Department of Medicine, Division of Rheumatology & Clinical Immunology, Pittsburgh, PA 15261, USA. The pro-inflammatory cytokine interleukin (IL)-17 (also known as IL-17) has been associated with induction of tissue inflammation. Obese individuals exhibit many symptoms of chronic low-grade inflammation, suggesting that IL-17 may impact adipose tissue. However, the role of IL-17 in obesity is largely unexplored. Emerging studies indicate that obesity selectively promotes expansion of the Th17 T-cell lineage, exacerbating disease in murine models of autoimmunity such as EAE and colitis. Human studies support this concept, as new clinical studies suggest that IL-17 is expressed at elevated levels in obese individuals. Conversely, however, an anti-adipogenic role for IL-17 is becoming evident, and therefore the interconnections between IL-17 and fat metabolism may be quite complex. Here, we consolidate the potential implications of IL-17 in relation to obesity and describe the emerging data regarding the role of IL-17 in adipose tissue. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3259710 PMID: 21084215 [PubMed - indexed for MEDLINE] 1086. Clin Exp Pharmacol Physiol. 2011 Jan;38(1):1-10. doi: 10.1111/j.1440-1681.2010.05460.x. Obesity, metabolic syndrome, adipocytes and vascular function: A holistic viewpoint. Achike FI(1), To NH, Wang H, Kwan CY. Author information: (1)International Medical University, Kuala Lumpur, Malaysia. 1. Obesity is a metabolic disease of pandemic proportions largely arising from positive energy balance, a consequence of sedentary lifestyle, conditioned by environmental and genetic factors. Several central and peripheral neurohumoral factors (the major ones being the anorectic adipokines leptin and adiponecin and the orexigenic gut hormone ghrelin) acting on the anorectic (pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript) and orexigenic (neuropeptide Y and agouti gene-related protein) neurons regulate energy balance. These neurons, mainly in the arcuate nucleus of the hypothalamus, project to parts of the brain modulating functions such as wakefulness, autonomic function and learning. A tilt in the anorectic-orexigenic balance, perhaps determined genetically, leads to obesity. 2. Excess fat deposition requires space, created by adipocyte (hypertrophy and hyperplasia) and extracellular matrix (ECM) remodelling. This process is regulated by several factors, including several adipocyte-derived Matrix metalloproteinases and the adipokine cathepsin, which degrades fibronectin, a key ECM protein. Excess fat, also deposited in visceral organs, generates chronic low-grade inflammation that eventually triggers insulin resistance and the associated comorbidities of metabolic syndrome (hypertension, atherosclerosis, dyslipidaemia and diabetes mellitus). 3. The perivascular adipose tissue (PVAT) has conventionally been considered non-physiological structural tissue, but has recently been shown to serve a paracrine function, including the release of adipose-derived relaxant and contractile factors, akin to the role of the vascular endothelium. Thus, PVAT regulates vascular function in vivo and in vitro, contributing to the cardiovascular pathophysiology of the metabolic syndrome. Defining the mechanism of PVAT regulation of vascular reactivity requires more and better controlled investigations than currently seen in the literature. © 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd. PMID: 21083697 [PubMed - indexed for MEDLINE] 1087. Methods Mol Biol. 2011;702:269-87. doi: 10.1007/978-1-61737-960-4_20. Endothelial and cardiac regeneration from adipose tissues. Casteilla L(1), Planat-Bénard V, Dehez S, De Barros S, Barreau C, André M. Author information: (1)UPS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, CNRS, Université de Toulouse, Toulouse, France. louis.casteilla@inserm.fr For a long time, adipose tissue was only considered for its crucial role in energy balance and associated diseases. The discovery of the presence of immature cells highlights a putative role for these tissues as reservoirs of therapeutic cells. Indeed, since fat pads can be sampled by liposuction under local anesthesia in adult patients, adipose tissue represents a promising source of regenerative cells, particularly in cardiovascular regeneration. Indeed among other potentials, we and others have demonstrated the great angiogenic properties of adipose-derived stromal cells (ASCs) and the existence of peculiar cells, at least in mice, that are able to spontaneously give rise to functional cardiomyocytes. This review deciphers the different steps necessary to isolate, characterize, and manipulate such striking cells. PMID: 21082409 [PubMed - indexed for MEDLINE] 1088. Adv Pharmacol. 2010;60:229-55. doi: 10.1016/B978-0-12-385061-4.00008-8. Vascular actions of adipokines molecular mechanisms and therapeutic implications. Xu A(1), Wang Y, Lam KS, Vanhoutte PM. Author information: (1)Department of Medicine, University of Hong Kong, Hong Kong, China. Adipose tissue is a critical regulator of vascular function, which until recently had been virtually ignored. Almost all blood vessels are surrounded by perivascular adipose tissue, which is actively involved in the maintenance of vascular homeostasis by producing "vasocrine" signals such as adipokines. Adiponectin and adipocyte fatty acid binding protein (A-FABP), both of which are major adipokines predominantly produced in adipose tissue, have recently been shown to be pivotal modulators of vascular function. Adiponectin has multiple beneficial effects on cardiovascular health. It prevents obesity-induced endothelial dysfunction by inducing nitric oxide production, suppressing endothelial cell activation, inhibiting reactive oxygen species and apoptosis, and promoting endothelial cell repair. By contrast, A-FABP plays a detrimental role in vascular dysfunction and atherosclerosis, mainly by acting as a lipid sensor to transmit toxic lipids-induced vascular inflammation through induction of endoplasmic reticulum stress. Decreased production of adiponectin and/or elevated expression of A-FABP are important contributors to the pathogenesis of obesity-induced endothelial dysfunction and cardiovascular disease. This chapter highlights recent advances in both clinical investigations and animal studies promoting the understanding of the roles of adiponectin and A-FABP in the modulation of vascular function, and discusses the possibilities of using these two adipokines as therapeutic targets to design new drugs for preventing vascular disease associated with obesity and diabetes. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21081220 [PubMed - indexed for MEDLINE] 1089. Nat Rev Endocrinol. 2011 Mar;7(3):137-50. doi: 10.1038/nrendo.2010.199. Epub 2010 Nov 16. Lipodystrophy: pathophysiology and advances in treatment. Fiorenza CG(1), Chou SH, Mantzoros CS. Author information: (1)Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Lipodystrophy is a medical condition characterized by complete or partial loss of adipose tissue. Not infrequently, lipodystrophy occurs in combination with pathological accumulation of adipose tissue at distinct anatomical sites. Patients with lipodystrophy exhibit numerous metabolic complications, which indicate the importance of adipose tissue as an active endocrine organ. Not only the total amount but also the appropriate distribution of adipose tissue depots contribute to the metabolic state. Genetic and molecular research has improved our understanding of the mechanisms underlying lipodystrophy. Circulating levels of hormones secreted by the adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subpopulations of patients with lipodystrophy. This finding rationalizes the use of these adipokines or of agents that increase their circulating levels, such as peroxisome proliferator-activated receptor γ (PPARγ) agonists, for therapeutic purposes. Other novel therapeutic approaches, including the use of growth hormone and growth-hormone-releasing factors, are also being studied as potential additions to the therapeutic armamentarium. New insights gained from research and clinical trials could potentially revolutionize the management of this difficult-to-treat condition. PMCID: PMC3150735 PMID: 21079616 [PubMed - indexed for MEDLINE] 1090. Annu Rev Pathol. 2011;6:457-78. doi: 10.1146/annurev-pathol-011110-130230. Mesenchymal stem cells: mechanisms of inflammation. Singer NG(1), Caplan AI. Author information: (1)MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109, USA. nora.singer@case.edu In adults, human mesenchymal stem cells (hMSCs) are found in vivo at low frequency and are defined by their capacity to differentiate into bone, cartilage, and adipose tissue, depending on the stimuli and culture conditions under which they are expanded. Although MSCs were initially hypothesized to be the panacea for regenerating tissues, MSCs appear to be more important in therapeutics to regulate the immune response invoked in settings such as tissue injury, transplantation, and autoimmunity. MSCs have been used therapeutically in clinical trials and subsequently in practice to treat graft-versus-host disease following bone marrow transplantation. Reports of successful immune modulation suggest efficacy in a wide range of autoimmune conditions, such as demyelinating neurological disease (multiple sclerosis), systemic lupus erythematosus, and Crohn's disease, among others. This review provides background information about hMSCs and also describes their putative mechanisms of action in inflammation. We provide a summary of ongoing clinical trials to allow (a) full comprehension of the range of diseases in which hMSC therapy may be beneficial and (b) identification of gaps in our knowledge about the mechanisms of action of therapeutic MSCs in disease. PMID: 21073342 [PubMed - indexed for MEDLINE] 1091. Arch Physiol Biochem. 2011 Feb;117(1):18-22. doi: 10.3109/13813455.2010.525239. Epub 2010 Nov 12. Does low testosterone affect adaptive properties of adipose tissue in obese men? Ruige JB(1). Author information: (1)Department of Endocrinology, Ghent University Hospital, Belgium. johannes.ruige@ugent.be Obesity and (pre)diabetes in males is associated with low serum testosterone and increased oestradiol levels. It is unknown whether these changes in sex steroids are part of a vicious circle resulting in an increase of risk for metabolic complications of obesity, or whether it presents merely an epiphenomenon. The risk for metabolic complications in obesity seems to be determined by adaptation and integrity of adipose tissue. It is unknown whether the typical changes in sex steroids seen in obese men are desirable or ominous with respect to these functions. However, it might be clinically relevant, as low serum testosterone can be treated, and well with different forms of interventional therapy. The present review provides a short summary on findings, obstacles and future research needed to gain better insight into consequences of changes in sex steroids for adaptation of adipose tissue in obese men. PMID: 21073297 [PubMed - indexed for MEDLINE] 1092. Orv Hetil. 2010 Nov 21;151(47):1946-50. doi: 10.1556/OH.2010.29003. [Fatty liver and global cardiometabolic risk]. [Article in Hungarian] Szollár L(1). Author information: (1)Semmelweis Egyetem, Általános Orvostudományi Kar Kórélettani Intézet Budapest Nagyvárad tér 4. 1089. szollaj@net.sote.hu Non-alcoholic fatty liver disease (NAFLD) can be found in approximately 30% of adults in industrialized societies. Non-alcoholic steatohepatitis (NASH) is its most severe histological form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with cirrhosis will suffer liver-related death. NAFLD is considered the hepatic manifestation of the metabolic syndrome. Recent findings linking the components of metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, adipocytokines, oxidative stress and diminished antioxidants within the liver in the exacerbation of these conditions. It is now widely accepted that non-hepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Insulin resistance, a key feature of metabolic syndrome, is crucial for NASH development. We have a classical chicken-egg problem: insulin resistance causes hepatic steatosis or vice-versa? A possible sequence of the pathogenetic events is the following: increased free fatty acid supply - increased de novo lipogenesis - triglyceride and VLDL overproduction - atherogenic dyslipidemia- oxidative stress (lipid oxidation and peroxidation) - exhaustion of antioxidant defense system- "Tsunami" of inflammatory cytokines- fibrosis- carcinogenesis. Given the strong association of NAFLD with metabolic syndrome, early recognition, assessment and management are essential. The management emphasizes weight reduction and attention to global cardiometabolic risk factors, similar to recommendations for management of the elements of metabolic syndrome. PMID: 21071306 [PubMed - indexed for MEDLINE] 1093. Int J Clin Pract. 2010 Dec;64(13):1808-12. doi: 10.1111/j.1742-1241.2010.02536.x. The procognitive effects of leptin in the brain and their clinical implications. Paz-Filho G(1), Wong ML, Licinio J. Author information: (1)Department of Translational Medicine, John Curtin School of Medical Research, The Australian National University, Canberra, Australia. BACKGROUND: Leptin is a pleiotropic hormone produced mainly by the adipose tissue. Its most well-known effect is to regulate food intake and energy metabolism within the hypothalamus. More recently, several peripheral and extra-hypothalamic effects have been described, expanding leptin's actions far beyond energy balance. AIMS: To review the extra-hypothalamic effects of leptin and their possible clinical implications. METHODS: We did a PubMed search using the terms "leptin" AND "brain" AND "neuron" AND "glial", and selected the most relevant articles. RESULTS: In extra-hypothalamic sites, leptin has remarkable effects on neurogenesis, axon growth, synaptogenesis, denditric morphology, development of oligodendroglial cells, neuron excitability, neuroprotection and regulation of beta-amyloid levels. Those effects have been shown to improve cognition and mood in animal models of depression and anxiety. In lean humans, leptin levels have been negatively correlated with the development of Alzheimer's disease. CONCLUSIONS: Leptin has extra-hypothalamic effects that may protect the brain against the development of mood and neurodegenerative disorders, such as Alzheimer's disease. Better understanding of those effects may lead to the development of potential leptin-based therapies against such conditions. © 2010 Blackwell Publishing Ltd. PMCID: PMC2998704 PMID: 21070531 [PubMed - indexed for MEDLINE] 1094. Ann N Y Acad Sci. 2010 Nov;1212:114-29. doi: 10.1111/j.1749-6632.2010.05800.x. Epub 2010 Nov 11. Hypothalamic control of energy metabolism via the autonomic nervous system. Kalsbeek A(1), Bruinstroop E, Yi CX, Klieverik LP, La Fleur SE, Fliers E. Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands. a.kalsbeek@amc.uva.nl The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic-, parasympathetic-, or sham-denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may "use" the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue. © 2010 New York Academy of Sciences. PMID: 21070249 [PubMed - indexed for MEDLINE] 1095. Ann N Y Acad Sci. 2010 Nov;1212:97-113. doi: 10.1111/j.1749-6632.2010.05799.x. Epub 2010 Nov 11. CNS leptin and insulin action in the control of energy homeostasis. Belgardt BF(1), Brüning JC. Author information: (1)Department of Mouse Genetics and Metabolism, Institute for Genetics, Center for Molecular Medicine, University of Cologne, Zülpicher Strasse 47a, Cologne, Germany. The obesity and diabetes pandemics have made it an urgent necessity to define the central nervous system (CNS) pathways controlling body weight, energy expenditure, and fuel metabolism. The pancreatic hormone insulin and the adipose tissue-derived leptin are known to act on diverse neuronal circuits in the CNS to maintain body weight and metabolism in a variety of species, including humans. Because these homeostatic circuits are disrupted during the development of obesity, the pathomechanisms leading to CNS leptin and insulin resistance are a focal point of research. In this review, we summarize the recent findings concerning the mechanisms and novel neuronal mediators of both insulin and leptin action in the CNS. © 2010 New York Academy of Sciences. PMID: 21070248 [PubMed - indexed for MEDLINE] 1096. Verh K Acad Geneeskd Belg. 2010;72(3-4):149-63. Endocrine and metabolic disturbances in critical illness: relation to mechanisms of organ dysfunction and adverse outcome. Langouche L(1), Mesotten D, Vanhorebeek I. Author information: (1)Division and Laboratory of Intensive Care Medicine, Department of Acute Medical Sciences, Faculty of Medicine, Katholieke Universiteit Leuven, O&N1 Herestraat 49 bus 503 - B-3000 Leuven. Critically ill patients face a high risk of death, which is mostly due to non-resolving multiple organ failure. The plethora of endocrine and metabolic disturbances that hallmark critical illness may play a key role. The major part of our research performed during the period 2004-2009 focused on the disturbed glucose metabolism that commonly develops during critical illness. The onset of this research interest was the landmark randomized clinical study on strict blood glucose control (80-110 mg/ dl) with intensive insulin therapy performed by Prof. Van den Berghe and our clinical team members. This study, published in 2001 in the New England Journal of Medicine, showed reduced morbidity and improved survival with intensive insulin therapy versus toleration of hyperglycemia up to 215 mg/dl. This review summarizes our findings in both patients and animal models on mechanisms contributing to the clinical benefits of strict blood glucose control. Intensive insulin therapy appeared to lower blood glucose levels by ameliorating insulin sensitivity and stimulation of glucose uptake in skeletal muscle, whereas hepatic insulin resistance was not affected. The therapy also improved the lipid profile and the immune response and attenuated inflammation. Maintenance of strict normoglycemia appeared essentially most important, rather than elevating insulin levels. Avoiding hyperglycemia protected the endothelium and the mitochondria. In our animal model, nutritional interventions counteracted the hypercatabolic state of critical illness and insulin improved myocardial contractility, but only when normoglycemia was maintained. Interestingly, we identified the adipose tissue as a functional storage depot for toxic metabolites during critical illness. PMID: 21067067 [PubMed - indexed for MEDLINE] 1097. Radiology. 2011 Jan;258(1):89-97. doi: 10.1148/radiol.10082176. Epub 2010 Nov 9. Combined optical and X-ray tomosynthesis breast imaging. Fang Q(1), Selb J, Carp SA, Boverman G, Miller EL, Brooks DH, Moore RH, Kopans DB, Boas DA. Author information: (1)Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129, USA. fangq@nmr.mgh.harvard.edu PURPOSE: To explore the optical and physiologic properties of normal and lesion-bearing breasts by using a combined optical and digital breast tomosynthesis (DBT) imaging system. MATERIALS AND METHODS: Institutional review board approval and patient informed consent were obtained for this HIPAA-compliant study. Combined optical and tomosynthesis imaging analysis was performed in 189 breasts from 125 subjects (mean age, 56 years ± 13 [standard deviation]), including 138 breasts with negative findings and 51 breasts with lesions. Three-dimensional (3D) maps of total hemoglobin concentration (Hb(T)), oxygen saturation (So(2)), and tissue reduced scattering coefficients were interpreted by using the coregistered DBT images. Paired and unpaired t tests were performed between various tissue types to identify significant differences. RESULTS: The estimated average bulk Hb(T) from 138 normal breasts was 19.2 μmol/L. The corresponding mean So(2) was 0.73, within the range of values in the literature. A linear correlation (R = 0.57, P < .0001) was found between Hb(T) and the fibroglandular volume fraction derived from the 3D DBT scans. Optical reconstructions of normal breasts revealed structures corresponding to chest-wall muscle, fibroglandular, and adipose tissues in the Hb(T), So(2), and scattering images. In 26 malignant tumors of 0.6-2.5 cm in size, Hb(T) was significantly greater than that in the fibroglandular tissue of the same breast (P = .0062). Solid benign lesions (n = 17) and cysts (n = 8) had significantly lower Hb(T) contrast than did the malignant lesions (P = .025 and P = .0033, respectively). CONCLUSION: The optical and DBT images were structurally consistent. The malignant tumors and benign lesions demonstrated different Hb(T) and scattering contrasts, which can potentially be exploited to reduce the false-positive rate of conventional mammography and unnecessary biopsies. © RSNA, 2010 PMCID: PMC3009384 PMID: 21062924 [PubMed - indexed for MEDLINE] 1098. Acta Physiol (Oxf). 2011 Sep;203(1):167-80. doi: 10.1111/j.1748-1716.2010.02216.x. Epub 2010 Dec 8. Cross-talk between adipose tissue and vasculature: role of adiponectin. Li FY(1), Cheng KK, Lam KS, Vanhoutte PM, Xu A. Author information: (1)Department of Medicine, University of Hong Kong, Hong Kong. Adipose tissue is a highly dynamic endocrine organ, secreting a number of bioactive substances (adipokines) regulating insulin sensitivity, energy metabolism and vascular homeostasis. Dysfunctional adipose tissue is a key mediator that links obesity with insulin resistance, hypertension and cardiovascular disease. Obese adipose tissue is characterized by adipocyte hypertrophy and infiltration of inflammatory macrophages and lymphocytes, leading to the augmented production of pro-inflammatory adipokines and vasoconstrictors that induce endothelial dysfunction and vascular inflammation through their paracrine and endocrine actions. By contrast, the secretion of adiponectin, an adipokine with insulin sensitizing and anti-inflammatory activities, is decreased in obesity and its related pathologies. Emerging evidence suggests that adiponectin is protective against vascular dysfunction induced by obesity and diabetes, through its multiple favourable effects on glucose and lipid metabolism as well as on vascular function. Adiponectin improves insulin sensitivity and metabolic profiles, thus reducing the classical risk factors for cardiovascular disease. Furthermore, adiponectin protects the vasculature through its pleiotropic actions on endothelial cells, endothelial progenitor cells, smooth muscle cells and macrophages. Data from both animal and human investigations demonstrate that adiponectin is an important component of the adipo-vascular axis that mediates the cross-talk between adipose tissue and vasculature. This review highlights recent work on the vascular protective activities of adiponectin and discusses the molecular pathways underlying the vascular actions of this adipokine. © 2010 The Authors. Acta Physiologica © 2010 Scandinavian Physiological Society. PMID: 21062420 [PubMed - indexed for MEDLINE] 1099. Ann N Y Acad Sci. 2010 Nov;1211:66-84. doi: 10.1111/j.1749-6632.2010.05806.x. Bone and muscle loss after spinal cord injury: organ interactions. Qin W(1), Bauman WA, Cardozo C. Author information: (1)Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA. Weiping.qin@mssm.edu Spinal cord injury (SCI) results in paralysis and marked loss of skeletal muscle and bone below the level of injury. Modest muscle activity prevents atrophy, whereas much larger--and as yet poorly defined--bone loading seems necessary to prevent bone loss. Once established, bone loss may be irreversible. SCI is associated with reductions in growth hormone, IGF-1, and testosterone, deficiencies likely to exacerbate further loss of muscle and bone. Reduced muscle mass and inactivity are assumed to be contributors to the high prevalence of insulin resistance and diabetes in this population. Alterations in muscle gene expression after SCI share common features with other muscle loss states, but even so, show distinct profiles, possibly reflecting influences of neuromuscular activity due to spasticity. Changes in bone cells and markers after SCI have similarities with other conditions of unloading, although after SCI these changes are much more dramatic, perhaps reflecting the much greater magnitude of unloading. Adiposity and marrow fat are increased after SCI with intriguing, though poorly understood, implications for the function of skeletal muscle and bone cells. © 2010 New York Academy of Sciences. PMID: 21062296 [PubMed - indexed for MEDLINE] 1100. Curr Med Chem. 2010;17(36):4511-20. Inflammation, adiponectin, obesity and cardiovascular risk. Mangge H(1), Almer G, Truschnig-Wilders M, Schmidt A, Gasser R, Fuchs D. Author information: (1)Clinical Institute of Medical and Chemical Laboratory Diagnosis, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria. harald.mangge@klinikum-graz.at The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines, and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity, especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immune-mediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution and pleiotropic drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed. PMID: 21062254 [PubMed - indexed for MEDLINE] 1101. Fiziol Cheloveka. 2010 Sep-Oct;36(5):121-39. [Homeostatic non-shivering thermogenesis in man: facts and speculations]. [Article in Russian] Son'kin VD, Kirdin AA, Andreev RS, Akimov EB. In this review it is considered up-to date researches of different forms of non-shivering thermogenesis that related to thermoregulatory and substrate homeostasis. Term "homeostatic non-shivering thermogenesis (HNST)" is proposed for explanation of facultative heat production stimulated by cold exposure, food intake and accumulation of lactate during intensive muscle load. There are common and different features of physiological activity displayed in three HNST types. Existence of these common points gets a probability to propose general physiological mechanisms of HNST realization. Between other candidates for HNST location brown adipose tissue (BAT) has real unquestionable advantage for this specific function. There is close relationship between thermogenic function in cold environment and diet-induced thermogenesis that allows to link two HNST types and BAT activity together. Here we present data indirectly confirming BAT functioning in processes of homeostatic normalization not due to cold acclimation or food intake. Also we give consideration to new data about BAT functional activity, its topographic body location, mechanisms of uncoupled respiration in different tissues in adult humans and methods of BAT diagnostics which include molecular marker using. We adduce a number of facts confirming our suggestion about BAT activity can be related to homeostatic normalization after physical load. At last, we bring forward experimental research program for examination of our hypothesis about BAT universal homeostatic function in humans. PMID: 21061677 [PubMed - indexed for MEDLINE] 1102. Int J Sports Med. 2010 Nov;31(11):761-7. doi: 10.1055/s-0030-1263117. Epub 2010 Nov 5. Menopause: highlighting the effects of resistance training. Leite RD(1), Prestes J, Pereira GB, Shiguemoto GE, Perez SE. Author information: (1)Universidade Federal de São Carlos, Physiological Sciences Department, Exercise Physiology Laboratory, São Carlos, Brazil. rixleite@gmail.com The increase in lifespan and in the proportion of elderly women has increased the focus on menopause induced physiological alterations. These modifications are associated with the elevated risk of several pathologies such as cardiovascular disease, diabetes, obesity, hypertension, dyslipidemia, non-alcoholic fat liver disease, among others. Because of estrogen levels decline, many tissue and organs (muscular, bone, adipose tissue and liver) are affected. Additionally, body composition suffers important modifications. In this sense, there is a growing body of concern in understanding the physiological mechanisms involved and establishing strategies to prevent and reverse the effects of menopause. The hormone reposition therapy, diet and physical exercise have been recommended. Among the diverse exercise modalities, resistance training is not commonly used as a therapeutic intervention in the treatment of menopause. Thus, the aim of this review was to analyze the physiological alterations on several organs and systems induced by menopause and ovariectomy (experimental model to reproduce menopause), as well as, to study the effects of resistance training in preventing and reverting these modifications. In conclusion, resistance training promotes beneficial effects on several organs and systems, mainly, on muscular, bone and adipose tissue, allowing for a better quality of life in this population. PMID: 21058218 [PubMed - indexed for MEDLINE] 1103. Int J Biochem Cell Biol. 2011 Jan;43(1):10-3. doi: 10.1016/j.biocel.2010.10.018. Epub 2010 Nov 5. Pancreatic beta-cells: Role of glycerol and aquaglyceroporin 7. Virreira M(1), Perret J, Delporte C. Author information: (1)Laboratory of Biological Chemistry and Nutrition, Université Libre de Bruxelles, Brussels, Belgium. Pancreatic β-cells originate from gut endoderm during development. Pancreatic endocrine cells represent about 10% of the mature pancreatic cells, and β-cells represent the majority of endocrine cells. β-cells secrete insulin in response to elevation of nutrient concentrations. Insulin maintains glucose homeostasis by stimulating glucose uptake into muscle and adipose tissue. Aquaglyceroporin 7, permeable to water, glycerol and urea, is expressed in pancreatic β-cells and was recently described as being involved in the control of insulin secretion. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 21056684 [PubMed - indexed for MEDLINE] 1104. Obes Rev. 2011 May;12(5):e282-9. doi: 10.1111/j.1467-789X.2010.00807.x. Epub 2010 Nov 3. Obesity, weight loss and conditional cardiovascular risk factors. Tzotzas T(1), Evangelou P, Kiortsis DN. Author information: (1)Department of Endocrinology, Diabetes andMetabolism, Panagia General Hospital,Thessaloniki, Greece. tzotzas@otenet.gr Obesity is a pathological condition aggregating a substantial number of proatherogenic factors, such as insulin resistance, type 2 diabetes mellitus, dyslipidaemia and hypertension. In addition to these classic cardiometabolic risk factors, atherosclerosis may be aggravated by other non-classic factors, which are characterized as conditional, including homocysteine, fibrinogen, lipoprotein(a), LDL particle size and high-sensitivity CRP. Some of these biomarkers are disturbed in obesity because of a combination of dietary factors, hypertrophic adipose tissue, low-grade inflammation, insulin resistance and other parameters under investigation. For the reduction of these risk factors, weight loss exceeding 10-20% of the initial body weight is probably necessary, achieved through either conventional lifestyle measures or more drastic interventions such as bariatric surgery. It has been shown that certain well-balanced diets, such as the Mediterranean diet, constitute a means of improving in a concerted manner the levels of CRP, fibrinogen, homocysteine and small dense LDL particles, regardless of weight loss. The significance of considering these factors in weight management intervention is an issue that needs further investigation. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 21054756 [PubMed - indexed for MEDLINE] 1105. Endocr J. 2010;57(11):939-46. Epub 2010 Oct 30. Roles of FoxO1 and Sirt1 in the central regulation of food intake. Sasaki T(1), Kitamura T. Author information: (1)Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, Japan. The hypothalamus is the center of controlling food intake and energy expenditure by integrating information on energy status, i.e. adiposity and nutrient signals. Especially, two types of neurons in the arcuate nucleus of the hypothalamus, anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, play vital roles in regulating feeding and energy expenditure. On the other hand, insulin and leptin are hormones that control food intake via regulating POMC and AgRP expression. FoxO1 is a downstream effecter of insulin signaling and Sirt1 is an NAD(+)-dependent deacetylase, both of which have been reported to play important roles in the regulation of metabolism in various organs including liver, pancreas, muscle, adipose tissue and hypothalamus. Histological analyses revealed that FoxO1 and Sirt1 are expressed in both AgRP and POMC neurons where FoxO1 localizes to the nucleus in the fasted, while to the cytoplasm in the refed condition. In contrast, hypothalamic Sirt1 protein is decreased in the fasted condition due to increased ubiquitination of Sirt1. In rodents, overexpression of FoxO1 in the hypothalamus by adenovirus microinjection induces hyperphagia and body weight gain, and simultaneous overexpression of Sirt1 suppresses these phenotypes. FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of AgRP and POMC through transcriptional squelching, and Sirt1 suppresses AgRP expression. In conclusion, we propose that FoxO1 and Sirt1 in hypothalamus are key regulators of energy homeostasis and are molecular targets for the development of new strategy of treating obesity. PMID: 21048357 [PubMed - indexed for MEDLINE] 1106. Indian Pediatr. 2010 Oct;47(10):829-39. Hormones and cytokines in childhood obesity. Arslan N(1), Erdur B, Aydin A. Author information: (1)Department of Pediatric Gastroenterology, Metabolism and Nutrition, Dokuz Eylul University School of Medicine, Izmir, Turkey. nur.arslan@deu.edu.tr OBJECTIVE: Obesity is a growing worldwide health problem affecting both adults and children. Effective prevention and treatment modalities can be achieved by understanding the pathogenesis of obesity better. This review addresses some of the issues related to the hormones and cytokines taking part in the pathogenesis of obesity, energy balance and inflammation. DESIGN: We reviewed current literature on this broad subject especially concentrating on the functions of the hormones and cytokines taking part in the pathogenesis of the childhood obesity. Using the key words obesity, children, hormones, cytokines publications and cross references were evaluated from PubMed database between 1957 and 2009. RESULTS: In children, leptin and ghrelin are two hormones which have major influence on energy balance. Leptin is responsible from long term regulation of energy balance and ghrelin functions as an appetite stimulatory signal. In contrast to ghrelin, obestatin acts as an anorexigenic hormone by suppressing food intake. Adipokines secreted from adipose tissue are the key regulators of inflammation in obesity. Increased TNF-alpha and IL-6 levels but decreased levels of adiponectin and IL-10 are associated with increased inflammation, tissue injury and complications of obesity. CONCLUSIONS: Development, pathogenesis and complications of childhood obesity consist of complex mechanisms including numerous cytokines and hormones. New treatment modalities depend on understanding these complex mechanisms. PMID: 21048235 [PubMed - indexed for MEDLINE] 1107. Am J Physiol Regul Integr Comp Physiol. 2011 Jan;300(1):R1-8. doi: 10.1152/ajpregu.00411.2010. Epub 2010 Nov 3. Uncoupling protein 1 expression and high-fat diets. Fromme T(1), Klingenspor M. Author information: (1)Else-Kröner Fresenius Center, Technische Universität München, Freising, Germany. tobias.fromme@wzw.tum.de Uncoupling protein 1 (Ucp1) is the key component of β-adrenergically controlled nonshivering thermogenesis in brown adipocytes. This process combusts stored and nutrient energy as heat. Cold exposure not only activates Ucp1-mediated thermogenesis to maintain normothermia but also results in adaptive thermogenesis, i.e., the recruitment of thermogenic capacity in brown adipose tissue. As a hallmark of adaptive thermogenesis, Ucp1 synthesis is increased proportionally to temperature and duration of exposure. Beyond this classical thermoregulatory function, it has been suggested that Ucp1-mediated thermogenesis can also be employed for metabolic thermogenesis to prevent the development of obesity. Accordingly, in times of excess caloric intake, one may expect a positive regulation of Ucp1. The general impression from an overview of the present literature is, indeed, an increased brown adipose tissue Ucp1 mRNA and protein content after feeding a high-fat diet (HFD) to mice and rats. The reported increases are very variable in magnitude, and the effect size seems to be independent of dietary fat content and duration of the feeding trial. In white adipose tissue depots Ucp1 mRNA is generally downregulated by HFD, indicating a decline in the number of interspersed brown adipocytes. PMID: 21048077 [PubMed - indexed for MEDLINE] 1108. J Am Coll Nutr. 2010 Aug;29(4):343-51. Body fat regulation: is it a result of a simple energy balance or a high fat intake? Pereira-Lancha LO(1), Coelho DF, de Campos-Ferraz PL, Lancha AH Jr. Author information: (1)School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil. lanchajr@hotmail.com The search for the causes of obesity has involved genetic abnormalities and endocrine and neural lesions. Although evidence suggests that genetics plays an important role in body weight regulation, rapid increases in obesity rates do not seem to be caused by significant genetic changes within populations. Total energy expenditure and total energy intake are not the only factors that regulate body fat. Nitrogen and carbohydrate balances are eased by the capacity of the organism for adjusting amino acids and glucose oxidation rates, respectively. Regarding fat, this mechanism is considerably less precise; a fat intake increase does not stimulate its oxidation on the same basis. In addition, dietary fat is stored very efficiently as body fat. Elevated carbohydrate ingestion enhances glycogen reserves, which usually are much smaller than the maximum capacity of storage and enlargement of these stores, thus stimulating this nutrient's oxidation. These data point to a very well controlled carbohydrate balance in the body. Various studies show lack of efficiency of the hyperlipidic diet in stimulating satiety. Signals arising from the gastrointestinal tract play a fundamental role in regulation of appetite and energy intake, and evidence indicates that the gastrointestinal and hormonal mechanisms involved in the suppression of appetite and in energy intake are compromised in obesity. A high-fat diet is important in its origin. Additional studies are necessary to explain the mechanisms that lead to adipose tissue retention resulting in a fat-rich diet. PMID: 21041808 [PubMed - indexed for MEDLINE] 1109. Acta Physiol (Oxf). 2011 Mar;201(3):297-312. doi: 10.1111/j.1748-1716.2010.02201.x. Tissue specificity on insulin action and resistance: past to recent mechanisms. Benito M(1). Author information: (1)Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. benito@farm.ucm.es Insulin resistance is the most important pathophysiological feature in many pre-diabetic states. Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion by pancreatic β-cells. The creation of monogenic or polygenic genetically manipulated mice models in a tissue-specific manner was of great help to elucidate the tissue specificity of insulin action and its contribution to the overall insulin resistance. However, a complete understanding of the molecular bases of insulin action and resistance requires the identification of intracellular pathways that regulate insulin-stimulated proliferation, differentiation and metabolism. Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin resistance or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B have been developed. Indeed, these cell lines have also been very useful to understand the tissue specificity of insulin action and inaction. Obesity is a risk factor for several components of the metabolic syndromes such as type 2 diabetes, dyslipidaemia and systolic hypertension, because white and brown adipose tissues as endocrine organs express and secrete a variety of adipocytokines that can act at both local and systemic levels, modulating the insulin sensitivity. Recent studies revealed that the subjects with the highest transcription rates of genes encoding TNF-α and IL-6 were prone to develop obesity, insulin resistance and type 2 diabetes. Accordingly, we specifically focus in this review on the impact of those adipocytokines on the modulation of insulin action in skeletal muscle. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society. PMID: 21040498 [PubMed - indexed for MEDLINE] 1110. Hepatology. 2010 Nov;52(5):1836-46. doi: 10.1002/hep.24001. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Tilg H(1), Moschen AR. Author information: (1)Christian Doppler Research Laboratory for Gut Inflammation, Medical University Innsbruck, Innsbruck, Austria. herbert.tilg@i-med.ac.at Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH. PMID: 21038418 [PubMed - indexed for MEDLINE] 1111. Prog Mol Biol Transl Sci. 2010;94:197-212. doi: 10.1016/S1877-1173(10)94007-6. Cutting the fat: the genetic dissection of body weight. Comuzzie AG(1), Higgins PB, Voruganti S, Cole S. Author information: (1)Chronic Disease and Genomics, Southwest National Primate Research Center, San Antonio, Texas, USA. Variation in body weight and composition, as well as adipose tissue function, is regulated by environmental and genetic factors, combined with a variety of interactions, including environment-by-environment, gene-by-gene, and gene-by-environment interactions. Although the recent increase in obesity can in large part be attributed to the increased availability of low-cost but energy-dense foods and an increasingly sedentary lifestyle throughout most of the developed world, the impact of these factors is more pronounced in individuals who are genetically susceptible to these environmental insults. Hence, it is likely to be the response of an individual's genetic background to a given environment that determines susceptibility to obesity. Candidate gene studies, genome-wide linkage studies, and more recently genome-wide association studies (GWASs) have been used to decipher the effect of genetics on obesity. Heritability estimates suggest that 40-70% of the variation in obesity-related phenotypes is attributable to underlying genetic variation. To date, the findings from human cohort studies (both family and case/control studies) summarized in this chapter suggest that there are likely numerous genes impacting the expression of obesity-related phenotypes, with many of these genes seeming to have modest effects. The establishment of many population-based studies that have collected genome-wide data on genetic variation has recently led to the formation of multiple consortia facilitating powerful meta-analyses in order to identify additional genetic variation influencing obesity-related traits through GWAS, as well as to replicate and further characterize previously identified genetic variants and their gene regions. These consortia may have the power to elucidate how genetic and environmental factors act and interact to produce variation in obesity-related phenotypes. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21036326 [PubMed - indexed for MEDLINE] 1112. Prog Mol Biol Transl Sci. 2010;94:159-96. doi: 10.1016/S1877-1173(10)94006-4. A translational view of the genetics of lipodystrophy and ectopic fat deposition. Lanktree MB(1), Johansen CT, Joy TR, Hegele RA. Author information: (1)Departments of Medicine and Biochemistry, Schulich School of Medicine & Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, University of Western Ontario, London, Canada. A wide range of lipodystrophy syndromes exist, each with varying clinical presentations, and yet cumulatively they underscore the importance of adipocyte biology in human metabolism. Loss of the ability to retain excess lipids in "classical" adipose tissue stores can lead to the overdevelopment of ectopic fat stores, often creating severe perturbations of both glucose and lipid homeostasis. Linkage analysis and candidate sequencing efforts have successfully identified responsible mutations for multiple forms of lipodystrophy. Recently, the reduction in the cost of DNA sequencing has resulted in discovery of many novel mutations within both known and novel loci. In this review, we present the steps involved in clinical characterization of a suspected lipodystrophy case, an overview of the clinical manifestations, molecular findings, and pathogenic basis of different forms of lipodystrophy, a discussion of therapeutic options for lipodystrophy patients, and an examination of genetic advances that will be used to identify additional pathogenic mechanisms. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21036325 [PubMed - indexed for MEDLINE] 1113. Prog Mol Biol Transl Sci. 2010;94:75-123. doi: 10.1016/S1877-1173(10)94004-0. The genetics of brown adipose tissue. Kozak LP(1), Koza RA. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA. Brown adipose tissue is highly differentiated and has evolved as a mechanism for heat production based upon uncoupling of mitochondrial oxidative phosphorylation. Additionally, large amounts of lipid can be stored in the cells to provide fuel necessary for heat production upon adrenergic stimulation from the central nervous system, and a highly developed vascular system evolved to rapidly deliver heat to vital organs. For unknown reasons, the development of brown adipocytes has two independent pathways: one originates from muscle progenitor cells in the fetus and leads to a fully functional cell at birth (interscapular-type brown fat), while the other transiently emerges in traditional white fat depots at weaning, regresses, and then can be induced in adult mice upon adrenergic stimulation. No genetic variants have been found for interscapular fat, but naturally occurring alleles at eight genetic loci in mice lead to over 100-fold variation for brown adipocytes in white fat upon adrenergic stimulation. The ability to activate this potential for energy expenditure is of great interest in obesity research. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21036323 [PubMed - indexed for MEDLINE] 1114. Prog Mol Biol Transl Sci. 2010;94:39-74. doi: 10.1016/S1877-1173(10)94003-9. Genetics of adipose tissue biology. Dahlman I, Arner P. Adipose tissue morphology and release of free fatty acids, as well as peptide hormones, are believed to contribute to obesity and related metabolic disorders. These adipose tissue phenotypes are influenced by adiposity, but there is also a strong hereditary impact. Polymorphisms in numerous adipose-expressed genes have been evaluated for association with adipocyte and clinical phenotypes. In our opinion, some results are convincing. Thus ADRB2 and GPR74 genes are associated with adipocyte lipolysis, GPR74 also with BMI; PPARG and SREBP1, which promote adipogenesis and lipid storage, are associated with T2D and possible adiposity; ADIPOQ and ARL15 are associated with circulating levels of adiponectin, ARL15 also with coronary heart disease. We anticipate that the use of complementary approaches such as expression profiling and RNAi screening, and studies of additional levels of gene regulation, that is, miRNA and epigenetics, will be important to unravel the genetics of adipose tissue function. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 21036322 [PubMed - indexed for MEDLINE] 1115. Placenta. 2011 Jan;32(1):1-7. doi: 10.1016/j.placenta.2010.09.019. Epub 2010 Oct 27. Obesity and the placenta: A consideration of nutrient exchange mechanisms in relation to aberrant fetal growth. Higgins L(1), Greenwood SL, Wareing M, Sibley CP, Mills TA. Author information: (1)Maternal and Fetal Health Research Centre, Research School of Biomedicine, University of Manchester, UK. Lucy.Higgins@doctors.org.uk The obesity epidemic, including childhood obesity, is rapidly gaining strength as one of the most significant challenges to the health of the global community in the 21st Century. The proportion of women who are obese at the beginning of pregnancy is also increasing. These women and their babies are at high risk of pregnancy complications, and of programming for metabolic disease in adult life. In particular, maternal obesity is associated with aberrant fetal growth, encompassing both growth restricted and large for gestational age, or macrosomic fetuses. This article considers the potential effect of obesity and adipose tissue on placental nutrient exchange mechanisms in relation to aberrant fetal growth. The review emphasizes the dearth of work on this topic to date despite its importance to current and future healthcare of the population. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 21030077 [PubMed - indexed for MEDLINE] 1116. Nutr Res Rev. 2010 Dec;23(2):270-99. doi: 10.1017/S0954422410000168. Epub 2010 Oct 27. High-fat diet-induced obesity in animal models. Hariri N(1), Thibault L. Author information: (1)School of Dietetics and Human Nutrition, McGill University, Quebec, Canada. Epidemiological studies have shown a positive relationship between dietary fat intake and obesity. Since rats and mice show a similar relationship, they are considered an appropriate model for studying dietary obesity. The present paper describes the history of using high-fat diets to induce obesity in animals, aims to clarify the consequences of changing the amount and type of dietary fats on weight gain, body composition and adipose tissue cellularity, and explores the contribution of genetics and sex, as well as the biochemical basis and the roles of hormones such as leptin, insulin and ghrelin in animal models of dietary obesity. The major factors that contribute to dietary obesity - hyperphagia, energy density and post-ingestive effects of the dietary fat - are discussed. Other factors that affect dietary obesity including feeding rhythmicity, social factors and stress are highlighted. Finally, we comment on the reversibility of high-fat diet-induced obesity. PMID: 20977819 [PubMed - indexed for MEDLINE] 1117. Obes Rev. 2011 May;12(5):e44-53. doi: 10.1111/j.1467-789X.2010.00812.x. Epub 2010 Oct 26. Metabolic flexibility and obesity in children and youth. Aucouturier J(1), Duché P, Timmons BW. Author information: (1)Children's Exercise & Nutrition Centre, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. aucoutu@mcmaster.ca The concept of metabolic flexibility describes the ability of skeletal muscle to switch between the oxidation of lipid as a fuel during fasting periods to the oxidation of carbohydrate during insulin stimulated period. Alterations in energy metabolism in adults with obesity, insulin resistance and/or type 2 diabetes induce a state of impaired metabolic flexibility, or metabolic inflexibility. Despite the increase in the prevalence of type 2 diabetes in obese children and youth, less is known about the factors involved in the development of metabolic inflexibility in the paediatric population. Metabolic flexibility is conditioned by nutrient partitioning in response to feeding, substrate mobilization and delivery to skeletal muscle during fasting or exercising condition, and skeletal muscle oxidative capacity. Our aim in this review was to identify among these factors those making obese children at risk of metabolic inflexibility. The development of ectopic rather than peripheral fat storage appears to be a factor strongly linked with a reduced metabolic flexibility. Tissue growth and maturation are determinants of impaired energy metabolism later in life but also as a promising way to reverse metabolic inflexibility given the plasticity of many tissues in youth. Finally, we have attempted to identify perspectives for future investigations of metabolic flexibility in obese children that will improve our understanding of the genesis of metabolic diseases associated with obesity. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 20977601 [PubMed - indexed for MEDLINE] 1118. Antioxid Redox Signal. 2011 Feb 1;14(3):519-30. doi: 10.1089/ars.2010.3424. Balancing mitochondrial redox signaling: a key point in metabolic regulation. Leloup C(1), Casteilla L, Carrière A, Galinier A, Benani A, Carneiro L, Pénicaud L. Author information: (1)Centre des Sciences du Goût et de l'Alimentation, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6265-Institut National de Recherche Agronomique 1324, Université de Bourgogne, Dijon, France. leloup@cict.fr Mitochondrial reactive oxygen species (mROS) have emerged as signaling molecules in physiology primarily as a result of studies of uncoupling mechanisms in mitochondrial respiration. The discovery that this mechanism negatively regulates mROS generation in many cell types has drawn the attention of the scientific community to the pathological consequences of excess mROS production. From reports of the energetic fluxes in cells grown under normal conditions, the hypothesis that mROS are an integrated physiological signal of the metabolic status of the cell has emerged. Here, we consider recent studies that support this point of view in two key nutrient sensors of the body, beta cells and the hypothalamus, which are the main coordinators of endocrine and nervous controls of energy metabolism and adipose tissue, which is of paramount importance in controlling body weight and, therefore, the development of obesity and type 2 diabetes. In this context, finely balanced mROS production may be at the core of proper metabolic maintenance, and unbalanced mROS production, which is largely documented, might be an important trigger of metabolic disorders. PMID: 20977349 [PubMed - indexed for MEDLINE] 1119. Ann N Y Acad Sci. 2010 Oct;1207 Suppl 1:E94-102. doi: 10.1111/j.1749-6632.2010.05752.x. Lymphatic system: a vital link between metabolic syndrome and inflammation. Chakraborty S(1), Zawieja S, Wang W, Zawieja DC, Muthuchamy M. Author information: (1)Division of Lymphatic Biology, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, College Station, Texas 77843, USA. Metabolic syndrome is defined by a cluster of different metabolic risk factors that include overall and central obesity, elevated fasting glucose levels, dyslipidemia, hypertension, and intimal atherogenesis. Metabolic syndrome leads to increased risk for the development of type 2 diabetes and cardiovascular disease (e.g., heart disease and stroke). The exacerbated progression of metabolic syndrome to cardiovascular disease has lead to intense study of the physiological ramifications of metabolic syndrome on the blood vasculature. These studies have particularly focused on the signaling and architectural alterations that manifest in hypertension and atherosclerosis. However, despite the overlap of metabolic syndrome pathology with lymphatic function, tangent effects on the lymphatic system have not been extensively documented. In this review, we discuss the current status of metabolic syndrome and provide evidence for, and the remaining challenges in studying, the connections among the lymphatic system, lipid transport, obesity, insulin resistance, and general inflammation. © 2010 New York Academy of Sciences. PMCID: PMC2965625 PMID: 20961312 [PubMed - indexed for MEDLINE] 1120. Stem Cell Rev. 2011 Jun;7(2):342-63. doi: 10.1007/s12015-010-9196-4. Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Anzalone R(1), Lo Iacono M, Loria T, Di Stefano A, Giannuzzi P, Farina F, La Rocca G. Author information: (1)Sezione di Anatomia Umana, Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Via del Vespro 129, Palermo, PA 90127, Italy. Mesenchymal stem cells (MSC) are uniquely capable of crossing germinative layers borders (i.e. are able to differentiate towards ectoderm-, mesoderm- and endoderm-derived cytotypes) and are viewed as promising cells for regenerative medicine approaches in several diseases. Type I diabetes therapy should potentially benefit from such differentiated cells: the search for alternatives to organ/islet transplantation strategies via stem cells differentiation is an ongoing task, significant goals having been achieved in most experimental settings (e.g. insulin production and euglycaemia restoration), though caution is still needed to ensure safe and durable effects in vivo. MSC are obtainable in high numbers via ex vivo culture and can be differentiated towards insulin-producing cells (IPC). Moreover, recent reports evidenced that MSC possess immunomodulatory activities (acting on both innate and acquired immunity effectors) which should result in a reduction of the immunogenicity of transplanted cells, thus limiting rejection. Moreover it has been proposed that MSC administration should be used to attenuate the autoimmune processes which lead to the destruction of beta cells. This review illustrates the recent advances made in differentiating human MSC to IPC. In particular, we compare the effectiveness of the differentiation protocols applied, the markers and functional assays used to characterize differentiated progeny, and the in vivo controls. We further speculate on how MSC derived from Wharton's jelly of human umbilical cord may represent a more promising regenerative medicine tool, as recently demonstrated for endoderm-derived organs (as liver) in human subjects, also considering their peculiar immunomodulatory features compared to other MSC populations. PMID: 20972649 [PubMed - indexed for MEDLINE] 1121. Prog Lipid Res. 2011 Jan;50(1):115-31. doi: 10.1016/j.plipres.2010.10.005. Epub 2010 Oct 21. Functional and pathological roles of the 12- and 15-lipoxygenases. Dobrian AD(1), Lieb DC, Cole BK, Taylor-Fishwick DA, Chakrabarti SK, Nadler JL. Author information: (1)Eastern Virginia Medical School, Department of Physiological Sciences, Lewis Hall, Room 2027, 700 W. Olney Road, Norfolk, VA 23507, United States. dobriaad@EVMS.EDU The 12/15-lipoxygenase enzymes react with fatty acids producing active lipid metabolites that are involved in a number of significant disease states. The latter include type 1 and type 2 diabetes (and associated complications), cardiovascular disease, hypertension, renal disease, and the neurological conditions Alzheimer's disease and Parkinson's disease. A number of elegant studies over the last thirty years have contributed to unraveling the role that lipoxygenases play in chronic inflammation. The development of animal models with targeted gene deletions has led to a better understanding of the role that lipoxygenases play in various conditions. Selective inhibitors of the different lipoxygenase isoforms are an active area of investigation, and will be both an important research tool and a promising therapeutic target for treating a wide spectrum of human diseases. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC3012140 PMID: 20970452 [PubMed - indexed for MEDLINE] 1122. Crit Care Clin. 2010 Oct;26(4):629-31. doi: 10.1016/j.ccc.2010.06.007. Immunologic changes in obesity. Craft MK(1), Reed MJ. Author information: (1)Division of Critical Care Medicine, Geisinger Medical Center, 100 North Academy Avenue, Danville, PA 17822, USA. A growing body of literature suggests multifaceted alterations to the immune function in obese patients compared with a lean cohort. Although treatment in the intensive care unit has an associated risk of infectious complications, which, if any, of these immunologic alterations are causal is unclear. Obesity clearly causes abundant alterations to the immune system. Overall, the aggregate effect seems to be chronic activation of inflammatory mediators. Copyright © 2010. Published by Elsevier Inc. PMID: 20970048 [PubMed - indexed for MEDLINE] 1123. Ageing Res Rev. 2011 Jan;10(1):153-62. doi: 10.1016/j.arr.2010.10.001. Epub 2010 Oct 20. Caloric restriction and longevity: effects of reduced body temperature. Carrillo AE(1), Flouris AD. Author information: (1)FAME Laboratory, Institute of Human Performance and Rehabilitation, Centre for Research and Technology Thessaly, Trikala, Greece. Caloric restriction (CR) causes a reduction in body temperature (T(b)) which is suggested to contribute to changes that increase lifespan. Moreover, low T(b) has been shown to improve health and longevity independent of CR. In this review we examine the connections between CR, T(b) and mechanisms that influence longevity and ageing. Recent findings regarding the overlapping mechanisms of CR and T(b) that benefit longevity are discussed, including changes in body composition, hormone regulation, and gene expression, as well as reductions in low-level inflammation and reactive oxygen species-induced molecular damage. This information is summarized in a model describing how CR and low T(b), both synergistically and independently, increase lifespan. Moreover, the nascent notion that the rate of ageing may be pre-programmed in response to environmental influences at critical periods of early development is also considered. Based on current evidence, it is concluded that low T(b) plays an integral role in mediating the effects of CR on health and longevity, and that low T(b) may exert independent biological changes that increase lifespan. Our understanding of the overlap between CR- and T(b)-mediated longevity remains incomplete and should be explored in future research. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 20969980 [PubMed - indexed for MEDLINE] 1124. Mol Biosyst. 2011 Jan;7(1):91-100. doi: 10.1039/c0mb00099j. Epub 2010 Oct 22. Which CIDE are you on? Apoptosis and energy metabolism. Yonezawa T(1), Kurata R, Kimura M, Inoko H. Author information: (1)Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Bohseidai, Ishehara, Kanagawa 259-1193, Japan. yonet2301@yahoo.co.jp Around 1998, cell death-inducing DNA fragmentation factor-alpha (DFFA)-like effector (CIDE) proteins including CIDEA, CIDEB and CIDEC/fat specific protein 27 (Fsp27) were first identified by their sequence homology with the N-terminal domain of the DNA fragmentation factor (DFF). Indeed, in vitro analysis revealed that all three CIDE proteins are involved in apoptosis. However, recent gene-targeting studies have provided novel insights into the physiological function of CIDE proteins. Mice deficient in each CIDE protein exhibit lean phenotypes, a reduction of lipid droplet size in white adipose tissue and increased metabolic rate. Thus, all CIDE proteins play an important role in energy metabolism and lipid droplet formation. More recently, a glycoproteomics approach has shown that post-translational regulation of CIDE proteins via glycosylation modulates transforming growth factor (TGF)-beta 1-dependent apoptosis. Another recent study using mouse embryonic fibroblasts derived from CIDEA-deficient mice revealed that 5'AMP-activated protein kinase (AMPK) activity is regulated by CIDEA-mediated ubiquitin-dependent proteasomal degradation via a protein interaction with the AMPK beta subunit. Even after a decade of study, the physiological roles of CIDE proteins have still not been completely elucidated. This review aims to shed light on the novel functions of CIDE proteins and their physiological roles. PMID: 20967381 [PubMed - indexed for MEDLINE] 1125. Free Radic Res. 2011 Jan;45(1):101-9. doi: 10.3109/10715762.2010.524643. Epub 2010 Oct 22. Succination of proteins in diabetes. Frizzell N(1), Lima M, Baynes JW. Author information: (1)Department of Exercise Science, School of Public Health, University of South Carolina, Columbia, SC 29208, USA. frizzeln@mailbox.sc.edu Cysteine is arguably the most reactive amino acid in protein. A wide range of cysteine derivatives is formed in vivo, resulting from oxidation, nitrosation, alkylation and acylation reactions. This review describes succination of proteins, an irreversible chemical modification of cysteine by the Krebs cycle intermediate, fumarate, yielding S-(2-succinyl)cysteine (2SC). Intracellular fumarate concentration and succination of proteins are increased by hyperpolarization of the inner mitochondrial membrane and develop in concert with mitochondrial and oxidative stress in diabetes. Increased succination of glyceraldehyde-3-phosphate dehydrogenase explains the loss in specific activity of this enzyme in muscle of streptozotocin-diabetic rats and increased succination of adiponectin may explain the decreased secretion of adiponectin from adipose tissue in type 2 diabetes. In addition to GAPDH and adiponectin, other succinated proteins identified in adipocytes include cytoskeletal proteins (tubulin, actin) and chaperone proteins in the endoplasmic reticulum. Succination of adipocyte protein in vitro is inhibited by uncouplers of oxidative phosphorylation and by inhibitors of ER stress. 2SC serves as a biomarker of mitochondrial stress and recent studies suggest that succination is the mechanistic link between mitochondrial and ER stress in diabetes. PMID: 20964553 [PubMed - indexed for MEDLINE] 1126. Endocrine. 2010 Feb;37(1):11-32. doi: 10.1007/s12020-009-9278-8. Epub 2009 Dec 1. Adiponectin action from head to toe. Brochu-Gaudreau K(1), Rehfeldt C, Blouin R, Bordignon V, Murphy BD, Palin MF. Author information: (1)Département de biologie, Université de Sherbrooke, Sherbrooke, QC, Canada. Adiponectin, the most abundant protein secreted by white adipose tissue, is known for its involvement in obesity-related disorders such as insulin resistance, type 2 diabetes mellitus and atherosclerosis. Moreover, modulation of the circulating adiponectin concentration is observed in pathologies that are more or less obesity-related, such as cancer and rheumatoid arthritis. The wide distribution of adiponectin receptors in various organs and tissues suggests that adiponectin has pleiotropic effects on numerous physiological processes. Besides its well-known insulin-sensitizing, anti-inflammatory and antiatherosclerotic properties, accumulating evidence suggests that adiponectin may also have anticancer properties and be cardioprotective. A beneficial effect of adiponectin on female reproductive function was also suggested. Since adiponectin has numerous beneficial biological functions, its use as a therapeutic agent has been suggested. However, the use of adiponectin or its receptors as therapeutic targets is complicated by the presence of different adiponectin oligomeric isoforms and production sites, by multiple receptors with differing affinities for adiponectin isoforms, and by cell-type-specific effects in different tissues. In this review, we discuss the known and potential roles of adiponectin in various tissues and pathologies. The therapeutic promise of administration of adiponectin and the use of its circulating levels as a diagnostic biomarker are further discussed based on the latest experimental studies. PMID: 20963555 [PubMed - indexed for MEDLINE] 1127. Seikagaku. 2010 Sep;82(9):832-6. [In vivo imaging reveals chronic inflammation and abnormal local immunity in obese adipose tissue]. [Article in Japanese] Nishimura S(1), Nagasaki M. Author information: (1)Department of Cardiovascular Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. PMID: 20960919 [PubMed - indexed for MEDLINE] 1128. Mt Sinai J Med. 2010 Sep-Oct;77(5):511-23. doi: 10.1002/msj.20212. Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Gallagher EJ(1), Leroith D, Karnieli E. Author information: (1)Mount Sinai School of Medicine, New York, NY, USA. The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic syndrome. PMID: 20960553 [PubMed - indexed for MEDLINE] 1129. Semin Liver Dis. 2010 Nov;30(4):391-401. doi: 10.1055/s-0030-1267539. Epub 2010 Oct 19. Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Feldstein AE(1). Author information: (1)Department of Cell Biology, Cleveland Clinic, Cleveland, OH, USA. feldsta@ccf.org Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. NAFLD encompasses a wide spectrum of conditions associated with overaccumulation of lipids in the liver. It is strongly associated with obesity and insulin resistance and has been growingly recognized as an independent risk factor for cardiovascular disease. In this review, recently uncovered novel aspects of the molecular events responsible for the development and progression of this highly prevalent and potentially serious disease are discussed. These studies bring new insights that may significantly impact the clinical approach to patients with NAFLD, from novel diagnostics to innovative therapeutic strategies. © Thieme Medical Publishers. PMID: 20960378 [PubMed - indexed for MEDLINE] 1130. Semin Liver Dis. 2010 Nov;30(4):378-90. doi: 10.1055/s-0030-1267538. Epub 2010 Oct 19. The role of lipid metabolism in the pathogenesis of alcoholic and nonalcoholic hepatic steatosis. Sozio MS(1), Liangpunsakul S, Crabb D. Author information: (1)Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. Hepatic steatosis is now understood to play an important role in the development of advanced liver disease. Alcoholic and nonalcoholic fatty liver each begin with the accumulation of lipids in the liver. Lipid accumulation in the liver can occur through maladaptations of fatty acid uptake (either through dietary sources or from fat tissue), fatty acid synthesis, fatty acid oxidation, or export of lipids from the liver. Alterations in mechanisms of fatty acid uptake through both dietary uptake and lipolysis in adipose tissue can contribute to the pathogenesis of both disorders, as can effects on fatty acid transporters. Effects on lipid synthesis in alcoholic and nonalcoholic fatty liver involve the endoplasmic reticulum (ER) stress response, homocysteine metabolism pathway, and different transcription factors regulating genes in the lipid synthesis pathway. Fatty acid oxidation, through effects on AMP-activated protein kinase (AMPK), adiponectin, peroxisome proliferator-activated receptors (PPARs), and mitochondrial function is predominantly altered in alcoholic liver disease, although studies suggest that activation of this pathway may improve nonalcoholic fatty liver disease. Finally, changes in fatty acid export, through effects on apolipoprotein B and microsomal transport protein are seen in both diseases. Thus, the similarities and differences in the mechanism of fat accumulation in the liver in nonalcoholic and alcoholic liver disease are explored in detail. © Thieme Medical Publishers. PMID: 20960377 [PubMed - indexed for MEDLINE] 1131. Stem Cell Res Ther. 2010 Oct 13;1(4):31. doi: 10.1186/scrt31. Chondrogenesis of mesenchymal stem cells: role of tissue source and inducing factors. Boeuf S(1), Richter W. Author information: (1)Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. stephane.boeuf@med.uni-heidelberg.de Multipotent mesenchymal stromal cells (MSCs) are an attractive cell source for cell therapy in cartilage. Although their therapeutic potential is clear, the requirements and conditions for effective induction of chondrogenesis in MSCs and for the production of a stable cartilaginous tissue by these cells are far from being understood. Different sources of MSCs have been considered for cartilage tissue engineering, mainly based on criteria of availability, as for adipose tissue, or of proximity to cartilage and the joint environment in vivo, as for bone marrow and synovial tissues. Focussing on human MSCs, this review will provide an overview of studies featuring comparative analysis of the chondrogenic differentiation of MSCs from different sources. In particular, it will examine the influence of the cells' origin on the requirements for the induction of chondrogenesis and on the phenotype achieved by the cells after differentiation. PMCID: PMC2983444 PMID: 20959030 [PubMed - indexed for MEDLINE] 1132. Nat Rev Endocrinol. 2010 Dec;6(12):689-97. doi: 10.1038/nrendo.2010.187. Epub 2010 Oct 19. The metabolic actions of glucagon revisited. Habegger KM(1), Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH. Author information: (1)Department of Medicine, University of Cincinnati, Metabolic Diseases Institute, Office E-217, 2170 East Galbraith Road, Cincinnati, OH 45237, USA. The initial identification of glucagon as a counter-regulatory hormone to insulin revealed this hormone to be of largely singular physiological and pharmacological purpose. Glucagon agonism, however, has also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity. Studies that describe novel preclinical applications of glucagon, alone and in concert with glucagon-like peptide 1 agonism, have revealed potential benefits of glucagon agonism in the treatment of the metabolic syndrome. Collectively, these observations challenge us to thoroughly investigate the physiology and therapeutic potential of insulin's long-known opponent. PMCID: PMC3563428 PMID: 20957001 [PubMed - indexed for MEDLINE] 1133. Med Sport Sci. 2010;55:56-68. doi: 10.1159/000321972. Epub 2010 Oct 14. Visfatin and adiponectin levels in children: relationships with physical activity and metabolic parameters. Mäestu J(1), Jürimäe J, Jürimäe T. Author information: (1)Faculty of Exercise and Sport Sciences, Centre of Behavioral and Health Sciences, University of Tartu, Tartu, Estonia. Jarek.Maestu@ut.ee Childhood obesity is increasing throughout the world and increases in adipose tissue are related to insulin resistance, cardiovascular diseases and metablic syndrome. Adipose tissue is not simply a storage depot for surplus energy but rather, is an active organ that modulates various biological functions and synthesizes and secretes multiple cytokines into the circulation. Adiponectin and visfatin are two cytokines which are considered to be possible links between obesity, insulin resistance and the metabolic syndrome. In turn, concentrations of adiponectin and visfatin are mainly influenced by the overall body fat mass which is one of the main determinants of insulin resistance and cardiovascular diseases. In contrast, physical activity and exercise are negatively related to body fat mass and also have an influence on cytokine concentrations in the blood. It is of particular interest whether physical activity or lifestyle interventions have a positive effect on adiponectin and visfatin concentrations in the blood. The aim of this review is to provide an overview of the contribution of vistafin and adiponectin to various metabolic parameters and their relationship with different physical activity patterns in children and adolescents. Copyright © 2010 S. Karger AG, Basel. PMID: 20956860 [PubMed - indexed for MEDLINE] 1134. Med Sport Sci. 2010;55:32-42. doi: 10.1159/000321970. Epub 2010 Oct 14. Body composition differences in normal weight, obese-overweight and anorexic adolescents: role of adipocytokines. Ondrak KS(1), Hackney AC. Author information: (1)Department of Exercise and Sport Science, Applied Physiology Laboratory, Fetzer Hall, University of North Carolina, Chapel Hill, N.C. 27599, USA. kondrak@unc.edu Adipocytokines are signaling molecules released by adipose tissue with numerous functions, including regulation of metabolism, inflammatory process, and body mass. They are particularly interesting in youth, considering the rising prevalence of overweight/obesity and the linkage of this condition to inflammation. This chapter examines the relationship between body composition and select adipocytokines: leptin, adiponectin, IL-6, TNF-α, and resistin, in overweight, normal weight and anorexic youth. Leptin, which stimulates energy expenditure and promotes satiety, is highest in overweight youth, followed by normal weight and lastly anorexic youth. Adiponectin has similar functions to leptin but is negatively correlated with measures of body composition. Anorexic youth have the highest adiponectin per kg fat mass, followed by normal weight and overweight. Conversely, IL-6 is positively associated with body composition; however, research in anorexic youth is inconclusive. It has some pro-inflammatory effects and promotes glucose and fat use, therefore beneficial for maintenance of normal weight status. TNF-α is also a pro-inflammatory adipocytokine thought to be somewhat protective against cancer. TNF-α is highest in overweight, followed by normal weight and anorexic youth, similar to leptin. Finally, resistin is also involved in the pro-inflammatory response and the development of insulin resistance. However, far less research exists on this adipocytokine and its relation to body composition in overweight or anorexic youth is equivocal. In conclusion, several consistent relationships exist regarding adipocytokines and body composition; however, there is a need for additional research on these relationships in youth especially at extremes of adiposity such as overweight and anorexics. Copyright © 2010 S. Karger AG, Basel. PMID: 20956858 [PubMed - indexed for MEDLINE] 1135. Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):695-708. doi: 10.1016/j.bpg.2010.08.005. Nonalcoholic fatty liver disease. Krawczyk M(1), Bonfrate L, Portincasa P. Author information: (1)Department of Medicine II, Saarland University Hospital, Homburg, Germany. Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 20955971 [PubMed - indexed for MEDLINE] 1136. Diabetologia. 2011 Jan;54(1):7-9. doi: 10.1007/s00125-010-1938-y. Epub 2010 Oct 16. Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase. Stefan N(1), Staiger H, Häring HU. Author information: (1)Department of Internal Medicine, University of Tübingen, Germany. norbert.stefan@med.uni-tuebingen.de Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance and type 2 diabetes in humans. Ongoing research aims to clarify the mechanisms involved in this relationship. Studying pathways that are involved in the dissociation between fatty liver and insulin resistance may help to achieve this goal. Among several enzymes that regulate the fate of hepatic lipids, adipose triacylglycerol lipase (ATGL) is of interest. This article briefly summarises novel information about the impact of ATGL in this process. PMID: 20953581 [PubMed - indexed for MEDLINE] 1137. Int J Oral Maxillofac Surg. 2011 Jan;40(1):50-6. doi: 10.1016/j.ijom.2010.06.025. Epub 2010 Oct 16. Versatility of full thickness skin-subcutaneous fat grafts as interpositional material in the management of temporomandibular joint ankylosis. Thangavelu A(1), Santhosh Kumar K, Vaidhyanathan A, Balaji M, Narendar R. Author information: (1)Division of Oral and Maxillofacial Surgery, Rajah Muthiah Dental College and Hospitals, Chidambaram, Tamil Nadu, India. omfsvat@hotmail.com The authors present a review of seven patients (eight joints) with temporomandibular ankylosis treated between 2007 and 2008. The aim of this retrospective study was to present the experience of using full thickness skin-subcutaneous fat grafts, harvested from the patient's abdomen as interpositional material after gap arthroplasty. All patients presented with osseous ankylosis and were graded according to Topazian's classification. Postoperative follow up ranged from 12 to 24 months. Maximal inter-incisal opening (MIO) on presentation ranged from 0 to 8mm, which stabilized to 27-44mm at follow up. There was no evidence of re-ankylosis. This study found merit in the use of autogenous full thickness skin-subcutaneous fat graft as an interpositional material for up to 2 years following ankylosis release. Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. PMID: 20952163 [PubMed - indexed for MEDLINE] 1138. J Atheroscler Thromb. 2010 Dec 26;17(12):1201-11. Epub 2010 Oct 8. Serum high-molecular-weight adiponectin as a marker for the evaluation and care of subjects with metabolic syndrome and related disorders. Hirose H(1), Yamamoto Y, Seino-Yoshihara Y, Kawabe H, Saito I. Author information: (1)Health Center, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. hhirose@hc.cc.keio.ac.jp In 1996, adiponectin was reported to be the most abundant transcript in adipose tissue. Animal studies revealed that administering adiponectin improves insulin resistance and blood glucose levels and inhibits atherosclerosis. In the present article, we review the significance of measuring serum high-molecular-weight (HMW) adiponectin levels in human subjects. Our cross-sectional studies revealed that the serum HMW adiponectin concentration was 1.9 times higher in healthy Japanese females than males and had a strong positive correlation with HDL-cholesterol but a negative correlation with BMI and the homeostasis model assessment insulin resistance index (HOMA-IR). They also indicated that the serum HMW adiponectin concentration had a stronger association with HOMA-IR and metabolic syndrome than the total adiponectin concentration. Our longitudinal study, a 6-year follow-up of Japanese men, suggested that a decreased level of HMW adiponectin is a predictor of progression to metabolic syndrome. In another intervention study, lifestyle modification for 3 months induced a decrease in BMI and waist circumference and an increase in serum HMW adiponectin but not the total adiponectin level in 16 Japanese males with metabolic syndrome. Administering thiazolidinediones to diabetic patients increased the serum HMW adiponectin concentration 3 fold and improved glucose and lipid profiles and blood pressure. Some people may inherit a lower serum concentration of adiponectin, and have a higher risk of developing cardiovascular diseases.It is suggested that HMW adiponectin is a useful marker for the evaluation and care of subjects with metabolic syndrome and related disorders. PMID: 20948162 [PubMed - indexed for MEDLINE] 1139. Nutrition. 2011 Mar;27(3):269-75. doi: 10.1016/j.nut.2010.07.004. Epub 2010 Oct 13. Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation. Yarandi SS(1), Hebbar G, Sauer CG, Cole CR, Ziegler TR. Author information: (1)Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, Georgia, USA. OBJECTIVE: Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract. METHODS: Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail. RESULTS: The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin. CONCLUSION: Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3066025 PMID: 20947298 [PubMed - indexed for MEDLINE] 1140. Kidney Int. 2011 Jan;79(2):162-8. doi: 10.1038/ki.2010.391. Epub 2010 Oct 13. Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity. Yvan-Charvet L(1), Quignard-Boulangé A. Author information: (1)Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York, USA. Obesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin-angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders. PMID: 20944545 [PubMed - indexed for MEDLINE] 1141. Wiad Lek. 2010;63(2):61-74. [Selected endocrine abnormalities in eating disorders]. [Article in Polish] Krysiak R(1), Kajdaniuk D, Marek B, Okopień B. Author information: (1)Klinika Chorób Wewnetrznych i Farmakologii Klinicznej Katedry Farmakologii, Slaski Uniwersytet Medyczny w Katowicach. r.krysiak@interia.pl Eating disorders belong to frequent health problems affecting people in developed countries. They are generally seen in young women and are particularly common in adolescence. Endocrine consequences of these disorders include: excessive activity of hypothalamic-pituitary-adrenal axis, hypogonadotropic hypogonadism, growth hormone resistance, low T3 syndrome, osteopenia, and abnormal activities of the hypothamus and adipose tissue. The endocrine changes associated with eating disorders have been studied in depth and as suggest the results of so far carried out studies, their aetiology is usually multifactoral. Most of these abnormalities are reversed, or at least alleviated, by weight gain. This review discusses the most important changes in the endocrine system related to eating disorders in the light of recent developments in this field. This article also tries to give insights into diagnosis and putative therapeutic strategies. PMID: 20941919 [PubMed - indexed for MEDLINE] 1142. Curr Diab Rep. 2011 Feb;11(1):41-6. doi: 10.1007/s11892-010-0155-x. Resistant hypertension in the high-risk metabolic patient. Chaudhary K(1), Buddineni JP, Nistala R, Whaley-Connell A. Author information: (1)Harry S. Truman Hospital, University of Missouri Health Sciences Center, 800 Hospital Drive, Columbia, MO 65201, USA. chaudharyk@health.missouri.edu The metabolic syndrome is a constellation of metabolic and vascular abnormalities that include insulin resistance with compensatory hyperinsulinemia, central or visceral obesity, hypertension, dyslipidemia, microalbuminuria, and oxidative stress as well as prothrombotic and inflammatory abnormalities that contribute to a hypercoagulable state and systemic endothelial dysfunction. Visceral adipose tissue is now known to secrete into the circulation a number of protein and nonprotein factors that regulate glucose metabolism in traditional insulin-sensitive tissue as well as nontraditional insulin-sensitive tissue including cardiovascular tissue. Collectively, this constellation of factors that lead to metabolic dysregulation contributes to a substantial risk for adverse cardiovascular and renal outcomes. The development of a particularly resistant form of hypertension in these individuals can be attributed to a number of factors including vasoconstriction from increased sympathetic activation, proinflammatory cytokines, and inappropriate activation of the renin-angiotensin-aldosterone system. The management of hypertension in such patients can be challenging and generally requires nonpharmacologic as well as pharmacologic interventions. PMID: 20941645 [PubMed - indexed for MEDLINE] 1143. PLoS Pathog. 2010 Sep 30;6(9):e1001032. doi: 10.1371/journal.ppat.1001032. Sequestration and tissue accumulation of human malaria parasites: can we learn anything from rodent models of malaria? Franke-Fayard B(1), Fonager J, Braks A, Khan SM, Janse CJ. Author information: (1)Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. The sequestration of Plasmodium falciparum-infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration. PMCID: PMC2947991 PMID: 20941396 [PubMed - indexed for MEDLINE] 1144. Neurogastroenterol Motil. 2010 Dec;22(12):1270-8. doi: 10.1111/j.1365-2982.2010.01609.x. Epub 2010 Oct 5. Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Khoo J(1), Rayner CK, Feinle-Bisset C, Jones KL, Horowitz M. Author information: (1)Centre of Clinical Research Excellence in Nutritional Physiology, School of Medicine, University of Adelaide, Royal Adelaide Hospital, Adelaide, SA, Australia. BACKGROUND: Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients. PURPOSE: This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying. © 2010 Blackwell Publishing Ltd. PMID: 20939851 [PubMed - indexed for MEDLINE] 1145. World J Gastroenterol. 2010 Oct 14;16(38):4762-72. Fat: a matter of disturbance for the immune system. Federico A(1), D'Aiuto E, Borriello F, Barra G, Gravina AG, Romano M, De Palma R. Author information: (1)Section of Clinical Immunology, Department of Clinical and Experimental Medicine, Second University of Naples, Napoli, Italy. raffaele.depalma@unina2.it Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. There is compelling evidence that both overnutrition and undernutrition negatively interfere with the immune system. Overnutrition has been found to increase susceptibility to the development of inflammatory diseases, autoimmune diseases and cancer. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role, not only as an energy store but also as an important endocrine organ. The obese state is characterised by a low-grade systemic inflammation, mainly as a result of increased adipocytes as well as fat resident- and recruited-macrophage activity. In the past few years, various products of adipose tissue including adipokines and cytokines have been characterised and a number of pathways linking adipose tissue metabolism with the immune system have been identified. Activation of the innate immune system plays a major role in hepatic steatosis. Non-alcoholic fatty liver disease includes a wide spectrum of diseases, from pure steatosis to non-alcoholic steatohepatitis in the absence of significant alcohol consumption. Although steatosis is considered a non-progressive disease, non-alcoholic steatohepatitis may deteriorate in advanced chronic liver diseases, cirrhosis, and hepatocellular carcinoma. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages, and growing evidence suggests that Kupffer cells critically contribute to progression of non-alcoholic fatty liver disease. Moreover, a close link between specific immune activation and atherosclerosis has been well established, suggesting that fat can directly trigger immune responses. This review discusses the role of fat as "a matter of disturbance for the immune system" with a focus on hepatic steatosis. PMCID: PMC2955245 PMID: 20939104 [PubMed - indexed for MEDLINE] 1146. Diabetes Metab Res Rev. 2010 Nov;26(8):622-30. doi: 10.1002/dmrr.1135. Epub 2010 Oct 11. Novel insights into the relationship between diabetes and osteoporosis. de Paula FJ(1), Horowitz MC, Rosen CJ. Author information: (1)Center for Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA. Only three decades ago adipose tissue was considered inert, with little relationship to insulin resistance. Similarly, bone has long been thought of purely in its structural context. In the last decade, emerging evidence has revealed important endocrine roles for both bone and adipose tissue. The interaction between these two tissues is remarkable. Bone marrow mesenchymal stem cells give rise to both osteoblasts and adipocytes. Leptin and adiponectin, two adipokines secreted by fat tissue, control energy homeostasis, but also have complex actions on the skeleton. In turn, the activities of bone cells are not limited to their bone remodelling activities but also to modulation of adipose cell sensitivity and insulin secretion. This review will discuss these new insights linking bone remodelling to the control of fat metabolism and the association between diabetes mellitus and osteoporosis. Copyright © 2010 John Wiley & Sons, Ltd. PMCID: PMC3259009 PMID: 20938995 [PubMed - indexed for MEDLINE] 1147. Expert Rev Cardiovasc Ther. 2010 Oct;8(10):1457-67. doi: 10.1586/erc.10.116. New evidence for nicotinic acid treatment to reduce atherosclerosis. Montecucco F(1), Quercioli A, Dallegri F, Viviani GL, Mach F. Author information: (1)Cardiology Division, Department of Medicine, Geneva University Hospital, Foundation for Medical Research, 64 Avenue Roseraie, Geneva, Switzerland. fabrizio.montecucco@unige.ch Nicotinic acid (at a daily dose of grams) has been shown to induce potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional anti-atherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future. PMID: 20936932 [PubMed - indexed for MEDLINE] 1148. Int J Obes (Lond). 2010 Oct;34 Suppl 1:S7-16. doi: 10.1038/ijo.2010.177. Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Cannon B(1), Nedergaard J. Author information: (1)Department of Physiology, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden. barbara.cannon@wgi.su.se Only with the development of the uncoupling protein 1 (UCP1)-ablated mouse has it become possible to strictly delineate the physiological significance of the thermogenic capacity of brown adipose tissue. Considering the presence of active brown adipose tissue in adult humans, these insights may have direct human implications. In addition to classical nonshivering thermogenesis, all adaptive adrenergic thermogeneses, including diet-induced thermogenesis, is fully dependent on brown adipocyte activity. Any weight-reducing effect of β(3)-adrenergic agonists is fully dependent on UCP1 activity, as is any weight-reducing effect of leptin (in excess of its effect on reduction of food intake). Consequently, in the absence of the thermogenic activity of brown adipose tissue, obesity develops spontaneously. The ability of brown adipose tissue to contribute to glucose disposal is also mainly related to thermogenic activity. However, basal metabolic rate, cold-induced thermogenesis, acute cold tolerance, fevers, nonadaptive adrenergic thermogenesis and processes such as angiogenesis in brown adipose tissue itself are not dependent on UCP1 activity. Whereas it is likely that these conclusions are also qualitatively valid for adult humans, the quantitative significance of brown adipose tissue for human metabolism--and the metabolic consequences for a single individual possessing more or less brown adipose tissue--awaits clarification. PMID: 20935668 [PubMed - indexed for MEDLINE] 1149. Int J Obes (Lond). 2010 Oct;34 Suppl 1:S43-6. doi: 10.1038/ijo.2010.183. Brown adipose tissue in humans. Enerbäck S(1). Author information: (1)Department of Medical and Clinical genetics, Göteborg University, Göteborg, Sweden. sven.enerback@medgen.gu.se Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its origin--it results when energy intake exceeds energy expenditure--at present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissue--brown adipose tissue (BAT)--with the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes. PMID: 20935666 [PubMed - indexed for MEDLINE] 1150. Int J Obes (Lond). 2010 Oct;34 Suppl 1:S36-42. doi: 10.1038/ijo.2010.182. Sympathetic and sensory innervation of brown adipose tissue. Bartness TJ(1), Vaughan CH, Song CK. Author information: (1)Department of Biology and Center for Behavioral Neuroscience, Georgia State University, Atlanta, GA, USA. bartness@gsu.edu The innervation of brown adipose tissue (BAT) by the sympathetic nervous system (SNS) is incontrovertible and, with its activation, functions as the principal, if not exclusive, stimulator of BAT thermogenesis. The parasympathetic innervation of BAT only appears in two minor BAT depots, but not in the major interscapular BAT (IBAT) depot. BAT thermogenesis is triggered by the release of norepinephrine from its sympathetic nerve terminals, stimulating β3-adrenoceptors that turns on a cascade of intracellular events ending in activation of uncoupling protein-1 (UCP-1). BAT also has sensory innervation that may function to monitor BAT lipolysis, a response necessary for activation of UCP-1 by fatty acids, or perhaps responding in a feedback manner to BAT temperature changes. The central sympathetic outflow circuits ultimately terminating in BAT have been revealed by injecting the retrograde viral transneuronal tract tracer, pseudorabies virus, into the tissue; moreover, there is a high degree of colocalization of melanocortin 4-receptor mRNA on these neurons across the neural axis. The necessary and sufficient central BAT SNS outflow sites that are activated by various thermogenic stimuli are not precisely known. In a chronic decerebration procedure, IBAT UCP-1 gene expression can be triggered by fourth ventricular injections of melanotan II, the melanocortin 3/4 receptor agonist, suggesting that there is sufficient hindbrain neural circuitry to generate thermogenic responses with this stimulation. The recent recognition of BAT in normal adult humans suggests a potential target for stimulation of energy expenditure by BAT to help mitigate increased body fat storage. PMCID: PMC3999344 PMID: 20935665 [PubMed - indexed for MEDLINE] 1151. Int J Obes (Lond). 2010 Oct;34 Suppl 1:S28-33. doi: 10.1038/ijo.2010.180. Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks. Collins S(1), Yehuda-Shnaidman E, Wang H. Author information: (1)Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL, USA. scollins@burnham.org Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in 'white' adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. β-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-γ coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRα as a cAMP- and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRα-null mice have increased expression of most 'markers' of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases. PMID: 20935662 [PubMed - indexed for MEDLINE] 1152. Int J Obes (Lond). 2010 Oct;34 Suppl 1:S23-7. doi: 10.1038/ijo.2010.179. Brown fat thermogenesis and body weight regulation in mice: relevance to humans. Kozak LP(1), Koza RA, Anunciado-Koza R. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA, USA. kozaklp@pbrc.edu Physiological, pharmacological and genetic studies in dogs, mice and rats have established that the uncoupling protein-1 (UCP1)-based brown adipose tissue system has an important role in the regulation of body temperature. Although it may be possible to create laboratory conditions in which mice with inactivated Ucp1 can survive in a modestly cooled environment, data overwhelmingly support the conclusion that the UCP1/BAT system has evolved to maintain body temperature at 37 °C. The corollary to this conclusion is that any influence UCP1/BAT might have on body weight regulation is a secondary function. The idea that BAT prevents obesity by burning off excess energy to maintain energy balance seems incompatible with evolutionary biology. Premodern humans spent an enormous amount of energy either running to catch their meal or avoiding becoming a meal themselves; consequently, there was no obesity. Nevertheless, although secondary to body temperature regulation, UCP1/BAT is extraordinarily effective at reducing adiposity and insulin resistance in mice and rats. Variation among mice in susceptibility to diet-induced obesity is correlated with the induction of brown adipocytes in traditional white fat depots (wBAT). Both genetic and cell biology-based experimentation have shown that the cellular origins of wBAT are different from those of interscapular-like brown adipocytes (iBAT). Do they have different functions? We have analyzed the effects of the early nutritional environment on the induction of brown adipocytes in inguinal fat to test the hypothesis that wBAT is primarily involved in body weight regulation. Although undernutrition during lactation severely suppresses wBAT at 21 days of age, undernourished mice fed a normal chow diet ad libitum at weaning recovered their normal wBAT and iBAT systems as young adults. The function of wBAT does not seem to be uniquely devoted to body weight regulation. PMID: 20935661 [PubMed - indexed for MEDLINE] 1153. J Anim Sci. 2011 Feb;89(2):591-6. doi: 10.2527/jas.2010-3395. Epub 2010 Oct 8. Copper and lipid metabolism in beef cattle: a review. Engle TE(1). Author information: (1)Department of Animal Sciences, Colorado State University, Fort Collins 80523-1171, USA. terry.engle@colostate.edu Results from experiments investigating Cu metabolism in ruminants indicate that Cu is involved in lipid metabolism. Copper supplementation ranging from 10 to 40 mg of Cu/kg of DM to high-concentrate finishing diets decreased subcutaneous adipose tissue deposition and decreased cholesterol concentrations but increased unsaturated fatty acid composition of LM. Serum norepinephrine tended to be greater in Cu-supplemented steers after a 24-h feed withdrawal and at 2 h postfeed consumption, potentially explaining the reduction in subcutaneous adipose tissue deposition. However, when exogenous norepinephrine was administrated, serum NEFA concentrations were less in Cu-supplemented steers, possibly due to the nonsupplemented control steers having a greater subcutaneous adipose tissue depth at slaughter relative to Cu-supplemented steers. Furthermore, in vitro basal and epinephrine-stimulated lipolytic rates of subcutaneous adipose tissue were greater in Cu-supplemented steers relative to controls. These data indicate that that Cu may influence lipogenic or lipolytic function in subcutaneous adipose tissue. In an attempt to further investigate the effect of Cu on lipid metabolism, lipogenic, lipolytic, and homeostatic mechanisms related to Cu are currently being studied. Recent data indicate that genes involved in bovine liver Cu homeostasis are correlated with Cu transporter protein gene expression in the bovine liver. Therefore, the overall intent of this review is to discuss possible mechanisms whereby Cu may affect lipid metabolism in ruminants. PMID: 20935142 [PubMed - indexed for MEDLINE] 1154. Diabetes Metab. 2010 Sep;36 Suppl 2:S3-18. doi: 10.1016/S1262-3636(10)70002-1. New injection recommendations for patients with diabetes. Frid A(1), Hirsch L, Gaspar R, Hicks D, Kreugel G, Liersch J, Letondeur C, Sauvanet JP, Tubiana-Rufi N, Strauss K; Scientific Advisory Board for the Third Injection Technique Workshop. Author information: (1)Endocrinologist, Clinic of Endocrinology, Skåne University Hospital, Malmö, Sweden. AIM: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. METHODS: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. RESULTS: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. CONCLUSION: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 20933208 [PubMed - indexed for MEDLINE] 1155. Diabetes Metab. 2010 Sep;36 Suppl 2:S19-29. doi: 10.1016/S1262-3636(10)70003-3. The Third Injection Technique Workshop in Athens (TITAN). Frid A(1), Hirsch L, Gaspar R, Hicks D, Kreugel G, Liersch J, Letondeur C, Sauvanet JP, Tubiana-Rufi N, Strauss K. Author information: (1)Endocrinologist, Clinic of Endocrinology, Skåne University Hospital, Malmö, Sweden. The first Injection Technique workshop brought together endocrinologists and injection experts from around the world in Strasbourg in 1997. From its work came groundbreaking recommendations which advanced best practices in areas such as the use of a skin fold when injecting. The second Injection Technique workshop, with an expanded format including nurses and diabetes educators, took place in Barcelona in 2000. The initial stimulus to use shorter injecting needles can be said to date from this meeting. The third Injection Technique workshop was held in Athens in September 2009 and involved 127 experts from across the globe. After a comprehensive review of all publications since 2000 as well as several unpublished studies, the attendees divided into smaller groups to debate and draft new injecting recommendations based on the new data and their collective experience. This paper summarizes all the formal presentations given at this practical consensus workshop. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 20933206 [PubMed - indexed for MEDLINE] 1156. Cardiovasc Hematol Disord Drug Targets. 2010 Dec 1;10(4):269-72. Exercise and cardiovascular disease. Smith JK(1). Author information: (1)Department of Academic Affairs, East Tennessee State University, Johnson City, TN 37614, USA. SMITHJ@mail.etsu.edu Cardiovascular disease is the main cause of death in the United States. Although it is recognized that moderate intensity long-term exercise can decrease the chances of dying from cardiovascular disease by favorably modifying risk factors such as hypertension, obesity, hyperlipidemia, and insulin resistance, physical activity also enhances longevity by mechanisms independent of these risk factors. This review briefly summarizes what is known about the inflammatory nature of atherosclerosis and how long-term aerobic exercise can reduce the atherogenic activity of endothelial cells, blood mononuclear cells, and adipose tissue. PMID: 20932264 [PubMed - indexed for MEDLINE] 1157. Obesity (Silver Spring). 2011 Apr;19(4):689-700. doi: 10.1038/oby.2010.230. Epub 2010 Oct 7. Systemic effects of white adipose tissue dysregulation and obesity-related inflammation. Guri AJ(1), Bassaganya-Riera J. Author information: (1)Nutritional Immunology and Molecular Medicine Laboratory, CyberInfrastructure Division, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA. PMID: 20930712 [PubMed - indexed for MEDLINE] 1158. Am J Hypertens. 2011 Mar;24(3):263-9. doi: 10.1038/ajh.2010.216. Epub 2010 Oct 7. Adiponectin and hypertension. Ohashi K(1), Ouchi N, Matsuzawa Y. Author information: (1)Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, Japan. Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function. PMID: 20930707 [PubMed - indexed for MEDLINE] 1159. Clin Sci (Lond). 2011 Jan;120(2):65-72. doi: 10.1042/CS20100327. The circadian clock and metabolism. Froy O(1). Author information: (1)Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel. froy@agri.huji.ac.il Mammals have developed an endogenous circadian clock located in the SCN (suprachiasmatic nuclei) of the anterior hypothalamus that responds to the environmental light-dark cycle. Human homoeostatic systems have adapted to daily changes in a way that the body anticipates the sleep and activity periods. Similar clocks have been found in peripheral tissues, such as the liver, intestine and adipose tissue. Recently it has been found that the circadian clock regulates cellular and physiological functions in addition to the expression and/or activity of enzymes and hormones involved in metabolism. In turn, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence to the relationship between the circadian clock and metabolic homoeostasis. The present review will summarize recent findings concerning the relationship between metabolism and circadian rhythms. PMID: 20929440 [PubMed - indexed for MEDLINE] 1160. Biomed Mater. 2010 Dec;5(6):062001. doi: 10.1088/1748-6041/5/6/062001. Epub 2010 Oct 6. Stem cells in bone tissue engineering. Seong JM(1), Kim BC, Park JH, Kwon IK, Mantalaris A, Hwang YS. Author information: (1)Department of Preventive and Social Dentistry & Institute of Oral Biology, College of Dentistry, Kyung Hee University, Seoul 130-701, Korea. Bone tissue engineering has been one of the most promising areas of research, providing a potential clinical application to cure bone defects. Recently, various stem cells including embryonic stem cells (ESCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), adipose tissue-derived stem cells (ADSCs), muscle-derived stem cells (MDSCs) and dental pulp stem cells (DPSCs) have received extensive attention in the field of bone tissue engineering due to their distinct biological capability to differentiate into osteogenic lineages. The application of these stem cells to bone tissue engineering requires inducing in vitro differentiation of these cells into bone forming cells, osteoblasts. For this purpose, efficient in vitro differentiation towards osteogenic lineage requires the development of well-defined and proficient protocols. This would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source for application to bone tissue engineering therapies. This review provides a critical examination of the various experimental strategies that could be used to direct the differentiation of ESC, BM-MSC, UCB-MSC, ADSC, MDSC and DPSC towards osteogenic lineages and their potential applications in tissue engineering, particularly in the regeneration of bone. PMID: 20924139 [PubMed - indexed for MEDLINE] 1161. Pharmacol Ther. 2011 Feb;129(2):206-19. doi: 10.1016/j.pharmthera.2010.09.003. Epub 2010 Oct 16. Adipocytokines, cardiovascular pathophysiology and myocardial protection. Smith CC(1), Yellon DM. Author information: (1)The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, United Kingdom. Reducing myocardial damage resulting from ischaemia-reperfusion (I/R) is vital in ensuring patient recovery and survival. It relies upon the activation of the so-called Reperfusion Injury Salvage Kinase (RISK) pathway. Experimentally various treatments, both mechanical and chemical, have been shown to protect the myocardium against I/R injury. Chemical facilitators of myocardial preservation include endogenous factors such as insulin, erythropoietin and glucagon-like peptide 1. The adipocytokines, products of white adipose tissue, are important peptide hormones with respect to metabolic control and satiety, and were formerly considered in the context of obesity and metabolic disease. More recently, however, evidence has been presented indicating that the adipocytokines play significant roles in cardiac function and, as we have suggested, in myocardial protection. To date leptin, adiponectin, apelin and visfatin have all been shown to protect against I/R injury. Significantly, the protection afforded by these peptides involves the activation of kinases which are key elements of the mechanisms underlying tissue preservation, including the RISK pathway components PI3K-Akt and p44/42, and inhibition of the mitochondrial permeability transition pore (MPTP). In this article we examine the roles played by the adipocytokines in cardiovascular function and disease. In particular, we focus on the evidence that these peptides promote myocardial survival, much of it having been obtained in this laboratory. To conclude, we discuss some future directions in the field, including the prospects for some of the adipocytokines finding application as therapeutic agents in myocardial infarction. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 20920528 [PubMed - indexed for MEDLINE] 1162. Reprod Biol Endocrinol. 2010 Sep 30;8:115. doi: 10.1186/1477-7827-8-115. Determinants of menarche. Karapanou O(1), Papadimitriou A. Author information: (1)Third Department of Pediatrics, University of Athens School of Medicine, Attikon University Hospital, Haidari, Athens 12462, Greece. Menarche is a milestone in a woman's life as it denotes the start of reproductive capacity. Aim of this report is to review the recent developments and the current knowledge in the neuroendocrinology of pubertal onset and the factors, genetic and environmental, that influence menarcheal age. We also review the implications of early or late menarcheal age on a young woman's life. PMCID: PMC2958977 PMID: 20920296 [PubMed - indexed for MEDLINE] 1163. Eur J Cancer. 2011 Jan;47(1):33-43. doi: 10.1016/j.ejca.2010.09.005. Molecular mechanisms of leptin and adiponectin in breast cancer. Jardé T(1), Perrier S, Vasson MP, Caldefie-Chézet F. Author information: (1)Cardiff School of Biosciences, Cardiff University, S. Wales, Cardiff CF10 3US, United Kingdom. jardethierry@yahoo.fr Obesity is associated with an increased risk of breast cancer in postmenopausal women. Accumulating evidence suggests that adipose tissue, which is an endocrine organ producing a large range of factors, may interfere with breast cancer development. Leptin and adiponectin are two major adipocyte-secreted hormones. The pro-carcinogenic effect of leptin and conversely, the anti-carcinogenic effect of adiponectin result from two main mechanisms: a modulation in the signalling pathways involved in proliferation process and a subtle regulation of the apoptotic response. This review provides insight into recent findings on the molecular mechanisms of leptin and adiponectin in mammary tumours, and discusses the potential interplay between these two adipokines in breast cancer. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 20889333 [PubMed - indexed for MEDLINE] 1164. Arch Physiol Biochem. 2011 Feb;117(1):23-43. doi: 10.3109/13813455.2010.513393. Epub 2010 Sep 30. Control of lipid storage and cell size between adipocytes by vesicle-associated glycosylphosphatidylinositol-anchored proteins. Müller G(1). Author information: (1)Ludwig-Maximilians-University Munich, Biocenter, Department Biology I, Genetics Martinsried, Germany. Guenter.Mueller@sanofi-aventis.com Adipose tissue mass in mammals is expanding by increasing the average cell volume as well as the total number of the adipocytes. Up-regulation of lipid storage in fully differentiated adipocytes resulting in their enlargement is well documented and thought to be a critical mechanism for the expansion of adipose tissue depots during the growth of both lean and obese animals and human beings. A novel molecular mechanism for the regulation of lipid storage and cell size in rat adipocytes has recently been elucidated for the physiological stimuli, palmitate and hydrogen peroxide, the anti-diabetic sulfonylurea drug, glimepiride, and insulin-mimetic phosphoinositolglycans. It encompasses (i) the release of small vesicles, so-called adiposomes, harbouring the glycosylphosphatidylinositol-anchored (c)AMP-degrading phosphodiesterase Gce1 and 5'-nuceotidase CD73 from large donor adipocytes, (ii) the transfer of the adiposomes and their interaction with detergent-insoluble glycolipid-enriched microdomains of the plasma membrane of small acceptor adipocytes, (iii) the translocation of Gce1 and CD73 from the adiposomes to the intracellular lipid droplets of the acceptor adipocytes and (iv) the degradation of (c)AMP at the lipid droplet surface zone by Gce1 and CD73 in the acceptor adipocytes. In concert, this sequence of events leads to up-regulation of esterification of fatty acids into triacylglycerol and down-regulation of their release from triacylglycerol. This apparent mechanism for shifting the triacylglycerol burden from large to small adipocytes may provide novel strategies for the therapy of metabolic diseases, such as type 2 diabetes and obesity. PMID: 20883086 [PubMed - indexed for MEDLINE] 1165. Drugs. 2010 Oct 22;70(15):1945-61. doi: 10.2165/11538100-000000000-00000. Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus: comparison with other oral antihyperglycaemic agents. Derosa G(1). Author information: (1)Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuseppe.derosa@unipv.it Diabetes mellitus is a debilitating disease that is estimated to affect 366 million people by the year 2030. Type 2 diabetes mellitus (T2DM) is characterized by a progressive decline in pancreatic β-cell function and increased insulin resistance, and accounts for approximately 90% of people with diabetes. Oral antihyperglycaemic agents are extensively used in the treatment of T2DM. Thiazolidinediones are insulin sensitizers developed specifically for T2DM, which act via activation of peroxisome proliferator-activated receptors (PPARs). Pioglitazone is a thiazolidinedione that displays high affinity for PPARγ(1) and PPARγ(2), which are predominately expressed in adipose tissue. This review examines the published literature comparing the efficacy and tolerability of pioglitazone with other oral antihyperglycaemic agents in the treatment of patients with T2DM. Glycosylated haemoglobin, fasting glucose, insulin parameters and β-cell function are all improved with pioglitazone treatment, with efficacy similar to third-generation sulfonylureas, metformin and dipeptidyl peptidase-4 inhibitors. Pioglitazone reduces vascular risk and inflammatory markers, and improves carotid intima media thickness independent of its glycaemic effect. When compared with rosiglitazone, pioglitazone is associated with a reduction in the risk of hospitalization for acute myocardial infarction. Blood pressure is reduced and lipid profiles are favourably improved with pioglitazone; however, an increased risk for the development/exacerbation of heart failure, which is related to the increased incidence of oedema due to fluid retention, and fractures remain a concern. A low incidence of hypoglycaemia is observed with pioglitazone, especially compared with sulfonylureas. In conclusion, pioglitazone is an effective oral antihyperglycaemic agent with additional cardiovascular and lipid benefits that allows for the successful management of patients with T2DM. PMID: 20883052 [PubMed - indexed for MEDLINE] 1166. Int J Obes (Lond). 2011 Jun;35(6):751-61. doi: 10.1038/ijo.2010.208. Epub 2010 Sep 28. mTORC1 signaling in energy balance and metabolic disease. Catania C(1), Binder E, Cota D. Author information: (1)INSERM U862, Avenir Group 'Physiopathology of Energy Balance and Obesity', Bordeaux, France. The mammalian target of rapamycin complex 1 (mTORC1) pathway regulates cellular responses to fuel availability. Recent studies have demonstrated that within the central nervous system, and in particular the hypothalamus, mTORC1 represents an essential intracellular target for the actions of hormones and nutrients on food intake and body weight regulation. By being at the crossroads of a nutrient-hormonal signaling network, mTORC1 also controls important functions in peripheral organs, such as muscle oxidative metabolism, white adipose tissue differentiation and β-cell-dependent insulin secretion. Notably, dysregulation of the mTORC1 pathway has been implicated in the development of obesity and obesity-related conditions, such as type 2 diabetes. This manuscript will therefore review recent progress made in understanding the role of the mTORC1 pathway in the regulation of energy balance and peripheral metabolism. Furthermore, we will critically discuss the potential relevance of this intracellular pathway as a therapeutic target for the treatment of metabolic disease. PMID: 20877289 [PubMed - indexed for MEDLINE] 1167. Diabetes Care. 2010 Oct;33(10):2277-84. doi: 10.2337/dc10-0556. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Musso G(1), Gambino R, Cassader M. Author information: (1)Gradenigo Hospital, Turin, Italy. giovanni_musso@yahoo.it The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle--including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake--may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders. PMCID: PMC2945175 PMID: 20876708 [PubMed - indexed for MEDLINE] 1168. J Neurol Sci. 2010 Dec 15;299(1-2):30-4. doi: 10.1016/j.jns.2010.08.036. Epub 2010 Sep 27. Adiposity hormones and dementia. Gustafson DR(1). Author information: (1)Section for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit at the Sahlgrenska Academy, University of Gothenburg, Sweden. deborah.gustafson@neuro.gu.se Adipose tissue is an endocrine and paracrine organ that contributes to both metabolic and vascular homeostasis. Overweight and obesity due to excess adipose tissue, are cornerstones of vascular risk and increase risk for late-onset dementia. Vascular risk does not exist in isolation, and is accompanied by alterations in hormonal metabolism and metabolic syndromes. Thus, while vascular risk is highlighted as a primary mechanism for elevated dementia occurrence due to obesity, hormonal risk states may also precede or result from underlying dementia-related neuropathologies and direct neuronal toxicity. This is exemplified during the prodromal phase of dementia, as vascular and metabolic parameters decline in relation to dementia development, and potentially in a way that is different from 'normal' aging. In this review will be presented a review of the epidemiology of adiposity and dementia; adipose tissue biology; and two major hormones produced by adipose tissue, leptin and adiponectin, that interact directly with the brain. In addition, a synthesis related to other lines of supporting evidence for the role of adipose hormones in dementia will be provided. Understanding the role of adipose tissue in health of the brain is pivotal to a deeper understanding of dementia processes. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 20875649 [PubMed - indexed for MEDLINE] 1169. Aesthet Surg J. 2010 Jul-Aug;30 Suppl:11S-24S. doi: 10.1177/1090820X10378696. Update on facial aging. Fitzgerald R(1), Graivier MH, Kane M, Lorenc ZP, Vleggaar D, Werschler WP, Kenkel JM. Author information: (1)University of Washington, Seattle, Washington, USA. Facial aging was once thought to be the result of the relentless downward pull of gravity on skin and underlying fat. In turn, facial fat was believed to be a contiguous sheet of tissue. However, over the past four decades, a number of investigators have examined more closely the causes of facial aging, leading to a better understanding of age-related changes, and have confirmed and further explored the proposal by Gonzalez-Ulloa and Flores in 1965 that facial aging involves changes in muscle and bone, as well as skin and fat. Further, the recent work of Rohrich and Pessa (and other authors) has demonstrated that facial fat is not a sheet of tissue, but rather is compartmentalized throughout the face. This discovery has allowed the evolution of improved techniques for facial rejuvenation. PMID: 20844296 [PubMed - indexed for MEDLINE] 1170. Curr Opin Investig Drugs. 2010 Oct;11(10):1143-50. Growth hormone-releasing factor agonists for the treatment of HIV-associated lipodystrophy. Hu M(1), Tomlinson B. Author information: (1)The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. HIV-associated lipodystrophy characterized by body composition changes and associated metabolic abnormalities, including dyslipidemia and insulin resistance, is a major challenge in the treatment of HIV infection. Growth hormone-releasing factor (GRF) analogs with greater stability than the natural hormone can induce growth hormone secretion in a physiological manner, and appear to be promising candidate therapies for these conditions. The most promising GRF agonist in development is tesamorelin (EMD Serono/Theratechnologies), which has exhibited efficacy for the treatment of excess visceral adipose tissue in patients with HIV infection in two recent phase III, randomized, placebo-controlled clinical trials. Additional long-term outcome trials are required to determine the long-term safety of tesamorelin and to evaluate whether this agent, or other GRF agonists, could reduce the cardiovascular risk associated with lipodystrophy-related metabolic complications and help to maintain a more normal distribution of body fat. PMID: 20872317 [PubMed - indexed for MEDLINE] 1171. Curr Opin Investig Drugs. 2010 Oct;11(10):1107-15. Plant-derived therapeutics for the treatment of metabolic syndrome. Graf BL(1), Raskin I, Cefalu WT, Ribnicky DM. Author information: (1)Rutgers University, SEBS, New Brunswick, NJ 08901, USA. Metabolic syndrome is defined as a set of coexisting metabolic disorders that increase an individual's likelihood of developing type 2 diabetes, cardiovascular disease and stroke. Medicinal plants, some of which have been used for thousands of years, serve as an excellent source of bioactive compounds for the treatment of metabolic syndrome because they contain a wide range of phytochemicals with diverse metabolic effects. In order for botanicals to be effectively used against metabolic syndrome, however, botanical preparations must be characterized and standardized through the identification of their active compounds and respective modes of action, followed by validation in controlled clinical trials with clearly defined endpoints. This review assesses examples of commonly known and partially characterized botanicals to describe specific considerations for the phytochemical, preclinical and clinical characterization of botanicals associated with metabolic syndrome. PMCID: PMC3755736 PMID: 20872313 [PubMed - indexed for MEDLINE] 1172. Hautarzt. 2010 Oct;61(10):838-46. doi: 10.1007/s00105-010-1983-y. [Adipose tissue. Cellular and molecular principles]. [Article in German] Grether-Beck S(1), Krutmann J. Author information: (1)Institut für umweltmedizinische Forschung, Auf'm Hennekamp 50, 40225, Düsseldorf. For many decades, cutaneous biology research has primarily focused on the dermis and epidermis. In recent years the subcutaneous far has attracted the attention of basic science, cosmetology and industry. Numerous new approaches are in the process of development, enabling us to better understand assembly, differentiation and function of adipose tissue. To understand these developments a background in the cellular and molecular basics of adipose tissue is indispensable. This state-of the art article provides the needed information. PMID: 20871971 [PubMed - indexed for MEDLINE] 1173. J Endocrinol. 2010 Dec;207(3):245-55. doi: 10.1677/JOE-10-0272. Epub 2010 Sep 24. Lipodystrophy: metabolic insights from a rare disorder. Huang-Doran I(1), Sleigh A, Rochford JJ, O'Rahilly S, Savage DB. Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK. Obesity, insulin resistance and their attendant complications are among the leading causes of morbidity and premature mortality today, yet we are only in the early stages of understanding the molecular pathogenesis of these aberrant phenotypes. A powerful approach has been the study of rare patients with monogenic syndromes that manifest as extreme phenotypes. For example, there are striking similarities between the biochemical and clinical profiles of individuals with excess fat (obesity) and those with an abnormal paucity of fat (lipodystrophy), including severe insulin resistance, dyslipidaemia, hepatic steatosis and features of hyperandrogenism. Rare lipodystrophy patients therefore provide a tractable genetically defined model for the study of a prevalent human disease phenotype. Indeed, as we review herein, detailed study of these syndromes is beginning to yield valuable insights into the molecular genetics underlying different forms of lipodystrophy, the essential components of normal adipose tissue development and the mechanisms by which disturbances in adipose tissue function can lead to almost all the features of the metabolic syndrome. PMID: 20870709 [PubMed - indexed for MEDLINE] 1174. Semin Reprod Med. 2010 Sep;28(5):426-34. doi: 10.1055/s-0030-1262902. Epub 2010 Sep 23. Metabolic implications of menopause. Polotsky HN(1), Polotsky AJ. Author information: (1)Weill-Cornell Medical Center and Memorial Sloan-Kettering Cancer Center, New York 10065, USA. hpolotsky@yahoo.com The incidence of metabolic syndrome increases substantially during perimenopause and early menopause. Postmenopausal women are at a higher risk of hypertension, proatherogenic lipid changes, diabetes, and severe cardiovascular disease as compared with their premenopausal counterparts. Whether or not menopause has a causative contribution to the deteriorating metabolic profile that is independent of chronological aging has been a subject of many studies. Menopausal transition is associated with significant weight gain (2 to 2.5 kg over 3 years on average), which is not dissimilar to that in premenopausal women of like age. Concomitantly, there is an increase in abdominal adiposity and a decrease in energy expenditure, phenomena that have been postulated to explain the higher risk of metabolic syndrome and increases in cholesterol and triglycerides. Hypertension and diabetes become more prevalent with age and should be timely diagnosed and treated. Lifestyle changes including moderately decreased caloric intake and aerobic exercise could prevent proatherogenic changes and weight gain observed with aging. Accurate prediction of cardiovascular risk in midlife women is essential to help identify the subset of women who are likely to benefit from intensive management of metabolic risk factors. This review focuses on metabolic changes associated with menopausal transition, specifically alterations in weight, waist circumference, body fat distribution, energy expenditure, and circulating biomarkers including adipokines. © Thieme Medical Publishers. PMID: 20865657 [PubMed - indexed for MEDLINE] 1175. Results Probl Cell Differ. 2010;52:189-201. doi: 10.1007/978-3-642-14426-4_16. Adipocyte-brain: crosstalk. Schulz C(1), Paulus K, Lehnert H. Author information: (1)Department of Internal Medicine I, Luebeck University, Ratzeburger Allee 160, 23538 Luebeck, Germany. The initial discovery of leptin, an appetite-suppressing hormone originating from fat tissue, substantially supported the idea that fat-borne factors act on the brain to regulate food intake and energy expenditure. Since then, a growing number of cytokines have been found to be released from adipose tissue, thus acting in an endocrine manner. These adipocytokines include not only, e.g., adiponectin, apelin, resistin, and visfatin, but also inflammatory cytokines and steroid hormones such as estrogens and glucocorticoids. They are secreted from their adipose depots and differ in terms of release stimuli, downstream signaling, and their action on the brain. Clearly, adipocytokines play a prominent role in the central control of body weight, and the deregulation of this circuit may lead to the development of obesity and related disorders. In this chapter, we will focus on crosstalk mechanisms and the deregulation of adipocytokines at the expression level and/or sites of central action that eventually will lead to the development and perpetuation of obesity and diabetes. PMID: 20865382 [PubMed - indexed for MEDLINE] 1176. Results Probl Cell Differ. 2010;52:183-8. doi: 10.1007/978-3-642-14426-4_15. Role of the gut Peptide glucose-induced insulinomimetic Peptide in energy balance. Pfeiffer AF(1), Rudovich N, Weickert MO, Isken F. Author information: (1)Department of Clinical Nutrition, German Institute of Human Nutrition - Potsdam Rehbrücke, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany. afhp@dife.de Glucose-induced insulinomimetic peptide (GIP) is a gut hormone produced by enteroendocrine K-cells in the intestinal mucosa in response to fat, glucose, and also protein. GIP releases insulin from the β cells of the pancreatic islets of Langerhans and therefore is an incretin hormone. GIP acts on a G-protein-coupled receptor that is widely distributed in the body including adipose tissue, stomach, brain, and others. Deletion of the GIP receptor (GIPR) renders mice resistant to weight gain induced by a high fat diet.We observed that weight gain induced by ovarectomy in female mice is prevented by GIPR deletion that is linked to reduced food intake and reduced hypothalamic expression of orectic neurotransmitters. Moreover, old male GIPR(-/-) mice placed on a high glycemic index diet maintained a high insulin sensitivity and were much more active than controls, which was not seen in young animals. Thus, GIP elicits central effects in response to nutrients that protect against obesity and insulin resistance. We then investigated the acute responses of humans to treatment with GIP over 4h in a dose mimicking postprandial plasma levels of about 100pmol/L. At basal glucose, GIP does not elicit insulin release. Fat biopsies taken before and after 4h of GIP treatment were analyzed for transcriptomic responses using Agilent whole human genome assays. There was a highly significant upregulation of an inflammatory expression pattern in a pathway analysis. PMID: 20865381 [PubMed - indexed for MEDLINE] 1177. Results Probl Cell Differ. 2010;52:175-81. doi: 10.1007/978-3-642-14426-4_14. Towards understanding regulation of energy homeostasis by ceramide synthases. Bauer R(1). Author information: (1)Life & Medical Sciences Institute (LIMES), Program Unit Development, Genetics & Molecular Physiology, Rheinische Friedrich-Wilhelms-University Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany. r.bauer@uni-bonn.de Energy homeostasis and growth require the coordinated regulation of lipid metabolism. The underlying molecular mechanisms are poorly understood. We are interested in identifying key regulators of lipid homeostasis and their functional mechanism. Recently, we identified the schlank gene as a major regulator of lipid homeostasis in Drosophila. Schlank encodes a conserved member of the Lass/CerS family of ceramide synthases , which contain a catalytic Lag1 motif and a homeobox transcription factor domain. Schlank mutant larvae, show decreased levels of sphingolipids and depleted fat stores due to an upregulation of triacylglycerol lipases and a downregulation of SREBP-dependent fatty acid synthesis. In addition, we have demonstrated that mammalian members of the conserved Lass/CerS family had also effects on lipid homeostasis. Therefore, we are currently interested to find how members of this family e.g., schlank may act as regulators coordinating cellular and organismic lipid homeostasis in animals mechanistically. We now address these issues by using a combination of genetics, biochemistry and integrative physiology. PMID: 20865380 [PubMed - indexed for MEDLINE] 1178. Results Probl Cell Differ. 2010;52:57-68. doi: 10.1007/978-3-642-14426-4_6. Role of zinc finger transcription factor zfp69 in body fat storage and diabetes susceptibility of mice. Scherneck S(1), Vogel H, Nestler M, Kluge R, Schürmann A, Joost HG. Author information: (1)German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. scherneck@dife.de Type 2 diabetes is a polygenic disease resulting from a combination of different disease alleles reflecting obesity, insulin resistance, and hyperglycemia. Using a positional cloning strategy with different inbred strains of mice, we mapped a disease locus for obesity-associated diabetes on chromosome 4. We analyzed all genes in this region and identified distinct differences in the expression levels of the transcription factor Zfp69. The expression of this gene mediated diabetes progression in a leptin-deficient congenic mouse line. The animals developed a disease pattern of hyperglycemia, reduced gonadal fat mass, and increased plasma and liver triglycerides, resembling a potential defect in triglyceride storage . In order to elucidate the impact of the human ortholog of Zfp69 in the development of type 2 diabetes, we tested its mRNA expression in human white adipose tissue. Consistent with the mouse data, mRNA-expression was significantly higher in diabetic subjects than in unaffected controls. PMID: 20865372 [PubMed - indexed for MEDLINE] 1179. Results Probl Cell Differ. 2010;52:35-46. doi: 10.1007/978-3-642-14426-4_4. Autophagy and regulation of lipid metabolism. Singh R(1). Author information: (1)Department of Medicine (Endocrinology) and Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 505, 1300 Morris Park Avenue, Bronx, NY 10461, USA. rajat.singh@einstein.yu.edu Macroautophagy (henceforth referred to as autophagy) is an in-bulk lysosomal degradative pathway that plays a crucial role in the maintenance of cellular homeostasis through the removal of damaged proteins and aged organelles. Following nutrient deprivation, a primary cellular response is the induction of autophagy that breaks down redundant cellular components and provides amino acids and additional precursor molecules for processes critical for cellular survival. In parallel, nutrient depletion leads to the mobilization of cellular lipid stores to supply free fatty acids for energy, thus pointing to regulatory and functional similarities between autophagy and lipid metabolism. The current chapter discusses the novel and mutually exclusive roles of autophagy in the regulation of lipid metabolism in the liver and of fat storage within the adipose tissue. Our studies in cultured hepatocytes and the murine liver have demonstrated that autophagy serves to degrade intracellular lipid stores through a process that we have termed "macrolipophagy" and that ablation of liver-specific autophagy leads to excessive hepatic lipid accumulation and the development of fatty liver. In contrast, preadipocytes in culture that lacked autophagy failed to differentiate into mature adipocytes and exhibited a reduction in fat storage that translated to decreased adipose tissue mass in an in vivo mouse model. These recent findings establish an association between autophagy and regulation of hepatic lipid metabolism and adipose tissue biology, thus providing new mechanistic insights into the regulation of these complex processes. These findings also highlight the possibility of novel therapeutic approaches, such as differential organ-specific regulation of autophagy to solve problems that arise from lipid over accumulation that occur in the metabolic syndrome and with aging. PMCID: PMC4052896 PMID: 20865370 [PubMed - indexed for MEDLINE] 1180. Results Probl Cell Differ. 2010;52:27-34. doi: 10.1007/978-3-642-14426-4_3. Lipid storage in large and small rat adipocytes by vesicle-associated glycosylphosphatidylinositol-anchored proteins. Müller G(1), Wied S, Dearey EA, Wetekam EM, Biemer-Daub G. Author information: (1)Sanofi-Aventis Deutschland GmbH, Research & Development, 65926 Frankfurt, Germany. Guenter.Mueller@sanofi-aventis.com Adipose tissue mass in mammals expands by increasing the average cell volume and/or total number of the adipocytes. Upregulated lipid storage in fully differentiated adipocytes resulting in their enlargement is well documented and thought to be a critical mechanism for the expansion of adipose tissue depots during the growth of both lean and obese animals and human beings. A novel molecular mechanism for the regulation of lipid storage and cell size in rat adipocytes was recently elucidated for the physiological stimuli, palmitate and H(2)O(2), and the antidiabetic sulfonylurea drug, glimepiride. It encompasses (1) the release of small vesicles, so-called adiposomes, harboring the glycosylphosphatidylinositol -anchored (c)AMP-degrading phosphodiesterase Gce1 and 5'-nucleotidase CD73 from donor adipocytes, (2) the transfer of the adiposomes and their interaction with detergent-insoluble glycolipid-enriched microdomains of the plasma membrane of acceptor adipocytes, (3) the translocation of Gce1 and CD73 from the adiposomes to the intracellular lipid droplets of the acceptor adipocytes, and (4) the degradation of (c)AMP at the lipid droplet surface zone by Gce1 and CD73 in the acceptor adipocytes, leading to the upregulation of the esterification of fatty acids into triacylglycerol s and the downregulation of their release from triacylglycerols. This mechanism may provide novel strategies for the therapy of metabolic diseases, such as type 2 diabetes and obesity. PMID: 20865369 [PubMed - indexed for MEDLINE] 1181. Results Probl Cell Differ. 2010;52:13-25. doi: 10.1007/978-3-642-14426-4_2. Regulation of nutrient metabolism and inflammation. Kersten S(1). Author information: (1)Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD, Wageningen, The Netherlands. sander.kersten@wur.nl Metabolic and immune-related pathways intersect at numerous levels. Their common regulation is effectuated by several hormonal signaling routes that involve specific nuclear hormone receptors and adipokines. Glucocorticoids and leptin are hormones that play a key role in coordinating energy metabolism and food-seeking behavior during energy deficiency as does the nuclear hormone receptor Peroxisome Proliferator Activated Receptor α (PPARalpha). Importantly, the glucocorticoid, leptin, and PPARalpha signaling routes share a profound role in governing inflammation and other immune-related processes. Using specific examples, this chapter aims at illustrating the interplay between metabolism and immunity/inflammation by discussing common endocrine and transcriptional regulators of metabolism and inflammation and by highlighting the interaction between macrophages and metabolically active cells in liver and adipose tissue. Convergence of metabolic and immune signaling is likely at least partially driven by the evolutionary need during times of food insufficiency to minimize loss of energy to processes that are temporarily nonessential to the survival of the species. PMID: 20865368 [PubMed - indexed for MEDLINE] 1182. Results Probl Cell Differ. 2010;52:1-11. doi: 10.1007/978-3-642-14426-4_1. The genetic basis of obesity and type 2 diabetes: lessons from the new zealand obese mouse, a polygenic model of the metabolic syndrome. Joost HG(1). Author information: (1)German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. joost@dife.de The New Zealand obese (NZO) mouse is a polygenic model of severe obesity and type 2 diabetes-like hyperglycaemia. Outcross experiments with lean strains have led to the identification of numerous susceptibility loci (quantitative trait loci (QTL)) for adiposity and/or hyperglycaemia. Several major QTL were successfully introgressed into lean strains, and two responsible genes, the RabGAP Tbc1d1 and the transcription factor Zfp69, were so far identified by a conventional strategy of positional cloning. Tbc1d1 controls substrate utilization in muscle; SJL mice carry a loss-of-function variant that shifts substrate oxidation from glucose to fat and suppresses adiposity as well as development of diabetes. The zinc finger domain transcription factor Zfp69 appears to regulate triglyceride storage in adipose tissue. Its normal allele Zfp69 causes a redistribution of triglycerides from gonadal stores to liver, and consequently enhances diabetes when introgressed from SJL into NZO, whereas the loss-of-function variant present in NZO and C57BL/6J reduces the prevalence of diabetes. Data from human patients suggest that the orthologs of both genes may play a role in the pathogenesis of the human metabolic syndrome. In addition to Tbc1d1 and Zfp69, variants of Lepr, Pctp, Abcg1, and Nmur2 located in other QTL were identified as potential candidates by sequencing and functional studies. These results indicate that dissection of the genetic basis of obesity and diabetes in mouse models can identify novel regulatory mechanisms that are relevant for the human disease. PMID: 20865367 [PubMed - indexed for MEDLINE] 1183. Hautarzt. 2010 Oct;61(10):864-72. doi: 10.1007/s00105-010-1986-8. [Cellulite]. [Article in German] Proebstle TM(1). Author information: (1)Universitätshautklinik Mainz, Mainz. info@privatklinik-proebstle.de Cellulite is a condition affecting the dermal and subdermal compartment and developing on thighs and buttocks of almost every woman. Macroscopically, cellulite is characterized by dimpling, visible either spontaneously or after provoking maneuvers. While published concepts on the pathophysiology of cellulite are in parts inconclusive or contradictory, there are at least some recent studies describing or confirming structural and anatomic changes on dermal and subdermal tissues: (1) A gender specific dimorphism with subdermal septae oriented orthogonally towards the skin surface as well as protrusion of fat tissue into the dermis. (2) These intradermal fat protrusions additionally correlate with the presence of cellulite. (3) There is also a correlation between the thickness of the subdermal fat layer and the presence of cellulite. (4) Cellulite also correlates with focal hypertrophic subcutaneous septae and a reduced density of septae in general. Treatment of cellulite aims at (1) the reduction of the subcutaneous fat layer, (2) increase in dermal thickness and elasticity and (3) dissection of hypertrophic connective tissue septae, responsible for the most pronounced dermal indentions. A variety of treatment options have evolved ranging from topical retinol to interstitial laser. PMID: 20865236 [PubMed - indexed for MEDLINE] 1184. Pol Arch Med Wewn. 2010 Sep;120(9):361-7. Relationship between body fat mass and bone metabolism. Holecki M(1), Wiecek A. Author information: (1)Department of Internal Medicine and Metabolic Diseases, Medical University of Silesia, Katowice, Poland. holomed@poczta.onet.pl The protective effect of obesity on bone tissue has not been unequivocally demonstrated. On one hand, it is known that obese people have a lower risk of osteoporotic fractures compared with normal-weight individuals. On the other hand, obese patients are characterized by disorders of calcium-phosphate homeostasis and bone metabolism. Moreover, it is not known whether it is fat or lean body mass that determines the development of bone mass. It can be assumed that adipose tissue exerts independent effects on bone remodeling by releasing a number of biologically active substances. Moreover, it seems that the main mechanism of action of these substances is closely related to the type and location of adipose tissue in the body. The present article describes the relationship between fat and bones, including the effect of body weight on bone tissue, the local mechanisms of osteoblast and adipocyte differentiation, and the hormonal activity of adipose tissue. PMID: 20864910 [PubMed - indexed for MEDLINE] 1185. Exp Biol Med (Maywood). 2010 Oct;235(10):1185-93. doi: 10.1258/ebm.2010.010063. Epub 2010 Sep 23. Cell line models for differentiation: preadipocytes and adipocytes. Poulos SP(1), Dodson MV, Hausman GJ. Author information: (1)The Coca-Cola Company, Research and Technology, Atlanta, GA 30313, USA. sypoulos@na.ko.com In vitro models have been invaluable in determining the mechanisms involved in adipocyte proliferation, differentiation, adipokine secretion and gene/protein expression. The cells presently available for research purposes all have unique advantages and disadvantages that one should be aware of when selecting cells. Established cell lines, such as 3T3-L1 cells, are easier and less costly to use than freshly isolated cells, even though freshly isolated cells allow for various comparisons such as the in vitro evaluation of different in vivo conditions that may not be possible using cell lines. Moreover, stem cells, transdifferentiated cells or dedifferentiated cells are relatively new cell models being evaluated for the study of adipocyte regulation and physiology. The focus of this brief review is to highlight similarities and differences in adipocyte models to aid in appropriate model selection and data interpretation for successful advancement of our understanding of adipocyte biology. PMID: 20864461 [PubMed - indexed for MEDLINE] 1186. Gastroenterol Clin Biol. 2010 Oct;34(10):529-33. doi: 10.1016/j.gcb.2010.07.021. Obesity, type 2 diabetes and risk of digestive cancer. Hillon P(1), Guiu B, Vincent J, Petit JM. Author information: (1)Université de Bourgogne, CHU de Dijon, rue de l'église, Dijon, France. patrick.hillon@chu-dijon.fr The frequency of obesity has been increasing worldwide for 20 years. Many epidemiological studies support a correlation between obesity and increased risk of cancer, particularly digestive cancers in both genders, and gynaecological cancer in women. Currently, about 5% of cancers could be directly related to overweight. Carcinogenesis mechanisms induced by obesity involve insulin resistance, adipokine and angiogenic factor secretions, and inflammation. Experimental and clinical evidence suggest that insulin resistance plays a major role in carcinogenesis. Insulin and non-protein banded IGF-1, whose levels are increased in type 2 diabetes, stimulate cellular growth and inhibit apoptosis. Abnormalities in adipokine secretion by the central adipose tissue play a role at different stages of obesity-induced carcinogenesis. Excess of leptin and PAI-1, associated with a decrease in adiponectin secretion in obese people, contributes to carcinogenesis through cellular growth and angiogenesis stimulation. Remodelling of the extracellular matrix due to metalloproteinase stimulation by PAI-1 is also able to promote cell migration. Obesity not only increases cancer frequency, but is also liable to modify the prognosis and the response to antiangiogenic therapy of digestive cancers. This data suggests the need for clinicians to take into account overweight in cancer risk evaluation and to consider obesity and metabolic disorders as confounding factors in designing therapeutic studies. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 20864282 [PubMed - indexed for MEDLINE] 1187. Drug News Perspect. 2010 Sep;23(7):409-17. doi: 10.1358/dnp.2010.23.7.1487083. Brown adipose tissue: a promising target to combat obesity. Vernochet C(1), McDonald ME, Farmer SR. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. Obesity has now reached pandemic proportions leading to a collection of morbidities referred to as metabolic syndrome including insulin resistance, type 2 diabetes and cardiovascular disease. The expansion of adipose tissue is a direct cause of these comorbidities due to excessive accumulation of triglycerides within adipocytes, causing disruption of normal adipose function. There are two major types of adipose tissue, white and brown. The former stores energy as triglycerides within large droplets, whereas the latter catabolizes lipids to produce heat. A strategy to combat obesity-associated disorders, therefore, includes enhancement of brown adipose tissue activity by targeting the recently identified regulators of brown adipocyte development and function, including its master regulator, PRDM16. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved. PMID: 20862392 [PubMed - indexed for MEDLINE] 1188. Am J Physiol Regul Integr Comp Physiol. 2010 Dec;299(6):R1423-39. doi: 10.1152/ajpregu.00126.2010. Epub 2010 Sep 22. Deficits in gastrointestinal responses controlling food intake and body weight. Covasa M(1). Author information: (1)L'Institute National de la Recherche Agronomique, Centre de Recherche, Microbiologie de l'Alimentation au service de la Santé Humaine (MICALIS), Neurobiology of Ingestive Behavior, Jouy-en-Josas, France. mcovasa@jouy.inra.fr The gastrointestinal tract serves as a portal sensing incoming nutrients and relays mechanical and chemosensory signals of a meal to higher brain centers. Prolonged consumption of dietary fat causes adaptive changes within the alimentary, metabolic, and humoral systems that promote a more efficient process for energy metabolism from this rich source, leading to storage of energy in the form of adipose tissue. Furthermore, prolonged ingestion of dietary fats exerts profound effects on responses to signals involved in termination of a meal. This article reviews the effects of ingested fat on gastrointestinal motility, hormone release, and neuronal substrates. It focuses on changes in sensitivity to satiation signals resulting from chronic ingestion of high-fat diet, which may lead to disordered appetite and dysregulation of body weight. PMID: 20861277 [PubMed - indexed for MEDLINE] 1189. Curr Opin Pharmacol. 2010 Oct;10(5):588-93. doi: 10.1016/j.coph.2010.05.008. Epub 2010 Jun 8. Contributions of adipocyte lipid metabolism to body fat content and implications for the treatment of obesity. Marcelin G(1), Chua S Jr. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA. Obesity is a chronic disease that increases susceptibility to various diseases, particularly cardiovascular dysfunction, type 2 diabetes, and some types of cancer. In this review, we highlighted recent evidence in mouse models that support a potential benefit of increasing adipose lipid utilization through stimulating lipolysis in adipose tissue and fatty acid oxidation. Brown adipocyte development within white adipose tissue of humans suggests that mouse models may be applicable to human obesity. Consequently, new therapies should target adipose tissue to specifically reduce fat mass through controlled triglyceride utilization. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC2945394 PMID: 20860920 [PubMed - indexed for MEDLINE] 1190. Expert Opin Biol Ther. 2010 Nov;10(11):1529-37. doi: 10.1517/14712598.2010.522987. Epub 2010 Sep 23. The pivotal role of VEGF in adipose-derived-stem-cell-mediated regeneration. Song SY(1), Chung HM, Sung JH. Author information: (1)Department of Plastic & Reconstructive Surgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Korea. IMPORTANCE OF THE FIELD: Several lines of evidence suggest that VEGF is a key regulator of the paracrine effects of adipose-derived stem cells (ASCs), but the mechanism of action remains to be identified. AREAS COVERED IN THIS REVIEW: This brief review discusses the following research questions: i) Does VEGF increase the proliferation/migration and differentiation of ASCs?; ii) Does VEGF mediate the paracrine effects of ASCs?; and iii) How is VEGF synthesized, and which factors regulate VEGF secretion? WHAT THE READER WILL GAIN: External stimuli such as hypoxia may activate receptor tyrosine kinases in the membrane of ASCs, which, in turn, phosphorylate extracellular signal regulated kinase (ERK) and members of the Akt signaling pathway, stabilizing hypoxia inducible factor 1α (HIF-1α) that are primary regulators of VEGF expression. Secreted VEGF directly stimulates ASCs via VEGF receptors in an autocrine manner and regenerates damaged neighboring cells in a paracrine manner. TAKE HOME MESSAGE: Most studies of stem cell regeneration have focused on differentiation of ASCs and their building block function; however, the paracrine effects of ASCs should also be the focus of attention. PMID: 20860536 [PubMed - indexed for MEDLINE] 1191. Handb Exp Pharmacol. 2011;(200):509-48. doi: 10.1007/978-3-642-13443-2_21. Methylxanthines and human health: epidemiological and experimental evidence. Beaudoin MS(1), Graham TE. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. When considering methylxanthines and human health, it must be recognized that in many countries most caffeine is consumed as coffee. This is further confounded by the fact that coffee contains many bioactive substances in addition to caffeine; it is rich in phenols (quinides, chlorogenic acid, and lactones) and also has diterpenes (fatty acid esters), potassium, niacin, magnesium, and the vitamin B(3) precursor trigonelline. There is a paradox as consumption of either caffeine or caffeinated coffee results in a marked insulin resistance and yet habitual coffee consumption has repeatedly been reported to markedly reduce the risk for type 2 diabetes. There is strong evidence that caffeine reduces insulin sensitivity in skeletal muscle and this may be due to a combination of direct antagonism of A(1) receptors and indirectly β-adrenergic stimulation as a result of increased sympathetic activity. Caffeine may also induce reduced hepatic glucose output. With the exception of bone mineral, there is little evidence that caffeine impacts negatively on other health issues. Coffee does not increase the risk of cardiovascular diseases or cancers and there is some evidence suggesting a positive relationship for the former and for some cancers, particularly hepatic cancer. PMID: 20859811 [PubMed - indexed for MEDLINE] 1192. Patol Fiziol Eksp Ter. 2010 Jul-Sep;(3):45-51. [Physiological and pathological role of adipose tissue innate immune system receptors]. [Article in Russian] Shvarts V. The data of TLR-4 and TLR-2 existance in adipose tissue cells is presented in the review, their signal pathway is described, and an idea of physiological and pathological role of innate immune system receptors is given proof. TLRs activation leads to insulin resistance of adipose, hepatic and muscle cells, which increases glucose and lipids level in blood. This reaction is defined as a condition of physiological insulin resistance, which role is in providing immune processes with energetic and plastic substances. Ligands of TLRs are components of microorganisms: bacterial lipoproteins and liopolysacharides, as well as nonsaturated fatty acids. Inadequate uptake of the latter with food activates TLR-4 and R-2, acting as a mechanism for pathological alterations. Under the conditions of innate imunity receptors excessive activation, there is an adipose tissue inflammation, overproduction of cytokines, along with insulin resistance. It promotes the progress of obesity, diabetes and atherosclerosis. PMID: 20853621 [PubMed - indexed for MEDLINE] 1193. Stem Cell Rev. 2011 Jun;7(2):269-91. doi: 10.1007/s12015-010-9193-7. The potential of adipose stem cells in regenerative medicine. Lindroos B(1), Suuronen R, Miettinen S. Author information: (1)Regea-Institute for Regenerative Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland. bettina.lindroos@regea.fi Adipose stem cells (ASCs) are an attractive and abundant stem cell source with therapeutic applicability in diverse fields for the repair and regeneration of acute and chronically damaged tissues. Importantly, unlike the human bone marrow stromal/stem stem cells (BMSCs) that are present at low frequency in the bone marrow, ASCs can be retrieved in high number from either liposuction aspirates or subcutaneous adipose tissue fragments and can easily be expanded in vitro. ASCs display properties similar to that observed in BMSCs and, upon induction, undergo at least osteogenic, chondrogenic, adipogenic and neurogenic, differentiation in vitro. Furthermore, ASCs have been shown to be immunoprivileged, prevent severe graft-versus-host disease in vitro and in vivo and to be genetically stable in long-term culture. They have also proven applicability in other functions, such as providing hematopoietic support and gene transfer. Due to these characteristics, ASCs have rapidly advanced into clinical trials for treatment of a broad range of conditions. As cell therapies are becoming more frequent, clinical laboratories following good manufacturing practices are needed. At the same time as laboratory processes become more extensive, the need for control in the processing laboratory grows consequently involving a greater risk of complications and possibly adverse events for the recipient. Therefore, the safety, reproducibility and quality of the stem cells must thoroughly be examined prior to extensive use in clinical applications. In this review, some of the aspects of examination on ASCs in vitro and the utilization of ASCs in clinical studies are discussed. PMID: 20853072 [PubMed - indexed for MEDLINE] 1194. Acta Reumatol Port. 2009 Oct-Dec;34(4):590-8. Metabolic syndrome, inflammation and atherosclerosis - the role of adipokines in health and in systemic inflammatory rheumatic diseases. Santos MJ(1), Fonseca JE. Author information: (1)Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa. mjps@netvisao.pt Cardiovascular (CV) events are among the leading causes of morbidity and mortality in patients with inflammatory rheumatic diseases. It has been hypothesized that, in addition to the traditional CV risk factors, inflammation is a major contributor to atherogenesis. Metabolic syndrome (MetS) stands for a cluster of risk factors associated with insulin resistance and increased abdominal fat. Inflammation and MetS are intimately linked. Inflammatory biomarkers are frequently elevated in people with MetS and, conversely, the prevalence of MetS is higher in patients with chronic inflammatory rheumatic diseases, such as Rheumatoid Arthritis and Systemic Lupus Erythematosus. Inflammatory cytokines impair insulin sensitivity and can induce an adverse lipoprotein profile as seen in MetS. Furthermore, the presence of MetS correlates with increased subclinical atherosclerosis, major adverse CV events and death, making an important contribution to the CV burden in inflammatory diseases. Adipose tissue has recently emerged as an active organ that produces and secretes numerous mediators - adipokines - particularly relevant in energy homeostasis, inflammation, immune regulation and angiogenesis. These mediators arise as a potential link between MetS, inflammation and atherogenesis. Understanding the complex regulation and function of adipokines in health and disease is a priority since it may lead to new preventive and therapeutic interventions aiming to decrease CV risk. PMID: 20852572 [PubMed - indexed for MEDLINE] 1195. Exp Gerontol. 2011 Feb-Mar;46(2-3):108-11. doi: 10.1016/j.exger.2010.08.020. Epub 2010 Sep 17. Growth hormone, insulin and aging: the benefits of endocrine defects. Bartke A(1). Author information: (1)Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62794-9628, USA. abartke@siumed.edu Longevity of mice can be increased by spontaneous or experimentally induced mutations that interfere with the biosynthesis or actions of growth hormone (GH), insulin-like growth factor 1 (IGF-1), or insulin in the adipose tissue. The effects of GH resistance and deficiency of GH (along with thyrotropin and prolactin) on aging and lifespan are the most pronounced and best established of these mutations. Potential mechanisms linking these endocrine deficits with delayed aging and extended longevity include increased stress resistance, alterations in insulin and mammalian target of rapamycin (mTOR) signaling and metabolic adjustments. Physiological relationships deduced from the extreme phenotypes of long-lived mouse mutants appear to apply broadly, encompassing genetically normal ("wild-type") mice and other mammalian species. The role of GH in the control of human aging continues to be hotly debated, but recent data indicate that reduced somatotropic signaling provides protection from cancer and other age-related diseases and may promote old age survival. Copyright © 2010 Elsevier Inc. All rights reserved. PMCID: PMC3408075 PMID: 20851173 [PubMed - indexed for MEDLINE] 1196. Exp Gerontol. 2011 May;46(5):376-81. doi: 10.1016/j.exger.2010.09.003. Epub 2010 Sep 16. Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Partridge L(1), Alic N, Bjedov I, Piper MD. Author information: (1)Institute of Healthy Ageing, London, WC1E 6BT, UK. l.partridge@ucl.ac.uk A remarkable discovery of recent years is that, despite the complexity of ageing, simple genetic interventions can increase lifespan and improve health during ageing in laboratory animals. The pathways involved have often proved to sense nutrients and to match costly activities of organisms, such as growth, metabolism and reproduction, to nutrient status. For instance, the insulin/insulin-like growth factor and Target of Rapamycin signalling network has proved to play a function in ageing, from yeast to mammals, seemingly including humans. In the fruit fly Drosophila, altered activity of several components of this network can increase lifespan and improve locomotor and cardiac function during ageing. The fly brain, fat body (equivalent of mammalian liver and white adipose tissue) and the germ line are important in determination of lifespan, with considerable communication between different tissues. Cellular detoxification pathways, increased autophagy and altered protein synthesis have all been implicated in increased lifespan from reduced IIS/TOR activity, with the role of defence against oxidative stress unresolved. Reduced IIS/TOR signalling can alter or block the response of lifespan to dietary restriction. Reduced IIS can act acutely to lower death rate, implying that it may ameliorate the effects of ageing-related damage, rather than preventing it. Copyright © 2010 Elsevier Inc. All rights reserved. PMCID: PMC3087113 PMID: 20849947 [PubMed - indexed for MEDLINE] 1197. Neuroendocrinology. 2010;92 Suppl 1:77-81. doi: 10.1159/000314319. Epub 2010 Sep 10. Pathophysiology of diabetes mellitus in Cushing's syndrome. Pivonello R(1), De Leo M, Vitale P, Cozzolino A, Simeoli C, De Martino MC, Lombardi G, Colao A. Author information: (1)Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy. rpivone@tin.it Cushing's syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing's syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing's syndrome. Copyright © 2010 S. Karger AG, Basel. PMID: 20829623 [PubMed - indexed for MEDLINE] 1198. Ital J Pediatr. 2010 Sep 16;36:63. doi: 10.1186/1824-7288-36-63. Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy. Distefano G(1), Praticò AD. Author information: (1)Department of Pediatrics, Division of Neonatology, University of Catania, Catania, Italy. distef@unict.it Hypoxic-ischemic encephalopathy (HIE) is the most important cause of cerebral damage and long-term neurological sequelae in the perinatal period both in term and preterm infant. Hypoxic-ischemic (H-I) injuries develop in two phases: the ischemic phase, dominated by necrotic processes, and the reperfusion phase, dominated by apoptotic processes extending beyond ischemic areas. Due to selective ischemic vulnerability, cerebral damage affects gray matter in term newborns and white matter in preterm newborns with the typical neuropathological aspects of laminar cortical necrosis in the former and periventricular leukomalacia in the latter. This article summarises the principal physiopathological and biochemical processes leading to necrosis and/or apoptosis of neuronal and glial cells and reports recent insights into some endogenous and exogenous cellular and molecular mechanisms aimed at repairing H-I cerebral damage. PMCID: PMC2954868 PMID: 20846380 [PubMed - indexed for MEDLINE] 1199. Vnitr Lek. 2010 Jul;56(7):727-35. [Distressful journey for the metabolic syndrome to its position in clinical practice]. [Article in Czech] Rybka J(1). Author information: (1)Diabetologické centrum Interní kliniky IPVZ Krajské nemocnice T Bati. rybka@bnzlin.cz MS is a major atherogenic syndrome in our population. The concept of MS has had a very positive effect on our knowledge of the most serious civilization diseases, the genotypic constellation of MS, although monogenic defects explain only a very small part of pathological defects. It is certain, however, that a crucial role played is by interactions between genetic factors and risk factors of external environment. Undoubtedly, insulin resistance, central obesity and impaired metabolism of adipose tissue play an important role in the pathogenesis of MS, and there are other pathogenetic theories. The author discusses briefly the history of MS and presents the best-known definitions starting with the 90s ofthe last century, ADA and EASD reservations towards MS, as well as the new harmonized definition from 2009. This modified definition ofMS has been adopted in practice in the Czech Republic due to the Czech Institute ofmetabolic syndrome. The author discusses in greater detail the WHO expert report from 2010, which indicates some limitations of diagnostic criteria for MS. Despite all the objections the expert report provides reasons to support the use of the term metabolic syndrome, and metabolic syndrome is considered to be a recognized concept that focuses attention on the importance of comprehensive, multifactorial health problems. Finally, the author mentions sub-problems related to MS, which will have to be resolved in collaboration with diabetologists. PMID: 20842921 [PubMed - indexed for MEDLINE] 1200. Swiss Med Wkly. 2010 Sep 15;140:w13071. doi: 10.4414/smw.2010.13071. Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels. Yessoufou A(1), Wahli W. Author information: (1)University of Lausanne, Centre for Integrative Genomics, Switzerland. Akadiri.Yessoufou@unil.ch Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies. PMID: 20842602 [PubMed - indexed for MEDLINE] 1201. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):647-55. doi: 10.1097/MCO.0b013e32833f1acd. Inflammatory signaling in skeletal muscle insulin resistance: green signal for nutritional intervention? Hommelberg PP(1), Langen RC, Schols AM, Mensink RP, Plat J. Author information: (1)Department of Human Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. PURPOSE OF REVIEW: To review the evidence implying a role of inflammatory signaling pathways, specifically nuclear factor-κB and c-Jun NH2-terminal kinase, in fatty acid-induced skeletal muscle insulin resistance and to discuss the potential of dietary interventions to interfere with these processes. RECENT FINDINGS: Fatty acids can induce skeletal muscle insulin resistance via inflammatory signaling after binding Toll-like receptors at the cell membrane of muscle cells or after accumulating as intramyocellular lipid metabolites. In both processes, activation of intracellular inflammatory signaling is involved. The majority of literature addressing the causality of muscle nuclear factor-κB activation in skeletal muscle insulin resistance suggests that insulin resistance does not require muscle nuclear factor-κB activation. Recently, strong evidence was given that c-Jun NH2-terminal kinase signaling is an important inflammatory pathway involved in skeletal muscle insulin resistance. Furthermore, it is well established that proinflammatory cytokines originating from the enlarged adipose tissue or from activated adipose tissue macrophages can cause muscle insulin resistance. Recently, also macrophages resided in the muscle have been proposed to play an important role in muscle insulin resistance. Because of their anti-inflammatory characteristics, several dietary components like polyphenols may be interesting candidates for manipulating skeletal muscle insulin resistance. SUMMARY: Several dietary components, like polyphenols, have been reported to interfere with inflammatory signaling. To test whether these compounds can be used to prevent or reverse insulin resistance, well controlled human intervention studies have to be designed. PMID: 20842028 [PubMed - indexed for MEDLINE] 1202. Ann N Y Acad Sci. 2010 Sep;1205:76-81. doi: 10.1111/j.1749-6632.2010.05667.x. The effects of adipose tissue and adipocytokines in human pregnancy. Valsamakis G(1), Kumar S, Creatsas G, Mastorakos G. Author information: (1)Endocrine Unit, 2nd Department of Obstetrics and Gynaecology, Aretaieion University Hospital, Athens Medical School, Athens, Greece. gedvalsamakis@yahoo.com During pregnancy, important changes take place in maternal metabolism because of the growing fetus and placental formation. The increase in insulin resistance during pregnancy is paralleled by the progressive increase of maternal adipose tissue deposition. This review examines the topography of fat mass deposition during pregnancy in relation to factors such as parity and maternal age that might affect this deposition. We also examine adipose tissue markers, such as pregravid weight and weight gain during pregnancy, and their effect on fetal growth and pregnancy outcomes. In addition, this review studies the possible effects of cytokines that are produced by adipose tissue and the placenta on maternal metabolism and its complications. Finally, we also consider the possible role of maternal adipocytokines and fetal adipocytokines on fetal growth. © 2010 New York Academy of Sciences. PMID: 20840256 [PubMed - indexed for MEDLINE] 1203. Curr Drug Targets. 2010 Oct;11(10):1262-9. The role of PGC-1α in the pathogenesis of neurodegenerative disorders. Róna-Vörös K(1), Weydt P. Author information: (1)Department of Neurology, Ulm University, Ulm, Germany. Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1α, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1α system in HD pathogenesis and explores the implications for ALS, AD and PD. PMID: 20840068 [PubMed - indexed for MEDLINE] 1204. J Mammary Gland Biol Neoplasia. 2010 Sep;15(3):365-76. doi: 10.1007/s10911-010-9192-y. Epub 2010 Sep 12. Synthetic adipose tissue models for studying mammary gland development and breast tissue engineering. Wang X(1), Reagan MR, Kaplan DL. Author information: (1)Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA. The mammary gland is a dynamic organ that continually changes its architecture and function. Reciprocal interactions between epithelium and adipocyte-containing stroma exert profound effects on all stages of its development, even though the details of these events are not fully understood. To address this issue, enormous potential exists in the utilization of synthetic adipose tissue model systems to uncover the properties and functions of adipocytes in the mammary gland. The first part of this review focuses on mammary adipose tissue (or adipocyte)-related model systems developed in recent years and their utility in investigating adipose-epithelial interactions, mammary gland morphogenesis, development and tumorigenesis. The second part shifts to the field of adipose-based breast tissue engineering, focusing on how these synthetic adipose tissue models are being constructed in vitro or in vivo for regeneration of the mammary gland, and their potentials in adipose tissue engineering also are discussed. PMID: 20835885 [PubMed - indexed for MEDLINE] 1205. Biochem Biophys Res Commun. 2010 Oct 22;401(3):321-6. doi: 10.1016/j.bbrc.2010.09.012. Epub 2010 Sep 15. Myocardial regeneration potential of adipose tissue-derived stem cells. Bai X(1), Alt E. Author information: (1)Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA. Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the underlying mechanisms for beneficial effect on cardiac function, and safety issues. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 20833143 [PubMed - indexed for MEDLINE] 1206. Best Pract Res Clin Endocrinol Metab. 2010 Aug;24(4):515-25. doi: 10.1016/j.beem.2010.05.006. Disturbances in lipid metabolism in diabetic pregnancy - Are these the cause of the problem? Herrera E(1), Ortega-Senovilla H. Author information: (1)Universidad San Pablo CEU, Boadilla del Monte, Madrid, Spain. eherrera@ceu.es The most common neonatal complication of gestational diabetes (GDM) is macrosomia. During early pregnancy an accumulation of maternal fat depots occurs followed by increased adipose tissue lipolysis and subsequent hyperlipidaemia, which mainly corresponds to increased triglycerides (TG) in all circulating lipoproteins. In GDM women, the enhanced insulin resistance and decreased oestrogens are responsible for the reported wide range of dyslipidaemic conditions. In GDM, decreased proportion of long chain polyunsaturated fatty acids in fetus plasma could result from decreased supply, impaired placental transfer or even altered intrauterine metabolism. A positive correlation between maternal TG and neonatal body weight or fat mass has been found in GDM. Augmented oxidative stress and altered adipokines have also been found, with an adverse outcome even in normoglycaemic conditions. Thus, although additional studies are required, overall these findings indicate that altered maternal lipid metabolism rather than hyperglycaemia constitutes a risk for macrosomia in GDM. 2010 Elsevier Ltd. All rights reserved. PMID: 20832733 [PubMed - indexed for MEDLINE] 1207. Aesthet Surg J. 2010 Jul-Aug;30(4):549-56. doi: 10.1177/1090820X10380859. Autogenous fat grafting and breast augmentation: a review of the literature. Parrish JN(1), Metzinger SE. Author information: (1)jnparr@hotmail.com Since the 1980s, there has been an increased interest in autogenous fat grafting for breast augmentation. However, concerns over graft survival and interference with breast cancer screening have limited its application. Since its introduction, refinements in harvesting and grafting techniques have improved results. The available literature consists primarily of case reports and series. There are no controlled trials, and outcomes thus far have not been measured in a standardized way. The limited data relating to breast cancer screening did not note a significant interference. Concerns have been raised that the placement of mature adipocytes and adipocyte-derived stem cells into the hormonally-active environment of the breast may potentiate breast cancer, but there are no clinical trials that investigate this possibility and a consensus regarding the basic science is still developing. Large multicenter, controlled, prospective trials are necessary to further investigate the many issues relating to the application of autogenous fat grafting for augmentation of the breast. PMID: 20829253 [PubMed - indexed for MEDLINE] 1208. Expert Rev Clin Immunol. 2010 Sep;6(5):801-8. doi: 10.1586/eci.10.48. At the crossroad between immunity and metabolism: focus on leptin. Conde J(1), Scotece M, Gómez R, Gómez-Reino JJ, Lago F, Gualillo O. Author information: (1)Research laboratory 9 (NEIRID LAB: Neuroendocrine Interactions in Rheumatology and Inflammation Disease), Building C, Level -2, Institute of Medical Research (IDIS), Santiago University Clinical Hospital, Calle Choupana s/n, Santiago de Compostela, 15706, Spain. oreste.gualillo@sergas.es White adipose tissue is currently considered to be an active endocrine organ that secretes a plethora of factors named adipokines, most of them proinflammatory in nature, which probably contribute to low-level systemic inflammation; a state that is often present in metabolic syndrome-associated chronic pathologies such as obesity and atherosclerosis. Leptin is historically and indisputably one of the most important adipokines secreted by fat cells, with a variety of physiological roles related to the control of metabolism, energy homeostasis and inflammatory response. One of these functions is the connection between nutritional status and immune competence. Indeed, leptin has been shown to modulate both the innate and adaptive immune responses in both normal and pathological conditions. It has been shown that conditions characterized by low leptin levels are associated with increased susceptibility to infection. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with increased secretion of leptin and the production of proinflammatory pathogenic cytokines. Thus, leptin can easily be considered a frank mediator of the inflammatory/immune response. PMID: 20828288 [PubMed - indexed for MEDLINE] 1209. Cell Biol Int. 2010 Oct;34(10):1051-3. doi: 10.1042/CBI20100509. Neuroadipology: a novel component of neuroendocrinology. Chaldakov GN(1), Fiore M, Tonchev AB, Aloe L. Author information: (1)Division of Cell Biology, Medical University, Varna, Bulgaria. chaldakov@yahoo.com Adipose tissue is a dynamic endocrine and paracrine organ producing a large number of signalling proteins collectively termed adipokines. Some of them are mediators in the cross-talk between adipose tissue and the brain in regulating food intake and energy homoeostasis. However, the hypothalamus is not the only brain target for adipokines, and food intake is not the only biological effect of these signals. Rather, some adipokines support various cognitive functions and exert neurotrophic activity. Current data on adipose-derived neuropeptides, neurotrophic factors, pituitary hormones and hypothalamic releasing factors is highlighted in this review. We propose that adipose tissue is a member of the diffuse neuroendocrine system. Cumulatively, this is conceptualized as neuroadipology, a new example of a link between neurobiology and other topics, such as neuroimmunology and neuroendocrinology. Because adipose tissue is a bona fide endocrine organ, neuroadipology may be considered a new discipline in neuroendocrinology. It may have a wide-ranging potential within a variety of neuronal and metabolic functions in health and disease. PMID: 20825365 [PubMed - indexed for MEDLINE] 1210. J Ren Nutr. 2010 Sep;20(5 Suppl):S19-23. doi: 10.1053/j.jrn.2010.05.006. Metabolic syndrome and chronic kidney disease. Guarnieri G(1), Zanetti M, Vinci P, Cattin MR, Pirulli A, Barazzoni R. Author information: (1)Department MTTS, Clinica Medica, University of Trieste, Trieste, Italy. guarnier@units.it Obesity is a global health threat because of its associated metabolic and cardiovascular complications. Metabolic and hemodynamic complications of obesity (insulin resistance and hyperglycemia, hypertension, atherogenic dyslipidemia) are often clustered in the metabolic syndrome, leading to high cardiovascular morbidity and mortality. In recent years, epidemiological studies have clearly indicated that both obesity and the metabolic syndrome are independent risk factors for chronic kidney disease and these associations are at least in part independent of diabetes and hypertension per se. Additional mechanisms associated with obesity and metabolic syndrome leading to reduced renal function may include altered levels of adipose tissue hormones, inflammation, and oxidative stress. The ongoing worldwide obesity epidemic is therefore likely to increase the number of patients with chronic uremia and features of the metabolic syndrome in the next few years. Moreover, the onset and maintenance of renal damage may worsen metabolic syndrome features including insulin resistance and hypertension, leading to potential vicious cycles with negative clinical effect. Further understanding of the interactions between obesity, metabolic syndrome, and chronic kidney disease represents a potential strategy to design more effective treatments aimed at reducing morbidity and mortality in uremic patients. Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 20797564 [PubMed - indexed for MEDLINE] 1211. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):703-8. doi: 10.1097/MCO.0b013e32833ec41b. Role of hepatic desaturases in obesity-related metabolic disorders. Bjermo H(1), Risérus U. Author information: (1)Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden. PURPOSE OF REVIEW: This review aims to address the latest research on hepatic desaturases and metabolic disorders, with focus on stearoyl-CoA desaturase-1 (SCD-1) indices in observational studies. RECENT FINDINGS: In animal studies, SCD-1 inhibition protects against features of the metabolic syndrome and is associated with improved hepatic insulin resistance and decreased steatosis. In human observational studies, higher estimated hepatic SCD-1 and Δ6-desaturase activities predict the metabolic syndrome, insulin resistance and mortality whereas Δ5-desaturase index is often inversely related. However, because the desaturase activities in the liver and adipose tissue may not be regulated in parallel, it is important to define used lipid fractions when comparing studies. It is also important to take the background diets of the populations into account when comparing studies. Moreover, there may be a divergence in desaturase regulation depending on glycaemic control among individuals. SUMMARY: Increased SCD-1 indices reflecting liver desaturase activity have been associated with insulin resistance, fatty liver, the metabolic syndrome and mortality. However, it remains to be determined if high hepatic SCD-1 activity plays a direct role in the development of metabolic disorders or rather is a marker for an unfavourable diet or hepatic insulin resistance. PMID: 20823776 [PubMed - indexed for MEDLINE] 1212. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):715-21. doi: 10.1097/MCO.0b013e32833eebe5. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Meijer K(1), de Vos P, Priebe MG. Author information: (1)Center for Medical Biomics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. PURPOSE OF REVIEW: High-fiber diets have been shown to reduce plasma concentrations of inflammation markers. Increased production of fermentation-derived short-chain fatty acids (SCFAs) is one of the factors that could exert these positive effects. This review examines the effects of SCFAs on immune cells and discusses the relevance of their effects on systemic inflammation, as frequently seen in obesity. RECENT FINDINGS: SCFAs have been shown to reduce chemotaxis and cell adhesion; this effect is dependent on type and concentration of SCFA. In spite of conflicting results, especially butyrate seems to have an anti-inflammatory effect, mediated by signaling pathways like nuclear factor-κB and inhibition of histone deacetylase. The discrepancies in the results could be explained by differences in cell types used and their proliferative and differentiation status. SUMMARY: SCFAs show anti-inflammatory effects and seem to have the potency to prevent infiltration of immune cells from the bloodstream in, for example, the adipose tissue. In addition, their ability to inhibit the proliferation and activation of T cells and to prevent adhesion of antigen-presenting cells could be important as it recently has been shown that obesity-associated inflammation might be antigen-dependent. More studies with concentrations in micromolar range are needed to approach more physiological concentrations. PMID: 20823773 [PubMed - indexed for MEDLINE] 1213. Am J Physiol Endocrinol Metab. 2010 Nov;299(5):E685-94. doi: 10.1152/ajpendo.00283.2010. Epub 2010 Sep 7. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Dekker MJ(1), Su Q, Baker C, Rutledge AC, Adeli K. Author information: (1)Research Institute, The Hospital for Sick Children, University of Toronto, Ontario, Canada. As dietary exposure to fructose has increased over the past 40 years, there is growing concern that high fructose consumption in humans may be in part responsible for the rising incidence of obesity worldwide. Obesity is associated with a host of metabolic challenges, collectively termed the metabolic syndrome. Fructose is a highly lipogenic sugar that has profound metabolic effects in the liver and has been associated with many of the components of the metabolic syndrome (insulin resistance, elevated waist circumference, dyslipidemia, and hypertension). Recent evidence has also uncovered effects of fructose in other tissues, including adipose tissue, the brain, and the gastrointestinal system, that may provide new insight into the metabolic consequences of high-fructose diets. Fructose feeding has now been shown to alter gene expression patterns (such as peroxisome proliferator-activated receptor-γ coactivator-1α/β in the liver), alter satiety factors in the brain, increase inflammation, reactive oxygen species, and portal endotoxin concentrations via Toll-like receptors, and induce leptin resistance. This review highlights recent findings in fructose feeding studies in both human and animal models with a focus on the molecular and biochemical mechanisms that underlie the development of insulin resistance, hepatic steatosis, and the metabolic syndrome. PMID: 20823452 [PubMed - indexed for MEDLINE] 1214. Cancer Metastasis Rev. 2010 Dec;29(4):641-53. doi: 10.1007/s10555-010-9252-1. Obesity and breast cancer: status of leptin and adiponectin in pathological processes. Grossmann ME(1), Ray A, Nkhata KJ, Malakhov DA, Rogozina OP, Dogan S, Cleary MP. Author information: (1)The Hormel Institute, University of Minnesota, 801-16th Avenue NE, Austin, MN 55912, USA. It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin. PMID: 20821253 [PubMed - indexed for MEDLINE] 1215. Nat Rev Endocrinol. 2010 Nov;6(11):629-36. doi: 10.1038/nrendo.2010.155. Epub 2010 Sep 7. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Kawai M(1), Rosen CJ. Author information: (1)Center for Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074-7205, USA. Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism. PMCID: PMC3132113 PMID: 20820194 [PubMed - indexed for MEDLINE] 1216. World J Gastroenterol. 2010 Sep 14;16(34):4243-52. Obstructive sleep apnea syndrome and fatty liver: association or causal link? Ahmed MH, Byrne CD. Obstructive sleep apnea (OSA) is a complex disorder that consists of upper airway obstruction, chronic intermittent hypoxia and sleep fragmentation. OSA is well known to be associated with hypoxia, insulin resistance and glucose intolerance, and these factors can occur in the presence or absence of obesity and metabolic syndrome. Although it is well established that insulin resistance, glucose intolerance and obesity occur frequently with non-alcoholic fatty liver disease (NAFLD), it is now becoming apparent that hypoxia might also be important in the development of NAFLD, and it is recognized that there is increased risk of NAFLD with OSA. This review discusses the association between OSA, NAFLD and cardiovascular disease, and describes the potential role of hypoxia in the development of NAFLD with OSA. PMCID: PMC2937104 PMID: 20818807 [PubMed - indexed for MEDLINE] 1217. Trends Immunol. 2010 Oct;31(10):384-90. doi: 10.1016/j.it.2010.08.001. Adaptive immunity and adipose tissue biology. Kaminski DA(1), Randall TD. Author information: (1)Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA. Studies of immunity typically focus on understanding how hematopoietic cells interact within conventional secondary lymphoid tissues. However, immune reactions and their regulation occur in various environments within the body. Adipose tissue is one tissue that can influence and be influenced by adjacent and embedded lymphocytes. Despite the abundance and wide distribution of such tissue, and despite a growing obesity epidemic, studies of these interactions have been only marginally appreciated in the past. Here, we review advances in understanding of lymphoid structures within adipose tissue, the relationship between adipose tissue and adaptive immune function, and evidence for how this relationship contributes to obesity-associated diseases. Copyright © 2010 Elsevier Ltd. All rights reserved. PMCID: PMC2949534 PMID: 20817556 [PubMed - indexed for MEDLINE] 1218. Peptides. 2010 Nov;31(11):2145-50. doi: 10.1016/j.peptides.2010.07.020. Epub 2010 Sep 15. Insulin-induced gene: a new regulator in lipid metabolism. Dong XY(1), Tang SQ. Author information: (1)College of Yingdong Agricultural Science and Engineering, Shaoguan University, Daxue Avenue, Zhenjiang District, Shaoguan 512005, PR China. Insulin-induced genes (Insigs) including Insig-1 and Insig-2, are proteins that mediate sterol regulation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). Insigs perform distinct tasks in the regulation of these effectors: they promote the endoplasmic reticulum (ER) retention of SCAP, but ubiquitin-mediated degradation of HMG-CoA reductase. Through these activities, Insig-1 and Insig-2 influence cholesterol metabolism, lipogenesis, and glucose homeostasis in diverse tissues such as adipose tissue and liver. In this article, we focus on the functions, expression and regulation, gene polymorphisms of Insigs, and their deficiency with diseases. Copyright © 2010. Published by Elsevier Inc. All rights reserved. PMID: 20817058 [PubMed - indexed for MEDLINE] 1219. Curr Osteoporos Rep. 2010 Dec;8(4):168-77. doi: 10.1007/s11914-010-0033-0. The skeletal subsystem as an integrative physiology paradigm. Weiss AJ(1), Iqbal J, Zaidi N, Mechanick JI. Author information: (1)Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. Homeostatic bone remodeling depends on precise regulation of osteoblast-osteoclast coupling through intricate endocrine, immune, neuronal, and mechanical factors. The osteoblast-osteoclast model of bone physiology with layers of regulatory complexity can be investigated as a component of a local skeletal subsystem or as a part of a complete whole-body system. In this review, we flip the traditional investigative paradigm of scientific experimentation ("bottom-top research") to a "top-bottom" approach using systems biology. We first establish the intricacies of the two-cell model at the molecular signaling level. We then provide, on a systems level, an integrative physiologic approach involving many recognized organ-level subsystems having direct and/or indirect effects on bone remodeling. Lastly, a hypothetical model of bone remodeling based on frequency and amplitude regulatory mechanisms is presented. It is hoped that by providing a thorough model of skeletal homeostasis, future progress can be made in researching and treating skeletal morbidities. PMID: 20814769 [PubMed - indexed for MEDLINE] 1220. Wien Med Wochenschr. 2010 Aug;160(15-16):377-90. doi: 10.1007/s10354-010-0781-6. [Adipokine update - new molecules, new functions]. [Article in German] Gelsinger C(1), Tschoner A, Kaser S, Ebenbichler CF. Author information: (1)Universitätsklinik für Innere Medizin I, Department Innere Medizin, Medizinische Universität Innsbruck, Innsbruck, Austria. The prevalence of obesity is rising worldwide. Recent research findings show that adipose tissue is a highly active endocrine organ, which is involved in many physiological processes. These metabolic processes are influenced by products of the adipose tissue, so-called adipokines, which play a crucial role in the pathogenesis of the metabolic syndrome and cardiovascular disease. In addition, the two major fat depots - intraabdominal and subcutaneous - differ in their ability to secrete adipokines. In recent years the importance of the association between intraabdominal fat and the development of insulin resistance, diabetes mellitus type 2 and dyslipidemia was recognized. Therefore, accumulation of visceral adipose tissue contributes due to its ability to secrete a different pattern of adipokines to increased morbidity and mortality. This review aims to characterize novel, newly recognized adipokines and to discuss their roles in the pathogenesis of insulin resistance and atherosclerosis, as well as other metabolic complications. PMID: 20812049 [PubMed - indexed for MEDLINE] 1221. Rinsho Ketsueki. 2010 Aug;51(8):620-4. [Pathogenesis of chronic inflammation revealed by in vivo imaging: thrombus formation and platelet function]. [Article in Japanese] Nishimura S. PMID: 20805667 [PubMed - indexed for MEDLINE] 1222. Biofactors. 2010 Nov-Dec;36(6):415-22. doi: 10.1002/biof.115. Epub 2010 Aug 27. Phytochemicals and adipogenesis. Andersen C(1), Rayalam S, Della-Fera MA, Baile CA. Author information: (1)Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark. Obesity is an increasing health problem all over the world. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing the amount of adipose tissue. Flavonoids and stilbenoids represent the most researched groups of phytochemicals with regards to their effect on adipogenesis, but there are also a number of in vitro and in vivo studies with phenolic acids, alkaloids, and vitamins, as well as other plant compounds. Although phytochemicals like epigallocatechin-3-gallate, genistein, and resveratrol reduce lipid accumulation and induce adipocyte apoptosis in vitro and reduce body weight and adipose tissues mass in animal models of diet-induced obesity, well-conducted clinical trials are lacking. Pharmacological doses are often used in vitro and when applied in physiological doses in animals or humans, the phytochemicals are often ineffective in affecting adipogenesis. However, by combining several phytochemicals or using them as templates for synthesizing new drugs, there is a large potential in targeting adipogenesis using phytochemicals. Copyright © 2010 International Union of Biochemistry and Molecular Biology, Inc. PMID: 20803522 [PubMed - indexed for MEDLINE] 1223. Curr Opin Lipidol. 2010 Dec;21(6):530-8. doi: 10.1097/MOL.0b013e32833ea9ec. Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus. Brouwers MC(1), de Graaf J, van Greevenbroek MM, Schaper N, Stehouwer CD, Stalenhoef AF. Author information: (1)Laboratory of Vascular Medicine and Metabolism, Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. PURPOSE OF REVIEW: Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach. RECENT FINDINGS: Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients. SUMMARY: Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy. PMID: 20739883 [PubMed - indexed for MEDLINE] 1224. Curr Med Chem. 2010;17(30):3542-74. Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Lóránd T(1), Vigh E, Garai J. Author information: (1)Department of Biochemistry and Medical Chemistry, University of Pécs, Medical School, Pécs, Hungary. Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and structural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added anthropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects. Here we review the endocrine effects of known phytoestrogens and xenoestrogens with special emphasis on molecular structure-activity relationships. Phytoestrogens include flavonoids, isoflavonoids, chalcons, coumestans, stilbenes, lignans, ginsenosides and other saponins, as well as the recently discovered tetrahydrofurandiols. Fungal estrogenic compounds may enter the food chain via infested crops. Since some phytoestrogens have been shown to display organ-specific actions, pharmaceutical estrogen analogues with similar properties (selective estrogen receptor modulators, SERMs) are also discussed. Xenoestrogens include dichlorodiphenyltrichloroethane (DDT) and its metabolites, bisphenols, alkylphenols, dichlorophenols, methoxychlor, chlordecone, polychlorinated benzol derivatives (PCBs), and dioxins. While most of these compounds act through estrogen receptors alpha and beta, some of their effects may be mediated by other nuclear or membrane-bound receptors or receptor-independent mechanisms. Some might also interfere with the production and metabolism of ovarian estrogens. Better understanding of the molecular pharmacology of phyto- and xenoestrogens may result in the development of novel compounds with therapeutic utility and improved environmental protection. PMID: 20738246 [PubMed - indexed for MEDLINE] 1225. Best Pract Res Clin Rheumatol. 2010 Aug;24(4):565-74. doi: 10.1016/j.berh.2010.01.008. Stem cells in the treatment of inflammatory arthritis. Tyndall A(1), van Laar JM. Author information: (1)Department of Rheumatology, University of Basel, Switzerland. Autologous haematopoietic stem cell transplantation in patients with rheumatoid arthritis (RA) resulted in a positive short-term outcome clinically with low treatment-related toxicity. However, early conditioning regimens were of low immunoablative intensity and most patients relapsed. Mechanistic studies suggest that residual lesional effector cells may have been responsible for the relapses. The introduction of biopharmaceuticals has, for the moment, reduced the need for further experimental studies. Juvenile idiopathic arthritis patients, mostly of the systemic subgroup, have shown nearly 33% durable drug-free remission, but with significant toxicity, including fatal macrophage-activation syndrome early in the programme. Later modifications to the protocol have reduced this toxicity. Mesenchymal stem cells (MSCs), derived from several sources including bone marrow and adipose tissue, are being tested as tissue-regenerative and immunomodulating agents in many autoimmune diseases and animal models of inflammatory arthritis have been positive. MSCs and other stromal cells derived from actively inflamed synovium and peripheral blood of RA patients do not always demonstrate a full range of differentiation potential compared with healthy MSCs, although their immunomodulalatory capacity is unimpaired. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20732653 [PubMed - indexed for MEDLINE] 1226. Cell Tissue Res. 2010 Oct;342(1):1-11. doi: 10.1007/s00441-010-1024-2. Epub 2010 Aug 24. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease. Itoh N(1). Author information: (1)Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan. itohnobu@pharm.kyoto-u.ac.jp Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgfs identified in invertebrates and vertebrates, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, are vertebrate-specific. The ancestral gene of hormone-like Fgfs was generated from the ancestral gene of canonical Fgfs by gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgfs acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function. PMCID: PMC2948652 PMID: 20730630 [PubMed - indexed for MEDLINE] 1227. Curr Opin Hematol. 2010 Nov;17(6):505-13. doi: 10.1097/MOH.0b013e32833e5b18. Emerging therapeutic approaches for multipotent mesenchymal stromal cells. Caimi PF(1), Reese J, Lee Z, Lazarus HM. Author information: (1)Department of Medicine, Case Western Reserve University, Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA. PURPOSE OF REVIEW: Multipotent mesenchymal stromal cells (MSCs) are rare cells resident in bone marrow and other organs capable of differentiating into mesodermal lineage tissues. MSCs possess immunomodulatory properties and have extensive capacity for ex-vivo expansion. Early clinical studies demonstrated safety and feasibility of infusing autologous MSCs and suggested a role in enhancing engraftment after hematopoietic cell transplant (HCT). Subsequent pilot studies using allogeneic MSCs showed safety but presented contradictory results regarding efficacy in treating graft-versus-host disease (GVHD). RECENT FINDINGS: Larger, phase II allogeneic MSC infusion studies, including cells obtained from haploidentical and third-party donors, showed efficacy in GVHD treatment; however, recent randomized, placebo-controlled studies failed to corroborate these results. New investigations include MSC infusions in umbilical cord blood transplantation, MSC therapy for tissue regeneration/repair, harvest and use of MSCs from adipose tissue and cell-tracking/imaging studies using radionuclides, gene and fluorescent dye-labeled MSCs. SUMMARY: MSCs remain the subject of intense investigation in HCT because of their differentiation potential and immunomodulatory properties. Whereas infusions of autologous, allogeneic and third-party donor MSCs are well tolerated, further research is needed to clarify the optimal methods for harvesting and expansion, optimal timing of administration and efficacy in the setting of HCT. PMCID: PMC3748957 PMID: 20729733 [PubMed - indexed for MEDLINE] 1228. Cell Transplant. 2011;20(2):145-52. doi: 10.3727/096368910X522081. Epub 2010 Aug 18. Transplantation of olfactory ensheathing cells as adjunct cell therapy for peripheral nerve injury. Radtke C(1), Wewetzer K, Reimers K, Vogt PM. Author information: (1)Department of Plastic, Hand- and Reconstructive Surgery, Hannover Medical School, Hannover, Germany. Radtke.Christine@MH-Hannover.de Traumatic events, such as work place trauma or motor vehicle accident violence, result in a significant number of severe peripheral nerve lesions, including nerve crush and nerve disruption defects. Transplantation of myelin-forming cells, such as Schwann cells (SCs) or olfactory ensheathing cells (OECs), may be beneficial to the regenerative process because the applied cells could mediate neurotrophic and neuroprotective effects by secretion of chemokines. Moreover, myelin-forming cells are capable of bridging the repair site by establishing an environment permissive to axonal regeneration. The cell types that are subject to intense investigation include SCs and OECs either derived from the olfactory bulb or the olfactory mucosa, stromal cells from bone marrow (mesenchymal stem cells, MSCs), and adipose tissue-derived cells. OECs reside in the peripheral and central nervous system and have been suggested to display unique regenerative properties. However, so far OECs were mainly used in experimental studies to foster central regeneration and it was not until recently that their regeneration-promoting activity for the peripheral nervous system was recognized. In the present review, we summarize recent experimental evidence regarding the regenerative effects of OECs applied to the peripheral nervous system that may be relevant to design novel autologous cell transplantation therapies. © 2011 Cognizant Comm. Corp. PMID: 20719095 [PubMed - indexed for MEDLINE] 1229. J Mammary Gland Biol Neoplasia. 2010 Sep;15(3):279-90. doi: 10.1007/s10911-010-9187-8. Epub 2010 Aug 19. Diverse and active roles for adipocytes during mammary gland growth and function. Hovey RC(1), Aimo L. Author information: (1)Department of Animal Science, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA. rchovey@ucdavis.edu The mammary gland is unique in its requirement to develop in close association with a depot of adipose tissue that is commonly referred to as the mammary fat pad. As discussed throughout this issue, the mammary fat pad represents a complex stromal microenvironment that includes a variety of cell types. In this article we focus on adipocytes as local regulators of epithelial cell growth and their function during lactation. Several important considerations arise from such a discussion. There is a clear and close interrelationship between different stromal tissue types within the mammary fat pad and its adipocytes. Furthermore, these relationships are both stage- and species-dependent, although many questions remain unanswered regarding their roles in these different states. Several lines of evidence also suggest that adipocytes within the mammary fat pad may function differently from those in other fat depots. Finally, past and future technologies present a variety of opportunities to model these complexities in order to more precisely delineate the many potential functions of adipocytes within the mammary glands. A thorough understanding of the role for this cell type in the mammary glands could present numerous opportunities to modify both breast cancer risk and lactation performance. PMCID: PMC2941079 PMID: 20717712 [PubMed - indexed for MEDLINE] 1230. J Biol Chem. 2010 Oct 22;285(43):32679-83. doi: 10.1074/jbc.R110.135210. Epub 2010 Aug 17. Tissue-specific functions in the fatty acid-binding protein family. Storch J(1), Thumser AE. Author information: (1)Department of Nutritional Sciences and the Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA. storch@aesop.rutgers.edu The intracellular fatty acid-binding proteins (FABPs) are abundantly expressed in almost all tissues. They exhibit high affinity binding of a single long-chain fatty acid, with the exception of liver FABP, which binds two fatty acids or other hydrophobic molecules. FABPs have highly similar tertiary structures consisting of a 10-stranded antiparallel β-barrel and an N-terminal helix-turn-helix motif. Research emerging in the last decade has suggested that FABPs have tissue-specific functions that reflect tissue-specific aspects of lipid and fatty acid metabolism. Proposed roles for FABPs include assimilation of dietary lipids in the intestine, targeting of liver lipids to catabolic and anabolic pathways, regulation of lipid storage and lipid-mediated gene expression in adipose tissue and macrophages, fatty acid targeting to β-oxidation pathways in muscle, and maintenance of phospholipid membranes in neural tissues. The regulation of these diverse processes is accompanied by the expression of different and sometimes multiple FABPs in these tissues and may be driven by protein-protein and protein-membrane interactions. PMCID: PMC2963392 PMID: 20716527 [PubMed - indexed for MEDLINE] 1231. J Cell Mol Med. 2010 Sep;14(9):2223-34. doi: 10.1111/j.1582-4934.2010.01141.x. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. Ouwens DM(1), Sell H, Greulich S, Eckel J. Author information: (1)The Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Centre, Düsseldorf, Germany. margriet.ouwens@ddz.uni-duesseldorf.de Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction. © 2010 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. PMCID: PMC3822561 PMID: 20716126 [PubMed - indexed for MEDLINE] 1232. J Drugs Dermatol. 2010 Aug;9(8 Suppl ODAC Conf Pt 2):s129-37. Facial shaping: beyond lines and folds with fillers. Patel U(1), Fitzgerald R. Author information: (1)Ronald O. Perelman Department of Dermatology, NewYork University School of Medicine, NewYork, NY, USA. Facial attractiveness is the most important determinant of physical attractiveness, and an important factor in social and interpersonal interactions. The field of facial rejuvenation using minimally invasive procedures has expanded exponentially over the last decade. Historically, aging and the resulting changes were primarily attributed to changes in the skin and the underlying musculoskeletal system. However, more recent understanding of the changes associated with facial aging has shifted the focus to changes in the distribution of subcutaneous fat. With the introduction of seemingly endless varieties of fillers over the last decade, restoration of volume loss by subcutaneous fat, and to some extent bone, has never been easier. Here, the authors review the basic principles that govern facial beauty, facial anatomy, the aging process, and the wide variety of fillers available on the market today that enable a dermatologic surgeon to revitalize the face. PMID: 20715395 [PubMed - indexed for MEDLINE] 1233. Radiology. 2010 Nov;257(2):353-63. doi: 10.1148/radiol.10092284. Epub 2010 Aug 16. Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes. Machann J(1), Thamer C, Stefan N, Schwenzer NF, Kantartzis K, Häring HU, Claussen CD, Fritsche A, Schick F. Author information: (1)Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany. juergen.machann@med.uni-tuebingen.de Comment in Radiology. 2010 Nov;257(2):307-8. PURPOSE: To assess adipose body compartments with magnetic resonance (MR) imaging and MR spectroscopy during a lifestyle intervention program that included optimized nutrition and controlled physical activity in subjects at increased risk for type 2 diabetes to determine factors that may help predict an increase in insulin sensitivity following the intervention. MATERIALS AND METHODS: This prospective study was approved by the local review board. All participants gave written informed consent. MR imaging and MR spectroscopy were performed in 243 subjects (99 men and 144 women) before and 9 months after enrollment in a lifestyle intervention program. The results of whole-body MR imaging were used to calculate tissue profiles, differentiating between adipose tissue--especially visceral adipose tissue--and lean tissue. The concentration of hepatic lipids and intramyocellular lipids in the anterior tibial and soleus muscles was determined with MR spectroscopy, and insulin sensitivity was estimated by using an oral glucose tolerance test. The Student t test was used to assess differences between groups, and multivariate regression models were used to assess the value of adipose tissue compartments in the prediction of insulin sensitivity. RESULTS: Compared with women, men had almost twice the amount of visceral adipose tissue and a smaller amount of total adipose tissue (25.9% for men and 36.9% for women) at baseline. In addition, their insulin sensitivity was significantly lower than that of women. The most pronounced changes in adipose tissue were detected for visceral adipose tissue (from 4.9 L to 4.1 L [ie, -15.1%] in men and from 2.3 L to 1.9 L [ie, -15.8%] in women) and hepatic lipids (from 8.6% to 5.4% [ie, -36.8%] in men and from 5.1% to 4.3% [ie, -16.5%] in women). The mean insulin sensitivity improved significantly (from 11.3 arbitrary units [au] to 14.6 au [ie, +29.9%] in men and from 13.6 au to 14.6 au [ie, +7.5%] in women), with 70 of the 99 men (71%) and 84 of 144 women (58%) showing an increase in insulin sensitivity. In men, low concentrations of visceral adipose tissue, hepatic lipids, and abdominal subcutaneous fat at baseline were predictive of successful intervention in terms of changes in insulin sensitivity; in women, only low hepatic lipid levels were significantly predictive of successful intervention. CONCLUSION: Visceral adipose tissue and hepatic lipids, as assessed with MR imaging and MR spectroscopy, can be significantly reduced during lifestyle intervention. Their baseline values emerged as predictive factors for an improvement of insulin sensitivity. © RSNA, 2010. PMID: 20713612 [PubMed - indexed for MEDLINE] 1234. Biochimie. 2011 Jan;93(1):78-86. doi: 10.1016/j.biochi.2010.08.001. Epub 2010 Aug 14. Hormonal and nutritional regulation of SCD1 gene expression. Mauvoisin D(1), Mounier C. Author information: (1)Département des Sciences Biologiques, Centre de recherche BioMed, Université du Québec À Montréal, C.P. 8888, Succursale Centre-ville, Montréal, Québec, Canada. Stearoyl-CoA Desaturase 1 (SCD1) is the rate limiting enzyme catalyzing the biosynthesis of monounsaturated fatty acids preferentially from palmitoyl-CoA and stearoyl-CoA forming respectively palmitoleyl-CoA and oleyl-CoA. These monounsaturated fatty acids are the key components of triglycerides and membrane phospholipids. Studying the regulation of SCD1 is of particular interest since alterations in phospholipids composition have been implicated in a variety of diseases including cancers, diabetes and cardiovascular disorders. Furthermore, oleic acid, the main product of SCD1 reaction, is the predominant fatty acid of human adipose tissue triacylglycerols, associating SCD1 with the development of obesity and the metabolic syndrome. In light of the key role of SCD1 in general metabolism, it is not surprising to observe a very tight and complex regulation of SCD1 gene expression in response to various parameters including hormonal and nutrient factors. In this review we analyze the anatomy and index the transcription factors that have been characterized to bind the SCD1 promoter. Then we present the current knowledge on how hormones regulate SCD1 expression with a particular interest on the role of insulin and leptin. We also describe how nutrients especially polyunsaturated fatty acids and carbohydrates modulate SCD1 gene expression. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 20713121 [PubMed - indexed for MEDLINE] 1235. J Exp Biol. 2010 Sep;213(Pt 17):2899-911. doi: 10.1242/jeb.043307. Oxidative stress in cold-induced hyperthyroid state. Venditti P(1), Di Stefano L, Di Meo S. Author information: (1)Department of the Biological Sciences, Section of Physiology, University Federico II of Naples, 80134, Naples, Italy. venditti@unina.it Exposure of homeothermic animals to low environmental temperature is associated with oxidative stress in several body tissues. Because cold exposure induces a condition of functional hyperthyroidism, the observation that tissue oxidative stress also happens in experimental hyperthyroidism, induced by 3,5,3'-triiodothyronine (T(3)) treatment, suggests that this hormone is responsible for the oxidative damage found in tissues from cold-exposed animals. Examination of T(3)-responsive tissues, such as brown adipose tissue (BAT) and liver, shows that changes in factors favoring oxidative modifications are similar in experimental and functional hyperthyroidism. However, differences are also apparent, likely due to the action of physiological regulators, such as noradrenaline and thyroxine, whose levels are different in cold-exposed and T(3)-treated animals. To date, there is evidence that biochemical changes underlying the thermogenic response to cold as well as those leading to oxidative stress require a synergism between T(3)- and noradrenaline-generated signals. Conversely, available results suggest that thyroxine (T(4)) supplies a direct contribution to cold-induced BAT oxidative damage, but contributes to the liver response only as a T(3) precursor. PMID: 20709918 [PubMed - indexed for MEDLINE] 1236. J Dtsch Dermatol Ges. 2010 Oct;8(10):776-8. doi: 10.1111/j.1610-0387.2010.07480.x. Epub 2010 Aug 5. Research in practice: More than skin deep -aging of subcutaneous fat tissue. [Article in English, German] Berneburg M(1). Author information: (1)Department of Dermatology, Eberhard Karls University, Tübingen, Germany. mark.berneburg@med.uni-tuebingen.de Mitochondria, responsible for the generation of energy in our cells, contain their own genome, mitochondrial (mt)DNA. It is known that mutations of mtDNA accumulate during normal aging and that this can be accelerated by oxidative stress, i.e. induced by ultraviolet radiation. These mutations are functionally relevant and they play a causative role in normal aging as well as premature aging induced by ultraviolet radiation. While the focus of scientific research was more on epidermis and dermis within the last years, alterations of subcutaneous fat tissue were not investigated thus far. Cockayne syndrome (CS) A and B are two proteins known to repair oxidatively induced DNA damage via nucleotide excision repair (NER) in the nucleus. We could show that these two proteins enrich in mitochondria upon oxidative stress, directly interact with mtDNA and the two repair-associated proteins mtSSBP-1 and mtOGG-1 and protect from deletions of mtDNA. If CSA or CSB are lacking, mtDNA mutations accumulate particularly in the cells of subcutaneous fat tissue which appears to mediate loss of adipocytes via apoptosis. Therefore, the two NER-associated proteins CSA and CSB appear to play a direct role in protection from mutations which in turn are causative in aging-associated loss of subcutaneous fat tissue. © The Author • Journal compilation © Blackwell Verlag GmbH, Berlin. PMID: 20707876 [PubMed - indexed for MEDLINE] 1237. Expert Rev Cardiovasc Ther. 2010 Dec;8(12):1777-801. doi: 10.1586/erc.10.125. Epub 2010 Aug 16. Phentermine, topiramate and their combination for the treatment of adiposopathy ('sick fat') and metabolic disease. Bays H(1). Author information: (1)L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. hbaysmd@aol.com Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and functional changes (termed adiposopathy or 'sick fat'), which may lead to pathogenic adipocyte and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy, and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of non-surgical weight loss therapies is often limited due to redundant physiological systems that help 'protect' against starvation and/or negative caloric balance. One strategy to overcome these limitations is to combine weight loss drug therapies having complementary mechanisms of action, thereby affecting more than one physiologic process influencing body fat accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose approved as a treatment for migraine headaches and seizure disorders. Although known to facilitate weight loss since its approval, topiramate monotherapy does not have a regulatory indication as an anti-obesity agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent containing immediate-release phentermine and controlled-release topiramate. Clinical trials involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the weight of patients, and also effective in improving adiposopathy-associated metabolic diseases. This review examines the pathophysiology of adiposopathy as a contributor to metabolic disease, the data supporting phentermine monotherapy, topiramate monotherapy and their combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve metabolic disease. PMID: 20707765 [PubMed - indexed for MEDLINE] 1238. Expert Opin Investig Drugs. 2010 Sep;19(9):1067-76. doi: 10.1517/13543784.2010.504713. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes. Morgan SA(1), Tomlinson JW. Author information: (1)University of Birmingham, Centre for Endocrinology, Diabetes & Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, 2nd floor, Room 230, Birmingham B15 2TH, UK. IMPORTANCE OF THE FIELD: The prevalence of obesity and type 2 diabetes is rising and reaching pandemic proportions. For this reason, identification of novel therapeutic targets is urgently needed. AREAS COVERED IN THIS REVIEW: The endoluminal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes glucocorticoid activation in key metabolic tissues including skeletal muscle, liver and adipose tissue, and is strongly implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome. Selective 11beta-HSD1 inhibitors limit local glucocorticoid availability and improve insulin sensitivity, glucose tolerance, lipid profiles and atherosclerosis. To date, there is a paucity of clinical studies using selective 11beta-HSD1 inhibitors; however, early indications show that these compounds have great therapeutic potential. WHAT THE READER WILL GAIN: We present a comprehensive overview of the background to the development of selective 11beta-HSD1 inhibitors, the preclinical data supporting 11beta-HSD1 as a therapeutic target, and the current status of clinical trials of these agents. TAKE HOME MESSAGE: Selective 11beta-HSD1 inhibitors have the potential to improve insulin sensitivity and may ultimately add to the treatment options available for patients with type 2 diabetes. However, further clinical studies are urgently required. PMID: 20707593 [PubMed - indexed for MEDLINE] 1239. Fa Yi Xue Za Zhi. 2010 Jun;26(3):206-9. [Advance of neurogenic erectile dysfunction therapy by stem cells]. [Article in Chinese] Shen HJ(1), Zhu GY. Author information: (1)Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, Shanghai 200063, PR China. shenhanjian@yahoo.com.cn Neurogenic erectile dysfunction (NED) commonly results from erectile nerve damage. Recent researches have focused on the preclinical study of stem cell-based therapies targeted at repairing and protecting nervi erigentes. In this paper, researches of NESCs, MDSCs, ASCs and MSCs in NED are reviewed. Early studies have demonstrated that stem cells and gene modified stem cells were effective to the therapy of ED, even likely to cure ED. Stem cells are expected to be applied in the clinical therapy of NED. Stem cells as a new therapy technique will bring up a new challenge in forensic clinical medicine. PMID: 20707282 [PubMed - indexed for MEDLINE] 1240. Mediators Inflamm. 2010;2010. pii: 289645. doi: 10.1155/2010/289645. Epub 2010 Jul 14. Chronic inflammation in obesity and the metabolic syndrome. Monteiro R(1), Azevedo I. Author information: (1)Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal. rosariom@med.up.pt The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks. PMCID: PMC2913796 PMID: 20706689 [PubMed - indexed for MEDLINE] 1241. Nat Rev Rheumatol. 2010 Sep;6(9):518-27. doi: 10.1038/nrrheum.2010.122. Epub 2010 Aug 10. Inherited human diseases of heterotopic bone formation. Shore EM(1), Kaplan FS. Author information: (1)Department of Orthopedic Surgery, University of Pennsylvania School of Medicine, 424 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA. shore@mail.med.upenn.edu Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells. PMCID: PMC3551620 PMID: 20703219 [PubMed - indexed for MEDLINE] 1242. Interdiscip Top Gerontol. 2010;37:64-83. doi: 10.1159/000319995. Epub 2010 Aug 10. Changes in body composition in response to challenges during aging in rats. Wolden-Hanson T(1). Author information: (1)Geriatric Research, Education, and Clinical Center and Research Service, Veterans Administration Puget Sound Health Care System, Seattle, WA 98108-1597, USA. twh@u.washington.edu Body composition changes over the lifespan of Brown Norway rats, in patterns similar to those of humans. Young adults are lean, with little fat, much of which is intra-abdominal. As they age, rats exhibit linear growth, and both lean and fat mass increase until late middle to early old age. Fat mass continues to accumulate throughout the lifespan, both viscerally and subcutaneously; aging animals carry a higher proportion of their fat mass peripherally. After middle age, skeletal muscle mass begins to decline, and sarcopenia develops when animals reach senescence. Finally, in late old age, or senescence, body weights begin to decline, and both fat and lean mass are lost. Healthy aged rats generally respond to negative energy balance challenges less robustly than younger adult animals, although they do appropriately regulate adipose tissue stores and preserve lean mass. The response to a positive energy balance challenge (high fat feeding) is less well regulated in aging animals, and dietary-induced obesity develops rapidly in aged animals. Here we present a summary of several studies of body composition in response to challenges of energy balance in aging male Brown Norway rats, with special emphasis on adipose tissue partitioning. Copyright © 2010 S. Karger AG, Basel. PMID: 20703056 [PubMed - indexed for MEDLINE] 1243. Nutr Clin Pract. 2010 Aug;25(4):357-61. doi: 10.1177/0884533610374061. Growth in cerebral palsy. Andrew MJ(1), Sullivan PB. Author information: (1)University of Oxford Department of Paediatrics, UK. morag.andrew@paediatrics.ox.ac.uk Cerebral palsy is often accompanied by abnormalities of growth and nutrition; children with severe motor impairments are most at risk. Nutrition, neurological, and endocrine factors all contribute to suboptimal growth. Poor growth and nutrition are associated with poor general health outcomes and reduced levels of participation, and therefore warrant careful evaluation and appropriate intervention. The lack of normative data combined with the complex interaction of nutrition and nonnutrition factors contributing to growth in this population present real difficulties in management. Particular care is needed to avoid overfeeding and the resultant increase in fat mass and associated morbidity. PMID: 20702841 [PubMed - indexed for MEDLINE] 1244. Aging Cell. 2010 Oct;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x. Epub 2010 Aug 15. Fat tissue, aging, and cellular senescence. Tchkonia T(1), Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Author information: (1)Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA. Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state. Other mesenchymal progenitors also can acquire a pro-inflammatory, adipocyte-like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro-inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress-responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent-like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro-inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role. © 2010 The Authors Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. PMCID: PMC2941545 PMID: 20701600 [PubMed - indexed for MEDLINE] 1245. Curr Diabetes Rev. 2010 Sep;6(5):341-7. Interrelationships between hepatic fat and insulin resistance in non-alcoholic fatty liver disease. Lockman KA(1), Nyirenda MJ. Author information: (1)Department of Diabetes, The Royal Infirmary of Edinburgh. Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance, and its prevalence is rising in parallel with worldwide increases in obesity and type 2 diabetes. However, the nature of this relationship remains debatable. In particular, it is unclear whether insulin resistance causes NAFLD or hepatic steatosis per se reduces insulin sensitivity. This review will examine data from recent studies on the link between insulin resistance and NAFLD, focusing on studies that have attempted to dissociate fatty liver and hepatic insulin resistance. PMID: 20701585 [PubMed - indexed for MEDLINE] 1246. Curr Opin Support Palliat Care. 2010 Dec;4(4):249-53. doi: 10.1097/SPC.0b013e32833e4aa5. Contribution of anorexia to tissue wasting in cachexia. Molfino A(1), Laviano A, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University of Rome, Italy. PURPOSE OF REVIEW: Anorexia is a severe debilitating symptom characterizing the clinical course of several chronic diseases. It negatively impacts on patient outcome by contributing to weight loss, lean body mass catabolism and adipose tissue wasting. Although disease-associated anorexia may stand alone as a clinically relevant symptom, it is now considered as a component of the cachexia syndrome. The present review discusses experimental and clinical data indicating that the pathogenic mechanisms of anorexia may also suggest a neural control of tissue wasting in cachexia. RECENT FINDINGS: Consistent data show that selective melanocortin receptor antagonism modulates food intake and reduces wasting in experimental models of chronic disease. Consequently, ghrelin administration, whose prophagic effects are related to melanocortin antagonism, has been tested both in animal studies and human trials, with promising effects, although restoration of lean body mass has been not achieved. More interest is driven by the use of small molecules selectively antagonising hypothalamic melanocortin receptors. SUMMARY: The 'brain-muscle axis' coordinated by the hypothalamus seems to mediate the onset of not only anorexia but also tissue wasting in cachexia, by centrally influencing energy homeostasis and the balance between anabolism and catabolism. PMID: 20693907 [PubMed - indexed for MEDLINE] 1247. Biochim Biophys Acta. 2010 Nov;1801(11):1175-83. doi: 10.1016/j.bbalip.2010.07.007. Epub 2010 Aug 4. Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Al-Lahham SH(1), Peppelenbosch MP, Roelofsen H, Vonk RJ, Venema K. Author information: (1)Top Institute Food and Nutrition, Wageningen, The Netherlands. Undigested food is fermented in the colon by the microbiota and gives rise to various microbial metabolites. Short-chain fatty acids (SCFA), including acetic, propionic and butyric acid, are the principal metabolites produced. However, most of the literature focuses on butyrate and to a lesser extent on acetate; consequently, potential effects of propionic acid (PA) on physiology and pathology have long been underestimated. It has been demonstrated that PA lowers fatty acids content in liver and plasma, reduces food intake, exerts immunosuppressive actions and probably improves tissue insulin sensitivity. Thus increased production of PA by the microbiota might be considered beneficial in the context of prevention of obesity and diabetes type 2. The molecular mechanisms by which PA may exert this plethora of physiological effects are slowly being elucidated and include intestinal cyclooxygenase enzyme, the G-protein coupled receptors 41 and 43 and activation of the peroxisome proliferator-activated receptor γ, in turn inhibiting the sentinel transcription factor NF-κB and thus increasing the threshold for inflammatory responses in general. Taken together, PA emerges as a major mediator in the link between nutrition, gut microbiota and physiology. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 20691280 [PubMed - indexed for MEDLINE] 1248. Acta Gastroenterol Belg. 2010 Apr-Jun;73(2):252-60. Retroperitoneal, mesenteric and multifocal fibrosis: review of their aetiopathogenesis. A possible role of adipocytes as in Crohn's disease? Jacobs E(1), Cosyns JP, Fiasse R. Author information: (1)Université Libre de Bruxelles, Belgium. jacobs.edouard@scarlet.be First observed during an autopsy by Simpson in 1867 as a cause of hydronephrosis, retroperitoneal fibrosis became a medical topic after the detailed report of two cases by Ormond in 1948. Initially considered to be chiefly an urological disease, it appeared progressively that it could possibly be a systemic disease because of its occasional association with inflammatory fibrosing processes in other sites of the body or with clinical and biological manifestations of hypersensitivity or autoimmunity. Mesenteric panniculitis and mesenteric fibrosis may occur independently or, occasionally, in association with retroperitoneal fibrosis. One third of the cases of retroperitoneal fibrosis can be attributed to specific causes. That the other cases (idiopathic retroperitoneal fibrosis) could be manifestations of an immunological (systemic) process with vasculitis is generally accepted. The authors present a survey of the various possible morphological aspects of the disease and a review of its aetiopathogenesis. Idiopathic retroperitoneal fibrosis is usually characterized by an overproduction of fibro-inflammatory tissue; however in few cases as well as in mesenteric panniculitis, extensive development of fatty tissue may also occur. The authors suggest that an initial proliferation of adipocytes, considered to account for the fat hyperplasia adjacent to Crohn's ileitis, could also play a role in the pathogenesis of the inflammatory fibrosing process in some cases of mesenteric and retroperitoneal fibrosis. PMID: 20690565 [PubMed - indexed for MEDLINE] 1249. Eur J Anaesthesiol. 2010 Nov;27(11):923-7. doi: 10.1097/EJA.0b013e32833d91aa. Airway management and morbid obesity. Kristensen MS(1). Author information: (1)Department of Anaesthesiology, Center of Head and Orthopaedics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. Michael.seltz.kristensen@rh.regionh.dk Morbidly obese patients present with excess fatty tissue externally on the breast, neck, thoracic wall and abdomen and internally in the mouth, pharynx and abdomen. This excess tissue tends to make access (intubation, tracheostomy) to and patency (during sedation or mask ventilation) of the upper airway and the function of the lungs (decreased residual capacity and aggravated ventilation perfusion mismatch) worse than in lean patients. Proper planning and preparation of airway management is essential, including elevation of the patient's upper body, head and neck. Preoxygenation is mandatory in morbidly obese patients and should be followed by actions to counteract atelectasis formation. The decision as to weather to use a rapid sequence induction, an awake intubation or a standard induction with hypnotics should depend on the thorough airway examination and comorbidity and should not be based solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more efficient in the morbidly obese patients than in lean patients and serves as a rescue device for both failed ventilation and failed intubation. In the 24 h following anaesthesia, morbidly obese patients experience frequent oxygen desaturation periods that can be counteracted by continuous positive airway pressure, noninvasive ventilation and physiotherapy. PMID: 20689440 [PubMed - indexed for MEDLINE] 1250. Curr Opin Organ Transplant. 2010 Oct;15(5):639-44. doi: 10.1097/MOT.0b013e32833deaee. Cardiac allograft vasculopathy: do adipocytes bridge alloimmune and metabolic risk factors? Wehner JR(1), Baldwin WM 3rd. Author information: (1)Department of Immunology NB30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio, USA. PURPOSE OF REVIEW: Cardiac allograft vasculopathy (CAV) is still a major cause of chronic graft failure. CAV develops in the coronary arteries as a diffuse, concentric expansion of the intima in conjunction with inflammation and fibrosis of the adventitia. We review recent publications that could link metabolic and immunologic risk factors for CAV.A concept is offered that periarterial adipocytes may provide proinflammatory cytokines that augment immune injury of the coronary arteries. RECENT FINDINGS: Clinical and experimental evidence indicate that some alloantibodies and autoantibodies are associated with CAV. Limited data are available on the expression of target antigens on coronary arteries at different times after transplantation. Perivascular adipose tissue is an abundant source of IL-6, IL-8 and MCP-1. Adding to the inflammatory bias, perivascular adipocytes secrete less of the anti-inflammatory adiponectin in comparison to other types of fat. Adiponectin modulates expression of adhesion molecules on the vascular endothelium. It also decreases neointimal formation in arteries following mechanical endovascular injury. SUMMARY: Alterations in the balance between proinflammatory and anti-inflammatory cytokines secreted by perivascular fat have been implicated in atherosclerosis and restenosis. This imbalance may also augment the immune responses in the coronary arteries of transplanted hearts. PMID: 20689436 [PubMed - indexed for MEDLINE] 1251. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):453-9. doi: 10.1097/MED.0b013e32833ddea0. Obesogens. Grün F(1). Author information: (1)Center for Complex Biological Systems, University of California Irvine, Irvine, California 92697-2280, USA. fgrun@uci.edu Comment in Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):440. PURPOSE OF REVIEW: The environmental obesogen hypothesis postulates chemical pollutants that are able to promote obesity by altering homeostatic metabolic set-points, disrupting appetite controls, perturbing lipid homeostasis to promote adipocyte hypertrophy, or stimulating adipogenic pathways that enhance adipocyte hyperplasia during development or in adults. This review focuses on recent experimental advances for candidate obesogens that target nuclear hormone receptors when a direct link between exposure, modulation of transcriptional networks and adipogenic phenotypes can be rationalized. RECENT FINDINGS: Various endocrine disrupting chemicals can disrupt hormonal signaling relevant to adipose tissue biology. In this review, progress on one identified obesogen, the organotin tributyltin, will be outlined to highlight principles and novel insights into its high-affinity nuclear hormone receptor-mediated mechanism, its effects on adipocyte biology, its potential to promote long-term obesogenic changes and its epidemiological relevance. When appropriate, important results for other suspected obesogenic ligands, including bisphenol A, phthalates, polybrominated diphenyl ethers and perfluoro-compounds, will highlight corroborating principles. SUMMARY: These examples serve to provide perspective on the potential harm that man-made obesogenic pollutants pose to human health, focus attention on areas in which knowledge remains inadequate and prompt a re-evaluation of the causative risk factors driving the current changes in obesity rates. PMID: 20689419 [PubMed - indexed for MEDLINE] 1252. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):641-6. doi: 10.1097/MCO.0b013e32833e341d. Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance; is there a role for thyroid hormone? Havekes B(1), Sauerwein HP. Author information: (1)Department of Endocrinology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands. bas.havekes@mumc.nl PURPOSE OF REVIEW: To review original research studies and reviews that present data on adipocyte-myocyte crosstalk in the development of skeletal muscle insulin resistance with a specific focus on thyroid hormone. RECENT FINDINGS: Adipose tissue communicates with skeletal muscle not only through free fatty acids but also through secretion of various products called adipokines. Adipokines came out as governors of insulin sensitivity and are deregulated in obesity. In addition to well known leptin, adiponectin, interleukin-6 and tumor necrosis factor-alpha, newer adipokines like retinol-binding protein 4 have been associated with insulin resistance. There is mounting evidence that not only adipose tissue but also skeletal muscle produces and secretes biologically active proteins or 'myokines' that facilitate metabolic crosstalk between organ systems. In recent years, increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Both hypothyroidism and hyperthyroidism affect insulin sensitivity in multiple ways that might overlap adipocyte-myocyte crosstalk. Recent studies have provided new insights in effects of processing of the parent hormone T4 to the active T3 at the level of the skeletal muscle. SUMMARY: Adipocyte-myocyte crosstalk is an important modulator in the development of skeletal muscle insulin resistance. Thyroid disorders are very common and may have detrimental effects on skeletal muscle insulin resistance, potentially by interacting with adipocyte-myocyte crosstalk. PMID: 20689414 [PubMed - indexed for MEDLINE] 1253. Curr Pharm Des. 2010 Oct;16(30):3361-71. Contribution of inflammation to fat redistribution and metabolic disturbances in HIV-1 infected patients. Stankov MV(1), Behrens GM. Author information: (1)Clinic for Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Antiretroviral therapy (ART) has significantly reduced the morbidity and mortality of patients infected with the human immunodeficiency virus 1 (HIV-1). In a significant number of patients, ART is associated with fat redistribution and metabolic alterations such as dyslipidemia, insulin resistance (IR) and type 2 diabetes, summarized under the term HIV-associated lipodystrophy syndrome (HIV-LS). The pathogenesis of HIV-LS is complex and involves a number of factors including ART, HIV-1, abnormal fat redistribution, metabolic abnormalities and chronic inflammation. In view of a novel understanding on how chronic inflammation contributes to the pathogenesis of HIV-1 infection, this review focuses on the interaction of the immune system and metabolic pathways and the potential consequences for the HIV-LS. Based on the current literature, we suggest a central role of systemic inflammation in triggering and deteriorating various components of the HIV-LS. PMID: 20687889 [PubMed - indexed for MEDLINE] 1254. Curr Pharm Des. 2010 Oct;16(30):3371-8. Lipotoxicity on the basis of metabolic syndrome and lipodystrophy in HIV-1-infected patients under antiretroviral treatment. Giralt M(1), Díaz-Delfín J, Gallego-Escuredo JM, Villarroya J, Domingo P, Villarroya F. Author information: (1)Department of Biochemistry and Molecular Biology, Facultat de Biologia, Universitat de Barcelona Avda Diagonal 645 08028-Barcelona, Spain. mgiralt@ub.edu The development of efficacious antiretroviral drugs that minimize adverse effects is a current challenge in HIV-1 therapy. Metabolic alterations reminiscent of the metabolic syndrome and overt lipodystrophy appear often in HIV-1-infected patients undergoing antiretroviral treatment. The etiopathogenesis of these alterations is complex, but lipotoxicity has recently emerged as a key concept for explaining the metabolic syndrome in HIV-1-infected patients, similarly to what has been observed in diseases such as obesity and genetic lipodystrophies. Antiretroviral drugs from distinct drug families may directly elicit such lipotoxic phenomena, via increased lipolysis, enhanced adipocyte apoptosis and impaired adipogenesis, which collectively lead to a reduced capacity of subcutaneous adipose tissue to enlarge to meet fat storage requirements. Thus, fatty acids that cannot be properly stored as triglycerides in subcutaneous adipose tissue are expected to accumulate in visceral fat as well as in organs and tissues, such as the pancreas, muscle and liver, leading to the pattern of metabolic alterations associated with abnormal ectopic fat accumulation, mainly insulin resistance. Inflammatory responses, evoked by the combined effects of antiretroviral drugs and the underlying HIV-1 infection, also contribute to lipotoxicity, reflecting the action of pro-inflammatory cytokines that enhance lipolytic activity in adipose tissue and impair adipogenesis. Minimizing the lipotoxic action of antiretroviral drugs is ultimately essential in reducing metabolic alterations in treated patients. Moreover, pharmacological strategies that reduce lipotoxicity and promote adipose tissue expandability can be expected to ameliorate the overall metabolic abnormalities in HIV-1-infected, antiretroviral-treated patients. PMID: 20687888 [PubMed - indexed for MEDLINE] 1255. Curr Pharm Des. 2010 Oct;16(30):3352-60. Adipose tissue as a target of HIV-1 antiretroviral drugs. Potential consequences on metabolic regulations. Caron-Debarle M(1), Boccara F, Lagathu C, Antoine B, Cervera P, Bastard JP, Vigouroux C, Capeau J. Author information: (1)INSERM, UMRS_938, CDR Saint-Antoine, 75012 Paris, France. Martine.caron@inserm.fr Adipose tissue redistribution occurred at first in HIV-infected patients about 15 years ago after initiation of combination antiretroviral treatment (ART) and the responsibility of drugs was rapidly considered. This lipodystrophic syndrome can associate lipoatrophy, affecting subcutaneous adipose tissue in priority with fat hypertrophy, in particular in the upper part of the body, and metabolic alterations, dyslipidemia and altered glucose tolerance with insulin resistance. The primary role of thymidine analogue reverse transcriptase inhibitors (tNRTI) in peripheral lipoatrophy has been clearly shown in vitro and in vivo, these drugs inducing a severe mitochondrial dysfunction and an increased oxidative stress together with fat inflammation leading to fat loss. In vitro and in vivo studies suggest that some protease inhibitors (PI) or non-NRTIs also exert adverse effects on adipocytes and could act in synergy to amplify the effect of tNRTI. While severe lipoatrophy is now less prevalent in HIV-infected patients, fat hypertrophy is frequently observed: a role for drugs from the different classes acting in synergy to induce fat hyperplasia and hypertrophy is suggested, with milder mitochondrial dysfunction but increased inflammation and activation of the cortisol system. In addition, it is now considered that long-term viral infection, even if controlled, could induce low-grade inflammation and prepare fat to the deleterious effect of ART. Both lipoatrophy and lipohypertrophy are involved in metabolic disorders and increased cardio-metabolic risk that likely participate to early aging reported in these patients. ART can also be directly responsible for metabolic alterations. Strategies to revert or reduce lipodystrophy are important to consider in these patients in addition to the required control of the metabolic disorders. PMID: 20687886 [PubMed - indexed for MEDLINE] 1256. Hepatology. 2010 Aug;52(2):774-88. doi: 10.1002/hep.23719. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Neuschwander-Tetri BA(1). Author information: (1)Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO 63110, USA. tetriba@slu.edu A significant body of evidence now forces us to rethink the causes of NASH. Once thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new data from animal studies and a limited number of human studies now provide convincing evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to focus our therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver. This can be accomplished by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver. Excess carbohydrates are the major substrates for de novo lipogenesis, and thus, reducing carbohydrate consumption through dietary changes and increasing muscle glucose uptake through exercise remain important cornerstones of treatment and prevention of lipotoxic liver injury, a disease hitherto called NASH. PMID: 20683968 [PubMed - indexed for MEDLINE] 1257. J Mol Endocrinol. 2010 Nov;45(5):281-90. doi: 10.1677/JME-10-0059. Epub 2010 Aug 3. Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation. García-Galiano D(1), Navarro VM, Gaytan F, Tena-Sempere M. Author information: (1)Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. Nesfatin-1 was originally identified as a hypothalamic neuropeptide, derived from the precursor NEFA (for DNA binding/EF-hand/acidic protein)/nucleobindin 2 (NUCB2), with the ability to suppress food intake, acting in a leptin-independent manner. Departing from this seminal finding, the patterns of expression of NUCB2/nesfatin-1 have been thoroughly characterized in different hypothalamic nuclei and brain areas with proven roles in energy homeostasis, and its potential interactions with other key neuropeptide regulators of appetite have been documented. Intriguingly, recent experimental evidence suggests that NUCB2/nesfatin-1 is also expressed in peripheral tissues with relevant metabolic functions, such as the pancreas, the adipose, and the gut. In addition, evidence is mounting that nesfatin signaling may participate in adaptative responses and in the control of body functions gated by the state of energy reserves, such as puberty onset. Altogether, these observations have broadened our perception of the biological profile of nesfatin-1 that, rather than a simple anorectic signal in the hypothalamus, might operate at different tissues as an integral regulator of energy homeostasis and closely related neuroendocrine functions. PMID: 20682642 [PubMed - indexed for MEDLINE] 1258. Postepy Hig Med Dosw (Online). 2010 Jul 27;64:326-32. [Use of adipose tissue as a source of mesenchymal stem cells]. [Article in Polish] Jezierska-Woźniak K(1), Nosarzewska D, Tutas A, Mikołajczyk A, Okliński M, Jurkowski MK. Author information: (1)Zakład Neurobiologii i Anatomii Człowieka, Katedra Neurologii i Neurochirurgii, Wydział Nauk Medycznych, Uniwersytet Warmińsko-Mazurski w Olsztynie, 10-082 Olsztyn. katarzyna.jezierska@uwm.edu.pl Enormous expectations are associated with stem cells with regard to cell therapy and tissue engineering. Stem cells have unlimited potential for self-renewal and develop into various cell types. For the mesodermal tissue engineering such a source of cells is the bone marrow stroma. However, isolation of the bone marrow requires general or spinal anesthesia and yields low number of mesodermal stem cells (MSCs) upon processing (1 MSC per 105 adherent stromal cells). An alternative source of autologous stem cells seems to be, apart from bone marrow: periosteum, muscular tissue or synovial membrane and adipose tissue. The adipose tissue is derived from the embryonic mesenchyme, contains a large number of stromal stem cells and is relatively easy to obtain in large quantities. It covers a widespread area of human body, and can be classified as white and brown adipose tissue in terms of location and function. Specimens of the adipose tissue are usually obtained from elective, laparoscopic or liposuction surgeries. Stromal stem cells, isolated from this tissue, exhibit characteristics common to mesodermal tissues, including: adherence to plastic, formation of fibroblastic- like colonies, extensive proliferative capacity, ability to differentiate into several mesodermal lineages (including bone, cartilage, muscle and fat), and expression of several common cell surface antigens. Recent evidence suggest that these cells can also form non-mesodermal tissues--neuron-like cells. The aim of this publication is to describe the application of the adipose tissue as a source of mesenchymal stem cells based on current literature data. PMID: 20679688 [PubMed - indexed for MEDLINE] 1259. Stem Cell Rev. 2011 Mar;7(1):195-207. doi: 10.1007/s12015-010-9168-8. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Fan CG(1), Zhang QJ, Zhou JR. Author information: (1)Neurosurgical Department of Peking University People's Hospital, Beijing, China. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), isolated from discarded extra-embryonic tissue after birth, are promising candidate source of mesenchymal stem cells (MSCs). Apart from their prominent advantages in abundant supply, painless collection, and faster self-renewal, hUC-MSCs have shown the potencies to differentiate into a variety of cells of three germ layers (such as bone, cartilage, adipose, skeletal muscle, cardiomyocyte, endothelium, hepatocyte-like cluster, islet-like cluster, neuron, astrocyte and oligodendrocyte), to synthesize and secret a set of trophic factors and cytokines, to support the expansion and function of other cells (like hematopoietic stem cells, embryonic stem cells, natural killer cells, islet-like cell clusters, neurons and glial cells), to migrate toward and home to pathological areas, and to be readily transfected with conventional methods. Two excellent previous reviews documenting the characteristics of this cell population with special emphasis on its niche, isolation, surface markers and primitive properties have been published recently. In this review, we will firstly give a brief introduction of this cell population, and subsequently dwell on the findings of differential capacities with emphasis on its therapeutic potentials. PMID: 20676943 [PubMed - indexed for MEDLINE] 1260. Expert Rev Mol Med. 2010 Aug 2;12:e24. doi: 10.1017/S1462399410001547. Molecular mechanisms controlling human adipose tissue development: insights from monogenic lipodystrophies. Rochford JJ(1). Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital, Hills Road Cambridge, Cambridge CB2 0QQ, UK. jjr30@cam.ac.uk Appropriately functioning adipose tissue is essential for human health, a fact most clearly illustrated by individuals with lipodystrophy, who have impaired adipose development and often suffer severe metabolic disease as a result. Humans with obesity display a similar array of metabolic problems. This reflects failures in fat tissue function in obesity, which results in consequences similar to those seen when insufficient adipose tissue is present. Thus a better understanding of the molecules that regulate the development of fat tissue is likely to aid the generation of novel therapeutic strategies for the treatment of all disorders of altered fat mass. Single gene disruptions causing lipodystrophy can give unique insights into the importance of the proteins they encode in human adipose tissue development. Moreover, the mechanisms via which they cause lipodystrophy can reveal new molecules and pathways important for adipose tissue development and function as well as confirming the importance of molecules identified from studies of cellular and animal models. PMID: 20673380 [PubMed - indexed for MEDLINE] 1261. Liver Int. 2011 Feb;31(2):163-75. doi: 10.1111/j.1478-3231.2010.02302.x. Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Wright G(1), Noiret L, Olde Damink SW, Jalan R. Author information: (1)UCL Institute of Hepatology, Division of Medicine, University College London, London, UK. Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia-regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches. © 2010 John Wiley & Sons A/S. PMID: 20673233 [PubMed - indexed for MEDLINE] 1262. Mediators Inflamm. 2010;2010:802078. doi: 10.1155/2010/802078. Epub 2010 Jul 1. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Balistreri CR(1), Caruso C, Candore G. Author information: (1)Immunosenescence Group, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, 90134 Palermo, Italy. Obesity is an energy-rich condition associated with overnutrition, which impairs systemic metabolic homeostasis and elicits stress. It also activates an inflammatory process in metabolically active sites, such as white adipose tissue, liver, and immune cells. As consequence, increased circulating levels of proinflammatory cytokines, hormone-like molecules, and other inflammatory markers are induced. This determines a chronic active inflammatory condition, associated with the development of the obesity-related inflammatory diseases. This paper describes the role of adipose tissue and the biological effects of many adipokines in these diseases. PMCID: PMC2910551 PMID: 20671929 [PubMed - indexed for MEDLINE] 1263. Med Sci Monit. 2010 Aug;16(8):RA163-70. Renal consequences of obesity. Naumnik B(1), Myśliwiec M. Author information: (1)Department of Nephrology and Transplantation with Dialysis Unit, Medical University, Bialystok, Poland. bnaumnik@poczta.onet.pl Comment in Med Sci Monit. 2010 Oct;16(10):LE15. The worldwide prevalence of obesity and its associated metabolic and cardiovascular disorders has risen dramatically within the past 2 decades. Our objective is to review the mechanisms that link obesity with altered kidney function. Current evidence suggests that excess weight gain may be responsible for 65-75% of the risk for arterial hypertension. Impaired renal pressure natriuresis, initially due to increased renal tubular sodium reabsorption, is a key factor linking obesity with hypertension. Obesity increases renal sodium reabsorption by activating the renin-angiotensin and sympathetic nervous systems, and by altering intrarenal physical forces. Adipose tissue functions as an endocrine organ, secreting hormones/cytokines (e.g., leptin) which may trigger sodium retention and hypertension. Additionally, excess visceral adipose tissue may physically compress the kidneys, increasing intrarenal pressures and tubular reabsorption. Eventually, sustained obesity via hyperinsulinemia, due to resistance to insulin, causes hyperfiltration, resulting in structural changes in the kidneys--glomerular hyperthrophy and occasionally focal segmental glomerulosclerosis. The consequences of kidney injury are continuous loss of glomerular filtration rate, further increase of arterial pressure and escalation of cardiovascular morbidity and mortality. There is a growing awareness of the renal consequences of obesity, and considerable progress is being made in understanding its pathophysiology. Weight reduction results in lowered proteinuria. Aside from low sodium diet and exercises, more widespread use of renoprotective therapy (e.g., ACE inhibitors and statins) in treatment of hypertension in obese subjects should be advocated. Renal protection should result in reducing the cardiovascular complications of obesity. PMID: 20671624 [PubMed - indexed for MEDLINE] 1264. Expert Rev Cardiovasc Ther. 2010 Aug;8(8):1057-67. doi: 10.1586/erc.10.98. Pioglitazone: beyond glucose control. de Pablos-Velasco P(1). Author information: (1)Department of Endocrinology & Diabetes and Metabolism, Dr Negrin Hospital, Las Palmas University, Spain. ppablos@dcmq.ulpgc.es Pioglitazone is an oral antidiabetic agent that decreases insulin resistance in adipose tissue, liver and muscles. This action is mediated by its link to a nuclear receptor called peroxisome proliferator-activated receptor-gamma. By improving insulin sensitivity, hepatic glucose production decreases and glucose uptake increases in the peripheral tissues. Beyond these effects on glucose metabolism, pioglitazone has positive effects on lipid metabolism, blood pressure, endothelial function, adiponectin and C-reactive protein levels. These make pioglitazone treatment effective beyond glucose control. In this article, current evidence concerning pioglitazone in the treatment of Type 2 diabetes will be reviewed. PMID: 20670183 [PubMed - indexed for MEDLINE] 1265. Bull Acad Natl Med. 2010 Jan;194(1):13-20; discussion 20-4. [Obesity, a disease]. [Article in French] Basdevant A(1), Ciangura C. Author information: (1)Pôle endocrinologie, diabètologie, nutrition, Hôpital de la Pitié-Salpêtrère, 47 bid de l'Hôpital, 75651 Paris cedex 13. arnaud.basdevant@psl.aphp.fr Obesity has been considered as a disease by the World Health Organisation since 1997. It was previously considered a simple risk factor and a manifestation of consumer society. This recognition was based on several developments, including epidemiological data showing the worldwide spread of the disease; the increasing health expenditure due to the obesity-related increase in type 2 diabetes; and progress in pathophysiological concepts. Obesity is a chronic and progressive disease. Management approaches range from prevention to surgery, and must be adapted to the individual situation. PMID: 20669556 [PubMed - indexed for MEDLINE] 1266. Biotechnol J. 2010 Sep;5(9):919-29. doi: 10.1002/biot.201000048. Insulin resistance at the crossroads of metabolic syndrome: systemic analysis using microarrays. Kim E(1). Author information: (1)Department of Food Sciences and Nutrition, Catholic University of Daegu, Gyeongsan, Food and Nutritional Genomics Research Center, Kyungpook National University, Daegu, Republic of Korea. kimeunj@cu.ac.kr Recently, it has been suggested that insulin resistance is a better predictor of metabolic syndrome than obesity. Numerous studies have been conducted to identify insulin resistance susceptibility genes in various model systems. This review focuses on recent findings in microarray analyses, which have indicated that (i) in the liver, genes involved in lipid synthesis and gluconeogenesis are increased in an animal model of insulin resistance that leads into liver steatosis and hyperglycemia; (ii) in adipose tissues, genes involved in fatty acid synthesis and adipogenesis are down-regulated both in insulin-resistant humans and in animals; and (iii) in muscle, overall gene expression, including genes involved in fatty acid oxidation and biosynthesis, is either decreased or unresponsive compared to that of insulin-sensitive control human subjects or animals. Considering the multifaceted effects of insulin resistance in various tissues, aiming at multi-targets rather than a single target will be a more promising strategy for the prevention or treatment of insulin resistance. PMID: 20669253 [PubMed - indexed for MEDLINE] 1267. Dermatol Ther. 2010 Jul-Aug;23(4):389-402. doi: 10.1111/j.1529-8019.2010.01339.x. Cytophagic histiocytic panniculitis and hemophagocytic lymphohistiocytosis: an overview. Aronson IK(1), Worobec SM. Author information: (1)Department of Dermatology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA. IAronson@uic.edu Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis that is associated with systemic features including fevers, hepatosplenomegaly, lymphadenopathy, pancytopenia, hepatic abnormalities, hypertriglyceridemia, and coagulopathy without an elevated erythrocyte sedimentation rate. The panniculitis lesions show adipose tissue lymphocytic and histiocytic infiltration along with hemophagocytosis, which may also appear in bone marrow, spleen, lymph nodes, and liver. Patients may have a rapidly fatal disease course, a longer disease course with intermittent remissions and exacerbations for many years prior to death, or a nonfatal acute or intermittent course responsive to treatment. The cytophagocytic disorder in these patients is a hemophagocytic lymphohistiocytosis (HLH), similar to the infection-activated reaction associated with perforin mutations found in familial hemophagocytic lymphohistiocytosis. HLH is a group of autoinflammatory disorders, which include macrophage activation syndrome and infection-associated hemophagocytic syndrome, which if not treated rapidly, can be fatal. The relationship of CHP and HLH is discussed. CHP associated diseases include: subcutaneous panniculitis-like T cell lymphomas; infections, connective tissue diseases, other malignancies, and the molecular disorders that cause HLH. Treatment of CHP includes: glucocorticoids in combination with cyclosporine, combined chemotherapeutic medications and most recently, anakinra, an Interleukin-1 receptor antagonist; along with supportive care, search for underlying malignancies and treatment thereof, and control of associated infections. PMID: 20666826 [PubMed - indexed for MEDLINE] 1268. J Diabetes Sci Technol. 2010 Jul 1;4(4):833-45. Diabetic foot biomechanics and gait dysfunction. Wrobel JS(1), Najafi B. Author information: (1)Center for Lower Extremity Ambulatory Research at Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA. James.wrobel@rosalindfranklin.edu BACKGROUND: Diabetic foot complications represent significant morbidity and precede most of the lower extremity amputations performed. Peripheral neuropathy is a frequent complication of diabetes shown to affect gait. Glycosylation of soft tissues can also affect gait. The purpose of this review article is to highlight the changes in gait for persons with diabetes and highlight the effects of glycosylation on soft tissues at the foot-ground interface. METHODS: PubMed, the Cochrane Library, and EBSCOhost on-line databases were searched for articles pertaining to diabetes and gait. Bibliographies from relevant manuscripts were also searched. FINDINGS: Patients with diabetes frequently exhibit a conservative gait strategy where there is slower walking speed, wider base of gait, and prolonged double support time. Glycosylation affects are observed in the lower extremities. Initially, skin thickness decreases and skin hardness increases; tendons thicken; muscles atrophy and exhibit activation delays; bones become less dense; joints have limited mobility; and fat pads are less thick, demonstrate fibrotic atrophy, migrate distally, and may be stiffer. INTERPRETATION: In conclusion, there do appear to be gait changes in patients with diabetes. These changes, coupled with local soft tissue changes from advanced glycosylated end products, also alter a patient's gait, putting them at risk of foot ulceration. Better elucidation of these changes throughout the entire spectrum of diabetes disease can help design better treatments and potentially reduce the unnecessarily high prevalence of foot ulcers and amputation. 2010 Diabetes Technology Society. PMCID: PMC2909514 PMID: 20663446 [PubMed - indexed for MEDLINE] 1269. Nutr Metab Cardiovasc Dis. 2010 Sep;20(7):481-90. doi: 10.1016/j.numecd.2010.05.005. Epub 2010 Jul 24. Ectopic fat and cardiovascular disease: what is the link? Gastaldelli A(1), Basta G. Author information: (1)Institute of Clinical Physiology, National Research Council, CNR, Cardiometabolic Risk Unit, Via Moruzzi 1 Pisa 56100, Italy. amalia@ifc.cnr.it AIM: of this paper is to review the recent literature on the relationship between ectopic fat accumulation and cardiovascular disease. DATA SYNTHESIS: Ectopic fat is an important predictor of metabolic (in particular insulin resistance) and cardiovascular disease, carrying more risk than general fat accumulation. Recent studies have shown a link between ectopic fat accumulation, as cardiac (epicardial or intra-myocardial fat) and/or visceral and/or hepatic fat, and development of atherosclerosis, coronary heart disease and hypertension. CONCLUSIONS: Ectopic fat accumulation is not only a marker of cardiometabolic disease, since through the release of adipocitokines, lipotoxic and glucotoxic agents, participates in the crosstalk with insulin-sensitive organs leading to metabolic, cardiac and vascular dysfunctions. Copyright 2010 Elsevier B.V. All rights reserved. PMID: 20659791 [PubMed - indexed for MEDLINE] 1270. Orv Hetil. 2010 Aug 1;151(31):1252-60. doi: 10.1556/OH.2010.28901. [New approach in the interpretation of adipose tissue]. [Article in Hungarian] Antal M(1), Regöly-Mérei A. Author information: (1)antalmagda@gmail.com Scientific results in the past fifteen years have proven that adipose tissue is an active endocrine organ secreting several hormones. Authors review and discuss the functions of leptin, adiponectin, resistin, visfatin and omentin with special references to metabolic actions. PMID: 20656662 [PubMed - indexed for MEDLINE] 1271. Arch Biochem Biophys. 2010 Nov 1;503(1):28-34. doi: 10.1016/j.abb.2010.07.020. Epub 2010 Jul 23. Bone and bone marrow: the same organ. Del Fattore A(1), Capannolo M, Rucci N. Author information: (1)Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. andrea.delf@gmail.com Interplays between bone and bone marrow are not limited to merely anatomic and histological connections, but include a tight functional correlation. Bone marrow resides within the medullary cavity of the bones and the process of hematopoiesis is regulated, at least in part, by bone cells. Moreover, osteoclasts and osteoblasts derive from precursors of hematopoietic and mesenchymal origin, respectively, both residing within the bone marrow. Alterations in one of these components typically cause impairment in the other, so diseases of the bone marrow compartment often affect the bone and vice versa. All these findings could make us to speculate that bone and bone marrow are not two separate districts, but can be considered as the two elements of the same unique functional unit, the bone-bone marrow organ. Here we will describe histological and functional interplays between bone and bone marrow, and will illustrate some diseases in which this tight correlation is evident. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 20655867 [PubMed - indexed for MEDLINE] 1272. Maturitas. 2010 Nov;67(3):197-202. doi: 10.1016/j.maturitas.2010.06.018. Epub 2010 Jul 23. The incretin pathway as a new therapeutic target for obesity. Barber TM(1), Begbie H, Levy J. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom. tom.barber@drl.ox.ac.uk The global obesity epidemic fuelled by our obesogenic environment, and the prevention and treatment of obesity are some of the most important health-care challenges of our time. Although influenced largely by genetic factors, body mass index (BMI) is also heavily dependent upon environmental (principally dietary) factors. Whilst bariatric surgery often results in weight loss, its associated cost is prohibitive for widespread application. Current options for medical treatment of obesity are limited by recent withdrawals of Rimonabant and Sibutramine, enhancing the need for further development of novel weight-loss drugs. The incretin effect results from release of the incretin hormones Glucagon like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) from intestinal cells in response to glucose ingestion. This in turn has direct effects on the endocrine pancreas to enhance insulin release in a glucose-dependent manner and suppress glucagon release, the net effects of which are to reduce post-prandial excursions of plasma glucose. Administration of novel GLP-1-mimetic therapies to patients with type 2 diabetes mellitus (T2D) has been shown to improve and stabilise glycaemic control. In addition, such treatment often leads to substantial and sustained weight loss through pleiotropic effects. These include primary central suppressive effects on hypothalamic appetite control and secondary central effects including inhibition of gastric emptying inducing a feeling of fullness during meals. Although not currently licensed for use as weight-loss therapies, application of GLP-1-mimetic drugs for such a purpose would seem to offer great potential, and should be a focus for further research including a full assessment of safety issues. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20655673 [PubMed - indexed for MEDLINE] 1273. Acta Physiol (Oxf). 2010 Oct;200(2):107-27. doi: 10.1111/j.1748-1716.2010.02171.x. Role of adipokines in obesity-associated hypertension. Vlasova M(1), Purhonen AK, Jarvelin MR, Rodilla E, Pascual J, Herzig KH. Author information: (1)Department of Pharmaceutics, University of Kuopio, Kuopio, Finland. It has been well documented that obesity is a major risk factor for the development of the hypertensive state. The correlation between body mass index and blood pressure level is well established. Nevertheless, the exact mechanisms which contribute to obesity-related hypertension remain poorly understood. In the last years, we have realized that the white adipose tissue is not just an inert organ for nutrient storage and isolation but rather depending on the body mass index the biggest endocrinological organ. Thus, the possible contribution of adipokines to the blood pressure elevation becomes an attractive hypothesis to explain the hypertensive state that often occurs in obesity. In this review, we consider direct and indirect effects of main adipokines on structural and functional changes in the cardiovascular system. PMID: 20653609 [PubMed - indexed for MEDLINE] 1274. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2010 Jul;53(7):699-706. doi: 10.1007/s00103-010-1088-x. [Juvenile obesity and the role of physical activity and inactivity]. [Article in German] Graf C(1). Author information: (1)Abteilung Bewegungs- und Gesundheitsförderung am Institut für Bewegungs- und Neurowissenschaft, Deutsche Sporthochschule Köln, Am Sportpark Müngersdorf 6, 50933, Köln, Deutschland. c.graf@dshs-koeln.de Physical activity has important health benefits. Despite of the use of different measurement instruments, a decrease in physical activity and an increase in sedentary habits has been described in children and adolescents. As a consequence, a reduction in physical performance and motor abilities and an increase in overweight and fat mass is found associated with comorbidities, e.g., ranging from insulin resistance up to the metabolic syndrome. Therefore, beside the therapeutic use of exercise in obesity programs, adequate preventive strategies are warranted. However, within this discussion, it must be taken into consideration that special subgroups are more affected by insufficient physical activity/sedentary habits, e.g., females, adolescents, ethnicity, lower socioeconomic status. In many other groups, recommendations for physical activity (1 h/day) are achieved. Hence, interventions must focus on these at-risk groups and intensified. In addition, recommendations related to physical activity and inactivity, in terms of TV consumption, must be critically analyzed as to whether the recommendations are sufficient and how they can be implemented to achieve lasting results. PMID: 20652483 [PubMed - indexed for MEDLINE] 1275. Mediators Inflamm. 2010;2010:174341. doi: 10.1155/2010/174341. Epub 2010 Jun 28. Adipocytokines in atherothrombosis: focus on platelets and vascular smooth muscle cells. Anfossi G(1), Russo I, Doronzo G, Pomero A, Trovati M. Author information: (1)Department of Clinical and Biological Sciences, Internal Medicine and Metabolic Disease Unit, San Luigi Gonzaga Hospital, San Luigi Gonzaga Faculty of Medicine of the Turin University, Orbassano, 10043 Turin, Italy. Visceral obesity is a relevant pathological condition closely associated with high risk of atherosclerotic vascular disease including myocardial infarction and stroke. The increased vascular risk is related also to peculiar dysfunction in the endocrine activity of adipose tissue responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. In particular, increased synthesis and release of different cytokines, including interleukins and tumor necrosis factor-alpha (TNF-alpha), and adipokines-such as leptin-have been reported as associated with future cardiovascular events. Since vascular cell dysfunction plays a major role in the atherothrombotic complications in central obesity, this paper aims at focusing, in particular, on the relationship between platelets and vascular smooth muscle cells, and the impaired secretory pattern of adipose tissue. PMCID: PMC2905911 PMID: 20652043 [PubMed - indexed for MEDLINE] 1276. Curr Opin Immunol. 2010 Aug;22(4):521-8. doi: 10.1016/j.coi.2010.06.010. Thymic fatness and approaches to enhance thymopoietic fitness in aging. Dixit VD(1). Author information: (1)Laboratory of Neuroendocrine-Immunology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. Vishwa.dixit@pbrc.edu With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are 'passive' cells that occupy non-epithelial thymic space or 'infiltrate' the non-cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route toward thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly. Copyright 2010 Elsevier Ltd. All rights reserved. PMCID: PMC2993497 PMID: 20650623 [PubMed - indexed for MEDLINE] 1277. Atherosclerosis. 2011 Jan;214(1):3-10. doi: 10.1016/j.atherosclerosis.2010.05.034. Epub 2010 Jun 1. Perivascular adipose tissue as a cause of atherosclerosis. Verhagen SN(1), Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, The Netherlands. Perivascular adipose tissue surrounds (coronary) arteries and may be involved in local stimulation of atherosclerotic plaque formation. Epicardial adipose tissue, the adipose tissue within the pericardium, is a frequently used measure of coronary perivascular adipose tissue and can be quantified with echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI). The quantity of (coronary) perivascular adipose tissue is correlated with parameters of the metabolic syndrome, such as increased waist circumference, hypertriglyceridemia and hyperglycemia, and with coronary atherosclerosis. Coronary artery segments covered by myocardium are not exposed to coronary perivascular adipose tissue and interestingly, atherosclerosis is absent in these intra-myocardial segments. Pro-inflammatory cytokines and adipokines are expressed and secreted at a higher level in epicardial adipose tissue of patients with coronary artery disease compared to patients without coronary artery disease. Furthermore, in vitro and ex vivo perivascular adipose tissue induces inflammation of the artery wall by secretion of pro-inflammatory proteins. Atherogenesis in the vascular wall is thus stimulated from 'outside to inside'. Based on the results of clinical, ex vivo and in vitro studies, it can be argued that perivascular adipose tissue may be involved in the process of atherosclerosis. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20646709 [PubMed - indexed for MEDLINE] 1278. Annu Rev Nutr. 2010 Aug 21;30:257-72. doi: 10.1146/annurev.nutr.012809.104729. Lipins: multifunctional lipid metabolism proteins. Csaki LS(1), Reue K. Author information: (1)Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. The lipin proteins are evolutionarily conserved proteins with roles in lipid metabolism and disease. There are three lipin protein family members in mammals and one or two orthologs in plants, invertebrates, and single-celled eukaryotes. Studies in yeast and mouse led to the identification of two distinct molecular functions of lipin proteins. Lipin proteins have phosphatidate phosphatase activity and catalyze the formation of diacylglycerol in the glycerol-3-phosphate pathway, implicating them in the regulation of triglyceride and phospholipid biosynthesis. Mammalian lipin proteins also possess transcriptional coactivator activity and have been implicated in the regulation of metabolic gene expression. Here we review key findings in the field that demonstrate roles for lipin family members in metabolic homeostasis and in rare human diseases, and we examine evidence implicating genetic variations in lipin genes in common metabolic dysregulation such as obesity, hyperinsulinemia, hypertension, and type 2 diabetes. PMCID: PMC3738581 PMID: 20645851 [PubMed - indexed for MEDLINE] 1279. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):408-13. doi: 10.1097/MED.0b013e32833d6d46. New insights into regulation of lipid metabolism by thyroid hormone. Zhu X(1), Cheng SY. Author information: (1)Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA. Comment in Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):395. PURPOSE OF REVIEW: Thyroid hormone (3,3',5-triiodo-L-thyronine) plays an important role in thermogenesis and maintenance of lipid homeostasis. The present article reviews the evidence that 3,3',5-triiodo-L-thyronine regulates lipid metabolism via thyroid hormone receptors, focusing particularly on in-vivo findings using genetically engineered mice. RECENT FINDINGS: That lipid metabolism is regulated via thyroid hormone receptor isoforms in a tissue-dependent manner was recently uncovered by using knockin mutant mice harboring an identical mutation in the Thra gene (Thra1(PV) mouse) or the Thrb gene (Thrb(PV) mouse). The mutation in the Thra gene dramatically decreases the mass of both white adipose tissue and liver. In contrast, the mutation in the Thrb gene markedly increases the mass of liver with an excess depot of lipids, but no significant abnormality is observed in white adipose tissue. Molecular studies show that the expression of lipogenic genes is decreased in white adipose tissue of Thra1(PV) mice, but not in Thrb(PV) mice. Markedly increased lipogenic enzyme expression, and decreased fatty acid beta-oxidation activity contribute to the adipogenic steatosis and lipid accumulation in the liver of Thrb(PV) mice. In contrast, reduced expression of genes critical for lipogenesis mediates decreased liver mass with lipid scarcity in Thra1(PV) mice. SUMMARY: Studies using Thra1(PV) and Thrb(PV) mice indicate that apo-thyroid hormone receptor-beta and apo-thyroid hormone receptor-alpha-1 mediate distinct deleterious effects on lipid metabolism. Thus, both thyroid hormone receptor isoforms contribute to the pathogenesis of lipid abnormalities in hypothyroidism, but in a target tissue-dependent manner. These studies suggest that thyroid hormone receptor isoform-specific ligands could be designed as therapeutic targets for lipid abnormalities. PMCID: PMC3457777 PMID: 20644471 [PubMed - indexed for MEDLINE] 1280. Curr Mol Med. 2010 Aug;10(6):522-32. Molecular aspects of adipokine-bone interactions. Magni P(1), Dozio E, Galliera E, Ruscica M, Corsi MM. Author information: (1)Department of Endocrinology, Pathophysiology and Applied Biology, School of Pharmacy, Universita' degli Studi di Milano, Milan, Italy. paolo.magni@unimi.it Adipose tissue is an endocrine organ able to produce a wide series of pleiotropic molecules, defined "adipokines". In addition to the regulation of food intake and energy metabolism, adipokines are also implicated in the complex control of bone biology and specifically of bone remodeling. Leptin, the most studied adipokine, promotes satiety and energy expenditure and its circulating levels are proportional to fat mass. Some paradoxical findings originally suggested the involvement of leptin in controlling bone mass. For example, obese postmenopausal women, with elevated circulating leptin and leptin resistance, appear protected against the development of osteoporosis. Moreover, genetically leptin-deficient mice, which are hypogonadal and obese, display a decreased trabecular volume in long bones, but an increased vertebral bone mass, which is reduced by leptin administration. The complex mechanisms of leptin regulation of bone mass appear to involve selected hypothalamic neuronal populations and the sympathetic outflow, with an important role of osteoblastic beta2-adrenergic receptors. Adiponectin is another adipokine, which promotes insulin sensitivity and is reduced in obese and diabetic subjects. Adiponectin appears to exert a negative effect on bone mass and seems to be an independent predictor of lower bone mass. Although the adipokines resistin and visfatin do not seem to significantly affect bone metabolism, the potential impact of them and other adipokines is still to be determined. Moreover, the molecular adipokine-bone interactions should also be considered in the context of the adipokine changes observed in diseases such as obesity and the metabolic syndrome. PMID: 20642443 [PubMed - indexed for MEDLINE] 1281. Gend Med. 2010 Jun;7(3):189-205. doi: 10.1016/j.genm.2010.05.002. Impact of triglycerides on lipid and lipoprotein biology in women. Dayspring TD(1), Pokrywka G. Author information: (1)UMDNJ-New Jersey Medical School, Newark, New Jersey, USA. tdayspring@aol.com BACKGROUND: Because atherosclerosis, a leading cause of morbidity and mortality in women, is thought of as a sterol (cholesterol and noncholesterol sterol)-mediated disease, plasma triglyceride (TG) levels (the concentration of all TG trafficked within all of the lipoproteins per dL of plasma), TG biology, and TG pathobiology historically have been ignored or frequently misunderstood in both risk assessment and treatment decisions. OBJECTIVES: This review presents information on the importance of TG (chemical name, triacylglycerol) in atherogenesis and the relationship of TG to gender, adiposopathy (the pathophysiological transformation of functional adipose tissue into an organ with pathogenic endocrine and immune responses), insulin resistance, sterol-trafficking lipoproteins, and overall vascular health. In addition, this review seeks to explain the complexities of lipid homeostasis and how it is influenced by lipid-modulating medications, reproductive hormones, and selective estrogen receptor modulators (SERMs). METHODS: Using peer-reviewed materials published in English from the extensive libraries of the authors, this narrative review references key epidemiologic, basic science lipid/lipoprotein publications as well as efficacy trials of lipid-modulating, hormonal, and SERM therapies. RESULTS: TG are associated with insulin resistance; the metabolic syndrome; increased atherogenic lipo-proteins; and rheologic, inflammatory, and coagulation abnormalities. TG can be influenced by lifestyle and multiple medications used by women, including hormonal therapies. Several studies, but not all, support sex differences in TG. CONCLUSIONS: Through effects on sterol-trafficking lipoproteins, TG have a significant influence on atherosclerotic cardiovascular disease risk in menopausal women. TG-rich lipoproteins are affected by lipid-modulating drugs, estrogen therapy, estrogen-progestogen therapy, and SERMs. Copyright (c) 2010 Excerpta Medica Inc. All rights reserved. PMID: 20638625 [PubMed - indexed for MEDLINE] 1282. Aliment Pharmacol Ther. 2010 Sep;32(6):697-711. doi: 10.1111/j.1365-2036.2010.04407.x. Review article: lymphatic system and associated adipose tissue in the development of inflammatory bowel disease. von der Weid PY(1), Rainey KJ. Author information: (1)Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology & Pharmacology, University of Calgary, AB, Canada. vonderwe@ucalgary.ca BACKGROUND: The lymphatic system plays critical roles in tissue fluid homoeostasis, immune defence and metabolic maintenance. Lymphatic vessels transport lymph, proteins, immune cells and digested lipids, allowing fluid and proteins to be returned to the blood stream, lipids to be stored and metabolized and antigens to be sampled in lymph nodes. Lymphatic drainage is mainly driven by rhythmic constrictions intrinsic to the vessels and critically modulated by fluid pressure and inflammatory mediators. AIM: To collect and discuss the compelling available information linking the lymphatic system, adiposity and inflammation. METHODS: A literature search was performed through PubMed focusing on lymphatic system, inflammation, immune cells and fat transport and function in the context of IBD. RESULTS: Evidence collected allows us to propose the following working model. Compromised lymph drainage, reported in IBD, leads to oedema, lymphangiogenesis, impaired immune cell trafficking and lymph leakage. Lymph factor(s) stimulate adipose tissue to proliferate and produce cytokines, which affect immune cell functions and exacerbate inflammation. CONCLUSIONS: Understanding the lymphatic system's role in immune cell trafficking and immune responses, contribution to fat transport, distribution, metabolism and implication in the pathogenesis of chronic intestinal inflammation may provide the basis for new therapeutic strategies and improved quality-of life. PMID: 20636483 [PubMed - indexed for MEDLINE] 1283. J Acupunct Meridian Stud. 2009 Jun;2(2):93-106. doi: 10.1016/S2005-2901(09)60041-8. Bonghan circulatory system as an extension of acupuncture meridians. Soh KS(1). Author information: (1)Biomedical Physics Laboratory, Department of Physics and Astronomy, Seoul National University, Seoul, Korea. kssoh1@gmail.com The Bonghan system is a newly-discovered circulatory system, which corresponds to classical acupuncture meridians and was discovered in the early 1960s by Bonghan Kim. Despite its potential importance in biology and medicine, it has been ignored or forgotten for a long time. Only recently have most of its significant parts, such as the Bonghan system (BHS) inside blood or lymph vessels, on the surfaces of internal organs, and in brain ventricles, been confirmed. For this, novel methods using modern technology were necessary because Bonghan Kim did not describe his methods. For example, Among other methods, the discovery of a BHS-specific dye, trypan blue, was one of the most important original contributions that made BHS observation possible. With this technique, the BHS in adipose tissue became traceable, and the BHS was discovered on the fascia surrounding tumor tissues, a finding which may have great significance in relation to serious health problems in modern society, namely, obesity and cancer. PMID: 20633480 [PubMed - indexed for MEDLINE] 1284. Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1529-34. doi: 10.1161/ATVBAHA.110.209098. Nuclear receptors linking circadian rhythms and cardiometabolic control. Duez H(1), Staels B. Author information: (1)Department of Nuclear Receptors, Cardiovascular Disease and Diabetes, University of Lille Nord de France, Inserm, UDSL, and Institut Pasteur de Lille, Lille, France. Helene.Duez@pasteur-lille.fr Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. The biological clock ensures proper metabolic alignment of energy substrate availability and processing. Studies in animals and humans highlight a strong link between circadian disorders and altered metabolic responses and cardiovascular events. Shift work, for instance, increases the risk to develop metabolic abnormalities resembling the metabolic syndrome. Nuclear receptors have long been known as metabolic regulators. Several of them (ie, Rev-erbalpha, RORalpha, and peroxisome proliferation-activated receptors) are subjected to circadian variations and are integral components of molecular clock machinery. In turn, these nuclear receptors regulate downstream target genes in a circadian manner, acting to properly gate metabolic events to the appropriate circadian time window. PMCID: PMC3056213 PMID: 20631353 [PubMed - indexed for MEDLINE] 1285. Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1513-8. doi: 10.1161/ATVBAHA.109.191197. Liver x receptor signaling pathways and atherosclerosis. Calkin AC(1), Tontonoz P. Author information: (1)Howard Hughes Medical Institute, University of California at Los Angeles, School of Medicine, Box 951662, Los Angeles, CA 90095-1662, USA. First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols. There are 2 LXR receptors encoded by distinct genes: LXRalpha is most highly expressed in the liver, adipose, kidney, adrenal tissues, and macrophages and LXRbeta is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development. In this brief review, we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis. PMCID: PMC2919217 PMID: 20631351 [PubMed - indexed for MEDLINE] 1286. Endocrinol Nutr. 2009 Dec;56 Suppl 4:38-42. Obesity and diabetes. Lois K(1), Kumar S. Author information: (1)Warwickshire Institute of Diabetes, Endocrinology & Metabolism (WISDEM), University Hospital Coventry & Warwickshire, Warwick Medical School Coventry, UK. PMID: 20629230 [PubMed - indexed for MEDLINE] 1287. Endocrinol Nutr. 2009 Dec;56 Suppl 4:5-7. The two-edged sword. Bergman RN(1). Author information: (1)University of Southern California, Los Angeles, CA 90033, USA. hfreed@usc.edu PMCID: PMC4423800 PMID: 20629221 [PubMed - indexed for MEDLINE] 1288. J Cell Physiol. 2010 Nov;225(2):348-53. doi: 10.1002/jcp.22313. Adipose tissue-derived progenitors for engineering osteogenic and vasculogenic grafts. Scherberich A(1), Müller AM, Schäfer DJ, Banfi A, Martin I. Author information: (1)Tissue Engineering, Department of Biomedicine, Basel University Hospital, Basel, Switzerland. The current need for bone grafts in orthopedic and reconstructive surgery cannot be satisfied by autologous tissue transplant due to its limited availability and significant associated morbidity. Tissue engineering approaches could supply sufficient amounts of bone substitutes by exploiting the ability to harvest autologous osteogenic progenitors associated with suitable porous materials. However, the generation of clinically relevant-sized constructs is critically hampered by limited vascularization, with consequent engraftment and survival only of a thin outer shell, upon in vivo implantation. To overcome this limitation, different non-mutually exclusive approaches have recently been developed to promote or accelerate graft vascularization, from angiogenic growth factor gene delivery to surgical pre-vascularization of the construct before implantation. A simple, promising strategy involves the co-culture of vasculogenic cells to form an intrinsic vascular network inside the graft in vitro, which can rapidly anastomose with the host blood vessels in vivo. Recent data have shown that adipose tissue-derived stromal vascular fraction (SVF) may provide an efficient, convenient, and autologous source for both osteogenic and endothelial cells. When SVF progenitors were cultured in appropriate bioreactor systems and ectopically implanted, a functional vascular network connected to the host was formed concomitantly to bone formation. Future studies should aim at demonstrating that this approach effectively supports survival of scaled up cell-based bone grafts at an orthotopic site. The procedure should also be adapted to become compatible with an intra-operative timeline and complemented with the definition of suitable potency markers, to facilitate its development into a simplified, reproducible, and cost-effective clinical treatment. PMID: 20626000 [PubMed - indexed for MEDLINE] 1289. Clin Orthop Relat Res. 2010 Sep;468(9):2530-40. doi: 10.1007/s11999-010-1410-9. Epub 2010 Jul 13. 2010 Nicolas Andry Award: Multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering. Guilak F(1), Estes BT, Diekman BO, Moutos FT, Gimble JM. Author information: (1)Departments of Surgery and Biomedical Engineering, Duke University Medical Center, Durham, NC 27710, USA. guilak@duke.edu BACKGROUND: Cell-based therapies such as tissue engineering provide promising therapeutic possibilities to enhance the repair or regeneration of damaged or diseased tissues but are dependent on the availability and controlled manipulation of appropriate cell sources. QUESTIONS/PURPOSES: The goal of this study was to test the hypothesis that adult subcutaneous fat contains stem cells with multilineage potential and to determine the influence of specific soluble mediators and biomaterial scaffolds on their differentiation into musculoskeletal phenotypes. METHODS: We reviewed recent studies showing the stem-like characteristics and multipotency of adipose-derived stem cells (ASCs), and their potential application in cell-based therapies in orthopaedics. RESULTS: Under controlled conditions, ASCs show phenotypic characteristics of various cell types, including chondrocytes, osteoblasts, adipocytes, neuronal cells, or muscle cells. In particular, the chondrogenic differentiation of ASCs can be induced by low oxygen tension, growth factors such as bone morphogenetic protein-6 (BMP-6), or biomaterial scaffolds consisting of native tissue matrices derived from cartilage. Finally, focus is given to the development of a functional biomaterial scaffold that can provide ASC-based constructs with mechanical properties similar to native cartilage. CONCLUSIONS: Adipose tissue contains an abundant source of multipotent progenitor cells. These cells show cell surface marker profiles and differentiation characteristics that are similar to but distinct from other adult stem cells, such as bone marrow mesenchymal stem cells (MSCs). CLINICAL RELEVANCE: The availability of an easily accessible and reproducible cell source may greatly facilitate the development of new cell-based therapies for regenerative medicine applications in the musculoskeletal system. PMCID: PMC2919887 PMID: 20625952 [PubMed - indexed for MEDLINE] 1290. Med Oncol. 2011 Dec;28(4):1288-95. doi: 10.1007/s12032-010-9617-x. Epub 2010 Jul 13. Adiponectin and breast cancer. Chen X(1), Wang Y. Author information: (1)Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomas Pereira S.J., Taipa, Macau, China. xpchen@umac.mo Adiponectin, an adipose tissue-derived hormone, has been studied intensively for the past decade because of its anti-inflammatory, anti-atherogenic, and anti-diabetic properties. Recent advances suggest that adiponectin also plays an important role in the development and progression of various cancers, especially obesity-related cancers. In this review, the authors focus on the potential role of adiponectin in breast cancer, an obesity- and endocrine-associated tumor. Epidemiological studies have shown that plasma adiponectin level is a risk factor for breast cancer in post-menopausal women. Adiponectin and its receptors are expressed on both breast cancer line cells and tumor tissues. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. Underlying mechanisms include the inhibition of cell proliferation and promotion of apoptosis, the regulation of tumorigenic-related factors, and the suppression of angiogenesis. The signaling pathways linking adiponectin with tumorigenesis might provide potential drug targets for the future. However, more convincing evidence is needed to fully elucidate the exact role of adiponectin in breast cancer, since both its beneficial effects and possible mechanisms remain controversial. PMID: 20625941 [PubMed - indexed for MEDLINE] 1291. Curr Opin Clin Nutr Metab Care. 2010 Sep;13(5):574-80. doi: 10.1097/MCO.0b013e32833cf0f4. Obesity, visceral fat and Crohn's disease. Bertin B(1), Desreumaux P, Dubuquoy L. Author information: (1)Université Lille Nord de France, France. PURPOSE OF REVIEW: Increasing evidence indicates that adipose tissue is an active endocrine organ involved in metabolic syndrome and regulation of inflammation. Visceral fat accumulation is a hallmark of both obesity and Crohn's disease. Here, we present recent data describing the immune properties of intra-abdominal adipose tissue that could link the innate immune response to obesity-related disorders and gut inflammation. RECENT FINDINGS: Innate immune properties of adipocytes have become well characterized since recent studies described the Toll-like receptor (TLR) expression repertoire and specific TLR ligand responses of adipocytes. Adipokine secretion profiles have also been elucidated both in obese patients, when they may be involved in obesity-associated metabolic disease, and in Crohn's disease. Whereas mesenteric fat hypertrophy and fat wrapping of the bowel are characteristic of Crohn's disease, there exists a paucity of information concerning this important pathophysiological aspect. Our current classical animal models are of limited interest when investigating the role of mesenteric fat in gut inflammation. Recent new alternative disease paradigms could help to design more specific models for elucidating chronic transmural inflammation of the gut. SUMMARY: Obesity and Crohn's disease share common features with the development of mesenteric fat that may be involved in gut inflammation. Further studies are required to clearly assess the origin and influence of intestinal fat deposits upon gut inflammation, notably during Crohn's disease development. PMID: 20625283 [PubMed - indexed for MEDLINE] 1292. Prog Histochem Cytochem. 2010 Sep;45(3):143-200. doi: 10.1016/j.proghi.2010.06.001. Epub 2010 Jul 10. Cross-talk between adipose and gastric leptins for the control of food intake and energy metabolism. Cammisotto PG(1), Levy E, Bukowiecki LJ, Bendayan M. Author information: (1)Department of Pathology and Cell Biology, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, QC, Canada. Philippe.cammisotto.1@ulaval.ca The understanding of the regulation of food intake has become increasingly complex. More than 20 hormones, both orexigenic and anorexigenic, have been identified. After crossing the blood-brain barrier, they reach their main site of action located in several hypothalamic areas and interact to balance satiety and hunger. One of the most significant advances in this matter has been the discovery of leptin. This hormone plays fundamental roles in the control of appetite and in regulating energy expenditure. In accordance with the lipostatic theory stated by Kennedy in 1953, leptin was originally discovered in white adipose tissue. Its expression by other tissues was later established. Among them, the gastric mucosa has been shown to secrete large amounts of leptin. Both the adipose and the gastric tissues share similar characteristics in the synthesis and storage of leptin in granules, in the formation of a complex with the soluble receptor and a secretion modulated by hormones and energy substrates. However while adipose tissue secretes leptin in a slow constitutive endocrine way, the gastric mucosa releases leptin in a rapid regulated exocrine fashion into the gastric juice. Exocrine-secreted leptin survives the extreme hydrolytic conditions of the gastric juice and reach the duodenal lumen in an intact active form. Scrutiny into transport mechanisms revealed that a significant amount of the exocrine leptin crosses the intestinal wall by active transcytosis. Leptin receptors, expressed on the luminal and basal membrane of intestinal epithelial cells, are involved in the control of nutrient absorption by enterocytes, mucus secretion by goblet cells and motility, among other processes, and this control is indeed different depending upon luminal or basal stimulus. Gastric leptin after transcytosis reaches the central nervous system, to control food intake. Studies using the Caco-2, the human intestinal cell line, in vitro allowed analysis of the mechanisms of leptin actions on the intestinal mucosa, identification of the mechanisms of leptin transcytosis and understanding the modulation of leptin receptors by nutrients and hormones. Exocrine-secreted gastric leptin thus participates in a physiological axis independent in terms of time and regulation from that of adipose tissue to rapidly control food intake and nutrient absorption. Adipocytes and gastric epithelial cells are two cell types the metabolism of which is closely linked to food intake and energy storage. The coordinated secretion of adipose and gastric leptins ensures proper management of food processing and energy storage. Copyright (c) 2010 Elsevier GmbH. All rights reserved. PMID: 20621336 [PubMed - indexed for MEDLINE] 1293. Medicine (Baltimore). 2010 Jul;89(4):245-50. doi: 10.1097/MD.0b013e3181e9442f. Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. Lupsa BC(1), Sachdev V, Lungu AO, Rosing DR, Gorden P. Author information: (1)Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. Lipodystrophy is a rare disorder characterized by loss of adipose tissue and low leptin levels. This condition is characterized by severe dyslipidemia, insulin resistance, diabetes mellitus, and steatohepatitis. Another phenotypic feature that occurs with considerable frequency in generalized lipodystrophy is cardiomyopathy. We report here the cardiac findings in a cohort of patients with generalized congenital and acquired lipodystrophy, and present a literature review of the cardiac findings in patients with generalized lipodystrophy. We studied 44 patients with generalized congenital and acquired lipodystrophy, most of them enrolled in a clinical trial of leptin therapy. Patients underwent electrocardiograms and transthoracic echocardiograms to evaluate their cardiac status. We followed these patients for an extended time period, some of them up to 8 years. Evaluation of our cohort of patients with generalized lipodystrophy shows that cardiomyopathy is a frequent finding in this population. Most of our patients had hypertrophic cardiomyopathy, and only a small number had features of dilated cardiomyopathy. Hypertrophic cardiomyopathy was more frequent in patients with seipin mutation, a finding consistent with the literature. The underlying mechanism for cardiomyopathy in lipodystrophy is not clear. Extreme insulin resistance and the possibility of a "lipotoxic cardiomyopathy" should be entertained as possible explanations. PMCID: PMC3090142 PMID: 20616664 [PubMed - indexed for MEDLINE] 1294. Antioxid Redox Signal. 2011 Feb 15;14(4):649-61. doi: 10.1089/ars.2010.3370. Epub 2010 Sep 16. Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Cheng Z(1), White MF. Author information: (1)Division of Endocrinology, Howard Hughes Medical Institute, Harvard Medical School, Children's Hospital Boston, Boston, Massachusetts 02115, USA. Forkhead box O (FOXO) transcription factors have been implicated in regulating the metabolism, cellular proliferation, stress resistance, apoptosis, and longevity. Through the insulin receptor substrate → phosphoinositide 3-kinase → Akt signal cascade, FOXO integrates insulin action with the systemic nutrient and energy homeostasis. Activation of FOXO1 in liver induces gluconeogenesis via phosphoenolpyruvate carboxykinase (PEPCK)/glucose 6-phosphate pathway, and disrupts mitochondrial metabolism and lipid metabolism via heme oxygenase 1/sirtuin 1/Ppargc1α pathway. In skeletal muscle, FOXO1 activation underpins the carbohydrate/lipid switch during fasting state. Inhibition of FOXO1 under physiological conditions accounts for maintenance of skeletal muscle mass/function and adipose differentiation. In pancreatic β-cells, nuclear translocation of FOXO1 antagonizes pancreatic and duodenal homeobox 1 and attenuates β-cells proliferation and insulin secretion. Regardless, FOXO1 promotes the proliferation of β-cells through induction of Cyclin D1 in low nutrition, and elicits antioxidant mechanism to protect against β-cell failure during oxidative insults. In the brain, FOXO1 controls food intake through transcriptional regulation of the orexigenic neuropeptide Y, agouti-related protein, and carboxypeptidase E. In this article, we review the role of FOXO1 in the regulation of metabolism and energy expenditure based on recent findings from mouse models, and discuss the therapeutic value of targeting FOXO1 in metabolic diseases. PMCID: PMC3025764 PMID: 20615072 [PubMed - indexed for MEDLINE] 1295. Am J Cardiol. 2010 Jul 1;106(1):56-61. doi: 10.1016/j.amjcard.2010.02.017. Epub 2010 May 13. Relation of C-reactive protein to abdominal adiposity. Brooks GC(1), Blaha MJ, Blumenthal RS. Author information: (1)Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland, USA. gbrook12@jhmi.edu Inflammation is a crucial element in the development of cardiovascular disease. Serum measurements of inflammation through high-sensitivity C-reactive protein (hsCRP) can lead to improved risk stratification of patients for risk for hard cardiovascular events. There is evidence that anthropomorphic measurements of obesity are important determinants of systemic inflammation. Online databases (e.g., PubMed and Medline) were searched for original research reports published in English from June 1990 to June 2009 examining the relations between hsCRP; anthropomorphic measurements of obesity including body mass index, waist-to-hip ratio, waist circumference, and visceral adiposity; and cardiovascular disease. When possible, correlation coefficients were used to compare data among studies. Measurements of abdominal obesity are associated with systemic inflammation as measured by hsCRP (r = 0.40 to 0.61). The association between hsCRP and abdominal adiposity persists when taking into account body mass index. Elevation of hsCRP might be reversible with weight loss and exercise. In conclusion, clinical measurements of abdominal adiposity readily provide data elucidating the systemic inflammatory state of patients and can help guide intensity of lifestyle modifications, thus leading to reduction of this inflammation. Copyright (c) 2010 Elsevier Inc. All rights reserved. PMID: 20609648 [PubMed - indexed for MEDLINE] 1296. Obes Rev. 2011 May;12(5):e119-29. doi: 10.1111/j.1467-789X.2010.00775.x. Objectively measured physical activity and obesity prevention in children, adolescents and adults: a systematic review of prospective studies. Wilks DC(1), Besson H, Lindroos AK, Ekelund U. Author information: (1)Medical Research Council Human Nutrition Research, Medical Research Council Epidemiology Unit, Cambridge, UK. This study aimed at synthesizing the prospective associations between measured physical activity (PA) and change in adiposity in children, adolescents and adults following from two previous reviews. Search terms were adapted and a systematic literature search was conducted (January 2000-September 2008) and later updated (up to October 2009), considering observational and intervention studies of weight gain that measured both PA and body composition. Sixteen observational studies (six comprising adults) and five trials (one comprising adults) were eligible. For consistency, whenever possible either baseline PA energy expenditure or accelerometer output (counts min(-1) ) and change in per cent body fat were the extracted exposure and outcome measures. Results of observational studies suggest that PA is not strongly prospectively related with adiposity: five studies on children and three on adults reported no association between baseline PA and change in adiposity, one study found a weak positive association and the other studies observed a weak negative association. Negative associations were more frequently observed in studies that analysed the association between change in the exposure and outcome. Intervention studies show generally no effect on either PA or adiposity. In conclusion, despite the well-established health benefits of PA, it may not be a key determinant of excessive gain in adiposity. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 20604868 [PubMed - indexed for MEDLINE] 1297. FEBS Lett. 2010 Aug 4;584(15):3250-9. doi: 10.1016/j.febslet.2010.06.035. Epub 2010 Jun 30. Brown vs white adipocytes: the PPARgamma coregulator story. Koppen A(1), Kalkhoven E. Author information: (1)Department of Metabolic and Endocrine Diseases, UMC Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands. The development of adipose tissue is a process which involves the concerted cooperation of numerous transcription factors together with their coactivators and corepressors. The peroxisome proliferator-activated receptor gamma (PPARgamma) is considered to be one of the master regulators of adipocyte differentiation. The presence of two functionally distinct types of adipose tissue, white and brown (WAT and BAT), requires an even more complex regulation of adipose tissue development. In this review we will focus on the role of PPARgamma coregulators in adipogenesis and especially on the role of PPARgamma coregulators in white and brown adipose tissue. Specificity in coregulator function in WAT and BAT may form an additional level of regulation of adipose tissue development. Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. PMID: 20600006 [PubMed - indexed for MEDLINE] 1298. Arch Biochem Biophys. 2010 Nov 1;503(1):20-7. doi: 10.1016/j.abb.2010.06.027. Epub 2010 Jul 3. Fat and bone. Reid IR(1). Author information: (1)Department of Medicine, University of Auckland, Auckland, New Zealand. i.reid@auckland.ac.nz Body weight is a principal determinant of bone density and fracture risk, and adipose tissue mass is a major contributor to this relationship. In contrast, some recent studies have argued that "fat mass after adjustment for body weight" actually has a deleterious effect on bone, but these analyses are confounded by the co-linearity between the variables studied, and therefore have produced misleading results. Mechanistically, fat and bone are linked by a multitude of pathways, which ultimately serve the function of providing a skeleton appropriate to the mass of adipose tissue it is carrying. Adiponectin, insulin/amylin/preptin, leptin and adipocytic estrogens are all likely to be involved in this connection. In the clinic, the key issues are that obesity is protective against osteoporosis, but underweight is a major preventable risk factor for fractures. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 20599663 [PubMed - indexed for MEDLINE] 1299. J Steroid Biochem Mol Biol. 2010 Oct;122(1-3):74-81. doi: 10.1016/j.jsbmb.2010.06.012. Epub 2010 Jul 3. Metabolic impact of estrogen signalling through ERalpha and ERbeta. Foryst-Ludwig A(1), Kintscher U. Author information: (1)Center for Cardiovascular Research (CCR), Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany. Estrogens, acting on both estrogen receptors alpha (ERalpha) and beta (ERbeta) are recognized as important regulators of glucose homeostasis and lipid metabolism. ERs belong to the family of nuclear hormone receptors which mainly act as ligand activated transcription factors. Both ERs are expressed in metabolic tissue such as adipose tissue, skeletal muscle, liver and pancreas, as well as in the central nervous system. Expression pattern of both ERs differ between species, sexes, and specific tissues. The present review will focus on the key effects of ERs on glucose- and lipid metabolism. It appears that ERalpha mainly mediates beneficial metabolic effects of estrogens such as anti-lipogenesis, improvement of insulin sensitivity and glucose tolerance, and reduction of body weight/fat mass. In contrast, ERbeta activation seems to be detrimental for the maintenance of regular glucose and lipid homeostasis. Metabolic actions of both receptors in relevant tissues will be discussed. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 20599505 [PubMed - indexed for MEDLINE] 1300. Otolaryngol Clin North Am. 2010 Aug;43(4):753-68. doi: 10.1016/j.otc.2010.04.003. A comprehensive review of the adverse effects of systemic corticosteroids. Poetker DM(1), Reh DD. Author information: (1)Division of Rhinology and Sinus Surgery, Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. dpoetker@mcw.edu Corticosteroids are widely used in otolaryngology to treat many disorders; however, the nature and extent of possible complications may not be completely understood. A comprehensive review of the physiology of systemic corticosteroids and literature discussing the known side effects associated with their use is presented. The pathophysiology and the clinical impact of these side effects are reviewed. There are various potential side effects from the use of corticosteroids. Practitioners using corticosteroids should be familiar with these and obtain the patient's informed consent when appropriate. PMID: 20599080 [PubMed - indexed for MEDLINE] 1301. Chin Med Sci J. 2010 Jun;25(2):119-24. A second protein marker of caveolae: caveolin-2. Zhu LL(1), Cui Y, Chang YS, Fang FD. Author information: (1)National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Caveolin-2, a protein about 20 kD, is a major component of the inner surface of caveolae, small invaginations of the plasma membrane. Similar with caveolin-1 and caveolin-3, it serves as a protein marker of caveolae. Caveolin-1 and -2 are located next to each other at 7q31.1 on human chromosome, the proteins encoded are co-localized and form a stable hetero-oligomeric complex, distributing similarly in tissue and cultured cells. Caveolin-3 is located on different chromosomes but confirmed to interact with caveolin-2. Caveolin-2 is similar to caveolin-1 in many respects but differs from the latter in functional domains, especially in G-protein binding domain and caveolin scaffolding domain. The mRNAs of both caveolin-1 and caveolin-2 are most abundantly expressed in white adipose tissue and are induced during differentiation of 3T3-L1 cells to adipocytes. Caveolin-2-deficient mice demonstrate clear pulmonary defects, with little or no change in caveolin-1 expression and caveolae formation, suggesting that caveolin-2 plays a selective role in lung functions. Caveolin-2 is also involved in lipid metabolism and human cancers. PMID: 20598236 [PubMed - indexed for MEDLINE] 1302. Proc Nutr Soc. 2010 Nov;69(4):511-7. doi: 10.1017/S0029665110001709. Epub 2010 Jul 2. The true cost of in-patient obesity: impact of obesity on inflammatory stress and morbidity. Grimble RF(1). Author information: (1)Institute of Human Nutrition, DOHaD Division, School of Medicine, University of Southampton, Mailpoint 887, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. rfg1@soton.ac.uk The objective of the present review is to provide an overview of the metabolic effects of pro-inflammatory cytokine production during infection and injury; to highlight the disadvantages of pro-inflammatory cytokine production and inflammatory stress on morbidity and mortality of patients; to identify the influence of genetics and adiposity on inflammatory stress in patients and to indicate how nutrients may modulate the inflammatory response in patients. Recent research has shown clearly that adipose tissue actively secretes a wide range of pro- and anti-inflammatory cytokines. Paradoxically, although inflammation is an essential part of the response of the body to infection, surgery and trauma, it can adversely affect patient outcome. The metabolic effects of inflammation are mediated by pro-inflammatory cytokines. Metabolic effects include insulin insensitivity, hyperlipidaemia, muscle protein loss and oxidant stress. These effects, as well as being present during infective disease, are also present in diseases with a covert inflammatory basis. These latter diseases include obesity and type 2 diabetes mellitus. Inflammatory stress also increases during aging. The level of cytokine production, within individuals, is influenced by single nucleotide polymorphisms (SNP) in cytokine genes. The combination of SNP controls the relative level of inflammatory stress in both overt and covert inflammatory diseases. The impact of cytokine genotype on the intensity of inflammatory stress derived from an obese state is unknown. While studies remain to be done in the latter context, evidence shows that these genomic characteristics influence morbidity and mortality in infectious disease and diseases with an underlying inflammatory basis and thereby influence the cost of in-patient obesity. Antioxidants and n-3 PUFA alter the intensity of the inflammatory process. Recent studies show that genotypic factors influence the effectiveness of immunonutrients. A better understanding of this aspect of nutrient-gene interactions and of the genomic factors that influence the intensity of inflammation during disease will help in the more effective targeting of nutritional therapy. PMID: 20598196 [PubMed - indexed for MEDLINE] 1303. Trends Endocrinol Metab. 2010 Oct;21(10):619-27. doi: 10.1016/j.tem.2010.06.004. Epub 2010 Jun 30. Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis? Harno E(1), White A. Author information: (1)Faculties of Life Sciences and Medical and Human Sciences, Manchester, Academic Health Sciences Centre, University of Manchester, UK. Inhibitors of 11β-HSD1 are in clinical trials for the treatment of type 2 diabetes. These compounds act by decreasing the cortisol generated in liver and adipose tissue, and therefore reducing tissue-specific gluconeogenesis and fatty acid metabolism. However, there is concern that reduction in tissue-regenerated cortisol might decrease feedback to the hypothalamic-pituitary-adrenal (HPA) axis, resulting in upregulation of cortisol from the adrenal gland. This review considers evidence from 11β-HSD1 knockout and transgenic mice, inhibitor studies and results from clinical trials evaluating HPA axis biomarkers. It is clear that analysis of the HPA axis is not sufficiently detailed, and there is a need to understand the subtle changes in the axis associated with pulsatility, diurnal rhythm and stress. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 20594868 [PubMed - indexed for MEDLINE] 1304. Curr Diabetes Rev. 2010 Sep;6(5):285-93. Dysregulation of glycogen synthase kinase-3 in skeletal muscle and the etiology of insulin resistance and type 2 diabetes. Henriksen EJ(1). Author information: (1)Muscle Metabolism Laboratory, Department of Physiology and Arizona Diabetes Program, University of Arizona College of Medicine, Tucson, AZ 85724, USA. ejhenrik@u.arizona.edu Insulin resistance of glucose transport and metabolism in insulin-sensitive tissues is a primary defect leading to the development of type 2 diabetes. While the etiology of insulin resistance is multifactorial, one factor associated with reduced insulin action is enhanced activity of the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) in skeletal muscle, liver, and adipose tissue. GSK-3 is involved in numerous cellular functions, including glycogen synthesis, protein synthesis, gene transcription, and cell differentiation. Evidence from muscle and fat cell lines and in skeletal muscle from a variety of obese rodent models and from type 2 diabetic humans supports a role of GSK-3 overactivity in the development of insulin resistance of glucose transport and glycogenesis. Studies utilizing highly selective GSK-3 inhibitors indicate that GSK-3 overactivity in obesity is associated with enhanced IRS-1 serine phosphorylation and defective IRS-1-dependent signaling, ultimately resulting in reduced GLUT-4 translocation and glucose transport activity in skeletal muscle. A role of GSK-3 overactivity in the exaggerated hepatic glucose production of type 2 diabetes has also been reported. Recent studies have demonstrated that oxidative stress, resulting from enhanced exposure to oxidants, causes impaired insulin signaling and insulin resistance of skeletal muscle glucose transport, in part due to reduced suppression of GSK-3 activity and increased IRS-1 Ser(307) phosphorylation. The evidence to date supports an important role of GSK-3 dysfunction in the multifactorial etiology of insulin resistance in skeletal muscle. GSK-3 remains an important target for interventions designed to improve insulin action in obesity-associated insulin resistance and type 2 diabetes. PMID: 20594161 [PubMed - indexed for MEDLINE] 1305. Horm Behav. 2011 Mar;59(3):279-89. doi: 10.1016/j.yhbeh.2010.06.007. Epub 2010 Jun 19. Glucocorticoids, prenatal stress and the programming of disease. Harris A(1), Seckl J. Author information: (1)University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Anjie.harris@ed.ac.uk An adverse foetal environment is associated with increased risk of cardiovascular, metabolic, neuroendocrine and psychological disorders in adulthood. Exposure to stress and its glucocorticoid hormone mediators may underpin this association. In humans and in animal models, prenatal stress, excess exogenous glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (HSD2; the placental barrier to maternal glucocorticoids) reduces birth weight and causes hyperglycemia, hypertension, increased HPA axis reactivity, and increased anxiety-related behaviour. Molecular mechanisms that underlie the 'developmental programming' effects of excess glucocorticoids/prenatal stress include epigenetic changes in target gene promoters. In the case of the intracellular glucocorticoid receptor (GR), this alters tissue-specific GR expression levels, which has persistent and profound effects on glucocorticoid signalling in certain tissues (e.g. brain, liver, and adipose). Crucially, changes in gene expression persist long after the initial challenge, predisposing the individual to disease in later life. Intriguingly, the effects of a challenged pregnancy appear to be transmitted possibly to one or two subsequent generations, suggesting that these epigenetic effects persist. Copyright © 2010 Elsevier Inc. All rights reserved. PMID: 20591431 [PubMed - indexed for MEDLINE] 1306. Br J Pharmacol. 2010 Jul;160(5):1029-44. doi: 10.1111/j.1476-5381.2010.00722.x. The role of monoamines in the changes in body temperature induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives. Docherty JR(1), Green AR. Author information: (1)Department of Physiology, Royal College of Surgeons in Ireland, Ireland. docherty@rcsi.ie Hyperthermia is probably the most widely known acute adverse event that can follow ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) by recreational users. The effect of MDMA on body temperature is complex because the drug has actions on all three major monoamine neurotransmitters [5-hydroxytryptamine (5-HT), dopamine and noradrenaline], both by amine release and by direct receptor activation. Hyperthermia and hypothermia can be induced in laboratory animals by MDMA, depending on the ambient temperature, and involve both central thermoregulation and peripheral changes in blood flow and thermogenesis. Acute 5-HT release is not directly responsible for hyperthermia, but 5-HT receptors are involved in modulating the hyperthermic response. Impairing 5-HT function with a neurotoxic dose of MDMA or p-chlorophenylalanine alters the subsequent MDMA-induced hyperthermic response. MDMA also releases dopamine, and evidence suggests that this transmitter is involved in both the hyperthermic and hypothermic effects of MDMA in rats. The noradrenergic system is also involved in the hyperthermic response to MDMA. MDMA activates central alpha(2A)-adrenoceptors and peripheral alpha(1)-adrenoceptors to produce cutaneous vasoconstriction to restrict heat loss, and beta(3)-adrenoceptors in brown adipose tissue to increase heat generation. The hyperthermia occurring in recreational users of MDMA can be fatal, but data reviewed here indicate that it is unlikely that any single pharmaceutical agent will be effective in reversing the hyperthermia, so careful body cooling remains the principal clinical approach. Crucially, educating recreational users about the potential dangers of hyperthermia and the control of ambient temperature should remain key approaches to prevent this potentially fatal problem. PMCID: PMC2936013 PMID: 20590597 [PubMed - indexed for MEDLINE] 1307. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):441-5. doi: 10.1097/MED.0b013e32833c3013. Molecular neuroendocrine targets for obesity therapy. de Kloet AD(1), Woods SC. Author information: (1)Program in Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237, USA. dekloead@mail.uc.edu PURPOSE OF REVIEW: Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy. RECENT FINDINGS: During the review period, considerable progress occurred in the understanding of previously described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of the neuroendocrine regulation of energy homeostasis has been expanded. SUMMARY: Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical-weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging. PMCID: PMC3918165 PMID: 20585249 [PubMed - indexed for MEDLINE] 1308. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):446-52. doi: 10.1097/MED.0b013e32833c3026. Mitochondrial dysfunction in obesity. Bournat JC(1), Brown CW. Author information: (1)aDepartments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. PURPOSE OF REVIEW: The review highlights recent findings regarding the functions of mitochondria in adipocytes, providing an understanding of their central roles in regulating substrate metabolism, energy expenditure, disposal of reactive oxygen species (ROS), and in the pathophysiology of obesity and insulin resistance, as well as roles in the mechanisms that affect adipogenesis and mature adipocyte function. RECENT FINDINGS: Nutrient excess leads to mitochondrial dysfunction, which in turn leads to obesity-related pathologies, in part due to the harmful effects of ROS. The recent recognition of 'ectopic' brown adipose in humans suggests that this tissue may play an underappreciated role in the control of energy expenditure. Transcription factors, PGC-1alpha and PRDM16, which regulate brown adipogenesis, and members of the TGF-beta superfamily that modulate this process may be important new targets for antiobesity drugs. SUMMARY: Mitochondria play central roles in ATP production, energy expenditure, and disposal of ROS. Excessive energy substrates lead to mitochondrial dysfunction with consequential effects on lipid and glucose metabolism. Adipocytes help to maintain the appropriate balance between energy storage and expenditure and maintaining this balance requires normal mitochondrial function. Many adipokines, including members of the TGF-beta superfamily, and transcriptional coactivators, PGC-1alpha and PRDM16, are important regulators of this process. PMID: 20585248 [PubMed - indexed for MEDLINE] 1309. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):472-7. doi: 10.1097/MED.0b013e32833c5c48. Obesity genes and insulin resistance. Belkina AC(1), Denis GV. Author information: (1)Boston Nutrition Obesity Research Center, Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. PURPOSE OF REVIEW: The exploding prevalence of insulin resistance and Type 2 diabetes (T2D) linked to obesity has become an alarming public health concern. Worldwide, approximately 171 million people suffer from obesity-induced diabetes and public health authorities expect this situation to deteriorate rapidly. An interesting clinical population of 'metabolically healthy but obese' (MHO) cases is relatively protected from T2D and its associated cardiovascular risk. The molecular basis for this protection is not well understood but is likely to involve reduced inflammatory responses. The inflammatory cells and pathways that respond to overnutrition are the primary subject matter for this review. RECENT FINDINGS: The chance discovery of a genetic mutation in the Brd2 gene, which is located in the class II major histocompatibility complex and makes mice enormously fat but protects them from diabetes, offers revolutionary new insights into the cellular mechanisms that link obesity to insulin resistance and T2D. These Brd2-hypomorphic mice have reduced inflammation in fat that is normally associated with insulin resistance, and resemble MHO patients, suggesting novel therapeutic pathways for obese patients at risk for T2D. SUMMARY: Deeper understanding of the functional links between genes that control inflammatory responses to diet-induced obesity is crucial to the development of therapies for obese, insulin-resistant patients. PMCID: PMC3079383 PMID: 20585247 [PubMed - indexed for MEDLINE] 1310. Curr Opin Lipidol. 2010 Aug;21(4):329-36. doi: 10.1097/MOL.0b013e32833b7782. Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance. Savage DB(1), Semple RK. Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. PURPOSE OF REVIEW: To summarize recent research into the mechanisms linking insulin resistance, nonalcoholic fatty liver disease and metabolic dyslipidaemia. RECENT FINDINGS: Pathologically increased nonesterified fatty acids have widely been viewed as a key driver of hepatic insulin resistance/nonalcoholic fatty liver disease/metabolic dyslipidaemia. However, this may have been overestimated, and growing evidence now also implicates dysregulated hepatic de-novo lipogenesis in the pathogenesis of these phenomena. This is driven by the action of hyperinsulinaemia on the liver, mediated by PI3 kinase, though consensus on the downstream effectors remains to be reached. Endoplasmic reticulum stress and/or components of the attendant unfolded protein response have also emerged as players in dysregulated hepatic metabolism due to nutritional overload. Several points of convergence between metabolic and unfolded protein response pathways have been described, notably centring on the transcription factor XBP1. SUMMARY: Insulin resistance, nonalcoholic fatty liver disease and metabolic dyslipidaemia are inextricably linked and need to be considered together. Modelling and dissecting prevalent forms of the disease is complex, but unrestrained de-novo lipogenesis driven by hyperinsulinaemia appears to play an important role. Endoplasmic reticulum stress and the associated unfolded protein response may also contribute to cellular mismatch between triglyceride secretion/metabolism and synthesis, though a complete picture has yet to emerge. PMID: 20581678 [PubMed - indexed for MEDLINE] 1311. Adv Drug Deliv Rev. 2010 Jul 31;62(9-10):967-78. doi: 10.1016/j.addr.2010.05.005. Epub 2010 May 24. Chronobiological aspects of nutrition, metabolic syndrome and obesity. Garaulet M(1), Madrid JA. Author information: (1)Department of Physiology, University of Murcia, Spain. garaulet@um.es The present review starts from the classical physiological and nutritional studies related with food intake control, digestion, transport and absorption of nutrients. It continues with studies related with the metabolism of adipose tissue, and finish with modern experiments in genetics and molecular biology - all from a fresh, chronobiological point of view. Obesity will be explained as a fault in the circadian system, as pathology associated with "chronodisruption". The main gaps in chronobiological research related to obesity will be also identified and chronobiological-based therapies will be proposed in order to allow the resetting of the circadian rhythm among obese subjects. 2010 Elsevier B.V. All rights reserved. PMID: 20580916 [PubMed - indexed for MEDLINE] 1312. Obes Rev. 2011 May;12(5):e21-31. doi: 10.1111/j.1467-789X.2010.00773.x. Melanin and melanogenesis in adipose tissue: possible mechanisms for abating oxidative stress and inflammation? Page S(1), Chandhoke V, Baranova A. Author information: (1)Department of Molecular and Microbiology, College of Science, George Mason University, Fairfax Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA. Obesity has become a worldwide epidemic and can lead to multiple chronic diseases. Adipose tissue is increasingly thought to play an active role in obesity-related pathologies such as insulin resistance and non-alcoholic fatty liver disease. Obesity has been strongly associated with systemic inflammation and, to a lesser degree, with oxidative stress, although the causal relationships among these factors are unclear. A recent study demonstrating an expression of the components of the melanogenic pathway and the presence of melanin in visceral adipose has raised questions regarding the possible role of melanogenesis in adipose tissue. As this study also found larger amounts of melanin in the adipose tissue of obese patients relative to lean ones, we hypothesize that melanin, a pigment known for its antioxidant and anti-inflammatory properties, may scavenge reactive oxygen species and abate oxidative stress and inflammation in adipose tissue. This review considers the evidence to support such a hypothesis, and speculates on the role of melanin within adipocytes. Furthermore, we consider whether the α-melanocyte-stimulating hormone or its synthetic analogues could be used to stimulate melanin production in adipocytes, should the hypothesis be supported in future experiments. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 20576005 [PubMed - indexed for MEDLINE] 1313. Epigenetics. 2010 Aug 16;5(6):476-82. doi: 10.4161/epi.5.6.12517. Epub 2010 Aug 16. Programming differentiation potential in mesenchymal stem cells. Collas P(1). Author information: (1)Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway. philippe.collas@medisin.uio.no Cell fate decisions are largely programmed by interactions between multiple layers of regulation of gene expression. Among these, epigenetic states have been extensively examined, mostly in the context of embryonic stem cell differentiation. Recent studies however have focused on understanding chromatin-based mechanisms of differentiation of adult progenitor cells into specific lineages but not others. The results point to the view that promoter DNA methylation patterns are not the primary determinant of gene activation potential and differentiation capacity of mesenchymal stem cells. Post-translational histone modifications on promoters contribute to establishing a permissive state of differentiation, but cannot either, based on current knowledge, predict transcriptional activation outcome. Additional regulatory layers need to be examined to be able to explain cell fate commitment and ultimately predict cell fate. PMID: 20574163 [PubMed - indexed for MEDLINE] 1314. Indian J Med Res. 2010 Jun;131:743-60. Molecular & genetic factors contributing to insulin resistance in polycystic ovary syndrome. Mukherjee S(1), Maitra A. Author information: (1)Department of Molecular Endocrinology, National Institute for Research in Reproductive Health (ICMR) Mumbai, India. mukherjees@nirrh.res.in Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of unknown etiology. Insulin resistance is very common and plays a central pathogenic role in PCOS. During last decade several studies have been conducted to understand the mechanisms contributing to the state of insulin resistance and insulin-induced hyperandrogenemia in PCOS. Insulin signaling pathways have been dissected in different insulin responsive tissues such as skeletal muscles, adipose tissues, fibroblasts as well as ovaries to elucidate the mechanism. These studies suggest a post receptor signaling defect where metabolic action of insulin is affected but not the steroidogenic and mitogenic actions. Despite advancement in these studies gaps exist in our understanding of the mechanism of insulin resistance as well as insulin- induced steroidogenesis in PCOS. The syndrome is now considered as a complex multigenic disorder. Efforts are ongoing to dissect the variants of genes from multiple logical pathways which are involved in pathophysiology of the syndrome. But still today no gene has been emerged as universally accepted susceptibility gene for PCOS. This review briefly describes the lacunae along with the current status of molecular events underlying insulin resistance and the contribution of insulin signaling pathway genes in pathogenesis of PCOS along with future researchable areas. PMID: 20571162 [PubMed - indexed for MEDLINE] 1315. Orv Hetil. 2010 Jul 11;151(28):1125-31. doi: 10.1556/OH.2010.28802. [Physical activity and training against obesity]. [Article in Hungarian] Apor P(1), Rádi A. Author information: (1)RISK Egészségügyi Szolgáltató Kft. Budapest. p.ap.md@freemail.hu A short review deals with the role of physical activity in the prevention and treatment of obesity, in order to avoid cardio-metabolic consequences of accumulation of the fat. Community-level interventions are necessary, based on estimations of the physical activity. Mechanisms and effects of the proper training on the body fat and muscle are summarized, and practical advices are presented for implementation of the regular physical activity. PMID: 20570792 [PubMed - indexed for MEDLINE] 1316. Reproduction. 2010 Sep;140(3):387-98. doi: 10.1530/REP-10-0077. Epub 2010 Jun 18. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Drake AJ(1), Reynolds RM. Author information: (1)Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Sciences, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 6TJ, UK. The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations. PMID: 20562299 [PubMed - indexed for MEDLINE] 1317. Fertil Steril. 2010 Nov;94(6):1949-57. doi: 10.1016/j.fertnstert.2010.05.010. Epub 2010 Jun 19. The role of adiponectin in reproduction: from polycystic ovary syndrome to assisted reproduction. Michalakis KG(1), Segars JH. Author information: (1)Reproductive Biology and Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. OBJECTIVE: To summarize the effects of the adipokine adiponectin on the reproductive endocrine system, from the hypothalamic-pituitary axis to the gonads and target tissues of the reproductive system. DESIGN: A Medline computer search was performed to identify relevant articles. SETTING: Research institution. INTERVENTION(S): None. RESULT(S): Adiponectin is a hormone secreted by adipose tissue that acts to reduce insulin resistance and atherogenic damage, but it also exerts actions in other tissues. Adiponectin mediates its actions in the periphery mainly via two receptors, AdipoR1 and AdipoR2. Adiponectin receptors are present in many reproductive tissues, including the central nervous system, ovaries, oviduct, endometrium, and testes. Adiponectin influences gonadotropin release, normal pregnancy, and assisted reproduction outcomes. CONCLUSION(S): Adiponectin, a beneficial adipokine, represents a major link between obesity and reproduction. Higher levels of adiponectin are associated with improved menstrual function and better outcomes in assisted reproductive cycles. Published by Elsevier Inc. PMCID: PMC3127205 PMID: 20561616 [PubMed - indexed for MEDLINE] 1318. J Cardiovasc Transl Res. 2009 Sep;2(3):321-7. doi: 10.1007/s12265-009-9101-1. Epub 2009 Apr 23. Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. Nedungadi TP(1), Clegg DJ. Author information: (1)Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd., K5.252, Dallas, TX 75390-8854, USA. The prevalence of obesity has dramatically increased over the past decade along with the cardiovascular and other health risks it encompasses. Adipose tissue, which is distributed in the abdominal viscera, carries a greater risk for cardiovascular disorders than adipose tissue subcutaneously. There is a sex difference in the regional fat distribution. Women have more subcutaneous fat, whereas men have more visceral fat. Therefore, obesity-related metabolic disorders are much lower in premenopausal women than men. Peripheral metabolic signals like leptin and insulin are involved in the food intake, body weight, body fat distribution, and cardiovascular disease. Key areas in the brain, including the hypothalamus, integrates these peripheral adiposity signals to maintain overall adiposity levels, and these brain regions are directly influenced by sex hormones. Therefore, differences in cardiovascular disease may be under the influence of sex hormones either directly in the brain or through their influence of body fat distribution. The role of estrogen in mediating body fat distribution and cardiovascular disease is the focus of this review. PMID: 20560019 [PubMed - indexed for MEDLINE] 1319. Obes Rev. 2011 Mar;12(3):167-88. doi: 10.1111/j.1467-789X.2010.00756.x. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Tan DX(1), Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ. Author information: (1)Department of Cellular and Structural Biology, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 20557470 [PubMed - indexed for MEDLINE] 1320. Curr Diab Rep. 2010 Aug;10(4):306-15. doi: 10.1007/s11892-010-0122-6. The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Cusi K(1). Author information: (1)The University of Texas Health Science Center at San Antonio, Diabetes Division, Room 3.380S, 7703 Floyd Curl Drive, San Antonio, TX 78284-3900, USA. cusi@uthscsa.edu The widespread epidemics of obesity and type 2 diabetes mellitus (T2DM) suggest that both conditions are closely linked. An increasing body of evidence has shifted our view of adipose tissue from a passive energy depot to a dynamic "endocrine organ" that tightly regulates nutritional balance by means of a complex crosstalk of adipocytes with their microenvironment. Dysfunctional adipose tissue, particularly as observed in obesity, is characterized by adipocyte hypertrophy, macrophage infiltration, impaired insulin signaling, and insulin resistance. The result is the release of a host of inflammatory adipokines and excessive amounts of free fatty acids that promote ectopic fat deposition and lipotoxicity in muscle, liver, and pancreatic beta cells. This review focuses on recent work on how glucose homeostasis is profoundly altered by distressed adipose tissue. A better understanding of this relationship offers the best chance for early intervention strategies aimed at preventing the burden of T2DM. PMID: 20556549 [PubMed - indexed for MEDLINE] 1321. Endocr Dev. 2010;19:84-92. doi: 10.1159/000316900. Epub 2010 Jun 15. The neural feedback loop between the brain and adipose tissues. Pénicaud L(1). Author information: (1)UMR 6265, CNRS Université de Bourgogne, Dijon, France. penicaud@cict.fr There are more and more data supporting the importance of nervous regulation of both white and brown adipose tissue mass. This short paper will review the different physiological parameters which are regulated such as metabolism (lipolysis and thermogeneis), secretory activity (leptin and other adipokines) but also to plasticity of adipose tissues (proliferation differentiation and apoptosis). The sensory innervation of white adipose issue and its putative role will be also described. Altogether these results showed the presence of a neural feedback loop between adipose tissues and the brain which plays a major role in the regulation of energy homeostasis and has been shown to be altered in physiologic as well as in metabolic pathologies. Copyright 2010 S. Karger AG, Basel. PMID: 20551671 [PubMed - indexed for MEDLINE] 1322. Endocr Dev. 2010;19:73-83. doi: 10.1159/000316899. Epub 2010 Jun 15. Pathophysiology of insulin resistance in small for gestational age subjects: a role for adipose tissue? Beltrand J(1), Meas T, Levy-Marchal C. Author information: (1)INSERM, U690 and Université Paris 7 Denis Diderot, Paris, France. Over the last 15 years a number of long-term health risks associated with reduced fetal growth have been identified, including cardiovascular diseases, hypertension, dyslipidemia, or type 2 diabetes. A common feature of these conditions is insulin resistance, which is thought to play a pathogenic role. However, despite abundant data in the literature, it is still difficult to trace the pathway by which fetal events, environmental or not, may lead to the increased morbidity later in life. To explain this association, several hypotheses have been proposed pointing to the role of either a detrimental fetal environment or a genetic susceptibility or an interaction between the two and of the particular dynamic changes in adiposity that occur during catch-up growth. The relative impact of early postnatal events in relation to fetal growth has to be considered for designing health policy strategies for early interventions aimed at decreasing the diseases risk throughout life. Copyright 2010 S. Karger AG, Basel. PMID: 20551670 [PubMed - indexed for MEDLINE] 1323. Endocr Dev. 2010;19:31-44. doi: 10.1159/000316895. Epub 2010 Jun 15. Adipose tissue and the reproductive axis: biological aspects. Hausman GJ(1), Barb CR. Author information: (1)USDA/ARS, Richard B. Russell Agriculture Research Center, Athens, GA, USA. gary.hausman@ars.usda.gov The discovery of leptin has clearly demonstrated a relationship between body fat and the neuroendocrine axis since leptin influences appetite and the reproductive axis. Since adipose tissue is a primary source of leptin, adipose tissue is no longer considered as simply a depot to store fat. Recent findings demonstrate that numerous other genes, i.e. neuropeptides, interleukins and other cytokines and biologically active substances such as leptin and insulin-like growth factors I and II, are also produced by adipose tissue, which could influence appetite and the reproductive axis. Targets of leptin in the hypothalamus include neuropeptide Y, proopiomelanocortin and kisspeptin. Transsynaptic connection of hypothalamic neurons to porcine adipose tissue may result in a direct influence of the hypothalamus on adipose tissue function. Nutritional signals such as leptin are detected by the central nervous system and translated by the neuroendocrine system into signals which ultimately regulates luteinizing hormone secretion. Furthermore, leptin directly affects gonadotropin-releasing hormone release from the hypothalamus, luteinizing hormone from the pituitary gland and ovarian follicular steroidogenesis. Although leptin is identified as a putative signal that links metabolic status and neuroendocrine control of reproduction, other adipocyte protein products may play key roles in regulating the reproductive axisin the pig. Copyright 2010 S. Karger AG, Basel. PMID: 20551666 [PubMed - indexed for MEDLINE] 1324. Endocr Dev. 2010;19:21-30. doi: 10.1159/000316894. Epub 2010 Jun 15. The emergence of adipocytes. Laharrague P(1), Casteilla L. Author information: (1)Laboratoire d'Hématologie, CHU Toulouse, Hôpital Rangueil, Toulouse, France. laharrague.p@chu-toulouse.fr In mammals, the adipose organ is composed of white adipocytes (primary site in energy storage) and of brown adipocytes (specialized in thermogenesis). Adipocytes arise from mesenchymal stem cells (MSCs) by a sequential pathway of differentiation. MSCs develop either from ectoderm or mesoderm and commit into different undifferentiated precursors, which upon the expression of key transcription factors enter a differentiation program to acquire their specific functions. When triggered by appropriate developmental cues, MSCs become committed to the adipocyte lineage. White adipocytes differentiate from various types of vascular cell types, probably located within the white adipose tissue itself. Brown adipocytes arise from myogenic precursors. The differentiation between white adipocyte and brown adipocyte lineages occurs in the earliest steps of the fetal development, and both phenotypes are acquired independently. A better knowledge of these differentiation pathways allows new therapeutic strategies for reconstruction of damaged conjunctive tissues and for the control or prevention of risks associated with obesity in humans. Copyright 2010 S. Karger AG, Basel. PMID: 20551665 [PubMed - indexed for MEDLINE] 1325. Endocr Dev. 2010;19:1-20. doi: 10.1159/000316893. Epub 2010 Jun 15. Human lipodystrophies: genetic and acquired diseases of adipose tissue. Capeau J(1), Magré J, Caron-Debarle M, Lagathu C, Antoine B, Béréziat V, Lascols O, Bastard JP, Vigouroux C. Author information: (1)INSERM, U938, CDR Saint-Antoine, Paris, France. jacqueline.capeau@inserm.fr Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications. Copyright 2010 S. Karger AG, Basel. PMCID: PMC3892722 PMID: 20551664 [PubMed - indexed for MEDLINE] 1326. Br J Sports Med. 2010 Jun;44(8):609-11. doi: 10.1136/bjsm.2010.074625. A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 9. Castell LM(1), Burke LM, Stear SJ, Pearce J, Borchers JR, Kaeding CC, Rawson ES, Shaw G. Author information: (1)University of Oxford, Green Templeton College, Oxford OX2 6HG, UK. lindy.castell@gtc.ox.ac.uk PMID: 20547670 [PubMed - indexed for MEDLINE] 1327. Proc Nutr Soc. 2010 Aug;69(3):324-32. doi: 10.1017/S0029665110001801. Epub 2010 Jun 14. Regulation of adipokine secretion by n-3 fatty acids. Moreno-Aliaga MJ(1), Lorente-Cebrián S, Martínez JA. Author information: (1)Department of Nutrition, Food Science, Physiology and Toxicology, University of Navarra, Pamplona, Spain. mjmoreno@unav.es Obesity leads to several chronic morbidities including type 2 diabetes, dyslipidaemia, atherosclerosis and hypertension, which are major components of the metabolic syndrome. White adipose tissue (WAT) metabolism and WAT-derived factors (fatty acids and adipokines) play an important role in the development of these metabolic disturbances. In fact, dysregulated adipokine secretion from the expanded WAT of obese individuals contributes to the development of systemic low-grade inflammation, insulin resistance and metabolic syndrome. The n-3 PUFA EPA and DHA have been widely reported to have protective effects in a range of chronic inflammatory conditions including obesity. In fact, n-3 PUFA have been shown to ameliorate low-grade inflammation in adipose tissue associated with obesity and up-regulate mitochondrial biogenesis and induce beta-oxidation in WAT in mice. Moreover, the ability of n-3 PUFA to regulate adipokine gene expression and secretion has been observed both in vitro and in vivo in rodents and human subjects. The present article reviews: (1) the physiological role of adiponectin, leptin and pre-B cell colony-enhancer factor/visfatin, three adipokines with immune-modulatory properties involved in the regulation of metabolism and insulin sensitivity and (2) the actions of n-3 PUFA on these adipokines focusing on the underlying mechanisms and the potential relationship with the beneficial effects of these fatty acids on obesity-associated metabolic disorders. It can be concluded that the ability of n-3 PUFA to improve obesity and insulin resistance conditions partially results from the modulation of WAT metabolism and the secretion of bioactive adipokines including leptin, adiponectin and visfatin. PMID: 20540825 [PubMed - indexed for MEDLINE] 1328. J Nutr Biochem. 2010 Nov;21(11):1015-32. doi: 10.1016/j.jnutbio.2010.01.005. Liver fatty acid-binding protein and obesity. Atshaves BP(1), Martin GG, Hostetler HA, McIntosh AL, Kier AB, Schroeder F. Author information: (1)Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA. While low levels of unesterified long chain fatty acids (LCFAs) are normal metabolic intermediates of dietary and endogenous fat, LCFAs are also potent regulators of key receptors/enzymes and at high levels become toxic detergents within the cell. Elevated levels of LCFAs are associated with diabetes, obesity and metabolic syndrome. Consequently, mammals evolved fatty acid-binding proteins (FABPs) that bind/sequester these potentially toxic free fatty acids in the cytosol and present them for rapid removal in oxidative (mitochondria, peroxisomes) or storage (endoplasmic reticulum, lipid droplets) organelles. Mammals have a large (15-member) family of FABPs with multiple members occurring within a single cell type. The first described FABP, liver-FABP (L-FABP or FABP1), is expressed in very high levels (2-5% of cytosolic protein) in liver as well as in intestine and kidney. Since L-FABP facilitates uptake and metabolism of LCFAs in vitro and in cultured cells, it was expected that abnormal function or loss of L-FABP would reduce hepatic LCFA uptake/oxidation and thereby increase LCFAs available for oxidation in muscle and/or storage in adipose. This prediction was confirmed in vitro with isolated liver slices and cultured primary hepatocytes from L-FABP gene-ablated mice. Despite unaltered food consumption when fed a control diet ad libitum, the L-FABP null mice exhibited age- and sex-dependent weight gain and increased fat tissue mass. The obese phenotype was exacerbated in L-FABP null mice pair fed a high-fat diet. Taken together with other findings, these data suggest that L-FABP could have an important role in preventing age- or diet-induced obesity. Copyright © 2010 Elsevier Inc. All rights reserved. PMCID: PMC2939181 PMID: 20537520 [PubMed - indexed for MEDLINE] 1329. Cell Immunol. 2010;264(1):7-17. doi: 10.1016/j.cellimm.2010.04.002. Epub 2010 Apr 8. Autologous stromal vascular fraction cells: a tool for facilitating tolerance in rheumatic disease. Ichim TE(1), Harman RJ, Min WP, Minev B, Solano F, Rodriguez JP, Alexandrescu DT, De Necochea-Campion R, Hu X, Marleau AM, Riordan NH. Author information: (1)Medistem Inc., San Diego, CA, USA. thomas.ichim@gmail.com Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immunologists. While knowledge of cellular and molecular mechanisms of this process has been increasing at an exponential rate, clinical progress has been minimal. To provide a mechanistic background of tolerogenesis, we overview common processes in the naturally occurring examples of: pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation. The case is made that an easily accessible byproduct of plastic surgery, the adipose stromal vascular fraction, contains elements directly capable of promoting tolerogenesis such as T regulatory cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells from this source provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. We discuss the application of this autologous cell source in the context of rheumatoid arthritis, concluding with some practical examples of its applications. 2010 Elsevier Inc. All rights reserved. PMID: 20537320 [PubMed - indexed for MEDLINE] 1330. Lupus. 2010 Oct;19(11):1302-6. doi: 10.1177/0961203310372938. Epub 2010 Jun 9. Primary antiphospholipid syndrome in premenopausal women: low vitamin D, high fat mass and maintained bone mineral mass. Paupitz JA(1), Freire de Carvalho J, Caparbo VF, Klack K, Pereira RM. Author information: (1)Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. The aim of this study was to analyze vitamin D levels and their association with bone mineral density and body composition in primary antiphospholipid syndrome. For this cross-sectional study 23 premenopausal women with primary antiphospholipid syndrome (Sapporo criteria) and 23 age- and race-matched healthy controls were enrolled. Demographic, anthropometric, clinical and laboratorial data were collected using clinical interview and chart review. Serum 25-hydroxyvitamin D levels, parathormone, calcium and 24-hour urinary calcium were evaluated in all subjects. Bone mineral density and body composition were studied by dual X-ray absorptiometry. The mean age of patients and controls was 33 years. Weight (75.61 [20.73] vs. 63.14 [7.34] kg, p = 0.009), body mass index (29.57 [7.17] vs. 25.35 [3.37] kg, p = 0.014) and caloric ingestion (2493 [1005.6] vs. 1990 [384.1] kcal/day, p = 0.03) were higher in PAPS than controls. All PAPS were under oral anticoagulant with INR within therapeutic range. Interestingly, biochemical bone parameters revealed lower levels of 25-hydroxyvitamin D [21.64 (11.26) vs. 28.59 (10.67) mg/dl, p = 0.039], serum calcium [9.04 (0.46) vs. 9.3 (0.46) mg/dl, p = 0.013] and 24-hour urinary calcium [106.55 (83.71) vs. 172.92 (119.05) mg/d, p = 0.027] in patients than in controls. Supporting these findings, parathormone levels were higher in primary antiphospholipid syndrome than in controls [64.82 (37.83) vs. 44.53 (19.62) pg/ml, p = 0.028]. The analysis of osteoporosis risk factors revealed that the two groups were comparable (p > 0.05). Lumbar spine, femoral neck, total femur and whole body bone mineral density were similar in both groups (p > 0.05). Higher fat mass [28.51 (12.93) vs. 20.01 (4.68) kg, p = 0.005] and higher percentage of fat [36.08 (7.37) vs. 31.23 (4.64)%, p = 0.010] were observed in PAPS in comparison with controls; although no difference was seen regarding lean mass. In summary, low vitamin D in primary antiphospholipid syndrome could be secondary to higher weight and fat mass herein observed most likely due to adipocyte sequestration. This weight gain may also justify the maintenance of bone mineral density even with altered biochemical bone parameters. PMID: 20534647 [PubMed - indexed for MEDLINE] 1331. Essays Biochem. 2010;47:53-67. doi: 10.1042/bse0470053. Mitochondrial proton and electron leaks. Jastroch M(1), Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Author information: (1)Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA. Mitochondrial proton and electron leak have a major impact on mitochondrial coupling efficiency and production of reactive oxygen species. In the first part of this chapter, we address the molecular nature of the basal and inducible proton leak pathways, and their physiological importance. The basal leak is unregulated, and a major proportion can be attributed to mitochondrial anion carriers, whereas the proton leak through the lipid bilayer appears to be minor. The basal proton leak is cell-type specific and correlates with metabolic rate. The inducible leak through the ANT (adenine nucleotide translocase) and UCPs (uncoupling proteins) can be activated by fatty acids, superoxide or lipid peroxidation products. The physiological role of inducible leak through UCP1 in mammalian brown adipose tissue is heat production, whereas the roles of non-mammalian UCP1 and its paralogous proteins, in particular UCP2 and UCP3, are not yet resolved. The second part of the chapter focuses on the electron leak that occurs in the mitochondrial electron transport chain. Exit of electrons prior to the reduction of oxygen to water at cytochrome c oxidase causes superoxide production. As the mechanisms of electron leak are crucial to understanding their physiological relevance, we summarize the mechanisms and topology of electron leak from complexes I and III in studies using isolated mitochondria. We also highlight recent progress and challenges of assessing electron leak in the living cell. Finally, we emphasize the importance of proton and electron leak as therapeutic targets in body mass regulation and insulin secretion. PMCID: PMC3122475 PMID: 20533900 [PubMed - indexed for MEDLINE] 1332. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):403-7. doi: 10.1097/MCO.0b013e32833a7737. Protein metabolic roles in treatment of obesity. Devkota S(1), Layman DK. Author information: (1)University of Chicago, Chicago, Illinois, USA. PURPOSE OF REVIEW: To understand the potential benefits of increased dietary protein during weight loss and the importance of distribution of high-quality protein at each meal. RECENT FINDINGS: Popular weight loss diets emphasize use of protein as a substitute for carbohydrates or fat to reduce insulin and minimize hunger and food cravings. These diets produce short-term weight loss, but long-term benefits remain obscured by failure to differentiate between outcomes of subject compliance and diet effectiveness. New molecular mechanisms have defined the benefits of protein as a meal threshold for the branched-chain amino acid leucine, which has been characterized as a unique signal regulator of muscle protein synthesis. Leucine consumed at 2.5 g triggers a postmeal anabolic response that protects metabolic active tissues during weight loss and increases loss of body fat. SUMMARY: Balanced daily distribution of protein with increased intake at breakfast and lunch protects metabolically active tissues including skeletal muscle during weight loss. PMID: 20531180 [PubMed - indexed for MEDLINE] 1333. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):371-6. doi: 10.1097/MCO.0b013e32833aabef. Adipose tissue remodeling in pathophysiology of obesity. Lee MJ(1), Wu Y, Fried SK. Author information: (1)Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University, School of Medicine, Boston, Massachusetts 02118, USA. PURPOSE OF REVIEW: Recent studies demonstrate that adipose tissue undergoes a continuous process of remodeling that is pathologically accelerated in the obese state. Contrary to earlier dogma, adipocytes die and are replaced by newly differentiated ones. This review will summarize recent advances of our knowledge of the mechanisms that regulate adipose tissue remodeling and highlight the influences of obesity, depot, and sex, as well as the relevance of rodent models to humans. RECENT FINDINGS: A substantial literature now points to the importance of dynamic changes in adipocyte and immune cell turnover, angiogenesis, and extracellular matrix remodeling in regulating the expandability and functional integrity of this tissue. In obesity, the macrophages are recruited, surrounding dead adipocytes and polarized toward an inflammatory phenotype. The number of dead adipocytes is closely associated with the pathophysiological consequences of obesity, including insulin resistance and hepatic steatosis. Further, there are substantial depot, sex and species differences in the extent of remodeling. SUMMARY: Adipose tissue undergoes a continuous remodeling process that normally maintains tissue health, but may spin out of control and lead to adipocyte death in association with the recruitment and activation of macrophages, and systemic insulin resistance. PMCID: PMC3235038 PMID: 20531178 [PubMed - indexed for MEDLINE] 1334. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):377-81. doi: 10.1097/MCO.0b013e32833bed6a. Adipose tissue lipolysis. Kolditz CI(1), Langin D. Author information: (1)Inserm, Unité 858, Obesity Research Laboratory, Rangueil Institute of Molecular Medicine (I2MR), IFR150, Toulouse, France. PURPOSE OF REVIEW: Adipose tissue lipolysis is a critical pathway for the maintenance of energy homeostasis through the degradation of triglycerides and the release of fatty acids into the circulation. The understanding of the cellular factors regulating triglyceride hydrolysis and the metabolic function of lipases has considerably expanded in the last few years, revealing an unexpected complexity. This review aims at describing recent discoveries related to the lipolytic pathway and its regulatory mechanisms. RECENT FINDINGS: Considerable progress has been made in understanding the role and the mechanisms of activation of the lipolytic enzymes. Recent discoveries have dramatically altered the view of adipose tissue lipolysis and highlighted the importance of additional molecular actors in regulating this process. Catecholamines, natriuretic peptides, and insulin are considered to be the major regulators of lipolysis in humans. However, autocrine/paracrine factors such as metabolites and prostaglandins may also participate in its regulation. SUMMARY: The manipulation of lipolysis has therapeutic potential in the metabolic disorders frequently associated with obesity. Unraveling the molecular events occurring during regulation of lipolysis may lead to novel therapeutic targets. PMID: 20531174 [PubMed - indexed for MEDLINE] 1335. Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E335-40. doi: 10.1152/ajpendo.00243.2010. Epub 2010 Jun 8. The metabolic coregulator RIP140: an update. Fritah A(1), Christian M, Parker MG. Author information: (1)Institute of Reproductive and Developmental Biology, Imperial College London, UK. RIP140 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis. PMID: 20530738 [PubMed - indexed for MEDLINE] 1336. Curr Stem Cell Res Ther. 2010 Dec;5(4):326-44. Mesenchymal stem cells: new approaches for the treatment of neurological diseases. Momin EN(1), Mohyeldin A, Zaidi HA, Vela G, Quiñones-Hinojosa A. Author information: (1)Department of Neurosurgery and Oncology, Brain Tumor Stem Cell Laboratory, The Johns Hopkins School of Medicine, Baltimore, MD 21231, USA. aquinon2@jhmi.edu Cellular therapies represent a new frontier in the treatment of neurological disease. Mesenchymal stem cells (MSCs), which can be harvested from bone marrow, adipose tissue, and umbilical cord blood, among many other sources, possess several qualities which may be used to treat diseases of the central nervous system. MSCs migrate to sites of malignancy, a property which may be used for the treatment of brain cancer. MSCs possess immunosuppressive properties, which may be used for the treatment of neurological disorders with an inflammatory etiology. Finally, MSCs restore injured neural tissue, a property which may be used for the treatment of neural injury. Approximately 23 clinical trials have been completed to date, with many more ongoing, and all have been listed in this review. The long-term safety of MSC-based therapies is not well established, and continues to be one major limitation to clinical translation. More broadly, only a small minority of clinical trials have employed rigorous designs that include prospective randomization, patients from multiple centers, clinically-relevant and reproducible endpoints, and adequate long-term follow-up. These limitations must be addressed before MSCs can enter widespread clinical use. Nevertheless, MSCs represent a promising new approach to treating diseases of the central nervous system that are traditionally associated with morbid outcomes. With additional pre-clinical and clinical studies that focus on their potential benefits as well as dangers, MSCs may one day find translation to clinical use in the setting of neurological disease. PMID: 20528757 [PubMed - indexed for MEDLINE] 1337. Facial Plast Surg. 2010 Aug;26(3):252-9. doi: 10.1055/s-0030-1254336. Epub 2010 Jun 3. Volumetric rejuvenation of the periorbital region. Glasgold M(1), Lam SM, Glasgold R. Author information: (1)Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA. drmark@glasgoldgroup.com Volumetric rejuvenation of the periorbital region is based on an analysis of the aesthetics of the attractive youthful eye contrasted with the typical characteristics of aging. Traditional rejuvenation techniques emphasized fat and skin removal leading to "done" appearing results. The incorporation of volume with these techniques based on the specific analysis of volume loss produces more natural appearing true rejuvenation. PMID: 20524173 [PubMed - indexed for MEDLINE] 1338. Ophthal Plast Reconstr Surg. 2010 Jul-Aug;26(4):273-6. doi: 10.1097/IOP.0b013e3181bf24db. Exposed porous orbital implants treated with simultaneous secondary implant and dermis fat graft. Lee BJ(1), Lewis CD, Perry JD. Author information: (1)Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. PURPOSE: To describe a technique for simultaneous secondary orbital implantation and dermis fat graft placement for exposed porous implants with significant conjunctival insufficiency. DESIGN: Retrospective review of 4 consecutive cases. METHODS: Charts were reviewed for type and size of exposed porous implant, size of conjunctival defect, history of previous reconstruction for exposure, size and type of implant placed, follow-up interval, complications, ability to retain prosthesis, and cosmesis. RESULTS: Four patients underwent simultaneous dermis fat graft placement and secondary implantation for exposed and completely avascular orbital implants. The rectus muscles were advanced over the new implant to act as the host bed for the dermis fat graft. All patients tolerated a new prosthesis well, with adequate motility and cosmesis. CONCLUSIONS: Simultaneous secondary implantation and dermis fat graft placement may adequately address avascular porous implant exposure with significant conjunctival insufficiency. PMID: 20523255 [PubMed - indexed for MEDLINE] 1339. Endocr Rev. 2010 Oct;31(5):663-79. doi: 10.1210/er.2009-0046. Epub 2010 Jun 2. Insulin action in hyperthyroidism: a focus on muscle and adipose tissue. Mitrou P(1), Raptis SA, Dimitriadis G. Author information: (1)Hellenic National Center for Research, Prevention, and Treatment of Diabetes Mellitus and Its Complications, 10675 Athens, Greece. Hyperthyroidism leads to an enhanced demand for glucose, which is primarily provided by increased rates of hepatic glucose production due to increased gluconeogenesis (in the fasting state) and increased Cori cycle activity (in the late postprandial and fasting state). Adipose tissue lipolysis is increased in the fasting state, resulting in increased production of glycerol and nonesterified fatty acids. Under these conditions, increased glycerol generated by lipolysis and increased amino acids generated by proteolysis are used as substrates for gluconeogenesis. Increased nonesterified fatty acid levels are necessary to stimulate gluconeogenesis and provide substrate for oxidation in other tissues (such as muscle). In the postprandial period, insulin-stimulated glucose uptake by the skeletal muscle has been found to be normal or increased, mainly due to increased blood flow. Under hyperthyroid conditions, insulin-stimulated rates of glycogen synthesis in skeletal muscle are decreased, whereas there is a preferential increase in the rates of lactate formation vs. glucose oxidation leading to increased Cori cycle activity. In hyperthyroidism, the Cori cycle could be considered as a large substrate cycle; by maintaining a high flux through it, a dynamic buffer of glucose and lactate is provided, which can be used by other tissues as required. Moreover, lipolysis is rapidly suppressed to normal after the meal to facilitate the disposal of glucose by the insulin-resistant muscle. This ensures the preferential use of glucose when available and helps to preserve fat stores. PMID: 20519325 [PubMed - indexed for MEDLINE] 1340. Cas Lek Cesk. 2010;149(4):155-9. [Adipose tissue blood flow and metabolic syndrome]. [Article in Czech] Sotorník R(1). Author information: (1)Univerzita Karlova v Praze, 3. lékarská fakulta, II. interní klinika FNKV, Praha. sotornik@yahoo.com Worldwide growth of obesity and prevalence of type 2 diabetes mellitus reach the extent of a pandemy and represent a considerable medical and economic problem. An attention devoted to adipose tissue has led to the shift in general perception of its importance. It becomes evident that adipose tissue is not by far only an energy store with thermal and mechanical protection of other organs and body. A number of important functions in intermediary metabolism and hormonal interactions with other tissues have been disclosed. Metabolic flexibility of adipose tissue represents an essential protection against undesirable effects of excessive energy intake. Nevertheless, after exceeding of its physiological capacity adipose tissue becomes an important cause of insulin resistance, oxidative stress and a number of other derangements leading to atherosclerosis progression and increase of cardiovascular morbidity and mortality. Not only adipocytes but also stromal cells and vascular bed participate in the physiological and pathological functions of adipose tissue. Adequate regulation of adipose tissue blood flow ensures communication with other systems and appropriate reactions to energy needs of the organism. Disturbances in adipose tissue blood flow evolve at early stages of obesity and participate in the worsening of metabolic syndrome. PMID: 20518247 [PubMed - indexed for MEDLINE] 1341. Discov Med. 2010 May;9(48):462-7. Adipostatic regulation of motivation and emotion. Davis JF(1). Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45237, USA. davisjo@ucmail.uc.edu The proper maintenance of body weight and mood are two of the most prevalent health issues present in society today. Obese humans display higher levels of mood-related disorders and the causality of such an association is unknown. A common feature of obesity is the imbalance of regulatory hormones which normally act to maintain stable energy balance and body weight. The adiposity hormone leptin is one such signal elevated in obesity with the capacity to dampen feeding behavior through action on brain circuits which regulate appetite and metabolism. Recent evidence suggests that leptin may regulate motivation through its actions within brain reward circuitry. In addition, leptin signaling within central nervous system regions that regulate cognition and emotion elicits anti-depressant like effects. Together, these data indicate that leptin may regulate the decreased motivation and mood present in obesity and depression. This review describes the capacity of leptin to regulate motivation and depression through actions within brain circuits that modulate effort-based behavior and emotion, respectively. PMID: 20515615 [PubMed - indexed for MEDLINE] 1342. Nat Rev Drug Discov. 2010 Jun;9(6):465-82. doi: 10.1038/nrd3138. Cellular bioenergetics as a target for obesity therapy. Tseng YH(1), Cypess AM, Kahn CR. Author information: (1)Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA. yu-hua.tseng@joslin.harvard.edu Obesity develops when energy intake exceeds energy expenditure. Although most current obesity therapies are focused on reducing calorific intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis - the physiological process whereby energy is dissipated in mitochondria of brown fat and skeletal muscle in the form of heat in response to external stimuli. There have been significant recent advances in identifying the factors that control the development and function of these tissues, and in techniques to measure brown fat in human adults. In this article, we integrate these developments in relation to the classical understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure. PMCID: PMC2880836 PMID: 20514071 [PubMed - indexed for MEDLINE] 1343. Int J Obes (Lond). 2010 Nov;34(11):1559-65. doi: 10.1038/ijo.2010.105. Epub 2010 Jun 1. Zinc-α2-glycoprotein: an adipokine modulator of body fat mass? Bing C(1), Mracek T, Gao D, Trayhurn P. Author information: (1)Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, Liverpool, UK. bing@liverpool.ac.uk The importance of white adipose tissue in the control of energy balance is now firmly recognized. In addition to fuel storage, adipocytes secrete an array of proteins factors (adipokines), which regulate multiple physiological and metabolic processes as well as influence body fat accumulation. Zinc-α2-glycoprotein (ZAG), a lipid mobilizing factor initially characterized as a tumor product associated with cachexia, has recently been identified as a novel adipokine. Although the exact role of ZAG in adipose tissue remains to be clarified, there is evidence that ZAG expression appears to be inversely related to adiposity, being upregulated in cachexia whereas reduced in obesity. Investigations on the regulation of ZAG give insights into its potential function in adipose tissue with a link to lipid mobilization and an anti-inflammatory action. Recent work shows that ZAG stimulates adiponectin secretion by human adipocytes. Data from genetic studies suggest that ZAG may be a candidate gene for body weight regulation; this is supported by the demonstration that ZAG-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing ZAG exhibit weight loss. The present review summarizes these new perspectives of ZAG and the potential mechanisms by which it might modulate adipose tissue mass and function. PMID: 20514048 [PubMed - indexed for MEDLINE] 1344. Semin Nucl Med. 2010 Jul;40(4):283-93. doi: 10.1053/j.semnuclmed.2010.02.001. Altered biodistribution on FDG-PET with emphasis on brown fat and insulin effect. Cohade C(1). Author information: (1)Department of Nuclear Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. ccohade2000@yahoo.com (18)F-fluorodeoxyglucose (FDG) is the radiotracer used in the vast majority of positron emission tomography (PET) cancer studies. FDG is a powerful radiotracer that provides valuable data in many cancer types. Normal FDG biodistribution is easily identified. In the PET-only era, physiological uptake provided important anatomical landmarks. However, the normal biodistribution of FDG is often variable and can be altered by intrinsic or iatrogenic factors. Recognizing these patterns of altered biodistribution is important for optimal FDG-PET interpretation. Altered FDG uptake in muscles, brown adipose tissue, bone marrow, the urinary tract, and the bowel is demonstrated in a significant proportion of patients, which can hide underlying malignant foci or mimic malignant lesions. The introduction of PET/computed tomography revolutionized PET imaging, bringing much-needed anatomical information. This modality allowed better characterization of some types of uptake, particularly brown adipose tissue FDG uptake. Different approaches to minimize interference from altered FDG biodistribution should be considered when performing PET scans. Otherwise, careful review and correlation of metabolic (FDG-PET) and anatomical (computed tomography) data should be performed to accurately characterize the foci of increased FDG uptake. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20513450 [PubMed - indexed for MEDLINE] 1345. J Cell Biochem. 2010 Jun 1;110(3):564-72. doi: 10.1002/jcb.22598. Cellular models for understanding adipogenesis, adipose dysfunction, and obesity. Armani A(1), Mammi C, Marzolla V, Calanchini M, Antelmi A, Rosano GM, Fabbri A, Caprio M. Author information: (1)Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy. Erratum in J Cell Biochem. 2010 Nov 1;111(4):1074. White adipose tissue (WAT) is no longer considered a depot for energy storage in the form of triglycerides, but is a secretory organ that releases factors, known as adipokines, capable of regulating several physiological processes. Alteration of WAT function with subsequent dysfunctional expression and secretion of adipokines plays a key role in the pathogenesis of obesity, diabetes, and other metabolic diseases. For this reason, a deeper understanding of the molecular mechanisms regulating adipocyte function is deemed necessary for planning strategies to treat and prevent obesity and its metabolic complications. This review examines cell culture models currently available for studying adipocyte biology. We focus on advantages, disadvantages and main differences between established preadipocyte cell lines and primary preadipocyte cultures. We revise protocols used to promote adipocyte differentiation and mature adipocytes dedifferentiation into preadipocytes. Finally, we briefly describe co-cultures of adipocytes with other cell types and three-dimensional adipocyte culture systems. These models allow investigation of cell-cell interactions with the cross-talk physiologically occurring between adipocytes and other cell types residing within or outside adipose tissue. (c) 2010 Wiley-Liss, Inc. PMID: 20512917 [PubMed - indexed for MEDLINE] 1346. Nutrients. 2010 Jun;2(6):586-98. doi: 10.3390/nu2060586. Epub 2010 May 28. Postprandial energy metabolism in the regulation of body weight: is there a mechanistic role for dietary calcium? Soares MJ(1), She-Ping-Delfos WL. Author information: (1)Curtin Health Innovation Research Institute, Program of Nutrition, School of Public Health, Curtin University of Technology, GPO Box U 1987, Perth WA 6845, Australia. m.soares@curtin.edu.au There has been much interest in the mechanisms by which calcium may attenuate weight gain or accelerate body fat loss. This review focuses on postprandial energy metabolism and indicates that dietary calcium increases whole body fat oxidation after single and multiple meals. There is, as yet, no conclusive evidence for a greater diet induced thermogenesis, an increased lipolysis or suppression of key lipogenic enzyme systems. There is however convincing evidence that higher calcium intakes promote a modest energy loss through increased fecal fat excretion. Overall, there is a role for dietary calcium in human energy metabolism. Future studies need to define threshold intakes for metabolic and gastrointestinal outcomes. PMCID: PMC3257665 PMID: 22254043 [PubMed - indexed for MEDLINE] 1347. Mediators Inflamm. 2010;2010:513948. doi: 10.1155/2010/513948. Epub 2010 May 23. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Fain JN(1). Author information: (1)Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA. jfain@uthsc.edu This paper considers the role of putative adipokines that might be involved in the enhanced inflammatory response of human adipose tissue seen in obesity. Inflammatory adipokines [IL-6, IL-10, ACE, TGFbeta1, TNFalpha, IL-1beta, PAI-1, and IL-8] plus one anti-inflammatory [IL-10] adipokine were identified whose circulating levels as well as in vitro release by fat are enhanced in obesity and are primarily released by the nonfat cells of human adipose tissue. In contrast, the circulating levels of leptin and FABP-4 are also enhanced in obesity and they are primarily released by fat cells of human adipose tissue. The relative expression of adipokines and other proteins in human omental as compared to subcutaneous adipose tissue as well as their expression in the nonfat as compared to the fat cells of human omental adipose tissue is also reviewed. The conclusion is that the release of many inflammatory adipokines by adipose tissue is enhanced in obese humans. PMCID: PMC2874930 PMID: 20508843 [PubMed - indexed for MEDLINE] 1348. Mediators Inflamm. 2010;2010:367838. doi: 10.1155/2010/367838. Epub 2010 May 25. Functional food targeting the regulation of obesity-induced inflammatory responses and pathologies. Hirai S(1), Takahashi N, Goto T, Lin S, Uemura T, Yu R, Kawada T. Author information: (1)Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan. Obesity is associated with a low-grade systemic chronic inflammatory state, characterized by the abnormal production of pro- and anti-inflammatory adipocytokines. It has been found that immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Obesity-induced inflammation is considered a potential mechanism linking obesity to its related pathologies, such as insulin resistance, cardiovascular diseases, type-2 diabetes, and some immune disorders. Therefore, targeting obesity-related inflammatory components may be a useful strategy to prevent or ameliorate the development of such obesity-related diseases. It has been shown that several food components can modulate inflammatory responses in adipose tissue via various mechanisms, some of which are dependent on peroxisome proliferator-activated receptor gamma (PPARgamma), whereas others are independent on PPARgamma, by attenuating signals of nuclear factor-kappaB (NF-kappaB) and/or c-Jun amino-terminal kinase (JNK). In this review, we introduce the beneficial effects of anti-inflammatory phytochemicals that can help prevent obesity-induced inflammatory responses and pathologies. PMCID: PMC2876247 PMID: 20508825 [PubMed - indexed for MEDLINE] 1349. Mediators Inflamm. 2010;2010:219583. doi: 10.1155/2010/219583. Epub 2010 May 20. Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Fuentes L(1), Roszer T, Ricote M. Author information: (1)Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain. Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia. PMCID: PMC2874923 PMID: 20508742 [PubMed - indexed for MEDLINE] 1350. J Cell Biochem. 2010 Sep 1;111(1):14-9. doi: 10.1002/jcb.22678. The IGF-I regulatory system and its impact on skeletal and energy homeostasis. Kawai M(1), Rosen CJ. Author information: (1)Center for Translational Research, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA. Erratum in J Cell Biochem. 2012 Apr;113(4):1447. Insulin-like growth factor (IGF)-I is important in the acquisition and maintenance of both soft and hard tissues. Skeletal remodeling requires energy and recent work has demonstrated that bone can influence insulin sensitivity and thereby regulate metabolic processes. New insights from mouse models into the role of IGF-binding proteins (IGFBPs) as more than mere depots for the IGFs has reignited investigations into the metabolic targets influenced by the IGF regulatory system and the pathways that link bone to adipose tissue. Although there remains continued uncertainty about the relative balance between the effects of circulating versus tissue IGF-I actions, the role of the IGFBPs has been redefined both as modulators of IGF-I action and as independent signaling factors. This review highlights several recent findings that shed new light on the physiologic role of the IGF regulatory system and its influence on skeletal and fat metabolism. (c) 2010 Wiley-Liss, Inc. PMCID: PMC3276304 PMID: 20506515 [PubMed - indexed for MEDLINE] 1351. Eur J Nucl Med Mol Imaging. 2010 Oct;37(10):1854-60. doi: 10.1007/s00259-010-1485-2. Epub 2010 May 27. Seasonal variation in the effect of constant ambient temperature of 24 degrees C in reducing FDG uptake by brown adipose tissue in children. Zukotynski KA(1), Fahey FH, Laffin S, Davis R, Treves ST, Grant FD, Drubach LA. Author information: (1)Department of Imaging, Division of Nuclear Medicine, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. kzukotynski@partners.org PURPOSE: It has been shown that warming patients prior to and during (18)F-FDG uptake by controlling the room temperature can decrease uptake by brown adipose tissue (BAT). The aim of this study is to determine if this effect is subject to seasonal variation. METHODS: A retrospective review was conducted of all patients referred for whole-body (18)F-FDG PET between December 2006 and December 2008. After December 2007, all patients were kept in the PET injection room at a constant 24 degrees C for 30 min before and until 1 h following FDG administration. Patients over 22 years of age and those who received pre-medication known to reduce FDG uptake by BAT were excluded. One hundred and three patients were warmed to 24 degrees C prior to scanning. The number of patients showing uptake by BAT in this group was compared to a control group of 99 patients who underwent PET prior to December 2007 when the injection room temperature was 21 degrees C. RESULTS: Uptake by BAT occurred in 9% of studies performed after patient warming (24 degrees C), compared to 27% of studies performed on the control group (21 degrees C) (p < 0.00001). The effect of warming on decreasing FDG accumulation in BAT was statistically significant in the winter (p < 0.005) and summer (p < 0.001). However, in the spring and autumn, though the effect of warming on decreasing FDG accumulation in BAT was evident, it was not statistically significant (p > 0.05). CONCLUSION: Maintaining room temperature at a constant 24 degrees C for 30 min prior to and 1 h after IV tracer administration significantly decreases FDG uptake by BAT in children. This effect is greatest in the summer and winter. PMID: 20505932 [PubMed - indexed for MEDLINE] 1352. Stem Cell Res Ther. 2010 Mar 15;1(1):2. doi: 10.1186/scrt2. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Ghannam S(1), Bouffi C, Djouad F, Jorgensen C, Noël D. Author information: (1)Inserm, U844, Montpellier F-34091, France. soufiane.ghannam@inserm.fr Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that are isolated from many adult tissues, in particular from the bone marrow and adipose tissue. Along with their capacity for differentiating into cells of mesodermal lineage, such as adipocytes, osteoblasts and chondrocytes, these cells have also generated great interest for their ability to display immunomodulatory capacities. Indeed, a major breakthrough came with the finding that they are able to induce peripheral tolerance, suggesting they may be used as therapeutic tools in immune-mediated disorders. The present review aims at discussing the current knowledge on the targets and mechanisms of MSC-mediated immunosuppression as well as the potential use of MSCs as modulators of immune responses in a variety of diseases related to alloreactive immunity or autoimmunity. PMCID: PMC2873698 PMID: 20504283 [PubMed - indexed for MEDLINE] 1353. Radiology. 2010 Jun;255(3):899-908. doi: 10.1148/radiol.10091547. T2 mapping in Duchenne muscular dystrophy: distribution of disease activity and correlation with clinical assessments. Kim HK(1), Laor T, Horn PS, Racadio JM, Wong B, Dardzinski BJ. Author information: (1)Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA. Erratum in Radiology. 2010 Sep;256(3):1016. PURPOSE: To analyze T2 maps of pelvic and thigh muscles in Duchenne muscular dystrophy (DMD), to identify the most severely affected muscle, and to correlate the T2 of muscle with the grade of fatty infiltration at nonquantitative magnetic resonance (MR) imaging and results of clinical assessment. MATERIALS AND METHODS: This prospective study was HIPAA compliant and was approved by the institutional review board; written consent was obtained from all participants' parents or guardians. Thirty-four boys with DMD (mean age, 8.4 years) were evaluated clinically (age, clinical function score, timed Gower score, time to run 30 feet, and serum creatine kinase [CK] level) and with nonquantitative MR imaging and axial T2 mapping from the iliac crest to the mid thigh. The T2 maps and mean T2 of 18 muscles in the pelvis and thighs were analyzed to identify the most severely involved muscle. The amount of fatty infiltration was assigned a grade of zero to four for all pelvic and thigh muscles by using T1-weighted nonquantitative MR images. The Spearman correlation coefficients model was used to correlate the mean T2, nonquantitative MR imaging score and clinical assessments. RESULTS: The gluteus maximus muscle had the highest T2. The mean T2 for this muscle showed a significant correlation with the nonquantitative MR imaging score for fatty infiltration (P < .001) and with all clinical assessments except CK level. CONCLUSION: Gluteus maximus muscles are most severely affected in patients with DMD. The T2 of the gluteus maximus muscle can be used as a quantitative and objective measure of disease severity. Copyright RSNA, 2010 PMID: 20501727 [PubMed - indexed for MEDLINE] 1354. Postepy Hig Med Dosw (Online). 2010 May 7;64:212-9. [The role of adipokines and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease]. [Article in Polish] Orlik B(1), Handzlik G, Olszanecka-Glinianowicz M. Author information: (1)Studenckie Koło Naukowe przy Katedrze Patofizjologii Slaskiego Uniwersytetu Medycznego w Katowicach. Nonalcoholic fatty liver disease (NAFLD) develops in 17-33% of the population of developed countries. The incidence of NAFLD is constantly growing due to the increasing prevalence of obesity. It is estimated that one third of subjects with NAFLD suffer from nonalcoholic steatohepatitis (NASH) and 15% of them develop liver cirrhosis within a five-year period. In recent years this important complication of obesity became the subject of numerous studies. It, the pathogenesis of NAFLD is still unclear. A key role in the development of this disease was attributed to insulin resistance. Hormones and cytokines produced by adipose tissue called adipokines may be a link between obesity, insulin resistance, and NAFLD. However, it is well known that increased levels of adipokines such as TNF-alpha, IL-6, and resistin and a decreased level of adiponectin augment inflammation in the liver. Further studies are necessary to explain the roles of leptin, visfatin, retinol binding protein-4, omentin, and vaspin in the pathogenesis of NAFLD. The aim this paper is to introduce new areas of study on the pathogenesis of NAFLD. PMID: 20498498 [PubMed - indexed for MEDLINE] 1355. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):382-90. doi: 10.1097/MCO.0b013e32833aabd9. Muscle insulin resistance: assault by lipids, cytokines and local macrophages. Kewalramani G(1), Bilan PJ, Klip A. Author information: (1)The Hospital for Sick Children, Toronto, Ontario, Canada. PURPOSE OF REVIEW: The present review outlines possible mechanisms by which high fatty acids, associated with high-fat diet and obesity, impose insulin resistance on glucose uptake into skeletal muscle. RECENT FINDINGS: It is well established that muscle insulin resistance arises in conditions of high-fatty acid availability, and correlates with accumulation of triglycerides within skeletal muscle fibres. However, it is debated whether triglycerides or other lipid metabolites such as diacylglycerols and ceramides are directly responsible. These lipid metabolites can activate serine kinases that impair insulin signalling. Accumulation of acylcarnitines and reactive oxygen species could be additional causative agents of insulin resistance. Further, the precise defects in insulin signalling in muscle caused by high intramuscular lipid (i.e. lipotoxicity) remain unclear. In parallel, proinflammatory activation within the adipose tissue of obese and high-fat fed animals or humans causes muscle insulin resistance, and is ascribed to circulating inflammatory cytokines. Recent evidence also shows proinflammatory macrophages infiltrating muscle tissue and/or intermuscular adipose tissue, and there is growing evidence that fatty acids trigger macrophages to secrete factors that directly impair insulin actions. These factors are postulated to activate stress-signalling pathways in muscle that act on the same insulin-signalling components affected by lipotoxicity. SUMMARY: Altered intramuscular lipid metabolism, circulating cytokines, and inflammatory macrophage infiltration of muscle tissue have been recently linked to muscle insulin resistance provoked by fatty acids. Each is analysed separately in this review, but they may act simultaneously and synergistically to render skeletal muscle insulin-resistant. PMID: 20495453 [PubMed - indexed for MEDLINE] 1356. Biochem Biophys Res Commun. 2010 May 21;396(1):101-4. doi: 10.1016/j.bbrc.2010.02.165. Fat cell turnover in humans. Arner P(1), Spalding KL. Author information: (1)Department of Medicine, Karolinska, University Hospital, SE-14186 Stockholm, Sweden. Peter.Arner@ki.se Obesity is a condition where excess body fat accumulates to such an extent that one's health may be affected. Owing to the cardiovascular and metabolic disorders associated with obesity, and the epidemic of obesity facing most countries today, life expectancy in the developed world may start to decrease for the first time in recent history. Other conditions, such as anorexia nervosa and cachexia, are characterised by subnormal levels of adipose tissue and as with obesity lead to morbidity and mortality. Given the significant personal and economic costs of these conditions and their increasing prevalence in society, understanding the factors that determine the fat mass is therefore of prime interest and may lead to effective treatments and/or interventions for these disorders. Fat mass can be regulated in two ways. The lipid filling of pre-existing fat cells could be altered and the number of fat cells could be changed by the generation of new fat cells or the dying of old ones (i.e. adipocyte turnover). This review summarizes what is known about fat cell turnover in humans and the potential clinical implications. 2010 Elsevier Inc. All rights reserved. PMID: 20494119 [PubMed - indexed for MEDLINE] 1357. Trends Mol Med. 2010 Jun;16(6):247-56. doi: 10.1016/j.molmed.2010.04.002. Epub 2010 May 20. Regulatory T cells in obesity: the leptin connection. Matarese G(1), Procaccini C, De Rosa V, Horvath TL, La Cava A. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy. gmatarese@napoli.com Studies to understand the pathogenesis of obesity have revealed mediators that are responsible for the control of food intake and metabolism at the hypothalamic level. However, molecular insight explaining the link between obesity and low-degree chronic inflammation remains elusive. The adipocyte-derived hormone leptin, and thereby the nutritional status, could control immune self-tolerance by affecting regulatory T (Treg) cell responsiveness and function. Furthermore, resident Treg cells, which are capable of modulating metabolism and glucose homeostasis, are abundant in adipose tissue. Here, we provide an update on recent findings relating Treg cells to obesity and discuss how the intricate network of interactions among leptin, Treg cells and adipose tissue might provide new strategies for therapeutic interventions. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20493774 [PubMed - indexed for MEDLINE] 1358. J Gastroenterol Hepatol. 2010 Apr;25(4):672-90. doi: 10.1111/j.1440-1746.2010.06253.x. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. Larter CZ(1), Chitturi S, Heydet D, Farrell GC. Author information: (1)Australian National University Medical School, Australia. The strong relationship between over-nutrition, central obesity, insulin resistance/metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over-nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over-nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non-alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over-nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same 'metabolic movers' that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver. Which lipids and how they cause injury, inflammation and fibrosis will be discussed in part two. PMID: 20492324 [PubMed - indexed for MEDLINE] 1359. J Food Sci. 2010 Jan-Feb;75(1):R1-8. doi: 10.1111/j.1750-3841.2009.01396.x. Allied industry approaches to alter intramuscular fat content and composition in beef animals. Dodson MV(1), Jiang Z, Chen J, Hausman GJ, Guan LL, Novakofski J, Thompson DP, Lorenzen CL, Fernyhough ME, Mir PS, Reecy JM. Author information: (1)Dept. of Animal Science, Washington State Univ., Pullman, WA 99164, USA. dodson@wsu.edu Biochemical and biophysical research tools are used to define the developmental dynamics of numerous cell lineages from a variety of tissues relevant to meat quality. With respect to the adipose cell lineage, much of our present understanding of adipogenesis and lipid metabolism was initially determined through the use of these methods, even though the in vitro or molecular environments are far removed from the tissues of meat animals. This concise review focuses on recent cellular and molecular biology-related research with adipocytes, and how the research might be extended to the endpoint of altering red meat quality. Moreover, economic and policy impacts of such in animal production regimens is discussed. These issues are important, not only with respect to palatability, but also to offer enhanced health benefits to the consumer by altering content of bioactive components in adipocytes. PMID: 20492190 [PubMed - indexed for MEDLINE] 1360. J Biomed Biotechnol. 2010;2010:182581. doi: 10.1155/2010/182581. Epub 2010 May 13. Dielectrophoresis: a review of applications for stem cell research. Pethig R(1), Menachery A, Pells S, De Sousa P. Author information: (1)Institute for Integrated Micro and Nano Systems, Joint Research Institute for Integrated Systems, School of Engineering, The University of Edinburgh, Edinburgh EH9 3JF, UK. ron.pethig@ed.ac.uk Dielectrophoresis can discriminate distinct cellular identities in heterogeneous populations, and monitor cell state changes associated with activation and clonal expansion, apoptosis, and necrosis, without the need for biochemical labels. Demonstrated capabilities include the enrichment of haematopoetic stem cells from bone marrow and peripheral blood, and adult stem cells from adipose tissue. Recent research suggests that this technique can predict the ultimate fate of neural stem cells after differentiation before the appearance of specific cell-surface proteins. This review summarises the properties of cells that contribute to their dielectrophoretic behaviour, and their relevance to stem cell research and translational applications. PMCID: PMC2871555 PMID: 20490279 [PubMed - indexed for MEDLINE] 1361. Curr Opin Pediatr. 2010 Aug;22(4):478-84. doi: 10.1097/MOP.0b013e32833a8d6e. The role and importance of brown adipose tissue in energy homeostasis. Cypess AM(1), Kahn CR. Author information: (1)Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA. PURPOSE OF REVIEW: Children and adults have two major types of adipocytes, which represent the predominant cells in white adipose tissue, which is involved in energy storage, and brown adipose tissue (BAT), which is responsible for thermogenesis and energy expenditure. This review discusses BAT physiology and evaluates the recent discoveries regarding its development, identification, and function. RECENT FINDINGS: Last year, multiple independent research teams using combined PET and computed tomography imaging, immunohistochemistry, and gene and protein expression have proven conclusively that adult humans have functional BAT. In parallel, basic studies defined BAT origins, its transcriptional regulation, and the role of hormones in BAT growth and activation. These methods have begun to be applied to children to understand pediatric BAT anatomy and physiology. SUMMARY: Adult humans have functional BAT, which plays a role in energy balance. BAT is more prevalent in children, suggesting an even greater physiological role than that seen in adults. Future studies will identify safe ways to quantify BAT mass and activity and which interventions might be used to increase BAT mass, thermogenesis, or both to treat obesity. PMCID: PMC3593062 PMID: 20489634 [PubMed - indexed for MEDLINE] 1362. Stem Cells Dev. 2010 Oct;19(10):1449-70. doi: 10.1089/scd.2010.0140. Human bone marrow and adipose tissue mesenchymal stem cells: a user's guide. Mosna F(1), Sensebé L, Krampera M. Author information: (1)Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, Policlinico G.B. Rossi-University of Verona, Verona, Italy. Mesenchymal stem cells (MSCs) are adult stem cells that hold great promise in the field of regenerative medicine. They can be isolated from almost any tissue of the body and display, after expansion, very similar properties and minor differences, probably due to their microenvironment of origin. Expansion in vitro can be obtained in cytokine-free, serum-enriched media, as well as in serum-free, basic fibroblast growth factor-enriched media. A detailed immunophenotypic analysis is required to test the purity of the preparation, but no unique distinguishing marker has been described as yet. Functional assays, that is, differentiation studies in vitro, are needed to prove multilineage differentiation of expanded cells, and demonstration of pluripotency is necessary to identify most immature precursors. MSCs show powerful immunomodulative properties toward most of the cells of the immune system: this strengthens the theoretical rationale for their use also in an allogeneic setting across the major histocompatibility complex (MHC) immunological barriers. Systemic intravenous injection and local use have been tried: after systemic injection, MSCs show a high degree of chemotaxis based on pro-inflammatory cytokines, and localize at inflamed and neoplastic tissues; local regeneration has been improved using synthetic, as well as organic scaffolds. On the other hand, inadequate heterotopic in vivo differentiation and neoplastic transformation are potential risks of this form of cell therapy, even if evidence of this sort has been collected only from studies in mice, and generally after prolonged in vitro expansion. This review tries to provide a detailed technical overview of the methods used for human bone-marrow (BM)-derived and adipose-tissue (AT)-derived MSC isolation, in vitro expansion, and characterization for tissue repair. We chose to use BM-MSCs as a model to describe techniques that have been used for MSC isolation and expansion from very different sources, and AT-MSCs as an example of a reliable and increasingly common alternative source. PMID: 20486777 [PubMed - indexed for MEDLINE] 1363. Arq Bras Endocrinol Metabol. 2010 Mar;54(2):150-7. Obesity, diabetes mellitus and last but not least, osteoporosis. Paula FJ(1), Rosen CJ. Author information: (1)Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil. Knowledge about the influence of bone on intermediary metabolism corresponds to a developing area that has gained prominence. The old concept of bone and adipose tissues as inert metabolic tissues, with minor contributions to metabolic adaptations has been reconsidered in light of findings that bone is involved in the development of insulin sensitivity. Similarly adipose tissue exerts important influences on bone mass development and maintenance. Moreover, the use of drugs in the treatment of metabolic disorders such as diabetes mellitus can impact bone metabolism. These networks linking osteoporosis to obesity and diabetes mellitus have reinvigorated investigations in the pathophysiology of osteoporosis. The present review examines this aspect and calls attention to health care providers and potential treatments of skeletal disorder. PMID: 20485903 [PubMed - indexed for MEDLINE] 1364. Minerva Gastroenterol Dietol. 2010 Jun;56(2):169-79. Obesity and the risk of severe acute pancreatitis. Evans AC(1), Papachristou GI, Whitcomb DC. Author information: (1)College of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Acute pancreatitis is an acute inflammatory response to pancreatic injury. In humans, the magnitude of the response and complications are highly variable and unpredictable. Recent clinical studies demonstrate that all major complications are more common and more severe in patients who are obese. This raises the question of how adipose tissue interacts with the immune response to worsen the severity of acute pancreatitis. Here we review the results of a series of new studies focusing on various fat-associated cytokines (adipokines) that are produced and released in proportion to the amount of visceral adipose tissue in the body. The primary adipokines that have been studied in acute pancreatitis include adiponectin, leptin, visfatin, resistin, and adipose tissue related MCP-1, TNF-a and IL-6. These new data provide strong evidence that susceptibility and severity in acute pancreatitis are associated with a number of these adipokines. Although no specific therapy exists to block the effects of these factors, recognizing the high risk and anticipating inflammation-associated complications of adipokine release is an important part of optimal patient management. For this review, a PubMed search was performed with the terms "acute pancreatitis", "severe acute pancreatitis", and "obesity". Additional searches were conducted to identify recent reviews on adipokines, Finally, PubMed searches on specific adipokines, including adiponectin, leptin, visfatin and resistin were conducted focusing on acute pancreatitis and systemic inflammation. PMID: 20485254 [PubMed - indexed for MEDLINE] 1365. Curr Opin Rheumatol. 2010 Sep;22(5):533-7. doi: 10.1097/BOR.0b013e32833b4682. The evolving role of obesity in knee osteoarthritis. Sowers MR(1), Karvonen-Gutierrez CA. Author information: (1)Department of Epidemiology, Unversity of Michigan School of Public Health, Ann Arbor, Michigan, USA. mfsowers@umich.edu PURPOSE OF REVIEW: The frequency of knee osteoarthritis continues to accelerate, likely because of the increasing proliferation of obesity, particularly in men and women 40-60 years of age at the leading edge of the 'baby boom' demographic expansion. The increasing pervasiveness of obesity and the growing appreciation of obesity's accompanying metabolic/inflammatory activities suggest rethinking the knee osteoarthritis paradigm. RECENT FINDINGS: Whereas once knee osteoarthritis was considered a 'wear-and-tear' condition, it is now recognized that knee osteoarthritis exists in the highly metabolic and inflammatory environments of adiposity. Cytokines associated with adipose tissue, including leptin, adiponectin, and resistin, may influence osteoarthritis though direct joint degradation or control of local inflammatory processes. Further, pound-for-pound, not all obesity is equivalent for the development of knee osteoarthritis; development appears to be strongly related to the co-existence of disordered glucose and lipid metabolism. Additionally, obesity loads may be detected by mechanoreceptors on chondrocyte surfaces triggering intracellular signaling cascades of cytokines, growth factors, and metalloproteinases. SUMMARY: This review summarizes recent literature about obesity, knee osteoarthritis and joint pain. Consideration of adipocytokines, metabolic factors, and mechanical loading-metabolic factor interactions will help to broaden the thinking about targets for both prevention and intervention for knee osteoarthritis. PMCID: PMC3291123 PMID: 20485173 [PubMed - indexed for MEDLINE] 1366. Mini Rev Med Chem. 2010 Aug;10(9):856-69. The role of the novel adipocyte-derived protein adiponectin in human disease: an update. Díez JJ(1), Iglesias P. Author information: (1)Servicio de Endocrinología, Hospital Ramón y Cajal, Madrid, Spain. jdiez.hrc@salud.madrid.org Adiponectin is a collagen-like protein expressed in adipose tissue. Low serum adiponectin is associated with insulin resistance, atherogenic hyperlipidemia and arterial hypertension. High serum adiponectin predicted a reduced risk of myocardial infarction. Other surveys have shown that high levels of serum adiponectin were a predictor of future cardiovascular disease and mortality. These paradoxical findings might be explained through the concept of the reversal epidemiology in the adiponectin physiology. According to this hypothesis, this protein would behave as an insulin sensitizing and cardioprotective factor in the health state and as a wasting marker in the advanced states of disease. PMID: 20482500 [PubMed - indexed for MEDLINE] 1367. Paediatr Drugs. 2010 Jun;12(3):187-99. doi: 10.2165/11532520-000000000-00000. Impact of antiretroviral therapy on growth, body composition and metabolism in pediatric HIV patients. Kim RJ(1), Rutstein RM. Author information: (1)Division of Endocrinology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. kimr@email.chop.edu Highly active antiretroviral therapy improves survival and growth in children with HIV infection. However, its use can be associated with adverse changes in body composition and metabolism. Bone mineral density can be adversely affected in HIV-positive children due to nutritional compromise or certain antiretrovirals. HIV-associated lipodystrophy, consisting of redistribution of adipose tissue, insulin resistance, and dyslipidemia, has also been described in children. Pediatric HIV patients may be at greater risk for these problems because of their longer potential lifetime exposure to these agents and because childhood is normally a period of rapid growth and tissue accretion. Healthcare providers for children with HIV infection must be aware of the potential complications associated with HIV antiretrovirals so that their antiviral efficacy can be balanced against their risk for side effects. In this review, we discuss the alterations in childhood growth and body composition that occur in HIV-infected children, and describe the impact of antiretroviral therapy on these outcomes. The problem of HIV-associated lipodystrophy syndrome in children is also discussed. Children with HIV should have their growth and body composition systematically monitored. Antiretroviral regimens should be tailored to optimize adherence and viral suppression while minimizing the potential for adverse side effects. PMID: 20481647 [PubMed - indexed for MEDLINE] 1368. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2010 Apr;27(2):476-80. [Adipocytokines: factors with various suggested functions]. [Article in Chinese] Zhu Y(1), Huang D. Author information: (1)Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China. Fat accumulation has been shown to play important roles in the development of obesity-related disorders such as atherosclerosis, diabetes mellitus and hypertension. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine functions. These are achieved predominantly through release of adipocytokines, which include several novel molecules released by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells, like TNF-alpha and IL-6. Adipocytokines may affect cardiovascular, hepatic, muscular and metabolic function. In this review, the recent research work of adipocytokines will be discussed. PMID: 20481343 [PubMed - indexed for MEDLINE] 1369. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2010 Apr;27(2):463-6. [Cell sources for engineered temporomandibular joint disc tissue: present and future]. [Article in Chinese] Su X(1), Kang H. Author information: (1)School of Stomatology, Lanzhou University, Lanzhou 730000, China. The purpose of this review is to provide a reference for researchers in investigating the tissue engineering of the temporomandibular joint (TMJ) disc. Currently tissue engineering of the TMJ disc is in its infancy, and cell source is one of the key factors that define the development of the tissue engineering of TMJ disc. In this paper, 6 kinds of cells: the TMJ disc native cells, chondrocytes, dermal fibroblasts, bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, and embryonic stem cells are introduced. In addition, the possibility that these cells can be used as cell sources for TMJ disc tissue engineering is described. PMID: 20481340 [PubMed - indexed for MEDLINE] 1370. Curr Opin Lipidol. 2010 Jun;21(3):247-52. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein. Romeo S(1), Huang-Doran I, Baroni MG, Kotronen A. Author information: (1)Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. sr517@medschl.cam.ac.uk PURPOSE OF REVIEW: Hepatic steatosis is a leading cause of adult and paediatric liver disease and is inextricably linked to obesity, insulin resistance and cardiovascular disease. Here we summarize our current understanding of the role of the patatin-like phospholipase domain-containing 3 gene (PNPLA3) in hepatic steatosis. RECENT FINDINGS: Multiple studies have revealed an association between the common I148M variant in PNPLA3 and increased hepatic fat. In the presence of obesity and chronic alcohol intake, the variant is associated with even more striking phenotypes such as hepatitis and cirrhosis, respectively. These findings suggest that genetic variants in PNPLA3 predispose towards hepatic steatosis and, in the context of other environmental stressors, its progression to irreversible liver failure. PNPLA3 is predominantly expressed in human liver and adipose tissue, possesses both lipolytic and lipogenic activity in vitro and localizes to the surface of lipid droplets in heptocytes. The 148M mutant protein has reduced lipolytic activity, with attendant increased cellular triglyceride accumulation. However, the precise physiological role of PNPLA3 remains mysterious. SUMMARY: Recent studies have implicated PNPLA3 in the pathogenesis of hepatic steatosis. Attempts to describe its function in vivo may provide us with both an opportunity to understand and a strategy to overcome this leading cause of human morbidity. PMID: 20480550 [PubMed - indexed for MEDLINE] 1371. Mol Biol Rep. 2011 Feb;38(2):873-8. doi: 10.1007/s11033-010-0179-y. Epub 2010 May 18. The emerging role of adipokines in osteoarthritis: a narrative review. Hu PF(1), Bao JP, Wu LD. Author information: (1)Zhejiang University College of Medicine, Hangzhou, People's Republic of China. Osteoarthritis (OA) is a most common multifactorial degenerative joint disease in elderly individuals. OA is affecting severely the quality of life of patients, while the causes of OA are not completely understood. Age, obesity, the female sex, and previous injury are considered as significant risk factors. Recently, increased levels of adipokines which are mainly produced by adipocytes have been detected in patients with osteoarthritis. Moreover, studies on different adipokines all reveal that they have played proinflammatory and catabolic/anabolic roles during the pathophysiology of OA. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones leptin, adiponectin, resistin and visfatin on initiation and progression of OA. PMID: 20480243 [PubMed - indexed for MEDLINE] 1372. Prog Brain Res. 2010;181:209-32. doi: 10.1016/S0079-6123(08)81012-6. The multiple roles of estrogens and the enzyme aromatase. Boon WC(1), Chow JD, Simpson ER. Author information: (1)Florey Neuroscience Institutes, Parkville, Victoria, Australia; Centre of Neuroscience, Melbourne University, Parkville, Victoria, Australia. wah.chin.boon@florey.edu.au Aromatase is the enzyme that catalyzes the last step of estrogen biosynthesis. It is expressed in many tissues such as the gonads, brain and adipose tissue. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine and autocrine effects on tissues. Estrogens play many roles in the body, regulating reproduction, metabolism and behavior. In the brain, cell survival and the activity of neurons are affected by estrogens and hence aromatase. PMID: 20478440 [PubMed - indexed for MEDLINE] 1373. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):366-70. doi: 10.1097/MCO.0b013e32833aab7f. Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes. Sell H(1), Eckel J. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes-Center, Düsseldorf, Germany. henrike.sell@ddz.uni-duesseldorf.de PURPOSE OF REVIEW: Obesity is associated with low-grade chronic inflammation in adipose tissue. This review presents an update on human and rodent studies analyzing the nature of fat-infiltrating immune cells, the time course of adipose tissue infiltration and underlying mechanisms. RECENT FINDINGS: Intensive studies in rodents have shown that not only cells of the innate immune system traffic into adipose tissue but also various lymphocytes of the adaptive immunity are involved in inflammatory processes in fat. Several studies also provide insight in the order of appearance of macrophages and lymphocytes during the onset of obesity. Adipocytes and preadipocytes are also active players by their secretion of chemotactic adipokines. SUMMARY: This review summarizes strong evidence for a link between the action of innate and adaptive immune systems in adipose tissue in the context of obesity and metabolism in rodents, but more studies in humans are necessary to relate this topic to human physiology. Targeting different immune cells at different stages of obesity may eventually lead to novel therapeutic approaches for the metabolic syndrome. PMID: 20473150 [PubMed - indexed for MEDLINE] 1374. Vet J. 2010 Jul;185(1):4-9. doi: 10.1016/j.tvjl.2010.04.004. Epub 2010 May 15. Obesity, its associated disorders and the role of inflammatory adipokines in companion animals. German AJ(1), Ryan VH, German AC, Wood IS, Trayhurn P. Author information: (1)School of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, Wirral CH64 7TE, UK. ajgerman@liv.ac.uk Obesity is characterised by an expansion of white adipose tissue mass that can lead to adverse health effects, such as decreased longevity, diabetes mellitus, orthopaedic and respiratory disease and neoplasia. Once thought a passive fuel depot, adipose tissue is now recognised as an active endocrine organ that communicates with the brain and peripheral tissues by secreting a wide range of hormones and protein factors, collectively termed adipokines. Examples include leptin, adiponectin, cytokines (tumour necrosis factor-alpha, interleukin-6), chemokines, acute phase proteins, haemostatic and haemodynamic factors and neurotrophins. Adipokines can influence various body systems, and perturbation of normal endocrine function is thought central to the development of many associated conditions. This review focuses on the medical consequences of obesity in companion animals, assesses the endocrine function of adipose tissue in disease pathogenesis, and highlights the potential role of adipokines as biomarkers of obesity-associated disease. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20472476 [PubMed - indexed for MEDLINE] 1375. Herz. 2010 May;35(3):198-205. doi: 10.1007/s00059-010-3344-0. [Obesity: ectopic fat distribution and the heart]. [Article in German] Müller-Wieland D(1), Knebel B, Haas J, Merkel M, Kotzka J. Author information: (1)Abteilung für Allgemeine Innere Medizin, Gastroenterologie, Endokrinologie, Diabetes und Stoffwechsel, Institut für diabetologische Versorgungsforschung, Asklepios Klinik St. Georg, Hamburg, Germany. d.mueller-wieland@asklepios.com The metabolic syndrome is usually associated with insulin resistance and visceral fat distribution, which appear to play a direct role in the development of clinical criteria of metabolic syndrome, like elevation of arterial blood pressure and dyslipidemia. In this review, the authors will first introduce the concept, that insulin resistance and increased visceral adipose tissue are also regularly associated with an abnormal or ectopic accumulation of lipids in nonadipocytes, like steatosis hepatis. Then, they will provide some evidence that epicardial fat can be associated with insulin resistance in a similar fashion as visceral intraabdominal fat. Furthermore, epicardial fat might directly affect the vessels and function of the heart. Accordingly, ectopic accumulation of fat within cardiac muscle cells can impair their function and possibly be related to heart failure. These new relations between obesity, fat distribution and cardiac function might help to identify and treat individuals at risk earlier and more appropriately. PMID: 20467932 [PubMed - indexed for MEDLINE] 1376. Nephrol Dial Transplant. 2010 Jul;25(7):2066-77. doi: 10.1093/ndt/gfq246. Epub 2010 May 11. Adipose tissue in renal disease: clinical significance and prognostic implications. Iglesias P, Díez JJ. PMID: 20466661 [PubMed - indexed for MEDLINE] 1377. Vnitr Lek. 2010 Apr;56(4):289-91. [Obesity and atherosclerosis--what's the link?]. [Article in Czech] Sucharda P(1). Author information: (1)3. interní klinika 1, lékarské fakulty UK a VFN Praha. petr.sucharda@lf1.cuni.cz Obesity, primarily abdominal obesity, is a significant risk factor for symptomatic atherosclerosis. Atherosclerotic vascular changes and the pandemic of obesity are connected with the civilization process, in particular with diet modification and shortage of exercise and physical effort. The clinically defined metabolic syndrome is the most prominent atherosclerotic risk factor based on adipose tissue dysfunction producing low grade inflammation and endothelial dysfunction. PMID: 20465097 [PubMed - indexed for MEDLINE] 1378. Endokrynol Pol. 2010 Mar-Apr;61(2):194-206. Neuroendocrine body weight regulation: integration between fat tissue, gastrointestinal tract, and the brain. Boguszewski CL(1), Paz-Filho G, Velloso LA. Author information: (1)Department of Internal Medicine, Endocrine Division (SEMPR), Federal University of Paraná, Curitiba, Brazil. cesarluiz@hc.ufpr.br Human body weight is maintained at a fairly stable level regardless of changes in energy intake and energy expenditure. Compensatory mechanisms within the central nervous system (CNS), which regulate food intake and energy expenditure, are triggered by other central and peripheral signals. Peripherally, the main sources of those signals are the adipose tissue, gastrointestinal tract, and pancreas. The main signal originating from the adipose tissue is leptin, which promotes the activation of anorexigenic pathways in the CNS. Similarly, the central action of insulin also reduces food intake and stimulates catabolic pathways. The gastrointestinal tract contributes with several peptides that influence food intake, such as ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin (OXM), and cholecystokinin (CCK). Other substances secreted by the pancreas, such as pancreatic polypeptide (PP) and amylin, a hormone co-secreted with insulin, also affect energy balance. More recently, the endocannabinoid system has also been identified as a contributor in the maintenance of energy balance. Better understanding of these mechanistic systems involved in the regulation of energy metabolism will hopefully lead to the development of new therapeutic approaches against obesity, metabolic syndrome, and other nutritional disorders. PMID: 20464707 [PubMed - indexed for MEDLINE] 1379. Dig Dis. 2010;28(1):285-93. doi: 10.1159/000282104. Epub 2010 May 7. Insulin resistance and response to antiviral therapy in chronic hepatitis C: mechanisms and management. del Campo JA(1), López RA, Romero-Gómez M. Author information: (1)Unit for Clinical Management of Digestive Diseases and CIBERehd, Valme University Hospital, Seville, Spain. Insulin resistance has been found to be an independent factor predicting sustained response to peginterferon plus ribavirin in patients with chronic hepatitis C. Insulin resistance seems to be involved in decreased sensitivity to interferon and could block interferon intracellular signaling. Insulin resistance promotes steatosis and fibrosis progression, induces pro-inflammatory cytokine secretion and increases adipose tissue, decreasing interferon availability. Moreover, suppressor of cytokines 3 and protein tyrosine-phosphatase seems to be able to block interferon and insulin signaling, building a feed-forward loop. Insulin resistance can be treated with exercise, diet or through the use of drugs that improve insulin sensitivity, like biguanides or glitazones. A recent controlled, randomized, double-blind clinical trial (TRIC-1) examined the effect of adding metformin to standard therapy in the treatment of hepatitis C. This study demonstrated that women infected with hepatitis C virus genotype 1 and HOMA >2 treated with metformin showed a greater drop in viral load during the first 12 weeks and a doubled sustained viral response in comparison with females receiving placebo. Pioglitazone has been used in previous nonresponders and naïve patients with disappointing results in two pilot trials. The mechanisms by which the virus promotes insulin resistance seems to be genotype-dependent and could explain, at least in part, the discrepancies between insulin sensitizers. Insulin resistance is a new target in the challenging management of chronic hepatitis C. Copyright 2010 S. Karger AG, Basel. PMID: 20460925 [PubMed - indexed for MEDLINE] 1380. Dig Dis. 2010;28(1):261-6. doi: 10.1159/000282100. Epub 2010 May 7. Endocannabinoids and their role in fatty liver disease. Mallat A(1), Lotersztajn S. Author information: (1)AP-HP, INSERM U841, Groupe hospitalier Henri Mondor-Albert Chenevier, Service d'Hépatologie et de Gastroentérologie, Créteil, France. ariane.mallat@hmn.aphp.fr The endocannabinoid system comprises receptors, CB1 and CB2, their endogenous lipidic ligands and machinery dedicated to endocannabinoid synthesis and degradation. An overactive endocannabinoid system appears to contribute to the pathogenesis of several diseases, including liver diseases. With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic, the development of effective therapies is gaining considerable interest. Several recent experimental lines of evidence identify CB receptors as potential novel therapeutic targets in the management of NAFLD. Endogenous activation of peripheral CB1 receptors is a key mediator of insulin resistance and enhances liver lipogenesis in experimental models of NAFLD. Moreover, we have shown that adipose tissue CB2 receptors are markedly upregulated and promote fat inflammation, thereby contributing to insulin resistance and liver steatosis. Data from our group also indicate that tonic activation of CB1 receptors is responsible for progression of liver fibrosis, whereas CB2 receptors display anti-fibrogenic properties. The clinical relevance of these findings is supported by studies in patients with chronic hepatitis C indicating that daily cannabis use is an independent predictor of both fibrosis and steatosis severity. Moreover, preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat. Tempering these promises, the first generation of CB1 antagonists raised concern due to an alarming rate of mood disorders and the development program of these molecules was suspended. Current research efforts are therefore focused on developing formulations of CB1 antagonists that do not enter the central nervous system, and preliminary experimental data obtained with such molecules are encouraging. Copyright 2010 S. Karger AG, Basel. PMID: 20460921 [PubMed - indexed for MEDLINE] 1381. Dig Dis. 2010;28(1):220-4. doi: 10.1159/000282091. Epub 2010 May 7. Bile acids as regulators of hepatic lipid and glucose metabolism. Trauner M(1), Claudel T, Fickert P, Moustafa T, Wagner M. Author information: (1)Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. michael.trauner@meduni-graz.at Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BA) also act as metabolically active signaling molecules. The flux of reabsorbed BA undergoing enterohepatic circulation, arriving in the liver with the co-absorbed nutrients (e.g. glucose, lipids), provides a signal that coordinates hepatic triglyceride (TG), glucose and energy homeostasis. As signaling molecules with systemic endocrine functions, BA can activate protein kinases A and C as well as mitogen-activated protein kinase pathways. Additionally, they are ligands for a G-protein-coupled BA receptor (TGR5/Gpbar-1) and activate nuclear receptors such as farnesoid X receptor (FXR; NR1H4). FXR and its downstream targets play a key role in the control of hepatic de novo lipogenesis, very-low-density lipoprotein-TG export and plasma TG turnover. BA-activated FXR and signal transduction pathways are also involved in the regulation of hepatic gluconeogenesis, glycogen synthesis and insulin sensitivity. Via TGR5, BA are able to stimulate glucagon-like peptide-1 secretion in the small intestine and energy expenditure in brown adipose tissue and skeletal muscle. Dysregulation of BA transport and impaired BA receptor signaling may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thus, BA transport and BA-controlled nuclear receptors and signaling pathways are promising drug targets for treatment of NAFLD. As such, FXR and/or TGR5 ligands have shown promising results in animal models of NAFLD and clinical pilot studies. Despite being a poor FXR and TGR5 ligand, ursodeoxycholic acid (UDCA) improves hepatic ER stress and insulin sensitivity. Notably, norUDCA, a side chain-shortened homologue of UDCA, improves fatty liver and atherosclerosis in Western diet-fed ApoE(-/-) mice. Collectively, these findings suggest that BA and targeting their receptor/signaling pathways may represent a promising approach to treat NAFLD and closely linked disorders such as obesity, diabetes, dyslipidemia and arteriosclerosis. Copyright 2010 S. Karger AG, Basel. PMID: 20460915 [PubMed - indexed for MEDLINE] 1382. Dig Dis. 2010;28(1):203-9. doi: 10.1159/000282087. Epub 2010 May 7. Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Yki-Järvinen H(1). Author information: (1)Department of Medicine, University of Helsinki, Helsinki, Finland. ykijarvi@cc.helsinki.fi The pathogenesis of type 2 diabetes involves both insulin resistance and defects in insulin secretion. Although obesity and physical inactivity have precipitated the epidemic of type 2 diabetes, the metabolic abnormalities associated with a sedentary lifestyle are better predictors of type 2 diabetes and cardiovascular disease than obesity alone. Some of these metabolic abnormalities, which are either causes or consequences of insulin resistance, have been called the metabolic syndrome. Fat accumulation in the liver due to non-alcoholic causes (non-alcoholic fatty liver disease) has also been shown to be an obesity-independent predictor of type 2 diabetes in multiple prospective studies. Since the liver is a key site of action of insulin, it seems reasonable to postulate that subjects who deposit excessive amounts of fat in the liver are those who also are at risk of developing the metabolic syndrome. Mechanistic studies support this hypothesis. Once fatty, the liver is resistant to the actions of insulin to inhibit both production of glucose and very-low-density lipoprotein, which results in mild hyperglycemia, compensatory hyperinsulinemia and hypertriglyceridemia. The latter leads to lowering of high-density lipoprotein cholesterol and formation of atherogenic small dense low-density lipoprotein particles. These data suggest that the metabolic syndrome and non-alcoholic fatty liver disease are essentially two definitions of the same problem. In subjects who cannot sustain hyperinsulinemia to maintain glucose concentrations in the nondiabetic range, overt hyperglycemia, i.e. type 2 diabetes, develops. Copyright 2010 S. Karger AG, Basel. PMID: 20460912 [PubMed - indexed for MEDLINE] 1383. Dig Dis. 2010;28(1):192-6. doi: 10.1159/000282085. Epub 2010 May 7. Chemokines as immune mediators of liver diseases related to the metabolic syndrome. Berres ML(1), Nellen A, Wasmuth HE. Author information: (1)Medical Department III, University Hospital Aachen, RWTH Aachen, Aachen, Germany. BACKGROUND/AIMS: Chemokines are small chemotactic molecules which regulate the infiltration of immune cells to sites of inflammatory injury. In recent years their contribution to the initiation and perpetuation of liver injury has been better defined. However, the role of chemokines in liver diseases related to the metabolic syndrome still needs to be elucidated in detail. METHODS: Chemokines were mostly detected at the mRNA level in the liver and as proteins in the serum of patients with non-alcoholic steatohepatitis (NASH) or fatty liver. Animals with targeted deletion of chemokines have recently been subjected to NASH models to functionally dissect the role of chemokines in fatty liver diseases. RESULTS: In human liver with features of NASH, different CC and CXC chemokines have been detected at elevated mRNA levels in comparison to healthy subjects. Some of these chemokines have also been associated with NASH by demonstrating higher serum levels in affected patients. Until now, only a few animal models have been analyzed with respect to the functional role of these molecules. However, data from CCL2 and CXCR3 knockout mice suggest that these pathways are important in liver injury. CCL2 seems to influence the infiltration of macrophages to adipose tissue and thereby modulate insulin resistance. CONCLUSIONS: The further elucidation of the pathophysiology of NASH will lead to new therapeutic options to halt or reverse progressive liver disease. In this respect, chemokines are attractive target molecules, as they influence immunologic and metabolic pathways and the first oral chemokine receptor antagonists have already been licensed for humans. Copyright 2010 S. Karger AG, Basel. PMID: 20460910 [PubMed - indexed for MEDLINE] 1384. Dig Dis. 2010;28(1):179-85. doi: 10.1159/000282083. Epub 2010 May 7. The role of cytokines in non-alcoholic fatty liver disease. Tilg H(1). Author information: (1)Department of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Innsbruck, Austria. Herbert.Tilg@i-med.ac.at Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity and diabetes, and is characterized by insulin resistance (IR). Cytokines and adipocytokines (i.e. mediators mainly derived from adipose tissue) play a major role in the orchestration of inflammatory processes throughout the body. In addition, many of these mediators are able to regulate very diverse functions including inflammatory, immune and metabolic processes such as IR. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are critically involved in the pathophysiology of various aspects of human NAFLD. The importance of TNF-alpha in human and animal fatty liver diseases, both due to genetic manipulation and overnutrition, has been demonstrated. Furthermore, neutralization of TNF-alpha activity improves IR and fatty liver disease in animals. IL-6 is derived from many cells throughout the body including adipocytes. Serum levels of this cytokine correlate remarkably well with the presence of IR, and adipose tissue-derived IL-6 has been shown to regulate hepatic IR via upregulation of SOCS3. Adiponectin is a potent TNF-alpha-neutralizing and anti-inflammatory adipocytokine, and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are mediated via suppression of TNF-alpha synthesis as well as induction of anti-inflammatory cytokines such as IL-10 or IL-1 receptor antagonist. Therefore, the balance between pro- and anti-inflammatory acting cytokines/adipocytokines appears to play a key role in hepatic and systemic insulin action, and they are supposed to have important functions in the development of NAFLD. Copyright 2010 S. Karger AG, Basel. PMID: 20460908 [PubMed - indexed for MEDLINE] 1385. ScientificWorldJournal. 2010 May 4;10:832-56. doi: 10.1100/tsw.2010.77. Resolution of adipose tissue inflammation. González-Périz A(1), Clària J. Author information: (1)Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS, CIBEK, CIBERehd, University of Barcelona. agonzal2@clinic.ub.es The presence of the so-called "low-grade" inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic "low-grade" inflammation in white adipose tissue is powerfully augmented through the infiltration of macrophages, which, together with adipocytes, perpetuate a vicious cycle of macrophage recruitment and secretion of free fatty acids and deleterious adipokines that predispose the development of obesity-related comorbidities, such as insulin resistance and nonalcoholic fatty liver disease. In the last decade, many factors have been identified that contribute to mounting uncontrolled inflammation in obese adipose tissue. Among them, bioactive lipid mediators derived from the cyclooxygenase and 5-lipoxygenase pathways, which convert the omega-6-polyunsaturated fatty acid (PUFA) arachidonic acid into potent proinflammatory eicosanoids (i.e., prostaglandins [PGs] and leukotrienes), have emerged. Interestingly, the same lipid mediators that initially trigger the inflammatory response also signal the termination of inflammation by stimulating the biosynthesis of anti-inflammatory and proresolving lipid autacoids. This review discusses the current status, characteristics, and progress in this class of "stop signals", including the lipoxins, which were the first identified omega-6 PUFA-derived lipid mediators with potent anti-inflammatory properties; the recently described omega-3 PUFA-derived lipid mediators resolvins and protectins; and the cyclopentenone PGs of the D series. Special emphasis is given to the participation of these bioactive lipid autacoids in the resolution of adipose tissue inflammation and in preventing the development of obesity-related complications. PMID: 20454765 [PubMed - indexed for MEDLINE] 1386. Mediators Inflamm. 2010;2010:495416. doi: 10.1155/2010/495416. Epub 2010 May 5. Peritoneal adipocytes and their role in inflammation during peritoneal dialysis. Lai KN(1), Leung JC. Author information: (1)Department of Medicine, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Road, Hong Kong. Adipose tissue is a major site of chronic inflammation associated with peritoneal dialysis (PD) frequently complicating peritonitis. Adiposity-associated inflammation plays a significant contributory role in the development of chronic inflammation in patients undergoing maintenance PD. However, the molecular and cellular mechanisms of this link remain uncertain. Adipose tissue synthesizes different adipokines and cytokines that orchestrate and regulate inflammation, insulin action, and glucose metabolism locally and systemically. In return, inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. An understanding of the inflammatory roles played by adipose tissue during PD and the healing mechanism of injured mesothelium will help to devise new therapeutic approach to slow the progression of peritoneal damage during peritoneal dialysis. This article reviews the roles of peritoneal adipose tissue in chronic peritoneal inflammation under PD and in serosal repair during PD. PMCID: PMC2864891 PMID: 20454534 [PubMed - indexed for MEDLINE] 1387. Med Clin North Am. 2010 May;94(3):465-78. doi: 10.1016/j.mcna.2010.02.003. Cardiovascular consequences of obese and nonobese obstructive sleep apnea. Ramar K(1), Caples SM. Author information: (1)Division of Pulmonary, Sleep and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, 200 First Street South West, Rochester, MN 55901, USA. ramar.kannan@mayo.edu Current evidence suggests a role for obstructive sleep apnea (OSA) in the development of cardiovascular disorders. However, obesity is an active confounder in this relationship. OSA and obesity share similar pathophysiologic mechanisms potentially leading to cardiovascular disorders. Presence of OSA in obese patients may further contribute to adverse cardiovascular outcomes when compared with each condition in isolation. In this review the authors explore the complex relationship between OSA and obesity (and nonobese subjects) in the development of cardiovascular disorders. PMCID: PMC4014075 PMID: 20451027 [PubMed - indexed for MEDLINE] 1388. Nihon Rinsho. 2010 May;68(5):931-42. [Incretin and incretin-based therapies]. [Article in Japanese] Harada N(1), Inagaki N. Author information: (1)Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University. GIP and GLP-1 are major incretins and secreted from K-cell and L-cell in response to meal ingestion, respectively. GIP and GLP-1 potentiate glucose-induced insulin secretion by binding GIP receptor and GLP-1 receptor, respectively, on pancreatic beta-cell and increasing intracellular cAMP concentration (incretin effect). GIP receptor and GLP-1 receptor are expressed in some different organs. GIP receptor is expressed in intestine, adipose tissue, brain, adrenal gland, and bone, while GLP-1 receptor is expressed in intestine, CNS, lung, kidney and heart. GIP and GLP-1 have not only pancreatic effect, such as potentiation of insulin secretion, but also many extrapancreatic effects. Incretin effect is known to be decreased in type 2 diabetes patients compared to that in healthy subjects. GLP-1 was target peptide as anti-diabetic drug, because insulin secretion in response to GLP-1 infusion was intact in type 2 diabetic patients. GLP-1 mimetics and DPP-4 inhibitor were produced as incretin-based therapy. Type 2 diabetic patients already use them in USA and Europe and get improved glycemic control. Both drugs are reported to improve in Japanese type 2 diabetic patients more glycemic controls compared to those in Caucasian type 2 diabetic patients. Thus, incretin-based therapies may have benefits for Asian patients who have less insulin secretory ability than Caucasian. PMID: 20446595 [PubMed - indexed for MEDLINE] 1389. Nihon Rinsho. 2010 May;68(5):819-22. [Inflammatory cytokines]. [Article in Japanese] Ishii H(1), Yoshida M. Author information: (1)Life Science and Bioethics Research Center, Tokyo Medical and Dental University. Diabetic macroangiopathy is severe complication for diabetes mellitus, and inflammatory cytokines induces various reactions for the formation of atherosclerosis in diabetes. In addition, recent reports indicate the accumulation of macrophages in the adipose tissue occurs in diabetes and these macrophages secret an inflammatory cytokines. It is also known macrophages produce most of circulating TNF-alpha. Accordingly, inflammatory cytokines, produced in adipose tissue, influence systemic inflammation possibly. Leukocyte-endothelial interactions are critical in the progression of inflammation and atherosclerosis. Recruitment of leukocytes to the sites of inflammation or atherosclerosis prone vasculature involves multistep complex cascades of adhesion events, which inflammatory cytokines induce. Inflammatory cytokines are not the only factor in diabetic macroangiopathy, however, it is certain that inflammation plays important role in diabetes and diabetic vascular complication. PMID: 20446575 [PubMed - indexed for MEDLINE] 1390. Cell Transplant. 2010;19(10):1217-23. doi: 10.3727/096368910X507187. Epub 2010 May 4. Adipocyte transplantation and stem cells: plastic surgery meets regenerative medicine. Tremolada C(1), Palmieri G, Ricordi C. Author information: (1)Istituto Image and San Paolo Hospital, Milan, Italy. The technologies for adipose tissue harvesting, processing, and transplantation have substantially evolved in the past two decades. Clinically driven advancements have paralleled a significant improvement in the understanding of cellular, molecular, and immunobiological events surrounding cell and tissue transplantation. These new mechanistic insights could be of assistance to better understand the mechanisms underlying some of the observed clinical improvements. In addition to plastic and reconstructive surgical applications, adipose tissue has become central to an increasing number of translational efforts involving adipose tissue-derived progenitor cells. The growing interest in this area of research has resulted in the exploration of many novel research and clinical applications that utilize adipose tissue grafting and/or progenitor/stem cell- derived cell products obtained from this tissue source. Progenitor, endothelial, and mesenchymal stem cells derived from adipose tissue could therefore not only be central to plastic and reconstructive surgery applications, but also become the focus of an array of therapeutic solutions for many disease conditions, such as those affecting bone, cartilage, muscle, liver, kidney, cardiac, neural, and the pancreas, expanding the possible indications and translational potential of tissue, cell-based, and regenerative medicine strategies. PMID: 20444320 [PubMed - indexed for MEDLINE] 1391. Aesthet Surg J. 2010 Jan;30(1):83-97; quiz 98-100. doi: 10.1177/1090820X10362728. Updates and advances in liposuction. Stephan PJ(1), Kenkel JM. Author information: (1)Department of Plastic Surgery, University of Texas Southwestern Medical Center Dallas, TX, USA. Liposuction has evolved tremendously over the past three decades. Since its introduction by Illouz it has progressed into one of the most popular procedures in plastic surgery. The objective of this CME is to provide a foundation of knowledge with respect to anatomy, physiology, preoperative, intraoperative, and postoperative management of patients scheduled to undergo liposuction. A review of both the immediate and delayed complications related to liposuction is addressed, as well as relevant surgical site-specific pearls for patients undergoing liposuction. Finally a summary of the various operative techniques available for surgeons is discussed along with information related to relevant emerging technology in body contouring. PMID: 20442081 [PubMed - indexed for MEDLINE] 1392. Brain Res. 2010 Sep 2;1350:77-85. doi: 10.1016/j.brainres.2010.04.056. Epub 2010 May 23. Metabolic impact of sex hormones on obesity. Brown LM(1), Gent L, Davis K, Clegg DJ. Author information: (1)Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA. Obesity and its associated health disorders and costs are increasing. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. Within the brain, the hypothalamus is an important regulator of energy homeostasis. Two of its sub-areas, the ventrolateral portion of the ventral medial nucleus (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large lesions are made in the hypothalamus which includes both the VL VMN and the ARC, animals eat more, have reduced energy expenditure, and become obese. The ARC and the VL VMN, in addition to other regions in the hypothalamus, have been demonstrated to contain estrogen receptors. There are two estrogen receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). We and others have previously demonstrated that activation of ERalpha by estrogens reduces food intake and increases body weight. This review focuses on the relative contribution of activation of ERalpha by estrogens in the ARC and the VL VMN in the regulation of food intake and body weight. Additionally, estrogen receptors have been found in many peripheral tissues including adipose tissue. Estrogens are thought to have direct effects on adipose tissue and estrogens may provide anti-inflammatory properties both in the periphery and the in the central nervous system (CNS) which may protect women from diseases associated with inflammation. Understanding the mechanisms by which estrogens regulate body weight and inflammation will assist in determining potential therapeutic agents for menopausal women to decrease the propensity of diseases associated with obesity. 2010 Elsevier B.V. All rights reserved. PMCID: PMC2924463 PMID: 20441773 [PubMed - indexed for MEDLINE] 1393. Minerva Pediatr. 2010 Apr;62(2):171-8. [Adipocytokines: potential biomarkers for childhood obesity and anorexia nervosa]. [Article in Italian] Leoni MC(1), Pizzo D, Marchi A. Author information: (1)Clinica Pediatrica, Fondazione IRCCS, Policlinico San Matteo, Pavia, Italia. mariachiara.leoni@gmail.com Adipose tissue is now considered an important endocrine organ that secretes a large number of physiologically active peptides affecting metabolic homeostasis of human body: they are collectively referred to as adipocytokines. Leptin is a key hormone in the regulation of food intake, energy expenditure, neuroendocrine and immune function. Leptin is related with obesity and its metabolic disorders; starvation-induced depletion of fat stores is accompanied by alterations of circulating adipocytokines that may have potential repercussions in the pathophysiology of anorexia nervosa. Adiponectin enhances insulin sensitivity, controls body weight, prevents atherosclerosis and negatively regulates immune functions. Plasma adiponectin relates inversely to adiposity and reflects the sequelae of accumulation of excess adiposity. Resistin is a protein hormone produced both by adipocytes and immunocompetent cells that affect fuel homeostasis and insulin action. Plasma resistin levels are decreased in anorectic patients, while plasma adiponectin levels are increased. Plasma ghrelin levels present opposite changes in obesity and anorexia nervosa, suggesting that ghrelin is a good marker of nutritional status. Visfatin shows to correlate with visceral fat mass in patients with obesity. Its possible role in patients with anorexia nervosa is unknown. In conclusion, obesity is defined as a state of low-grade inflammation, which is associated with increased leptin, resistin and ghrelin levels and decreased adiponectin levels; anorexia nervosa is characterized by opposite changes. Finally, plasma adipocytokines levels can represent a sensitive parameter of nutritional status that reflects changes in the level of body fat in children and adolescents with obesity and anorexia nervosa. PMID: 20440237 [PubMed - indexed for MEDLINE] 1394. Medicina (Kaunas). 2010;46(2):142-57. [Body composition and polycystic ovary syndrome]. [Article in Lithuanian] Zabuliene L(1), Tutkuviene J. Author information: (1)Department of Anatomy, Histology and Anthropology, Faculty of Medicine, Vilnius University, M. K. Ciurlionio 21/27, Vilnius, Lithuania. Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic disorders of reproductive age women. The main signs of PCOS are as follows: androgen excess, menstrual dysfunction, infertility, obesity, and other numerous health problems. By different authors, the disorder affects 2-28% of reproductive age women. Polycystic ovary syndrome is characterized by presence of hyperandrogenism, anovulation, menstrual cycle disturbances, also by the other metabolic changes. The lack of well-defined and universally accepted diagnostic criteria makes identification of this syndrome confusing to many clinicians. There are only few studies concerning the correlations between phenotypic expression, body composition and PCOS, and relationship with the processes of growth and sexual maturation and various environmental factors (nutrition, physical activity, stress, and other factors). There is a lack of knowledge about further PCOS development and prognosis, considering the individual and environmental factors. Variation in human body composition and shape ranges considerably: many body size and shape indices (height, weight, body composition, and proportions) are the result of long evolution process and adaptation to environment. Obviously, the morphological body parameters, physiological and biochemical indices are complex and compound the interdependent system. By current literature, more than 50% of women are overweight or obese. If waist circumference and waist-to-hip ratio of women with PCOS increase, reproductive function and metabolic state of a woman is altered more than in cases when there are no changes in these parameters. The investigations of the strongest sexual dimorphism sign--the subcutaneous and visceral fat topography--showed that women with PCOS have greater adipose tissue mass in the areas of the abdomen, waist, and upper arms than control women. It is known that some indices of sexual dimorphism may be considered as the morphological signs of hyperandrogenism, for example handgrip, waist-to-hip ratio, hand and foot length, 2nd-to-4th digit (finger length) ratio (2D:4D), certain facial characteristics. Only 2D:4D ratio was investigated for the women with PCOS. The early changes of certain morphological and other indices of physical status could help to predict some metabolic characteristics, development of PCOS, and outcome of this syndrome. PMID: 20440089 [PubMed - indexed for MEDLINE] 1395. Endocr Pract. 2010 Jul-Aug;16(4):692-8. doi: 10.4158/EP09340.RA. Pathophysiologic mechanisms linking adipose tissue and cardiometabolic risk. Allende-Vigo MZ(1). Author information: (1)Department of Medicine, Endocrine Section, University of Puerto Rico Medical Sciences, San Juan, Puerto Rico. myriam.allende@gmail.com OBJECTIVE: To describe the contribution of adipocytes and adipose tissue to increased cardiometabolic risk as well as the mechanisms by which adipose tissue and obesity contribute to dysglycemia, dyslipidemia, hypertension, and a prothrombotic, inflammatory state favoring atherogenesis. METHODS: A review was undertaken of the relevant available reports, compiled by means of a search (PubMed) of the English-language literature published between 1994 and 2010. RESULTS: Coronary risk factors cause susceptibility to development of atherosclerosis. Traditional coronary risk factors are obesity, smoking, hypertension, diabetes, elevated serum cholesterol levels, male sex, advancing age, and a family history of early coronary events. The currently preferred term of cardiometabolic risk encompasses both the traditional coronary risk factors and the additional contributing factors of insulin resistance, atherogenic dyslipidemia, physical inactivity, unhealthful eating, inflammation, and hypercoagulation. The accumulation of adipose tissue (adiposity) and dysfunctional adipose tissue (adiposopathy) contribute to most, if not all, of the cardiometabolic risk factors. Adipose tissue promotes atherosclerosis through several different pathologic mechanisms, which are reviewed in this report. The treatment of obesity should focus on reducing fat mass and minimizing adipocyte dysfunction. CONCLUSION: Adipose tissue contributes to the development of insulin resistance, hyperglycemia, atherogenic dyslipidemia, and arterial hypertension and favors a prothrombotic and proinflammatory state. Adipose tissue dysfunction increases cardiometabolic risk through a variety of mechanisms. PMID: 20439246 [PubMed - indexed for MEDLINE] 1396. Annu Rev Nutr. 2010 Aug 21;30:237-55. doi: 10.1146/annurev.nutr.012809.104742. Fatty acid supply to the human fetus. Haggarty P(1). Author information: (1)Nutrition and Epigenetics Group, Rowett Institute of Nutrition & Health, University of Aberdeen, Aberdeen, AB21 9SB, Scotland, United Kingdom. p.haggarty@abdn.ac.uk Deposition of fat in the fetus increases exponentially with gestational age, reaching its maximal rate-around 7 g/day or 90% of energy deposition-at term. In late pregnancy, many women consuming contemporary Western diets may not be able to meet the fetal demand for n-3 long chain polyunsaturated fatty acids (LCPUFAs) from the diet alone. Numerous mechanisms have evolved to protect human offspring from extreme variation or deficiency in the maternal diet during pregnancy. Maternal adipose tissue is an important source of LCPUFA. Temporal changes in placental function are synchronized with maternal metabolic and physiological changes to ensure a continuous supply of n-3 and n-6 LCPUFA-enriched fat to the fetus. LCPUFA storage in fetal adipose tissue provides an important source of LCPUFA during the critical first months of postnatal life. An appreciation of these adaptations is important in any nutritional strategy designed to improve the availability of fatty acids to the fetus. PMID: 20438366 [PubMed - indexed for MEDLINE] 1397. Amino Acids. 2010 Jul;39(2):349-57. doi: 10.1007/s00726-010-0598-z. Epub 2010 May 1. Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health. McKnight JR(1), Satterfield MC, Jobgen WS, Smith SB, Spencer TE, Meininger CJ, McNeal CJ, Wu G. Author information: (1)Department of Animal Science, Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA. Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of L-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary L-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of L-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that L-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, L-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans. PMID: 20437186 [PubMed - indexed for MEDLINE] 1398. Rev Port Pneumol. 2010 Mar-Apr;16(2):307-14. [The role of respiratory physiotherapy in the lung function of obese patients undergoing bariatric surgery. A review]. [Article in Portuguese] Tenório LH(1), de Lima AM, Brasileiro-Santos Mdo S. Author information: (1)Pós -Graduando em Fisioterapia Cardiorrespiratória da Universidade Federal de Pernambuco. tenorio@gmail.com INTRODUCTION: Obesity, considered a new worldwide epidemic, is characterised by excess adipose tissue and contributes to a series of chronic diseases and increased mortality. Obesity associated to surgical procedure in these patients makes respiratory physiotherapy a must to recover lung function and prevent postoperative pulmonary complications. AIMS: To assess the effects of respiratory physiotherapy on the lung function of obese patients undergoing weight loss surgery. MATERIAL AND METHODS: We conducted a literature review October 2008-June 2009 of data which had been published over the last thirty years and which was available on the Medline, Pubmed ans Scielo databases. CONCLUSION: Pre- and postoperative respiratory physiotherapy is vital for patients undergoing weight loss surgery irrespective of technique used, as it can prevent pulmonary complications inherent in the surgical procedure and aid lung function recovery. PMID: 20437006 [PubMed - indexed for MEDLINE] 1399. World Rev Nutr Diet. 2010;101:103-14. doi: 10.1159/000314515. Epub 2010 Apr 30. Changes in human adipose tissue gene expression during diet-induced weight loss. Svensson PA(1), Gummesson A, Carlsson LM, Sjöholm K. Author information: (1)Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. per-arne.svensson@medic.gu.se PMID: 20436257 [PubMed - indexed for MEDLINE] 1400. Trends Immunol. 2010 Jun;31(6):228-35. doi: 10.1016/j.it.2010.03.001. Innate immunity and adipose tissue biology. Schäffler A(1), Schölmerich J. Author information: (1)Department of Internal Medicine I, University Hospital of Regensburg, D-93042 Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de The understanding of the role of adipose tissue has changed from a lipid storage organ to an endocrine and immunologically active organ. Here, we summarize the evidence for an important role of adipose tissue in innate immunity. The review focuses on the expression and function of Toll-like receptors (TLRs) in adipocytes and on the role of adipose tissue macrophages. The dual activation of TLR4 in adipocytes by lipopolysaccharide and fatty acids represents a molecular gate that connects innate immunity with metabolism. Dichotomic molecules derived from ancient precursor molecules control metabolism and immune function. Visceral adipose tissue is infiltrated by macrophages in obesity, and there is local crosstalk between these two types of cells, leading to an inflammatory transformation of adipose tissue. 2010 Elsevier Ltd. All rights reserved. PMID: 20434953 [PubMed - indexed for MEDLINE] 1401. Recenti Prog Med. 2010 Feb;101(2):57-60. [Obesity and chronic kidney disease]. [Article in Italian] Parlongo G(1), Zoccali C. Author information: (1)Unità Operativa di Nefrologia, Dialisi e Trapianto di Rene, Ospedali Riuniti, Reggio Calabria. In the last century, life expectancy in the economically developed countries has significantly increased. In parallel there has been an increase in the prevalence of obesity and of chronic kidney disease. Abdominal obesity is a relevant risk factor for death and cardiovascular complications in chronic kidney disease and in dialysis patients as well. PMID: 20433001 [PubMed - indexed for MEDLINE] 1402. Horm Res Paediatr. 2010;74(3):223-8. doi: 10.1159/000295722. Epub 2010 May 1. Ovarian adrenal rest tumor in a congenital adrenal hyperplasia patient with adrenocorticotropin hypersecretion following adrenalectomy. Tiosano D(1), Vlodavsky E, Filmar S, Weiner Z, Goldsher D, Bar-Shalom R. Author information: (1)Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel. d_tiosano@rambam.health.gov.il OBJECTIVE: Ovarian adrenal rest tumors (OARTs) are rare in contrast to testicular adrenal rest tumors. We report a case of OART in a patient with congenital adrenal hyperplasia who developed Nelson's syndrome after bilateral adrenalectomy. METHODS: We describe the clinical, imaging, and laboratory findings of the patient and review the relevant literature regarding OART and the possible interaction between ACTH and brown adipose tissue. RESULTS: An 18-year-old female with congenital adrenal hyperplasia, who had undergone bilateral adrenalectomy at the age of 10 years, presented with severe hyperpigmentation and hirsutism. Rectal ultrasonography showed a mass in the right ovary. (18)F-fluorodeoxyglucose PET/CT revealed intense uptake both in this mass and in brown adipose tissue located in typical supradiaphragmatic sites. Laparoscopic removal of the ovarian mass confirmed the diagnosis of OART. A systematic review revealed 9 documented cases of OART. As in our case, all presented with elevated ACTH levels. CONCLUSIONS: Common to all documented cases of OART are sustained high ACTH levels that activate the adrenal anlagen tissue in the ovaries. 2010 S. Karger AG, Basel. PMID: 20431278 [PubMed - indexed for MEDLINE] 1403. Ann Med. 2010 May 6;42(4):265-75. doi: 10.3109/07853891003801123. Tenomodulin gene and obesity-related phenotypes. Tolppanen AM(1), Kolehmainen M, Pulkkinen L, Uusitupa M. Author information: (1)Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. am.tolppanen@bristol.ac.uk Different cells of adipose tissue secrete compounds which regulate various biological processes. Changes in body weight, body composition, and amount of fat mass can alter the secretory profile and function of adipose tissue. Comparison of adipose tissue mRNA expression profiles before versus after weight loss or between obese and lean subjects has promoted the identification of novel adipokines. Weight loss decreases the expression of the tenomodulin (TNMD) mRNA in the adipose tissue, and the expression level is strongly correlated with body mass index. TNMD (locus Xq22) is expressed in both adipocyte and stromal vascular fraction of adipose tissue. Tenomodulin inhibits angiogenesis, but its specific function in adipose tissue is still unknown. We have reported modest association between TNMD sequence variation and different obesity-related phenotypes, including anthropometric measurements, inflammation, glucose and lipid metabolism, and age-related macular degeneration. In this review, the potential mechanisms that could link TNMD with the pathogenesis of obesity and related disorders are discussed. PMID: 20429799 [PubMed - indexed for MEDLINE] 1404. Arq Bras Cardiol. 2010 Feb;94(2):255-61, 273-9, 260-6. [Obesity and coronary artery disease: role of vascular inflammation]. [Article in English, Portuguese, Spanish] Gomes F(1), Telo DF, Souza HP, Nicolau JC, Halpern A, Serrano CV Jr. Author information: (1)Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil. Obesity is becoming a global epidemic. Around 1.1 billion adults and 10% of the world's children are currently overweight or considered obese. Generally associated with risk factors for cardiovascular disease, such as Diabetes Mellitus and systemic arterial high blood pressure, the obesity has been more and more seen as an independent risk factor for Coronary Artery Disease (CAD). Coronary arteriosclerosis comprises a series of inflammatory responses at cellular and molecular level, whose reactions are stronger in obese patients. In the past, the adipose tissue was regarded as a mere fat deposition. Now it is seen from a totally different standpoint, as an active endocrine and paracrine organ that produces several inflammatory cytokines, such as the adipokines. This article aims to raise awareness about obesity as an increasingly significant public health issue over the past decades, as well as to relate the intense inflammatory process in obese individuals with an increased tendency for this group of individuals to develop CAD. PMID: 20428625 [PubMed - indexed for MEDLINE] 1405. Orv Hetil. 2010 May 9;151(19):763-73. doi: 10.1556/OH.2010.28812. [Role of phytotherapy in the prevention and treatment of obesity]. [Article in Hungarian] Balázs A(1). Author information: (1)Semmelweis Egyetem, Gyógyszerésztudományi Kar, Farmakognózia Intézet, Budapest. baland@drog.sote.hu The rapidly increasing prevalence of overweight and diabetes mellitus is a serious global threat to healthcare. Nowadays, medicinal plants and natural treatments are becoming more and more popular. Diabetes has historically been treated with plants or plant derived formulations in different cultures, mainly in China, Asia and India. Different mechanisms for the antidiabetic effect of plants have been proposed: increased release of insulin, reduction of intestinal glucose absorption, enhancement of glycogen synthesis. The scientific evidences for most of these plants are still incomplete. The large market for plant remedies has resulted in an array of unauthorized products or marketed as dietary supplements and, at the same time, no reliable pharmaceutical-grade products are registered for this purpose. PMID: 20427259 [PubMed - indexed for MEDLINE] 1406. Dtsch Med Wochenschr. 2010 May;135(18):930-4. doi: 10.1055/s-0030-1253682. Epub 2010 Apr 27. [Metabolic and cardiovascular effects of physical activity, exercise and fitness in patients with type 2 diabetes]. [Article in German] Blüher M(1), Zimmer P. Author information: (1)Universität Leipzig, Department für Innere Medizin, Klinik für Endokrinologie und Nephrologie, Leipzig, Germany. bluma@medizin.uni-leipzig.de Diabetes mellitus has reached epidemic proportions worldwide and is associated with an increased risk of cardiovascular disease and premature mortality. Chronic hyperglycemia is the clinical manifestation of diabetes and evolves through a multifactorial etiology of genetic, environmental, and behavioural factors. In the pathogenesis of type 2 diabetes, insulin resistance of the liver, skeletal muscle and fat as well as the inability of insulin secreting beta-cells to fully compensate for this insulin resistance are the central pathophysiological events. There are several lines of scientific evidence demonstrating a role of physical inactivity in the etiology and beneficial effects of exercise in both prevention and treatment of type 2 diabetes and its related morbidity. This review is focussing on recent studies that have examined the effects of increased physical activity and fitness on metabolic and cardiovascular parameters in patients with type 2 diabetes. PMID: 20425681 [PubMed - indexed for MEDLINE] 1407. Curr Osteoporos Rep. 2010 Jun;8(2):84-90. doi: 10.1007/s11914-010-0016-1. PPARs in bone: the role in bone cell differentiation and regulation of energy metabolism. Lecka-Czernik B(1). Author information: (1)Departments of Orthopaedic Surgery and Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH, 43614, USA. Beata.LeckaCzernik@utoledo.edu Obesity, diabetes, and osteoporosis are major public health concerns. Current estimates indicate that the US population consists of 25% obese, 30% diabetic and prediabetic, and, among the elderly, 50% of all osteoporotic individuals. Mechanistically, these pathologies share several features including common regulators of bone homeostasis and energy metabolism. Peroxisome proliferator-activated receptors (PPARs) represent a family of proteins that control energy turnover in adipose, liver, and muscle tissue. These proteins also control bone turnover and regulate bone cell differentiation. Recent evidence suggests that bone is an organ integral to energy metabolism not only with respect to energy storage, but also as an organ regulating systemic energy homeostasis. In this article, we review current knowledge on the role of PPARs in bone metabolism and bone cell differentiation. We also discuss the role of bone fat in modulation of bone marrow microenvironment and its possible contribution to the systemic regulation of energy metabolism. PMID: 20425615 [PubMed - indexed for MEDLINE] 1408. Curr Diab Rep. 2010 Jun;10(3):242-7. doi: 10.1007/s11892-010-0113-7. New insights on glucose pathophysiology in gestational diabetes and insulin resistance. Harlev A(1), Wiznitzer A. Author information: (1)Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer-Sheva, Israel. harlev@bgu.ac.il Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition of GDM does not preclude the possibility that unrecognized glucose intolerance may have existed before the pregnancy, and the definition applies whether insulin, oral antidiabetic agents, or dietary modification is used for treatment. Approximately 7% of all pregnancies in the United States are complicated by gestational diabetes resulting in more than 200,000 cases annually, but the prevalence ranges from 1% to 14% of all pregnancies depending on the population studied and the diagnostic tests used. Despite the better detection of GDM and recognition of its adverse consequences for mother and baby in many countries, there is still no consensus regarding GDM pathophysiology; as a result, diagnosis and treatment of GDM remain controversial. A better understanding of obesity along with new studies in GDM has identified the intra-abdominal metabolically active adipose tissue as a major factor in the pathophysiology of GDM. This review examines recent research regarding the link between obesity and glucose intolerance and highlights studies in the areas of genetics, glucose transport, and adipokines. PMID: 20425589 [PubMed - indexed for MEDLINE] 1409. Curr Diab Rep. 2010 Jun;10(3):184-91. doi: 10.1007/s11892-010-0115-5. Defects in insulin secretion and action in the pathogenesis of type 2 diabetes mellitus. Tripathy D(1), Chavez AO. Author information: (1)Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. tripathy@uthscsa.edu Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin action and insulin secretion. Although insulin resistance manifests early during the prediabetic state, a failing beta-cell function unable to overcome insulin resistance at target tissues determines the onset of T2DM. This review focuses on recent advances in the molecular mechanisms of insulin resistance and beta-cell dysfunction. The role of mitochondrial dysfunction, impaired regulation of the enteroinsular axis, and endoplasmic reticulum stress are currently the subjects of intensive research. In addition, the adipose tissue has emerged as a major endocrine organ that secretes a growing list of adipocytokines with diverse central and peripheral metabolic effects. The role of a growing number of candidate genes and transcription factors regulating insulin action and secretion is also discussed. PMID: 20425581 [PubMed - indexed for MEDLINE] 1410. Curr Rheumatol Rep. 2010 Feb;12(1):26-33. doi: 10.1007/s11926-009-0080-7. Molecular pathogenesis of skin fibrosis: insight from animal models. Smith GP(1), Chan ES. Author information: (1)New York University School of Medicine, 550 First Avenue, NBV 16N1, New York, NY 10016, USA. smithg07@nyumc.org Skin fibrosis occurs in a variety of human diseases, most notably systemic sclerosis (SSc). The end stage of scleroderma in human skin consists of excess collagen deposition in the dermis with loss of adnexal structures and associated adipose tissue. The initiating factors for this process and the early stages are believed to occur through vascular injury and immune dysfunction with a dysregulated inflammatory response. However, because of the insidious onset of the disease, this stage is rarely observed in humans and remains poorly understood. Animal models have provided a means to examine these early stages and to isolate and understand the effect of perturbations in signaling pathways, chemokines, and cytokines. This article summarizes recent progress in the understanding of the molecular pathogenesis of skin fibrosis in SSc from different animal models, both its initiation and its maintenance phases. PMCID: PMC2861786 PMID: 20425530 [PubMed - indexed for MEDLINE] 1411. Curr Hypertens Rep. 2010 Apr;12(2):99-104. doi: 10.1007/s11906-010-0096-4. Central adiposity, systemic inflammation, and the metabolic syndrome. Elks CM(1), Francis J. Author information: (1)Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA. Metabolic syndrome (MetS) is a constellation of metabolic derangements and underlying factors that significantly increases the risk for developing type 2 diabetes and cardiovascular diseases. MetS is a low-grade inflammatory condition, with systemic inflammation and inflammation of central abdominal fat as contributors. Systemic inflammation in MetS is thought to involve C-reactive protein and some proinflammatory cytokines; the nuclear factor-kappaB pathway also is believed to play a role. Inflammation of central adipose tissue leads to adipokine production, followed by secretion of adipokines into the general circulation to contribute to the overall inflammatory condition. The molecular mechanisms that contribute to this inflammation are still somewhat unclear, but several serine/threonine kinases are known to be involved. Dietary components may also contribute to central adiposity and the inflammation seen in MetS. PMID: 20424938 [PubMed - indexed for MEDLINE] 1412. Curr Hypertens Rep. 2010 Apr;12(2):105-12. doi: 10.1007/s11906-010-0097-3. The role of high-fructose corn syrup in metabolic syndrome and hypertension. Ferder L(1), Ferder MD, Inserra F. Author information: (1)Department of Physiology and Pharmacology, Ponce School of Medicine, 395 Zona Industrial Reparada 2, Ponce, PR 00716-2348, USA. leferder@psm.edu Obesity and related diseases are an important and growing health concern in the United States and around the world. Soft drinks and other sugar-sweetened beverages are now the primary sources of added sugars in Americans' diets. The metabolic syndrome is a cluster of common pathologies, including abdominal obesity linked to an excess of visceral fat, fatty liver, insulin resistance, hyperinsulinemia, dyslipidemia, and hypertension. Trends in all of these alterations are related to the consumption of dietary fructose and the introduction of high-fructose corn syrup (HFCS) as a sweetener in soft drinks and other foods. Experimental and clinical evidence suggests a progressive association between HFCS consumption, obesity, and the other injury processes. However, experimental HFCS consumption seems to produce some of the changes associated with metabolic syndrome even without increasing the body weight. Metabolic damage associated with HFCS probably is not limited to obesity-pathway mechanisms. PMID: 20424937 [PubMed - indexed for MEDLINE] 1413. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):247-56. doi: 10.1097/MED.0b013e32833919cf. Testosterone and type 2 diabetes. Grossmann M(1), Gianatti EJ, Zajac JD. Author information: (1)Department of Medicine, Austin Health/Northern Health, University of Melbourne, Heidelberg, Victoria, Australia. mathisg@unimelb.edu.au PURPOSE OF REVIEW: To describe the relationship between testosterone levels and type 2 diabetes (T2D). RECENT FINDINGS: Multiple epidemiological studies have shown that low testosterone levels are associated with and predict the future development of T2D and the metabolic syndrome. Although this relationship is confounded by the association of total testosterone with sex hormone-binding globulin, free testosterone remains associated with measures of insulin resistance and T2D in some, but not all studies. Although the link between low testosterone levels and insulin resistance is not solely a consequence of adiposity, current studies suggest that a substantial component is mediated through its association with body fat, in particular abdominal visceral adipose tissue. This testosterone-fat relationship is bi-directional, as both weight loss and testosterone therapy increase testosterone levels, reduce fat mass, and decrease insulin resistance. SUMMARY: Low testosterone levels are very commonly found in men with T2D and are associated with aging and obesity. Whether testosterone treatment in men with T2D decreases insulin resistance above that attributable to its fat-reducing effect is currently unknown. Future studies should compare testosterone treatment with lifestyle changes (exercise and weight loss measures), and other insulin-sensitizing agents. Until further evidence is available, testosterone therapy outside clinical trials should be reserved for diabetic men with unequivocal hypogonadism. PMID: 20418720 [PubMed - indexed for MEDLINE] 1414. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):224-32. doi: 10.1097/MED.0b013e3283398ee2. Androgens and obesity. Allan CA(1), McLachlan RI. Author information: (1)Prince Henry's Institute, Clayton, Victoria, Australia. PURPOSE OF REVIEW: As testosterone levels are frequently reduced in obesity, an understanding of the relationship between serum testosterone and adiposity is necessary in the clinical evaluation of these men, in particular when considering testosterone therapy. RECENT FINDINGS: Population and interventional data suggest a bi-directional relationship exists between testosterone and obesity in men, with lower total testosterone and sex hormone binding globulin (SHBG) (and to a lesser extent free testosterone) levels than their nonobese peers; obesity having an impact at least as important as ageing. Abnormalities in the hypothalamo-pituitary-testicular axis are seen with increasing obesity. Weight loss in massive obesity increases testosterone levels but its role in mild-moderate obesity is unclear. Testosterone supplementation reduces total body fat in hypogonadal and ageing men although the effects on regional fat distribution are less well described. SUMMARY: Favourable changes in total body fat and regional fat distribution suggest a potential role for testosterone in obesity. However, lifestyle advice to achieve sustained weight loss should be the mainstay of management. Obese men with confirmed androgen deficiency can be offered treatment, whereas in those with low-normal testosterone levels more research is needed. PMID: 20418719 [PubMed - indexed for MEDLINE] 1415. Biochimie. 2010 Nov;92(11):1580-6. doi: 10.1016/j.biochi.2010.04.011. Epub 2010 Apr 24. Cathepsins and cystatin C in atherosclerosis and obesity. Lafarge JC(1), Naour N, Clément K, Guerre-Millo M. Author information: (1)INSERM, U872, Eq7 Nutriomique, Paris, F-75006, France. Given the increasing prevalence of human obesity worldwide, there is an urgent need for a better understanding of the molecular mechanisms linking obesity to metabolic and cardiovascular diseases. Our knowledge is nevertheless limited regarding molecules linking adipose tissue to downstream complications. The importance of cathepsins was brought to light in this context. Through a large scale transcriptomic analysis, our group recently identified the gene encoding cathepsin S as one of the most deregulated gene in the adipose tissue of obese subjects and positively correlated with body mass index. Other members of the cathepsin family are expressed in the adipose tissue, including cathepsin K and cathepsin L. Given their implication in atherogenesis, these proteases could participate into the well established deleterious relationship between enlarged adipose tissue and increased cardiovascular risk. Here, we review the clinical and experimental evidence relevant to the role of cathepsins K, L and S and their most abundant endogenous inhibitor, cystatin C, in atherosclerosis and in obesity. Copyright © 2010 Elsevier Masson SAS. All rights reserved. PMID: 20417681 [PubMed - indexed for MEDLINE] 1416. Osteoarthritis Cartilage. 2010 Jul;18(7):876-82. doi: 10.1016/j.joca.2010.03.014. Epub 2010 Apr 22. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Clockaerts S(1), Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJ, Van Offel JF, Verhaar JA, De Clerck LS, Somville J. Author information: (1)University of Antwerp, Department of Medicine, Belgium. stefan.clockaerts@ua.ac.be INTRODUCTION: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by inflammation, in combination with biomechanical alterations. It is characterized by loss of articular cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process. This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an additional joint tissue involved in the development and progression of knee-OA. METHODS: A literature search was performed in Pubmed from 1948 until October 2009 with keywords InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipokine, inflammation, growth factor, arthritis, and OA. RESULTS: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P, which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema and extravasation of the immune cells. The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of pro-inflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium. CONCLUSION: These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue capable of modulating inflammatory and destructive responses in knee-OA. Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. PMID: 20417297 [PubMed - indexed for MEDLINE] 1417. Prog Neurobiol. 2010 Aug;91(4):275-99. doi: 10.1016/j.pneurobio.2010.04.004. Epub 2010 Apr 22. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Shelton RC(1), Miller AH. Author information: (1)Vanderbilt University, 1500 21st Avenue South, Suite 2200, Nashville, TN 37212, USA. richard.shelton@vanderbilt.edu Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor alpha (TNFalpha), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon alpha develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFalpha; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role. (c) 2010 Elsevier Ltd. All rights reserved. PMCID: PMC2929810 PMID: 20417247 [PubMed - indexed for MEDLINE] 1418. Diabetes Obes Metab. 2010 May;12(5):365-83. doi: 10.1111/j.1463-1326.2009.01176.x. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Polyzos SA(1), Kountouras J, Zavos C, Tsiaousi E. Author information: (1)Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece. stergios@endo.gr Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed. PMID: 20415685 [PubMed - indexed for MEDLINE] 1419. Annu Rev Nutr. 2010 Aug 21;30:341-64. doi: 10.1146/annurev.nutr.012809.104747. Physiological insights gained from gene expression analysis in obesity and diabetes. Keller MP(1), Attie AD. Author information: (1)Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706-1544, USA. Microarray technology permits the interrogation of nearly all expressed genes under a wide range of conditions. Patterns of gene expression in response to obesity and diabetes have yielded important insights into the pathogenesis of diabetes and its relationship to obesity. In muscle, microarray studies have motivated research into mitochondrial function. In adipose tissue, clues have pointed to the importance of inflammation in obesity. New adipocyte-derived hormones involved in insulin resistance have been found; a notable example is retinol binding protein 4. In liver, genes responsive to master regulators of lipid metabolism have been identified. In beta-cells, genes involved in cell survival, cell proliferation, and insulin secretion have been identified. These studies have greatly expanded our understanding of mechanisms underlying the pathogenesis of obesity-induced diabetes. When combined with genetic information, microarray data can be used to construct causal network models linking gene expression with disease. PMID: 20415584 [PubMed - indexed for MEDLINE] 1420. Mediators Inflamm. 2010;2010:585989. doi: 10.1155/2010/585989. Epub 2010 Apr 20. Systemic inflammation in chronic obstructive pulmonary disease: may adipose tissue play a role? Review of the literature and future perspectives. Tkacova R(1). Author information: (1)Department of Respiratory Medicine and Tuberculosis, Faculty of Medicine, P J Safarik University, L. Pasteur Teaching Hospital, Kosice, Slovakia. ruzena.tkacova@upjs.sk Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Low-grade systemic inflammation is considered a hallmark of COPD that potentially links COPD to increased rate of systemic manifestations of the disease. Obesity with/without the metabolic syndrome and cachexia represent two poles of metabolic abnormalities that may relate to systemic inflammation. On one hand systemic inflammatory syndrome likely reflects inflammation in the lungs, i.e. results from lung-to plasma spillover of inflammatory mediators. On the other hand, obesity-related hypoxia results in local inflammatory response within adipose tissue per se, and may contribute to elevations in circulatory mediators by spillover from the adipose tissue to the systemic compartment. The extent to which systemic hypoxia contributes to the adipose tissue inflammation remains unknown. We assume that in patients with COPD and concurrent obesity at least three factors play a role in the systemic inflammatory syndrome: the severity of pulmonary impairment, the degree of obesity-related adipose tissue hypoxia, and the severity of systemic hypoxia due to reduced pulmonary functions. The present review summarizes the epidemiological and clinical evidence linking COPD to obesity, the role of adipose tissue as an endocrine organ, and the role of hypoxia in adipose tissue inflammation. PMCID: PMC2857618 PMID: 20414465 [PubMed - indexed for MEDLINE] 1421. Rev Med Liege. 2010 Mar;65(3):140-6. [Modulation of tissue exposure to cortisol, new perspective for reducing the metabolic risk associated with obesity]. [Article in French] Iovino A(1), Scheen AJ. Author information: (1)Université de Liège. Pharmaceutical research is looking for new alternatives to manage the metabolic disorders associated with obesity. In this context, 11beta hydroxysteroid dehydrogenase type 1 (11HSD1) represents an interesting target. Indeed, this enzyme activates the transformation of inactive cortisone into active cortisol in various tissues. Therefore, it may be responsible for a local hypercortisolism, in adipose tissue and/or liver, which may be implicated in the pathogenesis of abdominal obesity, metabolic syndrome and type 2 diabetes. Thus, the inhibition of 11HSD1 may represent a potential pharmacological target and an innovative therapeutic goal. Several studies in both animals and humans led to the development of specific 11HSD1 inhibitors, with promising preliminary results. Indeed, a reduction in insulin resistance and significant improvements in carbohydrate and lipid profiles have been reported. The present article describes the rationale that led to the development of specific 11HSD1 inhibitors and briefly reports the first results obtained with these molecules, which may become a new class of antidiabetic agents in the future. PMID: 20411818 [PubMed - indexed for MEDLINE] 1422. J Physiol Pharmacol. 2009 Dec;60 Suppl 7:19-24. The metabolic syndrome - an ongoing story. Duvnjak L(1), Duvnjak M. Author information: (1)Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Zagreb, Croatia. lduvnjak@idb.hr The metabolic syndrome refers to the clustering of cardiovascular risk factors that include diabetes, obesity, dyslipidaemia and hypertension. Due to various definitions and unexplained pathophysiology it is still a source of medical controversy. Insulin resistance and visceral obesity have been recognized as the most important pathogenic factors. Insulin resistance could be defined as the inability of insulin to produce its numerous actions, in spite of the unimpaired secretion from the beta cells. Metabolic abnormalities result from the interaction between the effects of insulin resistance located primarily in the muscle and adipose tissue and the adverse impact of the compensatory hyperinsulinaemia on tissues that remain normally insulin-sensitive. The clinical heterogeneity of the syndrome can be explained by its significant impact on glucose, fat and protein metabolism, cellular growth and differentiation, and endothelial function. Visceral fat represents a metabolically active organ, strongly related to insulin sensitivity. Moderating the secretion of adipocytokines like leptin, adiponectin, plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor alfa (TNF-alfa), interleukin-6 (IL-6) and resistin, it is associated with the processes of inflammation, endothelial dysfunction, hypertension and atherogenesis. In 2005, the International Diabetes Federation (IDF) has proposed a new definition, based on clinical criteria and designed for global application in clinical practice. Visceral obesity measured by waist circumference is an essential requirement for diagnosis; other variables include increased triglyceride and decreased HDL levels, hypertension and glucose impairment. Whatever the uncertainties of definition and etiology, metabolic syndrome represents a useful and simple clinical concept which allows earlier detection of type 2 diabetes and cardiovascular disease. PMID: 20388942 [PubMed - indexed for MEDLINE] 1423. Curr Opin Lipidol. 2010 Jun;21(3):172-7. doi: 10.1097/MOL.0b013e3283393867. Adipose tissue recruitment of leukocytes. Anderson EK(1), Gutierrez DA, Hasty AH. Author information: (1)Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA. PURPOSE OF REVIEW: In December of 2003, two seminal articles describing the presence of macrophages in obese adipose tissue were published. These adipose tissue macrophages (ATMs) are inflammatory and promote local and systemic insulin resistance. Due to the continuing rise in obesity around the world, understanding how these ATMs contribute to metabolic disorders is of much interest. RECENT FINDINGS: Chemokines have been extensively studied for their role in ATM recruitment. Deficiency or antagonism of chemokine receptors that interact with multiple chemokine ligands reduces ATM accumulation. ATMs are now defined as either classically (M1) or alternatively (M2) activated. Peroxisome proliferator-activated receptor activation and adiponectin promote an M2-polarized state resulting in improved insulin sensitivity. Finally, recent studies have provided evidence that T lymphocytes, natural killer T cells, mast cells, and B cells also enter adipose tissue and may interact with macrophages and adipocytes. SUMMARY: Literature published during the past year has shown that macrophage recruitment to adipose tissue is only one of the important mediators of obesity-related insulin resistance. The phenotype of ATMs and recruitment of other immune cells to the adipose tissue play key roles in the overall contribution of adipose tissue to systemic metabolic outcomes of obesity. PMCID: PMC3381420 PMID: 20410821 [PubMed - indexed for MEDLINE] 1424. Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E3-9. doi: 10.1152/ajpendo.00157.2010. Epub 2010 Apr 20. The many facets of PPARgamma: novel insights for the skeleton. Kawai M(1), Sousa KM, MacDougald OA, Rosen CJ. Author information: (1)Maine Medical Center Research Institute, Scarborough, ME 04074, USA. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that functions as a master transcriptional regulator of adipocyte conversion. During PPARgamma transactivation, multiple signaling pathways interact with one another, leading to the differentiation of both white and brown adipose tissue. Ligand activation of the PPARgamma-RXR heterodimer complex also enhances insulin sensitivity, and this property has been heavily exploited to develop effective pharmacotherapies for the treatment of type 2 diabetes mellitus. PPARgamma is also expressed in stem cells and plays a critical role in mesenchymal stromal cell differentiation and lineage determination events. The many facets of PPARgamma activity within the bone marrow niche where adipocytes, osteoblasts, and hematopoietic cells reside make this molecule an attractive target for pharmacological investigation. Additional findings that osteoblasts can alter energy metabolism by influencing adiposity and insulin sensitivity, and observations of decreased bone turnover in diabetic subjects, underscore the contribution of the skeleton to systemic energy requirements. Studies into the role of PPARgamma in skeletal acquisition and maintenance may lead to a better understanding of the molecular mechanisms governing stromal cell differentiation in the mesenchyme compartment and whether PPARgamma activity can be manipulated to benefit skeletal remodeling events and energy metabolism. PMCID: PMC2904052 PMID: 20407009 [PubMed - indexed for MEDLINE] 1425. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):205-9. doi: 10.1097/MED.0b013e3283394441. Adrenal function in HIV infection. Lo J(1), Grinspoon SK. Author information: (1)Program in Nutritional Metabolism and Neuroendocrine Clinic, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. PURPOSE OF REVIEW: Adrenal dysfunction can increase morbidity and mortality among patients with HIV infection. Disorders and medications affecting cortisol, aldosterone or adrenal androgens in patients with HIV infection are reviewed. RECENT FINDINGS: Iatrogenic Cushing's syndrome and hypothalamic-pituitary-adrenal suppression from concomitant use of ritonavir with nonsystemic corticosteroids such as intra-articular triamcinolone in addition to the previously reported interactions with inhaled fluticasone are increasingly recognized in HIV patients. Integrated measure of aldosterone throughout the day is higher in patients with HIV-associated visceral adipose tissue accumulation. SUMMARY: Abnormalities in adrenal function are more common in HIV patients than in the general population. HIV care providers should pursue workup for adrenal dysfunction in HIV patients when symptoms or signs are present, especially in patients with advanced AIDS or receiving medications that can affect adrenal function. The clinical implications of aldosterone elevation in HIV patients with visceral adiposity will need to be examined in future research studies. PMID: 20404726 [PubMed - indexed for MEDLINE] 1426. Ann N Y Acad Sci. 2010 Apr;1193:36-42. doi: 10.1111/j.1749-6632.2009.05383.x. The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases. Cutolo M(1), Brizzolara R, Atzeni F, Capellino S, Straub RH, Puttini PC. Author information: (1)Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy. mcutolo@unige.it Immunological, epidemiological, and clinical evidence suggest that female sex hormones play an important role in the etiology and pathophysiology of chronic immune/inflammatory diseases. Several significant factors generate confusion and opposite conclusions in evaluating the role of estrogens in these diseases, including relatively superficial translational studies from animals to the human condition, the different effects of estrogens on their different receptors or on different target cells, the different estrogen concentrations employed, and opposite effects (especially on cell proliferation) exerted by different peripheral estrogen metabolites. A preponderance of 16alpha-hydroxylated estrogens, as observed in rheumatoid arthritis synovial fluids, is an unfavorable sign in synovial inflammation. Since 17beta-estradiol administered during hormone replacement therapy will rapidly increase estrone sulfate after conversion in adipose tissue by aromatases, hormone replacement therapy can have proinflammatory effects by providing estrone sulfate to the inflamed synovial tissue. In addition, it appears that the use of combined oral contraceptives is associated with an increased risk of at least systemic lupus erythematosus. In conclusion, estrogens are generally considered as enhancers of cell proliferation and humoral immune response. PMID: 20398006 [PubMed - indexed for MEDLINE] 1427. Obesity (Silver Spring). 2010 Nov;18(11):2071-6. doi: 10.1038/oby.2010.91. Epub 2010 Apr 15. Adipose "talks" to distant organs to regulate insulin sensitivity and vascular function. Zhang H(1), Zhang C. Author information: (1)Department of Internal Medicine, University of Missouri-Columbia, Columbia, Missouri, USA. zhangcu@missouri.edu PMCID: PMC2946982 PMID: 20395945 [PubMed - indexed for MEDLINE] 1428. Reproduction. 2010 Sep;140(3):347-64. doi: 10.1530/REP-09-0568. Epub 2010 Apr 15. The adverse effects of obesity on conception and implantation. Brewer CJ(1), Balen AH. Author information: (1)The Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, LS14 6UH, UK. Whilst many multiparous women are obese (body mass index >30 kg/m(2)), obesity has been associated with impaired fecundity; however, the mechanism which links obesity to reduced fertility remains to be fully elucidated. Obese women, particularly those with central obesity, are less likely to conceive per cycle. Obese women suffer perturbations to the hypothalamic-pituitary-ovarian axis, menstrual cycle disturbance and are up to three times more likely to suffer oligo-/anovulation. A fine hormonal balance regulates follicular development and oocyte maturation, and it has been observed that obesity can alter the hormonal milieu. Leptin, a hormone produced by adipocytes, is elevated in obese women, and raised leptin has been associated with impaired fecundity. Obesity impairs ovulation but has also been observed to detrimentally affect endometrial development and implantation. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, and so obese women with PCOS often have a more severe phenotype and experience more subfertility. Obesity also impairs the response of women to assisted conception treatments. Weight loss through lifestyle modification or bariatric surgery has been demonstrated to restore menstrual cyclicity and ovulation and improve the likelihood of conception. In this article, we will discuss the effect of obesity upon key reproductive mechanisms and its relation to fertility treatments. PMID: 20395425 [PubMed - indexed for MEDLINE] 1429. Adv Drug Deliv Rev. 2010 Jun 15;62(7-8):798-813. doi: 10.1016/j.addr.2010.04.003. Epub 2010 Apr 13. Cell-delivery therapeutics for adipose tissue regeneration. Bauer-Kreisel P(1), Goepferich A, Blunk T. Author information: (1)Department of Trauma, Hand, Plastic & Reconstructive Surgery, University of Würzburg, Germany. In reconstructive surgery, there is a tremendous clinical need for adequate implants to repair soft tissue defects resulting from traumatic injury, tumor resection, or congenital anomalies. Adipose tissue engineering holds the promise to provide answers to this still increasing demand. The current approaches to adipose tissue engineering are comprehensively reviewed detailing the different cell carriers under investigation. A special focus is put on the applied cells. The delivered mesenchymal stem cells act in a dual role as building block of the new tissue and modulators of the host response. The conditioning of the cells in vitro prior to implantation decisively influences the tissue development and long-term survival in vivo. The special role of vascularization in adipose engineering is discussed. In all parts, key messages are defined providing the base for future advances in the generation of fat substitutes. 2010 Elsevier B.V. All rights reserved. PMID: 20394786 [PubMed - indexed for MEDLINE] 1430. Mol Endocrinol. 2010 Oct;24(10):1891-903. doi: 10.1210/me.2010-0015. Epub 2010 Apr 14. Minireview: Nuclear hormone receptor 4A signaling: implications for metabolic disease. Pearen MA(1), Muscat GE. Author information: (1)Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia. m.pearen@uq.edu.au Numerous members of the nuclear hormone receptor (NR) superfamily have been demonstrated to regulate metabolic function in a cell- and tissue-specific manner. This review brings together recent studies that have associated members of the NR superfamily, the orphan NR4A subgroup, with the regulation of metabolic function and disease. The orphan NR4A subgroup includes Nur77 (NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3). Expression of these receptors is induced in multiple tissues by a diverse range of stimuli, including stimuli associated with metabolic function, such as: β-adrenoceptor agonists, cold, fatty acids, glucose, insulin, cholesterol, and thiazolidinediones. In vitro and in vivo gain- and loss-of-function studies in major metabolic tissues (including skeletal muscle, adipose, and liver cells and tissues) have associated the NR4A subgroup with specific aspects of lipid, carbohydrate, and energy homeostasis. Most excitingly, although these orphan receptors do not have known endogenous ligands, several small molecule agonists have recently been identified. The preliminary studies reviewed in this manuscript suggest that therapeutic exploitation of the NR4A subgroup may show utility against dyslipidemia, obesity, diabetes, and cardiovascular disease. PMID: 20392876 [PubMed - indexed for MEDLINE] 1431. Nutrition. 2010 Jul-Aug;26(7-8):686-93. doi: 10.1016/j.nut.2009.10.013. Epub 2010 Apr 14. Metabolic actions of insulin in men and women. Magkos F(1), Wang X, Mittendorfer B. Author information: (1)Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA. Insulin is an important regulator of glucose, lipid, and protein metabolism. It suppresses hepatic glucose and triglyceride production, inhibits adipose tissue lipolysis and whole-body and muscle proteolysis, and stimulates glucose uptake in muscle. In this review we discuss what is currently known about the control of substrate metabolism by insulin in men and women. The data available so far indicate that women are more sensitive to insulin with regards to glucose metabolism (both in the liver and in muscle), whereas there are no differences between men and women in insulin action on lipolysis. Potential differences exist in the regulation of plasma triglyceride concentration and protein metabolism by insulin and in changes in insulin action in response to stimuli (e.g., weight loss and exercise) that are known to alter insulin sensitivity. However, these areas have not been studied comprehensively enough to draw firm conclusions. 2010 Elsevier Inc. All rights reserved. PMCID: PMC2893237 PMID: 20392600 [PubMed - indexed for MEDLINE] 1432. Semin Thromb Hemost. 2010 Feb;36(1):41-8. doi: 10.1055/s-0030-1248723. Epub 2010 Apr 13. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Targher G(1), Zoppini G, Moghetti P, Day CP. Author information: (1)Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy. giovanni.targher@univr.it Abdominal obesity represents a public health concern because its prevalence is reaching epidemic proportions worldwide, and it is associated with an increased risk of cardiovascular morbidity and mortality and other pathological conditions. A large body of evidence suggests that abdominal obesity is associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombosis in these individuals. This review briefly summarizes the evidence of direct and indirect effects of the accumulation of excess lipid in visceral adipose tissue on coagulation and fibrinolysis. In addition, this article critically appraises the rapidly expanding body of experimental and clinical data that support a potential direct contribution for the accumulation of excess lipid in the liver (i.e., nonalcoholic fatty liver disease, a very frequent pathological condition in subjects with abdominal obesity) in the pathogenesis of the obesity-induced disorders of coagulation and fibrinolysis. PMID: 20391295 [PubMed - indexed for MEDLINE] 1433. Ann N Y Acad Sci. 2010 Mar;1190:15-24. doi: 10.1111/j.1749-6632.2009.05266.x. Fructose consumption: recent results and their potential implications. Stanhope KL(1), Havel PJ. Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA. In addition to acquiring a better understanding of foods that may have intrinsic health benefits, increasing our knowledge of dietary components that may adversely impact health and wellness, and the levels of consumption at which these adverse effects may occur, should also be an important priority for the Foods for Health initiative. This review discusses the evidence that additional research is needed to determine the adverse effects of consuming added sugars containing fructose. Current guidelines recommend limiting sugar consumption in order to prevent weight gain and promote nutritional adequacy. However, recent data suggest that fructose consumption in human results in increased visceral adiposity, lipid dysregulation, and decreased insulin sensitivity, all of which have been associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed model for the differential effects of fructose and glucose is presented. The only published study to directly compare the effects of fructose with those of commonly consumed dietary sweeteners, high fructose corn syrup and sucrose, indicates that high fructose corn syrup and sucrose increase postprandial triglycerides comparably to pure fructose. Dose-response studies investigating the metabolic effects of prolonged consumption of fructose by itself, and in combination with glucose, on lipid metabolism and insulin sensitivity in both normal weight and overweight/obese subjects are needed. PMCID: PMC3075927 PMID: 20388133 [PubMed - indexed for MEDLINE] 1434. Ann N Y Acad Sci. 2010 Mar;1190:1-14. doi: 10.1111/j.1749-6632.2009.05262.x. The importance of dietary modulation of cAMP and insulin signaling in adipose tissue and the development of obesity. Madsen L(1), Kristiansen K. Author information: (1)National Institute of Nutrition and Seafood Research, Bergen, Norway. lmad@nifes.no Adipose tissue plays a pivotal role in whole body energy homeostasis. In this review, we summarize knowledge of the seemingly paradoxical roles of insulin and cyclic adenosine monophosphate (cAMP) signaling in adipocyte differentiation and function, emphasizing the interplay between the two branches of cAMP signaling, the canonical protein kinase A-dependent pathways and the novel exchange protein activated by cAMP (Epac)-dependent pathways, and insulin signaling. We discuss how macronutrients via changes in the balance between insulin- and cAMP-dependent signaling can affect the development of obesity by changing energy expenditure and/or feed efficiency. We review results demonstrating how the balance between different classes of carbohydrates and proteins modulates the obesigenic action of saturated as well as unsaturated fatty acids pointing to insulin as a key determinant in the regulation of the metabolic/regulatory action of both n-3 and n-6 polyunsaturated fatty acids. PMID: 20388132 [PubMed - indexed for MEDLINE] 1435. Curr Pharm Des. 2010;16(6):609-18. Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches. Cevenini E(1), Caruso C, Candore G, Capri M, Nuzzo D, Duro G, Rizzo C, Colonna-Romano G, Lio D, Di Carlo D, Palmas MG, Scurti M, Pini E, Franceschi C, Vasto S. Author information: (1)Department of Experimental Pathology, University of Bologna, Italy. A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented. PMID: 20388071 [PubMed - indexed for MEDLINE] 1436. Int J Pediatr Obes. 2010 Oct;5(5):451-5. doi: 10.3109/17477161003770123. Interventions for improving metabolic risk in overweight Latino youth. Davis JN(1), Ventura EE, Shaibi GQ, Byrd-Williams CE, Alexander KE, Vanni AK, Meija MR, Weigensberg MJ, Spruijt-Metz D, Goran MI. Author information: (1)Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USA. jaimieda@usc.edu This review highlights various components of interventions that reduced obesity and type 2 diabetes risk factors among overweight Latino youth. A total of 114 overweight Latino adolescents completed one of four randomized controlled trials: 1) strength training (ST; boys only); 2) modified carbohydrate nutrition program (N); 3) combination of N+ST; or 4) N + Combination of Aerobic and ST (N+CAST; girls only). Measures included: strength by 1-repetition max, dietary intake by 3-d records, body composition by DEXA/MRI, glucose/insulin indices by oral and IV glucose tolerance tests. ST improved insulin sensitivity by 45% in Latino boys, and N, N+ST, and N+CAST improved glucose control in Latino boys and girls. The CAST approach reduced all adiposity measures by ∼3% in Latina girls. Participants who decreased added sugar, increased dietary fiber, and had increased parental attendance, regardless of intervention group, improved insulin action and reduced visceral adipose tissue. In conclusion, ST, CAST, and a modified carbohydrate nutrition program with separate parental classes were all successful components of the interventions that decreased obesity and related metabolic diseases. PMCID: PMC3752963 PMID: 20387989 [PubMed - indexed for MEDLINE] 1437. Nat Rev Endocrinol. 2010 Jun;6(6):319-25. doi: 10.1038/nrendo.2010.64. Epub 2010 Apr 13. Brown adipose tissue--a new role in humans? Lidell ME(1), Enerbäck S. Author information: (1)Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Box 440, SE-40530 Gothenburg, Sweden. New targets for pharmacological interventions are of great importance to combat the epidemic of obesity. Brown adipose tissue could potentially represent one such target. Unlike white adipose tissue, brown adipose tissue has the ability to dissipate energy by producing heat rather than storing it as triglycerides. In small mammals, the presence of active brown adipose tissue is pivotal for the maintenance of body temperature and possibly to protect against the detrimental effects of surplus energy intake. Animal studies have shown that expansion and/or activation of brown adipose tissue counteracts diet-induced weight gain and related disorders such as type 2 diabetes mellitus. Several independent studies have now confirmed the presence of functional brown adipose tissue in adult humans, for whom this tissue is probably metabolically beneficial given its association with both low BMI and low total adipose tissue content. Over the past few years, knowledge of the transcriptional control and development of brown adipose tissue has increased substantially. Thus, several possible targets that may be useful for the expansion and/or activation of this tissue by pharmacological means have been identified. Whether or not brown adipose tissue will be useful in the battle against obesity remains to be seen. However, this possibility is certainly well worth exploring. PMID: 20386559 [PubMed - indexed for MEDLINE] 1438. FEBS Lett. 2010 Jun 18;584(12):2689-98. doi: 10.1016/j.febslet.2010.04.004. Epub 2010 Apr 10. An allostatic control of membrane lipid composition by SREBP1. Hagen RM(1), Rodriguez-Cuenca S, Vidal-Puig A. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, UK. rmh51@cam.ac.uk The maintenance of membrane lipid composition within strict limits is critical to maintain optimum cellular function. The biophysical properties of the membrane can be influenced among other factors by the saturation/unsaturation of the phospholipid fatty acyl chain. The rate-limiting enzyme in unsaturated fatty acid biosynthesis is the desaturase enzyme which in turn is regulated by the lipid transcription factor sterol regulatory element binding protein (SREBP1). In this review, we collect some evidence suggesting SREBP1 network as an important allostatic regulator necessary to maintain the pool of unsaturated fatty acid lipid species that can be incorporated into biological membranes. Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. PMID: 20385130 [PubMed - indexed for MEDLINE] 1439. Physiol Behav. 2010 Jul 14;100(5):545-8. doi: 10.1016/j.physbeh.2010.03.019. Epub 2010 Apr 8. Glucagon regulation of energy metabolism. Heppner KM(1), Habegger KM, Day J, Pfluger PT, Perez-Tilve D, Ward B, Gelfanov V, Woods SC, DiMarchi R, Tschöp M. Author information: (1)Division of Endocrinology, Department of Medicine University of Cincinnati, Metabolic Diseases Institute, Cincinnati, Ohio 45237, United States. Glucagon has long been known as a counter-regulatory hormone to insulin of fundamental importance to glucose homeostasis. Its prominent ability to stimulate glycogenolysis and gluconeogenesis, has historically cast this peptide as one hormone where the metabolic consequences of increasing blood glucose levels, especially in obesity, are viewed largely as being deleterious. This perspective may be changing in light of emerging data and reconsideration of historic studies, which suggest that glucagon has beneficial effects on body fat mass, food intake, and energy expenditure. In this review, we discuss the mechanisms of glucagon-mediated body weight regulation as well as possible novel therapeutic approaches in the treatment of obesity and glucose intolerance that may arise from these findings. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. Published by Elsevier Inc. PMID: 20381509 [PubMed - indexed for MEDLINE] 1440. Histol Histopathol. 2010 Jun;25(6):807-15. Defining adipose tissue-derived stem cells in tissue and in culture. Lin CS(1), Xin ZC, Deng CH, Ning H, Lin G, Lue TF. Author information: (1)Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA. clin@urology.ucsf.edu Adipose tissue-derived stem cells (ADSC) are routinely isolated from the stromal vascular fraction (SVF) of homogenized adipose tissue. Similar to other types of mesenchymal stem cells (MSC), ADSC remain difficult to define due to the lack of definitive cellular markers. Still, many types of MSC, including ADSC, have been shown to reside in a perivascular location, and increasing evidence shows that both MSC and ADSC may in fact be vascular stem cells (VSC). Locally, these cells differentiate into smooth muscle and endothelial cells that are assembled into newly formed blood vessels during angiogenesis and neovasculogenesis. Additionally, MSC or ADSC can also differentiate into tissue cells such as adipocytes in the adipose tissue. Systematically, MSC or ADSC are recruited to injury sites where they participate in the repair/regeneration of the injured tissue. Due to the vasculature's dynamic capacity for growth and multipotential nature for diversification, VSC in tissue are individually at various stages and on different paths of differentiation. Therefore, when isolated and put in culture, these cells are expected to be heterogeneous in marker expression, renewal capacity, and differentiation potential. Although this heterogeneity of VSC does impose difficulties and cause confusions in basic science studies, its impact on the development of VSC as a therapeutic cell source has not been as apparent, as many preclinical and clinical trials have reported favorable outcomes. With this understanding, ADSC are generally defined as CD34+CD31- although loss of CD34 expression in culture is well documented. In adipose tissue, CD34 is localized to the intima and adventitia of blood vessels but not the media where cells expressing alpha-smooth muscle actin (SMA) exist. By excluding the intima, which contains the CD34+CD31+ endothelial cells, and the media, which contains the CD34-CD31- smooth muscle cells, it leaves the adventitia as the only possible location for the CD34+ ADSC. In the capillary, CD34 and CD140b (a pericyte marker) are mutually exclusively expressed, thus suggesting that pericytes are not the CD34+ ADSC. Many other cellular markers for vascular cells, stem cells, and stem cell niche have also been investigated as possible ADSC markers. Particularly the best-known MSC marker STRO-1 has been found either expressed or not expressed in cultured ADSC. In the adipose tissue, STRO-1 appears to be expressed exclusively in the endothelium of certain but not all blood vessels, and thus not associated with the CD34+ ADSC. In conclusion, we believe that ADSC exist as CD34+CD31-CD104b-SMA- cells in the capillary and in the adventitia of larger vessels. In the capillary these cells coexist with pericytes and endothelial cells, both of which are possibly progenies of ADSC (or more precisely VSC). In the larger vessels, these ADSC or VSC exist as specialized fibroblasts (having stem cell properties) in the adventitia. PMID: 20376787 [PubMed - indexed for MEDLINE] 1441. Cell Metab. 2010 Apr 7;11(4):268-72. doi: 10.1016/j.cmet.2010.03.007. The changed metabolic world with human brown adipose tissue: therapeutic visions. Nedergaard J(1), Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm University, SE-10691 Stockholm, Sweden. jan@metabol.su.se That adult humans possess active brown adipose tissue potentially leads to a paradigm shift in the understanding of human metabolism and of obesity. Adaptive adrenergic thermogenesis in humans represents brown adipose tissue activity, the absence of which may contribute to middle-age obesity. 2010 Elsevier Inc. All rights reserved. PMID: 20374959 [PubMed - indexed for MEDLINE] 1442. Cell Metab. 2010 Apr 7;11(4):263-7. doi: 10.1016/j.cmet.2010.03.009. Brown fat and the myth of diet-induced thermogenesis. Kozak LP(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. kozaklp@pbrc.edu The notion that brown adipose tissue (BAT) in mice or humans maintains energy balance by burning off excess calories seems incompatible with evolutionary biology. Studies in obese rats and mice lacking UCP1 indicate that diet-induced thermogenesis by BAT is unlikely. 2010 Elsevier Inc. All rights reserved. PMCID: PMC2867325 PMID: 20374958 [PubMed - indexed for MEDLINE] 1443. Cell Metab. 2010 Apr 7;11(4):257-62. doi: 10.1016/j.cmet.2010.03.005. Transcriptional control of brown fat development. Kajimura S(1), Seale P, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Deconvoluting the natural pathway of BAT development has defined key molecular events, which enables researchers to manipulate the amount or activity of brown fat. We review recent advances on the transcriptional regulation of BAT development and discuss the emerging questions. 2010 Elsevier Inc. All rights reserved. PMCID: PMC2857670 PMID: 20374957 [PubMed - indexed for MEDLINE] 1444. Cell Metab. 2010 Apr 7;11(4):253-6. doi: 10.1016/j.cmet.2010.03.004. Distribution and development of brown adipocytes in the murine and human adipose organ. Frontini A(1), Cinti S. Author information: (1)Department of Molecular Pathology and Innovative Therapies, University of Ancona (Politecnica delle Marche), IT-60020 Ancona, Italy. Murine white and brown adipocytes are found together in dissectible visceral and subcutaneous fat depots supplied by specific vessels and nerves, forming a multi-depot organ with plastic properties. Many of the anatomo-physiological features of murine fat depots apply to humans. 2010 Elsevier Inc. All rights reserved. PMID: 20374956 [PubMed - indexed for MEDLINE] 1445. Cell Metab. 2010 Apr 7;11(4):248-52. doi: 10.1016/j.cmet.2010.03.008. Human brown adipose tissue. Enerbäck S(1). Author information: (1)Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, P.O. Box 440, SE 40530 Göteborg, Sweden. sven.enerback@medgen.gu.se The BAT organ is unique in that it has evolved to safely dissipate large amounts of chemical energy--a quality that might be harnessed to help humans deal with a dangerously hypercaloric environment and still remain in good health. 2010 Elsevier Inc. All rights reserved. PMID: 20374955 [PubMed - indexed for MEDLINE] 1446. Curr Pharm Des. 2010 Jun;16(17):1941-51. Insulin resistance in nonalcoholic fatty liver disease. Bugianesi E(1), Moscatiello S, Ciaravella MF, Marchesini G. Author information: (1)Department of Gastroenterology and Hepatology, S. Giovanni Battista Hospital, University of Turin. Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is considered the hepatic component of the metabolic syndrome and insulin resistance represents its pathophysiological hallmark. Insulin resistance in NAFLD is characterized by reduced whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanism(s) underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Liver fat is highly correlated with all the components of the metabolic syndrome, independent of obesity, and NAFLD may increase the risk of type 2 diabetes and atherosclerosis. Overproduction of glucose, very low-density lipoproteins, C-reactive protein and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease. The reason(s) why some patients will develop NASH are poorly understood. Circulating free fatty acids may be cytotoxic by inducing lipid peroxidation and hepatocyte apoptosis. Insulin resistance is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes may contribute liver damage and liver disease progression. Understanding the molecular mediators of liver injury would promote the development of mechanism-based therapeutic interventions. This article briefly summarizes the recent advances in our understanding of the relationship between NAFLD/NASH, insulin resistance and the metabolic syndrome. PMID: 20370677 [PubMed - indexed for MEDLINE] 1447. Curr Pharm Des. 2010 Jun;16(17):1896-901. Adiponectin: a key player in obesity related disorders. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Recent studies revealed that adipose tissue is not only an energy storing organ, but is a kind of endocrine organ which secretes a variety of bioactive substances, so-called adipokines or adipocytokines. Visceral fat accumulation is associated with hypersecretion of adipocytokines such as tumor necrosis factor-alpha and plasminogen activator inhibitor-1 which may regulate inflammatory and atherogenic diseases. Adiponectin is a relatively new adipocytokine which we discovered in 1996 and has anti-diabetic, anti-atherogenic and anti-inflammatory properties. Adiponectin is present in plasma at a very high concentration, but in contrast to other adipocytokines, its production is reduced in subjects with visceral fat accumulation and the plasma levels are negatively correlated with visceral adiposity. Hypoadiponectinemia induced by visceral fat accumulation is closely associated with type 2 diabetes, lipid disorders, hypertension and also certain inflammatory diseases. In this review, the mechanisms of obesity-related diseases including nonalcoholic fatty liver disease will be discussed from the aspect of important roles of adipocytokines, especially adiponectin. PMID: 20370675 [PubMed - indexed for MEDLINE] 1448. Curr Pharm Des. 2010 Jun;16(17):1929-40. Role of adipocytokines in hepatic fibrosis. Bertolani C(1), Marra F. Author information: (1)Dipartimento di Medicina Interna, Viale Morgagni 85, I-50134 Florence, Italy. Hepatic fibrosis is a dynamic process whereby the liver responds to conditions of persistent damage. This leads to deposition of fibrillar extracellular matrix, altered hepatocyte regeneration, deranged microvascular architecture and cirrhosis. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process indifferent chronic liver diseases, and attention has focused on possible links between the adipose tissue and liver repair.ADIPOCYTOKINEs are cytokines secreted primarily by adipose tissue, they are relevant for adipose tissue physiology and metabolism.Alterations in the adipocytokine pattern are involved in different obesity-related diseases, such as hypertension, atherosclerosis and type II diabetes mellitus (T2DM).Numerous recent studies have analyzed the role played by adipocytokines in the process of hepatic 'wound healing' and fibrogenesis. In particular, data have accumulated on the role of adiponectin and leptin. This review summarizes the more significant and recent findings concerning the role played by different adipocytokines in hepatic fibrogenesis, discussing the actions of adipocytokines on the biology of liver cells, and their effects in different animal models. The variations in the circulating levels and intrahepatic expression of different adipocytokines in patients with fibrogenic liver diseases are also discussed. PMID: 20370673 [PubMed - indexed for MEDLINE] 1449. Curr Pharm Des. 2010 Jun;16(17):1921-8. Retinol-binding protein 4 and new adipocytokines in nonalcoholic fatty liver disease. Tönjes A(1), Blüher M, Stumvoll M. Author information: (1)University of Leipzig Department of Medicine Liebigstr. 20 D-04103 Leipzig, Germany. Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of hepatic dysfunction and is highly correlated with components of the metabolic syndrome such as obesity, insulin resistance and type 2 diabetes. Among others, nutritional factors, physical inactivity, genetic variants and visceral obesity have been identified as risk parameters for NAFLD. The complex pathophysiology of fatty liver degeneration, however, and especially the interaction between hepatocytes and adipose tissue has not been completely elucidated. Furthermore, it is not entirely understood whether insulin resistance generates fatty liver disease or vice versa. Nevertheless, adipocytokines are likely to be involved in the pathogenesis of NAFLD since they are secreted not only from adipose tissue but also from the liver. For several adipocytokines such as leptin, adiponectin, tumor necrosis factor-alpha, retinol binding protein 4 (RBP4) or fetuin-A a crucial role in the development and progression of fatty liver disease has been suggested. It has been accepted that obesity is an independent risk factor for NAFLD. Dysregulation of adipocytokines may represent an important mechanism linking increased fat mass in obesity with the development of fatty liver disease. Here, we discuss the association of RBP4 and other recently discovered adipocytokines and their relation with NAFLD. PMID: 20370670 [PubMed - indexed for MEDLINE] 1450. Drug News Perspect. 2010 Mar;23(2):112-7. doi: 10.1358/dnp.2010.23.2.1475909. Calcitonin gene-related peptide: A molecular link between obesity and migraine? Recober A(1), Goadsby PJ. Author information: (1)Headache Division-Department of Neurology, University of Iowa, IA, USA. Epidemiological studies have begun to suggest obesity is a risk factor for chronic migraine, although no causal relationship has been established and risk factors for progression from episodic to chronic migraine remain unknown. The neuropeptide calcitonin gene-related peptide (CGRP) plays a important role in the pathophysiology of migraine. Here, the potential role of CGRP as a molecular link between obesity and migraine is reviewed. A mechanistic association is supported by several lines of evidence: 1) common markers are elevated in obesity and migraine, 2) adipose tissue secretes proinflammatory cytokines and adipocytokines that have been implicated in migraine pathophysiology and 3) elevated levels of CGRP have been found in plasma of obese individuals. We propose that CGRP released from trigeminal neurons may represent a biological link between obesity and migraine. Enhanced trigeminal CGRP production in obese susceptible individuals may lower the threshold necessary to trigger migraine attacks, leading to more frequent episodes and eventually to chronic migraine. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved. PMCID: PMC2947336 PMID: 20369076 [PubMed - indexed for MEDLINE] 1451. Mediators Inflamm. 2010;2010:568343. doi: 10.1155/2010/568343. Epub 2010 Mar 23. Role of leptin in the activation of immune cells. Fernández-Riejos P(1), Najib S, Santos-Alvarez J, Martín-Romero C, Pérez-Pérez A, González-Yanes C, Sánchez-Margalet V. Author information: (1)Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Av Dr Fedriani 3, 41071 Seville, Spain. Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response. PMCID: PMC2846344 PMID: 20368778 [PubMed - indexed for MEDLINE] 1452. Arch Pathol Lab Med. 2010 Apr;134(4):545-51. doi: 10.1043/1543-2165-134.4.545. Amyloidosis-where are we now and where are we heading? Picken MM(1). Author information: (1)Department of Pathology, Loyola University Medical Center, Maywood, Illinois 60153, USA. mpicken@lumc.edu CONTEXT: Amyloidoses are disorders of diverse etiology in which deposits of abnormally folded proteins share distinctive staining properties and fibrillar ultrastructural appearance. Amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment of systemic amyloidoses the importance of an early diagnosis of amyloid, and a correct diagnosis of its type, has been realized. OBJECTIVE: To summarize current recommendations for the diagnosis of amyloidosis. DATA SOURCES: Presentation given at the 4th Annual Renal Pathology Society Satellite meeting in Istanbul based on discussions and recommendations formulated during an interactive diagnostic session held at the XIth International Symposium on Amyloidosis in Woods Hole, Massachusetts. CONCLUSIONS: Congo red stain is currently the gold standard for amyloid detection and the goal is to detect amyloid early. Diagnosis of the amyloid type must be based on the identification of amyloid protein within the deposits and not solely by reliance on clinical or DNA studies. However, the latter are recommended for confirmation of the amyloid type based on evaluation of the protein in deposits. Immunohistochemistry must be performed and interpreted with caution and inconclusive results must be evaluated further using the more sophisticated methods available in referral centers. An adequate amount and quality of tissue must be available for amyloid diagnosis and typing with emphasis on the use of fresh tissue and greater use of abdominal fat biopsy. The development of new technologies underscores the need for regular review of recommendations and standards for the clinical diagnosis of amyloidosis. PMID: 20367306 [PubMed - indexed for MEDLINE] 1453. Int J Food Sci Nutr. 2010 Nov;61(7):653-79. doi: 10.3109/09637481003702114. Medium-chain triglycerides are advantageous in promoting weight loss although not beneficial to exercise performance. Clegg ME(1). Author information: (1)Functional Food Centre, School of Life Sciences, Oxford Brookes University, Oxford, UK. mclegg@brookes.ac.uk Medium-chain triglycerides (MCT) are triglycerides with a fatty acid chain length varying between 6 and 10 carbon atoms. MCT differ from long-chain triglycerides as they are relatively soluble in water and, hence, rapidly hydrolysed and absorbed. MCT are transported in the blood through the portal system, consequently they bypass adipose tissue that makes them less susceptible to hormone-sensitive lipase and deposition into adipose tissue stores. Due to these properties, MCT have been researched for both benefits to exercise performance and health. The present review aims to assess whether MCT are beneficial in either of these situations. MCT have been proposed as a means to maximizing an athlete's ability to maintain their glycogen stores so they can be more competitive. However, only two studies to date have shown an improvement in exercise performance. From a health perspective, MCT increase fat oxidation and energy expenditure as well as reduce food intake and beneficially alter body composition. Results indicate that MCT feeding is ineffective in improving exercise performance and future work should focus on the health benefits and applications of MCT. PMID: 20367215 [PubMed - indexed for MEDLINE] 1454. Med Hypotheses. 2010 Aug;75(2):250-6. doi: 10.1016/j.mehy.2010.02.033. Epub 2010 Apr 3. Is thermogenesis a significant causal factor in preventing the "globesity" epidemic? Hansen JC(1), Gilman AP, Odland JØ. Author information: (1)School of Public Health, University of Aarhus, Denmark. During the last four decades the world has experienced an epidemic of overweight individuals in affluent as well as developing countries. The WHO has predicted a "globesity epidemic" with more than 1 billion adults being overweight and at least 300 million of these being clinically obese. Obesity among children and adolescents is of great significance. From a global population perspective, this epidemic in weight gain and its sequelae are the largest public health problems identified to date and have very significant adverse implications for population health, and have by now almost reached the proportion of a pandemic. While genetic changes have been discussed as a cause of the epidemic, there has been too little time since its start to enable enough genetic adaptation to take place for this to provide a valid explanation. Traditionally positive energy balance and sedentary life style have been regarded as the primary causal factors; however, these factors have so far failed to provide explanations for the entire problem. For these reasons it seems warranted to investigate other possible co-factors contributing to the "globesity epidemic" and to find efficient strategies to counteract further increases in the size and nature of the epidemic. The purpose of this paper is to discuss a potential preventive co-factor, thermogenesis. Special attention has been paid to the influence of ambient temperature as a grossly neglected factor in the debate. As most people today live and work at ambient temperatures close to their body temperature (the thermal neutral point), we hypothesise that this is an important causal co-factor in the "globesity" epidemic. The hypothesis: The null hypothesis that adaptive thermogenesis in brown adipose tissue in adult humans is not significant for weight loss is rejected. We propose the hypothesis that homoeothermic living conditions close to the thermogenic neutral level is an important causal co-factor in the "Globesity" Epidemic. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20363565 [PubMed - indexed for MEDLINE] 1455. Korean J Hepatol. 2009 Dec;15 Suppl 6:S34-9. doi: 10.3350/kjhep.2009.15.S6.S34. Current status of liver disease in Korea: nonalcoholic fatty liver disease. Park SH(1). Author information: (1)Department of Internal Medicine, Hallym University College of Medicine, Anyang, Korea. drpsh66@yahoo.co.kr Recently, obesity (BMI>or=25 kg/m2) and type II diabetes mellitus have reached epidemic proportions in Korea, and rates of nonalcoholic fatty liver disease (NAFLD) are between 10% and 25% of the general population. NAFLD in Korea is as closely associated with several components of metabolic syndrome including, obesity, hypertension, diabetes and dyslipidemia as it is in Western countries. Insulin resistance and hyperinsulinemia may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity. And, obesity induced accumulation of fat in the adipose tissue leads to an imbalance in the regulation of adipokines, such as downregulation of adiponectin and upregulation of retinol-binding protein 4 (RBP4) and ghrelin. High BMI, the AST/ALT ratio, and ALT levels could be used to distinguish NASH from simple steatosis in Korean patients. In large number of NAFLD patients who underwent a voluntary medical checkup, even a small weight reduction was associated with improvements in their hepatic steatosis grade on ultrasonography, serum aminotransferase levels, and related metabolic abnormalities. Subjects with fatty liver disease should be advised to lose weight through lifestyle modifications. Small animal and human studies of treatment with PPAR agonists and betaine have been reported in the Korean literature. It is now acknowledged that NAFLD is the most common liver disease in Korea, largely due to the considerable increase in metabolic abnormalities such as obesity and diabetes. Future studies should continue to focus both on the pathogenesis and the treatment of NAFLD in order to accumulate more of our own data. PMID: 20037278 [PubMed - indexed for MEDLINE] 1456. J Leukoc Biol. 2010 Jul;88(1):33-9. doi: 10.1189/jlb.0210072. Epub 2010 Apr 1. Adipose tissue macrophages: their role in adipose tissue remodeling. Suganami T(1), Ogawa Y. Author information: (1)Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. The adipose tissue secretes a large number of bioactive substances, adipocytokines, which may be involved in a variety of physiologic and pathologic processes. Unbalanced production of pro- and anti-inflammatory adipocytokines seen in visceral fat obesity contributes critically to the development of the metabolic syndrome. Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation, suggesting that inflammation may be a potential mechanism, whereby obesity leads to insulin resistance. Indeed, obese adipose tissue is characterized by adipocyte hypertrophy, followed by increased angiogenesis, immune cell infiltration, extracellular matrix overproduction, and thus, increased production of proinflammatory adipocytokines during the progression of chronic inflammation. The dynamic change found in the adipose tissue can be referred to as "adipose tissue remodeling," in which stromal cells change dramatically in number and cell type during the course of obesity. Among stromal cells, infiltration of macrophages in the adipose tissue precedes the development of insulin resistance in animal models, suggesting that they are crucial for obesity-related adipose tissue inflammation. We have demonstrated that a paracrine loop involving saturated fatty acids and TNF-alpha derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced lipolysis, serve as a naturally occurring ligand for TLR4 complex, thereby activating macrophages. Understanding the molecular mechanism underlying adipose tissue remodeling may lead to the identification of novel, therapeutic strategies to prevent or treat obesity-induced adipose tissue inflammation. PMID: 20360405 [PubMed - indexed for MEDLINE] 1457. J Physiol Biochem. 2009 Dec;65(4):423-36. doi: 10.1007/BF03185938. Adipose tissue lymphocytes: types and roles. Caspar-Bauguil S(1), Cousin B, Bour S, Casteilla L, Penicaud L, Carpéné C. Author information: (1)UPS, UMR 5241, Métabolisme, Plasticité et Mitochondrie, Université de Toulouse III, Toulouse, USA. casparbauguil.s@chu-toulouse.fr Erratum in J Physiol Biochem. 2011 Sep;67(3):497. Castiella, L [corrected to Casteilla, L]. Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development. PMID: 20358356 [PubMed - indexed for MEDLINE] 1458. Clin Calcium. 2010 Apr;20(4):543-50. doi: CliCa1004543550. [Musculoskeletal rehabilitation and bone. Abnormal bone metabolism in female elite athletes]. [Article in Japanese] Enatsu A(1). Author information: (1)Four Seasons Ladies Clinic. Recently, female athletes are particularly well, the other hand, many athletes suffer from amenorrhea due to excessive training. Especially, in sports with weight restrictions, they suffer from "Female athlete triad" , eating disorders, amenorrhea and osteoporosis. Amenorrhea is nothing else than a lack of estrogen, action on bone resorption and promote bone formation, by neglect this, it lead to osteoporosis and a stress fracture, and they would often give up their career as elite athletes. So we should consider it as serious sports injury. The problems of amenorrhea is should be recognized as a deficiency of estrogen. A Case of amenorrhea in female athletes, it is necessary to consider the hormone replacement therapy based on the appropriate diagnosis. However, it is important to start the management of body fat and body weight and strength of exercises since adolescent for the prevention the amenorrhea. PMID: 20354328 [PubMed - indexed for MEDLINE] 1459. Acta Physiol (Oxf). 2010 Aug;199(4):509-18. doi: 10.1111/j.1748-1716.2010.02128.x. Epub 2010 Mar 26. Fat as a fuel: emerging understanding of the adipose tissue-skeletal muscle axis. Frayn KN(1). Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. keith.frayn@oxlip.ox.ac.uk The early pioneers in the field of metabolism during exercise such as Lindhard and Krogh understood the importance of fat as a fuel for muscle contraction. But they could not have understood the details of the pathways involved, as neither the metabolic role of adipose tissue nor the transport role of non-esterified fatty acids (NEFA) in the plasma was clearly understood at the time. We now recognize that the onset of muscular contraction coincides with an increase in the delivery of NEFA from adipose tissue, probably coordinated by the sympatho-adrenal system. During light exercise, adipose tissue-derived NEFA make up the majority of the oxidative fuel used by muscle. As exercise is prolonged, the importance of NEFA increases. The onset of exercise is marked by an increased proportion of NEFAs entering beta-oxidation rather than re-esterification and recycling. At moderate intensities of exercise, other sources of fat, potentially plasma- and intramyocellular-triacylglycerol, supplement the supply of plasma NEFA. The delivery of NEFA is augmented by increased adipose tissue blood flow and by other stimuli such as atrial natriuretic peptide. Only during high-intensity exercise is there a failure of adipose tissue to deliver sufficient fatty acids for muscle (which is coupled with an inability of muscle to use them, even when fatty acids are supplied artificially). This limitation of adipose tissue NEFA delivery may reflect some feedback inhibition of lipolysis, perhaps via lactate, or possibly alpha-adrenergic inhibition of lipolysis at very high catecholamine concentrations. PMID: 20353493 [PubMed - indexed for MEDLINE] 1460. J Pediatr Pharmacol Ther. 2010 Apr;15(2):94-109. Pharmacokinetics and drug dosing in obese children. Kendrick JG(1), Carr RR, Ensom MH. Author information: (1)Faculty of Pharmaceutical Sciences, The University of British Columbia. OBJECTIVES: To review pharmacokinetics in obese children and to provide medication dosing recommendations. METHODS: EMBASE, MEDLINE, AND INTERNATIONAL PHARMACEUTICAL ABSTRACTS DATABASES WERE SEARCHED USING THE FOLLOWING TERMS: obesity, morbid obesity, overweight, pharmacokinetics, drug, dose, kidney function test, creatinine, pediatric, and child. RESULTS: We identified 10 studies in which the authors examined drug dosing or pharmacokinetics for obese children. No information was found for drug absorption or metabolism. Obese children have a higher percent fat mass and a lower percent lean mass compared with normal-weight children. Therefore, in obese children, the volume of distribution of lipophilic drugs is most likely higher, and that of hydrophilic drugs is most likely lower, than in normal-weight children. Serum creatinine concentrations are higher in obese than normal-weight children. Total body weight is an appropriate size descriptor for calculating doses of antineoplastics, cefazolin, and succinylcholine in obese children. Initial tobramycin doses may be determined using an adjusted body weight, although using total body weight in the context of monitoring serum tobramycin concentrations would also be an appropriate strategy. We found no information for any of the opioids; antibiotics such as penicillins, carbapenems, vancomycin, and linezolid; antifungals; cardiac drugs such as digoxin and amiodarone; corticosteroids; benzodiazepines; and anticonvulsants. In particular, we found no information about medications that are widely distributed to adipose tissue or that can accumulate there. CONCLUSIONS: The available data are limited because of the small numbers of participating children, study design, or both. The number and type of drugs that have been studied limit our understanding of the pharmacokinetics in obese children. In the absence of dosing information for obese children, it is important to consider the nature and severity of a child's illness, comorbidities, organ function, and side effects and physiochemical properties of the drug. Extrapolating from available adult data is possible, as long as practitioners consider the effects of growth and development on the pharmacokinetics relevant to the child's age. PMCID: PMC3018176 PMID: 22477800 [PubMed] 1461. Handchir Mikrochir Plast Chir. 2010 Apr;42(2):137-42. doi: 10.1055/s-0030-1249672. Epub 2010 Mar 29. [Current perspective and limitations of autologous fat transplantation--"consensus meeting" of the German Society of Plastic, Reconstructive and Aesthetic Surgeons at Hannover; September 2009]. [Article in German] Rennekampff HO(1), Reimers K, Gabka CJ, Germann G, Giunta RE, Knobloch K, Machens HG, Pallua N, Ueberreiter K, Heimburg Dv, Vogt PM. Author information: (1)Klinik für Plastische, Hand und Wiederherstellungschirurgie, Medizinische Hochschule Hannover, Carl Neubergstrasse 1, Hannover. rennekampff.oliver@mh-hannover.de One hundred years after the first description of autologous fat transplantation, this technique is receiving renewed attention. Initially, critically reviewed by plastic surgery societies, particularly those in the United States, the transfer of autologous fat was recently addressed at the September 2009 annual meeting of the German Society of Plastic Reconstructive and Aesthetic Surgeons in Hannover. In this consensus meeting, the panel reviewed both the current status of autologous fat transfer as well as established data concerning this evolving practice. In Germany, autologous fat transplantation is regulated by the Law on Tissue Transfer and Processing (Gewebegesetz). In an effort to facilitate future comparisons it is mandatory to describe harvesting, processing and reinjection techniques in detail. The consensus panel concluded that fat should be harvested using low vacuum settings and then transplanted in thin layers (Evidence V). Quantification of transplanted fat can best be performed by MRI (Evidence level III). Limited clinical studies are available with only some reaching a level of evidence II. At present, risk associated with autologous fat transplantation is considered to be minor. Tumor induction by autologous fat grafting is not proven. New techniques like stem cell enriched fat grafts may offer new promise for the Plastic and Reconstructive Surgeon. (c) Georg Thieme Verlag KG Stuttgart-New York. PMID: 20352577 [PubMed - indexed for MEDLINE] 1462. Handchir Mikrochir Plast Chir. 2010 Apr;42(2):124-8. doi: 10.1055/s-0030-1248269. Epub 2010 Mar 29. Adipose stem cells for soft tissue regeneration. Brayfield C(1), Marra K, Rubin JP. Author information: (1)Department of Plastic Surgery, University of Pittsburgh, 3380 Boulevard of the Allies, Pittsburgh, PA 15213, USA. Adipose-derived stem cells (ASCs) can be isolated from human adipose tissue with the exceptional potential for differentiation into mature adipocytes. Utilization of this system is very promising in developing improved techniques to repair soft tissue defects. Current reconstructive procedures, especially after trauma and oncological surgery, transfer autologous soft tissue grafts having limitations. However, ASCs offer the ability to either generate soft tissue with no donor-site morbidity (with the exception of a minor loss of adipose tissue) or enhance the viability and durability of other grafts. This review will discuss the relevant properties of human adult adipose-derived stem cells for the regeneration of adipose tissue. Discussion will focus on the biology of ASCs, cell delivery vehicles/scaffolds useful in applying ASCs as a therapy, and suitable IN VIVO animal models for studying adipose tissue engineering. Also included is a description of the current clinical studies with ASCs in Europe and Asia. (c) Georg Thieme Verlag KG Stuttgart-New York. PMID: 20352575 [PubMed - indexed for MEDLINE] 1463. J Biol Chem. 2010 Jun 4;285(23):17271-6. doi: 10.1074/jbc.R110.113175. Epub 2010 Mar 26. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. Hall JE(1), da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S, Smith G, Stec DE. Author information: (1)Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA. jehall@physiology.umsmed.edu Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors. PMCID: PMC2878489 PMID: 20348094 [PubMed - indexed for MEDLINE] 1464. Diabetol Metab Syndr. 2010 Mar 26;2:21. doi: 10.1186/1758-5996-2-21. Visfatin, glucose metabolism and vascular disease: a review of evidence. Saddi-Rosa P(1), Oliveira CS, Giuffrida FM, Reis AF. Author information: (1)Escola Paulista de Medicina, Diabetes Center, Federal University of São Paulo, São Paulo, Brazil. The adipose tissue is an endocrine organ producing substances called adipocytokines that have different effects on lipid metabolism, metabolic syndrome, and cardiovascular risk. Visfatin was recently described as an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Visfatin has been linked to several inflammatory conditions, beta cell function, and cardiovascular disease. The growing number of publications on the subject shall bring further evidence about this adipocytokine. Its findings may contribute in the identification of higher risk individuals for diabetes and cardiovascular disease with a better comprehension about the complex intercorrelation between adiposity, glucose metabolism and vascular disease. PMCID: PMC2857825 PMID: 20346149 [PubMed] 1465. Acta Physiol (Oxf). 2010 Aug;199(4):499-508. doi: 10.1111/j.1748-1716.2010.02122.x. Epub 2010 Mar 26. Lactate kinetics in human tissues at rest and during exercise. van Hall G(1). Author information: (1)Metabolic Mass-Spectrometry Facility, Rigshospitalet and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. gvanhall@cmrc.dk Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during exercise is much debated. In the early days skeletal muscle was mainly seen as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later it was recognized that skeletal muscle not only played an important role in lactate production but also in lactate clearance and this led to a renewed interest, not the least from the Copenhagen School in the 1930s, in the metabolic role of lactate in skeletal muscle. With the introduction of lactate isotopes muscle lactate kinetics and oxidation could be studied and a simultaneous lactate uptake and release was observed, not only in muscle but also in other tissues. Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate metabolism at rest and during exercise and suggestions are put forward to explain the simultaneous lactate uptake and release; and (2) lactate metabolism in the heart, liver, kidneys, brain, adipose tissue and lungs will be discussed and its potential importance in these tissues. PMID: 20345411 [PubMed - indexed for MEDLINE] 1466. Rev Assoc Med Bras. 2010 Jan-Feb;56(1):116-21. Adipose tissue, inflammation and cardiovascular disease. Ikeoka D(1), Mader JK, Pieber TR. Author information: (1)Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Obesity has become a very frequent condition with important consequences for the health of affected individuals. Current evidence shows that the excess of adipose tissue as observed in obesity is responsible for secreting inflammatory mediators in a deregulated manner, thus inducing a chronic state of systemic low-grade inflammation that underlies the metabolic and cardiovascular outcomes in these populations. This article reviews the state of the art regarding mediators produced in the adipose tissue, their roles in the pathophysiology of obesity-associated insulin resistance and diabetes, and finally, tries to build a bridge between these mechanistically oriented insights and clinical practice. PMID: 20339797 [PubMed - indexed for MEDLINE] 1467. Trends Endocrinol Metab. 2010 Jul;21(7):449-56. doi: 10.1016/j.tem.2010.02.001. Epub 2010 Mar 24. PC-TP/StARD2: Of membranes and metabolism. Kang HW(1), Wei J, Cohen DE. Author information: (1)Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) binds phosphatidylcholines, and catalyzes their intermembrane transfer and exchange in vitro. The structure of PC-TP comprises a hydrophobic pocket and a well-defined head group binding site, and its gene expression is regulated by peroxisome proliferator activated receptor-alpha. Recent studies have revealed key regulatory roles for PC-TP in lipid and glucose metabolism. Notably, Pctp(-/-) mice are sensitized to the action of insulin, and exhibit more efficient brown fat-mediated thermogenesis. PC-TP appears to limit access of fatty acids to mitochondria by stimulating the activity of thioesterase superfamily member 2, a newly characterized long-chain fatty acyl-coenzyme A thioesterase. Because PC-TP discriminates between phosphatidylcholines within lipid bilayers, it might function as a sensor that links metabolic regulation to membrane composition. Copyright 2010 Elsevier Ltd. All rights reserved. PMCID: PMC2897958 PMID: 20338778 [PubMed - indexed for MEDLINE] 1468. J Am Coll Nutr. 2009 Aug;28 Suppl:482S-491S. Anti-inflammatory diets for obesity and diabetes. Sears B(1). Author information: (1)Inflammation Research Foundation, Marblehead, Massachusetts, USA. bsears@drsears.com Obesity and type 2 diabetes are strongly associated with increased inflammation. As the inflammation in adipose tissue increases, this becomes a strong driving force for the development of increased systemic inflammation that results in metabolic syndrome, eventually followed by the development of overt type 2 diabetes. The potential reversal of both conditions can be achieved by reducing the levels of inflammation through the use of an anti-inflammatory diet. The composition of such a diet and its molecular mode of action will be discussed. PMID: 20234036 [PubMed - indexed for MEDLINE] 1469. Curr Opin Investig Drugs. 2010 Apr;11(4):385-93. GPR43: an emerging target for the potential treatment of type 2 diabetes, obesity and insulin resistance. Tiwari A(1). Author information: (1)Jubilant Biosys Ltd, Drug Discovery Unit, Metabolic Disorder Lab, 96, 2nd Stage, Industrial Suburb, Yeshwantpur, Bangalore, Karnatka, 560022, India. atul_tiwari@jubilantbiosys.com A new role for fatty acids as endocrine regulators of lipid and carbohydrate metabolism through the activation of their cognate receptors, GPCRs, has been discovered during the past decade. GPR43 is a GPCR that has been implicated in the regulation of fatty-acid and glucose homeostasis in adipose tissue and the intestines, thus having potential therapeutic relevance in the treatment of type 2 diabetes, insulin resistance and obesity. Ongoing drug discovery efforts are focused toward the development of a novel, potent and selective orthosteric or allosteric modulator that acts as an agonist for GPR43. This review summarizes data supporting a role for GPR43 in the pharmacological management of metabolic disorders. PMID: 20336586 [PubMed - indexed for MEDLINE] 1470. Cardiovasc Diabetol. 2010 Mar 23;9:11. doi: 10.1186/1475-2840-9-11. The role of interleukin-18 in the metabolic syndrome. Trøseid M(1), Seljeflot I, Arnesen H. Author information: (1)Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway. troseid@hotmail.com The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions. PMCID: PMC2858122 PMID: 20331890 [PubMed - indexed for MEDLINE] 1471. Mol Imaging Biol. 2010 Dec;12(6):652-6. doi: 10.1007/s11307-010-0298-9. Effective reduction of brown fat FDG uptake by controlling environmental temperature prior to PET scan: an expanded case series. Garcia C(1), Bandaru V, Van Nostrand D, Chennupati S, Atkins F, Acio E, Kulkarni K, Majd M. Author information: (1)Division of Nuclear Medicine, Department of Medicine, Washington Hospital Center, 110 Irving St. NW, Washington, DC 20010, USA. carlos.garcia@medstar.net INTRODUCTION: Brown fat uptake of 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) on a positron emission tomography (PET) scan may limit the ability to assess for cancer. Previously, Garcia et al. demonstrated in ten patients a significant decrease in brown fat uptake of 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) after controlling the patient's environmental temperature. OBJECTIVE: The objective of the current study is to validate the effectiveness of controlled environmental temperature (CET) to reduce physiologic brown fat (BF) FDG uptake on a PET scan in a larger series. METHOD: A retrospective review was performed from January 2002 to October 2007 of patients who had (1) a pattern of FDG uptake on PET scan consistent with BF, (2) no evidence of cancer by computed tomography in the regions of interest noted below, (3) repeat scan with CET within 4 months of the 1st PET scan, and (4) no use of drugs reported to reduce BF FDG uptake (e.g., benzodiazepine, beta-blockers, reserpine) unless they were used identically prior to and during both studies. The FDG-PET and controlled environmental temperature-positron emission tomography (CET-PET) scans were performed as per protocol. The non-CET and CET-PET images were blinded/randomized, and three physicians assessed three regions (right neck, left neck, and paraspinal area) semiquantitatively using the following scale: "0" (background [bkgd]), 1 + (> bkgd < liver), 2 + (equal to liver), 3 + (> liver). Standard uptake value (SUV) data was recorded. Results were analyzed using a two-tailed t test. RESULTS: Of 8,640 FDG-PET scans performed, 30 patients (four male, 26 female) met the above criteria. The median age was 36 years (range, 12-60 years). The mean (± 1 standard deviation) of differences in the scores between the two studies for right neck, left neck, and paraspinal regions, respectively, were for reader 1:(2.1 ± 1.37), (1.95 ± 1.43), and (1.85 ± 1.26); reader 2 (2.3 ± 1.40), (1.70 ± 1.13), and (1.77 ± 1.13); reader 3 (2.17 ± 1.17), (2.20 ± 1.18), and (0.50 ± 1.30); for maximum SUV score (3.4 ± 2.9), (3.3 ± 2.9), and (1.77 ± 1.13). All p values were <0.001. CONCLUSION: In this larger series, CET effectively reduced the false-positive (18)FDG uptake in BF on PET scans without the use of drugs. PMID: 20237858 [PubMed - indexed for MEDLINE] 1472. Biofactors. 2010 May-Jun;36(3):179-86. doi: 10.1002/biof.83. Effect of adiponectin on apoptosis: proapoptosis or antiapoptosis? Sun Y(1), Chen X. Author information: (1)Department of Pharmacy, Chengdu Medical College, Chengdu, China. Adiponectin is a protein hormone mainly secreted by adipose tissue that regulates energy homeostasis and glucose and lipid metabolism. Compared with other adipose-derived hormones, adiponectin is very abundant in plasma and is proposed to be a convenient biomarker for many diseases. A large number of in vitro and in vivo studies support the beneficial effects of adiponectin on metabolic syndrome, diabetes, and atherosclerosis. However, the protective actions were challenged occasionally by the controversies in its role in inflammation and in the specific functions of its different conformations. Recently, quite a few reports suggested that the antiapoptotic activity of adiponectin might contribute to its therapeutic potential during ischemia/reperfusion injury in vivo, whereas some studies demonstrated that adiponectin induced apoptosis both in vitro and in vivo. Herein, this review attempts to summarize the present consensus and divergence and to provide possible alternative and/or complementary explanations for this apparent paradox. PMID: 20232346 [PubMed - indexed for MEDLINE] 1473. Expert Opin Ther Targets. 2010 Apr;14(4):443-51. doi: 10.1517/14728221003716466. Leptin as a potential therapeutic target for breast cancer prevention and treatment. Ray A(1), Cleary MP. Author information: (1)University of Minnesota, The Hormel Institute, 801 16th Avenue NE, Austin, MN 55912, USA. mpcleary@hi.umn.edu IMPORTANCE OF THE FIELD: Obesity is considered to be an important risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, can also affect breast cancer development. Leptin is one of the adipokines that is measured in serum/plasma in increasing amounts as body weight/body fat increases. AREAS COVERED IN THIS REVIEW: We highlight important aspects of leptin in relationship to mammary/breast tumor development. This includes findings from human, in vitro and animal studies. Information on leptin-related compounds which may have therapeutic use is presented. Additionally strategies to alter serum leptin levels by dietary and pharmacological interventions are discussed. WHAT THE READER WILL GAIN: The reader will gain insights into the relationship of an adipose tissue protein and its potential role in breast cancer development as well as ways to intervene in leptin's actions. TAKE HOME MESSAGE: Continued research will determine if interfering with the action of leptin has preventive or therapeutic applications in breast cancer. PMID: 20230196 [PubMed - indexed for MEDLINE] 1474. Prog Cardiovasc Dis. 2010 Mar-Apr;52(5):401-9. doi: 10.1016/j.pcad.2009.12.004. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Whaley-Connell A(1), Johnson MS, Sowers JR. Author information: (1)Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65212, USA. The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria. and hypertension commonly cluster to comprise the cardiometabolic syndrome (CMS). Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic beta-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone's nongenomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the CMS, there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Furthermore, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, we have learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation as well as reduces the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD. Copyright 2010 Elsevier Inc. All rights reserved. PMCID: PMC2841057 PMID: 20226958 [PubMed - indexed for MEDLINE] 1475. Trends Endocrinol Metab. 2010 Jun;21(6):345-52. doi: 10.1016/j.tem.2010.01.009. Epub 2010 Mar 10. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Unger RH(1), Scherer PE. Author information: (1)Department of Internal Medicine, University of Texas Southwestern Medical Center, Touchstone Center for Diabetes Research, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Roger.Unger@utsouthwestern.edu Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin. Published by Elsevier Ltd. PMCID: PMC2880185 PMID: 20223680 [PubMed - indexed for MEDLINE] 1476. Expert Opin Biol Ther. 2010 Apr;10(4):495-503. doi: 10.1517/14712591003610598. Potential application of adipose-derived stem cells and their secretory factors to skin: discussion from both clinical and industrial viewpoints. Yang JA(1), Chung HM, Won CH, Sung JH. Author information: (1)CHA Stem Cell Institute, Stem Cell Research Laboratory, Seoul, Republic of Korea. IMPORTANCE OF THE FIELD: Adipose tissue is one of the richest sources of mesenchymal stem cells. Even more interesting is the fact that adipose-derived stem cells (ASCs) show an outstanding ability to regenerate damaged skin. Thus, ASCs are a popular and feasible treatment in clinical dermatology. AREAS COVERED IN THIS REVIEW: This review discusses the potential applications of ASCs and conditioned medium of ASC (ASC-CM) to skin, and briefly touches on the mechanisms by which ASCs promote skin regeneration. WHAT THE READER WILL GAIN: Clinically, processed lipo-aspirated (PLA) cells are commonly used for treatment of aged skin; however, the use of PLA cells for cosmetic purposes is not convenient, because PLA cells are prepared from patients. Alternatively, cosmetics that contain ASC-CM can be pre-made from healthy volunteers such that they are immediately available for clinical treatment of aged skin. Cell-based therapies are adequate for improvement of wrinkles or for soft tissue augmentation, whereas ASC-CM has merit for amelioration of skin tone. When culturing ASCs for the production of cosmetic raw materials, hypoxic culture conditions and transduction of specific genes into ASCs may increase the regenerative protein content of the conditioned medium. TAKE HOME MESSAGE: Application of ASCs and ASC-CM to dermatology shows promising results for skin regeneration. PMID: 20218919 [PubMed - indexed for MEDLINE] 1477. Adv Exp Med Biol. 2010;654:77-89. doi: 10.1007/978-90-481-3271-3_5. High fat programming of beta-cell failure. Cerf ME(1). Author information: (1)Diabetes Discovery Platform, Medical Research Council, Tygerberg, 7505, Cape Town, South Africa. marlon.cerf@mrc.ac.za High saturated fat intake contributes to insulin resistance, beta-cell failure, and type 2 diabetes. Developmental programming refers to a stimulus or insult during critical periods of life which includes fetal and subsequent early neonatal life. Programming alters offspring physiology and metabolism with both immediate and lasting consequences. Maternal nutrition in gestation and lactation shapes offspring development and health. A high saturated fat diet ingested by mothers during gestation and/or lactation is a form of nutritional insult that induces diabetogenic changes in offspring physiology and metabolism. High fat programming is induced by maternal high saturated fat intake during defined periods of gestation and/or lactation and programs the physiology and metabolism of the offspring in early life. This more recently adopted form of developmental programming reflects society in both affluent and developing countries. High fat programming induces adverse changes in beta-cell development and function in neonatal and weanling offspring. These changes are characterized by compromised beta-cell development and function, evident by altered expression of key factors that maintain the beta-cell phenotype. High fat programming is likely to result in beta-cell failure and eventual type 2 diabetes. PMID: 20217495 [PubMed - indexed for MEDLINE] 1478. Curr Opin Clin Nutr Metab Care. 2010 May;13(3):255-9. doi: 10.1097/MCO.0b013e328338236e. The interaction between adipokines, diet and exercise on muscle insulin sensitivity. Stefanyk LE(1), Dyck DJ. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. PURPOSE OF REVIEW: High-fat diets lead to obesity and increase the risk of developing insulin resistance and type 2 diabetes. Adipose tissue and skeletal muscle act as endocrine organs, and produce various cytokines that can potentially alter peripheral insulin sensitivity. The purpose of the present review is to briefly summarize the effects of major cytokines (leptin, adiponectin, tumor necrosis factor-alpha, and interleukin-6) on muscle metabolism and insulin response, with a focus on the effects of diet and exercise. RECENT FINDINGS: Leptin and adiponectin improve insulin sensitivity. However, in obesity there is a diminished response to these adipokines. This resistance can be induced very rapidly and may lead to subsequent impairments in insulin response. Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated as a mediator of insulin resistance, particularly in obesity. Interleukin-6 was the first identified myokine. There is evidence to implicate interleukin-6 both as a mediator of impaired insulin action in obesity, and also as a facilitator of increased fuel metabolism during exercise. The effect of each of these cytokines on muscle insulin sensitivity can be modulated by diet and exercise. SUMMARY: Much of the information summarized in the present review focuses on the effects of various cytokines in isolation, although in vivo there can be considerable interaction with each other. Future research should consider these potential interactions. PMID: 20216410 [PubMed - indexed for MEDLINE] 1479. Curr Opin Lipidol. 2010 Apr;21(2):128-35. doi: 10.1097/MOL.0b013e3283373b66. Sphingolipids and insulin resistance: the five Ws. Summers SA(1). Author information: (1)Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore. scott.summers@duke-nus.edu.sg PURPOSE OF REVIEW: Inhibition of sphingolipid synthesis increases insulin sensitivity, resolves hepatic steatosis, and prevents the onset of diabetes in obese rodents. I herein review these interventional studies, aiming to summarize the five Ws - the 'Who, What, Where, When, and Why' questions that need to be addressed to understand roles of sphingolipids in the pathogenesis of diabetes. RECENT FINDINGS: Who: ceramides and glucosylceramides are likely to be independent antagonists of insulin action. Where: recent data suggest that ceramides may inhibit insulin action in skeletal muscle, whereas glucosylceramides may be more efficacious in adipose tissue. In contrast, sphingolipid accumulation in the liver appears to be insufficient to induce insulin resistance. What: ceramides and glucosylceramides inhibit different insulin signaling events, but it is unclear whether these actions account for the broad spectrum of therapeutic benefits resulting from sphingolipid depletion. When: recent data suggest that obesity-induced inflammation is important for the induction of sphingolipid synthesis. Why: sphingolipids have an evolutionarily conserved role to starve cells of nutrients, and the inhibition of insulin action is possibly a component of this broader action. SUMMARY: Despite considerable attention to the question of how sphingolipids induce metabolic disease, there exist enormous gaps in knowledge. Further elucidation of these molecular details will be essential for the development of new therapeutic strategies for inhibiting sphingolipid action and ameliorating metabolic diseases. PMID: 20216312 [PubMed - indexed for MEDLINE] 1480. Obes Facts. 2010 Feb;3(1):47-58. doi: 10.1159/000277067. Epub 2010 Feb 11. Anti-fat prejudice reduction: a review of published studies. Daníelsdóttir S(1), O'Brien KS, Ciao A. Author information: (1)Division of Psychiatry, Landspítali-University Hospital, Reykjavík, Iceland. Prejudice against those who are perceived as 'fat' or obese (anti-fat prejudice) is rife, increasing, and associated with negative outcomes for those targeted for such treatment. The present review sought to identify and describe published research on interventions to reduce anti-fat prejudice. A systematic search of relevant databases (e.g. PsychInfo, PubMed, Scopus) found 16 published studies that had sought to reduce anti-fat prejudice. Most notable was the lack of research on interventions for reducing anti-fat prejudice. Methodological problems that limit the interpretability of results were identified in the majority of studies found. Interventions employing more rigorous experimental designs provided at best mixed evidence for effectiveness. Although several studies reported changes in beliefs and knowledge about the causes of obesity, reductions in anti-fat prejudice did not typically accompany these changes. Anti-fat prejudice interventions adopting social norm- and social consensus-based approaches appear encouraging but are scarce. The lack of prejudice reduction following most interventions suggests that psychological mechanisms other than, or additional to, those being manipulated may underpin anti-fat prejudice. New directions for researching anti-fat prejudice are suggested. Given the strength of antipathy displayed toward those who are perceived as 'fat' or obese, research in this area is urgently required. Copyright 2010 S. Karger AG, Basel. PMID: 20215795 [PubMed - indexed for MEDLINE] 1481. Reproduction. 2010 Sep;140(3):373-85. doi: 10.1530/REP-10-0074. Epub 2010 Mar 9. Obesity, pregnancy, inflammation, and vascular function. Denison FC(1), Roberts KA, Barr SM, Norman JE. Author information: (1)Queen's Medical Research Institute, Centre for Reproductive Biology, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. fiona.denison@ed.ac.uk Maternal obesity is associated with increased morbidity and mortality for both mother and offspring. The mechanisms underlying the increased risk associated with maternal obesity are not well understood. In non-pregnant populations, many of the complications of obesity are thought to be mediated in part by inflammation and its sequelae. Recent studies suggest that a heightened inflammatory response may also be involved in mediating adverse clinical outcomes during pregnancy. This review summarizes our current knowledge about adipose tissue biology, and its role as an endocrine and inflammatory organ. The evidence for inflammation as a key mediator of adverse pregnancy outcome is also presented, focusing on the role of inflammation in adipose tissue, systemic inflammation, the placenta, and vascular endothelium. PMID: 20215337 [PubMed - indexed for MEDLINE] 1482. J Intern Med. 2010 Jun;267(6):543-60. doi: 10.1111/j.1365-2796.2010.02218.x. Epub 2010 Jan 28. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. Straub RH(1), Cutolo M, Buttgereit F, Pongratz G. Author information: (1)From the Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital, Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de Energy regulation (EnR) is most important for homoeostatic regulation of physiological processes. Neuroendocrine pathways are involved in EnR. We can separate factors that provide energy-rich fuels to stores [parasympathetic nervous system (PSNS), insulin, insulin-like growth factor-1, oestrogens, androgens and osteocalcin] and those that provide energy-rich substrates to consumers [sympathetic nervous system (SNS), hypothalamic-pituitary-adrenal axis, thyroid hormones, glucagon and growth hormone]. In chronic inflammatory diseases (CIDs), balanced energy-rich fuel allocation to stores and consumers, normally aligned with circadian rhythms, is largely disturbed due to the vast fuel consumption of an activated immune system (up to 2000 kJ day(-1)). Proinflammatory cytokines such as tumour necrosis factor or interleukins 1beta and 6, circulating activated immune cells and sensory nerve fibres signal immune activation to the rest of the body. This signal is an appeal for energy-rich fuels as regulators are switched on to supply energy-rich fuels ('energy appeal reaction'). During evolution, adequate EnR evolved to cope with nonlife-threatening diseases, not with CIDs (huge negative selection pressure and reduced reproduction). Thus, EnR is inadequate in CIDs leading to many abnormalities, including sickness behaviour, anorexia, hypovitaminosis D, cachexia, cachectic obesity, insulin resistance, hyperinsulinaemia, dyslipidaemia, fat deposits near inflamed tissue, hypoandrogenaemia, mild hypercortisolaemia, activation of the SNS (hypertension), CID-related anaemia and osteopenia. Many of these conditions can contribute to the metabolic syndrome. These signs and symptoms become comprehensible in the context of an exaggerated call for energy-rich fuels by the immune system. We propose that the presented pathophysiological framework may lead to new therapeutical approaches and to a better understanding of CID sequence. PMID: 20210843 [PubMed - indexed for MEDLINE] 1483. Dig Liver Dis. 2010 May;42(5):320-30. doi: 10.1016/j.dld.2010.01.016. Epub 2010 Mar 6. From the metabolic syndrome to NAFLD or vice versa? Vanni E(1), Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. Author information: (1)Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, C. so Bramante 88, 10126 Turin, Italy. The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH. Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. PMID: 20207596 [PubMed - indexed for MEDLINE] 1484. Gastroenterol Hepatol. 2010 Oct;33(8):591-604. doi: 10.1016/j.gastrohep.2009.12.009. Epub 2010 Mar 4. [Obesity and liver disease]. [Article in Spanish] Miquilena Colina ME(1), García Monzón C. Author information: (1)Unidad de Investigación, Hospital Universitario Santa Cristina, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España. Obesity is associated with a higher risk of developing non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of liver diseases of distinct etiologies such as chronic hepatitis C virus (HCV) infection. The discovery that adipose tissue is submitted to a state of chronic inflammation able to secrete adipokines has allowed a connection to be established between the metabolic alterations that lead to triglyceride accumulation and liver inflammation, reinforcing the role of hepatocellular lipotoxicity in the pathogenesis of NAFLD. In addition, although HCV genotype 3 induces steatosis, it is currently believed that obesity and its associated alterations, such as insulin resistance, are involved in progression of HCV-mediated liver disease, as well as that of other chronic liver diseases of diverse etiologies. Copyright © 2009 Elsevier España, S.L. All rights reserved. PMID: 20206411 [PubMed - indexed for MEDLINE] 1485. Biochem Biophys Res Commun. 2010 Apr 2;394(2):241-2. doi: 10.1016/j.bbrc.2010.02.170. Epub 2010 Mar 3. Examination of adipose depot-specific PPAR moieties. Dodson MV(1), Vierck JL, Hausman GJ, Guan LL, Fernyhough ME, Poulos SP, Mir PS, Jiang Z. Author information: (1)Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA. dodson@wsu.edu Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals. 2010 Elsevier Inc. All rights reserved. PMID: 20206125 [PubMed - indexed for MEDLINE] 1486. Facial Plast Surg Clin North Am. 2010 Feb;18(1):1-6. doi: 10.1016/j.fsc.2009.11.001. A new paradigm for the aging face. Lam SM(1). Author information: (1)Willow Bend Wellness Center, Lam Facial Plastic Surgery Center & Hair Restoration Institute, Plano, TX 75093, USA. drlam@lamfacialplastics.com Fat transfer has become the primary method for facial rejuvenation in my clinical practice for all ethnicities. This technique can be effectively used to address panfacial volume loss so long as artistry, technical skill, and an in-depth understanding of fat grafting changes over the years are well applied and understood. Fat grafting can replace many traditional facial rejuvenation techniques or serve as an important adjunct to excisional and lifting procedures to temper the degree of excision and lifting that are required. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20206085 [PubMed - indexed for MEDLINE] 1487. Endokrynol Pol. 2010 Jan-Feb;61(1):126-34. Aromatase research and its clinical significance. Czajka-Oraniec I(1), Simpson ER. Author information: (1)Department of Endocrinology, Medical Centre for Postgraduate Education, Warszawa, Poland. Aromatase is a member of the cytochrome P450 superfamily that catalyzes the conversion of androgens (C(19)), namely testosterone and androstenedione, into oestrogens (C(18)), oestradiol, and oestrone, respectively. The enzyme is active in various tissues in both females and males, thus oestrogens are produced not only in gonads but also in extra-gonadal localizations such as brain, adipose tissue, breast, skin, and bone. Aromatase gene CYP19A1 located on chromosome 15 comprises nine coding exons and a number of alternative non-coding first exons that regulate tissue-specific expression. Studies on local regulation of aromatase expression and activity are important for understanding processes such as growth of oestrogen-dependent breast cancer. Rare clinical conditions of aromatase deficiency and excess have revealed some new and unexpected oestrogen functions in metabolism and bone health in both women and men. They were further studied using transgenic animal models such as aromatase knockout mice (ArKO) or (AROM+) mice overexpressing human aromatase. Research on aromatase was important for its practical outcome as it contributed to the development of aromatase inhibitors (AIs), an effective and safe group of drugs for the first-line endocrine therapy of breast cancer. Further studies are needed to establish AIs application in other oestrogen-dependent conditions, to overcome the resistance in breast cancer patients, and to develop tissue-specific selective inhibitors. (Pol J Endocrinol 2010; 61 (1): 126-134). PMID: 20205115 [PubMed - indexed for MEDLINE] 1488. Trends Endocrinol Metab. 2010 Jul;21(7):411-8. doi: 10.1016/j.tem.2010.02.004. Epub 2010 Mar 2. Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. Zengin A(1), Zhang L, Herzog H, Baldock PA, Sainsbury A. Author information: (1)Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, Sydney, New South Wales (NSW), Australia. The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20202858 [PubMed - indexed for MEDLINE] 1489. Tex Heart Inst J. 2010;37(1):82-4. Pericardial fat necrosis: a review and update. Fred HL(1). Author information: (1)Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. A previously healthy middle-aged person presents with excruciating left-sided chest pain of 6 hours' duration. The pain has come on abruptly, without warning, and is located in the lower part of the chest anteriorly. It radiates to the neck and left shoulder and worsens on deep inspiration. The patient appears seriously ill, with tachypnea, tachycardia, and diaphoresis. Otherwise, the physical examination is unremarkable. The electrocardiogram shows sinus tachycardia. Results of conventional blood studies and the chest radiograph are within normal limits. Three days later, a follow-up chest radiograph shows a 3.5 x 4-cm mass adjacent to the left side of the heart near the diaphragm. PMCID: PMC2829792 PMID: 20200633 [PubMed - indexed for MEDLINE] 1490. Clin Pharmacol Ther. 2010 Apr;87(4):407-16. doi: 10.1038/clpt.2009.311. Epub 2010 Mar 3. Obesity, inflammation, and cardiovascular risk. Mathieu P(1), Lemieux I, Després JP. Author information: (1)Quebec Heart and Lung Institute/Research Center, Québec, Québec, Canada. patrick.mathieu@chg.ulaval.ca Obesity, a highly prevalent condition, is heterogeneous with regard to its impact on cardiovascular disease (CVD) risk. Epidemiological observations and metabolic investigations have consistently demonstrated that the accumulation of excess visceral fat is related to an increased risk of CVD as well as several metabolic and inflammatory perturbations. In the past decade, data from several studies have served to emphasize that atherosclerosis has an inflammatory component that may contribute to several key pathophysiological processes. Study data have also highlighted the finding that the expanded visceral fat is infiltrated by macrophages that conduct "cross-talk" with adipose tissue through several significant mechanisms. In this review, we provide, in the context of CVD risk, an up-to-date account of the complex interactions that occur between a dysfunctional adipose tissue phenotype and inflammation. PMID: 20200516 [PubMed - indexed for MEDLINE] 1491. Curr Drug Targets. 2010 May;11(5):586-98. Obesity and inflammation--targets for OA therapy. Iannone F(1), Lapadula G. Author information: (1)DiMIMP-Rheumatology Unit, University of Bari, Italy. f.iannone@reumbari.uniba.it Obesity is one of the main risk factors for osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints, and epidemiological surveys have shown a strict correlation between an increased body mass index and the severity of knee or hip OA, as well as some relief of pain and disability following weight loss. Instead, there is now a growing body of evidence that obesity is a complex syndrome in which an abnormal activation of neuroendocrine and pro-inflammatory pathways leads to an altered control of food intake, fat expansion and metabolic changes. Activated white adipose tissue increases the synthesis of pro-inflammatory cytokines, such as IL-6, IL-1, IL-8, TNFalpha, IL-18, while regulatory cytokines, such as IL-10, are decreased. Adipocytes also produce peculiar cytokines, namely adipokines, that exert multiple effects, being capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling. Furthermore, pro-inflammatory cytokines stimulate adipocytes to synthesize neuropeptides, such as substance P and nerve growth factor, that have been shown to be critical in regulating both the appetite and cartilage homeostasis. In this scenario, where the influence of obesity on OA stems from a complex interaction of genetic, metabolic, neuroendocrine, and biomechanical factors, there may be various different potential targets for OA therapy. PMID: 20199391 [PubMed - indexed for MEDLINE] 1492. Nat Rev Endocrinol. 2010 Apr;6(4):225-35. doi: 10.1038/nrendo.2010.18. Epub 2010 Mar 2. SPARC: a key player in the pathologies associated with obesity and diabetes. Kos K(1), Wilding JP. Author information: (1)Department of Diabetes and Vascular Medicine, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, UK. katarina.kos@pcmd.ac.uk SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin or BM-40) is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions. Notably, SPARC is linked to human obesity; SPARC derived from adipose tissue is associated with insulin resistance and secretion of SPARC by adipose tissue is increased by insulin and the adipokine leptin. Furthermore, SPARC is associated with diabetes complications such as diabetic retinopathy and nephropathy, conditions that are ameliorated in the Sparc-knockout mouse model. As a regulator of the extracellular matrix, SPARC also contributes to adipose-tissue fibrosis. Evidence suggests that adipose tissue becomes increasingly fibrotic in obesity. Fibrosis of subcutaneous adipose tissue may restrict accumulation of triglycerides in this type of tissue. These triglycerides are, therefore, diverted and deposited as ectopic lipids in other tissues such as the liver or as intramyocellular lipids in skeletal muscle, which predisposes to insulin resistance. Hence, SPARC may represent a novel and important link between obesity and diabetes mellitus. This Review is focused on whether SPARC could be a key player in the pathology of obesity and its related metabolic complications. PMID: 20195270 [PubMed - indexed for MEDLINE] 1493. Nat Rev Endocrinol. 2010 Apr;6(4):195-213. doi: 10.1038/nrendo.2010.20. Epub 2010 Mar 2. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Tran TT(1), Kahn CR. Author information: (1)Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA. Humans and other mammals have three main adipose tissue depots: visceral white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue, each of which possesses unique cell-autonomous properties. In contrast to visceral adipose tissue, which can induce detrimental metabolic effects, subcutaneous white adipose tissue and brown adipose tissue have the potential to benefit metabolism by improving glucose homeostasis and increasing energy consumption. In addition, adipose tissue contains adipose-derived stem cells, which possess the ability to differentiate into multiple lineages, a property that might be of value for the repair or replacement of various damaged cell types. Adipose tissue transplantation has primarily been used as a tool to study physiology and for human reconstructive surgery. Transplantation of adipose tissue is, however, now being explored as a possible tool to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as adipose-derived stem cells. Ultimately, the clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments. PMCID: PMC4362513 PMID: 20195269 [PubMed - indexed for MEDLINE] 1494. Dig Liver Dis. 2010 May;42(5):310-9. doi: 10.1016/j.dld.2010.01.013. Epub 2010 Mar 2. Insulin resistance, adipose depots and gut: interactions and pathological implications. Gastaldelli A(1), Natali A, Vettor R, Corradini SG. Author information: (1)Institute of Clinical Physiology, Stable Isotope Laboratory, CNR-National Research Council, Pisa, Italy. amalia@ifc.cnr.it Erratum in Dig Liver Dis. 2014 Nov;46(11):1055. This review article focuses on the many metabolic actions of insulin at the level of muscle, liver and adipose tissue. In terms of pathogenetic mechanisms, the condition of insulin resistance is complex, as multiple genetic and environmental factors, among which an increasingly sedentary lifestyle associated with high-fat diet, mutually interact according to variable patterns in time in any given individual. It is well recognized that obesity (in particular abdominal obesity) favours the development of insulin resistance. Here we evaluate the impact of obesity and ectopic fat accumulation (visceral and hepatic) on insulin resistance at the level of different target organs, i.e., muscle, liver and adipose tissue. The roles of the gut and the liver, in particular of bile acids and gut microflora, are also discussed as possible determinants of energy balance and glucose metabolism. Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. PMID: 20194050 [PubMed - indexed for MEDLINE] 1495. Biol Pharm Bull. 2010;33(3):346-50. A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver. Matsusue K(1). Author information: (1)Faculty of Pharmaceutical Science, Fukuoka University, Japan. Fat specific protein 27 (FSP27) was originally isolated by screen for genes specifically expressed in fully differentiated mouse adipocytes. FSP27 and cell death-inducing DFF45-like effector C (CIDEC), the human homologue of FSP27, belong to the CIDE family. The FSP27 in adipocytes was recently reported to be a lipid droplet (LD)-associated protein, that promotes the formation of unilocular LDs. An FSP27 knockout mouse demonstrated lean phenotypes with atrophic adipose tissue as a result of high-energy expenditure; this mouse line was also resistant to diet-induced obesity and insulin resistance. Interestingly, FSP27 was also expressed in the steatoic liver of a type II diabetes model mouse. The expression of FSP27 was markedly decreased in livers lacking the nuclear receptor peroxisome proliferator-activated receptor gamma. Forced expression of FSP27 in hepatocytes in vitro or in vivo led to an increase of LD through increased triglyceride levels. The current status of the physiological roles of FSP27/CIDEC in adipose tissue and liver are discussed along with its significance as a factor involved in the development of metabolic disorders. PMID: 20190390 [PubMed - indexed for MEDLINE] 1496. Atherosclerosis. 2010 Aug;211(2):353-60. doi: 10.1016/j.atherosclerosis.2010.01.028. Epub 2010 Jan 29. Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes. Vergès B(1). Author information: (1)Service Endocrinologie, Diabétologie et Maladies Métaboliques, Dijon University Hospital, France. bruno.verges@chu-dijon.fr Increased Very Low Density Lipoprotein (VLDL) production is a major feature of diabetic dyslipidemia with consequences on the metabolism of other lipoproteins such as Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL). More precisely, we observe, in patients with type 2 diabetes, an increased production of VLDL(1) particles that is potentially detrimental by generating atherogenic remnants, small dense LDL particles and triglyceride-rich HDL particles. Several pathophysiological factors are responsible for increased VLDL production, in type 2 diabetes. Among those, insulin resistance plays an important role. Indeed, defective activation of PI3-kinase, secondary to insulin resistance, is associated with a reduction of apoB degradation in the hepatocytes, a rise in MTP expression (by increasing nuclear transcription factors Fox01 and Foxa2) and an increased activity of phospholipase D1 and ARF-1, which are involved in VLDL(1) formation. Moreover, peripheral insulin resistance is responsible for increased lipolysis of adipose tissue leading to augmented portal flux of FFA to the liver and, as a consequence, activation of VLDL production. In addition, increased de novo lipogenesis is observed in type 2 diabetes. This is secondary to increased activation of SREBP-1c (Sterol Regulatory Element-Binding Protein-1c), mainly by Endoplasmic Reticulum stress, and of ChREBP (Carbohydrate Responsive Element Binding Protein), mainly by hyperglycemia. Furthermore, decreased plasma adiponectin observed in type 2 diabetes, may also play a role in increased VLDL production by decreasing liver AMP-kinase activation and by increasing plasma FFA levels as a consequence of reduced muscle FFA oxidation. Copyright 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20189175 [PubMed - indexed for MEDLINE] 1497. Biochimie. 2010 Sep;92(9):1222-6. doi: 10.1016/j.biochi.2010.02.026. Epub 2010 Feb 25. Linking long-term toxicity of xeno-chemicals with short-term biological adaptation. Barouki R(1). Author information: (1)Inserm UMR-S 747, Université Paris Descartes, Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France. robert.barouki@parisdescartes.fr Understanding the mechanisms of long-term toxicities of chemicals is challenging. The present review discusses evidence suggesting that the biological adaptation to acute xenobiotic exposure could lead in the long run to toxic side effects. Upon acute exposure, hydrophobic xenobiotics are sequestered in the adipose tissue, which consequently protects other organs. However, this could also lead to the persistence of these xenochemicals and to a chronic low level internal exposure. The intrinsic properties of the xenobiotic detection and metabolism systems could also account for long-term toxicity. Indeed, hydrophobic xenochemicals are metabolized into more hydrophilic compounds; the first step of this pathway consists in the "activation" of the parent compound into a more reactive intermediate by cytochromes P450 activity. Those intermediates can be extremely reactive with DNA and proteins and thus could lead to toxic side effects that may become significant over time. Furthermore, recent evidence suggests that xenobiotic receptors also display endogenous functions. It is likely that repeated exposure to xenobiotics disrupts those endogenous functions with possibly dire cellular consequences. Altogether, The hypothesis presented here proposes that one mechanism for long-term toxicity stems from cumulative side effects due to the repeated activity of adaptive pathways triggered by acute intoxication. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved. PMID: 20188785 [PubMed - indexed for MEDLINE] 1498. Mol Nutr Food Res. 2010 May;54(5):693-709. doi: 10.1002/mnfr.200900575. Dietary alpha-tocopherol and neuromuscular health: search for optimal dose and molecular mechanisms continues! Gohil K(1), Vasu VT, Cross CE. Author information: (1)Department of Internal Medicine, Genome and Biomedical Sciences Facility, University of California, Davis, CA 95616, USA. kgohil@ucdavis.edu Rodents fed alpha-tocopherol (alphaT)-depleted diets develop neuromuscular deficits. Unequivocal role of alphaT in the prevention of these deficits is confounded by possible neurotoxic oxidant products generated, ex vivo in alphaT-depleted diets. The discovery that large doses of alphaT could ameliorate neuromuscular deficits, attributed to very low serum alphaT caused by mutations in either the microsomal triglyceride transfer protein or the alphaT-transfer protein (alphaTTP), underscores the necessity of alphaT for neuromuscular health in humans. The discovery of human alphaTTP provided physiological relevance to biochemical data from rodents documenting alphaT-binding transfer protein, expressed exclusively in liver. The cloning of alphaTTP gene and the creation of alphaTTP-knockout mice allowed to achieve severe systemic alphaT deficiency in brain and muscles, possibly at birth, eliminating the possible confounding effects of ex vivo-generated oxidant products in vitamin E-stripped diets. alphaTTP-knockout mice have proven useful models to discover alphaT-regulated phenotypes and molecular actions of alphaT in vivo. The results suggest that antioxidant and non-antioxidant actions of alphaT in vivo may not be mutually exclusive. These studies also suggest that low levels of dietary alphaT can achieve in excess of nanomolar alphaT levels in tissues and maintain normal neuromuscular functions. This is consistent with biochemical and crystallographic data of alpha-TTP and of other alphaT-binding proteins that have dissociation constants in nanomolar range. Molecular mechanisms that cause a long delay for the development of deficiency symptoms remain enigmatic. It is likely that alphaT is metabolically stable in post-mitotic neurons and myocytes and, if it undergoes redox-cycling in vivo, a large repertoire of alphaT-regenerating systems maintains its biological activity before it is totally depleted. PMID: 20187127 [PubMed - indexed for MEDLINE] 1499. Mol Nutr Food Res. 2010 May;54(5):710-8. doi: 10.1002/mnfr.200900460. Vitamin E and neurological function. Muller DP(1). Author information: (1)UCL Institute of Child Health, London WC1N 1EH, UK. D.Muller@ich.ucl.ac.uk The clinical, neuropathological and electrophysiological evidence that vitamin E (alpha-tocopherol) is essential for normal neurological function will be reviewed. The possible reasons why neural tissues should be particularly affected by a deficiency of this fat-soluble vitamin and the mechanism(s) involved will be considered. PMID: 20183831 [PubMed - indexed for MEDLINE] 1500. Maturitas. 2010 May;66(1):33-8. doi: 10.1016/j.maturitas.2010.01.019. Epub 2010 Feb 23. Interaction between menopausal status and obesity in affecting breast cancer risk. Rose DP(1), Vona-Davis L. Author information: (1)Department of Surgery, Mary Babb Randolph Cancer Center, West Virginia University Robert C. Byrd Health Sciences Center, Morgantown, WV 26506, USA. Obesity has a complex relationship to breast cancer risk that differs in premenopausal and postmenopausal women. Before the menopause, the level of adiposity is inversely related to risk, indicative of a protective effect, whereas in postmenopausal women, particularly the elderly, the association is a positive one, consistent with obesity being a risk factor. The importance of high estrogen production in adipose tissue, with consequent elevation of circulating biologically available estradiol, in the promotional effect of obesity on postmenopausal breast carcinogenesis is well established; the resulting tumors express both estrogen and progesterone receptors. The mechanism(s) for the protective effect in premenopausal women is less well understood, but the breast cancers that do develop in the presence of obesity are most often estrogen and progesterone receptor negative, consistent with the selection of non-estrogen-dependent tumor cells which are dependent on growth factors such as insulin, insulin-like growth factor-I and some adipokines. The influence of menopausal status on the relationships between adiposity and breast cancer appears to be modified within each category by age; the protective effect before the menopause may be limited to younger women (<35 years), and the adverse effect was found to apply specifically to older postmenopausal women. Although randomized trials of weight reduction for postmenopausal breast cancer prevention have not been performed, observational studies suggested that risk reduction does occur; in addition, other health benefits of weight control need to be considered regardless of menopausal status. Copyright 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20181446 [PubMed - indexed for MEDLINE] 1501. Med Hypotheses. 2010 Jul;75(1):59-64. doi: 10.1016/j.mehy.2009.12.034. Epub 2010 Feb 23. The straight line hypothesis elaborated: case reference obesity, an argument for acidosis, oxidative stress, and disease conglomeration? Berkemeyer S(1). Author information: (1)Department of Geriatrics, University of Bochum, Marienhospital Herne, Widumerstr. 8, D-44627 Herne, Germany. shoma.berkemeyer@ruhr-uni-bochum.de Studies report on the association between obesity and oxidative stress, with and without additional diseases. Macrophages in adipocytes, and hypoxia in adipose tissue have been suggested to explain how obesity can relate to oxidative stress. The straight line hypothesis using the lactic acid trap construct has been put forward to explain how proton imbalance can relate to obesity. Proton imbalance has been also reported to associate with the production of reactive oxygen species by inhibition of mitochondrial energy production. This review brings together existing literature and concepts to explain how obesity can relate to oxidative stress via protons, uniquely for itself or, as often observed, in conglomeration of additional diseases. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20181434 [PubMed - indexed for MEDLINE] 1502. Curr Vasc Pharmacol. 2010 Mar;8(2):155-68. Obesity and arterial compliance alterations. Seifalian AM(1), Filippatos TD, Joshi J, Mikhailidis DP. Author information: (1)Cardiovascular Hemodynamic Unit, UCL Division of Surgery and Interventional Science, University College London, London, UK. a.seifalian@ucl.ac.uk Obesity is associated with increased cardiovascular disease (CVD) risk, especially when excess body fat is distributed preferentially within the abdominal region. Obese subjects usually have increased arterial stiffness compared with non-obese subjects of similar age. The factors associated with increased arterial stiffness in obesity include endothelial dysfunction (decreased nitric oxide bioavailability), impaired smooth muscle cell function, insulin resistance, as well as elevated cholesterol and C-peptide levels. Furthermore, visceral fat, the adipose tissue-related renin-angiotensin-aldosterone system and hyperleptinaemia contribute to the obesity-associated impaired arterial compliance. Weight loss improves CVD risk factors and arterial compliance. Because increased arterial stiffness is a marker of CVD risk these findings support the concept that the presence of obesity has vascular implications. PMID: 20180777 [PubMed - indexed for MEDLINE] 1503. Curr Dir Autoimmun. 2010;11:145-56. doi: 10.1159/000289203. Epub 2010 Feb 18. TNF-alpha and obesity. Tzanavari T(1), Giannogonas P, Karalis KP. Author information: (1)Division of Developmental Biology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, Athens, Greece. Obesity, an epidemic of our times with rates rising to alarming levels, is associated with comorbidities including cardiovascular diseases, arthritis, certain cancers, and degenerative diseases of the brain and other organs. Importantly, obesity is a leading cause of insulin resistance and type 2 diabetes. As emerging evidence has shown over the last decade, inflammation is one of the critical processes associated with the development of insulin resistance, diabetes and related diseases, and obesity is now considered as a state of chronic low-grade inflammation. Adipose tissue, apart from its classical role as an energy storage depot, is also a major endocrine organ secreting many factors, whose local and circulating levels are affected by the degree of adiposity. Obesity leads to infiltration of the expanded adipose tissue by macrophages and increased levels in proinflammatory cytokines. The first indication for increased cytokine release in obesity was provided by the identification of increased expression of TNF-alpha, a proinflammatory cytokine, in the adipose tissue of obese mice in the early 1990s. TNF-alpha is expressed in and secreted by adipose tissue, its levels correlating with the degree of adiposity and the associated insulin resistance. Targeting TNF-alpha and/or its receptors has been suggested as a promising treatment for insulin resistance and type 2 diabetes. This review will summarize the available knowledge on the role of TNF-alpha in obesity and related processes and the potential implications of the above in the development of new therapeutic approaches for obesity and insulin resistance. Recent data from clinical studies will also be described together with late findings on the pathogenesis of obesity and insulin resistance. Copyright (c) 2010 S. Karger AG, Basel. PMID: 20173393 [PubMed - indexed for MEDLINE] 1504. J Steroid Biochem Mol Biol. 2010 Oct;122(1-3):10-20. doi: 10.1016/j.jsbmb.2010.02.010. Epub 2010 Feb 17. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations. Rose AJ(1), Vegiopoulos A, Herzig S. Author information: (1)Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue-specific contributions of the glucocorticoid pathway to the control of energy metabolism. Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 20170729 [PubMed - indexed for MEDLINE] 1505. Circ Res. 2010 Feb 19;106(3):447-62. doi: 10.1161/CIRCRESAHA.109.208355. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Maury E(1), Ramsey KM, Bass J. Author information: (1)Northwestern University, Pancoe-ENH Pavilion Room 4405, 2200 Campus Dr, Evanston, IL 60208, USA. The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics. PMCID: PMC2837358 PMID: 20167942 [PubMed - indexed for MEDLINE] 1506. Curr Med Chem. 2010;17(14):1382-93. CB(1) cannabinoid receptors and their associated proteins. Howlett AC(1), Blume LC, Dalton GD. Author information: (1)Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. ahowlett@wfubmc.edu CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB(1) receptor influence on memory and learning is well recognized, and disease states associated with CB(1) receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB(1) receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB(1) receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca(2+) channels, activate K(+) currents (K(ir)), and influence Nitric Oxide (NO) signaling. CB(1) receptors are observed in internal organelles as well as plasma membrane. beta-Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses. PMCID: PMC3179980 PMID: 20166926 [PubMed - indexed for MEDLINE] 1507. Tissue Eng Part B Rev. 2010 Aug;16(4):413-26. doi: 10.1089/ten.TEB.2009.0544. Adipose tissue engineering for soft tissue regeneration. Choi JH(1), Gimble JM, Lee K, Marra KG, Rubin JP, Yoo JJ, Vunjak-Novakovic G, Kaplan DL. Author information: (1)Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, USA. Current treatment modalities for soft tissue defects caused by various pathologies and trauma include autologous grafting and commercially available fillers. However, these treatment methods present a number of challenges and limitations, such as donor-site morbidity and volume loss over time. As such, improved therapeutic modalities need to be developed. Tissue engineering techniques offer novel solutions to these problems through development of bioactive tissue constructs that can regenerate adipose tissue in both structure and function. Recently, a number of studies have been designed to explore various methods to engineer human adipose tissue. This review will focus on these developments in the area of adipose tissue engineering for soft tissue replacement. The physiology of adipose tissue and current surgical therapies used to replace lost tissue volume, specifically in breast tissue, are introduced, and current biomaterials, cell sources, and tissue culture strategies are discussed. We discuss future areas of study in adipose tissue engineering. PMCID: PMC2946881 PMID: 20166810 [PubMed - indexed for MEDLINE] 1508. J Clin Endocrinol Metab. 2010 Apr;95(4):1544-54. doi: 10.1210/jc.2009-2286. Epub 2010 Feb 17. Hypoadiponectinemia--cause or consequence of human "insulin resistance"? Cook JR(1), Semple RK. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, United Kingdom. CONTEXT: Adiponectin is a highly abundant plasma protein synthesized nearly exclusively in adipose tissue from the ADIPOQ gene. It has excited intense interest because of robust correlation of its circulating levels with indices of insulin resistance (IR) and risk of type 2 diabetes, and their unusual inverse relationship with fat mass. It has been suggested that pharmacological strategies aimed at augmenting adiponectin levels or action may generate novel insulin-sensitizing drugs. EVIDENCE ACQUISITION: Relevant publications were identified by searching PubMed, with secondary searches of their bibliographies. EVIDENCE SYNTHESIS: Rodent studies suggest that adiponectin exerts a direct insulin-sensitizing effect on the liver, consistent with a role in the pathogenesis of prevalent forms of IR and its sequelae. However, the complex higher-order structure of adiponectin and inconsistent reports regarding its putative receptors have complicated efforts to understand the mechanistic basis of this. No proof yet exists that adiponectin modulates insulin sensitivity in humans, and genetic, biochemical, and physiological evidence suggests that low adiponectin levels may be a consequence of IR with compensatory hyperinsulinemia. This suggests that there may be a bidirectional relationship between IR and hypoadiponectinemia in humans. CONCLUSIONS: The relationship between adiponectin and insulin action in humans is more complex than often suggested. Further investigation of the direction of causality in this relationship, allied to studies of the cellular mechanisms involved, will be central to improving understanding of the physiological role of this enigmatic protein, and to efforts to exploit it for therapeutic benefit. PMID: 20164291 [PubMed - indexed for MEDLINE] 1509. Anim Sci J. 2010 Feb;81(1):21-7. doi: 10.1111/j.1740-0929.2009.00696.x. The role of intramuscular connective tissue in meat texture. Nishimura T(1). Author information: (1)Meat Science laboratory, Graduate School of Agriculture, Hokkaido University, Kita, Sapporo, Japan. nishi@anim.agr.hokudai.ac.jp The structure, composition and amount of intramuscular connective tissue (IMCT) vary tremendously between muscles, species and breeds, and certainly contribute to meat texture. With animal growth, collagen crosslinks become more stable, and the structural integrity of IMCT increases. These changes increase the mechanical properties of IMCT, contributing to the toughening of meat. Intramuscular fat deposits, mainly in the perimysium between muscle fiber bundles, result in marbling. This causes the remodeling of IMCT structures and reduces the mechanical strength of IMCT, contributing to the tenderization of beef. The IMCT has been thought to be rather immutable compared to myofibrils during postmortem ageing of meat. However, recent studies have shown the disintegration of IMCT during postmortem ageing of meat and its relationship to tenderization of raw meat, although its contribution to cooked meat is still controversial. Given the large influence of IMCT on meat texture, further elucidations of molecular mechanisms which change the structural integrity of IMCT during chronological ageing of animals and postmortem ageing of meat are needed. PMID: 20163668 [PubMed - indexed for MEDLINE] 1510. Curr Opin Endocrinol Diabetes Obes. 2010 Apr;17(2):143-9. doi: 10.1097/MED.0b013e328337a81f. Brown fat as a therapy for obesity and diabetes. Cypess AM(1), Kahn CR. Author information: (1)Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts, 02215, USA. PURPOSE OF REVIEW: Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure. This review evaluates the recent discoveries regarding the identification of functional BAT in adult humans and its potential as a therapy for obesity and diabetes. RECENT FINDINGS: Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression assays to prove conclusively that adult humans have functional BAT. This has occurred against a backdrop of basic studies defining the origins of BAT, new components of its transcriptional regulation, and the role of hormones in stimulation of BAT growth and differentiation. SUMMARY: Adult humans have functional BAT, a new target for antiobesity and antidiabetes therapies focusing on increasing energy expenditure. Future studies will refine the methodologies used to measure BAT mass and activity, expand our knowledge of critical-control points in BAT regulation, and focus on testing pharmacological agents that increase BAT thermogenesis and help achieve long-lasting weight loss and an improved metabolic profile. PMCID: PMC3593105 PMID: 20160646 [PubMed - indexed for MEDLINE] 1511. J Am Acad Dermatol. 2010 Mar;62(3):361-70; quiz 371-2. doi: 10.1016/j.jaad.2009.10.042. Treatment of cellulite: Part I. Pathophysiology. Khan MH(1), Victor F, Rao B, Sadick NS. Author information: (1)Department of Dermatology at Robert-Wood Johnson University Hospital, University of Medicine and Dentistry New Jersey, Somerset, New Jersey, USA. khanmisbah6@gmail.com Comment in J Am Acad Dermatol. 2011 Feb;64(2):439. Cellulite is a topographic skin change that is nearly ubiquitous in postpubertal women. Treatment remains elusive. The various treatments currently available are only partially or temporarily effective. Newer therapeutic modalities continue to evolve without much understanding of the complex nature of cellulite. The successful treatment of cellulite will ultimately depend upon our understanding of the pathophysiology of cellulite adipose tissue. Part I of this two-part series on cellulite reviews how the concept and perception of cellulite has evolved over time and its proposed etiologies. The article also focuses on the physiology of human adipose tissue, particularly regarding cellulite. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved. PMID: 20159304 [PubMed - indexed for MEDLINE] 1512. Proc Nutr Soc. 2010 May;69(2):232-43. doi: 10.1017/S0029665110000042. Epub 2010 Feb 17. The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA. Oliver E(1), McGillicuddy F, Phillips C, Toomey S, Roche HM. Author information: (1)Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Dublin 4, Republic of Ireland. The WHO estimate that >1 x 10(6) deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD and type 2 diabetes mellitus. Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. In recent years it has been established that activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms including (a) down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Long-chain (LC) n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-kappaB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. LC n-3 PUFA may therefore offer a useful anti-inflammatory strategy to decrease obesity-induced insulin resistance, which will be examined in the present review. PMID: 20158940 [PubMed - indexed for MEDLINE] 1513. Nihon Rinsho. 2010 Feb;68(2):210-6. [Regulation of differentiation and hypertrophy of adipocytes and adipokine network by PPARgamma]. [Article in Japanese] Waki H(1), Yamauchi T, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, the University of Tokyo. PPARgamma is a ligand-activated transcription factor that serves as a central regulator of adipocyte differentiation. PPARgamma has been the focus of intense research since its discovery as a molecular target of the thiazolidinedione class of drug. Here we review regulation of differentiation and hypertrophy of adipocytes and adipokine network by PPARgamma with an emphasis on their influences on systemic glucose and lipid metabolism. Specific topics include the mechanism by which both activation of PPARgamma by thiazolidinedione and haploinsufficiency of PPARgamma leads to insulin sensitivity and recent advance in our understanding of the role of adiponectin and adipose tissue macrophages in insulin sensitizing action of thiazolidinedione. PMID: 20158086 [PubMed - indexed for MEDLINE] 1514. Nihon Rinsho. 2010 Feb;68(2):181-8. [Recent advances in PPARgamma research]. [Article in Japanese] Waki H(1), Yamauchi T, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, the University of Tokyo. PPARgamma is a member of the nuclear receptor superfamily and a molecular target of the thiazolidinedione class of antidiabetic drugs. PPARgamma was initially characterized as a central regulator of adipocyte differentiation. Recent advances in PPARgamma research have revealed diverse pathophysiological actions of PPARgamma such as regulation of expression of adipokines and inflammatory mediators, adipose tissue macrophage polarization, atherosclerosis formation and bone development. Here, we highlight recent advances in our current understanding the biological actions of PPARgamma. PMID: 20158082 [PubMed - indexed for MEDLINE] 1515. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):343-8. doi: 10.1016/j.jsbmb.2010.02.009. Epub 2010 Feb 13. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. Krishnan AV(1), Swami S, Feldman D. Author information: (1)Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States. Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, inhibits the growth and induces the differentiation of many malignant cells including breast cancer (BCa) cells. Calcitriol exerts its anti-proliferative activity in BCa cells by inducing cell cycle arrest and stimulating apoptosis. Calcitriol also inhibits invasion, metastasis and tumor angiogenesis in experimental models of BCa. Our recent studies show additional newly discovered pathways of calcitriol action to inhibit the growth of BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels and biological activity of prostaglandins (PGs). Calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and the breast adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels and biological activity of PGE2, which is a major stimulator of aromatase transcription through promoter II in BCa. Calcitriol down-regulates the expression of estrogen receptor alpha and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. We hypothesize that the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in the use of calcitriol for the prevention and/or treatment of BCa. Copyright (c) 2010 Elsevier Ltd. All rights reserved. PMID: 20156557 [PubMed - indexed for MEDLINE] 1516. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(2):131-41. Establishment of a concept of visceral fat syndrome and discovery of adiponectin. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital. Although obesity is a major background of life style-related diseases such as diabetes mellitus, lipid disorder, hypertension and cardiovascular disease, the extent of whole body fat accumulation does not necessarily the determinant for the occurrence of these diseases. We developed the method for body fat analysis using CT scan and established the concept of visceral fat obesity, in other word metabolic syndrome in which intra-abdominal visceral fat accumulation has an important role in the development of diabetes, lipid disorder, hypertension and atherosclerosis. In order to clarify the mechanism that visceral fat accumulation causes metabolic and cardiovascular diseases, we have analyzed gene expression profile in subcutaneous adipose tissue and visceral adipose tissue. From the analysis, we found that adipose tissue, especially visceral adipose tissue expressed abundantly the genes encoding bioactive substances such as cytokines, growth factors and complements. In addition to known bioactive substances, we found a novel collagen-like protein which we named adiponectin. Adiponectin is present in plasma at a very high concentration and is inversely associated with visceral fat accumulation. Adiponectin has anti-diabetic, anti-hypertensive and anti-atherogenic properties and recent studies revealed that this protein has an anti-inflammatory and anti-oncogenic function. Therefore hypoadiponectinemia induced by visceral fat accumulation should become a strong risk factor for metabolic and cardiovascular diseases and also some kinds of cancers.In this review article, I would like to discuss the mechanism of life style-related diseases by focusing on the dysregulation of adiponectin related to obesity, especially visceral obesity. PMCID: PMC3417563 PMID: 20154470 [PubMed - indexed for MEDLINE] 1517. Maturitas. 2010 May;66(1):16-22. doi: 10.1016/j.maturitas.2010.01.009. Epub 2010 Feb 13. Testosterone and the aging male: to treat or not to treat? Bain J(1). Author information: (1)Department of Medicine, University of Toronto, Division of Endocrinology and Metabolism, Mount Sinai Hospital, Toronto, Ontario, Canada. j.bain@utoronto.ca It is well-established that total testosterone (TT) in men decreases with age and that bioavailable testosterone (bio-T) falls to an even greater extent. The clinical relevance of declining androgens in the aging male and use of testosterone replacement therapy (TRT) in this situation is controversial. Most studies have been short term and there are no large randomized placebo-controlled trials. Testosterone has many physiological actions in: muscles, bones, hematopoietic system, brain, reproductive and sexual organs, adipose tissue. Within these areas it stimulates: muscle growth and maintenance, bone development while inhibiting bone resorption, the production of red blood cells to increase hemoglobin, libido, enhanced mood and cognition, erectile function and lipolysis. Anabolic deficits in aging men can induce: frailty, sarcopenia, poor muscle quality, muscle weakness, hypertrophy of adipose tissue and impaired neurotransmission. The aging male with reduced testosterone availability may present with a wide variety of symptoms which in addition to frailty and weakness include: fatigue, decreased energy, decreased motivation, cognitive impairment, decreased self-confidence, depression, irritability, osteoporotic pain and the lethargy of anemia. In addition, testosterone deficiency is also associated with type-2 diabetes, the metabolic syndrome, coronary artery disease, stroke and transient ischemic attacks, and cardiovascular disease in general. Furthermore, there are early studies to suggest that TRT in men with low testosterone levels may improve metabolic status by: lowering blood sugar and HbA1C in men with type-2 diabetes, reducing abdominal girth, ameliorating features of the metabolic syndrome, all of which may be protective of the cardiovascular system. The major safety issue is prostate cancer but there is no evidence that supports the idea that testosterone causes the development of a de novo cancer. So on balance in a man with symptoms of hygonadism and low or lowish levels of testosterone with no evidence of prostate cancer such as a normal PSA a therapeutic (4-6 months) trial of TRT is justified. Treatment and monitoring of this duration will determine whether the patient is responsive. Copyright 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20153946 [PubMed - indexed for MEDLINE] 1518. Diabetes Metab. 2009 Dec;35(6 Pt 2):499-507. doi: 10.1016/S1262-3636(09)73456-1. What can bariatric surgery teach us about the pathophysiology of type 2 diabetes? Andreelli F(1), Amouyal C, Magnan C, Mithieux G. Author information: (1)CHU Bichat Claude Bernard, AP-HP, Service de Diabétologie-Endocrinologie-Nutrition,75877 Paris cedex 18, France. Bariatric surgery is indicated in cases of severe obesity. However, malabsorption-based techniques (gastric bypass and biliopancreatic diversion, both of which exclude the duodenum and jejunum from the alimentary circuit), but not restrictive techniques, can abolish type 2 diabetes within days of surgery, even before any significant weight loss has occurred. This means that calorie restriction alone cannot entirely account for this effect. In Goto-Kakizaki rats, a type 2 diabetes model, glycaemic equilibrium is improved by surgical exclusion of the proximal intestine, but deteriorates again when the proximal intestine is reconnected to the circuit in the same animals. This effect is independent of weight, suggesting that the intestine is itself involved in the immediate regulation of carbohydrate homoeostasis. In humans, the rapid improvement in carbohydrate homoeostasis observed after bypass surgery is secondary to an increase in insulin sensitivity rather than an increase in insulin secretion, which occurs later. Several mechanisms are involved--disappearance of hypertriglyceridaemia and decrease in levels of circulating fatty acids, disappearance of the mechanisms of lipotoxicity in the liver and skeletal muscle, and increases in secretion of GLP-1 and PYY--and may be intricately linked. In the medium term and in parallel with weight loss, a decrease in fatty tissue inflammation (which is also seen with restrictive techniques) may also be involved in metabolic improvement. Other mechanisms specific to malabsorption-based techniques (due to the required exclusion of part of the intestine), such as changes in the activity of digestive vagal afferents, changes in intestinal flora and stimulation of intestinal neoglucogenesis, also need to be studied in greater detail. The intestine is, thus, a key organ in the regulation of glycaemic equilibrium and may even be involved in the pathophysiology of type 2 diabetes. Copyright 2009 Elsevier Masson SAS. All rights reserved. PMID: 20152734 [PubMed - indexed for MEDLINE] 1519. J Am Coll Nutr. 2009 Jun;28(3):252-6. Vitamin D3 distribution and status in the body. Heaney RP(1), Horst RL, Cullen DM, Armas LA. Author information: (1)Creighton University, 601 N. 30 St., Suite 4841, Omaha, NE 68131, USA. rheaney@creighton.edu OBJECTIVE: To estimate the amount, type, and tissue distribution of vitamin D in the adult body under typical inputs. METHODS: Review and reanalysis of published measurements and analysis of tissue samples from growing pigs raised in confinement on diets providing about 2000 IU vitamin D/day. Cholecalciferol and 25-hydroxyvitamin D [25(OH)D] concentration measured by HPLC. RESULTS: Mean serum 25(OH)D in all studies combined was 45 nmol/L. At the level of vitamin D repletion represented by this concentration, total body vitamin D would be 14,665 IU for a 70 kg adult woman. 65% of this total was present as native cholecalciferol and 35% as 25(OH)D. Nearly three-quarters of the cholecalciferol was in fat, while 25(OH)D was more evenly distributed throughout the body (20% in muscle, 30% in serum, 35% in fat, and 15% in all other tissues). At the daily vitamin D consumption rates in these animals total body stores provided only a approximately 7-day reserve. CONCLUSIONS: At total intakes on the order of 2000 IU/day, an adult has very little vitamin D reserve, despite intakes 10x the current recommendations. Those recommended inputs need to be increased by at least an order of magnitude. Food tables that fail to take into account 25(OH)D content of various meat products lead to underestimation of dietary vitamin D intake. PMID: 20150598 [PubMed - indexed for MEDLINE] 1520. J Nutr Biochem. 2010 May;21(5):357-63. doi: 10.1016/j.jnutbio.2009.09.010. Epub 2010 Feb 9. N-3 polyunsaturated fatty acids regulate lipid metabolism through several inflammation mediators: mechanisms and implications for obesity prevention. Tai CC(1), Ding ST. Author information: (1)Department of Animal Science, National Taiwan University, Taipei, Taiwan. Obesity is a growing problem that threatens the health and welfare of a large proportion of the human population. The n-3 polyunsaturated fatty acids (PUFA) are dietary factors that have potential to facilitate reduction in body fat deposition and improve obesity-induced metabolic syndromes. The n-3 PUFA up-regulate several inflammation molecules including serum amyloid A (SAA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hepatocytes and adipocytes. Actions of these inflammation mediators resemble those of n-3 PUFA in the modulation of many lipid metabolism-related genes. For instance, they both suppress expressions of perilipin, sterol regulatory element binding protein-1 (SREBP-1) and lipoprotein lipase (LPL) to induce lipolysis and reduce lipogenesis. This review will connect these direct or indirect regulating pathways between n-3 PUFA, inflammation mediators, lipid metabolism-related genes and body fat reduction. A thorough knowledge of these regulatory mechanisms will lead us to better utilization of n-3 PUFA to reduce lipid deposition in the liver and other tissues, therefore presenting an opportunity for developing new strategies to treat obesity. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20149625 [PubMed - indexed for MEDLINE] 1521. Obes Rev. 2010 Dec;11(12):863-74. doi: 10.1111/j.1467-789X.2010.00718.x. Leptin and gastro-intestinal malignancies. Howard JM(1), Pidgeon GP, Reynolds JV. Author information: (1)Department of Clinical Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. Obesity is a well-established risk factor for the development and mortality from several cancers, including adenocarcinoma of the oesophagus, oesophago-gastric junction and colorectum. Despite a large body of epidemiological evidence describing this relationship, the mechanisms relating obesity and cancer are only starting to be uncovered. The altered secretion of metabolically active, pro-inflammatory adipocytokines from adipose tissue is believed to play a key role, and leptin is believed to be a key player in obesity-related carcinogenesis, as well as being the most extensively studied of the adipokines. In this literature review, we aim to examine the association between leptin and cancers of the gastro-intestinal tract. For each individual cancer, we examine and present the published data examining the role of leptin in both cell and animal models, the association between circulating leptin levels and cancer risk, and finally the expression of the leptin system in human gastro-intestinal tract tumours, in relation to tumour biology, stage and patient outcome. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity. PMID: 20149119 [PubMed - indexed for MEDLINE] 1522. Annu Rev Physiol. 2010;72:219-46. doi: 10.1146/annurev-physiol-021909-135846. Macrophages, inflammation, and insulin resistance. Olefsky JM(1), Glass CK. Author information: (1)Department of Medicine, University of California-San Diego, La Jolla, CA 92093-0651, USA. jolefsky@ucsd.edu Obesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, insulin resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-kappaB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention. PMID: 20148674 [PubMed - indexed for MEDLINE] 1523. J Pediatr. 2010 Feb;156(2 Suppl):S41-6. doi: 10.1016/j.jpeds.2009.11.020. Characteristics and potential functions of human milk adiponectin. Newburg DS(1), Woo JG, Morrow AL. Author information: (1)Massachusetts General Hospital, Charlestown, MA, USA. dnewburg@partners.org Adiponectin is a protein hormone produced by adipose tissue, whose circulating levels are inversely related to adiposity and inflammation. Adiponectin circulates as oligomers, from the low-molecular-weight trimer to the high-molecular-weight octodecamer (18 mer). Each oligomer has distinct biological activities, which include enhancement of insulin sensitivity and metabolic control and suppression of inflammation. Adiponectin occurs in human milk at higher concentrations than leptin. The adiponectin in human milk is almost entirely of the high-molecular-weight form, the form with the highest activity in controlling many types of metabolic processes. Human adiponectin fed to infant mice is transported across the intestinal mucosa into the serum. An inverse relationship between adiponectin levels in milk and adiposity (weight-for-height) of the breast-fed infant was observed and could be due to modulation of infant metabolism by milk adiponectin and may be related to the observed protection against obesity by breast-feeding. Human milk may be a medium whereby the hormonal milieu (in response to internal factors and the environment) of the mother can be used to communicate with the breast-fed infant to modify infant metabolic processes. Transmission of information from mother to infant through milk may allow adaptation to fluctuating environmental conditions. Copyright 2010 Mosby, Inc. All rights reserved. PMCID: PMC2875873 PMID: 20105665 [PubMed - indexed for MEDLINE] 1524. J Diabetes Sci Technol. 2009 Nov 1;3(6):1472-80. Reducing cardiometabolic risk in peritoneal dialysis patients: role of the dialysis solution. Holmes CJ(1). Author information: (1)Renal Division, Baxter Healthcare, McGaw Park, Illinois 60085, USA. cliff_holmes@baxter.com Peritoneal dialysis (PD) is a well-established form of therapy for stage 5 chronic kidney disease requiring renal replacement therapy. D-Glucose has been used successfully for several decades as the osmotic agent employed in dialysis solutions to achieve adequate fluid removal. The absorption of 100-200 grams of glucose per day has been suggested as potentially increasing cardiometabolic risk, particularly in patients with diabetes. Supporting and undermining evidence for this hypothesis is reviewed, with a focus on the role of glucose absorption in changes in body composition, dyslipidemia, and glycemic control in diabetic PD patients. Clinical strategies to optimize fluid removal while minimizing the metabolic impact of glucose absorption are also discussed. PMCID: PMC2787049 PMID: 20144403 [PubMed - indexed for MEDLINE] 1525. Int J Obes (Lond). 2010 Apr;34(4):659-69. doi: 10.1038/ijo.2009.299. Epub 2010 Feb 9. Thermogenic ingredients and body weight regulation. Hursel R(1), Westerterp-Plantenga MS. Author information: (1)Department of Human Biology, Nutrim, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. The global prevalence of obesity has increased considerably in the last decade. Tools for obesity management, including consumption of caffeine, capsaicin and different teas such as green, white and oolong tea, have been proposed as strategies for weight loss and weight maintenance, as they may increase energy expenditure (4-5%), fat oxidation (10-16%) and have been proposed to counteract the decrease in metabolic rate that is present during weight loss. Daily increases in thermogenesis of approximately 300-400 kJ can eventually lead to substantial weight loss. However, it becomes clearer that certain conditions have to be met before thermogenic ingredients yield an effect, as intra-variability with respect to body weight regulation has been shown between subjects. Furthermore, the sympathetic nervous system is involved in the regulation of lipolysis, and the sympathetic innervation of white adipose tissue may have an important role in the regulation of total body fat in general. Taken together, these functional ingredients have the potential to produce significant effects on metabolic targets such as satiety, thermogenesis and fat oxidation. A significant clinical outcome may sometimes appear straightforward and may also depend very strongly on full compliance of subjects. Nevertheless, thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity. PMID: 20142827 [PubMed - indexed for MEDLINE] 1526. J Pharmacol Toxicol Methods. 2010 Mar-Apr;61(2):113-21. doi: 10.1016/j.vascn.2010.01.013. Epub 2010 Feb 6. Troubleshooting: Quantification of mobilization of progenitor cell subsets from bone marrow in vivo. Pitchford SC(1), Hahnel MJ, Jones CP, Rankin SM. Author information: (1)Sackler Institute of Pulmonary Pharmacology, Division of Pharmaceutical Sciences, King's College London, SE1 9NH, UK. simon.pitchford@kcl.ac.uk INTRODUCTION: The molecular mechanisms that control the mobilization of specific stem cell subsets from the bone marrow are currently being intensely investigated. It is anticipated that boosting the mobilization of these stem cells via pharmacological intervention will not only produce more effective strategies for bone marrow transplant patients, but also provide novel therapeutic approaches for tissue regeneration. METHODS: Measurement of stem cell mobilization by sampling peripheral blood is problematic because it is technically difficult to accurately determine absolute numbers of rare progenitor cells by blood sampling. Furthermore a rise in progenitors may be caused by release of stem cells from tissues other than the bone marrow (e.g. spleen and adipose), or indeed an inhibition of stem cell homing back to the bone marrow or other tissues. Finally it is not possible to distinguish whether the pharmacological agent is acting directly at the level of the bone marrow or mobilizing progenitors by a distinct indirect mechanism. To resolve these problems, we have developed a technique that allows perfusion of the vasculature of the hind limb bone marrow in situ in mice. In this system, the femoral artery and vein are cannulated in situ such that the femur and tibia bone marrow are perfused in isolation under anaesthesia. As such, pharmacological agents can be administered directly into the bone marrow vasculature. Mobilized cells are then collected via the femoral vein and colony assays performed in defined growth media to allow identification of haematopoietic, endothelial, and mesenchymal progenitor cells. We have used this system to determine the ability of a CXCR4 antagonist to mobilize these distinct types of progenitor cells from the bone marrow of mice pre-conditioned with either G-CSF or VEGF. RESULTS AND CONCLUSION: This isolated hind limb perfusion system has allowed comparisons to be made between cytokines (G-CSF and VEGF) that act chronically, either alone or in combination with agents that act acutely on the bone marrow (CXCR4 antagonist) on their ability to directly mobilize specific populations of stem cells. Data obtained therefore gives a more accurate understanding of the efficacy of different mobilizing strategies compared to peripheral blood analysis. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20139021 [PubMed - indexed for MEDLINE] 1527. Curr Opin Nephrol Hypertens. 2010 May;19(3):227-34. doi: 10.1097/MNH.0b013e3283374c09. Scope and mechanisms of obesity-related renal disease. Hunley TE(1), Ma LJ, Kon V. Author information: (1)Division of Pediatric Nephrology, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-2574, USA. PURPOSE OF REVIEW: Obesity is established as an important contributor of increased diabetes mellitus, hypertension, and cardiovascular disease, all of which can promote chronic kidney disease (CKD). Recently, there is a growing appreciation that, even in the absence of these risks, obesity itself significantly increases CKD and accelerates its progression. RECENT FINDINGS: Experimental and clinical studies reveal that adipose tissue, especially visceral fat, elaborates bioactive substances that contribute to the pathophysiologic renal hemodynamic and structural changes leading to obesity-related nephropathy. Adipocytes contain all the components of the renin-angiotensin-aldosterone system, plasminogen activator inhibitor, as well as adipocyte-specific metabolites such as free fatty acids, leptin, and adiponectin, which affect renal function and structure. In addition, fat is infiltrated by macrophages that can alter their phenotype and foster a proinflammatory milieu, which advances pathophysiologic changes in the kidney associated with obesity. SUMMARY: Obesity is an independent risk factor for development and progression of renal damage. Although the current therapies aimed at slowing progressive renal damage include reduction in weight and rely on inhibition of the renin-angiotensin system, the approach will likely be supplemented by interventions aimed at obesity-specific targets including adipocyte-driven cytokines and inflammatory factors. PMCID: PMC2897176 PMID: 20134323 [PubMed - indexed for MEDLINE] 1528. J Atheroscler Thromb. 2010 Apr 30;17(4):332-41. Epub 2010 Feb 3. Adipose tissue, inflammation and atherosclerosis. Gustafson B(1). Author information: (1)The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden. a.fenton@liverpool.ac.uk Metabolic syndrome is associated with dysfunctional adipose tissue that is most likely a consequence of the enlargement of adipocytes and infiltration of macrophages into adipose tissue. Obesity and ectopic lipid deposition are major risk factors for diseases ranging from insulin resistance to type 2 diabetes and atherosclerosis. Enlargement of adipocytes, due to impaired adipocyte differentiation, leads to a chronic state of inflammation in the adipocytes and adipose tissue with a reduction in the secretion of adiponectin and increase in the secretion of proinflammatory cytokines such as interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1. The secretion of cytokines like tumour necrosis factor (TNF)- alpha, mainly from macrophages, enhances local inflammation. These proinflammatory cytokines might also substantially affect cardiovascular function and morphology. Furthermore, a proinflammatory state in adipose tissue can lead to local insulin resistance with an impaired inhibitory effect of insulin on the release of FFAs and endothelial dysfunction that clearly promotes cardiovascular diseases and type 2 diabetes. The underlying mechanisms of ectopic fat accumulation in various tissues and the impact on metabolic syndrome and its association with insulin resistance are discussed. PMID: 20124732 [PubMed - indexed for MEDLINE] 1529. Arch Pediatr Adolesc Med. 2010 Feb;164(2):131-8. doi: 10.1001/archpediatrics.2009.265. Roles of gastrointestinal and adipose tissue peptides in childhood obesity and changes after weight loss due to lifestyle intervention. Roth CL(1), Reinehr T. Author information: (1)Division of Endocrinology, Seattle Children's Hospital Research Institute, 1900 Ninth Ave, Seattle, WA 98101, USA. christian.roth@seattlechildrens.org Childhood obesity is a global epidemic and associated with an increased risk of hypertension, diabetes mellitus, and coronary heart disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modifications are often unsuccessful because of disturbed perceptions of satiety. New signaling peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and pancreas communicate with brain centers of energy homeostasis, such as the hypothalamus and hindbrain. This review discusses the major known gut- and adipose tissue-derived hormones involved in the regulation of food intake and energy homeostasis and their serum levels in childhood obesity before and after weight loss as well as their relationship to consequences of obesity. Since most of the changes of gastrointestinal hormones and adipokines normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weight- and food intake-regulating gut- and adipose tissue-derived hormones will help to find new strategies to treat obesity and its consequences. PMID: 20124141 [PubMed - indexed for MEDLINE] 1530. Vet Pathol. 2010 Mar;47(2):202-13. doi: 10.1177/0300985809357753. Epub 2010 Feb 1. Effect of obesity on breast cancer development. Cleary MP(1), Grossmann ME, Ray A. Author information: (1)Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA. mpcleary@hi.umn.edu In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models. PMID: 20124008 [PubMed - indexed for MEDLINE] 1531. Nat Rev Drug Discov. 2010 Feb;9(2):107-15. doi: 10.1038/nrd3055. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Cao Y(1). Author information: (1)Yihai Cao is at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institute, 171 77 Stockholm. yihai.cao@ki.se Current pharmacotherapeutic options for treating obesity and related metabolic disorders remain limited and ineffective. Emerging evidence shows that modulators of angiogenesis affect the expansion and metabolism of fat mass by regulating the growth and remodelling of the adipose tissue vasculature. Pharmacological manipulation of adipose tissue neovascularization by angiogenic stimulators and inhibitors might therefore offer a novel therapeutic option for the treatment of obesity and related metabolic disorders. This Perspective discusses recent progress in understanding the molecular mechanisms that control adipose tissue angiogenesis and in defining potential new vascular targets and approaches for the treatment of this group of diseases. PMID: 20118961 [PubMed - indexed for MEDLINE] 1532. Atherosclerosis. 2010 Jul;211(1):1-8. doi: 10.1016/j.atherosclerosis.2009.12.027. Epub 2009 Dec 29. The metabolism of triglyceride-rich lipoproteins revisited: new players, new insight. Dallinga-Thie GM(1), Franssen R, Mooij HL, Visser ME, Hassing HC, Peelman F, Kastelein JJ, Péterfy M, Nieuwdorp M. Author information: (1)Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. g.m.dallinga@amc.nl Peripheral lipoprotein lipase (LPL)-mediated lipolysis of triglycerides is the first step in chylomicron/VLDL clearance involving heparan sulfate proteoglycans (HSPGs) displayed at the cell surface of the capillaries in adipose tissue, heart and skeletal muscle. The newly generated chylomicron remnant particles are then cleared by the liver, whereas VLDL remnant particles are either further modified, through the action of hepatic lipase (HL) and cholesteryl ester transfer protein (CETP), into LDL particles or alternatively directly cleared by the liver. Two proteins, lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), have been recently identified and have revised our current understanding of LPL maturation and LPL-mediated lipolysis. Moreover, new insights have been gained with respect to hepatic remnant clearance using genetically modified mice targeting the sulfation of HSPGs and even deletion of the most abundant heparan sulfate proteoglycan: syndecan1. In this review, we will provide an overview of novel data on both peripheral TG hydrolysis and hepatic remnant clearance that will improve our knowledge of plasma triglyceride metabolism. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC3924774 PMID: 20117784 [PubMed - indexed for MEDLINE] 1533. Autophagy. 2010 Jan;6(1):179-81. Autophagy and adipogenesis: implications in obesity and type II diabetes. Goldman S(1), Zhang Y, Jin S. Author information: (1)Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ, USA. Obesity is a direct result of the accumulation of white adipose tissue (WAT). In this study, the role of autophagy in the differentiation of white adipose tissue was studied by deleting the autophagy-related 7 (atg7) gene from adipose tissue in mice. This deletion results in a striking phenotype at the cellular, tissue and whole-organism levels. Adipose tissue deposits in the mutant mice are much smaller in mass than those observed in their wild-type counterparts, and mutant adipocytes exhibit unusual morphological characteristics including multilocular lipid droplets and greatly increased numbers of mitochondria. The knockout mice are noticeably slimmer than their wild-type littermates, despite parity in food and water consumption. The mutant mice also exhibit higher basal physical activity levels and an array of metabolic changes revealed through blood tests. Most importantly, these mice show resistance to high-fat diet-induced obesity and markedly increased sensitivity to insulin. These findings establish a new function for autophagy and provide a new model system for use in the search for treatments for obesity and type II diabetes. PMCID: PMC2883858 PMID: 20110772 [PubMed - indexed for MEDLINE] 1534. Gerontology. 2011;57(1):66-75. doi: 10.1159/000279755. Epub 2010 Jan 29. Aging and regional differences in fat cell progenitors - a mini-review. Sepe A(1), Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Author information: (1)Department of Biomedical and Surgical Sciences, Division of Geriatrics, University of Verona, Verona, Italy. Fat mass and fat tissue distribution change dramatically throughout life. In old age, fat becomes dysfunctional and is redistributed from subcutaneous to intra-abdominal visceral depots as well as other ectopic sites, including bone marrow, muscle and the liver. These changes are associated with increased risk of metabolic syndrome. Fat tissue is a nutrient storage, endocrine and immune organ that undergoes renewal throughout the lifespan. Preadipocytes, which account for 15-50% of cells in fat tissue, give rise to new fat cells. With aging, declines in preadipocyte proliferation and differentiation likely contribute to increased systemic exposure to lipotoxic free fatty acids. Age-related fat tissue inflammation is related to changes that occur in preadipocytes and macrophages in a fat depot-dependent manner. Fat tissue inflammation frequently leads to further reduction in adipogenesis with aging, more lipotoxicity and activation of cellular stress pathways that, in turn, exacerbate inflammatory responses of preadipocytes and immune cells, establishing self-perpetuating cycles that lead to systemic dysfunction. In this review, we will consider how inherent, age-related, depot-dependent alterations in preadipocyte function contribute to age-related fat tissue redistribution and metabolic dysfunction. 2010 S. Karger AG, Basel. PMCID: PMC3031153 PMID: 20110661 [PubMed - indexed for MEDLINE] 1535. J Steroid Biochem Mol Biol. 2010 Aug;121(3-5):589-93. doi: 10.1016/j.jsbmb.2010.01.008. Epub 2010 Jan 28. Brief review: glucocorticoid excretion in obesity. Müssig K(1), Remer T, Maser-Gluth C. Author information: (1)Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Tübingen, Germany. karsten.muessig@med.uni-tuebingen.de Cortisol secretion and glucocorticoid excretion rates are regularly increased in obesity and associate with indices of body size and visceral adiposity. Different mechanisms may underlie the elevated urinary excretion rates of cortisol metabolites in obesity. In the present brief overview, potential mechanisms are discussed, paying special attention to cortisol metabolism. Besides, potential confounding factors in the evaluation of urinary glucocorticoid excretion are highlighted. Copyright 2010 Elsevier Ltd. All rights reserved. PMID: 20109546 [PubMed - indexed for MEDLINE] 1536. Cell Mol Life Sci. 2010 Apr;67(8):1277-92. doi: 10.1007/s00018-010-0263-4. Epub 2010 Jan 27. Adipocyte extracellular matrix composition, dynamics and role in obesity. Mariman EC(1), Wang P. Author information: (1)Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands. e.mariman@hb.unimaas.nl The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia. PMCID: PMC2839497 PMID: 20107860 [PubMed - indexed for MEDLINE] 1537. Br J Nutr. 2009 Dec;102 Suppl 1:S56-63. doi: 10.1017/S000711450999314X. Dietary assessment methods on n-3 fatty acid intake: a systematic review. Øverby NC(1), Serra-Majem L, Andersen LF. Author information: (1)Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway. In order to assess nutritional adequacy, valid estimates of nutrient intake are required. Specifically, the EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence needs clear guidelines for assessing the validity of reported micronutrient intakes and n-3 fatty acid (FA) intakes. The aim of the present study was to review the validity of methods used to measure the usual n-3 FA intake of a population. A systematic literature search was conducted for studies validating the methodology used for measuring the dietary intake of n-3 FA. The quality of the validation studies and the quality of the different dietary assessment methods were assessed using scoring systems developed by EURRECA. Fourteen papers, describing twenty studies, were identified for inclusion. According to the score system developed by EURRECA, all the studies were ranked as average, except two that were ranked as poor. The correlation coefficients between FA in subcutaneous fat and dietary intake of n-3 FA from four FFQ, one weighed record and one 24-h recall ranged between 0.40 and 0.60. Correlations between intake of n-3 FA from five FFQ, one dietary history and three weighed records and blood lipids were similar to the ones observed for subcutaneous fat. The summarised quality of the n-3 FA estimates derived from the FFQ was judged as good or acceptable according to the EURRECA scoring system. The literature describes subcutaneous fat as the best reference method, and the studies where this was used had moderate correlation coefficients and no dietary intake method was superior to any other. PMID: 20100368 [PubMed - indexed for MEDLINE] 1538. Nutrition. 2010 May;26(5):491-501. doi: 10.1016/j.nut.2009.09.012. Epub 2010 Jan 25. Acute and long-term nutrient-led modifications of gene expression: potential role of SIRT1 as a central co-ordinator of short and longer-term programming of tissue function. Holness MJ(1), Caton PW, Sugden MC. Author information: (1)Queen Mary University of London, Centre for Diabetes, Blizard Institute of Cell and Molecular Science, Bart's and the London, London, United Kingdom. m.j.holness@qmul.ac.uk Environmental factors can influence the acute and longer-term risks of developing diseases, including type 2 diabetes mellitus and cardiovascular disease; however, the underlying mechanism remains elusive. Increasing evidence suggests that these effects can be achieved by modification of metabolic gene expression. These include acute changes in histone methylation, acetylation, phosphorylation, and ubiquitination and longer-term DNA silencing elicited by DNA methylation. Thus, an increased risk of disease may reflect acute or chronic stable modification of genes that regulate nutrient handling, leading to altered nutrient utilization (increased lipid oxidation at the expense of glucose utilization) and/or changes in the balance between nutrient storage and energy production, thereby favoring the development of obesity. The review addresses the hypothesis that early-life epigenetic programming of gene expression could be mirrored by changes in acute function of nuclear receptors, in particular the peroxisome proliferator-activated receptors, achieved by enzymes that are more conventionally involved in regulating DNA methylation and post-transcriptional modification of histones. Emphasis is placed on the potential importance of the protein deacetylase sirtuin-1 as a central co-ordinator. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20097539 [PubMed - indexed for MEDLINE] 1539. J Pharmacol Sci. 2010;112(1):8-12. New frontiers in gut nutrient sensor research: nutrient sensors in the gastrointestinal tract: modulation of sweet taste sensitivity by leptin. Horio N(1), Jyotaki M, Yoshida R, Sanematsu K, Shigemura N, Ninomiya Y. Author information: (1)Section of Oral Neuroscience, Kyushu University, Graduate School of Dental Sciences, Japan. The ability to perceive sweet compounds is important for animals to detect an external carbohydrate source of calories and has a critical role in the nutritional status of animals. In mice, a subset of sweet-sensitive taste cells possesses leptin receptors. Increase of plasma leptin with increasing internal energy storage in the adipose tissue suppresses sweet taste responses via this receptor. The data from recent studies indicate that leptin may also act as a modulator of sweet taste sensation in humans with a diurnal variation in sweet sensitivity. The plasma leptin level and sweet taste sensitivity are proposed to link with post-ingestive plasma glucose level. This leptin modulation of sweet taste sensitivity may influence an individual's preference, ingestive behavior, and absorption of nutrients, thereby playing important roles in regulation of energy homeostasis. PMID: 20093782 [PubMed - indexed for MEDLINE] 1540. Postepy Hig Med Dosw (Online). 2010 Jan 20;64:1-10. [Disturbances of lipoprotein metabolism in metabolic syndrome]. [Article in Polish] Czyzewska M(1), Wolska A, Cwiklińska A, Kortas-Stempak B, Wróblewska M. Author information: (1)Zakład Medycyny Laboratoryjnej Katedra Biochemii Klinicznej, Gdański Uniwersytet Medyczny, Gdańsk. Dyslipidemia in metabolic syndrome (MS), called the atherogenic triad, includes elevated levels of plasma triglycerides (TGs), low levels of HDL-cholesterol (HDL-CH), and the presence of small dense low-density lipoproteins (sdLDLs) with normal or slightly elevated LDL-CH levels. Insulin resistance drives the increase in the three main sources of TG for VLDL synthesis: fatty-acid flux from adipose tissue, de novo lipogenesis, and uptake of remnant lipoproteins. Overproduction of VLDL, predominantly triglyceride-rich large VLDL1 particles, induces the cascade of events which lead to abnormalities of other plasma lipoproteins. The accumulation of VLDL in plasma and decreased activity of lipoprotein lipase (LPL) impair the catabolism of chylomicrons. Moreover, hyperinsulinemia induces increased intestinal production of chylomicrons. These factors cause augmented postprandial lipemia. Hepatic overproduction of VLDL leads to an increased level of VLDL remnants in plasma. Highly atherogenic sdLDLs are generated from VLDL1 particles by the action of LPL, cholesterol ester transfer protein (CETP), and hepatic lipase (HL). In the presence of hypertriglyceridemia, accelerated CETP-mediated lipid transfer generates TG-enriched HDL particles. This enhances HDL catabolism mediated by HL and endothelial lipase (EL). The assessment of risk of atherosclerotic cardiovascular disease in MS related to low HDL-CH and the presence of sdLDL particles may be improved by the incorporation of measurements of apolipoproteins (apo)-B and apoA-I into clinical practice. In addition, the concentration of non-HDL-CH may be useful in quantifying apo-B-containing atherogenic lipoproteins. PMID: 20093718 [PubMed - indexed for MEDLINE] 1541. Indian J Med Res. 2009 Nov;130(5):655-65. Modulation of macronutrient metabolism in the offspring by maternal micronutrient deficiency in experimental animals. Raghunath M(1), Venu L, Padmavathi I, Kishore YD, Ganeshan M, Anand Kumar K, Sainath PB, Rao KR. Author information: (1)Division of Endocrinology & Metabolism, National Institute of Nutrition, Hyderabad, India. mraghunath55@yahoo.com Epidemiological evidence indicates that poor early growth is associated with increased susceptibility to visceral obesity, insulin resistance and associated diseases in adulthood. Studies in experimental animals have demonstrated a robust association between nutrient imbalance during foetal life and disease prevalence in their later life specially of those involving macronutrient metabolism. There is very little data on the role of maternal micronutrient deficiencies widely prevalent in India. This review focuses on different animal models of micronutrient restriction, mimicking human situations during pregnancy and lactation that cause aberrations in macronutrient metabolism in the offspring. These aberrations consist of altered body composition, dyslipidaemia and altered insulin sensitivity associated with modulated insulin production. These phenotypic changes were associated with altered lipid profile, fatty acid synthesis / transport, oxidative stress, glucose tolerance / tissue uptake. Further, these were also associated with altered myogenesis and insulin expression and secretion from pancreatic beta-islets. While these changes during in utero or early postnatal life serve as essential adaptations to overcome adverse conditions, these become maladaptive subsequently and set the stage for obesity and type 2 diabetes. PMID: 20090123 [PubMed - indexed for MEDLINE] 1542. Am J Physiol Cell Physiol. 2010 May;298(5):C973-8. doi: 10.1152/ajpcell.00527.2009. Epub 2010 Jan 20. Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications. Czaja MJ(1). Author information: (1)Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. mark.czaja@einstein.yu.edu Autophagy is a lysosomal degradative pathway critical for the removal and breakdown of cellular components such as organelles and proteins. Despite striking similarities in the regulation and function of autophagy and lipid metabolism, the two processes have only recently been shown to be interrelated. This review details new findings of critical functions for autophagy in lipid metabolism and storage. Studies in hepatocytes and liver have demonstrated that macroautophagy mediates the breakdown of lipids stored in lipid droplets and that an inhibition of autophagy leads to the development of a fatty liver. In contrast, in adipocytes the loss of macroautophagy decreases the amount of lipid stored in adipose tissue through effects on white and brown adipocyte differentiation. Other investigations have indicated that the relationship between autophagy and lipids is bidirectional, with changes in cellular lipid content altering autophagic function. These newly described links between autophagy and lipid metabolism and storage have provided new insights into the mechanisms of both processes. The findings also suggest possible new therapeutic approaches to the problems of lipid overaccumulation and impaired autophagy that occur with aging and the metabolic syndrome. PMCID: PMC2867392 PMID: 20089934 [PubMed - indexed for MEDLINE] 1543. Adv Skin Wound Care. 2010 Feb;23(2):81-92; quiz 93-4. doi: 10.1097/01.ASW.0000363503.92360.91. Lipedema: a frequently misdiagnosed and misunderstood fatty deposition syndrome. Fife CE(1), Maus EA, Carter MJ. Author information: (1)Department of Medicine, Division of Cardiology, The University of Texas Health Science Center, Houston, TX, USA. PURPOSE: To enhance the learner's competence in caring for patients with lipedema through understanding the differential diagnoses, pathophysiology, and treatment/management options. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: 1. Differentiate lipedema from other similar diagnoses. 2. Tell patients with lipedema and their caregivers about treatment of this condition. 3. Construct assessments, treatment plans, and management options for patients with lipedema. PMID: 20087075 [PubMed - indexed for MEDLINE] 1544. Ann Intern Med. 2010 Jan 19;152(2):93-100. doi: 10.7326/0003-4819-152-2-201001190-00008. Narrative review: the role of leptin in human physiology: emerging clinical applications. Kelesidis T(1), Kelesidis I, Chou S, Mantzoros CS. Author information: (1)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically. PMCID: PMC2829242 PMID: 20083828 [PubMed - indexed for MEDLINE] 1545. Med Wieku Rozwoj. 2009 Oct-Dec;13(4):244-51. [Adipokines and obesity in children and adolescents]. [Article in Polish] Sledzińska M(1), Liberek A, Kamińska B. Author information: (1)Katedra i Klinika Pediatrii, Gastroenterologii, Hepatologii i zywienia Dzieci, Gdańskiego Uniwersytetu Medyczny, 80-803 Gdańsk. gielatam@gmail.com The alarming increase of the prevalence of overweight and obesity observed recently in childhood and adolescence is one of the major contemporary paediatric problems. The excess of the body weight leads to many co-morbidities that may develop during childhood, for example: cardiovascular diseases, metabolic disorders (diabetes and insulin resistance), orthopaedic and psychiatric disorders. The last decade research showed that adipose tissue is not only a body lipid store but also an endocrine organ producing hormones named adipokines, including leptin, adiponectin, resistin, visfatin and many others. Adipokines play an important role in regulation of lipids and carbohydrates metabolism, appetite and energy expenditure. Recent data suggest that these hormones also have immunomodulating features and they that are involved in inflammatory processes leading to atherogenesis. This article presents current information about adipokines in childhood and adolescent obesity. PMID: 20081272 [PubMed - indexed for MEDLINE] 1546. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2009 Dec;31(6):778-81. doi: 10.3881/j.issn.1000-503X.2009.06.026. [Research advances in the origin and formation of brown adipose]. [Article in Chinese] Yan ZT(1), Li NF. Author information: (1)Department of Hypertension, the People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China. Brown adipose tissue contributes to energy balance in humans by generating heat via the mitochondrial uncoupling of lipid oxidation. Currently it is believed that brown adipose has two origins: Myf5-negative progenitor (its source is same as that of white adipocyte) and Myf5-positive progenitor (its source is same as myocyte). Due to the different origins of brown adipocytes, they may be formed via multiple pathways which include the main pathway (by which Myf5-positive progenitors differentiate into brown adipocytes that distribute in classical locations) and alternative pathway (by which Myf5-negative progenitors differentiate into brown adipocytes that distribute in white adipose tissue). PMID: 20078952 [PubMed - indexed for MEDLINE] 1547. Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E162-8. doi: 10.1152/ajpendo.00698.2009. Epub 2010 Jan 13. Triacylglycerol lipases and metabolic control: implications for health and disease. Watt MJ(1), Spriet LL. Author information: (1)Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. matthew.watt@med.monash.edu.au Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during physical activity. This review outlines the identification of the new TG lipase, adipose triglyceride lipase, the current understanding of how cellular TG lipases are regulated, and the implications for understanding the integrated control of TG lipolysis. Furthermore, this review outlines recent advances that propose a "revised" role for TG lipases in cellular function, metabolic homeostasis, and disease prevention. PMID: 20071561 [PubMed - indexed for MEDLINE] 1548. Endocr Relat Cancer. 2010 Feb 25;17(2):R91-107. doi: 10.1677/ERC-09-0253. Print 2010 Jun. Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy. LaPensee EW(1), Ben-Jonathan N. Author information: (1)Department of Cancer and Cell Biology, University of Cincinnati, Ohio 45267-0521, USA. Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds, which mimic or antagonize their actions. The PRL receptor is activated by lactogens (PRL, GH, or placental lactogen) originating from the pituitary, breast, adipose tissue, or the placenta. Estrogen receptors exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here, we review evidence that low doses of PRL, estradiol (E(2)), and bisphenol A (BPA) antagonize multiple anticancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E(2), and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E(2) and BPA act by inducing the antiapoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed. PMID: 20071456 [PubMed - indexed for MEDLINE] 1549. Rom J Intern Med. 2009;47(2):123-32. The metabolic and inflammatory profile in obese patients with chronic obstructive pulmonary disease. Stanciu S(1), Iordache M, Busuioceanu A, Tănăseanu G, Zamfir L, Mureşan M, Bogdan MA. Author information: (1)Carol Davila Central Military Hospital, Bucharest. silviu.stanciu@yahoo.com Chronic obstructive pulmonary disease and obesity are major causes of morbidity and mortality worldwide and, according to current data, the global burden of these conditions will increase further. Obesity plays a major role in the development of the metabolic syndrome and has been identified as an important risk factor for chronic diseases such as type 2 diabetes mellitus and cardiovascular disease. Adiposity is associated with insulin resistance even over relatively normal ranges of body fatness. There is strong evidence that altered adipose tissue function plays a crucial role in the pathogenesis of obesity-related insulin resistance and type 2 diabetes, as has recently been reviewed. Obesity is linked to respiratory diseases such as obstructive sleep apnea syndrome and obesity hypoventilation syndrome and accumulating evidence suggests an association between obesity and asthma. A potential link between obesity and COPD is also increasingly recognized although little data is known about the mechanisms underlying this association. The inflammatory and metabolic profile differs between obese with COPD and normo or underweight with COPD in part due to dysfunction of adipose tissue. PMID: 20067162 [PubMed - indexed for MEDLINE] 1550. Riv Psichiatr. 2009 Mar-Apr;44(2):79-87. NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Chaldakov GN(1), Tonchev AB, Aloe L. Author information: (1)Division of Cell Biology, Medical University, Varna, Bulgaria. chaldakov@yahoo.com Neurotrophins, particularly, NGF and BDNF are now well recognized to mediate a dizzying number of trophobiological effects, ranging from the Rita Levi-Montalcini's neurotrophic through immunotrophic to metabotrophic effects.These are implicated in the pathogenesis of various diseases including neuropsychiatric and cardiometabolic diseases, such as dementia, depression, type 2 diabetes and obesity that may express a common phenotype and coexistence. Recently, adipobiology (adiposcience) as become a focus of numerous studies showing that the adipose tissue is the body's largest endocrine organ producing multiple signaling proteins, including NGF and BDNF, all these dubbed adipokines. On the basis of our and other authors' evidence that low NGF and/or BDNF levels are found in cardiometabolic diseases (atherosclerosis, obesity, type 2 diabetes, metabolic syndrome), a hypothesis of a critical role of neuro-metabotrophic deficit in the pathogenesis of these diseases has been raised. Since NGF and BDNF also exerts various synaptotrophic effects involved in cognitive enhancement, this hypothesis might also be related to neuropsychiatric diseases such as dementia, depression, schizophrenia, autism, Rett syndrome, anorexia nervosa, and bulimia nervosa. Finally, NGF- and BDNF-based therapeutic approach, including ampakines, antidepressants, selective deacetylase inhibitors, statins, peroxisome proliferator-activated receptor gamma agonists, and "brain food" and calorie restriction, is outlined. PMID: 20066808 [PubMed - indexed for MEDLINE] 1551. Int J Obes (Lond). 2010 Jun;34(6):949-59. doi: 10.1038/ijo.2009.286. Epub 2010 Jan 12. Gluteofemoral body fat as a determinant of metabolic health. Manolopoulos KN(1), Karpe F, Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. konstantinos.manolopoulos@ocdem.ox.ac.uk Comment in Int J Obes (Lond). 2010 Jun;34(6):1099-100; author reply 1101. Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition. PMID: 20065965 [PubMed - indexed for MEDLINE] 1552. J Trauma. 2010 Jan;68(1):57-61. doi: 10.1097/TA.0b013e3181c40262. Visceral adiposity is not associated with inflammatory markers in trauma patients. Collier B(1), Dossett L, Shipman J, Day M, Lawson G, Sawyer R, May A. Author information: (1)Division of Trauma and Surgical Critical Care, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA. bryan.collier@vanderbilt.edu BACKGROUND: Excess visceral adiposity induces chronic subclinical inflammation resulting in the metabolic syndrome. Whether excess visceral adiposity impacts posttraumatic inflammatory profiles more is unknown. We hypothesized that obese patients (body mass index >30 kg/m) with higher visceral to subcutaneous adipose tissue distribution would have increased inflammatory outcomes. METHODS: A secondary analysis of a prospective cohort of adult trauma patients requiring >48 hours of intensive care unit care over a 55-month period was analyzed. Body fat distribution was determined by radiologist review of computed tomography scans at L1. Concentric freeform regions were defined manually, and area was calculated. Visceral adiposity was defined as subcutaneous fat area: visceral area >1.35 (the median), whereas subcutaneous adiposity was defined as a ratio <1.35. Primary outcomes were proinflammatory biomarkers known to be associated with chronic visceral obesity (white blood cell count, interleukin 1, 2, 4, 6, 8, 10, and tumor necrosis factor alpha). Secondary outcomes were all-cause in-hospital mortality, adult respiratory distress syndrome, and nosocomial infections. RESULTS: Two hundred eighty-one (19%) obese patients with available computed tomography scans from 1,510 trauma patients were included. Visceral adiposity included 140 patients, subcutaneous adiposity included 141 patients. The two groups were similar in regards to age, Trauma Injury Severity Score, and Acute Physiology and Chronic Health Evaluation II score. There was no difference (p > 0.05) in proinflammatory biomarkers. Patients with visceral adiposity had similar clinical outcomes including mortality (p = 0.56), adult respiratory distress syndrome (p = 0.69), and infection (0.43). CONCLUSIONS: Visceral body fat distribution in obese patients is not associated with increased inflammatory profiles or clinical outcomes after trauma. The impact of injury severity on acute inflammation likely overwhelms the metabolic disturbances and subclinical inflammation associated with visceral obesity in the chronic setting. PMCID: PMC3371365 PMID: 20065758 [PubMed - indexed for MEDLINE] 1553. Circ J. 2010 Feb;74(2):213-20. Epub 2010 Jan 9. Inflammation in atherosclerosis: transition from theory to practice. Libby P(1), Okamoto Y, Rocha VZ, Folco E. Author information: (1)Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. plibby@rics.bwh.harvard.edu Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-gamma (IFN-gamma) expression. IFN-gamma deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy. PMID: 20065609 [PubMed - indexed for MEDLINE] 1554. Endocr Pract. 2010 Mar-Apr;16(2):310-23. doi: 10.4158/EP09154.RA. Clinical classification and treatment of congenital and acquired lipodystrophy. Chan JL(1), Oral EA. Author information: (1)Amylin Pharmaceuticals, Inc., San Diego, California, USA. Comment in Endocr Pract. 2010 Mar-Apr;16(2):162-6. OBJECTIVE: To review the initial clinical manifestations of congenital and acquired lipodystrophy syndromes, discuss novel classifications associated with genetic mutations, and assess currently available therapeutic options for patients with lipodystrophy. METHODS: This review is the result of the authors' collective clinical experience and a comprehensive MEDLINE literature search on the English-language literature published between January 1966 and October 2009 on "lipodystrophy." This review focuses primarily on severe dystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy. RESULTS: Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and classified on the basis of the extent of fat loss and heritability Paradoxically, they are associated with metabolic abnormalities often found in obese patients, including insulin resistance, diabetes, and severe hypertriglyceridemia. Patients with severe forms of lipodystrophy are also deficient in adipokines such as leptin, which may contribute to metabolic abnormalities. The search for molecular defects has revealed a role for genes that affect adipocyte differentiation (for example, peroxisome proliferator-activated receptor gamma), lipid droplet morphology (seipin, caveolin-1), or lipid metabolism (AGPAT2). Others (lamin A/C) are known to be associated with completely different diseases. There are also acquired forms of lipodystrophy that are thought to occur primarily attributable to autoimmune mechanisms. Recently, recombinant leptin has emerged as a useful therapy. CONCLUSION: Lipodystrophy syndromes have advanced our understanding of the physiologic role of adipose tissue and allowed identification of key molecular mechanisms involved in adipocyte differentiation. Novel therapeutic strategies are being developed on the basis of the pathophysiologic aspects of these syndromes. PMID: 20061300 [PubMed - indexed for MEDLINE] 1555. Curr Opin Pharmacol. 2010 Apr;10(2):191-6. doi: 10.1016/j.coph.2009.11.005. Epub 2010 Jan 7. Crosstalk between perivascular adipose tissue and blood vessels. Rajsheker S(1), Manka D, Blomkalns AL, Chatterjee TK, Stoll LL, Weintraub NL. Author information: (1)Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States. Crosstalk between cells in the blood vessel wall is vital to normal vascular function and is perturbed in diseases such as atherosclerosis and hypertension. Perivascular adipocytes reside at the adventitial border of blood vessels but until recently were virtually ignored in studies of vascular function. However, perivascular adipocytes have been demonstrated to be powerful endocrine cells capable of responding to metabolic cues and transducing signals to adjacent blood vessels. Accordingly, crosstalk between perivascular adipose tissue (PVAT) and blood vessels is now being intensely examined. Emerging evidence suggests that PVAT regulates vascular function through numerous mechanisms, but evidence to date suggests modulation of three key aspects that are the focus of this review: inflammation, vasoreactivity, and smooth muscle cell proliferation. Copyright 2009 Elsevier Ltd. All rights reserved. PMCID: PMC2843777 PMID: 20060362 [PubMed - indexed for MEDLINE] 1556. Obes Rev. 2010 Jun;11(6):446-56. doi: 10.1111/j.1467-789X.2009.00704.x. Epub 2010 Jan 6. Adipokines and dietary interventions in human obesity. Klimcakova E(1), Kovacikova M, Stich V, Langin D. Author information: (1)Department of Sport Medicine, 3rd Faculty of Medicine, Charles University Prague, Czech Republic. e.klimcakova@post.lf3.cuni.cz Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low-grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5-10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules. PMID: 20059706 [PubMed - indexed for MEDLINE] 1557. Annu Rev Med. 2010;61:287-300. doi: 10.1146/annurev.med.051508.215152. Stem cells in the treatment of heart disease. Janssens S(1). Author information: (1)Division of Cardiology and Vesalius Research Center, VIB, Gasthuisberg University Hospital, University of Leuven, B-3000 Leuven, Belgium. Stefan.janssens@med.kuleuven.be Progenitor cells residing in bone marrow, adipose tissue, and skeletal muscle or circulating in the blood are capable of improving myocardial function in preclinical models. In contrast, early clinical studies using bone marrow cells have shown mixed results and reflect our incomplete understanding of underlying mechanisms. Recent identification of various cardiac precursor cells has suggested an endogenous reservoir for cell-based repair. However, confronted with massive cardiac cell loss, inventive strategies and enabling technologies are required to mobilize or deliver functionally competent progenitor cells to sites of injury or to effectively stimulate endogenous repair. We review our present knowledge in this promising and rapidly evolving development in cardiovascular medicine and highlight obstacles as well as opportunities. PMID: 20059339 [PubMed - indexed for MEDLINE] 1558. Biochim Biophys Acta. 2010 Mar;1801(3):338-49. doi: 10.1016/j.bbalip.2009.12.006. Epub 2010 Jan 6. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective. Virtue S(1), Vidal-Puig A. Author information: (1)Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Box 289, Level 4, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Sv234@medschl.cam.ac.uk While the link between obesity and type 2 diabetes is clear on an epidemiological level, the underlying mechanism linking these two common disorders is not as clearly understood. One hypothesis linking obesity to type 2 diabetes is the adipose tissue expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes. All individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation, adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments. Copyright (c) 2009 Elsevier B.V. All rights reserved. PMID: 20056169 [PubMed - indexed for MEDLINE] 1559. Biochim Biophys Acta. 2010 Mar;1801(3):222-9. doi: 10.1016/j.bbalip.2009.12.016. Epub 2010 Jan 6. Obese and anorexic yeasts: experimental models to understand the metabolic syndrome and lipotoxicity. Kohlwein SD(1). Author information: (1)Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/II, A8010 Graz, Austria. sepp.kohlwein@uni-graz.at Lipotoxicity is the pathological consequence of lipid overflow in non-adipose tissue, mediated through reactive lipid moieties which may even lead to lipid-induced cell death (lipoapoptosis). This derailment of cellular and organismal fat homeostasis is the consequence of obesity due to continued over-feeding, and contributes substantially to the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease, which are all components of the metabolic syndrome. Now, does yeast, a single-celled eukaryote, ever suffer from the metabolic syndrome and what can we potentially learn from studies in this organism about the underlying molecular mechanism that lead to lipid-associated pathologies in human cells? In this review I will summarize the remarkably conserved metabolic and regulatory processes relevant to establishing cellular energy and lipid homeostasis, as well as recent findings that provide detailed insights into the molecular mechanisms underlying fat-induced cellular malfunction and cell death, with potential implications also for mammalian cells. Copyright (c) 2010 Elsevier B.V. All rights reserved. PMID: 20056167 [PubMed - indexed for MEDLINE] 1560. Obes Facts. 2009;2(2):117-25. doi: 10.1159/000208517. Epub 2009 Apr 9. Energy homoeostasis: The roles of adipose tissue-derived hormones, peptide YY and Ghrelin. Hall J(1), Roberts R, Vora N. Author information: (1)King's College London, UK. jocelin.hall@kcl.ac.uk This review discusses the physiology of the hormones leptin, adiponectin, resistin, peptide YY, and ghrelin and how each of these contributes to energy homoeostasis, weight regulation, and the pathogenesis of obesity. The relationship these hormones have with insulin and insulin resistance is also discussed, and the potential therapeutic use of each of these hormones is also considered. 2009 S. Karger AG, Basel. PMID: 20054215 [PubMed - indexed for MEDLINE] 1561. Cytotherapy. 2010 May;12(3):349-60. doi: 10.3109/14653240903479655. Liver tissue engineering: promises and prospects of new technology. Zheng MH(1), Ye C, Braddock M, Chen YP. Author information: (1)Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China. Today, many patients suffer from acute liver failure and hepatoma. This is an area of high unmet clinical need as these conditions are associated with very high mortality. There is an urgent need to develop techniques that will enable liver tissue engineering or generate a bioartificial liver, which will maintain or improve liver function or offer the possibility of liver replacement. Liver tissue engineering is an innovative way of constructing an implantable liver and has the potential to alleviate the shortage of organ donors for orthotopic liver transplantation. In this review we describe, from an engineering perspective, progress in the field of liver tissue engineering, including three main aspects involving cell sources, scaffolds and vascularization. PMID: 20053145 [PubMed - indexed for MEDLINE] 1562. J Mal Vasc. 2009 Nov;34(5):314-22. [Limb lymphedema: Diagnosis, explorations, complications. French Lymphology Society]. [Article in French] Vignes S(1), Coupé M, Baulieu F, Vaillant L; Groupe Recommandations de la Société Française de Lymphologie. Author information: (1)Unité de lymphologie, hôpital Cognacq-Jay, Centre national de référence des maladies vasculaires rares, 15, rue Eugène-Millon,75015 Paris, France. Lymphedema results from impaired lymphatic transport with increased limb volume. Primary and secondary forms can be distinguished. Secondary lymphedema of the upper limb is the most frequent in France. A 2-cm difference on any segment of the limb confirms the diagnosis of lymphedema. Calculated lymphedema volume using the formula for a truncated cone is required to assess the efficacy of treatment and to monitor follow-up. Primary lymphedema is sporadic but rarely familial. Lymphoscintigraphy is useful in the primary form to evaluate precisely lymphatic function of the two limbs. Erysipelas is the main complication,but psychological or functional discomfort may occur throughout the course of lymphedema. Lipedema is the main differential diagnosis, defined as an abnormal accumulation of fat from hip to ankle and occurs almost exclusively in obese women. PMID: 20050179 [PubMed - indexed for MEDLINE] 1563. Diabetologia. 2010 Mar;53(3):406-18. doi: 10.1007/s00125-009-1629-8. Epub 2010 Jan 5. Optimal dietary approaches for prevention of type 2 diabetes: a life-course perspective. Buyken AE(1), Mitchell P, Ceriello A, Brand-Miller J. Author information: (1)Nutrition and Health Unit, Research Institute of Child Nutrition, Heinstück 11, 44225 Dortmund, Germany. buyken@fke-do.de Comment in Diabetologia. 2010 Aug;53(8):1809-10. In recent years, several alternative dietary approaches, including high-protein and low-glycaemic-load diets, have produced faster rates of weight loss than traditional low-fat, high-carbohydrate diets. These diets share an under-recognised unifying mechanism: the reduction of postprandial glycaemia and insulinaemia. Similarly, some food patterns and specific foods (potatoes, white bread, soft drinks) characterised by hyperglycaemia are associated with higher risk of adiposity and type 2 diabetes. Profound compensatory hyperinsulinaemia, exacerbated by overweight, occurs during critical periods of physiological insulin resistance such as pregnancy and puberty. The dramatic rise in gestational diabetes and type 2 diabetes in the young may therefore be traced to food patterns that exaggerate postprandial glycaemia and insulinaemia. The dietary strategy with the strongest evidence of being able to prevent type 2 diabetes is not the accepted low-fat, high-carbohydrate diet, but alternative dietary approaches that reduce postprandial glycaemia and insulinaemia without adversely affecting other risk factors. PMID: 20049415 [PubMed - indexed for MEDLINE] 1564. Phys Sportsmed. 2009 Jun;37(2):29-39. doi: 10.3810/psm.2009.06.1707. Proposed role of calcium and dairy food components in weight management and metabolic health. Zemel MB(1). Author information: (1)The Nutrition Institute, The University of Tennessee, Knoxville, TN 37996-1920, USA. mzemel@utk.edu Dietary calcium and dairy foods have demonstrated an antiobesity effect in animal studies, observational and population studies, and randomized clinical trials. Moreover, there is a strong theoretical framework to explain the effects of dietary calcium on energy metabolism. The supporting mechanisms include dietary calcium-correcting suboptimal calcium intakes, thereby preventing the endocrine response (parathyroid hormone [PTH] and calcitriol), which favors adipocyte energy storage and inhibits adipocyte loss via apoptosis. Dietary calcium appears to further promote energy loss via formation of calcium soaps in the gastrointestinal tract and thereby modestly reduces net energy absorption. Dietary calcium appears to be responsible for approximately 50% of the antiobesity bioactivity of dairy foods. The additional dairy bioactivity has not been fully identified, but is primarily localized in whey protein. The major components are the angiotensin-converting enzyme (ACE) inhibitor activity of whey proteins and the high concentration of leucine in whey. This high leucine content appears to be primarily responsible for the repartitioning of dietary energy from adipose tissue to skeletal muscle during weight loss, resulting in greater preservation of skeletal muscle and accelerated loss of adipose tissue during negative energy balance. Finally, high-calcium diets suppress obesity-induced oxidative and inflammatory stress independently from its role in modulating adiposity; these effects are similarly augmented by other dairy food components. However, the number of randomized clinical trials conducted is still modest, and a small number have not confirmed significant effects in weight management. Thus, the protective effects of dairy foods against obesity and its comorbidities are promising, but warrant further large-scale studies. PMID: 20048507 [PubMed - indexed for MEDLINE] 1565. J Steroid Biochem Mol Biol. 2010 Mar;119(1-2):56-72. doi: 10.1016/j.jsbmb.2009.12.013. Epub 2010 Jan 5. 11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. Staab CA(1), Maser E. Author information: (1)Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany. Systemic glucocorticoid excess, as exemplified by the Cushing syndrome, leads to obesity and all further symptoms of the metabolic syndrome. The current obesity epidemic, however, is not characterized by increased plasma cortisol concentrations, but instead comes along with chronic low-grade inflammation in adipose tissue and concomitant increased levels of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1, gene HSD11B1), a parameter known to cause obesity in a mouse model. 11beta-HSD1 represents an intracellular amplifier of active glucocorticoid, thus enhances the associated effects on the inflammatory response as well as on nutrient and energy metabolism, and may therefore cause and exacerbate obesity by local increase of glucocorticoid concentrations. Obtained by extensive literature and database searching, the present review includes comprehensive lists of primary glucocorticoid-sensitive genes and gene products as well as of the thus far known regulators of HSD11B1 expression with implication in inflammation and metabolic disease. Collectively, the data clearly show that, in addition to amplifying active glucocorticoid and thus profoundly modulating inflammation and nutrient metabolism, 11beta-HSD1 is subject to tight control of multiple additional immunomodulatory and metabolic regulators. Hence, 11beta-HSD1 acts at the interface of inflammation and obesity and represents an efficient integrator and effector of local inflammatory and metabolic state. Copyright 2009 Elsevier Ltd. All rights reserved. PMID: 20045052 [PubMed - indexed for MEDLINE] 1566. Maturitas. 2010 Mar;65(3):219-24. doi: 10.1016/j.maturitas.2009.12.003. Epub 2009 Dec 30. Management of obesity in menopause: diet, exercise, pharmacotherapy and bariatric surgery. Mastorakos G(1), Valsamakis G, Paltoglou G, Creatsas G. Author information: (1)Endocrine Unit, 2nd University Department of Obstetrics & Gynaecology, Aretaieion Hospital, University of Athens Medical School, Athens, Greece. mastorakg@ath.forthnet.gr Menopause is characterized by the progressive reduction of estrogens resulting to cessation of menses. It is associated with an increase of cardiovascular risk factors such as hyperglycemia, hypertension, dyslipidemia and of abdominal and/or selective visceral fat mass deposition. Obesity, a modern day epidemic, is promoted by an obesogenic environment that interacts with the genetic background. The result is a positive energy balance materialized by the accumulation of the adipose tissue. This process is marked by great individual variation. Obesity is also associated with the presence of cardiovascular risk factors. In this review, the main pathophysiologic processes for the increase of obesity in menopause and the possible effects of pre-menopausal obesity regarding the cessation of ovarian function are described. The interactions among the hypothalamic-pituitary-gonadal and -adrenal (stress system) axes and the environment are explored. Furthermore, the therapeutic means that a clinician can employ to help menopausal women to overcome the menopause-associated increase of their weight are developed. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 20044222 [PubMed - indexed for MEDLINE] 1567. Hepatology. 2010 Feb;51(2):679-89. doi: 10.1002/hep.23280. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Fabbrini E(1), Sullivan S, Klein S. Author information: (1)Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St Louis, MO 63110-1093, USA. Comment in Hepatology. 2010 Apr;51(4):1470-1; author reply 1471-2. Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Steatosis, the hallmark feature of NAFLD, occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and export (as triglyceride within very low-density lipoprotein). Therefore, an excessive amount of intrahepatic triglyceride (IHTG) represents an imbalance between complex interactions of metabolic events. The presence of steatosis is associated with a constellation of adverse alterations in glucose, fatty acid, and lipoprotein metabolism. It is likely that abnormalities in fatty acid metabolism, in conjunction with adipose tissue, hepatic, and systemic inflammation, are key factors involved in the development of insulin resistance, dyslipidemia, and other cardiometabolic risk factors associated with NAFLD. However, it is not clear whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for IHTG accumulation, or possibly both. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD will provide important insights into the mechanisms responsible for the cardiometabolic complications of obesity. PMCID: PMC3575093 PMID: 20041406 [PubMed - indexed for MEDLINE] 1568. Endokrynol Pol. 2009 Nov-Dec;60(6):476-82. [Metabolic syndrome and bone]. [Article in Polish] Dytfeld J(1), Horst-Sikorska W. Author information: (1)Katedra i Zakład Medycyny Rodzinnej, Uniwersytet Medyczny im. Karola Marcinkowskiego, Poznań. dytfeld@poczta.onet.pl In recent years an increasing socioeconomic burden of two pressing problems has been observed: enormous prevalence of obesity and - along with aging of populations - great number of people affected with osteoporosis. Visceral obesity, expressed by increased waist circumference, is according to the latest guidelines a crucial component of metabolic syndrome (MS). So far the two entities have not been linked, as studies have proven beneficial effect of increased body weight on bone mineral density (BMD). It has been shown however, that adipose tissue is actually an endocrine tissue, secreting numerous biologically active substances that influence also bone. Moreover, an adipocyte and osteoblast derive from a common precursor cell. There is also increasing number of evidence showing common genetic determination of the diseases. Data from experimental and epidemiological studies proves that obesity itself as well as remaining components of MS might have negative influence on bone. BMD as well as fracture risk have been shown to be raised in patients diagnosed with MS. The same has been observed for high blood pressure. What's more, contradiction between high BMD and - simultaneously - high fracture risk in subjects with type 2 diabetes has not been convincingly explained. The paper discusses reports and controversies on coexistence and interactions between MS and osteoporosis and its complications. PMID: 20041366 [PubMed - indexed for MEDLINE] 1569. Kardiologiia. 2009;49(12):80-6. [Adipose tissue inflammation and atherosclerosis]. [Article in Russian] Shwarts V. Adipose tissue is an endocrine organ secreting more than 30 various adipokines which regulate wide spectrum of metabolic and immune processes. Obesity is associated with development of adipose tissue inflammation. This inflammation is characterized by infiltration with macrophages, alterations of adipokine secretion, development of insulin resistance. All these factors promote atherosclerosis. Inflammation of perivascular adipose tissue is especially important. Adipokines damage vascular endothelium via paracrine pathway. Cytokines released by macrophages as well as changes of adipokine secretion lead to endothelial dysfunction - the first stage of atherogenesis. Besides specific action curative factors used in obesity, metabolic syndrome, and diabetes mellitus also produce anti-inflammatory effect and thus diminish risk factors of cardiovascular diseases, rate of their development, and alleviate manifestations of atherosclerosis. Inflammation of adipose tissue is a connecting link between obesity and atherosclerosis. This review contains an outline of roles of various major adipokines in development of atherosclerosis as well as synopsis of anti-inflammatory and antiatherogenic effects of glytazones , metformin, rimonabant, statins, and of lowering of body weight. PMID: 20038288 [PubMed - indexed for MEDLINE] 1570. Front Biosci (Schol Ed). 2010 Jan 1;2:96-105. Persistent low-grade inflammation and regular exercise. Astrom MB(1), Feigh M, Pedersen BK. Author information: (1)Department of Infectious Diseases and CMRC Copenhagen University Hospital, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, The Centre of Inflammation and Metabolism, Copenhagen, Denmark. Persistent low-grade systemic inflammation is a feature of chronic diseases such as cardiovascular disease (CVD), type 2 diabetes and dementia and evidence exists that inflammation is a causal factor in the development of insulin resistance and atherosclerosis. Regular exercise offers protection against all of these diseases and recent evidence suggests that the protective effect of exercise may to some extent be ascribed to an anti-inflammatory effect of regular exercise. Visceral adiposity contributes to systemic inflammation and is independently associated with the occurrence of CVD, type 2 diabetes and dementia. We suggest that the anti-inflammatory effects of exercise may be mediated via a long-term effect of exercise leading to a reduction in visceral fat mass and/or by induction of anti-inflammatory cytokines with each bout of exercise. PMID: 20036931 [PubMed - indexed for MEDLINE] 1571. Front Biosci (Elite Ed). 2010 Jan 1;2:98-104. Influence of obesity, physical inactivity, and weight cycling on chronic inflammation. Strohacker K(1), McFarlin BK. Author information: (1)Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, Texas 77204-6015, USA. Obesity prevalence continues to rise due to excessive caloric intake and sedentary behavior. Weight loss can be achieved through diet and/or exercise, but maintenance of a reduced weight is rare and relapse is prevalent. Repeated periods of weight loss and regain have been termed "weight cycling." It has been speculated that weight cycling may further increase the elevated disease risk common with weight gain, obesity, and physical inactivity. Alterations in adipose tissue with weight cycling may create a more hypoxic environment; hypoxic adipose tissue secretes leptin, a stimulus for macrophage activation and accumulation within adipose tissue. Hypoxic adipocytes and macrophages release pro-inflammatory cytokines into circulation. Elevated body weight and adiposity are linked to cardiovascular disease and type 2 diabetes via an inflammatory mechanism. Thus, it is reasonable to speculate that weight cycling causes a more profound change in chronic inflammation than sustained weight gain. The purpose of this review is to explore inflammatory consequences associated with weight cycling as they are related to sustained weight gain, obesity, physical inactivity as well as relative disease risk. PMID: 20036858 [PubMed - indexed for MEDLINE] 1572. J Steroid Biochem Mol Biol. 2010 Oct;122(1-3):65-73. doi: 10.1016/j.jsbmb.2009.12.005. Epub 2009 Dec 24. Central effects of estradiol in the regulation of food intake, body weight, and adiposity. Brown LM(1), Clegg DJ. Author information: (1)Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC 27412, USA. In recent years, obesity and its associated health disorders and costs have increased. Accumulation of adipose tissue, or fat, in the intra-abdominal adipose depot is associated with an increased risk of developing cardiovascular problems, type-2 diabetes mellitus, certain cancers, and other disorders like the metabolic syndrome. Males and females differ in terms of how and where their body fat is stored, in their hormonal secretions, and in their neural responses to signals regulating weight and body fat distribution. Men and post-menopausal women accumulate more fat in their intra-abdominal depots than pre-menopausal women, resulting in a greater risk of developing complications associated with obesity. The goal of this review is to discuss the current literature on sexual dimorphisms in body weight regulation, adipose tissue accrual and deposition. Copyright © 2009 Elsevier Ltd. All rights reserved. PMCID: PMC2889220 PMID: 20035866 [PubMed - indexed for MEDLINE] 1573. Behav Brain Res. 2010 May 1;209(1):1-12. doi: 10.1016/j.bbr.2009.12.024. Epub 2009 Dec 23. Hypothalamic nutrient sensing in the control of energy homeostasis. Blouet C(1), Schwartz GJ. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. clemence.blouet@aecom.yu.edu The hypothalamus is a center of convergence and integration of multiple nutrient-related signals. It can sense changes in circulating adiposity hormones, gastric hormones and nutrients, and receives neuroanatomical projections from other nutrient sensors, mainly within the brainstem. The hypothalamus also integrates these signals with various cognitive forebrain-descending information and reward/motivation-related signals coming from the midbrain-dopamine system, to coordinate neuroendocrine, behavioral and metabolic effectors of energy balance. Some of the key nutrient-sensing hypothalamic neurons have been identified in the arcuate, the ventro-medial and the lateral nuclei of the hypothalamus, and the molecular mechanisms underlying intracellular integration of nutrient-related signals in these neurons are currently under intensive investigation. However, little is known about the neural pathways downstream from hypothalamic nutrient sensors, and how they drive effectors of energy homeostasis under physiological conditions. This manuscript will review recent progress from molecular, genetic and neurophysiological studies that identify and characterize the critical intracellular signalling pathways and neurocircuits involved in determining hypothalamic nutrient detection, and link these circuits to behavioral and metabolic effectors of energy balance. We will provide a critical analysis of current data to identify ongoing challenges for future research in this field. PMID: 20035790 [PubMed - indexed for MEDLINE] 1574. Pediatr Nephrol. 2010 Apr;25(4):669-77. doi: 10.1007/s00467-009-1407-3. Epub 2009 Dec 22. Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity. Morrison JL(1), Duffield JA, Muhlhausler BS, Gentili S, McMillen IC. Author information: (1)Sansom Institute of Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia. There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant. PMID: 20033220 [PubMed - indexed for MEDLINE] 1575. Adv Anat Pathol. 2010 Jan;17(1):38-41. doi: 10.1097/PAP.0b013e3181bb6b35. Giant hypopharyngeal atypical lipomatous tumor. McQueen C(1), Montgomery E, Dufour B, Olney MS, Illei PB. Author information: (1)Alamance Regional Medical Center, Burlington, NC, USA. The so-called "giant fibrovascular polyps" of the esophagus and hypopharynx typically present as sausage-like pedunculated structures that protrude into the lumen and cause obstructive symptoms. Most are cured by local resection but they may recur. Microscopically, they display an admixture of fibrovascular and adipose tissue that is coated by unremarkable squamous mucosa. Here, we report a case that had scattered hyperchromatic cells and lipoblasts within the adipose tissue component. In other anatomic sites similar appearing lesions have been interpreted as pedunculated liposarcomas/atypical lipomatous tumors that are more prone to local recurrences than classic giant fibrovascular polyps. Reports of dedifferentiation and metastases are lacking thus raising the possibility that the cytologic findings in such lesions are degenerative. To confirm our suspicion of liposarcomatous differentiation, we performed immunohistochemistry for MDM2 and p53, 2 markers that are known to be negative in benign lipomatous lesions and positive in well-differentiated liposarcomas/atypical lipomatous tumors. The scattered atypical hyperchromatic cells and the lipoblasts both exhibited strong nuclear staining for both markers and supported the diagnosis of pedunculated giant hypopharyngeal atypical lipomatous tumor. PMID: 20032637 [PubMed - indexed for MEDLINE] 1576. Nutr Metab Cardiovasc Dis. 2010 Mar;20(3):147-56. doi: 10.1016/j.numecd.2009.08.011. Epub 2009 Dec 22. Metabolic toxicity of the heart: insights from molecular imaging. Iozzo P(1). Author information: (1)Institute of Clinical Physiology, National Research Council (CNR), Via Moruzzi 1, 56124 Pisa, Italy. patricia.iozzo@ifc.cnr.it There is convincing evidence that alterations in myocardial substrate use play an important role in the normal and diseased heart. In this review, insights gained by using quantitative molecular imaging by positron emission tomography and magnetic resonance spectroscopy in the study of human myocardial metabolism will be discussed, and attention will be paid to the effects of nutrition, gender, aging, obesity, diabetes, cardiac hypertrophy, ischemia, and heart failure. The heart is an omnivore organ, relying on metabolic flexibility, which is compromised by the occurrence of defects in coronary flow reserve, insulin-mediated glucose disposal, and metabolic-mechanical coupling. Obesity, diabetes, and ischemic cardiomyopathy appear as states of high uptake and oxidation of fatty acids, that compromise the ability to utilize glucose under stimulated conditions, and lead to misuse of energy and oxygen, disturbing mechanical efficiency. Idiopathic heart failure is a complex disease frequently coexisting with diabetes, insulin resistance and hypertension, in which the end stage of metabolic toxicity manifests as severe mitochondrial disturbance, inability to utilize fatty acids, and ATP depletion. The current literature provides evidence that the primary events in the metabolic cascade outlined may originate in extra-cardiac organs, since fatty acid, glucose levels, and insulin action are mostly controlled by adipose tissue, skeletal muscle and liver, and that a broader vision of organ cross-talk may further our understanding of the primary and the adaptive events involved in metabolic heart toxicity. (c) 2009 Elsevier B.V. All rights reserved. PMID: 20031381 [PubMed - indexed for MEDLINE] 1577. Cell Commun Signal. 2009 Dec 23;7:27. doi: 10.1186/1478-811X-7-27. Leptin and Adiponectin: new players in the field of tumor cell and leukocyte migration. Lang K(1), Ratke J. Author information: (1)Institute of Immunology, Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany. Adipose tissue is no longer considered to be solely an energy storage, but exerts important endocrine functions, which are primarily mediated by a network of various soluble factors derived from fat cells, called adipocytokines. In addition to their responsibility to influence energy homeostasis, new studies have identified important pathways linking metabolism with the immune system, and demonstrating a modulatory role of adipocytokines in immune function. Additionally, epidemiological studies underline that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Whereas a possible influence of adipocytokines on the proliferation of tumor cells is already known, new evidence has come to light elucidating a modulatory role of this signaling substances in the regulation of migration of leukocytes and tumor cells. The migration of leukocytes is a key feature to fight cancer cells, whereas the locomotion of tumor cells is a prerequisite for tumor formation and metastasis. We herein review the latest tumor biological findings on the role of the most prominent adipocytokines leptin and adiponectin, which are secreted by fat cells, and which are involved in leukocyte migration, tumor growth, invasion and metastasis. This review thus accentuates the complex, interactive involvement of adipocytokines in the regulation of migration of both leukocytes and tumor cells, and gives an insight in the underlying molecular mechanisms. PMCID: PMC2804604 PMID: 20030801 [PubMed] 1578. Eur J Cancer Care (Engl). 2010 Sep;19(5):669-75. doi: 10.1111/j.1365-2354.2009.01102.x. Epub 2009 Dec 17. Cancer-related secondary lymphoedema due to cutaneous lymphangitis carcinomatosa: clinical presentations and review of literature. Damstra RJ(1), Jagtman EA, Steijlen PM. Author information: (1)Nij Smellinghe Hospital, Department of Dermatology and Phlebology and Lymphology, Compagnonsplein, Drachten, the Netherlands. r.damstra@nijsmellinghe.nl Lymphoedema is a clinical condition caused by impairment of the lymphatic system, leading to swelling of subcutaneous soft tissues. As a result, accumulation of protein-rich interstitial fluid and lymphostasis often causes additional swelling, fibrosis and adipose tissue hypertrophy leading to progressive morbidity and loss of quality of life for the patient. Lymphoedema can be distinguished as primary or secondary. Lymphoedema is a complication frequently encountered in patients treated for cancer, especially after lymphadenoectomy and/or radiotherapy based on destruction of lymphatics. However, although lymphatic impairment is sometimes caused by obstructive solid metastasis, we present three cases of secondary lymphoedema with minor dermatological features without detectable solid metastasis. Sometimes this type of lymphoedema is mistakenly called malignant lymphoedema. All patients were previously treated for cancer without clinical signs of recurrence, presented with progressive lymphoedema and minor dermatological features of unknown origin. Clinical and histopathological examination of the skin revealed diffuse lymphangitis carcinomatosa, leading to secondary lymphoedema and adjustment of the therapeutic approach and prognosis. We reviewed literature on these rare presentations of cancer recurrence and recommend, where appropriate, consulting a dermatologist when discrete skin abnormalities are seen in patients with a history of cancer and developing lymphoedema. PMID: 20030691 [PubMed - indexed for MEDLINE] 1579. J Investig Med. 2009 Oct;57(7):789-94. doi: 10.231/JIM.0b013e3181bb0d49. Central leptin receptor action and resistance in obesity. Bjørbaek C(1). Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. cbjorbae@bidmc.harvard.edu The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of additional processes via actions in the central nervous system. This symposium review covers current understandings of neuronal leptin receptor signaling and mechanisms of obesity-related leptin resistance in the central nervous system and provides recent insights into the regulation of peripheral glucose balance by central leptin action in rodents. PMCID: PMC2798145 PMID: 20029269 [PubMed - indexed for MEDLINE] 1580. Mol Cell Endocrinol. 2010 Aug 5;324(1-2):70-81. doi: 10.1016/j.mce.2009.12.017. Epub 2009 Dec 22. Metabolic signals in human puberty: effects of over and undernutrition. Martos-Moreno GA(1), Chowen JA, Argente J. Author information: (1)Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Universidad Autónoma de Madrid, Madrid, Spain. Puberty in mammals is associated with important physical and psychological changes due to the increase in sex steroids and growth hormone (GH). Indeed, an increase in growth velocity and the attainment of sexual maturity for future reproductive function are the hallmark changes during this stage of life. Both growth and reproduction consume high levels of energy, requiring suitable energy stores to face these physiological functions. During the last two decades our knowledge concerning how peptides produced in the digestive tract (in charge of energy intake) and in adipose tissue (in charge of energy storage) provide information regarding metabolic status to the central nervous system (CNS) has increased dramatically. Moreover, these peptides have been shown to play an important role in modulating the gonadotropic axis with their absence or an imbalance in their secretion being able to disturb pubertal onset or progression. In this article we will review the current knowledge concerning the role played by leptin, the key adipokine in energy homeostasis, and ghrelin, the only orexigenic and growth-promoting peptide produced by the digestive tract, on sexual development. The normal evolutionary pattern of these peripherally produced metabolic signals throughout human puberty will be summarized. The effect of two opposite situations of chronic malnutrition, obesity and anorexia, on these signals and how they influence the course of puberty will also be discussed. Finally, we will briefly mention other peptides derived from the digestive tract (such as PYY) that may be involved in the regulatory link between energy homeostasis and sexual development. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 20026379 [PubMed - indexed for MEDLINE] 1581. Pharmacol Ther. 2010 Mar;125(3):423-35. doi: 10.1016/j.pharmthera.2009.12.001. Epub 2009 Dec 22. Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions. Wagner KD(1), Wagner N. Author information: (1)INSERM U907, 06107 Nice, France. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors. They function as ligand activated transcription factors. They exist in three isoforms, PPARalpha, PPARbeta (formerly PPARdelta), and PPARgamma. For all PPARs lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and, upon ligand binding, modulate gene expression of downstream target genes dependent on the presence of co-repressors or co-activators. This results in cell-type specific complex regulations of proliferation, differentiation and cell survival. Specific synthetic agonists for all PPARs are available. PPARalpha and PPARgamma agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARbeta activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases. Although the initial notion was that PPARbeta is expressed ubiquitously, more recently extensive investigations have been performed demonstrating high PPARbeta expression in a variety of tissues, e.g. skin, skeletal muscle, adipose tissue, inflammatory cells, heart, and various types of cancer. In addition, in vitro and in vivo studies using specific PPARbeta agonists, tissue-specific over-expression or knockout mouse models have demonstrated a variety of functions of PPARbeta in adipose tissue, muscle, skin, inflammation, and cancer. We will focus here on functions of PPARbeta in adipose tissue, skeletal muscle, heart, angiogenesis and cancer related to modifications in metabolism and the identified underlying molecular mechanisms. 2009 Elsevier Inc. All rights reserved. PMID: 20026355 [PubMed - indexed for MEDLINE] 1582. Vascul Pharmacol. 2010 Jan-Feb;52(1-2):27-36. doi: 10.1016/j.vph.2009.12.004. Epub 2009 Dec 21. The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue. Surmi BK(1), Hasty AH. Author information: (1)Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. The role of the immune system is to recognize pathogens, tumor cells or dead cells and to react with a very specific and localized response. By taking advantage of a highly sophisticated system of chemokines and chemokine receptors, leukocytes such as neutrophils, macrophages, and T-lymphocytes are targeted to the precise location of inflammation. While this is a beneficial process for acute infection and inflammation, recruitment of immune cells to sites of chronic inflammation can be detrimental. It is becoming clear that these inflammatory cells play a significant role in the initiation and progression of metabolic disorders such as atherosclerosis and insulin resistance by infiltrating the artery wall and adipose tissue (AT), respectively. Data from human studies indicate that elevated plasma levels of chemokines are correlated with these metabolic diseases. Recruitment of macrophages to the artery wall is well known to be one of the first steps in early atherosclerotic lesion formation. Likewise, recruitment of macrophages to AT is thought to contribute to insulin resistance associated with obesity. Based on this knowledge, much recent work in these areas has focused on the role of chemokines in attracting immune cells (monocytes/macrophages in particular) to these 2 sites. Thus, understanding the potential for chemokines to contribute to metabolic disease can help direct studies of chemokines as therapeutic targets. In this article, we will review current literature regarding the role of chemokines in atherosclerosis and obesity-related insulin resistance. We will focus on novel work showing that chemokine secretion from endothelial cells, platelets, and adipocytes can contribute to immune cell recruitment, with a diagram showing the time course of chemokine expression and leukocyte recruitment to AT. We will also highlight a few of the less-commonly known chemokine-chemokine receptor pairs. Finally, we will discuss the potential for chemokines as therapeutic targets for treatment of atherosclerosis and insulin resistance. 2009 Elsevier Inc. All rights reserved. PMCID: PMC2823842 PMID: 20026286 [PubMed - indexed for MEDLINE] 1583. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):792-9. doi: 10.1016/j.bbabio.2009.12.005. Epub 2009 Dec 21. Mitochondrial uncoupling proteins in unicellular eukaryotes. Jarmuszkiewicz W(1), Woyda-Ploszczyca A, Antos-Krzeminska N, Sluse FE. Author information: (1)Laboratory of Bioenergetics, Faculty of Biology, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland. wiesiaj@amu.edu.pl Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier protein family that are present in the mitochondrial inner membrane and mediate free fatty acid (FFA)-activated, purine nucleotide (PN)-inhibited proton conductance. Since 1999, the presence of UCPs has been demonstrated in some non-photosynthesising unicellular eukaryotes, including amoeboid and parasite protists, as well as in non-fermentative yeast and filamentous fungi. In the mitochondria of these organisms, UCP activity is revealed upon FFA-induced, PN-inhibited stimulation of resting respiration and a decrease in membrane potential, which are accompanied by a decrease in membranous ubiquinone (Q) reduction level. UCPs in unicellular eukaryotes are able to divert energy from oxidative phosphorylation and thus compete for a proton electrochemical gradient with ATP synthase. Our recent work indicates that membranous Q is a metabolic sensor that might utilise its redox state to release the PN inhibition of UCP-mediated mitochondrial uncoupling under conditions of phosphorylation and resting respiration. The action of reduced Q (QH2) could allow higher or complete activation of UCP. As this regulatory feature was demonstrated for microorganism UCPs (A. castellanii UCP), plant and mammalian UCP1 analogues, and UCP1 in brown adipose tissue, the process could involve all UCPs. Here, we discuss the functional connection and physiological role of UCP and alternative oxidase, two main energy-dissipating systems in the plant-type mitochondrial respiratory chain of unicellular eukaryotes, including the control of cellular energy balance as well as preventive action against the production of reactive oxygen species. Copyright © 2009 Elsevier B.V. All rights reserved. PMID: 20026010 [PubMed - indexed for MEDLINE] 1584. Int J Biochem Cell Biol. 2010 May;42(5):555-9. doi: 10.1016/j.biocel.2009.12.009. Epub 2009 Dec 16. Lipolysis in adipocytes. Ahmadian M(1), Wang Y, Sul HS. Author information: (1)Departement of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, United States. Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs, is a unique function of white adipose tissue. Lipolysis in adipocytes occurs at the surface of cytosolic lipid droplets, which have recently gained much attention as dynamic organelles integral to lipid metabolism. Desnutrin/ATGL is now established as a bona fide TAG hydrolase and mutations in human desnutrin/ATGL/PNPLA2, as well as in its activator, comparative gene identification 58, are associated with Neutral Lipid Storage Disease. Furthermore, recent identification of AdPLA as the major adipose phospholipase A(2), has led to the discovery of a dominant autocrine/paracrine regulation of lipolysis through PGE(2). Here, we review emerging concepts in the key players in lipolysis and the regulation of this process. We also examine recent findings in mouse models and humans with alterations/mutations in genes involved in lipolysis and discuss activation of lipolysis in adipocytes as a potential therapeutic target. 2009 Elsevier Ltd. All rights reserved. PMCID: PMC2835819 PMID: 20025992 [PubMed - indexed for MEDLINE] 1585. Mol Cell Endocrinol. 2010 Jul 8;323(1):20-34. doi: 10.1016/j.mce.2009.12.011. Epub 2009 Dec 16. The development and endocrine functions of adipose tissue. Poulos SP(1), Hausman DB, Hausman GJ. Author information: (1)The Coca-Cola Company, Research and Technology, Atlanta, GA 30313, United States. sypoulos@na.ko.com White adipose tissue is a mesenchymal tissue that begins developing in the fetus. Classically known for storing the body's fuel reserves, adipose tissue is now recognized as an endocrine organ. As such, the secretions from adipose tissue are known to affect several systems such as the vascular and immune systems and play major roles in metabolism. Numerous studies have shown nutrient or hormonal manipulations can greatly influence adipose tissue development. In addition, the associations between various disease states, such as insulin resistance and cardiovascular disease, and disregulation of adipose tissue seen in epidemiological and intervention studies are great. Evaluation of known adipokines suggests these factors secreted from adipose tissue play roles in several pathologies. As the identification of more adipokines and determination of their role in biological systems, and the interactions between adipocytes and other cells types continues, there is little doubt that we will gain a greater appreciation for a tissue once thought to simply store excess energy. PMID: 20025936 [PubMed - indexed for MEDLINE] 1586. Obes Rev. 2010 Dec;11(12):875-86. doi: 10.1111/j.1467-789X.2009.00700.x. Obesity and post-operative complications in patients undergoing non-bariatric surgery. Doyle SL(1), Lysaght J, Reynolds JV. Author information: (1)Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College, Dublin, Ireland. As the prevalence of obesity continues to rise in society, an increasing number of patients undergoing non-bariatric surgery will be obese. Obesity is known to increase morbidity and mortality in the general population and thus is perceived as a risk factor for adverse post-surgical outcomes. This association is not clear-cut, however, and there is a lack of consensus in the literature on the risk between obesity and specific complications, in particular relating to infection, wound healing, respiratory and venous thromboembolism. The paucity of studies, as well as a lack of consistency of definition of obesity, with an over-reliance on body mass index rather than body composition analysis, may underlie this confusion. Emerging concepts position central/visceral adipose tissue as potentially key to the pathogenesis of the comorbidities associated with obesity, thus this article reviews emerging research investigating the association between visceral obesity, the metabolic syndrome and resulting post-operative complications. It is hypothesized that the state of chronic inflammation and dysmetabolism observed in visceral obese patients negatively influences post-operative outcomes and represents a potential target for pharmaconutrition. The need for further research investigating the influence of visceral adiposity on immune function post surgery and its impact on post-operative morbidity and mortality is highlighted. © 2009 The Authors. obesity reviews © 2009 International Association for the Study of Obesity. PMID: 20025695 [PubMed - indexed for MEDLINE] 1587. Obes Rev. 2010 Aug;11(8):560-7. doi: 10.1111/j.1467-789X.2009.00699.x. Epub 2009 Dec 21. Cholesterol imbalance in adipocytes: a possible mechanism of adipocytes dysfunction in obesity. Yu BL(1), Zhao SP, Hu JR. Author information: (1)Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. Studies of the past decade have increased our understanding of the role of adipose tissue dysfunction in obesity and obesity-related insulin resistance and type 2 diabetes. Although adipose tissue is the body's largest pool of free cholesterol, adipocytes have limited activity in cholesterol synthetic pathway. Thus, the majority of adipocyte cholesterol originates from circulating lipoproteins. To maintain cholesterol homeostasis, adipocytes have developed multiple pathways for cholesterol efflux. Several transcriptional factors, such as sterol regulatory element-binding proteins and liver X receptors may be responsible for the regulation of cholesterol homeostasis in adipocytes. Most notably, because altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied adipocytes, cholesterol imbalance is recognized as a characteristic for enlarged adipocytes per se in the obese state. In addition, plasma membrane cholesterol normalization by chromium picolinate can fully restore insulin-stimulated glucose transport, further supporting the role of the adipocyte cholesterol imbalance in obesity and insulin resistance. PMID: 20025694 [PubMed - indexed for MEDLINE] 1588. Biotechnol J. 2010 Jan;5(1):99-112. doi: 10.1002/biot.200900228. DNA microarrays to define and search for genes associated with obesity. Kim Y(1), Park T. Author information: (1)Department of Food and Nutrition, Brain Korea 21 Project, Yonsei University, Seoul, Korea. One of the major goals of this review was to identify obesity-specific gene profiles in animal models to help comprehend the pathogenic mechanisms and the prediction of the phenotypic outcomes of obesity and its associated metabolic diseases. The genomic examination of insulin-sensitive tissues, such as the adipose and hepatic tissues, has provided a wealth of information about the changes in gene expression in obesity and its associated metabolic diseases. The overexpression of genes related to inflammation, immune response, adhesion molecules, and lipid metabolism is a major characteristic of white adipose tissue, while the overexpression of the genes related to lipid metabolism, adipocyte differentiation, defense, and stress responses is noticeable in the non-alcoholic fatty liver of obese rodents. The hepatic-gene expression profiles led us to hypothesize that in obese rodents, the livers are supplied with large amounts of free fatty acids under conditions associated with obesity either through increased fatty acid biosynthesis or through decreased fatty acid oxidation, which may lead to increased mitochondrial respiratory activity. The wide list of genes that were identified in previous studies could be a source of potential therapeutic targets because most of these genes are involved in the key mechanisms of obesity development, from adipocyte differentiation to the disturbance of metabolism. PMID: 20024972 [PubMed - indexed for MEDLINE] 1589. Facial Plast Surg. 2009 Dec;25(5):337-46. doi: 10.1055/s-0029-1243083. Epub 2009 Dec 18. Current and new treatments of photodamaged skin. Shamban AT(1). Author information: (1)Laser Institute for Dermatology and European Skin Care, 2021 Santa Monica Blvd., # 600-E, Santa Monica, CA 90404-2208, USA. AvaSham@aol.com Patients with photodamaged skin need guidance in selecting treatment plans that optimize outcomes, minimize downtime, and reduce adverse effects. The gold standard among cosmeceuticals is the topical retinoids, such as tretinoin. A topical formulation of folic acid and creatine appears to be a viable treatment option for the treatment of photodamaged skin. The use of specific topical cosmeceuticals in combination with nonablative photorejuvenation is recommended in choosing modalities that address the concerns of the patient. A combination of intense pulsed light (IPL), low-intensity diode light, and biostimulating drugs has been shown to provide results superior to those of IPL alone for photorejuvenation. Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) is the treatment of choice for type C photodamage. Low-strength 5-ALA (1 to 2%) applied several times, every 10 to 15 minutes, and incubated for 30 to 60 minutes with 550 to 630 nm, 530 to 1200 nm, or 570 to 1200 nm light activation improved hyperpigmented lesions, skin smoothing, and skin elasticity with high patient satisfaction. The use of 0.5% liposome-encapsulated 5-ALA spraying has been shown to be an alternative to 20% 5-ALA in a cream base in patients undergoing photorejuvenation. Adipose-derived stem cells and their derived secretory factors may have potential as treatments of photodamage. Thieme Medical Publishers. PMID: 20024876 [PubMed - indexed for MEDLINE] 1590. Nutrition. 2010 May;26(5):459-73. doi: 10.1016/j.nut.2009.09.020. Epub 2009 Dec 22. Obesity: genes, brain, gut, and environment. Das UN(1). Author information: (1)UND Life Sciences, Shaker Heights, Ohio, USA. Undurti@hotmail.com Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obesity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mechanisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that regulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotrophic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion, and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut, liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that management of obesity needs a multifactorial approach. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20022465 [PubMed - indexed for MEDLINE] 1591. J Clin Hypertens (Greenwich). 2009 Dec;11(12):761-5. doi: 10.1111/j.1559-4572.2009.00054.x. Pathogenesis and pathophysiology of the cardiometabolic syndrome. Kirk EP(1), Klein S. Author information: (1)Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110-1093, USA. The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption, leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Noninfectious systemic inflammation associated with adipocyte and adipose tissue macrophage cytokine production can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very low-density lipoprotein triglyceride production, leading to dyslipidemia. PMCID: PMC2859214 PMID: 20021538 [PubMed - indexed for MEDLINE] 1592. Curr Mol Pharmacol. 2009 Jan;2(1):46-55. Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome. Coll T(1), Rodrïguez-Calvo R, Barroso E, Serrano L, Eyre E, Palomer X, Vázquez-Carrera M. Author information: (1)Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB University of Barcelona, Diagonal 643, E-08028 Barcelona, Spain. Metabolic syndrome is defined as the clustering of multiple metabolic abnormalities, including abdominal obesity, dyslipidemia (high serum triglycerides and low serum HDL-cholesterol levels), glucose intolerance and hypertension. The pathophysiology underlying metabolic syndrome involves a complex interaction of crucial factors, but two of these, insulin resistance and obesity (especially visceral obesity), play a major role. The nuclear receptors Peroxisome Proliferator-Activated Receptors (PPAR)alpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively. Evidence is now emerging that the PPARbeta/delta; isotype is a potential pharmacological target for the treatment of disorders associated with metabolic syndrome. PPARbeta/delta; activation increases lipid catabolism in skeletal muscle, heart and adipose tissue and improves the serum lipid profile and insulin sensitivity in several animal models. In addition, PPARbeta/delta; ligands prevent weight gain and suppress macrophage-derived inflammation. These data are promising and indicate that PPARbeta/delta; ligands may become a therapeutic option for the treatment of metabolic syndrome. However, clinical trials in humans assessing the efficacy and safety of these drugs should confirm these promising perspectives in the treatment of the metabolic syndrome. PMID: 20021445 [PubMed - indexed for MEDLINE] 1593. Turk Kardiyol Dern Ars. 2009 Sep;37(6):425-34. [Major influence of dysfunctions of protective serum proteins on cardiometabolic risk among Turks and gender difference]. [Article in Turkish] Onat A(1), Hergenç G, Can G. Author information: (1)Turkish Society of Cardiology; Department of Cardiology, Cerrahpaşa Medicine Faculy of Istanbul University, Istanbul, Turkey. alt_onat@yahoo.com.tr Knowledge obtained from the Turkish Adult Risk Factor (TARF) study on higher morbidity and mortality rates compared to other populations from coronary heart disease (CHD) among Turkish adults has been confirmed recently with greater power. This review provides insight that the dysfunctions of the protective serum proteins, attaining pro-inflammatory and atherogenic features, may be attributed to atherogenic dyslipidemia, oxidative stress, and systemic inflammation associated with the high prevalence of metabolic syndrome (MetS) among Turks. The mentioned protective protein dysfunctions, firstly described in a general population to date, are high-density lipoprotein (HDL), apolipoprotein (apo) A-I, A-II, and apoC-III, apart from adiponectin. Based on published findings of the TARF study, this review discusses the role of inflammatory mediators such as elevated C-reactive protein (CRP), apoB, apoC-III, fibrinogen, and low adiponectin serum levels in cardiometabolic risk comprising MetS, type 2 diabetes, and CHD, the degree of independence of these mediators from the ATP-III-defined MetS, and the influence of sex. Moreover, it is emphasized that dysfunctions of adiponectin and protective proteins related to HDL particles increase not only cardiometabolic risk significantly but also CHD risk among half of Turkish adults in a magnitude similar to or greater than that associated with traditional risk factors. Also underlined is the observation that cigarette smoking reduces the risk in Turkish women for the development of hypertension, MetS, and diabetes by mediation of positive effects on dysfunctional apoA-I, visceral fat accumulation and, above all, CRP levels. This knowledge is of utmost importance and sheds light to authorities and those concerned on the necessity of urgent and radical modifications regarding strategies in prevention and management of cardiovascular health of middle-aged Turks. PMID: 20019460 [PubMed - indexed for MEDLINE] 1594. Curr Drug Targets. 2010 Jan;11(1):122-35. Should adipokines be considered in the choice of the treatment of obesity-related health problems? Athyros VG(1), Tziomalos K, Karagiannis A, Anagnostis P, Mikhailidis DP. Author information: (1)Second Propedeutic Department of Internal Medicine, Aristotle University, Hippokration Hospital, Thessaloniki, Greece. White adipose tissue (WAT) is an important endocrine organ that secretes approximately 30 biologically active peptides and proteins, collectively termed "adipokines". These are either produced exclusively by WAT (mainly adiponectin, leptin and resistin) or also by other tissues [e.g. tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, angiotensinogen]. Adipokines play a central role in body homeostasis including the regulation of food intake and energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodelling, regulation of blood pressure and coagulation. Excess WAT, especially visceral obesity, is linked to obesity-related health problems through insulin resistance (IR) [leading to type 2 diabetes mellitus (T2DM)] and systemic low-grade inflammation [leading to cardiovascular disease (CVD)]. The adipokines are important mediators of these adverse effects. This review describes the role of proinflammatory adipokines in the pathogenesis of IR and of the chronic inflammatory state associated with visceral obesity. Moreover, it summarises treatment options for the normalisation of adipokine levels, which might confer an additional clinical benefit in the effort to prevent or treat obesity-related T2DM and CVD. PMID: 20017725 [PubMed - indexed for MEDLINE] 1595. Kardiol Pol. 2009 Oct;67(10):1119-24. [Proinflammatory capacity of adipose tissue--a new insights in the pathophysiology of atherosclerosis]. [Article in Polish] Mazurek T(1). Author information: (1)I Katedra i Klinika Kardiologii, Warszawski Uniwersytet Medyczny, ul. Banacha 1 a, 02-097 Warszawa. tmazurek@kardia.pl PMID: 20017080 [PubMed - indexed for MEDLINE] 1596. Curr Med Chem. 2010;17(5):412-22. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development. Ge R(1), Huang Y, Liang G, Li X. Author information: (1)School of Pharmacy, Wenzhou Medical College, 1# Jingguan Road, College Town, Wenzhou City 325035, China. Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes. PMID: 20015040 [PubMed - indexed for MEDLINE] 1597. Trends Endocrinol Metab. 2010 Apr;21(4):230-6. doi: 10.1016/j.tem.2009.11.008. Epub 2009 Dec 11. Novel neural pathways for metabolic effects of thyroid hormone. Fliers E(1), Klieverik LP, Kalsbeek A. Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. e.fliers@amc.uva.nl The relation between thyrotoxicosis, the clinical syndrome resulting from exposure to excessive thyroid hormone concentrations, and the sympathetic nervous system remains enigmatic. Nevertheless, beta-adrenergic blockers are widely used to manage severe thyrotoxicosis. Recent experiments show that the effects of thyrotoxicosis on hepatic glucose production and insulin sensitivity can be modulated by selective hepatic sympathetic and parasympathetic denervation. Indeed, thyroid hormone stimulates hepatic glucose production via a sympathetic pathway, a novel central pathway for thyroid hormone action. Rodent studies suggest that similar neural routes exist for thyroid hormone analogues (e.g. thyronamines). Further elucidation of central effects of thyroid hormone on autonomic outflow to metabolic organs, including the thyroid and brown adipose tissue, will add to our understanding of hyperthyroidism. Copyright 2009 Elsevier Ltd. All rights reserved. PMID: 20005733 [PubMed - indexed for MEDLINE] 1598. J Tissue Viability. 2011 May;20(2):37-48. doi: 10.1016/j.jtv.2009.11.005. Epub 2009 Dec 14. Materials for engineering vascularized adipose tissue. Chiu YC(1), Cheng MH, Uriel S, Brey EM. Author information: (1)Pritzker Institute of Biomedical Science and Engineering, Department of Biomedical Engineering, Illinois Institute of Technology Chicago, IL 60616, USA. Loss of adipose tissue can occur due to congenital and acquired lipoatrophies, trauma, tumor resection, and chronic disease. Clinically, it is difficult to regenerate or reconstruct adipose tissue. The extensive microvsacular network present in adipose, and the sensitivity of adipocytes to hypoxia, hinder the success of typical tissue transfer procedures. Materials that promote the formation of vascularized adipose tissue may offer alternatives to current clinical treatment options. A number of synthetic and natural biomaterials common in tissue engineering have been investigated as scaffolds for adipose regeneration. While these materials have shown some promise they do not account for the unique extracellular microenvironment of adipose. Adipose derived hydrogels more closely approximate the physical and chemical microenvironment of adipose tissue, promote preadipocyte differentiation and vessel assembly in vitro, and stimulate vascularized adipose formation in vivo. The combination of these materials with techniques that promote rapid and stable vascularization could lead to new techniques for engineering stable, vascularized adipose tissue for clinical application. In this review we discuss materials used for adipose tissue engineering and strategies for vascularization of these scaffolds.CLINICAL RELEVANCE: Materials that promote formation of vascularized adipose tissue have the potential to serve as alternatives or supplements to existing treatment options, for adipose defects or deficiencies resulting from chronic disease, lipoatrophies, trauma, and tumor resection. Copyright © 2009 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved. PMID: 20005717 [PubMed - indexed for MEDLINE] 1599. Nutrition. 2010 Feb;26(2):152-5. doi: 10.1016/j.nut.2009.07.004. Epub 2009 Dec 8. Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation? St-Onge MP(1), Gallagher D. Author information: (1)New York Obesity Research Center, St. Luke's/Roosevelt Hospital, New York, New York, USA. ms2554@columbia.edu It has been well documented that as individuals age, body composition changes, even in the absence of changes in body weight. Studies have shown that fat mass increases and muscle mass decreases with age. However, it is unclear why such changes occur. Resting metabolic rate (RMR) and substrate oxidation rates have been examined with aging. It has been proposed that reductions in RMR and fat oxidation may lead to changes in body composition. Alternatively, changes in body composition with aging may lead to reductions in RMR. The purpose of this review is to provide an overview of the literature surrounding the impact of aging on RMR and substrate oxidation. Although long-term longitudinal studies are lacking, most cross-sectional studies or short-term longitudinal studies show a reduction in RMR with aging that cannot be explained by changes in body composition including loss in fat-free mass, where the latter includes atrophy or decreases in the mass of high metabolic rate organs. There is indirect evidence suggesting that the metabolic rate of individual organs is lower in older compared with younger individuals. With aging, we conclude that reductions in the mass of individual organs/tissues and in tissue-specific organ metabolic rate contribute to a reduction in RMR that in turn promotes changes in body composition favoring increased fat mass and reduced fat-free mass. 2010 Elsevier Inc. All rights reserved. PMCID: PMC2880224 PMID: 20004080 [PubMed - indexed for MEDLINE] 1600. Biochem J. 2009 Dec 14;425(1):41-52. doi: 10.1042/BJ20091045. Transcriptional and post-translational regulation of adiponectin. Liu M(1), Liu F. Author information: (1)Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Adiponectin is an adipose-tissue-derived hormone with anti-diabetic, anti-atherogenic and anti-inflammatory functions. Adiponectin circulates in the bloodstream in trimeric, hexameric and high-molecular-mass species, and different forms of adiponectin have been found to play distinct roles in the regulation of energy homoeostasis. The serum levels of adiponectin are negatively correlated with obesity and insulin resistance, yet the underlying mechanisms remain elusive. In the present review, we summarize recent progress made on the mechanisms regulating adiponectin gene transcription, multimerization and secretion. We also discuss the potential relevance of these studies to the development of new clinical therapy for insulin resistance, Type 2 diabetes and other obesity-related metabolic disorders. PMID: 20001961 [PubMed - indexed for MEDLINE] 1601. Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E385-94. doi: 10.1152/ajpendo.00608.2009. Epub 2009 Dec 8. Metabolic functions of atypical protein kinase C: "good" and "bad" as defined by nutritional status. Farese RV(1), Sajan MP. Author information: (1)James A. Haley Veteran's Administration Medical Center, Tampa, FL 33612, USA. rfarese@health.usf.edu Atypical protein kinase C (aPKC) isoforms mediate insulin effects on glucose transport in muscle and adipose tissues and lipid synthesis in liver and support other metabolic processes, expression of enzymes needed for islet insulin secretion and hepatic glucose production/release, CNS appetite suppression, and inflammatory responses. In muscle, selective aPKC deficiency impairs glucose uptake and produces insulin resistance and hyperinsulinemia, which, by activating hepatic aPKC, provokes inordinate increases in lipid synthesis and produces typical "metabolic syndrome" features. In contrast, hepatic aPKC deficiency diminishes lipid synthesis and protects against metabolic syndrome features. Unfortunately, aPKC is deficient in muscle but paradoxically conserved in liver in obesity and type 2 diabetes mellitus; this combination is particularly problematic because it promotes lipid and carbohydrate abnormalities. Accordingly, metabolic effects of aPKCs can be "good" or "bad," depending upon nutritional status; thus, muscle glucose uptake, islet insulin secretion, hepatic glucose and lipid production/release, and adipose fat synthesis/storage would be important for survival during periods of limited food availability and therefore be "good." However, during times of food surfeit, excessive activation of hepatic aPKC, whether caused by overnutrition or impairments in extrahepatic effects of insulin, would lead to inordinate increases in hepatic lipid synthesis and metabolic syndrome features and therefore be "bad." In keeping with these ideas, the inhibition of hepatic aPKC markedly ameliorates lipid and carbohydrate abnormalities in experimental models of obesity and type 2 diabetes. We postulate that a similar approach may be useful for treating humans. PMCID: PMC3774273 PMID: 19996389 [PubMed - indexed for MEDLINE] 1602. Ageing Res Rev. 2010 Jan;9(1):69-76. doi: 10.1016/j.arr.2009.11.004. Epub 2009 Dec 5. Perspective: Does brown fat protect against diseases of aging? Mattson MP(1). Author information: (1)Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov The most commonly studied laboratory rodents possess a specialized form of fat called brown adipose tissue (BAT) that generates heat to help maintain body temperature in cold environments. In humans, BAT is abundant during embryonic and early postnatal development, but is absent or present in relatively small amounts in adults where it is located in paracervical and supraclavicular regions. BAT cells can 'burn' fatty acid energy substrates to generate heat because they possess large numbers of mitochondria in which oxidative phosphorylation is uncoupled from ATP production as a result of a transmembrane proton leak mediated by uncoupling protein 1 (UCP1). Studies of rodents in which BAT levels are either increased or decreased have revealed a role for BAT in protection against diet-induced obesity. Data suggest that individuals with low levels of BAT are prone to obesity, insulin resistance and cardiovascular disease, whereas those with higher levels of BAT maintain lower body weights and exhibit superior health as they age. BAT levels decrease during aging, and dietary energy restriction increases BAT activity and protects multiple organ systems including the nervous system against age-related dysfunction and degeneration. Future studies in which the effects of specific manipulations of BAT levels and thermogenic activity on disease processes in animal models (diabetes, cardiovascular disease, cancers, neurodegenerative diseases) are determined will establish if and how BAT affects the development and progression of age-related diseases. Data from animal studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity and age-related diseases. Examples include: diet and lifestyle changes; specific regimens of mild intermittent stress; drugs that stimulate BAT formation and activity; induction of brown adipose cell progenitors in muscle and other tissues; and transplantation of brown adipose cells. Copyright 2009. Published by Elsevier B.V. PMCID: PMC2818667 PMID: 19969105 [PubMed - indexed for MEDLINE] 1603. J Cell Mol Med. 2010 Jan;14(1-2):70-8. doi: 10.1111/j.1582-4934.2009.00978.x. Epub 2009 Nov 28. The vicious circle between oxidative stress and inflammation in atherosclerosis. Hulsmans M(1), Holvoet P. Author information: (1)Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Belgium. The initial event in atherogenesis is the increased transcytosis of low density lipoprotein, and its subsequent deposition, retention and modification in the subendothelium. It is followed by the infiltration of activated inflammatory cells from the coronary circulation into the arterial wall. There they secrete reactive oxygen species (ROS) and produce oxidized lipoproteins capable of inducing endothelial cell apoptosis, and thereby plaque erosion. Activated T lymphocytes, macrophages and mast cells, accumulate in the eroded plaque where they secrete a variety of proteases capable of inducing degradation of extracellular proteins, thereby rendering the plaques more prone to rupture. This review summarizes the recent advancements in the understanding of the roles of ROS and oxidized lipoproteins in the activation of inflammatory cells and inducing signalling pathways related to cell death and apoptosis. In addition, it presents evidence that this vicious circle between oxidative stress and inflammation does not only occur in the diseased arterial wall, but also in adipose tissues. There, oxidative stress and inflammation impair adipocyte maturation resulting in defective insulin action and adipocytokine signalling. The latter is associated with increased infiltration of inflammatory cells, loss of anti-oxidant protection and cell death in the arterial wall. PMCID: PMC3837590 PMID: 19968738 [PubMed - indexed for MEDLINE] 1604. Biochim Biophys Acta. 2010 Aug;1804(8):1652-7. doi: 10.1016/j.bbapap.2009.11.021. Epub 2009 Dec 2. Sirtuins regulate key aspects of lipid metabolism. Lomb DJ(1), Laurent G, Haigis MC. Author information: (1)Department of Pathology and Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA. Members of the sirtuin family of NAD(+)-dependent protein deacetylases are important regulators of longevity in yeast, worms, and flies. Mammals have seven sirtuins (SIRT1-7), each characterized by differences in subcellular localization, substrate preference, and biological function. While it is unclear whether sirtuins regulate aging in mammals, it is clear that sirtuins influence diverse aspects of their metabolism. Indeed, SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in liver, and lipid mobilization in white adipose tissue. Moreover, small-molecule activators of SIRT1 have recently been shown to protect mice from the negative effects of a high-fat diet. These findings suggest that sirtuins might provide important new targets for the treatment of obesity and related diseases. In this review, we discuss the major findings linking sirtuins with the regulation of lipid metabolism. Copyright 2009 Elsevier B.V. All rights reserved. PMID: 19962456 [PubMed - indexed for MEDLINE] 1605. Endocrinol Nutr. 2009 Oct;56(8):404-11. doi: 10.1016/S1575-0922(09)72710-X. [Adipose tissue as a therapeutic target in obesity]. [Article in Spanish] Medina-Gómez G(1), Vidal-Puig A. Author information: (1)Departamento de Bioquímica y Fisiología, Universidad Rey Juan Carlos, Facultad de Ciencias de la Salud, Alarcón, Madrid, España. gema.medina@urjc.es Obesity is characterized by an increase of adipose tissue as a result of a positive imbalance between food intake and energy expenditure. Recent studies have indicated that adipocyte function is more complex than expected, since these cells have multiple functions and are integrated in a homeostatic network to optimize energy resources. As metabolic sensors in the body, adipocytes and the surrounding stromal vascular cells produce and secrete autocrine, paracrine and endocrine factors, able to regulate aspects involved in the development of adipocytes, as well as effects in peripheral organs important for metabolism. Regulation of these endocrine factors could lead to new therapeutic approaches targeted at aspects related to adipogenesis, preadipocyte proliferation and differentiation, inflammatory cytokine release and secretion, adipose tissue vascularization, and regulation of lipid metabolism or, alternatively, regulation of energy dissipation in mitochondria. In the study of the mechanisms of adipogenesis and remodulation of adipose tissue with respect to adipocyte size and function, an alternative and unorthodox strategy to improve obesity-associated metabolic complications could consist of increasing the storage capacity of adipose tissue to prevent a toxic response known as lipotoxicity. PMID: 19959150 [PubMed - indexed for MEDLINE] 1606. Ross Fiziol Zh Im I M Sechenova. 2009 Oct;95(10):1024-40. [Prognostic, diagnostic, and therapeutic prospects of using adiponectine as a biomarker in cardiobascular diseases]. [Article in Russian] Pal'tseva EM, Rodina AV, Konstantinova SV, Ermakov NV, Andreev DA, Syrkin AL, Severin SE. The role of adipose tissue as an important endocrine organ is today beyond doubt. The adipose tissue is known to be a source of many biologically active substances, adipocitokines, one of them being the adiponectine possessing anti-inflammatory, antiatherogenic and cardioprotective properties; it is believed to be one of prospective biomarkers for risk assessment, for diagnostics and, possibly, for therapy of cardiovascular diseases. PMID: 19957894 [PubMed - indexed for MEDLINE] 1607. Forum Nutr. 2010;63:123-32. doi: 10.1159/000264400. Epub 2009 Nov 27. Leptin-signaling pathways and leptin resistance. Munzberg H(1). Author information: (1)Pennington Biomedical Research Center, LSU System, Baton Rouge, La., USA. heike.munzberg@pbrc.edu Leptin acts as an anorexigenic hormone in the brain, where the long form of the leptin receptor (LRb) is widely expressed in hypothalamic and extra-hypothalamic sites that are known to participate in diverse feeding circuits. The important role of leptin in energy homeostasis is demonstrated by the profound hyperphagia and morbid obesity in humans and rodents null for leptin or LRb. However, common forms of obesity are associated with high leptin levels and a failure to respond effectively to exogenous leptin; indicating a state of leptin resistance. Leptin resistance is thought to be an important component in the development of obesity. Several defects may contribute to the leptin resistant state, including a defective leptin transport across the blood-brain barrier, which reduces the availability of leptin at its receptor. Furthermore, defects in LRb signal transduction involving reduced LRb expression or the induction of feedback inhibitors have been found in leptin resistance; these defects are commonly termed cellular leptin resistance,. Finally, reduced leptin action can result in the disruption of proper neuronal interactions, by altering neuronal wiring. Interestingly, some leptin functions remain intact in the leptin-resistant state, such as cardiovascular leptin effects. The appearance of selective leptin resistance is mirrored by the observation that cellular leptin resistance has been found only in some subpopulations of hypothalamic LRb neurons. Current efforts to dissect leptin function in specific populations of LRb neurons will increase our understanding of these complexities of leptin physiology. Copyright (c) 2010 S. Karger AG, Basel. PMID: 19955780 [PubMed - indexed for MEDLINE] 1608. Forum Nutr. 2010;63:111-22. doi: 10.1159/000264399. Epub 2009 Nov 27. Do leptin and insulin signal adiposity? Hillebrand JJ(1), Geary N. Author information: (1)Physiology and Behaviour Group, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. jacquelien-hillebrand@ethz.ch The physiological regulation of adiposity is supposed to depend on endocrine 'adiposity signals' that inform the brain about the mass of the adipose tissue. Basal levels of insulin and leptin are widely accepted to be adiposity signals, and amylin, ghrelin and peptide YY have been hypothesized to be. Support for these ideas comes from associations between basal hormone levels and levels of adiposity, from demonstrations of receptors for these hormones in neural circuits supposed to regulate energy homeostasis, from neuropharmacological manipulations of the hormones' actions on eating and energy expenditure, and from the effects on energy balance in animals or people bearing mutations in these endocrine signaling pathways. This chapter focuses on only the first of these four types of evidence and only on insulin and leptin. We ask whether circulating levels of either hormone indeed encodes the necessary information to act as an adiposity signal. In considering this question, we emphasize the distinction between regulation of AT mass in steady versus dynamic states. We argue that the best experimental designs for identifying potentially effective adiposity signals involve situations in which the level of adiposity is changing as the organism responds to imposed perturbations. Traditionally, this is the type of design that most convincingly supports the idea that adiposity is actively regulated. Unfortunately, there are few of such studies for any of the hypothesized endocrine adiposity signals, and the evidence that is available does not strongly support the hypotheses. Therefore, we conclude that the question of how adiposity is signaled to the brain remains an open frontier in the physiology of energy homeostasis. Copyright (c) 2010 S. Karger AG, Basel. PMID: 19955779 [PubMed - indexed for MEDLINE] 1609. Endocr Dev. 2010;17:185-96. doi: 10.1159/000262539. Epub 2009 Nov 24. Hypothalamic obesity. Hochberg I(1), Hochberg Z. Author information: (1)Rambam Medical Center, Rappaport Family Faculty of Medicine and Research Institute, Technion, Israel Institute of Technology, Haifa, Israel. Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity, the so-called hypothalamic obesity (HyOb). HyOb complicates disorders related to the hypothalamus, including those that cause structural damage to the hypothalamus, pituitary macroadenoma with suprasellar extension, glioma, meningioma, teratoma, germ cell tumors, radiotherapy, Prader-Willi syndrome, and mutations in leptin, leptin receptor, POMC, MC4R and CART genes. It is conceivable that a subgroup of patients with 'simple obesity' also have HyOb. The hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and body fat tissue. Orexigenic and anorexigenic hypothalamic centers (hyperphagia when impaired) play a central role, connecting to adipose tissue by means of an intricate efferent and afferent signals circuit. Other mechanisms by which the brain regulates adipose tissue and beta cells of the pancreas include the sympathetic nervous system, vagally mediated hyperinsulinemia and the endocrine system, namely growth hormone, thyroid-stimulating hormone and the hypothalamo-pituitary-adrenal axis. Corticotropin-releasing hormone, adrenocorticotropic hormone glucocorticoids and the 11beta-HSD-1 shuttle regulate lipolysis both directly and indirectly. All the above mechanisms may be impaired in HyOb. Management of HyOb targets the major manifestations: hyperphagia, autonomic dysfunction, hyperinsulinemia and impaired energy expenditure. Individual variation is considerable. Satisfactory therapy is currently unavailable. Copyright 2010 S. Karger AG, Basel. PMID: 19955767 [PubMed - indexed for MEDLINE] 1610. Endocr Dev. 2010;17:86-95. doi: 10.1159/000262531. Epub 2009 Nov 24. Endocrine and metabolic actions of ghrelin. Gasco V(1), Beccuti G, Marotta F, Benso A, Granata R, Broglio F, Ghigo E. Author information: (1)Division of Endocrinology, Diabetology and Metabolism, University of Turin, Turin, Italy. The acylated form of ghrelin (GRLN) has been discovered as the natural ligand of the GH secretagogue (GHS) receptor-1a (GHS-R1a). This peptide, whose acylation is performed by a specific octanoyl-transferase, is predominantly produced by the stomach, although expressed by many other endocrine and nonendocrine, peripheral and central tissues. Also GHS-R1a shows wide distribution, being distributed in several central and peripheral tissues. GRLN displays strong GH-releasing activity but its action is not specific for GH exhibiting other neuroendocrine activities such as stimulation of PRL and ACTH and inhibition of LH. GRLN is now mostly recognized as a potent orexigenic factor stimulating food intake and modulating energy expenditure. At the peripheral level, GRLN modulates gastrointestinal motility and secretion and also exerts cardiovascular actions. Mostly, at the peripheral level, GRLN exerts probably its major physiological action regulating glucose and lipid metabolism. In fact, GRLN in its acylated form has a diabetogenic action while in its non-acylated form it has a favorable influence on glucose, lipid metabolism and insulin sensitivity as well as the inhibition of lipolysis. GRLN receptors have been well demonstrated either in the endocrine pancreas or the adipose tissue; at these levels there are receptors that bind GRLN independently of its acylation (therefore a non-GHS-R1a, still undefined receptor). In all, the products of the GRLN gene, i.e. acylated and nonacylated GRLN, as well as obestatin, play a major role in regulating peripheral metabolism and it is not by chance that their secretion is mostly under metabolic regulation. Copyright 2010 S. Karger AG, Basel. PMID: 19955759 [PubMed - indexed for MEDLINE] 1611. Eur J Appl Physiol. 2010 May;109(1):27-33. doi: 10.1007/s00421-009-1295-z. Epub 2009 Dec 1. Multiple thermoregulatory effectors with independent central controls. McAllen RM(1), Tanaka M, Ootsuka Y, McKinley MJ. Author information: (1)Howard Florey Institute, University of Melbourne, Melbourne, Victoria 3010, Australia. rmca@florey.edu.au This review first considers how mammalian body temperature regulation evolved, and how the brain's responses to thermoregulatory challenges are likely to be organised differently from the way an engineer would design them. This is because thermoregulatory effector mechanisms would have evolved one at a time, with each being superimposed on pre-existing mechanisms. There may be no functional need for the final ensemble of control loops to be coordinated by neural cross-connections: appropriate thermal thresholds would solve the problem sufficiently. Investigations first into thermoregulatory behaviours and later into unconscious thermoregulatory mechanisms (autonomic and shivering) have led investigators to the realisation that multiple control loops exist in the brain, with each effector system apparently regulated by its own central temperature sensors. This theme is developed with reference to data on four temperature-regulated neural outflows that have been studied on anaesthetized rats under standard conditions in the authors' laboratory. Direct comparisons were made between the behaviour of sympathetic nerves supplying the tail vasculature, vessels in the proximal hairy skin, interscapular brown adipose tissue (BAT) and fusimotor fibres to hind limb muscle. All four outflows were activated by cooling the skin, and all were silenced by neuronal inhibition in the medullary raphé. Their thermal thresholds were quite different, however, as were their relative responsiveness to core temperature. This was ranked as: tail > back skin > BAT > fusimotor. These and other data indicate that the four thermoeffector outflows are driven by separate neural pathways, each regulated by independent brain temperature sensors. PMID: 19949811 [PubMed - indexed for MEDLINE] 1612. Nat Rev Cardiol. 2010 Jan;7(1):22-9. doi: 10.1038/nrcardio.2009.224. Epub 2009 Dec 1. Cardiovascular effects of leptin. Sweeney G(1). Author information: (1)Institut Pasteur Korea, Bundang-gu, Gyeonggi-do, Korea. gsweeney@yorku.ca A wealth of investigations, ranging from clinical and animal model studies to in vitro analyses, have generated great interest in the cardiovascular effects of leptin. Accordingly, many studies have examined the contribution of leptin to cardiac remodeling in heart failure and whether the effects of leptin on metabolism, apoptosis, extracellular matrix remodeling, and hypertrophy could explain the so-called obesity paradox. Furthermore, obesity and hyperleptinemia have often been associated with hypertension, and regulation of sympathetic tone or direct effects of leptin on contributors such as atherosclerosis, endothelial dysfunction, and thrombosis have been documented. Unfortunately, translating basic research studies in vitro, or in animal models, to human physiology has proven difficult. The degree of leptin resistance in obesity is one intriguing issue that must be resolved. Furthermore, the importance of autocrine and paracrine effects of leptin derived from the heart and perivascular adipose tissue must be further studied. Carefully planned and executed research to conclusively establish distinct effects of leptin on the cardiovascular system in normal and diseased states will be essential to harness any therapeutic potential associated with leptin's effects. PMID: 19949425 [PubMed - indexed for MEDLINE] 1613. Curr Opin Organ Transplant. 2010 Feb;15(1):86-91. doi: 10.1097/MOT.0b013e328334f074. Therapeutic potential of adipose-derived stem cells in vascular growth and tissue repair. Hong SJ(1), Traktuev DO, March KL. Author information: (1)Krannert Institute of Cardiology, Indianapolis, Indiana, USA. PURPOSE OF REVIEW: Adipose-derived stem cells (ASCs) are readily available from autologous adipose tissue and have been demonstrated to provide significant potential for tissue rescue from, or repair of, damage in multiple animal models. These include models of myocardial infarction, heart failure, hind limb ischemia, and inflammatory conditions. Early clinical studies have now extended testing of the effects of ASC into patients. This review highlights some of the key reports underlining the potential of ASCs, focusing particularly on diseases involving the cardiovascular system, vascular growth, and tissue repair. RECENT FINDINGS: Clinical applications of ASCs have begun to show early safety results and promising possibility of efficacy in patients with a range of diseases, including acute myocardial infarction, peripheral vascular disease, and soft and bony tissue defects including cranial bone loss, Crohn's-related fistula, and skin wounds. These effects are importantly based on the secretion of trophic and survival factors by these cells and by their participations in the growth and remodeling of blood vessels. These results suggest that ASCs could be a valuable therapeutic option in vascular growth and tissue repair in various clinical settings. SUMMARY: ASCs may ultimately represent a valuable therapeutic option in tissue rescue and repair based on their ready availability, proangiogenesis and antiapoptotic factor secretion, immunomodulatory effects, and capacity for multilineage differentiation and ready expansion. PMID: 19949335 [PubMed - indexed for MEDLINE] 1614. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):69-78. doi: 10.1016/j.mce.2009.11.011. Epub 2009 Dec 3. The autocrine and paracrine roles of adipokines. Karastergiou K(1), Mohamed-Ali V. Author information: (1)Adipokines and Metabolism Research Group, Centre for Clinical Pharmacology, Division of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK. Obesity, defined by an excess of adipose tissue, is often associated with the development of various metabolic diseases. The increased and inappropriate deposition of this tissue contributes to hyperglycemia, hyperlipidemia, insulin resistance, endothelial dysfunction and chronic inflammation. Recent evidence suggests that factors expressed and secreted by the adipose tissue, adipokines, may contribute to the development of these abnormalities by mechanisms including inhibition of adipogenesis, adipocyte hypertrophy and death, immune cell infiltration and disruption of tissue metabolism. The presence of adipokine receptors in adipocytes renders these cells available to autocrine and paracrine effects of adipokines. In this review the reported local effects of adipokines on adipose tissue structure, inflammation and regulation of metabolic functions, in the face of over-nutrition and consequent obesity, are outlined. Elucidating the local regulation of white adipocyte development and function could help in the design of effective, tissue-specific therapies for obesity-associated diseases. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 19948207 [PubMed - indexed for MEDLINE] 1615. IUBMB Life. 2009 Dec;61(12):1123-31. doi: 10.1002/iub.264. Nutritional and hormonal regulation of uncoupling protein 2. Yonezawa T(1), Kurata R, Hosomichi K, Kono A, Kimura M, Inoko H. Author information: (1)Division of Basic Molecular Science and Molecular Medicine, School of Medicine, Tokai University, Bohseidai, Ishehara, Kanagawa, Japan. yonet2301@yahoo.co.jp Uncoupling proteins (UCPs) belong to a family of mitochondrial carrier proteins that are present in the mitochondrial inner membrane. Genetic and experimental studies have shown that UCP dysfunction can be involved in metabolic disorders and in obesity. Uncoupling protein-1 (UCP1; also known as thermogenin) was identified in 1988 and found to be highly expressed in brown adipose tissue. UCP1 allows the leak of protons in respiring mitochondria, dissipating the energy as heat; the enzyme has an important role in nonshivering heat production induced by cold exposure or food intake. In 1997, two homologs of UCP1 were identified and named UCP2 and UCP3. These novel proteins also lower mitochondrial membrane potential, but whether they can dissipate metabolic energy as heat as efficiently as UCP1 is open to dispute. Even after a decade of study, the physiological roles of these novel proteins have still not been completely elucidated. This review aims to shed light on the nutritional and hormonal regulation of UCP2 and on its physiological roles. (c) 2009 IUBMB PMID: 19946892 [PubMed - indexed for MEDLINE] 1616. Clin Geriatr Med. 2009 Nov;25(4):677-702, viii-ix. doi: 10.1016/j.cger.2009.07.004. Effects of physical activity on cardiovascular and noncardiovascular outcomes in older adults. Sattelmair JR(1), Pertman JH, Forman DE. Author information: (1)Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. Aging is associated with a cascade of morphologic and physiologic changes that naturally predispose older adults to progressive weakening, functional decline, morbidity, disability, poor quality of life, and increased mortality. Physical activity moderates such insidious aging patterns and is a vital preventive and therapeutic strategy to optimize health throughout the aging process. Regular exercise provides many physiologic benefits, reduces risk of disease outcomes, and triggers important psychological gains. Advanced age presents distinctive obstacles to maintaining a physically active lifestyle. Individualized exercise strategies and regimens make it possible, however, for every elderly adult to benefit from physical activity. PMID: 19944267 [PubMed - indexed for MEDLINE] 1617. Integr Zool. 2009 Dec;4(4):357-66. doi: 10.1111/j.1749-4877.2009.00176.x. Physiological adaptations of small mammals to desert ecosystems. Schwimmer H(1), Haim A. Author information: (1)Department of Biology, The University of Haifa, Haifa, Israel. Adaptations of animals to the xeric environment have been studied in various taxonomic groups and across several deserts. Despite the impressive data that have been accumulated, the focus in most of these studies is mainly on the significance of one variable at a time. Here, we attempt to integrate between responses of several physiological systems, challenged by increasing diet and water salinity and extreme temperatures, acquired in different studies of thermo and osmo-regulatory adaptations, of small rodents, to the xeric environment. Studies have shown differential thermoregulatory responses to increased dietary salinity, which were attributed to habitat and habits of the relevant species. In the thermoregulatory studies, a potential adaptive significance of low metabolic rate was demonstrated. From an evolutionary point of view, the most important adaptation is in the timing of reproduction, as it enables the transfer of genetic properties to the next generation in an unpredictable ecosystem, where reproduction might not occur every year. Results in this aspect show that increased dietary salinity, through an increase in vasopressin plasma levels, plays an important role as a regulator of the reproductive system. We assume that the amount of food existing in the habitat and the amount of reserves in the animal in the form of white adipose tissue are important for reproduction. Photoperiod affects all studied physiological responses, emphasizing the importance of pre-acclimation to seasonal characteristics. We summarize the existing data and suggest neuro-endocrine pathways, which have a central role in these adaptations by affecting thermoregulation, osmoregulation and reproduction to create the optimal response to xeric conditions. These hypotheses can be used as the basis for future studies. © 2009 ISZS, Blackwell Publishing and IOZ/CAS. PMID: 21392308 [PubMed - indexed for MEDLINE] 1618. Biochim Biophys Acta. 2010 Mar;1801(3):377-80. doi: 10.1016/j.bbalip.2009.11.006. Epub 2009 Nov 24. Antagonistic effects of thiazolidinediones and cytokines in lipotoxicity. Smith U(1), Hammarstedt A. Author information: (1)The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, SE-413 45 Gothenburg, Sweden. ulf.smith@medic.gu.se Ectopic lipid accumulation is promoted by obesity and an impaired ability to accumulate triglycerides in the subcutaneous depots. The adipose tissue is dysregulated in hypertrophic obesity, i.e., when the adipose cells have become enlarged. In some individuals, however, obesity is a consequence of a recruitment of new adipocytes, i.e., a hyperplastic obesity. This form of obesity is usually not associated with the metabolic complications and is termed "obese but metabolically normal". We here review recent findings showing that hypertrophic obesity is associated with an impaired differentiation of committed preadipocytes. This may be a primary (genetic?) event, thus leading to hypertrophic fat cells and the associated inflammation. However, it is also possible that the inflammation is a primary event allowing, in particular, TNFalpha to inhibit preadipocyte differentiation. TNFalpha, instead, promotes a partial transdifferentiation of the preadipocytes to assume a macrophage-like phenotype. PPARgamma activation promotes adipogenesis but can apparently not overcome the impaired preadipocyte differentiation seen in hypertrophic obesity. Copyright (c) 2009 Elsevier B.V. All rights reserved. PMID: 19941972 [PubMed - indexed for MEDLINE] 1619. Curr Stem Cell Res Ther. 2010 Jun;5(2):95-102. Characterization of adipose-derived stem cells: an update. Bailey AM(1), Kapur S, Katz AJ. Author information: (1)Department of Plastic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Adipose tissue is an attractive source of multipotent adult stem cells due to its wide-spread availability, accessibility, and ease of harvest. Adipose-derived stem cells (ASCs), the adherent stromal cell population present within adipose tissue, are easily expanded in culture, able to differentiate along multiple cell-lineage pathways, and have been shown to provide therapeutic benefit in models of injury and disease through immunomodulation, structural integation, and/or trophic support. Recent developments in the characterization of ASCs, specifically their isolation, gene and protein expression, differentiation, and expansion, are reviewed in this article. PMID: 19941461 [PubMed - indexed for MEDLINE] 1620. Curr Stem Cell Res Ther. 2010 Jun;5(2):103-10. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Salgado AJ(1), Reis RL, Sousa NJ, Gimble JM. Author information: (1)Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. asalgado@ecsaude.uminho.pt Stem cells have been long looked at as possible therapeutic vehicles for different health related problems. Among the different existing stem cell populations, Adipose- derived Stem Cells (ASCs) have been gathering attention in the last 10 years. When compared to other stem cells populations and sources, ASCs can be easily isolated while providing simultaneously higher yields upon the processing of adipose tissue. Similar to other stem cell populations, it was initially thought that the main potential of ASCs for regenerative medicine approaches was intimately related to their differentiation capability. Although this is true, there has been an increasing body of literature describing the trophic effects of ASCs on the protection, survival and differentiation of variety of endogenous cells/tissues. Moreover, they have also shown to possess an immunomodulatory character. This effect is closely related to the ASCs' secretome and the soluble factors found within it. Molecules such as hepatocyte growth factor (HGF), granulocyte and macrophage colony stimulating factors, interleukins (ILs) 6, 7, 8 and 11, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), adipokines and others have been identified within the ASCs' secretome. Due to its importance regarding future applications for the field of regenerative medicine, we aim, in the present review, to make a comprehensive analysis of the literature relating to the ASCs' secretome and its relevance to the immune and central nervous system, vascularization and cardiac regeneration. The concluding section will highlight some of the major challenges that remain before ASCs can be used for future clinical applications. PMID: 19941460 [PubMed - indexed for MEDLINE] 1621. Curr Stem Cell Res Ther. 2010 Jun;5(2):111-5. Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases. Cho KS(1), Roh HJ. Author information: (1)Department of ORL-HNS and Medical Research Institute, Pusan National University School of Medicine, Busan, South Korea. Allergic rhinitis and asthma are inflammatory airway allergic diseases caused by Th2-driven immune response. Several studies have shown that multipotent adipose-derived stem cells (ASCs) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathway, especially immunosuppressive effect on T cell activities. ASCs' ability to be readily isolated from a number of adipose tissues and expanded ex vivo makes them attractive candidate for use in clinical therapy in the context of allogeneic transplantation, in particular to modulate graft-versus-host disease and graft rejection. The authors have investigated whether ASCs can inhibit Th2-dependent airway allergic disease in the mouse model. In this article we review recent experimental data and discuss about the mechanisms by which ASCs inhibit allergic airway inflammation via immunomodulation from a Th2 to a Th1-biased response in the mouse model. PMID: 19941459 [PubMed - indexed for MEDLINE] 1622. Curr Stem Cell Res Ther. 2010 Jun;5(2):116-21. Adipose tissue regeneration. Brayfield CA(1), Marra KG, Rubin JP. Author information: (1)Division of Plastic Surgery, Department of Surgery, University of Pittsburgh School of Medicine, 3380 Blvd of the Allies, Pittsburgh, PA 15228, USA. The repair of soft tissue defects, particularly after trauma and oncologic surgery, represents a major clinical challenge. While current reconstructive procedures can move soft tissue from other areas of the body, there remains an unmet need for new modalities that are less invasive and more precise. Adipose tissue is the key component necessary for soft tissue reconstruction. This review will discuss the discovery and potential of adult stem therapies in the regeneration of adipose tissue. Adipose-derived stem cells (ASCs), are being examined as cell delivery systems for soft tissue reconstruction. In addition to a further understanding of the biology of ASCs, appropriate biomaterials (e.g., cell delivery vehicles), rapid expansion of stem cells using bioreactors, and suitable animal models for adipose tissue engineering are needed for successful stem cell therapies, and will be discussed in this review. Clinical studies with ASCs are being conducted in Europe and Asia and will be described. PMID: 19941458 [PubMed - indexed for MEDLINE] 1623. Curr Stem Cell Res Ther. 2010 Jun;5(2):122-8. Bone regeneration and repair. Panetta NJ(1), Gupta DM, Longaker MT. Author information: (1)Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA 94305-5148, USA. In the face of mounting clinical demand, and armed with reconstructive techniques that are technically challenging and frequently result in suboptimal patient outcomes, increasing focus is being placed on tissue engineering and regenerative medicine as a potential source of novel skeletal reconstructive approaches. Specifically, evidence is accumulating that highlights the promise of osteoprogenitor cell-based reconstructive strategies to meet the needs of an expanding patient population. Historically, the study of cell and molecular biology guiding physiologic and pathologic skeletal development, as well as endogenous bone regeneration following injury, has provided a wealth of information that lends insight toward potential parallel processes that may regulate the osteogenic differentiation of progenitor cells. Multiple progenitor cell populations are now known to possess a capacity to undergo robust osteogenic differentiation in the presence of appropriate environmental cues (hESC, BMSC, ASC, etc.) Recent investigations have put forth multiple advantages of ASC relative to BMSC. Of note, ASC exist in relative abundance, lack the need for in vitro expansion prior to utilization, and can be harvested with relative ease and reduced donor morbidity. Collectively, these factors, paired with promising in vitro and in vivo observations that speak toward the substantial osteogenic potential of ASC, have spurred enthusiasm to pursue the application of ASC in the maturation of skeletal tissue engineering applications. Yet, elucidating what structural and functional properties of scaffolds designed for ASC-mediated skeletal tissue engineering applications (porosity, pore size, composition, mechanical stability, degradation kinetics, etc.), as well as evolving our understanding and capacity to deliver spatiotemporally specific pro-osteogenic targeted molecular manipulation to progenitor cells, remain important hurdles to clear. The scope of this review encompasses the current state of ongoing investigations along these fronts, as well as what future direction will be critical to the transition of cell-based skeletal tissue engineering strategies to the bedside. PMID: 19941457 [PubMed - indexed for MEDLINE] 1624. Curr Stem Cell Res Ther. 2010 Jun;5(2):129-32. Cartilage regeneration using adipose-derived stem cells. Ogawa R(1), Mizuno S. Author information: (1)Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, 1-1-5 Sendagi Bunyko-ku, Tokyo 113-8603, Japan. r.ogawa@nms.ac.jp The first tissue engineering product, autologous chondrocytes implantation or transplantation (ACI or ACT), has been available for over a decade. Recently, adult tissue-derived stem cells have received great interest for their ability to promote tissue regeneration. To date, adipose-derived stem cells (ASCs) have been evaluated for new surgical procedures to reconstruct damaged and defective tissue, because they are easiest to harvest due to the large number of stem cells compared to other stem cell sources. However, there are issues in using ASCs for cartilage repair. Thus, we need more information regarding optimal culture conditions and methods to promote chondrogenic lineages of stem cells. The necessary information includes necessary differentiation factors, cell scaffolds, and cell culture conditions. We reviewed the methodology for manufacturing cell constructs using ASCs for clinical applications. PMID: 19941456 [PubMed - indexed for MEDLINE] 1625. Curr Stem Cell Res Ther. 2010 Jun;5(2):133-6. The potential for treatment of skeletal muscle disorders with adipose-derived stem cells. Mizuno H(1). Author information: (1)Department of Plastic and Reconstructive Surgery, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 1138603, Japan. hmizuno@nms.ac.jp Stem cell based therapies for the repair and regeneration of various tissues and organs offer a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. This review focuses on skeletal muscle regeneration and repair by adipose-derived stem cells (ASCs) with particular attention to their potential use as a therapy for disorders such as degenerative muscle diseases or skeletal muscle injuries. ASCs can differentiate into skeletal muscle cells in vitro either in co-culture with skeletal myoblasts, or when cultured in medium supplemented with horse serum and/or under reduced serum conditions. In particular, spontaneous fusion of ASCs and subsequent myotube-like formation was observed in early culture passages at high cell density. ASCs have also shown a capacity for myogenic differentiation in vivo. In a murine muscular dystrophy model, ASCs were able to restore muscle function following direct injection into the affected muscle as well as following intravenous systemic administration. Of great importance is the finding that allogeneic ASCs injected into the damaged muscle were not rejected, even without immunosuppressive therapy. Because human adipose tissue is ubiquitous and easily obtainable in large quantities under local anesthesia with little patient discomfort, it presents an appealing source of stem cells for mesenchymal tissue regeneration and engineering. PMID: 19941455 [PubMed - indexed for MEDLINE] 1626. Curr Stem Cell Res Ther. 2010 Jun;5(2):137-40. Adipose stem cells and skin repair. Jeong JH(1). Author information: (1)Oblige Plastic Surgery Clinic and StemTec Korea, 35-11 Samdeok-dong, Daegu 700-411, Republic of Korea. originaljjh@naver.com With the discovery of adipose stem cells (ASCs), 40 years after the identification of bone marrow stem cells, a new era of active stem cell therapy has opened. The abundance of stem cells harvested from adipose tissue enables us to instantly apply primary cells without culture expansion. ASCs are already clinically applied in many other purposes such as cell-enriched lipotransfer, wound healing, skin rejuvenation, scar remodeling and skin tissue engineering. Although cellular mechanism of ASCs is not completely understood, recent researches have disclosed some of their unique functions as mesenchymal stem cells. There have been increasing numbers of scientific reports on the therapeutic effect of ASCs on skin repair, scar remodeling and rejuvenation. Wound healing and scar remodeling are complex, multi-cellular processes that involve coordinated efforts of many cell types and various cytokines. Recent reports showed ASCs as a powerful source of skin regeneration because of their capability to provide not only cellular elements, but also numerous cytokines. Currently, other attractive functions of ASCs in the recovery of extrinsic aging and radiation damage are under active investigation. It seems that autologous ASCs have great promise for applications in repair of skin, rejuvenation of aging skin and aging-related skin lesions. This review will focus on the specific roles of ASCs in skin tissue, especially related with wound healing, radiation injury, scar remodeling, skin rejuvenation and skin engineering. PMID: 19941454 [PubMed - indexed for MEDLINE] 1627. Curr Stem Cell Res Ther. 2010 Jun;5(2):141-4. Vascular and endothelial regeneration. Casteilla L(1), Planat-Bénard V, Cousin B, Laharrague P, Bourin P. Author information: (1)Université de Toulouse, UPS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, BP 84225 - F-31 432 Toulouse, France. Louis.Casteilla@inserm.fr Adipose tissue is the final tissue to develop and is strongly involved in energy homeostasis. It can represent up to 50% of body weight in obesity. Beside its metabolic role, endocrine functions appeared to play a key role in interconnecting adipose tissue with other tissues of the organism and in numerous physiological functions. The presence of adipocyte progenitors has long been demonstrated throughout life in the stromal fraction of adipose tissue. Now, it appears that these cells are multipotent and share numerous features with mesenchymal stem cells (MSC) derived from bone marrow. They also display some specificities and a strong pro-angiogenic potential. Altogether, these data emphasize the need to reconsider the potential of adipose tissue. Moreover, since fat pads are easy to sample, numerous and promising perspectives are now opening up in regenerative medicine, particularly in ischemic situations. PMID: 19941453 [PubMed - indexed for MEDLINE] 1628. Curr Stem Cell Res Ther. 2010 Jun;5(2):145-52. Aesthetic cardiology: adipose-derived stem cells for myocardial repair. Palpant NJ(1), Metzger JM. Author information: (1)Department of Integrative Biology & Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. Stem cell biology has increasingly gained scientific and public interest in recent years. In particular, the use of stem cells for treatment of heart disease has been strongly pursued within the scientific and medical communities. Significant effort has gone into the use of adult tissue-derived stem cells for cardiac repair including bone marrow, blood, and cardiac-derived cell populations. Significant interest in this area has been balanced by the difficulties of understanding stem cells, cardiac injury, and the amalgamation of these areas of investigation in translational medicine. Recent studies have emerged on adipose-derived stem cells which show the potential for cardiac lineage development in vitro and may have application in cell-mediated in vivo therapy for the diseased heart. This review provides a summary of current findings within the field of adipose-derived stem cell biology regarding their cardiac differentiation potential. PMCID: PMC2896012 PMID: 19941452 [PubMed - indexed for MEDLINE] 1629. Curr Stem Cell Res Ther. 2010 Jun;5(2):153-60. Neural differentiation and therapeutic potential of adipose tissue derived stem cells. Erba P(1), Terenghi G, Kingham PJ. Author information: (1)Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital of Basel, CH-4031 Basel, Switzerland. erbapaolo@hotmail.com Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders. PMID: 19941451 [PubMed - indexed for MEDLINE] 1630. Curr Stem Cell Res Ther. 2010 Jun;5(2):161-7. Tendon regeneration and repair with adipose derived stem cells. Uysal AC(1), Mizuno H. Author information: (1)Department of Plastic and Reconstructive Surgery, Baskent University, Faculty of Medicine, Fevzi Cakmak Cad. 5. Sok. No: 48, 06490, Bahcelievler, Ankara, Turkey. cagriuysal@hotmail.com Tendon, the crucial element of the musculoskeletal system, when damaged, never restores the biological and biomechanical properties completely. Recently, tissue engineering and regenerative medicine have enabled the differentiation of postnatal somatic stem cells or mesenchymal stem cells (MSCs) to different cell lineages and tissues including tendon. In addition, the MSCs, mainly bone marrow derived stem cells (BSCs) were proven to enhance tendon healing. Adipose derived stem cells (ASCs) were shown to be as effective as the other MSCs by their multipotency and proliferative efficiency. However, neither the differentiation of ASCs to tenocytes nor the tendon regeneration using ASCs have been described in literature. Recently, we have studied the effect of ASCs on primary tendon repair in in-vivo model. In this paper, we sought to discuss tendon tissue engineering by focusing on culture of tenocytes, biomaterials, scaffolds, mechanical loading, fibroblasts and mesenchymal stem cells and mainly on adipose derived stem cells. Tendon regeneration using ASCs might be one of the clinical remedies in near future. In addition, the enhancing effect of ASCs on tendon repair and tendon defects might enable better clinical outcomes in musculoskeletal system reconstruction. Advances in biomaterial technology will improve the methodology in tendon regeneration however, up to date, ASCs present an ideal cell source for experimental and clinical research on tendon engineering. PMID: 19941450 [PubMed - indexed for MEDLINE] 1631. Curr Stem Cell Res Ther. 2010 Jun;5(2):168-74. Periodontal disease and periodontal tissue regeneration. Tobita M(1), Mizuno H. Author information: (1)Department of Plastic and Reconstructive Surgery, Nippon Medical School, Tokyo, Japan. tobitamorikuni@gmail.com Periodontal disease leads to destruction of the periodontium such as alveolar bone, cementum, the periodontal ligament, and gingiva. Effective treatment for periodontal tissue regeneration is important, because periodontal disease is related to several systemic diseases. However, various conventional therapies for periodontal tissue regeneration have shown limited and variable clinical outcomes. Thus, there are ongoing efforts to identify an alternative cell source, such as stem cells, for the development of new tissue engineering therapies. In this review, periodontal disease and the application of tissue engineering for periodontal tissue regeneration are discussed. In particular, adipose-derived stem cells are presented as an agent for restoring periodontal tissue defects. PMID: 19941449 [PubMed - indexed for MEDLINE] 1632. Curr Stem Cell Res Ther. 2010 Jun;5(2):175-81. Perspectives on adipose-derived stem/stromal cells as potential treatment for scarred vocal folds: opportunity and challenges. Kumai Y(1), Kobler JB, Herrera VL, Zeitels SM. Author information: (1)Department of Surgery - Harvard Medical School, Center for Laryngeal Surgery and Voice Rehabilitation - Massachusetts General Hospital, Boston, MA 02114, USA. kumayoshi426@gmail.com Regenerative therapy using stem cells for the treatment of vocal fold wound healing and fibrosis is a very active area of research in Otolaryngology. Although modern phonosurgical methods can deal with many types of vocal fold pathology, vocal fold scar remains a clinical challenge. Trauma (e.g. vocal abuse, phonosurgery) and inflammation (e.g. laryngitis) are the two main causes of the vocal fold scarring. Several recent reviews detail the problem of vocal fold scarring and the array of possible solutions under investigation. The search for solutions includes autologous tissues, biomaterial implants, growth factors, anti-fibrotic agents and stem cells. This review focuses on emerging research on stem cells for vocal fold regeneration and our own studies of interactions between adipose-derived stem/stromal cells and vocal fold fibroblasts using an in vitro model. While clearly an opportunity, the challenging approach of treating vocal scarring using ASCs has just started. For future in vivo studies, improvements in cell viability and markers of stem-cell differentiation into normal fibroblasts are needed. The roles of stem cell-derived cytokines in paracrine signaling need to be further explored at a cellular level in vitro, and then extended to in vivo experiments. PMID: 19941448 [PubMed - indexed for MEDLINE] 1633. Curr Stem Cell Res Ther. 2010 Jun;5(2):182-9. Stem cells for hepatic regeneration: the role of adipose tissue derived mesenchymal stem cells. Ishikawa T(1), Banas A, Hagiwara K, Iwaguro H, Ochiya T. Author information: (1)Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Severe hepatic dysfunctions including hepatic cirrhosis and hepatocarcinoma are life-threatening conditions for which effective medical treatments are needed. With the only effective treatment to date being orthotropic liver transplantation, alternative approaches are needed because of the limited number of donors and the possibility of immune-rejection. One alternative is regenerative medicine, which holds promise for the development of a cell-based therapy enabling hepatic regeneration through transplantation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) or hepatocyte-like cells generated from AT-MSCs. When compared with embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, the use of AT-MSCs as regenerative cells would be advantageous in regard to ethical and safety issues since AT-MSCs are somatic cells and have the potential to be used without in vitro culture. These autologous cells are immuno-compatible and exhibit controlled differentiation and multi-functional abilities and do not undergo post-transplantation rejection or unwanted differentiation such as formation of teratomas. AT-MSC-based therapies may provide a novel approach for hepatic regeneration and hepatocyte differentiation and thereby support hepatic function in diseased individuals. PMID: 19941447 [PubMed - indexed for MEDLINE] 1634. Curr Stem Cell Res Ther. 2010 Jun;5(2):190-4. Adipose tissue derived stem cells for regeneration and differentiation into insulin-producing cells. Kim SC(1), Han DJ, Lee JY. Author information: (1)Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736. Korea. drksc@amc.seoul.kr Stem cells are considered an ideal tool for the supply of insulin-producing cells or repairing damaged pancreatic tissues to treat diabetes mellitus, with the possibility of unlimited sources. This cell population includes embryonic, adult bone marrow, pancreatic stem cells, extra pancreatic (such as hepatic cells) and adipose-derived stem cells. Multipotent adipose tissue-derived stem cells (ADSCs) are abundant in the human body, and thus are an ideal donor source for autologous transplantation to generate insulin-producing cells. Moreover these cells are better sources than bone marrow stem cells (BMSCs) for clinical applications, owing to minimal invasive procedures, high proliferation and multi-differentiation potential. Human adipose tissue-derived stem cells (hADSCs) may thus provide an alternative stem cell source, replacing BM-MSCs or embryonic stem cells (ESCs) for future clinical use in diabetes mellitus treatment. PMID: 19941446 [PubMed - indexed for MEDLINE] 1635. Curr Stem Cell Res Ther. 2010 Jun;5(2):195-204. Cornea and ocular surface treatment. De Miguel MP(1), Alio JL, Arnalich-Montiel F, Fuentes-Julian S, de Benito-Llopis L, Amparo F, Bataille L. Author information: (1)Cell Engineering Laboratory, La Paz Hospital IdiPAZ, Maternity Building, Paseo Castellana 261, Madrid 28046 Spain. mariapdemiguel@gmail.com In addition to being a protective shield, the cornea represents two thirds of the eye's refractive power. Corneal pathology can affect one or all of the corneal layers, producing corneal opacity. Although full corneal thickness keratoplasty has been the standard procedure, the ideal strategy would be to replace only the damaged layer. Current difficulties in corneal transplantation, mainly immune rejection and shortage of organ supply, place more emphasis on the development of artificial corneas. Bioengineered corneas range from prosthetic devices that solely address the replacement of the corneal function, to tissue-engineered hydrogels that allow regeneration of the tissue. Recently, major advances in the biology of corneal stem cells have been achieved. However, the therapeutic use of these stem cell types has the disadvantage of needing an intact stem cell compartment, which is usually damaged. In addition, long ex vivo culture is needed to generate enough cell numbers for transplantation. In the near future, combination of advanced biomaterials with cells from abundant outer sources will allow advances in the field. For the former, magnetically aligned collagen is one of the most promising ones. For the latter, different cell types will be optimal: 1) for epithelial replacement: oral mucosal epithelium, ear epidermis, or bone marrow- mesenchymal stem cells, 2) for stromal regeneration: adipose-derived stem cells and 3) for endothelial replacement, the possibility of in vitro directed differentiation of adipose-derived stem cells towards endothelial cells provides an exciting new approach. PMID: 19941445 [PubMed - indexed for MEDLINE] 1636. Postgrad Med. 2009 Nov;121(6):148-57. doi: 10.3810/pgm.2009.11.2083. Understanding omega-3 polyunsaturated fatty acids. Calder PC(1), Yaqoob P. Author information: (1)Institute of Human Nutrition School of Medicine, Southampton General Hospital, Southampton, UK. pcc@soton.ac.uk Current intakes of very long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are low in most individuals living in Western countries. A good natural source of these fatty acids is seafood, especially oily fish. Fish oil capsules contain these fatty acids also. Very long-chain omega-3 fatty acids are readily incorporated from capsules into transport (blood lipids), functional (cell and tissue), and storage (adipose) pools. This incorporation is dose-dependent and follows a kinetic pattern that is characteristic for each pool. At sufficient levels of incorporation, EPA and DHA influence the physical nature of cell membranes and membrane protein-mediated responses, lipid-mediator generation, cell signaling, and gene expression in many different cell types. Through these mechanisms, EPA and DHA influence cell and tissue physiology and the way cells and tissues respond to external signals. In most cases the effects seen are compatible with improvements in disease biomarker profiles or health-related outcomes. As a result, very long-chain omega-3 fatty acids play a role in achieving optimal health and in protection against disease. Long-chain omega-3 fatty acids not only protect against cardiovascular morbidity but also against mortality. In some conditions, for example rheumatoid arthritis, they may be beneficial as therapeutic agents. On the basis of the recognized health improvements brought about by long-chain omega-3 fatty acids, recommendations have been made to increase their intake. The plant omega-3 fatty acid, alpha-linolenic acid (ALA), can be converted to EPA, but conversion to DHA appears to be poor in humans. Effects of ALA on human health-related outcomes appear to be due to conversion to EPA, and since this is limited, moderately increased consumption of ALA may be of little benefit in improving health outcomes compared with increased intake of preformed EPA + DHA. PMID: 19940425 [PubMed - indexed for MEDLINE] 1637. Postepy Hig Med Dosw (Online). 2009 Oct 23;63:485-91. [Resistin: a pathogenic factor or a biomarker of metabolic disorders and inflammation?]. [Article in Polish] Karbowska A(1), Boratyńska M, Klinger M. Author information: (1)Klinika Nefrologii i Medycyny Transplantacyjnej we Wrocławiu, 50-417 Wrocław. olaaw@poczta.onet.pl Cardiovascular diseases are currently the most frequent cause of death in Poland and their incidence continually rises. This is related to the high incidence of obesity associated with insulin resistance, which is present in type 2 diabetes mellitus. Adipose tissue produces multiple cytokines(TNF-alpha, IL-6, PAI-1, CRP, angiotensinogen, leptin, adiponectin, visfatin, apelin, resistin)which decrease insulin sensitivity and induce inflammatory processes, endothelial dysfunction,and atherosclerosis. This article presents the link between obesity, insulin resistance, and type 2 diabetes mellitus according to studies conducted in vitro and in animal models. In human studies, the influence of resistin on the development of insulin resistance is controversial. The article underlines the role of resisitin in the development of inflammatory processes and endothelial dysfunction in humans. In clinical studies, resistin was shown to be a predictive factor of coronary artery disease and mortality connected with cardiovascular diseases. PMID: 19940327 [PubMed - indexed for MEDLINE] 1638. Orv Hetil. 2009 Dec 6;150(49):2218-21. doi: 10.1556/OH.2009.28750. [Effect of moderate alcohol consumption on insulin sensitivity]. [Article in Hungarian] Abel T(1), Fehér J. Author information: (1)Allami Egészségügyi Központ, Szakrendelo Intézet, Budapest. drabelt@t-online.hu Moderate alcohol consumption has been reported to be associated with lower risk for both cardiovascular disease and type 2 diabetes. An explanation for these epidemiologic observations is not entirely clear. Alcohol raises high-density lipoprotein (HDL) cholesterol levels. Other potential beneficial mechanisms have been proposed including anti-inflammatory and anti-thrombotic effects. The association between moderate alcohol consumption and insulin sensitivity is still under debate. Possible mechanisms include elevation of adiponectin level, reduction of C-reactive protein and suppression of free fatty acid release from adipose tissue. PMID: 19939782 [PubMed - indexed for MEDLINE] 1639. Zh Nevrol Psikhiatr Im S S Korsakova. 2009;109(5):77-85. [Genes and cerebrovascular pathology (genes and nucleotide polymorphisms in some types of physiological shifts and pathological processes)]. [Article in Russian] Torshin IIu, Gromova OA, Nikonov AA. PMID: 19938280 [PubMed - indexed for MEDLINE] 1640. Eur Urol. 2010 Feb;57(2):179-92. doi: 10.1016/j.eururo.2009.11.009. Epub 2009 Nov 11. A critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. Walz J(1), Burnett AL, Costello AJ, Eastham JA, Graefen M, Guillonneau B, Menon M, Montorsi F, Myers RP, Rocco B, Villers A. Author information: (1)Department of Urology, Institut Paoli-Calmettes Cancer Center, 232, Bd Ste. Marguerite, 13009 Marseille, France. walzj@marseille.fnclcc.fr Comment in Eur Urol. 2010 Feb;57(2):193-5. CONTEXT: Detailed knowledge of the anatomy of the prostate and adjacent tissues is mandatory during radical prostatectomy to ensure reliable oncologic and functional outcomes. OBJECTIVE: To review critically and to summarize the available literature on surgical anatomy of the prostate and adjacent structures involved in cancer control, erectile function, and urinary continence. EVIDENCE ACQUISITION: A search of the PubMed database was performed using the keywords radical prostatectomy, anatomy, neurovascular bundle, fascia, pelvis, and sphincter. Relevant articles and textbook chapters were reviewed, analyzed, and summarized. EVIDENCE SYNTHESIS: Anatomy of the prostate and the adjacent tissues varies substantially. The fascia surrounding the prostate is multilayered, sometimes either fused with the prostate capsule or clearly separated from the capsule as a reflection of interindividual variations. The neurovascular bundle (NVB) is situated between the fascial layers covering the prostate. The NVB is composed of numerous nerve fibers superimposed on a scaffold of veins, arteries, and variable amounts of adipose tissue surrounding almost the entire lateral and posterior surfaces of the prostate. The NVB is also in close, cage-like contact to the seminal vesicles. The external urethral sphincter is a complex structure in close anatomic and functional relationship to the pelvic floor, and its fragile innervation is in close association to the prostate apex. Finally, the shape and size of the prostate can significantly modify the anatomy of the NVB, the urethral sphincter, the dorsal vascular complex, and the pubovesical/puboprostatic ligaments. CONCLUSIONS: The surgical anatomy of the prostate and adjacent tissues involved in radical prostatectomy is complex. Precise knowledge of all relevant anatomic structures facilitates surgical orientation and dissection during radical prostatectomy and ideally translates into both superior rates of cancer control and improved functional outcomes postoperatively. Copyright 2009 European Association of Urology. All rights reserved. PMID: 19931974 [PubMed - indexed for MEDLINE] 1641. Obesity (Silver Spring). 2009 Dec;17 Suppl 3:S27-33. doi: 10.1038/oby.2009.385. Exercise, abdominal obesity, skeletal muscle, and metabolic risk: evidence for a dose response. Slentz CA(1), Houmard JA, Kraus WE. Author information: (1)Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. Cris.Slentz@duke.edu The obese are at increased risk for cardiovascular disease and type 2 diabetes. However, some who are obese have no metabolic abnormalities. So, it is not adipose tissue per se, but perhaps where it is located that is important for determining metabolic consequences. Regular exercise is known to reduce risk for metabolic disease through numerous mechanisms. The purpose of this report is to highlight some of the efficacy-based data on the effects of exercise (and also a sedentary lifestyle) on abdominal obesity, visceral fat, and metabolic risk. We also discuss how impaired fatty acid oxidation (FAO) in skeletal muscle may be related to both insulin resistance and a contributor to weight gain. In summary, it is evident that exercise in sufficient amounts can lead to substantial decreases in body weight, total body fat, and visceral fat. Additionally, evidence now supports the conclusion that there is a dose-response relationship between exercise amount and these changes, i.e., more exercise leads to additional benefits. Additionally, there are a number of important cardiometabolic risk factors that were most favorably effected by moderate-intensity compared to vigorous-intensity exercise. Unfortunately, it is also apparent that in sedentary middle-aged men and women, short periods of physical inactivity lead to significant weight gain, substantial increases in visceral fat, and further metabolic deterioration. Finally, favorable modulation of mitochondrial oxidative capacity in skeletal muscle by exercise training may reduce a block for complete oxidation of fatty acids in muscle and thereby relieve a block to effective insulin signaling. PMCID: PMC3762482 PMID: 19927142 [PubMed - indexed for MEDLINE] 1642. J Appl Physiol (1985). 2010 Mar;108(3):744-53. doi: 10.1152/japplphysiol.00838.2009. Epub 2009 Nov 19. Obesity, adipokines, and lung disease. Sood A(1). Author information: (1)Department of Medicine, University of New Mexico, MSC 10 5550, Albuquerque, NM 87131-0001, USA. asood@salud.unm.edu This review summarizes the state of the current literature relating to the associations of lung disease on obesity and adipokines (proteins produced by adipose tissue) in humans. Obesity is an independent risk factor for asthma. Recent studies suggest that obesity is also an independent risk factor for chronic airflow obstruction, as is seen with chronic obstructive pulmonary disease (COPD). The mechanistic basis for these associations in humans is not established, although a possible role for adipokines has been invoked. Leptin, a proinflammatory adipokine, and adiponectin, an anti-inflammatory adipokine, are causally associated with asthma in mice. Although human studies are currently inconclusive, high-serum leptin and low-serum adiponectin concentrations predict asthma, independent of obesity, in select population groups, such as premenopausal women in the United States. In contradistinction, low-serum leptin and high-serum adiponectin concentrations are associated with stable COPD, although these associations are likely confounded by fat mass. Interestingly, leptin may promote systemic and airway inflammation in stable COPD patients. On the other hand, COPD may upregulate systemic and lung adiponectin expression. The precise mechanism and significance of the associations between these adipokines and lung disease at the current stage is confusing and frankly paradoxical in places. This area of research needs additional study that may open up novel therapeutic strategies for these lung diseases. PMCID: PMC2838636 PMID: 19926824 [PubMed - indexed for MEDLINE] 1643. Recent Pat Cardiovasc Drug Discov. 2009 Nov;4(3):164-76. Targeting MCP-1 to reduce vascular complications of obesity. Ohman MK(1), Eitzman DT. Author information: (1)Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan 48109, USA. Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction. Recent studies and several patents have demonstrated that the cardiovascular risk associated with obesity is correlated particularly with visceral adiposity. Excess visceral adiposity may increase vascular risk due to secretion of cytokines and chemokines by cellular constituents of the adipose tissue. The secretory profile of various adipose depots may be regulated by the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by visceral fat may contribute to an increased risk for vascular complications. While the vasculopathic effects of central obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or secretory products of adipose tissue may be potentially beneficial in reducing the vascular risk associated with obesity. A potential therapeutic target is monocyte chemoattractant 1 (MCP-1), which is a potent chemokine that is elevated in obesity. Since MCP-1 promotes atherosclerosis, inhibition of MCP-1 may be effective in reducing the vascular risk associated with obesity. PMID: 19925437 [PubMed - indexed for MEDLINE] 1644. Horm Metab Res. 2010 Feb;42(2):75-80. doi: 10.1055/s-0029-1241831. Epub 2009 Nov 18. FTO - Friend or foe? Tews D(1), Fischer-Posovszky P, Wabitsch M. Author information: (1)Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany. daniel.tews@uniklinik-ulm.de Fat mass and obesity associated gene ( FTO) is the most relevant polygene for obesity to date. It has been identified by genome wide association studies concerning body weight regulation. However, its functional relevance for the pathogenesis of obesity remains elusive. Studies in rodents provide data pointing to a central role of FTO through regulation of food intake. In addition, peripheral effects of FTO are also discussed in the literature. This review highlights the possible relevance of FTO for weight regulation and obesity development in central and peripheral tissues with a special focus on adipose tissue. Georg Thieme Verlag KG Stuttgart * New York. PMID: 19924617 [PubMed - indexed for MEDLINE] 1645. Exp Clin Endocrinol Diabetes. 2009 Nov;117(10):563-6. doi: 10.1055/s-0029-1241870. Epub 2009 Nov 18. Obesity and cancer. Percik R(1), Stumvoll M. Author information: (1)Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel. Epidemiological studies have suggested that obesity is associated with increased risk of several cancer types including colon, esophagus, breast (in postmenopausal women), endometrium, kidney, liver, gallbladder and pancreas. Suggested mechanisms include increased intake of potentially carcinogenic food ingredients along with excessive amount of calories, loss of cancer protective effects due to reduced physical activity, carcinogenic factors released from increased adipose tissue mass and "secondary" associations via "precursor" condition such as gallstones. The increased cancer risk in patients with obesity is a neglected topic which deserves more scientific attention. Because of its extreme chronicity and co-association with numerous other conditions true causality and underlying mechanisms are difficult to study. Nevertheless, a large body of literature is already available which provides concepts for future research. Copyright J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York. PMID: 19924603 [PubMed - indexed for MEDLINE] 1646. J Dairy Sci. 2009 Dec;92(12):5769-801. doi: 10.3168/jds.2009-2431. Invited review: Body condition score and its association with dairy cow productivity, health, and welfare. Roche JR(1), Friggens NC, Kay JK, Fisher MW, Stafford KJ, Berry DP. Author information: (1)DairyNZ Ltd, PO Box 3221, Hamilton, New Zealand. john.roche@dairynz.co.nz The body condition score (BCS) of a dairy cow is an assessment of the proportion of body fat that it possesses, and it is recognized by animal scientists and producers as being an important factor in dairy cattle management. The scale used to measure BCS differs between countries, but low values always reflect emaciation and high values equate to obesity. The intercalving profile of BCS is a mirror image of the milk lactation profile. Cows lose condition for 50 to 100 d postcalving, because of homeorhetic changes that occur in the somatotropic axis and the sensitivity of peripheral tissues to insulin, and the upregulation of lipolytic pathways in adipose tissue. Management and feeding have little effect on early postcalving BCS loss (wk 1 to 4 postcalving) until the natural period of insulin resistance has passed and the somatotropic axis has recoupled. There is evidence, however, that management and diet can influence the timing of recoupling of the somatotropic axis and the sensitivity of peripheral tissues to insulin, and gene expression differences in adipose tissue 30 d in milk confirm an effect of energy intake on lipogenic enzymes. The BCS in which a cow calves, nadir BCS, and the amount of BCS she loses postcalving are associated with milk production, reproduction, and health. Body condition score may also be a valid indicator of animal welfare, but further research is required to determine the effect of BCS and BCS change on how a cow "feels." Although the actual strength of the association may vary, there is relative consistency in the associations among calving and nadir BCS, and BCS change on milk production, postpartum anestrous, the likelihood of a successful pregnancy and days open, the risk of uterine infection, and the risk of metabolic disorders. For many production and health variables, the association with BCS is nonlinear, with an optimum calving BCS of 3.0 to 3.25 (5-point scale); lower calving BCS is associated with reduced production and reproduction, whereas calving BCS >/=3.5 (5-point scale) is associated with a reduction in early lactation dry matter intake and milk production and an increased risk of metabolic disorders. Ongoing research into the automation of body condition scoring suggests that it is a likely candidate to be incorporated into decision support systems in the near future to aid producers in making operational and tactical decisions. PMID: 19923585 [PubMed - indexed for MEDLINE] 1647. Am J Clin Nutr. 2010 Jan;91(1):262S-266S. doi: 10.3945/ajcn.2009.28449D. Epub 2009 Nov 18. Peroxisome proliferator-activated receptor translational research and clinical experience. Cheatham WW(1). Author information: (1)Bureau of Medicine and Surgery, US Navy, Washington, DC, USA. wayman.cheatham@med.navy.mil Since the early 1970s, pharmaceutical biochemists have sought to exploit the scientific findings that were uncovered when they studied the basis for the function and mode of action of fibric acid derivatives. In the early 1970s, little was known of peroxisome proliferator-activated receptors (PPARs), even in concept. Since then, however, the development of bioactive small molecules in medicinal science has resulted in tools developed to be inserted into the PPAR-binding domain, which has resulted in the recognition of literally thousands of possible biological effects of binding configurations. In diabetes care, the first of the marketed agents from these discoveries and developments was introduced in 1996. It was potent and did its job well. However, the use of this early form of thiazolidinedione sometimes, although rarely, led to fulminant liver failure, and ultimately the drug was removed from the market. Subsequent thiazolidinediones have been developed, and 2 have been relatively successful. However, they are not without their problems. This article describes the history of the development of these drugs, identifies the valuable attributes that they possess, and gives a clear rationale as to why a quest for a "safer" PPAR agonist is still being sought. PMID: 19923366 [PubMed - indexed for MEDLINE] 1648. Obes Rev. 2010 May;11(5):362-70. doi: 10.1111/j.1467-789X.2009.00689.x. Epub 2009 Nov 17. Obesity is a sign - over-eating is a symptom: an aetiological framework for the assessment and management of obesity. Sharma AM(1), Padwal R. Author information: (1)Department of Medicine, University of Alberta, Royal Alexandra Hospital, Edmonton, AB AB T5H 3V9, Canada. amsharm@ualberta.ca Obesity is characterized by the accumulation of excess body fat and can be conceptualized as the physical manifestation of chronic energy excess. Using the analogy of oedema, the consequence of positive fluid balance or fluid retention, obesity can be seen as the consequence of positive energy balance or calorie 'retention'. Just as the assessment of oedema requires a comprehensive assessment of factors related to fluid balance, the assessment of obesity requires a systematic assessment of factors potentially affecting energy intake, metabolism and expenditure. Rather than just identifying and describing a behaviour ('this patient eats too much'), clinicians should seek to identify the determinants of this behaviour ('why, does this patient eat too much?'). This paper provides an aetiological framework for the systematic assessment of the socio-cultural, biomedical, psychological and iatrogenic factors that influence energy input, metabolism and expenditure. The paper discusses factors that affect metabolism (age, sex, genetics, neuroendocrine factors, sarcopenia, metabolically active fat, medications, prior weight loss), energy intake (socio-cultural factors, mindless eating, physical hunger, emotional eating, mental health, medications) and activity (socio-cultural factors, physical and emotional barriers, medications). It is expected that the clinical application of this framework can help clinicians systematically assess, identify and thereby address the aetiological determinants of positive energy balance resulting in more effective obesity prevention and management. PMID: 19922430 [PubMed - indexed for MEDLINE] 1649. Curr Opin Gastroenterol. 2010 Mar;26(2):146-51. doi: 10.1097/MOG.0b013e3283347e77. Cancer cachexia. Tisdale MJ(1). Author information: (1)Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, UK. m.j.tisdale@aston.ac.uk PURPOSE OF REVIEW: Although cachexia has a major effect on both the morbidity and mortality of cancer patients, information on the mechanisms responsible for this condition is limited. This review summarizes recent data in this area. RECENT FINDINGS: Cachexia is defined as loss of muscle, with or without fat, frequently associated with anorexia, inflammation and insulin resistance. Loss of adipose mass is due to an increased lipolysis through an increased expression of hormone-sensitive lipase. Adipose tissue does not contribute to the inflammatory response. There is an increased phosphorylation of both protein kinase R (PKR) and eukaryotic initiation factor 2 on the alpha-subunit in skeletal muscle of cachectic cancer patients, which would lead to muscle atrophy through a depression in protein synthesis and an increase in degradation. Mice lacking the ubiquitin ligase MuRF1 are less susceptible to muscle wasting under amino acid deprivation. Expression of MuRF1 and atrogin-1 is increased by oxidative stress, whereas nitric oxide may protect against muscle atrophy. Levels of interleukin (IL)-6 correlate with cachexia and death due to an increase in tumour burden. Ghrelin analogues and melanocortin receptor antagonists increase food intake and may have a role in the treatment of cachexia. SUMMARY: These findings provide impetus for the development of new therapeutic agents. PMID: 19918173 [PubMed - indexed for MEDLINE] 1650. Curr Opin Lipidol. 2010 Feb;21(1):38-43. doi: 10.1097/MOL.0b013e3283346ccc. The distinction of metabolically 'healthy' from 'unhealthy' obese individuals. Blüher M(1). Author information: (1)Department of Medicine, University of Leipzig, Leipzig, Germany. bluma@medizin.uni-leipzig.de PURPOSE OF REVIEW: The prevalence and severity of obesity are dramatically increasing throughout the world. Obesity causes a decline in life expectancy due to its associated metabolic and cardiovascular comorbid disorders. Therefore, it will become more important to distinguish obese individuals at high risk for obesity-related metabolic diseases from those who are metabolically 'healthy'. This review focuses on recent evidence suggesting that normal adipose tissue function contributes to the healthy obese phenotype. RECENT FINDINGS: The majority of individuals with obesity develop insulin resistance, type 2 diabetes, dyslipidemia, gout, hypertension and cardiovascular disease. However, approximately 10-25% of obese individuals are metabolically healthy most likely due to preserved insulin sensitivity. Recent studies suggest that inflammation of visceral adipose tissue, ectopic fat deposition and adipose tissue dysfunction mediate insulin resistance in human obesity independently of total body fat mass. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity. SUMMARY: Recommendations for obesity treatment should distinguish the metabolically 'healthy' from 'unhealthy' obese phenotype to identify early the obese person who will benefit the most from losing weight. In addition, novel antiobesity treatment strategies targeting adipose tissue dysfunction are needed. PMID: 19915462 [PubMed - indexed for MEDLINE] 1651. Med Hypotheses. 2010 May;74(5):901-7. doi: 10.1016/j.mehy.2009.10.022. Epub 2009 Nov 12. Impact of oxygen availability on body weight management. Quintero P(1), Milagro FI, Campión J, Martínez JA. Author information: (1)Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, c/Irunlarrea 1, Pamplona, Spain. Obesity is nowadays a major public health problem. The World Health Organization reported that globally 400 million adults are obese, and the situation seems to raise in the future. Furthermore, obesity is a major risk factor for a number of chronic diseases such as type 2 diabetes, cardiovascular diseases and the metabolic syndrome. Interestingly, several studies have reported that appetite suppression and body weight loss are frequently observed at high altitude. This observation has opened some possibilities for losing weight under hypoxia or living in altitude. Nevertheless, the triggering mechanisms for the decrease in energy intake in hypoxic conditions still remain unclear as well as the impact on body mass components. On the other hand, obese subjects often present a chronic inflammatory state on the adipose tissue that might have a strong relationship with onset and development of obesity-related diseases. Thus, it has been consistently reported that adipose tissue of obese subjects is poorly oxygenated and that this hypoxia state is a new potential risk factor for the chronic inflammation in obesity. In this sense, oxygen therapy is a common technique used in current medicine for the treatment of several diseases, while animal studies have demonstrated that treatment with hyperoxia produces some beneficial effects in different diseases related with lack of oxygen in several organs. In this article, we review the role of oxygen availability in body weight homeostasis and hypothesize the possible applicability of hypoxia and hyperoxia for the treatment of obesity and related disorders. PMID: 19913361 [PubMed - indexed for MEDLINE] 1652. Plast Reconstr Surg. 2010 Jan;125(1):315-23. doi: 10.1097/PRS.0b013e3181c2a515. Transcutaneous lower eyelid blepharoplasty with orbitomalar suspension: retrospective review of 212 consecutive cases. Korn BS(1), Kikkawa DO, Cohen SR. Author information: (1)Division of Ophthalmic Plastic and Reconstructive Surgery and the Department of Ophthalmology, University of California San Diego, School of Medicine, La Jolla, Calif. 92093-0946, USA. bkorn@ucsd.edu BACKGROUND: Midfacial aging is associated with increased demarcation of the nasolabial, malar, and nasojugal folds; deflation of facial soft tissues and bones; and descent of the midface. The latter is primarily attributable to attenuation of the orbitomalar ligament. Traditional surgery of the lower eyelid and midface often requires removal of excess skin, orbicularis oculi muscle, and orbital fat, which can be complicated by postoperative lower eyelid malposition. The authors describe a novel adjunct to transcutaneous lower eyelid blepharoplasty that rejuvenates the lower eyelid and midface by reconstituting the orbitomalar ligament and minimizes the development of postoperative eyelid malposition. METHODS: This study was a retrospective, consecutive, nonrandomized, interventional case series. The authors reviewed the medical records of 212 consecutive patients who underwent transcutaneous lower eyelid blepharoplasty with orbitomalar suspension. The aesthetic outcome, patient satisfaction, and development of eyelid malposition were evaluated. RESULTS: Transcutaneous lower eyelid blepharoplasty with orbitomalar suspension resulted in improved lower eyelid dermatochalasis, contour, midfacial ptosis, and appearance of the nasojugal and malar folds. All patients reported satisfaction with the aesthetic outcome. One patient (0.5 percent) developed lower eyelid retraction requiring subsequent lower eyelid tightening. Three patients (1.4 percent) developed transient lagophthalmos from lower eyelid orbicularis paresis that resolved spontaneously. CONCLUSIONS: Transcutaneous lower eyelid blepharoplasty combined with orbitomalar suspension is a powerful technique that can be performed concomitantly with facial rejuvenative procedures. Orbitomalar suspension addresses midfacial ptosis by restoring the natural function of the orbitomalar ligament and minimizes the development of postoperative lower eyelid malposition. PMID: 19910859 [PubMed - indexed for MEDLINE] 1653. Reprod Biomed Online. 2009 Oct;19(4):552-63. Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment. Garruti G(1), Depalo R, Vita MG, Lorusso F, Giampetruzzi F, Damato AB, Giorgino F. Author information: (1)Department of Emergency and Organ Transplantation (DETO), Section of Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari Medical School, Bari, Italy. g.garruti@endo.uniba.it Erratum in Reprod Biomed Online. 2012 Sep.25(3):335. In the last few years, polycystic ovary syndrome (PCOS) has deserved major attention because it is linked to the same cluster of events that promote the metabolic syndrome. This review will point out the relationships between fat excess, insulin resistance and the metabolic syndrome. Adipocytes are actually considered as endocrine cells that synthesize and release molecules (adipokines) that play an endocrine/paracrine role, such as adiponectin, atrial natriuretic peptide, leptin, resistin, tumour necrosis factor alpha (TNFalpha). Metabolic syndrome is a chronic low-grade inflammatory condition in which adipokines play a major role. Isolated adipocytes from women with PCOS express higher mRNA concentrations of some adipokines involved in cardiovascular risk and insulin resistance. However, environmental factors and lifestyle play a major role in determining the appearance of the phenotypes of PCOS. In morbid obese women with PCOS, bariatric surgery decreases bodyweight and fat excess and reverses hyperandrogenism and sterility. In lean or overweight women with PCOS, changes in lifestyle in combination with drugs reducing visceral fat and insulin resistance reverse the symptoms and signs of PCOS. Promising treatments for PCOS seem to be insulin sensitizers such as metformin and glitazones. PMID: 19909598 [PubMed - indexed for MEDLINE] 1654. Endocr Regul. 2009 Oct;43(4):157-68. Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity. Stofkova A(1). Author information: (1)Department of Normal, Pathological, and Clinical Physiology, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. andrea.stofkava@lf3.cuni.cz There is a growing evidence that both overnutrition and undernutrition negatively interfere with immune system. The overnutrition has been found to increase susceptibility to the development of inflammatory or autoimmune diseases. On the other hand, starvation or malnutrition has been more associated with increased susceptibility to infections. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role as an endocrine organ which produces number of active peptides, called adipokines. The adipokines, leptin and adiponectin represent a critical link among nutritional status, metabolism and immunity. Leptin is primarily known as a satiety factor regulating body weight by suppression of appetite and stimulation of energy expenditure, and its serum levels and gene expression in adipocytes strongly correlate with proportion of body fat stores. On the other hand, leptin is a pro-inflammatory adipokine inducing T helper 1 cells and may contribute to the development and progression of autoimmune responses. Adiponectin plays an important role as an insulin-sensitizing adipokine which production is decreased in obesity and in conditions associated with insulin resistance. Adiponectin also acts as an anti-inflammatory factor especially with regard to atherosclerosis, but in some chronic inflammatory/autoimmune diseases adiponectin may have pro-inflammatory effects and its production correlates with inflammatory markers and disease activity. This review discusses the main biological activities of leptin and adiponectin as well as their contribution to inflammatory and autoimmune processes with particular focus on rheumatoid arthritis and its experimental models. PMID: 19908934 [PubMed - indexed for MEDLINE] 1655. Am J Clin Nutr. 2010 Jan;91(1):258S-261S. doi: 10.3945/ajcn.2009.28449C. Epub 2009 Nov 11. Adiponectin in insulin resistance: lessons from translational research. Ziemke F(1), Mantzoros CS. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Adiponectin is an adipose tissue-secreted endogenous insulin sensitizer, which plays a key role as a mediator of peroxisome proliferator-activated receptor gamma action. Adiponectin alters glucose metabolism and insulin sensitivity, exhibits antiinflammatory and antiatherogenic properties, and has been linked to several malignancies. Circulating concentrations of adiponectin are determined primarily by genetic factors, nutrition, exercise, and abdominal adiposity. Adiponectin concentrations are lower in subjects with obesity, metabolic syndrome, and cardiovascular disease. Adiponectin knockout mice manifest glucose intolerance, insulin resistance, and hyperlipidemia and tend to develop malignancies especially when on high-fat diets. Animal studies have also shown beneficial effects of adiponectin in rodents in vivo. Circulating concentrations of adiponectin are lower in patients with diabetes, cardiovascular disease, and several malignancies. Studies to date provide promising results for the diagnostic and therapeutic role of adiponectin in obesity, insulin resistance, diabetes, cardiovascular disease, and obesity-associated malignancies. PMCID: PMC2793112 PMID: 19906806 [PubMed - indexed for MEDLINE] 1656. Am J Clin Nutr. 2010 Jan;91(1):254S-257S. doi: 10.3945/ajcn.2009.28449B. Epub 2009 Nov 11. Fibroblast growth factor 21: from pharmacology to physiology. Kliewer SA(1), Mangelsdorf DJ. Author information: (1)Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 73590-9041, USA. steven.kliewer@utsouthwestern.edu Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. Pharmacologic studies show that FGF21 has broad metabolic actions in obese rodents and primates that include enhancing insulin sensitivity, decreasing triglyceride concentrations, and causing weight loss. In lean rodents, FGF21 expression is strongly induced in liver by prolonged fasting through a mechanism that involves the nuclear receptor peroxisome proliferator-activated receptor alpha. FGF21, in turn, induces the transcriptional coactivator protein peroxisome proliferator-activated receptor gamma coactivator protein 1alpha and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor. Thus, FGF21 plays a key role in eliciting and coordinating the adaptive starvation response. Interestingly, FGF21 expression is induced in white adipose tissue by peroxisome proliferator-activated receptor gamma, which suggests that it also regulates metabolism in the fed state. This article highlights recent advances in our understanding of FGF21's pharmacologic and physiologic actions. PMCID: PMC2793111 PMID: 19906798 [PubMed - indexed for MEDLINE] 1657. Diabetes Care. 2009 Nov;32 Suppl 2:S362-7. doi: 10.2337/dc09-S340. Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin. Esteve E(1), Ricart W, Fernández-Real JM. Author information: (1)Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute of Girona, CIBEROBN Fisiopatología de la Obesidad y Nutrición, Girona, Spain. PMCID: PMC2811453 PMID: 19875582 [PubMed - indexed for MEDLINE] 1658. Diabetes Care. 2009 Nov;32 Suppl 2:S168-73. doi: 10.2337/dc09-S304. Viewpoints on the way to the consensus session: where does insulin resistance start? The adipose tissue. Iozzo P(1). Author information: (1)Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy. patricia.iozzo@ifc.cnr.it PMCID: PMC2811447 PMID: 19875546 [PubMed - indexed for MEDLINE] 1659. Pediatr Nephrol. 2010 Apr;25(4):705-9. doi: 10.1007/s00467-009-1334-3. Epub 2009 Nov 10. Effects of GH in human muscle and fat. Jørgensen JO(1), Rubeck KZ, Nielsen TS, Clasen BF, Vendelboe M, Hafstrøm TK, Madsen M, Lund S. Author information: (1)Medical Department M, Aarhus University Hospital, DK-8000 C Aarhus, Denmark. joj@ki.au.dk Skeletal muscle is the major constituent of lean body mass and a major determinant of energy expenditure both at rest and during physical activity. Growth hormone, in turn, influences muscle mass as well as energy expenditure. Growth hormone substitution in adults increases muscle mass by 5-10%, but part of the effect is attributed to rehydration rather than protein accretion. In addition, GH regulates substrate metabolism in muscle and in particular antagonizes insulin-stimulated glucose disposal. This effect is linked to increased free fatty acid (FFA) flux but the molecular mechanisms remain unclear. During fasting, GH-induced insulin resistance may be favorable by reducing the demand of gluconeogenesis from protein. But in the postprandial phase, GH exposure may compromise glucose tolerance via the same mechanisms. Understanding the mechanisms whereby GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes. PMID: 19902270 [PubMed - indexed for MEDLINE] 1660. Expert Rev Cardiovasc Ther. 2009 Nov;7(11):1429-45. doi: 10.1586/erc.09.123. Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for 'sick fat' and metabolic disease. Bays HE(1). Author information: (1)Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville KY 40213, USA. hbaysmd@aol.com Agonists of 5-hydroxytryptamine (5-HT; serotonin) receptors promote loss of excessive body fat (adiposity) and improve metabolic parameters associated with adiposity-induced adipose tissue dysfunction (adiposopathy or 'sick fat'). By improving adipose tissue pathogenic endocrine and immune responses in overweight patients, 5-HT receptor agonists may improve metabolic disease. Lorcaserin (APD-356) is a selective 5-HT2c receptor agonist that promotes weight loss. Probably owing to its selectivity for the 5-HT2c receptor, clinical trial evidence supports that lorcaserin does not adversely affect heart valves or pulmonary artery pressure. This review examines: the mechanisms by which serotonergic pathways improve adiposity and adiposopathy; historical data and perspective regarding the efficacy and safety of prior 5-HT agonists; speculation regarding future paradigms in treating adiposopathy; and why lorcaserin may prove to be a safe and generally well-tolerated agent that not only improves the weight of patients, but also improves the health of patients. PMID: 19900026 [PubMed - indexed for MEDLINE] 1661. Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):523-31. doi: 10.1016/j.cytogfr.2009.10.019. Epub 2009 Nov 6. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Schulz TJ(1), Tseng YH. Author information: (1)Joslin Diabetes Center, One Joslin Place, and Harvard Medical School, Boston, MA 02215, USA. Bone morphogenetic proteins (BMPs) regulate many processes in embryonic development as well as in the maintenance of normal tissue function later in adult life. However, the role of this family of proteins in formation of adipose tissue has been underappreciated in the field of developmental biology. With the growing epidemic of obesity, improved knowledge of adipocyte development and function is urgently needed. Recently, there have been significant advances in understanding the role of different members of the BMP superfamily in control of adipocyte differentiation and systemic energy homeostasis. This review summarizes recent progress in understanding how BMPs specify adipose cell fate in stem/progenitor cells and their potential role in energy metabolism. We propose that BMPs provide instructive signals for adipose cell fate determination and regulate adipocyte function. These findings have opened up exciting opportunities for developing new therapeutic approaches for the treatment of obesity and its many associated metabolic disorders. PMCID: PMC2799934 PMID: 19896888 [PubMed - indexed for MEDLINE] 1662. Int J Cardiol. 2010 Jun 11;141(3):214-21. doi: 10.1016/j.ijcard.2009.09.548. Epub 2009 Nov 6. Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation? Ribeiro F(1), Alves AJ, Duarte JA, Oliveira J. Author information: (1)Faculty of Sport, University of Porto, Research Centre in Physical Activity, Health and Leisure, Porto, Portugal. fernando.silva.ribeiro@gmail.com There is an increasing evidence that endothelial dysfunction and vascular wall inflammation are present in all stages of atherosclerosis. Atherosclerosis does not have to necessarily progress to an acute clinical event. Several therapeutic strategies exist, such as exercise training, which mitigates endothelial dysfunction and inflammation. Exercise training consistently improves the nitric oxide bioavailability, and the number of endothelial progenitor cells, and also diminishes the level of inflammatory markers, namely pro-inflammatory cytokines and C-reactive protein. However, the mechanisms by which exercise improves endothelial function in coronary artery disease patients are not fully clarified. Several mechanisms have been proposed to explain the positive effect of exercise on the disease progression. They include the decrease in cytokine production by the adipose tissue, skeletal muscles, endothelial cells, and blood mononuclear cells, and also, the increase in the bioavailability of nitric oxide, antioxidant defences, and regenerative capacity of endothelium. This study aims to provide a critical review of the literature linking exercise, inflammation, and endothelial dysfunction in coronary artery patients, and to discuss the potential mechanisms behind the exercise-training improvement of endothelial function and inflammatory status. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 19896741 [PubMed - indexed for MEDLINE] 1663. Cell Stem Cell. 2009 Nov 6;5(5):472-81. doi: 10.1016/j.stem.2009.10.014. Fighting fat with fat: the expanding field of adipose stem cells. Zeve D(1), Tang W, Graff J. Author information: (1)Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, 75390-9133, USA. We are in the midst of a dire, unprecedented, and global epidemic of obesity and secondary sequelae, most prominently diabetes and hyperlipidemia. Underlying this epidemic is the most hated of cells, adipocytes, and their inherent dynamic ability to expand and renew. This capacity highlights a heretofore undefined stem compartment. Recent in vivo studies, relying upon lineage tracing and flow cytometry methods, have begun to unravel the identity of adipose stem cells, their niche, and the dynamism central to adipose expansion. Thus, the field is moving in a direction that may allow us to manipulate adipose stem cells to beneficial therapeutic ends. PMCID: PMC2876189 PMID: 19896439 [PubMed - indexed for MEDLINE] 1664. Postgrad Med J. 2009 Nov;85(1009):614-21. doi: 10.1136/pgmj.2008.078014. The metabolic syndrome: common origins of a multifactorial disorder. Bruce KD(1), Byrne CD. Author information: (1)Endocrinology and Metabolism Unit, DOHaD Division, Institute of Developmental Sciences, Southampton General Hospital, Southampton, UK. The metabolic syndrome (MetS) represents a combination of cardiometabolic risk determinants including obesity (central adiposity), insulin resistance, glucose intolerance, dyslipidaemia, non-alcoholic fatty liver disease and hypertension. MetS is rapidly increasing in prevalence worldwide as a consequence of the continued obesity "epidemic", and as a result will have a considerable impact on the global incidence of cardiovascular disease and type 2 diabetes. Currently, there is debate concerning whether the risk of cardiovascular disease is greater in patients diagnosed with MetS than that of the sum of the individual risk factors. At present, no unifying origin that can explain the pathogenesis of MetS has been identified and therefore no unique pharmacological treatment is available. This review summarises and critically evaluates the current clinical and scientific evidence supporting the existence of MetS as a multifactorial endocrine disease, for which maternal nutrition may be a common pathogenic mechanism. In addition, we suggest that ectopic fat accumulation (such as visceral and hepatic fat accumulation) and the proinflammatory state are central to the development of the MetS. PMID: 19892897 [PubMed - indexed for MEDLINE] 1665. J Drugs Dermatol. 2009 Oct;8(10 Suppl):s5-14. Using poly-L-lactic acid (PLLA) to mimic volume in multiple tissue layers. Fitzgerald R(1), Vleggaar D. Author information: (1)David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Fitzmd@earthlink.net Sculptra (Sanofi-Aventis, Bridgewater, NJ) was approved by the U.S. Food Drug Administration (FDA) for use in HIV-related lipoatrophy in 2004 and received FDA approval for cosmetic use as Sculptra Aesthetic in July 2009. The authors have experience with this product in both applications. The purpose of this article is to share their methodology. Both soft-tissue and supraperiosteal injections will be illustrated and discussed in detail. Much progress has been made in the last decade in understanding of volume changes in all structural layers of the face, and this will be briefly reviewed as it is pertinent to the methodology. Equally important is the issue of patient selection. Ultimately, the quality of the result, and the time and amount of product that it takes to achieve that result, is contingent on the quality of tissues with which one starts. A very lipoatrophic patient, or an elderly patient with advanced volume loss and poor skin integrity is more difficult to correct-requiring more product and more treatment sessions (with any product) than that needed for a younger or plumper face. PMID: 19891116 [PubMed - indexed for MEDLINE] 1666. Differentiation. 2010 Feb;79(2):65-73. doi: 10.1016/j.diff.2009.10.002. Epub 2009 Nov 1. Commitment of stem cells into functional hepatocytes. Ochiya T(1), Yamamoto Y, Banas A. Author information: (1)National Cancer Center Research Institute, Tsukiji, Chuoku, Tokyo, Japan. tochiya@ncc.go.jp Liver transplants represent the only way to treat patients suffering from terminal liver failure, but they are associated with numerous problems, including a chronic shortage of donors, high cost, rejection, and side effects for the donor. It is anticipated that regenerative medicine will provide an alternative to liver transplants for such patients. Regenerative medicine refers to the academic field of eliciting the inherent capacity of organisms for self-regeneration to the greatest possible extent in order to develop new methods of treatment for intractable disorders. From this perspective, much is expected from the use of human embryonic stem cells (ES cells) or induced pluripotent stem cells (iPS cells), and the vigorous development of technology to induce the differentiation of such stem cells into cells possessing hepatic functions is underway. Clinical applications of these human stem cells, however, have yet to reach even the earliest stages of implementation. Facing off against these versatile ES cells are stem cells derived from somatic cells present within organisms, which are attracting attention owing to their superiority in terms of ethics and safety, with many research institutes now in the process of elucidating the details of stem cell separation and identification as well as their plasticity and pluripotency. Bone marrow cells are the best-known somatic-cell-derived stem cells, but the use of mesenchymal stem cells (MSCs) found in adipose tissue has also recently attracted attention. This paper will review the differentiation ability and mechanisms of these various stem cell types to hepatocytes and their application to liver regeneration and the future outlook. 2009 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. PMID: 19883970 [PubMed - indexed for MEDLINE] 1667. J Appl Physiol (1985). 2010 Jan;108(1):206-11. doi: 10.1152/japplphysiol.00694.2009. Epub 2009 Oct 29. Physiology of obesity and effects on lung function. Salome CM(1), King GG, Berend N. Author information: (1)Woolcock Institute of Medical Research, P.O. Box M77, Missenden Rd. NSW 2050, Australia. cms@woolcock.org.au Comment in J Appl Physiol (1985). 2010 Jan;108(1):197-8. In obese people, the presence of adipose tissue around the rib cage and abdomen and in the visceral cavity loads the chest wall and reduces functional residual capacity (FRC). The reduction in FRC and in expiratory reserve volume is detectable, even at a modest increase in weight. However, obesity has little direct effect on airway caliber. Spirometric variables decrease in proportion to lung volumes, but are rarely below the normal range, even in the extremely obese, while reductions in expiratory flows and increases in airway resistance are largely normalized by adjusting for lung volumes. Nevertheless, the reduction in FRC has consequences for other aspects of lung function. A low FRC increases the risk of both expiratory flow limitation and airway closure. Marked reductions in expiratory reserve volume may lead to abnormalities in ventilation distribution, with closure of airways in the dependent zones of the lung and ventilation perfusion inequalities. Greater airway closure during tidal breathing is associated with lower arterial oxygen saturation in some subjects, even though lung CO-diffusing capacity is normal or increased in the obese. Bronchoconstriction has the potential to enhance the effects of obesity on airway closure and thus on ventilation distribution. Thus obesity has effects on lung function that can reduce respiratory well-being, even in the absence of specific respiratory disease, and may also exaggerate the effects of existing airway disease. PMID: 19875713 [PubMed - indexed for MEDLINE] 1668. J Appl Physiol (1985). 2010 Mar;108(3):735-43. doi: 10.1152/japplphysiol.00749.2009. Epub 2009 Oct 29. Obesity, airway hyperresponsiveness, and inflammation. Shore SA(1). Author information: (1)Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA. sshore@hsph.harvard.edu Epidemiological data indicate that obesity is a risk factor for asthma, but the mechanistic basis for this relationship is not established. Here we review data from human subjects and animal models investigating the relationship between obesity and airway hyperresponsiveness, a characteristic feature of asthma. We discuss obesity as a state of chronic systemic inflammation resulting from interactions between adipocytes and adipose tissue macrophages that are recruited to obese adipose tissue. Finally, we focus on the possibility that aspects of this inflammation, particularly obesity-related changes in TNF-alpha, leptin, and adiponectin, may contribute to airway hyperresponsiveness in obesity. Determining how obesity promotes asthma may uncover novel therapeutic strategies that are effective in the obese asthmatic subject. PMCID: PMC2838631 PMID: 19875711 [PubMed - indexed for MEDLINE] 1669. J Appl Physiol (1985). 2010 Mar;108(3):722-8. doi: 10.1152/japplphysiol.00781.2009. Epub 2009 Oct 29. Obesity and lung inflammation. Mancuso P(1). Author information: (1)Department of Environmental Health Sciences, School of Public Health, SPH IA Tower, 109 S. Observatory St., Ann Arbor, MI 48109-2029, USA. pmancuso@umich.edu The prevalence of obesity has increased dramatically worldwide, predisposing individuals to an increased risk of morbidity and mortality due to cardiovascular disease and type 2 diabetes. Less recognized is the fact that obesity may play a significant role in the pathogenesis of pulmonary diseases through mechanisms that may involve proinflammatory mediators produced in adipose tissue that contribute to a low-grade state of systemic inflammation. In animal models, inflammatory responses in the lung have been shown to influence the production of the adipocytokines, leptin and adiponectin, cytokines, acute phase proteins, and other mediators produced by adipose tissue that may participate in immune responses of the lung. An increased adipose tissue mass may also influence susceptibility to pulmonary infections, enhance pulmonary inflammation associated with environmental exposures, and exacerbate airway obstruction in preexisting lung disease. An increased understanding of the mechanisms by which obesity influences pulmonary inflammation may facilitate the development of novel therapeutic interventions for the treatment of lung disease. PMCID: PMC2838639 PMID: 19875709 [PubMed - indexed for MEDLINE] 1670. Adv Med Sci. 2009;54(2):150-7. doi: 10.2478/v10039-009-0035-2. Role of adipokines in complications related to obesity: a review. Gnacińska M(1), Małgorzewicz S, Stojek M, Łysiak-Szydłowska W, Sworczak K. Author information: (1)Department of Endocrinology and Internal Medicine, Medical University of Gdansk, Poland. Worldwide, the prevalence of overweight and obesity and associated complications is increasing. Cardiovascular complications are the most important factor determining survival and influencing clinical management. However, obesity is also associated with an increased risk of metabolic syndrome, type 2 diabetes, cancer and other diseases. The development of complications depends on the amount of body fat and its endocrine function. The hormones (leptin, adiponectin, resistin) and cytokines (TNF alpha, IL-6, PAI-1) produced by the adipose tissue are the link between obesity and obesity-related complications. The present article discusses the structure, function and clinical significance of adipokines. PMID: 19875356 [PubMed - indexed for MEDLINE] 1671. Endocr Rev. 2010 Feb;31(1):25-51. doi: 10.1210/er.2009-0003. Epub 2009 Oct 27. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Pagel-Langenickel I(1), Bao J, Pang L, Sack MN. Author information: (1)Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1454, USA. Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM. PMCID: PMC2852205 PMID: 19861693 [PubMed - indexed for MEDLINE] 1672. Obes Rev. 2009 Nov;10 Suppl 2:52-60. doi: 10.1111/j.1467-789X.2009.00665.x. Adipose tissue, adipocytes and the circadian timing system. Johnston JD(1), Frost G, Otway DT. Author information: (1)Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK. j.johnston@surrey.ac.uk Circadian clocks time the daily occurrence of multiple aspects of behaviour and physiology. Through studies of chronic misalignment between our internal clocks and the environment (e.g. during shift work), it has long been postulated that disruption of circadian rhythms is detrimental to human health. Recent advances in understanding of the cellular and molecular basis of mammalian circadian timing mechanisms have identified many key genes involved in circadian rhythm generation and demonstrated the presence of clocks throughout the body. Furthermore, clear links between sleep, circadian rhythms and metabolic function have been revealed, and much current research is studying these links in more detail. Here, we review the evidence linking circadian rhythms, clock genes and adipose biology. We also highlight gaps in our understanding and finally suggest avenues for future research. PMID: 19849802 [PubMed - indexed for MEDLINE] 1673. Obes Rev. 2009 Nov;10 Suppl 2:46-51. doi: 10.1111/j.1467-789X.2009.00661.x. Delta sleep-inducing peptide and glucocorticoid-induced leucine zipper: potential links between circadian mechanisms and obesity? Gimble JM(1), Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi XM, Floyd ZE. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu As the obesity pandemic has accelerated, investigators have begun to explore alternative mechanisms linking circadian biology and sleep to adipose tissue metabolism and obesity. This manuscript reviews recent findings in murine and human models demonstrating the oscillatory expression of the mRNAs encoding the core circadian regulatory proteins in adipose tissue. Comparative transcriptomic analyses of circadian oscillating genes have been used to identify the 'delta sleep-inducing peptide immunoreactor', also known as 'glucocorticoid-induced leucine zipper (GILZ)', as a potential link in this chain. The GILZ gene has been found to differentially regulate stromal stem cell adipogenic and osteogenic differentiation in a reciprocal manner. In adipose and other metabolically active tissues, the circadian oscillation of GILZ expression is subject to entrainment by external stimuli. Together, these observations suggest that GILZ is an attractive candidate for future studies evaluating the role of circadian mechanisms in adipose tissue physiology and pathology. PMID: 19849801 [PubMed - indexed for MEDLINE] 1674. Obes Rev. 2009 Nov;10 Suppl 2:25-36. doi: 10.1111/j.1467-789X.2009.00660.x. The regulation of central and peripheral circadian clocks in humans. Cermakian N(1), Boivin DB. Author information: (1)Laboratory of Molecular Chronobiology, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada. nicolas.cermakian@mcgill.ca Many circadian rhythms are controlled by the central clock of the suprachiasmatic nucleus of the hypothalamus, as well as clocks located in other brain regions and most peripheral tissues. These central and peripheral clocks are based on clock genes and their protein products. In recent years, the expression of clock genes has started to be investigated in human samples, primarily white blood cells, but also skin, oral mucosa, colon cells, adipose tissue as well as post-mortem brain tissue. The expression of clock genes in those peripheral tissues offers a way to monitor human peripheral clocks and to compare their function and regulation with those of the central clock, which is followed by markers such as melatonin, cortisol and core body temperature. We have recently used such an approach to compare central and peripheral rhythms in subjects under different lighting conditions. In particular, we have monitored the entrainment of the clock of blood cells in subjects undergoing a simulated night shift protocol with bright light treatment, known to efficiently reset the central clock. This line of research will be helpful for learning more about the human circadian system and to find ways to alleviate health problems of shift workers, and other populations experiencing altered circadian rhythms. PMID: 19849799 [PubMed - indexed for MEDLINE] 1675. Obes Rev. 2009 Nov;10 Suppl 2:14-24. doi: 10.1111/j.1467-789X.2009.00662.x. The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin-3 receptors? Begriche K(1), Sutton GM, Fang J, Butler AA. Author information: (1)Department of Metabolism and Aging, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA. Obesity, insulin resistance and increased propensity for type 2 diabetes and cardiovascular disease result from an imbalance between energy intake and expenditure. The cloning of genes involved in energy homeostasis produced a simple feedback model for the homeostatic regulation of adipose mass. Serum leptin secreted from adipocytes signals nutrient sufficiency, curbing appetite and supporting energy expenditure. A rapid decline in leptin during nutrient scarcity instigates adaptive mechanisms, including increased appetite and reduced energy expenditure. Hypothalamic melanocortin neurons are important mediators of this response, integrating inputs of energy status from leptin with other peripheral signals. While this feedback response prolongs survival during fasting, other mechanisms allowing the prediction of nutrient availability also confer a selective advantage. This adaptation has been commonly studied in rodents using restricted feeding paradigms constraining food intake to limited periods at 24-h intervals. Restricted feeding rapidly elicits rhythmic bouts of activity and wakefulness anticipating food presentation. While the response exhibits features suggesting a clock-like mechanism, the neuromolecular mechanisms governing expression of food anticipatory behaviours are poorly understood. Here we discuss a model whereby melanocortin neurons regulating the homeostatic adaptation to variable caloric availability also regulate inputs into neural networks governing anticipatory rhythms in wakefulness, activity and metabolism. PMID: 19849798 [PubMed - indexed for MEDLINE] 1676. Nat Rev Endocrinol. 2009 Dec;5(12):673-81. doi: 10.1038/nrendo.2009.212. Epub 2009 Oct 27. Testosterone deficiency, insulin resistance and the metabolic syndrome. Zitzmann M(1). Author information: (1)Center of Reproductive Medicine and Andrology, WHO Collaboration Center for Male Reproduction, Münster, Germany. michael.zitzmann@ukmuenster.de Changing lifestyles and an excess of food supply in developed countries have resulted in an increasing prevalence of overweight and obesity. As a consequence, a disorder of complex pathophysiology involving visceral adipose tissue as an endocrine organ, dyslipidemia, insulin resistance and hypertension has emerged-the so-called metabolic syndrome. This disorder can lead to the manifestation of type 2 diabetes mellitus and cardiovascular disease. In men, testosterone deficiency may contribute to the development of the metabolic syndrome. In turn, states of hyperinsulinemia and obesity lead to a reduction of testicular testosterone production. Testosterone has reciprocal effects on the generation of muscle and visceral adipose tissue by influencing the commitment of pluripotent stem cells and by inhibiting the development of preadipocytes. Insulin sensitivity of muscle cells is increased by augmenting mitochondrial capacity and fostering expression of oxidative phosphorylation genes. Testosterone has a protective effect on pancreatic beta cells, which is possibly exerted by androgen-receptor-mediated mechanisms and influence of inflammatory cytokines. As some, but not all, epidemiological and interventional studies indicate, testosterone substitution might be helpful in preventing or attenuating the metabolic syndrome in aging men with late-onset hypogonadism and in hypogonadal patients with type 2 diabetes mellitus, but larger controlled trials are needed to confirm such hypotheses. PMID: 19859074 [PubMed - indexed for MEDLINE] 1677. Panminerva Med. 2009 Sep;51(3):175-85. Metabolic consequences of peritoneal dialysis treatment. Gallieni M(1), Musetti C, Granata A, Olivi L, Bertoli S. Author information: (1)Department of Nephrology and Dialysis, A.O. San Paolo, D.M.C.O. University of Milan, Italy. Energy and protein metabolism are both altered in chronic kidney disease (CKD) from its early stages. Patients undergoing peritoneal dialysis (PD) use peritoneal solutions with glucose as osmotic agent, which exposes them to an increased glucose load (40-80 g/day) and during PD there is a net loss of proteins through the peritoneum (4-8 g/day). Insulin resistance may lead to a reduction of the anabolic effects of insulin, while its proliferative effects on adipose tissue are potentially enhanced. Insulin resistance is also an important factor in the development of hypertriglyceridemia in PD patients: it increases free fatty acid availability, which then stimulates the release of large triglyceride-rich VLDL. Moreover, inhibitors of lipolytic enzymes (apoC-III, inflammation, oxidative modification and carbamoylation of apolipoproteins) may reduce lipid clearance, contributing to the development of dyslipidemia. Inflammatory molecules also play an important role in regulating glucose metabolism, and the excessive activation of inflammatory pathways may represent a fundamental step in the development of insulin resistance, including an over-expression of cytokines. Frequently, protein intake is reduced in PD because of under-dialysis, glucose load, abdominal discomfort and abnormal hormones levels, leading to a complex "protein-energy malnutrition". Optimization of dialysis dose, correction of acidosis and anemia and nutritional counseling, together with "non-traditional" management strategies, such as the use of PD solutions without glucose, like icodextrin and amino acid based solutions, represent the best strategies to prevent and correct malnutrition in PD patients. The mainstay of therapy is a reduction of glucose-based PD solutions and a correct dietary prescription. PMID: 19859052 [PubMed - indexed for MEDLINE] 1678. Exp Clin Endocrinol Diabetes. 2010 Jul;118(7):427-33. doi: 10.1055/s-0029-1233448. Epub 2009 Oct 23. Obesity: a complex growing challenge. Pataky Z(1), Bobbioni-Harsch E, Golay A. Author information: (1)Service of Therapeutic Education for Chronic Diseases, WHO Collaborating Centre, Department of Community Medicine, University Hospitals of Geneva, Geneva, Switzerland. zoltan.pataky@hcuge.ch The prevalence of overweight and obesity is increasing worldwide. The physiological mechanisms involved in body weight regulation are complex and incompletely understood. Increasing evidence suggests that obesity is a multifactorial disease where many, if not all, organs of the body are involved. The adipose tissue was considered as a simple fat accumulation for a long period of time. However, nowadays it is fascinating to progressively discover its involvement in hormonal, inflammatory or immune system dysregulation. Adipokines and cytokines are involved in control and regulation of appetite and energy balance, glucose and lipid metabolism, neuroendocrine function, reproduction, immunity, and cardiovascular function. The inflammatory background associated with obesity is closely related to insulin resistance. Moreover, the inhibitory effect of endocannabinoids on the expression of adiponectin could be involved in insulin resistance. Gut microbiota related factor may be responsible for the development of diet-induced obesity and diabetes through metabolic endotoxemia which triggers the inflammatory tone. Based on recent research, several physiopathological mechanisms involved in the development of obesity are reviewed. J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart, New York. PMID: 19856250 [PubMed - indexed for MEDLINE] 1679. Curr Opin Endocrinol Diabetes Obes. 2010 Feb;17(1):51-6. doi: 10.1097/MED.0b013e32833327dd. Gastrointestinal regulatory peptides and their effects on fat tissue. Majumdar ID(1), Weber HC. Author information: (1)Section of Gastroenterology, Boston University School of Medicine, Boston, Massachusetts 02118-2518, USA. PURPOSE OF REVIEW: Regulation of body weight, food intake and appetite is complex and the gastrointestinal tract represents a central organ participating in the regulation of energy homeostasis by signaling to other tissues relevant in this context. This update will provide information regarding recent advances in the understanding of the interaction of gastrointestinal peptides with adipocytes in fat tissue and which biological effects they may exert. RECENT FINDINGS: Several gastrointestinal peptides signal to their functional cognate receptors on adipocytes in white adipose tissue (WAT) thereby regulating glucose homeostasis, lipogenesis, lipolysis, free fatty acid release and may also participate in adipocyte differentiation. SUMMARY: Gastrointestinal peptides emanate from enteroendocrine cells in the luminal digestive tract and are critical regulators of energy homeostasis, food intake and appetite. Recent studies have identified that gastrointestinal peptides communicate with WAT and exert their biological effects on fat cells. Fundamental understanding of gastrointestinal peptides and their interaction with adipocytes will provide future insights for the development of pharmacological targets in the treatment of obesity and insulin resistant states. PMID: 19855273 [PubMed - indexed for MEDLINE] 1680. Endocr Rev. 2010 Feb;31(1):1-24. doi: 10.1210/er.2009-0014. Epub 2009 Oct 23. Metabolism and circadian rhythms--implications for obesity. Froy O(1). Author information: (1)Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel. froy@agri.huji.ac.il Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Human homeostatic systems have adapted to daily changes in light and dark in a way that the body anticipates the sleep and activity periods. Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei of the anterior hypothalamus that responds to the environmental light-dark cycle. Similar clocks have been found in peripheral tissues, such as the liver, intestine, and adipose tissue, regulating cellular and physiological functions. The circadian clock has been reported to regulate metabolism and energy homeostasis in the liver and other peripheral tissues. This is achieved by mediating the expression and/or activity of certain metabolic enzymes and transport systems. In return, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. In addition, the core clock mechanism has been shown to be linked with lipogenic and adipogenic pathways. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence for the relationship between the circadian clock and metabolic homeostasis. In addition, clinical studies in shift workers and obese patients accentuate the link between the circadian clock and metabolism. This review will focus on the interconnection between the circadian clock and metabolism, with implications for obesity and how the circadian clock is influenced by hormones, nutrients, and timed meals. PMID: 19854863 [PubMed - indexed for MEDLINE] 1681. Curr Atheroscler Rep. 2009 Nov;11(6):423-33. Trans-fatty acids and nonlipid risk factors. Wallace SK(1), Mozaffarian D. Author information: (1)Department of Epidemiology, Harvard School of Public Health, Division of Cardiovascular Medicine and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Building 2-315, Boston, MA 02115, USA. Consumption of industrially produced trans-fatty acids (TFA) is associated with substantial risk of coronary heart disease (CHD). The magnitude of this relationship, as well as emerging associations with end points such as diabetes and sudden cardiac death, cannot be fully explained by the well-established adverse effects of TFA on serum lipids. We review the evidence for effects of TFA intake on nonlipid risk factors. Based on evidence from randomized controlled trials, observational studies, animal experiments, and in vitro studies, these include effects on systemic inflammation, endothelial dysfunction, visceral adiposity, insulin resistance, and arrhythmic risk. The types and strength of evidence for each of these nonlipid effects varies, but the overall constellation of findings is qualitatively and quantitatively unique among dietary fats. The multiple adverse effects and implicated pathways are consistent with the observed strong associations of TFA consumption with CHD risk. These nonlipid effects also explain why TFA consumption may adversely impact other non-CHD diseases and end points. PMID: 19852883 [PubMed - indexed for MEDLINE] 1682. Curr Opin Nephrol Hypertens. 2010 Jan;19(1):72-8. doi: 10.1097/MNH.0b013e328332fb49. Obesity hypertension: the emerging role of leptin in renal and cardiovascular dyshomeostasis. Kshatriya S(1), Reams GP, Spear RM, Freeman RH, Dietz JR, Villarreal D. Author information: (1)Department of Internal Medicine, SUNY Upstate Medical University and Veterans Affairs Medical Center, Syracuse, New York, USA. PURPOSE OF REVIEW: Adipose tissue is now considered to be an active physiologic system operating in concert with multiple other organs. Leptin is a peptide hormone that is primarily synthesized and secreted by adipose tissue whose principal action is the control of appetite and energy balance. However, current information suggests that leptin exerts pleiotropic effects on several organ systems. Herein, we review the potential role of leptin in cardiovascular and renal physiological conditions as well as pathophysiological situations including obesity and hypertension. RECENT FINDINGS: Increasing evidence suggests that leptin may function as a pressure and volume-regulating factor under conditions of health; however, in situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for adverse renal, vascular and cardiac remodeling. SUMMARY: Adipose tissue should be regarded as a potentially important mediator of cardiorenal physiology. Further research awaits the characterization of additional mechanisms of action of leptin, including its interface with other important endocrine and hemodynamic sodium-volume regulatory systems, in both health and disease, particularly in obesity and related comorbidities. This information could lead to the development of leptin analogues as well as leptin receptor blockers that given specific circumstances could optimize the beneficial actions of the hormone and minimize its deleterious effects. PMID: 19851106 [PubMed - indexed for MEDLINE] 1683. Obes Rev. 2010 Mar;11(3):185-201. doi: 10.1111/j.1467-789X.2009.00669.x. Epub 2009 Oct 21. Regulation of lipid metabolism by energy availability: a role for the central nervous system. Nogueiras R(1), López M, Diéguez C. Author information: (1)Department of Physiology, School of Medicine-Instituto de Investigación Sanitaria (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. ruben.nogueiras@usc.es The central nervous system (CNS) is crucial in the regulation of energy homeostasis. Many neuroanatomical studies have shown that the white adipose tissue (WAT) is innervated by the sympathetic nervous system, which plays a critical role in adipocyte lipid metabolism. Therefore, there are currently numerous reports indicating that signals from the CNS control the amount of fat by modulating the storage or oxidation of fatty acids. Importantly, some CNS pathways regulate adipocyte metabolism independently of food intake, suggesting that some signals possess alternative mechanisms to regulate energy homeostasis. In this review, we mainly focus on how neuronal circuits within the hypothalamus, such as leptin- ghrelin-and resistin-responsive neurons, as well as melanocortins, neuropeptide Y, and the cannabinoid system exert their actions on lipid metabolism in peripheral tissues such as WAT, liver or muscle. Dissecting the complicated interactions between peripheral signals and neuronal circuits regulating lipid metabolism might open new avenues for the development of new therapies preventing and treating obesity and its associated cardiometabolic sequelae. PMID: 19845870 [PubMed - indexed for MEDLINE] 1684. Obes Rev. 2010 Feb;11(2):118-26. doi: 10.1111/j.1467-789X.2009.00674.x. Epub 2009 Oct 21. Obesity and low-grade inflammation: a paediatric perspective. Tam CS(1), Clément K, Baur LA, Tordjman J. Author information: (1)Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, NSW, Australia. charmait@chw.edu.au Childhood obesity is a major public health problem. Low-grade inflammation, a hallmark characterizing adult obesity, may be a pivotal mechanism linking obesity to its numerous systemic complications, with adipose tissue depots secreting and producing inflammatory mediators and visceral fat displaying an increased inflammatory profile. While knowledge is relatively scarce regarding the importance of the adipose tissue inflammation process in children, identifying its contribution in childhood obesity and the associated influences of age, sex, weight status, growth, and adipose depot phenotypes are crucial for understanding physiopathology and implementing early intervention strategies. We review the latest research linking obesity and inflammation in childhood focusing on serum inflammatory markers and the effectiveness of lifestyle interventions in improving systemic inflammation. Generally, there are significant correlations between body mass index and increased c-reactive protein and decreased adiponectin levels in children; these levels tend to be improved in interventions resulting in approximately 5% weight loss, regardless of the type or length of intervention. There is a need for further research measuring other inflammatory mediators (e.g. tumour necrosis factor (TNF)-alpha, IL-6, IL-8) and histological studies examining immune cell infiltration in adipose tissue depots in obese children. PMID: 19845868 [PubMed - indexed for MEDLINE] 1685. Headache. 2010 Apr;50(4):631-48. doi: 10.1111/j.1526-4610.2009.01554.x. Epub 2009 Oct 21. Migraine and obesity: epidemiology, mechanisms, and implications. Peterlin BL(1), Rapoport AM, Kurth T. Author information: (1)Drexel University College of Medicine, Department of Neurology, Philadelphia, PA, USA. Comment in Headache. 2010 Apr;50(4):649. Adipose tissue is a dynamic neuroendocrine organ that is involved in multiple physiological and pathological processes, and when excessive, results in obesity. Clinical and population-based data suggest that migraine and chronic daily headache are associated with obesity, as estimated by anthropometric indices. In addition, translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. In this article, we first review the definition and ascertainment of obesity. This is followed by a review of the clinical and population-based studies evaluating the associations between obesity and chronic daily headache and migraine. We then discuss the central and peripheral pathways involved in the regulation of feeding, where it overlaps with migraine pathophysiology, and where future research may be headed in light of these data. PMCID: PMC3969571 PMID: 19845784 [PubMed - indexed for MEDLINE] 1686. Int J Biol Sci. 2009 Oct 1;5(6):622-36. Krüppel-like family of transcription factors: an emerging new frontier in fat biology. Brey CW(1), Nelder MP, Hailemariam T, Gaugler R, Hashmi S. Author information: (1)Center for Vector Biology, Rutgers University, New Brunswick, New Jersey 08901, USA. In mammals, adipose tissue stores energy in the form of fat. The ability to regulate fat storage is essential for the growth, development and reproduction of most animals, thus any abnormalities caused by excess fat accumulation can result in pathological conditions which are linked to several interrelated diseases, such as cardiovascular diseases, diabetes, and obesity. In recent years significant effort has been applied to understand basic mechanism of fat accumulation in mammalian system. Work in mouse has shown that the family of Krüppel-like factors (KLFs), a conserved and important class of transcription factors, regulates adipocyte differentiation in mammals. However, how fat storage is coordinated in response to positive and negative feedback signals is still poorly understood. To address mechanisms underlying fat storage we have studied two Caenorhabditis elegans KLFs and demonstrate that both worm klfs are key regulators of fat metabolism in C. elegans. These results provide the first in vivo evidence supporting essential regulatory roles for KLFs in fat metabolism in C. elegans and shed light on the human counterpart in disease-gene association. This finding allows us to pursue a more comprehensive approach to understand fat biology and provides an opportunity to learn about the cascade of events that regulate KLF activation, repression and interaction with other factors in exerting its biological function at an organismal level. In this review, we provide an overview of the most current information on the key regulatory components in fat biology, synthesize the diverse literature, pose new questions, and propose a new model organism for understanding fat biology using KLFs as the central theme. PMCID: PMC2757581 PMID: 19841733 [PubMed - indexed for MEDLINE] 1687. Nutr Clin Pract. 2009 Oct-Nov;24(5):560-77. doi: 10.1177/0884533609342436. The metabolic syndrome: definition, global impact, and pathophysiology. Potenza MV(1), Mechanick JI. Author information: (1)Mount Sinai Hospital, One Gustave L. Levy Place, New York, NY 10029, USA. doctor.potenza@gmail.com The metabolic syndrome (MS) is a cluster of metabolic derangements that are associated with primary disturbances in adipose tissue. Abnormal visceral fat accumulates from physical inactivity and excess calories in genetically susceptible individuals. This increased adipocyte mass acts as an endocrine organ and communicates with other organ systems via increases in inflammatory cytokines. The resulting disorders define MS as increased waist circumference, decreased serum high-density lipoprotein, and increased serum triglyceride levels, hypertension, and insulin resistance. MS accounts for the majority of cardiovascular disease risk in the U.S. population. Dietary interventions, such as the Mediterranean diet, have been shown to improve these metabolic derangements. Many substances found in these diets are being investigated as specific therapies for MS, and when scientific substantiation is lacking, they may be considered as part of complementary and alternative medicine (CAM). However, as scientific evidence accumulates, these CAM treatments may become part of conventional medicine. This review will scrutinize the emerging evidence behind many, though not all, CAM treatments currently thought to target the various derangements found in MS. PMID: 19841245 [PubMed - indexed for MEDLINE] 1688. CNS Neurol Disord Drug Targets. 2009 Dec;8(6):422-31. Signal transduction via cannabinoid receptors. Dalton GD(1), Bass CE, Van Horn CG, Howlett AC. Author information: (1)Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. The endocannabinoids anandamide and 2-arachidonoylglycerol are lipid mediators that signal via CB(1) and CB(2) cannabinoid receptors and Gi/o-proteins to inhibit adenylyl cyclase and stimulate mitogen-activated protein kinase. In the brain, CB(1) receptors interact with opioid receptors in close proximity, and these receptors may share G-proteins and effector systems. In the striatum, CB(1) receptors function in coordination with D(1) and D(2) dopamine receptors, and combined stimulation of CB(1)-D(2) receptor heteromeric complexes promotes a unique interaction to stimulate cAMP production. CB(1) receptors also trigger growth factor receptor signaling cascades in cells by engaging in cross-talk or interreceptor signal transmission with the receptor tyrosine kinase (RTK) family. Mechanisms for CB(1) receptor-RTK transactivation can include stimulation of signal transduction pathways regulated by second messengers such as phospholipase C, metalloprotease cleavage of membrane-bound precursor proteins such as epidermal growth factor which activate RTKs, RTK autophosphorylation, and recruitment of non-receptor tyrosine kinases. CB(1) and CB(2) receptors are expressed in peripheral tissues including liver and adipose tissue, and are induced in pathological conditions. Novel signal transduction resulting from endocannabinoid regulation of AMP-regulated kinase and peroxisome proliferator-activated receptors have been discovered from studies of hepatocytes and adipocytes. It can be predicted that drug discovery of the future will be based upon these novel signal transduction mechanisms for endocannabinoid mediators. PMCID: PMC3976677 PMID: 19839935 [PubMed - indexed for MEDLINE] 1689. J Clin Endocrinol Metab. 2009 Dec;94(12):4645-54. doi: 10.1210/jc.2009-1412. Epub 2009 Oct 16. 11Beta-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. Cooper MS(1), Stewart PM. Author information: (1)Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom B15 2TT. CONTEXT: 11Beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes are now appreciated to be important regulators of hormone action at a tissue level. 11Beta-HSD1 is widely expressed and increases glucocorticoid action through its unique ability to convert inactive glucocorticoids (cortisone in man, 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively). The enzyme has roles in the normal hypothalamus-pituitary-adrenal (HPA) axis, has been implicated in metabolic syndrome, and may modulate various aspects of the immune response. EVIDENCE ACQUISITION: A review of published, peer-reviewed medical literature (1990 to June 2009) on the physiology and pathophysiology of 11beta-HSD1 was performed with an emphasis on HPA axis consequences, the metabolic syndrome, and the inflammatory response. EVIDENCE SYNTHESIS: Studies of patients with genetic defects in 11beta-HSD1 action show abnormal HPA axis responses with hyperandrogenism being a major consequence. The mechanisms underlying these abnormalities have been explored in mouse models with targeted deletion of components of the 11beta-HSD1 system. A range of experimental studies emphasize the role of 11beta-HSD1 in the metabolic syndrome and the potential for treatment with chemical inhibitors. An emerging area is the role of 11beta-HSD1 in the inflammatory response. CONCLUSIONS: 11Beta-HSD1 activity is an important component of the HPA axis and contributes to the metabolic syndrome and the normal immune response. Ongoing clinical observations and the development of selective inhibitors will further clarify the role of 11beta-HSD1 in these areas. PMID: 19837912 [PubMed - indexed for MEDLINE] 1690. Nutr Res Rev. 2009 Dec;22(2):163-74. doi: 10.1017/S0954422409990126. Molecular mechanisms triggered by low-calcium diets. Centeno V(1), de Barboza GD, Marchionatti A, Rodríguez V, Tolosa de Talamoni N. Author information: (1)Laboratorio de Metabolismo Fosfocálcico y Vitamina D Dr. F. Cañas, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Ca is not only essential for bone mineralisation, but also for regulation of extracellular and intracellular processes. When the Ca2+ intake is low, the efficiency of intestinal Ca2+ absorption and renal Ca2+ reabsorption is increased. This adaptive mechanism involves calcitriol enhancement via parathyroid hormone stimulation. Bone is also highly affected. Low Ca2+ intake is considered a risk factor for osteoporosis. Patients with renal lithiasis may be at higher risk of recurrence of stone formation when they have low Ca2+ intake. The role of dietary Ca2+ on the regulation of lipid metabolism and lipogenic genes in adipocytes might explain an inverse relationship between dairy intake and BMI. Dietary Ca2+ restriction produces impairment of the adipocyte apoptosis and dysregulation of glucocorticosteroid metabolism in the adipose tissue. An inverse relationship between hypertension and a low-Ca2+ diet has been described. Ca2+ facilitates weight loss and stimulates insulin sensitivity, which contributes to the decrease in the blood pressure. There is also evidence that dietary Ca2+ is associated with colorectal cancer. Dietary Ca2+ could alter the ratio of faecal bile acids, reducing the cytotoxicity of faecal water, or it could activate Ca2+-sensing receptors, triggering intracellular signalling pathways. Also it could bind luminal antigens, transporting them into mucosal mononuclear cells as a mechanism of immunosurveillance and promotion of tolerance. Data relative to nutritional Ca2+ and incidences of other human cancers are controversial. Health professionals should be aware of these nutritional complications and reinforce the dairy intakes to ensure the recommended Ca2+ requirements and prevent diseases. PMID: 19835652 [PubMed - indexed for MEDLINE] 1691. Adv Gerontol. 2009;22(1):129-38. [Metabolic abnormalities as a basis for age-dependent diseases and aging? State of the art]. [Article in Russian] Tereshina EV. Metabolic syndrome (MS) is a number of certain criteria reflecting abnormalities in lipid and glucose metabolism. These abnormalities are considered to be a reason for atherosclerosis, cardiovascular diseases (CVD) and diabetes mellitus type 2. The prevalence of CVD among those with diabetes is 3-5 folds higher than without diabetes. MS demonstrates ethnic and gender variants, its frequency depends on the lifestyle and age. Attention to MS has been attracted in the last decades induced by the obesity epidemic in US. The adipose tissue and high triglyceride blood levels have been regarded as hallmark of MS. It has appeared that metabolic ways of cholesterol, fat and glucose were tightly connected and united in a system of energy expenditure and reproduction. The high prevalence of MS, heart attacks and diabetes in the elderly population makes the evidence of age to be an independent risk factor of the development of metabolic abnormalities. But this problem is still out of the field of interest in gerontology. There exist a number of unsolved questions concerning the function of visceral adipose tissue, the role of free fatty acids in the insulin resistance, mechanisms of inflammation in the old age and so on that can be an object of gerontology. So, a program of advanced researches in this field is discussed. PMID: 19827683 [PubMed - indexed for MEDLINE] 1692. Vestn Ross Akad Med Nauk. 2009;(9):43-8. [The role of adipokines in the development of obesity]. [Article in Russian] Goncharov NP. This review summarizes the most important results of numerous publications in which fat tissue is regarded not only as an accumulator and source of energy but also as a metabolic "machine". Its hormonal mechanisms serve to maintain remote functional links with other organs and systems including CNS. Much attention is given to metabolism of steroid hormones in the fat tissue. Differences in biosynthesis of cytokines and other hormones in visceral and subcutaneous fat tissue are emphasized. PMID: 19827642 [PubMed - indexed for MEDLINE] 1693. Curr Opin Support Palliat Care. 2009 Dec;3(4):288-93. doi: 10.1097/SPC.0b013e328331c897. Zinc-alpha2-glycoprotein in cachexia and obesity. Tisdale MJ(1). Author information: (1)Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. m.j.tisdale@aston.ac.uk PURPOSE OF REVIEW: Control of adipose mass is important in the treatment of both cachexia and obesity. This review focuses on a novel adipokine, zinc-alpha2-glycoprotein (ZAG), which plays an important role in the mobilization and utilization of stored lipids. RECENT FINDINGS: An increased lipolysis is responsible for the loss of adipose tissue in cachexia, through an increased lipolytic response to catecholamines, arising from an increased expression of hormone-sensitive lipase. In obesity, there is a decreased response of adipocytes to catecholamines and reduced expression of hormone-sensitive lipase. ZAG was identified as a lipolytic factor produced by certain cachexia-inducing tumours, and subsequently adipose tissue (both white and brown), the expression of which was found to increase in cachexia. In contrast, ZAG expression is low in obesity. ZAG not only increases lipolysis in white adipose tissue through the classical cyclic AMP pathway, but also stimulates an increase in expression of uncoupling protein-1 in brown adipose tissue, which would stimulate utilization of the release lipid to generate heat. Homozygous ZAG null mice show an increase in body weight, especially when fed a high-fat diet, whereas adipocytes from such animals show a resistance to lipolysis by catecholamines and agents that increase cyclic AMP levels. SUMMARY: These results suggest that ZAG may play an important role in the regulation of adipose mass in obesity and cachexia. PMID: 19823091 [PubMed - indexed for MEDLINE] 1694. Curr Opin Nephrol Hypertens. 2010 Jan;19(1):37-42. doi: 10.1097/MNH.0b013e328332fc2b. The emerging pleiotrophic role of adipokines in the uremic phenotype. Carrero JJ(1), Cordeiro AC, Lindholm B, Stenvinkel P. Author information: (1)Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. juan.jesus.carrero@ki.se PURPOSE OF REVIEW: The obesity epidemic is undoubtedly increasing the total end-stage renal disease population, which has a larger proportion of obese individuals on reaching the dialysis stage. This review discusses recent advances in the pathophysiology of adipose tissue and adipokines that may contribute to increased risk of progression towards end-stage renal disease and cardiovascular damage. RECENT FINDINGS: Although leptin effects on blood pressure may negatively affect kidney function, leptin may also induce vascular damage through central and direct effects on both vessels and heart. The contradictory results of adiponectin in uremia are possibly confounded by the disease circumstances. Visfatin may have previously unrecognized roles in angiogenesis and nutrient homeostasis. As visfatin is a ubiquitously expressed enzyme, it may be inaccurate to refer to it as an adipokine. SUMMARY: We still face many unknowns when understanding the putative pleiotrophic effects that adipokines exert in the uremic milieu. Mechanistic and interventional studies are needed to move forward in this area. Conflicting results in patients with ESRD, in whom both beneficial and detrimental effects in uremia outcome are found, are perhaps the consequence of different timing or context-sensitive effects. Specifically, the presence of protein energy wasting and the changing pattern of disease risk may hinder or even reverse the natural action of these molecules. PMID: 19823084 [PubMed - indexed for MEDLINE] 1695. Environ Int. 2010 Jan;36(1):122-30. doi: 10.1016/j.envint.2009.08.005. Epub 2009 Oct 8. Hexachlorobenzene sources, levels and human exposure in the environment of China. Wang G(1), Lu Y, Han J, Luo W, Shi Y, Wang T, Sun Y. Author information: (1)Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. This article summarizes the published scientific data on sources, levels and human exposure of hexachlorobenzene (HCB) in China. Potential sources of unintended HCB emission were assessed by production information, emission factors and environmental policies. HCB was observed in various environmental compartments in China. HCB levels increased from South China to North China in most of environmental compartments (air, soil and mussel). Some hotspots were identified near the factories producing and using HCB. In terms of spatial distribution, HCB concentrations in air and shellfish showed much variation, which indicated some primary emission sources in China. HCB levels in air and human milk in China were relatively higher than those in other countries, but HCB levels in other compartments were similar to those in Europe and other countries in Eastern Asia. In the limited studies on temporal trends of HCB levels in China, HCB concentrations in air, sediment, fish and human milk did not show a consistent downward trend. Although HCB levels in food and human milk does not pose a health risk in China at present, long-term exposure to HCB should not be overlooked. PMID: 19818502 [PubMed - indexed for MEDLINE] 1696. Mol Cell Endocrinol. 2010 Mar 25;316(2):172-9. doi: 10.1016/j.mce.2009.09.026. Epub 2009 Oct 7. Ovarian function and obesity--interrelationship, impact on women's reproductive lifespan and treatment options. Rachoń D(1), Teede H. Author information: (1)Department of Clinical Nutrition, Medical University of Gdańsk, Gdańsk, Poland. drachon@gumed.edu.pl Insulin resistance (IR) is a consequence of obesity, and in women it is often inextricably linked with ovarian function leading to clinical reproductive manifestations such as early menarche onset, subfertility and polycystic ovary syndrome (PCOS). Likewise, the dramatic fall in oestrogen production after menopause may contribute to weight gain and changes in adipose tissue distribution. Overall, women who are obese, especially those with reproductive complications including PCOS, have been identified as specific high risk subgroups for further progression through to prediabetes, type 2 diabetes mellitus (T2DM) and potentially cardiovascular disease (CVD). This review focuses on the interrelationship between the ovarian function and obesity as well as its treatment strategies. 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 19818376 [PubMed - indexed for MEDLINE] 1697. Clin Liver Dis. 2009 Nov;13(4):545-63. doi: 10.1016/j.cld.2009.07.009. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Cusi K(1). Author information: (1)Diabetes Division, The University of Texas Health Science Center at San Antonio, Room 3.380S, 7703 Floyd Curl Drive, San Antonio, TX 78284-3900, USA. cusi@uthscsa.edu It is well established that the development of NAFLD and NASH are closely linked to an excess flow of free fatty acids (FFA) arising from dysfunctional/insulin resistant adipose tissue causing ectopic fat deposition in many organs. In the liver, when chronic lipid supply surpasses the metabolic ability to adapt it will induce hepatocellular damage as FFA are redirected into harmful pathways of non-oxidative metabolism with intracellular accumulation of toxic lipid-derived metabolites. Multiple mechanisms have been implicated including mitochondrial dysfunction, endoplasmic reticulum stress, and activation of multiple inflammatory pathways. Understanding the role of insulin resistance and lipotoxicity in NASH as part of a broader metabolic disorder is likely to assist practitioners in the successful management of these challenging patients. PMID: 19818304 [PubMed - indexed for MEDLINE] 1698. Diabetes Metab. 2010 Feb;36(1):11-20. doi: 10.1016/j.diabet.2009.09.001. Epub 2009 Oct 7. Fetal origins of insulin resistance and the metabolic syndrome: a key role for adipose tissue? Meas T(1). Author information: (1)U690 INSERM, hôpital Robert-Debré, 48, boulevard Sérurier, Paris, France. talyphilip@free.fr For several years now, the epidemiological data have shown an inverse relationship between birth-weight and the development in later life of cardiovascular disease and metabolic disorders. The term "small for gestational age" (SGA) describes a neonate whose birth-weight is two standard deviations (SD) below the reference mean, corrected for gestational age and gender. SGA is associated with increased risks of developing hypertension, insulin resistance and type2 diabetes. However, the association with an atherogenic lipid profile is less clear. Nevertheless, all of the components of the metabolic syndrome are present. Yet, in spite of the large body of data in the literature, the biological mechanisms underlying this association are still unclear. To explain the association, various hypotheses have been proposed, pointing to the role of a detrimental fetal environment or genetic susceptibility, or interaction between the two, and to the particular dynamic changes in adiposity that occur during catch-up growth. However, not only quantitative, but also qualitative, abnormalities of adipose tissue have been observed, suggesting a critical role of this organ in the development of metabolic complications. Copyright (c) 2009 Elsevier Masson SAS. All rights reserved. PMID: 19815442 [PubMed - indexed for MEDLINE] 1699. Circulation. 2009 Oct 20;120(16):1640-5. doi: 10.1161/CIRCULATIONAHA.109.192644. Epub 2009 Oct 5. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Comment in Int J Cardiol. 2013 Oct 3;168(3):2954-5. A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used. PMID: 19805654 [PubMed - indexed for MEDLINE] 1700. Mol Cell Endocrinol. 2010 Mar 25;316(2):154-64. doi: 10.1016/j.mce.2009.09.024. Epub 2009 Oct 3. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Morton NM(1). Author information: (1)Molecular Metabolism Group after University of Edinburgh, Centre for Cardiovascular Sciences, Edinburgh, United Kingdom. nik.morton@ed.ac.uk The metabolic abnormalities found associated with high blood glucocorticoid levels (e.g. rare Cushing's syndrome) include insulin-resistance, visceral obesity, hypertension, dyslipidaemia and an increased risk of cardiovascular diseases. The same constellation of abnormalities is found in the highly prevalent idiopathic obesity/insulin-resistance (metabolic)-syndrome. It is now apparent that tissue-specific changes in cortisol metabolism explain these parallels rather than altered blood cortisol levels. Primary among these changes is increased intracellular glucocorticoid reactivation, catalysed by the enzyme 11beta-hydroxysteroid dehydrogenase type (HSD)-1 in obese adipose tissue. Liver, skeletal muscle, endocrine pancreas, blood vessels and leukocytes express 11beta-HSD1 and their potential role in metabolic disease is discussed. The weight of evidence, much of it gained from animal models, suggests that therapeutic inhibition of 11beta-HSD1 will be beneficial in most cellular contexts, with clinical trials supportive of this concept. 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 19804814 [PubMed - indexed for MEDLINE] 1701. Future Cardiol. 2008 Sep;4(5):481-94. doi: 10.2217/14796678.4.5.481. Mesenchymal stromal cell and mononuclear cell therapy in heart disease. Haack-Sorensen M(1), Friis T, Kastrup J. Author information: (1)Rigshospitalet University Hospital, Cardiac Stem Cell Laboratory, The Heart Centre, Copenhagen, Denmark. mandana.haack-sorensen@rh.regionh.dk Despite progress in percutaneous coronary intervention, bypass surgery and drug therapy, rates of mortality and morbidity after acute coronary syndrome are high due to ventricular remodeling and heart failure. Mesenchymal stromal cells (MSCs) from adult bone marrow or adipose tissue are considered potential candidates for therapeutic regenerative treatment in cardiovascular disease. Recent animal studies have demonstrated that MSCs can induce neovascularization and improve myocardial function in postinfarction myocardial ischemic hearts. This review will focus on the present preclinical and clinical knowledge about the use of mononuclear cells and MSCs for cardiac regenerative medicine, the source of MSCs for clinical use and problems to consider when conducting clinical MSC therapy. PMID: 19804342 [PubMed] 1702. Trends Endocrinol Metab. 2009 Dec;20(10):499-505. doi: 10.1016/j.tem.2009.07.002. Epub 2009 Oct 2. Actions of IGF binding proteins and related proteins in adipose tissue. Baxter RC(1), Twigg SM. Author information: (1)Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards NSW 2065, Australia. robaxter@med.usyd.edu.au The insulin-like growth factors (IGFs), their binding proteins (IGFBPs) and structurally related proteins have been identified in adipose tissue but their roles in adipose tissue are poorly understood. IGF-I and IGFBP-3 expression increase during human preadipocyte differentiation. However, whereas IGF-I stimulates this process, IGFBP-3 is inhibitory both to preadipocyte differentiation and to differentiated adipocyte function. The direct interaction of IGFBP-3 with peroxisome proliferator-activated receptor-gamma is believed to contribute to its inhibitory effect on differentiation. Connective tissue growth factor (CTGF/CCN2) shares weak structural homology and functional similarities with IGFBP-3, including inhibition of preadipocyte differentiation. This review examines the current knowledge of IGFBP regulation and actions in adipocytes and proposes a common regulatory pathway involving IGFBP-3 and CTGF/CCN2. PMID: 19801194 [PubMed - indexed for MEDLINE] 1703. Growth Horm IGF Res. 2010 Feb;20(1):1-7. doi: 10.1016/j.ghir.2009.09.002. Epub 2009 Oct 1. Biological effects of growth hormone on carbohydrate and lipid metabolism. Vijayakumar A(1), Novosyadlyy R, Wu Y, Yakar S, LeRoith D. Author information: (1)Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. This review will summarize the metabolic effects of growth hormone (GH) on the adipose tissue, liver, and skeletal muscle with focus on lipid and carbohydrate metabolism. The metabolic effects of GH predominantly involve the stimulation of lipolysis in the adipose tissue resulting in an increased flux of free fatty acids (FFAs) into the circulation. In the muscle and liver, GH stimulates triglyceride (TG) uptake, by enhancing lipoprotein lipase (LPL) expression, and its subsequent storage. The effects of GH on carbohydrate metabolism are more complicated and may be mediated indirectly via the antagonism of insulin action. Furthermore, GH has a net anabolic effect on protein metabolism although the molecular mechanisms of its actions are not completely understood. The major questions that still remain to be answered are (i) What are the molecular mechanisms by which GH regulates substrate metabolism? (ii) Does GH affect substrate metabolism directly or indirectly via IGF-1 or antagonism of insulin action? Copyright 2009 Elsevier Ltd. All rights reserved. PMCID: PMC2815161 PMID: 19800274 [PubMed - indexed for MEDLINE] 1704. Trends Endocrinol Metab. 2009 Nov;20(9):444-51. doi: 10.1016/j.tem.2009.05.006. Epub 2009 Sep 30. Mineralocorticoid receptors in the metabolic syndrome. Zennaro MC(1), Caprio M, Fève B. Author information: (1)INSERM, U970, Paris Cardiovascular Research Center - PARCC, 75015 Paris, France. maria-christina.zennaro@inserm.fr The mineralocorticoid receptor (MR) mediates aldosterone effects on salt homeostasis and blood pressure regulation. MR activation also promotes inflammation, cardiovascular remodelling and endothelial dysfunction, and affects adipose tissue differentiation and function. Some of these effects derive from MR activation by glucocorticoids. Recent epidemiological studies show that the incidence of metabolic syndrome increases across quartiles of aldosterone, implicating the MR as a central player in metabolic homeostasis, involving electrolyte, water and energy balance. This review summarizes the current understanding of MR-mediated effects in diverse tissues and the role of aldosterone as a cardiometabolic risk factor, and discusses the possible relationship between inappropriate MR activation (by both mineralocorticoids and glucocorticoids) and the development of metabolic syndrome. PMID: 19800255 [PubMed - indexed for MEDLINE] 1705. Trends Endocrinol Metab. 2009 Nov;20(9):452-9. doi: 10.1016/j.tem.2009.05.007. Epub 2009 Sep 30. Meta-regulation: microRNA regulation of glucose and lipid metabolism. Lynn FC(1). Author information: (1)Department of Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada. fclynn@interchange.ubc.ca Maintenance of homeostasis during environmental flux requires constant metabolic adjustment, achieved partly through the fine regulation of gene expression. MicroRNAs are key players in this regulatory milieu; they have been implicated in regulating gene expression within several metabolically active tissues including the endocrine pancreas, liver and adipose tissue. Recent studies, for example, implicate miR-375 in pancreatic islet cell viability and function, and removal or overexpression of miR-375 profoundly affects glucose metabolism. In the liver, miR-122 is important for normal lipid metabolism. In fact, misexpression of miRNAs can occur in some diseases, suggesting that restoring miRNA expression is a potential therapeutic approach for both metabolic syndrome and diabetes. PMID: 19800254 [PubMed - indexed for MEDLINE] 1706. Biochim Biophys Acta. 2010 Mar;1801(3):392-9. doi: 10.1016/j.bbalip.2009.09.018. Epub 2009 Sep 30. Drug-induced lipotoxicity: lipodystrophy associated with HIV-1 infection and antiretroviral treatment. Villarroya F(1), Domingo P, Giralt M. Author information: (1)Department of Biochemistry and Molecular Biology and Institute of Biomedicine of the University of Barcelona (IBUB), and Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. fvillarroya@ub.edu A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy. Copyright (c) 2009 Elsevier B.V. All rights reserved. PMID: 19800025 [PubMed - indexed for MEDLINE] 1707. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):44-53. doi: 10.1016/j.mce.2009.09.022. Epub 2009 Sep 30. Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes. Teo CF(1), Wollaston-Hayden EE, Wells L. Author information: (1)Complex Carbohydrate Research Center and Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA. Excess flux through the hexosamine biosynthesis pathway in adipocytes is a fundamental cause of "glucose toxicity" and the development of insulin resistance that leads to type II diabetes. Adipose tissue-specific elevation in hexosamine flux in animal models recapitulates whole-body insulin-resistant phenotypes, and increased hexosamine flux in adipocyte cell culture models impairs insulin-stimulated glucose uptake. Many studies have been devoted to unveiling the molecular mechanisms in adipocytes in response to excess hexosamine flux-mediated insulin resistance. As a major downstream event consuming and incorporating the final product of the hexosamine biosynthesis pathway, dynamic and inducible O-GlcNAc modification is emerging as a modulator of insulin sensitivity in adipocytes. Given that O-GlcNAc is implicated in both insulin-mediated signal transduction and transcriptional events essential for adipocytokine secretion, direct functional studies to pinpoint the roles of O-GlcNAc in the development of insulin resistance via excess flux through hexosamine biosynthesis pathway are needed. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC2855202 PMID: 19799964 [PubMed - indexed for MEDLINE] 1708. J Cell Mol Med. 2010 Jan;14(1-2):135-42. doi: 10.1111/j.1582-4934.2009.00915.x. Epub 2009 Oct 3. Stem cells for stress urinary incontinence: the adipose promise. Roche R(1), Festy F, Fritel X. Author information: (1)LBGM, Laboratoire de Biochimie et de Génétique Moléculaire, Université de l'île de la Réunion, Saint-Denis Messag Cedex, France. regis.roche@adipsculpt.com Stress urinary incontinence (SUI), the most common type of incontinence in women, is a frequent and costly ailment responsible for an alteration in the quality of life. Although medical treatment gives some rather deceiving results, surgical techniques that include colposuspension or tension-free vaginal tape, employed in cases of urethral support defect, give a 5-year cure rate of more than 80%. However, these techniques could lead to complications or recurrence of symptoms. Recently, the initiation of urethral cell therapy has been undertaken by doctors and researchers. One principal source of autologous adult stem cells is generally used: muscle precursor cells (MPCs) which are the progenitors of skeletal muscle cells. Recently, a few research groups have shown interest in the MPCs and their potential for the treatment of urinary incontinence. However, using MPCs or fibroblasts isolated from a striated muscle biopsy could be questionable on several points. One of them is the in vitro cultivation of cells, which raises issues over the potential cost of the technique. Besides, numerous studies have shown the multipotent or even the pluripotent nature of stromal vascular fraction (SVF) or adipose-derived stem cells (ASCs) from adipose tissue. These cells are capable of acquiring in vitro many different phenotypes. Furthermore, recent animal studies have highlighted the potential interest of SVF cells or ASCs in cell therapy, in particular for mesodermal tissue repair and revascularization. Moreover, the potential interest of SVF cells or ASCs for the treatment of urinary incontinence in women is supported by many other characteristics of these cells that are discussed here. Because access to these cells via lipoaspiration is simple, and because they are found in very large numbers in adipose tissue, their future potential as a stem cell reservoir for use in urethral or other types of cell therapy is enormous. PMCID: PMC3837591 PMID: 19799652 [PubMed - indexed for MEDLINE] 1709. Trends Endocrinol Metab. 2009 Nov;20(9):418-23. doi: 10.1016/j.tem.2009.06.003. Epub 2009 Sep 30. Adipose tissue expandability and the early origins of PCOS. de Zegher F(1), Lopez-Bermejo A, Ibáñez L. Author information: (1)Department of Woman & Child, University of Leuven, Belgium. Francis.deZegher@uzleuven.be The most prevalent phenotypes of polycystic ovary syndrome (PCOS) are characterized by insulin resistance and androgen excess. The adipose tissue (AT) expandability hypothesis explains the development of insulin resistance in obesity and in cases of AT deficit. In line with this hypothesis, we propose that hyperinsulinemic androgen excess in PCOS is often underpinned by exhaustion of the capacity to expand subcutaneous AT in a metabolically safe way. Such exhaustion might occur when a positive energy imbalance meets a normal fat-storage capacity and/or when a normal energy balance faces a low fat storage capacity. This concept thus explains how PCOS phenotypes might result from obesity, prenatal growth restraint or a genetic lipodystrophy, or, experimentally, from prenatal androgen excess. PMID: 19796964 [PubMed - indexed for MEDLINE] 1710. Trends Endocrinol Metab. 2009 Nov;20(9):424-8. doi: 10.1016/j.tem.2009.06.002. Epub 2009 Sep 30. The skinny on fat: lipolysis and fatty acid utilization in adipocytes. Ahmadian M(1), Duncan RE, Sul HS. Author information: (1)Department of Nutritional Science and Toxicology, University of California, Berkeley, California 9472, USA. Lipolysis for the provision of fatty acids (FA) for other organs during times of energy demand occurs uniquely in white adipose tissue (WAT). Recent findings have identified a bona fide TAG hydrolase and the major adipose phospholipase A(2), AdPLA. By controlling PGE(2) levels, AdPLA dominantly regulates lipolysis in an autocrine/paracrine manner. Moreover, recent findings demonstrate that, surprisingly, increasing lipolysis in adipose tissue does not necessarily increase serum FA levels, which are usually correlated with insulin resistance. Rather, increasing lipolysis in adipose tissue causes a shift within adipocytes towards increased FA utilization and energy expenditure and thus protects against obesity. Here, we discuss the regulation of lipolysis and its effects on FA utilization within WAT and on insulin resistance. PMCID: PMC2764815 PMID: 19796963 [PubMed - indexed for MEDLINE] 1711. Nat Rev Endocrinol. 2009 Nov;5(11):604-10. doi: 10.1038/nrendo.2009.195. Epub 2009 Sep 29. Nutritional programming of the metabolic syndrome. Symonds ME(1), Sebert SP, Hyatt MA, Budge H. Author information: (1)Early Life Nutrition Research Unit, Academic Child Health, Division of Human Development, School of Clinical Sciences, University Hospital, Nottingham, UK. michael.symonds@nottingham.ac.uk The primary markers of the metabolic syndrome are central obesity, insulin resistance and hypertension. In this review, we consider the effect of changes in maternal nutrition during critical windows in fetal development on an individual's subsequent predisposition to the metabolic syndrome. The fetal origins of obesity, cardiovascular disease and insulin resistance have been investigated in a wide range of epidemiological and animal studies; these investigations highlight adaptations made by the nutritionally manipulated fetus that aim to maintain energy homeostasis to ensure survival. One consequence of such developmental plasticity may be a long term re-setting of cellular energy homeostasis, most probably via epigenetic modification of genes involved in a number of key regulatory pathways. For example, reduced maternal-fetal nutrition during early gestation to midgestation affects adipose tissue development and adiposity of the fetus by setting an increased number of adipocyte precursor cells. Importantly, clinically relevant adaptations to nutritional challenges in utero may only manifest as primary components of the metabolic syndrome if followed by a period of accelerated growth early in the postnatal period and/or if offspring become obese. PMID: 19786987 [PubMed - indexed for MEDLINE] 1712. Nutr Rev. 2009 Oct;67(10):559-72. doi: 10.1111/j.1753-4887.2009.00228.x. Impact of micronutrient deficiencies on obesity. García OP(1), Long KZ, Rosado JL. Author information: (1)School of Natural Sciences, Universidad Autónoma de Querétaro, Juriquilla, Mexico. opgarciao@yahoo.com.mx Micronutrient deficiencies have been found in obese individuals across age groups worldwide. While the effects of micronutrient deficiencies on human functions have been studied widely in different populations, there is limited information on how these micronutrient deficiencies affect obese populations. An examination of the available literature suggests associations exist between micronutrient deficiencies and obesity in different populations. These associations and possible mechanisms of the deficiencies' metabolic effects, such as their influence on leptin and insulin metabolism, are discussed here. Further studies are needed to clarify the roles of the different micronutrient deficiencies with respect to obesity and its comorbid conditions. PMID: 19785688 [PubMed - indexed for MEDLINE] 1713. Vnitr Lek. 2009 Sep;55(9):788-91. [Diabetes and vascular diabetic disease]. [Article in Slovak] Murín J(1), Yaghy M. Author information: (1)I. interná klinika Lekárskej fakulty UK Bratislava, Slovenská republika. murin@faneba.sk The prevalence of type 2 diabetes mellitus is growing. Vascular disease is here the main cause of morbidity and mortality, and accelerated atherosclerosis is responsible for about 80% of mortality and for about 75% of hospitalizations. In diabetics there is 2-4 times greater risk of ischemic heart disease in comparison to non-diabetics, and this risk is even greater in diabetic-females. Authors put greater attention to pathophysiology of diabetic vascular disease (inflammation and adipose tissue, metabolic and other--AGEs, ADMA--abnormalities, their contribution to endothelial dysfunction). The main concern is devoted to the treatment possibilities of diabetic vascular disease. PMID: 19785377 [PubMed - indexed for MEDLINE] 1714. Biochim Biophys Acta. 2010 Mar;1801(3):372-6. doi: 10.1016/j.bbalip.2009.09.008. Epub 2009 Sep 24. Recruitment of brown fat and conversion of white into brown adipocytes: strategies to fight the metabolic complications of obesity? Langin D(1). Author information: (1)Inserm U858, Laboratoire de recherches sur les obésités, Toulouse, F-31432, France. dominique.langin@inserm.fr The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications. Copyright (c) 2009 Elsevier B.V. All rights reserved. PMID: 19782764 [PubMed - indexed for MEDLINE] 1715. Arch Physiol Biochem. 2009 Oct;115(4):218-26. doi: 10.1080/13813450903260864. Human adipose tissue precursor cells: a new factor linking regulation of fat mass to obesity and type 2 diabetes? Perrini S(1), Cignarelli A, Ficarella R, Laviola L, Giorgino F. Author information: (1)Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari School of Medicine, Bari, Italy. The current epidemic of obesity has caused a surge of interest in the study of the mechanisms regulating adipose tissue formation. It has been observed that adipose tissue contains a pool of adult stem cells with multipotent properties, which provide for the physiological cell turnover, and can be isolated and potentially utilized for tissue engineering and regenerative medical applications. These "stromal" cells exhibit pre-adipocyte characteristics, can be isolated from adipose tissue of adult subjects, propagated in vitro, and induced to differentiate into adipocytes. Different populations of multi-potent precursor cells can be isolated from human fat fragments. Thus, adipose precursors cells are a heterogeneous cells population, consisting of fibroblast-like multi-potential stem cells generally termed adipose-derived stem cells (ASCs). In this review, we discuss some aspects of ASCs basic biology, the methodology involved in ASCs isolation and culture, and some implications of ASCs availability for the understanding of metabolic diseases in humans. PMID: 19780715 [PubMed - indexed for MEDLINE] 1716. Expert Opin Biol Ther. 2009 Dec;9(12):1499-508. doi: 10.1517/14712590903307362. Responses of adipose-derived stem cells during hypoxia: enhanced skin-regenerative potential. Chung HM(1), Won CH, Sung JH. Author information: (1)CHA Stem Cell Institute, Stem Cell Research Laboratory, Seoul, Republic of Korea. Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue (i.e., adipose-derived stem cells (ASCs)), have been used for tissue engineering. In addition to serving a building-block function, ASCs are reported to secrete growth factors that are essential for their function. Increasing evidence indicates that ASCs play a significant role in skin regeneration, a function that is enhanced by hypoxia through upregulating secretion of growth factors. Although the anatomical sites of ASCs in the body are relatively oxygen-deficient, ASCs are usually cultured under normoxic conditions (i.e., atmospheric oxygen levels). Culturing ASCs under physiologically relevant low-oxygen-tension conditions may uniquely benefit the expansion, differentiation, adhesion, growth factor secretion and regenerative potential of ASCs. Therefore, understanding the response and adaptation of ASCs to hypoxia may be invaluable for developing novel cell- and cyto-therapy strategies. This review highlights our current understanding of cellular and molecular responses of ASCs to hypoxia, focusing on the enhancement of ASC function and secretory activity by hypoxic culture conditions. PMID: 19780713 [PubMed - indexed for MEDLINE] 1717. Curr Opin Lipidol. 2009 Dec;20(6):477-83. doi: 10.1097/MOL.0b013e3283321d37. Thiazolidinediones and the liver in humans. Yki-Järvinen H(1). Author information: (1)Department of Medicine, University of Helsinki, Helsinki, Finland. ykijarvi@cc.helsinki.fi PURPOSE OF REVIEW: To review recent advances in the understanding of the mechanism of action of thiazolidinediones (TZDs) in humans. RECENT FINDINGS: The liver is characterized by excess fat accumulation due to nonalcoholic causes (non-alcoholic fatty liver disease) in most patients with the metabolic syndrome and type 2 diabetes. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis. Both of the commercially available antihyperglycemic TZD agonists, pioglitazone and rosiglitazone, are markedly effective in reducing liver fat content by 30-50% and sensitizing the liver to insulin. This reduces the amount of endogenous and exogenous insulin needed to inhibit hepatic glucose production. Decreases in liver fat are closely correlated with increases in serum adiponectin, which is an insulin-sensitizing adipokine produced exclusively by adipose tissue. Both TZDs are equally effective in reducing liver fat. Regarding lipid metabolism, enhanced hepatic insulin sensitivity would be predicted to lower VLDL and serum triglycerides and increase HDL-cholesterol. Pioglitazone and rosiglitazone have different effects on serum lipids, which cannot be attributed to simple insulin sensitization. Very recently, TZDs have been shown to reduce not only steatosis but possibly also hepatocellular damage in NASH. SUMMARY: Given the uncertainties in benefits of TZDs in reducing cardiovascular disease in type 2 diabetes, as well as other side-effects (heart failure, fractures), TZDs may in the future be increasingly used in patients with nonalcoholic steatohepatitis. PMID: 19779336 [PubMed - indexed for MEDLINE] 1718. Curr Opin Investig Drugs. 2009 Oct;10(10):1069-77. Antagonists of the renin-angiotensin system and the prevention of obesity. Weisinger RS(1), Begg DP, Jois M. Author information: (1)La Trobe University, School of Psychological Science, Bundoora, Victoria 3086, Australia. r.weisinger@latrobe.edu.au In addition to its role as an energy store, adipose tissue also acts as an endocrine organ, synthesizing and secreting hormones and cytokines. This review discusses angiotensin II (Ang-II), the biologically active component of the renin-angiotensin system (RAS). Evidence suggests that a functioning RAS is present in adipose tissue. Animal studies have demonstrated that modifying the amount of Ang-II in the body (eg, using RAS knockout/transgenic animal models or the pharmacological treatment of animal models to prevent the formation or action of Ang-II) directly influences body weight and adiposity. In humans, body fat is correlated with levels of angiotensinogen, a precursor of Ang-II. Thus, the treatment of obesity could be improved through the use of substances that interfere with Ang-II. PMID: 19777395 [PubMed - indexed for MEDLINE] 1719. Curr Opin Investig Drugs. 2009 Oct;10(10):1061-8. Adipokines: emerging therapeutic targets. Kos K(1), Wilding JP. Author information: (1)University Hospital Aintree, Diabetes and Endocrinology Research Unit, Longmoor Lane, Liverpool L9 7AL, UK. katarina.kos@pcmd.ac.uk Adipose tissue can affect human physiology through its secreted products, collectively termed adipokines, which mediate complex crosstalk between organs. Adipokines have been linked to a wide range of pathologies in many tissues; however, the pathophysiological significance of these cytokines remains poorly understood, and more research is needed in this area. Adipokines may have both beneficial and potentially harmful effects; for example, leptin reduces body weight, but also impairs immune responses. A cautious approach is therefore warranted when considering the pharmacological manipulation of adipokines to treat diseases, and novel approaches may be required to target specific organs or actions to reduce the potential for adverse effects. PMID: 19777394 [PubMed - indexed for MEDLINE] 1720. Proc Nutr Soc. 2009 Nov;68(4):401-7. doi: 10.1017/S0029665109990255. Epub 2009 Sep 24. Thermogenesis challenges the adipostat hypothesis for body-weight control. Cannon B(1), Nedergaard J. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. barbara.cannon@wgi.su.se According to the adipostat hypothesis for body-weight control, alterations in body weight should always be compensated by adequate alterations in food intake and thermogenesis. Thus, increased thermogenesis should not be able to counteract obesity because food intake would be increased. However evidence is presented here that thermogenesis in different forms (through artificial uncouplers, exercise, cold exposure) may counteract obesity and is not always fully compensated by increased food intake. Correspondingly, a decreased capacity for metaboloregulatory thermogenesis (i.e. non-functional brown adipose tissue) may in itself lead to obesity. This is evident in mice and may be valid for human subjects, as a substantial proportion of adults possess brown adipose tissue, and those with less or without brown adipose tissue would seem to be more prone to obesity. Thus, increased thermogenesis may counteract obesity, without dietary intervention. PMID: 19775494 [PubMed - indexed for MEDLINE] 1721. Dis Markers. 2009;26(5-6):247-63. doi: 10.3233/DMA-2009-0634. Use of obesity biomarkers in cardiovascular epidemiology. Pischon T(1). Author information: (1)Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. pischon@dife.de Obesity is an established risk factor for cardiovascular disease (CVD), yet, the underlying mechanisms are only poorly understood. The adipose tissue produces a variety of hormones and cytokines and thereby actively participates in a network of biomarkers that may be relevant for the development of CVD. Such obesity biomarkers have a great potential to better characterize the obesity phenotype that may be relevant for the risk of CVD beyond anthropometric parameters. They may be used to support mechanistic studies, to help identify individuals at risk for CVD, and to evaluate the effect of preventive measures. The present article discusses the role of some of the most promising obesity biomarkers in cardiovascular epidemiology, including inflammatory markers, adiponectin, resistin, and fetuin-A. Importantly, some of these markers have been related to cardiovascular risk even after accounting for anthropometric parameters. Further, the potential ability to manipulate blood levels of some of these biomarkers through medication, diet and lifestyle make them attractive markers for cardiovascular risk. However, many open questions remain--especially with regard to the causal role of the factors as well as with regard to the extent of improvement in CVD prediction by these markers--before measurement of these biomarkers may be recommended on a public health level. PMCID: PMC3833608 PMID: 19773614 [PubMed - indexed for MEDLINE] 1722. Nutr Res Rev. 2009 Dec;22(2):111-7. doi: 10.1017/S0954422409990084. Is the use of resveratrol in the treatment and prevention of obesity premature? van der Spuy WJ(1), Pretorius E. Author information: (1)Department of Anatomy, Faculty of Health Sciences, School of Medicine, University of Pretoria, Pretoria, South Africa. Obesity is a multi-faceted disease, predisposing sufferers to numerous co-morbidities such as epithelial dysfunction and insulin resistance which ultimately result in CVD. Visceral adipose tissue in particular is associated with inflammation due to the release of pro-inflammatory cytokines by adipocytes. Inflammation seems to be rather central in causing damage to endothelial cells as well as exerting negative effects on glucose metabolism, ultimately leading to insulin resistance. Resveratrol is a naturally occurring phenolic substance which has been found to display anti-inflammatory, vasoprotective and insulin-sensitising effects, among others. The popularity of resveratrol use is escalating in the treatment of various ailments including obesity in adults. The use of the substance in childhood obesity is, however, a worrying factor, as no studies have as yet been performed on adolescent animals and there is evidence of kidney toxicity of resveratrol and its metabolites at intake levels below those currently approved as safe. Another cause for concern is the uncertainty surrounding long-term, low-dose administration of the substance in humans. The supplement should thus not be recommended for use in the prevention and treatment of obesity until conclusive research is established on the safety of long-term usage of resveratrol in both children and adults. PMID: 19772694 [PubMed - indexed for MEDLINE] 1723. Curr Opin Lipidol. 2010 Feb;21(1):1-7. doi: 10.1097/MOL.0b013e328331dd21. Cardiorespiratory fitness and metabolic risk factors in obesity. Hamer M(1), O'Donovan G. Author information: (1)Department of Epidemiology and Public Health, University College London, London, UK. m.hamer@ucl.ac.uk PURPOSE OF REVIEW: An increase in cardiorespiratory fitness (CRF) through exercise training appears to partly ameliorate the health hazards of obesity and a number of mechanisms might explain the potential benefits. We review recent evidence about the relationships between CRF, exercise training and metabolic risk factors in obesity. RECENT FINDINGS: Epidemiological data have shown that the anti-inflammatory effects of exercise could be an important mechanism in explaining cardio-protective effects of physical activity. Emerging evidence suggests that exercise training reduces markers of inflammation and improves glucose control in obesity, independent of weight loss. Novel mechanisms appear to involve exercise-induced changes in CD14+CD16+ cell populations, expression of toll-like receptors, and key changes in the metabolic regulation of visceral white adipose tissue. Other promising recent research has focused on exercise-induced signalling pathways governing glucose metabolism, such as insulin receptor substrate and Akt substrate. Using novel imaging techniques, studies have demonstrated exercise-induced improvements in lipoprotein subfraction particle size, and reduction in visceral adipose tissue and liver fat, independent of weight loss. These effects appear to be mostly restricted to interventions consisting of relatively high doses of exercise or exercise combined with calorie restriction, although further work is required to elucidate the dose-response relationships. SUMMARY: Physical activity and the pursuit of physical fitness are important in the treatment of obesity because exercise training can improve a number of metabolic risk factors independent of weight loss. Thus exercise can provide important health benefits irrespective of weight loss in obese and overweight individuals. PMID: 19770655 [PubMed - indexed for MEDLINE] 1724. J Endocrinol. 2010 Feb;204(2):93-104. doi: 10.1677/JOE-09-0359. Epub 2009 Sep 21. PPAR control: it's SIRTainly as easy as PGC. Sugden MC(1), Caton PW, Holness MJ. Author information: (1)Centre for Diabetes, Queen Mary University of London, Blizard Institute of Cell and Molecular Science, St Bartholomew's and the Royal London School of Medicine and Dentistry, Whitechapel, London E1 2AT, UK. m.c.sugden@qmul.ac.uk This review describes recent advances in our knowledge of the regulatory interactions influencing the expression of peroxisome proliferator-activated receptor (PPAR)-regulated genes. We address recent advances highlighting the role of PPARgamma (PPARG) coactivator-1 (PGC-1) and lipin-1 in co-ordinating the expression of genes controlling nutrient handling. We evaluate the possibility that SIRT1 lies at the heart of a regulatory loop involving PPARalpha, PGC-1alpha (PPARA, PPARGC1A as given in the HUGO Database), and lipin-1 (LPIN1 as listed in the HUGO Database) that ultimately controls the metabolic response to varying nutrient and physiological signals via a common mechanism mediated by post-translation modifications (deacetylation) of both PPARalpha and PGC-1s. Finally, we comment on the potential of pharmaceutical manipulation of these targets as well as the possible problems associated with this strategy. PMID: 19770177 [PubMed - indexed for MEDLINE] 1725. Arq Bras Endocrinol Metabol. 2009 Jul;53(5):582-94. [Control of adipogenesis by fatty acids]. [Article in Portuguese] Queiroz JC(1), Alonso-Vale MI, Curi R, Lima FB. Author information: (1)Laboratório de Fisiologia Celular, Departamento de Fisiologia e Biofísica, ICB, USP, São Paulo, SP, Brasil. Obesity is one of the major Public Health problems. Obese individuals are more susceptible to develop cardiovascular diseases and type 2 diabetes mellitus. The obesity results from the increase in size and number of the adipocytes. The balance between adipogenesis and adiposity determines the degree of obesity. Mature adipocytes secrete adipokines, such as TNFalpha, IL-6, leptine and adiponectin, and lipokine, the palmitoleic acid omega-7. The production of adipokines is increased in obesity, contributing to the onset of peripheral insulin resistance. The knowledge about the molecular events that regulate the differentiation of pre-adipocytes and mesenchymal stem cells into adipocytes (adipogenesis) is important for the comprehension of the genesis of obesity. Activation of transcription factor PPARgamma plays an essential role in the adipogenesis. Certain fatty acids are PPARgamma ligands and can control adipogenesis. Moreover, some fatty acids act as signaling molecules regulating their differentiation into adipocytes or death. Accordingly, the lipid composition of the diet and PPARgamma agonists can regulate the balance between adipogenesis and death of adipocytes and, therefore, the obesity. PMID: 19768249 [PubMed - indexed for MEDLINE] 1726. Trans Am Clin Climatol Assoc. 2009;120:287-95. Do the obese have lower body temperatures? A new look at a forgotten variable in energy balance. Landsberg L(1), Young JB, Leonard WR, Linsenmeier RA, Turek FW. Author information: (1)Northwestern University Comprehensive Center on Obesity, 750 N. Lake Shore Drive, Rubloff Suite 9-976, Chicago, IL 60611, USA. l-landsberg@northwestern.edu Understanding the pathogenesis of obesity is now more important than ever, given the remarkable world-wide epidemic. This paper explores the potential role of core temperature in energy balance, and develops the hypothesis that basal temperature and changes in the temperature response in various situations contribute to the enhanced metabolic efficiency of the obese state. The argument is based on the important contribution that heat production makes in establishing the basal or resting metabolic rate, as well as on an analysis of the adaptive role played by changes in temperature in response to environmental challenge. If this hypothesis is validated, new therapeutic approaches may ensue. PMCID: PMC2744512 PMID: 19768183 [PubMed - indexed for MEDLINE] 1727. Appl Physiol Nutr Metab. 2009 Aug;34(4):571-81. doi: 10.1139/H09-066. Physical activity and abdominal obesity in youth. Kim Y(1), Lee S. Author information: (1)Department of Health and Physical Activity, University of Pittsburgh, Pittsburgh, PA 15260, USA. Childhood obesity continues to escalate despite considerable efforts to reverse the current trends. Childhood obesity is a leading public health concern because overweight-obese youth suffer from comorbidities such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, metabolic syndrome, and cardiovascular disease, conditions once considered limited to adults. This increasing prevalence of chronic health conditions in youth closely parallels the dramatic increase in obesity, in particular abdominal adiposity, in youth. Although mounting evidence in adults demonstrates the benefits of regular physical activity as a treatment strategy for abdominal obesity, the independent role of regular physical activity alone (e.g., without calorie restriction) on abdominal obesity, and in particular visceral fat, is largely unclear in youth. There is some evidence to suggest that, independent of sedentary activity levels (e.g., television watching or playing video games), engaging in higher-intensity physical activity is associated with a lower waist circumference and less visceral fat. Several randomized controlled studies have shown that aerobic types of exercise are protective against age-related increases in visceral adiposity in growing children and adolescents. However, evidence regarding the effect of resistance training alone as a strategy for the treatment of abdominal obesity is lacking and warrants further investigation. PMID: 19767790 [PubMed - indexed for MEDLINE] 1728. J Med Invest. 2009 Aug;56(3-4):88-92. Saturated fatty acids and insulin resistance. Funaki M(1). Author information: (1)Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan. Insulin resistance is one of the pathophysiological features of obesity and type 2 diabetes. Recent findings have linked insulin resistance to chronic low-grade inflammation in white adipose tissue. Excess storage of saturated fat in white adipose tissue due to a modern life style causes hypertrophy and hyperplasia of adipocytes, which exhibit attenuated insulin signaling due to their production and release of saturated fatty acids. These adipocytes recruit macrophages to white adipose tissue and, together with them, initiate a proinflammatory response. Proinflammatory factors and saturated fatty acids secreted into the bloodstream from white adipose tissue impair insulin signaling in non-adipose tissues, which causes whole-body insulin resistance. PMID: 19763019 [PubMed - indexed for MEDLINE] 1729. Biol Trace Elem Res. 2010 Jun;135(1-3):16-21. doi: 10.1007/s12011-009-8504-9. Epub 2009 Sep 4. Zinc deficiency in chronic kidney disease: is there a relationship with adipose tissue and atherosclerosis? Lobo JC(1), Torres JP, Fouque D, Mafra D. Author information: (1)Federal University of Rio de Janeiro, Institute of Biophysics Carlos Chagas Filho, Health Science Centre, Rio de Janeiro, Brazil. Cardiovascular complications caused by an accelerated atherosclerotic disease consist the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). These patients present multiple atherosclerotic risk factors, considered traditional, as well as nontraditional risk factors such as inflammation and oxidative stress. These complications are also seen in obesity, in which endothelial dysfunction is one of the early stages of atherosclerosis. The impact of trace metal deficiencies on this process is not well studied in patients with CKD and in obese people, although the influence of trace elements depletion, particularly zinc (Zn), may have significant clinical implications. This brief review describes the functions of Zn as well as the respective role of this trace element in atherosclerosis processes, with a particular emphasis on obese patients with chronic kidney disease. PMID: 19760368 [PubMed - indexed for MEDLINE] 1730. J Endocrinol. 2010 Jan;204(1):13-20. doi: 10.1677/JOE-09-0262. Epub 2009 Sep 16. TSH receptor activation and body composition. de Lloyd A(1), Bursell J, Gregory JW, Rees DA, Ludgate M. Author information: (1)Centre for Endocrine and Diabetes Sciences, Department of Child Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. The impacts of hyper and hypothyroidism on body composition, i.e. the relative quantity and quality of bone, adipose tissue and muscle, have traditionally been attributed uniquely to abnormal levels of free thyroid hormones. The presence of biologically active TSH receptors in bone, fat and muscle, raises the possibility that both thyroid hormones and TSH contribute to the changes in body composition associated with thyroid disease. This review evaluates the evidence for this in terms of the in vitro experimental approaches applied, data from in vivo sources (i.e. mouse models) and patient-based studies. PMID: 19759194 [PubMed - indexed for MEDLINE] 1731. Apoptosis. 2009 Dec;14(12):1424-34. doi: 10.1007/s10495-009-0400-4. Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver? van der Kallen CJ(1), van Greevenbroek MM, Stehouwer CD, Schalkwijk CG. Author information: (1)Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands. c.vanderkallen@intmed.unimaas.nl Diabetes mellitus (DM) is a multifactorial chronic metabolic disease characterized by hyperglycaemia. Several different mechanisms have been implicated in the development of the disease, including endoplasmic reticulum (ER) stress. ER stress is increasingly acknowledged as an important mechanism in the development of DM, not only for beta-cell loss but also for insulin resistance. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of beta-cell loss and therefore important in the development of diabetes. Recent data also suggest a role of ER stress-induced apoptosis in liver and adipose tissue in relation to diabetes, but more extensive studies on human adipocyte and hepatocyte (patho)physiology and ER stress are needed to identify the exact interactions between environmental signals, ER stress and apoptosis in these organs. PMCID: PMC2773033 PMID: 19757063 [PubMed - indexed for MEDLINE] 1732. J Mol Med (Berl). 2010 Jan;88(1):5-10. doi: 10.1007/s00109-009-0523-7. Epub 2009 Sep 13. Modulation of bone marrow stromal cell functions in infectious diseases by toll-like receptor ligands. Nemeth K(1), Mayer B, Mezey E. Author information: (1)NIH, NIDCR, CSDB, Bethesda, MD 20892, USA. nemethk@mail.nih.gov Bone marrow-derived stromal cells (BMSCs, or as they are frequently referred to as mesenchymal stem cells) have been long known to support hematopoiesis and to regenerate bone, cartilage, and adipose tissue. In the last decade, however, a vast amount of data surfaced in the literature to suggest new roles for these cells including tissue regeneration and immunomodulation. A great number of review articles appeared that summarize these new data and focus on different aspects of the physiology of these cells. In this present short review, we will try to summarize the available data based on both mouse and human cells describing how the function of BMSCs might be affected by an infectious environment. These data strongly support the idea that different toll-like receptor ligands can lead to substantial changes in the function of BMSCs that affect their proliferation, apoptosis, migration, and their production and release of immunomodulatory factors. PMCID: PMC2928254 PMID: 19756450 [PubMed - indexed for MEDLINE] 1733. Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2569-78. doi: 10.1158/1055-9965.EPI-09-0372. Epub 2009 Sep 15. Obesity and cancer: the role of dysfunctional adipose tissue. van Kruijsdijk RC(1), van der Wall E, Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Overweight and obesity are health problems of epidemic proportions, increasing the risk not only of cardiovascular disease and type 2 diabetes mellitus but also of various types of cancer. Obesity is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation, and altered secretion of adipokines. Several of these factors, such as insulin resistance, increased levels of leptin, plasminogen activator inhibitor-1, and endogenous sex steroids, decreased levels of adiponectin, and chronic inflammation, are involved in carcinogenesis and cancer progression. This article reviews these mechanisms, focusing on adipose tissue dysfunction as a unifying causal factor. Although understanding of the link between obesity and cancer might provide therapeutic targets, preventing overweight and obesity still remains number one priority. PMID: 19755644 [PubMed - indexed for MEDLINE] 1734. Radiographics. 2009 Sep-Oct;29(5):1467-86. doi: 10.1148/rg.295085247. Pediatric FDG PET/CT: physiologic uptake, normal variants, and benign conditions. Shammas A(1), Lim R, Charron M. Author information: (1)Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, Canada. amershammas@yahoo.com Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) is increasingly being used in the evaluation of pediatric oncology patients. However, the normal distribution of (18)F FDG uptake in children is unique and may differ from that in adults. A number of physiologic variants are commonly encountered, including normal physiologic uptake in the head and neck, heart, breast, thymus, liver, spleen, gastrointestinal tract, genital system, urinary collecting system, bone marrow, muscles, and brown adipose tissue. Benign lesions with increased (18)F FDG uptake are also frequently seen and can be misinterpreted as malignancies. In addition, the use of combined PET/computed tomographic (CT) scanners is associated with pitfalls and artifacts such as attenuation correction and misregistration. Proper interpretation of pediatric (18)F FDG PET/CT studies requires knowledge of the normal distribution of (18)F FDG uptake in children, as well as of the aforementioned physiologic variants, benign lesions, and PET/CT-related artifacts. Knowing these potential causes of misinterpretation can increase accuracy in PET image interpretation, decrease the number of unnecessary follow-up studies or procedures, and improve patient treatment. (c) RSNA, 2009. PMID: 19755606 [PubMed - indexed for MEDLINE] 1735. FEBS J. 2009 Oct;276(20):5720-8. doi: 10.1111/j.1742-4658.2009.07301.x. Epub 2009 Sep 15. Mechanisms of obesity and related pathologies: role of apolipoprotein E in the development of obesity. Kypreos KE(1), Karagiannides I, Fotiadou EH, Karavia EA, Brinkmeier MS, Giakoumi SM, Tsompanidi EM. Author information: (1)Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio, Greece. kkypreos@med.upatras.gr Apolipoprotein E is a polymorphic glycoprotein in humans with a molecular mass of 34.5 kDa. It is a component of chylomicron remnants, very low density lipoprotein, low density lipoprotein and high density lipoprotein, and is primarily responsible for maintaining plasma lipid homeostasis. In addition to these well-documented functions, recent studies in experimental mouse models, as well as population studies, show that apolipoprotein E also plays an important role in the development of obesity and insulin resistance. It is widely accepted that disruption in homeostasis between food intake and energy expenditure, and the subsequent deposition of excess fatty acids into fat cells in the form of triglycerides, leads to the development of obesity. Despite the pivotal role of obesity and dyslipidemia in the development of the metabolic syndrome and heart disease, the functional interactions between adipose tissue and components of the lipoprotein transport system have not yet been investigated thoroughly. In this minireview, we focus on the current literature pertinent to the involvement of apolipoprotein E in the development of pathologies associated with the metabolic syndrome. PMID: 19754875 [PubMed - indexed for MEDLINE] 1736. FEBS J. 2009 Oct;276(20):5729-37. doi: 10.1111/j.1742-4658.2009.07302.x. Epub 2009 Sep 15. Mechanisms of obesity and related pathologies: transcriptional control of adipose tissue development. Vernochet C(1), Peres SB, Farmer SR. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. Obesity and its associated disorders, including diabetes and cardiovascular disease, have now reached epidemic proportions in the Western world, resulting in dramatic increases in healthcare costs. Understanding the processes and metabolic perturbations that contribute to the expansion of adipose depots accompanying obesity is central to the development of appropriate therapeutic strategies. This minireview focuses on a discussion of the recent identification of molecular mechanisms controlling the development and function of adipose tissues, as well as how these mechanisms contribute to the regulation of energy balance in mammals. PMID: 19754874 [PubMed - indexed for MEDLINE] 1737. FEBS J. 2009 Oct;276(20):5738-46. doi: 10.1111/j.1742-4658.2009.07303.x. Epub 2009 Sep 15. Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue. Rutkowski JM(1), Davis KE, Scherer PE. Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA. Adipose tissue is an endocrine organ made up of adipocytes, various stromal cells, resident and infiltrating immune cells, and an extensive endothelial network. Adipose secretory products, collectively referred to as adipokines, have been identified as contributors to the negative consequences of adipose tissue expansion that include cardiovascular disease, diabetes and cancer. Systemic blood circulation provides transport capabilities for adipokines and fuels for proper adipose tissue function. Adipose tissue microcirculation is heavily impacted by adipose tissue expansion, some adipokines can induce endothelial dysfunction, and angiogenesis is necessary to counter hypoxia arising as a result of tissue expansion. Tumors, such as invasive lesions in the mammary gland, co-opt the adipose tissue microvasculature for local growth and metastatic spread. Lymphatic circulation, an area that has received little metabolic attention, provides an important route for dietary and peripheral lipid transport. We review adipose circulation as a whole and focus on the established and potential interplay between adipose tissue and the microvascular endothelium. PMCID: PMC2896500 PMID: 19754873 [PubMed - indexed for MEDLINE] 1738. FEBS J. 2009 Oct;276(20):5747-54. doi: 10.1111/j.1742-4658.2009.07304.x. Epub 2009 Sep 15. Mechanisms of obesity and related pathology: linking immune responses to metabolic stress. Karalis KP(1), Giannogonas P, Kodela E, Koutmani Y, Zoumakis M, Teli T. Author information: (1)Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece. kkarali@bioacademy.gr There is a tightly regulated interaction, which is well-conserved in evolution, between the metabolic and immune systems that is deranged in states of over- or under-nutrition. Obesity, an energy-rich condition, is characterized by the activation of an inflammatory process in metabolically active sites such as adipose tissue, liver and immune cells. The consequence of this response is a sharp increase in circulating levels of proinflammatory cytokines, adipokines and other inflammatory markers. Activation of the immune response in obesity is mediated by specific signaling pathways, with Jun N-terminal kinase and IkappaB kinase beta/nuclear factor kappa-light-chain-enhancer of activated B cells being the most well studied. It is known that the above events modify insulin signaling and result in the development of insulin resistance. The nutrient overload characterizing obesity is a metabolic stressor associated with intracellular organelle (e.g. the endoplasmic reticulum) stress. The exact characterization of the series of events and the mechanisms that integrate the inflammatory response with metabolic homeostasis at the cellular and systemic level is a very active research field. In this minireview, we discuss the signaling pathways and molecules associated with the development of obesity-induced inflammation, as well as the evidence that supports a critical role for the stress response in this process. PMID: 19754872 [PubMed - indexed for MEDLINE] 1739. Endokrynol Pol. 2009 Jul-Aug;60(4):302-9. [Obesity and the relationship between somatotrophic axis and bone tissue]. [Article in Polish] Ostrowska Z(1), Kobielski A, Kos-Kudła B, Marek B, Kajdaniuk D. Author information: (1)Zakład Biochemii Klinicznej, Slaski Uniwersytet Medyczny, Zabrze. ozdrasiek@wp.pl In postmenopausal obese women often is observed increase bone mineral density in relation to slim women. Dominate the view that positive influence of adipose tissue on state of skeleton in postmenopausal women can be consequence of the boost to load carrying bone, may also result from the role of adipose tissue as endocrine organ. Interaction existence between somatotrophic axis and bone tissue suggests that revealing itself changes of constituents concentration of this axis in obesity individuals may have significance in bone tissue remodeling modification after menopause. It has been demonstrated that GH and IGF-I secretion decrease with age and this changes are major in obesity persons, particularly in women, and they depend on BMI and the percentage of body fat content. GH as well as IGF-I may directly and indirectly modulate bone remodeling, stimulating both bone formation and bone resorption. In the light of latest data this last effect is realized through their influence on expression of OPG and/or RANKL, cytokines belonging to the family of tumor necrosis factor alpha, which provide important controlling process element of the numbers of activated osteoclasts through osteoblasts. PMID: 19753545 [PubMed - indexed for MEDLINE] 1740. Endokrynol Pol. 2009 Jul-Aug;60(4):296-301. [Hormonal regulation of feeding]. [Article in Polish] Kocełak P(1), Zahorska-Markiewicz B, Olszanecka-Glinianowicz M. Author information: (1)Zakład Promocji Zdrowin i Leczenia Otyłości, Katedra Patofizjologii, Slaski Uniwersytet Medyczny, Katowice. pkocelak@sum.edu.pl Obesity is an important healthcare problem. Steady increase in its prevalence is observed worldwide. The underlying cause of obesity is mainly increased calories intake. The regulation of appetite is held by the hypothalamus. Satiety signals are sent to central nervous system via vagus due to distension of the walls of digestive tract and secretion of cytokine signaling after meal digestion. Additionally leptin excreted from adipose tissue reflects the state of energy storage and affects the hypothalamus. The study presents the literature on hormonal regulation of feeding. PMID: 19753544 [PubMed - indexed for MEDLINE] 1741. Mediators Inflamm. 2009;2009:831670. doi: 10.1155/2009/831670. Epub 2009 Jun 3. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Tsochatzis EA(1), Papatheodoridis GV, Archimandritis AJ. Author information: (1)2nd Department of Internal Medicine, Medical School of Athens University, Hippokration General Hospital, Athens, Greece. mtsochatzis@med.uoa.gr Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH. PMCID: PMC2694309 PMID: 19753129 [PubMed - indexed for MEDLINE] 1742. J Physiol. 2009 Dec 1;587(Pt 23):5559-68. doi: 10.1113/jphysiol.2009.179515. Epub 2009 Sep 14. The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk. Pedersen BK(1). Author information: (1)Centre of Inflammation and Metabolism, Rigshospitalet - Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. bkp@rh.dk Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation. PMCID: PMC2805368 PMID: 19752112 [PubMed - indexed for MEDLINE] 1743. Ann N Y Acad Sci. 2009 Sep;1173 Suppl 1:E10-9. doi: 10.1111/j.1749-6632.2009.04952.x. The role of sirtuins in the control of metabolic homeostasis. Yu J(1), Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur and Institut Clinique de la Souris, Illkirch, France. Recently the function of the sirtuin family, named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), has received a lot of attention, as their beneficial impact on longevity was linked to their effects on metabolic control. All sirtuins require nicotinamide adenine dinucleotide (NAD(+)) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels. SIRT1, the founding member of the sirtuin family, modulates many aspects of glucose and lipid homeostasis in almost all key metabolic tissues. Other members including SIRT2, SIRT3, and SIRT4 are also implicated in various metabolic processes. Here, we review the recent data related to the role of sirtuins in the control of metabolic homeostasis and possible underlying molecular mechanisms. PMCID: PMC3620552 PMID: 19751409 [PubMed - indexed for MEDLINE] 1744. Expert Rev Med Devices. 2009 Sep;6(5):533-51. doi: 10.1586/erd.09.37. Adipose tissue engineering: state of the art, recent advances and innovative approaches. Tanzi MC(1), Farè S. Author information: (1)Biomaterials Laboratory, Department of Bioengineering, Politecnico di Milano, 32 Piazza L da Vinci, 20133 Milano, Italy. mariacristina.tanzi@polimi.it Adipose tissue is a highly specialized connective tissue found either in white or brown forms, the white form being the most abundant in adult humans. Loss or damage of white adipose tissue due to aging or pathological conditions needs reconstructive approaches. To date, two main strategies are being investigated for generating functional adipose tissue: autologous tissue/cell transplantation and adipose tissue engineering. Free-fat transplantation rarely achieves sufficient tissue augmentation owing to delayed neovascularization, with subsequent cell necrosis and graft volume shrinkage. Tissue engineering approaches represent, instead, a more suitable alternative for adipose tissue regeneration; they can be performed either with in situ or de novo adipogenesis. In situ adipogenesis or transplantation of encapsulated cells can be useful in healing small-volume defects, whereas restoration of large defects, where vascularization and a rapid volumetric gain are strict requirements, needs de novo strategies with 3D scaffold/filling matrix combinations. For adipose tissue engineering, the use of adult mesenchymal stem cells (both adipose- and bone marrow-derived stem cells) or of preadipocytes is preferred to the use of mature adipocytes, which have low expandability and poor ability for volume retention. This review intends to assemble and describe recent work on this topic, critically presenting successes obtained and drawbacks faced to date. PMID: 19751125 [PubMed - indexed for MEDLINE] 1745. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):34-43. doi: 10.1016/j.mce.2009.08.031. Epub 2009 Sep 10. Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Bartness TJ(1), Shrestha YB, Vaughan CH, Schwartz GJ, Song CK. Author information: (1)Department of Biology and Center for Behavioral Neuroscience, Georgia State University, Atlanta, GA 30302-4010, USA. bartness@gsu.edu Circulating factors are typically invoked to explain bidirectional communication between the CNS and white adipose tissue (WAT). Thus, initiation of lipolysis has been relegated primarily to adrenal medullary secreted catecholamines and the inhibition of lipolysis primarily to pancreatic insulin, whereas signals of body fat levels to the brain have been ascribed to adipokines such as leptin. By contrast, evidence is given for bidirectional communication between brain and WAT occurring via the sympathetic nervous system (SNS) and sensory innervation of this tissue. Using retrograde transneuronal viral tract tracers, the SNS outflow from brain to WAT has been defined. Functionally, sympathetic denervation of WAT blocks lipolysis to a variety of lipolytic stimuli. Using anterograde transneuronal viral tract tracers, the sensory input from WAT to brain has been defined. Functionally, these WAT sensory nerves respond electrophysiologically to increases in WAT SNS drive suggesting a possible neural negative feedback loop to regulate lipolysis. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC2826518 PMID: 19747957 [PubMed - indexed for MEDLINE] 1746. Clin Immunol. 2009 Nov;133(2):157-70. doi: 10.1016/j.clim.2009.07.013. Epub 2009 Sep 8. The role of resistin as a regulator of inflammation: Implications for various human pathologies. Filková M(1), Haluzík M, Gay S, Senolt L. Author information: (1)Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Prague 2, 128 50, Czech Republic. Resistin was originally described as an adipocyte-secreted peptide that induced insulin resistance in rodents. Increasing evidence indicates its important regulatory roles in various biological processes, including several inflammatory diseases. Further studies have shown that resistin in humans, in contrast to its production by adipocytes in mice, is synthesized predominantly by mononuclear cells both within and outside adipose tissue. Possible roles for resistin in obesity-related subclinical inflammation, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, rheumatic diseases, malignant tumors, asthma, inflammatory bowel disease, and chronic kidney disease have already been demonstrated. In addition, resistin can modulate several molecular pathways involved in metabolic, inflammatory, and autoimmune diseases. In this review, current knowledge about the functions and pathophysiological implications of resistin in different human pathologies is summarized, although there is a significant lack of firm evidence regarding the specific role resistin plays in the "orchestra" of the numerous mediators of inflammation. PMID: 19740705 [PubMed - indexed for MEDLINE] 1747. Przegl Lek. 2009;66(5):257-62. [Variants of adiponectin gene as risk factors for the metabolic syndrome]. [Article in Polish] Szopa M(1), Malczewska-Malec M, Wybrańska I, Kieć-Wilk B. Author information: (1)Zakład Biochemii Klinicznej, Collegium Medicum, Uniwersytet Jagielloński, Kraków. Adiponectin, a protein secreted by adipose tissue but present at low levels in obesity, is now widely recognized as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. The adiponectin gene is very polymorphic and several of its variants contribute to adiponectin level, function and are associated with metabolic syndrome phenotypes. The results differ ethnically. The association of identified variants with obesity and its consequences, type 2 diabetes and cardiovascular disease is reviewed. This data may enable patients at greater risk of the adverse effects of obesity to be identified and, as such, benefit from more targeted therapy and prevention. PMID: 19739584 [PubMed - indexed for MEDLINE] 1748. Cell Cycle. 2009 Sep 15;8(18):2885-7. The hypothalamus bridges the gap between physiology and biochemistry in high-fat diet-induced hepatic insulin resistance. Ono H(1). Author information: (1)Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama Japan. hono@saitama-med.ac.jp The mechanisms of insulin resistance differ among tissues, and under various circumstances. A high-fat diet is known to induce insulin resistance, but the timing of this insulin resistance induction in the liver differs from that in other insulin-target tissues. Hyperinsulinemic-euglycemic clamp studies have revealed that a high-fat diet induces insulin resistance in the liver relatively quickly, while taking more time in muscle and adipose tissue. In contrast, biochemical studies have shown a high-fat diet to paradoxically enhance insulin signaling in the liver. The results of a recent study conducted by our group indicate that hypothalamic insulin resistance via p70 S6 kinase 1 (S6K1) activation induced by a high-fat diet may explain this discrepancy between physiological and biochemical observations. There are both direct and indirect pathways by which insulin suppresses hepatic glucose production, and the indirect pathway via the hypothalamus is particularly impaired under relatively short-term overfeeding conditions, which in turn leads to compensatory enhancement of insulin signaling in the liver. PMID: 19738432 [PubMed - indexed for MEDLINE] 1749. Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E987-98. doi: 10.1152/ajpendo.00229.2009. Epub 2009 Sep 8. The origin of intermuscular adipose tissue and its pathophysiological implications. Vettor R(1), Milan G, Franzin C, Sanna M, De Coppi P, Rizzuto R, Federspil G. Author information: (1)Dept. of Medical and Surgical Sciences, Univ. of Padua, via Ospedale, 105, 35128 Padua, Italy. roberto.vettor@unipd.it The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66(shc), mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia. PMID: 19738037 [PubMed - indexed for MEDLINE] 1750. Nutr Res Rev. 2009 Dec;22(2):137-47. doi: 10.1017/S0954422409990096. Visceral adipose tissue in children and adolescents: a review. Suliga E(1). Author information: (1)Institute of Public Health, Jan Kochanowski University, Aleja IX Wieków Kielc 19, 25-317 Kielce, Poland. Edyta.Suliga@pu.kielce.pl Research conducted among adults has mainly shown that visceral adipose tissue (VAT) is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of CVD or the metabolic syndrome. However, little is known about the aetiology, determinants and consequences of VAT in children. The present article reviews the current literature relating to the factors influencing visceral fat accumulation in children and adolescents. The literature used in the present study was collected by searching a PubMed database, in which studies up to 2008 exploring the factors influencing accumulation of visceral fat among children and youth were found on the basis of appropriate keywords. Further studies concerning different factors influencing deposition of VAT among children and youth should first of all concentrate on: carrying out long-term analyses among children of different ethnical groups, which should begin in the period of prepuberty and which should cover the whole period of puberty till adulthood; drawing up norms specifying the amount of VAT among healthy children; identification of anthropometric indicators which will help to determine the VAT:subcutaneous adipose tissue ratio in the most precise way; broader studies of the influence of eating habits on developing VAT deposit among children and youth. PMID: 19737436 [PubMed - indexed for MEDLINE] 1751. Saudi J Kidney Dis Transpl. 2009 Sep;20(5):770-4. Modifying cyclosporine associated renal allograft dysfunction. Mohapatra N(1), Vanikar AV, Patel RD, Trivedi HL. Author information: (1)Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, Ahmedabad, Gujarat, India. Transplantation is accepted therapy for chronic kidney disease. However the essential immunosuppressive agents for graft survival have their own side-effects. Renal biopsy is a reliable tool for diagnosing cyclosporine (CsA) nephrotoxicity. To present our observations on CsA toxicity in renal allograft biopsies, we studied prospectively 207 renal allograft biopsies performed for graft dysfunction as per Ahmedabad Tolerance Induction Protocol (ATIP) and compared them to 50 controls from January to October 2007. The ATIP comprised donor specific leucocyte infusions, low dose target specific irradiation; non-myeloablative condi-tioning with Anti-T +/- B cell antibodies followed by intraportal administration of cultured donor bone marrow (BM) +/- adipose tissue derived mesenchymal stem cells. Renal transplantation was performed following negative lymphocytotoxicity cross-matching. The post-transplant immunosuppressive agents included CsA 2.5 +/- 0.5 mg/kg BW/day and prednisone 0.2 mg/kg BW/day. The controls were transplanted using standard triple immunosuppressive agents including CsA 5 +/- 1 mg/Kg BW/day, prednisone 0.6 mg/kg BW/day, and MMF/ Azathioprine. The Institutional Review Board approved the ATIP. The biopsies were categorized into 2 groups; group A (N=97): performed < 6 months, group B (N= 160), > 6 months posttransplant. Acute CsA toxicity was observed in group A: 2.5% ATIP and 11.1% controls; group B: 16.2% ATIP and 8.8% controls. Chronic CsA toxicity was observed in group B: 10.8 % ATIP and 17.6 % controls. Acute toxicity was more in the ATIP, while chronic toxicity was more in the controls. CsA doses were reduced post-biopsy and resulted in improved graft function evaluated by serum creatinine. We conclude that CsA nephrotoxicity evaluated by allograft biopsy resulted in allograft function recovery by decreasing the cyclosporine dose, and the ATIP decreased the incidence of CsA nephrotoxicity. PMID: 19736471 [PubMed - indexed for MEDLINE] 1752. Fundam Clin Pharmacol. 2010 Jun;24(3):269-82. doi: 10.1111/j.1472-8206.2009.00765.x. Epub 2009 Sep 3. Effects of β-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity. Begriche K(1), Massart J, Fromenty B. Author information: (1)INSERM, U620, Université de Rennes 1, Rennes, France. Beta-aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this beta-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals. PMID: 19735301 [PubMed - indexed for MEDLINE] 1753. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):10-4. doi: 10.1016/j.mce.2009.08.023. Epub 2009 Sep 4. Transcriptional factors that promote formation of white adipose tissue. White UA(1), Stephens JM. Author information: (1)Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA. Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is a major risk factor for the development of type II diabetes (T2DM), cardiovascular disease, and hypertension. Obesity and its related disorders result in dysregulation of the mechanisms that control the expression of metabolic and endocrine related genes in adipocytes. Therefore, understanding adipocyte differentiation is relevant not only for gaining insight into the pathogenesis of metabolic diseases, but also for identifying proteins or pathways which might be appropriate targets for pharmacological interventions. Significant advances towards an understanding of the regulatory processes involved in adipocyte differentiation have largely been made by the identification of transcription factors that contribute to the adipogenic process. It is important to note that the developmental origin of white and brown fat is distinct and different precursor cells are involved in the generation of these different types of adipose tissue (reviewed in Lefterova and Lazar, 2009; Seale et al., 2009). Several transcription factors, notably PPAR gamma, several members of the C/EBP and KLF families, STAT5, and SREBP-1c, have been shown to have significant roles in promoting adipogenesis. More comprehensive reviews on negative and positive regulators of adipogenesis have been published in the past year (reviewed in Christodoulides et al., 2009; Lefterova and Lazar, 2009). Though many proteins are known to negatively regulate adipogenesis, including Wnts, KLFs, the E2F family of transcription factors, CHOP, Delta-interacting protein A, ETO/MTG8, and members of the GATA and forkhead transcription factor families, this review will focus on transcription factors that positively impact the development of white adipose tissue. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC3079373 PMID: 19733624 [PubMed - indexed for MEDLINE] 1754. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):15-23. doi: 10.1016/j.mce.2009.08.022. Epub 2009 Sep 4. Utility of transplantation in studying adipocyte biogenesis and function. Zhang Y(1). Author information: (1)Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY 10032, USA. yz84@columbia.edu Adipose tissue plays important roles in the regulation of energy homeostasis and metabolism. Two features distinguish adipose tissue from other organs--the ability to greatly expand its mass, via increases in cell size and/or number, and the wide anatomical distribution. While adipose tissue function is greatly affected by adipocyte size and anatomic location, regulations of adipocyte size, number, and body fat distribution are poorly understood. Transplantation of either mature adipose tissue or adipocyte progenitor cells has been used in studying adipocyte function and biogenesis. In this review, we will attempt to summarize methodological considerations for transplantation, including selections of donor material, transplantation site and the length of transplantation study, as well as effects of these factors and vascularization and innervation on the function of transplants. Specific studies are also reviewed to illustrate the utility of adipose tissue transplants in studying adipose tissue function and biogenesis. The focus is on studies in three areas: (1) use of transplants in demonstrating adipose tissue function, such as effects of adipose tissue transplants on metabolism and energy homeostasis of the recipient animals and depot-specific differences in adipose tissue function; (2) use of transplantation to dissect direct or cell-autonomous from indirect or non-cell-autonomous effects of leptin signaling and sex on adipocyte size; (3) use of transplantation in the identification of adipocyte progenitor cells and lineage analysis. Finally, future applications of transplantation in studying depot-specific adipocyte biogenesis, and genetic and hormonal effects of sex and age on adipocyte biogenesis and function are discussed. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC2826534 PMID: 19733623 [PubMed - indexed for MEDLINE] 1755. Vnitr Lek. 2009 Jul-Aug;55(7-8):659-65. [Chronic mild inflammation links obesity, metabolic syndrome, atherosclerosis and diabetes]. [Article in Czech] Andel M(1), Polák J, Kraml P, Dlouhý P, Stich V. Author information: (1)Centrum pro výzkum diabetu, metabolismu a výzivy 3. lékarské fakulty UK a FN Královské Vinohrady Praha. michal.andel@lf3.cuni.cz Chronic low grade inflammation is relatively new concept in metabolic medicine. This concept describes the relations between the inflammation and adipose tissue, insulin resistence, atherosclerosis and type 2 diabetes mellitus. Macrophages and lymphocytes deposed in adipose tissue produce proinflammatory cytokines which directly or through the CRP liver secretion are targeting endothelial cells, hepatocytes and beta cells of Langerhans islets of pancreas. The dysfunction of these cells follows often further disturbances and in case of beta cells - the cell death. The connection between the adipose tissue insulin resistence, atherosclerosis and type 2 diabetes was earlier described with endocrine and metabolic descriptors. The concept of chronic low grade inflammation creates also another description of multilateral connections in metabolic syndome. The salicylates and the drugs related to them seem to have some glucose lowering properties. The recent development in the field ofchronic low grade inflammation represents also certain therapeutic hope for antiinflammatory intervention in type 2 diabetes. PMID: 19731872 [PubMed - indexed for MEDLINE] 1756. J Mol Med (Berl). 2009 Oct;87(10):1029-39. doi: 10.1007/s00109-009-0515-7. Translational research of novel hormones: lessons from animal models and rare human diseases for common human diseases. Nakao K(1), Yasoda A, Ebihara K, Hosoda K, Mukoyama M. Author information: (1)Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. nakao@kuhp.kyoto-u.ac.jp Since the 1980s, a number of bioactive molecules, now known as cardiovascular hormones, have been isolated from the heart and blood vessels, particularly from the subset of vascular endothelial cells. The natriuretic peptide family is the prototype of the cardiovascular hormones. Over the following decade, a variety of hormones and cytokines, now known as adipokines or adipocytokines, have also been isolated from adipose tissue. Leptin is the only adipokine demonstrated to cause an obese phenotype in both animals and humans upon deletion. Thus, the past two decades have seen the identification of two important classes of bioactive molecules secreted by newly recognized endocrine cells, both of which differentiate from mesenchymal stem cells. To assess the physiological and clinical implications of these novel hormones, we have investigated their functions using animal models. We have also developed and analyzed mice overexpressing transgenic forms of these proteins and knockout mice deficient in these and related genes. Here, we demonstrate the current state of the translational research of these novel hormones, the natriuretic peptide family and leptin, and discuss how lessons learned from excellent animal models and rare human diseases can provide a better understanding of common human diseases. PMID: 19730806 [PubMed - indexed for MEDLINE] 1757. J Investig Med. 2009 Oct;57(7):784-8. doi: 10.231/JIM.0b013e3181b9163d. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. Blüher S(1), Shah S, Mantzoros CS. Author information: (1)Hospital for Children and Adolescents, University of Leipzig, Germany. The discovery of leptin has significantly advanced our understanding of the metabolic importance of adipose tissue and has revealed that both leptin deficiency and leptin excess are associated with severe metabolic, endocrine, and immunological consequences. We and others have shown that a prominent role of leptin in humans is to mediate the neuroendocrine adaptation to energy deprivation. Humans with genetic mutations in the leptin and leptin receptor genes have deregulated food intake and energy expenditure leading to a morbidly obese phenotype and a disrupted regulation in neuroendocrine and immune function and in glucose and fat metabolism. Observational and interventional studies in humans with (complete) congenital leptin deficiency caused by mutations in the leptin gene or with relative leptin deficiency as seen in states of negative energy balance such as lipoatrophy, anorexia nervosa, or exercise-induced hypothalamic and neuroendocrine dysfunction have contributed to the elucidation of the pathophysiological role of leptin in these conditions and of the clinical significance of leptin administration in these subjects. More specifically, interventional studies have demonstrated that several neuroendocrine, metabolic, or immune disturbances in these states could be restored by leptin administration. Leptin replacement therapy is currently available through a compassionate use program for congenital complete leptin deficiency and under an expanded access program to subjects with leptin deficiency associated with congenital or acquired lipoatrophy. In addition, leptin remains a potentially forthcoming treatment for several other states of energy deprivation including anorexia nervosa or milder forms of hypothalamic amenorrhea pending appropriate clinical trials. PMID: 19730134 [PubMed - indexed for MEDLINE] 1758. Trends Biochem Sci. 2009 Oct;34(10):500-10. doi: 10.1016/j.tibs.2009.06.008. Epub 2009 Sep 2. Adipokines as novel modulators of lipid metabolism. Lago F(1), Gómez R, Gómez-Reino JJ, Dieguez C, Gualillo O. Author information: (1)Research Laboratory 7 (Molecular and Cellular Cardiology), Institute of Medical Research (IDIS), University Clinical Hospital, Santiago de Compostela 15706, Spain. mfrancisca.lago@usc.es In the mid-1990s, interest in adipose tissue - until then generally regarded as a mere energy reserve - was revived by the discovery of leptin. Since then numerous other cytokine-like hormones have been isolated from white adipose tissue. These adipokines have been investigated in relation to obesity, metabolic syndrome, insulin resistance and other pathological conditions and processes. In addition, it is now established that adipokines play a role in the maintenance of an inflammatory state in adipose tissue and in the development of obesity and comorbidities. The contributions of individual adipokines in the pathophysiological features of obesity have yet to be determined in full, but recent data highlight important roles for adipokines in lipid metabolism. PMID: 19729309 [PubMed - indexed for MEDLINE] 1759. Front Neuroendocrinol. 2010 Jan;31(1):4-15. doi: 10.1016/j.yfrne.2009.08.002. Epub 2009 Sep 1. Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Sánchez-Lasheras C(1), Könner AC, Brüning JC. Author information: (1)Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Germany. Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic. 2009 Elsevier Inc. All rights reserved. PMID: 19729032 [PubMed - indexed for MEDLINE] 1760. Med Sci Sports Exerc. 2009 Oct;41(10):1869-75. doi: 10.1249/MSS.0b013e3181a645a6. In vivo alterations in skeletal muscle form and function after disuse atrophy. Clark BC(1). Author information: (1)Institute for Neuromusculoskeletal Research, Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH 45701, USA. clarkb2@ohio.edu Prolonged reductions in muscle activity and mechanical loading (e.g., bed rest, cast immobilization) result in alterations in skeletal muscle form and function. The purpose of this review article was to synthesize recent findings from several studies on the dramatic effects of disuse on skeletal muscle morphology and muscle performance in humans. Specifically, the following are discussed: 1) how the antigravity muscles are most susceptible to atrophy and how the degree of atrophy varies between muscle groups; 2) how disuse alters muscle composition by increasing intermuscular adipose tissue; 3) the influence of different disuse models on regulating the loss of muscle mass and strength, with immobilization causing greater reductions than bed rest and limb suspension do; 4) the observation that disuse decreases strength to a greater extent than muscle mass and the role of adaptations in both neural and contractile properties that influences this excessive loss of strength; 5) the equivocal findings on the effect of disuse on muscle fatigue resistance; and 6) the reduction in motor control after prolonged disuse. Lastly, emerging data warranting further inquiry into the modulating role of biological sex on disuse-induced adaptations are also discussed. PMID: 19727027 [PubMed - indexed for MEDLINE] 1761. Am J Med Sci. 2009 Oct;338(4):310-8. doi: 10.1097/MAJ.0b013e3181a4158c. Cytokine biomarkers, endothelial inflammation, and atherosclerosis in the metabolic syndrome: emerging concepts. Rizvi AA(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina 29203, USA. ali.rizvi@uscmed.sc.edu In recent years, an explosion of research related to the cellular and vascular accompaniments of the metabolic syndrome has generated intense interest and controversy. Attention has focused on the vascular endothelium, where heightened, low-grade inflammatory processes lead to a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis. Inflammatory biocytokines, such as C-reactive protein, have been speculated to be both markers and mediators of oxidative stress and endovascular toxicity. Adipocytokines originating from fatty tissue have reinforced the concept that fat is a metabolically active organ rather than inert tissue. To fully elucidate its complex pathogenetic mechanisms, further inquiry into the inflammatory components of the metabolic syndrome is warranted. Unraveling the role of emerging proinflammatory markers has the promising potential to shed light into the underlying pathophysiology of the epidemic of obesity and the metabolic syndrome and thus help devise effective therapies. PMID: 19726972 [PubMed - indexed for MEDLINE] 1762. Mol Cell Endocrinol. 2010 Mar 25;316(2):129-39. doi: 10.1016/j.mce.2009.08.018. Epub 2009 Aug 31. Adipose tissue as an endocrine organ. Galic S(1), Oakhill JS, Steinberg GR. Author information: (1)St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity. 2009 Elsevier Ireland Ltd. All rights reserved. PMID: 19723556 [PubMed - indexed for MEDLINE] 1763. An Acad Bras Cienc. 2009 Sep;81(3):453-66. Metabolism and secretory function of white adipose tissue: effect of dietary fat. Oller do Nascimento CM(1), Ribeiro EB, Oyama LM. Author information: (1)Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil. claudia.oller@unifesp.br Approximately 40% of the total energy consumed by western populations is represented by lipids, most of them being ingested as triacylglycerols and phospholipids. The focus of this review is to analyze the effect of the type of dietary fat on white adipose tissue metabolism and secretory function, particularly on haptoglobin, TNF-alpha, plasminogen activator inhibitor-1 and adiponectin secretion. Previous studies have demonstrated that the duration of the exposure to the high-fat feeding, amount of fatty acid present in the diet and the type of fatty acid may or may not have a significant effect on adipose tissue metabolism. However, the long-term or short-term high fat diets, especially rich in saturated fatty acids, probably by activation of toll-like receptors, stimulated the expression of proinflammatory adipokines and inhibited adiponectin expression. Further studies are needed to investigate the cellular mechanisms by which dietary fatty acids affect white adipose tissue metabolism and secretory functions. PMID: 19722015 [PubMed - indexed for MEDLINE] 1764. Proc Nutr Soc. 2009 Nov;68(4):385-92. doi: 10.1017/S0029665109990267. Epub 2009 Sep 1. New insights into adipose tissue atrophy in cancer cachexia. Bing C(1), Trayhurn P. Author information: (1)Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, Liverpool L69 3GA, UK. bing@liverpool.ac.uk Profound loss of adipose and other tissues is a hallmark of cancer cachexia, a debilitating condition associated with increased morbidity and mortality. Fat loss cannot be attributable to reduced appetite alone as it precedes the onset of anorexia and is much more severe in experimental models of cachexia than in food restriction. Morphological examination has shown marked remodelling of adipose tissue in cancer cachexia. It is characterised by the tissue containing shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix. The ultrastructure of 'slimmed' adipocytes has revealed severe delipidation and modifications in cell membrane conformation. Although the molecular mechanisms remain to be established, evidence suggests that altered adipocyte metabolism may lead to adipose atrophy in cancer cachexia. Increased lipolysis appears to be a key factor underlying fat loss, while inhibition of adipocyte development and lipid deposition may also contribute. Both tumour and host-derived factors are implicated in adipose atrophy. Zinc-alpha2-glycoprotein (ZAG), which is overexpressed by certain malignant tumours, has been identified as a novel adipokine. ZAG transcripts and protein expression in adipose tissue are up regulated in cancer cachexia but reduced with adipose tissue expansion in obesity. Studies in vitro demonstrate that recombinant ZAG stimulates lipolysis. ZAG may therefore act locally, as well as systemically, to promote lipid mobilisation in cancer cachexia. Further elucidation of ZAG function in adipose tissue may lead to novel targets for preventing adipose atrophy in malignancy. PMID: 19719894 [PubMed - indexed for MEDLINE] 1765. Proc Nutr Soc. 2009 Nov;68(4):393-400. doi: 10.1017/S002966510999022X. Epub 2009 Sep 1. Early programming of adipose tissue function: a large-animal perspective. Mostyn A(1), Symonds ME. Author information: (1)Early Life Nutrition Research Unit, Academic Child Health, Division of Human Development and Nottingham Respiratory Medicine Biomedical Research Unit, School of Clinical Sciences, Queen's Medical Centre, University Hospitals, Nottingham NG7 2UH, UK. alison.mostyn@nottingham.ac.uk The emerging role of adipose tissue as a dynamic endocrine organ with an extent of anatomical and physiological plasticity has generated numerous studies linking early-life events with long-term alterations in adipose tissue structure and function. Coupled with increasing rates of human obesity, which cannot be explained without some genetic component, the role of early programming of adipose tissue may provide an insight into potential mechanisms. The developmental origins of health and disease hypothesis investigates the potential association between a compromised fetal and postnatal environment and later disease, such as obesity and type 2 diabetes, in the offspring. A number of animal models have been developed to examine potential mechanisms that drive these physiological changes, including rodent and large-mammal models that provide mechanistic insights into the epidemiological findings. In utero challenges such as under- or over-provision of nutrients, placental insufficiency and glucocorticoid infusion, as well as postnatal nutritional challenges, can all result in the long-term programming of adipose tissue abundance and function. A range of hormones, enzymes, transcription factors and other metabolic signalling molecules have been implicated in adverse adipose tissue development, including leptin, glucocorticoids, members of the PPAR family, fatty acid-binding proteins and adipokines. The long-term structural and physiological consequences associated with these molecular and cellular changes are less well described. The experimental models, potential mechanisms and regulators of the early programming of adipose tissue in large mammalian species will be summarised in the present review. PMID: 19719893 [PubMed - indexed for MEDLINE] 1766. Proc Nutr Soc. 2009 Nov;68(4):416-21. doi: 10.1017/S0029665109990152. Epub 2009 Sep 1. The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health. Symonds ME(1), Sebert SP, Budge H. Author information: (1)Early Life Nutrition Research Unit, Academic Child Health, Division of Human Development, and Nottingham Respiratory Medicine Biomedical Research Unit, School of Clinical Sciences, Queen's Medical Centre, University Hospitals, Nottingham NG7 2UH, UK. michael.symonds@nottingham.ac.uk Changes in maternal diet at different stages of reproduction can have pronounced influences on the health and well-being of the resulting offspring, especially following exposure to an obesogenic environment. The mechanisms mediating adaptations in development of the embryo, placenta, fetus and newborn include changes in the maternal metabolic environment. These changes include reductions in a range of maternal counter-regulatory hormones such as cortisol, leptin and insulin. In the sheep, for example, targeted maternal nutrient restriction coincident with the period of maximal placental growth has pronounced effects on the development of the kidney and adipose tissue. As a consequence, the response of these tissues varies greatly following adolescent-onset obesity and ultimately results in these offspring exhibiting all the symptoms of the metabolic syndrome earlier in young adult life. Leptin administration to the offspring after birth can have some long-term differential effects, although much higher amounts are required to cause a response in small compared with large animal models. At the same time, the responsiveness of the offspring is gender dependent, which may relate to the differences in leptin sensitivity around the time of birth. Increasing maternal food intake during pregnancy, either globally or of individual nutrients, has little positive impact on birth weight but does impact on liver development. The challenge now is to establish which components of the maternal diet can be sustainably modified in order to optimise the maternal endocrine environment through pregnancy, thus ensuring feto-placental growth is appropriate in relation to an individual's gender and body composition. PMID: 19719891 [PubMed - indexed for MEDLINE] 1767. Pathol Int. 2009 Sep;59(9):650-5. doi: 10.1111/j.1440-1827.2009.02421.x. Perivascular epithelioid cell tumor (PEComa) of the pancreas: immunoelectron microscopy and review of the literature. Hirabayashi K(1), Nakamura N, Kajiwara H, Hori S, Kawaguchi Y, Yamashita T, Dowaki S, Imaizumi T, Osamura RY. Author information: (1)Department of Pathology, Tokai University School of Medicine, Kanagawa 259-1193, Japan. khira@is.icc.utokai.ac.jp A perivascular epithelioid tumor (PEComa) is a rare tumor probably arising from the perivascular epithelioid cells. Only three cases of pancreatic PEComa have been reported in the English-language literature. The present report describes an extremely rare case of pancreatic PEComa. A 47-year-old Japanese woman complained of lower abdominal pain and a well-demarcated solid tumor was found in the pancreatic head. There was no history of tuberous sclerosis complexes. Pylorus-preserving pancreaticoduodenectomy was thus performed. There was a well-demarcated, solid tumor measuring 17 mm in the pancreatic head. The tumor was composed of a diffuse proliferation of epithelioid tumor cells with many blood vessels but no adipose tissue. The tumor cells expressed HMB45 and alpha-smooth muscle actin. Ultrastructurally, the tumor cells possessed many membrane-bound granules that were positive for HMB45 on immunoelectron microscopy. The results of immunoelectron microscopy show that some PEComas possess not only typical melanosomes or premelanosomes but also aberrant melanosomes. PMID: 19712133 [PubMed - indexed for MEDLINE] 1768. Semin Dial. 2009 Jul-Aug;22(4):391-5. doi: 10.1111/j.1525-139X.2009.00587.x. Adiponectin in patients with chronic kidney disease. Adamczak M(1), Chudek J, Wiecek A. Author information: (1)Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland. Adiponectin is one of many so called "adipokines"--cytokines, chemokines, growth factors, and complement proteins secreted by adipose tissue--that can affect the function of other organs. This antiatherogenic and insulin-sensitizing polypeptide is eliminated from the circulation mostly by the kidneys. Thus, in patients with chronic kidney disease, adiponectin accumulates in the circulation; its plasma concentration is approximately three times higher in end stage kidney disease than in healthy subjects. As no biological consequences of these unusually high adiponectin concentrations have been demonstrated, this polypeptide cannot be considered as a uremic toxin. On the contrary, inadequately low instead of high plasma adiponectin concentration is recognized as a new nontraditional risk factor of cardiovascular morbidity and mortality in these patients. This review summarizes the causes and clinical consequences of adiponectin accumulation in the circulation of patients with chronic kidney disease. PMID: 19708988 [PubMed - indexed for MEDLINE] 1769. Semin Dial. 2009 Jul-Aug;22(4):373-7. doi: 10.1111/j.1525-139X.2009.00583.x. Resistin as a cardiovascular and atherosclerotic risk factor and uremic toxin. Cohen G(1), Hörl WH. Author information: (1)Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria. gerald.cohen@meduniwien.ac.at Resistin is a 12.5 kDa protein originally found to be secreted by mouse adipocytes. Whereas in rodents adipose tissue is the main source of resistin, in humans resistin is expressed primarily in macrophages. In a variety of pathophysiologic states, particularly in type 2 diabetes mellitus and in chronic kidney disease, the serum concentration of resistin is increased. Resistin reduces the glucose uptake in adipose tissue and skeletal muscle cells and may be involved in insulin resistance. A positive correlation between resistin levels and inflammatory markers has been described. Resistin has a potential role in cardiovascular disease and may contribute to an increased atherosclerotic risk by modulating the activity of endothelial cells. We recently found that resistin in concentrations measured in uremia is able to interfere with the chemotactic movement and the oxidative burst of neutrophils, cells of the first-line nonspecific immune defense. Therefore, resistin may also contribute to the disturbed immune response and as a consequence to the increased risk of infections in uremic and diabetic subjects. PMID: 19708984 [PubMed - indexed for MEDLINE] 1770. Acta Physiol Hung. 2009 Sep;96(3):251-65. doi: 10.1556/APhysiol.96.2009.3.1. Cardiac regenerative potential of adipose tissue-derived stem cells. Hoke NN(1), Salloum FN, Loesser-Casey KE, Kukreja RC. Author information: (1)Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA 23298-0281, USA. Myocyte loss due to ischemia/reperfusion injury leads to cardiac dysfunction and heart failure, and the concentration of current therapy is limited on preventing the progression. Recent interest has focused on transplantation of stem cells to differentiate and replenish the loss of myocytes. Adipose tissue represents an alternative and abundant source of adult stem cells with the ability to differentiate along multiple lineage pathways. Recent studies have demonstrated the potential of adipose tissue-derived stem cells for treatment of acute myocardial infarction. The aim of this review is to discuss the potential therapeutic benefits of adipose tissue-derived stem cells in improving cardiac function post-injury. PMID: 19706369 [PubMed - indexed for MEDLINE] 1771. Mol Cell Endocrinol. 2010 Apr 29;318(1-2):54-60. doi: 10.1016/j.mce.2009.08.013. Epub 2009 Aug 22. Stranger in a strange land: roles of glycogen turnover in adipose tissue metabolism. Markan KR(1), Jurczak MJ, Brady MJ. Author information: (1)Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA. Triglyceride storage in adipose tissue comprises the principal energy reserve in mammals. Additionally glucose can be stored as glycogen in the fed state, primarily in liver and skeletal muscle, for mobilization during times of energy deficit. Adipose tissue also contains glycogen stores albeit at very low levels. The physiological role of glycogen metabolism in adipocytes remains unclear. However, both classical literature and more recent work demonstrate that the dynamic regulation of adipose glycogen may serve as an energy sensing modality in the coordination of glucose and lipid metabolism in adipose tissue, especially during the fasted to fed transition. (c) 2009 Elsevier Ireland Ltd. All rights reserved. PMCID: PMC2826604 PMID: 19703517 [PubMed - indexed for MEDLINE] 1772. Nutr Rev. 2009 Sep;67(9):551-4. doi: 10.1111/j.1753-4887.2009.00227.x. Adipose-specific phospholipase as regulator of adiposity. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA. nutritionreviews@ilsi.org A white adipose-tissue-specific intracellular phospholipase, which releases arachidonic acid from position sn-2 of phospholipids, was recently discovered and named AdPLA. When AdPLA was induced by feeding or by insulin treatment, the arachidonic acid released from phospholipids acted as a precursor for the formation of prostaglandin E(2) (PGE(2)). Subsequent activation of the prostaglandin receptor EP3 caused decreased levels of cAMP that led to decreased lipolysis and increased adiposity. Ablation of AdPLA in knockout mice resulted in the reverse sequence of events, with a decline in arachidonic acid release and prostaglandin synthesis and an increase in levels of cAMP, leading to increased lipolysis and a decline in adiposity, even though food intake was not affected. The newly discovered AdPLA enzyme in white adipose tissue functions as a regulator of lipolysis by acting as an antilipolytic agent mediated by increased PGE(2) formation and decreased intracellular cAMP. PMID: 19703262 [PubMed - indexed for MEDLINE] 1773. Med Pregl. 2009;62 Suppl 3:47-53. [Adipokines and lipids]. [Article in Serbian] Sumarac-Dumanović M(1), Jeremić D. Author information: (1)Klinicki centar Srbije, Beograd, Institut za endokrinologiju, dijabetes i bolesti metabolizma. sumarac@eunet.yu Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. The functional capacity of the adipose tissue varies among subjects explaining the incomplete overlapping among the metabolic syndrome and obesity. Far turnover is determined by a complex equilibrium in which insulin is a main factor but not the only one. Chronically inadequate energy balance may be a key factor, stressing the system. In this situation, an adipose tissue functional failure occurs resulting in changes in systemic energy delivery, impaired glucose consumption and activation of self-regulatory mechanisms that extend their influence to the whole body homeostasis system. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. The activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in the fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. A decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, the alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS. PMID: 19702116 [PubMed - indexed for MEDLINE] 1774. Med Pregl. 2009;62 Suppl 3:43-6. [Obesity and coronary heart disease: the mechanism of atherogenic impact]. [Article in Serbian] Micić D(1), Polovina S. Author information: (1)Klinicki centar Srbije, Beograd, Institut za endokrinologiju, dijabetes i bolesti metabolizma. The epidemic of obesity and overweight leads to many diseases including cardiovascular disease. Having an influence on function and heart structure, obesity and overweight are in connection with coronary heart disease, heart failure and sudden heart death. Cardiomyopathy in obesity (adipositas cordis) appears due to accumulation of adipose tissue between the heart muscle fibers and degeneration of myocites. The degeneration of myocardial could be due to lipotoxicity of free fatty acids in adipose tissue. The left ventricle hypertrophy, diastolic dysfunction, increasing blood volume, ejection fraction lead to heart failure. Obesity is low inflammation state with increased adipocitokine production from truncal adipose tissue which causes endothelial dysfunction and insulin resistance. Adipocitokines include leptin, adiponectin, resistin, visfatin, RBP 4 (retinol binding protein), angiotenzinogen, TNF alpha (tumor necrosis factor), PAI 1 (plazminogen activator inhibitor), fatty acids, sex steroids and different growth factors. Adipocitokines act synergistically or competitively with insulin, that explaining their impact on insulin resistance. Inflammatory citokines from adipose tissue could have influence on blood vessels endothelial function without their increase in plasma concentrations. PMID: 19702115 [PubMed - indexed for MEDLINE] 1775. Rev Med Chil. 2009 May;137(5):685-94. doi: /S0034-98872009000500014. Epub 2009 Jul 17. [Metabolic Syndrome: clinical and pathophysiological basis for a rational therapeutical approach]. [Article in Spanish] Martínez R G(1), Alonso K R, Novik A V. Author information: (1)Unidad de Lípidos, Fundación Jiménez-Díaz, Madrid, España. Regardless of the diagnostic criteria, the metabolic syndrome is found at least in 20% of the population. The adipose tissue plays an important role in the insulin resistance found in this syndrome. Free fatty acids released by intra-abdominal adipocytes produce an inflammatory and pro-thrombotic response and the persistence of the insulin resistance state, phenomenon termed lipotoxicity. This altered phenotype explains the development of the different components of the metabolic syndrome, such as hypertension, dyslipidemia and altered glucose metabolism. The treatment is based on weight loss and healthy lifestyle. A balanced diet, physical activity and avoidance of smoking are key management features. The use of drugs with pleiotropic effects, which inhibit the renin angiotensin aldosterone axis or acts on the peroxisome proliferators-activated receptors (PPAR) seems promising. PMID: 19701560 [PubMed - indexed for MEDLINE] 1776. Am J Pathol. 2009 Sep;175(3):927-39. doi: 10.2353/ajpath.2009.081155. Epub 2009 Aug 21. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. De Pauw A(1), Tejerina S, Raes M, Keijer J, Arnould T. Author information: (1)Laboratory of Biochemistry and Cell Biology, University of Namur, 61 rue de Bruxelles, Namur, Belgium. In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. PMCID: PMC2731113 PMID: 19700756 [PubMed - indexed for MEDLINE] 1777. Proc Nutr Soc. 2009 Nov;68(4):350-60. doi: 10.1017/S0029665109990279. Epub 2009 Aug 24. Regulation of adipose tissue lipolysis revisited. Bézaire V(1), Langin D. Author information: (1)Inserm U858, Laboratoire de Recherches sur les Obésités, F-31432 Toulouse, France. Human obesity and its complications are an increasing burden in developed and underdeveloped countries. Adipose tissue mass and the mechanisms that control it are central to elucidating the aetiology of obesity and insulin resistance. Over the past 15 years tremendous progress has been made in several avenues relating to adipose tissue. Knowledge of the lipolytic machinery has grown with the identification of new lipases, cofactors and interactions between proteins and lipids that are central to the regulation of basal and stimulated lipolysis. The dated idea of an inert lipid droplet has been appropriately revamped to that of a dynamic and highly-structured organelle that in itself offers regulatory control over lipolysis. The present review provides an overview of the numerous partners and pathways involved in adipose tissue lipolysis and their interaction under various metabolic states. Integration of these findings into whole adipose tissue metabolism and its systemic effects is also presented in the context of inflammation and insulin resistance. PMID: 19698205 [PubMed - indexed for MEDLINE] 1778. Proc Nutr Soc. 2009 Nov;68(4):378-84. doi: 10.1017/S0029665109990218. Epub 2009 Aug 24. Chemotactic cytokines, obesity and type 2 diabetes: in vivo and in vitro evidence for a possible causal correlation? Sell H(1), Eckel J. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany. A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistance in vivo and in vitro. PMID: 19698204 [PubMed - indexed for MEDLINE] 1779. Proc Nutr Soc. 2009 Nov;68(4):370-7. doi: 10.1017/S0029665109990206. Epub 2009 Aug 24. Cellular hypoxia and adipose tissue dysfunction in obesity. Wood IS(1), de Heredia FP, Wang B, Trayhurn P. Author information: (1)Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, Duncan Building, Liverpool L69 3GA, UK. i.s.wood@liverpool.ac.uk Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFalpha, IL-1beta, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity. PMID: 19698203 [PubMed - indexed for MEDLINE] 1780. Proc Nutr Soc. 2009 Nov;68(4):361-9. doi: 10.1017/S0029665109990231. Epub 2009 Aug 24. n-3 PUFA: bioavailability and modulation of adipose tissue function. Kopecky J(1), Rossmeisl M, Flachs P, Kuda O, Brauner P, Jilkova Z, Stankova B, Tvrzicka E, Bryhn M. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic. kopecky@biomed.cas.cz Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. The n-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus, n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodents n-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects of n-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms. n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation of n-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects of n-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation by n-3 LC PUFA. PMID: 19698199 [PubMed - indexed for MEDLINE] 1781. Expert Opin Ther Targets. 2009 Nov;13(11):1295-302. doi: 10.1517/14728220903241641. Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease. Rychli K(1), Huber K, Wojta J. Author information: (1)Medical University of Vienna, Division of Cardiology, Department of Internal Medicine II, Waehringer Guertel 18-20, 1090 Vienna, Austria. In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation. PMID: 19694500 [PubMed - indexed for MEDLINE] 1782. Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R913-24. doi: 10.1152/ajpregu.91053.2008. Epub 2009 Aug 19. Modulation of myocellular fat stores: lipid droplet dynamics in health and disease. Meex RC(1), Schrauwen P, Hesselink MK. Author information: (1)Departments of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands. Storage of fatty acids as triacylglycerol (TAG) occurs in almost all mammalian tissues. Whereas adipose tissue is by far the largest storage site of fatty acids as TAG, subcellular TAG-containing structures--referred to as lipid droplets (LD)--are also present in other tissues. Until recently, LD were considered inert storage sites of energy dense fats. Nowadays, however, LD are increasingly considered dynamic functional organelles involved in many intracellular processes like lipid metabolism, vesicle trafficking, and cell signaling. Next to TAG, LD also contain other neutral lipids such as diacylglycerol. Furthermore, LD are coated by a monolayer of phospholipids decorated with a variety of proteins regulating the delicate balance between LD synthesis, growth, and degradation. Disturbances in LD-coating proteins may result in disequilibrium of TAG synthesis and degradation, giving rise to insulin-desensitizing lipid intermediates, especially in insulin-responsive tissues like skeletal muscle. For a proper and detailed understanding, more information on processes and players involved in LD synthesis and degradation is necessary. This, however, is hampered by the fact that research on LD dynamics in (human) muscle is still in its infancy. A rapidly expanding body of knowledge on LD dynamics originates from studies in other tissues and other species. Here, we aim to review the involvement of LD-coating proteins in LD formation and degradation (LD dynamics) and to extrapolate this knowledge to human skeletal muscle and to explore the role of LD dynamics in myocellular insulin sensitivity. PMID: 19692657 [PubMed - indexed for MEDLINE] 1783. Curr Pharm Des. 2009;15(24):2784-90. Autologous adipose-derived regenerative cells for therapeutic angiogenesis. Murohara T(1), Shintani S, Kondo K. Author information: (1)Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. murohara@med.nagoya-u.ac.jp Therapeutic angiogenesis is an important means to salvage tissues against severe ischemic diseases in patients with no option for other vascular intervention. A number of recent studies implicated potentials of cell-based therapeutic angiogenesis using autologous bone marrow mononuclear cells, CD34(+) cells, peripheral blood mononuclear cells, and so on. Subcutaneous adipose tissues can be harvested by relatively easy methods. Recent studies indicated that adipose tissues contain progenitor cells or regenerative cells that can give rise to several mesenchymal lineages. Moreover, these progenitor cells can release multiple angiogenic growth factors and cytokines/chomokines including vascular endothelial growth factor (VEGF), hypatocyte growth factor (HGF) and chemokine stromal cell-derived factor-1 (SDF-1). The combination of these biological properties of adipose-derived regenerative cells (ADRCs) implicates that autologous adipose tissue will be a useful cell source for therapeutic angiogenesis in the next generation. PMID: 19689349 [PubMed - indexed for MEDLINE] 1784. Curr Med Chem. 2009;16(23):2952-64. Novel insights into adipogenesis from omics data. Prokesch A(1), Hackl H, Hakim-Weber R, Bornstein SR, Trajanoski Z. Author information: (1)Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria. Obesity, the excess accumulation of adipose tissue, is one of the most pressing health problems in both the Western world and in developing countries. Adipose tissue growth results from two processes: the increase in number of adipocytes (hyperplasia) that develop from precursor cells, and the growth of individual fat cells (hypertrophy) due to incorporation of triglycerides. Adipogenesis, the process of fat cell development, has been extensively studied using various cell and animal models. While these studies pointed out a number of key factors involved in adipogenesis, the list of molecular components is far from complete. The advance of high-throughput technologies has sparked many experimental studies aimed at the identification of novel molecular components regulating adipogenesis. This paper examines the results of recent studies on adipogenesis using high-throughput technologies. Specifically, it provides an overview of studies employing microarrays for gene expression profiling and studies using gel based and non-gel based proteomics as well as a chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) or sequencing (ChIP-seq). Due to the maturity of the technology, the bulk of the available data was generated using microarrays. Therefore these data sets were not only reviewed but also underwent meta analysis. The review also shows that large-scale omics technologies in conjunction with sophisticated bioinformatics analyses can provide not only a list of novel players, but also a global view on biological processes and molecular networks. Finally, developing technologies and computational challenges associated with the data analyses are highlighted, and an outlook on the questions not previously addressed is provided. PMCID: PMC2765082 PMID: 19689276 [PubMed - indexed for MEDLINE] 1785. J Physiol. 2009 Nov 1;587(Pt 21):5031-7. doi: 10.1113/jphysiol.2009.177188. Epub 2009 Aug 17. The role of oestrogens in the adaptation of islets to insulin resistance. Nadal A(1), Alonso-Magdalena P, Soriano S, Ropero AB, Quesada I. Author information: (1)Instituto de Bioingeniería and CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Universidad Miguel Hernández de Elche, 03202 Elche, Alicante, Spain. nadal@umh.es Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of beta-cell mass. It is not completely understood why, in some individuals, beta-cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the beta-cell response to maternal hormones may play a key part. The role of the maternal hormone 17beta-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on beta-cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase beta-cell proliferation but it is involved in beta-cell survival. Classical oestrogen receptors ERalpha and ERbeta, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity. PMCID: PMC2790246 PMID: 19687125 [PubMed - indexed for MEDLINE] 1786. Prev Med. 2009 Oct;49(4):283-5. doi: 10.1016/j.ypmed.2009.08.002. Epub 2009 Aug 15. Evolution, body composition, insulin receptor competition, and insulin resistance. Eaton SB(1), Cordain L, Sparling PB. Author information: (1)Department of Anthropology, Emory University, 2887 Howell Mill NW, Atlanta, GA 30327, USA. sboydeaton@comcast.net Erratum in Prev Med. 2011 Jan;52(1):95. OBJECTIVE: Better understanding of the relationships between body composition and insulin resistance. RESULTS: Average human adiposity and sarcopenia have attained unprecedented levels and the resultantly abnormal body composition distorts insulin receptor balance. Compared to evolutionary norms we now have too many adipocyte insulin receptors (in adipose tissue and liver) and too few myocyte insulin receptors. The body's insulin receptors can be conceptualized as competing for insulin molecules released from the pancreas. When an insulin molecule docks on an adipocyte receptor, substantially fewer glucose molecules are cleared from the blood than when an insulin molecule docks on a myocyte insulin receptor. Populational insulin receptor imbalance would seem to parallel the secular rise in insulin resistance and offers an attractive pathophysiological explanation for the accompanying type 2 diabetes epidemic. CONCLUSION: An evolutionary perspective regarding body composition, insulin receptor imbalance, and the consequent impact on carbohydrate metabolism should enhance public acceptance of recommendations to increase physical activity. PMID: 19686772 [PubMed - indexed for MEDLINE] 1787. Acta Med Port. 2009 May-Jun;22(3):291-8. Epub 2009 Jul 15. [The role of leptin in the regulation of energy balance]. [Article in Portuguese] Sousa M(1), Brás-Silva C, Leite-Moreira A. Author information: (1)Universidade do Porto, Porto. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been the subject of intensive research. Recent experimental studies have implicated leptin as a crucial controller of body weight. Leptin is a 167-aminoacid peptide hormone, which is mainly produced by adipocytes, and its levels in the circulation are increased in proportion to fat mass. Circulating leptin conveys information to the hypothalamus regarding the amount of energy stored in adipose tissue, suppressing appetite and affecting energy expenditure. Considerable evidence shows that this hormone is also involved in the regulation of several physiological processes such as reproduction, angiogenesis, immunity, hematopoiesis and bone remodelling. Leptin acts through leptin receptors that are ubiquitously distributed and hence explain the pleiotropic roles of leptin. In the present review, we will summarize the recent developments in the leptin field, with particular attention to aspects related with physiological and molecular mechanisms regulating energy homeostasis, as well as their implications in the pathophysiology of weight disorders. PMID: 19686630 [PubMed - indexed for MEDLINE] 1788. Curr Opin Pharmacol. 2009 Dec;9(6):753-62. doi: 10.1016/j.coph.2009.07.004. Epub 2009 Aug 13. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Tanti JF(1), Jager J. Author information: (1)INSERM U895, Mediterranean Center of Molecular Medicine (C3M), Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France. tanti@unice.fr Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication. PMID: 19683471 [PubMed - indexed for MEDLINE] 1789. Mol Cell Endocrinol. 2010 Jan 15;314(1):1-16. doi: 10.1016/j.mce.2009.07.031. Epub 2009 Aug 12. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Maury E(1), Brichard SM. Author information: (1)Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, 1200 Brussels, Belgium. Obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines may link obesity to its co-morbidities. Most adipokines with pro-inflammatory properties are overproduced with increasing adiposity, while some adipokines with anti-inflammatory or insulin-sensitizing properties, like adiponectin are decreased. This dysregulation of adipokine production may promote obesity-linked metabolic disorders and cardiovascular disease. Besides considering adipokines, this review will also highlight the cellular key players and molecular mechanisms involved in adipose inflammation. Targeting the changes in the cellular composition of adipose tissue, the underlying molecular mechanisms, and the altered production of adipokines may have therapeutic potential in the management of the metabolic syndrome. PMID: 19682539 [PubMed - indexed for MEDLINE] 1790. Expert Rev Proteomics. 2009 Aug;6(4):353-61. doi: 10.1586/epr.09.53. Tackling the human adipose tissue proteome to gain insight into obesity and related pathologies. Peral B(1), Camafeita E, Fernández-Real JM, López JA. Author information: (1)Instituto de Investigaciones Biomédicas, Alberto Sols, CSIC & Universidad Autónoma de Madrid, Arturo Duperier, 4, E-28029 Madrid, Spain. bperal@iib.uam.es Obesity is becoming an important public health problem given its strong association with insulin resistance and Type 2 diabetes. Previously considered an inert depot, fat is now regarded as a highly metabolically active tissue in many pathophysiological processes. In humans, the accumulation of omental rather than subcutaneous adipose tissue appears to be tightly linked to cardiovascular disease and other important comorbidities. Proteomics has emerged as a method for the large-scale study of proteins in biological samples, for instance, fluids, cells or tissues, which encompasses not only the identities of the proteins present, but also quantification and post-translational modification events. Human adipose tissue proteome analysis, still in its early stages, may help understand the molecular mechanisms of obesity and the role of omental fat in the pathogenesis of obesity-associated diseases. This review covers recent advances in human adipose tissue proteomics, focusing on the analysis of the omental and the subcutaneous fat. PMID: 19681671 [PubMed - indexed for MEDLINE] 1791. Curr Opin Cell Biol. 2009 Oct;21(5):717-23. doi: 10.1016/j.ceb.2009.07.001. Epub 2009 Aug 11. The skinny on Fat: an enormous cadherin that regulates cell adhesion, tissue growth, and planar cell polarity. Sopko R(1), McNeill H. Author information: (1)Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Department of Molecular Genetics, University of Toronto, 600 University Avenue, Toronto, Ontario, Canada. Fat is an extremely large atypical cadherin involved in the regulation of cell adhesion, tissue growth, and planar cell polarity (PCP). Recent studies have begun to illuminate the mechanisms by which Fat performs these functions during development. Fat relays signals to the Hippo pathway to regulate tissue growth, and to PCP proteins to regulate tissue patterning. In this review we briefly cover the historical data demonstrating that Fat regulates tissue growth and tissue patterning, and then focus on advances in the past three years illuminating the mechanisms by which Fat controls growth and planar polarity in flies and mammals. PMID: 19679459 [PubMed - indexed for MEDLINE] 1792. Neuro Endocrinol Lett. 2009;30(2):153-79. Endocannabinoid system: An overview of its potential in current medical practice. Mouslech Z(1), Valla V. Author information: (1)1st Department of Internal Medicine Clinic, AHEPA University Hospital, Aristotle University, Thessaloniki, Greece. The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction system. The CB2R is mainly expressed in the immune system regulating its functions. Endocannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent advances have correlated the ECS with drug addiction and alcoholism. The growing number of preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a number of diseases currently treated inadequately. The ECS dysregulation has been correlated to obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters. However, safety conerns have led to its withrawal. The role of endocannabinoids in mammalian reproduction is an emerging research area given their implication in fertilization, preimplantation embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new perspectives as a target to improve infertility and reproductive health in humans. PMID: 19675519 [PubMed - indexed for MEDLINE] 1793. Expert Rev Cardiovasc Ther. 2009 Aug;7(8):911-9. doi: 10.1586/erc.09.84. Cellular cardiac regenerative therapy in which patients? Chachques JC(1). Author information: (1)Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, 75015 Paris, France. j.chachques@brs.aphp.fr Cell-based myocardial regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles owing to ischemic and nonischemic myocardial diseases. A variety of myogenic and angiogenic cell types have been proposed, such as skeletal myoblasts, mononuclear and mesenchymal bone marrow cells, circulating blood-derived progenitors, adipose-derived stromal cells, induced pluripotent stem cells, umbilical cord cells, endometrial mesenchymal stem cells, adult testis pluripotent stem cells and embryonic cells. Current indications for stem cell therapy concern patients who have had a left- or right-ventricular infarction or idiopathic dilated cardiomyopathies. Other indications and potential applications include patients with diabetic cardiomyopathy, Chagas heart disease (American trypanosomiasis), ischemic mitral regurgitation, left ventricular noncompacted myocardium and pediatric cardiomyopathy. Suitable sources of cells for cardiac implant will depend on the types of diseases to be treated. For acute myocardial infarction, a cell that reduces myocardial necrosis and augments vascular blood flow will be desirable. For heart failure, cells that replace or promote myogenesis, reverse apoptopic mechanisms and reactivate dormant cell processes will be useful. It is important to note that stem cells are not an alternative to heart transplantation; selected patients should be in an early stage of heart failure as the goal of this regenerative approach is to avoid or delay organ transplantation. Since the cell niche provides crucial support needed for stem cell maintenance, the most interesting and realistic perspectives include the association of intramyocardial cell transplantation with tissue-engineered scaffolds and multisite cardiac pacing in order to transform a passive regenerative approach into a 'dynamic cellular support', a promising method for the creation of 'bioartificial myocardium'. PMID: 19673669 [PubMed - indexed for MEDLINE] 1794. Arch Physiol Biochem. 2009 Oct;115(4):227-39. doi: 10.1080/13813450903164330. Molecular mechanisms involved in obesity-associated insulin resistance: therapeutical approach. Fernández-Veledo S(1), Nieto-Vazquez I, Vila-Bedmar R, Garcia-Guerra L, Alonso-Chamorro M, Lorenzo M. Author information: (1)Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain. soferve@farm.ucm.es Insulin resistance is an important contributor to the pathogenesis of T2D and obesity is a risk factor for its development. It has been demonstrated that these obesity-related metabolic disorders are associated with a state of chronic low-intensity inflammation. Several mediators released from adipocytes and macrophages, such as the pro-inflammatory cytokines TNF-alpha and IL-6, have been suggested to impair insulin action in peripheral tissues, including fat and skeletal muscle. Such insulin resistance can initially be compensated by increased insulin secretion, but the prolonged presence of the hormone is detrimental for insulin sensitivity. Stress and pro-inflammatory kinases as well as more recent players, phosphatases, seem to be involved in the molecular mechanisms by which pro-inflammatory cytokines and hyperinsulinemia disrupt insulin signalling at the level of IRSs. Pharmacological approaches, such as treatment with PPAR and LXR agonists, overcome such insulin resistance, exerting anti-inflammatory properties as well as controlling the expression of cytokines with tissular specificity. PMID: 19673658 [PubMed - indexed for MEDLINE] 1795. World J Gastroenterol. 2009 Aug 14;15(30):3827-30. Mesenteric panniculitis: various presentations and treatment regimens. Issa I(1), Baydoun H. Author information: (1)Department of Gastroenterology & Hepatology, Rafik Hariri University Hospital, Beirut 2034-7304, Lebanon. iyadissa71@gmail.com Comment in World J Gastroenterol. 2009 Dec 28;15(48):6139. Mesenteric panniculitis is a rare, benign and chronic fibrosing inflammatory disease that affects the adipose tissue of the mesentery of the small intestine and colon. The specific etiology of the disease is unknown. The diagnosis is suggested by computed tomography and is usually confirmed by surgical biopsies. Treatment is empirical and based on a few selected drugs. Surgical resection is sometimes attempted for definitive therapy, although the surgical approach is often limited. We report two cases of mesenteric panniculitis with two different presentations and subsequently varying treatment regimens. Adequate response was obtained in both patients. We present details of these cases as well as a literature review to compare various presentations, etiologies and potential treatment modalities. PMCID: PMC2726466 PMID: 19673029 [PubMed - indexed for MEDLINE] 1796. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1139-43. doi: 10.1111/j.1440-1681.2009.05275.x. Epub 2009 Aug 4. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha in muscle links metabolism to inflammation. Handschin C(1). Author information: (1)Biozentrum, University of Basel, Basel and Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. christoph.handschin@unibas.ch 1. In higher eukaryotes, metabolism and immunity are tightly coupled. However, whereas in evolutionary terms a compromised immune response due to undernourishment has been the predominant problem, the inflammatory response to obesity and other lifestyle-associated diseases has increased in relevance in Western societies in the past 100 years. 2. Traditionally, fat tissue has been considered as the major source of pro-inflammatory secreted factors in these pathologies. However, in recent years the contribution of other tissues to disease-causing chronic inflammation has been increasingly appreciated. 3. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is one of the key regulatory factors in active skeletal muscle. Aberrant expression of PGC-1alpha in inactive muscle fibres could be linked to a sedentary lifestyle, persistent systemic inflammation and a higher risk for many chronic diseases. Accordingly, modulation of PGC-1alpha activity in skeletal muscle may have a broad range of therapeutic effects. Here, recent advances in the understanding of the role of muscle PGC-1alpha in health and disease are reviewed. PMID: 19671064 [PubMed - indexed for MEDLINE] 1797. Expert Rev Anticancer Ther. 2009 Aug;9(8):1091-101. doi: 10.1586/era.09.71. Influence of obesity on breast cancer receptor status and prognosis. Rose DP(1), Vona-Davis L. Author information: (1)Department of Surgery and Mary Babb Randolph Cancer Center, West Virginia University Robert C. Byrd Health Sciences Center, Morgantown, WV 26506, USA. davidrosemd@hotmail.com Pre-existing obesity and postoperative weight gain are related to a poor prognosis in breast cancer regardless of menopausal status. Delayed diagnosis may be one cause, but of more biological significance, especially in younger women, is the association of adiposity with estrogen receptor-negative tumors with a propensity for distant metastasis. After the menopause, the major mechanism for the relationship is the elevated estrogen synthesis by adipose tissue; these hormone-dependent tumors are estrogen receptor-positive. Insulin and some adipokines also stimulate breast cancer growth and metastasis, both directly and most probably by enhanced angiogenesis. Weight control is important, not only to target breast cancer progression, but also to reduce the risk of nonbreast cancer mortality risk associated with excess adiposity. PMID: 19671029 [PubMed - indexed for MEDLINE] 1798. Arch Physiol Biochem. 2009 Oct;115(4):176-90. doi: 10.1080/13813450903079314. Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells. Bilan PJ(1), Samokhvalov V, Koshkina A, Schertzer JD, Samaan MC, Klip A. Author information: (1)Cell Biology Program, The Hospital for Sick Children, Toronto, Canada. Obesity is associated with insulin resistance and increased risk for developing type 2 diabetes. Enlarged adipocytes develop resistance to the anti-lipolytic action of insulin. Elevated levels of fatty acids in the plasma and interstitial fluids lead to whole-body insulin resistance by disrupting normal insulin-regulated glucose uptake and glycogen storage in skeletal muscle. A new understanding has been cultivated in the past 5 to 10 years that adipocytes and macrophages (resident or bone marrow-derived) in adipose tissue of obese animals and humans are activated in a pro-inflammatory capacity and secrete insulin resistance-inducing factors. However, only recently have fatty acids themselves been identified as agents that engage toll-like receptors of the innate immunity systems of macrophages, adipocytes and muscle cells to trigger pro-inflammatory responses. This review summarizes our observations that fatty acids evoke the release of pro-inflammatory factors from macrophages that consequently induce insulin resistance in muscle cells. PMID: 19671019 [PubMed - indexed for MEDLINE] 1799. Stem Cell Rev. 2009 Sep;5(3):256-65. doi: 10.1007/s12015-009-9084-y. Epub 2009 Aug 11. Adipose derived stem cells and smooth muscle cells: implications for regenerative medicine. de Villiers JA(1), Houreld N, Abrahamse H. Author information: (1)Laser Research Group, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa. The treatment of chronic wounds and other damaged tissues and organs remains a difficult task, in spite of greater adherence to recognised standards of care and a better understanding of pathophysiologic principles. Adipose derived stem cells (ADSCs), with their proliferative and impressive differentiation potential, may be used in the future in autologous cell therapy or grafting to replace damaged tissues. At this point in time, transplanted tissues are often rejected by the body. Autologous grafting would eliminate this problem. ADSCs are able to differentiate into a number of cells in vitro, for example smooth muscle cells (SMCs), when treated with lineage specific factors. SMCs play a key role in physiology and pathology as they form the principle layer of all SMC tissues. Smooth muscle biopsies are often impractical and morbid, and often lead to a low cell harvest. It has also been shown that SMCs derived from a diseased organ can lead to abnormal cells. Therefore, there is a great need for alternative sources of healthy SMCs. The use of ADSCs for cell-based tissue engineering (TE) represents a promising alternative for smooth muscle repair. This review discusses the potential uses of ADSCs and SMCs in regenerative medicine, and the potential of ADSCs to be differentiated into functional SMCs for TE and regenerative cellular therapies to repair diseased organs. PMID: 19669954 [PubMed - indexed for MEDLINE] 1800. Curr Opin Support Palliat Care. 2009 Dec;3(4):269-75. doi: 10.1097/SPC.0b013e328331124a. The emerging role of computerized tomography in assessing cancer cachexia. Prado CM(1), Birdsell LA, Baracos VE. Author information: (1)Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, Canada. PURPOSE OF REVIEW: The present review represents an overview of the potential opportunistic use of computerized tomography (CT) to enhance our understanding of abnormal body composition, specifically lean and adipose tissue changes in cancer cachexia. RECENT FINDINGS: One of the characteristics of cancer cachexia is the depletion of muscle with or without adipose tissue loss. Therefore, a body composition tool that specifically distinguishes between these tissues is essential in assessing this syndrome. Cancer patients are routinely evaluated by high resolution imaging such as CT for the purpose of diagnosis and follow-up. Recent work exploiting CT images for body composition analysis has revealed the natural history of cancer cachexia, including progressive alterations in skeletal muscle, adipose tissue, organs, and tumor mass. CT-based quantification of skeletal muscle has permitted identification of individuals with sarcopenia, and links between sarcopenia and functional status, chemotherapy toxicity, time to tumor progression, and mortality. SUMMARY: CT images routinely acquired from health records of cancer patients can be used to quantify specific lean and adipose tissues, to interpret body composition in population-based studies, and to evaluate individual patients in a clinical and therapeutic decision-making setting. PMID: 19667996 [PubMed - indexed for MEDLINE] 1801. Vnitr Lek. 2009 Jun;55(6):560-4. [Relationships of hormones of adipose tissue and ghrelin to bone metabolism]. [Article in Czech] Zofková I(1). Author information: (1)Endokrinologický ustav Praha. izofkova@endo.cz Body adipose tissue influences bone metabolism through mechanical load, as well as via hormones released into circulation. Such hormones are adipocytokines--leptin, adiponectin, TNF-alpha, IL-6, resistin and visfatin. Some of them exert an osteoanabolic effect, while the others activate bone resorption. An increasingly discussed adipocytokine is leptin, which fundamental role is regulation of food intake ensuring survival of the organism during starvation. Leptin also stimulates osteoblasts and activates bone formation. The direct osteotropic effect of leptin is modulated by interaction with hypothalamic centers and neurohormones. Apparently, the most important leptin sensitive pathway involved in bone regulation is the beta-adrenergic system. While activation of beta-1-adrenergic receptors by leptin enhances bone formation, activation of beta-2-adrenergic receptors in hypothalamus and in the skeleton increases bone resorption. In humans, an anabolic effect on the skeleton prevails. In pubertal girls, leptin extensively released into circulation at the moment when adipose tissue reaches a critical volume, stimulates synthesis of GnRH and induces puberty, which is followed by striking increases in bone mass. Low leptin levels in anorexia nervosa are associated with amenorrhoea, which slows down increase of bone mass and may induce osteopenia. Important adipocytokine with an unambiguous negative effect on bone is adiponectin. Decreased production of this hormone explains in part the lower prevalence of osteoporosis in obese persons. In this article, the osteotropic importance ofleptin-sensitive neurohormonal mechanisms and other hormones related to adipose tissue are discussed. Clinical importance of the above mentioned hormones to integrity of the skeleton has not yet been verified. PMID: 19662887 [PubMed - indexed for MEDLINE] 1802. Transplant Proc. 2009 Jul-Aug;41(6 Suppl):S31-8. doi: 10.1016/j.transproceed.2009.06.159. Epub 2009 Jul 19. Mammalian target of rapamycin and diabetes: what does the current evidence tell us? Vodenik B(1), Rovira J, Campistol JM. Author information: (1)Department of Nephrology and Renal Transplantation, Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. New-onset diabetes mellitus after transplantation (NODAT) is a serious complication in organ transplantation; not only does it enhance the risk of graft dysfunction, it also increases cardiovascular morbidity and mortality. The mammalian target of rapamycin (mTOR) is regulated independently by insulin, amino acids, and energy sufficiency. It integrates signal from growth factors, hormones, nutrients, and cellular energy levels to regulate protein translation and cell growth, proliferation, and survival. In addition, mTOR generates an inhibitory feedback loop on insulin receptor substrate (IRS) proteins. Therefore, it was suggested that mTOR might link nutrient excess with both obesity and insulin resistance. In this review, we summarize the role of mTOR and its inhibitor sirolimus (SRL) on chronic hyperglycemia and insulin resistance in beta cells, adipose tissue, liver, and muscle. We further hypothesize, based on data from the literature and generated in our laboratory, that SRL could counteract the development of NODAT in stable glucose homeostasis due to its positive effects on insulin-stimulated glucose uptake, whereas in conditions that require an adaptive beta cell proliferation (such as pregnancy and weight increase), the administration of SRL might have effects that would promote the development of NODAT. Therefore, it seems crucial for patient outcome to consider these potentially contrasting effects of SRL. PMID: 19651294 [PubMed - indexed for MEDLINE] 1803. Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S18-23. doi: 10.1002/dmrr.983. Physical inactivity and obesity: links with insulin resistance and type 2 diabetes mellitus. Venables MC(1), Jeukendrup AE. Author information: (1)Exercise Metabolism Research Group, Human Performance Laboratory, School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. michelle.venables@brookes.ac.uk Data from the health survey for England 2006, showed that the prevalence of type 2 diabetes mellitus (T2DM) has more than doubled in men and women since 1991. In the USA certain States have a prevalence of T2DM of greater than 10%. Globally it has been reported that this increase is by no means slowing down and that the number of individuals with the disease is expected to rise from 171 million cases reported in 2000 to 366 million by the year 2030. Physical inactivity and obesity are two major risk factors for the development of T2DM. In this review we will discuss evidence of an association between physical inactivity, obesity and T2DM from prospective cohort studies and clinical trials. We will also discuss some of the potential mechanisms that are thought to link obesity and physical inactivity with the major pathophysiological precursor of T2DM, insulin resistance. PMID: 19662619 [PubMed - indexed for MEDLINE] 1804. Lancet. 2009 Oct 3;374(9696):1179-85. doi: 10.1016/S0140-6736(09)60912-0. Epub 2009 Aug 5. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Sorg O(1), Zennegg M, Schmid P, Fedosyuk R, Valikhnovskyi R, Gaide O, Kniazevych V, Saurat JH. Author information: (1)Dermato-Toxicology, Swiss Centre for Applied Human Toxicology, and Department of Dermatology, University Hospital, Geneva, Switzerland. Comment in Lancet. 2009 Oct 3;374(9696):1131-2. BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a long half-life of 5-10 years in human beings as a result of its high lipophilicity, and little or no metabolism. We monitored TCDD, its form, distribution, and elimination in Victor Yushchenko after he presented with severe poisoning. METHODS: In late December, 2004, a patient presented with TCDD poisoning; the levels in his blood serum (108000 pg/g lipid weight) were more than 50 000-fold greater than those in the general population. We identified TCDD and its metabolites, and monitored their levels for 3 years using gas chromatography and high-resolution mass spectrometry in samples of blood serum, adipose tissue, faeces, skin, urine, and sweat, after they were extracted and cleaned with different organic solvents. FINDINGS: The amount of unmodified TCDD in the samples that were analysed accounted for about 60% of TCDD eliminated from the body during the same period. Two TCDD metabolites-2,3,7-trichloro-8-hydroxydibenzo-p-dioxin and 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin-were identified in the faeces, blood serum, and urine. The faeces contained the highest concentration of TCDD metabolites, and were the main route of elimination. Altogether, the different routes of elimination of TCDD and its metabolites accounted for 98% of the loss of the toxin from the body. The half-life of TCDD in our patient was 15.4 months. INTERPRETATION: This case of poisoning with TCDD suggests that the design of methods for routine assessment of TCDD metabolites in human beings should be a main aim of TCDD research in the metabolomic era. FUNDING: University of Geneva Dermatology Fund, and Swiss Centre for Applied Human Toxicology. PMID: 19660807 [PubMed - indexed for MEDLINE] 1805. Obes Rev. 2010 Jan;11(1):11-8. doi: 10.1111/j.1467-789X.2009.00623.x. Epub 2009 Jul 28. Subcutaneous and visceral adipose tissue: structural and functional differences. Ibrahim MM(1). Author information: (1)Cardiology Department, Cairo University, 1 El-Sherifein Street, Abdeen, Cairo 11111, Egypt. ehs@link.net Obesity is a heterogeneous disorder. Obese individuals vary in their body fat distribution, their metabolic profile and degree of associated cardiovascular and metabolic risk. Abdominal obesity carries greater risk of developing diabetes and future cardiovascular events than peripheral or gluteofemoral obesity. There are differences between adipose tissue present in subcutaneous areas (SCAT) and visceral adipose tissue (VAT) present in the abdominal cavity. These include anatomical, cellular, molecular, physiological, clinical and prognostic differences. Anatomically, VAT is present mainly in the mesentery and omentum, and drains directly through the portal circulaion to the liver. VAT compared with SCAT is more cellular, vascular, innervated and contains a larger number of inflammatory and immune cells, lesser preadipocyte differentiating capacity and a greater percentage of large adipocytes. There are more glucocorticoid and androgen receptors in VAT than in SCAT. VAT adipocytes are more metabolically active, more sensitive to lipolysis and more insulin-resistant than SCAT adipocytes. VAT has a greater capacity to generate free fatty acids and to uptake glucose than SCAT and is more sensitive to adrenergic stimulation, while SCAT is more avid in absorption of circulating free fatty acids and triglycerides. VAT carries a greater prediction of mortality than SCAT. PMID: 19656312 [PubMed - indexed for MEDLINE] 1806. Clin Exp Pharmacol Physiol. 2010 Jan;37(1):121-4. doi: 10.1111/j.1440-1681.2009.05259.x. Epub 2009 Jul 24. Targeting energy expenditure in muscle as a means of combating obesity. Clarke IJ(1), Henry BA. Author information: (1)Department of Physiology, Monash University, Melbourne, Victoria, Australia. iain.clarke@med.monash.edu.au 1. To date, an effective therapeutic agent that induces weight loss in obese subjects remains elusive. In order to establish a successful means to combat obesity, it is imperative that we identify novel targets that regulate energy balance. 2. Exciting new data have created resurgence in interest in the role of thermogenesis in energy balance. Recently, it has been demonstrated that functional brown adipocytes are present in adult humans and that brown adipocytes and myocytes are derived from a similar cell lineage and are thus likely to have similar physiological functions. 3. Recent work in the sheep has demonstrated that diffuse fat beds and skeletal muscle exhibit thermogenic properties. Furthermore, in sheep, central administration of leptin markedly increases postprandial thermogenesis in both fat and muscle tissues. This demonstrates that thermogenic processes in skeletal muscle can be manipulated in a similar way to thermogenesis in brown fat. 4. Given that skeletal muscle comprises a significant portion of bodyweight, approximately 30-40% of total body mass, we predict that energy expended by this tissue is likely to have significant ramifications for the regulation of bodyweight. 5. We propose that manipulation of skeletal muscle thermogenesis may provide a novel avenue for the development of anti-obesity therapies. PMID: 19650796 [PubMed - indexed for MEDLINE] 1807. Pol Merkur Lekarski. 2009 Jul;27(157):36-9. [Laboratory markers of nutritional state in patients treated with peritoneal dialysis]. [Article in Polish] Grzegorzewska AE(1). Author information: (1)Uniwersytet Medyczny w Poznaniu, Katedra i Klinika Nefrologii, Transplantologii i Chorób Wewnetrznych. alicja_grzegorzewska@yahoo.com Selected laboratory markers of nutritional state in patients treated with peritoneal dialysis (PD) are presented in this review. Parameters, which depend on intake of nutritional products and are related to consequences of nutrition, especially to development of abdominal obesity, are shown. Attention is paid on factors, which modify laboratory parameters of nutritional state, independently on quantity and quality of ingested products. These parameters include volume of extracellular water, inflammatory state, metrical age, duration of treatment with PD, metabolic acidosis, treatment with angiotensin converting enzyme inhibitors. Among laboratory parameters, which are related to excess of visceral fat tissue, the most important results of investigations on serum adipocytokine concentration and insulin resistance are presented, underlying their associations with anthropometric parameters of nutritional state of PD patients. PMID: 19650427 [PubMed - indexed for MEDLINE] 1808. Peptides. 2009 Oct;30(10):1957-63. doi: 10.1016/j.peptides.2009.07.021. Epub 2009 Aug 6. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Kalra SP(1). Author information: (1)Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, PO Box 100244, Gainesville, FL 32610-0244, United States. skalra@mbi.ufl.edu Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans. PMCID: PMC2755606 PMID: 19647774 [PubMed - indexed for MEDLINE] 1809. Trends Endocrinol Metab. 2009 Aug;20(6):295-302. doi: 10.1016/j.tem.2009.03.005. Epub 2009 Jul 31. eNOS, metabolic syndrome and cardiovascular disease. Huang PL(1). Author information: (1)Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. phuang1@partners.org Large epidemiologic studies have established that diabetes, hyperlipidemia and obesity all increase the risk for cardiovascular disease. However, the precise mechanisms by which these metabolic disorders increase the propensity to develop atherosclerosis are not known. Recently, the concept of the metabolic syndrome - a constellation of conditions including obesity, hypertension, hyperlipidemia and insulin resistance - has received much attention. Studies on the metabolic syndrome might enable a better understanding of the underlying biological mechanisms that lead to cardiovascular disease. This review focuses on endothelial nitric oxide synthase and summarizes evidence that a reduction in the bioavailability of endothelium-derived nitric oxide serves as a key link between metabolic disorders and cardiovascular risk. PMCID: PMC2731551 PMID: 19647446 [PubMed - indexed for MEDLINE] 1810. Pharmacol Res. 2009 Sep;60(3):141-50. doi: 10.1016/j.phrs.2009.03.014. Epub 2009 Apr 2. PPARs and the orchestration of metabolic fuel selection. Sugden MC(1), Zariwala MG, Holness MJ. Author information: (1)Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St Bartholomew's, London, UK. m.c.sugden@qmul.ac.uk This contribution describes recent advances in our knowledge of the regulatory interactions between the two major oxidative fuels glucose and lipid. It also addresses how the metabolic abnormalities associated with insulin resistance and ischemic diseases impair the ability of skeletal muscle to switch between the use of alternative metabolic fuels and the ability of adipose tissue to function appropriately in relation to the body's requirements for triglyceride mobilisation or storage, as appropriate to nutritional status. We discuss how targeting PPARs might ameliorate metabolic inflexibility in muscle through altered expression of pyruvate dehydrogenase kinase (PDK) isoforms and impact the functions of the adipocyte in lipid buffering and energy homeostasis. Focus has been placed on the participation of the regulatory pyruvate dehydrogenase kinases, PPAR targets, both in the beneficial and the potentially adverse actions of the PPARs in metabolic control. PMID: 19646653 [PubMed - indexed for MEDLINE] 1811. Expert Opin Drug Saf. 2009 Sep;8(5):523-35. doi: 10.1517/14740330903190674. The potential adverse effects of aromatase inhibitors on wound healing: in vitro and in vivo evidence. Howgate DJ(1), Gamie Z, Panteliadis P, Bhalla A, Mantalaris A, Tsiridis E. Author information: (1)University of Leeds, School of Medicine, Leeds General Infirmary Teaching Hospitals NHS Trust, Academic Department of Trauma and Orthopaedics, Clarendon Wing A, Great George Street, Leeds, LS1 3EX, UK. BACKGROUND: Estrogens and several other endogenous substances are recognised as being important in the process of wound healing. However, the effect of aromatase and aromatase inhibition in the wound healing process has yet to be fully defined. OBJECTIVE: A review of the in vitro and in vivo evidence on the effect of aromatase inhibition on wound healing. METHODS: The primary medical search engines used for the study were Ovid MEDLINE (1950 - March 2009) and EMBASE (1980 - March 2009) databases. RESULTS/CONCLUSION: The delayed healing of cutaneous wounds in aged individuals may in part reflect the decline in circulating levels of dehydroepiandrosterone (DHEA) and estrogens. The beneficial response on wound healing that DHEA and estrogen exert may be blocked by aromatase inhibition. Based on animal models, aromatase inhibitors may adversely affect cutaneous wound healing in the acute setting. So far, there have been no clinical trials investigating the adverse affect of aromatase inhibitors on the process of cutaneous wound healing in humans. Postmenopausal patients who take aromatase inhibitors as an adjunct to breast cancer therapy may, therefore, be at increased risk of delayed wound healing. Further studies are necessary to assess the extent of the effects on the wound healing process. PMID: 19645634 [PubMed - indexed for MEDLINE] 1812. Cardiology. 2009;114(3):212-25. doi: 10.1159/000230691. Epub 2009 Jul 29. Role of the endocannabinoid system in abdominal obesity and the implications for cardiovascular risk. Rosenson RS(1). Author information: (1)SUNY Downstate, Brooklyn, NY 11203, USA. robert.rosenson@downstate.edu Several cardiometabolic factors present in obese and insulin-resistant individuals represent a continuum of increasing risk for the development of type 2 diabetes and cardiovascular disease. The importance of abdominal obesity as an independent risk factor is underscored by its association with adverse endocrine function. Recent evidence from animal and human studies has shown a role for the endocannabinoid system in maintaining energy balance and glucose and lipoprotein metabolism, with overactivity linked to aberrant glycemic and lipoprotein control, and a link to adiposity. Modulation of this system through endocannabinoid-receptor blockade has resulted in an improvement in a number of important risk factors in clinical trials, including visceral and subcutaneous abdominal adipose tissue, glucose tolerance, dyslipidemia and measures of inflammation. These findings may have significant implications for the management of patients at risk of developing cardiovascular and metabolic disease; however, the occurrence of psychiatric adverse events with rimonabant may preclude further development of centrally active endocannabinoid receptor antagonists for the treatment of cardiometabolic disorders. Future research is needed to explore the role of selective peripheral CB(1) receptor antagonists in the treatment of patients at high cardiometabolic risk. Copyright 2009 S. Karger AG, Basel. PMID: 19641317 [PubMed - indexed for MEDLINE] 1813. Handb Exp Pharmacol. 2009;(193):271-95. doi: 10.1007/978-3-540-89615-9_9. A1 adenosine receptor: role in diabetes and obesity. Dhalla AK(1), Chisholm JW, Reaven GM, Belardinelli L. Author information: (1)Department of Pharmacological Sciences, CV Therapeutics Inc., Palo Alto, CA 94304, USA. arvinder.dhalla@cvt.com Adenosine mediates its diverse effects via four subtypes (A(1), A(2A), A(2B) and A(3)) of G-protein-coupled receptors. The A(1) adenosine receptor (A(1)AR) subtype is the most extensively studied and is well characterized in various organ systems. The A(1)ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A(1)ARs. Activation of the A(1)ARs in adipocytes reduces adenylate cyclase and cAMP content and causes inhibition of lipolysis. The role of A(1)ARs in lipolysis has been well characterized by using several selective A(1)AR agonists as well as A(1)AR knockout mice. However, the contribution of A(1)ARs to the regulation of lipolysis in pathological conditions like insulin resistance, diabetes and dyslipidemia, where free fatty acids (FFA) play an important role, has not been well characterized. Pharmacological agents that reduce the release of FFA from adipose tissue and thus the availability of circulating FFA have the potential to be useful for insulin resistance and hyperlipidemia. Toward this goal, several selective and efficacious agonists of the A(1)ARs are now available, and some have entered early-phase clinical trials; however, none have received regulatory approval yet. Here we review the existing knowledge on the role of A(1)ARs in insulin resistance, diabetes and obesity, and the progress made in the development of A(1)AR agonists as antilipolytic agents, including the challenges associated with this approach. PMID: 19639285 [PubMed - indexed for MEDLINE] 1814. Cas Lek Cesk. 2009;148(3):116-23. [Fatty acids--2. Clinical and physiological significance]. [Article in Czech] Tvrzická E(1), Stanková B, Vecka M, Zák A. Author information: (1)Univerzita Karlova v Praze 1, LF UK a VFN, Praha. eva.tvrzicka@vfn.cz Fatty acids play multiple roles in humans and other organisms. In triglycerides they are the source of metabolic energy, in adipose tissue they serve also as temperature and mechanical isolators, in the form of phospholipids they are structural components of membranes. Fatty acids originating from the sn-2 glycerol carbon of phosphatidylcholine can influence the activity of diglycerides as second messengers. Unsaturated FA with 18-20 carbon atoms are precursors of prostaglandins, leucotrienes and thromboxanes, which have a broad scale of regulatory properties and have autocrine as well as paracrine effects. Fatty acids are ligands of several nuclear receptors, which take part in the subcellular control of a number of metabolic pathways. Covalent modification of proteins by FA (acylation) enables FA incorporation into the membranes. Number of pathological stages is accompanied with changes in fatty acid composition, often expressed as decreased content of unsaturated and increased content of saturated fatty acids (e.g. dyslipidemia, malnutrition, inflammation and inherited diseases). Polyunsaturated fatty acids as dietary supplements are used in prevention and in the therapy of cardiovascular diseases and other metabolic disturbances. PMID: 19634271 [PubMed - indexed for MEDLINE] 1815. Med Clin (Barc). 2010 Jul 17;135(6):274-9. doi: 10.1016/j.medcli.2009.04.046. Epub 2009 Jul 23. [Bone metabolism and fracture risk in anorexia nervosa]. [Article in Spanish] Fernández Soto ML(1), González Jiménez A, Varsavsky M. Author information: (1)Servicio de Endocrinología y Nutrición, Unidad de Nutrición Clínica y Dietética, Hospital Universitario San Cecilio, Granada, España. mlfernan@ugr.es The prevalence of anorexia nervosa has increased in recent years and a large proportion of patients with this disorder have low bone density at diagnosis and, therefore, an increased risk of early and late fractures. The mechanism of bone loss in anorexia nervosa is not well understood, yet it likely includes hypogonadism, alterations of the GH-IGF-1 axis and hypercortisolism. DEXA is the most effective tool for assessing and monitoring bone density in these patients, and it is important to improve or at least stabilize bone metabolism in those with low bone mass. No agent has yet been proven to be effective in improving bone density. However, sustained weight recovery and menses besides an adequate intake of calcium and vitamin D are recommended to optimize the conditions in which bone mass accrual may occur. Copyright © 2009 Elsevier España, S.L. All rights reserved. PMID: 19631350 [PubMed - indexed for MEDLINE] 1816. Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1723-9. doi: 10.1161/ATVBAHA.109.187179. Epub 2009 Jul 23. Adipose tissue-derived stem cells: characterization and potential for cardiovascular repair. Madonna R(1), Geng YJ, De Caterina R. Author information: (1)Institute of Cardiology, G. d'Annunzio University, Chieti, Italy. Experimental studies have shown that cardiac transfer of unfractionated or partially purified bone marrow cells, as well as stem cells and progenitor cells derived from the bone marrow or peripheral blood, can enhance functional recovery after an acute myocardial infarction. However, the relatively low abundance, small tissue volume, difficult accessibility, and disease-related malfunction of bone marrow-derived stem cells hamper their clinical usefulness. Numerous studies have provided evidence that stromal cells derived from the adipose tissue (adipose tissue-derived stromal cells [ADSCs]) contain a population of adult multipotent mesenchymal stem cells and endothelial progenitor cells that can differentiate into several lineages, including endothelial cells, smooth muscle cells, and cardiomyocytes. The similarities between stem cells extracted from the bone marrow and the adipose tissue suggest the potential for the adipose tissue to act as an alternative, and perhaps preferable, cell source for repairing damaged tissues, such as the ischemic or infarcted heart. We have here reviewed the medical literature describing molecular and functional characterization, differentiation, potential role, and results obtained so far using ADSCs in tissue repair, with a particular focus on the role for ADSCs in cardiovascular repair and regeneration. PMID: 19628786 [PubMed - indexed for MEDLINE] 1817. Biofactors. 2009 Sep-Oct;35(5):417-28. doi: 10.1002/biof.54. Uncoupling proteins: a complex journey to function discovery. Cioffi F(1), Senese R, de Lange P, Goglia F, Lanni A, Lombardi A. Author information: (1)Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Caserta, Italy. Since their discovery, uncoupling proteins have aroused great interest due to the crucial importance of energy-dissipating system for cellular physiology. The uncoupling effect and the physiological role of UCP1 (the first-described uncoupling protein) are well established. However, the reactions catalyzed by UCP1 homologues (UCPs), and their physiological roles are still under debate, with the literature containing contrasting results. Current hypothesis propose several physiological functions for novel UCPs, such as: (i) attenuation of reactive oxygen species production and protection against oxidative damage, (ii) thermogenic function, although UCPs do not generally seem to affect thermogenesis, UCP3 can be thermogenic under certain conditions, (iii) involvement in fatty acid handling and/or transport, although recent experimental evidence argues against the previously hypothesized role for UCPs in the export of fatty acid anions, (iv) fatty acid hydroperoxide export, although this function, due to the paucity of the experimental evidence, remains hypothetical, (v) Ca(2+) uptake, although results for and against a role in Ca(2+) uptake are still emerging, (vi) a signaling role in pancreatic beta cells, where it attenuates glucose-induced insulin secretion. From the above, it is evident that more research will be needed to establish universally accepted functions for UCPs. Copyright 2009 International Union of Biochemistry and Molecular Biology, Inc. PMID: 19626697 [PubMed - indexed for MEDLINE] 1818. Eur J Clin Nutr. 2009 Sep;63(9):1045-56. doi: 10.1038/ejcn.2009.55. Epub 2009 Jul 22. Functional body composition: insights into the regulation of energy metabolism and some clinical applications. Müller MJ(1), Bosy-Westphal A, Later W, Haas V, Heller M. Author information: (1)Institut für Humanernährung und Lebensmittelkunde, Christian-Albrechts-Universität, Kiel, Germany. mmueller@nutrfoodsc.uni-kiel.de The application of advanced methods and techniques and their continuous development enable detailed body composition analyses (BCAs) and modeling of body composition at different levels (e.g., at atomic, molecular, organ-tissue and whole body level). Functional body composition integrates body components into regulatory systems (e.g., on energy balance). Regulation of body weight is closely linked to the mass and function of individual body components. Fat mass is part of the energy intake regulatory feedback system. In addition, fat-free mass (FFM) and fat mass are both determinants of resting energy expenditure (REE). Up to 80% of the variance in energy intake and energy expenditure is explained by body composition. A deviation from normal associations between body components and function suggests a metabolic disequilibrium (e.g., in the REE-FFM relationship or in the plasma leptin-fat mass association) that may occur in response to weight changes and diseases. The concept of functional body composition adds to a more sophisticated view on nutritional status and diseases, as well as to a characterization of biomedical traits that will provide functional evidence relating genetic variants. PMID: 19623201 [PubMed - indexed for MEDLINE] 1819. Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E999-E1003. doi: 10.1152/ajpendo.00377.2009. Epub 2009 Jul 21. Inflammation and impaired adipogenesis in hypertrophic obesity in man. Gustafson B(1), Gogg S, Hedjazifar S, Jenndahl L, Hammarstedt A, Smith U. Author information: (1)Dept. of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 45 Gothenburg, Sweden. Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications. PMID: 19622783 [PubMed - indexed for MEDLINE] 1820. Mymensingh Med J. 2009 Jan;18(1 Suppl):S140-144. Leptin: a mysterious hormone; its physiology and pathophysiology. Akther A(1), Khan KH, Begum M, Parveen S, Kaiser MS, Chowdhury AZ. Author information: (1)Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh. tamimasmaki@yahoo.com Leptin (meaning thin) is attracting the attention of many scientists of the world recently. It is an adipocyte-derived protein hormone discovered in 1994. Human leptin gene is located on chromosome 7. It is mainly expressed in adipose tissue but also in skeletal muscle, stomach, placenta and mammary gland. Leptin play key role in food intake, energy balance, and adiposity as well as in immune and endocrine system. It acts as feedback loop to maintain the constant store of body fat. Leptin acts as an antiobesity hormone raising the potential of its use as antiobesity drugs. In future, leptin or its analogue may offer noble therapeutic approach for obesity or other leptin related disorders. This review focuses on current knowledge of leptin biology and the role of leptin in various physiological and pathophysiological states. PMID: 19436260 [PubMed - indexed for MEDLINE] 1821. AJR Am J Roentgenol. 2009 Aug;193(2):359-66. doi: 10.2214/AJR.08.2081. Brown fat: atypical locations and appearances encountered in PET/CT. Paidisetty S(1), Blodgett TM. Author information: (1)Department of Radiology, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave., Pittsburgh, PA 15232, USA. OBJECTIVE: The purpose of this article is to review the physiology and describe the typical and atypical presentations of brown fat on (18)F-FDG PET. CONCLUSION: The presence of brown fat on FDG PET has the potential to lead to misinterpretation and unneeded invasive tests, which can be avoided by using measures such as ensuring the patient is warm, reducing FDG uptake in brown fat before the procedure, and correlating PET uptake to a specific anatomic location with PET/CT fusion imaging. PMID: 19620432 [PubMed - indexed for MEDLINE] 1822. Obes Rev. 2010 Apr;11(4):322-8. doi: 10.1111/j.1467-789X.2009.00638.x. Epub 2009 Jul 10. Iron in obesity. An ancient micronutrient for a modern disease. Zafon C(1), Lecube A, Simó R. Author information: (1)Endocrinology Division, Hospital Universitari Vall, d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain. 26276czl@comb.es Iron is a necessary constituent of several macromolecules involved in cell metabolism, but, at the same time, it could be a potentially dangerous element. For this reason iron balance must be finely regulated. At present, obesity has been recognized as a worldwide public health problem. Excess body fat is associated with increased all-cause mortality and increased risk for several medical morbidities. Many studies have shown that obesity might increase the risk of iron deficiency but, at the same time, obese subjects exhibit high serum ferritin levels. Recent studies seem to indicate that obesity is associated with iron deficiency although the aetiology appears to be multifactorial and includes (i) A decrease in iron food intake; (ii) An impairment of intestinal iron uptake and iron release from stores because of an overexpression of hepcidin and (iii) Inadequate iron bioavailability because of inflammation. In addition, abnormal ferritin concentrations can be explained by chronic inflammation rather than by iron overload. The aim of the present article is to review current knowledge of iron and obesity. PMID: 19619262 [PubMed - indexed for MEDLINE] 1823. J Appl Physiol (1985). 2009 Oct;107(4):1339-47. doi: 10.1152/japplphysiol.00473.2009. Epub 2009 Jul 16. Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function. Young ME(1). Author information: (1)USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Dept. of Pediatrics, 1100 Bates St., Houston, TX 77030, USA. meyoung@bcm.edu Diurnal rhythms in myocardial physiology (e.g., metabolism, contractile function) and pathophyiology (e.g., sudden cardiac death) are well establish and have classically been ascribed to time-of-day-dependent alterations in the neurohumoral milieu. Existence of an intramyocellular circadian clock has recently been exposed. Circadian clocks enable the cell to anticipate environmental stimuli, facilitating a timely and appropriate response. Generation of genetically modified mice with a targeted disruption of the cardiomyocyte circadian clock has provided an initial means for deciphering the functions of this transcriptionally based mechanism and allowed predictions regarding which environmental stimuli the heart anticipates (i.e., "anticipating anticipation"). Recent studies show that the cardiomyocyte circadian clock influences myocardial gene expression, beta-adrenergic signaling, transcriptional responsiveness to fatty acids, triglyceride metabolism, heart rate, and cardiac output, as well as ischemia-reperfusion tolerance. In addition to reviewing current knowledge regarding the roles of the cardiomyocyte circadian clock, this article highlights putative frontiers in this field. The latter includes establishing molecular links between the cardiomyocyte circadian clock with identified functions, understanding the pathophysiological consequences of disruption of this mechanism, targeting resynchronization of the cardiomyocyte circadian clock for prevention/treatment of cardiovascular disease, linking the circadian clock with the cardiobeneficial effects of caloric restriction, and determining whether circadian clock genes are subject to epigenetic regulation. Information gained from studies investigating the cardiomyocyte circadian clock will likely translate to extracardiac tissues, such as skeletal muscle, liver, and adipose tissue. PMCID: PMC2763844 PMID: 19608929 [PubMed - indexed for MEDLINE] 1824. Eur Spine J. 2009 Nov;18(11):1564-72. doi: 10.1007/s00586-009-1092-8. Epub 2009 Jul 15. Nucleus pulposus tissue engineering: a brief review. Yang X(1), Li X. Author information: (1)Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. xy3c@virginia.edu Symptomatic intervertebral disc degeneration is associated with several spinal diseases, which cause losses of life quality and money. Tissue engineering provides a promising approach to recover the functionality of the degenerative intervertebral disc. Most studies are directed toward nucleus pulposus (NP) tissue engineering because disc degeneration is believed to originate in NP region, and considerable progress has been made in the past decade. Before this important technique is utilized for clinical treatment of disc degeneration, many challenges need to address including in all three principal components of tissue engineering, i.e., seed cells, signals and biomaterial scaffolds. This article briefly gives certain aspects of state of the art in this field, as well as pays a little more attention to our work published in the past 5 years, on growth and differentiation factor-5 (GDF-5), adipose-derived stem cells (ADSCs) and heparin functionalization of scaffold. We suggest that combinatorial application of ADSCs, GDF-5, heparin functionalization and injectable hydrogels will be advantageous in NP tissue engineering. PMCID: PMC2899402 PMID: 19603198 [PubMed - indexed for MEDLINE] 1825. J Nutr Sci Vitaminol (Tokyo). 2009 Jun;55(3):201-7. Is glycemic index of food a feasible predictor of appetite, hunger, and satiety? Niwano Y(1), Adachi T, Kashimura J, Sakata T, Sasaki H, Sekine K, Yamamoto S, Yonekubo A, Kimura S. Author information: (1)Carbohydrate Task Force, International Life Sciences Institute Japan, Tokyo. y.niwano@sunnyhealth.co.jp This review assesses the feasibility of using glycemic index (GI) as a predictor of appetite, hunger and satiety by surveying published human intervention studies. We also discuss the relationship between GI and two appetite/satiety control hormones, leptin and ghrelin. Ingestion of high-GI food increased hunger and lowered satiety in short-term human intervention studies. This effect may be attributed to the rapid decline in blood glucose level following a hyperinsulinemic response caused by a sharp and transient increase in blood glucose level that occurs after the ingestion of high-GI food, which is defined as the glucostatic theory. However, appetite, hunger and satiety after the ingestion of foods with varying GI were inconsistent among long-term human intervention studies. From the few relevant long-term studies available, we selected two recent well-designed examples for analysis, but they failed to elicit clear differences in glycemic and insulinemic responses between high- and low-GI meals (consisting of a combination of different foods or key carbohydrate-rich foods incorporated into habitual diets). One of the reasons that these studies could not predict glycemic response to mixed meals is presumably that the GI of each particular food was not reflected in that of the mixed meals as a whole. Thus, it is difficult to conclude that the GI values of foods or mixed meals are a valid long-term predictor for appetite, hunger and satiety. Both insulin and insulin-mediated glucose uptake and metabolism in adipose tissue affect blood leptin concentration and its diurnal pattern. Circulating ghrelin level is suppressed by carbohydrate-rich meals, presumably via glycemia and insulinemia. Accordingly, low-GI foods may not necessarily increase satiety or suppress appetite and/or hunger because of the lack of insulin-mediated leptin stimulation and ghrelin suppression. However, insulin-mediated leptin stimulation and ghrelin suppression per se is not consistent among studies; thus we were not able to identify a clear relationship among GI, satietogenic leptin, and appetitic ghrelin. PMID: 19602827 [PubMed - indexed for MEDLINE] 1826. Transl Res. 2009 Aug;154(2):52-60. doi: 10.1016/j.trsl.2009.05.003. Epub 2009 Jun 11. Fat storage and the biology of energy expenditure. Redinger RN(1). Author information: (1)Department of Medicine, University of Louisville, Louisville, KY 40292, USA. rnredi01@louisville.edu Excessive adiposity results from an imbalance in energy homeostasis, whereby the consequences of excessive food intake are not balanced by increased energy expenditure. The increasing prevalence of excessive adiposity now involves more than 1 billion individuals worldwide. Of these, one half is obese and susceptible to comorbidities such as insulin resistance, type 2 diabetes, hyperlipidemia, and hypertension, which accelerate atherosclerosis. Lifestyle changes that have resulted largely in decreased physical activity now require a greater understanding of energy use that may allow better strategies for obesity control, because traditional methods of decreasing food intake and/or increasing exercise have not been successful without considerable behavioral counseling. This review focuses on the cell biology of white and brown fat tissue as well as on the central obesity that explains the comorbidities of the metabolic syndrome. Recent advances regarding the roles of central and autonomic nervous system regulation involved in fat remodeling are discussed, including the hypothalamic regulation of food intake and intestinal modulation, which affects satiety and peripheral energy expenditure. Finally, the new knowledge of cellular transcription factor regulation of energy expenditure is explained, whereby genes regulate mitochondriogenesis within adipocytes, liver, and muscle for both coupled and uncoupled oxidative phosphorylation-induced energy and heat expenditure, respectively. Newly discovered agonists of these transcription factors may now be realized that enhance energy expenditure. Strategies that combine such pharmacotherapies with lifestyle changes including enhanced physical activity and proper dietary intake may then provide the deterrents to excessive adiposity and its comorbidities, which now threaten human longevity. PMID: 19595436 [PubMed - indexed for MEDLINE] 1827. Endocr Metab Immune Disord Drug Targets. 2009 Sep;9(3):269-76. Epub 2009 Sep 1. Human exposure to endocrine disruptors and breast milk. Stefanidou M(1), Maravelias C, Spiliopoulou C. Author information: (1)Department of Forensic Medicine and Toxicology, University of Athens, Athens, Greece. mstefan@med.uoa.gr Endocrine system is one of the most sensitive communication networks of the human body which influences all aspects of human health and well-being, including reproductive potential, cognitive functions, thyroid and metabolism, digestion and hormonal balance. In recent years basic laboratory research has been focused on the potential relationship between environmental contaminants and cellular endocrine function. Environmental contaminants are ubiquitous in the environment, alter endocrine physiology and produce endocrine disruption without acting as classic toxicants. These endocrine disruptors (EDCs) are lipophilic and stored for long periods of time in the adipose tissue. Maternal exposure to EDCs during pregnancy and lactation has as a result the exposure of the fetus and neonate through placenta and breast milk. It has been recognized that human milk is the best natural food for neonates providing immunologic, developmental and practical advantages throughout childhood. However, contamination of human milk by the presence of environmental toxicants is widespread through the past decades due to inadequately controlled pollution. Persistent pesticides, chemical solvents and others tend to invade slowly the environment, to bioaccumulate in the food chain and to have long half-lives in animals and humans. During the past fifteen years, the scientific interest has been focused on xenoestrogens, i.e.,environmental chemicals with estrogen disrupting activity. Certain adverse health and reproductive outcomes are attributed to these chemicals in wildlife, in laboratory animals, as well as in humans. Although most toxic agents are hazardous in high doses, the human health risks associated with EDCs concern exposure to low doses. The human health risks that may be associated with these low-level but constant exposures are still largely unknown and highly controversial. In this paper, we review available data on environmental chemicals present in breast milk that may affect child health through breastfeeding. Specifically, we focused on the breast-feeding pharmacokinetic aspects related to infant exposure of chemical pollutants that have estrogen and antiandrogen activities, such as environmental estrogen disruptors or xenoestrogens. PMID: 19594415 [PubMed - indexed for MEDLINE] 1828. Domest Anim Endocrinol. 2009 Oct;37(3):170-80. doi: 10.1016/j.domaniend.2009.05.003. Epub 2009 Jul 2. Presenilin enhancer-2 (PSENEN), a component of the gamma-secretase complex, is involved in adipocyte differentiation. Lee SM(1), Jeong YH, Kim HM, Park HY, Yoon D, Kim DH, Saeki S, Moon SJ, Kang MJ. Author information: (1)Department of Animal Science, College of Agriculture and Life Science, Institute of Agricultural Science and Technology, Chonnam National University, Gwangju 500-757, Korea. This study was conducted to identify genes expressed during adipocyte differentiation of bovine intramuscular fibroblast-like cells using differential display reverse-transcriptase polymerase chain reaction. The presenilin enhancer-2 (PSENEN) gene was found to be down-regulated during adipocyte differentiation of bovine intramuscular fibroblast-like cells. The ectopic expression of bovine PSENEN in 3T3-L1 reduced adipogenesis and the inhibition of endogenous PSENEN by siRNA induced adipogenesis on d 4 of adipocyte differentiation of 3T3-L1 cells. Interestingly, the expression of gamma-secretase complex gene-related Notch signaling was decreased at d 2 and d 4 during adipocyte differentiation. In addition, expression of the Notch-signaling genes (Notch-1, Hes-1, Pref-1, adipsin) was regulated during adipocyte differentiation by regulation of PSENEN expression. These results suggest that PSENEN plays an important role in adipocyte differentiation and that Notch signaling is involved in adipogenesis. PMID: 19592191 [PubMed - indexed for MEDLINE] 1829. Nihon Rinsho. 2009 Jul;67(7):1402-6. [Regenerative medicine for anti-aging]. [Article in Japanese] Ebisawa K(1), Kagami H, Kato R, Yamada Y, Ueda M. Author information: (1)Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine. Regenerative medicine refers to research and treatments that restore damaged tissues. It consists of three factors: cells, chemical substances, and scaffolds. One of its purposes is rejuvenation, and from this point of view, it really resembles anti-aging medicine. Recently, studies concerning stem cells such as embryonic stem cells (ES) and induce pluripotent stem cells (iPS) have made remarkable progress and seem promising, but are still far from clinical use. In contrast, we introduce a few examples of anti-aging medicine using regenerative medicine methods that have been applied successfully in clinical use such as cultured fibroblast, adipose tissue derived stem cells and platelet rich plasma (PRP), and continue researching cultured dermal papilla cells. PMID: 19591293 [PubMed - indexed for MEDLINE] 1830. Stem Cell Rev. 2009 Sep;5(3):247-55. doi: 10.1007/s12015-009-9069-x. Epub 2009 May 23. Isolation of mesenchymal stem cells from human placental decidua basalis and resistance to hypoxia and serum deprivation. Huang YC(1), Yang ZM, Chen XH, Tan MY, Wang J, Li XQ, Xie HQ, Deng L. Author information: (1)Division of Stem cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. Mesenchymal stem cells (MSCs) are the most promising seed cells for cell therapy and tissue engineering, which can be isolated from various sources of human adult tissues such as bone marrow and adipose tissue. However, cells from these tissues must be obtained through invasive procedures and sometimes the individual difference is hard to control. Hence, the search continues for an ethically conducive, easily accessible and controllable source of stem cells. We herein report the isolation of a population of stem cells from the human placental decidua basalis (termed as PDB-MSCs), a maternal portion of placenta. PDB-MSCs were further shown to express markers common to MSCs and positive for SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81 and Oct-4. In order to facilitate the further utility in ischemic diseases, we tested the apoptosis of PDB-MSCs in hypoxia and serum deprivation, two components of ischemia in vivo. Taken together, our findings indicate that PDB-MSCs are resistant to hypoxia and serum deprivation, which may relate to Bcl-2. PMID: 19590988 [PubMed - indexed for MEDLINE] 1831. Am J Dermatopathol. 2009 Aug;31(6):520-6. doi: 10.1097/DAD.0b013e3181a84f32. Subcutaneous panniculitis-like T-cell lymphoma with overlapping clinicopathologic features of lupus erythematosus: coexistence of 2 entities? Pincus LB(1), LeBoit PE, McCalmont TH, Ricci R, Buzio C, Fox LP, Oliver F, Cerroni L. Author information: (1)Departments of Dermatology and daggerPathology, University of California San Francisco, San Francisco, CA, USA. We observed 5 patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) who were unusual, in that they also exhibited features of lupus erythematosus (LE). This observation is in keeping with a recent study that reported an increased rate of autoimmune disease, including systemic lupus erythematosus (SLE), among patients with SPTCL. In all cases, attributes indicating SPTCL included an infiltrate of lymphocytes with pleomorphic nuclei involving subcutaneous lobules exhibiting a cytotoxic T-cell (CD3/CD8/betaF1) immunophenotype. Additionally, a high proliferation rate and a monoclonal T-cell receptor-gamma gene rearrangement were observed in most cases. The manifestations of LE in these patients included a spectrum of clinical and histopathological abnormalities. Clinical manifestations of LE included, in some patients, morphologic evidence of lupus erythematosus panniculitis (LEP) with subcutaneous nodules that healed with lipoatrophy on the face. In addition, all the patients exhibited serologic and/or extracutaneous end-organ abnormalities seen in patients with SLE, with 2 patients having sufficient findings to meet American College of Rheumatology criteria for SLE. Histopathological evidence of LE included vacuolar change at the dermal-epidermal interface in 3 patients, 2 of whom also showed interstitial deposition of mucin in the reticular dermis. One of these patients also had findings of LEP in the subcutaneous lobules with clusters of CD20 B cells partially arranged within germinal centers. In 2 patients in which neither the epidermis nor dermis was available for review, histopathological features of LE included, in one patient, a few small clusters of CD123 plasmacytoid dendritic cells within the adipose tissue and, in the other patient, a positive direct immunofluorescence test (lupus band) on clinically uninvolved and lesional skin. Our study shows that some patients show overlap between SPTCL and LE. We suspect that these patients may suffer from both diseases concomitantly. Furthermore, patients with LE, particularly LEP, should be monitored for evolution into SPTCL with biopsy of any subcutaneous lesion that is not typical of LEP. Additionally, screening for cutaneous LE and SLE could be considered in patients with SPTCL. PMID: 19590424 [PubMed - indexed for MEDLINE] 1832. Fertil Steril. 2010 Aug;94(3):795-825. doi: 10.1016/j.fertnstert.2009.03.079. Epub 2009 Jul 8. Adipose tissue and reproduction in women. Bohler H Jr(1), Mokshagundam S, Winters SJ. Author information: (1)Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Women's Health, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. h.bohler@louisville.edu Adipose tissue has been viewed as the primary source of stored energy, but with the discovery of novel adipose tissue gene products, i.e., adipokines, another equally important role has emerged. Adipose tissue is a key endocrine organ involved in multiple processes, including glucose homeostasis, steroid production, immunoregulation, hematopoesis, and reproduction. The distribution of adipose tissue may also have a significant impact on reproductive function. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. PMID: 19589523 [PubMed - indexed for MEDLINE] 1833. Hepatology. 2009 Sep;50(3):957-69. doi: 10.1002/hep.23046. Adipokines in liver diseases. Marra F(1), Bertolani C. Author information: (1)Department of Internal Medicine, University of Florence, Florence, Italy. f.marra@dmi.unifi.it Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases. PMID: 19585655 [PubMed - indexed for MEDLINE] 1834. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):340-6. doi: 10.1097/MED.0b013e32832fa137. Stress and obesity: the role of the hypothalamic-pituitary-adrenal axis in metabolic disease. Bose M(1), Oliván B, Laferrère B. Author information: (1)New York Obesity Research Center, St Luke's Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York, USA. mb3103@columbia.edu PURPOSE OF REVIEW: Chronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. RECENT FINDINGS: Dysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. SUMMARY: The present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases. PMCID: PMC2858344 PMID: 19584720 [PubMed - indexed for MEDLINE] 1835. JAMA. 2009 Jul 8;302(2):179-88. doi: 10.1001/jama.2009.976. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. Li S(1), Shin HJ, Ding EL, van Dam RM. Author information: (1)Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. CONTEXT: The association of obesity with development of type 2 diabetes may be partly mediated by altered secretion of adipokines by adipose tissue. Greater adiposity down-regulates secretion of adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties. The strength and consistency of the relation between plasma adiponectin and risk of type 2 diabetes is unclear. OBJECTIVE: To systematically review prospective studies of the association of plasma adiponectin levels and risk of type 2 diabetes. DATA SOURCES: A systematic search of the MEDLINE, EMBASE, and Science Citation Index Expanded databases using adiponectin and diabetes and various synonyms and reference lists of retrieved articles up to April 10, 2009. STUDY SELECTION: We included prospective studies with plasma adiponectin levels as the exposure and incidence of type 2 diabetes as the outcome variable. DATA EXTRACTION: Two reviewers independently extracted data and assessed study quality. Generalized least-squares trend estimation was used to assess dose-response relationships. Pooled relative risks and 95% confidence intervals were calculated using random-effects models to incorporate between-study variation. RESULTS: Thirteen prospective studies with a total of 14 598 participants and 2623 incident cases of type 2 diabetes were included in the meta-analysis. Higher adiponectin levels were monotonically associated with a lower risk of type 2 diabetes. The relative risk of type 2 diabetes was 0.72 (95% confidence interval, 0.67-0.78) per 1-log microg/mL increment in adiponectin levels. This inverse association was consistently observed in whites, East Asians, Asian Indians, African Americans, and Native Americans and did not differ by adiponectin assay, method of diabetes ascertainment, duration of follow-up, or proportion of women. The estimated absolute risk difference (cases per 1000 person-years) per 1-log microg/mL increment in adiponectin levels was 3.9 for elderly Americans and 30.8 for Americans with impaired glucose tolerance. CONCLUSION: Higher adiponectin levels are associated with a lower risk of type 2 diabetes across diverse populations, consistent with a dose-response relationship. PMID: 19584347 [PubMed - indexed for MEDLINE] 1836. J Assoc Physicians India. 2009 Feb;57:163-70. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. Misra A(1), Chowbey P, Makkar BM, Vikram NK, Wasir JS, Chadha D, Joshi SR, Sadikot S, Gupta R, Gulati S, Munjal YP; Concensus Group. Collaborators: Chowbey P, Misra A, Makkar BM, Misra A, Ghosh A, Jhingan AK, Sidhu A, Makkar BM, Singh BI, Sivakumar B, Batra CM, Sridhar CR, Bhatia D, Toteja GS, Wasir J, Srinath J, Sawney JP, Madan J, Narwaria M, Karmarkar MG, Vikram NK, Chowbey P, Mishra P, Joshi P, Mathur P, Sharma R, Gupta R, Goel R, Sadikot S, Kale S, Joshi S, Borude S, Shah S, Madhu SV, Sharma V, Munjal YP, Gadpayle AK, Kriplani AK, Batavia A, Contractor A, Arora A, Ajmani A, Bijani A, Gainda A, Kondal A, Khare A, Gurtoo A, Sharma A, Garg A, Gupta AT, Maheshwari A, Agarwala A, Kurpad A, Prasad A, Dey A, Kohli A, Sadana A, Vashishtha A, Gupta A, Jhingan A, Das AK, Mishra A, Luthra A, Sardana A, Wadhwa A, Sivakumar B, Makkar BM, Singh B, Saboo B, Shah B, Kohli C, Ramachandran CS, Yajnik CS, Hazra DK, Rajyasree D, Singh D, Chadha, Gupta D, Khanna D, Singh D, Gaba DA, Nandan D, Kondal D, Wadhawan, Sridhar GR, Kaur GD, Ghosh G, Kaur G, Chandalia HB, Kaur H, Vardhan H, Kochar IP, Khosla I, Sharma JK, Sawhney JP, Benjamin J, Todkar J, Sood J, Aggarwal KK, Srivastava KN, Singh K, Trehan KK, Rai K, Vijay K, Dhawan K, Khanna K, Khurana L, Karmarkar MG, Mahar MS, Ramesh M, Ahmed M, Janakiraman M, Baijal M, Bansal M, Kumar M, Lall M, Mathur M, Jain M, Vasishta M, Bagchi N, Singh N, Singhi N, Bhatia N, Garg N, Gera N, Singhal N, Tandon N, Shah N, Mohanty PC, Srinath PJ, Dewan PK, Reddy PK, Patankar P, Sinha P, Sodhi PK, Kaur P, Singh P, Biswas P, Bhatia P, Ganguly P, Jain P, Choudhry P, Mohanty PCh, Kolhe P, Reddy PK, Goel P, Shah P, Nigam P, Narayan RR, Prasad RK, Kasliwal RR, Lalwani RK, Marya RK, Pandey RM, Chawla R, Bhojwani R, Khullar R, Rajput R, Gupta R, Gupta R, Kukreja R, Meswani R, Parikh R, Vaidya R, Kishore R, Jaiswal R, Khanna R, Datta R, Kapoor SK, Singh SK, Wangnoo SK, Kapoor S, Dembla SP, Arya SV, Kothari SY, Agarwal S, Dave S, Malhotra S, Chaurey S, Bhambani S, Passi SJ, Khatri S, Gulati S, Puri S, Sesikeran, Kale S, Chawla S, Gopalan S, Joshi SR, Shah S, Mathur S, Sadikot SM, Saluja S, Shipra, Chopra S, Dhorepatil S, Passi SJ, Mittal S, Lalwani S, Arya S, Aggarwal S, Kalhan SK, Tripathi S, Sehra S, Jha S, Jain S, Shah S, Kaur S, Kumar S, Abrol SK, Chhabra SK, Bhatt SP, Sharma S, John S, Chaturvedi S, Bhardwaj S, Bhave S, Kothari SY, Mittal T, Jain T, Biswal UC, Mani UV, Kapil U, Srivastava U, Prakash V, Jain V, Soni V, Verma V, Nambiar V, Ramesh V, Seth V, Kumari V, Singh VL, Viswanathan V, Ahluwalia V, Kapur V, Sabharwal V, Gujral V, Mittal V, Singhal V, Mishra V, Naik VG, Aggarwal V, Goyal VK, Gupta YK, Krishnamohan Y, Kusuma YS, Agarwala Y, Gautam Y, Sarin YK. Asian Indians exhibit unique features of obesity; excess body fat, abdominal adiposity, increased subcutaneous and intra-abdominal fat, and deposition of fat in ectopic sites (liver, muscle, etc.). Obesity is a major driver for the widely prevalent metabolic syndrome and type 2 diabetes mellitus (T2DM) in Asian Indians in India and those residing in other countries. Based on percentage body fat and morbidity data, limits of normal BMI are narrower and lower in Asian Indians than in white Caucasians. In this consensus statement, we present revised guidelines for diagnosis of obesity, abdominal obesity, the metabolic syndrome, physical activity, and drug therapy and bariatric surgery for obesity in Asian Indians after consultations with experts from various regions of India belonging to the following medical disciplines; internal medicine, metabolic diseases, endocrinology, nutrition, cardiology, exercise physiology, sports medicine and bariatric surgery, and representing reputed medical institutions, hospitals, government funded research institutions, and policy making bodies. It is estimated that by application of these guidelines, additional 10-15% of Indian population would be labeled as overweight/obese and would require appropriate management. Application of these guidelines on countrywide basis is also likely to have a deceleration effect on the escalating problem of T2DM and cardiovascular disease. These guidelines could be revised in future as appropriate, after another large and countrywide consensus process. Till that time, these should be used by clinicians, researchers and policymakers dealing with obesity and related diseases. PMID: 19582986 [PubMed - indexed for MEDLINE] 1837. Ageing Res Rev. 2009 Oct;8(4):339-48. doi: 10.1016/j.arr.2009.06.001. Epub 2009 Jul 1. Age-related changes in total and regional fat distribution. Kuk JL(1), Saunders TJ, Davidson LE, Ross R. Author information: (1)School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. Aging is associated with progressive changes in total and regional fat distribution that have negative health consequences. Indeed, a preferential increase in abdominal fat, in particular visceral fat, combined with a decrease in lower body subcutaneous fat are commonly cited in the literature. These age-related changes in body composition can occur independent of changes in total adiposity, body weight or waist circumference, and represent a phenotype closely associated with increased morbidity and mortality risk. Tissues such as the heart, liver and skeletal muscle in the elderly have increased fat deposition, which increases risk for insulin resistance and cardiovascular disease. Furthermore, aging is associated with increased fat content within bone marrow, which exposes the elderly to fracture risk beyond that associated with low bone mineral density alone. Many of the age-associated body compositional changes cannot be detected by simple anthropometric measures alone, and the influence of gender, race or ethnicity, and physical activity patterns on these changes is unclear. This review will explore some of these age-related changes in total and regional fat distribution. Consideration will also be given to the strengths and limitations associated with some of the anthropometric methodologies employed for assessing these changes. PMID: 19576300 [PubMed - indexed for MEDLINE] 1838. Enferm Infecc Microbiol Clin. 2008 Dec;26 Suppl 16:8-11. [The "induction-maintenance" strategy]. [Article in Spanish] Arribas López JR(1). Author information: (1)Consulta de Medicina Interna-II, Unidad VIH, Hospital La Paz, Madrid, España. jrarribas.hulp@salud.madrid.org The strategy of induction-maintenance therapy with lopinavir-ritonavir (LPV7r) consists of initiating antiretroviral therapy in a treatment-naïve patient with two nucleosides plus LPV/r. When the patient has achieved an undetectable HIV RNA viral load of < 50 copies/mL for a specified time period, the nucleosides are withdrawn and the patient continues to receive antiretroviral therapy with LPV/r monotherapy. The induction-maintenance strategy with LPV/r has been analyzed in the M03-613 clinical trial. In this trial, antiretroviral-naïve patients were randomized to receive zidovudine/lamivudine plus LPV/r (n = 104) or efavirenz (n = 51). In patients randomized to receive LPV/r who achieved an HIV RNA viral load of < 50 copies/mL for 3 consecutive months, nucleoside therapy was suspended. In an intention-to-treat analysis (missing equals failure), 60% of the patients randomized to receive LPV/r and 63% of those randomized to receive efavirenz maintained an HIV RNA viral load of < 50 copies/mL at 96 weeks of follow-up (p = 0.73; 95% confidence interval for the difference -19% to 13%). Moreover, this study showed that patients randomized to LPV/r experienced less lipoatrophy than those randomized to efavirenz. The M03-613 trial suggests that the induction-maintenance strategy with LPV/r is safe in most patients. However, rates of virological efficacy are lower than those achieved with the simplification strategy. Moreover, this trial demonstrates that LPV/r monotherapy may have major benefits in peripheral fat preservation. PMID: 19572438 [PubMed - indexed for MEDLINE] 1839. Eur Respir J. 2009 Jul;34(1):243-60. doi: 10.1183/09031936.00166808. Sleep, sleep-disordered breathing and metabolic consequences. Lévy P(1), Bonsignore MR, Eckel J. Author information: (1)INSERM ERI 17, HP2 laboratory, Joseph Fourier University and Sleep Laboratory, EFCR, Pôle Rééducation et Physiologie, CHU Grenoble, Grenoble, France. PLevy@chu-grenoble.fr Comment in Eur Respir J. 2009 Nov;34(5):1209-10; author reply 1210-1. Sleep profoundly affects metabolic pathways. In healthy subjects, experimental sleep restriction caused insulin resistance (IR) and increased evening cortisol and sympathetic activation. Increased obesity in subjects reporting short sleep duration leads to speculation that, during recent decades, decreased sleeping time in the general population may have contributed to the increasing prevalence of obesity. Causal inference is difficult due to lack of control for confounders and inconsistent evidence of temporal sequence. In the general population, obstructive sleep apnoea (OSA) is associated with glucose intolerance. OSA severity is also associated with the degree of IR. However, OSA at baseline does not seem to significantly predict the development of diabetes. Prevalence of the metabolic syndrome is higher in patients with OSA than in obese subjects without OSA. Treatment with continuous positive airway pressure seems to improve glucose metabolism both in diabetic and nondiabetic OSA but mainly in nonobese subjects. The relative role of obesity and OSA in the pathogenesis of metabolic alterations is still unclear and is intensively studied in clinical and experimental models. In the intermittent hypoxia model in rodents, strong interactions are likely to occur between haemodynamic alterations, systemic inflammation and metabolic changes, modulated by genetic background. Molecular and cellular mechanisms are currently being investigated. PMID: 19567607 [PubMed - indexed for MEDLINE] 1840. Obes Rev. 2009 Nov;10(6):617-26. doi: 10.1111/j.1467-789X.2009.00624.x. Epub 2009 Jun 26. Natriuretic peptides: linking heart and adipose tissue in obesity and related conditions--a systematic review. Beleigoli AM(1), Diniz MF, Ribeiro AL. Author information: (1)Department of Clinical Medicine, Medical School, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. beleigoli@yahoo.com The objective of this study was to investigate the association between natriuretic peptides, obesity and related comorbidities. A systematic review of the English language literature from 1996 to 2008 was performed with Pubmed/MEDLINE and the ISI Web of Knowledge. 'Natriuretic peptides', 'atrial natriuretic factor', 'brain natriuretic peptide', 'obesity', 'body mass index', 'lipolysis' and 'adipose tissue' were used as Mesh terms. We also conducted a handle search among the references of the original articles selected. Finally, seventy-five studies were considered eligible for inclusion in the review. Natriuretic peptides are widely known as body homeostasis regulators. Recently, their action as lipolytic agents has been identified. Obese patients, especially those with hypertension and metabolic risk factors, have reduced plasma levels of natriuretic peptides. Whether this precedes or follows obesity and its complications remains undefined. The lipolytic effect of natriuretic peptides indicates that they may be involved in the pathophysiology of obesity. In general, studies with obese patients support paradoxical reduced levels of natriuretic peptides. However, the selection of subjects and classification of obesity and heart failure varied among the reviewed studies, rendering comparison unreliable. PMID: 19563456 [PubMed - indexed for MEDLINE] 1841. Rheumatology (Oxford). 2009 Oct;48(10):1185-9. doi: 10.1093/rheumatology/kep162. Epub 2009 Jun 26. Multipotent mesenchymal stromal cells and rheumatoid arthritis: risk or benefit? Bouffi C(1), Djouad F, Mathieu M, Noël D, Jorgensen C. Author information: (1)Inserm U844, CHU Saint-Eloi, Bâtiment INM, 80 avenue Augustin Fliche, Montpellier F-34295, France. Multipotent mesenchymal stromal cells (MSCs) have raised interest mainly because of cartilage/bone differentiation potential which is now partly eclipsed by their capacity to counteract inflammation and suppress host immune responses as well as to prevent fibrosis. MSCs have been identified within joint tissues including synovium, cartilage, subchondral bone, periosteum or adipose tissue. They are characterized by their phenotype and their ability to differentiate into three lineages, chondrocytes, osteoblasts and adipocytes. MSCs have also paracrine effects through the secretion of a number of cytokines and growth factors. This may explain the trophic effects that may be of therapeutic value for rheumatic diseases including OA and RA. On the other hand, MSCs have been associated with tumour growth. MSCs migrate to the tumour stroma, express chemokines involved in the attraction of carcinoma cells in metastasis. Indeed, the aim of this review is not only to focus on new potential therapeutic applications in osteo-articular diseases, but also to assess the potential risk of MSC-based cell therapy. PMID: 19561159 [PubMed - indexed for MEDLINE] 1842. Pharmacol Res. 2009 Aug;60(2):93-8. doi: 10.1016/j.phrs.2009.04.004. Epub 2009 Apr 14. The endocannabinoid system: role in glucose and energy metabolism. Nogueiras R(1), Diaz-Arteaga A, Lockie SH, Velásquez DA, Tschop J, López M, Cadwell CC, Diéguez C, Tschöp MH. Author information: (1)Department of Physiology, University of Santiago de Compostela - Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela 15782, Spain. ruben.nogueiras@usc.es The endocannabinoid system (ECS) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two cannabinoid receptors: types 1 and 2 (CB1 and CB2). CB1 receptors are widely expressed in the brain, but are also expressed in adipose tissue, skeletal muscle, the liver, the gut, and the pancreas. Blockade of CB1 receptors causes a reduction in food intake and a sustained weight loss. This system contributes also to the control of lipid and glucose metabolism, and it is well established that blockade of CB1 receptors enhances insulin sensitivity in both humans and rodents. In obese states, endocannabinoid levels are increased and might exert unfavorable effects on insulin-sensitive tissues. This review summarizes the effects of the endocannabinoid system on glucose metabolism in humans and rodents. PMID: 19559361 [PubMed - indexed for MEDLINE] 1843. Genes Nutr. 2009 Sep;4(3):179-87. doi: 10.1007/s12263-009-0128-3. Epub 2009 Jun 26. beta-Carotene conversion products and their effects on adipose tissue. Tourniaire F(1), Gouranton E, von Lintig J, Keijer J, Bonet ML, Amengual J, Lietz G, Landrier JF. Author information: (1)School of Agriculture, Food, and Rural Development, Newcastle University, King's Road, NE2 1PN, Newcastle upon Tyne, UK. Recent epidemiological data suggest that beta-carotene may be protective against metabolic diseases in which adipose tissue plays a key role. Adipose tissue constitutes the major beta-carotene storage tissue and its functions have been shown to be modulated in response to beta-carotene breakdown products, especially retinal produced after cleavage by beta-carotene 15,15'-monooxygenase (BCMO1), and retinoic acid arising from oxidation of retinal. However, the possibility exists that beta-carotene in its intact form can also affect adipocyte function. Development of a knock out model and identification of a loss-of-function mutation have pointed out BCMO1 as being probably the sole enzyme responsible for provitamin A conversion into retinal in mammals. The utilisation of BCMO1(-/-)mice should provide insights on beta-carotene effect on its own in the future. In humans, intervention studies have highlighted the huge interindividual variation of beta-carotene conversion efficiency, possibly due to genetic polymorphisms, which might impact on response to beta-carotene. This brief review discusses the processes involved in beta-carotene conversion and the effect of cleavage products on body fat and adipose tissue function. PMCID: PMC2745744 PMID: 19557453 [PubMed] 1844. J Am Osteopath Assoc. 2009 Jun;109(6):314-7. The role of the adipocytokines adiponectin and leptin in migraine. Peterlin BL(1). Author information: (1)lee.peterlin@drexelmed.edu Erratum in J Am Osteopath Assoc. 2009 Aug;109(8):399. Although it has long been known that fasting or the consumption of certain foods can trigger headaches, abdominal and total body obesity have only recently been linked to migraine. Several adipocytokines appear to play an integral role in feeding and obesity--and have also been linked to pain. Among these proteins are adiponectin and leptin. The author reviews the regulation of adipose tissue and feeding and provides an in-depth examination of adiponectin and leptin and their association with migraine. PMID: 19556389 [PubMed - indexed for MEDLINE] 1845. Ann Hepatol. 2009;8 Suppl 1:S60-6. Is exercise an effective treatment for NASH? Knowns and unknowns. Caldwell S(1), Lazo M. Author information: (1)The University of Virginia, Division of GI/Hepatology, Charlottesville, Virginia, Charlottesville, VA 22908-0708, USA. shc5c@virginia.edu Non-alcoholic steatohepatitis has emerged as one of the most common causes of chronic liver disease in many regions of the world. Exercise and dietary changes constitute cornerstones of overall therapy aimed at achieving weight loss in hopes of ameliorating lipid-induced hepatocellular injury by mobilizing fat out of the liver. Indeed weight loss is known to be effective as evident in several controlled trials and, in the extreme, with bariatric surgery. However, less is known about exercise in the absence of weight loss especially in terms of altering hepatic fat metabolism. As with steatosis, adipose tissue function and other targets of insulin activity, skeletal muscle physiology is closely integrated with overall energy homeostasis and calorie disposal. Although much remains to be learned, increased physical conditioning appears to be closely linked to improved hepatic metabolism independent of changes in body weight. This is of practical importance to patients attempting lifestyle changes who may become unnecessarily discouraged if there is not evidence of associated weight loss as a result of increased activity. Moreover, the degree of physical conditioning represents an unmeasured and potentially confounding variable in most clinical trials of pharmacological intervention in NASH. Clinical investigation is needed to better understand the effects of exercise on liver fat metabolism and on how best to measure the degree of physical conditioning both as a baseline indicator of overall energy homeostasis and an end-point of treatment. PMID: 19381126 [PubMed - indexed for MEDLINE] 1846. Ann Hepatol. 2009;8 Suppl 1:S9-17. New insights into the pathophysiology of nonalcoholic fatty liver disease. Chávez-Tapia NN(1), Uribe M, Ponciano-Rodríguez G, Medina-Santillán R, Méndez-Sánchez N. Author information: (1)Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. The consequences of pathologic adipose tissue accumulation have been described for almost all organs. Nonalcoholic fatty liver disease (NAFLD) is considered the most relevant hepatic manifestation of obesity. There is great interest in the study of NAFLD, and new insights into its pathogenic process have been described. Currently, in addition to insulin resistance, which was considered the hallmark of this disease, endocrine, immunologic, and central nervous system factors are attracting interest as explanatory variables. In this review, new factors associated with the main theories on the pathophysiology of NAFLD are analyzed. PMID: 19381119 [PubMed - indexed for MEDLINE] 1847. Inflamm Res. 2009 Nov;58(11):727-36. doi: 10.1007/s00011-009-0060-4. Epub 2009 Jun 19. The major inflammatory mediator interleukin-6 and obesity. Eder K(1), Baffy N, Falus A, Fulop AK. Author information: (1)Research Group for Inflammation Biology and Immunogenomics, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. ederkati@gmail.com Adipose tissue is one of the main sources of inflammatory mediators, with interleukin-6 (IL-6) among them. Although high systemic levels of inflammatory mediators are cachectogenic and/or anorexic, today it is a widely propagated thesis that in the background of obesity, a low level of chronic inflammation can be found, with IL-6 being one of the many suggested mediators. This paper reviews the studies describing elevated IL-6 levels in obese patients and the role of adipocytes and adipose-tissue macrophages in the production of IL-6. The secretion of IL-6 is regulated by several physiologic or pathologic factors: hormones, cytokines, diet, physical activity, stress, hypoxia, and others. Adipose tissue-derived IL-6 may have an effect on metabolism through several mechanisms, including adipose tissue-specific gene expression, triglyceride release, lipoprotein lipase downregulation, insulin sensitivity, and so on. Having a better understanding of these mechanisms may contribute to the prevention and treatment of obesity. PMID: 19543691 [PubMed - indexed for MEDLINE] 1848. Am J Dermatopathol. 2009 Jul;31(5):423-6. doi: 10.1097/DAD.0b013e3181a129b7. Low-fat and fat-free pleomorphic lipomas: a diagnostic challenge. Sachdeva MP(1), Goldblum JR, Rubin BP, Billings SD. Author information: (1)Department of Dermatology, Cleveland Clinic, Cleveland, OH 44195, USA. Pleomorphic lipomas are benign tumors that most commonly present as subcutaneous masses in the head and neck, shoulder, or back region of middle-aged to elderly men. They are related to spindle cell lipomas based on shared cytogenetic aberrations and histologic features. When little or no fat is present, the diagnosis can be challenging. A review of 38 pleomorphic lipomas seen in consultation revealed 7 cases in which fat was present in reduced (<5%) amounts (n = 5) or absent (n = 2). Six of 7 cases were from men with a mean age of 59 years. Excluding 1 case where the site was not specified, they all presented as solitary well-circumscribed subcutaneous masses in the head and neck (n = 3) or shoulder (n = 2) region. The seventh case was an intradermal tumor from the nose of a 48-year-old woman. All displayed pleomorphic and multinucleated floret cells interspersed among bland spindle cells and ropey collagen. They were diffusely immunoreactive for CD34. Referring diagnoses, when provided, included myxofibrosarcoma, giant cell fibroblastoma, and granulomatous rosacea for the tumor from the nose; none considered pleomorphic lipomas. When fat is absent or present in reduced amounts, clinical context and identification of classic nonlipogenic components are essential for the diagnosis of pleomorphic lipomas. PMID: 19542913 [PubMed - indexed for MEDLINE] 1849. Mol Endocrinol. 2009 Nov;23(11):1717-25. doi: 10.1210/me.2009-0160. Epub 2009 Jun 18. Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. Sul HS(1). Author information: (1)Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA. hsul@nature.berkeley.edu Preadipocyte factor-1 [Pref-1; also called Dlk1 (Delta-like protein 1)] is made as an epidermal growth factor-repeat containing transmembrane protein that produces a biologically active soluble form by TNF-alpha-converting enzyme (TACE)-mediated cleavage. Soluble Pref-1 activates the MAPK kinase/ERK pathway. In adipose tissue, Pref-1 is specifically expressed in preadipocytes but not in adipocytes and thus is used as a preadipocyte marker. Inhibition of adipogenesis by Pref-1 has been well established in vitro as well as in vivo by ablation and overexpression of Pref-1. SRY (sex determining region Y)-box 9 (Sox9), a transcription factor expressed in preadipocytes to suppress CCAAT enhancer binding protein beta and (C/EBP) delta expression, is required to be down-regulated before adipocyte differentiation can proceed. By activating MAPK kinase/ERK, Pref-1 prevents down-regulation of Sox9, resulting in inhibition of adipogenesis. Furthermore, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation. Thus, Pref-1 directs multipotent mesenchymal cells toward the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes. Pref-1, encoded by an imprinted gene, has also been detected in progenitor cells in various tissues during regeneration and therefore may have a more general role in maintaining cells in an undifferentiated state. PMCID: PMC2775937 PMID: 19541743 [PubMed - indexed for MEDLINE] 1850. Diabetes Metab. 2009 Sep;35(4):251-60. doi: 10.1016/j.diabet.2009.05.001. Epub 2009 Jun 17. Role of macrophage tissue infiltration in obesity and insulin resistance. Bourlier V(1), Bouloumie A. Author information: (1)Inserm U, département Métabolisme et Obésité, institut de médecine moléculaire de Rangueil, IFR, université Toulouse-III Paul-Sabatier, France. virginie.bourlier@inserm.fr Obesity is associated with systemic chronic low-grade inflammation, a major contributor to the aetiology of insulin resistance (IR). An inflammatory response in the presence of obesity appears to be triggered by, and to reside predominantly in, adipose tissue (AT). The discovery that the AT in obese mice and humans is infiltrated with macrophages has provided a major advance in our understanding of how obesity propagates inflammation. Interestingly, AT-infiltrating macrophages exhibit a proinflammatory phenotype (classical activation) whereas macrophages residing in AT have a reparative phenotype (alternative activation). In this review, the processes involved in monocyte/macrophage recruitment into the AT, and the events underlying the activation of infiltrating and/or resident AT macrophages (ATM) are described. Also, the localized roles of ATM on AT growth, metabolism and remodelling, as well as their systemic effects in promoting IR, are revealed. Finally, the new therapeutic targets that have recently emerged, and which have the potential to modulate the recruitment and/or activation of ATM, are discussed. PMID: 19539513 [PubMed - indexed for MEDLINE] 1851. Expert Opin Drug Saf. 2009 Sep;8(5):573-84. doi: 10.1517/14740330903081725. Diabetes medications and body weight. Mitri J(1), Hamdy O. Author information: (1)Boston University Medical School, Roger Williams Hospital, Providence, RI, USA. Tight diabetes control sometimes comes with a price: weight gain and hypoglycemia. Two of the three major recent trials that looked at the relationship between intensive diabetes control and cardiovascular events reported significant weight gain among the intensively treated groups. There is a growing concern that the weight gain induced by most diabetes medications diminishes their clinical benefits. On the other hand, there is a claim that treating diabetes with medications that are weight neutral or induces weight loss or less weight gain while minimizing those that increase body weight may emerge as the future direction for treating overweight and obese patients with diabetes. This review clarifies the weight effect of each of the currently available diabetes medications, and explains the mechanism of action behind this effect. Despite the great variability among reviewed clinical trials, the currently available evidence is quite sufficient to demonstrate the change in body weight in association with most of the currently available medications. This review also provides some guidelines on using diabetes medications during weight management programs. PMID: 19538102 [PubMed - indexed for MEDLINE] 1852. Actas Urol Esp. 2009 Mar;33(3):242-8. [Advances on the influence of adipose tissue on prostate cancer]. [Article in Spanish] López Fontana C(1), Maselli Artola ME, Vanrell Rodríguez MC, Di Milta Mónaco NA, Pérez Elizalde R, López Laur JD. Author information: (1)Laboratorio de Enfermedades Metabólicas y Cáncer, Facultad de Farmacia y Bioquímica, Universidad Juan Agustín Maza, Mendoza, Argentina. investigacioncap@yahoo.com.ar Comment in Actas Urol Esp. 2009 Mar;33(3):219. Numerous studies have investigated the association between obesity and prostate cancer (CaP), although the results have not been concluding due to the great difficulty to evaluate the effects of obesity on the development of this type of tumor. The aim of this study was to carry out a comprehensive over-view of the existing evidence about the role of adipose tissue in the prostate carcinogenesis. Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in PC progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. The potential mechanisms by which obesity may initiate, promote or facilitate the progression of CaP are low levels of testosterone and high levels of estrogen, coexisting metabolic syndrome, increased secretion of leptin, VEGF, IL-6 and TNF-alpha and decreased adiponectin, and excessive intake of saturated fat.CONCLUSION: Obesity may promote the progression of established PC rather than being a risk factor for the development of this tumour. However, additional studies are needed to clarify the relationship between adipokines and PC before developing new preventive or treatment strategies for this tumor. PMID: 19537061 [PubMed - indexed for MEDLINE] 1853. Adv Exp Med Biol. 2009;646:149-57. doi: 10.1007/978-1-4020-9173-5_17. Adipose tissue-muscle interactions and the metabolic effects of n-3 LCPUFA - implications for programming effects of early diet. Janovska P(1), Kopecky J. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic. Studies in adult animals as well as in humans have demonstrated beneficial effects of increased intake of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) on lipid metabolism, obesity, and insulin sensitivity. The lipid composition of breast milk, and in particular, the role of n-3 LCPUFA in imprinting of metabolism and its hormonal control need clarification as far as the long-term beneficial effects of breastfeeding on health are concerned. In this respect, animal studies have brought inconclusive results. However, the involvement of adipose tissue-muscle interactions in the short term effects of n-3 LCPUFA during perinatal development, as well as the lasting effects of n-3 LCPUFA intake, are likely to occur and should be further investigated. PMID: 19536674 [PubMed - indexed for MEDLINE] 1854. Adv Exp Med Biol. 2009;646:141-8. doi: 10.1007/978-1-4020-9173-5_16. Pharmacological and gene modification-based models for studying the impact of perinatal metabolic disturbances in adult life. Villarroya F(1), Bocos C, Giralt M, Pilar Ramos M, Herrera E, Sevillano J, Gual M, Rosell M, Iglesias R. Author information: (1)Department of Biochemistry and Molecular Biology and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain. fvillarroya@ub.edu Genetic modification approaches or pharmacological interventions may be useful for understanding the molecular mechanisms by which nutrient derivatives and metabolites exert their effects in the perinatal period and how they may influence longterm metabolism in adults. Examples for such experimental settings in rodents are targeted disruption of the gene for peroxisome proliferator-activated receptor (PPAR)-a, a lipid sensor and master regulator of lipid catabolism, or maternal treatment with agonists of PPARgamma, a master regulator of adipogenesis and target of insulin sensitizing drugs in adults. All these interventions show differential effects in the perinatal period compared to adults and indicate that altered activity of master regulators of metabolism results in profound metabolic alterations in the perinatal period that may influence adult metabolism. PMID: 19536673 [PubMed - indexed for MEDLINE] 1855. Adv Exp Med Biol. 2009;646:133-9. doi: 10.1007/978-1-4020-9173-5_15. PGC-1beta: a co-activator that sets the tone for both basal and stress-stimulated mitochondrial activity. Lelliott CJ(1), Vidal-Puig A. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. christopher.lelliott@astrazeneca.com The peroxisomal proliferator-activated receptor-gamma coactivator (PGC) family of transcriptional coactivators are central regulators of a wide-range of metabolic processes, which combine to control whole-body homeostasis. However, the specific function of each PGC in a tissue and pathway-specific context is only now being elucidated. In order to define the specific roles of PGC-1beta, we generated a mouse lacking this gene and studied its phenotype using a combination of physiological experiments, guided by a systems biology approach. We found that despite the predicted obese phenotype, PGC1betaKO were leaner than wild-type and had elevated energy expenditure in the resting state, probably due to upregulation of a wide-range of oxidative and fuel-handling genes in the brown adipose tissue (BAT), including PGC family member PGC-1alpha. Nonetheless, we identified that PGC-1beta ablation results in a global reduction in oxidative phosphorylation and electron transport chain genes and this translates into mitochondrial dysfunction in selected tissues. PGC1betaKO mice also demonstrate blunted responses to physiological stresses such as cold exposure in BAT, adrenergic stimulation in BAT and heart and acute dietary lipid loads in liver. In summary, while lack of PGC-1beta is not deleterious, it is essential for the normal expression of mitochondrial metabolic genes and for the optimal ability to handle physiological stresses. PMID: 19536672 [PubMed - indexed for MEDLINE] 1856. Adv Exp Med Biol. 2009;646:105-12. doi: 10.1007/978-1-4020-9173-5_11. Early nutrition and later obesity: animal models provide insights into mechanisms. Metges CC(1). Author information: (1)Research Institute of Farm Animal Biology, Research unit Nutritional Physiology, Dummerstorf, Germany. metges@fbn-dummerstorf.de Epidemiological evidence suggests that in utero as well as early postnatal life exposure to an imbalanced nutrition are both related to a greater propensity to become obese in later life. Rodent and sheep models of metabolic programming of obesity by early life nutrition include maternal low and high dietary protein and energy or food intake as well as high fat diets. Maternal nutritional imbalance during pregnancy and/or lactation programs energy expenditure, food intake and physical activity in the offspring. Underlying mechanisms of altered energy balance in programmed offspring are associated with disturbances of ontogeny of hypothalamic feeding circuits, leptin and glucocorticoid action which have long-lasting effects on food intake, energy expenditure and fat tissue metabolism. PMID: 19536668 [PubMed - indexed for MEDLINE] 1857. Adv Exp Med Biol. 2009;646:83-93. doi: 10.1007/978-1-4020-9173-5_9. Developmental origins of obesity: programming of food intake or physical activity? Gardner DS(1), Rhodes P. Author information: (1)Centre for Reproduction and Early Life, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK. david.gardner@nottingham.ac.uk Mans ability to capture, harness and store energy most efficiently as fat in adipose tissue has been an evolutionary success story for the majority of human existence. Only over the last 30-40 years has our remarkable metabolic efficiency been revealed as our energy balance increasingly favours storage without regular periods of depletion. Historical records show us that while the composition of our diet has changed markedly over this time, our overall energy intake has significantly reduced. The inevitable conclusion therefore is that habitual physical activity and thus energy expenditure has reduced by a greater extent. Recent studies have illustrated how the finely tuned long-term control of energy intake and of energy expenditure are both developmentally plastic and susceptible to environmentally-induced change that may persist with that individual throughout their adult life, invariably rendering them more susceptible to greater adipose tissue deposition. The central role that lean body mass has upon the 'gating' of energy sensing and the importance of regular physical activity for its potential to reduce the burden of a 'thrifty phenotype' will be briefly discussed in the present review. PMCID: PMC2701542 PMID: 19536666 [PubMed - indexed for MEDLINE] 1858. Diabetologia. 2009 Sep;52(9):1724-31. doi: 10.1007/s00125-009-1422-8. Epub 2009 Jun 17. Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Irwin N(1), Flatt PR. Author information: (1)School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, UK. n.irwin@ulster.ac.uk Gastric inhibitory polypeptide (GIP) is a physiological gut peptide secreted from the intestinal K-cells with well documented insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex and brain, suggesting that it may have other functions. The presence of functional GIP receptors on adipocytes and the key role played by GIP in lipid metabolism and fat deposition suggest a possible beneficial effect of compromised GIP action in obesity and insulin resistance. Several key observations in animal models of obesity-related diabetes with chemically or genetically mediated biological GIP deficiency support this concept. Thus, obese diabetic animals with compromised GIP action due to peptide-based GIP receptor antagonists, small molecular weight GIP receptor antagonists, vaccination against GIP, genetic knockout of GIP receptor or targeted K-cell destruction are protected against obesity and associated metabolic disturbances. In addition, by causing preferential oxidation of fat, blockade of GIP signalling clears triacylglycerol deposits from liver and muscle, thereby restoring mechanisms for suppression of hepatic glucose output and improving insulin sensitivity. Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine. PMID: 19533083 [PubMed - indexed for MEDLINE] 1859. Orv Hetil. 2009 Jul 5;150(27):1259-65. doi: 10.1556/OH.2009.28666. [Use of mesenchymal stem cells from adult bone marrow for injured tissue repair]. [Article in Hungarian] Salamon A(1), Toldy E. Author information: (1)Vas Megyei Markusovszky Lajos Altalános és Rehabilitációs Gyógyfürdo Kórház, Egyetemi Oktató Kórház, Baleseti, Helyreállító és Kézsebészeti Osztály, Szombathely. salamon.antal@chello.hu Mesenchymal stem cells are known as being multipotent and exhibit the potential for differentiation into different cells/tissue lineages, including cartilage, bone, adipose tissue, tendon, and ligament. These pluripotent mesenchymal progenitor cells are denoted as stromal or mesenchymal stem cells. Bone marrow contains two main cell types: hematopoietic cells and stromal cells. The stem cells for non hematopoietic tissues are referred as mesenchymal cells because of their ability to differentiate as mesenchymal or stromal cells. Mesenchymal cells are easily obtainable from bone marrow by means of minimally invasive approach and can be expanded in culture and permitted to differentiate into the desired lineage. The differentiation can be reached by the application of bioactive signaling molecules, specific growth factors. The transforming growth factor beta (TGF-beta) superfamily member proteins such as the bone morphogenetic proteins (BMP-s) are the most important factors of chondrogenic and osteogenic differentiation of mesenchymal stem cells. From the series of recently identified factors, BMP 2,4 and 7 may play an important role in chondrogenic and osteogenic differentiation proteins. Little is known, however, about the signaling pathway involved in tenogenesis of mesenchymal stem cells, but there are some encouraging data about fibroblastic differentiation. The success of growth factor therapy needs a delivery system with biomaterials. Mesenchymal stem cells have become promising vehicles for gene therapy, cell therapy and tissue engineering. In present review, authors deal with the experimental investigations and with the clinical application of the adult bone marrow derived mesenchymal stem cells with bioactive molecules, growth factors. PMID: 19531459 [PubMed - indexed for MEDLINE] 1860. Semin Reprod Med. 2009 Jul;27(4):306-15. doi: 10.1055/s-0029-1225258. Epub 2009 Jun 15. Androgens in polycystic ovary syndrome: the role of exercise and diet. Giallauria F(1), Palomba S, Vigorito C, Tafuri MG, Colao A, Lombardi G, Orio F. Author information: (1)Department of Clinical Medicine, Cardiovascular and Immunological Sciences, University of Naples Federico II, Naples, Italy. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women and is characterized by chronic ovulatory dysfunction and hyperandrogenism. Clinical studies have shown that hyperandrogenism is linked with insulin resistance/metabolic syndrome in PCOS women. This review article summarizes the several potential mechanisms for the association of androgen excess with insulin resistance, including both direct and indirect actions of androgens on insulin target tissues. This review article also focuses on the beneficial effects of exercise training and diet on glucose metabolism and hyperandrogenism in PCOS women, pointing out that whether in conjunction with pharmacotherapy or as a stand-alone treatment, diet and exercise training represent a fundamental strategy in the treatment of PCOS women. PMID: 19530064 [PubMed - indexed for MEDLINE] 1861. Expert Opin Biol Ther. 2009 Jul;9(7):879-87. doi: 10.1517/14712590903039684. The wound-healing and antioxidant effects of adipose-derived stem cells. Kim WS(1), Park BS, Sung JH. Author information: (1)Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Department of Dermatology, Seoul, Korea. BACKGROUND: The aim of tissue engineering is to repair and regenerate damaged organs using a combination of cells, biomaterials and growth factors. Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue, that is adipose-derived stem cells (ADSCs) have been used in skin repair with satisfactory results. The production and secretion of growth factors has been reported to be an essential function of ADSCs, and diverse regenerative effects of ADSCs in the skin have been demonstrated. OBJECTIVE: Recent research developments concerning the wound-healing and antioxidant effects of ADSCs are briefly described. METHODS: Various experimental results regarding the wound-healing and antioxidant effect of ADSCs are introduced, and the mechanisms and identification of active proteins involved in these function are further discussed. RESULTS/CONCLUSION: Evidence of ADSC differentiation of skin has not been reported in vivo, but ADSCs accelerate wound-healing and exhibit antioxidant effects under various conditions. The wound-healing and antioxidant effects of ADSCs are mainly mediated by the activation of dermal fibroblasts and keratinocytes via the paracrine mechanism. Since ADSCs are easily obtained in large quantities and have an advantage over other stem cell sources, ADSCs and their secretory factors show promise for use in skin repair and regeneration. PMID: 19522555 [PubMed - indexed for MEDLINE] 1862. Laryngoscope. 2009 Aug;119(8):1652-7. doi: 10.1002/lary.20529. Laryngeal complications after lipoinjection for vocal fold augmentation. Sanderson JD(1), Simpson CB. Author information: (1)Department of Otolaryngology, University of Texas Health Science Center at San Antonio, 78229, USA. OBJECTIVES/HYPOTHESIS: Vocal fold augmentation with autologous fat has been widely used for the last 15 years with varying success. Autologous fat is biocompatible, readily available, and easily harvested, making it a commonly used material for vocal fold augmentation. Although felt to be a relatively safe procedure, few studies have looked at the complication rate of lipoinjection for vocal fold augmentation. STUDY DESIGN: Retrospective review. METHODS: Ninety-eight vocal fold injections were performed at one institution from 1997 to 2008. The charts were reviewed retrospectively, and age, diagnosis, side of procedure, concurrent procedures, length of follow-up, and complications during or subsequent to the injection were recorded in a database. Patients were excluded if data was inadequate to make a determination regarding complication during or after lipoinjection. RESULTS: Eighty-eight patients met the criteria for review with an average age of 57.4 years. The most common indications for injection were vocal fold paresis, vocal fold scarring, and presbylaryngeus. Mean follow-up was 20.2 months with a range of 0 months to 126 months. Overall, four laryngeal complications occurred (4.5%), including three over-injections (3.4%) leading to poor voice quality and one granuloma formation (1.1%). The over-injections were managed using cordotomy with fat removal, resulting in vocal improvement in all cases. CONCLUSIONS: Although lipoinjection vocal fold augmentation is a safe procedure, over-injection of autologous fat is a risk. Lipoinjection for vocal fold augmentation can lead to over-injection with dysphonia in a small number of patients. The complications can be managed with lateral cordotomy and fat removal. PMID: 19522003 [PubMed - indexed for MEDLINE] 1863. Nihon Ronen Igakkai Zasshi. 2009 May;46(3):225-7. [Adipose tissue function and human longevity: a possible relationship between the metabolic syndrome and frailty]. [Article in Japanese] Arai Y, Hirose N. PMID: 19521041 [PubMed - indexed for MEDLINE] 1864. Cytokine Growth Factor Rev. 2009 Jun;20(3):193-201. doi: 10.1016/j.cytogfr.2009.05.007. Epub 2009 Jun 10. Angiogenesis, adipokines and breast cancer. Vona-Davis L(1), Rose DP. Author information: (1)Department of Surgery and Breast Cancer Research Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, United States. lvdavis@hsc.wvu.edu The prevalence of overweight and obesity is rapidly increasing world wide. Numerous epidemiological studies have shown that obesity is a risk factor for postmenopausal breast cancer and relapse. However, the biological factors that drive the growth and progression of these tumors and how obesity contributes to the tumor microenvironment are poorly understood. Tumor development and metastasis are dependent on the process of angiogenesis or the formation of new blood vessels. More importantly, a ready supply of adipose tissue-derived angiogenic adipokines, notably VEGF and leptin, and the production of inflammatory cytokines by infiltrating macrophages that occurs in adipose tissues with obesity, promotes the paracrine stimulation of vascular endothelial cell growth needed for adipogenesis, while maintaining a microenvironment that is favorable for breast tumorigenesis. PMID: 19520599 [PubMed - indexed for MEDLINE] 1865. Thromb Res. 2009;123 Suppl 4:S46-9. doi: 10.1016/S0049-3848(09)70143-4. Role of fibrinolysis in obesity and thrombosis. Lijnen HR(1). Author information: (1)Center for Molecular and Vascular Biology, KU Leuven, Belgium. roger.lijnen@med.kuleuven.be Obesity is a common disorder and a known risk factor for thrombotic complications. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) system plays an important role in these processes. Studies using a nutritionally induced obesity model in transgenic mice support a role of the fibrinolytic system in adipogenesis and obesity. Studies using venous or arterial thrombosis models in obese mice, with impaired fibrinolytic activity, confirm a prothrombotic risk associated with obesity. PMID: 19303504 [PubMed - indexed for MEDLINE] 1866. Gend Med. 2009;6 Suppl 1:60-75. doi: 10.1016/j.genm.2009.02.002. Gender differences in insulin resistance, body composition, and energy balance. Geer EB(1), Shen W. Author information: (1)Division of Endocrinology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. eliza.geer@mssm.edu BACKGROUND: Men and women differ substantially in regard to degrees of insulin resistance, body composition, and energy balance. Adipose tissue distribution, in particular the presence of elevated visceral and hepatic adiposity, plays a central role in the development of insulin resistance and obesity-related complications. OBJECTIVE: This review summarizes published data on gender differences in insulin resistance, body composition, and energy balance, to provide insight into novel gender-specific avenues of research as well as gender-tailored treatments of insulin resistance, visceral adiposity, and obesity. METHODS: English-language articles were identified from searches of the PubMed database through November 2008, and by reviewing the references cited in these reports. Searches included combinations of the following terms: gender, sex, insulin resistance, body composition, energy balance, and hepatic adipose tissue. RESULTS: For a given body mass index, men were reported to have more lean mass, women to have higher adiposity. Men were also found to have more visceral and hepatic adipose tissue, whereas women had more peripheral or subcutaneous adipose tissue. These differences, as well as differences in sex hormones and adipokines, may contribute to a more insulin-sensitive environment in women than in men. When normalized to kilograms of lean body mass, men and women had similar resting energy expenditure, but physical energy expenditure was more closely related to percent body fat in men than in women. CONCLUSION: Greater amounts of visceral and hepatic adipose tissue, in conjunction with the lack of a possible protective effect of estrogen, may be related to higher insulin resistance in men compared with women. PMCID: PMC2908522 PMID: 19318219 [PubMed - indexed for MEDLINE] 1867. J Clin Endocrinol Metab. 2009 Sep;94(9):3171-82. doi: 10.1210/jc.2008-2534. Epub 2009 Jun 9. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. Goldberg RB(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida 33101, USA. rgoldberg@med.miami.edu CONTEXT: Recent developments indicate that pathophysiological mechanisms leading to beta-cell damage, insulin resistance, and the vascular complications of diabetes include an activation of the inflammation cascade, endothelial dysfunction, and procoagulant imbalance. Their circulating biomarkers may therefore provide opportunities for early diagnosis and targets for novel treatments. EVIDENCE: Circulating biomarkers of these pathways such as TNFalpha, IL-6, C-reactive protein (CRP) (inflammation), vascular cellular adhesion molecule-1, interstitial cellular adhesion molecule-1, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin (procoagulant state), and adiponectin (antiinflammation) may be associated with development of both type 1 and type 2 diabetes and some studies, particularly in type 2 diabetes, have demonstrated that certain biomarkers may have independent predictive value. Similarly studies have shown that these biomarkers may be associated with development of diabetic nephropathy and retinopathy, and again, particularly in type 2 diabetes, with cardiovascular events as well. Finally, the comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to ameliorate them. CONCLUSIONS: Increased CRP, IL-6, and TNFalpha, and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with nephropathy, retinopathy, and cardiovascular disease in both type 1 and type 2 diabetes. Whereas further work is needed, it seems clear that these biomarkers are predictors of increasing morbidity in prediabetic and diabetic subjects and should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions. PMID: 19509100 [PubMed - indexed for MEDLINE] 1868. Growth Horm IGF Res. 2009 Aug;19(4):308-19. doi: 10.1016/j.ghir.2009.04.023. Epub 2009 Jun 7. The physiology of growth hormone and sport. Widdowson WM(1), Healy ML, Sönksen PH, Gibney J. Author information: (1)Department of Endocrinology and Diabetes, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. The growth hormone (GH)/ insulin-like growth factor-I (IGF-I) axis exerts short-and long-term metabolic effects that are potentially important during exercise. Exercise is a potent stimulus to GH release and there is some evidence that the acute increase in GH is important in regulating substrate metabolism post-exercise. Regular exercise also increases 24-hour GH secretion rates, which potentially contributes to the physiologic changes induced by training. The effects of GH replacement in GH-deficient adults provide a useful model with which to study the effects of the more long-term effects of the GH/ IGF-I axis. There is convincing evidence that GH replacement increases exercise capacity. Measures of exercise performance including maximal oxygen uptake (VO2max) and ventilatory threshold (VeT) are impaired in GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition and improved thermoregulation. Administration of supraphysiologic doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss particularly during exercise, and increases lean body mass. It is not known whether these effects translate to improved athletic performance, although recombinant human GH is known to be widely abused in sport. The model of acromegaly provides evidence that long-term GH excess does not result in improved performance but it is possible that a "window" exists in which the protein anabolic effects of supraphysiologic GH might be advantageous. PMID: 19505835 [PubMed - indexed for MEDLINE] 1869. Clin Biochem. 2009 Sep;42(13-14):1331-46. doi: 10.1016/j.clinbiochem.2009.05.018. Epub 2009 Jun 6. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Meshkani R(1), Adeli K. Author information: (1)Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. BACKGROUND: The metabolic syndrome is a constellation of common metabolic disorders that is associated with cardiovascular disease. Insulin resistance has a central role in the pathophysiology of metabolic syndrome. RECENT ADVANCES: It is now commonly accepted that chronic inflammation associated with visceral obesity induces insulin resistance in the liver. Chronic inflammation is characterized by the production of abnormal adipokines and cytokines such as TNF-alpha, FFA, IL-1, IL-6, leptin and resistin. These factors inhibit insulin signalling in hepatocytes by activating SOCS proteins, several kinases such as JNK, IKK-beta and PKC and protein tyrosine phosphatases such as PTP1B and PTEN, that in turn impair insulin signalling at insulin receptor and insulin receptor substrate (IRS) level. Hepatic insulin resistance in turn causes impaired suppression of glucose production by insulin in hepatocytes leading to hyperglycemia. An important and early complication of hepatic insulin resistance is the induction of hepatic VLDL production, via changes in the rate of apoB synthesis and degradation and de novo lipogenesis, or increased FFA flux from adipose tissue into the liver. Insulin resistance also stimulates the production of CRP and PAI-1, both markers of an inflammatory state. All metabolic abnormalities related to hepatic insulin resistance have been shown to directly or indirectly promote atherosclerosis. Hyperglycemia induces a series of alterations including endothelial dysfunction, cellular proliferation, changes in extracellular matrix conformation and impairment of LDL receptor-mediated uptake decreasing the in vivo clearance of LDL. Small dense LDLs associated with high circulating VLDL have higher affinity to the intimal proteoglycans leading to the penetration of more LDL particles into the arterial wall. CRP can also accelerate atherosclerosis by increasing the expression of PAI-1 and adhesion molecules in endothelial cells, inhibition of nitric oxide formation and increasing LDL uptake into macrophages. CONCLUSIONS: Overall, growing evidence suggests that hepatic insulin resistance is sufficient to induce several components of the metabolic syndrome and promote progression to cardiovascular disease. Many unresolved questions remain however on the molecular and cellular mechanisms that trigger hepatic insulin resistance and promote the development of clinical metabolic syndrome. PMID: 19501581 [PubMed - indexed for MEDLINE] 1870. Prim Care. 2009 Jun;36(2):271-85. doi: 10.1016/j.pop.2009.01.009. Comorbidities of obesity. Schelbert KB(1). Author information: (1)Department of Family Medicine, University of Pittsburgh School of Medicine, 3518 Fifth Avenue, Pittsburgh, PA 15261, USA. Obesity, especially visceral adiposity, is associated with morbidity and mortality through endocrine and mechanical processes. Clinical manifestations due to effects of obesity on the cardiovascular, respiratory, gastrointestinal, musculoskeletal, immune, and integumentary systems have been described. Further studies are needed to understand the pathologic processes underlying these clinical manifestations to improve disease prevention. PMID: 19501243 [PubMed - indexed for MEDLINE] 1871. Curr Atheroscler Rep. 2009 Jul;11(4):264-71. Metabolic syndrome: perception or reality? Lau DC(1). Author information: (1)Julia McFarlane Diabetes Research Centre, University of Calgary, Calgary, AB, Canada. dcwlau@ucalgary.ca Metabolic syndrome is associated with increased risk for type 2 diabetes and cardiovascular disease. It has garnered considerable clinical and research interest as a potential target to reduce cardiovascular risk in addition to the classical risk factors. Whether it exists as a distinct clinical entity has become a subject of controversy and debate. This review appraises the evidence in support of or against recognizing metabolic syndrome as a clinical condition that requires therapeutic intervention. Proper evaluation of cardiovascular disease risk should start with consideration of traditional risk factors using validated tools, such as the short-term 10-year Framingham risk score. Individuals with abdominal obesity should be further assessed for associated cardiometabolic risks. Global cardiovascular disease risk should take into consideration not only short-term but also lifetime risks. PMID: 19500489 [PubMed - indexed for MEDLINE] 1872. Curr Opin Lipidol. 2009 Aug;20(4):300-8. doi: 10.1097/MOL.0b013e32832d4a33. Inherited lipodystrophies and hypertriglyceridemia. Simha V(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. PURPOSE OF REVIEW: Inherited lipodystrophies are rare autosomal recessive and dominant disorders characterized by selective, but variable, loss of adipose tissue. Marked hypertriglyceridemia is a common feature of these disorders and highlights the role of adipose tissue in lipid homeostasis. In the last decade, advances have been made in elucidating the molecular basis of many inherited lipodystrophies. We review the new insights in the pathophysiology and treatment of these disorders based on the current understanding of the biologic role of these lipodystrophy genes. RECENT FINDINGS: Eight different genetic loci, including 1-acylglycerol-3-phosphate-O-acyltransferase 2, Berardinelli-Seip congenital lipodystrophy 2, caveolin 1, lamin A/C, peroxisome proliferator-activated receptor gamma, v-AKT murine thymoma oncogene homolog 2, zinc metalloprotease and lipase maturation factor 1 have been described linked to different lipodystrophy syndromes. Mutations in these genes may cause fat loss and dyslipidemia through multiple mechanisms, which remain fully elucidated; however, they may involve defects in development and differentiation of adipocytes, and premature death and apoptosis of adipocytes. Hypertriglyceridemia is a consequence of increased VLDL synthesis from the liver, which is also loaded by ectopic triglyceride deposition, reduced clearance of triglyceride-rich lipoproteins or both. A recent study in mice with Agpat2 deficiency reports marked reduction in serum triglyceride upon feeding a fat-free diet, which suggests that low-fat diets are likely to be beneficial in lipodystrophic patients. Leptin replacement therapy is also a promising therapeutic option for lipodystrophic patients with hypoleptinemia. SUMMARY: Inherited lipodystrophies are an important cause for monogenic hypertriglyceridemia and serve to highlight the role of adipocytes in maintaining normolipidemia. PMID: 19494770 [PubMed - indexed for MEDLINE] 1873. Curr Opin Clin Nutr Metab Care. 2009 Sep;12(5):482-6. doi: 10.1097/MCO.0b013e32832da22c. Body composition determination by bioimpedance: an update. Jaffrin MY(1). Author information: (1)Department of Biological Engineering, UMR CNRS 6600, University of Technology of Compiegne, Compiegne, France. michel.jaffrin@utc.fr PURPOSE OF REVIEW: To review various methods for measuring body composition by bioimpedance and their limitations, as well as available impedance meters, including body fat analyzers for home use. RECENT FINDINGS: Bioimpedance spectroscopy, which requires multifrequency impedance meters, is preferable for fluid volume measurements, especially extracellular fluid, whereas bioimpedance analysis at 50 kHz is more widely used for measuring fat-free mass. A method for using bioimpedance spectroscopy equations with 50 kHz impedance meters has been recently proposed and successfully tested. Low cost foot-to-foot impedance meters (body fat analyzers) with plantar electrodes on a body scale, that are easy and fast to use, have been compared with medical impedance meters and with dual X-ray absorptiometry measurements and found reasonably accurate, except for individuals with very low or high BMI. SUMMARY: Body composition by bioimpedance is gaining acceptance in nutrition, hemodialysis, gerontology and sports medicine. Body fat analyzers that have been validated by comparison with dual x-ray absorptiometry could be useful to general practitioners, nutritionists and cardiologists. PMID: 19494768 [PubMed - indexed for MEDLINE] 1874. Curr Stem Cell Res Ther. 2009 Sep;4(3):210-23. Lost in translation: what is limiting cardiomyoplasty and can tissue engineering help? Simpson D(1), Dudley SC Jr. Author information: (1)Georgia Institute of Technology, Atlanta, GA 30332, USA. Heart failure accounts for more deaths in the United States than any other detrimental human pathology. Recently, repairing the heart after seemingly irreversible injury leading to heart failure appears to have come within reach. Cellular cardiomyoplasty, transplanting viable cell alternatives into the diseased myocardium, has emerged as a promising possible solution. Translating this approach from the laboratory to the clinic, however, has been met with several challenges, leaving many questions unanswered. This review assesses the state of investigation of several progenitor cell sources, including induced pluripotent stem cells, embryonic stem cells, bone marrow stem cells, adipose-derived adult stem cells, amniotic fluid stem cells, skeletal muscle progenitors, induced pluripotent stem cells and cardiac progenitors. Several current roadblocks to maximum success are discussed. These include understanding the need for cardiomyocyte differentiation, appreciating the role of paracrine factors, and addressing the low engraftment rates using current techniques. Tissue engineering strategies to address these obstacles and to help maximize cellular cardiomyoplasty success are reviewed. PMCID: PMC3164232 PMID: 19492979 [PubMed - indexed for MEDLINE] 1875. Curr Diab Rep. 2009 Jun;9(3):208-14. The role of FOXO in the regulation of metabolism. Gross DN(1), Wan M, Birnbaum MJ. Author information: (1)University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. Forkhead box O (FOXO) transcription factors play an important role in modulating metabolic functions. FOXO is regulated by several modifications, but one of the most critical is phosphorylation and nuclear exclusion by Akt. Given the impact of insulin signaling on Akt-mediated phosphorylation of FOXO and the relatively high expression of Foxo1 in insulin-responsive tissues, this transcription factor is highly poised to regulate energy metabolism. When nutrient and insulin levels are low, Foxo1 promotes expression of gluconeogenic enzymes. Conversely, in the fed state, insulin levels rise and stimulate uptake of glucose primarily into skeletal muscle and other organs, including adipose tissue. Under certain pathophysiologic conditions, including insulin resistance, negative signaling to Foxo1 is compromised. Further clarification of the role of Foxo1 in insulin-responsive tissues will strengthen our understanding and allow us to better combat insulin resistance and diabetes mellitus. PMID: 19490822 [PubMed - indexed for MEDLINE] 1876. Curr Diab Rep. 2009 Jun;9(3):200-7. Lessons learned from studying families genetically predisposed to type 2 diabetes mellitus. Cusi K(1). Author information: (1)Diabetes Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. cusi@uthscsa.edu Early interventions to prevent type 2 diabetes mellitus (T2DM) demand a better understanding of its underlying mechanisms. Nonobese healthy subjects with a strong family history of T2DM (FH(+) subjects) hold a key to this end by allowing the study of the disease before the development of confounding factors, such as obesity or hyperglycemia. In this article, we share our experience over the past decade in studying FH(+) subjects and how lipotoxicity alters glucose metabolism in such individuals, in particular pancreatic beta-cell function. FH(+) subjects have no obvious clinical abnormalities, but when carefully studied, reveal severe hepatic/muscle/adipose tissue insulin resistance and subtle defects in beta-cell function. In most subjects, metabolic adaption allows freedom from diabetes for decades. However, the obesity epidemic is drastically changing this. Given the unique susceptibility of pancreatic beta cells to free fatty acids in FH(+) subjects, interventions that protect against obesity-induced lipotoxicity may hold the greatest promise for preventing T2DM in genetically predisposed individuals. PMID: 19490821 [PubMed - indexed for MEDLINE] 1877. Proc Nutr Soc. 2009 Aug;68(3):321-6. doi: 10.1017/S0029665109001402. Epub 2009 Jun 3. Session on 'Obesity'. Adipose tissue development, nutrition in early life and its impact on later obesity. Budge H(1), Sebert S, Sharkey D, Symonds ME. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham NG7 2UH, UK. helen.budge@nottingham.ac.uk It is now apparent that one key factor determining the current obesity epidemic within the developed world is the extent to which adipose tissue growth and function can be reset in early life. Adipose tissue can be either brown or white, with brown fat being characterised as possessing a unique uncoupling protein (uncoupling protein 1) that enables the rapid generation of heat by non-shivering thermogenesis. In large mammals this function is recruited at approximately the time of birth, after which brown fat is lost, not normally reappearing again throughout the life cycle. The origin and developmental regulation of brown fat in large mammals is therefore very different from that of small mammals in which brown fat is retained throughout the life cycle and may have the same origin as muscle cells. In contrast, white adipose tissue increases in mass after birth, paralleled by a rise in glucocorticoid action and macrophage accumulation. This process can be reset by changes in the maternal nutritional environment, with the magnitude of response being further determined by the timing at which such a challenge is imposed. Importantly, the long-term response within white adipocytes can occur in the absence of any change in total fat mass. The present review therefore emphasises the need to further understand the developmental regulation of the function of fat through the life cycle in order to optimise appropriate and sustainable intervention strategies necessary not only to prevent obesity in the first place but also to reverse excess fat mass in obese individuals. PMID: 19490741 [PubMed - indexed for MEDLINE] 1878. Ann Intern Med. 2009 Jun 2;150(11):776-83. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Sowers JR(1), Whaley-Connell A, Epstein M. Author information: (1)University of Missouri, Columbia, Missouri, USA. The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease. PMCID: PMC2824330 PMID: 19487712 [PubMed - indexed for MEDLINE] 1879. Mol Pharmacol. 2009 Sep;76(3):453-65. doi: 10.1124/mol.109.055244. Epub 2009 Jun 1. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients. Wellendorph P(1), Johansen LD, Bräuner-Osborne H. Author information: (1)UNIK centre for life-style diseases, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium-sensing receptor, the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3, which are sensing L-alpha-amino acids, the carbohydrate-sensing T1R2/T1R3 receptor, the proteolytic degradation product sensor GPR93 (also termed GPR92), and the free fatty acid (FFA) sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. The involvement of the individual receptors in sensing of food intake has been validated to different degrees because of limited availability of specific pharmacological tools and/or receptor knockout mice. However, as a group, the receptors represent potential drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance. PMID: 19487246 [PubMed - indexed for MEDLINE] 1880. Curr Vasc Pharmacol. 2010 Jan;8(1):12-28. Visfatin/PBEF and atherosclerosis-related diseases. Filippatos TD(1), Randeva HS, Derdemezis CS, Elisaf MS, Mikhailidis DP. Author information: (1)Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital campus, University College London (UCL), London, UK. Visfatin is highly expressed in adipose tissue (mainly by the stromal cells), but it is also ubiquitously present in most tissues. Visfatin, which plays a role in nicotinamide adenine dinucleotide (NAD) biosynthesis, has been implicated in inflammatory states. Controversial results exist about the expression, circulating levels and the role of visfatin in atherosclerosis-related diseases. Most studies showed increased levels of visfatin in diabetes mellitus, obesity, hypertension, renal and cardiovascular disease. However, other studies reported lower levels of visfatin in these diseases. The discrepancies in clinical studies may be attributed to the multifactorial regulation of visfatin. There is evidence that visfatin expression and circulating levels are influenced by fat area and distribution, inflammatory state, renal function, iron metabolism, hormones as well as several other factors. Furthermore, discrepancies and lack of correlation between commercially available visfatin assays have been reported. More research is needed to better understand the factors that control its synthesis/release and to evaluate the role of visfatin in atherosclerosis-related disease. Large studies with homogeneous populations will probably be needed to answer these questions. Whether visfatin will eventually become a therapeutic target remains to be established. PMID: 19485930 [PubMed - indexed for MEDLINE] 1881. Front Biosci (Schol Ed). 2009 Jun 1;1:329-57. Targeting the adiponectin:leptin ratio for postmenopausal breast cancer prevention. Cleary MP(1), Ray A, Rogozina OP, Dogan S, Grossmann ME. Author information: (1)The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. mpcleary@smig.net Obesity is a risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, specifically adiponectin and leptin, impact breast cancer development. Serum adiponectin levels are reduced in women diagnosed with breast cancer and in vitro studies using human breast cancer cell lines have shown antiproliferative action of adiponectin. In contrast, elevated serum leptin levels were associated with breast cancer in some studies. In mice which lack the leptin receptor or are leptin deficient oncogene-induced mammary tumors were not detected while leptin enhanced proliferation of breast cancer cell lines, particularly those that express estrogen receptors. Of particular interest, one recent study reported that the adiponectin:leptin ratio was reduced in women with breast cancer. Here we speculate that the ratio of these adipokines may be more important in breast cancer than their absolute concentrations. Additionally, we propose strategies to alter this ratio and thus provide protection against the development of breast cancer. PMID: 19482706 [PubMed - indexed for MEDLINE] 1882. Front Biosci (Schol Ed). 2009 Jun 1;1:92-107. Skeletal morphofunctional considerations and the pituitary-thyroid axis. Iqbal J(1), Davies TF, Sun L, Abe E, Carpi A, Mechanick JI, Zaidi M. Author information: (1)Mount Sinai Bone Program and Department of Medicine, Mount Sinai School of Medicine, New York 10029, USA. The past decade has unraveled novel molecular mechanisms not only of skeletal remodeling, which is the process by which the skeleton is restructured throughout adult life, but also the precision by which the skeleton is put together during embryogenesis and later modeled during growth. It is now possible to delete single genes in individual cells and during specified periods of life. This has allowed us to pin down specific molecular events that underlie individual cellular processes, and also importantly, to identify molecular defects underlying disorders of skeletal morphogenesis and remodeling. Particularly novel has been the demonstration of cross-talk, some of which is humoral, between the skeleton and organs as diverse as the brain, pituitary, and even adipose tissue and pancreas. The current review describes these molecular mechanisms in relation to the way thyroid hormones, and the pituitary hormone thyrotropin (TSH), regulate skeletal morphogenesis and remodeling. PMID: 19482685 [PubMed - indexed for MEDLINE] 1883. J Cutan Pathol. 2009 May;36(5):565-9. doi: 10.1111/j.1600-0560.2008.01067.x. Epub 2008 Oct 6. Extra-abdominal subcutaneous metastasis of a gastrointestinal stromal tumor: report of a case and a review of the literature. Kroep JR(1), Bovée JV, van der Molen AJ, Hogendoorn PC, Gelderblom H. Author information: (1)Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. j.r.kroep@lumc.nl Gastrointestinal stromal tumors (GISTs) metastasize primarily within the peritoneal cavity and to the liver. Superficial soft tissue metastases occur in about 1% of advanced GIST and are mostly associated with abdominal laparotomy scars and advanced disease. Extra-abdominal subcutaneous metastases of GIST have not been previously reported. Subcutaneous spindle cell tumors constitute a diagnostic challenge of which the differential diagnostic list can be limited by recognition of morphological, immunohistochemical en molecular genetic patterns. A 69-year-old woman presented with a fast growing subcutaneous nodule on her right upper arm. She was known with an imatinib-resistant advanced GIST, treated with sunitinib. The nodule was excised. Histopathological examination revealed a sharply demarcated tumor nodule in the subcutaneous fat with slightly spindled tumor cells, with pleomorphic nuclei and multiple mitoses. There was a hemangiopericytomatous vascular pattern. The cells stained positive for CD117 (KIT) and CD34. No KIT or platelet-derived growth factor receptor-alpha mutations were detected. We report the first case of an extra-abdominal subcutaneous metastasis of GIST. Although rare, metastatic GIST should therefore be included in the differential diagnosis of subcutaneous spindle cell tumors. A comparative survey of the histological, immunohistochemical and molecular genetic features of spindle cell tumors of the subcutis and a review of the literature is presented. PMID: 19476525 [PubMed - indexed for MEDLINE] 1884. Curr Opin Clin Nutr Metab Care. 2009 Jul;12(4):438-43. doi: 10.1097/MCO.0b013e32832c6db7. Healthy obesity. Wildman RP(1). Author information: (1)Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA. rwildman@aecom.yu.edu PURPOSE OF REVIEW: To introduce the healthy obese phenotype, characterized by favorable cardiometabolic risk factors despite excess adipose tissue. The epidemiology of the healthy obese phenotype is presented, including associated risk of cardiovascular disease (CVD), and potential biologic mechanisms which may give rise to the phenotype are discussed. RECENT FINDINGS: Although it appears that approximately 30% of obese individuals maintain healthy cardiometabolic profiles, little published data exist examining the healthy obese phenotype. The healthy obese do not appear to be at increased risk of incident CVD events compared with at-risk obese, and the location of adipose tissue and the metabolic characteristics of the fat in a given location, including the presence of ectopic fat and associated adipocytokine response, may give rise to the phenotype. Recent data also suggest that weight loss among healthy obese may adversely impact their favorable cardiometabolic profile. SUMMARY: A high prevalence of the healthy obese phenotype has been reported, and these individuals appear to be at no increased risk of CVD. Further research is needed into the mechanisms that allow these individuals to maintain low risk of CVD despite excess adiposity and appropriate weight loss recommendations for this group. PMID: 19474713 [PubMed - indexed for MEDLINE] 1885. Reprod Sci. 2009 Oct;16(10):921-37. doi: 10.1177/1933719109336614. Epub 2009 May 27. Reviews: adipocytokines in normal and complicated pregnancies. Briana DD(1), Malamitsi-Puchner A. Author information: (1)Neonatal Division, 2nd Department of Obstetrics and Gynecology, Athens University Medical School, Athens, Greece. Human pregnancy is characterized by insulin resistance, traditionally attributed to the effects of placental hormones. Normal pregnancy-induced insulin resistance is further enhanced in pregnancy complications, associated with disturbed placental function, such as gestational diabetes mellitus, preeclampsia, and intrauterine growth restriction. Compelling evidence suggests that these pregnancy disorders are associated with future development of maternal metabolic syndrome. However, the pathogenetic mechanisms underlying the association between abnormal placental development, insulin resistance, and maternal metabolic syndrome are not fully understood. A large body of evidence has recently supported the role of adipose tissue in the regulation of insulin resistance in both nonpregnant and pregnant participants. In this respect, adipocytokines, which are adipocyte-derived hormones, have been implicated in the regulation of maternal metabolism and gestational insulin resistance. Adipocytokines, including leptin, adiponectin, tumor necrosis factor alpha, interleukin 6, as well as the newly discovered resistin, visfatin, and apelin, are also known to be produced within the intrauterine environment. However, data concerning the pattern of adipocytokines secretion in normal and complicated pregnancies are still limited and partially contradictory. Given the importance of adipose tissue and its hormones in terms of adequate metabolic control and energy homeostasis, we present a review of published data related to the role of adipocytokines in pregnancy, especially in relation to pregnancy complications. Focus will be placed on the functions and other potential roles of the novel adipocytokines resistin, visfatin, and apelin. PMID: 19474287 [PubMed - indexed for MEDLINE] 1886. Clin Exp Rheumatol. 2009 Mar-Apr;27(2):347-53. A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation. Masuko K(1), Murata M, Suematsu N, Okamoto K, Yudoh K, Nakamura H, Kato T. Author information: (1)Department of Biochemistry, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan. k_msk@mac.com Osteoarthritis (OA) is considered to be linked to obesity and body fat mass. Recent investigations, however, are aimed at clarifying the roles of adipose tissue-derived proteins and a wide variety of lipid mediators, including fatty acids, sphingolipids, and eicosanoids, in cartilage degradation in OA, in addition to the effects body weight itself. Here, we review recent progress in studies of OA, focusing on the potential role of lipid mediators in articular cartilage and introducing the concept that "OA is a metabolic disease" in which lipids essentially contribute to the pathophysiology of cartilage degradation. PMID: 19473582 [PubMed - indexed for MEDLINE] 1887. Nihon Naika Gakkai Zasshi. 2009 Apr 10;98(4):731-6. [Efficacy of diet and exercise therapy for diabetes mellitus--visceral fat obesity and intracellular fat obesity]. [Article in Japanese] Tanaka Y. PMID: 19472522 [PubMed - indexed for MEDLINE] 1888. J Appl Physiol (1985). 2009 Nov;107(5):1629-37. doi: 10.1152/japplphysiol.00090.2009. Epub 2009 May 21. Fat circadian biology. Gimble JM(1), Floyd ZE. Author information: (1)Pennington Biomedical Research Center, Louisiana State Univ., Stem Cell Biology Laboratory, 6400 Perkins Rd., Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu While adipose tissue has long been recognized for its major role in metabolism, it is now appreciated as an endocrine organ. A growing body of literature has emerged that identifies circadian mechanisms as a critical regulator of adipose tissue differentiation, metabolism, and adipokine secretory function in both health and disease. This concise review focuses on recent data from murine and human models that highlights the interplay between the core circadian regulatory proteins and adipose tissue in the context of energy, fat, and glucose metabolism. It will be important to integrate circadian mechanisms and networks into future descriptions of adipose tissue physiology. PMCID: PMC2777788 PMID: 19470701 [PubMed - indexed for MEDLINE] 1889. J Clin Endocrinol Metab. 2009 Aug;94(8):2692-701. doi: 10.1210/jc.2009-0370. Epub 2009 May 26. Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. Anagnostis P(1), Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Author information: (1)Department of Clinical Biochemistry, Royal Free Hospital Campus, University College Medical School, University College London, Pond Street, London, United Kingdom. CONTEXT: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities that increase the risk for type 2 diabetes mellitus and vascular disease. The common characteristics of MetS and hypercortisolemic conditions such as Cushing's syndrome (CS) suggest that the pathogenesis of MetS and central obesity might involve prolonged and excessive exposure to glucocorticoids. The present review summarizes the evidence on the potential role of cortisol in the pathogenesis of MetS and discusses new therapeutic approaches for these patients. EVIDENCE ACQUISITION: Using PubMed, we searched for publications during the last 20 yr regarding the possible pathogenetic role of cortisol in the development of MetS. EVIDENCE SYNTHESIS: Emerging data suggest that patients with MetS show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to a state of "functional hypercortisolism." The cause for this activation of the HPA axis remains uncertain but may be partly associated with chronic stress and/or low birth weight, which are both associated with increased circulating cortisol levels and greater responsiveness of the HPA axis. Increased exposure to cortisol contributes to increased fat accumulation in visceral depots. However, cortisol metabolism is not only centrally regulated. The action of 11beta-hydroxysteroid dehydrogenase-1 at the tissue level also modulates cortisol metabolism. Increased 11beta-hydroxysteroid dehydrogenase-1 activity in adipose tissue and liver might contribute to the development of several features of the MetS. CONCLUSIONS: MetS shares many characteristics of CS, and cortisol might play a role in the development of MetS at both a central and a peripheral level. PMID: 19470627 [PubMed - indexed for MEDLINE] 1890. Nat Rev Rheumatol. 2009 Jul;5(7):365-72. doi: 10.1038/nrrheum.2009.102. Epub 2009 May 26. Fat targets for skeletal health. Kawai M(1), Devlin MJ, Rosen CJ. Author information: (1)Maine Medical Center Research Institute, Scarborough, ME 04074-7205, USA. Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium. PMCID: PMC3661210 PMID: 19468288 [PubMed - indexed for MEDLINE] 1891. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):238-45. Metabolic disturbances linked to obesity: the role of impaired tissue perfusion. Villela NR(1), Kramer-Aguiar LG, Bottino DA, Wiernsperger N, Bouskela E. Author information: (1)Laboratório de Pesquisas Clínicas e Experimentais em Biologia Vascular, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Rua São Francisco Xavier 524, Rio de Janeiro, RJ, Brazil. Associated with elevated risk of cardiovascular events and cancer, obesity is a worldwide problem affecting developed and developing countries. Microcirculatory vessels, represented by arterioles, capillaries and venules (mean internal diameter < 100 microm), are the place where blood/tissue nutrition and exchange effectively take place. Microvascular dysfunction is an early event in obesity probably secondary to endothelial dysfunction and capillaries rarefaction. New research techniques allow the investigation of the microcirculation in different vascular beds in humans. Studies suggest a link between endothelial dysfunction and visceral obesity. Oxidative stress, inflammation and renin-angiotensin system are among factors considered to be involved on microvascular dysfunction in obesity. Microcirculatory impairment present in obesity suggests that it could be an important causal factor in obesity-related disorders such as insulin resistance and hypertension. PMID: 19466216 [PubMed - indexed for MEDLINE] 1892. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):213-26. Epidemiological and molecular mechanisms aspects linking obesity and cancer. Osório-Costa F(1), Rocha GZ, Dias MM, Carvalheira JB. Author information: (1)Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil. About 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. These results are alarming, as the world knows a pandemic of obesity and, in consequence, insulin resistance. Obesity may increase risk for various cancers by several mechanisms, including increasing sex and metabolic hormones, and inflammation. Here, we present a review of epidemiological and molecular evidences linking obesity and cancer--particularly colorectal, post-menopausal breast, endometrial, pancreatic, high grade prostate, hepatocellular, gallbladder, kidney and esophageal adenocarcinoma. The expected striking increase in the incidence of cancer in the near future related to obesity turns the knowledge of this field of great impact as it is needed to the development of strategies to prevent and treat this disease. PMID: 19466214 [PubMed - indexed for MEDLINE] 1893. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):201-12. Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications. Wang Y(1), Zhou M, Lam KS, Xu A. Author information: (1)Department of Pharmacology, University of Hong Kong, 21 Sassoon Road, Hong Kong, China. yuwanghk@hku.hk Adiponectin is an insulin-sensitizing adipokine possessing multiple beneficial effects on obesity-related medical complications. This adipokine is secreted from adipocytes into the circulation as three oligomeric isoforms, including trimer, hexamer and the high molecular weight (HMW) oligomeric complex. Each oligomeric isoform of adiponectin possesses distinct biological properties and activates different signaling pathways in various target tissues. The hepato-protective activities have been demonstrated by many clinical and experimental studies. The decreased level of serum adiponectin represents an independent risk factor for nonalcoholic fatty liver disease (NAFLD) and liver dysfunctions in humans. In animals, elevation of circulating adiponectin by either pharmacological or genetic approaches leads to a significant alleviation of hepatomegaly, steatosis and necro-inflammation associated with various liver diseases. In adiponectin knockout mice, there is a pre-existing condition of hepatic steatosis and mitochondria dysfunction, which might contribute to the increased vulnerabilities of these mice to the secondary liver injuries induced by obesity and other conditions. This review aims to summarize recent advances on delineation of the structural, molecular and cellular mechanisms underlying the hepato-protective properties of adiponectin. PMID: 19466213 [PubMed - indexed for MEDLINE] 1894. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):190-200. Adiposity in childhood cancer survivors: insights into obesity physiopathology. Siviero-Miachon AA(1), Spinola-Castro AM, Guerra-Junior G. Author information: (1)Departamento de Pediatria, Divisão de Endocrinologia Pediátrica, Universidade Federal de São Paulo, Rua Dr. Diogo de Faria 307, São Paulo, SP, Brazil. As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor gamma. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy. PMID: 19466212 [PubMed - indexed for MEDLINE] 1895. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):183-9. Impact of adiposity on immunological parameters. Moulin CM(1), Marguti I, Peron JP, Rizzo LV, Halpern A. Author information: (1)Departamento de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Rua Dr. Enéas de Carvalho Aguiar 255, São Paulo, SP, Brazil. crismoulin@yahoo.com.br Studies evaluating immune function in obese humans and experimental animals indicate that the excess adiposity is associated with impaired in immune responses. Obesity is related to a higher rate of infections and to some types of cancer. Nutritional, metabolic and endocrine factors are implicated in the immunological changes. The adipose tissue directly produces substances with various functions related to immune system. Furthermore, some investigations suggest that certain types of weight reduction strategies can alter the immune function. Nevertheless, long-term studies should be carried out to address whether these changes positively affects the ability of these obese individuals to control infections and tumor development. PMID: 19466211 [PubMed - indexed for MEDLINE] 1896. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):159-64. Infeccions as the etiology for obesity. Suplicy Hde L(1), Bornschein A. Author information: (1)Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Universidade Federal do Paraná, Rua Agostinho Leão Jr. 285, Curitiba, PR, Brazil. The role of infection on obesity development has been questioned since the early 1980's. Several studies on animals have shown that physiopathologic mechanisms through which infections can produce obesity do exist. At least eight types of obesity-inducing viruses have been identified in animals, especially poultry and mice. Studies on humans are far less convincing; however, two adenoviruses, Ad-36 and SMAM-1, have shown adipogenic properties. In vitro studies with 3T3-L1 cells stated the activation of the enzymatic pathway that leads to fatty tissue accumulation; in vivo studies have also detected higher levels of antibodies against such viruses on obese subjects. Although most known infections nowadays cause obesity through central nervous system lesions, the Ad-36 adenovirus infection affects fatty tissue directly, raising doubts regarding central role component in this case. PMID: 19466208 [PubMed - indexed for MEDLINE] 1897. Arq Bras Endocrinol Metabol. 2009 Mar;53(2):145-50. Adipose tissue at the crossroads in the development of the metabolic syndrome, inflammation and atherosclerosis. Wajchenberg BL(1), Nery M, Cunha MR, Silva ME. Author information: (1)Serviço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo 455, São Paulo, SP, Brazil. bernarwaj@globo.com The authors analyze insulin resistance, the metabolic syndrome and endothelial dysfunction as consequence of a common antecedent, a low grade inflammation, indicating that in obesity there is a chronically activated inflammatory state of the adipose tissue. Furthermore, the inflammatory signaling is discussed according to the adipose tissue depot, visceral or subcutaneous. PMID: 19466206 [PubMed - indexed for MEDLINE] 1898. Prog Lipid Res. 2009 Sep;48(5):275-97. doi: 10.1016/j.plipres.2009.05.001. Epub 2009 May 21. Lipolysis and lipid mobilization in human adipose tissue. Lafontan M(1), Langin D. Author information: (1)Inserm U, Institut de Médecine Moléculaire de Rangueil, IFR-BMT, Toulouse, France. max.lafontan@inserm.fr Triacylglycerol (TAG) stored in adipose tissue (AT) can be rapidly mobilized by the hydrolytic action of the three main lipases of the adipocyte. The non-esterified fatty acids (NEFA) released are used by other tissues during times of energy deprivation. Until recently hormone-sensitive lipase (HSL) was considered to be the key rate-limiting enzyme responsible for regulating TAG mobilization. A novel lipase named adipose triglyceride lipase/desnutrin (ATGL) has been identified as playing an important role in the control of fat cell lipolysis. Additionally perilipin and other proteins of the surface of the lipid droplets protecting or exposing the TAG core of the droplets to lipases are also potent regulators of lipolysis. Considerable progress has been made in understanding the mechanisms of activation of the various lipases. Lipolysis is under tight hormonal regulation. The best understood hormonal effects on AT lipolysis concern the opposing regulation by insulin and catecholamines. Heart-derived natriuretic peptides (i.e., stored in granules in the atrial and ventricle cardiomyocytes and exerting stimulating effects on diuresis and natriuresis) and numerous autocrine/paracrine factors originating from adipocytes and other cells of the stroma-vascular fraction may also participate in the regulation of lipolysis. Endocrine and autocrine/paracrine factors cooperate and lead to a fine regulation of lipolysis in adipocytes. Age, anatomical site, sex, genotype and species differences all play a part in the regulation of lipolysis. The manipulation of lipolysis has therapeutic potential in the metabolic disorders frequently associated with obesity and probably in several inborn errors of metabolism. PMID: 19464318 [PubMed - indexed for MEDLINE] 1899. Obesity (Silver Spring). 2009 Oct;17(10):1814-20. doi: 10.1038/oby.2009.152. Epub 2009 May 21. Mitochondrial DNA: an up-and-coming actor in white adipose tissue pathophysiology. Villarroya J(1), Giralt M, Villarroya F. Author information: (1)Departament de Bioquimica i Biologia Molecular, i Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain. PMID: 19461585 [PubMed - indexed for MEDLINE] 1900. Obes Rev. 2009 Sep;10(5):554-63. doi: 10.1111/j.1467-789X.2009.00593.x. Epub 2009 May 12. Role of adipose tissue in haemostasis, coagulation and fibrinolysis. Faber DR(1), de Groot PG, Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. Obesity is associated with an increased incidence of insulin resistance (IR), type 2 diabetes mellitus and cardiovascular diseases. The increased risk for cardiovascular diseases could partly be caused by a prothrombotic state that exists because of abdominal obesity. Adipose tissue induces thrombocyte activation by the production of adipose tissue-derived hormones, often called adipokines, of which some such as leptin and adiponectin have been shown to directly interfere with platelet function. Increased adipose tissue mass induces IR and systemic low-grade inflammation, also affecting platelet function. It has been demonstrated that adipose tissue directly impairs fibrinolysis by the production of plasminogen activator inhibitor-1 and possibly thrombin-activatable fibrinolysis inhibitor. Adipose tissue may contribute to enhanced coagulation by direct tissue factor production, but hypercoagulability is likely to be primarily caused by affecting hepatic synthesis of the coagulation factors fibrinogen, factor VII, factor VIII and tissue factor, by releasing free fatty acids and pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-1beta and interleukin-6) into the portal circulation and by inducing hepatic IR. Adipose tissue dysfunction could thus play a causal role in the prothrombotic state observed in obesity, by directly and indirectly affecting haemostasis, coagulation and fibrinolysis. PMID: 19460118 [PubMed - indexed for MEDLINE] 1901. Obes Rev. 2009 Nov;10(6):648-59. doi: 10.1111/j.1467-789X.2009.00584.x. Epub 2009 May 12. Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Buckley JD(1), Howe PR. Author information: (1)Nutritional Physiology Research Centre and Australian Technology Network (ATN) Centre for Metabolic Fitness, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia. jon.buckley@unisa.edu.au Animal studies suggest that increased consumption of the long-chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, can protect against the development of obesity in animals exposed to an obesogenic diet and reduce body fat when already obese. There is also evidence that increased intakes of these fatty acids can reduce body fat in humans, but human studies are relatively few and have generally been conducted over short time periods with small sample sizes, making it difficult to draw definitive conclusions. Reported reductions in body fat may result from appetite-suppressing effects, adipocyte apoptosis and changes of gene expression in skeletal muscle, heart, liver, intestine and adipose tissues that suppress fat deposition and increase fat oxidation and energy expenditure. We conclude that increased intakes of long-chain omega-3 fatty acids may improve body composition, but longer-term human studies are needed to confirm efficacy and determine whether increasing omega-3 intakes might be an effective strategy to combat obesity. PMID: 19460115 [PubMed - indexed for MEDLINE] 1902. Obes Rev. 2009 Nov;10(6):660-70. doi: 10.1111/j.1467-789X.2009.00592.x. Epub 2009 May 12. Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives. Macciò A(1), Madeddu C, Mantovani G. Author information: (1)Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, Italy. a.maccio@tin.it Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Despite many undeniable therapeutic successes obtained, breast cancer still remains, however, a major health issue. In the last few years, thanks to aromatase inhibitors, the hormone therapy for oestrogen-dependent breast cancer has evolved in terms of efficacy and tolerability; at the same time, it has enabled us to better define the role of oestrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. A more recent hypothesis suggests that adipocytes and their autocrine (paracrine and endocrine actions) are at the centre of such an etiopathogenetic mechanism. A better understanding of the main mechanisms that link together menopause, body-weight increase and hormone-dependent breast cancer is paramount to enable the identification of key molecules involved in the development of breast carcinoma and suggest new therapeutic options. The present review will discuss important findings on the therapeutic aspects of adipose tissue and adipokines as a target for treatment of hormone-dependent breast cancer. PMID: 19460113 [PubMed - indexed for MEDLINE] 1903. Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E977-86. doi: 10.1152/ajpendo.00183.2009. Epub 2009 May 19. Transdifferentiation properties of adipocytes in the adipose organ. Cinti S(1). Author information: (1)Faculty of Medicine, Univ. of Ancona (Politecnica delle Marche Via Tronto 10a, 60020 Ancona, Italy. cinti@univpm.it Mammals have two types of adipocytes, white and brown, but their anatomy and physiology is different. White adipocytes store lipids, and brown adipocytes burn them to produce heat. Previous descriptions implied their localization in distinct sites, but we demonstrated that they are mixed in many depots, raising the concept of adipose organ. We explain the reason for their cohabitation with the hypothesis of reversible physiological transdifferentiation; they are able to convert one into each other. If needed, the brown component of the organ could increase at the expense of the white component and vice versa. This plasticity is important because the brown phenotype of the organ associates with resistance to obesity and related disorders. Another example of physiological transdifferetiation of adipocytes is offered by the mammary gland; the pregnancy hormonal stimuli seems to trigger a reversible transdifferentiation of adipocytes into milk-secreting epithelial glands. The obese adipose organ is infiltrated by macrophages inducing chronic inflamation that is widely considered as a causative factor for insulin resistance. We showed that the vast majority of macrophages infiltrating the obese organ are arranged around dead adipocytes, forming characteristic crown-like structures. We recently found that visceral fat is more infiltrated than the subcutaneous fat despite a smaller size of visceral adipocytes. This suggests a different susceptibility of visceral and subcutaneous adipocytes to death, raising the concept of smaller critical death size that could be important to explain the key role of visceral fat for the metabolic disorders associated with obesity. PMID: 19458063 [PubMed - indexed for MEDLINE] 1904. Immunobiology. 2010 Aug;215(8):617-28. doi: 10.1016/j.imbio.2009.03.005. Epub 2009 May 19. Endocannabinoids, FOXO and the metabolic syndrome: redox, function and tipping point--the view from two systems. Nunn AV(1), Guy GW, Bell JD. Author information: (1)Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College, Du Cane Road, London W12OHS, UK. alistair.nunn@btconnect.com The endocannabinoid system (ECS) was only 'discovered' in the 1990s. Since then, many new ligands have been identified, as well as many new intracellular targets--ranging from the PPARs, to mitochondria, to lipid rafts. It was thought that blocking the CB-1 receptor might reverse obesity and the metabolic syndrome. This was based on the idea that the ECS was dysfunctional in these conditions. This has met with limited success. The reason may be that the ECS is a homeostatic system, which integrates energy seeking and storage behaviour with resistance to oxidative stress. It could be viewed as having thrifty actions. Thriftiness is an innate property of life, which is programmed to a set point by both environment and genetics, resulting in an epigenotype perfectly adapted to its environment. This thrifty set point can be modulated by hormetic stimuli, such as exercise, cold and plant micronutrients. We have proposed that the physiological and protective insulin resistance that underlies thriftiness encapsulates something called 'redox thriftiness', whereby insulin resistance is determined by the ability to resist oxidative stress. Modern man has removed most hormetic stimuli and replaced them with a calorific sedentary lifestyle, leading to increased risk of metabolic inflexibility. We suggest that there is a tipping point where lipotoxicity in adipose and hepatic cells induces mild inflammation, which switches thrifty insulin resistance to inflammation-driven insulin resistance. To understand this, we propose that the metabolic syndrome could be seen from the viewpoint of the ECS, the mitochondrion and the FOXO group of transcription factors. FOXO has many thrifty actions, including increasing insulin resistance and appetite, suppressing oxidative stress and shifting the organism towards using fatty acids. In concert with factors such as PGC-1, they also modify mitochondrial function and biogenesis. Hence, the ECS and FOXO may interact at many points; one of which may be via intracellular redox signalling. As cannabinoids have been shown to modulate reactive oxygen species production, it is possible that they can upregulate anti-oxidant defences. This suggests they may have an 'endohormetic' signalling function. The tipping point into the metabolic syndrome may be the result of a chronic lack of hormetic stimuli (in particular, physical activity), and thus, stimulus for PGC-1, with a resultant reduction in mitochondrial function and a reduced lipid capacitance. This, in the context of a positive calorie environment, will result in increased visceral adipose tissue volume, abnormal ectopic fat content and systemic inflammation. This would worsen the inflammatory-driven pathological insulin resistance and inability to deal with lipids. The resultant oxidative stress may therefore drive a compensatory anti-oxidative response epitomised by the ECS and FOXO. Thus, although blocking the ECS (e.g. via rimonabant) may induce temporary weight loss, it may compromise long-term stress resistance. Clues about how to modulate the system more safely are emerging from observations that some polyphenols, such as resveratrol and possibly, some phytocannabinoids, can modulate mitochondrial function and might improve resistance to a modern lifestyle. 2009 Elsevier GmbH. All rights reserved. PMID: 19457573 [PubMed - indexed for MEDLINE] 1905. Ann N Y Acad Sci. 2009 Apr;1163:221-32. doi: 10.1111/j.1749-6632.2008.03627.x. Feeding behavior in mammals including humans. Magni P(1), Dozio E, Ruscica M, Celotti F, Masini MA, Prato P, Broccoli M, Mambro A, Morè M, Strollo F. Author information: (1)University of Milan, Institute of Endocrinology, Milano, Italy. The complex control of food intake and energy metabolism in mammals relies on the ability of the brain to integrate multiple signals indicating the nutritional state and the energy level of the organism and to produce appropriate responses in terms of food intake, energy expenditure, and metabolic activity. Central regulation of feeding is organized as a long-loop mechanism involving humoral signals and afferent neuronal pathways to the brain, processing in hypothalamic neuronal circuits, and descending commands using vagal and spinal neurons. Sensor mechanisms or receptors sensitive to glucose and fatty acid metabolism, neuropeptide and cannabinoid receptors, as well as neurotransmitters and neuromodulators synthesized and secreted within the brain itself are all signals integrated in the hypothalamus, which therefore functions as an integrator of signals from central and peripheral structures. Homeostatic feedback mechanisms involving afferent neuroendocrine inputs from peripheral organs, like adipose tissue, gut, stomach, endocrine pancreas, adrenal, muscle, and liver, to hypothalamic sites thus contribute to the maintenance of normal feeding behavior and energy balance. In addition to transcriptional events, peripheral hormones may also alter firing and/or connection (synaptology) of hypothalamic neuronal networks in order to modulate food intake. Moreover, intracellular energy sensing and subsequent biochemical adaptations, including an increase in AMP-activated protein kinase activity, occur in hypothalamic neurons. Understanding the regulation of appetite is clearly a major research effort but also seems promising for the development of novel therapeutic strategies for obesity. PMID: 19456343 [PubMed - indexed for MEDLINE] 1906. Ross Fiziol Zh Im I M Sechenova. 2009 Mar;95(3):283-9. [Hypoxia as the main activator of angiogenesis and fatty tissue growth]. [Article in Russian] Kalinina NI, Efimenko AIu, Starostina EE, Parfenova EV, Tkachuk VA. Poor content of oxygen indices gene expression for angiogenic growth factors both in adipocytes and in stromal cells of the fatty tissue. Stimulation of blood vessels by these factors leads to hyperplasia ofpregenitior cells and by their differentiation. This review mentions functional changes occurring in the fatty tissue cells under the effect of hypoxy. PMID: 19449784 [PubMed - indexed for MEDLINE] 1907. Appl Physiol Nutr Metab. 2009 Jun;34(3):454-8. doi: 10.1139/H09-036. Toll-like receptor signalling induced by endurance exercise. Francaux M(1). Author information: (1)Research Group in Muscle and Exercise Physiology, Institute of Neuroscience, Universite catholique de Louvain, Place Pierre de Coubertin-1, 1348 Louvain-la-Neuve, Belgium. marc.francaux@uclouvain.be Toll-like receptors (TLRs) are transmembrane proteins that detect a variety of molecular components mostly derived from microorganisms. TLR2 and TLR4 are amongst others present in liver, adipose tissue, and skeletal muscle. Extracellular long-chain fatty acids bind TLR2 and 4 and induce downstream signalling cascades implicated in cellular stress and inflammatory processes. Evidence indicates that TLR activation by non-esterified fatty acids (NEFAs) may participate in the development of insulin resistance. Exercise seems to induce a downregulation of TLR expression in various tissues, a mechanism that may take part in the protective effect of exercise against insulin resistance. Moreover, TLRs seem to mediate the activation of mitogen-activated protein kinase p38 and Jun-amino-terminal kinase by extracellular NEFAs during endurance exercise. During this type of exercise, circulating NEFAs are known to regulate the expression of various genes including pyruvate dehydrogenase kinase 4, uncoupling protein 3, carnitine palmitoyltransferase 1, and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Whether these events are initiated by a TLR-dependent signal transduction remains to be investigated. PMID: 19448714 [PubMed - indexed for MEDLINE] 1908. Appl Physiol Nutr Metab. 2009 Jun;34(3):396-402. doi: 10.1139/H09-037. Adipokines as regulators of muscle metabolism and insulin sensitivity. Dyck DJ(1). Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada. ddyck@uoguelph.ca Skeletal muscle is the largest tissue responsible for the insulin-stimulated disposal of glucose. However, identifying the link between excess body fat and impaired insulin sensitivity in skeletal muscle has been difficult. Several adipose-derived cytokines (adipokines) have been implicated in the impairment of insulin sensitivity, while adipokines such as leptin and adiponectin exert an insulin-sensitizing effect. Leptin and adiponectin have each been shown to increase fatty acid (FA) oxidation and decrease triglyceride storage in muscle, which may explain, in part, the insulin-sensitizing effect of these cytokines. Recent evidence strongly implicates an increased localization of the FA transporters to the plasma membrane (PM) as an important factor in the accumulation of intramuscular lipids with high-fat diets and obesity. Perhaps surprisingly, relatively little attention has been paid to the ability of insulin-sensitizing compounds, such as leptin and adiponectin, to decrease the abundance of FA transporters in the PM, thereby decreasing lipid accumulation. In the case of both adipokines, there is also evidence that a resistance to their ability to stimulate FA oxidation in skeletal muscle develops during obesity. One of our recent studies indicates that this development can be very rapid (i.e., within days), and precedes the increase in lipid uptake and accumulation that leads to insulin resistance. It is noteworthy that leptin resistance can be modulated by both diet and training in rodents. Further studies examining the underlying mechanisms of the development of leptin and adiponectin resistance are warranted. PMID: 19448705 [PubMed - indexed for MEDLINE] 1909. Appl Physiol Nutr Metab. 2009 Jun;34(3):362-7. doi: 10.1139/H09-026. Control of skeletal muscle metabolic properties by the nuclear receptor corepressor RIP140. Fritah A(1). Author information: (1)Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of Medicine, Du Cane Road, London W12 0NN, UK. The transcriptional control of metabolism in response to environmental changes plays an important role in energy homeostasis. A number of nuclear receptors control both anabolic and catabolic pathways in metabolic tissues. Their transcriptional activity is mediated by recruitment of coactivators or corepressors to target genes. The corepressor receptor-interacting protein 140 (RIP140) is recruited by many nuclear receptors, including peroxisome proliferator-activated receptors and estrogen-related receptors, and by a number of other transcription factors such as nuclear receptor factor 1. It is responsible for the suppression of gene networks that control catabolism in adipose tissue and skeletal muscle, including glucose uptake, glycolysis, tricarboxylic acid cycle, fatty-acid oxidation, mitochondrial biogenesis, oxidative phosphorylation, and mitochondrial uncoupling. In this review, we focus on the role of RIP140 in regulating energy expenditure and highlight issues to address RIP140 action in skeletal muscle. PMID: 19448699 [PubMed - indexed for MEDLINE] 1910. Appl Physiol Nutr Metab. 2009 Jun;34(3):340-7. doi: 10.1139/H09-019. Triglyceride lipases alter fuel metabolism and mitochondrial gene expression. Watt MJ(1). Author information: (1)Department of Physiology, Monash University, Clayton, Victoria, Australia. matthew.watt@med.monash.edu.au Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during prolonged moderate-intensity exercise. Hormone sensitive lipase (HSL) was long considered to be the rate-limiting enzyme for adipocyte and skeletal muscle TG lipolysis. However, the understanding of TG lipolysis regulation was recently challenged by the finding that adipose TG lipase (ATGL) is the predominant TG lipase in adipose tissue and an important regulator of TG degradation in skeletal muscle. Thus, it is now proposed that ATGL and HSL regulate lipolysis in a serial manner, with ATGL cleaving the first fatty acid and HSL the second fatty acid of TG. Further to this biochemical evaluation, the generation and metabolic characterization of ATGL-/- and HSL-/- mice have revealed distinct phenotypes. ATGL-/- mice are obese, exhibit impaired thermogenesis, oxidize more carbohydrate, and die prematurely due to cardiac dysfunction. Studies in HSL-/- mice report defective beta-adrenergic stimulated lipolysis, protection against high-fat diet-induced obesity, and possible impairments in insulin secretion. This review outlines the current understanding of the cellular regulation of TG lipases, lipolytic regulation, and the functional implications of manipulating ATGL and HSL in vivo. PMID: 19448696 [PubMed - indexed for MEDLINE] 1911. Appl Physiol Nutr Metab. 2009 Jun;34(3):315-22. doi: 10.1139/H09-009. Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exercise. Steinberg GR(1). Author information: (1)St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia. gsteinberg@mcmaster.ca During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise. PMID: 19448692 [PubMed - indexed for MEDLINE] 1912. Arch Esp Urol. 2009 Mar;62(2):103-8. [Influence of leptin and adiponectin on prostate cancer]. [Article in Spanish] Lopez Fontana CM(1), Maselli Artola ME, Di Milta Monaco N, Recalde Rincon GM, Vanrell Rodriguez MC, Uvilla Recupero A, Messina Lombino D, Perez Elizalde RF, Lopez Laur JD. Author information: (1)Metabolic and Cancer Laboratory, Faculty of Pharmacy and Biochemistry, University Juan Agustin Maza, Argentina. BACKGROUND: Many studies have investigated the association between obesity, adipose tissue-derived factors (leptin and adiponectin) and prostate cancer (CaP) but the results are still inconsistent. METHODS: The aim of this study was to carry out a comprehensive review of the existing evidence about the role of leptin and adiponectin in prostate carcinogenesis and to provide an overview of it. RESULTS: Recent evidence suggests that leptin may play a rol in prostate cancer progression, while adiponectin may act as an "antiprostatic cancer" adipokine. CONCLUSIONS: Obesity may promote the progression of established prostate cancer and and adipokines may provide a molecular mechanism whereby obesity exerts its effects on prostate tumour biology. PMID: 19448276 [PubMed - indexed for MEDLINE] 1913. J Hepatol. 2009 Jul;51(1):212-23. doi: 10.1016/j.jhep.2009.03.008. Epub 2009 Mar 31. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. Baffy G(1). Author information: (1)Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Section of Gastroenterology, 150 S. Huntington Ave., Boston, MA 02130, USA. gbaffy@partners.org Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder of our times. Simple steatosis, a seemingly innocent manifestation of NAFLD, may progress into steatohepatitis and cirrhosis, but this process is not well understood. Since NAFLD is associated with obesity and insulin resistance, mechanisms that link lipid metabolism to inflammation offer insights into the pathogenesis. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages and evidence is growing that Kupffer cells critically contribute to progression of NAFLD. Toll-like receptors, in particular TLR4, represent a major conduit for danger recognition linked to Kupffer cell activation and this process may be perturbed at multiple steps in NAFLD. Steatosis may interfere with sinusoid microcirculation and hepatocellular clearance of microbial and host-derived danger signals, enhancing responsiveness of Kupffer cells. Altered lipid homeostasis in NAFLD may unfavourably affect TLR4 receptor complex assembly and sorting, interfere with signalling flux redistribution, promote amplification loops, and impair negative regulation including alternative activation of Kupffer cells. These events are further promoted by altered adipokine secretion and reactive oxygen species production. Specific targeting of these interactions may provide more effective strategies in the treatment of NAFLD. PMCID: PMC2694233 PMID: 19447517 [PubMed - indexed for MEDLINE] 1914. Mol Biol Rep. 2010 Mar;37(3):1513-22. doi: 10.1007/s11033-009-9550-2. Epub 2009 May 15. The polymorphisms of UCP1 genes associated with fat metabolism, obesity and diabetes. Jia JJ(1), Tian YB, Cao ZH, Tao LL, Zhang X, Gao SZ, Ge CR, Lin QY, Jois M. Author information: (1)Yunnan Provincial Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Yunnan Province, People's Republic of China. junjingli2003@yahoo.com.cn Uncoupling protein 1 (UCP1), a 32-kDa protein located in the inner mitochondrial membrane, is abundant in brown adipose tissue, as a proton transporter in mitochondria inner membrane which uncouples oxidative metabolism from ATP synthesis and dissipates energy through the heat. UCP1 has been reported to play important roles for energy homeostasis in rodents and neonate of larger mammals including human. Recently, numerous candidate genes were searched to determine the genetic factors implicated in the pathogenesis of obesity, related metabolic disorders and diabetes. UCP-1, which plays a major role in thermogenesis, was suggested to be one of the candidates. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans, and the genetic variety association with the fat metabolism, obesity and diabetes. PMID: 19444646 [PubMed - indexed for MEDLINE] 1915. J Formos Med Assoc. 2009 May;108(5):353-66. doi: 10.1016/S0929-6646(09)60079-6. The clinical implications of blood adiponectin in cardiometabolic disorders. Chang LC(1), Huang KC, Wu YW, Kao HL, Chen CL, Lai LP, Hwang JJ, Yang WS. Author information: (1)Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Adipose tissue is now accepted by the scientific and medical community to be a genuine endocrine organ, in addition to its classical role as an energy store. Adiponectin is one of the many adipocytokines that are secreted almost exclusively by adipose tissue. Alteration in blood adiponectin concentrations has been linked to many human diseases in numerous cross-sectional and prospective studies. In this review, we describe briefly the biological effects of adiponectin as revealed by basic scientific investigations. We also summarize the principles of blood adiponectin assays. Overall, lower blood adiponectin concentration is found in subjects with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. These medical conditions are components of the metabolic syndrome and major risk factors for accelerated atherosclerosis. Plasma adiponectin levels are also expected to be lower in subjects with cardiovascular diseases, such as coronary artery disease, ischemic stroke and peripheral artery disease. Congestive heart failure (CHF) and cardiac arrhythmia are common end points in cardiovascular diseases. Surprisingly, higher blood adiponectin levels are frequently reported to predict mortality associated with CHF. Few human data regarding adiponectin and cardiac arrhythmia are available. Higher blood adiponectin level has been documented only in atrial fibrillation. We also summarize data on the role of the high molecular weight (HMW) isoforms of adiponectin and the effects of clinical treatment on the levels of total or HMW adiponectin. Whether adiponectin is a risk marker or a risk factor for the diseases reviewed in this article, and in many other human diseases, and their detailed pathogenic links awaits further investigation. PMID: 19443289 [PubMed - indexed for MEDLINE] 1916. J Nutr Biochem. 2009 Jul;20(7):485-93. doi: 10.1016/j.jnutbio.2009.02.012. Epub 2009 May 14. Diet and the role of 11beta-hydroxysteroid dehydrogenase-1 on obesity. London E(1), Castonguay TW. Author information: (1)Department of Nutrition and Food Science, University of Maryland, MD 20742, USA. 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD-1) is a key regulatory enzyme in glucocorticoid metabolism, specifically in regulating intracellular concentrations of cortisol, the primary glucocorticoid. While the excessive level of circulating cortisol in Cushing's disease is of adrenal origin, it is the intracellular and not the systemic level of cortisol that is elevated in obesity. This tissue-specific dysregulation of glucocorticoids observed in obesity results from alterations in 11beta-HSD-1 in both liver and mesenteric adipose. While cortisol has been identified as playing a permissive role in obesity, little is known about how diet may regulate message, expression and activity of 11beta-HSD-1. In this review, we have integrated three lines of evidence that, taken together, suggest that dietary composition can play a primary role in promoting increased intracellular cortisol and in that way form the basis of a mechanism that results in excessive adiposity. We review evidence from studies of adrenalectomized rats, as well as studies linking 11beta-HSD-1 to the pentose phosphate pathway and other metabolic pathways via the enzyme hexose-6-phosphate dehydrogenase. Emerging evidence from dietary manipulation experiments suggesting that macronutrient composition may elicit changes in 11beta-HSD-1 and promote obesity is discussed. PMID: 19443197 [PubMed - indexed for MEDLINE] 1917. Curr Stem Cell Res Ther. 2009 May;4(2):107-17. Adult stem cells as an alternative source of multipotential (pluripotential) cells in regenerative medicine. Kuçi S(1), Kuçi Z, Latifi-Pupovci H, Niethammer D, Handgretinger R, Schumm M, Bruchelt G, Bader P, Klingebiel T. Author information: (1)University Children's Hospital III, Department of Hematology/Oncology, Frankfurt am Main, Germany. selim.kuci@kgu.de Embryonic stem cells are by definition the master cells capable of differentiating into every type of cells either in vitro or in vivo. Several lines of evidence suggest, however, that adult stem cells and even terminally differentiated somatic cells under appropriate microenvironmental cues are able to be reprogrammed and contribute to a much wider spectrum of differentiated progeny than previously anticipated. This has been demonstrated by using tissue- specific stem cells, which like embryonic stem cells do not express CD45 as an exclusive hematopoietic marker (skin, adipose, cord blood and bone marrow- derived stem cells). On the other side, there is a great number of reports which demonstrate that hematopoietic cells (CD45+) from different sources (peripheral blood, cord blood, bone marrow) are also able to cross the tissue boundaries and give rise to the cells of the other germ layers. Herein we discuss the differentiation and reprogramming potential of both hematopoietic and non- hematopoietic stem cells along endodermal, mesodermal and neuroectodermal lineage and their importance for regenerative medicine. PMID: 19442195 [PubMed - indexed for MEDLINE] 1918. Chirurg. 2009 May;80(5):398, 400-4, 406-9. doi: 10.1007/s00104-008-1630-7. [The unsolved problem of diabetes mellitus type 2 and associated complications]. [Article in German] Morcos M(1), Humpert P, Bierhaus A, Nawroth P. Author information: (1)Medizinische Klinik (Krehl-Klinik), Abteilung Innere Medizin 1 und Klinische Chemie, Universitätsklinikum Heidelberg, INF 410, 69120 Heidelberg, Deutschland. Michael.Morcos@med.uni-heidelberg.de Type 2 diabetes and impaired glucose tolerance are an increasing burden not only for affected patients, but also for the whole health care system. The pathophysiology of diabetes and its late complications are far from being understood with hyperglycaemia being only the last sign of a long lasting and complex metabolic dysfunction. One major problem in finding therapeutic targets is the fact that the cellular disorders responsible for the development of diabetes involve phylogenetically ancient repair mechanisms. This is one of the reasons why therapeutic targeting of these mechanisms is difficult with the exception of life-style interventions which are, however, limited by individual compliance. In addition, the impact of many therapeutic agents on the entire organism is not well understood. Blood glucose control cannot be considered "high tech" medicine and requires non-medical personnel to reach defined blood glucose targets. Non-adherence to treatment and life-style changes, however, facilitate the interaction of patients and medical personnel and individuals with diabetes are therefore often considered themselves to "blame" for being affected by diabetes. Finally, generating treatment guidelines is extremely difficult as clinical studies targeting vascular endpoints need more than 10 years to become informative, partly due to the so-called glycaemic memory. PMID: 19440747 [PubMed - indexed for MEDLINE] 1919. Semin Immunopathol. 2009 Sep;31(3):359-69. doi: 10.1007/s00281-009-0152-9. Epub 2009 May 14. The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease? Valenti L(1), Fracanzani AL, Fargion S. Author information: (1)Department of Internal Medicine, Università degli Studi di Milano, Padiglione Granelli, Ospedale Policlinico IRCCS, via F Sforza 35, 20122, Milan, Italy. Alcoholic liver disease and nonalcoholic liver disease represent a leading cause of liver disease and share similar pathogenic mechanisms among which activation of the immune system plays a key role. The main events consist in (a) activation of Kupffer cells via TLR-4 by LPS and fatty acids (b) complement activation (c) increased release of proinflammatory mediators (d) alteration in NK and NKT cell number/activity (e) activation of the adaptive immune system. At the same time, activation of intracellular pro-inflammatory pathways by cytokines and bacterial products, inhibit insulin signaling favoring lipogenesis, metabolic alterations, and cell damage. PMID: 19440711 [PubMed - indexed for MEDLINE] 1920. Neurosurg Focus. 2009 Feb;26(2):E2. doi: 10.3171/FOC.2009.26.2.E2. Practical considerations concerning the use of stem cells for peripheral nerve repair. Walsh S(1), Midha R. Author information: (1)Hotchkiss Brain Institute, University of Calgary, Alberta. In this review the authors intend to demonstrate the need for supplementing conventional repair of the injured nerve with alternative therapies, namely transplantation of stem or progenitor cells. Although peripheral nerves do exhibit the potential to regenerate axons and reinnervate the end organ, outcome following severe nerve injury, even after repair, remains relatively poor. This is likely because of the extensive injury zone that prevents axon outgrowth. Even if outgrowth does occur, a relatively slow growth rate of regeneration results in prolonged denervation of the distal nerve. Whereas denervated Schwann cells (SCs) are key players in the early regenerative success of peripheral nerves, protracted loss of axonal contact renders Schwann cells unreceptive for axonal regeneration. Given that denervated Schwann cells appear to become effete, one logical approach is to support the distal denervated nerve environment by replacing host cells with those derived exogenously. A number of different sources of stem/precursor cells are being explored for their potential application in the scenario of peripheral nerve injury. The most promising candidate, transplant cells are derived from easily accessible sources such as the skin, bone marrow, or adipose tissue, all of which have demonstrated the capacity to differentiate into Schwann cell-like cells. Although recent studies have shown that stem cells can act as promising and beneficial adjuncts to nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting. The authors investigate the relevance of the delivery method (both the number and differentiation state of cells) on experimental outcomes, and seek to clarify whether stem cells must survive and differentiate in the injured nerve to convey a therapeutic effect. As our laboratory uses skin-derived precursor cells (SKPCs) in various nerve injury paradigms, we relate our findings on cell fate to other published studies to demonstrate the need to quantify stem cell survival and differentiation for future studies. PMID: 19435443 [PubMed - indexed for MEDLINE] 1921. Transplantation. 2009 May 15;87(9 Suppl):S49-53. doi: 10.1097/TP.0b013e3181a28635. Mesenchymal stem cells for therapeutic purposes. Sensebé L(1), Bourin P. Author information: (1)Etablissement Français du Sang Centre-Atlantique (EFS-CA), Tours, France. luc.sensebe@efs.sante.fr Mesenchymal stem cells (MSC) are multipotent adult stem cells harboring a wide range of differentiations and non-human leukocyte antigen-restricted immunosuppressive properties that lead to an increasing use of MSC in immunomodulation and in regenerative medicine. To produce MSC, definitive standards are still lacking. Whatever the starting material used (e.g., bone marrow, adipose tissue, or cord blood), numerous parameters including cell plating density, number of passages, and culture medium, play a major role in the culture process and have to be determined. To date, the different production processes have been effective, and based on phenotypic analysis and differentiation potential, a first set of simple controls have been defined. However, controls of the final product should provide precise data on efficacy and safety. The next challenge will be to develop production processes that reach good manufacturing practices goals and to define more accurate control methods of cultivated MSC. PMID: 19424006 [PubMed - indexed for MEDLINE] 1922. Toxicol Lett. 2009 Jul 10;188(1):1-10. doi: 10.1016/j.toxlet.2009.03.017. Epub 2009 Mar 31. Current understanding of the mechanisms involved in metabolic detoxification of warfare nerve agents. Jokanović M(1). Author information: (1)Experta Consulting, Nehruova 57, 11070 Belgrade, Serbia. milan.jokanovic@gmail.com This study reviews current understanding of chemical, biochemical and toxicological aspects and mechanisms of metabolism of warfare nerve agents. Among enzymes participating in metabolism of nerve agents the role of A-esterases, serum cholinesterase and carboxylesterases is discussed. This article also discusses other aspects of metabolism of the agents such as protein binding and the role of tissue depots for these compounds. PMID: 19433263 [PubMed - indexed for MEDLINE] 1923. Mol Cell Endocrinol. 2009 May 25;304(1-2):49-54. doi: 10.1016/j.mce.2009.02.022. Epub 2009 Mar 9. Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome. Ben-Jonathan N(1), Hugo ER, Brandebourg TD. Author information: (1)Department of Cancer and Cell Biology, University of Cincinnati, OH 45267, USA. Nira.Ben-Jonathan@uc.edu Bisphenol A (BPA) is one of the most prevalent and best studied endocrine disruptors. After years of exposure to consumer products containing BPA, most individuals tested have circulating BPA at the low nanomolar levels. In addition to its well documented actions on the reproductive system, BPA exerts a wide variety of metabolic effects. This review summarizes recent findings on the ability of BPA, at environmentally relevant doses, to inhibit adiponectin and stimulate the release of inflammatory adipokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) from human adipose tissue. Expression of several classical and non-classical estrogen receptors in human adipose tissue raises the possibility of their involvement as mediators of BPA actions. The implications of these observations to the obesity-related metabolic syndrome and its sequelae are discussed. PMCID: PMC2775425 PMID: 19433247 [PubMed - indexed for MEDLINE] 1924. Mol Cell Endocrinol. 2009 May 25;304(1-2):19-29. doi: 10.1016/j.mce.2009.02.018. Epub 2009 Mar 9. Endocrine disrupters as obesogens. Grün F(1), Blumberg B. Author information: (1)Department of Developmental & Cell Biology, University of California Irvine, 92697-2300, USA. The recent dramatic rise in obesity rates is an alarming global health trend that consumes an ever increasing portion of health care budgets in Western countries. The root cause of obesity is thought to be a prolonged positive energy balance. Hence, the major focus of preventative programs for obesity has been to target overeating and inadequate physical exercise. Recent research implicates environmental risk factors, including nutrient quality, stress, fetal environment and pharmaceutical or chemical exposure as relevant contributing influences. Evidence points to endocrine disrupting chemicals that interfere with the body's adipose tissue biology, endocrine hormone systems or central hypothalamic-pituitary-adrenal axis as suspects in derailing the homeostatic mechanisms important to weight control. This review highlights recent advances in our understanding of the molecular targets and mechanisms of action for these compounds and areas of future research needed to evaluate the significance of their contribution to obesity. PMCID: PMC2713042 PMID: 19433244 [PubMed - indexed for MEDLINE] 1925. ANZ J Surg. 2009 Apr;79(4):235-44. doi: 10.1111/j.1445-2197.2009.04852.x. Human adipose-derived stem cells: isolation, characterization and applications in surgery. Locke M(1), Windsor J, Dunbar PR. Author information: (1)Dunbar Laboratory, School of Biological Sciences,University of Auckland, 3a Symonds Street, Auckland, New Zealand. michellebjoyce@yahoo.co.nz Comment in ANZ J Surg. 2009 Nov;79(11):856. ANZ J Surg. 2009 Nov;79(11):856-7. The ideal stem cell for use in functional tissue engineering needs to be abundantly available, harvested with minimal morbidity, differentiated reliably down various pathways and able to be transplanted safely and efficaciously. Adult human adipose tissue contains a population of mesenchymal stem cells, termed 'adipose-derived stem cells' (ASC), which seem to fulfil most, if not all, of these criteria. ASC can be harvested readily, safely, and in relative abundance by modern liposuction techniques. They are capable of differentiating into other mesenchymal tissue types, including adipocytes, chondrocytes, myocytes and osteoblasts. They also show angiogenic properties, with recent evidence of a potential role in healing radiotherapy-damaged tissue, possibly due to their secretion of vascular endothelial growth factor. Similarly, they may have a role in healing chronic wounds, and as such are being investigated in phase 1 trials for their ability to aid healing of recurrent Crohn's fistulae. Subsequently they have a wide range of potential clinical uses in all fields of surgery. This article reviews the current and potential clinical applications of ASC in relation to surgery, as well as methods for their isolation, differentiation and molecular characterization. PMID: 19432707 [PubMed - indexed for MEDLINE] 1926. Int J Epidemiol. 2009 Aug;38(4):1072-81. doi: 10.1093/ije/dyp202. Epub 2009 May 7. Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations? Bhopal RS(1), Rafnsson SB. Author information: (1)Public Health Sciences Section, School of Clinical Sciences and Community Health and Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK. BACKGROUND: South Asians are susceptible to cardiovascular disease (CVD), especially after migration to affluent countries. Contributing factors include high prevalence of diabetes, and possibly insulin resistance. Excess adiposity centrally may underlie such metabolic disturbances. The thrifty genotype, thrifty phenotype, adipose tissue compartment and variable disease selection hypotheses are among the explanations posed. METHODS: Data from individual studies and review articles known to the authors were examined. A Medline bibliographic database search was also performed. Reference lists were reviewed to identify additional relevant data sources. Key references were examined by both authors. RESULTS: We propose, and evaluate, the evidence for a 'mitochondrial efficiency hypothesis' i.e. that ancestral changes in mitochondrial coupling efficiency enhanced the successful adaptation of South Asians to environmental stressors by maximizing the conversion of energy to adenosine triphosphate (ATP) rather than heat. This adaptation may be disadvantageous when South Asians are physically inactive and consume high-caloric diets. There is evidence that common mitochondrial mutations vary geographically. Mutations, including those affecting the function of mitochondrial uncoupling proteins (UCPs), may influence the balance of energy and heat production. These may influence basal metabolic rate (BMR), energy efficiency, the tendency to gain weight and hence metabolic disease. UCP gene polymorphisms are related to differences in BMR between African-Americans and Europeans. Similar data for South Asians are lacking but the few studies comparing BMR indicate that South Asians have a lower BMR, which is explained by a lower lean body mass, and higher fat mass. Once adjusted for body composition, BMR is similar. A high fat mass, per se, is a strategy for reducing energy use while conserving body size. Indians in the USA had higher oxidative phosphorylation capacity than Northern European Americans. CONCLUSION: The evidence justifies full exploration of this mitochondrial efficiency hypothesis in South Asians, which may also be relevant to other warm-climate adapted populations. PMID: 19423659 [PubMed - indexed for MEDLINE] 1927. Am J Med. 2009 Apr;122(4 Suppl 1):S12-8. doi: 10.1016/j.amjmed.2009.01.003. Regulation of energy homeostasis and health consequences in obesity. Korner J(1), Woods SC, Woodworth KA. Author information: (1)Department of Medicine, Columbia University College of Physicians and Surgeons, and Weight Control Center, Columbia University Medical Center, New York, New York 10032, USA. Jk181@columbia.edu The growing awareness of the obesity epidemic as a critical matter of health concern has prompted research into the mechanisms underlying energy homeostasis and the pathophysiology of obesity. Food intake, energy expenditure, and fat storage all are regulated by a complex neuroendocrine system. It is now recognized that in addition to central neurohumoral pathways, adipose tissue has an independent endocrine function that contributes to energy homeostasis. Moreover, adipose tissue exerts inflammatory effects that are linked to the most important health problems associated with obesity, including cardiovascular disease and type 2 diabetes mellitus, each of which has the potential to confer long-term morbidity and increased mortality risks. This inflammatory effect of adipose tissue is more pronounced in abdominal obesity, which is reflected by the heightened cardiometabolic risk observed in persons with excess abdominal adiposity. The endocrine impact of adipose tissue on energy homeostasis and inflammation highlights the critical health implications of obesity, particularly abdominal obesity, and the importance of effective prevention and management strategies in clinical practice. PMID: 19410672 [PubMed - indexed for MEDLINE] 1928. Mt Sinai J Med. 2009 Jun;76(3):216-26. doi: 10.1002/msj.20113. Emerging concepts in the pathophysiology of type 2 diabetes mellitus. Surampudi PN(1), John-Kalarickal J, Fonseca VA. Author information: (1)Tulane University Medical Center, New Orleans, LA, USA. psurampu@tulane.edu Type 2 diabetes mellitus is a multifactorial metabolic disorder. It is characterized by chronic hyperglycemia, insulin resistance, and a relative insulin secretion defect. The prevalence of type 2 diabetes mellitus has risen worldwide in large part because of an increase in obesity and sedentary lifestyles. The underlying pathophysiology and complications of type 2 diabetes mellitus are still being elucidated. Recent advances in diabetes research have helped us to gain a better understanding about insulin resistance and insulin secretion defects. The evolving understanding about the influence of the incretin effect, insulin signal transduction, adipose tissue, intra-islet cell communication, and inflammation is changing the way in which we view type 2 diabetes mellitus. This new understanding will eventually provide us with new treatment approaches to help patients who have type 2 diabetes mellitus. This article gives a review of the current and emerging concepts of the pathophysiology of type 2 diabetes mellitus. (c) 2009 Mount Sinai School of Medicine. PMID: 19421965 [PubMed - indexed for MEDLINE] 1929. Apoptosis. 2009 Dec;14(12):1484-95. doi: 10.1007/s10495-009-0352-8. Diabetes and apoptosis: lipotoxicity. Kusminski CM(1), Shetty S, Orci L, Unger RH, Scherer PE. Author information: (1)Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA. Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid 'spill over' to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease. PMID: 19421860 [PubMed - indexed for MEDLINE] 1930. Mol Cell Endocrinol. 2009 Apr 29;302(2):111-7. The adipose renin-angiotensin system: role in cardiovascular disease. Thatcher S(1), Yiannikouris F, Gupte M, Cassis L. Author information: (1)Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0200, USA. Several reviews have highlighted the importance of local tissue production of components of the renin-angiotensin system (RAS) [Bader, M., Ganten, D., 2008. Update on tissue renin-angiotensin systems. J. Mol. Med. 86, 615-621; Krop, M., Danser, A.H., 2008. Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin. Curr. Hypertens. Rep. 10, 112-118; Paul, M., Poyan Mehr, A., Kreutz, R., 2006. Physiology of local renin-angiotensin systems. Physiol. Rev. 86, 747-803]. While the concept of tissue RAS is gaining more widespread acceptance, the concept of local angiotensin II (AngII) production, acting in coordinate or independently of the endocrine RAS, continues to be debated. The primary reasons that local AngII production has been studied by many investigators are that components of the RAS are expressed by multiple cell types, and that the endocrine RAS cannot fully explain all effects of AngII. Moreover, through the development and study of genetically altered models for over-expression or knockdown of individual RAS components within specific cell types, it is becoming increasingly more evident that local RAS contribute to effects of AngII in normal physiology and disease. The purpose of this review is to define the presence and physiological significance of a local RAS in adipose tissue in relation to cardiovascular disease. PMCID: PMC2748818 PMID: 19418627 [PubMed - indexed for MEDLINE] 1931. Biochim Biophys Acta. 2009 May;1787(5):377-83. doi: 10.1016/j.bbabio.2009.01.003. Epub 2009 Jan 20. UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing. Bouillaud F(1). Author information: (1)Université Paris Descartes, CNRS, UPR9078, Faculté de Médecine, Necker Enfants Malades, 75730 Paris, France. frederic.bouillaud@inserm.fr In mammals the two proteins UCP2 and UCP3 are highly similar to the mitochondrial uncoupling protein found in the brown adipose tissue (UCP1). Accordingly, it was proposed that UCP2 and UCP3 are also uncoupling proteins i.e. protonophores with impact on mitochondrial ROS production and glucose signaling. However, it appears now impossible to explain the physiological relevance of the new UCPs uniquely by their uncoupling activity as observed in vitro. Therefore, we propose a metabolic hypothesis in which UCP2 acts through a transport distinct of the proton transport. A consequence of this transport activity would be a decrease of the mitochondrial oxidation of the pyruvate originating from glucose. This would put UCP2 and UCP3 in a crucial position to influence cellular metabolism. The tight control exerted on UCP2 expression appears consistent with it. In this hypothesis, UCP2/3 would allow a cell to remain glycolytic within an aerobic organism. This tallies with the high expression level of UCP2 or UCP3 in glycolytic cells. The metabolic hypothesis would explain the spectacular modifications associated with UCP2 manipulation as well as the uncoupling activity usually called for and which in fact remains elusive in vivo. PMID: 19413946 [PubMed - indexed for MEDLINE] 1932. Obes Rev. 2009 Jul;10(4):403-11. doi: 10.1111/j.1467-789X.2009.00586.x. Epub 2009 Apr 21. Plasma phospholipid transfer protein (PLTP): review of an emerging cardiometabolic risk factor. Tzotzas T(1), Desrumaux C, Lagrost L. Author information: (1)Department of Nutrition and Dietetics, Technological Educational Institution, Thessaloniki, Greece. tzotzas@otenet.gr Plasma phospholipid transfer protein (PLTP) is a lipid transfer glycoprotein that binds to and transfers a number of amphipathic compounds. In earlier studies, the attention of the scientific community focused on the positive role of PLTP in high-density lipoprotein (HDL) metabolism. However, this potentially anti-atherogenic role of PLTP has been challenged recently by another picture: PLTP arose as a pro-atherogenic factor through its ability to increase the production of apolipoprotein B-containing lipoproteins, to decrease their antioxidative protection and to trigger inflammation. In humans, PLTP has mostly been studied in patients with cardiometabolic disorders. Both PLTP and related cholesteryl ester transfer protein (CETP) are secreted proteins, and adipose tissue is an important contributor to the systemic pools of these two proteins. Coincidently, high levels of PLTP and CETP have been found in the plasma of obese patients. PLTP activity and mass have been reported to be abnormally elevated in type 2 diabetes mellitus (T2DM) and insulin-resistant states, and this elevation is frequently associated with hypertriglyceridemia and obesity. This review article presents the state of knowledge on the implication of PLTP in lipoprotein metabolism, on its atherogenic potential, and the complexity of its implication in obesity, insulin resistance and T2DM. PMID: 19413703 [PubMed - indexed for MEDLINE] 1933. Med Hypotheses. 2009 Sep;73(3):347-56. doi: 10.1016/j.mehy.2008.09.059. Epub 2009 May 1. Acid-base balance and weight gain: are there crucial links via protein and organic acids in understanding obesity? Berkemeyer S(1). Author information: (1)Ruhr-Universität-Bochum, Klinik für Altersmedizin und Frührehabilitation, Studienbüro, Room 23, Widumerstr. 8, 44627 Herne, Germany. shoma.berkemeyer@ruhr-uni-bochum.de Obesity is associated with ever increasing social costs posing a general public health challenge. The most obvious reason for obesity, given healthy body functioning, is a positive calorie balance. This article delves into the lesser studied realm of the relationship of weight gain, in particular adipose tissue gain, with increased hydrogen ion concentration, taking protein and organic acids as important caveats in this discussion. The review opens the topic with the contradictory result of various studies reporting a positive relationship between chronic metabolic acidosis and weight loss. It goes to explain a process of weight gain, primarily adipose tissue gain, on acidogenic diets. Insufficient dietary protein could lead to muscle loss, and individual organic acids might indicate if there is any fatty acid oxidation or accumulation of hydrogen ion. The solution to the acid accumulation is discussed not in protein limitation but an increase in the consumption of vegetables and fruits. Finally, this review article based on studies published puts forward a physiological basis including a hypothesis to explain the possible link between hydrogen ion concentration and weight gain. This link could possibly explain the development of diseases and aging partially, and warrants research. PMID: 19410381 [PubMed - indexed for MEDLINE] 1934. Prog Lipid Res. 2009 Sep;48(5):257-74. doi: 10.1016/j.plipres.2009.04.002. Epub 2009 May 4. Ghrelin - Defender of fat. Wells T(1). Author information: (1)Cardiff University, UK. wellst@cardiff.ac.uk With one quarter of the population of the Western world now considered obese, it is essential that we understand the factors giving rise to elevated fat deposition. This review summarizes the cellular and molecular mechanisms governing the volume of white adipose tissue (WAT), and outlines the physiological signals that regulate these processes. Particular attention is given to the role of the gastric hormone, ghrelin, describing its actions in general and presenting detailed evidence of its role in regulating adipocyte biology. Combining this evidence with an analysis of the factors governing ghrelin secretion, leads to the hypothesis that during periods of food deprivation ghrelin acts as an energy deficit signal, defending the fat stored in responsive WAT against the forces of utilization. This scenario has clear implications for programmes of sustainable weight loss. PMID: 19409927 [PubMed - indexed for MEDLINE] 1935. Sheng Li Ke Xue Jin Zhan. 2009 Jan;40(1):19-23. [Glucocorticoids, adipose metabolism and insulin resistance]. [Article in Chinese] Xu C(1), Xu GH. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China. Obesity, insulin resistance, and type 2 diabetes are associated with elevated concentration of circulating free fatty acid (FFA), which is critically governed by the process of triglyceride lipolysis in adipocytes. Endogenous and exogenous glucocorticoids excess could induce insulin resistance and diabetes. Thus, the effects of glucocorticoids stimulating adipose lipolysis and elevating FFA release may contribute to glucocorticoids-induced insulin resistance and diabetes. This review focuses on the regulation and function of glucocorticoids in adipose lipolysis and metabolism. PMID: 19408698 [PubMed - indexed for MEDLINE] 1936. Pain Pract. 2009 May-Jun;9(3):167-72. Cell types obtained from the epidural space of patients with low back pain/radiculopathy. Heavner JE(1), Bosscher HA, Wachtel MS. Author information: (1)Department of Anesthesiology, TTUHSC, Lubbock, Texas 79430, USA. james.heavner@ttuhsc.edu Comment in Pain Pract. 2009 May-Jun;9(3):165-6. BACKGROUND: We investigated if correlations exist between medical history, tissue abnormalities, and cell types retrieved from the epidural space of patients with chronic low back pain (LBP) and chronic radicular pain (RP). METHODS: Approval was obtained from the Institutional Review Board for the Protection of Human Subjects to study 191 patients undergoing epiduroscopy. Visual inspection was performed and abnormal areas were identified. A specimen obtained from the area using a cytology brush was processed by the Thin Prep technique. Patients were divided into four groups based on the presence or absence and intensity of LBP and RP. The gender and age of the patients were recorded, as was any history of prior back surgery. Areas of tissue abnormalities were rated according to changes in vascularity and amount of fat, fibrosis, and inflammation. Stenosis was assessed from magnetic resonance imaging or computerized tomography scan images. Cytologic assessments included notations of the presence or absence of erythrocytes, leukocytes, cell groups, lipocytes, spindled cells, and large round cells. RESULTS: There was a significant difference in the number of patients from whom big round cells were obtained who had a high degree of LBP compared with the number of patients who had a high degree of both LBP and RP. CONCLUSIONS: The findings provide a foundation for future studies of cells obtained from similar patients with the goal of furthering the understanding of the pathogenesis of LBP/RP. PMID: 19408363 [PubMed - indexed for MEDLINE] 1937. Inflamm Bowel Dis. 2009 Dec;15(12):1897-905. doi: 10.1002/ibd.20937. Epub 2009 Apr 30. Adipokine signaling in inflammatory bowel disease. Batra A(1), Zeitz M, Siegmund B. Author information: (1)Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. While the incidence of inflammatory bowel disease (IBD) is still increasing, the etiology has not finally been dissected. The main hypothesis suggests that the mucosal immune system is hyperresponsive to dietary factors and commensal bacteria in genetically predisposed individuals. Burrill Crohn himself described a local hypertrophy of the mesenteric fat tissue adjacent to the segments of inflamed intestine. In addition, more recent data indicate altered local expression and serum levels of some adipocyte-derived mediators (adipokines) with immune-modulating capacities in IBD. This review focuses on the role of adipose tissue and adipokines in the immune system, with particular focus on the mucosal immune system. The available data will serve to establish a working hypothesis on how the mesenteric fat tissue contributes to the pathogenesis of Crohn's disease. Copyright © 2009 Crohn's & Colitis Foundation of America, Inc. PMID: 19408337 [PubMed - indexed for MEDLINE] 1938. Hypertens Res. 2009 Jun;32(6):425-7. doi: 10.1038/hr.2009.55. Epub 2009 May 1. Role of renin-angiotensin system in adipose tissue dysfunction. Iwai M(1), Horiuchi M. Author information: (1)Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. Blockade of angiotensin II type 1 (AT(1)) receptor improves insulin sensitivity and diabetic condition. In short-term regulation, angiotensin II changes lipid metabolism and in long-term regulation, it affects insulin sensitivity and adipocyte differentiation in adipose tissue. These effects are mainly mediated by AT(1) receptor. AT(1) receptor blocker improves insulin sensitivity and induces adipocyte differentiation by increasing peroxisome proliferator-activated receptor-gamma (PPARgamma) and transcription factors in adipose tissue in diabetic and atherosclerotic models. Clinical studies indicate that AT(1) receptor blockers prevent the new onset of diabetes and improve insulin sensitivity. On the other hand, AT(2) receptor stimulation appears to cause antagonistic actions against AT(1) receptor signaling. Although further investigations are necessary on the AT(2) receptor function in adipose tissue, studies using AT(2) receptor agonists, in addition to those using AT(1) receptor blockers, would contribute to the treatment of metabolic syndrome and associated pathological disorders. PMID: 19407825 [PubMed - indexed for MEDLINE] 1939. J Nutr. 2009 Jun;139(6):1236S-1241S. doi: 10.3945/jn.109.106641. Epub 2009 Apr 29. Fructose consumption: considerations for future research on its effects on adipose distribution, lipid metabolism, and insulin sensitivity in humans. Stanhope KL(1), Havel PJ. Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. Results from a recent study investigating the metabolic effects of consuming fructose-sweetened beverages at 25% of energy requirements for 10 wk demonstrate that a high-fructose diet induces dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity. The purpose of this review is to present aspects of the study design which may be critical for assessment of the metabolic effects of sugar consumption. Collection of postprandial blood samples is required to document the full effects of fructose on lipid metabolism. Fasting triglyceride (TG) concentrations are an unreliable index of fructose-induced dyslipidemia. Differences in the short-term (24-h) and long-term (>2 wk) effects of fructose consumption on TG and apolipoprotein-B demonstrate that acute effects can differ substantially from those occurring after sustained fructose exposure. Investigating the effects of fructose when consumed ad libitum compared with energy-balanced diets suggest that additive effects of fructose-induced de novo lipogenesis and positive energy balance may contribute to dyslipidemia and decreased insulin sensitivity. Increases of intra-abdominal fat observed in subjects consuming fructose, but not glucose, for 10 wk indicate that the 2 sugars have differential effects on regional adipose deposition. However, the increase of fasting glucose, insulin, and homeostasis model assessment-insulin resistance at 2 wk and the lack of increase of 24-h systemic FFA concentrations suggest that fructose decreases insulin sensitivity independently of visceral adiposity and FFA. The lower postprandial glucose and insulin excursions in subjects consuming fructose and increased excursions in those consuming glucose do not support a relationship between dietary glycemic index and the development of dyslipidemia, decreased insulin sensitivity, or increased visceral adiposity. PMCID: PMC3151025 PMID: 19403712 [PubMed - indexed for MEDLINE] 1940. Nat Rev Endocrinol. 2009 Jun;5(6):305-11. doi: 10.1038/nrendo.2009.62. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Fève B(1), Bastard JP. Author information: (1)Faculté de Médecine Paris-sud, Université Paris 11, Le Kremlin-Bicêtre, France. bfeve@free.fr In the past few years, several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote beta-cell destruction and alter insulin sensitivity. The effects of IL-1 are likely to be counteracted by IL-1 receptor antagonist protein (IL-1ra), as suggested by interventional studies in patients with T2DM who were treated with a recombinant form of this protein. However, studies in IL-1ra-deficient mice provided controversial results on the exact effect of the IL-1 signaling pathway on insulin secretion, insulin sensitivity and accumulation of adipose tissue. Likewise, IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and beta-cell function. PMID: 19399017 [PubMed - indexed for MEDLINE] 1941. Expert Opin Ther Targets. 2009 May;13(5):593-603. doi: 10.1517/14728220902915310 . Molecular switching of osteoblastogenesis versus adipogenesis: implications for targeted therapies. Takada I(1), Kouzmenko AP, Kato S. Author information: (1)University of Tokyo, Institute of Molecular and Cellular Biosciences, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032 Japan. Osteoblasts and adipocytes differentiate from a common precursor, the pluripotent mesenchymal stem cell (MSC) found in bone marrow (BMSC) and adipose tissue (AD-MSC). Numerous transcription factors and multiple extracellular and intracellular signals regulating adipogenesis and osteoblastogenesis have been identified and analyzed. Significantly, inducers of differentiation towards one lineage may inhibit cell differentiation into an alternative lineage. For example, the canonical Wnt/beta-catenin pathway induces osteoblastogenesis and inhibits adipogenesis, whereas the peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a prime inducer of adipogenesis and, as shown in recent studies, inhibits osteoblastogenesis. We have identified two signaling pathways that switch the cell fate decision from adipocytes to osteoblasts by suppressing the transactivation function of PPAR-gamma. In the first pathway, the TNF-alpha- or IL-1-induced TAK1/TAB1/NIK signaling cascade attenuates PPAR-gamma-mediated adipogenesis by inhibiting the binding of PPAR-gamma to the DNA response element. The second is the noncanonical Wnt pathway through the CaMKII-TAK1/TAB2-NLK (nemo-like kinase) signaling cascade. Specifically, Wnt-5a-induced phosphorylation of NLK triggers formation of a complex with the histone methyltransferase SETDB1 (SET domain, bifurcated 1) that represses PPAR-gamma transactivation through histone H3-K9 methylation at the target genes. Thus, two signaling cascades promote osteoblastic differentiation from MSC through two distinct modes of PPAR-gamma transrepression. PMID: 19397478 [PubMed - indexed for MEDLINE] 1942. Expert Opin Ther Targets. 2009 May;13(5):583-91. doi: 10.1517/14728220902914834 . Novel factors as therapeutic targets to treat diabetes. Focus on leptin and ghrelin. Gómez R(1), Lago F, Gómez-Reino JJ, Gualillo O. Author information: (1)University Clinical Hospital, (NEIRID LAB: Neuroendocrine Interactions in Rheumatology and Inflammatory Disease), Research Laboratory 9, Santiago de Compostela, Spain. BACKGROUND: Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain. OBJECTIVE/METHODS: To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes. RESULTS/CONCLUSIONS: A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified. PMID: 19397477 [PubMed - indexed for MEDLINE] 1943. Arch Dermatol Res. 2009 Jun;301(5):329-36. doi: 10.1007/s00403-009-0951-9. Epub 2009 Apr 26. Protective role of adipose-derived stem cells and their soluble factors in photoaging. Kim WS(1), Park BS, Sung JH. Author information: (1)Department of Dermatology, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, Korea. As individuals age, the skin undergoes changes, such as irregular pigmentation, thinning and loss of elasticity, that are due to both genetic and environmental factors. These changes may worsen, progressing to precancerous and cancerous diseases. Various medical treatments and topical cosmeceuticals have been used to treat some symptoms of photoaging, however, the results have been less than satisfactory. Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue, adipose-derived stem cells (ADSCs), display multi-lineage developmental plasticity and secrete various growth factors that control and manage the damaged neighboring cells. Recently, the production and secretion of growth factors has been reported as an essential function of ADSCs, and diverse regenerative effects of ADSCs have been demonstrated in the skin. For example, conditioned medium from ADSCs (ADSC-CM) stimulated both collagen synthesis and migration of dermal fibroblasts, which improved the wrinkling and accelerated wound healing in animal models. ADSC-CM also inhibited melanogenesis in B16 melanoma cells, and protected dermal fibroblasts from oxidative stress induced by chemicals and UVB irradiation. Therefore, ADSCs and soluble factors show promise for the treatment of photoaging, and this review introduces recent research developments of the ADSCs and ADSC-derived secretory factors regarding this issue. PMID: 19396609 [PubMed - indexed for MEDLINE] 1944. Rev Med Interne. 2009 Sep;30(9):824-32. doi: 10.1016/j.revmed.2009.03.363. Epub 2009 Apr 25. [Inflammation, adipokines and obesity]. [Article in French] Clément K(1), Vignes S. Author information: (1)Service de nutrition, pôle d'endocrinologie, hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, U872 (équipe 7), Inserm, centre de recherche des Cordeliers, université Pierre-et-Marie-Curie Paris-6, 75006 Paris, France. karine.clement@psl.aphp.fr In obese subjects, there is a "low grade" inflammatory state characterized by the moderate but chronic systemic rise of a panel of molecules (adipokines), which carry out, in addition to pro- or anti-inflammatory actions, several immune or metabolic functions, associated with a macrophagic infiltration in adipose tissue. These two factors provide a better understanding of the pathophysiology of obesity and its potential metabolic, cardiovascular or hepatic complications. A small or even moderate reduction of weight significantly reduces circulating inflammatory markers, modulates adipose tissue profile of inflammatory genes and the risks associated with obesity. PMID: 19394723 [PubMed - indexed for MEDLINE] 1945. Fertil Steril. 2010 Jul;94(2):690-3. doi: 10.1016/j.fertnstert.2009.03.058. Epub 2009 Apr 25. Ovarian and adipose tissue dysfunction in polycystic ovary syndrome: report of the 4th special scientific meeting of the Androgen Excess and PCOS Society. Yildiz BO(1), Azziz R; Androgen Excess and PCOS Society. Author information: (1)Hacettepe University School of Medicine, Ankara, Turkey. Significant advances have been made in our understanding of ovarian dysfunction in polycystic ovary syndrome (PCOS), and alterations in adipose tissue function are likely to play an important role in its pathophysiology. This review highlights the principal novel concepts presented at the 4th special scientific meeting of the Androgen Excess and PCOS Society, "Ovarian and Adipose Tissue Dysfunction: Potential Roles in Polycystic Ovary Syndrome," which occurred on June 6, 2008 in San Francisco, California. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. PMCID: PMC3727143 PMID: 19394000 [PubMed - indexed for MEDLINE] 1946. J Transl Med. 2009 Apr 24;7:29. doi: 10.1186/1479-5876-7-29. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. Riordan NH(1), Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B. Author information: (1)Medistem Inc, San Diego, CA, USA. riordan@medisteminc.com The stromal vascular fraction (SVF) of adipose tissue is known to contain mesenchymal stem cells (MSC), T regulatory cells, endothelial precursor cells, preadipocytes, as well as anti-inflammatory M2 macrophages. Safety of autologous adipose tissue implantation is supported by extensive use of this procedure in cosmetic surgery, as well as by ongoing studies using in vitro expanded adipose derived MSC. Equine and canine studies demonstrating anti-inflammatory and regenerative effects of non-expanded SVF cells have yielded promising results. Although non-expanded SVF cells have been used successfully in accelerating healing of Crohn's fistulas, to our knowledge clinical use of these cells for systemic immune modulation has not been reported. In this communication we discuss the rationale for use of autologous SVF in treatment of multiple sclerosis and describe our experiences with three patients. Based on this rationale and initial experiences, we propose controlled trials of autologous SVF in various inflammatory conditions. PMCID: PMC2679713 PMID: 19393041 [PubMed - indexed for MEDLINE] 1947. Vet Clin Pathol. 2009 Jun;38(2):136-56. doi: 10.1111/j.1939-165X.2009.00133.x. Epub 2009 Apr 6. Adipokines: a review of biological and analytical principles and an update in dogs, cats, and horses. Radin MJ(1), Sharkey LC, Holycross BJ. Author information: (1)Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA. radin.1@osu.edu In addition to its role as an energy storage depot, adipose tissue is now recognized as a complex endocrine organ. Adipose tissue releases a variety of factors, termed adipokines, that regulate energy metabolism, cardiovascular function, reproductive status, and immune function. Some of the better-studied adipokines include leptin, adiponectin, and components of the renin-angiotensin system such as angiotensinogen. The function of more recently discovered adipokines such as resistin are under intense scrutiny. Abnormal production or regulation of adipokines occurs in obese individuals and is implicated in the development of a variety of associated co-morbidities including metabolic syndrome, type 2 diabetes, atherosclerosis, heart disease, and cancer in people, although evaluation in domestic species is just beginning. Adipokines are now being examined as potential biomarkers for risk assessment for development of complications related to obesity. This article summarizes the function and regulation of some better-characterized adipokines. It also reviews the current information on the characterization of adipokines in some domestic species in which rates of obesity and obesity-related disorders are increasing, such as the dog, cat, and horse. PMID: 19392760 [PubMed - indexed for MEDLINE] 1948. Immunol Allergy Clin North Am. 2009 May;29(2):381-93. doi: 10.1016/j.iac.2009.02.011. Exercise, inflammation, and innate immunity. Woods JA(1), Vieira VJ, Keylock KT. Author information: (1)Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 906 South Goodwin Avenue, Urbana, IL 6180, USA. woods1@uiuc.edu Exercise has beneficial effects on chronic disease, and the drive to understand the mechanisms of these benefits is strong. This article presents several compelling potential mechanisms for the anti-inflammatory effect of exercise, including reduced percentage of body fat and macrophage accumulation in adipose tissue, muscle-released interleukin-6 inhibition of tumor necrosis factor-a, and the cholinergic anti-inflammatory pathway. PMID: 19389588 [PubMed - indexed for MEDLINE] 1949. J Invest Dermatol. 2009 Aug;129(8):1861-7. doi: 10.1038/jid.2009.97. Epub 2009 Apr 23. FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. Katoh M(1). Author information: (1)Genetics and Cell Biology Section, National Cancer Center, Tokyo, Japan. mkatoh-kkr@umin.ac.jp Fibroblast growth factor receptor (FGFR)2 is regulated on the basis of the balance of FGFs, heparan-sulfate proteoglycans, FGFR2 isoforms, endogenous inhibitors, and microRNAs. FGFR2 signals cross-talk with hedgehog, bone morphogenetic protein, and other regulatory networks. Some cases of congenital skeletal disorders with an FGFR2 mutation show skin phenotypes, including acne, cutis gyrata, and acanthosis nigricans. Gain-of-function mutations or variations of human FGFR2 occur in estrogen receptor-positive breast cancer, diffuse-type gastric cancer, and endometrial uterine cancer. Oral administration of AZD2171 or Ki23057 inhibits in vivo proliferation of cancer cells with aberrant FGFR2 activation in rodent therapeutic models. However, loss-of-function mutations of FGFR2 are reported in human melanoma. Conditional Fgfr2b knockout in the rodent epidermis leads to increased macrophage infiltration to the dermis and adipose tissue, epidermal thickening accompanied by basal-layer dysplasia and parakeratosis, and the promotion of chemically induced squamous-cell carcinoma. Dysregulation of FGFR2 results in a spectrum of bone and skin pathologies and several types of cancer. PMID: 19387476 [PubMed - indexed for MEDLINE] 1950. Orv Hetil. 2009 May 3;150(18):821-9. doi: 10.1556/OH.2009.28606. [From the metabolic syndrome to the concept of global cardiometabolic risk]. [Article in Hungarian] Nádas J(1), Jermendy G. Author information: (1)Fôvárosi Bajcsy-Zsilinszky Kórház, III. Belgyógyászati Osztály, Budapest Maglódi út 89-91., 1106. nadasjudit@gmail.com Although the clustering of cardiovascular risk factors is unquestionable, the clinical significance of the metabolic syndrome as a distinct entity has been debated in the past years. Recently, the term 'metabolic syndrome' has been replaced by 'global cardiometabolic risk' which implies cardiovascular risk factors beyond the metabolic syndrome. The metabolic syndrome can be frequently detected among people in western and developing countries affecting 25-30% of adult population, and its prevalence rate is increasing. Prospective studies show that the metabolic syndrome is a significant predictor of incident diabetes but has a weaker association with cardiovascular morbidity and mortality. At the same time the metabolic syndrome is inferior to established predicting models for either type 2 diabetes or cardiovascular disease.The underlying pathomechanism of the metabolic syndrome is still poorly understood. The role of insulin resistance--although not as a single factor--is still considered as a key component. In the last decade the importance of abdominal obesity has received increased attention but some studies, mainly in the Asian population, showed that central obesity is not an essential component of the syndrome. Regardless of the theoretical debates the practical implications are indisputable. The frequent clustering of hypertension, dyslipidaemia and glucose intolerance, that often accompanies central obesity, can not be ignored. Following the detection of one risk factor, the presence of other, traditional and non-traditional factors should be searched for, as the beneficial effect of intensive, target oriented, continuous treatment of metabolic and cardiovascular risk factors has been proven in both the short and long term. PMID: 19383573 [PubMed - indexed for MEDLINE] 1951. Am J Med. 2009 May;122(5):409-14. doi: 10.1016/j.amjmed.2008.11.027. Bone, fat, and body composition: evolving concepts in the pathogenesis of osteoporosis. Rosen CJ(1), Klibanski A. Author information: (1)Maine Medical Center Research Institute, Scarborough, ME 04074, USA. rosenc@mmc.org Disorders of body composition, including obesity and osteoporosis, have reached record proportions. Coincidentally, our understanding of the mechanisms controlling body mass also has greatly improved. Shared regulation at the hypothalamus and the bone marrow highlight major bone-fat interactions. The hypothalamus modulates fat and bone via the sympathetic nervous system by regulating appetite, insulin sensitivity, energy use, and skeletal remodeling. In the bone marrow, fat and bone cells arise from the same stem cells. Insights from disorders such as anorexia nervosa provide a new rationale for examining the mechanisms that link bone to fat. This article explores these relationships in the context of a new paradigm with implications for obesity and osteoporosis. PMID: 19375545 [PubMed - indexed for MEDLINE] 1952. Exp Clin Endocrinol Diabetes. 2009 Sep;117(8):440-5. doi: 10.1055/s-0029-1202274. Epub 2009 Apr 16. Myelolipomatous adrenal masses causing Cushing's syndrome. Lamas C(1), López LM, Lozano E, Atienzar M, Ruiz-Mondéjar R, Alfaro JJ, Botella F. Author information: (1)Department of Endocrinology, Complejo Hospitalario Universitario de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain. clamaso@sescam.jccm.es Adrenal myelolipomas are uncommon benign tumors, composed of mature adipose tissue and haematopoietic elements in varying proportions. They are usually asymptomatic, non-functioning adrenal incidentalomas, but there have been a few reports of myelolipomatous masses associated with adrenocortical hypersecretion. We report two cases of large mixed adrenal tumors, with heterogeneous appearance and areas of fat density in imaging techniques, and with autonomous cortisol production leading to Cushing's syndrome. Both underwent adrenalectomy and the histological study showed an adrenocortical adenoma with widespread myelolipomatous metaplasia. Hypercortisolism resolved in the one patient that could be evaluated after surgery. We review all the previous reported cases of hypercortisolism associated with adrenal myelolipomas. We also discuss the recommended diagnostic approach and therapeutic management of adrenal masses of lipomatous appearance. J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart.New York. PMID: 19373749 [PubMed - indexed for MEDLINE] 1953. Mol Endocrinol. 2009 Aug;23(8):1127-34. doi: 10.1210/me.2008-0485. Epub 2009 Apr 16. Minireview: the case for obesogens. Grün F(1), Blumberg B. Author information: (1)Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-2300, USA. Obesity and obesity-related disorders, such as type 2 diabetes, hypertension, and cardiovascular disease, are epidemic in Western countries, particularly the United States. The conventional wisdom holds that obesity is primarily the result of a positive energy balance, i.e. too many calories in and too few calories burned. Although it is self-evident that fat cannot be accumulated without a higher caloric intake than expenditure, recent research in a number of laboratories suggests the existence of chemicals that alter regulation of energy balance to favor weight gain and obesity. These obesogens derail the homeostatic mechanisms important for weight control, such that exposed individuals are predisposed to weight gain, despite normal diet and exercise. This review considers the evidence for obesogens, how they might act, and where future research is needed to clarify their relative contribution to the obesity epidemic. PMCID: PMC2718750 PMID: 19372238 [PubMed - indexed for MEDLINE] 1954. Endocrinology. 2009 Jun;150(6):2531-6. doi: 10.1210/en.2009-0046. Epub 2009 Apr 16. Minireview: Endocannabinoids and their receptors as targets for obesity therapy. de Kloet AD(1), Woods SC. Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45237, USA. As the incidence of obesity continues to increase, the development of effective therapies is a high priority. The endocannabinoid system has emerged as an important influence on the regulation of energy homeostasis. The endocannabinoids anandamide and 2-arachidonoylglycerol act on cannabinoid receptor-1 (CB1) in the brain and many peripheral tissues causing a net anabolic action. This includes increasing food intake, and causing increased lipogenesis and fat storage in adipose tissue and liver. The endocannabinoid system is hyperactive in obese humans and animals, and treating them with CB1 antagonists causes weight loss and improved lipid and glucose profiles. Although clinical trials with CB1 antagonists have yielded beneficial metabolic effects, concerns about negative affect have limited the therapeutic potential of the first class of CB1 antagonists available. PMID: 19372200 [PubMed - indexed for MEDLINE] 1955. Endocrinology. 2009 Jun;150(6):2537-42. doi: 10.1210/en.2009-0070. Epub 2009 Apr 16. Minireview: Obesity and breast cancer: the estrogen connection. Cleary MP(1), Grossmann ME. Author information: (1)The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA. mpcleary@smig.net There is now substantial evidence that overweight and/or obesity and/or weight gain are risk factors for the development of postmenopausal breast cancer. In addition, obesity and/or elevated body mass index at breast cancer diagnosis has a negative impact on prognosis for both premenopausal and postmenopausal women. Therefore, understanding the mechanism of how obesity affects the mammary tumorigenesis process is an important health issue. Elevated serum estrogen levels as well as enhanced local production of estrogen have been considered primary mediators of how increased body weight promotes breast cancer development in postmenopausal women. Here, we provide an overview of estrogen's relationship with both obesity and breast cancer as separate entities. Human and relevant preclinical studies are cited. In addition, other growth factors that may be involved in this relationship are considered. PMCID: PMC2689796 PMID: 19372199 [PubMed - indexed for MEDLINE] 1956. Curr Opin Lipidol. 2009 Jun;20(3):211-6. doi: 10.1097/MOL.0b013e32832ac026. GPIHBP1 and lipolysis: an update. Beigneux AP(1), Weinstein MM, Davies BS, Gin P, Bensadoun A, Fong LG, Young SG. Author information: (1)Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA. abeigneux@mednet.ucla.edu PURPOSE OF REVIEW: This review will provide an update on the structure of GPIHBP1, a 28-kDa glycosylphosphatidylinositol-anchored glycoprotein, and its role in the lipolytic processing of triglyceride-rich lipoproteins. RECENT FINDINGS: Gpihbp1 knockout mice on a chow diet have milky plasma and plasma triglyceride levels of more than 3000 mg/dl. GPIHBP1 is located on the luminal surface of endothelial cells in tissues where lipolysis occurs: heart, skeletal muscle, and adipose tissue. The pattern of lipoprotein lipase (LPL) release into the plasma after an intravenous injection of heparin is abnormal in Gpihbp1-deficient mice, suggesting that GPIHBP1 plays a direct role in binding LPL within the tissues of mice. Transfection of CHO cells with a GPIHBP1 expression vector confers on cells the ability to bind both LPL and chylomicrons. Two regions of GPIHBP1 are required for the binding of LPL - an amino-terminal acidic domain and the cysteine-rich Ly6 domain. GPIHBP1 expression in mice changes with fasting and refeeding and is regulated in part by peroxisome proliferator-activated receptor-gamma. SUMMARY: GPIHBP1, an endothelial cell-surface glycoprotein, binds LPL and is required for the lipolytic processing of triglyceride-rich lipoproteins. PMCID: PMC2810420 PMID: 19369870 [PubMed - indexed for MEDLINE] 1957. Curr Opin Lipidol. 2009 Jun;20(3):165-70. doi: 10.1097/MOL.0b013e32832adee5. The lipin family: mutations and metabolism. Reue K(1). Author information: (1)Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA. reuek@ucla.edu PURPOSE OF REVIEW: The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that regulate expression of lipid metabolism genes. The genes for lipin-1, lipin-2 and lipin-3 are expressed in key metabolic tissues, including adipose tissue, skeletal muscle and liver, but the physiological functions of each member of the family have not been fully elucidated. Here we examine the most recent studies that provide information about the roles of lipin proteins in metabolism and human disease. RECENT FINDINGS: Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively. The effects of lipin-1 deficiency appear to include both the loss of glycerolipid building blocks and the accumulation of lipid intermediates that disrupt cellular function. Several studies have demonstrated that polymorphisms in the LPIN1 and LPIN2 genes are associated with metabolic disease traits, including insulin sensitivity, diabetes, blood pressure and response to thiazolidinedione drugs. Furthermore, lipin-1 expression levels in adipose tissue and/or liver are positively correlated with insulin sensitivity. Studies of lipin-1 in adipocytes have shed some light on its relationship with insulin sensitivity. SUMMARY: Lipin-1 and lipin-2 are required for normal lipid homeostasis and have unique physiological roles. Future studies, for example using engineered mouse models, will be required to fully elucidate their specific roles in normal physiology and disease. PMCID: PMC2875192 PMID: 19369868 [PubMed - indexed for MEDLINE] 1958. Forum Nutr. 2009;61:136-46. doi: 10.1159/000212746. Epub 2009 Apr 7. Function of marine carotenoids. Miyashita K(1). Author information: (1)Faculty of Fisheries Sciences, Hokkaido University, Hakodate, Japan. kmiya@fish.hokudai.ac.jp Although an effort is made to review marine carotenoids as important bioactive compounds with reference to their presence, and chemical and biofunctional benefits, there has been a relatively little information on the impact of these carotenoids on human health. The potential beneficial effects of marine carotenoids have been studied particularly in astaxanthin and fucoxanthin as they are major marine carotenoids. Both carotenoids show strong antioxidant activity which is attributed to quenching singlet oxygen and scavenging free radicals. The potential role of the carotenoids as dietary anti-oxidants has been suggested to be one of the main mechanisms for their preventive effects against cancer and inflammatory diseases. However, it would be difficult to explain their biological activities only by their antioxidant activity. We have found the antiobesity and antidiabetic effects as specific and novel bio-functions of fucoxanthin. A nutrigenomic study revealed that fucoxanthin induces uncoupling protein 1 expression in white adipose tissue (WAT) mitochondria to lead to oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose level, at least in part, through the downregulation of tumor necrosis factor-alpha in WAT of animals. Thus, the specific regulation of fucoxanthin on a particular bio-molecule will be responsible for the characteristic chemical structures which differ depending on the length of the polyene, nature of the end group and various substituents they contain. The key structure of carotenoids for the expression of antiobesity effect was suggested to be carotenoid end of the polyene chromophore containing an allenic bond and two hydroxyl groups. PMID: 19367118 [PubMed - indexed for MEDLINE] 1959. Forum Nutr. 2009;61:95-103. doi: 10.1159/000212742. Epub 2009 Apr 7. Inflammatory components of adipose tissue as target for treatment of metabolic syndrome. Yu R(1), Kim CS, Kang JH. Author information: (1)Department of Food Science and Nutrition, University of Ulsan, Ulsan, South Korea. rinayu@ulsan.ac.kr Obesity is an independent risk factor in the etiology of various metabolic diseases such as insulin resistance, type 2 diabetes and cardiovascular diseases. In this chapter, we discuss obesity-induced inflammation as a potential link with obesity-related metabolic syndrome, and discuss how obesity-related inflammatory components such as immune cells, and cytokines/chemokines and adipocy-tokines, provoke obesity-related pathologies. In particular, we focus on the hypothesis that anti-inflammatory food factors/phytochemicals may be useful for inhibiting the initiation and development of obesity-induced inflammation and metabolic syndrome. PMID: 19367114 [PubMed - indexed for MEDLINE] 1960. Gerontology. 2009;55(4):379-86. doi: 10.1159/000212758. Epub 2009 Apr 8. Obesity, inflammation, and insulin resistance--a mini-review. Zeyda M(1), Stulnig TM. Author information: (1)Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. The association of obesity, insulin resistance, and chronic low-grade inflammation has been evident for several years by now. Since obesity, insulin resistance, and inflammation all are related to aging as well, the mechanisms underlying this association are of critical importance for gerontology. Although several molecular and cellular mechanisms by which inflammatory events decrease the sensitivity to insulin in obese patients have recently been elucidated, the pathogenesis of obesity-induced insulin resistance is still obscure in many aspects. This review aims at giving a general view on the known mechanisms and summarizing the recent progress. Research currently focuses on adipose tissue inflammation as predominantly driven by adipose tissue macrophages, but also related alterations in other organs (liver, muscle, pancreas) have to be considered. Moreover, novel approaches for treatment and prevention of insulin resistance and type 2 diabetes by targeting obesity-induced inflammatory processes are discussed here. Copyright 2009 S. Karger AG, Basel. PMID: 19365105 [PubMed - indexed for MEDLINE] 1961. Endocr Pract. 2009 Apr;15(3):254-62. Excess thyroid hormone and carbohydrate metabolism. Potenza M(1), Via MA, Yanagisawa RT. Author information: (1)Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029, USA. matthew.potenza@mssm.edu OBJECTIVE: To review the pertinent basic and clinical research describing the complex effects of excess thyroid hormone on carbohydrate metabolism. METHODS: We performed a MEDLINE search of the English-language literature using a combination of words (ie, "thyrotoxicosis and diabetes," "diabetic ketoacidosis and thyroid storm," "carbohydrate metabolism and hyperthyroid," "glucose homeostasis and thyrotoxicosis") to identify key articles addressing various aspects of the thyroid's influence on carbohydrate metabolism. RESULTS: Thyroid hormone affects glucose homeostasis via its actions on a variety of organs including increased hepatic glucose output, increased futile cycling of glucose degradation products between the skeletal muscle and the liver, decreased glycogen stores in the liver and skeletal muscle, altered oxidative and non-oxidative glucose metabolism, decreased active insulin output from the pancreas, and increased renal insulin clearance. Thyroid hormone also affects adipokines and adipose tissue, further predisposing the patient to ketosis. CONCLUSIONS: Thyrotoxicosis can alter carbohydrate metabolism in a type 2 diabetic patient to such an extent that diabetic ketoacidosis develops if untreated. Based on the current understanding of this relationship, all diabetic patients should be screened for thyroid dysfunction because correcting hyperthyroidism can profoundly affect glucose homeostasis. Similarly, patients presenting in diabetic ketoacidosis should undergo a thyroid function assessment. PMID: 19364696 [PubMed - indexed for MEDLINE] 1962. Biochim Biophys Acta. 2009 Oct;1790(10):1117-23. doi: 10.1016/j.bbagen.2009.01.008. Epub 2009 Jan 31. Role of visceral adipose tissue in aging. Huffman DM(1), Barzilai N. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA. BACKGROUND: Visceral fat (VF) accretion is a hallmark of aging in humans. Epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes, cardiovascular disease, metabolic syndrome and death. METHODS: Studies utilizing novel rodent models of visceral obesity and surgical strategies in humans have been undertaken to determine if subcutaneous (SC) abdominal or VF are causally linked to age-related diseases. RESULTS: Specific depletion or expansion of the VF depot using genetic or surgical tools in rodents has been shown to have direct effects on disease risk. In contrast, surgically removing large quantities of SC fat does not consistently improve metabolic parameters in humans or rodents, while benefits were observed with SC fat expansion in mice, suggesting that SC fat accrual is not an important contributor to metabolic decline. There is also compelling evidence in humans that abdominal obesity is a stronger risk factor for mortality risk than general obesity. Likewise, we have shown that surgical removal of VF improves mean and maximum lifespan in rats, providing the first causal evidence that VF depletion may be an important underlying cause of improved lifespan with caloric restriction. GENERAL SIGNIFICANCE: This review provides both corollary and causal evidence for the importance of accounting for body fat distribution, and specifically VF, when assessing disease and mortality risk. Given the hazards of VF accumulation on health, treatment strategies aimed at selectively depleting VF should be considered as a viable tool to effectively reduce disease risk in humans. PMCID: PMC2779572 PMID: 19364483 [PubMed - indexed for MEDLINE] 1963. Int J Obes (Lond). 2009 Apr;33 Suppl 1:S41-7. doi: 10.1038/ijo.2009.16. Genetics, physiology and perinatal influences in childhood obesity: view from the Chair. Mitchell GA(1). Author information: (1)Medical Genetics Division, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, 3175 Côte Ste-Catherine, Montréal, Quebec, Canada. grant.mitchell@recherche-ste-justine.qc.ca The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programming, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex. PMID: 19363507 [PubMed - indexed for MEDLINE] 1964. Orv Hetil. 2009 Apr 26;150(17):771-80. doi: 10.1556/OH.2009.28608. [Molecular mechanisms and correlations of insulin resistance, obesity, and type 2 diabetes mellitus]. [Article in Hungarian] Winkler G(1), Cseh K. Author information: (1)Fovárosi Onkormányzat Szent János Kórház és Eszak-budai Egyesített Intézményei II. Belgyógyászati Osztály Budapest. gabor.winkler@mail.janoskorhaz.hu Comment in Orv Hetil. 2009 Sep 13;150(37):1753-4; author reply 1754. Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed. PMID: 19362933 [PubMed - indexed for MEDLINE] 1965. Exp Clin Endocrinol Diabetes. 2009 Jun;117(6):241-50. doi: 10.1055/s-0029-1192044. Epub 2009 Apr 8. Adipose tissue dysfunction in obesity. Blüher M(1). Author information: (1)Department of Medicine, University of Leipzig, Leipzig, Germany. bluma@medizin.uni-leipzig.de The incidence of obesity has increased dramatically during recent decades. Obesity will cause a decline in life expectancy for the first time in recent history due to numerous co-morbid disorders. Adipocyte and adipose tissue dysfunction belong to the primary defects in obesity and may link obesity to several health problems including increased risk of insulin resistance, type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, atherosclerosis, dementia, airway disease and some cancers. However, not all obese individuals develop obesity related metabolic or cardiovascular disorders potentially due to a preserved normal adipose tissue architecture and function. The majority of patients with obesity have an impaired adipose tissue function caused by the interaction of genetic and environmental factors which lead to adipocyte hypertrophy, hypoxia, a variety of stresses and inflammatory processes within adipose tissue. Ectopic fat accumulation including visceral obesity may be considered as a consequence of adipose tissue dysfunction, which is further characterized by changes in the cellular composition, increased lipid storage and impaired insulin sensitivity in adipocytes, and secretion of a proinflammatory, atherogenic, and diabetogenic adipokine pattern. This review focuses on the discussion of mechanisms causing or maintaining impaired adipose tissue function in obesity and potentially linking obesity to its associated disorders. A model is proposed how different pathogenic factors and mechanisms may cause dysfunction of adipose tissue. PMID: 19358089 [PubMed - indexed for MEDLINE] 1966. Trends Endocrinol Metab. 2009 May;20(4):186-93. doi: 10.1016/j.tem.2009.01.004. Epub 2009 Apr 7. Mitochondrial protein phosphorylation: instigator or target of lipotoxicity? Graier WF(1), Malli R, Kostner GM. Author information: (1)Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University Graz, Graz, Austria. wolfgang.graier@medunigraz.at Lipotoxicity occurs as a consequence of chronic exposure of non-adipose tissue and cells to elevated concentrations of fatty acids, triglycerides and/or cholesterol. The contribution of mitochondria to lipotoxic cell dysfunction, damage and death is associated with elevated production of reactive oxygen species and initiation of apoptosis. Although there is a broad consensus on the involvement of these phenomena with lipotoxicity, the molecular mechanisms that initiate, mediate and trigger mitochondrial dysfunction in response to substrate overload remain unclear. Here, we focus on protein phosphorylation as an important phenomenon in lipotoxicity that harms mitochondria-related signal transduction and integration in cellular metabolism. Moreover, the degradation of mitochondria by mitophagy is discussed as an important landmark that leads to cellular apoptosis in lipotoxicity. PMID: 19356948 [PubMed - indexed for MEDLINE] 1967. Curr Vasc Pharmacol. 2009 Apr;7(2):169-79. Visceral adipose tissue and atherosclerosis. Ohman MK(1), Wright AP, Wickenheiser KJ, Luo W, Eitzman DT. Author information: (1)University of Michigan, Department of Internal Medicine, Division of Cardiology, Ann Arbor, MI 48109, USA. Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Recent studies have demonstrated that the vascular risk associated with obesity is correlated particularly with visceral adiposity. These clinical observations indicate that various adipose tissue depots may have differential effects on vascular risk. Cellular constituents of adipose tissue secrete cytokines and chemokines that may affect vascular disease. Visceral fat has been demonstrated to express more inflammatory cytokines than subcutaneous fat in obese states. The adipose tissue secretory profile may reflect the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by adipose tissue may contribute to increased vascular disease. While the vasculopathic effects of visceral obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or the adipocyte expression profile may be potentially beneficial in reducing the vascular risk associated with obesity. Further characterization of the factors responsible for promoting atherosclerosis in the setting of visceral obesity may lead to new targets for the prevention of atherosclerosis. PMID: 19356000 [PubMed - indexed for MEDLINE] 1968. Curr Mol Med. 2009 Apr;9(3):299-314. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Polyzos SA(1), Kountouras J, Zavos C. Author information: (1)Department of Medicine, Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece. Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of common hepatic disorders in western countries, with multiple consequences and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. The pathogenesis of NAFLD is thought to be related mainly with insulin resistance (IR) syndrome and oxidative stress; the latter resulting from mitochondrial fatty acids (FFAs) oxidation, nuclear factor-kappaB (NFkappaB)-dependent inflammatory cytokine expression and adipocytokines may promote hepatocellular damage, inflammation, fibrosis and progressive liver disease. Adipocytokines and other recognized cytokines produced partially by inflammatory cells infiltrating adipose tissue, play an important role in the pathogenesis of IR and NAFLD, through complex and interactive paracrine and endocrine mechanisms. Some adipocytokines, including adiponectin and leptin decrease IR, while others, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and resistin enhance IR. The multi-hit hypothesis provides a model that summarizes the complex factors and interactions leading from adipocytokines, FFAs metabolism and IR to NAFLD. This review outlines the pathways involved in adipocytokines, IR and NAFLD sequence; the first part describes the impaired IR pathway leading to NAFLD and the second part the mechanisms by which adipocytokines influence IR and NAFLD development and progression. Understanding these complex mechanisms has evoked new therapeutic approaches, which may provide promising results to date. PMID: 19355912 [PubMed - indexed for MEDLINE] 1969. Physiol Rev. 2009 Apr;89(2):381-410. doi: 10.1152/physrev.00016.2008. Mechanisms of cancer cachexia. Tisdale MJ(1). Author information: (1)Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, UK. m.j.tisdale@aston.ac.uk Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the alpha-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFkappaB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-alpha, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment. PMID: 19342610 [PubMed - indexed for MEDLINE] 1970. Front Neuroendocrinol. 2009 Aug;30(3):396-404. doi: 10.1016/j.yfrne.2009.03.004. Epub 2009 Mar 31. Sexual differences in the control of energy homeostasis. Shi H(1), Seeley RJ, Clegg DJ. Author information: (1)Obesity Research Center, University of Cincinnati, Cincinnati, OH, USA. The prevalence of obesity has reached epidemic proportion with enormous costs in both human lives and healthcare dollars spent. Obesity-related metabolic disorders are much lower in premenopausal women than men; however, there is a dramatic increase following menopause in women. The health risks associated with obesity vary depending on the location of adipose tissue. Adipose tissue distributed in the abdominal visceral carry a much greater risk for metabolic disorders than does adipose tissue distributed subcutaneously. There are distinct sex-dependent differences in the regional fat distribution, women carry more fat subcutaneously whereas men carry more fat viscerally. Males and females differ with respect to their regulation of energy homeostasis. Peripheral adiposity hormones such as leptin and insulin as well as sex hormones directly influence energy balance. Sexual dimorphisms in energy balance, body fat distribution, and the role sex hormones have in mediating these differences are the focus of this review. PMID: 19341761 [PubMed - indexed for MEDLINE] 1971. Clin Chim Acta. 2009 Jul;405(1-2):1-7. doi: 10.1016/j.cca.2009.03.050. Epub 2009 Mar 31. The search for a pathophysiological link between gender, cardiac endocrine function, body mass regulation and cardiac mortality: proposal for a working hypothesis. Clerico A(1), Fontana M, Vittorini S, Emdin M. Author information: (1)Fondazione Gabriele Monasterio CNR-Regione Toscana, Pisa, Italy. clerico@ifc.cnr.it BACKGROUND: The discovery of cardiac natriuretic hormones determined a radical revision of the concept of heart function. It is now clear that the heart is not merely a pump but, through its endocrine function, exerts a nodal role in a complex information network. As a matter of fact the heart plays a key role in the regulation of circulation, salt-water homeostasis, and can exchange physiologically relevant information with other organs and systems. CONTENT: Highlighting the most important recent literature observations, this review discusses the inter-relationship between endocrine function of the heart and gonadal function. We have first considered the cross-talk between cardiac endocrine system and sex steroid hormones, examining the different actions of female sex steroid hormones and androgens on cardiac endocrine function, and then the action of cardiac natriuretic hormones on female and male gonadal function. Then, we have highlighted the clinical relevance of the relationships between cardiac endocrine function and sex steroid hormones in several clinical conditions associated with cardiovascular risk, focusing on mechanisms linking adipose tissue to natriuretic peptide and sex steroid hormone actions. CONCLUSION: The knowledge of the relation between cardiac endocrine function and other neurohormonal systems, including gonadal function, is crucial to explain the increased cardiovascular risk in some clinical conditions, such as obesity, arterial hypertension and metabolic syndrome. PMID: 19341716 [PubMed - indexed for MEDLINE] 1972. Genes Dev. 2009 Apr 1;23(7):788-97. doi: 10.1101/gad.1779209. Transcriptional control of brown adipocyte development and physiological function--of mice and men. Seale P(1), Kajimura S, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. The last several years have seen an explosion of information relating to the transcriptional control of brown fat cell development. At the same time, new data have emerged that clearly demonstrate that adult humans do indeed have substantial amounts of functioning brown adipose tissue (BAT). Together, these advances are stimulating a reassessment of the role of brown adipose tissue in human physiology and pathophysiology. These data have also opened up exciting new opportunities for the development of entirely novel classes of therapeutics for metabolic diseases like obesity and type 2 diabetes. PMCID: PMC2763499 PMID: 19339685 [PubMed - indexed for MEDLINE] 1973. Curr Opin Investig Drugs. 2009 Apr;10(4):346-52. The adipocyte IKK/NFkappaB pathway: a therapeutic target for insulin resistance. Ruan H(1), Pownall HJ. Author information: (1)University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Physiology and Biophysics, 683 Hoes Lane West, Piscataway, NJ 08854, USA. ruanho@umdnj.edu Insulin suppresses the release of non-esterified fatty acids from adipocytes and suppresses glucose production from hepatocytes, but stimulates glucose uptake by skeletal muscle, liver and adipose tissue. Insulin resistance, the failure of an ample supply of insulin to mediate these effects, is an early and fundamental defect in type 2 diabetes (T2D) associated with obesity. Adipose tissue not only acts as an energy depot, but also secretes a variety of endocrine, paracrine and autocrine factors, which regulate energy metabolism and insulin activity. In addition, adipose tissue from obese individuals has a distinct secretory profile that alters both adipocyte function and overall in vivo insulin sensitivity. Obesity is coupled to insulin resistance and diabetes through the action of adipose-derived factors, in a process that involves intricate signaling pathways and transcriptional regulators in various cell types of adipose tissue, in addition to cross-talk between adipose and non-adipose tissues. Thus, the dissection of the specific pathways that contribute to insulin resistance in obese individuals is a crucial component in understanding obesity-linked T2D. In this review, recent in vitro and in vivo data that implicate the IKK (inhibitor of kappaB kinase)/NFkappaB pathway, a component of both fatty acid and inflammatory cytokine signaling cascades, in the regulation of insulin sensitivity are discussed, and the value of this pathway as a therapeutic target in T2D is evaluated. PMID: 19337955 [PubMed - indexed for MEDLINE] 1974. Curr Opin Organ Transplant. 2009 Feb;14(1):51-5. doi: 10.1097/MOT.0b013e328320d2cf. Adipose stem cells and solid organ transplantation. Tholpady SS(1), Ogle RC, Katz AJ. Author information: (1)Department of Plastic and Reconstructive Surgery, University of Virginia, Health Sciences Center, Charlottesville, Virginia, USA. PURPOSE OF REVIEW: This review will cover the basic research performed with adipose stem cells (ASCs) over the past several years as well as pertinent translational research. The properties of ASCs that make them particularly interesting to the transplant surgeon will then be covered. These properties include regeneration of native tissue, support of microvasculature, and immunomodulation. These properties will undoubtedly expand the future utility of these cells. RECENT FINDINGS: Recent literature demonstrates that ASCs are able to differentiate into phenotypes resembling hepatic and pancreatic lineages. In addition, several groups have shown that ASCs possess immunomodulatory properties similar to bone marrow-derived mesenchymal stem cells. Several clinical case reports also suggest that ASCs are an effective treatment option for graft-versus-host disease. SUMMARY: Due to their ability to differentiate into pertinent target lineages, their ability to enhance angiogenesis, and their ability to impact immunologic responses, ASCs may prove clinically useful for the transplant surgeon. PMID: 19337147 [PubMed - indexed for MEDLINE] 1975. J Endocrinol Invest. 2009 Jan;32(1):85-90. Growth and puberty in children with HIV infection. Majaliwa ES(1), Mohn A, Chiarelli F. Author information: (1)Department of Paediatrics, University of Chieti, 66100 Chieti, Italy. dr_esma@yahoo.com Children with perinatal HIV infection may present with clinical features of endocrine dysfunction such as growth failure and pubertal delay. Pediatric care providers and pediatric endocrinologists should implement appropriate preventive, screening, and therapeutic strategies to maximize survival and quality of life in these children. Growth and pubertal delay can be exacerbated by a variety of treatable infectious, endocrine, nutritional, and immunological disorders. Timely diagnosis and appropriate treatment of these conditions may lead to improvement or even normalization of growth and puberty. HIV-infected children with advanced disease should undergo periodic growth evaluation, including GH levels, IGF-I, IGF binding protein 3 and androgens, in order to identify subclinical endocrine dysfunction. However, little is known about the association between HIV infection and endocrine dysfunction in children. Highly active antiretroviral therapy may also be associated with endocrine dysfunction with consequences on growth and puberty. Growth retardation and pubertal delay are always seen in children with advanced HIV infection and are often related to the proinflammatory milieu found in advanced AIDS. Growth and pubertal impairment are markers of advanced disease and require proper evaluation. A dysregulation of the hypothalamic-pituitary axis, toxic or allergic drug reactions may play a role in growth and pubertal delay of HIV-infected children. These dysfunctions require careful monitoring, in order to assess metabolic alterations that may be important in regulation of growth among HIV infected children. Better understanding of the mechanisms leading to impairment of growth and puberty in children with perinatal HIV-1 infection might lead to appropriate treatment when required. PMID: 19337023 [PubMed - indexed for MEDLINE] 1976. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1195-209. doi: 10.1152/ajpendo.90958.2008. Epub 2009 Mar 31. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Takeuchi K(1), Reue K. Author information: (1)Dept. of Human Genetics, Gonda 6506A, David Geffen School of Medicine at UCLA, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Triacylglycerol (TAG) synthesis and storage in tissues such as adipose tissue and liver have important roles in metabolic homeostasis. The molecular identification of genes encoding enzymes that catalyze steps in TAG biosynthesis from glycerol 3-phosphate has revealed an unexpected number of protein isoforms of the glycerol phosphate acyltransferase (GPAT), acylglycerolphosphate acyltransferase (AGPAT), and lipin (phosphatidate phosphatase) families that appear to catalyze similar biochemical reactions. However, on the basis of available data for a few members in which genetic deficiencies in mouse and/or human have been studied, we postulate that each GPAT, AGPAT, and lipin family member likely has a specialized role that may be uncovered through careful biochemical and physiological analyses. PMCID: PMC2692402 PMID: 19336658 [PubMed - indexed for MEDLINE] 1977. Physiol Res. 2009;58(1):1-7. Fibroblast growth factor 21: a novel metabolic regulator with potential therapeutic properties in obesity/type 2 diabetes mellitus. Dostálová I(1), Haluzíková D, Haluzík M. Author information: (1)Third Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator produced primarily by the liver that exerts potent antidiabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes mellitus. This hormone contributes to body weight regulation and is strongly involved in the response to nutritional deprivation and ketogenic state in mice. The principal sites of metabolic actions of FGF21 are adipose tissue, liver and pancreas. Experimental studies have shown marked improvements in diabetes compensation and dyslipidemia after FGF21 administration in diabetic mice and primates. Positive metabolic actions of FGF21 without the presence of apparent side effects make this factor a hot candidate to treat type 2 diabetes and accompanying metabolic diseases. The aim of this review is to summarize the current knowledge about the metabolic effects of FGF21 including some preliminary data on changes of its levels in humans with a special emphasis on its therapeutic potential in type 2 diabetes mellitus. PMID: 19331512 [PubMed - indexed for MEDLINE] 1978. Am J Clin Nutr. 2009 May;89(5):1558S-1564S. doi: 10.3945/ajcn.2009.26736E. Epub 2009 Mar 25. The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis. Simon JA(1), Chen YH, Bent S. Author information: (1)General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center, San Francisco, CA, USA. joel.simon@ucsf.edu BACKGROUND: alpha-Linolenic acid (ALA; 18:3n-3) has been associated inconsistently with an increased risk of prostate cancer. Additional studies have become available since the publication of 2 previous meta-analyses. OBJECTIVE: The objective was to review the published data on the relation between ALA and prostate cancer. DESIGN: We conducted a systematic review to identify studies that included data on ALA and risk of prostate cancer. Data were pooled from studies that compared the highest ALA quantile with the lowest ALA quantile, and risk estimates were combined by using a random-effects model. RESULTS: The relation between ALA and prostate cancer is inconsistent across studies. We pooled data from 8 case-control and 8 prospective studies. The summary estimate revealed that high ALA dietary intakes or tissue concentrations are weakly associated with prostate cancer risk (relative risk [RR]: 1.20; 95% CI: 1.01, 1.43). When examined by study type (ie, retrospective compared with prospective or dietary ALA compared with tissue concentration) or by decade of publication, only the 6 studies examining blood or tissue ALA concentrations revealed a statistically significant association. With the exception of these studies, there was significant heterogeneity and evidence of publication bias. After adjustment for publication bias, there was no association between ALA and prostate cancer (RR: 0.96; 95% CI: 0.79, 1.17). CONCLUSIONS: Studies examining the relation between ALA and prostate cancer have produced inconsistent findings. High ALA intakes or high blood and adipose tissue concentrations of ALA may be associated with a small increased risk of prostate cancer. However, these conclusions are qualified because of the heterogeneity across studies and the likelihood of publication bias. PMID: 19321563 [PubMed - indexed for MEDLINE] 1979. IUBMB Life. 2009 Apr;61(4):424-30. doi: 10.1002/iub.169. Adipose tissue: a motor for the inflammation associated with obesity. Vachharajani V(1), Granger DN. Author information: (1)Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Obesity is a worldwide epidemic that continues to grow at an alarming rate. This condition increases the morbidity and mortality associated with both acute and chronic diseases. Some of the deleterious consequences of obesity have been attributed to its induction of a low-grade chronic inflammatory state that arises from the production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. This review focuses on the mechanisms that underlie the proposed link between obesity and inflammation, and it addresses how obesity-induced inflammation may account for increased morbidity and mortality that is associated with a diverse group of diseases. PMCID: PMC2695566 PMID: 19319966 [PubMed - indexed for MEDLINE] 1980. Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E271-88. doi: 10.1152/ajpendo.90920.2008. Epub 2009 Mar 24. Lipoprotein lipase: from gene to obesity. Wang H(1), Eckel RH. Author information: (1)Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, USA. Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels in a tissue-specific manner. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL, and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. Ultimately, this leads to increased lipid partitioning to other tissues, insulin resistance, and obesity. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation. PMID: 19318514 [PubMed - indexed for MEDLINE] 1981. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1230-8. doi: 10.1152/ajpendo.90927.2008. Epub 2009 Mar 24. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Lee MJ(1), Fried SK. Author information: (1)Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA. This review summarizes recent advances in our understanding of the pre- and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMP-activated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5'- and 3'-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production. PMCID: PMC2692400 PMID: 19318513 [PubMed - indexed for MEDLINE] 1982. Pharmacol Ther. 2009 Jun;122(3):246-63. doi: 10.1016/j.pharmthera.2009.03.003. Epub 2009 Mar 24. Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Robinson E(1), Grieve DJ. Author information: (1)Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 3rd Floor, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL UK. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that belong to the nuclear receptor superfamily. Three isoforms of PPAR have been identified, alpha, delta and gamma, which play distinct roles in the regulation of key metabolic processes, such as glucose and lipid redistribution. PPARalpha is expressed predominantly in the liver, kidney and heart, and is primarily involved in fatty acid oxidation. PPARgamma is mainly associated with adipose tissue, where it controls adipocyte differentiation and insulin sensitivity. PPARdelta is abundantly and ubiquitously expressed, but as yet its function has not been clearly defined. Activators of PPARalpha (fibrates) and gamma (thiazolidinediones) have been used clinically for a number of years in the treatment of hyperlipidaemia and to improve insulin sensitivity in diabetes. More recently, PPAR activation has been found to confer additional benefits on endothelial function, inflammation and thrombosis, suggesting that PPAR agonists may be good candidates for the treatment of cardiovascular disease. In this regard, it has been demonstrated that PPAR activators are capable of reducing blood pressure and attenuating the development of atherosclerosis and cardiac hypertrophy. This review will provide a detailed discussion of the current understanding of basic PPAR physiology, with particular reference to the cardiovascular system. It will also examine the evidence supporting the involvement of the different PPAR isoforms in cardiovascular disease and discuss the current and potential future clinical applications of PPAR activators. PMID: 19318113 [PubMed - indexed for MEDLINE] 1983. Regen Med. 2009 Mar;4(2):265-73. doi: 10.2217/17460751.4.2.265. Adipose-derived stem/progenitor cells: roles in adipose tissue remodeling and potential use for soft tissue augmentation. Yoshimura K(1), Suga H, Eto H. Author information: (1)Department of Plastic Surgery, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. yoshimura-pla@h.u-tokyo.ac.jp Many features of adipose tissue-specific stem/progenitor cells, such as physiological function and localization, have recently been examined. Adipose-tissue turnover is very slow and its perivascular progenitor cells differentiate into adipocytes in the next generation. The progenitor cells play important roles in physiological turnover, hyperplasia and atrophy of adipose tissue, as well as in incidental remodeling, such as postinjury repair. Adipose tissue has been used as an autologous filler for soft tissue defects, despite unpredictable clinical results and a low rate of graft survival, which may be due to the relative deficiency of progenitor cells in graft materials. A novel transplantation strategy, termed cell-assisted lipotransfer, involves the enrichment of adipose progenitor cells in grafts; preliminary results suggest this approach to be safe and effective. PMID: 19317645 [PubMed - indexed for MEDLINE] 1984. Rev Med Liege. 2009 Jan;64(1):16-24. [Metabolically obese with normal weight individuals: an intriguing phenotype]. [Article in French] Beck E(1), Scheen AJ. Author information: (1)Service de Diabétologie, Nutrition et Maladies métaboliques et Unité de Pharmacologie clinique, Département de Medecine, CHU de Liege. Obesity, especially abdominal obesity, is the main risk factor of metabolic syndrome. However, there are obviously non obese individuals who are metabolically abnormal and therefore exposed to an increased risk of cardiovascular complications. Unfortunately, those persons fail to be detected because of a falsely reassuring body weight. The present paper aims at better understanding the etiopathogenesis and pathophysiology of this particular phenotype, at evaluating its potential clinical consequences and at describing the main principles of its therapeutic management. PMID: 19317097 [PubMed - indexed for MEDLINE] 1985. Clin Plast Surg. 2009 Apr;36(2):195-209, v-vi; discussion 211-3. doi: 10.1016/j.cps.2008.11.001. Refinement of technique in injection lipolysis based on scientific studies and clinical evaluation. Duncan D(1), Rubin JP, Golitz L, Badylak S, Kesel L, Freund J, Duncan D. Author information: (1)Private Practice, Ft. Collins, CO, USA. momsurg@aol.com The unusual evolution of the practice of injection lipolysis has generated doubt regarding its safety and efficacy among many physicians. During the early years of this decade, mesotherapy was practiced by a few physicians, but the practice was not widespread. Paramedical practitioners and business developers saw the market potential for nonsurgical fat reduction, and the practice of injection lipolysis was packaged and sold before the mechanism of action was understood. Because of the early lack of scientific research and understanding of the limitations of injection lipolysis, many unsuitable patients were treated with this modality. To better understand the way injection lipolysis works, the inclusion and exclusion criteria for patients desiring treatment, and an accurate clinical evaluation format for potential treatment regions, a series of scientific studies was performed in 2007 and early 2008. These studies included a serial histopathology evaluation of treated patients over time, a stem cell study performed with the McGowan Research Institute in Pittsburgh, an animal study performed in conjunction with the Colorado State University veterinary school, and a prospective multicenter clinical trial using injection lipolysis in the back roll region. The purpose of these studies was to determine the way injection lipolysis works, how modifications of the formula and technique change the outcome, the role of each constituent component of various formulas, and the degree of fat reduction and skin retraction that is attainable with these treatments. The influence of depth of injection, distance between injection points, volume of injection, and ratios of constituent components was studied. The degree of topographic contour correction and the amount of volume reduction were evaluated. Following a review of these recent studies, an updated recommendation for the clinical practice of injection lipolysis was formulated. PMID: 19309643 [PubMed - indexed for MEDLINE] 1986. Curr Opin Endocrinol Diabetes Obes. 2009 Apr;16(2):178-82. Dead adipocytes and metabolic dysfunction: recent progress. West M(1). Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. mwest12@jhmi.edu PURPOSE OF REVIEW: Dead adipocytes are at the heart of crown-like structures (CLSs), which represent a still relatively novel interface of adipocytes and adipose tissue macrophages (ATMs) and may be significant to human health conditions such as obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular disease. In order to provide a concise and pertinent discussion, this review highlights recent reports examining CLSs and projects the likely directions of future research in this budding and fascinating field. RECENT FINDINGS: In mice, there is recent progress in understanding the differences in distribution of two distinct phenotypes of ATM classes with respect to dead adipocytes. Furthermore, a detailed atlas of fat depot-specific differences in adipocyte size and CLS prevalence has begun in two genetic models of mouse obesity. In humans, fat cell aging and turnover have been quantified. The correlation between human CLSs and early cardiovascular disease has also been established. The predominant ATM phenotype in obese humans may be M2, which would contrast with the M1 ATMs of obese mouse models. Finally, osteopontin has been established in both humans and mice as an important macrophage chemoattractant to dead adipocytes, in addition to monocyte chemoattractant protein 1 and C-C motif chemokine receptor 2. SUMMARY: Recent updates in research on dead adipocytes and the biology of CLSs with clinical implications for metabolic dysfunction are discussed. PMID: 19306530 [PubMed - indexed for MEDLINE] 1987. J Cardiopulm Rehabil Prev. 2009 Mar-Apr;29(2):67-75. doi: 10.1097/HCR.0b013e318199ff69. Resistance training in the treatment of diabetes and obesity: mechanisms and outcomes. Tresierras MA(1), Balady GJ. Author information: (1)Boston University School of Medicine, Boston, Massachusetts, USA. Resistance exercise training (RET) is gaining broad acceptance as a complement to endurance exercise in the treatment of cardiovascular risk factors. This article reviews the most current and reliable literature regarding the biological mechanisms and potential clinical effectiveness of RET in the treatment of 2 major cardiovascular risk factors, diabetes and obesity, obtained from human subject studies found by querying MEDLINE Plus/Ovid literature search system for the years 1950-2008. RET appears to enhance insulin sensitivity and improve glucose tolerance in a wide range of study groups. In addition, studies have shown that improved glucose uptake is not a mere consequence of the typical increase in fat-free mass associated with RET but is likely a result of qualitative changes in resistance-trained muscle. There is also substantial evidence that regular RET can effectively alter body composition in both men and women. It has been shown to increase total fat-free mass, muscular strength, and resting metabolic rate, and preferentially mobilize the visceral and subcutaneous adipose tissue in the abdominal region. The studies presented in this review demonstrate that RET should remain an important focus of translational research, where clinical trials of RET encourage the performance of mechanistic studies and where mechanistic studies lead to further clinical trials. PMID: 19305230 [PubMed - indexed for MEDLINE] 1988. J Cardiol. 2009 Apr;53(2):155-63. doi: 10.1016/j.jjcc.2009.01.003. Epub 2009 Feb 10. Autologous adipose tissue as a new source of progenitor cells for therapeutic angiogenesis. Murohara T(1). Author information: (1)Department of Cardiology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. murohara@med.nagoya-u.ac.jp Therapeutic angiogenesis is an important means for salvaging tissues from severe ischemic diseases in patients with no option for other vascular interventions. A number of recent studies examined the possibilities of cell transplantation-mediated angiogenesis using autologous bone marrow mononuclear cells, CD34(+) cells, peripheral mononuclear cells, etc. Subcutaneous adipose tissue can be harvested by relatively easy technology. Recent studies indicate that adipose tissue contains progenitor cells that can give rise to several mesenchymal lineages. Moreover, these progenitor cells can release multiple angiogenic growth factors including vascular endothelial growth factor, hepatocyte growth factor, and chemokine stromal cell-derived factor. The combination of these biological properties of adipose-derived regenerative cells indicates that autologous adipose tissue will be a useful cell source for therapeutic angiogenesis. PMID: 19304117 [PubMed - indexed for MEDLINE] 1989. Prog Lipid Res. 2009 May-Jul;48(3-4):196-205. doi: 10.1016/j.plipres.2009.03.002. Epub 2009 Mar 20. Glycosphingolipids and insulin resistance. Langeveld M(1), Aerts JM. Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple sphingolipid, directly inhibits phosphorylation of the insulin signaling mediator Akt/Protein Kinase B. More complex glycosphingolipids, so-called gangliosides, block phosphorylation of the insulin receptor and down-stream signaling, possibly by exclusion of the insulin receptor from specific membrane domains. Pharmacological inhibition of glycosphingolipid synthesis is found to markedly improve insulin sensitivity in rodent models of insulin resistance. Partial glycosphingolipid reduction is well tolerated and may thus offer an attractive new treatment modality for obesity-induced insulin resistance and type II diabetes. PMID: 19303901 [PubMed - indexed for MEDLINE] 1990. Hypertens Res. 2009 May;32(5):321-4. doi: 10.1038/hr.2009.29. Epub 2009 Mar 20. Effects of eplerenone, a selective mineralocorticoid receptor antagonist, on clinical and experimental salt-sensitive hypertension. Takeda Y(1). Author information: (1)Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. takeday@ med.kanazawa-u.ac.jp Mineralocorticoid receptors (MRs) are expressed in non-epithelial tissues, such as blood vessels, the heart and adipose tissue. The combined effects of aldosterone and insulin link the metabolic syndrome with hypertension and salt sensitivity. Eplerenone is the newly developed inhibitor of MRs that has significantly fewer adverse effects than similar doses of spironolactone. Eplerenone has been reported to have anti-hypertensive and protective effects on cardiovascular and renal injury in salt-sensitive hypertensive animal models, such as the Dahl salt-sensitive (DS) hypertensive rat and leptin receptor-deficient spontaneously hypertensive rat (SHR/cp). Eplerenone also increases nitric oxide bioavailability and improves impaired endothelial function by decreasing oxidative stress. Clinical studies support the concept that eplerenone is effective for the treatment of salt-sensitive hypertension as well as idiopathic hyperaldosteronism and does not have adverse anti-androgenic adverse effects. In Japan, eplerenone has been used clinically since 2007 for the treatment of hypertension, with its price being marginally lower than all types of angiotensin II receptor antagonists. This will inevitably result in an increasing number of hypertensive patients and those with primary aldosteronism being treated with this agent in the near future. PMID: 19300447 [PubMed - indexed for MEDLINE] 1991. Expert Rev Cardiovasc Ther. 2009 Mar;7(3):281-8. doi: 10.1586/14779072.7.3.281. The emerging obesity problem in Latin America. Cuevas A(1), Alvarez V, Olivos C. Author information: (1)Clinica Las Condes, Lo Fontecilla 441, Las Condes, Santiago, Chile. acuevas@clinicalascondes.cl Obesity and overweight prevalence is increasing rapidly in Latin America. This increase has been attributed to lifestyle changes occurring in recent decades related to rapid socioeconomic development, including a more Westernized diet, physical inactivity, urbanization, rural-urban migration and some maternal-fetal factors. In addition, genetic factors may have a role, inducing a higher predisposition to accumulate abdominal fat and develop metabolic syndrome. This increase in obesity and metabolic syndrome is leading to higher morbidity and mortality due to Type 2 diabetes and cardiovascular disease. In a few poor countries, obesity coexists with undernutrition, making the situation even more difficult. Global intervention, from both governments and nongovernmental organizations, is necessary. They must play an active role, monitoring the food market and facilitating community-based initiatives that promote a healthy lifestyle. PMID: 19296766 [PubMed - indexed for MEDLINE] 1992. J Mol Med (Berl). 2009 Jul;87(7):663-8. doi: 10.1007/s00109-009-0459-y. Epub 2009 Mar 17. The dysregulation of the endocannabinoid system in diabesity-a tricky problem. Scherer T(1), Buettner C. Author information: (1)Department of Medicine and Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, P.O. Box 1055, New York, NY 10029-6574, USA. Endocannabinoids (ECs) are small lipid mediators that play a critical role in energy metabolism. Human studies have shown that the EC tone in peripheral tissues positively correlates with increased adiposity. Furthermore, pharmacological inhibition of EC signaling results in weight loss in humans. However, the mechanisms that cause the dysregulation of the EC system in obesity are not well-understood. Since the clinical utility of currently available EC blockers is severely limited due to their side effects like depression and suicidal ideation that are caused by central effects, it is important to delineate the role of central and peripheral effects of EC signaling in regulating glucose and lipid metabolism. PMCID: PMC3253348 PMID: 19290485 [PubMed - indexed for MEDLINE] 1993. Eur Psychiatry. 2009 Apr;24(3):164-70. doi: 10.1016/j.eurpsy.2009.01.001. Epub 2009 Mar 14. How can antipsychotics cause Diabetes Mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins. Starrenburg FC(1), Bogers JP. Author information: (1)Rivierduinen Psychiatric Centre, Midden Holland District, JP Thijsselaan 45, 2803RT Gouda, Netherlands. f.starrenburg@ggzmiddenholland.nl The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle. PMID: 19285836 [PubMed - indexed for MEDLINE] 1994. Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):87-102. doi: 10.1016/j.beem.2008.10.012. The role of the pancreatic endocannabinoid system in glucose metabolism. Bermúdez-Silva FJ(1), Suárez Pérez J, Nadal A, Rodríguez de Fonseca F. Author information: (1)Laboratorio de Medicina Regenerativa, Fundación IMABIS, Hospital Carlos Haya, Avda. Carlos Haya, Pabellón de Gobierno, sótano, 29010, Málaga, Spain. franciscoj.bermudez@fundacionimabis.org The endogenous cannabinoid system participates in the regulation of energy homeostasis, and this fact led to the identification of a new group of therapeutic agents for complicated obesity and diabetes. Cannabinoid receptor antagonists are now realities in clinical practice. The use of such antagonists for reducing body weight gain, lowering cholesterol and improving glucose homeostasis is based on the ability of the endocannabinoids to coordinately regulate energy homeostasis by interacting with central and peripheral targets, including adipose tissue, muscle, liver and endocrine pancreas. In this review we will analyse the presence of this system in the main cell types of the islets of Langerhans, as well as the physiological relevance of the endocannabinoids and parent acylethanolamides in hormone secretion and glucose homeostasis. We will also analyse the impact that these findings may have in clinical practice and the potential outcome of new therapeutic strategies for modulating glucose homeostasis and insulin/glucagon secretion. PMID: 19285263 [PubMed - indexed for MEDLINE] 1995. Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):79-86. doi: 10.1016/j.beem.2008.10.005. The role of the endocannabinoid system in the regulation of energy expenditure. Cavuoto P(1), Wittert GA. Author information: (1)Discipline of Medicine, School of Medicine, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia 5000, Australia. Endocannabinoids, a lipid-derived signaling system, regulate appetite and motivation to eat via effects in the hypothalamus and nucleus accumbens. Not all the effects of endocannabinoids on fat mass can be explained by the regulation of food intake alone. Endocannabinoids and their receptors are located in areas of the central nervous system and multiple peripheral tissues involved in the regulation of intermediary metabolism and energy expenditure. In addition to regulating food intake by both central and peripherally mediated effects, endocannabinoids modify glucose and lipid metabolism so as to promote energy storage via lipogenesis and reduce energy expenditure. The endocannabinoid system appears to be overactive in obesity and may serve to maintain fat mass and underlies some of the metabolic consequences of obesity. Inhibition of the cannabinoid type-1 receptor ameliorates the effects of endocannabinoids on food intake and energy metabolism; lipogenesis is inhibited, lipolysis, fatty acid oxidation and glucose uptake increase. PMID: 19285262 [PubMed - indexed for MEDLINE] 1996. Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):51-63. doi: 10.1016/j.beem.2008.10.002. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Vettor R(1), Pagano C. Author information: (1)Internal Medicine 3, Endocrine-metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padova, via Ospedale 105, 35128 Padova, Italy. denis.richard@crhl.ulaval.ca Endocannabinoids (ECs) regulate energy balance by modulating hypothalamic circuits controlling food intake and energy expenditure. However, convincing evidence has accumulated indicating that the EC system is present also in peripheral tissues, in particular in adipose tissue. Fat cells produce and are targets of ECs. Glucose uptake and lipoprotein lipase (LPL) activity, lipogenesis and adipogenesis are stimulated by ECs through cannabinoid 1 (CB1) receptors. Moreover, CB1 activation leads to a decreased mitochondrial biogenesis and function through inhibition of endothelial nitric oxide synthase (eNOS). All these effects are blocked by the CB1 antagonist rimonabant, suggesting that the weight-reducing effect of CB1 blockade is due not only to the transient suppression of food intake and reduction of lipogenesis but also to an increased mitochondrial biogenesis and oxidative metabolism which counteracts the inhibitory effects of ECs, levels of which are increased in fat tissues of obese rodents and humans. This review focuses on the role of ECs in adipose tissue metabolism, adipokine production, and interactions between ECs and peroxisome proliferator-activated receptors (PPARs) during adipogenesis. PMID: 19285260 [PubMed - indexed for MEDLINE] 1997. Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):33-49. doi: 10.1016/j.beem.2008.10.003. Role of acylethanolamides in the gastrointestinal tract with special reference to food intake and energy balance. Borrelli F(1), Izzo AA. Author information: (1)Department of Experimental Pharmacology, University of Naples Federico II and Endocannabinoid Research Group, via D. Montesano 49, 80131 Naples, Italy. Acylethanolamides (AEs) are a group of lipids occurring in both plants and animals. The best-studied AEs are the endocannabinoid anandamide (AEA), the anti-inflammatory compound palmitoylethanolamide (PEA), and the potent anorexigenic molecule oleoylethanolamide (OEA). AEs are biosynthesized in the gastrointestinal tract, and their levels may change in response to noxious stimuli, food deprivation or diet-induced obesity. The biological actions of AEs within the gut are not limited to the modulation of food intake and energy balance. For example, AEs exert potential beneficial effects in the regulation of intestinal motility, secretion, inflammation and cellular proliferation. Molecular targets of AEs, which have been identified in the gastrointestinal tract, include cannabinoid CB(1) and CB(2) receptors (activated by AEA), transient receptor potential vanilloid type 1 (TRPV1, activated by AEA and OEA), the nuclear receptor peroxisome proliferators-activated receptor-alpha (PPAR-alpha, activated by OEA and, to a less extent, by PEA), and the orphan G-coupled receptors GPR119 (activated by OEA) and GPR55 (activated by PEA and, with lower potency, by AEA and OEA). Modulation of AE levels in the gut may provide new pharmacological strategies not only for the treatment of feeding disorders but also for the prevention or cure of widespread intestinal diseases such as inflammatory bowel disease and colon cancer. PMID: 19285259 [PubMed - indexed for MEDLINE] 1998. J Sex Med. 2009 Mar;6 Suppl 3:320-7. doi: 10.1111/j.1743-6109.2008.01190.x. Potential of adipose-derived stem cells for treatment of erectile dysfunction. Lin G(1), Banie L, Ning H, Bella AJ, Lin CS, Lue TF. Author information: (1)School of Medicine, Department of Urology, University of California-Knuppe Molecular Urology Laboratory, San Francisco, CA 94143-0738, USA. glin@urology.ucsf.edu INTRODUCTION: Adipose-derived stem cells (ADSCs) are a somatic stem cell population contained in fat tissue that possess the ability for self-renewal, differentiation into one or more phenotypes, and functional regeneration of damaged tissue, which may benefit the recovery of erectile function by using a stem cell-based therapy. AIM: To review available evidence concerning ADSCs availability, differentiation into functional cells, and the potential of these cells for the treatment of erectile dysfunction (ED). METHODS: We examined the current data (from 1964 to 2008) associated with the definition, characterization, differentiation, and application of ADSCs, as well as other kinds of stem cells for the cell-based therapies of ED. MAIN OUTCOME MEASURES: There is strong evidence supporting the concept that ADSCs may be a potential stem cell therapy source in treating ED. RESULTS: The ADSCs are paravascularly localized in the adipose tissue. Under specific induction medium conditions, these cells differentiated into neuron-like cells, smooth muscle cells, and endothelium in vitro. The insulin-like growth factor/insulin-like growth factor receptor (IGF/IGFR) pathway participates in neuronal differentiation while the fibroblast growth factor 2 (FGF2) pathway is involved in endothelium differentiation. In a preliminary in vivo experiment, the ADSCs functionally recovered the damaged erectile function. However, the underlying mechanism needs to be further examined. CONCLUSION: The ADSCs are a potential source for stem cell-based therapies, which imply the possibility of an effective clinical therapy for ED in the near future. PMCID: PMC2895916 PMID: 19267855 [PubMed - indexed for MEDLINE] 1999. Nat Rev Immunol. 2009 Apr;9(4):259-70. doi: 10.1038/nri2528. Trophic macrophages in development and disease. Pollard JW(1). Author information: (1)Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 607, Bronx, New York 10461, USA. pollard@aecom.yu.edu Specialized phagocytes are found in the most primitive multicellular organisms. Their roles in homeostasis and in distinguishing self from non-self have evolved with the complexity of organisms and their immune systems. Equally important, but often overlooked, are the roles of macrophages in tissue development. As discussed in this Review, these include functions in branching morphogenesis, neuronal patterning, angiogenesis, bone morphogenesis and the generation of adipose tissue. In each case, macrophage depletion impairs the formation of the tissue and compromises its function. I argue that in several diseases, the unrestrained acquisition of these developmental macrophage functions exacerbates pathology. For example, macrophages enhance tumour progression and metastasis by affecting tumour-cell migration and invasion, as well as angiogenesis. PMCID: PMC3648866 PMID: 19282852 [PubMed - indexed for MEDLINE] 2000. Differentiation. 2009 Feb;77(2):115-20. doi: 10.1016/j.diff.2008.09.009. Epub 2008 Oct 21. New aspects of adipogenesis: radicals and oxidative stress. Gummersbach C(1), Hemmrich K, Kröncke KD, Suschek CV, Fehsel K, Pallua N. Author information: (1)Department of Plastic Surgery and Hand Surgery, Burn Centre, University Hospital of the RWTH Aachen University, 52074 Aachen, Germany. Preadipocytes are multipotent adipogenic precursor cells that can be isolated from mature adipose tissue. They have been receiving increasing attention in the context of obesity, type 2 diabetes, and other nutrition-associated diseases. Understanding the physiological and pathophysiological processes in fat neo-formation, energy homeostasis, and adipose tissue physiology is the basis for research on metabolic diseases and the respective pharmaceutical intervention. While the hormonal influence on intracellular signaling in adipogenesis has been intensively investigated, the effects of free radical formation and oxidative stress have just started to gain scientific attention. This review summarizes the present knowledge on the main molecular pathways in preadipocyte maturation and focuses on recent findings indicating that besides hormonal stimuli reactive oxygen species (ROS) and free radicals may also interact with preadipocyte differentiation. PMID: 19281770 [PubMed - indexed for MEDLINE] 2001. Cell Mol Life Sci. 2009 Jul;66(13):2067-73. doi: 10.1007/s00018-009-0003-9. Epub 2009 Mar 11. Fibroblast growth factor 21: an overview from a clinical perspective. Rydén M(1). Author information: (1)Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, 141 86, Huddinge, Stockholm, Sweden. mikael.ryden@ki.se Fibroblast growth factor 21 (FGF21) has been proposed as a novel putative therapeutic agent in type 2 diabetes. A large amount of data, predominantly obtained from murine models but also from non-human primates, suggest that FGF21 ameliorates obesity-associated hyperglycemia and hyperlipidemia primarily via effects on adipose tissue and the pancreas. In addition, FGF21 has been reported to play a pivotal regulatory role in starvation and ketosis. However, while it is clear that FGF21 has potent effects in vivo in several animal models, the exact mechanisms remain elusive. Moreover, very recent results from different human cohort studies have shown a paradoxical regulation of plasma FGF21 in obesity and type 2 diabetes as well as other important qualitative differences in the effects and regulation of FGF21 between rodents and humans. This review focuses on the most recently published data on FGF21 with emphasis on results obtained in humans. PMID: 19277467 [PubMed - indexed for MEDLINE] 2002. Curr Opin Lipidol. 2009 Apr;20(2):127-34. doi: 10.1097/MOL.0b013e3283292399. Chronobiology, genetics and metabolic syndrome. Garaulet M(1), Madrid JA. Author information: (1)Department of Physiology, University of Murcia, Murcia, Spain. garaulet@um.es PURPOSE OF REVIEW: Circadian rhythms are such an innate part of our lives that we rarely pause to speculate why they even exist. Recently, some studies have suggested that the disruption of the circadian system may be causal for the manifestations of metabolic syndrome (MetS). This review summarizes the latest evidence of the existing interaction among chronobiology, genetics and MetS. RECENT FINDINGS: Shift work, sleep deprivation and bright light exposure at night are related to increased adiposity and prevalence of MetS. Animal models have revealed that mice with circadian locomotor output cycles kaput (clock) gene disruption are prone to develop a phenotype resembling MetS. Moreover, studies in humans have shown that clock genes are expressed in adipose tissue, and that both their levels of expression and their genetic variants correlate with different components of the MetS. Current studies are illustrating the particular role of different clock gene variants and their predicted haplotypes in MetS. SUMMARY: The circadian system has an important impact on metabolic disturbances and vice versa. Although the precise mechanism linking the MetS to chronodisruption is not well known, hypotheses point to the internal desynchronization between different circadian rhythms. The novelty of this area of research is contributing to the development of new and intriguing studies, particularly those focused on the association between different clock genes polymorphisms and MetS traits. PMID: 19276891 [PubMed - indexed for MEDLINE] 2003. Endocr Metab Immune Disord Drug Targets. 2009 Mar;9(1):38-46. p38 mitogen-activated protein kinase: a critical node linking insulin resistance and cardiovascular diseases in type 2 diabetes mellitus. Liu Z(1), Cao W. Author information: (1)Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA. zl3e@virginia.edu Type 2 diabetes is associated with insulin resistance, endothelial dysfunction and accelerated atherosclerotic diseases. Though underlying mechanisms remain to be unraveled, p38 mitogen-activated protein kinase (MAPK) appears to play important roles in their pathogenesis. As a member of the MAPK family, it regulates the activities of many transcription factors and proteins/enzymes and thus has a wide-spectrum of biological effects. Patients with insulin resistance and/or type 2 diabetes have high levels of plasma free fatty acids, inflammatory cytokines, and/or glucose, and over-activation of the cardiovascular renin-angiotensin system, all are capable of activating p38 MAPK. p38 MAPK plays a central role in hepatic glucose and lipid metabolism, leading to increased hepatic glucose production and decreased hepatic lipogenesis. The roles of p38 MAPK in insulin-mediated glucose uptake in skeletal muscle and adipose tissue remain controversial. p38 MAPK also mediates inflammatory processes and cell apoptosis. Recent evidence suggests that p38 MAPK may be the key node linking cardiovascular insulin resistance, endothelial dysfunction and the pathogenesis of atherosclerotic diseases through its influences on monocytes/macrophages, vascular endothelial cells, and vascular smooth muscle cells in type 2 diabetes. In addition, p38 MAPK also contributes significantly to cardiac injury during ischemia-reperfusion. PMID: 19275680 [PubMed - indexed for MEDLINE] 2004. Curr Protein Pept Sci. 2009 Feb;10(1):75-84. Angiotensin II in type 2 diabetes mellitus. Chu KY(1), Leung PS. Author information: (1)Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Angiotensin II (Ang II) is well-known as a systemic vasoconstrictor but recently a novel role for the peptide in endocrine function has been suggested and it has been linked to the pathophysiology of type 2 diabetes mellitus. According to several large-scale clinical studies, blocking Ang II prevented the onset of type 2 diabetes in potential patients. Type 2 diabetes is a complicated disease that is primarily characterized by insulin resistance and relative insulin deficiency mediated by numerous organs. Among these organs, the pancreas, adipose tissue, skeletal muscle and liver are the most prominent in maintaining glucose homeostasis. Interestingly, locally generated Ang II has been identified in these organs, where it plays different physiological roles and is produced in relatively high amounts with significant function. In type 2 diabetic human patients or animal models, Ang II, its generating enzymes and receptors are up-regulated and trigger detrimental effects. Moreover, Ang II seems to play roles in the regulation of insulin secretion by the pancreatic beta-cell and insulin sensitivity by peripheral tissues, which are two critical factors contributing to the development of type 2 diabetes. Accordingly, inhibiting Ang II produced beneficial effects on individual organs and throughout the body. Therefore, the present review discusses the role of Ang II in particular organs during normal physiological conditions as well as in type 2 diabetes. PMID: 19275674 [PubMed - indexed for MEDLINE] 2005. Curr Protein Pept Sci. 2009 Feb;10(1):56-74. The endocannabinoid system: a promising target for the management of type 2 diabetes. Scheen AJ(1). Author information: (1)Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, CHU Sart Tilman, University of Liege, Liege, Belgium. andre.scheen@chu.ulg.ac.be Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease. PMID: 19275673 [PubMed - indexed for MEDLINE] 2006. Front Biosci (Landmark Ed). 2009 Jan 1;14:4658-72. AMP-activated protein kinase and muscle insulin resistance. Kraegen EW(1), Bruce C, Hegarty BD, Ye JM, Turner N, Cooney G. Author information: (1)Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia. e.kraegen@garvan.org.au The Metabolic Syndrome, which includes obesity and type 2 diabetes, is reaching alarming proportions. A key factor is insulin resistance, defined as a reduced ability of insulin to stimulate glucose utilization and storage. Compelling evidence links insulin resistance with an excess fatty acid supply over energy need, resulting in lipid accumulation in non-adipose tissues. The AMPK pathway plays a key role in sensing and regulating tissue energy metabolism, influencing fuel metabolism in tissues including muscle and liver. A number of its actions could improve muscle insulin sensitivity at least partly by increasing fatty acid oxidation and diminishing synthesis of malonyl CoA, glycerolipids, ceramide and other molecules linked to insulin resistance, although the extent of these effects, particularly in the human context, is uncertain. Secondly, its activation could bypass the metabolic block associated with insulin resistance. Thirdly, it is possible that a dysregulation of the AMPK pathway may itself contribute to the metabolic derangement associated with insulin resistance. These issues are important in considering the AMPK pathway as a therapeutic target in insulin resistant states. PMID: 19273380 [PubMed - indexed for MEDLINE] 2007. Front Biosci (Landmark Ed). 2009 Jan 1;14:1902-16. Cytokine Regulation of AMPK signalling. Steinberg GR(1), Watt MJ, Febbraio MA. Author information: (1)St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. gsteinberg@svi.edu.au The dynamic control of energy metabolism is dependent on balancing energy demand with energy supply. In mammals this balance is maintained through the integration of many different cytokine signals that communicate the nutrient status of the organism to the hypothalamus, liver and skeletal muscle. Adipose tissue and resident macrophages secrete many of these cytokine factors including leptin, tumour necrosis factor a, adiponectin, interleukin-6 and resistin. Other secreted factors including ciliary neurotrophic factor and ghrelin have also been shown to regulate energy metabolism. The AMP-activated protein kinase (AMPK) has emerged as an important integrator of these cytokine signals regulating both central and peripheral pathways controlling food intake, energy expenditure and substrate utilization and as such is the focus of this review. PMID: 19273172 [PubMed - indexed for MEDLINE] 2008. Front Biosci (Landmark Ed). 2009 Jan 1;14:210-24. Stromal cells. Vayssade M(1), Nagel MD. Author information: (1)CNRS UMR 6600, Technological University of Compiegne, BP 20529 60205 Compiegne Cedex, France. Stromal cells, or mesenchymal stem cells, are adherent clonogenic cells that can form colonies. They are mainly isolated from bone marrow but can also be found in umbilical cord blood, adipose tissues and amniotic fluids. These stem cells are easy to culture in vitro, and can differentiate into osteoblasts, chondrocytes, or adipocytes when stimulated appropriately. When seeded on a natural (titanium, ceramics, collagen fibers, silk, etc.) or synthetic (PLLA, PLGA, etc.) biomaterial scaffold, they adhere and differentiate to form a new tissue. Many studies have also explored stromal cell differentiation in bioreactors to form a 3-dimensional culture. This review focuses on the biomaterials used for tissue engineering with stromal cells. PMID: 19273064 [PubMed - indexed for MEDLINE] 2009. Front Biosci (Landmark Ed). 2009 Jan 1;14:19-44. AMPK: Lessons from transgenic and knockout animals. Viollet B(1), Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, Lantier L, Hebrard S, Devin-Leclerc J, Beauloye C, Foretz M, Andreelli F, Ventura-Clapier R, Bertrand L. Author information: (1)Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Department Endocrinology, Metabolism and Cancer, Paris, France. viollet@cochin.inserm.fr AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been proposed to function as a fuel gauge to monitor cellular energy status in response to nutritional environmental variations. AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Numerous observations obtained with pharmacological activators and agents that deplete intracellular ATP have been supportive of AMPK playing a role in the control of energy metabolism but none of these studies have provided conclusive evidence. Relatively recent developments in our understanding of precisely how AMPK complexes might operate to control energy metabolism is due in part to the development of transgenic and knockout mouse models. Although there are inevitable caveats with genetic models, some important findings have emerged. In the present review, we discuss recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway. PMCID: PMC2666987 PMID: 19273052 [PubMed - indexed for MEDLINE] 2010. Trends Endocrinol Metab. 2009 Apr;20(3):107-14. doi: 10.1016/j.tem.2008.11.005. Epub 2009 Mar 9. New developments in adipogenesis. Lefterova MI(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. The obesity epidemic has focused attention on adipose tissue and the development of fat cells (i.e. adipocytes), which is known as adipogenesis. Peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding proteins have emerged as master regulators of adipogenesis, and recent genome-wide studies have indicated widespread overlap in their transcriptional targets. In addition, new evidence has implicated many other factors as positive and negative regulators of adipocyte development. This review highlights recent advances in the field of adipogenesis, including newly identified determinants of brown adipocytes, the function of which is to burn rather than store energy. Improved understanding of brown and white adipocyte origins and the integrative biology of adipogenesis might lead to more effective strategies for the treatment of obesity and metabolic disease. PMID: 19269847 [PubMed - indexed for MEDLINE] 2011. Rev Esp Cardiol. 2009 Mar;62(3):294-304. Knowledge of the biological actions of extra virgin olive oil gained from mice lacking apolipoprotein E. [Article in English, Spanish] Guillén N(1), Acín S, Navarro MA, Surra JC, Arnal C, Lou-Bonafonte JM, Muniesa P, Martínez-Gracia MV, Osada J. Author information: (1)CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain. The low incidence of cardiovascular disease in countries bordering the Mediterranean basin, where olive oil is the main source of dietary fat, has stimulated interest in the chemical composition of olive oil and in the production of other oils enriched with its minor components. This review summarizes what has been learned about the effects of different olive oil preparations on the development of atherosclerosis and about the prognostic value of associated plasma variables in the disease from experiments on genetically modified mice that spontaneously develop atherosclerosis. The limitations of this animal model associated with its morphological and physiological differences with humans are minimized by the similarity of the two genomes and by the potential for increased understanding attainable, given that the dietary interventions reported here would have taken 400 years to achieve in humans. As observed in traditional Mediterranean populations, it has been confirmed that extra virgin olive oil is beneficial when consumed judiciously and in a diet that is low in cholesterol due to the relative scarcity of animal products. Furthermore, the use of genomic techniques has led to the identification of new markers of response to olive oil. In conclusion, multidisciplinary research into extra virgin olive oil is expanding our knowledge of the substance's biological properties. PMID: 19268075 [PubMed - indexed for MEDLINE] 2012. Hypertens Res. 2009 Apr;32(4):229-37. doi: 10.1038/hr.2009.5. Epub 2009 Feb 27. Inhibition of the renin-angiotensin system and target organ protection. Iwanami J(1), Mogi M, Iwai M, Horiuchi M. Author information: (1)Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan. The renin-angiotensin system (RAS) is involved in the pathological mechanisms of target organ damage, as well as in the induction of hypertension. RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers can prevent tissue damage by inhibition of Ang II type 1 receptor signaling. A beneficial effect of RAS inhibition on the heart, vasculature and kidney in cardiovascular disease has been reported. However, RAS inhibition can also prevent fibroproliferative diseases and damage of other tissues, such as brain, adipose tissue and muscle, because local RAS has an important role in tissue damage compared with circulating RAS. Moreover, other players, such as Ang II type 2 receptor signaling, aldosterone and ACE2 have been highlighted. Furthermore, there has also been a focus on the emerging concept of regulation of RAS, such as receptor-interacting proteins and receptor modifications, in the new discovery of therapeutic agents for tissue protection. The RAS has a pivotal role in various target organ damage, with complicated mechanisms; therefore, blockade of RAS may be therapeutically effective in preventing organ damage, as well as in having an antihypertensive effect. PMID: 19262496 [PubMed - indexed for MEDLINE] 2013. J Hypertens. 2009 Mar;27(3):441-51. doi: 10.1097/HJH.0b013e32831e13e5. Mechanisms of hypertension in the cardiometabolic syndrome. Redon J(1), Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, Mancia G. Author information: (1)University of Valencia, CIBER 06/03 Fisiopatología de la Obesidad y Nutrición, Institute of Health Carlos III, Madrid, Spain. josep.redon@uv.es Comment in J Hypertens. 2009 Oct;27(10):2116; author reply 2116-7. Arterial hypertension is often part of a constellation of anthropometric and metabolic abnormalities that occur simultaneously to a higher degree than would be expected by chance alone, supporting the existence of a discrete disorder, the so-called metabolic syndrome. It is the result of interactions among a large number of interconnected mechanisms, which eventually lead to both an increase in cardiovascular and renal risk, and the development of diabetes. Mechanisms involved in the metabolic syndrome are obesity, insulin resistance, and a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with pro-inflammatory properties. At each of these key points are interactions of demographics, lifestyle, genetic factors, and environmental fetal programming. Superimposing upon these are infections or chronic exposure or both to certain drugs that can also make their contribution. Skeletal muscle and the liver, not adipose tissue, are the two key insulin-response tissues involved in maintaining glucose balance, although abnormal insulin action in the adipocytes also plays a role in development of the syndrome. Factors commonly associated with and partly dependent on obesity, insulin resistance, such as overactivity of the sympathetic, stimulation of the renin-angiotensin-aldosterone systems, abnormal renal sodium handling, endothelial dysfunction, and large vessels' alterations, may play a key role in the blood pressure elevation of the syndrome. PMID: 19262221 [PubMed - indexed for MEDLINE] 2014. Circ J. 2009 Apr;73(4):608-14. Epub 2009 Mar 3. Adiponectin and cardiovascular disease. Shibata R(1), Ouchi N, Murohara T. Author information: (1)Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. rshibata@med.nagoya-u.ac.jp Obesity is strongly associated with metabolic and cardiovascular disorders. Adiponectin is an adipose-derived plasma protein that is downregulated in subjects with obesity-related disorders. Low levels of adiponectin are associated with the increased prevalence of obesity-linked cardiovascular diseases, including ischemic heart disease and peripheral artery disease. Experimental findings have shown that adiponectin has beneficial effects in the cardiovascular system by directly acting on the component cells of the heart and blood vessels. Adiponectin protects cardiovascular tissues under conditions of stress through a number of mechanisms: inhibition of pro-inflammatory and hypertrophic responses, and stimulation of endothelial cell responses. These effects of adiponectin are mainly attributed to the modulation of signaling molecules, including AMP-activated protein kinase. Thus, adiponectin could be a promising therapeutic target for cardiovascular diseases. PMID: 19261992 [PubMed - indexed for MEDLINE] 2015. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1210-29. doi: 10.1152/ajpendo.00015.2009. Epub 2009 Mar 3. Getting the message across: mechanisms of physiological cross talk by adipose tissue. Lee DE(1), Kehlenbrink S, Lee H, Hawkins M, Yudkin JS. Author information: (1)Department of Internal Medicine, Division of Endocrinology, Winthrop University Hospital, London, United Kingdom. Obesity is associated with resistance of skeletal muscle to insulin-mediated glucose uptake, as well as resistance of different organs and tissues to other metabolic and vascular actions of insulin. In addition, the body is exquisitely sensitive to nutrient imbalance, with energy excess or a high-fat diet rapidly increasing insulin resistance, even before noticeable changes occur in fat mass. There is a growing acceptance of the fact that, as well as acting as a storage site for surplus energy, adipose tissue is an important source of signals relevant to, inter alia, energy homeostasis, fertility, and bone turnover. It has also been widely recognized that obesity is a state of low-grade inflammation, with adipose tissue generating substantial quantities of proinflammatory molecules. At a cellular level, the understanding of the signaling pathways responsible for such alterations has been intensively investigated. What is less clear, however, is how alterations of physiology, and of signaling, within one cell or one tissue are communicated to other parts of the body. The concepts of cell signals being disseminated systemically through a circulating "endocrine" signal have been complemented by the view that local signaling may similarly occur through autocrine or paracrine mechanisms. Yet, while much elegant work has focused on the alterations in signaling that are found in obesity or energy excess, there has been less attention paid to ways in which such signals may propagate to remote organs. This review of the integrative physiology of obesity critically appraises the data and outlines a series of hypotheses as to how interorgan cross talk takes place. The hypotheses presented include the "fatty acid hypothesis,", the "portal hypothesis,", the "endocrine hypothesis,", the "inflammatory hypothesis,", the "overflow hypothesis,", a novel "vasocrine hypothesis," and a "neural hypothesis," and the strengths and weaknesses of each hypothesis are discussed. PMID: 19258492 [PubMed - indexed for MEDLINE] 2016. Postepy Hig Med Dosw (Online). 2009 Feb 11;63:39-46. [Menopause, obesity, and bone status]. [Article in Polish] Ostrowska Z(1). Author information: (1)Zakład Biochemii Klinicznej w Zabrzu Slaskiego Uniwersytetu Medycznego w Katowicach, Poland. Recent studies indicate that obesity is not a risk factor of osteoporosis. On the contrary, increased adipose tissue mass may have a protective effect against osteoporosis. This suggests that the positive influence of adipose tissue on bone tissue may be a consequence of the boost in load on the bone tissue, leading to increased bone anabolism. It may also be connected with changes frequently occurring in postmenopausal women in the formation of some osteotropic factors, mainly hormones such as estrogens, androgens, calciotropic hormones, somatotrophin axis hormones, leptin, and melatonin. The antiresorption effects of the above hormones on the bone are to a considerable extent executed through the RANKL/RANK/OPG system (receptor activator of nuclear factor-kB ligand/receptor activator of nuclear factor-kB/osteoprotegerin), the principal signaling pathway through which osteoblasts regulate the rate of the activated osteoclast pool. This effect may be achieved through a direct effect on the expressions OPG and/or RANKL in osteoblasts and marrow stroma cells and/or indirectly through cytokines, mainly interleukins (IL)-1 and -6, tumor necrosis factor-alpha(TNF-alpha), macrophage colony-stimulating factor (M-CSF), and tumor necrosis factor-beta (TNF-beta). PMID: 19252463 [PubMed - indexed for MEDLINE] 2017. J Clin Pathol. 2009 Mar;62(3):206-11. doi: 10.1136/jcp.2007.049171. Adipokines and the clinical laboratory: what to measure, when and how? Hill MJ(1), Kumar S, McTernan PG. Author information: (1)Warwick Medical School, UK. This review summarises current experimental adipokine investigations and will focus on some of the procedures and techniques that are currently important in the clinical research laboratory. The complexity of measuring adipokines is discussed and the relative success of the various applications in the transition from the laboratory to clinical diagnosis assessed. In addition, as new adipokines continue to emerge, this review will consider the direction research is taking at the cutting edge of novel adipokine discovery. Finally, how a more comprehensive understanding of the pathobiology related to adipokines may enhance innovative therapeutic strategies designed to attenuate the predicted explosion in obesity related diseases will be discussed. PMID: 19251951 [PubMed - indexed for MEDLINE] 2018. Vitam Horm. 2009;80:613-33. doi: 10.1016/S0083-6729(08)00621-3. Interleukin-6 and insulin resistance. Kim JH(1), Bachmann RA, Chen J. Author information: (1)Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Chronic low-grade inflammation has been well recognized as a key feature of obesity that is correlated with insulin resistance and type 2 diabetes. Among the adipose-secreted factors (adipokines), the inflammatory regulator interleukin-6 (IL-6) has emerged as one of the potential mediators that link obesity-derived chronic inflammation with insulin resistance. Adipose tissue contributes to up to 35% of circulating IL-6, the systemic effects of which have been best demonstrated in the liver, where a STAT3-SOCS-3 pathway mediates IL-6 impairment of insulin actions. However, this cytokine displays pleiotropic functions in a tissue-specific and physiological context-dependent manner. In contrast to its role in liver, IL-6 is believed to be beneficial for insulin-regulated glucose metabolism in muscle. Furthermore, the effects of the cytokine are seemingly influenced by whether it is present acutely or chronically; the latter is the setting associated with insulin resistance. Herein we review the in vivo and in vitro studies that have examined the role of IL-6 in insulin signaling and glucose metabolism in the insulin target tissues: liver, adipose, and skeletal muscle. PMID: 19251052 [PubMed - indexed for MEDLINE] 2019. Vitam Horm. 2009;80:409-71. doi: 10.1016/S0083-6729(08)00615-8. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP). McIntosh CH(1), Widenmaier S, Kim SJ. Author information: (1)Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. Glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) is a 42 amino acid hormone that is produced by enteroendocrine K-cells and released into the circulation in response to nutrient stimulation. Both GIP and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion in a glucose-dependent manner and are thus classified as incretins. The structure of mammalian GIP is well conserved and both the N-terminus and central region of the molecule are important for biological activity. Following secretion, GIP is metabolized by the endoprotease dipeptidyl peptidase IV (DPP-IV). In addition to its insulinotropic activity, GIP exerts a number of additional actions including promotion of growth and survival of the pancreatic beta-cell and stimulation of adipogenesis. The brain, bone, cardiovascular system, and gastrointestinal tract are additional targets of GIP. The GIP receptor is a member of the B-family of G protein-coupled receptors and activation results in the stimulation of adenylyl cyclase and Ca(2+)-independent phospholipase A(2) and activation of protein kinase (PK) A and PKB. The Mek1/2-Erk1/2 and p38 MAP kinase signaling pathways are among the downstream pathways involved in the regulation of beta-cell function. GIP also increases expression of the anti-apoptotic Bcl-2 and decreases expression of the pro-apoptotic Bax, resulting in reduced beta-cell death. In adipose tissue, GIP interacts with insulin to increase lipoprotein lipase activity and lipogenesis. There is significant interest in potential clinical applications for GIP analogs and both agonists and antagonists have been developed for preclinical studies. PMID: 19251046 [PubMed - indexed for MEDLINE] 2020. Physiol Behav. 2009 May 25;97(2):199-204. doi: 10.1016/j.physbeh.2009.02.017. Epub 2009 Feb 27. Sex differences in the regulation of body weight. Shi H(1), Clegg DJ. Author information: (1)Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, OH 45237, USA. Obesity and its associated health disorders and costs are increasing. Males and females differ in terms of how and where body fat is stored, the hormones they secrete in proportion to their fat, and the way their brains respond to signals that regulate body fat. Fat accumulation in the intra-abdominal adipose depot is associated with the risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders. Men and postmenopausal women accumulate more fat in the intra-abdominal depot than do pre-menopausal women, and therefore have a greater risk of developing metabolic complications associated with obesity. The goal of this review is to explore what we know about sexual dimorphisms in adipose tissue accrual and deposition. Elucidating the mechanisms by which sex hormones may modulate the way in which fat is accumulated and stored is a critical area of research due to the prevalence of obesity and the metabolic syndrome, and the rapid increase in propensity for these diseases following menopause. PMID: 19250944 [PubMed - indexed for MEDLINE] 2021. Ann N Y Acad Sci. 2009 Feb;1155:121-31. doi: 10.1111/j.1749-6632.2009.03705.x. Regulation of aromatase expression in breast cancer tissue. Bulun SE(1), Lin Z, Zhao H, Lu M, Amin S, Reierstad S, Chen D. Author information: (1)Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-bulun@northwestern.edu Epithelial-stromal interactions play key roles for aromatase expression and estrogen production in breast cancer tissue. Upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which then activates a large number of carcinogenic genes via estrogen receptor-alpha (ERalpha) in malignant epithelial cells. This clinically pertains, since aromatase inhibitors (AIs) are the most effective hormonal treatment of ERalpha-positive breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an AI effectively eliminates E2 production. Since alternative promoters regulated by distinct signaling pathways control aromatase expression, it is possible to target these pathways and inhibit estrogen production in a tissue-selective fashion. We and others previously found that the majority of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the proximal promoter I.3/II region. PGE(2) that is secreted in large amounts by malignant breast epithelial cells is the most potent known natural inducer of this promoter region in breast adipose fibroblasts. Signaling effectors/transcriptional regulators that mediate PGE(2) action include the activator pathways p38/CREB-ATF and JNK/jun and the inhibitory factor BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat breast cancer while permitting aromatase expression via alternative promoters in the brain and bone and thus obviate the key side effects of the current AIs. The signaling pathways that mediate the regulation of the promoter I.3/II region in undifferentiated fibroblasts in malignant breast tumors are reviewed. PMID: 19250199 [PubMed - indexed for MEDLINE] 2022. Obes Res Clin Pract. 2009 Mar;3(1):1-52. doi: 10.1016/j.orcp.2008.10.005. Obesity and cardiovascular dysfunction: A role for resveratrol? Naderali EK(1). Author information: (1)Obesity Biology Unit, School of Clinical Science, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK. Electronic address:naderali@liv.ac.uk. SUMMARY: Obesity, characterized by excess adipose tissue is now becoming a worldwide epidemic. Various studies have suggested that obesity per se is an independent cardiovascular risk factor, as well as predisposing to type 2 diabetes, hypertension and dyslipidaemia. Furthermore, obesity induces insulin resistance, which is associated with development of cardiovascular diseases that include hypertension, and reduced endothelial function. A variety of pharmacological and physiological as well as surgical interventions have been used to counteract deleterious effects of obesity with some degree of success. A number of new medicinal agents are being considered as a candidate for managing obesity and its associated cardiovascular abnormalities. Resveratrol, a naturally occurring phenolic trihydroxystilbene substance, which is present in a variety of plants have been shown to reverse detrimental effects of diet-induced obesity. This review examines role of resveratrol as a future anti-obesity agent.: © 2009 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved. PMID: 24345541 [PubMed] 2023. Acta Physiol (Oxf). 2009 May;196(1):115-27. doi: 10.1111/j.1748-1716.2009.01969.x. Epub 2009 Feb 19. AMPK-dependent hormonal regulation of whole-body energy metabolism. Dzamko NL(1), Steinberg GR. Author information: (1)Protein Chemistry & Metabolism, St Vincent's Institute of Medical Research and The University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, Australia. AMP-dependent protein kinase (AMPK) is an evolutionarily conserved serine/threonine protein kinase central to the regulation of energy balance at both the cellular and whole-body levels. In its classical role as an intracellular metabolic stress-sensing kinase, AMPK switches on fatty acid oxidation and glucose uptake in muscle, while switching off hepatic gluconeogenesis. AMPK also has a broader role in metabolism through the control of appetite. Regulation of AMPK activity at the whole-body level is coordinated by a growing number of hormones and cytokines secreted from adipose tissue, skeletal muscle, pancreas and the gut including leptin, adiponectin, insulin, interluekin-6, resistin, TNF-alpha and ghrelin. Understanding how these secreted signalling proteins regulate AMPK activity to control fatty acid oxidation, glucose uptake, gluconeogenesis and appetite may yield therapeutic treatments for metabolic disorders such as diabetes, insulin resistance and obesity. PMID: 19245657 [PubMed - indexed for MEDLINE] 2024. Womens Health (Lond Engl). 2009 Mar;5(2):191-203. doi: 10.2217/17455057.5.2.191. Nonalcoholic fatty liver disease in women. Suzuki A(1), Abdelmalek MF. Author information: (1)Division of Gastroenterology & Hepatology, Duke University Medical Center, Durham, NC 27710, USA. suzuk004@mc.duke.edu Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries and is increasing in prevalence with the rise of diabetes and obesity. In addition to obesity and age, gender may also influence the prevalence and severity of NAFLD. However, mechanisms underlying gender-based differences in NAFLD have not been clearly defined. Furthermore, alterations in body composition, fat distribution and/or hormonal or metabolic changes that occur following menopause and in the setting of polycystic ovary syndrome may influence the development and progression of NAFLD. In this article, we will summarize known gender differences as well as the proposed mechanisms for gender differences in NAFLD, review two women-specific issues that may influence the prevalence and severity of NAFLD, menopause and polycystic ovary syndrome, and discuss potential therapeutic options for women with NAFLD who are postmenopausal or have polycystic ovary syndrome. PMID: 19245356 [PubMed - indexed for MEDLINE] 2025. Am J Clin Nutr. 2009 Apr;89(4):1173-9. doi: 10.3945/ajcn.2008.27273. Epub 2009 Feb 25. A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands. Lieffers JR(1), Mourtzakis M, Hall KD, McCargar LJ, Prado CM, Baracos VE. Author information: (1)Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. BACKGROUND: Cancer cachexia-associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer. OBJECTIVE: The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression. DESIGN: A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n = 18). RESULTS: Eleven months from death, the liver (2.3 +/- 0.7 kg) and spleen (0.32 +/- 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 +/- 1.5 kg (P = 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r(2) = 0.35, P = 0.010); because liver accounted for a larger percentage of FFM, measured REE . kg FFM(-1) . d(-1) increased (r(2) = 0.35, P = 0.010). CONCLUSIONS: Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of approximately 17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss. PMCID: PMC2667460 PMID: 19244378 [PubMed - indexed for MEDLINE] 2026. J Postgrad Med. 2009 Jan-Mar;55(1):45-54. Dietary factors and cancer chemoprevention: an overview of obesity-related malignancies. Murthy NS(1), Mukherjee S, Ray G, Ray A. Author information: (1)Hormel Institute, University of Minnesota, Austin, MN 55912, USA. Obesity is a growing health problem in developed nations and in countries that are in the process of westernization like India. Obesity is linked with several health disorders such as hypertension and cardiovascular diseases, Type 2 diabetes, dyslipidemia and certain cancers. Currently, obesity-related malignancies, e.g., cancers of the breast, prostate and colon are the leading cancers in the industrialized societies. An increased amount of fat or adipose tissue in an overweight or obese person probably influences the development of cancer by releasing several hormone-like factors or adipokines. The majority of adipokines are pro-inflammatory, which promote pathological conditions like insulin resistance and cancer. On the other hand, many recent studies have shown that adiponectin, an anti-inflammatory adipokine, has anti-cancer and insulin-sensitizing effects. Adiponectin exerts its physiological functions chiefly by activation of AMP kinase via adiponectin receptors. Interestingly, several fruits and vegetables may contain adiponectin-like molecules or may increase the biosynthesis of adiponectin in our body. Studies on adiponectin analogues or adiponectin receptor agonists are a promising area of cancer chemoprevention research. In general, fruits and vegetables contain various dietary substances such as vitamins, minerals (like calcium and selenium), fiber and phytochemicals or phenolic compounds (like flavonoids and vanilloids), which may act as anti-cancer agents. Similarly, several dietary constituents including phytochemicals may have anti-obesity effects. Consumption of such dietary compounds along with caloric restriction and physical activity may be helpful in preventing obesity-related cancers. For this review article, we searched PubMed primarily to get the relevant literature. PMID: 19242081 [PubMed - indexed for MEDLINE] 2027. Ortop Traumatol Rehabil. 2009 Jan-Feb;11(1):1-6. Leptin as a modulator of osteogenesis. Włodarski K(1), Włodarski P. Author information: (1)Department and Division of Histology and Embryology, Center for Bioastructure Research, Medical University of Warsaw. kwlodar@ib.amwaw.edu.pl Leptin, a hormone secreted by adipose tissue, but also by several other tissues, has a dual effect on bone, acting by two independent mechanisms. As a signal molecule with growth factor characteristics, leptin is able to stimulate osteoblastic cells and to inhibit osteoclast formation and activity, thus promoting osteogenesis. However, as a molecule which stimulates sympathetic neurons in the hypothalamus, leptin indirectly inhibits bone formation. This inhibitory effect of leptin mediated by activation of sympathetic nervous system can be abrogated by application of blood pressure-reducing beta-blockers, which also inhibit receptors of hypothalamic adrenergic neurons. PMID: 19240679 [PubMed - indexed for MEDLINE] 2028. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Møller N(1), Jørgensen JO. Author information: (1)Medical Department M, Aarhus University Hospital, Aarhus Sygehus, DK, Aarhus, Denmak. In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of "stress" diabetes during fasting and inflammatory illness, and perhaps for the "Dawn" phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant-probably related to increased adiposity, reduced LBM, and impaired physical performance-which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment. PMID: 19240267 [PubMed - indexed for MEDLINE] 2029. J Mol Endocrinol. 2009 Jul;43(1):11-8. doi: 10.1677/JME-08-0131. Epub 2009 Feb 24. Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases. Gomez R(1), Lago F, Gomez-Reino J, Dieguez C, Gualillo O. Author information: (1)Research Laboratory 9, (NEIRID LAB, Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Santiago de Compostela, Spain. The discovery of leptin in 1994 marked the beginning of a new understanding about white adipose tissue (WAT) and modified a static vision of this tissue which was viewed up to the end of the 20th century as an inert tissue, devoted to body protection from heat loss and to passively storing energy. The identification of the product of the gene obese accentuated the role of adipose tissue in the physiopathology of obesity-linked diseases, and led to the discovery of various adipokines, many of a pro-inflammatory nature. It has become progressively manifest that WAT-derived adipokines can now be considered as the fulcrum between obesity-related environmental causes, such as nutrition and lifestyle, and the biochemical shifts that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. Herein, we review recent adipokine research, with particular emphasis to the role of leptin, adiponectin, resistin, and visfatin in chondrocyte function and skeleton, as well as in inflammatory and degenerative cartilage joint diseases. PMID: 19240195 [PubMed - indexed for MEDLINE] 2030. Nutr Rev. 2009 Mar;67(3):167-71. doi: 10.1111/j.1753-4887.2009.00184.x. Brown adipose tissue: the molecular mechanism of its formation. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA. nutritionreviews@ilsi.org The function of brown adipose tissue (BAT) is to oxidize fat and to dissipate the energy produced as heat, providing a source of heat to the organism. Preadipocytes are stimulated by expression of the PRDM16 gene to differentiate into BAT cells. The PRDM16 protein is greatly enriched in BAT and causes increased expression of mitochondrial genes and greater density of mitochondria. It increases expression of the uncoupling factor UCP1 and thereby causes a large stimulation of uncoupled respiration with resultant heat production, enhanced by cAMP. Recent evidence strongly supports the idea that the PRDM16 gene determines BAT identity. PMID: 19239631 [PubMed - indexed for MEDLINE] 2031. Hypertension. 2009 Apr;53(4):577-84. doi: 10.1161/HYPERTENSIONAHA.108.110320. Epub 2009 Feb 23. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Mathieu P(1), Poirier P, Pibarot P, Lemieux I, Després JP. Author information: (1)Laval Hospital, 2725 Chemin Ste-Foy, Quebec, Canada. patrick.mathieu@chg.ulaval.ca PMID: 19237685 [PubMed - indexed for MEDLINE] 2032. Expert Opin Ther Targets. 2009 Feb;13(2):235-46. doi: 10.1517/14712590802680141 . The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function. Hallenborg P(1), Feddersen S, Madsen L, Kristiansen K. Author information: (1)University of Southern Denmark, Department of Biochemistry and Molecular Biology, Campusvej 55, 5230 Odense M, Denmark. BACKGROUND: The retinoblastoma protein (pRB) and p53 are crucial members of regulatory networks controlling the cell cycle and apoptosis, and a hallmark of virtually all cancers is dysregulation of expression or function of pRB or p53. Although they are best known for their role in cancer development, it is now evident that both are implicated in metabolism and cellular development. OBJECTIVE/METHODS: To review the role of pRB and p53 in adipocyte differentiation and function emphasizing that pRB and p53, via their effects on adipocyte development and function, play a role in the regulation of energy metabolism and homeostasis. RESULTS/CONCLUSIONS: pRB is required for adipose conversion and also involved in determining its mitochondrial capacity. p53 inhibits adipogenesis and results suggest that it is involved in maintaining function of adipose tissue. PMID: 19236241 [PubMed - indexed for MEDLINE] 2033. Expert Opin Pharmacother. 2009 Feb;10(2):239-54. doi: 10.1517/14656560802618811 . Adipokines in the treatment of diabetes mellitus and obesity. Catalán V(1), Gómez-Ambrosi J, Rodríguez A, Salvador J, Frühbeck G. Author information: (1)Metabolic Research Laboratory, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain. vcatalan@unav.es BACKGROUND: The physiology of adipose tissue plays a main role in the pathogenesis of type 2 diabetes mellitus. The secretion of adipocyte-derived hormones, in either an autocrine or a paracrine manner, has been proposed as a relevant mechanism in this process. In this sense, the administration and regulation of hormones derived from adipose tissue arises as an attractive option for treating metabolic disorders. OBJECTIVE: To review the current understanding of the implication of adipokines in the development of obesity and insulin resistance, as well as their potential use as therapeutic agents. METHODOLOGY: Review of scientific literature. CONCLUSIONS: This review describes the role of adipokines in generating insulin resistance and the chronic low-grade inflammatory profile accompanying visceral obesity. PMID: 19236196 [PubMed - indexed for MEDLINE] 2034. Presse Med. 2009 Apr;38(4):609-13. doi: 10.1016/j.lpm.2009.01.006. Epub 2009 Feb 23. [Hypertension in obese patients: Pathophysiology and management]. [Article in French] Girerd X(1), Hansel B. Author information: (1)Service d'endocrinologie métabolisme, Hôpital de la Pitié, F-75013 Paris, France. xavier.girerd@psl.aphp.fr Obesity is a major risk factor for hypertension. Adipose tissue releases numerous substances that act on the pathophysiologic mechanisms of blood pressure. Management of obese patients with high blood pressure includes weight loss efforts, but antihypertensive treatment is most often necessary. Beta-blockers, alone or with thiazide diuretics, increase the risk of diabetes in hypertensive patients. Treatment against hypertension must include a renin-angiotensin system blocker, with a calcium channel blocker or a thiazide diuretic, if necessary. PMID: 19233604 [PubMed - indexed for MEDLINE] 2035. Surgery. 2009 Mar;145(3):255-9. doi: 10.1016/j.surg.2008.08.038. Epub 2008 Oct 30. Inflammation in obesity-related diseases. O'Rourke RW(1). Author information: (1)Oregon Health and Science University, Division of General Surgery, L223A, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. orourkro@ohsu.edu PMCID: PMC2749322 PMID: 19231576 [PubMed - indexed for MEDLINE] 2036. Liver Int. 2009 Mar;29 Suppl 2:38-46. doi: 10.1111/j.1478-3231.2008.01951.x. Hepatitis C, human immunodeficiency virus and metabolic syndrome: interactions. Kotler DP(1). Author information: (1)Division of Gastroenterology and Liver Disease, St Lukes-Roosevelt Hospital Center, New York, NY 10025, USA. dkotler@chpnet.org Erratum in Liver Int. 2009 Apr;29(4):617. Significant concerns have been raised about the metabolic effects of antiretroviral medication, including the classic triad of dyslipidaemia, insulin resistance (IR) and characteristic alterations in fat distribution (lipoatrophy and lipohypertrophy). Co-infection with hepatitis C appears to exacerbate IR, reduce serum lipids and induce prothrombotic changes in the treated human immunodeficiency virus patient. The effects of co-infection are complex. While combination antiretroviral therapy has been shown to be associated with an increased risk of cardiovascular events through promotion of dyslipidaemia, IR and fat redistribution, co-infection exacerbates IR while reducing serum lipids. Co-infection also promotes a prothrombotic state characterized by endothelial dysfunction and platelet activation, which may enhance risk for cardiovascular disease. Consideration must be given to selection of appropriate treatment regimens and timing of therapy in co-infected patients to minimize metabolic derangements and, ultimately, reduce cardiovascular risk. PMID: 19187071 [PubMed - indexed for MEDLINE] 2037. Liver Int. 2009 Mar;29 Suppl 2:13-25. doi: 10.1111/j.1478-3231.2008.01952.x. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Serfaty L(1), Capeau J. Author information: (1)UPMC University Paris 06, F-75005, Paris, France. Epidemiological data indicate a strong risk for development of insulin resistance (IR), and, ultimately, overt diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection. Steatosis, or fatty liver, is closely linked with IR in persons without HCV, such as those with metabolic syndrome, primarily due to increased visceral fat leading to altered adipokine production and increased free fatty acid (FFA) release. Moreover, there is evidence that liver fat can have an impact on the development of hepatic IR independently of changes in adipose tissue. Multiple mechanisms can account for the development of IR in patients with chronic HCV. In particular, there is evidence for a triangular interaction between steatosis, inflammatory processes and IR. In patients infected by the genotype 1 virus, steatosis is strongly related to IR, leading to a metabolic steatosis, while, in genotype 3 patients, steatosis is related to viral load in the context of a viral steatosis. Chronic inflammatory processes in the liver may be mediated by persistently activated macrophages and other immune cells, with concomitant overproduction of pro-inflammatory cytokines such as tumour necrosis factor-alpha. Activation of inflammatory pathways, together with increased levels of FFAs, can disrupt hepatocyte intracellular pathways and inhibit insulin signalling, leading to IR. Molecular studies have also shown that the HCV core protein can directly inhibit the insulin signalling pathway and increase reactive oxygen species production, both of which can further exacerbate IR. The available data provide an understanding of chronic HCV whereby chronic inflammatory processes, steatosis and IR contribute to each other, leading to an increased risk of DM, and its associated poor outcomes, in persons with chronic HCV. PMID: 19187069 [PubMed - indexed for MEDLINE] 2038. J Cell Biochem. 2009 Apr 15;106(6):984-91. doi: 10.1002/jcb.22091. Trafficking and differentiation of mesenchymal stem cells. Liu ZJ(1), Zhuge Y, Velazquez OC. Author information: (1)The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of MiamiJackson Memorial Medical Center, Miami, FL 33136, USA. ovelazquez@med.miami.edu Mesenchymal stem cells (MSCs) are a heterogeneous population of stem/progenitor cells with pluripotent capacity to differentiate into mesodermal and non-mesodermal cell lineages, including osteocytes, adipocytes, chondrocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epithelial cells, and neurons. MSCs reside primarily in the bone marrow, but also exist in other sites such as adipose tissue, peripheral blood, cord blood, liver, and fetal tissues. When stimulated by specific signals, these cells can be released from their niche in the bone marrow into circulation and recruited to the target tissues where they undergo in situ differentiation and contribute to tissue regeneration and homeostasis. Several characteristics of MSCs, such as the potential to differentiate into multiple lineages and the ability to be expanded ex vivo while retaining their original lineage differentiation commitment, make these cells very interesting targets for potential therapeutic use in regenerative medicine and tissue engineering. The feasibility for transplantation of primary or engineered MSCs as cell-based therapy has been demonstrated. In this review, we summarize the current knowledge on the signals that control trafficking and differentiation of MSCs. Copyright 2009 Wiley-Liss, Inc. PMID: 19229871 [PubMed - indexed for MEDLINE] 2039. Rev Port Cardiol. 2008 Nov;27(11):1431-49. Cardiovascular actions of adiponectin: pathophysiologic implications. [Article in English, Portuguese] Maia-Fernandes T(1), Roncon-Albuquerque R Jr, Leite-Moreira AF. Author information: (1)Serviço de Fisiologia, Faculdade de Medicina do Porto, Porto, Portugal. The classical view of adipose tissue as a passive reservoir for energy storage is no longer valid. In the past decade, adipose tissue has been shown to have endocrine functions regulating cardiovascular physiology. In the present review we will analyze current knowledge about adiponectin, the most abundant peptide secreted by adipocytes, with particular focus on its cardiovascular actions. Adiponectin secretion is inhibited by TNF-alpha and by catecholamines, and is stimulated by PPAR gamma activation. Adiponectin acts through two main receptors, AdipoR1 and AdipoR2. In the liver, adiponectin modulates lipid and energy metabolism, stimulating fatty acid catabolism and reducing gluconeogenesis. In skeletal muscle, it promotes fatty acid oxidation and glucose uptake. Taken together, the metabolic actions of adiponectin enhance insulin sensitivity and reduce circulating lipid levels. Adiponectin also has a protective effect against atherogenesis, acting on the endothelium and smooth muscle cells, raising NO secretion and inhibiting production of adhesion factors. In the heart, adiponectin inhibits cardiomyocyte hypertrophy and myocardial fibrosis, through poorly understood mechanisms. Adiponectin production has also been shown to be reduced in patients with obesity and type 2 diabetes, and its circulating levels have prognostic significance in various cardiovascular diseases. Finally, the role of this peptide as a therapeutic target has been evaluated, through various lifestyle and pharmacological interventions. Weight loss, physical exercise, renin-angiotensin system inhibitors and PPAR alpha and PPAR gamma agonists enhance adiponectin production. Further studies are needed, however, to clarify the clinical relevance of adiponectin in the pathophysiology and treatment of cardiovascular diseases. PMID: 19227810 [PubMed - indexed for MEDLINE] 2040. Adolesc Med State Art Rev. 2008 Dec;19(3):475-97, ix. The metabolic syndrome: a gathering challenge in a time of abundance. Bricker LA(1), Greydanus DE. Author information: (1)Department of Internal Medicine, Michigan State University/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49008-1284, USA. The metabolic syndrome (also known as dysmetabolic syndrome, MetS, Reaven syndrome, syndrome X, and insulin-resistance syndrome) is a well-recognized and all-too-frequently encountered fact of modern life, with staggering economic consequences. Various aspects of the metabolic syndrome are considered in this review, including such features as insulin resistance with glucose intolerance, hypertension, beta-cell failure, hyperinsulinemia, frank diabetes mellitus, dyslipidemia, and release of inflammatory and procoagulant factors into the circulation. Issues of management for the adolescent are considered also. Much can be accomplished for such youth by using the knowledge we currently have in hand, but many additional issues that are noted make the prospects for success extremely challenging for clinicians who deal with adolescent patients. PMID: 19227387 [PubMed - indexed for MEDLINE] 2041. Cell Biochem Funct. 2009 Mar;27(2):71-5. doi: 10.1002/cbf.1540. Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise. Lira FS(1), Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, Batista ML Jr, Seelaender M. Author information: (1)Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. The paraneoplastic syndrome of cachexia is considered a degenerative chronic inflammatory disease, being deeply related to the increase of pro-inflammatory factors, especially tumour necrosis factor alpha (TNF-alpha). It is known that the adipose tissue is affected by cachexia and contributing with the secretion of pro-inflammatory factors which reach the adjacent tissues and the circulation. The effect of pro-inflammatory factors is balanced by the effect of anti-inflammatory factors, such as interleukin 10 (IL-10). The IL-10/TNF-alpha ratio has been recently postulated as a marker for the assessment of the degree of inflammation, which correlates with disease-associated morbidity and mortality. In order to counteract inflammation in chronic disease, our group has currently adopted chronic endurance exercise in models of cancer cachexia and chronic heart failure. Since it is clear that white adipose tissue is strongly implicated in the secretion of both pro- and anti-inflammatory factors in disease, we chose to address its contribution to cachexia-related inflammation and the effect of endurance training on the capacity of cytokine expression and secretion by this tissue. Our results show an enhancement of IL-10 adipose tissue content, and increased IL-10/TNF-alpha ratio induced by endurance training. The mechanisms are discussed. PMID: 19226603 [PubMed - indexed for MEDLINE] 2042. Dig Liver Dis. 2009 Sep;41(9):615-25. doi: 10.1016/j.dld.2009.01.004. Epub 2009 Feb 14. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Petta S(1), Muratore C, Craxì A. Author information: (1)Cattedra & Unità Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy. petsa@inwind.it Non-alcoholic fatty liver disease is the clinical hepatic expression of metabolic syndrome. The prevalence of non-alcoholic fatty liver disease is around 20-30%, and with a rapid increase in the metabolic risk factors in the general population, non-alcoholic fatty liver disease has become the most common cause of liver disease worldwide. A fraction (20-30%) of non-alcoholic fatty liver disease patients develop a potentially progressive hepatic disorder, namely non-alcoholic steatohepatitis, leading to end-stage liver disease. The pathogenesis of non-alcoholic fatty liver disease is not entirely understood, and even if insulin resistance is a major pathogenetic key, many other factors are implicated in both liver fat accumulation and disease progression to non-alcoholic steatohepatitis. In this review we aim to examine the literature, principally concerning human non-alcoholic fatty liver disease pathogenesis, and to identify the newest, most promising clinical and basic research data. PMID: 19223251 [PubMed - indexed for MEDLINE] 2043. Radiology. 2009 Apr;251(1):67-76. doi: 10.1148/radiol.2511080666. Epub 2009 Feb 12. Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T. Yokoo T(1), Bydder M, Hamilton G, Middleton MS, Gamst AC, Wolfson T, Hassanein T, Patton HM, Lavine JE, Schwimmer JB, Sirlin CB. Author information: (1)Department of Radiology, University of California, San Diego Medical Center, University of California at San Diego, MR3 Laboratory, 408 Dickinson St, San Diego, CA 92103-8226, USA. PURPOSE: To assess the accuracy of four fat quantification methods at low-flip-angle multiecho gradient-recalled-echo (GRE) magnetic resonance (MR) imaging in nonalcoholic fatty liver disease (NAFLD) by using MR spectroscopy as the reference standard. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA-compliant prospective study, 110 subjects (29 with biopsy-confirmed NAFLD, 50 overweight and at risk for NAFLD, and 31 healthy volunteers) (mean age, 32.6 years +/- 15.6 [standard deviation]; range, 8-66 years) gave informed consent and underwent MR spectroscopy and GRE MR imaging of the liver. Spectroscopy involved a long repetition time (to suppress T1 effects) and multiple echo times (to estimate T2 effects); the reference fat fraction (FF) was calculated from T2-corrected fat and water spectral peak areas. Imaging involved a low flip angle (to suppress T1 effects) and multiple echo times (to estimate T2* effects); imaging FF was calculated by using four analysis methods of progressive complexity: dual echo, triple echo, multiecho, and multiinterference. All methods except dual echo corrected for T2* effects. The multiinterference method corrected for multiple spectral interference effects of fat. For each method, the accuracy for diagnosis of fatty liver, as defined with a spectroscopic threshold, was assessed by estimating sensitivity and specificity; fat-grading accuracy was assessed by comparing imaging and spectroscopic FF values by using linear regression. RESULTS: Dual-echo, triple-echo, multiecho, and multiinterference methods had a sensitivity of 0.817, 0.967, 0.950, and 0.983 and a specificity of 1.000, 0.880, 1.000, and 0.880, respectively. On the basis of regression slope and intercept, the multiinterference (slope, 0.98; intercept, 0.91%) method had high fat-grading accuracy without statistically significant error (P > .05). Dual-echo (slope, 0.98; intercept, -2.90%), triple-echo (slope, 0.94; intercept, 1.42%), and multiecho (slope, 0.85; intercept, -0.15%) methods had statistically significant error (P < .05). CONCLUSION: Relaxation- and interference-corrected fat quantification at low-flip-angle multiecho GRE MR imaging provides high diagnostic and fat-grading accuracy in NAFLD. PMCID: PMC2663579 PMID: 19221054 [PubMed - indexed for MEDLINE] 2044. Horm Metab Res. 2009 Feb;41(2):123-31. doi: 10.1055/s-0028-1119378. Epub 2009 Feb 12. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients. Forst T(1), Hohberg C, Pfützner A. Author information: (1)Institute for Clinical Research and Development, Mainz, Germany. thomasf@ikfe.de The metabolic syndrome is associated with an excess of increase in cardiovascular complications. Disturbances in insulin efficacy and insulin secretion are major features of the metabolic syndrome and might precede the development of diabetes mellitus by decades. Recent investigations highlighted the link between disturbances in insulin physiology and subsequent mechanisms of atherosclerosis. Insulin resistance is an early feature of increasing visceral adipose tissue and is directly associated to the activation of a couple of atherogenic pathways, including inflammation and the activation of the mitogen-activated proteinkinase pathway accelerating the atherogenic process. In patients with normal beta-cell function, insulin resistance is compensated by increased insulin release from the beta cells to keep blood glucose levels compensated. In those patients, genetically predisposed to type 2 diabetes, beta-cell function deteriorates with the development of timely, qualitative and quantitative insulin secretion disorders, and the development of overt diabetes mellitus. The coexistence of insulin resistance with functional beta cell failure results in loss of blood glucose control especially after a meal and increases the cardiovascular risk of these patients far beyond the increased glucose levels. PMID: 19214922 [PubMed - indexed for MEDLINE] 2045. Am J Clin Nutr. 2009 Mar;89(3):980S-984S. doi: 10.3945/ajcn.2008.26788C. Epub 2009 Feb 11. Leptin: a pivotal regulator of human energy homeostasis. Farooqi IS(1), O'Rahilly S. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom. isf20@cam.ac.uk The identification of the hormone leptin by Friedman et al (1) in 1994 has proved to be a seminal observation in biomedical science. The discovery that a circulating protein secreted almost exclusively by adipocytes could regulate body weight through its effects on food intake and energy expenditure represented a remarkable breakthrough in our understanding of the molecular components of the systems involved in energy homeostasis. In this article, we describe how the identification of humans with mutations in the gene encoding leptin and the characterization of the associated clinical phenotype of congenital leptin deficiency, which includes hyperphagia, severe obesity, hypogonadism, and impaired immunity, has provided insights into the role of leptin-responsive pathways in the regulation of eating behavior, intermediary metabolism, and the onset of puberty. We and others have also been able to demonstrate that leptin signaling plays a critical role in the regulation of reproductive and immune function in humans, which places leptin at the center of the complex networks that coordinate changes in nutritional state with many diverse aspects of mammalian biology. PMID: 19211814 [PubMed - indexed for MEDLINE] 2046. J Cell Mol Med. 2008 Dec;12(6B):2552-65. doi: 10.1111/j.1582-4934.2008.00516.x. Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool. García-Castro J(1), Trigueros C, Madrenas J, Pérez-Simón JA, Rodriguez R, Menendez P. Author information: (1)Andalusian Stem Cell Bank (BACM), University of Granada, Granada, Spain. Mesenchymal stem cells (MSCs) from adult somatic tissues may differentiate in vitro and in vivo into multiple mesodermal tissues including bone, cartilage, adipose tissue, tendon, ligament or even muscle. MSCs preferentially home to damaged tissues where they exert their therapeutic potential. A striking feature of the MSCs is their low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes and antigen-presenting cells. Instead, MSCs appear to be immunosuppressive in vitro. Their multilineage differentiation potential coupled to their immuno-privileged properties is being exploited worldwide for both autologous and allogeneic cell replacement strategies. Here, we introduce the readers to the biology of MSCs and the mechanisms underlying immune tolerance. We then outline potential cell replacement strategies and clinical applications based on the MSCs immunological properties. Ongoing clinical trials for graft-versus-host-disease, haematopoietic recovery after co-transplantation of MSCs along with haematopoietic stem cells and tissue repair are discussed. Finally, we review the emerging area based on the use of MSCs as a target cell subset for either spontaneous or induced neoplastic transformation and, for modelling non-haematological mesenchymal cancers such as sarcomas. PMCID: PMC3828873 PMID: 19210755 [PubMed - indexed for MEDLINE] 2047. Obes Rev. 2009 May;10(3):290-7. doi: 10.1111/j.1467-789X.2008.00555.x. Epub 2009 Jan 16. The interface between obesity and periodontitis with emphasis on oxidative stress and inflammatory response. Boesing F(1), Patiño JS, da Silva VR, Moreira EA. Author information: (1)Post Graduate Program in Nutrition at the Federal University of Santa Catarina, Florianópolis, Brazil. Obesity is characterized by the abnormal or excessive deposition of fat in the adipose tissue. Its consequences go far beyond adverse metabolic effects on health, causing an increase in oxidative stress that leads not only to endothelial dysfunction but also to negative effects in relation to periodontitis, because of the increase in proinflammatory cytokines. Thus, obesity appears to participate in the multifactorial phenomenon of causality of periodontitis through the increased production of reactive oxygen species. Within this context, this paper aims to highlight, by analysis and description of previous studies, the interface between obesity and periodontitis, with emphasis on oxidative stress and the inflammatory response. PMID: 19207875 [PubMed - indexed for MEDLINE] 2048. Cardiovasc Ther. 2009 Spring;27(1):59-75. doi: 10.1111/j.1755-5922.2008.00069.x. Adiponectin, an unlocking adipocytokine. Sun Y(1), Xun K, Wang C, Zhao H, Bi H, Chen X, Wang Y. Author information: (1)School of Pharmacy, Chengdu Medical College, Chengdu, China. A large number of studies revealed that adiponectin, a protein secreted specifically by adipose tissue, exhibits antiinflammatory, antiatherogenic, and antidiabetic properties. This 247-amino acid protein contains four differentiable domains and exists in five different configurations, which binds three kinds of receptors. The plasma adiponectin concentration is at amazing microgram level and the gender difference is very clear. Obese subjects showed decreased plasma level of adiponectin while exercise seems to restore it. Many researchers demonstrated that it could be a reliable biomarker for multiple diseases. However, there is controversy about its role in inflammation since its plasma concentration decreases in some inflammatory diseases and increases under some other inflammatory conditions. The signal transduction pathway is still not very clear yet. Could adiponectin be a promising drug target? PMID: 19207481 [PubMed - indexed for MEDLINE] 2049. Cell Biochem Funct. 2009 Mar;27(2):63-70. doi: 10.1002/cbf.1538. Leptin transport in the central nervous system. Ziylan YZ(1), Baltaci AK, Mogulkoc R. Author information: (1)Department of Physiology, Istanbul Medical School, Istanbul University, Capa, Istanbul, Turkey. Synthesized and released by the adipose tissue, leptin is the widely studied 167-amino acid hormonal protein product of the obesity gene. Originally leptin was defined in association with satiety and energy balance and claimed to be an anti-obesity factor that functioned via a feedback effect from adipocytes to hypothalamus. There is a growing body of evidence that emphasizes the importance of leptin in the regulation of food intake and body weight in animals and humans, alike. Other research findings point out that it plays a role in the regulation of the metabolism, sexual development, reproduction, hematopoiesis, immunity, gastrointestinal functions, sympathetic activation, and angiogenesis. The aim of this review is to evaluate the relation between leptin and the central nervous system (CNS). PMID: 19205004 [PubMed - indexed for MEDLINE] 2050. Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):110-6. doi: 10.1097/MCO.0b013e32832182ee. Saturated with fat: new perspectives on lipotoxicity. Garbarino J(1), Sturley SL. Author information: (1)Institute of Human Nutrition, Columbia University Medical Center, New York, New York 10032, USA. PURPOSE OF REVIEW: To present current perspectives on the mediators and mechanisms of cyto-lipotoxic events and their relevance to human health. RECENT FINDINGS: The relatively recent isolation of lipid acyltransferase genes from yeast to mice and humans has resulted in a paradigm shift that now establishes all fatty acids as toxic, albeit in tissue specific patterns and by different mechanisms. Furthermore, the dysregulation of glucose homeostasis in combination with excess fatty acids provides a synergistic effect leading to glucolipotoxicity and cell death. These findings are relevant to the development of disease states associated with the pathogenesis of the metabolic syndrome. SUMMARY: In an era when an astounding number of people are diagnosed with metabolic disorders, it is imperative that we understand the consequences of a chronic metabolic surplus. Excessive fat, saturated or otherwise, has to be accommodated. Multiple aspects of this homeostasis are emerging, some of which are described here. PMID: 19202381 [PubMed - indexed for MEDLINE] 2051. Biochem J. 2009 Mar 1;418(2):261-75. doi: 10.1042/BJ20082055. AMPK and the biochemistry of exercise: implications for human health and disease. Richter EA(1), Ruderman NB. Author information: (1)Molecular Physiology Group, Department of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, August Krogh Building, 13 Universitetsparken, 2100 Copenhagen, Denmark. erichter@ifi.ku.dk AMPK (AMP-activated protein kinase) is a phylogenetically conserved fuel-sensing enzyme that is present in all mammalian cells. During exercise, it is activated in skeletal muscle in humans, and at least in rodents, also in adipose tissue, liver and perhaps other organs by events that increase the AMP/ATP ratio. When activated, AMPK stimulates energy-generating processes such as glucose uptake and fatty acid oxidation and decreases energy-consuming processes such as protein and lipid synthesis. Exercise is perhaps the most powerful physiological activator of AMPK and a unique model for studying its many physiological roles. In addition, it improves the metabolic status of rodents with a metabolic syndrome phenotype, as does treatment with AMPK-activating agents; it is therefore tempting to attribute the therapeutic benefits of regular physical activity to activation of AMPK. Here we review the acute and chronic effects of exercise on AMPK activity in skeletal muscle and other tissues. We also discuss the potential role of AMPK activation in mediating the prevention and treatment by exercise of specific disorders associated with the metabolic syndrome, including Type 2 diabetes and Alzheimer's disease. PMCID: PMC2779044 PMID: 19196246 [PubMed - indexed for MEDLINE] 2052. Tissue Eng Part B Rev. 2009 Jun;15(2):113-25. doi: 10.1089/ten.teb.2008.0423. Adipose tissue-derived stem cells and their application in bone and cartilage tissue engineering. Rada T(1), Reis RL, Gomes ME. Author information: (1)3B's Research Group-Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering, University of Minho, Braga, Portugal. The adipose tissue was considered a reserve of energy until the '80s, when it was found that this tissue was involved in the metabolism of sex steroids such as estrogens. From then on, the importance attributed to this tissue radically changed as it was then considered an active organ, involved in important functions of the human body. In 2001, for the first time, the existence of stem cells within this tissue was reported, and since then, this tissue has been gaining an increased importance as a stem cell source for a wide range of potential applications in cell therapies and/or tissue engineering and regenerative medicine strategies, mainly due to its wide availability and easy access. This manuscript provides an overview on adipose stem cells (i.e., adipose tissue-derived stem cells, ASCs) considering the tissue of origin, the niche of the ASCs, and their phenotype in all aspects. In this paper it is also discussed the markers that have been used for the characterization of these cells, their differentiation properties, and their immunological reactivity, reporting studies from 2001 until this date. The ASCs are also compared with bone marrow stem cells (BMSCs), until now considered as the gold standard source of stem cells, underlining the common characteristics and the differences between the stem cells obtained from these two sources, as well as the advantages and disadvantages of their potential use in different applications. Finally, this review will also focus on the potential application of ASCs in tissue engineering applications, particularly in the regeneration of bone and cartilage, commenting on the progress of this approach and future trends of the field. PMID: 19196117 [PubMed - indexed for MEDLINE] 2053. Diabetes Metab. 2008 Dec;34(6 Pt 2):658-63. doi: 10.1016/S1262-3636(08)74601-9. Adipose tissue inflammation and liver pathology in human obesity. Tordjman J(1), Guerre-Millo M, Clément K. Author information: (1)Inserm, U872, 15, rue de l'Ecole de Médecine, 75007 Paris, F-75006 France. The increase in circulating inflammatory factors found in obese subjects and the recent discovery of macrophage infiltration in white adipose tissue (WAT) have opened up new fields of investigation, allowing a reevaluation of the pathophysiology of human obesity. The so-called 'low-grade' inflammatory state, which characterizes this complex disease, is revealed by the moderate, but chronic, systemic rise of a growing panel of molecules with proinflammatory functions. The qualitative and quantitative alterations in the production of these molecules (free fatty acids, cytokines) by the different WAT cell types, particularly in the omental fat depot, are considered new factors with the potential to modify local WAT biology and to contribute, via the portal system, to liver alteration. The aim of this review is to present the most upto-date knowledge regarding the relationships between inflammatory processes in WAT and non-alcoholic liver disease in human obesity. PMID: 19195627 [PubMed - indexed for MEDLINE] 2054. Diabetes Metab. 2008 Dec;34(6 Pt 2):649-57. doi: 10.1016/S1262-3636(08)74600-7. Insulin resistance and steatosis in humans. Capeau J(1). Author information: (1)Univ-Paris 6, Inserm UMR_S893 Equipe 9, Faculté de Médecine Pierre et Marie Curie, 75571 Paris cedex 12, France. jacqueline.capeau@inserm.fr Insulin resistance is commonly found in a large number of adults-in particular, those with android obesity, the metabolic syndrome or type 2 diabetes. Strong adverse relationships between adipose tissue, liver and muscles in these patients result in lipotoxicity, with deposition of triglycerides (TG) within the liver and muscles together with insulin resistance. Such a situation is also seen in lipodystrophic patients with fat loss. Insulin signals in the liver through its tyrosine-kinase receptors to negatively control hepatic glucose production (HGP), replenish glycogen stores and synthesize fatty acids (FA), leading to TG exported as VLDL. In liver insulin resistance, HGP is increased mainly by activation of the gluconeogenic pathway, resulting in increased fasting glycemia. Lipogenesis is also increased possibly due to direct activation of the SREBP-1 transcription factor and together with increased FA availability results in an increased production of VLDL-TG. An imbalance between the pathways of TG synthesis and oxidation or export results in 'metabolic' steatosis. Increased cellular FA derivatives activate stress kinases, leading to phosphorylation of serine in insulin receptor substrate (IRS) proteins and, hence, insulin resistance. A number of studies in normal subjects and patients have revealed a strong association between insulin resistance and metabolic steatosis. Moreover, when insulin resistance is decreased by weight loss in obese subjects or by treatment with insulin sensitizers such as thiazolidinediones, the levels of liver fat and insulin resistance vary accordingly. An important question that remains unanswered concerns the relationship between steatosis and non-alcoholic steatohepatitis (NASH), and the potential roles of insulin resistance together with inflammation and oxidative stress in such a setting. PMID: 19195626 [PubMed - indexed for MEDLINE] 2055. Diabetes Metab. 2008 Dec;34(6 Pt 2):643-8. doi: 10.1016/S1262-3636(08)74599-3. The role of the lipogenic pathway in the development of hepatic steatosis. Postic C(1), Girard J. Author information: (1)Département d'Endocrinologie, Métabolisme et Cancer, Université Paris-Descartes, Paris, France. catherine.postic@inserm.fr Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of diseases, ranging from simple fatty liver (hepatic steatosis) through steatosis with inflammation and necrosis to cirrhosis. NAFLD, which is strongly associated with obesity, insulin resistance and type 2 diabetes, is now well recognized as being part of the metabolic syndrome. The metabolic pathways leading to the development of hepatic steatosis are multiple, including enhanced non-esterified fatty acid release from adipose tissue (lipolysis), increased de novo fatty acids (lipogenesis) and decreased beta-oxidation. Recently, several mouse models have helped to clarify the molecular mechanisms leading to the development of hepatic steatosis in the pathogenesis of NAFLD. This review describes the models that have provided evidence implicating lipogenesis in the development and/or prevention of hepatic steatosis. PMID: 19195625 [PubMed - indexed for MEDLINE] 2056. Antivir Ther. 2008;13(8):1115-27. Key data from the 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 6-8 November 2008, London, UK. Tadayyon M(1), Cameron S. Author information: (1)International Medical Press, London, UK. info@intmedpress.com Although the list of clinical complications associated with HIV therapy continues to grow, the underlying mechanisms remain incompletely understood. Metabolic abnormalities, such as dyslipidaemia, insulin resistance and cardiovascular disease continue to top the list, but there is an increasing appreciation of the effect of HIV and antiretroviral therapy on body composition, bone metabolism, muscle function and autonomic nervous system control of lipid and glucose metabolism. The 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV brought together physicians and researchers in the area of HIV management with world experts involved in adipose tissue metabolism and lipid regulation, bone and muscle metabolism and renin-angiotensin and blood pressure control to review and discuss recent findings in these areas. The data presented at the meeting highlight that studies of adipose tissue remain a major focus of attempts to unravel the pathophysiology that accompany lipodystrophy associated with HIV infection and/ or its therapy. There is also a growing appreciation and understanding of the direct role of HIV in the development of various comorbidities, including bone disease, cardiac dysfunction and neuropathologies, including peripheral neuropathy. Two key emerging themes were those of mitochondrial dysfunction and a heightened basal inflammatory state, exemplified by increased levels of proinflammatory cytokines, chemokines and markers such as C-reactive protein. These might prove to be the common denominators that link HIV-associated pathologies with diverse organ systems. PMID: 19195338 [PubMed - indexed for MEDLINE] 2057. Curr Diab Rep. 2009 Feb;9(1):18-25. Lipids versus glucose in inflammation and the pathogenesis of macrovascular disease in diabetes. Averill MM(1), Bornfeldt KE. Author information: (1)Department of Pathology and Diabetes and Obesity Center of Excellence, University of Washington School of Medicine, 815 Mercer Street, Seattle, WA 98109, USA. Type 1 and type 2 diabetes both accelerate cardiovascular disease, yet the triggers are likely different for the two types of diabetes. Results from large-scale clinical trials suggest that intense blood glucose control can reduce cardiovascular events many years later in patients with type 1 diabetes. In type 2 diabetes, mechanisms related to insulin resistance and obesity may be more prominent in promoting atherosclerosis. In this article, we discuss the potential effects of hyperglycemia and diabetes-induced lipid abnormalities on atherosclerosis, particularly focusing on advanced stages of atherosclerosis and evidence from mouse models. In addition, we discuss new research findings in monocyte/macrophage biology that may present intriguing new areas of research related to diabetes and atherosclerosis. PMCID: PMC3148110 PMID: 19192420 [PubMed - indexed for MEDLINE] 2058. Am J Clin Nutr. 2009 Mar;89(3):973S-979S. doi: 10.3945/ajcn.2008.26788B. Epub 2009 Feb 3. Leptin at 14 y of age: an ongoing story. Friedman JM(1). Author information: (1)Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, Campus Box 305, New York, NY 10065, USA. friedj@rockefeller.edu The cloning of the ob gene and its gene product leptin has led to the elucidation of a robust physiologic system that maintains constancy of fat stores. Leptin is a peptide hormone secreted by adipose tissue and regulates adipose tissue mass and energy balance. Recessive mutations in the leptin gene are associated with massive obesity in mice and in some humans, which establishes a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass decreases, plasma leptin concentrations decrease, which stimulates appetite and suppresses energy expenditure until fat mass is restored. When fat mass increases, leptin concentrations increase, which suppresses appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. PMCID: PMC2667654 PMID: 19190071 [PubMed - indexed for MEDLINE] 2059. Przegl Lek. 2008;65(10):692-5. [Is tobacco smoking an effective means of body weight control--review of literature]. [Article in Polish] Wierzejska R(1), Jarosz M. Author information: (1)Zakład Dietetyki i Zywienia Szpitalnego z Klinika Chorób Metabolicznych i Gastroenterologii, Instytut Zywności i Zywienia w Warszawie. R.Wierzejska@izz.waw.pl A lot of people, particularly young people begin smoking tobacco with the belief, that it is an effective means of body weight control. The decision to quit coming in a later stage of life is accompanied by the fear of gaining weight after stopping smoking. The mechanism through which nicotine may be an agent in the process of controlling body weight consists in increased energy expenditure of the organism and reduced appetite. However tobacco smoking is not an effective means of combating excessive weight. This is because it stimulates formation of abdominal adipose tissue, thus increasing the risk of type 2 diabetes and heart diseases. Therapy of tobacco addiction should be combined with diet counselling and promotion of physical activity, which will help to limit the increase of body weight. PMID: 19189580 [PubMed - indexed for MEDLINE] 2060. J Physiol. 2009 Mar 15;587(Pt 6):1145-52. doi: 10.1113/jphysiol.2008.167072. Epub 2009 Feb 2. The hungry fetus? Role of leptin as a nutritional signal before birth. Forhead AJ(1), Fowden AL. Author information: (1)Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. ajf1005@cam.ac.uk In adult animals, leptin is an adipose-derived hormone that is important primarily in the regulation of energy balance during short- and long-term changes in nutritional state. Expression of leptin and its receptors is widespread in fetal and placental tissues, although the role of leptin as a nutritional signal in utero is unclear. Before birth, leptin concentration correlates with several indices of fetal growth, and may be an endocrine marker of fetal size and energy stores in the control of metabolism and maturation of fetal tissues. In addition, leptin synthesis and plasma concentration can be modified by insulin, glucocorticoids, thyroid hormones and oxygen availability in utero, and therefore, leptin may be part of the hormonal response to changes in the intrauterine environment. Evidence is emerging to show that leptin has actions before birth that are tissue-specific and may occur in critical periods of development. Some of these actions are involved in the growth and development of the fetus and others have long-term consequences for the control of energy balance in adult life. PMCID: PMC2674987 PMID: 19188249 [PubMed - indexed for MEDLINE] 2061. Acta Med Port. 2008 Sep-Oct;21(5):489-96. Epub 2009 Jan 16. [The role of adipose tissue and macrophages in chronic inflammation associated with obesity: clinical implications]. [Article in Portuguese] Ramalho R(1), Guimarães C. Author information: (1)Serviço e Laboratório de Imunologia, Faculdade de Medicina da Universidade do Porto, Porto. In the last decades, life style modifications particularly those related to food patterns and food choices, gave risen to a worldwide pandemic disease with no precedent in Human History: obesity. Energy storing and free fatty acids production were the only adipose tissue functions. However, it has been well established other adipose tissue functions like low grade pro-inflammatory molecules production (cytokines, adipokines and chemotactic factors) evolved in obese inflammatory condition. In this inflammatory state, adipocytes active role is inflammatory mediators (adipokines) production and and cell to cell interaction with resident macrophages. Adipose tissue low vascularization is even lower in the obese; so, hypoxia can be a critical factor in inflammatory obese state manifestation. Adipose tissue cytokines production and pre-adipocyte conversion into macrophage results in adipose tissue and macrophages interactions. One of the mononuclear phagocytic system components, macrophage, has an important role in obese-related inflammatory state. These cells have been found to be increased in number and shape proportional to Body Mass Index, rising to up to 60% of total adipose tissue components. The macrophages proportional accumulation could lead to an increase in pro-inflammatory molecules expression and contribute to the inflammatory state in a significant way. The reversion of the low grade inflammation and the reduction of risk factors in obese individuals seem to occur when a reduction in Body Mass Index is achieved and loss of adipose tissue is observed. We performed a critical review of last five years literature in order to better describe the impact of adipose tissue and macrophages interactions in low grade chronic inflammatory condition in the obese and their role in comorbidities pathogenesis. PMID: 19187692 [PubMed - indexed for MEDLINE] 2062. Trends Cardiovasc Med. 2008 Aug;18(6):199-205. doi: 10.1016/j.tcm.2008.10.001. Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure. Schram K(1), Sweeney G. Author information: (1)Department of Biology, York University, Toronto, Ontario, Canada. Owing to the increased incidence of obesity and its association with heart failure, there is now great interest in elucidating the underlying molecular mechanisms linking these pathologies. Since the discovery of adipose-derived hormones and cytokines, their important regulatory role in myocardial function has emerged. The events that these adipokines can regulate include alterations in myocardial metabolism, cardiomyocyte hypertrophy, cell death, and structure and composition of the extracellular matrix. Here, we focus on the last of these and review current research demonstrating an important role for adipokines, with particular emphasis on leptin and adiponectin, in regulating matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and collagens. From this, it is clear that adipokines are capable of contributing to remodeling of the myocardial extracellular matrix, and the altered adipokine profiles observed in obese individuals may be important in the pathogenesis of heart failure. The feasibility of adipokine manipulation as a potential therapeutic treatment in preventing maladaptive cardiac remodeling is also discussed. PMID: 19185809 [PubMed - indexed for MEDLINE] 2063. ANZ J Surg. 2009 Jan-Feb;79(1-2):70-4. doi: 10.1111/j.1445-2197.2008.04802.x. Aortic fat pad and atrial fibrillation: cardiac lymphatics revisited. Lupinski RW(1). Author information: (1)Department of Cardiothoracic Surgery, Waikato Hospital, Hamilton, New Zealand. rlupinski@yahoo.com.sg The lymphatics of the heart have not generated any broad or sustained interest among clinicians. Few publications on cardiac lymphatics are available, the anatomy is not routinely known and the true role of cardiac lymphatics remains doubtful. One important anatomical concept needing clarification is that of the lymphatic drainage of conduction tissue. The sinoatrial node lymphatic collector and right principal lymphatic trunk are both incorporated into the aortic fat pad of the ascending aorta and are the most frequently damaged lymphatic vessels during cardiac surgery. Thus, preservation of the aortic fat pad and its lymphatic collectors should reduce the incidence of new atrial fibrillation observed in patients after cardiac surgery. This review assesses current knowledge of cardiac lymphatics and shows their possible role in triggering arrhythmias in the postoperative period. PMID: 19183382 [PubMed - indexed for MEDLINE] 2064. Trends Endocrinol Metab. 2009 Mar;20(2):58-65. doi: 10.1016/j.tem.2008.11.002. Epub 2009 Jan 31. Fat synthesis and adiposity regulation in Caenorhabditis elegans. Watts JL(1). Author information: (1)School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA. jwatts@wsu.edu Understanding the regulation of fat synthesis and the consequences of its misregulation is of profound significance for managing the obesity epidemic and developing obesity therapeutics. Recent work in the roundworm Caenorhabditis elegans has revealed the importance of evolutionarily conserved pathways of fat synthesis and nutrient sensing in adiposity regulation. The powerful combination of mutational and reverse genetic analysis, genomics, lipid analysis, and cell-specific expression studies enables dissection of complicated pathways at the level of a whole organism. This review summarizes recent studies in C. elegans that offer insights into the regulation of adiposity by conserved transcription factors, insulin and growth factor signaling, and unsaturated fatty acid synthesis. Increased understanding of fat-storage pathways might lead to future obesity therapies. PMCID: PMC2665873 PMID: 19181539 [PubMed - indexed for MEDLINE] 2065. Nutr Rev. 2009 Feb;67(2):105-8. doi: 10.1111/j.1753-4887.2008.00146.x. Is calcium supplementation a risk factor for cardiovascular diseases in older women? Sabbagh Z(1), Vatanparast H. Author information: (1)College of Medicine, University of Saskatchewan, Saskatoon, Canada. Comment in Nutr Rev. 2009 Jul;67(7):424; author reply 425. Low intake of dietary calcium is related to bone loss and fragility fracture in older adults, especially postmenopausal women. Contradictory findings have been reported from studies that investigated the association between calcium supplementation and hypertension and the risk of stroke and cardiovascular disease. Misinterpretation of findings from studies that are not primarily designed to address these issues might overshadow the benefits of dietary calcium. Until well-designed studies address the current uncertainties, the possible detrimental effect (e.g., hypercalcemia and its complications) of higher-than-recommended calcium intake should be balanced against the likely benefits of calcium on bone, particularly in elderly women. PMID: 19178652 [PubMed - indexed for MEDLINE] 2066. Nutr Rev. 2009 Feb;67(2):100-4. doi: 10.1111/j.1753-4887.2008.00145.x. Iron deficiency and obesity: the contribution of inflammation and diminished iron absorption. McClung JP(1), Karl JP. Author information: (1)Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, Massachussetts 01760, USA. James.McClung@amedd.army.mil Poor iron status affects billions of people worldwide. The prevalence of obesity continues to rise in both developed and developing nations. An association between iron status and obesity has been described in children and adults. The mechanism explaining this relationship remains unknown; however, findings from recent reports suggest that body mass index and inflammation predict iron absorption and affect the response to iron fortification. The relationship between inflammation and iron absorption may be mediated by hepcidin, although further studies will be required to confirm this potential physiological explanation for the increased prevalence of iron deficiency in the obese. PMID: 19178651 [PubMed - indexed for MEDLINE] 2067. Klin Med (Mosk). 2008;86(11):15-22. [On the problem of obesity in internal diseases]. [Article in Russian] Rapoport SI, Loboda AIu. A review of available data on epidemiology of obesity, its classification, physiological role and morphological structure of adipose tissue, effect of obesity on metabolic processes depending on fat distribution in the body. The influence of obesity on the function of cardio-vascular, respiratory, digestive, urinary, and endocrine systems is considered along with its role in the clinical picture and outcome of somatic diseases. PMID: 19177787 [PubMed - indexed for MEDLINE] 2068. Obes Rev. 2009 May;10(3):265-8. doi: 10.1111/j.1467-789X.2008.00559.x. Epub 2009 Jan 19. Have we entered the brown adipose tissue renaissance? Ravussin E(1), Kozak LP. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Ravusse@pbrc.edu In the 1970s and 1980s, it was observed that rodents could offset excess calories ingested when they were fed a human-like 'cafeteria diet'. Although it was erroneously concluded that this so-called diet-induced thermogenesis was because of brown adipose tissue (BAT), it led to efforts to test whether variations in brown fat in humans may explain the susceptibility to obesity. However, from evidence on the inability of ephedrine or beta-3 adrenergic agonists to induce BAT thermogenesis, it was concluded that the thermogenic role of BAT was unimportant in adult humans largely because humans had low numbers of brown adipocytes. Solid evidence on the actual numbers of brown adipocytes in humans was not available. We are now re-evaluating the role of BAT for the treatment of obesity given the following recent observations (i) studies in nuclear medicine by using PET/CT scanning reveal the presence of BAT in adult humans; and (ii) recent data suggest that a new transcription factor called PDRM16 may control the induction of BAT. These recent discoveries should revamp our effort to target the molecular development of brown adipogenesis in the treatment of obesity. PMCID: PMC3960797 PMID: 19175509 [PubMed - indexed for MEDLINE] 2069. Toxicol Pathol. 2009 Jan;37(1):65-77. doi: 10.1177/0192623308327119. Epub 2009 Jan 26. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Flint OP(1), Noor MA, Hruz PW, Hylemon PB, Yarasheski K, Kotler DP, Parker RA, Bellamine A. Author information: (1)Pharmaceutical Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. oliver.flint@bms.com Metabolic complications associated with HIV infection and treatment frequently present as a relative lack of peripheral adipose tissue associated with dyslipidemia and insulin resistance. In this review we explain the connection between abnormalities of intermediary metabolism, observed either in vitro or in vivo, and this group of metabolic effects. We review molecular mechanisms by which the HIV protease inhibitor (PI) class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage. We then propose that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism. The physiologic outcome is such that total adipocyte storage capacity is decreased, and the remaining adipocytes resist further fat storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue, where they impair insulin action. This process leads to a pathologic cycle of lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome. PMCID: PMC3170409 PMID: 19171928 [PubMed - indexed for MEDLINE] 2070. Nutr Metab Cardiovasc Dis. 2009 Feb;19(2):146-52. doi: 10.1016/j.numecd.2008.10.010. Epub 2009 Jan 25. From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Lionetti L(1), Mollica MP, Lombardi A, Cavaliere G, Gifuni G, Barletta A. Author information: (1)Department of Biological Sciences, Section of Physiology, University of Naples Federico II, Via Mezzocannone 8, 80134 Naples, Italy. AIMS: We analyze how the inflammatory state in adipose tissue caused by a condition of chronically positive energy balance can lead to insulin resistance first in adipose tissue, then in all insulin-sensitive tissues. DATA SYNTHESIS: Chronic nutrient overload causes an increase in adipose depots that, if adipose tissue expandability is low, are characterized by an increased presence of hypertrophic adipocytes. This adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER) that would lead to a proinflammatory state in adipose tissue. In this condition, ER stress would activate metabolic pathways that trigger insulin resistance, release of macrophage chemoattractant proteins, and in chronic inflammation, the death of the hypertrophic adipocyte. The infiltrated macrophages in turn release inflammatory proteins causing further recruitment of macrophages to adipose tissue and the release of inflammatory cytokines. Following these events, insulin resistance becomes extended to all adipose tissue. Insulin-resistant adipocytes, characterized by low liposynthetic capacity and high lipolytic capacity, cause increased release of free fatty acids (FFA). FFA released by lipolitic adipocytes may also activate Toll-like receptors 4 and then chemokines and cytokines release amplifying insulin resistance, lipolysis and inflammation in all adipose tissue. Moreover, increased circulating FFA levels, reduced circulating adiponectin levels and leptin resistance lead to decreased lipid oxidation in non-adipose tissues, thereby triggering ectopic accumulation of lipids, lipotoxicity and insulin resistance. CONCLUSION: All the conditions that increase circulating fatty acids and cause lipid overloading (obesity, lipoatrophy, lipodystrophy, catabolic states, etc.) induce a lipotoxic state in non-adipose tissues that gives rise to insulin resistance. PMID: 19171470 [PubMed - indexed for MEDLINE] 2071. J Sex Med. 2009 Mar;6 Suppl 3:254-61. doi: 10.1111/j.1743-6109.2008.01143.x. Beneficial impact of exercise and obesity interventions on erectile function and its risk factors. Hannan JL(1), Maio MT, Komolova M, Adams MA. Author information: (1)Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada. INTRODUCTION: Erectile dysfunction (ED) is a multifaceted disease involving cardiovascular, metabolic, and hormonal factors and affects over 100 million men worldwide. ED has been shown to be a harbinger of underlying cardiovascular diseases (CVD), as there are common risk factors (aging, hypertension, obesity) and mechanistic basis. AIM: To provide an update on clinical and experimental evidence regarding the impact of lifestyle modifications, such as exercise and diet, with respect to changes in erectile function. MAIN OUTCOME MEASURES: Published evidence regarding the impact of aging, hypertension, and obesity on ED and CVD, as well as new experimental data linking obesity and diminished erectile responses. METHODS: We reviewed the literature regarding common risk factors of ED and CVD, particularly involving obesity, as well as performed new analysis on the findings of other experimental studies involving diet and exercise interventions. RESULTS: Physical inactivity negatively impacts on erectile function, and experimental and clinical exercise interventions have been shown to improve sexual responses and overall cardiovascular health. Mediterranean-style diets and a reduction in caloric intake have been found to improve erectile function in men with the aspects of the metabolic syndrome. In addition, both clinical and experimental studies have confirmed that combining the two interventions provides additional benefit to erectile function, likely via reduced metabolic disturbances (e.g., inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (e.g., increased endothelial function). CONCLUSIONS: Lifestyle modifications provide significant benefits to vascular health and erectile function in a population that is increasingly aged and more obese. PMID: 19170860 [PubMed - indexed for MEDLINE] 2072. Biochim Biophys Acta. 2009 Jun;1791(6):479-85. doi: 10.1016/j.bbalip.2008.12.015. Epub 2009 Jan 8. Effect of plasma triglyceride metabolism on lipid storage in adipose tissue: studies using genetically engineered mouse models. Voshol PJ(1), Rensen PC, van Dijk KW, Romijn JA, Havekes LM. Author information: (1)Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. The obesity epidemic is associated with an increased incidence of type 2 diabetes, cardiovascular morbidity and various types of cancer. A better insight into the molecular mechanisms that underlie adipogenesis and obesity may result in novel therapeutic handles to fight obesity and these associated diseases. Adipogenesis is determined by the balance between uptake of fatty acids (FA) from plasma into adipocytes, intracellular FA oxidation versus esterification of FA into triglycerides (TG), lipolysis of TG by intracellular lipases, and secretion of FA from adipocytes. Here, we review the mechanisms that are specifically involved in the entry of FA into adipose tissue. In plasma, these originating FA are either present as TG within apoB-containing lipoproteins (i.e. chylomicrons and VLDL) or as free FA bound to albumin. Kinetic studies, however, have revealed that TG are the major source of FA entering adipose tissue, both in the fed and fasted condition. In fact, studies with genetically engineered mice have revealed that the activity of lipoprotein lipase (LPL) is a major determinant for the development of obesity. As a general rule, high fat diet-induced adipogenesis is aggravated by stimulated LPL activity (e.g. by adipose tissue-specific overexpression of LPL or deficiency for apoCIII), and attenuated by inhibited LPL activity (e.g. by adipose-specific deficiency for LPL, overexpression of apoCI or angptl4, or by deficiency for apoE or the VLDL receptor). In addition, we describe that the trans-membrane transport of FA and cytoplasmic binding of FA in adipocytes can also dramatically affect adipogenesis. The relevance of these findings for human pathophysiology is discussed. PMID: 19168150 [PubMed - indexed for MEDLINE] 2073. Clin Chim Acta. 2009 Apr;402(1-2):1-6. doi: 10.1016/j.cca.2008.12.032. Epub 2009 Jan 9. Clinical and molecular aspects of Berardinelli-Seip Congenital Lipodystrophy (BSCL). Gomes KB(1), Pardini VC, Fernandes AP. Author information: (1)COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. karina@coltec.ufmg.br Congenital Generalized Lipodystrophy (CGL) or Berardinelli-Seip Syndrome (BSCL) is a rare autosomal recessive disease characterized by complete absence of adipose tissue and by several metabolic alterations in carbohydrate (diabetes mellitus) and lipid metabolism and involvement of heart, bone and ovaries. Mental retardation and psychiatric disturbances are present in a variable proportion of affected patients. In the present review, the major advances in clinical, molecular and genetic characterization of BSCL affected subjects are recorded and discussed. PMID: 19167372 [PubMed - indexed for MEDLINE] 2074. Kardiologiia. 2009;49(1):51-8. [The role of adiponectin in development and progression of cardiovascular diseases]. [Article in Russian] Kobalava ZhD, Villeval'de SV, Isikova KhV. Arterial hypertension, insulin resistance, diabetes mellitus are associated with obesity. However exact mechanisms of this association have not been determined yet. Biologically active substances produced by adipose tissue participate in pathogenesis of cardiovascular diseases and complications. In this review we present data on the role of adiponectin -- adipocytokine with unique antiatherogenic, antiinflammatory, and insulin sensitizing properties. Hypoadiponectinemia is considered to be potentially modifiable cardiovascular risk factor and novel therapeutic target. Therapy with PPAR gamma agonists, blockers of renin-angiotensin and sympathetic nervous systems is associated with elevation of concentration of adiponectin. PMID: 19166402 [PubMed - indexed for MEDLINE] 2075. IUBMB Life. 2009 Feb;61(2):112-33. doi: 10.1002/iub.156. Water channel proteins (later called aquaporins) and relatives: past, present, and future. Benga G(1). Author information: (1)Department of Cell and Molecular Biology, Iuliu HaTieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania. gbenga@umfcluj.ro Water channels or water channel proteins (WCPs) are transmembrane proteins that have a specific three-dimensional structure with a pore that can be permeated by water molecules. WCPs are large families (over 450 members) that are present in all kingdoms of life. The first WCP was discovered in the human red blood cell (RBC) membrane in 1980s. In 1990s other WCPs were discovered in plants, microorganisms, various animals, and humans; and it became obvious that the WCPs belong to the superfamily of major intrinsic proteins (MIPs, over 800 members). WCPs include three subfamilies: (a) aquaporins (AQPs), which are water specific (or selective water channels); (b) aquaglyceroporins (and glycerol facilitators), which are permeable to water and/or other small molecules; and (c) "superaquaporins" or subcellular AQPs. WCPs (and MIPs) have several structural characteristics which were better understood after the atomic structure of some MIPs was deciphered. The structure-function relationships of MIPs expressed in microorganisms (bacteria, archaea, yeast, and protozoa), plants, and some multicellular animal species [nematodes, insects, fishes, amphibians, mammals (and humans)] are described. A synthetic overview on the WCPs from RBCs from various species is provided. The physiological roles of WCPs in kidney, gastrointestinal system, respiratory apparatus, central nervous system, eye, adipose tissue, skin are described, and some implications of WCPs in various diseases are briefly presented. References of detailed reviews on each topic are given. This is the first review providing in a condensed form an overview of the whole WCP field that became in the last 20 years a very hot area of research in biochemistry and molecular cell biology, with wide and increasing implications. PMID: 19165894 [PubMed - indexed for MEDLINE] 2076. J Craniofac Surg. 2009 Jan;20(1):53-7. doi: 10.1097/SCS.0b013e3181945a9e. Obese oral and maxillofacial surgical patient. Krishnan B(1). Author information: (1)Department of Oral and Maxillofacial Surgery, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Pondicherry, India. krishident@yahoo.co.uk The incidence of obesity is rising in many countries around the world. With obesity exerting a direct impact on oral health, more obese patients are likely to report for oral and maxillofacial surgical procedures. The obese patient population presents with unique anatomic and physiologic challenges that can significantly influence treatment strategies. The implications of obesity must be understood by the maxillofacial surgeon to avoid potential pitfalls. This study focuses on the relevant issues concerning obesity with regard to oral and maxillofacial surgery. PMID: 19164989 [PubMed - indexed for MEDLINE] 2077. Biochim Biophys Acta. 2009 Jun;1791(6):507-13. doi: 10.1016/j.bbalip.2008.12.014. Epub 2009 Jan 7. Lipodystrophies: disorders of adipose tissue biology. Garg A(1), Agarwal AK. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. abhimanyu.garg@utsouthwestern.edu The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARgamma and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation. PMCID: PMC2693450 PMID: 19162222 [PubMed - indexed for MEDLINE] 2078. J Am Coll Nutr. 2008 Dec;27(6):667-76. Nonalcoholic fatty liver disease in children. Manco M(1), Bottazzo G, DeVito R, Marcellini M, Mingrone G, Nobili V. Author information: (1)Catholic University, Rome, Italy. melaniamanco@tiscali.it In view of the epidemic obesity in childhood, facing the disease and its associated morbidities early at this age becomes crucial for public health researchers and care givers. The present review focuses on pediatric Non Alcoholic Fatty Liver Disease (NAFLD) among co-morbidities, being the disease yet under diagnosed and under treated despite a prevalence growing exponentially. Evidences suggest that the environmental background for the development of NAFLD may be established in early life, and that the duration of the disease affects probably the likelihood of progression to more severe disease (necro-inflammation or Non Alcoholic SteatoHepatitis, also termed, NASH; fibrosis and cirrhosis). NAFLD associates with abdominal obesity, insulin resistance and features of metabolic syndrome. In genetically prone individuals, malnutrition (i.e., excessive consumption of saturated fats and refined sugars) leads to the derangement of the adipose tissue architecture and homeostasis, the peripheral and hepatic resistance to insulin-stimulated glucose uptake, thus favoring a condition of chronic low-grade inflammation. Excessive nutrients cannot be stored in the adipose tissue and overflow elsewhere, mainly to the muscle tissue and liver. Fat deposition in both sites enhances insulin resistance and further deposition of fats in a vicious manner. What is of special interest comparing NAFLD in children and adults is that the histological appearance of the disease differs significantly, likely representing a yet physiological response to environmental stressors in children and a long-term adaptation in adults. In this article, we review the current concepts about paediatric NAFLD, its pathogenesis, diagnosis and treatment, with particular regard to lifestyle and foods habits. PMID: 19155426 [PubMed - indexed for MEDLINE] 2079. Med Sci (Paris). 2009 Jan;25(1):45-50. doi: 10.1051/medsci/200925145. [The two sides of ADAM17 in inflammation: implications in atherosclerosis and obesity]. [Article in French] Peiretti F(1), Canault M, Morange P, Alessi MC, Nalbone G. Author information: (1)Inserm U626, Faculté de Médecine, 27, boulevard Jean Moulin, 13385 Marseille Cedex 5, France. franck.peiretti@univmed.fr ADAM17 was initially characterized as the TNF Alpha Converting Enzyme (TACE) and, until now, has been the most studied member of the ADAM family. It is a type I transmembrane metalloproteinase involved in the shedding of the extracellular domain of several transmembrane proteins (at least 40) such as cytokines, growth factors, receptors or adhesion molecules. As a consequence, depending on the transmembrane molecule cleaved, one may expect possible opposite effects of ADAM17 activity on inflammation (e.g. TNF and its receptors). The role of ADAM17 in regulating inflammatory cellular processes is clearly demonstrated in cells deficient in active ADAM17 or expressing substrates mutated for the ADAM17 cleavage site. As ADAM17-deficient mice died at birth, mice overexpressing the mutated uncleavable form of some substrates and recently conditional knock-out of ADAM17 are used to approach in vivo the role of this metalloprotease in regulating inflammation. Arguments are provided that ADAM17 plays a role in atherosclerosis, in adipose tissue metabolism, insulin resistance and diabetes. The multitude of substrates cleaved by ADAM17 makes this enzyme an attractive candidate to study its role in inflammation-driven pathologies. PMID: 19154693 [PubMed - indexed for MEDLINE] 2080. Mol Cell Endocrinol. 2009 Apr 29;302(2):128-39. doi: 10.1016/j.mce.2008.12.011. Epub 2008 Dec 25. Angiotensin II and the development of insulin resistance: implications for diabetes. Olivares-Reyes JA(1), Arellano-Plancarte A, Castillo-Hernandez JR. Author information: (1)Department of Biochemistry, Center for Research and Advanced Studies of the National Polytechnic Institute, CINVESTAV-IPN, Mexico, DF, Mexico. jolivare@cinvestav.mx Angiotensin II (Ang II), the major effector hormone of the renin-angiotensin system (RAS), has an important role in the regulation of vascular and renal homeostasis. Clinical and pharmacological studies have recently shown that Ang II is a critical promoter of insulin resistance and diabetes mellitus type 2. Ang II exerts its actions on insulin-sensitive tissues such as liver, muscle and adipose tissue where it has effects on the insulin receptor (IR), insulin receptor substrate (IRS) proteins and the downstream effectors PI3K, Akt and GLUT4. The molecular mechanisms involved have not been completely identified, but the role of serine/threonine phosphorylation of the IR and IRS-1 proteins in desensitization of insulin action has been well established. The purpose of this review is to highlight recent advances in the understanding of Ang II actions which lead to the development of insulin resistance and its implications for diabetes. PMID: 19150387 [PubMed - indexed for MEDLINE] 2081. Curr Pharm Des. 2009;15(1):110-7. NAD(+), sirtuins, and cardiovascular disease. Borradaile NM(1), Pickering JG. Author information: (1)Vascular Biology Group, Robarts Research Institute, London, Ontario, Canada, N6A 5K8. Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD(+)-dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latter by modulating whole body metabolism. SIRT1-4 regulate the activities of a variety of transcription factors, coregulators, and enzymes that improve metabolic control in adipose tissue, liver, skeletal muscle, and pancreas, particularly during obesity and aging. SIRT1 and 7 can control myocardial development and resist stress- and aging-associated myocardial dysfunction through the deacetylation of p53 and forkhead box O1 (FoxO1). By modulating the activity of endothelial nitric oxide synthase (eNOS), FoxO1, and p53, and the expression of angiotensin II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory and regenerative functions in endothelial and smooth muscle cells of the vascular wall. Given the array of potentially beneficial effects of SIRT activation on cardiovascular health, interest in developing specific SIRT agonists is well-substantiated. Because SIRT activity depends on cellular NAD+ availability, enzymes involved in NAD+ biosynthesis, including nicotinamide phosphoribosyltransferase (Nampt), may also be valuable pharmaceutical targets for managing CVD. Herein we review the actions of the SIRT proteins on the cardiovascular system and consider the potential of modulating SIRT activity and NAD+ availability to control CVD. PMID: 19149606 [PubMed - indexed for MEDLINE] 2082. Mcgill J Med. 2008 Jul;11(2):177-84. Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity? Brown RE(1). Author information: (1)Russell.Brown@mail.mcgill.ca Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain. PMCID: PMC2582659 PMID: 19148319 [PubMed] 2083. Obesity (Silver Spring). 2009 Apr;17(4):632-9. doi: 10.1038/oby.2008.604. Epub 2009 Jan 15. Mathematical modeling of glucose homeostasis and its relationship with energy balance and body fat. Smith JM(1), Maas JA, Garnsworthy PC, Owen MR, Coombes S, Pillay TS, Barrett DA, Symonds ME. Author information: (1)School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK. PMID: 19148129 [PubMed - indexed for MEDLINE] 2084. J Musculoskelet Neuronal Interact. 2008 Oct-Dec;8(4):346-7. Local and systemic functions of bone fat and its contribution to the energy metabolism--the effect of diabetes and obesity on bone. Lecka-Czernik B(1). Author information: (1)University of Toledo Medical Center, Department of Orthopaedic Surgery, Center for Diabetes and Endocrine Research, Toledo, OH 43614, USA. beata.leckaczernik@utoledo.edu PMID: 19147970 [PubMed - indexed for MEDLINE] 2085. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S98-108. doi: 10.1038/ijo.2008.245. Molecular physiology of weight regulation in mice and humans. Leibel RL(1). Author information: (1)Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. rl232@columbia.edu Evolutionary considerations relating to efficiency in reproduction, and survival in hostile environments, suggest that body energy stores are sensed and actively regulated, with stronger physiological and behavioral responses to loss than gain of stored energy. Many physiological studies support this inference, and suggest that a critical axis runs between body fat and the hypothalamus. The molecular cloning of leptin and its receptor-projects based explicitly on the search for elements in this axis-confirmed the existence of this axis and provided important tools with which to understand its molecular physiology. Demonstration of the importance of this soma-brain reciprocal connection in body weight regulation in humans has been pursued using both classical genetic approaches and studies of physiological responses to experimental weight perturbation. This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis. PMCID: PMC2682360 PMID: 19136999 [PubMed - indexed for MEDLINE] 2086. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S83-92. doi: 10.1038/ijo.2008.243. The role of fat topology in the risk of disease. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Professor Emeritus Osaka University, Kita-Ku, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Clustering of multiple risk factors such as impaired glucose metabolism, lipid disorders and hypertension has been shown to be the major background of atherosclerotic diseases, and disease entities such as the metabolic syndrome represent a highly atherogenic state. Although these common risks may generally co-exist by accident in one individual, clustering of multiple risk factors in the metabolic syndrome does not occur by accident, and there should be a key player for the syndrome. In 1983, we reported the method for fat analysis using computed tomography scan, which enables us to analyze intra-abdominal visceral adiposity as well as subcutaneous fat. Visceral fat accumulation has been shown to cause impaired glucose metabolism, lipid disorders, and hypertension, and therefore it is considered to be a key player in the metabolic syndrome. To clarify the mechanism by which visceral fat accumulation causes a variety of metabolic and vascular diseases, we studied the molecular characteristics of adipose tissue and adipocytes by investigating expressed genes in visceral and subcutaneous adipocytes and revealed that adipocytes, especially visceral adipocytes, secrete a variety of bioactive substances, the so-called adipocytokines. We showed that visceral fat accumulation causes abnormalities in adipocytokine secretion, such as hypersecretion of plasminogen activator inhibitor 1, which is related to thrombogenic vascular diseases. More importantly, we discovered an important benign adipocytokine named adiponectin, which protects against the development of diabetes mellitus, hypertension, inflammation, and atherosclerotic vascular diseases. Plasma levels of adiponectin decreased in individuals with visceral fat accumulation, and hypoadiponectinemia caused by visceral fat accumulation might be one of the major causes of metabolic syndrome. PMID: 19136997 [PubMed - indexed for MEDLINE] 2087. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S52-4. doi: 10.1038/ijo.2008.238. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Hotamisligil GS(1). Author information: (1)Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA, USA. ghotamis@hsph.harvard.edu Obesity is associated with chronic low-grade inflammation. Inflammatory signals interfere with insulin action and disrupt metabolic homeostasis. The c-Jun N-terminal kinase (JNK) has been identified as a central mediator of insulin resistance. Recent studies showed that in obesity compromising endoplasmic reticulum (ER) function results in insulin resistance and type 2 diabetes that are dependent on JNK activation. In contrast, enhancing ER function in transgenic mice or by the use of chemical chaperones protects against diet-induced insulin resistance. Hence, ER stress and the related signaling networks present a critical mechanism underlying obesity-induced JNK activity, inflammatory response and insulin resistance. PMCID: PMC2885768 PMID: 19136991 [PubMed - indexed for MEDLINE] 2088. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S39-51. doi: 10.1038/ijo.2008.237. Advances in adipose tissue metabolism. Lafontan M(1). Author information: (1)Inserm U858, Institute of Molecular Medicine of Rangueil, BP84225, 31432 Toulouse cedex 4, Toulouse, France. Max.Lafontan@inserm.fr This review will focus on the recent findings in adipose tissue metabolism with special attention to human adipocyte biology and physiology. There are major advances stemming from the concomitant results obtained from studies on mature human adipocytes, human preadipocytes differentiated in vitro and murine adipose cell lines. Physiological developments have been based on the expanded utilization of various kinds of murine transgenic models and physiological techniques such as microdialysis, open-flow microperfusion, arteriovenous techniques and the utilization of deuterium- or tritium-labelled metabolites that have provided a number of physiological advances in the understanding of human adipose tissue physiology. Gene expression profiling studies and nutrigenomics are emerging methods that herald interesting approaches for the future. An overview of recent discoveries in the mechanisms involved in the control of free fatty acid uptake, triacylglycerol synthesis and fat deposition will be discussed, as well as recent advances in the mechanisms involved in the lipolytic pathways, the role of lipases and perilipins. In addition, the in vivo validation of catecholamine action and the discovery of the lipolytic effects of natriuretic peptides will also be covered. PMID: 19136990 [PubMed - indexed for MEDLINE] 2089. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S32-8. doi: 10.1038/ijo.2008.236. UCP1: its involvement and utility in obesity. Kozak LP(1), Anunciado-Koza R. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. kozaklp@pbrc.edu Energy balance to prevent the development of obesity is dependent on energy expenditure. Although physical activity is the dominant mechanism for dissipating excess energy, a system of thermogenesis that evolved to protect the body from hypothermia is based upon the uncoupling of oxidative phosphorylation in brown adipocytes by the mitochondrial uncoupling protein (UCP1). It has been shown that upregulation of UCP1 by genetic manipulations or pharmacological agents can reduce obesity and improve insulin sensitivity. Recent evidence has shown the existence of two sources for brown adipocytes, one appearing as discrete brown fat depots during fetal development and the other appears during post-natal development as diffuse populations in traditional white fat depots. The latter can be induced by adrenergic stimulation depending on the genetic background of the animals and the nutritional environment. Understanding the biological and environmental factors controlling the expression of these two brown adipocyte populations promises to provide new strategies by which enhanced thermogenesis can be used to reduce obesity.International Journal of Obesity (2008) 32, S32-S38; doi:10.1038/ijo.2008.236. PMCID: PMC2746324 PMID: 19136989 [PubMed - indexed for MEDLINE] 2090. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S2-7. doi: 10.1038/ijo.2008.231. How much progress have we made over the last few decades? Bouchard C(1). Author information: (1)Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Bouchac@pbrc.edu To recognize the 20th anniversary of the opening of the Pennington Biomedical Research Center in Baton Rouge, Louisiana, USA, a conference was held featuring some of the most prominent obesity researchers worldwide, addressing the most significant advances in obesity research. The Center had been founded with a gift from wealthy oilman Claude B Pennington with the mission of 'promoting healthier lives through research and education in nutrition and preventive medicine.' The purpose of the conference was to provide a cohesive presentation of the key events and steps that led to the major discoveries or advances in obesity science and give insight into new research directions. Only 20 of many possible topics could be adequately covered in the program of the conference. Their increasing importance is reflected in the increasing number of related publications as extracted from PubMed. The broad general areas in which these topics fall include measurement and evaluation of obesity, measurement of body composition and fat distribution, adipose tissue biology, genetics, bariatric surgery and public policy. Advances in the areas covered at the conference have had a major impact on our understanding of adipogenesis, central and peripheral regulation of body weight, health consequences of excess body weight, challenges of weight loss, magnitude of the worldwide epidemic and impact of public health policies. PMID: 19136987 [PubMed - indexed for MEDLINE] 2091. Int J Obes (Lond). 2008 Dec;32 Suppl 7:S143-51. doi: 10.1038/ijo.2008.251. Obesity research in the next decade. Eckel RH(1). Author information: (1)Department of Physiology and Biophysics, University of Colorado Denver, Aurora, CO 80045, USA. robert.eckel@uchsc.edu The obesity epidemic demands more insight into genetic predisposition, mechanisms, prevention and therapeutic interventions. Opinions about how to prioritize obesity research in the next decade are many and highly varied. However, in this article I have chosen three areas of focus that arguably should be at the top of the list. These include: (1) the physiologic basis of body weight and body fat regulation; (2) epigenetic mechanisms of energy balance; and (3) the prevention of obesity. The approach needs to be translational and bi-directional with a strong emphasis on basic science including studies of relevant gene expression and animal models of energy balance. Clinical research into mechanisms can challenge the existing paradigms that could direct research back to more basic understanding or to applications to populations at risk. Communication between scientists and physicians at the far end of the spectrum needs new and ongoing emphasis. PMID: 19136985 [PubMed - indexed for MEDLINE] 2092. Curr Opin Lipidol. 2009 Feb;20(1):50-6. Ectopic lipids and organ function. Szendroedi J(1), Roden M. Author information: (1)Department of Medicine/Metabolic Diseases, Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University Düsseldorf, Düsseldorf, Germany PURPOSE OF REVIEW: To summarize recent studies that shed more light on possible mechanisms by which ectopic lipid storage affects organ function. RECENT FINDINGS: Although ectopic lipids have been considered as biomarkers of lipotoxicity, adaptation of metabolic fluxes and of mitochondrial function seem to be more important than actual cellular fat contents in liver and muscle. Diabetic and obese humans have elevated myocardial lipid contents, which are associated with mitochondrial and contractile dysfunction and could even precede the development of heart failure. Although pancreatic fat content is negatively associated with insulin secretion, [beta]-cell triglycerides are not easily accessible to measurement in humans rendering their role for [beta]-cell function unclear. New approaches to quantify energy metabolism in various organs could help to identify novel biomarkers of organ function in humans. SUMMARY: Dietary intake of high-caloric high-fat diets and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues. Intracellular lipid contents in skeletal muscle and liver have been related to insulin resistance and inflammatory processes. Myocardial fat is increased in heart failure, whereas pancreatic fat could relate to insulin secretion. PMID: 19133412 [PubMed - indexed for MEDLINE] 2093. Curr Opin Lipidol. 2009 Feb;20(1):45-9. Dietary fat oxidation as a function of body fat. Westerterp KR(1). Author information: (1)Department of Human Biology, Maastricht University, Maastricht, The Netherlands. K.Westerterp@HB.Unimaas.NL PURPOSE OF REVIEW: Is trafficking of dietary fat involved in the development of obesity? RECENT FINDINGS: Studies on energy expenditure and substrate utilization during overfeeding, studies on individual differences in substrate utilization between individuals fed at energy balance, and differences in responses in energy expenditure and substrate utilization in individuals after weight reduction, illustrate that the capacity of fat oxidation is a potential determinant for the development of obesity. SUMMARY: The ability to store dietary fat seems to be involved in the susceptibility to gain weight during a positive energy balance. Obese individuals show less oxidation and more storage of dietary fat as compared with the lean phenotype. Differences in fuel trafficking make individuals prone to overeating in the current obesogenic environment with a high availability of energy-dense fatty foods. It is difficult to get rid of excess body fat as energy requirement for weight maintenance after weight reduction is lower than predicted from the new body composition reached and thus, there is a high risk for weight regain. PMID: 19133411 [PubMed - indexed for MEDLINE] 2094. Curr Opin Lipidol. 2009 Feb;20(1):39-44. The effect of dietary cholesterol on macrophage accumulation in adipose tissue: implications for systemic inflammation and atherosclerosis. Subramanian S(1), Chait A. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Washington, USA. PURPOSE OF REVIEW: It is well recognized that adipose tissue in obesity is characterized by macrophage accumulation and local inflammation. This review summarizes current evidence regarding dietary cholesterol on adipose tissue macrophage accrual, systemic inflammation and its potential link to atherosclerosis. RECENT FINDINGS: Based upon epidemiological data and animal studies, both obesity and dietary cholesterol have been associated with coronary artery disease. However, the effect of dietary cholesterol on adipose tissue has not been widely studied. In an animal model of obesity/metabolic syndrome, feeding a diabetogenic diet high in saturated fat and refined carbohydrate with 0.15% cholesterol added resulted in increased adipose tissue macrophage accumulation, local inflammation and chronic systemic inflammation compared to animals that received the same diet without added cholesterol. There also was an increased macrophage content of atherosclerotic lesions observed in the added cholesterol group. SUMMARY: Mechanisms involved in adipose tissue macrophage accrual continue to be elusive. There are limited data that dietary cholesterol may worsen macrophage accumulation in adipose tissue and the artery wall. Cytokines produced by inflamed adipose tissue may lead to inflammatory changes in the liver, which could then play a role in atherogenesis. PMID: 19133410 [PubMed - indexed for MEDLINE] 2095. Ann Plast Surg. 2009 Jan;62(1):97-103. doi: 10.1097/SAP.0b013e3181788ec9. Tissue engineering in plastic surgery: an up-to-date review of the current literature. Sterodimas A(1), De Faria J, Correa WE, Pitanguy I. Author information: (1)Department of Plastic Surgery, Pontifical Catholic University of Rio de Janeiro and the Carlos Chagas Post-Graduate Medical Institute, Rio de Janeiro, Brazil. Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function. This field has enjoyed tremendous growth in the past 10 years fuelled by its potential role in regenerating new tissues and naturally healing injured or diseased organs. Stem cells due to their pluripotentiality and unlimited capacity for self-renewal, may allow significant advances for distinct reconstructive and cosmetic procedures. This review aims at outlining the principles of tissue engineering, focusing on the use of adult-derived stem cells as applied to the research and practice of plastic surgery. Review categories have been divided into tissue engineering of the skin and connective tissue, bone marrow, cartilage, adipose tissue, and breast tissue. An analytical review of the current literature on stem cell technology on the above mentioned areas is presented. There have been reports of side effects and unsuccessful treatments. The key to the progress of tissue engineering is an understanding between basic scientists, biochemical engineers, clinicians, and industry. Although there has been an ongoing research pointing to the enormous potential of using stem cells in cosmetic and reconstructive surgery, at this stage, stem cell therapy is still a hope that has not been fully studied and approved. More long-term studies are needed and many questions remain to be answered. PMID: 19131730 [PubMed - indexed for MEDLINE] 2096. Circ J. 2009 Feb;73(2):214-20. Epub 2009 Jan 8. Peroxisome proliferator-activated receptor gamma and cardiovascular diseases. Takano H(1), Komuro I. Author information: (1)Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. htakano-cib@umin.ac.jp Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and form heterodimers with retinoid X receptor. Three PPAR isoforms have been isolated and termed alpha, beta (or delta) and gamma. Although PPARgamma is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, PPARgamma is also present in a variety of cell types. Synthetic antidiabetic thiazolidinediones (TZDs) are well known as ligands and activators for PPARgamma. After it was reported that activation of PPARgamma suppressed production of pro-inflammatory cytokines in activated macrophages, medical interest in PPARgamma has grown and there has been a huge research effort. PPARgamma is currently known to be implicated in various human chronic diseases such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimer's disease. Many studies suggest that TZDs not only ameliorate insulin sensitivity, but also have pleiotropic effects on many tissues and cell types. Although activation of PPARgamma seems to have beneficial effects on cardiovascular diseases, the mechanisms by which PPARgamma ligands prevent their development are not fully understood. Recent data about the actions and its mechanisms of PPARgamma-dependent pathway in cardiovascular diseases are discussed here. PMID: 19129679 [PubMed - indexed for MEDLINE] 2097. J Investig Allergol Clin Immunol. 2008;18(6):420-5. Obesity and asthma. Delgado J(1), Barranco P, Quirce S. Author information: (1)Allergy Service, University Hospital Virgen Macarena, Sevilla, Spain. juliodelgadoromero@gmail.com Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous studies have linked these disorders. Most prospective studies show that obesity is a risk factor for asthma and have found a positive correlation between baseline body mass index and the subsequent development of asthma. Furthermore, several studies suggest that whereas weight gain increases the risk of asthma, weight loss improves the course of the illness. Different factors could explain this association. Obesity is capable of reducing pulmonary compliance, lung volumes, and the diameter of peripheral respiratory airways as well as affecting the volume of blood in the lungs and the ventilation-perfusion relationship. Furthermore, the increase in the normal functioning of adipose tissue in obese subjects leads to a systemic proinflammatory state, which produces a rise in the serum concentrations of several cytokines, the soluble fractions of their receptors, and chemokines. Many of these mediators are synthesized and secreted by cells from adipose tissue and receive the generic name of adipokines, including IL-6, IL-10, eotaxin, tumor necrosis factor-alpha, transforming growth factors-beta1, C-reactive protein, leptin, and adiponectin. Finally, specific regions of the human genome related to both asthma and obesity have been identified. Most studies point out that obesity is capable of increasing the prevalence and incidence of asthma, although this effect appears to be modest. The treatment of obese asthmatics must include a weight control program. PMID: 19123432 [PubMed - indexed for MEDLINE] 2098. Hormones (Athens). 2008 Oct-Dec;7(4):287-93. Chronic stress, visceral obesity and gonadal dysfunction. Kyrou I(1), Tsigos C. Author information: (1)Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital, Athens University Medical School, Athens, Greece. Chronic stress represents a prolonged state of dyshomeostasis caused by intense and frequently imposed stressors. Obesity constitutes a chronic dysmetabolic state, leading progressively to a spectrum of metabolic complications, such as diabetes, dyslipidemia, hypertension and cardiovascular disease. Alpha growing body of evidence supports the existence of significant interactions between stress and obesity, with chronic stress promoting weight gain, and consequently excessive fat accumulation especially visceral, all these factors contributing to the development of a chronic stressful state. Maintaining body homeostasis is a prerequisite for normal reproductive function, which is vital for the survival of the species and an important process of natural selection. Under chronic stress, reproductive function is suspended and disrupted due to central and peripheral actions of hormones, adipokines and pro-inflammatory cytokines that inhibit the activity of the hypothalamic-pituitary gonadal (HPG) axis at various levels. Clinical and experimental data link both obesity and chronic stress to dysregulation of the gonadal axis, via independent and synergistic mechanisms, which may chronically lead to reproductive dysfunction and reduced fertility. PMID: 19121989 [PubMed - indexed for MEDLINE] 2099. Semin Nephrol. 2009 Jan;29(1):3-14. doi: 10.1016/j.semnephrol.2008.10.002. Why is protein-energy wasting associated with mortality in chronic kidney disease? Kovesdy CP(1), Kalantar-Zadeh K. Author information: (1)Division of Nephrology, Salem Veterans Affairs Medical Center, Salem, VA 24153, USA. csaba.kovesdy@va.gov Observational studies in chronic kidney disease (CKD) populations consistently have shown the strong mortality-predictability of such markers of protein-energy wasting (PEW) as hypoalbuminemia, low serum cholesterol levels, low body mass index, and reduced dietary protein intake. Even though the PEW-mortality association data traditionally are reported mostly in maintenance dialysis patients, emerging studies extend the existence of these associations to predialysis stages of CKD. Paradoxic risk factor patterns (reverse epidemiology) for both obesity and cholesterol recently have been reported in predialysis CKD, underscoring the overwhelming impact of PEW, a short-term killer, on reversing the long-term effect of conventional cardiovascular risk factors. Multiple pathophysiologic mechanisms have been suggested to explain the link between PEW and mortality in CKD, including derangements in muscle, adipose tissue, and the gastrointestinal, hematopoietic, and immune systems; complications related to deficiencies of multiple micronutrients; and the maladaptive activation of the inflammatory cascade. In addition to well-described pathophysiologic mechanisms involved in the higher mortality seen with PEW, we also discuss the potential role of novel factors such as circulating actin, gelsolin, and proinflammatory high-density lipoprotein. Whether PEW is causally related to adverse outcomes in CKD needs to be verified in randomized controlled trials of nutritional interventions. The initiation of major clinical trials targeting nutritional interventions with the goal of improving survival in CKD offer the promise of extending the survival of this vulnerable patient population. PMID: 19121469 [PubMed - indexed for MEDLINE] 2100. Am J Med. 2009 Jan;122(1 Suppl):S26-37. doi: 10.1016/j.amjmed.2008.10.015. "Sick fat," metabolic disease, and atherosclerosis. Bays HE(1). Author information: (1)Louisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, Kentucky 40213, USA. HBaysMD@aol.com Atherosclerotic coronary heart disease (CHD) is the most common cause of morbidity and mortality among men and women in developed nations. The obesity epidemic contributes to the increasing prevalence of high blood sugar (as may be found in patients with diabetes mellitus and metabolic syndrome), high blood pressure, and dyslipidemia--all CHD risk factors. Metabolic syndrome describes the common clinical finding wherein component CHD risk factors cluster within a single patient, but this term does not identify any unified pathophysiologic process. However, a component of the metabolic syndrome is abdominal obesity, which does reflect an anatomic manifestation of a "common-soil" pathophysiologic process that promotes the onset of CHD risk factors, and thus increases CHD risk. Adiposopathy ("sick fat") is anatomically characterized by visceral adiposity and adipocyte hypertrophy; it is manifested physiologically by a net increase in release of free fatty acids and by pathogenic adipose tissue metabolic/immune responses that promote metabolic disease and increase CHD risk. Understanding the relation of adiposopathy to CHD risk factors and recognizing the importance of treating both the "cause and effect" of metabolic diseases are critical toward a comprehensive approach in reducing CHD risk. Regarding the "cause," clinicians and their patients should be diligent regarding appropriate nutritional and lifestyle interventions that may favorably affect health. Regarding the "effect," clinicians and their patients should be equally diligent toward appropriate pharmaceutical interventions that reduce CHD risk factors when nutritional and lifestyle interventions do not sufficiently achieve desired metabolic treatment goals. PMID: 19110085 [PubMed - indexed for MEDLINE] 2101. Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E10-8. doi: 10.1152/ajpendo.90949.2008. Epub 2008 Dec 30. Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Shi Y(1), Cheng D. Author information: (1)Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA, USA. YSHI@hmc.psu.edu Monoacyglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze two consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT enzymes that differ in catalytic properties, subcellular localization, tissue distribution, and physiological functions. MGAT and DGAT enzymes play fundamental roles in the metabolism of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiological functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT enzymes and the development of chemical inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT enzymes by synthetic compounds may provide novel treatment for obesity and its related metabolic complications. PMCID: PMC3735925 PMID: 19116371 [PubMed - indexed for MEDLINE] 2102. Curr Opin Endocrinol Diabetes Obes. 2009 Feb;16(1):10-5. Effect of puberty on body composition. Loomba-Albrecht LA(1), Styne DM. Author information: (1)University of California Davis Medical Center, Department of Pediatrics, Sacramento, California 95817, USA. PURPOSE OF REVIEW: Here we examine the effect of puberty on components of human body composition, including adiposity (total body fat, percentage body fat and fat distribution), lean body mass and bone mineral content and density. New methods and longitudinal studies have expended our knowledge of these remarkable changes. RECENT FINDINGS: Human differences in adiposity, fat free mass and bone mass reflect differences in endocrine status (particularly with respect to estrogens, androgens, growth hormone and IGF-1), genetic factors, ethnicity and the environment. During puberty, males gain greater amounts of fat free mass and skeletal mass, whereas females acquire significantly more fat mass. Both genders reach peak bone accretion during the pubertal years, though males develop a greater skeletal mass. Body proportions and fat distribution change during the pubertal years as well, with males assuming a more android body shape and females assuming a more gynecoid shape. Pubertal body composition may predict adult body composition and affects both pubertal timing and future health. SUMMARY: Sexual dimorphism exists to a small degree at birth, but striking differences develop during the pubertal years. The development of this dimorphism in body composition is largely regulated by endocrine factors, with critical roles played by growth hormone and gonadal steroids. It is important for clinicians and researchers to know the normal changes in order to address pathologic findings in disease states. PMID: 19115520 [PubMed - indexed for MEDLINE] 2103. Int J Exerc Sci. 2009;2(3):191-201. Consequences of Weight Cycling: An Increase in Disease Risk? Strohacker K(1), Carpenter KC(1), McFarlin BK(1). Author information: (1)Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA. Research indicates that weight cycling, or "yo-yo dieting" is a common occurrence in overweight and obese populations. The long term negative health consequences of weight cycling are debated and it is unclear whether or not this weight change pattern poses a greater disease risk compared to obesity maintenance. This review discusses the prevalence of weight cycling and physiological alterations occurring during weight loss that promotes weight regain. We also discuss the effect weight regain has upon adipose tissue in terms of rate and type of accumulation. Also within this review are discussions surrounding the previously published literature based upon human and rodent research. We focus on previous limitations and difference in experimental design that have perhaps resulted in mixed findings concerning independent effects of weight cycling on health parameters. The final purpose of this review is to discuss future directions in evaluating the pro-inflammatory response to weight cycling in order to compare the disease risk compared to obesity maintenance. PMCID: PMC4241770 PMID: 25429313 [PubMed] 2104. Pediatr Endocrinol Diabetes Metab. 2009;15(4):260-5. The perspectives of adjunctive drugs usage in the treatment of glucose metabolism disturbances in adolescent patients. Otto-Buczkowska E(1), Machnica Ł. Author information: (1)Górnoślaskie Centrum Zdrowia Dziecka w Katowicach. em.buczkowski@pro.onet.pl Tightening of the diabetes control criteria in the last few years induces searches for adjunctive drugs to reinforce the basic treatment typical for the specific type of the disease. These agents are meant to stimulate insulin secretion, increase insulin sensitivity or inhibit the antagonists of the hormone. Up till now that kind of studies included adults, mainly with type 2 diabetes. Nowadays, however, the increasing number of research focuses on type 1 diabetic patients. The attempts to introduce this type of treatment in adolescent patients encounter many limitations, mostly of formal nature due to drug registration requirements. Nevertheless, more and more studies point at the efficacy of these agents and the possibility of their usage also in adolescents with different types of diabetes. PMID: 20455421 [PubMed - indexed for MEDLINE] 2105. Wiad Lek. 2009;62(3):190-6. [The role of visfatin in the pathophysiology of human]. [Article in Polish] Skoczylas A(1). Author information: (1)Oddział Wewnetrzny Szpitala Powiatowego w Oleśnie. a.skoczylas@onet.eu Fat tissue produces a variety of secreted proteins with important roles in metabolism. Isolated and newly identified adipocytokine - visfatin is highly enriched in the visceral fat and it's expression level in plasma increases during the development of obesity. Visfatin exerts insulin - mimetic effects and lowers plasma glucose level throughout binding and activating the insulin receptor in animal model. However studies in humans' subjects reported conflicting results in regard to its relation with adiposity, insulin resistance, dyslipidemia, suggesting that the role of this protein in the development of obesity and insulin resistance is unclear. Visfatin - the cytokine-like protein pre-B cell colony - enhancing factor 1 was also identified as cytosolic nicotinamide phosphoribosyltransferase. This enzyme is involved in nicotinamide adenine dinucleotide (NAD) biosynthesis, related to the glucose and lipid metabolism in humans. Further study of visfatin's physiological may lead to new insights into glucose homeostasis an and or new therapies not only for metabolic disorders but also for disturbance of the immune system. PMID: 20229717 [PubMed - indexed for MEDLINE] 2106. FEBS Lett. 2009 Jan 22;583(2):259-65. doi: 10.1016/j.febslet.2008.12.030. Epub 2008 Dec 25. IL-1 family in breast cancer: potential interplay with leptin and other adipocytokines. Perrier S(1), Caldefie-Chézet F, Vasson MP. Author information: (1)Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. s.perrier@dundee.ac.uk Obesity is associated with an increased risk of breast cancer. interleukin-1 (IL-1), a pro-inflammatory cytokine secreted by adipose tissue, is involved in breast cancer development. There is also convincing evidence that other adipocytokines including leptin not only have a role in haematopoiesis, reproduction and immunity but are also growth factors in cancer. Therefore, IL-1 family and leptin family are adipocytokines which could represent a major link between obesity and breast cancer progression. This minireview provides insight into recent findings on the prognostic significance of IL-1 and leptin in mammary tumours, and discusses the potential interplay between IL-1 family members and adipocyte-derived hormones in breast cancer. PMID: 19111549 [PubMed - indexed for MEDLINE] 2107. Acta Dermatovenerol Croat. 2008;16(4):231-5. Obesity and allergic diseases. Gorgievska-Sukarovska B(1), Lipozencić J, Susac A. Author information: (1)University Department of Dermatology and Venereology, Zagreb University Hospital Center, Zagreb, Croatia. biljana@alkaloid.hr In the last few decades, the prevalence of allergic diseases, asthma, allergic rhinoconjunctivitis and atopic dermatitis in particular, has been observed to increase in urban settings. In addition, epidemiological data show the proportion of overweight individuals to rise in the last two decades. Obesity and overweight are a major public health problem not only in industrialized countries but also in developing ones because the morbidity and mortality rates are greater in the obese. An increased body mass index is considered a risk factor for the occurrence of myocardial infarction, stroke, atherosclerosis, hypertension, insulin resistance, dyslipidemia and some types of carcinoma. An ever greater body of available data point to the possible association of allergic diseases with obesity and overweight. Impaired immune tolerance is considered to be a sequel of immune changes due to the activity of adipokines, bioactive molecules secreted in white adipose tissue. About 50 adipokines are currently known to be secreted in adipose tissue, some of them belonging to the group of cytokines such as tumor necrosis factor alpha and interleukin-6. The association between obesity and allergic diseases has not yet been fully clarified. While the observations recorded to date should not be neglected, additional studies are necessary to help understand the complex function of adipokines involved in allergic events. PMID: 19111150 [PubMed - indexed for MEDLINE] 2108. Nat Clin Pract Nephrol. 2009 Feb;5(2):101-11. doi: 10.1038/ncpneph1022. Epub 2008 Dec 23. The role of obesity in the pathogenesis of hypertension. Bogaert YE(1), Linas S. Author information: (1)University of Colorado School of Medicine and Denver VA Medical Center, Denver, CO, USA. The rapid rise in the incidence and prevalence of obesity and the concomitant increase in the incidence and prevalence of hypertension have fueled investigation into the role of obesity in the pathogenesis of hypertension. The genetic background that predisposes obese individuals to hypertension is being elucidated, and the importance of adipose tissue as an endocrine organ in the pathogenesis of hypertension is increasingly being recognized. Visceral adipose tissue is critical in the production of pathologic cytokines that are thought to mediate obesity-induced hypertension. Changes in the types and levels of adipocytokines that result from the accumulation of aberrant adipose tissue directly leads to alterations in systemic vascular resistance, sodium retention and sympathetic nervous system activity. Key changes in adipocytokine levels seen in obesity-induced hypertension include increased leptin and adiponectin levels. Another important mechanism in obesity-induced hypertension is the generation of angiotensin II and direct stimulation of aldosterone production. The increased sympathetic nervous system activity seen in obesity-associated hypertension leads to increased renal sodium retention and increased systemic vascular resistance. Increased systemic vascular resistance can also occur directly in obese individuals through vascular fibrosis and lipid deposition. Obesity should no longer be simply considered as a marker of cardiovascular risk but should be regarded as an important and primary contributor to the pathophysiology of hypertension. PMID: 19107106 [PubMed - indexed for MEDLINE] 2109. Expert Rev Cardiovasc Ther. 2009 Jan;7(1):85-93. doi: 10.1586/14779072.7.1.85. Pharmacologic therapy for coronary atherosclerosis in patients with Type 2 diabetes mellitus. Galla JM(1), Nicholls SJ. Author information: (1)Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, USA. nd.grad.88@gmail.com Accelerated progression of coronary atherosclerosis underlies the heightened cardiovascular risk observed in diabetic patients. As the worldwide prevalence of diabetes escalates in association with the incidence of abdominal obesity, the global burden of cardiovascular disease will continue to rise. Therapeutic strategies that have had the greatest cardiovascular benefit in diabetes have focused on lowering LDL-cholesterol and blood pressure, rather than glucose-lowering specifically. More recently, arterial wall imaging has helped characterize the natural history of coronary atherosclerosis in diabetes, the impact of associated risk factors and the influence of medical therapies. PMID: 19105770 [PubMed - indexed for MEDLINE] 2110. Regen Med. 2009 Jan;4(1):109-17. doi: 10.2217/17460751.4.1.109. Adipose-derived stem cells for soft tissue reconstruction. Cherubino M(1), Marra KG. Author information: (1)Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA. In soft tissue repair, there are several surgical options such as nondegradable, inert, synthetic, biodegradable implants or autologous tissue transplantation. However, the potential of using autologous adult stem cells derived from fat tissue is quickly becoming a clinical reality. The possibility of using an abundant source of extraneous tissue as a soft tissue implant has significant implications for plastic and reconstructive surgeons. This strategy would be particularly useful after tumor removal or trauma. The ability of adult stem cells derived from adipose tissue (termed adipose-derived stem cell) to proliferate and differentiate in vivo or in vitro is actively being studied owing to the potential implementation in reconstructive surgery. This review describes innovative research strategies and discusses the first clinical studies involving adipose-derived stem cells as a motif for soft tissue reconstruction. PMID: 19105620 [PubMed - indexed for MEDLINE] 2111. Curr Opin Endocrinol Diabetes Obes. 2009 Feb;16(1):47-52. doi: 10.1097/MED.0b013e328321306c. Substance P, obesity, and gut inflammation. Karagiannides I(1), Pothoulakis C. Author information: (1)Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7019, USA. PURPOSE OF REVIEW: The purpose of this review is to present recent data on the effects of substance P on the development of two common pathological conditions, namely obesity and gut inflammation, and elucidate the role of this neuropeptide as a potential regulator between increased adiposity and exacerbated inflammatory responses during inflammatory bowel disease. RECENT FINDINGS: We present data that demonstrate a role for substance P in both obesity and inflammatory bowel disease and investigate potential effects on fat tissue that may influence the progression of intestinal inflammation. More specifically, we discuss new evidence for direct effects of substance P on fat tissue that determine fat depot size and overall weight in mice and analyze some of the potential mechanisms. Furthermore, we present data that describe changes in the intestinal sensory innervation, in particular substance P-positive innervation, during gut inflammation and new direct evidence of the effects of preestablished obesity in the outcome of experimental inflammation of the colon in mice. In the end we propose a link between the role of substance P in the promotion of obesity and the potential consequences on inflammatory bowel disease. SUMMARY: We propose that substance P may promote fat tissue expansion either centrally or peripherally and thus create a proinflammatory environment (as is the case with obesity) which may in turn affect the progression (exacerbate) of gut inflammation. Further studies are required on the effects of 'creeping fat' in inflammatory bowel disease in order to decipher the role of this type of fat-depot expansion in the development of the disease. PMCID: PMC4404028 PMID: 19104238 [PubMed - indexed for MEDLINE] 2112. J Adolesc Health. 2009 Jan;44(1):94-5. doi: 10.1016/j.jadohealth.2008.06.007. Epub 2008 Sep 27. Lipoatrophic diabetes: a case report with a brief review of the literature. Lawson MA(1). Author information: (1)Department of Child Health, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212, USA. lawsonma@health.missouri.edu Lipoatrophy syndromes are characterized by an absence of adipose tissue and low leptin levels. Metabolic derangements associated with these syndromes can include diabetes mellitus, insulin resistance, and hyperlipidemia. PMID: 19101466 [PubMed - indexed for MEDLINE] 2113. Eur J Endocrinol. 2009 Mar;160(3):337-47. doi: 10.1530/EJE-08-0621. Epub 2008 Dec 18. Intrauterine growth restriction and adult disease: the role of adipocytokines. Briana DD(1), Malamitsi-Puchner A. Author information: (1)Neonatal Division, Second Department of Obstetrics and Gynecology, Athens University Medical School, Athens, Greece. Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve his/her intrinsic growth potential, due to anatomical and/or functional disorders and diseases in the feto-placental-maternal unit. IUGR results in significant perinatal and long-term complications, including the development of insulin resistance/metabolic syndrome in adulthood. The thrifty phenotype hypothesis holds that intrauterine malnutrition leads to an adaptive response that alters the fetal metabolic and hormonal milieu designed for intrauterine survival. This fetal programming predisposes to an increased susceptibility for chronic diseases. Although the mechanisms controlling intrauterine growth are poorly understood, adipose tissue may play an important role in linking poor fetal growth to the subsequent development of adult diseases. Adipose tissue secretes a number of hormones, called adipocytokines, important in modulating metabolism and recently involved in intrauterine growth. This review aims to summarize reported findings concerning the role of adipocytokines (leptin, adiponectin, ghrelin, tumor necrosis factor (TNF), interleukin-6 (IL6), visfatin, resistin, apelin) in early life, while attempting to speculate mechanisms through which differential regulation of adipocytokines in IUGR may influence the risk for development of chronic diseases in later life. PMID: 19095781 [PubMed - indexed for MEDLINE] 2114. Trends Endocrinol Metab. 2009 Mar;20(2):51-7. doi: 10.1016/j.tem.2008.10.006. Epub 2008 Dec 16. Early-life origins of metabolic dysfunction: role of the adipocyte. Muhlhausler B(1), Smith SR. Author information: (1)Early Origins of Adult Health Research Group, Sansom Institute, University of South Australia, Adelaide, SA 5001, Australia. beverly.muhlhausler@unisa.edu.au More than 60% of adults in the US are classified as overweight, with most developing associated metabolic problems. It is increasingly clear that the origins of obesity and metabolic disease are early in life, yet the physiological basis for this is not well understood. We propose that perturbations to nutrient supply in utero affect adipocyte development, altering functional properties and promoting excess body fat accumulation after birth. We also propose that excessive body fat accumulation leads to leptin and insulin resistance in these individuals, rendering them more susceptible to further weight gain and metabolic deterioration. Finally, we propose that interventions that inhibit this early increase in fat deposition have the potential to interrupt the pathway to obesity. PMID: 19095460 [PubMed - indexed for MEDLINE] 2115. Appl Physiol Nutr Metab. 2008 Dec;33(6):1311-8. doi: 10.1139/H08-129. Does caffeine alter muscle carbohydrate and fat metabolism during exercise? Graham TE(1), Battram DS, Dela F, El-Sohemy A, Thong FS. Author information: (1)Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G2W1, Canada. terrygra@uoguelph.ca Caffeine, an adenosine receptor antagonist, has been studied for decades as a putative ergogenic aid. In the past 2 decades, the information has overwhelmingly demonstrated that it indeed is a powerful ergogenic aid, and frequently theories have been proposed that this is due to alterations in fat and carbohydrate metabolism. While caffeine certainly mobilizes fatty acids from adipose tissue, rarely have measures of the respiratory exchange ratio indicated an increase in fat oxidation. However, this is a difficult measure to perform accurately during exercise, and small changes could be physiologically important. The few studies examining human muscle metabolism directly have also supported the fact that there is no change in fat or carbohydrate metabolism, but these usually have had a small sample size. We combined the data from muscle biopsy analyses of several similar studies to generate a sample size of 16-44, depending on the measure. We examined muscle glycogen, citrate, acetyl-CoA, glucose-6-phosphate, and cyclic adenosine monophosphate (cAMP) in resting samples and in those obtained after 10-15 min of exercise at 70%-85% maximal oxygen consumption. Exercise decreased (p < 0.05) glycogen and increased (p < 0.05) citrate, acetyl-CoA, and glucose-6-phosphate. The only effects of caffeine were to increase (p < 0.05) citrate in resting muscle and cAMP in exercise. There is very little evidence to support the hypothesis that caffeine has ergogenic effects as a result of enhanced fat oxidation. Individuals may, however, respond differently to the effects of caffeine, and there is growing evidence that this could be explained by common genetic variations. PMID: 19088793 [PubMed - indexed for MEDLINE] 2116. Nutr Res Rev. 2008 Dec;21(2):207-34. doi: 10.1017/S0954422408138744. Neuroendocrine and physiological regulation of intake with particular reference to domesticated ruminant animals. Roche JR(1), Blache D, Kay JK, Miller DR, Sheahan AJ, Miller DW. Author information: (1)DairyNZ Ltd, Hamilton, New Zealand. john.roche@dairynz.co.nz The central nervous system undertakes the homeostatic role of sensing nutrient intake and body reserves, integrating the information, and regulating energy intake and/or energy expenditure. Few tasks regulated by the brain hold greater survival value, particularly important in farmed ruminant species, where the demands of pregnancy, lactation and/or growth are not easily met by often bulky plant-based and sometimes nutrient-sparse diets. Information regarding metabolic state can be transmitted to the appetite control centres of the brain by a diverse array of signals, such as stimulation of the vagus nerve, or metabolic 'feedback' factors derived from the pituitary gland, adipose tissue, stomach/abomasum, intestine, pancreas and/or muscle. These signals act directly on the neurons located in the arcuate nucleus of the medio-basal hypothalamus, a key integration, and hunger (orexigenic) and satiety (anorexigenic) control centre of the brain. Interest in human obesity and associated disorders has fuelled considerable research effort in this area, resulting in increased understanding of chronic and acute factors influencing feed intake. In recent years, research has demonstrated that these results have relevance to animal production, with genetic selection for production found to affect orexigenic hormones, feeding found to reduce the concentration of acute controllers of orexigenic signals, and exogenous administration of orexigenic hormones (i.e. growth hormone or ghrelin) reportedly increasing DM intake in ruminant animals as well as single-stomached species. The current state of knowledge on factors influencing the hypothalamic orexigenic and anorexigenic control centres is reviewed, particularly as it relates to domesticated ruminant animals, and potential avenues for future research are identified. PMID: 19087372 [PubMed - indexed for MEDLINE] 2117. Nutr Res Rev. 2008 Dec;21(2):148-57. doi: 10.1017/S0954422408116997. Dairy product consumption and the metabolic syndrome. van Meijl LE(1), Vrolix R, Mensink RP. Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. The metabolic syndrome is an important risk factor for type 2 diabetes mellitus and CVD. Epidemiological studies have now suggested protective effects of dairy product consumption on the development of this syndrome. Here we review the physiological effects and possible mechanisms involved of three main dairy constituents (Ca, protein, fat) on important components of the metabolic syndrome. Ca supplements improve the serum lipoprotein profile, particularly by decreasing serum total and LDL-cholesterol concentrations. They also lower systolic and diastolic blood pressure. Insufficient evidence exists for a significant role of Ca supplements or dairy in body-weight management. Effects of Ca may be related to intestinal binding to fatty acids or bile acids, or to changes in intracellular Ca metabolism by suppressing calciotropic hormones. Dietary proteins may increase satiety in both the short and longer term, which may result in a reduced energy intake. They have also been reported to improve the serum lipoprotein profile as compared with carbohydrates. Dairy proteins are precursors of angiotensin-I-converting enzyme-inhibitory peptides, which may lower blood pressure. Such effects, however, have inconsistently been reported in human studies. Finally, conjugated linoleic acid, which effectively lowers body weight in animals, has no such effect in humans in the quantities provided by dairy products. To reduce the intake of SFA, the consumption of low-fat instead of high-fat dairy products is recommended. In conclusion, more research is warranted to better understand the physiological effects and the mechanisms involved of dairy products in the prevention and treatment of the metabolic syndrome. PMID: 19087368 [PubMed - indexed for MEDLINE] 2118. Nutr Res Rev. 2008 Dec;21(2):117-33. doi: 10.1017/S0954422408138732. Obesity and inflammation: the effects of weight loss. Forsythe LK(1), Wallace JM, Livingstone MB. Author information: (1)Northern Ireland Centre for Food and Health, Centre for Molecular Biosciences, University of Ulster, Coleraine BT52 1SA, UK. Following the discovery of TNF-alpha and leptin as secretory products of adipocytes in the early 1990s, subsequent obesity research focused on the new functional role of adipose tissue, as an active endocrine organ. Many more inflammatory peptides have been linked to adiposity, which ultimately characterised obesity as a state of low-grade systemic inflammation, or 'metaflammation' which may link obesity to its co-morbidities. The aim of the present review is to examine the effects of weight loss on inflammation in overweight and obese, but otherwise healthy, populations. Studies were broadly classified into four types (diet, physical activity, diet and physical activity combined, and surgical interventions) and discussed according to the method used to induce weight loss. All studies measured at least one obesity-related inflammatory marker (ORIM). The overall finding from the present review is that weight loss does improve inflammation in terms of both the inflammatory (C-reactive protein, TNF-alpha, IL-6 and leptin) and anti-inflammatory (adiponectin) ORIM. Within this, the greatest improvements in ORIM are observed in studies achieving a weight loss of at least 10 %. However, a number of methodological issues have been identified as potential limitations within the literature including the sex and age of subjects, sample size, study duration and the assessment of body composition. In conclusion, although a period of weight loss per se is capable of reversing the unfavourable inflammatory profile evident in the obese state, further studies are required to determine the time needed, in which a reduced weight is maintained, in order to benefit from improved inflammatory status long term. PMID: 19087366 [PubMed - indexed for MEDLINE] 2119. Expert Rev Proteomics. 2008 Dec;5(6):827-39. doi: 10.1586/14789450.5.6.827. Adipose proteome analysis: focus on mediators of insulin resistance. Chen X(1), Hess S. Author information: (1)University of Minnesota, Food Science and Nutrition - Room 139, 1334 Eckles Avenue, St. Paul, MN 55108-1038, USA. xlchen@umn.edu As is well known, adipose tissue is an important site for lipid metabolism and insulin-responsive glucose uptake. The recent discovery of the endocrine function of adipose tissue and the association of obesity with chronic low-grade inflammation in adipose tissue has reinforced the concept of the central role of adipose tissue in mediating obesity-linked insulin resistance and metabolic dysregulation. The study of adipose cells has provided new insights into the mechanism underlying insulin resistance as well as the therapeutic strategies for diabetes. Numerous efforts have been made in identifying key molecular regulators of insulin action and metabolism, including the utilization of advanced proteomics technology. Various proteomic approaches have been applied to identify the adipose secretome, protein-expression profiling and post-translational modifications in adipose cells in the pathological state. In this review, we summarize the recent advances in the proteomics of adipose tissue, and discuss the identified proteins that potentially play important roles in insulin resistance and diabetes. PMCID: PMC2651673 PMID: 19086862 [PubMed - indexed for MEDLINE] 2120. J Bodyw Mov Ther. 2008 Apr;12(2):121-32. doi: 10.1016/j.jbmt.2007.11.006. Epub 2008 Jan 30. Leptin hormone and other biochemical influences on systemic inflammation. DeLany J(1). Author information: (1)NMT Center, St. Petersburg, FL 33705, USA. jbmtdelany@aol.com Over the past 30 years, a sharp rise in the prevalence of overweight and obesity has been noted in both children and adults. Health consequences include biomechanical, biochemical and psychosocial factors, with broad implications toward central adiposity and a number of conditions with which it relates. Substantial new information has surfaced within the last decade that alters previous concepts regarding the role of adipose tissue in health and in disease. This literature review explores the role that white adipose tissue (WAT) plays within a cascade of endocrine interfaces that have significant health consequences. WAT is now known to be an active participant in regulating physiological and pathological processes, including immunity and inflammation and to play a primary role in the development of a triad of hormonal imbalance (leptin resistance, adrenaline resistance, insulin resistance). Particular focus is placed on leptin hormone and its potential influences on inflammation and a host of other metabolic disturbances. PMID: 19083664 [PubMed - indexed for MEDLINE] 2121. Aesthet Surg J. 2008 May-Jun;28(3):313-21; quiz 322-4. doi: 10.1016/j.asj.2008.02.004. The science of autologous fat grafting: views on current and future approaches to neoadipogenesis. Bucky LP(1), Percec I. Author information: (1)Division of Plastic Surgery, University of Pennsylvania, Philadelphia, PA, USA. Lou.Bucky@uphs.upenn.edu LEARNING OBJECTIVES: The reader is presumed to have a broad understanding of plastic surgical procedures and concepts. After studying this article, the participant should be able to: 1. Describe the current clinical applications and limitations of autologous fat grafting. 2. Identify the important physiological steps and molecular pathways of neoadipogenesis. 3. Cite current in vitro and in vivo models for the analysis of fat grafting techniques. Physicians may earn 1 AMA PRA Category 1 credit by successfully completing the examination based on material covered in this article. The examination begins on page 322. ASAPS members can also complete this CME examination online by logging on to the ASAPS Members-Only website (http://www.surgery.org/members) and clicking on "Clinical Education" in the menu bar. Autologous fat transplantation has become a well established and frequently applied method of soft tissue augmentation for both cosmetic and reconstructive indications. There is no consensus, however, about the best fat grafting technique, nor is there reproducible data regarding its durability. The most significant drawback to autologous fat grafting remains its largely unpredictable rate of resorption. A thorough understanding of the developmental biology and molecular regulation of adipogenesis and adipocyte survival is critical to optimizing the fat grafting technique. Consequently, numerous in vitro and in vivo studies on fat graft viability have recently been undertaken. Here, we discuss the latest advances in the basic science of adipogenesis, adipocyte viability, and its clinical application to fat grafting, arguing that the data produced by in vitro and in vivo studies still fail to produce a clear picture of the required components for successful, consistent, and durable fat transplantation; however, it is undetermined if this lack of clarity may simply be a lack of systematic scientific data acquisition or if these findings truly reflect the biology of neoadipogenesis. As a first step in strengthening autologous fat grafting scientific data collection, we recommend that a collective, multidisciplinary, multicenter effort be undertaken to establish in vitro and in vivo models of neoadipogenesis that are clearly reproducible from one investigator to another. With the implementation of systematic scientific approaches to the study of neoadipogenesis, we anticipate the future of autologous fat transplantation for correction of soft tissue volume loss to be extremely promising. PMID: 19083543 [PubMed - indexed for MEDLINE] 2122. Panminerva Med. 2008 Dec;50(4):279-94. Insulin resistance in skeletal muscle and adipose tissue in polycystic ovary syndrome: are the molecular mechanisms distinct from type 2 diabetes? Corbould A(1). Author information: (1)Prince Henry's Institute of Medical Research, Australia. anne.corbould@princehenrys.org The association of polycystic ovary syndrome (PCOS) with insulin resistance was recognized almost three decades ago. Despite the pivotal role of insulin resistance in the pathogenesis of PCOS, the precise cellular and molecular mechanisms of impaired insulin action remain elusive. This review has two aims: 1) to review the mechanisms of insulin resistance, specifically impaired insulin-stimulated glucose transport, in skeletal muscle and adipose tissue in PCOS, and 2) to assess whether mechanisms of insulin resistance in PCOS are distinct from those in type 2 diabetes. As in type 2 diabetes, studies in skeletal muscle in PCOS support the existence of intrinsic defects in insulin signalling but also underscore the importance of in vivo environmental factors for the development of insulin resistance. In PCOS and type 2 diabetes, similar insulin signalling defects in muscle have been described i.e. impaired signalling via IRS-1 and up-regulation of ERK signalling. Similar defects in insulin signalling have also been described in adipose tissue in PCOS and type 2 diabetes, but data are limited. As for type 2 diabetes, PCOS is characterized by chronic inflammation, mitochondrial dysfunction and cellular stress. Androgen excess, a key feature of PCOS, has a genetic component: the relationship of hyperandrogenemia to the development of insulin resistance requires further study. In conclusion, although similar insulin signalling defects have been identified in muscle and adipose tissue in PCOS and type 2 diabetes, these defects probably reflect a common final pathway resulting from genetic and environmental influences on insulin action that are unique to each disorder. PMID: 19078869 [PubMed - indexed for MEDLINE] 2123. Ann N Y Acad Sci. 2008 Nov;1144:127-35. doi: 10.1196/annals.1418.009. Neuropeptides, mesenteric fat, and intestinal inflammation. Karagiannides I(1), Pothoulakis C. Author information: (1)Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7019, USA. The ability of fat tissue cells to produce proinflammatory cytokines and the concept that obesity represents a low-grade inflammatory response have been well documented during the past decade. The effects of fat-mediated inflammation on metabolic pathologies have also been drawing increasing interest. However, very little is known on the potential effects of adipose tissue in the pathophysiology of gastrointestinal diseases with an inflammatory component, such as inflammatory bowel disease (IBD). The development of large fat masses around the inflamed intestine during Crohn's disease makes this tissue a candidate for more intense investigation in studies aiming to gain insights into the pathogenesis and progress of the disease. Furthermore, neuropeptides act in many cases in a proinflammatory manner and are shown to participate in the pathogenesis of intestinal inflammation in animal models of IBD. However, the potential of these molecules to interact with fat cells in the context of IBD has not been investigated. In this review the authors' most recent data related to the effects of neuropeptides on noninflammatory fat tissue components are described. In addition, a discussion to associate neuropeptide-induced, adipose tissue-mediated responses with the generation of intestinal inflammatory conditions such as Crohn's disease is included. PMCID: PMC4404029 PMID: 19076372 [PubMed - indexed for MEDLINE] 2124. Curr Med Chem. 2008;15(28):2991-9. Metabolic-inflammatory changes, and accelerated atherosclerosis in HIV patients: rationale for preventative measures. De Lorenzo F(1), Collot-Teixeira S, Boffito M, Feher M, Gazzard B, McGregor JL. Author information: (1)Beta cell Diabetes Centre, Chelsea and Westminster Hospital NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, UK. FDL@vodafone.net Human immunodeficiency virus (HIV)-infected patients are at a significantly higher risk from coronary heart diseases (CHD) and myocardial infarction (MI) compared to gender- and age-matched non-infected individuals. Combination antiretroviral therapy (cART) has transformed a fatal illness into a chronic stable condition. However, cART induces metabolic abnormalities in HIV-infected patients, while its role in vascular atherosclerosis is still under investigation. The use of cART is linked to inflammation - a key mechanism in atherosclerotic progression and destabilisation that precedes clinical events like MI. There is evidence of visceral fat abnormal distribution in HIV infected patients, and inflammatory changes in HIV infected patients drive the initiation, progression and, ultimately, thrombotic clinical complications induced by atherosclerosis. Visceral adipose tissue, a virtual factory for manufacturing pro-inflammatory mediators, affects the liver function. The inflamed liver promotes the development of pro-atherogenic dyslipidaemia. Pro-inflammatory cytokines released by adipocytes travel to the skeletal muscles and other peripheral tissues, worsening insulin sensitivity and leading to hyperglycaemia. Increased high sensitivity C-reactive protein (hs-CRP) inflammatory marker is associated with endothelial dysfunction in HIV-infected patients. Increased levels of monocytic nuclear factor kappa-B (NFkappa-B), a master switch in the inflammatory cascade, are documented in patients with elevated hs-CRP levels. It can be assumed that, as a result of NFkappa-B activation, hs-CRP up-regulates cytokines that contribute to MI by recruiting leukocytes and promoting thrombosis. This review focuses on the association of HIV-infection, metabolic abnormalities and known mechanisms involved in inducing accelerated atherosclerosis and inflammation in HIV-infected patients, as well as the role of lipid lowering agents in potentially preventing CHD. PMID: 19075647 [PubMed - indexed for MEDLINE] 2125. Toxicol Pathol. 2009 Jan;37(1):47-51. doi: 10.1177/0192623308329476. Epub 2008 Dec 15. Caloric restriction and aging: studies in mice and monkeys. Anderson RM(1), Shanmuganayagam D, Weindruch R. Author information: (1)Wisconsin National Primate Research Center, Madison, Wisconsin, USA. rmanderson5@wisc.edu It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008). PMCID: PMC3734859 PMID: 19075044 [PubMed - indexed for MEDLINE] 2126. Orv Hetil. 2008 Dec 21;149(51):2403-11. doi: 10.1556/OH.2008.28507. [The metabolic syndrome and type-2 diabetes mellitus as conditions predisposing for malignant tumors]. [Article in Hungarian] Halmos T(1), Suba I. Author information: (1)Mazsihisz Szeretetkórház Diabéteszambulancia Budapest Amerikai út 53-55. 1145. fishwash@t-online.hu Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes. PMID: 19073451 [PubMed - indexed for MEDLINE] 2127. Expert Rev Gastroenterol Hepatol. 2008 Feb;2(1):47-57. doi: 10.1586/17474124.2.1.47. Roles of adipokines in liver injury and fibrosis. Wang J(1), Brymora J, George J. Author information: (1)Storr Liver Unit, Westmead Millennium Institute, University of Sydney, NSW 2145, Australia. jianhua_wang@wmi.usyd.edu.au Adipose tissue is now recognized as the largest endocrine organ in the body, secreting over 100 proteins termed adipokines that influence energy homeostasis, lipid physiology, inflammation, immune function and wound healing. Some of these proteins, such as TNFalpha, have important proinflammatory effects, but during hepatic injury are principally secreted at a local level within the liver. Their role in liver injury and fibrosis is beyond the scope of this review. However, circulating adipose-derived proteins such as leptin, adiponectin and resistin have important systemic effects, including the modulation of injury and fibrosis. The activities of these adipokines in the pathogenesis of liver injury and fibrosis will be the topic of this review. PMID: 19072370 [PubMed - indexed for MEDLINE] 2128. Expert Rev Gastroenterol Hepatol. 2008 Apr;2(2):207-15. doi: 10.1586/17474124.2.2.207. Interaction of metabolic syndrome, nonalcoholic fatty liver disease and chronic hepatitis C. Rafiq N(1), Younossi ZM. Author information: (1)Center for Liver Diseases at Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA. nila.rafiq@inova.org Nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent liver diseases in the Western world. NAFLD represents a wide spectrum of histologic subgroups, with nonalcoholic steatohepatitis as the most aggressive form. The risk of developing NAFLD is strongly associated with metabolic syndrome and insulin resistance. The pathogenesis of NAFLD is a multiple-hit process resulting from hepatic fat deposition that is related to several conditions, including insulin resistance and central obesity. Additional hits, such as oxidative stress or adipocytokines produced by white adipose tissue, can further enhance liver damage leading to nonalcoholic steatohepatitis or fibrosis. Although NAFLD is often the primary liver disease of metabolic conditions, it can also exacerbate other liver diseases such as hepatitis C (HCV); indeed, more than 50% of patients with HCV have hepatic steatosis. Hepatic steatosis can be related to host factors (e.g., obesity, metabolic syndrome or insulin resistance) or to the genotype of virus (e.g., HCV genotype 3). Increasing evidence suggests that hepatic steatosis, insulin resistance and obesity in the setting of HCV have a negative impact on the efficacy of treatment and hepatic progression of fibrosis. PMID: 19072356 [PubMed - indexed for MEDLINE] 2129. Curr Opin Support Palliat Care. 2008 Dec;2(4):256-61. Catabolic mediators of cancer cachexia. Tisdale MJ(1). Author information: (1)Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, UK. M.J.Tisdale@aston.ac.uk PURPOSE OF REVIEW: This review compares the catabolic actions of tumour necrosis factor-alpha (TNF-alpha) and proteolysis-inducing factor (PIF) and their involvement in human cancer cachexia. RECENT FINDINGS: TNF-alpha has a direct catabolic effect on skeletal muscle and adipose tissue, whereas PIF only has an effect on skeletal muscle. Both produce muscle atrophy through a depression of protein synthesis and an increase in protein degradation through the ubiquitin-proteasome proteolytic pathway, and this involves formation of reactive oxygen species leading to upregulation of the transcription factor nuclear factor-kappaB (NF-kappaB). TNF-alpha depresses protein synthesis through decreased phosphorylation of eukaryotic initiation factor-4E (eIF4E) binding protein (4E-BP1) leading to increased binding of eIF4E and a reduction in the active eIF4F complex, whereas with PIF depression of protein synthesis is due to an increased phosphorylation of eIF2 on the alpha-subunit. In general, serum levels of TNF-alpha do not correlate with weight loss in cancer patients and attempts to treat cachexia by interfering with TNF-alpha production, or action, have not been successful. Most studies show that PIF is detectable in the urine of cachectic cancer patients and its presence is indicative of weight loss. It is best to confirm that the band on Western blotting is PIF using both antibodies to the core peptide and the oligosaccharide chains. SUMMARY: These results suggest that blocking the PIF receptor or signalling pathways in skeletal muscle might yield new types of agents for the treatment of cancer cachexia. PMID: 19069310 [PubMed - indexed for MEDLINE] 2130. J Endocrinol Invest. 2008 Sep;31(9 Suppl):79-84. Metabolic implications of growth hormone therapy. Perrini S(1), Carreira MC, Conserva A, Laviola L, Giorgino F. Author information: (1)Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari, I-70124 Bari, Italy. GH regulates important physiological processes, including somatic growth and development, and carbohydrate and lipid metabolism. GH deficiency and GH replacement therapy exert opposite effects on body composition and fat accumulation, suggesting that GH may directly regulate adipocyte functions. Multiple studies have shown that in tissues previously deprived of GH, short-term stimulation with GH is able to mimic the actions of insulin, including stimulation of amino-acid and glucose transport, and lipogenesis. However, the antagonistic effects of GH on insulin-mediated metabolic responses are well-documented: GH excess in patients with GH-producing pituitary tumors causes hyperinsulinemia, insulin resistance, and even clinical diabetes mellitus. These apparently contradictory effects may be explained at the molecular level by the complex interplay between GH and insulin signaling. In this review, we examine the consequences of acute and chronic effects of GH on visceral fat and on metabolic responses in adipocytes, and discuss experimental data illustrating the integrated crosstalk between GH and insulin. PMID: 19020393 [PubMed - indexed for MEDLINE] 2131. Proc Nutr Soc. 2009 Feb;68(1):71-7. doi: 10.1017/S0029665108008872. Epub 2008 Dec 10. Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Diabetes and health". Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention? Symonds ME(1). Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, NG72UH, UK. michael.symonds@nottingham.ac.uk Whilst previously type 2 diabetes occurred in older adults, its incidence, together with obesity, has increased rapidly in children. An improved understanding of this disease pathway from a developmental view point is critical. It is likely that subtle changes in dietary patterns over an extended period of time contribute to diabetes, although this type of rationale is largely ignored in animal studies aimed at determining the mechanisms involved. Small-animal studies in which large, and often extreme, changes in the diet are imposed at different stages of the life cycle can have substantial effects on fat mass and/or pancreatic functions. These responses are not representative of the much more gradual changes seen in the human population. An increasing number of studies indicate that it is growth rate per se, rather than the type of dietary intervention that determines pancreatic function during development. Epigenetic mechanisms that regulate insulin secretion by the pancreas can be re-set by more extreme changes in dietary supply in early life. The extent to which these changes may contribute to more subtle modulations in glucose homeostasis that can accompany excess fat growth in childhood remains to be established. For human subjects there is much less information as to whether specific dietary components determine disease onset. Indeed, it is highly likely that genotype has a major influence, although recent data relating early diet to physical activity and the FTO gene indicate the difficulty of establishing the relative contribution of diet and changes in body mass to diabetes. PMID: 19068149 [PubMed - indexed for MEDLINE] 2132. Genetika. 2008 Oct;44(10):1338-55. [Adipokine genetics: unbalanced protein secretion by human adipose tissue as a cause of the metabolic syndrome]. [Article in Russian] Baranova AV. Subcutaneous and visceral adipose compartments act, not only as fatty acid depots, but also as active endocrine organs that undergo hyperplastic changes and significantly enhance their function in obesity. Akipokines and other proteins secreted by both adipocytes and stromal cells play a central role in peripheral insulin resistance and the metabolic syndrome (MS). Minor alleles of the adipokine genes substantially contribute to MS. The most important consequence of MS is low-level systemic inflammation supported by adipose-specific synthesis of proinflammatory soluble molecules. Proinflammatory signals are secreted into the bloodstream and spread to peripheral tissues that contain their receptors. The signals provided by adipose tissue stimulate the development of secondary complications of MS, including cardiovascular disorders (CVDs) and nonalcoholic fatty liver disease. The review describes the physiological effects of adiponectin, leptin, resistin, visfatin, and apelin and the influence of the minor alleles of the adipokine genes on the development of the secondary complications of MS. PMID: 19062531 [PubMed - indexed for MEDLINE] 2133. Curr Opin Support Palliat Care. 2008 Dec;2(4):267-74. doi: 10.1097/SPC.0b013e3283186be2. Cachexia, survival and the acute phase response. Stephens NA(1), Skipworth RJ, Fearon KC. Author information: (1)Clinical and Surgical Sciences (Surgery), University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK. PURPOSE OF REVIEW: To review current knowledge of the relationship between cytokines, the acute phase response (APR) and the development of cachexia. RECENT FINDINGS: Cytokines important in the initiation of the APR are also important in the genesis of cachexia. The presence of an APR or high circulating levels of pro-inflammatory cytokines are known to be related to adverse outcome in cancer patients. Studies of host cytokine genotype have demonstrated that specific host cytokine polymorphisms are associated with both the development of cachexia and reduced patient survival. The desire to be able to predict accurately survival in cancer patients has led to the description of various APR-based prognostic scoring systems. SUMMARY: Cachexia is an important clinical problem affecting up to two thirds of cancer patients. It results from anorexia and metabolic change and leads to loss of both adipose tissue and lean body mass, particularly in the skeletal muscle compartment. An APR is seen in half of cancer patients at presentation, and is most often determined clinically by raised plasma C-reactive protein concentrations. Adverse outcome and shortened survival have been linked to the presence of an APR. This article explores the cause and consequences of the APR in cancer cachexia. PMID: 19060563 [PubMed - indexed for MEDLINE] 2134. J Mol Cell Cardiol. 2009 Feb;46(2):142-8. doi: 10.1016/j.yjmcc.2008.11.002. Epub 2008 Nov 13. Novel insights into the role of cardiotrophin-1 in cardiovascular diseases. Calabrò P(1), Limongelli G, Riegler L, Maddaloni V, Palmieri R, Golia E, Roselli T, Masarone D, Pacileo G, Golino P, Calabrò R. Author information: (1)Division of Cardiology, Second University of Naples-A.O. Monaldi, Via L. Bianchi, 80131 Naples, Italy. paolo.calabro@unina2.it Cardiotrophin-1 (CT-1), a member of interleukin (IL)-6 family, was originally isolated for its ability to induce a hypertrophic response in neonatal cardiac myocytes. This cytokine mediates a pleiotropic set of growth and differentiation activities through a unique receptor system, consisting of IL-6 receptor (IL-6R) and a common signal transducer, the glycoprotein 130 (gp130). Both in humans and in mice, CT-1 mRNA has been detected in several tissues, such as liver tissue, adipose tissue, and tissues in the respiratory and nervous systems; in each of these tissues it performs different functions. Predominant actions of CT-1 are on the heart, where it is synthesized and where it provides first myocardial protection by promoting cell survival and proliferation, it carries on its haemodynamic effects and endocrine properties, and finally, it predisposes the heart to pathological conditions. The aim of this review is to describe the pathophysiological mechanisms through which CT-1 carries out its activities, especially on the heart, and its potential contribution as a disease marker in clinical cardiology. Recent studies have confirmed its active role in promoting structural changes typical of most common cardiovascular disease, such as hypertension, valve diseases, congestive heart failure, and coronary artery disease. In fact, CT-1 induces myocyte hypertrophy and collagen synthesis, thereby participating in the progression of ventricular remodelling, which results in cardiac muscle failure at the latest stage. CT-1 plasma levels are elevated in patients with hypertension and coronary artery diseases, and they are also correlated with the severity of valve diseases and heart failure. Therefore, CT-1 may represent a diagnostic, staging, and prognostic biomarker of cardiovascular diseases. PMID: 19059413 [PubMed - indexed for MEDLINE] 2135. Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):8-14. doi: 10.1097/MCO.0b013e32831b9c5b. Body composition analysis techniques in the aged adult: indications and limitations. Woodrow G(1). Author information: (1)Renal Unit, St James's University Hospital, Leeds, UK. graham.woodrow@leedsth.nhs.uk PURPOSE OF REVIEW: Body composition analysis allows division of the body into different compartments on the basis of differing physical properties. A variety of techniques are available for measuring body composition. This review describes the changes that occur with increasing age, their significance and also the limitations of available body composition analysis techniques when applied to the elderly. RECENT FINDINGS: Studies have shown the development of changes in body composition with ageing that have important consequences for health. Alterations in body fat content and particularly body fat distribution are associated with adverse metabolic effects and increased cardiovascular risk. Reduced skeletal muscle mass and strength (sarcopenia) are common in the elderly with important effects on function and outcome. A range of techniques are available for measuring body composition. However, changes in body composition with ageing, particularly altered composition of the constituents of fat-free mass, and changes in fat distribution, may lead to measurement errors with standard body composition assessment methodology. SUMMARY: Measurement of body composition provides information of importance to health and function. Techniques used for assessment should be those unaffected by age-related changes in body composition, or those that have been adapted or validated in this age group. Particular roles of these techniques in the elderly include screening or surveillance of those at risk of malnutrition, and monitoring a range of chronic illnesses that are prevalent in older individuals. PMID: 19057181 [PubMed - indexed for MEDLINE] 2136. Nihon Shokakibyo Gakkai Zasshi. 2008 Dec;105(12):1728-36. [Visceral fat and liver disease]. [Article in Japanese] Eguchi Y(1), Mizuta T, Fujimoto K. Author information: (1)Saga Medical School, Internal Medicine. PMID: 19057158 [PubMed - indexed for MEDLINE] 2137. Nihon Shokakibyo Gakkai Zasshi. 2008 Dec;105(12):1722-7. [Visceral fat and digestive disease]. [Article in Japanese] Inamori M(1), Akiyama T, Takahashi H, Abe Y, Nakajima A. Author information: (1)Gastroenterology Division, Yokohama City University Hospital. PMID: 19057157 [PubMed - indexed for MEDLINE] 2138. Nihon Shokakibyo Gakkai Zasshi. 2008 Dec;105(12):1711-21. [Digestive organ diseases and metabolic syndrome]. [Article in Japanese] Hojo M(1), Nagahara A, Miyazaki A, Watanabe S. Author information: (1)Department of Gastroenterology, Juntendo University School of Medicine. PMID: 19057156 [PubMed - indexed for MEDLINE] 2139. Circ J. 2009 Jan;73(1):27-34. Epub 2008 Dec 4. Cardiac adiposity and global cardiometabolic risk: new concept and clinical implication. Shimabukuro M(1). Author information: (1)Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan. mshimabukuro-ur@umin.ac.jp The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD), and threatens to reduce life expectancy around the world. The concept of the metabolic syndrome (MetS) takes into account the essential role that visceral fat plays in the development of metabolic and CVDs, and indicates how waist circumference measurement aids patient identification in the clinical setting. However, MetS cannot be used to assess global CVD risk and is, at best, another modifiable risk factor. Thus, the global cardiometabolic risk (ie, global risk of CVD resulting from traditional risk factors combined with the additional contribution of MetS) should be considered individually. The contribution of abdominal obesity to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance, lipotoxicity and ectopic fat deposition in the heart components: (1) circulatory and locally recruited fat, (2) intra-and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. PMID: 19057089 [PubMed - indexed for MEDLINE] 2140. Stem Cells. 2009 Mar;27(3):577-605. doi: 10.1634/stemcells.2008-0963. In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Snykers S(1), De Kock J, Rogiers V, Vanhaecke T. Author information: (1)Department of Toxicology, Vrije Universiteit Brussel, Belgium. sarah.snykers@vub.ac.be Stem cells are a unique source of self-renewing cells within the human body. Before the end of the last millennium, adult stem cells, in contrast to their embryonic counterparts, were considered to be lineage-restricted cells or incapable of crossing lineage boundaries. However, the unique breakthrough of muscle and liver regeneration by adult bone marrow stem cells at the end of the 1990s ended this long-standing paradigm. Since then, the number of articles reporting the existence of multipotent stem cells in skin, neuronal tissue, adipose tissue, and bone marrow has escalated, giving rise, both in vivo and in vitro, to cell types other than their tissue of origin. The phenomenon of fate reprogrammation and phenotypic diversification remains, though, an enigmatic and rare process. Understanding how to control both proliferation and differentiation of stem cells and their progeny is a challenge in many fields, going from preclinical drug discovery and development to clinical therapy. In this review, we focus on current strategies to differentiate embryonic, mesenchymal(-like), and liver stem/progenitor cells into hepatocytes in vitro. Special attention is paid to intracellular and extracellular signaling, genetic modification, and cell-cell and cell-matrix interactions. In addition, some recommendations are proposed to standardize, optimize, and enrich the in vitro production of hepatocyte-like cells out of stem/progenitor cells. PMCID: PMC2729674 PMID: 19056906 [PubMed - indexed for MEDLINE] 2141. J Int Assoc Physicians AIDS Care (Chic). 2008 Nov-Dec;7(6):292-305. doi: 10.1177/1545109708328931. Epub 2008 Dec 3. Body-fat abnormalities in patients with HIV: progress and challenges. Bedimo RJ(1). Author information: (1)Internal Medicine, Infectious Diseases Section, VA North Texas Healthcare System, UT Southwestern Medical School, Dallas, Texas, USA. roger.bedimo@va.gov The introduction of newer antiretroviral drugs has provided greater levels of HIV suppression with fewer of the metabolic effects, lipoatrophy, and body habitus changes associated with earlier therapies. Previously classified under the collective term, lipodystrophy, lipoatrophy and body-fat changes are now known to occur independently in some HIV-infected patients, depending on the type and duration of antiretroviral therapy and a myriad of factors including HIV infection alone that contribute significantly to these changes. This article reviews the current scientific literature and recent clinical trial results that distinguish lipoatrophy or dyslipidemia pathophysiologically from body-fat changes seen as central and peripheral lipohypertrophy and fat redistribution, as well as the nature and extent of changes associated with HIV infection alone and newer antiretroviral therapies. This information may assist physicians in identifying individual risk factors and choosing the type of antiretroviral therapy that may minimize these changes without loss of virologic suppression. PMID: 19056708 [PubMed - indexed for MEDLINE] 2142. J Nutr. 2009 Jan;139(1):1-4. doi: 10.3945/jn.108.098269. Epub 2008 Dec 3. Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. Kennedy A(1), Martinez K, Chuang CC, LaPoint K, McIntosh M. Author information: (1)Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402, USA. This review highlights the inflammatory and insulin-antagonizing effects of saturated fatty acids (SFA), which contribute to the development of metabolic syndrome. Mechanisms responsible for these unhealthy effects of SFA include: 1) accumulation of diacylglycerol and ceramide; 2) activation of nuclear factor-kappaB, protein kinase C-, and mitogen-activated protein kinases, and subsequent induction of inflammatory genes in white adipose tissue, immune cells, and myotubes; 3) decreased PPARgamma coactivator-1 alpha/beta activation and adiponectin production, which decreases the oxidation of glucose and fatty acids (FA); and 4) recruitment of immune cells like macrophages, neutrophils, and bone marrow-derived dendritic cells to WAT and muscle. Several studies have demonstrated potential health benefits of substituting SFA with unsaturated FA, particularly oleic acid and (n-3) FA. Thus, reducing consumption of foods rich in SFA and increasing consumption of whole grains, fruits, vegetables, lean meats and poultry, fish, low-fat dairy products, and oils containing oleic acid or (n-3) FA is likely to reduce the incidence of metabolic disease. PMID: 19056664 [PubMed - indexed for MEDLINE] 2143. Facial Plast Surg Clin North Am. 2008 Nov;16(4):443-8, vi-vii. doi: 10.1016/j.fsc.2008.05.005. The scientific basis for lipotransfer: is it the ideal filler? Jatana KR(1), Smith SP Jr. Author information: (1)Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, 456 West 10th Avenue, Suite 4A, Columbus, OH 43210, USA. kris.jatana@osumc.edu A loss of volume results from a reduction in the subcutaneous fat, muscle atrophy, and changes in skeletal framework. Such loss of tissue volume compounded with tissue laxity leads to the aged appearance of the periorbital, perioral, cheek, and mandibular areas. Many facial plastic surgeons have sought to replace this volume with various injectable agents, both synthetic and autologous, in search for the ideal soft tissue filler. This article reviews the literature on lipotransfer and specifically the scientific basis underlying the approach. PMID: 19056057 [PubMed - indexed for MEDLINE] 2144. Facial Plast Surg Clin North Am. 2008 Nov;16(4):383-90, v. doi: 10.1016/j.fsc.2008.05.006. Fat transfer in conjunction with facial rejuvenation procedures. DeFatta RJ(1), Williams EF 3rd. Author information: (1)Facial Plastic and Reconstructive Surgery, Williams Center for Excellence, 1072 Troy Schenectady Road, Latham, NY 12110, USA. Age is the most significant factor contributing to the overall change in the appearance of an individual's facial features over time. The purpose of any cosmetic procedure is to reverse the aging process that has occurred in an individual. During the last 5 years, volume restoration through lipotransfer combined with lifting procedures has been instrumental in elevating these procedures to a new level of excellence in comprehensive facial rejuvenation. The authors believe that restoration of facial volume can be achieved safely, precisely and reliably by lipotransfer. In this article they describe their techniques of lipotransfer. PMID: 19056050 [PubMed - indexed for MEDLINE] 2145. Ned Tijdschr Geneeskd. 2008 Nov 1;152(44):2385-8. [Estimating the individual risk of diabetes: not on the grounds of overweight only]. [Article in Dutch] van 't Riet E(1), Alssema M, Nijpels G, Dekker JM. Author information: (1)VU Medisch Centrum, EMGO Instituut, Van der Boechorststraat 7, kamer D-528, io8x BT Amsterdam. e.vantriet@vumc.nl Overweight (BMI level > or =25 kg/m2) and in particular high abdominal fat levels (waist circumference > or =88 cm in women and > or =102 cm in men), are among the main risk factors for the development of type 2 diabetes mellitus. Results from the Hoorn Study show that 16.3% of overweight participants with high abdominal fat levels developed diabetes within 6 years, compared with 6.8% of those who were not overweight and had low abdominal fat levels. Information on overweight and abdominal fat level is not enough to properly estimate the risk of type 2 diabetes in an individual patient. The combination of information on overweight with information on other important risk factors for diabetes, such as family history, age, blood pressure and elevated blood glucose levels in the form of a calculated diabetes risk score, gives a better estimate of the individual diabetes risk. PMID: 19055136 [PubMed - indexed for MEDLINE] 2146. J Med Food. 2008 Dec;11(4):606-9. doi: 10.1089/jmf.2008.0058. Leucine for retention of lean mass on a hypocaloric diet. Jitomir J(1), Willoughby DS. Author information: (1)Exercise and Biochemical Nutrition Laboratory, Department of Health, Human Performance, Recreation, Baylor University, Waco, Texas 76798-7313, USA. Jean_Jitomir@baylor.edu As obesity rates continue to climb, there is a pressing need for novel weight loss techniques. However, the energy-restricted diets recommended for weight loss typically result in significant amounts of lean tissue loss, in addition to the desired body fat loss. Leucine, a supported anticatabolic agent, has shown promise in research at many levels. First, leucine is known to stimulate the mammalian target of rapamycin pathway, which initiates translation and protein synthesis in muscle cells. Furthermore, leucine may help to regulate blood glucose levels by promoting gluconeogenesis. Finally, several recent studies provide evidence that leucine aids in the retention of lean mass in a hypocaloric state. The aim of this paper is to review relevant leucine research in the three areas described and assess its potential as supplement for obese individuals. PMID: 19053849 [PubMed - indexed for MEDLINE] 2147. Dig Dis Sci. 2009 Sep;54(9):1847-56. doi: 10.1007/s10620-008-0585-3. Epub 2008 Dec 4. Adipose tissue: the new endocrine organ? A review article. Wozniak SE(1), Gee LL, Wachtel MS, Frezza EE. Author information: (1)Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity's comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses. PMID: 19052866 [PubMed - indexed for MEDLINE] 2148. Intern Emerg Med. 2009 Feb;4(1):25-34. doi: 10.1007/s11739-008-0207-2. Epub 2008 Dec 4. Adipose tissue-mediated inflammation: the missing link between obesity and cardiovascular disease? Calabrò P(1), Golia E, Maddaloni V, Malvezzi M, Casillo B, Marotta C, Calabrò R, Golino P. Author information: (1)Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy. paolo.calabro@unina2.it Until relatively recently, the role of adipose tissue in the development of obesity and its consequences was considered to be a passive one. Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. It is now clear that, in addition to storing calories as triglycerides, adipocytes secrete a large variety of cytokines, chemokines and hormone-like factors, such as leptin, resistin, and acute-phase proteins. In addition, insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of intraabdominal fat. This production of pro-atherogenic substances is of particular interest since an increase in the plasma levels of these mediators may provide a novel mechanistic link between obesity and its vascular complications. PMID: 19052701 [PubMed - indexed for MEDLINE] 2149. Nutr Rev. 2008 Oct;66(10 Suppl 2):S139-46. doi: 10.1111/j.1753-4887.2008.00099.x. Calcitriol and energy metabolism. Zemel MB(1), Sun X. Author information: (1)The Department of Nutrition, The University of Tennessee, Knoxville, Tennessee 37996-1920, USA. mzemel@utk.edu Calcitriol, a calcitrophic hormone that can be suppressed by high dietary calcium, favors fatty acid synthesis and inhibits lipolysis via non-genomic modulation of Ca(2+) influx. Calcitriol also suppresses UCP2 expression via the nVDR and thereby increases energy efficiency. Calcitriol exerts a dose-dependent impact on adipocyte apoptosis and regulates adipose tissue fat depot location and expansion by promoting glucocorticoid production and release. Recent data also demonstrate a pivotal role of calcitriol in the modulation of cytokines, with potential roles in energy metabolism in adipocytes, macrophages, and skeletal muscle. PMID: 18844841 [PubMed - indexed for MEDLINE] 2150. Int J Obes (Lond). 2009 Jan;33(1):54-66. doi: 10.1038/ijo.2008.229. Epub 2008 Dec 9. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Ye J(1). Author information: (1)Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA. Comment in Int J Obes (Lond). 2009 May;33(5):605; author reply 606. Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed. PMCID: PMC2650750 PMID: 19050672 [PubMed - indexed for MEDLINE] 2151. Prog Lipid Res. 2009 Mar;48(2):73-91. doi: 10.1016/j.plipres.2008.11.002. Epub 2008 Nov 21. The evolution of plasma cholesterol: direct utility or a "spandrel" of hepatic lipid metabolism? Babin PJ(1), Gibbons GF. Author information: (1)Université Bordeaux 1, Génomique et Physiologie des Poissons, UMR NuAGe, 33405 Talence, France. Fats provide a concentrated source of energy for multicellular organisms. The efficient transport of fats through aqueous biological environments raises issues concerning effective delivery to target tissues. Furthermore, the utilization of fatty acids presents a high risk of cytotoxicity. Improving the efficiency of fat transport while simultaneously minimizing the cytotoxic risk confers distinct selective advantages. In humans, most of the plasma cholesterol is associated with low-density lipoprotein (LDL), a metabolic by-product of very-low-density lipoprotein (VLDL), which originates in the liver. However, the functions of VLDL are not clear. This paper reviews the evidence that LDL arose as a by-product during the natural selection of VLDL. The latter, in turn, evolved as a means of improving the efficiency of diet-derived fatty acid storage and utilization, as well as neutralizing the potential cytotoxicity of fatty acids while conserving their advantages as a concentrated energy source. The evolutionary biology of lipid transport processes has provided a fascinating insight into how and why these VLDL functions emerged during animal evolution. As causes of historical origin must be separated from current utilities, our spandrel-LDL theory proposes that LDL is a spandrel of VLDL selection, which appeared non-adaptively and may later have become crucial for vertebrate fitness. PMID: 19049814 [PubMed - indexed for MEDLINE] 2152. J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S64-73. doi: 10.1210/jc.2008-1613. Adipocytokines and the metabolic complications of obesity. Rasouli N(1), Kern PA. Author information: (1)The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. CONTEXT: Adipose tissue is increasingly recognized as an active endocrine organ with many secretory products and part of the innate immune system. With obesity, macrophages infiltrate adipose tissue, and numerous adipocytokines are released by both macrophages and adipocytes. Adipocytokines play important roles in the pathogenesis of insulin resistance and associated metabolic complications such as dyslipidemia, hypertension, and premature heart disease. EVIDENCE ACQUISITION: Published literature was analyzed with the intent of addressing the role of the major adipose secretory proteins in human obesity, insulin resistance, and type 2 diabetes. EVIDENCE SYNTHESIS: This review analyzes the characteristics of different adipocytokines, including leptin, adiponectin, pro-inflammatory cytokines, resistin, retinol binding protein 4, visfatin, and others, and their roles in the pathogenesis of insulin resistance. CONCLUSIONS: Inflamed fat in obesity secretes an array of proteins implicated in the impairment of insulin signaling. Further studies are needed to understand the triggers that initiate inflammation in adipose tissue and the role of each adipokine in the pathogenesis of insulin resistance. PMCID: PMC2585759 PMID: 18987272 [PubMed - indexed for MEDLINE] 2153. J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S57-63. doi: 10.1210/jc.2008-1585. Role of body fat distribution and the metabolic complications of obesity. Jensen MD(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA. jensen@mayo.edu CONTEXT: An upper body/visceral fat distribution in obesity is closely linked with metabolic complications, whereas increased lower body fat is independently predictive of reduced cardiovascular risk. EVIDENCE ACQUISITION: The measured functions of different fat depots with regards to fatty acid storage and release in health and obesity were reviewed. The adverse effects of experimentally increasing free fatty acid (FFA) concentrations on liver, muscle, pancreatic beta-cell, and endothelial function were noted. EVIDENCE SYNTHESIS: The most dramatic abnormality in FFA metabolism is failure to suppress FFA concentrations/adipose tissue lipolysis normally in response to postprandial hyperinsulinemia. Upper body sc fat delivers the majority of FFA to the systemic circulation under postabsorptive and postprandial conditions. In upper body obesity, portal FFA concentrations resulting from both systemic and visceral adipose tissue lipolysis may be significantly greater than arterial FFA concentrations, exposing the liver to even greater amounts of FFA. Visceral fat also releases sufficient IL-6 to increase portal vein IL-6 concentrations, which can affect hepatic metabolism as well. CONCLUSIONS: Lower body, upper body sc, and visceral fat depots have unique characteristics with regards to fatty acid metabolism. Selective dysregulation of these depots probably plays an important role with the metabolic complications of obesity. PMCID: PMC2585758 PMID: 18987271 [PubMed - indexed for MEDLINE] 2154. J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S31-6. doi: 10.1210/jc.2008-1363. Obesity in children and adolescents. Cali AM(1), Caprio S. Author information: (1)Yale University School of Medicine, Department of Pediatrics, New Haven, Connecticut 06520, USA. CONTEXT: Although the prevalence rates of childhood obesity have seemingly been stable over the past few years, far too many children and adolescents are still obese. Childhood obesity, and its associated metabolic complications, is rapidly emerging as one of the greatest global challenges of the 21st century. About 110 million children are now classified as overweight or obese. EVIDENCE ACQUISITION: In this review we first describe the most recent data on the prevalence, severity, and racial/ethnic differences in childhood obesity. Obesity is associated with significant health problems in the pediatric age group and is an important early risk factor for much of adult morbidity and mortality. EVIDENCE SYNTHESIS: We review the metabolic complications associated with childhood obesity. Particular emphasis is given to the description of studies regarding the impact of varying degrees of obesity on the cardiometabolic risk factors in youth. We further describe studies in obese adolescents that have examined the importance of ectopic lipid deposition in the visceral abdominal depot and in insulin sensitive tissues in relation to the presence of insulin resistance. We end by describing studies that have examined beta-cell function in obese adolescents with normal glucose tolerance. CONCLUSIONS: The growing number of obese children and adolescents worldwide is of great concern. Many obese children and adolescents already manifest some metabolic complications, and these children are at high risk for the development of early morbidity. Understanding the underlying pathogenesis of this peculiar phenotype is of critical importance. PMCID: PMC2585761 PMID: 18987268 [PubMed - indexed for MEDLINE] 2155. Neuroimmunomodulation. 2008;15(4-6):224-40. doi: 10.1159/000156466. Epub 2008 Nov 26. Immunosenescence and immunogenetics of human longevity. Ostan R(1), Bucci L, Capri M, Salvioli S, Scurti M, Pini E, Monti D, Franceschi C. Author information: (1)Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy. At present, individuals can live up to 80-120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. In this complex scenario, the role of genetic background likely represents a fundamental variable to attain successful aging and longevity. Accordingly, centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors. The remarkable features of the genetics of aging and longevity are reviewed, stressing the unexpected and unusual results obtained regarding such a postreproductive type of genetics. Copyright 2008 S. Karger AG, Basel. PMID: 19047800 [PubMed - indexed for MEDLINE] 2156. Clin Cornerstone. 2008;9(1):32-8; discussion 39-40. Endocrine functions of adipose tissue: focus on adiponectin. Sowers JR(1). Author information: (1)University of Missouri-Columbia School of Medicine, Department of Medicine, Harry S. Truman VA Medical Center, USA. sowersj@health.missouri.edu Accumulating evidence indicates that obesity and overweight are associated with, and contribute to, the development of type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD). The adipocyte-derived cytokine, adiponectin, has been shown to improve insulin sensitivity, increase rates of fatty acid oxidation, decrease muscle lipid content, and reduce inflammation and vascular injury. However, adiponectin levels have been found to be reduced in persons with obesity and type 2 DM. Furthermore, adiponectin levels are inversely associated with those of tumor necrosis factor-alpha and C-reactive protein-markers of endothelial dysfunction and systemic inflammation. The 2 receptors for adiponectin-Adipo R(1) and Adipo R(2), which are expressed in muscle and liver tissue and in human fat cells-are hormonally regulated, with increased insulin levels causing a reduction in their abundance. The hyperinsulinemia observed in obesity, therefore, may be partially responsible for the reduction in the numbers of adiponectin receptors. Adiponectin aggregates range from a hexamer of low molecular weight to larger multimeric structures of high molecular weight. A smaller proteolytic fragment-the globular head domain of adiponectin, or gAd-interacts specifically with skeletal muscle. The relation of circulating adiponectin to its biologic actions is more complex than originally believed; therefore, it is the multimeric forms of the adiponectin molecule that need to be measured and evaluated in relation to associated metabolic, cardiovascular, and renal functions. Furthermore, strategies to measure the numbers of adiponectin receptors on available tissue need to be developed to fully assess the clinical role of adiponectin in type 2 DM, CVD, and CKD. PMID: 19046738 [PubMed - indexed for MEDLINE] 2157. Int J Cardiol. 2009 Mar 20;133(1):3-7. doi: 10.1016/j.ijcard.2008.10.027. Epub 2008 Nov 29. Interaction between remnant-like lipoprotein particles and adipocytes. Zheng XY(1), Liu L, Yang DG. Author information: (1)Departments of Cardiology, PR China. Inflammation plays a pivotal role in the pathophysiology of atherosclerosis. Remnant-like lipoprotein particles (RLPs) have been implicated as potentially atherogenic lipoproteins. RLPs can induce a pronounced inflammatory response especially during the postprandial phase. Increasing evidence demonstrates that adipose tissue may be a significant contributor to the increased systemic inflammation through secretion of various proinflammatory adipocytokines. In addition, adipocytes may potentially regulate RLPs metabolism. Therefore, we hypothesized that there might be an interaction between RLPs and adipocytes. PMID: 19042042 [PubMed - indexed for MEDLINE] 2158. Arch Cardiovasc Dis. 2008 Sep;101(9):577-83. doi: 10.1016/j.acvd.2008.06.011. Epub 2008 Sep 25. Recent advances in metabolic syndrome and cardiovascular disease. Guize L(1), Pannier B, Thomas F, Bean K, Jégo B, Benetos A. Author information: (1)Centre IPC, 6/14, rue La Pérouse, 75116 Paris, France. Metabolic syndrome is defined as an association of central obesity and several other cardiometabolic risk factors. Dysfunctional visceral adipose tissue and inflammatory status appear to be involved in its genesis. New definitions have decreased the threshold for glycaemia and one has lowered the threshold for waist circumference, leading to an increase in the prevalence of metabolic syndrome. However, the impact on mortality with these new definitions is lower than with the National Cholesterol Education Program-Adult Treatment Panel III 2001 definition. An increase in waist circumference, along with increased glycaemia, triglycerides and/or blood pressure is more highly associated with an increased risk of mortality than are other associations, while a decrease in high density lipoprotein cholesterol increases risk of coronary heart disease. The risk of sudden death and stroke is particularly notable with metabolic syndrome. Metabolic syndrome is associated with an increase in heart rate, pulse pressure, arterial stiffness and left ventricular hypertrophy, impairment of diastolic function, enlargement of the left atrium and atrial fibrillation. In the 2007 European recommendations for the management of high blood pressure, metabolic syndrome is now taken into consideration for both risk stratification and in selecting the optimal therapeutic strategy for arterial hypertension. PMID: 19041842 [PubMed - indexed for MEDLINE] 2159. Cell Metab. 2008 Dec;8(6):454-7. doi: 10.1016/j.cmet.2008.11.001. Before they were fat: adipocyte progenitors. Park KW(1), Halperin DS, Tontonoz P. Author information: (1)Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA. Adipose tissue mass can expand throughout adult life. Therefore, proliferative adipocyte precursor cells must stand at the ready to respond to increased demand for energy storage. Recent provocative studies have identified discrete immature cell populations from which brown and white adipocytes are derived. This work not only brings fundamental insight into adipose tissue formation but also provides new tools to study how adipogenesis is regulated in pathological conditions such as obesity and diabetes. PMID: 19041761 [PubMed - indexed for MEDLINE] 2160. Biochim Biophys Acta. 2009 Feb;1792(2):83-92. doi: 10.1016/j.bbadis.2008.10.019. Epub 2008 Nov 5. Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Fröjdö S(1), Vidal H, Pirola L. Author information: (1)INSERM, U870, IFR62, Oullins, F-69921, France. A generally accepted view posits that insulin resistant condition in type 2 diabetes is caused by defects at one or several levels of the insulin-signaling cascade in skeletal muscles, adipose tissue and liver, that quantitatively constitute the bulk of the insulin-responsive tissues. Hence, the gradual uncovering of the biochemical events defining the intracellular signaling of insulin has been quickly followed by clinical studies on humans attempting to define the molecular defect(s) responsible for the establishment of the insulin resistant state. While the existence of molecular defects within the insulin signal transduction machinery is undisputed, contrasting data exist on what is the principal molecular alteration leading to insulin resistance. Such discrepancies in the literature may depend on: 1) different subject characteristics, 2) methodological differences 3) small cohorts of subjects, and - not least - 4) intrinsic limitations in studying every detail of the insulin signaling cascade. Here, we review the studies on humans exploring the defects of the insulin signaling cascade generated by insulin resistance and type 2 diabetes, focusing on muscle and adipose tissue - which account for most of the glucose disposal capacity of the body - with focus on the unresolved discrepancies present in the literature. PMID: 19041393 [PubMed - indexed for MEDLINE] 2161. J Clin Res Pediatr Endocrinol. 2008;1(2):53-60. doi: 10.4008/jcrpe.v1i2.35. Epub 2008 Nov 1. Obesity in children. Lifshitz F(1). Author information: (1)Sansum Medical Research Institute, Santa Barbara, CA, USA. DrLfshtz@aol.com The prevalence of childhood obesity has increased dramatically during the past decades all over the world. The majority of obesity in adulthood has its origins in childhood which makes obesity a pediatric concern and the period when interventions should be done. Obesity is associated with increased morbidity and mortality in adult life and several adverse consequences in childhood like insulin resistance, type 2 diabetes, dyslipidemia, polycystic ovarian syndrome, pulmonary and orthopedic disorders and psychological problems. Both genetic and environmental factors play a role in the development of obesity. Prevention of obesity is critical, since effective treatment of this disease is limited. Food management and increased physical activity must be encouraged, promoted, and prioritized to protect children. PMCID: PMC3005642 PMID: 21318065 [PubMed - indexed for MEDLINE] 2162. Enferm Infecc Microbiol Clin. 2008 Dec;26 Suppl 17:34-40. doi: 10.1016/S0213-005X(08)76618-7. [Lipid profile of atazanavir]. [Article in Spanish] Martínez Chamorro E(1). Author information: (1)Servicio de Infecciones, Hospital Clínic-Institut d'Investigaciones Biomèdiques August Pi i Sunyer, Universidad de Barcelona, España. esteban@fundsoriano.es It is currently known that exposure to antiretroviral treatment, particularly to the classic protease inhibitors, is associated with an increased risk of suffering from cardiovascular disease, although stopping antiretroviral treatment can cause an even greater risk. Recommendations have been made on how to deal with dyslipaemia and cardiovascular risk in seropositive patients. These recommendations are similar to those for the general population, but include the particular feature of considering including benign treatment with lipids wherever possible. Atazanavir has different characteristics from other protease inhibitors as regards its effects on adipose tissue and metabolism in general. Atazanavir is not associated with increases in total cholesterol, LDL-cholesterol or triglycerides as with other PI in initial, rescue or simplification therapy. The results of in vitro studies and clinical studies are clear and convincing. These characteristics give it a particular role that is very attractive when deciding the most suitable antiretroviral treatment for a proportion of HIV-infected patients in whom the reduction in cardiovascular risk is seen as a priority. PMID: 20116615 [PubMed - indexed for MEDLINE] 2163. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):112-26. doi: 10.1016/j.mce.2008.11.016. Epub 2008 Nov 21. Hypoglycemic pharmacological treatment of type 2 diabetes: targeting the endothelium. Nathanson D(1), Nyström T. Author information: (1)Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, Södersjukhuset, Ringvägen 52, SE-118 83 Stockholm, Sweden. david.nathanson@sodersjukhuset.se Cardiovascular disease is by far the most common complication of type 2 diabetes and also the most serious one. Suffering from type 2 diabetes mellitus not only dramatically increases the risk of cardiovascular disease but is also associated with poor survival, both acutely and in the long term after a myocardial infarction. In fact, total mortality from coronary artery disease in subjects with type 2 diabetes mellitus, without a previous myocardial infarction, is as high as that of non-diabetic individuals with a previous infarction. Intense research efforts have thus been directed towards exploring the reasons for why particularly type 2 diabetic patients have such a poor prognosis suffering from cardiovascular disease. Obesity-related type 2 diabetes ("diabesity"), including the metabolic syndrome, is rapidly rising in prevalence. About 80% of all type 2 diabetes co-exists with insulin resistance. Endothelial dysfunction is a ubiquitous abnormality in insulin-resistant states that might contribute to premature atherosclerosis in a multifactorial and complex way. Low grade inflammation may play a role in development insulin resistance and type 2 diabetes and it has been proposed that atherosclerosis is basically an inflammatory disease. Thus, the pathophysiology of insulin resistance, the metabolic syndrome, and atherosclerosis may share inflammatory basis as a common denominator. Also, insulin resistance is not confined to skeletal muscle, adipose tissue and the liver, but also to the endothelium. Insulin resistance and endothelial dysfunction co-exist, where chronic inflammation may be a crucial factor. Accordingly, the possibility that physical activity or pharmacological agents that increase insulin sensitivity also improve endothelial function, or vice versa, has been investigated. Many different alterations in life style and drugs that improve endothelial function are known to lower the risk of contracting diabetes. In this review, the pharmacological treatment available against type 2 diabetes mellitus is discussed with particular emphasis on its impact on the endothelium. PMID: 19038307 [PubMed - indexed for MEDLINE] 2164. Clin Sci (Lond). 2009 Jan;116(1):1-16. doi: 10.1042/CS20070456. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Flachs P(1), Rossmeisl M, Bryhn M, Kopecky J. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic. Adipose tissue and its secreted products, adipokines, have a major role in the development of obesity-associated metabolic derangements including Type 2 diabetes. Conversely, obesity and its metabolic sequelae may be counteracted by modulating metabolism and secretory functions of adipose tissue. LC-PUFAs (long-chain polyunsaturated fatty acids) of the n-3 series, namely DHA (docosahexaenoic acid; C(22:6n-3)) and EPA (eicosapentaenoic acid; C(20:5n-3)), exert numerous beneficial effects, such as improvements in lipid metabolism and prevention of obesity and diabetes, which partially result from the metabolic action of n-3 LC-PUFAs in adipose tissue. Recent studies highlight the importance of mitochondria in adipose tissue for the maintenance of systemic insulin sensitivity. For instance, both n-3 LC-PUFAs and the antidiabetic drugs TZDs (thiazolidinediones) induce mitochondrial biogenesis and beta-oxidation. The activation of this 'metabolic switch' in adipocytes leads to a decrease in adiposity. Both n-3 LC-PUFAs and TZDs ameliorate a low-grade inflammation of adipose tissue associated with obesity and induce changes in the pattern of secreted adipokines, resulting in improved systemic insulin sensitivity. In contrast with TZDs, which act as agonists of PPARgamma (peroxisome-proliferator-activated receptor-gamma) and promote differentiation of adipocytes and adipose tissue growth, n-3 LC-PUFAs affect fat cells by different mechanisms, including the transcription factors PPARalpha and PPARdelta. Some of the effects of n-3 LC-PUFAs on adipose tissue depend on their active metabolites, especially eicosanoids. Thus treatments affecting adipose tissue by multiple mechanisms, such as combining n-3 LC-PUFAs with either caloric restriction or antidiabetic/anti-obesity drugs, should be explored. PMID: 19037880 [PubMed - indexed for MEDLINE] 2165. Diabetes Metab. 2008 Dec;34(6 Pt 1):550-9. doi: 10.1016/j.diabet.2008.09.001. Epub 2008 Nov 25. The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions. Girard J(1). Author information: (1)CNRS UMR8104, InsermU567, département endocrinologie, métabolisme et cancer, université Paris-Descartes, institut Cochin, 24, rue du Faubourg-Saint-Jacques, 75014 Paris, France. gean.girard@inserm.fr This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the Kcells of the duodenum, while GLP-1 is released by the Lcells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review. PMID: 19036624 [PubMed - indexed for MEDLINE] 2166. Kidney Int Suppl. 2008 Dec;(111):S10-4. doi: 10.1038/ki.2008.517. Metabolic syndrome pathophysiology: the role of adipose tissue. Ordovas JM(1), Corella D. Author information: (1)Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA. jose.ordovas@tufts.edu The metabolic syndrome comprises a set of metabolic and physiological risk factors associated with elevated cardiovascular disease risk. The expression of each one of its major factors (hypertriglyceridemia, low high-density lipoprotein cholesterol levels, hypertension, abdominal obesity, and insulin resistance) has been found to be the result of complex interactions between genetic and environmental factors. Moreover, one of them, obesity, may play a major role in triggering the metabolic syndrome by interacting with genetic variants at candidate genes for dyslipidemia, hypertension, and insulin resistance. In support of this hypothesis, several studies at several candidate genes, mainly adipokines and perilipin, have already demonstrated the significance of these interactions; however, the information and its solidity are still very limited and in many cases, replication studies are still lacking in the literature. Therefore, more studies with better epidemiological design and standardized adiposity measures are needed to estimate the contribution of body weight and fat distribution to the genetic predisposition to the metabolic syndrome, the most common CVD risk factor in industrialized societies. PMCID: PMC4426988 PMID: 19034318 [PubMed - indexed for MEDLINE] 2167. J Proteomics. 2009 Jan 30;71(6):576-91. doi: 10.1016/j.jprot.2008.10.002. Epub 2008 Nov 5. Glucotoxicity and pancreatic proteomics. Brunner Y(1), Schvartz D, Priego-Capote F, Couté Y, Sanchez JC. Author information: (1)Biomedical Proteomics Research Group, University Medical Center, Geneva, Switzerland. yannick.brunner@unige.ch Chronic hyperglycaemia is one of the main characteristics of a diabetic state. This is also the first cause of diabetic complications. However, it is now generally accepted that glucotoxicity also participates in the worsening of type 2 diabetes, by affecting the secretion of beta-cells. So far, different mechanisms have been proposed to explain the adverse effects of chronic hyperglycaemia. One of them suggests that the modulation of expression of several key proteins during a hyperglycaemia state, may explain the toxic effect of glucotoxicity. Therefore, proteomic analysis of biological samples represents an interesting method to study the effect of chronic hyperglycaemia on protein expression. The discovery of new proteins for which the expression could be modulated by chronic hyperglycaemia may probably help to better understand the mechanisms underlying glucotoxicity. In this review, we will first present an introduction of the different mechanisms known to be involved in the control of glucose homeostasis and in the development of glucotoxicity. In a second part, some proteomic data linked with the effect of glucotoxicity in pancreas, pancreatic islets and beta-cells will be presented and discussed. PMID: 19027091 [PubMed - indexed for MEDLINE] 2168. Endocrinol Metab Clin North Am. 2008 Dec;37(4):841-56. doi: 10.1016/j.ecl.2008.09.002. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Lara-Castro C(1), Garvey WT. Author information: (1)Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Boulevard,Birmingham, AL 35294-3360, USA. This article emphasizes intrahepatocellular and intramyocellular lipid accumulation as components of the insulin resistance syndrome. It examines the mechanisms responsible for the interrelationships among ectopic fat deposition, insulin resistance, and associated metabolic traits. These relationships are complex and vary according to diet, exercise, weight loss, and racial identity. Overall, there is a high degree of association of both intrahepatocellular and intramyocellular lipids with insulin resistance and associated cardiometabolic risk factors. It concludes that further research is necessary to determine the orchestrated roles of adipose and nonadipose tissue compartments in the regulation of insulin sensitivity, and mechanisms explaining racial differences in the insulin resistance syndrome-trait cluster. PMCID: PMC2621269 PMID: 19026935 [PubMed - indexed for MEDLINE] 2169. Endocrinol Metab Clin North Am. 2008 Dec;37(4):811-23. doi: 10.1016/j.ecl.2008.08.005. Brain regulation of appetite and satiety. Ahima RS(1), Antwi DA. Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu Interest in the control of feeding has increased as a result of the obesity epidemic and rising incidence of metabolic diseases. The brain detects alterations in energy stores and triggers metabolic and behavioral responses designed to maintain energy balance. Energy homeostasis is controlled mainly by neuronal circuits in the hypothalamus and brainstem, whereas reward and motivation aspects of eating behavior are controlled by neurons in limbic regions and the cerebral cortex. This article provides an integrated perspective on how metabolic signals emanating from the gastrointestinal tract, adipose tissue, and other peripheral organs target the brain to regulate feeding, energy expenditure, and hormones. The pathogenesis and treatment of obesity and abnormalities of glucose and lipid metabolism are discussed. PMCID: PMC2710609 PMID: 19026933 [PubMed - indexed for MEDLINE] 2170. Mol Cancer. 2008 Nov 21;7:85. doi: 10.1186/1476-4598-7-85. Tissue inhibitor of metalloproteinases-4. The road less traveled. Melendez-Zajgla J(1), Del Pozo L, Ceballos G, Maldonado V. Author information: (1)Instituto Nacional de Medicina Genomica, Mexico. jorgezajgla@gmail.com Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer. PMCID: PMC2599898 PMID: 19025595 [PubMed - indexed for MEDLINE] 2171. Adv Exp Med Biol. 2008;632:1-21. Adipokines and the immune system: an adipocentric view. MacLaren R(1), Cui W, Cianflone K. Author information: (1)Department of Experimental Medicine, McGill University, Montreal, Canada. There is increasing evidence of close interactions between the adipose and the immune systems. Adipocytes secrete multiple factors, including adipokines such as leptin and adiponectin that have both pro- and anti-inflammatory effects, and influence diseases involving the immune system. Further, adipose tissue also secretes various chemokines and cytokines, derived from either the adipocytes themselves, or the neighbouring cells including both resident and infiltrating macrophages. This close physical and paracrine interaction results in reciprocal actions of adipocytes, preadipocytes and macrophages within the microenvironment of the adipose tissue. Adipose tissue is a source of Acylation Stimulating Protein (ASP)/C3adesArg which interacts with the receptor C5L2 to stimulate triglyceride synthesis and glucose transport. C5L2, present on adipocytes, preadipocytes, macrophages, and numerous other myeloid and non-myeloid cells is also postulated to be a decoy receptor for C5a in immune cells. Several reviews within the past year have recently examined the role of C5L2 in C5a-mediated physiology. The present mini-review is an adipocentric view with emphasis on the role of ASP and C5L2 in lipid metabolism. C5L2 may play a role in mediating, on one hand, ASP stimulation of triglyceride synthesis in adipose, and, on the other hand, a role as mediator of C5a immune function. Both roles remain controversial, and will only be resolved with further studies. PMID: 19025110 [PubMed - indexed for MEDLINE] 2172. Mol Cell Endocrinol. 2009 Mar 25;301(1-2):97-103. doi: 10.1016/j.mce.2008.10.035. Epub 2008 Nov 5. Androgen metabolism in adipose tissue: recent advances. Blouin K(1), Veilleux A, Luu-The V, Tchernof A. Author information: (1)Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, Canada; Department of Nutrition, Laval University, Canada. Androgens modulate adipocyte function and affect the size of adipose tissue compartments in humans. Aldo-keto reductase 1C (AKR1C) enzymes, especially AKR1C2 and AKR1C3, through local synthesis and inactivation of androgens, may be involved in the fine regulation of androgen availability in adipose tissue. This review article summarizes recent findings on androgen metabolism in adipose tissue. Primary culture models and whole tissue specimens of human adipose tissue obtained from the abdominal subcutaneous and intra-abdominal (omental) fat compartments were used in our studies. The non-aromatizable androgen dihydrotestosterone (DHT) inhibits adipocyte differentiation in subcutaneous and omental adipocytes in humans. This inhibitory effect is partially reversed by anti-androgens. Activity and mRNA expression of AKR1C1, 2 and 3 were detected in SC and OM adipose tissue, in men and women, with higher levels in the SC depot than the omental depot of both sexes. The abundance of AKR1C enzyme mRNAs was particularly elevated compared to other steroid-converting enzymes. Significant positive associations were observed between AKR1C enzyme mRNA levels or DHT inactivation rates and visceral fat accumulation as well as OM adipocyte size in women and in men, at least in the normal weight to moderately obese range. Mature adipocytes had significantly higher DHT inactivation rates compared to preadipocytes. Accordingly, adipocyte differentiation significantly increased AKR1C enzyme expression and DHT inactivation rates. Treatment of preadipocytes with dexamethasone alone led to significant increases in the formation of 5alpha-androstan-3alpha,17beta-diol. This stimulation was completely abolished by RU486, suggesting that androgen inactivation is stimulated by a glucocorticoid receptor-dependent mechanism. In conclusion, higher AKR1C activity and expression in mature adipocytes may explain the associations between these enzymes and obesity. We speculate that glucocorticoid-induced androgen inactivation could locally decrease the exposure of adipose cells to active androgens and partially remove their inhibitory effect on adipogenesis. We hypothesize that body fat distribution patterns likely emerge from the local adipose tissue balance between active androgens and glucocorticoids in each fat compartment. PMID: 19022338 [PubMed - indexed for MEDLINE] 2173. Obes Rev. 2009 Mar;10(2):218-26. doi: 10.1111/j.1467-789X.2008.00538.x. Epub 2008 Oct 23. Recent advances in adaptive thermogenesis: potential implications for the treatment of obesity. Wijers SL(1), Saris WH, van Marken Lichtenbelt WD. Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. s.wijers@hb.unimaas.nl Large inter-individual differences in cold-induced (non-shivering) and diet-induced adaptive thermogenesis exist in animals and humans. These differences in energy expenditure can have a large impact on long-term energy balance and thus body weight (when other factors remain stable). Therefore, the level of adaptive thermogenesis might relate to the susceptibility to obesity; efforts to increase adaptive thermogenesis might be used to treat obesity. In small mammals, the main process involved is mitochondrial uncoupling in brown adipose tissue (BAT), which is regulated by the sympathetic nervous system. For a long time, it was assumed that mitochondrial uncoupling is not a major physiological contributor to adaptive thermogenesis in adult humans. However, several studies conducted in recent years suggest that mitochondrial uncoupling in BAT and skeletal muscle tissue in adult humans can be physiologically significant. Other mechanisms besides mitochondrial uncoupling that might be involved are futile calcium cycling, protein turnover and substrate cycling. In conjunction with recent advances on signal transduction studies, this knowledge makes manipulation of adaptive thermogenesis a more realistic option and thus a pharmacologically interesting target to treat obesity. PMID: 19021870 [PubMed - indexed for MEDLINE] 2174. Obes Rev. 2009 Mar;10(2):168-77. doi: 10.1111/j.1467-789X.2008.00539.x. Epub 2008 Oct 23. Does oestrogen allow women to store fat more efficiently? A biological advantage for fertility and gestation. O'Sullivan AJ(1). Author information: (1)Department of Medicine, St George Hospital, University of New South Wales, Sydney, Australia. a.osullivan@unsw.edu.au In normal healthy-weight humans, women have a higher percentage body fat than men, a difference that commences at puberty and continues throughout adult life, suggesting that the mechanism is related to sex steroids. The first half of pregnancy is also a stage of body fat gain in women. From an energy balance point, there is no explanation why women should be fatter than men, as the latter consume more calories proportionately. Moreover, women store fat in early pregnancy when caloric intake does not significantly change. The aim of this review is to focus on evidence supporting one mechanism that may account for these findings. That is, oestrogen reduces postprandial fatty acid oxidation leading to an increase in body fat which may account for the greater fat mass observed in women compared with men and the fat gain in early pregnancy. Therefore, female puberty and early pregnancy could be seen as states of efficient fat storage of energy in preparation for fertility, foetal development and lactation providing an obvious biological advantage. Further research into this mechanism of fat storage may provide further insights into the regulation of body fat. PMID: 19021869 [PubMed - indexed for MEDLINE] 2175. Thorax. 2008 Dec;63(12):1110-7. doi: 10.1136/thx.2007.086827. Obesity and the lung: 5. Obesity and COPD. Franssen FM(1), O'Donnell DE, Goossens GH, Blaak EE, Schols AM. Author information: (1)Department of Respiratory Medicine, University Hospital Maastricht, Maastricht, The Netherlands. Comment in Thorax. 2009 Jul;64(7):640; author reply 640-1. Chronic obstructive pulmonary disease (COPD) and obesity are common and disabling chronic health conditions with increasing prevalence worldwide. A relationship between COPD and obesity is increasingly recognised, although the nature of this association remains unknown. This review focuses on the epidemiology of obesity in COPD and the impact of excessive fat mass on lung function, exercise capacity and prognosis. The evidence for altered adipose tissue functions in obesity--including reduced lipid storage capacity, altered expression and secretion of inflammatory factors, adipose tissue hypoxia and macrophage infiltration in adipose tissue--is also reviewed. The interrelationship between these factors and their contribution to the development of insulin resistance in obesity is considered. It is proposed that, in patients with COPD, reduced oxidative capacity and systemic hypoxia may amplify these disturbances, not only in obese patients but also in subjects with hidden loss of fat-free mass. The potential interaction between abnormal adipose tissue function, systemic inflammation and COPD may provide more insight into the pathogenesis and reversibility of systemic pathology in this disease. PMID: 19020276 [PubMed - indexed for MEDLINE] 2176. J Lipid Res. 2009 Apr;50 Suppl:S395-9. doi: 10.1194/jlr.R800057-JLR200. Epub 2008 Nov 17. Adipocyte metabolism and obesity. Attie AD(1), Scherer PE. Author information: (1)Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA. adattie@wisc.edu Adipose tissue metabolism exerts a profound impact on whole-body metabolism. We review how fuel partitioning between adipocytes and other tissues affects insulin signaling pathways. We discuss the role of adipose tissue inflammation in adipocyte metabolism and whole-body insulin sensitivity. Finally, we mention the role of adipokines in autocrine and paracrine signaling. PMCID: PMC2674728 PMID: 19017614 [PubMed - indexed for MEDLINE] 2177. Stress. 1999 Aug;3(1):1-15. doi: 10.3109/10253899909001108. Melancholic depression and abdominal fat distribution: a mini-review. Mann JN(1), Thakore JH. Author information: (1)St Vincent's Hospital, Dublin 3, Ireland. Fat is stored around the abdomen in both subcutaneous and intra abdominal (visceral) sites. Visceral fat is associated in its own right with a set of metabolic abnormalities, including non insulin dependent diabetes, hypertension and dyslipidaemias. States of marked hypercortisolaemia, for example Cushing's syndrome, lead to the preferential accumulation of visceral fat. Since melancholic depression is known to be associated with elevated plasma Cortisol levels, this review explores whether depressed patients are prone to excess visceral fat storage, with the subsequent risk of developing the associated metabolic disturbances. Though the literature is limited, there is evidence that intra abdominal fat is increased in major depression. There is also evidence that depression is associated with increased risk of death from cardiovascular disease. Is visceral fat and its association with metabolic abnormalities the link between depression and physical illness? PMID: 19016189 [PubMed - indexed for MEDLINE] 2178. Arch Physiol Biochem. 2008 Dec;114(5):357-68. doi: 10.1080/13813450802535812 . Adipose tissue and skeletal muscle plasticity modulates metabolic health. Ukropec J(1), Ukropcova B, Kurdiova T, Gasperikova D, Klimes I. Author information: (1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic. Jozef.Ukropec@savba.sk Obesity, accumulation of adipose tissue, develops when energy intake exceeds energy expenditure. Adipose tissue is essential for buffering the differences between energy intake and expenditure by accumulating lipids while skeletal muscle is the energy burning machine. Here we adopted the concept that (i) adipose tissue ability to regulate the storage capacity for lipids as well as (ii) dynamic regulation of muscle and adipose tissue secretory and metabolic activity is important for maintaining the metabolic health. This might be at least in part related to tissue plasticity, a phenomenon enabling dynamic modulation of the tissue phenotype in different physiological and pathophysiological situations. Recent advances in our understanding of the complex endocrine function of adipose tissue in regulating lipid metabolism, adipogenesis, angiogenesis, extracellular matrix remodelling, inflammation and oxidative stress prompted us to review the role of tissue plasticity--dynamic changes in adipose tissue and skeletal muscle metabolic and endocrine phenotype--in determining the difference between metabolic health and disease. PMID: 19016045 [PubMed - indexed for MEDLINE] 2179. J Gastroenterol. 2008;43(11):811-22. doi: 10.1007/s00535-008-2213-6. Epub 2008 Nov 18. Adipocytokines and liver disease. Kamada Y(1), Takehara T, Hayashi N. Author information: (1)Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka 565-0871, Japan. Adipose tissue is a massive source of bioactive substances known as adipocytokines, including tumor necrosis factor (TNF)-alpha, resistin, leptin, and adiponectin. Recent advances in medical research view obesity as a chronic low-grade inflammatory state. Hypertrophied adipocytes in obesity release chemokines that induce macrophage accumulation in adipose tissue. Accumulated macrophages in obese adipose tissue produce proinflammatory cytokines and nitric oxide, and these inflammatory changes induce adipocytokine dysregulation. The latter is characterized by a decrease in insulinsensitizing and anti-inflammatory adipocytokines, and an increase in proinflammatory adipocytokines. Adipocytokine dysregulation induces obesity-related metabolic disorders, the so-called metabolic syndrome. Metabolic syndrome is a cluster of metabolic abnormalities, including diabetes mellitus, hypertension, hyperlipidemia, and nonalcoholic steatohepatitis (NASH). Recent studies have revealed that obesity is an independent risk factor for chronic liver diseases, such as NASH, alcoholic liver disease, chronic hepatitis C, and hepatocellular carcinoma. A common mechanism underlying these hepatic clinical states is thought to be adipocytokine dysregulation. In this review, we discuss the association of adipocytokines, especially leptin, adiponectin, TNF-alpha, and resistin, with liver diseases. PMID: 19012034 [PubMed - indexed for MEDLINE] 2180. Amino Acids. 2009 May;37(1):55-63. doi: 10.1007/s00726-008-0202-y. Epub 2008 Nov 15. Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Stipanuk MH(1), Ueki I, Dominy JE Jr, Simmons CR, Hirschberger LL. Author information: (1)Division of Nutritional Sciences, Cornell University, 227 Savage Hall, Ithaca, NY 14853, USA. mhs6@cornell.edu Cysteine catabolism in mammals is dependent upon cysteine dioxygenase (CDO), an enzyme that adds molecular oxygen to the sulfur of cysteine, converting the thiol to a sulfinic acid known as cysteinesulfinic acid (3-sulfinoalanine). CDO is one of the most highly regulated metabolic enzymes responding to diet that is known. It undergoes up to 45-fold changes in concentration and up to 10-fold changes in catalytic efficiency. This provides a remarkable responsiveness of the cell to changes in sulfur amino acid availability: the ability to decrease CDO activity and conserve cysteine when cysteine is scarce and to rapidly increase CDO activity and catabolize cysteine to prevent cytotoxicity when cysteine supply is abundant. CDO in both liver and adipose tissues responds to changes in dietary intakes of protein and/or sulfur amino acids over a range that encompasses the requirement level, suggesting that cysteine homeostasis is very important to the living organism. PMCID: PMC2736881 PMID: 19011731 [PubMed - indexed for MEDLINE] 2181. Sports Med Arthrosc. 2008 Dec;16(4):246-54. doi: 10.1097/JSA.0b013e31818d56b3. Emerging technologies and fourth generation issues in cartilage repair. Kessler MW(1), Ackerman G, Dines JS, Grande D. Author information: (1)Department of Orthopaedic Surgery, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040, USA. The goals of successful cartilage repair include reducing pain, improving symptoms, and long-term function; preventing early osteoarthritis and subsequent total knee replacements; and rebuilding hyaline cartilage instead of fibrous tissue. Current methods such as microfracture, osteoarticular autograft transfer system, mosaicplasty, and autologous chondrocyte implantation are somewhat successful in regenerating cartilage; however, they also have significant limitations. The future of fourth generation cartilage repair focuses on gene therapy, the use of stem cells (bone marrow, adipose, or muscle derived), and tissue engineering. Emerging techniques include creating elastin-like polymers derived from native elastin sequences to serve as biocompatible scaffolds; using hydrogels to obtain a homogeneous distribution of cells within a 3-dimensional matrix; and using nonviral gene delivery via nucleofection to allow mesenchymal stem cells the ability to express osteogenic growth factors. Although many of the techniques mentioned have yet to be used in a cartilage regeneration model, we have tried to anticipate how methods used in other specialties may facilitate improved cartilage repair. PMID: 19011557 [PubMed - indexed for MEDLINE] 2182. Front Horm Res. 2009;37:91-107. doi: 10.1159/000176047. Testosterone and coronary artery disease. Nettleship JE(1), Jones RD, Channer KS, Jones TH. Author information: (1)Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, UK. The strongest independent risk factors for coronary artery disease (CAD) are increasing age and male gender. Whilst a wide variation in CAD mortality exists between countries, a male to female ratio of approximately 2:1 is consistently observed. These observations have led to the assumption that testosterone may exert a detrimental influence on the cardiovascular system. Despite this, coronary atherosclerosis increases with age, whilst a marked fall in serum bioavailable testosterone levels is observed. Similarly, low testosterone levels are also associated with other cardiovascular risk factors and increased expression of mediators of the atherosclerotic process. This in itself suggests that testosterone does not promote atheroma formation. Moreover, epidemiological studies show an inverse relationship between testosterone levels and surrogate markers of atherosclerosis, which suggests that it may be a testosterone deficient state, rather than male sex which is associated with CAD. In cholesterol-fed animal models, atherosclerosis is accelerated by castration and reduced after testosterone replacement therapy. Testosterone has also been shown to improve myocardial ischemia in men with angina pectoris. Consequently, increasing evidence suggests that the process of atherosclerosis is beneficially modulated by testosterone. These studies are the focus of this chapter. PMID: 19011291 [PubMed - indexed for MEDLINE] 2183. Front Horm Res. 2009;37:74-90. doi: 10.1159/000176046. Testosterone in obesity, metabolic syndrome and type 2 diabetes. Stanworth RD(1), Jones TH. Author information: (1)Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, and Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield Medical School, Sheffield, UK. rogerstanworth@btinternet.com Testosterone levels are reduced in obesity, the metabolic syndrome and type 2 diabetes. Low testosterone levels are now being recognised as an independent risk factors for these conditions. Findings from men undergoing androgen suppression as treatment for prostate cancer confirm that the hypogonadal state increases body fat mass and serum insulin and there is a high rate of developing new diabetes in this population. Clinical trial data are consistent in showing reductions in body fat mass during testosterone replacement therapy. There are also trials showing improvements in insulin resistance and glycaemic control with testosterone. Most of the trials in this area to date have been of small size and the promising results require confirmation in larger trials, which are underway. In the longer term, large trials should be conducted to assess the potentially beneficial effects of testosterone on cardiovascular risk in this and other patient groups. In the meantime physicians involved in the care of men with diabetes should remain vigilant for the symptoms and signs of hypogonadism. Testosterone replacement therapy should be considered for those men with subsequently confirmed hypogonadism. PMID: 19011290 [PubMed - indexed for MEDLINE] 2184. Front Horm Res. 2009;37:5-20. doi: 10.1159/000175839. Current guidelines for the diagnosis of testosterone deficiency. Arver S(1), Lehtihet M. Author information: (1)Centre for Andrology and Sexual Medicine, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. stefan.arver@ki.se Hypogonadism in males is a clinical syndrome complex which comprises symptoms with or without signs as well as biochemical evidence of testosterone deficiency. The diagnosis of hypogonadism thus includes both clinical history and examination as well as biochemical assessment of serum testosterone levels. Hypogonadal symptoms depend on the age at onset of hypogonadism, severity of the deficiency, its duration and sensitivity to androgen action. Prepubertal onset results in lack of virilization and pubertal development and produces features such as eunuchoid body proportions and undeveloped secondary sex characteristics. Development of hypogonadism in adult life is characterized by a loss of androgen-dependent functions such as reduction in muscle mass, a shift in body composition towards more adipose tissue, decreased sexual function with diminished libido, depressed mood, loss of psychological energy osteoporosis and several other possible symptoms. The majority of men who suffer from hypogonadism do not have classical endocrine disorders. These men present with concomitant disease such as metabolic syndrome or type 2 diabetes, chronic infections, inflammatory disease, COPD, or cardiovascular disease. All these conditions are associated with a high prevalence of hypogonadism. Pharmacological therapy with opiates and corticosteroids are also known to cause hypogonadism. Hypogonadal symptoms are precipitated at different testosterone levels. Total testosterone levels of less than 8 nmol/l highly support a diagnosis of hypogonadism whereas levels greater than 12 nmol/l are likely to be normal. The grey zone between 8 and 12 nmol/l requires further evaluation and assessment of free or non-sex hormone-binding globulin-bound (bioavailable) testosterone. A trial period of testosterone treatment may be required. PMID: 19011285 [PubMed - indexed for MEDLINE] 2185. Biochim Biophys Acta. 2009 Jun;1791(6):494-500. doi: 10.1016/j.bbalip.2008.10.005. Epub 2008 Oct 29. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Zimmermann R(1), Lass A, Haemmerle G, Zechner R. Author information: (1)Insitute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria. Lipolysis, the coordinated catabolism of triacylglycerol (TG) stored in cellular lipid droplets, provides fatty acids, di-, and monoglycerides. These products are important energy substrates, precursors for other lipids, or lipid signaling molecules. Following their discovery by Hollenberg, C.H., Raben, M.S., and Astwood, E.B.(1961) and Vaughan, M., Berger, J.E., and Steinberg, D. (1964), hormone-sensitive lipase (HSL) and monoacylglycerol lipase stayed in the focus of research for three decades. Within the last decade, however, it became evident that the lipolytic pathway is incompletely understood. Studies on the regulation of lipolysis and the characterization of HSL-deficient mice indicated that additional previously unrecognized factors that contribute to fat catabolism must exist. This led to the discovery of the perilipin, adipophilin, Tip47 (PAT) family of lipid droplet binding proteins and the identification of a novel TG hydrolase named adipose triglyceride lipase (ATGL). This review focuses on the importance of ATGL as TG lipase within the "lipolytic machinery" and the current knowledge of molecular mechanisms that regulate ATGL activity. PMID: 19010445 [PubMed - indexed for MEDLINE] 2186. Mol Med. 2008 Nov-Dec;14(11-12):741-51. doi: 10.2119/2008-00058.Rabe. Epub 2008 Sep 17. Adipokines and insulin resistance. Rabe K(1), Lehrke M, Parhofer KG, Broedl UC. Author information: (1)Department of Internal Medicine II, University of Munich, Munich, Germany. Obesity is associated with an array of health problems in adult and pediatric populations. Understanding the pathogenesis of obesity and its metabolic sequelae has advanced rapidly over the past decades. Adipose tissue represents an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive mediators (adipokines) that signal to organs of metabolic importance including brain, liver, skeletal muscle, and the immune system--thereby modulating hemostasis, blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones adiponectin, chemerin, leptin, omentin, resistin, retinol binding protein 4, tumor necrosis factor-alpha and interleukin-6, vaspin, and visfatin on insulin resistance. PMCID: PMC2582855 PMID: 19009016 [PubMed - indexed for MEDLINE] 2187. Trends Endocrinol Metab. 2009 Jan;20(1):16-24. doi: 10.1016/j.tem.2008.09.002. Epub 2008 Nov 13. Adipogenesis and WNT signalling. Christodoulides C(1), Lagathu C, Sethi JK, Vidal-Puig A. Author information: (1)Institute of Metabolic Science, MRC Centre for Obesity and Associated Diseases, Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. constantinos.christodoulides@orh.nhs.uk An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications. PMCID: PMC4304002 PMID: 19008118 [PubMed - indexed for MEDLINE] 2188. Eur Spine J. 2008 Dec;17 Suppl 4:492-503. doi: 10.1007/s00586-008-0750-6. Epub 2008 Nov 13. Cell transplantation in lumbar spine disc degeneration disease. Hohaus C(1), Ganey TM, Minkus Y, Meisel HJ. Author information: (1)Department of Neurosurgery, BG-Clinic Bergmannstrost, Halle, Germany. Low back pain is an extremely common symptom, affecting nearly three-quarters of the population sometime in their life. Given that disc herniation is thought to be an extension of progressive disc degeneration that attends the normal aging process, seeking an effective therapy that staves off disc degeneration has been considered a logical attempt to reduce back pain. The most apparent cellular and biochemical changes attributable to degeneration include a decrease in cell density in the disc that is accompanied by a reduction in synthesis of cartilage-specific extracellular matrix components. With this in mind, one therapeutic strategy would be to replace, regenerate, or augment the intervertebral disc cell population, with a goal of correcting matrix insufficiencies and restoring normal segment biomechanics. Biological restoration through the use of autologous disc chondrocyte transplantation offers a potential to achieve functional integration of disc metabolism and mechanics. We designed an animal study using the dog as our model to investigate this hypothesis by transplantation of autologous disc-derived chondrocytes into degenerated intervertebral discs. As a result we demonstrated that disc cells remained viable after transplantation; transplanted disc cells produced an extracellular matrix that contained components similar to normal intervertebral disc tissue; a statistically significant correlation between transplanting cells and retention of disc height could displayed. Following these results the Euro Disc Randomized Trial was initiated to embrace a representative patient group with persistent symptoms that had not responded to conservative treatment where an indication for surgical treatment was given. In the interim analyses we evaluated that patients who received autologous disc cell transplantation had greater pain reduction at 2 years compared with patients who did not receive cells following their discectomy surgery and discs in patients that received cells demonstrated a significant difference as a group in the fluid content of their treated disc when compared to control. Autologous disc-derived cell transplantation is technically feasible and biologically relevant to repairing disc damage and retarding disc degeneration. Adipose tissue provides an alternative source of regenerative cells with little donor site morbidity. These regenerative cells are able to differentiate into a nucleus pulposus-like phenotype when exposed to environmental factors similar to disc, and offer the inherent advantage of availability without the need for transporting, culturing, and expanding the cells. In an effort to develop a clinical option for cell placement and assess the response of the cells to the post-surgical milieu, adipose-derived cells were collected, concentrated, and transplanted under fluoroscopic guidance directly into a surgically damaged disc using our dog model. This study provides evidence that cells harvested from adipose tissue might offer a reliable source of regenerative potential capable of bio-restitution. PMCID: PMC2587656 PMID: 19005697 [PubMed - indexed for MEDLINE] 2189. Postepy Hig Med Dosw (Online). 2008 Nov 3;62:593-8. [Biological role of phosphatidylcholine-specific phospholipase C in mammalian cells]. [Article in Polish] Szumiło M(1), Rahden-Staroń I. Author information: (1)Katedra i Zakład Biochemii, Warszawski Uniwersytet Medyczny, 02-097 Warszawa. mszumilo@amwaw.edu.pl Phosphatidylcholine-specific phospholipase C (PC-PLC) catalyzes the hydrolysis of the ester linkage between glycerol and phosphate in phosphocholine (PC) and other phosphatides, such as sphingomylin (SM) and phosphatidylethanolamine (PE). PC-PLC activity has been described in many organisms, from bacteria to mammals. In mammalian cells the enzyme has been found in erythrocytes, lymphocytes, muscular tissue, adipose tissue, and the nervous system. Hydrolysis of PC by PC-PLC results in the production of phosphocholine and diacylglycerol (DAG), a well-characterized lipid second-messenger molecule. The PC-degradation pathway by PC-PLC is activated by many factors, including cytokines, growth factors, mitogens, and calcium ions. Degradation of PC has been implicated in intracellular signal transduction involved in the regulation of cell metabolism, growth, differentiation, and induction of apoptosis. In this review the structure and biological function of mammalian PC-PLC are discussed. PMID: 19002082 [PubMed - indexed for MEDLINE] 2190. J Anim Sci. 2009 Apr;87(14 Suppl):E72-82. doi: 10.2527/jas.2008-1340. Epub 2008 Nov 7. Cellular regulation of bovine intramuscular adipose tissue development and composition. Smith SB(1), Kawachi H, Choi CB, Choi CW, Wu G, Sawyer JE. Author information: (1)Department of Animal Science, Texas A&M University, College Station, TX 77843-2471, USA. sbsmith@tamu.edu It is well documented that grain feeding stimulates adipogenesis in beef cattle, whereas pasture feeding depresses the development of adipose tissues, including intramuscular (i.m.) adipose tissue. Additionally, production practices that depress adipocyte differentiation also limit the synthesis of MUFA. Marbling scores and MUFA increase in parallel suggesting that stearoyl-coenzyme A desaturase (SCD) gene expression is closely associated with and necessary for marbling adipocyte differentiation. Similarly, marbling scores and fatty acid indices of SCD activity are depressed in response to dietary vitamin A restriction. In bovine preadipocytes, vitamins A and D both decrease glycerol-3-phosphate dehydrogenase (GPDH) activity, an index of adipocyte differentiation, whereas incubation of bovine preadipocytes with l-ascorbic acid-2-phosphate increases GPDH activity. Exposing bovine preadipocytes to zinc also stimulates adipogenesis, putatively by inhibiting nitric oxide (NO) production. However, incubation of bovine preadipocytes with arginine, a biological precursor of NO, strongly promotes differentiation in concert with increased SCD expression. This suggests that the effect of either arginine or zinc on adipogenesis is independent of NO synthesis in bovine preadipocytes. Enhanced expression of SCD is associated with a greater accumulation of MUFA both in bovine preadipocyte cultures and during development in growing steers. In bovine preadipocytes, trans-10, cis-12 CLA strongly depresses adipocyte differentiation and SCD gene expression, thereby reducing MUFA concentrations. The bovine preadipocyte culture studies suggest that any production practice that elevates vitamins A or D or trans-10, cis-12 CLA in bovine adipose tissue will reduce i.m. adipose tissue development. Conversely, supplementation with vitamin C or zinc may promote the development of i.m. adipose tissue. PMID: 18997081 [PubMed - indexed for MEDLINE] 2191. Brain Behav Immun. 2009 May;23(4):405-10. doi: 10.1016/j.bbi.2008.10.007. Epub 2008 Oct 25. Three questions about leptin and immunity. Fantuzzi G(1). Author information: (1)Department of Kinesiology and Nutrition, University of Illinois at Chicago, 1919 W Taylor Street MC517, Chicago, IL 60612, USA. giamila@uic.edu Leptin is a protein produced by adipocytes (and other cell types) that acts in the brain to regulate appetite and energy expenditure according to the amount of energy stored in adipose tissue. Leptin also exerts a variety of other functions, including important roles as a regulator of immune and inflammatory reactions. The present article is not meant to be a comprehensive review on leptin and immunity, but rather highlights a few controversial issues about leptin's place in the complex network of mediators regulating immune and inflammatory responses. Three issues are discussed: (1) Where am I going, or What is the cellular target of leptin for modulation of immune responses?; (2) Where am I coming from, or Is the cellular source important in determining leptin's effects on immune responses? and (3) What am I doing, or What are leptin's effects on immune and inflammatory responses? PMCID: PMC2699448 PMID: 18996468 [PubMed - indexed for MEDLINE] 2192. Arch Med Res. 2008 Nov;39(8):715-28. doi: 10.1016/j.arcmed.2008.09.005. White adipose tissue as endocrine organ and its role in obesity. Vázquez-Vela ME(1), Torres N, Tovar AR. Author information: (1)Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México. Due to the public health problem represented by obesity, the study of adipose tissue, particularly of the adipocyte, is central to the understanding of metabolic abnormalities associated with the development of obesity. The concept of adipocyte as endocrine and functional cell is not totally understood and can be currently defined as the capacity of the adipocyte to sense, manage, and send signals to maintain energy equilibrium in the body. Adipocyte functionality is lost during obesity and has been related to adipocyte hypertrophy, disequilibrium between lipogenesis and lipolysis, impaired transcriptional regulation of the key factors that control adipogenesis, and lack of sensitivity to external signals, as well as a failure in the signal transduction process. Thus, dysfunctional adipocytes contribute to abnormal utilization of fatty acids causing lipotoxicity in non-adipose tissue such as liver, pancreas and heart, among others. To understand the metabolism of the adipocyte it is necessary to have an overview of the developmental process of new adipocytes, regulation of adipogenesis, lipogenesis and lipolysis, endocrine function of adipocytes and metabolic consequences of its dysfunction. Finally, the key role of adipose tissue is shown by studies in transgenic animals or in animal models of diet-induced obesity that indicate the contribution of adipose tissue during the development of metabolic syndrome. Thus, understanding of the molecular process that occurs in the adipocyte will provide new tools for the treatment of metabolic abnormalities during obesity. PMID: 18996284 [PubMed - indexed for MEDLINE] 2193. Recent Pat Cardiovasc Drug Discov. 2008 Nov;3(3):187-93. Rimonabant for the treatment of obesity. Samat A(1), Tomlinson B, Taheri S, Thomas GN. Author information: (1)Department of Medicine, University of Birmingham, Edgbaston, Birmingham, UK. Obesity is a growing public health problem that is already reaching epidemic proportions and is increasingly encompassing young children and adolescents. Despite the increasing prevalence and the health risks associated with obesity, the pharmacotherapeutic options for treating obesity are limited. The endogenous cannabinoid or endocan-nabinoid system (ECS) was discovered in the early 1990s in relation to work on the action of components of marijuana. Central activation of the ECS promotes food ingestion. The endogenous cannabinoids exert their pharmacologic action through interaction with the specific receptors, CB(1) and CB(2). CB(1) receptors are located predominantly in the brain and peripherally in adipose tissue, liver, skeletal muscle and the gastrointestinal tract. In July 2006, European regulatory authorities approved the use of rimonabant, SR141716, a selective CB1 receptor antagonist, in obese patients (BMI > or =30kg/m(2), or >27kg/m(2) with complications). However, in June 2007, despite extensive clinical trial data, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the safety of rimonabant had not been adequately demonstrated by the manufacturer Sanofi-Aventis; the full application was subsequently withdrawn. This review article provides evidence and outlines some patents for the use of rimonabant and potential safety concerns which still prevent its use in the single largest market for drugs of its kind. PMID: 18991793 [PubMed - indexed for MEDLINE] 2194. Cas Lek Cesk. 2008;147(9):459-70. [Atherogenic dyslipidemia and the metabolic syndrome: pathophysiological mechanisms]. [Article in Czech] Zák A(1), Slabý A. Author information: (1)IV interní klinika 1, LF UK a VFN U Nemocnice 2, 128 08 Praha. azak@vfn.cz Atherogenic dyslipidemia (ADL), a frequent metabolic derangement found in patients with manifest atherosclerosis, is characterized by hypertriglyceridemia, low plasma HDL cholesterol and prevalence of small dense LDL particles. The key pathogenetic mechanisms of ADL are closely linked to insulin resistance, the lack of appropriate responses to insulin in peripheral cells, especially in adipose tissue, skeletal muscles and liver. Impaired insulin signalling leads to a decreased suppression of lipolysis, defective fat storage in adipocytes, and increased flux of free fatty acids to the liver, which together with posttranslational stabilization of apolipoprotein B enhances the assembly and secretion of VLDL particles. Decreased activity of lipoprotein lipase contributes to slow clearance of triglyceride-rich particles, with negative consequences in LDL metabolism. Impaired HDL synthesis, intravascular remodelling, and catabolism decreases reverse cholesterol transport from peripheral tissues, hepatocytes and macrophages. Small dense LDL particles are considered to be highly atherogenic, due to increased penetration of arterial intima, and decreased antioxidant capacity. Better understanding of pathophysiological mechanisms involved in ADL could promote new therapeutic methods, as well as increase the compliance with essential lifestyle interventions. PMID: 18988488 [PubMed - indexed for MEDLINE] 2195. Aesthetic Plast Surg. 2009 Jan;33(1):14-21. doi: 10.1007/s00266-008-9258-z. Epub 2008 Nov 6. A comparison of lipoatrophy and aging: volume deficits in the face. Coleman S(1), Saboeiro A, Sengelmann R. Author information: (1)Center for Aesthetics, Rejuvenation, and Enhancement, 44 Hudson Street, New York, NY, 10013, USA. lipostructure@yahoo.com BACKGROUND: Insight into the physical processes of aging can be gained by comparing the loss of facial volume that occurs during aging with the dramatic fat loss resulting from acquired lipoatrophy, including human immunodeficiency virus (HIV) treatment-associated lipoatrophy. The superficial effects of aging, such as rhytid formation, often are the focus of investigations into this phenomenon. However, age-related volume loss often is ignored. METHODS: A review of the relevant literature was conducted to provide an overview of age-related lipoatrophy and its etiology and to compare it by facial region with HIV-associated facial lipoatrophy. RESULTS: As a side effect of highly active antiretroviral therapy, HIV-associated lipoatrophy results in fat lipodystrophy (including both lipoatrophy and lipohypertrophy) and progresses toward nearly complete subdermal facial fat loss. Aging is accompanied by changes in the soft tissues of the face, leaving atrophic regions of generalized tissue ptosis. Some facial regions are affected differently by fat loss, depending on its cause. In the aging patient, certain parts of the face display only minimal fat loss. CONCLUSIONS: The role of fat loss in facial aging is slight compared with its considerable role in HIV-associated lipoatrophy. The losses of various facial tissues and the ptosis of some soft tissues are strong contributors to the appearance of the aged face. This regional anatomic assessment of the face engenders a more thorough understanding of the progression that characterizes volume changes associated with aging. PMID: 18987910 [PubMed - indexed for MEDLINE] 2196. Clin Exp Pharmacol Physiol. 2009 Jan;36(1):5-11. doi: 10.1111/j.1440-1681.2008.05075.x. Epub 2008 Oct 15. Storing up trouble: does accumulation of intramyocellular triglyceride protect skeletal muscle from insulin resistance? Watt MJ(1). Author information: (1)Department of Physiology, Monash University, Melbourne, Victoria, Australia. matthew.watt@med.monash.edu.au 1. Insulin resistance occurs when normal amounts of insulin are inadequate to produce a normal insulin response from cells. This is important in the context of whole-body glucose homeostasis because skeletal muscle is the main tissue for insulin-stimulated glucose disposal. 2. In obesity, lipid deposition in peripheral tissues, such as skeletal muscle, is linked to the activation of stress kinases and the development of insulin resistance. Accumulation of intramyocellular triglyceride (IMTG) is positively associated with insulin resistance; however, it is unknown whether IMTG causes insulin resistance or protects cells from insulin resistance by preventing the accrual of bioactive lipid metabolites. 3. The role of IMTG in the development of insulin resistance is not resolved. Stable overexpression of the triglyceride lipase adipose triglyceride lipase (ATGL) reduced IMTG content in myotubes, but resulted in a concomitant increase in diacylglycerol (DAG) and ceramide and caused insulin resistance. Increasing TG content by muscle-specific overexpression of diacylglycerol acyltransferase (DGAT) 1 protected mice from insulin resistance. Conversely, overexpression of DGAT2 in glycolytic muscle resulted in accumulation of TG and ceramide and insulin resistance in these tissues. This was sufficient to induce whole-body insulin and glucose insensitivity. 4. It is unlikely that IMTG causes cause insulin resistance directly. Instead, it appears as though TG accumulates in skeletal muscle to sequester fatty acids and to protect from the deleterious actions of lipids, such as ceramide and DAG. Whether lipase inhibitors are viable therapeutics to prevent obesity induced insulin resistance is unknown, but future studies examining tissue-specific ATGL/hormone-sensitive lipase knockouts will hopefully resolve this question. PMID: 18986321 [PubMed - indexed for MEDLINE] 2197. J Cardiometab Syndr. 2008 Summer;3(3):168-72. doi: 10.1111/j.1559-4572.2008.00011.x. Obesity, hypertension, and the heart. Good D(1), Morse SA, Ventura HO, Reisin E. Author information: (1)Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA. Controversy exists regarding the amount of risk caused by obesity, but there is general consensus that it is associated with many serious disorders, mostly cardiovascular and neoplastic. Obesity is clearly associated with hypertension, ventricular remodeling with subsequent congestive heart failure, sleep-disordered breathing, and sudden death. The physiologic alterations associated with establishing and perpetuating the obese state are complex but are becoming clear. In discussing the cardiovascular consequences of obesity, the implications and mechanism of the associated hypertension need to be understood. There is growing recognition that adipose tissue is a very active in the neurohormonal axis and is not simply a passive storage depot. Among other things, adipocyte-related hormonal activity and resistance to feedback mechanisms are associated with increased plasma volume and increased sympathetic tone. PMID: 18983334 [PubMed - indexed for MEDLINE] 2198. Biol Chem. 2008 Aug;389(8):1037-41. doi: 10.1515/BC.2008.110. Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle. Motrescu ER(1), Rio MC. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U596, ULP, C.U. de Strasbourg, BP 10142, F-67404 Illkirch Cedex, France. This brief review focuses on the emerging role of matrix metalloproteinase 11 (MMP-11) in cancer progression. It has recently been shown that MMP-11 is induced in adipose tissue by cancer cells as they invade their surrounding environment. MMP-11 negatively regulates adipogenesis by reducing pre-adipocyte differentiation and reversing mature adipocyte differentiation. Adipocyte dedifferentiation in turn leads to the accumulation of nonmalignant peritumoral fibroblast-like cells, which favor cancer cell survival and tumor progression. This MMP-11-mediated bi-directional cross-talk between invading cancer cells and adjacent adipocytes/pre-adipocytes highlights the central role that MMP-11 plays during tumor desmoplasia and represents a molecular link between obesity and cancer. PMID: 18979628 [PubMed - indexed for MEDLINE] 2199. Future Lipidol. 2008;3(5):545-556. Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Surmi BK(1), Hasty AH. Author information: (1)Vanderbilt University Medical Center, Department of Molecular Physiology & Biophysics, Nashville, TN 37232, USA Tel.: +1 615 322 5972; ; bonnie.k.wasson@vanderbilt.edu. It has long been known that adipose tissue in obesity is in a heightened state of inflammation. Recently, our understanding of this has been transformed by the knowledge that immune cells such as macrophages and T cells can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. These seminal findings have opened up a new area in biology that is garnering the interest of scientists involved in research relating to cell motility, inflammation, obesity, physiology, diabetes and cardiovascular disease. Some important general questions relevant to this field are: how are macrophages recruited to adipose tissue in obesity? What are the physiological consequences of macrophage-adipocyte interactions? Do these inflammatory macrophages contribute to pathophysiological conditions associated with obesity, such as insulin resistance, dyslipidemia, diabetes and cardiovascular disease? This review focuses on the first of these important questions. PMCID: PMC2575346 PMID: 18978945 [PubMed] 2200. Orv Hetil. 2008 Nov 9;149(45):2121-7. doi: 10.1556/OH.2008.28490. [Lipedema, a barely known disease: diagnosis, associated diseases and therapy]. [Article in Hungarian] Wenczl E(1), Daróczy J. Author information: (1)Fovárosi Onkormányzat Egyesített Szent István és Szent László Kórház és Rendelôintézet, Bôrgyógyászati és Limfológiai Rehabilitációs Osztály, Budapest. ewenczl@yahoo.com Lipedema is a common but rarely diagnosed disease or frequently confused with obesity. Patients are almost exclusively women. It is characterised by symmetrical, circumscribed, in advanced form deforming fat tissue accumulation on the legs that is associated with lymphedema. Spontaneous pain, pain to pressure and tendency to hematoma are characteristic. One of the possible causes of a fat leg, that is a very common complaint, is lipedema. Main differential diagnoses are obesity, lipohypertrophy and primary and secondary lymphedema. It is often associated with chronic venous and lymphatic insufficiency, early degenerative articular disease and obesity. The disease is rarely recognized and the treatment modalities are not widely known. Therefore patients feel very frustrated that leads to psychologic disorders. Until recently only conservative treatment was possible (combination of manual or intermittent pneumatic drainage, compression bandages and garments and physiotherapy). More recently surgical intervention (liposuction) is also included in the treatment options. The significance of lipedema is due not only to the disease itself, but also to the combination of lipedema and the group of associated and secondary diseases (articular and venous diseases, lymphedema, obesity, psychologic disorders). The more diseases coexist, the worse is the prognosis of lipedema itself. To prevent and delay this disease, it is indispensable to recognise it as early as possible and to treat it expertly and follow up patients suffering from lipedema. PMID: 18977739 [PubMed - indexed for MEDLINE] 2201. Diabetes Res Clin Pract. 2008 Dec 15;82 Suppl 2:S127-34. doi: 10.1016/j.diabres.2008.09.023. Epub 2008 Oct 31. Fatty acid binding proteins in adipose tissue: a promising link between metabolic syndrome and atherosclerosis? Krusinová E(1), Pelikánová T. Author information: (1)Diabetes Centre, Institute for Clinical and Experimental Medicine, Vídenská 1958/9, 14021 Prague, Czech Republic. Adipocyte/macrophage fatty acid binding protein (A-FABP) has been shown to be closely associated with metabolic syndrome, obesity and development of atherosclerosis. Moreover, A-FABP has been recently suggested as a potential therapeutic target of these abnormalities in animal models. The present review aims to summarize current knowledge on A-FABP functions and regulations both in animal models and humans, since the role of A-FABP in human physiology and disease has not been presently clarified. PMID: 18977052 [PubMed - indexed for MEDLINE] 2202. JPEN J Parenter Enteral Nutr. 2008 Nov-Dec;32(6):645-7. doi: 10.1177/0148607108326070. Obesity and inflammation: lessons from bariatric surgery. Compher C(1), Badellino KO. Author information: (1)University of Pennsylvania School of Nursing, Philadelphia, PA 19104-6096, USA. compherc@nursing.upenn.edu BACKGROUND: Obesity is associated with a series of comorbid conditions that are characterized by an inflammatory state. The purpose of this review is to update knowledge about obesity, adipose tissue, and inflammation. METHODS: Review of the published literature using search terms of adipose, inflammation, obesity, and insulin resistance in combinations. RESULTS: Adipose tissue elaborates proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha, with greater secretion from the stromal vascular fraction than from adipocytes and with greater secretion from visceral than subcutaneous adipose tissue sites. This proinflammatory state is associated with insulin resistance and ameliorated by weight loss, with concurrent increase in production of the anti-inflammatory adipokine adiponectin. CONCLUSION: Although these associations between obesity and inflammation are clearly important, many questions remain unresolved. It is unclear if benefits of weight loss pertain only to those with a proinflammatory profile, who receive a particular type of obesity surgical procedure, or whether these benefits are sustained over a lifetime. The outcomes associated with anti-inflammatory nutrient supplementation, with or without weight loss, in the obese would also increase our understanding. PMID: 18974245 [PubMed - indexed for MEDLINE] 2203. JPEN J Parenter Enteral Nutr. 2008 Nov-Dec;32(6):638-44. doi: 10.1177/0148607108325251. Adipose inflammation, insulin resistance, and cardiovascular disease. Shah A(1), Mehta N, Reilly MP. Author information: (1)Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA. Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll-like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro-inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator-activated receptor-gamma and NFkappaB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin-resistant state promoting meta-bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity. PMCID: PMC3088110 PMID: 18974244 [PubMed - indexed for MEDLINE] 2204. Int J Stem Cells. 2008 Nov;1(1):43-8. Adipose stem cells as a clinically available and effective source of adult stem cell therapy. Jeong JH(1). Author information: (1)Department of Plastic and Reconstructive Surgery, College of Medicine, Yeungnam University, Daegu, Korea. The greatest advantage of adipose-derived stem cells (ASCs) over other types of adult stem cells is its large number when we harvest primarily. The number of ASCs within adipose tissue reaches more than hundreds of times compared with BMSCs contained in the same amount of bone marrow. The major role of 'regenerative medicine' in 21st century is based on cell therapy and ASC is going to take the core position. It is important to know the characteristics of ASCs for successful clinical application. There are several unique features of ASCs which is known common characteristic of mesenchymal stem cells (MSCs). Cellular plasticity is one of the most important features of ASCs as in other adult stem cells and the cells also have a special function of immune modulation and immunosuppression. Strong angiogenic potential is another important nature of ASCs. In many reports, ASCs are known not only to be differentiated into osteoblasts, chondrocytes, vascular endothelial cells, but also to be cardiomyocytes and neuronal cells. In conclusion, the new knowledge of ASCs is going to impact on the regenerative medicine. To take the advantage of this new type of cells and utilize the cells, we need to understand the function of ASCs and future possibilities of ASCs. We plastic surgeons continue to stimulate the our curiosity and creativity, as well as our clinical inspiration. PMCID: PMC4021774 PMID: 24855507 [PubMed] 2205. Adv Ther. 2008 Nov;25(11):1141-74. doi: 10.1007/s12325-008-0110-2. Angiotensin receptor blockers in the treatment of NASH/NAFLD: could they be a first-class option? Georgescu EF(1). Author information: (1)Department of Internal Medicine 2, Filantropia University Hospital, Craiova, 200136 Romania. efg@usa.net Nonalcoholic fatty liver disease (NAFLD) is a condition pathogenically linked to metabolic syndrome (MS) by insulin resistance (IR), and characterized by hepatic steatosis in the absence of significant alcohol use, hepatotoxicity, and/or other known liver diseases.The principles of NAFLD therapy target IR: the key point of MS. As the renin-angiotensin system (RAS) plays a central role in IR, and subsequently in NAFLD and nonalcoholic steatohepatitis (NASH), an attempt to block the deleterious effects of RAS overexpression seems a logical target. While many potential therapies tested in NASH target only the consequences of this condition, or try to "get rid" of excessive fat, angiotensin receptor blockers (ARBs) could act as an elegant tool for adequate correction of the various imbalances that act in harmony in NASH/NAFLD. Indeed, by inhibiting RAS we can improve the intracellular insulin signaling pathway, better control adipose tissue proliferation and adipokine production, and produce more balanced local and systemic levels of various cytokines. At the same time, by controlling the local RAS in the liver we might be able to prevent at least fibrosis and also slow down the vicious cycle that links steatosis to necroinflammation. By targeting the pancreatic effects of angiotensin we should be able to preserve an adequate insulin secretion and acquire a better metabolic balance.In our opinion there are two major advantages of ARBs that make them a possible therapeutic option for treating NASH and MS: their specific antihypertensive effect, and their impact on liver fibrosis. In light of this, and based on the current evidence (including existent human studies), we can speculate that some ARBs like telmisartan, candesartan, and losartan can be beneficial in treating NASH/NAFLD and its consequences, and further larger controlled clinical trials will bring consistent data into this field. PMID: 18972077 [PubMed - indexed for MEDLINE] 2206. Minerva Med. 2008 Oct;99(5):519-32. [Molecular aspects of obesity and related-pathologies]. [Article in Italian] Buonsanti G(1). Author information: (1)Laboratorio di Analisi Cliniche del dott. A. Montemurro & C. S.a.s., Matera, Italia. giovanni.buonsanti@gmail.com The structure of human genetic machinery aimed at energy homeostasis has been set-up to face food deficiency rather than availability of a larger amount of calories compared with those needed for activities and works characterized by a little expenditure of energy. A epidemiologic-like, global-extended trend of obesity growth is observable, a condition associated with other pathologies that increase mobility and mortality in all ranges of ages. A correct management of obesity is a global challenge that involves both health improvement and socioeconomic aspects (i.e. costs sustained for management of obesity-linked pathologies, such the cardiovascular diseases, the type 2 diabetes as well as some type of tumors or neurologic diseases). This article analyzes recent scientific advancements on the mechanisms linking obesity to type 2 diabetes as well as the adipose tissue and intestinal apparatus' molecular mechanisms that control the energy balance. PMID: 18971916 [PubMed - indexed for MEDLINE] 2207. Cardiology. 2009;113(1):35-49. doi: 10.1159/000165919. Epub 2008 Oct 30. The quest for the optimal assessment of global cardiovascular risk: are traditional risk factors and metabolic syndrome partners in crime? Arsenault BJ(1), Pibarot P, Després JP. Author information: (1)Department of Anatomy and Physiology, Université Laval, Québec, Qué., Canada. Global risk calculators such as the Framingham risk score generally take into account traditional risk factors such as age, sex, blood pressure, smoking status, total cholesterol and high-density lipoprotein cholesterol levels, and the presence of diabetes which are recommended to be used in clinical practice to estimate patients' cardiovascular disease (CVD) risk. Over the last decades, the prevalence of obesity has dramatically increased all over the world. The deleterious form of obesity, visceral obesity, is the most prevalent form of the so-called metabolic syndrome, a constellation of risk factors associated with perturbations of the lipoprotein-lipid profile and of the plasma glucose-insulin homeostasis also likely to be associated with increased blood pressure and a proinflammatory and prothrombotic state. To this date, metabolic syndrome is still in need of a place in global CVD risk prediction. As the metabolic syndrome is not likely to replace currently used global risk scoring algorithms, both traditional risk factors and emerging metabolic markers associated with the metabolic syndrome should be incorporated in future risk scoring systems to be developed in order to adapt CVD risk prediction tools to the epidemic of obesity which has direct consequences on the daily life of health professionals. Copyright 2008 S. Karger AG, Basel. PMID: 18971578 [PubMed - indexed for MEDLINE] 2208. Curr Hypertens Rep. 2008 Dec;10(6):434-9. Leptin and mechanisms of endothelial dysfunction and cardiovascular disease. Knudson JD(1), Payne GA, Borbouse L, Tune JD. Author information: (1)Baylor College of Medicine, Department of Pediatrics, Houston, TX 77030, USA. knudson@bcm.edu Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor. PMID: 18959828 [PubMed - indexed for MEDLINE] 2209. Can J Cardiol. 2008 Sep;24 Suppl D:7D-12D. Abdominal obesity: the cholesterol of the 21st century? Després JP(1), Arsenault BJ, Côté M, Cartier A, Lemieux I. Author information: (1)Québec Heart Institute, Quebec City, Quebec. Jean-Pierre.Despres@crhl.ulaval.ca Cardiovascular disease (CVD) is a leading cause of morbidity and death in many countries worldwide. With the help of epidemiological, metabolic and clinical studies conducted over the past decades, the key factors contributing to the development of CVD have been identified. In this regard, several modifiable (hypertension, smoking, elevated cholesterol or low-density lipoprotein-cholesterol concentrations, reduced levels of high-density lipoprotein-cholesterol, type 2 diabetes) and nonmodifiable (age, sex, genetic predisposition) CVD risk factors have been recognized. Although better acute care and chronic pharmacological management have contributed to reduce CVD mortality, CVD morbidity remains very high. It has been proposed that this situation could be the consequence of the evolving landscape of CVD risk factors, which include, among others, poor nutritional habits and a reduction in physical activity contributing to the epidemic of obesity sweeping the world. However, obesity is heterogeneous both in terms of its etiology and its metabolic complications. Body fat distribution, especially visceral adipose tissue accumulation, has been found to be a major correlate of a cluster of diabetogenic and atherogenic abnormalities that has been described as the metabolic syndrome. The importance of abdominal obesity in association with the development of CVD and type 2 diabetes has been recognized in several studies, beyond the contribution of overall obesity. Additional evidence also suggests that the CVD risk related to the hyperglycemic state observed in subjects with the metabolic syndrome or type 2 diabetes is largely explained by the high prevalence of the metabolic complications of abdominal obesity. Although the presence of the metabolic syndrome clearly increases CVD risk, its clinical diagnosis is not sufficient to classify a patient at high risk for a cardiovascular event because attention must also be paid to the presence of traditional risk factors in the calculation of global CVD risk. The additional information provided by the metabolic syndrome to the risk attributed to traditional risk factors in the calculation of global CVD risk has been defined as global cardiometabolic risk. The fight against abdominal obesity as a major cause of CVD morbidity and mortality will require major societal changes and the involvement of dieticians, kinesiologists and behaviour modification specialists in clinical practice to reshape our physical activity and dietary habits. Finally, the early prevention of overweight/obesity/abdominal obesity in children, starting as early as conception, and the identification of key drivers of unhealthy nutritional and sedentary behaviours are the cornerstone of a successful comprehensive plan to fight CVD morbidity. PMCID: PMC2794449 PMID: 18787730 [PubMed - indexed for MEDLINE] 2210. J Bioenerg Biomembr. 2008 Oct;40(5):457-61. doi: 10.1007/s10863-008-9172-8. Epub 2008 Oct 29. Uncoupling protein 1: a short-circuit in the chemiosmotic process. Porter RK(1). Author information: (1)School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. rkporter@tcd.ie One of the significant naturally occurring short-circuits in the chemiosmotic process is manifest through the activity of uncoupling protein 1, most notably present in the inner membrane of mitochondria in brown adipose tissue. Much has been learnt about the mechanism of action of uncoupling protein 1 since its discovery in the 1970's, yet many areas of controversy surround (i) the mechanism of its action, (ii) novel regulators of its activity, and (iii) the tissue specificity of its expression. In this mini-review, areas of controversy are highlighted from the aforementioned categories using selected key experiments to demonstrate the arguments. PMID: 18958609 [PubMed - indexed for MEDLINE] 2211. Hypertens Res. 2008 Jul;31(7):1283-91. doi: 10.1291/hypres.31.1283. The metabolic syndrome as a concept of adipose tissue disease. Oda E(1). Author information: (1)Medical Check-up Center, Tachikawa Medical Center, Nagamachi 2-2-16, Nagaoka 940-0053, Japan. ijie@venus.sannet.ne.jp The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to directly promote the development of diabetes and cardiovascular disease. However, in 2005, the American Diabetes Association and the European Association for the Study of Diabetes jointly stated that no existing definition of the metabolic syndrome meets the criteria of a syndrome, and there have been endless debates on the pros and cons of using the concept of this syndrome. The controversy may stem from confusion between the syndrome and obesity. Obesity is an epidemic, essentially contagious disease caused by an environment of excess nutritional energy and reinforced by deeply rooted social norms. The epidemic of obesity should be prevented or controlled by social and political means, similar to the approaches now being taken to combat global warming. The diagnosis of metabolic syndrome is useless for this public purpose. The purpose of establishing criteria for diagnosing metabolic syndrome is to find individuals who are at increased risk of diabetes and cardiovascular disease and who require specific therapy including diet and exercise. The syndrome may be an adipose tissue disease different from obesity; in that case, it would be characterized by inflammation clinically detected through systemic inflammatory markers such as high-sensitivity C-reactive protein and insulin resistance reflecting histological changes in adipose tissue. However, many problems in defining the optimal diagnostic criteria remain unresolved. PMID: 18957797 [PubMed - indexed for MEDLINE] 2212. Semin Liver Dis. 2008 Nov;28(4):407-26. doi: 10.1055/s-0028-1091985. Epub 2008 Oct 27. Role of fatty acids in the pathogenesis of obesity and fatty liver: impact of bariatric surgery. Verna EC(1), Berk PD. Author information: (1)Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York 10032, USA. Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis. PMID: 18956297 [PubMed - indexed for MEDLINE] 2213. Semin Liver Dis. 2008 Nov;28(4):370-9. doi: 10.1055/s-0028-1091981. Epub 2008 Oct 27. Mechanisms of disease progression in nonalcoholic fatty liver disease. Jou J(1), Choi SS, Diehl AM. Author information: (1)Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia. PMID: 18956293 [PubMed - indexed for MEDLINE] 2214. Semin Liver Dis. 2008 Nov;28(4):351-9. doi: 10.1055/s-0028-1091979. Epub 2008 Oct 27. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Cheung O(1), Sanyal AJ. Author information: (1)Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA. Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in the United States and is strongly associated with the metabolic syndrome. Although many of the risk factors are well defined, the pathogenesis of NAFLD remains poorly understood. Recent studies have implicated several important cellular processes and signaling pathways that are affected by abnormal lipid metabolism, resulting in specific biochemical, histological, and clinical changes associated with NAFLD. Pharmacotherapy for NAFLD is limited and treatments are mainly to minimize risk factors. Understanding the disease pathogenesis is therefore important in identifying individuals with increased susceptibility for disease progression so lifestyle and risk modifications can be initiated early on. In this review, recent advances in the study of abnormal lipid metabolism and its impacts on histology and dysregulation of various cellular processes implicated in the genesis of NAFLD will be discussed. PMID: 18956291 [PubMed - indexed for MEDLINE] 2215. Mol Immunol. 2009 Feb;46(5):755-60. doi: 10.1016/j.molimm.2008.09.013. Epub 2008 Oct 26. Dual role of complement in adipose tissue. Pattrick M(1), Luckett J, Yue L, Stover C. Author information: (1)Dept. of Infection, Immunity and Inflammation, University of Leicester, University Road, Leicester LE 1 9HN, United Kingdom. Once thought of as purely the body's chief energy store, adipose tissue and its constituent adipocytes have emerged as both a metabolic entity and an endocrine one. Complement is generally thought of as originating mainly from hepatic synthesis but also from synthesis by the macrophage phagocyte system. This review revisits early descriptions of adipocytic synthesis of complement components and highlights the need of a systematic analysis of the contribution of adipose tissue to systemic inflammation in order to appreciate the immunological activity of this tissue. PMID: 18954909 [PubMed - indexed for MEDLINE] 2216. Amino Acids. 2009 Oct;37(4):555-8. doi: 10.1007/s00726-008-0194-7. Epub 2008 Oct 25. Visfatin in pregnancy: proposed mechanism of peptide delivery. Katwa LC(1), Seidel ER. Author information: (1)Department of Physiology, The Brody School of Medicine at East Carolina University, 600 Moye Blvd., Greenville, NC, 27834, USA. Visfatin is a newly identified 52 kD adipocytokine that appears to have insulinomimetic properties. We examined visfatin expression in visceral fat from lean and pregnant women. Visfatin gene expression was seven times higher in omental fat of pregnant women than in lean women. Both immunohistochemistry and immunoblot confirmed that visfatin protein was much higher in pregnant women than in nonpregnant women. However, serum visfatin was 20.8 +/- 7.7 ng/ml (n = 7) in lean women as compared to only a slight increase to 40.3 ng/ml in pregnant women (n = 4). We measured visfatin mRNA content of human placenta and found that placenta expresses high levels of visfatin mRNA and protein. At a concentration of 2 nM, visfatin and insulin produced nearly identical increase in glucose transport. The discrepancy between the elevated visfatin expression and tissue visfatin compared to only a small increase in serum visfatin is a matter of controversy. The data on serum visfatin concentrations are replete with contradictory data. Taken together, we suggest that visfatin is not a hormone. Instead, we propose that visfatin acts in either a paracrine or autocrine mode. This hypothesis would explain what various laboratories have found widely discrepant values for serum visfatin. Since visfatin potently and efficaciously induced glucose transport in a cell culture model, any hypothetical role for visfatin in pregnancy should include the possibility that it may play a role in maternal/fetal glucose metabolism or distribution and that it may do so by acting locally. PMID: 18953631 [PubMed - indexed for MEDLINE] 2217. J Lipid Res. 2009 Jan;50(1):3-21. doi: 10.1194/jlr.R800031-JLR200. Epub 2008 Oct 23. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. Zechner R(1), Kienesberger PC, Haemmerle G, Zimmermann R, Lass A. Author information: (1)Institute of Molecular Biosciences, University of Graz, Austria. rudolf.zechner@uni-graz.at Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL- and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzyme's activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the "lipolysome," a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL. PMID: 18952573 [PubMed - indexed for MEDLINE] 2218. Methods. 2009 Feb;47(2):116-21. doi: 10.1016/j.ymeth.2008.10.013. Epub 2008 Oct 24. Bioengineering strategies to generate vascularized soft tissue grafts with sustained shape. Stosich MS(1), Moioli EK, Wu JK, Lee CH, Rohde C, Yoursef AM, Ascherman J, Diraddo R, Marion NW, Mao JJ. Author information: (1)Tissue Engineering and Regenerative Medicine Laboratory, Department of Biomedical Engineering, Columbia University Medical Center, College of Dental Medicine, New York, NY 10032, USA. Tissue engineering offers the possibility for soft tissue reconstruction and augmentation without autologous grafting or conventional synthetic materials. Two critical challenges have been addressed in a number of recent studies: a biology challenge of angiogenesis and an engineering challenge of shape maintenance. These two challenges are inter-related and are effectively addressed by integrated bioengineering strategies. Recently, several integrated bioengineering strategies have been applied to improve bioengineered adipose tissue grafts, including internalized microchannels, delivery of angiogenic growth factors, tailored biomaterials and transplantation of precursor cells with continuing differentiation potential. Bioengineered soft tissue grafts are only clinically meaningful if they are vascularized, maintain shape and dimensions, and remodel with the host. Ongoing studies have begun to demonstrate the feasibility towards an ultimate goal to generate vascularized soft tissue grafts that maintain anatomically desirable shape and dimensions. PMCID: PMC4035046 PMID: 18952179 [PubMed - indexed for MEDLINE] 2219. Drug Discov Today. 2009 Feb;14(3-4):192-7. doi: 10.1016/j.drudis.2008.09.009. Epub 2008 Nov 10. Adiponectin normalization: a clue to the anti-metabolic syndrome action of rimonabant. Maynadier M(1), Basile I, Gary-Bobo M. Author information: (1)Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France. Obesity, currently associated with metabolic syndrome is characterized by an excessive fat storage in different organs, in particular adipose tissue, inducing the loss of its structural and functional integrity. Being aware of the importance of adipose tissue endocrine function and the key role of adipocytokines, such as adiponectin, in obesity and metabolic syndrome drives the necessity to develop new drugs that can exert a specific action on adipose tissue and on adiponectin levels. Rimonabant, an antiobesity drug, presents a dual effect by decreasing food intake and importantly increasing adiponectin. This review focuses on the key role of adiponectin regulation in the success of rimonabant and suggests that this adipohormone may be considered as a therapeutic target to design innovative and promising antiobesity and anti-metabolic syndrome drugs. PMID: 18951999 [PubMed - indexed for MEDLINE] 2220. Tijdschr Psychiatr. 2008;50(10):645-54. [Schizophrenia and antipsychotics associated with the metabolic syndrome. An overview]. [Article in Dutch] Scheepers-Hoeks AM(1), Wessels-Basten SJ, Scherders MJ, Bravenboer B, Loonen AJ, Kleppe RT, Grouls RJ. Author information: (1)Catharinaziekenhuis Eindhoven, apotheek, Postbus 1350, 5602 ZA Eindhoven. anne-marie.scheepers@catharina-ziekenhuis.nl BACKGROUND: Cardiovascular morbidity and mortality are higher in patients with schizophrenia than in the general population because the metabolic side-effects of antipsychotics and schizophrenia increase the risk of cardiovascular disease (cvd) and diabetes mellitus type 2 (DM2). The metabolic syndrome is defined in order to discover which patients have a high risk of developing cvd and DM2. AIM: To survey the current knowledge about the relationship between schizophrenia and the metabolic syndrome, the influence of the use of antipsychotics on the development of the metabolic syndrome, and the possible differences in the effects that first and second generation antipsychotics have on the syndrome. METHOD: The PubMed and Medscape databases were searched for relevant articles published between 2000 and July 2008. results Schizophrenia and the use of antipsychotics increase the prevalence of abdominal obesity, dyslipidemia and DM2 (i.e. the metabole syndrome). Second generation antipsychotics tend to cause a marked increase in the prevalence of abdominal obesity and dyslipidemia, whereas first generation antipsychotics hardly have any of these effects. Both first and second generation antipsychotics increase the risk of DM2. CONCLUSION: The metabolic syndrome has a significant effect on the morbidity and mortality of patients with schizophrenia because it increases the risk they will develop cvd and DM2. The risk increases still further if patients are taking antipsychotics. The risk of cvd can be decreased if patients with schizophrenia are screened in time and are monitored regularly. PMID: 18951343 [PubMed - indexed for MEDLINE] 2221. Curr Cardiol Rep. 2008 Nov;10(6):464-9. Is hypertension an immunologic disease? Harrison DG(1), Guzik TJ, Goronzy J, Weyand C. Author information: (1)Department of Medicine, Division of Cardiology, Emory University School of Medicine, Room 319 WMRB, 1639 Pierce Drive, Atlanta, GA 30322, USA. dharr02@emory.edu Several studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the blood pressure elevation caused by angiotensin II and in response to sodium and volume challenge. Hypertensive stimuli cause effector T cells to enter visceral fat, in particular perivascular fat, where they release cytokines that promote vasoconstriction. Similarly, effector T cells accumulate in the kidney in hypertension and contribute to renal dysfunction, promoting sodium and volume retention. These findings provide some insight into the relationship between inflammation and hypertension and suggest that efforts to reduce T-cell activation may be useful in preventing or treating this disease. PMID: 18950555 [PubMed - indexed for MEDLINE] 2222. Cell Cycle. 2008 Nov 1;7(21):3338-43. Epub 2008 Nov 15. Insulin and aging. Bartke A(1). Author information: (1)Department of Internal Medicine and Department of Physiology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9628, USA. abartke@siumed.edu In invertebrates, signaling pathways homologous to mammalian insulin and insulin-like growth factor (IGF-1) signal transduction have a major role in the control of longevity. There are numerous indications that these pathways also influence aging in mammals, but separating the role of insulin from the effects of IGF-1 and growth hormone (GH) is difficult. In mice, selective disruption of the insulin receptor in the adipose tissue extends longevity. Increases in lifespan were also reported in mice with deletion of insulin receptor substrate 1 (IRS1) in whole body or IRS2 only in the brain. GH deficiency or resistance in mutant mice leads to hypoinsulinemia and enhanced insulin sensitivity along with remarkably extended longevity. These characteristics resemble animals subjected to calorie restriction. Studies of physiological characteristics and polymorphisms of insulin-related genes in exceptionally long-lived people suggest a role of insulin signaling in the control of human aging. PMID: 18948730 [PubMed - indexed for MEDLINE] 2223. Mol Cell Endocrinol. 2009 Apr 29;302(2):193-202. doi: 10.1016/j.mce.2008.09.020. Epub 2008 Oct 1. The sweeter side of ACE2: physiological evidence for a role in diabetes. Bindom SM(1), Lazartigues E. Author information: (1)Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Diabetes mellitus is a growing problem in all parts of the world. Both clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of angiotensin-II (Ang-II) signaling pathways contribute to the development of diabetes and diabetic complications. Of clinical relevance, blockade of the renin-angiotensin system prevents new-onset diabetes and reduces the risk of diabetic complications. Angiotensin-converting enzyme (ACE) 2 is a recently discovered mono-carboxypeptidase and the first homolog of ACE. It is thought to inhibit Ang-II signaling cascades mostly by cleaving Ang-II to generate Ang-(1-7), which effects oppose Ang-II and are mediated by the Mas receptor. The enzyme is present in the kidney, liver, adipose tissue and pancreas. Its expression is elevated in the endocrine pancreas in diabetes and in the early phase during diabetic nephropathy. ACE2 is hypothesized to act in a compensatory manner in both diabetes and diabetic nephropathy. Recently, we have shown the presence of the Mas receptor in the mouse pancreas and observed a reduction in Mas receptor immuno-reactivity as well as higher fasting blood glucose levels in ACE2 knockout mice, indicating that these mice may be a new model to study the role of ACE2 in diabetes. In this review we will examine the role of the renin-angiotensin system in the physiopathology and treatment of diabetes and highlight the potential benefits of the ACE2/Ang-(1-7)/Mas receptor axis, focusing on recent data about ACE2. PMCID: PMC2676688 PMID: 18948167 [PubMed - indexed for MEDLINE] 2224. Arch Physiol Biochem. 2008 Oct;114(4):287-98. doi: 10.1080/13813450802404761 . Novel aspects of adipocyte-induced skeletal muscle insulin resistance. Eckardt K(1), Sell H, Eckel J. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Dusseldorf, Germany. kristin.eckardt@ddz.uni-duesseldorf.de Insulin resistance in skeletal muscle is an early event in the development of diabetes with obesity being one of the major contributing factors. Conditioned medium (CM) from differentiated human adipocytes impairs insulin signalling in human skeletal muscle cells. Recent data on adipocyte-induced insulin resistance in skeletal muscle cells describes underlying mechanisms of this process. Skeletal muscle insulin resistance involves multiple pathways and irreversible changes in the expression level of critical proteins. Furthermore, the reversibility of insulin resistance could be demonstrated. Several strategies to combat insulin resistance have been developed. One recent approach to treat obesity and the metabolic syndrome is the use of endocannabinoid receptor antagonists such as rimonabant. These compounds might also reduce insulin resistance in type 2 diabetes with effects on adipose tissue and liver and possibly skeletal muscle. PMID: 18946789 [PubMed - indexed for MEDLINE] 2225. Arch Physiol Biochem. 2008 Oct;114(4):277-86. doi: 10.1080/13813450802334752 . Biological specificity of visceral adipose tissue and therapeutic intervention. Perrini S(1), Leonardini A, Laviola L, Giorgino F. Author information: (1)Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari School of Medicine, Bari, Italy. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular diseases. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension, dyslipidaemia, sleep apnea, and other complications of obesity. Visceral adiposity, manifested as a high waist circumference, is now accepted as a major component of the metabolic syndrome. However, the biological mechanisms underlying the adverse impact of visceral fat accumulation remain to be established. This review will focus on the analysis of the biological specificity of adipose tissue located in the abdominal region, and will explore intervention strategies targeting the impaired function of the visceral adipocyte as potential therapies for the cardio-metabolic outcomes of patients with the metabolic syndrome. PMID: 18946788 [PubMed - indexed for MEDLINE] 2226. Arch Physiol Biochem. 2008 Oct;114(4):267-76. doi: 10.1080/13813450802306602 . Hypoxia and the endocrine and signalling role of white adipose tissue. Trayhurn P(1), Wang B, Wood IS. Author information: (1)Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, University Clinical Departments, Liverpool, UK. p.trayhurn@liverpool.ac.uk White adipose tissue is a major endocrine and signalling organ. It secretes multiple protein hormones and factors, termed adipokines (such as adiponectin, leptin, IL-6, MCP-1, TNFalpha) which engage in extensive cross-talk within adipose tissue and with other tissues. Many adipokines are linked to inflammation and immunity and these include cytokines, chemokines and acute phase proteins. In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related adipokines. It has been proposed that hypoxia may underlie the inflammatory response in adipose tissue and evidence that the tissue is hypoxic in obesity has been obtained in animal models. Cell culture studies have demonstrated that the expression and secretion of key adipokines, including leptin, IL-6 and VEGF, are stimulated by hypoxia, while adiponectin (with an anti-inflammatory action) production falls. Hypoxia also stimulates glucose transport by adipocytes and may have a pervasive effect on cell function within adipose tissue. PMID: 18946787 [PubMed - indexed for MEDLINE] 2227. Arch Physiol Biochem. 2008 Oct;114(4):237-43. doi: 10.1080/13813450802306685 . Metabolic syndrome in children and adolescents--risk for sleep-disordered breathing and obstructive sleep-apnoea syndrome? Körner A(1), Kratzsch J, Gausche R, Blüher S, Kapellen T, Pulzer F, Behrens M, Kiess W. Author information: (1)University Hospital for Children and Adolescents, University of Leipzig, Germany. The clinical relevance of the term "metabolic syndrome", the definition criteria, and predictive power are being disputed. Inclusion of sleep-disordered breathing and sleep apnoea into a definition of metabolic syndrome is also controversial once children and/or adolescents are affected. Nevertheless, along with the increasing prevalence of childhood obesity, the prevalence of the metabolic syndrome in obese children is reported at 30%, irrespective of the definition applied. Moreover, childhood obesity is associated with sleep-disordered breathing. Adipocytokines, cytokines secreted from adipose tissue, are thought to play a major role in the pathophysiology of metabolic syndrome. Leptin was initially suggested as a promising "anti-obesity" hormone. New concepts indicate that in humans leptin and its soluble receptor may be more important in states of energy deficiency rather than a predictor of the metabolic syndrome. Adiponectin, on the other hand, is not only related to obesity and insulin resistance, but appears to be the strongest predictor for metabolic syndrome, even in children. In newborns and infants, both adipocytokines occur in high concentrations, even though this cannot completely explain the increased risk for ensuing metabolic disease later in life. Finally, low-grade systemic inflammation may underlie the clustering of metabolic risk factors. Overall factors from the adipose tissue may constitute not only markers but also mediators of metabolic sequelae of obesity. PMID: 18946784 [PubMed - indexed for MEDLINE] 2228. Arch Physiol Biochem. 2008 Oct;114(4):211-23. doi: 10.1080/13813450802364627 . Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance? Vgontzas AN(1). Author information: (1)Department of Psychiatry, Sleep Research and Treatment Center, Hershey, PA 17033, USA. avgontzas@psu.edu Despite the early recognition of the strong association between obstructive sleep apnoea (OSA) and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a "local abnormality" of the respiratory track rather than as a "systemic illness". In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. In subsequent studies, it was shown that IL-6, TNFalpha, and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat was the primary parameter linked with sleep apnoea. Further studies showed that women with the polycystic ovary syndrome (PCOS) were much more likely than controls to have sleep-disordered breathing (SDB) and daytime sleepiness, suggesting a pathogenetic role of insulin resistance in OSA. Additional accumulated evidence that supports the role of obesity and the associated metabolic aberrations in the pathogenesis of sleep apnoea and related symptoms include: obesity without sleep apnoea is associated with daytime sleepiness; the protective role of gonadal hormones as suggested by the increased prevalence of sleep apnoea in post-menopausal women and the significantly reduced risk for OSA in women on hormonal therapy; partial effects of continuous positive airway pressure (CPAP) in obese patients with apnoea on hypercytokinemia, insulin resistance indices, and visceral fat; and that the prevalence of the metabolic syndrome in the U.S. population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnoea in general random samples. Furthermore, the beneficial effect of a cytokine antagonist on EDS and apnoea in obese, male apnoeics and that of exercise and weight loss on SDB and EDS in general random or clinical samples, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnoea in humans. Finally, our recent finding that in obese, hypothalamic CRH neuron is hypoactive, provides additional evidence on the potential central neural mechanisms for depressed ventilation and consequent development of sleep apnoea in obese individuals. In conclusion, accumulating evidence provides support to our thesis that obesity via inflammation, insulin resistance, visceral adiposity, and central neural mechanisms, e.g. hypofunctioning hypothalamic CRH, play a major role in the pathogenesis of sleep apnoea, sleepiness, and the associated cardiovascular co-morbidities. PMID: 18946782 [PubMed - indexed for MEDLINE] 2229. Anim Genet. 2009 Feb;40(1):115-8. doi: 10.1111/j.1365-2052.2008.01798.x. Epub 2008 Oct 17. Differentially expressed transcripts in adipose tissue between Korean native pig and Yorkshire breeds. Moon JK(1), Kim KS, Kim JJ, Choi BH, Cho BW, Kim TH, Lee CK. Author information: (1)Division of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul, South Korea. We measured and compared the transcripts of adipose tissue from Korean native pig (KNP) and Yorkshire (YS) breeds to investigate breed-specific transcription changes. We employed both the Affymetrix porcine genome array and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We found eight genes showing significant changes between the two breeds. Based on a literature review, these genes were indicative of differences in extracellular structure density and differences in the potential to metabolize xenobiotic chemicals and lipids. The differentially expressed genes indicated that KNP has a lower extracellular structure density and a lower potential to metabolize xenobiotic chemicals than YS. PMID: 18945290 [PubMed - indexed for MEDLINE] 2230. Cell Tissue Res. 2009 Jan;335(1):165-89. doi: 10.1007/s00441-008-0685-6. Epub 2008 Oct 22. Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Bakker W(1), Eringa EC, Sipkema P, van Hinsbergh VW. Author information: (1)Laboratory of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands. w.bakker@vumc.nl Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes. PMID: 18941783 [PubMed - indexed for MEDLINE] 2231. Postepy Hig Med Dosw (Online). 2008 Oct 16;62:543-58. [The metabolic syndrome. Part II: its mechanisms of development and its complications]. [Article in Polish] Pacholczyk M(1), Ferenc T, Kowalski J. Author information: (1)Zakład Biologii i Genetyki Uniwersytetu Medycznego w Łodzi, Łódź. arta-mp17@o2.pl The metabolic syndrome is a cluster of interrelated metabolic factors such as insulin resistance, hyperinsulinemia, abdominal obesity, impaired glucose tolerance, dyslipidemia, hypertension, and a proinflammatory and prothrombotic state. It is a common cause of the development of atherosclerotic vascular disease and type 2 diabetes. Genetic predisposition and environmental factors such as physical inactivity and increased caloric intake are responsible for the predisposition to metabolic syndrome. Available studies on the pathogenesis of metabolic syndrome are discrepant. Insulin resistance and abdominal obesity are the dominant causes of metabolic syndrome. Increased visceral adipose tissue mass and its proinflammatory activity are thought to underlie all the changes observed in metabolic syndrome. Adipose tissue is a dynamic endocrine and paracrine organ that produces and secretes inflammatory factors called adipokines, which link obesity, insulin resistance, atherosclerosis, and type 2 diabetes. Recent data suggest that oxidative stress is a primary pathogenic mechanism leading to the development of insulin resistance associated with over-nutrition. In this study the authors analyze the association between abdominal obesity, hyperinsulinemia, and insulin resistance and show some pathogenic mechanisms which may be responsible for the proatherogenic action of insulin resistance, hyperinsulinemia, and impaired glucose tolerance. Here the association among the disorders mentioned in the definitions of metabolic syndrome is discussed in more detail and it is shown that their clustering is not accidental in patients with insulin resistance. The role of adipose tissue in the development of insulin resistance and metabolic syndrome leading to overt cardiovascular disease and type 2 diabetes is also described. PMID: 18936730 [PubMed - indexed for MEDLINE] 2232. Prostaglandins Leukot Essent Fatty Acids. 2008 Sep-Nov;79(3-5):93-6. doi: 10.1016/j.plefa.2008.09.004. Epub 2008 Oct 18. The lipidome as a composite biomarker of the modifiable part of the risk of breast cancer. Bougnoux P(1), Hajjaji N, Couet C. Author information: (1)INSERM U921 Nutrition, Croissance et Cancer, HS Kaplan Cancer Center - CHU Bretonneau, 2 bis Boulevard Tonnellé, 37044 Tours, France. bougnoux@med.univ-tours.fr The potential for dietary fat to prevent breast cancer makes identification of defined molecules a mandatory step. In order to circumvent the limitations and/or bias of dietary exposure assessment tools, we have used the fatty acid composition of white adipose tissue as biomarker of past lipid intake. When considered separately, candidate fatty acids identified as favourable on the basis of their association with breast cancer risk have usually led to inconsistent results in dietary intervention studies carried out in rats. This inconsistency indicates that any approach based on a single fatty acid should be abandoned for an integrated view over the complex lipid interactions, which finally determines the lipidome, the lipid profile that is found in individuals. We reappraised the role of the complete lipid profile through a comprehensive study of adipose tissue fatty acids obtained in patients with benign or malignant breast tumors. Rather than a single fatty acid, a composite indicator combining elevated monounsaturates and low n-6/n-3 fatty acid ratio was associated with decreased breast cancer risk. The lipidome may provide the opportunity to quantify the modifiable part of the risk of breast cancer. The lipidome may be used as a template for designing proper dietary modifications in order to delay the occurrence of breast cancer. Which dietary modifications should be undertaken in order to bring a pertinent change to the lipidome with respect to the risk of breast cancer is currently unknown. The lipidome may allow the individualization of a high risk population of women, who may be targeted for a dietary prevention of breast cancer. The setting and validation of a high-throughput lipidomic station with analytical capabilities fitted to the need of mass screening is required. These two locks must be resolved before a primary prevention of breast cancer by diet could be contemplated. PMID: 18930643 [PubMed - indexed for MEDLINE] 2233. Trends Endocrinol Metab. 2009 Jan;20(1):1-7. doi: 10.1016/j.tem.2008.08.006. Epub 2008 Oct 17. Robust signaling networks of the adipose secretome. Breitling R(1). Author information: (1)Groningen Bioinformatics Centre, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands. r.breitling@rug.nl Type 2 diabetes is a prototypical complex systems disease that has a strong hereditary component and etiologic links with a sedentary lifestyle, overeating and obesity. Adipose tissue has been shown to be a central driver of type 2 diabetes progression, establishing and maintaining a chronic state of low-level inflammation. The number and diversity of identified endocrine factors from adipose tissue (adipokines) is growing rapidly. Here, I argue that a systems biology approach to understanding the robust multi-level signaling networks established by the adipose secretome will be crucial for developing efficient type 2 diabetes treatment. Recent advances in whole-genome association studies, global molecular profiling and quantitative modeling are currently fueling the emergence of this novel research strategy. PMID: 18930409 [PubMed - indexed for MEDLINE] 2234. Trends Endocrinol Metab. 2008 Dec;19(10):380-9. doi: 10.1016/j.tem.2008.09.001. Epub 2008 Oct 17. O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity. Issad T(1), Kuo M. Author information: (1)Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France. tarik.issad@inserm.fr Regulation of proteins by O-GlcNAc modification is becoming a major area of research. This reversible modification depends on glucose concentrations and, therefore, constitutes a powerful mechanism to regulate protein activities according to glucose availability. Its importance in glucose-dependent gene transcription is underlined by its role in pancreatic insulin biosynthesis (through PDX-1 and NeuroD1 O-GlcNAc modifications) and leptin synthesis in adipose tissue (through Sp1 O-GlcNAc modification). Moreover, in chronic hyperglycaemia, O-GlcNAc modifications of Sp1, p53 and NFkappaB participate in glucotoxicity, resulting in cardiovascular and renal alterations. The recent discovery by two independent groups that FoxO1 is regulated by O-GlcNAc modification provides a potential mechanism by which hyperglycaemia promotes gluconeogenesis and worsening of glucose intolerance, opening new research perspectives in the field. PMID: 18929495 [PubMed - indexed for MEDLINE] 2235. Trends Endocrinol Metab. 2008 Dec;19(10):356-61. doi: 10.1016/j.tem.2008.08.003. Epub 2008 Oct 15. Reassessing triglyceride synthesis in adipose tissue. Nye C(1), Kim J, Kalhan SC, Hanson RW. Author information: (1)Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-3549, USA. The synthesis and breakdown of triglycerides in adipose tissue and muscle is a crucial element of energy metabolism because it ensures that adequate fuel is available during starvation. Triglyceride turnover determines the availability of fatty acids for utilization by mammalian tissues, and any dysfunction in this process can lead to alterations in glucose metabolism, insulin resistance and type 2 diabetes. Our understanding of the reactions involved in triglyceride synthesis is currently being reassessed, primarily because of the recently identified role that re-esterification of fatty acids plays in triglyceride deposition and, thus, in controlling fatty-acid availability. Here, we review recent information on triglyceride synthesis and introduce the pathway of glyceroneogenesis as an important and highly regulated source of glyceride-glycerol in adipose tissue. PMID: 18929494 [PubMed - indexed for MEDLINE] 2236. Br J Sports Med. 2010 Jul;44(9):620-30. doi: 10.1136/bjsm.2008.046151. Epub 2008 Oct 16. Review on leptin and adiponectin responses and adaptations to acute and chronic exercise. Bouassida A(1), Chamari K, Zaouali M, Feki Y, Zbidi A, Tabka Z. Author information: (1)Laboratoire des adaptations cardio-circulatoires, respiratoires, métaboliques et hormonales à I'exercice musculaire, Faculté de Médecine Ibn El Jazzar, Sousse, 4002 Tunisia. bouassida_anissa@yahoo.fr Leptin and adiponectin represent two newly discovered adipose tissue derived hormones; that are both associated with health status and glucose and free fatty acid (FFA) metabolism. Moreover, acute and chronic exercises affect body composition, carbohydrate and lipid metabolism. It is thus interesting to evaluate the effects of physical exercise and training on leptin and adiponectin levels. It seems that leptin concentration is not modified after short-term exercise (<60 min) or exercise that generates an energy expenditure lower than 800 kcal. Leptin levels decrease after long-term exercise (> or =60 min) stimulating FFA release, or after exercise that generates energy expenditure higher than 800 kcal. Adiponectin concentration presents a delayed increase (30 min) after short-term intense exercise (<60 min) performed by trained athletes. For adiponectin, limited data suggest that adiponectin concentration presents a delayed increase (30 min) after short-term intense exercise (<60 min) performed by trained athletes. It seems that adiponectin concentrations do not change in response to long-term exercise (> or =60 min). Short-term training (<12 weeks) and long-term training (> or =12 weeks) show contrasting results regarding leptin and adiponectin. Most training studies which improve fitness levels and affect body composition could decrease leptin and increase adiponectin concentrations. PMID: 18927166 [PubMed - indexed for MEDLINE] 2237. Diabetes Obes Metab. 2008 Nov;10 Suppl 4:205-11. doi: 10.1111/j.1463-1326.2008.00957.x. Cell therapy for type 2 diabetes: is it desirable and can we get it? Halban PA(1). Author information: (1)Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland. philippe.halban@medecine.unige.ch The functional mass of beta-cells is decreased in type 2 diabetes. Replacing missing beta-cells or triggering their regeneration may thus allow for improved treatment of type 2 diabetes, to the extent that this is combined with therapy for improved insulin sensitivity. Although progress has been made in deriving beta-cell-like cells from stem or precursor cells in vitro, these cannot yet be obtained in sufficient quantities or well enough differentiated to envisage their therapeutic use in beta-cell replacement therapy. Likewise, our very limited understanding of beta-cell regeneration in adult man does not yet allow for development of a valid strategy for kick-starting such a process in individuals with type 2 diabetes, whether by bona fide neogenesis or self-replication of existing beta-cells. Regardless of how beta-cell mass is restored in type 2 diabetes, it will be important to prevent any renewed decrease thereafter. Current understanding suggests that islet inflammation as well as signals from (insulin-resistant/inflamed) adipose tissue and skeletal muscle contribute towards decreased beta-cell mass in type 2 diabetes. It will likely be important to protect newly formed or implanted beta-cells from these negative influences to ensure their long-term survival. PMID: 18834449 [PubMed - indexed for MEDLINE] 2238. Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E22-36. doi: 10.1152/ajpendo.90731.2008. Epub 2008 Oct 14. APPL1: role in adiponectin signaling and beyond. Deepa SS(1), Dong LQ. Author information: (1)Dept. of Cellular & Structural Biology, Univ. of Texas Health Science Ctr., 7703 Floyd Curl Dr., San Antonio, TX 78229, USA. Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues. A decrease in the circulating level of adiponectin has been linked to insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. Adiponectin exerts its effects through two membrane receptors, AdipoR1 and AdipoR2. APPL1 is the first identified protein that interacts directly with adiponectin receptors. APPL1 is an adaptor protein with multiple functional domains, the Bin1/amphiphysin/rvs167, pleckstrin homology, and phosphotyrosine binding domains. The PTB domain of APPL1 interacts directly with the intracellular region of adiponectin receptors. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in insulin-signaling pathway and is an important mediator of adiponectin-dependent insulin sensitization in skeletal muscle. Adiponectin signaling through APPL1 is necessary to exert its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 also acts as a mediator of other signaling pathways by interacting directly with membrane receptors or signaling proteins, thereby playing critical roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling. This review focuses mainly on our current understanding of adiponectin signaling in various tissues, the role of APPL1 in mediating adiponectin signaling, and also its role in the cross-talk between adiponectin/insulin-signaling pathways. PMCID: PMC2636986 PMID: 18854421 [PubMed - indexed for MEDLINE] 2239. J Lipid Res. 2009 Apr;50 Suppl:S57-62. doi: 10.1194/jlr.R800030-JLR200. Epub 2008 Oct 14. GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins. Beigneux AP(1), Davies BS, Bensadoun A, Fong LG, Young SG. Author information: (1)Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. abeigneux@mednet.ucla.edu GPIHBP1, a small glycosylphosphatidylinositol-anchored glycoprotein, is required for the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 knockout mice exhibit chylomicronemia, even on a low-fat diet, with plasma triglyceride levels of 3,500-5,000 mg/dl. GPIHBP1 is expressed highly in heart, adipose tissue, and skeletal muscle, the same tissues that express high levels of lipoprotein lipase (LPL). In each of these tissues, GPIHBP1 is located in capillary endothelial cells. Chinese hamster ovary (CHO) cells transfected with a GPIHBP1 expression vector bind LPL and chylomicrons avidly. The expression of GPIHBP1 in mice is modulated by fasting and refeeding and is also regulated by peroxisome proliferator-activated receptor (PPAR)gamma agonists. Here, we review recent progress in understanding GPIHBP1 and discuss its role in lipolysis. PMCID: PMC2674691 PMID: 18854402 [PubMed - indexed for MEDLINE] 2240. Nuklearmedizin. 2008;47(5):181-7. [Obesity, energy regulation and thyroid function: is borderline elevated TSH-level the cause or secondary phenomenon of obesity]. [Article in German] Dietlein M(1), Kahaly G, Kobe C, Schmidt M, Derwahl KM, Schicha H. Author information: (1)Klinik und Poliklinik für Nuklearmedizin der Universität zu Köln, Köln. markus.dietlein@uni-koeln.de Several population-based studies have shown a significant association between TSH-level and BMI (body mass index). About 30% of the rest energy expenditure are regulated by thyroid hormones, which generated the hypothesis that thyroid hormone substitution with TSH-titration into the lower reference levels may prevent body weight gain. The opposite effect of thyroid hormones is appetite stimulation, which may be responsible for body weight gain in case of substitutive medication. The association between TSH and BMI has become a complex topic in the light of the endocrine activity of adipocytes. Adipocytes are not a silent fat mass, but increase the hormone level of leptin, which influences neurones in the hypothalamus, the thyreotropic axis and TSH secretion. BMI is positively correlated with serum leptin. Elevated leptin levels, endogenous in individuals with high BMI or exogenous after leptin injection for treatment of hypothalamic amenorrhoea, shift TSH in the upper reference level. Borderline elevated TSH levels are reversible in case of body weight reduction in obese persons. It remains unclear whether high TSH levels or high leptin level are responsible for obesity or represent secondary phenomenon. Recommendation for daily practice: Borderline elevated TSH-levels in obese patients will decrease in case of body weight reduction without hormone medication. After definitive treatment of hyperthyroidism patient's history for use of carbohydrates (increased during hyperthyroidism) should be noticed and substitution with thyroid hormones aims at TSH in the lower reference level. As body weight gain is observed in all TSH groups, a special concept for prevention and therapy of obesity (diet, daily exercise, behaviour training) should be initiated early and additionally to medication. PMID: 18852923 [PubMed - indexed for MEDLINE] 2241. Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):627-34. doi: 10.1038/ncpendmet0980. Epub 2008 Oct 14. Metabolic impact of adipose and hepatic glycerol channels aquaporin 7 and aquaporin 9. Maeda N(1), Funahashi T, Shimomura I. Author information: (1)Graduate School of Medicine, Osaka University, Osaka, Japan. nmaeda@imed2.med.osaka-u.ac.jp The discovery of aquaporins, which are plasma-membrane-associated water channels, has greatly influenced the medical sciences. So far, thirteen aquaporins have been identified in humans. Among them, types 3, 7, 9, and 10 are subcategorized as aquaglyceroporins, which enable the transport of glycerol as well as water. Although aquaporins have a proven crucial role in water homeostasis, the physiological and pathological importance of aquaporins as glycerol channels is not fully understood. Adipocytes are a major source of glycerol, one of the substrates for hepatic gluconeogenesis. Aquaporin subtypes 7 and 9 (AQP7 and AQP9) are the glycerol channels in adipocytes and hepatocytes, respectively. The coordinated regulation of these channels leads to the optimum balance between release of glycerol by adipocytes and its uptake by the liver. In addition, studies of AQP7 and AQP9 knockout or knockdown mice have clearly demonstrated in vivo the pathophysiological relevance of glycerol channels through effects on glycerol metabolism. Associations between various AQP7 gene mutations and obesity in humans have also been shown. Thus, further research of these two aquaporins might uncover novel targets for therapy. PMID: 18852723 [PubMed - indexed for MEDLINE] 2242. Genes Nutr. 2006 Jun;1(2):95-106. doi: 10.1007/BF02829951. Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors. Bordoni A(1), Di Nunzio M, Danesi F, Biagi PL. Author information: (1)Centro Ricerche sulla Nutrizione - Department of Biochemistry "G. Moruzzi", University of Bologna Via Irnerio, 48-40126, Bologna, Italy, alessandra.bordoni@unibo.it. Dietary polyunsaturated fatty acids (PUFAs) function not only by altering membrane lipid composition, cellular metabolism, signal transduction, but possess also effects on gene expression by regulating the activity/abundance of different nuclear transcription factors: peroxisome proliferator activated receptors, retinoid X receptors, liver X receptors, hepatic nuclear factors-4a, and sterol regulatory binding proteins 1 and 2. PUFAs regulate the expression of genes in various tissues, including the liver, heart, adipose tissue, and brain, playing a major role in carbohydrate, fatty acid, triglyceride, and cholesterol metabolism. Before binding to transcription factors, PUFAs must be absorbed in the intestine and delivered to cells, and then they must enter the cell and the nucleus. PUFA concentration within the cell depends on many different factors, and regulate their possibility to act as transcription modulators. The aim of this review is to summarize recent knowledge about PUFAs destiny from dietto nuclear factors binding, examining the different variables which can modulate their interaction with nuclear factors themselves and therefore their effect on gene expression. PMCID: PMC3454679 PMID: 18850203 [PubMed] 2243. J Anim Sci. 2009 Apr;87(4):1218-46. doi: 10.2527/jas.2008-1427. Epub 2008 Oct 10. Board-invited review: the biology and regulation of preadipocytes and adipocytes in meat animals. Hausman GJ(1), Dodson MV, Ajuwon K, Azain M, Barnes KM, Guan LL, Jiang Z, Poulos SP, Sainz RD, Smith S, Spurlock M, Novakofski J, Fernyhough ME, Bergen WG. Author information: (1)USDA-ARS, Richard B. Russell Agricultural Research Station, Athens, GA 30604, USA The quality and value of the carcass in domestic meat animals are reflected in its protein and fat content. Preadipocytes and adipocytes are important in establishing the overall fatness of a carcass, as well as being the main contributors to the marbling component needed for consumer preference of meat products. Although some fat accumulation is essential, any excess fat that is deposited into adipose depots other than the marbling fraction is energetically unfavorable and reduces efficiency of production. Hence, this review is focused on current knowledge about the biology and regulation of the important cells of adipose tissue: preadipocytes and adipocytes. PMID: 18849378 [PubMed - indexed for MEDLINE] 2244. Expert Opin Biol Ther. 2008 Nov;8(11):1733-47. doi: 10.1517/14712598.8.11.1733 . Hormone-based therapies in the regulation of fuel metabolism and body weight. Kesty NC(1), Roth JD, Maggs D. Author information: (1)Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, CA 92121, USA. nicole.kesty@amylin.com BACKGROUND: The integrated central actions of hormones secreted from pancreatic islets, the gut and adipocytes regulate both energy homeostasis and body weight. Dysregulation in these neurohormonal pathways probably contributes to pathogenesis of obesity and type 2 diabetes. OBJECTIVE: To examine hormone-based therapies targeting these interrelated pathways as potential treatments for obesity and diabetes. METHODS: Preclinical and clinical data on therapies based on hormones secreted from the pancreas (glucagon, insulin, amylin and pancreatic polypeptide), gut (glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, cholecystokinin and peptide YY) and adipose tissue (leptin and adiponectin) as potential treatments for diabetes and obesity are reviewed. RESULTS/CONCLUSIONS: In diabetes, hormone-based treatments have translated into new clinical platforms including insulin analogs, the GLP-1-like peptide receptor agonist exenatide and amylinomimetic pramlintide, which due to their complex interplay and the progressive nature of diabetes, can be utilized in different settings. Various peptide hormones and agonists/antagonists are currently under investigation as new approaches to treatment of obesity and diabetes. PMID: 18847308 [PubMed - indexed for MEDLINE] 2245. Int J Impot Res. 2009 Mar-Apr;21(2):89-98. doi: 10.1038/ijir.2008.42. Epub 2008 Oct 9. Obesity, low testosterone levels and erectile dysfunction. Diaz-Arjonilla M(1), Schwarcz M, Swerdloff RS, Wang C. Author information: (1)Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90803, USA. Obesity is an important risk factor for many common diseases including cardiovascular disease (CVD), type 2 diabetes, cancer and erectile dysfunction (ED). Adipose tissues produce a number of adipokines and cytokines, which affect endothelial and metabolic function resulting in insulin resistance and the metabolic syndrome (risks factors for CVD). Both ED and metabolic syndrome improve with a reduction in body mass index (BMI). The relationships among obesity, metabolic syndrome, ED, sex hormone-binding globulin (SHBG) and serum total and free testosterone levels are complex and often confusing to the physician. It is known that BMI is inversely proportional to serum total testosterone concentrations; low serum SHBG levels in obesity contribute to the low serum total testosterone. Recent studies show that BMI is also inversely proportional to free testosterone concentration. The characteristic low serum testosterone concentrations observed in obese men are also present in men with the metabolic syndrome and type 2 diabetes mellitus. A small proportion of men with ED have hypogonadism; however, the proportion increases if these men are obese with manifestations of the metabolic syndrome or type 2 diabetes mellitus. ED is a common symptom in patients with type 2 diabetes who also have low testosterone levels. This review describes the relationships between low serum testosterone concentrations and ED in obese patients and those with metabolic syndrome and type 2 diabetes mellitus. PMID: 18843273 [PubMed - indexed for MEDLINE] 2246. Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):619-26. doi: 10.1038/ncpendmet0976. Epub 2008 Oct 7. Mechanisms of macrophage activation in obesity-induced insulin resistance. Odegaard JI(1), Chawla A. Author information: (1)Graduate Program in Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5103, USA. Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism. PMCID: PMC3381907 PMID: 18838972 [PubMed - indexed for MEDLINE] 2247. Arch Immunol Ther Exp (Warsz). 2008 Sep-Oct;56(5):331-45. doi: 10.1007/s00005-008-0037-y. Structure and physiological functions of the human peroxisome proliferator-activated receptor gamma. Zieleniak A(1), Wójcik M, Woźniak LA. Author information: (1)Department of Structural Biology, Chair of General Endocrinology, Medical University of Łódź, Zeligowskiego 7/9, 90-752, Łódź, Poland. The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. To date, three different PPAR isotypes, namely PPAR-alpha, -delta, and -gamma, have been identified in vertebrates and have distinct patterns of tissue distribution. Like all nuclear receptors, the human PPAR-gamma (hPPAR-gamma) is characterized by a modular structure composed of an N-terminal A/B domain, a DNA-binding domain with two zinc fingers (C domain), a D domain, and a C-terminal ligand-binding domain (E/F domain). Human PPAR-gamma exists in two protein isoforms, hPPAR-gamma(1) and -gamma(2), with different lengths of the N-terminal. The hPPAR-gamma(2) isoform is predominantly expressed in adipose tissue, whereas hPPAR-gamma(1) is relatively widely expressed. Human PPAR-gamma plays a critical physiological role as a central transcriptional regulator of both adipogenic and lipogenic programs. Its transcriptional activity is induced by the binding of endogenous and synthetic lipophilic ligands, which has led to the determination of many roles for PPAR-gamma in pathological states such as type 2 diabetes, atherosclerosis, inflammation, and cancer. Of the synthetic ligands, the thiazolidinedione class of insulin-sensitizing drugs (ciglitazone, pioglitazone, troglitazone, rosiglitazone) is employed clinically in patients with type 2 diabetes. PMID: 18836859 [PubMed - indexed for MEDLINE] 2248. Neonatology. 2008;94(4):245-54. doi: 10.1159/000151643. Epub 2008 Oct 2. Strategies for feeding the preterm infant. Hay WW Jr(1). Author information: (1)Department of Pediatrics, Perinatal Research Center, Colorado Clinical Translational Science Institute, University of Colorado School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA. bill.hay@uchsc.edu According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestational age. Unfortunately, most preterm infants, especially those born very preterm with extremely low birth weight, are not fed sufficient amounts of nutrients to produce normal fetal rates of growth and, as a result, end up growth-restricted during their hospital period after birth. Growth restriction is a significant problem, as numerous studies have shown definitively that undernutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, and both neuronal deficits of number and dendritic connections as well as later behavioral and cognitive outcomes. Furthermore, clinical follow-up studies have shown that among infants fed formulas, the nutrient content of the formula is directly and positively related to mental and motor outcomes later in life. Nutritional requirements do not stop at birth. Thus, delaying nutrition after birth 'until the infant is stable' ignores the fundamental point that without nutrition starting immediately after birth, the infant enters a catabolic condition, and catabolism does not contribute to normal development and growth. Oxygen is necessary for all metabolic processes. Recent trends to limit oxygen supply to prevent oxygen toxicity have the potential, particularly when the blood hemoglobin concentration falls to less than 8 g/dl, to develop growth failure. Glucose should be provided at 6-8 mg/min/kg as soon after birth as possible and adjusted according to frequent measurements of plasma glucose to achieve and maintain concentrations >45 mg/dl but <120 mg/dl to avoid the frequent problems of hyperglycemia and hypoglycemia. Similarly, lipid is required to provide at least 0.5 g/kg/day to prevent essential fatty acid deficiency. However, the high rate of carbohydrate and lipid supply that preterm infants often get, based on the incomplete assumption that this is necessary to promote protein growth, tends to produce increased fat in organs like the liver and heart as well as adipose tissue. More and better essential fatty acid nutrition is valuable, but more organ and adipose fat has no known benefit and many problems. Amino acids and protein are essential not only for body growth but for metabolic signaling, protein synthesis, and protein accretion. 3.5-4.0 g/kg/day are necessary to produce normal protein balance and growth in very preterm infants. Attempts to promote protein growth with insulin has many problems - it is ineffective while contributing to even further organ and adipose tissue fat deposition. Enteral feeding always is indicated and to date nearly all studies have shown that minimal enteral feeding approaches (e.g., 'trophic feeds') promote the capacity to feed enterally. Milk has distinct advantages over formulas in avoiding necrotizing enterocolitis (NEC), and while feeding is associated with NEC, minimal enteral feeding regimens produce less NEC than those geared towards more aggressive introduction of enteral feeding. Finally, overfeeding has the definite potential to produce adipose tissue, or obesity, which then leads to insulin resistance, glucose intolerance, and diabetes. This scenario occurs more commonly as infants are fed more and gain weight more rapidly after birth, regardless of their birth weight. Infants with IUGR and postnatal growth failure may be uniquely 'set up' for this outcome, while infants with in utero obesity, such as infants of diabetic mothers, already are well along this adverse outcome pathway. Copyright 2008 S. Karger AG, Basel. PMCID: PMC2912291 PMID: 18836284 [PubMed - indexed for MEDLINE] 2249. Arch Pathol Lab Med. 2008 Oct;132(10):1679-82. doi: 10.1043/1543-2165(2008)132[1679:HA]2.0.CO;2. Hepatic angiomyolipoma. Petrolla AA(1), Xin W. Author information: (1)Department of Pathology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA. Amber.petrolla@UHhospitals.org Hepatic angiomyolipoma is a rare, benign, hepatic mesenchymal neoplasm found in both males and females, and most commonly in adult females. Angiomyolipoma occurs most commonly in the kidneys. The liver represents the second most frequent site of involvement. Hepatic angiomyolipomas are composed of varying amounts of smooth muscle cells, adipose tissue, and vessels. The smooth muscle cell component is the most specific to the diagnosis. The smooth muscle cells can have varying morphologies and are positive for homatropine methylbromide-45 but are negative for hepatocyte paraffin 1 and S100 protein. The definitive diagnostic study remains the histologic examination of the surgically resected lesion coupled with immunohistochemical stains. The differential diagnosis includes hepatocellular carcinoma, hepatic adenoma, leiomyoma, hepatoblastoma, melanoma, and gastrointestinal stromal tumor. The immunohistochemical staining pattern differentiates this lesion from other malignant and benign liver lesions. If the diagnosis of hepatic angiomyolipoma has been made, it can be followed conservatively or surgically resected. PMID: 18834230 [PubMed - indexed for MEDLINE] 2250. Clin Calcium. 2008 Oct;18(10):1451-9. doi: CliCa081014511459. [Effect of anabolic steroids on osteoporosis]. [Article in Japanese] Adachi M(1), Takayanagi R. Author information: (1)Kyushu University, Graduate School of Medical Science, Department of Medicine and Bioregulatory Science. Androgen inhibits osteoclastic bone resorption with increase of bone formation through androgen receptor in bone tissue. Anabolic steroids are synthetic derivates of testoterone. Anobolic steroids have favorable anabolic actions, lessening virilizing effects. Several anabolic steroids have been synthesized and some of them have been approved as a drug for anti osteoporosis. Anabolic steroids have revealed the increased bone mineral content or bone mineral density at the radius, and the lumbar spine in osteoporosis patients. Anabolic steroids have also decreased fat mass with increase of lean body mass and muscle mass, and lessened bone pain in osteoporosis patients having bone fracture, which seem to be favorable effects for especially elder osteoporosis patients. But in recent years the number of osteoporosis patients treated with anabolic steroids has been decreasing. Furthermore recently few clinical trials about the effect of anabolic steroids on osteoporosis have been reported, and prospective study for bone fracture using anabolic steroids has not reported yet. We would like to expect additional effects except on bone formation will enhance the frequency in use of anabolic steroids, and the prospective clinical study about the prevention against bone fracture will be reported in the future. PMID: 18830042 [PubMed - indexed for MEDLINE] 2251. Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):766-73. doi: 10.1097/MCO.0b013e328312c353. Nonalcoholic fatty liver disease: the potential role of nutritional management. Leclercq IA(1), Horsmans Y. Author information: (1)Laboratory of Gastroenterology, Université Catholique de Louvain (UCL), Brussels, Belgium. isabelle.leclercq@uclouvain.be PURPOSE OF REVIEW: To review available data pertaining to dietary imbalances and metabolic alterations leading to the development of fatty liver disease and nutritional managements. RECENT FINDINGS: The importance of treating fatty liver disease is now firmly recognized not only because of the risk of progression toward a more aggressive liver disease but also because the fatty liver is an important provider of cardiovascular risks. The ideal diet for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis patients should reduce fat mass and inflammation in the adipose tissue, restore insulin sensitivity, and provide low amounts of substrates for de-novo lipogenesis, but scientific evidence to recommend specific diets is currently lacking. Moderate weight loss, low-calorie diets, reduction in saturated fatty acids intake, together with an increase in monosaturated and n-3 polyunsaturated fatty acids appear to be beneficial. Excessive consumption of high glycemic index carbohydrates appears deleterious, as it favors hyperglycemia and hyperinsulinemia and stimulates de-novo lipogenesis. Physical exercise is an important component of the approach, as it improves insulin sensitivity. Behavioral therapy promotes long-term compliance to lifestyle modifications. SUMMARY: One panacea is unlikely to be found, the more useful approach is probably multimodal and includes tailored lifestyle modifications. Randomized controlled trials are needed to establish dietary recommendations. While awaiting such trials, reduced consumption of simple sugar, especially sweetened beverages, and incremental increase in physical activity must be encouraged. PMID: 18827582 [PubMed - indexed for MEDLINE] 2252. Nephrology (Carlton). 2008 Oct;13(7):622-8. doi: 10.1111/j.1440-1797.2008.01022.x. Epub 2008 Sep 25. Review article: The role of adipose tissue in uraemia-related insulin resistance. Manolescu B(1), Stoian I, Atanasiu V, Busu C, Lupescu O. Author information: (1)Department of Biochemistry, Faculty of Medicine, UMF Carol Davila, Bucharest, Romania. manolescub@yahoo.fr Adipose tissue is no longer considered to be an inert tissue of which function is to store fat. It actively secretes a number of biologic active compounds that are involved in the regulation of many processes like food intake, energy expenditure, metabolism homeostasis, immunity and blood pressure homeostasis. General metabolism alteration in patients with chronic kidney disease has a profound impact on biology of adipocytes. Chronic renal failure is a pathological condition, of which two major hallmarks are chronic inflammation and insulin resistance. In uraemic patients, adipose tissue became an important source of molecules that are responsible, at least in part, for the metabolic disturbances seen in these patients. Some of these molecules act as pro-inflammatory agents contributing to the maintenance and enhancement of the chronic inflammatory response. These pro-inflammatory molecules, along with other molecules secreted by the adipose tissue, have a central position in the aetiology of uraemia-associated insulin resistance. In this review, we intend to summarize some aspects of the biology of adipokines in uraemia, with emphasis on the link between these molecules and insulin resistance. PMID: 18826486 [PubMed - indexed for MEDLINE] 2253. Curr Opin Investig Drugs. 2008 Oct;9(10):1095-102. The anti-aging, metabolism potential of SIRT1. Ghosh HS(1). Author information: (1)Columbia University Medical Center, Department of Microbiology, HHSC 609, 701 W 168th Street, New York, NY 10032, USA. hg2238@columbia.edu SIRT1 (sirtuin 1) is the human ortholog of the yeast Sir2 (silent information regulator 2) protein, which is implicated in lifespan extension in model organisms, such as yeast, worms and flies. It is an NAD+-dependent protein deacetylase with over two dozen known substrates that affect a wide variety of cellular processes, ranging from metabolism, cell cycle, growth and differentiation, inflammation, senescence, apoptosis, stress response and aging. Even though SIRT1 has been linked to calorie restriction-mediated longevity in model organisms, the mechanism by which it extends lifespan in mammals is not fully understood. A growing body of evidence suggests a role of SIRT1 in maintaining energy and nutrient homeostasis, thereby linking its anti-aging property to its role in metabolism. PMID: 18821472 [PubMed - indexed for MEDLINE] 2254. Int J Epidemiol. 2009 Feb;38(1):63-71. doi: 10.1093/ije/dyn183. Epub 2008 Sep 27. Ethnic variability in adiposity and cardiovascular risk: the variable disease selection hypothesis. Wells JC(1). Author information: (1)Childhood Nutrition Research Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. j.wells@ich.ucl.ac.uk Evidence increasingly suggests that ethnic differences in cardiovascular risk are partly mediated by adipose tissue biology, which refers to the regional distribution of adipose tissue and its differential metabolic activity. This paper proposes a novel evolutionary hypothesis for ethnic genetic variability in adipose tissue biology. Whereas medical interest focuses on the harmful effect of excess fat, the value of adipose tissue is greatest during chronic energy insufficiency. Following Neel's influential paper on the thrifty genotype, proposed to have been favoured by exposure to cycles of feast and famine, much effort has been devoted to searching for genetic markers of 'thrifty metabolism'. However, whether famine-induced starvation was the primary selective pressure on adipose tissue biology has been questioned, while the notion that fat primarily represents a buffer against starvation appears inconsistent with historical records of mortality during famines. This paper reviews evidence for the role played by adipose tissue in immune function and proposes that adipose tissue biology responds to selective pressures acting through infectious disease. Different diseases activate the immune system in different ways and induce different metabolic costs. It is hypothesized that exposure to different infectious disease burdens has favoured ethnic genetic variability in the anatomical location of, and metabolic profile of, adipose tissue depots. PMID: 18820320 [PubMed - indexed for MEDLINE] 2255. Int J Colorectal Dis. 2009 Jan;24(1):1-4. doi: 10.1007/s00384-008-0585-y. Epub 2008 Sep 25. The "creeping fat sign"-really diagnostic for Crohn's disease? Golder WA(1). Author information: (1)Association d'Imagerie Médicale, 65, rue Raymond Poincaré, F-10000, Troyes, France, werner.golder@orange.fr BACKGROUND: Focal or regionally prominent mesenteric fat adjacent to wall-thickened bowel loops can be readily identified by computed tomography. The so-called creeping fat of the right lower quadrant is usually considered to be an important clue for diagnosing Crohn's disease. However, when the sign is isolated, indistinct, and not set in the proper clinical context, the radiologist should consider other inflammatory conditions of the bowel and its appendages. CONCLUSION: Controlled studies are needed to confirm the diagnostic use of the "creeping fat sign" in clinical practice. PMID: 18815796 [PubMed - indexed for MEDLINE] 2256. Postepy Biochem. 2008;54(2):188-97. [Uncoupling proteins in modulation of mitochondrial functions--therapeutic prospects]. [Article in Polish] Woyda-Płoszczyca A(1), Jarmuszkiewicz W. Author information: (1)Instytut Biologii Molekularnej i Biotechnologii, Uniwersytet im. Adama Mickiewicza w Poznaniu. Enormous interest in mitochondrial uncoupling proteins (UCPs) is caused by relevant impact of these energy-dissipating systems on cellular energy transduction. A key role of UCPs in regulation of mitochondrial metabolism is supported by existence of their different isoforms in various mammalian tissues. Recent studies have shown that UCPs have an important part in pathogenesis of various disorders, such as obesity, type-2 diabetes, cachexia, aging or tumor. The obscure roles of UCPs in normal physiology and their emerging role in pathophysiology, provide exciting potential for further investigation. However, neither the exact physiological nor biochemical roles of UCP homologues are well understood. Therefore, providing mechanistic explanation of their functions in cellular physiology may be the basis for potential farmacological targeting of UCPs in future on clinical scale. PMID: 18807930 [PubMed - indexed for MEDLINE] 2257. Postepy Biochem. 2008;54(2):179-87. [Mitochondrial uncoupling proteins: regulation and physiological role]. [Article in Polish] Jarmuszkiewicz W(1), Woyda-Płoszczyca A. Author information: (1)Instytut Biologii Molekularnej i Biotechnologii, Uniwersytet im. Adama Mickiewicza, Poznań. wiesiaj@amu.adu.pl Uncoupling proteins (UCPs), members of mitochondrial carrier family, are present in mitochondrial inner membrane and mediate free fatty acid-activated, purine-nucleotide-inhibited H+ re-uptake. UCPs can modulate the tightness of coupling between mitochondrial respiration and ATP synthesis. A physiological function of the first described UCP, UCP1 or termogenin, present in mitochondria of mammalian brown adipose tissues is well established. UCP1 plays a role in nonshivering thermogenesis in mammals. The widespread presence of UCPs in eukaryotes, in non-thermogenic tissues of animals, plants and in unicellular organisms implies that these proteins may elicit other functions than thermogenesis. However, the physiological functions of UCP1 homologues are still under debate. They can regulate energy metabolism through modulation of the electrochemical proton gradient and production of ROS. Functional activation of UCPs is proposed to decrease ROS production. Moreover, products of lipid peroxidation can activate UCPs and promote feedback down-regulation of mitochondrial ROS production. PMID: 18807929 [PubMed - indexed for MEDLINE] 2258. Pediatr Endocrinol Rev. 2008 Sep;6(1):24-31. The inflammatory process of adipose tissue. Blüher M(1). Author information: (1)Department of Medicine, University of Leipzig, Leipzig, Germany. bluma@medizin.uni-leipzig.de Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, atherosclerosis, and non-alcoholic fatty liver disease. The evidence that obesity can be regarded as an inflammatory disease comes from numerous studies showing a moderate increase of circulating inflammatory factors in obese patients and the identification of different types of immune cells infiltrating the human adipose tissue. Obesity may induce a pro-inflammatory state, which can cause or worsen insulin resistance in adipose tissue, skeletal muscle, and liver. The causative factors of this inflammation process in obesity are not entirely understood, but adipose tissue seems to play an important role in the relationship between obesity and chronic inflammation. Increased infiltration of adipose tissue with immune cells could cause adipose tissue insulin resistance via autocrine and paracrine cytokine/adipokine signalling, which contributes to systemically decreased insulin sensitivity via endocrine signalling. On the other hand, obesity-induced inflammation could represent a compensatory mechanism for increased adipose tissue turnover in obese states, which might protect obese individuals against deleterious effects of fat accumulation. A better understanding of the mechanisms and molecular components of obesity induced inflammatory response might lead to identifying novel therapeutic targets to prevent obesity-related complications. PMID: 18806722 [PubMed - indexed for MEDLINE] 2259. World Rev Nutr Diet. 2008;98:51-61. doi: 10.1159/000152921. Omega-6 fatty acids and excessive adipose tissue development. Ailhaud G(1). Author information: (1)ISDBC, CNRS UMR 6543, Centre de Biochimie, Nice, France. ailhaud@unice.fr PMID: 18806461 [PubMed - indexed for MEDLINE] 2260. Eur J Endocrinol. 2008 Dec;159 Suppl 1:S67-74. doi: 10.1530/EJE-08-0245. Epub 2008 Sep 19. Insulin resistance and obesity in childhood. Chiarelli F(1), Marcovecchio ML. Author information: (1)Department of Paediatrics, University of Chieti, Via dei Vestini 5, I-66100 Chieti, Italy. chiarelli@unich.it Childhood obesity is a significant health problem that has reached epidemic proportions around the world and is associated with several metabolic and cardiovascular complications. Insulin resistance is a common feature of childhood obesity and is considered to be an important link between adiposity and the associated risk of type 2 diabetes and cardiovascular disease. Insulin resistance is also a key component of the metabolic syndrome, and its prevalence in the paediatric population is increasing, particularly among obese children and adolescents. Several factors are implicated in the pathogenesis of obesity-related insulin resistance, such as increased free fatty acids and many hormones and cytokines released by adipose tissue. Valid and reliable methods are essential to assess the presence and the extent of insulin resistance, the associated risk factors and the effect of pharmacological and lifestyle interventions. The two most common tests to assess insulin resistance are the hyperinsulinemic euglycemic clamp and the frequently sampled i.v. glucose tolerance test utilizing the minimal model. However, both these tests are not easily accomplished, are time consuming, expensive and invasive. Simpler methods to assess insulin resistance based on surrogate markers derived from an oral glucose tolerance test or from fasting insulin and glucose levels have been validated in children and adolescents and widely used. Given the strong association between obesity, insulin resistance and the development of metabolic syndrome and cardiovascular disease, prevention and treatment of childhood obesity appear to be essential to prevent the development of insulin resistance and the associated complications. PMID: 18805916 [PubMed - indexed for MEDLINE] 2261. Gynecol Obstet Fertil. 2008 Oct;36(10):969-77. doi: 10.1016/j.gyobfe.2008.05.006. Epub 2008 Sep 19. [Environmental endocrine disruptors and breast cancer: new risk factors?]. [Article in French] Fénichel P(1), Brucker-Davis F. Author information: (1)Inserm U895, service d'endocrinologie et médecine de la reproduction, hôpital de l'Archet I, CHU de Nice, BP 3079, 06202 Nice cedex 03, France. fenichel.p@chu-nice.fr Human epidemiological studies and experimental animal data strongly suggest that xenobiotics with estrogenic activity may participate in to the increasing incidence of breast cancer, the most frequent cancer all around the world. Several reports have since 15 years reported positive correlations between blood or peritumoral adipose tissue levels of persistent organic compounds including organochloride pesticides and breast cancer risk. Moreover, fetal or perinatal exposition to low doses of such endocrine disruptors induce premalignant or malignant transformation of adult mammary gland in rodents. However, this environmental endocrine disrupter hypothesis still needs to be demonstrated. Further human studies are needed which will consider the exposition window, the association of several xenoestrogens, the molecular mechanisms involved and the possible individual genetic susceptibility in order to identify pertinent biomarkers and to define acceptable environmental concentration levels for agricultural or industrial chemical new products to be used. PMID: 18805035 [PubMed - indexed for MEDLINE] 2262. Phys Ther. 2008 Nov;88(11):1265-78. doi: 10.2522/ptj.20080034. Epub 2008 Sep 18. Intricacies of fat. Stehno-Bittel L(1). Author information: (1)Department of Physical Therapy and Rehabilitation Science, and Scientific Director, Great Plains Diabetes Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. LBITTEL@kumc.edu One of the most exciting cell biology fields of study concerns the physiology and pathology of fat. The basic assumptions once held concerning the function of adipose tissue have been shown to be oversimplified or sometimes completely wrong. Fat does more than store excess energy; it is actually the largest endocrine organ in the body, and it may be one of the most active. Adipocytes release hormones and other molecules that act on nearby tissues and travel through the vasculature to distant sites, such as the brain, skeletal muscle, and liver. Under conditions of normal weight, those signals help the body to suppress hunger, utilize glucose, and decrease the risk of cardiovascular disease. However, under conditions of obesity, the hormones (or the proteins that bind the hormones) become abnormal and can result in states of chronic inflammation leading to diabetes and heart disease. In addition, excessive fat can lead to the accumulation of lipid droplets in nonfat cells, including skeletal and cardiac muscle. Although some lipid droplets are used as an immediate source of energy for cells, large numbers of stored droplets can cause cellular damage and cell death. The purposes of this article are to review the normal and deviant signals released by fat cells, to draw a link between those signals and chronic diseases such as diabetes, and to discuss the role of exercise in reversing some of the deviant signaling perpetrated by excess fat. PMID: 18801855 [PubMed - indexed for MEDLINE] 2263. Rinsho Byori. 2008 Aug;56(8):705-11. [Vaspin and insulin resistance]. [Article in Japanese] Wada J(1). Author information: (1)Department of Medicine, Okayama University Hospital, Okayama 700-8558. We have identified the vaspin gene(serpina12), which is up-regulated in visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity and type 2 diabetes. Vaspin mRNA was barely detectable at 6 weeks of age, but was abundantly and exclusively expressed in visceral WATs at 30 weeks of age, when OLETF rats reach their peak body weight. However, vaspin mRNA decreased with worsening of diabetes and body weight loss. Vaspin mRNA increased with administration of thiazolidinediones, i.e. pioglitazone. Administration of recombinant vaspin into high fat high sucrose (HFHS) chow-induced obese ICR mice improved glucose tolerance and insulin sensitivity. Vaspin may be the compensatory molecule in the pathogenesis of metabolic syndrome and vaspin recombinant protein or vaspin-mimicking agents such as vaspin analogues, antibodies or small molecule agents would link to drug discovery and development. PMID: 18800627 [PubMed - indexed for MEDLINE] 2264. Kidney Int. 2008 Oct;74(7):851-3. doi: 10.1038/ki.2008.391. Renin-angiotensin system blockade and diabetes: moving the adipose organ from the periphery to the center. Lenz O(1), Fornoni A. Author information: (1)Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, Florida 33136, USA. Comment on Kidney Int. 2008 Oct;74(7):890-900. Lee et al. report that an angiotensin II type 1 receptor blocker (ARB) improved glucose intolerance in OLETF rats, an experimental model of type 2 diabetes. ARB treatment resulted in modulation of the adipose tissue, leading to an increased number of small, differentiated adipocytes able to produce more adiponectin and less monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1. This supports the relevance of the functional interplay between adipose tissue and the renin-angiotensin system in states of insulin resistance. PMID: 18794817 [PubMed - indexed for MEDLINE] 2265. Int J Clin Pract. 2008 Sep;62(9):1432-40. doi: 10.1111/j.1742-1241.2008.01823.x. Neuropeptide Y and alpha-melanocyte-stimulating hormone: interaction in obesity and possible role in the development of hypertension. Baltatzi M(1), Hatzitolios A, Tziomalos K, Iliadis F, Zamboulis Ch. Author information: (1)1st Propedeutic Medical Department, AXEPA Hospital, Aristotles University of Thessaloniki, Thessaloniki, Greece. AIM: Obesity and hypertension frequently coexist and both represent important risk factors for cardiovascular disease. The mechanisms implicated in the regulation of food intake have not been completely elucidated. Recent data suggests that peripheral and central neuropeptides play an important role in the maintenance of energy balance. More specifically, leptin, neuropeptide Y (NPY) and alpha-melanocyte-stimulating hormone (a-MSH) appear to be implicated in the pathogenesis of obesity and also contribute to the development of hypertension in obesity. METHODS: Analysis of the pertinent bibliography published in PubMed database. RESULTS: Leptin is produced in the adipose tissue directly correlated with fat tissue mass. Leptin acts on two distinct neural populations in the hypothalamus: the first expresses the orexigenic peptides NPY and agouti-related protein (AgRP), the second pro-opiomelanocortin (POMC). The activation of POMC neurons increases the production of the anorexigenic hormone a-MSH and inhibits the release of NPY and AgRP. In addition, the hypothalamus integrates the neuroendocrine systems with the autonomic nervous system and controls the activity of the latter. Stimulation of hypothalamic nuclei elicits sympathetic responses including blood pressure elevation. Both NPY and a-MSH appears to be implicated in the hypothalamic regulation of sympathetic nervous system (SNS) activity. CONCLUSION: Alterations in leptin, NPY and a-MSH are frequently observed in obesity and might stimulate SNS activity, contributing to the development of hypertension in obese patients. These neuropeptides might provide a pathophysiologic link between excess weight and hypertension. However, more research is needed before the pharmacologic manipulation of these complex neuroendocrine systems can be applied in the treatment of obesity and hypertension. PMID: 18793378 [PubMed - indexed for MEDLINE] 2266. Biochem Soc Trans. 2008 Oct;36(Pt 5):935-40. doi: 10.1042/BST0360935. Adipose tissue expandability: the metabolic problems of obesity may arise from the inability to become more obese. Tan CY(1), Vidal-Puig A. Author information: (1)Metabolic Research Laboratories, Level 4, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. The prevalence of obesity is increasing and with it the prevalence of associated metabolic complications. Precisely how obesity results in metabolic disturbances remains unclear. In the face of persistent positive caloric balance, it has been postulated that the capacity of adipose tissue to safely store fat may be vital. This paper explores some of the evidence suggesting that the risk of developing metabolic disturbances is not related to how much fat an individual has, but how well their fat can expand to accommodate the caloric excess. If this is true, the metabolic consequences of obesity may arise from the inability to become more obese. PMID: 18793164 [PubMed - indexed for MEDLINE] 2267. Biol Cell. 2008 Oct;100(10):563-75. doi: 10.1042/BC20080011. Developmental origin of adipocytes: new insights into a pending question. Billon N(1), Monteiro MC, Dani C. Author information: (1)Institut de Recherche, Signalisation, Biologie du Développement et Cancer, CNRS UMR 6543, Centre de Biochimie, Faculté des Sciences, Université Nice Sophia-Antipolis, Nice, France. billon@unice.fr The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of preadipocytes into mature adipocytes. However, the mechanisms that direct MSCs (mesenchymal stem cells) down the adipocyte lineage remain largely unknown. Similarly, although adipocytes are generally described to derive from mesoderm, the study of the developmental origin of MSCs and adipose tissues has been largely disregarded until now. Functional variations do exist between different adipose tissues, which suggest possible differences in their developmental origin and might explain why some depots are more associated than other to metabolic disorders. This review summarizes the surprising findings that have recently emerged from both embryonic stem cells and lineage-tracing studies in vivo, unravelling an unsuspected developmental origin for MSCs and adipocytes in the neural crest. PMID: 18793119 [PubMed - indexed for MEDLINE] 2268. Horm Metab Res. 2008 Sep;40(9):593-606. doi: 10.1055/s-0028-1082326. Epub 2008 Sep 15. The potential beneficial role of glucagon-like peptide-1 in endothelial dysfunction and heart failure associated with insulin resistance. Nyström T(1). Author information: (1)Karolinska Institute, Department of Internal Medicine, Stockholm South Hospital, Stockholm, Sweden. thomas.nystrom@sodersjukhuset.se Endothelial dysfunction is a major characteristic of the atherosclerotic process and can be used to predict the outcome of cardiovascular disease in humans. Together with obesity and insulin resistance, such dysfunction is common among patients with type 2 diabetes and may explain their poor prognosis in connection with such a disease. Insulin resistance in skeletal muscle, adipose tissue, and the liver, a well-characterized feature of obesity and type 2 diabetes, contributes to the impairment of glucose homeostasis. Furthermore, the myocardial muscle can also be resistant to insulin, which might, at least in part, explain the frequent development of heart failure in individuals suffering from type 2 diabetes. The relationship between insulin resistance and endothelial dysfunction has prompted investigations, which reveal that regular exercise, dietary changes, and/or pharmacological agents can both increase insulin sensitivity and improve endothelial function. Glucagon-like peptide-1, an incretin, lowers blood levels of glucose and offers a promising new approach to the treatment of type 2 diabetes mellitus. Its extensive extra-pancreatic effects, including a favorable influence on cardiovascular parameters, are extremely interesting in this connection. The potential pharmacological effects of glucagon-like peptide-1 and its analogues on the endothelium and the heart are discussed in the present review. PMID: 18792870 [PubMed - indexed for MEDLINE] 2269. J Lipid Res. 2008 Dec;49(12):2493-503. doi: 10.1194/jlr.R800019-JLR200. Epub 2008 Sep 12. Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. Reue K(1), Brindley DN. Author information: (1)Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. reuek@ucla.edu Phosphatidate phosphatase-1 (PAP1) enzymes have a key role in glycerolipid synthesis through the conversion of phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. PAP1 activity in mammals is determined by the lipin family of proteins, lipin-1, lipin-2, and lipin-3, which each have distinct tissue expression patterns and appear to have unique physiological functions. In addition to its role in glycerolipid synthesis, lipin-1 also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression. The requirement for different lipin activities in vivo is highlighted by the occurrence of lipodystrophy, insulin resistance, and neuropathy in a lipin-1-deficient mutant mouse strain. In humans, variations in lipin-1 expression levels and gene polymorphisms are associated with insulin sensitivity, metabolic rate, hypertension, and risk for the metabolic syndrome. Furthermore, critical mutations in lipin-2 result in the development of an inflammatory disorder in human patients. A key goal of future studies will be to further elucidate the specific roles and modes of regulation of each of the three lipin proteins in key metabolic processes, including triglyceride and phospholipid synthesis, fatty acid metabolism, and insulin sensitivity. PMCID: PMC2582367 PMID: 18791037 [PubMed - indexed for MEDLINE] 2270. Med Hypotheses. 2008 Dec;71(6):900-8. doi: 10.1016/j.mehy.2008.06.042. Epub 2008 Sep 10. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Centeno CJ(1), Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Author information: (1)Regenerative Sciences Inc, Centeno-Schultz Clinic, Westminster, CO 80020, USA. Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC's) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient's own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume. PMID: 18786777 [PubMed - indexed for MEDLINE] 2271. Curr Stem Cell Res Ther. 2008 Sep;3(3):185-96. Adult stem cell transplantation in stroke: its limitations and prospects. Roh JK(1), Jung KH, Chu K. Author information: (1)Stroke & Neural Stem Cell Laboratory, Stem Cell Research Center, Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Seoul, South Korea. rohjk@snu.ac.kr A growing number of studies have demonstrated stem cell-based therapy provides a feasible, realistic approach to the restoration of lost brain function after stroke. Moreover, adult stem cells may provide more appropriate clinical strategies. Leading candidate sources include bone marrow, peripheral blood, adipose tissue, skeletal muscle, and olfactory mucosa, which act as central repositories for multipotent stem cells that can repopulate neural tissues. The medical society is currently enthusiastic concerning the clinical applications of autologous adult stem cells in stroke, based on promising results obtained during experimental studies and initial clinical trials. However, before embracing clinical applications, several essential precautions must be properly addressed. For example, the regenerative potentials of adult stem cells decline with age, and stem cells isolated from aged patients may retain dysfunctional characteristics. Are the natures and amounts of available autologous cells appropriate for therapeutic application in stroke? Do transplanted cells remain functional in the diseased brain, and if so what are the optimal injection routes, cell doses, and timings? Thus, we believe that success in future clinical trials will depend on careful investigation at the experimental level, to allow us to understand not only the practicalities of stem cell use, but also the underlying biological principles involved. Here, we review the advantages and disadvantages of the different adult stem cell sources and discuss the challenges that must be negotiated to achieve transplantation success. PMID: 18782001 [PubMed - indexed for MEDLINE] 2272. Cardiovasc Hematol Disord Drug Targets. 2008 Sep;8(3):228-37. Adipose tissue: the link between obesity and cardiovascular disease. DeClercq V(1), Taylor C, Zahradka P. Author information: (1)Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada. The ever-increasing prevalence of cardiovascular disease (CVD) associated with obesity is linked through signaling pathways within adipose tissue. Adipose tissue functions as an endocrine organ, producing and secreting a variety of bioactive molecules. In obesity, the adipose tissue itself undergoes changes in cell size which alters its normal physiological function. Altered adipocyte function changes production and secretion of adipokines, such as leptin, adiponectin, angiotensinogen, plasminogen activator inhibitor-1, resistin, and several inflammatory molecules. Adipokines interact with other tissues and cells in the body, including many pathways linked to CVD. Future research in the area of obesity-related CVD requires further investigation into a combination of lifestyle and pharmacological therapies that alter adipokine production by reducing adipocyte size. PMID: 18781935 [PubMed - indexed for MEDLINE] 2273. Neuroimmunomodulation. 2008;15(3):176-88. doi: 10.1159/000153422. Epub 2008 Sep 9. Neonatal programming of neuroimmunomodulation--role of adipocytokines and neuropeptides. de Moura EG(1), Lisboa PC, Passos MC. Author information: (1)Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brasil. egberto@pq.cnpq.br Programming is an epigenetic phenomenon by which nutrition, environment and stress acting in a critical period earlier in life change the organism's development. This process was evolutionarily selected as an adaptive tool for the survival of organisms living in nutritionally deficient areas and submitted to stressful conditions. Thus, perinatal malnutrition turns on different genes that provide the organism with a thrifty phenotype. In conditions of abundant supply of nutrients, those programmed organisms can be at risk of developing metabolic diseases (obesity, dyslipidemia, diabetes and hypertension). How nutrition or neonatal stress can program the immune system is less well known. Here, we discuss some of the hormonal and metabolic changes that occur in mothers and neonates and how those factors can imprint hormonal or metabolic changes that program neuroimmunomodulatory effects. Some of these changes involve thyroid hormones, leptin, insulin, glucocorticoids and prolactin as potential imprinting factors. Most of them can be transferred through the milk and may change with malnutrition or stress. We discuss the programming effects of these hormones upon body weight, body composition, insulin action, thyroid, adrenal and immune and inflammatory responses, with special emphasis on leptin, a cytokine that seems to play a central role in these events. 2008 S. Karger AG, Basel. PMID: 18781082 [PubMed - indexed for MEDLINE] 2274. Nutr J. 2008 Sep 9;7:26. doi: 10.1186/1475-2891-7-26. Is bioelectrical impedance accurate for use in large epidemiological studies? Dehghan M(1), Merchant AT. Author information: (1)Population Health Research Institute, McMaster University, Hamilton, ON, Canada. mahshid@ccc.mcmaster.ca Percentage of body fat is strongly associated with the risk of several chronic diseases but its accurate measurement is difficult. Bioelectrical impedance analysis (BIA) is a relatively simple, quick and non-invasive technique, to measure body composition. It measures body fat accurately in controlled clinical conditions but its performance in the field is inconsistent. In large epidemiologic studies simpler surrogate techniques such as body mass index (BMI), waist circumference, and waist-hip ratio are frequently used instead of BIA to measure body fatness. We reviewed the rationale, theory, and technique of recently developed systems such as foot (or hand)-to-foot BIA measurement, and the elements that could influence its results in large epidemiologic studies. BIA results are influenced by factors such as the environment, ethnicity, phase of menstrual cycle, and underlying medical conditions. We concluded that BIA measurements validated for specific ethnic groups, populations and conditions can accurately measure body fat in those populations, but not others and suggest that for large epidemiological studies with diverse populations BIA may not be the appropriate choice for body composition measurement unless specific calibration equations are developed for different groups participating in the study. PMCID: PMC2543039 PMID: 18778488 [PubMed - indexed for MEDLINE] 2275. J Magn Reson Imaging. 2008 Sep;28(3):543-58. doi: 10.1002/jmri.21492. Dixon techniques for water and fat imaging. Ma J(1). Author information: (1)Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. jma@di.mdacc.tmc.edu In 1984, Dixon published a first paper on a simple spectroscopic imaging technique for water and fat separation. The technique acquires two separate images with a modified spin echo pulse sequence. One is a conventional spin echo image with water and fat signals in-phase and the other is acquired with the readout gradient slightly shifted so that the water and fat signals are 180 degrees out-of-phase. Dixon showed that from these two images, a water-only image and a fat-only image can be generated. The water-only image by the Dixon's technique can serve the purpose of fat suppression, an important and widely used imaging option for clinical MRI. Additionally, the availability of both the water-only and fat-only images allows direct image-based water and fat quantitation. These applications, as well as the potential that the technique can be made highly insensitive to magnetic field inhomogeneity, have generated substantial research interests and efforts from many investigators. As a result, significant improvement to the original technique has been made in the last 2 decades. The following article reviews the underlying physical principles and describes some major technical aspects in the development of these Dixon techniques. Copyright (c) 2008 Wiley-Liss, Inc. PMID: 18777528 [PubMed - indexed for MEDLINE] 2276. Eur Heart J. 2008 Dec;29(24):2959-71. doi: 10.1093/eurheartj/ehn387. Epub 2008 Sep 5. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Hajer GR(1), van Haeften TW, Visseren FL. Author information: (1)Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described. PMID: 18775919 [PubMed - indexed for MEDLINE] 2277. Endocrinol Metab Clin North Am. 2008 Sep;37(3):753-68, x-xi. doi: 10.1016/j.ecl.2008.07.002. The adipocyte as an endocrine cell. Halberg N(1), Wernstedt-Asterholm I, Scherer PE. Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8549, USA. Adipose tissue contains many cell types. Among the more abundant are adipocytes, preadipocytes, immune cells, and endothelial cells. During times of excess caloric intake, these cells have to adjust and remodel to accommodate the increased demand for triglyceride storage. Based on a comprehensive analysis of the total adipose tissue secretome, this article focuses on three areas of adipokine biology: (1) How does the adipocyte interact with the extracellular matrix over the course of obesity? (2) Does the adipocyte, per se, play a role in the innate immune response? (3) How is the angiogenic profile of adipose tissue linked to the development of insulin resistance? The authors present a comprehensive overview of all of the currently available secreted adipose tissue products that have been identified at the protein level. PMCID: PMC2659415 PMID: 18775362 [PubMed - indexed for MEDLINE] 2278. G Ital Cardiol (Rome). 2008 Apr;9(4 Suppl 1):74S-82S. [Endocannabinoid system and energy metabolism: physiology and pathophysiology]. [Article in Italian] Pagotto U(1), Vicennati V, Pasquali R. Author information: (1)UO di Endocrinologia e Centro di Ricerca Biomedica Applicata (CRBA), Dipartimento di Medicina Interna e Gastroenterologia, Policlinico S. Orsola-Malpighi, Università Alma Mater Studiorum, Bologna. uberto.pagotto@unibo.it The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, therefore drugs interfering with this overactivation by blocking CB1 receptor are considered as valuable candidates for the treatment of obesity and related cardiometabolic risk factors. PMID: 18773754 [PubMed - indexed for MEDLINE] 2279. G Ital Cardiol (Rome). 2008 Apr;9(4 Suppl 1):23S-28S. [Adipose tissue: a multifunctional organ]. [Article in Italian] Bon GB(1). Author information: (1)UO di Medicina Interna, Dipartimento di Medicina Clinica, Ospedale Umberto I, Mestre-Venezia. g.bittolobon@ulss12.ve.it There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardiometabolic risk. Although the basis of this differential risk has not been established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Adipose tissue is, in fact, now recognized not simply a store of excess energy but a major endocrine and secretory organ, releasing a wide range of protein factors and signals, termed adipokines, in addition to fatty acids and other lipid moieties. These factors are derived from adipocyte or non-adipocyte fractions, and include proteins, metabolites and hormones. This paper reviews some of the advances in the understanding of biologically active molecules produced by adipose tissue and how dysregulated production of these factors could be implicated in the association between central adiposity, cardiovascular pathology and comorbidities, including metabolic syndrome, type 2 diabetes and systemic inflammation. PMID: 18773748 [PubMed - indexed for MEDLINE] 2280. Int J Med Sci. 2008 Aug 29;5(5):248-62. The usefulness of circulating adipokine levels for the assessment of obesity-related health problems. Inadera H(1). Author information: (1)Department of Public Health, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. inadera@med.u-toyama.ac.jp Because the prevalence of obesity has increased dramatically in recent years, one of the key targets of public health is obesity and its associated pathological conditions. Obesity occurs as a result of white adipose tissue enlargement, caused by adipocyte hyperplasia and/or hypertrophy. Recently, endocrine aspects of adipose tissue have become an active research area and these adipose tissue-derived factors are referred to as adipokines. These adipokines interact with a range of processes in many different organ systems and influence a various systemic phenomena. Therefore, dysregulated production of adipokines has been found to participate in the development of metabolic and vascular diseases related to obesity. The obese state is also known to be associated with increased local and systemic inflammation. Adipokines influence not only systemic insulin resistance and have pathophysiological roles in the metabolic syndrome and cardiovascular disease, but also contribute toward an increase in local and systemic inflammation. Thus, circulating levels of adipokines can be used as high-throughput biomarkers to assess the obesity-related health problems, including low grade inflammation. This review focuses on the usefulness of measuring circulating adipokine levels for the assessment of obesity-related health problems. PMCID: PMC2528071 PMID: 18773088 [PubMed - indexed for MEDLINE] 2281. J Clin Invest. 2008 Sep;118(9):2992-3002. doi: 10.1172/JCI34260. Insulin sensitivity: modulation by nutrients and inflammation. Schenk S(1), Saberi M, Olefsky JM. Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California 92093, USA. Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity. PMCID: PMC2522344 PMID: 18769626 [PubMed - indexed for MEDLINE] 2282. Curr Opin Endocrinol Diabetes Obes. 2008 Oct;15(5):403-8. doi: 10.1097/MED.0b013e32830ce95c. Putative environmental-endocrine disruptors and obesity: a review. Elobeid MA(1), Allison DB. Author information: (1)Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. PURPOSE OF REVIEW: There has been a substantial increase in the prevalence of obesity in the last several decades. Recent evidence suggests that endocrine-disrupting chemicals, for example halogenated aromatic hydrocarbons, may cause perturbations in endogenous hormonal regulation and alter other mechanisms involved in weight homeostasis, which may lead to weight gain by increased volume of adipose tissue. Synthetic chemicals derived from industrial processes are suspected to play a contributory role. Yet of the approximately 70,000 documented synthetic chemicals, few have been examined to determine their effects on the endocrine system. RECENT FINDINGS: The present study examines prior laboratory, epidemiological and experimental research findings. Data demonstrate migration of endocrine disruptors in the environment and are beginning to catalogue their effects on adiposity. We present postulated relationships between these chemicals, their mechanisms of action, and the obesity epidemic. SUMMARY: Endocrine disruptors may adversely impact human and environmental health by altering the physiological control mechanism. Obesity, which is known to increase medical costs and reduce quality and length of life, may be increasing as a function of endocrine disruptor exposure. This merits concern among scientists and public health officials and warrants additional vigorous research in this area. PMCID: PMC2566897 PMID: 18769210 [PubMed - indexed for MEDLINE] 2283. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1009-17. doi: 10.1152/ajpendo.90558.2008. Epub 2008 Sep 2. Metabolic flexibility and insulin resistance. Galgani JE(1), Moro C, Ravussin E. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this "metabolic inflexibility" is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate (amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high-fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics. PMCID: PMC2584808 PMID: 18765680 [PubMed - indexed for MEDLINE] 2284. Semin Dial. 2008 Sep-Oct;21(5):390-4. doi: 10.1111/j.1525-139X.2008.00470.x. Epub 2008 Aug 29. Lipid metabolism in dialysis patients-the story gets more complicated. Ponda MP, Barash I. Cardiovascular disease continues to be the foremost cause of morbidity and mortality in dialysis patients. Compared with the general population, dialysis patients suffer from an accelerated disease course that is, at least in part, resistant to conventional therapy. While there are a myriad of potential explanations for this resistance, derangements in lipid metabolism probably play an important role. Here, we discuss the significance of altered lipid metabolism in uremia, such as oxidative lipoprotein modification and the pathophysiology of adipose tissue; limitations of conventional approaches to dyslipidemia such as statin therapy and traditional lipid profiles; and areas of investigation with potential for new therapy, such as reverse cholesterol transport. PMID: 18764791 [PubMed - indexed for MEDLINE] 2285. J Periodontol. 2008 Aug;79(8 Suppl):1527-34. doi: 10.1902/jop.2008.080246. The role of inflammatory cytokines in diabetes and its complications. King GL(1). Author information: (1)Section on Vascular Cell Biology, Joslin Diabetes Center and Clinic, One Joslin Place, Boston, MA 02215, USA. george.king@joslin.harvard.edu The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies. PMID: 18673007 [PubMed - indexed for MEDLINE] 2286. Diabetes Metab Res Rev. 2008 Nov-Dec;24(8):595-603. doi: 10.1002/dmrr.889. Inflamed adipose tissue, insulin resistance and vascular injury. Andersson CX(1), Gustafson B, Hammarstedt A, Hedjazifar S, Smith U. Author information: (1)The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine/Diabetes, The Sahlgrenska Academy at Göteborg University, Sweden. christian.andersson@gu.se Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall. Copyright 2008 John Wiley & Sons, Ltd. PMID: 18756581 [PubMed - indexed for MEDLINE] 2287. Subcell Biochem. 2008;49:241-68. doi: 10.1007/978-1-4020-8831-5_9. Altered lipid metabolism in brain injury and disorders. Adibhatla RM(1), Hatcher JF. Author information: (1)Department of Neurological Surgery, Cardiovascular Research Center, Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI., William S. Middleton Veterans Affairs Hospital, Madison, WI 53792, USA. Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies. PMCID: PMC2293298 PMID: 18751914 [PubMed - indexed for MEDLINE] 2288. Subcell Biochem. 2008;49:3-47. doi: 10.1007/978-1-4020-8831-5_1. Transcriptional regulation of hepatic fatty acid metabolism. Guillou H(1), Martin PG, Pineau T. Author information: (1)Laboratoire de Pharmacologie et Toxicologie UR66, INRA, F-3100 Toulouse, France. The liver is a major site of fatty acid synthesis and degradation. Transcriptional regulation is one of several mechanisms controlling hepatic metabolism of fatty acids. Two transcription factors, namely SREBP1-c and PPARalpha, appear to be the main players controlling synthesis and degradation of fatty acids respectively. This chapter briefly presents fatty acid metabolism. The first part focuses on SREBP1-c contribution to the control of gene expression relevant to fatty acid synthesis and the main mechanisms of activation for this transcriptional program. The second part reviews the evidence for the involvement of PPARalpha in the control of fatty acid degradation and the key features of this nuclear receptor. Finally, the third part aims at summarizing recent advances in our current understanding of how these two transcription factors fit in the regulatory networks that sense hormones or nutrients, including cellular fatty acids, and govern the transcription of genes implicated in hepatic fatty acid metabolism. PMID: 18751906 [PubMed - indexed for MEDLINE] 2289. Arch Physiol Biochem. 2008 Oct;114(4):255-60. doi: 10.1080/13813450802307451 . Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk. Bonsignore MR(1), Zito A. Author information: (1)Department of Medicine, Pneumology, Physiology and Nutrition, University of Palermo, Italy. marisa@ibim.cnr.it The obstructive sleep apnea syndrome (OSAS) is characterized by collapse of the upper airway during sleep, recurring apneas, intermittent hypoxemia and daytime somnolence. OSAS is often associated with obesity, and its prevalence is expected to rise due to the obesity epidemics worldwide. OSAS is associated with increased cardiovascular risk which appears to be normalized by treatment with nasal continuous positive airway pressure (nCPAP) during sleep, suggesting an independent role of OSAS in accelerating atherosclerosis. Insulin resistance (IR) and the metabolic syndrome (MetS) are often found in OSAS patients, but the relative role played by OSAS and obesity is still unclear. Both OSAS and MetS may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (hypoxemia, sleep disruption, activation of the sympathetic nervous system, inflammatory activation). Besides nCPAP treatment, pharmacologic interventions to treat obesity and the MetS could improve cardiovascular prevention in OSAS. PMID: 18726787 [PubMed - indexed for MEDLINE] 2290. Nutrition. 2008 Sep;24(9):832-42. doi: 10.1016/j.nut.2008.06.027. Weight regain after Roux-en-Y: a significant 20% complication related to PYY. Meguid MM(1), Glade MJ, Middleton FA. Author information: (1)Surgical Metabolism and Nutrition Laboratory, Department Surgery, Neuroscience and Physiology Program, SUNY Upstate Medical University, Syracuse, New York, USA. meguidm@upstate.edu OBJECTIVE: Roux-en-Y gastric bypass (RYGB) produces rapid and dramatic weight loss in very heavy obese patients. Up to 20% cannot sustain their weight loss beyond 2 to 3 y after surgery. METHODS: To identify putative etiologic factors producing post-RYGB weight regain, a literature survey of metabolic changes in very obese and a review of our diet-induced obese RYGB rat model data was done. RESULTS: Weight regain suggests an imbalance in physiologic mechanisms regulating appetite and metabolic rate. Weight regain occurred in 25% of our rats, produced by return to presurgical energy intake levels. The 75% of rats that sustained weight loss secreted a significantly larger amount of peptide YY (PYY) while suppressing leptin secretion; those that failed were unable to develop or sustain a sufficiently large plasma PYY:leptin ratio. Metabolic consequences of this failure included reversal of initial postsurgical increases in peripheral fatty acid oxidation, anorexigenic activity in the hypothalamic arcuate nucleus and paraventricular nucleus, and the expression of uncoupling protein-2 in adipose tissues, and decreases in hepatic lipogenesis, free tri-iodothyronine secretion, expression of orexigenic activity in the arcuate nucleus and paraventricular nucleus, expression of adenosine monophosphate kinase in adipose tissues, skeletal muscle mitochondrial mass, and endocannabinoid content and appetite. CONCLUSION: Weight regain after RYGB occurs in approximately 20% of patients and constitutes a serious complication. Weight regain-promoting consequences are attributed to a failure to sustain elevated plasma PYY concentrations, indicating that combining RYGB with pharmacologic stimulation of PYY secretion in patients after RYGB who exhibit inadequate PYY concentration may increase long-term success of surgical weight reduction in morbidly obese adults. PMID: 18725080 [PubMed - indexed for MEDLINE] 2291. Nutrition. 2008 Sep;24(9):827-31. doi: 10.1016/j.nut.2008.06.014. Hypothalamic neuronal histamine regulates body weight through the modulation of diurnal feeding rhythm. Yoshimatsu H(1). Author information: (1)Department of Internal Medicine I, Faculty of Medicine, Oita University, Oita, Japan. hiroy@med.oita-u.ac.jp Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R), a leptin signaling pathway in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Glucagon-like peptide-1 and/or corticotrophin-releasing hormone mediate leptin signaling to neuronal histamine. Leptin-induced suppression of food intake and upregulation of uncoupling protein-1 expression in brown adipose tissue were partially attenuated in histamine H(1)-R knockout (H(1)KO) mice. H(1)KO mice developed maturity-onset obesity. Hyperphagia and decreased energy expenditure assessed by the expression of uncoupling protein-1 mRNA were observed in older (48-wk-old) obese H(1)KO mice but not in younger (12-wk-old) non-obese H(1)KO mice. However, the diurnal feeding rhythm was impaired even in younger non-obese animals. Specifically, disruption of the feeding rhythm developed before the onset of obesity in H(1)KO mice. Correction of these abnormal feeding rhythms with scheduled feeding improved the obesity and associated metabolic disorders in the H(1)KO mice. These findings suggest that histamine H(1)-R is crucial for regulating the feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H(1)KO mice may lead to hyperphagia and decreased energy expenditure, which may contribute to the development of obesity in these animals. PMID: 18725079 [PubMed - indexed for MEDLINE] 2292. Nutrition. 2008 Sep;24(9):815-9. doi: 10.1016/j.nut.2008.06.020. Cachexia and neuropeptide Y. Morley JE(1), Farr SA. Author information: (1)Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA. morley@slu.edu Cachexia or wasting disease occurs commonly in diseases that have an overproduction of proinflammatory cytokines associated with them. The hallmarks of cachexia are loss of lean and adipose tissue, anorexia, anemia, memory disturbance, and sickness behavior. This review suggests that increased inducible nitric oxide synthase production in the hypothalamus leads to severe anorexia and that this is the pathway through which proinflammatory cytokines produce anorexia. Orexigenic peptides, such as neuropeptide, ghrelin, and orexin A, and anorectic peptides, such as leptin, produce their effects through neuronal nitric oxide synthase. Activation of neuronal nitric oxide synthase results in increased adenosine monophosphate kinase and a decrease in malonyl coenzyme A, leading to increased food intake. PMID: 18725077 [PubMed - indexed for MEDLINE] 2293. Autoimmun Rev. 2009 Jan;8(3):250-5. doi: 10.1016/j.autrev.2008.07.038. Epub 2008 Aug 21. Osteoimmunology--the hidden immune regulation of bone. Caetano-Lopes J(1), Canhão H, Fonseca JE. Author information: (1)Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. Osteoimmunology is an emerging field of research dedicated to the investigation of the interactions between the immune and skeletal systems. These interactions are not only mediated by the release of cytokines and chemokines but also by direct cell-cell contact. Recently, it was proposed that immunoreceptors found in the immune cells are also an essential signal for osteoclasts activation, along with receptor activator NF-kappaB (RANK) ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). In addition, adipose tissue also produces several factors (adipokines) that are known to interfere with the immune system and bone homeostasis. Chronic inflammation strongly influences osteoimmunology determining profound metabolic, structural and functional changes in bone. PMID: 18722561 [PubMed - indexed for MEDLINE] 2294. J Oral Maxillofac Surg. 2008 Sep;66(9):1794-803. doi: 10.1016/j.joms.2008.04.004. Outcomes of total alloplastic replacement with periarticular autogenous fat grafting for management of reankylosis of the temporomandibular joint. Mercuri LG(1), Ali FA, Woolson R. Author information: (1)Stritch School of Medicine, Department of Surgery, Division of Oral and Maxillofacial Surgery, Loyola University Medical Center, Maywood, IL 60153, USA. LMERCUR@lumc.edu PURPOSE: The purpose of this investigation was to review the subjective, objective, and quality of life outcomes in a group of temporomandibular joint (TMJ) reankylosis patients managed by total alloplastic replacement surgery with a patient fitted system augmented with periarticular autogenous fat grafts to prevent the reformation of heterotopic bone. A review of the literature regarding the use of autogenous fat as evidence for its efficacy in such cases is also presented. PATIENTS AND METHODS: All 20 TMJ reankylosis patients (4 males, 16 females) who had undergone total TMJ replacement with the TMJ Concepts (Ventura, CA) Patient-Fitted Total TMJ Prosthesis System were studied. Thirteen patients had bilateral, 7 unilateral for a total of 33 joint replacements. All patients had autogenous fat harvested from the abdomen and grafted around the articulating portion of the prostheses at implantation. The patients' subjective variable outcomes of TMJ pain, mandibular function, diet consistency, quality of life since the reconstruction, and objective variable of maximal interincisal opening were obtained in a detailed questionnaire and follow-up phone calls. RESULTS: Analysis of the subjective outcomes data showed improvement in reported pain, increased jaw function, and diet consistency. Further, a significant number of these patients reported improvement in their quality of life after surgery. Analysis of the objective outcomes data showed a significant increase in the maximum interincisal opening postreplacement that was maintained. CONCLUSIONS: In the patients followed over the course of this study, total alloplastic replacement with a patient-fitted prosthesis seemed to provide a safe and effective management for reankylosis of the TMJ. Autogenous fat transplantation seems to be a useful adjunct as its use seems to minimize the recurrence of joint heterotopic calcification, consequently providing improved and consistent range of mandibular motion. PMID: 18718385 [PubMed - indexed for MEDLINE] 2295. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1000-8. doi: 10.1152/ajpendo.90252.2008. Epub 2008 Aug 19. Neural control of the anorexia-cachexia syndrome. Laviano A(1), Inui A, Marks DL, Meguid MM, Pichard C, Rossi Fanelli F, Seelaender M. Author information: (1)Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy. alessandro.laviano@uniroma1.it The anorexia-cachexia syndrome is a debilitating clinical condition characterizing the course of chronic diseases, which heavily impacts on patients' morbidity and quality of life, ultimately accelerating death. The pathogenesis is multifactorial and reflects the complexity and redundancy of the mechanisms controlling energy homeostasis under physiological conditions. Accumulating evidence indicates that, during disease, disturbances of the hypothalamic pathways controlling energy homeostasis occur, leading to profound metabolic changes in peripheral tissues. In particular, the hypothalamic melanocortin system does not respond appropriately to peripheral inputs, and its activity is diverted largely toward the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. These catabolic effects represent the central response to peripheral challenges (i.e., growing tumor, renal, cardiac failure, disrupted hepatic metabolism) that are likely sensed by the brain through the vagus nerve. Also, disease-induced changes in fatty acid oxidation within hypothalamic neurons may contribute to the dysfunction of the hypothalamic melanocortin system. Ultimately, sympathetic outflow mediates, at least in part, the metabolic changes in peripheral tissues. Other factors are likely involved in the pathogenesis of the anorexia-cachexia syndrome, and their role is currently being elucidated. However, available evidence shows that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state. PMID: 18713954 [PubMed - indexed for MEDLINE] 2296. IUBMB Life. 2008 Dec;60(12):790-7. doi: 10.1002/iub.124. Adiponectin and alcoholic fatty liver disease. Rogers CQ(1), Ajmo JM, You M. Author information: (1)Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center,Tampa, FL 33612, USA. Worldwide, one of the most prevalent forms of chronic disease is alcoholic fatty liver, which may progress to more severe forms of liver injury including steatohepatitis, fibrosis, and cirrhosis. The molecular mechanisms by which ethanol consumption causes accumulation of hepatic lipid are multiple and complex. Chronic ethanol exposure is thought to cause enhanced hepatic lipogenesis and impaired fatty acid oxidation by inhibiting key hepatic transcriptional regulators such as AMP-activated kinase (AMPK), sirtuin 1 (SIRT1), PPAR-gamma coactivator alpha (PGC-1alpha), peroxisome proliferator-activated receptor alpha (PPARalpha), and sterol regulatory element-binding protein 1 (SREBP-1). Adiponectin is an adipose-derived hormone with a variety of beneficial biological functions. Increasing evidence suggests that altered adiponectin production in adipose tissue and impaired expression of hepatic adiponectin receptors (AdipoRs) are associated with the development of alcoholic liver steatosis in several rodent models. More importantly, studies have demonstrated a protective role of adiponectin against alcoholic liver steatosis. The hepato-protective effect of adiponectin is largely mediated by the coordination of multiple signaling pathways in the liver, leading to enhanced fat oxidation, reduced lipid synthesis and prevention of hepatic steatosis. This review begins with an assessment of the current understanding of the role of adiponectin and its receptors in the regulation of lipid homeostasis in liver, with emphasis on their relationship to the development of alcoholic liver steatosis. Following sections will review hepatic signaling molecules involved in the protective actions of adiponectin against alcoholic fatty liver and summarize the current knowledge of regulatory mechanisms of adiponectin expression and secretion in response to chronic ethanol exposure. We will conclude with a discussion of potential strategies for treating human alcoholic fatty liver disease (AFLD), including nutritional and pharmacological modulation of adiponectin and its receptors. (c) 2008 IUBMB. PMID: 18709650 [PubMed - indexed for MEDLINE] 2297. Atheroscler Suppl. 2008 Sep;9(2):63-8. doi: 10.1016/j.atherosclerosissup.2008.05.014. Epub 2008 Aug 6. Intestinally derived lipids: metabolic regulation and consequences--an overview. Cianflone K(1), Paglialunga S, Roy C. Author information: (1)Department of Biochemistry, McGill University, Montreal, Canada. katherine.cianflone@crhl.ulaval.ca Various dietary factors affect postprandial metabolism yet precise mechanisms have not necessarily been pinpointed. The effects of various meal components on postprandial lipemia lead to the following question: do we need a standardized oral lipid tolerance test? A number of transporters, enzymes, receptors and hormones directly influence and act as "gatekeepers" of these processes. Each protein appears to have specific and individual functional roles in the overall process and selected developments in these areas will be reviewed. Within the intestinal cells, FABP2 (fatty acid-binding protein 2) and MTP (microsomal triglyceride transfer protein) are required for the formation of chylomicrons. Niemann-Pick C1-like 1 (NPC1-L1) plays an important role in cholesterol absorption and provides a pharmacological target. Hormones such as GLP1 and GLP2 influence this absorption process. Within the periphery, lipoprotein lipase (LPL) is a key gatekeeper of clearance. Of the massive amounts of fatty acids released by LPL, 36% escape peripheral adipose and muscle uptake and fatty acid overload can result in LPL product inhibition. Acylation stimulating protein (ASP) and insulin are two key hormones in maintaining efficient tissue uptake and re-esterification of fatty acids while TNFalpha negatively influences this process. In both ASP deficient (C3 KO) and C5L2 KO mice, postprandial lipemia increased with reduced adipose tissue storage. This is compensated by increased energy expenditure and muscle lipid oxidation. Clearance of hepatic remnants is controlled through many factors, including SR-B1 and ABCA1. Intestinal, peripheral and hepatic gatekeepers serve important and individual roles in regulating postprandial lipemia and provide potential targets for regulation. PMID: 18693144 [PubMed - indexed for MEDLINE] 2298. Curr Med Chem. 2008;15(18):1851-62. Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. Adeghate E(1). Author information: (1)Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE. eadeghate@uaeu.ac.ae Visfatin is a newly discovered adipocyte hormone with a direct relationship between plasma visfatin level and type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from that of insulin and causes hypoglycaemia by reducing glucose release from liver cells and stimulating glucose utilization in adipocytes and myocytes. Visfatin is upregulated by hypoxia, inflammation and hyperglycaemia and downregulated by insulin, somatostatin and statins. This hormone is found in the cytoplasm as well as the nucleus of cells and has been identified in many tissues and organs including the brain, kidney, lung, spleen and testis but preferentially expressed in visceral adipose tissue and upregulated in some animal models of obesity. Visceral adipose tissue is regarded to be more pernicious than subcutaneous adipose tissue. Visfatin is an endocrine, autocrine as well as paracrine peptide with many functions including enhancement of cell proliferation, biosynthesis of nicotinamide mono- and dinucleotide and hypoglycaemic effect. Visfatin, also known as a pre-B cell colony-enhancing factor, consists of 491 amino acids (aa) in human, chimpanzee, cattle, pig, rat and mouse, 490 aa in rhesus monkey, 285 aa in sheep, 587 in opossum and 588 aa in canines. Visfatin gene is well preserved during evolution. For example, the canine visfatin protein sequence is 96% and 94% identical to human and rodent visfatin, respectively. Since evidence of a direct link between visfatin genotype and human type 2 diabetes mellitus is still weak, more molecular, physiological and clinical studies are needed to determine the role of visfatin in the etiology and pathogenesis of type 2 diabetes mellitus. PMID: 18691043 [PubMed - indexed for MEDLINE] 2299. Curr Clin Pharmacol. 2008 May;3(2):77-84. Pioglitazone and rosiglitazone: effects of treatment with a thiazolidinedione on lipids and non conventional cardiovascular risk factors. Derosa G(1), Salvadeo SA. Author information: (1)Department of Internal Medicine and Therapeutics, University of Pavia, Piazzale C. Golgi 2, Pavia, Italy. giuseppe.derosa@unipv.it The so-called central or upper-body obesity has been shown to play a key role in the development of insulin resistance and lipid abnormalities that commonly are associated with metabolic syndrome. Reducing free fatty acids (FFA) levels improves insulin resistance and lipid profile in metabolic syndrome. The established approach to improving FFA metabolism in obesity is based on inhibition of lipolysis, weight loss and treatment with thiazolidinediones (TZDs). Thiazolidinediones effect on lipids and lipid metabolism will be reviewed, particularly as regard their activity on the abnormal FFA metabolism, related to insulin-resistance. The many questions still unsolved about the molecular mechanisms, the large spectrum of action and the similarities and differences between rosiglitazone and pioglitazone action on lipid metabolism have been reviewed as well as the effect of these new insulin-sensitizers on non conventional cardiovascular risk factors. PMID: 18690882 [PubMed - indexed for MEDLINE] 2300. Am J Clin Nutr. 2008 Aug;88(2):582S-586S. Pharmacokinetics of vitamin D toxicity. Jones G(1). Author information: (1)Departments of Biochemistry and Medicine, Queen's University, Kingston, Ontario, Canada. gj1@queensu.ca Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin. PMID: 18689406 [PubMed - indexed for MEDLINE] 2301. Obes Surg. 2009 Apr;19(4):407-11. doi: 10.1007/s11695-008-9631-7. Epub 2008 Aug 7. Limb contouring after massive weight loss: functional rather than aesthetic improvement. Bruschi S(1), Datta G, Bocchiotti MA, Boriani F, Obbialero FD, Fraccalvieri M. Author information: (1)Department of Plastic, Reconstructive and Aesthetic Surgery, University of Turin, Turin, Italy. BACKGROUND: After massive weight loss, both upper and lower limbs show a similar deformity which consists of redundancy and ptosis of the cutaneous mantle. Many disturbances are associated with this abnormality, which can be treated surgically. A retrospective review of limb-contouring procedures after massive weight loss is presented. METHODS: Thigh lift and arm lift procedures are described. All surgeries of upper and lower limbs contouring performed between 2003 and 2006 are reviewed with regard to quantity of tissue removed, comorbidities, complications and patients' satisfaction, which was surveyed through a questionnaire exploring functional and esthetic results (maximum score 3). RESULTS: Among 48 bilateral limb-contouring procedures, medial thigh lifts were 35 (73%) and brachioplasties were 13 (27%). Mean age was 46 and average body mass index variation was 20 kg/m(2). The most frequent comorbidity was gallstones (28%). In 46% of the whole group of patients, there was no complication to mention. The most frequent complication was acute anaemia in both procedures (43% in thigh lift and 54% in arm lift). Mean quantity of adipose-dermoid tissue removed was 766 g in thigh lift and 463 g in arm lift. In case of surgery combined with liposuction, the average aspirated volume was 1,933 ml (thighs) and 1,117 ml (arms). Patients' satisfaction was 2.7 for thighs and 2.6 for arms, as average. CONCLUSION: The rate of complications in limb contouring after weight loss is higher than the analogue esthetic procedures. Nevertheless, due to the rehabilitative significance of limb surgery after weight loss, this step is to be included as fundamental in obese patients' surgical therapy. PMID: 18685905 [PubMed - indexed for MEDLINE] 2302. Curr Opin Support Palliat Care. 2007 Dec;1(4):293-8. doi: 10.1097/SPC.0b013e3282f34738. Mechanisms to explain wasting of muscle and fat in cancer cachexia. Argilés JM(1), López-Soriano FJ, Busquets S. Author information: (1)Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain. jargiles@ub.edu PURPOSE OF REVIEW: To describe the most relevant recent findings concerning the molecular mechanisms involved in both fat and muscle tissues in cachectic cancer patients. RECENT FINDINGS: Relevant progress has been made in the mechanism of signalling protein metabolism in skeletal muscle. PI3K has a dual role inhibiting protein degradation by inhibition of Atrogin-1 and MuRF1 gene expression and facilitating AKT phosphorylation, leading to increased protein synthesis. Interestingly, Caspase-3 activity is intimately associated with myofibrillar protein degradation in muscle tissue. With respect to fat metabolism, increased lipolysis in human cancer cachexia seems to be directly connected to increased hormone-sensitive lipase activity. SUMMARY: The results and findings described in this review represent important progress in wasting disease mechanisms and may provide hints for future therapeutic approaches in cancer cachexia. PMID: 18685378 [PubMed - indexed for MEDLINE] 2303. Int J Clin Pract. 2008 Oct;62(10):1474-83. doi: 10.1111/j.1742-1241.2008.01848.x. Epub 2008 Aug 4. Is adiposopathy (sick fat) an endocrine disease? Bays HE(1), González-Campoy JM, Henry RR, Bergman DA, Kitabchi AE, Schorr AB, Rodbard HW; Adiposopathy Working Group. Author information: (1)L-MARC Research Center, Louisville, KY 40213,, USA. hbaysmd@aol.com OBJECTIVE: To review current consensus and controversy regarding whether obesity is a 'disease', examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of 'adiposopathy' and 'sick fat' as scientifically and clinically useful terms in defining when excessive body fat may represent a 'disease'. METHODS: A group of clinicians and researchers, all with a background in endocrinology, assembled to evaluate the medical literature, as it pertains to the pathologic and pathogenic potential of adipose tissue, with an emphasis on metabolic diseases that are often promoted by excessive body weight. RESULTS: The data support pathogenic adipose tissue as a disease. Challenges exist to convince many clinicians, patients, healthcare entities and the public that excessive body fat is often no less a 'disease' than the pathophysiological consequences related to anatomical abnormalities of other body tissues. 'Adiposopathy' has the potential to scientifically define adipose tissue anatomic and physiologic abnormalities, and their adverse consequences to patient health. Adiposopathy acknowledges that when positive caloric balance leads to adipocyte hypertrophy and visceral adiposity, then this may lead to pathogenic adipose tissue metabolic and immune responses that promote metabolic disease. From a patient perspective, explaining how excessive caloric intake might cause fat to become 'sick' also helps provide a rationale for patients to avoid weight gain. Adiposopathy also better justifies recommendations of weight loss as an effective therapeutic modality to improve metabolic disease in overweight and obese patients. CONCLUSION: Adiposopathy (sick fat) is an endocrine disease. PMCID: PMC2658008 PMID: 18681905 [PubMed - indexed for MEDLINE] 2304. Stem Cell Rev. 2008 Dec;4(4):269-74. doi: 10.1007/s12015-008-9039-8. Epub 2008 Aug 5. Cord blood stem cells: a review of potential neurological applications. Harris DT(1). Author information: (1)Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA. davidh@email.arizona.edu It is estimated that as many as 128M individuals in the United States, or 1 in 3 people, might benefit from regenerative medicine therapy. Many of these usages include applications that affect the nervous system, including cerebral palsy, stroke, spinal cord injury and neurodegenerative disease such as Parkinson's. The numbers of such individuals affected range from 10,000 (for cerebral palsy) to 700,000 annually (for stroke) at a cost of more than $65B. For the foreseeable future, regenerative medicine entrée to the clinic will depend upon the development of adult or non-embryonic stem (ES) cell therapies. Currently, non-ES cells easily available in large numbers from affected individuals can be found in the bone marrow, adipose tissue and umbilical cord blood (CB). It is our belief that CB stem cells are the best alternative to ES cells as these stem cells can be used to derive tissues from the mesodermal, endodermal and ectodermal germ lineages. CB contains a mixture of different types of stem cells in numbers not seen in any other location including embryonic-like stem cells, hematopoietic stem cells, endothelial stem cells, epithelial stem cells, mesenchymal stem cells and unrestricted somatic stem cells. This review will summarize the findings reported in the literature with regards to the use of CB stem cells to neurological applications including in vitro work, pre-clinical animal studies, and patient clinical trials. PMID: 18679834 [PubMed - indexed for MEDLINE] 2305. Cas Lek Cesk. 2008;147(7):360-6. [Gene expression changes during insulin resistance and "diabesity" in insulin-sensitive tissues and possibilities of their regulation]. [Article in Czech] Hosek J(1), Bartos M. Author information: (1)Farmaceutická fakulta, Veterinárni a farmaceutická univerzita, Brno. hhosek@gmail.com Type 2 diabetes mellitus (T2DM) gains considerable and pandemic proportions and becomes noticeable problem in a social and economic sphere. In spite of all effort, exact mechanism of T2DM origin has not been elucidated yet. Studying of transcriptom is one possibility how to explain pathophysiological processes in insulin-sensitive tissues. Obtained data can serve as a base for predicting of new therapeutic targets of this disease. This overall review introduces crucial genes whose level of products changes during T2DM. The article gives notice to a diet composition, which is an important environmental factor, which is able to influence a disease outbreak. Not only the role of fats, but also influence of some plant compounds, which would be able to serve as an alternative to present prophylaxis or treatment of T2DM, have been discussed. PMID: 18678094 [PubMed - indexed for MEDLINE] 2306. Curr Drug Targets. 2008 Jul;9(7):565-70. WNT signaling in stem cell biology and regenerative medicine. Katoh M(1). Author information: (1)Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo 104-0045, Japan. mkatoh-kkr@umin.ac.jp WNT family members are secreted-type glycoproteins to orchestrate embryogenesis, to maintain homeostasis, and to induce pathological conditions. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, and ROR2 are transmembrane receptors transducing WNT signals based on ligand-dependent preferentiality for caveolin- or clathrin-mediated endocytosis. WNT signals are transduced to canonical pathway for cell fate determination, and to non-canonical pathways for regulation of planar cell polarity, cell adhesion, and motility. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 and Glucagon are target genes of canonical WNT signaling cascade, while CD44, Vimentin and STX5 are target genes of non-canonical WNT signaling cascades. However, target genes of WNT signaling cascades are determined in a context-dependent manner due to expression profile of transcription factors and epigenetic status. WNT signaling cascades network with Notch, FGF, BMP and Hedgehog signaling cascades to regulate the balance of stem cells and progenitor cells. Here WNT signaling in embryonic stem cells, neural stem cells, mesenchymal stem cells, hematopoietic stem cells, and intestinal stem cells will be reviewed. WNT3, WNT5A and WNT10B are expressed in undifferentiated human embryonic stem cells, while WNT6, WNT8B and WNT10B in endoderm precursor cells. Wnt6 is expressed in intestinal crypt region for stem or progenitor cells. TNF/alpha-WNT10B signaling is a negative feedback loop to maintain homeostasis of adipose tissue and gastrointestinal mucosa with chronic inflammation. Recombinant WNT protein or WNT mimetic (circular peptide, small molecule compound, or RNA aptamer) in combination with Notch mimetic, FGF protein, and BMP protein opens a new window to tissue engineering for regenerative medicine. PMID: 18673242 [PubMed - indexed for MEDLINE] 2307. Curr Pharm Des. 2008;14(16):1606-14. The blood-brain barrier as a cause of obesity. Banks WA(1). Author information: (1)Veterans Affairs Medical Center-St. Louis, Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, MO 63106, USA. bankswa@slu.edu The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight, and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called "peripheral resistance" to leptin. In this sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect of the starvation response, inducing leptin resistance at the BBB. Thus, the BBB plays important roles in both obesity and starvation. PMID: 18673202 [PubMed - indexed for MEDLINE] 2308. Curr Pharm Des. 2008;14(18):1815-20. Role of the autonomic nervous system and neuropeptides in the development of obesity in humans: targets for therapy? Greenfield JR(1), Campbell LV. Author information: (1)Diabetes and Obesity Research Program, Garvan Institute of Medical Research and Diabetes Centre and Department of Endocrinology, St. Vincent's Hospital, Sydney, Australia. j.greenfield@garvan.org.au Obesity and type 2 diabetes have reached epidemic proportions worldwide. These metabolic disorders, particularly obesity, are characterised by increased basal sympathetic nervous system (SNS) activity but an impaired sympathetic response to certain stimuli, such as insulin. Although targeting the SNS may seem an attractive avenue for the pharmacological prevention and treatment of obesity and related metabolic disorders, it remains unknown whether changes in SNS tone are primary and contribute to the development of these metabolic conditions or whether they develop secondary to the obese state. This question can be answered by the study of insulin-resistant individuals prior to the development of obesity and type 2 diabetes. Using this model, it has been shown that early insulin resistance is associated with increased SNS activity in genetically-predisposed humans. It has been suggested that in insulin-resistant states, hyperinsulinaemia is the initiating factor that increases sympathetic neural activity. Over time, adrenoreceptor down-regulation and/or reduced sensitivity are likely to develop, resulting in reduced sympathetic responsiveness. In the postprandial state, this will lead to impaired diet-induced thermogenesis and post-prandial fat oxidation, promoting the accumulation of body fat. More recent evidence demonstrates that stress-induced SNS overactivity up-regulates Neuropeptide Y, an orexigenic hormone, and its Y2 receptor, in visceral adipose tissue, the fat depot most strongly linked to insulin resistance and type 2 diabetes. There is evidence that SNS overactivity specifically contributes to the development of abdominal obesity via this pathway, which could represent a novel target for the prevention and treatment of abdominal obesity and related metabolic consequences. PMID: 18673184 [PubMed - indexed for MEDLINE] 2309. Verh K Acad Geneeskd Belg. 2008;70(3):193-219. Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Holvoet P(1). Author information: (1)Atherosclerose en Metabolisme Eenheid, Departement Hart- en Vaatziekten, KULeuven, Campus Gasthuisberg, Herestraat 49-B 3000 Leuven. The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated that plaque oxidized LDL correlated with coronary plaque complexity in a swine atherosclerosis model. Oxidized LDL correlated positively with the expression of IRF1 and TLR2 suggesting a relation between oxidative stress and inflammation in coronary atherosclerotic plaques. Oxidized LDL induced further the expression of TLR2 and IRF1 in macrophages in vitro suggesting a causative link. As in the mouse model described above, plaque oxidized LDL correlated negatively with SOD1 expression and ox-LDL inhibited the expression of SOD1 in macrophages in vitro. We showed that TLR2, CXCR4 and MYC are overexpressed in monocytes of obese women at high cardiovascular risk and that weight loss was associated with a concomitant decrease of their expression. This suggests that the transcription factor cMYC has an atherogenic effect by inducing pro-inflammatory genes. The increased expression of TLR2 and CXCR4 were observed in the absence of an increase in ox-LDL but in the presence of an increase in SOD1. Interestingly, the expression of SOD1 correlated also with that of MYC, suggesting that it has an atherogenic effect by inducing the expression of an anti-oxidant enzyme. How ox-LDL prevents this increase remains to be determined. How we plan to do this is explained in the next part. In aggregate, our studies contributed to a better understanding of the relationships between metabolic syndrome, insulin signalling, oxidative stress and inflammation and atherosclerosis. We identified paraoxonase, interferon regulatory factor-1, toll-like receptors, CXCR4 and SOD1 as possible targets for intervention. PMID: 18669160 [PubMed - indexed for MEDLINE] 2310. Nutr Rev. 2008 Jul;66(7):415-21. doi: 10.1111/j.1753-4887.2008.00051.x. Conjugated linoleic acids: why the discrepancy between animal and human studies? Plourde M(1), Jew S, Cunnane SC, Jones PJ. Author information: (1)Research Center on Aging and Departments of Medicine, and Physiology and Biophysics, Université de Sherbrooke, Sherbrooke, Québec, Canada. melanie.plourde2@usherbrooke.ca Conjugated linoleic acids (CLA) are positional and geometric isomers of linoleic acid. In animals, CLA consumption reduces body fat but results in humans are less conclusive. This review of the literature on CLA and loss of body fat or body weight in humans was conducted to explore the reasons for the discrepancy between animal and clinical trials. It indicates that the incongruity between human and animal data is largely related to methodological differences in the experimental design, including age and gender and, to a lesser extent, to CLA dose and isomers. The relatively unknown metabolic fate of CLA in humans may also be a contributing factor that helps explain the lack of consistency for CLA efficacy across studies. PMID: 18667017 [PubMed - indexed for MEDLINE] 2311. Expert Rev Cardiovasc Ther. 2008 Aug;6(7):1007-22. doi: 10.1586/14779072.6.7.1007. Dyslipidemia in insulin resistance: clinical challenges and adipocentric therapeutic frontiers. Toh SA(1), Rader DJ. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania, 1 Maloney Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. sue-anne.toh@uphs.upenn.edu The ever-increasing rates of obesity and diabetes worldwide have the potential to further fuel the epidemic of cardiovascular disease that we are experiencing today. To slow this epidemic successfully, insulin resistance and associated lipid abnormalities that frequently accompany it are key clinical targets. Yet, we are still challenged to reach the mandated clinical goals for lipids that would minimize the development and progression of cardiovascular disease. Adoption of a comprehensive approach by clinicians, in line with recent recommendations for stricter treatment goals for the at-risk patient, is essential to achieving cardiovascular risk reduction. The challenge for clinicians is integrating strategies, approaches and treatments that address the multiple metabolic defects in patients with insulin resistance and dyslipidemia. New perspectives can help effectively meet this ongoing challenge. Emerging evidence suggests that adipose tissue is intimately involved in the inter-relationships between insulin resistance and dyslipidemia. The future probably involves therapeutic strategies that directly target adipose tissue to optimally reduce cardiometabolic risk. PMID: 18666851 [PubMed - indexed for MEDLINE] 2312. Hepatology. 2008 Aug;48(2):670-8. doi: 10.1002/hep.22399. Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis. Maher JJ(1), Leon P, Ryan JC. Author information: (1)Department of Medicine, University of California, San Francisco, CA, USA. jmaher@medsfgh.ucsf.edu Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease. PMCID: PMC3592568 PMID: 18666225 [PubMed - indexed for MEDLINE] 2313. Nutrition. 2008 Sep;24(9):802-5. doi: 10.1016/j.nut.2008.06.005. Epub 2008 Jul 26. NPY and brain monoamines in the pathogenesis of cancer anorexia. Laviano A(1), Inui A, Meguid MM, Molfino A, Conte C, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy. alessandro.laviano@uniroma1.it Cancer anorexia frequently characterizes the clinical journey of patients with cancer and affects patients' morbidity, mortality, and quality of life. A constellation of symptoms concur to the diagnosis of anorexia, and early satiety, changes in taste/smell, and nausea are the more frequently reported. The pathogenesis of cancer anorexia is multifactorial, but accumulating evidence indicates that the hypothalamic melanocortin and neuropeptide Y systems become resistant to peripheral inputs. This results in increased melanocortin activity and reduced neuropeptide Y function, thereby leading to the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Interestingly, hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. In the clinical setting, cancer anorexia develops with heterogeneous presenting symptoms (i.e., early satiety and/or nausea and/or changes of taste) and varying degrees of severity. Available evidence suggests that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state. PMID: 18662859 [PubMed - indexed for MEDLINE] 2314. J Int Med Res. 2008 Jul-Aug;36(4):625-9. A novel adipocytokine, visceral adipose tissue-derived serine protease inhibitor (vaspin), and obesity. Li Q(1), Chen R, Moriya J, Yamakawa J, Sumino H, Kanda T, Takahashi T. Author information: (1)School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an interesting novel adipocytokine with insulin-sensitizing effects. Some studies have suggested that vaspin could play an important role in the development of obesity and metabolic disorders. The induction of vaspin mRNA expression could represent a compensatory mechanism associated with obesity, severe insulin resistance and type 2 diabetes mellitus, however it is unclear whether a correlation exists between human vaspin serum levels and markers of insulin sensitivity and glucose or lipid metabolism. Vaspin serum concentrations have been shown to be lower in lean subjects and competitive sportsmen with long-term physical training, but they are increased with weight loss associated with a physical training programme. In conclusion, there is at present no clear proof of a causal link between vaspin and visceral fat accumulation, or insulin resistance. This article reviews the role of vaspin in obesity-associated diseases and its potential as a new biomarker for obesity and impaired insulin sensitivity. PMID: 18652756 [PubMed - indexed for MEDLINE] 2315. Med Phys. 2008 Jun;35(6):2339-46. Comparison of slot scanning digital mammography system with full-field digital mammography system. Lai CJ(1), Shaw CC, Geiser W, Chen L, Arribas E, Stephens T, Davis PL, Ayyar GP, Dogan BE, Nguyen VA, Whitman GJ, Yang WT. Author information: (1)Department of Imaging Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. chaolai@di.mdacc.tmc.edu The purpose of this study was to evaluate and compare microcalcification detectability of two commercial full-field digital mammography (DM) systems. The first unit was a flat panel based DM system (FFDM) which employed an anti-scatter grid method to reject scatter, and the second unit was a charge-coupled device-based DM system (SSDM) which used scanning slot imaging geometry to reduce scatter radiation. Both systems have comparable scatter-to-primary ratios. In this study, 125-160 and 200-250 microm calcium carbonate grains were used to simulate microcalcifications and imaged by both DM systems. The calcium carbonate grains were overlapped with a 5-cm-thick 50% adipose/50% glandular simulated breast tissue slab and an anthropomorphic breast phantom (RMI 165, Gammex) for imaging at two different mean glandular dose levels: 0.87 and 1.74 mGy. A reading study was conducted with seven board certified mammographers with images displayed on review workstations. A five-point confidence level rating was used to score each detection task. Receiver operating characteristic (ROC) analysis was performed and the area under the ROC curve (A(z)) was used to quantify and compare the performances of these two systems. The results showed that with the simulated breast tissue slab (uniform background), the SSDM system resulted in higher A(z)'s than the FFDM system at both MGD levels with the difference statistically significant at 0.87 mGy only. With the anthropomorphic breast phantom (tissue structure background), the SSDM system performed better than the FFDM system at 0.87 mGy but worse at 1.74 mGy. However, the differences were not found to be statistically significant. PMCID: PMC2809719 PMID: 18649467 [PubMed - indexed for MEDLINE] 2316. Reprod Domest Anim. 2008 Jul;43 Suppl 2:324-30. doi: 10.1111/j.1439-0531.2008.01173.x. Energy metabolism and leptin: effects on neuroendocrine regulation of reproduction in the gilt and sow. Barb CR(1), Hausman GJ, Lents CA. Author information: (1)USDA/ARS, Richard B. Russell Agriculture Research Center, University of Georgia, Athens, GA 30604, USA. richard.barb@ars.usda.gov It is well established that reproductive function is metabolically gated. However, the mechanisms whereby energy stores and metabolic cues influence appetite, energy homeostasis and fertility are yet to be completely understood. Adipose tissue is no longer considered as only a depot to store excess energy. Recent findings have identified numerous genes, several neurotrophic factors, interleukins, insulin-like growth factor binding protein-5, ciliary neurotrophic factor and neuropeptide Y (NPY) as being expressed by adipose tissue during pubertal development. These studies demonstrated for the first time the expression of several major adipokines or cytokines in pig adipose tissue which may influence local and central metabolism and growth. Leptin appears to be the primary metabolic signal and is part of the adipose tissue-hypothalamic regulatory loop in the control of appetite, energy homeostasis and luteinizing hormone (LH) secretion. Leptin's actions on appetite regulation are mediated by inhibition of hypothalamic NPY and stimulation of proopiomelanocortin. Its effects on gonadotropin-releasing hormone (GnRH)/LH secretion are mediated by NPY and kisspeptin. Thus, leptin appears to be an important link between metabolic status, the neuroendocrine axis and subsequent fertility in the gilt and sow. PMID: 18638142 [PubMed - indexed for MEDLINE] 2317. Appl Physiol Nutr Metab. 2008 Aug;33(4):791-6. doi: 10.1139/H08-038. About unsuspected potential determinants of obesity. Tremblay A(1), Chaput JP. Author information: (1)Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada. angelo.tremblay@kin.msp.ulaval.ca The positive energy balance underlying obesity is generally attributed to factors exerting a direct measurable impact on energy intake or expenditure. Thus, sedentariness and (or) excess caloric intake represent the "Big Two" factors on which almost all the attention of health professionals is devoted in preventive and therapeutic programs for obesity. However, recent research reveals that other more discrete factors can also promote a positive energy balance and body fat gain. Accordingly, this paper documents the effects of low micronutrient intake, short sleep duration, knowledge-based work, and organochlorine compounds on components of energy balance and body composition. These effects aid in the understanding as to why modernity accentuates the risk of obesity. Furthermore, they also suggest that body fat gain is not only a problem, but also a solution in maintaining body homeostasis, i.e., a state of optimal body functionality, in the context of modernity and globalization. PMID: 18641724 [PubMed - indexed for MEDLINE] 2318. J Pediatr Surg. 2008 Jul;43(7):1295-300. doi: 10.1016/j.jpedsurg.2007.10.068. Contemporary management of lipoblastoma. Speer AL(1), Schofield DE, Wang KS, Shin CE, Stein JE, Shaul DB, Mahour GH, Ford HR. Author information: (1)Department of Surgery at the University of Southern California, Los Angeles, CA 90033, USA. PURPOSE: Lipoblastoma is a rare, benign, adipose tissue tumor. We report the largest single institution experience managing these uncommon neoplasms. METHODS: We retrospectively reviewed 32 cases of lipoblastoma entered in the pathology database at our institution between January 1991 and August 2005. We conducted a comprehensive literature review of lipoblastoma and summarized the results of the largest series published. RESULTS: Most patients presented with an enlarging, palpable, firm, nontender, mobile mass. The male-to-female ratio was 1.9:1. The anatomical distribution was trunk (n = 12), extremity (n = 12), groin (n = 5), and neck (n = 3). Average age at resection was 2.8 years (range, 2.6 months to 12 years). Thirty-one cases were completely excised, although 1 patient underwent staged partial excision to preserve nerve function. Chromosomal analysis performed in selected patients revealed characteristic aberrations in chromosome 8. Complications included keloid formation (n = 3), wound infection/dehiscence (n = 2), wound seroma (n = 1), and transient brachial plexus neurapraxia (n = 1). Average follow-up was 7.4 months (range, 1 day to 6.5 years); 2 patients were lost to follow-up. There were no recurrences. CONCLUSIONS: A staged approach with meticulous sparing of the neurovascular bundle provides excellent functional outcome for patients with large tumors. Nonmutilating surgical excision is the treatment of choice. PMID: 18639685 [PubMed - indexed for MEDLINE] 2319. Adv Exp Med Biol. 2008;630:112-32. Aromatase expression in women's cancers. Bulun SE(1), Simpson ER. Author information: (1)Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA. sbulun@northwestern.edu Estrogen has been positively linked to the pathogenesis and growth of three common women's cancers (breast, endometrium and ovary). A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less dear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue specific promoters distributed over a 93 kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers ofbreast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter 1.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE2 via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE2 secreted by malignant epithelial cells, activation of PKC potentiates cAMP-PKA-dependent induction ofaromatase. Thus, inflammatory substances such as PGE2 may play important roles in inducing local production of estrogen that promotes tumor growth. PMID: 18637488 [PubMed - indexed for MEDLINE] 2320. Adv Exp Med Biol. 2008;630:35-51. Role of endocrine-genotoxic switchings in cancer and other human diseases: basic triad. Berstein LM(1). Author information: (1)Laboratory of Oncoendocrinology, Prof. N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia. levmb@endocrin.spb.ru Cancer is one of the leading causes of human death and belongs to the group of main chronic noncommunicable diseases (NCD). Certain specific features ofNCD have raised the concept of 'normal' and 'successful' aging. The apparent paradox of simultaneous increase with aging of the diseases connected with estrogen deficiency as well as with estrogenic excess can be explained by the existence of the phenomenon of the switching of estrogen effects. An isolated or combined with the weakening of hormonal effect increase in genotoxic action of estrogens can modify the course ofage-associated pathology. In particular, such changes in estrogen effect may alter the biology of tumors to make them less favorable/more aggressive. Two other endocrine-genotoxic switchings (EGS) involving phenomena ofJanus (dual) function of glucose and adipogenotoxicosis may produce similar influences on tumor and other NCD biology. These three phenomena form a'basic triad' and can act independently of each other or in concert. EGS and their inductors may serve as targets for prevention and, probably, treatment of main noncommunicable diseases. The measures to correct components of the 'triad' can be divided into several groups aimed to optimally orchestrate the balance between endocrine and DNA-damagingeffects of estrogens, glucose and adipose tissue-related factors. PMID: 18637483 [PubMed - indexed for MEDLINE] 2321. Dig Dis Sci. 2008 Sep;53(9):2293-9. doi: 10.1007/s10620-008-0410-z. Epub 2008 Jul 18. The epidemiology of obesity and gastrointestinal and other diseases: an overview. Moayyedi P(1). Author information: (1)Division of Gastroenterology, Department of Medicine, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada. moayyep@mcmaster.ca The worldwide prevalence of obesity continues to increase, with devastating implications for overall health. Epidemiological trends indicate the primary contributors are environmental (e.g., increased caloric intake, lack of exercise), although the evidence is surprisingly equivocal. Increased body mass index (BMI) is associated with an increase in all-cause mortality and in diseases related to this increasing mortality rate, such as diabetes mellitus, cardiovascular disease, and cancer, including those of the gastrointestinal system. Some of these associations are even more pronounced when obesity is measured by waist-to-hip ratio, a marker of visceral adipose tissue, versus BMI. Higher BMI is related to increased risk of developing gall stones, and obese patients experience GI symptoms, such as vomiting and diarrhea, more often compared with those of normal body mass. Although the exact cause remains uncertain, these symptoms may be connected to eating habits or to changes in gastrointestinal motility. PMID: 18636328 [PubMed - indexed for MEDLINE] 2322. Hum Mol Genet. 2008 Apr 15;17(R1):R93-8. doi: 10.1093/hmg/ddn071. Cell-based therapies for skeletal regenerative medicine. Kwan MD(1), Slater BJ, Wan DC, Longaker MT. Author information: (1)Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford, CA, USA. Skeletal deficits represent a substantial biomedical burden on the US healthcare system. Current strategies for reconstructing bony defects are fraught with inadequacies. Cell-based therapies for skeletal regeneration offer a paradigm shift that may provide alternative solutions. Substantial work has identified a host of cellular sources that possess the potential for osteogenic differentiation. Significant efforts have been devoted toward characterizing the role of postnatal cellular sources that are relatively abundant and easily accessible. Among these, the potential of using adipose-derived stromal cells for skeletal regeneration has garnered much interest. Integral to these efforts directed at characterizing cellular sources are studies that seek to understand the factors that initiate and regulate osteogenic differentiation of progenitor cells. Specifically, focus has been directed on elucidating the role of bone morphogenetic protein and fibroblast growth factor signaling in regulating osteogenic differentiation of osteoprogenitor cells. Concurrent studies in the field of scaffold design have also helped to advance the potential for cell-based therapies. PMID: 18632703 [PubMed - indexed for MEDLINE] 2323. Nephrol Dial Transplant. 2008 Oct;23(10):3041-6. doi: 10.1093/ndt/gfn376. Epub 2008 Jul 16. The emerging biology of adipose tissue in chronic kidney disease: from fat to facts. Axelsson J. PMID: 18632589 [PubMed - indexed for MEDLINE] 2324. Bratisl Lek Listy. 2008;109(5):224-30. Adult obesity at the beginning of the 21st century: epidemiology, pathophysiology and health risk. Ginter E(1), Simko V. Author information: (1)Institute of Preventive and Clinical Medicine, Bratislava, Slovakia. ginter.emil@mail.t-com.sk Obesity is defined as increased body weight caused by excessive accumulation of fat. Due to a very long period of undernutrition in human history, the contemporary human body regulation mechanisms seem to be biased in favor of preserving fat rather to eliminate it. At the highest risk are populations that suddenly gained wealth. The shift from undernutrition to overnutrition has occurred in a very short time, in many population groups in less than in one generation. The increase of obesity prevalence observed in the 20th century continues until present and it appears this trend will further continue in almost all countries in the world. Contemporary prevalence of adult obesity is very high in USA (33% in both gender), in oil-rich Arabian countries (30% in males, 40 % in females) and in European Union (up to 25% in both gender). The aim of contemporary research is to understand the molecular and neural systems which the body uses to regulate its storage of energy in the form of fat and how these systems can become unbalanced, leading to obesity. In spite of discovery of new hormones (e.g. leptin produced in adipose tissue) and of new mechanisms, the prevention and treatment of obesity remains an open problem. Obesity is associated with an increased risk of numerous comorbidities such as type 2 diabetes, metabolic syndrome, hypertension, cardiovascular diseases and osteoarthritis. In USA the impact of obesity on mortality may have decreased over time, perhaps because of improvements in public health and medical care. New data from USA and China suggest the lowest all-cause mortality in persons with a body mass index, BMI between 23.0 and 27.0 (Fig. 6, Tab. 1, Ref. 29). Full Text (Free, PDF) www.bmj.sk. PMID: 18630807 [PubMed - indexed for MEDLINE] 2325. Vnitr Lek. 2008 May;54(5):508-10. [System renin-aldosterone in fat tissue and other organ and tissues]. [Article in Czech] Svacina S(1). Author information: (1)III. interní klinika 1. lékarské fakulty UK a VFN Praha. svacinas@lf1.cuni.cz Important mechanism of pathogenesis of hypertension in obesity is renin-aldosterone system in adipose tissue. Adrenal cells can be also stimulated to aldosterone secretion by local adrenal fat cells and also by other factors from fat tissue (lipids, endocrine disruptors). Local system renin-aldosteron is active also in other tissues and organs in obesity related hypertension. Feed back is closed by recently investigated fact that aldosteron hypersecretion can cause metabolic syndrome. Between systemic approach to obesity a new phenomenon of organ obesity is coming - adipokines from local fat cells can influence organ and tissue function e.g. in essential hypertension. PMID: 18630637 [PubMed - indexed for MEDLINE] 2326. Vnitr Lek. 2008 Apr;54(4):368-76. [Pathogenesis of insulin resistance in different endocrinopathies]. [Article in Czech] Durovcová V(1), Krsek M, Haluzík M. Author information: (1)III. interní klinika 1. lékarské fakulty UK a VFN Praha. viktoria.durovcova@gmail.com Visceral obesity, insulin resistance and increased cardiovascular morbidity and mortality are strongly related. Development of visceral obesity and regulation of body fat distribution in general are influenced by many factors. This article is a summary of current knowledge about pathogenesis of insulin resistance in different endocrinopathies, particularly in the Cushing's syndrome and acromegaly, as they are both connected with the pathological conditions mentioned above. PMID: 18630616 [PubMed - indexed for MEDLINE] 2327. Arch Physiol Biochem. 2008 Jul;114(3):183-94. doi: 10.1080/13813450802181047 . Insulin resistance associated to obesity: the link TNF-alpha. Nieto-Vazquez I(1), Fernández-Veledo S, Krämer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Author information: (1)Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Erratum in Arch Physiol Biochem. 2009 May;115(2):117. Adipose tissue secretes proteins which may influence insulin sensitivity. Among them, tumour necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissue from obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. The activation of proinflammatory pathways after exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and adipocytes that impair insulin signalling at the level of the insulin receptor substrate (IRS) proteins. The mechanism found in brown adipocytes involves Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of MAPKs. The Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB kinase being involved in the phosphorylation of this residue. Moreover, up-regulation of protein-tyrosine phosphatase (PTP)1B expression was recently found in cells and animals treated with TNF-alpha. PTP1B acts as a physiological negative regulator of insulin signalling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in peripheral tissues from obese and diabetic humans and rodents. Accordingly, down-regulation of PTP1B activity by treatment with pharmacological agonists of nuclear receptors restores insulin sensitivity in the presence of TNF-alpha. Furthermore, mice and cells deficient in PTP1B are protected against insulin resistance induced by this cytokine. In conclusion, the absence or inhibition of PTP1B in insulin-target tissues could confer protection against insulin resistance induced by cytokines. PMID: 18629684 [PubMed - indexed for MEDLINE] 2328. Nat Clin Pract Cardiovasc Med. 2008 Jul;5 Suppl 1:S15-8. doi: 10.1038/ncpcardio0808. The metabolic syndrome in Japan. Fujita T(1). Author information: (1)Internal Medicine at Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Japan. fujita-dis@h.u-tokyo.ac.jp Since its conception, the metabolic syndrome has received worldwide recognition as a useful clinical aid for predicting cardiovascular risk. The earliest definition, which included risk factors such as insulin resistance, hyperglycemia, hypertension, and cholesterol, has undergone many transformations. Two revisions have focused on visceral adiposity as an essential component of the syndrome, particularly in Asian populations. The Japanese national guidelines have also suggested that abnormalities in adipose tissue metabolism are an underlying molecular cause of the syndrome. In addition, emerging evidence suggests that lowering the threshold of waist circumference in Asian populations increases the prevalence of the metabolic syndrome. Inevitably, this widening of the threshold will capture more patients at risk of cardiovascular events. The aim of this Article is to consider the country-specific impact of the metabolic syndrome, using the evolution of the definition in Japan as a model. PMID: 18580861 [PubMed - indexed for MEDLINE] 2329. Curr Opin Otolaryngol Head Neck Surg. 2008 Aug;16(4):347-51. doi: 10.1097/MOO.0b013e3283079cc0. Update on perioral cosmetic enhancement. Suryadevara AC(1). Author information: (1)Department of Otolaryngology and Communication Sciences, Upstate Medical University, Syracuse, New York 13210, USA. amarsuryad@yahoo.com PURPOSE OF REVIEW: As our understanding of the perioral region advances and procedures available for its treatment increase, we are more able to successfully treat the aged perioral region with minimal risk. The aged perioral region has traditionally been rejuvenated by direct surgical excision, chemical peels, and laser resurfacing. Many minimally invasive techniques are now employed for this purpose, including chemodenervation, use of soft tissue fillers, and fat grafting. RECENT FINDINGS: Over the last couple of decades, rejuvenation techniques have evolved to include chemodenervation, soft tissue fillers, fat grafting, and dermabrasion. The present article will review the most recent literature regarding the use of these techniques for various perioral age-related changes, including rhytids, labiomental folds, nasolabial folds, lip-cheek grooves, and thinning lips. Often, these modalities are combined to give the most natural aesthetic result. SUMMARY: An increase in our armamentarium of techniques and general understanding of the complex perioral region allows us to treat the area quite effectively with minimal risk. Volume loss, a key component of perioral aging, is best addressed with soft tissue fillers and autologous fat. In addition, botulinum toxin helps rest some of the key muscles responsible for perioral rhytids. Facial resurfacing techniques are still crucial adjuncts in the rejuvenation of this area, and they may be the only treatment that adequately addresses multiple deeper perioral rhytids. PMID: 18626254 [PubMed - indexed for MEDLINE] 2330. Curr Opin Otolaryngol Head Neck Surg. 2008 Aug;16(4):335-8. doi: 10.1097/MOO.0b013e3283079c9b. Current concepts in midfacial rejuvenation. Downs BW(1), Wang TD. Author information: (1)Department of Otolaryngology/Head and Neck Surgery, Facial Plastic and Reconstructive Surgery, Oregon Health and Science University, Portland, Oregon, USA. downsb@ohsu.edu PURPOSE OF REVIEW: Treatment of the aging midface is an underappreciated element of overall facial rejuvenation. The anatomy of the midface and the pathophysiology of midface aging both remain somewhat controversial. The quest for ideal long-lasting midfacial rejuvenation continues. The purpose of this paper is to outline the latest progress in the field of midface rejuvenation. RECENT FINDINGS: The complexity of midface anatomy has sparked many new investigations. Minimally invasive techniques such as threadlifts have shown promise but require further study. Volume augmentation with autologous fat and fillers is an important aspect of midface rejuvenation. Nonablative therapies offer an attractive concept, but the ideal modality still does not exist. Enthusiasm for cheek implants seems to be decreasing in favor of soft-tissue-based treatments. Open surgical treatment via suspension techniques continues to be an important option for surgeons when rejuvenating the aging midface. SUMMARY: Cadaver dissection and clinical observation have recently been used to further define the complex anatomy of the aging midface. New developments in both minimally invasive and open surgical procedures continue to both advance and redefine the field. PMID: 18626252 [PubMed - indexed for MEDLINE] 2331. Curr Opin Pediatr. 2008 Aug;20(4):453-7. doi: 10.1097/MOP.0b013e328305e439. Physiological roles of 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase. White PC(1), Rogoff D, McMillan DR. Author information: (1)Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. Perrin.white@utsouthwestern.edu PURPOSE OF REVIEW: Inactive cortisone is converted to active cortisol by the reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1, which can thus increase glucocorticoid effects in target tissues. This paper reviews the functional role(s) of 11 beta-hydroxysteroid dehydrogenase type 1 and examines factors influencing its activity. RECENT FINDINGS: In obese humans, 11 beta-hydroxysteroid dehydrogenase type 1 is relatively highly expressed in adipose tissue. In mice, overexpression of 11 beta-hydroxysteroid dehydrogenase type 1 in adipose or liver causes obesity or insulin resistance, respectively, whereas mice lacking 11 beta-hydroxysteroid dehydrogenase type 1 resist diet-induced obesity and are insulin-sensitive. Thus, 11 beta-hydroxysteroid dehydrogenase type 1 is a promising drug target for treating the metabolic syndrome and type 2 diabetes. Studies in vitro and in mutant mice demonstrate that the reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 depends on reduced nicotinamide adenine dinucleotide phosphate synthesized within the endoplasmic reticulum by hexose-6-phosphate dehydrogenase. Apparent cortisone reductase deficiency is characterized by androgen excess in women or children and decreased urinary excretion of cortisol metabolites. Although polymorphisms in the genes encoding 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase were initially implicated in this condition, subsequent reports have not confirmed this. SUMMARY: Hexose-6-phosphate dehydrogenase and 11 beta-hydroxysteroid dehydrogenase type 1 may play important roles in the pathogenesis of obesity and metabolic syndrome. Although the importance of polymorphisms in the corresponding genes remains uncertain, rare mutations have not been ruled out. PMID: 18622204 [PubMed - indexed for MEDLINE] 2332. J Clin Endocrinol Metab. 2008 Jul;93(7):2439-46. doi: 10.1210/jc.2008-0752. Update in female reproduction: a life-cycle approach. Barbieri RL(1). Author information: (1)Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. rbarbieri@partners.org CONTEXT: Female reproduction spans a developmental life arc from fetal life and childhood, through puberty to the reproductive years, and, finally, ovarian follicle depletion and the onset of menopause. OBJECTIVE: This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause. SYNTHESIS: During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause. CONCLUSIONS: The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction. PMID: 18617698 [PubMed - indexed for MEDLINE] 2333. Methods Cell Biol. 2008;88:411-29. doi: 10.1016/S0091-679X(08)00421-4. Electron microscopy of lamin and the nuclear lamina in Caenorhabditis elegans. Cohen M(1), Santarella R, Wiesel N, Mattaj I, Gruenbaum Y. Author information: (1)Division of Cell Biology, MRC-Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. The nuclear lamina is found between the inner nuclear membrane and the peripheral chromatin. Lamins are the main components of the nuclear lamina, where they form protein complexes with integral proteins of the inner nuclear membrane, transcriptional regulators, histones and chromatin modifiers. Lamins are required for mechanical stability, chromatin organization, Pol II transcription, DNA replication, nuclear assembly, and nuclear positioning. Mutations in human lamins cause at least 13 distinct human diseases, collectively termed laminopathies, affecting muscle, adipose, bone, nerve and skin cells, and range from muscular dystrophies to accelerated aging. Caenorhabditis elegans has unique advantages in studying lamins and nuclear lamina genes including low complexity of lamina genes and the unique ability of bacterially expressed C. elegans lamin protein to form stable 10 nm fibers. In addition, transgenic techniques, simple application of RNA interference, sophisticated genetic analyses, and the production of a large collection of mutant lines, all make C. elegans especially attractive for studying the functions of its nuclear lamina genes. In this chapter we will include a short review of our current knowledge of nuclear lamina in C. elegans and will describe electron microscopy techniques used for their analyses. PMID: 18617045 [PubMed - indexed for MEDLINE] 2334. Diabetes Metab Res Rev. 2008 Oct;24(7):520-32. doi: 10.1002/dmrr.872. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome? Corbould A(1). Author information: (1)Prince Henry's Institute of Medical Research, Clayton, VIC, Australia. anne.corbould@princehenrys.org Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd. PMID: 18615851 [PubMed - indexed for MEDLINE] 2335. J Cell Physiol. 2008 Nov;217(2):296-300. doi: 10.1002/jcp.21521. The mesenchymal stromal cell contribution to homeostasis. Valtieri M(1), Sorrentino A. Author information: (1)Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. valtieri@iss.it Adult mesenchymal stromal cells (MSCs) are undifferentiated multi-potent cells predominantly residing in the bone marrow (BM), but also present with similar but not identical features in many other tissues such as blood, placenta, dental pulp, and adipose tissue. MSCs have the potential to differentiate into multiple skeletal phenotypes like osteoblasts, chondrocytes, adipocytes, stromal cells, fibroblasts, and possibly tendons. MSCs differentiation potential, ex vivo expansion capacity, nurturing and immunomodulatory proficiencies oriented these versatile cells in several areas of ongoing clinical applications. However, the absence of MSC-specific markers for isolation and characterization together with the lack of a comprehensive view of the molecular pathways governing their particular biological properties, remains a primary obstacle to their research and application. In this review we discuss some areas of growing interest in MSCs biology: their contribution to the hematopoietic stem cell (HSC) niche, to regenerative medicine, their role in cancer and in therapy as delivery tools and their micro-RNA (miRNA) signatures. Despite rapid progress in the MSC field, it is generally thought that only a fraction of their full potential has been realized thus far. (c) 2008 Wiley-Liss, Inc PMID: 18615579 [PubMed - indexed for MEDLINE] 2336. Endokrynol Pol. 2008 May-Jun;59(3):218-23. [Obesity and bone metabolism]. [Article in Polish] Holecki M(1), Zahorska-Markiewicz B, Wiecek A, Nieszporek T, Zak-Gołab A. Author information: (1)Katedra Patofizjologii, Slaski Uniwersytet Medyczny, Katowice. holomed@poczta.onet.pl Both bone and adipose tissue change their size, shape and distribution during the whole human being's life. Many factors, including genetic factors, hormones and activity of nervous system are responsible for these changes. It is generally accepted that obesity has a protective effect on bone tissue. On the other hand some authors present an opposite results--the lack of beneficial effect of obesity on development of osteoporosis fractures. The aim of this article was to present and discuss the relations between adipose tissue and bone metabolism. PMID: 18615396 [PubMed - indexed for MEDLINE] 2337. Cancer Lett. 2009 Jan 8;273(1):15-27. doi: 10.1016/j.canlet.2008.05.038. Epub 2008 Jul 9. Regulation of breast cancer-associated aromatase promoters. Chen D(1), Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE. Author information: (1)Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, 303 E Superior Street, Chicago, IL 60611, USA. dong-chen@northwestern.edu By converting androstenedione to estrone, or testosterone to estradiol, aromatase is a key enzyme in estrogen biosynthesis. Encoded by a single gene CYP19, aromatase is expressed in various tissues, including ovary, placenta, bone, brain, skin, and adipose tissue, via partially tissue-specific promoters, and is essential for normal estrogen-dependent physiological functions. In disease-free breast tissue, aromatase mRNA is primarily transcribed from the weak promoter I.4 and maintained at low levels in breast adipose stromal fibroblasts. In breast cancer a distinct set of aromatase promoters, i.e. I.3, II, and I.7, is activated, leading to a marked increase in aromatase expression in breast tumors and breast adipose tissue adjacent to a breast tumor, and a consequent local overproduction of estrogen that promotes growth and progression of breast cancer. In addition, the total amount of promoter I.4-specific aromatase transcript in breast adipose fibroblasts may also be increased due to both cytokine-induced desmoplastic reaction and cytokine-stimulated promoter I.4 activity in breast cancer. Targeting aromatase has proven beneficial in treating breast cancer, since aromatase inhibitors are the most effective endocrine treatment of breast cancer to date. However, aromatase inhibitors cause major side effects such as bone loss and abnormal lipid metabolism, due to indiscriminate reduction of aromatase activity in all expression sites of the body. Therefore, inhibition of aromatase expression via breast cancer-associated aromatase promoters is a useful strategy to selectively block local aromatase production, and hence estrogen synthesis, in breast cancer. This review will summarize the significant findings on regulation of the breast cancer-associated aromatase promoters, and highlight the discovery of chemical compounds and nuclear receptor ligands that specifically inhibit activation of these aromatase promoters. Clinical side effects of these agents require development of new drugs with better specificity and efficacy, and epigenetic therapies with breast cancer tissue-selective aromatase siRNA-conjugated nanoparticles. PMID: 18614276 [PubMed - indexed for MEDLINE] 2338. Aesthetic Plast Surg. 2008 Sep;32(5):785-9. doi: 10.1007/s00266-008-9210-2. Epub 2008 Jul 9. Arcus marginalis release in blepharoplasty I: technical facilitation. Stark GB(1), Iblher N, Penna V. Author information: (1)Department of Plastic Surgery, University Medical Center Freiburg, Freiburg, Germany. Resection of intraorbital fat compartments in lower-lid blepharoplasty has been widely replaced by their realignment over the orbital rim. For older patients this usually includes an open subciliary approach with skin resection and orbicularis muscle modification. In younger patients this may be done transconjunctivally. Fixation of the adipose tissue is controversial. Whereas reliance of realignment on spontaneous prolapse may be unpredictable, suture fixations may be tedious and even cause scleral show or ectropion. A monofilament, double-armed, polypropylene suture on bent straight needles can be used safely to transfix the three compartments across maxilla and zygoma. These transcutaneous pullout sutures are simply fixed with steri-strips. After only 2 days the orbital fat will be sufficiently adherent to its new bed. PMID: 18612676 [PubMed - indexed for MEDLINE] 2339. J Biol Chem. 2008 Oct 17;283(42):28005-9. doi: 10.1074/jbc.R800042200. Epub 2008 Jul 8. The gregarious lipid droplet. Goodman JM(1). Author information: (1)Department of Pharmacology, University of Texas Southwestern Medical School, Dallas, Texas 75390-9041, USA. joel.goodman@utsouthwestern.edu PMCID: PMC2568941 PMID: 18611863 [PubMed - indexed for MEDLINE] 2340. Ann Med. 2008;40(7):514-23. doi: 10.1080/07853890802004959. The concept of cardiometabolic risk: Bridging the fields of diabetology and cardiology. Després JP(1), Cartier A, Côté M, Arsenault BJ. Author information: (1)Hôpital Laval Research Centre, Québec, Canada. Jean-Pierre.Despres@crhl.ulaval.ca The lack of physical activity and the adoption of poor nutritional habits is the major cause of the obesity epidemic that is currently sweeping the world. The expansion of adipose tissue mass, especially of the visceral adipose tissue depot, is observed in the vast majority of individuals carrying the clinical features of the metabolic syndrome, an important (and reversible) risk factor of type 2 diabetes and cardiovascular disease. As waist circumference can be used as a crude estimate of visceral fat accumulation, its measurement provides further information on cardiovascular and type 2 diabetes risk, at any given body mass index value. However, an elevated waist circumference might also be the result of an increased 'cardioprotective' subcutaneous adipose tissue mass. We have proposed that the measurement of plasma triglycerides along with waist circumference, the so-called 'hypertriglyceridemic waist' might better quantify visceral obesity and its health hazards than waist circumference alone. "Hypertriglyceridemic waist" is thought to represent an altered, dysfunctional, and highly lipolytic adipose tissue that is a major culprit abnormality behind the metabolic syndrome and associated cardiometabolic risk, independently from classical cardiovascular disease risk factors such as age, sex, and plasma low density lipoprotein (LDL) cholesterol levels. PMID: 18608131 [PubMed - indexed for MEDLINE] 2341. Curr Opin Lipidol. 2008 Aug;19(4):344-8. doi: 10.1097/MOL.0b013e328304b62b. Endocannabinoid system in food intake and metabolic regulation. Jesudason D(1), Wittert G. Author information: (1)University of Adelaide, Adelaide, Australia. PURPOSE OF REVIEW: As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology. RECENT FINDINGS: The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood. SUMMARY: The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes. PMID: 18607180 [PubMed - indexed for MEDLINE] 2342. Clin Chem Lab Med. 2008;46(4):429-34. doi: 10.1515/CCLM.2008.118. Free fatty acids as a cardiovascular risk factor. Pilz S(1), März W. Author information: (1)Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria. stefan.pilz@chello.at Free fatty acids (FFAs) serve as physiologically important energy substrates and their release from the adipose tissue by lipolysis is regulated according to the energy demands of the body. FFAs are increased in obese patients and contribute to type 2 diabetes, hepatic steatosis and several cardiovascular diseases. In patients with heart failure and acute coronary syndromes, elevated FFA levels are a consequence of an increased lipolysis due to a surge in catecholamines and natriuretic peptides. FFAs contribute to myocardial dysfunction and are proarrhythmic, and their oxidation requires more oxygen than does glycolysis. Therapeutic approaches have already emerged that aim to reduce the uptake and/or oxidation of fatty acids in the myocardium. The routine use of FFAs as a diagnostic tool is limited by their high variability, this being strongly influenced by nutrition and the effects of several hormones. In addition, it remains to be clarified whether fasting or postprandial values or dynamic measurements such as changes in FFA concentrations induced by stress are better parameters for evaluating cardiovascular risk. In this review, we present an overview of the metabolism and role of FFAs as a cardiovascular risk factor and discuss the potential of FFAs in the diagnosis and treatment of cardiovascular diseases. PMID: 18605928 [PubMed - indexed for MEDLINE] 2343. Burns. 2009 Mar;35(2):171-80. doi: 10.1016/j.burns.2008.03.009. Epub 2008 Jul 7. A review of gene and stem cell therapy in cutaneous wound healing. Branski LK(1), Gauglitz GG, Herndon DN, Jeschke MG. Author information: (1)Department of Surgery, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, TX 77550, United States. Different therapies that effect wound repair have been proposed over the last few decades. This article reviews the emerging fields of gene and stem cell therapy in wound healing. Gene therapy, initially developed for treatment of congenital defects, is a new option for enhancing wound repair. In order to accelerate wound closure, genes encoding for growth factors or cytokines showed the greatest potential. The majority of gene delivery systems are based on viral transfection, naked DNA application, high pressure injection, or liposomal vectors. Embryonic and adult stem cells have a prolonged self-renewal capacity with the ability to differentiate into various tissue types. A variety of sources, such as bone marrow, peripheral blood, umbilical cord blood, adipose tissue, skin and hair follicles, have been utilized to isolate stem cells to accelerate the healing response of acute and chronic wounds. Recently, the combination of gene and stem cell therapy has emerged as a promising approach for treatment of chronic and acute wounds. PMCID: PMC3899575 PMID: 18603379 [PubMed - indexed for MEDLINE] 2344. Pathophysiology. 2008 Aug;15(2):91-101. doi: 10.1016/j.pathophys.2008.05.001. Epub 2008 Jul 7. The role of adipokines in liver fibrosis. Bertolani C(1), Marra F. Author information: (1)Dipartimento di Medicina Interna, University of Florence, Viale Morgagni 85, I-50134 Florence, Italy. Liver fibrosis is a dynamic process consisting of the chronic activation of the wound healing reaction in response to reiterated liver damage, leading to the excessive deposition of fibrillar extracellular matrix into the liver and eventually, if the cause of injury is not removed, to liver cirrhosis. The term "adipokines" identifies a group of polypeptide molecules secreted primarily by adipose tissue, which exert local, peripheral and/or central actions. Additionally to their well-established role in controlling adipose tissue physiology, adipokines have been shown to be involved in different obesity-related diseases, such as hypertension, atherosclerosis and type 2 diabetes. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process in different chronic liver diseases. Therefore, numerous recent studies have analyzed the role played by adipokines in the hepatic wound healing process, identifying novel roles as modulators of liver pathophysiology. This review summarizes the more significant and recent findings concerning the role played by adipocyte-derived molecules, such as leptin, adiponectin and resistin, in the liver fibrogenic process. The actions of different adipokines on the biology of liver resident cells, as well as their effects in different animal models of liver injury are discussed. The variations in the circulating levels and in the intrahepatic expression of these molecules occurring in patients with different chronic liver diseases will be also analyzed. PMID: 18602801 [PubMed] 2345. Neurosci Biobehav Rev. 2009 Feb;33(2):116-24. doi: 10.1016/j.neubiorev.2008.05.024. Epub 2008 May 28. Sympathetic nervous system behavior in human obesity. Davy KP(1), Orr JS. Author information: (1)Human Integrative Physiology Laboratory, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. kdavy@vt.edu The sympathetic nervous system (SNS) plays an essential role in the regulation of metabolic and cardiovascular homeostasis. Low SNS activity has been suggested to be a risk factor for weight gain and obesity development. In contrast, SNS activation is characteristic of a number of metabolic and cardiovascular diseases that occur more frequently in obese individuals. Until recently, the relation between obesity and SNS behavior has been controversial because previous approaches for assessing SNS activity in humans have produced inconsistent findings. Beginning in the early 1990s, many studies using state of the art neurochemical and neurophysiological techniques have provided important insight. The purpose of the present review is to provide an overview of our current understanding of the region specific alterations in SNS behavior in human obesity. We will discuss findings from our own laboratory which implicate visceral fat as an important depot linking obesity with skeletal muscle SNS activation. The influence of weight change on SNS behavior and the potential mechanisms and consequences of region specific SNS activation in obesity will also be considered. PMCID: PMC2630381 PMID: 18602694 [PubMed - indexed for MEDLINE] 2346. J Neuroendocrinol. 2008 Jun;20(6):850-7. doi: 10.1111/j.1365-2826.2008.01728.x. The endocannabinoid system and energy metabolism. Bellocchio L(1), Cervino C, Pasquali R, Pagotto U. Author information: (1)Department of Internal Medicine and Gastroenterology, Endocrinology Unit and Center of Applied Biomedical Research, S Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors [cannabinoid receptor type 1 (CB1) and CB2] participate in the physiological modulation of many central and peripheral functions. The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received considerable attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptors and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, and therefore drugs interfering with this overactivation by blocking CB1 receptors are considered as potentially valuable candidates for the treatment of obesity and related cardiometabolic risk factors. PMID: 18601709 [PubMed - indexed for MEDLINE] 2347. J Neuroendocrinol. 2008 Jun;20(6):842-9. doi: 10.1111/j.1365-2826.2008.1730.x. Adipose tissue hormones and the regulation of food intake. Henry BA(1), Clarke IJ. Author information: (1)Department of Physiology, Monash University, Melbourne, Vic, Australia. Over the past decade, adipose tissue has been shown to produce numerous factors that act as hormones. Many of these act on the brain to regulate energy balance via dual effects on food intake and energy expenditure. These include well-characterised hormones such as leptin, oestrogen and glucocorticoids and novel factors such as adiponectin and resistin. This review provides a perspective on the role of these factors as lipostats. PMID: 18601708 [PubMed - indexed for MEDLINE] 2348. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):104-11. doi: 10.1016/j.mce.2008.05.010. Epub 2008 May 27. Neuroendocrine mechanisms in insulin resistance. Sjöstrand M(1), Eriksson JW. Author information: (1)The Lundberg Laboratory for Diabetes Research, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes. PMID: 18599191 [PubMed - indexed for MEDLINE] 2349. Expert Rev Mol Diagn. 2008 May;8(3):289-99. doi: 10.1586/14737159.8.3.289. Retinol-binding protein-4 in experimental and clinical metabolic disease. von Eynatten M(1), Humpert PM. Author information: (1)Department of Nephrology, Technical University of Munich, Munich, Germany. maximilian.eynatten@lrz.tum.de Retinol-binding protein-4 (RBP4), a 21-kDa protein synthesized in the liver and adipose tissue, has recently been described as a murine adipokine involved in the development of insulin resistance. The expression of the gene encoding RBP4 was increased in the adipose tissue, but not in the liver, of insulin-resistant adipose GLUT4(-/-) mice and five other mouse models of obesity and insulin resistance. In addition, intraperitoneal injection or transgenic overexpression of RBP4 in mice induced insulin resistance. While experimental clinical approaches (mostly applying clamp techniques) in humans confirmed correlations of RBP4 with insulin resistance, studies in larger groups out of clinical routine failed to demonstrate a connection with alternative measures of insulin sensitivity. Yet, significant associations of RBP4 with atherogenic lipids were found and a focus of future studies should be the influence on atherosclerosis and related complications. Based on current data, the function of RBP4 as an adipokine exerting metabolic effects in glucose metabolism in humans remains uncertain and might be restricted to rodent models. PMID: 18598108 [PubMed - indexed for MEDLINE] 2350. Methods. 2008 Jun;45(2):115-20. doi: 10.1016/j.ymeth.2008.03.006. Epub 2008 May 29. Adipose-derived stem cells: isolation, expansion and differentiation. Bunnell BA(1), Flaat M, Gagliardi C, Patel B, Ripoll C. Author information: (1)Division of Gene Therapy, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA 70433, USA. bbunnell@tulane.edu The emerging field of regenerative medicine will require a reliable source of stem cells in addition to biomaterial scaffolds and cytokine growth factors. Adipose tissue has proven to serve as an abundant, accessible and rich source of adult stem cells with multipotent properties suitable for tissue engineering and regenerative medical applications. There has been increased interest in adipose-derived stem cells (ASCs) for tissue engineering applications. Here, methods for the isolation, expansion and differentiation of ASCs are presented and described in detail. While this article has focused on the isolation of ASCs from human adipose tissue, the procedure can be applied to adipose tissues from other species with minimal modifications. PMCID: PMC3668445 PMID: 18593609 [PubMed - indexed for MEDLINE] 2351. Clin Calcium. 2008 Jul;18(7):904-11. doi: CliCa0807904911. [Calcium homeostasis and osteoporosis in diabetes mellitus and the metabolic syndrome]. [Article in Japanese] Yamaguchi T(1), Sugimoto T. Author information: (1)Shimane University, Faculty of Medicine, Internal Medicine 1. Hyperglycemia and increase in advanced glycation end products in patients with diabetes are known to cause impaired calcium homeostasis such as reduction in parathyroid hormone secretion, decrease in calcium (Ca) absorption resulting from impaired vitamin D action, increase in urinary Ca excretion, impaired osteoblastic function, and deterioration of bone quality. On the other hand, fat deposition accompanied by the metabolic syndrome are positively linked to increased bone mineral density (BMD) and reduced fracture risk through increased body weight. However, body fat has a detrimental effect on BMD after adjustment for weight, and gives less mechanical stress on bone than muscle tissue that is firmly attached to bone via the tendon. Thus, converting fat into muscle tissue by regular exercise and healthy diet helps not only prevent hyperglycemia but also osteoporosis. PMID: 18591740 [PubMed - indexed for MEDLINE] 2352. Endocr Rev. 2008 Aug;29(5):513-34. doi: 10.1210/er.2008-0003. Epub 2008 Jun 30. Clinical, agricultural, and evolutionary biology of myostatin: a comparative review. Rodgers BD(1), Garikipati DK. Author information: (1)Department of Animal Sciences, 124 ASLB, Washington State University, Pullman, Washington 99164, USA. danrodgers@wsu.edu The discovery of myostatin and our introduction to the "Mighty Mouse" over a decade ago spurred both basic and applied research and impacted popular culture as well. The myostatin-null genotype produces "double muscling" in mice and livestock and was recently described in a child. The field's rapid growth is by no means surprising considering the potential benefits of enhancing muscle growth in clinical and agricultural settings. Indeed, several recent studies suggest that blocking myostatin's inhibitory effects could improve the clinical treatment of several muscle growth disorders, whereas comparative studies suggest that these actions are at least partly conserved. Thus, neutralizing myostatin's effects could also have agricultural significance. Extrapolating between studies that use different vertebrate models, particularly fish and mammals, is somewhat confusing because whole genome duplication events have resulted in the production and retention of up to four unique myostatin genes in some fish species. Such comparisons, however, suggest that myostatin's actions may not be limited to skeletal muscle per se, but may additionally influence other tissues including cardiac muscle, adipocytes, and the brain. Thus, therapeutic intervention in the clinic or on the farm must consider the potential of alternative side effects that could impact these or other tissues. In addition, the presence of multiple and actively diversifying myostatin genes in most fish species provides a unique opportunity to study adaptive molecular evolution. It may also provide insight into myostatin's nonmuscle actions as results from these and other comparative studies gain visibility in biomedical fields. PMCID: PMC2528853 PMID: 18591260 [PubMed - indexed for MEDLINE] 2353. Ned Tijdschr Geneeskd. 2008 May 31;152(22):1260-4. [Metabolic side effects of antiretroviral therapy]. [Article in Dutch] van der Valk M(1), Reiss P. Author information: (1)Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Inwendige Geneeskunde, onderafd. Infectieziekten, Tropische Geneeskunde en AIDS, Center for Infection and Immunity Amsterdam (CINIMA), Meibergdreef 9, 1105 AZ Amsterdam. m.vandervalk@amc.uva.nl Antiretroviral therapy for HIV-I-infections is accompanied with the occurrence of several metabolic side effects. An often encountered complication of antiretroviral therapy is the adipose redistribution syndrome characterised by an altered distribution of body fat, and linked with protease inhibitor (PI) and nucleoside-reverse-transcriptase inhibitors (NRTIs). Some NRTIs have lactate acidosis as a side effect in rare cases (0.1%), which is accompanied by a high mortality. The far less serious side effect hyperlactaemia is more frequently observed; this is a symptomatic elevation of the lactate level without acidosis. Insulin resistance is not only ascribed to therapy-induced lipoatrophy and visceral fat accumulation, it is also directly related to the use of some PIs and NRTIs. PIs and abacavir and to a lesser extend didanosine result in a high risk of cardiovascular disease. Moreover, the prevalence of traditional cardiovascular risk factors in HIV-infected subjects is higher than that in HIV-seronegative subjects. Clinically relevant interactions exist between PIs and statins. Pravastatin seems to be accompanied with the lowest chance of interaction and is therefore recommended as cholesterol-lowering therapy. The metabolic side effects are outweighed by the favourable effect of the antiretroviral agents. Counteraction of these side effects may therefore not be at the expense of the antiretroviral therapy. PMID: 18590059 [PubMed - indexed for MEDLINE] 2354. Am J Cardiol. 2008 Jun 2;101(11A):16E-21E. doi: 10.1016/j.amjcard.2008.02.075. Intracellular mechanisms of metabolism regulation: the role of signaling via the mammalian target of rapamycin pathway and other routes. Flati V(1), Pasini E, D'Antona G, Speca S, Toniato E, Martinotti S. Author information: (1)Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. vincenzo.flati@univaq.it The development of diabetes mellitus is the consequence of defects in the action of insulin in skeletal muscles and adipose tissue other than pancreas and liver defects. Insulin action defects are mostly the results of defects of the insulin intracellular signaling transduction pathway. This review summarizes the main mechanisms involved in insulin signaling and possible intracellular defects that lead to insulin resistance. We also report preliminary experimental data that suggest the existence of intracellular alternatives to insulin metabolic pathways stimulated by nutrients such as amino acids (AAs). Indeed, we found that oral supplements with AAs stimulated both glucose transporter-4 and protein synthesis through independent insulin signals in rat hearts. Evidence suggests that the mammalian target of rapamycin and/or other molecules could be involved in this insulin-independent metabolic pathway. This hypothesis suggests the presence of an ancestral metabolic pathway in eukaryotic cells that is not active when insulin intracellular signaling is efficient but can be activated by alternative stimuli, such as AAs, when insulin signaling is impaired. Our observations provide molecular evidence that supports the use of anabolic nutrients such as AAs, together with standard therapies, to overcome insulin resistance syndrome. PMID: 18514621 [PubMed - indexed for MEDLINE] 2355. Thorax. 2008 Jul;63(7):649-54. doi: 10.1136/thx.2007.086801. Obesity and the lung: 1. Epidemiology. McClean KM(1), Kee F, Young IS, Elborn JS. Author information: (1)Queen's University of Belfast, Belfast, UK. Comment in Thorax. 2008 Jul;63(7):576-7. Obesity is the most common metabolic disease in the world and its prevalence has been increasing over several decades. The World Health Organization (WHO) predicts that, by 2015, around 700 million adults will be obese (at least 10% of the projected global population). This will be a huge health and economic burden with associated increases in diabetes, cardiovascular and musculoskeletal disease, and malignancy. While there has been little focus on the impact of obesity on respiratory disease, there are clear effects on pulmonary function and inflammation which will increase the prevalence and morbidity of lung disease. There is an inverse relationship between body mass index and forced expiratory volume in 1 s. Increases in body weight lead to worsening of pulmonary function. The reasons for this include the mechanical effects of truncal obesity and the metabolic effects of adipose tissue. Obesity is linked to a wide range of respiratory conditions including chronic obstructive pulmonary disease, asthma, obstructive sleep apnoea, pulmonary embolic disease and aspiration pneumonia. It is important for those providing care for people with respiratory disease to appreciate the impact of obesity and to provide appropriate advice for weight reduction. Healthcare planners should consider the impact of obesity for future resources in respiratory care. PMID: 18587034 [PubMed - indexed for MEDLINE] 2356. PPAR Res. 2008;2008:102737. doi: 10.1155/2008/102737. The Role of PPARs in Cancer. Tachibana K(1), Yamasaki D, Ishimoto K, Doi T. Author information: (1)Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARalpha is mainly expressed in the liver, where it activates fatty acid catabolism. PPARalpha activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARdelta is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARdelta activators have been proposed for the treatment of metabolic disease. PPARgamma2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARgamma is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth. PMCID: PMC2435221 PMID: 18584037 [PubMed] 2357. J Leukoc Biol. 2008 Oct;84(4):882-92. doi: 10.1189/jlb.0108028. Epub 2008 Jun 25. Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span. Dixit VD(1). Author information: (1)Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. Vishwa.dixit@pbrc.edu Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan. PMCID: PMC2638733 PMID: 18579754 [PubMed - indexed for MEDLINE] 2358. Exp Gerontol. 2009 Jan-Feb;44(1-2):20-5. doi: 10.1016/j.exger.2008.05.005. Epub 2008 May 20. Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Carrascosa JM(1), Ros M, Andrés A, Fernández-Agulló T, Arribas C. Author information: (1)Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Nicolás Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain. jmcarrascosa@cbm.uam.es Energy balance in mammals is modulated by peripheral signals that inform the brain about the magnitude of fat stores, the amount of food in the gastrointestinal tract, and the level of nutrients such as glucose in the circulation. Among these, insulin and leptin are considered adiposity signals involved in the long-term maintenance of fat stores. Here we review the mechanisms of action of leptin and insulin in the hypothalamus and how these mechanisms are altered during aging in rat models. Aged rats are characterized by increased fat mass, central leptin and insulin resistance, and hyperleptinemia. Leptin resistance is manifested by its failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose tissue, and increase energy expenditure. Moreover, leptin and insulin signaling are decreased in hypothalamus from aged rats. Calorie restriction and fasting studies provide controversial data on the cause-effect interrelationship between increased adiposity and development of central leptin resistance. Although in the absence of obesity leptin resistance seems to be a characteristic of aged animals, adiposity could either reinforce it or cause an early onset of this resistance. More studies are necessary to clarify the role of the hypothalamus in the development of age-associated obesity and insulin resistance. PMID: 18572339 [PubMed - indexed for MEDLINE] 2359. J Genet Genomics. 2008 Jun;35(6):321-6. doi: 10.1016/S1673-8527(08)60047-8. Adiponectin and its association with insulin resistance and type 2 diabetes. Sheng T(1), Yang K. Author information: (1)School of Basic Medicine, Yanbian University, Yanji, China. Adiponectin is an adipokine, which is expressed in adipose tissue and is thought to play an important role in glucose metabolism. Hypoadiponectinemia can cause reduction of fatty acid oxidation, decreased glucose uptake in skeletal muscle cells, and increased gluconeogenesis in hepatic cells. The level of plasma glucose can be increased. On the other hand, the decrease of fatty acid oxidation increases the level of free fatty acid (FFA), which increases the insulin resistance, and then decreases the glucose uptake, which ultimately causes increased plasma glucose and type 2 diabetes (T2D). This review describes the process from hypoadiponectinemia to T2D and the genesis of hypoadiponectinemia at a molecular level. PMID: 18571119 [PubMed - indexed for MEDLINE] 2360. Aging Male. 2008 Jun;11(2):51-5. doi: 10.1080/13685530801954026. Lower urinary tract symptoms and its potential relation with late-onset hypogonadism. Pradidarcheep W(1). Author information: (1)Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Sukhumvit, Bangkok, Thailand. pthongp@gmail.com The study of the health status of the aging male takes presently a more integrative approach and it appears that ailments typical of male aging, such as lower urinary tract symptoms (LUTS), (visceral) obesity, metabolic syndrome and erectile failure are significantly interrelated. A common denominator of the above ailments is lower-than-normal testosterone levels occurring in a significant proportion of elderly men. This review addresses the potential connections between LUTS and late-onset hypogonadism. In animal studies there appear to be androgen and estrogen receptors in the urothelium and smooth muscle cells of the urethra and bladder of the rat and rabbit, as well as in the neurons in the autonomic ganglia of the prostatic plexus of the male rat. Upon castration electrically evoked relaxations of the smooth muscle of the prostatic urethra were decreased. There is a Rho-kinase activation/endothelin pathway; possibly involved in the increased smooth muscle activity found in both LUTS/benign prostate hyperplasia. Nitric oxide (NO) appears to have a smooth muscle relaxing effect in the urogenital organs. Studies in humans have convincingly shown that phosphodiestererase inhibitors have a beneficial effect on LUTS. More intervention studies should be undertaken to test the clinical validity of the theoretically plausible interrelationship between LUTS and late-onset hypogonadism. PMID: 18570055 [PubMed - indexed for MEDLINE] 2361. J Cosmet Laser Ther. 2008 Jun;10(2):114-8. doi: 10.1080/14764170802074680. Phospholipids do not have lipolytic activity. A critical review. Motolese P(1). Author information: (1)Center of Cosmetology, University of Ferrara, Ferrara, Italy. motolese@esteticamed.com This article re-examines and refutes the theories of intra-adipocyte lipolysis activated by phosphatidylcholine and by phospholipids in general, when injected into adipose tissue to reduce localized adiposity. These theories have not been confirmed and at times they conflict with current, although incomplete, knowledge relative to adipocyte metabolism. In particular, those regarding adipose tissues with little-known biochemical characteristics such as the primary localized adiposities. The use of the term 'lipolysis' is considered inappropriate; instead, these types of treatments should be indicated by the term 'adipocytolysis', given the demonstrated lytic activity of sodium deoxycholate on cell membranes, whose action, if not unique, is certainly prominent. PMID: 18569265 [PubMed - indexed for MEDLINE] 2362. Climacteric. 2008 Jun;11(3):258-64. doi: 10.1080/13697130802162608. Potential role of progestogens in the control of adipose tissue and salt sensitivity via interaction with the mineralocorticoid receptor. Caprio M(1), Zennaro MC, Fève B, Mammi C, Fabbri A, Rosano G. Author information: (1)IRCCS San Raffaele Pisana, Rome, Italy. Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects. Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders. PMID: 18568791 [PubMed - indexed for MEDLINE] 2363. J Gastrointestin Liver Dis. 2008 Jun;17(2):193-8. Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. Garruti G(1), Cotecchia S, Giampetruzzi F, Giorgino F, Giorgino R. Author information: (1)Unit of Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantations, University of Bari Medical School, Piazza G. Cesare 11, Bari, Italy. g.garruti@endo.uniba.it Erratum in J Gastrointestin Liver Dis. 2008 Sep;17(3):368. Obesity is an excess of fat mass. Fat mass is an energy depot but also an endocrine organ. A deregulation of the sympathetic nervous system (SNS) might produce obesity. Stress exaggerates diet-induced obesity. After stress, SNS fibers release neuropeptide Y (NPY) which directly increases visceral fat mass producing a metabolic syndrome (MbS)-like phenotype. Adrenergic receptors are the main regulators of lipolysis. In severe obesity, we demonstrated that the adrenergic receptor subtypes are differentially expressed in different fat depots. Liver and visceral fat share a common sympathetic pathway, which might explain the low-grade inflammation which simultaneously occurs in liver and fat of the obese with MbS. The neuroendocrine melanocortinergic system and gastric ghrelin are also greatly deregulated in obesity. A specific mutation in the type 4 melanocortin receptor induces early obesity onset, hyperphagia and insulin-resistance. Nonetheless, it was recently discovered that a mutation in the prohormone convertase 1/3 simultaneously produces severe gastrointestinal dysfunctions and obesity. PMID: 18568142 [PubMed - indexed for MEDLINE] 2364. J Gastroenterol Hepatol. 2008 Jun;23(6):829-32. doi: 10.1111/j.1440-1746.2008.05474.x. VAT fat is bad for the liver, SAT fat is not! Fan JG, Farrell GC. Comment on J Gastroenterol Hepatol. 2008 Jun;23(6):900-7. J Gastroenterol Hepatol. 2008 Jun;23(6):914-21. J Gastroenterol Hepatol. 2008 Jun;23(6):894-9. J Gastroenterol Hepatol. 2008 Jun;23(6):888-93. PMID: 18565017 [PubMed - indexed for MEDLINE] 2365. Obes Surg. 2008 Sep;18(9):1134-43. doi: 10.1007/s11695-008-9548-1. Epub 2008 Jun 19. The bone-adipose axis in obesity and weight loss. Gómez-Ambrosi J(1), Rodríguez A, Catalán V, Frühbeck G. Author information: (1)Metabolic Research Laboratory, Clínica Universitaria de Navarra, University of Navarra, Avenida Pio XII 36, Pamplona, Spain. Body fat and lean mass are correlated with bone mineral density, with obesity apparently exerting protection against osteoporosis. The pathophysiological relevance of adipose tissue in bone integrity resides in the participation of adipokines in bone remodeling through effects on deposition and resorption. On the other hand, the skeleton has recently emerged as an endocrine organ with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin. The cross-talk between adipose tissue and the skeleton constitutes a homeostatic feedback system with adipokines and molecules secreted by osteoblasts and osteoclasts representing the links of an active bone-adipose axis. Given the impact of bariatric surgery on absorption and the adipokine secretory pattern, to focus on the changes taking place following surgical-induced weight loss on this dynamic system merits detailed consideration. PMID: 18563500 [PubMed - indexed for MEDLINE] 2366. Diabetologia. 2008 Aug;51(8):1356-67. doi: 10.1007/s00125-008-1048-2. Epub 2008 Jun 18. The endocannabinoid system in obesity and type 2 diabetes. Di Marzo V(1). Author information: (1)Endocannabinoid Research Group at the Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078, Pozzuoli (NA), Italy. vdimarzo@icmib.na.cnr.it Endocannabinoids (ECs) are defined as endogenous agonists of cannabinoid receptors type 1 and 2 (CB1 and CB2). ECs, EC anabolic and catabolic enzymes and cannabinoid receptors constitute the EC signalling system. This system participates in the control of lipid and glucose metabolism at several levels, with the possible endpoint of the accumulation of energy as fat. Following unbalanced energy intake, however, the EC system becomes dysregulated, and in most cases overactive, in several organs participating in energy homeostasis, particularly, in intra-abdominal adipose tissue. This dysregulation might contribute to excessive visceral fat accumulation and reduced adiponectin release from this tissue, and to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes. This phenomenon might form the basis of the mechanism of action of CB1 antagonists/inverse agonists, recently developed by several pharmaceutical companies as adjuvants to lifestyle modification for weight reduction, glycaemic control and dyslipidaemia in obese and type 2 diabetes patients. It also helps to explain why some of the beneficial actions of these new therapeutics appear to be partly independent from weight loss. PMID: 18563385 [PubMed - indexed for MEDLINE] 2367. Diabetes Metab. 2008 Nov;34(5):439-45. doi: 10.1016/j.diabet.2008.04.002. Epub 2008 Jun 17. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism. Girard J(1), Lafontan M. Author information: (1)Institut Cochin, Inserm U567, CNRS (UMR 8104), université Paris-Descartes, 22, rue Méchain, 75014 Paris, France. girard@cochin.inserm.fr Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver. PMID: 18562233 [PubMed - indexed for MEDLINE] 2368. Nutr Hosp. 2008 May-Jun;23(3):191-202. [Usefulness and controversial issues of middle-chain fatty acids consumption on lipid-protein metabolism and obesity]. [Article in Spanish] Sáyago-Ayerdi SG(1), Vaquero MP, Schultz-Moreira A, Bastida S, Sánchez-Muniz FJ. Author information: (1)Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid, España. Middle-chain fatty acids (MCFA) contain 6-12 carbon atoms and are digested, absorbed and metabolized differently than long-chain fatty acids (LCFA). This work reviews some of the potential and real utilities of MCFA and their role on health. For this reason, they are used in enteral and parenteral nutrition because of their good absorption, and in premature-feeding milk-based formulas in order to improve calcium absorption. MCFA have become particularly important because of their possible role in treating and preventing obesity. Since they are more water soluble, they are taken-up by chylomicrons, and it is believed that they do not directly participate in lipogenesis. They are able to increase the thermogenic effect of foods, and its metabolism increases the production of ketonic agents with the subsequent anorexigenic effect. However, high doses of MCFA are required to obtain significant effects on weight reduction. The effects on lipid-protein metabolism are controversial. So, although they seem to reduce the post-prandial triglyceridemic response, the results their effects are not uniform regarding triglyceridemia and cholesterolemia. In spite of this, more and more products are being designed incorporating MCFA to treat obesity and overweight, having been considered as "GRAS" (Generally Recommended as Safe") components by the ADA. Further long-term studies are needed to warrant the usefulness of consumption of these compounds, particularly in the treatment and prevention of obesity. PMID: 18560695 [PubMed - indexed for MEDLINE] 2369. Transplant Proc. 2008 May;40(4):1135-9. doi: 10.1016/j.transproceed.2008.03.113. Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Trivedi HL(1), Vanikar AV, Thakker U, Firoze A, Dave SD, Patel CN, Patel JV, Bhargava AB, Shankar V. Author information: (1)Department of Nephrology and Transplantation Medicine, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Ahmedabad, Anand, India. ikdrcadl@sancharnet.in BACKGROUND: Type 1 diabetes mellitus (DM) is an autoimmune disorder with disturbed glucose/insulin metabolism, which has no medical treatment other than life-long insulin therapy, despite which 30% of subjects develop organ failure. Herein we have reported the use of human adipose-tissue-derived, insulin-making mesenchymal stem cells (h-AD-MSC) transfused with unfractionated cultured bone marrow (CBM) in 5 insulinopenic DM patients. PATIENTS AND METHODS: Five (M:F, 2:3) insulinopenic DM patients of 0.6 to 10 years' duration, ages 14 to 28 years under treatment insulin (Human with 14-70 U/d) showed postprandial blood sugars between 156 to 470 mg%, glycosylated hemoglobin 6.8% to 9.9% and c-peptide levels of 0.02 to 0.2 ng/mL. They underwent intraportal administration of xenogeneic-free h-AD-MSC (mean dose = 1.5 mL; cell counts, 2.1 x 10(3)/muL). The CD45-/90+/73(+) cells (29.8/16.8%) showed c-peptide levels of 3.08 ng/mL, insulin level of 1578 micro IU/mL. The aliquot was supplemented with CBM (mean dose 94 mL with cell counts: 18.7 x 10(3)/microL) containing CD45-/34+ elements of 0.93%. The Institutional Review Board approved the study protocol and consent forms. RESULTS: All patients were successfully infused CBM plus h-AD-MSC without any untoward effects and showed 30% to 50% decreased insulin requirements with 4- to 26-fold increased serum c-peptide levels, with a mean follow-up of 2.9 months. CONCLUSION: This report describes safe and effective treatment of insulinopenic diabetics using insulin-producing h-AD-MSC plus CBM without xenogeneic materials. PMID: 18555133 [PubMed - indexed for MEDLINE] 2370. QJM. 2008 Oct;101(10):767-76. doi: 10.1093/qjmed/hcn066. Epub 2008 Jun 10. Adipokines--targeting a root cause of cardiometabolic risk. Bakhai A(1). Author information: (1)Thames House, Barnet General Hospital, Barnet & Chase Farm NHS Trust, Wellhouse Lane, Barnet EN5 3DJ, England, UK. Ameet.Bakhai@bcf.nhs.uk Obesity often co-presents with other cardiometabolic risk factors such as dyslipidaemia, insulin resistance and hypertension. Less well appreciated is that dysregulation of adipokine production by excess adipose tissue also promotes a state of low-level systemic chronic inflammation and a prothrombotic state, implicated in the development of both atherosclerosis and subsequently cardiovascular events. Lifestyle modification and pharmacological therapy can reduce cardiometabolic risk, a benefit that may be partly due to their effects on adipokine levels. PMID: 18550581 [PubMed - indexed for MEDLINE] 2371. Diabetes Metab. 2008 Sep;34(4 Pt 1):317-27. doi: 10.1016/j.diabet.2008.04.001. Epub 2008 Jun 11. Impact of visceral adipose tissue on liver metabolism. Part I: heterogeneity of adipose tissue and functional properties of visceral adipose tissue. Lafontan M(1), Girard J. Author information: (1)Inserm-U858, institut de médecine moléculaire Rangueil, IFR31-institut Louis-Bugnard, 1, avenue Jean-Poulhès, B.P. 84225, 31432 Toulouse cedex 4, France. max.lafontan@toulouse.inserm.fr Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low high-density lipoprotein cholesterol that contribute to the later appearance of type 2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver, and interact with hepatocytes and various immune cells in the liver. The functional characteristics of visceral adipose tissue will be compared with subcutaneous adipose tissue to clarify the major mechanisms affecting free fatty acid metabolism and cytokine production. PMID: 18550411 [PubMed - indexed for MEDLINE] 2372. Expert Opin Biol Ther. 2008 Jul;8(7):885-93. doi: 10.1517/14712598.8.7.885 . Mesenchymal cells for skeletal tissue engineering. Slater BJ(1), Kwan MD, Gupta DM, Panetta NJ, Longaker MT. Author information: (1)Stanford University School of Medicine, Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, 257 Campus Drive, Stanford, CA 94305-5148, USA. BACKGROUND: Skeletal defects represent a significant socioeconomic burden to the US healthcare system. Current options for reconstructing osseous deficits have shortcomings. OBJECTIVE: To review the use of mesenchymal stem cells for skeletal tissue engineering. METHODS: We focused on the application of mesenchymal cells in skeletal regeneration, optimization of this technique, tropic effects of multipotent mesenchymal cells, and future directions. RESULTS/CONCLUSION: A number of cell-based modalities have been investigated. We have been interested in the role of adipose-derived stromal cells in bone regeneration and understanding the mechanisms behind osteogenic differentiation of progenitor cells and acceleration of this process. Future clinical applications of multipotent mesenchymal cells will depend on better understanding of the molecular signaling involved in osteogenic differentiation and maintaining pluripotency. PMID: 18549320 [PubMed - indexed for MEDLINE] 2373. Am J Cardiol. 2008 Apr 17;101(8A):20B-26B. doi: 10.1016/j.amjcard.2008.02.029. Mechanism of action of niacin. Kamanna VS(1), Kashyap ML. Author information: (1)Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California 90822, USA. Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin. PMID: 18375237 [PubMed - indexed for MEDLINE] 2374. Int Rev Cell Mol Biol. 2008;266:157-206. doi: 10.1016/S1937-6448(07)66004-3. Role of nuclear lamins in nuclear organization, cellular signaling, and inherited diseases. Parnaik VK(1). Author information: (1)Center for Cellular and Molecular Biology, Hyderabad, India. Lamins are the major architectural proteins of the nucleus and are essential for nuclear integrity and assembly. Lamins are also involved in the organization of nuclear functions such as DNA replication, transcription, and repair. Mutations in the human lamin genes lead to highly debilitating genetic diseases that affect a number of different tissues such as muscle, adipose, and neuronal tissues, or cause premature aging syndromes. The observed interactions of lamins with inner nuclear membrane proteins, chromatin, and various regulatory factors have given important insights into the role of lamins in cellular processes and tissue-specific signaling pathways. PMID: 18544494 [PubMed - indexed for MEDLINE] 2375. Tissue Eng Part B Rev. 2008 Jun;14(2):167-78. doi: 10.1089/ten.teb.2007.0402. Animal models for adipose tissue engineering. Patrick CW(1), Uthamanthil R, Beahm E, Frye C. Author information: (1)Department of Biomedical Engineering, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA. cpatrick@mdanderson.org There is a critical need for adequate reconstruction of soft tissue defects resulting from tumor resection, trauma, and congenital abnormalities. To be sure, adipose tissue engineering strategies offer promising solutions. However, before clinical translation can occur, efficacy must be proven in animal studies. The aim of this review is to provide an overview of animal models currently employed for adipose tissue engineering. PMCID: PMC2962856 PMID: 18544014 [PubMed - indexed for MEDLINE] 2376. Postepy Hig Med Dosw (Online). 2008 May 27;62:249-57. [Obesity as inflammatory disease]. [Article in Polish] Olszanecka-Glinianowicz M(1), Zahorska-Markiewicz B. Author information: (1)Katedra Patofi zjologii Slaskiego Uniwersytetu Medycznego w Katowicach. magols@esculap.pl Studies of the role of immune system activation in the pathogenesis of obesity and its concomitant diseases have been conducted for some years. Numerous recent studies revealed an association between increased immune activation in obesity and the development of insulin resistance. On the other hand there is the hypothesis that immune activation in obesity is a homeostatic mechanism to protect the organism from reaching the point at which the over-accumulation of fat decreases the possibility to move. The aim of the present study was to review the current literature on immune activation in obesity and the participation of adipokines produced by adipose tissue in the development of insulin resistance. Attention is drawn to the similarities in function and gene expression of adipocytes and macrophages. PMID: 18542045 [PubMed - indexed for MEDLINE] 2377. Curr Opin Clin Nutr Metab Care. 2008 Jul;11(4):505-11. doi: 10.1097/MCO.0b013e3282fcea11. Inhibitors of cannabinoid receptors and glucose metabolism. Scheen AJ(1), Paquot N. Author information: (1)Division of Diabetes, Nutrition and Metabolic Disorders, CHU Sart Tilman, University of Liège, Liège, Belgium. andre.scheen@chu.ulg.ac.be PURPOSE OF REVIEW: Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes. RECENT FINDINGS: Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, the gut, the liver, the skeletal muscle and even the pancreas, all organs playing a key role in glucose metabolism and type 2 diabetes. Rimonabant, the first selective cannabinoid 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, glycated haemoglobin, triglycerides, insulin resistance index, and to increase HDL cholesterol and adiponectin concentrations in patients with type 2 diabetes, confirming data on nondiabetic overweight/obese patients. Almost half of the metabolic changes, including glycated haemoglobin reduction, could not be explained by weight loss, in agreement with direct peripheral effects. SUMMARY: Cannabinoid 1 blockade reduces food intake and body weight and improves metabolic regulation beyond just weight loss. Because of its positive effect on glucose metabolism, rimonabant deserves consideration in the treatment of overweight/obese patients with type 2 diabetes. PMID: 18542014 [PubMed - indexed for MEDLINE] 2378. Best Pract Res Clin Endocrinol Metab. 2008 Jun;22(3):503-15. doi: 10.1016/j.beem.2008.01.015. Pathophysiology of insulin resistance in subjects born small for gestational age. Beltrand J(1), Lévy-Marchal C. Author information: (1)INSERM, U690, Paris, FR-75019, France; Université Paris 7, Paris, FR-75205 cedex 13, France. jacques.beltrand@inserm.fr Over the last 15 years, a number of long-term health risks associated with reduced fetal growth have been identified, including cardiovascular diseases, hypertension, dyslipidaemia and type 2 diabetes. A common feature of these conditions is insulin resistance, which is thought to play a pathogenic role. However, despite abundant data in the literature, it is still difficult to trace the pathway by which fetal events, environmental or not, may lead to increased morbidity later in life. To explain this association, several hypotheses have been proposed pointing to the role of a detrimental fetal environment, a genetic susceptibility or an interaction between the two, and of the particular dynamic changes in adiposity that occur during catch-up growth. The relative impact of early postnatal events in relation to fetal growth has to be considered for designing health policy strategies for early interventions aimed at decreasing disease risk throughout life. PMID: 18538289 [PubMed - indexed for MEDLINE] 2379. Best Pract Res Clin Endocrinol Metab. 2008 Jun;22(3):489-502. doi: 10.1016/j.beem.2008.02.002. Early childhood predictors of adult body composition. Druet C(1), Ong KK. Author information: (1)MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Cambridge CB2 0QQ, UK. cd403@medschl.ca.ac.uk Intra-uterine life has been identified as a possible critical period for the development of obesity risk in both adults and children; others have highlighted the importance of growth and nutrition in the first few years. It is suggested that fetal growth, as assessed by birth weight, may programme lean body mass later in life. Children who are born small for gestational age also have a predisposition to accumulating fat mass, particularly intra-abdominal fat. It is not yet clear whether this predisposition is due to their prenatal growth restraint, their rapid postnatal catch-up growth or a combination of both. Recently, genetic and heritable factors have been shown to contribute to both rapid postnatal growth and childhood obesity risk in children and adults. Future studies should explore their timing of action and potential interactions with markers of antenatal growth restraint. PMID: 18538288 [PubMed - indexed for MEDLINE] 2380. Diab Vasc Dis Res. 2008 Jun;5(2):76-81. doi: 10.3132/dvdr.2008.013. Mammalian hibernation: a naturally reversible model for insulin resistance in man? Martin SL(1). Author information: (1)University of Colorado School of Medicine, Department of Cell and Developmental Biology and Program in Molecular Biology, 12801 E. 17th Ave. Aurora, CO 80045, USA. sandy.martin@uchsc.edu Mammalian hibernators such as ground squirrels store massive amounts of fat each autumn. These fat depots serve as the main source of metabolic fuel throughout the winter, gradually decreasing over a period of months until the animals emerge from hibernation each spring. Fat deposition occurs on an approximately annual, i.e. on a circannual, basis. Although this rhythm occurs in the absence of environmental temperature and light cues, it is entrained by the length of daylight, with peak fat deposition occurring as days shorten in the autumn. Here we examine the circ-annual cycle of hibernation, and then explore the similarities and differences between the obligatory, yet reversible, natural obesity and accompanying insulin resistance of natural hibernation, and the pandemic of human obesity and metabolic syndrome. PMID: 18537093 [PubMed - indexed for MEDLINE] 2381. J Biomed Sci. 2008 Sep;15(5):565-76. doi: 10.1007/s11373-008-9261-z. Epub 2008 Jun 6. Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond. Lu JY(1), Huang KC, Chang LC, Huang YS, Chi YC, Su TC, Chen CL, Yang WS. Author information: (1)Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan, ROC. Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders. PMID: 18535923 [PubMed - indexed for MEDLINE] 2382. Cell Metab. 2008 Jun;7(6):467-9. doi: 10.1016/j.cmet.2008.05.002. PPARdelta/beta: the lobbyist switching macrophage allegiance in favor of metabolism. Desvergne B(1). Author information: (1)Center of Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland. beatrice.desvergne@unil.ch Comment on Cell Metab. 2008 Jun;7(6):485-95. Macrophages, which belong to the immune system, are increasingly being recognized for their contribution to metabolic regulation. In two studies by Kang et al. (2008) and Odegaard et al. (2008) in this issue of Cell Metabolism, we learn that alternative activation (M2a) of resident macrophages in liver and adipose tissue depends highly on PPARdelta/beta activity, leading to improved fatty acid metabolism and insulin sensitivity. PMID: 18522825 [PubMed - indexed for MEDLINE] 2383. Nutr Rev. 2008 Jun;66(6):333-42. doi: 10.1111/j.1753-4887.2008.00041.x. Do calorie restriction or alternate-day fasting regimens modulate adipose tissue physiology in a way that reduces chronic disease risk? Varady KA(1), Hellerstein MK. Author information: (1)Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, California 94720-3104, USA. kvarady@nature.berkeley.edu Adipose tissue physiology plays an important role in the development of several obesity-related disorders. Dietary restriction regimens, i.e., daily calorie restriction (CR) or alternate-day fasting (ADF), have been shown to decrease the risk of these disorders. Whether changes in adipose mass or physiology are required for the beneficial effects of CR or ADF is an important question. Accordingly, this review summarizes the effects of CR and ADF regimens on parameters of adipose physiology, i.e., adipose tissue morphology, triglyceride metabolism, and adipokine release, and attempts to link these changes to indicators of chronic disease risk. PMID: 18522622 [PubMed - indexed for MEDLINE] 2384. Ann N Y Acad Sci. 2008;1131:206-14. doi: 10.1196/annals.1413.018. Lymphatic involvement in lymphangioleiomyomatosis. Glasgow CG(1), Taveira-Dasilva AM, Darling TN, Moss J. Author information: (1)Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg. 10, Rm. 6D03 MSC 1590, Bethesda, MD 20892-1590, USA. Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease affecting primarily premenopausal women. The disease is characterized by cystic lung disease, at times leading to respiratory compromise, abdominal tumors (in particular, renal angiomyolipomas), and involvement of the axial lymphatics (e.g., adenopathy, lymphangioleiomyomas). Disease results from the proliferation of neoplastic cells (LAM cells), which, in many cases, have a smooth muscle cell phenotype, express melanoma antigens, and have mutations in one of the tuberous sclerosis complex genes (TSC1 or TSC2). In the lung, LAM cells found in the vicinity of cysts are, at times, localized in nodules and may be responsible for cyst formation through the production of proteases. Lymphatic channels, expressing characteristic lymphatic endothelial cell markers, are found within the LAM lung nodules. LAM cells may also be localized within the walls of the axial lymphatics, and, in some cases, penetrate the wall and proliferate in the surrounding adipose tissue. Consistent with extensive lymphatic involvement in LAM, the serum concentration of VEGF-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers. PMCID: PMC3392168 PMID: 18519973 [PubMed - indexed for MEDLINE] 2385. Ann N Y Acad Sci. 2008;1131:155-84. doi: 10.1196/annals.1413.015. The clinical spectrum of lymphatic disease. Radhakrishnan K(1), Rockson SG. Author information: (1)Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94306, USA. Lymphatic disease is quite prevalent, and often not well clinically characterized. Beyond lymphedema, there is a broad array of human disease that directly or indirectly alters lymphatic structure and function. The symptomatic and objective presentation of these patients can be quite diverse. In this review, we have attempted to provide a systematic overview of the subjective and objective spectrum of lymphatic disease, with consideration of all of the categories of disease that primarily or secondarily impair the functional integrity of the lymphatic system. Lymphedema is discussed, along with chromosomal disorders, lymphangioma, infectious diseases, lymphangioleiomyomatosis, lipedema, heritable genetic disorders, complex vascular malformations, protein-losing enteropathy, and intestinal lymphangiectasia. PMID: 18519969 [PubMed - indexed for MEDLINE] 2386. Ann N Y Acad Sci. 2008;1131:82-8. doi: 10.1196/annals.1413.007. The link between lymphatic function and adipose biology. Harvey NL(1). Author information: (1)Florey Research Fellow, Division of Haematology, The Hanson Institute, IMVS, Rundle Mall, Adelaide, South Australia, 5000, Australia. natasha.harvey@imvs.sa.gov.au Despite observations of a link between lymphatic vessels and lipids that date as far back as 300, a link between lymphatic vessels and adipose tissue has only recently been recognized. This review will summarize documented evidence that supports a close relationship between lymphatic vessels and adipose tissue biology. Lymphatic vessels mediate lipid absorption and transport, share an intimate spatial association with adipose tissue, and regulate the traffic of immune cells that rely on specialized adipose tissue depots as a reservior of energy deployed to fight infection. Important links between inflammation and adipose tissue biology will also be discussed in this article, as will recent evidence connecting lymphatic vascular dysfunction with the onset of obesity. There seems little doubt that future research in this topical field will ensure that the link between lymphatic vascular function and adipose tissue is firmly established. PMID: 18519961 [PubMed - indexed for MEDLINE] 2387. Methods Mol Biol. 2008;456:1-22. doi: 10.1007/978-1-59745-245-8_1. Overview of adipose tissue and its role in obesity and metabolic disorders. Frühbeck G(1). Author information: (1)Department of Endocrinology and Metabolic Research Laboratory, Clínica Universitaria, University of Navarra, Pamplona, Spain. As the result of its apparent structural and histological simplicity, adipose tissue (AT) functions initially were limited to energy storage, insulation, and thermoregulation. Only decades later was the extraordinarily dynamic role of AT recognized, revealing its participation in a broad range of physiological processes, including reproduction, apoptosis, inflammation, angiogenesis, blood pressure, atherogenesis, coagulation, fibrinolysis, immunity and vascular homeostasis with either direct or indirect implications in the regulation of proliferation. The functional pleiotropism of AT relies on its ability to synthesize and, in some cases,secrete a large number of enzymes, hormones, growth factors, cytokines, complement factors, and matrix and membrane proteins, collectively termed adipokines. At the same time, white AT expresses receptors for most of these factors, warranting a wide cross-talk at both local and systemic levels in response to metabolic changes or other external stimuli. In this chapter, mounting evidence on the specific characteristics of AT from different depots is outlined in relation to fat distribution and comorbidity development. The current knowledge in this field is reviewed with a broad perspective ranging from classification, structure, and distribution to the key functional roles of AT with a particular focus on the role of adipokines and their involvement in the metabolic disorders accompanying obesity. PMID: 18516549 [PubMed - indexed for MEDLINE] 2388. Vasa. 2008 Feb;37(1):39-51. Lymphoedema and lipoedema of the extremities. Kröger K(1). Author information: (1)Klinik und Poliklinik für Angiologie, Universitätsklinik Essen, Germany. knut.kroeger@uk-essen.de Lymphoedema is a clinical manifestation of an impaired lymphatic drainage with accumulation of lymphatic fluid. Lipoedema is characterized by bilateral enlargement of the legs and/or arms due to abnormal deposition of fatty tissue, which accumulates fluid. Conservative treatment including compressions garments and lymphatic drainage is suitable to prevent ongoing clinical deterioration although both diseases cannot be cured. The ability to properly diagnose lymphoedema and lipoedema is crucial to prevent the significant morbidity and loss of quality of life that is associated with this condition. It is imperative that patients with lymphoedema are referred to specially trained healthcare professionals to ensure optimal treatment. Continuous therapy with strict compliance of the patients is essential, and premature interruption is the most frequent mistake. Lipoedema is a different entity but patients are still fighting for acceptance. The mutual relation of lipoedema and obesity and the poor knowledge of the underlying mechanisms limit the acceptance of lipoedema as a relevant disease. PMID: 18512541 [PubMed - indexed for MEDLINE] 2389. Curr HIV/AIDS Rep. 2008 May;5(2):55-63. Pathogenesis and management of lipoatrophy. Tungsiripat M(1), McComsey G. Author information: (1)Cleveland Clinic Foundation, 9500 Euclid Avenue, S-32, Cleveland, OH 44195, USA. tungsim@ccf.org Despite impressive decreases in mortality and morbidity, significant adverse events have surfaced as a result of combination antiretroviral therapy (ART). They include lipoatrophy, or subcutaneous fat wasting of the face, arms, buttocks, or legs, which can be associated with central fat accumulation. Although the underlying mechanism of ART-related body fat abnormalities has not been definitively established, mitochondrial toxicity is increasingly implicated in the lipoatrophy component of these fat abnormalities. Several studies evaluating switches off of nucleoside analogues have showed modest but statistically significant increases in limb fat. Because ART switches result in slow and small improvements and are not an option in many patients, other therapeutic interventions are needed. Although peroxisome proliferator-activated receptor chi agonist thiazolidinediones would be expected to have positive effects on lipoatrophy, initial clinical studies are conflicting. Other interventions of uridine, pravastatin, and facial fillers have been evaluated in small studies. PMID: 18510890 [PubMed - indexed for MEDLINE] 2390. Acta Physiol (Oxf). 2008 Dec;194(4):293-309. doi: 10.1111/j.1748-1716.2008.01878.x. Epub 2008 Jul 9. Contribution of FAT/CD36 to the regulation of skeletal muscle fatty acid oxidation: an overview. Holloway GP(1), Luiken JJ, Glatz JF, Spriet LL, Bonen A. Author information: (1)Department of Human Health and Nutritional Sciences University of Guelph, Guelph, ON, Canada. Long chain fatty acids (LCFAs) are an important substrate for ATP production within the skeletal muscle. The process of LCFA delivery from adipose tissue to muscle mitochondria involves many regulatory steps. Recently, it has been recognized that LCFA oxidation is not only dependent on LCFA delivery to the muscle, but also on regulatory steps within the muscle. Increasing selected fatty acid binding proteins/transporters on the plasma membrane facilitates a very rapid LCFA increase into the muscle, independent of any changes in LCFA delivery to the muscle. Such a mechanism of LCFA transporter translocation is activated by muscle contraction. Intramuscular triacylglycerols may also be hydrolysed to provide fatty acids for mitochondrial oxidation, particularly during exercise, when hormone-sensitive lipase and other enzymes are activated. Mitochondrial LCFA entry is also highly regulated. This however does not involve only the malonyl CoA carnitine palmitoyltransferase-I (CPTI) axis. Exercise-induced fatty acid entry into mitochondria is also regulated by at least one of the proteins (FAT/CD36) that also regulates plasma membrane fatty acid transport. Among individuals, differences in mitochondrial fatty acid oxidation appear to be correlated with the content of mitochondrial CPTI and FAT/CD36. This paper provides a brief overview of mechanisms that regulate LCFA uptake and oxidation in skeletal muscle during exercise and in obesity. We focus largely on our own work on FAT/CD36, which contributes to regulating, in a coordinated fashion, LCFA uptake across the plasma membrane and the mitochondrial membrane. Very little is known about the roles of FATP1-6 on fatty acid transport in skeletal muscle. PMID: 18510711 [PubMed - indexed for MEDLINE] 2391. Metab Syndr Relat Disord. 2008 Jun;6(2):87-102. doi: 10.1089/met.2007.0029. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Swarbrick MM(1), Havel PJ. Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA. Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes. This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans. PMCID: PMC3190268 PMID: 18510434 [PubMed - indexed for MEDLINE] 2392. Physiol Behav. 2008 Aug 6;94(5):660-3. doi: 10.1016/j.physbeh.2008.04.009. Epub 2008 Apr 12. Leptin resistance and the response to positive energy balance. Morrison CD(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. morriscd@pbrc.edu Animals readily reduce food intake and normalize body weight following a period of involuntary overfeeding, suggesting that regulatory systems are engaged to defend against excess weight gain. However, these data exist in the background of an ongoing obesity epidemic, where the ready availability of palatable, energy dense foods often leads to obesity. Currently we know very little about the mechanisms underlying the normalization of body weight following involuntary overfeeding, nor do we fully understand why select individuals successfully remain lean despite living in an obesigenic environment. Recent progress in the study of leptin signaling indicates that manipulations which enhance leptin sensitivity reduce food intake and attenuate diet-induced obesity, while reductions in leptin signaling predispose to obesity. While it remains unclear whether a failure or insufficiency in the weight regulatory system contributes to obesity, this work highlights the importance of this system for the regulation of body weight and its potential value for the treatment of obesity. Nonetheless, it is necessary to more clearly identify those mechanisms that protect lean individuals from weight gain and mediate the normalization of body weight that follows involuntary overfeeding, because it is only with this knowledge that we can clearly determine whether obesity is dependent on, or independent of, a failure in the weight regulatory system. PMCID: PMC2517010 PMID: 18508097 [PubMed - indexed for MEDLINE] 2393. Arq Bras Endocrinol Metabol. 2008 Apr;52(3):452-64. [Human energetic expenditure: concepts, assessment methods and relationship to obesity]. [Article in Portuguese] Melo CM(1), Tirapegui J, Ribeiro SM. Author information: (1)Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brasil. Despite many studies in the last years, obesity still needs more investigation, including its relation with energetic expenditure (EE). This manuscript consisted of a review considering: the existing techniques to measure EE, showing their advantages and limitations and modifications in EE due to obesity. EE can be evaluated by calorimetric methods, spectroscopic methods, or by questionnaires. According to the researches objectives and possibilities, all techniques present advantages and limitations. Obese individuals have been recognized as "economics" in metabolic point of view, which means that they are able to expend little energy, compared to non-obese individuals. This economy has been investigated in many aspects. They have been analyzed every component of daily energetic expenditure (resting EE, thermogenic response to feeding and EE by physical activity), and the results are controversial, mainly because of the lack on standardization of procedures and techniques. Together with evaluation of EE in humans, molecular studies have contributed to clarify many aspects. They have been identified hormones and cellular proteins located in different kinds of cells. Studies are still necessary, and it is imperative to standardize the procedures and techniques to allow the reproducibility of the results. PMID: 18506270 [PubMed - indexed for MEDLINE] 2394. Asia Pac J Clin Nutr. 2008;17 Suppl 1:387-90. New strategies to overcome cancer cachexia: from molecular mechanisms to the 'Parallel Pathway'. Muscaritoli M(1), Costelli P, Aversa Z, Bonetto A, Baccino FM, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza - University of Rome. Viale dell'Universita, 37 - 00185 Rome, Italy. maurizio.muscaritoli@uniromal.it Cancer has always a negative impact on nutritional status, weight loss being a common feature in patients with neoplastic diseases. If left untreated, weight loss may evolve into cancer cachexia, a complex syndrome characterized by marked depletion of body weight, associated with profound alterations of both nutritional status and metabolic homeostasis. Progressive wasting of skeletal muscle mass and adipose tissue is a typical feature of cancer cachexia. Cachexia has a large impact on morbidity and mortality, and significantly affects patients' response and tolerance to treatments and quality of life. On this line, understanding the pathogenic mechanisms of cachexia is of crucial importance to define targeted therapeutic strategies. Well structured, systematic and timely appropriate nutritional intervention in cancer patients is of pivotal importance. Indeed, it has been shown that malnutrition in cancer patients can be delayed when nutritional supplementation is adopted early in the course of the disease. The preservation of a good nutritional status, in particular when it is achieved concurrently with specific antineoplastic treatments, will prevent or at least delay the onset of overt cachexia, allowing the use of more aggressive therapeutic regimens. The inclusion of specific, metabolically active nutritional substrates, such as branched chain amino acids or eicosapentaenoic acid may be helpful in interfering with the mechanisms responsible for the metabolic alterations and the perturbations of molecular pathways ultimately leading to the clinical picture of cancer cachexia. PMID: 18296386 [PubMed - indexed for MEDLINE] 2395. Asia Pac J Clin Nutr. 2008;17 Suppl 1:320-3. The application of medium-chain fatty acids: edible oil with a suppressing effect on body fat accumulation. Takeuchi H(1), Sekine S, Kojima K, Aoyama T. Author information: (1)Central Research Laboratory, The Nisshin OilliO Group, Ltd., 1 Shinmei-cho, Yokosuka, Kanagawa 239-0832, Japan. h-takeuchi@nisshin-oillio.com The bulk of fatty acids found in our diets consists of long-chain fatty acids (LCFA), which are molecules containing 12 or more carbon atoms. In contrast, medium-chain fatty acids (MCFA) are composed of 8-10 carbon atoms, and are found in palm kernel oil, among other types of foods. MCFA have attracted attention as being part of a healthy diet, because they are absorbed directly into the portal vein, transported rapidly to the liver for beta-oxidation, and thus increase diet-induced thermogenesis. In contrast, long-chain triacylglycerols are absorbed via the intestinal lymphatic ducts and transported by chylomicrons through the thoracic duct into the systemic circulation. Because medium-chain triacylglycerols (MCT) containing solely MCFA have a few disadvantages when used for deep frying, we have developed a new kind of triacylglycerol product: medium- and long-chain triacylglycerol (MLCT). MLCT is produced by lipase-catalyzed enzymatic transesterification. Long-term clinical trials have demonstrated that MLCT and MCT result in less body fat accumulation in humans. MLCT oil has been approved as FOSHU (Food for Specified Health Use) for use as cooking oil with a suppressing effect on body fat accumulation. PMID: 18296368 [PubMed - indexed for MEDLINE] 2396. Asia Pac J Clin Nutr. 2008;17 Suppl 1:126-30. Dietary regulation of nuclear receptors in obesity-related metabolic syndrome. Kawada T(1), Goto T, Hirai S, Kang MS, Uemura T, Yu R, Takahashi N. Author information: (1)Kyoto University, Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto 611-0011, Japan. fat@kais.kyoto-u.ac.jp In Western culture, excess visceral fat accumulation or obesity has reached epidemic proportions, resulting in metabolic syndrome. However, more than 10 years of research has shown that adipocytes also function as endocrine cells that release various bioactive substances, so called "adipocytokines or adipokines", that play a major role in the regulation of food intake, insulin sensitivity, energy metabolism, and the vascular microenvironment. Adiponectin, an adipocytokine, is considered to improve insulin sensitivity. Recently, monocyte chemoattractant protein (MCP)-1 has been reported to be a novel adipocytokine involved in the development of obesity-associated insulin resistance and atherosclerosis. Nuclear receptors, especially peroxisome proliferator-activated receptor-alpha (PPAR alpha) and PPAR gamma are ligand-activated transcription factors that regulate the metabolism of glucose and lipids. PPAR gamma is strongly expressed in adipocytes and plays a significant role in the transcriptional activation of adipocytokines including adiponectin. PPAR alpha, another PPAR isoform, is involved in the control of lipid metabolism in the liver and skeletal muscle. PPAR alpha activation causes lipid clearance via beta-oxidation enhancement. We showed that various dietary terpenoids and other natural ingredients regulate the transcription of PPAR target genes, induces the expression and secretion of adiponectin, and inhibits those of MCP-1 in adipocytes and beta-oxidation in liver. These findings indicate that dietary factor acts as an agonist of PPARs and is a valuable medical and food component for the gradual improvement of metabolic syndrome. PMID: 18296319 [PubMed - indexed for MEDLINE] 2397. Asia Pac J Clin Nutr. 2008;17 Suppl 1:37-42. Epidemiology of metabolic syndrome in Asia. Pan WH(1), Yeh WT, Weng LC. Author information: (1)Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Nankang, Taipei 11529, Taiwan. pan@ibms.sinica.edu.tw Metabolic syndrome (MS) is a rising disease entity characterized by a clustering of metabolic conditions. Although prevalence of obesity as defined by the World Health Organization (WHO) is relatively low in Asia compared to western countries, metabolic syndrome is growing into a significant public health problem. Comparative studies indicate that metabolic responses to obesity may be greater in South and East Asians than their western counterparts at given Body Mass Indexes (BMIs). Higher percentage body fat in Asians at given BMIs and over-responsiveness to obesity may in part explain the phenomenon for which the underlying causes are not clear. Furthermore, aborigines may be at an even greater MS risk. The metabolic syndrome definition itself as well as whether it should be defined are controversial. The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) gives equal weight to each component disorder, while the International Diabetes Federation (IDF) takes central obesity as a pre-requisite. Both criteria adopt ethnic-specific cut-off points for waist circumference. Asian data favour the new NCEP-ATP III definition, as individuals that were selected through the NCEP criteria but disregarded by the IDF criteria had similar Framingham cardiovascular disease risk scores to those picked by both definitions. Prospective data show that the metabolic syndrome not only increases the risk of coronary artery disease but also cerebrovascular disease in Asians. Macronutrient composition and the quality of the diet are associated with the risk of metabolic syndrome. More research is needed to relate diet and metabolic syndrome in Asians. PMID: 18296297 [PubMed - indexed for MEDLINE] 2398. Exp Gerontol. 2009 Jan-Feb;44(1-2):41-5. doi: 10.1016/j.exger.2008.04.005. Epub 2008 Apr 12. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Fontana L(1). Author information: (1)Division of Geriatrics and Nutritional Science, Center for Human Nutrition, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, MO 63110, USA. lfontana@im.wustl.edu Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of C-reactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic, and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR. PMCID: PMC2652518 PMID: 18502597 [PubMed - indexed for MEDLINE] 2399. Lancet. 2008 May 24;371(9626):1800-9. doi: 10.1016/S0140-6736(08)60768-0. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Mazzone T(1), Chait A, Plutzky J. Author information: (1)Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. tmazzone@uic.edu Individuals with type 2 diabetes mellitus have increased cardiovascular disease risk compared with those without diabetes. Treatment of the residual risk, other than blood pressure and LDL-cholesterol control, remains important as the rate of diabetes increases worldwide. The accelerated atherosclerosis and cardiovascular disease in diabetes is likely to be multifactorial and therefore several therapeutic approaches can be considered. Results of mechanistic studies done in vitro and in vivo--animals and people--can provide important insights with the potential to improve clinical management decisions and outcomes. In this Review, we focus on three areas in which pathophysiological considerations could be particularly informative--ie, the roles of hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL-cholesterol concentrations), and inflammation (including that in adipose tissue) in the acceleration of vascular injury. PMCID: PMC2774464 PMID: 18502305 [PubMed - indexed for MEDLINE] 2400. Physiol Behav. 2008 Aug 6;94(5):637-42. doi: 10.1016/j.physbeh.2008.04.005. Epub 2008 Apr 13. Molecular and neural mediators of leptin action. Robertson SA(1), Leinninger GM, Myers MG Jr. Author information: (1)Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0678, USA. The adipose tissue-derived hormone, leptin, acts via its receptor (LepRb) in the brain to regulate energy balance and neuroendocrine function. Parsing the biology of leptin requires understanding LepRb signaling and the roles for specific signaling pathways in neural and physiological leptin action. Since the leptin acts via a broadly distributed network of LepRb-expressing neurons, understanding the function of each of these LepRb neural populations will also be crucial. Here, we review the status of knowledge regarding the molecular mediators of leptin action and the neural substrate via which leptin acts to regulate physiologic processes. PMCID: PMC2516921 PMID: 18501391 [PubMed - indexed for MEDLINE] 2401. Minerva Med. 2008 Jun;99(3):307-21. [Metabolic syndrome: from insulin resistance to adipose tissue dysfunction]. [Article in Italian] Camera A(1), Hopps E, Caimi G. Author information: (1)Cattedra di Semeiotica e Metodologia Medica, Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Università di Palermo, Palermo, Italia. Recently the definition, the pathophysiology and even the clinical utility of metabolic syndrome (MS) have been discussed. The risk induced by each component of the metabolic syndrome is higher than the risk induced by MS alone. MS alone is, in fact, a weaker predictor of cardiovascular disease than diabetes. New criteria to define the metabolic syndrome have been proposed, as adipokines, CRP and PAI-1. IGFBP-1 is related to hyperinsulinemia/insulin resistance and to the risk of diabetes and fatal ischemic heart disease development. IGF/IGFBP system could be a link between insulin resistance and cardiovascular disease. RBP-4 can attenuate insulin signalling in skeletal muscle and induce hepatic gluconeogenesis. The belief that insulin-resistance is the main cause of MS could change in favour of the adipose tissue dysfunction. The most common cause of a reduced capacity of the adipose tissue to store fats is the increased dietary intake, also present in lipodistrophy, type 1 diabetes mellitus and polycystic ovarian syndrome. The adipose tissue production of adipokines and cytokines (such as IL-6, TNF-alpha and TGF-beta) and the excessive lipid flux towards muscles, heart and liver (Ectopic fat storage syndrome) contribute to the MS genesis and to an increased cardiovascular risk. The comprehension of adipose tissue dysfunction mechanisms offers new possibilities of prevention and therapy. PMID: 18497727 [PubMed - indexed for MEDLINE] 2402. Minerva Med. 2008 Jun;99(3):241-51. Mitochondria, body fat and type 2 diabetes: what is the connection? Maasen JA(1). Author information: (1)Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands. j.a.maassen@lumc.nl This review will consider the concept that the development of a mitochondrial dysfunction in adipocytes is an early step in the pathogenesis for type 2 diabetes. Upon expansion of the adipose mass it becomes gradually inflamed and hypoxic. TNF-alpha, locally produced, induces insulin resistance of adipocytes leading to enhanced lipolysis. The excess of fatty acids, in combination with local hypoxia, results in the induction of mitochondrial damage in the adipocytes. As a result of this decline in mitochondrial activity less fatty acids can be removed within adipocytes by uncoupled mitochondrial beta-oxidation and by re-esterification, as mitochondrial activity provides substrates for glyceroneogenesis. As a result these fatty acids redistribute to other compartments of the body where they are stored as ectopic triglyceride deposits. This situation is associated with the development of insulin resistance of the liver and muscle. Furthermore, it contributes to damage the pancreatic beta-cells. Ultimately, this situation results in the development of a hyperglycemic state. PMID: 18497722 [PubMed - indexed for MEDLINE] 2403. J Nutr Biochem. 2008 Nov;19(11):717-26. doi: 10.1016/j.jnutbio.2007.12.007. Epub 2008 May 20. Phytochemicals and regulation of the adipocyte life cycle. Rayalam S(1), Della-Fera MA, Baile CA. Author information: (1)Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602, USA. Natural products have potential for inducing apoptosis, inhibiting adipogenesis and stimulating lipolysis in adipocytes. The objective of this review is to discuss the adipocyte life cycle and various dietary bioactives that target different stages of adipocyte life cycle. Different stages of adipocyte development include preadipocytes, maturing preadipocytes and mature adipocytes. Various dietary bioactives like genistein, conjugated linoleic acid (CLA), docosahexaenoic acid, epigallocatechin gallate, quercetin, resveratrol and ajoene affect adipocytes during specific stages of development, resulting in either inhibition of adipogenesis or induction of apoptosis. Although numerous molecular targets that can be used for both treatment and prevention of obesity have been identified, targeted monotherapy has resulted in lack of success. Thus, targeting several signal transduction pathways simultaneously with multiple natural products to achieve additive or synergistic effects might be an appropriate approach to address obesity. We have previously reported two such combinations, namely, ajoene+CLA and vitamin D+genistein. CLA enhanced ajoene-induced apoptosis in mature 3T3-L1 adipocytes by synergistically increasing the expression of several proapoptotic factors. Similarly, genistein potentiated vitamin D's inhibition of adipogenesis and induction of apoptosis in maturing preadipocytes by an enhanced expression of VDR (vitamin D receptor) protein. These two examples indicate that combination therapy employing compounds that target different stages of the adipocyte life cycle might prove beneficial for decreasing adipose tissue volume by inducing apoptosis or by inhibiting adipogenesis or both. PMID: 18495457 [PubMed - indexed for MEDLINE] 2404. Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E531-5. doi: 10.1152/ajpendo.90357.2008. Epub 2008 May 20. Why are we shaped differently, and why does it matter? Santosa S(1), Jensen MD. Author information: (1)Mayo Clinic, Rochester, MN 55905, USA. Erratum in Am J Physiol Endocrinol Metab. 2009 Feb;296(2):E403. Body fat distribution is an important predictor of metabolic abnormalities in obese humans. Dysregulation of free fatty acid (FFA) release, especially from upper body subcutaneous adipose tissue, appears to contribute substantially to these metabolic disturbances. Why different individuals preferentially store fat in upper vs. lower body subcutaneous fat or subcutaneous vs. visceral fat is not completely understood. Current evidence suggests that defects in regional lipolysis are not the cause of net fat retention in larger fat depots. Regional variations in the storage of fatty acids, both meal derived and direct reuptake, and storage of circulating FFAs that may help to explain why some depots expand at the expense of others have been reported. We review the quantitative data on regional lipolysis, meal, and FFA storage in adults to provide an overview of fat balance differences in adults with different fat distribution patterns. PMCID: PMC2536731 PMID: 18492764 [PubMed - indexed for MEDLINE] 2405. Arthritis Res Ther. 2008;10(3):207. doi: 10.1186/ar2397. Epub 2008 May 8. Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications. Sidiropoulos PI(1), Karvounaris SA, Boumpas DT. Author information: (1)Department Rheumatology, Clinical Immunology and Allergy, University Hospital, Medical School, University of Crete, 1, Voules Str, Heraklion 71110, Greece. sidiropp@med.uoc.gr Subjects with metabolic syndrome--a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic--are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity. PMCID: PMC2483433 PMID: 18492218 [PubMed - indexed for MEDLINE] 2406. Int J Clin Pract. 2008 Jul;62(7):1087-95. doi: 10.1111/j.1742-1241.2008.01789.x. Epub 2008 May 16. Modulating an oxidative-inflammatory cascade: potential new treatment strategy for improving glucose metabolism, insulin resistance, and vascular function. Lamb RE(1), Goldstein BJ. Author information: (1)REL & Associates, LLC, Downingtown, PA 19335-4803, USA. rel@relscience.com Type 2 diabetes is a result of derangement of homeostatic systems of metabolic control and immune defense. Increases in visceral fat and organ adipose, environmental factors and genetic predisposition create imbalances of these homeostatic mechanisms, ultimately leading to a condition in which the oxidative environment cannot be held in check. A significant imbalance between the production of reactive oxygen species and antioxidant defenses, a condition called to oxidative stress, ensues, leading to alterations in stress-signalling pathways and potentially end-organ damage. Oxidative stress and metabolic inflammation upregulate the expression pro-inflammatory cytokines, including tissue necrosis factor alpha, monocyte chemoattractant protein-1 and interleukin-6, as well as activating stress-sensitive kinases, such as c-Jun N-terminal kinase (JNK), phosphokinase C isoforms, mitogen-activated protein kinase and inhibitor of kappa B kinase. The JNK pathway (specifically JNK-1) appears to be a regulator that triggers the oxidative-inflammation cascade that, if left unchecked, can become chronic and cause abnormal glucose metabolism. This can lead to insulin resistance and dysfunction of the vasculature and pancreatic beta-cell. The series of events set in motion by the interaction between metabolic inflammation and oxidative stress constitutes an 'oxidative-inflammatory cascade', a delicate balance driven by mediators of the immune and metabolic systems, maintained through a positive feedback loop. Modulating an oxidative-inflammation cascade may improve glucose metabolism, insulin resistance and vascular function, thereby slowing the development and progression to cardiovascular diseases and type 2 diabetes. PMCID: PMC2440526 PMID: 18489578 [PubMed - indexed for MEDLINE] 2407. Artif Life. 2008 Summer;14(3):375-86. doi: 10.1162/artl.2008.14.3.14310. Full body: the importance of the phenotype in evolution. Kampis G(1), Gulyás L. Author information: (1)History and Philosophy of Science, Eötvös University, Budapest, Hungary. gk@hps.elte.hu This is a position paper on phenotype-based evolution modeling. It argues that evolutionary complexity is essentially a functional kind of complexity, and for it to evolve, a full body, or, in other words, a dynamically defined, deeply structured, and plasticity-bound phenotype is required. In approaching this subject, we ask and answer some key questions, which we think are interrelated. The questions we discuss and the answers we propose are: (a) How should complexity growth be measured or operationalized in natural and artificial systems? Evolutionary complexity is akin to that of machines, and to operationalize it, we need to study how machinelike organismic functions work and develop. Inspired by studies on causality, we propose the notion of mechanism. A mechanism is a simplified causal system that carries out a function. A growth of functional complexity involves interconversions between a deep (or unused) process and that of a mechanism. (b) Are the principles of natural selection, as they are currently understood, sufficient to explain the evolution of complexity? Our answer is strongly negative. Natural selection helps adapting mechanisms to carry out a given task, but will not generate a task. Hence there is a tradeoff between available tasks and mechanisms fulfilling them. To escape, we argue that competition avoidance is required for new complexity to emerge. (c) What are the environmental constraints on complexity growth in living systems? We think these constraints arise from the structure of the coevolving ecological system, and the basic frames are given by the niche structure. We consider the recently popular idea of niche construction and relate it to the plasticity of the phenotype. We derive a form of phenotype plasticity from the hidden (unused) and explicit (functional) factors discussed in the causality part. (d) What are the main hypotheses about complexity growth that can actually be tested? We hypothesize that a rich natural phenotype that supports causality-function conversions is a necessary ingredient of complexity growth. We review our work on the FATINT system, which incorporates similar ideas in a computer simulation, and shows that full-body phenotypes are sufficient for achieving functional evolution. (e) What language is most appropriate for speaking about the evolution of complexity in living systems? FATINT is developed using advanced agent-based modeling techniques, and we discuss the general relevance of this methodology for understanding and simulating the phenomena discussed. PMID: 18489249 [PubMed - indexed for MEDLINE] 2408. Genes Dev. 2008 May 15;22(10):1269-75. doi: 10.1101/gad.1681308. Molecular determinants of brown adipocyte formation and function. Farmer SR(1). Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. Comment on Genes Dev. 2008 May 15;22(10):1397-409. Humans contain essentially two types of adipose tissue: brown adipose tissue (BAT) and white adipose tissue (WAT). The function of WAT is to store fat while that of BAT is to burn fat for heat production. A potential strategy to combat obesity and its related disorders is to induce the conversion of WAT into BAT. In this issue of Genes & Development, Kajimura and colleagues (pp. 1397-1409) have identified a mechanism by which PRDM16, the principal regulator of brown adipocyte formation and function, can simultaneously induce BAT gene expression, while suppressing WAT gene expression. The studies suggest that PRDM16 and its associated coregulators PPARgamma coactivator-1alpha (PGC-1alpha) and C-terminal-binding protein 1/2 (CtBP1/2), which control the switch from WAT to BAT, are potential targets for development of obesity-related therapeutics. PMCID: PMC2732411 PMID: 18483216 [PubMed - indexed for MEDLINE] 2409. J Neurooncol. 2008 Aug;89(1):109-12. doi: 10.1007/s11060-008-9598-1. Epub 2008 May 15. Sellar angiolipomas: two case reports and a review of the literature. Kolenc D(1), Zarković K, Jednacak H, Ozretić D, Habek M. Author information: (1)University Department of Neuropathology, Zagreb School of Medicine and University Hospital Center, Kispatićeva 12, Zagreb, Croatia. Angiolipomas are mesenchymal hamartomas composed of abnormal blood vessels and mature adipose tissue, most commonly found in the subcutaneous tissue of the extremities. Intracranial location is extremely rare, and only five cases have been described in the sellar region. We report on two patients that were initially diagnosed with pituitary adenomas that were postoperatively verified as angiolipomas. Sellar angiolipomas should be considered in the differential diagnosis of pituitary lesions due to the potential catastrophic bleeding during surgery. Preoperative diagnosis is very difficult; however, some MRI characteristics can help make an accurate diagnosis. Adequate MRI sequences should be used in the evaluation of pituitary lesions, as they can help optimize the microsurgical management. PMID: 18480966 [PubMed - indexed for MEDLINE] 2410. Int J Clin Pract. 2008 Jun;62(6):932-8. doi: 10.1111/j.1742-1241.2008.01773.x. Obesity; epiphenomenon or cause of metabolic syndrome? Lois K(1), Young J, Kumar S. Author information: (1)Warwickshire Institute of Diabetes Endocrinology and Metabolism (WISDEM), University Hospital (Walsgrave site), Warwick Medical School, University of Warwick, Coventry, UK. kblois03@yahoo.gr Metabolic syndrome is a combination of metabolic-related health issues such as hypertension, hyperlipidaemia and hyperinsulinaemia that together increase significantly the risk of cardiovascular disease and type 2 diabetes. Its prevalence has dramatically increased over the last several decades throughout the world following that of obesity. Insulin resistance and abdominal obesity are considered its core, while the latter may generate via complex metabolic and biochemical pathways the rest parameters of metabolic syndrome. The current approach of treatment is based on treating the chronic cardiovascular malfunctions but there is increasing interest in approaches to managing abdominal obesity as the underlying cause. PMID: 18479286 [PubMed - indexed for MEDLINE] 2411. Cancer Genet Cytogenet. 2008 May;183(1):60-3. doi: 10.1016/j.cancergencyto.2008.01.017. Cytogenetic and molecular cytogenetic findings in lipoblastoma. Bartuma H(1), Domanski HA, Von Steyern FV, Kullendorff CM, Mandahl N, Mertens F. Author information: (1)Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden. Lipoblastoma is a rare benign tumor that arises from embryonic adipose tissue and usually occurs in young children. Here, we present a review of available cytogenetic data and the karyotypes of 10 new cases of lipoblastoma, of which 7 could be studied further by fluorescence in situ hybridization (FISH) with regard to the involvement of the PLAG1 gene. All seven tumors with clonal aberrations harbored breakpoints in 8q11 approximately q13, in agreement with literature data. Including previously published cases, 33/40 (82%) lipoblastomas had rearrangement of the 8q11 approximately q13 region. These rearrangements target the PLAG1 gene, which becomes upregulated through promoter swapping. FISH revealed that five of seven cases in our series had a rearrangement of the PLAG1 gene. Occasionally, there can be difficulties in distinguishing a lipoblastoma from a conventional lipoma or a myxoid liposarcoma. As 8q11 approximately q13 rearrangements have been reported in only 3% of conventional lipomas and never in myxoid liposarcoma, cytogenetic analysis or FISH for the PLAG1 gene can provide useful differential diagnostic information. PMID: 18474299 [PubMed - indexed for MEDLINE] 2412. Curr Hypertens Rep. 2008 Apr;10(2):156-64. The link between abdominal obesity and the metabolic syndrome. Phillips LK(1), Prins JB. Author information: (1)Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich Road, Woolloongabba 4102, Queensland, Australia. The clustering of cardiovascular risk factors associated with abdominal obesity is well established. Although currently lacking a universal definition, the metabolic syndrome describes a constellation of metabolic abnormalities, including abdominal obesity, and was originally introduced to characterize a population at high cardiovascular risk. Adipose tissue is a dynamic endocrine organ that secretes several inflammatory and immune mediators known as adipokines. Dysregulation of adipokine secretion, free fatty acid toxicity, and the site-specific differences in abdominal (visceral) versus subcutaneous fat support abdominal obesity as a causal factor mediating the insulin resistance, increased risk of diabetes, and cardiovascular disease in the metabolic syndrome. PMID: 18474184 [PubMed - indexed for MEDLINE] 2413. Curr Hypertens Rep. 2008 Apr;10(2):93-8. Local adipose tissue renin-angiotensin system. Cassis LA(1), Police SB, Yiannikouris F, Thatcher SE. Author information: (1)Graduate Center for Nutritional Sciences, Wethington Building, Room 521b, 900 South Limestone Street, University of Kentucky, Lexington, KY 40536-0200, USA. lcassis@uky.edu A local renin-angiotensin system (RAS) has been proposed in adipocytes. Adipocytes are a suggested source of components of the RAS, with regulation of their production related to obesity-hypertension. Both angiotensin type 1 and 2 receptors have been localized to adipocytes. Angiotensin II has been demonstrated to regulate adipocyte growth and differentiation, lipid metabolism, and expression and release of adipokines and RAS components, and to promote oxidative stress. Differences in regional expression of RAS components in visceral versus subcutaneous adipose tissue have been suggested as a link between abdominal obesity and cardiovascular disease. Finally, several studies support antihypertensive efficacy of RAS blockade in patients with type 2 diabetes and obesity. Future studies should address the role of adipocyte-specific deficiency of RAS components to definitively determine the relevance of the adipose RAS to normal physiology and to the development of hypertension. PMCID: PMC2702858 PMID: 18474174 [PubMed - indexed for MEDLINE] 2414. Infect Disord Drug Targets. 2008 Mar;8(1):52-60. Estrogen regulation of adipose tissue functions: involvement of estrogen receptor isoforms. Pallottini V(1), Bulzomi P, Galluzzo P, Martini C, Marino M. Author information: (1)Department of Biology, University Roma Tre, Viale G. Marconi 446, I-00146 Roma, Italy. Adipose tissue has recently been described as one of the major endocrine gland that plays a role in energy homeostasis, lipid metabolism, immune response, and reproduction. An excess of white adipose tissue, caused by a complex interaction between genetic, hormonal, behavioral, and environmental factors, results in obesity: a heterogeneous disorder that predisposes humans to a variety of diseases. Among several hormones, estrogens promote, maintain, and control the typical distribution of body fat and adipose tissue metabolism through still unknown mechanisms. These steroids are known to regulate fat mass, adipose deposition and differentiation, and adipocyte metabolism. Moreover, estrogen deficiency results in increases in adipose tissue, preferentially in visceral fat, which would link obesity to the susceptibility of related disorders. In this review the role of estrogens in adipose tissue differentiation and in the protection against the onset of obesity will be discussed with particular attention being drawn to the underlying molecular mechanisms mediated by estrogen receptor isoforms ERalpha and ERbeta. PMID: 18473908 [PubMed - indexed for MEDLINE] 2415. Curr Pharm Des. 2008;14(12):1225-30. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Heilbronn LK(1), Campbell LV. Author information: (1)Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst NSW 2010, Australia. l.heilbronn@garvan.org.au Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes. PMID: 18473870 [PubMed - indexed for MEDLINE] 2416. Curr Diabetes Rev. 2008 May;4(2):122-8. Metabolic syndrome--risk factors for atherosclerosis and diabetes. Mihic M(1), Modi P. Author information: (1)Diabetes Care and Research Clinic, St. Joseph Hospital, University of Toronto, Toronto, Canada. OBJECTIVE: To evaluate the lipoprotein profiles, triglycerides and glycemia along with the abdominal fat to explore the risk factors associated with non-diabetic state to IGF, IGT and Type-2 diabetes in Canadian population. METHODS: We examined 780 subjects using the ADA and WHO criteria to classify them into groups based on (1) normal glucose tolerance with FBS <6.0 and 2hBS <7.0 mmol/l), (2) IFG; FPG > or =6.1 mmol/l but 2hBS >7.8-11.1 mmol/l; (3) combined IFG/IGT (FPG > or =7.0 mmol/l and 2hBS >11.1 mmol/l). We compared the three groups for glycemia, insulin secretion and insulin sensitivity based on their WHR, abdominal and visceral fat measurements. RESULTS: The subjects with higher 2 hrs glucose levels 5.2 for NGT vs. 9.1 for IGT and 13.4 mmol/l for NIDDM, p<0.001, apo C-III level (12.8 (DM) vs. 8.9 mg/dl (normal), p<0.001), waist to hip ratio (0.91 (IGT) vs. 0.89 (Normal), p<0.01) and abdominal fat and were found to be highly insulin resistant. CONCLUSIONS: The higher apolipoproteins levels, BMI and abdominal and visceral fat accompanied by poor glycemia were shown to be associated strongly with the metabolic abnormalities. These factors led to the worsening of insulin secretory dysfunction and insulin resistance and were strong predictors of diabetes. PMID: 18473759 [PubMed - indexed for MEDLINE] 2417. Arch Gynecol Obstet. 2008 Sep;278(3):201-8. doi: 10.1007/s00404-008-0676-6. Epub 2008 May 10. Restrictive dermopathy: a rare laminopathy. Thill M(1), Nguyen TD, Wehnert M, Fischer D, Hausser I, Braun S, Jackisch C. Author information: (1)Department of Gynecology and Obstetrics, Klinikum Offenbach, Starkenburgring 66, 63069, Offenbach, Germany. marc.thill@uk-sh.de BACKGROUND: Restrictive dermopathy (RD) belongs to the laminopathies and mostly shows an autosomal recessive heredity pattern. This rare genetic disorder is lethal for the newborn in the neonatal period. Clinical and pathological findings are distinctive and allow for a specific diagnosis in most cases. Furthermore, polyhydramnios, decreased foetal movement, facial dysmorphisms and arthrogryposis are characteristic of RD. Respiratory insufficiency leads to an early neonatal death. METHODS: We present the case of an affected infant and a review of the previously reported cases in the literature. RESULTS: The infant showed thin, shiny skin with exfoliating desquamation, a small, round and open mouth, low-set ears, a small pinched nose, joint contractures at all four extremities and distinctive pulmonic atelectasis. It died 3 h and 20 min post-partum. Histologically, the skin showed the typical pattern of an RD with the epidermis covered by an exfoliated, hyperkeratotic horn layer, clearly hypoplastic hair follicles and a considerably reduced dermis thickness, although it had a massive subcutaneous adipose tissue. Electron microscopically, the diagnosis was confirmed. CONCLUSIONS: It is important to know about this disease and to distinguish it from others like keratinization malfunctions such as ichtyosis, congenital, developmental and akinesia disturbance, etc., to know the prognosis for the affected newborn and to provide sufficient (genetic) counselling to the families. This disorder is caused by dominant mutations of the LMNA (primary laminopathy) or recessive mutations of the ZMPSTE24 (FACE1) (secondary laminopathy) genes. PMID: 18470519 [PubMed - indexed for MEDLINE] 2418. Exp Physiol. 2008 Jul;93(7):773-97. doi: 10.1113/expphysiol.2007.041848. Epub 2008 May 9. Central control of thermogenesis in mammals. Morrison SF(1), Nakamura K, Madden CJ. Author information: (1)Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. morrisos@ohsu.edu Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E(2), to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis. PMCID: PMC2496891 PMID: 18469069 [PubMed - indexed for MEDLINE] 2419. Med Sci (Paris). 2008 May;24(5):505-10. doi: 10.1051/medsci/2008245505. [Gut microflora is a key player in host energy homeostasis]. [Article in French] Delzenne NM(1), Cani PD. Author information: (1)Université catholique de Louvain, Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Bruxelles, Belgique. UCL, Unit PMNT-7369, Avenue E. Mounier, 73/69, B-1200 Bruxelles, Belgique. nathalie.delzenne@uclouvain.be Gut microflora is now considered as a key organ involved in host energy homeostasis. Recent data suggest that the alterations of the gut bacteria ecosystem could contribute to the development of metabolic disorders such as type 2 diabetes and obesity. First, gut microflora may increase energy efficiency of non digested food via the fermentation, thus providing more energy to the host. Secondly, fatty acids flux and storage in the adipose tissue is under the control of the fasting-induced adipocyte factor FIAF, which expression depends on gut microflora. Third, high-fat diet feeding changes gut bacteria profile, leading to a drop in bifidobacteria content, which correlates with a higher LPS plasma levels, thereby participating to the onset of inflammation, insulin resistance and type 2 diabetes associated with obesity. Changing gut microflora composition could be a useful tool to prevent or to treat high-fat/low fibres diet-induced metabolic syndrome. double dagger. PMID: 18466728 [PubMed - indexed for MEDLINE] 2420. Nihon Rinsho. 2008 May;66(5):978-83. [Regenerative medicine for heart failure]. [Article in Japanese] Nagaya N(1), Kitamura S. Author information: (1)Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute. Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of angiogenic and antiapoptotic factors. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure. PMID: 18464520 [PubMed - indexed for MEDLINE] 2421. Endocr Pract. 2008 Apr;14(3):373-80. Role of insulin signaling in maintaining energy homeostasis. Sharma MD(1), Garber AJ, Farmer JA. Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA. OBJECTIVE: To examine the role that insulin signaling plays in modulating metabolic functions involving both peripheral and hypothalamic systems. METHODS: We review the literature regarding insulin signaling as it relates to energy homeostasis. RESULTS: Insulin signaling in the periphery is known to affect hepatic glucose production and glucose uptake in muscle and adipose tissue. In the brain, insulin is involved in a variety of signaling pathways that control positive and negative aspects of food intake and energy metabolism. Disruption of insulin signaling can affect key cellular pathways that serve to maintain energy balance and glucose homeostasis, which can then lead to insulin resistance and progression toward various metabolic disorders, including cardiovascular disease, obesity, and type 2 diabetes. The use of exogenous insulin as therapy for patients with type 2 diabetes is traditionally associated with increases in weight. CONCLUSION: An enhanced understanding of how these insulin signaling pathways function may provide answers about how to control weight gain associated with exogenous insulin use. Pharmacologic agents, such as the long-acting insulin analogues and particularly insulin detemir, that may reduce these weight effects hold considerable advantage. PMID: 18463047 [PubMed - indexed for MEDLINE] 2422. J Neuroendocrinol. 2008 May;20 Suppl 1:147-51. doi: 10.1111/j.1365-2826.2008.01692.x. The endocannabinoid system and the control of glucose homeostasis. Nogueiras R(1), Rohner-Jeanrenaud F, Woods SC, Tschöp MH. Author information: (1)Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, OH, USA. Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity. PMID: 18426514 [PubMed - indexed for MEDLINE] 2423. J Neuroendocrinol. 2008 May;20 Suppl 1:130-8. doi: 10.1111/j.1365-2826.2008.01682.x. Cannabinoid type 1 receptor: another arrow in the adipocytes' bow. Bellocchio L(1), Cervino C, Vicennati V, Pasquali R, Pagotto U. Author information: (1)Center of Applied Biomedical Research (CRBA), Department of Internal Medicine and Gastroenterology, S.Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy. The endocannabinoid system has recently emerged as an important modulator of several functions of adipose tissue, including cell proliferation, differentiation and secretion. Here, we will review the effects of cannabinoid type 1 (CB(1)) receptor activation/blockade in adipocytes by summarising the data in the literature since the discovery of the presence of this receptor in adipose tissue. We will also discuss our original data obtained in mouse 3T3-L1 adipocyte cells using WIN55 212, a CB(1)/CB(2) receptor agonist and SR141716 (rimonabant), a specific CB(1) receptor antagonist, respectively, in different experimental settings. PMID: 18426512 [PubMed - indexed for MEDLINE] 2424. J Neuroendocrinol. 2008 May;20 Suppl 1:124-9. doi: 10.1111/j.1365-2826.2008.01690.x. Endocannabinoids, adipose tissue and lipid metabolism. Pagano C(1), Rossato M, Vettor R. Author information: (1)Endocrine-Metabolic Laboratory, Clinica Medica 3, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy. claudio.pagano@unipd.it Endocannabinoids regulate energy balance by modulating hypothalamic circuits controlling food intake and energy expenditure. However, convincing evidence has accumulated indicating that the endocannabinoid system is present also in peripheral tissues, in particular in adipose tissue. Fat cells produce (and are targets of) endocannabinoids. Adipogenesis, lipogenesis and glucose uptake are stimulated by endocannabinoids through CB(1) receptors and these effects are blocked by the CB(1) receptor antagonist rimonabant, suggesting that the weight-lowering effect of CB(1) receptor blockade is partly due to peripheral mechanisms. This review will focus on the role of endocannabinoids in adipose tissue metabolism, adipokine production and interactions between endocannabinoids and peroxisome proliferator activated receptors during adipogenesis. PMID: 18426511 [PubMed - indexed for MEDLINE] 2425. J Neuroendocrinol. 2008 May;20 Suppl 1:110-5. doi: 10.1111/j.1365-2826.2008.01683.x. Dysregulation of the endocannabinoid system in obesity. Engeli S(1). Author information: (1)Franz Volhard Clinical Research Center, Medical Faculty of the Charité, Berlin, Germany. stefan.engeli@charite.de An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB(1) blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation. PMID: 18426509 [PubMed - indexed for MEDLINE] 2426. J Neuroendocrinol. 2008 May;20 Suppl 1:100-9. doi: 10.1111/j.1365-2826.2008.01678.x. Endocannabinoids: some like it fat (and sweet too). Matias I(1), Cristino L, Di Marzo V. Author information: (1)U862 Centre de Recherche INSERM François Magendie, Université de Bordeaux, Bordeaux, France. isabelle.matias@bordeaux.inserm.fr There is growing interest in the commercialisation of the CB(1) receptor antagonist Rimonabant in Europe for the treatment of obesity and the metabolic syndrome. Clinical trials have shown that CB(1) receptor blockers are able to reduce not only food intake but also abdominal adiposity and its metabolic sequelae. Accordingly, CB(1) receptors, and tissue concentrations of endocannabinoids sufficient to activate them, are present in all brain and peripheral organs involved in the control of energy balance, including the hypothalamus, nucleus accumbens, pancreas, adipose tissue, skeletal muscle and liver. At the central level, the endocannabinoid system seems to play a dual role in the regulation of food intake by hedonic and homeostatic energy regulation. At the peripheral level, the endocannabinoid system seems to behave as a system that reduces energy expenditure and directs energy balance towards energy storage into fat. The emerging role of the endocannabinoid system in energy balance at both central and peripheral levels will be discussed in this review. PMID: 18426508 [PubMed - indexed for MEDLINE] 2427. Curr Opin Lipidol. 2008 Jun;19(3):248-56. doi: 10.1097/MOL.0b013e3282f9b54d. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Flowers MT(1), Ntambi JM. Author information: (1)Department of Biochemistry , University of Wisconsin, Madison, Wisconsin 53706, USA. PURPOSE OF REVIEW: Stearoyl-coenzyme A desaturase 1 is a delta-9 fatty acid desaturase that catalyzes the synthesis of monounsaturated fatty acids and has emerged as a key regulator of metabolism. This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease. RECENT FINDINGS: Scd1-deficient mice have reduced lipid synthesis and enhanced lipid oxidation, thermogenesis and insulin sensitivity in various tissues including liver, muscle and adipose tissue due to transcriptional and posttranscriptional effects. These metabolic changes protect Scd1-deficient mice from a variety of dietary, pharmacological and genetic conditions that promote obesity, insulin resistance and hepatic steatosis. Stearoyl-coenzyme A desaturase 1 is required to guard against dietary unsaturated fat deficiency, leptin deficiency-induced diabetes, and palmitate-induced lipotoxic insults in muscle and pancreatic beta-cells. Paradoxical observations of increased muscle stearoyl-coenzyme A desaturase 1 during obesity, starvation and exercise raise questions as to the role of stearoyl-coenzyme A desaturase 1 in this tissue. Mice with a liver-specific loss of stearoyl-coenzyme A desaturase 1, and inhibition of stearoyl-coenzyme A desaturase 1 via antisense or RNA interference, recapitulate only a subset of the phenotypes observed in global Scd1 deficiency, indicating the involvement of multiple tissues. SUMMARY: Recent studies in humans and animal models have highlighted that modulation of stearoyl-coenzyme A desaturase 1 activity by dietary intervention or genetic manipulation strongly influences several facets of energy metabolism to affect susceptibility to obesity, insulin resistance, diabetes and hyperlipidemia. PMCID: PMC4201499 PMID: 18460915 [PubMed - indexed for MEDLINE] 2428. Curr Opin Lipidol. 2008 Jun;19(3):235-41. doi: 10.1097/01.mol.0000319118.44995.9a. Free fatty acids and skeletal muscle insulin resistance. Kraegen EW(1), Cooney GJ. Author information: (1)Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, Australia. e.kraegen@garvan.org.au PURPOSE OF REVIEW: Acute exposure to fatty acids causes insulin resistance in muscle, and excess dietary lipid and obesity are also strongly associated with muscle insulin resistance. Relevant mechanisms, however, are still not fully elucidated. Here we examine the latest evidence as to why lipids might accumulate in muscle and the possible mechanisms for lipid-induced insulin resistance. RECENT FINDINGS: Muscle lipid metabolites such as long chain fatty acid coenzyme As, diacylglycerol and ceramides may impair insulin signalling directly. Crosstalk between inflammatory signalling pathways and insulin signalling pathways, mitochondrial dysfunction and oxidative stress have also been put forward as major contributors to the development or maintenance of lipid-induced insulin resistance in muscle. Several animal models with gene deletions in pathways of fatty acid synthesis and storage also show increased metabolic rate, reduced intramuscular lipid storage and improved insulin action when challenged with a high lipid load. SUMMARY: Studies in genetic and dietary obese animal models, genetically modified animals and humans with obesity or type 2 diabetes suggest plausible mechanisms for effects of fatty acids, lipid metabolites, inflammatory pathways and mitochondrial dysfunction on insulin action in muscle. Many of these mechanisms, however, have been demonstrated in situations in which lipid accumulation (obesity) already exists. Whether the initial events leading to muscle insulin resistance are direct effects of fatty acids in muscle or are secondary to lipid accumulation in adipose tissue or liver remains to be clarified. PMID: 18460913 [PubMed - indexed for MEDLINE] 2429. J Physiol Biochem. 2007 Dec;63(4):359-73. Expanding role for the apelin/APJ system in physiopathology. Carpéné C(1), Dray C, Attané C, Valet P, Portillo MP, Churruca I, Milagro FI, Castan-Laurell I. Author information: (1)INSERM, U858, Toulouse, F-31432 France. carpene@toulouse.inserm.fr Apelin is a bioactive peptide known as the ligand of the G protein-coupled receptor APJ. Diverse active apelin peptides exist under the form of 13, 17 or 36 amino acids, originated from a common 77-amino-acid precursor. Both apelin and APJ mRNA are widely expressed in several rodent and human tissues and have functional effects in both the central nervous system and peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular functions, fluid homeostasis, vessel formation and cell proliferation. More recently, apelin has been described as an adipocyte-secreted factor (adipokine), up-regulated in obesity. By acting as circulating hormone or paracrine factor, adipokines are involved in physiological regulations (fat depot development, energy storage, metabolism or eating behavior) or in the promotion of obesity-associated disorders (type 2 diabetes and cardiovascular dysfunctions). In this regard, expression of apelin gene in adipose tissue is increased by insulin and TNFalpha. This review will consider the main roles of apelin in physiopathology with particular attention on its role in energy balance regulation and in obesity-associated disorders. PMID: 18457011 [PubMed - indexed for MEDLINE] 2430. Regul Pept. 2008 Aug 7;149(1-3):70-8. doi: 10.1016/j.regpep.2007.10.008. Epub 2008 Mar 25. Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide release in humans. Karhunen LJ(1), Juvonen KR, Huotari A, Purhonen AK, Herzig KH. Author information: (1)Food and Health Research Centre, Department of Clinical Nutrition, University of Kuopio, Finland. Leila.Karhunen@uku.fi Short-term regulation of food intake controls what, when and how much we eat within a single day or a meal. This regulation results from an integrated response to neural and humoral signals that originate from the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach, duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related peptides in humans is discussed. PMID: 18456350 [PubMed - indexed for MEDLINE] 2431. Am J Med. 2008 May;121(5):366-70. doi: 10.1016/j.amjmed.2008.01.032. Endocrine and metabolic effects of fat: cardiovascular implications. Govindarajan G(1), Alpert MA, Tejwani L. Author information: (1)Division of Cardiology, University of Missouri-Columbia, School of Medicine, Columbia, MO 65212, USA. The prevalence of obesity is increasing rapidly in both industrialized and developing nations. Obesity causes complex metabolic, endocrine, and hemodynamic changes that may lead to adverse cardiovascular outcomes such as coronary heart disease and congestive heart failure. Adipose tissue is no longer considered to be an inert organ of energy storage, but in fact possesses important endocrine and metabolic functions that are closely involved in energy homeostasis. During the past decade, our understanding of the unique pathophysiologic changes that occur with obesity has rapidly grown. This review discusses our current understanding of the endocrine and metabolic effects of fat and their potential relation to cardiovascular disease. PMID: 18456027 [PubMed - indexed for MEDLINE] 2432. Nutr Rev. 2008 May;66(5):272-9. doi: 10.1111/j.1753-4887.2008.00032.x. Dairy and weight loss hypothesis: an evaluation of the clinical trials. Lanou AJ(1), Barnard ND. Author information: (1)University of North Carolina at Asheville, Department of Health and Wellness, Asheville, North Carolina 28804, USA. alanou@unca.edu Comment in Nutr Rev. 2008 Sep;66(9):544-5; author reply 546-7. Nutr Rev. 2008 Sep;66(9):542-3; author reply 546-7. This review evaluates evidence from clinical trials that assessed the effect of dairy product or calcium intake, with or without concomitant energy restriction, on body weight and adiposity. Of 49 randomized trials assessing the effect of dairy products or calcium supplementation on body weight, 41 showed no effect, two demonstrated weight gain, one showed a lower rate of gain, and five showed weight loss. Four of 24 trials report differential fat loss. Consequently, the majority of the current evidence from clinical trials does not support the hypothesis that calcium or dairy consumption aids in weight or fat loss. PMID: 18454813 [PubMed - indexed for MEDLINE] 2433. Regul Pept. 2008 Aug 7;149(1-3):26-31. doi: 10.1016/j.regpep.2007.09.034. Epub 2008 Apr 1. Central nervous system regulation of adipocyte metabolism. Nogueiras R(1), Wilson H, Rohner-Jeanrenaud F, Tschöp MH. Author information: (1)Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, OH 45226, USA. ruben.nogueiras@psychiatry.uc.edu The white adipose tissue was initially largely known only as an energy storage tissue. It is now well recognized that white adipose tissue is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. The regulation of adipocyte metabolism is an important factor for the understanding of obesity, and some mechanisms are still unknown. Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the central nervous system. There is substantial evidence demonstrating that the central nervous system also directly regulates adipocyte metabolism. In this review, we discuss the central actions of some peptides with an important role in energy balance regulation on adipocyte metabolism and the physiological relevance of these actions. PMID: 18453013 [PubMed - indexed for MEDLINE] 2434. Clin Cornerstone. 2007;8(3):38-52. Dyslipidemia and glucose dysregulation in overweight and obese patients. LeRoith D(1). Author information: (1)Division of Endocrinology, Diabetes and Bone Disease Department, Medicine Mount Sinai School of Medicine, New York, New York 10024, USA. Derek.leroith@mssm.edu Inactivity and a sedentary lifestyle contribute to overweight, obesity, and cardiometabolic risk. Overweight and obesity can lead to metabolic abnormalities, insulin resistance, type 2 diabetes mellitus (DM), lipid disorders, and cardiovascular disease. Diet and exercise can effectively reverse overweight and obesity and their related comorbidities. Modest weight loss (5%-10%) and modest physical activity (30 minutes a day) are first-line recommendations for the prevention of type 2 DM. Clinical trials have demonstrated that insulin sensitivity can be improved and type 2 DM can be prevented through lifestyle modification and pharmacologic therapy, including antiobesity drugs, antidiabetic drugs, statins, and antihypertensive drugs. The endocannabinoid system plays an important role in regulating metabolism through its effects on food intake at the level of the hypothalamus and on body composition through peripheral effects on adipose tissue. PMID: 18452841 [PubMed - indexed for MEDLINE] 2435. Biol Pharm Bull. 2008 May;31(5):775-84. Cold-induced changes in gene expression in brown adipose tissue: implications for the activation of thermogenesis. Watanabe M(1), Yamamoto T, Mori C, Okada N, Yamazaki N, Kajimoto K, Kataoka M, Shinohara Y. Author information: (1)Institute for Genome Research, University of Tokushima, Kuramotocho-3, Tokushima 770-8503, Japan. Brown adipose tissue (BAT) is the site of heat production (thermogenesis). This unique function is performed by uncoupling protein 1 (UCP1) specifically expressed in mitochondria of BAT. UCP1 dissipates the driving force of ATP synthesis, and thus causes heat production followed by energy expenditure. The thermogenic function of BAT has the role of maintaining body temperature under cold conditions. When animals are exposed to cold, the expression of UCP1 gene is increased to activate thermogenesis. To date, functional analysis of BAT has been focused on UCP1, because it plays an indispensable role in thermogenesis. However, the gene expression of not only UCP1 but also that of other genes in BAT is expected to be regulated to achieve effective thermogenesis. Our previous investigations showed increased expression of genes that encode several energy metabolic enzymes in the BAT of rats kept in the cold. These changes in gene expression imply that the enhancement of energy metabolism is needed to activate thermogenesis. Furthermore, various reports from studies focused on genes whose expression is changed in response to cold stimulation have provided new insights into the function of BAT. In this review, to understand the thermogenic function of BAT systematically, we have provided an overview of previous findings on changes in the expression of genes thought to be related to the activation of thermogenesis in BAT. PMID: 18451493 [PubMed - indexed for MEDLINE] 2436. Horm Metab Res. 2008 Aug;40(8):515-7. doi: 10.1055/s-2008-1073154. Epub 2008 Apr 30. Adrenocortical dysfunction in obesity and the metabolic syndrome. Krug AW(1), Ehrhart-Bornstein M. Author information: (1)Carl Gustav Carus University Hospital, Department of Internal Medicine III, Dresden, Germany. Alexander.Krug@uniklinikum-dresden.de Recently, it has become evident that the adrenals play a key role in obesity as well as in the metabolic syndrome and their complications. On the one hand, adrenal steroids are involved in physiological regulation of adipose tissue and energy homeostasis and in the pathogenesis of cardiometabolic complications. On the other hand, fat cell-derived factors, adipocytokines, and lipids released from adipose tissue are involved in the modulation of adrenal steroidogenesis. Aldosterone plasma levels are elevated in obesity and in patients with the metabolic syndrome. Recent research has provided evidence that adipocytes secrete factors that stimulate adrenal mineralocorticoid release and sensitize the adrenal cortex to angiotensin II. PMID: 18446685 [PubMed - indexed for MEDLINE] 2437. Clin Calcium. 2008 May;18(5):623-30. doi: CliCa0805623630. [Role of adipocytokine in bone metabolism]. [Article in Japanese] Ebina K(1), Fukuhara A, Shimomura I. Author information: (1)Osaka University, Graduate School of Medicine, Department of Orthopaedics. Growing evidence suggests that positive association between fat mass and bone mineral density (BMD) is mediated not only biomechanical but also biochemical factors. Recent studies on adipocyte function have revealed that adipose tissue is not merely an energy-storing organ but it secretes a variety of biological active molecules, conceptualized as "adipocytokines", including leptin and adiponectin. Adipocyte also exist in bone marrow, and experimental finding indicate the dynamic involvement of adipocytokines in bone metabolism. This report aims to review some of the effects of adipocytokines in bone metabolism, in relation to visceral fat accumulation. PMID: 18445880 [PubMed - indexed for MEDLINE] 2438. Curr Diab Rep. 2008 Apr;8(2):141-8. Genetics of metabolic syndrome. Joy T, Lahiry P, Pollex RL, Hegele RA. Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS. PMID: 18445357 [PubMed - indexed for MEDLINE] 2439. Atherosclerosis. 2008 Aug;199(2):248-56. doi: 10.1016/j.atherosclerosis.2008.03.011. Epub 2008 Mar 20. The endocannabinoid system and cardiometabolic risk. Szmitko PE(1), Verma S. Author information: (1)Division of General Internal Medicine, University of Toronto, Canada. Worldwide, the rates of obesity are rapidly rising. Abdominal obesity in particular is associated with increased cardiovascular risk factors, namely increased triglycerides, low high-density lipoprotein (HDL) cholesterol, elevated blood pressure and increased plasma glucose. The cluster of these obesity-related metabolic disorders identifies individuals with the cardiometabolic syndrome, who are at particular risk for cardiovascular disease and type 2 diabetes. The accumulation of intra-abdominal fat and the subsequent development of visceral obesity rely on the body's mechanisms to store energy and to stimulate appetite. The endocannabinoid system has been implicated in the regulation of energy balance and has emerged as a critical target for the modulation of visceral obesity and insulin resistance. Its overactivity appears to be associated with the development of obesity. The current review examines the role of the endocannabinoid system in cardiometabolic disease and its basis as a target for modulating cardiovascular risk. PMID: 18440538 [PubMed - indexed for MEDLINE] 2440. Clin Chem. 2008 Jun;54(6):945-55. doi: 10.1373/clinchem.2007.100156. Epub 2008 Apr 24. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. de Ferranti S(1), Mozaffarian D. Author information: (1)Department of Cardiology, Children's Hospital Boston, Boston, MA 02115, USA. Sarah.deferranti@cardio.chboston.org BACKGROUND: As the prevalence of adiposity soars in both developed and developing nations, appreciation of the close links between obesity and disease increases. The strong relationships between excess adipose tissue and poor health outcomes, including cardiovascular disease, diabetes, and cancer, mandate elucidation of the complex cellular, hormonal, and molecular pathophysiology whereby adiposity initiates and maintains adverse health effects. CONTENT: In this report we review adipocyte metabolism and function in the context of energy imbalance and postprandial nutrient excess, including adipocyte hypertrophy and hyperplasia, adipocyte dysfunction, and other systemic consequences. We also discuss implications for laboratory evaluation and clinical care, including the role of lifestyle modifications. Chronic energy imbalance produces adipocyte hypertrophy and hyperplasia, endoplasmic reticulum stress, and mitochondrial dysfunction. These processes lead to increased intracellular and systemic release of adipokines, free fatty acids, and inflammatory mediators that cause adipocyte dysfunction and induce adverse effects in the liver, pancreatic beta-cells, and skeletal muscle as well as the heart and vascular beds. Several specialized laboratory tests can quantify these processes and predict clinical risk, but translation to the clinical setting is premature. Current and future pharmacologic interventions may target these pathways; modest changes in diet, physical activity, weight, and smoking are likely to have the greatest impact. SUMMARY: Adipocyte endoplasmic reticulum and mitochondrial stress, and associated changes in circulating adipokines, free fatty acids, and inflammatory mediators, are central to adverse health effects of adiposity. Future investigation should focus on these pathways and on reversing the adverse lifestyle behaviors that are the fundamental causes of adiposity. PMID: 18436717 [PubMed - indexed for MEDLINE] 2441. Prog Lipid Res. 2008 Sep;47(5):348-80. doi: 10.1016/j.plipres.2008.03.003. Epub 2008 Apr 4. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Hodson L(1), Skeaff CM, Fielding BA. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK. leanne.hodson@oxlip.ox.ac.uk Accurate assessment of fat intake is essential to examine the relationships between diet and disease risk but the process of estimating individual intakes of fat quality by dietary assessment is difficult. Tissue and blood fatty acids, because they are mainly derived from the diet, have been used as biomarkers of dietary intake for a number of years. We review evidence from a wide variety of cross-sectional and intervention studies and summarise typical values for fatty acid composition in adipose tissue and blood lipids and changes that can be expected in response to varying dietary intake. Studies in which dietary intake was strictly controlled confirm that fatty acid biomarkers can complement dietary assessment methodologies and have the potential to be used more quantitatively. Factors affecting adipose tissue and blood lipid composition are discussed, such as the physical properties of triacylglycerol, total dietary fat intake and endogenous fatty acid synthesis. The relationship between plasma lipoprotein concentrations and total plasma fatty acid composition, and the use of fatty acid ratios as indices of enzyme activity are also addressed. PMID: 18435934 [PubMed - indexed for MEDLINE] 2442. J Endocrinol. 2008 May;197(2):189-204. doi: 10.1677/JOE-08-0054. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. Macfarlane DP(1), Forbes S, Walker BR. Author information: (1)Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK. Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushing's syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome. PMID: 18434349 [PubMed - indexed for MEDLINE] 2443. Mol Med. 2008 Jul-Aug;14(7-8):485-92. doi: 10.2119/2008-00038.Nathan. Epidemic inflammation: pondering obesity. Nathan C(1). Author information: (1)Department of Microbiology & Immunology, Weill Cornell Medical College, New York, NY, USA. cnathan@med.cornell.edu Over the past two decades, inflammation has been recognized as a major driver in the pathogenesis of several common diseases, including atherosclerosis, diabetes, cancer, and asthma. Over the same period, there has been a steep rise in the incidence of obesity, a major risk factor for these disorders. Inflammation of adipose tissue is now recognized to accompany obesity and contribute to its sequelae. Thus, whereas obesity is primarily a disorder of energy balance, it may be helpful to consider it also as a form of epidemic inflammation that predisposes to other forms of epidemic inflammation. It is a fundamental biologic challenge to understand how a positive energy balance and inflammation are linked. This work reviews evidence that reactive oxygen and nitrogen intermediates (ROI and RNI) help drive chronic inflammation in the obese. This is proposed to be a maladaptive instance of our evolved dependence on ROI and RNI for both homeostatic signaling and host defense. ROI and RNI are well suited for these seemingly contradictory dual functions by their metabolic origin, high diffusibility in water and lipid, atomic specificity, and large number of molecular targets. When we eat so much and work so little that we repeatedly generate reactive compounds at levels normally reserved for emergencies, we treat our own cells like invading microbes. PMCID: PMC2323335 PMID: 18431463 [PubMed - indexed for MEDLINE] 2444. Rev Physiol Biochem Pharmacol. 2008;160:93-125. doi: 10.1007/112_2008_802. Lipid homeostasis in macrophages - implications for atherosclerosis. Schmitz G(1), Grandl M. Author information: (1)Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany. gerd.schmitz@klinik.uni-regensburg.de In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann-Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism. PMID: 18425439 [PubMed - indexed for MEDLINE] 2445. Pharmacol Ther. 2008 May;118(2):181-91. doi: 10.1016/j.pharmthera.2008.02.003. Epub 2008 Mar 2. Prevention and treatment of type 2 diabetes: current role of lifestyle, natural product, and pharmacological interventions. Hays NP(1), Galassetti PR, Coker RH. Author information: (1)Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Common complications of type 2 diabetes (T2D) are eye, kidney and nerve diseases, as well as an increased risk for the development of cardiovascular disease and cancer. The overwhelming influence of these conditions contributes to a decreased quality of life and life span, as well as significant economic consequences. Although obesity once served as a surrogate marker for the risk of T2D, we know now that excess adipose tissue secretes inflammatory cytokines that left unchecked, accelerate the progression to insulin resistance and T2D. In addition, excess alcohol consumption may also increase the risk of T2D. From a therapeutic standpoint, lifestyle interventions such as dietary modification and/or exercise training have been shown to improve glucose homeostasis but may not normalize the disease process unless weight loss is achieved and increased physical activity patterns are established. Furthermore, utilization of natural products may serve as a significant adjunct in the fight against insulin resistance but further research is needed to ascertain their validity. Since it is clear that pharmaceutical therapy plays a significant role in the treatment of insulin resistance, this review will also discuss some of the newly developed pharmaceutical therapies that may work in conjunction with lifestyle interventions, and lessen the burden of behavioral change as the only strategy against the development of T2D. PMCID: PMC2441900 PMID: 18423879 [PubMed - indexed for MEDLINE] 2446. Eur J Pharmacol. 2008 May 6;585(1):163-75. doi: 10.1016/j.ejphar.2008.01.052. Epub 2008 Mar 4. A life course of adiposity and dementia. Gustafson D(1). Author information: (1)Institute of Neuroscience and Physiology, Section for Psychiatry and Neurochemistry, Sahlgrenska Academy at Göteborg University, Sweden. deb.gustafson@neuro.gu.se Adiposity, commonly measured as body mass index (BMI), may influence or be influenced by brain structures and functions involved in dementia processes. Adipose tissue changes in degree and intensity over the lifespan, and has been shown to influence brain development in relationship to early and late measures of cognitive function, intelligence, and disorders of cognition such as dementia. A lower BMI is associated with prevalent dementia, potentially due to underlying brain pathologies and correspondingly greater rates of BMI or weight decline observed during the years immediately preceding clinical dementia onset. However, high BMI during mid-life or at least approximately 5-10 years preceding clinical dementia onset may increase risk. The interplay of adiposity and the brain occurring over the course of the lifespan will be discussed in relationship to developmental origins, mid-life sequelae, disruptions in brain structure and function, and late-life changes in cognition and dementia. Characterizing the life course of adiposity among those who do and do not become demented enhances understanding of biological underpinnings relevant for understanding the etiologies of both dementia and obesity and their co-existence. PMID: 18423446 [PubMed - indexed for MEDLINE] 2447. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):550-6. doi: 10.1016/j.bbabio.2008.03.014. Epub 2008 Mar 29. Forty years of Mitchell's proton circuit: From little grey books to little grey cells. Nicholls DG(1). Author information: (1)Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA. dnicholls@buckinstitute.org It is more than forty years since Peter Mitchell published his first 'little grey book' laying out his chemiosmotic hypothesis. Although ideas about the molecular mechanisms of the proton pumps have evolved considerably since then, his concept of 'coupling through proton circuits' remains remarkably prescient, and has provided the inspiration for the research careers of this author and many others. This review is a personal account of how the proton circuit has been followed from the little grey book, via brown fat and calcium transport to investigations into the life and death of neurons, Hercule Poirot's 'little grey cells'. PMCID: PMC2475803 PMID: 18423395 [PubMed - indexed for MEDLINE] 2448. Obes Rev. 2008 May;9(3):219-35. doi: 10.1111/j.1467-789X.2007.00390.x. The potential role of soyfoods in weight and adiposity reduction: an evidence-based review. Cope MB(1), Erdman JW Jr, Allison DB. Author information: (1)Department of Nutrition Sciences, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA. Evidence concerning the relationship between soyfoods and weight loss was reviewed. Detailed searches of PubMed and Web of Science were performed to identify and evaluate evidence for or against four propositions related to soyfoods and weight loss (Data from in vitro, animal, epidemiologic, and clinical studies were evaluated and summarized). (1) Certain soyfoods will improve weight and/or fat loss when fed at isolcaloric levels (similar calories given across experimental conditions, but not necessarily at a level to maintain current body weight); generally supportive evidence in animal studies, but there is no compelling support in human studies. (2) Certain soyfoods will improve weight and fat loss when included as part of a diet by affecting caloric intake; limited supportive evidence in animal and human studies. (3) Certain soyfoods will prevent/improve risk factors related to glucoregulatory function and cardiovascular health during weight loss; some evidence supporting this proposition, but additional evidence is needed before conclusions can be made. (4) Certain soyfoods will minimize the loss of bone mass during weight loss; no data available pertinent to this proposition. Limitations in existing data make it difficult to reach conclusions regarding these four propositions. Overall, the current data suggest that soyfoods are as good as other protein sources for promoting weight loss and there is a suggestive body of evidence that soyfoods may confer additional benefits, but results must be carefully interpreted and additional evidence is needed before making firm conclusions concerning soyfoods and weight loss. PMID: 18419671 [PubMed - indexed for MEDLINE] 2449. J Dig Dis. 2008 May;9(2):63-7. doi: 10.1111/j.1751-2980.2008.00323.x. Impact of non-alcoholic fatty liver disease on accelerated metabolic complications. Fan JG(1). Author information: (1)Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China. fanjiangao@gmail.com Insulin resistance is the basis of both non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS), the two conditions are often found in the same individual. The mortality of patients with NAFLD is significantly higher than that among the general population and cardiovascular risk may compete with liver-related risk in dictating the final outcome. Recent prospective studies have reported that NAFLD is associated with an increased incidence of MetS and type 2 diabetes mellitus, independent of obesity and other components of MetS. Thus, NAFLD may not only be a liver disease but also an early mediator of type 2 diabetes mellitus and MetS. The biological mechanisms by which NAFLD contributes to a higher risk of developing metabolic disorders are not fully understood. However, the fatty liver could contribute in the same way as visceral adipose tissue to insulin resistance, systemic inflammation and oxidative stress, while the decreased serum adiponectin concentrations might also be part of the mechanism. In contemporary clinical practice, it has become mandatory to evaluate the metabolic risk factors in NAFLD patients and to consider careful surveillance and aggressive treatment, not only of the resultant liver disease, but also of the possible underlying metabolic and vascular complications. Future studies might address the question whether earlier adjustment to a more efficient lifestyle or a pharmacological treatment that mobilizes fat out of the liver could reduce these risks. PMID: 18419637 [PubMed - indexed for MEDLINE] 2450. Presse Med. 2008 Oct;37(10):1407-14. doi: 10.1016/j.lpm.2008.01.021. Epub 2008 Apr 15. [Abdominal obesity: a health threat]. [Article in French] Bruckert E(1). Author information: (1)Service d'endocrinologie-métabolisme, Hôpital Pitié-Salpêtrière, F-75013 Paris, France. eric.bruckert@psl.aphp.fr Abdominal obesity is often associated with a constellation of comorbidities that include central adiposity, insulin resistance, dyslipidemia, and hypertension. Clinical evaluations should include a measurement of waist circumference, which is a good marker of abdominal obesity. Abdominal obesity is closely associated with an elevated outflow of free fatty acids from the visceral fat compartment and dysregulation of adipokine expression, accompanied by increased inflammation. The most serious consequences of abdominal obesity are coronary heart disease and stroke. It is also associated, however, with polycystic ovary syndrome and hepatic steatosis. Weight reduction and increased physical activity should be recommended to patients with a high waist circumference. Patients with abdominal obesity and other classic risk factors are at high cardiovascular risk and require strict monitoring of their blood pressure, LDL-c, and blood glucose. New pharmacological strategies might help manage both abdominal obesity and its metabolic consequences. PMID: 18417315 [PubMed - indexed for MEDLINE] 2451. Biochem Biophys Res Commun. 2008 Jun 27;371(2):177-9. doi: 10.1016/j.bbrc.2008.04.013. Epub 2008 Apr 14. The PPARgamma coding region and its role in visceral obesity. Boon Yin K(1), Najimudin N, Muhammad TS. Author information: (1)School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia. kboonyin@yahoo.com Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor, plays many essential roles of biological function in higher organisms. The PPARgamma is mainly expressed in adipose tissue. It regulates the transcriptional activity of genes by binding with other transcription factor. The PPARgamma coding region has been found to be closest to that of monkey in ours and other research groups. Thus, monkey is a more suitable animal model for future PPARgamma studying, although mice and rat are frequently being used. The PPARgamma is involved in regulating alterations of adipose tissue masses result from changes in mature adipocyte size and/or number through a complex interplay process called adipogenesis. However, the role of PPARgamma in negatively regulating the process of adipogenesis remains unclear. This review may help we investigate the differential expression of key transcription factor in adipose tissue in response to visceral obesity-induced diet in vivo. The study may also provide valuable information to define a more appropriate physiological condition in adipogenesis which may help to prevent diseases cause by negative regulation of the transcription factors in adipose tissue. PMID: 18413145 [PubMed - indexed for MEDLINE] 2452. Przegl Lek. 2007;64(7-8):498-501. [The conjugated linoleic acids in prevention and treatment of obesity]. [Article in Polish] Swierczynski J(1), Szolkiewicz M, Rutkowski B. Author information: (1)Katedra i Zakład Biochemii Akademii Medycznej w Gdańsku. The results of up-to-date performed experimental studies indicated that conjugated linoleic acids (CLA) contained in diet lead to significant both adipose tissue and body mass decrease. It suggests that the CLA-rich diet or CLA-contained medicines can be useful in prevention and treatment of obesity in humans. The CLA-contained medicines are more and more popular, therefore the principle aim of this review is a description of CLA chemical structure, presence in natural products and moreover, their potential influence on adipose tissue mass in humans. Unfortunately, the results of recent trials are disappointing. Most of them indicated that (contrary to experimental studies) CLA were not profitable in adipose tissue mass decrease in humans. Moreover, in a few cases a deterioration of serum lipid profile, glycemia enhancement and decrease of tissue insulin sensitivity were observed. Thus, there is no evidence confirming the positive influence of CLA on adipose tissue mass in humans. However, there are also a few publications, in which the CLA-associated decrease of adipose tissue mass in humans was noted. The results of these studies do not let us totally decline the opinion that CLA are profitable also in humans. This contradictory data definitely needs further studies. PMID: 18409352 [PubMed - indexed for MEDLINE] 2453. Med Sci (Paris). 2008 Apr;24(4):407-13. doi: 10.1051/medsci/2008244407. [Glyceroneogenesis and PEPCK-C: pharmacological targets in type 2 diabetes]. [Article in French] Cadoudal T(1), Fouque F, Benelli C, Forest C. Author information: (1)Inserm UMR-S 747 ; Université Paris Descartes, Centre universitaire des Saints-Pères, 45, rue des Saints-Pères, 75006 Paris, France. Obesity is a major risk factor for insulin resistance and type 2 diabetes. The link between hypertrophied adipose tissue and this pathology is thought to be non-esterified fatty acids (NEFA) arising from adipocyte lipolysis. Sustained increase in plasma NEFA induces insulin resistance. In adipocytes, a significant part of lipolytic NEFA is re-esterified to triacylglycerol. Re-esterification requires glycerol-3-phosphate which, during fasting, is synthesized from lactate, pyruvate or certain amino acids in a metabolic pathway named glyceroneogenesis. The key enzyme in this pathway is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). In this review, we postulate that thiazolidinediones exert their hypolipidemic and antidiabetic effects in adipose tissue at least in part through a rapid and selective induction of PEPCK-C gene transcription leading to increased PEPCK-C and glyceroneogenesis. Subsequent fatty acid re-esterification participates in the reduction in blood NEFA and insulin resistance. PMID: 18405640 [PubMed - indexed for MEDLINE] 2454. J Nat Med. 2008 Apr;62(2):132-48. doi: 10.1007/s11418-007-0169-0. Epub 2008 Jan 18. Pharmacologically active compounds in the Anoectochilus and Goodyera species. Du XM(1), Irino N, Furusho N, Hayashi J, Shoyama Y. Author information: (1)Seiwa Pharmaceuticals Ltd., 1-12-15 Shiba-Daimon, Minato-ku, Tokyo, 105-8585, Japan. The extract of Anoectochilus formosanus showed significant activity in decreasing the levels of the cytosolic enzymes LDH, GOT, and GPT, and the result demonstrated that A. formosanus possessed prominent hepatoprotective activity against CCl(4)-induced hepatotoxicity. Moreover, in the results of the test using aurothioglucose-induced obese mice, the extract showed a significant antihyperliposis effect. A. formosanus grown in the wild and propagated by tissue culture contain ten compounds, including a major known component, (3R)-3-(beta-D-glucopyranosyloxy)butanolide (kinsenoside; 1), and two new components, (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanoic acid (2) and 2-[(beta-D-glucopyranosyloxy)methyl]-5-hydroxymethylfuran (3), along with the known compounds, isopropyl-beta-D-glucopyranoside (4), (R)-3,4-dihydroxybutanoic acid gamma-lactone (5), 4-(beta-D-glucopyranosyloxy) benzyl alcohol (6), (6R,9S)-9-(beta-D-glucopyranosyloxy)megastigma-4,7-dien-3-one (7), and (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanolide (8). Since a higher concentration of kinsenoside (1) was detected in the crude drugs A. formosanus and A. koshunensis by high-performance liquid chromatography (HPLC) analysis, we proved a simple purification system for kinsenoside (1), giving 180 mg of kinsenoside (1) from 1 g of dried samples for further pharmacological experiments. In an anti-hyperliposis assay using high-fat-diet rats, 1 significantly reduced the weights of the body and the liver, and also decreased the triglyceride level in the liver compared to those of control rats. On the other hand, the epimer of 1, (3S)-3-(beta-D-glucopyranosyloxy)butanolide, goodyeroside A (9), which was isolated from the Goodyera species, had no effect for anti-hyperliposis. In aurothioglucose-induced obese mice, 1 suppressed the body and liver weight increase, significantly ameliorated the triglyceride level in the liver, and also reduced the deposition of uterine fat pads. The anti-hepatoxic activities of 9 and goodyerosides B (10) were studied on injury induced by CCl(4) in primary cultured rat hepatocytes by measuring the levels of LDH, GOT, and GPT. In the CCl(4)-treated control group, there were marked increases in LDH, GOT, and GPT activities compared with the normal group. In contrast, these levels were suppressed in 9- and 10-treated groups. Goodyerin (11), a new typical flavone glycoside, exhibited a significant and dose-dependent sedative and anticonvulsant effect. PMID: 18404313 [PubMed - indexed for MEDLINE] 2455. J Cardiovasc Med (Hagerstown). 2008 May;9(5):450-60. doi: 10.2459/JCM.0b013e3282eee9a8. The role of adiposity as a determinant of an inflammatory milieu. Calabrò P(1), Limongelli G, Pacileo G, Di Salvo G, Golino P, Calabrò R. Author information: (1)Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, A O Monaldi, Naples, Italy. paolo.calabro@unina2.it With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they have been shown increasingly to affect several aspects of the pathogenesis of obesity-related diseases. Until relatively recently, the role of adipose tissue itself in the development of obesity and its consequences was considered to be a passive one. It is now clear that, in addition to storing energy in the form of triglycerides, adipocytes also secrete a large variety of proteins, including cytokines, chemokines and hormone-like factors. This production of proatherogenic chemokines by adipose tissue is of particular interest, since their local secretion, for example by perivascular adipose depots, may provide a novel mechanistic link between obesity and associated vascular complications. PMID: 18403996 [PubMed - indexed for MEDLINE] 2456. Curr Opin Clin Nutr Metab Care. 2008 May;11(3):214-21. doi: 10.1097/MCO.0b013e3282f9ae4d. Computational modeling of cancer cachexia. Hall KD(1), Baracos VE. Author information: (1)Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-5621, USA. kevinh@niddk.nih.gov PURPOSE OF REVIEW: Measurements of whole-body energy expenditure, body composition, and in-vivo metabolic fluxes are required to quantitatively understand involuntary weight loss in cancer cachexia. Such studies are rare because cancer cachexia occurs near the end of life when invasive metabolic tests may be precluded. Thus, models of cancer-associated weight loss are an important tool for helping to understand this debilitating condition. RECENT FINDINGS: A computational model of human macronutrient metabolism was recently developed that simulates the normal metabolic adaptations to semi-starvation and re-feeding. Here, this model was used to integrate data on the metabolic changes in patients with cancer cachexia. The resulting computer simulations show how the known metabolic disturbances synergize with reduced energy intake to result in a progressive loss of body weight, fat mass, and fat-free mass. The model was also used to simulate the effects of nutritional support and investigate inhibition of lipolysis versus proteolysis as potential therapeutic approaches for cancer cachexia. SUMMARY: Computational modeling is a new tool that can integrate clinical data on the metabolic changes in cancer cachexia and provide a conceptual framework to help understand involuntary weight loss and predict the effects of potential therapies. PMCID: PMC2693333 PMID: 18403915 [PubMed - indexed for MEDLINE] 2457. Curr Opin Clin Nutr Metab Care. 2008 May;11(3):201-7. doi: 10.1097/MCO.0b013e3282f948e2. Regulation of adipose tissue metabolism in cancer cachexia. Bing C(1), Trayhurn P. Author information: (1)Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, Liverpool, UK. bing@liverpool.ac.uk PURPOSE OF REVIEW: Body-fat depletion is a hallmark of cancer cachexia, a complex clinical syndrome associated with increased morbidity and mortality. Understanding the fat-loss disorder in cachexia is essential for the development of better treatments for the syndrome. This review presents recent studies focusing on the mechanisms of adipose atrophy in cancer cachexia, particularly the potential mediators. RECENT FINDINGS: Fat loss cannot be explained by poor appetite alone, and may also result from altered lipid metabolism in adipocytes. Increased lipolysis appears to be a key factor underlying fat loss in cancer cachexia though decreases in lipid deposition and adipocyte development may also contribute. Both tumour and host-derived factors are implicated in adipose tissue atrophy. Tumour necrosis factor-alpha has been associated with increased lipolysis in adipocytes. The novel adipokine zinc-alpha2-glycoprotein may function locally, as well as systemically, to promote lipid mobilization and utilization in cancer cachexia. SUMMARY: Clarifying the role of cachexia mediators in adipose tissue atrophy will add to our understanding of adipocyte metabolism in wasting disease. Elucidating their mode of action may lead to novel therapeutic targets for counteracting the cachexia syndrome. PMID: 18403913 [PubMed - indexed for MEDLINE] 2458. Am J Hosp Palliat Care. 2008 Oct-Nov;25(5):407-11. doi: 10.1177/1049909108315518. Epub 2008 Apr 10. Cytokines and cancer anorexia cachexia syndrome. Bennani-Baiti N(1), Davis MP. Author information: (1)Harry R. Horvitz Center for Palliative Medicine (a World Health Organization demonstration project in palliative medicine), Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio 44195, USA. Cancer anorexia cachexia syndrome is frequent yet still a not well understood cancer-related problem. The pathophysiology of cancer cachexia is multifactorial. It is suggested to be the result of tumor-host interactions and studies of the disturbances seen during cancer anorexia cachexia syndrome, such as anorexia, hyper-metabolism, tissue wasting, metabolic abnormalities, and hormonal changes, all point to the involvement in one way or another of one key factor: cytokines. The purpose of this review is to summarize the latest developments in the field of cytokines and their role in cancer anorexia cachexia syndrome. The emphasis is on the role of cytokines in anorexia and tissue wasting. PMID: 18403577 [PubMed - indexed for MEDLINE] 2459. Rev Invest Clin. 2007 Nov-Dec;59(6):458-69. [AMPK as a cellular energy sensor and its function in the organism]. [Article in Spanish] Miranda N(1), Tovar AR, Palacios B, Torres N. Author information: (1)Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México. The adenine monophosphate (AMP) activated protein kinase (AMPK), is a heterotrimeric complex that is activated by an increase in the AMP/ATP ratio, and is considered to be a cellular energy sensor that contributes to regulate energy balance and caloric intake. AMPK is activated by LKB1 hinase and it can phophorylate several enzymes involved in anabolism to prevent further ATP consumption, and induces some catabolic enzymes to increase ATP generation. Furthermore, AMPK regulates the expression of genes involved in lipogenesis and mitochondrial biogenesis, among others. AMPK is distributed in most organs including, liver, skeletal muscle, heart and hypothalamus; and even in adipose cells. In addition, AMPK is activated in the hypothalamus stimulating appetite due to energy depletion. AMPK also participates in glycolysis regulation, glucose uptake, lipid oxidation, fatty acid synthesis, cholesterol synthesis and gluconeogenesis, and it has been considered as a possible target enzyme in the treatment of some diseases such as obesity, type 2 diabetes and hepatic steatosis. This review provides a general overview of AMPK structure, its activators and its function in the organism. PMID: 18402338 [PubMed - indexed for MEDLINE] 2460. Nat Rev Mol Cell Biol. 2008 May;9(5):367-77. doi: 10.1038/nrm2391. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Guilherme A(1), Virbasius JV, Puri V, Czech MP. Author information: (1)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids. PMCID: PMC2886982 PMID: 18401346 [PubMed - indexed for MEDLINE] 2461. Diab Vasc Dis Res. 2008 Mar;5(1):9-14. doi: 10.3132/dvdr.2008.002. The importance of treating cardiometabolic risk factors in patients with type 2 diabetes. Barnett AH(1). Author information: (1)Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Birmingham, B9 5SS, UK. anthony.barnett@heartofengland.nhs.uk Cardiometabolic risk factors are the combined vascular and metabolic components of risk that may lead to a cardiovascular event. There are numerous such factors. Underlying the concept of cardiometabolic risk is an association with excess visceral fat, leading to the dysregulation of the adipokines, the signalling proteins derived from adipose tissue. Changes in the levels of the adipokines - tumour necrosis factor-alpha, cholesteryl ester transfer protein and adiponectin, for example - can lead to alterations in insulin sensitivity and high-density lipoprotein cholesterol metabolism. At present, specific cardiometabolic risk factors are commonly managed on an individual basis. We are now moving from the era of single risk factor intervention, however, to multiple risk factor intervention in people at high cardiovascular risk, with the additional possibility of using new drug classes to target the underlying cardiometabolic problems more effectively. PMID: 18398806 [PubMed - indexed for MEDLINE] 2462. J Hypertens. 2008 May;26(5):831-43. doi: 10.1097/HJH.0b013e3282f624a0. Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans. Sarzani R(1), Salvi F, Dessì-Fulgheri P, Rappelli A. Author information: (1)Department of Internal Medicine, Centre for Atherosclerosis and Metabolic Syndrome (Hypertension Excellence Centre of the European Society of Hypertension), University of Ancona - Politecnica delle Marche, Ancona, Italy. r.sarzani@univpm.it Comment in J Hypertens. 2009 Mar;27(3):658-9. The obesity pandemic is closely related to hypertension and metabolic syndrome. Visceral adipose tissue plays a key role in the metabolic and cardiovascular complications of being overweight. The pathophysiological link between visceral adiposity and cardiometabolic complications focuses on insulin sensitivity, sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS) and, only recently, on cardiac natriuretic peptide system (CNPS). RAAS and CNPS are endogenous antagonistic systems on sodium balance, cardiovascular system, and metabolism. The circulating RAAS is dysregulated in obese patients, and adipose tissue has a full local renin-angiotensin system that is active at local and systemic level. Adipocyte biology and metabolism are influenced by local renin-angiotensin system, with angiotensin II acting as a 'growth factor' for adipocytes. CNPS induces natriuresis and diuresis, reduces blood pressure, and, moreover, has powerful lipolytic and lipomobilizing activity in humans but not in rodents. In obesity, lower plasmatic natriuretic peptides levels with increasing BMI, waist circumference, and metabolic syndrome have been documented. Thus, reduced CNPS effects coupled with increased RAAS activity have a central role in obesity and its deadly complications. We propose herein an integrated view of the dysregulation of these two antagonistic systems in human obesity complicated with hypertension, metabolic syndrome, and increased cardiovascular risk. PMID: 18398321 [PubMed - indexed for MEDLINE] 2463. Neurol Res. 2008 Mar;30(2):123-30. doi: 10.1179/174313208X281136. Walking performance, medical outcomes and patient training in FES of innervated muscles for ambulation by thoracic-level complete paraplegics. Graupe D(1), Cerrel-Bazo H, Kern H, Carraro U. Author information: (1)University of Illinois, 851 South Morgan St., Chicago, IL 60607-7053, USA. Erratum in Neurol Res. 2008 Sep;30(7):768-9. OBJECTIVE: To discuss functional electric stimulation (FES) gait training of upper motoneuron spinal cord injured complete paraplegics considering ambulation performance, physiologic and metabolic responses as well as psychologic outcome, while providing myologic insight into ambulation via FES when training starts many years post-injury. METHODS: Transcutaneous FES using the Parastep stimulation system, gait training methods with and without major emphasis on muscle reinforcement, cardiovascular and respiratory conditioning. Examination of myofiber tissues and correlation of normal muscles histology versus innervated muscles of upper motor neuron and of denervated muscles of lower motor neuron paraplegics. RESULTS: Published works in literature reviewed in this paper report average walking distance of 440 m/walk when major muscle reinforcement and preconditioning cardiovascular and respiratory systems precedes gait training, versus average 115 m/walk when undergoing direct gait training. Medical, metabolic and psychologic outcomes, as reported in several works, point to benefits of FES walking, including 60% increase in blood flow to lower extremities. Myofiber tissues of patients with upper motor neuron paralysis compare well with those of normal tissue even many years post-injury, while adipose tissue substitute muscle fibers in patients with lower motor neuron lesions. DISCUSSION: Transcutaneous FES allows considerably longer walking distances and speed at the end of training when training involves an extensive pre-conditioning program than with direct gait training. Medical and psychologic benefits are observed, especially concerning blood flow to the lower extremities. Myofiber examinations provide myologic understanding of effectiveness of FES many years post-injury. PMID: 18397602 [PubMed - indexed for MEDLINE] 2464. Br J Nutr. 2008 Aug;100(2):227-35. doi: 10.1017/S0007114508971282. Epub 2008 Apr 9. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Trayhurn P(1), Wang B, Wood IS. Author information: (1)Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, University Clinical Department, Duncan Building, Liverpool L69 3GA, UK. p.trayhurn@liverpool.ac.uk Comment in Br J Nutr. 2008 Aug;100(2):236-7. White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-alpha, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr 92, 347-355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1 alpha, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome. PMID: 18397542 [PubMed - indexed for MEDLINE] 2465. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):637-41. doi: 10.1016/j.bbabio.2008.03.006. Epub 2008 Mar 18. An ancient look at UCP1. Klingenspor M(1), Fromme T, Hughes DA Jr, Manzke L, Polymeropoulos E, Riemann T, Trzcionka M, Hirschberg V, Jastroch M. Author information: (1)Technische Universität München, Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Freising-Weihenstephan, Germany. martin.klingenspor@wzw.tum.de Brown adipose tissue serves as a thermogenic organ in placental mammals to defend body temperature in the cold by nonshivering thermogenesis. The thermogenic function of brown adipose tissue is enabled by several specialised features on the organ as well as on the cellular level, including dense sympathetic innervation and vascularisation, high lipolytic capacity and mitochondrial density and the unique expression of uncoupling protein 1 (UCP1). This mitochondrial carrier protein is inserted into the inner mitochondrial membrane and stimulates maximum mitochondrial respiration by dissipating proton-motive force as heat. Studies in knockout mice have clearly demonstrated that UCP1 is essential for nonshivering thermogenesis in brown adipose tissue. For a long time it had been presumed that brown adipose tissue and UCP1 emerged in placental mammals providing them with a unique advantage to survive in the cold. Our subsequent discoveries of UCP1 orthologues in ectotherm vertebrates and marsupials clearly refute this presumption. We can now initiate comparative studies on the structure-function relationships in UCP1 orthologues from different vertebrates to elucidate when during vertebrate evolution UCP1 gained the biochemical properties required for nonshivering thermogenesis. PMID: 18396149 [PubMed - indexed for MEDLINE] 2466. Nutr Metab Cardiovasc Dis. 2008 Jun;18(5):388-95. doi: 10.1016/j.numecd.2007.10.002. Epub 2008 Apr 18. Sarcopenic obesity: a new category of obesity in the elderly. Zamboni M(1), Mazzali G, Fantin F, Rossi A, Di Francesco V. Author information: (1)Geriatric Medicine, Cattedra di Geriatria, University of Verona, Ospedale Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. mauro.zamboni@univr.it BACKGROUND AND AIM: In elderly patients, age-related changes in body composition, as well as the increased prevalence of obesity, determine a combination of excess weight and reduced muscle mass or strength, recently defined as sarcopenic obesity (SO). This review examines the main studies regarding sarcopenic obesity in the elderly. DATA SYNTHESIS: Definition of SO necessarily combines those of sarcopenia and obesity. The prevalence of sarcopenia and SO increases with age. Muscle and fat mass are strongly interconnected from a pathogenetic point of view. A better understanding of the mechanisms which lead from loss of muscle mass to fat gain or vice versa from fat gain to muscle loss seems to be crucial. Recent data suggest that peptides produced by adipose tissue may play an important role in the pathophysiology of SO, thus more research is needed to better characterize this new area. Obesity and sarcopenia in the elderly may potentiate each other maximizing their effects on disability, morbidity and mortality. Identifying elderly subjects with SO should be mandatory; effective treatment of sarcopenia and SO may attenuate its clinical impact. CONCLUSION: The concept of SO may help to clarify the relationship between obesity, morbidity and mortality in the elderly. PMID: 18395429 [PubMed - indexed for MEDLINE] 2467. Biochimie. 2008 Jun;90(6):838-42. doi: 10.1016/j.biochi.2008.03.009. Epub 2008 Apr 3. Born to run; the story of the PEPCK-Cmus mouse. Hanson RW(1), Hakimi P. Author information: (1)Department of Biochemistry, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA. rwh@case.edu In order to study the role of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) in skeletal muscle, PEPCK-Cmus mice were created by introducing the cDNA for the enzyme, linked to the human alpha-skeletal actin gene promoter, into their germ line. Two founder lines generated by this procedure were bred together, creating a line of mice that have 9.0 units/g skeletal muscle of PEPCK-C, as compared to 0.080 units/g in muscle from control animals. The mice were more active than controls in their cages and could run for up to 5 km, at a speed of 20 m/min without stopping (control mice run for 0.2 km at the same speed). Male PEPCK-Cmus mice are extremely aggressive, as well as hyperactive. During strenuous exercise, they use fatty acids as a fuel more efficiently than do controls and produce far less lactate than do control animals, perhaps due to the greatly increased number of mitochondria in their skeletal muscle. PEPCK-Cmus mice also store up to five-times more triglyceride in their skeletal muscle, but have only marginal amounts of triglyceride in their adipose tissue depots, despite eating 60% more than controls. The concentration of leptin and insulin the blood of 8-12 months of PEPCK-Cmus mice is far lower than noted in the blood of control animals of the same age. These mice live longer than controls and the females remain reproductively active for as long as 35 months. The possible reasons for the profound alteration in activity and longevity caused the introduction of a simple metabolic enzyme into the skeletal muscle of the mice will be discussed. PMCID: PMC2491496 PMID: 18394430 [PubMed - indexed for MEDLINE] 2468. Dermatol Ther. 2008 Mar-Apr;21(2):118-30. doi: 10.1111/j.1529-8019.2008.00179.x. Esthetic and cosmetic dermatology. Wollina U(1), Goldman A, Berger U, Abdel-Naser MB. Author information: (1)Department of Dermatology and Allergology, Hospital Dresden-Friedrichstadt, Dresden, Germany. wollina-uw@khdf.de The field of esthetic and cosmetic dermatology has gained remarkable interest all over the world. The major advantage of recent years is the high scientific levels of the most significant new developments in techniques and pharmacotherapy and other nonsurgical approaches. The present paper reviews selected fields of interest under this view. Sexual hormones are involved in the aging process of men and women. Skin function, in particular the epidermal barrier, is affected by a loss of endocrine activity. Hormone replacement therapy has only recently been introduced in treatment of aging males. This is an area of gender-medicine in dermatology with a strong well-aging attempt. Botulinum toxin therapy for hyperfunctional lines has become not only well-established but evidence-based medicine on its highest level. Recent advantages were gained in objective evaluation and monitoring the effect. Digital imaging techniques with various facets have been introduced to assess the achievements of treatment in the most objective way. This may become an example for other techniques as peeling, laser therapy, or radiofrequency in esthetic and cosmetic dermatology. Botulinum toxin has become a valuable tool for brow lifts. Details of the technique are discussed. Cellulite is a strongly female gender-related condition. During the past decades numerous treatments had been recommended but only recently a more critical scientific approach led to improvements in therapy of this common and disfiguring condition. Three major approaches are developed: (a) skin loosing with techniques such as subcision, (b) skin tightening with radiofrequency and other approaches, and (c) improving circulation in blood and lymphatic microvasculature using both physical treatments and pharmacotherapy. The last two chapters are devoted to body sculpturing by lipotransfer and lipolysis. Lipotransfer for facial or body sculpturing has a history of about 100 years. Nevertheless, recently the role of adult stem cells in adipose tissue has gained much interest. By optimizing the harvesting, storage, and transplantation of adipose tissue, remarkable long-standing results have been obtained. Here the present authors will focus on midface contouring, where lipotransfer competes with dermal fillers. Lipolysis is another effective tool in body sculpturing. The present authors will focus on recent advances in laser-assisted lipolysis for delicate body sculpturing in the submental region but also for gynecomastia abdominal region, flanks, and hips. In conclusion, esthetic and cosmetic dermatology has become a scientific-based subspeciality of dermatology with evidence-based treatments and a great variety of high-tech approaches to provide more effective, more selective, and safer therapeutic options. PMID: 18394086 [PubMed - indexed for MEDLINE] 2469. Curr Gene Ther. 2008 Apr;8(2):79-87. Virus-based gene transfer approaches and adipose tissue biology. Casteilla L(1), Cousin B, Planat-Benard V, Laharrague P, Carmona M, Pénicaud L. Author information: (1)UMR 5241 CNRS UPS IFR31, IFR109 Institut Louis Bugnard BP 84225, 31432 Toulouse Cedex 4, France. casteil@toulouse.inserm.fr The status of adipose tissue changes rapidly. From a simple filler tissue, it successively acquires the status of metabolic active tissue, endocrine tissue, plastic tissue, and finally that of a large reservoir of cells suitable for cell therapy and regenerative medicine. All throughout this story, our knowledge has been largely dependent on genetic tools and gene transfer. Now, the time has come where gene transfer in adipose derived cells can be envisioned, not only for understanding the role or importance of one gene, but also to engineer adipose derived cells for the purpose of therapy by delivering secreted products. In this paper, after a brief overview of adipose tissues, a large part will be devoted to the use of virus-based gene transfer in transducing adipose tissue and cells which reside therein. We also critically review the use of adipose "specific" promoters and the applications already described in the literature. PMID: 18393829 [PubMed - indexed for MEDLINE] 2470. Oncogene. 2008 Apr 7;27(16):2320-36. doi: 10.1038/onc.2008.25. The role of FoxO in the regulation of metabolism. Gross DN(1), van den Heuvel AP, Birnbaum MJ. Author information: (1)Institute for Diabetes, Obesity and Metabolism, Cox Institute, University of Pennsylvania School of Medicine and the Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA. Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. Glucose homeostasis is achieved by adjusting endogenous glucose production as well as glucose uptake by peripheral tissues in response to insulin. In the fasted state, the liver is primarily responsible for maintaining glucose levels, with FoxO1 playing a key role in promoting the expression of gluconeogenic enzymes. Following feeding, pancreatic beta cells secrete insulin, which promotes the uptake of glucose by peripheral tissues including skeletal muscle and adipose tissue, and can in part suppress gluconeogenic enzyme expression in the liver. In addition to directly regulating metabolism, FoxO1 also plays a role in the formation of both adipose tissue and skeletal muscle, two major organs that are critical for maintaining energy homeostasis. The importance of FoxO1 in energy homeostasis is particularly striking under conditions of metabolic dysfunction or insulin resistance. In obese or diabetic states, FoxO1-dependent gene expression promotes some of the deleterious characteristics associated with these conditions, including hyperglycemia and glucose intolerance. In addition, the increase in pancreatic beta cell mass that normally occurs in response to a rise in insulin demand is blunted by nuclear FoxO1 expression. However, under these same pathophysiological conditions, FoxO1 expression may help drive the expression of genes involved in combating oxidative stress, thereby preserving cellular function. FoxO1 may also be involved in promoting the switch from carbohydrate to fatty acid as the major energy source during starvation. PMID: 18391974 [PubMed - indexed for MEDLINE] 2471. Physiol Rev. 2008 Apr;88(2):389-419. doi: 10.1152/physrev.00017.2007. Cardiac remodeling in obesity. Abel ED(1), Litwin SE, Sweeney G. Author information: (1)Department of Biology, York University, Toronto, Canada. The dramatic increase in the prevalence of obesity and its strong association with cardiovascular disease have resulted in unprecedented interest in understanding the effects of obesity on the cardiovascular system. A consistent, but puzzling clinical observation is that obesity confers an increased susceptibility to the development of cardiac disease, while at the same time affording protection against subsequent mortality (termed the obesity paradox). In this review we focus on evidence available from human and animal model studies and summarize the ways in which obesity can influence structure and function of the heart. We also review current hypotheses regarding mechanisms linking obesity and various aspects of cardiac remodeling. There is currently great interest in the role of adipokines, factors secreted from adipose tissue, and their role in the numerous cardiovascular complications of obesity. Here we focus on the role of leptin and the emerging promise of adiponectin as a cardioprotective agent. The challenge of understanding the association between obesity and heart failure is complicated by the multifaceted interplay between various hemodynamic, metabolic, and other physiological factors that ultimately impact the myocardium. Furthermore, the end result of obesity-associated changes in the myocardial structure and function may vary at distinct stages in the progression of remodeling, may depend on the individual pathophysiology of heart failure, and may even remain undetected for decades before clinical manifestation. Here we summarize our current knowledge of this complex yet intriguing topic. PMCID: PMC2915933 PMID: 18391168 [PubMed - indexed for MEDLINE] 2472. Eur J Pharmacol. 2008 May 6;585(1):119-29. doi: 10.1016/j.ejphar.2008.02.048. Epub 2008 Mar 4. Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: an epidemiological perspective. Luchsinger JA(1). Author information: (1)Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. jal94@columbia.edu The objective of this manuscript is to provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer's disease. The mechanisms for these associations remain to be elucidated, but may include direct actions from insulin, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of Alzheimer's disease. The evidence relating adiposity in old age to Alzheimer's disease is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer's disease. Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer's disease risk. Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer's disease. The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer's disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes. However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer's disease. PMCID: PMC2474785 PMID: 18384771 [PubMed - indexed for MEDLINE] 2473. Mol Nutr Food Res. 2008 Aug;52(8):855-66. doi: 10.1002/mnfr.200700050. Leptin, adiponectin, resistin, and ghrelin--implications for inflammatory bowel disease. Karmiris K(1), Koutroubakis IE, Kouroumalis EA. Author information: (1)Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Crete, Greece. Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells, are involved in these manifestations of IBD. Among adipokines leptin, adiponectin and resistin hold a fundamental role while the role of ghrelin in inflammation is not well established. Preliminary studies have shown overexpression of leptin, adiponectin, and resistin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of these adipokines in IBD. It has also been demonstrated that intestinal inflammation causes an increase in endogenous ghrelin production. In animal models of intestinal inflammation, existing data suggest that leptin, adiponectin, and resistin are pivotal mediators of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of adipokines in IBD. PMID: 18383234 [PubMed - indexed for MEDLINE] 2474. Leg Med (Tokyo). 2008 Sep;10(5):229-35. doi: 10.1016/j.legalmed.2008.01.006. Epub 2008 Apr 1. Objective post-mortem diagnosis of chronic alcohol abuse--a review of studies on new markers. Rainio J(1), De Giorgio F, Bortolotti F, Tagliaro F. Author information: (1)Institute of Legal Medicine, Catholic University of the Sacred Heart, School of Medicine, Rome, Italy. juha.rainio@uta.fi Identification of chronic excessive alcohol consumption in living and deceased individuals is a fundamental task in forensic pathology. Reliable methods for post-mortem diagnosis of chronic alcohol abuse are required because morphological findings are unspecific and ante-mortem data are often unreliable. In clinical practice, several biochemical markers indirectly demonstrating chronic alcohol abuse are employed, but thus far these methods have not been used in routine post-mortem investigations. We reviewed publications in which these markers have been applied to autopsy material. Based on this review, some of these biochemical parameters are useful in post-mortem diagnostics, although further systematic research is required. PMID: 18381246 [PubMed - indexed for MEDLINE] 2475. Mayo Clin Proc. 2008 Apr;83(4):460-9. doi: 10.4065/83.4.460. Gut microbiota and its possible relationship with obesity. DiBaise JK(1), Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Author information: (1)Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. dibaise.john@mayo.edu Obesity results from alterations in the body's regulation of energy intake, expenditure, and storage. Recent evidence, primarily from investigations in animal models, suggests that the gut microbiota affects nutrient acquisition and energy regulation. Its composition has also been shown to differ in lean vs obese animals and humans. In this article, we review the published evidence supporting the potential role of the gut microbiota in the development of obesity and explore the role that modifying the gut microbiota may play in its future treatment. Evidence suggests that the metabolic activities of the gut microbiota facilitate the extraction of calories from ingested dietary substances and help to store these calories in host adipose tissue for later use. Furthermore, the gut bacterial flora of obese mice and humans include fewer Bacteroidetes and correspondingly more Firmicutes than that of their lean counterparts, suggesting that differences in caloric extraction of ingested food substances may be due to the composition of the gut microbiota. Bacterial lipopolysaccharide derived from the intestinal microbiota may act as a triggering factor linking inflammation to high-fat diet-induced metabolic syndrome. Interactions among microorganisms in the gut appear to have an important role in host energy homeostasis, with hydrogen-oxidizing methanogens enhancing the metabolism of fermentative bacteria. Existing evidence warrants further investigation of the microbial ecology of the human gut and points to modification of the gut microbiota as one means to treat people who are over-weight or obese. PMID: 18380992 [PubMed - indexed for MEDLINE] 2476. J Drugs Dermatol. 2008 Mar;7(3):209-20. Dermatological implications of skeletal aging: a focus on supraperiosteal volumization for perioral rejuvenation. Vleggaar D(1), Fitzgerald R. Author information: (1)Le Col, Les Escombes, Roussas, France. drdanny@vleggaar.net It is becoming widely accepted that volume changes in the skin and soft tissue contribute greatly to age-related facial reshaping. A significant contribution to these volume changes is the loss of craniofacial skeletal support to the overlying soft tissue. Gravity, once considered the major culprit in facial aging, is now recognized to determine the direction, rather than the extent, of tissue deflation. Although the sequence of events observed in aging is somewhat predictable, its pace among individuals is variable and may be influenced by both intrinsic (e.g., gender, genetics) and extrinsic (e.g., photoaging, smoking, stress) factors. Changes in different tissue layers within a single individual do not occur independently, but interdependently; changes in one tissue within an individual may influence subsequent changes in other tissues. Midfacial soft tissue descent has been observed in response to decreased craniofacial support in both congenital craniofacial hypoplasia and following trauma, leading to a hypothesis that the loss of underlying bony support for any reason, including aging, leads to soft tissue descent in the face. As craniofacial support (the "table") decreases, it leaves less surface area for the outer soft tissue envelope (the "tablecloth") causing it to fold or sag. Replacing this deep support with craniofacial implants has been shown to reposition the overlying soft tissue. Following a brief review of the current literature on aging changes in the skin, soft tissue, and bone; the authors describe their experience with the use of poly-L-lactic acid (PLLA), both as a soft tissue volumizer and as an injectable craniofacial implant in a supraperiosteal location to address both soft tissue volume loss and loss of craniofacial support. In the cases presented, the most striking result noted was the ability to restore a youthful proportion to the perioral area, which had not been achieved previously with soft tissue treatment alone. PMID: 18380202 [PubMed - indexed for MEDLINE] 2477. Curr Atheroscler Rep. 2007 Dec;9(6):486-93. Trans fatty acids and cardiovascular risk: a unique cardiometabolic imprint? Mozaffarian D(1), Willett WC. Author information: (1)Departments of Nutrition and Epidemiology, Harvard School of Public Health, 665 Huntington Avenue, Building 2-319, Boston, MA 02115, USA. dmozaffa@hsph.harvard.edu Evidence from randomized controlled trials indicates that consumption of trans fatty acids (TFA) leads to harmful changes in serum lipids, systemic inflammation, endothelial function, and, in nonhuman primates, visceral adiposity and insulin resistance. Prospective observational studies demonstrate strong positive associations between TFA consumption and risk of myocardial infarction, coronary heart disease death, and sudden death. Links have also been seen between TFA intake and incidence of diabetes, adiposity, and other chronic conditions. The physiologic effects demonstrated in randomized trials suggest that TFA consumption produces a unique cardiometabolic imprint via pathways linked to the insulin resistance syndrome. The strength and consistency of the evidence for harmful effects of TFA, together with the feasibility of elimination of industrially produced TFA from foods, indicates little reason for continued use of partially hydrogenated oils containing TFA in food preparation and manufacturing. Consumer education regarding the sources and hazards of TFA, combined with voluntary or legislated adoption by restaurants and food manufacturers of alternatives to partially hydrogenated oils, could avert tens of thousands of coronary events each year in the United States and around the world. PMID: 18377789 [PubMed - indexed for MEDLINE] 2478. Mitochondrion. 2008 Sep;8(4):329-37. doi: 10.1016/j.mito.2008.02.001. Epub 2008 Feb 26. Nuclear receptors, mitochondria and lipid metabolism. Alaynick WA(1). Author information: (1)Gene Expression Laboratory,The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, United States. alaynick@salk.edu Comment in Mitochondrion. 2008 Sep;8(4):328. Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs), acting in concert with PPARgamma Coactivator 1alpha (PGC-1alpha), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia and obesity). Recently, additional partners of PGC-1alpha have moved to the forefront of metabolic research, the estrogen-related receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function. PMCID: PMC2831104 PMID: 18375192 [PubMed - indexed for MEDLINE] 2479. Obes Rev. 2008 May;9(3):246-50. doi: 10.1111/j.1467-789X.2008.00481.x. Epub 2008 Mar 26. FTO: the first gene contributing to common forms of human obesity. Loos RJ(1), Bouchard C. Author information: (1)MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK. ruth.loos@mrc-epid.cam.ac.uk Genome-wide association, the latest gene-finding strategy, has led to the first major success in the field of obesity genetics with the discovery of FTO (fat mass and obesity associated gene) as an obesity-susceptibility gene. A cluster of variants in the first intron of FTO showed a strong and highly significant association with obesity-related traits in three independent genome-wide association studies, a finding that has been replicated in several other studies including adults and children of European descent. Homozygotes for the risk allele weigh on average 3-4 kg more and have a 1.67-fold increased risk of obesity compared with those who did not inherit a risk allele. We are still at an early stage in our understanding of the pathways through which FTO confers to increased obesity risk. Studies in humans and rodents have suggested a central role for FTO through regulation of food intake, whereas others have proposed a peripheral role through an effect on lipolytic activity in adipose tissue. There is no doubt that many more obesity-susceptibility loci remain to be discovered. Progress on this front will therefore require major collaborative efforts and pooling of compatible datasets. We stand to learn a lot about the genetic architecture of human obesity in the coming years. The expectations are high but many challenges remain. Among the latter, translating new advances into useful guidelines for prevention and treatment of obesity will be the most demanding. PMID: 18373508 [PubMed - indexed for MEDLINE] 2480. Metab Syndr Relat Disord. 2005 Summer;3(2):147-73. doi: 10.1089/met.2005.3.147. Evaluating the cardiovascular effects of the thiazolidinediones and their place in the management of type 2 diabetes in relation to the metabolic syndrome. Drexler AJ(1), Nesto RW, Abrahamson MJ, Bakris G, Bell D, Brunzell J, Dandona P, Davidson J, Fonseca V, Fowler M, Frye R, Giles T, Haffner S, Hollenberg N, Hsueh W, Law R, Plutzky J, Ratner R, Reusch J, Selwyn A, Sowers J, Wyne K, Young LH. Author information: (1)Clinical Associate Professor of Medicine, New York University School of Medicine, New York University, New York, New York. BACKGROUND: The aim of this work was to review evidence on the contribution of the metabolic syndrome to diabetes and atherosclerosis, to evaluate the effects of the thiazolidinediones (TZDs) on cardiovascular risk, and to assess the clinical use of TZDs and their associated risks and benefits. METHODS: Participants were a multidisciplinary panel of experts in endocrinology, cardiology, and nephrology. Available studies on hyperglycemia, hyperinsulinemia, beta-cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial dysfunction, and vascular reactivity were reviewed through presentations by the experts. Assessments were made regarding the associations between characteristics of the metabolic syndrome, type 2 diabetes, and cardiovascular disease, along with the place of TZDs in therapy and management of related adverse clinical events. A panel was convened in November 2002 to develop conclusions based on scientific evidence presented during the meeting. Summary statements were evaluated based on strength and clinical relevance of the data and approved by all panel members. RESULTS AND CONCLUSIONS: Many characteristics of the metabolic syndrome are present before diabetes develops that greatly contribute to the cardiovascular disease burden associated with the progression of diabetes, such as atherosclerosis and coronary artery disease. Insulin resistance is a fundamental component of the metabolic syndrome, and interventions to improve insulin sensitivity are associated with positive cardiovascular effects. From current experimental and clinical data, TZDs appear to reduce risk factors for future cardiovascular events in patients with type 2 diabetes. Study data up to 2 years have demonstrated that TZDs effectively maintain glycemic control in patients with type 2 diabetes, which is attributed to their insulin-sensitizing effects and preservation of beta-cell function. Potential adverse events of TZDs include weight gain and edema, which are generally manageable. Aside from improving insulin sensitivity, TZDs improve lipid profiles, favorably alter deposition of adipose tissue to the periphery rather than visceral areas, decrease markers of inflammation and endothelial dysfunction, and restore vascular reactivity. These pleiotropic effects have the potential to improve cardiovascular outcomes in patients with type 2 diabetes. Trials are underway to confirm this potentially beneficial addition to proven therapies for hypertension, dyslipidemia, and atherosclerosis. PMID: 18370723 [PubMed] 2481. Metab Syndr Relat Disord. 2004 Jun;2(2):114-23. doi: 10.1089/met.2004.2.114. Adiponectin and leptin in relation to insulin sensitivity. Soodini GR(1). Author information: (1)Clinical Research Center, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts. An increased amount of adipose tissue or its disproportionate distribution between central and peripheral body regions is related to the development of insulin resistance, type 2 diabetes mellitus, dyslipidemia, atherosclerosis, and coronary artery disease. Until recently, adipose tissue was regarded as a storage depot for lipids. It is now viewed as a hormonally active organ that plays a crucial metabolic role. The most important products of adipose tissue collectively referred to as adipocytokines, include adiponectin, leptin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), resistin, plasminogen-activating inhibitor-I (PAI-1), and angiotensinogen. These low and medium molecular weight proteins play an important role in the adipose tissue physiology and are believed to be a link between obesity, insulin resistance and endothelial dysfunction. This review describes the metabolic role of two of these proteins, adiponectin and leptin, in relation to insulin sensitivity. PMID: 18370642 [PubMed] 2482. Methods Mol Biol. 2008;423:449-60. doi: 10.1007/978-1-59745-194-9_35. Muscle and fat mass modulation in different clinical models. Draghia-Akli R(1), Khan AS. Author information: (1)VGX Pharmaceuticals, Immune Therapeutics Division, The Woodlands, TX, USA. Studies described in the recent literature support the idea that gene therapy can lead to genuine clinical benefits when mediated by plasmid delivery in conjunction with electroporation. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical-grade therapy delivered by simple intramuscular injection. This approach is particularly appropriate for modulating muscle and fat mass and their intrinsic properties, from treatment of conditions such as cachexia associated with chronic diseases, autoimmune diseases, e.g., myasthenia gravis, to stimulation or suppression of appetite, and further to in vivo manipulation of glucose metabolism and fat deposition in patients with diabetes, or to basic studies of muscle-specific transcription factors and their impact in development. Recent innovations, including in situ electroporation, enabling sustained systemic protein delivery within the therapeutic range, are reviewed. Translation of these advances to human clinical trials will enable muscle- and fat-targeted gene therapy to become a viable therapeutic alternative. PMID: 18370221 [PubMed - indexed for MEDLINE] 2483. Int Urol Nephrol. 2008;40(2):443-51. doi: 10.1007/s11255-008-9373-4. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Hayden MR(1), Goldsmith D, Sowers JR, Khanna R. Author information: (1)Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Research Group, University of Missouri School of Medicine, Health Sciences Center, MA410, DC043.00, Columbia, MO 65212, USA. mrh29@usmo.com Calciphylaxis-calcific uremic arteriolopathy, is a serious disorder of arteriolar calcification of the arteriole media and is associated with endovascular fibrosis and thrombosis in subcutaneous adipose tissue. It frequently results in severe ischemia, intense pain, and tissue necrosis with nonhealing skin ulcerations. It usually occurs in chronic kidney disease and especially in patients requiring renal replacement therapy. It is associated with a very high mortality rate, and the number of reports and reviews seemed to have increased over the past 5 years. Advances in therapy and salvaging patients from this high mortality risk have recently been reported with the use of sodium thiosulfate. The new application for this old drug used to treat cyanide poisoning and recently preventing neurotoxic effects resulting in hearing loss in those patients with head and neck cancer receiving cisplatin and carboplatin therapy are discussed. Recently, multiple case reports have demonstrated that sodium thiosulfate therapy has resulted in rapid pain relief, healing of skin ulcerations, and prevention of high mortality risk. This emerging treatment and its success are relatively unknown to many physicians. The purpose of this report is to share with others the emerging role of sodium thiosulfate and its new application as a treatment option to be used in combination with other treatment modalities for calciphylaxis-calcific uremic arteriolopathy. Indeed, as with any new treatment this emerging therapy should be studied in greater detail, but this old drug seems to have a new life in the hands of treating physicians. PMID: 18369733 [PubMed - indexed for MEDLINE] 2484. J Perinatol. 2008 Jul;28(7):453-60. doi: 10.1038/jp.2008.33. Epub 2008 Mar 27. Sclerema neonatorum: a review of nomenclature, clinical presentation, histological features, differential diagnoses and management. Zeb A(1), Darmstadt GL. Author information: (1)Department of International Health, International Center for Advancing Neonatal Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. OBJECTIVE: To review published literature on sclerema neonatorum (SN) in order to clarify its clinical presentation, histological features and management compared with two other diseases: subcutaneous fat necrosis of the newborn (SCFN) and scleredema. STUDY DESIGN: PubMed database was searched using the key words Sclerema neonatorum. A total of 55 articles from peer-reviewed journals were reviewed and summarized. RESULT: SN, SCFN and scleredema are diseases of the subcutaneous adipose tissue. SN is characterized by hardening of the skin that gets bound down to the underlying muscle and bone, hindering respiration and feeding and is associated with congenital anomalies, cyanosis, respiratory illnesses and sepsis. Histology of the skin biopsy shows thickening of the trabeculae supporting the subcutaneous adipose tissue and a sparse inflammatory infiltrate of lymphocytes, histiocytes and multinucleate giant cells. SCFN has circumscribed hardening of skin on bony prominences with necrosis of adipocytes in subcutaneous tissue and a dense granulomatous infiltrate on histology. Scleredema is characterized by hardening of the skin along with edema; histology shows inflammatory infiltrate and edema in skin and subcutaneous tissues. SN has a high case fatality rate whereas SCFN and scleredema are self-limiting and lesions resolve within a few weeks to months. Exchange transfusion may improve survival in SN. CONCLUSION: The histological features of skin biopsy should be used to establish diagnosis of SN, SCFN and scleredema as disease-specific treatment is imperative in SN due to high fatality. PMID: 18368059 [PubMed - indexed for MEDLINE] 2485. Korean J Hepatol. 2008 Mar;14(1):12-27. doi: 10.3350/kjhep.2008.14.1.12. [Nonalcoholic steatohepatitis: pathogenesis and treatment]. [Article in Korean] Park SH(1). Author information: (1)Department of Internal Medicine, Hallym University College of Medicine, Anyang, Korea. sanghoon@hallym.or.kr Nonalcoholic fatty liver disease (NAFLD) is characterized by a wide spectrum of liver damage spanning steatosis, nonalcoholic steatohepatitis (NASH), cryptogenic liver cirrhosis, and even to hepatocellular carcinoma. Investigations in the last few years have focused on NASH, a relatively aggressive form of liver disease, due largely to the explosion of information provided by clinical and basic science studies related to the widespread presence of risk factors, such as obesity, type II diabetes mellitus, and dyslipidemia. This is especially important given that obesity and type II diabetes mellitus have recently reached epidemic proportions in Korea. The pathogenesis of NASH is multifactorial, with insulin resistance and increased fatty acid possibly being important factors in the accumulation of hepatocellular fat, and oxidant stress, lipid peroxidation, mitochondrial dysfunction, and dysregulation of variable cytokines possibly being important causes of hepatocellular injury in steatotic liver. Because not all steatotic livers progress to NASH, some other environmental factors or a combination of genetic factors are thought to be required for progression to NASH and fibrosis. Lifestyle modifications continue to be the cornerstone therapy in NAFLD, but some insulin-sensitizing drugs might be more effective in treating NASH. Many pilot trials for antioxidants and lipid-lowering and hepatic protective agents have yielded promising initial results in improving liver enzymes or features of liver histology. However, the efficacy of these agents remains questionable. Despite recent gains in understanding NASH, several issues related to its natural history, pathogenesis, and treatment remain unresolved. PMID: 18367854 [PubMed - indexed for MEDLINE] 2486. Curr Hypertens Rep. 2008 Feb;10(1):32-8. Intra-abdominal adiposity, inflammation, and cardiovascular risk: new insight into global cardiometabolic risk. Calabro P(1), Yeh ET. Author information: (1)Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy. paolo.calabro@unina2.it Increasing evidence supports the role of adipose tissue in the development of a systemic inflammatory state, which contributes to obesity-associated vasculopathy and cardiovascular risk. In addition to storing calories as triglycerides, adipocytes secrete a large variety of proteins, including cytokines, chemokines, and -hormone-like factors (eg, leptin, adiponectin, resistin). This production of pro chemokines by adipose tissue is of particular interest, because their local secretion by perivascular adipose depots may provide a new mechanistic link between obesity and its associated vascular complications. Insulin resistance, in subjects with or without diabetes, is frequently associated with obesity, particularly with an excess of intra-abdominal fat. Recently, the endocannabinoid system, among others, has been shown to be involved in the pathophysiology of visceral obesity and global cardiometabolic risk, as represented by the overall risk of developing type 2 diabetes or cardiovascular diseases. PMID: 18367024 [PubMed - indexed for MEDLINE] 2487. Curr Hypertens Rep. 2007 Dec;9(6):512-9. Adrenal steroids and the metabolic syndrome. Thomson SP(1), Stump CS, Kurukulasuriya LR, Sowers JR. Author information: (1)Southern Arizona VA Health Care System and University of Arizona, Tucson, AZ 85723, USA. Stephen.Thomson@va.gov The many similarities between the metabolic syndrome and Cushing's syndrome led to the hypothesis that excess glucocorticoids (GC) are part of the pathogenesis linking their features. We review recent work that confirms the initial similarities (obesity, glucose intolerance, hypertension, and hyperlipidemia) and extends them to associated features of both syndromes (osteopenia, hypogonadism, leukocytosis, depression, and muscle weakness). Recent studies report that these features also occur in subclinical Cushing's syndrome, hypercortisolemic depression, and the transgenic overexpression of 11beta-hydoxysteroid dehydrogenase type 1 (11beta-HSD1) in mouse models of excess GC in adipose tissue. Reducing excess GC--in the clinical syndromes and in the mouse model-reverses many of these features. Because local tissue excess GC may have a central role in the pathogenesis of the metabolic syndrome, selective 11beta-HSD1 inhibitors are under active development by several pharmaceutical companies. PMID: 18367016 [PubMed - indexed for MEDLINE] 2488. Curr Diab Rep. 2008 Feb;8(1):42-7. The metabolic syndrome in primary aldosteronism. Fallo F(1), Federspil G, Veglio F, Mulatero P. Author information: (1)Department of Medical and Surgical Sciences, Clinica Medica 3, University of Padova, Via Ospedale 105, 35128 Padova, Italy. francesco.fallo@unipd.it Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder. PMID: 18366998 [PubMed - indexed for MEDLINE] 2489. Curr Diab Rep. 2008 Feb;8(1):20-4. Do cardiac and perivascular adipose tissue play a role in atherosclerosis? Iacobellis G(1), Gao YJ, Sharma AM. Author information: (1)Department of Medicine, St. Joseph's Hospital, 50 Charlton Avenue East, 5th Fontbonne Building, Hamilton, Ontario, L8N 4A6, Canada. gianluca@ccc.mcmaster.ca Recent evidence suggests that epicardial and perivascular adipose tissue could mechanically and functionally affect the heart and vasculature, thereby possibly playing a role in adiposity-related atherosclerosis. Experimental and clinical observations suggest both favorable and unfavorable effects of epicardial and perivascular fat. The double role of epicardial and perivascular adipose tissue in the development of cardiovascular pathology and/or in protecting the heart and arteries warrants further studies. PMID: 18366994 [PubMed - indexed for MEDLINE] 2490. Curr Diab Rep. 2008 Feb;8(1):7-11. Effects of exercise on adipokines and the metabolic syndrome. You T(1), Nicklas BJ. Author information: (1)Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY 14214, USA. tyou@buffalo.edu Adipokines, or adipose tissue-derived cytokines/proteins, may be important factors linking excess adipose tissue to individual metabolic risk factors, and the overall metabolic syndrome. Current evidence supports that aerobic exercise, alone or combined with hypocaloric diet, improves symptoms of the metabolic syndrome, possibly by altering systemic levels of inflammatory adipokines. A number of studies show that increased physical activity leads to lower circulating levels of proinflammatory cytokines and higher levels of adiponectin. However, limited data show that exercise training does not influence adipose tissue adipokine expression or release. Conversely, exercise training may influence cytokine production by circulating mononuclear cells, another important source of elevated inflammation. Future studies are needed to investigate the cellular mechanisms by which exercise training affects inflammation and whether alterations in inflammation are one mechanism by which exercise improves components of the metabolic syndrome in at-risk individuals. PMID: 18366992 [PubMed - indexed for MEDLINE] 2491. Curr Atheroscler Rep. 2008 Feb;10(1):71-8. Rimonabant: new data and emerging experience. Wright SM(1), Dikkers C, Aronne LJ. Author information: (1)Comprehensive Weight Control Program, New York-Presbyterian Hospital, Weill Medical College of Cornell University, 1165 York Avenue, New York, NY 10065, USA. smw2004@med.cornell.edu The endogenous cannabinoid system has been identified as playing a central role in the regulation of energy homeostasis, and its overactivity has been associated with obesity. Rimonabant is a selective endocannabinoid CB(1) receptor antagonist that has been shown to be an effective treatment for obesity and cardiometabolic risk factors. Studies comparing 20 mg/d of rimonabant with placebo show a placebo-subtracted weight loss between 6.3 and 6.9 kg at 1 year. In addition to the health benefits already associated with weight loss, rimonabant has shown additional improvements in lipid and glycemic cardiometabolic biomarkers such as low-density lipoprotein cholesterol, triglycerides, C-reactive protein, glucose, and adiponectin. The use of endocannabinoid antagonists such as rimonabant provides a promising therapeutic approach to the treatment of obesity and its associated cardiometabolic risks. PMID: 18366988 [PubMed - indexed for MEDLINE] 2492. Curr Atheroscler Rep. 2008 Feb;10(1):61-70. HIV therapy, metabolic syndrome, and cardiovascular risk. Pao V(1), Lee GA, Grunfeld C. Author information: (1)Department of Veterans Affairs Medical Center, Metabolism Section (Box 111F), 4150 Clement Street, San Francisco, CA 94121, USA. People with HIV infection have metabolic abnormalities that resemble metabolic syndrome (hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance), which is known to predict increased risk of cardiovascular disease (CVD). However, there is not one underlying cause for these abnormalities and they are not linked to each other. Rather, individual abnormalities can be affected by the host response to HIV itself, specific HIV drugs, classes of HIV drugs, HIV-associated lipoatrophy, or restoration to health. Furthermore, one component of metabolic syndrome, increased waist circumference, occurs less frequently in HIV infection. Thus, HIV infection supports the concept that metabolic syndrome does not represent a syndrome based on a common underlying pathophysiology. As might be predicted from these findings, the prevalence of CVD is higher in people with HIV infection. It remains to be determined whether CVD rates in HIV infection are higher than might be predicted from traditional risk factors, including smoking. PMCID: PMC3166347 PMID: 18366987 [PubMed - indexed for MEDLINE] 2493. Obes Rev. 2008 Jul;9(4):340-54. doi: 10.1111/j.1467-789X.2008.00478.x. Epub 2008 Mar 18. Obesity and obstructive sleep apnea-hypopnea syndrome. de Sousa AG(1), Cercato C, Mancini MC, Halpern A. Author information: (1)Obesity and Metabolic Diseases Group, Endocrinology and Metabology Service, Clinics Hospital, University of São Paulo Medical School, São Paulo, Brazil. agpsousa@ig.com.br Obstructive sleep apnea-hypopnea syndrome involves recurring episodes of total obstruction (apnea) or partial obstruction (hypopnea) of airways during sleep. Obstructive sleep apnea-hypopnea syndrome affects mainly obese individuals and it is defined by an apnea-hypopnea index of five or more episodes per hour associated with daytime somnolence. In addition to anatomical factors and neuromuscular and genetic factors, sleep disorders are also involved in the pathogenesis of sleep apnea. Obesity affects upper airway anatomy because of fat deposition and metabolic activity of adipose tissue. Obstructive sleep apnea-hypopnea syndrome and metabolic syndrome have several characteristics such as visceral obesity, hypertension and insulin resistance. Inflammatory cytokines might be related to the pathogenesis of sleep apnea and metabolic syndrome. Sleep apnea treatment includes obesity treatment, use of equipment such as continuous positive airway pressure, drug therapy and surgical procedures in selected patients. Currently, there is no specific drug therapy available with proven efficacy for the treatment of obstructive sleep apnea-hypopnea syndrome. Body-weight reduction results in improvement of sleep apnea, and obesity treatment must be emphasized, including lifestyle changes, anti-obesity drugs and bariatric surgery. PMID: 18363635 [PubMed - indexed for MEDLINE] 2494. Expert Opin Investig Drugs. 2008 Apr;17(4):481-96. doi: 10.1517/13543784.17.4.481 . 11-Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors in type 2 diabetes mellitus and obesity. Hughes KA(1), Webster SP, Walker BR. Author information: (1)Clinical Fellow University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. BACKGROUND: Glucocorticoids such as cortisol are important regulators of fuel metabolism during starvation and stress. Chronic glucocorticoid excess induces obesity with multiple features of the metabolic syndrome. OBJECTIVE: In this article, we review the importance of glucocorticoids in metabolic syndrome and the approaches that have been explored to reduce glucocorticoid action as the basis for novel therapy of Type 2 diabetes and obesity. METHOD: We focus on the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which amplifies glucocorticoid concentrations in key metabolic tissues including liver and adipose tissue. RESULTS/CONCLUSION: Several 11beta-HSD1 inhibitors are in late preclinical or early clinical development and we review here the properties of the class leaders and their potential as the next generation of drugs with multiple benefits in metabolic syndrome. PMID: 18363514 [PubMed - indexed for MEDLINE] 2495. Sheng Li Ke Xue Jin Zhan. 2008 Jan;39(1):10-4. [Adipose triglyceride lipase regulates adipocyte lipolysis]. [Article in Chinese] Xu C(1), Xu GH. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083, China. Obesity, insulin resistance, and type 2 diabetes are associated with elevated concentration of circulating free fatty acids (FFAs), which are critically governed by the process of triglyceride lipolysis in adipocytes. Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are two major enzymes in the control of triacylglycerol hydrolysis in adipose tissue. ATGL expressed predominantly in white adipose tissue specifically initiates triacylglycerol hydrolysis to generate diacylglycerols and FFA, a role distinguished from HSL that mainly hydrolyzes diacylglycerols. The transcription of ATGL is regulated by several factors. ATGL activity is regulated by CGI-58. Under basal conditions, interaction of CGI-58 with a lipid droplet associating protein, perilipin, results in an inactivation of ATGL activity. During PKA-stimulated lipolysis, CGI-58 is released from phosphorylated perilipin and in turn, binds to ATGL. This action facilitates triglyceride lipolysis. This review focuses on the regulation and function of ATGL in adipose lipolysis and metabolism. PMID: 18357681 [PubMed - indexed for MEDLINE] 2496. Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1039-49. doi: 10.1161/ATVBAHA.107.159228. Epub 2008 Mar 20. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Després JP(1), Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, Rodés-Cabau J, Bertrand OF, Poirier P. Author information: (1)Hôpital Laval Research Centre, 2725 Chemin Ste-Foy, Pavilion Marguerite-D'Youville, 4th Floor, Québec City, QC G1V4G5, Canada. jean-pierre.despres@crhl.ulaval.ca Erratum in Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):e151. There is currently substantial confusion between the conceptual definition of the metabolic syndrome and the clinical screening parameters and cut-off values proposed by various organizations (NCEP-ATP III, IDF, WHO, etc) to identify individuals with the metabolic syndrome. Although it is clear that in vivo insulin resistance is a key abnormality associated with an atherogenic, prothrombotic, and inflammatory profile which has been named by some the "metabolic syndrome" or by others "syndrome X" or "insulin resistance syndrome", it is more and more recognized that the most prevalent form of this constellation of metabolic abnormalities linked to insulin resistance is found in patients with abdominal obesity, especially with an excess of intra-abdominal or visceral adipose tissue. We have previously proposed that visceral obesity may represent a clinical intermediate phenotype reflecting the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink for the clearance and storage of the extra energy derived from dietary triglycerides, leading to ectopic fat deposition in visceral adipose depots, skeletal muscle, liver, heart, etc. Thus, visceral obesity may partly be a marker of a dysmetabolic state and partly a cause of the metabolic syndrome. Although waist circumference is a better marker of abdominal fat accumulation than the body mass index, an elevated waistline alone is not sufficient to diagnose visceral obesity and we have proposed that an elevated fasting triglyceride concentration could represent, when waist circumference is increased, a simple clinical marker of excess visceral/ectopic fat. Finally, a clinical diagnosis of visceral obesity, insulin resistance, or of the metabolic syndrome is not sufficient to assess global risk of cardiovascular disease. To achieve this goal, physicians should first pay attention to the classical risk factors while also considering the additional risk resulting from the presence of abdominal obesity and the metabolic syndrome, such global risk being defined as cardiometabolic risk. PMID: 18356555 [PubMed - indexed for MEDLINE] 2497. Diabetes Metab. 2008 Apr;34(2):97-107. doi: 10.1016/j.diabet.2007.10.009. Epub 2008 Mar 18. Postprandial fatty acid metabolism in the development of lipotoxicity and type 2 diabetes. Carpentier AC(1). Author information: (1)Department of Medicine, Division of Endocrinology, University of Sherbrooke, Québec, J1H 5N4, Canada. andre.carpentier@usherbrooke.ca Insulin resistance (IR) and impaired glucose-stimulated insulin secretion (GSIS) are the two primary pathophysiological abnormalities leading to the development of type 2 diabetes (T2D). Over the past two decades, a large body of work has implicated enhanced delivery of fatty acids to non-adipose tissues in the development of both IR and impaired GSIS. As the net whole-body import of fatty acids occurs in the postprandial state, tissue fatty acid overexposure has been linked to this physiological state. Although many advances have been made in our understanding of these lipotoxic effects at the cellular level, the precise mechanisms of lipotoxicity at the whole-body level in humans during the development of T2D is still a subject of debate. Important advances continue to be made in our understanding of the mechanisms that regulate postprandial fatty acid delivery to tissues and their metabolism. This review focuses on those mechanisms and on the potential implication of their dysregulation for tissue lipotoxicity in the development of T2D. PMID: 18353699 [PubMed - indexed for MEDLINE] 2498. Wiad Lek. 2007;60(9-10):454-6. [Carbohydrate metabolism and aging-controversy of ethiopathogenesis and pathophysiology. Part II. Changes in beta-cell function]. [Article in Polish] Sokup A(1), Swiatkowski M. Author information: (1)Katedry i Kliniki Gastroenterologii, Chorób Naczyń i Chorób Wewnetrznych Collegium Medicum w Bydgoszczy Uniwersytetu Mikołaja Kopernika w Toruniu. alinasokup@o2.pl Many studies suggest the decrease of beta-cell function in people older than 60 years. Age-associated defect of beta-cell function can be detected in loading tests, especially with prolonged intravenous infusion glucose infusion. Pathogenetic mechanisms consist abnormalities in insulin processing, insulin secretion, insulin release kinetics with parallel lower insulin secretion capacity and impossibility of increasing insulin release properly to age-increasing insulin resistance. These pathogenetic changes are related to increase of visceral fat deposits and other mechanisms such as defects in beta cell structure, decrease in glucose and incretins sensing and defective course of replication/neogenesis processes. PMID: 18350721 [PubMed - indexed for MEDLINE] 2499. Clin Dev Immunol. 2008;2008:639803. doi: 10.1155/2008/639803. Feeding our immune system: impact on metabolism. Wolowczuk I(1), Verwaerde C, Viltart O, Delanoye A, Delacre M, Pot B, Grangette C. Author information: (1)Laboratoire de Neuro-Immuno-Endocrinologie, Institut Pasteur de Lille, BP 447, 1 rue A. Calmette, 59019 Lille Cedex, France. isabelle.wolowczuk@ibl.fr Endogenous intestinal microflora and environmental factors, such as diet, play a central role in immune homeostasis and reactivity. In addition, microflora and diet both influence body weight and insulin-resistance, notably through an action on adipose cells. Moreover, it is known since a long time that any disturbance in metabolism, like obesity, is associated with immune alteration, for example, inflammation. The purpose of this review is to provide an update on how nutrients-derived factors (mostly focusing on fatty acids and glucose) impact the innate and acquired immune systems, including the gut immune system and its associated bacterial flora. We will try to show the reader how the highly energy-demanding immune cells use glucose as a main source of fuel in a way similar to that of insulin-responsive adipose tissue and how Toll-like receptors (TLRs) of the innate immune system, which are found on immune cells, intestinal cells, and adipocytes, are presently viewed as essential actors in the complex balance ensuring bodily immune and metabolic health. Understanding more about these links will surely help to study and understand in a more fundamental way the common observation that eating healthy will keep you and your immune system healthy. PMCID: PMC2266987 PMID: 18350123 [PubMed - indexed for MEDLINE] 2500. Br J Neurosurg. 2008 Apr;22(2):187-94. doi: 10.1080/02688690701827340. Idiopathic intracranial hypertension: can studies of obesity provide the key to understanding pathogenesis? Ooi LY(1), Walker BR, Bodkin PA, Whittle IR. Author information: (1)Department of Clinical Neurosciences, Western General Hospital and Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. Comment in Br J Neurosurg. 2008 Apr;22(2):141-2. The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved. PMID: 18348012 [PubMed - indexed for MEDLINE] 2501. BioDrugs. 2008;22(2):101-12. Recombinant human growth hormone: rationale for use in the treatment of HIV-associated lipodystrophy. Benedini S(1), Terruzzi I, Lazzarin A, Luzi L. Author information: (1)Clinical Research Unit II, San Raffaele Scientific Institute, Milan, Italy. The role of hormonal and metabolic alterations in HIV-associated lipodystrophy syndrome is not yet clear. In patients with HIV-1 undergoing antiretroviral treatment, lipodystrophy is associated with peripheral fat wasting and central adiposity, dyslipidemia, insulin resistance, and increased intramuscular fat accumulation. In HIV lipodystrophy, changes in fat distribution are heterogeneous and can include reduced subcutaneous fat as well as increased visceral fat. In the literature, there is evidence showing that overnight growth hormone (GH) secretion and pulse amplitude decrease in patients with HIV lipodystrophy, with rates of response to standardized GH stimulation being abnormal in at least 20% of these patients. Excess accumulation of visceral fat, central obesity, and increased intra-abdominal adiposity are also typical features of patients with GH deficiency. Recombinant human GH (rhGH) is a potential treatment to diminish excess visceral fat. Our group recently demonstrated that GH therapy in HIV-infected patients with syndromes of fat accumulation produced a significant decrease in body fat and a gain in lean tissue. In this article, we discuss the origin of lipodystrophy in HIV patients, and the use of rhGH treatment (benefits and adverse effects) in HIV-related lipodystrophy. PMID: 18345707 [PubMed - indexed for MEDLINE] 2502. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007 Dec;151(2):195-9. Action of leptin on bone and its relationship to menopause. Petzel M(1). Author information: (1)Department of gynaecology and obstetrics, University hospital Ostrava, Ostrava-Poruba, Czech Republic. m.petzel@seznam.cz BACKGROUND: Leptin a cytokine protein secreted by adipose tissue raises considerable interest as a potential mediator of the protective effects of fat mass on bone tissue. After menopause heavier women conserve bone mass better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. As Leptin levels reflect the body fat content it has emerged as a possible mediator of these protective effects. METHODS: A search of the available literature focused on the role of leptin on bone tissue. RESULTS: Both peripheral and central action of leptin on bone metabolism have been proposed. In vitro and in vivo evidence supports the hypothesis that leptin can act directly or indirectly on bone remodelling by modulating both osteoblast and osteoclast activities. However, studies in humans have not yet been able to confirm these actions possibly because of the shifting balance between stimulatory direct action and suppressive indirect action of leptin on bones via the hypothalamus. The effects of oestrogen decline and deficiency during natural or artificially induced menopause and administration of hormone replacement therapy has on leptin production remains controversial. Various studies have shown differences in leptin values in pre- and postmenopausal women. The existing clinical data on this issue are discordant. CONCLUSION: Larger clinical studies are necessary to clarify leptin's role in vivo and to assess the contribution of the central and peripheral role of leptin in the overall maintenance of bone turnover in human beings. PMID: 18345251 [PubMed - indexed for MEDLINE] 2503. Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S66-78. doi: 10.1016/j.mce.2008.01.026. Epub 2008 Feb 9. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Effect of high fat diets. Matias I(1), Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy. Increasing evidence indicates that endocannabinoid (EC) signalling is dysregulated during hyperglycemia and obesity, particularly at the level of anandamide (AEA) and/or 2-arachidonoylglycerol (2-AG) concentrations in tissues involved in the control of energy intake and processing, such as the liver, white adipose tissue and pancreas. Here we review this previous evidence and provide new data on the possible dysregulation of EC levels in organs with endocrine function (adrenal glands and thyroid), involved in energy expenditure (brown adipose tissue and skeletal muscle), or affected by the consequences of metabolic disorders (heart and kidney), obtained from mice fed for 3, 8 and 14 weeks with two different high fat diets (HFDs), with different fatty acid compositions and impact on fasting glucose levels. Statistically significant elevations (in the skeletal muscle, heart and kidney) or reductions (in the thyroid) of the levels of either AEA or 2-AG, or both, were found. Depending on the diet, these changes preceded or accompanied the development of overt obesity and/or hyperglycemia. In the adrenal gland, first a reduction and then an elevation of EC levels were observed. In the brown fat, a very early elevation of both AEA and 2-AG normalized levels was observed with one of the diets, whereas delayed decreases were explained by an increase of the amount of fat tissue weight induced by the HFDs. The potential implications of these and previous findings in the general framework of the proposed roles of the EC system in the control of metabolic, endocrine and cardiovascular and renal functions are discussed. PMID: 18343566 [PubMed - indexed for MEDLINE] 2504. Drug Discov Today. 2008 Mar;13(5-6):211-8. doi: 10.1016/j.drudis.2008.01.006. Epub 2008 Mar 7. From a glucocentric to a lipocentric approach towards metabolic syndrome. Mittra S(1), Bansal VS, Bhatnagar PK. Author information: (1)Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, R&D III, Plot No. 20, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122 001, Haryana, India. shivani.mittra@ranbaxy.com Insulin resistance, the essential component of metabolic syndrome, has traditionally been defined from a glucocentric viewpoint, with glucotoxicity playing a lead role. However, as overabundant circulating fatty acids are now known to be overt contributors, there is a paradigm shift in the understanding of metabolic syndrome acknowledging the importance of lipotoxicity as a major perpetuator of insulin resistance. Ectopic accumulation of fat in liver, adipose, muscle and pancreatic islets, provokes insulin resistance through various mechanisms. Chronic inflammation/adipocytokine generation, endoplasmic reticulum stress and mitochondrial dysfunction/oxidative stress also contribute significantly towards insulin resistance. Targets that can act as counter regulators/master switches at the converging point of all these metabolic pathways are currently under intense development. PMID: 18342796 [PubMed - indexed for MEDLINE] 2505. Pituitary. 2009;12(2):96-104. doi: 10.1007/s11102-008-0097-3. The effects of hyperprolactinemia on bone and fat. Shibli-Rahhal A(1), Schlechte J. Author information: (1)Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USA. Many patients with prolactin secreting pituitary tumors have decreased bone mineral. The bone loss is associated with an increase in bone resorption and is secondary to prolactin-induced hypogonadism. In both sexes trabecular bone in the spine and hip is more affected than cortical bone in the distal radius. Normalization of prolactin and restoration of gonadal function increases bone density but is not associated with normalization of bone mass. It is not known whether the bone loss in hyperprolactinemic subjects represents a failure to achieve peak bone mass or is due to accelerated bone loss. Despite low bone density hyperprolactinemic subjects do not demonstrate increased fractures. The association between prolactin, weight gain and obesity suggests that prolactin may also be a modulator of body composition and body weight. It is not known whether hyperprolactinemia associated weight gain is due to stimulation of lipogenesis or due to disruption of central nervous system dopaminergic tone. Hyperprolactinemia is also associated with insulin resistance and endothelial dysfunction which may improve after normalization of prolactin. The clinical significance of these findings and the precise role of prolactin in regulation of weight and metabolism remain to be elucidated. PMID: 18338266 [PubMed - indexed for MEDLINE] 2506. Trends Endocrinol Metab. 2008 May-Jun;19(4):130-7. doi: 10.1016/j.tem.2007.11.006. Epub 2008 Mar 11. Control of lipolysis by natriuretic peptides and cyclic GMP. Lafontan M(1), Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J. Author information: (1)Inserm (Institut National de la Santé et de la Recherche Médicale) U858, I2MR-Institut de Médecine Moléculaire de Rangueil, BP 84225, Toulouse CEDEX 4, France. Max.Lafontan@toulouse.inserm.fr Human fat cell lipolysis was, until recently, thought to be mediated exclusively by a cAMP-dependent protein kinase (PKA)-regulated pathway under the control of catecholamines and insulin. We have shown that atrial- and B-type natriuretic peptides (ANP and BNP respectively) stimulate lipolysis in human fat cells through a cGMP-dependent protein kinase (PKG) signaling pathway independent of cAMP production and PKA activity. Pharmacological or physiological (exercise) increases in plasma ANP levels stimulate lipid mobilization in humans. This pathway becomes important during chronic treatment with beta-adrenoceptor antagonists, which inhibit catecholamine-induced lipolysis but enhance cardiac ANP release. These findings have metabolic implications and point to potential problems when natriuretic peptide secretion is altered or during therapeutic use of recombinant BNP. PMID: 18337116 [PubMed - indexed for MEDLINE] 2507. J Am Acad Nurse Pract. 2008 Mar;20(3):128-35. doi: 10.1111/j.1745-7599.2007.00299.x. Implications of the biology of weight regulation and obesity on the treatment of obesity. Bellar A(1), Jarosz PA, Bellar D. Author information: (1)College of Nursing, Wayne State University, Detroit, Michigan 48202, USA. ae9724@wayne.edu Erratum in J Am Acad Nurse Pract. 2008 Apr;20(4):230. PURPOSE: The purposes of this article are to provide a brief review of the complex biology of weight regulation and obesity, to explain some of the effects of diet and exercise on the biology of weight regulation and obesity, and to propose a coherent way to assess and treat people related to weight and obesity. DATA SOURCES: Scientific publications, clinical guidelines, and government sources. CONCLUSIONS: Obesity is a complex problem requiring an understanding of how interventions interact with the biology of weight regulation in people who are obese. Promoting health in obese people requires a focus on improving insulin sensitivity. IMPLICATIONS FOR PRACTICE: Helping individuals maintain normal weight throughout life is important in order to keep the long- and short-term weight signals in balance and reflective of true energy requirements. Exercise is associated with loss of total and abdominal adipose tissue and improved insulin sensitivity. Diets inducing gradual weight loss are less likely to stimulate appetite. Diets should include antioxidants to neutralize the increase in free radical production associated with obesity and exercise. Other interventions in the treatment of obesity may include treating sleep deficits and the dysregulated endocannabinoid system. PMID: 18336689 [PubMed - indexed for MEDLINE] 2508. Curr Med Chem. 2008;15(7):642-9. The role of 11beta-hydroxysteroid dehydrogenase in metabolic disease and therapeutic potential of 11beta-hsd1 inhibitors. Saiah E(1). Author information: (1)Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. esaiah@wyeth.com Glucocorticoids play an essential role in the regulation of multiple physiological processes, including energy metabolism, maintenance of blood pressure and stress responses, as well as cognitive functions. On a tissue-specific level, glucocorticoid action is controlled by 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme (11beta-HSD1) is a NADP(H)-dependent bidirectional enzyme in vitro and reduces cortisone to active cortisol in vivo. 11beta-HSD1 is expressed in many tissues including the liver, adipose and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity has been associated with the metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that the inhibition of 11beta-HSD1 mitigates the adverse effects of excessive glucocorticoid levels on metabolic parameters and provides promising opportunities for the development of therapeutic interventions. This review discusses recently disclosed 11beta-HSD1 inhibitors and their potential for the treatment of metabolic disorders. PMID: 18336279 [PubMed - indexed for MEDLINE] 2509. Cardiovasc Hematol Disord Drug Targets. 2008 Mar;8(1):7-46. Adiponectin and its role in cardiovascular diseases. Bełtowski J(1), Jamroz-Wiśniewska A, Widomska S. Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. Jerzy.beltowski@am.lublin.pl Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as "adipokines". In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor gamma agonists) are most effective in elevating adiponectin level. PMID: 18336252 [PubMed - indexed for MEDLINE] 2510. Rom J Intern Med. 2007;45(2):149-57. Pathogenic role of abnormal fatty acids and adipokines in the portal flow. Relevance for metabolic syndrome, hepatic steatosis and steatohepatitis. Brudaşcă I(1), Cucuianu M. Author information: (1)Department of Clinical Biochemistry, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. ioanabrudasca@yahoo.com Evidence has been provided that increased levels of non esterified fatty acids (NEFA) in the portal flow would produce insulin resistance and would also stimulate the hepatic protein synthesis, thereby explaining the increased plasma levels not only of apolipoprotein B, but also of other liver-derived enzymes and proteins occurring in overweight and hypertriglyceridemic patients. The high plasma concentration of triglyceride-rich lipoprotein would facilitate the transfer of cholesteryl esters from HDL and LDL to VLDL in exchange for triglycerides, a process mediated by liver-derived cholesteryl ester transfer protein (CETP). The triglyceride thereby acquired in HDL and LDL would then be hydrolyzed by hepatic lipase. The resulting association of increased triglycerides, low HDL cholesterol and small dense LDL is considered to be an atherogenic profile. The prothrombotic state, another feature of the metabolic syndrome, may also be explained by an enhanced hepatic synthesis of clotting factors and of the inhibitors of fibrinolysis. It was recently shown that adipocyte synthesized adiponectin reduces the release of fatty acids from the adipose tissue and would also enhance their uptake and oxidation in the muscle, thereby limiting their uptake in the liver. Decreased adiponectin production in obesity would therefore promote the development of insulin resistance, of atherogenic dyslipidemia and of the prothrombotic state. Because adiponectin also exerts an antiinflammatory activity by antagonizing TNFalpha, hypoadiponectinemia may be involved in atherogenesis and in the progression of hepatic steatosis to steatohepatitis. PMID: 18333368 [PubMed - indexed for MEDLINE] 2511. Vet J. 2008 Apr;176(1):10-20. doi: 10.1016/j.tvjl.2007.12.033. Epub 2008 Mar 10. Nutritional and management strategies for the prevention of fatty liver in dairy cattle. Grummer RR(1). Author information: (1)Department of Dairy Science, University of Wisconsin, Madison, 1675 Observatory Dr. Madison, WI 53706, USA. rgrummer@wisc.edu Fatty liver occurs in dairy cattle during periods of elevated blood non-esterified fatty acids (NEFAs). Elevated blood NEFAs are associated with hormonal changes at parturition and negative energy balance. Approaches for preventing fatty liver include inhibition of fatty acid mobilization from adipose tissues and altering hepatic metabolism to enhance fatty acid oxidation or export as a constituent of very low-density lipoproteins (VLDL). Nutritional and management strategies to implement these approaches have been examined. Increasing energy density of diet, either by increasing non-fiber carbohydrate or fat, has failed to prevent fatty liver. Two nutritional supplements, ruminally-protected choline and propylene glycol, have proven effective at preventing fatty liver. Choline probably enhances hepatic VLDL secretion. Propylene glycol most likely reduces fatty acid mobilization from adipose tissue. Shortening or eliminating the dry period is a management strategy that reduces the magnitude of negative energy balance after calving and triglyceride accumulation in the liver. PMID: 18329917 [PubMed - indexed for MEDLINE] 2512. Expert Rev Cardiovasc Ther. 2008 Mar;6(3):343-68. doi: 10.1586/14779072.6.3.343. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Bays HE(1), González-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, Rodbard HW, Henry RR. Author information: (1)L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. hbaysmd@aol.com When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. 'Disease' is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of 'cross-talk' and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk. PMID: 18327995 [PubMed - indexed for MEDLINE] 2513. J Cardiometab Syndr. 2008 Winter;3(1):40-4. The endocannabinoid system: a promising novel mechanistic pathway in the cardiometabolic syndrome. Al-Jaghbeer E(1), Khraisat A, Singh SP. Author information: (1)Department of Internal Medicine, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 600064, USA. The endocannabinoid system (ECS) is a neuroendocrine system that modulates several cardiometabolic processes. An overactive ECS is implicated as a significant contributor to the cardiometabolic syndrome and obesity, in addition to a large number of other physiologic processes. Endocannabinoid receptors have been detected centrally and peripherally, regulating appetite, food intake, metabolism, and storage. ECS blockade is thought to be a promising new pharmacologic modality of improving the unfavorable metabolic risk profile in patients with the cardiometabolic syndrome and obesity. PMID: 18326971 [PubMed - indexed for MEDLINE] 2514. Pituitary. 2009;12(2):105-15. doi: 10.1007/s11102-008-0098-2. The pituitary-adrenal axis and body composition. Fernandez-Rodriguez E(1), Stewart PM, Cooper MS. Author information: (1)Division of Medical Sciences, The Institute of Biomedical Research, The Medical School, The University of Birmingham, Birmingham , B15 2TH, UK. The activity of the pituitary-adrenal axis can profoundly impact on body composition. This is dramatically seen in Cushing's syndrome (CS) but changes in body composition are also implicated in depression and alcoholic pseudocushing's. The pathophysiological mechanisms underlying these changes remain poorly understood. Changes to body composition in CS include increased fat mass, decreased bone mass, thinning of the skin and reduced lean mass. Why these tissues are affected so dramatically is unclear. Additionally, the change in body composition between individuals varies considerably for reasons which are only now becoming evident. This paper reviews the phenotypic changes with altered pituitary-adrenal axis activity and discusses the mechanisms involved. The primary focus is on adipose, bone, muscle and skin since the most dramatic changes are seen in these tissues. PMID: 18324475 [PubMed - indexed for MEDLINE] 2515. Expert Opin Investig Drugs. 2008 Mar;17(3):327-33. doi: 10.1517/13543784.17.3.327 . Vaspin: a novel serpin with insulin-sensitizing effects. Wada J(1). Author information: (1)Okayama University Graduate School of Medicine, Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. junwada@md.okayama-u.ac.jp BACKGROUND: A variety of substances, including free fatty acids, leptin, tumor necrosis factor-alpha, acylation-stimulating protein, adiponectin, and resistin, are secreted by adipocytes. They modulate insulin sensitivity and are new therapeutic targets in metabolic syndrome. OBJECTIVE: To identify novel adipokines derived from visceral adipose tissues. METHOD: We used the PCR-based cDNA subtraction method to screen the genes predominantly expressed in visceral white adipose tissues (WATs) in Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of abdominal obesity and type 2 diabetes. RESULTS/CONCLUSIONS: We identified the vaspin gene (Serpina12) which is upregulated in visceral WATs of OLETF rats. Vaspin mRNA was barely detectable at 6 weeks of age and it was abundantly and exclusively expressed in visceral WATs at 30 weeks of age, when OLETF rats reach their peak body weight. However, vaspin mRNA decreased with worsening of diabetes and body weight loss. Vaspin mRNA increased with treatment of thiazolidinediones (pioglitazone). Administration of recombinant vaspin into high-fat high-sucrose chow-induced obese ICR mice improved glucose tolerance and insulin sensitivity. Vaspin may be the compensatory molecule in the pathogenesis of metabolic syndrome and vaspin recombinant protein or vaspin-mimicking agents such as vaspin analogs, antibodies or small molecule agents may be the link to drug discovery and development. PMID: 18321232 [PubMed - indexed for MEDLINE] 2516. Vestn Ross Akad Med Nauk. 2008;(1):12-8. [Endocrine-genotoxic switchings as promoter of main noninfectious diseases]. [Article in Russian] Bershteĭn LM, Tsyrlina EV, Kovalevskiĭ AIu, Vasil'ev DA, Poroshina TE, Kovalenko IG, Kotov AV, Pozharisskiĭ KM. Peculiarities of the incidence and spread of main non-infectious diseases (MNID) are in one or another way connected with the conception of "normal" and "successful" aging. The age-related increase in the frequency of MNID, associated with estrogen deficiency or excess, can be explained by the presence of estrogen effect switching phenomenon. The increase in the genotoxic effect of estrogens, isolated or combined with the weakening of the hormonal effect, can worsen the clinical course of MNID (including malignant tumors of hormone-dependent tissues). The effects of two other endocrine-genotoxic switchings (the joker function of glucose and adipogenotoxicosis) may realize in the same direction. The three mentioned phenomena form the so called basic triad, separate elements of which can interact. Endocrine-genotoxic switchings and their inductors are targets for prophylactic measures and, possibly, therapeutic ones. Both approaches may be divided into several groups with different points of application, whereas their ultimate goal is optimal balance between hormonal and DNA-damaging effects of estrogens, glucose, and adipose tissue-associated factors. PMID: 18318150 [PubMed - indexed for MEDLINE] 2517. Br J Nutr. 2008 Sep;100(3):461-70. doi: 10.1017/S0007114508911569. Epub 2008 Feb 28. An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development? Ailhaud G(1), Guesnet P, Cunnane SC. Author information: (1)ISDBC, Université de Nice Sophia-Antipolis, CNRS, 28 avenue Valrose, Nice 06100, France. ailhaud@unice.fr A positive energy balance (energy intake>energy expenditure), in which total fat intake plays an important role, is commonly regarded as a major factor contributing to obesity. Adipose tissue development, i.e. both size (hypertrophy) and number (hyperplasia), is stimulated by high dietary fat intake during early postnatal development, a susceptibility that now appears to continue well into adulthood. Recent human and animal studies suggest that by altering rates of adipocyte differentiation and proliferation, differences in the composition of dietary fat may also contribute to adipose tissue development. At least in rodent models, the relative intake of n-6 to n-3 PUFA is clearly emerging as a new factor in this development. In these models, higher linoleate intake raises tissue arachidonic acid, which increases prostacyclin production and, in turn, stimulates signalling pathways implicated in adipogenesis. Signalling pathways stimulated by arachidonic acid probably include phospholipase and/or cyclo-oxygenase activation and may be linked as much to relatively low intake of n-3 PUFA as to excessive dietary linoleate. One factor potentially contributing to oversight about the apparent role of dietary n-6 PUFA (especially excess dietary linoleate) in adipose tissue development is the historical overestimation of linoleate requirements and the enthusiasm for higher intake of 'essential fatty acids'. More research is needed to address whether disequilibration of dietary PUFA intake contributes to the risk of obesity in humans. PMID: 18307824 [PubMed - indexed for MEDLINE] 2518. J Cardiovasc Transl Res. 2008 Mar;1(1):55-63. doi: 10.1007/s12265-007-9006-9. Epub 2008 Jan 29. Adipose tissue-derived stem cells: the friendly side of a classic cardiovascular foe. Sanz-Ruiz R(1), Santos ME, Muñoa MD, Martín IL, Parma R, Fernández PL, Fernández-Avilés F. Author information: (1)Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Recently, the existence of a population of stem cells located in the adipose tissue has been observed. Adipose-derived stem cells are able to differentiate into multiple cell lineages including cardiac myocytes. Hence, adipose-derived cells are emerging as a new source of adult stem cells for cardiovascular repair. In this review, we discuss the basic principles of adipose-derived stem cells (types and characteristics, obtention processes, immunophenotypic characterization, and cell potency), the initial experimental studies, and the currently ongoing clinical trials. PMID: 20559958 [PubMed - indexed for MEDLINE] 2519. J Anat. 2008 Mar;212(3):211-28. doi: 10.1111/j.1469-7580.2008.00864.x. Structure-function relationships in tendons: a review. Benjamin M(1), Kaiser E, Milz S. Author information: (1)School of Biosciences, Cardiff University, Cardiff, UK. benjamin@cardiff.ac.uk The purpose of the current review is to highlight the structure-function relationship of tendons and related structures to provide an overview for readers whose interest in tendons needs to be underpinned by anatomy. Because of the availability of several recent reviews on tendon development and entheses, the focus of the current work is primarily directed towards what can best be described as the 'tendon proper' or the 'mid-substance' of tendons. The review covers all levels of tendon structure from the molecular to the gross and deals both with the extracellular matrix and with tendon cells. The latter are often called 'tenocytes' and are increasingly recognized as a defined cell population that is functionally and phenotypically distinct from other fibroblast-like cells. This is illustrated by their response to different types of mechanical stress. However, it is not only tendon cells, but tendons as a whole that exhibit distinct structure-function relationships geared to the changing mechanical stresses to which they are subject. This aspect of tendon biology is considered in some detail. Attention is briefly directed to the blood and nerve supply of tendons, for this is an important issue that relates to the intrinsic healing capacity of tendons. Structures closely related to tendons (joint capsules, tendon sheaths, pulleys, retinacula, fat pads and bursae) are also covered and the concept of a 'supertendon' is introduced to describe a collection of tendons in which the function of the whole complex exceeds that of its individual members. Finally, attention is drawn to the important relationship between tendons and fascia, highlighted by Wood Jones in his concept of an 'ectoskeleton' over half a century ago - work that is often forgotten today. PMCID: PMC2408985 PMID: 18304204 [PubMed - indexed for MEDLINE] 2520. Curr Opin Gastroenterol. 2008 Mar;24(2):223-9. doi: 10.1097/MOG.0b013e3282f3f4d8. Neuroendocrine regulation of food intake. Chaptini L(1), Peikin S. Author information: (1)Division of Gastroenterology and Liver Diseases, Cooper University Hospital, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Camden, New Jersey, USA. chaptini-louis@cooperhealth.edu PURPOSE OF REVIEW: The majority of adults in many developed countries are overweight or obese. The obesity epidemic is also affecting children worldwide. Obesity increases the risk of several diseases leading to life-threatening complications. Weight regulation depends on food intake (energy intake) and energy expenditure. The purpose of this review is to provide updated information on the neuroendocrine regulation of food intake and energy homeostasis. RECENT FINDINGS: New knowledge about the role of the prefrontal cortex in the regulation of food intake has emerged. The pathways responsible for energy homeostasis are now increasingly being understood, and as a consequence, an increasing number of pharmacologic agents targeting these pathways are being actively developed. Emphasis on the concept of long-term (as opposed to short-term) homeostasis has guided the search for therapeutic molecules or combination of molecules that would inhibit food intake constantly and thus lead to maintained weight loss. SUMMARY: Complex and intricate neuroendocrine pathways control food intake and energy homeostasis. The increasing understanding of the different components orchestrating the regulation of food intake provides new and exciting targets for much needed pharmacotherapy for obesity. PMID: 18301275 [PubMed - indexed for MEDLINE] 2521. Trends Endocrinol Metab. 2008 Apr;19(3):100-3. doi: 10.1016/j.tem.2008.01.004. Epub 2008 Mar 4. Adipose cell-adrenal interactions: current knowledge and future perspectives. Ronconi V(1), Turchi F, Bujalska IJ, Giacchetti G, Boscaro M. Author information: (1)Division of Endocrinology, Università Politecnica delle Marche, 60020 Ancona, Italy. The central role of adipose tissue in the development of cardiovascular and metabolic pathology has been highlighted by the discovery of mediators (adipokines) secreted by adipose tissue and their involvement in the regulation of various biological processes. In light of recent experimental data, cross-talk between adipose tissue and the adrenal gland, particularly via the mineralocorticoid aldosterone, has been proposed. Aldosterone can induce adipogenesis, and human white adipose tissue is reported to release as-yet-uncharacterized factors that stimulate adrenocortical steroidogenesis and aldosterone production. These data could provide new insights into the pathophysiology of obesity-related disorders, including hypertension and aldosterone excess, with further studies necessary for confirming and better defining such adipose-adrenal interactions. PMID: 18299203 [PubMed - indexed for MEDLINE] 2522. J Cell Mol Med. 2008 Aug;12(4):1155-68. doi: 10.1111/j.1582-4934.2008.00288.x. Epub 2008 Feb 24. Mesenchymal stem cells: biology and clinical potential in type 1 diabetes therapy. Liu M(1), Han ZC. Author information: (1)State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, PR China. Mesenchymal stem cells (MSCs) can be derived from adult bone marrow, fat and several foetal tissues. In vitro, MSCs have the capacity to differentiate into multiple mesodermal and non-mesodermal cell lineages. Besides, MSCs possess immunosuppressive effects by modulating the immune function of the major cell populations involved in alloantigen recognition and elimination. The intriguing biology of MSCs makes them strong candidates for cell-based therapy against various human diseases. Type 1 diabetes is caused by a cell-mediated autoimmune destruction of pancreatic beta-cells. While insulin replacement remains the cornerstone treatment for type 1 diabetes, the transplantation of pancreatic islets of Langerhans provides a cure for this disorder. And yet, islet transplantation is limited by the lack of donor pancreas. Generation of insulin-producing cells (IPCs) from MSCs represents an attractive alternative. On the one hand, MSCs from pancreas, bone marrow, adipose tissue, umbilical cord blood and cord tissue have the potential to differentiate into IPCs by genetic modification and/or defined culture conditions In vitro. On the other hand, MSCs are able to serve as a cellular vehicle for the expression of human insulin gene. Moreover, protein transduction technology could offer a novel approach for generating IPCs from stem cells including MSCs. In this review, we first summarize the current knowledge on the biological characterization of MSCs. Next, we consider MSCs as surrogate beta-cell source for islet transplantation, and present some basic requirements for these replacement cells. Finally, MSCs-mediated therapeutic neovascularization in type 1 diabetes is discussed. PMCID: PMC3865657 PMID: 18298656 [PubMed - indexed for MEDLINE] 2523. J Cell Mol Med. 2008 Dec;12(6A):2205-16. doi: 10.1111/j.1582-4934.2008.00291.x. Epub 2008 Feb 24. Adipose stem cells for intervertebral disc regeneration: current status and concepts for the future. Hoogendoorn RJ(1), Lu ZF, Kroeze RJ, Bank RA, Wuisman PI, Helder MN. Author information: (1)Department of Orthopaedic Surgery, VU University Medical Center, Amsterdam, The Netherlands. New regenerative treatment strategies are being developed for intervertebral disc degeneration of which the implantation of various cell types is promising. All cell types used so far require in vitro expansion prior to clinical use, as these cells are only limited available. Adipose-tissue is an abundant, expendable and easily accessible source of mesenchymal stem cells. The use of these cells therefore eliminates the need for in vitro expansion and subsequently one-step regenerative treatment strategies can be developed. Our group envisioned, described and evaluated such a one-step procedure for spinal fusion in the goat model. In this review, we summarize the current status of cell-based treatments for intervertebral disc degeneration and identify the additional research needed before adipose-derived mesenchymal stem cells can be evaluated in a one-step procedure for regenerative treatment of the intervertebral disc. We address the selection of stem cells from the stromal vascular fraction, the specific triggers needed for cell differentiation and potential suitable scaffolds. Although many factors need to be studied in more detail, potential application of a one-step procedure for intervertebral disc regeneration seems realistic. PMID: 18298653 [PubMed - indexed for MEDLINE] 2524. Cell Transplant. 2007;16(9):963-70. Adipose-derived cells. Meliga E(1), Strem BM, Duckers HJ, Serruys PW. Author information: (1)Thoraxcenter, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands. Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 10(6) stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebo-controlled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI. PMID: 18293895 [PubMed - indexed for MEDLINE] 2525. Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1101-4. doi: 10.1152/ajpgi.00057.2008. Epub 2008 Feb 21. Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. Kunos G(1), Osei-Hyiaman D. Author information: (1)NIAAA, NIH, Bethesda, MD 20892-9413, USA. gkunos@mail.nih.gov Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptin-regulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences. PMID: 18292184 [PubMed - indexed for MEDLINE] 2526. Curr Opin Pharmacol. 2008 Apr;8(2):211-8. doi: 10.1016/j.coph.2008.01.001. Epub 2008 Mar 4. Heart regeneration: what cells to use and how? Tousoulis D(1), Briasoulis A, Antoniades C, Stefanadi E, Stefanadis C. Author information: (1)A' Cardiology Department, Athens University Medical School, Athens, Greece. drtousoulis@hotmail.com Coronary artery disease (CAD) is the leading cause of death in modern societies. Recent achievements in the treatment of CAD including statins, ACE inhibitors, beta blockers, and interventional procedure improved the outcome of patients with CAD, but this conventional approach failed to control cardiovascular mortality. Nowadays, cells (stem cells) and their potential role in managing patients with heart disease is a field of intensive research. Various types of cells have been used for transplantation targeting heart regeneration, including bone marrow cells (BMCs), cardiac stem cells (CSCs), endothelial progenitor cells (EPCs), skeletal myoblasts (SMs), adipose stroma tissue cells (ATSCs), mesenchymal cells (MCs), and embryonic stem cells (ESCs). Several routes have been used to deliver these cells to human myocardium or to the coronary circulation such as, intracoronary injection, intravenous infusion, direct injection into the ventricular wall, or transepicardial/transendocardial infusions. Although the results of the recent clinical trials in this area are rather conflicting, these therapeutic approaches seem to be promising for the treatment of ischemic heart disease. PMID: 18291721 [PubMed - indexed for MEDLINE] 2527. Diabetes Res Clin Pract. 2008 Apr;80(1):8-15. doi: 10.1016/j.diabres.2007.12.012. Epub 2008 Mar 4. Adipokines and insulin resistance during pregnancy. Zavalza-Gómez AB(1), Anaya-Prado R, Rincón-Sánchez AR, Mora-Martínez JM. Author information: (1)Division of Research, Hospital of Obstetrics and Gynecology at Western Medical Center, Mexican Institute of Social Security, Jalisco, Mexico. postmen71@yahoo.com.mx Normal pregnancy has been characterized as a "diabetogenic state". On the other hand, the adipose tissue is now considered an active organ, capable of secreting substances such as adipokines, which may play a role in the pathogenesis of insulin resistance. Resistin, leptin serum and placental levels increase as pregnancy progresses, which is in contrast to levels of adiponectin. These levels correlate with the state of reduced insulin sensitivity often developed in the latter stages of pregnancy. The objective of this article is to review recent advances in our understanding of adipokines and insulin resistance during pregnancy. PMID: 18291552 [PubMed - indexed for MEDLINE] 2528. Asian J Androl. 2008 Mar;10(2):171-5. doi: 10.1111/j.1745-7262.2008.00389.x. Recent advances in andrology-related stem cell research. Lin CS(1), Xin ZC, Deng CH, Ning H, Lin G, Lue TF. Author information: (1)Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, CA 94143, USA. clin@urology.ucsf.edu Stem cells hold great promise for regenerative medicine because of their ability to self-renew and to differentiate into various cell types. Although embryonic stem cells (BSC) have greater differentiation potential than adult stem cells, the former is lagging in reaching clinical applications because of ethical concerns and governmental restrictions. Bone marrow stem cells (BMSC) are the best-studied adult stem cells (ASC) and have the potential to treat a wide variety of diseases, including erectile dysfunction (ED) and male infertility. More recently discovered adipose tissue-derived stem cells (ADSC) are virtually identical to bone marrow stem cells in differentiation and therapeutic potential, but are easier and safer to obtain, can be harvested in larger quantities, and have the associated benefit of reducing obesity. Therefore, ADSC appear to be a better choice for future clinical applications. We have previously shown that ESC could restore the erectile function of neurogenic ED in rats, and we now have evidence that ADSC could do so as well. We are also investigating whether ADSC can differentiate into Leydig, Sertoli and male germ cells. The eventual goal is to use ADSC to treat male infertility and testosterone deficiency. PMID: 18286209 [PubMed - indexed for MEDLINE] 2529. Diabetes Obes Metab. 2008 Nov;10(11):973-93. doi: 10.1111/j.1463-1326.2008.00852.x. Epub 2008 Feb 18. Leptin and its metabolic interactions: an update. Anubhuti(1), Arora S. Author information: (1)Department of Biochemistry, GB Pant Hospital, New Delhi, India. anubhuti.vishesh@gmail.com Obesity results from an abnormal accumulation of fat in the white adipose tissue. Recent research utilizing genetic models of obesity in rodents has implicated a major role of leptin as a controller of obesity. Leptin is a 167-amino acid peptide hormone encoded by the obesity gene (ob), which is secreted by adipocytes and plays an important role in regulating food intake, energy expenditure and adiposity. Leptin receptors (OB-R) are expressed in the central nervous system mainly in afferent satiety centres of hypothalamus and in peripheral organs such as adipose tissues, skeletal muscles, pancreatic beta-cells and liver, thus indicating the autocrine and paracrine role of leptin in energy regulation. In human beings, a highly organized circadian pattern of leptin secretion is observed with peak levels in the midnight probably resulting from cumulative hyperinsulinemia of entire day. Leptin has a dual role in weight maintenance. Leptin reflects total body adipose tissue mass whereas in conditions of negative and positive energy balance, the dynamic changes in plasma leptin concentration function as a sensor of energy balance and influence the efferent energy regulation pathways. Many effects of leptin on metabolism are mediated by interaction with Insulin and also by synergistic action with cholecystokinin. Besides physiological roles, leptin may influence pathological conditions like obesity-associated atherosclerosis, oxidative stress and cancers. The purpose of the present review is to summarize the important aspects of the biology, actions, and regulation of leptin and to serve as an update of new information. PMID: 18284436 [PubMed - indexed for MEDLINE] 2530. Orv Hetil. 2008 Feb 24;149(8):339-46. doi: 10.1556/OH.2008.28291. [Mesenchymal stem cells and the immune system--immunosuppression without drugs?]. [Article in Hungarian] Kiss J(1), Urbán VS, Dudics V, Vas V, Uher F. Author information: (1)Országos Vérellátó Szolgálat, Ossejt-biológia Budapest. Mesenchymal stem cells (MSC) - isolated from various tissues in humans and other species - are one of the most promising adult stem cell types due to their availability and the relatively simple requirements for in vitro expansion. They have the capacity to differentiate into several tissues, including bone, cartilage, tendon, muscle and adipose, and produce growth factors and cytokines that promote hematopoietic cell expansion and differentiation. In vivo, MSCs are able to repair damaged tissue from kidney, heart, liver, pancreas and gastrointestinal tract. Furthermore, they also have anti-proliferative, immunomodulatory and anti-inflammatory effects, but evoke only little immune reactivity. Although the mechanism underlying the immunosuppressive effects of MSCs has not been clearly defined, their immunosuppressive properties have already been exploited in the clinical setting. Therefore, in the future, MSCs might have implications for treatment of allograft rejection, graft-versus-host disease, rheumatoid arthritis, autoimmune inflammatory bowel disease and other disorders in which immunomodulation and tissue repair are required. The aim of this review is to critically analyze the field of MSC biology, particularly with respect to their immunomodulatory properties and potential clinical use in the future. PMID: 18281229 [PubMed - indexed for MEDLINE] 2531. Best Pract Res Clin Endocrinol Metab. 2008 Feb;22(1):155-71. doi: 10.1016/j.beem.2007.08.001. Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance. Dulloo AG(1). Author information: (1)Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland. abdul.dulloo@unifr.ch Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance. PMID: 18279786 [PubMed - indexed for MEDLINE] 2532. Best Pract Res Clin Endocrinol Metab. 2008 Feb;22(1):135-53. doi: 10.1016/j.beem.2007.10.002. Adipocytes and adipose tissue. Kiess W(1), Petzold S, Töpfer M, Garten A, Blüher S, Kapellen T, Körner A, Kratzsch J. Author information: (1)Hospital for Children and Adolescents, University of Leipzig, Liebigstr. 20a, D-04103 Leipzig, Germany. wieland.kiess@medizin.uni-leipzig.de An epidemic of obesity is taking place in most societies around the world. Overall obesity substantially increases the risk of subsequent morbidity. In children and adolescents the degree of body fat mass depends upon ethnic background, gender, developmental stage and age. Obesity is characterized by increases in the number or size of fat cells, or a combination of both. It is generally believed that the number of fat cells depends on age of onset and degree of obesity. This chapter provides information on intrauterine growth of fetal adipose tissue, the earliest period of onset of proliferation, and some of the factors that interact to enhance or suppress development. Fetal adipose tissue development is regulated by the complex interaction of transcription factors, nutrients and adipocytokines. Maternal, endocrine, and paracrine factors also influence specific changes in angiogenesis, adipogenesis, and metabolism. During embryogenesis and in fetal life, leptin and adiponectin, two important adipocytokines, are present at high concentrations in the circulation and in tissues. Developmental stages and metabolic processes influenced by specific hormones and paracrine factors have been identified through examination of the offspring of obese and diabetic pregnancies, hormonal manipulation during late pregnancy in animal models, and the use of cell cultures. Collectively, the results of the studies cited herein delineate the basis for imprinting or conditioning of fetal pre-adipocytes at the paracrine/autocrine level, and of fetal adipose tissue development and metabolism. PMID: 18279785 [PubMed - indexed for MEDLINE] 2533. Thyroid. 2008 Feb;18(2):185-95. doi: 10.1089/thy.2007.0254. Thyroid hormone and adipocyte differentiation. Obregon MJ(1). Author information: (1)Instituto de Investigaciones Biomedicas, Centro mixto from Consejo Superior de Investigaciones Cientificas (CSIC), Universidad Autonoma de Madrid (UAM), Madrid, Spain. mjobregon@iib.uam.es Thyroid hormones act as pleiotropic factors in many tissues during development, by regulating genes involved in differentiation. The adipose tissue, a target of thyroid hormones, is the main place for energy storage and acts as a regulator of energy balance, sending signals to keep metabolic control. Adipogenesis is a complex process that involves proliferation of preadipocytes and its differentiation into mature adipocytes. This process is regulated by several transcription factors (CCAAT/enhancer-binding proteins [C/EBPs], peroxisome proliferator-activated receptors [PPARs]) that act coordinately, activating adipocyte-specific genes that will provide the adipocytic phenotype. Thyroid hormones regulate many of those genes, markers of differentiation of adipocytes, those involved in lipogenesis, lipolysis, and thermogenesis in the brown adipose tissue (BAT). Triiodothyronine (T3) actions are achieved either directly through specific thyroid response elements (TREs), by regulating other key genes as PPARs, or through specific isoforms of the nuclear T3 receptors. The availability of T3 is regulated through the deiodinases D3, D2, and D1. D3 is activated by serum and mitogens during proliferation of preadipocytes, while D2 is linked to the differentiation program of adipocytes, through the C/EBPs that govern its functionality, providing the T3 required for thermogenesis and lipogenesis. The relationship between white adipose tissue (WAT) and BAT and the possible reactivation of WAT by activation of uncoupling protein-1 (UCP1) is discussed. PMID: 18279019 [PubMed - indexed for MEDLINE] 2534. Thyroid. 2008 Feb;18(2):175-83. doi: 10.1089/thy.2007.0296. The multiple facets of the fat tissue. Rocha VZ(1), Libby P. Author information: (1)Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. vrocha@rics.bwh.harvard.edu After a long history of relative neglect by the scientific community, white adipose tissue is finally emerging as a central component of body homeostasis. Indeed, the explosion of obesity statistics worldwide encouraged the study of adipose tissue and the complications of increased adiposity, such as insulin resistance, type 2 diabetes, and accelerated vascular disease. Far beyond merely furnishing free fatty acids from triglyceride depots, a growing list of fat tissue-derived mediators has increased the understanding of the regulatory role of adipose tissue in metabolic control. Recently, inflammation within the obese adipose tissue has surfaced as another important link of obesity to its undesirable metabolic consequences. PMID: 18279018 [PubMed - indexed for MEDLINE] 2535. Thyroid. 2008 Feb;18(2):167-74. doi: 10.1089/thy.2007.0255. Bile acids and the membrane bile acid receptor TGR5--connecting nutrition and metabolism. Thomas C(1), Auwerx J, Schoonjans K. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, Illkirch, France. A multitude of endocrine, neural, and metabolic signaling pathways are activated upon food intake to coordinate the effective use of the available energy. Bile acids (BAs) are released from the gallbladder after each meal and subsequently facilitate the digestion of nutrients. Since concentrations of BAs increase postprandially in the serum, they are also signals of food availability that bridge nutrition with metabolism. Both nuclear and membrane receptors mediate BA signaling. Whereas the nuclear receptor farnesoid X receptor mainly affects enterohepatic lipid homeostasis, the G protein-coupled receptor TGR5 stimulates glucagon-like protein 1 production in enteroendocrine cells and activates thyroid hormone in brown adipose tissue and muscle, through the stimulation of type 2 iodothyronine deiodinase (D2). Through its insulinotropic effects, TGR5 may improve glucose homeostasis; through the activation of D2, it will stimulate energy expenditure and protect against the onset of obesity. These properties position TGR5 as an attractive and "drugable" target in our fight against the metabolic syndrome. PMID: 18279017 [PubMed - indexed for MEDLINE] 2536. Thyroid. 2008 Feb;18(2):157-65. doi: 10.1089/thy.2007.0252. Thyroid-adrenergic interactions: physiological and clinical implications. Silva JE(1), Bianco SD. Author information: (1)Baystate Medical Center, Tufts University Medical School, Springfield, Massachusetts 01199, USA. enrique.silva@bhs.org The sympathoadrenal system, including the sympathetic nervous system and the adrenal medulla, interacts with thyroid hormone (TH) at various levels. Both systems are evolutionary old and regulate independent functions, playing probably independent roles in poikilothermic species. With the advent of homeothermy, TH acquired a new role, which is to stimulate thermogenic mechanisms and synergize with the sympathoadrenal system to produce heat and maintain body temperature. An important part of this new function is mediated through coordinated and, most of the time, synergistic interactions with the sympathoadrenal system. Catecholamines can in turn activate TH in a tissue-specific manner, most notably in brown adipose tissue. Such interactions are of great adaptive value in cold adaptation and in states needing high-energy output. Conversely, in states of emergency where energy demand should be reduced, such as disease and starvation, both systems are turned down. In pathological states, where one of the systems is fixed at a high or a low level, coordination is lost with disruption of the physiology and development of symptoms. Exaggerated responses to catecholamines dominate the manifestations of thyrotoxicosis, while hypothyroidism is characterized by a narrowing of adaptive responses (e.g., thermogenic, cardiovascular, and lipolytic). Finally, emerging results suggest the possibility that disrupted interactions between the two systems contribute to explain metabolic variability, for example, fuel efficiency, energy expenditure, and lipolytic responses. PMID: 18279016 [PubMed - indexed for MEDLINE] 2537. Thromb Haemost. 2008 Feb;99(2):290-4. doi: 10.1160/TH07-10-0589. Role of proteolysis in development of murine adipose tissue. Christiaens V(1), Scroyen I, Lijnen HR. Author information: (1)Center for Molecular and Vascular Biology, KU Leuven, Campus Gasthuisberg, O & N 1, Herestraat 49, Leuven, Belgium. Obesity is a common disorder, and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity, and suggest that modulation of proteolytic activity may affect development of adipose tissue. PMID: 18278177 [PubMed - indexed for MEDLINE] 2538. Pathol Res Pract. 2008;204(4):277-81. doi: 10.1016/j.prp.2007.10.004. Epub 2008 Feb 13. Omental lipoblastoma. Koplin SA(1), Twohig MH, Lund DP, Hafez GR. Author information: (1)Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, CSC-3224, 600 Highland Avenue, Madison, WI 53792, USA. A large intra-abdominal mass was discovered in a 6-month-old boy during a routine well-child examination. Imaging studies revealed a solid mass which appeared to arise from the left lobe of the liver, extending caudally and filling the entire pelvis. At the time of surgical excision, the mass was found to be unassociated with the liver, but was instead localized to the omentum. Histologic examination revealed adipocytes of varying stages of maturation arranged in a lobular architecture, consistent with a lipoblastoma. This unusual tumor is only the eighth reported omental lipoblastoma [J. Hicks, A. Dilley, D. Patel, J. Barrish, S. Zhu, M. Brandt, Lipoblastoma and lipoblastomatosis in infancy and childhood: histologic, ultrastructural, and cytogenetic features. Ultrastruct. Pathol. 25 (2001) 321-333; J. Harrer, G. Hammon, T. Wagner, M. Bolkenius, Lipoblastoma and lipoblastomatosis: a report of two cases and review of the literature. Eur. J. Pediatr. Surg. 11 (2001) 342-349; S. Weiss and J. Goldblum, Enzinger and Weiss's Soft Tissue Tumors, fourth ed., Mosby, St. Louis, MO, 2001, pp. 601-605, 670-686; S. Soin, S. Andronikou, R. Lisle, K. Platt, K. Lakhoo, Omental lipoblastoma in a child; diagnosis based in CT density measurements. J. Pediatr. Hematol. Oncol. 28(1) (2006) 57-58; A. Prando, S. Wallace, J.L. Marins, R.M. Pereira, E.R. de Oliveira, M. Alvarenga, Sonographic features of benign intraperitoneal lipomatous tumors in children-report of 4 cases. Pediatr. Radiol. 20(8) (1990) 571-574; C. Blank, E. Schoenmakers, P. Rogalla, E. Huys, A. Van Rijk, N. Drieschner, J. Bullerdiek, Intragenic breakpoint within RAD51L1 in a t(6;14)(p21.3;q24) of a pulmonary chondroid hamartoma. Cytogenet. Cell Genet. 95 (2001) 17-19; S. Ingraham, R. Lynch, S. Kathiresan, A. Buckler, A. Menon, hREC2, a RAD51-like gene, is disrupted by t(12;14)(q15;q24.1) in a uterine leiomyoma. Cancer Genet. Cytogenet. 115 (1999) 56-61]. Cytogenetics revealed a karyotype of 46,XY,t(8;14)(q13;q24). While lipoblastomas characteristically involve 8q, only one prior case has been reported with 14q24 as its fusion partner [M. He, K. Das, M. Blacksin, J. Benevenia, M. Hameed, A translocation involving the placental growth factor gene is identified in an epithelioid hemangioendothelioma. Cancer Genet. Cytogenet. 168 (2006) 150-154]. We report this unique case of an omental lipoblastoma with a focus on its unusual karyotype, as well as its differentiation from myxoid liposarcoma. PMID: 18276084 [PubMed - indexed for MEDLINE] 2539. Biochem Biophys Res Commun. 2008 Apr 11;368(3):815-9. doi: 10.1016/j.bbrc.2008.02.008. Epub 2008 Feb 12. A putative role for apelin in the etiology of obesity. Rayalam S(1), Della-Fera MA, Krieg PA, Cox CM, Robins A, Baile CA. Author information: (1)Department of Animal & Dairy Science, University of Georgia, 444 Animal Science Complex, Athens, GA 30602-2771, USA. Apelin, the endogenous ligand of the G protein-coupled APJ receptor has been shown to promote tumor angiogenesis. However, the effect of apelin on inducing angiogenesis in adipose tissue has not been investigated. In this review, we propose a putative role for apelin in promoting angiogenesis in adipose tissue. We further propose that targeting adipose tissue vasculature by blocking apelin signaling with anti-apelin antibodies will lead not only to inhibition of angiogenesis in adipose tissue but also to decreased adiposity. PMID: 18275845 [PubMed - indexed for MEDLINE] 2540. Rom J Morphol Embryol. 2008;49(1):13-20. Nonalcoholic fatty liver disease and metabolic syndrome: a concise review. Streba LA(1), Cârstea D, Mitruţ P, Vere CC, Dragomir N, Streba CT. Author information: (1)Department of Internal Medicine 1, Filantropia University Hospital of Craiova, University of Medicine and Pharmacy of Craiova, Romania. letitiastreba@yahoo.com Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological entity increasingly recognized as a major health burden in developed countries. In the last decade, several studies have independently provided evidence for a strong association between NAFLD and each component of the metabolic syndrome, including central obesity, hyperglycemia, dyslipidemia, and hypertension. This article focuses on epidemiological, clinical, pathogenic and therapeutic aspects, which link these two syndromes. PMID: 18273497 [PubMed - indexed for MEDLINE] 2541. Physiol Res. 2008;57 Suppl 1:S159-69. Epub 2008 Feb 13. Hormonal aspects of the muscle-bone unit. Zofková I(1). Author information: (1)Institute of Endocrinology, Prague, Czech Republic. izofkova@endo.cz Osteoporotic fractures are the result of low density and especially inferior bone quality (microarchitecture) caused by both internal (genes, hormones) and external (life style) influences. Bone mechanosensors are extremely important for the overall integrity of the skeleton, because in response to mechanical load they activate its modeling, resulting in an increase in bone density and strength. The largest physiological loads are caused by muscle contractions. Bone mass in adult men has a closer relationship to muscle mass than is case in women. The sexual differences in the relationship between bone and muscle mass are also apparent in children. Based on the mechanostatic theory, the muscle-bone unit has been defined as a functional system whose components are under the common control of the hormones of the somatotropin-IGF-I axis, sexual steroids, certain adipose tissue hormones and vitamin D. The osteogenic effects of somatotropin-IGF-I system are based on the stimulation of bone formation, as well as increase in muscle mass. Moreover, somatotropin decreases the bone mechanostat threshold and reinforces the effect of physical stress on bone formation. The system, via the muscle-bone unit, plays a significant role in the development of the childhood skeleton as well as in its stability during adulthood. The muscle and bone are also the targets of androgens, which increase bone formation and the growth of muscle mass in men and women, independently of IGF-I. The role of further above-mentioned hormones in regulation of this unified functional complex is also discussed. PMID: 18271680 [PubMed - indexed for MEDLINE] 2542. Pediatrics. 2008 Feb;121 Suppl 3:S208-17. doi: 10.1542/peds.2007-1813F. Link between body fat and the timing of puberty. Kaplowitz PB(1). Author information: (1)Department of Endocrinology, Children's National Medical Center, Washington, DC, USA. pkaplowi@cnmc.org Several recent studies suggest that the timing of the onset of puberty in girls has become earlier over the past 30 years, and there is strong evidence that the increasing rates of obesity in children over the same time period is a major factor. This article reviews studies from the United States that examined the age of menarche and the age of onset of breast development and pubic hair as a function of body mass index, which is a good surrogate measure of body fat. These studies are nearly all cross-sectional, so many questions remain unanswered. However, at least several studies show that girls who have relatively higher body mass index are more likely to have earlier menses, as well as a relationship between body mass index and other measures of pubertal onset. The evidence published to date suggests that obesity may be causally related to earlier puberty in girls rather than that earlier puberty causes an increase in body fat. In contrast, few studies have found a link between body fat and earlier puberty in boys. A growing body of evidence from both rodent and human studies suggests that leptin may be the critical link between body fat and earlier puberty. Leptin-deficient mice and humans fail to enter puberty unless leptin is administered, and rodent studies indicate that very low levels of leptin stimulate gonadotropin secretion both at the hypothalamic and the pituitary level. Current evidence indicates that leptin appears to play a permissive role rather than act as the critical metabolic signal initiating puberty. The linkage between body fat and the reproductive axis in girls may have evolved in mammals as a mechanism for ensuring that pregnancy will not occur unless there are adequate fat stores to sustain both the mother and the growing fetus. PMID: 18245513 [PubMed - indexed for MEDLINE] 2543. Diabetes Care. 2008 Feb;31 Suppl 2:S303-9. doi: 10.2337/dc08-s272. Abdominal fat and sleep apnea: the chicken or the egg? Pillar G(1), Shehadeh N. Author information: (1)Sleep Lab, Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel. gpillar@tx.technion.ac.il Comment in Diabetes Care. 2008 Jul;31(7):e61; author reply e62. Obstructive sleep apnea (OSA) syndrome is a disorder characterized by repetitive episodes of upper airway obstruction that occur during sleep. Associated features include loud snoring, fragmented sleep, repetitive hypoxemia/hypercapnia, daytime sleepiness, and cardiovascular complications. The prevalence of OSA is 2-3% and 4-5% in middle-aged women and men, respectively. The prevalence of OSA among obese patients exceeds 30%, reaching as high as 50-98% in the morbidly obese population. Obesity is probably the most important risk factor for the development of OSA. Some 60-90% of adults with OSA are overweight, and the relative risk of OSA in obesity (BMI >29 kg/m(2)) is >or=10. Numerous studies have shown the development or worsening of OSA with increasing weight, as opposed to substantial improvement with weight reduction. There are several mechanisms responsible for the increased risk of OSA with obesity. These include reduced pharyngeal lumen size due to fatty tissue within the airway or in its lateral walls, decreased upper airway muscle protective force due to fatty deposits in the muscle, and reduced upper airway size secondary to mass effect of the large abdomen on the chest wall and tracheal traction. These mechanisms emphasize the great importance of fat accumulated in the abdomen and neck regions compared with the peripheral one. It is the abdomen much more than the thighs that affect the upper airway size and function. Hence, obesity is associated with increased upper airway collapsibility (even in nonapneic subjects), with dramatic improvement after weight reduction. Conversely, OSA may itself predispose individuals to worsening obesity because of sleep deprivation, daytime somnolence, and disrupted metabolism. OSA is associated with increased sympathetic activation, sleep fragmentation, ineffective sleep, and insulin resistance, potentially leading to diabetes and aggravation of obesity. Furthermore, OSA may be associated with changes in leptin, ghrelin, and orexin levels; increased appetite and caloric intake; and again exacerbating obesity. Thus, it appears that obesity and OSA form a vicious cycle where each results in worsening of the other. PMCID: PMC2453667 PMID: 18227501 [PubMed - indexed for MEDLINE] 2544. Gac Med Mex. 2007 Nov-Dec;143(6):505-12. [Macrophages, inflammation, adipose tissue, obesity and insulin resistance]. [Article in Spanish] Bastarrachea RA(1), López-Alvarenga JC, Bolado-García VE, Téllez-Mendoza J, Laviada-Molina H, Comuzzie AG. Author information: (1)Department of Genetics, Auxology and Metabolism Working Group, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA. raulbs@sfbrgenetics.org Obesity is associated with a complex systemic inflammatory reaction that has been associated with the development of atherosclerosis and insulin resistance. Obesity also induces macrophage accumulation in adipose tissue. Macrophages produce many of the pro inflammatory molecules released by adipose tissue and have been implicated in the development of obesity-induced adipose tissue inflammation. Monocyte chemoattractant proteins (MCPs) and their receptors play key roles in the development of inflammatory responses and are crucial for the recruitment of immune cells towards inflammation sites. Adipose tissue expression of at least 1 MCP, C-C motif chemokine ligand-2 (CCL2 or MCP1), increases in proportion to adiposity. The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Because CCR2 regulates monocyte and macrophage chemotaxis and local inflammatory responses, it has been hypothesized that monocyte chemoattractant molecules acting through CCR2 might regulate obesity-induced inflammation in adipose tissue. Our study focuses on the molecular and genetic mechanisms that recruit and retain macrophages in adipose tissue. PMID: 18269082 [PubMed - indexed for MEDLINE] 2545. Physiology (Bethesda). 2008 Feb;23:41-8. doi: 10.1152/physiol.00036.2007. Physiology of nucleoside transporters: back to the future. . . . Rose JB(1), Coe IR. Author information: (1)Department of Biology, York University, Toronto, Ontario, Canada. Nucleoside transporters (NTs) are integral membrane proteins responsible for mediating and facilitating the flux of nucleosides and nucleobases across cellular membranes. NTs are also responsible for the uptake of nucleoside analog drugs used in the treatment of cancer and viral infections, and they are the target of certain compounds used in the treatment of some types of cardiovascular disease. The important role of NTs as drug transporters and therapeutic targets has necessarily led to intense interest into their structure and function and the relationship between these proteins and drug efficacy. In contrast, we still know relatively little about the fundamental physiology of NTs. In this review, we discuss various aspects of the physiology of NTs in mammalian systems, particularly noting tissues and cells where there has been little recent research. Our central thesis is reference back to some of the older literature, combined with current findings, will provide direction for future research into NT physiology that will lead to a fuller understanding of the role of these intriguing proteins in the everyday lives of cells, tissues, organs, and whole animals. PMID: 18268364 [PubMed - indexed for MEDLINE] 2546. Am J Clin Nutr. 2007 Sep;86(3):s867-71. Metabolic syndrome, hyperinsulinemia, and cancer. Hsu IR(1), Kim SP, Kabir M, Bergman RN. Author information: (1)Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA 90033, USA. The term metabolic syndrome describes the association between obesity, insulin resistance, and the risk of several prominent chronic diseases, including cancer. The causal link between many of these components remains unexplained, however. What is clear are the events that precede the development of the syndrome itself. In animal models, a fat-supplemented diet causes 1) lipid deposition in adipose depots, 2) insulin resistance of liver and skeletal muscle, and 3) hyperinsulinemia. One hypothesis relating fat deposition and insulin resistance involves enhanced lipolysis in the visceral depot, which leads to an increase in free fatty acid (FFA) flux. Increased mass of stored lipid and insulin resistance of visceral adipocytes favors lipolysis. Additionally, hypersensitivity of visceral adipose cells to sympathetic nervous system stimulation leads to increased lipolysis in the obese state. However, little evidence is available for enhanced plasma FFA concentrations in the fasting state. We measured FFA concentrations over a 24-h day in obese animals and found that plasma FFAs are elevated in the middle of the night, peaking at 0300. Therefore, it is possible that nocturnal lipolysis increases exposure of liver and muscle to FFAs at night, thus causing insulin resistance, which may play a role in hyperinsulinemic compensation to insulin resistance. Nocturnal lipolysis secondary to sympathetic stimulation may not only cause insulin resistance but also be responsible for hyperinsulinemia by stimulating secretion and reducing clearance of insulin by the liver. The resulting syndrome-elevated nocturnal FFAs and elevated insulin-may synergize and increase the risk of some cancers. This possible scenario needs further study. PMID: 18265480 [PubMed - indexed for MEDLINE] 2547. Am J Clin Nutr. 2007 Sep;86(3):s843-57. Obesity, metabolic syndrome, and prostate cancer. Hsing AW(1), Sakoda LC, Chua S Jr. Author information: (1)Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852-7234, USA. hsinga@mail.nih.gov Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification. PMID: 18265478 [PubMed - indexed for MEDLINE] 2548. J Cell Physiol. 2008 Jul;216(1):3-13. doi: 10.1002/jcp.21386. The secretory function of adipocytes in the physiology of white adipose tissue. Wang P(1), Mariman E, Renes J, Keijer J. Author information: (1)Functional Genomics Group, Department of Human Biology, The Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. White adipose tissue, previously regarded as a passive lipid storage site, is now viewed as a dynamic tissue. It has the capacity to actively communicate by sending and receiving different types of signals. An overview of these signals, the external modulators that affect adipose tissue and the secreted signaling molecules, the adipokines, is presented. The secretory function is highlighted in relation to energy metabolism, inflammation and the extracellular matrix and placed in the context of adipose tissue biology. We observe that the endocrine function of adipocytes receives much attention, while its paracrine and autocrine functions are underestimated. Also, we provide examples that species specificity should not be neglected. We conclude that adipose tissue primarily is an energy storage organ, well supported by its secretory function. (c) 2008 Wiley-Liss, Inc. PMID: 18264975 [PubMed - indexed for MEDLINE] 2549. Physiol Behav. 2008 May 23;94(2):219-30. doi: 10.1016/j.physbeh.2008.01.002. Epub 2008 Jan 11. Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity. Jocken JW(1), Blaak EE. Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. j.jocken@hb.unimaas.nl Increased fat storage in adipose and non-adipose tissue (e.g. skeletal muscle) characterizes the obese insulin resistant state. Disturbances in pathways of lipolysis may play a role in the development and maintenance of these increased fat stores. A reduced catecholamine-induced lipolysis may contribute to the development and maintenance of increased adipose tissue stores. To data, a reduced hormone-sensitive lipase (HSL) expression is the best characterized defect contributing to this catecholamine resistance. The recently discovered adipose triglyceride lipase (ATGL) seems not to be involved in the catecholamine resistance of lipolysis observed in abdominal subcutaneous adipose tissue of obese subjects, which contrasts with findings in mice studies. So far, little is known on the regulation of skeletal muscle lipolysis. There is evidence of both HSL and ATGL activity and/or expression in skeletal muscle. A blunted fasting and/or catecholamine-induced lipolysis has been reported in skeletal muscle, but data require confirmation. It is tempting to speculate that an imbalance between ATGL and HSL expression results in incomplete lipolysis and increased accumulation of lipid intermediates in skeletal muscle of obese insulin resistant subjects. The latter may inhibit insulin signalling and play a role in the development of type 2 diabetes. This review summarizes the current knowledge on (intracellular) adipose tissue and skeletal muscle lipolysis in obesity, discusses the underlying mechanisms of these disturbances and will finally address the question whether disturbances in the lipolytic pathways may be primary factors in the etiology of obesity or adaptational responses to the obese insulin resistant state. PMID: 18262211 [PubMed - indexed for MEDLINE] 2550. Hum Pathol. 2008 Mar;39(3):463-8. doi: 10.1016/j.humpath.2007.08.008. Mixed epithelial and stromal tumor of kidney with malignant transformation: report of two cases and review of literature. Jung SJ(1), Shen SS, Tran T, Jun SY, Truong L, Ayala AG, Ro JY. Author information: (1)Department of Pathology, Weill Medical College of Cornell University, The Methodist Hospital, Houston, TX 77030, USA. We present 2 cases of mixed epithelial and stromal tumor of the kidney with sarcomatous transformation. One patient was a 53-year-old woman who presented with macroscopic hematuria. The resected tumor involved the right renal parenchyma, measuring 13.0 x 8.0 x 4.0 cm, and extended to perirenal adipose tissue. The second patient was a 56-year-old woman who presented with right flank colic pain. The tumor measured 6.0 x 5.5 x 4.0 cm, with an intact capsule at the upper pole. Both tumors showed a well-circumscribed, multilocular, cystic, and focally solid mass. Sections of both tumors revealed benign and malignant components. The benign component consisted of multilocular cysts and fibrous stroma with a focally ovarian stromalike component. The malignant component in both cases was predominantly composed of undifferentiated cellular spindle cell sarcoma with frequent mitoses. One case showed additional heterologous malignant elements, including rhabdomyosarcomatous, chondrosarcomatous, and focal carcinomatous components. We report 2 additional cases of sarcomatous transformation in mixed epithelial and stromal tumor of the kidney. PMID: 18261632 [PubMed - indexed for MEDLINE] 2551. Biochem Biophys Res Commun. 2008 Apr 11;368(3):455-7. doi: 10.1016/j.bbrc.2008.01.113. Epub 2008 Feb 4. Mature adipocytes may be a source of stem cells for tissue engineering. Fernyhough ME(1), Hausman GJ, Guan LL, Okine E, Moore SS, Dodson MV. Author information: (1)Department of Animal Sciences, Washington State University, P.O. Box 646310, Pullman, WA 99164, USA. Adipose tissue contains a large portion of stem cells. These cells appear morphologically like fibroblasts and are primarily derived from the stromal cell fraction. Mature (lipid-filled) adipocytes possess the ability to become proliferative cells and have been shown to produce progeny cells that possess the same morphological (fibroblast-like) appearance as the stem cells from the stromal fraction. A closer examination of mature adipocyte-derived progeny cells may prove to be an emerging area of growth/metabolic physiology that may modify present thinking about adipose tissue renewal capabilities. Knowledge of these cells may also prove beneficial in cell-based therapies for tissue repair, regeneration, or engineering. PMID: 18252194 [PubMed - indexed for MEDLINE] 2552. Horm Res. 2007;68 Suppl 5:2-4. doi: 10.1159/000110461. Epub 2007 Dec 10. Mouse models for understanding the growth hormone insulin-like growth factor-I axis. Rosen CJ(1). Author information: (1)Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, Bangor, Me. 04401, USA. crosen@maine.maine.edu BACKGROUND: Mouse models that include spontaneous mutations, as well as those carrying allelic differences, have been extremely useful in clarifying the role of skeletal and circulating insulin-like growth factor I (IGF-I) in peak bone acquisition. The role of peroxisome proliferator-activated receptor gamma, a nuclear receptor and key differentiation factor for adipogenesis, has provided new insights into the relationship of marrow fat to skeletal mass. CONCLUSIONS: Mouse models continue to deepen our understanding of IGF-I signaling and the role of IGF-I in determining marrow stromal cell fate. Copyright (c) 2007 S. Karger AG, Basel. PMID: 18174693 [PubMed - indexed for MEDLINE] 2553. J Endocrinol Invest. 2007 Dec;30(11):962-76. Central dysregulations in the control of energy homeostasis and endocrine alterations in anorexia and bulimia nervosa. Torsello A(1), Brambilla F, Tamiazzo L, Bulgarelli I, Rapetti D, Bresciani E, Locatelli V. Author information: (1)Department of Experimental Medicine, University of Milano-Bicocca, 20052 Monza, Italy. antonio.torsello@unimib.it In the last decades we have come to understand that the hypothalamus is a key region in controlling energy homeostasis. A number of control models have been proposed to explain the regulation of feeding behavior in physiological and pathological conditions, but all those based on imbalances of single factors fail to explain the disrupted regulation of energy supply in eating disorders such as anorexia nervosa and bulimia nervosa, as well as other psychiatric disorders. A growing amount of evidence demonstrates that many signaling molecules originated within the brain or coming from the adipose tissue or the gastro-enteric tract are involved in the highly complex process controlling food intake and energy expenditure. The recent discovery of leptin, ghrelin, and other factors have made it possible to penetrate in the still undefined pathophysiology of eating disorders with the hope of finding effective treatments for such diseases. PMID: 18250619 [PubMed - indexed for MEDLINE] 2554. Proc Am Thorac Soc. 2008 Feb 15;5(2):185-92. doi: 10.1513/pats.200708-137MG. Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Schwartz AR(1), Patil SP, Laffan AM, Polotsky V, Schneider H, Smith PL. Author information: (1)Johns Hopkins Sleep Disorders Center, Baltimore, MD 21224, USA. aschwar2@jhmi.edu Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Collapsibility can be increased by underlying anatomic alterations and/or disturbances in upper airway neuromuscular control, both of which play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. They can increase pharyngeal collapsibility through mechanical effects on pharyngeal soft tissues and lung volume, and through central nervous system-acting signaling proteins (adipokines) that may affect airway neuromuscular control. Specific molecular signaling pathways encode differences in the distribution and metabolic activity of adipose tissue. These differences can produce alterations in the mechanical and neural control of upper airway collapsibility, which determine sleep apnea susceptibility. Although weight loss reduces upper airway collapsibility during sleep, it is not known whether its effects are mediated primarily by improvement in upper airway mechanical properties or neuromuscular control. A variety of behavioral, pharmacologic, and surgical approaches to weight loss may be of benefit to patients with sleep apnea, through distinct effects on the mass and activity of regional adipose stores. Examining responses to specific weight loss strategies will provide critical insight into mechanisms linking obesity and sleep apnea, and will help to elucidate the humoral and molecular predictors of weight loss responses. PMCID: PMC2645252 PMID: 18250211 [PubMed - indexed for MEDLINE] 2555. Eur J Intern Med. 2008 Mar;19(2):75-82. doi: 10.1016/j.ejim.2007.02.034. Evolving trends in nonalcoholic fatty liver disease. Delgado JS(1). Author information: (1)The University of Chicago, Section of Gastroenterology, Department of Medicine, Chicago, 5841 S. Maryland Ave., MC 4076 Chicago, IL 60637, USA. jdelgado@medicine.bsd.uchicago.edu Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide. NALFD encompasses a continuum of histological findings ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH) with steatosis, inflammation, hepatocyte ballooning, fibrosis and eventually liver cirrhosis. The pathogenesis of NAFLD might be related to a deregulated cross-talk between liver and visceral adipose tissue, originating an impairment of normal insulin signaling. A better comprehension of the immunologic and metabolic roles of adipose tissue in modulating inflammatory pathways will enhance our understanding of the molecular mechanisms leading to progression of fatty liver disease. These insights, moreover, will suggest new strategies to improve insulin sensitivity and reduce obesity-associated morbidities and mortality. PMID: 18249301 [PubMed - indexed for MEDLINE] 2556. Cell Metab. 2008 Feb;7(2):97-8. doi: 10.1016/j.cmet.2008.01.003. Fighting fat with muscle: bulking up to slim down. Harrison BC(1), Leinwand LA. Author information: (1)Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309, USA. Comment on Cell Metab. 2008 Feb;7(2):159-72. Akt1 is a well-characterized mediator of muscle hypertrophy. In this issue of Cell Metabolism, Izumiya et al. (2008) reveal a striking link between Akt1 signaling, fast muscle fiber size, and whole-body metabolism. These results provide new insights into the ability of muscle to combat diet-induced obesity and metabolic dysfunction. PMID: 18249167 [PubMed - indexed for MEDLINE] 2557. Curr Atheroscler Rep. 2007 Sep;9(3):230-7. Transcriptional regulation of peroxisome proliferator-activated receptors and liver X receptors. Villacorta L(1), Garcia-Barrio MT, Chen YE. Author information: (1)Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) regulate a plethora of biologic processes and key metabolic and physiologic events. Deregulation of their transcription and activity is commonly associated with dyslipidemic disorders, diabetes, cancer, and cardiovascular disease. This review addresses recent advances in our understanding of the molecular mechanisms regulating transcription of these nuclear receptors. The heterogeneity of factors regulating their transcription and activity suggests intricate regulatory networks that determine their tissue expression pattern and their responses to pharmacologic agents. Understanding such mechanisms will facilitate unraveling their protective effects in disease as well as the design of effective targeted therapies. PMID: 18241618 [PubMed - indexed for MEDLINE] 2558. Curr Atheroscler Rep. 2007 Sep;9(3):204-10. Genetic links between diabetes mellitus and coronary atherosclerosis. Ordovas JM(1). Author information: (1)Nutrition and Genetics, JM-USDA-HNRCA at Tufts University, Boston, MA 02111, USA. jose.ordovas@tufts.edu Diabetes mellitus is one of the most common endocrine disorders. It affects almost 6% of the world's population, and its prevalence continues to increase. The causes of diabetes mellitus are multifactorial, and in the general population both genetic and environmental factors contribute evenly to its development. Several genes have been consistently associated with type 2 diabetes mellitus; however, it is not clear how many of those translate into increased cardiovascular disease risk. Recent evidence suggests that genetic variation at the CALPN10, FABP4, GK, GST, PPARA, and PPARG loci may confer higher cardiovascular disease risk in patients with type 2 diabetes mellitus. However, the evidence is scattered and inconclusive and its translation into practical clinical testing will require studies properly designed to examine not only simple genetic associations but also gene-gene and gene-environment interactions. PMID: 18241614 [PubMed - indexed for MEDLINE] 2559. World J Gastroenterol. 2008 Feb 14;14(6):831-44. The blind men 'see' the elephant-the many faces of fatty liver disease. Sanal MG(1). Author information: (1)Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India. sanalmg@gmail.com Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual's immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis 'NAFLD' can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse. PMCID: PMC2687050 PMID: 18240340 [PubMed - indexed for MEDLINE] 2560. Obesity (Silver Spring). 2008 Feb;16(2):241-56. doi: 10.1038/oby.2007.53. Effects of exercise on adiponectin: a systematic review. Simpson KA(1), Singh MA. Author information: (1)School of Exercise and Sport Science, University of Sydney, Sydney, NSW, Australia. Secreted from white adipose tissue, circulating concentrations of adiponectin are reduced in the presence of metabolic and cardiovascular disease such as obesity and type 2 diabetes. The aim of this systematic review is to assess the body of evidence critically for the effects of exercise on adiponectin levels. Literature searches using the Medline, CINAHL, Cochrane Controlled Trials registry, EMBASE, and SportDiscus databases were conducted from 1966 to September 2006 using keywords pertaining to "adiponectin" and "exercise." Thirty-three trials met the inclusion criteria. Study designs consisted of 5 cross-sectional studies, 7 trials of acute exercise, 11 uncontrolled trials, 2 non-randomized controlled trials, and 8 randomized controlled trials (RCTs). Exercise of varying prescription has been shown to increase serum adiponectin in 38% of RCTs, demonstrating small-to-moderate effect sizes (ESs). One study reported a dose-response effect of resistance training intensity and the augmentation of adiponectin. Inconsistent support in the literature exists for increasing adiponectin levels after short-term exposure to robust aerobic or resistance training of moderate-to-high intensities. Particular attention should be directed toward high-risk cohorts, in whom augmentation of the anti-inflammatory cytokine adiponectin may assume critical importance. PMID: 18239630 [PubMed - indexed for MEDLINE] 2561. Circ Res. 2008 Feb 1;102(2):140-2. doi: 10.1161/CIRCRESAHA.107.170274. Adiponectin and adaptive immunity: linking the bridge from obesity to atherogenesis. Steffens S, Mach F. Comment on Circ Res. 2008 Feb 1;102(2):218-25. PMID: 18239140 [PubMed - indexed for MEDLINE] 2562. Front Horm Res. 2008;36:229-59. doi: 10.1159/0000115368. Emerging concepts in the medical and surgical treatment of obesity. Aylwin S(1), Al-Zaman Y. Author information: (1)Department of Endocrinology, King's College Hospital NHS Foundation Trust, London, UK. simon.aylwin@kingsch.nhs.uk The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery. PMID: 18230906 [PubMed - indexed for MEDLINE] 2563. Front Horm Res. 2008;36:198-211. doi: 10.1159/0000115366. The role of AMP-activated protein kinase in obesity. Kola B(1), Grossman AB, Korbonits M. Author information: (1)Department of Endocrinology, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK. AMP-activated protein kinase (AMPK) is a major regulator of energy metabolism at both the cell and at the whole body level. Numerous genetic and obesity models as well as human studies have suggested a role for AMPK in the physiological regulation of fatty acid and glucose metabolism, and in the regulation of appetite. Changes in AMPK activity have been reported in obesity, type 2 diabetes, the metabolic syndrome and cardiovascular disease, which jointly represent a major health and economical problem worldwide. Whether AMPK changes are one of the causes or the consequence of these pathological conditions remains a matter of debate, but AMPK clearly represents a major potential pharmacological target in the treatment of these conditions. PMID: 18230904 [PubMed - indexed for MEDLINE] 2564. Front Horm Res. 2008;36:182-97. doi: 10.1159/0000115365. Adipokines in obesity. Ahima RS(1), Osei SY. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu Adipose tissue is the source of soluble mediators (adipokines), secreted mainly by adipocytes. Leptin acts on the brain and peripheral organs to regulate energy homeostasis and the neuroendocrine axis. Adiponectin regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. Adiposederived proinflammatory cytokines, vasoactive peptides, coagulation and complement factors, visfatin, vaspin and retinol-binding protein signal through paracrine and hormonal mechanisms. Understanding the biology of adipose tissue and the rapidly growing list of adipokines provides new insights into normal physiological regulation, as well as the pathogenesis and treatment of obesity, diabetes and disorders of lipid metabolism and cardiovascular system. PMID: 18230903 [PubMed - indexed for MEDLINE] 2565. Front Horm Res. 2008;36:146-64. doi: 10.1159/0000115363. 11beta-hydroxysteroid dehydrogenase type 1 and obesity. Morton NM(1), Seckl JR. Author information: (1)Endocrinology Unit, Centre for Cardiovascular Sciences, Queens Medical Research Institute, Edinburgh University, Edinburgh, UK. The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing's syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects - despite the opposing plasma glucocorticoid profiles of Cushing's and idiopathic metabolic syndrome - remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11beta -hydroxysteroid dehydrogenase type 1 (11beta -HSD1). In order to determine whether elevated tissue 11beta -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11beta -HSD1 in adipose tissue or liver were made. Adipose-selective 11beta -HSD1 transgenic mice exhibited elevated intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11beta -HSD1 in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hypertension and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective 11beta -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment of the metabolic syndrome. Further, a transgenic model of therapeutic 11beta -HSD1 inhibition, 11beta -HSD1 gene knock-out (11beta -HSD1-/-) mice, exhibited improved glucose tolerance, a 'cardioprotective' lipid profile, reduced weight gain and visceral fat accumulation with chronic high-fat feeding. Recent evidence further suggests that high fat-mediated downregulation of adipose 11beta -HSD1 may be an endogenous pathway that underpins adaptive disease resistance in genetically predisposed mouse strains. This mechanism could feasibly make up a genetic component of innate obesity resistance in humans. The efficacy of 11beta -HSD1 inhibitors has recently been extended to include increased energy expenditure and reduction of arteriosclerosis, and therefore may be of significant therapeutic value in the metabolic syndrome, with complementary effects upon liver adipose tissue, muscle, pancreas and plaque-prone vessels. PMID: 18230901 [PubMed - indexed for MEDLINE] 2566. Front Horm Res. 2008;36:135-45. doi: 10.1159/0000115362. Role of the endocannabinoid system in energy balance regulation and obesity. Cota D(1). Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a role in the regulation of various aspects of eating behavior and energy balance through central and peripheral mechanisms. In the central nervous system, cannabinoid type 1 receptors and their endogenous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume palatable food. Moreover, the ECS is present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it seems to be involved in the regulation of lipid and glucose homeostasis. Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may provide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease. PMID: 18230900 [PubMed - indexed for MEDLINE] 2567. Front Horm Res. 2008;36:97-106. doi: 10.1159/0000115358. Obesity in old age. Chapman IM(1). Author information: (1)Department of Medicine, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia. ian.chapman@adelaide.edu.au Many older people in developed countries are overweight or obese. The prevalence is increasing as more people reach old age already overweight. Obesity in old age is associated with increased morbidity and a reduction in quality of life. The relative increase in mortality is less in older than young adults and the body weight associated with maximal survival increases with advancing age. Although intentional weight loss by overweight older people is probably safe and beneficial, caution should be exercised in recommending weight loss to overweight older people on the basis of body weight alone. Methods of achieving weight loss in older adults are the same as in younger adults. Weight loss diets should be combined with an exercise program to preserve muscle mass, as dieting results in loss of muscle as well as fat, and older people have reduced skeletal muscle mass in any case. Weight loss drugs have not been extensively studied in older people, and there is the potential for drug side effects and interactions. Weight loss surgery appears to be safe and effective, albeit slightly less so than in younger adults, but little is known about the outcomes of such surgery in those over 65 years. PMID: 18230897 [PubMed - indexed for MEDLINE] 2568. Front Horm Res. 2008;36:61-72. doi: 10.1159/0000115337. Fetal and neonatal pathways to obesity. Gluckman PD(1), Hanson MA, Beedle AS, Raubenheimer D. Author information: (1)Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland, New Zealand. Evolutionary and developmental perspectives add considerably to our understanding of the aetiology of obesity and its related disorders. One pathway to obesity represents the maladaptive consequences of an evolutionarily preserved mechanism by which the developing mammal monitors nutritional cues from its mother and adjusts its developmental trajectory accordingly. Prediction of a nutritionally sparse environment leads to a phenotype that promotes metabolic parsimony by favouring fat deposition, insulin resistance, sarcopenia and low energy expenditure. But this adaptive mechanism evolved to accommodate gradual changes in nutritional environment; rapid transition to a situation of high energy density results in a mismatch between predicted and actual environments and increased susceptibility to metabolic disease. This pathway may also explain why breast and bottle feeding confer different risks of obesity. We discuss how early environmental signals act through epigenetic mechanisms to alter metabolic partitioning, glucocorticoid action and neuroendocrine control of appetite. A second pathway involves alterations in fetal insulin levels, as seen in gestational diabetes, leading to increased prenatal fat mass which is subsequently amplified by postnatal factors. Both classes of pathway may coexist in an individual. This developmental approach to obesity suggests that potential interventions will vary according to the target population. PMID: 18230894 [PubMed - indexed for MEDLINE] 2569. Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):82-9. doi: 10.1111/j.1742-7843.2007.00188.x. Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. McMillen IC(1), MacLaughlin SM, Muhlhausler BS, Gentili S, Duffield JL, Morrison JL. Author information: (1)Early Origins of Adult Health Research Group, Sansom Research Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia. caroline.mcmillen@unisa.edu.au The 'developmental origins of adult health and disease' hypothesis stated that environmental factors, particularly maternal undernutrition, act in early life to programme the risks for adverse health outcomes, such as cardiovascular disease, obesity and the metabolic syndrome in adult life. Early physiological tradeoffs, including activation of the foetal hypothalamo-pituitary-adrenal (HPA) axis, confer an early fitness advantage such as foetal survival, while incurring delayed health costs. We review the evidence that such tradeoffs are anticipated from conception and that the periconceptional nutritional environment can programme the developmental trajectory of the stress axis and the systems that maintain and regulate arterial blood pressure. There is also evidence that restriction of placental growth and function, results in an increased dependence of the maintenance of arterial blood pressure on the sequential recruitment of the sympathetic nervous system and HPA axis. While the 'early origins of adult disease' hypothesis has focussed on the impact of maternal undernutrition, an increase in maternal nutritional intake and in maternal body mass intake has become more prevalent in developed countries. Exposure to overnutrition in foetal life results in a series of central and peripheral neuroendocrine responses that in turn programme development of the fat cell and of the central appetite regulatory system. While the physiological responses to foetal undernutrition result in the physiological trade off between foetal survival and poor health outcomes that emerge after reproductive senescence, exposure to early overnutrition results in poor health outcomes that emerge in childhood and adolescence. Thus, the effects of early overnutrition can directly impact on reproductive fitness and on the health of the next generation. In this context, the physiological responses to relative overnutrition in early life may directly contribute to an intergenerational cycle of obesity. PMID: 18226059 [PubMed - indexed for MEDLINE] 2570. Bull Acad Natl Med. 2007 Apr-May;191(4-5):897-908; discussion 908-10. [White adipose tissue, inflammation and atherosclerosis]. [Article in French] Meier CA(1), Thalmann S. Author information: (1)Départment de Médecine Interne, Triemli Hôpital, Birmensdorferstrasse 497, CH-8063 Zürich, Suisse. Our view of white adipose tissue (WAT) has changed over the last decade, from an inert triglyceride storage tissue to a highly active metabolic organ. Indeed, WAT secretes proinflammatory cytokines such TNF-a, interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-6 (IL-6), and chemokines such as monocyte chemoattractant protein-1 (MCP-1), interferon gamma inducible protein 10 (IP-10), interleukin-8 (IL-8), RANTES, and peptides with hormone-like actions such as adiponectin, leptin and resistin. Through their paracrine actions these factors contribute to local WAT inflammation, neoangiogenesis and differentiation. On entering the systemic circulation they can contribute to creating or maintaining a systemic inflammatory state, hypertension and insulin resistance, and can also affect central control of food intake. When located around organs such as the kidney, heart and blood vessels, WAT can adversely affect organ function by secreting cytokines and chemokines. For example, perivascular WAT which secretes proatherogenic cytokines and chemokines and which is present around large and medium-sized arteries, could contribute to the development of atherosclerotic lesions by attracting inflammatory cells and stimulating neoangiogenesis, thereby amplifying the chronic vascular inflammation which is the hallmark of atherosclerosis. PMID: 18225444 [PubMed - indexed for MEDLINE] 2571. Neuromolecular Med. 2008;10(3):169-78. doi: 10.1007/s12017-008-8022-5. Epub 2008 Jan 26. Perturbed autonomic nervous system function in metabolic syndrome. Tentolouris N(1), Argyrakopoulou G, Katsilambros N. Author information: (1)1st Department of Propaedeutic Medicine, Athens University Medical School, Athens, Greece. ntentol@med.uoa.gr The metabolic syndrome is characterized by the clustering of various common metabolic abnormalities in an individual and it is associated with increased risk for the development of type 2 diabetes and cardiovascular diseases. Its prevalence in the general population is approximately 25%. Central fat accumulation and insulin resistance are considered as the common denominators of the abnormalities of the metabolic syndrome. Subjects with metabolic syndrome have autonomic nervous system dysfunction characterized by predominance of the sympathetic nervous system in many organs, i.e. heart, kidneys, vasculature, adipose tissue, and muscles. Sympathetic nervous system activation in metabolic syndrome is detected as increased heart rate and blood pressure, diminished heart rate variability, baroreceptor dysfunction, enhanced lipolysis in visceral fat, increased muscle sympathetic nerve activity, and high urine or plasma catecholamine concentrations as well as turnover rates. The augmented sympathetic activity in individuals with metabolic syndrome worsens prognosis of this high-risk population. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not clearly understood. Whether sympathetic overactivity is involved in the development of the metabolic syndrome or is a consequence of it remains to be elucidated since data from prospective studies are missing. Intervention studies have demonstrated that the autonomic disturbances of the metabolic syndrome may be reversible. PMID: 18224460 [PubMed - indexed for MEDLINE] 2572. Arch Mal Coeur Vaiss. 2007 Dec;100(12):979-84. [Dyslipidemia and abdominal obesity: mechanisms and characteristics (Part I)]. [Article in French] Farnier M(1). Author information: (1)Point Médical, dijon. michelfarnier@nerim.net The dyslipidemia classically associated with abdominal obesity is characterised by a metabolic atherogenic triad including an elevation of triglycerides, a low HDL-cholesterol and an excess of small dense LDL fractions. All of these lipid anomalies contribute to an increased cardio-metabolic risk, and are engendered by an excess of visceral adipose tissue. This excess adipose tissue seems to be the direct origin of the dyslipidemia associated with abdominal obesity, causing more free fatty acids to flow into the liver and contributing to insulin resistance. PMID: 18223510 [PubMed - indexed for MEDLINE] 2573. Physiol Behav. 2008 May 23;94(2):231-41. doi: 10.1016/j.physbeh.2007.11.049. Epub 2007 Dec 5. Lipid accumulation in non-adipose tissue and lipotoxicity. van Herpen NA(1), Schrauwen-Hinderling VB. Author information: (1)Top Institute Food and Nutrition, 6700 AN Wageningen, The Netherlands. noud.vanherpen@hb.unimaas.nl Obesity is a well-known risk factor for the development of type 2 diabetes mellitus and cardiovascular disease. Importantly, obesity is not only associated with lipid accumulation in adipose tissue, but also in non-adipose tissues. The latter is also known as ectopic lipid accumulation and may be a possible link between obesity and its comorbidities such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. In skeletal muscle and liver, lipid accumulation has been associated with the development of insulin resistance, an early hallmark of developing type 2 diabetes mellitus. More specifically, accumulation of intermediates of lipid metabolism, such as diacylglycerol (DAG) and Acyl-CoA have been shown to interfere with insulin signaling in these tissues. Initially, muscular and hepatic insulin resistance can be overcome by an increased insulin production by the pancreas, resulting in hyperinsulinemia. However, during the progression towards overt type 2 diabetes, pancreatic failure occurs resulting in reduced insulin production. Interestingly, also in the pancreas lipid accumulation has been shown to precede dysfunction. Finally, accumulation of fat in the heart has been associated with cardiac dysfunction and heart failure, which may be an explanation for diabetic cardiomyopathy. Taken together, we conclude that evidence for deleterious effects of lipid accumulation in non-adipose tissue (lipotoxicity) is strong. However, while ample human data is available for skeletal muscle and the liver, future research should focus on lipid accumulation in the pancreas and the heart. PMID: 18222498 [PubMed - indexed for MEDLINE] 2574. Recent Pat Cardiovasc Drug Discov. 2007 Jun;2(2):100-9. Leptin and the cardiovascular system: a review. Ashwin PJ(1), Dilipbhai PJ. Author information: (1)Department of Pharmacology, Institute of Pharmacy, Nirma University of Science and Technology, Sarkhej-Gandhinagar Highway, Ahmedabad-382481, Gujarat, India. jagrutiap@gmail.com Obesity is an increasing health problem not only in the industrialized western countries but, also in the developing countries like India. The adipose tissue specific obese (ob) gene and its peptide product leptin were discovered in 1994. Leptin binding to specific receptors in the hypothalamus results in altered expression of orexigenic and anorexigenic neuropeptides that regulate neuroendocrine functions and energy homeostasis. Recent patents and experimental evidence suggest that leptin plays an important role in the pathogenesis of obesity and eating disorders. Central leptin action also includes regulation of blood pressure, bone mass, and immune function. Peripherally also, leptin plays an important role in direct regulation of immune cells, pancreatic beta cells, adipocytes and muscle cells. Leptin receptors are present on human endothelial cells, and it has been shown to induce angiogenesis both in vitro and in vivo. Further, leptin appears to be a potential pressure and volume regulating factor and may function pathophysiologically as a common link to obesity and hypertension. Obesity is also a risk factor for several other cardiovascular diseases like myocardial hypertrophy, myocardial infarction, coronary atherosclerosis and increased cardiovascular morbidity and mortality. Recent progress in understanding central and peripheral leptin receptor signaling pathways may provide potential new targets to combat obesity, hypertension etc. PMID: 18221108 [PubMed - indexed for MEDLINE] 2575. Mini Rev Med Chem. 2008 Jan;8(1):91-6. The Adipocyte as a novel TSH target. Sorisky A(1), Antunes TT, Gagnon A. Author information: (1)Ottawa Health Research Institute, Ottawa ON K1Y 4E9 Canada. asorisky@ohri.ca Thyroid stimulating hormone (TSH; also known as thyrotropin), binds cognate receptors on the surface of thyrocytes to regulate proliferation and thyroid hormone synthesis. This unidimensional view of TSH is being transformed as new evidence indicates that TSH acts on adipose tissue. Adipocyte inflammatory responses that predispose to cardiovascular disease may occur in thyroid disorders associated with elevated TSH levels. PMID: 18220988 [PubMed - indexed for MEDLINE] 2576. Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):250-8. Does global gene expression analysis in type 2 diabetes provide an opportunity to identify highly promising drug targets? Buechler C(1), Schäffler A. Author information: (1)Department of Internal Medicine I, University Hospital of Regensburg, D-93042 Regensburg, Germany. christa.buechler@klinik.uni-regensburg.de The recent technological advances in high-throughput gene expression analysis allow the simultaneous investigation of thousands of genes. These technologies represent promising tools for the identification of new drug targets and considerable progress has been achieved in cancer research where microarray data provide a basis to design new drugs and to predict adverse reactions and the efficacy of chemotherapy. The metabolic syndrome represents a cluster of disorders including high blood pressure, insulin resistance/type 2 diabetes mellitus, visceral obesity and dyslipidaemia with fatty liver disease being a common associated complication. High-throughput gene expression analyses using GeneChips, microarrays and serial analysis of gene expression (SAGE) have been applied to study global gene expression in insulin resistance/type 2 diabetes mellitus. Type 2 diabetes mellitus is a multifactorial and polygenic disease by which several organs are affected. Therefore, the identification of both, disease causing and therapeutically relevant target genes is an ambitious challenge. In the present review we focus on genomic approaches that used biopsies from human skeletal muscle, liver and adipose tissue, the main organs affected by insulin resistance. Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators are decreased in skeletal muscle in insulin resistance accounting for the reduced expression of genes involved in mitochondrial oxidative phosphorylation. Hepatic steatosis is also linked to alterations in mitochondrial phosphorylation and oxidative metabolism. An up regulation of pro-inflammatory genes can be detected in early stages of fatty liver disease without histological signs of inflammation. Impaired adipogenesis, intra-adipose accumulation of macrophages and a sustained release of inflammatory and acute phase proteins are characteristic features of adipose tissue in obesity and may aggravate systemic insulin resistance. PMID: 18220945 [PubMed - indexed for MEDLINE] 2577. Curr Stem Cell Res Ther. 2007 Dec;2(4):301-9. Umbilical cord blood: a unique source of pluripotent stem cells for regenerative medicine. Harris DT(1), Rogers I. Author information: (1)Department of Immunobiology, 1501 N. Campbell Avenue, LSN 643, University of Arizona, Tucson, AZ 85724, USA. davidh@email.arizona.edu It is estimated that almost 1 in 3 individuals in the United States might benefit from regenerative medicine therapy. Unfortunately, embryonic stem (ES) cell therapies are currently limited by ethical, political, biological and regulatory hurdles. Thus, for the foreseeable future, the march of regenerative medicine to the clinic will depend upon the development of non-ES cell therapies. Current sources of non-ES cells easily available in large numbers can be found in the bone marrow, adipose tissue and umbilical cord blood. Each of these types of stem cells has already begun to be utilized to treat a variety of diseases. This review will show that cord blood (CB) contains multiple populations of ES-like and other pluripotential stem cells, capable of giving rise to hematopoietic, epithelial, endothelial, and neural tissues both in vitro and in vivo. Cumulatively, the identification and isolation of these populations of pluripotent stem cells within cord blood represents a scientific breakthrough that could potentially impact every field of medicine, via their use in regenerative medicine. Thus, CB stem cells are amenable to treatment of a wide variety of diseases including cardiovascular, hepatic, ophthalmic, orthopaedic, neurological and endocrine diseases. PMID: 18220914 [PubMed - indexed for MEDLINE] 2578. Curr Stem Cell Res Ther. 2006 Sep;1(3):365-9. Adult mesenchymal stem cells: a pluripotent population with multiple applications. Porada CD(1), Zanjani ED, Almeida-Porad G. Author information: (1)Department of Animal Biotechnology, University of Nevada, Reno 89557-0104, USA. Mesenchymal stem cells (MSCs) have been isolated not only from bone marrow, but also from many other tissues such as adipose tissue, skeletal muscle, liver, brain and pancreas. Because MSC were found to have the ability to differentiate into cells of multiple organs and systems such as bone, fat, cartilage, muscle, neurons, hepatocytes and insulin-producing cells, MSCs have generated a great deal of interest for their potential use in regenerative medicine and tissue engineering. Furthermore, given the ease of their isolation and their extensive expansion rate and differentiation potential, mesenchymal stem cells are among the first stem cell types that have a great potential to be introduced in the clinic. Finally, mesenchymal stem cells seem to be not only hypoimmunogenic and thus be suitable for allogeneic transplantation, but they are also able to produce immunosuppression upon transplantation. In this review we summarize the latest research in the use of mesenchymal stem cells in transplantation for generalized diseases, local implantation for local tissue defects, and as a vehicle for genes in gene therapy protocols. PMID: 18220880 [PubMed - indexed for MEDLINE] 2579. Curr Stem Cell Res Ther. 2006 Sep;1(3):345-64. Adult stem cells in bone and cartilage tissue engineering. Salgado AJ(1), Oliveira JT, Pedro AJ, Reis RL. Author information: (1)3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal. asalgado@ecsaude.uminho.pt The progressive increase in life expectancy within the last century has led to the appearance of novel health related problems, some of those within the musculoskeletal field. Among the latter, one can find diseases such as osteoporosis, rheumatoid arthritis and bone cancer, just to mention some of the most relevant. Other related problems are those that arise from serious injuries, often leading to non-recoverable critical size defects. The therapies currently used to treat this type of diseases/injuries are based on the use of pharmaceutical agents, auto/allotransplant and synthetic materials. However, such solutions present a number of inconveniences and therefore, there is a constant search for novel therapeutic solutions. The appearance of a novel field of science called Tissue engineering brought some hope for the solution of the above mentioned problems. In this field, it is believed that by combining a 3D porous template--scaffold--with an adequate cell population, with osteo or chondrogenic potential, it will be possible to develop bone and cartilage tissue equivalents that when implanted in vivo, could lead to the total regeneration of the affected area. This ideal cell population should have a series of properties, namely a high osteo and chondrogenic potential and at the same time, should be easily expandable and maintained in cultures for long periods of time. Due to its natural and intrinsic properties, stem cells are one of the best available cell types. However, after this sentence, the readers may ask, "Which Stem Cells?". During the last 10/15 years, the scientific community witnessed and reported the appearance of several sources of stem cells with both osteo and chondrogenic potential. Therefore, the present review intends to make an overview of data reported on different sources of adult stem cells (bone marrow, periosteum, adipose tissue, skeletal muscle and umbilical cord) for bone and cartilage regenerative medicine, namely those focusing on the differentiation potential of the latter as well as in vivo proof of concept of their applicability. Simultaneously novel aspects of adult stem cells biotechnology such as their immunogenic characteristics and cell expansion methodologies will also be put forward. The present review also points out on issues such as the bone and cartilage regenerative market, and gives a brief description on bone and cartilage bone biology, so the readers can have a true idea of the current state of the art, and how adult stem cells can be an added value to this field. PMID: 18220879 [PubMed - indexed for MEDLINE] 2580. Curr Stem Cell Res Ther. 2006 Jan;1(1):13-20. The importance of adipose-derived stem cells and vascularized tissue regeneration in the field of tissue transplantation. Ogawa R(1). Author information: (1)Department of Plastic and Reconstructive Surgery, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan. r.ogawa@nms.ac.jp The importance of stem cells in regenerating or repairing damaged or diseased tissues is well established, but three factors have to be considered in employing stem cells clinically. The first is how to harvest, handle, and multiply them non-invasively, easily, and effectively. From this standpoint, adipose-derived stem cells are considered to be the best to work with among mesenchymal stem cells; since they were first reported in 2001, their pluripotency, proliferative efficiency, and low donor morbidity have been amply confirmed. The second factor is how to differentiate stem cells into the required cells and use them effectively to construct three-dimensional tissues; here, tissue-specific scaffolds and signaling systems are essential. The third factor is how to ensure survival of the differentiated cells and regenerated tissues. Regenerated tissues need to contain vascular systems to allow both the tissues themselves and the differentiated cells to survive. Thus, we believe that the vascularization of regenerated tissues will be an important field of research in the near future. In this paper, we focus on adipose-derived stem cells and vascularized tissue regeneration within the context of tissue transplantation. PMID: 18220849 [PubMed - indexed for MEDLINE] 2581. Curr Pharm Des. 2007;13(36):3676-80. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis. Matarese G(1), Mantzoros C, La Cava A. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli 80131, Italy. gmatarese@napoli.com The role of the adipose tissue in immunity has recently emerged, and there is now ample evidence that this role is elucidated by a number of cytokine-like hormones produced by adipocytes - called adipokines. The most relevant adipokines are leptin, adiponectin and visfatin, and all have marked effects on metabolic and immune function. The discovery of adipokines has led to the development of a novel concept that the pathogenesis of atherosclerosis can be associated with low-degree inflammation associated with slow (auto)immune attack of the endothelial wall of arteries. This model considers therefore adipokines as the bridge between atherosclerosis, inflammation and immunity. We review here the most recent advances on adipokine research, with a particular emphasis on the model that considers atherosclerotic lesions as effects of the (auto)immune-mediated damage of the endothelium that is sustained by low-degree chronic inflammation typical of obesity and metabolic syndrome. PMID: 18220805 [PubMed - indexed for MEDLINE] 2582. Curr Pharm Des. 2007;13(35):3637-47. Weight loss in older persons: new therapeutic approaches. Morley JE(1). Author information: (1)Division of Geriatric Medicine, Saint Louis University Medical Center, St. Louis, MO 63104, USA. morley@slu.edu There is now a large body of evidence that weight loss in older persons not only increases mortality, but also increases the incidence of hip fracture, functional deterioration and institutionalization. Weight loss is a central component of frailty. There is evidence that it is not only muscle, but also fat loss that leads to these deleterious effects. The reasons why fat loss can be harmful in older persons are reviewed. There are four major causes of weight loss in older persons viz. anorexia, sarcopenia, cachexia and dehydration. This review concentrates on the major causes of anorexia and sarcopenia. In particular, the emergence of new medications such as selective androgen receptor molecules, antimyostatin analogues, megestrol acetate (nanocrystal formulation), and ghrelin agonists are reviewed. The potential role of anabolic steroids is also discussed. PMID: 18220800 [PubMed - indexed for MEDLINE] 2583. Curr Med Chem. 2008;15(2):195-209. Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists. Bennett DJ(1), Carswell EL, Cooke AJ, Edwards AS, Nimz O. Author information: (1)Department of Chemistry, Organon Laboratories Ltd., Newhouse, Motherwell, ML1 5SH, UK. The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as a heterodimer with the Retinoid X Receptor (RXR). Upon agonist binding, the formation of the LXR/RXR heterodimer takes place and ultimately the regulation of a number of genes begins. The LXR isoforms share 77% sequence homology, with LXRalpha having highest expression in liver, intestine, adipose tissue, and macrophages and LXRbeta being ubiquitously expressed. The aim of this article is to review the reported medicinal chemistry strategies towards the optimisation of novel non-steroidal chemotypes as LXR agonists. An analysis of the structural features important for LXR ligand binding will be given, utilising both structural activity relationship data obtained from LXR assays as well as X-ray co-crystallographic data obtained with LXR ligands and the LXR ligand binding domain (LBD). The X-ray co-crystallographic data analysis will detail the key structural interactions required for LXR binding/agonist activity and reveal the differences observed between chemotype classes. It has been postulated that a LXRbeta selective compound may have a beneficial outcome on the lipid profile for a ligand by dissociating the favourable and unfavourable effects of LXR agonists. Whilst there have been a few examples of compounds showing a modest level of LXRalpha selectivity, obtaining a potent LXRbeta selective compound has been more challenging. Analysis of the SAR and X-ray co-crystallographic data suggests that the rational design of a LXRbeta selective compound will not be trivial. PMID: 18220775 [PubMed - indexed for MEDLINE] 2584. Curr Diabetes Rev. 2007 Aug;3(3):204-11. An overview of the effect of weight loss on cardiovascular autonomic function. Maser RE(1), Lenhard MJ. Author information: (1)Department of Medical Technology, University of Delaware, Newark, DE 19716, USA. rmaser@udel.edu The prevalence of obesity is rising to epidemic proportions in many countries worldwide. Obesity seriously increases an individual's risk of developing many health problems including diabetes. Diabetes, like obesity, is also in epidemic proportions with 300 million adults predicted to have the disease by 2025. Investigating strategies for the prevention and treatment of obesity and diabetes is vitally important. Autonomic dysfunction is evident in both obesity and diabetes. In persons with diabetes, impaired cardiovascular autonomic activity is characterized by a reduction in parasympathetic tone with a relative increase in sympathetic activity and is specifically associated with a number of clinically significant manifestations including exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, silent myocardial ischemia, and increased risk of mortality. In obesity, parasympathetic function is decreased while regional heterogeneity of increased sympathetic activity may occur. Autonomic dysfunction increases cardiovascular workload, hemodynamic stress, serious dysrhythmias, and significant cardiac pathology. Thus, cardiac autonomic imbalance may also be an important link between obesity and increased morbidity and mortality. Beyond the obese and diabetic state, multiple variables associated with these conditions such as insulin, glucose, leptin, adiponectin and free fatty acids have an affect on the autonomic nervous system. Autonomic disturbances, however, appear to be reversible with weight reduction. Since autonomic imbalance is a marker of adverse risk, improvement obtained from weight loss should be beneficial for the health of individuals with obesity and diabetes. This overview will examine the relationship of the autonomic nervous system in obesity and diabetes and explore the effect of weight loss on autonomic function. PMID: 18220673 [PubMed - indexed for MEDLINE] 2585. Curr Diabetes Rev. 2007 Aug;3(3):176-84. Physical activity, insulin action, and diabetes prevention and control. Colberg SR(1). Author information: (1)Exercise Science, Sport, Physical Education, and Recreation Department, Old Dominion University, Norfolk, Virginia 23529, USA. scolberg@odu.edu Control of blood glucose levels in individuals with diabetes mellitus (DM) is directly affected by the balance between insulin and glucose-raising endocrine hormones, along with other metabolic factors, including fuel use and availability, exercise intensity and duration, training status, and visceral fat levels, all of which can impact the effect of physical activity on insulin action in diabetic or prediabetic individuals. Current research suggests that type 2 DM can be prevented and controlled with increased physical activity, largely through improvements in the muscles' sensitivity to insulin that are affected by changes in both glucose and fat metabolism. In addition, abnormal insulin action in the body is associated with a host of other health conditions, including cardiovascular disease and hypertension, which can be better controlled when their associations are fully understood. This article discusses the importance of varying types of physical activity on insulin action to enhance metabolic control and how they can be undertaken safely by all diabetic individuals. PMID: 18220669 [PubMed - indexed for MEDLINE] 2586. Curr Diabetes Rev. 2006 Nov;2(4):367-73. Metabolic obesity: the paradox between visceral and subcutaneous fat. Hamdy O(1), Porramatikul S, Al-Ozairi E. Author information: (1)Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. osama.hamdy@joslin.harvard.edu In contrast to the accumulation of fat in the gluteo-femoral region, the accumulation of fat around abdominal viscera and inside intraabdominal solid organs is strongly associated with obesity-related complications like Type 2 diabetes and coronary artery disease. The association between visceral adiposity and accelerated atherosclerosis was shown to be independent of age, overall obesity or the amount of subcutaneous fat. Recent evidence revealed several biological and genetic differences between intraabdominal visceral-fat and peripheral subcutaneous-fat. Such differences are also reflected in their contrasting roles in the pathogenesis of obesity-related cardiometabolic problems, in either lean or obese individuals. The functional differences between visceral and the subcutaneous adipocytes may be related to their anatomical location. Visceral adipose tissue and its adipose-tissue resident macrophages produce more proinflamatory cytokines like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and less adiponectin. These cytokines changes induce insulin resistance and play a major role in the pathogenesis of endothelial dysfunction and subsequent atherosclerosis. The rate of visceral fat accumulation is also different according to the individual's gender and ethnic background; being more prominent in white men, African American women and Asian Indian and Japanese men and women. Such differences may explain the variation in the cardiometabolic risk at different waist measurements between different populations. However, it is unclear how much visceral fat reduction is needed to induce favorable metabolic changes. On the other hand, peripheral fat mass is negatively correlated with atherogenic metabolic risk factors and its selective reduction by liposuction does improve cardiovascular risk profile. The increasing knowledge about body fat distribution and its modifiers may lead to the development of more effective treatment strategies for people with/or at high risk for Type 2 diabetes and coronary artery disease. These accumulating observations also urge our need for a new definition of obesity based on the anatomical location of fat rather than on its volume, especially when cardiometabolic risk is considered. The term "Metabolic Obesity", in reference to visceral fat accumulation in either lean or obese individuals may identify those at risk for cardiovascular disease better than the currently used definitions of obesity. PMID: 18220642 [PubMed - indexed for MEDLINE] 2587. Curr Diabetes Rev. 2006 Aug;2(3):271-83. Uncoupling proteins: role in insulin resistance and insulin insufficiency. Chan CB(1), Harper ME. Author information: (1)Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada. cchan@upei.ca Uncoupling proteins (UCPs) are modulators of mitochondrial metabolism that have been implicated in the development of both insulin resistance and insulin insufficiency, the two major pathophysiological events associated with type 2 diabetes. UCP2 mRNA is expressed in a wide range of tissues; however UCP2 protein expression is restricted to fewer tissues, including the endocrine pancreas, spleen, stomach, brain and the lung. To date, its role in the pathophysiology of diabetes has been most strongly associated with impaired glucose-stimulated insulin secretion from the beta-cell, particularly after its induction by free fatty acids. The physiological role of UCP2 remains controversial, but it may act as a downstream signal transducer of superoxide. UCP3 mRNA and protein are expressed in relatively few tissues, predominantly skeletal muscle, brown adipose tissue and heart. Increased expression of UCP3 in skeletal muscle is associated with protection from diet-induced insulin resistance in mice. In patients with type 2 diabetes UCP3 protein in muscle is reduced by 50% compared to healthy controls. The primary physiological role of the novel UCPs does not appear to be protection against positive energy balance and obesity; this is based largely on findings from studies of UCP2 and UCP3 knockout mice and from observed increases in UCP3 expression with fasting. The mechanism(s) of action of UCP2 and UCP3 are poorly understood. However, findings support roles for UCP2 and UCP3 as modifiers of fatty acid metabolism and in mitigating damage from reactive oxygen species. PMCID: PMC3060851 PMID: 18220632 [PubMed - indexed for MEDLINE] 2588. Curr Diabetes Rev. 2006 May;2(2):195-211. Relationship between inflammation, insulin resistance and type 2 diabetes: 'cause or effect'? Greenfield JR(1), Campbell LV. Author information: (1)Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia. Inflammation has been implicated as an important aetiological factor in the development of both insulin resistance and type 2 diabetes mellitus. This conclusion is predominantly drawn from studies demonstrating associations between elevated (but 'normal range') levels of circulating acute phase inflammatory markers, typified by C-reactive protein (CRP), and indices of insulin resistance and the development of type 2 diabetes. There is debate as to whether these associations are independent of body fatness or, rather, an epiphenomenon of obesity, particularly central obesity, a strong predictor of insulin resistance and type 2 diabetes and an important source of inflammatory cytokines, such as interleukin-6. Some of this controversy and the inability to draw definitive conclusions from these studies relate to the fact that most studies measure body fat and its distribution indirectly using anthropometric estimates, such as Body Mass Index and waist circumference, rather than directly by dual-energy X-ray absorptiometry, computed tomography or magnetic resonance imaging. Furthermore, use of the term inflammation may be inappropriate when describing mild elevations of CRP in the 'normal range' in the absence of the other changes that characterise classical inflammatory diseases, such as a reduction in levels (or evidence of consumption) of complement proteins. Debate as to whether obesity mediates the association between circulating levels of inflammatory markers and insulin resistance can be resolved by well-designed studies using body fat measured by gold-standard methods. In this review, we present evidence to support the suggestion that body fat is the primary determinant of circulating inflammatory marker levels in the basal state and that marginally elevated levels of circulating interleukin-6 and CRP in obesity are a consequence rather than a cause of insulin resistance. The importance of genetic influences in determining both body fatness and circulating CRP levels will also be discussed. The review will conclude with a discussion of possible mechanisms linking body fat and insulin resistance to elevated circulating levels of inflammatory markers, including the possible role of the toll-like family of immune receptors. PMID: 18220627 [PubMed - indexed for MEDLINE] 2589. Curr Diabetes Rev. 2006 Feb;2(1):29-37. Chronic inflammation: role of adipose tissue and modulation by weight loss. You T(1), Nicklas BJ. Author information: (1)J. Paul Sticht Center on Aging, Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA. tyou@wfubmc.edu Chronic inflammation has been linked with an increased risk of type 2 diabetes and cardiovascular disease. As an endocrine and inflammatory organ, adipose tissue is an important source of circulating pro-inflammatory cytokines. Current evidence strongly supports that chronic inflammation is associated with enlarged body fat mass. Moreover, inflammation is independently linked with abdominal, especially visceral fat mass, possibly due to the regional variation in adipose tissue cytokine production. In addition to pharmacological approaches, lifestyle modifications have been advocated for the treatment of chronic inflammation. A number of studies have indicated that either weight loss via energy restriction, or energy restriction plus other strategies (aerobic exercise, behavioral counseling, and liposuction), could reduce chronic inflammation. While the amount of weight loss tends to be important, exercise and other strategies may have additional effects. A few studies have reported weight loss effects on adipose tissue cytokine production. Weight loss reduces subcutaneous adipose tissue production of pro-inflammatory cytokines (i.e. interleukin 6, tumor necrosis factor alpha) and increases adipose expression of anti-inflammatory cytokines (i.e. interleukin 10, interleukin 1 receptor antagonist). More studies are needed to investigate the role of regional adipose tissue cytokine production in regulation of inflammation and the modulating effects of weight loss. PMID: 18220615 [PubMed - indexed for MEDLINE] 2590. Curr Diabetes Rev. 2006 Feb;2(1):19-28. The new adipose tissue and adipocytokines. Bulcão C(1), Ferreira SR, Giuffrida FM, Ribeiro-Filho FF. Author information: (1)Division of Endocrinology, Department of Internal Medicine, Federal University of Sao Paulo, Brazil. cbulcao@uol.com.br Obesity is a well-known risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total amount of fat, central distribution of adipose tissue is very important in the pathophysiology of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded only as an energy storage organ until the last decade, is now known as the biggest endocrine organ of the human body. This tissue secretes a number of substances--adipocytokines--with multiple functions in metabolic profile and immunological process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal signalers. In this review we discuss visceral obesity, the potential mechanisms by which it would be related to insulin resistance, methods for its assessment and focus on the main adipocytokines expressed and secreted by the adipose tissue. Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-alpha, and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area. PMID: 18220614 [PubMed - indexed for MEDLINE] 2591. Curr Diabetes Rev. 2005 Aug;1(3):227-34. Evidence for the involvement of resistin in inflammation and cardiovascular disease. Gómez-Ambrosi J(1), Frühbeck G. Author information: (1)Metabolic Research Laboratory, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain. jagomez@unav.es The prevalence of obesity continues to increase throughout the world in an analogous way to that of type 2 diabetes mellitus (T2DM). Excess adiposity and accompanying insulin resistance is frequently associated to the development of cardiovascular disease. The circulating hormone resistin, which is produced mainly by adipocytes and appears to be increased in obesity and inflammation, seems to play a role in this association. Some studies indicate that T2DM patients have increased circulating concentrations of resistin, although these results need further confirmation. Increased resistin concentrations have been described in patients with severe inflammatory disease. However, the precise physiological role of resistin in the pathogenesis and perpetuation of inflammation remains unclear. Resistin exerts direct effects to promote the activation of endothelial cells inducing the release of endothelin-1, increasing the expression of adhesion molecules and chemokines, and potentiating the effect of the CD40 ligand. The present review summarizes recent advances in understanding the physiology of resistin and analyzes the involvement of this hormone in inflammation and cardiovascular disease. PMID: 18220599 [PubMed - indexed for MEDLINE] 2592. Curr Diabetes Rev. 2005 May;1(2):167-74. Molecular mechanisms of skeletal muscle insulin resistance in type 2 diabetes. Bouzakri K(1), Koistinen HA, Zierath JR. Author information: (1)Department of Surgical Sciences, Karolinska Institutet, Stockholm, Sweden. Type 2 (non-insulin-dependent) diabetes mellitus afflicts millions of people worldwide and is one of the main causes of morbidity and mortality. Current therapeutic agents to treat Type 2 diabetes are insufficient and thus, newer approaches are desperately needed. Type 2 diabetes is manifested by progressive metabolic impairments in tissues such as skeletal muscle, adipose tissue and liver, such that these tissues become less responsive to insulin. Skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions, and is a major site of insulin resistance in Type 2 diabetic patients. At the cellular level, glucose transport into skeletal muscle is the rate-limiting step for whole body glucose uptake and a primary site of insulin resistance in Type 2 diabetes. Thus, skeletal muscle is a key insulin target tissue that harbours intrinsic defects that impinges upon whole body glucose homeostasis. Here, we review the current knowledge of signalling events that regulate glucose transport in human skeletal muscle. PMID: 18220592 [PubMed - indexed for MEDLINE] 2593. Adv Med Sci. 2007;52:246-50. Markers of pro-inflammatory and pro-thrombotic state in the diagnosis of metabolic syndrome. Odrowaz-Sypniewska G(1). Author information: (1)Department of Laboratory Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland. odes@cm.umk.pl The metabolic syndrome refers to the clustering of upper body obesity, atherogenic dyslipidemia, insulin resistance and elevated blood pressure. Both, obesity and metabolic syndrome, have the potential to influence on the incidence and severity of cardiovascular disease with serious implications for worldwide health care systems. Obesity plays a central role in the development of insulin resistance and dyslipidemia through the mediation of a pro-inflammatory and pro-thrombotic state. Adipose tissue has been shown to exert important endocrine and immune functions. Pathogenesis of obesity associated metabolic syndrome is mediated by disturbed production and release of biologically active molecules by fat cells and other cells infiltrating fat tissue. In obese subjects synthesis of several bioactive compounds--adipokines and cytokines/chemokines by adipose tissue cells is dysregulated. Those bioactive molecules participate in regulation of apetite and energy homeostasis, lipid metabolism (tumour necrosis factor alpha--TNF-alpha), insulin sensitivity (TNF-alpha, adiponectin, resistin, visfatin) immunity (monocyte chemoattractant protein-1--MCP-1, TNF-alpha, IL-6), angiogenesis, blood pressure and hemostasis (plasminogen activator inhibitor--PAI-1). The effects of major pro-/anti-inflammatory and pro-thrombotic adipokines on several physiological processes will be discussed in this review. Also, an evidence-based approach to the laboratory diagnosis and treatment of metabolic syndrome will be presented. PMID: 18217426 [PubMed - indexed for MEDLINE] 2594. J Mol Med (Berl). 2008 Apr;86(4):353-61. doi: 10.1007/s00109-007-0286-y. Epub 2008 Jan 22. CNTF: a target therapeutic for obesity-related metabolic disease? Matthews VB(1), Febbraio MA. Author information: (1)Division of Diabetes and Metabolism, Cellular and Molecular Metabolism Laboratory, Baker Heart Research Institute, P.O. Box 6492, St Kilda Road Central, VIC 8008, Australia. Obesity and type 2 diabetes are the most prevalent metabolic diseases in the western world. Alarmingly, the cluster of pathologies characteristic of obesity-induced disease have started to emerge in children, a phenomenon that up until a decade ago was inconceivable. Hence, the development of new strategies to treat 'metabolic disease' is most warranted. Growing evidence suggests that during type 2 diabetes, a state of chronic low-grade inflammation exists in metabolically active tissues such as the liver, adipose tissue and skeletal muscle. This inflammation is often secondary to lipid accumulation in insulin-responsive tissues. Recent studies have focused on the therapeutic potential of ciliary neurotrophic factor (CNTF). CNTF is a pluripotent neurocytokine and, has shown promise as a potential anti-obesogenic therapy. CNTF acts both centrally and peripherally, mimics the biological actions of leptin while overcoming "leptin resistance", remains effective even after termination of therapy if administered centrally, and appears to reduce inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. The advantages and disadvantages of CNTF as a therapeutic strategy to alleviate obesity-associated diseases will be highlighted in this review. PMID: 18210031 [PubMed - indexed for MEDLINE] 2595. Mol Endocrinol. 2008 May;22(5):1023-31. doi: 10.1210/me.2007-0529. Epub 2008 Jan 17. Adipokines and the peripheral and neural control of energy balance. Ahima RS(1), Lazar MA. Author information: (1)Department of Medicine, University of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania 19104, USA. ahima@mail.med.upenn.edu Adipokines are secreted by adipose tissue and control various physiological systems. Low leptin levels during fasting stimulate feeding, reduce energy expenditure, and modulate neuroendocrine and immune function to conserve energy stores. On the other hand, rising leptin levels in the overfed state prevent weight gain by inhibiting food intake and increasing energy expenditure. These actions are mediated by neuronal circuits in the hypothalamus and brainstem. Leptin also controls glucose and lipid metabolism by targeting enzymes such as AMP-activated protein kinase and stearoyl-coenzyme A desaturase-1 in liver and muscle. Likewise, adiponectin and resistin control energy balance and insulin sensitivity via central and peripheral targets. As highlighted in this review, there are distinct as well as common signaling pathways for adipokines. Understanding adipokine signaling in the brain and other organs will provide insights into the pathogenesis and treatment of obesity, diabetes and various metabolic disorders. PMCID: PMC2366188 PMID: 18202144 [PubMed - indexed for MEDLINE] 2596. Endocrinology. 2008 Mar;149(3):925-34. doi: 10.1210/en.2007-1355. Epub 2008 Jan 17. Obesity and lipodystrophy--where do the circles intersect? Chehab FF(1). Author information: (1)University of California, San Francisco, Department of Laboratory Medicine, 185 Berry Street, Suite 290, San Francisco, California 94107-0134, USA. chehabf@labmed2.ucsf.edu Adipose tissue is unique in that it can undergo significant hypertrophy and atrophy, resulting in wide ranges of obesities and lipodystrophies. At the base of this elasticity is the lipid-filled adipocyte, which can either overfill by storing large amounts of triglycerides or shrink to a tiny cell by depleting its lipids and as such is remarkable in sustaining insults. As a major energy reservoir, the adipocyte may hold considerable calories necessary for survival and reproduction, two functions that are essential for the survival of the species. This review will summarize some of the recent studies that have advanced our understanding of the central and peripheral mechanisms that are initiated by adipocyte-secreted factors such as leptin, adiponectin, resistin, and retinol-binding protein 4. The intersection of obesity and lipodystrophy results in insulin resistance, which may be unlocked by elucidating the roles of these factors in pathways that control insulin sensitivity and glucose uptake. PMCID: PMC2275358 PMID: 18202137 [PubMed - indexed for MEDLINE] 2597. Int J Biochem Cell Biol. 2008;40(5):821-36. doi: 10.1016/j.biocel.2007.12.001. Epub 2007 Dec 8. Visceral obesity and the heart. Mathieu P(1), Pibarot P, Larose E, Poirier P, Marette A, Després JP. Author information: (1)Laval Hospital Research Center/Quebec Heart Institute, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, Quebec, Canada, G1V-4G5. patrick.mathieu@chg.ulaval.ca Obesity and particularly its deleterious form, visceral adiposity, has reached a high prevalence in the industrialized world owing to the lack of exercise and the widely available energy-dense diet. As a consequence, cardiovascular diseases and metabolic disorders are afflicting an unprecedented number of individuals at a world-wide scale. Over the last decades, investigations have established firm links between visceral obesity and the development of cardiovascular diseases. Moreover, studies in the field of lipid partitioning have demonstrated that inadequacy of homeostatic mechanism ensuring adequate handling of energy surplus is associated with accumulation of visceral fat and lipid overload of internal organs, which are participating to the development of heart diseases. Visceral obesity and its metabolic consequences often referred to as the metabolic syndrome is associated with the production of an atherosclerosis prone milieu. In this review, clinical implications of visceral obesity on the development of cardiovascular disorders are reviewed along with important mechanisms participating to the development of these disorders. Implications and failure of lipid partitioning and some of the potential pathways mediating development of heart diseases are also covered in view of recent development of therapeutic options. PMID: 18201922 [PubMed - indexed for MEDLINE] 2598. Arch Pediatr. 2008 Feb;15(2):170-8. doi: 10.1016/j.arcped.2007.10.022. Epub 2008 Jan 16. [Involvement of hypothalamopituitary adrenal axis in abdominal obesity]. [Article in French] Barat P(1), Duclos M, Moisan MP, Mormède P. Author information: (1)Endocrinologie et diabétologie de l'enfant et de l'adolescent, hôpital des enfants, CHU de Bordeaux, place Amélie-Raba-Léon, Bordeaux cedex, France. pascal.barat@chu-bordeaux.fr Obesity is increasing worldwide. Abdominal obesity, which is due to the development of visceral adipose tissue, leads to metabolic disorders. Because abdominal obesity is associated with Cushing syndrome, many studies have been performed to find out how the hypothalamopituitary adrenal axis is involved in this disorder. Here, we propose to review these data before giving our experience on changes in hypothalamopituitary adrenal axis activity regarding fat mass distribution in prepubertal children. PMID: 18201880 [PubMed - indexed for MEDLINE] 2599. J Bras Pneumol. 2007 Nov-Dec;33(6):712-9. [Smoking and changes in body weight: can physiopathology and genetics explain this association?]. [Article in Portuguese] Chatkin R(1), Chatkin JM. Author information: (1)Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brasil. Tobacco use is the leading preventable cause of death in most countries, including Brazil. Smoking cessation is an important strategy for reducing the morbidity and mortality associated with tobacco-related diseases. An inverse relationship between nicotine use and body weight has been reported, in which body weight tends to be lower among smokers than among nonsmokers. Smoking abstinence results in an increase in body weight for both males and females. On average, sustained quitters gain from 5 to 6 kg, although approximately 10% gain more than 10 kg. Pharmacological treatment for smoking cessation attenuates weight gain. The importance of smoking cessation as a contributing cause of the current obesity epidemic has been little studied. In the USA, the rate of obesity attributable to smoking cessation has been estimated at approximately 6.0 and 3.2% for males and females, respectively. Although the mechanisms are unclear, there is evidence that dopamine and serotonin are appetite suppressants. The administration of nicotine, regardless of the delivery system, acutely raises the levels of these neurotransmitters in the brain, reducing the need for energy intake and consequently suppressing appetite. In addition, nicotine has a direct effect on adipose tissue metabolism, influencing the rate of weight gain following smoking cessation. Leptin, ghrelin and neuropeptide Y are substances that might constitute factors involved in the inverse relationship between nicotine and body mass index, although their roles as determinants or consequences of this relationship have yet to be determined. PMID: 18200373 [PubMed - indexed for MEDLINE] 2600. Endocr Rev. 2008 Feb;29(1):62-75. doi: 10.1210/er.2007-0004. Epub 2008 Jan 16. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Goldfine ID(1), Maddux BA, Youngren JF, Reaven G, Accili D, Trischitta V, Vigneri R, Frittitta L. Author information: (1)Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA. ira.goldfine@ucsf.edu Erratum in Endocr Rev. 2009 Feb;30(1):117. Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both. PMCID: PMC2244935 PMID: 18199690 [PubMed - indexed for MEDLINE] 2601. Curr Opin Lipidol. 2008 Feb;19(1):16-24. doi: 10.1097/MOL.0b013e3282f2b24a. Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Stanhope KL(1), Havel PJ. Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA. PURPOSE OF REVIEW: Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome. RECENT FINDINGS: The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance. SUMMARY: Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome. PMCID: PMC4151171 PMID: 18196982 [PubMed - indexed for MEDLINE] 2602. Curr Opin Lipidol. 2008 Feb;19(1):4-10. doi: 10.1097/MOL.0b013e3282f39f95. Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components. Keijer J(1), van Schothorst EM. Author information: (1)RIKILT-Institute of Food Safety, Wageningen, The Netherlands. jaap.keijer@wur.nl PURPOSE OF REVIEW: Adipose tissue is an essential, highly dynamic and metabolically active tissue that vigorously communicates to support its primary function: the storage of lipids. It performs this function to secure energy supply and prevent lipotoxicity. Adipose tissue is essential for maintaining a healthy glucose and lipid homeostasis and failure results in disease. This review discusses causes of adipose tissue failure and four categories of bioactive food components that may help to prevent this. RECENT FINDINGS: Based on recent findings, it is argued that initial adipose failure following long-term excess energy intake may be the result of reduced mitochondrial capacity associated with altered mitochondrial reactive oxygen species signaling and adipose tissue hypoxia. Current data suggest that different classes of bioactive food components, including vitamin B3, retinoids, fatty acids and polyphenols, may have the potential to modulate mitochondrial function and consequently prevent adipose dysfunction in obesity. SUMMARY: It seems most attractive to aim nutritional intervention at the prevention of initial adipose dysfunction and hence to target dietary intervention at improvement of mitochondrial function. PMID: 18196980 [PubMed - indexed for MEDLINE] 2603. J Physiol Pharmacol. 2007 Dec;58(4):591-610. Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction. Guzik TJ(1), Marvar PJ, Czesnikiewicz-Guzik M, Korbut R. Author information: (1)Department of Pharmacology, Jagiellonian University School of Medicine, Krakow, Poland. tguzik@cm-uj.krakow.pl Perivascular adipose tissue AT is a critical regulator of vascular function, which until recently has been greatly overlooked. Virtually all arteries are surrounded by a significant amount of perivascular adipose tissue, which has long been considered to serve primarily a supportive, mechanical purpose. Recent studies show that both visceral and perivascular fat is a very active endocrine and paracrine source of inflammatory cytokines and adipokines. The latter include beneficial adipocytokines such as adiponectin or so far unidentified adipocyte derived relaxing factor (ADRF) as the presence of perivascular AT may decrease contractile responses to vasoconstrictive agents. However, in pathological states such as obesity, hypertension, diabetes metabolic syndrome and other cardiovascular disorders perivascular tissue becomes dysfunctional and production of protective factors diminishes while detrimental adipocytokines such as leptin, resistin, IL-6, TNF-alpha or IL-17 increases. Moreover the dysfunction of perivascular fat can lead to imbalance between vascular nitric oxide (NO) and superoxide production. Adipokines also regulate immune system as chemokines (such as MIP-1 or RANTES) and induce inflammation with infiltration of T cells and macrophages to the vessel wall. Interestingly central nervous system can affect vascular function through mediation of perivascular adipose tissue dysfunction. In particular sympathetic nervous system endings are present in both visceral and perivascular AT. This powerful relationship between the brain and the vessel can be termed "brain-vessel axis" in which--we propose in the Review--perivascular adipose tissue may take center stage. The role of perivascular fat in the regulation of blood vessels depends on metabolic state, inflammation and clinical risk factors. In health protective and vasorelaxant properties of perivascular AT dominate while in pathology pathogenetic influences including neural stimulation of sympathetic nerve endings or humoral effects of certain hormones and adipocytokines dominates. We propose to term this state "perivascular adipose tissue dysfunction" in similarity to endothelial dysfunction. PMID: 18195475 [PubMed - indexed for MEDLINE] 2604. Endocr Pract. 2007 Nov-Dec;13(7):790-804. Role of the endocannabinoid system in management of patients with type 2 diabetes mellitus and cardiovascular risk factors. Davis SN(1), Perkins JM. Author information: (1)Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. OBJECTIVE: To review the role of the endogenous cannabinoid system (ECS) in the peripheral and central regulation of food intake, appetite, and energy storage and discuss the potential for the ECS to be an important target for lowering cardiovascular risk. METHODS: Materials used for this article were identified through a MEDLINE search of the pertinent literature (1975 to present), including English-language randomized controlled, prospective, cohort, review, and observational studies. We summarize the available experimental and clinical data. RESULTS: The ECS is composed of two 7-transmembrane G protein-coupled cannabinoid receptor subtypes, CB1 and CB2, endogenous cannabinoid ligands (anandamide and 2-arachidonoylglycerol), and the enzymes that synthesize and break down the ligands. Understanding the role of the ECS in central and peripheral metabolic processes related to the regulation of food intake and energy balance as well as the endocrine role of excess adipose tissue, particularly visceral adipose tissue, and its promotion of global cardiometabolic risk has led to the development of pharmacologic agents with potential for blockade of CB1 receptors. In several studies, rimonabant (20 mg daily) demonstrated a favorable effect on various risk factors for cardiovascular disease, including dyslipidemia, abdominal obesity, insulin resistance, blood pressure, and measures of inflammation. CONCLUSION: The ECS has been shown to have a key role in the regulation of energy balance, and modulation of this system may affect multiple cardiometabolic risk factors. Clinical studies involving pharmacologic blockade of CB1 receptors in overweight patients with and without type 2 diabetes have demonstrated effective weight loss and improvements in several risk factors for cardiovascular disease. PMID: 18194939 [PubMed - indexed for MEDLINE] 2605. Clin Sci (Lond). 2008 Feb;114(4):275-88. doi: 10.1042/CS20070196. Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases. Tilg H(1), Moschen AR. Author information: (1)Christian Doppler Research Laboratory for Gut Inflammation, Department of Medicine, Innsbruck Medical University, 6020 Innsbruck, Austria. Obesity and obesity-related disorders play an important role in clinical medicine. Adipose tissue, with its soluble mediators called adipocytokines, has emerged as a major endocrine organ. These adipocytokines comprise many mediators such as adiponectin, PBEF (pre-B-cell-enhancing factor)/visfatin, leptin, resistin, retinol-binding protein-4 and others. They play major roles in key aspects of metabolism, such as insulin resistance, fatty acid oxidation, inflammation and immunity. Adiponectin, a prototypic adipocytokine, is of importance in the regulation of insulin resistance, as circulating levels are decreased in obesity and diseases associated with insulin resistance. Besides its major role in regulation of insulin sensitivity, recent evidence suggests potent anti-inflammatory functions for adiponectin. These effects are paralleled by other immune-regulatory properties, such as regulation of endothelial cell function. The in vitro effects of adiponectin have been corroborated by several studies demonstrating potent in vivo anti-inflammatory effects. Many other adipocytokines, such as PBEF/visfatin, leptin, resistin or retinol binding protein-4, are involved in the physiology and pathophysiology of adipocytes, adipose tissue and related diseases. PBEF/visfatin, another recently characterized adipocytokine, has been linked to several inflammatory disease states beyond insulin resistance, such as acute lung injury or inflammatory bowel diseases. It has been recognized for many decades that obesity is accompanied by an increase in cancer and potentially some immune-mediated diseases. Understanding this new exciting world of adipocytokines will be of importance in the development of novel therapies for obesity-associated diseases. PMID: 18194136 [PubMed - indexed for MEDLINE] 2606. World J Gastroenterol. 2008 Jan 14;14(2):185-92. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. Rector RS(1), Thyfault JP, Wei Y, Ibdah JA. Author information: (1)Division of Gastroenterology and Hepatology, University of Missouri-Columbia, Columbia, MO 65212, United States. Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries, subsequently increasing the risk for developing the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). NAFLD is estimated to affect approximate 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome. Recent findings linking the components of the metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis (NASH) will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, and adipocytokines in the exacerbation of these conditions. While no therapy has been proven effective for treating NAFLD/NASH, common recommendations will be discussed. PMCID: PMC2675112 PMID: 18186553 [PubMed - indexed for MEDLINE] 2607. Curr Opin Endocrinol Diabetes Obes. 2008 Feb;15(1):9-20. doi: 10.1097/MED.0b013e3282f43a5b. Obesity: the hormonal milieu. Lenz A(1), Diamond FB Jr. Author information: (1)University of South Florida College of Medicine, Tampa, Florida, USA. PURPOSE OF REVIEW: Obesity has reached epidemic proportions throughout the world and poses significant health and economic burdens to both developed and developing societies. Most recent data from the NHANES study (2003-2004) report that 17.1% of US children are overweight and 32.2% of adults are obese, a significant increase compared with data obtained only 6 years earlier. RECENT FINDINGS: The neurohormonal control of appetite, body composition, and glucose homeostasis is mediated by hormones secreted from adipose tissue, endocrine glands, and enteroendocrine cells, which converge at the vagus nerve, brainstem and hypothalamus to modulate complex interactions of neurotransmitters and central appetite-regulating peptides. These hormonal signals are tightly regulated to maintain body weight/adiposity within a narrow, individually defined range that may be further impacted by variables such as ingested calories, meal composition, and lifestyle. SUMMARY: Clinical manifestations of obesity, the metabolic syndrome and impaired glucose tolerance reflect biochemical alterations in a complex hormonal milieu. Elucidation of these hormonal perturbations in obese patients has already provided novel pharmacologic treatments to improve weight management and address the metabolic sequelae of obesity. The remarkable redundancy of these hormones, however, and their interactions make a monopharmaceutical approach unlikely to be successful. PMID: 18185058 [PubMed - indexed for MEDLINE] 2608. Clin Sci (Lond). 2008 Feb;114(3):183-93. doi: 10.1042/CS20070115. Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome. Aguilera CM(1), Gil-Campos M, Cañete R, Gil A. Author information: (1)Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, School of Pharmacy, University of Granada, Campus de Cartuja 18071 Granada, Spain. agil@ugr.es The MS (metabolic syndrome) is a cluster of clinical and biochemical abnormalities characterized by central obesity, dyslipidaemia [hypertriglyceridaemia and decreased HDL-C (high-density lipoprotein cholesterol)], glucose intolerance and hypertension. Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. This review focuses on lipid metabolism alterations associated with the MS, paying special attention to changes in plasma lipids and cellular fatty acid oxidation. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. Activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. Decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS. PMID: 18184112 [PubMed - indexed for MEDLINE] 2609. Adv Exp Med Biol. 2008;606:67-108. doi: 10.1007/978-0-387-74087-4_2. Expression and nutritional regulation of lipogenic genes in the ruminant lactating mammary gland. Bernard L(1), Leroux C, Chilliard Y. Author information: (1)Adipose Tissue and Milk Lipid Laboratory, Herbivore Research Unit, INRA-Theix, 63 122 St Genès-Champanelle, France. laurence.bernard@clermont.inra.fr The effect of nutrition on milk fat yield and composition has largely been investigated in cows and goats, with some differences for fatty acid (FA) composition responses and marked species differences in milk fat yield response. Recently, the characterization of lipogenic genes in ruminant species allowed in vivo studies focused on the effect of nutrition on mammary expression of these genes, in cows (mainly fed milk fat-depressing diets) and goats (fed lipid-supplemented diets). These few studies demonstrated some similarities in the regulation of gene expression between the two species, although the responses were not always in agreement with milk FA secretion responses. A central role for trans-10 C18:1 and trans-10, cis-12 CLA as regulators of milk fat synthesis has been proposed. However, trans-10 C18:1 does not directly control milk fat synthesis in cows, despite the fact that it largely responds to dietary factors, with its concentration being negatively correlated with milk fat yield response in cows and, to a lesser extent, in goats. Milk trans-10, cis-12 CLA is often correlated with milk fat depression in cows but not in goats and, when postruminally infused, acts as an inhibitor of the expression of key lipogenic genes in cows. Recent evidence has also proven the inhibitory effect of the trans-9, cis-11 CLA isomer. The molecular mechanisms by which nutrients regulate lipogenic gene expression have yet to be well identified, but a central role for SREBP-1 has been outlined as mediator of FA effects, whereas the roles of PPARs and STAT5 need to be determined. It is expected that the development of in vitro functional systems for lipid synthesis and secretion will allow future progress toward (1) the identification of the inhibitors and activators of fat synthesis, (2) the knowledge of cellular mechanisms, and (3) the understanding of differences between ruminant species. PMID: 18183925 [PubMed - indexed for MEDLINE] 2610. Blood Purif. 2008;26(1):23-9. doi: 10.1159/000110559. Epub 2008 Jan 10. Obesity in chronic kidney disease: good or bad? Axelsson J(1). Author information: (1)Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. jonas.axelsson@ki.se Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in chronic kidney disease (CKD) patients. As traditional risk factors cannot alone explain the high prevalence and incidence of CVD in this high-risk population, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as important non-traditional risk factors. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has recently been shown that fat tissue secretes a number of adipokines - including leptin, adiponectin and retinol-binding protein, as well as cytokines such as resistin, visfatin, tumor necrosis factor and interleukin-6. Adipokine serum levels are furthermore markedly elevated in CKD, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and putatively CVD. As fat tissue is also a storage depot for energy, much needed in the catabolic milieu of uremia, further research is still needed to elucidate the likely complex interactions between these signaling networks, vascular health and outcome in this high-risk population. (c) 2008 S. Karger AG, Basel. PMID: 18182791 [PubMed - indexed for MEDLINE] 2611. Cell Prolif. 2008 Feb;41 Suppl 1:146-64. doi: 10.1111/j.1365-2184.2008.00488.x. Progenitor cells and vascular disease. Jevon M(1), Dorling A, Hornick PI. Author information: (1)Department of Cardiothoracic Surgery, National Heart & Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. m.jevon@imperial.ac.uk Vascular progenitor cells have been the focus of much attention in recent years; both from the point of view of their pathophysiological roles and their potential as therapeutic agents. However, there is as yet no definitive description of either endothelial or vascular smooth muscle progenitor cells. Cells with the ability to differentiate into mature endothelial and vascular smooth muscle reportedly reside within a number of different tissues, including bone marrow, spleen, cardiac muscle, skeletal muscle and adipose tissue. Within these niches, vascular progenitor cells remain quiescent, until mobilized in response to injury or disease. Once mobilized, these progenitor cells enter the circulation and migrate to sites of damage, where they contribute to the remodelling process. It is generally perceived that endothelial progenitors are reparative, acting to restore vascular homeostasis, while smooth muscle progenitors contribute to pathological changes. Indeed, the number of circulating endothelial progenitor cells inversely correlates with exposure to cardiovascular risk factors and numbers of animal models and human studies have demonstrated therapeutic roles for endothelial progenitor cells, which can be enhanced by manipulating them to overexpress vasculo-protective genes. It remains to be determined whether smooth muscle progenitor cells, which are less well studied than their endothelial counterparts, can likewise be manipulated to achieve therapeutic benefit. This review outlines our current understanding of endothelial and smooth muscle progenitor cell biology, their roles in vascular disease and their potential as therapeutic agents. PMID: 18181954 [PubMed - indexed for MEDLINE] 2612. Clin Sci (Lond). 2008 Apr;114(8):543-5. doi: 10.1042/CS20070461. Is adipose tissue lipolysis always an adaptive response to starvation?: implications for non-alcoholic fatty liver disease. Gan SK(1), Watts GF. Author information: (1)Metabolic Research Centre, School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, GPO Box X2213, Perth, WA 6847, Australia. Comment on Clin Sci (Lond). 2008 Apr;114(8):547-52. The physiological response to starvation involves increased muscle proteolysis and adipose tissue lipolysis that supply amino acids and non-esterified fatty acids ('free fatty acids') for gluconeogenesis, oxidation and ketogenesis. In the present issue of Clinical Science, Moller and co-workers show that, in humans, IHL (intrahepatic lipid) content, measured using (1)H-magnetic resonance spectroscopy, increases following 36 h of fasting, with a direct association with plasma levels of 3-hydroxybutyrate. The observation raises interesting questions as to how IHL levels increase in a situation of increased mitochondrial fatty acid oxidation and ketogenesis. Possible mechanisms for increased IHLs include reduced apoB-100 (apolipoprotein B-100) production and hepatic lipid export, and/or impaired mitochondrial function resulting from increased oxidative stress, with diversion of fatty acids for esterification. The accumulation of IHL during prolonged fasting may, therefore, reflect a maladaptive response to increased non-esterified fatty acid delivery to the liver that unmasks a subtle defect in mitochondrial function. This could have implications for the pathogenesis of the common human disorder of non-alcoholic fatty liver disease. The accumulation of IHLs observed with prolonged fasting may also explain exacerbations of steatohepatitis seen sometimes with rapid weight loss, anorexia nervosa and parenteral nutrition. The findings also suggest caution against promoting excessive ketogenesis with weight-loss regimens. PMID: 18181765 [PubMed - indexed for MEDLINE] 2613. Int J Obes (Lond). 2008 Apr;32(4):619-28. doi: 10.1038/sj.ijo.0803761. Epub 2008 Jan 8. Factors associated with percent change in visceral versus subcutaneous abdominal fat during weight loss: findings from a systematic review. Chaston TB(1), Dixon JB. Author information: (1)Australian Centre for Obesity Research and Education, Monash University, Melbourne, Victoria, Australia. Comment in Int J Obes (Lond). 2008 Apr;32(4):722. BACKGROUND: Visceral adipose tissue (VAT) is associated with greater obesity-related metabolic disturbance. Many studies have reported preferential loss of VAT with weight loss. OBJECTIVE: This systematic review looks for factors associated with preferential loss of VAT relative to subcutaneous abdominal fat (SAT) during weight loss. DESIGN: Medline and Embase were searched for imaging-based measurements of VAT and subcutaneous abdominal adipose tissue (SAT) before and after weight loss interventions. We examine for factors that influences the percentage change in VAT versus SAT (%deltaV/%deltaS) with weight loss. Linear regression analyses were performed on the complete data set and on subgroups of studies. Factors examined included percentage weight loss, degree of caloric restriction, exercise, initial body mass index (BMI), gender, time of follow-up and baseline VAT/SAT. RESULTS: There were 61 studies with a total of 98 cohort time points extracted. Percentage weight loss was the only variable that influenced %deltaV/%deltaS (r=-0.29, P=0.005). Modest weight loss generated preferential loss of VAT, but with greater weight loss this effect was attenuated. The method of weight loss was not an influence with one exception. Very-low-calorie diets (VLCDs) provided exceptional short-term (<4 weeks) preferential VAT loss. But this effect was lost by 12-14 weeks. CONCLUSIONS: Visceral adipose tissue is lost preferentially with modest weight loss, but the effect is attenuated with greater weight loss. Acute caloric restriction, using VLCD, produces early preferential loss of VAT. These observations may help to explain the metabolic benefits of modest weight loss. PMID: 18180786 [PubMed - indexed for MEDLINE] 2614. Prog Lipid Res. 2008 Mar;47(2):127-46. doi: 10.1016/j.plipres.2007.12.002. Epub 2007 Dec 15. Bioactive lipids in metabolic syndrome. Nagao K(1), Yanagita T. Author information: (1)Laboratory of Nutrition Biochemistry, Department of Applied Biological Sciences, Saga University, Honjo-1, Saga 840-8502, Japan. knagao@cc.saga-u.ac.jp The metabolic syndrome is a cluster of metabolic disorders, such as abdominal obesity, dyslipidemia, hypertension and impaired fasting glucose that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated and the precise mechanisms have not been elucidated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. This review explores the physiological functions and molecular actions of bioactive lipids, such as n-3 polyunsaturated fatty acids, conjugated fatty acids, sterols, medium-chain fatty acids, diacylglycerols and phospholipids, in the development of metabolic syndrome. Dietary bioactive lipids suppress the accumulation of abdominal adipose tissue and lipids in the liver and serum, and alleviate hypertension and type 2 diabetes through the transcriptional regulation of lipid and glucose metabolism. Peroxisome proliferator-activated receptors (PPARs), sterol regulatory element binding proteins, liver X receptor alpha, retinoid X receptor alpha, farnesoid X receptor alpha, hepatic nuclear factor 4alpha and nuclear factor kappaB contribute to these nuclear actions of bioactive lipids with complex interactions. Recent studies have demonstrated the striking ability of bioactive lipids to regulate the production of physiologically active adipocytokines through PPARgamma activation. In particular, the function of bioactive lipids as dietary adiponectin inducers (dietary insulin sensitizers) deserves attention with respect to alleviation of metabolic syndrome by dietary manipulation. PMID: 18177744 [PubMed - indexed for MEDLINE] 2615. Gastroenterol Clin Biol. 2007 Dec;31(12):1127-34. [Metabolic fatty liver diseases: hepatic consequences of the metabolic syndrome]. [Article in French] Anty R(1), Gual P, Huet PM, Marchand-Brustel YL, Tran A. Author information: (1)Inserm, U568, Nice. anty@unice.fr Metabolic fatty liver diseases (Non Alcoholic Fatty Liver Diseases-NAFLD) are liver abnormalities (steatosis and steatohépatitis) commonly related to visceral obesity and to the metabolic syndrome. The pathogenesis of metabolic fatty liver diseases is most probably linked to the adipose tissue insulin resistance with a very high free fatty acids release, an abnormal secretion of factors produced by the adipose tissue (adipokines) and a low grade of chronic inflammation. The link between metabolic fatty liver diseases and the metabolic syndrome is further supported by epidemiological studies, as well as the frequently encountered cardio-vascular complications in both diseases. Changes in lifestyle with dietary restriction and increased physical activity are mandatory and similar for both conditions. Drugs such as thiazolidinediones, known to reduce insulin resistance and inflammation, still need further evaluation. PMID: 18176372 [PubMed - indexed for MEDLINE] 2616. Acta Physiol (Oxf). 2008 Jan;192(1):103-15. doi: 10.1111/j.1748-1716.2007.01786.x. RNAi screens reveal novel metabolic regulators: RIP140, MAP4k4 and the lipid droplet associated fat specific protein (FSP) 27. Puri V(1), Virbasius JV, Guilherme A, Czech MP. Author information: (1)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Adipose tissue modulates whole body metabolism and insulin sensitivity by controlling circulating lipid levels and producing molecules that can regulate fatty acid metabolism in such tissues as muscle and liver. We have developed RNA interference (RNAi) screens to identify genes in cultured adipocytes that regulate insulin signalling and key metabolic pathways. These short interfering RNA (siRNA)-based screens identified the transcriptional corepressor receptor interacting protein 140 (RIP140) (J Clin Invest 116: 125, 2006) and the mitogen-activated protein kinase (MAP4k4) (Proc Natl Acad Sci USA 103: 2087, 2006) as negative regulators of insulin-responsive hexose uptake and oxidative metabolism. Gene expression profiling revealed that RIP140 depletion upregulates the expression of clusters of genes in the pathways of glucose uptake, glycolysis, tricarboxylic acid cycle, fatty acid oxidation, mitochondrial biogenesis and oxidative phosphorylation. RIP140-null mice resist weight gain on a high-fat diet and display enhanced glucose tolerance. MAP4k4 depletion in adipocytes increases many of the RIP140-sensitive genes, increases adipogenesis and mediates some actions of tumour necrosis factor-alpha (TNF-alpha). Remarkably, another hit in our RNAi screens was fat specific protein 27 (FSP27), a highly expressed isoform of Cidea. We discovered that FSP27 unexpectedly associates specifically with lipid droplets and regulates fat storage. We conclude that RIP140, MAP4k4 and the novel lipid droplet protein FSP27 are powerful regulators of adipose tissue metabolism and are potential therapeutic targets for controlling metabolic disease. The discovery of these novel proteins validates the power of RNAi screening for discovery of new therapeutic approaches to type 2 diabetes and obesity. PMCID: PMC2880506 PMID: 18171433 [PubMed - indexed for MEDLINE] 2617. Acta Physiol (Oxf). 2008 Jan;192(1):49-59. doi: 10.1111/j.1748-1716.2007.01784.x. LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action. Leinninger GM(1), Myers MG Jr. Author information: (1)Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0678, USA. The adipose tissue-derived hormone, leptin, acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. In order to understand leptin action we have explored the physiological function of LRb signalling pathways, defining important roles for signal transducer and activator of transcription-3 (STAT3) in positive signalling and for LRbTyr(985)-mediated feedback inhibition in leptin signal attenuation. As the cells on which leptin acts are not homogeneous, but rather represent a broadly distributed network of neurones with divergent projections and functions, it is also crucial to consider how each of these populations responds to LRb signals to contribute to leptin action. While well-known LRb-expressing neurones within the arcuate nucleus of the hypothalamus mediate crucial effects on satiety and energy expenditure, other populations of LRb-expressing neurones in the ventral tegmental area and elsewhere likely control the mesolimbic dopamine system. Additional populations of LRb-expressing neurones likely contribute to other aspects of neuroendocrine regulation. It will be important to define the molecular mechanisms by which leptin acts to regulate neurophysiology in each of these LRb-expressing neural populations in order to understand the totality of leptin action. PMID: 18171429 [PubMed - indexed for MEDLINE] 2618. Histopathology. 2008 Jan;52(1):45-57. doi: 10.1111/j.1365-2559.2007.02893.x. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Lee AH(1). Author information: (1)Histopathology Department, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK. andrew.lee@nuh.nhs.uk This article reviews recent advances in the diagnosis of these three unusual tumours of the breast. Spindle cell carcinoma needs to be considered in the differential diagnosis of many mammary spindle cell lesions: it is important to be aware of the wide range of appearances, including the recently described fibromatosis-like variant. Immunohistochemistry using a broad panel of cytokeratin antibodies is needed to exclude spindle cell carcinoma; there is frequent expression of basal cytokeratins and p63. CD34 is often expressed by the stroma of phyllodes tumours, but does not appear to be expressed by spindle cell carcinoma or fibromatosis. Nuclear beta-catenin is found in about 80% of fibromatoses, but can also be seen in spindle cell carcinomas and phyllodes tumours. Two recent studies have described features useful in the distinction of phyllodes tumour and fibroadenoma on core biopsy, including increased cellularity, mitoses and overgrowth of the stroma, adipose tissue in the stroma and fragmentation of the biopsy specimen. Periductal stromal tumour is a recently described biphasic tumour composed of spindle cells around open tubules or ducts (but no leaf-like architecture) with frequent CD34 expression. The overlap of morphology with phyllodes tumour suggests that it may be best regarded as a variant of phyllodes tumour. PMID: 18171416 [PubMed - indexed for MEDLINE] 2619. Obes Facts. 2008;1(4):184-9. doi: 10.1159/000145784. Epub 2008 Aug 14. Human SGBS cells - a unique tool for studies of human fat cell biology. Fischer-Posovszky P(1), Newell FS, Wabitsch M, Tornqvist HE. Author information: (1)Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany. The human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain provides a unique and useful tool for studies of human adipocyte biology. The cells originate from an adipose tissue specimen of a patient with SGBS. They are neither transformed nor immortalized, and provide an almost unlimited source due to their ability to proliferate for up to 50 generations with retained capacity for adipogenic differentiation. So far, the cells have been used for a number of studies on adipose differentiation, adipocyte glucose uptake, lipolysis, apoptosis, regulation of expression of adipokines, and protein translocation. The cells are efficiently differentiated in the presence of PPARgammaagonists and in the absence of serum and albumin. SGBS adipocytes respond to insulin stimulation by increasing glucose uptake several-fold (EC50 approximately 100 pmol/l), and by very effectively inhibiting (IC50 approximately 10 pmol/l) catecholamine-stimulated lipolysis. Copyright (c) 2008 S. Karger AG, Basel. PMID: 20054179 [PubMed - indexed for MEDLINE] 2620. Obes Facts. 2008;1(4):176-82. doi: 10.1159/000145930. Epub 2008 Aug 14. Fat tissue and long life. Bluher M(1). Author information: (1)Department of Medicine, University of Leipzig, Germany. bluma@medizin.uni-leipzig.de Studies over the last several years have revealed important roles of the body fat content, caloric intake and nutrition, insulin/IGF-1 signaling systems, and pathways involved in oxidative stress and control of protein acetylation on life span. Although the discovery of longevity genes supports the concept that life span is genetically determined, adipose tissue seems to be a pivotal organ in the aging process and in the determination of life span. Leanness and caloric restriction have been shown to increase longevity in organisms ranging from yeast to mammals. Increased longevity in mice with a fat-specific disruption of the insulin receptor gene (FIRKO) suggests that reduced adiposity, even in the presence of normal or increased food intake, leads to an extended life span. Reduced fat mass has an impact on longevity in a number of other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends life span. Sirtuin 1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking life span to adipose tissue. Moreover, in the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. On the other hand, overweight and obesity seem to be associated with decreased life span in humans. In addition, it was recently shown that modifiable risk factors during the later years of life, including smoking, obesity, and hypertension, are associated not only with lower life expectancy, but also with poor health and function during older age. There is growing evidence that the effect of reduced adipose tissue mass on life span could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis. Copyright (c) 2008 S. Karger AG, Basel. PMID: 20054178 [PubMed - indexed for MEDLINE] 2621. Obes Facts. 2008;1(3):128-37. doi: 10.1159/000137673. Epub 2008 Jun 20. Pathogenesis, risk assessment and prevention of type 2 diabetes mellitus. Joost HG(1). Author information: (1)German Institute of Human Nutrition Potsdam-Rehbrucke, Nuthetal, Germany. joost@dife.de Type 2 diabetes mellitus is a complex, polygenic disease with a heterogeneous pathophysiology, mainly characterised by obesity-associated insulin resistance and a progressive failure of pancreatic beta-cells. Predominant risk factors for its development are abdominal obesity and age; other factors that augment the individual disease risk independent of obesity are the nutritional pattern (low consumption of fibres, high consumption of red meat, saturated and trans fat), lifestyle (smoking, low physical activity), and biomarkers such as blood pressure, HbA1c, serum adiponectin and inflammatory cytokines. These variables can provide the basis for a precise risk assessment and a personalised prevention. Genotyping for the presently known gene variants conferring an increased disease risk adds relatively little to the information provided by the phenotypic risk factors and biomarkers. However, genetic information is necessary for a personalised risk assessment and intervention that begins before phenotypic risk factors are detectable. The incidence of type 2 diabetes can significantly be lowered by reduction of the intraabdominal fat mass (by nutritional intervention and exercise), and by pharmacological control of post-prandial blood glucose excursions. Because of the high portion of non-responders to a preventive intervention, current efforts aim at the identification of phenotypic and genetic variables predicting the success of the intervention. Copyright 2008 S. Karger AG, Basel. PMID: 20054172 [PubMed - indexed for MEDLINE] 2622. Obes Facts. 2008;1(1):8-15. doi: 10.1159/000114255. Epub 2008 Feb 8. Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. Engeli S(1). Author information: (1)Franz Volhard Clinical Research Center at the Experimental and Clinical Research Center, Charité - Campus Buch, Berlin, Germany. stefan.engeli@charite.de The endocannabinoid system consists of endogenous arachidonic acid derivates that activate cannabinoid receptors. The two most prominent endocannabinoids are anandamide and 2-arachidonoyl glycerol. In obesity, increased concentrations of circulating and tissue endocannabinoid levels have been described, suggesting increased activity of the endocannabinoid system. Increased availability of endocannabinoids in obesity may over-stimulate cannabinoid receptors. Blockade of cannabinoid type 1 (CB1) receptors was the only successful clinical development of an anti-obesity drug during the last decade. Whereas blockade of CB1 receptors acutely reduces food intake, the long-term effects on metabolic regulation are more likely mediated by peripheral actions in liver, skeletal muscle, adipose tissue, and the pancreas. Lipogenic effects of CB1 receptor signalling in liver and adipose tissue may contribute to regional adipose tissue expansion and insulin resistance in the fatty liver. The association of circulating 2-arachidonoyl glycerol levels with decreased insulin sensitivity strongly suggests further exploration of the role of endocannabinoid signalling for insulin sensitivity in skeletal muscle, liver, and adipose tissue. A few studies have suggested a specific role for the regulation of adiponectin secretion from adipocytes by endocannabinoids, but that has to be confirmed by more experiments. Also, the potential role of CB1 receptor blockade for the stimulation of energy expenditure needs to be studied in the future. Despite the current discussion of safety issues of cannabinoid receptor blockade, these findings open a new and exciting perspective on endocannabinoids as regulators of body weight and metabolism. Copyright 2008 S. Karger AG, Basel. PMID: 20054157 [PubMed - indexed for MEDLINE] 2623. J Nutrigenet Nutrigenomics. 2008;1(3):126-35. doi: 10.1159/000112460. Epub 2008 Feb 20. Dietary modulators of peroxisome proliferator-activated receptors: implications for the prevention and treatment of metabolic syndrome. Guri AJ(1), Hontecillas R, Bassaganya-Riera J. Author information: (1)Laboratory of Nutritional Immunology and Molecular Nutrition, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. In its simplest form, obesity is a state characterized by nutrient overabundance leading to hypertrophy of storage cells in white adipose tissue and the deposition of excess lipids into key metabolic regions, such as skeletal muscle and liver. Ever so steadily, this condition begins to manifest itself as progressive insulin resistance and thus ensues a myriad of other chronic diseases, such as type 2 diabetes, cardiovascular disease, and hypertension, which all fall into the realm of the metabolic syndrome. To offset imbalances in nutrient availability, however, it appears that nature has developed the peroxisome proliferator-activated receptors (PPARs), a family of endogenous lipid sensors that adeptly modulate our rates of macronutrient oxidation and regulate the systemic inflammatory response, which itself is tightly linked to the development of obesity-induced chronic disease. By understanding how PPARs alpha, delta and gamma act jointly to maintain metabolic homeostasis and reduce the chronic inflammation associated with obesity, we may one day discover that the machinery needed to defeat obesity and control the devastating consequences of the metabolic syndrome have been with us the entire time. PMID: 19776622 [PubMed - indexed for MEDLINE] 2624. Clin Chem. 2008 Jan;54(1):24-38. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Packard RR(1), Libby P. Author information: (1)Leducq Center for Cardiovascular Research, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Recent investigations of atherosclerosis have focused on inflammation, providing new insight into mechanisms of disease. Inflammatory cytokines involved in vascular inflammation stimulate the generation of endothelial adhesion molecules, proteases, and other mediators, which may enter the circulation in soluble form. These primary cytokines also induce production of the messenger cytokine interleukin-6, which stimulates the liver to increase production of acute-phase reactants such as C-reactive protein. In addition, platelets and adipose tissue can generate inflammatory mediators relevant to atherothrombosis. Despite the irreplaceable utility of plasma lipid profiles in assessment of atherosclerotic risk, these profiles provide an incomplete picture. Indeed, many cardiovascular events occur in individuals with plasma cholesterol concentrations below the National Cholesterol Education Program thresholds of 200 mg/dL for total cholesterol and 130 mg/dL for low-density lipoprotein (LDL) cholesterol. The concept of the involvement of inflammation in atherosclerosis has spurred the discovery and adoption of inflammatory biomarkers for cardiovascular risk prediction. C-reactive protein is currently the best validated inflammatory biomarker; in addition, soluble CD40 ligand, adiponectin, interleukin 18, and matrix metalloproteinase 9 may provide additional information for cardiovascular risk stratification and prediction. This review retraces the biology of atherothrombosis and the evidence supporting the role of inflammatory biomarkers in predicting primary cardiovascular events in this biologic context. PMID: 18160725 [PubMed - indexed for MEDLINE] 2625. Physiol Behav. 2008 Apr 22;94(1):17-28. Epub 2007 Nov 22. Early life programming of obesity and metabolic disease. Cottrell EC(1), Ozanne SE. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QR, United Kingdom. It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life. PMID: 18155097 [PubMed - indexed for MEDLINE] 2626. Am J Cardiol. 2007 Dec 17;100(12A):18P-26P. Cannabinoid-1 receptor blockade in cardiometabolic risk reduction: efficacy. Aronne LJ(1), Isoldi KK. Author information: (1)Weill Medical College of Cornell University, New York, New York 10021-7917, USA. ljaronne@med.cornell.edu Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend that if dietary and lifestyle interventions fail to produce favorable outcomes in individuals with a body mass index >27 and weight-related comorbidities, as well as those with a body mass index >30, treatment plans may include weight loss medication. The endocannabinoid system has recently emerged as a viable target for the pharmacologic treatment of obesity and cardiometabolic risk factors. This article provides an in-depth review of efficacy results from clinical trials of rimonabant, a selective cannabinoid-1 receptor. (Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies.) Compared with placebo, rimonabant 20 mg significantly decreased body weight and waist circumference measurements. In addition, rimonabant was associated with favorable changes in several other cardiometabolic risk factors, including significant increases in serum levels of high-density lipoprotein cholesterol and adiponectin, as well as reductions in serum levels of triglycerides, small, dense low-density lipoprotein particles, C-reactive protein, insulin resistance, and glycosylated hemoglobin. PMID: 18154742 [PubMed - indexed for MEDLINE] 2627. Clin Cornerstone. 2007;8 Suppl 7:S30-42. Metabolic consequences of hyperglycemia and insulin resistance. Jellinger PS(1). Author information: (1)The Center for Diabetes & Endocrine Care, Voluntary Faculty, University of Miami, Hollywood, Florida 33201, USA. pjellinger@diabetes-endocare.com Insulin is a pleiotropic hormone that exerts a multitude of effects on metabolism and various cellular processes in the body. The main metabolic actions of insulin are to stimulate glucose uptake in skeletal muscle and the heart and to suppress the production of glucose and very-low-density lipoprotein in the liver. Other metabolic effects of insulin include inhibition of glucose release from the liver, inhibition of the release of free fatty acids (FFAs) from adipose tissue, and stimulation of the process by which amino acids are incorporated into protein. Insulin resistance (IR) is a condition in which defects in the action of insulin are such that normal levels of insulin do not trigger the signal for glucose absorption. An excess of FFAs is implicated in the pathogenesis of IR. The effects of this condition can have profound pathophysiologic effects on various organs and tissues of the body. For example, IR is associated with impaired insulin signaling, impaired fibrinolysis, and inflammation. The clinical consequences include hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular disease. Pharmacotherapies that target IR include metformin and the thiazolidinediones. Endocannabinoid antagonists, agents that target obesity and associated cardiovascular and metabolic risk factors, are currently being developed. PMID: 18154189 [PubMed - indexed for MEDLINE] 2628. Diabetologia. 2008 Mar;51(3):394-7. Epub 2007 Dec 21. Fatty acid-induced mitochondrial uncoupling in adipocytes is not a promising target for treatment of insulin resistance unless adipocyte oxidative capacity is increased. Frayn KN(1), Langin D, Karpe F. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. Comment in Diabetologia. 2008 May;51(5):907-8. Comment on Diabetologia. 2007 Oct;50(10):2036-41. The release of fatty acids from white adipose tissue is regulated at several levels. We have examined the suggestion that fatty acid release might be diminished by upregulation of mitochondrial fatty acid oxidation in the adipocyte, through increasing mitochondrial uncoupling. The intrinsic oxidative capacity of white adipose tissue is low, and older studies suggest that there is little fatty acid oxidation in white adipocytes, human or rodent. We have examined data on fatty acid metabolism and O(2) consumption in human white adipose tissue in vivo, and conclude that increasing fatty acid oxidation within the oxidative capacity of the tissue would produce only small changes (a few percent) in fatty acid release. The major locus of control of fatty acid release beyond the stimulation of lipolysis is the pathway of fatty acid esterification, already probably targeted by the thiazolidinedione insulin-sensitising agents. An alternative approach would be to upregulate the mitochondrial capacity of the adipocyte. We review proof-of-concept studies in which the phenotype of the white adipocyte has been changed to resemble that of the brown adipocyte by expression of peroxisome proliferator-activated receptor coactivator-1alpha. This increases oxidative capacity and also leads to fatty acid retention through upregulation of glycerol-3-phosphate production, and hence increased fatty acid re-esterification. We conclude that prevention or treatment of insulin resistance through alteration of adipocyte fatty acid handling will require more than a simple alteration of the activity of mitochondrial beta-oxidation within normal limits. PMID: 18097647 [PubMed - indexed for MEDLINE] 2629. Genet Sel Evol. 2008 Jan-Feb;40(1):129-43. Epub 2007 Dec 21. Genetic and metabolic aspects of androstenone and skatole deposition in pig adipose tissue: a review. Robic A(1), Larzul C, Bonneau M. Author information: (1)INRA, UMR 444 de Génétique cellulaire, BP52627, 31326 Castanet-Tolosan, France. annie.robic@toulouse.inra.fr Erratum in Genet Sel Evol. 2008 Sep-Oct;40(5):581-2. High levels of androstenone and skatole in fat tissues are considered the primary causes of boar taint, an unpleasant odour and flavour of the meat from non-castrated male pigs. The aim of this article is to review our current knowledge of the biology and genetic control of the accumulation of androstenone and skatole in fat tissue. Two QTL mapping studies have shown the complexity of the genetic control of these traits. During the last ten years, several authors have taken a more physiological approach to investigate the involvement of genes controlling the metabolism of androstenone and skatole. Although some authors have claimed the identification of candidate genes, it is more appropriate to talk about target genes. This suggests that genes affecting androstenone and skatole levels will have to be sought for among specific or non-specific transcription factors interacting with these target genes. PMCID: PMC2674915 PMID: 18096119 [PubMed - indexed for MEDLINE] 2630. Diabetes Metab. 2008 Feb;34(1):2-11. Adipokines: the missing link between insulin resistance and obesity. Antuna-Puente B(1), Feve B, Fellahi S, Bastard JP. Author information: (1)Inserm U680, faculté de médecine Saint-Antoine, université Pierre-et-Marie-Curie-Paris-6, 75012 Paris, France. White adipose tissue was believed to be just an energy-storage organ, but it is now recognized to be an active participant in energy homoeostasis and physiological functions such as immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Adipose tissue is known to express and secrete a variety of products known as 'adipokines', including leptin, adiponectin, resistin and visfatin, as well as cytokines and chemokines such as tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, and the increased risk of cardiovascular disease associated with obesity. PMID: 18093861 [PubMed - indexed for MEDLINE] 2631. Curr Opin Nephrol Hypertens. 2008 Jan;17(1):25-31. Role of fat mass and adipokines in chronic kidney disease. Axelsson J(1), Stenvinkel P. Author information: (1)Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. PURPOSE OF REVIEW: As traditional risk factors cannot alone explain the high prevalence and incidence of cardiovascular disease in chronic kidney disease, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as an important non-traditional risk factor. Recent studies show that the adipose tissue is a complex organ with pleiotropic functions far beyond the mere storage of energy. Fat tissue secretes a number of adipokines including leptin and adiponectin, as well as cytokines, such as resistin, visfatin, tumor-necrosis factor-alpha and interleukin-6. RECENT FINDINGS: Adipokine serum levels are markedly elevated in chronic kidney disease, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and vascular outcome. SUMMARY: Fat tissue is a storage depot for energy and a source of circulating signaling molecules. It plays an important role in the catabolic uremic milieu, and has been linked to systemic inflammation and uremic anorexia. Further research is needed to investigate the complex interactions between adipokine signaling networks and its effects on vascular health and outcome in chronic kidney disease. PMID: 18090666 [PubMed - indexed for MEDLINE] 2632. Curr Opin Nephrol Hypertens. 2008 Jan;17(1):11-7. Genetically altered animals in the study of the metabolic functions of peptide hormone systems. Mori MA(1), Bader M, Pesquero JB. Author information: (1)Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil. PURPOSE OF REVIEW: Here we review the use of genetically altered animals to address the roles of peptide hormone systems in the modulation of energy homeostasis. Despite the disseminated use of transgenic techniques to establish the functional relevance of several peptide hormone systems, we focus on two multifunctional systems, the renin-angiotensin and the kallikrein-kinin systems. Initially, we explored the background information supporting the functional aspects of these systems, followed by novel knowledge obtained with the phenotypic characterization of genetically altered animals. RECENT FINDINGS: A role for the renin-angiotensin system in the regulation of adiposity and glucose metabolism has been suggested. Studies using genetically altered animals not only confirmed the physiological relevance of angiotensin II in the control of energy homeostasis, but also revealed that the adipose tissue renin-angiotensin system participates in the endocrine modulation of cardiovascular and renal function. On the other hand, the involvement of the kallikrein-kinin system with metabolic processes was not so obvious. Recent reports using genetically altered animals, however, provided strong evidence to support an important role for kinins in the control of glucose homeostasis and energy balance. SUMMARY: Here we present examples of how genetically altered animals contribute to a final postulation of the physiological roles of certain hormone systems, bringing new insights into the field. PMID: 18090664 [PubMed - indexed for MEDLINE] 2633. Curr Opin Nephrol Hypertens. 2008 Jan;17(1):1-10. Role of the endocannabinoid system in metabolic control. Wang J(1), Ueda N. Author information: (1)Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan. PURPOSE OF REVIEW: Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid receptors, endocannabinoids, and related enzymes. In this short review, we describe the latest advances in this research field, including the antiobesity effect of the cannabinoid receptor CB1 antagonist rimonabant and the anorexic effect of N-oleoylethanolamine, an endocannabinoid-related, endogenous substance. RECENT FINDINGS: CB1 is expressed not only in various brain regions, including hypothalamus, but also in peripheral organs such as adipose tissue and liver. The endocannabinoid system appears to function as a physiological system regulating food intake, energy balance, and lipid metabolism through both central and peripheral mechanisms. Obesity may be associated with hyperactivity of the endocannabinoid system. Large phase III trials of rimonabant confirmed significant weight loss and waist circumference reduction in overweight and obese patients. The levels of HDL-cholesterol, triglycerides, and HbA1c were also improved. The anorexic effect of N-oleoylethanolamine was suggested to be mediated by peroxisome proliferator-activated receptor-alpha and the G protein-coupled receptor GPR119. SUMMARY: These results highlight the importance of an endocannabinoid tone in metabolic control and therapeutic usefulness of CB1 antagonists. Derivatives of N-oleoylethanolamine may be developed as new antiobesity drugs. PMID: 18090663 [PubMed - indexed for MEDLINE] 2634. Curr Opin Nephrol Hypertens. 2007 Nov;16(6):572-6. Body fat measurement in chronic kidney disease: implications in research and clinical practice. Shoji T(1), Ishimura E, Nishizawa Y. Author information: (1)Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan. t-shoji@med.osaka-cu.ac.jp PURPOSE OF REVIEW: The paradoxical and inverse association between body mass index and mortality risk in patients with end-stage renal disease has raised a question of whether an increased fat mass is good or bad for patients with chronic kidney disease. The purpose of this review is to update the concept on body fat in patients with chronic kidney disease. RECENT FINDINGS: A greater fat mass is an independent predictor of better survival in patients on maintenance hemodialysis. Following the initiation of dialysis, chronic kidney disease patients gain body weight due mainly to increased fat mass. Fat mass gain over time predicts better survival in hemodialysis patients. In predialysis chronic kidney disease, there is also an inverse association between body mass index and mortality risk. The metabolic syndrome and a high body mass index are independent predictors for development of chronic kidney disease and end-stage renal disease, respectively. In diabetic patients with chronic kidney disease, however, a high initial body mass index is associated with a slower decline in glomerular filtration rate. SUMMARY: The impacts of fat mass on survival and renal function appear to vary depending upon the absence or presence, and stages of chronic kidney disease. Further research is required for optimal nutritional management and improved outcomes of patients with chronic kidney disease. PMID: 18089973 [PubMed - indexed for MEDLINE] 2635. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):698-703. Muscular mitochondrial dysfunction and type 2 diabetes mellitus. Schrauwen-Hinderling VB(1), Roden M, Kooi ME, Hesselink MK, Schrauwen P. Author information: (1)Department of Human Biology, Maastricht University, Maastricht, The Netherlands. PURPOSE OF REVIEW: Muscular mitochondrial dysfunction, leading to the accumulation of fat in skeletal muscle, has been proposed to be involved in the development of type 2 diabetes mellitus. Here, we review human studies that investigated various aspects of mitochondrial function in relation to muscular insulin sensitivity and/or diabetes. RECENT FINDINGS: In-vivo magnetic resonance spectroscopy allows assessment of mitochondrial functionality from adenosine triphosphate flux in the nonexercising state and from phosphocreatine recovery from (sub)maximal exercising. Application of both approaches revealed reduced mitochondrial oxidative capacity in insulin-resistant (pre)diabetic humans. Reductions in mitochondrial density may contribute to, or even underlie, these findings as well as intrinsic defects in mitochondrial respiration. So far, only two studies reported measurements of mitochondrial respiratory capacity in intact mitochondria in diabetic patients, with inconsistent findings. SUMMARY: Muscular mitochondrial aberrations in type 2 diabetes mellitus can be detected, but it is so far unclear if these aberrations are causally related to the development of the disease. Alternatively, mitochondrial dysfunction may simply be the consequence of elevated plasma fatty acids or glucose levels. PMID: 18089950 [PubMed - indexed for MEDLINE] 2636. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):693-7. Lessons that can be learned from patients with diabetogenic mutations in mitochondrial DNA: implications for common type 2 diabetes. Maassen JA(1), 't Hart LM, Ouwens DM. Author information: (1)Department of Molecular Cell Biology, Leiden University Medical Centre, Albinusdreef 2, 2300RC Leiden, the Netherlands. j.a.maassen@lumc.nl PURPOSE OF REVIEW: To discuss the role of mitochondria in the development of type 2 diabetes. RECENT FINDINGS: Some mutations in mitochondrial DNA are diabetogenic due to a gradual decline in insulin secretion by the pancreas. These mutations also result in abnormalities in lipid metabolism. A similar situation is seen in patients treated with nucleoside analogues as part of highly active antiretroviral therapy to suppress human immunodeficiency virus infection. These drugs induce a 30-50% reduction in mitochondrial DNA copy number in multiple tissues. Treated individuals develop a redistribution of body fat with concomitant development of markers of the metabolic syndrome and an elevated risk of developing type 2 diabetes. Studies have also shown the presence of reduced mitochondrial activity in muscle and adipose tissue in individuals with type 2 diabetes. SUMMARY: These observations suggest a pathogenic model for obesity-associated type 2 diabetes, in which mitochondrial activity in peripheral adipocytes is essential to keep triacylglycerol stored within these cells. Mitochondria protect the organism against fatty acid-induced insulin resistance and lipotoxicity to the pancreas. In adipocytes, mitochondria may remove fatty acids through uncoupled beta oxidation, whereas in muscle fatty acids, removal is largely driven by adenosine diphosphate production through physical activity. PMID: 18089949 [PubMed - indexed for MEDLINE] 2637. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):671-8. Mitochondrial uncoupling as a target in the treatment of obesity. Costford S(1), Gowing A, Harper ME. Author information: (1)Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. PURPOSE OF REVIEW: Obesity is associated with many health problems and its prevalence is rapidly increasing worldwide. Very few pharmaceutical compounds are available for obesity treatment. Strategies for the development of compounds can be targeted to the outcomes of reduced dietary energy intake and/or increased energy expenditure/thermogenesis. In this review, we focus on recent discoveries that advance our understanding of mitochondrial uncoupling as a target for the treatment of obesity. There are various mechanisms whereby uncoupling can occur and for the purpose of this review, we elaborate upon the uncoupling that can occur (1) through the original uncoupling protein, UCP1, in brown adipocytes, or in 'converted' white adipose tissue, and (2) in skeletal muscle. RECENT FINDINGS: Studies have identified a number of novel receptors and regulatory proteins involved in the emergence of brown adipocytes in white adipose tissue. Molecular and pharmacologic approaches in knockout and transgenic mice have demonstrated their relevance to obesity treatment. Recent research into uncoupling mechanisms in skeletal muscle indicates that uncoupling can occur through basal and inducible processes. SUMMARY: Uncoupling is a naturally occurring phenomenon whose underlying mechanisms require substantial further study for the development of antiobesity therapies. PMID: 18089946 [PubMed - indexed for MEDLINE] 2638. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):664-70. Mitochondrial thermogenesis and obesity. Gambert S(1), Ricquier D. Author information: (1)Biologie des transporteurs mitochondriaux et métabolisme, Université Paris Descartes, CNRS, Paris, France. PURPOSE OF REVIEW: Thermogenesis is activated at the expense of carbon molecules. Mitochondria play a dominant role in oxidation and parallel heat production since the recovery of oxidation energy is less than perfect. Recent data of mitochondriogenesis and mitochondrial thermogenesis may boost research into certain aspects of obesity. RECENT FINDINGS: Recent studies have outlined the unexpected decreased thermogenesis that limits fat loss during prolonged food restriction. Activation of fat oxidation in skeletal muscle remains a strategy against fat accumulation, however. Certain adipose depots have the potential to promote thermogenesis, either using mitochondrial uncoupling protein or independently. Peroxisome proliferator-activated receptor gamma coactivators alpha and ss are important regulators of mitochondria thermogenesis. Brain mitochondria are involved in the control of refeeding after starvation. This dual action of mitochondria inform their role in thermogenesis and energy partitioning. The importance of thyroid hormones in mitochondria thermogenesis is also confirmed. SUMMARY: The clinical and research implications of these findings are that the mechanisms inhibiting adaptive thermogenesis during diet restriction should be investigated. An important field of research is the contribution of transcriptional coactivators to adipocyte plasticity since adipocytes have an underestimated ability to oxidise fatty acids in addition to their role in triglyceride storage. PMID: 18089945 [PubMed - indexed for MEDLINE] 2639. J Ren Nutr. 2008 Jan;18(1):70-5. Inflammation and insulin resistance in uremia. Zanetti M(1), Barazzoni R, Guarnieri G. Author information: (1)Clinica Medica, Department Clinical, Morphological, Technological Sciences, University of Trieste, Trieste, Italy. Low-grade systemic inflammation is an important potential factor in the pathogenesis of insulin resistance in end-stage renal disease (ESRD). Insulin resistance and diabetes, characterized by impaired skeletal muscle glucose uptake or excess hepatic glucose production, are in turn relevant contributors to morbidity and mortality in ESRD patients. Oxidative stress is increased in ESRD, in conservative therapy as well as hemodialysis treatment. Recent evidence suggests that oxidative stress contributes, at least in part, to both inflammation and insulin resistance by modulating the production of proinflammatory cytokines and adipokines in monocytes and in adipose tissue. This review focuses on the pathogenesis of inflammation and oxidative stress, and the effects of their interplay on insulin resistance in ESRD. PMID: 18089448 [PubMed - indexed for MEDLINE] 2640. Trends Endocrinol Metab. 2008 Jan;19(1):10-6. Epub 2007 Dec 21. Innate immunity, insulin resistance and type 2 diabetes. Fernández-Real JM(1), Pickup JC. Author information: (1)University Hospital of Girona Dr Josep Trueta and CIBER Fisiopatología de la Obesidad (CB06/03/010) 17007 Girona, Spain. uden.jmfernandezreal@htrueta.scs.es Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized. PMID: 18082417 [PubMed - indexed for MEDLINE] 2641. Drug News Perspect. 2007 Oct;20(8):527-31. Molecular basis of insulin action. González-Sánchez JL(1), Serrano-Ríos M. Author information: (1)Department of Internal Medicine II, Hospital Clinico San Carlos, Madrid, Spain. Insulin is the main anabolic and anticatabolic hormone in mammals. The stimulatory effect of insulin on glucose uptake in muscle and adipose tissue is a consequence of the rapid translocation of GLUT4 glucose transporters from an intracellular site to the cell surface. The actions of insulin are initiated by hormone binding to its cell surface receptors. Insulin receptors are ligand-stimulated protein tyrosine kinases and phosphorylate a number of proteins, known as insulin receptor substrate proteins. Insulin resistance has been recognized as a main pathogenic factor in the development of type 2 diabetes, and has been associated with dyslipidemia, hypertension, endothelial dysfunction, inflammation and coagulative state. The current challenge is the study of impaired insulin signaling pathways leading to beta-cell dysfunction and its progression to type 2 diabetes, as well as control of chronic inflammation processes that may improve insulin action. (c) 2007 Prous Science. All rights reserved. PMID: 18080040 [PubMed - indexed for MEDLINE] 2642. Vasc Health Risk Manag. 2007;3(5):721-31. A review of pioglitazone HCL and glimepiride in the treatment of type 2 diabetes. Dorkhan M(1), Frid A. Author information: (1)Department of Clinical Sciences, Division of Diabetes and Endocrinology, Lund University, Malmö University Hospital, Malmö, Sweden. mozhgan.dorkhan@med.lu.se Type 2 diabetes (T2D) is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c) over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/ glinides) or insulin, biguanides, and thiazolidinediones (TZDs) respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health. PMCID: PMC2291316 PMID: 18078023 [PubMed - indexed for MEDLINE] 2643. Expert Opin Ther Targets. 2008 Jan;12(1):91-100. AMP activated protein kinase: a next generation target for total metabolic control. Misra P(1). Author information: (1)Discovery Research, Dr Reddy's, Hyderabad, India. parimal@drreddys.com Metabolic syndrome is characterized by a cluster of metabolic disorders, such as reduced glucose tolerance, hyperinsulinemia, hypertension, visceral obesity and lipid disorders. The benefit of exercise in maintaining total metabolic control is well known and recent research indicates that AMP-activated protein kinase (AMPK) may play an important role in exercise-related effects. AMPK is considered as a master switch in regulating glucose and lipid metabolism. AMPK is an enzyme that works as a fuel gauge, being activated in conditions of high phosphate depletion. In the liver, activation of AMPK results in decreased production of plasma glucose, cholesterol, triglyceride and enhanced fatty acid oxidation. AMPK is also robustly activated by skeletal muscle contraction and myocardial ischemia, and is involved in the stimulation of glucose transport and fatty acid oxidation by these stimuli. In adipose tissue, activated AMPK inhibits deposition of fat, but enhances breakdown and burning of stored fat, resulting in reduction of body weight. The two leading diabetic drugs, namely metformin and rosiglitazone, and adipokines, such as adiponectin and leptin, show their metabolic effects partially through AMPK. These data suggest that AMPK may be a key player in the development of new treatments for obesity, Type 2 diabetes and the metabolic syndrome. In this review, the author provide insight into the role of AMPK as a probable target for treatment of metabolic syndrome. PMID: 18076373 [PubMed - indexed for MEDLINE] 2644. Novartis Found Symp. 2007;287:70-80; discussion 80-91. Novel uncoupling proteins. Affourtit C(1), Crichton PG, Parker N, Brand MD. Author information: (1)MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK. Mitochondria are incompletely coupled because of proton leaks that short-circuit oxidative phosphorylation. Basal proton leak is unregulated and is associated with the presence (but not catalytic activity) of the adenine nucleotide translocase. Inducible proton leak is regulated and is catalysed by the adenine nucleotide translocase and specific uncoupling proteins (UCPs). UCP1 catalyses proton conductance in mammalian brown adipose tissue. It is activated by fatty acids, which overcome nucleotide inhibition. UCP2, UCP3 and UCPs from birds, fish and plants also catalyse proton conductance that is inhibited by nucleotides. However, they require activation by superoxide or other reactive oxygen species (ROS). The mechanism of proton transport by the UCPs is unresolved. UCPs may also transport fatty acids or fatty acyl peroxides. Several physiological functions of UCPs are postulated. (1) UCP1 is specialised for thermogenesis; UCP3 and avian UCPs possibly share this function. (2) UCPs may attenuate ROS production and protect against oxidative damage, degenerative diseases and ageing. (3) UCP3 may catalyse fatty acid transport. (4) UCP2 has a signalling role in pancreatic beta cells, where it attenuates insulin secretion. Other roles remain to be discovered. PMID: 18074632 [PubMed - indexed for MEDLINE] 2645. Diabetes Metab. 2008 Feb;34(1):12-8. Adiponectin: an update. Guerre-Millo M(1). Author information: (1)Service de nutrition, Inserm U872, hôpital Hôtel-Dieu, 1, place du Parvis-de-Notre-Dame, 75181 Paris cedex 04, France. mguerre@bhdc.jussieu.fr The discoveries of leptin and adiponectin were breakthroughs in the field of metabolic diseases. Adipose cells produce both proteins and release them into the circulation. Leptin acts as a fundamental signal for the brain to modulate food intake as a function of energy status. Loss of leptin function results in obesity. Although a biological role for adiponectin has not been firmly established, clinical and experimental observations indicate that low plasma levels contribute to the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular diseases in obese or overweight patients. Adiponectin circulates as several multimeric species, including a high-molecular-weight form thought to be the most clinically relevant. Adiponectin exerts anti-atherogenic effects by targeting vascular endothelial cells and macrophages and insulin-sensitizing effects, mainly predominantly in muscle and liver. The best-characterized molecular mechanism mediating adiponectin's metabolic and vascular activities involved stimulation of AMP kinase activity. Adiponectin signaling pathways comprise at least two putative receptors (AdipoR1 and AdipoR2). Ways to enhance adiponectin bioactivity are actively being sought. In obesity, reducing chronic adipose-tissue inflammation and macrophage infiltration into it could be beneficial to reverse downregulation of adiponectin gene expression by pro-inflammatory cytokines. Pharmacologically, thiazolidinediones and cannabinoid-1 receptor blockers (e.g., rimonabant) increase plasma adiponectin and gene expression in adipocytes. Finally, AdipoR activation to mimic adiponectin actions could prove beneficial to reduce metabolic risk factors in conditions, such as obesity, where low adiponectinemia prevails. PMID: 18069030 [PubMed - indexed for MEDLINE] 2646. An Acad Bras Cienc. 2007 Dec;79(4):617-38. Microcirculation in obesity: an unexplored domain. Wiernsperger N(1), Nivoit P, Bouskela E. Author information: (1)Laboratório de Pesquisas em Microcirculação, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Obesity is traditionally linked to diabetes and cardiovascular diseases. Very recent experimental, clinical and epidemiological, sometimes provocative, data challenge this automaticity by showing that not the amount but the distribution of fat is the important determinant. Moderate abdominal fat accumulation may thus be more harmful than even consequent overweight. In view of the worldwide burden of obesity, factors leading to it in children and young adults must urgently be identified. Since obesity is a very complex cardiometabolic situation, this will require to focus investigations on uncomplicated obese subjects and adequate animal models. The recent discovery of intergenerational transmissions of obesity risk factors and also the key role played by gestational and perinatal events (epigenetic factors) give rise to completely new concepts and research avenues. Considering the potential close relationship between microcirculation and tissue metabolism, demonstrations of structural and/or functional abnormalities in microvascular physiology very early in life of subjects at risk for obesity might provide a solid basis for further investigations of such links. Microcirculation(arterioles, capillaries and venules) is conceivably a key compartment determining over one or several decades the translation of genetic and epigenetic factors into fat accumulation. Available animal models should serve to answer this cardinal question. PMID: 18066432 [PubMed - indexed for MEDLINE] 2647. Pediatr Blood Cancer. 2008 Feb;50(2 Suppl):456-61; discussion 468. Body composition, exercise and energy expenditure in survivors of acute lymphoblastic leukaemia. Warner JT(1). Author information: (1)Department of Child Health, University Hospital of Wales, Cardiff, Wales, UK. justin.warner@cardiffandvale.wales.nhs.uk Survivors of acute lymphoblastic leukaemia (ALL) are recognised to become overweight and this seems to worsen with increasing length of follow up. Increases in body fat appear to be more marked in girls than in boys and in those who have received prophylactic cranial irradiation. Physiological responses to exercise, both at submaximal and maximal levels, are different in ALL survivors compared to controls. Heart rate appears to be increased at low intensity exercise, possibly to maintain adequate cardiac output. Maximal aerobic capacity is reduced, signifying a lower level of physical fitness. Total daily energy expenditure (TDEE) under free living conditions appears limited due to low participation in physical activity. Associations exist between measures of energy expenditure and body fat, but whether these are cause or effect has yet to proven. (c) 2007 Wiley-Liss, Inc. PMID: 18064643 [PubMed - indexed for MEDLINE] 2648. Clin Perinatol. 2007 Dec;34(4):515-26, v. In utero exposure to maternal obesity and diabetes: animal models that identify and characterize implications for future health. Nathanielsz PW(1), Poston L, Taylor PD. Author information: (1)Department of Obstetrics and Gynecology, Center for Pregnancy and Newborn Research, The University of Texas of Health Science Center, 7703 Floyd Curl Drive, MSC 7836, San Antonio, TX 78229, USA. nathanielsz@uthscsa.edu The developed and developing worlds are experiencing an epidemic of obesity and associated predisposition to diabetes. This epidemic places a major drain on health care resources. It is now clear that maternal obesity and gestational diabetes have major adverse effects on the developing fetus that lead to increased neonatal morbidity and mortality, as discussed elsewhere in this issue. Obesity in pregnancy and gestational diabetes represent a special problem, not only as a result of their immediate adverse effects on maternal health and pregnancy outcome, but also because of growing evidence for their persistent and deleterious effects on the developing child. PMID: 18063102 [PubMed - indexed for MEDLINE] 2649. Clin Ter. 2007 Sep-Oct;158(5):457-64. [Therapeutic options for metabolic syndrome in obese patients]. [Article in Italian] Carella AM(1), Conte M. Author information: (1)Struttura Complessa di Medicina Interna, Presidio Ospedaliero T. Masselli-Mascia, ASL FG/1 San Severo (FG), Italia. mic.carella@virgilio.it The metabolic syndrome (MS), a cluster of risk factors, such as obesity, hyperglycemia, hypertension and dyslipidemia, contributes to the development of cardio-vascular diseases and type 2 diabetes mellitus (DM2). Insulin resistance (IR) plays a key role in MS being strongly linked to abdominal visceral fat. Treatment for obese patients with MS should aim at improving IR, delaying the onset of DM2 and at reducing cardio-vascular risk. Weight loss, first therapeutic target, may be obtained through life-style modifications and anti-obesity drugs or bariatric surgery, at need. In these patients drug therapy is necessary if therapeutic life-style changes are not sufficient. Some drugs have adverse metabolic effects, therefore the therapeutic choices must be specific and rational. Metformin, Thiazolidinediones and Acarbose are anti-hyperglycemic drugs of choice: they reduce the incidence of DM2 and IR (or improve insulin sensitivity) and they decrease or stabilize the visceral adipose tissue mass (Thiazolidinediones increases subcutaneous fat only). Also Angiotensin II receptor blockers and Angiotensin-converting enzyme inhibitors reduce the incidence of DM2 and insulin resistance and they are first-line antihypertensive drugs in MS. Calcium channel blockers, Alpha-1 antagonists and Alpha-2 agonists drugs are metabolically neutral and slight weight gains are related to the hydro-sodium retention. Beta-blockers and Diuretics, except for Indapamide and Anti-aldosterone drugs, can reduce insulin sensitivity, impair lipid profile and increase DM2 incidence; they are not first-line therapy yet they are necessary in selected cases only. Statins, Fibrates and omega-3 Fatty acids are indicated to normalize dyslipidemia. Low doses of acetylsalicylic acid are also recommended. PMID: 18062354 [PubMed - indexed for MEDLINE] 2650. J Allergy Clin Immunol. 2008 Feb;121(2):326-30. Epub 2007 Dec 3. Adiponectin and inflammation: consensus and controversy. Fantuzzi G(1). Author information: (1)Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA. giamila@uic.edu Comment in J Allergy Clin Immunol. 2008 Dec;122(6):1236. Circulating levels of adiponectin decrease with increasing visceral obesity and are lower in patients with type 2 diabetes, the metabolic syndrome, and cardiovascular disease compared with controls matched by body mass index. Several reports demonstrated anti-inflammatory effects of adiponectin. Because increased adipose tissue is associated with low-grade chronic inflammation and proinflammatory factors inhibit adiponectin production, the current hypothesis states that chronic inflammation associated with visceral obesity inhibits production of adiponectin, perpetuating inflammation. The negative correlation between adiponectin and markers of inflammation in the aforementioned conditions supports this hypothesis. In contrast with disorders typically associated with excess adiposity and positive energy balance, adiponectin levels are elevated--rather than decreased--in classic chronic inflammatory/autoimmune diseases that are unrelated to increased adipose tissue, such as rheumatoid arthritis, SLE, inflammatory bowel disease, type 1 diabetes, and cystic fibrosis. In these patients, adiponectin levels positively--rather than negatively--correlate with inflammatory markers. Furthermore, proinflammatory effects of adiponectin have been reported in tissues such as joint synovium and colonic epithelium. Thus, adiponectin is regulated in the opposite direction and may exert differential functions in classic versus obesity-associated inflammatory conditions. This article discusses this apparent paradox and presents possible alternative and/or complementary explanations. PMID: 18061654 [PubMed - indexed for MEDLINE] 2651. Appl Physiol Nutr Metab. 2007 Oct;32(5):884-94. The energetic implications of uncoupling protein-3 in skeletal muscle. Costford SR(1), Seifert EL, Bézaire V, F Gerrits M, Bevilacqua L, Gowing A, Harper ME. Author information: (1)Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak. PMID: 18059613 [PubMed - indexed for MEDLINE] 2652. Appl Physiol Nutr Metab. 2007 Oct;32(5):833-9. The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15. Nielsen AR(1), Pedersen BK. Author information: (1)The Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, Faculty of Health Sciences, DK-2100 Copenhagen, Denmark. Skeletal muscle fibers express several cytokines, including interleukin (IL)-6, IL-8, and IL-15. Solid evidence exists that muscular IL-6 and IL-8 are regulated by muscle contractions, at both the mRNA and the protein levels. IL-6 increases insulin-stimulated glucose disposal and fatty acid oxidation in humans in vivo. Both IL-6 and IL-8 are released from working skeletal muscle, but because IL-6 contributes to the systemic circulation only a small transient net release of IL-8 is found from working muscle, suggesting that IL-8 may exert its effects locally in the muscle. IL-15 is a recently discovered growth factor, which is highly expressed in skeletal muscle. Interestingly, although IL-15 has been demonstrated as having anabolic effects on skeletal muscle in vitro and in vivo, it seems to play a role in reducing adipose tissue mass, and a role for IL-15 in muscle-fat cross-talk has been hypothesized. In conclusion, muscle-derived cytokines appear to have important roles in metabolism, and exercise plays a role in orchestrating the interplay between cytokines and metabolism. PMID: 18059606 [PubMed - indexed for MEDLINE] 2653. Endokrynol Pol. 2007 Jul-Aug;58(4):330-42. [Adipose tissue. Pathophysiology, distribution, sex differences and the role in inflammation and cancerogenesis]. [Article in Polish] Siemińska L(1). Author information: (1)Zakład Patofizjologii Katedry Patofiziologii i Endokcynologii, Slaski Uniwersytet Medyczny, Zabrze. lusiem@poczta.onet.pl The role of adipose tissue is energy storage, but there is increasing evidence that adipocytes and adipokines are involved in metabolic and inflammatory processes. This paper reviews the pathophysiology of different adipose tissue depots. Interrelationships between sex hormones, adipose tissue and risk factors are also discussed. Present study focuses on the effects of adipokines on immune system and on the mechanisms relating adiposity to cancer risk. PMID: 18058725 [PubMed - indexed for MEDLINE] 2654. Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):641-55. Potential therapies based on antidiabetic peptides. Billyard T(1), McTernan P, Kumar S. Author information: (1)Warwick Medical School, University of Warwick, Clifford Bridge Road, University Hospital, Coventry CV2 2DX, UK. Since adipose tissue was shown to be more than a storage organ, the many cytokines it produces have been identified, along with their roles in energy homeostasis, appetite, and insulin resistance. Concurrently, numerous gut hormones with a diversity of effects have been discovered. They include, amongst many others, peptide YY, ghrelin and oxyntomodulin. As these peptides have been investigated, the potential for their use as novel anti-obesity and antidiabetic therapies has been realized. In this chapter we describe the actions of four of the peptides that have been proposed as the basis for promising new therapies for diabetes: leptin, adiponectin, obestatin and peptide YY. They each have an effect on appetite and, directly or indirectly, on glucose metabolism. We synthesize available data for these peptides and consider the therapeutic potential of each. PMID: 18054740 [PubMed - indexed for MEDLINE] 2655. FEBS Lett. 2008 Jan 9;582(1):74-80. Epub 2007 Dec 3. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. Kadowaki T(1), Yamauchi T, Kubota N. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. A decrease in the circulating levels of adiponectin by interactions between genetic factors and environmental factors causing obesity has been shown to contribute to the development of insulin resistance, type 2 diabetes, metabolic syndrome and atherosclerosis. In addition to its insulin sensitizing actions, adiponectin has central actions in the regulation of energy homeostasis. Adiponectin enhances AMP-activated protein kinase activity in the arcuate hypothalamus via its receptor AdipoR1 to stimulate food intake and decreases energy expenditure. We propose a hypothesis on the physiological role of adiponectin: a starvation gene in the course of evolution by promoting fat storage on facing the loss of adiposity. PMID: 18054335 [PubMed - indexed for MEDLINE] 2656. J Nutr Biochem. 2008 May;19(5):277-86. Epub 2007 Nov 28. Role of adipocytokines in obesity-associated insulin resistance. Zou C(1), Shao J. Author information: (1)Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA. The rapid increase of obese population in the United States has made obesity into epidemic proportion. Obesity is a strong risk factor for metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, cancer and other diseases. Compelling evidence has demonstrated that increased adipose tissue mass is not only the consequence of obesity, but also plays a central role in the development of obesity-associated diseases. Recent studies have profoundly changed the concept of adipose tissue from being an energy depot to an active endocrine organ. The development of obesity alters adipocyte-derived hormones or cytokines expression, which provide a link between obesity and impaired insulin sensitivity and metabolic defects in other tissues. This review summarizes the current knowledge on how major adipose-derived hormones or adipocytokines influence insulin sensitivity. PMID: 18054218 [PubMed - indexed for MEDLINE] 2657. FEBS Lett. 2008 Jan 9;582(1):97-105. Epub 2007 Nov 29. Inflammation and insulin resistance. de Luca C(1), Olefsky JM. Author information: (1)University of California at San Diego, Department of Medicine (0673), 225 Stein Clinical Research Building, 9500 Gilman Drive, La Jolla, CA 92093, USA. Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMCID: PMC2246086 PMID: 18053812 [PubMed - indexed for MEDLINE] 2658. J Sports Sci. 2007;25 Suppl 1:S73-82. Nutrition for the young athlete. Meyer F(1), O'Connor H, Shirreffs SM; International Association of Athletics Federations. Author information: (1)Department of Physical Education, ESEF-UFRGS, Porto Alegre, Brazil. flaviameyer@uol.com.br Erratum in J Sports Sci. 2009 Apr;27(6):667. Athletics is a popular sport among young people. To maintain health and optimize growth and athletic performance, young athletes need to consume an appropriate diet. Unfortunately, the dietary intake of many young athletes follows population trends rather than public health or sports nutrition recommendations. To optimize performance in some disciplines, young athletes may strive to achieve a lower body weight or body fat content and this may increase their risk for delayed growth and maturation, amenorrhoea, reduced bone density, and eating disorders. Although many of the sports nutrition principles identified for adults are similar to those for young athletes, there are some important differences. These include a higher metabolic cost of locomotion and preferential fat oxidation in young athletes during exercise. Young athletes, particularity children, are at a thermoregulatory disadvantage due to a higher surface area to weight ratio, a slower acclimatization, and lower sweating rate. An appropriate dietary intake rather than use of supplements (except when clinically indicated) is recommended to ensure young athletes participate fully and safely in athletics. PMID: 18049985 [PubMed - indexed for MEDLINE] 2659. J Sports Sci. 2007;25 Suppl 1:S49-60. Physique and performance for track and field events. O'Connor H(1), Olds T, Maughan RJ; International Association of Athletics Federations. Author information: (1)Exercise and Sport Science, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Australia. h.oconnor@fhs.usyd.edu.au Erratum in J Sports Sci. 2009 Apr;27(6):667. Evidence of the importance of physique in the athletics disciplines is supported by the persistence of certain characteristics over long periods, despite marked secular changes in the source population. These characteristics may also result in physiological benefits such as effective thermoregulation or a greater power-to-weight ratio. Coaches and athletes are often convinced of weight or fat loss benefits based on personal or anecdotal experience, intuition, and "trained eye" observation of successful competitors. This may entice athletes into adopting unbalanced, erratic or highly restrictive eating patterns that increase the risk for nutrient deficiencies, and disordered eating. Despite heavy training loads and often extreme diets, some athletes fall short of their physique goals as ultimately phenotype is under genetic control. Professionals assisting athletes with physique management need to be highly skilled in anthropometry and require a thorough understanding of sports-specific nutrition requirements. Careful assessment of the risks and benefits of various approaches to weight and fat loss is required before they are recommended to athletes. PMID: 18049983 [PubMed - indexed for MEDLINE] 2660. Pediatr Diabetes. 2007 Dec;8 Suppl 9:48-54. Metabolic syndrome in youths. Amemiya S(1), Dobashi K, Urakami T, Sugihara S, Ohzeki T, Tajima N. Author information: (1)Department of Pediatrics, Saitama Medical University, Saitama, Japan. The metabolic syndrome (MetS), characterized by a clustering of cardiovascular disease and type 2 diabetes (T2DM) risk factors, has become prevalent in children and adolescents in recent years. However, the reported prevalence data on the MetS in youths has varied markedly, in large part, because of the disagreement among the variously proposed definitions of the MetS. Obesity is defined by using body mass index, waist circumference, or percent overweight, pointing to the need for standardized use of anthropometric variables to define obesity with a well-defined reference year for each ethnic population. In addition, slightly different cutoff values are used for triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting plasma glucose. Therefore, International Diabetes Federation recently proposed unified, easy-to-use criteria for diagnosing the MetS in youths. To provide insight into the mechanisms underlying the MetS in youths, the degree of insulin sensitivity/resistance and its correlation with the serum lipid and blood pressure levels have been evaluated. In addition, the serum levels of adipocytokines, such as adiponectin, leptin, tumor necrosis factor-alpha, resistin, interleukin-6, plasminogen activator inhibitor-1, and their correlation with childhood obesity have been extensively investigated. Recommendations for future research include exploring ways to assess visceral adiposity, to identify better biochemical markers for prediction of T2DM and disease progression, and to effectively intervene to prevent the MetS in youths. PMID: 17991133 [PubMed - indexed for MEDLINE] 2661. Can J Cardiol. 2007 Oct;23 Suppl B:32B-39B. The 'valvulo-metabolic' risk in calcific aortic valve disease. Mathieu P(1), Després JP, Pibarot P. Author information: (1)Laboratoire d'Etudes Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Laval Hospital Research Center/Quebec Heart Institute, Department of Surgery, Québec, Quebec. patrick.mathieu@chg.ulaval.ca Erratum in Can J Cardiol. 2009 Mar;25(3):140. Calcific aortic stenosis (AS) has been considered a degenerative and unmodifiable process resulting from aging and 'wear and tear' of the aortic valve. Over the past decade, studies in the field of epidemiology, molecular biology and lipid metabolism have highlighted similarities between vascular atherosclerosis and calcific AS. In particular, work from the Quebec Heart Institute and from that of others has documented evidence of valvular infiltration by oxidized low-density lipoproteins and the presence of inflammatory cells, along with important tissue remodelling in valves explanted from patients with AS. Recent studies have also emphasized the role of visceral obesity in the development and progression of AS. In addition, visceral obesity, with its attendant metabolic complications, commonly referred to as the metabolic syndrome, has been associated with degenerative changes in bioprosthetic heart valves. The purpose of the present review is to introduce the concept of 'valvulo-metabolic risk' and to provide an update on the recent and important discoveries regarding the pathogenesis of heart valve diseases in relation to obesity, and to discuss how these novel mechanisms might translate into clinical practice. PMCID: PMC2794466 PMID: 17932585 [PubMed - indexed for MEDLINE] 2662. Can J Cardiol. 2007 Aug;23 Suppl A:23A-27A. Genetic contributors to obesity. McPherson R(1). Author information: (1)University of Ottawa Heart Institute, Ontario. rmcpherson@ottawaheart.ca Genetic and environmental factors interact to regulate body weight. Overall, the heritability of obesity is estimated at 40% to 70%. More than 244 genes have been found to strongly affect adiposity when overexpressed or deleted in mice. These genes can be considered in four broad categories: regulation of food intake by molecular signalling in the hypothalamus and hindbrain by signals originating in adipose tissue, gut and other organs; regulation of adipocyte differentiation and fat storage; regulation of spontaneous exercise activity; and effect on basal and postprandial thermogenesis. Rare variants in the coding sequences of major candidate genes account for an obese phenotype in 5% to 10% of individuals. PMCID: PMC2787002 PMID: 17668084 [PubMed - indexed for MEDLINE] 2663. Rev Neurol. 2007 Dec 1-15;45(11):672-82. [Brain regulation of food intake and expenditure energy: molecular action of insulin, leptin and physical exercise]. [Article in Spanish] Cintra DE(1), Ropelle ER, Pauli JR. Author information: (1)Departamento de Clínica Médica, Faculdade de Ciencias Medicas da Universidade Estadual de Campinas, São Paulo, Brasil. INTRODUCTION: Overweight and obesity present significant public health concerns because of the link with numerous chronic health conditions. During the last ten years, since the discovery of leptin, great advances were obtained in the characterization oh the hypothalamic mechanisms involved in the control of food intake and thermogenesis. DEVELOPMENT: This review will present some the most recent findings in this field. It will be focused on the actions of leptin and insulin in the hypothalamus and will explore the hypothesis that hypothalamic resistance to the action of these hormones may play a key role in the development of obesity. CONCLUSIONS: The physical activity is an important component on long-term weight control. The exercise markedly increased phosphorylation activity of several proteins involved in leptin and insulin signal transduction in the hypothalamus. Recently our laboratory showed that physical activity increase in sensitivity to leptin- and insulin-induced anorexia after enhances interleukin-6 production. These findings provide support for the hypothesis that the appetite-suppressive actions of exercise may be mediated by the hypothalamus. PMID: 18050100 [PubMed - indexed for MEDLINE] 2664. JAAPA. 2007 Nov;Suppl Endocannabinoid:11-4. Clinical aspects of cardiometabolic risk-factor reduction: a case-based approach. Urquhart BS(1). Author information: (1)American Society of Endocrine PAs, USA. PMID: 18047037 [PubMed - indexed for MEDLINE] 2665. Curr Med Chem. 2007;14(27):2918-24. Estrogens and glucocorticoid hormones in adipose tissue metabolism. Mattsson C(1), Olsson T. Author information: (1)Department of Medicine and Public Health, Umeå University Hospital, Umeå, Sweden. cecilia.mattsson@medicin.umu.se Women have a higher percentage of body fat than men, and there is a gender-specific difference in fat distribution: Females tend to accumulate fat around the hips, buttocks, and thighs while men have a larger intra-abdominal (visceral) fat mass. After menopause, there is a redistribution of fat depots, and post-menopausal women develop increased amounts of visceral fat. The risk of developing obesity-related diseases is significantly lower in pre-menopausal women compared to men, a difference that is abolished after menopause, suggesting that the female sex steroid estrogen influences adipogenesis and adipose metabolism. Experimentally, estrogen increases the size and number of subcutaneous adipocytes and attenuates lipolysis. Post-menopausal women also develop a more atherogenic lipid pattern and decreased levels of the prothrombotic protein plasminogen activator inhibitor-1, which attenuates fibrinolysis. Pathologically increased circulating cortisol concentration is associated with dysmetabolic features e.g., central obesity, elevated blood pressure, insulin resistance, and dyslipidemia. In "simple obesity," glucocorticoid production is elevated. Peak levels of circulating cortisol are however low or normal, possibly because of increased clearance and/or tissue-specific changes in cortisol production. In addition to the adrenal production of cortisol, cortisol is also generated in adipose tissue by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inactive cortisone to active cortisol. The enzyme activity in subcutaneous fat increases with increasing body weight. Estrogen seems to have a tissue-specific influence on 11betaHSD1 enzyme activity, attenuating it in liver, kidney, and testis but upregulating 11betaHSD1 mRNA expression in preadipocytes from women. In the present review, we summarize and discuss the interaction between glucocorticoids and sex steroids and their influence on adipocyte metabolism. PMID: 18045137 [PubMed - indexed for MEDLINE] 2666. Curr Drug Targets. 2007 Nov;8(11):1190-5. Adipose tissue and the vessel wall. Mazzone T(1). Author information: (1)University of Illinois at Chicago, Chicago, Illinois, USA. tmazzone@uic.edu The prevalence of obesity is rising dramatically in developed and developing countries. Obesity contributes to increased mortality from numerous causes, but the most important of these is cardiovascular death. The relationship between obesity and atherogenesis is multifactorial, including alterations in the composition and level of lipoproteins, changes in blood pressure, and changes in circulating coagulation and inflammatory factors. Mouse models can be useful for dissecting selected aspects of this complex relationship. One area in which these models can be of particular value is in investigating the effect of secretory products of adipose tissue on the vessel wall. Adipocytes and adipose tissue secrete numerous factors and their level of expression is altered in obese states. Adipose tissue and adipocytes produce adiponectin, resistin, leptin, and apolipoproteins (serum amyloid A and apoE); all of which can directly impact vessel wall homeostasis. Mouse models utilizing deletion or overexpression of many of these factors have demonstrated an important impact of these on vessel wall homeostasis. Subsequent to the development of obesity, factors secreted from adipose tissue have also been shown to have direct effect on liver production of systemic inflammatory factors. Mouse models have validated the importance of angiotensin II, TNFalpha, and MCP-1 for impacting vessel wall health in obese states. In summary, excess adipose tissue produces myriad changes in organismal homeostasis with potential impact on the vessel wall. The power of mouse genetics permits targeted mechanistic investigation for understanding how obesity accelerates atherosclerosis in a complex in vivo milieu. PMID: 18045097 [PubMed - indexed for MEDLINE] 2667. Int J Obes (Lond). 2007 Nov;31 Suppl 2:S8-13; discussion S31-2. Role of obesity and adiposity in polycystic ovary syndrome. Diamanti-Kandarakis E(1). Author information: (1)1st Department of Internal Medicine, Athens University Medical School, Athens, Greece. akandara@otenet.gr Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Obesity may have a marked impact on both the development and progression of the syndrome. A high proportion of women with PCOS are obese. Regardless of the degree of obesity, women with PCOS are more likely to have central (abdominal) distribution of body fat, which is associated with insulin resistance and hyperandrogenaemia. PCOS is not only a reproductive disorder, but is also associated with significant increase in metabolic aberrations and cardiovascular risk factors. It has been shown that weight loss improves the metabolic and reproductive abnormalities that characterise the syndrome. PMID: 17968437 [PubMed - indexed for MEDLINE] 2668. Annu Rev Pathol. 2007;2:31-56. Endocrine functions of adipose tissue. Waki H(1), Tontonoz P. Author information: (1)Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, USA. hwaki@mednet.ucla.edu Obesity is a risk factor for type 2 diabetes, dyslipidemia, and cardiovascular disease. Dissection of the molecular mechanisms underlying obesity and its relationship to insulin resistance and the metabolic syndrome are essential for developing new strategies for prevention and treatment of these disorders. Both excess adipose tissue and lack of adipose tissue cause insulin resistance and dyslipidemia, suggesting that normal fat is required for the maintenance of systemic glucose and lipid homeostasis. Recent advances in obesity research have led to the recognition that adipose tissue is an active endocrine organ that secretes multiple bioactive factors termed adipokines. Secretion of adipokines provides a link between adipose tissue lipid accumulation and the metabolic function of other tissues such as liver and muscle. Dysregulation of adipokines is emerging as an important mechanism by which adipose tissue contributes to systemic insulin resistance and metabolic disease. PMID: 18039092 [PubMed - indexed for MEDLINE] 2669. Nat Clin Pract Rheumatol. 2007 Dec;3(12):716-24. Adipokines as emerging mediators of immune response and inflammation. Lago F(1), Dieguez C, Gómez-Reino J, Gualillo O. Author information: (1)Molecular and Cellular Cardiology Research Laboratory, Santiago University Clinical Hospital, Santiago de Compostela, Spain. The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases. PMID: 18037931 [PubMed - indexed for MEDLINE] 2670. Physiol Behav. 2008 May 23;94(2):206-18. Epub 2007 Oct 22. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Goossens GH(1). Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. G.Goossens@hb.unimaas.nl Research of the past decade has increased our understanding of the role adipose tissue plays in health and disease. Adipose tissue is now recognized as a highly active metabolic and endocrine organ. Adipocytes are of importance in buffering the daily influx of dietary fat and exert autocrine, paracrine and/or endocrine effects by secreting a variety of adipokines. The normal function of adipose tissue is disturbed in obesity, and there is accumulating evidence to suggest that adipose tissue dysfunction plays a prominent role in the development and/or progression of insulin resistance. Obese individuals often have enlarged adipocytes with a reduced buffering capacity for lipid storage, thereby exposing other tissues to an excessive influx of lipids, leading to ectopic fat deposition and insulin resistance in situations where energy intake exceeds energy expenditure. In addition, adipose tissue blood flow is decreased in obesity. This impairment may affect lipid handling in adipose tissue and, thereby, further contribute to excessive fat storage in non-adipose tissues. On the other hand, adipose tissue hypoperfusion may induce hypoxia in this tissue. Adipose tissue hypoxia may result in disturbances in adipokine secretion and increased macrophage infiltration in adipose tissue, events that are frequently observed in obesity. In this review, it is discussed how enlarged adipocytes, an impaired blood flow through adipose tissue, adipose tissue hypoxia, adipose tissue inflammation and macrophage infiltration are interrelated and may induce insulin resistance. PMID: 18037457 [PubMed - indexed for MEDLINE] 2671. FEBS Lett. 2008 Jan 9;582(1):117-31. Epub 2007 Nov 26. TNF-alpha and adipocyte biology. Cawthorn WP(1), Sethi JK. Author information: (1)Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-alpha). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-alpha can also impact the endocrine functions of adipose tissue. Taken together, TNF-alpha contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed. PMCID: PMC4304634 PMID: 18037376 [PubMed - indexed for MEDLINE] 2672. Biomed Pharmacother. 2007 Dec;61(10):665-78. Epub 2007 Nov 1. Overweight/obesity and cancer genesis: more than a biological link. Irigaray P(1), Newby JA, Lacomme S, Belpomme D. Author information: (1)Cancer Research Center, Association for Research and Treatments Against Cancer (ARTAC), 57-59 rue de la Convention, F-75015 Paris, France. philippei.artac@gmail.com The classical view according to which overweight/obesity is related to cancer considers adipose tissue as an active and metabolic "organ", acting through endocrine, autocrine and paracrine processes. Consequently, it has been hypothesized, that genesis and progression of cancer may be caused by different biological factors acting through diverse mechanisms including changes in the synthesis and bioavailability of sex hormones, insulin resistance, release of growth factors and/or proinflammatory cytokines and abnormal energetic disposal and expenditure. We have shown that overweight/obesity can be experimentally induced by benzo[a]pyrene, a universal well characterized chemical pollutant and that overweight/obesity may in fact be caused by several types of chemical pollutants. In this paper we propose that in addition to the above hypothetical biological mechanisms, adipose tissue acts as a reservoir for lipophilic, liposoluble environmental carcinogens, so that chemical pollution may in fact generate both overweight/obesity and cancer. More precisely, we propose that many carcinogens, be they mutagens or promotors can be stored in the adipose tissue, be released at convenient dose in the blood circulation and therefore target peripheral tissues to induce carcinogenesis. Such carcinogens mainly include organochlorine pesticides and PCBs. Their association with an increased risk of cancer seems to be demonstrated for breast and prostate carcinoma, as well as for lymphoma, not only in obese patients, but also in normal weight or even leaner patients suggesting that the adipose tissue may act as a reservoir for environmental carcinogens in obese as well as in non-obese patients. PMID: 18035514 [PubMed - indexed for MEDLINE] 2673. J Neuroendocrinol. 2008 Feb;20(2):269-77. Epub 2007 Nov 22. Leptin resistance during pregnancy in the rat. Ladyman SR(1). Author information: (1)Centre for Studies in Behavioural Neurobiology, Concordia University, Montreal, Quebec, Canada. sladyman@alcor.concordia.ca The adipose-derived hormone leptin primarily acts in the hypothalamus to decrease appetite and increase energy expenditure, thereby maintaining body fat levels around a set point. Pregnancy is a physiological state where this feedback mechanism is not beneficial. Successful reproductive efforts are highly demanding on the resources of the mother; thus, it is imperative that the maternal body can increase energy stores without restraint. Food intake, fat mass and serum leptin concentrations increase during pregnancy in the rat, suggesting that the feedback loop between adipose tissue and appetite is disrupted and a state of leptin resistance exists. In support of this, there is an attenuation of the satiety response to exogenous leptin administration in pregnant rats. This state of leptin resistance is associated with impaired activation of the leptin-induced Janus activating kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway in the ventromedial nucleus of the hypothalamus (VMH) and arcuate nucleus, and reduced expression of leptin receptor mRNA in the VMH. Furthermore, pregnant rats do not show a satiety response to exogenous alpha-melanocyte stimulating hormone. This model offers the possibility of examining how hypothalamic leptin signalling can be modified in response to changes in physiological conditions. PMID: 18034869 [PubMed - indexed for MEDLINE] 2674. Am J Dermatopathol. 2007 Dec;29(6):568-72. Congenital hamartoma of the scalp with meningothelial, sebaceus, muscular, and immature glandular components. Ferran M(1), Tribó MJ, González-Rivero MA, Alameda F, Pujol RM. Author information: (1)Department of Dermatology, Hospital del Mar-IMAS, Barcelona, Spain. mferran@imas.imim.es A 4-month-old boy presented with a congenital, solitary, yellowish-red, eroded tumor on the scalp, histologically characterized by an ectopic proliferation of vascular and meningothelial elements intimately admixed with mature connective-tissue elements, adipose tissue, and smooth-muscular fibers. In addition, the presence of characteristic histopathological features of a nevus sebaceus and areas with immature glandular differentiation were observed. The diagnosis of a congenital hamartoma of the scalp with meningothelial, sebaceus, immature glandular, and muscular components was established. We review the heterogeneous group of cutaneous lesions with meningothelial elements and their pathogenesis. PMID: 18032955 [PubMed - indexed for MEDLINE] 2675. Pharmacol Res. 2007 Dec;56(6):459-67. Epub 2007 Sep 22. Adiponectin circulating levels: a new emerging biomarker of cardiovascular risk. Giannessi D(1), Maltinti M, Del Ry S. Author information: (1)CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy. danielag@ifc.cnr.it Fat is now considered as an endocrine organ that produces a lot of molecules having biological activity, called adipocytokines. Among these, adiponectin, a 247 amino acid protein produced abundantly and specifically by adipose tissue, besides its effects on glucose metabolism, plays important protective function against cardiovascular diseases. Circulating levels lower than those of healthy control subjects have found to be associated to conditions such as obesity, diabetes and cardiovascular diseases. In animal experimental models, administration of adiponectin has been shown to have beneficial effects against the development of obesity-related vascular diseases, including atherosclerosis. In humans, circulating levels can be raised by life style modification (weight loss or exercise training) or pharmacological treatments. Adiponectin is present in the human plasma in different isoforms: a large multimeric structure of high molecular weight and in a trimer and examer form, whereas the monomeric form is found only in the adipose tissue. The biological activities of the different multimers are not yet fully known, although the different isoforms appear to have different functional importance following the different diseases. This paper reports the main biological features of adiponectin in order to highlight its possible role as diagnostic/prognostic marker in cardiovascular diseases. Particular attention is paid to practical considerations relative to the analytical determination of this protein in humans. PMID: 18029194 [PubMed - indexed for MEDLINE] 2676. Expert Opin Ther Targets. 2007 Nov;11(11):1503-20. Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes. Pascual G(1), Ricote M, Hevener AL. Author information: (1)University of California, Department of Cellular Molecular Medicine, La Jolla, San Diego, California 92093, USA. The peroxisome proliferator activated receptor gamma is a member of the nuclear receptor superfamily of ligand-dependent transcription factors and is the molecular target of antidiabetic thiazolidinediones that exert insulin sensitizing effects in adipose tissue, skeletal muscle and the liver. In addition to the well described effects of peroxisome proliferator activated receptor gamma in insulin target tissues, it is now apparent that its expression in macrophages is critical in the regulation of macrophage phenotype, whole body glucose metabolism and in mediating, in part, the antidiabetic actions of thiazolidinediones. As macrophages are major contributors to tissue inflammation and are resident in tissues responsible for maintaining glucose homeostasis, the therapeutic potential of these cells in the treatment of Type 2 diabetes is of significant clinical interest. PMID: 18028013 [PubMed - indexed for MEDLINE] 2677. Perit Dial Int. 2007 Jun;27 Suppl 2:S298-302. Adipokines and gut hormones in end-stage renal disease. Mak RH(1), Cheung W. Author information: (1)Division of Pediatric Nephrology, Oregon Health and Science University, Portland, Oregon, USA. romak@ucsd.edu Cachexia is common in end-stage renal disease (ESRD) patients, and it is an important risk factor for poor quality of life and increased mortality and morbidity. Chronic inflammation is an important cause of cachexia in ESRD patients. In the present review, we examine recent evidence suggesting that adipokines or adipocytokines such as leptin, adiponectin, resistin, tumor necrosis factor alpha, interleukin-6, and interleukin-1beta may play important roles in uremic cachexia. We also review the physiology and the potential roles of gut hormones, including ghrelin, peptide YY, and cholecystokinin in ESRD. Understanding the molecular pathophysiology of these novel hormones in ESRD may lead to novel therapeutic strategies. PMID: 17556323 [PubMed - indexed for MEDLINE] 2678. FEBS Lett. 2008 Jan 9;582(1):90-6. Epub 2007 Nov 20. The lipin protein family: dual roles in lipid biosynthesis and gene expression. Reue K(1), Zhang P. Author information: (1)Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States. reuek@ucla.edu The prevalence of obesity in the western world has focused attention on factors that influence triglyceride biosynthesis, storage, and utilization. Members of the lipin protein family have a newly discovered enzymatic role in triglyceride and phospholipid biosynthesis as a phosphatidate phosphatase, and also act as an inducible transcriptional coactivator in conjunction with peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha and PPAR alpha. Through these activities, the founding member of the family, lipin-1, influences lipid metabolism and glucose homeostasis in diverse tissues including adipose tissue, skeletal muscle, and liver. The physiological roles of lipin-2 and lipin-3 are less well defined, but are likely to carry out similar functions in glycerolipid biosynthesis and gene expression in a distinct tissue distribution. PMCID: PMC2848953 PMID: 18023282 [PubMed - indexed for MEDLINE] 2679. Trends Cardiovasc Med. 2007 Nov;17(8):275-83. The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Gualillo O(1), González-Juanatey JR, Lago F. Author information: (1)Research Laboratory 4 (Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain. Interest in the biology of white adipose tissue has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases and spurred the identification of numerous other adipokines, many of a proinflammatory nature. It has become increasingly evident that white adipose tissue-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome, inflammation, and cardiovascular diseases. Here we review recent adipokine research, with particular attention to the roles of adiponectin, leptin, resistin, visfatin, apelin, omentin, and chemerin in such conditions. PMID: 18021938 [PubMed - indexed for MEDLINE] 2680. Clin Chem Lab Med. 2008;46(1):43-56. The entero-insular axis: implications for human metabolism. Ranganath LR(1). Author information: (1)Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK. lrang@liv.ac.uk Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are intestinal hormones that are released in response to ingestion of nutrients, especially carbohydrate. They have a number of important biological effects, which include release of insulin, inhibition of glucagon and somatostatin, maintenance of beta-cell mass, delay of gastric emptying, and inhibition of feeding. These properties allow them to be potentially suitable agents for the treatment of type 2 diabetes (T2D). Incretin receptors are also present in other parts of the body including the brain, where their effects are beginning to be understood and their relevance to disorders of nutrition and ageing are being explored. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of T2D. There is increasing evidence that current treatments do not address the issue of progressive beta-cell failure in T2D. As obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D. Incretin metabolism is abnormal in T2D, evidenced by a decreased incretin effect, reduction in nutrient-mediated secretion of GIP and GLP-1 in T2D, and resistance to GIP. GLP-1, on the other hand, when administered intravenously in T2D is able to increase insulin secretion and improve glucose homeostasis. As GLP-1 has a very short half-life, due to rapid degradation by the enzyme dipeptidyl peptidase IV (DPPIV), analogues of GIP and GLP-1 that are resistant to the action of DPPIV have been developed and clinical trials have shown their effectiveness. Another novel agent, naturally resistant to DPPIV that is given by subcutaneous injection is a synthetic peptide called exenatide, has recently been approved for treatment of T2D in the USA. Efforts are underway to develop agents that can be given orally and include a DPPIV inhibitor that has been licensed for the treatment of T2D in the USA, and several other agents are undergoing clinical trials. Strategies to augment the biological actions of GIP and/or GLP-1 in T2D are expected to minimise weight gain, reduce hypoglycaemic episodes and prevent progressive beta-cell failure by increasing beta-cell mass. The optimal agent(s) that may mimic and replace the endogenous incretin effect is not fully known and awaits the outcome of clinical trials that are still ongoing. The potential therapeutic role in non-diabetic states, including obesity and neurodegenerative disease, is intriguing and depends upon results from ongoing research. PMID: 18020966 [PubMed - indexed for MEDLINE] 2681. Ann Behav Med. 2007 Nov-Dec;34(3):240-52. Are psychological characteristics related to risk of the metabolic syndrome? A review of the literature. Goldbacher EM(1), Matthews KA. Author information: (1)Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. BACKGROUND: We evaluate the evidence that depression, anger, hostility, and anxiety are related to risk for the metabolic syndrome, focusing as well on its components of central adiposity and insulin resistance. In addition, we identify possible moderators of these associations and summarize plausible underlying biobehavioral pathways. METHODS: Medline, PsycINFO, PubMed, and Web of Science searches were conducted using the keywords metabolic syndrome, syndrome x, central adiposity/obesity, visceral adiposity/obesity, body fat distribution, waist circumference, waist hip ratio, insulin resistance/sensitivity, glucose tolerance, psychological, depression, hostility, anger, cynicism, and anxiety. RESULTS: The current literature provides cross-sectional evidence for an association between psychological characteristics and the metabolic syndrome. Prospective data, though limited, suggest that depression, hostility, and anger predict increased risk for the metabolic syndrome. Data on modifiers are too limited to permit definitive conclusions. Negative health behaviors and hypothalamic and sympathetic dysregulation are identified as plausible underlying pathways. CONCLUSIONS: More prospective studies, conducted with diverse samples, are needed to delineate the direction of this relationship and the proposed biobehavioral mechanisms; experimental investigations are needed to test for causality. Nevertheless, findings suggest that psychological characteristics, especially depression, hostility, and anger, may increase risk for the metabolic syndrome, providing a novel direction for prevention and treatment interventions. PMID: 18020934 [PubMed - indexed for MEDLINE] 2682. Br J Nutr. 2007 Oct;98 Suppl 1:S121-6. Altered signalling and gene expression associated with the immune system and the inflammatory response in obesity. Gil A(1), María Aguilera C, Gil-Campos M, Cañete R. Author information: (1)Institute of Nutrition and Food Technology, Department of Biochemistry and Molecular Biology, University of Granada, Granada, Spain. agil@ugr.es White adipose tissue functions not only as an energy store but also as an important endocrine organ and is involved in the regulation of many pathological processes. The obese state is characterised by a low-grade systemic inflammation, mainly a result of increased adipocyte as well as fat resident- and recruited-macrophage activity. In the past few years, various products of adipose tissue including adipokines and cytokines have been characterised and a number of pathways linking adipose tissue metabolism with the immune system have been identified. In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signalling pathways mainly involve the nuclear factor kappa B (NF-kappaB) and the Jun N-terminal kinase (JNK) systems as well as the I kappa B kinase beta (IKK-beta). Mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinase (ERK) pathways, which lead to signal transducer and activator of transcription 3 (STAT3) activation, are also important in the production of pro-inflammatory cytokines. Obesity increases the expression of leptin and other cytokines, as well as some macrophage and inflammatory markers, and decreases adiponectin expression in adipose tissue. A number of cytokines, e.g. tumour necrosis factor alpha (TNF-alpha) and monocyte chemotactic protein 1 (MCP-1), and some pro-inflammatory interleukins, leuckocyte antigens, chemochines, surface adhesion molecules and metalloproteases are up-regulated whereas other factors are down-regulated. The present paper will focus on the molecular mechanisms linking obesity and inflammation with emphasis on the alteration of signalling and gene expression in adipose cell components. PMID: 17922949 [PubMed - indexed for MEDLINE] 2683. Public Health Nutr. 2007 Oct;10(10A):1181-6. Conjugated linoleic acid (CLA) and obesity. Silveira MB(1), Carraro R, Monereo S, Tébar J. Author information: (1)Servicio de Endocrinología y Nutrición, Hospital Universitario de La Princesa, Diego de León, 62. 28006 Madrid, Spain. belensilveira@telefonica.net BACKGROUND: The term conjugated linoleic acid (CLA) refers to several positional and geometric conjugated dienoic isomers of linoleic acid (LA), of which the trans-10,cis-12 isomer has been reported to reduce adiposity and increase lean mass in mice and other animals when included at desacyl ghrelin = insulin > or = DXM. Additionally, desacyl ghrelin was able to enhance medium glucose consumption by mature adipocytes in culture. These data strongly support that adipogenesis and adipocyte function are processes directly and positively modulated by ghrelin gene-derived peptides, thus further indicating that, besides their effects on food intake, ghrelin gene-derived peptides could play an important role on adiposity for maintaining homeostasis. PMID: 17983857 [PubMed - indexed for MEDLINE] 2704. Vitam Horm. 2008;77:121-48. Appetite and metabolic effects of ghrelin and cannabinoids: involvement of AMP-activated protein kinase. van Thuijl H(1), Kola B, Korbonits M. Author information: (1)Department of Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK. Obesity is one of the most important health threats to the Western world, and the physiology of appetite-regulating hormones has become a major interest in the last decades. One of the orexigenic hormones, ghrelin is the stomach-derived "brain-gut" peptide, which stimulates energy consumption and storage. Ghrelin promotes gluconeogenesis and adipose tissue deposition. Endocannabinoids, such as anandamide and 2-arachydoglycerol, are lipid-like neurotransmitter molecules activating the cannabinoid receptors. Endocannabinoids, apart from the well-known psychological effects, cause an increase in appetite, and they peripherally promote de novo fatty acid synthesis and gluconeogenesis. Adenosine monophosphate-activated protein kinase (AMPK) is an energy-sensing kinase, which responds to changes in the energy levels of the cell and the whole body in order to maintain adequate ATP levels in the cell. Recently, several hormones have been shown to regulate AMPK activity, and interestingly in a strictly tissue-specific manner. Orexigenic agents such as ghrelin and cannabinoids stimulate hypothalamic AMPK leading to increase in appetite while inhibiting AMPK activity in the liver and adipose tissue, therefore leading to lipogenic and diabetogenic effects. Here we summarize the recent data on hormonal AMPK regulation. PMID: 17983855 [PubMed - indexed for MEDLINE] 2705. Therapie. 2007 Jul-Aug;62(4):285-92. Epub 2007 Nov 6. [Obesity, inflammation and insulin resistance: which role for adipokines]. [Article in French] Antuna-Puente B(1), Feve B, Fellahi S, Bastard JP. Author information: (1)INSERM U680, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, Paris 6, Paris, France. Adipose tissue is now recognized as an endocrine organ involved in regulating physiologic and pathologic processes including inflammation. It synthesizes and secretes hormones such as leptin and adiponectin. It can secrete other products namely adipokines including cytokines and chemokines. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic sub-inflammatory state that likely plays a major role in cardiovascular complications linked to obesity and insulin resistance. PMID: 17983554 [PubMed - indexed for MEDLINE] 2706. Clin Obstet Gynecol. 2007 Dec;50(4):980-9. Etiology, detection, and management of fetal macrosomia in pregnancies complicated by diabetes mellitus. Sacks DA(1). Author information: (1)Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Kaiser Foundation Hospital, Bellflower, California 90706, USA. david.a.sacks@kp.org. Babies of mothers who have diabetes are more likely than babies of nondiabetic women to be large for gestational age. A greater proportion of their birth weight consists of fat mass, much of which is distributed to the trunk and abdomen. The maternal and fetal consequences of diabetic fetopathy, theories and evidence of how it develops, and management considerations relative to excessive growth of the fetus of a diabetic woman are explored in this chapter. PMID: 17982341 [PubMed - indexed for MEDLINE] 2707. Br Med Bull. 2007;84:49-68. Epub 2007 Nov 2. HIV and HIV treatment: effects on fats, glucose and lipids. Gkrania-Klotsas E(1), Klotsas AE. Author information: (1)Department of Infectious diseases, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Box 25, Hills Road, Cambridge CB22QQ, UK. eg318@cam.ac.uk BACKGROUND: Since the advent of effective antiretroviral therapy, infection with the human immunodeficiency virus has been transformed, in the Western world, to a chronic disease associated with a variety of metabolic complications. Aims This review provides a brief summary of our current understanding of the epidemiology, clinical presentation and therapeutic approaches of what is termed 'the HIV-associated lipodystrophy syndrome' and of HIV-associated lipid and glucose metabolic abnormalities. Other metabolic associations including lactic acidosis, HIV-associated bone disease and the effect of the virus on other endocrine pathways are outside the scope of this article. METHODS: A bibliographic search was performed using Entrez Pubmed, edition 2.0, by the National Library of Medicine for articles only in the English language using Boolean operators and the terms 'HIV, HAART, lipodystrophy, lipoatrophy, lipohypertrophy, hyperlipidemia, diabetes and metabolism, cost of illness'. The Program and Abstract Books of the 8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (September 24-26, 2006, San Francisco, USA), the 4th International AIDS Society Conference on HIV Pathogenesis (July 22-25, 2007, Sydney, Australia) and the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (September 17-20, Chicago, USA) were searched for relative abstracts. Previous publications were used to identify further references. Approximately 1400 articles and abstracts were identified of which 104 were selected for review. RESULTS: Specific medications and medication classes increase the lipoatrophy and lipodystrophy risk. A change of treatment strategy might be beneficial in improving adipose tissue deposition. The effects of HIV on metabolism offer new insights into cardiovascular disease pathogenesis. PMID: 17981955 [PubMed - indexed for MEDLINE] 2708. Br J Nutr. 2008 May;99(5):931-40. Epub 2007 Nov 1. Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins. Power ML(1), Schulkin J. Author information: (1)Research Department, American College of Obstetricians and Gynecologists, Washington DC 20024, USA. mpower@acog.org Human beings are susceptible to sustained weight gain in the modern environment. Although both men and women can get fat, they get fat in different ways, and suffer different consequences. We review differences between men and women in the incidence of obesity, fat deposition patterns, fat metabolism, and the health consequences of obesity, and examine potential evolutionary explanations for these differences. Women generally have a larger proportion of body mass as fat, and are more likely to deposit fat subcutaneously and on their lower extremities; men are more likely to deposit fat in the abdominal region. Excess adipose tissue in the abdominal region, especially visceral fat, is associated with more health risks. Women have higher rates of reuptake of NEFA into adipose tissue; however, they also have higher rates of fat oxidation during prolonged exercise. Oestrogen appears to underlie many of these differences. Women bear higher nutrient costs during reproduction. Fat and fertility are linked in women, through leptin. Low leptin levels reduce fertility. Ovarian function of adult women is associated with their fatness at birth. In our evolutionary past food insecurity was a frequent occurrence. Women would have benefited from an increased ability to store fat in easily metabolisable depots. We suggest that the pattern of central obesity, more commonly seen in men, is not adaptive, but rather reflects the genetic drift hypothesis of human susceptibility to obesity. Female obesity, with excess adiposity in the lower extremities, reflects an exaggeration of an adaptation for female reproductive success. PMID: 17977473 [PubMed - indexed for MEDLINE] 2709. J Sex Med. 2008 Apr;5(4):765-76. Epub 2007 Oct 30. Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females. Gooren LJ(1), Giltay EJ. Author information: (1)Department of Endocrinology, Andrology Unit, VU University Medical Center, Amsterdam, The Netherlands. ljgooren@truemail.co.th INTRODUCTION: Testosterone supplementation in ovariectomized or elderly women may improve their sense of well-being and libido, muscle mass and strength, and bone mineral density. Naturally, androgens may have virilizing effects in women. It is often believed that androgens have deleterious effects on cardiovascular risks. AIM: To obtain an inventory of the effects of administration of testosterone on female biological functions. METHODS: We reviewed here our publications on the effects of high-dose androgen administration to female-to-male transsexuals treated between 1975 and 2004 (N = 712). Annual accrual was at a steady rate of 22-30 persons. Dosages administered were far above those suited for women. MAIN OUTCOME MEASURES: There was special focus on the potential negative effects on cardiovascular risk markers. RESULTS: The standard treatment was administration of testosterone esters, 250 mg/2-3 weeks, parenterally). With this dose, virilizing effects on the skin and clitoris were prominent. Spatial ability improved, while verbal fluency deteriorated. The ovaries developed polycystic characteristics. Adequate dosages of testosterone preserved bone mass in females. Androgens increased kallikreins, such as prostate-specific antigen, in female reproductive tissues. High-dose testosterone administration appeared to increase weight, visceral fat, and hematocrit, decrease high-density lipoprotein cholesterol, increase endothelin-1, increase C-reactive protein, and increase total homocysteine. But blood pressure, insulin sensitivity, fibrinolytic markers, arterial stiffness, and levels of von Willebrand factor, fibrinogen, and interleukin-6 remained largely unchanged. CONCLUSIONS: Our studies demonstrated that, while some markers of cardiovascular risk factors showed a shift to a more negative risk profile, others were not affected. Androgen effects on cardiovascular risk markers are therefore not universally negative, and it is reasonable to assume that the latter effects will not be negative with the much lower doses suited for administration to women. PMID: 17971101 [PubMed - indexed for MEDLINE] 2710. Nutr Hosp. 2007 Sep-Oct;22(5):511-27. [Inflammatory biomarkers: the link between obesity and associated pathologies]. [Article in Spanish] Zulet MA(1), Puchau B, Navarro C, Martí A, Martínez JA. Author information: (1)Departamento de Ciencias de la Alimentación, Fisiología y Toxicología, Universidad de Navarra, Pamplona, España. THE OBJECTIVE: [corrected] of this article is to review biomarkers that have been suggested in recent years as the link between inflammation, obesity and associated co-morbidities, as well as some questions that yet remain unclear. Increasing evidence indicates the important role of inflammation in the etiology of major public health problems. In the last years, several studies have proposed that obesity might be a inflammatory disorder. In addition, oxidative stress has been suggested as a potential inductor of inflammatory status and susceptibility to obesity and related disorders. Several biomarkers are being suggested as the link between obesity, insulin resistance, cardiovascular disease and metabolic syndrome, such as tumor necrosis factor alfa, interleukin-6 and -18, angiotensinogen, transforming grow factor beta, plasminogen activator inhibitor-1, leptin, resistin, C-reactive protein, serum amyloid A, sialic acid, fibrinogen, markers of endothelial dysfunction (von Willebrand factor, ICAMs, VCAMs), complement factor 3, haptoglobin, Zinc-alpha2-glycoprotein, eotaxin, visfatin, apelin, alpha1-antitrypsin, vaspin, omentin, retinol binding protein 4, ceruloplasmin, adiponectin and desnutrin. Some of this biomarkers are good predictors of cardiovascular risk (plasminogen activator inhibitor-1, sialic acid, fribrinogen, complement factor 3, C-reactive protein), adiposity (leptin, visfatin, resistin, haptoglobin) and/or insulin resistance (sialic acid, C-reactive protein, plasminogen activator inhibitor-1, von Willebrand factor). However, it is currently unclear the role of many of them concerning inflammatory processes in humans, as well as the factors involved in their regulation. PMID: 17970534 [PubMed - indexed for MEDLINE] 2711. Vasc Health Risk Manag. 2007;3(4):511-20. The burden of type 2 diabetes: strategies to prevent or delay onset. Iqbal N(1). Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania, Philadelphia VA Medical Center, PA, USA. nayyar.iqbal2@med.va.gov Type 2 diabetes is widespread and its prevalence is increasing rapidly. In the US alone, approximately 41 million individuals have prediabetes, placing them at high risk for the development of diabetes. The pathogenesis of type 2 diabetes involves inadequate insulin secretion and resistance to the action of insulin. Suggestive data link insulin resistance and accompanying hyperglycemia to an excess of abdominal adipose tissue, a link that appears to be mediated partially by adipocyte secretion of multiple adipokines that mediate inflammation, thrombosis, atherogenesis, hypertension, and insulin resistance. The adipokine adiponectin has reduced expression in obesity and appears to be protective against the development of type 2 diabetes. Current recommendations to prevent type 2 diabetes center on lifestyle modifications, such as diet and exercise. Clinical trials have established the efficacy of lifestyle intervention, as well as pharmacologic interventions that target glycemic control or fat metabolism. However, diabetes did develop in a substantial percentage of individuals who received intensive intervention in these trials. Thus there is an unmet need for additional strategies in high-risk individuals. Recent data suggest thiazolidinediones and blockade of the endocannabinoid system represent novel therapeutic approaches that may be used for the prevention of diabetes. PMCID: PMC2291325 PMID: 17969381 [PubMed - indexed for MEDLINE] 2712. J Anim Sci. 2008 Apr;86(14 Suppl):E226-35. Epub 2007 Oct 26. Application of cellular mechanisms to growth and development of food producing animals. Chung KY(1), Johnson BJ. Author information: (1)Department of Animal Sciences and Industry, Kansas State University, Manhattan, Kansas 66506, USA. Retraction in Reynolds LP. J Anim Sci. 2008 Jul;86(7):1724. Postnatal skeletal muscle growth is a result of hypertrophy of existing skeletal muscle fibers in food producing animals. Accumulation of additional nuclei, as a source of DNA, to the multinucleated skeletal muscle fiber aids in fiber hypertrophy during periods of rapid skeletal muscle growth. Muscle satellite cells are recognized as the source of nuclei to support muscle hypertrophy. Exogenous growth-enhancing compounds have been used to modulate growth rate and efficiency in meat animals for over a half century. In cattle, these compounds enhance efficiency of growth by preferentially stimulating skeletal muscle growth compared with adipose tissue. There are 2 main classes of compounds approved for use in cattle in the United States, anabolic steroids and beta-adrenergic agonists (beta-AA). Administration of both trenbolone acetate and estradiol-17beta, as implants, increased carcass protein accumulation 8 to 10% in yearling steers. Muscle satellite cells isolated from steers implanted with trenbolone acetate/ estradiol-17beta had a shorter lag phase in culture compared with satellite cells isolated from control steers. Collectively, these data indicate that activation, increased proliferation, and subsequent fusion of satellite cells in muscles of implanted cattle may be an important mechanism by which anabolic steroids enhance muscle hypertrophy. Oral administration of beta-AA to ruminants does not alter DNA accumulation in skeletal muscle over a typical feeding period (28 to 42 d). Enhanced muscle hypertrophy observed due to beta-AA feeding occurs by direct, receptor-mediated changes in protein synthesis and degradation rates of skeletal muscle tissue. Proper timing of anabolic steroid administration when coupled with beta-AA feeding could result in a synergistic response in skeletal muscle growth due to the effects of anabolic steroids at increasing satellite cell activity, which then can support the rapid hypertrophic changes of the muscle fiber when exposed to beta-AA. At the same time each of these classes of compounds are stimulating lean tissue deposition, they appear to repress adipogenesis in meat animals. Increased knowledge of the mechanism by which growth promoters regulate lean tissue deposition and adipogenesis in meat animals will allow for effective application of these techniques to optimize lean tissue growth and minimize the negative effects on meat quality. PMID: 17965330 [PubMed - indexed for MEDLINE] 2713. Nutr J. 2007 Oct 26;6:32. Measurement and definitions of obesity in childhood and adolescence: a field guide for the uninitiated. Sweeting HN(1). Author information: (1)MRC Social and Public Health Sciences Unit, 4, Lilybank Gardens, Glasgow, G12 8RZ, UK. helen@sphsu.mrc.ac.uk This paper aims to guide readers embarking on the complex literature in respect of childhood and adolescent obesity. It opens with a discussion of definitions of 'obesity' based on overall fat levels and the significance of fat distribution. This is followed by simple descriptions of the various techniques used to measure fat, including density-based, scanning, bioelectrical impedance and anthropometric methods. The paper then turns to 'overweight' and the measurement of weight in relation to height, particularly via body mass index (BMI). While it is a relatively simple measure and a valuable tool, BMI has several disadvantages, which are described. These include a lack of consensus on which values should be used to define 'overweight' or 'obese', with the result that the literature contains a confusing multiplicity of child and adolescent obesity rates. PMCID: PMC2164947 PMID: 17963490 [PubMed - indexed for MEDLINE] 2714. Cell. 2007 Oct 19;131(2):242-56. Developmental origin of fat: tracking obesity to its source. Gesta S(1), Tseng YH, Kahn CR. Author information: (1)Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Erratum in Cell. 2008 Oct 17;135(2):366. The development of obesity not only depends on the balance between food intake and caloric utilization but also on the balance between white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specialized for energy expenditure. In addition, some sites of white fat storage in the body are more closely linked than others to the metabolic complications of obesity, such as diabetes. In this Review, we consider how the developmental origins of fat contribute to its physiological, cellular, and molecular heterogeneity and explore how these factors may play a role in the growing epidemic of obesity. PMID: 17956727 [PubMed - indexed for MEDLINE] 2715. Obes Rev. 2008 Jan;9(1):20-9. Epub 2007 Oct 23. The role of interleukin-6 in insulin resistance, body fat distribution and energy balance. Hoene M(1), Weigert C. Author information: (1)Department of Internal Medicine, Division of Endocrinology, Metabolism, Nephrology, Angiology, Pathobiochemistry and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany. Interleukin-6 (IL-6) is a central player in the regulation of inflammation, haematopoiesis, immune response and host defense mechanisms. During the last decade, an accumulating amount of data suggested a pivotal role for IL-6 in metabolic processes, thus fortifying the picture of IL-6 as a multifaceted, pleiotropic cytokine. Because of its secretion by adipose tissue and contracting skeletal muscle and its broad action on central and peripheral organs, IL-6 has been termed an adipokine and a myokine. Its quantitative release from adipose tissue results in a subclinical, systemic elevation of IL-6 plasma levels with increasing body fat content, which may be implicated in the proinflammatory state leading to insulin resistance. On the other hand, IL-6 produced in the working muscle during physical activity could act as an energy sensor by activating AMP-activated kinase and enhancing glucose disposal, lipolysis and fat oxidation. In addition, both impaired IL-6 secretion and action are risk factors for weight gain. Thus, IL-6 clearly has lipolytic effects and anti-obesity potential. However, the application of IL-6 itself is at least limited by a narrow therapeutic range and its important function for a balanced inflammatory response. Further studies on the molecular basis of the metabolic effects of IL-6 could elucidate novel therapeutic strategies for custom-designed, IL-6-related substances. PMID: 17956545 [PubMed - indexed for MEDLINE] 2716. Cell Mol Life Sci. 2007 Dec;64(24):3248-60. Mammary stem cells and breast cancer. Molyneux G(1), Regan J, Smalley MJ. Author information: (1)The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK. The mammary gland undergoes major developmental changes during puberty and pregnancy. It is thought that stem cells drive mammary gland development during puberty and are responsible for tissue maintenance as well as the major growth and remodelling that occurs with every pregnancy. The use of sophisticated cell separation procedures has facilitated the prospective isolation of mammary epithelial stem and differentiated cell subpopulations from the mouse mammary gland, while studies of primary human breast cancers have described sub-populations of tumourigenic cells capable of initiating tumour growth in immuno-compromised mice. These potential tumour 'stem cells' constitute an important therapeutic target population with respect to cancer therapy, as these are likely to be the cells which maintain tumour growth. Understanding the origin of these cells, their relationship to breast cancer subtypes, and how and why they differ from normal breast stem cells will lead to a revolution in tumour understanding, treatment and prevention. (Part of a Multi-author Review). PMID: 17955177 [PubMed - indexed for MEDLINE] 2717. Nihon Rinsho. 2007 Sep 28;Suppl 5 Pt 2:7-11. [Metabolic syndrome]. [Article in Japanese] Hanada H(1), Okumura K. Author information: (1)Division of Cardiology, Hirosaki University Graduate School of Medicine. PMID: 17952966 [PubMed - indexed for MEDLINE] 2718. Horm Metab Res. 2007 Oct;39(10):739-42. Adipose tissue: a key target for diabetes pathophysiology and treatment? Frayn KN(1), Tan GD, Karpe F. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. keith.frayn@oxlip.ox.ac.uk Excess adipose tissue brings with it a number of adverse consequences, many of which may stem from the development of insulin resistance. An emerging view is that inflammatory changes occurring in expanding adipose tissue are associated with the secretion of peptide and other factors that can adversely affect metabolic processes in other key insulin-target tissues, especially liver and skeletal muscle. However, there is still a commonly-expressed view that the adverse changes in other tissues are ultimately due to an excess of fatty acids, liberated by a metabolically-challenged adipose tissue. Our own studies of adipose tissue metabolism and physiological function (especially blood flow) IN VIVO suggest that these two views of adipose tissue function may be closely linked. Enlarged adipocytes are less dynamic in their responses, just as 'enlarged adipose tissue' is less dynamic in blood flow regulation. Adipocytes seem to be able to sense the appropriate level of fat storage. If the normal mechanisms regulating adipocyte fat storage are interfered with (either in genetically-modified animals or by increasing the size of the adipocytes), then perhaps some sort of cellular stress sets in, leading to the inflammatory and endocrine changes. Some evidence for this comes from the effects of the thiazolidinediones, which improve adipose tissue function and in parallel reduce inflammatory changes. PMID: 17952837 [PubMed - indexed for MEDLINE] 2719. Horm Metab Res. 2007 Oct;39(10):734-8. Adipose tissue and diabetes therapy: do we hit the target? Pfeiffer AF(1). Author information: (1)German Institute of Human Nutrition, Department of Clinical Nutrition - Potsdam Rehbrücke and Charité University Medicine, Berlin, Germany. AFHP@dife.de Factors derived from adipose tissue are believed to play a central role in the development and progression of diabetes and its vascular complications. Insulin resistance and vascular function are directly affected these factors, i.e., by free fatty acids, inflammatory adipocytokines, thrombotic and antifibrinolytic factors and by adiponectin, and adipokine with insulin sensitizing and anti-inflammatory actions. Targeting these factors by antidiabetic agents should result in improved metabolism and in a reduction of vascular risk. We therefore analyzed antidiabetic treatment strategies with regard to improvements of adipose tissue derived risk factors. This shows that weight loss remains an extremely powerful tool to reduce all of these risk factors. Thiazolidinediones and rimonabant are most potent in improving numerous adipose derived risk factors but studies demonstrating reduced mortality are not yet available. Metformin has little effect on any of the adipose tissue derived factors but appears to reduce diabetes related mortality according to limited evidence. Sulfonylureas and insulin have rather limited effects on adipose tissue derived factors and are likely to exert beneficial effects mainly by improved glucose metabolism and its consequences. PMID: 17952836 [PubMed - indexed for MEDLINE] 2720. Horm Metab Res. 2007 Oct;39(10):730-3. The role of the lymphoid system in the regulation of the blood glucose level. Newsholme EA(1), Dimitriadis G. Author information: (1)Merton College, Oxford, UK. Recent findings have led to a new hypothesis in which it is proposed that the immune system plays a role in regulating the increase in blood glucose levels after a meal. The relevant findings are: (1) the primary lymphoid tissue, the lymph nodes are mostly present within adipose tissue depots throughout the body (there are at least 12 such depots and about 10 (12) lymphocytes, 99% of which are present in lymph nodes); (2) lymphocytes and other immune cells utilize glucose at a high rate but almost all of it is converted to lactate which accumulates in the cells prior to release; (3) glutamine, some of which is synthesized in muscle from glucose, is utilized at a high rate by immune cells, the end-product of which is mainly aspartate, which also accumulates in the cells prior to release; and (4) finally, there is a common blood supply to the lymph node and the adipose tissue depot and the blood flow through the depot and hence the node is increased after a meal. It is proposed that, after a meal, some of the absorbed glucose is taken up from the blood by the lymphocytes and converted to lactate and glutamine is converted to aspartate. These are released slowly into the blood from where they are removed and converted to glycogen by the liver. Hence the immune cells provide a temporary buffer for glucose in the form of lactate and aspartate and, in this way, restrict the rise in blood glucose during and after a meal. PMID: 17952835 [PubMed - indexed for MEDLINE] 2721. Horm Metab Res. 2007 Oct;39(10):726-9. Contribution of triglyceride-rich lipoproteins to plasma free fatty acids. Miles JM(1), Nelson RH. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. miles.john@mayo.edu Free fatty acids are the major lipid fuel of the body. Dysregulation of adipose tissue lipolysis results in increased plasma free fatty acid concentrations, and via that mechanism contributes to insulin resistance in obesity and type 2 diabetes mellitus. Adipose tissue hormone sensitive lipase is thought to be responsible for the production of the majority of free fatty acids. However, a separate contribution comes from the action of endothelial lipases, especially lipoprotein lipase, on triglyceride-rich lipoproteins via a process known as spillover. The primary substrate for spillover appears to be chylomicrons derived from dietary fat. The spillover of fatty acids into the free fatty acid pool varies from one tissue to another. For example, spillover is low ( approximately 14%) in the forearm of healthy volunteers, suggesting that triglyceride fatty acid storage is relatively efficient in skeletal muscle. In contrast, spillover appears to be higher in adipose tissue and may also be higher in the splanchnic bed, based on preliminary data. If systemic spillover is increased in insulin resistant states such as diabetes, this could represent a mechanism contributing to the abnormal increases in plasma concentrations of free fatty acids in that condition. PMID: 17952834 [PubMed - indexed for MEDLINE] 2722. Horm Metab Res. 2007 Oct;39(10):722-5. Adipose tissue metabolism -- an aspect we should not neglect? Jensen MD(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, M55905, USA. jensen.michael@mayo.edu Free fatty acids (FFAs) are the most metabolically important products of adipose tissue lipolysis. Experimentally creating high FFA concentrations can reproduce the metabolic abnormalities of obesity in lean, healthy persons and lowering FFA concentrations can improve the metabolic health of upper body obese individuals. FFA concentrations are determined by both the release of FFAs into the bloodstream and the clearance of FFAs from the bloodstream. Normal FFA release rates are different in men and women and total FFA release is closely linked to resting energy expenditure. Upper body subcutaneous fat, visceral fat, and leg fat depots contribute differently to the exposure of various tissues to FFAs. The implications of regional adipose tissue lipolysis to systemic FFA availability and the effect of different approaches to treatment of obesity are discussed. PMID: 17952833 [PubMed - indexed for MEDLINE] 2723. Horm Metab Res. 2007 Oct;39(10):717-21. Tissue-specific alterations of glucose transport and molecular mechanisms of intertissue communication in obesity and type 2 diabetes. Graham TE(1), Kahn BB. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Insulin resistance plays a major role in the pathogenesis of type 2 diabetes. Insulin regulates blood glucose levels primarily by promoting glucose uptake from the blood into multiple tissues and by suppressing glucose production from the liver. The glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in muscle and adipose tissue. Decreased GLUT4 expression in adipose tissue is a common feature of many insulin resistant states. GLUT4 expression is preserved in skeletal muscle in many insulin resistant states. However, functional defects in the intracellular trafficking and plasma membrane translocation of GLUT4 result in impaired insulin-stimulated glucose uptake in muscle. Tissue-specific genetic knockout of GLUT4 expression in adipose tissue or muscle of mice has provided new insights into the pathogenesis of insulin resistance. We recently determined that the expression of serum retinol binding protein (RBP4) is induced in adipose tissue as a consequence of decreased GLUT4 expression. We found that RBP4 is elevated in the serum of insulin resistant humans and mice. Furthermore, we found that increasing serum RBP4 levels by transgenic overexpression or by injection of purified RBP4 protein into normal mice causes insulin resistance. Therefore, RBP4 appears to play an important role in mediating adipose tissue communication with other insulin target tissues in insulin resistant states. PMID: 17952832 [PubMed - indexed for MEDLINE] 2724. Horm Metab Res. 2007 Oct;39(10):710-6. Resistin- and Obesity-associated metabolic diseases. Lazar MA(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6149, USA. lazar@mail.med.upenn.edu The link between obesity and diabetes is strong as well as complex. Fat cells produce many circulating regulators of insulin sensitivity, including pro-inflammatory cytokines. In rodents, resistin is produced by adipose tissue, and is a significant regulator of glucose metabolism and insulin sensitivity. In humans, resistin is derived made mainly from macrophages. Given the emerging interrelationship between inflammation and metabolic disease, hyperresistinemia may be a biomarker, and/or a mediator, of metabolic and inflammatory diseases in humans as well as in rodents. PMID: 17952831 [PubMed - indexed for MEDLINE] 2725. Obes Rev. 2007 Nov;8(6):525-30. Oscillations in total body fat content through life: an evolutionary perspective. Zafon C(1). Author information: (1)Division of Endocrinology, Hospital General i Universitari Vall d'Hebron, Barcelona, Spain. 26276czl@comb.es Adipose tissue is considered an efficient system in which to store energy. Throughout life, the total amount of body fat exhibits some oscillations. Typically, there are three specific periods in which there are notable increases in fat mass, specifically early in life, during pregnancy and lactation, and with ageing. The existence of the first two peaks in fat mass has been interpreted, from an evolutionary point of view, as a beneficial manoeuvre to protect against the scarcity of energy to the offspring of the species. Nevertheless, the role of increasing body fat with ageing is more dubious. However, recent evidence suggests that the gain in adiposity in senescence may also be interpreted in the same evolutionary context. The aim of this review is to focus on the age-related changes in fat depots. In addition, an evolutionary explanation to the observed changes has been emphasized. PMID: 17949356 [PubMed - indexed for MEDLINE] 2726. Nihon Rinsho. 2007 Sep 28;Suppl 5 Pt 2:382-6. [Deposition of subepicardial fat]. [Article in Japanese] Iwasaka T(1), Koito H, Nishiue T, Miyasaka Y, Haiden M. Author information: (1)Second Department of Internal Medicine, Division of Cardiovascular Center, Kansai Medical University. PMID: 17948714 [PubMed - indexed for MEDLINE] 2727. Clin Cornerstone. 2007;8 Suppl 6:S6-13. Treatment of dyslipidemia to reduce cardiovascular risk in patients with multiple risk factors. Ballantyne CM(1). Author information: (1)Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Section of Atherosclerosis and Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. cmb@bcm.tmc.edu Individuals with metabolic syndrome typically have atherogenic dyslipidemia, characterized by increased concentrations of triglycerides, reduced concentrations of high-density lipoprotein cholesterol, and increased concentrations of small dense low-density lipoprotein particles. Statins have been shown to improve atherogenic dyslipidemia in patients with metabolic syndrome in a number of studies. Fibrates and niacin have also been shown to be effective therapy in these patients. Post hoc analyses suggest that lipid-regulating therapy reduces cardiovascular risk in patients with metabolic syndrome. Other approaches to the treatment of atherogenic dyslipidemia in these patients include targeting insulin resistance and adipose tissue. Agents such as the peroxisome proliferator-activated receptor-gamma agonist pioglitazone and the CB1 receptor antagonist rimonabant improve insulin resistance as well as atherogenic dyslipidemia. Weight loss has also been shown to improve risk factors associated with metabolic syndrome. PMID: 17948362 [PubMed - indexed for MEDLINE] 2728. J Steroid Biochem Mol Biol. 2008 Feb;108(3-5):272-80. Epub 2007 Sep 7. Androgens and body fat distribution. Blouin K(1), Boivin A, Tchernof A. Author information: (1)Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, 2705 Laurier Boulevard T3-67, Québec, Que, Canada. An important sex difference in body fat distribution is generally observed. Men are usually characterized by the android type of obesity, with accumulation of fat in the abdominal region, whereas women often display the gynoid type of obesity, with a greater proportion of their body fat in the gluteal-femoral region. Accordingly, the amount of fat located inside the abdominal cavity (intra-abdominal or visceral adipose tissue) is twice as high in men compared to women. This sex difference has been shown to explain a major portion of the differing metabolic profiles and cardiovascular disease risk in men and women. Association studies have shown that circulating androgens are negatively associated with intra-abdominal fat accumulation in men, which explains an important portion of the link between low androgens and features of the metabolic syndrome. In women, the low circulating sex hormone-binding globulin (SHBG) levels found in abdominal obesity may indirectly indicate that elevated free androgens are related to increased visceral fat accumulation. However, data on non SHBG-bound and total androgens are not unanimous and difficult to interpret for total androgens. These studies focusing on plasma levels of sex hormones indirectly suggest that androgens may alter adipose tissue mass in a depot-specific manner. This could occur through site-specific modulation of preadipocyte proliferation and/or differentiation as well as lipid synthesis and/or lipolysis in mature adipocytes. Recent results on the effects of androgens in cultured adipocytes and adipose tissue have been inconsistent, but may indicate decreased adipogenesis and increased lipolysis upon androgen treatment. Finally, adipose tissue has been shown to express several steroidogenic and steroid-inactivating enzymes. Their mere presence in fat indirectly supports the notion of a highly complex enzymatic system modulating steroid action on a local basis. Recent data obtained in both men and women suggest that enzymes from the aldoketoreductase 1C family are very active and may be important modulators of androgen action in adipose tissue. PMID: 17945484 [PubMed - indexed for MEDLINE] 2729. Rev Cardiovasc Med. 2007;8 Suppl 4:S3-8. The progression of cardiovascular risk to cardiovascular disease. Rosin BL(1). Author information: (1)Department of Cardiology, Torrance Memorial Medical Center, Torrance, California, USA. A cluster of risk factors associated with obesity defines the metabolic syndrome and identifies cardiometabolic risk. Accumulation of fat in the visceral depot is a more reliable predictor of cardiovascular disease than is total body mass or body mass index. The recent discovery of the endocannabinoid-CB1 receptor system and its impact on the regulation of energy metabolism represents a significant advance that will help target visceral fat and its metabolic implications. As a highly active endocrine organ, visceral fat secretes many bioactive molecules, known as adipokines. Dysregulation of these adipokines contributes to the pathogenesis of the obesity-associated metabolic syndrome, resulting in insulin resistance, type 2 diabetes, hypertension, hyperlipidemia, and vascular disease. Even modest weight reduction leads to reduced cardiometabolic risk by affecting the individual components comprising the metabolic syndrome. PMID: 17934392 [PubMed - indexed for MEDLINE] 2730. Rev Cardiovasc Med. 2007;8 Suppl 4:S17-24. Unmet needs in controlling metabolic disease. Haffner SM(1). Author information: (1)Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio, Texas, USA. In the past 10 years, there has been interest in a "metabolic syndrome" that might be associated with cardiovascular disease or diabetes. The first sets of criteria differed markedly, and their accuracy was equivocal. More recent definitions may be an improvement over previous ones. The metabolic syndrome may be most useful as a predictor of cardiovascular disease in nondiabetic subjects. It encourages healthcare providers who are confronted with a single risk factor to look for others. When multiple risk factors are found, it promotes consideration of behavioral interventions, such as weight loss and increased physical activity, instead of a pharmacological treatment for each risk factor. Such behavioral interventions were more effective than metformin in reducing the incidence of diabetes and of other components of the metabolic syndrome in one randomized, controlled study. PMID: 17934390 [PubMed - indexed for MEDLINE] 2731. Sheng Li Xue Bao. 2007 Oct 25;59(5):614-8. [Effect of AMP-activated protein kinase on cardiovascular protection of adiponectin]. [Article in Chinese] Li L(1), Wu LL. Author information: (1)Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100083, China. Adiponectin, derived mainly from white adipose tissue, regulates glucose and fatty acid metabolism and has anti-inflammatory and anti-atherosclerotic properties. The decrease in plasma adiponectin concentration contributes to the development of metabolic and cardiovascular diseases. AMP-activated protein kinase (AMPK) is a serine/threonine kinase which plays an important role in regulating many cellular processes, particularly pathways involved in cellular energy status. AMPK is now recognized as a fuel gauge in mammalian cells. Adiponectin activates AMPK phosphorylation and then promotes ATP-generating pathways in heart, including glucose transport, glycolysis, and fatty acid oxidation. The recent evidence has shown that AMPK activation has an important role in the vasculature where it may exert anti-atherosclerotic effects. Phosphorylation of AMPK induced by adiponectin inhibits protein synthesis, and may be an adaptive response to pathological cardiac hypertrophy. AMPK also has a cardioprotective role against myocardial injury and apoptosis in the ischemic heart. This review will discuss the role of AMPK in adiponectin-mediated protective properties of cardiovascular diseases. PMID: 17940701 [PubMed - indexed for MEDLINE] 2732. Curr Opin Endocrinol Diabetes Obes. 2007 Oct;14(5):359-64. Dietary lipids in early development: relevance to obesity, immune and inflammatory disorders. Innis SM(1). Author information: (1)Department of Paediatrics, Nutrition Research Program, Child and Family Research Institute, Faculty of Medicine, Vancouver, British Columbia, Canada. Sinnis@interchange.ubc.ca PURPOSE OF REVIEW: Regardless of social, cultural and behavioural environments, obesity is usually caused by an energy intake above requirements, which is accommodated by the accumulation of triacylglycerols. The composition of dietary fat impacts tissue fatty acids, which are important modulators of multiple cell functions, including differentiation, lipogenesis, lipolysis and the generation of inflammatory mediators. This review focuses on the possible contribution of fatty acids to the link between obesity and inflammation in young children. RECENT FINDINGS: Adipose tissue is a complex organ that functions to regulate fatty acid balance, clearing and releasing fatty acids, and synthesizing protein and signaling molecules that act as local and distant inflammatory mediators. Obesity, even in young children, is associated with increased circulating inflammatory mediators. As a result of changes in dietary fat compositions, infants are exposed to high n-6, saturated and trans fatty acids and low n-3 fatty acids. Saturated and trans fatty acids increase and n-3 fatty acids decrease many metabolic and inflammatory changes that accompany diet-induced triacylglycerol storage. High linoleic acid is associated with increased oxidative stress. SUMMARY: There is a biological reason to consider that dietary fatty acids may contribute to oxidative stress and heightened inflammatory responses in young children. PMID: 17940463 [PubMed - indexed for MEDLINE] 2733. J Anim Sci. 2008 Apr;86(14 Suppl):E94-104. Epub 2007 Oct 16. Insulin resistance induced by tumor necrosis factor-alpha in myocytes and brown adipocytes. Lorenzo M(1), Fernández-Veledo S, Vila-Bedmar R, Garcia-Guerra L, De Alvaro C, Nieto-Vazquez I. Author information: (1)Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain. mlorenzo@farm.ucm.es Insulin resistance is an important contributor to the pathogenesis of type 2 diabetes, and obesity is a risk factor for its development, in part because adipose tissue secretes proteins, called adipokines, that may influence insulin sensitivity. Among these molecules, tumor necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. Direct exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and brown adipocytes because of the activation of proinflammatory pathways that impair insulin signaling at the level of the insulin receptor substrate (IRS) proteins. In this regard, the Ser(307) residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase and inhibitor kB kinase being involved in the phosphorylation of this residue. Conversely, Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of mitogen-activated protein kinase was the mechanism found in brown adipocytes. Protein-Tyr phosphatase (PTP)1B acts as a physiological, negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in muscle and white adipose tissue of obese and diabetic humans and rodents. Moreover, up-regulation of PTP1B expression was recently found in cells treated with TNF-alpha Accordingly, myocytes and primary brown adipocytes deficient in PTP1B are protected against insulin resistance induced by this cytokine. Furthermore, down-regulation of PTP1B activity is possible by the use of pharmacological agonists of nuclear receptors that restore insulin sensitivity in the presence of TNF-alpha. In conclusion, the lack of PTP1B in muscle and brown adipocytes increases insulin sensitivity and glucose uptake and could confer protection against insulin resistance induced by adipokines. PMID: 17940160 [PubMed - indexed for MEDLINE] 2734. Annu Rev Physiol. 2008;70:537-56. Mechanisms of leptin action and leptin resistance. Myers MG(1), Cowley MA, Münzberg H. Author information: (1)Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. mgmyers@umich.edu The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity. PMID: 17937601 [PubMed - indexed for MEDLINE] 2735. Thyroid. 2007 Oct;17(10):1013-8. Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies. Khoo TK(1), Bahn RS. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage. PMCID: PMC3902014 PMID: 17935483 [PubMed - indexed for MEDLINE] 2736. Exp Physiol. 2008 Jan;93(1):158-63. Epub 2007 Oct 12. Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Kearney MT(1), Duncan ER, Kahn M, Wheatcroft SB. Author information: (1)Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. m.t.kearney@leeds.ac.uk Type 2 diabetes and obesity are major risk factors for the development of cardiovascular atherosclerosis. Resistance to the metabolic effects of insulin on its traditional target tissues (muscle, liver and adipose tissue) is a central pathogenic feature of these disorders. However, the role of insulin resistance in non-canonical tissues, such as the endothelium, is less clear. Several large studies support a role for insulin resistance in the development of premature cardiovascular atherosclerosis independent of type 2 diabetes and obesity. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived nitric oxide. Nitric oxide is a signalling molecule which has a portfolio of potential antiatherosclerotic effects. The presence of insulin receptors on endothelial cells is well documented, and the endothelium has now emerged as a potentially important target tissue for insulin, with insulin-stimulated production of nitric oxide a feature of the action of insulin on endothelial cells. The role of insulin resistance at the level of the endothelial cell in vascular pathophysiology is unclear. A number of studies in humans and gene-modified mice have demonstrated a close association between insulin resistance and nitric oxide bioactivity. In this review, we discuss the link between insulin resistance and endothelial cell function in humans and demonstrate the complimentary information provided by murine models of obesity and insulin resistance in our understanding of the vasculopathy associated with type 2 diabetes and obesity. PMID: 17933859 [PubMed - indexed for MEDLINE] 2737. Rocz Panstw Zakl Hig. 2007;58(2):403-15. [Polybrominated diphenyl ethers (PBDE)--new threats?]. [Article in Polish] Hernik A(1), Góralczyk K, Czaja K, Struciński P, Korcz W, Ludwicki JK. Author information: (1)Zakład Toksykologii Srodowiskowej, Państwowy Zakład Higieny, 00-791 Warszawa, ul. Chocimska 24. Polybrominated diphenyl ethers (PBDE) because of their physical and chemical properties belong to Persistent Organic Pollutants (POPs). They are stable in the environment and due to lipophilic properties, have potential impact to human health. Currently these compounds are present in all kind of environmental samples all over the world. Levels of PBDE in samples originated from U.S. are higher than levels reported from Europe and Japan, what may be linked to common use these flame retardants in this country. Environmental (including humans) concentration of PBDE have increased rapidly in the last decade. Predominant congeners detected in all matrices are BDE-47, -99, -153, -209. Recent Swedish report however noticed decrease of PBDE concentrations what can be consequence of phase-out of these compounds in this country. It has been suggested that the environmental levels of PBDE may influence human nervous and immunological system as well as they may disrupt hormonal homeostasis. Research studies suggest also that the exposure to polybrominated diphenyl ethers may be associated with increased risk of cancers. Therefore, continuation of research concerning occurrence and toxicity of PBDE has reasonable grounds. PMID: 17929587 [PubMed - indexed for MEDLINE] 2738. J Neuroendocrinol. 2007 Nov;19(11):831-8. The genetic basis for the timing of human puberty. Banerjee I(1), Clayton P. Author information: (1)Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK. Puberty is a complex, coordinated biological process with multiple levels of regulation. Epidemiological observations suggest that the timing of pubertal events is a heritable trait, although environmental factors can modulate such genetic influence. The study of pathological states of early and late puberty has provided valuable insight into those genes that regulate gonadotrophin-releasing hormone (GnRH) activity. The development of pulsatile release of GnRH secretion mediated through kisspeptin-1 activation of G-protein coupled receptor-54 appears to be a central event at the onset and during progression of puberty. Stimulating and restraining influences (e.g. in the form of glutamatergic and GABAergic neuronal inputs) are likely to influence the timing of this process. The study of extreme variants of 'normality', such as constitutional delay of growth and puberty and early puberty, may lead to the recognition of additional genes and pathways that can modulate both the timing of pubertal onset and its tempo. PMID: 17927661 [PubMed - indexed for MEDLINE] 2739. Gastroenterol Clin Biol. 2007 Aug-Sep;31(8-9 Pt 1):643-54. [Steatosis during chronic hepatitis C: the role of insulin resistance and viral factors]. [Article in French] Moucari R(1), Marcellin P, Asselah T. Author information: (1)Pôle des maladies de l'appareil digestif, Service d'hépatologie et INSERM U773 CRB3, Université Paris VII, Hôpital Beaujon, Clichy. Liver steatosis is frequent in patients with chronic hepatitis C. Two main types are described: (1) "viral steatosis" induced by the virus, especially genotype 3, which probably inhibits the "Microsomal Triglyceride Transfer Protein", thus decreasing "Very Low Density Lipoprotein" secretion and leading to triglyceride accumulation within hepatocytes; (2) "metabolic steatosis" which is a feature of the metabolic syndrome and insulin resistance, a systemic disorder associated with a high risk of cardiovascular disease and diabetes mellitus. Insulin resistance induces intrahepatic triglyceride accumulation due to excess free fatty acid flux from increased adipose tissue lipolysis as well as increased intrahepatic lipogenesis through activation of the "Sterol Response Element Binding Protein". Hepatitis C Virus itself can also be responsible for insulin resistance, possibly through impairment of the insulin signalling pathway because of increased"Tumor Necrosis Factor Alpha" levels and/or upregulated "Cytokine Signalling Suppressor" expression. Insulin resistance and steatosis, appear to be associated with fibrosis progression and impairment of sustained response to antiviral treatment. PMID: 17925761 [PubMed - indexed for MEDLINE] 2740. Int Wound J. 2007 Sep;4(3):222-31. The biomechanics of sitting-acquired pressure ulcers in patients with spinal cord injury or lesions. Gefen A(1). Author information: (1)Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel. gefen@eng.tau.ac.il Sitting-acquired pressure ulcers (SAPU) in permanent wheelchair users with traumatic or non traumatic disorders of the central nervous system (CNS) are a great medical challenge. The purpose of this review is to summarise what is currently known concerning the aetiology of SAPU, particularly in its severe form, which may now be classified as a 'deep tissue injury' according to the US National Pressure Ulcer Advisory Panel. Specifically, this review focuses on biomechanical aspects of deep SAPU and describes the relevant bioengineering methodologies and research evidence. It discusses the unique biomechanical conditions in deep tissues, which are caused by chronic sitting associated with CNS disorders, and overall, the present review indicates that avoiding interface pressures above 32 mmHg in such patients is not necessarily a 'pressure relief.' PMID: 17924879 [PubMed - indexed for MEDLINE] 2741. J Arthroplasty. 2007 Sep;22(6 Suppl 2):47-50. Epub 2007 Jul 27. The effect of retropatellar fat pad excision on patellar tendon contracture and functional outcomes after total knee arthroplasty. Meneghini RM(1), Pierson JL, Bagsby D, Berend ME, Ritter MA, Meding JB. Author information: (1)Joint Replacement Surgeons of Indiana Research Foundation; USA. Excision of the fat pad is common in total knee arthroplasty to enhance surgical exposure. However, the effect of this has not been clearly established. A retrospective review of 1055 primary total knee arthroplasties was preformed in 720 patients from 1997 to 1998. Regression analysis was performed to determine the effect of excising the fat pad on patellar tendon contracture, range of motion, Knee Society Score, function, and pain scores. Fat pad excision had no significant effect on patellar tendon contracture (P = .4599), range of motion (P = .7361), Knee Society Score (P = .7247), or function scores (P = .6786). Patients whose fat pad had been removed were nearly twice as likely to experience postoperative pain (P = .0005). PMID: 17823015 [PubMed - indexed for MEDLINE] 2742. Int J Obes (Lond). 2008 Feb;32(2):223-31. Epub 2007 Oct 9. The 'beneficial' adipokines in reproduction and fertility. Campos DB(1), Palin MF, Bordignon V, Murphy BD. Author information: (1)Faculté de Médecine Vétérinaire, Centre de Recherche en Reproduction Animale, Université de Montréal, Québec, Canada. The objective of this study was to review the available information on the signaling proteins produced by adipose tissue in the context of their role in regulating reproductive processes, including ovarian and uterine function. It is well known that both obesity and excessive leanness are associated with reproductive dysfunction. Adipokines are cytokines predominantely or exclusively expressed by adipose tissue that circulate and affect target tissues. Four known adipokines, adiponectin, visfatin/PBEF, omentin and vaspin, all increase tissue sensitivity to insulin, and are thus described as 'beneficial'. There is strong support for a role for adiponectin in the function of the ovary and placenta. There is evidence for direct effects of this adipokine on the late stages of folliculogenesis, and additive interactions of adiponectin with insulin and gonadotropins in inducing periovulatory changes in ovarian follicles. In addition, clinical and genomic studies associate hypoadiponectinemia with obesity-related reproductive disorders, including the polycystic ovarian syndrome. The roles for visfatin/PBEF, omentin and vaspin in reproduction remain to be established. The conclusion thus drawn is that the expression of insulin-sensitizing adipokines varies with adipose abundance. These adipokines have demonstrated both the potential effects on ovarian function and the possible effects on the formation of the placenta, acting through multiple mechanisms. PMID: 17923861 [PubMed - indexed for MEDLINE] 2743. Cytotherapy. 2007;9(8):717-26. Epub 2007 Oct 4. UC blood-derived mesenchymal stromal cells: an overview. Flynn A(1), Barry F, O'Brien T. Author information: (1)Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science (NCBES), National University of Ireland (NUI), Galway, Ireland. The UC is a readily available source of blood that may be used for analysis and treatment. Some authors suggest that within the UC blood (UCB) are cells with potential for differentiation down mesenchymal lineages. Isolation and characterization of these cells has been accomplished in some centers. Differentiation of these cells down multiple lineages has been documented. Surface marker expression and gene expression profiling has been performed, and mesenchymal stromal cells (MSC) from BM and adipose tissue have been compared with those derived from UCB. The use of UCB-derived stem cells has been investigated in pre-clinical studies. As this field is rapidly advancing, this review summarizes the current state of our knowledge of MSC derived from UCB. PMID: 17917891 [PubMed - indexed for MEDLINE] 2744. Cytotherapy. 2007;9(8):712-6. Epub 2007 Oct 4. Adipose-derived stem cells and chondrogenesis. Wei Y(1), Sun X, Wang W, Hu Y. Author information: (1)Institute of Orthopaedics and Traumatology, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China. Cartilage has only a very limited capacity to renew its original structure. Stem cells have been used to repair damaged cartilage, and recent studies have indicated that stem cells from adipose tissue are attractive cell sources that have the capacity of multipotentiality to differentiate into osteogenic, chondrogenic, myogenic, neurogenic and endothelial cells. Adipose-derived stem cells (ASC) have unique characteristics compared with stem cells from BM. At present, ASC have been studied to promote chondrogenesis. This review discusses the application of ASC to cartilage formation. PMID: 17917888 [PubMed - indexed for MEDLINE] 2745. Mol Nutr Food Res. 2007 Oct;51(10):1260-7. Obesity and the metabolic syndrome in Mediterranean countries: a hypothesis related to olive oil. Soriguer F(1), Rojo-Martínez G, de Fonseca FR, García-Escobar E, García Fuentes E, Olveira G. Author information: (1)Service of Endocrinology and Nutrition, Hospital Universitario Carlos Haya (Fundación Imabis), Málaga, Spain. federico.soriguer.sspa@juntadeandalucia.es In Mediterranean countries people would previously have consumed a diet with a high proportion of MUFA. Physical activity would have been intense with a low level of stress. The stearoyl-CoA desaturase (SCD1) system selected over thousands of years of this type of behavior must have adapted to a particular capacity of self regulation. Now, this pattern, called the "Mediterranean diet", has been broken and many people living by the Mediterranean consume a high quantity of calories, mainly from saturated or n-6-rich fats and the relative intake of MUFA has decreased. Simultaneously, physical activity has decreased and the pattern of stress has changed towards what is called a western lifestyle. In this new context, if people have a favorable, genetically conditioned SCD1 activity that will let them confront the new situation or else have some other compensatory mechanism, such as being keen on sport, etc, then they can prevent the appearance of some of the complications associated with the metabolic syndrome. If, on the other hand, the SCD1 pattern is genetically unfavorable for this new situation and they have a new cultural context, then they do not have the alternative compensatory mechanisms and the probability of developing the metabolic syndrome is high. PMID: 17912723 [PubMed - indexed for MEDLINE] 2746. Minerva Endocrinol. 2007 Sep;32(3):173-83. Energy expenditure: a critical determinant of energy balance with key hypothalamic controls. Richard D(1). Author information: (1)Laval Hospital Research Center and Merck Frosst/CIHR Research Chair in Obesity Chemin Sainte-Foy, Québec, Canada. denis.richard@crhl.ulaval.ca Energy stores are regulated through complex neural controls exerted on both food intake and energy expenditure. These controls are insured by interconnected neurons that produce different peptides or classic neurotransmitters, which have been regrouped into anabolic' and catabolic' systems. While the control of energy intake has been addressed in numerous investigations, that of energy expenditure has, as yet, only received a moderate interest, even though energy expenditure represents a key determinant of energy balance. In laboratory rodents, in particular, a strong regulatory control is exerted on brown adipose tissue (BAT), which represent an efficient thermogenic effector. BAT thermogenesis is governed by the sympathetic nervous system (SNS), whose activity is controlled by neurons comprised in various brain regions, which include the paraventricular hypothalamic nucleus (PVH), the arcuate nucleus (ARC) and the lateral hypothalamus (LH). Proopiomelanocortin neurons from the ARC project to the PVH and terminate in the vicinity of the melanocortin-4 receptors, which are concentrated in the descending division of the PVH, which comprise neurons controlling the SNS outflow to BAT. The LH contains neurons producing melanin-concentrating hormone or orexins, which also are important peptides in the control of energy expenditure. These neurons are not only polysynaptically connected to BAT, but also linked to brains regions controlling motivated behaviors and locomotor activity and, consequently, their role in the control of energy expenditure could go beyond BAT thermogenesis. PMID: 17912156 [PubMed - indexed for MEDLINE] 2747. Minerva Endocrinol. 2007 Sep;32(3):161-71. Adipokines in diabetes and cardiovascular diseases. Kralisch S(1), Sommer G, Deckert CM, Linke A, Bluher M, Stumvoll M, Fasshauer M. Author information: (1)Department of Internal Medicine III, University of Leipzig, Leipzig, Germany. Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed. PMID: 17912155 [PubMed - indexed for MEDLINE] 2748. Minerva Endocrinol. 2007 Sep;32(3):141-59. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Stimson RH(1), Walker BR. Author information: (1)Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. roland.stimson@ed.ac.uk Central obesity is associated with type 2 diabetes mellitus, hypertension and dyslipidaemia. This cluster of risk factors is known as the metabolic syndrome, and also occurs in people with primary glucocorticoid excess (Cushing's syndrome). Exogenous glucocorticoid use also increases the risk of cardiovascular disease. Circulating glucocorticoid concentrations are tightly controlled by the hypothalamic-pituitary-adrenal axis, however tissue glucocorticoid levels are also enhanced by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity. Although plasma glucocorticoid levels are not elevated in obesity, dysregulation of 11beta-HSD1 is observed with decreased activity in the liver and increased activity in adipose tissue. 11beta-HSD1 is highly regulated, and dietary composition may be a powerful determinant of activity. Polymorphisms in the 11beta-HSD1 gene are also associated with components of the metabolic syndrome. Inhibition of this enzyme appears to be an attractive option to treat metabolic disease. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease. Trials in humans though will be the ultimate test to determine if inhibition of 11beta-HSD1 offers a new tool in the treatment of metabolic disease. PMID: 17912154 [PubMed - indexed for MEDLINE] 2749. Minerva Endocrinol. 2007 Sep;32(3):129-40. Obesity and the polycystic ovary syndrome. Martínez-Bermejo E(1), Luque-Ramírez M, Escobar-Morreale HF. Author information: (1)Department of Endocrinology, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain. The polycystic ovary syndrome (PCOS) is a mostly hyperandrogenic disorder and is possibly the most common endocrinopathy of premenopausal women. The primary defect in PCOS appears to be an exaggerated androgen synthesis and secretion by the ovaries and the adrenal glands. In a substantial proportion of PCOS patients, the primary defect in androgen secretion is triggered by factors such as the hyperinsulinism resulting from insulin resistance and/or the secretion of metabolically active substances by visceral adipose tissue, because these factors may facilitate androgen synthesis at the ovaries and the adrenals of predisposed women. The prevalence of obesity in PCOS patients is increased when compared to the general female population and, conversely, the prevalence of PCOS is increased in overweight and obese women when compared to their lean counterparts. Obesity exerts a major impact on the PCOS phenotype, particularly on the metabolic associations and complications of the syndrome. Among others, the presence obesity is clearly related to the infertility of PCOS, and increases the risk for the metabolic syndrome and its constellation of cardiovascular risk factors in these women. This review will summarize the pathophysiological mechanisms underlying the association of obesity and PCOS, the impact of obesity on the PCOS phenotype and on the association of PCOS with metabolic disorders and cardiovascular risk factors, and the new developments in the management of obese PCOS patients. PMID: 17912153 [PubMed - indexed for MEDLINE] 2750. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1465-78. Epub 2007 Oct 2. Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Roberge C(1), Carpentier AC, Langlois MF, Baillargeon JP, Ardilouze JL, Maheux P, Gallo-Payet N. Author information: (1)Department of Medicine, Faculty of Medicine, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC, Canada J1H 5N4. The aim of this review is to explore the dysregulation of adrenocortical secretions as a major contributor in the development of obesity and insulin resistance. Disturbance of adipose tissue physiology is one of the primary events in the development of pathologies associated with the metabolic syndrome, such as obesity and type 2 diabetes. Several studies indicate that alterations in metabolism of glucocorticoids (GC) and androgens, as well as aldosterone in excess, are involved in the emergence of metabolic syndrome. Cross talk among adipose tissue, the hypothalamo-pituitary complex, and adrenal gland activity plays a major role in the control of food intake, glucose metabolism, lipid storage, and energy balance. Perturbation of this cross talk induces alterations in the regulatory mechanisms of adrenocortical steroid synthesis, secretion, degradation, and/or recycling, at the level of the zonae glomerulosa (aldosterone), fasciculata (GC and GC metabolites), and reticularis (androgens and androgen precursors DHEA and DHEAS). As a whole, these adrenocortical perturbations contribute to the development of metabolic syndrome at both the paracrine and systemic level by favoring the physiological dysregulation of organs responsive to aldosterone, GC, and/or androgens, including adipose tissue. PMID: 17911338 [PubMed - indexed for MEDLINE] 2751. J Anim Sci. 2008 Apr;86(14 Suppl):E64-74. Epub 2007 Oct 2. Integrating the immune system with the regulation of growth and efficiency. Gabler NK(1), Spurlock ME. Author information: (1)Departments of Food Science & Human Nutrition and Animal Science, Iowa State University, Ames, IA 50011, USA. Muscle growth in meat animals is a complex process governed by integrated signals emanating from multiple endocrine and immune cells. A generalized phenomenon among meat animal industries is that animals commonly fail to meet their genetic potential for growth in commercial production settings. Recent evidence indicates that adipocytes and myofibers are equipped with functional pattern recognition receptors and are capable of responding directly to the corresponding pathogens and other receptor ligands. Thus, these cells are active participants in the innate immune response and, as such, produce a number of immune and metabolic regulators, including proinflammatory cytokines and adiponectin. Specifically, the transcription factor, nuclear factor kappa B, is activated in adipocytes and muscle cells by bacterial lipopolysaccharide and certain saturated fatty acids, which are potent agonists for the Toll-like receptor-4 pattern recognition receptor. Receptor activation results in the local production of interleukin-6 and tumor necrosis factor-alpha, and creates a local environment by which these cytokines regulate both metabolic and immunological pathways. However, adipocytes are also the predominant source of the antiinflammatory hormone, adiponectin, which suppresses the activation of nuclear factor kappa B and the production of proinflammatory cytokines. The molecular ability to recognize antigens and produce regulatory molecules strategically positions adipocytes and myofibers to regulate growth locally and to reciprocally regulate metabolism in peripheral tissues. PMID: 17911231 [PubMed - indexed for MEDLINE] 2752. Intern Emerg Med. 2007 Oct;2(3):165-76. Epub 2007 Oct 1. Adiponectin and the cardiovascular system: from risk to disease. Tarquini R(1), Lazzeri C, Laffi G, Gensini GF. Author information: (1)Internal Medicine Department, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy. rtarquini@unifi.it Adiponectin is known to play a role in fatty acid and glucose metabolism through a change in insulin sensitivity and activation of fuel oxidation by AMP-activated protein kinase. Adiponectin can be considered an important factor able to modulate the adipovascular axis which, through genomic and environmental influences, affects the cardiovascular risk milieu, from the pre-metabolic syndrome-- through the metabolic syndrome--to the overt atherosclerotic process and its clinical manifestations. Hypoadiponectinaemia can be viewed as an early sign of a complex cardiovascular risk factor predisposing to the atherosclerosis process as well as a contributing factor accelerating the progress of the atherosclerotic plaque. In addition, adiponectin per se holds a protective role thanks to its anti-inflammatory and antiatherogenic properties. The early identification of patients "at cardiovascular risk" means in the current practice to search for indexes of metabolic derangements and pro-inflammatory status (adiponectin) from adolescence and childhood. PMID: 17909707 [PubMed - indexed for MEDLINE] 2753. Br J Pharmacol. 2008 Feb;153(4):636-45. Epub 2007 Oct 1. Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Quinn CE(1), Hamilton PK, Lockhart CJ, McVeigh GE. Author information: (1)Department of Therapeutics and Pharmacology, Queen's University Belfast, Belfast, UK. cathyquinn25@hotmail.com Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured. PMCID: PMC2259217 PMID: 17906687 [PubMed - indexed for MEDLINE] 2754. Curr Opin Gastroenterol. 2007 Nov;23(6):661-6. Obesity, innate immunity and gut inflammation. Karagiannides I(1), Pothoulakis C. Author information: (1)Gastrointestinal Neuropeptide Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. PURPOSE OF REVIEW: The purpose of this review is to present recent data on how obesity-associated conditions may affect innate immunity and its role in the development of gut inflammation. RECENT FINDINGS: Here we present studies that demonstrate the participation of adipose tissue components in the generation of inflammation. More specifically, we describe increases in the release of proinflammatory cytokines during obesity as well as the expression of receptors involved in innate immune responses by adipocytes. Furthermore, we present data on the involvement of adipose tissue-specific molecules (adipokines) in the generation of an environment that is favorable for diseases with an immune cause and in some cases (leptin) directly contribute to the development of inflammatory bowel disease. Finally, we present evidence supporting a putative association between obesity and gut inflammation through the link of inflammation with angiogenesis and neovascularization and the favorable conditions created for these responses in obesity. SUMMARY: We believe that obesity-related systemic changes may create conditions that predispose to the development of gut inflammation or even worsen the progression of ongoing disease. PMID: 17906444 [PubMed - indexed for MEDLINE] 2755. Yi Chuan. 2007 Oct;29(10):1167-72. [Progress in the study on mammalian diacylgycerol acyltransgerase (DGAT) gene and its biological function]. [Article in Chinese] Wang Y(1), Xu HY, Zhu Q. Author information: (1)Animal Science and Technological College, Sichuan Agricultural University, Ya'an 625014, China. as519723614@163.com Diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is a microsomal enzyme that plays a central role in the metabolism of cellular glycerolipids. DGAT catalyzes the final step in triacylglycerol (TAG) biosynthesis by converting diacylgycerol (DAG) and fatty acyl-coenzyme A (CoA) into triacylglycero1. DGAT plays a fundamental role in the metabolism of cellular diacylglycerol and is important in higher eukaryotes for physiologic processes involving triacylglycerol metabolism such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation. Therefore, DGAT is not only an key factor for control triglycerides and fatty acids, but also may play a key modulatory role in animal fat deposition. PMID: 17905705 [PubMed - indexed for MEDLINE] 2756. Am J Med. 2007 Sep;120(9 Suppl 1):S18-24; discussion S24. Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system? Kunos G(1). Author information: (1)National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20817, USA. gkunos@mail.nih.gov Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB1) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB1 blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences. PMID: 17720356 [PubMed - indexed for MEDLINE] 2757. Am J Med. 2007 Sep;120(9 Suppl 1):S10-6; discussion S16-7. Abdominal adiposity and cardiometabolic risk: do we have all the answers? Haffner SM(1). Author information: (1)Department of Medicine and Clinical Epidemiology, University of Texas Health Science Center, San Antonio, Texas 78240, USA. haffner@uthscsa.edu Overweight and obesity, particularly abdominal adiposity, increase the risk for type 2 diabetes mellitus and cardiovascular disease (CVD). Metabolic syndrome, a constellation of risk factors that includes elevated triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure, elevated fasting glucose, and abdominal obesity, predicts the development of CVD and diabetes to an even greater degree. Excess abdominal adipose tissue is associated with insulin resistance, the precursor to type 2 diabetes, and creates an atherogenic inflammatory milieu, characterized by high levels of C-reactive protein and other inflammatory markers (e.g., fibrinogen, plasminogen activator inhibitor-1, cytokines, and adhesion molecules). High levels of these biomarkers correlate with an increased incidence of diabetes and CVD. Recent evidence suggests that patients with nonalcoholic fatty liver disease have an increased incidence of obesity, metabolic syndrome, and insulin resistance and/or type 2 diabetes. Relatively small reductions in body weight may significantly reduce abdominal adipose tissue, reduce insulin resistance, lower triglycerides and low-density lipoprotein cholesterol, reduce inflammation, and decrease overall cardiometabolic risk. PMID: 17720354 [PubMed - indexed for MEDLINE] 2758. Clin Pharmacol Ther. 2007 Nov;82(5):591-4. Epub 2007 Sep 26. Endocannabinoid system and cardiometabolic risk. Saavedra LE(1). Author information: (1)General Cardiology & Coronary Care Unit Services, CCR ASCARDIO, Barquisimeto, Venezuela. leonardosaavedra@intercable.net.ve The increasing prevalence of overweight and obesity counteracts the favorable advances of risk factor management achieved for cardiovascular disease (CVD) prevention. Obese and overweight individuals are at increased risk for CVDs and diabetes mellitus, a risk pattern called "cardiometabolic risk." There is a growing interest concerning the role of the endocannabinoid system in energy metabolism and how blockade of cannabinoid receptors (CB(1)) may optimize fat distribution, insulin sensitivity, and blood lipids to improve cardiovascular risk profile. PMID: 17898706 [PubMed - indexed for MEDLINE] 2759. Obesity (Silver Spring). 2007 Sep;15(9):2163-70. Advances and controversies in the design of obesity prevention trials. Stevens J(1), Taber DR, Murray DM, Ward DS. Author information: (1)Department of Nutrition, CB 7461, University of North Carolina, Chapel Hill, NC 27599, USA. June_Stevens@unc.edu Because randomized controlled trial designs are used more frequently to evaluate obesity prevention programs, nuances in the methodology used for this application become apparent. Areas of attention are the selection of outcome measures with high validity, attention to the description of the intervention, the use of analyses that match the sampling design, and dealing with loss to follow-up. We recommend increased use of preliminary or evidentiary research designed to develop and test intervention components and hypothesized mediators before fully powered, randomized, obesity prevention trials are attempted. Both randomized and observational designs can be used for the purpose. Attention to design issues will ultimately lead to more successful, cost-effective randomized trials, and more rapid movement toward efficacious and effective obesity prevention programs. PMID: 17890483 [PubMed - indexed for MEDLINE] 2760. Orv Hetil. 2007 Sep 30;148(39):1827-36. [The regulation of body mass and its relation to the development of obesity]. [Article in Hungarian] Juhász A(1), Katona E, Csongrádi E, Paragh G. Author information: (1)Sopron MJV Erzsébet Kórház, a DE OEC Oktató Kórháza Belgyógyászat Sopron Gyori. juhasza@sopkorh.elender.hu Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively. PMID: 17890170 [PubMed - indexed for MEDLINE] 2761. Curr HIV/AIDS Rep. 2007 Aug;4(3):126-34. The role of protease inhibitors in the pathogenesis of HIV-associated insulin resistance: cellular mechanisms and clinical implications. Noor MA(1). Author information: (1)Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 4500, Princeton, NJ 08543, USA. Mustafa.noor@verizon.net HIV-associated insulin resistance frequently presents as relative lack of peripheral adipose tissue storage associated with dyslipidemia. This review discusses explanations for the links between acute and subacute abnormalities in glucose metabolism and chronic changes in adipose tissue distribution. Specifically, the molecular mechanisms by which the HIV protease inhibitor class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. It is proposed that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiologic outcome is such that total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue where they impair insulin action. This leads to a pathologic cycle of insulin resistance, lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome. PMID: 17883998 [PubMed - indexed for MEDLINE] 2762. Curr HIV/AIDS Rep. 2007 Aug;4(3):119-25. Considering metabolic issues when initiating HIV therapy. Wohl DA(1). Author information: (1)The University of North Carolina, 130 Mason Farm Road, Chapel Hill, NC 27599, USA. wohl@med.unc.edu Patients with HIV infection and their clinicians are increasingly considering the risk of metabolic complications when choosing HIV therapies. Fear of the potential metabolic consequences of antiretroviral agents may lead some to delay HIV therapy and threaten medication adherence once treatment is initiated. Until recently, there has been limited objective study of the relative contributions of specific antiretrovirals and particular combinations of these drugs to dyslipidemia and body fat changes; in lieu of data, unsupported perceptions regarding the links between therapies and these metabolic complications have predominated. Over the past year, a number of comparative clinical trials have clarified the association between exposure to antiretrovirals and lipid and fat disorders and, in some cases, have yielded results that challenge our perceptions regarding the causes of these complications. PMID: 17883997 [PubMed - indexed for MEDLINE] 2763. Klin Med (Mosk). 2007;85(7):20-7. [The role of the fat tissue and its hormones in the mechanisms of insulin resistance and the development of type 2 diabetes mellitus]. [Article in Russian] Klebanova EM, Balabolkin MI, Kreminskaia VM. The fact that fat issue is an endocrine gland secreting several hormones participating in the pathogenesis of type 2 diabetes mellitus (DM2) is universally recognized. Fat issue secretes leptin, tumor necrosis factor alpha, resistin, adiponectin, interleukin-6, free fatty acids, visfatin, omentin, perilipin, and other substances that influence the condition of insulinoresistance, one of the main factors responsible for DM2. Subcutaneous fat and visceral depot fat tissue differ in the spectrum of hormones they produce; the list of these hormones is presented in the article. The presence of abdominal or visceral obesity is combined with significant insulinoresistance, which, in its turn, increases the risk of vascular complications of diabetes. The article also cover the participation of other mechanisms - insulin secretion defect, oxidation stress, low secretion of glucagon-like peptide 1, apoptosis, an increased quantity of amyloid and the fl-cell pull in the pancreatic island--in DM2 pathogenesis. The authors present data on the secretion of leptin, resistin, adiponectin, and tumor necrosis factor a, as well as the condition of the functional activity of beta-cells and the degree of insulinoresistance in 30 DM2 patients receiving dietotherapy. PMID: 17882804 [PubMed - indexed for MEDLINE] 2764. J Med Invest. 2007 Aug;54(3-4):385-8. Research on the nutritional characteristics of medium-chain fatty acids. Aoyama T(1), Nosaka N, Kasai M. Author information: (1)Central Research Laboratory, The Nisshin OilliO Group, Ltd., Kanagawa, Japan. Medium-chain fatty acids (MCFA) have attracted attention as part of a healthy diet, because they are absorbed and transported directly into the liver via the portal vein, metabolized rapidly by beta-oxidation, and increase diet-induced thermogenesis. Because medium-chain triacylglycerols (MCT) containing only MCFA has a few weak points as frying oils, we have developed medium- and long-chain triacylglycerols (MLCT). MLCT is produced by lipase-catalyzed enzymatic transesterification. Recently, long-term clinical trials have demonstrated that MLCT and MCT result in less body fat-deposition. MLCT oil (Trade name: Healthy Resseta) is safe and can be substitute for common edible vegetable oils. Healthy Resseta has been approved as FOSHU (Food for Specified Health Use), by the Ministry of Health, Labour and Welfare of Japan in December 2002 for use as a cooking oil with a suppressing effect on body fat accumulation. Healthy Resseta is widely sold in Japan. PMID: 17878693 [PubMed - indexed for MEDLINE] 2765. Curr Atheroscler Rep. 2007 Aug;9(2):134-8. Obesity and inflammation: a new look at an old problem. Mehta S(1), Farmer JA. Author information: (1)Section of Cardiology, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Room 525 D, Houston, TX 77030, USA. Obesity is a highly prevalent disease with multiple implications for cardiovascular morbidity and mortality. The traditional view of obesity is that excessive adipose tissue represents a passive storage depot of excess energy. However, obesity has been demonstrated to be a highly active endocrine organ with multiple metabolic pathways that interact with classic cardiac risk factors. The role of inflammation in atherosclerosis has been clarified by the ready availability of a variety of markers, including C-reactive protein, adiponectin, tumor necrosis factor-alpha, hemostatic markers, resistin, and a variety of emerging markers such as interleukins and adhesion molecules. Adipose tissue has been demonstrated to be the site of synthesis of a variety of proteins that are intimately involved in the regulation of inflammation. The concept that obesity represents an inflammatory state has gained credence over the past decade and has provided insights into the mechanisms of atherosclerosis and risk factor interaction. PMID: 17877922 [PubMed - indexed for MEDLINE] 2766. J Intern Med. 2007 Oct;262(4):431-8. Tumour necrosis factor-alpha in human adipose tissue -- from signalling mechanisms to clinical implications. Rydén M(1), Arner P. Author information: (1)Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden. mikael.ryden@ki.se From its initial implication in the development of cachexia in the early 1980s, it is now almost 15 years ago that tumour necrosis factor-alpha (TNF-alpha) was first shown to be involved in the development of insulin resistance in obesity. Since the original findings in mice, a wealth of data has been obtained in a variety of settings and species. This intensive research has demonstrated both similarities and differences between rodents and humans regarding the molecular mechanisms and metabolic consequences of TNF-alpha overexpression. This review will focus on the role of TNF-alpha in human white adipose tissue with particular emphasis on its regulation of lipolysis - an important pathway in adipocytes which is linked to insulin-resistant phenotypes in obesity and the metabolic syndrome. PMID: 17875179 [PubMed - indexed for MEDLINE] 2767. J Intern Med. 2007 Oct;262(4):422-30. Regulation of inflammation-related genes in human adipose tissue. Clement K(1), Langin D. Author information: (1)Inserm, U872 Nutriomique, Paris, France. karine.clement@htd.ap-hop-paris.fr The identification of a moderate increase in circulating inflammatory factors in obese subjects, the description of changes in inflammatory gene expression in adipose tissue (AT) and the discovery that macrophage cells infiltrate AT are observations contributing to the concept that human obesity is a chronic inflammatory illness. This concept has led to some revision of the physiopathology of obesity and of its related metabolic and cardiovascular co-morbidities. Low-grade inflammation in the AT and the subsequent production of specific biomarkers could actually link expanded fat mass to obesity complications. This review aims at providing an overview of the current knowledge brought up by human gene expression studies, notably those performed on a large scale in AT depots. The regulation of specific biomarkers related to inflammation and putative new candidates (i.e. cathepsins and serum amyloid A) is discussed in the context of weight loss programmes based on calorie restriction and physical exercise. The foreseen clinical and technological challenges are also summarized. PMID: 17875178 [PubMed - indexed for MEDLINE] 2768. J Intern Med. 2007 Oct;262(4):415-21. The role of endothelial cells in inflamed adipose tissue. Sengenès C(1), Miranville A, Lolmède K, Curat CA, Bouloumié A. Author information: (1)Inserm, Equipe Avenir, Unité de Recherches sur les Obésités, Toulouse, France. In recent years, the general concept has emerged that chronic low-grade inflammation can be the condition linking excessive development of adipose tissue (AT) and obesity-associated pathologies such as type II diabetes and atherosclerosis. Moreover, the evidence that the growth of the fat mass was associated with an accumulation of adipose tissue macrophages (ATM) has raised the hypothesis that the development of an inflammatory process within the growing fat mass is a primary event involved in the genesis of systemic metabolic and vascular alterations. As ATM originate from the bone marrow/blood compartment, enhanced macrophage recruitment to growing AT is suspected. However, the mechanisms responsible for attracting the blood cells and their entry into the fat mass remain to be clearly defined. The present review highlights the key role of endothelial cells in the control of the inflammatory process and describes the potential involvement of AT-endothelial cells as well as the factors involved in the regulation of their phenotype in the 'inflamed fat tissue'. PMID: 17875177 [PubMed - indexed for MEDLINE] 2769. J Intern Med. 2007 Oct;262(4):408-14. Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. Ferrante AW Jr(1). Author information: (1)Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA. awf7@columbia.edu Obesity induces an inflammation state that is implicated in many clinically important complications, including insulin resistance, diabetes, atherosclerosis and non-alcoholic fatty liver disease. Although the cause and the molecular participants in this process remain incompletely defined, adipose tissue has a central role. Obesity-induced production of pro-inflammatory molecules, typified by TNF-alpha was recognized more than a dozen years ago, and since then more than two dozen other pro-inflammatory molecules induced by obesity have been identified. More recently a critical role for immune cells, specifically mononuclear phagocytes, in generating the obesity-induced inflammation has been identified. Defining the molecular and cellular components of obesity-induced inflammation offers the potential of identifying therapeutic targets that can ameliorate the complications associated with obesity. PMID: 17875176 [PubMed - indexed for MEDLINE] 2770. Semin Nephrol. 2007 Sep;27(5):529-37. The association of aldosterone with obesity-related hypertension and the metabolic syndrome. Vogt B(1), Bochud M, Burnier M. Author information: (1)Department of Medecine, Service of Nephrology and Hypertension, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. bruno.vogt@chuv.ch Overweight and obesity are associated with arterial hypertension. Given the large increase in the obesity prevalence worldwide, the number of obese patients with hypertension is likely to increase substantially in the near future. Overweight and obese patients are exposed to an important metabolic and cardiovascular risk. The understanding of the mechanisms linking obesity to hypertension is important for specific prevention and therapy in this population. There is some evidence that obesity is associated with an increased aldosterone level. To date, 2 mechanisms may explain the interaction of fat tissue with the renin-angiotensin-aldosterone system, and therefore explain, in part, obesity-related hypertension. First, human adipose tissue produces several components of the renin-angiotensin-aldosterone system, mainly adipose tissue-derived angiotensinogen. Second, increased fatty acid production in the obese patient, especially nonesterified fatty acids, might stimulate aldosterone production, independent of renin. A better understanding of these mechanisms might have implications for the management of hypertension in overweight and obese patients. Because aldosterone also is associated with blood glucose and blood lipids, selective aldosterone blockade may represent a particularly attractive therapeutic strategy in obese patients with a clustering of cardiovascular risk factors. PMID: 17868790 [PubMed - indexed for MEDLINE] 2771. Nutr Rev. 2007 Aug;65(8 Pt 2):S124-6. Do body fat and exercise modulate vitamin D status? Looker AC(1). Author information: (1)National Center for Health Statistics Centers for Disease Control and Prevention, 3311 Toledo Road, Room 4310, Hyattsville, MD 20782, USA. acl1@cdc.gov PMID: 17867388 [PubMed - indexed for MEDLINE] 2772. Trends Endocrinol Metab. 2007 Oct;18(8):291-9. Epub 2007 Sep 12. Adipose stress-sensing kinases: linking obesity to malfunction. Rudich A(1), Kanety H, Bashan N. Author information: (1)Department of Clinical Biochemistry Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84103 Israel. Obesity has been proposed to inflict a variety of stresses on adipose tissue, including inflammatory, metabolic, oxidative and endoplasmic reticulum stress. Through the activation of 'stress-sensing pathways', metabolic and endocrine alterations are produced, which probably contribute to the co-morbidities associated with obesity. Here, we review the evidence supporting the development of various obesity-related stresses and the activation of several stress-sensing pathways, specifically in adipocytes and/or adipose tissue, which manifest metabolic and endocrine dysfunction frequently in obesity. As the central role of adipose tissue in regulating whole-body metabolism is elucidated, understanding adipose tissue stress-sensing pathways might provide potential new therapeutic targets to attenuate obesity-related morbidity. PMID: 17855109 [PubMed - indexed for MEDLINE] 2773. Ann Med. 2007;39(7):482-94. Metabolic syndrome: clinical concept and molecular basis. Funahashi T(1), Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. tohru@imed2.med.osaka-u.ac.jp The metabolic syndrome is a cluster of insulin resistance, elevated blood pressure, and atherogenic dyslipidemia and is a common basis of cardiovascular diseases (CVD). Although the precise mechanism remains to be elucidated, a practical definition is needed. A worldwide definition that considers increased waist circumference as an essential component has been settled. Visceral fat locates upstream of the liver. Free fatty acids and glycerol derived from visceral fat reach the liver and stimulate lipoprotein synthesis and gluconeogenesis, respectively. The adipose tissue produces a variety of bioactive substances conceptualized as 'adipocytokines'. Overproduction of plasminogen activator inhibitor-1 and tumor necrosis factor- seems to relate to the thrombotic and inflammatory tendency. On the other hand, adiponectin, which has antiatherogenic and antidiabetic activities, is reduced in subjects with metabolic syndrome. In Japan, the waist circumference criterion based on visceral fat accumulation has been adopted. The concept of this syndrome has been widely publicized, and health promotion programs based on the concept have commenced in various areas of the country. Such 'Adipo-Do-It' movement is an incentive to encourage physical exercise to reduce visceral fat and is a big challenge to prevent life-style-related diseases and CVD. PMID: 17852038 [PubMed - indexed for MEDLINE] 2774. Stem Cell Rev. 2006;2(4):319-29. Epigenetic programming of mesenchymal stem cells from human adipose tissue. Boquest AC(1), Noer A, Collas P. Author information: (1)Institute of Basic Medical Sciences, Department of Biochemistry, Faculty of Medicine, University of Oslo, Blindern, 0317 Oslo, Norway. Stromal stem cells identified in various adult mesenchymal tissues (commonly called mesenchymal stem cells [MSCs]) have in past years received more attention as a result of their potential interest as replacement cells in regenerative medicine. An abundant and easily accessible source of adult human MSCs are stem cells harvested from liposuction material. Similarly to bone marrow-derived MSCs, human adipose tissue-derived stem cells (ASCs) can give rise to a variety of cell types in vitro and in vivo; however, they have a propensity to differentiate into primarily mesodermal lineages. Even so, their capacity to differentiate into nonadipogenic mesodermal pathways seems to be restricted. Emerging DNA methylation profiles at adipogenic and nonadipogenic gene promoters in freshly isolated, cultured, or differentiated ASCs aim to provide an epigenetic explanation for this restrictive differentiation potential. A review of these studies indicates that human ASCs are epigenetically marked by mosaic hypomethylation of adipogenic promoters, whereas nonadipogenic lineage-specific promoters are hypermethylated. Surprisingly, in vitro differentiation toward various pathways maintains the overall methylation profiles of undifferentiated cells, raising the hypothesis that ASCs are at least epigenetically preprogrammed for adipogenesis. Novel attempts at reprogramming the epigenome of MSCs have been initiated to enhance the differentiation capacity of these cells. PMID: 17848719 [PubMed - indexed for MEDLINE] 2775. Allergy. 2007 Oct;62(10):1205-13. The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Hersoug LG(1), Linneberg A. Author information: (1)Research Centre for Prevention and Health, Copenhagen County, Denmark. There is increasing epidemiological evidence that obesity increases the risk of asthma, atopic, and autoimmune diseases. We hypothesize that the increase in these diseases is caused, at least in part, by decreased immunological tolerance as a consequence of immunological changes induced by adipokines (e.g. leptin and adiponectin) and cytokines [e.g. interleukin 6 (IL6) and tumor necrosis factor alpha (TNFalpha)] secreted by white adipose tissue. The increasing body weight increases the levels of circulating IL6, leptin, and TNFalpha. IL6 and leptin down-regulate the activity of regulatory T-lymphocytes (Tregs). Additionally, adiponectin, which decreases with increasing obesity, down-regulates the secretion of IL10 from macrophages and adipocytes. These changes in IL6, leptin, and IL10 decrease the regulatory effect of Tregs resulting in decreased immunological tolerance to antigens. In pregnant women, these obesity-induced immunological changes might be transmitted to the fetus by epigenetic inheritance thereby increasing the risk of atopic disease. We propose that obesity results in immunological changes resulting in decreased immunological tolerance to antigens and skewing of the immune system towards a Th2 cytokine profile increasing the risk of allergy and other immune-mediated diseases. Furthermore, this hypothesis offers a unifying explanation for the observation that older siblings appear to confer protection against atopic diseases, preeclampsia, and certain autoimmune diseases. More studies are definitely needed to explore further the immunological effects of obesity and its possible effects on allergic disease. PMID: 17845592 [PubMed - indexed for MEDLINE] 2776. Diabetes Obes Metab. 2008 Sep;10(9):699-718. Epub 2007 Sep 6. Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agents. Home PD(1), Pacini G. Author information: (1)School of Clinical Medical Sciences - Diabetes, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. philip.home@newcastle.ac.uk The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity. PMID: 17825080 [PubMed - indexed for MEDLINE] 2777. Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2276-83. Epub 2007 Sep 6. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Gustafson B(1), Hammarstedt A, Andersson CX, Smith U. Author information: (1)The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. Comment in Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2275. The metabolic syndrome is associated with a dysregulated adipose tissue; in part a consequence of adipose cell enlargement and the associated infiltration of macrophages. Adipose cell enlargement leads to a proinflammatory state in the cells with reduced secretion of adiponectin and with increased secretion of several cytokines and chemokines including interleukin (IL)-6, IL-8, and MCP-1. MCP-1 has been shown to play an important role for the associated recruitment of macrophages into the adipose tissue. The increased release of cytokines leads to an impaired differentiation of the preadipocytes with reduced lipid accumulation and induction of adiponectin, thus promoting ectopic lipid storage. In particular tumor necrosis factor (TNF) alpha, but also IL-6, has been shown to induce these effects in preadipocytes and this is associated with an increased Wnt signaling maintaining the cells in an undifferentiated and proinflammatory state. The proinflammatory state in the adipose tissue also leads to a local insulin resistance including an impaired inhibitory effect of insulin on FFA release. The insulin resistance further supports the proinflammatory state because insulin, by itself, is both antilipolytic and antiinflammatory by antagonizing cytokine-induced activation of STAT signaling. PMID: 17823366 [PubMed - indexed for MEDLINE] 2778. Ophthalmology. 2007 Dec;114(12):2345-9. Epub 2007 Sep 6. Floretlike cells in in situ and prolapsed orbital fat. Ebrahimi KB(1), Ren S, Green WR. Author information: (1)Eye Pathology Laboratory, Wilmer Institute, and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-9248, USA. PURPOSE: Orbital pleomorphic lipoma has been rarely reported in the literature. Although floretlike cells are characteristic of pleomorphic lipoma, they are not pathognomonic. We reviewed cases of prolapsed orbital fat and exenteration specimens to determine the significance of presence of these cells in the diagnosis of orbital pleomorphic lipoma. DESIGN: Retrospective interventional case series with clinicopathologic correlation. PARTICIPANTS: Seventy-two specimens of 45 patients with prolapsed orbital fat and 74 exenteration specimens as controls. INTERVENTION: Histologic review of the specimens including light microscopy, Masson trichrome staining, immunostaining for S100, CD34, CD68, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, and transmission electron microscopy and review of clinical records and analysis of the data with generalized estimation equation. MAIN OUTCOME MEASURE: Evidence of histologic abnormalities in histologic specimens and clinical and demographic data. RESULTS: Floretlike cells were present in 31 of 72 (43%) specimens of prolapsed orbital fat and in 12 of 74 (16%) orbital exenterations. Fewer than 6 florets were present in twenty 40x high-power fields in 15 (48%), 6 to 10 in 9 (29%), and >10 in 7 (23%) specimens. The florets stained positive for CD34 but not for S100 or CD68. TUNEL assay revealed significant nuclear pyknosis, and transmission electron microscopy disclosed spindle-shaped cells with abundant rough endoplasmic reticulum and no basement membrane. The mean age of patients with prolapsed orbital fat with florets was 67 years (range, 52-86). Of 31 samples, 29 (94%) were from males. Of 30 samples, 29 (97%) were located in the superotemporal conjunctiva; only one was located in the lower lid. There was significant association between the presence of florets and location of the prolapsed orbital fat (P = 0.0013) and gender (P = 0.0015). CONCLUSION: Floretlike cells may be present in in situ and prolapsed orbital fat as a degenerative process. What some have called "orbital pleomorphic lipoma" is in fact only age-related orbital fat prolapse. PMID: 17822769 [PubMed - indexed for MEDLINE] 2779. Adv Drug Deliv Rev. 2007 Aug 31;59(9-10):985-1014. Epub 2007 Jul 14. Chronobiology in the endocrine system. Haus E(1). Author information: (1)Department of Laboratory Medicine and Pathology, University of Minnesota, Health Partners Medical Group, Regions Hospital, 640 Jackson Street, St. Paul, Minnesota 55101, USA. Erhard.X.Haus@Healthpartners.com Biological signaling occurs in a complex web with participation and interaction of the central nervous system, the autonomous nervous system, the endocrine glands, peripheral endocrine tissues including the intestinal tract and adipose tissue, and the immune system. All of these show an intricate time structure with rhythms and pulsatile variations in multiple frequencies. Circadian (about 24-hour) and circannual (about 1-year) rhythms are kept in step with the cyclic environmental surrounding by the timing and length of the daily light span. Rhythmicity of many endocrine variables is essential for their efficacy and, even in some instances, for the qualitative nature of their effects. Indeed, the continuous administration of certain hormones and their synthetic analogues may show substantially different effects than expected. In the design of drug-delivery systems and treatment schedules involving directly or indirectly the endocrine system, consideration of the human time organization is essential. A large amount of information on the endocrine time structure has accumulated, some of which is discussed in this review. PMID: 17804113 [PubMed - indexed for MEDLINE] 2780. J Cardiometab Syndr. 2007 Summer;2(3):183-9. The cardiometabolic syndrome and sarcopenic obesity in older persons. Dominguez LJ(1), Barbagallo M. Author information: (1)Geriatric Unit, Department of Internal Medicine, University of Palermo, Italy. The aging of the world's population is a major contributor to the growing prevalence of the cardiometabolic syndrome (CMS) because older persons are more affected by the constellation of cardiovascular risk factors that constitute the syndrome. The prevalence of CMS has been related to the increasing prevalence of obesity, which is growing progressively even among older age groups. Indeed, obesity and aging are 2 overlapping mounting public health problems. It is currently accepted that CMS predicts cardiovascular mortality and/or the development of type 2 diabetes mellitus, and this is also true in studies including older persons. CMS is further complicated by modifications in body composition and fat redistribution during aging; older adults are at higher risk for developing central obesity and sarcopenia or sarcopenic obesity, a condition characterized by an important reduction in lean body mass associated with obesity, linked to an increased production of inflammatory adipokines that may alter insulin sensitivity and muscle mass and strength. A better understanding of the pathophysiologic mechanisms of sarcopenic obesity may help to elucidate the complex relationship between CMS and mortality/morbidity in older adults. PMID: 17786082 [PubMed - indexed for MEDLINE] 2781. J Cardiometab Syndr. 2007 Summer;2(3):174-82. Hypoadiponectinemia as a marker of adipocyte dysfunction -- Part I: the biology of adiponectin. Stern N(1), Osher E, Greenman Y. Author information: (1)Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. stern@tasmc.health.gov.il Adiponectin is the most abundantly secreted adipocyte-derived peptide hormone, possessing an array of antidiabetogenic and cardiovascular protective effects. Acting through 2 distinct membrane receptors, adiponectin receptors 1 and 2 (which utilize 5'-adenosine monophosphate-activated protein kinase phosphorylation, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha as key cell signaling elements), adiponectin increases hepatic and skeletal muscle sensitivity to insulin, enhances fatty acid oxidation, suppresses monocyte-endothelial interaction, supports endothelial cell growth, lowers blood pressure, and moderates adipose tissue growth. The secretion of adiponectin can be suppressed by adipose factors, which are turned on once fat cell mass increases, such as cytokines, adipose renin-angiotensin system, and increased oxidative stress. Inhibition of adiponectin secretion results in the loss of an array of mechanisms, which under normal conditions of fat cell homeostasis provide protection from insulin resistance, diabetes, and atherosclerosis. PMID: 17786081 [PubMed - indexed for MEDLINE] 2782. J Bone Miner Res. 2008 Jan;23(1):17-29. Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. Zhao LJ(1), Jiang H, Papasian CJ, Maulik D, Drees B, Hamilton J, Deng HW. Author information: (1)Department of Orthopedic Surgery, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA. It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years. PMCID: PMC2663586 PMID: 17784844 [PubMed - indexed for MEDLINE] 2783. J Am Osteopath Assoc. 2007 Apr;107(4 Suppl 2):S12-20. The endocannabinoid system as a novel approach for managing obesity. Lillo JL(1). Author information: (1)Midwestern University/Arizona College of Osteopathic Medicine in Glendale, USA. jlillo3@cox.net The recent discovery of the endocannabinoid system has led to the development of promising treatments for patients with obesity and associated cardiometabolic risk factors. Basic research has demonstrated that the endocannabinoid system plays an integral role in the regulation of food intake, metabolism, and storage. Research with the endocannabinoid receptor antagonist rimonabant has demonstrated statistically significant improvements in body weight, fasting insulin levels, glucose tolerance, high-density lipoprotein cholesterol levels, serum triglyceride levels, and waist circumference, compared with placebo. Rimonabant has also produced statistically significant improvements in inflammatory markers. Research with rimonabant has demonstrated sustained efficacy for as long as 2 years when used in conjunction with a reduced-calorie diet and moderate physical activity. Rimonabant is the first cannabinoid receptor 1 antagonist to be marketed in Europe and the first to file an New Drug Application in the United States. It may provide a novel therapeutic strategy for the treatment of patients with obesity and associated cardiometabolic risk factors. PMID: 17784530 [PubMed - indexed for MEDLINE] 2784. J Am Osteopath Assoc. 2007 Apr;107(4 Suppl 2):S4-11. Challenges and strategies in managing cardiometabolic risk. Repas TB(1). Author information: (1)Department of Medicine, University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792-3284, USA. tb.repas@hosp.wisc.edu The obesity epidemic is associated with numerous health-related sequelae, including alterations in glucose metabolism, dyslipidemia, and hypertension. These conditions, in turn, are associated with an increased incidence of type 2 diabetes mellitus and cardiovascular disease, which ultimately leads to increased morbidity and mortality. Abdominal obesity, in particular, has been identified as a key risk factor. Accordingly, therapeutic lifestyle change remains the cornerstone of treatment for patients with obesity. Therapeutic lifestyle change is effective; even moderate weight loss leads to clinical improvements. However, lifestyle change is often challenging to implement, and pharmacologic therapies may become necessary. Available pharmacologic and surgical treatment modalities for patients with obesity are fraught with challenges of their own, including poor patient adherence and presence of adverse events. The author outlines available modes of treatment and their consequences for patients with obesity. PMID: 17784529 [PubMed - indexed for MEDLINE] 2785. Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2284-91. Epub 2007 Aug 30. Links between adipose tissue and thrombosis in the mouse. Bodary PF(1). Author information: (1)Department of Nutrition and Food Science, College of Liberal Arts and Sciences, Wayne State University, Detroit, Mich, USA. pfbodary@wayne.edu Obesity has become a global epidemic and carries a considerable negative impact in regard to quality of life and life expectancy. A primary problem is that obese individuals are at increased risk of suffering from cardiovascular disease complications such as myocardial infarction and stroke. Because fat accumulation is a consistent aspect of obesity, mechanisms that may link adipose tissue to cardiovascular disease complications should be considered. Proteins expressed from adipose tissue, known as adipokines, are hypothesized to have important effects on the progression and incidence of cardiovascular disease complications. This review examines the evidence that adipokines play a direct role in vascular thrombosis, an important event in cardiovascular disease complications. PMID: 17761944 [PubMed - indexed for MEDLINE] 2786. Diabet Med. 2007 Sep;24(9):934-45. The importance of free fatty acids in the development of Type 2 diabetes. Wilding JP(1). Author information: (1)Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK. j.p.h.wilding@liv.ac.uk The recent increase in the prevalence of obesity has been associated with a coincident rise in the prevalence of Type 2 diabetes, whereas weight loss has been shown to decrease the risk of Type 2 diabetes. The pathophysiological mechanisms that have been proposed to explain this link are fundamentally concerned with insulin resistance and the decline in pancreatic B-cell function that accompanies an increase in visceral obesity. They involve the rise in the plasma concentrations of free fatty acids (FFAs) that are associated with an increase in fat mass. Elevated levels of FFAs can lead to insulin resistance, and evidence is growing that B-cell function is impaired through lipotoxicity. Factors such as tumour necrosis factor-alpha (TNF-alpha) and adiponectin, released from adipose tissue, can also modulate insulin resistance. Many interventions that are helpful in treating or preventing Type 2 diabetes, such as weight loss and certain pharmacological interventions, reduce circulating FFA concentrations to a greater or lesser extent. Recent study results suggest that peroxisome proliferator-activated receptor (PPAR)gamma agonists have an effect on the development of Type 2 diabetes. However, in light of concerns over the apparent increase in congestive heart failure with PPARgamma agonists, their place in the prevention of Type 2 diabetes remains to be determined. PMID: 17725706 [PubMed - indexed for MEDLINE] 2787. Hormones (Athens). 2007 Jul-Sep;6(3):210-7. Early onset adiposity: a pathway to polycystic ovary syndrome in adolescents? Diamanti-Kandarakis E(1), Christakou CD, Kandaraki E, Alexandraki KI. Author information: (1)First Department of Medicine, Endocrine Section, Athens University School of Medicine, Athens, Greece. akandara@otenet.gr Polycystic Ovary Syndrome is a heterogenous syndrome of unknown causation commonly associated with obesity. The particular timing of the onset of obesity may be important, since the earlier the onset of obesity the greater the severity of the metabolic and hormonal aberrations. Early postnatal life and peripubertal periods may be critical windows for the development of the "adiposity insult". The interaction of adiposity with genetic traits as well as with prenatal environmental factors may further aggravate the metabolic and endocrine abnormalities, which become more pronounced in adolescence. PMID: 17724005 [PubMed - indexed for MEDLINE] 2788. Morfologiia. 2007;131(3):7-15. [Using stromal stem cells for the periodontal tissue regeneration and their interaction with tissue microenvironment]. [Article in Russian] Perova MD, Shubich MG, Karpiuk VB, Fomicheva AV, Mel'nik EA. This review paper describes the evolution of the ideas of periodontal tissue regeneration, starting with the concept of selective cellular repopulation, stimulation of resident precursor cells in the regeneration focus, up to the application of versatile potential of the stromal stem cells (SSC). Effects of stem cells isolated from an embryo, bone marrow, and adipose tissue, are described, as well as the immunophenotype of freshly isolated SSC, that of precultured vascular cell fraction as compared with the immunophenotype of SSC cultured during various time periods. The results of the study of the processes of proliferation and cell differentiation of SSC transplanted into the deep periodontal defects, are analyzed using proliferating cell nuclear antigen (PCNA) and green fluorescent protein. During the process of regeneration, the interaction of transplanted SSC with the local microenvironment is mediated by special membranous cell receptors. The coordination of cell behavior by means of adhesive and communicative contacts which provide a signal platform for the control of cellular functions, is discussed. PMID: 17722565 [PubMed - indexed for MEDLINE] 2789. Immunol Lett. 2007 Oct 15;112(2):61-7. Epub 2007 Jul 31. Adipose tissue macrophages. Zeyda M(1), Stulnig TM. Author information: (1)Department of Internal Medicine III, Clin. Div. Endocrinology and Metabolism, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. It is now broadly accepted that low-grade chronic inflammation associated with obesity leads to the onset of insulin resistance and type 2 diabetes mellitus. Obesity-associated inflammation is characterized by an increased abundance of macrophages in adipose tissue along with production of inflammatory cytokines. Adipose tissue macrophages (ATMs) are suspected to be the major source of inflammatory mediators such as TNF-alpha and IL-6 that interfere with adipocyte function by inhibiting insulin action. However, ATMs phenotypically resemble alternatively activated (M2) macrophages and are capable of anti-inflammatory mediator production challenging the concept that ATMs are simply the "bad guys" in obese adipose tissue. Triggers promoting ATM recruitment, ATM functions and dysfunctions, and stimuli and molecular mechanisms that drive them into becoming detrimental to their environment are subject to current research. Strategies to interfere with ATM recruitment and adverse activation could give rise to novel options for treatment and prevention of insulin resistance and type 2 diabetes mellitus. PMID: 17719095 [PubMed - indexed for MEDLINE] 2790. Postepy Biochem. 2007;53(1):46-52. [The role of lamins and mutations of LMNA gene in physiological and premature aging]. [Article in Polish] Sliwińska MA(1). Author information: (1)Pracownia Molekularnych Podstaw Starzenia, Zakład Biochemii, Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN, Warszawa. m.sliwinska@nencki.gov.pl Lamins belong to type V intermediate filaments superfamily. They are the main structural constituencies of the nuclear lamina but they also influence on chromatin structure, regulation of gene expression, localization and probably protein degradation. Because lamins play many different roles within the cell, mutations in their genes can results in variety of pathological phenotypes. Mutations in LMNA gene are the cause of many different diseases, called laminopathies. Among laminopathies are muscle tissue diseases, adipose tissue diseases and also progerias, the premature aging syndromes. One of the progerias, which results from mutation in LMNA gene, is Hutchinson-Gilford progeria syndrome (HGPS). It seems that the same molecular mechanisms which are responsible for premature aging of cells of HGPS patients, are involved in physiological aging. PMID: 17718387 [PubMed - indexed for MEDLINE] 2791. Obes Rev. 2007 Sep;8(5):395-408. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Vona-Davis L(1), Howard-McNatt M, Rose DP. Author information: (1)Department of Surgery and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9238, USA. lvdavis@hsc.wvu.edu Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression. PMID: 17716297 [PubMed - indexed for MEDLINE] 2792. J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S11-9. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver)? Caldwell SH(1), Ikura Y, Iezzoni JC, Liu Z. Author information: (1)Division of GI/Hepatology, Digestive Health Center of Excellence, University of Virginia, Charlottesville, Virginia 22908-0708, USA. shc5c@virginia.edu Erratum in J Gastroenterol Hepatol. 2008 Mar;23(3):501-2. Fatty liver is closely related to the development of the insulin resistance syndrome that largely results from abnormal insulin signaling in three major organs: (i) skeletal muscle in which insulin sensitivity depends on fat content and metabolic activity (exercise); (ii) adipose tissue, which serves as a reservoir of energy in the form of triglycerides; and (iii) the liver, which variably serves as a source or storage site of carbohydrates and lipids. In many respects, the fatty liver resembles a mixture of brown adipose tissue (microvesicular steatosis) and white adipose tissue (macrovesicular steatosis) including the stages of fatty droplet accumulation, and the expression of uncoupling proteins and perilipin-like substances. Furthermore, the development of an inflammatory infiltrate and the increased production of cytokines as occurs in adipose tissue, suggest that the liver in some individuals serves as an extension of adipose tissue. Moreover, current evidence indicates that these morphological changes represent altered gene expression similar to that of adipocytes. However, fatty liver does not appear to be a uniform feature of the metabolic syndrome and there is substantial variation in humans in the development of fatty liver independent of insulin resistance. In this regard, the variable development of fatty liver in Palmipedes (migratory fowl) and its close relationship to skeletal muscle utilization of fatty acids, lipoprotein metabolism and thermoregulation are instructive. The predilection to non-alcoholic fatty liver disease among some varieties of Palmipedes suggests that the development of fatty liver represents an adaptive process, closely integrated with skeletal muscle fat utilization and adipose tissue distribution, and facilitates survival in a very cold, resource-scarce environment. Variation in human populations with metabolic syndrome likewise suggests that the trait evolved in populations exposed in ancient times to different environmental challenges and, because the liver plays a central role in lipid metabolism, the presence or absence of fatty liver is likely to be integrated with insulin sensitivity in other target organs and with lipoprotein metabolism. PMID: 17567458 [PubMed - indexed for MEDLINE] 2793. Biochem Cell Biol. 2007 Aug;85(4):397-410. Chromatin and chromatin-modifying proteins in adipogenesis. Musri MM(1), Gomis R, Párrizas M. Author information: (1)Endocrinology and Nutrition Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Universitat de Barcelona, Barcelona 08036, Spain. Long considered scarcely more than an uninteresting energy depot, adipose tissue has recently achieved star status. Far from being mere fat droplets, the adipocytes secrete a number of hormones and bioactive peptides, collectively known as adipokines, which participate in the regulation of a variety of functions, from haemostasis to angiogenesis to energy balance. Adipose tissue constitutes a bona-fide endocrine organ whose main dysfunctions, obesity and lipodystrophy, are related to the development of diabetes, hypertension, or dyslipidemia. The renewed interest in this tissue has prompted an escalation in the number of studies focusing on every aspect of the biology of the adipose cell, in the belief that a detailed knowledge of the mechanisms involved in the differentiation and function of adipocytes may contribute new therapeutical approaches to the treatment of such alarming medical problems. Adipogenesis is the result of an intertwined network of transcription factors and coregulators with chromatin-modifying activities that together, are responsible for the establishment of the gene expression pattern of mature adipocytes. Although the exquisitely regulated transcription factor cascade controlling adipogenesis has been extensively studied, the role of chromatin and chromatin-modifying proteins has become apparent only in recent times. PMID: 17713575 [PubMed - indexed for MEDLINE] 2794. Nat Clin Pract Endocrinol Metab. 2007 Sep;3(9):651-61. Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy. Falutz J(1). Author information: (1)Montreal General Hospital, McGill University Health Center, Montreal, Quebec, Canada. julian.falutz@muhc.mcgill.ca Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of-life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients. PMID: 17710086 [PubMed - indexed for MEDLINE] 2795. Cell Biochem Biophys. 2007;48(2-3):89-95. PCK1 and PCK2 as candidate diabetes and obesity genes. Beale EG(1), Harvey BJ, Forest C. Author information: (1)Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Mail Stop 6540, Lubbock, TX 79430, USA. elmus.beale@ttuhsc.edu The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities. PMID: 17709878 [PubMed - indexed for MEDLINE] 2796. J Anim Sci. 2008 Apr;86(14 Suppl):E75-83. Epub 2007 Aug 20. Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. Quinn LS(1). Author information: (1)Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98195, USA. quinnL@u.washington.edu An increasing body of literature links immune and inflammatory factors to modulation of growth and control of fat:lean body composition. Recent progress in understanding the control of body composition has been made through identification of inflammatory cytokines and other factors produced by adipose tissue that affect body composition, often by direct effects on skeletal muscle tissue. Adipose-derived factors such as leptin, tumor necrosis factor-alpha, resistin, and adiponectin have been shown to affect muscle metabolism, protein dynamics, or both, by direct actions. This review summarizes recent results that support the existence of a reciprocal muscle-to-fat signaling pathway involving release of the cytokine IL-15 from muscle tissue. Cell culture studies, short-term in vivo studies, and human genotype association studies all support the model that muscle-derived IL-15 can decrease fat deposition and adipocyte metabolism via a muscle-to-fat endocrine pathway. Fat:lean body composition is an important factor determining the efficiency of meat production, as well as the fat content of meat products. Modulation of the IL-15 signaling axis may be a novel mechanism to affect body composition in meat animal production. PMID: 17709786 [PubMed - indexed for MEDLINE] 2797. Br J Pharmacol. 2007 Nov;152(5):676-90. Epub 2007 Aug 20. Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. Matias I(1), Gonthier MP, Petrosino S, Docimo L, Capasso R, Hoareau L, Monteleone P, Roche R, Izzo AA, Di Marzo V. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry National Research Council, Naples, Italy. The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively. PMCID: PMC2190005 PMID: 17704823 [PubMed - indexed for MEDLINE] 2798. Curr Drug Targets. 2007 Aug;8(8):888-93. Maternal nutrient restriction is not equivalent to maternal biological stress. Budge H(1), Stephenson T, Symonds ME. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, UK. helen.budge@nottingham.ac.uk An increase in fetal glucocorticoid exposure has long been considered to be a primary mechanism by which maternal nutritional manipulation may result in long term adaptations in the fetus such that it is at increased risk of a range of adult diseases including hypertension, diabetes and obesity. Animal studies in which high doses of synthetic glucocorticoids have been administered to the mother shown some long term programming effects, but these are nearly always accompanied by a reduction in maternal food intake. In this review, we will, therefore, consider the extent to which maternal food restriction and elevated maternal glucocorticoid concentrations can result in the same or different adaptations within the fetus such that they exhibit developmental changes in blood pressure control and/or metabolic homeostasis. One factor that appears to be critical in determining the mother's response is the stage of gestation at which her nutrient intake is manipulated. This may be explained in part by the placenta's ability to inactivate glucocorticoids. Irrespective of the mechanisms involved, it is clear that long term tissue specific adaptations within a range of organs, including adipose tissue and the kidney, can be greatly altered following changes in maternal glucocorticoid secretion. PMID: 17691925 [PubMed - indexed for MEDLINE] 2799. Expert Opin Pharmacother. 2007 Aug;8(12):1871-84. Strategies in the treatment of HIV-1-associated adipose redistribution syndromes. del Mar Gutierrez M(1), Mateo G, Domingo P. Author information: (1)Autonomous University of Barcelona, Infectious Diseases Unit, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain. HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is presently the most common long-term adverse effect limiting the doubtless efficacy of antiretroviral therapy. It has a great impact on the quality of life of patients, it is stigmatising and its psychologically devastating consequences may ultimately impact on the adherence to treatment of patients, eventually leading to treatment failure. Despite considerable advances in recent times, the pathogenesis of HALS remains elusive. Factors involved belong to three categories: those intrinsic to the host, some of them modifiable and some not, those associated with antiretroviral therapy, that are sometimes modifiable as well, and finally those related to HIV-1 infection and its consequences, most often not modifiable. The most commonly used strategies for HALS reversion have included host-dependent factors such as lifestyle and dietary modifications and antiretroviral-dependent factors such as switching or avoiding the use of drugs more prone to promote HALS. Lifestyle modifications and switching thymidine analogues have been associated with moderate success. Pharmacological interventions have included the use of insulin-sensitising agents and hormone therapy with disappointing results, whereas treatment with pravastatin or pioglitazone, and uridine supplementation seem to be associated with fat gain in preliminary studies. The only interventions with almost immediate results that may render a patient's appearance similar to his past one have included filling techniques for facial lipoatrophy and ultrasound-assisted liposuction for cervical fat pad hypertrophy. Among the filling options, semipermanent reabsorbable materials and autologous fat transfer have been associated with acceptable outcomes. As of now, the best hope should rely on the use of drugs friendly for fat, on defining the appropriate timing for starting antiretroviral and on continuing the research effort to understand the basic mechanisms underlying HALS pathogenesis. Only through this effort can the best chances for preventing or reverting established HALS be recognised. PMID: 17696790 [PubMed - indexed for MEDLINE] 2800. Asian Pac J Cancer Prev. 2007 Apr-Jun;8(2):167-77. Impact of C-reactive protein on disease risk and its relation to dietary factors. Nanri A(1), Moore MA, Kono S. Author information: (1)Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. nnrakiko@phealth.med.kyushu-u.ac.jp C-reactive protein (CRP) is one of the acute-phase proteins in inflammation and CRP serum concentrations are therefore of interest. Data for high-sensitivity CRP (hs-CRP) with a low detection limit of approximately 0.04 mg/L have become available over the past decade and research has shown a link between high concentrations of hs-CRP and obesity as well as smoking. Expanded adipose tissue is in fact known to secrete proinflammatory cytokines which enhance hepatic synthesis of CRP. Moderate alcohol consumption and high physical activity have been associated with low levels of hs-CRP, but the evidence in these cases is not conclusive. It has been suggested that hs-CRP is an independent marker of the risk of cardiovascular disease, but the predictive capacity remains controversial. However, many prospective studies have observed increased risk of type 2 diabetes mellitus associated with high concentrations of hs-CRP, independent of obesity and other cardiovascular risk factors. On the other hand, no measurable increase in the risk associated with high levels of hs-CRP was observed with multivariate adjustment in several studies. A number of authors have reported that high concentrations of hs-CRP are associated with increased risks of colorectal and other cancers, but the findings again are inconsistent. Diet and hs-CRP are also of increasing research interest. High intakes of carotenoids and vitamin C, but not of vitamin E, seem to decrease the level of circulating hs-CRP. In addition, high consumption of vegetables and fruit are associated with lower levels of circulating hs-CRP, perhaps by exerting anti-inflammatory effects. Both mechanistic and epidemiologic studies regarding dietary factors and low-grade inflammation are necessary to add to our knowledge of dietary influence on chronic disease development. PMID: 17696726 [PubMed - indexed for MEDLINE] 2801. Trends Endocrinol Metab. 2007 Sep;18(7):266-72. Epub 2007 Aug 10. Abdominal adiposity and the polycystic ovary syndrome. Escobar-Morreale HF(1), San Millán JL. Author information: (1)Department of Endocrinology, Hospital Universitario Ramón y Cajal & Universidad de Alcalá, Carretera de Colmenar km 9'1, E-28034 Madrid, Spain. hescobarm.hrc@salud.madrid.org Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients. PMID: 17693095 [PubMed - indexed for MEDLINE] 2802. Trends Biotechnol. 2007 Sep;25(9):409-16. Epub 2007 Aug 9. Stem cells in veterinary medicine--attempts at regenerating equine tendon after injury. Richardson LE(1), Dudhia J, Clegg PD, Smith R. Author information: (1)Department of Veterinary Clinical Sciences, The Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK. Stem cells have evoked considerable excitement in the animal-owning public because of the promise that stem cell technology could deliver tissue regeneration for injuries for which natural repair mechanisms do not deliver functional recovery and for which current therapeutic strategies have minimal effectiveness. This review focuses on the current use of stem cells within veterinary medicine, whose practitioners have used mesenchymal stem cells (MSCs), recovered from either bone marrow or adipose tissue, in clinical cases primarily to treat strain-induced tendon injury in the horse. The background on why this treatment has been advocated, the data supporting its use and the current encouraging outcome from clinical use in horses treated with bone-marrow-derived cells are presented together with the future challenges of stem-cell therapy for the veterinary community. PMID: 17692415 [PubMed - indexed for MEDLINE] 2803. Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):27-38. Epub 2007 Aug 9. Fatty liver: a novel component of the metabolic syndrome. Kotronen A(1), Yki-Järvinen H. Author information: (1)Department of Medicine, Division of Diabetes, University of Helsinki, Finland, FIN-00029 HUCH, Helsinki, Finland. Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy. PMID: 17690317 [PubMed - indexed for MEDLINE] 2804. J Anim Sci. 2008 Apr;86(14 Suppl):E236-43. Epub 2007 Aug 8. The influence of thiazolidinediones on adipogenesis in vitro and in vivo: potential modifiers of intramuscular adipose tissue deposition in meat animals. Hausman GJ(1), Poulos SP, Pringle TD, Azain MJ. Author information: (1)USDA, ARS, APRU, Athens, GA 30605, USA. Gary.Hausman@ARS.USDA.GOV Thiazolidinediones (TZD) are insulin sensitizing agents currently used for the treatment of type 2 diabetes and are widely used as adipogenic agents because they are ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), a key adipogenic transcription factor. In vivo and in vitro studies of TZD as potential modifiers of intramuscular or marbling adipogenesis are reviewed. Thiazolidinedione-induced adipogenesis has been reported in numerous cell culture systems, including rodent, human, bovine, and porcine adipose tissue stromal-vascular (S-V) cell cultures. Studies of porcine S-V cell cultures derived from semitendinosus muscle show that TZD can potentially modify intramuscular or marbling adipogenesis. Preadipocyte recruitment was TZD-dependent in muscle S-V cultures but TZD-independent in adipose S-V cultures. There appear to be differences between adipocytes in muscle and subcutaneous adipose tissue, reminiscent of differences observed in adipocytes from different adipose tissue depots. Troglitazone, a TZD, induces marbling adipogenesis without inhibiting myogenesis when cells are grown on laminin precoated culture dishes. Additionally, troglitazone treatment does not increase lipid content in porcine adipose tissue or muscle S-V cell cultures. Thiazolidinedione treatment increases lipid content of muscle in rodents and humans; however, rosiglitazone treatment for 49 d in pigs did not influence muscle lipid content and meat quality, but several significant changes in muscle fatty acid composition were observed. Although timing of treatment with TZD needs to be optimized, evidence suggests these compounds may enhance marbling deposition in swine. PMID: 17686902 [PubMed - indexed for MEDLINE] 2805. Expert Opin Investig Drugs. 2007 Aug;16(8):1241-53. Novel treatments for cancer cachexia. Bossola M(1), Pacelli F, Doglietto GB. Author information: (1)Catholic University of the Sacred Heart, Department of Surgery, Largo A. Gemelli, Roma, Italy. maubosso@tin.it Cancer cachexia is a debilitating and life-threatening syndrome characterised by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, and accounts for > or = 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to antineoplastic therapies, increasing the morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of cancer cachexia and the principle cause of function impairment, fatigue and respiratory complications, and is mainly related to a hyperactivation of muscle proteolytic pathways. Existing therapeutic strategies have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle has been attempted pharmacologically, giving encouraging results in animal models and through preliminary clinical trials. PMID: 17685872 [PubMed - indexed for MEDLINE] 2806. Recenti Prog Med. 2007 Jul-Aug;98(7-8):398-400. [Obesity and hypertension. Recent advances in etiopathogenesis]. [Article in Italian] Cesareo R(1), Iozzino M, Napolitano C, De Rosa P, De Rosa B, Orsini A. Author information: (1)U.O. Medicina Interna, Ospedale Santa Maria Goretti, Latina. The aim of the study is to evaluate the pathogenetic factors which determine the association between obesity and hypertension. In particular we consider the role of adipose tissue. Activity of sympathetic nervous system, hyperinsulinemia, lower action of the atrial natriuretic peptide are important to understand the correlation between these pathologies. PMID: 17685189 [PubMed - indexed for MEDLINE] 2807. Forum Nutr. 2007;60:127-39. Gene expression in low glycemic index diet - impact on metabolic control. Takeda E(1), Arai H, Muto K, Matsuo K, Sakuma M, Fukaya M, Yamanaka-Okumura H, Yamamoto H, Taketani Y. Author information: (1)Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan. takeda@nutr.med.tokushima-u.ac.jp BACKGROUND: Correcting postprandial hyperglycemia forms an important part of the prevention and management of type 2 diabetes. METHODS: A low-glycemic-index liquid formula designated as Inslow was prepared by replacing dextrin in the standard balanced formula (SBF) with 55.7% palatinose. Long-term administration of Inslow prevented fatty liver and improved insulin resistance in rats. Expressions of mRNA of factors involved in glucose and lipid metabolism were determined to clarify its mechanism. RESULTS: Analysis of mRNA expressions revealed that Inslow increased the expression of enzymes involved in Beta -oxidation and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in the liver, and increased PPAR-gamma, adiponectin and uncoupling protein 2 as well as decreased tumor necrosis factor alpha in adipose tissue in comparison with those of SBF. CONCLUSIONS: Inslow may induce improvement of insulin resistance by accelerated Beta-oxidation through increased expression of the hepatic PPAR-alpha gene and adipocyte PPAR-gamma gene. Therefore, Inslow is a functional food which prevents and treats type 2 diabetes. PMID: 17684409 [PubMed - indexed for MEDLINE] 2808. Diabetes Metab Res Rev. 2007 Oct;23(7):507-17. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Cota D(1). Author information: (1)Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu Insulin resistance, dyslipidaemia and obesity are the major cardiometabolic risk factors contributing to the development of type 2 diabetes and cardiovascular disease (CVD). Owing to the increasing prevalence of obesity, type 2 diabetes, and CVD, new and effective pharmacologic therapies are urgently needed. In this regard, the endogenous cannabinoid system (ECS), a neuromodulatory system involved in the regulation of various aspects of energy balance and eating behaviour through central and peripheral mechanisms, may present the potential to meet this need. In the central nervous system (CNS), cannabinoid type 1 (CB1) receptors and their respective ligands, the endocannabinoids, have a significant role in the modulation of food intake and motivation to consume palatable food. CB1 receptors have also been found in organs involved in the regulation of metabolic homeostasis, such as liver, white adipose tissue, muscle and pancreas. Dysregulation of the ECS has been associated with the development of dyslipidaemia, glucose intolerance, and obesity, and CB1 receptor blockade may have a role in ameliorating these metabolic abnormalities. Thus, pharmacologic options targeting the ECS may provide a novel, effective approach to the prevention and management of CVD, type 2 diabetes and obesity. (c) 2007 John Wiley & Sons, Ltd. PMID: 17683024 [PubMed - indexed for MEDLINE] 2809. Trends Immunol. 2007 Sep;28(9):393-9. Epub 2007 Aug 2. Adipose tissue as an immunological organ: Toll-like receptors, C1q/TNFs and CTRPs. Schäffler A(1), Schölmerich J, Salzberger B. Author information: (1)Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de Adipose tissue has long been regarded as a mostly resting tissue that is dedicated solely to energy storage and release. However, in recent years, this view has changed dramatically following new insights into the metabolic and immunological functions of preadipocytes and adipocytes. There are several lines of evidence for the involvement of adipose tissue in innate and acquired immune responses. First, adipocytes are potent producers of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor (TNF), and chemokines. Furthermore, adipocytes secrete high amounts of adipokines, such as leptin, adiponectin and resistin, that regulate monocyte/macrophage function, and also secrete molecules associated with the innate immune system, such as the C1qTNF-related protein superfamily. Finally, preadipocytes and adipocytes express a broad spectrum of functional Toll-like receptors and the former can convert into macrophage-like cells. Collectively, these data clearly establish the role of adipose tissue as a new member of the immune system. PMID: 17681884 [PubMed - indexed for MEDLINE] 2810. J Cardiometab Syndr. 2006 Spring;1(2):115-20. Perivascular fat: innocent bystander or active player in vascular disease? Stern N(1), Marcus Y. Author information: (1)Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. stern@tasmc.health.gov.il Although nearly all arteries are surrounded by perivascular fat, its role in vascular function and disease is clearly understudied. At least one type of perivascular fat, epicardial adipose tissue, appears to be related to both weight and age and tends to express proatherogenic/proinflammatory products in subjects with cardiovascular disease. Perivascular fat may evolve from primordial cells in the adventitia or from circulating precursors migrating through the arterial wall. Once deposited periarterially, adipose tissue may release locally a large number of products, which potentially interact with the arterial wall. Additionally, the authors propose that perivascular fat, per se, may attract circulating monocytes through the release of chemokines such as monocyte chemoattractant protein-1. Some of the macrophages traversing the arterial wall en route to the perivascular fat may be redirected and eventually populate the arterial wall itself, thereby enhancing vascular inflammatory processes and accelerating atherosclerosis. PMID: 17679830 [PubMed - indexed for MEDLINE] 2811. J Cardiometab Syndr. 2006 Summer;1(3):217-9. Is salt sensitivity of blood pressure linked to the cardiometabolic syndrome? Weinberger MH(1). Author information: (1)Department of Medicine/Hypertension, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mweinbe@IUPUI.edu PMID: 17679824 [PubMed - indexed for MEDLINE] 2812. J Cardiometab Syndr. 2006 Spring;1(2):121-4. Fat cell-derived modulators of vascular cell pathophysiology: the list keeps growing. Marcus Y(1), Stern N. Author information: (1)Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Independent of the association of obesity with dyslipidemia, hypertension, and increased propensity for diabetes, fatness per se is increasingly recognized as a cardiovascular offender. That adipose tissue releases a wide range of adipokines, growth factors, enzymes, and enzyme substrates linked to vascular injury provides a plausible explanation for the role of fat in vascular disease: tumor necrosis factor-alpha, leptin, resistin, interleukin-1, -6, -8, and -18, serum amyloid A, monocyte chemoattractant protein I, macrophage inhibitory factor, aortic carboxypeptidase, hepa-rin-binding epidermal growth factor-like growth factor, vascular endothelial growth factor, transforming growth factor beta, angiotensinogen, cathepsin S, estradiol, cortisol, mineralocorticoid releasing factor, and calcitonin peptides are probable fat-derived prothrombotic, proinflammatory, and proatherosclerotic agents acting in a paracrine and/or endocrine manner. Other adipocyte products such as adiponectin, transforming growth factor beta, and interleukin-10 exert some antiatherogenic effects. The following is a short overview of how adipose tissue products affect the vasculature. PMID: 17679816 [PubMed - indexed for MEDLINE] 2813. J Vasc Surg. 2007 Jun;45 Suppl A:A99-103. Tissue engineering applications to vascular bypass graft development: the use of adipose-derived stem cells. DiMuzio P(1), Tulenko T. Author information: (1)Division of Vascular Surgery, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. paul.dimuzio@jefferson.edu The burgeoning field of vascular tissue engineering holds promise for the creation of a practical and successful small-diameter arterial bypass graft. Many creative combinations of autologous cells and scaffolds exist along with an equally long list of microenvironmental cues used to create a functional arterial conduit. This review outlines our work using abdominal wall fat as a source of autologous stem cells for vascular tissue engineering, focusing specifically on this stem cell's availability and potency to differentiate into endothelial-like cells. In a series of 49 patients undergoing elective peripheral vascular surgery, an abundant quantity of adult stem cells was harvested from fat obtained by liposuction. The efficacy of the isolation did not appear influenced by advanced age, obesity, renal failure, or vascular disease, although fat from diabetic patients yielded significantly less stem cells. In addition, these adipose-derived stem cells acquired several morphologic and molecular endothelial phenotypes when exposed to growth factors (endothelial cell growth supplement and vascular endothelial growth factor) and physiologic shear stress in vitro. Taken together, these studies suggest that fat appears to be a viable source of autologous stem cells for use in vascular tissue engineering. PMCID: PMC1941665 PMID: 17544030 [PubMed - indexed for MEDLINE] 2814. J Cardiometab Syndr. 2006 Winter;1(1):29-35. The role of renin-angiotensin system blockade in the management of hypertension associated with the cardiometabolic syndrome. Sharma AM(1), Engeli S. Author information: (1)Michael G. deGroote Medical School, McMaster University, Hamilton, Ontario, Canada. sharma@ccc.mcmaster.ca The mounting epidemic of overweight and obesity has made understanding the relationship between excess weight and associated comorbidities more urgent. Obesity is one of the strongest predictors of the development of hypertension and is an independent risk factor for cardiovascular disease, renal disease, and diabetes mellitus. The concomitant presence of obesity and hypertension, as commonly occurs in the cardiometabolic syndrome, magnifies the risk for cardiovascular and renal disease. The term "obesity-hypertension" thus serves to underscore the link between these two deleterious conditions and to emphasize the imperative for clinical intervention. Adipose tissue is now known to produce hormones and cytokines that promote inflammation, lipid accumulation, and insulin resistance. In addition, adipose tissue contains all the components of the renin-angiotensin system (RAS), which is upregulated in the presence of obesity. Evidence implicates activation of the systemic and adipose tissue RAS, as well as the sympathetic nervous system, as key obesity-related mechanisms of hypertension and other components of the cardiometabolic syndrome. RAS blockade therefore becomes a potential therapeutic strategy in patients with obesity-related hypertension and in persons with the cardiometabolic syndrome. Clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers conducted in predominantly overweight/obese populations have demonstrated significant reductions in cardiovascular and renal disease risk among a range of at-risk patients. RAS blockade also is associated with a reduced risk of new-onset diabetes compared with other classes of antihypertensive therapy. Randomized, controlled trials conducted specifically in patients with obesity and hypertension are needed to determine the optimal therapeutic approach for these patients. PMID: 17675902 [PubMed - indexed for MEDLINE] 2815. Int J Hematol. 2007 Jul;86(1):17-21. Mesenchymal stem cells for the treatment of heart failure. Ohnishi S(1), Ohgushi H, Kitamura S, Nagaya N. Author information: (1)Department of Regenerative Medicine & Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan. Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. The ability of MSC to differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells, make them an attractive therapeutic tool for heart failure. Recent in vitro and in vivo studies have revealed the underlying mechanisms of MSC in cardiac repair. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of a variety of angiogenic, antiapoptotic, and mitogenic factors. Endogenous MSC as well as exogenously administered MSC have also been suggested to migrate and participate in cardiac repair. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure. PMID: 17675261 [PubMed - indexed for MEDLINE] 2816. Crit Pathw Cardiol. 2007 Mar;6(1):5-14. Managing cardiometabolic risk: an evolving approach to patient care. Watson K(1). Author information: (1)UCLA Cholesterol, Hypertension, and Atherosclerosis Management Program, University of California, Los Angeles Geffen School of Medicine, Los Angeles, CA 90095, USA. kwatson@mednet.ucla.edu Cardiometabolic risk encompasses a cluster of risk factors that may predispose individuals to cardiovascular disease and type 2 diabetes. These risk factors, some of which are currently undermanaged in clinical practice, involve multiple pathways and physiologic systems and point to a need for a comprehensive management approach. Abdominal obesity is a key component of cardiometabolic risk, increasing the incidence of insulin resistance, vascular inflammation, dyslipidemia, and hypertension. Adipose tissue, now recognized as an endocrine organ, and its hormonal products appear to play a significant role in the regulation of fat and glucose metabolism throughout the body. These mechanisms are clearly involved in the development of cardiovascular and metabolic disease. Current treatment protocols generally involve a fragmented approach to care, advocating management of only the clinically evident conditions. As cardiometabolic risk factors tend to cluster, patients often have additional subclinical conditions that would be discovered through comprehensive evaluation for the entire constellation of risk factors, thereby enabling clinicians to recommend optimal treatment to prevent cardiovascular and metabolic morbidities. PMID: 17667880 [PubMed - indexed for MEDLINE] 2817. Crit Pathw Cardiol. 2007 Jun;6(2):51-9. Cardiovascular disease under the influence of excess visceral fat. Després JP(1). Author information: (1)Québec Heart Institute, Québec, QC, Canada. jean-pierre.despres@crhl.ulaval.ca Diabetes and cardiovascular disease have emerged as major threats to human health, and the risk of developing these chronic conditions is increased in individuals with abdominal obesity and the metabolic syndrome. Excess visceral abdominal tissue (VAT) accumulation appears to be a key feature of abdominal obesity contributing to the development of the metabolic syndrome. For instance, excess VAT is accompanied by elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure, and/or elevated fasting plasma glucose. In addition, the rather normal or only marginally elevated low-density lipoprotein (LDL) cholesterol concentrations in patients with excess VAT could provide misleading information as viscerally obese patients have an increased plasma concentration of small, dense LDL particles. Prospective studies have suggested that even among patients with LDL cholesterol concentrations within normal limits, an increased concentration of small LDL particles is associated with higher risk of cardiovascular disease. With the treatment of abdominal obesity and excess VAT, an increase in patients' LDL particle size and improvements in other cardiovascular risk factors (eg, insulin levels, glucose tolerance, HDL, C-reactive protein [CRP], and adiponectin levels) can be achieved. Waist circumference can be used in clinical practice as a first approach and as a crude index to identify patients who have excess VAT, particularly when the elevated waistline is accompanied by the clinical features of the metabolic syndrome, among which an elevated fasting triglyceride concentration appears to be predictive of a reduced LDL particle size and of further metabolic abnormalities frequently referred to as the metabolic syndrome. Lifestyle changes, including more physical activity and healthier nutritional habits, are the cornerstone of therapy for high-risk abdominally obese patients with an excess of VAT. In addition, results from the RIO-Lipids study, which was conducted in high-risk obese, dyslipidemic patients, have provided evidence that CB1 receptor blockade with rimonabant can induce significant weight loss, and, more importantly, improve the cardiometabolic risk profile beyond what could be explained by the weight loss effects of the drug. PMID: 17667865 [PubMed - indexed for MEDLINE] 2818. Crit Pathw Cardiol. 2007 Jun;6(2):46-50. The endocannabinoid system: a new target for the regulation of energy balance and metabolism. Després JP(1). Author information: (1)Québec Heart Institute, Québec QC, Canada. jean-pierre.despres@crhl.ulaval.ca Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to "fix" the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk. PMID: 17667864 [PubMed - indexed for MEDLINE] 2819. Trends Cardiovasc Med. 2007 Aug;17(6):206-11. Leptin as a cardiac hypertrophic factor: a potential target for therapeutics. Karmazyn M(1), Purdham DM, Rajapurohitam V, Zeidan A. Author information: (1)Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1. morris.karmazyn@schulich.uwo.ca The satiety factor leptin has received extensive attention especially in terms of its potential role in appetite suppression and regulation of energy expenditure. Once considered to be solely derived from adipose tissue, which accounts for the greatly increased levels observed in obese subjects, it is now apparent that leptin can be produced by a multiplicity of tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Plasma leptin concentrations are also elevated in patients with heart disease including those with congestive heart failure. Leptin exerts its biological effects via a family of receptors termed Ob-R. In cardiac cells, one of leptin's primary actions is to produce cardiomyocyte hypertrophy through multifaceted cell signaling mechanisms including stimulation of mitogen-activated protein kinase and activation of the RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin suggests that it may contribute to myocardial remodeling after cardiac injury and offers the potential targeting of the leptin system as a novel cardiac therapy. PMID: 17662916 [PubMed - indexed for MEDLINE] 2820. World J Gastroenterol. 2007 Jul 14;13(26):3540-53. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. Qureshi K(1), Abrams GA. Author information: (1)Department of Medicine, University of Alabama at Birmingham, 1918 University Blvd 286 MCLM Birmingham, AL 35294, USA. Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver-related morbidity and mortality. It can develop secondary to numerous causes but a great majority of NAFLD cases occur in patients who are obese or present with other components of metabolic syndrome (hypertension, dyslipidemia, diabetes). This is called primary NAFLD and insulin resistance plays a key role in its pathogenesis. Obesity is characterized by expanded adipose tissue, which is under a state of chronic inflammation. This disturbs the normal storage and endocrine functions of adipose tissue. In obesity, the secretome (adipokines, cytokines, free fatty acids and other lipid moieties) of fatty tissue is amplified, which through its autocrine, paracrine actions in fat tissue and systemic effects especially in the liver leads to an altered metabolic state with insulin resistance (IR). IR leads to hyperglycemia and reactive hyperinsulinemia, which stimulates lipid-accumulating processes and impairs hepatic lipid metabolism. IR enhances free fatty acid delivery to liver from the adipose tissue storage due to uninhibited lipolysis. These changes result in hepatic abnormal fat accumulation, which may initiate the hepatic IR and further aggravate the altered metabolic state of whole body. Hepatic steatosis can also be explained by the fact that there is enhanced dietary fat delivery and physical inactivity. IR and NAFLD are also seen in various lipodystrophic states in contrary to popular belief that these problems only occur due to excessive adiposity in obesity. Hence, altered physiology of adipose tissue is central to development of IR, metabolic syndrome and NAFLD. PMCID: PMC4146793 PMID: 17659704 [PubMed - indexed for MEDLINE] 2821. Stem Cells. 2007 Nov;25(11):2739-49. Epub 2007 Jul 26. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Chamberlain G(1), Fox J, Ashton B, Middleton J. Author information: (1)Leopold Muller Arthritis Research Centre, School of Medicine, Keele University, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, Shrops SY10 7AG, UK. MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules. PMID: 17656645 [PubMed - indexed for MEDLINE] 2822. Int J Obes (Lond). 2007 Dec;31(12):1763-76. Epub 2007 Jul 24. Lipodystrophy in HIV 1-infected patients: lessons for obesity research. Villarroya F(1), Domingo P, Giralt M. Author information: (1)Department of Biochemistry and Molecular Biology, University of Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain. fvillarroya@ub.edu Lipodystrophy is a common alteration in HIV 1-infected patients under anti-retroviral treatment. This syndrome is usually associated with peripheral lipoatrophy, central adiposity and, in some cases, lipomatosis, as well as systemic insulin resistance and hyperlipidemia. Research on the ethiopathogenesis of the disease revealed novel aspects of adipose tissue biology highly relevant to obesity research: the pivotal role of mitochondria in white adipose tissue function, the role that interference with master transcription factors of adipogenesis may have in human adipose tissue, the capacity of human white adipose tissue to acquire brown fat-like features, as well as the importance of apoptosis and the potential impact of viral infections in adipose tissue. The dramatic difference between subcutaneous adipose depots, prone to lipoatrophy, and the visceral adipose depots, prone to enlargement, has been further evidenced in the study of the lipodystrophy syndrome. The recognition of a local pro-inflammatory environment in lipoatrophic adipose tissue from affected patients, including macrophage infiltration and enhanced expression of chemokines and cytokines, points to events paradoxically similar to those in the hypertrophied adipose tissue in obesity. However, this also potentially provides an explanation for the existence of systemic alterations common to lipodystrophy and obese patients and reminiscent of the metabolic syndrome. PMID: 17653062 [PubMed - indexed for MEDLINE] 2823. J Intern Med. 2007 Aug;262(2):199-207. How can we prevent cardiovascular disease in diabetes. Wiklund O(1), Håversen L, Pettersson C, Hultén LM. Author information: (1)Department for Molecular and Clinical Medicine and the Wallenberg Laboratory, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. olov.wiklund@wlab.gu.se Evidence based goals for the treatment and prevention of atherosclerosis in diabetes are given in international and national guidelines. The importance of optimal control of lipids and blood pressure has been shown in several studies. With available drugs and behavioural modifications the treatment goals can be reached in most cases. However, only a few patients with diabetes are treated optimally today. A major possibility to reduce cardiovascular disease in diabetes is to treat patients according to guidelines. New treatment targets may include specific treatment of the dyslipidaemia, manifested in high levels of small dense LDL and low HDL, active anti-inflammatory treatments, specific reduction of inflammatory activity in adipose tissue, reduced volume of adipose tissue, antioxidants and reduction of advanced glycosylation endproducts production. Possible strategies for these treatments are available, and should be evaluated in clinical trials. PMID: 17645587 [PubMed - indexed for MEDLINE] 2824. J Intern Med. 2007 Aug;262(2):173-83. Endothelial dysfunction in insulin resistance and type 2 diabetes. Jansson PA(1). Author information: (1)Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine/Diabetes, The Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, Sahlgrenska S-413 45, Göteborg, Sweden. Per-anders.jansson@medic.gu.se Macrovascular disease is the number one killer in type 2 diabetes patients. The cluster of risk factors in the insulin resistance syndrome (IRS) partly explains this notion. Insulin action in muscle, liver or adipose tissue has been thoroughly described in the literature, whilst this has been less described for the endothelium. Insulin stimulates nitric oxide (NO) production in the endothelium and reduced bioavailability of NO is usually defined as endothelial dysfunction. This impairment might be related to defective insulin signalling in the endothelial cell. Therefore, insulin resistance mechanisms in the endothelial cell will be emphasized in this review. Imbalance between the vasodilating agent NO and the vasoconstrictor endothelin-1 (ET-1) contributes to endothelial dysfunction. Different methods and circulating markers to assess endothelial function will be outlined. Circulating markers of an activated endothelium appear long before type 2 diabetes develops suggesting a unique role of the endothelium in the pathophysiology of the disease. Hampered blood flow in nutritive capillaries due to endothelial dysfunction is coupled with decreased glucose uptake and hyperglycemia. The forearm model combined with muscle microdialysis enables us to measure interstitial glucose and an index for capillary recruitment, the permeability surface area (PS). Available data from this method suggest that capillary recruitment in response of insulin is impaired in insulin resistant human subjects. PMID: 17645585 [PubMed - indexed for MEDLINE] 2825. Diabetes Obes Metab. 2008 May;10(5):367-75. Epub 2007 Jul 21. The effect of thiazolidinediones on adiponectin serum level: a meta-analysis. Riera-Guardia N(1), Rothenbacher D. Author information: (1)Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. n.riera-guardia@dkfz-heidelberg.de BACKGROUND AND AIMS: Adiponectin is a hormone mainly produced by white adipose tissue. Decreased levels of adiponectin are linked with visceral obesity, insulin resistance states, and cardiovascular diseases. Recently, several studies have pointed out an increase in adiponectin serum levels in subjects undergoing treatment with thiazolidinediones (TZD). The aim of this study is to systematically review the current state of evidence of the effect of TZD on adiponectin serum level with special attention to avoid publication bias. MATERIALS AND METHODS: An extensive literature search was performed. Meta Analysis Version 2.0 computer program was used to calculate statistical differences in means and 95% confidence interval (CI). Publication bias was assessed using different statistical approaches. RESULTS: In the meta-analysis including 19 studies the overall standardized mean difference was 0.94 (95% CI, 0.81-1.06) which means that subjects treated with TZDs on average had means of adiponectin concentration that were about 1 standard deviation higher than the comparison groups even after controlling for possible biases. CONCLUSIONS: The results obtained agree with a moderate increase of serum adiponectin. The results clearly reveal an increase of endogenous serum adiponectin levels by intake of TZDs and may point to a potential new option to manage obesity-related diseases. PMID: 17645557 [PubMed - indexed for MEDLINE] 2826. Eat Weight Disord. 2002 Jun;7(2):82-93. The metabolic syndrome. Bosello O(1), Zamboni M. Author information: (1)Division of Geriatrics, University of Verona, Italy. obosello@univr.it PMID: 17644862 [PubMed - indexed for MEDLINE] 2827. Curr Opin Cell Biol. 2007 Aug;19(4):466-73. Epub 2007 Jul 17. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Hou JC(1), Pessin JE. Author information: (1)Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA. hou@pharm.stonybrook.edu Glucose transporter 4 (GLUT4) is the major insulin-regulated glucose transporter expressed mainly in muscle and adipose tissue. GLUT4 is stored in a poorly characterized intracellular vesicular compartment and translocates to the cell surface in response to insulin stimulation resulting in an increased glucose uptake. This process is essential for the maintenance of normal glucose homeostasis and involves a complex interplay of trafficking events and intracellular signaling cascades. Recent studies have identified sortilin as an essential element for the formation of GLUT4 storage vesicles during adipogenesis and Golgi-localized gamma-ear-containing Arf-binding protein (GGA) as a key coat adaptor for the entry of newly synthesized GLUT4 into the specialized compartment. Insulin-stimulated GLUT4 translocation from this compartment to the plasma membrane appears to require the Akt/protein kinase B substrate termed AS160 (Akt substrate of 160kDa). In addition, the VPS9 domain-containing protein Gapex-5 in complex with CIP4 appears to function as a Rab31 guanylnucleotide exchange factor that is necessary for insulin-stimulated GLUT4 translocation. Here, we attempt to summarize recent advances in GLUT4 vesicle biogenesis, intracellular trafficking and membrane fusion. PMCID: PMC2041936 PMID: 17644329 [PubMed - indexed for MEDLINE] 2828. Endocr Relat Cancer. 2007 Jun;14(2):189-206. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Vona-Davis L(1), Rose DP. Author information: (1)Department of Surgery & Mary Babb Randolph Cancer Center, West Virginia University, PO Box 9238, Morgantown, West Virginia 26506, USA. lvdavis@hsc.wvu.edu Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk. In this review, we discuss the direct and indirect effects of these protein factors on the biological and clinical aspects of breast cancer biology, and emphasize their distinctive modes of action through endocrine-, paracrine-, and autocrine-mediated pathways. The stimulatory effects of leptin on breast cancer growth were considered to occur primarily via activation of the estrogen receptor; however, new evidence suggests that leptin may be acting on downstream cell signaling pathways in both estrogen-dependent and -independent cell types. Another secretory adipokine, HGF, may act largely not only to promote tumor cell invasion, but also to enhance tumor growth indirectly by stimulating angiogenesis. In contrast, adiponectin, an endogenous insulin sensitizer, exerts a direct growth-inhibitory effect on tumor cells by downregulating cell proliferation and upregulating apoptosis, and also inhibits tumor-related angiogenesis. PMID: 17639037 [PubMed - indexed for MEDLINE] 2829. Int J Obes (Lond). 2007 Dec;31(12):1786-97. Epub 2007 Jul 17. A dose-response relation between aerobic exercise and visceral fat reduction: systematic review of clinical trials. Ohkawara K(1), Tanaka S, Miyachi M, Ishikawa-Takata K, Tabata I. Author information: (1)Health Promotion and Exercise Program, National Institute of Health and Nutrition, Shinjuku-ku, Tokyo, Japan. ohkawara@nih.go.jp Erratum in Int J Obes (Lond). 2008 Feb;32(2):395. OBJECTIVE: It has been suggested that exercise has preferential effects on visceral fat reduction. However, the dose-response effect remains unclear because of limited evidence from individual studies. The purpose of this study was to systematically review the current literature to establish whether reduction of visceral fat by aerobic exercise has a dose-response relationship. METHODS: A database search was performed (PubMed, 1966-2006) with appropriate keywords to identify studies exploring the effects of aerobic exercise as a weight loss intervention on visceral fat reduction. Visceral fat reduction was expressed as the percentage of visceral fat change per week (%DeltaVF/w). The energy expenditure by aerobic exercise was expressed as Sigma (metabolic equivalents x h per week (METs x h/w)). RESULTS: Nine randomized control trials and seven non-randomized control trials were selected. In most of the studies, the subjects performed aerobic exercise generating 10 METs x h/w or more. Among all the selected groups (582 subjects), visceral fat decreased significantly (P<0.05) in 17 groups during the intervention, but not in the other 4 groups. There was no significant relationship between METs x h/w from aerobic exercise and %DeltaVF/w in all the selected groups. However, when subjects with metabolic-related disorders were not included (425 subjects), METs x h/w from aerobic exercise had a significant relationship with %DeltaVF/w (r=-0.75). Moreover, visceral fat reduction was significantly related to weight reduction during aerobic exercise intervention, although a significant visceral fat reduction may occur without significant weight loss. CONCLUSION: These results suggest that at least 10 METs x h/w in aerobic exercise, such as brisk walking, light jogging or stationary ergometer usage, is required for visceral fat reduction, and that there is a dose-response relationship between aerobic exercise and visceral fat reduction in obese subjects without metabolic-related disorders. PMID: 17637702 [PubMed - indexed for MEDLINE] 2830. Proc Nutr Soc. 2007 Aug;66(3):351-61. Metabolic cross talk between the colon and the periphery: implications for insulin sensitivity. Denise Robertson M(1). Author information: (1)School of Biomedical and Molecular Sciences, University of Surrey, Guildford GU2 7XH, UK. m.robertson@surrey.ac.uk Until recently, a glance at a standard undergraduate textbook would have given the impression that the colon was merely a storage organ for faeces and maybe something about the absorption of electrolytes and water. In reality, the colon is a highly-metabolically-active organ, the function of which has implications not only for the remainder of the digestive tract, but also for peripheral organs such as adipose tissue (AT), liver and skeletal muscle. The present review focuses on two distinct but complementary areas: (1) the metabolic adaptation that occurs following surgical removal of colonic tissue; (2) the effect of modulating the colon in situ in terms of postprandial metabolism, insulin sensitivity and disease risk. Work in these two areas points to the colon being important in modulating normal tissue insulin sensitivity. The role of fatty acids is central to the insulin sensitivity hypothesis. AT acts as a daily 'buffer' for fatty acids. However, following colonic resection there is an apparent change in AT function. There is an increase in the AT lipolysis rate, resulting in the release of excess fatty acids into the circulation and consequently the take up of excess fatty acids into skeletal muscle. This resultant increase in either storage of lipid or its oxidation would result in a reduction in insulin sensitivity. The insulin-sensitising effects of high-fibre diets are also related to changes in AT function and fatty acid metabolism, but manipulating colonic tissue in situ allows the mechanisms to be elucidated. This research area is an exciting one, involving the potential role of SCFA (the absorbed by-products of colonic bacterial fermentation) acting directly on peripheral tissues, following the recent identification of G-protein-coupled receptors specific for these ligands. PMID: 17637087 [PubMed - indexed for MEDLINE] 2831. Sheng Li Ke Xue Jin Zhan. 2007 Apr;38(2):181-3. [The function of adipose tissue in inflammatory state]. [Article in Chinese] Wu J, Wang HW, Wen Y. PMID: 17633242 [PubMed - indexed for MEDLINE] 2832. Sheng Li Ke Xue Jin Zhan. 2007 Apr;38(2):129-32. [The development of adipose derived stem cells]. [Article in Chinese] Li HX, Qu CQ, Luo X. PMID: 17633226 [PubMed - indexed for MEDLINE] 2833. Biochim Biophys Acta. 2007 Aug;1771(8):1046-64. Epub 2007 Jun 2. Exploration of PPAR functions by microarray technology--a paradigm for nutrigenomics. Bünger M(1), Hooiveld GJ, Kersten S, Müller M. Author information: (1)Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, NL-6700 EV Wageningen, The Netherlands. Traditionally, nutritional science was mainly concentrated on nutrient deficiencies and their effects on health and disease. However, over the past few decades, research emphasis has gradually shifted to the link between (over)-nutrition and chronic diseases. Driven by the continuing and accelerating discoveries in omics technology, unique possibilities have emerged to investigate the genome-wide effects of nutrients at the molecular level. Nutrigenomics uses these techniques in combination with a range of models and molecular tools as a strategy to understand the mechanistic basis of nutrition. As a paradigm for this strategy microarray analysis of genes regulated by peroxisome proliferator-activated receptors (PPARs) can serve. PPARs are ligand-activated transcription factors mediating the effect of unsaturated fatty acids and certain drugs on gene expression. Physiologically they act as fatty acid sensors in metabolic active organs, regulating a wide range of metabolic and signaling pathways. This allows cells to modulate their function and metabolic capacity, for example according to diet/nutrient-related changes in ligand concentration. Although much is already known about PPARs, gaps in our knowledge remain. In so far as the biological role of a particular PPAR is directly coupled to the function of its target genes, probing PPAR-regulated genes via the application of genomics tools can greatly improve our understanding of PPAR function. In this review we summarize and discuss the application of transcriptomics to study PPAR function, and discuss some of the challenges inherent to the application of transcriptomics to nutrigenomics research. PMID: 17632033 [PubMed - indexed for MEDLINE] 2834. C R Biol. 2007 Jun-Jul;330(6-7):521-9. Epub 2007 May 10. Neural crest progenitors and stem cells. Dupin E(1), Calloni G, Real C, Gonçalves-Trentin A, Le Douarin NM. Author information: (1)CNRS UPR2197 DEPSN, Institut de neurobiologie Alfred-Fessard, 91198 Gif-sur-Yvette, France. Elisabeth.dupin@inaf.cnrs-gif.fr In the vertebrate embryo, multiple cell types originate from a common structure, the neural crest (NC), which forms at the dorsal tips of the neural epithelium. The NC gives rise to migratory cells that colonise a wide range of embryonic tissues and later differentiate into neurones and glial cells of the peripheral nervous system (PNS), pigment cells (melanocytes) in the skin and endocrine cells in the adrenal and thyroid glands. In the head and the neck, the NC also yields mesenchymal cells that form craniofacial cartilages, bones, dermis, adipose tissue, and vascular smooth muscle cells. The NC is therefore a model system to study cell diversification during embryogenesis and phenotype maintenance in the adult. By analysing the developmental potentials of quail NC cells in clonal cultures, we have shown that the migratory NC is a collection of heterogeneous progenitors, including various types of intermediate precursors and highly multipotent cells, some of which being endowed of self-renewal capacity. We also have identified common progenitors for mesenchymal derivatives and neural/melanocytic cells in the cephalic NC. These results are consistent with a hierarchical model of lineage segregation wherein environmental cytokines control the fate of progenitors and stem cells. One of these cytokines, the endothelin3 peptide, promotes the survival, proliferation, and self-renewal capacity of common progenitors for glial cells and melanocytes. At post-migratory stages, when they have already differentiated, NC-derived cells exhibit phenotypic plasticity. Epidermal pigment cells and Schwann cells from peripheral nerves in single-cell culture are able to reverse into multipotent NC-like progenitors endowed with self-renewal. Therefore, stem cell properties are expressed by a variety of NC progenitors and can be re-acquired by differentiated cells of NC origin, suggesting potential function for repair. PMID: 17631447 [PubMed - indexed for MEDLINE] 2835. Drug Discov Today. 2007 Jul;12(13-14):504-20. Epub 2007 Jun 27. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Wamil M(1), Seckl JR. Author information: (1)Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11beta-HSD1 in adipose tissue. Transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11beta-HSD1 knockout mice have a 'cardioprotective' phenotype, whose effects are also seen with 11beta-HSD1 inhibitors in rodents. However, any major metabolic effects of 11beta-HSD1 inhibition in humans are, as yet, unreported. 11beta-HSD1 null mice also resist cognitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11beta-HSD1 inhibition is an emerging pleiotropic therapeutic target. PMID: 17631244 [PubMed - indexed for MEDLINE] 2836. FEBS Lett. 2007 Jul 31;581(19):3734-42. Epub 2007 Jun 27. Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance. Eriksson JW(1). Author information: (1)The Lundberg Laboratory for Diabetes Research, Institute of Medicine, Sahlgrenska University Hospital, SE 41345 Gothenburg, Sweden. jan.eriksson@medic.gu.se The metabolic syndrome is a cluster of cardiovascular risk factors, and visceral adiposity is a central component that is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. It is likely that adipose tissue, particularly in the intra-abdominal depot, is part of a complex interplay involving several tissues and that dysregulated hormonal, metabolic and neural signalling within and between organs can trigger development of metabolic disease. One attractive hypothesis is that many factors leading to insulin resistance are mediated via the generation of abnormal amounts of reactive oxygen species (ROS). There is much evidence supporting that detrimental effects of glucose, fatty acids, hormones and cytokines leading to insulin resistance can be exerted via such a common pathway. This review paper mainly focuses on metabolic and other 'stress' factors that affect insulin's target cells, in particular adipocytes, and it will highlight oxidative stress as a potential unifying mechanism by which these stress factors promote insulin resistance and the development and progression of type 2 diabetes. PMID: 17628546 [PubMed - indexed for MEDLINE] 2837. Curr Pharm Des. 2007;13(21):2208-13. Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome. Barbaro G(1). Author information: (1)Cardiology Unit, Department of Medical Pathophysiology, University La Sapienza, Rome, Italy. g.barbaro@tin.it HIV-associated lipodystrophy or lipoatrophy, unreported before the introduction of highly active antiretroviral therapy (HAART), was first described in 1998, and has a prevalence ranging from 18% to 83%. As in genetic lipodystrophy syndromes, fat redistribution may precede the development of metabolic complications (dyslipidemia, insulin resistance) in HIV-infected patients receiving HAART. The pathogenesis of HAART-associated lipodystrophy and metabolic syndrome is complex and a number of factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, and mitochondria. Protease inhibitors are responsible for a decrease in cytoplasmic retinoic-acid protein-1, in low density lipoprotein-receptor-related protein and in peroxisome proliferator activated receptor type-gamma. Nucleoside reverse transcriptase inhibitors, and thymidine analogues, are responsible for mitochondrial dysfunction as demonstrated by a decrease in subcutaneous adipose tissue mitochondrial DNA content. Both phenomena are responsible for a decreased differentiation of adipocytes, increased levels of free fatty acids and lipoatrophy. The increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-6 may further contribute in development of lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid dehydrogenase type-1, which converts inactive cortisone to active cortisol, resulting in increased lipid accumulation in adipocytes and insulin resistance. HAART drugs and inflammatory cytokines are associated with a decrease in adiponectin. The levels of adiponectin and adiponectin-to-leptin ratio correlate positively with insulin resistance in HIV-infected patients with lipodystrophy. HAART-associated metabolic syndrome is an increasingly recognized clinical entity. The atherogenic profile of this syndrome may increase the risk of cardiovascular disease even in young HIV-infected patients. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients receiving HAART. PMID: 17627554 [PubMed - indexed for MEDLINE] 2838. Curr Pharm Des. 2007;13(21):2199-207. Targeting the liver in the metabolic syndrome: evidence from animal models. Petruzzelli M(1), Lo Sasso G, Portincasa P, Palasciano G, Moschetta A. Author information: (1)Clinica Medica A. Murri, University of Bari, Italy. The metabolic syndrome is an emerging global epidemic characterized by clustering of metabolic abnormalities leading to increased cardiovascular risk: glucose intolerance or type 2 diabetes, dyslipidemia, hypertension, and "central" obesity. Scientists are decoding and piecing together the molecular texture underlying the metabolic syndrome: insulin resistance and dyslipidemia stand out as central pathophysiological events. In this picture, the liver rises as the leading organ in the maintenance of metabolic fitness; it serves as the first relay station for processing dietary information, and encloses the whole biochemical machinery for both glucose and lipid storage and disposal. In addition, the liver is a target of the different endocrine molecules secreted by pancreatic beta-cells and adipose tissue. Evidence collected in animal models supports the central role of the liver in the metabolic syndrome. While specific bereft of insulin sensitivity in skeletal muscle and adipose tissue fails to induce diabetes at certain extent, this is constantly the outcome in case of hepatic insulin resistance. Also, dyslipidemia is currently interpreted as the result of increased flux of free fatty acids to the liver with ensuing misbalance of lipoprotein synthesis and removal. In this review we bring together recent advances in the field of lipid sensing nuclear receptors, adipokines and other molecules responsible for metabolic fitness, and provide a putative coherent frame to conceive the pathophysiology of the metabolic syndrome. PMID: 17627553 [PubMed - indexed for MEDLINE] 2839. Curr Pharm Des. 2007;13(21):2185-92. Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction. Gao YJ(1). Author information: (1)Smooth Muscle Research Program and Dept of Anaesthesia, McMaster University, Hamilton, Ontario, Canada. gaoyu@univmail.cis.mcmaster.ca Almost every systemic vessel is surrounded by a layer of perivascular adipose tissue (PVAT), which had been mainly considered as a mechanical support for vasculature. However, recent advances have revealed that PVAT is an active player in controlling vessel function. PVAT releases relaxation factor(s) with unknown chemical identity (named perivascular adipocyte-derived relaxation factor, PVRF) that attenuates vasoconstriction to various agonists including phenylephrine, serotonin, angiotensin II, and U 46619 (a thromboxane A(2) mimic), through activation of K(+) channels. PVAT also promotes vasoconstriction to perivascular nerve stimulation by producing vasoconstrictor or facilitator (named perivascular adipocyte-derived constricting factor, PVCF), which includes superoxide and was mediated through activation of tyrosine kinase and MAPK/ERK pathways. Therefore, PVAT has a dual regulatory role in modulating vessel function, attenuating vasoconstriction to agonists by PVRF and promoting constriction to perivascular nerve excitation by PVCF. In vivo, normal amount of PVAT (total body fat as well) is likely to be important in maintaining the homeostasis of vascular tone and blood pressure, since lipoatrophic mice developed hypertension. On the other end, excessive accumulation of body fat (obesity) impaired PVRF production/action, despite an increase in the amount of PVAT. In spontaneously hypertensive rats, an animal model of hypertension without obesity, the ability of PVAT to attenuate vasoconstriction to agonists was reduced, and treatment with atorvastatin improved PVAT function. PVAT, vasodilating and constricting factors of PVAT origin, and signalling pathways of these factors may represent new targets for developing new strategies to treat vascular disorders associated with abnormal adiposity. PMID: 17627551 [PubMed - indexed for MEDLINE] 2840. Curr Pharm Des. 2007;13(21):2180-4. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Iacobellis G(1), Sharma AM. Author information: (1)Department of Medicine, Cardiovascular Obesity Research and Management, McMaster University Hamilton, Ontario, Canada. gianluca@ccc.mcmaster.ca Increased visceral adiposity, is an emerging cardiovascular risk factor. There is now a compelling need to quantify visceral adipose tissue not only for diagnostic purposes, but also for therapeutic interventions with weight reduction drugs or pharmaceuticals targeted to adipose tissue, as well as anti-obesity medications, thiazolidinediones, fibrates, angiotensin receptor blockers, highly active antiretroviral therapy and hormone replacement therapy. Among visceral adipose tissues, growing evidences suggest that cardiac adiposity may play an important role in the development of an unfavorable cardiovascular risk profile. Recent papers suggest that epicardial fat, index of cardiac and visceral adiposity, could locally modulate the morphology and function of the heart. The close anatomical relationship between epicardial adipose tissue and the adjacent myocardium should readily allow local paracrine interactions between these tissues. Echocardiography has been recently proposed for the direct assessment of epicardial adipose tissue. Echocardiographic assessment of epicardial fat may be a helpful tool not only for diagnostic purposes, as marker of visceral adiposity and inflammation, but also for therapeutic interventions with drugs that can modulate the adipose tissue. In this article, epicardial adipose tissue's structure, function, method of assessment and reliability as a diagnostic tool and potential therapeutic target is reviewed. PMID: 17627550 [PubMed - indexed for MEDLINE] 2841. Curr Pharm Des. 2007;13(21):2169-75. Visceral and subcutaneous adiposity: are both potential therapeutic targets for tackling the metabolic syndrome? Rodríguez A(1), Catalán V, Gómez-Ambrosi J, Frühbeck G. Author information: (1)Metabolic Research Laboratory, University of Navarra, Pamplona, Spain. The metabolic syndrome represents a constellation of co-morbidities that include central adiposity, insulin resistance, dyslipidemia and hypertension, which results from an elevated prevalence of obesity. An increased abdominal adiposity is observed in upper-body obesity with preferential accumulation of fat in the visceral depot, which renders these individuals more prone to metabolic and cardiovascular problems. The pathophysiology of the metabolic syndrome seems to be closely associated to an elevated efflux of free fatty acids from the visceral fat compartment and a dysregulation of the expression of adipose tissue-derived factors (also termed "adipokines"). Weight reduction and increased physical activity represent the main approach to tackle the "diabesity" epidemic. Nonetheless, taking advantage of the different biochemical and molecular characteristics of visceral and subcutaneous adipose tissue may open up novel pharmacological strategies to combat the metabolic and cardiovascular derangements accompanying the metabolic syndrome. PMID: 17627548 [PubMed - indexed for MEDLINE] 2842. Curr Pharm Des. 2007;13(21):2148-68. Metabolic syndrome and adipose tissue: new clinical aspects and therapeutic targets. Iannucci CV(1), Capoccia D, Calabria M, Leonetti F. Author information: (1)Department of Clinical Sciences. University Sapienza-Rome, Italy. The metabolic syndrome is a long-term process, explained by the interaction of genetic and environmental factors, that starts early in life and is involved in the pathophysiology of a large percentage of cases with type 2 diabetes and atherosclerosis. A number of clinical studies have demonstrated the importance of fat distribution and especially the contribution of visceral fat accumulation to the development of metabolic disorders. Visceral adipose tissue can be studied through different imaging techniques. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing metabolic disease and cardiovascular diseases (CVD). Visceral adipocytes secrete a variety of cytokines known as adipocytokines suggesting that adipose tissue is an endocrine organ that may affect the function of other organs. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, reducing the risk of developing chronic disease and CVD. Waist circumference is a required component of metabolic syndrome under the International Diabetes Federation (IDF) criteria, rather than an optional component as used by other previous classifications. Studies have shown that using a lower waist circumference threshold within the context of metabolic syndrome increases the prevalence, but decreases the risk of mortality and type 2 diabetes. It is possible that waist circumference acts as a marker for other risk factors. These findings reinforce the notion that reductions in visceral adipose tissue should be a primary aim of strategies designed to reduce health risks associated with metabolic syndrome. PMID: 17627547 [PubMed - indexed for MEDLINE] 2843. Antioxid Redox Signal. 2007 Aug;9(8):1143-56. Developments in quantitative oxygen-saturation imaging of breast tissue in vivo using multispectral near-infrared tomography. Srinivasan S(1), Pogue BW, Carpenter C, Jiang S, Wells WA, Poplack SP, Kaufman PA, Paulsen KD. Author information: (1)Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755, USA. subha@dartmouth.edu Imaging of oxygen saturation provides a spatial map of the tissue metabolic activity and has potential in diagnosis and treatment monitoring of breast cancer. Oxygen-saturation imaging is possible through near-infrared (NIR) tomography, but has low signal-to-noise ratio (SNR). This can be augmented by using NIR tomography as an add-on to MRI. Presented are results from a free-standing NIR system and a hybrid MR-guided system for breast imaging. In results from imaging 60 healthy volunteers in the initial NIR system, oxygen saturation was a significant discriminator between the BIRADS classifications of adipose tissue, heterogeneously dense, and extremely dense tissue. By using the MR-guided NIR system, more accurate tissue-specific data were obtained on adipose and fibroglandular volumes, with 11 healthy volunteers. In these data, oxygen saturation in the adipose tissue correlated with percentage of adipose tissue. In two case studies of infiltrating ductal carcinomas, oxygen saturation was reduced at the site of the tumor, as compared with the surrounding healthy tissue, agreeing with conventional thought that hypoxia exists in larger solid tumors. The MRI-guided NIR images of oxygen saturation provide higher resolution and superior SNR and will likely be used in the future to study and characterize specific tissue volumes. PMID: 17627478 [PubMed - indexed for MEDLINE] 2844. Neuroendocrinology. 2007;86(3):147-64. Epub 2007 Jul 2. Heterogeneity of ghrelin/growth hormone secretagogue receptors. Toward the understanding of the molecular identity of novel ghrelin/GHS receptors. Muccioli G(1), Baragli A, Granata R, Papotti M, Ghigo E. Author information: (1)Division of Pharmacology, Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy. Ghrelin is a gastric polypeptide displaying strong GH-releasing activity by activation of the type 1a GH secretagogue receptor (GHS-R1a) located in the hypothalamus-pituitary axis. GHS-R1a is a G-protein-coupled receptor that, upon the binding of ghrelin or synthetic peptidyl and non-peptidyl ghrelin-mimetic agents known as GHS, preferentially couples to G(q), ultimately leading to increased intracellular calcium content. Beside the potent GH-releasing action, ghrelin and GHS influence food intake, gut motility, sleep, memory and behavior, glucose and lipid metabolism, cardiovascular performances, cell proliferation, immunological responses and reproduction. A growing body of evidence suggests that the cloned GHS-R1a alone cannot be the responsible for all these effects. The cloned GHS-R1b splice variant is apparently non-ghrelin/GHS-responsive, despite demonstration of expression in neoplastic tissues responsive to ghrelin not expressing GHS-R1a; GHS-R1a homologues sensitive to ghrelin are capable of interaction with GHS-R1b, forming heterodimeric species. Furthermore, GHS-R1a-deficient mice do not show evident abnormalities in growth and diet-induced obesity, suggesting the involvement of another receptor. Additional evidence of the existence of another receptor is that ghrelin and GHS do not always share the same biological activities and activate a variety of intracellular signalling systems besides G(q). The biological actions on the heart, adipose tissue, pancreas, cancer cells and brain shared by ghrelin and the non-acylated form of ghrelin (des-octanoyl ghrelin), which does not bind GHS-R1a, represent the best evidence for the existence of a still unknown, functionally active binding site for this family of molecules. Finally, located in the heart and blood vessels is the scavenger receptor CD36, involved in the endocytosis of the pro-atherogenic oxidized low-density lipoproteins, which is a pharmacologically and structurally distinct receptor for peptidyl GHS and not for ghrelin. This review highlights the most recently discovered features of GHS-R1a and the emerging evidence for a novel group of receptors that are not of the GHS1a type; these appear involved in the transduction of the multiple levels of information provided by GHS and ghrelin. (c) 2007 S. Karger AG, Basel. PMID: 17622734 [PubMed - indexed for MEDLINE] 2845. Curr Opin Lipidol. 2007 Aug;18(4):389-96. GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons. Young SG(1), Davies BS, Fong LG, Gin P, Weinstein MM, Bensadoun A, Beigneux AP. Author information: (1)Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. sgyoung@mednet.ucla.edu PURPOSE OF REVIEW: To summarize recent data indicating that glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) plays a key role in the lipolytic processing of chylomicrons. RECENT FINDINGS: Lipoprotein lipase hydrolyses triglycerides in chylomicrons at the luminal surface of the capillaries in heart, adipose tissue, and skeletal muscle. The endothelial cell molecule that facilitates the lipolytic processing of chylomicrons has never been clearly defined. Mice lacking GPIHBP1 manifest chylomicronemia, with plasma triglyceride levels as high as 5000 mg/dl. In wild-type mice, GPIHBP1 is expressed on the luminal surface of capillaries in heart, adipose tissue, and skeletal muscle. Cells transfected with GPIHBP1 bind both chylomicrons and lipoprotein lipase avidly. SUMMARY: The chylomicronemia in Gpihbp1-deficient mice, the fact that GPIHBP1 is located within the lumen of capillaries, and the fact that GPIHBP1 binds lipoprotein lipase and chylomicrons suggest that GPIHBP1 is a key platform for the lipolytic processing of triglyceride-rich lipoproteins. PMCID: PMC2888298 PMID: 17620854 [PubMed - indexed for MEDLINE] 2846. Acta Gastroenterol Belg. 2007 Jan-Mar;70(1):25-31. Pathogenesis of steatohepatitis: insights from the study of animal models. Leclercq IA(1). Author information: (1)Laboratoire de gastroenterologie, Université catholique de Louvain (UCL), Brussels, Belgium. isabelle.leclercq@gaen.ucl.ac.be Non-alcoholic steatohepatitis (NASH) is a disease of expanded clinical importance. Its pathogenesis remains poorly understood. Tools to identify patients at risk and targeted treatments are lacking. The aim of this work was to analyse potential pathogenic mechanisms for inflammatory recruitment and fibrogenesis in NASH, using animal models. We demonstrated that oxidative stress, invariably associated with NASH, is a primary and necessary event for disease progression. Inhibition of stress-activated transcription factor NF-chiB prevents NASH. NF-chiB therefore appears as a pathogenic link between oxidative stress and NASH. Increased lipid beta-oxidation in NASH could generate oxidative stress. We used a potent inducer of PPAR-alpha to stimulate beta-oxidation in a model of steatohepatitis. Such treatment induced a complete clearance of steatosis together with a significant reduction of oxidative stress and oxidative injuries and prevention of inflammation and fibrosis. Thus in a situation of steatosis, stimulation of lipid combustion depletes the substrates for lipid peroxidation and thereby decreases oxidative stress. This effect is sufficiently powerful to prevent the development of steatohepatitis. We demonstrated that leptin is a pro-fibrogenic adipocytokine and is implicated in the regulation of liver regeneration. Leptin plays this crucial physiological role in hepatic wound healing by controlling the production and the activation of cytokines. The insulin sensitising drugs thiazolidinediones have antiinflammatory and anti-fibrotic properties in rats. We demonstrated that such drugs are poorly effective in the treatment of preestablished hepatic fibrosis in rats and unable to prevent fibrogenesis in vitro as well as in vivo in mice. Direct anti-fibrotic effect of such substances remains to be demonstrated in humans. In conclusion, our work demonstrates the importance of oxidative stress in the pathogenesis of NASH, the role of intrahepatic lipid overload and underlies the links between adipose tissue and the liver. PMID: 17619535 [PubMed - indexed for MEDLINE] 2847. Cell Metab. 2007 Jul;6(1):5-12. A nonadaptive scenario explaining the genetic predisposition to obesity: the "predation release" hypothesis. Speakman JR(1). Author information: (1)Aberdeen Centre for Energy Regulation and Obesity, School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland AB24 2TZ, UK. j.speakman@abdn.ac.uk The "thrifty gene hypothesis" suggests we evolved genes for efficient food collection and fat deposition to survive periods of famine and that now that food is continuously available, these genes are disadvantageous because they make us obese in preparation for a famine that never comes. However, famines are relatively infrequent modern phenomena that involve insufficient mortality for thrifty genes to propagate. I suggest here that early hominids would have been subjected to stabilizing selection for body fatness, with obesity selected against by the risk of predation. Around two million years ago predation was removed as a significant factor by the development of social behavior, weapons, and fire. The absence of predation led to a change in the population distribution of body fatness due to random mutations and drift. Because this novel hypothesis involves random drift, rather than directed selection, it explains why, even in Western society, most people are not obese. PMID: 17618852 [PubMed - indexed for MEDLINE] 2848. J Nutr Biochem. 2008 Feb;19(2):71-84. Epub 2007 Jul 6. Effects of dietary fibers on disturbances clustered in the metabolic syndrome. Galisteo M(1), Duarte J, Zarzuelo A. Author information: (1)Department of Pharmacology, CIBEREHD, School of Pharmacy, University of Granada, 18071 Granada, Spain. mgalist@ugr.es Because of its growing prevalence in Western countries, the metabolic syndrome, a common metabolic disorder that clusters a constellation of abnormalities, including central obesity, hypertension, dyslipidemia and insulin resistance, is emerging as one of the most important public health problems in the world, taking into account that it is a major risk factor mainly for type 2 diabetes and cardiovascular diseases, and also for many types of cancer. Although the pathogenesis of this syndrome is complex and not fully understood, obesity and insulin resistance, accompanied by an altered profile of number of hormones and cytokines produced by the adipose tissue, seem to be the main causative agents. A prime therapeutic approach to the prevention and treatment of this syndrome involves lifestyle changes. Among dietary modifications, dietary fiber intake could play an interesting role in the management of metabolic syndrome through different mechanisms related to its dietary sources, specific chemical structure and physical properties, or fermentability in the gut. According to all of these variables, the different types of dietary fibers have been reported to take part in the control of body weight, glucose and lipid homeostasis, insulin sensitivity and in the regulation of many inflammation markers involved in the pathogenesis of metabolic syndrome, and which are also considered to be among its features. PMID: 17618108 [PubMed - indexed for MEDLINE] 2849. Clin Chem Lab Med. 2007;45(7):815-21. Impact of genetic polymorphisms on the risk of lipid disorders in patients on anti-HIV therapy. Bonnet E(1), Genoux A, Bernard J, Fauvel J, Massip P, Perret B. Author information: (1)INSERM U563, Department of Lipoproteins and Lipid Mediators, CHU, Toulouse, France. Active anti-HIV therapy can induce hypertriglyceridemia, low high-density lipoprotein (HDL) and insulin resistance, eventually accompanied by clinical lipodystrophy, associated loss of subcutaneous adipose tissue and an increase in abdominal adiposity. The frequency of these metabolic disorders is approximately 50% and host genetic factors might confer particular susceptibility. Variants of apolipoproteins (apo) A5 and C3, interacting with APOE genotypes, have been associated with the severity of antiretroviral therapy-induced dyslipidemia and with occurrence of lipodystrophy, and for APOC3, with objective criteria of fat redistribution. Genetic polymorphisms of the nuclear transcription-factor sterol response element-binding proteins (SREBP1c) and of tumor necrosis factor-alpha (TNFalpha) have yielded contrasting results. Other candidate genes will be explored to define a pharmacogenomic strategy to identify patients at high risk of metabolic disorders upon antiretroviral therapy. PMID: 17617020 [PubMed - indexed for MEDLINE] 2850. Circ Res. 2007 Jul 6;101(1):27-39. Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting of humoral and neuronal signals. Katagiri H(1), Yamada T, Oka Y. Author information: (1)Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. katagiri@mail.tains.tohoku.ac.jp Erratum in Circ Res. 2007 Sep 14;101(6):e79. Obesity, a major healthcare issue, is associated with significant cardiovascular morbidities, including hypertension and atherosclerosis. Numerous intensive studies conducted this decade have revealed that adipose tissue is a major endocrine organ that secretes a variety of bioactive substances, termed adipocytokines. Adipocytokine secretion profiles are altered as obesity develops, which may increase the risk of obesity-related cardiovascular disorders. For instance, leptin is upregulated in obese subjects and plays important roles in the pathophysiology of obesity-related atherogenesis through multiple mechanisms, such as its proliferative, proinflammatory, prothrombotic, and prooxidant actions. In contrast, adiponectin, which is downregulated in obese subjects, has protective effects against cardiovascular disorders at various atherogenic stages. In addition to these factors secreted by adipose tissue, neuronal circuits involving autonomic nerves are now being recognized as an important metabolic regulatory system and have thus attracted considerable attentions. Alterations in fat accumulation in intraabdominal organs, such as visceral adipose tissue and the liver, send afferent neuronal signals to the brain, leading to modulation of sympathetic tonus and thereby affecting the vasculature. Moreover, these humoral and neuronal signaling pathways communicate with each other, resulting in cooperative metabolic regulation among tissues/organs throughout the body. Further elucidation of these regulatory systems is anticipated to lead to new approaches to devising therapeutic strategies for the metabolic syndrome. PMID: 17615379 [PubMed - indexed for MEDLINE] 2851. Microcirculation. 2007 Jun-Jul;14(4-5):389-402. Regulation of vascular function and insulin sensitivity by adipose tissue: focus on perivascular adipose tissue. Eringa EC(1), Bakker W, Smulders YM, Serné EH, Yudkin JS, Stehouwer CD. Author information: (1)Laboratory for Physiology, UV University Medical Center, Amsterdam, The Netherlands. e.eringa@vumc.nl Obesity is associated with insulin resistance, hypertension and cardiovascular disease, but the mechanisms underlying these associations are incompletely understood. Microvascular dysfunction may play an important role in the pathogenesis of both insulin resistance and hypertension in obesity. Adipose tissue-derived substances (adipokines) and especially inflammatory products of adipose tissue control insulin sensitivity and vascular function. Recently, adipose tissue associated with the arterial tree, called perivascular adipose tissue (PAT) has been shown to produce a variety of adipokines and to trigger vascular inflammation. This review summarizes the mechanisms linking adipose tissue to (micro)vascular function, inflammation and insulin resistance with a special focus on the role of PAT in the regulation of vascular tone, endothelial function, inflammation and insulin sensitivity. PMID: 17613810 [PubMed - indexed for MEDLINE] 2852. Microcirculation. 2007 Jun-Jul;14(4-5):349-62. Obesity, insulin resistance, and renal function. Knight SF(1), Imig JD. Author information: (1)Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA. There is a growing body of evidence indicating that obesity and insulin resistance contribute to the progression of renal disease. A low-grade inflammatory response occurs in obesity and insulin resistance that causes an increase in macrophage infiltration into the adipose tissue and the kidney. The infiltration of macrophages gives rise to the production of an array of pro-inflammatory cytokines and downstream elements such as interleukin-6, NFkappaB, and cellular adhesion molecules. In addition, increased adiposity triggers the release of adipokines such as leptin that can cause vascular remodeling and disruption of renal function. Insulin resistance can alter the balance between endogenous vasoactive molecules such as nitric oxide and reactive oxygen species, resulting in altered renal endothelial function. Moreover, hyperinsulinemia has direct renal effects such as induced relaxation of the afferent arteriole, resulting in glomerular hyperfiltration and renal damage. High insulin levels also stimulate angiogenesis and mesangial cell proliferation, associated with the development of diabetic nephropathy. Current evidence indicates a direct link between increased adiposity and insulin resistance with renal vascular injury; however, further investigation into the renal microvascular effects of obesity and insulin resistance are required to better understand this disease process. PMID: 17613807 [PubMed - indexed for MEDLINE] 2853. Microcirculation. 2007 Jun-Jul;14(4-5):269-71. Vascular dysfunction in obesity and insulin resistance. Frisbee JC(1). Author information: (1)Center for Interdisciplinary Research in Cardiovascular Sciences, Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26505, USA. jfrisbee@hsc.wvu.edu With the growing prevalence of obesity and impaired glycemic control, and the correlation between these conditions and an elevated predisposition for the development of vascular disease, research emphases are increasingly being targeted to the mechanistic bases and functional outcomes of these relationships. Given this, the current issue of Microcirculation, presents a series of reviews that summarize knowledge on an array of topics relevant to obesity, insulin resistance, and vascular dysfunction. The first chapters discuss altered patterns of blood flow regulation, vascular reactivity, microvascular density, and vascular wall mechanics. The second grouping details alterations to coronary, renal, and hepatic circulations and the implications of these effects for organ function. Additionally, one article presents knowledge and outlines future research directions for the study of endothelial permeability and barrier function within insulin resistance. The last group of articles discusses the effects of inflammation with obesity and insulin resistance on vascular function, and also details the role of perivascular adipose tissue in contributing to vascular dysfunction. The final review extends this general topic to the effects of the metabolic syndrome on microvascular dysfunction, wherein obesity and impaired glycemic control are contributing elements to a larger constellation of systemic pathologies. The authors hope that this Special Topics Issue will be informative for its readers and will provide a basis for future investigation into microvasculopathy in obesity and insulin-resistance. PMID: 17613800 [PubMed - indexed for MEDLINE] 2854. Leuk Lymphoma. 2007 Jul;48(7):1283-9. Multipotent mesenchymal stromal cells and immune tolerance. Noël D(1), Djouad F, Bouffi C, Mrugala D, Jorgensen C. Author information: (1)Université Montpellier 1, Montpellier, France. noel@montp.inserm.fr Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSC) are isolated mainly from bone marrow and adipose tissue but are identified in other tissues such as synovium, periosteum or placenta. They are characterised by their property to adhere to plastic, their phenotype and their ability to differentiate into three lineages (chondrocytes, osteoblasts and adipocytes). More recently, these cells were shown to escape immune recognition and inhibit immune responses. MSC may modulate the function of the major immune cell populations, including antigen-presenting cells, T cells, B cells and natural killer cells. The aim of this review is to focus on the molecular mechanisms, still poorly understood, which are responsible of the immunosuppressive effects mediated by the MSC. Finally, the data obtained from in vivo experimentation in various animal models as well as potential therapeutic applications will be presented. PMID: 17613755 [PubMed - indexed for MEDLINE] 2855. Subcell Biochem. 2007;42:63-91. Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Calabro P(1), Yeh ET. Author information: (1)Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, Italy, paolo.calabro@unina2.it Insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of central fat. With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to influence several aspects in the pathogenesis of obesity-related diseases Until relatively recently, the role of fat itself in the development of obesity and its consequences was considered to be a passive one; adipocytes were considered to be little more than storage cells for fat. It is now clear that, in addition to storing calories as triglycerides, they also secrete a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. This production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications. Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This remarkable understanding is allowing us to more clearly define the role that adipocytes play in health and in obesity and how inflammatory mediators act as signaling molecules in this process. Moreover, on a molecular level, we are beginning to comprehend how such variables as hormonal control, exercise, food intake, and genetic variation interact and result in a given phenotype, and how pharmacological intervention may modulate adipose tissue biology. PMID: 17612046 [PubMed - indexed for MEDLINE] 2856. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Jun;32(3):359-67. Genetic polymorphisms of human beta-adrenergic receptor genes and their association with obesity. Liu ZQ(1), Mo W, Huang Q, Zhou HH. Author information: (1)Institut eof Clinical Pharmacology, Xiangya School of Medicine, Central South University, Changsha 410078, China. The prevalent rates of overweight and obesity are steadily increasing all over the world. Previous studies of some candidate genes have indicated that most of the genes are associated with obesity in human adipose tissue. As much as 40% of the variations in body mass could be attributed to genetic difference. The beta-adrenergic receptor (beta-AR) plays a major role in the regulation of energy balance in humans. A high sympathetic nervous system activity has been shown to be associated with obesity and is believed to have pathogenetic relevance. Several common single nucleotide polymorphisms (SNPs) including Gly389Arg in beta(1)-AR, Gln27Glu in beta(2)-AR, and Trp64Arg in beta(3)-AR in humans could alter receptor function and these variations of beta-ARs were shown to have certain association with obesity. Here we summarize the genetic polymorphisms of human beta-ARs and their potential impacts to obesity. PMID: 17611309 [PubMed - indexed for MEDLINE] 2857. Tissue Antigens. 2007 Aug;70(2):87-95. Leptin in autoimmunity: many questions, some answers. Matarese G(1), Leiter EH, La Cava A. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy. gmatarese@napoli.com It has recently become apparent that several molecules involved in the control of metabolism also play an important function in the regulation of immune responses. Among those molecules, the adipocyte-derived cytokine leptin has been shown to significantly influence innate and adaptive immune responses both in normal and in pathological conditions. For example, levels of leptin are typically low in infection and high in autoimmunity, both systemically and at the site of inflammation. Moreover, in addition to its long-known effects on the promotion of T helper 1 immune responses and cell-mediated immunity, leptin has more recently been found capable to constrain proliferation of regulatory T cells. As such, leptin represents not only a link between metabolism and immune responses in general but also a pivotal modulator of the magnitude of selected mechanisms of peripheral immunity in relation to body fat mass. We review here the most recent advances on the role of leptin in the control of immune tolerance and critically discuss how strategies aimed at neutralizing the leptin axis could represent innovative tools for the therapy of autoimmune disorders. PMID: 17610413 [PubMed - indexed for MEDLINE] 2858. Vet Clin North Am Food Anim Pract. 2007 Jul;23(2):321-32, viii. Alterations in the physiology of growth of cattle with growth-enhancing compounds. Johnson BJ(1), Chung KY. Author information: (1)Nutritional Growth and Development, Department of Animal Sciences and Industry, Kansas State University, Manhattan, KS 66506-1600, USA. bjohnson@ksu.edu Commonly used growth promotants such as steroidal implants and beta-adrenergic agonists have recently been implicated in the reduction of marbling scores in beef cattle. These compounds are effective at improving lean tissue deposition in cattle, thus significantly improving feed efficiency. This article discusses skeletal muscle growth and development in cattle, the process of transdifferentiation between two cell types, and how growth promotants may push a nondifferentiated cell to become a certain lineage of cells. Increased understanding of how these agents affect cellular aspects of growth and development of skeletal muscle and adipose tissue will allow cattle feeders, consultants, and researchers to instigate intervention strategies to ameliorate the reduced marbling scores. Successful strategies would allow maximal lean tissue growth and result in carcasses with optimal quality. PMID: 17606154 [PubMed - indexed for MEDLINE] 2859. Vet Clin North Am Food Anim Pract. 2007 Jul;23(2):247-68, vi-vii. Feed value of supplemental fats used in feedlot cattle diets. Zinn RA(1), Jorquera AP. Author information: (1)Department of Animal Science, University of California, Davis, CA 95616-8521, USA. razinn@ucdavis.edu The inclusion of supplemental fats in growing-finishing diets for feedlot cattle also improves diet "condition." Quality factors that may influence the feeding value of fat include the source of fat; moisture, impurities, and unsaponifiables; free fatty acid concentration; degree of saturation or titer; and rancidity (peroxide value). The net energy value of fat declines linearly with an increasing level of supplementation because of constraints on postruminal fatty acid digestion. The authors recommend that receiving diets not contain more than 2% supplemental fat. Little evidence suggests that the feeding value of fat is different for Holsteins than for conventional beef breeds. Fat supplementation is not consistent in its effect on intramuscular fat distribution (marbling), longissimus (rib eye) area, and fat thickness, but can be expected to increase dressing percentage and kidney, pelvic, and heart fat percentage. PMID: 17606149 [PubMed - indexed for MEDLINE] 2860. Nutr Rev. 2007 Jun;65(6 Pt 2):S64-8. The role of dietary protein on lipotoxicity. Torres N(1), Tovar AR. Author information: (1)Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico. The worldwide increase in degenerative diseases is in part due to modifications in the lifestyle including the diet. Epidemiological, clinical, and experimental evidence shows that soy protein may prevent lipotoxicity in non-adipose tissues during obesity. The molecular mechanism by which soy protein prevents lipotoxicity involves a reduction in the insulin/glucagon ratio, resulting in a down-regulation of lipogenic genes mediated by the transcription factor sterol regulatory element-binding protein (SREBP)-1, and up-regulation of SREBP-2 to reduce serum cholesterol. In addition, soy protein maintains the functionality of adipose tissue-liver axis to prevent hepatic steatosis during the development of obesity. PMID: 17605316 [PubMed - indexed for MEDLINE] 2861. Nutr Rev. 2007 Jun;65(6 Pt 2):S24-9. Visceral adipocytes and the metabolic syndrome. Tchernof A(1). Author information: (1)Molecular Endocrinology and Oncology Research Center, Department of Nutrition, Laval University Medical Research Center and Laval University, Quebec City, Province of Quebec, Canada. andre.tchernof@crchul.ulaval.ca Recently, the high responsiveness of omental adipocytes to positive lipolytic stimuli has been clearly demonstrated in women. We conclude that adipose tissue fatty acid release, storage capacity, and secreted cytokines may all be involved in the etiology of the metabolic syndrome. The anatomical location of visceral adipocytes close to the liver, combined with possible depot-specific alterations in various adipocyte or adipose tissue features likely play critical roles in this process. This highly complex etiology is concordant with the heterogeneous clinical manifestations of the metabolic syndrome, and suggests possible interindividual variability in the extent to which each pathophysiological mechanism is involved. PMID: 17605310 [PubMed - indexed for MEDLINE] 2862. Nutr Rev. 2007 Jun;65(6 Pt 2):S7-12. Adipose tissue expandability in the maintenance of metabolic homeostasis. Gray SL(1), Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, United Kingdom. Adipose tissue expands to accommodate increased lipid through hypertrophy of existing adipocytes and by initiating differentiation of preadipocytes. The capacity of adipose tissue to expand is critical for accommodating changes in energy availability, but this capacity is not an unlimited process and likely varies between individuals. We suggest that it is not the absolute amount of adipose tissue but rather the capacity of adipose tissue to expand that affects metabolic homeostasis. Here we highlight examples of disease states and transgenic animal models with altered adipose tissue function that support this hypothesis and discuss possible mechanisms by which altered adipose tissue expandability impairs metabolic homeostasis. PMID: 17605308 [PubMed - indexed for MEDLINE] 2863. Curr Opin HIV AIDS. 2007 Jul;2(4):247-52. doi: 10.1097/COH.0b013e3281e66919. From lipodystrophy and insulin resistance to metabolic syndrome: HIV infection, treatment and aging. Capeau J. PURPOSE OF REVIEW: The rapid occurrence of lipodystrophy and metabolic alterations in the late 1990s at the same time as antiretroviral treatments were able to control HIV infection led to defining a new field of HIV-related complications. Even if their pathophysiology is partly but incompletely understood, the different antiretroviral drugs play the leading role. In addition, Western countries' populations face a major metabolic risk due to high-fat diet and sedentary lifestyle. RECENT FINDINGS: The mechanisms whereby antiretroviral drugs, including first-generation protease inhibitors and thymidine analogues, alter adipose function have been partly deciphered. Lipodystrophic adipose tissue presents an inflammatory state with insulin resistance which can impact on the liver and muscles, leading to metabolic alterations. In addition, some drugs are also responsible for direct effects on metabolic parameters. These abnormalities occur in the context of patients' aging, nutritional excess, sedentariness and smoking, leading to increased metabolic and cardiovascular risks. SUMMARY: More research is required to find antiretroviral drugs devoid of adverse metabolic effects and to find and validate molecules able to reverse the lipodystrophic phenotype. At present, it is critical to optimize the patients' antiretroviral treatment by considering drugs with a friendly adipose and metabolic profile. The specific metabolic alterations require adapted treatment interventions to decrease the occurrence of cardiovascular and hepatic complications and of diabetes. PMID: 19372895 [PubMed] 2864. J Assoc Physicians India. 2007 Mar;55:203-10. Fat and muscle component of body mass index (BMI): relation with hyperinsulinemia. Lele RD(1). Author information: (1)Nuclear Medicine Department, Jaslok Hospital and Research Centre, Mumbai. Currently there is tremendous interest in obesity and its harmful donsequences. Height, weight and body mass index (BMI) along with waist girth are routinely used parameters. One snag in the interpretation of BMI >25 as a measure of obesity is the assumption that the increase is mainly due to fat. This review emphasizes the importance of assessing the muscle component of BMI (by simple somatoscopy or somatotyping). 75 percent of Indian T2DM patients have a normal or low BMI, only 25 percent have BMI >25, wherein muscle mass also contributes as well as fat. Hyperinsulinemia is anabolic to both fat and muscle. Since skeletal muscle is a primary site of insulin resistance, greater the muscle mass, greater the importance of physical exercise to overcome the insulin resistance and greater the importance of dietary supplement of n3-PUFA to optimize the phospholipid composition of the muscle membrane (increasing membrane fluidity and thereby permitting longer residence of GLUT-4 in the plasma membrane). I propose three testable hypotheses: (1) Brown fat (FDG-PET imaging) and UCP2 and UCP3 expression in muscle are positively correlated with ectomorphy and mesomorphy, and negatively correlated with endomorphy and obesity. BAT is absent in obese people. (2) Indian T2DM patients with normal or low BMI have increased UCP2 and UCP3 expession in their muscle, as well as increased high molecular weight adiponectin which promote fatty acid oxidation and prevent obesity. (3) Indian T2DM with BMI >25 and obesity have dysfunction of UCP2 and UCP3. They have high leptin with leptin resistance (induced by hyperinsulinemia) and low adiponectin. There is inverse relationship between adipose mass and adiponectin production. PMID: 17598332 [PubMed - indexed for MEDLINE] 2865. Rinsho Byori. 2007 May;55(5):447-51. [PPARgamma and metabolic syndrome]. [Article in Japanese] Terauchi Y(1). Author information: (1)Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been suggested to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, beta, and beta/delta, have distinct expression patterns. We have investigated the role of PPARgamma in the pathogenesis of type 2 diabetes. Heterozygous PPARgamm-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy on a high-fat diet. A Pro12Ala polymorphism in the human PPARgamma2 gene, which has been reported to cause a reduction in PPARy activity, was associated with a decreased risk of type 2 diabetes in various ethnic groups including Japanese subjects. Consistent with these results, moderate reduction of PPARgamma activity by RXR antagonist decreased the triglyceride content of white adipose tissue (WAT)/muscle/liver, due to an increase in fatty-acid combustion and a decrease in lipogenesis, thereby ameliorating high-fat diet-induced obesity and insulin resistance. By contrast, potent activation of PPARy by thiazolidinedione (TZD) stimulated adipocyte differentiation and apoptosis, thereby preventing adipocyte hypertrophy, which is associated with the alleviation of insulin resistance, presumably due to decreases in FFA, and TNFa, and the up-regulation of adiponectin. TZD increased the triglyceride content of WAT, but decreased that of the liver/muscle, leading to the amelioration of insulin resistance at the expense of obesity. It should also be noted that TZD has an anti-atherogenic effect in vivo. Uncovering the regulatory mechanisms and transcriptional targets of PPARgamma will provide insights into the pathogenesis of metabolic syndrome and offer valuable information for rational drug design. PMID: 17593690 [PubMed - indexed for MEDLINE] 2866. Diabetologia. 2007 Aug;50(8):1576-86. Epub 2007 Jun 26. Insulin resistance and the metabolic syndrome--or the pitfalls of epidemiology. Yudkin JS(1). Author information: (1)Department of Medicine, University College London, Archway Campus, Highgate Hill, London, UK. j.yudkin@ucl.ac.uk The clustering of dyslipidaemia, hypertension and glucose intolerance, predominantly in overweight individuals, has been ascribed many names, including syndrome X and the metabolic syndrome. In Reaven's original description of syndrome X, a central aetiological role was attributed to insulin resistance, and this assumption has remained as the dominant paradigm for the metabolic syndrome. There are a number of conceptual problems in such a model, particularly those arising from observations that several novel markers, including measures of endothelial dysfunction and of low-grade inflammation, are as closely related to insulin resistance as are the classic components of the syndrome. Because it is difficult to envisage how these traits might develop as a consequence of insulin resistance, such observations indicate the need for a new paradigm to explain the mechanisms of association better. It has been proposed that a state of low-grade inflammation, consequent upon the production of adipocytokines, particularly from truncal fat, explains the observed relationships between insulin resistance and endothelial dysfunction better than does a model revolving around insulin resistance. Furthermore, the inflammatory cytokines generated from adipose tissue may influence vessel endothelial function without elevations in circulating concentrations. This review alludes to several problems inherent in the epidemiological method in understanding disease mechanisms. These include crude biological measures, the use of venous systemic fasting samples, imprecision of assays, naive physiological models, simplistic statistical approaches and, without clinical trials, an inability to test causation. Integrated systems biology needs more complex approaches to investigate disease mechanisms, involving cell, organ, whole organism and population studies. PMID: 17593345 [PubMed - indexed for MEDLINE] 2867. Trends Mol Med. 2007 Jul;13(7):298-309. Epub 2007 Jun 27. Targeting farnesoid X receptor for liver and metabolic disorders. Fiorucci S(1), Rizzo G, Donini A, Distrutti E, Santucci L. Author information: (1)Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Perugia, Italy. fiorucci@unipg.it The farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver, intestine, kidney and adipose tissue. By regulating the expression and function of genes involved in bile acid (BA) synthesis, uptake and excretion, FXR has emerged as a key gene involved in the maintenance of cholesterol and BA homeostasis. FXR ligands are currently under clinical investigation for the treatment of cholestasis, dyslipidemic disorders and conditions of insulin resistance in type 2 diabetes and non-alcoholic steatohepatitis (NASH). Because activation of FXR impacts a considerable number of genes, development of FXR modulators that selectively regulate specific pathways will limit potentially undesirable side effects. Interaction of FXR with other BAs and xenobiotics sensors such as the constitutive androstane receptor and the pregnane X receptor might allow the development of combination therapies for liver and metabolic disorders. PMID: 17588816 [PubMed - indexed for MEDLINE] 2868. Diabetes Obes Metab. 2007 Jul;9(4):464-76. Adipocyte prolactin: regulation of release and putative functions. Brandebourg T(1), Hugo E, Ben-Jonathan N. Author information: (1)Department of Cell Biology, University of Cincinnati School of Medicine, Cincinnati, OH, USA. Pituitary-derived prolactin (PRL) is a well-known regulator of the lactating mammary gland. However, the recent discovery that human adipose tissue produces PRL as well as expresses the PRL receptor (PRLR) highlights a previously unappreciated action of PRL as a cytokine involved in adipose tissue function. Biologically active PRL is secreted by all adipose tissue depots examined: breast, visceral and subcutaneous. The expression of adipose PRL is regulated by a non-pituitary, alternative superdistal promoter. PRL expression and release increases during early pre-adipocyte differentiation and is stimulated by cyclic AMP activators, including beta adrenergic receptor agonists. PRL release from subcutaneous adipose explants is attenuated during obesity, suggesting that adipose PRL production is altered by the metabolic state. Several lines of evidence indicate that PRL suppresses lipid storage as well as the release of adipokines such as adiponectin, interleukin-6 and possibly leptin. PRL has also been implicated in the regulation of adipogenesis. A newly developed PRL-secreting human adipocyte cell line, LS14, should allow comprehensive examination of the regulation and function of adipocyte-derived PRL. Collectively, these studies raise the prospect that PRL affects energy homeostasis through its action as an adipokine and is involved in the manifestation of insulin resistance. PMID: 17587388 [PubMed - indexed for MEDLINE] 2869. Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2009-23. Epub 2007 Jun 22. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Cooper SA(1), Whaley-Connell A, Habibi J, Wei Y, Lastra G, Manrique C, Stas S, Sowers JR. Author information: (1)Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri 65212, USA. Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue. PMID: 17586614 [PubMed - indexed for MEDLINE] 2870. J Physiol. 2007 Sep 1;583(Pt 2):425-30. Epub 2007 Jun 21. Why some of us get fat and what we can do about it. Levin BE(1). Author information: (1)Neurology Service, VA Medical Center, East Orange, NJ 07018-1095, USA. levin@umdnj.edu Comment in J Physiol. 2007 Sep 1;583(Pt 2):423. There is a widespread obesity epidemic in the developed world which is having an adverse impact on the health of affected individuals. Many of the afflicted have a genetic predisposition to become obese. These individuals become obese when they over consume highly palatable, calorically dense foods which are readily available at low cost. Once obesity occurs, fewer than 10% of affected individuals can sustain significant weight loss permanently. The hypothesis of this review is that some obesity-prone individuals have an inborn reduction in their ability to sense and respond to inhibitory signals from adipose stores and other organs which should limit their intake of energy when it exceeds their metabolic needs. Furthermore, the physiological processes which drive all of us to seek and ingest food and limit energy expenditure during periods of negative energy balance provide an irresistible drive to regain lost adipose stores in weight-reduced obese individuals. For this reason, prevention of obesity and the identification factors which promote the development of neural pathways which enhance the negative feedback signals from the periphery should be a major focus of ongoing research in this field. PMCID: PMC2277034 PMID: 17584845 [PubMed - indexed for MEDLINE] 2871. Endocr Metab Immune Disord Drug Targets. 2007 Jun;7(2):125-40. Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity? Atanasov AG(1), Odermatt A. Author information: (1)Department of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland. Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11-dehydrocorticosterone) into active 11beta-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11beta-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11beta-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11beta-HSD1 function. PMID: 17584152 [PubMed - indexed for MEDLINE] 2872. Cardiovasc Hematol Disord Drug Targets. 2007 Jun;7(2):79-85. The metabolic syndrome and vascular disease in Asia. Cheung BM(1), Thomas GN. Author information: (1)Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. mycheung@hkucc.hku.hk The metabolic syndrome is a constellation of vascular disease risk factors that includes hyperglycaemia, hypertension, and dyslipidaemia, which are largely mediated by accumulating fat depots, particularly when centrally deposited. Increasing adiposity promotes insulin resistance, low grade inflammation and endothelial dysfunction, which promote the development of atherogenic vascular disease. Increases in percentage body fat result from a number of parameters, including ageing, and changes in lifestyle factors that promote a metabolic imbalance, such as decreasing physical activity and adverse dietary patterns. As Asian populations continue to modernize, levels of physical activity are declining as home and workplace jobs become more automated and sedentary and transportation more readily available. Similarly, dietary changes are introduced, with healthy traditional plant-based diets being replaced by cheaper calorie dense high fat foods. These changes are resulting in rapid increases in the prevalence of obesity throughout Asia, and the subsequent development of the metabolic syndrome. To minimise further development of the obesity pandemic and subsequent vascular disease, innovative population-based preventative lifestyle and therapeutic strategies interventions need to be introduced. PMID: 17584042 [PubMed - indexed for MEDLINE] 2873. Vasc Health Risk Manag. 2007;3(1):55-63. Cardiometabolic aspects of polycystic ovarian syndrome. Cho LW(1), Randeva HS, Atkin SL. Author information: (1)Department of Medicine, University of Hull, UK. l.cho@hull.ac.uk It is estimated that 60%-7% of women of reproductive age have polycystic ovarian syndrome (PCOS). Women with this condition exhibit an adverse cardiovascular risk profile, characteristic of the cardiometabolic syndrome and given the high prevalence of PCOS in the female population, this condition may contribute towards the acceleration of cardiovascular disease among young women. This article summarizes the recent development and findings in the cardiometabolic abnormalities in patients with PCOS. Patients with PCOS have the clinical features of oligomenorrhoea, hirsutism and infertility; however, they also exhibit hyperinsulinemia, obesity, hypertension, dyslipidemia, and an increased pro-thrombotic state. They have an increased risk of type 2 diabetes and impaired glucose tolerance, and sleep apnea is also found more commonly in this population. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease it is unclear if they have accelerated atherosclerosis. End point studies are currently lacking and the available evidence are conflicting. Adipose tissue has emerged as an important endocrine organ over the last decade and gained recognition in having an important role in the cardiometabolic syndrome. Adiponectin that is secreted exclusively by adipocytes has recently been recognized as an important marker of cardiometabolic syndrome, obesity, type 2 diabetes, and coronary artery disease. Other adipocytokines like leptin and resistin have also recently been recognized. This article will address the current evidence for the adverse cardiovascular risk in PCOS and the other factors that may be implicated. Finally the therapeutic options for treatment will be discussed. PMCID: PMC1994046 PMID: 17583175 [PubMed - indexed for MEDLINE] 2874. Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R974-80. Epub 2007 Jun 20. Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. Henriksen EJ(1). Author information: (1)Department of Physiology, Ina E. Gittings Bldg. #93, University of Arizona, Tucson, AZ 85721-0093, USA. ejhenrik@u.arizona.edu The reduced capacity of insulin to stimulate glucose transport into skeletal muscle, termed insulin resistance, is a primary defect leading to the development of prediabetes and overt type 2 diabetes. Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) produced from this system can act on ANG II type 1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of reactive oxygen species (ROS). Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole body and skeletal muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. Collectively, these findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with prediabetes and type 2 diabetes. PMID: 17581838 [PubMed - indexed for MEDLINE] 2875. Folia Biol (Praha). 2007;53(3):97-108. Growth-inhibiting activity of transcription factor C/EBPalpha, its role in haematopoiesis and its tumour suppressor or oncogenic properties in leukaemias. Fuchs O(1). Author information: (1)Institute of Haematology and Blood Transfusion, Prague, Czech Republic. Ota.Fuchs@uhkt.cz The CCAAT/enhancer binding protein alpha (C/EBPalpha or CEBPA) is the founding member of a family of related leucine zipper transcription factors that play important roles in myeloid differentiation. Targeted inactivation of C/EBPalpha in mice demonstrates its importance in the proper development and function of liver, adipose tissue, lung and haematopoietic tissues. C/EBPalpha is highly expressed in these differentiated tissues where it controls differentiation-dependent gene expression and inhibits cell proliferation. Learning more about the precise molecular functions of the C/EBPalpha protein and how these are affected by leukaemogenic mutations should lead to an improved understanding of the cellular functions that are disrupted in patients with AML. Decreased expression of C/EBPalpha but not C/EBPalpha mutation has been shown in patients with granulocytic leukaemias that are associated with translocations t(8;21), inv (16) or t(15;17). Derived fusion proteins repress C/EBPalpha expression. Differentiation therapy of some AML types is based on restoring C/EBPalpha function. However, apparently normal C/EBPalpha is overexpressed in BCP-ALL harbouring the translocation t(14; 19)(q32; q13). C/EBPalpha may exhibit oncogenic as well as tumour suppressor properties in human leukaemogenesis. C/EBPalpha mutations were not found in non-haematopoietic cancers. DNA hypermethylation of the upstream C/EBPalpha promoter region is responsible for very low C/EBPalpha expression in human lung and endometrial cancer. C/EBPalpha expression may be a biomarker for early detection of these cancers and DNA-modifying drugs such as demethylating agents and/or histone deacetylase inhibitors could be used in the treatment of these malignancies. PMID: 17580000 [PubMed - indexed for MEDLINE] 2876. Vnitr Lek. 2007 Apr;53(4):359-63. [Adiponectin and atherosclerosis]. [Article in Czech] Haluzíková D(1), Roubícek T, Haluzík M. Author information: (1)II. interní klinika 1. lékarské fakulty UK a VFN Praha. dhalu@lf1.cuni.cz Obesity combined with other components of the insulin resistance syndrome is an important risk factor for atherosclerosis and its complications. The exact mechanisms through which the above diseases are linked have not yet been fully elucidated. One of the possible links may be a disturbance of the endocrine function of the adipose tissue of obese persons which produces an increased amount of proinflammatory and proatherogenic hormones and a lower amount of factors protecting against such pathologies. Adiponectin is the only hormone produced by the adipose tissue with a proven antiinflammatory and antiatherosclerotic effect. This hormone is predominantly produced by adipocytes and its concentrations are decreased in patients with obesity, insulin resistance and atherosclerosis. The objective of the article is to summarize current experimental and clinical knowledge of the links between adiponectin and atherosclerosis and to discuss possible utilization of adiponectin as a marker for atherosclerosis, and the potential for its exploitation in the prevention and/or treatment of atherosclerosis. PMID: 17578166 [PubMed - indexed for MEDLINE] 2877. Genes Dev. 2007 Jun 15;21(12):1443-55. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Qatanani M(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. Obesity-associated insulin resistance is a major risk factor for type 2 diabetes and cardiovascular disease. In the past decade, a large number of endocrine, inflammatory, neural, and cell-intrinsic pathways have been shown to be dysregulated in obesity. Although it is possible that one of these factors plays a dominant role, many of these factors are interdependent, and it is likely that their dynamic interplay underlies the pathophysiology of insulin resistance. Understanding the biology of these systems will inform the search for interventions that specifically prevent or treat insulin resistance and its associated pathologies. PMID: 17575046 [PubMed - indexed for MEDLINE] 2878. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):237-51. Tissue uptake of thyroid hormone by amino acid transporters. Taylor PM(1), Ritchie JW. Author information: (1)Division of Molecular Physiology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, UK. p.m.taylor@dundee.ac.uk Thyroid hormones (THs) -- thyroxine (T4) and tri-iodothyronine (T3) -- are iodinated derivatives of the amino acid tyrosine, which regulates growth, development and critical metabolic functions. THs are taken up by target cells and act at the genomic level via nuclear thyroid receptors. Saturable transport mechanisms mediate the greater part of TH movement across the plasma membrane. System L1 permease is a transporter of THs and amino acids in mammalian adipose tissue, placenta and brain. T(3) is also a substrate of a putative System T transporter, which is selective for aromatic amino acids. The activity and functional mechanisms of these transporters can be crucial to cells in determining both their hormone sensitivity and their responses to change in circulating hormone concentrations or availability of competing substrates (e.g. amino acids). TH transporters are potentially important pharmacological targets in the design of novel or improved therapies for thyroid-related disorders. PMID: 17574006 [PubMed - indexed for MEDLINE] 2879. Med Mol Morphol. 2007 Jun;40(2):55-67. Epub 2007 Jun 18. Pathophysiological significance of adiponectin. Nishida M(1), Funahashi T, Shimomura I. Author information: (1)Health Care Center, Osaka University 1-17 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan. makoton@imed2.med.osaka-u.ac.jp Adipose tissue, which classically has been considered as an energy-storing organ, is now viewed as a massive source of bioactive substances such as leptin, tumor necrosis factor (TNF)-alpha, and adiponectin. Adiponectin was discovered to be the most abundant adipose-specific transcript. Its function had been unclear, but epidemiological and clinical studies have demonstrated that serum levels of adiponectin are inversely associated with body weight, especially abdominal visceral fat accumulation. In addition, adiponectin was inversely related to cardiovascular risk factors, such as insulin resistance, blood pressure, and low-density lipoprotein (LDL) cholesterol and triglyceride levels, and was positively related to high-density lipoprotein (HDL) cholesterol levels. Moreover, low adiponectin concentration is associated with a high incidence of cardiovascular disease (CVD), diabetes, some kinds of cancer, and other various diseases. These associations suggest the clinical significance of adiponectin, and a number of investigations are now being conducted to clarify the biological functions of adiponectin. Recent studies have revealed that adiponectin exhibits antiinflammatory, antiatherogenic, and antidiabetic properties. In addition, adiponectin has been thought to be a key molecule in "metabolic syndrome," which is an epidemiological target for preventing cardiovascular disease. Various functions of adiponectin may possibly serve to prevent and treat obesity-related diseases and CVD. Furthermore, enhancement of adiponectin secretion or action may become a promising therapeutic target. PMID: 17572841 [PubMed - indexed for MEDLINE] 2880. Postepy Hig Med Dosw (Online). 2007 Jun 13;61:384-402. [Microdialysis: its application in experimental and clinical studies of disturbances in tissue metabolism]. [Article in Polish] Maruniak-Chudek I(1), Swietliński J. Author information: (1)Klinika Intensywnej Terapii i Patologii Noworodka, Slaska Akademia Medyczna w Katowicach, Katowice, Poland. ich@mp.pl Homeostasis of human and animal organisms and its disturbance are explored mainly by evaluating metabolic substrates and metabolite concentrations and their changes under different clinical conditions. This review describes a method of tissue biochemistry monitoring by analysis of extracellular fluid dialysate. Microdialysis not only provides information about the general disturbances of the body, but allows insight into the local metabolism of tissues and organs. It can be applied both in experimental conditions (e.g. animal neurophysiology) and in clinical practice (episodes of brain ischemia, glycemic disturbances, pharmacodynamic studies). The technique of microdialysis is relatively simple and is based on microdialysis probe implantation into the studied organ or tissue, followed by measurement of the obtained samples of extracellular fluid dialysate. During the last twenty years, microdialysis probes have been inserted into different part of the living organism: brain, skeletal muscles, subcutaneous adipose tissue, transplanted tissues (myocutaneous flap) and organs (liver), tendons, skin, breast gland, lungs, heart muscle, intestines, and body cavities. The possibility of frequent sampling (every 20-60 minutes) and measuring the concentrations of glucose, glycerol, lactates, and pyruvates with a bedside analyzer in an average time of 2-3 minutes is considered a great advantage of this method. Microdialysis gives many opportunities for a better understanding of how living organisms are functioning, but it requires cautious application and validation in clinical observations in order to make standards and recommendations (diseases and clinical conditions, substances for monitoring, referenced values and trends) for its common medical usage. PMID: 17572658 [PubMed - indexed for MEDLINE] 2881. Plast Reconstr Surg. 2007 Jul;120(1):109-23. Transpalpebral decompression of endocrine ophthalmopathy by intraorbital fat removal (Olivari technique): experience and progression after more than 3000 operations over 20 years. Richter DF(1), Stoff A, Olivari N. Author information: (1)Department of Plastic and Reconstructive Surgery, Dreifaltigkeits Hospital, Wesseling, Germany. Comment in Plast Reconstr Surg. 2008 Apr;121(4):1507-8. BACKGROUND: Graves' ophthalmopathy is a chronic, multisystem disorder characterized by increased intraorbital fat tissue and hypertrophic extraocular muscles caused by an autoimmune process. Graves' ophthalmopathy represents the most frequent extrathyroidal manifestation of Graves' disease. Clinical findings are impaired ocular motility, diplopia, lid retraction, and impaired visual acuity up to optic neuropathy, with menacing blindness. METHODS: Transpalpebral decompression by intraorbital fat removal was first described by Olivari in 1988. From 1984 to 2004, a consecutive series of 1635 patients (3210 eyes) with Graves' ophthalmopathy underwent this operation at the authors' institution. The medical records of 1374 patients (84 percent) could be evaluated retrospectively. RESULTS: Postoperatively, the majority of patients showed significant improvements of major symptoms such as ocular protrusion, diplopia, decreased visual acuity, swelling of the eyelids, retrobulbar pressure, and headache. In addition, complications-most of them temporary and reversible-were rare. Because the osseous orbita is not touched, no complications, such as penetration of the dura, infection of the sinus maxillaris, meningitis, irritation of the infraorbital nerve, or obstruction of the lacrimal system, were observed. However, the high number of additional eyelid corrections (average, 2.5 individual corrections) following the decompression indicated the complexity of surgical treatment in endocrine orbitopathy. CONCLUSION: Transpalpebral decompression has proved to be reliable, effective, and safe, with good, lasting results leading to an improvement not only in visual function but also in the patient's personal well-being and social life, with a high-benefit-to-low-risk ratio. PMID: 17572552 [PubMed - indexed for MEDLINE] 2882. Obstet Gynecol Clin North Am. 2007 Jun;34(2):201-12, vii-viii. In utero exposure to maternal obesity and diabetes: animal models that identify and characterize implications for future health. Nathanielsz PW(1), Poston L, Taylor PD. Author information: (1)Department of Obstetrics & Gynecology, Center for Pregnancy and Newborn Research, The University of Texas of Health Science Center, 7703 Floyd Curl Drive, MSC 7836, San Antonio, TX 78229, USA. nathanielsz@uthscsa.edu The developed and developing worlds are experiencing an epidemic of obesity and associated predisposition to diabetes. This epidemic places a major drain on health care resources. It is now clear that maternal obesity and gestational diabetes have major adverse effects on the developing fetus that lead to increased neonatal morbidity and mortality, as discussed elsewhere in this issue. Obesity in pregnancy and gestational diabetes represent a special problem, not only as a result of their immediate adverse effects on maternal health and pregnancy outcome, but also because of growing evidence for their persistent and deleterious effects on the developing child. PMID: 17572267 [PubMed - indexed for MEDLINE] 2883. Rev Med Chir Soc Med Nat Iasi. 2006 Jul-Sep;110(3):657-61. [Pathogenic mechanisms for fat redistribution in patients with HIV disease]. [Article in Romanian] Ion DA(1), Chivu LI, Chivu RD. Author information: (1)Universitatea de Medicing si Farmacie Carol Davila Bucureşti, Facultatea de Medicină, Disciplina de Fiziopatologie. Lipodystrophy syndrome is a common term in the literature traditionally used to describe several morphologic (lipoatrophy; lipohypertrophy; mixed syndrome) and metabolic (dyslipidemia, insulin resistance) disturbances found in patients with HIV disease, with or without treatment with highly active antiretroviral therapy (HAART). Increasing evidence suggests these disorders, though commonly clustering in a syndrome pattern, have distinct pathologic pathways and can occur independently of each other. The pathogenesis of these disorders is complex, but recent hypotheses and evidence suggest that impairment to adipocyte differentiation, in particular through alterations in the expression of the transcription factor sterol responsive element binding protein-lc (SREBP1c), impairment of adipokine regulation, unopposed production of proinflammatory cytokines, adipocyte apoptosis mediated by proinflammatory cytokines such as tumor necrosis factor (TNF-alpha) and IL-6, dysregulation of 1l-beta-hydroxysteroid dehydrogenase, and mitochondrial toxicity may play a role. PMID: 17571562 [PubMed - indexed for MEDLINE] 2884. J Cardiovasc Med (Hagerstown). 2007 Jul;8(7):473-82. Reducing diabetes incidence through the inhibition of the renin-angiotensin system: a strategy for reducing cardiovascular mortality and morbidity? Zanolla L(1), Vassanelli C. Author information: (1)Divisione Clinicizzata di Cardiologia, Azienda Ospedaliera Istituti Ospitalieri di Verona, Verona, Italy. luisa.zanolla@univr.it The prevalence of type 2 diabetes is increasing worldwide, and prevention of the disease is a key objective. Several clinical trials reported a consistent reduction in the incidence of newly diagnosed diabetes in high-risk patients treated with renin-angiotensin system-inhibiting drugs. In all those trials, however, diabetes reduction was either a post-hoc analysis result or a secondary endpoint. Therefore, we need the results of ongoing specific prospectively designed trials, with new-onset diabetes as the principal endpoint. PMID: 17568278 [PubMed - indexed for MEDLINE] 2885. Int J Obes (Lond). 2007 Nov;31(11):1629-41. Epub 2007 Jun 12. Obesity and polymorphisms in genes regulating human adipose tissue. Dahlman I(1), Arner P. Author information: (1)Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden. Ingrid.dahlman@ki.se Obesity is the result of an imbalance between food intake and energy expenditure resulting in the storing of energy as fat. Adipose tissue contains the largest store of energy in the body and plays important roles in regulating energy partitioning. Developments in genomics, in particular microarray-based expression profiling, have provided scientists with a number of new candidate genes whose expression in adipose tissue is regulated by obesity. Integrating expression profiles with genome-wide linkage and/or association analyses is a promising strategy to identify new genes underlying susceptibility to obesity. This article provides a comprehensive review of adipose-tissue-expressed genes implicated in predisposition to human obesity. The authors consider the following genes of particular interest: peroxisome proliferator-activated receptor gamma and, potentially, INSIG2 acting in adipogenesis; the adrenoreceptors beta 2 and 3, as well as hormone-sensitive lipase acting on lipolysis; uncoupling protein 2 acting in mitochondria energy expenditure; and among secreted molecules the cytokine tumor necrosis factor alpha and the hormone leptin. With the rapid development in genome research, we predict that additional alleles in genes regulating adipose tissue function will be established as risk factors for common obesity in the coming years. This has important implications for the prevention of obesity and may also offer new therapeutic targets. PMID: 17563763 [PubMed - indexed for MEDLINE] 2886. Cell Res. 2007 Jun;17(6):486-511. Fat poetry: a kingdom for PPAR gamma. Anghel SI(1), Wahli W. Author information: (1)Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne CH-1015, Switzerland. Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARgamma agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARgamma in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARgamma modulators. PMID: 17563755 [PubMed - indexed for MEDLINE] 2887. Clin Endocrinol (Oxf). 2007 Oct;67(4):479-84. Epub 2007 Jun 11. Inherited lipodystrophies and the metabolic syndrome. Monajemi H(1), Stroes E, Hegele RA, Fliers E. Author information: (1)Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. h.monajemi@amc.nl Lipodystrophies represent a heterogeneous group of diseases characterized by an abnormal subcutaneous fat distribution, the extent of which can vary from localized, to partial, to generalized lipoatrophy. Whereas partial and generalized lipodystrophies are each associated with metabolic abnormalities, the localized form is not. These metabolic changes include insulin resistance with type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed HDL cholesterol, liver steatosis and hypertension. Affected women are often hirsute and this can be associated with the presence of polycystic ovarian syndrome (PCOS). Most of these clinical features are present to some extent in patients with the common metabolic syndrome. As the prevalence of metabolic syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder may often be overlooked with the affected patient diagnosed as merely being 'yet' another case of metabolic syndrome. In this article, we draw attention to the importance of recognizing patients with lipodystrophy who present with metabolic abnormalities, as both the diagnostic as well as the therapeutic approach of these patients differ profoundly from patients with the metabolic syndrome. PMID: 17561981 [PubMed - indexed for MEDLINE] 2888. Expert Opin Biol Ther. 2007 Jun;7(6):791-8. Adult stem cells for cardiovascular diseases: the adipose tissue potential. Roche R(1), Hoareau L, Mounet F, Festy F. Author information: (1)Université de La Réunion, Laboratoire de Biochimie et Génétique Moléculaire, Faculté des Sciences, Saint Denis Messag. 9, Ile de La Réunion, France. regis.roche@univ-reunion.fr Cardiovascular diseases, as well as cardiac ischemia and lower limb vascularization, are associated with obesity and Type II diabetes, and pose a major public health problem. Recent advances in understanding stem cell biology have prompted the initiation of clinical trials of cardiac and vascular cell therapy. Autologous adult stem cells are generally taken from bone marrow or circulating blood. Although significant and encouraging results have been obtained in human studies where these cells have been employed, obtaining sufficient numbers of these cells is a major constraint. Recent studies have identified adipose tissue as a new source of stem cells; some of which may be suitable for the restoration of cardiovascular function. As lipoaspiration provides relatively simple access to this stem cell pool, and with the very large numbers of cells present in adipose tissue, its future potential as a stem cell reservoir for cardiovascular cell therapy is promising. PMID: 17555365 [PubMed - indexed for MEDLINE] 2889. Acta Vet Hung. 2007 Jun;55(2):229-39. Veterinary aspects and perspectives of nutrigenomics: a critical review. Fekete SG(1), Brown DL. Author information: (1)Institute of Animal Breeding, Nutrition and Laboratory Animal Science, Faculty of Veterinary Science, Szent István University, H-1400 Budapest, P.O. Box 2, Hungary. Fekete.Sandor@aotk.szie.hu Nutrigenomics examines nutrient-gene interactions on a genome-wide scale. Increased dietary fat or higher non-esterified fatty acids (NEFA) from starvation-induced mobilisation may enhance hepatic oxidation and decrease esterification of fatty acids by reducing the expression of the fatty acid synthase gene. The key factors are the peroxisome proliferator-activated receptors (PPARs). Dietary carbohydrates--both independently and through insulin effect--influence the transcription of the fatty acid synthase gene. Oleic acid or n-3 fatty acids downregulate the expression of leptin, fatty acid synthase and lipoprotein lipase in retroperitoneal adipose tissue. Protein-rich diets entail a shortage of mRNA necessary for expression of the fatty acid synthase gene in the adipocytes. Conjugated linoleic acids (CLAs) are activators of PPAR and also induce apoptosis in adipocytes. Altered rumen microflora produces CLAs that are efficient inhibitors of milk fat synthesis in the mammary gland ('biohydrogenation theory'). Oral zinc or cadmium application enhances transcription rate in the metallothionein gene. Supplemental CLA in pig diets was found to decrease feed intake and body fat by activating PPARgamma-responsive genes in the adipose tissue. To prevent obesity and type II diabetes, the direct modulation of gene expression by nutrients is also possible. Nutrigenomics may help in the early diagnosis of genetically determined metabolic disorders and in designing individualised diets for companion animals. PMID: 17555288 [PubMed - indexed for MEDLINE] 2890. Br J Dermatol. 2007 Jul;157(1):92-9. Epub 2007 Jun 6. Lipomas after blunt soft tissue trauma: are they real? Analysis of 31 cases. Aust MC(1), Spies M, Kall S, Gohritz A, Boorboor P, Kolokythas P, Vogt PM. Author information: (1)Department of Plastic, Hand and Reconstructive Surgery, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30659 Hannover, Germany. aust_matthias@gmx.de BACKGROUND: Soft tissue trauma and lipomas are common occurrences in surgical practice. Lipomas are defined as benign tumours of adipose tissue with so far unexplained pathogenesis and aetiology. A link between preceding blunt soft tissue trauma at the site of the tumour and the formation of lipomas has been described earlier. These soft tissue tumours have been named 'post-traumatic lipomas'. OBJECTIVES: In a retrospective review, to analyse all patients with benign adipose tissue tumours treated at our institution between August 2001 and January 2007. METHODS: All cases were reviewed regarding medical history, magnetic resonance imaging findings, intraoperative findings, clinical chemistry and histology. RESULTS: In 170 patients presenting with lipomas, 34 lipomas in 31 patients were identified as post-traumatic. The mean +/- SD age of the patients with post-traumatic lipomas was 52 +/- 14.5 years. The mean time elapsed between soft tissue trauma and lipoma formation was 2.0 years (range 0.5-5). Twenty-five of the 31 patients reported an extensive and slowly resolving haematoma after blunt tissue trauma at the site of lipoma formation. The mean +/- SD body mass index was 29.0 +/- 7.6 kg m(-2). Fourteen of 31 patients presented with an elevated partial thromboplastin time. Eleven of 34 lipomas were found on the upper extremities, five on the lower extremities, 13 on the trunk, and two on the face. All tumours were located subcutaneously, superficial to the musculofascial system. Thirty-three lipomas were removed by surgical excision and one by liposuction following an incisional biopsy. Histological examination revealed capsulated and noncapsulated benign adipose tissue in all 34 tumours. CONCLUSIONS: The existence of a pathogenic link between blunt soft tissue trauma and the formation of post-traumatic lipomas is still controversial. Two potential mechanisms are discussed. Firstly, the formation of so-called post-traumatic 'pseudolipomas' may result from a prolapse of adipose tissue through fascia induced by direct impact. Alternatively, lipoma formation may be explained as a result of preadipocyte differentiation and proliferation mediated by cytokine release following soft tissue damage after blunt trauma and haematoma formation. PMID: 17553055 [PubMed - indexed for MEDLINE] 2891. Lakartidningen. 2007 May 9-15;104(19):1517-21. [Systemic amyloidoses--new treatment methods make early and exact diagnosis more and more important]. [Article in Swedish] Westermark P(1). Author information: (1)Institutionen för genetik och patologi, Rudbeck-laboratoriet, Uppsal Universitet. per.westermark@genpat.uu.se PMID: 17550030 [PubMed - indexed for MEDLINE] 2892. Eksp Klin Gastroenterol. 2007;(1):20-3. [Genetic mechanisms of abdominal obesity]. [Article in Russian] Samsonova NG, Ovsiannikova ON. PMID: 17547108 [PubMed - indexed for MEDLINE] 2893. Clin Chim Acta. 2007 Aug;383(1-2):1-20. Epub 2007 Apr 14. Oxidative mechanisms at rest and during exercise. Ghanassia E(1), Brun JF, Mercier J, Raynaud E. Author information: (1)INSERM, ERI 25, F-34000, Montpellier, France. Carbohydrates (CHO) and lipids provide the amount of energy required for physical and chemical reactions inside the human body. The various constraints the body has to resolve explain the use of these two substrates, catabolized via distinct pathways to one common final reaction. In the classic model, three main organs/tissues for substrate fluxes (liver, adipose tissue and skeletal muscle) and one organ regulating main reactions by adaptation of hormonal secretions (endocrine pancreas) are described. From this point of view, the only interactions between CHO and lipid metabolisms are mediated by glycaemic changes via insulin/glucagon ratio (IGR). However, according to recent advances, this concept seems to have a limited validity as it does take into account neither the many other interactions between CHO and lipid metabolism that are likely to occur in addition to the coarse control by IGR, nor the long-term regulation of energy balance, whose description began with the discovery of leptin. Moreover, it does not include the effects of energy expenditure. Therefore, this review focuses on three topics: (i) describe interactions between CHO and lipid metabolism at the level of each tissue and organ implied, via hormonal signaling as well as direct action of nutrients, (ii) integrate fluxes of substrates and signals between those tissues at rest in a global view of the metabolism taking into account short-term and long-term regulating factors and (iii) describe separately, to avoid confusion or extrapolation, the short-term and long-term influence of exercise on these regulation loops. PMID: 17544388 [PubMed - indexed for MEDLINE] 2894. Phys Med Rehabil Clin N Am. 2007 May;18(2):333-51, vii. Obesity after spinal cord injury. Gater DR Jr(1). Author information: (1)Spinal Cord Injury and Disorders Center, Hunter Holmes McGuire VAMC (652/128), 1201 Broad Rock Boulevard, Richmond, VA 23249, USA. David.Gater@va.gov America is in the midst of an obesity epidemic, and individuals who have spinal cord injury (SCI) are perhaps at greater risk than any other segment of the population. Recent changes in the way obesity has been defined have lulled SCI practitioners into a false sense of security about the health of their patients regarding the dangers of obesity and its sequelae. This article defines and uses a definition of obesity that is more relevant to persons who have SCI, reviews the physiology of adipose tissue, and discusses aspects of heredity and environment that contribute to obesity in SCI. The pathophysiology of obesity is discussed relative to health risks for persons who have SCI, particularly those contributing to cardiovascular disease. Prevalence of obesity and its comorbidities are discussed and management options reviewed. PMID: 17543776 [PubMed - indexed for MEDLINE] 2895. Cell Mol Biol (Noisy-le-grand). 2006 Oct 30;52(7):40-5. Impact of glycerol gateway molecule in adipocytes. Funahashi T(1), Nagasawa A, Hibuse T, Maeda N. Author information: (1)Department of Internal Medicine and Molecular Science, School of Medicine, Osaka University, Yamada-oka, Suita, Osaka, Japan. tohru@imed2.med.osaka-u.ac.jp Glycerol is one of the essential nutrients in the mammalian body. Glycerol released from adipocytes is delivered to the liver and used for gluconeogenesis. The molecular mechanism of glycerol transport across the cell membrane remains unclear. AQPadipose, which we identified in human adipose cDNA project and later found to be human AQP7, is expressed in adipose tissue, and upregulated during fasting. AQP7 belongs to the aquaglyceroporin subfamily to permealize glycerol as well as water. Loss of function mutation of AQP7 in human caused disturbance of normal rise of plasma glycerol. Disruption of AQP7 gene in mice resulted in profound hypoglycemia during prolonged fasting because of impaired glycerol supply to the liver. In obesity, AQP7 is overexpressed in visceral fat,accompanied by portal hyperglycerolemia and systemic hyperglycemia. Considered together, these works indicate that AQP7 functions as a glycerol gateway molecule in adipocytes. PMID: 17543220 [PubMed - indexed for MEDLINE] 2896. Thyroid. 2007 May;17(5):433-45. Appetite regulation: an overview. Dhillo WS(1). Author information: (1)Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom. w.dhillo@imperial.ac.uk Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design. PMID: 17542673 [PubMed - indexed for MEDLINE] 2897. Thyroid. 2007 May;17(5):421-31. Basic endocrine products of adipose tissue in states of thyroid dysfunction. Pontikides N(1), Krassas GE. Author information: (1)Department of Endocrinology, Diabetes, and Metabolism, Panagia General Hospital, Thessaloniki, Greece. Over the past decade it has been established that adipose tissue is capable of secreting a variety of hormones, cytokines, growth factors, and other peptides that are capable of changing adipocyte biology as well as different organ systems, like the central nervous system, liver, pancreas, and skeletal muscles. Also, it is well known that changes of thyroid function are associated with marked changes in both body weight and energy expenditure. In recent years an extensive research is under way to explore the mutual roles of different adipokines and thyroid hormones. The aim of this review is to summarize our current knowledge on the role of basic peptides of adipose tissue, such as adiponectin, interleukin-6, tumor necrosis factor-alpha, and resistin, in states of altered thyroid function. PMID: 17542672 [PubMed - indexed for MEDLINE] 2898. Rev Alerg Mex. 2007 Jan-Feb;54(1):24-8. [Asthma and obesity: related inflammatory diseases]. [Article in Spanish] Hilda Segura N(1), Hernández L, Velázquez C, Rodríguez J, Murillo E. Author information: (1)Servicio de Alergia e Inmunología, Centro Médico Nacional Siglo XXI, DF México. Asthma and obesity are diseases that have increased their prevalence parallely in the last years, becoming health problems in our country. Asthma is a chronic inflammatory disease and in the last years obesity has also been catalogued as a systemic inflammatory disease considering that adipose tissue is an endocrine organ that produces cytokines that can promote severity of asthma; therefore generating interest in the investigators to perform studies that can relate both conditions. PMID: 17542252 [PubMed - indexed for MEDLINE] 2899. Peptides. 2007 Jun;28(6):1317-30. Epub 2007 May 6. Adipokines and the blood-brain barrier. Pan W(1), Kastin AJ. Author information: (1)Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, United States. weihong.pan@pbrc.edu Just as the blood-brain barrier (BBB) is not a static barrier, the adipocytes are not inert storage depots. Adipokines are peptides or polypeptides produced by white adipose tissue; they play important roles in normal physiology as well as in the metabolic syndrome. Adipokines secreted into the circulation can interact with the BBB and exert potent CNS effects. The specific transport systems for two important adipokines, leptin and tumor necrosis factor alpha, have been characterized during the past decade. By contrast, transforming growth factor beta-1 and adiponectin do not show specific permeation across the BBB, but modulate endothelial functions. Still others, like interleukin-6, may reach the brain but are rapidly degraded. This review summarizes current knowledge and recent findings of the rapidly growing family of adipokines and their interactions with the BBB. PMCID: PMC2040301 PMID: 17540480 [PubMed - indexed for MEDLINE] 2900. Am Heart J. 2007 Jun;153(6):907-17. Human epicardial adipose tissue: a review. Sacks HS(1), Fain JN. Author information: (1)Division of Endocrinology and Metabolism, University of Tennessee, and Baptist Hospital Heart Institute, Memphis, TN, USA. hsacks@hotmail.com We discuss the anatomy, physiology, and pathophysiology of epicardial adipose tissue and its relationship to coronary atherosclerosis. Epicardial fat stores triglyceride to supply free fatty acids for myocardial energy production and produces adipokines. It shares a common embryological origin with mesenteric and omental fat. Like visceral abdominal fat, epicardial fat thickness, measured by echocardiography, is increased in obesity. Epicardial fat could influence coronary atherogenesis and myocardial function because there is no fibrous fascial layer to impede diffusion of free fatty acids and adipokines between it and the underlying vessel wall as well as the myocardium. Segments of coronary arteries lacking epicardial fat or separated from it by a bridge of myocardial tissue are protected against the development of atherosclerosis in those segments. However, when epicardial fat is totally absent in congenital generalized lipodystrophy, coronary atherosclerosis can still occur. Macrophages are more numerous and densely packed in the periadventitial fat of human atherosclerotic coronary arteries with lipid cores than in that of fibrocalcific or nonatherosclerotic coronary arteries. In obese patients with multiple cardiovascular risk factors, epicardial fat around atheromatous coronaries secretes several proinflammatory cytokines and is infiltrated by macrophages, lymphocytes, and basophils. Epicardial adipokine expression in obesity without coronary atherosclerosis has not been determined. In nonobese patients, epicardial fat around atheromatous coronary arteries expresses proinflammatory cytokines but produces either less adiponectin, a vasoprotective adipokine, than fat around nonatheromatous coronaries or a similar amount compared with thoracic subcutaneous fat. Further studies should be done to test the hypothesis that adipokines produced by and released from human epicardial adipose tissue might contribute locally to the pathogenesis of coronary atherosclerosis. PMID: 17540190 [PubMed - indexed for MEDLINE] 2901. World J Urol. 2007 Oct;25(5):491-7. Epub 2007 May 30. The impact of obesity on prostate cancer. van Roermund JG(1), Witjes JA. Author information: (1)Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. F.Witjes@uro.umcn.nl Increasing prevalence of obesity in many parts of the world emphasizes the importance of learning more about the relationship between obesity and prostate cancer (PC). The present paper reviews the impact of obesity on PC using knowledge obtained from the available literature. Search of published literature in PUBMED database. Adipose tissue constitutes an active endocrine and metabolic organ which may be relevant in the development and progression of PC by different potential mechanisms. Furthermore, obesity could have an impact on the outcome of different treatment modalities for PC, both functionally as anatomically. Obesity is a growing problem, however, the exact role in the development and progression of PC has not been elucidated. Regarding the optimal treatment of PC in obese patients, comparative prospective studies are needed. PMID: 17534626 [PubMed - indexed for MEDLINE] 2902. Horm Metab Res. 2007 May;39(5):314-21. Endocrinology of adipose tissue - an update. Fischer-Posovszky P(1), Wabitsch M, Hochberg Z. Author information: (1)Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany. Adipose tissue is the body's largest repository of energy and it plays an important role in total energy homeostasis. Moreover, it is now well recognized as an endocrine organ. A wide range of different factors including complex proteins as well as fatty acids, prostaglandins, and steroids are either synthesized de novo or converted in adipose tissue and released into the blood stream. These so-called adipokines contribute to the development of obesity-related disorders, particularly type-2 diabetes (T2D) and cardiovascular disease. In this review, we present an overview on the endocrine functions of adipose tissue with a special focus on discoveries reported within the past 5 years. PMID: 17533572 [PubMed - indexed for MEDLINE] 2903. Exp Biol Med (Maywood). 2007 Jun;232(6):727-36. Adipokines and coronary vasomotor dysfunction. Knudson JD(1), Dick GM, Tune JD. Author information: (1)Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. Research in the last 10-15 years has shown that fat cells (adipocytes) produce and release proteins with specific biologic activities. These proteins, termed adipokines, include the hormones leptin, adiponectin, and resistin. Adipose tissue is now recognized as an active endocrine organ. With the obesity pandemic swelling in the Western world, ongoing research is aimed at determining the biologic links between obesity and cardiovascular disease. This review presents basic historical background information on the major adipokines, introduces findings from clinical studies associating adipokines with cardiovascular disease, and summarizes results from recent basic science research studies of mechanisms of adipokine-induced cardiovascular dysfunction. Particular emphasis is placed on the action of adipokines in the coronary circulation-especially effects of adipokines on endothelial function, as endothelial damage is likely a critical event initiating atherosclerotic coronary artery disease. PMID: 17526764 [PubMed - indexed for MEDLINE] 2904. Physiol Behav. 2007 Jul 24;91(4):343-51. Epub 2007 Apr 12. Brain-adipose tissue neural crosstalk. Bartness TJ(1), Song CK. Author information: (1)Department of Biology, Neurobiology and Behavior Program, Georgia State University, Atlanta, GA 30302-4010, USA. bartness@gsu.edu The preponderance of basic obesity research focuses on its development as affected by diet and other environmental factors, genetics and their interactions. By contrast, we have been studying the reversal of a naturally-occurring seasonal obesity in Siberian hamsters. In the course of this work, we determined that the sympathetic innervation of white adipose tissue (WAT) is the principal initiator of lipid mobilization not only in these animals, but in all mammals including humans. We present irrefutable evidence for the sympathetic nervous system (SNS) innervation of WAT with respect to neuroanatomy (including its central origins as revealed by transneuronal viral tract tracers), neurochemistry (norepinephrine turnover studies) and function (surgical and chemical denervation). A relatively unappreciated role of WAT SNS innervation also is reviewed--the control of fat cell proliferation as shown by selective chemical denervation that triggers adipocyte proliferation, although the precise mechanism by which this occurs presently is unknown. There is no, however, equally strong evidence for the parasympathetic innervation of this tissue; indeed, the data largely are negative severely questioning its existence and importance. Convincing evidence also is given for the sensory innervation of WAT (as shown by tract tracing and by markers for sensory nerves in WAT), with suggestive data supporting a possible role in conveying information on the degree of adiposity to the brain. Collectively, these data offer an additional or alternative view to the predominate one of the control of body fat stores via circulating factors that serve as efferent and afferent communicators. PMCID: PMC1986714 PMID: 17521684 [PubMed - indexed for MEDLINE] 2905. Radiol Technol. 2007 May-Jun;78(5):361-6. 18FDG uptake in brown fat: potential for false positives. Evans KD(1), Tulloss TA, Hall N. Author information: (1)Radiologic Sciences and Therapy, Division of the School of Allied Medical Professions and the Department of Radiology at the Ohio State University, Columbus, OH, USA. CONTEXT: (18)FDG is used widely to enhance PET and PET-CT images. However, this radiotracer tends to be taken up by brown fat, which can lead to false-positive diagnoses. Purpose To determine which patients, areas of the body and circumstances are more likely to be associated with false-positive diagnoses due to (18)FDG uptake in brown fat. METHOD: A review of the literature was conducted on factors that contribute to false-positive diagnoses caused by (18)FDG uptake in brown fat. RESULTS: Brown fat commonly is found in women and children and can be located in the supraclavicular, mediastinal, paravertebral and perirenal areas of the body. Research has shown that these areas can be sources of a false-positive diagnosis because of (18)FDG uptake. Studies also have indicated that cold climate affects the uptake of (18)FDG, contributing to false-positive results on PET-CT examinations. CONCLUSIONS: This literature review should stimulate continued research into and awareness of the potential for false-positive PET findings in women and children during the winter months and in cold climates. This information is especially applicable to young female patients undergoing PET or PET-CT. PMID: 17519372 [PubMed - indexed for MEDLINE] 2906. Tissue Eng. 2007 Aug;13(8):1799-808. Stem cells from adipose tissue allow challenging new concepts for regenerative medicine. Helder MN(1), Knippenberg M, Klein-Nulend J, Wuisman PI. Author information: (1)Department of Orthopedic Surgery, VU University Medical Center (VUMC), Amsterdam, The Netherlands. m.helder@vumc.nl The perspective of an innovative new concept integrating tissue-engineering techniques with an established surgical technique is described. The focus is primarily on a one-step surgical procedure using adipose tissue-derived mesenchymal stem cells, a calcium phosphate scaffold as a carrier, and a bioresorbable polymer cage to facilitate spinal interbody fusion. We address the harvesting and processing of clinically relevant quantities of adipose tissue-derived mesenchymal stem cells, triggering of these stem cells toward lineage-specific differentiation, seeding of the triggered stem cells on a bioresorbable scaffold, and implantation of the resulting tissue-engineered construct. The integrated steps can be accomplished within one surgical procedure in a surgical theater. Although the proposed concept has been developed for spinal fusion, potential application in other surgical disciplines is presumed realistic. PMID: 17518736 [PubMed - indexed for MEDLINE] 2907. Tissue Eng. 2006 Nov;12(11):3007-19. Review: ex vivo engineering of living tissues with adult stem cells. Barrilleaux B(1), Phinney DG, Prockop DJ, O'Connor KC. Author information: (1)Department of Chemical and Biomolecular Engineering, Tulane University, New Orleans, Louisiana 70118, USA. Adult stem cells have the potential to revolutionize regenerative medicine with their unique abilities to self-renew and differentiate into various phenotypes. This review examines progress and challenges in ex vivo tissue engineering with adult stem cells. These rare cells are harvested from a variety of tissues, including bone marrow, adipose, skeletal muscle, and placenta, and differentiate into cells of their own lineage and in some cases atypical lineages. Insight into the stem cell niche leads to the identification of matrix components, soluble factors, and physiological conditions that enhance the ex vivo amplification and differentiation of stem cells. Scaffolds composed of metals, naturally occurring materials, and synthetic polymers organize stem cells into complex spatial groupings that mimic native tissue. Cell signals from covalently bound ligands and slowly released regulatory factors in scaffolds direct stem cell fate. Future advances in stem cell biology and scaffold design will ultimately improve the efficacy of tissue substitutes as implants, in research, and as extracorporeal devices. PMID: 17518617 [PubMed - indexed for MEDLINE] 2908. Tissue Eng. 2007 Jun;13(6):1135-50. Review: gene- and stem cell-based therapeutics for bone regeneration and repair. Kimelman N(1), Pelled G, Helm GA, Huard J, Schwarz EM, Gazit D. Author information: (1)Skeletal Biotech Lab, The Hebrew University of Jerusalem-Hadassah Medical Campus, Ein Kerem, Jerusalem, Israel. Many clinical conditions require regeneration or implantation of bone. This is one focus shared by neurosurgery and orthopedics. Current therapeutic options (bone grafting and protein-based therapy) do not provide satisfying solutions to the problem of massive bone defects. In the past few years, gene- and stem cell-based therapy has been extensively studied to achieve a viable alternative to current solutions offered by modern medicine for bone-loss repair. The use of adult stem cells for bone regeneration has gained much focus. This unique population of multipotential cells has been isolated from various sources, including bone marrow, adipose, and muscle tissues. Genetic engineering of adult stem cells with potent osteogenic genes has led to fracture repair and rapid bone formation in vivo. It is hypothesized that these genetically modified cells exert both an autocrine and a paracrine effects on host stem cells, leading to an enhanced osteogenic effect. The use of direct gene delivery has also shown much promise for in vivo bone repair. Several viral and nonviral methods have been used to achieve substantial bone tissue formation in various sites in animal models. To advance these platforms to the clinical setting, it will be mandatory to overcome specific hurdles, such as control over transgene expression, viral vector toxicity, and prolonged culture periods of therapeutic stem cells. This review covers a prospect of cell and gene therapy for bone repair as well as some very recent advancements in stem cell isolation, genetic engineering, and exogenous control of transgene expression. PMID: 17516852 [PubMed - indexed for MEDLINE] 2909. Arch Pathol Lab Med. 2007 Mar;131(3):481-7. The role of periadventitial fat in atherosclerosis. Vela D(1), Buja LM, Madjid M, Burke A, Naghavi M, Willerson JT, Casscells SW, Litovsky S. Author information: (1)Texas Heart Institute at St Luke's Episcopal Hospital, Houston, USA. Comment in Arch Pathol Lab Med. 2007 Mar;131(3):346-7. Arch Pathol Lab Med. 2007 Dec;131(12):1766; author reply 1766-7. CONTEXT: It has become increasingly evident that adipose tissue is a multifunctional organ that produces and secretes multiple paracrine and endocrine factors. Research into obesity, insulin resistance, and diabetes has identified a proinflammatory state associated with obesity. Substantial differences between subcutaneous and omental fat have been noted, including the fact that omental fat produces relatively more inflammatory cytokines. Periadventitial fat, as a specific adipose tissue subset, has been overlooked in the field of atherosclerosis despite its potential diagnostic and therapeutic implications. OBJECTIVE: To review (1) evidence for the role of adventitial and periadventitial fat in vessel remodeling after injury, (2) the relationship between adventitial inflammation and atherosclerosis, (3) the association between periadventitial fat and plaque inflammation, and (4) the diagnostic and therapeutic implications of these roles and relationships for the progression of atherosclerosis. DATA SOURCES: We present new data showing greater uptake of iron, administered in the form of superparamagnetic iron oxide, in the periadventitial fat of atherosclerotic mice than in control mice. In addition, macrophage density in the periadventitial fat of lipid-rich plaques is increased compared with fibrocalcific plaques. CONCLUSIONS: There is a striking paucity of data on the relationship between the periadventitial fat of coronary arteries and atherosclerosis. Greater insight into this relationship might be instrumental in making strides into the pathophysiology, diagnosis, and treatment of coronary artery disease. PMID: 17516753 [PubMed - indexed for MEDLINE] 2910. Ann N Y Acad Sci. 2007 Oct;1113:256-75. Epub 2007 May 18. Metabolic syndrome: psychosocial, neuroendocrine, and classical risk factors in type 2 diabetes. Abraham NG(1), Brunner EJ, Eriksson JW, Robertson RP. Author information: (1)New York Medical College, Department of Pharmacology, Valhalla, NY 10595. USA. nader_abraham@nymc.edu This article summarizes some aspects of stress in the metabolic syndrome at the psychosocial, tissue, and cellular levels. The metabolic syndrome is a valuable research concept for studying population health and social-biological translation. The cluster of cardiovascular risk factors labeled the metabolic syndrome is linked with low socioeconomic status. Systematic differences in diet and physical activity contribute to social patterning of the syndrome. In addition, psychosocial factors including chronic work stress are linked with its development. Psychosocial factors could lead to metabolic perturbations and increase cardiovascular risk via activation of neuroendocrine responses, for example, in the autonomic nervous system and in several hormonal pathways. High glucocorticoid levels will promote lipid storage in visceral rather than subcutaneous adipose tissue. Adipocytes secrete several proinflammatory cytokines, which considered major contributors to increase in oxidants and cell injury. Upregulation of heme oxygenase 1 (HO-1) and peroxidase in the early development of diabetes produces a decrease in oxidative-mediated injury. Increased HO activity is associated with a significant decrease in superoxide, endothelial cell shedding and blood pressure. Finally, it is proposed that overexpression of glutathione peroxidase in beta cells may protect beta cell deterioration from oxidative stress during development of diabetes and hyperglycemia and this may result in attenuation of beta cell failure. If this proves to be the case, then the scene will be set to develop glutathione peroxidase mimetics for use in preclinical and clinical trials. PMID: 17513461 [PubMed - indexed for MEDLINE] 2911. Biochem Soc Trans. 2007 Jun;35(Pt 3):472-6. Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation. Karpe F(1), Bickerton AS, Hodson L, Fielding BA, Tan GD, Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. Fredrik.Karpe@ocdem.ox.ac.uk The triacylglycerol content of chylomicrons and VLDL (very-low-density lipoprotein) compete for the same lipolytic pathway in the capillary beds. Although chylomicron triacylglycerols appear to be the favoured substrate for lipoprotein lipase, VLDL particles compete in numbers. Methods to quantify the specific triacylglycerol removal from VLDL and chylomicrons may involve endogenous labelling of the triacylglycerol substrate with stable isotopes in combination with arteriovenous blood sampling in humans. Arteriovenous quantification of remnant lipoproteins suggests that adipose tissue with its high lipoprotein lipase activity is a principal site for generation of remnant lipoproteins. Under circumstances of reduced efficiency in the removal of triacylglycerols from lipoproteins, there is accumulation of remnant lipoproteins, which are potentially atherogenic. PMID: 17511631 [PubMed - indexed for MEDLINE] 2912. Endocr J. 2007 Aug;54(4):497-505. Epub 2007 May 18. Avenues of communication between the brain and tissues/organs involved in energy homeostasis. Yamada T(1), Katagiri H. Author information: (1)Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Obesity is a rapidly increasing public health concern worldwide as a major risk factor for numerous disorders, including diabetes, hypertension and heart disease. Despite remarkable advances in obesity research over the past 10 years, the molecular mechanisms underlying obesity are still not completely understood. To maintain systemic energy homeostasis, it is important that organs/tissues communicate metabolic information among each other. Obesity-related disorders can be thought of as resulting from dysregulation of this inter-tissue communication. This system has both afferent sensing components and efferent effecter limbs. The afferent signals consist of not only humoral factors, such as nutrients (glucose, fatty acids and amino acids) and adipocytokines (leptin, adiponectin and so on), but also autonomic afferent nerve systems. Both converge on brain centers, most importantly within the hypothalamus, where the signals are integrated, and the direction and magnitude of efferent responses are determined. The efferent elements of this physiological system include those regulating energy inputs and outputs, i.e. food intake and metabolic rates. In this review, we will summarize recent advances in research on metabolic information avenues to the brain, which are important for energy homeostasis. PMID: 17510499 [PubMed - indexed for MEDLINE] 2913. Int J Epidemiol. 2007 Feb;36(1):220-5. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Sniderman AD(1), Bhopal R, Prabhakaran D, Sarrafzadegan N, Tchernof A. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, Division of Cardiology, McGill University Health Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada. allan.sniderman@muhc.mcgill.ca Comment in Int J Epidemiol. 2007 Feb;36(1):226-7. The rates of coronary disease have accelerated dramatically amongst South Asians, driven to an important extent by the atherogenic dyslipidemia and type 2 diabetes that have become so common amongst them. These precursors of vascular disease appear at lower absolute amounts of adipose tissue in South Asians than in whites. In this paper, we set out a new hypothesis--the adipose tissue overflow hypothesis--to account for these findings. The adipose tissue mass within our bodies can be divided into three different compartments: superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue and visceral adipose tissue. The superficial subcutaneous adipose tissue compartment is the primary compartment, is present throughout the body, and constitutes the vast majority of the adipose tissue in the lower limb. With energy excess, the secondary adipose tissue compartments--the deep subcutaneous (mainly upper body) and the visceral adipose tissue compartments--become more prominent. Superficial subcutaneous adipose tissue is relatively inert metabolically, whereas the other two compartments are characterized by higher transmembrane fatty acid flux rates and thus are more closely linked to dyslipidemia and dysglycemia. We hypothesize that the superficial subcutaneous adipose tissue compartment is larger in whites than in South Asians. If so, as obesity develops, South Asians exhaust the storage capacity of their superficial subcutaneous adipose tissue compartment before whites do and that is why they develop the metabolic complications of upper body obesity at lower absolute masses of adipose tissue than white people. PMID: 17510078 [PubMed - indexed for MEDLINE] 2914. Cytokine Growth Factor Rev. 2007 Jun-Aug;18(3-4):313-25. Epub 2007 May 15. The emerging role of adipokines as mediators of inflammation and immune responses. Lago F(1), Dieguez C, Gómez-Reino J, Gualillo O. Author information: (1)Santiago University Clinical Hospital, Research Laboratory 1 (Molecular and Cellular Cardiology), Santiago de Compostela, Spain. Interest in the biology of white adipose tissue (WAT) has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases, and spurred the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome and inflammatory and/or autoimmune conditions. Here, we review recent adipokine research, with particular attention to the roles of leptin, adiponectin, resistin, visfatin, apelin, vaspin and hepcidin in such conditions. PMID: 17507280 [PubMed - indexed for MEDLINE] 2915. Atherosclerosis. 2007 Jul;193(1):1-10. Epub 2007 May 15. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Harris WS(1), Poston WC, Haddock CK. Author information: (1)Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, United States. bill.harris@usd.edu BACKGROUND: Tissue proportions of long chain n-6 [especially arachidonic acid (AA)] and n-3 fatty acids [FA; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) acids], or some ratio of these may be markers of risk for coronary heart disease (CHD). The purpose of this paper is to evaluate the published associations between risk for CHD events and tissue n-3 and n-6 FA composition. METHODS: Case-control or prospective cohort data sets examining the risk for CHD endpoints as a function of tissue FA composition were identified. Effect sizes were computed for case versus control comparisons using standard meta-analytic methods. RESULTS: Twenty-five studies were included, 18 examining the FA composition of phospholipid-rich and 7 of triglyceride-rich samples. DHA, with or without EPA, was significantly lower in cases than controls in all studies combined, in those with fatal endpoints, in those with prospective designs, and in both tissue types. The only setting where increased AA was associated with case status was in adipose tissue. The AA/EPA ratio in phospholipid-rich samples did not distinguish cases from controls. Lower linoleic acid content was associated with increased risk for non-fatal events. CONCLUSIONS: The long-chain n-3 FA, especially DHA, were consistently and significantly reduced in patients experiencing CHD events. These findings add further support to the view that long-chain n-3 FA are cardioprotective. PMID: 17507020 [PubMed - indexed for MEDLINE] 2916. Annu Rev Nutr. 2007;27:149-63. Regional fat deposition as a factor in FFA metabolism. Votruba SB(1), Jensen MD. Author information: (1)Endocrine Research Unit, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Humans have a large variability in body fat distribution, which has tremendous implications for metabolic health. Obese individuals with an upper-body-fat distribution have increased health complications such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes in comparison with lower-body-obese individuals. Additionally, females have more body fat, a greater proportion of fat in their lower body, and much less visceral fat than do lean males at the same body mass index. The reasons for these differences in body fat distribution have not been clearly identified but could be important. Herein we review what has been learned about regional differences in triglyceride storage capacity and lipolysis as they relate to the causes and consequences of regional fat accumulation. Both sex and site differences in regional fat storage have been described. In contrast, with the exception of variations between men and women in the contribution of visceral adipose tissue to hepatic FFA delivery, most studies have failed to show important sex differences in regional lipolysis in vivo. PMID: 17506663 [PubMed - indexed for MEDLINE] 2917. Gastroenterology. 2007 May;132(6):2191-207. Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease. Parekh S(1), Anania FA. Author information: (1)Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, Georgia, USA. Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease. PMID: 17498512 [PubMed - indexed for MEDLINE] 2918. Gastroenterology. 2007 May;132(6):2181-90. Obesity and atherogenic dyslipidemia. Bamba V(1), Rader DJ. Author information: (1)Division of Endocrinology, Children's Hospital of Philadelphia, USA. Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk. PMID: 17498511 [PubMed - indexed for MEDLINE] 2919. Gastroenterology. 2007 May;132(6):2169-80. Obesity, inflammation, and insulin resistance. Shoelson SE(1), Herrero L, Naaz A. Author information: (1)Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. steven.shoelson@joslin.harvard.edu . Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus. PMID: 17498510 [PubMed - indexed for MEDLINE] 2920. Gastroenterology. 2007 May;132(6):2158-68. The role of CNS fuel sensing in energy and glucose regulation. Cota D(1), Proulx K, Seeley RJ. Author information: (1)Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237, USA. Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes. PMID: 17498509 [PubMed - indexed for MEDLINE] 2921. Gastroenterology. 2007 May;132(6):2131-57. Biology of incretins: GLP-1 and GIP. Baggio LL(1), Drucker DJ. Author information: (1)Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada. This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. PMID: 17498508 [PubMed - indexed for MEDLINE] 2922. Gastroenterology. 2007 May;132(6):2103-15. The adipocyte as an active participant in energy balance and metabolism. Badman MK(1), Flier JS. Author information: (1)Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect. PMID: 17498506 [PubMed - indexed for MEDLINE] 2923. Indian J Med Res. 2007 Mar;125(3):411-24. Endoplasmic reticulum (ER) stress & diabetes. Sundar Rajan S(1), Srinivasan V, Balasubramanyam M, Tatu U. Author information: (1)Department of Biochemistry, Indian Institute of Science, Bangalore, India. The endoplasmic reticulum (ER) is a central organelle entrusted with lipid synthesis, protein folding and protein maturation. It is endowed with a quality control system that facilitates the recognition and targeting of aberrant proteins for degradation. When the capacity of this quality control system is exceeded, a stress response (ER stress) is switched on. Prolonged stress leads to apoptosis and may thus be an important factor in the pathogenesis of many diseases. A complex homeostatic signaling pathway, known as the unfolded protein response (UPR), has evolved to maintain a balance between the load of newly synthesized proteins and the capacity of the ER to aid in their maturation. Dysfunction of the UPR plays an important role in certain diseases, especially those involving tissues dedicated to extracellular protein synthesis. Diabetes is an example of such a disease, since pancreatic beta-cells depend on efficient UPR signaling to meet the demands for constantly varying levels of insulin synthesis. Recent studies have indicated that the importance of the UPR in diabetes is not restricted to the beta-cell but also to tissues of peripheral insulin resistance such as liver and adipose tissue. Better understanding of the basic mechanisms of ER stress and development of insulin resistance/type 2 diabetes is pivotal for the identification of newer molecular targets for therapeutic interventions. PMID: 17496365 [PubMed - indexed for MEDLINE] 2924. Curr Opin Lipidol. 2007 Jun;18(3):289-97. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Kuipers F(1), Stroeve JH, Caron S, Staels B. Author information: (1)Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, The Netherlands. f.kuipers@med.umcg.nl PURPOSE OF REVIEW: Bile acids are amphiphilic molecules synthesized from cholesterol exclusively in the liver that are essential for effective absorption of dietary fat. In addition to this 'classical role', bile acids act as signalling molecules that control their own metabolism by activating the nuclear receptor, farnesoid X receptor. RECENT FINDINGS: Recent work demonstrates that farnesoid X receptor exerts metabolic control beyond bile acid homeostasis, notably effects on HDL, triglyceride and glucose metabolism. Farnesoid X receptor influences insulin sensitivity of tissues that are not part of the enterohepatic circulation, for example, adipose tissue. Certain metabolic effects in the liver appear to be mediated via farnesoid X receptor-stimulated release of an intestinal growth factor. In addition, novel signalling pathways independent of farnesoid X receptor have been identified that may contribute to bile acid-mediated metabolic regulation. SUMMARY: Farnesoid X receptor represents a potentially attractive target for treatment of various aspects of the metabolic syndrome and for prevention of atherosclerosis. Yet, in view of its pleiotropic effects and apparent species-specificity, it is evident that successful interference of the farnesoid X receptor signalling system will require the development of gene-specific and/or organ-specific farnesoid X receptor modulators and extensive testing in human models of disease. PMID: 17495603 [PubMed - indexed for MEDLINE] 2925. Curr Opin Lipidol. 2007 Jun;18(3):271-6. Fatty acid transport proteins. Gimeno RE(1). Author information: (1)Department of Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, Massachusetts 02140, USA. rgimeno@wyeth.com PURPOSE OF REVIEW: Fatty acid transport proteins are a family of proteins involved in fatty acid uptake and activation. This review summarizes recent progress in elucidating the function of fatty acid transport proteins. RECENT FINDINGS: Recent experiments clearly establish FATP1 as a regulated fatty acid transporter in both adipose tissue and muscle with important roles in energy homeostasis, thermogenesis and insulin resistance. Knockout of FATP5 in mice show it to be a bifunctional protein required for both hepatic fatty acid uptake and bile acid reconjugation. The most striking phenotype of FATP4 deletion is a defect in skin homeostasis, which may be due to its very long chain acyl-coenzyme A synthetase activity. Fatty acid transport proteins are increasingly being recognized as multifunctional proteins that can mediate the uptake of fatty acids as well as catalyze the formation of coenzyme A derivatives using long-chain and very-long chain fatty acids, bile acids and bile acid precursors as substrates. SUMMARY: Modulation of fatty acid transport protein function can result in altered energy homeostasis and insulin sensitivity, defective skin homeostasis, and altered bile acid metabolism. Both fatty acid uptake and enzymatic activity of fatty acid transport proteins likely contribute to these phenotypes. Future studies are needed to better understand the molecular mechanism of fatty acid transport protein function and the physiological role of FATP2, FATP3, and FATP6. PMID: 17495600 [PubMed - indexed for MEDLINE] 2926. Curr Opin Lipidol. 2007 Jun;18(3):263-70. Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease. Lara-Castro C(1), Fu Y, Chung BH, Garvey WT. Author information: (1)Department of Nutrition Sciences, University of Alabama at Birmingham, 35294, USA. PURPOSE OF REVIEW: Adiponectin is secreted exclusively by adipocytes, aggregates in multimeric forms, and circulates at high concentrations in blood. This review summarizes recent studies highlighting cellular effects of adiponectin and its role in human lipid metabolism and atherosclerosis. RECENT FINDINGS: Adiponectin is an important autocrine/paracrine factor in adipose tissue that modulates differentiation of preadipocytes and favors formation of mature adipocytes. It also functions as an endocrine factor, influencing whole-body metabolism via effects on target organs. Adiponectin multimers exert differential biologic effects, with the high-molecular-weight multimer associated with favorable metabolic effects (i.e. greater insulin sensitivity, reduced visceral adipose mass, reduced plasma triglycerides, and increased HDL-cholesterol). Adiponectin influences plasma lipoprotein levels by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and HDL. It thus influences atherosclerosis by affecting the balance of atherogenic and antiatherogenic lipoproteins in plasma, and by modulating cellular processes involved in foam cell formation. SUMMARY: Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions. PMID: 17495599 [PubMed - indexed for MEDLINE] 2927. Curr Opin Lipidol. 2007 Jun;18(3):258-62. Monocyte chemotactic protein-1 and its role in insulin resistance. Sell H(1), Eckel J. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany. PURPOSE OF REVIEW: In obesity, there is a strong link between increased adipose tissue mass and development of insulin resistance in tissues such as liver and muscle. Under these conditions, adipose tissue synthesizes various pro-inflammatory chemokines such as monocyte chemotactic protein-1. This review provides a summary of recent knowledge on the role of monocyte chemotactic protein-1 in adipose tissue inflammation and insulin resistance. RECENT FINDINGS: Monocyte chemotactic protein-1 is a proinflammatory adipokine that is believed to play a role in the pathogenesis of obesity and diabetes. New in-vitro data demonstrate that monocyte chemotactic protein-1 has the ability to induce insulin resistance in adipocytes and skeletal muscle cells. By using mice that either overexpress monocyte chemotactic protein-1 or are deficient in monocyte chemotactic protein-1 or its receptor, exciting new insights have been obtained into the role of monocyte chemotactic protein-1 in adipose tissue inflammation and insulin resistance. SUMMARY: Monocyte chemotactic protein-1 is an adipokine with insulin-resistance-inducing capacity that is related to increased adipose tissue mass in obesity and insulin resistance. It plays an important role in adipose tissue inflammation by recruiting macrophages into fat. Monocyte chemotactic protein-1 is thus a therapeutic target, and may represent an important factor linking adipose tissue inflammation, obesity and type 2 diabetes. PMID: 17495598 [PubMed - indexed for MEDLINE] 2928. Curr Opin Lipidol. 2007 Jun;18(3):246-50. The role of neutral lipases in human adipose tissue lipolysis. Arner P(1), Langin D. Author information: (1)Karolinska Institute at the Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden. peter.arner@ki.se PURPOSE OF REVIEW: The aim of this article is to describe the relative roles of hormone sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis. RECENT FINDINGS: Until recently, only hormone sensitive lipase was considered important for the regulation of lipolysis within fat cells. Recent rodent studies have suggested that adipose triglyceride lipase may, however, be more important. The few human adipose triglyceride lipase studies that have been published point to species differences between humans and rodents. Selective inhibition of hormone sensitive lipase in human fat cells completely counteracts hormone-activated lipolysis, though there is a considerable (>>50%) residual nonhormonal (basal) lipolysis. In rodents, adipose triglyceride lipase enzyme activity is stimulated by a cofactor termed CGI-58. In the absence of CGI-58, lipase activity in fat cells is much higher for hormone sensitive lipase than adipose triglyceride lipase. Hormone sensitive lipase expression is regulated by obesity and body weight reduction (decreased and increased, respectively), but this is not the case for adipose triglyceride lipase. A role of adipose triglyceride lipase in human lipolysis is suggested by studies of gene polymorphisms. SUMMARY: Two lipases the 'old' hormone sensitive lipase and the 'new' adipose triglyceride lipase are of importance for the regulation of lipolysis in rodent fat cells. In humans, adipose triglyceride lipase seems essential for maintaining basal lipolytic activity, while hormone sensitive lipase is the enzyme most responsive to stimulated lipolysis. PMID: 17495596 [PubMed - indexed for MEDLINE] 2929. Curr Opin Lipidol. 2007 Jun;18(3):240-5. Plasminogen activator inhibitor-1, adipose tissue and insulin resistance. Alessi MC(1), Poggi M, Juhan-Vague I. Author information: (1)Laboratoire d'hématologie-Inserm UMR 626, Faculty of Medicine, Marseilles, France. marie-christine.alessi@medecine.univ-mrs.fr PURPOSE OF REVIEW: Plasminogen activator inhibitor (PAI)-1 is a physiological inhibitor of plasminogen activators (urokinase and tissue types) and vitronectin. It is synthesized by adipose tissue, and its levels in plasma are increased in obesity and reduced with weight loss. Circulating PAI-1 level predicts development of type 2 diabetes, suggesting that it may be causally related to development of obesity. A role for PAI-1 in development of obesity has only partially been established, however. This review summarizes current knowledge, gives context to developments thus far and discusses controversies. RECENT FINDINGS: In addition to its role in atherothrombosis, PAI-1 might be involved in adipose tissue development. PAI-1 is produced by ectopic fat depots under the influence of inducers. Among the most recently described inducers are inflammation, oxidative stress and circadian clock protein. PAI-1 may play several roles in contributing to obesity: through indirect effects on insulin signalling, by influencing adipocyte differentiation and by regulating recruitment of inflammatory cells within adipose tissue. SUMMARY: These recent findings emphasize the involvement of PAI-1 in controlling the biology of adipose tissue; PAI-1 is an attractive new therapeutic target to retard the metabolic complications that accompany obesity. PMID: 17495595 [PubMed - indexed for MEDLINE] 2930. Exp Cell Res. 2007 Jun 10;313(10):2144-56. Epub 2007 Mar 31. Mouse models of the laminopathies. Stewart CL(1), Kozlov S, Fong LG, Young SG. Author information: (1)Laboratory of Cancer and Developmental Biology, National Cancer Institute, Frederick, Maryland 21702, USA. stewartc@ncifcrf.gov The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease. PMCID: PMC1949387 PMID: 17493612 [PubMed - indexed for MEDLINE] 2931. Exp Cell Res. 2007 Jun 10;313(10):1981-94. Epub 2007 Apr 11. Intermediate filaments: a historical perspective. Oshima RG(1). Author information: (1)Oncodevelopmental Biology Program, Cancer Research Center, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. rgoshima@burnham.org Intracellular protein filaments intermediate in size between actin microfilaments and microtubules are composed of a surprising variety of tissue specific proteins commonly interconnected with other filamentous systems for mechanical stability and decorated by a variety of proteins that provide specialized functions. The sequence conservation of the coiled-coil, alpha-helical structure responsible for polymerization into individual 10 nm filaments defines the classification of intermediate filament proteins into a large gene family. Individual filaments further assemble into bundles and branched cytoskeletons visible in the light microscope. However, it is the diversity of the variable terminal domains that likely contributes most to different functions. The search for the functions of intermediate filament proteins has led to discoveries of roles in diseases of the skin, heart, muscle, liver, brain, adipose tissues and even premature aging. The diversity of uses of intermediate filaments as structural elements and scaffolds for organizing the distribution of decorating molecules contrasts with other cytoskeletal elements. This review is an attempt to provide some recollection of how such a diverse field emerged and changed over about 30 years. PMCID: PMC1950476 PMID: 17493611 [PubMed - indexed for MEDLINE] 2932. Endocr Pract. 2007 Mar-Apr;13(2):187-93. Noninsulinoma pancreatogenous hypoglycemia syndrome: quantitative and immunohistochemical analyses of islet cells for insulin, glucagon, somatostatin, and pancreatic and duodenal homeobox protein. Sahloul R(1), Yaqub N, Driscoll HK, Leidy JW Jr, Parkash J, Matthews KA, Chertow BS. Author information: (1)Section of Endocrinology and Metabolism, Department of Medicine, Marshall University, VA Medical Center Medical Service, Huntington, West Virginia 25701-3655, USA. OBJECTIVE: To present a case of an elderly man with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and to determine the pathogenesis of this syndrome. METHODS: The pancreas of our patient with NIPHS was immunocytochemically stained for insulin-, glucagon-, and somatostatin-secreting cells and pancreatic and duodenal homeobox protein (PDX-1). The clinical findings and morphologic and immunocytochemical analyses of the islets of our patient are described, along with a review of related published reports. RESULTS: A 78-year-old man presented with hyperinsulinemic hypoglycemia, with episodes unrelated to meals or fasting. An insulinoma could not be localized by preoperative imaging or by intraoperative ultrasonography or palpation. He underwent a 70% distal pancreatectomy. For assessment of the possibility that a nuclear transcription factor regulating islet beta-cell growth and development is overexpressed in this disease and is responsible for diffuse islet hyperfunction and proliferation of beta-cells, pancreatic sections from our patient were stained immunocytochemically for PDX-1, insulin, glucagon, and somatostatin. Morphologic findings were compared with pancreatic sections from normal control patients and normative data reported in the literature. Clinical findings and morphologic analyses were consistent with NIPHS. Islets were arranged in long clusters, both in the pancreatic tissue and in peripancreatic adipose tissue. Islets were small but increased in number, and insulin, glucagon, and somatostatin were present in the islets. The relative intensity of insulin staining was increased in our patient in comparison with that in the control patients, and PDX-1 was not overexpressed. CONCLUSION: The etiopathogenesis of NIPHS in this patient involved (1) an increased number of islets with development of ectopic islets in the peripancreatic adipose tissue; (2) alpha- and delta- as well as beta-cell proliferation; and (3) an early step in the development of the islet not involving overexpression of PDX-1. PMID: 17490935 [PubMed - indexed for MEDLINE] 2933. Scand J Med Sci Sports. 2007 Aug;17(4):303-15. Epub 2007 May 9. Structure-function relationships of entheses in relation to mechanical load and exercise. Shaw HM(1), Benjamin M. Author information: (1)Cardiff School of Biosciences, Cardiff University, Cardiff, UK. Entheses are regions of high-stress concentration that are commonly affected by overuse injuries in sport. This review summarizes current knowledge of their structure-function relationships - at the macroscopic, microscopic and molecular levels. Consideration is given to how stress concentration is reduced at fibrocartilaginous entheses by various adaptations which ensure that stress is dissipated away from the hard-soft tissue interface. The fundamental question of how a tendon or ligament is anchored to bone is addressed - particularly in relation to the paucity of compact bone at fibrocartilaginous entheses. The concept of an "enthesis organ" is reviewed - i.e. the idea of a collection of tissues adjacent to the enthesis itself, which jointly serve a common function - stress dissipation. The archetypal enthesis organ is that of the Achilles tendon and the functional importance of its subtendinous bursa, with its fibrocartilaginous walls and protruding fat pad, is emphasized. The distribution of adipose tissue elsewhere at entheses is also explained and possible functions of insertion-site fat are evaluated. Finally, a brief consideration is given to enthesopathies, with attention drawn to the possibility of degenerative changes affecting other regions of an enthesis organ, besides the enthesis itself. PMID: 17490450 [PubMed - indexed for MEDLINE] 2934. IUBMB Life. 2007 Mar;59(3):134-45. Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes. Im SS(1), Kwon SK, Kim TH, Kim HI, Ahn YH. Author information: (1)Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemoon-gu, Seoul, Korea. The gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF-alpha, TR-1alpha, KLF15, SREBP-1c, C/EBP-alpha, O/E-1, free fatty acids, PAPRgamma, LXRalpha, NF-1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM. PMID: 17487684 [PubMed - indexed for MEDLINE] 2935. Can J Physiol Pharmacol. 2007 Jan;85(1):113-32. Type 2 diabetes and cardiovascular disease: getting to the fat of the matter. Goralski KB(1), Sinal CJ. Author information: (1)College of Pharmacy, Department of Pharmacology, Dalhousie University, Halifax, NS B3H 1X5, Canada. The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease. PMID: 17487251 [PubMed - indexed for MEDLINE] 2936. Appl Physiol Nutr Metab. 2007 Apr;32(2):161-76. Rat models of caloric intake and activity: relationships to animal physiology and human health. Young GS(1), Kirkland JB. Author information: (1)Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada. Every rodent experiment is based on important parameters concerning the levels of caloric intake and physical activity. In many cases, these decisions are not made consciously, but are based on traditional models. For experimental models directed at the study of caloric intake and activity, the selection of parameters is usually aimed at modeling human conditions, the ultimate goal of which is to gain insight into the pathophysiology of the disease process in man. In each model, it is important to understand the influence of diet, exercise, and genetic background on physiology and the development of disease states. Along the continuum of energy intake from caloric restriction to high-fat feeding, and of energy output from total inactivity to forced exercise, a number of models are used to study different disease states. In this paper, we will evaluate the influence of the quantity and composition of diet and exercise in several animal models, and will discuss how each model can be applied to various human conditions. This review will be limited to traditional models using the rat as the experimental animal, and although it is not an exhaustive list, the models presented are those most commonly represented in the literature. We will also review the mechanisms by which each affects rat physiology, and will compare these to the analogous mechanisms in the modeled human disease state. We hope that the information presented here will help researchers make choices among the available models and will encourage discussion on the interpretation and extrapolation of results obtained from traditional and novel rodent experiments on diet, exercise, and chronic disease. PMID: 17486157 [PubMed - indexed for MEDLINE] 2937. Front Biosci. 2007 May 1;12:3545-53. Discovery of new peptides from old prohormones: insights for energy balance and beyond. Mulcahy LR(1), Nillni EA. Author information: (1)Division of Endocrinology, Department of Medicine, Brown Medical School/Rhode Island Hospital, Brown University, Providence, RI 02903, USA. A complex network of peptide hormones secreted from the gut, adipose tissue, the brain, and other tissues regulate energy balance. Intensive investigation has uncovered the role of many of the major players in energy balance. However, many of these peptide hormones are derived from precursor proteins whose in vivo processing have not been fully studied. In this review we highlight the importance of fully understanding the processing of prohormones and highlight a particular case of why this is important with the recent discovery of the peptide obestatin. PMID: 17485320 [PubMed - indexed for MEDLINE] 2938. Epidemiol Rev. 2007;29:77-87. Epub 2007 May 2. Abdominal obesity and fatty liver. Jakobsen MU(1), Berentzen T, Sørensen TI, Overvad K. Author information: (1)Institute of Preventive Medicine, Centre for Health And Society, Copenhagen University Hospital, Copenhagen, Denmark. muj@dce.au.dk It has been hypothesized that visceral fat releases free fatty acids and adipokines and thereby exposes the liver to fat accumulation. The authors aimed to evaluate current epidemiologic evidence for an association between abdominal fat and liver fat content. Clinical and epidemiologic studies with data on abdominal fat and liver fat content were reviewed. Studies using waist circumference to estimate abdominal fat mass suggested a direct association between abdominal fat and liver fat content. Studies using imaging methods suggested a direct association between intraabdominal fat and liver fat content, but not between subcutaneous abdominal fat and liver fat content. In conclusion, clinical and epidemiologic studies of abdominal fat and liver fat content suggest a direct association between abdominal fat and liver fat content which is probably accounted for by visceral fat. However, results from the included studies do not allow strong conclusions regarding the temporal sequence of events. Future longitudinal studies are recommended to obtain additional information on associations and mechanisms. Both abdominal fat depots and other body compartments of interest should be included to further investigate the association between specific fat depots and liver fat content. Biomarkers may provide insight into underlying mechanisms. PMID: 17478441 [PubMed - indexed for MEDLINE] 2939. Pol Merkur Lekarski. 2007 Jan;22(127):58-61. [Fibrates and markers of inflammation]. [Article in Polish] Broncel M(1). Author information: (1)Department of Internal Diseases with Clinical Pharmacology and Therapy Monitoring Unit, Medical University of Łódź, Poland. ttm@ttm.org.pl Inflammatory processes have important roles in the etiology of atherosclerosis. Several studies have shown that elevated plasma levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), adhesions molecules, monocyte chemoattractant protein-1 (MCP-1) are associated with the risk of coronary heart disease. Fibrates, agonists of peroxisome proliferator-activated receptors alpha (PPARalpha), act to modulate the expression of key genes of lipid transport and metabolism in the liver and adipose tissue. Besides the hipolipemic effects they exert pleiotropic, anti-inflammatory properties downregulating expression of genes encoding acute phase proteins and inflammatory cytokines. In this article, we briefly review the clinical trial data on the effects of fibrates on the inflammatory markers. PMID: 17477093 [PubMed - indexed for MEDLINE] 2940. Biochim Biophys Acta. 2007 Aug;1771(8):999-1013. Epub 2007 Mar 27. PPARgamma in human and mouse physiology. Heikkinen S(1), Auwerx J, Argmann CA. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France. The peroxisome proliferator activated receptor gamma (PPARgamma) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARgamma also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARgamma has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARgamma activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARgamma. It is now evident that the full activation of PPARgamma is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARgamma signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARgamma biology. PMCID: PMC2020525 PMID: 17475546 [PubMed - indexed for MEDLINE] 2941. J Cardiopulm Rehabil Prev. 2007 Jan-Feb;27(1):2-10. Abdominal obesity and cardiovascular disease risk: the emerging role of the adipocyte. Lee YH(1), Pratley RE. Author information: (1)Diabetes and Metabolism Translational Medicine Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA. PMID: 17474638 [PubMed - indexed for MEDLINE] 2942. Yakugaku Zasshi. 2007 May;127(5):851-6. [Safety evaluation of tissue engineered medical devices using normal human mesenchymal stem cells]. [Article in Japanese] Sawada R(1), Ito T, Tsuchiya T. Author information: (1)Division of Medical Devices, National Institute of Health Sciences, Tokyo, Japan. rsawada@nihs.go.jp Several recent studies demonstrated the potential of bioengineering using somatic stem cells in regenerative medicine. Adult human mesenchymal stem cells (hMSCs) derived from bone marrow have the pluripotency to differentiate into cells of mesodermal origin, e.g., bone, cartilage, adipose, and muscle cells; they, therefore, have many potential clinical applications. On the other hand, stem cells possess a self-renewal capability similar to cancer cells. For safety evaluation of tissue engineered medical devices using normal hMSCs, in this study, we investigated the expression levels of several genes that affect cell proliferation in hMSCs during in vitro culture. We focused on the relationship between the hMSC proliferation and their transforming growth factor beta (TGFbeta) signaling during in vitro culture. The proliferation rate of hMSCs gradually decreased and cellular senescence was observed for about 3 months. The mRNA expressions of TGFbeta1, TGFbeta2, and TGFbeta receptor type I (TGFbetaRI) in hMSCs increased with the length of cell culture. The mRNA expressions of Smad3 increased, but those of c-myc and nucleostemin decreased with the length hMSCs were in in vitro culture. In addition, the expression profiles of the genes which regulate cellular proliferation in hMSCs were significantly different from those of cancer cells. In conclusion, hMSCs derived from bone marrow seldom underwent spontaneous transformation during 1-2 months in vitro culture for use in clinical applications. In hMSCs as well as in epithelial cells, growth might be controlled by the TGFbeta family signaling. PMID: 17473528 [PubMed - indexed for MEDLINE] 2943. Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E444-52. Epub 2007 May 1. Unexpected evidence for active brown adipose tissue in adult humans. Nedergaard J(1), Bengtsson T, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se Comment in Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E1129. The contention that brown adipose tissue is absent in adult man has meant that processes attributed to active brown adipose tissue in experimental animals (mainly rodents), i.e., classical nonshivering thermogenesis, adaptive adrenergic thermogenesis, diet-induced thermogenesis, and antiobesity, should be either absent or attributed to alternative (unknown) mechanisms in man. However, serendipidously, as a consequence of the use of fluorodeoxyglucose positron emission tomography (FDG PET) to trace tumor metastasis, observations that may change that notion have recently been made. These tomography scans have visualized symmetrical areas of increased tracer uptake in the upper parts of the human body; these areas of uptake correspond to brown adipose tissue. We examine here the published observations from a viewpoint of human physiology. The human depots are somewhat differently located from those in rodents, the main depots being found in the supraclavicular and the neck regions with some additional paravertebral, mediastinal, para-aortic, and suprarenal localizations (but no interscapular). Brown adipose tissue activity in man is acutely cold induced and is stimulated via the sympathetic nervous system. The prevalence of active brown adipose tissue in normal adult man can be only indirectly estimated, but it would seem that the prevalence of active brown adipose tissue in the population may be at least in the range of some tens of percent. We conclude that a substantial fraction of adult humans possess active brown adipose tissue that thus has the potential to be of metabolic significance for normal human physiology as well as to become pharmaceutically activated in efforts to combat obesity. PMID: 17473055 [PubMed - indexed for MEDLINE] 2944. Ann Plast Surg. 2007 Mar;58(3):255-63. Surgical management of HIV-associated lipodystrophy: role of ultrasonic-assisted liposuction and suction-assisted lipectomy in the treatment of lipohypertrophy. Hultman CS(1), McPhail LE, Donaldson JH, Wohl DA. Author information: (1)Division of Plastic and Reconstructive Surgery, University of North Carolina, Chapel Hill, North Carolina 27599-7195, USA. cshult@med.unc.edu PURPOSE: HIV-associated lipodystrophy is a frequent consequence of highly active antiretroviral therapy and has been associated with several metabolic disorders (increased triglycerides, hypercholesterolemia, insulin resistance) as well as altered fat distribution, including lipohypertrophy (neck, trunk, breasts) and lipoatrophy (nasolabial fold, cheek, extremities). Medical treatment of fat redistribution is usually ineffective. We evaluated the efficacy and safety of the surgical management of HIV lipodystrophy. METHODS: We performed a retrospective review of 12 consecutive patients (3 female, 9 male; mean age, 44.4 years; mean CD4+ cell count, 554/mm3; mean body mass index, 28.9 kg/m2; mean triglycerides, 421 mg/dL; no active opportunistic infections; mean duration of HIV infection, 11.4 years) who underwent surgical management of HIV lipodystrophy at a university hospital from 2001 to 2006. RESULTS: Surgical intervention included a combination of ultrasonic-assisted liposuction (UAL) and suction-assisted lipectomy (SAL) of the anterior neck (7 patients), posterior neck (10 patients), and trunk (2 patients); direct excision of mastoid fat pads (1 patient); direct excision of thigh lipomata (1 patient); facelift/necklift (1 patient); browlift (1 patient); fat injections (1 patient); and blepharoplasty (2 patients). Mean lipoaspirate volume was 701 mL (range, 270-1400 mL). Complications and sequelae included seroma (1 patient), ecchymosis (1 patient), need for revision (2 patients), and recurrence (3 patients) but did not include nerve injury, fat necrosis, skin loss, or infection. Although all patients reported improvement in form and function, UAL/SAL of the anterior neck had limited efficacy in 3 of 7 patients. UAL/SAL of the cervicodorsal fat pad was initially successful in 10 of 10 patients, but 3 patients developed partial late (>1 year) recurrence, all associated with weight gain. Mean follow up was 30 months (range, 1-66 months). CONCLUSIONS: Despite the potential for recurrence, surgical management of HIV-associated lipodystrophy is efficacious with minimal morbidity. UAL/SAL is particularly beneficial in reducing the cervicodorsal fat pad, whereas facelift and necklift may be necessary to adequately address anterior neck lipohypertrophy. PMID: 17471128 [PubMed - indexed for MEDLINE] 2945. Arch Cardiol Mex. 2006 Oct-Dec;76 Suppl 4:S173-88. [Syndrome X vs metabolic syndrome]. [Article in Spanish] Morales Villegas E(1). Author information: (1)Investigación Cardiometabólica S.C. Hospital Central Médico-Quirúrgica de Aguascalientes, Mexico. drmorvi@prodigy.net.mx Himsworth in 1939 postulated that Diabetes Mellitus type 2 (DM2) was not only an insulin deficiency state but also a cellular insulin insensitivity disease. Thirty years later, DeFronzo and Reaven demonstrated that insulin resistance (IR) preceded and predisposed for DM2 and atherosclerotic-cardiovascular-disease (ACVD). Reaven was the first to point out the relationship between IR and with hyperglycemia, dyslipidosis, and hypertension as mediators for ACVD, creating the concept of Syndrome X (SX) in 1988. WHO and, thereafter, other medical societies and medical groups, mainly ATP-III, in 2002, based on the difficulty of diagnosing IR in a simple, reliable, and inexpensive way, proposed and published the Metabolic Syndrome (MS) concept, as a group of five variables, i.e., obesity, hyperglycemia, hypertriglyceridemia, low HDL, and hypertension, as an easy clinical approximation to suspect and treat an increased cardiometabolic risk. Nowadays, there are deep and extensive controversies on this issue; however, these controversies do not really exist since all discordant points of view are rather quantitative and not qualitative in nature. This article is aimed at differentiating and harmonizing the complementary concepts of SX and MS, at analyzing why MS is a good "clinical window" to look for IR and its underlying manifestations, and finally to accept that the MS concept complements, but does not substitute or antagonize, traditional scales used to asses cardiovascular risk, such as the Framingham scale. PMID: 17469345 [PubMed - indexed for MEDLINE] 2946. Nutr Metab Cardiovasc Dis. 2008 Jan;18(1):1-6. Epub 2007 Apr 30. Surgical treatment of obesity: impact on diabetes and other comorbidities. Pontiroli AE. PMID: 17467961 [PubMed - indexed for MEDLINE] 2947. Exp Cell Res. 2007 Jun 10;313(10):2134-43. Epub 2007 Mar 30. Phenomics and lamins: from disease to therapy. Hegele RA(1), Oshima J. Author information: (1)Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8. hegele@robarts.ca Systematic correlation of phenotype with genotype is a key goal of the emerging field of phenomics, which is expected to help define complex diseases. Careful evaluation of phenotype-genotype associations in monogenic disorders, such as laminopathies, might provide new hypotheses to be tested with molecular and cellular studies and might also suggest potential new intervention strategies. For instance, evaluation of the clinical features of carriers of mutant LMNA in kindreds with familial partial lipodystrophy suggests rational, staged intervention using established pharmaceutical agents to prevent cardiovascular complications not just for patients with lipodystrophy but by extension for patients with the common metabolic syndrome. Careful non-invasive imaging shows phenotypic differences between partial lipodystrophy due to mutant LMNA and not due to mutant LMNA. Furthermore, hierarchical cluster analysis detects systematic relationships between organ involvement in laminopathies and mutation position in the LMNA genomic sequence. However, sometimes the same LMNA mutation can underlie markedly different clinical phenotypes; cellular and molecular experiments can help to explain the mechanistic basis for such differences. Finally, promising novel treatment modalities for laminopathies, such as farnesyl transferase inhibition and gene-based therapies, might help not only to illuminate mechanisms that link genotype to phenotype, but also to provide hope for patients suffering with laminopathies, since these treatments are designed to modulate key early or proximal steps in the pathogenesis of these disorders. PMID: 17466974 [PubMed - indexed for MEDLINE] 2948. J Gastroenterol. 2007 Apr;42(4):267-74. Epub 2007 Apr 26. Metabolic syndrome and gastrointestinal diseases. Watanabe S(1), Hojo M, Nagahara A. Author information: (1)Department of Gastroenterology, Juntendo University, School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan. Metabolic syndrome is a cluster of metabolic abnormalities consisting essentially of obesity, especially abdominal obesity. Metabolic syndrome has been highlighted as a risk factor for cardiovascular and other chronic diseases. Obesity has been implicated in various gastrointestinal diseases such as gastroesophageal reflux diseases and colorectal cancer. Recently, abdominal obesity has been shown to be more important than obesity as expressed by an elevated body mass index as a causative factor for the development of these diseases. In addition to the mechanical effects of obesity, such as an increase in intra-abdominal pressure from large amounts of adipose tissue, substances that adipose tissues secrete, such as tumor necrosis factor-alpha, interleukin-6, leptin, and insulin-like growth factor-1, have been proposed to be pathogenic links to these diseases. In this review, we discuss the association of metabolic syndrome or the individual components of metabolic syndrome, focusing on obesity and abdominal obesity, with gastrointestinal diseases. PMID: 17464454 [PubMed - indexed for MEDLINE] 2949. Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S46-8. Epub 2007 Apr 25. The modulating effects of the overexpression of uncoupling protein 2 on the formation of reactive oxygen species in vascular cells. Kim HS(1), Park KG, Koo TB, Huh S, Lee IK. Author information: (1)Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea. Uncoupling protein 2 (UCP-2) is a newly identified member of the mitochondrial anion carrier family and shares 60% sequence identity with the well-characterized thermogenic UCP-1 from brown adipose tissue. Several lines of evidence suggest that UCP-2 is involved in the control of reactive oxygen species (ROS) production by mitochondria. More recently, a direct role for UCP-2 in the regulation of atherogenesis has been suggested by the observation that bone marrow transplantation from UCP-2-deficient mice to low-density lipoprotein receptor-deficient mice markedly increased atherosclerotic lesion size. This review introduces the possible role of UCP-2 in the regulation of atherogenesis in vascular cells. Although the relative contribution of the individual ROS generating systems in the vasculature is still ambiguous, both cell membrane NAD(P)H oxidase and the mitochondrial electron-transport chain have been proposed to play significant roles in the overproduction of ROS. UCP-2 can possibly modify atherosclerotic processes initiated in vascular cells and agents that increase UCP-2 expression in vascular cells may help prevent the development and progression of atherosclerosis in patients with diabetes or hypertension. PMID: 17462780 [PubMed - indexed for MEDLINE] 2950. Sheng Wu Gong Cheng Xue Bao. 2007 Mar;23(2):195-200. [Multipotential differentiation and potential applications of adipose-derived stem cells]. [Article in Chinese] Han ZB(1), Chen HX, Deng JX. Author information: (1)Institute of Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China. hanzhengbin@yahoo.com.cn Adipose tissue contains a population of multipotent cells called adipose-derived stem cells (ADSCs). With the similar properties of marrow-derived mesenchymal stem cells, ADSCs have the ability to differentiate differentiate towards adipogenic, osteogenic, chondrogenic, myogenic, endothelial, hematopoietic, hepatic, islet, and neurogenic cell lineages. As adipose tissue in harvested in large amounts with minimal morbidity, it can be widely used in tissue engineering, organ repair and gene therapy. This paper focused on the plasticity of ADSCs and reviewed the new advances of this field. Finally, the problems and prospect for application was also discussed. PMID: 17460887 [PubMed - indexed for MEDLINE] 2951. J Lipid Res. 2007 Aug;48(8):1655-72. Epub 2007 Apr 25. Thematic review series: adipocyte biology. Sympathetic and sensory innervation of white adipose tissue. Bartness TJ(1), Song CK. Author information: (1)Department of Biology, Neurobiology and Behavior Program, Georgia State University, Atlanta, GA 30302-4010, USA. bartness@gsu.edu During our study of the reversal of seasonal obesity in Siberian hamsters, we found an interaction between receptors for the pineal hormone melatonin and the sympathetic nervous system (SNS) outflow from brain to white adipose tissue (WAT). This ultimately led us and others to conclude that the SNS innervation of WAT is the primary initiator of lipid mobilization in these as well as other animals, including humans. There is strong neurochemical (norepinephrine turnover), neuroanatomical (viral tract tracing), and functional (sympathetic denervation-induced blockade of lipolysis) evidence for the role of the SNS in lipid mobilization. Recent findings suggest the presence of WAT sensory innervation based on strong neuroanatomical (viral tract tracing, immunohistochemical markers of sensory nerves) and suggestive functional (capsaicin sensory denervation-induced WAT growth) evidence, the latter implying a role in conveying adiposity information to the brain. By contrast, parasympathetic nervous system innervation of WAT is characterized by largely negative neuroanatomical evidence (viral tract tracing, immunohistochemical and biochemical markers of parasympathetic nerves). Functional evidence (intraneural stimulation and in situ microdialysis) for the role of the SNS innervation in lipid mobilization in human WAT is convincing, with some controversy regarding the level of sympathetic nerve activity in human obesity. PMID: 17460327 [PubMed - indexed for MEDLINE] 2952. J Steroid Biochem Mol Biol. 2007 May;104(3-5):161-8. Epub 2007 Mar 23. Endogenous inhibitors (GALFs) of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2: derivatives of adrenally produced corticosterone and cortisol. Morris DJ(1), Latif SA, Hardy MP, Brem AS. Author information: (1)Brown University Medical School, Providence, RI 02906, USA. dmorris@lifespan.org Two isoforms of 11beta-HSD exist; 11beta-HSD1 is bi-directional (the reductase usually being predominant) and 11beta-HSD2 functions as a dehydrogenase, conferring kidney mineralocorticoid specificity. We have previously described endogenous substances in human urine, "glycyrrhetinic acid-like factors (GALFs)", which like licorice, inhibit the bi-directional 11beta-HSD1 enzyme as well as the dehydrogenase reaction of 11beta-HSD2. Many of the more potent GALFs are derived from two major families of adrenal steroids, corticosterone and cortisol. For example, 3alpha5alpha-tetrahydro-corticosterone, its derivative, 3alpha5alpha-tetrahydro-11beta-hydroxy-progesterone (produced by 21-deoxygenation of corticosterone in intestinal flora); 3alpha5alpha-tetrahydro-11beta-hydroxy-testosterone (produced by side chain cleavage of cortisol); are potent inhibitors of 11beta-HSD1 and 11beta-HSD2-dehydrogenase, with IC50's in range 0.26-3.0 microM, whereas their 11-keto-3alpha5alpha-tetrahydro-derivatives inhibit 11beta-HSD1 reductase, with IC50's in range 0.7-0.8 microM (their 3alpha5beta-derivatives being completely inactive). Inhibitors of 11beta-HSD2 increase local cortisol levels, permitting it to act as a mineralocorticoid in kidney. Inhibitors of 11beta-HSD1 dehydrogenase/11beta-HSD1 reductase serve to adjust the set point of local deactivation/reactivation of cortisol in vascular and other glucocorticoid target tissues, including adipose, vascular, adrenal tissue, and the eye. These adrenally derived 11-oxygenated C21- and C19 -steroidal substances may serve as 11beta-HSD1- or 11beta-HSD2-GALFs. We conclude that adrenally derived products are likely regulators of local cortisol bioactivity in humans. PMID: 17459698 [PubMed - indexed for MEDLINE] 2953. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:349-55. [Clinical features of the metabolic syndrome and its molecular mechanism]. [Article in Japanese] Sato N(1), Ogawa Y. Author information: (1)National Hospital Organization, Kyoto Medical Center, Clinical Research Institute for Endocrine & Metabolic Diseases. PMID: 17458245 [PubMed - indexed for MEDLINE] 2954. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:259-62. [PPARalpha, PPARgamma, PPARdelta]. [Article in Japanese] Takahashi S(1), Sakai J. Author information: (1)Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui. PMID: 17458228 [PubMed - indexed for MEDLINE] 2955. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:244-8. [Role of TFAP2B and Wnt5B in adipose tissue]. [Article in Japanese] Maegawa H(1), Maeda S. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science. PMID: 17458225 [PubMed - indexed for MEDLINE] 2956. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:231-6. [Angiotensinogen]. [Article in Japanese] Tomono Y(1), Iwai M, Horiuchi M. Author information: (1)Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine. PMID: 17458223 [PubMed - indexed for MEDLINE] 2957. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:212-6. [Adiponectin, visfatin, PAI-1]. [Article in Japanese] Matsuda M(1), Funahashi T. Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University. PMID: 17458220 [PubMed - indexed for MEDLINE] 2958. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:198-202. [Pathophysiologic role of macrophages infiltrated into obese adipose tissue]. [Article in Japanese] Suganami T(1), Ogawa Y. Author information: (1)Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University. PMID: 17458218 [PubMed - indexed for MEDLINE] 2959. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:192-7. [Adiposteroid: pathophysiologic role of intracellular glucocorticoid reamplification in adipocytes]. [Article in Japanese] Masuzaki H(1), Yasue S, Nakao K. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. PMID: 17458217 [PubMed - indexed for MEDLINE] 2960. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:188-91. [Fat distribution and its regulation]. [Article in Japanese] Maeda N(1), Funahashi T. Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University. PMID: 17458216 [PubMed - indexed for MEDLINE] 2961. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:132-8. [The roles of adipokines in the regulation of insulin sensitivity]. [Article in Japanese] Yamauchi T(1), Kadowaki T. Author information: (1)Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, University of Tokyo Hospital. PMID: 17458207 [PubMed - indexed for MEDLINE] 2962. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:121-5. [Insulin action and its regulatory mechanisms]. [Article in Japanese] Noguchi T(1), Kasuga M. Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine. PMID: 17458205 [PubMed - indexed for MEDLINE] 2963. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:110-5. [Brain-adipose axis and leptin resistance]. [Article in Japanese] Shimizu H(1), Oh SI, Mori M. Author information: (1)Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine. PMID: 17458203 [PubMed - indexed for MEDLINE] 2964. Nihon Rinsho. 2006 Dec 28;64 Suppl 9:17-22. [Metabolic syndrome: convergence of metabolic diseases based on obesity and dysfunction of adipose tissue]. [Article in Japanese] Masuzaki H(1), Tanaka T, Nakao K. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. PMID: 17458189 [PubMed - indexed for MEDLINE] 2965. Curr Med Chem. 2007;14(10):1095-100. The contribution of adipose tissue and adipokines to inflammation in joint diseases. Toussirot E(1), Streit G, Wendling D. Author information: (1)Department of Rheumatology, Jean Minjoz University Hospital, Bd Fleming, F-25030 Besançon Cedex, France. eric.toussirot@ufc-chu.univ-fcomte.fr Adipokines are proteins produced by white adipose tissue, which is an active secretory organ. Regulation of immune and inflammatory responses is among the multiple physiological processes involving adipokines. Leptin, adiponectin and resistin are the most extensively studied adipokines. Leptin may promote inflammation by inducing Th1 phenotype development, whereas adiponectin may combat inflammation by reducing the production of pro-inflammatory cytokines. Resistin belongs to a family of proteins found in foci of inflammation, where they contribute to the inflammatory response. All three adipokines have been detected in synovial fluid from joints affected with the inflammatory disease rheumatoid arthritis (RA) or the degenerative disease osteoarthritis (OA). Recent evidence points to involvement of leptin in RA and OA and indicates that adiponectin and/or resistin mediate inflammation in arthritis. Thus, fat tissue is an active organ whose products contribute to inflammatory and degenerative processes underlying common joint diseases. PMID: 17456023 [PubMed - indexed for MEDLINE] 2966. J Dent Res. 2007 May;86(5):400-9. Obesity, inflammation, and periodontal disease. Pischon N(1), Heng N, Bernimoulin JP, Kleber BM, Willich SN, Pischon T. Author information: (1)Dept. of Periodontology, Charité University Medical Center, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. nicole.pischon@charite.de The prevalence of obesity has increased substantially over the past decades in most industrialized countries. Obesity is a systemic disease that predisposes to a variety of co-morbidities and complications that affect overall health. Cross-sectional studies suggest that obesity is also associated with oral diseases, particularly periodontal disease, and prospective studies suggest that periodontitis may be related to cardiovascular disease. The possible causal relationship between obesity and periodontitis and potential underlying biological mechanisms remain to be established; however, the adipose tissue actively secretes a variety of cytokines and hormones that are involved in inflammatory processes, pointing toward similar pathways involved in the pathophysiology of obesity, periodontitis, and related inflammatory diseases. We provide an overview of the definition and assessment of obesity and of related chronic diseases and complications that may be important in the periodontist's office. Studies that have examined the association between obesity and periodontitis are reviewed, and adipose-tissue-derived hormones and cytokines that are involved in inflammatory processes and their relationship to periodontitis are discussed. Our aim is to raise the periodontist's awareness when treating obese individuals. PMID: 17452558 [PubMed - indexed for MEDLINE] 2967. Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S11-6. Epub 2007 Apr 23. New evaluations of redox regulating system in adipose tissue of obesity. Park J(1), Chung JJ, Kim JB. Author information: (1)Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul, Korea. During the past several decades, the incidence of obesity has significantly increased worldwide. Enormous efforts have been devoted to understanding the molecular mechanisms underlying obesity and its related metabolic disorders such as type 2 diabetes, cardiovascular disease, atherosclerosis, and hypertension. It is now well-established that altered adipocyte metabolism in obese patients is closely associated with the induction of various metabolic stresses including hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic inflammation. However, the cellular factor(s) which sense metabolic changes and/or initiate the pathological progression of obesity-induced metabolic disorders remain to be elucidated. In this review, we will discuss the possible roles of cellular NADP(+)/NADPH, which function as redox potential regulators, in the induction of obesity-associated oxidative stress, chronic inflammation, and insulin resistance and suggest G6PD, a NADPH-generating enzyme, as a novel target for treating metabolic disorders. PMID: 17452057 [PubMed - indexed for MEDLINE] 2968. Ideggyogy Sz. 2007 Mar 30;60(3-4):97-108. Brain insulin signalling in the regulation of energy balance and peripheral metabolism. Diamant M(1). Author information: (1)Department of Endocrinology, VU University Medical Center, PO BOX 7057, 1007 MB Amsterdam, The Netherlands. m.diamant@vumc.nl The unparalleled global rates of obesity and type 2 diabetes, together with the associated cardiovascular morbidity and mortality, are referred to as the "diabesity pandemic". Changes in lifestyle occurring worldwide, including the increased consumption of high-caloric foods and reduced exercise, are regarded as the main causal factors. Central obesity and insulin resistance have emerged as important linking components. Understanding the aetiology of the cluster of pathologies that leads to the increased risk is instrumental in the development of preventive and therapeutic strategies. Historically, skeletal muscle, adipose tissue and liver were regarded as key insulin target organs involved in insulin-mediated regulation of peripheral carbohydrate, lipid and protein metabolism. The consequences of impaired insulin action in these organs were deemed to explain the functional and structural abnormalities associated with insulin resistance. The discovery of insulin receptors in the central nervous system, the detection of insulin in the cerebrospinal fluid after peripheral insulin administration and the well-documented effects of intracerebroventricularly injected insulin on energy homeostasis, have identified the brain as an important target for insulin action. In addition to its critical role as a peripheral signal integrating the complex network of hypothalamic neuropeptides and neurotransmitters that influence parameters of energy balance, central nervous insulin signalling is also implicated in the regulation of peripheral glucose metabolism. This review summarizes the evidence of insulin action in the brain as part of the multifaceted circuit involved in the central regulation of energy and glucose homeostasis, and discuss the role of impaired central nervous insulin signalling as a pathogenic factor in the obesity and type 2 diabetes epidemic. PMID: 17451048 [PubMed - indexed for MEDLINE] 2969. Cephalalgia. 2007 May;27(5):435-46. Migraine and adiponectin: is there a connection? Peterlin BL(1), Bigal ME, Tepper SJ, Urakaze M, Sheftell FD, Rapoport AM. Author information: (1)Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. lee.peterlin@drexelmed.edu Erratum in Cephalalgia. 2007 Jun;27(6):570. Migraine is a common disorder, characterized by recurrent episodes of headache and associated symptoms. The full pathophysiology of migraine is incompletely delineated. Current theories suggest that it is a neurovascular disorder involving cortical depression, neurogenic inflammation and vasodilation. Various neuropeptides and cytokines have been implicated in the pathophysiology of migraine including calcitonin gene-related peptide, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha. There is evidence demonstrating an association between migraine and processes associated with inflammation, atherosclerosis, immunity and insulin sensitivity. Similarly, adiponectin, an adipocytokine secreted by adipose tissue, has protective roles against the development of insulin resistance, dyslipidaemia and atherosclerosis and exhibits anti-inflammatory properties. The anti-inflammatory activities of adiponectin include inhibition of IL-6 and TNF-induced IL-8 formation, as well as induction of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Adiponectin levels are also inversely correlated with C-reactive protein (CRP), TNF-alpha and IL-6 levels. Likewise, recent studies have shown a possible correlation between CRP, TNF-alpha and IL-6 and migraine attacks. In addition, insulin sensitivity is impaired in migraine and obesity is a risk factor for the transformation from episodic to chronic migraine. In this review we discuss the basic science of adiponectin and its potential connection to the pathophysiology of migraine. Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy. PMID: 17448181 [PubMed - indexed for MEDLINE] 2970. Obes Rev. 2007 May;8(3):263-76. The Collaborative Study of Obesity and Diabetes in Adults (CODA) project: meta-analysis design and description of participating studies. Duval S(1), Vazquez G, Baker WL, Jacobs DR Jr; CODA study group. Author information: (1)Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454-1015, USA. duval@epi.umn.edu The Collaborative Study of Obesity and Diabetes in Adults (CODA) project was formed to establish an international database of studies of abdominal obesity and type 2 diabetes mellitus (T2DM), and to provide analyses of these associations using individual participant data (IPD) meta-analytic techniques. The collaboration involves obtaining raw data from existing studies. The main objectives of the collaboration are to assess which simple anthropometric indices most closely predict the risk of T2DM in adults, and to investigate ethnicity and other factors that potentially modify that prediction. A second task related to primary prevention of diabetes subsequently evolved, the CODA-2 project, and is concerned with population-based methods to identify people most likely to benefit from diabetes interventions. This article describes the meta-analysis design and the studies involved. The collaboration currently has 37 studies enrolled, providing data on 260,000 participants. The proposed IPD meta-analyses will help resolve several outstanding issues in diabetes. PMID: 17444967 [PubMed - indexed for MEDLINE] 2971. Obes Rev. 2007 May;8(3):253-61. Epicardial fat: properties, function and relationship to obesity. Rabkin SW(1). Author information: (1)Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, BC, Canada. rabkin@interchange.ubc.ca Epicardial fat is a relatively neglected component of the heart. The purpose of this review was to examine the anatomic and biochemical data on epicardial fat; to examine the relationship of epicardial fat to obesity and to explore the potential role of epicardial fat in the relationship of obesity to coronary atherothrombotic disease. Epicardial fat covers 80% of the heart's surface and constitutes 20% of total heart weight. It is present along the distribution of the coronary arteries, over the right ventricle especially along the right border, anterior surface and at the apex. There is three- to fourfold more epicardial fat associated with the right than the left ventricle. Putative physiologic functions of epicardial fat are based on observational data and include: buffering coronary arteries against the torsion induced by the arterial pulse wave and cardiac contraction, facilitating coronary artery remodelling, regulating fatty acid homeostasis in the coronary microcirculation and providing fatty acids to cardiac muscle as a local energy source in times of high demand. A considerable amount of the data on epicardial fat originates from autopsy series that have the inherent problem that conditions leading to death may have altered body composition and adiposity. With this caveat, data indicate that epicardial fat mass increases age until age 20-40 years but thereafter the amount of epicardial fat is not dependent on age. The amount of epicardial fat correlates with heart weight but the presence of myocardial ischemia and hypertrophy does not alter the ratio of epicardial fat to cardiac muscle mass. A number of properties differentiate epicardial fat from other fat depots specifically its smaller adipocytes size; different fatty acid composition, high protein content; high rates of fatty acid incorporation, fatty acid synthesis, insulin-induced lipogenesis or fatty acid breakdown; low rates of glucose utilization, low expression (mRNA) of lipoprotein lipase, stearoyl-CoA desaturase and acetyl-CoA carboxylase-alpha, and slow regression during weight loss. There is a significant direct relationship between the amount of epicardial fat and general body adiposity. Clinical imaging studies have demonstrated a strong direct correlation between epicardial fat and abdominal visceral adiposity. Several lines of evidence support a role for epicardial fat in the pathogenesis of coronary artery disease, namely the close anatomic relationship between epicardial fat and coronary arteries; the positive correlation between the amount of epicardial fat and the presence of coronary atherosclerosis and the ability of adipose tissue to secrete hormones and cytokines that modulate coronary artery atherothrombosis. Thus, epicardial fat maybe an important factor responsible for cardiovascular disease in obesity. PMID: 17444966 [PubMed - indexed for MEDLINE] 2972. Obes Rev. 2007 May;8(3):231-51. Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects. Iannello S(1), Milazzo P, Belfiore F. Author information: (1)Department of Medicina Interna e Patologie Sistemiche, University of Catania, Ospedale Garibaldi, Catania, Italy. The sodium(Na)- and potassium(K)-activated adenosine-triphosphatase (Na,K-ATPase) is a membrane enzyme that energizes the Na-pump by hydrolysing adenosine triphosphate and wasting energy as heat, so playing a role in thermogenesis and energy balance. Na,K-ATPase regulation by insulin is controversial; in tissue of hyperglycemic-hyperinsulinemic ob/ob mice, we reported a reduction, whereas in streptozotocin-treated hypoinsulinemic-diabetic Swiss and ob/ob mice we found an increased activity, which is against a genetic defect and suggests a regulation by hyperinsulinemia. In human adipose tissue from obese patients, Na,K-ATPase activity was reduced and negatively correlated with body mass index, oral glucose tolerance test-insulinemic area and blood pressure. We hypothesized that obesity is associated with tissue Na,K-ATPase reduction, apparently linked to hyperinsulinemia, which may repress or inactivate the enzyme, thus opposing thyroid hormones and influencing thermogenesis and obesity development. Insulin action on Na,K-ATPase, in vivo, might be mediated by the high level of non-esterified fatty acids, which are circulating enzyme inhibitors and increase in obesity, diabetes and hypertension. In this paper, we analyse animal and human tissue Na,K-ATPase, its level, and its regulation and behaviour in some hyperinsulinemic and insulin-resistant states; moreover, we discuss the link of the enzyme with non-esterified fatty acids and attempt to interpret and organize in a coherent view the whole body of the exhaustive literature on this complicated topic. PMID: 17444965 [PubMed - indexed for MEDLINE] 2973. Curr Hypertens Rep. 2007 Apr;9(2):106-11. The metabolic syndrome in primary aldosteronism. Fallo F(1), Federspil G, Veglio F, Mulatero P. Author information: (1)Department of Medical and Surgical Sciences, Clinica Medica 3, University of Padova, Via Ospedale 105, Padova, Italy. francesco.fallo@unipd.it Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder. PMID: 17442220 [PubMed - indexed for MEDLINE] 2974. Rev Esp Anestesiol Reanim. 2007 Mar;54(3):173-83. [Epidural fat in various diseases: contribution of magnetic resonance imaging and potential implications for neuro axial anesthesia]. [Article in Spanish] Reina MA(1), Pulido P, Castedo J, Villanueva MC, López A, De Andrés JA, Sola RG. Author information: (1)Servicio de Anestesiología, Hospital Madrid Montepríncipe, Madrid. miguelangel.rei@terra.es Epidural fat is a reservoir of lipophilic substances that cushions the pulsatile movements of the dural sac, protects nerve structures, and facilitates the movement of the dural sac over the periosteum of the spinal canal during flexion and extension. Excessive epidural fat can compress the underlying structures, however, and affect the placement of catheters and the distribution of injected solutions. This review discusses changes in epidural fat related to various diseases and events: lipomatosis, epidural lymphoma, arachnoid cysts, epidural hematoma, meningiomas, angiolipomas, spondylolysis, scoliosis, spinal stenosis, and liposarcoma. Also discussed are the sequencing and protocols for magnetic resonance imaging that enable epidural fat to be observed and distinguished from neighboring structures. The relevance of epidural fat in spinal surgery is considered. Finally, we discuss the possible anesthetic implications of the abnormal deposition of epidural fat, to explain the unexpected complications that can arise during performance of epidural anesthesia. PMID: 17436656 [PubMed - indexed for MEDLINE] 2975. Arq Bras Endocrinol Metabol. 2007 Feb;51(1):11-24. [Leptin: aspects on energetic balance, physical exercise and athletic amenorhea]. [Article in Portuguese] Ribeiro SM(1), dos Santos ZA, da Silva RJ, Louzada E, Donato J Jr, Tirapegui J. Author information: (1)Grupo de Estudos em Nutrição e Atividade Física, Programa de Pós Graduação Stricto Sensu em Educação Física da Universidade São Judas Tadeu, São Paulo. smlribeiro@uol.com.br The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals. PMID: 17435851 [PubMed - indexed for MEDLINE] 2976. Peptides. 2007 May;28(5):1129-43. Epub 2007 Mar 14. Adrenomedullin is a novel adipokine: adrenomedullin in adipocytes and adipose tissues. Li Y(1), Jiang C, Wang X, Zhang Y, Shibahara S, Takahashi K. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100083, PR China. Adrenomedullin (AM) is a multifunctional regulatory peptide that is produced and secreted by various types of cells. The production and the secretion of AM have been demonstrated in cultured adipocytes and adipose tissues. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide are strong stimulators for AM expression in adipocytes. Furthermore, AM expression in the adipose tissue is increased in obesity, and plasma concentrations of AM are increased in obese subjects. One possible (patho)physiological role of AM secreted by adipose tissue may be actions against complications of the metabolic syndrome characterized by obesity, type 2 diabetic mellitus and hypertension, via its antioxidant and potent vasodilator effects. These findings indicate that AM is a new member of the adipokine family. PMID: 17433499 [PubMed - indexed for MEDLINE] 2977. J Mammary Gland Biol Neoplasia. 2007 Mar;12(1):25-35. Mammary gland involution as a multi-step process. Stein T(1), Salomonis N, Gusterson BA. Author information: (1)Division of Cancer Sciences and Molecular Pathology, Section of Gene Regulation and Mechanisms of Disease, Western Infirmary, University of Glasgow, Glasgow G11 6NT, UK. Mammary gland involution is a highly complex multi-step process in which the lactating gland returns to a morphologically near pre-pregnant state. This developmental stage is characterized by a high degree of epithelial cell death, redevelopment of the mammary adipose tissue and tissue remodelling. Many factors involved have been described and these have been reviewed intensively in this journal (Furth, P. A., J. Mammary Gland Biol. Neoplasia, 4:123-127, 1999) and elsewhere. Microarray analysis technology has now not only allowed us to identify genes not previously associated with involution (Stein, T., Morris, J.S., Davis, C.R.,Weber-Hall, S.J., Duffy, M.A., Heath, V.J., et al., Breast Cancer Res., 6: R75-R91, 2004; Clarkson, R.W., Wayland, M.T., Lee, J., Freeman, T., Watson, C.J., Breast Cancer Res., 6: R92-R109, 2004; Clarkson, R.W., Watson, C.J., J. Mammary Gland Biol. Neoplasia, 8: 309-319, 2003), it has also enabled us to define multiple phases of the controlled regulatory response to forced weaning on the basis of their transcriptional profiles. This review provides a synthesis of published data, integrating the time course of transcriptional activity in the mouse mammary gland with a gene ontology approach to identify the pathways involved. PMID: 17431797 [PubMed - indexed for MEDLINE] 2978. Curr Alzheimer Res. 2007 Apr;4(2):127-34. Adiposity and Alzheimer's disease. Luchsinger JA(1), Mayeux R. Author information: (1)Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. jal94@columbia.edu The objective of this manuscript is to provide a comprehensive review of the relation between adiposity and Alzheimer's disease (AD), its potential mechanisms, and issues in its study. Adiposity represents the body fat tissue content. When the degree of adiposity increases it can be defined as being overweight or obese by measures such as the body mass index. Being overweight or obese is a cause of hyperinsulinemia and diabetes, both of which are risk factors for AD. However, the epidemiologic evidence linking the degree of adiposity and AD is conflicting. Traditional adiposity measures such as body mass index have decreased validity in the elderly. Increased adiposity in early or middle adult life leads to hyperinsulinemia which may lead to diabetes later in life. Thus, the timing of ascertainment of adiposity and its related factors is critical in understanding how it might fit into the pathogenesis of AD. We believe that the most plausible mechanism relating adiposity to AD is hyperinsulinemia, but it is unclear whether specific products of adipose tissue also have a role. Being overweight or obese is increasing in children and adults, thus understanding the association between adiposity and AD has important public health implications. PMCID: PMC1890025 PMID: 17430235 [PubMed - indexed for MEDLINE] 2979. Curr Alzheimer Res. 2007 Apr;4(2):117-22. The epidemiology of adiposity and dementia. Whitmer RA(1). Author information: (1)Kaiser Permanente Division of Research, Etiology and Prevention, 2000 Broadway, Oakland, CA 94612, USA. Rachel.Whitmer@kp.org Adipose tissue is the largest endocrine gland in the body, yet only recently has its role in neurodegenerative disease been considered. Prospective population level evidence has emerged to show that both obesity and overweight, is associated with an increased risk of all cause dementia, Alzheimer's disease (AD), and underlying neurodegenerative changes. Weight loss in late life however is associated with dementia, and those categorized as underweight are also at a greater risk of dementia. Given the current epidemic of obesity, and the expected age-related increase in dementia incidence, even a small association between these two diseases has far reaching public health implications. However, due to the effects of both AD-associated weight loss and age-related changes in body composition, there are methodological challenges in appropriately evaluating obesity as a risk factor for developing dementia. There is a need to take a 'life course approach' and to consider the role of risk factors prior to the onset of old age. Our work has shown that both obesity and overweight, as measured by body mass index and skinfold thickness, in middle-age are strongly associated with an increased risk of all cause dementia, Alzheimer disease & Vascular dementia, independent of the development of diabetes and cardiovascular-related morbidities. There is also value in assessing regional body shape distributions of adiposity, particular the role of abdominal obesity. Mechanistic pathways such as adipocyte secreted proteins and hormones, and inflammatory cytokines could explain the association between obesity and increased risk of dementia. PMID: 17430233 [PubMed - indexed for MEDLINE] 2980. Curr Drug Metab. 2007 Apr;8(3):289-95. Chronic immune activation underlies morbid obesity: is IDO a key player? Brandacher G(1), Hoeller E, Fuchs D, Weiss HG. Author information: (1)Department of General and Transplant Surgery, D. Swarovski Research Laboratory, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Morbid obesity is associated with low-grade systemic inflammation and immune activation. Thereby various pro-inflammatory cytokines like TNF-alpha, IL-1, IL-6, IFN-gamma and hormones, such as leptin are synthesized and released in human adipose tissue. The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is widely distributed in mammals and is inducible preferentially by IFN-gamma. IDO degrades the essential amino acid tryptophan to form N-formyl kynurenine which, depending on cell type and enzymatic repertoires, is subsequently converted to finally form niacin. More recently, it has been proposed that activation of IDO is also critically involved in the regulation of immune responses. In obesity plasma tryptophan concentrations have been shown to be decreased and to be independent of weight reduction or dietary intake. In addition, we previously demonstrated that IDO mediated tryptophan catabolism due to chronic immune activation is the cause for such reduced tryptophan plasma levels in morbidly obese patients compared to lean individuals. Furthermore, these tryptophan metabolic changes may subsequently reduce serotonin production and cause mood disturbances, depression, and impaired satiety ultimately leading to increased caloric uptake and obesity. IDO-mediated tryptophan degradation due to chronic immune activation can therefore be considered as the driving force for food intake. We here review the potential pathogenic links between chronic immune activation and decreased IDO mediated tryptophan and serotonin levels in morbid obesity. PMID: 17430117 [PubMed - indexed for MEDLINE] 2981. Physiol Rev. 2007 Apr;87(2):507-20. Disordered lipid metabolism and the pathogenesis of insulin resistance. Savage DB(1), Petersen KF, Shulman GI. Author information: (1)Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536-8012, USA. Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight. PMCID: PMC2995548 PMID: 17429039 [PubMed - indexed for MEDLINE] 2982. Pediatr Res. 2007 Jun;61(6):636-9. Is your metabolism determined by (cell) fate? Feldman BJ(1). Author information: (1)Department of Pediatrics, University of California, San Francisco, CA 94143, USA. bfeldman@cmp.ucsf.edu The rise in the incidence of metabolic disease to become a major public health problem has been met with a substantial increase in research into both the clinical and basic science of metabolism. This work has revealed that the origins of metabolic diseases of adults can begin early in life. Furthermore, the age of onset of symptoms has been rapidly decreasing. Therefore, pediatricians should be critically involved in both the generation of new therapies as well as the institution of measures of disease prevention. This perspective examines how recent advances have improved our understanding of the development of metabolic diseases. A connection between glucocorticoids and the origins of metabolic disease is one enticing clue because of the clinical similarity between patients with glucocorticoid excess and those with metabolic disease. A unifying link was found by investigating the role of glucocorticoids on cell fate and differentiation of mesenchymal stem cells. We conclude that understanding the mechanisms by which glucocorticoids can modify how cell fate decisions are made holds promise for developing new therapies and preventative measures. PMID: 17426662 [PubMed - indexed for MEDLINE] 2983. Pediatr Res. 2007 Jun;61(6):653-9. Obesity, metabolic syndrome, and cardiovascular disease. Aggoun Y(1). Author information: (1)Department of Paediatrics, Paediatric Cardiology Unit. University Hospital of Geneva, 1211 Geneva, Switzerland. yacine.aggoun@hcuge.ch Early childhood overweight and obesity have alarmingly increased over the years. Adulthood obesity is a well demonstrated significant independent predictor of cardiovascular risk (CVR) and/or mortality, which predisposes to the major components of metabolic syndrome (MS). Evidence of MS in obese children has been also reported associated with biochemical and inflammatory factors that affect vascular physiologic function. Assessment of vascular function can be measured noninvasively in children allowing early detection of endothelial dysfunction and severe increase of arterial stiffness before clinical manifestations of atherosclerosis. Impairment of endothelial function related to the severity of obesity and to the degree of insulin resistance is considered as a condition that confers a premature atherogenicity status and is linked to adult conventional cardiovascular risk factors. Adipose tissue factors that interfere with insulin action and endothelial cell function have also been identified as major precursors of CVR factors. The metabolic and cardiovascular consequences of childhood obesity are well demonstrated and have a major impact on the development of atherosclerosis and lifetime CVR. The development of programs involving both diet and exercise for children with overt overweight/obesity appears to be essential to improve vascular function and metabolic disorders. Such interventions should be complemented by a primary prevention against childhood obesity. PMID: 17426660 [PubMed - indexed for MEDLINE] 2984. Pediatr Res. 2007 Jun;61(6):640-5. New predictors of the metabolic syndrome in children--role of adipocytokines. Körner A(1), Kratzsch J, Gausche R, Schaab M, Erbs S, Kiess W. Author information: (1)University Hospital for Children and Adolescents, University of Leipzig, 04317 Leipzig, Germany. antje.koerner@medizin.uni-leipzig.de There is ample discussion of the relevance of the metabolic syndrome, the definition criteria, and predictive power. Nevertheless, along with the increasing prevalence of childhood obesity, the prevalence of the metabolic syndrome in obese children is reported at 30%, irrespective of the definition applied. Because children are otherwise relatively free of co-morbidities, they constitute an interesting population in which to study the sequence of events of obesity-related pathology. The adipocytokines appear to be important in this respect. Leptin was initially suggested as a promising "antiobesity" hormone. New concepts indicate that, in humans, leptin and its soluble receptor may be more important in states of energy deficiency rather than a predictor of the metabolic syndrome. Adiponectin, on the other hand, is not only related to obesity and insulin resistance, but appears to be the strongest predictor for metabolic syndrome, even in children. In newborns and infants, both adipocytokines occur in high concentrations, even though this cannot completely explain the increased risk for ensuing metabolic disease later in life. Finally, low-grade systemic inflammation may underlie the clustering of metabolic risk factors, but their role in children remains to be specified. Overall factors from the adipose tissue may constitute not only markers but also mediators of metabolic sequelae of obesity. PMID: 17426657 [PubMed - indexed for MEDLINE] 2985. Nutr Rev. 2007 Mar;65(3):130-4. Identification of a functional polymorphism at the adipose fatty acid binding protein gene (FABP4) and demonstration of its association with cardiovascular disease: a path to follow. Ordovas JM(1). Author information: (1)Nutrition and Genomics Laboratory, Jean Meyer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., Boston, MA 02111, USA. jose.ordovas@tufts.edu Fatty acid binding proteins (FABPs) are proteins that reversibly bind fatty acids and other lipids. So far, nine tissue-specific cytoplasmic FABPs have been identified. Adipose tissue FABP (FABP4) has been suggested to be a bridge between inflammation and other pathways related to the metabolic syndrome. In this regard, genetic variability at the FABP4 locus has been shown to be associated with plasma lipid levels, type 2 diabetes, and coronary heart disease risk. PMID: 17425064 [PubMed - indexed for MEDLINE] 2986. Diabetes Metab. 2007 Apr;33(2):85-95. Epub 2007 Apr 5. Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients. Lafontan M(1), Piazza PV, Girard J. Author information: (1)Institut Louis-Bugnard IFR31, institut de médecine moléculaire de Rangueil-I2MR, INSERM-UPS U858, BP 84225, 31432 Toulouse cedex 04, France. Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies. PMID: 17418607 [PubMed - indexed for MEDLINE] 2987. Semin Nucl Med. 2007 May;37(3):195-205. Determination of age-related changes in structure and function of skin, adipose tissue, and skeletal muscle with computed tomography, magnetic resonance imaging, and positron emission tomography. Wehrli NE(1), Bural G, Houseni M, Alkhawaldeh K, Alavi A, Torigian DA. Author information: (1)Department of Radiology, Division of Nuclear Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. In this article, we report quantitative preliminary data obtained from retrospective analysis of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and combined PET-computed tomography (PET/CT) examinations in subjects ages 3 to 84 years pertaining to changes in the metabolism of skin, subcutaneous adipose tissue, visceral adipose tissue, and skeletal muscle with age, as well as age-related changes in skeletal muscle attenuation. We also propose a new method for identifying hypermetabolic brown fat on FDG-PET. Finally, we present a review of the literature regarding reported age-related structural and functional changes that occur in skin, fat, and skeletal muscle. Using FDG-PET, We evaluated 213 subjects for changes in the metabolism of skin, adipose tissue, and skeletal muscle with aging. Thirty-two separate subjects were chosen to measure maximum standardized uptake value (SUV) of hypermetabolic brown fat on dual-time point PET imaging. Finally, 15 subjects evaluated by PET/CT were selected to measure changes in metabolism and attenuation of skeletal muscle, and changes in metabolism of adipose tissue with aging. We found that skin, fat, and skeletal muscle all demonstrate significant (P < 0.05) increases in SUV with increasing age on PET imaging. Dual-time point PET imaging demonstrates increasing FDG uptake of hypermetabolic brown fat in various regions studied. Finally, our PET/CT studies revealed statistically insignificant (P > 0.05) decreases in SUV of adipose tissue with aging and the opposite trend in skeletal muscles (P > 0.05). Skeletal muscle attenuation in the various regions studied was found to significantly decrease with age (P < 0.05). Our study shows notable trends in metabolism and attenuation of skeletal muscle and metabolism of skin and adipose tissue that occur with normal aging. We hope that the methodologies and data we present here will serve as a useful starting point for those interested in conducting future prospective research on age-related changes in these structures. PMID: 17418152 [PubMed - indexed for MEDLINE] 2988. Exerc Sport Sci Rev. 2007 Apr;35(2):56-61. Primary cell cultures in the study of human muscle metabolism. Berggren JR(1), Tanner CJ, Houmard JA. Author information: (1)Human Performance Laboratory and Department of Exercise and Sport Science, East Carolina University, Greenville, NC 27858, USA. Skeletal muscle plays an important role in whole-body metabolism. Some research has used cell cultures raised from human biopsy tissue to study mechanisms that regulate skeletal muscle metabolism. The purpose of the current paper is to provide evidence indicating the efficacy of primary human skeletal muscle cell cultures as a tool to study substrate regulation and control in human tissue. PMID: 17417051 [PubMed - indexed for MEDLINE] 2989. Cardiovasc Res. 2007 Sep 1;75(4):690-701. Epub 2007 Mar 14. Local adipose tissue depots as cardiovascular risk factors. Thalmann S(1), Meier CA. Author information: (1)Department of Internal Medicine, Triemli Hospital, Birmensdorferstrasse 497, CH-8063 Zürich, Switzerland. Obesity is associated with increased cardiovascular morbidity and mortality. Although obesity-associated hypertension, dyslipidemia and insulin resistance account in part for this association, it becomes increasingly apparent that a systemic and local pro-inflammatory response of adipose tissue might also be a contributing factor. White adipose tissue (WAT) is a highly active organ secreting various peptides such as cytokines, chemokines and hormone-like proteins. Besides the visceral and subcutaneous depots, WAT is also found in the close vicinity of blood vessels (perivascular adipose tissue), where it secretes cytokines such as interleukin-1, tumor necrosis factor alpha, pro-atherogenic chemokines, and pro-angiogenic peptides. These factors appear to contribute directly to alterations of the function and structure of the vascular wall, including chronic inflammation, alterations of vascular tone, proliferation of smooth muscle cells, neo-angiogenesis and hence to the development of atherosclerosis and cardiovascular complications. PMID: 17412312 [PubMed - indexed for MEDLINE] 2990. Yakugaku Zasshi. 2007 Apr;127(4):579-86. Insulin resistance as a membrane microdomain disorder. Inokuchi J(1). Author information: (1)Division of Glycopathology and CREST, Japan Science and Technology Agency, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan. jin@tohoku-pharm.ac.jp Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNFalpha induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFalpha, suggesting a specific function for GM3. We were able to extend these in vitro observations to living animals using obese Zucker fa/fa rats and ob/ob mice, in which the GM3 synthase mRNA levels in the white adipose tissues are significantly higher than in their lean controls. In the DRMs from TNFalpha-treated 3T3-L1 adipocytes, GM3 levels were doubled, compared to results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. GM3 depletion was able to counteract the TNFalpha-induced inhibition of IR accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3. PMID: 17409686 [PubMed - indexed for MEDLINE] 2991. Nihon Shokakibyo Gakkai Zasshi. 2007 Apr;104(4):483-91. [Molecular basis of metabolic syndrome]. [Article in Japanese] Tamori Y(1), Kasuga M. Author information: (1)Division of Diabetes, Digestive, and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine. PMID: 17409656 [PubMed - indexed for MEDLINE] 2992. Nihon Hoshasen Gijutsu Gakkai Zasshi. 2007 Mar 20;63(3):276-84. [Relationship between the criteria for metabolic syndrome and the evaluation of abdominal fat distribution measured by CT scan]. [Article in Japanese] Yoshizumi T. PMID: 17409616 [PubMed - indexed for MEDLINE] 2993. Endocr J. 2007 Jun;54(3):347-57. Epub 2007 Apr 3. New therapeutic target for metabolic syndrome: PPARdelta. Takahashi S(1), Tanaka T, Sakai J. Author information: (1)Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Japan. PMID: 17409576 [PubMed - indexed for MEDLINE] 2994. Altern Ther Health Med. 2007 Mar-Apr;13(2):S134-9. Systems biology, toxins, obesity, and functional medicine. Hyman M(1). Author information: (1)Faculty of Food as Medicine, Center for Mind Body Medicine, Georgetown University School of Medicine, USA. By recognizing the role of toxins in obesity and altered function of the neuro-endocrine-immune and mitochondrial and redox systems, and by creating a comprehensive strategy for both the reduction of exposure to and elimination of toxins, as well as the development of effective clinical strategies, treatment resistance in obesity may be more successfully addressed. Further research is needed to explore the clinical relevance and the mechanisms that underlie this hypothesis and to examine clinical detoxification methods. Through the prism of functional medicine, a context and road map exist for tackling many treatment-resistant and complex chronic diseases, including obesity. PMID: 17405691 [PubMed - indexed for MEDLINE] 2995. Magnes Res. 2006 Dec;19(4):237-43. High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Rayssiguier Y(1), Gueux E, Nowacki W, Rock E, Mazur A. Author information: (1)INRA, Unité de Nutrition Humaine, Clermont Ferrand/Theix, 63122 Saint-Genès-Champanelle, France. yrayssig@clermont.inra.fr The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenic factor in the development of metabolic syndrome. Pro-inflammatory molecules produced by adipose tissue have been implicated in the development of insulin resistance. The present review will discuss experimental evidence showing that the metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. In many ways, fructose-fed rats display the changes observed in the metabolic syndrome and recent studies indicate that high-fructose feeding is associated with NADPH oxidase and renin-angiotensin activation. The production of reactive oxygen species results in the initiation and development of insulin resistance, hyperlipemia and high blood pressure in this model. In this rat model, a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration. Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels, activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB (NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress. PMID: 17402291 [PubMed - indexed for MEDLINE] 2996. Eur Urol. 2007 Jul;52(1):46-53. Epub 2007 Mar 26. Obesity and prostate cancer: a role for adipokines. Mistry T(1), Digby JE, Desai KM, Randeva HS. Author information: (1)Molecular Medicine Research Group, Biomedical Research Institute, University of Warwick Medical School, Coventry, UK. mistrytina@hotmail.com Comment in Eur Urol. 2007 Jul;52(1):3-4. OBJECTIVES: Many studies have investigated the association between obesity and prostate cancer risk but have yielded inconsistent results. Recent evidence suggests a particular role for obesity in prostate cancer progression. Many studies have investigated the roles of adipose tissue-derived factors (adipokines) as putative molecular mediators between obesity and prostate cancer. This review provides an overview of current evidence that supports such a role for adipokines. METHODS: A comprehensive literature review was carried out using PubMed to search for articles relating to prostate cancer and the following adipokines: leptin, interleukin 6, vascular endothelial growth factor (VEGF), and adiponectin. RESULTS: Prostate cancer cells are exposed to adipokines either via the circulation or through locally produced adipokines following invasion of the retropubic fat pad. Circulating levels of most adipokines are positively correlated with obesity; adiponectin is inversely correlated with obesity. High circulating levels of leptin, interleukin 6, and VEGF are associated with increased prostate cancer risk and increased aggressiveness. Adiponectin levels are lower in patients with prostate cancer and are inversely associated with grade of disease. Adipokines exert a variety of biologic effects on prostate cancer cells, modulating cellular differentiation, apoptosis, proliferation, and angiogenesis. CONCLUSIONS: Evidence suggests a role for obesity and adipokines in promoting the progression of established prostate cancer. Adipokines may contribute to the molecular basis for the association between obesity and prostate cancer, but the complex pathophysiology of both these disease states requires further studies. PMID: 17399889 [PubMed - indexed for MEDLINE] 2997. Med Clin (Barc). 2007 Mar 24;128(11):429-37. [Identification, diagnosis and control of patients with abdominal obesity and cardiovascular and metabolic risk factors]. [Article in Spanish] Moreno B(1), Casanueva F. Author information: (1)Obesity Unit, Hospital Gregorio Marañón, C/Doctor Esquerdo 46, 28007 Madrid, Spain. bmoreno@anakis.es PMID: 17394860 [PubMed - indexed for MEDLINE] 2998. Diabetologia. 2007 Jun;50(6):1127-39. Epub 2007 Mar 29. Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer? Yang X(1), Smith U. Author information: (1)Centre of Excellence for Metabolic and Cardiovascular Research/The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. The relative effect of visceral and subcutaneous obesity on the risk of chronic metabolic disease has been a matter of long-term dispute. While ample data support either of the fat depots being causative or associative, valid argument for one depot often automatically belittles the other. Paradigms such as the visceral/portal hypothesis and the acquired lipodystrophy/ectopic fat storage and endocrine hypothesis have been proposed. Nevertheless, neither hypothesis alone explains the entire pathophysiological setting. Treatment of diabetes with thiazolidinediones selectively increases fat partitioning to the subcutaneous adipose depot but does not change visceral fat accumulation. This is in contrast to the preferential visceral fat mobilisation by diet and exercise. Surgical removal of visceral or subcutaneous adipose tissue yields relatively long-lasting metabolic improvement only when combined with procedures that ameliorate adipose tissue cell composition. These studies illustrate that human adipose tissue in different anatomic locations does not work in isolation, and that there is a best-fit relationship in terms of volume and function among different fat depots that needs to be met to maintain the systemic energy balance and to prevent the complications related to obesity. PMID: 17393135 [PubMed - indexed for MEDLINE] 2999. Asia Pac J Clin Nutr. 2007;16 Suppl 1:359-67. The problem of obesity: is there a role for antagonists of the renin-angiotensin system? Weisinger RS(1), Begg DP, Chen N, Jois M, Mathai ML, Sinclair AJ. Author information: (1)School of Psychological Science, La Trobe University, Bundoora 3086, Victoria, Australia. r.weisinger@latrobe.edu.au Obesity is a major health problem worldwide; it is associated with more than 30 medical conditions and is a leading cause of unnecessary deaths. Adipose tissue not only acts as an energy store, but also behaves like an endocrine organ, synthesising and secreting numerous hormones and cytokines. Angiotensin II (ANG II) is the biologically active component of the renin-angiotensin system (RAS). The RAS is present in adipose tissue and evidence suggests that ANG II is intimately linked to obesity. Indeed, ANG II increases fat cell growth and differentiation, increases synthesis, uptake and storage of fatty acids and triglycerides and possibly inhibits lipolysis. Evidence obtained using genetically modified animals has shown that the amount of body fat is directly related to the amount of ANG II, i.e., animals with low levels of ANG II have reduced fat stores while animals with excessive ANG II have increased fat stores. In humans, epidemiological evidence has shown that body fat is correlated with angiotensinogen, a precursor of ANG II, or other components of the RAS. Furthermore, blocking the production and/or actions of ANG II with drugs or natural substances decreases body fat. The decrease in body fat caused by such treatments predominantly occurs in abdominal fat depots and appears to be independent of energy intake and digestibility. Clearly, ANG II has an important role in the accumulation of body fat and the possibility exists that treatment of obesity will be enhanced by the use of natural or synthetic substances that interfere with ANG II. PMID: 17392133 [PubMed - indexed for MEDLINE] 3000. Diabetes Obes Metab. 2007 May;9(3):282-9. Adiponectin in health and disease. Oh DK(1), Ciaraldi T, Henry RR. Author information: (1)Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Adipose tissue is an active metabolic tissue that secretes multiple metabolically important proteins, known as adipokines. Adiponectin is an important adipokine because of its beneficial effects on glucose and lipid metabolism. Low levels of adiponectin are associated with disease states such as diabetes and cardiovascular disease. Direct administration of adiponectin has been shown to be beneficial in animal models of diabetes, obesity and atherosclerosis. Adiponectin levels in humans can be increased through indirect methods such as weight loss or treatment with thiazolidinediones. This article will review the epidemiology and therapeutic options with adiponectin. PMID: 17391153 [PubMed - indexed for MEDLINE] 3001. Head Neck. 2007 May;29(5):497-507. Cancer cachexia syndrome in head and neck cancer patients: Part II. Pathophysiology. George J(1), Cannon T, Lai V, Richey L, Zanation A, Hayes DN, Shores C, Guttridge D, Couch M. Author information: (1)Doris Duke Clinical Research Fellowship, The Verne S. Caviness General Clinical Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7070, USA. Cancer cachexia is a morbid wasting syndrome common among patients with head and neck cancer. While its clinical manifestations have been well characterized, its pathophysiology remains complex. A comprehensive literature search on cancer cachexia was performed using the National Library of Medicine's PubMed. The Cochrane Library and Google search engine were also used. Recent evidence and new concepts on the pathophysiology of cancer cachexia are summarized. Targeted therapies are presented, and new concepts are highlighted. Cancer cachexia is characterized by complex, multilevel pathogenesis. It involves up-regulated tissue catabolism and impaired anabolism, release of tumor-derived catabolic factors and inflammatory cytokines, and neuroendocrine dysfunction. These culminate to create an energy-inefficient state characterized by wasting, chronic inflammation, neuroendocrine dysfunction, and anorexia. (c) 2007 Wiley Periodicals, Inc. PMID: 17390378 [PubMed - indexed for MEDLINE] 3002. Reprod Fertil Dev. 2007;19(1):53-63. Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows. Symonds ME(1), Stephenson T, Gardner DS, Budge H. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham, NG7 2UH, UK. michael.symonds@nottingham.ac.uk The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases. PMID: 17389135 [PubMed - indexed for MEDLINE] 3003. Public Health Nutr. 2006 Dec;9(8A):1073-6. Mediterranean diet, endothelial function and vascular inflammatory markers. Esposito K(1), Ciotola M, Giugliano D. Author information: (1)Division of Metabolic Diseases, University of Naples SUN, Naples, Italy. katherine.esposito@unina2.it OBJECTIVES: To discuss present knowledge about the relation between adipose tissue, inflammation and the Mediterranean-style diet. DESIGN: Review of the literature and personal perspectives. SETTING AND RESULTS: Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, which play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation which is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. An increased release of proinflammatory adipokines from the visceral adipose tissue, associated with a reduced secretion of anti-inflammatory adipokines and cytokines, could determine a low-grade chronic inflammatory state which might play a role in the future development of the metabolic syndrome, diabetes and atherosclerosis through both insulin resistance and endothelial dysfunction. Interventions aimed at decreasing weight loss and improving adherence to a Mediterranean-style diet in people with obesity or metabolic syndrome decrease the inflammatory milieu and ameliorate both insulin resistance and endothelial dysfunction. CONCLUSIONS: Appropriate dietary patterns, as those associated with the eating model of Mediterranean-type diets, represent therapeutic strategies to reduce inflammation and the associated metabolic and cardiovascular risk. PMID: 17378943 [PubMed - indexed for MEDLINE] 3004. Clin Chem Lab Med. 2007;45(3):328-32. Emerging role of cathepsin S in obesity and its associated diseases. Taleb S(1), Clément K. Author information: (1)Inserm, U755 Nutriomique, Hôtel-Dieu Hospital, Paris, France. Obesity is thought to be a major determinant in the development of cardiovascular diseases, but the mechanisms whereby enlarged adipose tissue affects vascular function remain poorly defined. Chronic inflammation is a common feature of obesity and atherosclerosis, and several inflammatory markers produced by adipose tissue have been considered as candidates that potentially favor the development of atherosclerotic lesions in humans. To identify other effective candidates, we combined bioclinical data for individuals of increasing weight with adipose tissue gene-expression profiling. This strategy led to the discovery of cathepsin S (CTSS), for which gene expression was strongly correlated with subjects' body mass index (BMI). CTSS is an elastolytic cysteine protease that has been implicated in the development of atherosclerotic lesions in both animal models and humans. In this review, we discuss the role of CTSS in obesity and atherosclerosis, and emphasize the potential mechanisms that could link the two diseases. We also position this protease as a potential therapeutic target to reduce associated cardiovascular risks in obese patients. PMID: 17378727 [PubMed - indexed for MEDLINE] 3005. Nat Clin Pract Endocrinol Metab. 2007 Apr;3(4):345-54. Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer. Schäffler A(1), Schölmerich J, Buechler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de A vast number of epidemiological studies suggest an important, but still controversial, role for obesity and adipose tissue mass in breast cancer risk and an association with tumor phenotype. The main conclusions from these studies raise the possibility that the adipose tissue can act as an effector organ that influences both cancer risk and tumor behavior. Here we also review heterotypic mechanisms in breast-cancer tumorigenesis; these mechanisms involve soluble secreted factors from peritumoral cells, extracellular-matrix components and interactions between stromal cells and tumor cells that create a specific and local peritumoral microenvironment. As a special focus, we discuss the increasing evidence for a role of peritumoral adipose tissue and secreted adipokines (such as adiponectin and leptin) in breast cancer; furthermore, the cellular and molecular basis of the peritumoral 'desmoplastic' tissue reaction observed in breast cancer is reviewed in detail. PMID: 17377617 [PubMed - indexed for MEDLINE] 3006. J Lipid Res. 2007 Jul;48(7):1433-44. Epub 2007 Mar 20. Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism. Hegele RA(1), Joy TR, Al-Attar SA, Rutt BK. Author information: (1)Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. hegele@robarts.ca The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immunodeficiency virus infection. PMID: 17374881 [PubMed - indexed for MEDLINE] 3007. J Lipid Res. 2007 Jun;48(6):1253-62. Epub 2007 Mar 20. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. Sethi JK(1), Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom. jks30@cam.ac.uk This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome. PMCID: PMC4303760 PMID: 17374880 [PubMed - indexed for MEDLINE] 3008. Obesity (Silver Spring). 2007 Mar;15(3):539-43. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Zvonic S(1), Floyd ZE, Mynatt RL, Gimble JM. Author information: (1)Stem Cell Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. sanjin.zvonic@gmail.com Circadian oscillators play an indispensable role in the coordination of physiological processes with the cyclic changes in the physical environment. A significant number of recent clinical and molecular studies suggest that circadian biology may play an important role in the regulation of adipose and other metabolic tissue functions. In this discussion, we present the hypothesis that circadian dysfunction may be involved in the pathogenesis of obesity, type 2 diabetes, and the metabolic syndrome. PMID: 17372301 [PubMed - indexed for MEDLINE] 3009. Postepy Hig Med Dosw (Online). 2007;61:99-105. [The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans]. [Article in Polish] Komorowski J(1), Stepień H. Author information: (1)Klinika Endokrynologii Katedry Endokrynologii Uniwersytetu Medycznego w Łodzi, Łódź, Poland. komorowski.j@wp.pl The endocannabinoid system has been recently recognized as an important modulatory system in the function of brain, endocrine, and immune tissues. It appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and response to stress. The important elements of this system are: endocannabinoid receptors (types CB1 and CB2), their endogenous ligands (N-arachidonoylethanolamide, 2-arachidonoyl glycerol), enzymes involved in their synthesis and degradation, as well as cannabinoid antagonists. In humans this system also controls energy homeostasis and mainly influences the function of the food intake centers of the central nervous system and gastrointestinal tract activity. The endocannabinoid system regulates not only the central and peripheral mechanisms of food intake, but also lipids synthesis and turnover in the liver and adipose tissue as well as glucose metabolism in muscle cells. Rimonabant, a new and selective central and peripheral cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factor (metabolic syndrome) in obese patients by increasing HDL-cholesterol and adiponectin blood levels as well as decreasing LDL-cholesterol, leptin, and C-reactive protein (a proinflammatory marker) concentrations. It is therefore possible to speculate about a future clinical use of CB1 antagonists, as a means of improving gonadotrophin pulsatility and fertilization capacity as well as the prevention of cardiovasculary disease and type 2 diabetes mellitus. Drugs acting as agonists of CB1 receptors (Dronabinol, Dexanabinol) are currently proposed for evaluation as drugs to treat neurodegenerative disorders (Alzheimer's and Parkinson's diseases), epilepsy, anxiety, and stroke. PMID: 17369778 [PubMed - indexed for MEDLINE] 3010. Ann Endocrinol (Paris). 2007 Oct;68(5):349-56. Epub 2007 Mar 26. [11beta-hydroxysteroide dehydrogenases. Recent advances]. [Article in French] Vantyghem MC(1), Marcelli-Tourvieille S, Defrance F, Wemeau JL. Author information: (1)Service d'endocrinologie et métabolisme, clinique d'endocrinologie Marc-Linquette, 6, rue du Professeur-Laguesse, CHRU de Lille, 59037 Lille cedex, France. mc-vantyghem@chru-lille.fr 11beta-hydroxysteroide dehydrogenase (11beta-OHSD) enzymes exhibit a regulating action upon cortisol metabolism before access to its receptors. Two types of isoenzymes have been described, type 2 being the most anciently known. Type 2 11beta-OHSD, which changes cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney, that protects mineralocorticoid receptors from illicit activation by glucocorticoids. Mutations of the gene coding for this enzyme has been demonstrated in apparent mineralocorticoid excess, which induces hypertension and hypokalemia with low renin and aldosterone levels. Polymorphisms of this gene could modulate essential hypertension and also be responsible for certain forms of acquired apparent mineralocorticoid excess especially after liquorice intoxication, in hypothyroidism, Cushing syndrome, and chronic renal insufficiency. Type 1 11beta-OHSD, which changes cortisone into cortisol, is a reductase, mainly located in liver and adipose tissue. Functional defects of this enzyme have been shown in polycystic ovaries and cortisone reductase deficiency. By contrast, metabolic syndrome, corticoid-induced osteoporosis, and glaucoma are linked to a local over-activity of this enzyme. The understanding of action mechanisms of these two enzymes currently leads to 11beta-OHSD inhibitors development, therefore opening new therapeutic strategies, especially in metabolic syndrome. PMID: 17368420 [PubMed - indexed for MEDLINE] 3011. Cancer Res. 2007 Mar 15;67(6):2391-3. The obesity-cancer link: lessons learned from a fatless mouse. Hursting SD(1), Nunez NP, Varticovski L, Vinson C. Author information: (1)Division of Nutritional Sciences, University of Texas, Austin, Texas, USA. Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. Recent studies in fatless A-Zip/F1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other factors frequently associated with obesity (insulin, insulin-like growth factor-1, and proinflammatory cytokines) and activation of several signaling pathways associated with carcinogenesis. In view of this information, the risk factors underlying the obesity-cancer link need to be revisited. We postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention and therapeutic targets for disrupting the obesity-cancer link. PMID: 17363554 [PubMed - indexed for MEDLINE] 3012. Curr Hypertens Rep. 2007 Mar;9(1):33-8. Is PBEF/visfatin/Nampt an authentic adipokine relevant to the metabolic syndrome? Sethi JK(1). Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QR, UK. jks30@cam.ac.uk Adipokines are peptides secreted by adipose tissue that affect whole-body energy metabolism. Their dysregulated production in obesity has implicated them as important mediators in the pathogenesis of obesity-related risk factors for diabetes and cardiovascular disease. PBEF/visfatin/Nampt has recently been described as a novel adipokine with insulin mimetic properties. However, whether it is an authentic adipokine relevant to the metabolic syndrome remains a matter of some debate. PMCID: PMC4301309 PMID: 17362669 [PubMed - indexed for MEDLINE] 3013. Adv Med Sci. 2006;51:111-4. Metabolic effects associated with adipose tissue distribution. Zahorska-Markiewicz B(1). Author information: (1)Department of Pathophysiology, Medical University of Silesia, Katowice, Poland. bmarkiewicz@slam.katowice.pl Cardiovascular and metabolic risk depends not only on the overall obesity but also fat distribution is more powerfull predictor for risk factors. Adipose tissue produces and secretes a variety of bioactive peptides - adipokines The most recently described adipocyte secretory proteins contribute to the pathogenesis of impaired insulin secretion and insulin resistance, endothelial dysfunction, a proinflammatory state and promote progression of atherosclerosis. This review presents an overview of the adipose tissue secreted proteins (leptin, TNF-alpha, IL-6, adiponectin, resistin, visfatin, ASP, FIAF, MT) role and their regulation in the context of abdominal obesity and the adverse metabolic consequences. PMID: 17357288 [PubMed - indexed for MEDLINE] 3014. Endokrynol Pol. 2007 Jan-Feb;58(1):34-41. Metabolic syndrome in polycystic ovary syndrome. Barber TM(1), McCarthy MI, Franks S, Wass JA. Author information: (1)Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, UK. tom.barber@drl.ox.ac.uk Both metabolic syndrome (MS) and polycystic ovary syndrome (PCOS) are common among women. The exact prevalence of MS in women with PCOS is dependent upon the diagnostic criteria used for each. However, the frequent co-occurrence of both MS and PCOS in women is suggestive of a common aetiology. In this short review article we argue that insulin resistance, as a consequence of abdominal obesity, may represent such a common aetiology. We also review the literature on the prevalence of MS in women with PCOS and consider the impact that the particular criteria used to diagnose both MS and PCOS may have had on these estimates of prevalence. PMID: 17354203 [PubMed - indexed for MEDLINE] 3015. Minerva Endocrinol. 2007 Mar;32(1):35-47. Polycystic ovarian syndrome: the commonest cause of hyperandrogenemia in women as a risk factor for metabolic syndrome. Diamanti-Kandarakis E(1), Christakou C, Kandarakis H. Author information: (1)Endocrine Section, First Department of Medicine, Laiko General Hospital, University of Athens Medical School, Athens, Greece. akandara@otenet.gr Polycystic ovarian syndrome (PCOS), the commonest endocrine disorder of women, is currently emerging as a potential facet of the metabolic syndrome (MBS) in women. Available data suggest that the MBS or, alternatively, individual metabolic risk factors may be overly present and most importantly that MBS may arise at a significantly younger age among PCOS women. The concept that a conventionally considered reproductive disorder may entail a significant metabolic impact on affected women has warranted medical interest on the mechanisms underlying the multiplicative sequelae of PCOS. Although obesity indisputably compounds the clinical course of women with PCOS, this appears to be just the tip of the iceberg. Insulin resistance and hyperinsulinemia have been intuitively involved as a critical link due to their contribution to the pathophysiology and clinical presentation of both PCOS and MBS. Hyperandrogenemia, the predominant endocrine hallmark of PCOS, has also been implicated as a contributing factor to the suggested interrelationship. PMID: 17353865 [PubMed - indexed for MEDLINE] 3016. Curr Opin Lipidol. 2007 Apr;18(2):152-6. The role of perilipin in human obesity and insulin resistance. Tai ES(1), Ordovas JM. Author information: (1)Department of Endocrinology, Singapore General Hospital, Singapore. eshyong@pacific.net.sg PURPOSE OF REVIEW: More than 1.1 billion people worldwide are overweight or obese. We know that obesity is determined by a combination of environmental and genetic factors. Although hundreds of obesity candidate genes have been identified through different metabolic pathways, the fundamental basis of obesity resides with excessive storage of triacylglycerides in adipose tissue. RECENT FINDINGS: The mechanisms that control the storage and release of triacylglycerides in lipid droplets are complex and poorly understood; yet, they are likely to be crucial to the understanding of the regulation of body weight. In this regard, the family of perilipin, adipophilin and TIP47 proteins may play key roles in obesity. It has recently been shown that variants at the perilipin locus were associated with BMI and obesity risk in females from several population studies. Moreover, the reported interactions between perilipin and dietary factors may shed light on the complex relation between dietary intake and body weight changes observed on an individual basis. SUMMARY: These findings support an important role for PLIN as a candidate gene for obesity risk in humans as well as a modulator of dietary response to therapies aimed to reduce body weight and decrease metabolic syndrome risk. PMID: 17353663 [PubMed - indexed for MEDLINE] 3017. Stem Cells Dev. 2007 Feb;16(1):7-23. Mesenchymal stem cells: molecular targets for tissue engineering. Satija NK(1), Gurudutta GU, Sharma S, Afrin F, Gupta P, Verma YK, Singh VK, Tripathi RP. Author information: (1)Stem Cell Gene Therapy Research Group, Institute of Nuclear Medicine & Allied Sciences, Timarpur, Delhi, India. Mesenchymal stem cells (MSCs) represent an adherent, fibroblast-like population present not only in the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro. PMID: 17348802 [PubMed - indexed for MEDLINE] 3018. J Appl Physiol (1985). 2007 Sep;103(3):1093-8. Epub 2007 Mar 8. Role of myokines in exercise and metabolism. Pedersen BK(1), Akerström TC, Nielsen AR, Fischer CP. Author information: (1)Centre of Inflammation and Metabolism, 7641 Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. bkp@rh.dk During the past 20 yr, it has been well documented that exercise has a profound effect on the immune system. With the discovery that exercise provokes an increase in a number of cytokines, a possible link between skeletal muscle contractile activity and immune changes was established. For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an "exercise factor," which could mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We suggest that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either paracrine or endocrine effects should be classified as "myokines." Since the discovery of interleukin (IL)-6 release from contracting skeletal muscle, evidence has accumulated that supports an effect of IL-6 on metabolism. We suggested that muscle-derived IL-6 fulfils the criteria of an exercise factor and that such classes of cytokines should be named "myokines." Interestingly, recent research demonstrates that skeletal muscles can produce and express cytokines belonging to distinctly different families. Thus skeletal muscle has the capacity to express several myokines. To date the list includes IL-6, IL-8, and IL-15, and contractile activity plays a role in regulating the expression of these cytokines in skeletal muscle. The present review focuses on muscle-derived cytokines, their regulation by exercise, and their possible roles in metabolism and skeletal muscle function and it discusses which cytokines should be classified as true myokines. PMID: 17347387 [PubMed - indexed for MEDLINE] 3019. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Feb;32(1):1-14. p38 mitogen-activated protein kinase plays a critical role in the control of energy metabolism and development of cardiovascular diseases. Cao WH(1), Xiong Y, Collins QF, Liu HY. Author information: (1)Endocrine Programs, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA. wcao@thehamner.org p38 mitogen-activated protein kinase (p38) is a member of MAP kinase family. Its wide-spectrum roles in the control of energy metabolism have been indicated in numerous studies. p38 participates in the energy metabolism in all major tissues/organs involved in the control of energy metabolism, including adipose tissue, skeletal muscles, islet cells, and liver. In white adipose tissue, p38 plays an important role in adipose differentiation and glucose uptake although it is still inconclusive whether this role of p38 is stimulatory or inhibitory. The stimulatory role of p38 in transcription of the uncoupling protein 1 (UCP1) gene in brown adipose tissue is relatively clear. A fundamental role for p38 in the differentiation of skeletal muscles and mitochondrial biogenesis in skeletal muscles is rather definitive although the role of p38 in glucose uptake of skeletal muscles remains controversial. In islet cells, p38 appears to be involved in beta-cell apoptosis. p38 has been indicated in the control of preproinsulin gene transcription, but remains controversial. However, it seems clear that p38 does not play a significant role in insulin secretion. In the liver, p38 plays a central role in hepatic glucose and lipid metabolism. Activation of p38 participates in the processes to increase blood glucose levels through reducing glycogen synthesis and increasing hepatic gluconeogenesis. p38 appears to prevent fat storage by inhibiting hepatic lipogenesis and promoting fatty acid oxidation in the liver. Additionally, p38 may play a critical role in cholesterol metabolism by regulating expression of the LDLR gene and bile metabolism. p38 does not only participate in various physiological and pathophysiological processes in cardiomyocytes, but also is heavily involved in the development of atherosclerotic lessions through its influences on monocytes/macrophages, vascular endothelial cells, and vascular smooth muscle cells. PMID: 17344580 [PubMed - indexed for MEDLINE] 3020. Clin Chim Acta. 2007 May 1;380(1-2):24-30. Epub 2007 Feb 2. Adiponectin as an anti-inflammatory factor. Ouchi N(1), Walsh K. Author information: (1)Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA. nouchi@bu.edu Obesity is characterized by low-grade systemic inflammation. Adiponectin is an adipose tissue-derived hormone, which is downregulated in obesity. Adiponectin displays protective actions on the development of various obesity-linked diseases. Several clinical studies demonstrate the inverse relationship between plasma adiponectin levels and several inflammatory markers including C-reactive protein. Adiponectin attenuates inflammatory responses to multiple stimuli by modulating signaling pathways in a variety of cell types. The anti-inflammatory properties of adiponectin may be a major component of its beneficial effects on cardiovascular and metabolic disorders including atherosclerosis and insulin resistance. In this review, we focus on the role of adiponectin in regulation of inflammatory response and discuss its potential as an anti-inflammatory marker. PMCID: PMC2755046 PMID: 17343838 [PubMed - indexed for MEDLINE] 3021. Proc Nutr Soc. 2007 Feb;66(1):52-9. Metabolic interaction of dietary sugars and plasma lipids with a focus on mechanisms and de novo lipogenesis. Chong MF(1), Fielding BA, Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK. mary.chong@oxlip.ox.ac.uk The elevation of blood lipid concentrations in response to the consumption of low-fat high-carbohydrate diets is known as carbohydrate-induced hypertriacylglycerolaemia (HPTG). An understanding of the mechanisms involved in the interaction between carbohydrates and plasma lipids may help determine whether carbohydrate-induced HPTG would increase cardiovascular risk. There is growing evidence to suggest that the sugar component of the diet may be largely responsible, rather than the total carbohydrate. In most studies designed to investigate the mechanisms of carbohydrate-induced HPTG, the amounts and types of sugars and starches used in the diets are not specified. Findings have been mixed and inconsistent. It is proposed that the elucidation of mechanisms from current studies could have been confounded by the different ways in which sugars are metabolized in the body. At present, there are few studies that have evaluated the independent effects of dietary sugars. Interest has been focused on de novo lipogenesis (DNL), as it has recently been found to be positively correlated with increases in fasting TAG levels produced on high-carbohydrate diets, indicating that DNL may contribute to carbohydrate-induced HPTG. DNL has been found to be determined by starch:sugar in a high-carbohydrate diet and affected by different types of sugars. The presence of DNL in adipose tissue is supported by emerging gene-expression studies in human subjects. In the wake of rising intakes of sugars, further research is needed to investigate the mechanisms associated with different sugars, so that appropriate therapeutic strategies can be adopted. PMID: 17343772 [PubMed - indexed for MEDLINE] 3022. Nutr Metab Cardiovasc Dis. 2007 Jun;17(5):394-408. Epub 2007 Mar 2. Physical activity: an effective way to control weight in children? Maffeis C(1), Castellani M. Author information: (1)Department of Mother and Child, Biology-Genetics, Pediatrics Section, University of Verona, Verona, Italy. claudio.maffeis@univr.it Physical activity is the only component of total energy expenditure that can be voluntarily modified. Therefore, it is a reasonable behavioral target for the prevention and treatment of obesity. Most of the fat oxidized daily in the body occurs in skeletal muscle. Physical activity increases the amount of oxidized fat, which helps control fat mass. Moreover, skeletal muscle is an efficient blood glucose utilizer, and regular physical activity promotes insulin sensitivity and glucose homeostasis independently of its effect on body fat. The primary purpose of this study was to provide further insight into the metabolic effects of physical activity, especially on the regulation of energy expenditure, substrate oxidation and body composition. Also of interest is the analysis of available evidence that justifies the recommendation of physical activity programs in the treatment of childhood obesity. PMID: 17336508 [PubMed - indexed for MEDLINE] 3023. Curr Gastroenterol Rep. 2007 Mar;9(1):47-53. Treatment of fibrosis in nonalcoholic fatty liver disease. Hoteit MA(1), Anania FA. Author information: (1)Division of Digestive Diseases, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Room 248, Atlanta, GA 30322, USA. Nonalcoholic steatohepatitis (NASH) is one of the most common liver disorders in North America. The mechanism of liver injury in NASH involves insulin resistance and oxidative stress as well as cytokine release. Therapeutic interventions aimed at enhancing insulin sensitivity or reducing oxidative stress have been studied. The role of peptide hormones secreted by adipose tissue--adipocytokines--in the potential pathogenesis of NASH is an area of intense research. As the function of adipokines in modulating hepatic inflammation and fibrosis is elucidated, the potential for novel treatment strategies in patients with NASH is likely to be realized. PMID: 17335677 [PubMed - indexed for MEDLINE] 3024. Z Rheumatol. 2007 Mar;66(2):139-41. [Adipocytokines as driving forces in rheumatoid arthritis]. [Article in German] Neumann E(1), Knedla A, Meier F, Tarner IH, Büchler C, Schäffler A, Müller-Ladner U. Author information: (1)Innere Medizin mit Schwerpunkt Rheumatologie, Justus-Liebig-Universität Giessen, Kerckhoff-Klinik, Bad Nauheim, Benekestr. 2-8, 61231 Bad Nauheim. e.neumann@kerckhoff-klinik.de PMID: 17333076 [PubMed - indexed for MEDLINE] 3025. Appl Physiol Nutr Metab. 2007 Feb;32(1):89-114. Genetics of the metabolic syndrome. Terán-García M(1), Bouchard C. Author information: (1)Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. The concept of a metabolic syndrome (MetS), a cluster of pre-clinical metabolic alterations commonly associated with obesity, is the object of much debate. Genetic studies have the potential to contribute to some of the key questions, including the true nature of the cluster of pre-clinical features and whether it is associated with human genetic variation. This review summarizes the evidence for the presence of familial aggregation for the individual components of MetS and their heritability levels. It also provides an overview of the studies that have dealt with candidate genes for MetS. Potential leads from genome-wide linkage scans are also discussed. The assumption is made that obesity, ectopic fat deposition and abnormal adipose tissue metabolism are responsible for alterations in lipid metabolism, which in turn generates the commonly observed pre-clinical shifts in glucose tolerance, lipids and lipoprotein profile, blood pressure, inflammatory markers, endothelial function, and a prothrombotic state. Progress in the understanding of the genetic basis of MetS should occur as soon as a consensus is reached on the true nature of MetS, its components and diagnostic criteria. PMID: 17332787 [PubMed - indexed for MEDLINE] 3026. Pharmacol Rep. 2006;58 Suppl:81-8. Adipose tissue, inflammation and endothelial dysfunction. Chudek J(1), Wiecek A. Author information: (1)Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Francuska 20/24, PL 40-027, Katowice, Poland. During the last decade, white adipose tissue was recognized to be an active endocrine organ and a source of many proinflammatory cytokines, chemokines, growth factors and complement proteins. Many of these adipokines seem to play an important role in the pathogenesis of obesity-related diseases including accelerated atherosclerosis, arterial hypertension and some glomerulopathies. As endothelial dysfunction is one of the early stages of atherosclerosis, it is reasonable to consider that substances secreted by adipose tissue may influence directly or indirectly (for instance by induction of microinflammation) the function of endothelial cells. The aim of this review is to summarize the evidences and hypotheses concerning the role of adipokines in the pathogenesis of endothelial dysfunction. PMID: 17332676 [PubMed - indexed for MEDLINE] 3027. J Diabetes Complications. 2007 Mar-Apr;21(2):128-36. Metabolic complications of obesity: inflated or inflamed? Chandalia M(1), Abate N. Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, Dallas, TX 75390-9169, USA. Manisha.chandalia@UTSouthwestern.edu Adipose tissue dysfunction rather than excess adipose tissue mass (defined as obesity) is mechanistically related to development of metabolic diseases traditionally linked to obesity: metabolic syndrome, type 2 diabetes and cardiovascular disease. Inflammation of adipose tissue seems to be an important manifestation of adipose tissue dysfunction and closely relates to insulin resistance, the mediator of obesity-related morbidity. However, it is not completely clear whether inflammation in adipose tissue leads to first, local, and then systemic insulin resistance or insulin resistance leads to adipose tissue inflammation, which, in turn, increases insulin resistance. These questions can only be answered by studying models of insulin resistance, independent of obesity. The conceptual shift from adipose tissue mass to adipose tissue function will have significant diagnostic and therapeutic implications. Our efforts in establishing markers to identify "at risk" population and finding newer therapeutic agents must focus on adipose tissue dysfunction and not on obesity alone. PMID: 17331862 [PubMed - indexed for MEDLINE] 3028. Expert Rev Mol Diagn. 2007 Mar;7(2):195-205. Adipokines and melanocortins in the hepatic manifestation of metabolic syndrome: nonalcoholic fatty liver disease. Baranova A(1), Randhawa M, Jarrar M, Younossi ZM. Author information: (1)Center for Liver Diseases, Inova Fairfax Hospital, VA, USA. abaranov@gmu.edu Metabolic syndrome is associated with nonalcoholic fatty liver disease and its more aggressive form, nonalcoholic steatohepatitis. Adipokines produced by white adipose tissue possess broad physiological activity and play an important autocrine role in obesity-associated complications, including metabolic syndrome, nonalcoholic fatty liver disease and cardiovascular disease. Various adipokines may have beneficial or harmful effects. Other tissues, particularly stomach and intestine, produce active molecules that can influence the function of adipocytes and, possibly, the levels of adipokine secretion. In some cases, the production sites of these molecules remain unknown. The review focuses on our current understanding of the disease-related effects of the adipokines and the melanocortins on various peripheral tissues, and discusses some of their potential interactions with each other. Potential therapeutic applications are also considered. PMID: 17331066 [PubMed - indexed for MEDLINE] 3029. Vasc Health Risk Manag. 2006;2(3):285-302. Metabolic syndrome: the danger signal in atherosclerosis. Mathieu P(1), Pibarot P, Després JP. Author information: (1)Department of Surgery, Centre de Recherche de l'Hôpital Laval/Institut de Cardiologie de Québec, Québec, Canada. patrick.mathieu@chg.ulaval.ca Comment in Vasc Health Risk Manag. 2006;2(3):193-4. Atherosclerosis is a chronic inflammatory disease characterized by infiltration of blood vessels by lipids and leukocytes. There is a growing body of evidence that among risk factors that promote atherosclerosis, the metabolic syndrome is a powerful and prevalent predictor of cardiovascular events. The systemic inflammatory process associated with the metabolic syndrome has numerous deleterious effects that promote plaque activation, which is responsible for clinical events. Interactions between the innate immune system with lipid-derived products seem to play a major role in the pathophysiology of atherosclerosis in relation with the metabolic syndrome. The multiple links among adipose tissue, the vascular wall, and the immune system are the topics of this review, which examines the roles of oxidized low-density lipoprotein, inflammatory cytokines, and adipokines in triggering and perpetuating a danger signal response that promotes the development of atherosclerosis. Furthermore, therapeutic options that specifically target the metabolic syndrome components are reviewed in light of recent developments. PMCID: PMC1993986 PMID: 17326334 [PubMed - indexed for MEDLINE] 3030. Am J Med. 2007 Mar;120(3 Suppl 1):S19-25. Role of the endocannabinoid system in regulating cardiovascular and metabolic risk factors. Woods SC(1). Author information: (1)Obesity Research Center at the University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. steve.woods@uc.edu Increased endocannabinoid (EC) system activity promotes excessive food intake and obesity in animals and humans. The EC system regulates food intake and hedonic reward through central mechanisms located within the hypothalamus and limbic forebrain. In rodent models, cannabinoid1 (CB1) receptor blockade reduces appetite and weight and prevents obesity and insulin resistance. The EC system also regulates food intake and metabolic factors through peripheral CB1 receptors located at multiple sites throughout the body, including adipose tissue, skeletal muscle, liver, and the gastrointestinal (GI) tract. In rodent models, CB1 receptor antagonists act in the liver to decrease lipogenesis, act in the GI tract to increase satiety, and function in adipose tissue to normalize adiponectin levels and reduce fat storage. The CB1 receptor antagonist rimonabant has been shown to reduce food intake and improve metabolic parameters, such as insulin resistance and fatty liver, in animal models of obesity. In preliminary human studies, upregulation of the EC system has been linked to obesity through mechanisms that include high-fat diet, insulin resistance, and genetic malfunction of an EC inactivation enzyme. Evidence suggests that CB1 receptor blockade is a novel therapeutic strategy that addresses the underlying mechanisms of both obesity and cardiometabolic risk. PMID: 17320518 [PubMed - indexed for MEDLINE] 3031. Am J Med. 2007 Mar;120(3 Suppl 1):S12-8. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Rader DJ(1). Author information: (1)Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. rader@mail.med.upenn.edu Abdominal obesity contributes to insulin resistance, a metabolic abnormality linked to the development of type 2 diabetes mellitus and cardiovascular disease (CVD). Insulin resistance generally precedes the development of type 2 diabetes. Currently, an estimated 10 million US adults have diabetes and another 25 million have impaired glucose tolerance (IGT), an intermediate step between insulin resistance and diabetes. The pathophysiologic mechanisms known to increase CVD risk in individuals with insulin resistance include formation of advanced glycation end products, hypertension, proinflammatory and prothrombotic states, and dyslipidemia (i.e., low levels of high-density lipoprotein cholesterol, increased levels of triglycerides, small, dense low-density lipoprotein cholesterol particles, apoplipoprotein B, and inflammation). The increased flux of free fatty acids from adipose tissue to the liver promotes dyslipidemia. Insulin resistance and impaired glucose tolerance are associated with increased CVD risk. Individuals with coexisting metabolic syndrome and diabetes have the highest prevalence rates of CVD. The Nurses' Health Study showed that CVD risk was elevated even before the development of diabetes compared with women who never developed diabetes. Lifestyle modification is recommended as the first-line treatment for obesity and its metabolic sequelae. Pharmacotherapy may be useful in patients for whom nonpharmacologic approaches alone are ineffective or insufficient. Primary care physicians play a critical role in the early identification and treatment of patients at increased risk for the development of type 2 diabetes and CVD because of their obesity and associated complications. PMID: 17320517 [PubMed - indexed for MEDLINE] 3032. Vasc Health Risk Manag. 2006;2(2):171-87. Vascular risks and management of obesity in children and adolescents. Jolliffe CJ(1), Janssen I. Author information: (1)School of Physical and Health Education, Queen's University, Kingston, Ontario, Canada. Childhood obesity has reached epidemic proportions in many countries. Pediatric obesity is associated with the development of cardiovascular (CV) risk factors including type 2 diabetes, hypertension, dyslipidemia, and the metabolic syndrome. It is also associated with an increased risk of CV disease (CVD) in adulthood. Moreover, obesity and CVD risk factors in obese youth tend to track into adulthood, further increasing the risk of adult CVD. Consequently, the treatment and prevention of childhood overweight and obesity has become a public health priority. Proper nutrition and increased physical activity are the main focus of these efforts; however, few studies have shown positive results. Treatment options for obesity in youth also include pharmacotherapy and surgery. While pharmacotherapy appears promising, additional evidence is needed, especially with respect to the long-term impact, before it becomes a widespread treatment option in the pediatric population. PMCID: PMC1994001 PMID: 17319462 [PubMed - indexed for MEDLINE] 3033. Vasc Health Risk Manag. 2006;2(2):163-9. Leptin and hypertension in obesity. Bravo PE(1), Morse S, Borne DM, Aguilar EA, Reisin E. Author information: (1)Section of Nephrology, Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Leptin, a peptide discovered more than 10 years ago, decreases food intake and increases sympathetic nerve activity to both thermogenic and non-thermogenic tissue. Leptin was initially believed to be an anti-obesity hormone, owing to its metabolic effects. However, obese individuals, for unknown reasons, become resistant to the satiety and weight-reducing effect of the hormone, but preserve leptin-mediated sympathetic activation to non-thermogenic tissue such as kidney, heart, and adrenal glands. Leptin has been shown to influence nitric oxide production and natriuresis, and along with chronic sympathetic activation, especially to the kidney, it may lead to sodium retention, systemic vasoconstriction, and blood pressure elevation. Consequently, leptin is currently considered to play an important role in the development of hypertension in obesity. PMCID: PMC1993994 PMID: 17319461 [PubMed - indexed for MEDLINE] 3034. Obes Rev. 2007 Mar;8 Suppl 1:41-4. Adipocyte biology. Trayhurn P(1). Author information: (1)Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, Liverpool, UK. p.trayhurn@liverpool.ac.uk PMID: 17316300 [PubMed - indexed for MEDLINE] 3035. Annu Rev Nutr. 2007;27:79-101. Regulation of lipolysis in adipocytes. Duncan RE(1), Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes. PMCID: PMC2885771 PMID: 17313320 [PubMed - indexed for MEDLINE] 3036. J Rheumatol. 2007 Mar;34(3):488-92. Epub 2007 Feb 15. Adipose tissue as a modulator of clinical inflammation: does obesity reduce the prevalence of rheumatoid arthritis? Bartfai T(1), Waalen J, Buxbaum JN. Author information: (1)Department of Molecular and Integrative Neurosciences and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. OBJECTIVE: Obese individuals display circulating proinflammatory cytokine elevations similar to those in patients with rheumatoid arthritis (RA). We wished to determine if extremely obese individuals were overrepresented among a group of patients with RA. METHODS: We performed both multi- and univariate analyses of data from a large, community-based population attending the "wellness" clinic of a large health maintenance organization in Southern California. We also examined the data from 5 other studies that examined the relationship between various environmental factors and the incidence and prevalence of RA. RESULTS: We found no relationship between the prevalence of RA and body mass index (BMI) in our own data or in the preponderance of previously published studies examining the same question. CONCLUSION: Although both RA and obesity have been reported to be characterized by high serum levels of inflammatory cytokines, the frequency of one disorder was not increased in the other. We propose that the lack of association in prevalence between the 2 inflammatory states, rather than reflecting a post-hoc effect of the disease on BMI, is a function of the relative amounts of pro- and antiinflammatory mediators produced in adipose tissue, which under many circumstances leads to an overall systemic antiinflammatory tone. PMID: 17309131 [PubMed - indexed for MEDLINE] 3037. Am J Cardiol. 2007 Feb 19;99(4A):6B-14B. Epub 2006 Dec 20. Role of insulin resistance and hyperglycemia in the development of atherosclerosis. Bansilal S(1), Farkouh ME, Fuster V. Author information: (1)The Zena and Michael A. Wiener Cardiovascular Institute and The Marie-Josee and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, New York 10029-6574, USA. Insulin resistance (IR) is the underlying defect in >90% of patients with type 2 diabetes mellitus and the major pathologic mechanism for the associated susceptibility to premature cardiovascular disease (CVD). The progression of IR to diabetes parallels the progression of endothelial dysfunction to atherosclerosis. The downregulation of the antiatherogenic phosphatidylinositol-3-kinase-mediated insulin receptor-signaling pathway, and maintained activity of the proatherogenic mitogenic-activated protein kinase pathway in insulin-resistant states, leads to accelerated atherosclerosis. Efforts to prevent or slow the epidemic of atherothrombotic CVD must focus on the reversal of the disturbances in glucose and lipid homeostasis through the amelioration of IR. PMID: 17307054 [PubMed - indexed for MEDLINE] 3038. Diabetes. 2007 May;56(5):1198-209. Epub 2007 Feb 15. Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Menzaghi C(1), Trischitta V, Doria A. Author information: (1)Research Unit of Diabetology and Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. c.menzaghi@operapadrepio.it Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as possible links between increased adipose mass and metabolic abnormalities. Among these molecules, adiponectin has drawn much attention because of its insulin-sensitizing and antiatherogenic actions, suggesting that genetic deficits in its production or action may contribute to insulin resistance and coronary artery disease (CAD). A meta-analysis of the data published to date supports this hypothesis. Two independent effects, corresponding to the two linkage disequilibrium blocks that can be identified at the adiponectin locus, appear to be present. In the 5' block, the g.-11391G-->A variant has a modest but significant effect on adiponectinemia, with a mean difference between genotypes of 1.64 ng/ml (95% CI 0.88-2.41). In the 3' block, the g.+276G-->T variant is a strong determinant of insulin resistance and CAD, with minor allele homozygotes having a lower homeostasis model assessment of insulin resistance (HOMA(IR)) index (-0.36 units, 95% CI 0.24-0.47) and a lower cardiovascular risk (odds ratio 0.55, 95% CI 0.38-0.80) than carriers of other genotypes. No consistent effect on BMI or risk of type 2 diabetes is evident. Polymorphisms in the genes coding for the adiponectin receptors may also influence the risk of insulin resistance and CAD, but data on these genes are still too sparse to draw firm conclusions. In summary, the studies published to date indicate that polymorphisms at the adiponectin locus are indeed predictors of circulating adiponectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis. PMID: 17303804 [PubMed - indexed for MEDLINE] 3039. Arterioscler Thromb Vasc Biol. 2007 May;27(5):996-1003. Epub 2007 Feb 15. Adipose tissue and atherosclerosis: exploring the connection. Fantuzzi G(1), Mazzone T. Author information: (1)Department of Human Nutrition, University of Illinois at Chicago, USA. The prevalence of obesity, especially among the young, is dramatically increasing in the United States. Obesity is associated with accelerated atherosclerosis and increased rates of cardiovascular death. There are many plausible mechanisms by which an increase in adipose tissue could adversely affect the vessel wall. These include the changes in blood pressure, glucose level, lipid/lipoprotein metabolism, and systemic inflammation. In addition, factors secreted by adipose tissue may directly influence vessel wall homeostasis by influencing the function of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall. There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardio-metabolic risk. Although the basis of this differential risk has not been not established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Numerous studies have shown the beneficial effects of weight loss on markers of cardiovascular risk but fewer have demonstrated improvement in direct measures of large vessel disease. The unfolding role of adipose tissue as an important metabolic and secretory organ provides new opportunities for developing more effective approaches for preventing obesity and its atherosclerotic complications. PMID: 17303782 [PubMed - indexed for MEDLINE] 3040. Obes Rev. 2007 Mar;8(2):169-81. Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Bray MS(1), Young ME. Author information: (1)Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX77030, USA. mbray@bcm.edu Obesity is one of the most profound public health problems today, and simplistic explanations based on excessive nutritional consumption or lack of physical activity are inadequate to account for this dramatic and literal growth in our world population. Recent reports have suggested that disruptions in sleep patterns, often linked to our '24-h' lifestyle, are associated with increased body fat and altered metabolism, although the cause-effect relationship for these associations has yet to be elucidated. Abnormal sleep/wake patterns likely alter intracellular circadian clocks, which are molecular mechanisms that enable the cell/tissue/organism to anticipate diurnal variations in its environment. The environment may include circulating levels of nutrients (e.g. glucose, fatty acids and triglycerides) and various hormones (e.g. insulin, glucocorticoids). As such, alterations in this molecular mechanism, in particular within the adipocyte, likely induce metabolic changes that may potentiate disrupted metabolism, adipose accumulation and/or obesity. Although diurnal variations in adipokines and adipose tissue metabolism have been observed, little is known regarding the molecular mechanisms that influence these events. PMID: 17300281 [PubMed - indexed for MEDLINE] 3041. Obes Rev. 2007 Mar;8(2):119-27. Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states. Alam I(1), Lewis K, Stephens JW, Baxter JN. Author information: (1)Department of Surgery, Morriston Hospital Swansea/University of Wales Swansea, Swansea, UK. Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically. PMID: 17300278 [PubMed - indexed for MEDLINE] 3042. J Nutr Biochem. 2007 Mar;18(3):163-7. Enterohepatic circulation of organochlorine compounds: a site for nutritional intervention. Jandacek RJ(1), Tso P. Author information: (1)Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237, USA. ronald.jandacek@uc.edu Erratum in J Nutr Biochem. 2007 May;18(5):355. Organochlorine compounds enter the body primarily as components of the diet. Their removal from the body is via excretion into the feces. There is evidence that many people are in a positive balance, with the rate of intake of organochlorines exceeding that of their excretion. A desirable nutritional approach to this problem would both reduce dietary intake and increase fecal excretion. Nonabsorbable dietary lipids reduce the absorption of dietary organochlorines and also increase the rate of their fecal excretion. Organochlorine compounds that are stored in the body enter the intestine both in bile and through a poorly understood nonbiliary mechanism. Part of the amount that enters the intestine is excreted, and part is reabsorbed in an enterohepatic circulation. There is evidence that an increase in excretion can be achieved by interference with the enterohepatic circulation of organochlorine compounds and their metabolites. Data from animals and humans show that the presence of nonabsorbed lipid in the intestine can increase the rate of excretion in a clinically significant manner. PMID: 17296488 [PubMed - indexed for MEDLINE] 3043. Am J Med. 2007 Feb;120(2 Suppl 1):S9-17; discussion S29-32. The endocannabinoid system: mechanisms behind metabolic homeostasis and imbalance. Woods SC(1). Author information: (1)Obesity Research Center, University of Cincinnati, 231 Albert Sabin Way, Room G-059, Cincinnati, Ohio, 45267, USA. steve.woods@psychiatry.uc.edu Scientific interest in the endocannabinoid (EC) system developed as a result of the known effects of tetrahydrocannabinol, including an increased desire to consume food. Further investigation has led to the belief that the EC system plays a role in accumulation of intra-abdominal fat and worsening of cardiovascular disease (CVD) risk factors. The EC system has been identified as a neuromodulatory system that is normally inactive but can be overstimulated to cause and exacerbate numerous metabolic pathologies. EC agonists and receptors have been identified in the brain, liver, and peripheral adipose tissue, and the EC system is known to affect metabolism in these areas and others through neuromodulatory signals. Meal size, body weight, and numerous metabolic factors such as triglyceride and cholesterol levels, insulin resistance, and glucose intolerance can be affected via the EC system. Further research into the EC system is warranted to elucidate its role in metabolic homeostasis. PMID: 17296344 [PubMed - indexed for MEDLINE] 3044. Am J Med. 2007 Feb;120(2 Suppl 1):S3-8; discussion S29-32. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Bergman RN(1), Kim SP, Hsu IR, Catalano KJ, Chiu JD, Kabir M, Richey JM, Ader M. Author information: (1)Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. rbergman@usc.edu Visceral adiposity has been identified as an independent risk factor for cardiovascular disease and the so-called metabolic syndrome. The canine obesity model closely recapitulates the correlation between human visceral adiposity and insulin resistance. A recent canine study indicates that insulin expands the volume of distribution associated with skeletal muscle, and that its ability to enhance macromolecular distribution within this space is blunted in the fat-fed obese canine model. Our canine study supports the portal theory of insulin resistance, in which free fatty acids (FFAs) from visceral fat directly enter the liver and have a detrimental effect on insulin action. The role of adipokines in this condition remains less clear. Sympathetic nervous system hyperactivity in obesity may also contribute to excessive FFA release, hypertension, and insulin resistance. Pathologies interrelated with insulin resistance include beta-cell hypersecretion, reduced insulin clearance, and resultant hyperinsulinemia. An observed nocturnal increase in plasma FFA levels may account for both insulin resistance and compensatory hyperinsulinemia and warrants further investigation. The elucidation of these interrelated pathologies may help reveal points where medical intervention can reduce metabolic disease. PMID: 17296343 [PubMed - indexed for MEDLINE] 3045. Trends Cardiovasc Med. 2007 Feb;17(2):35-43. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity. Duffy D(1), Rader D. Author information: (1)Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA. Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects. PMID: 17292044 [PubMed - indexed for MEDLINE] 3046. Am J Hum Biol. 2007 Mar-Apr;19(2):218-27. Human cold adaptation: an unfinished agenda. Steegmann AT Jr(1). Author information: (1)Department of Anthropology, University at Buffalo, Buffalo, New York 14261, USA. atsjr@buffalo.edu 1975 marked the end of a 20-year period of human biology research on physical environment. The focus then shifted from climatic adaptation to problems of nutrition, disease, and stress. However, many questions about human environmental patterns, especially in reference to their evolution, were abandoned rather than resolved. Assumptions about cold protective functions of low surface area/body mass ratio are entrenched in physical anthropology, despite lack of experimental validation. Since heat loss is controlled by vasoregulation and tissue insulation, a simple physics model of SA:mass may not apply. The issue merits investigation, as do the assumed thermal advantages of foreshortened extremities. Physiological assessment remains our primary research tool. In cold climate natives, elevated basal metabolic rates now appear to be genetically induced. During cold exposure, the body manages heat conservation through well known channels but also by specialized thermogenic functions such as metabolism in brown adipose tissue (BAT). The powerful protective capacity of BAT is largely unexplored either within or between populations of cold exposed human adults. An irony of our profession is that many biological variables seem to have minor effects when compared to behavioral cold protections. This is partly because biological anthropologists may have made incorrect assumptions about what most threatens the well being of cold climate people. Contrasts in environmental behaviors when comparing northern cultures such as Inuit, Athabaskan, and Norse are particularly instructive. Adaptations to life in the cold may ultimately reveal their secrets through biocultural research design modeling of environmental research. With both practical and theoretical gains still wide open, the field needs renewed attention from human biology. PMID: 17286254 [PubMed - indexed for MEDLINE] 3047. Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):142-8. Free fatty acids and insulin resistance. Delarue J(1), Magnan C. Author information: (1)Laboratoire Régional de Nutrition Humaine and EA-948, CHU de Brest et Université de Bretagne Occidentale, Brest, France. jacques.delarue@univ-brest.fr PURPOSE OF REVIEW: Dysregulation of free fatty acid metabolism is a key event responsible for insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle of Randle, preferential oxidation of free fatty acids over glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. However, other mechanisms are now described to explain the molecular basis of insulin resistance. RECENT FINDINGS: Recent studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver, may activate a serine kinase cascade leading to defects in insulin signalling and glucose transport. Inflammation and oxidative stress are also potent mechanisms which could lead to a state of insulin resistance. Finally, modulation of transcription by free fatty acids through their binding to peroxisome proliferator-activated receptors could also contribute to impaired glucose metabolism. SUMMARY: The increase in free fatty acid flux resulting from increased lipolysis secondary to adipose-tissue insulin resistance induces or aggravates insulin resistance in liver and muscle through direct or indirect (from triglyceride deposits) generation of metabolites, altering the insulin signalling pathway. Alleviating the excess of free fatty acids is a target for the treatment of insulin resistance. PMID: 17285001 [PubMed - indexed for MEDLINE] 3048. Pol Arch Med Wewn. 2006 Jan;115(1):73-84. [Physical activity and selected adipokines: adiponectin, leptin and resistin]. [Article in Polish] Kopff B(1), Jegier A. Author information: (1)Zakład Medycyny Sportowej, Katedry Medycyny Spolecznej i Zapobiegawczej Uniwersytetu Medycznego w Lodzi. bkopff@mp.pl PMID: 17278789 [PubMed - indexed for MEDLINE] 3049. J Assoc Nurses AIDS Care. 2007 Jan-Feb;18(1 Suppl):S11-6. Current clinical issues impacting the lives of patients living with HIV/AIDS. Gallagher DM(1). Author information: (1)New England AIDS Education and Traning Center, Boston, Massachusetts, USA. By significantly delaying the onset of AIDS, highly active antiretroviral therapy (HAART) decreases the high rates of mortality and morbidity previously associated with HIV type 1 infection. However, to gain the therapeutic benefits of HAART, patients must commit to lifelong therapy, which carries an increased risk of multiple metabolic comorbidities, including dyslipidemia and hyperglycemia. Hyperlipidemia associated with HAART can be accompanied by abnormal accumulation of adipose tissue in the abdominal and dorsocervical regions, collectively known as lipodystrophy. Additionally, hyperglycemia associated with HAART causes development of type 2 diabetes mellitus. Moreover, patients experiencing adverse metabolic effects associated with HAART have an increased risk for developing cardiovascular disease. Currently, metabolic comorbidities in patients infected with HIV are managed by interventional pharmacotherapy. However, because HAART regimens already have such high pill burdens, treatment of comorbidities with additional drugs may lead to nonadherence. This article will review the differential metabolic effects of various HAART regimens and the clinical implications for patients living with HIV/AIDS. PMID: 17275717 [PubMed - indexed for MEDLINE] 3050. Diabetes Res Clin Pract. 2007 Aug;77(2):263-8. Epub 2007 Feb 1. Outcomes of pregnancies affected by impaired glucose tolerance. Kwik M(1), Seeho SK, Smith C, McElduff A, Morris JM. Author information: (1)Perinatal Research Group, Kolling Institute, University of Sydney, Royal North Shore Hospital, Pacific Highway, St. Leonards, NSW 2065, Sydney, Australia. mkwik8@hotmail.com Comment in Diabetes Res Clin Pract. 2007 Nov;78(2):302-3. OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with an increase in both maternal and neonatal morbidity. There remains uncertainty, however, about the diagnostic criteria for GDM. We compared pregnancy outcomes across three groups of women, with the aim of establishing a threshold for diagnosis of GDM at our institution. METHODS: Women with a glucose tolerance test (GTT) were identified on the hospital's pathology database. Those women with a singleton pregnancy, in whom a GTT had demonstrated a fasting value /=7.8mmol/L and who confined /=5.5mmol/L and/or 2h >/=7.8mmol/L on 75g GTT. PMID: 17275121 [PubMed - indexed for MEDLINE] 3051. Breast Cancer Res. 2007;9(1):301. Obesity hormone leptin: a new target in breast cancer? Surmacz E(1). Author information: (1)Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA. surmacz@temple.edu Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer. PMCID: PMC1851379 PMID: 17274833 [PubMed - indexed for MEDLINE] 3052. J Am Dent Assoc. 2007 Feb;138(2):179-87; quiz 248. Metabolic syndrome: pathogenesis, medical care and dental implications. Friedlander AH(1), Weinreb J, Friedlander I, Yagiela JA. Author information: (1)Graduate Medical Education, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. arthur.friedlander@med.va.gov Comment in J Am Dent Assoc. 2007 Jun;138(6):712, 714; author reply 714, 716. BACKGROUND: The dental literature contains little information about metabolic syndrome (MetS) and its dental implications. TYPES OF STUDIES REVIEWED: The authors conducted a MEDLINE search for the period 2000 through 2005, using the term "metabolic syndrome" to define its pathophysiology, medical treatment and dental implications. RESULTS: MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke. CLINICAL IMPLICATIONS: Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis. PMID: 17272372 [PubMed - indexed for MEDLINE] 3053. Nutr Metab Cardiovasc Dis. 2007 Feb;17(2):125-39. Epub 2007 Jan 30. Metabolic syndrome pathophysiology: the role of adipose tissue. Laclaustra M(1), Corella D, Ordovas JM. Author information: (1)Nutrition and Genomics Laboratory, JM-USDA-HNRCA at Tufts University, 711 Washington Street, Boston, MA 02111, USA. Several pathophysiological explanations for the metabolic syndrome have been proposed involving insulin resistance, chronic inflammation and ectopic fat accumulation following adipose tissue saturation. However, current concepts create several paradoxes, including limited cardiovascular risk reduction with intensive glucose control in diabetics, therapies that result in weight gain (PPAR agonists), and presence of some of the metabolic traits among some lipodystrophies. We propose the functional failure of an organ, in this case, the adipose tissue as a model to interpret its manifestations and to reconcile some of the apparent paradox. A cornerstone of this model is the failure of the adipose tissue to buffer postprandial lipids. In addition, homeostatic feedback loops guide physiological and pathological adipose tissue activities. Fat turnover is determined by a complex equilibrium in which insulin is a main factor but not the only one. Chronically inadequate energy balance may be a key factor, stressing the system. In this situation, an adipose tissue functional failure occurs resulting in changes in systemic energy delivery, impaired glucose consumption and activation of self-regulatory mechanisms that extend their influence to whole body homeostasis system. These include changes in adipokines secretion and vascular effects. The functional capacity of the adipose tissue varies among subjects explaining the incomplete overlapping among the metabolic syndrome and obesity. Variations at multiple gene loci will be partially responsible for these interindividual differences. Two of those candidate genes, the adiponectin (APM1) and the perilipin (PLIN) genes, are discussed in more detail. PMID: 17270403 [PubMed - indexed for MEDLINE] 3054. Mini Rev Med Chem. 2007 Jan;7(1):31-8. Lessons from Leptin's molecular biology: Potential therapeutic actions of recombinant leptin and leptin-related compounds. Correia ML(1), Haynes WG. Author information: (1)General Clinical Research Center, Department of Internal Medicine-157 MRF, University of Iowa, Iowa City, IA, 52242, USA. marcelo-correia@uiowa.edu Leptin, a peptide secreted by the white adipose tissue, circulates to the central nervous system and signals the status of body energy stores, regulating feeding behavior and energy balance. As human obesity is characterized by hyperleptinemia and leptin resistance, increasing leptin sensitivity is an attractive target for obesity treatment. PMID: 17266635 [PubMed - indexed for MEDLINE] 3055. Cardiovasc Hematol Agents Med Chem. 2007 Jan;5(1):1-10. Putative role for apelin in pressure/volume homeostasis and cardiovascular disease. Charles CJ(1). Author information: (1)Christchurch Cardioendocrine Research Group, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand. chris.charles@chmeds.ac.nz Apelin is a peptide recently isolated from bovine stomach extracts which appears to act as an endogenous ligand for the previously orphaned G-protein-coupled APJ receptor. The apelin gene encodes for a pre-propeptide consisting of 77 amino acids with mature apelin likely to be derived from the C-terminal region as either a 36, 17 or 13 amino acid peptide. Apelin mRNA expression and peptide immunoreactivity has been described in a variety of tissues including gastrointestinal tract, adipose tissue, brain, kidney, liver, lung and at various sites within the cardiovascular system. Apelin is strongly expressed in the heart with expression also present in the large conduit vessels, coronary vessels and endothelial cells. Message expression for the APJ receptor is similarly distributed throughout the brain and periphery, again including cardiovascular tissue. Consistent with this pattern of distribution, apelin and APJ have been shown to exhibit some role in the regulation of fluid homeostasis. In addition, a growing number of studies have reported cardiovascular actions of apelin. Not only has apelin been observed to alter arterial pressure, but the peptide also exhibits endothelium-dependent vasodilator actions in vivo and positive inotropic actions in the isolated heart. Furthermore, differences in apelin and APJ expression have been described in patients with congestive heart failure and circulating levels of apelin are also reported to change in heart failure. Taken together, these studies suggest a role for apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease. As such, manipulation of this peptide system may offer benefit to the syndrome of heart failure with potential clinical applications in humans. PMID: 17266543 [PubMed - indexed for MEDLINE] 3056. Rinsho Byori. 2006 Dec;54(12):1247-56. [Metabolic syndrome and small dense LDL]. [Article in Japanese] Yoshino G(1). Author information: (1)Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University School of Medicine, Ota-ku, Tokyo. Due to the recent westernization of our lifestyle, it is speculated that the prevalence of metabolic syndrome in the young generation will increase in Japan. Different from Western populations, because of our lifestyle as "farmers" from ancient times, excess energy has been stored outside of the body, and the accumulation of visceral fat might have serious adverse effects on glucose and lipid metabolism. Therefore, we must carefully diagnose and treat patients with metabolic syndrome, which is diagnosed based on the existence of visceral obesity. On the other hand, much attention has been paid recently to the atherogenicity of small dense LDL. In this chapter I will introduce a newly established method for estimating the plasma concentration of small dense LDL-cholesterol. Furthermore, the relationship between subclinical atherosclerosis and small dense LDL in metabolic syndrome will be discussed. PMID: 17265899 [PubMed - indexed for MEDLINE] 3057. Int J Clin Pract. 2007 Feb;61(2):269-80. Obesity-hypertension: an ongoing pandemic. Francischetti EA(1), Genelhu VA. Author information: (1)Hypertension Clinic, Laboratory of Clinical and Experimental Pathophysiology, CLINEX, Rio de Janeiro State University, Rio de Janeiro, Brazil. eafranc@uerj.br Considerable evidence has suggested that excessive weight gain is the most common cause of arterial hypertension. This association has been observed in several populations, in different regions of the world. Obesity-hypertension, a term that underscores the link between these two deleterious conditions, is an important public health challenge, because of its high frequency and concomitant risk of cardiovascular and kidney diseases. The obesity-hypertension pandemic imposes a considerable economic burden on societies, directly reflecting on healthcare system costs. Increased renal sodium reabsorption and blood volume expansion are central features in the development of obesity-hypertension. Overweight is also associated with increased sympathetic activity. Leptin, a protein expressed in and secreted by adipocytes, is the main factor linking obesity, increased sympathetic nervous system activity and hypertension. The renin-angiotensin-aldosterone system has also been causally implicated in obesity-hypertension, because angiotensinogen is expressed in and secreted by adipose tissue. Hypoadiponectinemia, high circulating levels of free fatty acids and increased vascular production of endothelin-1 (ET-1) have been reported as potential mechanisms for obesity-hypertension. Lifestyle changes are effective in obesity-hypertension control, though pharmacological treatment is frequently necessary. Despite the consistency of the mechanistic approach in explaining the causal relation between hypertension and obesity, there is yet no evidence that one class of drug is superior to the others in controlling obesity-hypertension. In this review, we present the current knowledge and research in obesity-hypertension, exploring the epidemiologic evidence of the association, its probable pathophysiological mechanisms and treatment issues. PMID: 17263714 [PubMed - indexed for MEDLINE] 3058. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2006 Dec;28(6):840-4. [Adipokine and metabolic syndrome]. [Article in Chinese] Zhou LB(1), Chen MD. Author information: (1)Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology, Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Adipose tissue is not simply a depot of energy, but is an active endocrine organ. The adipokines play an important role in the pathogenesis of metabolic syndrome. The proinflammatory adipokines secreted from expanded visceral adipose tissue directly induce insulin resistance and vascular injuries. A better understanding of the endocrine function of adipose tissue may lead to more rational therapy for metabolic syndrome. PMID: 17260479 [PubMed - indexed for MEDLINE] 3059. Med Hypotheses. 2007;68(5):1159-71. Epub 2007 Jan 25. Obesity - a perspective based on the biochemical interrelationship of lipids and carbohydrates. Jeffcoat R(1). Author information: (1)Hawthorn House, Higham Road, Chelveston, Wellingborough, Northants NN9 6AH, UK. rjgdj@aol.com Many factors affect the onset of obesity including satiety control, reduced levels of physical exercise as well as hormonal and genetic parameters which influence the metabolic pathways leading to the net accumulation of triacylglycerol (TAG). The predominant fatty acid of human adipose tissue TAGs is oleic acid, reflecting primarily the composition of the diet but also the product of de novo lipogenesis. Consequently, both carbohydrates and lipids are potential sources of these stored fats. Many studies have been carried out using a variety of differing experimental protocols on healthy, obese or diabetic humans and animals in positive or neutral energy balance to establish the underlying molecular basis for obesity particularly in humans. This short review discusses the interdependence and control of the metabolism of lipids and carbohydrates as it relates to lipogenesis and proposes a unified hypothesis for obesity which brings together a number of different approaches focusing on (i) the interaction of dietary fat and carbohydrate, which typically represent approximately 80% of the daily caloric intake, and their role in the synthesis of TAGs, (ii) the biochemical pathways which control the amount of TAG produced by controlling the composition of their fatty acids via the action of stearoyl-CoA desaturase (SCD), (iii) the control of lipogenesis and SCD by dietary polyunsaturated fatty acid (PUFA) and (iv) the interaction of PUFAs with the transcription factors, peroxisome proliferator activated receptors (PPAR) alpha and gamma, which maintain the balance between oxidation and storage of lipids. The hypothesis focuses on the central role of stearoyl-CoA desaturase (SCD) and its inhibition by polyunsaturated fatty acids (PUFAs) acting via transcription factors based upon data obtained from both animal and human studies. From these observations it should be possible to determine the relevance of the hypothesis to humans and to speculate how these aspects of metabolism may impact the risk of developing related diseases such as coronary heart disease, Type 2 diabetes and certain forms of cancer. PMID: 17257774 [PubMed - indexed for MEDLINE] 3060. Am J Surg Pathol. 2007 Feb;31(2):193-8. Subconjunctival herniated orbital fat: A benign adipocytic lesion that may mimic pleomorphic lipoma and atypical lipomatous tumor. Schmack I(1), Patel RM, Folpe AL, Wojno T, Zaldivar RA, Balzer B, Kang SJ, Weiss SW, Grossniklaus HE. Author information: (1)Emory Eye Center, Emory University School of Medicine, Atlanta, GA, USA. Prolapse of subconjunctival intraconal orbital fat is a rare cause of an intraorbital mass lesion. Over the past several years, we have seen a number of cases in which this prolapsed fat was confused pathologically with a neoplasm of adipocytic lineage, specifically pleomorphic lipoma and atypical lipomatous neoplasm (well-differentiated liposarcoma). We report the clinical, histopathologic, and immunohistochemical findings in 21 specimens from 17 patients, all of whom presented with prolapsed intraconal orbital fat. All specimens were routinely examined and processed for light microscopy. Immunohistochemistry for CD34, CD68, S100 protein, vimentin, alpha-smooth muscle actin, and Ki-67, and Giemsa, Masson trichrome, and alcian blue histochemical stains were performed. Clinical and follow-up information was extracted from a chart review. The mean age (+/-SD) of the patients was 65.6+/-11.9 years (range: 41 to 85 y); 2 were women and 15 were men. Subconjunctival prolapsed orbital fat was localized in the superotemporal quadrant or lateral canthus around the rectus muscle below the lacrimal gland. The lesions were unilateral in 10 and bilateral in 7 patients. No recurrence was clinically evident over a mean (+/-SD) follow-up time of 2.5+/-3.2 years (range: 1 mo to 13.5 y). Histopathologically, all specimens showed an admixture of mature fat, fibrous septae lacking hyperchromatic cells, adipocytes with intranuclear vacuoles (Lochkern cells), multinucleated giant cells with a wreathlike configuration of normochromatic nuclei (floret cells), and varying numbers of histiocytes, lymphocytes, plasma cells, and mast cells. "Control" sections of normal orbital fat showed occasional Lochkern cells but lacked floret cells. By immunohistochemistry, the floret cells expressed only CD34 and vimentin, whereas the Lochkern cells expressed CD34, S100 protein, and vimentin. We conclude that subconjunctival herniated orbital fat commonly contains multinucleated floretlike giant cells, fibrous septae, and Lochkern cells, features that may result in diagnostic confusion with pleomorphic lipoma and atypical lipomatous neoplasms. Importantly, specific diagnostic features, such as aggregates of bland spindled cells associated with wiry collagen, as seen in pleomorphic lipoma, and enlarged hyperchromatic cells within fibrous septae, as in atypical lipomatous neoplasms, are entirely absent in herniated orbital fat. Multinucleated floret cells present in prolapsed orbital fat likely represent a reactive phenomenon, as they are not present in normal orbital fat. PMID: 17255763 [PubMed - indexed for MEDLINE] 3061. Biomed Pharmacother. 2007 Feb-Apr;61(2-3):105-12. Epub 2007 Jan 2. Dietary omega-3 fatty acids for women. Bourre JM(1). Author information: (1)INSERM U 705, CNRS UMR 7157, Universités Paris 7 et 5, Hôpital Fernand Widal, 200 rue du Faubourg Saint Denis, 75745 Paris cedex 10, France. jean-marie.bourre@fwidal.inserm.fr This review details the specific needs of women for omega-3 fatty acids, including alpha linoleic acid (ALA) and the very long chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acid (dietary or in capsules) ensures that a woman's adipose tissue contains a reserve of these fatty acids for the developing fetus and the breast-fed newborn infant. This ensures the optimal cerebral and cognitive development of the infant. The presence of large quantities of EPA and DHA in the diet slightly lengthens pregnancy, and improves its quality. Human milk contains both ALA and DHA, unlike that of other mammals. Conditions such as diabetes can alter the fatty acid profile of mother's milk, while certain diets, like those of vegetarians, vegans, or even macrobiotic diets, can have the same effect, if they do not include seafood. ALA, DHA and EPA, are important for preventing ischemic cardiovascular disease in women of all ages. Omega-3 fatty acids can help to prevent the development of certain cancers, particularly those of the breast and colon, and possibly of the uterus and the skin, and are likely to reduce the risk of postpartum depression, manic-depressive psychosis, dementias (Alzheimer's disease and others), hypertension, toxemia, diabetes and, to a certain extend, age-related macular degeneration. Omega-3 fatty acids could play a positive role in the prevention of menstrual syndrome and postmenopausal hot flushes. The normal western diet contains little ALA (less than 50% of the RDA). The only adequate sources are rapeseed oil (canola), walnuts and so-called "omega-3" eggs (similar to wild-type or Cretan eggs). The amounts of EPA and DHA in the diet vary greatly from person to person. The only good sources are fish and seafood, together with "omega-3" eggs. PMID: 17254747 [PubMed - indexed for MEDLINE] 3062. Curr Diab Rep. 2007 Feb;7(1):25-33. Adipokines and vascular disease in diabetes. Goldstein BJ(1), Scalia R. Author information: (1)Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Suite 349, 1020 Locust Street, Philadelphia, PA 19107, USA. Barry.Goldstein@jefferson.edu Adipokines, in particular adiponectin, have been highlighted in the pathogenesis of obesity-related illnesses, including type 2 diabetes, because of their role in the regulation of insulin sensitivity as well as vascular endothelial function. Since cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with diabetes, researchers are actively seeking a better understanding of the role that adipokines play in the vasculature with the hope that the use of these agents, or activation of their signaling pathways, might help prevent micro- and macrovascular complications. This brief review highlights recent work on the vascular effects of circulating adipokines, focusing on adiponectin, and includes some recent findings with leptin and resistin. This highly active area of investigation has identified novel hormonal mechanisms by which the adipose tissue mass can influence vascular function with important consequences for cardiovascular risk. PMID: 17254515 [PubMed - indexed for MEDLINE] 3063. Endokrynol Pol. 2006 Nov-Dec;57(6):626-32. [The role of adiponectin in pathogenesis of metabolic syndrome and cardiovascular disease]. [Article in Polish] Kozłowska A(1), Kowalska I. Author information: (1)Department of Endocrinology, Diabetology and Internal Medicine, Medical University, Bialystok. The aim of this review is to present the up-to-date data about adiponectin and it's role in pathogenesis of cardiovascular disease. Adiponectin is a hormone derived from adipose tissue which regulates energy metabolism, and plays an important role in the pathogenesis of insulin resistance. Serum levels of adiponectin are reduced in obesity, hypertension, metabolic syndrome and type 2 diabetes. Moreover, plasma adiponectin concentration is inversely associated with LDL-cholesterol, TG and is positively related to HDL-cholesterol. Recent studies have indicated that adiponectin has antiinflammatory and antiatherogenic properties. Review of the data confirmed the hypothesis that adiponectin plays an important role in pathogenesis of cardiovascular disease. PMID: 17253436 [PubMed - indexed for MEDLINE] 3064. J Expo Sci Environ Epidemiol. 2007 Sep;17(6):510-24. Epub 2007 Jan 24. Recent global trends and physiologic origins of dioxins and furans in human milk. LaKind JS(1). Author information: (1)LaKind Associates, LLC, 106 Oakdale Avenue, Catonsville, MD 21228, USA. lakindassoc@comcast.net Restrictions on releases of polychlorinated dibenzo-dioxins and polychlorinated dibenzofurans (PCDDs/Fs) to the environment from industrial practices have resulted in an attendant decrease in levels of these compounds in the environment. Continued environmental monitoring and biomonitoring of PCDDs/Fs ensure that exposures do not increase unexpectedly or unnoticed. Perhaps the most highly exposed part of the population, however, is the breastfed infant and a periodic assessment of levels of dioxins and furans in human milk provides exposure information for infants. A previous international review of levels of PCDDs/Fs in human milk based on data from the 1970's to the mid-1990's showed a decline in many countries for which data were available. In this paper, recent (1998-2005) global data on PCDDs/Fs in human milk are described. A comparison of these recent data to pre-1998 data suggests a continuing decline in global levels of PCDDs/Fs in human milk. In addition, this paper explores research on physiological origins of these compounds in human milk (e.g., adipose tissue mobilization, recent dietary exposures). The question of whether the presence of PCDDs/Fs in milk is from the lifetime accumulation of PCDDs/Fs in adipose tissue or current diet (or, as is more likely, a complex combination of both) remains unanswered. Whether diet during lactation has a greater influence on milk levels PCDDs/Fs levels than previously suspected, and whether infant exposures to PCDDs/Fs via breastfeeding could be reduced by changes in diet during lactation, are important--and currently unexplored--lines of inquiry. PMID: 17245392 [PubMed - indexed for MEDLINE] 3065. Int J Vitam Nutr Res. 2006 Jul;76(4):172-7. From obesity to diabetes. Keller U(1). Author information: (1)University Hospital Basel, CH-4031 Basel, Switzerland. ukeller@uhbs.ch The prevalence of obesity has been increasing dramatically in the last decades in the whole world, not only in industrialized countries but also in developing areas. A major complication of obesity is insulin resistance and type 2 diabetes. Diabetes is also rapidly increasing world-wide--reaching a prevalence in adults of approx. 5-6% in Central Europe and in the US, and more than 50% in specific, genetically prone populations. This article reviews pathogenetic mechanisms linking obesity and type 2 diabetes. Emphasis is placed on the observation that excessive amounts of adipocytes are associated with an impairment of insulin sensitivity, a key feature of the "metabolic syndrome". This is a cluster of metabolic abnormalities such as type 2 diabetes, hypertension and dyslipidemia; all of them are enhanced by the presence of visceral (abdominal) obesity and all contribute to the increased cardiovascular risk observed in these patients. Besides release of free fatty acids, adipocytes secrete substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. Increased turnover of free fatty acids interferes with intracellular metabolism of glucose in the muscle, and they exert lipotoxic effect on pancreatic beta-cells. The pre-receptor metabolism of cortisol is enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. A new class of anti-diabetic drugs (thiazolidinediones, or glitazones) bind to peroxisome proliferator activated receptor (PPAR-gamma) and lower thereby plasma free fatty acids and cytokine production in adipocytes, in addition to a decrease of resistin and an increase in adiponectin observed in animals, resulting in an overall increase in insulin sensitivity and in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance and prevent the development of diabetes should be a reduction in body weight in overweight subjects, and an increase in physical activity. There are now three published randomized controlled trials demonstrating that in high risk individuals, life style changes with modest weight lost, associated with diminished fat intake and an increase in fruit and vegetable consumption result in marked inhibition of the transition from the prediabetic state to manifest type 2 diabetes. PMID: 17243079 [PubMed - indexed for MEDLINE] 3066. Pediatr Endocrinol Rev. 2006 Dec;3 Suppl 4:544-54. The brain-gut axis in regulation of appetite and obesity. Dham S(1), Banerji MA. Author information: (1)SUNY Downstate Medical Center, Brooklyn, NY 11203, USA. Shefali.dham@downstate.edu Obesity is the most common metabolic disease globally. It is increasingly a problem of children and individuals in poor countries characterized by food insecurity. This is of great concern as childhood obesity predicts increased future adult obesity. To curb the epidemic of obesity, it is essential to understand the regulation of appetite. Energy stores and nutrient homeostasis are maintained by hypothalamic regulation of energy balance. The hypothalamus receives neural and endocrine signals from the gut, adipose tissue and pancreas in response to food intake. These are integrated, interpreted and directed to other centers in the brain and peripheral organs to orchestrate energy homeostasis. This brain-gut axis is disrupted in obesity. This review discusses the various hormones involved in the regulation of energy balance both at the level of the gut and in the central nervous system. PMID: 17237741 [PubMed - indexed for MEDLINE] 3067. Pediatr Endocrinol Rev. 2006 Dec;3 Suppl 4:537-43. Roles of adipose tissue-derived factors in obesity. Umpaichitra V(1). Author information: (1)Division of Pediatric Endocrinology, Department of Pediatrics, The Brookdale University Hospital and Medical Center, Brooklyn, New York 11212, USA. vumpaich@brookdale.edu Discoveries of factors involved in energy metabolism from "adipose tissue" have defined it as an "endocrine organ." Examples of adipose tissue-derived factors are listed and briefly described. Factors involved in obesity are described in detail. Among these factors, adiponectin is emphasized because of its unique association with adiposity. PMID: 17237740 [PubMed - indexed for MEDLINE] 3068. Pediatr Ann. 2006 Dec;35(12):898-902, 905-7. The 'skinny' on childhood obesity: how our western environment starves kids' brains. Lustig RH(1). Author information: (1)Division of Endocrinology, University of California at San Francisco Center for Obesity Assessment, Study and Ttreatment, 94143-0434, USA. lustig@peds.ucsf.edu Comment in Pediatr Ann. 2007 Apr;36(4):176. In this review, the mechanism of our "toxic environment's" effects on insulin and weight gain in the genesis of obesity is elaborated. The composition of our diet is highly insulinogenic. The insulin drives energy into fat, and interferes with leptin signaling in the VMH. This results in weight gain and the sense of starvation, which results in decreased SNS activity, reducing energy expenditure and physical activity; and increased vagal activity, which promotes yet further insulin release and energy storage. Thus, hyperinsulinemia turns the leptin negative feedback system into a "vicious cycle" of obesity (see Figure 3, page 905). Externally, this appears as "gluttony and sloth" but it is biochemically driven. How does this work? A thin, insulin-sensitive, 13-year-old boy might consume a daily allotment of 2,000 kcal, and burn 2,000 kcal daily (or 50 kcal/kg fat-free mass) in order to remain weight-stable, with a stable leptin level. However, if that same 13-year-old became hyperinsulinemic and/or insulin resistant, perhaps as many as 250 kcal of the daily allotment would be shunted to storage in adipose tissue, promoting a persistent obligate weight gain. Due to the obligate energy storage, he now only has 1,750 kcal per day to burn. The hyperinsulinemia also results in a lower level of leptin signal transduction, conveying a CNS signal of energy insufficiency. The remaining calories available are lower than his energy expenditure; the CNS would sense starvation. Through decreased SNS tone, he would reduce his physical activity, resulting in decreased quality of life; and through increased vagal tone, he would increase caloric intake and insulin secretion, but now at a much higher level. Thus, the vicious cycle of gluttony, sloth, and obesity is promulgated. Is this personal responsibility, when a kid's brain thinks it's starving? Is it personal responsibility when the American Academy of Pediatrics still recommends juice for toddlers? Is it personal responsibility when the Women, Infant and Children program subsidizes fruit juice but not fruit? Is it personal responsibility when the first ingredient in the barbecue sauce is high-fructose corn syrup? Is it personal responsibility when high-fiber fresh produce is unavailable in poor neighborhoods? Is it personal responsibility when the local fast food restaurant is the only neighborhood venue that is clean and air-conditioned? Is it personal responsibility when in order to meet the criteria for No Child Left Behind, the school does away with physical education class? Is it personal responsibility when children are not allowed out of the house to play for fear of crime? We must get the insulin down. Fixing the "toxic environment" by altering the food supply and promoting physical activity for all children can't be done by government, and won't be done by Big Food. This will require a grassroots, bottom-up effort on the part of parents and community leaders. We as pediatricians must lead the way. PMID: 17236437 [PubMed - indexed for MEDLINE] 3069. Z Gastroenterol. 2007 Jan;45(1):35-41. Lipid metabolism in the liver. Canbay A(1), Bechmann L, Gerken G. Author information: (1)Division of Gastroenterology and Hepatology, Department of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. ali.Canbay@uni-due.de As a key metabolic organ, the liver is central to the imbalance of high-caloric diets, and particularly dietary fat consumption, in the industrialized countries and their association with the increasing prevalence of morbid obesity. By interacting with the intestinal tract and adipose tissue, the liver plays a key role in various aspects of lipid metabolism. Increasing activation of transcription factors, such as carbohydrate responsive element binding protein (ChREBP), sterol response element binding protein-1c (SREBP-1c), or forkhead box 01 (Fox01), may contribute to fatty acid synthesis. Their translocation occurs via fatty acid transporters such as fatty acid transport proteins (FATP), fatty acid translocase (FAT/CD36), caveolin-1 and fatty acid binding protein (FABP) . Eventually, the accumulation of fat in the form of lipid droplets within the hepatocytes results in hepatic steatosis which, indeed, is a hallmark of liver diseases such as non-alcoholic fatty liver disease, alcoholic fatty liver, acute fatty liver in pregnancy, and hepatitis C. In contrast, lipid accumulation within hepatocytes during liver regeneration is essential. It is thus now becoming clear that steatosis is not only a mere consequence of metabolic imbalance, but that it is also a result of discrete alterations in the beta-oxidation, transport mechanisms, and signaling pathways involved in the synthesis, systemic traffic modalities, and cellular effects of fatty acids. Such a novel insight offers potential options for improved treatment. PMID: 17236119 [PubMed - indexed for MEDLINE] 3070. Acta Med Port. 2006 May-Jun;19(3):251-6. Epub 2006 Sep 7. [Adipose tissue and adipokines]. [Article in Portuguese] Costa JV(1), Duarte JS. Author information: (1)Serviço de Endocrinologia, Hospital Egas Moniz, Lisboa, Portugal. Adipose tissue is an organ with an endocrine function among others. Adipokines there produced have several roles and can be, according to their main function, grouped in our groups: immunologic, cardiovascular, metabolic and endocrine adipokines. Interleukin-6, tumour necrosis factor a and complement factors B, C3 and D (adipsin) and are within the first group. Adipsin was the one of the first adipokines identified. Ali this molecules have well defined roles in inflammation. It is well known the association between obesity and cardiovascular risk, which is demonstrated by the improvement of cardiovascular risk factors associated with weight loss. Among the adipokines with cardiovascular main function the renin--angiotensin axis molecules and plasminogen activator inhibitor--I will be highlighted. Metabolic function is attributed to molecules taught to have a role in energy homeostasis. Adipose tissue is mainly involved in lipid and glucose metabolism. Free fatty acids, adiponectin, resistin, agouti related peptide and visfatin are molecules involved in those metabolic pathways. Leptin is the paradigm of the adipose tissue endocrine function. It is almost exclusively produced by the adipocyte and it has a central role in energy storage regulation and fertility. Steroid inter-conversion also occurs in adipose tissue. Although knowledge regarding these molecules, their function and relations with other systems has increased lately; more studies are necessary in order to clarify mechanisms and clinical applications. Only that way it will be possible to effectively correct the obesity associated metabolic dysfunction and decrease the morbidity and mortality obesity related. PMID: 17234088 [PubMed - indexed for MEDLINE] 3071. J Physiol Pharmacol. 2006 Dec;57(4):505-28. Adipocytokines - novel link between inflammation and vascular function? Guzik TJ(1), Mangalat D, Korbut R. Author information: (1)Department of Internal Medicine, Jagiellonian University School of Medicine, Krakow, Poland. Obesity and obesity related diseases are a major public health problem. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine and immune functions. These are achieved predominantly through release of adipocytokines, which include several novel and highly active molecules released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells infiltrating fat, like TNF-alpha, IL-6, MCP-1 (CCL-2), IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation and may also affect vascular (endothelial) function by modulating vascular nitric oxide and superoxide release and mediating obesity related vascular disorders (including hypertension, diabetes, atherosclerosis, and insulin resistance) but also cancer or non-alcoholic fatty liver diseases. Present review, in a concise form, focuses on the effects of major adipocytokines, characteristic for adipose tissue like leptin, adiponectin, resistin and visfatin on the immune system, particularly innate and adaptive immunity as well as on blood vessels. Macrophages and T cells are populating adipose tissue which develops into almost an organized immune organ. Activated T cells further migrate to blood vessels, kidney, brain and other organs surrounded by infiltrated fat leading to their damage, thus providing a link between metabolic syndrome, inflammation and cardiovascular and other associated disorders. Ceretain treatments may lead to significant changes in adipocytokine levels. For example include beta-2 adrenoreceptor agonists, thiazolidinediones as well as androgens lead to decrease of plasma leptin levels. Moreover future treatments of metabolic system associated disorders should focus on the regulation of adipocytokines and their modes of action. PMID: 17229978 [PubMed - indexed for MEDLINE] 3072. Endocr Pract. 2006 Nov-Dec;12(6):682-9. Cardiovascular risk in patients with growth hormone deficiency: effects of growth hormone substitution. Burger AG(1), Monson JP, Colao AM, Klibanski A. Author information: (1)Department of Medicine, University of Geneva, Cologny (Geneva), Switzerland. OBJECTIVE: To review the literature on the increased cardiovascular risk in patients with growth hormone (GH) deficiency and the positive effects of GH replacement. METHODS: We analyze the factors that contribute to cardiovascular risk in GH deficiency, including body composition and lipid profile, and summarize GH treatment strategies and results described in the literature. RESULTS: The prominent clinical finding in patients with GH deficiency is the increased abdominal fat, even in patients with normal weight. Cardiac ejection volume tends to be decreased, and arterial distensibility is diminished. The lipid status is also worsened, accompanied by increased inflammatory markers, such as highly sensitive C-reactive protein. Typically, GH treatment reduces visceral fat and increases muscle mass, changes that diminish cardiovascular risk. Because of direct effects as well as increased hemodynamic performance and increased blood volume, cardiac performance is improved. With GH therapy, total cholesterol and low-density lipoprotein levels decrease by 10% to 20%, and inflammatory markers such as C-reactive protein decline. Carbohydrate metabolism during moderate to long-term treatment is minimally affected, although obese patients with GH deficiency on rare occasion may have hyperglycemia or even diabetes. CONCLUSION: The relevance of the beneficial effects of GH on the cardiovascular system is strongly suggested but not fully proved. The results in a large cohort of GH-treated patients (the KIMS or Pharmacia and Upjohn International Metabolic Surveillance database) demonstrated no difference in cardiovascular risk in comparison with that in a control population after a mean of 3 years of treatment. PMID: 17229667 [PubMed - indexed for MEDLINE] 3073. Clin Chim Acta. 2007 Mar;378(1-2):7-12. Epub 2006 Dec 13. Serum lipoprotein lipase mass: clinical significance of its measurement. Kobayashi J(1), Nohara A, Kawashiri MA, Inazu A, Koizumi J, Nakajima K, Mabuchi H. Author information: (1)Department of Lipidology, Kanazawa University Graduate School of Medical Science Takara-machi 13-1, Kanazawa 920-8640, and Department of General Medicine, Kanazawa University Hospital, Japan. junji@med.kanazawa-u.ac.jp Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, increasing attention has been paid to the clinical significance of measuring serum LPL protein mass without heparin injection to the study subjects. In earlier studies, this marker was utilized to classify LPL deficient subjects, which is an extremely rare metabolic disorder with a frequency of one in one million. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma or serum LPL mass has significant relationships with serum lipids and lipoproteins, visceral fat area, insulin resistance, and even the development of coronary atherosclerosis in cross-sectional studies, although this might be a metabolic surrogate marker with almost no catalytic activities, which does not appear to be involved in catalyzing hydrolysis of TG in TG-rich lipoproteins. Recently, a prospective study has demonstrated that low serum LPL concentration predicts future coronary events. Taken together, we suggest that pre-heparin LPL mass in plasma or sera provide us with useful and important information on the development of metabolic disorders leading to atherosclerotic disease. PMID: 17223095 [PubMed - indexed for MEDLINE] 3074. Intern Med. 2007;46(2):101-3. Epub 2007 Jan 15. 1. Fatty liver and non-alcoholic steatohepatitis. Saito T(1), Misawa K, Kawata S. Author information: (1)The Department of Gastroenterology, Yamagata University. tasaitoh@med.id.yamagata-u.ac.jp Although steatohepatitis can be induced by an excessive intake of alcohol, it can also arise through various other causes, in which case it is known as non-alcoholic fatty liver disease (NAFLD). NAFLD is classified into two categories:simple fatty liver with a favorable clinical outcome, and non-alcoholic steatohepatitis (NASH), which is intractable and progressive. Recently in Japan, there has been an increase in the number of individuals at risk of lifestyle-related diseases, due to increased insulin resistance and visceral fat obesity. The metabolic syndrome (MS) is associated with several risk factors for atherosclerosis, including diabetes mellitus (DM), hypertension, and hyperlipidemia. Visceral fat obesity is the prime cause of NASH in the liver, and is therefore considered to be one of the phenotypic features of MS. Furthermore, most chronic liver diseases are associated with hepatitis C virus (HCV) infection. Fatty degeneration of hepatocytes is often observed in the liver of HCV-infected individuals, and results from viral suppression of mitochondrial beta-oxidation of fatty acid. The natural outcome of HCV infection is worse in patients with lifestyle-related high insulin resistance and visceral fat obesity. In this review, we describe the recent advances in research on progressive liver diseases that are the result of fat accumulation in the liver, with special reference to MS. PMID: 17220609 [PubMed - indexed for MEDLINE] 3075. Folia Histochem Cytobiol. 2006;44(4):215-30. Mesenchymal stem cells: characteristics and clinical applications. Bobis S(1), Jarocha D, Majka M. Author information: (1)Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland. Mesenchymal stem cells (MSCs) are bone marrow populating cells, different from hematopoietic stem cells, which possess an extensive proliferative potential and ability to differentiate into various cell types, including: osteocytes, adipocytes, chondrocytes, myocytes, cardiomyocytes and neurons. MSCs play a key role in the maintenance of bone marrow homeostasis and regulate the maturation of both hematopoietic and non-hematopoietic cells. The cells are characterized by the expression of numerous surface antigens, but none of them appears to be exclusively expressed on MSCs. Apart from bone marrow, MSCs are located in other tissues, like: adipose tissue, peripheral blood, cord blood, liver and fetal tissues. MSCs have been shown to be powerful tools in gene therapies, and can be effectively transduced with viral vectors containing a therapeutic gene, as well as with cDNA for specific proteins, expression of which is desired in a patient. Due to such characteristics, the number of clinical trials based on the use of MSCs increase. These cells have been successfully employed in graft versus host disease (GvHD) treatment, heart regeneration after infarct, cartilage and bone repair, skin wounds healing, neuronal regeneration and many others. Of special importance is their use in the treatment of osteogenesis imperfecta (OI), which appeared to be the only reasonable therapeutic strategy. MSCs seem to represent a future powerful tool in regenerative medicine, therefore they are particularly important in medical research. PMID: 17219716 [PubMed - indexed for MEDLINE] 3076. Skeletal Radiol. 2007 Jul;36(7):607-8. Measuring muscle lipids with 1H-MR spectroscopy. Torriani M(1). Author information: (1)Musculoskeletal Radiology, Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, YAW 6048, Boston, MA 02114, USA. mtorriani@hms.harvard.edu PMID: 17219228 [PubMed - indexed for MEDLINE] 3077. Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G1-4. Epub 2007 Jan 11. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Jaworski K(1), Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. Triacylglycerol (TAG) stored in adipose tissue can be rapidly mobilized by the hydrolytic action of lipases, with the release of fatty acids (FA) that are used by other tissues during times of energy deprivation. Unlike synthesis of TAG, which occurs not only in adipose tissue but also in other tissues such as liver for very-low-density lipoprotein formation, hydrolysis of TAG, lipolysis, predominantly occurs in adipose tissue. Until recently, hormone-sensitive lipase was considered to be the key rate-limiting enzyme responsible for regulating TAG mobilization. However, recent studies on hormone-sensitive lipase-null mice have challenged such a concept. A novel lipase named desnutrin/ATGL has been recently discovered to play a key role in lipolysis in adipocytes. Lipolysis is under tight hormonal regulation. Although opposing regulation of lipolysis in adipose tissue by insulin and catecholamines is well understood, autocrine/paracrine factors may also participate in its regulation. Intricate cooperation of these endocrine and autocrine/paracrine factors leads to a fine regulation of lipolysis in adipocytes, needed for energy homeostasis. In this review, we summarize and discuss the recent progress made in the regulation of adipocyte lipolysis. PMCID: PMC2887286 PMID: 17218471 [PubMed - indexed for MEDLINE] 3078. J Physiol Biochem. 2006 Jun;62(2):137-47. The body fat-lowering effect of conjugated linoleic acid: a comparison between animal and human studies. Navarro V(1), Fernández-Quintela A, Churruca I, Portillo MP. Author information: (1)Department of Nutrition and Food Science, University of Pais Vasco, Paseo de la Universidad 7, 01006 Vitoria, Spain. Different reasons which justify differences between rodents and humans in body fat reduction produced by conjugated linoleic acid (CLA) could be proposed. The doses used in humans are lower than those used in rodents. Human experiments have been performed with CLA isomer mixtures instead of isolated isomers. The variable dilution of t-10, c-12, the active isomer, among different preparations might explain the reduced responsiveness in humans. Diet composition may modulate CLA effects on body fat accumulation. As far as human studies are concerned, a specific dietary pattern has not been established. As a result differences among studies and also among subjects in the same study are likely. In rodents, the effects of CLA vary with genotype, suggesting that genetic predisposition to fat accumulation can play an important role in the effectiveness of CLA. Human volunteers with different body mass index have participated in the published studies and even in the same experiment. So, differences in lipid metabolism among subjects could help to explain the discrepancies observed in the literature. Age and maturity may also be crucial. Experiments using rodents have been conducted with growing animals and there is little evidence of CLA effectiveness in adult animals. By contrast, human studies have been performed with adults. Inhibition of lipogenesis in white adipose tissue is one of the mechanisms which have been proposed to explain the body-fat lowering effect of CLA, but lipogenesis in this tissue is very low in humans. Another mechanism suggested is increased fatty acid oxidation in the liver associated with peroxisome proliferation, but humans are relatively insensitive to this effect. PMID: 17217167 [PubMed - indexed for MEDLINE] 3079. Internist (Berl). 2007 Feb;48(2):126-33. [The biology of visceral fat]. [Article in German] Klöting N(1), Stumvoll M, Blüher M. Author information: (1)Medizinische Klinik und Poliklinik III, Universität Leipzig, 04103 Leipzig, Deutschland. Visceral obesity is an independent risk factor for the development of cardiovascular diseases and type 2 diabetes. This is likely to be due to biological characteristics of visceral tissue, which are different from those of subcutaneous adipose tissue in terms of decreased insulin sensitivity and increased lipolytic activity. In addition, the anatomical site of visceral fat could be one potential reason for the increased cardio-metabolic risk associated with visceral obesity. Visceral adipose tissue drains into the portal vein and therefore the liver is exposed to the undiluted metabolites and adipokines released from visceral fat. There are profound differences between visceral and subcutaneous adipocytes in the metabolism, expression of specific receptors and secretion of a specific adipokine pattern, which could contribute to the adverse consequences of visceral obesity. PMID: 17216235 [PubMed - indexed for MEDLINE] 3080. Anticancer Res. 2006 Nov-Dec;26(6C):4857-67. Liposarcoma of the oral cavity--case reports of the pleomorphic and the dedifferentiated variants and a review of the literature. Angiero F(1), Sidoni A, Stefani M. Author information: (1)Institute of Pathological Anatomy, Oral Pathology Section, Milan, Italy. Liposarcoma is one of the commonest soft-tissue sarcomas, but very rare in the oral cavity. We present two cases of liposarcoma of the oral cavity, together with the related clinical, histopathological and immunohistochemical findings: one affecting the cheek of a 62-year-old man and the other the gingival maxillary tuber of a 41-year-old woman. At histological examination a diagnosis of liposarcoma was made in both cases. In the first case, immunohistochemical analysis revealed intense positivity for p53, MIB-1, MDM2, and focal positivity for S100 protein and CD34, but was negative for alpharsmooth muscle actin, desmin and CD68. The second case it was intensely positive for p53, MIB-1, S-100, and focal positive for MDM2, but negative for alpha smooth muscle actin, CD34, CD68 and desmin. Histological examination and immunohistochemical profiles in the first case were consistent with pleomorphic liposarcoma, whilst that in the second case with dedifferentiated liposarcoma. Both patients were subjected to surgical treatment with wide surgical margins, without adjuvant radio- or chemotherapy. The first case was lost at follow-up one year after surgery, while the second case has not undergone relapse after seven years. We discuss differential diagnosis, examining the histopathological and immunohistochemical features that are potentially useful for distinguishing this tumor from other malignant adipose tissue tumors. PMID: 17214352 [PubMed - indexed for MEDLINE] 3081. Clin Cornerstone. 2006;8 Suppl 4:S7-S13. Adipose tissue dysfunction in obesity and lipodystrophy. Garg A(1). Author information: (1)Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Abhimanyu.garg@utsouthwestern.edu The primary function of adipose tissue is to store energy in the form of triglycerides during periods of energy excess and to release the energy during fasting or starvation as free fatty acids and glycerol. Adipose tissue secretes a variety of peptides called adipocytokines (eg, leptin, adiponectin, tumor necrosis factor-alpha, interleukin-6, resistin, visfatin) that have endocrine, autocrine, and paracrine effects on the brain, liver, and skeletal muscles. These peptides play an important role in the regulation of energy homeostasis and intermediary metabolism. Adipose tissue also aromatizes androgens to estrogens, and some adipose tissue depots (mechanical fat) serve a protective or cushioning function. Dysfunction of adipose tissue can result in insulin resistance and its metabolic complications in patients with excess body fat (obesity) or markedly reduced body fat (lipodystrophy). Alterations in free fatty acid and adipocytokine release from adipose tissue may underlie metabolic complications. PMID: 17208666 [PubMed - indexed for MEDLINE] 3082. Clin Cornerstone. 2006;8 Suppl 4:S24-35. The endocannabinoid system: body weight and metabolic regulation. Engeli S(1), Jordan J. Author information: (1)Franz Volhard Clinical Research Center, University Clinic Charité Campus Buch, Humboldt University of Berlin, Wiltbergstrasse 50, 13125 Berlin, Germany. stefan.engeli@charite.de The endocannabinoid system elicits multiple physiologic functions that are not fully understood. Antagonism of cannabinoid type 1 (CB(1)) receptors has been the only successful new pharmacologic treatment approach in Phase III studies in obesity in the last 8 years. Whereas antagonism of (CB(1)) receptors acutely reduces food intake, the long-term effects on weight reduction and metabolic regulation appear to be mediated by stimulation of energy expenditure and by peripheral effects related to liver, skeletal muscle, adipose tissue, and pancreas physiology. For example, in the liver, lipogenic enzymes and fatty acid synthesis are upregulated by endocannabinoids, and in adipose tissue, antagonism of (CB(1)) receptors increases secretion of adiponectin. Some studies suggest that endocannabinoid formation is increased in obesity, perhaps because endocannabinoid degradation is decreased. Although many questions remain unanswered at present, the emerging concept of endocannabinoids as metabolic regulators helps to explain the success of rimonabant (SR141716), an antagonist of (CB(1)) receptors, currently in Phase III studies. PMID: 17208664 [PubMed - indexed for MEDLINE] 3083. Clin Cornerstone. 2006;8 Suppl 4:S14-23. The relation of adipose tissue to cardiometabolic risk. Pi-Sunyer FX(1). Author information: (1)Obesity Research Center, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025, USA. fxp1@columbia.edu Adipose tissue is an active and complex endocrine organ that secretes numerous bioactive substances, including hormones, growth factors, and cytokines. Central obesity, one of the components of metabolic syndrome, is a cardiometabolic risk factor associated with a state of chronic inflammation and coagulation, one in which the expression of certain adipocytokines, including tumor necrosis factor-alpha (TNF-(alpha), interleukin (IL)-6, and plasminogen activator inhibitor-1 (PAI-1) is more abundantly increased, while adiponectin expression is decreased. TNF-alpha initiates and organizes inflammatory changes in vascular tissue. IL-6, an inflammatory cytokine directly implicated in atherogenesis, exerts pleiotropic effects on a variety of tissues. An increased concentration of PAI-1, an important regulator of the endogenous fibrinolytic system, promotes continued clotting. Adiponectin, on the other hand, has potent vasculoprotective, angiogenic, anti-inflammatory, and antiatherogenic properties. Adiponectin levels are low in obese individuals and increase when weight is lost, thereby serving as a marker for cardioprotection. Weight loss has long been promoted as a means to reduce the risk of type 2 diabetes and cardiovascular disease; for example, exercise and a hypocaloric diet have been shown to decrease PAI-1 levels. Weight loss drugs, such as orlistat, a lipase inhibitor, and sibutramine, a serotonin and norepinephrine reuptake inhibitor, have both been shown to produce a decrease in C-reactive protein levels and an increase in serum adiponectin. Rimonabant, a selective cannabinoid 1 receptor antagonist in Phase III studies, also has been shown to increase adiponectin levels. These agents may play a role in the regulation of adipocytokines, which may directly affect the risk for cardiometabolic disease. PMID: 17208662 [PubMed - indexed for MEDLINE] 3084. Int J Biochem Cell Biol. 2007;39(4):678-84. Epub 2006 Nov 7. Sphincter incontinence: is regenerative medicine the best alternative to restore urinary or anal sphincter function? Feki A(1), Faltin DL, Lei T, Dubuisson JB, Jacob S, Irion O. Author information: (1)Embryonic Stem Cell Research Laboratory, Switzerland. anis.feki@hcuge.ch Incontinence is a major public health concern in aging societies. It is caused by age-dependent spontaneous apoptosis of muscle cells in the urinary and fecal sphincters, and is aggravated in women due to birth trauma. Compared to other currently employed invasive surgical management techniques associated with morbidity and recurrence, replacement or regeneration of dysfunctional sphincter through stem cell therapy and tissue engineering techniques hold great promise. This review focuses on the pathophysiological analysis of urinary incontinence and the possible application of muscle-derived-stem cells, satellite cells, chondrocytes and adipose-derived-stem cells in restoring sphincter functions. PMID: 17208507 [PubMed - indexed for MEDLINE] 3085. J Med Food. 2006 Winter;9(4):451-8. Green tea extract thermogenesis-induced weight loss by epigallocatechin gallate inhibition of catechol-O-methyltransferase. Shixian Q(1), VanCrey B, Shi J, Kakuda Y, Jiang Y. Author information: (1)South China Institute of Botany, Chinese Academy of Sciences, Guangzhou, China. Epidemiological studies have shown that intake of tea catechins is associated with a lower risk of cardiovascular disease. The antioxidative activity of tea-derived catechins has been extensively studied. Reports have shown that green tea extract intake is associated with increased weight loss due to diet-induced thermogenesis, which is generally attributed to the catechin epigallocatechin gallate. That catechin-polyphenols are known to be capable of inhibiting catechol-O-methyltransferase (the enzyme that degrades norepinephrine) is a possible explanation for why the green tea extract is effective in stimulating thermogenesis by epigallocatechin gallate to augment and prolong sympathetic stimulation of thermogenesis. Knowledge about thermogenesis-induced weight loss produced by green tea's epigallocatechin gallate and its ability to inhibit catechol-O-methyltransferase is important for health benefits and for prolonging the action of norepinephrine in the synaptic cleft. PMID: 17201629 [PubMed - indexed for MEDLINE] 3086. Exerc Immunol Rev. 2006;12:6-33. Interleukin-6 in acute exercise and training: what is the biological relevance? Fischer CP(1). Author information: (1)Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet and Faculty of Health Sciences, University of Copenhagen, Denmark. cfischer@dadlnet.dk It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercise involving a significant muscle mass in the contractile activity is necessary in order to produce a marked systemic IL-6 response. Furthermore, exercise training may reduce basal IL-6 production as well as the magnitude of the acute exercise IL-6 response by counteracting several potential stimuli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation. PMID: 17201070 [PubMed - indexed for MEDLINE] 3087. J Pathol. 2007 Jan;211(2):232-40. The aged breast. Walker RA(1), Martin CV. Author information: (1)Breast Cancer Research Unit, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK. rawl4@le.ac.uk There is a clear association between the development of breast cancer and increasing age, with 80% of cancers occurring in women more than 50 years of age and one-third in women over 70 years. Following the menopause the breast undergoes involution, with the main changes affecting the terminal ductal lobular unit. There is an increase in oestrogen receptor alpha (ERalpha)-positive cells, a decrease in proliferation but, in comparison to premenopausal breasts, a greater number of ERalpha-proliferating cells. The breast cancers that occur in women >/= 75 years are more likely to be ER-positive, with a low growth rate and limited expression of HER-2 and p53. It is proposed that uneven involution of the breast, the persistence of at-risk lesions, the presence of ERalpha-proliferating cells and local oestrogen metabolism in breast adipose tissue are factors in the development of breast cancers with a well-differentiated phenotype. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. PMID: 17200937 [PubMed - indexed for MEDLINE] 3088. J Clin Invest. 2007 Jan;117(1):13-23. Gastrointestinal regulation of food intake. Cummings DE(1), Overduin J. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA. davidec@u.wasington.edu Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes. PMCID: PMC1716217 PMID: 17200702 [PubMed - indexed for MEDLINE] 3089. Diabetes Obes Metab. 2007 Jan;9(1):11-22. Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults. Yuen KC(1), Dunger DB. Author information: (1)Division of Endocrinology, Oregon Health and Science University, Portland, Oregon, USA. yuenk@ohsu.edu Growth hormone (GH) is generally considered to exert anti-insulin actions, whereas insulin-like growth factor I (IGF-I) has insulin-like properties. Paradoxically, GH deficient adults and those with acromegaly are both predisposed to insulin resistance, but one cannot extrapolate from these pathological conditions to determine the normal metabolic roles of GH and IGF-I on glucose homeostasis. High doses of GH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects, whereas IGF-I acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is only evident after feeding when the bioavailability of circulating IGF-I is increased. In contrast, many studies in GH deficient adults have consistently shown that GH replacement improves the body composition profile although these studies differ considerably in terms of age, the presence or absence of multiple pituitary hormone deficiency, and whether GH deficiency was childhood or adult-onset. However, the improvement in body composition does not necessarily translate into improvements in insulin sensitivity presumably due to the anti-insulin effects of high doses of GH therapy. More recently, we have found that a very low dose GH therapy (0.1 mg/day) improved insulin sensitivity without affecting body composition in GH-deficient adults and in subjects with metabolic syndrome, and we postulate that these effects are mediated by its ability to increase free 'bioavailable' IGF-I without the induction of lipolysis. These results raise the possibility that this low GH dose may play a role in preventing the decline of beta-cell function and the development of type 2 diabetes in these "high risk" subjects. PMID: 17199714 [PubMed - indexed for MEDLINE] 3090. Diabetes Obes Metab. 2007 Jan;9(1):1-10. Ectopic fat accumulation and metabolic syndrome. Rasouli N(1), Molavi B, Elbein SC, Kern PA. Author information: (1)The Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. rasoulineda@uams.edu The recent escalation of obesity from an individual health problem to a major public health issue reaching epidemic proportions has drawn attention to a constellation of abnormalities (abdominal obesity, hypertension and dyslipidaemia) collectively referred to as metabolic syndrome. As an indicator of insulin resistance and a harbinger of diabetes, this syndrome has been associated with major cardiovascular mortality and morbidity. Yet, the exact pathophysiological events leading to the development of metabolic syndrome remain unknown. We review some of the current literature on the pathogenesis of metabolic syndrome with an emphasis on the role of ectopic lipid accumulation. PMID: 17199713 [PubMed - indexed for MEDLINE] 3091. J Ren Nutr. 2007 Jan;17(1):62-5. The potential role of sterol regulatory element binding protein transcription factors in renal injury. Szolkiewicz M(1), Chmielewski M, Nogalska A, Stelmanska E, Swierczynski J, Rutkowski B. Author information: (1)Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Gdansk, Poland. The disturbed lipid metabolism is a permanent finding in renal failure. It is supposed to be a main reason for the accelerated atherosclerosis and high cardiovascular and cerebrovascular mortality of patients with renal failure. Sterol regulatory element binding proteins (SREBPs) are the transcription factors involved in the regulation of lipid homeostasis. They are responsible for the transcription activation of genes associated with the synthesis of fatty acids, triglycerides, and cholesterol. SREBP-1 gene expression in adipose tissue and SREBP-2 in liver are significantly elevated in renal failure. This is accompanied with the up-regulation of genes encoding enzymes of both fatty acids and cholesterol synthesis and significant serum lipid enhancement. Moreover, it has been shown that a destructive accumulation of lipids in the kidney structures is associated with enhanced kidney SREBP gene expression and increased lipid production. This was found even in the absence of any abnormalities in serum lipids. One may suppose that SREBP transcription factors play an important role in disturbed lipid metabolism in renal failure. PMID: 17198935 [PubMed - indexed for MEDLINE] 3092. Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1465-8. Epub 2006 Dec 28. Regulation of Triglyceride Metabolism. III. Emerging role of lipid droplet protein ADFP in health and disease. Chang BH(1), Chan L. Author information: (1)Division of Diabetes, Endocrinology, and Metabolism, Depts. of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ADFP is the major lipid droplet protein present in all cells that accumulate lipids either normally or abnormally. Although discovered about 15 years ago, it was only in the last few years that we began to have a working knowledge of its possible role in lipid droplet homeostasis at the whole organism level. In this perspective, we concentrate on the potential function of ADFP in various tissues. Space limitation has precluded a complete cataloging of all publications on the topic. We instead highlight some of the salient developments in the last few years. PMID: 17194897 [PubMed - indexed for MEDLINE] 3093. Ann N Y Acad Sci. 2006 Nov;1088:207-18. PPARgamma, a lipid-activated transcription factor as a regulator of dendritic cell function. Szatmari I(1), Rajnavolgyi E, Nagy L. Author information: (1)Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4010, Hungary. In recent years it became apparent that PPARgamma, besides being a key component of adipose tissue development and a target of insulin-sensitizing drugs, also has a role in immune cell differentiation and function. This receptor has been identified by us and others as a conductor of lipid handling in macrophages, and has roles also in inflammation control. Here we review recent advances on the role of this nuclear receptor in another key cell type of myeloid origin, dendritic cells (DCs). DCs are professional antigen-presenting cells having essential roles in antigen-uptake processing and presentation and in initiation of various forms of immune responses. It appears that PPARgamma is expressed and is active in myeloid DCs and likely to be a regulator of DC function by altering antigen uptake, maturation, activation, migration, cytokine production, and lipid antigen presentation. Thus PPARgamma is at the crossroads of lipid metabolism and innate immune response, and by studying its functions one has a unique opportunity to discern how these two seemingly distant fields (lipid metabolism and immune response) are interrelated. It is also possible that this receptor is a relevant target for pharmacological intervention in immune diseases such as chronic inflammation and autoimmune conditions. PMID: 17192567 [PubMed - indexed for MEDLINE] 3094. Sports Med. 2007;37(1):31-46. The effects of exercise training on fat-mass loss in obese patients during energy intake restriction. Hansen D(1), Dendale P, Berger J, van Loon LJ, Meeusen R. Author information: (1)Human Physiology and Sports Medicine, Vrije Universiteit Brussel (VUB), Faculty LK, Brussels, BelgiumRehabilitation and Health Centre, Virga Jesse Hospital, Hasselt, Belgium. Dietary restriction combined with endurance exercise training represents an effective strategy to promote weight loss and reduce fat mass in obese patients. Exercise programmes without dietary restriction are less efficient. However, addition of exercise to a dietary restriction programme does not induce a greater fat-mass loss than dietary restriction alone. The latter is likely attributed to a compensatory reduction in daily physical activity following the implementation of exercise training. Nonetheless, inclusion of an exercise training programme is important to prevent a decrease in fat-free mass, increase relative visceral fat-mass loss, improve dietary compliance and eventually maintain long-term weight control. Obese male patients with the highest fat mass are most likely to lose the largest amount of fat mass in such lifestyle intervention programmes. Influences of training modalities during energy intake restriction on fat-mass loss are reviewed. The relationship between total energy expenditure during exercise training and overall fat-mass loss has been firmly established. The amount of training forms a more important predictor of fat-mass loss than training intensity. The sort of exercise (e.g. walking, cycling, swimming) plays another important predictor of fat-mass loss in intervention programmes. The implementation of resistance training in such programmes does not augment fat-mass loss but improves body composition by increasing fat-free mass. Further studies are needed to define the optimal interventional programme for obese patients. PMID: 17190534 [PubMed - indexed for MEDLINE] 3095. J Appl Physiol (1985). 2007 Apr;102(4):1687-95. Epub 2006 Dec 21. Ventilatory muscle activation and inflammation: cytokines, reactive oxygen species, and nitric oxide. Vassilakopoulos T(1), Hussain SN. Author information: (1)Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, Greece. Strenuous diaphragmatic contractions that are induced by inspiratory resistive breathing initiate an inflammatory response that involves the elevation of pro- and anti-inflammatory cytokines within the diaphragm, which may then spill into the circulation. The production of reactive oxygen species within working respiratory muscles increases in response to these strenuous diaphragmatic contractions. At the same time, diaphragmatic nitric oxide (NO) production declines significantly, despite a time-dependent increase in NO synthase isoform protein expression. The increase in adhesion molecule expression and infiltration of granulocytes and macrophages that follows may contribute to the contraction-induced diaphragm injury. Enhanced generation of reactive oxygen species, oxidative stress augmentation, reduced NO production, and glycogen depletion are potential stimuli for the cytokine induction that is secondary to strenuous diaphragmatic contractions. This production of cytokines within the diaphragm may contribute to the diaphragmatic muscle fiber injury that occurs with strenuous contractions or to the expected repair process. TNF-alpha is a cytokine that compromises diaphragmatic contractility and may contribute to muscle wasting. IL-6 is a cytokine that may have beneficial systemic effects by mobilizing glucose from the liver and free fatty acids from the adipose tissue and providing them to the strenuously working respiratory muscles. Thus cytokine upregulation within the working diaphragm may be adaptive and maladaptive. PMID: 17185492 [PubMed - indexed for MEDLINE] 3096. Eur J Vasc Endovasc Surg. 2007 Feb;33(2):223-33. Epub 2006 Dec 20. Obesity and thrombosis. Darvall KA(1), Sam RC, Silverman SH, Bradbury AW, Adam DJ. Author information: (1)Department of Vascular Surgery, City Hospital, Birmingham, UK. katydarvall@btinternet.com OBJECTIVES: To describe the pathophysiological mechanisms by which obesity increases the propensity to thrombosis, the leading cause of death in the Western World, with particular emphasis on the role of inflammation, oxidative stress, dyslipidaemia, insulin resistance and the coagulation cascade. DESIGN: Review article. MATERIALS AND METHODS: Medline (1966-2005) and Cochrane library review of literature examining the relationship between obesity and thrombosis. Search terms included obesity, overweight, body mass index, thrombosis, cardiovascular disease, venous thromboembolism, peripheral arterial disease, and coronary heart disease. RESULTS: Obesity is an important and growing public health issue that is estimated to affect more than half of the UK adult population. Obesity, in particular central (visceral) obesity, is associated with significant, and largely preventable, morbidity and mortality including an increased incidence and prevalence of arterial and venous thrombotic events. The various mechanisms by which obesity may cause thrombosis include: the actions of so-called adipocytokines from adipose tissue, e.g. leptin and adiponectin; increased activity of the coagulation cascade and decreased activity of the fibrinolytic cascade; increased inflammation; increased oxidative stress and endothelial dysfunction; and disturbances of lipids and glucose tolerance in association with the metabolic syndrome. CONCLUSIONS: Obesity appears to be associated with thrombosis via several mechanisms. These pro-thrombotic factors are all improved by weight loss. PMID: 17185009 [PubMed - indexed for MEDLINE] 3097. Clin Exp Pharmacol Physiol. 2006 Dec;33(12):1265-8. Differential control of cardiac and sympathetic vasomotor activity from the dorsomedial hypothalamus. Horiuchi J(1), McDowall LM, Dampney RA. Author information: (1)Discipline of Physiology and Institute for Biomedical Research, The University of Sydney, Sydney, New South Wales, Australia. joujih@physiol.usyd.edu.au 1. The dorsomedial hypothalamus (DMH) plays a crucial role in mediating the cardiovascular responses to different stressors, including acute psychological stress and cold stress. Activation of neurons in the DMH evokes increases in arterial pressure and in the activity of sympathetic nerves innervating the heart, blood vessels and brown adipose tissue. The descending pathways from the DMH to the spinal sympathetic outflow include synapses with neurons in medullary nuclei and possibly other brain stem regions. 2. Recent studies from our and other laboratories have indicated that neurons in the rostral ventrolateral medulla (RVLM) and in the region of the raphe pallidus (RP) in the medulla are important components of the descending pathways that mediate the cardiovascular response to activation of the DMH. Neurons in the RP primarily mediate the sympathetic cardiac components of the DMH-evoked response, whereas the RVLM neurons primarily mediate the sympathetic vasomotor component. 3. Activation of DMH neurons not only increases heart rate and sympathetic vasomotor activity, but also resets the baroreceptor reflex such that it remains effective, without any decrease in sensitivity, over a higher operating range of arterial pressure. 4. Activation of 5-hydroxytryptamine 5-HT(1A) receptors in the medulla oblongata leads to a selective suppression of cardiac and sympathetic vasomotor components of the DMH-evoked response, but does not affect sympathetic reflex responses evoked from baroreceptors or chemoreceptors. Thus, central 5-HT(1A) receptors modulate cardiovascular responses evoked from the DMH in a highly potent but selective fashion. PMID: 17184513 [PubMed - indexed for MEDLINE] 3098. Proc Nutr Soc. 2006 Nov;65(4):385-92. Body fat measurements in children as predictors for the metabolic syndrome: focus on waist circumference. McCarthy HD(1). Author information: (1)Institute for Health Research & Policy, London Metropolitan University, Holloway Road, London N7 8DB, UK. d.mccarthy@londonmet.ac.uk The global epidemic of obesity in children will see a rise in the number of cases of metabolic syndrome, which is a clustering of CVD risk factors, including atherogenic levels of blood lipids, hyperinsulinaemia and raised blood pressure. Rather than excess general fatness (assessed by BMI), more specifically it is excess abdominal fatness, quantified by waist circumference measurement, which is a better measure of risk for these metabolic abnormalities in children of all ages. Insulin resistance, a consequence of excess visceral fat, is understood to be the driving force underpinning the metabolic syndrome. Consequently, assessment of abdominal fatness in children is proving to be more clinically useful. Waist circumference centile charts have now been developed for the UK and other paediatric populations to assist in this process. Furthermore, studies in the UK and elsewhere have shown that abdominal fatness has increased in infants, children and adolescents to a greater extent than overall fatness over the past 10-20 years, suggesting that obesity prevalence may be underestimated when based entirely on BMI. Additionally, ethnic differences in fat distribution have been demonstrated in children, with those from south Asian backgrounds having a greater abdominal distribution compared with Caucasian children and consequently having a much greater risk for type 2 diabetes. The information that can be provided by waist circumference measurement in children, as in adults, together with the recent changes in body fat distribution should provide the impetus for its measurement to be standardised and routinely taken in clinical and epidemiological settings. PMID: 17181905 [PubMed - indexed for MEDLINE] 3099. Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Rask-Madsen C(1), King GL. Author information: (1)Joslin Diabetes Center, Harvard Medical School, Boston, MA 02120, USA. Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed. PMID: 17179929 [PubMed - indexed for MEDLINE] 3100. Arch Physiol Biochem. 2006 Oct-Dec;112(4-5):254-9. Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. Christiaens V(1), Lijnen HR. Author information: (1)Center for Molecular and Vascular Biology, KULeuven, Leuven, Belgium. Obesity is a common disorder and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity; the role of specific members of these families, however, remains to be determined. PMID: 17178599 [PubMed - indexed for MEDLINE] 3101. J Dtsch Dermatol Ges. 2006 Dec;4(12):1037-44. Calciphylaxis: no therapeutic concepts for a poorly understood syndrome? [Article in English, German] Meissner M(1), Gille J, Kaufmann R. Author information: (1)Dept. of Dermatology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. meissner.markus@gmx.de Comment in J Dtsch Dermatol Ges. 2007 May;5(5):435; author reply 435. Calciphylaxis is a very uncommon and severe disease which mainly appears in patients with chronic renal insufficiency. It presents with ischemia and necrosis of the skin, subcutaneous adipose tissue, muscles and rarely viscera. The pathogenetic mechanisms inducing calciphylaxis are for the most part unknown. The mortality rate of 80% in the first year is very high. Patients experience marked pain, recurrent infections and the constant risk of secondary sepsis. Even multidisciplinary therapeutic strategies are limited, although there are recent case reports providing promising new therapeutic options including sodium thiosulfate and cinacalcet. This review summarizes the important aspects of diagnosis, pathogenesis, prevention and the possible therapeutic strategies of this intriguing, rare and often fatal disease. PMID: 17176411 [PubMed - indexed for MEDLINE] 3102. Expert Rev Cardiovasc Ther. 2006 Nov;4(6):871-95. Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients? Bays H(1), Blonde L, Rosenson R. Author information: (1)L-MARC Research Center, Medical Director/President, 3288 Illinois Avenue, Louisville, KY 40213, USA. hbaysmd@aol.com An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction ('sick fat'), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-gamma agonists increase the recruitment, proliferation and differentiation of preadipocytes ('healthy fat') and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced 'cross-talk' with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD. PMID: 17173503 [PubMed - indexed for MEDLINE] 3103. Magnes Res. 2006 Sep;19(3):180-9. Update on the relationship between magnesium and exercise. Nielsen FH(1), Lukaski HC. Author information: (1)U.S. Department ofAgriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA. fnielsen@gfhnrc.ars.usda.gov Magnesium is involved in numerous processes that affect muscle function including oxygen uptake, energy production and electrolyte balance. Thus, the relationship between magnesium status and exercise has received significant research attention. This research has shown that exercise induces a redistribution of magnesium in the body to accommodate metabolic needs. There is evidence that marginal magnesium deficiency impairs exercise performance and amplifies the negative consequences of strenuous exercise (e.g., oxidative stress). Strenuous exercise apparently increases urinary and sweat losses that may increase magnesium requirements by 10-20%. Based on dietary surveys and recent human experiments, a magnesium intake less than 260 mg/day for male and 220 mg/day for female athletes may result in a magnesium-deficient status. Recent surveys also indicate that a significant number of individuals routinely have magnesium intakes that may result in a deficient status. Athletes participating in sports requiring weight control (e.g., wrestling, gymnastics) are apparently especially vulnerable to an inadequate magnesium status. Magnesium supplementation or increased dietary intake of magnesium will have beneficial effects on exercise performance in magnesium-deficient individuals. Magnesium supplementation of physically active individuals with adequate magnesium status has not been shown to enhance physical performance. An activity-linked RNI or RDA based on long-term balance data from well-controlled human experiments should be determined so that physically active individuals can ascertain whether they have a magnesium intake that may affect their performance or enhance their risk to adverse health consequences (e.g., immunosuppression, oxidative damage, arrhythmias). PMID: 17172008 [PubMed - indexed for MEDLINE] 3104. Curr Atheroscler Rep. 2007 Jan;9(1):72-7. PPAR delta agonists and metabolic diseases. Kang K, Hatano B, Lee CH. Peroxisome proliferator-activated receptors (PPARs) are the key transcription factors regulating lipid metabolism and energy homeostasis. PPARalpha and PPARgamma are known therapeutic targets for hypertriglyceridemia and type 2 diabetes, respectively. The physiologic function of the third member, PPARdelta, has been difficult to define due to its broad tissue distribution. Through the creation of transgenic mouse models and identification of high-affinity synthetic ligands, the diverse activities of PPARdelta in several metabolically active tissues, including skeletal muscle, adipose tissue, liver, and macrophages, have recently been revealed. These metabolic activities of PPARdelta implicate the potential use of PPARdelta agonists to treat metabolic diseases, including atherosclerosis and insulin resistance. PMID: 17169250 [PubMed - indexed for MEDLINE] 3105. Nature. 2006 Dec 14;444(7121):881-7. Abdominal obesity and metabolic syndrome. Després JP(1), Lemieux I. Author information: (1)Québec Heart Institute, Hôpital Laval Research Centre, 2725 chemin Sainte-Foy, Pavilion Marguerite-D'Youville, 4th Floor, Quebec City, QC G1V 4G5, Canada. jean-pierre.despres@crhl.ulaval.ca Metabolic syndrome is associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Proposed criteria for identifying patients with metabolic syndrome have contributed greatly to preventive medicine, but the value of metabolic syndrome as a scientific concept remains controversial. The presence of metabolic syndrome alone cannot predict global cardiovascular disease risk. But abdominal obesity - the most prevalent manifestation of metabolic syndrome - is a marker of 'dysfunctional adipose tissue', and is of central importance in clinical diagnosis. Better risk assessment algorithms are needed to quantify diabetes and cardiovascular disease risk on a global scale. PMID: 17167477 [PubMed - indexed for MEDLINE] 3106. Nature. 2006 Dec 14;444(7121):875-80. Mechanisms linking obesity with cardiovascular disease. Van Gaal LF(1), Mertens IL, De Block CE. Author information: (1)University of Antwerp, Faculty of Medicine, Department of Diabetology, Metabolism and Clinical Nutrition, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. luc.van.gaal@uza.be Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance - the core feature of type 2 diabetes - as well as alterations in lipids, blood pressure, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health. PMID: 17167476 [PubMed - indexed for MEDLINE] 3107. Nature. 2006 Dec 14;444(7121):860-7. Inflammation and metabolic disorders. Hotamisligil GS(1). Author information: (1)Department of Genetics & Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA. ghotamis@hsph.harvard.edu Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare. PMID: 17167474 [PubMed - indexed for MEDLINE] 3108. Nature. 2006 Dec 14;444(7121):847-53. Adipocytes as regulators of energy balance and glucose homeostasis. Rosen ED(1), Spiegelman BM. Author information: (1)Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Centre, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions. PMCID: PMC3212857 PMID: 17167472 [PubMed - indexed for MEDLINE] 3109. Nature. 2006 Dec 14;444(7121):840-6. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Kahn SE(1), Hull RL, Utzschneider KM. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, 1660 South Columbian Way, Seattle, Washington 98108, USA. skahn@u.washington.edu Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention. PMID: 17167471 [PubMed - indexed for MEDLINE] 3110. BMC Pediatr. 2006 Dec 13;6:33. The muscle--fat duel or why obese children are taller? Ralt D(1). Author information: (1)Izun & Tmura, Integrative Health Inst, 6 Nezach Israel st, Tel Aviv, 64352, Israel. Izun.Tmura@gmail.com BACKGROUND: Obesity the epidemic of our times appears to be a problem that is easy to resolve: just eat less and move more. However, this very common condition has turned out to be extremely troublesome, and in some cases even irreversible. METHODS: The interplay between less muscle and more fat tissue is discussed from physiological perspectives with an emphasis on the early years of childhood. RESULTS: It is suggested that the coordinated muscle-fat interactions lead to a fluctuating exchange economy rate. This bodily economic decision, slides between thrift (more fat) and prodigal (more muscle) strategies. The thrift strategy results not only in obesity and less physical activity but also in other maladies which the body is unable to manage. What leads to obesity (less muscle, more fat) might be very difficult to reverse at adulthood, prevention at childhood is thus recommended. CONCLUSION: Early recognition of the ailment (low muscle mass) is crucial. Based on studies demonstrating a 'rivalry' between muscle build-up and height growth at childhood, it is postulated that among the both taller and more obese children the percentage of children with lower muscle mass will be higher. A special, body/muscle-building gymnastics program for children is suggested as a potential early intervention to prevent the ill progress of obesity. PMCID: PMC1713231 PMID: 17166286 [PubMed - indexed for MEDLINE] 3111. Clin Liver Dis. 2006 Nov;10(4):793-819. Role of obesity, insulin resistance, and steatosis in hepatitis C virus infection. Puri P(1), Sanyal AJ. Author information: (1)Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Health System, 1200 East Broad Street, Richmond, VA 23298, USA. Hepatitis C, nonalcoholic fatty liver characterized by hepatic steatosis, and obesity inflict significant health and economic burdens on the Western world. Insulin resistance is the key player in these disease processes. Complex interplay between these conditions results in the ultimate phenotype of liver disease. This article focuses on the current understanding of host and viral interactions as well as on consequent clinical implications. PMID: 17164118 [PubMed - indexed for MEDLINE] 3112. Clin Sci (Lond). 2007 Jan;112(2):93-111. Diet, obesity and diabetes: a current update. Walker CG(1), Zariwala MG, Holness MJ, Sugden MC. Author information: (1)Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary's Hospital, University of London, UK. The prevalence of obesity has been increasing at a rapid rate over the last few decades. Although the primary defect can be attributed to an imbalance of energy intake over energy expenditure, the regulation of energy balance is now recognized to be complex. Adipose-tissue factors play a central role in the control of energy balance and whole-body fuel homoeostasis. The regulation of adipose-tissue function, in particular its secretion of adipokines, is impaired by increases in adipose mass associated with obesity, and with the development of insulin resistance and Type 2 diabetes. This review analyses adipose-regulated energy input and expenditure, together with the impact of dietary macronutrient composition on energy balance in relation to susceptibility to the development of obesity and Type 2 diabetes, and how these metabolic conditions may be exacerbated by the consequences of abnormal adipose function. By gaining a greater understanding of how energy balance is controlled in normal, and in obese and diabetic states, a more practical approach can be employed to prevent and better treat obesity and metabolic disorders. PMID: 17155931 [PubMed - indexed for MEDLINE] 3113. Ann N Y Acad Sci. 2006 Nov;1084:89-117. Inflammatory process in type 2 diabetes: The role of cytokines. Alexandraki K(1), Piperi C, Kalofoutis C, Singh J, Alaveras A, Kalofoutis A. Author information: (1)Laboratory of Biological Chemistry, University of Athens Medical School, M. Asias 75, Goudi 11527, Athens, Greece. Population-based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a "common soil" between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic beta cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin-1beta (IL-1beta), with an action similar to the one present in type 1 diabetes, tumor necrosis factor-alpha (TNF-alpha), and IL-6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein-1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune system's unbalance. PMID: 17151295 [PubMed - indexed for MEDLINE] 3114. Ann N Y Acad Sci. 2006 Nov;1084:30-48. Inflammation in metabolic syndrome and type 2 diabetes: Impact of dietary glucose. Kempf K(1), Rose B, Herder C, Kleophas U, Martin S, Kolb H. Author information: (1)German Diabetes Clinic, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. kerstin.kempf@ddz.uni-duesseldorf.de Chronic overnutrition combined with a lack of exercise is the main cause for the rapidly increasing prevalence of overweight and obesity. It seems accepted that adipositis (macrophage infiltration and inflammation of adipose tissue in obesity) and systemic low grade inflammation affect the pathogenesis of the metabolic syndrome or type 2 diabetes mellitus (T2DM). Therefore, modern weight reduction programs additionally focus on strategies to attenuate the inflammation state. Exercise is one major factor, which contributes to the reduction of both the incidence of T2DM and inflammation, and the immunomodulatory effects of exercise are supported by similarly beneficial effects of dietary changes. In this context, glucose is the most extensively studied nutrient and current investigations focus on postprandial glucose-induced inflammation, one possible reason why hyperglycemia is detrimental. Indeed, glucose may modulate the mRNA expression and serum concentrations of immune parameters but these alterations rapidly normalize in normoglycemic subjects. In case of an impaired metabolic state, however, postprandial hyperglycemia increases magnitude and duration of systemic inflammatory responses, which probably promotes the development of T2DM and of cardiovascular disease. PMID: 17151291 [PubMed - indexed for MEDLINE] 3115. Vascular. 2006 Nov-Dec;14(6):338-42. Development of a tissue-engineered bypass graft seeded with stem cells. DiMuzio P(1), Fischer L, McIlhenny S, DiMatteo C, Golesorhki N, Grabo D, Tarola N, Mericli A, Shapiro I, Tulenko T. Author information: (1)Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. The gold standard conduit for bypass of diseased small-diameter arteries remains autologous vascular tissue. In the absence of such tissue, patients are offered bypass with prosthetic material, with far less durable results. Vascular tissue engineering, the creation of a vascular conduit by seeding a tubular scaffold with various cells, may offer an alternative approach to this difficult situation. Herein we review some of the significant challenges that remain in designing an ideal vascular conduit and outline potential solutions offered by a graft created by seeding natural vascular tissue (decellularized vein allograft) with readily available autologous cells (adipose-derived stem cells). PMID: 17150154 [PubMed - indexed for MEDLINE] 3116. Histol Histopathol. 2007 Feb;22(2):199-210. Leptin secretion by white adipose tissue and gastric mucosa. Cammisotto PG(1), Bendayan M. Author information: (1)Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Canada. Leptin is a hormone that plays a central role in the regulation of food intake and energy expenditure. Originally discovered in mature white adipocytes, it was subsequently isolated from the gastric mucosa. This tissue contains a large number of epithelial endocrine and exocrine cells secreting leptin in the blood stream and in the gastric lumen, respectively. Light and electron microscopy have shown that adipocytes and gastric epithelial cells contain leptin along their rough endoplasmic reticulum-Golgi-granules secretory pathway. Both tissues synthesize a soluble form of the leptin receptor that is secreted bound to leptin in the blood and into the gastric juice. This soluble receptor protect leptin and enhances its half-life. Despite the similarities in the mechanisms of leptin secretion by adipocytes and gastric epithelial cells, they are in fact radically different. In gastric cells leptin follows a rapid regulated secretion pathway whereas adipocytes secrete leptin in a constitutive slow fashion. These differences can be explained by the specific roles play by leptin originating from these two different tissues. Gastric leptin is involved in the short-term regulation of digestion, including delay of gastric emptying, absorption of nutrients by the intestinal wall and secretion of gastric, intestinal and pancreatic hormones. On the other hand, leptin secreted by white adipocytes acts primarily on the hypothalamus for the long-term regulation of food intake. Therefore, the coordination of adipose and gastric leptins ensures the proper management of food processing and energy storage. PMID: 17149693 [PubMed - indexed for MEDLINE] 3117. Ann N Y Acad Sci. 2006 Nov;1083:306-18. Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors. Yumuk VD(1). Author information: (1)Istanbul University Cerrahpasa Medical Faculty, Department of Medicine, Division of Endocrinology and Metabolism, Istanbul 34303, Turkey. volkanyumuk@superonline.com The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis. PMID: 17148746 [PubMed - indexed for MEDLINE] 3118. Ann N Y Acad Sci. 2006 Nov;1083:270-305. The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome. Kyrou I(1), Valsamakis G, Tsigos C. Author information: (1)Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital, Athens University Medical School, Athens 115 28, Greece. The endogenous cannabinoid system is a novel, remarkably elaborate physiological signaling system, comprising the recently identified endogenous cannabinoid ligands, their corresponding selective receptors, and the machinery of proteins and enzymes that is involved in their biosynthesis, release, transport, and degradation. This system extends widely in both the central nervous system (CNS) and the periphery and exhibits a variety of actions implicated in vital functions (e.g., behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic). Particular interest has been focused on the apparent participation of endocannabinoids in metabolic homeostasis by modulating the activity of CNS circuits that control food intake and energy expenditure, the neuroendocrine response of the stress system, and the metabolic functions of crucial peripheral tissues, such as the adipose tissue, the gastrointestinal tract, the liver, and the skeletal muscles. These effects are predominantly CB(1) receptor mediated and, thus, selective antagonists of this receptor subtype are being vigorously investigated as potential therapeutic agents for the treatment of various metabolic derangements (e.g., obesity, insulin resistance, dyslipidemia, and metabolic syndrome). The first selective CB(1) receptor antagonist, rimonabant, has already successfully completed phase III clinical trials as adjunctive obesity treatment, with significant improvements in several associated metabolic and cardiovascular risk factors that led to the recent approval of its clinical use by the Food and Drug Administration. PMID: 17148745 [PubMed - indexed for MEDLINE] 3119. Ann N Y Acad Sci. 2006 Nov;1083:252-69. Serotonin and norepinephrine reuptake inhibition and eating behavior. Hainer V(1), Kabrnova K, Aldhoon B, Kunesova M, Wagenknecht M. Author information: (1)Institute of Endocrinology, Narodni 8, 116 94 Prague 1, Czech Republic. vhainer@endo.cz Brain neurotransmitters, serotonin and norepinephrine, play an important role in the central nervous control of energy balance and are involved in symptomatology related to both obesity and depression. Therefore both serotonin and norepinephrine neural pathways have been paid a special attention as targets for the antiobesity drugs, antidepressants, and drugs used in the treatment of eating disorders. Selective serotonin reuptake inhibitors (SSRI) have been used in the treatment of depression and eating disorders but have failed to achieve sustained weight loss in the treatment of obesity. Sibutramine, a serotonin and norepinephrine reuptake inhibitor, which induces satiety and prevents decline in metabolic rate associated with a hypocaloric diet, is currently the sole centrally acting drug indicated for the long-term treatment of obesity. Depression, dietary disinhibition (evaluated by the Eating Inventory [EI]), and stress are associated with the accumulation of abdominal fat and the development of metabolic syndrome and related diseases. Subjects with abdominal obesity demonstrate neuroendocrine abnormalities which result in disturbances in hypothalamo-pituitary-adrenal (HPA) function. Treatment with SSRI might interrupt the vicious circle which leads to endocrine abnormalities and the accumulation of abdominal fat. Obesity treatment with sibutramine results, not only in significant weight loss, but also in reduction of abdominal fat and in the improvement of health risks associated with metabolic syndrome (lipid profile, blood glucose, insulin, HbA1c, and uric acid), as well as in the decline in disinhibition score of the EI. In a 1-year sibutramine trial, only a decrease in the disinhibition score remained a significant correlate of weight loss among the psychobehavioral and nutritional factors which were taken into account. PMID: 17148744 [PubMed - indexed for MEDLINE] 3120. Ann N Y Acad Sci. 2006 Nov;1083:165-84. Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease. Walker BR(1), Andrew R. Author information: (1)Endocrinology Unit, Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom. B.Walker@ed.ac.uk Activation of intracellular glucocorticoid receptors is determined not only by the plasma concentrations of cortisol, under the influence of the hypothalamic-pituitary-adrenal (HPA) axis, but also by 11HSD enzymes within the target cell which interconvert cortisol with its inert metabolite cortisone. Data from cells in culture, isolated tissues, and transgenic mouse models have established that 11HSD type 1 regenerates glucocorticoids and amplifies glucocorticoid receptor activation. In humans, the rate of cortisol regeneration in peripheral tissues is of similar magnitude to adrenal secretion of cortisol at most times of day, and occurs principally in the splanchnic circulation. Approximately two-thirds of the splanchnic activity appears to reside in visceral adipose tissue, sufficient to allow visceral adipose tissue to "deliver" cortisol to the liver via the portal vein. In obesity, 11HSD1 activity in subcutaneous adipose tissue is increased, putatively explaining the link between obesity and other features of the metabolic syndrome. The regulation of 11HSD1, and the basis for its upregulation in obesity, are now being explored. Against this background, inhibition of 11HSD1 has become a major therapeutic target in metabolic syndrome. Preclinical results with novel selective 11HSD1 inhibitors are encouraging, and clinical proof of principle has been achieved with the nonselective inhibitor carbenoxolone. Although the parallels between metabolic syndrome and Cushing's syndrome were originally drawn with reference to patients with elevated plasma cortisol concentrations, it now appears that manipulating tissue concentrations of cortisol will allow the subtle level of control required for long-term therapy to reduce the risks of cardiovascular disease. PMID: 17148739 [PubMed - indexed for MEDLINE] 3121. Ann N Y Acad Sci. 2006 Nov;1083:153-64. A brief update of glucocorticoid receptor variants and obesity risk. Rosmond R(1), Radulovic V, Holm G. Author information: (1)The Cardiovascular Institute, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. rolandrosmond@hotmail.com Excess body fat, obesity, is one of the most common disorders in clinical practice. Obese individuals are at increased risk for physical ailments, such as type 2 diabetes, coronary heart disease, hypertension, and several types of cancer. The location of the body fat is a major determinant of the degree of excess morbidity and mortality due to obesity. More specifically, the amount of subcutaneous truncal or abdominal fat, and the amount of visceral fat located in the abdominal cavity independently predicts obesity-related adverse health outcomes. The obesity gene map shows putative loci on all chromosomes except Y. More than 300 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. These genes can be divided into two broad categories: (a) rare gene variants that have a strong influence, and (b) common gene variants that have a weaker influence on obesity phenotypes. Studies in humans have suggested a positive association between obesity, hypertension, and insulin resistance, with alleles at the glucocorticoid receptor gene. In this article, we will estimate the risk by which such gene polymorphism mediates a role in obesity. PMID: 17148738 [PubMed - indexed for MEDLINE] 3122. Ann N Y Acad Sci. 2006 Nov;1083:77-110. Stress, visceral obesity, and metabolic complications. Kyrou I(1), Chrousos GP, Tsigos C. Author information: (1)Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital, Athens University Medical School, Athens, 115 28, Greece. Stress is a state of threatened homeostasis or disharmony caused by intrinsic or extrinsic adverse forces and is counteracted by an intricate repertoire of physiologic and behavioral responses that aim to reestablish the challenged body equilibrium. The adaptive stress response depends upon an elaborate neuroendocrine, cellular, and molecular infrastructure, the stress system. Crucial functions of the stress system response are mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the central and peripheral components of the autonomic nervous system (ANS). The integrity of the HPA axis and the ANS and their precise interactions with other CNS components are essential for a successful response to the various stressors. Chronic stress represents a prolonged threat to homeostasis by persistent or frequently repeated stressors and may lead to manifestations that characterize a wide range of diseases and syndromes. Such states progressively lead to a deleterious overload with complications caused by both the persistent stressor and the detrimental prolongation of the adaptive response. The metabolic syndrome can be described as a state of deranged metabolic homeostasis characterized by the combination of central obesity, insulin resistance, dyslipidemia, and hypertension. The incidence of both obesity and the metabolic syndrome in modern Western societies has taken epidemic proportions over the past decades and often correlates with indices of stress in the affected populations. Stress, primarily through hyperactivation of the HPA axis, appears to contribute to the accumulation of fat tissue, and vice versa, obesity itself seems to constitute a chronic stressful state and may cause HPA axis dysfunction. In addition, the description of obesity as a systemic low grade inflammatory condition that contributes to the derangement of the metabolic equilibrium implies that the proinflammatory cytokines which are secreted by the adipocytes hold a potentially important pathogenetic role. In this article we describe the physiology of the stress system response, with emphasis on metabolism, and review the recent data that implicate several neuroendocrine and inflammatory mechanisms mobilized during chronic stress in the development of the metabolic complications that characterize central obesity and the metabolic syndrome. PMID: 17148735 [PubMed - indexed for MEDLINE] 3123. J Clin Endocrinol Metab. 2007 Feb;92(2):386-95. Epub 2006 Dec 5. Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism. Sharma AM(1), Staels B. Author information: (1)Canada Research Chair for Cardiovascular Obesity Research and Management, McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. sharma@cardio.on.ca CONTEXT: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). EVIDENCE ACQUISITION: Articles on the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990-2006). EVIDENCE SYNTHESIS: Articles were assessed to provide a comprehensive overview of how PPARgamma-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. CONCLUSIONS: PPARgamma is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARgamma activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFalpha, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARgamma also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARgamma activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARgamma-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis. PMID: 17148564 [PubMed - indexed for MEDLINE] 3124. Transl Res. 2006 Nov;148(5):223-48. Differential gene expression identifies subgroups of ovarian carcinoma. Skubitz AP(1), Pambuccian SE, Argenta PA, Skubitz KM. Author information: (1)Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minn 55455, USA. skubi002@umn.edu Papillary serous ovarian carcinoma, the most common type of ovarian cancer, displays different biological behavior in different patients. This heterogeneity cannot be recognized by light microscopy. In this study, gene expression in 29 papillary serous ovarian carcinoma samples (21 invasive tumors and 8 borderline tumors), and 17 nonmalignant tissue types comprising 512 samples, was determined using Affymetrix U_133 oligonucleotide microarrays (Affymetrix, Inc., Santa Clara, Calif) representing approximately 40,000 known genes and expression sequence tags (ESTs). Differences in gene expression were quantified as the fold change in gene expression between the various sets of samples. A set of genes was identified that was over-expressed in the invasive ovarian carcinoma samples compared with the normal ovary samples. Principle component analysis of the set of invasive ovarian carcinomas using this set of genes revealed the existence of 2 major subgroups among the invasive ovarian carcinomas. A series of principle component analyses of the ovarian carcinomas using different gene sets composed of genes involved in different metabolic pathways also revealed the same 2 major subgroups of the invasive ovarian carcinomas. Review of the pathology by a single pathologist in a blinded manner suggested that these 2 subgroups differed in pathologic grade. Genes differentially expressed between the 2 ovarian carcinoma subsets were identified. Examination of gene expression in each ovarian carcinoma subset compared with that in 17 different normal tissue types (512 samples) revealed genes specifically over-expressed in ovarian carcinoma compared with these normal tissues. It is concluded that gene expression patterns may be useful in helping to further classify subtypes of papillary serous ovarian carcinoma that may have clinical significance. In addition, the genes identified as over-expressed in each set of serous ovarian carcinoma compared with normal tissues may represent potential biomarkers and/or targets for therapy. PMID: 17145569 [PubMed - indexed for MEDLINE] 3125. Essays Biochem. 2006;42:89-103. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Frayn KN(1), Arner P, Yki-Järvinen H. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. keith.frayn@oxlip.ox.ac.uk Fat is the largest energy reserve in mammals. Most tissues are involved in fatty acid metabolism, but three are quantitatively more important than others: adipose tissue, skeletal muscle and liver. Each of these tissues has a store of triacylglycerol that can be hydrolysed (mobilized) in a regulated way to release fatty acids. In the case of adipose tissue, these fatty acids may be released into the circulation for delivery to other tissues, whereas in muscle they are a substrate for oxidation and in liver they are a substrate for re-esterification within the endoplasmic reticulum to make triacylglycerol that will be secreted as very-low-density lipoprotein. These pathways are regulated, most clearly in the case of adipose tissue. Adipose tissue fat storage is stimulated, and fat mobilization suppressed, by insulin, leading to a drive to store energy in the fed state. Muscle fatty acid metabolism is more sensitive to physical activity, during which fatty acid utilization from extracellular and intracellular sources may increase enormously. The uptake of fat by the liver seems to depend mainly upon delivery in the plasma, but the secretion of very-low-density lipoprotein triacylglycerol is suppressed by insulin. There is clearly cooperation amongst the tissues, so that, for instance, adipose tissue fat mobilization increases to meet the demands of skeletal muscle during exercise. When triacylglycerol accumulates excessively in skeletal muscle and liver, sometimes called ectopic fat deposition, then the condition of insulin resistance arises. This may reflect a lack of exercise and an excess of fat intake. PMID: 17144882 [PubMed - indexed for MEDLINE] 3126. Essays Biochem. 2006;42:47-59. Lipid metabolism, exercise and insulin action. Bonen A(1), Dohm GL, van Loon LJ. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1. abonen@uoguelph.ca Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation. PMID: 17144879 [PubMed - indexed for MEDLINE] 3127. Essays Biochem. 2006;42:13-29. Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise. Joseph AM(1), Pilegaard H, Litvintsev A, Leick L, Hood DA. Author information: (1)Department of Biology, York University, Toronto, Ontario, Canada, M3J 1P3. Every time a bout of exercise is performed, a change in gene expression occurs within the contracting muscle. Over the course of many repeated bouts of exercise (i.e. training), the cumulative effects of these alterations lead to a change in muscle phenotype. One of the most prominent of these adaptations is an increase in mitochondrial content, which confers a greater resistance to muscle fatigue. This essay reviews current knowledge on the regulation of exercise-induced mitochondrial biogenesis at the molecular level. The major steps involved include, (i) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the coactivator peroxisome-proliferator-activated receptor g coactivator-1, (ii) control of mitochondrial DNA gene expression by the transcription factor Tfam, (iii) mitochondrial fission and fusion mechanisms, and (iv) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. It is now known that exercise can modify the rates of several of these steps, leading to mitochondrial biogenesis. An understanding of how exercise can produce this effect could help us decide whether exercise is beneficial for patients suffering from mitochondrial disorders, as well as a variety of metabolic diseases. PMID: 17144877 [PubMed - indexed for MEDLINE] 3128. J Soc Biol. 2006;200(1):93-7. [Obesity, diabetes and insulin resistance. Alterations of insulin signalling]. [Article in French] Le Marchand-Brustel Y(1), Gual P, Aouadi M, Grémeaux T, Binétruy B, Bost F, Tanti JF. Author information: (1)INSERM, U568, Faculté de Mèdecine, Université de Nice Sophia Antipolis, Avenue de Valombrose, 06107 Nice 02, France. lemarcha@unice.fr Obesity is often associated with diabetes and insulin resistance. This review summarizes evidence obtained in our lab on the role of the serine phosphorylation of the insulin receptor substrate 1 in the down regulation of insulin signalling. The role of the ERK1 isoform in the development of adipose tissue and insulin sensitivity is also presented. PMID: 17144167 [PubMed - indexed for MEDLINE] 3129. J Soc Biol. 2006;200(1):83-91. [Fatty acid mobilization and their use in adipose tissue]. [Article in French] Mazzucotelli A(1), Langin D. Author information: (1)INSERM U586, Unité de recherche sur les obésités, Toulouse, F-31432 France. An excess of fat mass excess predisposes to multiple complications such as type 2 diabetes, cardiovascular diseases or cancer. A dysregulation of lipid metabolism contributes to the development of obesity and the metabolic syndrome. Recent data on lipid mobilization in adipose tissue have revealed a complex pathway involving a human specific hormonal control of lipolysis via the natriuretic peptides and a new triglyceride lipase, ATGL. Activation of fatty acid reesterification and oxidation can lead to an increase in fatty acid utilization. Targeting these key steps of lipid metabolism (adipose tissue lipolysis and fatty acid oxidation) constitutes a potential strategy for the treatment of obesity and associated metabolic disorders. PMID: 17144166 [PubMed - indexed for MEDLINE] 3130. J Soc Biol. 2006;200(1):67-76. [Physiological and pathophysiological features of the control of lipolysis and lipid mobilization by natriuretic peptides]. [Article in French] Moro C(1), Berlan M, Lafontan M. Author information: (1)Inserm, U586, Unité de Recherche sur les Obésités, F-31432 Toulouse. moro@cict.fr We have demonstrated a potent and specific lipolytic effect of natriuretic peptides (NP) in human and primates' fat cells. The lipolytic effect of NP is mediated through intracellular production of cGMP and activation of the cGMP-dependent kinase 1alpha. Local infusion of atrial-NP (ANP), directly within the subcutaneous adipose tissue through a microdialysis catheter, increases lipolysis and stimulates blood flow through its vasodilating effect in lean healthy men. This effect is blunted in overweight men and can be recovered by endurance training. Intravenous infusion of physiological doses of ANP induces lipid mobilization. Higher concentrations of ANP that are encountered during heart failure also stimulate lipid oxidation. ANP activates lipolysis and free fatty acids release from adipose tissue during endurance exercise. This effect is paradoxically amplified when exercise is performed under beta-blockade treatment, because of an enhanced cardiac release of ANP. No gender differences in ANP-induced lipid mobilization during exercise have been found. Heart failure is associated with high circulating levels of NP that could participate to the progression toward cachexia. On contrary, a negative correlation between NP levels and body mass index is found in obese persons. The molecular basis of this inverse correlation is not yet demonstrated from a functional standpoint. Further studies are needed to clearly define the pathophysiological role of NP in obesity and heart failure. PMID: 17144164 [PubMed - indexed for MEDLINE] 3131. J Soc Biol. 2006;200(1):37-43. [Adipose tissue secretory function: implication in metabolic and cardiovascular complications of obesity]. [Article in French] Guerre-Millo M(1). Author information: (1)Inserm, U755 Nutriomique, 75004 Paris, France. mguerre@bhdc.jussieu.fr The adipose tissue exerts a double function that is crucial for energy homeostasis. On the one hand, it is the only organ suited to stock triglycerides in highly specialized cells, the adipocytes. On the other hand, the adipose tissue produces biologically active molecules, collectively named "adipokines", which have been implicated in energy balance and glucose and lipid metabolism. Both adipocytes and cells of the stromal fraction participate in this function of secretion. The adipokines acts locally, in an autocrine or paracrine manner, and distantly (endocrine), on various targets, including muscles, the liver and the hypothalamus. Some adipokines, as TNFalpha and IL6, promote insulin resistance and inflammation, whereas others, as leptin and adiponectin, are required for energy and glucose homeostasis. In obesity, adipose cell hypertrophy and the recruitment of macrophages alter the secretory function and induce an inflammatory profile in the adipose tissue. Analyses of gene expression suggest that hypoxia is one of the factors favoring the attraction of the macrophages. The local and systemic consequences of interactions between macrophages and adipocytes are currently actively studied, to understand their potential implication in the metabolic and cardiovascular complications associated with obesity. PMID: 17144160 [PubMed - indexed for MEDLINE] 3132. J Soc Biol. 2006;200(1):7-16. [Feeding regulatory peptides: hopes and limits for the treatment of obesities]. [Article in French] Beck B(1). Author information: (1)INSERM U724 et UHP/Neurocal, Faculté de Médecine, 9, avenue de la Forêt de Haye BP 184, 54505 Vandoeuvre-lès-Nancy, France. Bernard.Beck@nancy.inserm.fr Excessive weight gain is directly related to a positive energy balance which is due to both a decreased physical activity and overeating. Obesity prevalence is increasing since thirty years and the treatment of obesities is particularly necessary to solve this public health and economical problem. The receptors of numerous hypothalamic neuropeptides are potential targets for such drug treatments. Hormones of the gastro-intestinal tract or produced by the adipose tissue directly interact with these central pathways to regulate feeding behavior. The use of leptin, an adipose tissue hormone that inhibits food intake, has not been conclusive because of the development of leptin resistance in obese subjects. Similar disappointing results have been obtained with antagonists of neuropeptide Y (NPY), one of the most potent orexigenic peptide. This was linked to the complexity and redundancy of the circuits involved in feeding regulation. Consequently, a multitherapy targeting several pathways simultaneously is probably the best option to cure obesity. Among these pathways, PYY 3-36 has been tested in man and some encouraging data have been obtained in animals with antagonists of some other orexigenic peptides such as orexins and melanin-concentrating hormone. A few gene therapy trials in the rat brain have restored interest for the leptin and NPY pathways. Their general use is however not planed in a next future. According to the type of obesity, these new treatments might be associated with either current (or almost current) drugs acting either on serotoninergic/catecholaminergic or cannabinoid pathways, or with surgery. Behavioral changes (food intake, exercise) and preventive actions during early life (in utero, young children) will remain for a while the best solutions to limit overweight development. The new treatments will help obese people to adhere to these behavioral changes by improving their efficiency to induce weight loss. PMID: 17144157 [PubMed - indexed for MEDLINE] 3133. Nat Clin Pract Endocrinol Metab. 2006 Dec;2(12):694-701. Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors. Abate N(1), Chandalia M, Di Paola R, Foster DW, Grundy SM, Trischitta V. Author information: (1)University of Texas Southwestern Medical Center, Dallas 75390-9169, USA. nicola.abate@utsouthwestern.edu Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its beta-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described. The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease. PMID: 17143316 [PubMed - indexed for MEDLINE] 3134. Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1655-63. Epub 2006 Dec 1. Adiponectin and cardiovascular disease: state of the art? Szmitko PE(1), Teoh H, Stewart DJ, Verma S. Author information: (1)Department of General Internal Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease. PMID: 17142348 [PubMed - indexed for MEDLINE] 3135. Dtsch Med Wochenschr. 2006 Dec;131 Suppl 8:S268-73. [Current laboratory parameters in the differential diagnosis of type 2 diabetes mellitus. Proinsulin, adiponectin and others]. [Article in German] Forst T(1), Pfützner A. Author information: (1)Institut für klinische Forschung und Entwicklung, Mainz, Mainz, Germany. thomasf@ikfe.de During the recent years increasing knowledge has been obtained in the understanding of the coincidence of type 2 diabetes and cardiovascular disease. Insulin resistance and beta cell failure were shown to have a direct impact in the pathogenesis of arteriosclerosis which goes far beyond the effects of elevated glucose levels. The use of additional laboratory parameters for the characterisation of patients with type 2 diabetes on a pathophysiological basis might improve treatment strategies and might help to reduce the cardiovascular risk in patients with type 2 diabetes. Intact proinsulin is secreted from the beta cell and increasing levels of intact proinsulin serve as an indicator of beta cell failure. In addition, increased levels of intact proinsulin were shown to predict insulin resistance with a specificity of 100 % and a sensitivity of about 50 %. On the other side, adiponectin, derived from the visceral adipose tissue, serves as a marker closely correlated to insulin sensitivity. Plasma adiponectin is a very sensitive marker of insulin resistance and might be used for the judgement of therapeutical interventions aimed to improve insulin sensitivity. In addition, both markers are predictive for the estimation of cardiovascular risk in patients with type 2 diabetes. Measurement of inflammation, by high sensitive CRP might add further information about the cardiovascular risk of a patient with type 2 diabetes. PMID: 17139585 [PubMed - indexed for MEDLINE] 3136. Dtsch Med Wochenschr. 2006 Dec;131 Suppl 8:S231-5. [Role of muscle and fat tissue in the pathogenesis of type 2 diabetes]. [Article in German] Blüher M(1), Stumvoll M. Author information: (1)Medizinische Klinik und Poliklinik III, Universität Leipzig, Leipzig, Germany. bluma@medizin.uni-leipzig.de In the last years type 2 diabetes has reached almost epidemic proportions. More than 170 million individuals are affected worldwide, about 6 million in Germany. In the pathogenesis of type 2 diabetes, insulin resistance in liver, fat and muscle as well as the inability of the pancreatic beta-cell to fully compensate for this insulin resistance are the central pathophysiological events. Both genetic and environmental factors, such as lack of physical exercise and hypercaloric nutrition play a major role in this process, although the precise mechanisms for type 2 diabetes development remain largely unknown. In the characterization of the role of liver, adipose tissue and skeletal muscle in the pathogenesis of type 2 diabetes, tissue specific knockout mouse models have challenged our concepts of glucose homeostasis. PMID: 17139576 [PubMed - indexed for MEDLINE] 3137. Cardiovasc Drugs Ther. 2006 Dec;20(6):441-4. Cardiac metabolism and mechanics are altered by genetic loss of lipoprotein triglyceride lipolysis. Noh HL(1), Yamashita H, Goldberg IJ. Author information: (1)Division of Preventive Medicine and Nutrition, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, NY 10032, USA. INTRODUCTION: Most circulating fatty acids are contained in lipoprotein triglycerides. For the heart to acquire these lipids, they must be broken down into free fatty acids via the enzyme lipoprotein lipase (LpL). Although it has long been known that hearts primarily use esterified fatty acids as fuel, different sources of fatty acids were thought to be interchangeable. MATERIALS AND METHODS: By creating mice with neonatal and acute LpL deletion we showed that lipoprotein-derived fatty acids could not be replaced by albumin-associated free fatty acids. Loss of cardiac LpL forces the heart to increase its uptake of glucose, reduce fatty acid oxidation, and eventually leads to cardiac dysfunction. In contrast, cardiomyocyte specific overexpression of an anchored form of LpL leads to excess lipid uptake, induction of fatty acid oxidation genes, and dilated cardiomyopathy. CONCLUSION: Increasing lipid secretion from the heart or redirecting lipids to adipose tissue can alleviate this lipotoxic situation. PMID: 17139480 [PubMed - indexed for MEDLINE] 3138. Rinsho Byori. 2006 Oct;54(10):1044-51. [Feeding-related disorders in medicine, with special reference to cancer anorexia-cachexia syndrome]. [Article in Japanese] Inui A(1). Author information: (1)Department of Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520. Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life. PMID: 17133993 [PubMed - indexed for MEDLINE] 3139. Pharmacol Rev. 2006 Dec;58(4):726-41. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Michalik L(1), Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W. Author information: (1)Center for Integrative Genomics, National Research Centre "Frontiers in Genetics," University of Lausanne, Lausanne, Switzerland. The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities. PMID: 17132851 [PubMed - indexed for MEDLINE] 3140. Nutr Rev. 2006 Nov;64(11):502-7. Effects of intended weight loss on morbidity and mortality: possible explanations of controversial results. Berentzen T(1), Sørensen TI. Author information: (1)Institute for Preventive Medicine, Copenhagen University Hospital, Centre for Health and Society, Copenhagen, Denmark. Long-term, population-based, observational studies have shown that intended weight loss does not always reduce the mortality associated with obesity. The effects of weight loss on mortality may be a balance between the effects of the loss of harmful abdominal and ectopic fat mass and the loss of beneficial peripheral subcutaneous fat mass and lean body mass. PMID: 17131946 [PubMed - indexed for MEDLINE] 3141. Rev Endocr Metab Disord. 2006 Sep;7(3):187-96. Adiponectin and leptin: potential tools in the differential diagnosis of pediatric diabetes? Huerta MG(1). Author information: (1)University of Florida College of Medicine, Box 100296, Gainesville, FL 32608, USA. mhuerta@peds.ufl.edu The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes. PMID: 17131205 [PubMed - indexed for MEDLINE] 3142. Int J Obes (Lond). 2007 May;31(5):731-42. Epub 2006 Nov 28. The entero-insular axis and adipose tissue-related factors in the prediction of weight gain in humans. Hivert MF(1), Langlois MF, Carpentier AC. Author information: (1)Division of Endocrinology, Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Québec, Canada. Obesity has now reached epidemic proportions. Epidemiological studies in the past decades have shown that adults gain weight and adiposity from the early twenties until their sixties. In the paediatric population, growing numbers of children and adolescents put on unhealthy weight. Many environmental, socio-economical and biological determinants that predispose to weight gain have been identified thus far. The aim of the present review is to summarize the current knowledge on the role of the circulating levels of adipokines and other entero-insular hormones and biological markers of obesity to predict weight gain in humans. The review focuses on relationship between hormonal and biochemical markers (insulin, insulin-like growth factors, gastrointestinal hormones, leptin, adiponectin, resistin, inflammatory proteins and cytokines) and weight gain in prospective studies. The complex relationships displayed by these hormonal factors with future weight gain in humans are critically reviewed and integrative models are proposed. Overall, most of the studies reported to date made adjustments for baseline body mass index but failed to consider dietary intake and physical activity as confounding factors. Outstanding questions are raised and new directions for future prospective studies are proposed in order to improve our understanding of the role of biological determinants of energy balance and development of obesity in humans. PMID: 17130851 [PubMed - indexed for MEDLINE] 3143. Otol Neurotol. 2006 Dec;27(8):1126-30. Preservation of conductive hearing in approaches to tumors of the jugular foramen. Gold SR(1), Kamerer DB Jr. Author information: (1)Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, North Carolina 28226, USA. sgold@carolina.rr.com OBJECTIVE: Surgical approaches to the jugular foramen, most often used for the resection of glomus jugulare tumors, may include removal of the external auditory canal wall and overclosure of the meatus, resulting in maximal conductive hearing loss. Modifications have been described that maintain hearing by preserving the canal wall at the price of decreased exposure and are, therefore, suitable only for small and favorably located tumors. Our technique for removal and then reconstruction of the canal wall with hydroxyapatite cement allows for complete anterior translocation of the facial nerve as far proximal as the geniculate ganglion, giving uncompromising exposure of even the most extensive tumors, with the potential for preservation of normal hearing. The purpose of this study was to describe and report our experience with this technique. STUDY DESIGN: : Retrospective review. SETTING: Private otology practice. PATIENTS: Between 2000 and 2005, seven patients between the ages of 34 and 77 years were identified who underwent procedures using this technique. INTERVENTION: Surgical management of jugular foramen tumors. MAIN OUTCOME MEASURES: Successful anatomical reconstruction of the external auditory canal and middle ear. Preoperative and postoperative audiograms are compared, and facial nerve function is reported. Complications are discussed. RESULTS: All seven patients had successful reconstruction of the external auditory canal. Complications were minor and did not require additional surgical intervention. Postoperative pure-tone average differed from the preoperative average by a mean of 7.5 dB. Facial nerve function ranged from House-Brackmann Grades I to III when checked at least 7 months after surgery. CONCLUSION: This study reveals that this technique of external auditory canal reconstruction using hydroxyapatite cement allows complete anterior translocation of the facial nerve, while safely and reliably preserving the potential for normal hearing, without any compromise in exposure of the jugular foramen in the setting of an infratemporal fossa approach. PMID: 17130802 [PubMed - indexed for MEDLINE] 3144. Diabetes. 2006 Dec;55 Suppl 2:S48-54. Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Ruderman NB(1), Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen BK, Kelly M. Author information: (1)Section of Endocrinology, Diabetes Unit, Boston Medical Center, 650 Albany St., X-820, Boston, MA 02118, USA. Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined. PMID: 17130644 [PubMed - indexed for MEDLINE] 3145. Diabetes. 2006 Dec;55 Suppl 2:S145-54. Brain adipocytokine action and metabolic regulation. Ahima RS(1), Qi Y, Singhal NS, Jackson MB, Scherer PE. Author information: (1)University of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 764 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases. PMID: 17130638 [PubMed - indexed for MEDLINE] 3146. Front Biosci. 2007 Jan 1;12:297-307. Molecular control of ovulation and luteinization in the primate follicle. Stouffer RL(1), Xu F, Duffy DM. Author information: (1)Division of Reproductive Sciences, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA. stouffri@ohsu.edu In recent years, significant progress was made, particularly through the use of the macaque monkey, in identifying three types of local factors that are induced by the midcycle LH surge and play a critical role in ovulation and/or luteinization of the primate follicle. The ovulatory gonadotropin surge increases prostaglandin (PTG, typically abbreviated PG) levels in follicles prior to rupture; although considerable attention has focused on LH stimulation of the "inducible" form of PG G/H synthase (PTGS2), other aspects of PG synthesis (notably a phospholipase A2, cPLA2, and a PGE synthase, PTGES) and metabolism (15-hydroxy PG dehydrogenase, HPGD) also appear LH-regulated and may control the timing of the PG rise in the ovulatory follicle. Local (intrafollicular) ablation and replacement of PGs suggests that PGE2 is essential for release of the oocyte; but not necessarily for follicle rupture, and not for luteinization. Novel PGE-regulated genes are being identified in macaque granulosa cells, including adipose differentiation-related protein (ADFP). Similar types of studies indicate that the rise in progesterone (P) synthesis, as well as the induction of the genomic P receptor in granulosa cells, is essential for both ovulation and luteinization of the primate follicle. Limited data suggest that P action controls cell cycle activity (via cyclin B1 and cyclin-dependent kinase inhibitor p27), cholesterol uptake and utilization (e.g., low density lipoprotein or LDL receptor), proteases and their inhibitors (matrix metalloproteinase or MMP1; tissue inhibitor of MMP or TIMP1) and cell health in the granulosa cell layer. Finally, members of two classes of angiogenic factors, originally proposed as important for embryonic and pathologic (tumorigenic) vasculogenesis, appear induced in the granulosa layer of the preovulatory follicle, i.e., vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT). Local injection of antagonists to VEGF (soluble VEGF receptor) and ANGPT (the natural antagonist ANGPT2) into the preovulatory follicle suppressed ovulation and luteinization in monkeys, possibly by disrupting the structure-function of existing vessels or preventing angiogenesis in the avascular granulosa layer. Further studies using high-throughput genomic and proteomic analysis, particularly on specific cell types (e.g., granulosa, theca and microvascular cells) and distinct follicular regions (apex, base and cumulus-oocyte complex) of the dominant follicle in natural menstrual cycles, are needed. Such information is essential to advance our understanding of the cascade of events leading to ovulation and luteinization of the primate follicle, to unravel the causes of ovary-based infertility and to consider novel ovary-selective approaches to contraception. PMID: 17127300 [PubMed - indexed for MEDLINE] 3147. Pharmacotherapy. 2006 Dec;26(12 Pt 2):218S-221S. The endocannabinoid system. Boyd ST(1). Author information: (1)Xavier University, Natchitoches, Louisiana 71457, USA. The endocannabinoid system is a complex physiologic system. One of the most important discoveries related to the endocannabinoid system is that cannabinoid-1 receptors are present throughout the body and that they are linked to obesity and cardiometabolic risk. Adipose tissue was historically thought to be an inert, passive storage vehicle. However, recent findings prove that adipose tissue is a complex endocrine organ that releases adipokines, which influence cardiometabolic risk factors. Elevated endocannabinoid system activity is associated with obesity and coupled with excessive food intake and fat accumulation. Strong evidence suggests that the endocannabinoid system affects the surrogate cardiometabolic end points that greatly influence morbidity and mortality. PMID: 17125448 [PubMed - indexed for MEDLINE] 3148. Panminerva Med. 2006 Sep;48(3):151-64. Metabolic syndrome and renal failure: similarities and differences. Kaysen GA(1). Author information: (1)Division of Nephrology, Department of Medicine, University of California, Davis, CA 95616, USA. gakaysen@ucdavis.edu The metabolic syndrome (MS) and chronic kidney disease (CKD) share many similar risk factors for cardiovascular disease. Both are associated with increased triglyceride (TG) levels, both associated with increased small dense low density lipoprotein (LDL), both with decreased high density lipoprotein (HDL) levels. In both cases HDL particle size is reduced. The TG content of HDL and very low density lipoprotein (VLDL) and remnants are increased, resulting in a dyslipidemia. Both are associated with increased inflammation, a hypercoagulable state and insulin resistance. Establishing whether these similarities are the result of identical biological processes or instead represent similar end results of different processes is further confounded by the associated both of adiposity and of MS with the incidence and progression of renal failure. Differences are present however. In MS hepatic VLDL synthesis is increased driven by increased flux of free fatty acids from muscle, adipose tissue and gut to the liver. VLDL is catabolized to LDL and the transfer of TG to HDL by cholesterol ester transfer protein destabilizes HDL leading to its rapid clearance. In CKD HDL fails to mature due to reduced activity of lecithin cholesterol transfer protein. In MS inflammation primarily arises from increased visceral adipose tissue, while inflammation is largely unrelated to body composition in CKD. Increased production of TG rich lipoproteins predominates in MS, while decreased disposal of TG rich proteins predominates as the cause of increased TG levels in CKD. Whether treatment of elements of MS, with the exception of hypertension, will avoid the onset and progression of renal failure is unknown. PMID: 17122751 [PubMed - indexed for MEDLINE] 3149. Adv Exp Med Biol. 2006;585:403-12. Adipose tissue induction in vivo. Stillaert FB(1), Blondeel P, Hamdi M, Abberton K, Thompson E, Morrison WA. Author information: (1)Department of Plastic and Reconstructive Surgery, University Hospital Ghent, Belgium. Engineering adipogenic tissue in vivo requires the concomitant induction of angiogenesis to generate a stable long-term three-dimensional construct. Histioconductive tissue engineering strategies have been used. The disadvantage of using biodegradable scaffolds is a delayed angiogenic induction resulting in ischemic necrosis of the central cell population in the scaffold. We evaluated an histioinductive approach for adipose tissue engineering by combining essential key components for adipogenic induction: (1) a precursor cell source, (2) a vascular pedicle, (3) a supportive matrix, and (4) a chamber to preserve space for the new tissue to develop. We observed concomitant adipogenic and angiogenic induction after 6 weeks in three-dimensional adipose tissue constructs. PMID: 17120798 [PubMed - indexed for MEDLINE] 3150. Acta Med Indones. 2006 Jul-Sep;38(3):160-6. New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). Tjokroprawiro A(1). Author information: (1)Diabetes and Nutrition Center, Dr. Soetomo Teaching Hospital-Airlangga University, Faculty of Medicine, Surabaya. Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin. PMID: 17119268 [PubMed - indexed for MEDLINE] 3151. Infect Immun. 2007 Mar;75(3):1066-78. Epub 2006 Nov 21. Adipocyte, adipose tissue, and infectious disease. Desruisseaux MS(1), Nagajyothi, Trujillo ME, Tanowitz HB, Scherer PE. Author information: (1)Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. PMCID: PMC1828569 PMID: 17118983 [PubMed - indexed for MEDLINE] 3152. Ernst Schering Res Found Workshop. 2007;(59):101-9. Clinical trials in elderly patients. Jackson SH(1). Author information: (1)Department of Clinical Gerontology, King's College Hospital, London, UK. Stephen.Jackson@kcl.ac.uk The increasing size of the elderly population means that both the relative and absolute numbers of prescriptions for elderly patients are increasing. Depending on the age group, between 60% and 80% of elderly people are taking medication, and between 20% and 30% are taking at least three drugs. Prescribing for elderly patients as opposed to younger patients is thus ever more important. This has inevitably meant that the drug development process must increasingly recognise the importance of identifying and developing therapeutic targets relevant to older patients. Clearly, the scientific ethical and regulatory principles that determine conduct of clinical trials in younger individuals apply equally to older people. In addition, the development of drugs to be used in older patients requires an awareness of a number of physiological, pathophysiological and sociological considerations. PMID: 17117717 [PubMed - indexed for MEDLINE] 3153. Nutr Metab Cardiovasc Dis. 2006 Dec;16(8):569-74. Epub 2006 Nov 17. The role of brown adipose tissue in human obesity. Cinti S(1). Author information: (1)Institute of Normal Human Morphology, University of Ancona, Via Tronto 10 A, 60020 Ancona, Italy. cinti@univpm.it It is widely accepted that newborn humans are provided with brown adipose tissue (BAT) and that adult humans lack, or have only a small amount, of it. Therefore the physiological role of BAT in humans is debated. It is quite clear that BAT in rodents has an important role in the prevention and therapy of obesity and diabetes and specific drugs can induce BAT development in adult animals. New concepts regarding the biology of adipose tissues in mammals have been developed during the last years leading to the hope for the development of BAT in human adults as a new challenge for the treatment of obesity and related diseases. These new concepts are basic to understanding the above-proposed therapeutic strategy and are the concept of the adipose organ and the concept of transdifferentiation. In this paper these new concepts will be explained together with a review of available scientific data on human BAT. PMID: 17113764 [PubMed - indexed for MEDLINE] 3154. Expert Rev Mol Med. 2006 Nov 20;8(27):1-12. Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies. Vasseur F(1), Meyre D, Froguel P. Author information: (1)Biostatistics Department Medical School and Public Health Clinics, University Hospital, Lille, France. Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity. PMID: 17112391 [PubMed - indexed for MEDLINE] 3155. Vestn Ross Akad Med Nauk. 2006;(9-10):99-104. [Adiponectin, a new hormone: its role in the pathogenesis of diabetes mellitus]. [Article in Russian] Pankov IuA. Adiponectin is a hormone of adipose tissue, activating lipid metabolism and other physiological functions. Adiponectin deficiency induces obesity and decreases insulin-regulated carbohydrate metabolism, thus leading to insulin resistance. Blood level of adiponectin falls in type 2 diabetes. Adiponectin receptors--AdipoR1 and AdipoR2--are proteins with 7 transmembrane domains, which are synthesized mostly in muscles and the liver and function in a close connection with G proteins. Obesity and diabetes lower the tissue concentration of the receptors, thus impeding adiponectin regulation of lipid exchange and lowering the effectiveness of the insulin control of carbohydrate exchange. Adiponectin also influences cardiovascular functions and prevents atherosclerosis and some of the other kinds of vascular pathology. PMID: 17111933 [PubMed - indexed for MEDLINE] 3156. Diabetes Metab. 2006 Nov;32(5 Pt 1):393-401. Adipose tissue-derived cells: from physiology to regenerative medicine. Casteilla L(1), Dani C. Author information: (1)UMR 5018 CNRS-UPS, IFR 31, Institut Louis-Bugnard, BP 84225, 31432 Toulouse Cedex 4, France. casteil@toulouse.inserm.fr During the last past years, the importance and the role of adipose tissues have been greatly expanded. After finding that adipose tissues are metabolically very active, the discovery of leptin moved the status of adipose tissue towards an endocrine tissue able to interact with all major organs via secretion of adipokines. Some years ago, the presence of adipocyte precursors, termed preadipocytes, has been described in all adipose tissue depots from various species of different age. More recently, the discovery that different phenotypes can be obtained from stroma cells of adipose tissue has largely emphazised the concept of adipose tissue plasticity. Therefore, raising great hope in regenerative medicine as adipose tissue can be easily harvested in adults it could represent an abundant source of therapeutic cells. Thus, adipose tissue plays the dual role of Mr Obese Hyde as a main actor of obesity and of Dr Regenerative Jekyll as a source of therapeutic cells. Adipose tissue has not yet revealed all its mysteries although one facet could not be well understood without the other one. PMID: 17110894 [PubMed - indexed for MEDLINE] 3157. Autoimmun Rev. 2006 Nov;6(1):48-53. Epub 2006 Aug 2. Insulin resistance, chronic inflammatory state and the link with systemic lupus erythematosus-related coronary disease. Escárcega RO(1), García-Carrasco M, Fuentes-Alexandro S, Jara LJ, Rojas-Rodriguez J, Escobar-Linares LE, Cervera R. Author information: (1)Systemic Autoimmune Diseases Research Unit, HGR 36, Instituto Mexicano del Seguro Social, Puebla, México. The association of SLE with atherosclerosis suggests a common pathogenic mechanism. SLE and atherosclerosis are immune complex-mediated diseases. The integration of metabolism and immunity, which under normal conditions is beneficial for the maintenance of good health, can become deteriorative under conditions of metabolic challenge, as exemplified by the immunosuppression characteristic of malnourished or starving individuals. It is now apparent that obesity is associated with a state of chronic inflammation, particularly in white adipose tissue. However, in the absence of obesity, infusion of animals with inflammatory cytokines or lipids can cause insulin resistance. It is possible that the stresses of obesity are similar enough to the stresses of an infection and the body reacts to obesity as it would to an infection. Atherosclerosis can be considered to have a significant chronic inflammatory component. Inflammation also contributes to the typical dyslipidemia associated with SLE that is characterized by elevations of VLDL, LDL and triglycerides as well as reduced HDL. The link between insulin resistance and SLE can be explained by the chronic inflammatory state, and the consequent dyslipoproteinemia. PMID: 17110317 [PubMed - indexed for MEDLINE] 3158. Nutr Metab Cardiovasc Dis. 2007 May;17(4):319-26. Epub 2006 Nov 15. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Ritchie SA(1), Connell JM. Author information: (1)BHF Cardiovascular Research Centre, Glasgow University, 26 University Place, Glasgow G12 8TA, UK. sar9j@clinmed.gla.ac.uk AIM: The prevalence of metabolic syndrome has increased dramatically in recent years, and the cluster of metabolic abnormalities it encompasses results in increased cardiovascular morbidity and mortality. The role of abdominal (visceral) obesity and the underlying molecular and cellular mechanisms central to this association have been the subject of intensive research in recent times. The aim of this review is to correlate data in this area, highlighting the central role of excess visceral fat and its secreted adipokines, and to review existing and emerging therapies. DATA SYNTHESIS: Data were generated from a search of the PubMed database using the terms 'abdominal obesity', 'metabolic syndrome', 'insulin resistance', 'adipokines', 'interleukin-6 (IL-6)', 'adiponectin', 'tumour necrosis factor-alpha (TNF-alpha)' and 'cardiovascular disease'. CONCLUSION: Metabolic syndrome is associated with a pro-inflammatory state, and the role of visceral obesity is thought to be central to this. Visceral obesity leads to alteration of the normal physiological balance of adipokines, insulin resistance, endothelial dysfunction and a pro-atherogenic state. In association with this, the presence of conventional cardiovascular risk factors such as hypertension, dyslipidaemia and smoking results in a significantly elevated cardiovascular and metabolic (cardiometabolic) risk. Better understanding of the molecular mechanisms central to this association has led to the development of potential therapeutic agents. PMID: 17110092 [PubMed - indexed for MEDLINE] 3159. Int J Clin Pract. 2006 Dec;60(12):1697-706. Rimonabant: endocannabinoid inhibition for the metabolic syndrome. Wierzbicki AS(1). Author information: (1)Lipid Unit, St. Thomas' Hospital, London, UK. anthony.wierzbicki@kcl.ac.uk Erratum in Int J Clin Pract. 2007 Mar;61(3):534. Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss > 5% in 30-40% of patients and > 10% in 10-20% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 8-10% increase in HDL-C and a 10-30% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype. PMID: 17109677 [PubMed - indexed for MEDLINE] 3160. Swiss Med Wkly. 2006 Oct 14;136(41-42):647-54. Stem cells with potential to generate insulin producing cells in man. Zulewski H(1). Author information: (1)Division of Endocrinology, Diabetes and Clinical Nutrition, and Department of Research, University Hospital, Basel, Switzerland. henryk.zulewski@unibas.ch Republished in Swiss Med Wkly. 2007 Mar 2;137 Suppl 155:60S-67S. Replacement of insulin-producing cells represents an almost ideal treatment for patients with diabetes mellitus type 1. Transplantation of pancreatic islets of Langerhans--although successful in experienced centres--is limited by the lack of donor organs. Generation of insulin-producing cells from stem cells represents an attractive alternative. Stem cells with the potential to differentiate into insulin-producing cells include embryonic stem cells (ESC) as well as adult stem cells from various tissues including the pancreas, liver, central nervous system, bone marrow and adipose tissue. The use of human ESC is hampered by ethical concerns and the inability to create patient specific ESC with therapeutic cloning. Among adult stem cells mesenchymal stem cells appear to have a particular developmental plasticity ex vivo that include their ability to adopt a pancreatic endocrine phenotype. The present review summarises the current knowledge on the development of insulin-producing cells from stem cells with special emphasis on human mesenchymal stem cells isolated from the pancreas and adipose tissue. PMID: 17103343 [PubMed - indexed for MEDLINE] 3161. Endocr Regul. 2006 Sep;40(3):91-104. Alcohol intake modulates hormonal activity of adipose tissue. Pravdova E(1), Fickova M. Author information: (1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic. ueenelis@savba.sk White adipose tissue (WAT) is now recognized as a highly active metabolic tissue and important endocrine organ producing numerous peptides and proteins with broad biological activity. The term adipokines has been coined to refer to a series of adipocyte-derived biologically active molecules, which may influence the function as well as the structural integrity of other tissues. Adipokines are implicated in control of food intake, energy balance and body weight (leptin), glucose homeostasis (e.g., adiponectin, resistin, adiponutrin), lipid metabolism (e.g., retinol-binding protein, cholesterolester transfer protein), angiogenesis (vascular endothelial growth factor VEGF), fibrinolytic system (plasminogen activator inhibitor-1 PAI-1), pro- and anti-inflammatory effects (e.g., tumor necrosis factor-alpha TNF-alpha, interleukin-6 IL-6) or sexual development and reproduction (leptin). Alterations of WAT mass in obesity or lipoatrophy effect the production of most adipose secreted factors. Besides others, alcohol consumption affects also hormonal system leading to non-physiological increase/decrease of hormone gene expression and plasma hormone concentrations appearing as final poor or stronger effects on target tissues. As mentioned above, white adipose tissue is important endocrine organ, so alcohol intake can alter also adipokines expression in WAT and adipokines plasma levels and in this way it can affect the adipokine-targeted tissues and their functions. PMID: 17100551 [PubMed - indexed for MEDLINE] 3162. Paediatr Respir Rev. 2006 Dec;7(4):239-46. Epub 2006 Oct 12. Obesity and inflammation in children. Schwarzenberg SJ(1), Sinaiko AR. Author information: (1)Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. schwa005@umn.edu Systemic inflammation is present in children and adults with obesity. Inflammation associated with obesity appears to be central to the development of insulin resistance and atherosclerosis and may be important in the pathogenesis of other comorbid conditions. Although generally considered an inert energy storage tissue, white adipose tissue is a metabolically active organ. It produces a number of inflammatory cytokines and acute-phase reactants. Inflammation associated with obesity declines after weight loss and with exercise. It may also be possible to modify obesity-associated inflammation with medications, reducing comorbidities without weight loss. The study of inflammation in the context of excessive adipose tissue is central to understanding obesity and modifying its impact on patients. PMID: 17098638 [PubMed - indexed for MEDLINE] 3163. Clin Nutr. 2007 Feb;26(1):1-6. Epub 2006 Nov 13. Fat loss in cachexia--is there a role for adipocyte lipolysis? Rydén M(1), Arner P. Author information: (1)Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, M61, 141 86 Stockholm, Sweden. mikael.ryden@ki.se A number of chronic diseases are associated with pronounced loss of fat and muscle mass (cachexia). The negative correlation between cachexia and survival probability, implies that prevention and treatment of this condition is essential. The mechanisms promoting cachexia are yet to be determined although several theories have been proposed. Most studies on cachexia have concentrated on muscle wasting and its possible impact on complications and survival. In this review, we present a synopsis of previous and recent studies focusing on the loss of adipose tissue. It appears that increased adipocyte lipolysis is an important factor in the cachexic process. PMID: 17095126 [PubMed - indexed for MEDLINE] 3164. Ann Surg Oncol. 2007 Feb;14(2):276-85. Epub 2006 Nov 9. Cancer cachexia: it's time for more clinical trials. Bossola M(1), Pacelli F, Tortorelli A, Doglietto GB. Author information: (1)Istituto di Clinica Chirurgica, Università Cattolica del Sacro Cuore, Roma, Italia. maubosso@tin.it Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most current therapeutic strategies to counteract CC have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle have been attempted pharmacologically with encouraging results in animal models and through preliminary clinical trials. However, data in the clinical setting are still scanty and non definitive. It is time to start prospective, randomized, controlled trials to evaluate which drugs are effective in counteracting the loss of lean of muscle mass and in improving nutritional status and quality of life in patients affected by cancer-related cachexia. PMID: 17094025 [PubMed - indexed for MEDLINE] 3165. J Mal Vasc. 2006 Sep;31(4 Pt 1):190-201. [Metabolic syndrome]. [Article in French] Boursier V(1). Author information: (1)Service de Médecine Vasculaire, Hôpital Saint-Joseph, Paris. vboursier@hopital-saint-joseph.org Metabolic syndrome is public health problem. The characteristic feature is an association between factors contributing to increased cardiovascular risk. Several definitions have been proposed from 1998 to 2005. All proposed definitions take into consideration insulin resistance and its corollary hyperglycemia, overweight, hypertriglyceridemia, and LDL-cholesterol lowering. The most widely used definitions are proposed by the World Health Organization (WHO) and the American "Cholesterol" program (NCEP-ATpIII). The prevalence of metabolic syndrome varies by geographic region as a function of the chosen definition, the study methodology, the selection criteria, the age and gender of the study population, and the period of the study. Prevalence is higher in the United States than Europe and increases with age. A growing number of adolescents appear to meet the criteria of metabolic syndrome. Irrespective of the definition retained, metabolic syndrome is associated with increased cardiovascular risk and increased risk of type II diabetes. Sound evidence is however lacking on whether the risk is greater than that of taking into account each individual factor. Several points remain to be clarified concerning the underlying mechanisms. Visceral adipose tissue appears to be a key element in the process via anomalous function related to obesity and insulin resistance. Management is based mainly on reduction of body weight and regular physical activity. Drugs may be necessary to correct for the dyslipidemia, normalize blood glucose and reduce blood pressure. PMID: 17088787 [PubMed - indexed for MEDLINE] 3166. Curr Opin Investig Drugs. 2006 Oct;7(10):891-7. Insulin resistance and PPAR insulin sensitizers. Bhatia V(1), Viswanathan P. Author information: (1)State University of New York, Department of Diabetes, Endocrinology and Metabolism, Buffalo, NY 14209, USA. vbhatia@buffalo.edu Drugs that reverse insulin resistance are of importance as insulin resistance is frequently associated with type 2 diabetes. The three peroxisome proliferator-activated receptors (PPARs) PPARalpha, PPAR90 and PPARgamma are essential for the actions of the many insulin sensitizers. PPARalpha activation enhances free fatty acid oxidation and potentiates anti-inflammatory effects, while PPARgamma is essential for normal adipocyte differentiation and proliferation, as well as fatty acid uptake and storage. Thiazolidinediones (TZDs) are selective ligands of PPARgamma and act as insulin sensitizers. TZDs also suppress free fatty acids via the inhibition of lipolysis in adipose tissue. Insulin sensitizers currently under development include partial PPARgamma agonists and antagonists, and dual PPARalpha/PPARgamma agonists. Given that TZDs show anti-inflammatory, anti-oxidant and antiprocoagulant properties in addition to their insulin sensitizing and antilipotoxic properties, a case may be made for initiating TZD therapy early in the treatment of type 2 diabetes, particularly in those patients at risk of cardiovascular disease. TZDs may also be an important therapeutic option in the treatment of metabolic syndrome. PMID: 17086933 [PubMed - indexed for MEDLINE] 3167. Trends Endocrinol Metab. 2006 Dec;17(10):416-22. Epub 2006 Nov 3. The adipocyte-myocyte axis in insulin resistance. Sell H(1), Dietze-Schroeder D, Eckel J. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany. Insulin resistance in skeletal muscle is linked to an elevated adipose tissue mass, as is found in obesity, but can also be observed in lipodystrophy, in which adipose tissue is greatly reduced. Adipose tissue releases endocrine and metabolic mediators and is actively involved in crosstalk with skeletal muscle, a process that precedes and underlies the development of insulin resistance in muscles. Adipokines including tumor necrosis factor alpha, interleukin-6, leptin and adiponectin influence insulin signaling in skeletal muscle. Free fatty acids, their metabolites and ectopic fat in muscle also contribute to insulin resistance. Recent research indicates inflammation, endoplasmic reticulum stress and oxidative stress could be underlying mechanisms at the center of the development of insulin resistance. Insights into the role of macrophages in adipose tissue add to the complicated interplay between adipose tissue and skeletal muscle. PMID: 17084639 [PubMed - indexed for MEDLINE] 3168. Aesthetic Plast Surg. 2006 Nov-Dec;30(6):655-8. Intraabdominal pressure in abdominoplasty patients. Graça Neto L(1), Araújo LR, Rudy MR, Auersvald LA, Graf R. Author information: (1)Regional Paraná, Curitiba, Paraná, Brazil. Abdominal compartment syndrome is directly related to an increase in intraabdominal pressure (IAP), which can lead in severe cases to serious clinical consequences. Routine measurement of IAP in specific cases has been advocated by some surgical specialties. However, few studies in plastic surgery have focused on the use of IAP. The authors review the literature and describe a method of IAP analysis used for 12 patients who underwent abdominoplasty. PMID: 17077957 [PubMed - indexed for MEDLINE] 3169. Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E654-67. Epub 2006 Oct 31. Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism. Qi D(1), Rodrigues B. Author information: (1)Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity". In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease. PMID: 17077342 [PubMed - indexed for MEDLINE] 3170. Prog Mol Subcell Biol. 2006;44:199-232. Altered splicing in prelamin A-associated premature aging phenotypes. De Sandre-Giovannoli A(1), Lévy N. Author information: (1)Laboratoire de Génétique Moléculaire, Département de Génétique Médicale, Hôpital d'Enfants la Timone, 264 Rue St. Pierre, 13385 Marseille, Cedex 5, France. Hutchinson-Gilford progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and restrictive dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary "laminopathies." These are heterogeneous disorders due to altered function of lamins A/C or related proteins. In physiological conditions, mature lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, prelamin A. The major pathophysiological mechanism involved in progeria is an aberrant splicing of pre-mRNAs issued from the LMNA gene, due to a de novo heterozygous point mutation, leading to the production and accumulation of truncated lamin A precursors. Aberrant splicing of prelamin A pre-mRNAs causing the production of more extensively truncated precursors is involved in the allelic disease restrictive dermopathy. Other restrictive dermopathy cases are due to the inactivation of a key enzyme involved in the maturation of lamin A precursors (ZMPSTE24). In functional terms, all these conditions share the same pathophysiological basis: intranuclear accumulation of lamin A precursors, which cannot be fully processed (due to primary or secondary events) and exert toxic, dominant negative effects on nuclear homeostasis. Most other laminopathies are due to autosomal dominant LMNA point mutations inferred to cause single amino acid substitutions. In any case, the impact of these mutations on pre-mRNA splicing has rarely been assessed. These disorders affect different tissues and organs, mainly including bone, skin, striated muscles, adipose tissue, vessels, and peripheral nerves in isolated or combined fashions, giving rise to syndromes whose severity ranges from mild to perinatally lethal. In this chapter we review the structure and functions of lamins A/C in physiological and pathological conditions, describe their known or putative roles, namely, in the pathogenesis of HGPS and RD in relation to existing animal models, and envisage possible targeted therapeutic strategies on the basis of recent research results. PMID: 17076270 [PubMed - indexed for MEDLINE] 3171. Biochem Soc Trans. 2006 Dec;34(Pt 6):1103-6. The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks. Parker MG(1), Christian M, White R. Author information: (1)Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. m.parker@imperial.ac.uk NRs (nuclear receptors) regulate the expression of specific gene networks in target cells by recruiting cofactor complexes involved in chromatin remodelling and in the assembly of transcription complexes. The importance of activating gene expression, in metabolic tissues, is well established, but the contribution of transcriptional inhibition is less well defined. In this review, we highlight a crucial role for RIP140 (receptor-interacting protein 140), a transcriptional co-repressor for NR, in the regulation of metabolic gene expression. Many genes involved in lipid and carbohydrate metabolism are repressed by RIP140 in adipose and muscle. The repressive function of RIP140 results from its ability to bridge NRs to repressive enzyme complexes that modify DNA and histones. In the absence of RIP140, expression from many metabolic genes is increased so that mice exhibit a lean phenotype and resistance to high-fat-diet-induced obesity and display increased glucose tolerance and insulin sensitivity. We propose that a functional interplay between transcriptional activators and the co-repressor RIP140 is an essential process in metabolic regulation. PMID: 17073760 [PubMed - indexed for MEDLINE] 3172. Curr Vasc Pharmacol. 2006 Oct;4(4):383-93. Leptin and vascular smooth muscle. Zeidan A(1), Karmazyn M. Author information: (1)Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada. Leptin has received extensive attention as an endogenously produced satiety factor. Although once considered to be solely derived from adipose tissue, it is now apparent that leptin can be produced by various tissues including those comprising the cardiovascular system such as blood vessels and cardiomyocytes. Moreover, leptin receptors (OBR) have been identified in cardiovascular tissues. The increased cardiovascular risk associated with obesity is well known and many of the effects of leptin appear to be compatible with its potential role as a contributing factor to increased cardiovascular morbidity associated with obesity. Evidence from both animal and human studies implicated leptin as a potential contributor to the increased incidence of cardiovascular morbidity associated with hyperleptinemic conditions. This review focuses on some of the complex vascular actions of leptin and the emerging role of leptin as a cardiovascular regulator in terms of normal homeostatic function, but particularly in cardiovascular pathology. PMID: 17073703 [PubMed - indexed for MEDLINE] 3173. Curr Vasc Pharmacol. 2006 Oct;4(4):349-81. The etiology of hypertension in the metabolic syndrome part four: the systemic perspective--the role of the neuroendocrine and immune systems, and the challenge of integration. Sharma V(1), McNeill JH. Author information: (1)Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, V6T 1Z3, Canada. vijaysha@interchange.ubc.ca Insulin resistance can be regarded to be a cause, a consequence, a sustainer or a marker of the wider neuroendocrine dysfunction within which it occurs. In the final part of our series of reviews, we examine the systemic influences which operate within the metabolic syndrome: the endocrine system, the central nervous system and the immune system. We discuss strategies for integrating the array of information that is being gathered, in particular the need for computer simulation. We also advocate the need to move beyond the linear paradigm of 'cause and effect' and use causal networks to think about this system. We also discuss the need to understand the temperospatial organisation of the factors being studied. Finally, we draw together the data, concepts and hypotheses we have reviewed over the course of these four articles. PMID: 17073702 [PubMed - indexed for MEDLINE] 3174. Arch Mal Coeur Vaiss. 2006 Sep;99(9):848-55. Heart involvement in lamin A/C related diseases. Ben Yaou R(1), Gueneau L, Demay L, Stora S, Chikhaoui K, Richard P, Bonne G. Author information: (1)Institut national de la santé et de la recherche médicale, Paris. The LMNA gene encodes lamins A and C, components of the nuclear envelope. Its mutations cause a wide range of diseases named laminopathies involving either specific tissues in isolated fashion (cardiac and skeletal muscles, peripheral nerve, adipose tissue) or several tissues in a generalized way (premature ageing syndromes and related disorders). The striated muscle laminopathies include a variety of well clinically characterized disorders where cardiac muscle involvement represents the common feature that coexists with or without skeletal muscle disease. The cardiac disease of LMNA mutated patients is classically defined by conduction system and rhythm disturbances occurring early in the course of the disease, followed by dilated cardiomyopathy and heart failure. These features are life threatening and often responsible of cardiac sudden death. When associated, the skeletal muscle involvement is characterized by muscle weakness and wasting of variable topography with or without early joint contractures and spinal rigidity. Specific management of the cardiac disease to includes antiarrhythmic drugs, cardiac devices such as implantable cardioverter for primary and secondary prevention of sudden death, and heart transplantation at the end stage of heart failure. A large number of LMNA mutations leading to striated muscle laminopathies have been reported without so far any clear and definite phenotype/genotype relation. Finally, among the diverse hypotheses for pathomechanisms of LMNA mutations, the structural hypothesis suggesting a defective role of lamins A/C in maintaining the structural integrity of the nuclear envelope in striated muscles under constant mechanical stress is highly attractive to link the LMNA mutations and the cardiac disease. PMID: 17067107 [PubMed - indexed for MEDLINE] 3175. Interdiscip Top Gerontol. 2007;35:18-38. Metabolic reprogramming in dietary restriction. Anderson RM(1), Weindruch R. Author information: (1)Department of Medicine, University of Wisconsin, and VA Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA. rmanderson5@wisc.edu It is widely accepted that energy intake restriction without essential nutrient deficiency delays the onset of aging and extends life span. The mechanism underlying this phenomenon is still unknown though a number of different, nonmutually exclusive explanations have been proposed. In each of these, different facets of physiology play the more significant role in the mechanism of aging retardation. Some examples include the altered lipid composition model, the immune response model and models describing changes in endocrine function. In this paper we propose the hypothesis that metabolic reprogramming is the key event in the mechanism of dietary restriction, and the physiological effects at the cellular, tissue and organismal level may be understood in terms of this initial event. PMID: 17063031 [PubMed - indexed for MEDLINE] 3176. J Dent Res. 2006 Nov;85(11):966-79. Craniofacial tissue engineering by stem cells. Mao JJ(1), Giannobile WV, Helms JA, Hollister SJ, Krebsbach PH, Longaker MT, Shi S. Author information: (1)Columbia University College of Dental Medicine and Biomedical Engineering, 630 W. 168 St.--PH7 CDM, New York, NY 10032, USA. jmao@columbia.edu Craniofacial tissue engineering promises the regeneration or de novo formation of dental, oral, and craniofacial structures lost to congenital anomalies, trauma, and diseases. Virtually all craniofacial structures are derivatives of mesenchymal cells. Mesenchymal stem cells are the offspring of mesenchymal cells following asymmetrical division, and reside in various craniofacial structures in the adult. Cells with characteristics of adult stem cells have been isolated from the dental pulp, the deciduous tooth, and the periodontium. Several craniofacial structures--such as the mandibular condyle, calvarial bone, cranial suture, and subcutaneous adipose tissue--have been engineered from mesenchymal stem cells, growth factor, and/or gene therapy approaches. As a departure from the reliance of current clinical practice on durable materials such as amalgam, composites, and metallic alloys, biological therapies utilize mesenchymal stem cells, delivered or internally recruited, to generate craniofacial structures in temporary scaffolding biomaterials. Craniofacial tissue engineering is likely to be realized in the foreseeable future, and represents an opportunity that dentistry cannot afford to miss. PMCID: PMC2571078 PMID: 17062735 [PubMed - indexed for MEDLINE] 3177. Int J Obes (Lond). 2007 May;31(5):829-41. Epub 2006 Oct 24. A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice. Wuschke S(1), Dahm S, Schmidt C, Joost HG, Al-Hasani H. Author information: (1)Department of Pharmacology, German Institute for Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany. OBJECTIVE: Cross-breeding experiments with different mouse strains have successfully been used by many groups to identify genetic loci that predispose for obesity. In order to provide a statistical assessment of these quantitative trait loci (QTL) as a basis for a systematic investigation of candidate genes, we have performed a meta-analysis of genome-wide linkage scans for body weight and body fat. DATA: From a total of 34 published mouse cross-breeding experiments, we compiled a list of 162 non-redundant QTL for body weight and 117 QTL for fat weight and body fat percentage. Collectively, these studies include data from 42 different parental mouse strains and >14,500 individual mice. METHODS: The results of the studies were analyzed using the truncated product method (TPM). RESULTS: The analysis revealed significant evidence (logarithm of odds (LOD) score >4.3) for linkage of body weight and adiposity to 49 different segments of the mouse genome. The most prominent regions with linkage for body weight and body fat (LOD scores 14.8-21.8) on chromosomes 1, 2, 7, 11, 15, and 17 contain a total of 58 QTL for body weight and body fat. At least 34 candidate genes and genetic loci, which have been implicated in regulation of body weight and body composition in rodents and/or humans, are found in these regions, including CCAAT/enhancer-binding protein alpha (C/EBPA), sterol regulatory element-binding transcription factor 1 (SREBP-1), peroxisome proliferator activator receptor delta (PPARD), and hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1). Our results demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control body weight and body composition. An interactive physical map of the QTL is available online at (http://www.obesitygenes.org). PMID: 17060928 [PubMed - indexed for MEDLINE] 3178. Curr Cardiol Rep. 2006 Nov;8(6):433-8. Surgical risk in patients with metabolic syndrome: focus on lipids and hypertension. Watson K(1). Author information: (1)UCLA Cholesterol, Hypertension, and Atherosclerosis Management Program, University of California, Los Angeles Geffen School of Medicine, Los Angeles, CA 90095, USA. kwatson@mednet.ucla.edu The metabolic syndrome describes a clustering of risk factors that predispose individuals to cardiovascular disease and type 2 diabetes mellitus. Abdominal obesity is a key component of the metabolic syndrome, increasing the incidence of insulin resistance, vascular inflammation, dyslipidemia, and hypertension. Adipose tissue (now recognized as an endocrine organ) and its hormonal products appear to play a significant role in signaling organs throughout the body in the regulation of fat and glucose metabolism. These mechanisms are clearly involved in the development of cardiovascular and metabolic disease and may also lead to increased surgical risks. The components of the syndrome that are most likely to affect surgical patients are obesity, hypertension, and disorders of glucose metabolism. This article focuses on each of these risk factors, the effects on surgical patients, and strategies to improve outcomes in the perioperative period. PMID: 17059795 [PubMed - indexed for MEDLINE] 3179. Curr Cardiol Rep. 2006 Nov;8(6):427-32. Operative risk factors in the metabolic syndrome: is it lipids and high blood pressure or are there direct vascular effects of insulin resistance and obesity? Ukkola O(1). Author information: (1)Department of Internal Medicine and Biocenter Oulu, University of Oulu, Kajaanintie 50/P.O. Box 5000, Oulu, FIN-90014, Finland. olavi.ukkola@oulu.fi The metabolic syndrome is associated with an increased risk for cardiovascular disease. Dyslipidemia, high blood pressure, and impaired glucose tolerance, components of the metabolic syndrome, are all clearly atherogenic. Insulin resistance is an important correlate of other risk factors. Excess abdominal fat, as often seen in overweight people and commonly observed in obese individuals, is the single most important central feature of the metabolic syndrome. In addition to insulin resistance, an excess amount of abdominal fat is associated with all the features of metabolic clustering. Adipocytes secrete several peptide hormones that have been related to the metabolic syndrome and related cardiovascular disease. The role of traditional versus novel adipose tissue-related risk factors in the background of atherosclerosis in the metabolic syndrome are discussed. PMID: 17059794 [PubMed - indexed for MEDLINE] 3180. Endocr Rev. 2006 Dec;27(7):762-78. Epub 2006 Oct 20. Adipose tissue-derived factors: impact on health and disease. Trujillo ME(1), Scherer PE. Author information: (1)Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. The endocrine functions of the adipose organ are widely studied at this stage. The adipose organ, and in particular adipocytes, communicate with almost all other organs. Although some adipose tissue pads assume the functions as distinct "miniorgans," adipocytes can also be present in smaller numbers interspersed with other cell types. Although fat pads have the potential to have a significant systemic impact, adipocytes may also affect neighboring tissues through paracrine interactions. These local or systemic effects are mediated through lipid and protein factors. The protein factors are commonly referred to as adipokines. Their expression and posttranslational modifications can undergo dramatic changes under different metabolic conditions. Due to the fact that none of the mutations that affect adipose tissue trigger embryonic lethality, the study of adipose tissue physiology lends itself to genetic analysis in mice. In fact, life in the complete absence of adipose tissue is possible in a laboratory setting, making even the most extreme adipose tissue phenotypes genetically amenable to be analyzed by disruption of specific genes or overexpression of others. Here, we briefly discuss some basic aspects of adipocyte physiology and the systemic impact of adipocyte-derived factors on energy homeostasis. PMID: 17056740 [PubMed - indexed for MEDLINE] 3181. Curr Opin Clin Nutr Metab Care. 2006 Nov;9(6):685-90. Field studies of exercise and food deprivation. Hoyt RW(1), Friedl KE. Author information: (1)Biophysics and Biomedical Modeling Division, US Army Research Institute of Environmental Medicine, Kansas Street, Natick, MA 01760, USA. reed.hoyt@us.army.mil PURPOSE OF REVIEW: The increase in obesity in developed societies drives interest in the interplay of energy intake, metabolic energy expenditure, and body energy stores. A better understanding of energy management in physically active and undernourished humans should help guide strategies to manage obesity safely and effectively. This review focuses on field studies of men and women engaged in prolonged strenuous activities, ranging from ranger training to extreme expeditions. RECENT FINDINGS: Although scientifically unconventional and limited, field studies of exercise and food deprivation have yielded interesting findings: 4-5% body fat is the normal lower limit to fat reserves in physically active underfed young adult men, and in response to exercise and underfeeding, women used more fat mass and less fat-free mass to meet metabolic fuel requirements. SUMMARY: Field studies have shown that fat energy reserves in young adult men can be estimated as percentage body fat minus 5%, and initial body fat mass has a significant positive influence on fat oxidation rates per kilogram of fat-free mass during rapid weight loss associated with underfeeding and exercise. Data logging pedometers, activity monitors, global positioning systems, and wireless body and personal-area networks promise to make it easier to study and care for free-living humans. PMID: 17053420 [PubMed - indexed for MEDLINE] 3182. Clin Nutr. 2006 Dec;25(6):871-85. Epub 2006 Oct 18. Peroxisome proliferator-activated receptors: bridging metabolic syndrome with molecular nutrition. Guri AJ(1), Hontecillas R, Bassaganya-Riera J. Author information: (1)Laboratory of Nutritional Immunology and Molecular Nutrition, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Over recent years, obesity rates and the onset of obesity-induced chronic diseases have risen dramatically. The more we learn about the physiological and morphological changes that occur during obesity, the more it is becoming clear that obesity-related disorders can be traced back to adipocyte hypertrophy and inflammation at white adipose tissue (WAT). To combat this problem, the body has developed a regulatory system specifically designed at mediating the systemic response to obesity, utilizing free fatty acids (FFAs) and their metabolites as nutrient messengers to signal adaptations from peripheral tissues. These messages are predominantly interceded through the peroxisome proliferator-activated receptors (PPARs), a family of ligand-induced transcription factors that serve as a net of lipid sensors throughout the body. Understanding how and why nutrients, nutrient derivatives and metabolites exert their physiological effects are the key goals in the study of molecular nutrition. By learning about the mechanisms and tissue-specific effects of endogenous PPAR ligands and expanding our knowledge of the body's integrated homeostatic system, we will significantly increase our odds of designing safe and effective preventive and therapeutic interventions that keep us one step ahead of obesity-related diseases. PMID: 17052808 [PubMed - indexed for MEDLINE] 3183. Chem Biol. 2006 Oct;13(10):1019-27. Small-molecule compounds that modulate lipolysis in adipose tissue: targeting strategies and molecular classes. Wang M(1), Fotsch C. Author information: (1)Department of Metabolic Disorders, Amgen Incorporated, Thousand Oaks, California 91320, USA. mwang@amgen.com Lipolysis is an important pathway in maintaining energy homeostasis through the degradation of triglycerides in adipose tissue and the release of fatty acids into the circulation as an energy source. However, an elevated level of circulating fatty acids leads to unfavorable metabolic effects such as insulin resistance and dyslipidemia. Cell surface receptors and intracellular components of the lipolytic pathway have been targeted to develop antilipolytic agents, among which are G-protein-coupled receptor agonists and lipase inhibitors. In addition, molecules that stimulate lipolysis have been tested in clinical trials as a treatment for obesity. Together, these molecules represent a diverse group of regulators for this pathway. This review will discuss strategies to target lipolysis and the major issues with representative small-molecule modulators of this pathway. PMID: 17052606 [PubMed - indexed for MEDLINE] 3184. Vet Q. 2006 Sep;28(3):90-104. Studies on hepatic lipidosis and coinciding health and fertility problems of high-producing dairy cows using the "Utrecht fatty liver model of dairy cows". A review. Geelen MJ(1), Wensing T. Author information: (1)Department of Nutrition, Graduate School of Animal Health, Faculty of Veterinary Medicine, Utrecht University, The Netherlands. m.geelen@vet.uu.nl Fatty liver or hepatic lipidosis is a major metabolic disorder of high-producing dairy cows that occurs rather frequently in early lactation and is associated with decreased health, production and fertility. A background section of the review explores reasons why high-producing dairy cows are prone to develop fatty liver post partum. Hepatic lipidosis and coinciding health and fertility problems seriously endanger profitability and longevity of the dairy cow. Results from a great number of earlier epidemiological and clinical studies made it clear that a different approach was needed for elucidation of pathogenesis and etiology of this complex of health problems. There was a need for an adequate animal model in which hepatic lipidosis and production, health and fertility problems could be provoked under controlled conditions. It was hypothesized that overconditioning ante partum and feed restriction post partum might induce lipolysis in adipose tissue and triacylglycerol accumulation in the liver following calving. This consideration formed the basis for the experiments, which resulted in the "Utrecht fatty liver model of dairy cows". In this model, post partum triacylglycerol-lipidosis as well as the whole complex of health and fertility problems are induced under well-controlled conditions. The experimental protocol based on this hypothesis produced in all cases (10 feeding trials with over 150 dairy cattle) the intended result, i.e. all experimental cows developed post partum higher hepatic triacylglycerol concentrations than did control cows. The model was evaluated in biochemical, clinical pathology, immunological, clinical and fertility terms. It turned out that in this model, post partum triacylglycerol-lipidosis as well as the whole complex of health and fertility problems were induced under well-controlled conditions. PMID: 17052073 [PubMed - indexed for MEDLINE] 3185. Journ Annu Diabetol Hotel Dieu. 2006:129-40. [Secretion o cytokines by adipose tissue: metabolic and vascular effects]. [Article in French] Juge-Aubry CE(1), Meier CA. Author information: (1)Laboratoire d'Endocrinologie Moléculaire, Département de Physiologie Cellulaire et Métabolisme, Faculté de Médecine, rue Michel Servet 1, 1211 Genève 4, Suisse. PMID: 17051856 [PubMed - indexed for MEDLINE] 3186. Journ Annu Diabetol Hotel Dieu. 2006:115-28. [Is obesity an inflammatory disease?]. [Article in French] Cancello R(1), Taleb S, Poitou C, Tordjman J, Lacasa D, Guerre-Millo M, Clément K. Author information: (1)INSERM, Nutriomique U755, 75004 Paris. PMID: 17051855 [PubMed - indexed for MEDLINE] 3187. Nihon Rinsho. 2006 Oct;64(10):1955-62. [Regulation of adipose functions by molecular clocks]. [Article in Japanese] Shimba S(1). Author information: (1)Department of Health Science, College of Pharmacy, Nihon University. Adipocytes play essential metabolic roles, not only serving as massive energy reserves but also secreting hormones and cytokines that regulate metabolic activities. The link between metabolic activity in adipocytes and circadian rhythm has long been studied, e.g., glucose and lipid homeostasis are well known to exhibit circadian variation. Therefore, molecular clock may play important roles in regulation of metabolic activity in adipocytes. In a previous study, we reported that white adipose tissue contains functional molecular clock and expression of several adipocytokines including leptin and plasminogen activator inhibitor-1 displays circadian rhythm. The diurnal rhythm in the level of these molecules suggests that molecular clock is, at least partly, associated with the onset of metabolic syndrome. PMID: 17037374 [PubMed - indexed for MEDLINE] 3188. Nihon Naika Gakkai Zasshi. 2006 Sep 10;95(9):1731-6. [Diagnosis of metabolic syndrome]. [Article in Japanese] Nakamura T, Okauchi Y, Ryo M, Funahashi T, Shimomura I. PMID: 17037307 [PubMed - indexed for MEDLINE] 3189. Nihon Naika Gakkai Zasshi. 2006 Sep 10;95(9):1726-30. [Metabolic syndrome and aldosterone]. [Article in Japanese] Nagase M, Fujita T. PMID: 17037306 [PubMed - indexed for MEDLINE] 3190. Nihon Naika Gakkai Zasshi. 2006 Sep 10;95(9):1721-5. [Metabolic syndrome and lipotoxicity]. [Article in Japanese] Shimabukuro M. PMID: 17037305 [PubMed - indexed for MEDLINE] 3191. Nihon Naika Gakkai Zasshi. 2006 Sep 10;95(9):1710-5. [Metabolic syndrome]. [Article in Japanese] Kiyohara Y, Doi Y, Ninomiya T. PMID: 17037303 [PubMed - indexed for MEDLINE] 3192. Obesity (Silver Spring). 2006 Sep;14(9):1485-97. Obesity in older adults: a systematic review of the evidence for diagnosis and treatment. McTigue KM(1), Hess R, Ziouras J. Author information: (1)Center for Research on Health Care, Division of General Internal Medicine, Pittsburgh, Pennsylvania 15213, USA. mctiguekm@upmc.edu OBJECTIVE: Although obesity is increasing in older U.S. adults, treatment is controversial in this age group. We sought to examine evidence concerning obesity's health-related risks, diagnostic methods, and treatment outcomes in older individuals. RESEARCH METHODS AND PROCEDURES: We searched MEDLINE and Cochrane Library databases, consulted with experts, and examined bibliographies for English language studies discussing obesity in older adults (mean age > or = 60), published between January 1980 and November 2005. Inclusion criteria were met by 32 longitudinal analyses, seven diagnostic studies, and 17 randomized controlled trial articles. At least two authors independently reviewed and abstracted study design, population, results, and quality information. RESULTS: Correlations between body fat and three anthropometric measures (BMI, waist circumference, waist-to-hip ratio) decrease with age but remain clinically significant. Obesity contributes to risk for several cardiovascular endpoints, some cancers, and impaired mobility but protects against hip fracture. The association between obesity and mortality declines as age increases. Intensive counseling strategies incorporating behavioral, dietary, and exercise components promote a weight loss of 3 to 4 kg over 1 to 3.3 years. The loss is linked with improved glucose tolerance, improved physical functioning, reduced incidence of diabetes and a combined hypertension and cardiovascular endpoint, and reduced bone density. DISCUSSION: In older adults, obesity can be diagnosed with standard clinical measures. Intensive counseling can promote modest sustained weight loss, but data are insufficient to evaluate surgical or pharmacological options. Obesity treatment is most likely to benefit individuals with high cardiovascular risk. Limited data suggest possible functional improvement. Treatment should incorporate measures to avoid bone loss. PMID: 17030958 [PubMed - indexed for MEDLINE] 3193. Vitam Horm. 2006;74:443-77. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Fain JN(1). Author information: (1)Department of Molecular Sciences, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids. PMID: 17027526 [PubMed - indexed for MEDLINE] 3194. Obesity (Silver Spring). 2006 Aug;14 Suppl 5:254S-258S. Leptin resistance and obesity. Enriori PJ(1), Evans AE, Sinnayah P, Cowley MA. Author information: (1)Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. The prevalence of obesity, and the human and economic costs of the disease, creates a need for better therapeutics and better understanding of the physiological processes that balance energy intake and energy expenditure. Leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. In common obesity, leptin loses the ability to inhibit energy intake and increase energy expenditure; this is termed leptin resistance. This review discusses the evidence in support of leptin resistance in mouse models and humans and the possible mechanisms of leptin resistance. PMID: 17021377 [PubMed - indexed for MEDLINE] 3195. Obesity (Silver Spring). 2006 Aug;14 Suppl 5:250S-253S. Gut peptide signaling in the controls of food intake. Moran TH(1). Author information: (1)Department of Psychiatry and Behavioral Sciences, Ross 618, 720 Rutland Avenue, Johns Hopkins University School of Medicine, Baltimore, MD 21286, USA. tmoran@jhmi.edu During a meal and after a meal, ingested nutrients alter the release of a variety of gut peptides that have the potential to modulate food intake. Such feedback peptide signaling can be conceptualized as having three outcomes: meal termination, inhibitory modulation of intake in subsequent meals, and orexigenic modulation. Cholecystokinin, pancreatic glucagons, and amylin are examples of peptides involved in meal termination. They are released rapidly with the onset of feeding and have short durations of action. Peptide YY(3-36) and glucagon-like peptide 1 are peptides for which longer-term feeding inhibitory actions have been proposed. They are released from the distal intestine and have longer durations of actions. Ghrelin is a gastric peptide that stimulates food intake after its exogenous administration. Plasma ghrelin levels fall with feeding and rise with food deprivation. All of these gut peptides have vagal or dorsal hindbrain mediation. Their potential as targets for the development of anti-obesity treatments is under study. PMID: 17021376 [PubMed - indexed for MEDLINE] 3196. Obesity (Silver Spring). 2006 Aug;14 Suppl 5:242S-249S. Adipose tissue as an endocrine organ. Ahima RS(1). Author information: (1)University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver. PMID: 17021375 [PubMed - indexed for MEDLINE] 3197. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2006;12(3):223-8. [Obesity related complications in children and adolescents]. [Article in Polish] Fichna P(1), Skowrońska B. Author information: (1)Klinika Endokrynologii i Diabetologii Wieku Rozwojowego II Katedry Pediatrii AM im. Karola Marcinkowskiego w Poznaniu, Poznań. pfichna@amp.edu.pl The epidemic of obesity concerns also children and adolescents. Excess weight increases the risk of metabolic complications, diabetes type 2, hypertension, cardiovascular disease, pulmonary and musculoskeletal disorders, psychosocial problems. Simple obesity leads to secondary endocrine disturbances. Long lasting insulin resistance and proinflammatory state induced by cytokines, which are produced in adipose tissue, play the main role in the development of obesity associated complications. Many disturbances can be reversed at the early stage, if even small weight loss is achieved. PMID: 17020660 [PubMed - indexed for MEDLINE] 3198. Expert Opin Pharmacother. 2006 Oct;7(14):1919-30. Update on the use of aromatase inhibitors in breast cancer. Brueggemeier RW(1). Author information: (1)Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. Brueggemeier.1@osu.edu Estrogens are biosynthesised from androgens by the CYP450 enzyme complex called aromatase. Aromatase is expressed in the ovary, placenta, brain, bone, adipose tissue and breast tissue. In breast cancer, intratumoural aromatase is the source for local estrogen production in the tissue. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. The potent and selective third-generation aromatase inhibitors anastrozole, letrozole and exemestane were introduced to the market as endocrine therapy in postmenopausal patients failing anti-estrogen therapy alone, or multiple hormonal therapies. Anastrozole and letrozole are both non-steroidal aromatase inhibitors that compete with the substrate for binding to the enzyme active site. Exemestane is a mechanism-based steroidal inhibitor that mimics the substrate, is converted by the enzyme to a reactive intermediate, and results in inactivation of aromatase. These third-generation aromatase inhibitors are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. The use of an aromatase inhibitor as initial therapy, or after treatment with tamoxifen, is now recommended as adjuvant hormonal therapy for postmenopausal women with hormone-dependent breast cancer. Several clinical studies of aromatase inhibitors focus on the use of these agents in the adjuvant setting, for the treatment of early breast cancer. Recently published results show improved responses with these agents compared with tamoxifen. PMID: 17020418 [PubMed - indexed for MEDLINE] 3199. Int J Mol Med. 2006 Nov;18(5):969-74. Hemostasis alterations in metabolic syndrome (review). Palomo I(1), Alarcón M, Moore-Carrasco R, Argilés JM. Author information: (1)Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile. ipalomo@utalca.cl Metabolic syndrome (MS) is characterized by the presence of at least three of the following alterations: enlargement of the waist diameter, higher levels of arterial pressure, low density lipoprotein cholesterol and glycemia, and reduction of high density lipoprotein cholesterol. The prevalence of MS reaches 23% in young adults, a percentage that increases with age. People with MS have a greater risk of suffering from cardiovascular disease (CVD). The physiopathologic alterations now found to exist in MS are diverse; among them is endothelial dysfunction, which triggers atherogenic lesions and hypercoagulability characterized by alterations of the coagulation factors and the regulatory proteins of fibrinolysis such as the plasminogen activator inhibitor (PAI-1). The increase in oxidative stress and/or the reactive oxygen species in patients with MS is partially related to the oxidation state of the lipoproteins, especially of the low density lipoproteins. This fact favors atherogenesis. Moreover, the oxidative stress produces alterations in the production of adipokines, cytokines secreted by the adipose tissues. The abnormality in the transport of lipoprotein diminishes the catabolism of the very low density lipoprotein (VLDL) and increases the catabolism of the high density lipoprotein (HDL), which creates insulin resistance. This process is associated with a lower concentration of adiponectin that in turn regulates the catabolism of VLDL and HDL; consequently increasing the flow of fatty acids from the adipose tissue to the liver and muscles. The proinflammatory cytokines, among them tumor necrosis factor alpha (TNF-alpha), are of great importance in MS regulating different processes and molecules such as PAI-1. PAI-1 is controlled by the group of transcription factors peroxisome proliferator-activated receptor (PPAR), especially by PPAR gamma and alpha ligands. In summary, MS includes multiple alterations related to insulin resistance at several levels: hepatic, muscular, adipose and vascular tissue (endothelium). The exact mechanism that underlies the relationship between MS and CVD are not sufficiently known yet; pathogenic explanations are lacking for the mechanisms relating metabolic factors to insulin resistance and the association with the development of atherosclerosis and thrombosis. MS alterations and the main aspects related to homeostasis alterations are examined in this report. PMID: 17016629 [PubMed - indexed for MEDLINE] 3200. Postepy Hig Med Dosw (Online). 2006;60:447-52. [The role of leptin in the development of hypertension]. [Article in Polish] Dubiński A(1), Zdrojewicz Z. Author information: (1)Powiatowe Centrum Zdrowia w Kamiennej Górze, Sp. z o.o. NZOZ, Szpital Powiatowy. pcz@pcz.org.pl Leptin, the product the ob gene, is secreted by adipocytes to regulate energy homeostasis. This hormone may have an important influence on blood pressure, leading to hypertension. Leptin, acting in the hypothalamic melanocortin system, can activate or inactivate neuropeptides and produce hypertension, mainly by renal, adrenal, and muscular sympathoactivation. The role of leptin in regulating cardiovascular function in obesity is presented based on contemporary literature. Both intracellular signaling pathways activated by leptin and the role of leptin receptors are also discussed. The roles of endogens, neuropeptides in food intake, and energy expenditure are also presented. PMID: 17013364 [PubMed - indexed for MEDLINE] 3201. Cell Metab. 2006 Oct;4(4):263-73. Transcriptional control of adipocyte formation. Farmer SR(1). Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. farmer@biochem.bumc.bu.edu A detailed understanding of the processes governing adipose tissue formation will be instrumental in combating the obesity epidemic. Much progress has been made in the last two decades in defining transcriptional events controlling the differentiation of mesenchymal stem cells into adipocytes. A complex network of transcription factors and cell-cycle regulators, in concert with specific transcriptional coactivators and corepressors, respond to extracellular stimuli to activate or repress adipocyte differentiation. This review summarizes advances in this field, which constitute a framework for potential antiobesity strategies. PMCID: PMC1958996 PMID: 17011499 [PubMed - indexed for MEDLINE] 3202. Kardiol Pol. 2006 Oct;64(10 Suppl 6):S561-6. [Obesity--insulin resistance--type 2 diabetes mellitus]. [Article in Polish] Małecki MT(1). Author information: (1)Katedra i Klinika Chorób Metabolicznych, Collegium Medicum, Uniwersytet Jagielloński, Kraków. mmalecki@cm-uj.krakow.pl Millions of people worldwide suffer from type 2 diabetes mellitus. There are two major factors that play a role in its pathogenesis: insulin resistance and impaired secretion of insulin by beta-cells. Impaired insulin action is closely linked to the phenomenon of obesity. The adipose tissue releases free fatty acids but also hormones and cytokines such as leptin, adiponectin, resistin, TNF-alpha and others. All those particles modify insulin action. This review article summarizes contemporary opinions on the role of obesity in the generation of resistance to insulin and subsequently impaired glucose tolerance as well as overt type 2 diabetes mellitus. PMID: 20527377 [PubMed - indexed for MEDLINE] 3203. Mol Nutr Food Res. 2006 Oct;50(10):885-96. Risk assessments of polychlorinated dibenzo- p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in food. Larsen JC(1). Author information: (1)Danish Institute of Food and Veterinary Research, Søborg, Denmark. jcl@dfvf.dk The polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and dioxin-like polychlorinated biphenyls (dioxin-like PCB) are ubiquitous in food of animal origin and accumulate in fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The toxic responses include dermal toxicity, immunotoxicity, carcinogenicity, and reproductive and developmental toxicity. Toxic equivalency factors have been established for the other PCDD, PCDF and dioxin-like PCB relative to TCDD, and the combined toxicity of a sample can be expressed as toxic equivalent (WHO-TEQ). The EC Scientific Committee for Food evaluated these compounds in 2001. The assessment used the most sensitive adverse toxicological end-points of TCDD in experimental animals. These were developmental and reproductive effects in the male offspring of rats administered TCDD during pregnancy. Because of the large difference between rats and humans in the biological half-life of TCDD, the assessment used a body burden approach to compare across species and derived a tolerable weekly intake of 14 pg TCDD/kg of body weight (bw), which was extended to include all the 2,3,7,8-substituted PCDD and PCDF, and the dioxin-like PCB, and expressed as a group tolerable weekly intake of 14 pg WHO-TEQ/kg bw. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) performed a similar assessment whereas the US Environmental Protection Agency (US EPA) has paid more attention to human data on carcinogenicity. PMID: 17009211 [PubMed - indexed for MEDLINE] 3204. Ann Med. 2006;38(6):389-402. The metabolic syndrome: role of skeletal muscle metabolism. Stump CS(1), Henriksen EJ, Wei Y, Sowers JR. Author information: (1)MU Diabetes and Cardiovascular Research Center, Columbia, Missouri, USA. stumpc@health.missouri.edu Skeletal muscle constitutes the largest insulin-sensitive tissue in the body and is the primary site for insulin-stimulated glucose utilization. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity, and contributes to the development of the metabolic syndrome (MS). The inability to efficiently take up and store fuel, and to transition from fat to glucose as the primary source of fuel during times of caloric abundance (high insulin) or scarcity (low insulin) has been termed metabolic inflexibility which contributes to a whole body metabolic dysregulation and cardiovascular risk. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle includes adipose tissue expansion and increased inflammatory adipokines, increased renin-angiotensin-aldosterone system (RAAS) activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid accumulation, and increased reactive oxygen species. Future research is focused upon understanding these and other potential mechanisms in order to identify therapeutic targets for reducing MS risk. Strategies will include adequate physical activity and maintaining a healthy weight, but may also require specific pharmacologic interventions. PMID: 17008303 [PubMed - indexed for MEDLINE] 3205. Pol Merkur Lekarski. 2006 Jun;20(120):727-30. [Sex hormones and adipocytokines in postmenopausal women]. [Article in Polish] Siemińska L(1), Cichoń-Lenart A, Kajdaniuk D, Kos-Kudła B, Marek B, Lenart J, Nowak M. Author information: (1)Slaska Akademia Medyczna w Zabrzu, Katedra Patofizjologii i Endokrynologii. lusiem@poczta.onet.pl Visceral fat accumulation occuring in postmenopausal women is connected with hypoestrogenism, decreased production of sex-hormone binding globuline (SHBG) and with rise in free testosterone. They have been identified as risk factors for cardiovascular diseases. The exact mechanisms mediating relationships between the excess of visceral adiposity, hormonal variations after menopause and metabolic disturbances, remain unknown. We speculate that adipocytokines produced by adipose tissue: adiponectin, leptin and resistin, might play a role. Adiponectin is a hormone which plays a role in insulin sensitivity and lipid oxidation, and possesses anti-inflammatory properties. Increased levels of androgens post menopause and low SHBG are connected with decreased production of adiponectin. Leptin is another of the adipocytokines which has been shown to be linked to insulin resistance, increased pressure and hypertriglyceridaemia. Sex steroids have effect on leptin secretion but the associations between leptin and menopause are controversial. Recently it was found that resistin, another bioactive substance produced by adipose tissue may related to insulin resistance. Studies on animals indicate that ovariectomy and testosterone significantly increased resistin expression. It seems that adipocytokines may be a link connecting postmenopasual hormonal changes, the excess of visceral fat and increased risk of cardiovascular diseases. PMID: 17007280 [PubMed - indexed for MEDLINE] 3206. Pol Merkur Lekarski. 2006 Jun;20(120):713-6. [Leptin--adipose tissue hormone and its role in cardiovascular diseases]. [Article in Polish] Racek-Król B(1). Author information: (1)Akademia Medyczna w Gdańsku, Katedra i Zakład Farmakologii. bea.rk@wp.pl The discovery of leptin in 1994 led to research into the participation of that hormone in the development of many pathologic states. This article presents current knowledge on the role of leptin, in the pathogenesis of cardiovascular diseases. Leptin is a circulating peptide hormone produced by adipose cells which plays the main role in the regulation of metabolism in humans. Leptin, in the physiological range of plasma levels, is a regulator of cardiovascular function. In fact, higher plasma leptin levels as well as insulin resistance are directly correlated with adiposity. Hyperleptinemia accompanying obesity leads to many pathologic states: stimulation in platelets aggregation, tachycardia, hypertension, increases in plasma levels of pro-thrombotic factors and in levels of CRP and ET-1. In a multicenter study, hyperleptinemia turned out to be the main risk factor responsible for the ischemic disease, especially acute myocardial infarction. Elevated plasma leptin levels play a key role in increased incidence of cardiovascular mortality in obese. PMID: 17007277 [PubMed - indexed for MEDLINE] 3207. J Pediatr Hematol Oncol. 2006 Sep;28(9):594-600. A thoracic wall lipoblastoma in a 3-month-old infant: A case report and review of the literature. Spinelli C(1), Costanzo S, Severi E, Giannotti G, Massart F. Author information: (1)Department of Pediatrics, University of Pisa, Pisa, Italy. Lipoblastoma is a rare benign tumor of adipose tissue seen almost always in infancy and early childhood. Lipoblastoma is present in 2 forms which are pathologically identical: circumscribed and diffuse. It is typically located in the extremities, and less frequently in head-neck region, trunk, and various organs. Lipoblastoma is a tumor with good prognosis with no reported metastases, despite its potential for local invasion and rapid growth. Our patient was a 3-month-old boy who was brought to our clinic for rapidly growing mass in the right hemithorax. With the aim of both diagnosis and treatment, the lipomatous mass was removed by local resection. In addition to the patient's age, histologic and cytogenetic analyses assisted the diagnosis of diffuse lipoblastoma. In the postoperative period, the thorax wall was unaffected, and after 6 years of follow-up no recurrence was observed. In the English literature, 8 cases of thoracic wall lipoblastoma have been previously reported, and only 3 of diffuse form. Here, we report, at our knowledge, the fourth case of thoracic diffuse lipoblastoma, in which cytogenetic analysis showed a previously undescribed karyotype aberration involving chromosomes 8, 13, and 16. PMID: 17006266 [PubMed - indexed for MEDLINE] 3208. J Biosci. 2006 Sep;31(3):405-21. Laminopathies: multiple disorders arising from defects in nuclear architecture. Parnaik VK(1), Manju K. Author information: (1)Centre for Cellular and Molecular Biology, Hyderabad, India. veenap@ccmb.res.in Lamins are the major structural proteins of the nucleus in an animal cell. In addition to being essential for nuclear integrity and assembly, lamins are involved in the organization of nuclear processes such as DNA replication, transcription and repair. Mutations in the human lamin A gene lead to highly debilitating genetic disorders that primarily affect muscle, adipose, bone or neuronal tissues and also cause premature ageing syndromes. Mutant lamins alter nuclear integrity and hinder signalling pathways involved in muscle differentiation and adipocyte differentiation, suggesting tissue-specific roles for lamins. Furthermore, cells expressing mutant lamins are impaired in their response to DNA damaging agents. Recent reports indicate that certain lamin mutations act in a dominant negative manner to cause nuclear defects and cellular toxicity, and suggest a possible role for aberrant lamins in normal ageing processes. PMID: 17006023 [PubMed - indexed for MEDLINE] 3209. Clin Biochem. 2006 Nov;39(11):1047-56. Epub 2006 Aug 22. Leptin: a potential biomarker for childhood obesity? Venner AA(1), Lyon ME, Doyle-Baker PK. Author information: (1)Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada. aavenner@ucalgary.ca Leptin, a hormone made by adipocytes, is an important circulating signal for the regulation of body weight. A review of the scientific literature (PubMed Search 1994 to 2005) for studies examining the relationship among leptin, pediatric obesity and the impact of exercise intervention programmes on leptin concentrations are summarized. The potential utility of leptin as a biomarker for identifying children at risk of obesity is discussed. This literature review demonstrated that (1) leptin directly interacts with the hypothalamus for energy balance regulation; (2) the measurement of free, bound and total leptin as well as soluble leptin receptor concentration are critical for our understanding of obesity in children; and (3) leptin concentration may be an important factor for determining intervention programme responsiveness in pediatric obesity. PMID: 17005171 [PubMed - indexed for MEDLINE] 3210. Bioessays. 2006 Oct;28(10):994-1009. Of bears, frogs, meat, mice and men: complexity of factors affecting skeletal muscle mass and fat. Shavlakadze T(1), Grounds M. Author information: (1)School of Anatomy and Human Biology, The University of Western Australia, 6009, Western Australia. sthea@anhb.uwa.edu.au Extreme loss of skeletal muscle mass (atrophy) occurs in human muscles that are not used. In striking contrast, skeletal muscles do not rapidly waste away in hibernating mammals such as bears, or aestivating frogs, subjected to many months of inactivity and starvation. What factors regulate skeletal muscle mass and what mechanisms protect against muscle atrophy in some species? Severe atrophy also occurs with ageing and there is much clinical interest in reducing such loss of muscle mass and strength (sarcopenia). In the meat industry, a key aim is optimizing the control of skeletal muscle growth and meat quality. The impaired response of muscle to insulin resulting in diabetes, that is a consequence of the metabolic impact of increasing obesity and fat deposition in humans, is also of increasing clinical concern. Intensive research in these fields, combined with mouse models, is reviewed with respect to the molecular control of muscle growth (myogenesis) and atrophy/hypertrophy and fat deposition (adipogenesis) in skeletal muscle, with a focus on IGF-1/insulin signaling. (c) 2006 Wiley Periodicals, Inc. PMID: 16998828 [PubMed - indexed for MEDLINE] 3211. Nat Rev Immunol. 2006 Oct;6(10):772-83. Epub 2006 Sep 22. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Tilg H(1), Moschen AR. Author information: (1)Christian Doppler Research Laboratory for Gut Inflammation and Department of Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. herbert.tilg@uibk.ac.at There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases. PMID: 16998510 [PubMed - indexed for MEDLINE] 3212. Nature. 2006 Sep 21;443(7109):289-95. Central nervous system control of food intake and body weight. Morton GJ(1), Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Author information: (1)Department of Medicine, Harborview Medical Center and University of Washington, Seattle, Washington 98104, USA. The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future research. PMID: 16988703 [PubMed - indexed for MEDLINE] 3213. Int J Clin Pract. 2006 Oct;60(10):1272-80. Thiazolidinediones, insulin resistance and obesity: Finding a balance. Wilding J(1). Author information: (1)Diabetes and Endocrinology Clinical Research Group, Department of Medicine, Clinical Sciences Centre,University Hospital Aintree, Liverpool, UK. j.p.h.wilding@liverpool.ac.uk The clinical efficacy of currently available thiazolidinediones (TZDs) in improving glycaemic control and ameliorating several risk factors for cardiovascular disease (linked to their insulin-sensitising actions as well as direct vascular effects) is well established. Treatment-associated weight gain, however, which has been identified as a class effect of the TZDs, is seen in a number of patients. The magnitude of weight gain correlates in part with improved metabolic control, i.e. better responders are more prone to increases in body weight. The cardiovascular risk associated with obesity appears to be depot specific; while peripheral obesity is associated with a low risk of cardiovascular complications, central obesity confers a greater degree of risk. Evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, the adipose depot that is associated with central obesity. PMID: 16981971 [PubMed - indexed for MEDLINE] 3214. Plast Reconstr Surg. 2006 Sep 15;118(4):1048-57; discussion 1058-9. Role of adipokines in the obesity-inflammation relationship: the effect of fat removal. Esposito K(1), Giugliano G, Scuderi N, Giugliano D. Author information: (1)Department of Geriatrics and Metabolic Diseases, Cardiovascular Research Center, University of Naples SUN, Italy. Comment in Plast Reconstr Surg. 2007 Jul;120(1):358. During the past 10 years, there has been a dramatic increase in the prevalence of obesity in the United States and other developed nations. Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, that play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation. Inflammation is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. According to a hypothesis, stimuli such as overnutrition, physical inactivity, and aging would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. This article discusses the current understanding of important adipokines thought to be involved in the metabolic and cardiovascular risk associated with obesity. Available evidence linking fat removal by liposuction to modification of cardiovascular risk and vascular inflammatory markers in the obese patient is also presented. Most studies have shown that liposuction produces beneficial effects on insulin resistance and vascular inflammation in the obese patient, reducing its cardiovascular risk. Besides having a significant role in body contouring of the obese patient at the end of the lengthy process of bariatric surgery and massive weight loss, plastic surgery should be incorporated into a multifaceted program of lifestyle changes that allows the obese patient to obtain weight loss and, more importantly, to maintain the reduced weight in the long term. PMID: 16980868 [PubMed - indexed for MEDLINE] 3215. Anim Reprod Sci. 2006 Dec;96(3-4):227-39. Epub 2006 Aug 3. The effect of the supply of rumen degradable protein and metabolisable protein on negative energy balance and fertility in dairy cows. Tamminga S(1). Author information: (1)Animal Nutrition Group, Department of Animal Science, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands. seerp.tamminga@wur.nl Reproduction in dairy cattle is negatively affected by a negative energy balance (NEB), a combination of the deposition or mobilisation of fat and protein. The mode of action of NEB on fertility is not always clear, but the severity, length, and probably also the nature of the NEB may be involved. Extensive mobilisation of fat is expected to have detrimental effects on liver function due to the accumulation of non-esterified long chain fatty acids, impairing the detoxification of ammonia into urea. Protein evaluation systems nowadays use the concept of metabolisable protein (MP) and distinguish between rumen degradable protein (RDP) and rumen undegradable protein (RUP). Mobilisation of protein itself does not seem to have negative effects on reproduction. However, when protein is extensively degraded in the rumen or used as an energy source, metabolic residues like ammonia and urea will result. Such residues may exert metabolic effects that are often detrimental to reproduction and fertility. Ammonia is believed to play a role starting before ovulation, whereas urea mainly interferes negatively after fertilisation. But, urea is also believed to aggravate the severity of NEB and its effect on fertility by preventing or delaying the start of cyclicity. Besides, urea has been shown to lower the pH in the uterine fluid, giving rise to disturbances in follicular development and embryonic growth. It is recommended to limit the level of rumen degradable protein in the diet to 10% in the DM. PMID: 16979310 [PubMed - indexed for MEDLINE] 3216. Intern Med. 2006;45(16):941-6. Epub 2006 Sep 15. Regulation of body weight by leptin, with special reference to hypoxia-induced regulation. Yingzhong Y(1), Droma Y, Rili G, Kubo K. Author information: (1)The Research Center for High Altitude Medicine, Qinghai University. Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product-leptin has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment. PMID: 16974055 [PubMed - indexed for MEDLINE] 3217. Maturitas. 2007 Feb 20;56(2):113-21. Epub 2006 Sep 12. Clinical aspects of obesity in the gynecological endocrinologicaly practice. Milewicz A(1), Jedrzejuk D. Author information: (1)Department of Endocrinology, Diabetology and Isotope Treatment Medical University Wroclaw, Poland. milewicz@endo.am.wroc.pl Obesity is epidemic of 21st century, its visceral form is associated with increased risk for type 2 diabetes, cardiovascular disease, hypertension and increased mortality due to consequences of the disease. This type of obesity is a common diagnostic and therapeutic problem in gynecological practice. This especially concerns polycystic ovary disease, in which this type of obesity with its metabolic consequences is one of the important factors in etiology and additionally may lead to remote metabolic and cardiovascular problems. Another group of women in which this type of obesity plays an important role are climacteric women in whom redistribution of adipose tissue with increase in visceral fat deposit occurs. On the basis of current viewpoints and own experiences, the authors propose a diagnostic-therapeutic algorithm in women with visceral obesity and polycystic ovary disease or climacteric period. In case with cardiovascular risk factors (waist circumference over than 80cm, serum triglycerides over 1.7mmol/l, HDL cholesterol lower than 1.0mmol/l, blood pressure over 130/85mmHg and fast serum glucose levels over 100mg/dl) the therapeutic model focuses on the recognize risk factors. It must be considered that diet and physical activity play a very important role in the therapy. PMID: 16973313 [PubMed - indexed for MEDLINE] 3218. Biomaterials. 2006 Dec;27(36):6052-63. Epub 2006 Sep 14. Stem cells and adipose tissue engineering. Gomillion CT(1), Burg KJ. Author information: (1)Department of Bioengineering, 501 Rhodes Engineering Research Center, Clemson University, Clemson, SC 29634, USA. A large proportion of the plastic and reconstructive surgical procedures performed each year are to repair soft tissue defects that result from traumatic injury, tumor resection, and congenital defects. These defects typically result from the loss of a large volume of adipose tissue. To date, no ideal filler material which is successful in all cases has been developed. Additionally, the success of using autologous fat tissue grafts to repair soft tissue defects has been limited. Researchers are thus investigating strategies to engineer volumes of adipose tissue that may be used in these cases. A necessary component for engineering a viable tissue construct is an appropriate cell source. Attempts to engineer adipose tissue have involved the use of preadipocytes and adipocytes as the base cell source. Increased interest surrounding the research and development of stem cells as a source of cells for tissue engineering has, however, led to a new path of investigation for developing adipose tissue-engineering strategies. This manuscript serves as a review of the current state of adipose tissue-engineering methods and describes the shift toward tissue-engineering strategies using stem cells. PMID: 16973213 [PubMed - indexed for MEDLINE] 3219. Praxis (Bern 1994). 2006 Aug 30;95(35):1305-16. [Does running increase the risk of osteoarthritis?]. [Article in German] Frohnauer A(1), Neff A, Knechtle B. Author information: (1)Gesundheitszentrum. There is no doubt that the mean body weight of our population is continuously rising. In this context it is interesting to know that running--compared to cycling--results in a higher decrease of subcutaneous adipose tissue and has therefore a favourable influence on body weight. But public opinion still assumes that running provokes arthritis. This is used as a pretext against regular running training. In this overview we would like to show that running does not increase the risk of arthritis contrary to physical inactivity and overweight. Runners do not show a higher risk of developing joint arthritis on their lower extremities. However, frequency of arthritis is significantly higher in inactive and obese persons. PMID: 16970140 [PubMed - indexed for MEDLINE] 3220. Nestle Nutr Workshop Ser Clin Perform Programme. 2002;6:63-74; discussion 74-8. Aging and body composition. Kehayias JJ(1). Author information: (1)Body Composition Laboratory, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. kehayias@hnrc.tufts.edu PMID: 16969967 [PubMed - indexed for MEDLINE] 3221. J Clin Endocrinol Metab. 2006 Dec;91(12):4753-61. Epub 2006 Sep 12. Review: The role of insulin resistance in nonalcoholic fatty liver disease. Utzschneider KM(1), Kahn SE. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108, USA. kutzschn@u.washington.edu CONTEXT: Insulin resistance is an almost universal finding in nonalcoholic fatty liver disease (NAFLD). This review outlines the evidence linking insulin resistance and NAFLD, explores whether liver fat is a cause or consequence of insulin resistance, and reviews the current evidence for treatment of NAFLD. EVIDENCE ACQUISITION: Evidence from epidemiological, experimental, and clinical research studies investigating NAFLD and insulin resistance was reviewed. EVIDENCE SYNTHESIS: Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by the effect of hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metformin, and thiazolidinediones, all treatments aimed at improving insulin sensitivity, as well as other agents such as vitamin E, have been evaluated in patients with NAFLD and have shown some benefit. However, most intervention studies have been small and uncontrolled. CONCLUSION: Insulin resistance is a major feature of NAFLD that, in some patients, can progress to steatohepatitis. Treatments aimed at reducing insulin resistance have had some success, but larger placebo-controlled studies are needed to fully establish the efficacy of these interventions and possibly others in reducing the deleterious effects of fat accumulation in the liver. PMID: 16968800 [PubMed - indexed for MEDLINE] 3222. FEBS Lett. 2006 Oct 9;580(23):5484-91. Epub 2006 Sep 1. A proposed model of fat packaging by exchangeable lipid droplet proteins. Wolins NE(1), Brasaemle DL, Bickel PE. Author information: (1)Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110, USA. Humans have evolved mechanisms of efficient fat storage to survive famine, but these mechanisms contribute to obesity in our current environment of plentiful food and reduced activity. Little is known about how animals package fat within cells. Five related structural proteins serve roles in packaging fat into lipid droplets. The proteins TIP47, S3-12, and OXPAT/MLDP/PAT-1 move from the cytosol to coat nascent lipid droplets during rapid fat storage. In contrast, perilipin and adipophilin constitutively associate with lipid droplets and play roles in sustained fat storage and regulation of lipolysis. Different tissues express different complements of these lipid droplet proteins. Thus, the tissue-specific complement of these proteins determines how tissues manage lipid stores. PMID: 16962104 [PubMed - indexed for MEDLINE] 3223. Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R47-63. Epub 2006 Sep 7. The dorsomedial hypothalamus: a new player in thermoregulation. Dimicco JA(1), Zaretsky DV. Author information: (1)Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. jdimicco@iupui.edu Neurons in the dorsomedial hypothalamus (DMH) play key roles in physiological responses to exteroceptive ("emotional") stress in rats, including tachycardia. Tachycardia evoked from the DMH or seen in experimental stress in rats is blocked by microinjection of the GABA(A) receptor agonist muscimol into the rostral raphe pallidus (rRP), an important thermoregulatory site in the brain stem, where disinhibition elicits sympathetically mediated activation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail. Disinhibition of neurons in the DMH also elevates core temperature in conscious rats and sympathetic activity to least significant difference interscapular BAT (IBAT) and IBAT temperature in anesthetized preparations. The latter effects are blocked by microinjection of muscimol into the rRP, while microinjection of muscimol into either the rRP or DMH suppresses increases in sympathetic nerve activity to IBAT, IBAT temperature, and core body temperature elicited either by microinjection of PGE(2) into the preoptic area (an experimental model for fever), or central administration of fentanyl. Neurons concentrated in the dorsal region of the DMH project directly to the rRP, a location corresponding to that of neurons trans-synaptically labeled from IBAT. Thus these neurons control nonshivering thermogenesis in rats, and their activation signals its recruitment in diverse experimental paradigms. Evidence also points to a role for neurons in the DMH in thermoregulatory cutaneous vasoconstriction, shivering, and endocrine adjustments. These directions provide intriguing avenues for future exploration that may expand our understanding of the DMH as an important hypothalamic site for the integration of autonomic, endocrine, and behavioral responses to diverse challenges. PMID: 16959861 [PubMed - indexed for MEDLINE] 3224. J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S30-3. Regulation of Kupffer cell activity during chronic ethanol exposure: role of adiponectin. Park PH(1), Thakur V, Pritchard MT, McMullen MR, Nagy LE. Author information: (1)Department of Nutrition, Case Western Reserve University, Cleveland and Departments of Gastroenterology and Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio 44106-4906, USA. There is a growing appreciation that adipose tissue is a multifunctional organ. In addition to its central role in lipid storage, adipose tissue secretes a diverse group of proteins, called adipokines, involved in lipid metabolism, insulin sensitivity, angiogenesis etc. Adipocytes also secrete various inflammatory and anti-inflammatory mediators. Adiponectin, an adipokine with potent anti-inflammatory properties, is thought to play an important role in the regulation of inflammation. The development of alcoholic liver disease is thought to involve increased pro-inflammatory activity, mediated in part by the activation of Kupffer cells. Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha). Recent studies have demonstrated a hepato-protective effect of adiponectin in the progression of alcoholic liver disease. Herein are summarized recent data demonstrating that adiponectin treatment can normalize LPS-stimulated ROS production and TNF-alpha expression in Kupffer cells after chronic ethanol feeding. These studies suggest that the hepato-protective activity of adiponectin is due, at least in part, to a direct anti-inflammatory effect of adiponectin on Kupffer cells. PMID: 16958668 [PubMed - indexed for MEDLINE] 3225. Dig Dis Sci. 2006 Oct;51(10):1685-96. Leptin in the field of hepatic fibrosis: a pivotal or an incidental player? Bethanis SK(1), Theocharis SE. Author information: (1)Department of Forensic Medicine and Toxicology, University of Athens, School of Medicine, 75 M. Asias str Goudi, GR 115 27 Athens, Greece. Leptin is a 16-kDa nonglycosylated protein primarily secreted from the adipocytes of white fat; minor levels of regulated leptin expression also occurs at other sites such as placenta, skeletal muscle, the stomach fundus, and culture-activated hepatic stellate cells (HSCs). Leptin is primarily involved in the regulation of food intake and body composition through a central feedback mechanism linking food ingestion, hypothalamus, and adipose tissue mass. In recent years, however, emerging evidence has suggested a critical role of leptin in hepatic inflammation and fibrogenesis and the influence of leptin on chronic liver disease has been an area of active research worldwide. In this review the data on the in vivo and in vitro actions of leptin on liver cells in experimental animal models of liver injury and the effects of leptin on human liver are discussed, with a focus on three distinct fields of chronic liver diseases: nonalcoholic steatohepatitis, alcoholic liver disease, chronic viral hepatitis, and, especially, hepatitis C. PMID: 16958000 [PubMed - indexed for MEDLINE] 3226. Gut. 2007 Apr;56(4):577-83. Epub 2006 Sep 6. Mesenteric fat in Crohn's disease: a pathogenetic hallmark or an innocent bystander? Peyrin-Biroulet L(1), Chamaillard M, Gonzalez F, Beclin E, Decourcelle C, Antunes L, Gay J, Neut C, Colombel JF, Desreumaux P. Author information: (1)INSERM U795, F-59037 Lille cedex, France. PMCID: PMC1856873 PMID: 16956921 [PubMed - indexed for MEDLINE] 3227. Clin Chim Acta. 2007 Jan;375(1-2):20-35. Epub 2006 Jul 14. Molecular mechanisms of insulin resistance and associated diseases. Mlinar B(1), Marc J, Janez A, Pfeifer M. Author information: (1)Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana, Slovenia. Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases. PMID: 16956601 [PubMed - indexed for MEDLINE] 3228. Crit Rev Food Sci Nutr. 2006;46(7):543-50. Procyanidin effects on adipocyte-related pathologies. Pinent M(1), Bladé C, Salvadó MJ, Blay M, Pujadas G, Fernández-Larrea J, Arola L, Ardévol A. Author information: (1)Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, Spain. Procyanidins, a class of flavonoids, have clear and well-defined beneficial effects against several pathologies including cardiovascular heart disease. Now, studies in vivo are revealing the effects of procyanidins against obesity, where they prevent weight gain and adipose tissue mass increase, and against diabetes and insulin resistance, where they act as antihiperglycemic agents. Several mechanisms may be responsible for these effects. One of these, due to the key role of adipose tissue in the development of obesity and insulin resistance, is their effect on adipocytes. In this review we compile the studies that indicate a protective role for procyanidins in obesity and insulin resistance, focusing on their effects on the adipocyte, where procyanidins modify lipid synthesis, lipid degradation, glucose uptake, and adipose differentiation. PMID: 16954063 [PubMed - indexed for MEDLINE] 3229. Panminerva Med. 2006 Jun;48(2):77-85. Obesity: a main factor of metabolic syndrome? Licata G(1), Argano C, Di Chiara T, Parrinello G, Scaglione R. Author information: (1)Department of Internal Medicine, University of Palermo, Palermo, Italy. medintli@unipa.it The metabolic syndrome (MS) is a common metabolic disorder that has been recently related to the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology has been largely attributed, in the past years, to insulin-resistance, even if several epidemiological and pathophysiological data are attractive to indicate visceral obesity as a main factor in the occurrence of the MS, promoting new definitions and re-evaluation of the pathogenesis of this syndrome. In this review, we have analyzed the role of visceral obesity in the new definition of the MS such as the pathophysiological role of the abnormal fat distribution in the occurrence of this syndrome. In view of this, relationships between visceral obesity, free fatty acids, dyslipidaemia and insulin-resistance have been reported. In addition, the effects of some adipocytokines and other proinflammatory factors produced by fat accumulation on the appearance of the MS have been also emphasized. Finally, according to recommendations of several international societies, the role of the life-style change and of the weight loss in the prevention and treatment both of obesity and of other associated risk factors has been analyzed. PMID: 16953145 [PubMed - indexed for MEDLINE] 3230. Am J Gastroenterol. 2006 Nov;101(11):2629-40. Epub 2006 Sep 4. The evolving role of leptin and adiponectin in chronic liver diseases. Tsochatzis E(1), Papatheodoridis GV, Archimandritis AJ. Author information: (1)2nd Department of Internal Medicine, Medical School of Athens University, Hippokration General Hospital, Athens, Greece. Erratum in Am J Gastroenterol. 2006 Dec;101(12):2915. Leptin and adiponectin, the main metabolic products of adipose tissue, have been implicated in a wide spectrum of human diseases. Given the frequent presence of hepatic steatosis in several chronic liver diseases, there is currently increasing interest in the role of these adipokines in the development of hepatic steatosis and also in necroinflammation and fibrosis, mostly in patients with nonalcoholic fatty liver disease or chronic hepatitis C. According to experimental data, reduced adiponectin levels and increased leptin levels associated with leptin resistance, which are usually observed in obese patients with or without metabolic syndrome, may result in fat accumulation in the liver and in the enhancement of liver inflammation and mostly fibrogenesis. Increased leptin and decreased adiponectin serum levels have been detected initially in patients with nonalcoholic steatohepatitis and more recently in patients with chronic hepatitis C compared to healthy controls in most but not all studies, while the data on the associations between these adipokine levels and the severity of hepatic steatosis or fibrosis are still rather conflicting. However, several potential confounding parameters were not evaluated in all studies. Therefore, the associations between adipokines and liver histological lesions and their effects on liver cells should be evaluated further in prospective, carefully designed studies, including larger cohorts of patients with detailed assessment of metabolic and other potential confounding factors. PMID: 16952281 [PubMed - indexed for MEDLINE] 3231. Exp Biol Med (Maywood). 2006 Sep;231(8):1287-99. Flavonoids attenuate cardiovascular disease, inhibit phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. Peluso MR(1). Author information: (1)mpeluso@earthlink.net Plant flavonoids are widely distributed polyphenolic compounds of the human diet. They consist of six major classes based on specific structural differences: flavonols, flavones, flavanones, catechins, anthocyanidins, and isoflavones. All of the major classes of flavonoids are comprised of three six-membered rings: an aromatic A-ring fused to a heterocyclic C-ring that is attached through a single carbon-carbon bond to an aromatic Bring. Population studies have shown that flavonoid intake is inversely correlated with mortality from cardiovascular disease, and numerous flavonoids of dietary significance have been shown to beneficially impact parameters associated with atherosclerosis, including lipoprotein oxidation, blood platelet aggregation, and vascular reactivity. Therapeutic effects of flavonoids on platelet aggregability and blood pressure have been attributed to competitive inhibition of cyclic nucleotide phosphodiesterase (PDE), an elevation in cAMP level, and subsequent activation of protein kinase A (cAMP-dependent protein kinase). In addition, flavonoids may induce neutral lipid hydrolysis from lipid stores through PDE inhibition in adipose tissue and liver. Indeed, the three-dimensional structure of many flavonoids is sterically and electrostatically compatible with the catalytic site of cAMP PDE3 and PDE4. Flavonoids have also been reported to suppress pathways of lipid biosynthesis and of very low-density lipoprotein production in cultured hepatocytes. Continued studies of the biochemical mechanisms underlying the biological effects of plant flavonoids may uncover new strategies for the treatment of cardiovascular disease, as well as associated conditions such as obesity, hepatic steatosis, and Type 2 diabetes. PMID: 16946397 [PubMed - indexed for MEDLINE] 3232. Endocrinology. 2006 Dec;147(12):5542-8. Epub 2006 Aug 31. Minireview: vitamin D receptor: new assignments for an already busy receptor. Norman AW(1). Author information: (1)Department of Biochemistry and Biomedical Sciences, University of California, Riverside, California 92506, USA. Anthony.norman@ucr.edu With its discovery in 1920, the molecule vitamin D achieved prominence as a nutritionally essential vitamin important for calcium homeostasis, particularly in the intestine and bone. Then in 1932, the elucidation of vitamin D's chemical structure revealed that this vitamin was in fact a steroid. But it was not until the late 1960s that it was appreciated that the steroid vitamin D was a precursor of a new steroid hormone, 1alpha,25(OH)2-vitamin D3 [1alpha,25(OH)2D3], that is produced by the kidney acting as an endocrine gland. The discovery in 1969 of the nuclear vitamin D receptor (VDR) for 1alpha,25(OH)2D3 initiated a two-decade-long proliferation of reports that collectively described the broad sphere of influence of the vitamin D endocrine system that is defined by the presence of the VDR in over 30 tissue/organs of man. The new genomic frontiers defined by the cellular presence of the VDR include the immune system's B and T lymphocytes, hair follicle, muscle, adipose tissue, bone marrow, and cancer cells. Unexpectedly in the mid 1980s, a new world of 1alpha,25(OH)2D3-mediated rapid responses (RR) was discovered. These were responses that occurred too rapidly (minutes to an hour) to be explained as the simple consequence of the nuclear VDR regulating gene transcription. Some RR examples include the rapid intestinal absorption of calcium (transcaltachia), secretion of insulin by pancreatic beta-cells, opening of voltage-gated Ca2+ and Cl- channels in osteoblasts, and the rapid migration of endothelial cells. The question then arose as to whether there was a second receptor, apart from the nuclear VDR, which responded to the presence of 1alpha,25(OH)2D3 to generate RR? After some false starts, it now appears that the classic VDR, long known to reside in the cell nucleus, in some cells is also associated with caveolae present in the plasma membrane. Furthermore, the chemical properties of the conformationally flexible 1alpha,25(OH)2D3 allow it to generate different shaped ligands for the VDR that are selective either for genomic or for RR. This minireview summarizes a proposed conformational ensemble model of the VDR that provides insight into how different ligand shapes of 1alpha,25(OH)2D3 acting through the VDR in different cellular locations can selectively mediate both genomic and RR. PMID: 16946007 [PubMed - indexed for MEDLINE] 3233. Nat Clin Pract Nephrol. 2006 Sep;2(9):527-34. Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia. Mak RH(1), Cheung W, Cone RD, Marks DL. Author information: (1)Division of Pediatric Nephrology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA. makr@ohsu.edu Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia. PMID: 16941045 [PubMed - indexed for MEDLINE] 3234. Med Eng Phys. 2007 May;29(4):413-31. Epub 2006 Aug 28. Needle insertion into soft tissue: a survey. Abolhassani N(1), Patel R, Moallem M. Author information: (1)Canadian Surgical Technologies & Advanced Robotics (CSTAR), London, Ontario, Canada. nabolhas@uwo.ca Needle insertion in soft tissue has attracted considerable attention in recent years due to its application in minimally invasive percutaneous procedures such as biopsies and brachytherapy. This paper presents a survey of the current state of research on needle insertion in soft tissue. It examines the topic from several aspects, e.g. modeling needle insertion forces, modeling tissue deformation and needle deflection during insertion, robot-assisted needle insertion, and the effect of different trajectories on tissue deformation. All studies show that the axial force of a needle during insertion in soft tissue is the summation of different forces distributed along the needle shaft such as stiffness force, frictional force and cutting force. Some studies have modeled these forces. The force data in some procedures is used for identifying tissue layers as the needle is inserted or for path planning. Needle deflection and tissue deformation are major problems for accurate needle insertion and attempts have been made to model them. Using current models several insertion techniques have been developed which are briefly reviewed in this paper. PMID: 16938481 [PubMed - indexed for MEDLINE] 3235. Trends Endocrinol Metab. 2006 Oct;17(8):314-20. Epub 2006 Aug 30. Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. Langin D(1), Arner P. Author information: (1)INSERM U586, Unité de Recherches sur les Obésités, F-31432 Toulouse, France. langin@toulouse.inserm.fr Catecholamines and natriuretic peptides stimulate human adipocyte lipolysis through an increase in cAMP and cGMP levels, resulting in phosphorylation and activation of hormone-sensitive lipase. A defect in hormone-sensitive lipase expression might contribute to the resistance to catecholamine-induced lipolysis observed in obesity. The respective roles and regulation of hormone-sensitive lipase and adipose triglyceride lipase in spontaneous and hormone-stimulated lipolysis remain to be determined. Tumor necrosis factor alpha stimulates triglyceride hydrolysis by multiple intracellular pathways acting on insulin signaling, G proteins and perilipins, and might contribute to enhanced plasma fatty acid levels in obesity. Characterization of the lipolytic pathways might provide novel strategies to decrease free fatty acid production and reverse insulin resistance and other obesity-related metabolic complications. PMID: 16938460 [PubMed - indexed for MEDLINE] 3236. Oncogene. 2006 Aug 28;25(38):5210-9. RB, the conductor that orchestrates life, death and differentiation. Khidr L(1), Chen PL. Author information: (1)Department of Biological Chemistry, University of California-Irvine Med Sci 1, Irvine, CA 92697, USA. The retinoblastoma susceptibility gene was the first tumor suppressor gene identified in humans and the first tumor suppressor gene knocked out by targeted deletion in mice. RB serves as a transducer between the cell cycle machinery and promoter-specific transcription factors, its most documented activity being the repression of the E2F family of transcription factors, which regulate the expression of genes involved in cell proliferation and survival. Recent investigations of RB function suggest that it works as a fundamental regulator to coordinate pathways of cellular growth and differentiation. In this review, we unravel the novel role of an equally important aspect of RB in downregulating the differentiation inhibitor EID-1 during cellular differentiation by teasing apart the signal, which elicit differentiation and limit cell cycle progression, since the molecular mechanisms relating to RB activation of differentiation is much less understood. We review the various roles for RB in differentiation of neurons, muscle, adipose tissue, and the retina. In addition, we provide an update for the current models of the role of RB in cell cycle to entry and exit, extending the view toward chromatin remodeling and expose the dichotomies in the regulation of RB family members. We conclude with a discussion of a novel RB regulatory network, incorporating the dynamic contribution of EID family proteins. PMID: 16936739 [PubMed - indexed for MEDLINE] 3237. J Hypertens Suppl. 2006 Aug;24(5):S18-20. Arteries, inflammation and insulin resistance. Amar J(1), Perez L, Burcelin R, Chamontin B. Author information: (1)Department of internal medicine and arterial hypertension, Hôpital Rangueil, Toulouse, France. amar.j@chu-toulouse.fr Inflammation plays a role in all stages of atherosclerosis from the formation to the rupture of the plaque. Guided by inflammatory mediators, monocytes bind to an endothelium damaged by cardiovascular risk factors, and then migrate towards the intima where, after incorporating oxidized low-density lipoprotein particles, they are transformed into foam cells. The lipid streak forms and develops as an atherosclerotic plaque, which is susceptible to erosion and rupture. Inflammation fed by excess adipose tissue decreases insulin sensitivity, which is the central feature of the metabolic syndrome. Inflammation therefore appears to be a common factor of atherosclerosis and the metabolic syndrome. The factors triggering this inflammation have yet to be determined. One line of thought would appear to point to diet. PMID: 16936531 [PubMed - indexed for MEDLINE] 3238. Horm Metab Res. 2006 Jul;38(7):437-41. Metabolic syndrome and the endocrine stress system. Lamounier-Zepter V(1), Ehrhart-Bornstein M, Bornstein SR. Author information: (1)Medical Clinic III, University of Dresden, Dresden, Germany. valaria.zepter@uniklinikum-dresden.de Obesity constitutes one of the most serious public health problems, with rapidly increasing prevalence in western societies. Consequently, metabolic syndrome, a condition strongly associated with obesity, has become an epidemic problem. Recent studies have implicated chronic alterations to the stress system as playing a major role in the metabolic syndrome's pathophysiology. This brief review discusses the role of stress and hypothalamic-pituitary-adrenal axis dysfunction in the development of metabolic syndrome as well as new insights into the crosstalk between adipose tissue and endocrine stress system. PMID: 16933178 [PubMed - indexed for MEDLINE] 3239. Nat Clin Pract Rheumatol. 2006 Jan;2(1):35-43. Mechanisms of disease: is osteoporosis the obesity of bone? Rosen CJ(1), Bouxsein ML. Author information: (1)The Jackson Laboratory in Bar Harbor, ME 04401, USA. rofe@aol.com Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity. PMID: 16932650 [PubMed - indexed for MEDLINE] 3240. Nat Clin Pract Endocrinol Metab. 2006 Aug;2(8):447-58. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Lustig RH(1). Author information: (1)Division of Endocrinology, University of California San Francisco, San Francisco, CA 94143-0434, USA. rlustig@peds.ucsf.edu Childhood obesity has become epidemic over the past 30 years. The First Law of Thermodynamics is routinely interpreted to imply that weight gain is secondary to increased caloric intake and/or decreased energy expenditure, two behaviors that have been documented during this interval; nonetheless, lifestyle interventions are notoriously ineffective at promoting weight loss. Obesity is characterized by hyperinsulinemia. Although hyperinsulinemia is usually thought to be secondary to obesity, it can instead be primary, due to autonomic dysfunction. Obesity is also a state of leptin resistance, in which defective leptin signal transduction promotes excess energy intake, to maintain normal energy expenditure. Insulin and leptin share a common central signaling pathway, and it seems that insulin functions as an endogenous leptin antagonist. Suppressing insulin ameliorates leptin resistance, with ensuing reduction of caloric intake, increased spontaneous activity, and improved quality of life. Hyperinsulinemia also interferes with dopamine clearance in the ventral tegmental area and nucleus accumbens, promoting increased food reward. Accordingly, the First Law of Thermodynamics can be reinterpreted, such that the behaviors of increased caloric intake and decreased energy expenditure are secondary to obligate weight gain. This weight gain is driven by the hyperinsulinemic state, through three mechanisms: energy partitioning into adipose tissue; interference with leptin signal transduction; and interference with extinction of the hedonic response to food. PMID: 16932334 [PubMed - indexed for MEDLINE] 3241. Nat Clin Pract Endocrinol Metab. 2006 Jul;2(7):374-83. The role of 'adipotropins' and the clinical importance of a potential hypothalamic-pituitary-adipose axis. Schäffler A(1), Schölmerich J, Buechler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de Since adipocytes express specific receptors for pituitary hormones and hypothalamic releasing factors, adipose tissue has to be regarded as a fast-acting endocrine gland under the control of the brain. Expanding on this suggestion, the existence and clinical impact of a hypothalamic-pituitary-adipose axis is reviewed. The term 'adipotropins' is introduced in order to describe pituitary and hypothalamic hormones or releasing factors that directly target adipocytes by their specific receptors. PMID: 16932320 [PubMed - indexed for MEDLINE] 3242. Nat Clin Pract Endocrinol Metab. 2006 Jun;2(6):335-48. Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance. Roden M(1). Author information: (1)First Medical Department 1 (Diabetology, Gastroenterology, Nephrology), Hanusch Hospital, Heinrich Collin Strasse 30, A-1140 Vienna, Austria. michael.roden@meduniwien.ac.at Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus. PMID: 16932311 [PubMed - indexed for MEDLINE] 3243. Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2200-7. Epub 2006 Aug 24. PAI-1 and the metabolic syndrome: links, causes, and consequences. Alessi MC(1), Juhan-Vague I. Author information: (1)Laboratory of Hematology, INSERM UMR 626, Faculty of Medicine, Marseilles, France. The link between plasminogen activator inhibitor (PAI)-1 and the metabolic syndrome with obesity was established many years ago. Increased PAI-1 level can be now considered a true component of the syndrome. The metabolic syndrome is associated with an increased risk of developing cardiovascular disease, and PAI-1 overexpression may participate in this process. The mechanisms of PAI-1 overexpression during obesity are complex, and it is conceivable that several inducers are involved at the same time at several sites of synthesis. Interestingly, recent in vitro and in vivo studies showed that besides its role in atherothrombosis, PAI-1 is also implicated in adipose tissue development and in the control of insulin signaling in adipocytes. These findings suggest PAI-1 inhibitors serve in the control of atherothrombosis and insulin resistance. PMID: 16931789 [PubMed - indexed for MEDLINE] 3244. Obesity (Silver Spring). 2006 Jul;14 Suppl 4:156S-159S. Obesity: person and population. Cope MB(1), Allison DB. Author information: (1)Department of Nutrition Sciences, University of Alabama at Birmingham, Ryals Public Health Building 327, 1665 University Boulevard, Birmingham, AL 35294, USA. Obesity is a problem among all ages and races, in both genders, and across all socioeconomic classes, and the prevalence of obesity has been increasing. Efforts are being made to combat the increasing prevalence, but only modest success has been achieved. Obesity is affected by multiple factors. There are genetic and environmental components involved, yet pinpointing specific genetic and environmental influences has been difficult. Development of treatments has ranged from pharmaceuticals to behavioral modification. Extant treatments aimed at the individual and administered for relatively brief portions of the lifespan have shown only modest results. If we are to make pervasive and enduring changes to population adiposity levels, it is likely that we will need to make pervasive and enduring changes to the ways in which we live across the lifespan. PMID: 16931498 [PubMed - indexed for MEDLINE] 3245. Obesity (Silver Spring). 2006 Jun;14 Suppl 3:143S-149S. Potential role of new therapies in modifying cardiovascular risk in overweight patients with metabolic risk factors. Jensen MD(1). Author information: (1)Endocrine Research Unit, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Jensen.Michael@Mayo.edu The serotonin, norepinephrine, dopamine, and endocannabinoid systems, as well as a host of other systems, mediate hunger and satiety signals. Weight loss agents that modulate appetite through pure central nervous system pathways (e.g., APD356, a selective serotonin receptor agonist) and peripheral signals to central nervous system pathways (e.g., cholecystokinin receptor agonists and ghrelin receptor antagonists) are in preclinical or early phase studies. Both devices and pharmacological compounds that facilitate weight loss and/or target multiple components of metabolic risk also are in development. One of the medications that has completed extensive phase III clinical trials and may become available in the foreseeable future is rimonabant, a selective cannabinoid 1-receptor antagonist. Drugs that improve adipose tissue function or fatty acid metabolism (e.g., AOD9604) also are in clinical trials. Some currently available medications may reduce metabolic complications without treating obesity per se (e.g., acipimox, pioglitazone). Surgically implanted gastric pacemaker systems that modulate vagus nerve activity and delay gastric emptying are under study. PMID: 16931496 [PubMed - indexed for MEDLINE] 3246. Arch Physiol Biochem. 2006 Apr;112(2):105-13. Pathways leading to muscle insulin resistance--the muscle--fat connection. Sell H(1), Eckel J, Dietze-Schroeder D. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany. Type 2 diabetes is a heterogeneous disease characterized by hyperglycemia and insulin resistance in peripheral tissues such as adipose tissue and skeletal muscle. This review focuses on obesity as one of the major environmental factors contributing to the development of diabetes. It has become evident that adipose tissue represents an active secretory organ capable of releasing a variety of cytokines such as TNFalpha, IL-6, adiponectin and other still unknown factors that might constitute the missing link between adipose tissue and insulin resistance. In fact, adipocyte-derived factors are significantly increased in obesity and represent good predictors of the development of type 2 diabetes. The negative crosstalk between adipocytes and skeletal muscle cells leads to disturbances in muscle cell insulin signalling and insulin resistance involving major pathways in inflammation, cellular stress and mitogenesis. Positive regulators of insulin sensitivity include the adipocyte hormone adiponectin and inhibitors of inflammatory pathways such as JNK-, IKK- and ERK-inhibitors. In summary, a better knowledge of intracellular and intercellular mechanisms by which adipose tissue affects skeletal muscle cell physiology may help to develop new strategies for diabetes treatment. PMID: 16931452 [PubMed - indexed for MEDLINE] 3247. Arch Physiol Biochem. 2006 Apr;112(2):82-8. Insulin signalling in human adipose tissue. Laviola L(1), Perrini S, Cignarelli A, Giorgino F. Author information: (1)Section of Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. Adipose tissue is a critical regulator of energy balance and substrate metabolism, and synthesizes several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. An excessive amount of adipose tissue has been associated with the development of type 2 diabetes, premature atherosclerosis, and cardiovascular disease. It is believed that the adverse metabolic impact of visceral fat relies on a relative resistance to the action of insulin in this depot compared to other adipose tissue depots. However, information on insulin signalling reactions in human fat is limited. In this paper, we review the major insulin signalling pathways in adipocytes and their relevance for metabolic regulation, and discuss recent data indicating different signalling properties of visceral fat as compared to other fat depots, which may explain the metabolic and hormonal specificity of this fat tissue depot in humans. PMID: 16931450 [PubMed - indexed for MEDLINE] 3248. Front Neuroendocrinol. 2006 Sep;27(3):285-307. Epub 2006 Aug 23. Neuroendocrine mechanisms of innate states of attenuated responsiveness of the hypothalamo-pituitary adrenal axis to stress. Tilbrook AJ(1), Clarke IJ. Author information: (1)Department of Physiology, Monash University, Victoria, Australia. alan.tilbrook@med.monash.edu.au Neuroendocrine responses to stress vary between sexes and reproductive states and are influenced by the type of stressor. Stress responses are attenuated in some physiological states, such as lactation and conditions of low visceral adipose tissue. Moreover, some individuals within a species characteristically display reduced stress responses. The neuroendocrine mechanisms for stress hyporesponsiveness are likely to include reduced synthesis and secretion of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus as a result of enhanced glucocorticoid negative feedback and/or reduced noradrenergic stimulatory input from the brain stem. A major limitation of research to date is the lack of direct measures of CRH and AVP secretion. Attenuated stress responsiveness is also commonly associated with reduced pituitary responsiveness to CRH and AVP. The possible roles of inhibitory central inputs to CRH and AVP neurons and of oxytocin and prolactin in attenuating the HPA axis responses to stress are unknown. PMID: 16930683 [PubMed - indexed for MEDLINE] 3249. Korean J Gastroenterol. 2006 Aug;48(2):67-74. [Adipocyte signals in energy balance and digestive diseases]. [Article in Korean] Chun HJ(1), Keum B, Uhm CS. Author information: (1)Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University College of Medicine, Seoul, Korea. For the regulation of energy balance in various internal organs including gut, pancreas and liver, visceral adipose tissue and brain perform important sensing and signaling roles via neural and endocrine pathway. Among these, adipose tissue has been known as a simple energy-storing organ, which stores excess energy in triglyceride. However, it became apparent that adipocytes have various receptors related to energy homeostasis, and secrete adipocytokines by endocrine, paracrine and autocrine mechanisms. In this review, basic roles of adipocytes in energy homeostasis and the correlation between adipocyte signals and digestive diseases are discussed. PMID: 16929149 [PubMed - indexed for MEDLINE] 3250. Contrib Nephrol. 2006;151:175-83. Leptin and renal fibrosis. Wolf G(1), Ziyadeh FN. Author information: (1)Department of Internal Medicine III, Friedrich-Schiller-University, Jena, Germany. Gunter.Wolf@med.uni-jena.de Leptin is a peptide hormone that is mainly, but not exclusively, produced in adipose tissue and plays a pivotal role in regulating food intake and energy expenditure. Besides its effects on regulation of body weight, appetite and energy expenditure, leptin exhibits influence on the immune system and may contribute to the deterioration of renal function. These direct and indirect renal effects of leptin could partly explain obesity-associated kidney disease and may be also relevant for diabetic nephropathy in type 2 diabetes. Leptin is primarily metabolized in the kidney, presumably by binding to megalin, a multiligand receptor in the proximal tubule, tubular uptake and endocytosis. The kidney expresses abundant concentrations of the small isoform of the leptin receptor (Ob-Ra). In cultured renal rat endothelial cells and mesangial cells obtained from db/db mice, leptin can signal through the Ob-Ra receptor isoform. The peptide stimulates proliferation of glomerular endothelial cells, increases TGF-beta1 synthesis, and collagen type IV production. In contrast, leptin did not influence TGF-beta1 production in mesangial cells, but the peptide stimulates glucose transport in these cells, increased collagen type I synthesis, and lead to an upregulation of surface TGF-beta type II receptors through signal transduction pathways involving phosphatidylinositol-3-kinase. Leptin also stimulates hypertrophy, but not proliferation in cultured rat mesangial cells. Infusion of leptin for 3 weeks into normal rats fosters development of glomerulosclerosis and proteinuria. In addition, transgenic mice with leptin overexpression demonstrated a increase in collagen type IV and fibronectin mRNA in the kidney. Additional previously described direct and indirect effects of leptin on the kidney include natriuretic effects, an increase in sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is a target organ for leptin and that this hormone might play an important role in renal pathophysiology. PMID: 16929141 [PubMed - indexed for MEDLINE] 3251. Contrib Nephrol. 2006;151:165-74. Adipose tissue and inflammation in chronic kidney disease. Axelsson J(1), Heimbürger O, Stenvinkel P. Author information: (1)Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Division of Renal Medicine, Stockholm, Sweden. Cardiovascular disease remains a major cause of morbidity and mortality in end-stage renal disease patients. As traditional risk factors cannot alone explain the unacceptable high prevalence and incidence of cardiovascular disease in this high-risk population, inflammation (interrelated to insulin resistance, oxidative stress, wasting and endothelial dysfunction) has been suggested to be a significant contributor. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has been shown that fat tissue secretes a number of adipokines including leptin, adiponectin and visfatin, as well as a cytokines (here defined as signaling proteins mainly secreted by other cells present in adipose tissue, but sometimes also to a lesser degree by adipocytes per se), such as resistin, tumor-necrosis factor-alpha and interleukin-6. Adipokine serum levels are markedly elevated in chronic kidney disease, probably due to decreased renal excretion. Evidence suggests that they may have pro-inflammatory effects as well as contribute to metabolic derangements. Much research is thus still needed to elucidate the likely complex interactions between different fat tissue depots, muscle tissue and its' effects on inflammation, vascular health and outcome in this high-risk population. PMID: 16929140 [PubMed - indexed for MEDLINE] 3252. Contrib Nephrol. 2006;151:122-34. Role of the renin-angiotensin- aldosterone system in the metabolic syndrome. Engeli S(1). Author information: (1)Franz Volhard Clinical Research Center, Charité Campus Buch, Berlin, Germany. stefan.engeli@charite.de Clinical trials of angiotensin-converting enzyme inhibitors and angiotensin type 1- receptor blockers have demonstrated a significant reduction in cardiovascular, renal and new-onset diabetes risk. This finding raises the question on the pathophysiological role of the renin-angiotensin-aldosterone system (RAAS) in the Metabolic Syndrome. Inappropriate activation of the RAAS in the circulation but also on the tissue level, suggests profound changes in the regulation of this system in the Metabolic Syndrome. Possible physiological and molecular mechanisms that link the RAAS with the Metabolic Syndrome include interactions between insulin and angiotensin type 1-receptors, hemodynamic effects that change nutrient partition to tissues such as skeletal muscle and adipose tissue, inhibition of adipogenesis which may limit the storage capacity of adipose tissue and allows ectopic lipid storage which leads to lipotoxicity, influence on adipokine secretion, and influence on insulin secretion from pancreatic Beta-cells. Most of these mechanisms are linked with decreased insulin sensitivity. Convincing experimental evidence on these possible mechanisms, however, is rare, and several obscurities remain, which are partly due to species differences between rodent models and humans. Thus, data from clinical trials clearly suggest that the RAAS plays an important role for the pathophysiology of the Metabolic Syndrome, but the molecular mechanisms are not understood very well at present. PMID: 16929137 [PubMed - indexed for MEDLINE] 3253. Contrib Nephrol. 2006;151:91-105. Renal handling of adipokines. Kataoka H(1), Sharma K. Author information: (1)Dorrance Hamilton Research Laboratories, Division of Nephrology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Chronic kidney disease (CKD) is now considered as one of the strongest risk factors for all cause mortality and cardiovascular events. However, the link between CKD and systemic events is unclear. The role of the kidney is primarily considered a target organ during the development of obesity as altered production of adipokines from visceral adipocytes, however, it should also be recognized that the kidney itself could alter the clearance and production of adiopokines. In this chapter, we provide a discussion of renal handling of a variety of adipokines. Specifically, there is a growing body of data supporting a major role for the kidney in clearance of insulin, leptin, and TGF-Beta. In addition, plasminogen activator inhibitor-1, vascular endothelial growth factor, angiotensin II, and resistin may also be altered by the kidney. The mechanistic regulation of renal handling by the kidney of a variety of circulating adipokines, however is poorly defined. We conclude that the kidney has pivotal roles in the regulation of adipokines and that altered renal handling of adipokines may contribute to the imbalance of factors that ultimately lead to progressive cardiovascular and systemic disease. PMID: 16929135 [PubMed - indexed for MEDLINE] 3254. Contrib Nephrol. 2006;151:70-90. The adipose tissue as an endocrine organ--a nephrologists' perspective. Chudek J(1), Adamczak M, Nieszporek T, Wiecek A. Author information: (1)Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland. During the last decade white adipose tissue was recognized as an active endocrine organ and a source of many proinflammatory cytokines, chemokines, growth factors and complement proteins called 'adipokines' or 'adipocytokines'. The contribution of different cell types which compose the adipose tissue: adipocytes, preadipocytes, stromal/vascular cells and macrophages in secretion of above-mentioned adipokines varies remarkably. These adipokines seem to play an important role in the pathogenesis of obesity-related comorbidities. In this review, we have summarized the present knowledge on the most important adipokines in patients with obesity, arterial hypertension and chronic kidney diseases. PMID: 16929134 [PubMed - indexed for MEDLINE] 3255. Contrib Nephrol. 2006;151:57-69. Obesity paradox in patients on maintenance dialysis. Kalantar-Zadeh K(1), Kopple JD. Author information: (1)Division of Nephrology and Hypertension, Los Angeles Biomedical Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. kamkal@ucla.edu Overweight (body mass index [BMI]=25-30 kg/m2) and obesity (BMI>30 kg/m2) have become mass phenomena with a pronounced upward trend in prevalence in most countries throughout the world and are associated with increased cardiovascular risk and poor survival. In patients with chronic kidney disease (CKD) undergoing maintenance hemodialysis an 'obesity paradox' has been consistently reported, i.e., a high BMI is incrementally associated with better survival. While this 'reverse epidemiology' of obesity is relatively consistent in maintenance hemodialysis patients, studies in peritoneal dialysis patients have yielded mixed results. A similar obesity paradox has been described in patients with chronic heart failure as well as in 20 million members of other distinct medically 'at risk' populations in the USA. Possible causes of the reverse epidemiology of obesity include: (1) time-discrepancies between the competing risks for the adverse events that are associated with overnutrition and undernutrition; (2) sequestration of uremic toxins in adipose tissue; (3) selection of a gene pool favorable to longer survival in dialysis patients during the course of CKD progression, which eliminates over 95% of the CKD population before they commence maintenance dialysis therapy; (4) a more stable hemodynamic status; (5) alterations in circulating cytokines; (6) unique neurohormonal constellations; (7) endotoxin-lipoprotein interactions; and (8) reverse causation. Examining the causes and consequences of the obesity paradox in dialysis patients can improve our understanding of similar paradoxes observed both for other conventional risk factors in chronic dialysis patients, such as blood pressure and serum cholesterol, and in other populations, such as patients with heart failure, cancer or AIDS or geriatric populations. PMID: 16929133 [PubMed - indexed for MEDLINE] 3256. Physiol Res. 2007;56(4):375-81. Epub 2006 Aug 22. White adipose tissue: storage and effector site for environmental pollutants. Müllerová D(1), Kopecký J. Author information: (1)Institute of Public Health, Medical Faculty in Pilsen, Charles University, Pilsen, Czech Republic. dana.mullerova@lfp.cuni.cz White adipose tissue (WAT) represents a reservoir of lipophilic environmental pollutants, especially of those which are resistant to biological and chemical degradation - so-called persistent organic pollutants (POPs). Large amounts of different congeners and isomers of these compounds exhibit a variety of adverse biological effects. Interactions among different classes of compounds, frequently with opposing effects, complicate hazard evaluation and risk assessment. WAT is the key organ for energy homeostasis and it also releases metabolites into the circulation and adipokines with systemic effects on insulin sensitivity and fuel partitioning in muscles and other tissues. Its beneficial role is lost in obesity when excessive accumulation of WAT contributes to severe diseases, such as diabetes. POPs may crossroad or modulate the effect of endogenous ligands of nuclear transcription factors, participating in differentiation, metabolism and the secretory function of adipocytes. These mechanisms include, most importantly: i) endocrine disrupting potency of POPs mixtures on androgen, estrogen or thyroid hormone metabolism/functions in WAT, ii) interference of dioxin-like chemicals with retinoic acid homeostasis, where impact on retinoid receptors is expected, and iii) interaction with transcriptional activity of peroxisome proliferator-activated receptors is likely. Thus, the accumulation and action of POPs in WAT represents a unitary mechanism explaining, at least in part, the effects of POPs in the whole organism. By modulating WAT differentiation, metabolism and function, the POPs could affect not only the physiological role of WAT, but they may also influence the development of obesity-associated diseases. PMID: 16925464 [PubMed - indexed for MEDLINE] 3257. Surg Obes Relat Dis. 2005 Sep-Oct;1(5):486-95. Epub 2005 Jul 21. Neurohormonal pathways regulating food intake and changes after Roux-en-Y gastric bypass. Orlando FA(1), Goncalves CG, George ZM, Halverson JD, Cunningham PR, Meguid MM. Author information: (1)Surgical Metabolism and Nutrition Laboratory, Department of Surgery, Neuroscience Program, SUNY Upstate Medical University, Syracuse, New York 13210, USA. PMID: 16925275 [PubMed - indexed for MEDLINE] 3258. Surg Obes Relat Dis. 2005 Jan-Feb;1(1):25-34. The pathogenesis of obesity: Stress and the brain-gut axis. Kral JG(1). Author information: (1)Department of Surgery, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. jkral@downstate.edu PMID: 16925198 [PubMed - indexed for MEDLINE] 3259. Indian J Exp Biol. 2006 Aug;44(8):597-617. Environmental contaminants in pathogenesis of breast cancer. Mukherjee S(1), Koner BC, Ray S, Ray A. Author information: (1)Department of Pharmacology, Meharry Medical College, Nashville, TN 37208, USA. This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer. PMID: 16924830 [PubMed - indexed for MEDLINE] 3260. Cell Biochem Funct. 2006 Nov-Dec;24(6):475-81. Role of fatty acids in the transition from anaerobic to aerobic metabolism in skeletal muscle during exercise. Hirabara SM(1), Silveira LR, Abdulkader FR, Alberici LC, Procopio J, Carvalho CR, Pithon-Curi TC, Curi R. Author information: (1)Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, CEP 05508-900 Butantã, São Paulo, SP, Brazil. sandromh@icb.usp.br In moderate physical exercise, the transition from predominantly anaerobic towards predominantly aerobic metabolism is a key step to improve performance. Increase in the supply of oxygen and nutrients, such as free fatty acids (FFA) and glucose, which accompanies high blood flow, is required for this transition. The mechanisms involved in the vasodilation in skeletal muscle during physical activity are not completely known yet. In this article, we postulate a role of FFA and heat production in this process. The presence of uncoupling protein-2 and -3 (UCP-2 and -3) in skeletal muscle, whose activity is dependent on FFA, suggests that these metabolites can act as mitochondrial uncouplers in this tissue. Evidence indicates however that UCPs act as uncouplers only when coenzyme Q is predominantly in the reduced state (i.e. under nonphosphorylation conditions or state 4 respiration) as is observed in resting muscles and in the beginning of physical activity (predominantly anaerobic metabolism). The increase in the lipolytic activity in adipose tissue in the beginning of physical activity results in elevated plasma FFA levels. The FFA can then act on the UCPs, increasing the local heat production. We propose that this calorigenic effect of FFA is important to activate nitric oxide synthase, resulting in nitric oxide production and consequent vasodilation. Therefore, FFA would be important mediators for the changes that occur in muscle metabolism during prolonged physical activity, ensuring the appropriate supply of oxygen and nutrients by increasing blood flow at the beginning of exercise in the contracting skeletal muscles. Copyright (c) 2006 John Wiley & Sons, Ltd. PMID: 16924590 [PubMed - indexed for MEDLINE] 3261. FEBS Lett. 2006 Sep 4;580(20):4771-6. Epub 2006 Aug 8. Role of aquaporin-7 in the pathophysiological control of fat accumulation in mice. Rodríguez A(1), Catalán V, Gómez-Ambrosi J, Frühbeck G. Author information: (1)Metabolic Research Laboratory, Department of Endocrinology, Clinica Universitaria de Navarra, University of Navarra, Avda. Pio XII 36, 31008 Pamplona, Spain. Aquaporins are channels that allow the movement of water across the cell membrane. Some members of the aquaporin family, the aquaglyceroporins, also allow the transport of glycerol, which is involved in the biosynthesis of triglycerides and the maintenance of fasting glucose levels. Aquaporin-7 (AQP7) is a glycerol channel mainly expressed in adipocytes. The deletion of AQP7 gene in mice leads to obesity and type 2 diabetes. AQP7 modulates adipocyte glycerol permeability thereby controlling triglyceride accumulation and fat cell size. Furthermore, the coordinated regulation of fat-specific AQP7 and liver-specific AQP9 may be key to determine glucose metabolism in insulin resistance. PMID: 16919625 [PubMed - indexed for MEDLINE] 3262. Curr Opin Nephrol Hypertens. 2006 Sep;15(5):487-92. Antihypertensive therapy in the obese hypertensive patient. Chrostowska M(1), Szczech R, Narkiewicz K. Author information: (1)Department of Hypertension and Diabetology, Medical University of Gdańsk, Gdańsk, Poland. PURPOSE OF REVIEW: Obesity is becoming recognized as one of the most important risk factors for the development of hypertension. The purpose of the review is to examine the latest evidence linking hypertension to obesity, summarize the benefits of weight reduction and present results of recent clinical trials evaluating antihypertensive treatment in obese patients. RECENT FINDINGS: Adipose tissue has been directly implicated in the pathogenesis of hypertension. Obesity has been associated with unequivocal changes in cardiovascular structure and function. In contrast to earlier studies, several recent trials included overweight and obese patients. Evidence of potential benefits of angiotensin blockade in the management of obesity hypertension is growing. Hypertension management in obese individuals is complicated by poorer response to treatment, and the increased need for multiple medications. It is important to consider obstructive sleep apnea in obese patients with resistant hypertension. SUMMARY: Several new lines of evidence suggest that drugs blocking the renin-angiotensin system might be considered as first-line therapy of obesity-related hypertension. Recent progress in understanding the mechanisms of obesity and associated disease processes might lead to development of novel therapeutic strategies. Further research in this area holds great promise for prevention of obesity-related cardiovascular disease. PMID: 16914960 [PubMed - indexed for MEDLINE] 3263. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):589-95. Assessment of metabolic profile in a clinical setting. Pervanidou P(1), Kanaka-Gantenbein C, Chrousos GP. Author information: (1)First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, University of Athens, Aghia Sophia Children's Hospital, Athens, Greece. ppervanid@med.uoa.gr PURPOSE OF REVIEW: The metabolic syndrome, a clustering of abnormalities such as hyperglycemia, insulin resistance, hypertension, dyslipidemia, and central obesity, is a principal risk factor for cardiovascular disease, the leading cause of morbidity and mortality in the Western world. There are several definitions of the metabolic syndrome, all aiming at including as many persons at risk as possible. The assessment and, hence, the identification of such persons in a clinical setting is of utmost importance. RECENT FINDINGS: Clinicians should document the presence of central obesity, assessed by waist circumference measurement or determination of body composition using dual X-ray absorptiometry or measurement of visceral fat using computed tomography or magnetic resonance imaging. The presence of dyslipidemia, insulin resistance, and arterial hypertension constitutes the full profile of the metabolic syndrome. Nevertheless, elevated uric acid levels or presence of nonalcoholic fatty liver, or the diagnosis of the polycystic ovary syndrome in women of reproductive age, all are reflected in high risk of later occurrence of the full metabolic syndrome and atherosclerotic cardiovascular disease. SUMMARY: Although no unified definition for the metabolic syndrome exists, it is important to identify persons at risk, in order to reduce the resultant high morbidity and mortality rates. PMID: 16912555 [PubMed - indexed for MEDLINE] 3264. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):560-7. Methods for assessing body composition, cardiovascular and metabolic function in children and adolescents: implications for exercise studies. Nassis GP(1), Sidossis LS. Author information: (1)Laboratory of Nutrition and Clinical Dietetics, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece. PURPOSE OF REVIEW: To critically evaluate the most recent literature on the methods used to assess body composition, cardiovascular and metabolic function in children and adolescents. RECENT FINDINGS: Although regional body composition can be fairly accurately calculated by dual-energy X-ray absorptiometry, the accuracy of noninvasive estimations of visceral adipose tissue is questionable. Regarding the cardiovascular and metabolic adaptations, there is no doubt that direct and invasive methods provide high accuracy and reproducibility. For instance, exercise until exhaustion, direct Fick equation, nuclear magnetic resonance and magnetic resonance imaging are valid methods to determine maximum oxygen uptake, cardiac output and tissue substrate metabolism, respectively. Except for the direct Fick equation, all have been successfully used in pediatric studies. Relatively new techniques for the assessment of exercise training-induced adaptations in youths include the thoracic bioimpedance and the Modelflow method for cardiac output determination, and magnetic resonance spectroscopy for intramuscular and intrahepatic lipid content. Additional validation and reliability studies in pediatric populations are needed for some of these techniques (e.g. the Modelflow method). SUMMARY: Most of the techniques used in adults appear not directly applicable to youths. A combination of techniques and/or the application of new, promising and easy to use ones, such as near-infrared spectroscopy and Laser Doppler flowmetry, may advance our knowledge in pediatric exercise science. PMID: 16912551 [PubMed - indexed for MEDLINE] 3265. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):540-6. Physical activity, cardiorespiratory fitness, and adiposity: contributions to disease risk. LaMonte MJ(1), Blair SN. Author information: (1)The Cooper Institute, Dallas, Texas 75230, USA. mlamonte@cooperinst.org PURPOSE OF REVIEW: To discuss assessing physical activity, cardiorespiratory fitness, and adiposity in the context of examining their prospective joint associations with mortality in cohort studies. RECENT FINDINGS: Accurate and comprehensive assessment of free-living physical activity patterns and related energy expenditure is difficult. Cardiorespiratory fitness is a reproducible measure associated with recent physical activity patterns; however, its assessment has been considered impractical in epidemiologic studies. Likewise, objective measures of adiposity and fat distribution often are not feasible in large studies. Thus, physical activity and adiposity exposures typically are quantified using self-reports of physical activity habits and of height and weight to compute body mass index. When considered jointly, adults with higher levels of fitness or reported physical activity tend to have lower mortality risk than their unfit and inactive peers within the same body mass index group. SUMMARY: Accumulating evidence suggests that higher physical activity or fitness attenuates the health risks of obesity. Available data largely are based on crude measures of physical activity and body habitus, which may obscure their association with disease risk. Accurate measures must be included in epidemiologic studies to improve estimation of the independent and joint associations of these exposures with health outcomes. PMID: 16912548 [PubMed - indexed for MEDLINE] 3266. Rev Esp Anestesiol Reanim. 2006 Jun-Jul;53(6):363-72. [Characteristics and distribution of normal human epidural fat]. [Article in Spanish] Reina MA(1), Pulido P, Castedo J, Villanueva MC, López A, Sola RG. Author information: (1)Servicio de Anestesiología y Reanimación, Hospital de Móstoles, Madrid. miguelangel.rei@terra.es Epidural fat provides sufficient cushion for the pulsatile movements of the dural sac, protects nerve structures, facilitates the movement of the dural sac over the periosteum of the spinal column during flexion and extension, and forms a pharmacologic reservoir of lipophilic substances. We review epidural fat and related structures, including their development during the fetal period when the epidural space is filled by undifferentiated loose, areolar mesenchymal tissue that surrounds the dural sac. In the adult, epidural fat has a continuous distribution and follows a certain metameric pattern. It is located mainly on the dorsal side of the epidural space, where it is organized in triangular capsules joined to the midline of the ligamentum flavum by a vascular pedicle. We consider the distribution of epidural fat in the axial and sagittal planes; its presence in the anterior, lateral and posterior epidural space; its presence in the cervical, thoracic and lumbar portions of the spinal column; and its characteristics and variations according to differing body habits and sex. Finally, we speculate on the possible anesthetic implications of epidural fat in terms of the pharmacokinetics of drugs injected into the epidural space and the tasks of locating the epidural space and inserting an epidural catheter during anesthetic procedures. PMID: 16910144 [PubMed - indexed for MEDLINE] 3267. Cell Mol Life Sci. 2006 Oct;63(19-20):2317-28. The Foxa family of transcription factors in development and metabolism. Friedman JR(1), Kaestner KH. Author information: (1)Division of Gastroenterology and Nutrition, Department of Pediatrics, University of Pennsylvania School of Medicine, Abramson Research Center, Room 1007B, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors has been the subject of genetic and biochemical study for over 15 years. During this time its three members, Foxa1, Foxa2 and Foxa3, have been found to play important roles in multiple stages of mammalian life, beginning with early development, continuing during organogenesis, and finally in metabolism and homeostasis in the adult. Foxa2 is required for the formation of the node and notochord, and in its absence severe defects in gastrulation, neural tube patterning, and gut morphogenesis result in embryonic lethality. Foxa1 and Foxa2 cooperate to establish competence in foregut endoderm and are required for normal development of endoderm-derived organs such as the liver, pancreas, lungs, and prostate. In post-natal life, members of the Foxa family control glucose metabolism through the regulation of multiple target genes in the liver, pancreas, and adipose tissue. Insight into the unique molecular basis of Foxa function has been obtained from recent genetic and genomic data, which identify the Foxa proteins as 'pioneer factors' whose binding to promoters and enhancers enable chromatin access for other tissue-specific transcription factors. PMID: 16909212 [PubMed - indexed for MEDLINE] 3268. Pathol Biol (Paris). 2006 Sep;54(7):375-86. Epub 2006 Aug 14. The metabolic syndrome. Fulop T(1), Tessier D, Carpentier A. Author information: (1)Research Centre on Aging, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, 1036, rue Belvedere Sud, Sherbrooke, Que., Canada J1H 4C4. tamas.fulop@usherbrooke.ca The metabolic syndrome (MS) is a cluster of metabolic abnormalities leading to increased risk for cardiovascular diseases and diabetes type 2. Its prevalence is increasing with aging. There exists actually an epidemic of MS. Visceral obesity and the resulting insulin resistance (IR) are the major determinant in the development of the MS. Abdominal obesity results in a low grade inflammation via the adipose tissue and macrophages secreted adipokines. This inflammation, via the generated pro-inflammatory molecules, interferes with the normal insulin signalling and thus contributes to the etiopathogenesis of the MS. Large clinical studies showed that CRP is increased in obese subjects and concomitantly to the number of existing component of the MS. Treatment of the MS is aimed to improve the IR by lifestyle changes including exercise and diet alone or in combination with medication targeting the individual components but having also anti-inflammatory actions. More research is needed to bring new therapies to be able to decrease the incidence and prevalence of the MS among the population and thus increasing their quality of life. PMID: 16904849 [PubMed - indexed for MEDLINE] 3269. Biochemistry (Mosc). 2006 Jul;71(7):701-6. Protein kinase Czeta and glucose uptake. Liu LZ(1), He AB, Liu XJ, Li Y, Chang YS, Fang FD. Author information: (1)National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China. Protein kinase Czeta (PKCzeta) is a member of the PKC family, serving downstream of insulin receptor and phosphatidylinositol (PI) 3-kinase. Many evidences suggest that PKCzeta plays a very important role in activating glucose transport response. Not only insulin but also glucose and exercise can activate PKCzeta through diverse pathways. PKCzeta activation and activity are impaired with insulin resistance in muscle and adipose tissues of type II diabetes individuals, but heightened in liver tissue, wherein it also increases lipid synthesis mediated by SREBP-1c (sterol-regulatory element-binding protein). Many studies have focused on linkage between PKCzeta and GLUT4 translocation and activation. Exploring the molecular mechanisms and pathways by which PKCzeta mediates glucose transport will highlight the insulin-signaling pathway. PMID: 16903823 [PubMed - indexed for MEDLINE] 3270. Clin Cornerstone. 2006;8 Suppl 1:S21-7. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Grundy SM(1). Author information: (1)Center for Human Nutrition University of Texas Southwestern Medical Center Dallas, Texas 75390-9052, USA. scott.grundy@utsouthwestern.edu Atherogenic dyslipidemia, a component of metabolic syndrome, is characterized by high levels of apolipoprotein B (apo B)-containing lipoproteins, including very-low-density lipoprotein remnants and small low-density lipoprotein particles, and reduced levels of high-density lipoprotein cholesterol. Although the National Cholesterol Education Program Adult Treatment Panel III includes elevations in blood pressure and plasma glucose in the definition of metabolic syndrome, the broader scope of metabolic syndrome includes proinflammatory and prothrombotic states, which derive from the secretory activity of adipose tissue. Abdominal fat can adversely affect insulin action and the disposal of glucose through an increase in the release of free fatty acid, resulting in accumulation of triglyceride in muscle and liver, thereby depressing insulin action and increasing output of apo B-containing lipoproteins. Impaired regulation of adipokines, bioactive substances secreted from adipose tissue, likely produces systemic inflammation, which can promote atherogenesis. Insulin resistance is recognized as an important metabolic defect linking the components of metabolic syndrome. One molecule that may play an important role in metabolic syndrome to regulate metabolic and vascular pathways is the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have established PPAR-gamma deficiency as a cause of lipodystrophy and confirmed its adipogenic role. Patients with atherogenic dyslipidemia and metabolic syndrome should undergo global risk assessment for cardiovascular disease and future cardiovascular events to determine an overall treatment strategy. PMID: 16903166 [PubMed - indexed for MEDLINE] 3271. Curr Atheroscler Rep. 2006 Sep;8(5):433-8. Hypoadiponectinemia: a common basis for diseases associated with overnutrition. Funahashi T(1), Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2,Yamada-oka, Suita, Osaka 565-0871, Japan. tohru@imed2.med.osaka-u.ac.jp Adiponectin is a plasma protein derived from adipose tissue, which we discovered from a human adipose cDNA project. Adiponectin exists in circulating plasma at concentrations ranging from 4 to 30 microg/mL, which is much higher than the concentrations of various other hormones and cytokines. Adiponectin has a sticky nature, binding to collagen I, III, and V, which are present in vascular intima. Adiponectin exhibits various antiatherogenic effects on vascular cells, suppressing the expression of adhesion molecules in vascular endothelial cells, proliferation of smooth muscle cells, and cholesteryl-ester accumulation in macrophages. However, its plasma levels are low in subjects with excess intra-abdominal fat. Adiponectin also has antidiabetic properties, and plasma adiponectin levels correlate positively with insulin sensitivity. Several clinical studies have demonstrated that hypoadiponectinemia is a risk factor for new-onset diabetes. Recent studies suggest that hypoadiponectinemia may partly contribute to the development of salt-sensitive hypertension and hypertensive heart failure, and can be also a risk factor for overnutrition-related cancers such as breast, colon, uterine, and prostate cancers. Hypoadiponectinemia might be at least in part the molecular basis of various diseases associated with overnutrition. PMID: 16901415 [PubMed - indexed for MEDLINE] 3272. Curr Opin Cardiol. 2006 Sep;21(5):479-85. The prevention and treatment of metabolic syndrome and high-risk obesity. Molavi B(1), Rasouli N, Kern PA. Author information: (1)The Central Arkansas Veterans Healthcare System, Arkansas 72205, USA. molavibehzad@uams.edu PURPOSE OF REVIEW: The prevalence of obesity is increasing at an alarming rate, and the obesity epidemic is driving the epidemic in type 2 diabetes. High-risk obesity is characterized by abdominal obesity with evidence of abnormal glucose and lipid metabolism, and a state of heightened inflammation. RECENT FINDINGS: With increasing body weight, lipid accumulation occurs not only in adipose tissue, but in other organs as well. This 'lipotoxicity' in liver, muscle, islets, and elsewhere may account for many of the features of the metabolic syndrome. Adipose tissue produces many proteins, some of which are inflammatory cytokines, and others of which are antiinflammatory or which improve insulin sensitivity. SUMMARY: The treatment of obesity requires the identification of the high-risk patient, and the institution of lifestyle measures with a long-term outlook, and an avoidance of heavily marketed fads. Current research will likely lead to improved medications in the future. PMID: 16900012 [PubMed - indexed for MEDLINE] 3273. Biochem J. 2006 Sep 1;398(2):153-68. Regulatory circuits controlling white versus brown adipocyte differentiation. Hansen JB(1), Kristiansen K. Author information: (1)Department of Medical Biochemistry and Genetics, the Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark. j.hansen@imbg.ku.dk Adipose tissue is a major endocrine organ that exerts a profound influence on whole-body homoeostasis. Two types of adipose tissue exist in mammals: WAT (white adipose tissue) and BAT (brown adipose tissue). WAT stores energy and is the largest energy reserve in mammals, whereas BAT, expressing UCP1 (uncoupling protein 1), can dissipate energy through adaptive thermogenesis. In rodents, ample evidence supports BAT as an organ counteracting obesity, whereas less is known about the presence and significance of BAT in humans. Despite the different functions of white and brown adipocytes, knowledge of factors differentially influencing the formation of white and brown fat cells is sparse. Here we summarize recent progress in the molecular understanding of white versus brown adipocyte differentiation, including novel insights into transcriptional and signal transduction pathways. Since expression of UCP1 is the hallmark of BAT and a key factor determining energy expenditure, we also review conditions associated with enhanced energy expenditure and UCP1 expression in WAT that may provide information on processes involved in brown adipocyte differentiation. PMCID: PMC1550312 PMID: 16898874 [PubMed - indexed for MEDLINE] 3274. Przegl Lek. 2006;63 Suppl 3:25-8. [Influence of obesity in children on kidney]. [Article in Polish] Roszkowska-Blaim M(1). Author information: (1)Katedra i Klinika Pediatrii i Nefrologii, Akademia Medyczna w Warszawie. nefrologia@litewskaedu.pl According to the WHO report the rapid increase of obesity in adults and children is noted in developing and developed countries, resulting the epidemic state. Overweight (obesity) is noted in 50% adults; among children and teens aged 6-19 years, 16% of them are considered as overweight. The adipose tissue is a large endocrine organ secreting biologically active substances as leptin, adiponectin and many growth factors regulating lipids metabolism. Obesity is associated with many complications as: hypertension, dyslipidemia, hyperglycemia (insulin resistance, glomerular hyperperfusion and hyperfiltration resulting renal injury with proteinuria) "obesity related glomerulopathy". The excess body weight in children may be a risk factor for kidney damage. PMID: 16898481 [PubMed - indexed for MEDLINE] 3275. Am J Cardiol. 2006 Aug 15;98(4):544-8. Epub 2006 Jun 28. Enhanced 11beta-hydroxysteroid dehydrogenase activity, the metabolic syndrome, and systemic hypertension. Sukhija R(1), Kakar P, Mehta V, Mehta JL. Author information: (1)Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Metabolic syndrome, with its attendant cardiovascular complications, is reaching epidemic proportions worldwide; hence, there is intense interest in understanding the pathogenesis of and developing therapy for these common disorders. Recent studies have suggested that metabolic syndrome may be a stress response, with an underlying abnormality in the enzyme 11beta-hydroxysteroid dehydrogenase. At the cellular level, the enzyme hydroxysteroid dehydrogenase type 1 (HSD1) locally regenerates active cortisol from inactive cortisone, amplifying glucocorticoid receptor activation and promoting preadipocyte differentiation and adipocyte hypertrophy. Although initial studies in transgenic mice and humans are encouraging, more data are required to conclusively prove the hypothesis that the adipose-tissue-specific overexpression of HSD1 and the resultant increase in tissue-specific cortisol concentrations result in human obesity, insulin resistance, high blood pressure, and metabolic syndrome. Currently, selective inhibitors of HSD1 are not available for human use; however, their development is under way. The use of potent and selective HSD1 inhibitors will finally confirm or refute this hypothesis and may turn out to be an effective strategy for combating these common maladies. PMID: 16893715 [PubMed - indexed for MEDLINE] 3276. Cell Metab. 2006 Aug;4(2):103-5. Dirty dealing: hepatic vagal afferents reshuffle fat distribution. Schwartz GJ(1). Author information: (1)Albert Einstein College of Medicine of Yeshiva University, Diabetes Research and Training Center, Department of Medicine, 1300 Morris Park Avenue, Golding 501, Bronx, New York 10463, USA. To evaluate the role of hepatic peroxisome-proliferator-activated receptor (PPAR) gamma 2 in the control of energy balance, Uno and colleagues examined the metabolic effects of overexpression of PPAR gamma 2 selectively in mouse and rat liver. Mice demonstrated a surprising degree of hepatic steatosis accompanied by significant reductions in peripheral adiposity. This crosstalk between liver and adipose tissue appears to be mediated by both the sensory component of the hepatic vagus nerve and sympathetic efferents. These data suggest a novel hepatic-adipose neuraxis that regulates the distribution of stored fat. PMID: 16890537 [PubMed - indexed for MEDLINE] 3277. Med Princ Pract. 2006;15(5):325-37. Human obesity: its hormonal basis and the role of gastric inhibitory polypeptide. Marks V(1). Author information: (1)Department of Clinical Biochemistry, Post-Graduate Medical School, University of Surrey Guildford, Surrey, UK. vincentmarks@bigfoot.com Obesity is an abnormal expansion of the adipose organ and is a pathophysiological response to an imbalance between energy intake and energy expenditure. It is the result of a large number of diverse factors involving heritable and environmental characteristics. A simple definition of obesity is difficult and unsatisfactory and its age dependency has largely been ignored. Differentiation between healthy, age-related plumpness and obesity is often blurred and responsible for overdiagnosis of obesity in the developed world. In the past, epidemiological studies have often ignored the different prognostic significance of the two major phenotypes of human obesity making their conclusions of limited value. The role of heritable factors in determining both the propensity to develop obesity under favourable environmental conditions, including inactivity and unlimited access to fat-rich foods, and the phenotype it assumes received an enormous fillip from experiments involving genetically modified animals. The most important of these have demonstrated the key role played by a number of newly discovered or recently resurrected polypeptide hormones that are released from the intestine in response to food. Molecular manipulation of these hormones, especially of glucose-dependent insulin-stimulatory polypeptide offers a new therapeutic approach. PMID: 16888389 [PubMed - indexed for MEDLINE] 3278. Clin Endocrinol (Oxf). 2006 Aug;65(2):137-45. Obesity and polycystic ovary syndrome. Barber TM(1), McCarthy MI, Wass JA, Franks S. Author information: (1)Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, UK. tom.barber@drl.ox.ac.uk The aetiology of Polycystic Ovary Syndrome (PCOS) is complex and multifactorial. There is much evidence, however, to suggest that adipose tissue plays an important role in the development and maintenance of PCOS pathology. There is a close correlation between adiposity and symptom severity in women with PCOS, and even modest reductions in weight generally translate into significant improvements in menstrual regularity, fertility and hyperandrogenic features. This review article considers the various mechanisms that might underlie this link between excess adiposity and PCOS - including the effects of differential insulin sensitivity, abnormal steroid hormone metabolism and adipocytokine secretion. Greater attention to the therapeutic options available to reduce the impact of excess adiposity on ovarian and metabolic function is essential to the management of PCOS. PMID: 16886951 [PubMed - indexed for MEDLINE] 3279. Pol Merkur Lekarski. 2006 Apr;20(118):494-6. [The role of adiponectin in atherosclerosis]. [Article in Polish] Lewicki M(1), Kotyla P, Jankiewicz-Ziobro K, Kucharz EJ. Author information: (1)Slaska Akademia Medyczna w Katowicach, Katedra i Klinika Chorób Wewnetrznych i Reumatologii. kmnlewiccy@interia.pl Adiponectin is a adipose tissue-derived protein. In the light of current investigations, the role of adiponectin goes far beyond only adipose tissue regulatory factor, being involved in some pathological processes as endothelium damage or atherosclerosis. Unique properties of adiponectin make it a very promising agent that posses ability to slow down the progression of atherosclerosis. In this article, a structure and a function of adiponectin have been reviewed. The special emphasis was put upon the role of adiponectin in atherosclerosis. PMID: 16886584 [PubMed - indexed for MEDLINE] 3280. Pol Merkur Lekarski. 2006 Apr;20(118):490-3. [Obesity influence on renal function]. [Article in Polish] Sudoł A(1), Wnuk RS, Duława J. Author information: (1)Szpital Specjalistyczny w Dabrowie Górniczej, Oddział Nefrologii i Dializoterapii. annaczajka@poczta.onet.pl Obesity is an increasing problem in all over the developed world. The paper describes the substances secreted by adipose tissue and the altered renal hemodynamics in obese subjects. The review pays attention to diagnostic difficulties and discusses the medical trials of this pathology. PMID: 16886583 [PubMed - indexed for MEDLINE] 3281. Sci STKE. 2006 Aug 1;2006(346):re7. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Marshall S(1). Author information: (1)Hexos Inc., 18304 NE 153rd Street, Woodinville, WA 98072, USA. hexos06@comcast.net Traditionally, nutrients such as glucose and amino acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, it is now apparent that nutrients also function as signaling molecules in functionally diverse signal transduction pathways. Glucose and amino acids trigger signaling cascades that regulate various aspects of fuel and energy metabolism and control the growth, proliferation, and survival of cells. Here, we provide a functional and regulatory overview of three well-established nutrient signaling pathways-the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Nutrient signaling pathways are interconnected, coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Thus, nutrient signaling pathways do not function in isolation. Rather, they appear to serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. Understanding the diverse roles of nutrients and delineating nutrient signaling pathways should facilitate drug discovery research and the search for novel therapeutic compounds to prevent and treat various human diseases such as diabetes, obesity, and cancer. PMID: 16885148 [PubMed - indexed for MEDLINE] 3282. Clin Calcium. 2006 Aug;16(8):1332-42. [The effects of visceral fat accumulation by diabetes mellitus on bone metabolism]. [Article in Japanese] Oshima K(1), Shimomura I, Iwahashi H. Author information: (1)Osaka University, Graduate School of Medicine, Department of Medicine and Pathophysiology. The number of obesity and diabetes mellitus in the world has been rapidly increasing in population. Current lifestyle initiates obesity, especially visceral fat accumulation, and leads to the onset of metabolic syndrome, such as cardiovascular events, hyperlipidemia and diabetes mellitus, based on insulin resistance. Several studies of adipocyte function have revealed that adipose tissue is not merely an energy-storing organ but it secretes a variety of biologically active molecules, conceptualized as "adipocytokines", including tumor necrosis factor-alpha, estrogen, leptin and adiponectin and that abnormal secretion of these adipocytokines causes metabolic syndrome. Adipocytes exist not only in the visceral and subcutaneous tissue but also in the bone marrow. Therefore, it is important to know their effects not only on glucose and lipid metabolism but also on bone metabolism. This report aims to review some of the effects of visceral fat accumulation by diabetes mellitus on bone metabolism. PMID: 16883042 [PubMed - indexed for MEDLINE] 3283. Acta Paediatr. 2006 Aug;95(8):909-17. Postnatal growth, neurodevelopment and altered adiposity after preterm birth--from a clinical nutrition perspective. Yeung MY(1). Author information: (1)Department of Pharmacy, The Children's Hospital at Westmead, New South Wales, Australia. melinday@chw.edu.au Comment in Acta Paediatr. 2006 Aug;95(8):904-8. Evidence reveals a dilemma that under-nutrition and growth retardation during brain growth are associated with neurodevelopmental deficits, and nutritional supplement resulting in catch-up growth and relative visceral adiposity leads to metabolic/cardiovascular morbidities. Hyperinsulinaemia secondary to insulin resistance appears to play a central role in the development of visceral adiposity through its action on adipocyte beta3-adrenoceptor.CONCLUSION: Optimal nutritional management to minimize hyperinsulinaemia and insulin resistance may potentially improve neurodevelopment and facilitate catch-up growth with normal body composition. PMID: 16882561 [PubMed - indexed for MEDLINE] 3284. Matern Child Nutr. 2005 Jul;1(3):142-8. Animal models of programming: early life influences on appetite and feeding behaviour. Langley-Evans SC(1), Bellinger L, McMullen S. Author information: (1)Center for Reproduction and Early Life, University of Nottingham, School of Biosciences, Sutton Bonington, Leicestershire LE12 5RD, UK. Simon.Langley-Evans@Nottingham.ac.uk Epidemiological observations of associations between early life nutrition and long-term disease risk have prompted detailed experimental investigation of the biological basis of programming. Studies using rodent or large animal models have clearly established the biological plausibility of nutritional programming and are now yielding important information on underlying mechanisms. Nutritional interventions in pregnancy, including global food restriction, protein restriction, micronutrient restriction and excess fat feeding, determine a consistent cluster of disorders in the resulting offspring. The common association of such diverse nutritional disturbances with hypertension, glucose intolerance and adiposity suggests that a small number of simple common mechanisms are active in response to fetal nutrient imbalance. Studies of rodent models indicate that fetal undernutrition determines adult adiposity. It is unclear whether the increase in central adiposity is related to increased food intake or reduced energy expenditure, although evidence exists to suggest that both may act together. Rats subject to intrauterine protein restriction exhibit increased preference for high fat foods. Feeding of energy dense foods to rats that were undernourished in utero promotes a greater degree of obesity than is noted in animals subject to adequate nutrition in fetal life. There is evidence to suggest that programming of appetite may stem from remodelling of hypothalamic structures that control feeding and programming of the expression of genes involved in responses to orexogenic hormones. The early life programming of appetite and obesity is a complex phenomenon and our understanding of how maternal nutrition determines later energy balance is at a very early stage. PMID: 16881893 [PubMed - indexed for MEDLINE] 3285. Curr Opin Immunol. 2006 Oct;18(5):586-91. Epub 2006 Aug 1. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Le Blanc K(1), Ringdén O. Author information: (1)Division of Clinical Immunology, Karolinska Institutet, Karolinska University Hospital Huddinge, F79, SE-141 86 Stockholm, Sweden. katarina.leblanc@ki.se Mesenchymal stem cells (MSCs) can be isolated from bone marrow, adipose tissue, cord blood and various fetal tissues. They have the capacity to differentiate into several tissues, including bone, cartilage, tendon, muscle and adipose, and produce growth factors and cytokines that promote hematopoietic cell expansion and differentiation. MSCs also have anti-proliferative, immunomodulatory and anti-inflammatory effects, but only evoke little immune reactivity. In vivo, MSCs prolong skin allograft survival and reverse severe acute graft-versus-host disease. Furthermore, they repair damaged tissue from kidney, heart, liver and gastrointestinal tract. Therefore, in the future, MSCs might have implications for treatment of allograft rejection, graft-versus-host disease, autoimmune inflammatory bowel disease and other disorders in which immunomodulation and tissue repair are required. PMID: 16879957 [PubMed - indexed for MEDLINE] 3286. Neurol Clin. 2006 Aug;24(3):585-99. Exercise, inflammation, and innate immunity. Woods JA(1), Vieira VJ, Keylock KT. Author information: (1)Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 906 South Goodwin Avenue, Urbana, IL 6180, USA. woods1@uiuc.edu Regular exercise is protective against several chronic diseases ranging from physiologic diseases such as cardiovascular disease to neurologic diseases such as dementia and depression. Exciting recent research points to chronic inflammation as an underlying contributor to many age-related chronic diseases. Cross-sectional and longitudinal studies in animals and humans have shown both an acute and a chronic anti-inflammatory effect. Because innate immunity is a key regulator of inflammatory processes, and chronic inflammation contributes to many illnesses, the effect of regular exercise on innate immunity, most importantly macrophages, holds much promise in terms of defining these mechanisms. Unfortunately, the mechanisms responsible for the observed anti-inflammatory effect of regular exercise have not been elucidated. This article presents several compelling potential mechanisms for the anti-inflammatory effect of exercise, including loss of body fat, reductions in macrophage accumulation in adipose tissue, altered macrophage phenotype in adipose tissue, exercise-induced muscle production of IL-6, or alterations in the balance between the sympathetic and parasympathetic nervous systems. Further investigation to confirm or reject these testable hypotheses will allow better application of exercise therapy to treat and prevent illnesses associated with chronic inflammation. PMID: 16877125 [PubMed - indexed for MEDLINE] 3287. Prog Brain Res. 2006;153:367-405. Hypothalamic integration of immune function and metabolism. Guijarro A(1), Laviano A, Meguid MM. Author information: (1)Surgical Metabolism and Nutrition Laboratory, Neuroscience Program, University Hospital, SUNY Upstate Medical University, 750 Adams St., Syracuse, NY 13210, USA. The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity. PMID: 16876587 [PubMed - indexed for MEDLINE] 3288. Prog Brain Res. 2006;153:325-37. What can we learn from seasonal animals about the regulation of energy balance? Morgan PJ(1), Ross AW, Mercer JG, Barrett P. Author information: (1)Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, UK. p.morgan@rowett.ac.uk Weight loss in humans requires, except during an illness, some form of imposed restriction on food intake or increase in energy expenditure. This necessitates overcoming powerful peripheral and central signals that serve to protect against negative energy balance. The identification of the systems and pathways involved has come from mouse models with genetic and targeted mutations, e.g., ob/ob and MC4 R(-/-) as well as rat models of obesity. Study of seasonal animals has shown that they undergo annual cycles of body fattening and adipose tissue loss as important adaptations to environmental change, yet these changes appear to involve mechanisms distinct from those known already. One animal model, the Siberian hamster, exhibits marked, but reversible, weight loss in response to shortening day length. The body weight is driven by a decrease in food intake with the magnitude of the loss of body weight being directly related to the length of time of exposure to short photoperiod. The most important facet of this response is that the point of energy balance is continuously re-adjusted during the transition in body weight reflecting an apparent 'sliding set point'. Studies have focused on identifying the neural basis of this mechanism. Initial studies of known genes (e.g., NPY, POMC, and AgRP) both through the measurement of gene expression in the arcuate nucleus as well as following intracerebroventricular (i.c.v.) injection indicated that the systems involved are not those involved in restoring energy balance following energy deficits. Instead, a novel mechanism of regulation is implied. Recent studies have begun to explore the neural basis of the seasonal body weight response. A discrete and novel region of the posterior arcuate nucleus, the dorsal medial posterior arcuate nucleus (dmpARC) has been identified, where a battery of gene expression changes for signalling molecules (vgf and histamine H3 receptor) and transcription factors (RXRgamma and RAR) occur in association with seasonal changes in body weight. This work provides the basis of a potentially novel mechanism of energy balance regulation. PMID: 16876584 [PubMed - indexed for MEDLINE] 3289. Prog Brain Res. 2006;153:155-74. Adipokines that link obesity and diabetes to the hypothalamus. Ahima RS(1), Qi Y, Singhal NS. Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. ahima@mail.med.upenn.edu Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders. PMID: 16876574 [PubMed - indexed for MEDLINE] 3290. Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1284-91. Epub 2006 Jun 17. UCP2, UCP3, avUCP, what do they do when proton transport is not stimulated? Possible relevance to pyruvate and glutamine metabolism. Criscuolo F(1), Mozo J, Hurtaud C, Nübel T, Bouillaud F. Author information: (1)CNRS UPR-9078, Université René Descartes Site Necker, 156 rue de Vaugirard 75730 Paris Cedex 15, France. Uncoupling proteins (UCPs) are specialized members of the mitochondrial transporter family. They allow passive proton transport through the mitochondrial inner membrane. This activity leads to uncoupling of mitochondrial respiration and to energy waste, which is well documented with UCP1 in brown adipose tissue. The uncoupling activity of the new UCPs (discovered after 1997), such as UCP2 and UCP3 in mammals or avUCP in birds, is more difficult to characterize. However, extensive data support the idea that the new UCPs are involved in the control of reactive oxygen species (ROS) generation. This fits with the hypothesis that mild uncoupling caused by the UCPs prevents ROS production. Activators and inhibitors regulate the proton transport activity of the UCPs. In the absence of activators of proton transport, the UCP allows the permeation of other ions. We suggest that this activity has physiological significance and, for example, UCP3 expressed in glycolytic muscle fibres may be a passive pyruvate transporter ensuring equilibrium between glycolysis and oxidative phosphorylation. Induction of UCP2 expression by glutamine strengthens the proposal that new UCPs could act to determine the choice of mitochondrial substrate. This would obviously have an impact on mitochondrial bioenergetics and ROS production. PMID: 16872578 [PubMed - indexed for MEDLINE] 3291. Yi Chuan. 2006 Aug;28(8):993-1001. [PPARgamma variants and complex diseases]. [Article in Chinese] Ji SL(1), Huang QY. Author information: (1)College of life sciences, Central China Normal University, Wuhan, 430079, China. jisenlin2003@yahoo.com Peroxisome proliferator-activated receptor gamma is a member of the nuclear hormone receptor superfamily. Mainly expressed in adipose tissue, PPARgamma promotes the differentiation of adipocytes and modulates the expression of many genes involved in the synthesis of adipocytokines in the adipose tissue. It is also the target molecule of the thiazolidinediones. Polymorphisms of the PPARgamma gene may influence pancreatic beta-cell function and result in changes in insulin secretion and insulin sensitivity of the peripheral tissues. They are also associated with risks of type 2 diabetes, obesity, cardiovascular diseases and cancer. Elucidation of its mechanism could be of major importance to the diagnosis, prevention and treatment of complex diseases. PMID: 16870588 [PubMed - indexed for MEDLINE] 3292. Obes Rev. 2006 Aug;7(3):239-50. Musculoskeletal disorders associated with obesity: a biomechanical perspective. Wearing SC(1), Hennig EM, Byrne NM, Steele JR, Hills AP. Author information: (1)School of Human Movement Studies, Queensland University of Technology, Qld, Australia. Despite the multifactorial nature of musculoskeletal disease, obesity consistently emerges as a key and potentially modifiable risk factor in the onset and progression of musculoskeletal conditions of the hip, knee, ankle, foot and shoulder. To date, the majority of research has focused on the impact of obesity on bone and joint disorders, such as the risk of fracture and osteoarthritis. However, emerging evidence indicates that obesity may also have a profound effect on soft-tissue structures, such as tendon, fascia and cartilage. Although the mechanism remains unclear, the functional and structural limitations imposed by the additional loading of the locomotor system in obesity have been almost universally accepted to produce aberrant mechanics during locomotor tasks, thereby unduly raising stress within connective-tissue structures and the potential for musculoskeletal injury. While such mechanical theories abound, there is surprisingly little scientific evidence directly linking musculoskeletal injury to altered biomechanics in the obese. For the most part, even the biomechanical effects of obesity on the locomotor system remain unknown. Given the global increase in obesity and the rapid rise in musculoskeletal disorders, there is a need to determine the physical consequences of continued repetitive loading of major structures of the locomotor system in the obese and to establish how obesity may interact with other factors to potentially increase the risk of musculoskeletal disease. PMID: 16866972 [PubMed - indexed for MEDLINE] 3293. Soc Reprod Fertil Suppl. 2006;62:45-53. Transsynaptic connections between the hypothalamus and adipose tissue: relationship to reproduction. Czaja K(1). Author information: (1)Department of Veterinary, Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99163-6520, USA. czajak@vetmed.wsu.edu Neurophysiological mechanisms that control energy balance are reciprocally linked to those that control reproduction. Neuromorphological studies using retrograde tracing methods revealed that nerve cells within the central (CNS) and autonomic (ANS) nervous systems in different species, including the pig, are transsynaptically connected to different fat tissue depots. In the pig, neurons localised in the paraventricular nucleus, supraoptic nucleus and arcuate nucleus were infected with pseudorabies virus (PRV) 9 days after injections into both the perirenal and subcutaneous adipose tissue depots. Infected neurons were in the ventromedial nucleus, dorsomedial nucleus and preoptic area after injection of PRV into perirenal adipose tissue, while infected cells in the lateral hypothalamic area projected only to the subcutaneous adipose tissue depot. Additionally, numerous centres of the ANS innervate adipose tissue depots in the pig. Fast blue stained (FB+) neurons, which projected to the subcutaneous adipose tissue overlaying the thoracolumbar area were located in the thoraco-lumbar region of the sympathetic chain ganglia (SChG). However, neurons supplying perirenal and mesentery adipose tissue depots were found in both the SChG and prevertebral ganglia. The vast majority of labelled neurons, in both the CNS and ANS, which innervated adipose tissue depots, expressed leptin receptor (OBR) immunoreactivity. The purpose of this brief review is to establish evidence for a multisynaptic circuit of neurons, which innervate adipose tissue in the pig and demonstrate that hypothalamic nuclei and sympathetic ganglion neurons involved in reproductive processes are transsynaptically connected to different adipose tissue depots. PMID: 16866308 [PubMed - indexed for MEDLINE] 3294. Soc Reprod Fertil Suppl. 2006;62:33-44. Gene expression in the brain-pituitary adipose tissue axis and luteinising hormone secretion during pubertal development in the gilt. Barb CR(1), Hausman GJ, Rekaya R. Author information: (1)Animal Physiology Research Unit, USDA/ARS, Richard B. Russell Agriculture Research Center, PO Box 5677, Athens, GA 30604, USA. rbarb@saa.ars.usda.gov The occurrence of puberty in the female is due to the interplay of central and peripheral mechanisms in which the hypothalamic-pituitary-ovarian axis regulates growth and gonadal function, as well as adipocyte hormone secretion. Hypothalamic GnRH mRNA expression increased at 3.5 months of age and declined by 6 months of age. Concomitant with the age related reduction in the oestrogen negative feedback on LH secretion was a decline in hypothalamic oestrogen receptor-alpha (ERalpha) expression and increased expression of repressor of ER activity gene (REA) at 210 days of age. Hypothalamic proopiomelanocortin expression increased at 6 months of age followed by increased expression of progesterone receptor (PR) membrane compliment-1 and steroid membrane binding protein gene at 210 days of age. This represents development of the endogenous opioid peptide-progesterone dependent LH inhibitory pathway. Adipose tissue leptin and insulin like growth factor-I (IGF-I) gene expression increased with age and adiposity. Pituitary transcription factors, steroidogenic factor 1 (SF1) and Lhx3, and LHbeta and FSHbeta gene expression increased with age. These results identify key hypothalamic and pituitary genes associated with changes in LH secretion and growth during pubertal development and adipose tissue genes and secreted proteins related to maturation of the neuroendocrine axis and puberty. PMID: 16866307 [PubMed - indexed for MEDLINE] 3295. Eur Neuropsychopharmacol. 2006 Sep;16 Suppl 3:S142-8. Epub 2006 Jul 24. Long-term health considerations in schizophrenia: metabolic effects and the role of abdominal adiposity. Van Gaal LF(1). Author information: (1)Antwerp University Hospital, Department of Diabetology, Metabolism and Clinical Nutrition, Edegem, Antwerp, Belgium. luc.van.gaal@uza.be Patients with schizophrenia have increased rates of morbidity and mortality compared with the general population, primarily due to cardiovascular disease. Thus there is an increasing need for clinicians in the psychiatric field to recognise and address cardiovascular risk factors such as abdominal obesity, dyslipidaemia, high blood pressure and elevated fasting blood glucose levels that contribute to this long-term health burden. The combination of three or more of these risk factors leads to a diagnosis of metabolic syndrome, further predisposing individuals to cardiovascular disease. A cluster of risk factors, such as in the metabolic syndrome, is being increasingly seen in patients with schizophrenia. Abdominal obesity is a key contributor to overall cardiovascular risk and is a particularly important consideration in schizophrenia as some atypical antipsychotics are associated with drug-induced weight gain. Lifestyle factors such as smoking, lack of exercise and poor diet undoubtedly contribute further. Psychiatrists need to be aware of metabolic risk when initiating treatment in patients with schizophrenia and should take steps to identify and monitor patients. A first step is to establish a risk profile for the patient based on medical, lifestyle and genetic factors, and measurement of waist circumference is a good indicator of overall cardiovascular and metabolic risk. Strategies recommended to reduce risk include promoting healthy lifestyle/behavioural habits and close monitoring of weight, glucose, and lipid profiles both before and during treatment. Established risk factors should also be considered when selecting the most appropriate antipsychotic medication for an individual patient, based on differences in the potential effect of individual medications to induce weight gain, risk of diabetes or worsening lipid profile. PMID: 16863690 [PubMed - indexed for MEDLINE] 3296. Expert Opin Drug Metab Toxicol. 2006 Jun;2(3):429-45. Toxic metabolic syndrome associated with HAART. Haugaard SB(1). Author information: (1)Clinical Research Unit, Department of Endocrinology and Internal Medicine, Hvidovre University Hospital, DK 2650 Hvidovre, Copenhagen, Denmark. sbhau@dadlnet.dk Acquired fat redistribution, that is, peripheral fat loss often accompanied by central fat accumulation in patients with HIV infection is the most common form of lipodystrophy in man. Approximately 30 - 50% of HIV-infected individuals after > or = 12 months on highly active antiretroviral therapy (HAART) may encounter the HIV-associated lipodystrophy syndrome (HALS), which attenuates patient compliance to this treatment. HALS is characterised by impaired glucose and lipid metabolism and other risk factors for cardiovascular disease. This review depicts the metabolic abnormalities associated with HAART by describing the key cell and organ systems that are involved, emphasising the role of insulin resistance. An opinion on the remedies available to treat the metabolic abnormalities and phenotype of HALS is provided. PMID: 16863444 [PubMed - indexed for MEDLINE] 3297. C R Biol. 2006 Aug;329(8):598-607; discussion 653-5. Epub 2006 Apr 27. Control of fatty acid and glycerol release in adipose tissue lipolysis. Langin D(1). Author information: (1)Unité de recherches sur les obésités, INSERM UPS U586, institut Louis-Bugnard, université Paul-Sabatier, CHU Rangueil, BP 84225, 31432 Toulouse cedex 4, France. langin@toulouse.inserm.fr Adipose tissue lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and the release of fatty acids and glycerol. Recent work has revealed that lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. New discoveries on the regulation of lipolysis by endocrine and paracrine factors and on the proteins involved in triglyceride hydrolysis have led to a reappraisal of the complexity of the various signal transduction pathways. The steps involved in the dysregulation of lipolysis observed in obesity have partly been identified. PMID: 16860278 [PubMed - indexed for MEDLINE] 3298. C R Biol. 2006 Aug;329(8):587-97; discussion 653-5. Epub 2006 May 5. [Relationship between obesity, inflammation and insulin resistance: new concepts]. [Article in French] Fève B(1), Bastard JP, Vidal H. Author information: (1)Inserm U693, université Paris-11 et service d'endocrinologie, CHU de Bicêtre, 63, rue Gabriel-Péri, 94270 Le Kremlin-Bicêtre, France. White adipose tissue is the main site of energy storage, but it is now recognized as an active participant in regulating physiologic and pathologic processes including immunity and inflammation. It has an endocrine function by secreting at least two main hormones, leptin and adiponectin. It can secrete other products, named adipokines, including cytokines and chemokines, involved in inflammation process. The release of adipokines by either adipocytes or adipose tissue infiltrated macrophages lead to a chronic sub-inflammatory state that could play a central role in cardiovascular complications linked to obesity and insulin resistance, a risk factor to develop type-2 diabetes. PMID: 16860277 [PubMed - indexed for MEDLINE] 3299. C R Biol. 2006 Aug;329(8):570-7; discussion 653-5. Epub 2006 May 3. Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. Ailhaud G(1). Author information: (1)ISDBC, centre de biochimie, UMR 6543 CNRS, laboratoire developpement du tissu adipeux, faculté des sciences, parc Valrose, 06108 Nice cedex 2, France. ailhaud@unice.fr Adipose tissue contains various types of cells that include preadipocytes and adipocytes. Studies have emphasized that (i) preadipocytes secrete factors involved in their own differentiation and (ii) adipocytes acquire the ability to communicate systemically with other organs (brain, liver, skeletal muscle) and locally with other cells (preadipocytes, endothelial cells and monocytes/macrophages). Adipocytes secrete proteins exhibiting either beneficial (leptin, adiponectin) or deleterious effects (angiotensinogen). Associated to the effect of secretory products from macrophages (cytokines), a disturbance in the balance between these various secreted factors leads to the development of a metabolic syndrome. PMID: 16860275 [PubMed - indexed for MEDLINE] 3300. Lancet Neurol. 2006 Aug;5(8):713-20. Adiposity indices and dementia. Gustafson D(1). Author information: (1)Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, SE 413-45, Göteborg, Sweden. deb.gustafson@neuro.gu.se Indicators of adiposity, such as body-mass index (BMI), may be markers for changes in energy metabolism that influence dementia risk, progression, and ultimately death. Cross-sectional studies show that people with dementia have a lower BMI than those without dementia, which is potentially due to a greater rate of BMI decline occurring during the years immediately preceding dementia onset. However, a high BMI can also increase the risk for dementia when measured before clinical dementia onset, which might be due to vascular disorders or bioactive hormonal compounds that are secreted by adipose tissue. In this personal view, I consider how dementia is associated with BMI by looking at the role of BMI and obesity syndromes, mechanisms associated with adiposity, and the potential for hypothalamic dysregulation during the life course. Understanding the life course of adiposity by use of common surrogate measures, such as BMI, among those who do and do not develop dementia is relevant for understanding the causes of dementia and for shaping possible treatment options. PMID: 16857578 [PubMed - indexed for MEDLINE] 3301. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD002968. Exercise for type 2 diabetes mellitus. Thomas DE(1), Elliott EJ, Naughton GA. Author information: (1)University of Sydney, Children's Hospital at Westmead, CEBPGAN (Centre for Evidence Based Paediatrics Gastroenterology and Nutrition), Locked Bag 4001, Westmead, Australia, NSW 2145. dianat@chw.edu.au Comment in Evid Based Nurs. 2007 Jan;10(1):11. BACKGROUND: Exercise is generally recommended for people with type 2 diabetes mellitus. However, some studies evaluate an exercise intervention including diet or behaviour modification or both, and the effects of diet and exercise are not differentiated. Some exercise studies involve low participant numbers, lacking power to show significant differences which may appear in larger trials. OBJECTIVES: To assess the effects of exercise in type 2 diabetes mellitus. SEARCH STRATEGY: Trials were identified through the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and manual searches of bibliographies. Date of last search was March 3, 2005. SELECTION CRITERIA: All randomised controlled trials comparing any type of well-documented aerobic, fitness or progressive resistance training exercise with no exercise in people with type 2 diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed trial quality and extracted data. Study authors were contacted for additional information. Any information on adverse effects was collected from the trials. MAIN RESULTS: Fourteen randomised controlled trials comparing exercise against no exercise in type 2 diabetes were identified involving 377 participants. Trials ranged from eight weeks to twelve months duration. Compared with the control, the exercise intervention significantly improved glycaemic control as indicated by a decrease in glycated haemoglobin levels of 0.6% (-0.6 % HbA(1c), 95% confidence interval (CI) -0.9 to -0.3; P < 0.05). This result is both statistically and clinically significant. There was no significant difference between groups in whole body mass, probably due to an increase in fat free mass (muscle) with exercise, as reported in one trial (6.3 kg, 95% CI 0.0 to 12.6). There was a reduction in visceral adipose tissue with exercise (-45.5 cm(2), 95% CI -63.8 to -27.3), and subcutaneous adipose tissue also decreased. No study reported adverse effects in the exercise group or diabetic complications. The exercise intervention significantly increased insulin response (131 AUC, 95% CI 20 to 242) (one trial), and decreased plasma triglycerides (-0.25 mmol/L, 95% CI -0.48 to -0.02). No significant difference was found between groups in quality of life (one trial), plasma cholesterol or blood pressure. AUTHORS' CONCLUSIONS: The meta-analysis shows that exercise significantly improves glycaemic control and reduces visceral adipose tissue and plasma triglycerides, but not plasma cholesterol, in people with type 2 diabetes, even without weight loss. PMID: 16855995 [PubMed - indexed for MEDLINE] 3302. Ann N Y Acad Sci. 2006 Jun;1069:454-62. Leptin is a link between adipose tissue and inflammation. Härle P(1), Straub RH. Author information: (1)Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital, 93042 Regensburg, Germany. peter.haerle@klinik.uni-regensburg.de Leptin is a hormone of the pluripotent white adipose tissue and confers a multitude of regulatory functions within the organism. It controls the energy storage, lipoprotein metabolism, acute phase reactants, sex hormones and glucocorticoid metabolism, and immune function. In this review, we describe these multiple functions of leptin, the regulation of leptin expression, and how leptin can modulate the immune system via direct and indirect mechanisms. We show how leptin can be a link between the adipose tissue and inflammation. PMID: 16855173 [PubMed - indexed for MEDLINE] 3303. Expert Opin Ther Targets. 2006 Aug;10(4):573-81. Targeting adiponectin for cardioprotection. Ouchi N(1), Shibata R, Walsh K. Author information: (1)Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA. Adiponectin is an adipose tissue-derived plasma protein which has a reduced concentration in subjects with obesity-related diseases. Adiponectin has antidiabetic and anti-inflammatory characteristics, which lead to beneficial actions on various obesity-linked complications. Recent experimental findings have shown that adiponectin contributes to protection against cardiac remodelling after pressure overload and cardiac injury following ischaemia-reperfusion. Thus, adiponectin could emerge as a potential cardioprotective agent for the treatment of several pathological heart conditions. PMID: 16848693 [PubMed - indexed for MEDLINE] 3304. Pharmacol Ther. 2006 Dec;112(3):799-809. Epub 2006 Jul 13. Lipid phosphatases as a possible therapeutic target in cases of type 2 diabetes and obesity. Sasaoka T(1), Wada T, Tsuneki H. Author information: (1)Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. tsasaoka@pha.u-toyama.ac.jp Phosphatidyl inositol 3-kinase (PI3-kinase) functions as a lipid kinase to produce PI(3,4,5)P(3) from PI(4,5)P(2) in vivo. PI(3,4,5)P(3) is crucial as a lipid second messenger in various metabolic effects of insulin. Lipid phosphatases, src homology 2 domain containing inositol 5'-phosphatase 2 (SHIP2) and skeletal muscle and kidney-enriched inositol phosphatase (SKIP) hydrolyze PI(3,4,5)P(3) to PI(3,4)P(2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) hydrolyzes PI(3,4,5)P(3) to PI(4,5)P(2). SHIP2 negatively regulates insulin signaling relatively specifically via its 5'-phosphatase activity. Targeted disruption of the SHIP2 gene in mice resulted in increased insulin sensitivity and conferred protection from obesity induced by a high-fat diet. Polymorphisms in the human SHIP2 gene are associated, at least in part, with the insulin resistance of type 2 diabetes. Importantly, inhibition of endogenous SHIP2 through the liver-specific expression of a dominant-negative SHIP2 improves glucose metabolism and insulin resistance in diabetic db/db mice. Overexpression of PTEN and SKIP also inhibited insulin-induced phosphorylation of Akt and the uptake of glucose in cultured cells. Although a homozygous disruption of the PTEN gene in mice results in embryonic lethality, either skeletal muscle or adipose tissue-specific disruption of PTEN ameliorated glucose metabolism without formation of tumors in animal models of diabetes. The role of SKIP in glucose metabolism remains to be further clarified in vivo. Taken together, inhibition of endogenous SHIP2 in the whole body appears to be effective at improving the insulin resistance associated with type 2 diabetes and/or obesity. Inhibition of PTEN in the tissues specifically targeted, including skeletal muscle and fat, may result in an amelioration of insulin resistance in type 2 diabetes, although caution against the formation of tumors is needed. PMID: 16842857 [PubMed - indexed for MEDLINE] 3305. Curr Vasc Pharmacol. 2006 Jul;4(3):175-83. Dyslipidaemia, hypercoagulability and the metabolic syndrome. Kakafika AI(1), Liberopoulos EN, Karagiannis A, Athyros VG, Mikhailidis DP. Author information: (1)Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, London, UK. MIKHAILIDIS@aol.com. The metabolic syndrome is a clustering of risk factors including central obesity, insulin resistance, dyslipidaemia and hypertension. This syndrome is associated with increased risk of cardiovascular disease and is a common early abnormality in the development of type 2 diabetes. The pathogenesis of the syndrome has multiple origins. Obesity and sedentary lifestyle coupled with genetic factors interact to produce the syndrome. Here, we consider two components of the metabolic syndrome, dyslipidaemia and hypercoagulability. PMID: 16842135 [PubMed - indexed for MEDLINE] 3306. Mini Rev Med Chem. 2006 Jul;6(7):765-70. Myostatin: biology and clinical relevance. Carnac G(1), Ricaud S, Vernus B, Bonnieu A. Author information: (1)Adult stem cells and Facio Scapulo Humeral dystrophy, CRBM, CNRS FRE 2593, 1919 Route de Mende, 34293 Montpellier Cedex 5, France. Myostatin is a negative regulator of muscle mass. Important advances in our understanding of the complex biology of this factor have revealed the therapeutic potential of antagonizing the myostatin pathway. Here we present the rationale for evaluating anti-myostatin therapies in human muscle-wasting disorders. PMID: 16842126 [PubMed - indexed for MEDLINE] 3307. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1467S-1476S. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Arterburn LM(1), Hall EB, Oken H. Author information: (1)Martek Biosciences Corporation, Columbia, MD, USA. larterburn@martekbio.com n-3 Fatty acids have important visual, mental, and cardiovascular health benefits throughout the life cycle. Biodistribution, interconversion, and dose response data are reviewed herein to provide a basis for more rational n-3 dose selections. Docosahexaenoic acid (DHA) is the principal n-3 fatty acid in tissues and is particularly abundant in neural and retinal tissue. Limited storage of the n-3 fatty acids in adipose tissue suggests that a continued dietary supply is needed. A large proportion of dietary alpha-linolenic acid (ALA) is oxidized, and because of limited interconversion of n-3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n-3 fatty acids in plasma. Eicosapentaenoic acid (EPA) but not DHA concentrations in plasma increase in response to dietary EPA. Dietary DHA results in a dose-dependent, saturable increase in plasma DHA concentrations and modest increases in EPA concentrations. Plasma DHA concentrations equilibrate in approximately 1 mo and then remain at steady state throughout supplementation. DHA doses of approximately 2 g/d result in a near maximal plasma response. Both dietary DHA and EPA reduce plasma arachidonic acid concentrations. Tissue contents of DHA and EPA also increase in response to supplementation with these fatty acids. Human milk contents of DHA are dependent on diet, and infant DHA concentrations are determined by their dietary intake of this fatty acid. We conclude that the most predictable way to increase a specific long-chain n-3 fatty acid in plasma, tissues, or human milk is to supplement with the fatty acid of interest. PMID: 16841856 [PubMed - indexed for MEDLINE] 3308. Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R77-85. Epub 2006 Jul 13. Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Diepvens K(1), Westerterp KR, Westerterp-Plantenga MS. Author information: (1)Department of Human Biology, Maastricht University, Maastricht, The Netherlands. K.Diepvens@HB.Unimaas.NL The global prevalence of obesity has increased considerably in the last decade. Tools for obesity management, including caffeine, ephedrine, capsaicin, and green tea have been proposed as strategies for weight loss and weight maintenance, since they may increase energy expenditure and have been proposed to counteract the decrease in metabolic rate that is present during weight loss. A combination of caffeine and ephedrine has shown to be effective in long-term weight management, likely due to different mechanisms that may operate synergistically, e.g., respectively inhibiting the phosphodiesterase-induced degradation of cAMP and enhancing the sympathetic release of catecholamines. However, adverse effects of ephedrine prevent the feasibility of this approach. Capsaicin has been shown to be effective, yet when it is used clinically it requires a strong compliance to a certain dosage, that has not been shown to be feasible yet. Also positive effects on body-weight management have been shown using green tea mixtures. Green tea, by containing both tea catechins and caffeine, may act through inhibition of catechol O-methyl-transferase, and inhibition of phosphodiesterase. Here, the mechanisms may also operate synergistically. In addition, tea catechins have antiangiogenic properties that may prevent development of overweight and obesity. Furthermore, the sympathetic nervous system is involved in the regulation of lipolysis, and the sympathetic innervation of white adipose tissue may play an important role in the regulation of total body fat in general. PMID: 16840650 [PubMed - indexed for MEDLINE] 3309. Nihon Rinsho. 2006 Jul;64(7):1381-9. [Insulin signaling and pathophysiology of type 2 diabetes mellitus]. [Article in Japanese] Ogawa W(1), Kasuga M. Author information: (1)Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine. The pathophysiology of type 2 diabetes is characterized by defects in insulin action and in insulin secretion. Metabolic actions of insulin are mediated by the insulin receptor/IRS/PI 3-kinase signaling pathway in insulin's target organs including the liver, skeletal muscle and adipose tissue. Recent evidence suggests that insulin action in the brain also plays an important role in the regulation of glucose metabolism in the liver. Insulin signaling in pancreatic beta cells appears to regulate glucose-induced insulin secretion. Although the mechanism how insulin resistance develops is not fully understood, dysregulation of fatty acid metabolism, abnormalities of the function and the secretion of adipokines, as well as the increase in stress signaling might contribute to the development of insulin resistance. PMID: 16838661 [PubMed - indexed for MEDLINE] 3310. Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):437-43. Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Schindhelm RK(1), Diamant M, Dekker JM, Tushuizen ME, Teerlink T, Heine RJ. Author information: (1)Department of Endocrinology/Diabetes Centre, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands. rk.schindhelm@vumc.nl Comment in Atherosclerosis. 2007 Jan;190(1):18-9; author reply 20-1. For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed. Copyright (c) 2006 John Wiley & Sons, Ltd. PMID: 16832839 [PubMed - indexed for MEDLINE] 3311. Ann Chir Plast Esthet. 2007 Feb;52(1):51-61. Epub 2006 Jul 10. [Facial fat: descriptive and functional anatomy, from a review of literature and dissections of 10 split-faces]. [Article in French] Dumont T(1), Simon E, Stricker M, Kahn JL, Chassagne JF. Author information: (1)Service de chirurgie maxillofaciale et plastique, CHU de Nancy, hôpital central, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 34, 54035 Nancy cedex, France. tomdumont69@yahoo.fr The aim of this study is to describe the anatomy of the fat in the face, based on a review of the literature and dissections of 10 half-faces. The facial fat can be divided in two layers. The first-one is superficial, between the skin and the superficialis fascia. Its function is essentially protective and its morphological implications are major, especially according to the facial aging. The other layer is deep, under the superficialis fascia. Its principal function is mechanical and its morphological implications are less important. This layer is made of several fat pads in continuity, excepted the buccal fat pad which is separated from the others by its own capsula. The other fat pads are the intra orbialis fat pad, the sub orbicularis oculi fat pad (SOOF), the retro orbicularis oculi fat pad (ROOF), the galeal fat pad and the temporal fat pad. PMID: 16828948 [PubMed - indexed for MEDLINE] 3312. BJOG. 2006 Oct;113(10):1148-59. Epub 2006 Jul 7. The impact of obesity on reproduction in women with polycystic ovary syndrome. Pasquali R(1), Gambineri A, Pagotto U. Author information: (1)Division of Endocrinology, Department of Internal Medicine, University Alma Mater Studiorum and Centre for Advanced Biology Research (C.R.B.A.), S. Orsola-Malpighi Hospital, Bologna, Italy. renato.pasquali@unibo.it The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS. PMID: 16827825 [PubMed - indexed for MEDLINE] 3313. Am J Physiol Cell Physiol. 2006 Aug;291(2):C203-17. Orphan nuclear receptors: therapeutic opportunities in skeletal muscle. Smith AG(1), Muscat GE. Author information: (1)Institute for Molecular Bioscience, Univ. of Queensland, St. Lucia 4072, Queensland, Australia. a.smith@imb.uq.edu.au Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for approximately 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease. PMID: 16825600 [PubMed - indexed for MEDLINE] 3314. J Ren Nutr. 2006 Jul;16(3):204-7. Inflammation and adipose tissue in uremia. Barazzoni R(1), Biolo G, Zanetti M, Bernardi A, Guarnieri G. Author information: (1)Department SCMT, Clinica Medica, University of Trieste, Trieste, Italy. Enhanced chronic systemic inflammation and reduced insulin sensitivity are often associated in patients with chronic renal failure, contributing to cardiovascular morbidity and mortality in these patients. Adipose tissue produces several hormones (adipocytokines including leptin, resistin, tumor necrosis factor-alpha, and adiponectin) that modulate both systemic inflammatory response and insulin action. High leptin, resistin, and tumor necrosis factor-alpha and low adiponectin are associated with proinflammatory conditions, whereas opposite patterns are commonly observed in the presence of increased insulin sensitivity, low inflammation, and reduced cardiovascular risk. Oxidative stress has also been shown recently to modulate adipocytokine production, resulting in a proinflammatory profile. Increments of plasma concentrations of both proinflammatory and anti-inflammatory adipocytokines have been reported in chronic renal failure, possibly caused by both passive accumulation from reduced renal excretion and metabolic abnormalities induced by uremia. The potential role of altered adipose tissue adipocytokine production in the onset of renal failure-associated inflammatory and metabolic derangements remains largely to be elucidated and is discussed in the current report. PMID: 16825020 [PubMed - indexed for MEDLINE] 3315. Reprod Nutr Dev. 2006 Jul-Aug;46(4):447-60. Epub 2006 Jul 7. Endocrine and metabolic factors involved in the effect of nutrition on the production of colostrum in female sheep. Banchero GE(1), Perez Clariget R, Bencini R, Lindsay DR, Milton JT, Martin GB. Author information: (1)National Institute of Agricultural Research, INIA La Estanzuela, Ruta 50 Km 12 Colonia, Uruguay. banchero@inia.org.uy We investigated the physiological relationship between diet during pregnancy and colostrum production in ewes to test the hypothesis that for ewes that are in low body condition, with low fat reserves, the food supply will be the main source of energy for colostrum synthesis. To this end, we measured the amount of colostrum accumulated by ewes under two levels of nutrition. We also measured the circulating concentrations of metabolites and hormones associated with lactogenesis (beta-hydroxybutyrate, glucose, progesterone, prolactin, cortisol, growth hormone, leptin, insulin and insulin-like growth factor-I) Ewes were either under-fed at 70 (n = 15) or well-fed at 110% (n = 10) of their daily metabolisable energy requirement during the last two months of pregnancy. Colostrum accumulation up to parturition was 168 +/-48 g for under-fed ewes and 451 +/-103 g for well-fed ewes. After birth, under-fed ewes produced less colostrum than well-fed ewes but the difference was no longer significant. The level of nutrition also influenced the plasma concentrations of hormones and metabolites related to lactogenesis. Progesterone concentrations decreased before lambing in all animals but in under-fed ewes the fall appeared to be too small to initiate the onset of colostrum production. Beta-hydroxybutyrate concentrations were higher in under-fed than in well-fed ewes, suggesting that the under-fed ewes were mobilising more adipose tissue but they still did not meet their ME requirements for colostrum production. We concluded that, in underfed ewes, there are insufficient nutrients for adequate lactation and the hormone regime is inappropriate for good udder development and colostrum synthesis. PMID: 16824452 [PubMed - indexed for MEDLINE] 3316. J Clin Invest. 2006 Jul;116(7):1784-92. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. Kadowaki T(1), Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. PMCID: PMC1483172 PMID: 16823476 [PubMed - indexed for MEDLINE] 3317. J Cardiovasc Nurs. 2006 Jul-Aug;21(4):285-90. What is the metabolic syndrome? Prediabetes and cardiovascular risk. Borgman M(1), McErlean E. Author information: (1)Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. borgmam@ccf.org The metabolic syndrome has been referred to as a clustering of cardiovascular risk factors, including abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance, proinflammatory state, and a prothrombotic state. The metabolic syndrome has become one of the leading clinical issues discussed by physicians and the media, leading to increased public awareness to this potentially catastrophic multiplex risk factor for cardiovascular disease. With increasing prevalence in the United States, the metabolic syndrome has been equated to cigarette smoking as a contributing factor to premature cardiovascular heart disease and one of the underlying causes of type 2 diabetes. The identification and modification of the root causes, overweight/obesity, physical inactivity, and the closely associated condition, insulin resistance, needs to be one of the initial strategies that are addressed by the clinician. PMID: 16823282 [PubMed - indexed for MEDLINE] 3318. Nestle Nutr Workshop Ser Clin Perform Programme. 2006;11:1-9; discussion 9-13. The dysmetabolic syndrome: epidemiology and etiology. Sauerwein HP(1). Author information: (1)Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands. The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. It also refers to a clustering of specific cardiovascular disease risk factors whose underlying pathophysiology is thought to be related to insulin resistance with an excessive flux of fatty acids implicated. Opinions have varied as to whether the metabolic syndrome should be defined to indicate mainly insulin resistance, the metabolic consequences of obesity, risk of cardiovascular disease, or simply a collection of statistically related factors. Based on these different viewpoints 4 definition sets of the metabolic syndrome are formulated. The pros and cons of each of them are extensively discussed. A major role in the etiology of the metabolic syndrome is ascribed to the occurrence of insulin resistance. Data are provided that insulin resistance can worsen the expression of this syndrome, but cannot have a primary role. Therefore, insulin resistance is not the main player of the metabolic syndrome, but central obesity is. Free fatty acid induced insulin resistance is found and induced by central obesity. The metabolic syndrome is a cluster of abnormalities in which each of them deserves its own (maximal) treatment to diminish the risk for cardiovascular disease. PMID: 16820727 [PubMed - indexed for MEDLINE] 3319. Pediatr Endocrinol Rev. 2006 Jun;3(4):365-78. Catch-up growth: an overview. Kay's SK(1), Hindmarsh PC. Author information: (1)London Centre for Paediatric Endocrinology and Metabolism, University College London, UK. Normal growth in humans results from interactions between several mechanisms (genetic, nutritional, environmental, social and economic) that lead in concert to gain in weight and height. Many systemic diseases and environmental conditions do impair linear growth. When remission occurs, growth often resumes at a rate faster and beyond the normal rate for age. This phase of accelerated growth constitutes the "catch-up growth" phenomenon, which may be complete or incomplete depending upon the final height with reference preferably to the genetic target height. The exact mechanisms of catch-up growth remain unknown, but two hypotheses have been proposed: the neuroendocrine or sizostat hypothesis; and the growth plate hypothesis. Although no experimental data supports the former, it is most likely that the catch-up growth process involves both systemic and local (growth plate) factors, with the participation of a normally functioning GH-Thyroid-IGF-I axis. The Ob gene protein, leptin serves as an afferent signal in a negative feedback loop to regulate the size of adipose tissue mass (body weight). Experimental studies have demonstrated its links with the GH - Thyroid - IGF-I and growth plate axis. To resume normal growth or initiate catch-up growth, an undernourished child must regain up to 85% of weight for height. This may mean that a close relationship exists between mechanisms regulating weight and those regulating linear growth. More studies are needed to determine the links that probably exist between the chondrocyte, adipocyte, leptin, and GH - Thyroid - IGF-I axis on one side and the catch-up growth on the other. PMID: 16816805 [PubMed - indexed for MEDLINE] 3320. Philos Trans R Soc Lond B Biol Sci. 2006 Jul 29;361(1471):1237-49. Appetite and energy balance signals from adipocytes. Trayhurn P(1), Bing C. Author information: (1)Obesity Biology Unit (Liverpool Centre for Nutritional Genomics and Liverpool Obesity Research Network), School of Clinical Sciences, University of Liverpool, UK. p.trayhurn@liverpool.ac.uk Interest in the biology of white adipose tissue has risen markedly with the recent surge in obesity and its associated disorders. The tissue is no longer viewed simply as a vehicle for lipid storage; instead, it is recognized as a major endocrine and secretory organ. White adipocytes release a multiplicity of protein hormones, signals and factors, termed adipokines, with an extensive range of physiological actions. Foremost among these various adipokines is the cytokine-like hormone, leptin, which is synthesized predominantly in white fat. Leptin plays a critical role in the control of appetite and energy balance, with mutations in the genes encoding the hormone or its receptor leading to profound obesity in both rodents and man. Leptin regulates appetite primarily through an interaction with hypothalamic neuroendocrine pathways, inhibiting orexigenic peptides such as neuropeptide Y and orexin A, and stimulating anorexigenic peptides such as proopiomelanocortin. White fat also secretes several putative appetite-related adipokines, which include interleukin-6 and adiponectin, but whether these are indeed significant signals in the regulation of food intake has not been established. Through leptin and the other adipokines it is evident that adipose tissue communicates extensively with other organs and plays a pervasive role in metabolic homeostasis. PMCID: PMC1642696 PMID: 16815801 [PubMed - indexed for MEDLINE] 3321. Philos Trans R Soc Lond B Biol Sci. 2006 Jul 29;361(1471):1219-35. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Woods SC(1), Lutz TA, Geary N, Langhans W. Author information: (1)Department of Psychiatry, University of Cincinnati, OH 45237 USA. steve.woods@psychiatry.uc.edu The control of food intake and body weight by the brain relies upon the detection and integration of signals reflecting energy stores and fluxes, and their interaction with many different inputs related to food palatability and gastrointestinal handling as well as social, emotional, circadian, habitual and other situational factors. This review focuses upon the role of hormones secreted by the endocrine pancreas: hormones, which individually and collectively influence food intake, with an emphasis upon insulin, glucagon and amylin. Insulin and amylin are co-secreted by B-cells and provide a signal that reflects both circulating energy in the form of glucose and stored energy in the form of visceral adipose tissue. Insulin acts directly at the liver to suppress the synthesis and secretion of glucose, and some plasma insulin is transported into the brain and especially the mediobasal hypothalamus where it elicits a net catabolic response, particularly reduced food intake and loss of body weight. Amylin reduces meal size by stimulating neurons in the hindbrain, and there is evidence that amylin additionally functions as an adiposity signal controlling body weight as well as meal size. Glucagon is secreted from A-cells and increases glucose secretion from the liver. Glucagon acts in the liver to reduce meal size, the signal being relayed to the brain via the vagus nerves. To summarize, hormones of the endocrine pancreas are collectively at the crossroads of many aspects of energy homeostasis. Glucagon and amylin act in the short term to reduce meal size, and insulin sensitizes the brain to short-term meal-generated satiety signals; and insulin and perhaps amylin as well act over longer intervals to modulate the amount of fat maintained and defended by the brain. Hormones of the endocrine pancreas interact with receptors at many points along the gut-brain axis, from the liver to the sensory vagus nerve to the hindbrain to the hypothalamus; and their signals are conveyed both neurally and humorally. Finally, their actions include gastrointestinal and metabolic as well as behavioural effects. PMCID: PMC1642707 PMID: 16815800 [PubMed - indexed for MEDLINE] 3322. Rom J Intern Med. 2005;43(3-4):173-85. Clinical impact of cachexia on survival and outcome of cancer patients. Dimitriu C(1), Martignoni ME, Bachmann J, Fröhlich B, Tintărescu G, Buliga T, Lică I, Constantinescu G, Beuran M, Friess H. Author information: (1)Surgical Department, Clinical Emergency Hospital Bucharest, Romania. Approximately one half of all cancer patients experience a complex metabolic status involving progressive exhaustion of adipose and skeletal muscle tissue. This condition, known as cachexia, is responsible for more than 20% of the overall deaths in cancer patients. Although its main mechanisms remain unknown, several hypotheses have been proposed. One of the pathogenic mechanisms involves leptin and hypothalamic neuropeptide-containing pathways. Orexigenic and anorexigenic neuropeptides are down-regulated respectively upregulated as a result of cancer. Other pathogenic theories consider tumour derived factors, such as LMF (Lipid Mobilising Factor) and PIF (Proteolysis-inducing Factor), to be responsible for the weight losing pattern of cancer patients via activation of various catabolic pathways (e.g. ubiquitin-proteasome proteolytic-pathway, etc.). Despite the controversial discussion of cachexia-inducing mechanisms it is clear that proinflammatory cytokines, such as TNFalpha, IFNgamma, IL-1, IL-6 and IL-8, are linked to all pathways that induce cachexia. Although only limited treatment exists for patients with cancer cachexia, recent studies with eicosapaentanoic acid showed promising effects in reversing weight losing pattern of cachectic patients. Cytokine targeted monoclonal antibodies, cytokine traps and genetic therapies are also evaluated for future therapeutic strategies. PMID: 16812978 [PubMed - indexed for MEDLINE] 3323. Front Horm Res. 2006;35:102-14. Ghrelin: from somatotrope secretion to new perspectives in the regulation of peripheral metabolic functions. Broglio F(1), Prodam F, Riganti F, Muccioli G, Ghigo E. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, IT-10126 Turin, Italy. Ghrelin, a peptide predominantly produced by the stomach, has been discovered as natural ligand of the GH secretagogue (GHS) receptor type 1a (GHS-R1a), suggesting the existence a new endogenous modulator of somatotrope secretion. Subsequently, ghrelin turned out to exert pleiotropic actions, consistent with the widespread distribution of ghrelin and GHS-R expression in central and peripheral tissues. Despite that the binding to GHS-R1a requires ghrelin to be acylated in serine 3, some ghrelin actions are independent of such acylation; thus suggesting the possibility of the existence of other GHS-R subtypes. Ghrelin secretion (70% in its unacylated form) is mainly under metabolic control being modulated by glucose, insulin and feeding. On the other hand, ghrelin influences energy metabolism acting both as a central orexigenic factor and directly on the endocrine pancreas, liver and adipose tissue. Recently, another gastric hormone derived from the same ghrelin gene has been isolated and named obestatin. Obestatin in rats resulted in reduced food intake, jejunal contraction and body weight gain, via specific distinct receptors. Thus, all these data indicate that we are exploring a very complex system deeply involved in the modulation of metabolic functions, whose understanding will probably increase our knowledge about diabetes mellitus and the metabolic syndrome. PMID: 16809926 [PubMed - indexed for MEDLINE] 3324. J Behav Med. 2006 Dec;29(6):593-606. Epub 2006 Jun 29. Anger expression and pain: an overview of findings and possible mechanisms. Bruehl S(1), Chung OY, Burns JW. Author information: (1)Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. Stephen.Bruehl@vanderbilt.edu A tendency to manage anger via direct expression (anger-out) is increasingly recognized as influencing responses to pain. Elevated trait anger-out is associated with increased responsiveness to acute experimental and clinical pain stimuli, and is generally related to elevated chronic pain intensity in individuals with diverse pain conditions. Possible mechanisms for these links are explored, including negative affect, psychodynamics, central adipose tissue, symptom specific muscle reactivity, endogenous opioid dysfunction, and genetics. The opioid dysfunction hypothesis has some experimental support, and simultaneously can account for anger-out's effects on both acute and chronic pain. Factors which may moderate the anger-out/pain link are described, including narcotic use, gender, and genetic polymorphisms. Pain exacerbating effects of trait anger-out are contrasted with the apparent pain inhibitory effects of behavioral anger expression exhibited in anger-provoking contexts. Conceptual issues related to the state versus trait effects of expressive anger regulation are discussed. PMID: 16807797 [PubMed - indexed for MEDLINE] 3325. J Perinatol. 2006 Jul;26 Suppl 2:S13-8. Early postnatal nutritional requirements of the very preterm infant based on a presentation at the NICHD-AAP workshop on research in neonatology. Hay WW(1). Author information: (1)Neonatal Clinical Research Center and the UCHSC Perinatal Research Center, University of Colorado Health Sciences Center, Aurora, 80045, USA. bill.hay@uchsc.edu Normal fetal nutrition is a useful guide for understanding postnatal nutrition of infants born very preterm. Fetal lipid uptake gradually increases towards term and is primarily used to produce fat in adipose tissue, with essential fatty acid uptake providing necessary structural and functional elements in membranes of cells in the central nervous system. Fetal glucose uptake and utilization rates are nearly twice as high at 23-26 weeks gestation as they are at term, contributing primarily to energy production and glycogen formation. Amino-acid uptake by the fetus is two-to threefold greater at 23-26 weeks gestation than at term and is required to meet the very high fractional protein synthesis and growth rates at this gestational period; amino acids also contribute significantly to fetal energy production. In contrast, after birth most of the very preterm infants are fed more lipid and glucose and less amino acids and protein than they need. Not surprisingly, therefore, very preterm infants accumulate fat but remain relatively growth restricted at term gestational age compared to those infants who grew normally in utero, and this postnatal growth restriction has long-term adverse growth, development, and health consequences. More thorough understanding of the unique nutritional, metabolic, and growth requirements of the normally growing fetus and the very preterm infant, once born, are needed to determine optimal nutritional strategies to improve the outcome of preterm infants. PMID: 16801962 [PubMed - indexed for MEDLINE] 3326. Biochim Biophys Acta. 2006 Jul;1761(7):655-66. Epub 2006 May 4. Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Cavelier C(1), Lorenzi I, Rohrer L, von Eckardstein A. Author information: (1)Institute of Clinical Chemistry, University Hospital Zurich, University Zurich, Rämistrasse 100, CH 8091 Zurich, Switzerland. Plasma levels of high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated with the risk of cardiovascular disease. One major atheroprotective mechanism of HDL and apoA-I is their role in reverse cholesterol transport, i.e., the transport of excess cholesterol from foam cells to the liver for secretion. The ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, respectively. In the liver, ABCA1 activity is one rate-limiting step in the formation of HDL. In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and thereby protect the arteries from developing atherosclerotic lesions. However, the mechanisms by which ABCA1 and ABCG1 mediate lipid removal are still unclear. Particularly, three questions remain controversial and are discussed in this review: (1) Do apoA-I and HDL directly interact with ABCA1 and ABCG1, respectively? (2) Does cholesterol efflux involve retroendocytosis of apoA-I or HDL? (3) Which lipids are directly transported by ABCA1 and ABCG1? PMID: 16798073 [PubMed - indexed for MEDLINE] 3327. Infez Med. 2006 Mar;14(1):5-12. [Effect of anti-retroviral therapy on body composition changes: a literature review]. [Article in Italian] Dell'Isola C(1), Aprea L, Pizzella T, Izzo C. Author information: (1)VIII Divisione Dipartimento Urgenze Infettivologiche ad Alta Complessita, A.O. D. Cotugno, Napoli, Italy. Protein-energetic malnutrition, characterized by both lean mass and fat depletion, was common in the pre-HAART era, and was associated with shortened survival and diminished quality of life. The pathogenesis of protein-energy malnutrition was multifactorial, and nutritional treatments were largely ineffective in the absence of disease stabilization. The introduction of HAART brought markedly improved outcomes, including a decrease in the incidence of malnutrition. However, other nutritional and metabolic alterations were noticed, and included changes in body shape, both lipoatrophy and lipohypertrophy, as well as changes in metabolism, notably hyperlipidemia and insulin resistance. These conditions, though sometimes occurring together, may occur independently, suggesting a complex, multifactorial cause. Several mechanisms have been hypothesized, including impairment to adipocyte differentiation and adipokine regulation, production of proinflammatory cytokines and mitochondrial toxicity. The role of the single drug class is still unclear, because both PI and NRTI have been associated with the syndrome, and the therapeutic protocols include both groups. Most of the medical therapies proposed for lipodystrophy are ineffective, and even if surgery remains an alternative, it is not associated with long lasting outcomes. PMID: 16794374 [PubMed - indexed for MEDLINE] 3328. Exp Cell Res. 2006 Aug 1;312(13):2401-14. Epub 2006 May 3. Myostatin regulation of muscle development: molecular basis, natural mutations, physiopathological aspects. Joulia-Ekaza D(1), Cabello G. Author information: (1)UMR 866 Différenciation Cellulaire et Croissance, INRA-Université Montpellier II-ENSA-M, 2 Place Viala, 34060 Montpellier Cedex 1, France. Erratum in Exp Cell Res. 2006 Oct 15;312(17):3458. Dominique, Joulia-Ekaza [corrected to Joulia-Ekaza, Dominique]; Gérard, Cabello [corrected to Cabello, Gérard]. Since its identification in 1997, myostatin has been considered as a novel and unique negative regulator of muscle growth, as mstn-/- mice display a dramatic and widespread increase in skeletal muscle mass. Myostatin also appears to be involved in muscle homeostasis in adults as its expression is regulated during muscle atrophy. Moreover, deletion of the myostatin gene seems to affect adipose tissue mass in addition to skeletal muscle mass. Natural myostatin gene mutations occur in cattle breeds such as Belgian Blue, exhibiting an obviously increased muscle mass, but also in humans, as has recently been demonstrated. Here we review these natural mutations and their associated phenotypes as well as the physiological influence of the alterations in myostatin expression and the physiopathological consequences of changes in myostatin expression, especially with regard to satellite cells. Interestingly, studies have demonstrated some rescue effects of myostatin in muscular pathologies such as myopathies, providing a novel pharmacological strategy for treatment. Furthermore, the myostatin pathway is now better understood thanks to in vitro studies and it consists of inhibition of myoblast progression in the cell cycle, inhibition of myoblast terminal differentiation, in both cases associated to protection from apoptosis. The molecular pathway driving the myogenic myostatin influence is currently under extensive study and many molecular partners of myostatin have been identified, suggesting novel potent muscle growth enhancers for both human and agricultural applications. PMID: 16793037 [PubMed - indexed for MEDLINE] 3329. Mini Rev Med Chem. 2006 Jun;6(6):651-6. Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver disease. Méndez-Sánchez N(1), Chavez-Tapia NC, Zamora-Valdés D, Uribe M. Author information: (1)Liver Unit and Biomedical Research Department, Medica Sur Clinic and Foundation, Mexico City, Mexico. nmendez@medicasur.org.mx Obesity is a major risk factor for the development of the metabolic syndrome, a cluster of diseases including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, microalbuminuria, atherosclerosis, and non-alcoholic steatohepatitis. On the other hand, it is now generally accepted that adipose tissue acts as an endocrine organ producing a number of substances with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adiponectin is a recently discovered hormone produced exclusively by adipocytes. In fact, adiponectin is considered currently as a major factor in obesity-related insulin resistance and atherosclerosis. This new hormone differs from other adipocytokines in that its production and concentrations are actually decreased in insulin resistant subjects. The aim of this review is to summarize the current knowledge about the chemistry and physiology of adiponectin and to discuss its implications in the pathophysiology and potential treatment of insulin resistance and non-alcoholic fatty liver disease. PMID: 16787375 [PubMed - indexed for MEDLINE] 3330. Diab Vasc Dis Res. 2006 May;3(1):12-21. Adipose tissue metabolism, diabetes and vascular disease--lessons from in vivo studies. Summers LK(1). Author information: (1)The Academic Unit of Molecular Vascular Medicine, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK. l.k.m.summers@leeds.ac.uk Comment in Diab Vasc Dis Res. 2006 May;3(1):5-6. There is an epidemic of obesity, insulin resistance and cardiovascular disease. Adipose tissue plays a major metabolic role and produces hormones with important physiological effects. In vitro studies remove regulatory factors, such as blood flow, making results difficult to interpret, and animal studies cannot necessarily be extrapolated to humans. Fortunately, adipose tissue can be studied in vivo with microdialysis, adipose tissue vein cannulation, measurement of blood flow using 133Xenon washout, stable isotope tracers and biopsies. In vivo studies have shown that adipose tissue is an efficient buffer against the postprandial flux of non-esterified fatty acids (NEFA) in the circulation, protecting other tissues. When there is excess adipose tissue, this buffering effect may be impaired. The postprandial blood flow response is also reduced, potentially causing an atherogenic lipid profile and atheroma. A systems biology approach, combining in vivo techniques with genomics, proteomics and metabolomics, will clarify links between adipose tissue and vascular disease. PMID: 16784176 [PubMed - indexed for MEDLINE] 3331. Surgery. 2006 Jun;139(6):711-6. Is all fat the same? The role of fat in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus. Hansen E(1), Hajri T, Abumrad NN. Author information: (1)Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. PMCID: PMC3182097 PMID: 16782424 [PubMed - indexed for MEDLINE] 3332. Trends Cardiovasc Med. 2006 Jul;16(5):141-6. Cardioprotection by adiponectin. Ouchi N(1), Shibata R, Walsh K. Author information: (1)Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. Obesity-related disorders are closely associated with the pathogenesis of cardiovascular disease. Adiponectin is a circulating adipose tissue-derived hormone that is down-regulated in obese individuals. Hypoadiponectinemia has been identified as an independent risk factor for type 2 diabetes, coronary artery disease, and hypertension, and experimental studies show that adiponectin plays a protective role in the development of insulin resistance, atherosclerosis, and inflammation. More recent findings have shown that adiponectin directly affects signaling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. This review focuses on the role of adiponectin in the regulation of myocardial remodeling and acute cardiac injury. PMCID: PMC2749293 PMID: 16781946 [PubMed - indexed for MEDLINE] 3333. Biochim Biophys Acta. 2006 May-Jun;1757(5-6):467-73. Epub 2006 May 12. Certain aspects of uncoupling due to mitochondrial uncoupling proteins in vitro and in vivo. Dlasková A(1), Spacek T, Skobisová E, Santorová J, Jezek P. Author information: (1)Department No.75, Membrane Transport Biophysics, Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 14220 Prague 4, Czech Republic. Thermogenic uncoupling has been proven only for UCP1 in brown adipose tissue. All other isoforms of UCPs are potentially acting in suppression of mitochondrial reactive oxygen species (ROS) production. In this contribution we show that BAT mitochondria can be uncoupled by lauric acid in the range of approximately 100 nM when endogenous fatty acids are combusted by carnitine cycle and beta-oxidation is properly separated from the uncoupling effect. Respiration increased up to 3 times when related to the lowest fatty acid content (BSA present plus carnitine cycle). We also illustrated that any effect leading to more coupled states leads to enhanced H2O2 generation and any effect resulting in uncoupling gives reduced H2O2 generation in BAT mitochondria. Finally, we report doubling of plant UCP transcript in cells as well as amount of protein detected by 3H-GTP-binding sites in mitochondria of shoots and roots of maize seedlings subjected to the salt stress. PMID: 16781660 [PubMed - indexed for MEDLINE] 3334. Pol Merkur Lekarski. 2006 Mar;20(117):355-7. [Adiponectin and its role in the pathogenesis of obesity, diabetes mellitus and insulin resistance]. [Article in Polish] Owecki M(1), Sowiński J. Author information: (1)Akademia Medyczna w Poznaniu, Katedra i Klinika Endokrynologii, Przemiany Materii i Chorób Wewnetrznych. mowecki@amp.edu.pl The paper reviews the structure and role of adiponectin in the regulation of metabolic balance. Adiponectin is the most abundant adipocytokine that is produced exclusively in the fat tissue. Its high concentration protects from diabetes mellitus, atherosclerosis and insulin resistance, its low concentration increases the risk of these disorders. The adiponectin gene is one of the many candidate genes in type 2 diabetes. Adiponectin binds to two types of receptors: 1 and 2, encoded by two genes: AdipoR1, and AdipoR2, respectively. The receptors are found in all tissues, with type 1 predominant in the muscles, and type 2 in the liver. Most importantly, the role of adiponectin in the body and the results of animal model experiments suggest the possible future use of adiponectin in the treatment of diabetes, atherosclerosis and obesity. PMID: 16780274 [PubMed - indexed for MEDLINE] 3335. Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):482-8. Epigenetic regulation of metabolism in children born small for gestational age. Holness MJ(1), Sugden MC. Author information: (1)Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Bart's and the London, Queen Mary's School of Medicine and Dentistry, London, UK. m.j.holness@qmul.ac.uk PURPOSE OF REVIEW: Epigenetic alterations are responsible for modulation of tissue-specific gene expression and genomic imprinting. Mechanisms include posttranslational modifications of core histones and DNA methylation. The review focuses on emerging data highlighting the potential for epigenetic modulation of gene expression in mediating early-life programming of increased risk of adult-onset disease. To illustrate these concepts, we focus on epigenetic programming of insulin resistance, obesity and type 2 diabetes, with emphasis on the potential role of the adipocyte and three of its products, fatty acids, leptin and tumour necrosis factor alpha. RECENT FINDINGS: Recent studies have highlighted potential mechanisms underlying epigenetic modification of tissue function that may predispose to later development of insulin resistance. These include altered regulation of adipocyte clonal expansion and terminal differentiation via epigenetic modification of peroxisome proliferator-activated receptor gamma, Foxo1 or cyclin D1 expression and signalling that, via altered adipocyte lipid sequestration, alters lipid delivery to nonadipose tissue and, therefore, insulin action or modification of adipokine or cytokine expression and signalling. Direct epigenetic modification of insulin action in muscle may be achieved through altered stearoyl-CoA desaturase 1 expression, which correlates with low fatty acid oxidation. SUMMARY: While poor early growth and an increased risk of type 2 diabetes in adulthood are undisputedly linked, the relative impact of environment or genotype remains unclear. Altered DNA methylation patterns could, potentially, serve as biomarkers for assessment of prognosis and could help in the development of prophylactic strategies. PMID: 16778581 [PubMed - indexed for MEDLINE] 3336. Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):436-41. Metabolic consequences of lipodystrophy in mouse models. Reue K(1), Phan J. Author information: (1)Department of Human Genetics, David Geffen School of Medicine at UCLA, USA. reuek@ucla.edu PURPOSE OF REVIEW: Adipose tissue is a key player in metabolic homeostasis through its role as an energy depot and endocrine organ. The characterization of mouse models of lipodystrophy, in which adipose tissue development and function are impaired, has shed new light on the mechanisms by which adipose tissue dysregulation may contribute to conditions such as insulin resistance, fatty liver, and beta-cell toxicity. RECENT FINDINGS: Here we review recent findings from mouse models with genetic alterations leading to reduced adipose tissue mass. The metabolic consequences depend on the basis for the adipose tissue reduction, and we classify mouse models into three categories based on whether they confer (1) lipoatrophy accompanied by insulin resistance, (2) reduced adipose tissue storage associated with enhanced energy expenditure, or (3) both lipoatrophic and energetic effects. SUMMARY: Reductions in the capacity of adipose tissue to store triglycerides or to secrete adipokine hormones lead to altered lipid metabolism and insulin resistance. In contrast, depletion of fat stores by virtue of enhanced energy metabolism does not produce undesirable metabolic effects. However, enhanced energy metabolism cannot overcome the deleterious effects of impaired adipokine production, as revealed by studies of models with both lipoatrophic and energetic effects. PMID: 16778573 [PubMed - indexed for MEDLINE] 3337. Vascul Pharmacol. 2006 Jul;45(1):29-35. Epub 2006 Jun 14. Effects of PPAR gamma agonists on cardiovascular function in obese, non-diabetic patients. Panunti B(1), Fonseca V. Author information: (1)Department of Medicine, Tulane University Health Sciences Center, and Department of Medicine, Veterans Affairs Medical Center, New Orleans, LA 70112, United States. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and when activated by their ligands, they induce perixosome proliferation. Three receptors have been identified: PPAR gamma, PPAR delta, and PPAR alpha, all with different tissue expression. PPAR gamma is predominantly expressed in adipose tissue and regulates the formation of fat cells and their function. The effect of PPAR gamma activation is to enhance the action of insulin in insulin-sensitive tissue by increasing peripheral glucose disposal and decreasing hepatic glucose production. The thiazolidinediones (TZDs) are a class of medications used for treatment and possibly the prevention of type 2 diabetes, which are potent agonists for the PPAR gamma receptor. Because the thiazolidinediones target insulin resistance, these agents may improve many of the risk factors associated with obesity and insulin resistance including dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. The impact of the thiazolidinediones on cardiovascular mortality is currently unclear but it appears that the thiazolidinediones exert numerous non-glycemic effects that may improve cardiovascular outcomes. Several non-TZD PPAR gamma agonists and combined PPAR gamma/alpha effect on cardiovascular disease are also being evaluated. These drugs have anti-inflammatory and vascular properties and are currently the subject of numerous studies targeting the primary and secondary prevention of macrovascular disease in patients with diabetes and insulin resistance and might be developed as anti-atherogenic agents on the basis of their actions. PMID: 16777491 [PubMed - indexed for MEDLINE] 3338. Physiol Behav. 2006 Jun 30;88(3):227-33. Epub 2006 Jun 13. Energy balance and food intake: the role of PPARgamma gene polymorphisms. Cecil JE(1), Watt P, Palmer CN, Hetherington M. Author information: (1)Bute Medical School, University of St Andrews, UK. jc100@st-andrews.ac.uk Mechanisms regulating energy balance involve complex interactions between genetic, environmental and behavioural (learnt and intrinsic) factors. Genotype may drive the partitioning of energy metabolism and predispose to site-specific adiposity, culminating in a state of energy imbalance. One candidate gene with a direct link to adiposity is the peroxisome proliferator-activated receptor gamma (PPARG) gene. PPARG is a cell nuclear receptor expressed almost exclusively in adipose tissue that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity. PPARgamma appears to be a key regulator of energy balance, with polymorphisms on the PPARG gene linked to obesity and effects on body composition. Our research has confirmed an association between the pro12ala allele and reduced incidence of obesity in pre-pubertal children and there are strong associations between genetic variation at the PPARG locus and percentage body fat. Moreover, our evidence suggests that PPARG C-681G and pro12ala polymorphisms display opposing effects in terms of growth phenotype, with pro12Ala associated with deficient energy utilisation, leading to reduced growth and the G-681 variant associated with accelerated growth compared with wildtypes. Common differences in this gene have also been associated with variations in body weight in response to dietary macronutrients. Preliminary evidence suggests that PPARG variants may even be involved in the control of short term energy compensation. Taken together these data suggest that the role of PPARG is varied and complex, influencing fat deposition and growth velocity early in life, with potential impact in the control of energy intake and appetite regulation, and could provide a key target for future research and anti-obesity agents. PMID: 16777151 [PubMed - indexed for MEDLINE] 3339. Nihon Rinsho. 2006 May 28;Suppl 1:753-5. [Inherited corticosteroid-binding globulin (CBG) deficiency]. [Article in Japanese] Tamaya T(1). Author information: (1)Department of Obstetrics and Gynecology, Gifu University School of Medicine. PMID: 16776267 [PubMed - indexed for MEDLINE] 3340. Hum Reprod Update. 2006 Sep-Oct;12(5):585-601. Epub 2006 Jun 14. Obesity and the role of gut and adipose hormones in female reproduction. Gosman GG(1), Katcher HI, Legro RS. Author information: (1)Department of Obstetrics and Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. ggosman@mail.magee.edu Reproductive function declines at both extremes of human energy balance. The relationship between obesity and reproductive function is complex and incompletely understood. The literature has established the negative impact of excess energy stores on ovulatory function and investigated the mechanisms whereby this occurs. Furthermore, weight loss in obese anovulatory women increases ovulation and conception. Obesity and anti-obesity therapy effects on the endometrium, implantation and early fetal development have received less attention. The discovery of adipokines and enterokines greatly expands the ability to investigate the relationship between obesity, therapies to produce weight loss and reproductive function. In this review, we discuss select adipose and enteric signals. We focus on in vitro, animal and human data that lend biological plausibility to adipokines and enterokines as mediators of obesity and reproduction. Very little published work exists that directly addresses adipocyte and enteric signals in this specific role; therefore, much of this review is on the basis of a synthesis of the literature in three areas: (i) in vitro and in vivo evidence regarding the reproductive effects of these signals; (ii) adipokine and enterokine changes that occur with weight-loss therapies, focusing on hypocaloric diets, bariatric surgery and drugs that target adipocyte or enteric signals and (iii) reproductive changes produced by these weight-loss therapies. PMID: 16775192 [PubMed - indexed for MEDLINE] 3341. J Nutr. 2006 Jul;136(7 Suppl):1935S-1939S. Adipose tissue and adipokines--energy regulation from the human perspective. Trayhurn P(1), Bing C, Wood IS. Author information: (1)Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, Liverpool L69 3GA, UK. p.trayhurn@liverpool.ac.uk There has been a rapid rise in the incidence of obesity, primarily as a result of changes in lifestyle (diet and activity levels). Obesity has provided considerable impetus for the investigation of the fundamental mechanisms involved in the regulation of energy balance. Important developments include the identification of novel factors involved in the control of appetite, such as ghrelin, orexin A, and the endogenous cannabinoids, and the emergence of the concept of "nonexercise activity thermogenesis" (NEAT) provided new perspectives on energy expenditure. Studies on white adipose tissue have led to the recognition that it is an important endocrine organ, communicating with the brain and peripheral tissues through the secretion of leptin and other adipokines. There is a rapidly expanding list of protein factors released by white adipose tissue, including the key hormone, adiponectin. Of particular note is the range of cytokines, chemokines, and other inflammation-related proteins secreted by white fat as tissue mass rises; indeed, obesity is characterized by chronic mild inflammation. The adipokines provide an extensive network of communication both within adipose tissue and with other organs, and some are implicated directly in the pathologies associated with obesity, particularly the metabolic syndrome. Although the focus remains very much on obesity in humans, the disorder and its sequelae are also a growing concern in companion animals. PMID: 16772463 [PubMed - indexed for MEDLINE] 3342. Best Pract Res Clin Endocrinol Metab. 2006 Jun;20(2):293-310. Role of lifestyle modification in the management of polycystic ovary syndrome. Hoeger KM(1). Author information: (1)Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 668, Rochester, NY 14642, USA. kathy_hoeger@urmc.rochester.edu Overweight and obesity are common findings in polycystic ovary syndrome (PCOS). Obesity-particularly central obesity-is strongly indicated as a cause of insulin resistance, a central feature of PCOS. The prevalence of obesity is reaching epidemic proportions in many developed countries, and this increase is of particular concern in adolescent women. Obesity worsens both the metabolic and endocrine profiles in PCOS and may decrease the response to treatment. In the short term, weight reduction improves both metabolic and endocrine aspects of PCOS as well as clinical markers such as ovulation. However, extreme non-surgical efforts to lose weight are rarely successful and are associated with high rates of weight regain. Lifestyle modification with modest weight loss goals of 5-10% appear to be equally effective in restoring fertility and may be more compatible with long-term success; however, further research is needed. PMID: 16772159 [PubMed - indexed for MEDLINE] 3343. Herz. 2006 May;31(3):200-6. Molecular basis of obesity and the risk for cardiovascular disease. Soufi M(1), Sattler AM, Herzum M, Maisch B, Schaefer JR. Author information: (1)Department of Internal Medicine, Cardiology, Angiology and CAD Prevention, University Hospital Giessen and Marburg, Philipps University, Marburg, Germany. Atherosclerosis and cardiovascular disease (CVD) are the main causes of death in the Western world, for both men and women. The onset and development of diseases of the cardiovascular and cerebrovascular system are strongly dependent on multiple risk factors that promote pathologic conditions like atherosclerosis, hypertension and thrombosis. Besides genetic factors also environmental influences such as diet composition are known to be closely related to CVD. In this context obesity has been postulated as an independent cardiovascular risk factor. Data from the Framingham Heart Study have consistently shown that increasing degrees of obesity are accompanied by greater rates of CVD. At present, obesity affects 10-35% of the European and US population and increases steadily. As obesity is a serious health problem which promotes metabolic abnormalities (insulin resistance, hyperinsulinemia and dyslipidemia) and dramatically increases the risk for CVD, this review will focus on the epidemiologic and genetic background of obesity. Furthermore, the molecular mechanisms involved in obesity development and their contribution to CVD will be discussed. PMID: 16770555 [PubMed - indexed for MEDLINE] 3344. J Thorac Imaging. 2006 May;21(2):154-66. Extrathoracic PET/CT findings in thoracic malignancies. Marom EM(1), Bruzzi JF, Truong MT. Author information: (1)Department of Radiology, Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. emarom@di.mdacc.tmc.edu The routine use of integrated positron emission tomography computed tomography in the staging and follow-up of patients diagnosed with non-small-cell lung cancer has improved diagnostic accuracy but many incidental extrathoracic findings are routinely encountered. These include physiologic fluorodeoxy glucose avid foci, normal computed tomography variants, and second primary malignancies, all of which have to be differentiated from extrathoracic metastatic disease. Knowledge of these findings is important for correct staging and identification of second primaries. PMID: 16770232 [PubMed - indexed for MEDLINE] 3345. Trends Mol Med. 2006 Jul;12(7):324-32. Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Diamanti-Kandarakis E(1), Papavassiliou AG. Author information: (1)Endocrine Section, 1st Department of Medicine, Laiko General Hospital, University of Athens Medical School, GR-11527 Athens, Greece. akandara@otenet.gr Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology that affects women of reproductive age. During the past ten years, defective insulin activity in PCOS has been demonstrated in target tissues and causes insulin resistance and hyperinsulinaemia. Furthermore, presence of insulin receptors in the ovarian tissue and overproduction of androgens by theca cells leads to characteristic hyperandrogenaemia. Recent data suggest a divergence in post-receptor signalling pathways for insulin in its target tissues (muscle, adipocytes and ovarian tissue), where the metabolic pathway of insulin activity is defective, whereas the activation of steroidogenesis is maintained. Investigators are still searching for clues to understand the cause of this enigmatic syndrome, despite great advances in molecular medicine and genetics. PMID: 16769248 [PubMed - indexed for MEDLINE] 3346. Nihon Rinsho. 2006 Jun;64(6):1168-72. [NASH in children]. [Article in Japanese] Ida S(1), Yoshimura N. Author information: (1)Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health. It has long been recognized that hepatic steatosis (fatty liver) occurs in obese children as in adults. Steatosis of any etiology can be associated with the development of necro-inflammation and fibrosis, so called steatohepatitis, and even cirrhosis. Nonalcoholic steatohepatitis (NASH) has been proposed as a component of insulin resistant syndrome and exists in pediatric population. The other etiology of NASH in children has not been clearly understood. In addition to obesity, adipose tissue distribution also appears to influence metabolic complications. Subjects with visceral fat adiposity appear to be at risk for fatty liver because of their ability to transport free fatty acids directly into the portal vein for conversion to triglycerides within the liver. A stronger relationship of serum ALT to visceral adiposity than BMI was demonstrated. Many metabolic diseases such as Wilson's disease, NICCD, OTC deficiency, carnitine deficiency have steatohepatitis and cirrhosis. It may play the important role to reveal the mechanism of progress to NASH. PMID: 16768127 [PubMed - indexed for MEDLINE] 3347. Nutr Hosp. 2006 May;21 Suppl 3:84-93. [Cardiac cachexia]. [Article in Spanish] Miján A(1), Martín E, de Mateo B. Author information: (1)Area de Nutrición y Bromatología, Facultad de Medicina, UVA, Valladolid. mijan@hgy.es Chronic heart failure (CHF), especially affecting the right heart, frequently leads to malnutrition. If the latter is severe and is combined to other factors, it may lead to cardiac cachexia. This one is associated to increased mortality and lower survival of patients suffering from it. The causes of cardiac cachexia are diverse, generally associated to maintenance of a negative energy balance, with increasing evidence of its multifactorial origin. Neurohumoral, inflammatory, immunological, and metabolic factors, among others, are superimposed in the patient with CHF, leading to involvement and deterioration of several organs and systems, since this condition affects both lean (or active cellular) mass and adipose and bone tissue osteoporosis. Among all, the most pronounced deterioration may be seen at skeletal muscle tissue, at both structural and functional levels, the heart not being spared. As for treatment, it should be based on available scientific evidence. Assessment of nutritional status of any patient with CHF is a must, with the requirement of nutritional intervention in case of malnutrition. In this situation, especially if accompanied by cardiac cachexia, it is required to modify energy intake and oral diet quality, and to consider the indication of specific complementary or alternative artificial nutrition. Besides, the causal relationship of the beneficial role of moderate physical exertion is increasing, as well as modulation of metabolic and inflammatory impairments observed in cardiac cachexia with several drugs, leading to a favorable functional and structural response in CHF patients. PMID: 16768035 [PubMed - indexed for MEDLINE] 3348. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):390-9. Epub 2006 May 23. [The endocannabinoid system: a new paradigm in the metabolic syndrome treatment]. [Article in Portuguese] de Godoy-Matos AF(1), Guedes EP, de Souza LL, Valério CM. Author information: (1)Serviço de Metabologia e Nutrologia, Instituto Estadual de Diabetes e Endocrinologia, Rio de Janeiro, RJ. godoymatos@openlink.com.br Energetic balance is a fundamental homeostasis mechanism, which contributes to the species' survival. The endocannabinoid system is a new and important component among such mechanisms. Its receptors and endogenous agonists are expressed in central nervous system (CNS) and at various peripheral organs, establishing a CNS-periphery net communication. A relevant aspect is its expression in the adipose tissue, where it regulates lipogenesis and increases the expression of influent genes on lipids and carbohydrate metabolism. Interestingly, it seems to be upregulated in human and animal obesity, although it is activated on demand and rapidly deactivated. Its activation increases food intake and promotes weight gain, contributing to Metabolic Syndrome (MS). Rimonabant is a specific antagonist to the main endocannabinoid receptor (CB1). In animal models of obesity and MS, as well as in humans, Rimonabant has demonstrated to be a useful tool in controlling weight and metabolic aspects. Indeed, some new human trials suggest a possible role for this substance in controlling cardiovascular risk factors related to MS. PMID: 16767305 [PubMed - indexed for MEDLINE] 3349. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):304-12. Epub 2006 May 23. [Cytokines, endothelial dysfunction, and insulin resistance]. [Article in Portuguese] de Carvalho MH(1), Colaço AL, Fortes ZB. Author information: (1)Laboratório de Hipertensão e Diabetes, Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São PauloSão Paulo, SP. mhcarvalho@icb.usp.br Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity. PMID: 16767296 [PubMed - indexed for MEDLINE] 3350. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):271-80. Epub 2006 May 23. [Glitazones and the metabolic syndrome: mechanism of action, pathophysiology and therapeutic indications]. [Article in Portuguese] Gomes MB(1). Author information: (1)Faculdade de Ciências Médicas, UERJ, Rio de Janeiro, RJ. marilliab@uerj.br Diabetes mellitus (DM) is considered a major public health problem in both developed and developing countries due to its chronic complications, at the macro or microcirculation, with great impact on mortality and morbidity in all patients. The disease is considered the end of a pathophysiologic process involving peripheral and hepatic insulin resistance and reduced insulin secretion that have been started years before the clinical diagnosis. Metabolic syndrome (MS) is a disorder that results from the increasing prevalence of obesity worldwide. DM is frequently associated with clinical and laboratory features of MS, like abdominal obesity, hypertension, dyslipidemia and microalbuminuria that are also risk factors for cardiovascular disease. Populational studies have demonstrated increasing prevalence of all the features of MS from pre-diabetes to clinical DM resulting in a great risk of cardiovascular disease. The prevalence of MS in DM type 2 is estimated to be >80%. Glitazones are PPAR-gamma agonists that improve insulin sensitivity. These drugs induce the transcription of genes related to glucose and lipid metabolism, and expression of inflammatory and endothelial proteins associated with atherosclerosis process resulting in an improvement in endothelial function. However several questions need to be clarified regarding the glitazones, in special those associated with their adverse effects such as weight gain, edema and heart failure. PMID: 16767293 [PubMed - indexed for MEDLINE] 3351. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):230-8. Epub 2006 May 23. [Visceral fat and metabolic syndrome: more than a simple association]. [Article in Portuguese] Ribeiro Filho FF(1), Mariosa LS, Ferreira SR, Zanella MT. Author information: (1)Centro Integrado de Assistência, EPM, UNIFESP, São Paulo, SP. fflexa@uol.com.br Metabolic syndrome (MS) is seen nowadays as a worldwide epidemic event associated with high cardiovascular morbi-mortality and high socioeconomic cost. The ponderal gain is an independent predictor for the development of MS, although not all obese individuals present it. On the other hand, some populations with low obesity prevalence present high prevalence of MS and cardiovascular mortality. The distribution of corporal fat is relevant and visceral fat (VF), specifically, seems to be the link between adipose tissue and insulin resistance (IR), a mean feature of MS. Adipose tissue is now considered a complex organ with multiple functions. VF presents metabolic properties, which are different from the gluteo-femoral subcutaneous fat and related to IR. Several studies show the narrow relationship of abdominal adiposity with the glucose tolerance, hyperinsulinemia, hypertriglyceridemia and arterial hypertension. More than a simple association, recently it is thought that the VF plays a central part in the physiopathology of MS. Consequently, the quantification of VF plays an important role to identify individuals with larger risk for development of MS, who should be chosen for early interventions in the attempt of reducing the impact of metabolic abnormalities on cardiovascular mortality. This article discusses particularities of the central distribution of fat in MS context, possible physiopathogenic mechanisms related to the VF and available methods for the evaluation of abdominal adiposity. PMID: 16767289 [PubMed - indexed for MEDLINE] 3352. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):216-29. Epub 2006 May 23. [The adipose tissue as a regulatory center of the metabolism]. [Article in Portuguese] Fonseca-Alaniz MH(1), Takada J, Alonso-Vale MI, Lima FB. Author information: (1)Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP. fabio@icb.usp.br The recent progress in the research about the metabolic properties of the adipose tissue and the discovery of its ability to produce hormones that are very active in pathophysiologic as well as physiologic processes is rebuilding the concepts about its biology. Its involvement in conditions like obesity, type 2 diabetes mellitus, arterial hypertension, arteriosclerosis, dislipidemias and chronic and acute inflammatory processes indicate that the understanding of its functional capacities may contribute to improve the prognosis of those diseases whose prevalence increased in a preoccupying manner. Here we review some functional aspects of adipocytes, such as the metabolism, its influence on energy homeostasis, its endocrine ability and the adipogenesis, i.e., the potential of pre-adipocytes present in adipose tissue stroma to differentiate into new adipocytes and regenerate the tissue. In addition, we are including some studies on the relationship between the adipose tissue and the pineal gland, a new and poorly known, although, as will be seen, very promising aspect of adipocyte physiology together with its possible favorable repercussions to the therapy of the obesity related diseases. PMID: 16767288 [PubMed - indexed for MEDLINE] 3353. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):190-7. Epub 2006 May 23. [Experimental models of insulin resistance and obesity: lessons learned]. [Article in Portuguese] Cesaretti ML(1), Kohlmann Junior O. Author information: (1)Laboratório de Hipertensão Arterial, Universidade Federal de São Paulo, São Paulo, SP. cesaretti@nefro.epm.br For better understanding the role of each element involved in the physiopathology of obesity and insulin resistance, researchers can use experimental models, which may in controlled manner evaluate the participation of each element on the obesity and insulin resistance and provide information for better understanding the physiopathology and treatment of obesity and insulin resistance. Experimental obesity and insulin resistance can be due to a deficient response to leptin, secondary to hypoleptinemia and/or mutations on leptin receptor, by modifications on insulin receptor, deletion or diminished insulin signal transduction, enhancement of the effects of orexigen peptides and/or diminution of anorexigen peptides actions on hypothalamus, as well as secondary to arterial hypertension, as in the spontaneously hypertension. Obesity and insulin resistance can also be induced by glucocorticoid excess, frutose enriched and cafeteria diet and due to hypothalamus lesions induced by neonatal administration of monossodium glutamate. PMID: 16767285 [PubMed - indexed for MEDLINE] 3354. Climacteric. 2006 Jun;9(3):169-80. Adipose tissue, insulin resistance and low-grade inflammation: implications for atherogenesis and the cardiovascular harm of estrogen plus progestogen therapy. Tankó LB(1), Christiansen C. Author information: (1)Center for Clinical and Basic Research, Ballerup, Denmark. OBJECTIVE: To summarize recent findings providing mechanistic insight into why the relative presence of central to peripheral fat mass is a critical determinant of atherogenesis and why postmenopausal women with android obesity represent a risk population with increased susceptibility to the cardiovascular harm of estrogen plus progestin therapy (EPT). METHODS: Review of own research and related literature in PubMed. RESULTS: In postmenopausal women, android obesity characterized by excessive upper-body combined with relatively poorly developed lower-body fat mass is frequently associated with insulin resistance, low-grade inflammation, and early atherosclerosis. Underlying mechanisms involve disequilibrium between proinflammatory cytokines (high interleukin-6/C-reactive protein) and the anti-inflammatory adipokine (low adiponectin). Recent findings point out that women with abnormal glucose tolerance, a metabolic alteration closely linked to android adiposity, respond with increases in low-grade inflammation and accelerated atherogenesis to EPT that collectively may promote acute complications. We recently pointed out that a progestin could exert a dose-dependent inhibitory effect on circulating adiponectin. Thus, when EPT is prescribed to women with android obesity, further decreases in the protective adiponectin pool may become critical and act as a promoter of thromboembolic complications via its effects on plaque formation and stability. Since android obesity is associated with the highest levels of free estradiol, women with this phenotype might not be trivial candidates for EPT. CONCLUSIONS: The herein summarized findings shed light on important interactions between sex steroids and body fat mass, with functional implications for cardiovascular risk. Since previous trials have not optimized the dose of the progestin for its effect on circulating adiponectin, utmost caution should be exercised in the prescription of available estrogen plus progestin therapies to women with android obesity and/or symptoms of the insulin resistance syndrome. PMID: 16766431 [PubMed - indexed for MEDLINE] 3355. Endocr Rev. 2006 Oct;27(6):575-605. Epub 2006 Jun 9. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Turgeon JL(1), Carr MC, Maki PM, Mendelsohn ME, Wise PM. Author information: (1)Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California Davis, Davis, California 95616, USA. jlturgeon@ucdavis.edu Recent publications describing the results of the Women's Health Initiative (WHI) and other studies reporting the impact of hormone therapy on aging women have spurred reexamination of the broad use of estrogens and progestins during the postmenopausal years. Here, we review the complex pharmacology of these hormones, the diverse and sometimes opposite effects that result from the use of different estrogenic and progestinic compounds, given via different delivery routes in different concentrations and treatment sequence, and to women of different ages and health status. We examine our new and growing appreciation of the role of estrogens in the immune system and the inflammatory response, and we pose the concept that estrogen's interface with this system may be at the core of some of the effects on multiple physiological systems, such as the adipose/metabolic system, the cardiovascular system, and the central nervous system. We compare and contrast clinical and basic science studies as we focus on the actions of estrogens in these systems because the untoward effects of hormone therapy reported in the WHI were not expected. The broad interpretation and publicity of the results of the WHI have resulted in a general condemnation of all hormone replacement in postmenopausal women. In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should be interpreted within the narrow context of the study design. We argue that these results should encourage us to perform new studies that take advantage of a dialogue between basic scientists and clinician scientists to ensure appropriate design, incorporation of current knowledge, and proper interpretation of results. Only then will we have a better understanding of what hormonal compounds should be used in which populations of women and at what stages of menopausal/postmenopausal life. PMID: 16763155 [PubMed - indexed for MEDLINE] 3356. Am J Clin Nutr. 2006 Jun;83(6):1265-71. Carotenoids and cardiovascular health. Voutilainen S(1), Nurmi T, Mursu J, Rissanen TH. Author information: (1)Research Institute of Public Health and Department of Public Health and General Practice, University of Kuopio, Kuopio, Finland. sari.voutilainen@uku.fi Cardiovascular disease (CVD) is the main cause of death in Western countries. Nutrition has a significant role in the prevention of many chronic diseases such as CVD, cancers, and degenerative brain diseases. The major risk and protective factors in the diet are well recognized, but interesting new candidates continue to appear. It is well known that a greater intake of fruit and vegetables can help prevent heart diseases and mortality. Because fruit, berries, and vegetables are chemically complex foods, it is difficult to pinpoint any single nutrient that contributes the most to the cardioprotective effects. Several potential components that are found in fruit, berries, and vegetables are probably involved in the protective effects against CVD. Potential beneficial substances include antioxidant vitamins, folate, fiber, and potassium. Antioxidant compounds found in fruit and vegetables, such as vitamin C, carotenoids, and flavonoids, may influence the risk of CVD by preventing the oxidation of cholesterol in arteries. In this review, the role of main dietary carotenoids, ie, lycopene, beta-carotene, alpha-carotene, beta-cryptoxanthin, lutein, and zeaxanthin, in the prevention of heart diseases is discussed. Although it is clear that a higher intake of fruit and vegetables can help prevent the morbidity and mortality associated with heart diseases, more information is needed to ascertain the association between the intake of single nutrients, such as carotenoids, and the risk of CVD. Currently, the consumption of carotenoids in pharmaceutical forms for the treatment or prevention of heart diseases cannot be recommended. PMID: 16762935 [PubMed - indexed for MEDLINE] 3357. Am J Clin Nutr. 2006 Jun;83(6):1237-47. The metabolic syndrome: is this diagnosis necessary? Reaven GM(1). Author information: (1)Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. greaven@cvmed.stanford.edu Erratum in Am J Clin Nutr. 2006 Nov;84(5):1253. Comment in Am J Clin Nutr. 2006 Jun;83(6):1248-51. Values of insulin-mediated glucose disposal vary continuously throughout a population of apparently healthy persons, and a difference of > or = 600% exists between the most insulin-sensitive and the most insulin-resistant persons. Approximately 50% of this variability can be attributed to differences in adiposity (25%) and fitness (25%), with the remaining 50% likely of genetic origin. The more insulin-resistant a person, the more likely that he or she will develop some degree of glucose intolerance, high triacylglycerol and low HDL concentrations, essential hypertension, and procoagulant and proinflammatory states, all of which increase the risk of cardiovascular disease (CVD). To identify persons at greater CVD risk because of these abnormalities, the World Health Organization, the Adult Treatment Panel III, and the International Diabetes Federation created a new diagnostic category, the metabolic syndrome. Although the components of the 3 versions of the metabolic syndrome are similar, the specific values for those components that define an abnormality are somewhat different, and the manner in which the abnormalities are used to make a positive diagnosis varies dramatically from version to version. This review will summarize the similarities in and differences between the 3 versions of the metabolic syndrome, point out that the clustering of components that make up all 3 definitions of the metabolic syndrome is not accidental and occurs only in insulin-resistant persons, develop the argument that diagnosing the metabolic syndrome in a person has neither pedagogical nor clinical utility, and suggest that the clinical emphasis should be on treating effectively any CVD risk factor that is present. PMID: 16762930 [PubMed - indexed for MEDLINE] 3358. Fertil Steril. 2006 Jun;85(6):1563-81. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Budak E(1), Fernández Sánchez M, Bellver J, Cerveró A, Simón C, Pellicer A. Author information: (1)Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain. OBJECTIVE: To summarize the effects of novel hormones (leptin, ghrelin, adiponectin, resistin, and PYY3-36) secreted from adipose tissue and the gastrointestinal tract that have been discovered to exert different effects on several reproductive functions, such as the hypothalamic-pituitary-gonadal axis, embryo development, implantation physiology, and clinically relevant conditions. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Leptin and ghrelin exert important roles on body weight regulation, eating behavior, and reproduction, acting on the central nervous system and target reproductive organs. As a marker of adequate nutritional stores, these hormones may act on the central nervous system to initiate the complex process of puberty and maintain normal reproductive function. In addition, leptin and ghrelin and their receptors are involved in reproductive events such as gonadal function, embryo development, and embryo-endometrial interaction. CONCLUSION(S): Leptin and ghrelin and other adipose tissue-secreted hormones have significant effects on reproduction. Acting through the brain, these hormones may serve as links between adipose tissue and the reproductive system to supply and regulate energy needs for normal reproduction and pregnancy. Future studies are needed to further clarify the role of these hormones in reproductive events and other related gynecological conditions. PMID: 16759918 [PubMed - indexed for MEDLINE] 3359. J Pediatr Endocrinol Metab. 2006 Apr;19(4):455-65. Growth hormone and premature atherosclerosis in childhood obesity. Smotkin-Tangorra M(1), Anhalt H, Ten S. Author information: (1)Department of Pediatrics, Division of Endocrinology, Maimonides Infants and Children 's Hospital of Brooklyn, Brooklyn, NY 11219, USA. BACKGROUND: The role of growth hormone (GH) in obesity is controversial. Childhood obesity is characterized by reduced GH secretion. Low, high and normal serum insulin-like growth factor-I (IGF-I) levels have been described in obese children in the face of low GH secretion. There is conflicting information on the interaction of GH and obesity upon components of the GH-IGF-I-insulin-like growth factor binding proteins (IGFBPs) system and its relationship to cardiovascular risk factors. OBJECTIVE: This review highlights the role of GH modulating cardiovascular risk factors, including lipid levels, inflammatory markers, cardiac and endothelial function in children and adolescents with obesity and insulin resistance. CONCLUSIONS: The interplay between GH secretion, NO production, IGF-I, IGFBP-1, and IGFBP-3 levels, lipid profile, insulin sensitivity and the degree of visceral obesity necessitates further study. These metabolic parameters may be useful markers of premature atherosclerosis in children with obesity. Further studies should address the question of optimal dose and duration of GH therapy in non-GH deficient obese patients with metabolic disturbances at risk for premature atherosclerosis. PMID: 16759030 [PubMed - indexed for MEDLINE] 3360. Annu Rev Biochem. 2006;75:367-401. Obesity-related derangements in metabolic regulation. Muoio DM(1), Newgard CB. Author information: (1)Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology, Medicine, Duke University Medical Center, Durham, North Carolina 27704, USA. muoio@duke.edu An epidemic surge in the incidence of obesity has occurred worldwide over the past two decades. This alarming trend has been triggered by lifestyle habits that encourage overconsumption of energy-rich foods while also discouraging regular physical activity. These environmental influences create a chronic energy imbalance that leads to persistent weight gain in the form of body fat and a host of other abnormalities in metabolic homeostasis. As adiposity increases, so does the risk of developing comorbidities such as diabetes, hypertension, and cardiovascular disease. The intimate association between obesity and systemic metabolic dysregulation has inspired a new area of biochemistry research in which scientists are seeking to understand the molecular mechanisms that link chronic lipid oversupply to tissue dysfunction and disease development. The purpose of this chapter is to review recent findings in this area, placing emphasis on lipid-induced functional impairments in the major peripheral organs that control energy flux: adipose tissue, the liver, skeletal muscle, and the pancreas. PMID: 16756496 [PubMed - indexed for MEDLINE] 3361. Curr Opin Cardiol. 2006 Jul;21(4):353-60. The obesity epidemic and its cardiovascular consequences. Behn A(1), Ur E. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. PURPOSE OF REVIEW: Obesity has reached global epidemic proportions because of an increasingly obesogenic environment. This review examines the association between obesity, and in particular visceral fat, as a risk factor for cardiovascular disease and mortality. RECENT FINDINGS: The World Health Organization defines obesity based on the body mass index. Recently the waist-to-hip ratio has been shown to be a significantly stronger predictor of cardiovascular events than body mass index. The metabolic syndrome and its evolving definition represent a cluster of metabolic risk factors which help predict cardiovascular disease and mortality. Although insulin resistance plays a central role in the pathophysiology of the metabolic syndrome, there is limited support for therapy with insulin sensitizers, thiazolidinediones, in patients with coronary artery disease. The current anti-obesity drugs, orlistat and sibutramine, have only a modest effect on weight loss. The blockade of the endocannabinoid system with rimonabant, however, may be a promising new strategy. SUMMARY: Obesity is associated with significant increase in cardiovascular risk. Lifestyle modification remains the cornerstone of management although anti-obesity medications may be indicated in high risk individuals with comorbid disease. PMID: 16755205 [PubMed - indexed for MEDLINE] 3362. Cell Metab. 2006 Jun;3(6):393-402. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Um SH(1), D'Alessio D, Thomas G. Author information: (1)Department of Genome Science, Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, Ohio 45237, USA. Nutrient overload leads to obesity, insulin resistance, and often type 2 diabetes. Whereas increased fat intake is commonly cited as the major factor in diet-induced dysmetabolic states, increased protein consumption also contributes, through elevated circulating amino acids. Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. PMID: 16753575 [PubMed - indexed for MEDLINE] 3363. J Endocrinol Invest. 2006;29(3 Suppl):77-82. Intra-abdominal obesity: an untreated risk factor for Type 2 diabetes and cardiovascular disease. Després JP(1). Author information: (1)Québec Heart Institute, Laval Hospital Research Center, Ste-Foy (Québec), Canada. jean-pierre.despres@crhl.ulaval.ca The prevalence of Type 2 diabetes is showing a rapid progression worldwide, a phenomenon largely resulting from the epidemic proportions reached by obesity in various populations of the world. However, physicians have been puzzled by the heterogeneity of obesity as not every obese patient is characterized by chronic complications. In this regard, body fat distribution, especially intra-abdominal adipose tissue accumulation, has been found to be a key correlate of a cluster of diabetogenic, atherogenic, prothrombotic and inflammatory metabolic abnormalities increasing the risk of Type 2 diabetes and cardiovascular disease. In this regard, it has been recently demonstrated that abdominal obesity was independently associated with an increased risk of coronary heart disease and Type 2 diabetes independently of overall adiposity. Lifestyle modification programs have shown the benefits on cardiometabolic risk variables of a moderate weight loss as it has been found to be associated with a substantial loss of intra-abdominal fat in viscerally obese patients. However, to be successful, such programs require the support of a multidisciplinary team not available to most clinicians. In this context, it is proposed that pharmacotherapy of obesity should target abdominally obese patients at high risk of Type 2 diabetes and cardiovascular disease, such risk being encompassed by the notion of "cardiometabolic risk". The recent discovery of the endocannabinoid-cannabinoid receptor type 1 (CB1 receptor) system and of its impact on the regulation of energy metabolism represents a significant advance which could help physicians to target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant (the first CB1 blocker developed) therapy could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its marked effects on both abdominal adiposity and related metabolic risk factors. PMID: 16751711 [PubMed - indexed for MEDLINE] 3364. J Endocrinol Invest. 2006;29(3 Suppl):15-26. Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. Matias I(1), Di Marzo V. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (Napoli), Italy. Endocannabinoids are endogenous substances capable of binding to and functionally activating the two types of cannabinoid receptors identified to date, the cannabinoid receptors type 1 and 2 (CB1 and CB2 receptors). The anabolic and catabolic pathways for the two most studied endocannabinoids, N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl glycerol (2- AG), have been elucidated, thus leading to the molecular characterization of some of their catabolic and biosynthetic enzymes. These proteins are hydrolytic enzymes that also recognize as substrates other congeners of anandamide and 2-AG or of their biosynthetic precursors, respectively. CB1 receptor and tissue concentrations of endocannabinoids sufficient to activate them are more widely distributed than originally believed, and are present in all brain and peripheral organs involved in the control of energy homeostasis, including the hypothalamus, nucleus accumbens, brainstem, vagus nerve, gastrointestinal trad, adipose tissue, muscle and liver. Hypothalamic and peripheral neuropeptides and hormones involved in energy balance, as well as the type of diet, regulate endocannabinoid biosynthetic and inactivating pathways, whereas endocannabinoids, in turn, regulate the expression and action of mediators involved in nutrient intake and processing. The perturbation of these cross-talks might contribute to the development of eating disorders. PMID: 16751706 [PubMed - indexed for MEDLINE] 3365. Tsitologiia. 2006;48(2):83-94. [Adipose stromal cells--plastic type of cells with high therapeutic potential]. [Article in Russian] Traktuev DO, Parfenova EV, Tkachuk VA, March KL. Much effort has been made in searching for multipotent cell types with high therapeutic potentials for repair of damaged tissue. Through enzymatic digestion of fat tissue, it is possible to obtain a large number of stromal cells. Isolated cells show a high proliferate capacity in culture. All this makes adipose stromal cells (ASC) promising candidates for their use in cell therapy. This review is focused on analyzing the surface antigen profile of isolated population of ASC, expression of angiogenic factors by these cells, as well as on their differentiation potential. A high percentage of ASC population initially express the progenitor cell marker CD34, but during culturing, cells exhibit a mesenchymal cell phenotype and express CD29, CD105, CD106, CD166. Culturing ASC in specific differentiation media induces expression of early markers of differentiated mesenchymal cells, such as adipocytes, chondrocytes and osteoblasts, as well as myoblasts, cardiomyocytes and neural cells. It has been also shown that ASC have a strong pro-angiogenic potential, they are able to secret growth factors, such as VEGF, HGF, bFGF and others, which stimulate survival and proliferation of endothelial cells. In addition, systemic or local delivery of ASC to mice with hindlimb ischemia stimulates recovery of injured tissue and blood flow. Potential clinical uses of ASCs are discussed in the review. PMID: 16737175 [PubMed - indexed for MEDLINE] 3366. Clin Rheumatol. 2007 Jul;26(7):1201-3. Epub 2006 May 31. Liposynovitis prepatellaris in athletic runner (Hoffa's syndrome): case report and review of the literature. Emad Y(1), Ragab Y. Author information: (1)Rheumatology & Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, Egypt. yasseremad68@yahoo.com A 37-year-old male patient, who is an athletic runner, developed anterior knee pain of acute onset after prolonged running and swelling of his right knee. The patient experiences more pain when he flexes the knee and a sense of catching together with grade 1 effusion. The patient was clinically suspected to have internal derangement and MRI study of his right knee was ordered to exclude such possible diagnosis. The MRI study revealed the following: a hypointense lesion in the infrapatellar pad of fat in T2-weighted images (WI), postcontrast T1 WI with fat saturation demonstrated no enhancement, and STIR sequence showed slightly hyperintense lesion with minimal knee effusion. The MRI findings supported the diagnosis of Hoffa's syndrome, and arthroscopic resection of the fat pad was performed. There was a significant improvement in the symptoms and function after the surgery. PMID: 16736123 [PubMed - indexed for MEDLINE] 3367. Vestn Ross Akad Med Nauk. 2006;(3):3-6. [The blood system and the adaptation of the organism to extreme factors]. [Article in Russian] Iushkov BG. Study of hemopoesis under extremal conditions has revealed a range of new mechanisms providing the participation of the blood system in adaptive reactions, such as the reconstruction of the microcirculation bed of hemopoetic tissue; the involvement of large erythrocytes containing acid-resistant hemoglobin fractions; qualitative and quantitative changes in the content of erythroblastic islands, depending on the functional condition of macrophages; gaining of morphogenic properties by macrophages and lymphocytes; increased secretion of glycosaminoglicans, which play the role of local hemopoetic regulators, by mastocytes and adipose cells. The correlation between blood cells and angiogenesis allowed proposing a new method of creating auto prostheses for angioplasty by growing them on plastic basis implanted subcutaneously. PMID: 16734334 [PubMed - indexed for MEDLINE] 3368. Med Sci Monit. 2006 Jun;12(6):RA112-9. Epub 2006 May 29. Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity? Bełtowski J(1). Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@am.lublin.pl Comment in Med Sci Monit. 2006 Sep;12(9):LE17-8. Recent studies suggest that adipose tissue hormones ("adipokines") are involved in the pathogenesis of various complications of obesity, including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Apelin and visfatin are two recently described adipokines, although they are also synthesized outside adipose tissue. Apelin exists in at least three forms, consisting of 13, 17, or 36 amino acids, all originating from a common 77-amino-acid precursor. In the cardiovascular system, apelin elicits endothelium-dependent, nitric oxide-mediated vasorelaxation and reduces arterial blood pressure. In addition, apelin demonstrates potent and long-lasting positive inotropic activity which is preserved even in injured myocardium and is not accompanied by myocardial hypertrophy. Apelin synthesis in adipocytes is stimulated by insulin, and plasma apelin level markedly increases in obesity associated with insulin resistance and hyperinsulinemia. In addition to regulating cardiovascular function, apelin inhibits water intake and vasopressin production. Visfatin, previously recognized as a pre-B cell colony-enhancing factor (PBEF), is abundantly expressed in visceral adipose tissue and is upregulated in some, but not all, animal models of obesity. Preliminary studies suggest that plasma visfatin concentration is also increased in humans with abdominal obesity and/or type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. Thus, apelin and visfatin are unique among adipose tissue hormones in that they are upregulated in the obese state and both exert primarily beneficial effects. PMID: 16733497 [PubMed - indexed for MEDLINE] 3369. Med Wieku Rozwoj. 2005 Oct-Dec;9(4):629-36. [Presence of leptin in mammalian colostrum and milk and in artificial milk formulas]. [Article in Polish] Woliński J(1), Zabielski R. Author information: (1)Zakład Fizjologii Przewodu Pokarmowego, Instytut Fizjologii i Zywienia Zwierzat im. Jana Kielanowskiego, Polska Akademia Nauk, ul. Instytucka 3, 05-110 Jabłonna, Poland. j.wolinski@ifzz.pan.pl Leptin is a 167-amino acid protein, involved in the regulation of adipose tissue, food intake and body weight in humans and animals. Recently, leptin synthesis has been found in the placenta and mammary glands in human and numerous animal species suggesting a role in controlling growth of the foetus and neonate. Colostrum and milk contain high amounts of leptin, in particular during the first few days of lactation. Milk leptin is associated with milk fats what may affect the results of analysis. In humans, a correlation was found between the milk leptin and plasma leptin, body weight and body mass index. In sows, no correlation have been found between the concentration of leptin in blood plasma and milk during the first week of lactation. Milk replacer formulas contain less leptin and leptin supplementation reverses the negative influence of formula feeding on the functional development of the gastro-intestinal tract in neonatal piglets. Data obtained so far suggest that breast milk leptin may control the gut development in newborns. PMID: 16733273 [PubMed - indexed for MEDLINE] 3370. Diabetes. 2006 Jun;55(6):1537-45. Adipose tissue: from lipid storage compartment to endocrine organ. Scherer PE(1). Author information: (1)Department of Cell Biology, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. scherer@aecom.yu.edu Adipose tissue, when carried around in excessive amounts, predisposes to a large number of diseases. Epidemiological data show that the prevalence of obesity has significantly increased over the past 20 years and continues to do so at an alarming rate. Here, some molecular aspects of the key constituent of adipose tissue, the adipocyte, are reviewed. While the adipocyte has been studied for many years and remarkable insights have been gained about some processes, many areas of the physiology of the fat cell remain unexplored. Our understanding of how cellular events in the adipocyte affect the local environment through paracrine interactions and how systemic effects are achieved through endocrine interactions is rudimentary. While storage and release of lipids are major functions of adipocytes, the adipocyte also uses specific lipid molecules for intracellular signaling and uses a host of protein factors to communicate with essentially every organ system in the body. The intensity and complexity of these signals are highly regulated, differ in each fat pad, and are dramatically affected by various disease states. PMID: 16731815 [PubMed - indexed for MEDLINE] 3371. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8828-33. Epub 2006 May 26. Imaging breast adipose and fibroglandular tissue molecular signatures by using hybrid MRI-guided near-infrared spectral tomography. Brooksby B(1), Pogue BW, Jiang S, Dehghani H, Srinivasan S, Kogel C, Tosteson TD, Weaver J, Poplack SP, Paulsen KD. Author information: (1)Thayer School of Engineering, Dartmouth College, 8000 Cummings Hall, Hanover, NH 03755, USA. Magnetic resonance (MR)-guided near-infrared spectral tomography was developed and used to image adipose and fibroglandular breast tissue of 11 normal female subjects, recruited under an institutional review board-approved protocol. Images of hemoglobin, oxygen saturation, water fraction, and subcellular scattering were reconstructed and show that fibroglandular fractions of both blood and water are higher than in adipose tissue. Variation in adipose and fibroglandular tissue composition between individuals was not significantly different across the scattered and dense breast categories. Combined MR and near-infrared tomography provides fundamental molecular information about these tissue types with resolution governed by MR T1 images. PMCID: PMC1482663 PMID: 16731633 [PubMed - indexed for MEDLINE] 3372. Biochim Biophys Acta. 2006 May-Jun;1757(5-6):446-8. Epub 2006 Apr 19. A new look at UCP 1. Porter RK(1). Author information: (1)School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. rkporter@tcd.ie There has been a resurgence of interest in mitochondrial uncoupling protein 1 due to a desire to understand the regulation of the prominent role it plays in control of metabolic flux in brown adipose tissue and non-shivering thermogenesis, combined with the fact that UCP 1 acts as a paradigm for other novel less abundant uncoupling proteins. In this manuscript, we review the recent evidence for detection, purification, identification and function of UCP 1 in thymus mitochondria. In addition, we review the two proposed mechanisms for fatty acid dependent UCP 1 activity, namely (a) the flippase (flip-flop) model and (b) the cofactor/activation model, and the implication for these models of recent data showing that glucose-O-omega-palmitate cannot facilitate UCP 1 activity. PMID: 16730638 [PubMed - indexed for MEDLINE] 3373. Endocr Relat Cancer. 2006 Jun;13(2):279-92. Molecular links between obesity and breast cancer. Lorincz AM(1), Sukumar S. Author information: (1)Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 410 CRB, Baltimore, MD 21231-1000, USA. Breast cancer continues to be a major health problem for women in the USA and worldwide. There is a need to identify and take steps to alter modifiable breast cancer risks. Conditions of obesity and overweight are risk factors that have reached epidemic proportions. This article reviews the evidence in the literature that test mechanism-based hypotheses which attempt to provide a molecular basis for a causal link between obesity and breast cancer risk, particularly the effects of metabolic syndrome and insulin resistance, peripheral estrogen aromatization in adipose tissue, and direct effect of adipokines. Future areas for study and implications for therapy are discussed. PMID: 16728564 [PubMed - indexed for MEDLINE] 3374. Biochim Biophys Acta. 2006 May-Jun;1757(5-6):459-66. Epub 2006 Mar 6. The physiological regulation of uncoupling proteins. Nicholls DG(1). Author information: (1)Buck Institute for Age Research, Mitochondrial Physiology, Novato, CA 94945, USA. dnicholls@buckinstitute.org Despite the enormous interest in the roles of novel uncoupling proteins, there is still great uncertainty as to their mechanism and regulation. The regulation of the architypal uncoupling protein 1 from brown adipose tissue was elucidated more than 20 years ago. This review suggests that a number of the approaches and criteria developed for the study of UCP1 could with profit be applied to current investigations of the novel UCPs. PMID: 16725104 [PubMed - indexed for MEDLINE] 3375. Curr Pharm Biotechnol. 2006 Apr;7(2):125-32. The role of insulin-like growth factor I components in the regulation of vitamin D. Gómez JM(1). Author information: (1)Endocrinology Service, Ciudad Sanitaria de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain. jmgs@csub.scs.es Several factors are known to be involved in the regulation of vitamin D and sunlight and diet are the two sources in humans, but the relative importance of each of them is not well defined. Vitamin D, parathyroid hormone and serum insulin-like growth factor-I (IGF-I) were found to be independent predictors of total bone density. Thus, the growth hormone (GH)/IGF-I is thought to play an important role in the regulation of bone mineral density and the skeleton is second only to the liver as a source of circulating levels of IGF-I. The mechanisms by which IGF-I may influence bone metabolism is not fully understood but they are a predictor of bone mass density and are positively associated with vitamin D concentrations. There is a physiological decline of the GH/IGF axis with ageing. The high affinity IGF-binding proteins (IGFBP-I to 6) have also been involved in IGF-I regulation, and it is important to include the IGF-independent properties, particularly those of IGFBP3 that may be involved in the osteoblastic differentiation observed in human bone marrow stromal cell cultures. These hormones have been shown to up regulate each other. 1,25-(OH) D(3) has been shown to promote the action of IGF-I by increasing IGF-I receptors and IGF-I can also elevate 1,25-(OH) D(3) concentrations by stimulating the hydroxylation of 25-(OH) D(3) in the active 1,25-(OH) D(3) hormone. Both GH and IGF-I significantly increased renal 1alpha-hydroxylase expression and serum 1, 25-(OH) D(3) concentrations. In prostate cells, 1,25-(OH) D(3) is growth inhibitory for many established cell lines and the role of IGFBPs, especially IGFBP-3, can be growth inhibitory or stimulatory and IGFBP-3 expression increases in response to 1,25-(OH) D(3), or its analogs, in established prostate cancer cell lines. Body fat is inversely associated with 25-(OH) D(3) in relation to with anthropometric measures, indicating a specific role of adipose tissue. IGF-I may be involved in both normal and abnormal fetal growth and stimulation of IGF-I synthesis during normal pregnancy may be associated with an increase in GH production by the placenta. Thus, maternal and umbilical cord serum IGF-I and 1,25-(OH) D(3) concentrations are lower in preeclampsia and umbilical cord serum IGF-I, IGFBP-1 and IGFBP-3 concentrations are associated with low newborn birth weights. PMID: 16724947 [PubMed - indexed for MEDLINE] 3376. Annu Rev Genomics Hum Genet. 2006;7:175-99. Genetic disorders of adipose tissue development, differentiation, and death. Agarwal AK(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9052, USA. Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations. PMID: 16722806 [PubMed - indexed for MEDLINE] 3377. Curr Opin Oncol. 2006 Jul;18(4):335-40. On our way to targeted therapy for cachexia in cancer? Boddaert MS(1), Gerritsen WR, Pinedo HM. Author information: (1)Department of Medical Oncology, VUMC Cancer Center Amsterdam, Amsterdam, The Netherlands. msa.boddaert@Vumc.nl PURPOSE OF REVIEW: Cachexia, the occurrence of involuntary weight loss due to loss of adipose tissue and skeletal muscle mass, is among the most common and devastating symptoms in patients with advanced cancer. It is a significant factor contributing to the poor performance status and high mortality rate of these patients, and is a distressing problem for both patients and their families. Despite extensive research in an attempt to better understand the mechanisms involved, progress in the management of cancer cachexia has been slow. RECENT FINDINGS: The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumour-derived factors are known to play a significant role, thereby representing suitable therapeutic targets. Moreover, recent advances in the field of molecular biology have shed light on other mediators involved in the mechanisms leading to muscle wasting, thus increasing potential targets for new therapies. SUMMARY: This review will focus on recent findings in relation to the molecular pathways leading to muscle wasting that have improved our current understanding of cachexia and will direct the future management of cachexia in cancer towards targeted therapies. PMID: 16721127 [PubMed - indexed for MEDLINE] 3378. Contrib Nephrol. 2006;150:166-73. Adipokine signaling in the peritoneal dialysis patient. Axelsson J(1), Carrero JJ, Avesani CM, Heimbürger O, Lindholm B, Stenvinkel P. Author information: (1)Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. Patients on peritoneal dialysis suffer from an increased incidence of cardiovascular disease, obesity, insulin resistance, as well as a markedly increased mortality rate. In both the general population and in renal patients current research implicates fat tissue as an important factor in modulating many of these complications through the secretion of various signaling peptides, mainly cytokines and adipokines. Whereas hemodialysis patients tend to lose fat mass after initiation of renal replacement therapy, peritoneal dialysis-patients instead gain fat, probably as a result of continuous glucose absorption. In the present overview we summarize some recent findings indicating that fat mass actively contributes to systemic inflammation and metabolic disturbances in chronic kidney disease. We conclude that adipokines are likely to influence several key survival factors in peritoneal dialysis patients, including systemic inflammation, endothelial health and appetite. PMID: 16721007 [PubMed - indexed for MEDLINE] 3379. Atheroscler Suppl. 2006 May;7(2):5-8. Epub 2006 May 19. Trans fatty acids and cardiovascular disease-epidemiological data. Willett WC(1). Author information: (1)Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. wwillett@hsph.harvard.edu Prospective epidemiologic studies and case-control studies using adipose tissue analyses support a major role of trans fatty acids (TFA) in risk of coronary heart disease (CHD). The magnitude of the association with CHD is considerably stronger than for saturated fat, and is stronger than predicted by the effects of TFA on LDL and HDL cholesterol. The apparent gap between the epidemiologic findings and effects of TFA on LDL:HDL has been bridged, at least in part, by recent metabolic studies showing effects of TFA on inflammatory factors and other indicators of insulin resistance. PMID: 16713753 [PubMed - indexed for MEDLINE] 3380. Pharmacol Res. 2006 Jun;53(6):501-7. Epub 2006 Mar 29. Peroxisome proliferator-activated receptor delta (PPARdelta), a novel target site for drug discovery in metabolic syndrome. Takahashi S(1), Tanaka T, Kodama T, Sakai J. Author information: (1)Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-0063, Japan. The development of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and diabetes mellitus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR)alpha and gamma agonists have shed light on the treatment of hypertriglyceridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPARdelta functions is lagging behind because specific PPARdelta agonists have not been developed. The appearance of new PPARdelta agonists is brightening the prospects for elucidating the physiological role of PPARdelta. PPARdelta is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation in skeletal muscle and adipose tissue by PPARdelta agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough. It seems that treatment of PPARdelta agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role of PPARdelta may be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPARdelta agonists against metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions of PPARdelta itself and its agonists in the future. PMID: 16713711 [PubMed - indexed for MEDLINE] 3381. Vascul Pharmacol. 2006 Jul;45(1):46-53. Epub 2006 May 19. Can PPARgamma agonists have a role in the management of obesity-related hypertension? Chetty VT(1), Sharma AM. Author information: (1)Michael deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. chetty@hhsc.ca Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARgamma is the most extensively studied amongst the three subtypes (alpha, delta and gamma). This receptor is a key modulator of lipid and glucose homeostasis and is predominantly expressed in adipose tissue. Expression of PPARgamma is also found in non-adipose tissues including heart, kidney, spleen, and interestingly, in all relevant components of the vasculature: endothelial and smooth muscle cells. These receptors may therefore also play a role in the regulation of vascular tone and blood pressure. Genetic variants of PPARgamma have also been associated with features of the metabolic syndrome, including obesity and increased blood pressure. The discovery of synthetic ligands for PPARgamma, the Thiazolidinediones (TZDs) has greatly enhanced our understanding of their ligand dependent activation and more importantly their role in vascular pathobiology. Approximately 10 years ago, serendipitous animal experiments demonstrated that despite causing sodium retention, the TZDs actually lowered blood pressure. This review will highlight the role of TZDs in various models of hypertension and discuss their potential role in the management of obesity-related hypertension. PMID: 16713364 [PubMed - indexed for MEDLINE] 3382. J Physiol. 2006 Jul 1;574(Pt 1):55-62. Epub 2006 May 18. Functions of AMP-activated protein kinase in adipose tissue. Daval M(1), Foufelle F, Ferré P. Author information: (1)INSERM Unit 671, Paris 75006, France. AMP-activated protein kinase (AMPK) is involved in cellular energy homeostasis. Its functions have been extensively studied in muscles and liver. AMPK stimulates pathways which increase energy production (glucose transport, fatty acid oxidation) and switches off pathways which consume energy (lipogenesis, protein synthesis, gluconeogenesis). This has led to the concept that AMPK has an interesting pharmaceutical potential in situations of insulin resistance and it is indeed the target of existing drugs and hormones which improve insulin sensitivity. Adipose tissue is a key player in energy metabolism through the release of substrates and hormones involved in metabolism and insulin sensitivity. Activation of AMPK in adipose tissue can be achieved through situations such as fasting and exercise. Leptin and adiponectin as well as hypoglycaemic drugs are activators of adipose tissue AMPK. This activation probably involves changes in the AMP/ATP ratio and the upstream kinase LKB1. When activated, AMPK limits fatty acid efflux from adipocytes and favours local fatty acid oxidation. Since fatty acids have a key role in insulin resistance, especially in muscles, activating AMPK in adipose tissue might be found to be beneficial in insulin-resistant states, particularly as AMPK activation also reduces cytokine secretion in adipocytes. PMCID: PMC1817807 PMID: 16709632 [PubMed - indexed for MEDLINE] 3383. Expert Opin Biol Ther. 2006 Jun;6(6):567-78. Adipose-derived stem cells for the regeneration of damaged tissues. Parker AM(1), Katz AJ. Author information: (1)Department of Plastic Surgery, University of Virginia, Charlottesville, VA 22908, USA. annamparker@gmail.com As the promise of stem cell-based therapies begins to be realised, and efforts to bring advances to the clinic mount, the source of these cells is increasingly important. The morbidity associated with harvesting stem cells from solid organs and the invasive nature of bone marrow biopsies may limit their practicality for wider clinical applications. An emerging body of literature suggests that adipose tissue may provide an abundant, readily accessible source of cells with similar potential to that described of other adult stem cells. This review will address advances in the use of adipose stem cells in fields as divergent as soft tissue reconstruction and cerebral infarction recovery. Numerous challenges will also be discussed; however, rapidly accumulating advances suggest that adipose stem cells may be as effective as they are abundant. PMID: 16706604 [PubMed - indexed for MEDLINE] 3384. Annu Rev Nutr. 2006;26:481-511. Results of bariatric surgery. Hansen EN(1), Torquati A, Abumrad NN. Author information: (1)Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2736; email: naji.abumrad@vanderbilt.edu. Overweight and obesity are rapidly growing to epidemic proportions in the United States and globally. Since sustainable weight loss is only achieved by bariatric surgery, medicine has seen an explosion in the diversity and number of bariatric procedures performed over the past few years. Systematic studies of postoperative outcomes and investigations into the physiology and biology of weight loss provide a more comprehensive understanding of the sequelae of bariatric surgery. Adipose tissue is the predominant site of fat stores. Increasing obesity results in an overload of lipids within the body's natural storage sink (i.e., the adipocyte) followed by the necessary deposition of fat within ectopic sites such as muscle, liver, and pancreas. The resulting metabolic derangements are associated with insulin resistance, central obesity, and chronic inflammation as adipose tissue acts as an endocrine organ, producing and secreting a host of biologic mediators. Whereas there are conflicting data on the cardiovascular effects of peripheral, subcutaneous liposuction, malabsorptive bariatric procedures result almost universally in significant amelioration of insulin resistance, hypertension, dyslipidemia, and hepatic steatosis. Concomitant changes in adipocyte-derived hormones may provide mechanistic explanations to the observed improvements. PMID: 16704354 [PubMed - indexed for MEDLINE] 3385. Endocr J. 2006 Jun;53(3):267-93. Epub 2006 May 12. Insulin receptor signals regulating GLUT4 translocation and actin dynamics. Kanzaki M(1). Author information: (1)TUBERO/Tohoku University Biomedical Engineering Research Organization, Tohoku University, Sendai, Japan. In skeletal muscle and adipose tissue, insulin-stimulated glucose uptake is dependent upon translocation of the insulin-responsive glucose transporter GLUT4 from intracellular storage compartments to the plasma membrane. This insulin-induced redistribution of GLUT4 protein is achieved through a series of highly organized membrane trafficking events, orchestrated by insulin receptor signals. Recently, several key molecules linking insulin receptor signals and membrane trafficking have been identified, and emerging evidence supports the importance of subcellular compartmentalization of signaling components at the right time and in the right place. In addition, the translocation of GLUT4 in adipocytes requires insulin stimulation of dynamic actin remodeling at the inner surface of the plasma membrane (cortical actin) and in the perinuclear region. This results from at least two independent insulin receptor signals, one leading to the activation of phosphatidylinositol (PI) 3-kinase and the other to the activation of the Rho family small GTP-binding protein TC10. Thus, both spatial and temporal regulations of actin dynamics, both beneath the plasma membrane and around endomembranes, by insulin receptor signals are also involved in the process of GLUT4 translocation. PMID: 16702775 [PubMed - indexed for MEDLINE] 3386. Aliment Pharmacol Ther. 2006 Jun 1;23(11):1511-23. Systematic review: adipose tissue, obesity and gastrointestinal diseases. John BJ(1), Irukulla S, Abulafi AM, Kumar D, Mendall MA. Author information: (1)Department of Colorectal Surgery, Mayday University Hospital, Croydon, UK. Comment in Aliment Pharmacol Ther. 2006 Oct 1;24(7):1127-8; author reply 1129-31. BACKGROUND: Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. Insulin resistance is the most widely accepted link between obesity and disease, particularly colorectal cancer. The recognition that intra-abdominal fat is immunologically active sheds new light not only on the pathogenesis of obesity-related gastrointestinal conditions, but also on inflammatory conditions such as Crohn's disease. AIM: To describe the biology of adipose tissue, its impact on the immune system and explores the possible underlying mechanisms linking obesity to gastrointestinal diseases. It also looks at the role of mesenteric fat in determining severity and course of Crohn's disease. METHODS: Relevant English-language literature and abstracts cited on MEDLINE database were reviewed. RESULTS: Our recent finding of an association between obesity and subclinical bowel inflammation suggests that, apart from promoting generalized immune activation, fat also evokes local immune responses. We propose that the proinflammatory milieu promoted by obesity could underlie many of these associations and that the mechanism implicating insulin resistance may merely represent an epiphenomenon. In Crohn's disease, on the other hand, intra-abdominal fat may provide a protective mechanism. CONCLUSION: The potential of adipose tissue as a therapeutic target is vast and needs exploration. PMID: 16696799 [PubMed - indexed for MEDLINE] 3387. Ann Ital Chir. 2005 Sep-Oct;76(5):413-6. [Obesity and immune function]. [Article in Italian] D'Orazio N(1). Author information: (1)Unita di Nutrizione Umana, Dipartimento di Scienze Biomediche, Università G. d'Annunzio, Chieti. n.dorazio@unich.it The perspective of obesity as a low grade systemic inflammatory condition has triggered a new interest on the many overlapping areas between this pathology and the immune system. White adipose tissue production of proteins related to the immune function has shown that many of these adipokines are implied in the ethiopathogenesis of some of the major metabolic diseases such as diabetes, hypertension, cardiovascular diseases, which share with obesity an important role in the Metabolic Syndrome. Besides, dysregulation of immune system may be present due to a dysregulation in the factors produced by adipose tissue. Weight loss through diet or surgery has proved to be beneficial for the recovery of the physiological levels of some of these pro-inflammatory molecules, but other studies are needed to clarify to which extent its possible to pursue risk reduction by this way. PMID: 16696213 [PubMed - indexed for MEDLINE] 3388. Ann Ital Chir. 2005 Sep-Oct;76(5):407-11. [The "problem obesity": viewpoint of the internist]. [Article in Italian] Guagnano MT(1), Manigrasso MR, Capani F, Davì G. Author information: (1)Dipartimento di Medicina e Scienza dell'Invecchiamento, Università G. d'Annunzio Chieti, Pescara. The prevalence of obesity has reached epidemic dimension in industrialized countries and it is known that obesity is associated with increased risk of cardiovascular morbidity and mortality. Commonly, obesity is defined by the Body Mass Index (BMI). However, BMI fails to consider body fat distribution. The relationship between the risk of metabolic-cardiovascular diseases and body fat distribution indices such as the waist-to-hip ratio (WHR) and the waist circumference, rather than measures of the degree of body fatness as expressed by BMI, has long been recognized. Recently, clinical and epidemiological research has found waist circumference to be the best anthropometric indicator of both total body fat and intra-abdominal fat mass. Android or visceral obesity is associated with metabolic syndrome and increased cardiovascular morbidity and mortality through a variety of molecular mechanisms possibly linking the metabolic syndrome to hemostatic and vascular abnormalities. Obesity guidelines suggest the need for weight reduction using behavioural change to reduce caloric intake and increasing physical activity. A realistic goal for weight reduction is to reduce body weight by 5% to 10% over a period of 6 to 12 months. Combined intervention of a low calories diet, increased physical activity, and behaviour therapy provides better outcomes for long-term weight reduction and weight maintenance than programs that use only one or two of these modalities. The drugs used to promote weight loss have been anorexic drugs or appetite suppressants. All classes of anorexic drugs affect neurotransmitters in the brain. The new agent sibutramine has norepinephrine and serotonin effects. Another new agent, orlistat, has a different mechanism of action, the reduction of fat absorption. Weight loss drugs approved by the FDA for long-term use may be useful as an adjunct to diet, physical activity and behaviour therapy for patients with a BMI of > or =30 with no concomitant obesity-related risk factors or diseases, and for patients with a BMI of > or =27 with concomitant obesity-related risk factors or diseases. PMID: 16696212 [PubMed - indexed for MEDLINE] 3389. Growth Horm IGF Res. 2006 Jul;16 Suppl A:S41-8. Epub 2006 May 11. Beginning to end: cardiovascular implications of growth hormone (GH) deficiency and GH therapy. Colao A(1), Di Somma C, Savanelli MC, De Leo M, Lombardi G. Author information: (1)Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples, Via S. Pansini 5, 80123 Naples, Italy. colao@unina.it Both growth hormone (GH) and insulin-like growth factor I (IGF-I) are involved in heart development and in maintenance of cardiac structure and performance. Cardiovascular disease has been reported to reduce life expectancy in both GH deficiency (GHD) and GH excess. Patients with GHD suffer from a cluster of abnormalities associated with increased cardiovascular risk, including abnormal body composition, unfavorable lipid profile, increased fibrinogen and C-reactive protein levels, insulin resistance, early atherosclerosis and endothelial dysfunction, and impaired left ventricular (LV) performance (i.e., reduced diastolic filling and impaired response to peak exercise). Long-term GH replacement therapy reverses most of these abnormalities. More consistently, GH replacement reduces body fat and visceral adipose tissue, reduces low-density lipoprotein cholesterol and triglyceride levels, and improves endothelial function. GH replacement also reduces intima media thickness at major arteries and improves LV performance, but these results have been observed only in small series of patients treated on a short-term basis. This review discusses the roles of GHD and GH replacement therapy in the development of cardiovascular disease. PMID: 16690338 [PubMed - indexed for MEDLINE] 3390. Chronobiol Int. 2006;23(1-2):419-26. Are G protein-coupled receptor heterodimers of physiological relevance?--Focus on melatonin receptors. Levoye A(1), Jockers R, Ayoub MA, Delagrange P, Savaskan E, Guillaume JL. Author information: (1)Department of Cell Biology, Institut Cochin, Université Paris-Descartes, Faculté de Médecine, France. In mammals, the circadian hormone melatonin targets two seven-transmembrane-spanning receptors, MT1 and MT2, of the G protein-coupled receptor (GPCR) super-family. Evidence accumulated over the last 15 yrs convincingly demonstrates that GPCRs, classically considered to function as monomers, are actually organized as homodimers and heterodimerize with other GPCR family members. These dimers are formed early in the biosynthetic pathway and remain stable throughout the entire life cycle. A growing number of observations demonstrate that GPCR oligomerization may occur in native tissues and may have important consequences on receptor function. The formation of MT1 and MT2 homodimers and MT1/MT2 heterodimers has been shown in heterologous expression systems at physiological expression levels. Formation of MT1/MT2 heterodimers remains to be shown in native tissues but is suggested by the documented co-expression of MT1 and MT2 in many melatonin-sensitive tissues, such as the hypothalamic suprachiasmatic nuclei, retina, arteries, and adipose tissue. Considering that multiple GPCRs are expressed simultaneously in most cells, the possible engagement into heterodimeric complexes has to be considered and taken into account for the interpretation of experimental data obtained from native tissues and knockout animals. PMID: 16687315 [PubMed - indexed for MEDLINE] 3391. Med Sci (Paris). 2006 May;22(5):531-6. [Lipodystrophies related to antiretroviral treatment of HIV infection]. [Article in French] Capeau J(1), Caron M, Vigouroux C, Cervera P, Kim M, Maachi M, Lagathu C, Bastard JP. Author information: (1)Inserm U680, Faculté de Médecine et Université Pierre et Marie Curie, Hôpital Tenon AP-HP, 27, rue Chaligny, 75012 Paris, France. capeau@st-antoine.inserm.fr HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFalpha, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue. PMID: 16687123 [PubMed - indexed for MEDLINE] 3392. Horm Res. 2006;66(1):33-9. Epub 2006 May 24. Prematurity--another example of perinatal metabolic programming? Hofman PL(1), Regan F, Cutfield WS. Author information: (1)Liggins Institute, University of Auckland, Auckland, New Zealand. p.hofman@auckland.ac.nz Low birth weight is associated with both later adult diseases such as type 2 diabetes mellitus and a number of metabolic abnormalities, the foremost of which is insulin resistance. Indeed the link between an adverse perinatal environment, manifested by low birth weight, and adult life pathology may be an early, permanent reduction in insulin sensitivity. A reduction in insulin sensitivity has been demonstrated in small for gestational age (SGA), term subjects from childhood through to adulthood. Less is known about children born premature into an adverse neonatal environment. We present data demonstrating that premature infants also have metabolic abnormalities similar to those observed in term, SGA children and that these occur irrespective of whether they are SGA or appropriate for gestational age (AGA). Copyright 2006 S. Karger AG, Basel. PMID: 16685134 [PubMed - indexed for MEDLINE] 3393. J Lipid Res. 2006 Aug;47(8):1643-50. Epub 2006 May 9. Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity. Koutsari C(1), Jensen MD. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. Adipose tissue lipolysis provides circulating FFAs to meet the body's lipid fuel demands. FFA release is well regulated in normal-weight individuals; however, in upper-body obesity, excess lipolysis is commonly seen. This abnormality is considered a cause for at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with upper-body obesity. "Normal" lipolysis is sex-specific and largely determined by the individual's resting metabolic rate. Women have greater FFA release rates than men without higher FFA concentrations or greater fatty acid oxidation, indicating that they have greater nonoxidative FFA disposal, although the processes and tissues involved in this phenomenon are unknown. Therefore, women have the advantage of having greater FFA availability without exposing their tissues to higher and potentially harmful FFA concentrations. Upper-body fat is more lipolytically active than lower-body fat in both women and men. FFA released by the visceral fat depot contributes only a small percentage of systemic FFA delivery. Upper-body subcutaneous fat is the dominant contributor to circulating FFAs and the source of the excess FFA release in upper-body obesity. We believe that abnormalities in subcutaneous lipolysis could be more important than those in visceral lipolysis as a cause of peripheral insulin resistance. Understanding the regulation of FFA availability will help to discover new approaches to treat FFA-induced abnormalities in obesity. PMID: 16685078 [PubMed - indexed for MEDLINE] 3394. Endocr Rev. 2006 Aug;27(5):449-67. Epub 2006 May 9. Role of adipose tissue as an inflammatory organ in human diseases. Schäffler A(1), Müller-Ladner U, Schölmerich J, Büchler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de Reviews on the inflammatory role of adipose tissue outside the field of metabolism are rare. There is increasing evidence provided by numerous basic research studies from nearly all internal medicine subspecializations that adipocytes and adipocytokines are involved in primary inflammatory processes and diseases. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge on the inflammatory role of adipocytokines and special types of regional adipocytes such as retroorbital, synovial, visceral, subdermal, peritoneal, and bone marrow adipocytes in internal medicine diseases. Future clinical and therapeutic implications are discussed. PMID: 16684901 [PubMed - indexed for MEDLINE] 3395. Curr Opin Lipidol. 2006 Jun;17(3):302-8. Plasma lipid transfer proteins. Jiang XC(1), Zhou HW. Author information: (1)Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA. xjiang@downstate.edu PURPOSE OF REVIEW: Plasma cholesteryl ester transfer protein and phospholipid transfer protein are involved in lipoprotein metabolism. Conceivably, manipulation of either transfer protein could impact atherosclerosis and other lipid-driven diseases. RECENT FINDINGS: Cholesteryl ester transfer protein mediates direct HDL cholesteryl ester delivery to the liver cells; adipose tissue-specific overexpression of cholesteryl ester transfer protein in mice reduces the plasma HDL cholesterol concentration and adipocyte size; cholesteryl ester transfer protein TaqIB polymorphism is associated with HDL cholesterol plasma levels and the risk of coronary heart disease. In apolipoprotein B transgenic mice, phospholipid transfer protein deficiency enhances reactive oxygen species-dependent degradation of newly synthesized apolipoprotein B via a post-endoplasmic reticulum process, as well as improving the antiinflammatory properties of HDL in mice. Activity of this transfer protein in cerebrospinal fluid of patients with Alzheimer's disease is profoundly decreased and exogenous phospholipid transfer protein induces apolipoprotein E secretion by primary human astrocytes in vitro. SUMMARY: Understanding the relationship between lipid transfer proteins and lipoprotein metabolism is expected to be an important frontier in the search for a therapy for atherosclerosis. PMID: 16680037 [PubMed - indexed for MEDLINE] 3396. Cell. 2006 May 5;125(3):429-31. Forcing the third dimension. Boudreau N(1), Weaver V. Author information: (1)Surgical Research Laboratory, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Comment on Cell. 2006 May 5;125(3):577-91. One goal of biomedical research is to reliably construct surrogate tissues for replacement therapy and to promote tissue regeneration. In this issue of Cell, Chun et al. (2006) provide insight into the molecular basis of tissue-specific differentiation. The authors show that remodeling of the extracellular matrix by the matrix metalloproteinase MT1-MMP contributes to the three-dimensional development of white adipose tissue in mice. PMID: 16678088 [PubMed - indexed for MEDLINE] 3397. Biol Rev Camb Philos Soc. 2006 May;81(2):183-205. The evolution of human fatness and susceptibility to obesity: an ethological approach. Wells JC(1). Author information: (1)MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. J.Wells@ich.ucl.ac.uk Human susceptibility to obesity is an unusual phenomenon amongst animals. An evolutionary analysis, identifying factors favouring the capacity for fat deposition, may aid in the development of preventive public health strategies. This article considers the proximate causes, ontogeny, fitness value and evolutionary history of human fat deposition. Proximate causes include diet composition, physical activity level, feeding behaviour, endocrine and genetic factors, psychological traits, and exposure to broader environmental factors. Fat deposition peaks during late gestation and early infancy, and again during adolescence in females. As in other species, human fat stores not only buffer malnutrition, but also regulate reproduction and immune function, and are subject to sexual selection. Nevertheless, our characteristic ontogenetic pattern of fat deposition, along with relatively high fatness in adulthood, contrasts with the phenotype of other mammals occupying the tropical savannah environment in which hominids evolved. The increased value of energy stores in our species can be attributed to factors increasing either uncertainty in energy availability, or vulnerability to that uncertainty. Early hominid evolution was characterised by adaptation to a more seasonal environment, when selection would have favoured general thriftiness. The evolution of the large expensive brain in the genus Homo then favoured increased energy stores in the reproducing female, and in the offspring in early life. More recently, the introduction of agriculture has had three significant effects: exposure to regular famine; adaptation to a variety of local niches favouring population-specific adaptations; and the development of social hierarchies which predispose to differential exposure to environmental pressures. Thus, humans have persistently encountered greater energy stress than that experienced by their closest living relatives during recent evolution. The capacity to accumulate fat has therefore been a major adaptive feature of our species, but is now increasingly maladaptive in the modern environment where fluctuations in energy supply have been minimised, and productivity is dependent on mechanisation rather than physical effort. Alterations to the obesogenic environment are predicted to play a key role in reducing the prevalence of obesity. PMID: 16677431 [PubMed - indexed for MEDLINE] 3398. Postepy Biochem. 2005;51(4):430-9. [Aromatase--key enzyme of estrogen biosynthesis]. [Article in Polish] Milczarek R(1), Klimek J. Author information: (1)Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, 1 Debinki St., 80-211 Gdańsk, Poland. rysmil@amg.gda.pl Estrogens control a large range pivotal life functions as reproductive development and fertility, bone growth and sexual behavior. Aromatase is a key enzyme of estrogen biosynthesis. The property, structure and reaction mechanism of aromatase as well as detailed structure of human aromatase cytochrome P450 gene (CYP19) was discussed in this article. It was pointed that unique human CYP19 gene expression results from presence of many tissue specific promoters and alternative splicing. The molecular mechanism of control aromatase cytochrome P450 gene expression in various species ovaries, testes and human adipose tissue and placenta was discussed in details. Because of a very important role of estrogen in breast cancer a molecular base of aberrant expression CYP19 gene in breast tumor and adipose tissue proximal to breast tumor and potential possibility of pharmacological silencing of this gene expression was discussed in the article. PMID: 16676578 [PubMed - indexed for MEDLINE] 3399. FEBS Lett. 2006 May 22;580(12):2917-21. Epub 2006 Apr 21. The metabolic syndrome and adipocytokines. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Professor Emeritus Osaka University, 5-3-20 Nakanoshima, Kita-Ku, Osaka 530-0005, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases. PMID: 16674947 [PubMed - indexed for MEDLINE] 3400. Fundam Clin Pharmacol. 2006 Jun;20(3):311-20. Clinical methods for the evaluation of endothelial function-- a focus on resistance arteries. Joannides R(1), Bellien J, Thuillez C. Author information: (1)Department of Pharmacology, INSERM U644, IFRMP 23, Rouen University Hospital, CHU de Rouen, 76031 Rouen Cedex, France. robinson.joannides@chu-rouen.fr Endothelial dysfunction is a key event in the pathophysiology of cardiovascular diseases and appears as a strong independent predictor of cardiovascular events. In this context, biological evaluation of endothelial circulating markers can be helpful. However, functional tests using pharmacological stimuli appear more specific for the study of resistance arteries. These methods consist in the evaluation of the endothelium-dependent changes in regional vascular flow in response to local infusion of substances that act through endothelial receptors without modification of systemic arterial pressure and in comparison with a non endothelium-dependent relaxation. Flow is measured by Doppler and intravascular ultrasound in coronary circulation, laser Doppler in skin and by venous occlusion plethysmography in peripheral muscular arteries. Similar studies can be performed ex vivo using isolated resistance arteries obtained from fat subcutaneous biopsies. In addition, other information can be obtained from reactive hyperemia and the study of the flow-mediated dilatation of conduit arteries to enable a selective and comprehensive approach of the heterogeneity of endothelial function in pathophysiology. PMID: 16671967 [PubMed - indexed for MEDLINE] 3401. Obesity (Silver Spring). 2006 Mar;14(3):357-67. Intramyocellular lipid content in human skeletal muscle. Schrauwen-Hinderling VB(1), Hesselink MK, Schrauwen P, Kooi ME. Author information: (1)Department of Radiology, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. vhi@rdia.azm.nl Fat can be stored not only in adipose tissue but also in other tissues such as skeletal muscle. Fat droplets accumulated in skeletal muscle [intramyocellular lipids (IMCLs)] can be quantified by different methods, all with advantages and drawbacks. Here, we briefly review IMCL quantification methods that use biopsy specimens (biochemical quantification, electron microscopy, and histochemistry) and non-invasive alternatives (magnetic resonance spectroscopy, magnetic resonance imaging, and computed tomography). Regarding the physiological role, it has been suggested that IMCL serves as an intracellular source of energy during exercise. Indeed, IMCL content decreases during prolonged submaximal exercise, and analogously to glycogen, IMCL content is increased in the trained state. In addition, IMCL content is highest in oxidative, type 1 muscle fibers. Together, this, indeed, suggests that the IMCL content is increased in the trained state to optimally match fat oxidative capacity and that it serves as readily available fuel. However, elevation of plasma fatty acid levels or dietary fat content also increases IMCL content, suggesting that skeletal muscle also stores fat simply if the availability of fatty acids is high. Under these conditions, the uptake into skeletal muscle may have negative consequences on insulin sensitivity. Besides the evaluation of the various methods to quantify IMCLs, this perspective describes IMCLs as valuable energy stores during prolonged exercise, which, however, in the absence of regular physical activity and with overconsumption of fat, can have detrimental effects on muscular insulin sensitivity. PMID: 16648604 [PubMed - indexed for MEDLINE] 3402. Pharmacol Res. 2006 Jun;53(6):482-91. Epub 2006 Mar 27. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Langin D(1). Author information: (1)Obesity Research Unit Inserm UPS U586, Institut Louis Bugnard, Université Paul Sabatier, CHU Rangueil, Toulouse, France. langin@toulouse.inserm.fr Adipose tissue lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and release of fatty acids and glycerol. Recent work has revealed that lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. There have been new discoveries on the endocrine and paracrine regulation of lipolysis and on the molecular mechanisms of triglyceride hydrolysis. Catecholamines modulate lipolysis through lipolytic beta-adrenoceptor and antilipolytic alpha2-adrenoceptor. Recent studies have allowed a better understanding of the relative contribution of the two types of receptors and provided evidence for the in vivo involvement of alpha2-adrenoceptors in the physiological control of subcutaneous adipose tissue lipolysis. A puzzling observation is the characterization of a residual catecholamine-induced lipolysis in mice deficient in beta-adrenoceptors. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. There are other lipolytic pathways active in human fat cells which importance is not fully understood. Forty years after the description of the antilipolytic effect of nicotinic acid, the receptors have been identified. Adrenomedullin which is produced by adipocytes exert an antilipolytic effect through an indirect mechanism involving nitric oxide. The molecular details of the lipolytic reaction are not fully understood. The role of the lipases has been re-evaluated with the cloning of adipose triglyceride lipase. Hormone-sensitive lipase appears as the major lipase for catecholamine and natriuretic peptide-stimulated lipolysis whereas adipose triglyceride lipase mediates the hydrolysis of triglycerides during basal lipolysis. Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation. Re-organization of the lipid droplet coating by perilipins facilitates the access of the enzyme. The role of other lipid-interacting proteins in lipolysis is still unclear. The proteins involved in the lipolytic process constitute drug targets for the treatment of obesity and the metabolic syndrome. The oldest example is nicotinic acid (niacin) used as a hypolipidaemic drug. A first approach consists in molecules stimulating lipolysis and oxidation of the released fatty acids to decrease fat stores. A second approach is a chronic inhibition of lipolysis to diminish plasma fatty acid level which is a central feature of the metabolic syndrome. PMID: 16644234 [PubMed - indexed for MEDLINE] 3403. J Nutr Biochem. 2006 Jun;17(6):374-8. Epub 2006 Apr 27. Role of amino acids in insulin signaling in adipocytes and their potential to decrease insulin resistance of adipose tissue. Hinault C(1), Van Obberghen E, Mothe-Satney I. Author information: (1)INSERM, Unité 145, Institut Fédératif de Recherche (IFR 50), 06107 Nice Cedex 02, France. Recently, our knowledge concerning the role of amino acids in signal transduction in mammals has greatly improved. This significant advance is mainly due to the remarkable discovery that the mammalian target of rapamycin (mTOR) protein kinase, known to be activated in response to a large number of hormones, growth factors and cytokines, is also under the tight control of branched-chain amino acids. Actually, both inputs are necessary to fully activate the mTOR pathway, the main function of which is to increase cell size, via the regulation of translational processes. However, amino acids are able to modulate other biological effects and appear to have unexpected actions, as evidenced by our recent work in rat adipocytes. The aim of this review is to summarize novel findings on the role of mTOR and amino acids in insulin signaling in adipocytes. A possible beneficial impact of the use of amino acids in the treatment of insulin resistance is discussed, and hypotheses about the molecular mechanisms underlying their effect are proposed. PMID: 16644198 [PubMed - indexed for MEDLINE] 3404. Obesity (Silver Spring). 2006 Feb;14 Suppl 1:20S-24S. Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model. Jensen MD(1). Author information: (1)Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, USA. jensen@mayo.edu OBJECTIVE: To review the evidence for and against the role of visceral adipose tissue as a major contributor to the metabolic complications of obesity through abnormal regulation of lipolysis. RESEARCH METHODS AND PROCEDURES: Data from investigators in the field who have studied visceral adiposity and metabolic health and/or regional and systemic free fatty acid (FFA) release were considered. RESULTS: Although visceral fat mass was positively correlated with adverse health consequences and excess FFA availability, visceral fat was not the source of excess systemic FFA availability. Upper body non-visceral fat contributes the majority of FFAs in lean, obese, diabetic, and non-diabetic humans. Increasing amounts of visceral fat probably result in greater hepatic FFA delivery. DISCUSSION: Systemic, as opposed to hepatic, insulin resistance is unlikely to be caused by high rates of visceral adipose tissue lipolysis. PMID: 16642959 [PubMed - indexed for MEDLINE] 3405. Obesity (Silver Spring). 2006 Feb;14 Suppl 1:16S-19S. Why visceral fat is bad: mechanisms of the metabolic syndrome. Bergman RN(1), Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, Hucking K, Ader M. Author information: (1)Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rbergman@usc.edu PMID: 16642958 [PubMed - indexed for MEDLINE] 3406. Obesity (Silver Spring). 2006 Feb;14 Suppl 1:9S-15S. Metabolic actions of adipocyte hormones: focus on adiponectin. Ahima RS(1). Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu The obesity epidemic has focused attention on the endocrine function of adipose tissue. Adipose tissue secretes leptin, cytokines, complement factors, and components of the coagulation cascade, most of which are increased in obesity. In contrast, a strong negative correlation exists between adiponectin and adiposity, insulin sensitivity, diabetes, vascular inflammation, and atherosclerosis. Adiponectin treatment in rodents increases insulin sensitivity and reduces lipids and atherogenesis. Chronic and central adiponectin treatment reduces weight, glucose, and lipids. The insulin-sensitizing action of thiazolidinediones is mediated, in part, through adiponectin. A causal role of adiponectin in diabetes, dyslipidemia, and atherosclerosis has been established in knockout mice. Therefore, adiponectin seems to be a marker of obesity-related diseases and a potential therapeutic target. PMID: 16642957 [PubMed - indexed for MEDLINE] 3407. Horm Res. 2006;65(6):300-10. Respiration under control of uncoupling proteins: Clinical perspective. Nübel T(1), Ricquier D. Author information: (1)Centre National de la Recherche Scientifique, Unit 9078, Faculty of Medicine René Descartes Paris 5, Paris, France. The term 'uncoupling protein' was originally used for the mitochondrial membrane protein UCP1, which is uniquely present in mitochondria of brown adipocytes, thermogenic cells that regulate body temperature in small rodents, hibernators and mammalian newborns. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP-synthase resulting in a futile proton cycling and dissipation of oxidation energy as heat. Recent identification of new homologues to UCP1 expressed in brown and white adipose tissue, muscle, brain and other tissues together with the hypothesis that these novel uncoupling proteins (UCPs) may regulate thermogenesis and/or fatty acid metabolism and furthermore may protect against free radical oxygen species production have generated considerable optimism for rapid advances in the identification of new targets for pharmacological management of complex pathological syndromes such as obesity, type 2 diabetes or chronic inflammatory diseases. However, since the physiological and biochemical roles of the novel UCPs are not yet clear, the main challenge today consists first of all in providing mechanistic explanation for their functions in cellular physiology. This lively awaited information may be the basis for potential pharmacological targeting of the UCPs in future. Copyright 2006 S. Karger AG, Basel. PMID: 16641553 [PubMed - indexed for MEDLINE] 3408. J Cutan Pathol. 2006 May;33(5):369-72. Ectopic hamartomatous thymoma: a case report with immunohistochemical study and review of the literature. Kushida Y(1), Haba R, Kobayashi S, Ishikawa M, Doi T, Kadota K. Author information: (1)Department of diagnostic pathology, Kagawa University, Japan. ykushida@med.kagawa-u.ac.jp Ectopic hamartomatous thymoma (EHT) is a rare benign tumor. We present a case of EHT, which was seen as subcutaneous mass on the left supraclavicular area in a 19-year-old man. The tumor consisted of spindle cells, epithelial cells, adipose cells, and a small amount of lymphocytes, as described previously. Immunohistochemically, spindle cells were positive for keratin, a-smooth muscle actin, CD34 and vimentin, but negative for desmin and S-100 protein. Lymphocytes were positive for CD45RO but negative for CD20, CD1a, and CD99. Approximately, 5% of cells were positive for MIB-1 and no cells stained for p53 and bcl-2. Recognition of EHT is important and needs to be differentiated from high-grade sarcomas such as synovial sarcoma or glandular malignant peripheral nerve sheath tumor. PMID: 16640545 [PubMed - indexed for MEDLINE] 3409. Srp Arh Celok Lek. 2005 Sep-Oct;133(9-10):441-5. [Adipose tissue as an endocrine organ]. [Article in Serbian] Jakovljević B, Paunović K, Stojanov V. The traditional function attributed to white adipose tissue of energy storage in the form of triglycerides has been challenged by results from recent studies, showing that adipose tissue is, in fact, a highly active metabolic and endocrine organ. A radical change in perspective followed the discovery of a large number of proteins secreted from white adipocytes, such as leptin, resistin, adiponectin, adipsin, acylation-stimulating protein, angiotensinogen, tumour necrosis factor a, interleukin-6, retinol-binding protein, plasminogen activator inhibitor-1, tissue factor, fasting-induced adipose factor, fibrinogen/angiopoetin-related protein, and metallothionein. The effects of specific proteins may be either autocrine or paracrine, meaning that they might act in adipose tissue itself or in more distant target tissues. Some of these proteins induce insulin resistance, some play a role in glucose and lipid metabolism, some are inflammatory cytokines, while others are involved in vascular haemostasis. The key challenges for future investigations of adipose tissue's secretory functions will be to identify all of its secreted proteins, to establish the function of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production due to problems, such as obesity, fasting, or diabetes mellitus type 2. PMID: 16640191 [PubMed - indexed for MEDLINE] 3410. J Anat. 2006 Apr;208(4):471-90. Where tendons and ligaments meet bone: attachment sites ('entheses') in relation to exercise and/or mechanical load. Benjamin M(1), Toumi H, Ralphs JR, Bydder G, Best TM, Milz S. Author information: (1)School of Biosciences, Cardiff University, UK. benjamin@cardiff.ac.uk Entheses (insertion sites, osteotendinous junctions, osteoligamentous junctions) are sites of stress concentration at the region where tendons and ligaments attach to bone. Consequently, they are commonly subject to overuse injuries (enthesopathies) that are well documented in a number of sports. In this review, we focus on the structure-function correlations of entheses on both the hard and the soft tissue sides of the junction. Particular attention is paid to mechanical factors that influence form and function and thus to exploring the relationship between entheses and exercise. The molecular parameters indicative of adaptation to mechanical stress are evaluated, and the basis on which entheses are classified is explained. The application of the 'enthesis organ' concept (a collection of tissues adjacent to the enthesis itself, which jointly serve the common function of stress dissipation) to understanding enthesopathies is considered and novel roles of adipose tissue at entheses are reviewed. A distinction is made between different locations of fat at entheses, and possible functions include space-filling and proprioception. The basic anchorage role of entheses is considered in detail and comparisons are explored between entheses and other biological 'anchorage' sites. The ability of entheses for self-repair is emphasized and a range of enthesopathies common in sport are reviewed (e.g. tennis elbow, golfer's elbow, jumper's knee, plantar fasciitis and Achilles insertional tendinopathies). Attention is drawn to the degenerative, rather than inflammatory, nature of most enthesopathies in sport. The biomechanical factors contributing to the development of enthesopathies are reviewed and the importance of considering the muscle-tendon-bone unit as a whole is recognized. Bony spur formation is assessed in relation to other changes at entheses which parallel those in osteoarthritic synovial joints. PMCID: PMC2100202 PMID: 16637873 [PubMed - indexed for MEDLINE] 3411. Diabetes Obes Metab. 2006 May;8(3):264-80. Adiponectin--a key adipokine in the metabolic syndrome. Whitehead JP(1), Richards AA, Hickman IJ, Macdonald GA, Prins JB. Author information: (1)Centre for Diabetes and Endocrine Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia. jwhitehead@cder.soms.uq.edu.au Adiponectin is a recently described adipokine that has been recognized as a key regulator of insulin sensitivity and tissue inflammation. It is produced by adipose tissue (white and brown) and circulates in the blood at very high concentrations. It has direct actions in liver, skeletal muscle and the vasculature, with prominent roles to improve hepatic insulin sensitivity, increase fuel oxidation [via up-regulation of adenosine monophosphate-activated protein kinase (AMPK) activity] and decrease vascular inflammation. Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in the liver. In contrast to other adipokines, adiponectin secretion and circulating levels are inversely proportional to body fat content. Levels are further reduced in subjects with diabetes and coronary artery disease. Adiponectin antagonizes many effects of tumour necrosis factor-alpha(TNF-alpha) and this, in turn, suppresses adiponectin production. Furthermore, adiponectin secretion from adipocytes is enhanced by thiazolidinediones (which also act to antagonize TNF-alpha effects). Thus, adiponectin may be the common mechanism by which TNF-alpha promotes, and the thiazolidinediones suppress, insulin resistance and inflammation. Two adiponectin receptors, termed AdipoR1 and AdipoR2, have been identified and these are ubiquitously expressed. AdipoR1 is most highly expressed in skeletal muscle and has a prominent action to activate AMPK, and hence promote lipid oxidation. AdipoR2 is most highly expressed in liver, where it enhances insulin sensitivity and reduces steatosis via activation of AMPK and increased peroxisome-proliferator-activated receptor alpha ligand activity. T-cadherin, which is expressed in endothelium and smooth muscle, has been identified as an adiponectin-binding protein with preference for HMW adiponectin multimers. Given the low levels of adiponectin in subjects with the metabolic syndrome, and the beneficial effect of the adipokine in animal studies, there is exciting potential for adiponectin replacement therapy in insulin resistance and related disorders. PMID: 16634986 [PubMed - indexed for MEDLINE] 3412. Diabetes Obes Metab. 2006 May;8(3):237-49. Insulin resistance--a common link between type 2 diabetes and cardiovascular disease. Lebovitz HE(1). Author information: (1)Division of Endocrinology and Metabolism/Diabetes, State University of New York, Health Science Center, Brooklyn, NY, USA. hlebovitz@attglobal.net Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the 'common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPARgamma agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPARalpha (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPARalpha and PPARgamma activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD. PMID: 16634983 [PubMed - indexed for MEDLINE] 3413. Panminerva Med. 2006 Mar;48(1):3-12. Insulin resistance: trigger or concomitant factor in the metabolic syndrome. Avogaro A(1). Author information: (1)Unit of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. angelo.avogaro@unipd.it The metabolic syndrome (MS) is a cluster of metabolic abnormalities with insulin resistance as a major characteristic. The main adverse consequence of the MS is cardiovascular disease (CVD). Complex, mutually reinforcing interactions between obesity and insulin resistance largely account for the pathogenesis of MS. Central pathophysiologic features include: insulin resistance, atherogenic dyslipidemia, chiefly present as low HDL-C together with increases in triglycerides and small dense, low density lipoprotein particles, hypertension, a proinflammatory state, with increases in acute-phase reactants, and a prothrombotic state. Although lifestyle and overeating seem to be the triggering pathogenic factors, genetic elements are also involved in the pathogenesis of MS. When present, insulin resistance results in impaired insulin action in insulin-sensitive tissues such as muscle, fat, and liver. Insulin resistance results in abnormalities of glucose metabolism, with reduced peripheral disposal of glucose in muscle and increased hepatic glucose output in the fasting state. But, most importantly, the progressively increasing concentration in circulating glucose leads to various abnormalities in insulin secretion. Elevated insulin levels themselves are atherogenic by inducing an oxidative stress and by stimulating sympathetic-nerve activity. Ectopic fat deposition, stress, proinflammatory state, and a maladaptive response of innate immunity may together concur to the development of the MS. When this condition is acknowledged, substantial modification of life style and correction of each single risk factor should be pursued without uncertainties and without hierarchical approach; this means that each risk factor should be treated and brought to target. PMID: 16633326 [PubMed - indexed for MEDLINE] 3414. Nestle Nutr Workshop Ser Pediatr Program. 2006;57:235-42; discussion 243-5. The crucial role of dietary n-6 polyunsaturated fatty acids in excessive adipose tissue development: relationship to childhood obesity. Massiera F(1), Guesnet P, Ailhaud G. Author information: (1)ISDBC, Centre de Biochimie UMR 6543 CNRS, Faculté des Sciences, Nice, France. PMID: 16632969 [PubMed - indexed for MEDLINE] 3415. Nestle Nutr Workshop Ser Pediatr Program. 2006;57:31-43; discussion 43-50. Childhood obesity: potential mechanisms for the development of an epidemic. Maffeis C(1). Author information: (1)Department of Mother and Child, Biology-Genetics, Unit of Pediatrics, University of Verona, Verona, Italy. PMID: 16632958 [PubMed - indexed for MEDLINE] 3416. Pharmacol Res. 2006 Jun;53(6):469-77. Epub 2006 Mar 22. Cellular inflammatory responses: novel insights for obesity and insulin resistance. Chen H(1). Author information: (1)Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, MA 02139, USA. hong.chen@novartis.com Type 2 diabetes is rapidly becoming a worldwide epidemic. Obesity and sedentary lifestyle are the main environmental causes for the development of insulin resistance and type 2 diabetes. In the past decade, it has been increasingly recognized that obesity and insulin resistance are associated with chronic, low-grade systemic inflammation. This review will cover the recent advances in this field and provide a working model explaining how cellular inflammatory responses arise to cope with obesity-induced metabolic stresses and how these inflammatory responses underlie insulin resistance. PMID: 16632376 [PubMed - indexed for MEDLINE] 3417. Ageing Res Rev. 2006 May;5(2):144-64. Epub 2006 Apr 21. Lipotoxicity, overnutrition and energy metabolism in aging. Slawik M(1), Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, UK. The safest place to store lipids is the white adipose tissue, but its storage capacity may become saturated resulting in excess of fat "overspilled" to non-adipose tissues. This overspill of fat occurs in apparently opposite pathological states such as lipodistrophy or obesity. When the excess of energy is redirected towards peripheral organs, their initial response is to facilitate the storage of the surplus in the form of triacylglycerol, but the limited triacylglycerol buffer capacity becomes saturated soon. Under these conditions excess of lipids enter alternative non-oxidative pathways that result in production of toxic reactive lipid species that induce organ-specific toxic responses leading to apoptosis. Reactive lipids can accumulate in non-adipose tissues of metabolically relevant organs such as pancreatic beta-cells, liver, heart and skeletal muscle leading to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. The effects of this lipotoxic insult can be minimised by several strategies: (a) decreased incorporation of energy, (b) a less orthodox approach such as increased adipose tissue expandability and/or (c) increased oxidation of fat in peripheral organs. Aging should be considered as physiological degenerative process potentially accelerated by concomitant lipotoxic insults. Conversely, the process of aging can sensitise cells to effects of lipid toxicity. PMID: 16630750 [PubMed - indexed for MEDLINE] 3418. Obes Rev. 2006 May;7(2):183-200. The influence of physical activity on abdominal fat: a systematic review of the literature. Kay SJ(1), Fiatarone Singh MA. Author information: (1)School of Exercise and Sport Science, University of Sydney, Faculty of Health Sciences, Cumberland Campus, East Street, Lidcombe, NSW 2141, Australia. mkay3363@mail.usyd.edu.au The relationship between excess abdominal adipose tissue, metabolic and cardiovascular health risk has stimulated interest in the efficacy of physical activity in specifically perturbing this adipose depot. The evolution of imaging techniques has enabled more direct measurement of changes in abdominal and visceral fat. The purpose of this summary was to systematically review the relationship between physical activity and abdominal fat.METHODS: Database searches were performed on MEDLINE, CINAHL, SPORT DISCUS and PUBMED, from 1985 to 2005 with keywords "exercise", "abdominal fat" and "visceral fat". RESULTS: Nineteen randomized controlled trials (RCTs) and eight non-randomized controlled trials were selected. In RCTs using imaging techniques to measure change in abdominal fat in overweight or obese subjects, seven out of 10 studies (including three trials with type 2 diabetics) reported significant reductions compared with controls. Reductions in visceral and total abdominal fat may occur in the absence of changes in body mass and waist circumference. Waist-to-hip ratio is not a sensitive measure of change in regional adiposity in exercise studies. No studies fulfil the Consolidated Standards of Reporting Trials (CONSORT) statement's criteria for the highest quality of randomized trial; however, many studies were in progress or published before the opportunity to comply with these recommendations. Therefore, limited evidence from a number of studies suggests a beneficial influence of physical activity on reduction in abdominal and visceral fat in overweight and obese subjects when imaging techniques are used to quantify changes in abdominal adiposity. More rigorous studies are needed to confirm these observations. PMID: 16629874 [PubMed - indexed for MEDLINE] 3419. Arterioscler Thromb Vasc Biol. 2006 May;26(5):968-76. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Poirier P(1), Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH. Author information: (1)Quebec Heart and Lung Institute, Sainte-Foy, Canada. paul.poirier@crhl.ulaval.ca Obesity is becoming a global epidemic in both children and adults, and it is associated with numerous co-morbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, is an independent risk factor for CVD and CVD risks have been also documented in obese children, and is associated with reduced life expectancy. A variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amount. As a whole, overweight/obesity predispose or is associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death through its impact on the cardiovascular system. PMID: 16627822 [PubMed - indexed for MEDLINE] 3420. Growth Horm IGF Res. 2006 Jul;16 Suppl A:S55-61. Epub 2006 Apr 18. Impact of treatment with recombinant human GH and IGF-I on visceral adipose tissue and glucose homeostasis in adults. Yuen KC(1), Dunger DB. Author information: (1)Division of Endocrinology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L607 Portland, OR 97239-3098, USA. yuenk@ohsu.edu Supraphysiological doses of growth hormone (GH) therapy are generally thought to antagonize the effects of insulin, whereas the insulin-like growth factor I (IGF-I) potentiates insulin-like actions. Paradoxically, adults with GH deficiency and patients with acromegaly are both predisposed to glucose intolerance and insulin resistance; however, one cannot extrapolate from these pathological conditions to determine the true metabolic roles of GH and IGF-I in glucose homeostasis. Growth hormone also promotes lipolysis, which has been shown to be the principal determinant of its insulin-antagonistic properties; on the other hand, IGF-I, which acts as an insulin sensitizer, does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is evident only after feeding, when the bioavailability of circulating IGF-I is increased. In contrast to supraphysiological GH doses, low doses of GH treatment have been shown to increase circulating IGF-I levels and IGF-I bioavailability and, thus, may theoretically enhance insulin sensitivity without inducing lipolysis. We have recently reported that a fixed administration of a very low GH dose (1.7 microg/kg/day or 0.1mg/day) improved insulin sensitivity in adults with GH deficiency and increased peripheral glucose uptake in subjects with impaired glucose tolerance and the metabolic syndrome. Our data raise the possibility that this very low GH dose may play a role in maintaining beta-cell function and possibly delay the progression to type 2 diabetes in these high-risk patients. PMID: 16624605 [PubMed - indexed for MEDLINE] 3421. Growth Horm IGF Res. 2006 Jul;16 Suppl A:S62-7. Epub 2006 Apr 18. Visceral obesity, impaired glucose tolerance, metabolic syndrome, and growth hormone therapy. Attallah H(1), Friedlander AL, Hoffman AR. Author information: (1)Department of Medicine, Wayne State University, Detroit, MI, USA. Overweight adults with impaired glucose tolerance have a 5-10% risk of developing diabetes per year, and insulin resistance is an important cause of progression to diabetes in these individuals. Weight loss has been shown to improve insulin sensitivity and prevent or delay progression to diabetes. According to recent studies, the improvement in insulin sensitivity that occurs with weight loss is closely linked to the reduction of visceral adipose tissue (VAT), the collection of intra-abdominal adipose depots that includes omental and intrahepatic fat. After controlling for BMI, whole body fat, and subcutaneous fat, only VAT is an independent predictor of endogenous insulin sensitivity and glucose tolerance before or after weight loss. This, in turn, suggests that reducing VAT is crucial to improving insulin sensitivity and preventing diabetes in high-risk individuals. Recombinant human growth hormone (GH) is a lipolytic drug that reduces total body, abdominal, and visceral fat in growth hormone-deficient (GHD) adults. Several studies have reported substantial reductions in VAT following GH treatment in this population. Like GHD adults, abdominally obese individuals have increased VAT, insulin resistance, and growth hormone levels that are below normal during continuous 24-h monitoring. These similarities have prompted a number of recent investigations in abdominally obese adults that reported significant reductions in truncal and visceral fat and an improvement in insulin sensitivity following prolonged GH administration. However, other studies have shown that insulin resistance and glucose concentrations transiently worsen during the first few weeks of GH treatment and that these deleterious effects can persist even after VAT reduction has occurred. Prior studies involving GH treatment were generally limited to adults who were normoglycemic at baseline. Less is known about the effects of GH in adults with impaired glucose tolerance or diabetes. The effects of GH used in conjunction with insulin sensitizers on glycemic control and VAT in patients with impaired glucose tolerance will be reviewed. PMID: 16624603 [PubMed - indexed for MEDLINE] 3422. Endocrine. 2006 Feb;29(1):101-8. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity. Wake DJ(1), Walker BR. Author information: (1)University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh EH16 4TJ. Excessive glucocorticoid exposure (Cushing's syndrome) results in increased adiposity associated with dysmetabolic features (including insulin resistance, hyperlipidaemia, and hypertension). Circulating cortisol levels are not elevated in idiopathic obesity, although cortisol production and clearance are increased. However, tissue glucocorticoid exposure may be altered independently of circulating levels by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme which generates active glucocorticoid within tissues, including in adipose tissue. Transgenic overexpression of 11HSD1 in mice causes obesity. In human obesity, 11HSD1 is altered in a tissue-specific manner with reduced levels in liver but elevated levels in adipose, which may lead to glucocorticoid receptor activation and contribute to the metabolic phenotype. The reasons for altered 11HSD1 in obesity are not fully understood. Although some polymorphisms have been demonstrated in intronic and upstream regions of the HSD11B1 gene, the functional significance of these is not clear. In addition, there is mounting evidence that 11HSD1 may be dysregulated secondarily to factors that are altered in obesity, including substrates for metabolism, hormones, and inflammatory mediators. 11HSD1 is a potential therapeutic target for the treatment of the metabolic syndrome. 11HSD1 knockout mice are protected from diet-induced obesity and associated metabolic dysfunction. Although many specific inhibitors of 11HSD1 have now been developed, and published data support their efficacy in the liver to reduce glucose production, their efficacy in enhancing insulin sensitivity in adipose tissue remains uncertain. The therapeutic potential of 11HSD1 in human obesity therefore remains highly promising but as yet unproven. PMID: 16622297 [PubMed - indexed for MEDLINE] 3423. Endocrine. 2006 Feb;29(1):81-90. Adipocyte-derived hormones, cytokines, and mediators. Rondinone CM(1). Author information: (1)Department Metabolic Diseases, Hoffmann-La Roche, Nutley, New Jersey 07110, USA. cristina.rondinone@roche.com Adipose tissue is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. These secreted proteins, which include tumor necrosis factor (TNF)-alpha, resistin, IL-6, IL-8, acylation-stimulating protein (ASP), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1) ("bad" adipokines) and leptin, adiponectin ("good" adipokines) seem to play important regulatory roles in a variety of complex processes, including fat metabolism, feeding behavior, hemostasis, vascular tone, energy balance, and insulin sensitivity, but none is without controversy regarding its respective mechanism and scope of action. The present review is focused on the effects of free fatty acids and a restricted number of adipokines, which have been implicated in vascular (angiotensinogen, PAI-1) and energy and glucose homeostasis (ASP, TNFalpha, IL-6, resistin, leptin, adiponectin). PMID: 16622295 [PubMed - indexed for MEDLINE] 3424. Hormones (Athens). 2005 Oct-Dec;4(4):189-199. Obesity in childhood and adolescence: a review in the interface between adipocyte physiology and clinical challenges. Körner A(1), Blüher S, Kapellen T, Garten A, Klammt J, Kratzsch J, Kiess W. Author information: (1)Hospital for Children and Adolescents, University of Leipzig, Oststr. 21-25, D 04317 Leipzig, Germany. Body weight is regulated by a feedback loop in which peripheral signals report nutritional information to an integratory center in the brain. The cloning of the ob gene is consistent with this concept and suggests that body fat content in adult rodents is regulated by a negative feedback loop centered in the hypothalamus. In recent years a number of additional signaling molecules secreted by adipose tissue have been discovered. These hormones, named adipocytokines, include resistin, adiponectin, and visfatin. Among the adipocytokines, adiponectin is perhaps the most interesting compound for the clinician since low adiponectin serum levels have been found in obese subjects and in particular in insulin resistant subjects. The definition and diagnosis of obesity in children and adolescents are surprisingly difficult. The level of fatness at which morbidity increases is determined on an acturial basis. In children and adolescents the degree of body fat mass depends upon ethnic background , gender, developmental stage, and age. Treatment and prevention of obesity in childhood and adolescence are major challenges for today's health care providers and societies. PMID: 16613817 [PubMed - indexed for MEDLINE] 3425. Eur Cytokine Netw. 2006 Mar;17(1):4-12. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Bastard JP(1), Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Author information: (1)Inserm U680, Faculté de Médecine Pierre et Marie Curie, site Saint-Antoine, Université Pierre et Marie Curie, Paris 6 et Service de Biochimie et Hormonologie, Hôpital Tenon, AP-HP, 75970 Paris cedex 20, France. jean-philippe.bastard@tnn.ap-hop-paris.fr It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance. PMID: 16613757 [PubMed - indexed for MEDLINE] 3426. J Hypertens. 2006 May;24(5):789-801. Role of leptin in blood pressure regulation and arterial hypertension. Bełtowski J(1). Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@am.lublin.pl Leptin is a 16-kDa protein secreted by white adipose tissue that is primarily involved in the regulation of food intake and energy expenditure. Plasma leptin concentration is proportional to the amount of adipose tissue and is markedly increased in obese individuals. Recent studies suggest that leptin is involved in cardiovascular complications of obesity, including arterial hypertension. Acutely administered leptin has no effect on blood pressure, probably because it concomitantly stimulates the sympathetic nervous system and counteracting depressor mechanisms such as natriuresis and nitric oxide (NO)-dependent vasorelaxation. By contrast, chronic hyperleptinemia increases blood pressure because these acute depressor effects are impaired and/or additional sympathetic nervous system-independent pressor effects appear, such as oxidative stress, NO deficiency, enhanced renal Na reabsorption and overproduction of endothelin. Although the cause-effect relationship between leptin and high blood pressure in humans has not been demonstrated directly, many clinical studies have shown elevated plasma leptin in patients with essential hypertension and a significant positive correlation between leptin and blood pressure independent of body adiposity both in normotensive and in hypertensive individuals. In addition, leptin may contribute to end-organ damage in hypertensive individuals such as left ventricular hypertrophy, retinopathy and nephropathy, independent of regulating blood pressure. Here, current knowledge about the role of leptin in the regulation of blood pressure and in the pathogenesis of arterial hypertension is presented. PMID: 16612235 [PubMed - indexed for MEDLINE] 3427. Horm Res. 2006;65 Suppl 3:137-43. Epub 2006 Apr 10. Metabolic aspects of insulin resistance in individuals born small for gestational age. Vaag A(1), Jensen CB, Poulsen P, Brøns C, Pilgaard K, Grunnet L, Vielwerth S, Alibegovic A. Author information: (1)Steno Diabetes Centre, Gentofte, Denmark. Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19-23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-zeta, the two subunits of phosphoinositol 3-kinase (i.e., p85alpha and p110beta) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association. Copyright 2006 S. Karger AG, Basel. PMID: 16612127 [PubMed - indexed for MEDLINE] 3428. Horm Res. 2006;65 Suppl 3:123-30. Epub 2006 Apr 10. Small for gestational age and the metabolic syndrome: which mechanism is suggested by epidemiological and clinical studies? Lévy-Marchal C(1), Czernichow P. Author information: (1)INSERM Units 457 and 690, Robert Debré Hospital, Paris, France. clairelm@rdebre.inserm.fr The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk of development of cardiovascular diseases, the insulin-resistance syndrome or one of its components (i.e., hypertension, dyslipidaemia, impaired glucose tolerance and type 2 diabetes). Insulin resistance appears to be a key component underlying these metabolic complications. Although the mechanism remains unclear, several pieces of evidence support an active role of adipose tissue in the emergence of insulin resistance (an abnormal growth pattern and repartition, hypersensitivity to catecholamines, regulation of leptin and adiponectin secretion and modulation of peroxisome proliferator-activated receptor gamma). Among individuals born SGA, those who are more at risk of gaining excess adiposity are those who are thin at birth following a period of fetal growth restriction. This period of undernutrition is followed by a neonatal period of catch-up growth and renutrition. This pattern induces important modifications in adipose tissue, with long-term consequences, among which is a high risk of early development of insulin resistance. Not all individuals born SGA will show such modifications in adipose tissue, meaning that not all of those born SGA are at risk of insulin resistance and diabetes. From a broader point of view, several hypotheses have been proposed over the past 10 years to explain this unexpected association between being born SGA and the later development of disease. Each of them points to a detrimental fetal environment, to a genetic susceptibility or to interactions between these two components playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains the most attractive. Copyright 2006 S. Karger AG, Basel. PMID: 16612125 [PubMed - indexed for MEDLINE] 3429. Horm Res. 2006;65 Suppl 3:90-7. Epub 2006 Apr 10. Regulation of fat storage via suppressed thermogenesis: a thrifty phenotype that predisposes individuals with catch-up growth to insulin resistance and obesity. Dulloo AG(1). Author information: (1)Department of Medicine, Division of Physiology, University of Fribourg, Switzerland. abdul.dulloo@unifr.ch Catch-up growth during infancy and childhood is increasingly recognized as a major risk factor for later development of insulin-related complications and chronic diseases, namely abdominal obesity, type 2 diabetes and cardiovascular disease. As catch-up growth per se is characterized by insulin resistance, hyperinsulinaemia and an accelerated rate of fat storage (i.e., catch-up fat) even in the absence of hyperphagia, the possibility arises that suppressed thermogenesis in certain organs/tissues - for the purpose of enhancing the efficiency of catch-up fat - also plays a role in the pathophysiological consequences of catch-up growth. Here, the evidence for the existence of an adipose-specific control of thermogenesis, the suppression of which contributes to catch-up fat, is reviewed. Recent findings suggest that such suppression of thermogenesis is accompanied by hyperinsulinaemia, insulin resistance in skeletal muscle and insulin hyperresponsiveness in adipose tissue, all of which precede the appearance of excess body fat, central fat distribution and elevations in intramyocellular triglyceride or circulating lipid concentrations. These findings underscore a role for suppressed thermogenesis per se as an early event in the pathophysiology of catch-up growth. It is proposed that, in its evolutionary adaptive role to spare glucose for the rapid rebuilding of an adequate fat reserve (for optimal survival capacity during intermittent famine), suppressed thermogenesis in skeletal muscle constitutes a thrifty phenotype that confers to the phase of catch-up growth its high sensitivity to the development of insulin resistance and hyperinsulinaemia. In the context of the complex interactions between earlier reprogramming and a modern lifestyle characterized by nutritional abundance and low physical activity, this thrifty 'catch-up fat phenotype' is a central event that predisposes individuals with catch-up growth to abdominal obesity, type 2 diabetes and cardiovascular disease. Copyright 2006 S. Karger AG, Basel. PMID: 16612120 [PubMed - indexed for MEDLINE] 3430. Horm Res. 2006;65 Suppl 3:59-64. Epub 2006 Apr 10. Maternal lipid metabolism and placental lipid transfer. Herrera E(1), Amusquivar E, López-Soldado I, Ortega H. Author information: (1)Department of Biochemistry, Molecular and Cellular Biology, University San Pablo-CEU, Madrid, Spain. eherrera@ceu.es During early pregnancy, long-chain polyunsaturated fatty acids (LC-PUFA) may accumulate in maternal fat depots and become available for placental transfer during late pregnancy, when the fetal growth rate is maximal and fetal requirements for LC-PUFAs are greatly enhanced. During this late part of gestation, enhanced lipolytic activity in adipose tissue contributes to the development of maternal hyperlipidaemia; there is an increase in plasma triacylglycerol concentrations, with smaller rises in phospholipid and cholesterol concentrations. Besides the increase in plasma very-low-density lipoprotein, there is a proportional enrichment of triacylglycerols in both low-density lipoproteins and high-density lipoproteins. These lipoproteins transport LC-PUFA in the maternal circulation. The presence of lipoprotein receptors in the placenta allows their placental uptake, where they are hydrolysed by lipoprotein lipase, phospholipase A(2) and intracellular lipase. The fatty acids that are released can be metabolized and diffuse into the fetal plasma. Although present in smaller proportions, maternal plasma non-esterified fatty acids are also a source of LC-PUFA for the fetus, their placental transfer being facilitated by the presence of a membrane fatty acid-binding protein. There is very little placental transfer of glycerol, whereas the transfer of ketone bodies may become quantitatively important under conditions of maternal hyperketonaemia, such as during fasting, a high-fat diet or diabetes. The demands for cholesterol in the fetus are high, but whereas maternal cholesterol substantially contributes to fetal cholesterol during early pregnancy, fetal cholesterol biosynthesis rather than cholesterol transfer from maternal lipoproteins seems to be the main mechanism for satisfying fetal requirements during late pregnancy. Copyright 2006 S. Karger AG, Basel. PMID: 16612115 [PubMed - indexed for MEDLINE] 3431. Hokkaido Igaku Zasshi. 2006 Mar;81(2):95-9. [To know is to relieve; "lifestyle-related diseases"; as they are now and how to prevent them]. [Article in Japanese] Yoshioka N(1), Yoshioka M, Furuta Y, Asaka M. Author information: (1)Immunology and Metabolism, Hokkaido University Graduate School of Medicine, Sapporo 060-8538, Japan. Hypertension, diabetes mellitus, hyperlipidemia and obesity have recently defined as lifestyle-related diseases. A common background of these lifestyle-related disease is nutritional excess and its consequence, obesity. Recent advances in the biology of adipose tissue have revealed that adipose is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Dysregulation in the secretion of these adipose-specific secretory proteins may have important roles in the lifestyle-related diseases. It may be a great concern for many people to know about lifestyle-related diseases and how to manage and prevent them. The purpose of this citizen joint symposium is to broaden citizen's knowledge on the mechanism and appropriate management of lifestyle-related disease. We hope that this symposium provide useful informations to the participants about the current information in the management of lifestyle-related diseases. PMID: 16607881 [PubMed - indexed for MEDLINE] 3432. Nurse Pract. 2006 Apr;31(4):29-37, quiz 37-9. A physical activity Rx for the hypertensive patient. Frost KL(1), Topp R. Author information: (1)School of Nursing, University of Louisville, Louisville, KY, USA. Comment in Nurse Pract. 2006 Apr;31(4):6. PMID: 16607209 [PubMed - indexed for MEDLINE] 3433. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005 Dec;149(2):237-41. The metabolic syndrome: relationship between insulin sensitivity and the role of peroxisome proliferator-activated receptors (PPARs) in saccharide and lipid metabolism. Yahia RB(1), Lichnovská R, Brychta T. Author information: (1)Institute of Physiology, Palacký University, 775 15 Olomouc, Czech Republic. yahiarab@yahoo.com Peroxisome proliferator-activated receptors (PPARs) are subgroups of nuclear hormonal receptors of transcripting factors mostly found in adipose tissue. They are described as important regulators of lipid and saccharide metabolism including insulin sensitivity; therefore they are taken as marker of metabolic syndrome. Their synthetic ligands could be used as drugs for insulin resistance and type 2 diabetes mellitus. PMID: 16601762 [PubMed - indexed for MEDLINE] 3434. Curr Opin Cardiol. 2006 May;21(3):159-65. Lamin A/C and cardiac diseases. Sylvius N(1), Tesson F. Author information: (1)University of Ottawa Heart Institute, Ottawa, Ontario, Canada. PURPOSE OF REVIEW: In this review, we will outline the most recent and significant findings on the role of the lamin A/C in cardiac diseases. RECENT FINDINGS: Mutations in the lamin A/C gene (LMNA) are associated with numerous diseases involving the heart, skeletal muscles, bones, adipose and nervous tissues. LMNA is one of the most prevalent genes in dilated cardiomyopathy in which it is associated with a high risk of dysrhythmias, sudden death and heart failure. Lamins A and C interact with several proteins reflecting their multiple functions, some of which are likely still unknown. No abnormalities specific to dilated cardiomyopathy are emerging from investigations of striated muscles biopsies or fibroblasts from LMNA mutation carriers. An early diagnosis of the disease is difficult. Both animal and cellular models tend to confirm that lamins A and C play a key role in maintaining the nuclear architecture as well as in regulating transcription. SUMMARY: The cardiac phenotype associated to LMNA mutations is now much clearer, but the molecular mechanisms underlying cellular and tissue specific phenotypes are still puzzling. Systematic mutation screenings and cardioverter-defibrillator implantation have been recommended in patients with cardiac symptoms. PMID: 16601451 [PubMed - indexed for MEDLINE] 3435. Physiol Rev. 2006 Apr;86(2):435-64. Thermogenic mechanisms and their hormonal regulation. Silva JE(1). Author information: (1)Baystate Medical Education and Research Foundation, Department of Medicine, Division of Endocrinology, Baystate Medical Center, Tufts University Medical School, Springfield, Massachusetts, USA. enrique.silva@bhs.org Increased heat generation from biological processes is inherent to homeothermy. Homeothermic species produce more heat from sustaining a more active metabolism as well as from reducing fuel efficiency. This article reviews the mechanisms used by homeothermic species to generate more heat and their regulation largely by thyroid hormone (TH) and the sympathetic nervous system (SNS). Thermogenic mechanisms antecede homeothermy, but in homeothermic species they are activated and regulated. Some of these mechanisms increase ATP utilization (same amount of heat per ATP), whereas others increase the heat resulting from aerobic ATP synthesis (more heat per ATP). Among the former, ATP utilization in the maintenance of ionic gradient through membranes seems quantitatively more important, particularly in birds. Regulated reduction of the proton-motive force to produce heat, originally believed specific to brown adipose tissue, is indeed an ancient thermogenic mechanism. A regulated proton leak has been described in the mitochondria of several tissues, but its precise mechanism remains undefined. This leak is more active in homeothermic species and is regulated by TH, explaining a significant fraction of its thermogenic effect. Homeothermic species generate additional heat, in a facultative manner, when obligatory thermogenesis and heat-saving mechanisms become limiting. Facultative thermogenesis is activated by the SNS but is modulated by TH. The type II iodothyronine deiodinase plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulating the responses to SNS. Other hormones affect thermogenesis in an indirect or permissive manner, providing fuel and modulating thermogenesis depending on food availability, but they do not seem to have a primary role in temperature homeostasis. Thermogenesis has a very high energy cost. Cold adaptation and food availability may have been conflicting selection pressures accounting for the variability of thermogenesis in humans. PMID: 16601266 [PubMed - indexed for MEDLINE] 3436. Curr Hypertens Rep. 2006 Apr;8(1):30-4. Fat tissue metabolism and adrenal steroid secretion. Lamounier-Zepter V(1), Ehrhart-Bornstein M. Author information: (1)Medical Clinic III, Technical University of Dresden, MTZ, room B.00.002, Fetscherstrasse 74, 01307 Dresden, Germany. Obesity has reached epidemic proportions in Western societies, contributing to metabolic diseases, hypertension, and vascular diseases. White adipose tissue has traditionally been regarded merely as lipid, and consequently, as energy storage. However, recent data revealed the importance of adipose tissue as a highly active endocrine organ and its involvement in the body's metabolism and homeostasis. Obesity is associated with several endocrine disorders, including adrenocortical malfunction. Because of the central role of adrenal function in the body's homeostasis, adrenal malfunction is important in the development of other obesity-related abnormalities. Therefore, in this short review, we summarize recent data on obesity-induced changes in adrenocortical mineralocorticoid, glucocorticoid, and androgen secretions and their consequences for metabolism. PMID: 16600157 [PubMed - indexed for MEDLINE] 3437. Med Sci (Paris). 2005 Dec;21 Spec No:40-3. [Gluco-incretin hormones in insulin secretion]. [Article in French] Thorens B(1). Author information: (1)Institut de Physiologie, Suisse. Bernard.Thorens@ipharm.unil.ch Nutrient ingestion triggers a complex hormonal response aimed at stimulating glucose utilization in liver, muscle and adipose tissue to minimize the raise in blood glucose levels. Insulin secretion by pancreatic beta cells plays a major role in this response. Although the beta cell secretary response is mainly controlled by blood glucose levels, gut hormones secreted in response to food intake have an important role in potentiating glucose-stimulated insulin secretion. These gluco-incretin hormones are GLP-1 (glucagon-like peptide-1) and GIP (gluco-dependent insulinotropic polypeptide). Their action on pancreatic beta cells depends on binding to specific G-coupled receptors linked to activation of the adenylyl cyclase pathway. In addition to their effect on insulin secretion both hormones also stimulate insulin production at the transcriptional and translational level and positively regulate beta cell mass. Because the glucose-dependent insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide is now developed as a novel therapeutic drug for this disease. PMID: 16598904 [PubMed - indexed for MEDLINE] 3438. Med Sci (Paris). 2005 Dec;21 Spec No:34-9. [Insulin signaling: mechanisms altered in insulin resistance]. [Article in French] Capeau J(1). Author information: (1)Faculté de médecine Saint-Antoine, Université Pierre-et-Marie-Curie, 27, rue Chaligny, 75571 Paris Cedex 12, Paris, France. capeau@st-antoine.inserm.fr Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome. PMID: 16598903 [PubMed - indexed for MEDLINE] 3439. Med Sci (Paris). 2005 Dec;21 Spec No:29-33. [Natriuretic peptides: a new lipolytic pathway in human fat cells]. [Article in French] Sengenes C(1), Moro C, Galitzky J, Berlan M, Lafontan M. Author information: (1)Unité de recherches sur les obésités, Inserm U.586, Institut Louis Bugnard, CHU de Toulouse, TSA50032, 31059 Toulouse Cedex 9, France. Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity. PMID: 16598902 [PubMed - indexed for MEDLINE] 3440. Med Sci (Paris). 2005 Dec;21 Spec No:10-8. [Adipocytokins, obesity and development of type 2 diabetes]. [Article in French] Lacquemant C(1), Vasseur F, Leprêtre F, Froguel P. Author information: (1)Hammersmith Genome Centre, Imperial College, Londres, Royaume-Uni. Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin. PMID: 16598899 [PubMed - indexed for MEDLINE] 3441. Med Sci (Paris). 2005 Dec;21 Spec No:3-9. [Impact of obesity in contemporary cardiology]. [Article in French] Poirier P(1), Després JP. Author information: (1)Institut universitaire de cardiologie et de pneumologie, Centre de recherche de I'Hôpital Laval, 2725, chemin Sainte-Foy, Sainte-Foy;-Québec, G1V 4G5, Canada. Paul.Poirier@crhl.ulaval.ca Available evidence clearly indicates a rapid progression in the prevalence of obesity worldwide. As a consequence, there has also been a marked increase in the prevalence of type 2 diabetes all over the world and this chronic metabolic disease is now considered as a coronary heart disease risk equivalent. However, even in the absence of the hyperglycaemic state which characterizes type 2 diabetic patients, non diabetic individuals with a specific form of obesity, named abdominal obesity, often show clustering metabolic abnormalities which include high triglyceride levels, increased apolipoprotein B, small dense low dendity lipoproteins and decreased high density lipoproteins-cholesterol levels, a hyperinsulinemic-insulin resistant state, alterations in coagulation factors as well as an inflammatory profile. This agglomeration of abnormalities has been referred to as the metabolic syndrome which can be identified by the presence of three of the five following variables: abdominal obesity, elevated triglyceride concentrations, low HDL-cholesterol levels, increased blood pressure and elevated fasting glucose. Post-mortem analyses of coronary arteries have indicated that obesity (associated with a high accumulation of abdominal fat measured at autopsy) was predictive of earlier and greater extent of large vessels atherosclerosis as well as increase of coronary fatty streaks. Metabolic syndrome linked to abdominal obesity is also predictive of recurrent coronary events both in post-myocardial infarction patients and among coronary artery disease men who underwent a revascularization procedures. It is suggested that until the epidemic progression of obesity is stopped and obesity prevented or at least properly managed, cardiologists will be confronted to an evolving contribution of risk factors where smoking, hypercholesterolemia and hypertension may be relatively less prevalent but at the expense of a much greater contribution of abdominal obesity and related features of the metabolic syndrome. PMID: 16598898 [PubMed - indexed for MEDLINE] 3442. Biochim Biophys Acta. 2006 May-Jun;1757(5-6):480-5. Epub 2006 Mar 6. Mitochondrial UCPs: new insights into regulation and impact. Sluse FE(1), Jarmuszkiewicz W, Navet R, Douette P, Mathy G, Sluse-Goffart CM. Author information: (1)Laboratory of Bioenergetics, Department of Life Sciences, Institute of Chemistry B6c, University of Liège, Sart Tilman, B-4000 Liege, Belgium. f.sluse@ulg.ac.be Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins sustaining an inducible proton conductance. They weaken the proton electrochemical gradient built up by the mitochondrial respiratory chain. Brown fat UCP1 sustains a free fatty acid (FA)-induced purine nucleotide (PN)-inhibited proton conductance. Inhibition of the proton conductance by PN has been considered as a diagnostic of UCP activity. However, conflicting results have been obtained in isolated mitochondria for UCP homologues (i.e., UCP2, UCP3, plant UCP, and protist UCP) where the FFA-activated proton conductance is poorly sensitive to PN under resting respiration conditions. Our recent work clearly indicates that the membranous coenzyme Q, through its redox state, represents a regulator of the inhibition by PN of FFA-activated UCP1 homologues under phosphorylating respiration conditions. Several physiological roles of UCPs have been suggested, including a control of the cellular energy balance as well as the preventive action against oxidative stress. In this paper, we discuss new information emerging from comparative proteomics about the impact of UCPs on mitochondrial physiology, when recombinant UCP1 is expressed in yeast and when UCP2 is over-expressed in hepatic mitochondria during steatosis. PMID: 16597432 [PubMed - indexed for MEDLINE] 3443. Handb Exp Pharmacol. 2005;(170):591-617. Correction of insulin resistance and the metabolic syndrome. Müller-Wieland D(1), Kotzka J. Author information: (1)Deutsches Diabetes-Zentrum, Institut für Klinische Biochemie und Pathobiochemie, Düsseldorf, Germany. mueller-wieland@ddfi.uni-duesseldorf.de Insulin resistance is a common phenomenon of the metabolic syndrome, which is clinically characterized by a clustering of various cardiovascular risk factors in a single individual and a higher prevalence of respective complications, such as coronary heart disease and stroke. At the cellular level, insulin resistance is defined as a reduced insulin action, which can affect not only glucose uptake, but also gene regulation. Elucidation of novel signaling networks within the cell which are mediating and affecting insulin action will reveal many new genes and drug targets that are potentially of clinical relevance in the future. In this chapter, we propose that the metabolic syndrome might be a clinical consequence of altered gene regulation. This is illuminated in the context of transcription factors, e.g., sterol regulatory element binding proteins (SREBPs), coupling signals from nutrients, metabolites, and hormones at the gene regulatory level with pathobiochemical features of increased lipid accumulation in lean nonadipose tissues. The phenomenon of ectopic lipid accumulation (lipotoxicity) appears to be a novel link between insulin resistance, obesity, and possibly other features of the metabolic syndrome. Therefore, the investigation of specific gene regulatory networks and their alterations might be a clue to understanding the development and clustering of different cardiovascular risk factors in different individuals. As cellular sensors transcription factors--as common denominators of gene regulatory networks--might thereby also determine the susceptibility of individuals to cardiovascular risk factors and their complications. PMID: 16596816 [PubMed - indexed for MEDLINE] 3444. Handb Exp Pharmacol. 2005;(170):137-63. Physical activity, obesity and cardiovascular diseases. Lakka TA(1), Bouchard C. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808-4124, USA. Sedentary lifestyle and overweight are major public health, clinical, and economical problems in modern societies. The worldwide epidemic of excess weight is due to imbalance between physical activity and dietary energy intake. Sedentary lifestyle, unhealthy diet, and consequent overweight and obesity markedly increase the risk of cardiovascular diseases. Regular physical activity 45-60 min per day prevents unhealthy weight gain and obesity, whereas sedentary behaviors such as watching television promote them. Regular exercise can markedly reduce body weight and fat mass without dietary caloric restriction in overweight individuals. An increase in total energy expenditure appears to be the most important determinant of successful exercise-induced weight loss. The best long-term results may be achieved when physical activity produces an energy expenditure of at least 2,500 kcal/week. Yet, the optimal approach in weight reduction programs appears to be a combination of regular physical activity and caloric restriction. A minimum of 60 min, but most likely 80-90 min of moderate-intensity physical activity per day may be needed to avoid or limit weight regain in formerly overweight or obese individuals. Regular moderate intensity physical activity, a healthy diet, and avoiding unhealthy weight gain are effective and safe ways to prevent and treat cardiovascular diseases and to reduce premature mortality in all population groups. Although the efforts to promote cardiovascular health concern the whole population, particular attention should be paid to individuals who are physically inactive, have unhealthy diets or are prone to weight gain. They have the highest risk for worsening of the cardiovascular risk factor profile and for cardiovascular disease. To combat the epidemic of overweight and to improve cardiovascular health at a population level, it is important to develop strategies to increase habitual physical activity and to prevent overweight and obesity in collaboration with communities, families, schools, work sites, health care professionals, media and policymakers. PMID: 16596798 [PubMed - indexed for MEDLINE] 3445. Wiad Lek. 2005;58(11-12):670-4. [The role of tumor necrosis factor (TNF-alpha) in control of metabolism]. [Article in Polish] Olszanecka-Glinianowicz M(1), Zahorska-Markiewicz B, Zurakowski A, Glinianowicz M. Author information: (1)Katedry Patofizjologii Sla,skiej Akademii Medycznej, Katowicach. magols@esculap.pl Tumor necrosis factor is multifunctional cytokine involved in various cell functions, such as differentiation, mitosis, angiogenesis, inflammation and immune controls. TNF-alpha plays also an important role in the control of metabolism. Its action on adipocytes includes increasing secretion of triglicerydes and inhibiting insulin action, controlling expression of some genes and modulating free fatty acid and leptin secretion. The review of the current literature on the TNF-alpha role in metabolism is presented in this paper. PMID: 16594480 [PubMed - indexed for MEDLINE] 3446. Clin Endocrinol (Oxf). 2006 Apr;64(4):355-65. The endocrine function of adipose tissue: an update. Ronti T(1), Lupattelli G, Mannarino E. Author information: (1)Internal Medicine, Angiology and Atherosclerosis, Department of Clinical and Experimental Medicine, University of Perugia, Italy. Adipose tissue secretes bioactive peptides, termed 'adipokines', which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-alpha and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients. PMID: 16584505 [PubMed - indexed for MEDLINE] 3447. J Anim Sci. 2006 Apr;84 Suppl:E94-104. Stable isotope methods for the in vivo measurement of lipogenesis and triglyceride metabolism. Murphy EJ(1). Author information: (1)Department of Medicine, University of California, San Francisco, CA 94110, USA. emurphy@kinemed.com Synthesis of fatty acids (via de novo lipogenesis) and triglycerides are important factors in fat accumulation and the efficiency of animal production. Recently, new stable isotope methods using heavy water (2H2O) have made possible the safe, and relatively easy, measurement of both of these processes in vivo in animals and humans over prolonged periods. These methods also provide information on the relative contribution of glycolysis and glyceroneogenesis to triglyceride synthesis under different physiological settings. The data suggest that numerous dietary factors, including nutrient composition and caloric content, may affect de novo lipogenesis. Significant differences in de novo lipogenesis have also been seen across species and in different tissues. The rates of triglyceride synthesis have been shown to be affected by diet and to differ significantly between different adipose depots, with metabolically active depots (e.g., visceral fat) having much more rapid triglyceride turnover than subcutaneous depots. Dietary fat and the peroxisome proliferator-activated-gamma agonist rosiglitazone have both been shown to influence triglyceride synthesis rates and to increase glyceroneogenesis. A significant portion of triglyceride synthesis is not related to triglyceride accumulation but rather is secondary to active lipolysis and reesterification. The application of these new techniques to animals other than rodents will undoubtedly enhance our understanding of adipose tissue biology and could lead to new methods for improving animal production. PMID: 16582096 [PubMed - indexed for MEDLINE] 3448. Atherosclerosis. 2006 Oct;188(2):231-44. Epub 2006 Apr 3. Adiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease. Gable DR(1), Hurel SJ, Humphries SE. Author information: (1)Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free & UCL Medical School, The Rayne Institute, 5 University Street, London WC1E 6JF, United Kingdom. d.gable@ucl.ac.uk The increasing prevalence of obesity and metabolic syndrome/insulin resistance has attracted considerable interest due to their identification as risk factors for cardiovascular disease and, hence, targets for cardiovascular disease prevention. This review focuses on adiponectin, the most profusely secreted protein from adipose tissue, which itself is being increasingly recognised as an important and very active endocrine organ, secreting a wide range of biologically active substances known as adipokines or adipocytokines. Adiponectin has been demonstrated to have insulin sensitising effects, and secretion of adiponectin is reduced as adipose tissue mass increases. Adiponectin has also been demonstrated to have anti-inflammatory and anti-atherogenic properties, and is independently associated with cardiovascular disease. The evidence that suggests adiponectin plays a role in the relationship between obesity and insulin resistance, and also insulin resistance and cardiovascular disease, is examined. Variation in the adiponectin gene is one tool to determine whether this relationship is causal. The association of identified variants with human disease, specifically obesity and its consequences, type 2 diabetes and cardiovascular disease is reviewed. This data may enable patients at greater risk of the adverse effects of obesity to be identified and, as such, benefit from more targeted therapy of its consequences. PMID: 16581078 [PubMed - indexed for MEDLINE] 3449. Atherosclerosis. 2006 Nov;189(1):47-60. Epub 2006 Apr 3. Leptin and atherosclerosis. Beltowski J(1). Author information: (1)Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland. jerzy.beltowski@am.lublin.pl Leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Leptin receptors are expressed in many tissues including the cardiovascular system. Plasma leptin concentration is proportional to body adiposity and is markedly increased in obese individuals. Recent studies suggest that hyperleptinemia may play an important role in obesity-associated cardiovascular diseases including atherosclerosis. Leptin exerts many potentially atherogenic effects such as induction of endothelial dysfunction, stimulation of inflammatory reaction, oxidative stress, decrease in paraoxonase activity, platelet aggregation, migration, hypertrophy and proliferation of vascular smooth muscle cells. Leptin-deficient and leptin receptor-deficient mice are protected from arterial thrombosis and neointimal hyperplasia in response to arterial wall injury. Several clinical studies have demonstrated that high leptin level predicts acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors. In addition, plasma leptin correlates with markers of subclinical atherosclerosis such as carotid artery intima-media thickness and coronary artery calcifications. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects. PMID: 16580676 [PubMed - indexed for MEDLINE] 3450. Biomech Model Mechanobiol. 2006 Nov;5(4):203-15. Epub 2006 Mar 31. Fractional calculus in biomechanics: a 3D viscoelastic model using regularized fractional derivative kernels with application to the human calcaneal fat pad. Freed AD(1), Diethelm K. Author information: (1)Bio Science & Technology Branch, MS 49-3, NASA's John H. Glenn Research Center at Lewis Field, 21000 Brookpark Road, Cleveland, OH 44135, USA. Alan.D.Freed@nasa.gov A viscoelastic model of the K-BKZ (Kaye, Technical Report 134, College of Aeronautics, Cranfield 1962; Bernstein et al., Trans Soc Rheol 7: 391-410, 1963) type is developed for isotropic biological tissues and applied to the fat pad of the human heel. To facilitate this pursuit, a class of elastic solids is introduced through a novel strain-energy function whose elements possess strong ellipticity, and therefore lead to stable material models. This elastic potential - via the K-BKZ hypothesis - also produces the tensorial structure of the viscoelastic model. Candidate sets of functions are proposed for the elastic and viscoelastic material functions present in the model, including two functions whose origins lie in the fractional calculus. The Akaike information criterion is used to perform multi-model inference, enabling an objective selection to be made as to the best material function from within a candidate set. PMID: 16575573 [PubMed - indexed for MEDLINE] 3451. Crit Care Resusc. 2003 Jun;5(2):109-20. Nutrition in the critically ill patient: part I. Essential physiology and pathophysiology. Atkinson M(1), Worthley LI. Author information: (1)Department of Critical Care Medicine, Flinders Medical Centre, Adelaide, South Australia. OBJECTIVE: To review the human nutrition in the critically ill patient in a three-part presentation. DATA SOURCES: Articles and published peer-review abstracts and a review of studies reported and identified through a MEDLINE search of the English language literature on parenteral nutrition. SUMMARY OF REVIEW: In a healthy individual, nutrition involves an alternating system of feeding and fasting, with periods of fasting longer than 72 hr inducing a state of starvation. The hormonal response to nutrition is substrate controlled with glucose and amino acids, during the fed state, stimulating insulin secretion and decreasing glucagon secretion. Glycogen reserves and protein synthesis increase and the excess carbohydrate, amino acids and fats are stored as lipid. During the fasted state, plasma levels of glucose and amino acids fall, reducing insulin secretion and increasing glucagon secretion, stimulating gluconeogenesis and glycogenolysis. A further reduction in insulin and increase in glucagon secretion occurs during starvation and mild sympathetic activation stimulates hormone.sensitive lipoprotein lipase to increase the release of free fatty acids (FFAs) from adipose tissue. Much of the excess FFAs are converted by the liver to ketone bodies. During injury and sepsis the nutritional hormones are no longer substrate controlled. For example, during injury, to maintain haemodynamic homeostasis, an increase in sympathetic tone and catecholamine (i.e. adrenaline and noradrenaline) secretion occurs, and in the septic state, in addition to the hormonal stress response, polypeptide mediators of tumour necrosis factor (TNF-alpha) and interleukin-1 are liberated, causing an increase in glucose intolerance and an increase in skeletal muscle protein catabolism. Optimal nutritional support in the critically ill patient can only be achieved when the patient is in the convalescent phase of injury, as nutritional supplementation will not reverse the factors causing proteolysis, gluconeogenesis or lipolysis associated with stress or sepsis. Therapy should therefore focus upon decreasing or reducing the factors causing the acute illness before nutritional supplementation can be given with benefit. CONCLUSIONS: In the critically ill patient nutritional hormones are no longer substrate controlled with glucose, amino acid and lipid intolerance often occurring when given to excess. While nutritional supplementation is often required, particularly during a prolonged illness, the influence of stress and sepsis should be minimised while the nutritional substrates are being provided. PMID: 16573469 [PubMed] 3452. Soc Biol. 2006 Spring-Summer;53(1-2):13-23. Adaptive variation in testosterone levels in response to immune activation: empirical and theoretical perspectives. Muehlenbein MP(1). Author information: (1)Department of Anthropology, Indiana University, Bloomington, IN 47405, USA. mpml@indiana.edu High testosterone levels reflect investment in male reproductive effort through the ability to produce and maintain muscle tissue and thus augment mate attraction and competitive ability. However, high testosterone levels can also compromise survivorship by increasing risk of prostate cancer, production of oxygen radicals, risk of injury due to hormonally-augmented behaviors such as aggression, violence and risk taking, reduced tissue and organ maintenance, negative energy balance from adipose tissue catabolism, and suppression of immune functions. Here, I briefly discuss how inter- and intra-individual variation in human male testosterone levels is likely an adaptive mechanism that facilitates the allocation of metabolic resources, particularly in response to injury, illness or otherwise immune activation. Maintaining low testosterone levels in resource-limited and/or high pathogen-risk environments may avoid some immunosuppression and suspend energetically-expensive anabolic functions. Augmenting testosterone levels in the presence of fertile and receptive mates, areas of high food resource availability, and low disease risk habitats will function to maximize lifetime reproductive success. PMID: 21516947 [PubMed - indexed for MEDLINE] 3453. Int J Obes (Lond). 2006 Apr;30 Suppl 1:S7-S12. Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake. Matias I(1), Bisogno T, Di Marzo V. Author information: (1)Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy. Endocannabinoids were first defined in 1995 as 'endogenous substances capable of binding to and functionally activating the cannabinoid receptors'. To date, two well-established endocannabinoids, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as a few other putative ligands, all derived from long-chain polyunsaturated fatty acids, have been identified in animal tissues. The biosynthetic and metabolic pathways for anandamide and 2-AG have been elucidated, and most of the enzymes therein involved have been cloned. We now know that CB1 receptors, and endocannabinoids in tissue concentrations sufficient to activate them, are more widely distributed than originally thought, and are found in brain and peripheral organs involved in the control of energy intake and processing, including the hypothalamus, nucleus accumbens, brainstem, vagus nerve, gastrointestinal tract, adipose tissue and liver. Endocannabinoid biosynthetic and inactivating pathways are under the regulation of neuropeptides and hormones involved in energy homeostasis, and endocannabinoid levels are directly affected by the diet. Endocannabinoids, in turn, regulate the expression and action of mediators involved in nutrient intake and processing. These cross-talks are at the basis of the proposed role of endocannabinoid signalling in the control of food intake, from invertebrates to lower vertebrates and mammals, and their perturbation appears to contribute to the development of eating disorders. PMID: 16570107 [PubMed - indexed for MEDLINE] 3454. Int J Obes (Lond). 2006 Apr;30 Suppl 1:S44-52. Contribution of CB1 blockade to the management of high-risk abdominal obesity. Després JP(1), Lemieux I, Alméras N. Author information: (1)Québec Heart Institute, Hôpital Laval Research Center, Québec, Québec, Canada. jean-pierre.despres@crhl.ulaval.ca The worldwide increase in the prevalence of type 2 diabetes represents a tremendous challenge for our healthcare system, especially if we consider that this phenomenon is largely explained by the epidemic of obesity. However, despite the well-recognized increased morbidity and mortality associated with an elevated body weight, there is now more and more evidence highlighting that abdominal adipose tissue is the fat depot that conveys the greatest risk of metabolic complications. This cluster of metabolic abnormalities has been referred to as the metabolic syndrome and this condition is largely the consequence of abdominal obesity, especially when accompanied by a high accumulation of visceral adipose tissue. This cluster of metabolic complications has also been found to be predictive of a substantially increased risk of coronary heart disease beyond the presence of traditional risk factors. Moreover, a moderate weight loss in initially abdominally obese patients is associated with a selective mobilization of visceral adipose tissue, leading to improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes. The recent discovery of the endocannabinoid-CB1 receptor system and of its impact on the regulation of energy metabolism represents a significant advance, which will help physicians target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant therapy (the first developed CB1 blocker) could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its effects not only on energy balance but also on adipose tissue metabolism. For instance, the presence of CB1 receptors in adipose tissue and the recently reported effect of rimonabant on adiponectin production by adipose cells may represent a key factor responsible for the weight loss-independent effect of this CB1 blocker on cardiometabolic risk variables. PMID: 16570106 [PubMed - indexed for MEDLINE] 3455. Int J Obes (Lond). 2006 Apr;30 Suppl 1:S39-43. How many sites of action for endocannabinoids to control energy metabolism? Pagotto U(1), Cervino C, Vicennati V, Marsicano G, Lutz B, Pasquali R. Author information: (1)Department of Internal Medicine and Gastroenterology, Endocrinology Unit, Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi General Hospital, Bologna, Italy. pagube@med.unibo.it The promising results obtained by clinical trials using Rimonabant to tackle visceral obesity and related disorders recently promoted a remarkable impulse to carry out detailed investigations into the mechanisms of action of endocannabinoids in regulating food intake and energy metabolism. The endocannabinoid system has been known for many years to play an important role in the modulation of the neuronal pathways mediating the rewarding properties of food. However, in the last few years, with the advanced understanding of the crucial role of the hypothalamic neuronal network in the regulation of appetite, several studies have also directed attention to the orexigenic role of the endocannabinoid system, substantiating the well known appetite stimulating properties of derivatives of Cannabis sativa. Furthermore, the last 2 years have seen a number of relevant publications emphasizing the role of endocannabinoids as significant players in various peripheral metabolic processes. To date, the roles of the endocannabinoid system in influencing energy metabolism have proved to be more complex than was formerly believed. However, the diverse ability to modulate both central and peripheral processes highlights the pivotal involvement of the endocannabinoid system in the control of metabolic processes. This review describes the roles of endocannabinoids and the cannabinoid type 1 receptor (CB1) in the control of energy balance. PMID: 16570104 [PubMed - indexed for MEDLINE] 3456. Int J Obes (Lond). 2006 Apr;30 Suppl 1:S33-8. The role of the endocannabinoid system in the control of energy homeostasis. Osei-Hyiaman D(1), Harvey-White J, Bátkai S, Kunos G. Author information: (1)Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA. The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1-/- mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids. PMID: 16570103 [PubMed - indexed for MEDLINE] 3457. Int J Obes (Lond). 2006 Apr;30 Suppl 1:S30-2. The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action? Horvath TL(1). Author information: (1)Department of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510-8016, USA. Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system. PMID: 16570102 [PubMed - indexed for MEDLINE] 3458. J Pharmacol Toxicol Methods. 2007 Jan-Feb;55(1):3-15. Epub 2006 Mar 6. Applicability of reverse microdialysis in pharmacological and toxicological studies. Höcht C(1), Opezzo JA, Taira CA. Author information: (1)Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina. chocht@ffyb.uba.ar A recent application of microdialysis is the introduction of a substance into the extracellular space via the microdialysis probe. The inclusion of a higher amount of a drug in the perfusate allows the drug to diffuse through the microdialysis membrane to the tissue. This technique, actually called as reverse microdialysis, not only allows the local administration of a substance but also permits the simultaneous sampling of the extracellular levels of endogenous compounds. Local effects of exogenous compounds have been studied in the central nervous system, hepatic tissue, dermis, heart and corpora luteae of experimental animals by means of reverse microdialysis. In central nervous studies, reverse microdialysis has been extensively used for the study of the effects on neurotransmission at different central nuclei of diverse pharmacological and toxicological agents, such as antidepressants, antipsychotics, antiparkinsonians, hallucinogens, drugs of abuse and experimental drugs. In the clinical setting, reverse microdialysis has been used for the study of local effects of drugs in the adipose tissue, skeletal muscle and dermis. The aim of this review is to describe the principles of the reverse microdialysis, to compare the technique with other available methods and finally to describe the applicability of reverse microdialysis in the study of drugs properties both in basic and clinical research. PMID: 16567112 [PubMed - indexed for MEDLINE] 3459. Minerva Med. 2006 Feb;97(1):5-12. [The future of the metabolic syndrome: certainties, open questions and discussions]. [Article in Italian] Manzato E(1), Romanato G, Zambon S. Author information: (1)Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Padova, Padova. enzo.manzato@unipd.it The metabolic syndrome is a topic of hot debate among experts due to different opinions about its definition and its clinical relevance. The metabolic syndrome is identified by the presence of abnormalities of the glucose metabolism, blood pressure, fat deposition, and some plasma lipids. Several authors have attempted to find a physiopathological explanation for the association of the abnormalities in this syndrome. Recently, some aspects of the inflammation seem relevant to understand the association of visceral fat deposition, insulin-resistance and diabetes and vascular complications. From a clinical point of view this syndrome must be considered an important vascular risk factor. PMID: 16565691 [PubMed - indexed for MEDLINE] 3460. Korean J Hepatol. 2006 Mar;12(1):16-30. [Insulin resistance in non-alcoholic fatty liver disease]. [Article in Korean] Park JH(1). Author information: (1)Paik Diabetes Center, Molecular Therapy Lab, Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan Paik Hospital, College of Medicine, Inje University, Busan, Korea. Insulin resistance is the pathophysiological hallmark of various kinds of clinical diseases, including non- alcoholic fatty liver disease. Insulin resistance is the common characteristic of metabolic syndrome and its related features. Insulin resistance is a systemic disease that affects the nervous system, muscles, pancreas, kidney, heart and immune system, in addition to the liver. A complex interaction between genes and environment factors enhances insulin resistance and the phenotypic expression of NAFLD (non- alcoholic fatty liver disease) in individual patients. Advanced fibrotic liver disease is associated with many features of metabolic syndrome, and the risk of progressive liver disease should not be underestimated for the individuals suffering with metabolic disorders. Abnormalities of insulin signaling can cause the state of insulin resistance, but there is no clear cut scientific evidence that distorted insulin signaling is the primary pathophysiological defect. Increased adipose tissue mass can cause peripheral tissue insulin resistance via the changes of the adipocytokine secretory patterns. We discuss in this article the sequences of the insulin signaling cascades and the possible molecular targets of insulin resistance, the humoral "cross talk" between the distorted secretory patterns of the adipocytokines, and the peripheral tissue insulin resistance along with the pathophysiology of NAFLD. PMID: 16565603 [PubMed - indexed for MEDLINE] 3461. Am J Med. 2006 May;119(5 Suppl 1):S17-23. The obese patient with diabetes mellitus: from research targets to treatment options. Sharma AM(1). Author information: (1)Michael G. deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. sharma@ccc.mcmaster.ca Abdominal obesity is a recognized risk factor for both type 2 diabetes mellitus and cardiovascular disease. The metabolic consequences of obesity, such as insulin resistance and impaired glucose tolerance, are primarily attributable to visceral, rather than to subcutaneous, adipose tissue. As a result, liposuction, which mainly removes subcutaneous fat, has no significant effect on insulin sensitivity; by contrast, weight loss resulting from bariatric surgical procedures is associated with resolution of type 2 diabetes in almost 80% of patients. Even modest weight loss in overweight or obese individuals is associated with significant reductions in the risk of diabetes and increased survival. Recent studies have suggested that the renin-angiotensin system (RAS) functions in the regulation of adipogenesis. Activation of this system is increased in obese individuals and angiotensin II, acting via angiotensin type 1 receptors, inhibits the differentiation of preadipocytes into mature adipocytes. This might be expected to result in ectopic storage of fat in tissues such as skeletal muscle and liver, thereby decreasing insulin sensitivity. Evidence from animal studies suggests that angiotensin-receptor blockers can promote redistribution of excess fat from these ectopic sites to mature adipocytes, resulting in improved insulin sensitivity. Clinical trials with telmisartan are currently investigating the effects of RAS blockade on insulin sensitivity in humans. PMID: 16563943 [PubMed - indexed for MEDLINE] 3462. Rev Med Suisse. 2006 Mar 1;2(55):576-8, 580-1. [Obesity: what impact on renal function?]. [Article in French] Mathieu C(1), Teta D, Vogt B, Burnier M. Author information: (1)Service de néphrologie et Consultation d'hypertension, CHUV, 1011 Lausanne. claudine.mathieu@chuv.ch The increasing prevalence of obesity is a major public health concern, affecting more than one third of the Swiss population. The renal effects of obesity per se, independent of hypertenison or diabetes, though, are less known. Obesity is positively correlated with proteinuria and the development of glomerulomegaly and focal segmental glomerulosclerosis. The pathophysiology of the obesity-associated kidney disease is complex, including hemodynamic and physical factors and increased synthesis of vasoactive and fibrogenic substances by adipose tissue. The most important therapeutic approach is weight reduction. Angiotension converting enzyme (ACE) inhibition is effective in reducing proteinuria, but longer follow-up is required to determine the long term benfits of ACE inhibition. PMID: 16562600 [PubMed - indexed for MEDLINE] 3463. Nutr Clin Pract. 2006 Apr;21(2):168-74. Clinical anticachexia treatments. Tisdale MJ(1). Author information: (1)Molecular Biosciences, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom. m.j.tisdale@aston.ac.uk Cachexia involves progressive loss of adipose tissue and skeletal muscle mass and is common in a number of end-stage diseases. Cachexia causes weakness and immobility, reduces the quality of life of the patient, and eventually results in death. We reviewed the medical literature concentrating upon agents that have undergone clinical evaluation for the treatment of patients with cachexia. These agents are discussed, together with their mechanisms of action. Megestrol acetate, corticosteroids, eicosapentaenoic acid, and thalidomide have shown some success in the treatment of cachexia. beta-hydroxy-beta-methylbutyrate, cyclooxygenase inhibitors, adenosine 5'-triphosphate, and growth hormone are undergoing clinical evaluation. Appetite stimulants such as cannabinoids and antiserotonic agents have been shown to be ineffective in preventing progressive weight loss in cachexia. Much of the success in the treatment of cachexia has come from agents capable of blocking protein degradation through the ubiquitin-proteasome proteolytic pathway. Muscle mass can be increased when such agents are combined with agents that stimulate protein synthesis. In order to develop new agents, more fundamental research is required on the cellular mechanisms governing protein synthesis and degradation in skeletal muscle in cachexia. PMID: 16556927 [PubMed - indexed for MEDLINE] 3464. Nutr Clin Pract. 2006 Apr;21(2):155-67. Nutrition modulation of cachexia/proteolysis. Siddiqui R(1), Pandya D, Harvey K, Zaloga GP. Author information: (1)Methodist Research Institute, 1812 N Capitol Ave, Wile Hall, Room 120, Indianapolis, IN 46202, USA. Cachexia represents progressive wasting of muscle and adipose tissue and is associated with increased morbidity and mortality. Although anorexia usually accompanies cachexia, cachexia rarely responds to increased food intake alone. Our knowledge of the underlying mechanisms responsible for cachexia remains incomplete. However, most states of cachexia are associated with underlying inflammatory processes and/or cancer. These processes activate protein degradation and lipolytic pathways, resulting in tissue loss. In this article, we briefly review the pathophysiology of cachexia and discuss the role of specific nutrient supplements for the treatment of cachexia. The branched chain amino acid leucine, the leucine metabolite beta-hydroxy-beta-methylbutyrate, arginine, glutamine, omega-3 long chain fatty acids, conjugated linoleic acid, and polyphenols have demonstrated some efficacy in animal and/or human studies. Optimal treatment for cachexia is likely aimed at maximizing muscle and adipose synthesis while minimizing degradation. PMID: 16556926 [PubMed - indexed for MEDLINE] 3465. Endocr Rev. 2006 May;27(3):318-29. Epub 2006 Mar 23. Roles of skeletal muscle and peroxisome proliferator-activated receptors in the development and treatment of obesity. López-Soriano J(1), Chiellini C, Maffei M, Grimaldi PA, Argilés JM. Author information: (1)Department of Endocrinology and Metabolism, Ospedale di Cisanello, University of Pisa, Italy. Metabolic disturbances associated with alterations in lipid metabolism, such as obesity, type 2 diabetes, and syndrome X, are becoming more and more prominent in Western societies. Despite extensive research in such pathologies and their molecular basis, we are still far from completely understanding how these metabolic perturbations are produced and interrelate and, consequently, how to treat them efficiently. The discovery that adipose tissue is, in fact, an endocrine tissue able to secrete active molecules related to lipid homeostasis--the adipokines--has dramatically changed our understanding of the molecular events that take place in such diseases. This knowledge has been further improved by the discovery of peroxisome proliferator-activated receptors and their ligands, at present commonly used for the clinical treatment of lipid disturbances. However, a key point remains to be solved, and that is the role of muscle lipid metabolism, notably because of the main role played by this tissue in the development of such pathologies. In addition, a reciprocal regulation between adipose tissue and skeletal muscle has been proposed. New discoveries on the role of peroxisome proliferator-activated receptor-delta in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders. PMID: 16556851 [PubMed - indexed for MEDLINE] 3466. Eur J Gynaecol Oncol. 2006;27(1):73-7. Mesenchymal tumors of the uterine corpus with heterologous and hematopoietic components: a study of ten cases and review of the literature. Kondi-Pafiti A(1), Grapsa D, Kairi-Vassilatou E, Kontogianni-Katsarou K, Koliopoulos C, Botsis D. Author information: (1)Pathology Laboratory, University of Athens, Aretaieion Hospital, Athens, Greece. OBJECTIVE: To study the histopathological features of mesenchymal tumors of the uterine corpus with heterologous and hematopoietic components, and review their histogenesis and differential diagnosis from other neoplastic and non-neoplastic lesions. METHODS: Ten cases of mesenchymal tumors of the uterine corpus, massively infiltrated by hematopoioetic cells, or composed of other benign heterologous elements (adipose tissue in the present cases) were retrieved from the archival files of our laboratory and studied histopathologically. Immunohistochemistry was applied in selected cases. RESULTS: Six of our studied cases were diagnosed as leiomyomas, two as lipoleiomyomas, one as a symplastic lipoleiomyoma, and one as an endometrial stromal tumor. The leiomyomas were massively infiltrated by lymphocytes (5 cases) or eosinophils (one case). Immunohistochemical study of the leiomyomas with massive lymphocytic infiltration revealed the presence of a predominantly B-cell population within the infiltrate, which was polyclonal in nature. The endometrial stromal tumor was severely infiltrated by histiocytes, and was positive for vimentin, CD10, PgR and negative for actin, desmin, ER and caldesmon. CONCLUSION: The presence of hematopoietic or heterologous elements within an otherwise bland uterine leiomyoma or endometrial stromal tumor may give rise to diagnostic difficulties. Regularity of the tumor margins, low mitotic activity and absence of nuclear atypia or necrosis should be established for the exclusion of a malignancy. In the presence of massive lymphocytic infiltration of a leiomyoma the clonality of the infiltrate may aid in differentiating it from a malignant lymphoma. The pathogenesis and clinical significance of these rare neoplasms remain to be clarified. PMID: 16550975 [PubMed - indexed for MEDLINE] 3467. Acta Myol. 2005 Oct;24(2):104-9. Laminopathies affecting skeletal and cardiac muscles: clinical and pathophysiological aspects. Decostre V(1), Ben Yaou R, Bonne G. Author information: (1)Institut National de la Santé et de la Recherche Médicale, U582, Paris, France. Laminopathies are caused by mutations in the LMNA gene encoding the ubiquitous proteins lamins A/C that are components of the lamina, a fibrous meshwork located at the inner face of the nuclear envelope. Laminopathies may affect one or several tissues such as striated muscles, peripheral nerves and adipose tissue in isolate or combined fashion. This review focuses on laminopathies affecting the striated muscle tissue only, namely Emery-Dreifuss muscular dystrophy (EDMD), limb girdle muscular dystrophy type 1B (LGMD1B) and dilated cardiomyopathy with conduction defects (DCM-CD). The phenotype of animal models in which the same mutation as that identified in EDMD or DCM-CD patients has been reproduced is presented as well as the pathophysiological mechanisms known to date. PMID: 16550926 [PubMed - indexed for MEDLINE] 3468. J Endocrinol Invest. 2005;28(10 Suppl):61-5. Is leptin the link between fat and bone mass? Isaia GC(1), D'Amelio P, Di Bella S, Tamone C. Author information: (1)Department of Internal Medicine, University of Turin, Turin, Italy. giancarlo.isaia@unito.it Leptin is a cytokine-like hormone which is considered the link between fat and bone; it is produced by adipocytes and osteoblasts, regulates food intake via specific receptors located in the central nervous system (CNS) and bone mass through alternate pathways: one involving a direct stimulatory effect on bone formation; and another indirect effect through the CNS that suppresses bone formation. Leptin exerts a direct stimulatory effect on osteoblast differentiation and on bone growth if directly administered, while it exerts an inhibitory effect on bone formation if administered in the CNS. It is therefore unclear whether leptin should be considered an antiosteogenic factor or an anabolic agent for bone formation: in all probability, leptin has a broader role in human physiology and in particular its action has evolved in order to synchronize periods of bone growth, mineral accretion and fertility with periods of food availability, while it restricts growth and reproduction during periods of nutritional stress. PMID: 16550725 [PubMed - indexed for MEDLINE] 3469. Drug News Perspect. 2006 Jan-Feb;19(1):21-6. Leptin: a metabolic hormone that functions like a proinflammatory adipokine. Otero M(1), Lago R, Gómez R, Lago F, Gómez-Reino JJ, Gualillo O. Author information: (1)Beth Israel Deaconess Medical Center, New England Baptist Bone & Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts, USA. Initially described as a satiety factor with neuroendocrine properties, leptin has been shown to regulate immune and inflammatory processes. Mainly produced by white adipose tissue, this hormone was first known to regulate energy homeostasis by inhibiting food intake and by upregulating energy consumption. Leptin is a dual molecule: apart from its actions as a hormone involved in energy homeostasis, increasing evidence suggests that leptin is a novel proinflammatory adipocyte-derived factor that operates in the cytokine network by linking immune and inflammatory processes to the neuroendocrine system. In fact, recent findings have shown that leptin regulates and participates both in immune homeostasis and inflammatory processes not only by acting as a modulator of T-cell activity, but also by playing a key role in a host of autoimmune inflammatory conditions such as autoimmune encephalomyelitis, type 1 diabetes, bowel inflammation and articular degenerative diseases such as osteoarthritis and rheumatoid arthritis. This review will more closely address leptin's cytokine properties rather than its role as a metabolic hormone by focusing on its biological actions in inflammatory processes, specifically those related to degenerative inflammatory diseases of the joints. 2006 Prous Science. All rights reserved. PMID: 16550253 [PubMed - indexed for MEDLINE] 3470. Cell Mol Immunol. 2006 Feb;3(1):29-34. Role of resistin in inflammation and inflammation-related diseases. Pang SS(1), Le YY. Author information: (1)Laboratory of Immunologic and Inflammatory Diseases, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, China. Resistin is a newly identified adipocyte secreted hormone belonging to a cysteine-rich protein family. It is expressed in white adipose tissues in rodents and has also been found in several other tissues in human. Insulin, glucose, many cytokines and anti-diabetic thiazolidinediones are regulators of resistin gene expression. Resistin was firstly proposed to be involved in insulin resistance and type 2 diabetes. Recently, it was found to be relevant to inflammation and inflammation-related diseases like atherosclerosis and arthritis. PMID: 16549046 [PubMed - indexed for MEDLINE] 3471. Biol Cell. 2006 Apr;98(4):203-14. Muscling in on stem cells. Sinanan AC(1), Buxton PG, Lewis MP. Author information: (1)Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, University College London, 256 Gray's Inn Road, London WC1X 8LD, UK. Skeletal muscle is one of the few adult tissues that possesses the capacity for regeneration (restoration of lost functional tissue) as opposed to repair. This capacity is due to the presence of 'muscle stem cells' known as satellite cells. Detailed investigation of these cells over the past 50 years has revealed that both these and other cells within the skeletal muscle complex are capable of regenerating both muscle and other cell types as well. Here, we review this information, and suggest that skeletal muscle is an exciting reservoir of cells for regenerating skeletal muscle itself, as well as other cell types. PMID: 16545076 [PubMed - indexed for MEDLINE] 3472. Przegl Lek. 2005;62(9):919-23. [Adipose tissue: a new endocrine organ]. [Article in Polish] Krysiak R(1), Okopień B, Herman ZS. Author information: (1)Katedra Farmakologii, Zakład Farmakologii, Klinicznej Slaskiej Akademii Medycznej, Katowice. r.krysiak@pharmanet.com.pl In the recent years we have begun to appreciate that adipose tissue is more than just a passive repository for excess energy. It is a highly active endocrine organ secreting a range of bioactive peptides with both local and distant action collectively called 'adipokines' or 'adipose tissue hormones'. They include leptin, adiponectin, resistin, acylation-stimulating protein (ASP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNFalpha), interleukin 6, and angiotensinogen. Some of these are specific fat-related hormones that are involved in regulating energy homeostasis, carbohydrate and lipid metabolism, vascular homeostasis and immune response. Moreover, the tissue is implicated in the metabolism of some steroid hormones. Disturbances in adipokine production may have potential repercussions in the pathophysiology of obesity, insulin resistance, and dyslipidemia. Reversal or alleviation of these changes seem to be a promising target for management of the mentioned disorders. The objective of this review is to summarise the most important aspects of biology, actions and regulation of these hormones with a special emphasis on the most recent literature. PMID: 16541730 [PubMed - indexed for MEDLINE] 3473. Przegl Lek. 2005;62(9):908-15. [Important functions of estrogens in men--breakthrough in contemporary medicine]. [Article in Polish] Kula K(1), Walczak-Jedrzejowska R, Słowikowska-Hilczer J, Wranicz JK, Kula P, Oszukowska E, Marchlewska K. Author information: (1)Katedra Andrologii i Endokrynologii Płodności, Uniwersytet Medyczny w Lodzi. kkula@csk.am.lodz.pl Estradiol (E2) is traditionally recognised as the female sex hormone. Since discovery of estrogens in the early forties of XX century it has been believed, that these hormones caused impairment of the gonadal function in men or didn't exert any influence. New studies are contradictory, but indicate also a possible involvement of estrogens in the pathogenesis of some systemic diseases of men. The main source of E2 in men is adipose tissue and the brain. E2 is also produced in adrenals, liver, mammary glands, hair and in male gonads. Daily production and blood level of E2 in men are higher than those in postmenopausal women. In 1988 we were the first to demonstrate that E2 is an important hormonal signal for initiation of spermatogenesis. The traditional view about unimportant or inhibitory role of E2 in male physiology was finally refuted thanks to discovery of the estrogen receptors in males. In the middle 90ties transgenic mice with the lack of estrogen receptor (ER knockout) or enzyme aromatase, that enable the conversion of testosterone into E2, were produced. Observations of men with inherited mutations of these genes, considerably extended our knowledge about stimulatory role of E2 in men in the formation of bone stroma, inhibition of their linear growth, lipids metabolism and sexual maturation, the effects that were attributed to testosterone action until today. New data indicate role of estrogens and ER in the function of the cardio-vascular system. Their link with development of arteriosclerosis seems, however, to be bipolar. In single reported cases of men with the inactivating mutations of ERalpha or aromatase genes, a precocious arteriosclerosis is noted. From the other site, men homozygous for the most common variant of ERalpha gene (ESR1c.454-397cc) have a significantly increased risk of myocardial infraction. Estrogens are the risk factors in prostatic cancer and their local tissue increase in autoimmune diseases is connected with aggravation of the proliferative complications of these disorders. PMID: 16541728 [PubMed - indexed for MEDLINE] 3474. J Dairy Sci. 2006 Apr;89(4):1324-36. Major advances in fundamental dairy cattle nutrition. Drackley JK(1), Donkin SS, Reynolds CK. Author information: (1)Department of Animal Sciences, University of Illinois, Urbana, 61801, USA. drackley@uiuc.edu Fundamental nutrition seeks to describe the complex biochemical reactions involved in assimilation and processing of nutrients by various tissues and organs, and to quantify nutrient movement (flux) through those processes. Over the last 25 yr, considerable progress has been made in increasing our understanding of metabolism in dairy cattle. Major advances have been made at all levels of biological organization, including the whole animal, organ systems, tissues, cells, and molecules. At the whole-animal level, progress has been made in delineating metabolism during late pregnancy and the transition to lactation, as well as in whole-body use of energy-yielding substrates and amino acids for growth in young calves. An explosion of research using multicatheterization techniques has led to better quantitative descriptions of nutrient use by tissues of the portal-drained viscera (digestive tract, pancreas, and associated adipose tissues) and liver. Isolated tissue preparations have provided important information on the interrelationships among glucose, fatty acid, and amino acid metabolism in liver, adipose tissue, and mammary gland, as well as the regulation of these pathways during different physiological states. Finally, the last 25 yr has witnessed the birth of "molecular biology" approaches to understanding fundamental nutrition. Although measurements of mRNA abundance for proteins of interest already have provided new insights into regulation of metabolism, the next 25 yr will likely see remarkable advances as these techniques continue to be applied to problems of dairy cattle biology. Integration of the "omics" technologies (functional genomics, proteomics, and metabolomics) with measurements of tissue metabolism obtained by other methods is a particularly exciting prospect for the future. The result should be improved animal health and well being, more efficient dairy production, and better models to predict nutritional requirements and provide rations to meet those requirements. PMID: 16537964 [PubMed - indexed for MEDLINE] 3475. Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):416-21. Diet, cancer, and the lipidome. Bougnoux P(1), Giraudeau B, Couet C. Author information: (1)INSERM E 0211, University Hospital of Tours, 2 Boulevard Tonnellé, 37044 Tours Cedex, France. bougnoux@med.univ-tours.fr The potential for dietary fat to interfere with the development of breast cancer by delaying its occurrence makes the identification of defined molecules a mandatory step in cancer prevention. In order to circumvent the limitations and/or bias of dietary exposure assessment tools, biomarkers of past lipid intake such as the fatty acid composition of white adipose tissue have been used. When considered separately, candidate fatty acids identified as favorable on the basis of their association with breast cancer risk have usually led to inconsistent results in animal intervention studies. This inconsistency indicates that any approach based on a single fatty acid should be abandoned for an integrated view over the complex lipid interactions which finally determines the lipidome, the lipid profile that is found in individuals. This article presents a reappraisal of the role of the lipid profile through a comprehensive reanalysis of adipose tissue fatty acid composition obtained in patients with benign or malignant breast tumors as well as in experimental animals during dietary interventions. Rather than a single fatty acid, a composite indicator combining elevated monounsaturates and low omega6/omega3 fatty acid ratio was associated with breast cancer protection. This lipidome may become the template for identifying breast cancer risk related to diet, and for designing proper dietary modifications to delay the occurrence of breast cancer, although the universality of the findings cannot be assessed from a single study. PMCID: PMC2755770 PMID: 16537692 [PubMed - indexed for MEDLINE] 3476. Nutr Rev. 2006 Feb;64(2 Pt 1):89-92. Calorie restriction increases life span: a molecular mechanism. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA. nutritionreviews@ilsi.org Calorie restriction increases the life span of many organisms, from yeast to mammals. In yeast, the life span gene affected by calorie restriction is Sir2 (silent information regulator 2). In mammals, Sirt1, an ortholog of Sir2, controls the metabolism of white adipose tissue. Calorie restriction activates Sirt1, and the expressed Sirt1 protein inhibits the action of peroxysome proliferator-activator receptor gamma (PPARgamma), the nuclear receptor that promotes adipogenesis. The effect is lipolysis and loss of fat. Lowering of adiposity appears to be one mechanism whereby calorie restriction affects life span. PMID: 16536186 [PubMed - indexed for MEDLINE] 3477. Int J Obes (Lond). 2006 Jul;30(7):1027-40. Epub 2006 Mar 14. Efficacy of exercise for treating overweight in children and adolescents: a systematic review. Atlantis E(1), Barnes EH, Singh MA. Author information: (1)School of Exercise and Sport Science, Faculty of Health Sciences, University of Sydney, NSW, Australia. E.Atlantis@fhs.usyd.edu.au BACKGROUND: Overweight prevalence among children/adolescents is increasing, while adult obesity may potentially cause a decline in life expectancy. More exercise is uniformly recommended, although treatment efficacy remains unclear. OBJECTIVE: To determine the efficacy of exercise alone for treating overweight in children/adolescents. DESIGN: A systematic review and meta-analysis of randomized trials published in English were completed following multiple database searches performed on December 10, 2004. Studies of isolated or adjunctive exercise/physical activity treatment in overweight/obese children or adolescents which reported any overweight outcome were included. Literature searches identified 645 papers which were manually searched, of which 45 were considered for inclusion, of which 13 papers which reported 14 studies were included (N=481 overweight boys and girls, aged approximately 12 years). Two reviewers independently identified relevant papers for potential inclusion and assessed methodological quality. Principal measures of effects included the mean difference (MD) (between treatment and control groups), the weighted MD (WMD), and the standardized MD (SMD). RESULTS: Few studies were of robust design. The pooled SMD was -0.4 (-0.7, -0.1, P=0.006) for percent body fat, and -0.2 (-0.6, 0.1, P=0.07) for central obesity outcomes, whereas the pooled WMD was -2.7 kg (-6.1 kg, 0.8 kg, P=0.07) for body weight, all of which favored exercise. Pooled effects on body weight were significant and larger for studies of higher doses, whereas nonsignificant and smaller effects were seen for studies of lower doses of exercise (155-180 min/weeks vs 120-150 min/weeks). CONCLUSIONS: Based on the small number of short-term randomized trials currently available, an aerobic exercise prescription of 155-180 min/weeks at moderate-to-high intensity is effective for reducing body fat in overweight children/adolescents, but effects on body weight and central obesity are inconclusive. Recommendations for future study designs are discussed. PMID: 16534526 [PubMed - indexed for MEDLINE] 3478. Scand J Med Sci Sports. 2006 Apr;16(2):74-82. The possible role of myostatin in skeletal muscle atrophy and cachexia. Jespersen J(1), Kjaer M, Schjerling P. Author information: (1)Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen, Denmark. jakob.jespersen@humanbiolog.dk The presence of sufficient skeletal muscle is of paramount importance for body function. Cachexia can be defined as a wasting syndrome describing the progressive loss of both adipose and skeletal muscle tissue in concert with severe injury, chronic or end-stage malignant and infectious diseases. Generally, cachexia predisposes to poor prognosis, co-morbidities and death. One signaling pathway possibly involved in muscle atrophy and cachexia is the myostatin cascade. This transforming growth factor-beta superfamily member myostatin is a strong candidate for regulating muscle mass, and is shown to inhibit muscle growth in different in vivo mammalian models. Overall, the modulation of the myostatin pathway seems interesting from the perspective of both pathology and sports medicine. Hence, myostatin signaling components and post-translational modulators are possible targets of pharmacological and other treatments against muscle loss, thus potentially contributing to the understanding and mitigation of muscle atrophies associated with inactivity, senescence and disease. PMID: 16533345 [PubMed - indexed for MEDLINE] 3479. Curr Opin Lipidol. 2006 Apr;17(2):162-9. Lipodystrophy: lessons in lipid and energy metabolism. Simha V(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. PURPOSE OF REVIEW: Lipodystrophies are rare inherited and acquired disorders characterized by the selective loss of adipose tissue. Despite marked phenotypic and genotypic heterogeneity, most lipodystrophic syndromes predispose to similar metabolic complications seen in patients with obesity, such as insulin resistance, diabetes mellitus, hepatic steatosis and dyslipidemia. The purpose of this review is to highlight the current understanding of the mechanisms underlying dyslipidemia in patients with lipodystrophies. RECENT FINDINGS: Marked hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol are commonly seen, and the severity of these metabolic abnormalities seems to be related to the extent of fat loss. The precise mechanisms by which the lack of adipose tissue causes hypertriglyceridemia remain unknown. Anecdotal kinetic studies in hyperglycemic patients with lipodystrophies have revealed accelerated lipolysis and increased free fatty acid turnover, which drives hepatic triglyceride and very low-density lipoprotein synthesis. Other mechanisms may also be involved in causing dyslipidemia and ectopic triglyceride accumulation in the liver and skeletal muscles that remain to be identified. SUMMARY: Understanding the pathophysiology of dyslipidemia in these rare disorders of lipodystrophies may offer insights into the normal role of adipocytes in maintaining metabolic homeostasis, and its disturbances in common forms of obesity. PMID: 16531753 [PubMed - indexed for MEDLINE] 3480. Curr Opin Lipidol. 2006 Apr;17(2):128-31. An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity. Stephens JM(1), Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. PURPOSE OF REVIEW: The aim of this article is to summarize all of the recent studies on pre-B cell colony-enhancing factor visfatin, a ubiquitously expressed secreted protein that has been implicated in obesity and insulin resistance. Although pre-B-cell colony-enhancing factor was discovered over 10 years ago, there are many remaining questions about the regulation and function of this protein. RECENT FINDINGS: Studies in the last decade have revealed the endocrine properties of fat cells. One of the most recent proteins shown to be highly expressed in adipose tissue is visfatin, originally identified as pre-B-cell colony-enhancing factor. Visfatin/pre-B-cell colony-enhancing factor appears to be preferentially produced by the visceral adipose tissue and has insulin mimetic actions. Studies by many groups indicate that obesity-related diabetes and accompanying metabolic disorders in humans have been specifically linked to increased visceral adipose tissue mass. The different roles of various adipocyte depots, however, are still poorly understood. It has been hypothesized that understanding the differences in the biology of visceral and subcutaneous human adipose tissue may hold the key to therapeutic strategies aimed at reducing obesity-induced insulin resistance and alleviating symptoms of the metabolic syndrome. Interestingly, some observed actions of visfatin indicate that this secreted protein may be an interesting therapeutic target. Several recent studies, however, indicate that our understanding of visfatin is still speculative. SUMMARY: This review summarizes all of the papers in the last year on the expression and function of visfatin/pre-B-cell colony-enhancing factor and highlights inconsistent observations from various investigators studying this protein. It also highlights previous observations on the role of pre-B-cell colony-enhancing factor. We suggest that the pathophysiologic role of visfatin/pre-B-cell colony-enhancing factor in humans remains largely unknown. PMID: 16531748 [PubMed - indexed for MEDLINE] 3481. Nutr Metab Cardiovasc Dis. 2006 Mar;16 Suppl 1:S35-8. Epub 2006 Feb 9. The dysregulated adipose tissue: a connecting link between insulin resistance, type 2 diabetes mellitus and atherosclerosis. Murdolo G(1), Smith U. Author information: (1)Department of Internal Medicine, Division of Endocrine and Metabolic Sciences, Perugia University, Perugia, Italy. giuseppe.murdolo@medic.gu.se An emerging paradigm supports the view that adipose tissue (AT) dysregulation might play a crucial role in the pathogenesis of insulin-resistance and atherosclerosis. The net result of such a dysregulation is a state of low-grade, chronic, systemic inflammation that, in turn, links both the metabolic and the vascular pathologies. Overwhelming evidence shows that high circulating levels of markers of chronic inflammation predict the development of T2DM and atherosclerotic manifestations. Therefore, atherosclerotic cardiovascular disease and T2DM seem to arise from a "common soil", and chronic inflammation is a candidate. In this scenario, the dysfunctional AT provide a common hallmark for these apparently divergent disorders. An important question then is whether dysregulated and inflamed AT can be converted to healthy fat and, consequently, the development or the progression of metabolic and vascular impairment can be prevented or reversed by the modulation of the inflammatory profile. The beneficial effects of weight loss on obesity-related complications are clearly associated with the modification of the inflammatory profile in the AT. Furthermore, the thiazolidinediones (TZDs) possess both anti-inflammatory and anti-atherogenic properties. Intriguingly, in contrast to the paradoxical weight gain, TZDs influence favorably the pattern of adipokines. In conclusion, accepting the paradigm of AT dysfunction, the use of TZDs will represent an additional therapeutic approach that, in association with lifestyle interventions, would improve inflammation, ameliorate insulin sensitivity, and alleviate the related risk of atherosclerosis. PMID: 16530128 [PubMed - indexed for MEDLINE] 3482. Curr Opin Pharmacol. 2006 Jun;6(3):230-6. Epub 2006 Mar 9. Obesity and asthma: cause for concern. Shore SA(1). Author information: (1)Physiology Program, Harvard School of Public Health, 665 Huntington Avenue, Boston MA 02115, USA. sshore@hsph.harvard.edu Epidemiological data indicate that obesity is a risk factor for incident asthma, and that obesity is also associated with increased asthma severity. Importantly, obesity antedates asthma. The observations that weight loss improves asthma and that obese mice have innate airway hyperresponsiveness and increased responses to asthma triggers also support a relationship between obesity and asthma. The basis for this relationship is unknown, but might be the result of common etiologies, comorbidities, effects of obesity on lung volume or adipokines. Understanding the mechanistic basis for the relationship between obesity and asthma could lead to new therapeutic strategies for treatment of this susceptible population. PMID: 16530012 [PubMed - indexed for MEDLINE] 3483. Histol Histopathol. 2006 Jun;21(6):663-72. Conjugated linoleic acids (CLAs) and white adipose tissue: how both in vitro and in vivo studies tell the story of a relationship. Domeneghini C(1), Di Giancamillo A, Corino C. Author information: (1)Department of Veterinary Sciences and Technologies for Food Safety, University of Milan, Milan, Italy. cinzia.domeneghini@unimi.it The distribution of adipose tissue in mammals is dependent on genetic and environmental factors, and in health the fundamental role of adipocytes is to store triacylglycerol during energetic excess and to mobilize this reserve during energy expenditure or reduced food intake. This requires an accurate balance, which is maintained through the interactions of several regulatory factors, as well as dietary manipulations. Dietary supplementation with CLAs (conjugated linoleic acids) is regarded as promising in many mammalian species for obtaining good body mass repartition and diminution of fat depots. CLAs are a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid, naturally present in foods originating from ruminant species, and normally present in human adipose tissue. CLAs can, however, also be obtained as commercial supplements, usually containing synthetically prepared isomeric mixtures, and as dietary supplements CLAs are widely used by obese people, above all in the USA and Europe. CLAs are claimed to have protective effects against human degenerative pathologies, such as cancer, atherosclerosis, and diabetes, as well as showing beneficial effects on immune functions and food and energy intakes. The mechanisms of action of CLAs are not fully clarified at present, because in vitro and in vivo studies are not always in agreement, and possibly because CLAs act in different ways and with different consequences when administered in the diet to different species. The present review summarizes the ascertained mechanisms of action of CLAs, the mammalian species of major interest in which important studies have been conducted, and the future prospects for the use of CLAs in both humans and food animal species. The following topics will be discussed, taking evidence from both in vitro and in vivo studies, to provide a possible rationale for the therapeutic or dietary utilization of CLAs: decreased energy/food intake, increased energy expenditure, decreased pre-adipocyte differentiation and proliferation, and increased apoptosis of adipocytes. All of these parameters, in turn, affect decreased lipogenesis and increased lipolysis. For the future, interactions with individual hormonal substrates, changes in gene expression of proteins involved in lipid metabolism, and anti-tumorigenic effects will possibly constitute areas for scientific development and deepening of knowledge of dietary CLAs. PMID: 16528676 [PubMed - indexed for MEDLINE] 3484. J Dairy Sci. 2006 Mar;89 Suppl 1:E52-64. Metabolic models of ruminant metabolism: recent improvements and current status. Hanigan MD(1), Bateman HG, Fadel JG, McNamara JP. Author information: (1)Virginia Polytechnic Institute and State University, Blacksburg, 24061, USA. MHanigan@vt.edu The NC-1009 regional research project has two broad goals of quantifying the properties of feeds and the metabolic interactions among nutrients that influence nutrient availability for milk production and that alter synthesis of milk, and using those quantitative relationships to challenge and refine computer-based nutrition systems for dairy cattle. The objective of this paper was to review progress in modeling. Significant progress has been made in model refinements over the past 10 yr as exemplified by the most recent NRC model (2001) and work on the Molly model of Baldwin and colleagues (1987). These models have different objectives but share many properties. The level of aggregation of the NRC model (2001) does not allow detailed analyses of specific metabolic reactions that affect nutritional efficiency. The Baldwin model is aggregated at the pathway level and is therefore amenable to assessment with a broad range of biological measurements. Recent improvements to that model include the addition of an ingredient based input scheme, use of in situ data to set ruminal protein degradation rates, and refinement of the representation of mammary cell numbers and activity. Although the Baldwin model appears to be appropriate structurally, several parameters are known to be inadequate. Predictions of ruminal N metabolism and total-tract starch digestions have similar accuracy as the NRC model. However, the NRC more accurately predicts total-tract fiber digestion and both models significantly overpredict total-tract lipid digestion. These errors contribute to overpredictions of weight retention when simulating full lactations with the Baldwin model and may result in performance prediction errors with the NRC model. Limitations remain in the descriptions of metabolism and metabolic regulation of the splanchnic, viscera, adipose tissue, body muscle, and mammary tissue. Integration of genetic control mechanisms can expand these efforts to assist genetic selection as well as feeding management decisions. PMID: 16527877 [PubMed - indexed for MEDLINE] 3485. J Nutr Biochem. 2006 Sep;17(9):571-88. Epub 2006 Jan 9. Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. Jobgen WS(1), Fried SK, Fu WJ, Meininger CJ, Wu G. Author information: (1)Texas A&M University, College Station, TX 77843, USA. Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance. PMID: 16524713 [PubMed - indexed for MEDLINE] 3486. Best Pract Res Clin Endocrinol Metab. 2006 Mar;20(1):121-43. Environmental oestrogens, cosmetics and breast cancer. Darbre PD(1). Author information: (1)School of Biological Sciences, The University of Reading, P.O. Box 228, Whiteknights, Reading RG6 6AJ, UK. p.d.darbre@reading.ac.uk The established role of oestrogen in the development and progression of breast cancer raises questions concerning a potential contribution from the many chemicals in the environment which can enter the human breast and which have oestrogenic activity. A range of organochlorine pesticides and polychlorinated biphenyls possess oestrogen-mimicking properties and have been measured in human breast adipose tissue and in human milk. These enter the breast from varied environmental contamination of food, water and air, and due to their lipophilic properties can accumulate in breast fat. However, it is emerging that the breast is also exposed to a range of oestrogenic chemicals applied as cosmetics to the underarm and breast area. These cosmetics are left on the skin in the appropriate area, allowing a more direct dermal absorption route for breast exposure to oestrogenic chemicals and allowing absorbed chemicals to escape systemic metabolism. This review considers evidence in support of a functional role for the combined interactions of cosmetic chemicals with environmental oestrogens, pharmacological oestrogens, phyto-oestrogens and physiological oestrogens in the rising incidence of breast cancer. PMID: 16522524 [PubMed - indexed for MEDLINE] 3487. Curr Diab Rep. 2006 Feb;6(1):47-54. Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Trost S(1), Pratley R, Sobel B. Author information: (1)Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine, One South Prospect Street, Burlington, VT 05401, USA. Susanne.trost@vtmednet.org Patients with the metabolic syndrome are insulin resistant and manifest a cluster of risk factors for cardiovascular disease. Impaired fibrinolysis and increased concentrations in blood of plasminogen activator inhibitor-1 (PAI-1) are related to insulin resistance and abdominal obesity and may contribute to the increased risk for cardiovascular disease in this group. Weight loss, metformin, and thiazolidinediones ameliorate insulin resistance and decrease concentrations of PAI-1. Thus, they may lower risk in patients with the metabolic syndrome. PMID: 16522281 [PubMed - indexed for MEDLINE] 3488. Przegl Lek. 2005;62 Suppl 3:69-72. [Adipokines: adiponectin, leptin, resistin and coronary heart disease risk]. [Article in Polish] Kopff B(1), Jegier A. Author information: (1)Zakład Medycyny Sportowej Katedry Medycyny Społecznej i Zapobiegawczej UM w Lodzi. bkopff@mp.pl Visceral obesity is among the known risk factors of atherosclerotic cardiovascular diseases. As long as adipose tissue was considered only an inert store of excess energy, accumulated in triglycerides, explanation of the mechanisms causing increased cardiovascular risk in obesity was difficult. Finding that the adipose tissue is an active endocrine organ and that the adipokines secreted in it influence several metabolic processes, allowed better understanding of this correlation. Several disturbances in secretion, function and balance of adipokines occur in the course of obesity. Changes of adiponectin, leptin and resistin concentrations are among the reasons of accelerated atherosclerosis occurring in the visceral adiposity. Adiponectin concentrations are decreased in visceral adiposity. Adiponectin is adipokine possessing antiatherogenic properties. It's effects exerted though the specific receptors in skeletal muscles and liver include decreased insulin resistance and improved plasma lipid profile. Acting directly in the vessel wall adiponectin prevents development of atheromatic lesions by inhibiting production of adhesive molecules and formation of foam cells. It has been found that decreased adiponectin concentrations are connected not only with increased coronary risk but also with progression of atherosclerosis in coronary vessels. Moreover it was found that adiponectin plasma concentration is significantly decreased in acute coronary incidences. Leptin regulates energy metabolism and balance. The concentrations of this adipokine are increased in obesity and correlate with insulin resistance. Hiperleptinemia has been also recognized as cardiovascular diseases risk factor. Resistin is considered to be a substance increasing insulin resistance, however the exact mechanisms are not known. Resistin plasma concentrations are increased in obese subjects and correlate with the inflammatory state that underlies the initiation and progression of atherosclerotic lesions. Correlation between resistin concentration and the extent of atherosclerotic plaques in the coronary vessels has also been found. The disturbances in secretion, function and balance of adiponectin, leptin and resistin are to be considered not only a link between visceral adiposity and cardiovascular risk but also independent risk factor of coronary heart disease. PMID: 16521924 [PubMed - indexed for MEDLINE] 3489. Izv Akad Nauk Ser Biol. 2006 Jan-Feb;(1):6-25. [Mesenchymal stem cells: sources, phenotype, and differentiation potential]. [Article in Russian] Paniushin OV, Domaratskaia EI, Starostin VI. Mesenchymal stem cells present in the bone marrow and some other organs are primitive pluripotent precursors of osseous, cartilaginous, adipose, and other mesenchymal tissues. The recently revealed capacity of these cells for differentiation into nonmesenchymal derivatives is of considerable theoretical and practical interest. However, many aspects of the biology of these cells remain obscure despite active research. This review considers possible sources and methods for the isolation of mesenchymal stem cells, their potential for proliferation and differentiation in different directions, and outlooks of their therapeutic application. A model of parent-progeny relationships of stromal cells is proposed, and the problems of regulation of proliferation and differentiation of mesenchymal precursors as well as their role in the maintenance of regeneration and tissue functioning are discussed. PMID: 16521535 [PubMed - indexed for MEDLINE] 3490. Crit Rev Clin Lab Sci. 2006;43(2):183-202. Function of PPARgamma and its ligands in lung cancer. Li MY(1), Lee TW, Yim AP, Chen GG. Author information: (1)Department of Surgery, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Peroxisome proliferator-activated receptors gamma (PPAR?) is a transcriptional factor belonging to the ligand-activated nuclear receptor superfamily. PPAR? is highly expressed in adipose tissue and has a dominant regulatory role in adipocyte differentiation. In humans, PPAR? is expressed in multiple tissues such as the breast, colon, lung, ovary, and placenta. In addition to adipogenic and anti-inflammatory effects, PPAR? activation has been shown to be anti-proliferative by virtue of its differentiation-promoting effect, suggesting that activation of PPAR? may be useful in slowing or arresting the proliferation of de-differentiated tumor cells. A number of PPAR? ligands, such as natural prostaglandins and synthetic anti-diabetic thiazolidinediones (TZDs), have been identified. The discovery of PPAR? agonists has enabled the elucidation of the mechanisms involved in the multiple effects of PPAR? on the inhibition of tumor cell growth. The importance of this transcription factor in physiology and pathophysiology has stimulated much research in this field. This review describes structural features of PPAR?, mechanisms of PPAR? gene transcription, and recent developments in the discovery of its biological functions on growth inhibition of lung tumors. Prospects for future research leading to new therapies for lung cancer are also discussed. PMID: 16517422 [PubMed - indexed for MEDLINE] 3491. Trends Endocrinol Metab. 2006 Apr;17(3):110-6. Epub 2006 Mar 6. Focus on prolactin as a metabolic hormone. Ben-Jonathan N(1), Hugo ER, Brandebourg TD, LaPensee CR. Author information: (1)Department of Cell Biology, University of Cincinnati Medical School, Cincinnati, OH 45267-0521, USA. nira.ben-jonathan@uc.edu New information about the effects of prolactin (PRL) on metabolic processes warrants re-evaluation of the overall metabolic actions of PRL. PRL affects metabolic homeostasis by regulating key enzymes and transporters that are associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose and lipids. In adipose tissue, PRL generally suppresses lipid storage and adipokine release. PRL supports the growth of pancreatic islets, stimulates insulin secretion and increases citrate production in the prostate. A specific case is made for PRL in the human breast and adipose tissue, where it acts as a circulating hormone and an autocrine or paracrine factor. Although the overall effects of PRL on body composition are modest and species specific, PRL might be involved in the manifestation of insulin resistance. PMID: 16517173 [PubMed - indexed for MEDLINE] 3492. Prog Lipid Res. 2006 May;45(3):203-36. Epub 2006 Feb 10. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Ailhaud G(1), Massiera F, Weill P, Legrand P, Alessandri JM, Guesnet P. Author information: (1)ISDBC, Centre de Biochimie UMR 6543 CNRS, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France. ailhaud@unice.fr The importance of a high fat intake in the increasing prevalence of childhood and adult obesity remains controversial. Moreover, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. Herein is reviewed the role of polyunsaturated fatty acids (PUFAs) of the n-6 series in promoting adipogenesis in vitro and favouring adipose tissue development in rodents during the gestation/suckling period. Epidemiological data from infant studies as well as the assessment of the fatty acid composition of mature breast milk and infant formulas over the last decades in the Western industrialized world are revisited and appear consistent with animal data. Changes over decades in the intake of n-6 and n-3 PUFAs, with a striking increase in the linoleic acid/alpha-linolenic ratio, are observed. In adults, using a consumption model based upon production data, similar changes in the PUFA content of ingested lipids have been found for France, and are associated with an increase of fat consumption over the last 40 years. These profound quantitative and qualitative alterations can be traced in the food chain and shown to be due to changes in human dietary habits as well as in the feeding pattern of breeding stock. If prevention of obesity is a key issue for future generations, agricultural and food industry policies should be thoroughly reevaluated. PMID: 16516300 [PubMed - indexed for MEDLINE] 3493. Orv Hetil. 2006 Jan 22;147(3):107-13. [The genetics of obesity]. [Article in Hungarian] Hagymási K(1), Tulassay Z. Author information: (1)Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Budapest. hagymasikriszti@freemail.hu Obesity is a major health problem. It increases the risk of cardiovascular diseases, 2-type diabetes mellitus, cancers, and premature mortality. Apart from some monogenic forms, it's a polygenic disorder, the result of interaction of genes and environmental factors. Genetic variants of proteins taking part in the regulation of food intake or thermogenesis and tissue mediators produced by the adipose tissue are responsible the genetic components of obesity. Identification of the genetic background of the obesity will help to understand the exact molecular mechanism of the pathogenesis, make possible the prevention, as well as individual therapeutic interventions. PMID: 16515029 [PubMed - indexed for MEDLINE] 3494. Reproduction. 2006 Mar;131(3):415-27. Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity. McMillen IC(1), Edwards LJ, Duffield J, Muhlhausler BS. Author information: (1)Research Centre for the Early Origins of Adult Health, Discipline of Physiology, School of Molecular and Biomedical Sciences, University of Adelaide, South Australia 5000, Australia. caroline.mcmillen@unisa.edu.au A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat-brain' axis in early life that precede the development of adult obesity. PMID: 16514185 [PubMed - indexed for MEDLINE] 3495. J Clin Invest. 2006 Mar;116(3):590-7. PPAR delta: a dagger in the heart of the metabolic syndrome. Barish GD(1), Narkar VA, Evans RM. Author information: (1)Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037-1099, USA. Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis. PMCID: PMC1386117 PMID: 16511591 [PubMed - indexed for MEDLINE] 3496. Diabetes Metab Res Rev. 2006 Jul-Aug;22(4):274-83. Diabetes in chronic liver disease: from old concepts to new evidence. Picardi A(1), D'Avola D, Gentilucci UV, Galati G, Fiori E, Spataro S, Afeltra A. Author information: (1)Internal Medicine and Hepatology Laboratory, Center of Interdisciplinary Investigations CIR, University Campus Bio-Medico of Rome, Via E. Longoni 83, I-00155 Rome, Italy. a.picardi@unicampus.it The liver is one of the principal organs involved in glucose metabolism together with skeletal muscle and adipose tissue. A link between diabetes and chronic liver disease (CLD) was first observed in the early half of the last century, but to date several questions remain unsolved. Altered glucose tolerance has been well described in alcoholic CLD, non-alcoholic fatty liver disease, chronic hepatitis C and portal hypertension. Moreover, insulin resistance is assuming an ever-growing importance in CLD; chronic hepatitis C has recently been proposed as a metabolic disease and insulin sensitivity as a predictive factor for liver fibrosis.CLD is also complicated by acquired growth hormone (GH) resistance, characterized by low concentrations of insulin-like growth factor-1 (IGF-1) with respect to normal or elevated GH levels. GH resistance in CLD is determined by several factors, including malnutrition, impaired liver function and reduced expression of hepatic GH receptors. We recently described the possible role of tumour necrosis factor-alpha (TNF-alpha) in blunting the hepatic response to GH in patients with chronic hepatitis C. The role of GH in impaired glucose metabolism is well known, and recent evidence suggests a receptor and/or post-receptor modulation of insulin signalling. Moreover, as in other chronic inflammatory conditions, pro-inflammatory cytokines may directly modulate the signal cascade that follows insulin binding to its receptor in the course of CLD. In this review, the proposed links between impaired glucose tolerance and CLD are analysed, special emphasis being focussed on the most recent findings concerning the interplay of chronic inflammation, GH resistance and insulin resistance. Copyright (c) 2006 John Wiley & Sons, Ltd. PMID: 16506276 [PubMed - indexed for MEDLINE] 3497. Eur J Med Res. 2006 Feb 21;11(2):47-57. Appendix to the German-Austrian HIV Therapeutic Guidelines: strategies for treating morphological and metabolic alterations under antiretroviral treatment (current as of December 2004). Mauss S(1), Behrens G, Walker U. Author information: (1)Center for HIV and Hepatogastroenterology, Düsseldorf, Germany. The recommendations made in this review are based on the current clinical knowledge with regard to the origin and therapy of lipodystrophy. They should be regarded as provisional and will change with expanding knowledge. The recommendations for treating dyslipidaemia in particular are oriented closely on the American recommendations of the National Cholesterol Education Program (NCEP III), and may be regarded both by HIV practitioners and patients as excessive and too rigid. The therapeutic goals of the NCEP in the first intervention studies in HIV-positive individuals were only achieved for a small proportion of the HIV patients. In addition, preliminary results suggest a potentially higher risk of adverse events in HIV-patients under statins or fibrates. The clinical efficacy of interventions with lipid lowering drugs has not been validated in HIV-seropositive patients. However, therapeutic decisions so far have been based on data obtained in non-HIV cardiovascular intervention studies. With more and more results becoming available from the HIV patient population a revision of these recommendations will be required. PMID: 16504961 [PubMed - indexed for MEDLINE] 3498. Pol Merkur Lekarski. 2005 Nov;19(113):723-6. [The role of adiponectin in pathogenesis of insulin resistance and metabolic syndrome]. [Article in Polish] Miczke A(1), Bryl W, Szulińska M, Pupek-Musialik D. Author information: (1)Katedra i Klinika Chorób Wewnetrznych i Zaburzeń Metabolicznych Akademii Medycznej w Poznaniu. Metabolic syndrome occurs in about 25% of the adult population in industrialised countries. The pathogenesis of this syndrome is associated with insulin resistance. There are growing evidence that proteins produced in adipose tissue can play a role in development of insulin resistance. One of them is adiponectin (APM1), that circulates in human plasma at high level (5-30 microg/ml). A reduction in APM1 expression is closely associated with insulin resistance in animal models and in studies in humans. APM1 correlates with typical features of metabolic syndrome: BMI, WHR, total cholesterol, HDL, LDL and triglyceride levels, glucose, insulin, degree of insulin resistance in hyperinsulinemic-euglycemic clamp, blood pressure, hyperuricemia. There are some hypotheses that in the future therapy with APM1 may play a role in reversing insulin resistance in many disorders. PMID: 16498821 [PubMed - indexed for MEDLINE] 3499. Minerva Endocrinol. 2006 Mar;31(1):47-60. Aromatase in the context of breast and endometrial cancer. A review. Jongen VH(1), Hollema H, Van Der Zee AG, Heineman MJ. Author information: (1)Department of Obstetrics, Diaconessenhuis Meppel, Meppel, The Netherlands. Jongvuur@hetnet.nl Generally, estrogens are considered to be involved in the neoplastic transformation of endometrium. After the menopause these estrogens mainly originate from conversion of adrenal androgens by aromatization in body fat. However, in case of stromal hyperplasia of the ovaries, it cannot be excluded that production of aromatizable androgens by postmenopausal ovaries leads to increased availability of androgen precursors for intratumoral estrogen synthesis in the endometrial tissue as well. The local presence of androgens and the local expression and activity of aromatase is considered important for this steroidogenesis. In this review, we will discuss the available evidence that androgens, produced in hyperplastic ovarian stroma or body fat tissues, play a role in the development of endometrial cancer through conversion into estrogens, a reaction catalyzed in the endometrium by the enzyme aromatase cytochrome P450. As the presence of aromatase appeared to be a pathophysiological factor in the formation of breast cancer, the latter will be evaluated in relation to the development of endometrioid endometrial cancer as well, since both disorders appear partly estrogen dependent. As treatment with aromatase inhibitors appeared feasible in breast cancer, current knowledge of comparable treatment modalities in hormone dependent endometrial cancer will be reviewed. PMID: 16498363 [PubMed - indexed for MEDLINE] 3500. Minerva Endocrinol. 2006 Mar;31(1):27-46. Aromatase inhibitors and breast cancer. Miller WR(1). Author information: (1)Breast Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK. wmiller@staffmail.ed.ac.uk Oestrogens are involved in risk to, and progression of, breast cancer. Drugs that inhibit the production of oestrogens (aromatase inhibitors, AIs), are therefore extremely attractive strategies both to prevent the disease and to treat established tumours. AIs now have a central role in the treatment of established breast cancer and are being considered for prevention. Third generation agents have been derived from rational drug design. They are able to block oestrogen production and reduce oestrogen levels to a degree that has not been observed previously and without affecting levels of other hormones. Such selective reduction of endogenous oestrogen provides targeted therapy for hormone-dependent breast cancer. This has led to improved clinical benefits in patients with these tumours. Anastrozole, letrozole and exemestane all have impressive antitumour effects in postmenopausal women with breast cancer and they are at least as beneficial as or better than other established endocrine agents when used to treat hormone-sensitive cancer in the advanced setting or as an adjuvant to surgery in earlier stages of the disease; ongoing trials are exploring the use of AIs in the preventative setting. Third generation inhibitors are well tolerated, having no greater side effects than might be expected from oestrogen suppression. Important differences in endocrinological and molecular effects exist between AIs and SERMs. These have implications for the preferred drug sequence and setting in which AIs are used. Since the major obstacle to more widespread use is primary/acquired resistance, discovery of the mechanisms by which resistance occurs offers hope for the future. More detailed study of AIs will yield important information about the involvement of oestrogen on the development and progression of breast cancer. Consequently AIs offer major clinical benefits to patients with breast cancer and the promise of relatively nontoxic intervention in women at high risk of the disease. PMID: 16498362 [PubMed - indexed for MEDLINE] 3501. Minerva Endocrinol. 2006 Mar;31(1):13-26. Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches. Brueggemeier RW(1), Díaz-Cruz ES. Author information: (1)Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Brueggemeier.1@osu.edu Estrogens are biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in several tissues in the body and aromatase (CYP19) gene expression is regulated in a tissue-specific manner via use of alternative promoters. Aromatase transcript expression and enzyme activity in breast tumor tissue is greater than that in the normal breast tissue, and prostaglandins can increase CYP19 expression and aromatase activity in breast cancer cells. Cyclooxygenase (COX) is a key enzyme in the production of prostaglandins. Higher levels of COX-2 isoform were observed in breast cancer tissue when compared to normal breast tissue, and a strong association between CYP19 gene expression and the expression of COX genes are found. Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may be beneficial in reducing the incidence of breast cancer, although the exact mechanisms remain unclear. Both NSAIDs and COX-selective inhibitors suppress aromatase mRNA expression and enzyme activity in breast cancer cells. Real time PCR results demonstrate that this suppression occurs through regulation of CYP19 expression involving promoters I.4 and II, the promoters involved in the development of breast cancer. High levels of COX-2 expression result in higher levels of prostaglandin E2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE2 produced by COX enzymes may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development. PMID: 16498361 [PubMed - indexed for MEDLINE] 3502. Acta Physiol (Oxf). 2006 Feb;186(2):87-101. Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes. Rattarasarn C(1). Author information: (1)Division of Endocrinology & Metabolism, Department of Medicine, Ramathibodi Hospital, Bangkok, Thailand. racrt@mucc.mahidol.ac.th AIM: To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes. METHODS: Data from the English-language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra-islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed. RESULTS: It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra-abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra-islet fat also adversely affects beta-cell function and number (beta-cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and beta-cell function and to delay the development of type 2 diabetes. CONCLUSION: These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes. PMID: 16497186 [PubMed - indexed for MEDLINE] 3503. Acta Physiol (Oxf). 2006 Jan;186(1):5-16. The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity. Dyck DJ(1), Heigenhauser GJ, Bruce CR. Author information: (1)Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada. ddyck@uoguelph.ca Several adipose-derived cytokines (adipokines) have been suggested to act as a link between accumulated fat mass and altered insulin sensitivity. Resistin and tumour necrosis factor-alpha (TNF-alpha) have been implicated in impairing insulin sensitivity in rodents; conversely, two other adipokines, leptin and adiponectin, increase insulin sensitivity in lean and obese rodents. Currently, there is considerable focus on the concept that lipid accumulation in skeletal muscle leads to the development of insulin resistance. Adiponectin and leptin have each been demonstrated to increase rates of fatty acid (FA) oxidation and decrease muscle lipid content, which may in part be the underlying mechanism to their insulin sensitizing effect. These effects on FA metabolism appear to be mediated in part through the activation of AMP-activated protein kinase. Evidence derived from animal and human studies suggests that the ability of leptin and adiponectin to stimulate FA oxidation in muscle is impaired in the obese condition. Thus, leptin and adiponectin resistance may be an initiating factor in the accumulation of intramuscular lipids, such as diacylglycerol and ceramide, and the ensuing development of insulin resistance. Lifestyle factors such as diet and exercise are able to restore the sensitivity of muscle to leptin. The actual physiological roles of resistin and TNF-alpha in altering muscle lipid metabolism are more controversial, but each has been shown to directly impair insulin signalling and consequently, insulin stimulated glucose uptake in muscle. However, the possibility that resistin and TNF-alpha reduces insulin sensitivity in muscle by directly impairing FA metabolism in this tissue leading to lipid accumulation, has been virtually unexamined. Thus, the contribution of various adipokines to the development of insulin resistance is complex and not fully understood. Finally, the effects of these adipokines on metabolism and insulin sensitivity are generally studied in isolation, making it difficult to predict the interactive effects and the net impact on insulin sensitivity. PMID: 16497175 [PubMed - indexed for MEDLINE] 3504. Physiol Res. 2007;56(1):1-15. Epub 2006 Feb 23. Glucose-fatty acid interaction in skeletal muscle and adipose tissue in insulin resistance. Cahová M(1), Vavrínková H, Kazdová L. Author information: (1)Institute for Clinical and Experimental Medicine, Prague, Czech Republic. moca@medicon.cz Insulin resistance (IR) is the result of long-lasting positive energy balance and the imbalance between the uptake of energy rich substrates (glucose, lipids) and energy output. The defects in the metabolism of glucose in IR and type 2 diabetes are closely associated with the disturbances in the metabolism of lipids. In this review, we have summarized the evidence indicating that one of the important mechanisms underlying the development of IR is the impaired ability of skeletal muscle to oxidize fatty acids as a consequence of elevated glucose oxidation in the situation of hyperglycemia and hyperinsulinemia and the impaired ability to switch easily between glucose and fat oxidation in response to homeostatic signals. The decreased fat oxidation results into the accumulation of intermediates of fatty acid metabolism that are supposed to interfere with the insulin signaling cascade and in consequence negatively influence the glucose utilization. Pathologically elevated fatty acid concentration in serum is now accepted as an important risk factor leading to IR. Adipose tissue plays a crucial role in the regulation of fatty acid homeostasis. The adipose tissue may be the primary site where the early metabolic disturbances leading to the development of IR take place and the development of IR in other tissues follows. In this review we present recent evidence of mutual interaction between skeletal muscle and adipose tissue in the establishment of IR and type 2 diabetes. PMID: 16497094 [PubMed - indexed for MEDLINE] 3505. Nutr Rev. 2006 Jan;64(1):47-50. Gut microbiota: a factor in energy regulation. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA. nutritionreviews@ilsi.org Studies of germ-free and conventional mice revealed that the intestinal bacterial population of the latter contributed to the provision of calories to the host by hydrolysis of indigestible plant polysaccharides to absorbable monosaccharides. The gut microbiota at the same time caused the suppression of a circulating inhibitor of lipoprotein lipase, resulting in increased lipoprotein lipase activity and thus fat deposition. Both of these effects bring about a significantly increased body fat deposition in conventional mice compared with germ-free mice. Therefore, the intestinal microbiota, living in mutual beneficial symbiosis with the host organism, is an important regulator of energy uptake and storage. PMID: 16491670 [PubMed - indexed for MEDLINE] 3506. Minerva Gastroenterol Dietol. 2002 Dec;48(4):303-8. [Obesity etiology: role of leptin]. [Article in Italian] Cena H(1), Zaccardo A, Roggi C. Author information: (1)Dipartimento di Scienze Sanitarie Applicate e Psicocomportamentali, Sezione di Scienza dell'Alimentazione, Università degli Studi di Pavia, Pavia. hcena@unipv.it A huge interest in the scientific community has been aroused since leptin's discovery (from greek leptos=thin), due to its important role in the body energetic balance regulation. This protein is synthesized from ob gene and secreted by the adipose tissue when fat mass increases, decreasing hunger and increasing energy expenditure in order to restore energetic balance. In the latest years many human genetic studies have been conducted showing that sometimes obesity may be due to mutations of genes involved in energetic balance mediated by leptin. These findings amplified the knowledge of obesity etiopathogenesis, thus arousing hopes and expectations for new therapeutic horizons in this disease. Latest researches also outlined many other functions of leptin, some of which are presented in this review. In this paper we collected the most significant data about leptin's physiology and its role in body energetic homeostasis, looking also to the effects on hypothalamus-hypophysis-endocrine axes regulation, on body thermoregulation, on the reproductive function and on foetus and child growth. A wide section is thus reserved to the most recent findings about the role of leptin in obesity and about its therapeutic applications in this field. PMID: 16491055 [PubMed] 3507. Panminerva Med. 2005 Dec;47(4):229-44. Insulin resistance (metabolic) syndrome in children. Rosenberg B(1), Moran A, Sinaiko AR. Author information: (1)Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA. The insulin resistance (metabolic) syndrome (IRS), also known as syndrome X, is characterized by a clustering of factors associated with cardiovascular risk (obesity, impaired glucose metabolism, hypertension, and dyslipidemia). As reported from the third National Health and Nutrition Examination survey, the IRS is present in approximately 24% of adults in the United States and is strongly associated with coronary heart disease, stroke, type 2 diabetes, and all-cause mortality. Of equal importance, it is now clear that the origins of the IRS extend back into childhood (the IRS is found in approximately 4-10% of children and adolescents) and that the high prevalence of adult IRS is strongly linked to the development of cardiovascular risk during childhood and tracking of the components of the IRS into adulthood. The goal of this review is to present a summary of the currently available information on the IRS in the pre-adult age group with reference to adult studies only when necessary for clarification. The review will specifically summarize insulin resistance in childhood; the important influence of obesity and, in particular, visceral fat, on insulin resistance and the IRS; differences between ethnic groups; relations to adipocytokines, inflammatory factors and oxidative stress; relations of hypertension and lipids to insulin resistance; familial factors; endocrine complications; and potential therapeutic effects from diet and physical activity. Despite the lesser amount of basic and clinical information on childhood IRS in comparison to information available from adult studies, there can now be little doubt that the adverse associations among risk factors comprising the IRS begin in childhood. The challenge is to identify etiologic relations and develop intervention strategies designed to reduce the increasing prevalence of type 2 diabetes and cardiovascular disease. PMID: 16489322 [PubMed - indexed for MEDLINE] 3508. Nutr Metab Cardiovasc Dis. 2006 Mar;16(2):156-62. Epub 2006 Jan 18. Rimonabant: a cannabinoid receptor blocker for the treatment of metabolic and cardiovascular risk factors. Tonstad S(1). Author information: (1)Department of Preventive Cardiology, Ullevål University Hospital, N-0407 Oslo, Norway. serena.tonstad@uus.no AIMS: The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence. DATA SYNTHESIS: Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date. CONCLUSION: Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors. PMID: 16487916 [PubMed - indexed for MEDLINE] 3509. Life Sci. 2006 Jun 27;79(5):417-22. Epub 2006 Feb 17. Diabetes and semicarbazide-sensitive amine oxidase (SSAO) activity: a review. Obata T(1). Author information: (1)Department of Analytical Chemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611, Japan. t-obata@pha.ohu-u.ac.jp The enzyme of semicarbazide-sensitive amine oxidase (SSAO) activity has been reported to be elevated in blood from diabetic patients. SSAO are widely distributed in plasma membranes of various tissues and blood plasma. SSAO-mediated production of toxic aldehydes has been proposed to be related to pathophysiological conditions. Cytotoxic metabolites by SSAO may cause endothelial injury and subsequently induce atherosclerosis. The precise physiological functions of SSAO could play an important role in the control of energy balance in adipose tissue. It is possible that the increased SSAO activity in diabetes may be a result of up-regulation due to increase of SSAO substrates, such as methylamine or aminoacetone. SSAO could play an important role in the regulation of adipocyte homeostasis. Inhibition of SSAO could be of therapeutic value for treatment of diabetic patient. PMID: 16487546 [PubMed - indexed for MEDLINE] 3510. Biochim Biophys Acta. 2006 Aug;1758(8):1004-11. Epub 2006 Jan 31. Aquaporins and glycerol metabolism. Hibuse T(1), Maeda N, Nagasawa A, Funahashi T. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Osaka 565-0871, Japan. The discovery of aquaporin (AQP) has made a great impact on life sciences. AQPs are a family of homologous water channels widely distributed in plants, unicellular organisms, invertebrates, and vertebrates. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in maintaining water homeostasis, but the physiological significance of some AQPs as a glycerol channel is not fully understood. Adipose tissue is a major source of glycerol and glycerol is one of substrates for gluconeogenesis. This review focuses on recent studies of glycerol metabolism through aquaglyceroporins, and briefly discusses the importance of glycerol channel in adipose tissues and liver. PMID: 16487477 [PubMed - indexed for MEDLINE] 3511. Curr Opin Nephrol Hypertens. 2006 Mar;15(2):173-8. From big fat cells to high blood pressure: a pathway to obesity-associated hypertension. Pausova Z(1). Author information: (1)Brain and Body Centre, University of Nottingham, Nottingham, UK. zdenka.pausova@nottingham.ac.uk PURPOSE OF REVIEW: The environment created by modern industrialized societies has caused an unprecedented rise in the prevalence of obesity and obesity-related disorders, including hypertension. Mechanisms that underlie the development of hypertension in obese individuals are not very well understood; they are thought to involve activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and oxidative stress. RECENT FINDINGS: Recent research suggests that obesity-associated hypertension may be causally related to the accumulation of 'dysfunctional' adipose tissue characterized by the presence of 'large' lipid-laden adipocytes. SUMMARY: Excess energy-intake leads to an expansion of adipose tissue, a hallmark of obesity. But morphology of the expanded adipose tissue differs across individuals, including the size of adipocytes. The presence of 'large' rather than 'small' adipocytes is associated with functional and structural abnormalities of adipose tissue. These include increased production of bioactive molecules, such as leptin, angiotensinogen, pro-inflammatory cytokines, and reactive oxygen species; insufficient capacity to accommodate excess energy-intake leading to ectopic fat storage in tissues and in turn insulin resistance and hyperinsulinemia; and augmented macrophage infiltration enhancing the production of pro-inflammatory cytokines and reactive oxygen species. Such a 'dysfunctional' adipose tissue may, in turn, induce activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and oxidative stress and, hence, promote the development of obesity-associated hypertension. PMID: 16481885 [PubMed - indexed for MEDLINE] 3512. Clin Chim Acta. 2006 Jun;368(1-2):1-19. Epub 2006 Feb 9. Lipid and lipoprotein dysregulation in insulin resistant states. Avramoglu RK(1), Basciano H, Adeli K. Author information: (1)Clinical Biochemistry Division, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. Insulin resistant states are commonly associated with an atherogenic dyslipidemia that contributes to significantly higher risk of atherosclerosis and cardiovascular disease. Indeed, disorders of carbohydrate and lipid metabolism co-exist in the majority of subjects with the "metabolic syndrome" and form the basis for the definition and diagnosis of this complex syndrome. The most fundamental defect in these patients is resistance to cellular actions of insulin, particularly resistance to insulin-stimulated glucose uptake. Insulin insensitivity appears to cause hyperinsulinemia, enhanced hepatic gluconeogenesis and glucose output, reduced suppression of lipolysis in adipose tissue leading to a high free fatty acid flux, and increased hepatic very low density lipoprotein (VLDL) secretion causing hypertriglyceridemia and reduced plasma levels of high density lipoprotein (HDL) cholesterol. Although the link between insulin resistance and dysregulation of lipoprotein metabolism is well established, a significant gap of knowledge exists regarding the underlying cellular and molecular mechanisms. Emerging evidence suggests that insulin resistance and its associated metabolic dyslipidemia result from perturbations in key molecules of the insulin signaling pathway, including overexpression of key phosphatases, downregulation and/or activation of key protein kinase cascades, leading to a state of mixed hepatic insulin resistance and sensitivity. These signaling changes in turn cause an increased expression of sterol regulatory element binding protein (SREBP) 1c, induction of de novo lipogensis and higher activity of microsomal triglyceride transfer protein (MTP), which together with high exogenous free fatty acid (FFA) flux collectively stimulate the hepatic production of apolipoprotein B (apoB)-containing VLDL particles. VLDL overproduction underlies the high triglyceride/low HDL-cholesterol lipid profile commonly observed in insulin resistant subjects. PMID: 16480697 [PubMed - indexed for MEDLINE] 3513. J Cell Biochem. 2006 May 15;98(2):251-66. Playing with bone and fat. Gimble JM(1), Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Author information: (1)Stem Cell Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, 70808, USA. gimblejm@pbrc.edu The relationship between bone and fat formation within the bone marrow microenvironment is complex and remains an area of active investigation. Classical in vitro and in vivo studies strongly support an inverse relationship between the commitment of bone marrow-derived mesenchymal stem cells or stromal cells to the adipocyte and osteoblast lineage pathways. In this review, we focus on the recent literature exploring the mechanisms underlying these differentiation events and discuss their implications relevant to osteoporosis and regenerative medicine. Copyright 2006 Wiley-Liss, Inc. PMID: 16479589 [PubMed - indexed for MEDLINE] 3514. Clin Cornerstone. 2005;7(2-3):61-72. The metabolic syndrome, hyperlipidemia, and insulin resistance. Fonseca VA(1). Author information: (1)Department of Medicine, Section of Endocrinology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA. vfonseca@tulane.edu The metabolic syndrome is a cluster of cardiovascular risk factors associated with obesity. The defining components of the metabolic syndrome, according to the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), are elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose. The pathophysiologic basis of metabolic syndrome is complex and reflects several interrelated disturbances of glucose and lipid homeostasis. Metabolic syndrome is prevalent in the United States and developed nations, and patients with this disorder are at risk for type 2 diabetes mellitus and cardiovascular disease, underscoring the need for prompt patient identification and management. The first-line approach to control of metabolic syndrome is weight control and exercise. A wide range of pharmacologic interventions (eg, statins, antihypertensive drugs, insulin sensitizers, and thiazolidinediones) have been shown to be effective in controlling the individual components of metabolic syndrome. Obesity, which is a necessary component of metabolic syndrome, has reached epidemic proportions in the United States. Although lifestyle management or medications can control the underlying risk factors and most of the components of metabolic syndrome, long-term weight loss is difficult to achieve. Several promising pharmacologic interventions that may have an important role in the management of metabolic syndrome by treating adipose tissue-mediated metabolic disturbances are in the early stages of development. PMID: 16473262 [PubMed - indexed for MEDLINE] 3515. Clin Cornerstone. 2005;7(2-3):52-60. Pharmacotherapy to reduce visceral fat. Blackburn GL(1), Waltman BA. Author information: (1)Division of Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. gblackbu@bidmc.harvard.edu Cardiovascular disease (CVD) is the leading cause of death of men and women in the United States. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing CVD and metabolic disease. Because visceral adipose tissue uniquely contributes to the pathophysiology of CVD and insulin resistance, waist circumference is now being considered as a more useful marker of potential health risks associated with overweight and obesity than body mass index. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, thereby reducing the risk of developing chronic disease and CVD. PMID: 16473261 [PubMed - indexed for MEDLINE] 3516. Clin Cornerstone. 2005;7(2-3):27-35. The metabolic basis of atherogenic dyslipidemia. Vinik AI(1). Author information: (1)The Leonard R. Strelitz Diabetes Research Institute, Eastern Virginia Medical School, Norfolk 23510, USA. vinikai@evms.edu Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia. PMID: 16473258 [PubMed - indexed for MEDLINE] 3517. Clin Cornerstone. 2005;7(2-3):17-26. The endocannabinoid system: a new approach to control cardiovascular disease. Cannon CP(1). Author information: (1)Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors--cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)--and their natural ligands. The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism. When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance. Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome. Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease. Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors. PMID: 16473257 [PubMed - indexed for MEDLINE] 3518. Curr Drug Discov Technol. 2004 Dec;1(4):269-85. Microdialysis in drug discovery. Höcht C(1), Opezzo JA, Taira CA. Author information: (1)Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina. chocht@ffyb.uba.ar Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites. The development of microdialysis for the purpose of measuring drugs was initiated during the late eighties. This technique provides a means of continuous plasma sampling without repeated blood sampling and the applicability to the study of drug metabolism and pharmacokinetics in experimental animals and human. Also, the microdialysis technique allows the study of plasma protein binding and the saturation of protein binding. The implantation of the microdialysis probe in other tissues and organs, like central nervous system, adipose tissue and heart, allows the study of drug distribution. On the other hand, the measurement of endogenous substances using the microdialysis technique permits the study of the effect of drugs on neurotransmission and metabolism. Moreover, as this technique allows the simultaneous determination of different physiological parameters such as blood pressure, locomotor and convulsive activity, it is a suitable tool for pharmacokinetic-pharmacodynamic studies of drugs and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Lastly, the reverse microdialysis is a powerful technique for the study of local actions of drugs in different tissues such as specific brain nuclei, myocardium, liver or skeletal muscle. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs. PMID: 16472243 [PubMed - indexed for MEDLINE] 3519. Curr Vasc Pharmacol. 2006 Jan;4(1):79-85. The effects of obesity-related peptides on the vasculature. Skilton MR(1), Celermajer DS. Author information: (1)Department of Medicine, University of Sydney, Australia. Obesity and its related metabolic diseases, including type 2 diabetes, are associated with alterations in the circulating levels of various peptides. These include the adipocytokines (peptides released by adipocytes which circulate, such as leptin, adiponectin and resistin), and other peptides whose levels are altered in association with obesity (such as ghrelin, neuropeptide Y, interleukin-1 beta and tumour necrosis factor-alpha). While the primary action of these peptides is linked with the regulation and maintenance of energy balance and metabolism, many of them have also been shown to possess vasoactive, inflammatory and other properties that influence vascular biology, vascular physiology and atherogenesis. As such, they may form an important mechanistic link between obesity and cardiovascular disease. In this review, we will outline the vasoactive properties of adipocytokines and other obesity-related peptides. In particular, as pharmacotherapies suggested to achieve weight loss will alter the pathways associated with these peptides, such treatments might have either beneficial or deleterious effects on the incidence and progression of cardiovascular disease. PMID: 16472179 [PubMed - indexed for MEDLINE] 3520. Diabetes Technol Ther. 2006 Feb;8(1):55-66. Genetic predispositions to low-grade inflammation and type 2 diabetes. Fernández-Real JM(1). Author information: (1)Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr Josep Trueta, Girona, Spain. uden.jmfernandezreal@htrueta.scs.es Insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defense and is constituted by different barriers (e.g., epithelia, adipose tissue) and different blood and tissue components (e.g., macrophages, neutrophils). This system generates the acute-phase response in which different acute-phase proteins and cytokines are produced in response to different aggressions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e., brain and the immune system). Evolutionary pressures have led to survival of the fittest individuals, those with the genetics that allows the best defense against infection and periods of famine. Evidence is reported according to which gene polymorphisms in the molecules regulating the inflammatory cascade are associated with body composition, insulin action, and characteristics of the metabolic syndrome. The evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-18], or decreased anti-inflammatory molecules (adiponectin, certain TNF-alpha isoforms, soluble CD14, etc.), would lead in westernized countries to chronic inflammation conditions, such as obesity and type 2 diabetes, resulting in cardiovascular disease. PMID: 16472051 [PubMed - indexed for MEDLINE] 3521. Mol Nutr Food Res. 2006 Feb;50(2):176-87. Anti-obesity effects of green tea: from bedside to bench. Wolfram S(1), Wang Y, Thielecke F. Author information: (1)DSM Nutritional Products, Department of Human Nutrition and Health, Basel, Switzerland. swen.wolfram@dsm.com During the last decade, the traditional notion that green tea consumption benefits health has received significant scientific attention and, particularly, the areas of cardiovascular disease and cancer were subject to numerous studies. Due to the ever-growing obesity pandemic, the anti-obesity effects of green tea are being increasingly investigated in cell, animal, and human studies. Green tea, green tea catechins, and epigallocatechin gallate (EGCG) have been demonstrated in cell culture and animal models of obesity to reduce adipocyte differentiation and proliferation, lipogenesis, fat mass, body weight, fat absorption, plasma levels of triglycerides, free fatty acids, cholesterol, glucose, insulin and leptin, as well as to increase beta-oxidation and thermogenesis. Adipose tissue, liver, intestine, and skeletal muscle are target organs of green tea, mediating its anti-obesity effects. Studies conducted with human subjects report reduced body weight and body fat, as well as increased fat oxidation and thermogenesis and thereby confirm findings in cell culture systems and animal models of obesity. There is still a need for well-designed and controlled clinical studies to validate the existing and encouraging human studies. Since EGCG is regarded as the most active component of green tea, its specific effects on obesity should also be investigated in human trials. PMID: 16470636 [PubMed - indexed for MEDLINE] 3522. Am J Clin Nutr. 2006 Feb;83(2):461S-465S. Obesity and the role of adipose tissue in inflammation and metabolism. Greenberg AS(1), Obin MS. Author information: (1)Obesity and Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston 02111-1524,USA. andrew.greenberg@tufts.edu Recent discoveries, notably of the hormones leptin and adiponectin, have revised the notion that adipocytes are simply a storage depot for body energy. Instead, adipocytes are also endocrine organs, with multiple metabolic roles in regulating whole-body physiology. Small adipocytes in lean individuals promote metabolic homeostasis; the enlarged adipocytes of obese individuals recruit macrophages and promote inflammation and the release of a range of factors that predispose toward insulin resistance. Exercise activates the AMP-activated protein kinase (AMPK) in muscle and other tissues, a pathway that increases fat oxidation and glucose transport. Importantly, the adipocyte hormones leptin and adiponectin also activate AMPK; remarkably, the same pathway is activated by certain antidiabetic agents such as thiazolidinediones. Increasingly, our understanding of the adipocyte as an endocrine organ is leading to new insights into obesity and health. PMID: 16470013 [PubMed - indexed for MEDLINE] 3523. Cas Lek Cesk. 2006;145(1):14-8. [Acylation stimulating protein--its role in control of metabolism in the adipose tissue]. [Article in Czech] Hlavatý P(1), Kunesová M. Author information: (1)Endokrinologický ustav - Centrum pro diagnostiku a lécbu obezity, Praha. phlavaty@endo.cz Multiple hormones and enzymes participate in the lipid storage. One of them is acylation stimulating protein. Acylation stimulating protein is produced predominantly by adipocytes. After the binding on specific receptor at the surface of adipocytes, acylation stimulating protein leads to enhancement of triglyceride synthesis. This process is mediated by protein-kinase C. Concurrently, glucose transporters move from the cytoplasm to the adipocyte surface. Higher glucose disposal leads to a sufficient substrate availability for triglyceride synthesis. Acylation stimulating protein also stimulates pancreatic insulin secretion. Total acylation stimulating protein level in plasma is related to the adipose tissue mass and it positively correlates with many anthropometric parameters and with serum insulin level. In acylation stimulating protein deficient mice, resistance to the obesity development after a high fat diet was observed. Adipose tissue mass is lower in the acylation stimulating protein deficient mice and higher insulin sensitivity was shown in acylation stimulating protein deficient mice compared to a wild type mice. Acylation stimulating protein pathway may have an important role in the obesity development. PMID: 16468236 [PubMed - indexed for MEDLINE] 3524. Nutr Rev. 2005 Dec;63(12 Pt 1):419-22. Gender differences in amino acid use during endurance exercise. Lamont LS(1). Author information: (1)Exercise Science Program, University of Rhode Island, Kingston, RI, USA. LLA4983U@postoffice.uri.edu There are gender differences in the substrate used to fuel prolonged physical activity. Males rely on carbohydrate and amino acids (97%), while females use predominantly fat (62%) to fuel endurance exercise. This review looks at the mechanisms that regulate these gender differences, with a focus on amino acid metabolism. Gender-selective nutritional recommendations are indicated for physically active individuals and some cardiac patients who engage in intense aerobic activity. PMID: 16466078 [PubMed - indexed for MEDLINE] 3525. Int J Oncol. 2006 Mar;28(3):737-45. Obesity, adipokines, and prostate cancer (review). Baillargeon J(1), Rose DP. Author information: (1)Center for Epidemiology and Biostatistics, Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. baillargeon@uthscsa.edu Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin. PMID: 16465380 [PubMed - indexed for MEDLINE] 3526. Clin Sci (Lond). 2006 Mar;110(3):267-78. Adiponectin: a key adipocytokine in metabolic syndrome. Okamoto Y(1), Kihara S, Funahashi T, Matsuzawa Y, Libby P. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan. okamotoy@imed2.med.osaka-u.ac.jp The metabolic syndrome, a cluster of metabolic disorders often associated with visceral obesity, increases cardiovascular mortality and morbidity. As the body's largest endocrine organ, adipose tissue not only stores excess body energy, but also secretes a variety of bioactive adipocytokines. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific adipocytokine. Although the association of adiponectin with several diseases remains controversial, many clinical studies have demonstrated that low plasma concentrations of adiponectin (hypoadiponectinaemia) associate closely with obesity-related diseases, including atherosclerotic cardiovascular diseases, Type II diabetes mellitus, hypertension and dyslipidaemia. Accumulating experimental evidence indicates that adiponectin possesses anti-atherogenic, anti-inflammatory and anti-diabetic properties and may also participate importantly in the mechanism of metabolic syndrome and other diseases. Despite these associations, further clinical and experimental investigations will be needed to illuminate the in vivo pathophysiological significance of this protein. Although evaluation of adiponectin as a novel therapy will ultimately require clinical intervention studies, this mediator may represent a novel target for the prevention and treatment of visceral obesity metabolic syndrome. PMID: 16464169 [PubMed - indexed for MEDLINE] 3527. Trends Endocrinol Metab. 2006 Mar;17(2):72-8. Epub 2006 Feb 3. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Thirone AC(1), Huang C, Klip A. Author information: (1)Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. In type 2-diabetes and impaired glucose tolerance, the muscle, fat and liver become resistant to insulin, and recent developments place dysregulation of insulin receptor substrate (IRS) expression and activation at the center of such defects. IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. The majority of the published literature in this field suggests that IRS1 is the major substrate leading to stimulation of glucose transport in muscle and adipose tissues, whereas in liver, IRS1 and IRS2 have complementary roles in insulin signaling and metabolism. PMID: 16458527 [PubMed - indexed for MEDLINE] 3528. J Physiol. 2006 Apr 1;572(Pt 1):17-24. Epub 2006 Feb 2. Recent observations on the regulation of fetal metabolism by glucose. Hay WW Jr(1). Author information: (1)University of Colorado Health Sciences Center, Perinatal Research Center, F441, 13243 E. 23rd Avenue, PO Box 6508, Aurora, CO 80045, USA. bill.hay@uchsc.edu Glucose is the principal energy substrate for the the fetus and is essential for normal fetal metabolism and growth. Fetal glucose metabolism is directly dependent on the fetal plasma glucose concentration. Fetal glucose utilization is augmented by insulin produced by the developing fetal pancreas in increasing amounts as gestation proceeds, which enhances glucose utilization among the insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue) that increase in mass and thus glucose need during late gestation. Glucose-stimulated insulin secretion increases over gestation. Both insulin secretion and insulin action are affected by prevailing glucose concentrations and the amount and activity of tissue glucose transporters. In cases of intrauterine growth restriction (IUGR), fetal weight-specific tissue glucose uptake rates and glucose transporters are maintained or increased, while synthesis of amino acids into protein and corresponding insulin-IGF signal transduction proteins are decreased. These observations demonstrate the mixed phenotype of the IUGR fetus that includes enhanced glucose utilization capacity, but diminished protein synthesis and growth. Thus, the fetus has considerable capacity to adapt to changes in glucose supply by relatively common and understandable mechanisms that regulate fetal metabolism and growth and could underlie certain later life metabolic disorders such as insulin resistance, obesity and diabetes mellitus. PMCID: PMC1779657 PMID: 16455683 [PubMed - indexed for MEDLINE] 3529. Altern Ther Health Med. 2006 Jan-Feb;12(1):10-6. Systems biology: the gut-brain-fat cell connection and obesity. Hyman MA. PMID: 16454140 [PubMed - indexed for MEDLINE] 3530. Ann Med. 2006;38(1):52-63. Is visceral obesity the cause of the metabolic syndrome? Després JP(1). Author information: (1)Québec Heart Institute, Laval Hospital Research Center, Ste-Foy, Québec, Canada. jean-pierre.despres@crhl.ulaval.ca Despite the fact that controversy remains around the underlying pathophysiological processes leading to the development of the metabolic syndrome (insulin resistance and/or hyperinsulinemia versus abdominal obesity), there is increased recognition that abdominal obesity is the most prevalent form of the metabolic syndrome. Although it has been well established that there is a greater prevalence of chronic metabolic diseases such as diabetes and cardiovascular diseases in obese patients than among normal weight individuals, obesity is a remarkably heterogeneous condition and not every obese patient is characterized by co-morbidities. In this regard, body fat distribution, especially visceral adipose tissue accumulation, has been found to be a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities referred to as the metabolic syndrome. Due to its anatomic location and peculiar metabolic, hyperlipolytic activity, the expanded visceral adipose depot is a key correlate of the altered cardiometabolic risk profile observed among individuals with a high-risk abdominal obesity phenotype. Evidence suggests that this dysmetabolic profile is predictive of a substantially increased risk of coronary heart disease even in the absence of classical risk factors. Finally, a moderate weight loss in initially abdominally obese patients is associated with a preferential mobilization of visceral adipose tissue, which in turn leads to substantial improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes. PMID: 16448989 [PubMed - indexed for MEDLINE] 3531. Fundam Clin Pharmacol. 2006 Feb;20(1):41-9. Cardiovascular and metabolic effects of natriuretic peptides. Moro C(1), Berlan M. Author information: (1)Department of Medical and Clinical Pharmacology, Faculty of Medicine, Toulouse, France. moro@cict.fr Natriuretic peptides (NP) are essential in mammals to regulate blood volume and pressure. The functional roles of NP are not limited to natriuresis and diuresis. Several peripheral and central actions of the peptides have been characterized. Studies on transgenic mice have revealed their key function in the regulation of cardiomyocyte growth. Plasma NP levels increase in patients with cardiovascular disorders and heart failure. They represent useful clinical markers for clinicians to diagnose heart diseases. The recent discovery of their potent lipolytic action in adipose tissue is a breakthrough in cardiovascular medicine. This new function of NP in the regulation of lipid metabolism offers interesting questions in the field of obesity, diabetes and cardiovascular diseases. This review will briefly describe the effects of NP on the cardiovascular system and lipid metabolism. PMID: 16448393 [PubMed - indexed for MEDLINE] 3532. Prog Lipid Res. 2006 Jan;45(1):42-72. Epub 2005 Dec 19. Ceramides in insulin resistance and lipotoxicity. Summers SA(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, University of Utah School of Medicine, Building 585, Room 110, Salt Lake City, UT 84132, USA. scott.summers@hsc.utah.edu Obesity predisposes individuals to the development of insulin resistance in skeletal muscle and the liver, and researchers have recently proposed two mechanisms by which excess adiposity antagonizes insulin action in peripheral tissues. First, when adipocytes exceed their storage capacity, fat begins to accumulate in tissues not suited for lipid storage, leading to the formation of specific metabolites that inhibit insulin signal transduction. Second, obesity triggers a chronic inflammatory state, and cytokines released from either adipocytes or from macrophages infiltrating adipose tissue antagonize insulin action. The sphingolipid ceramide is a putative intermediate linking both excess nutrients (i.e. saturated fatty acids) and inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNFalpha) to the induction of insulin resistance. Moreover, ceramide has been shown to be toxic in a variety of different cell types (e.g. pancreatic beta-cells, cardiomyocytes, etc.), and review of the literature reveals putative roles for the sphingolipid in the damage of cells and tissues which accompany diabetes, hypertension, cardiac failure, atherosclerosis, etc. In this review, I will evaluate the contribution of ceramides in the development of insulin resistance and the complications associated with metabolic diseases. PMID: 16445986 [PubMed - indexed for MEDLINE] 3533. Environ Res. 2006 Jul;101(3):419-28. Epub 2006 Jan 30. Dioxins: an overview. Schecter A(1), Birnbaum L, Ryan JJ, Constable JD. Author information: (1)University of Texas Health Science Center, School of Public Health, Dallas Campus, Dallas, TX 75390, USA. arnold.schecter@utsouthwestern.edu Comment in Environ Res. 2007 Jan;103(1):145-6; author reply 147-8. This review article summarizes what is known about human health following exposure to dioxins. It is meant primarily for health professionals but was also written with the general public in mind. The need for such an article became apparent to the authors following media inquiries at the time the then Ukraine presidential candidate Victor Yushchenko was deliberately poisoned with the most toxic dioxin, tetrachlorodibenzodioxin or TCDD. PMID: 16445906 [PubMed - indexed for MEDLINE] 3534. Vasc Med. 2005 Jul;10 Suppl 1:S35-43. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Sydow K(1), Mondon CE, Cooke JP. Author information: (1)Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, CA 94305-5406, USA. ksydow@cvmed.stanford.edu The insulin resistance syndrome (IRS) is considered to be a new target of risk-reduction therapy. The IRS is a cluster of closely associated and interdependent abnormalities and clinical outcomes that occur more commonly in insulin-resistant/hyperinsulinemic individuals. This syndrome predisposes individuals to type 2 diabetes, cardiovascular diseases, essential hypertension, certain forms of cancer, polycystic ovary syndrome, nonalcoholic fatty liver disease, and sleep apnea. In patients at high risk for cardiovascular diseases, endothelial dysfunction is observed in morphologically intact vessels even before the onset of clinically manifest vascular disease. Indeed, there are several lines of evidence that indicate that endothelial function is compromised in situations where there is reduced sensitivity to endogenous insulin. It is well established that a decreased bioavailability of nitric oxide (NO) contributes to endothelial dysfunction. Furthermore, NO may modulate insulin sensitivity. Activation of NO synthase (NOS) augments blood flow to insulin-sensitive tissues (i.e. skeletal muscle, liver, adipose tissue), and its activity is impaired in insulin resistance. Inhibition of NOS reduces the microvascular delivery of nutrients and blunts insulin-stimulated glucose uptake in skeletal muscle. Furthermore, induction of hypertension by administration of the NOS inhibitor NG-monomethyl-L-arginine is also associated with insulin resistance in rats. Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial vasodilator dysfunction and increased risk of cardiovascular diseases. An intriguing relationship exists between insulin resistance and ADMA. Plasma levels of ADMA are positively correlated with insulin resistance in nondiabetic, normotensive people. New basic research insights that provide possible mechanisms underlying the development of insulin resistance in the setting of impaired NO bioavailability will be discussed. PMID: 16444867 [PubMed - indexed for MEDLINE] 3535. Pediatr Endocrinol Rev. 2004 Aug;1 Suppl 3:465-70. Obesity and gonadal function of women. Diamanti-Kandarakis E(1), Kandarakis HA. Author information: (1)First Dept. of Medical School in the University of Athens, Greece. akandara@otenet.gr Excessive visceral adiposity is associated with metabolic and reproductive abnormalities. Adipose tissue is an active endocrine gland and participates in multiple mechanisms in the reproductive function of women. The nature of the complex interaction of obesity with the female reproductive function remains a challenge. Several links have been implicated in the gonadal dysfunction of obese women, like insulin resistance and hyperinsulinemia, via which ovarian androgen production is stimulated resulting in hyperandrogenemia, increased peripheral aromatization of androgens to estrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased GH and IGFBPs, increased leptin levels and altered neuroregulation of the hypothalamic-pituitary-gonadal axis. The impact of obesity in these mechanisms and their influence on female reproductive function are discussed in this article. PMID: 16444176 [PubMed - indexed for MEDLINE] 3536. Expert Opin Ther Targets. 2006 Feb;10(1):119-34. Adipose targets for obesity drug development. Boss O(1), Bergenhem N. Author information: (1)Adipogenix, Inc., Boston, MA 02118, USA. oboss@vzavenue.net The prevalence of obesity is increasing rapidly in most parts of the world and effective therapeutic drugs are urgently needed. The discovery of leptin in 1994 initiated a new understanding of adipose tissue function, and adipose tissue is now known to not only store and release fatty acids, but also to produce a wealth of factors that have an impact on the regulation of body weight and blood glucose homeostasis. Also, adipocytes express proteins that engage signalling pathways playing important roles in fuel substrate and energy metabolism. These proteins constitute a diverse array of adipose target candidates for the development of drugs to treat obesity. Some of these potential targets have been validated and are now in drug development stages, providing hope that the current obesity epidemic can be addressed by effective drug treatments in the near future. PMID: 16441232 [PubMed - indexed for MEDLINE] 3537. Genet Couns. 2005;16(4):353-62. Mandibuloacral dysplasia: a report of two Egyptian cases. Afifi HH(1), El-Bassyouni HT. Author information: (1)Clinical Genetics Department, National Research Centre, Giza, Cairo, Egypt. hhafifi@hotmail.com Mandibuloacral dysplasia (MAD) is a rare disorder. Only 35 patients, coming from 22 families, have been reported worldwide. We report on two Egyptian unrelated girls with MAD. The first patient presented at the age of 5 years with acral defect and partial alopecia. The second patient presented at the age of 17 years with progressive micrognathia and loss of subcutaneous fat from the limbs. Physical examination detected the craniofacial, skeletal and cutaneous changes characteristic of MAD. Both patients were short with progeroid facies and loss of subcutaneous fat from the extremities, which fits lipodystrophy type A pattern. Radiological examination revealed delayed closure of cranial sutures, hypoplastic mandible, hypoplastic clavicles, and acroosteolysis. Both patients had normal glucose tolerance, but had fasting and post-prandial hyperinsulinemia, suggestive of insulin resistance. One patient had elevated serum triglycerides and low normal cholesterol levels, while the other patient had normal levels. Serum leptin was normal in both patients. We review the literature on mandibuloacral dysplasia and discuss the differential diagnosis. PMID: 16440877 [PubMed - indexed for MEDLINE] 3538. Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):706-15. Epub 2006 Jan 26. Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis. Klerkx AH(1), El Harchaoui K, van der Steeg WA, Boekholdt SM, Stroes ES, Kastelein JJ, Kuivenhoven JA. Author information: (1)Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points. PMID: 16439711 [PubMed - indexed for MEDLINE] 3539. Acta Neurochir (Wien). 2006 Apr;148(4):457-62. Epub 2006 Jan 27. Ruptured intracranial dermoid cysts. El-Bahy K(1), Kotb A, Galal A, El-Hakim A. Author information: (1)Department of Neurosurgery, Ain Shams University, Cairo, Egypt. khaledbahy@yahoo.com Rupture of intracranial dermoid cysts (RICDC) is a rare phenomenon. The mechanism of rupture, pathophysiology of fat in the ventricles and subarachnoid spaces, possible complications, and proper management of such conditions are proposed on the basis of a review of the literature and experience with two cases of ruptured intracranial dermoid cysts (One was in the pineal region, while another was in the fourth ventricle). It is concluded that rupture of intracranial dermoid cysts is usually spontaneous and non-fatal. Persistence of fat in the subarachnoid spaces postoperatively may last asymptomatically for years. Surgery is the only way to deal with these benign lesions. If the capsule is adherent to vital areas, incomplete removal is advised as recurrence and malignant transformation are unlikely to occur. PMID: 16437187 [PubMed - indexed for MEDLINE] 3540. Pediatr Endocrinol Rev. 2004 Mar;1(3):310-9. Adipotoxicity and the insulin resistance syndrome. Anderwald C(1), Roden M. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine III, Vienna Medical University, Vienna, Austria. During the last decades, nutritional fat intake has continuously inflated in parallel with an enormous rise in the prevalence of obesity and type-2 diabetes in adults but increasingly also in adolescents and even children. Augmented fat intake is associated with an increased mass of adipose tissue which releases free fatty acids (FFA) but also hormones and cytokines such as leptin, adiponectin, resistin, tumor necrosis factor-a and interleukin-6. In particular, FFA decrease insulin-mediated glucose transport/ phosphorylation in skeletal muscle and impair suppression of glucose production by the liver, indicating insulin resistance. In addition, ectopic lipid storage in both liver and skeletal muscle has recently been related to reduced insulin sensitivity. In conclusion, increased fat intake and expanded body fat are now held responsible for increased FFA availability and hormonal changes which may lead to insulin resistance and type- 2 diabetes. PMID: 16437024 [PubMed - indexed for MEDLINE] 3541. Int J Exp Pathol. 2006 Feb;87(1):1-16. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Anstee QM(1), Goldin RD. Author information: (1)Department of Medicine A, St Mary's Campus, Imperial College, London, UK. Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis. PMCID: PMC2517349 PMID: 16436109 [PubMed - indexed for MEDLINE] 3542. Obes Rev. 2006 Feb;7(1):59-78. Metabolically active functional food ingredients for weight control. Kovacs EM(1), Mela DJ. Author information: (1)Unilever Health Institute, Unilever R&D Vlaardingen, Vlaardingen, the Netherlands. eva.kovacs@unilever.com The scale of the obesity epidemic creates a pressing consumer need as well as an enormous business opportunity for successful development and marketing of food products with added benefits for weight control. A number of proposed functional food ingredients have been shown to act post-absorptively to influence substrate utilization or thermogenesis. Characteristics and supporting data on conjugated linoleic acid, diglycerides, medium-chain triglycerides, green tea, ephedrine, caffeine, capsaicin and calcium, are reviewed here, giving examples of how these could act to alter energy expenditure or appetite control. Consideration is also given to other factors, in addition to efficacy, which must be satisfied to get such ingredients into foods. We conclude that, for each of the safe, putatively metabolically active agents, there remain gaps in clinical evidence or knowledge of mechanisms, which need to be addressed in order to specify the dietary conditions and food product compositions where these ingredients could be of most benefit for weight control. PMID: 16436103 [PubMed - indexed for MEDLINE] 3543. Obes Rev. 2006 Feb;7(1):33-47. Energy balance adiposity and breast cancer - energy restriction strategies for breast cancer prevention. Harvie M(1), Howell A. Author information: (1)CRUK University Department of Medical Oncology, Christie Hospital, Manchester, UK. michelle.harvie@smtr.nhs.uk Excess adiposity over the pre- and postmenopausal years is linked to risk of postmenopausal breast cancer. Weight loss could potentially reduce risk amongst those with excess weight via beneficial effects on the hormonal (decreased circulating levels of oestradiol, testosterone, insulin) and secretory profiles of adipocytes (decreased production of leptin, tumour necrosis factor-alpha, interleukin 6 and increased production of adiponectin). Only modest reductions in adipose tissue are achieved and sustained with current weight loss programmes, which makes strategies to mitigate the adverse metabolic effect of adiposity a priority for cancer prevention. The adverse hormonal and secretory effects of adipose tissue are influenced substantially by acute changes in energy balance prior to changes in adiposity. Human and animal studies have shown dietary energy restriction to bring about favourable changes in circulating levels of insulin, leptin, sex hormone binding globulin, insulin-like growth factor-1, oestradiol, testosterone, reactive oxygen species, and the production and secretion of locally acting adipokines and inflammatory cytokines, that is, increased adiponectin and decreased interleukin-6. Achieving and sustaining energy restriction remains a difficult challenge. Intermittent energy restriction is a potential strategy for promoting periods of energy restriction on a long-term basis. Animal and human data suggest that intermittent energy restriction may have cancer preventative effects beyond that of chronic energy restriction and weight loss. Intermittent energy restriction may be a potential strategy for the primary prevention of breast cancer. PMID: 16436101 [PubMed - indexed for MEDLINE] 3544. Asian Pac J Cancer Prev. 2005 Oct-Dec;6(4):547-52. Obesity, breast cancer and the role of adipocytokines. Kaur T(1), Zhang ZF. Author information: (1)Division of Non Communicable Diseases, Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India. tankaur@yahoo.com Obesity is a worldwide problem which impacts the risk and prognosis of some of the more common forms of cancer, including breast cancer in post-menopausal women. As the basis for understanding the potential mechanisms of obesity and cancer relationship has advanced, a number of new hypotheses have emerged. The adipocytokines are a complex group of biologically active polypeptides. Leptin is a growth hormone, secreted by adipose tissue, whose levels are normally elevated in obese individuals and may have a promoting effect on carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Leptin interferes with the insulin signaling pathway and in type 2 diabetes plasma leptin levels are found to be correlated with the degree of insulin resistance, a relationship independent of body mass. This relationship might provide a mechanistic explanation for promotion potential. PMID: 16436010 [PubMed - indexed for MEDLINE] 3545. Clin Plast Surg. 2006 Jan;33(1):55-62, vi. Adipose tissue: stem cells and beyond. Tholpady SS(1), Llull R, Ogle RC, Rubin JP, Futrell JW, Katz AJ. Author information: (1)Department of Plastic and Reconstructive Surgery, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. sst8a@virginia.edu This article highlights potential uses for harvested fat and describes the current state of the art regarding adipose stem cells. PMID: 16427974 [PubMed - indexed for MEDLINE] 3546. An Sist Sanit Navar. 2005 Sep-Dec;28(3):357-66. [Role of IL-6 and its -174G>C polymorphism in weight management and in the metabolic comorbidities associated with obesity]. [Article in Spanish] Goyenechea E(1), Parra MD, Martínez Hernández JA. Author information: (1)Departamento de Fisiología y Nutrición, Universidad de Navarra, 31008, Spain. Obesity and its comorbidities have been associated with a low grade proinflammatory state, in which the adipose tissue seems to be involved. In fact, this tissue produces different proinflammatory cytokines, such as IL-6 and others. High circulating concentrations of IL-6 have been related to high body mass index, to diabetes mellitus type 2, to lipid abnormalities and to high blood pressure. There are some studies, which reported a relationship between IL-6 and energy metabolism, so this cytokine and its -174G>C gene polymorphism could be factors involved in the development of obesity. Different studies have associated the G allele of the IL-6 gene with obesity, with insulin resistance and with different cardiovascular risk factors. However, other published reports have associated the C allele of this gene to these metabolic disturbances and pathologies. This paper reviews recently published evidences about IL-6 and its physiopathological involvement in obesity and comorbidities, with emphasis on the role of the -174G>C polymorphism in the aetiology of these disturbances, in which obesity is a major risk factor. PMID: 16421614 [PubMed - indexed for MEDLINE] 3547. Adv Psychosom Med. 2006;27:1-23. Recent advances in obesity: adiposity signaling and fat metabolism in energy homeostasis. Aja S(1), Moran TH. Author information: (1)Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Interactions between our conserved 'thrifty genotype' and current trends toward reduced physical activity and increased food intake are posited as the root cause of the rising prevalence of obesity in the modern era. The past decade has seen tremendous advances in our understanding of the physiological regulation of energy balance and adiposity, and important insights into the pathogenesis of obesity. We have gained a more comprehensive view of the energy homeostasis system from the discovery of the adiposity hormone leptin, the subsequent identification of hypothalamic and other brain neuropeptide systems controlling energy balance, and the progress in understanding the molecular mechanisms by which cells can sense and respond to changes in metabolic state. Numerous targets have been identified for potential pharmacological and genetic approaches to obesity management. Some of the most recent developments are prototypic compounds that manipulate fat metabolism, both in peripheral tissues and in the brain, to reduce body fat synthesis and storage and to increase fat oxidation, to reduce food intake, and to increase energy expenditure. PMID: 16418539 [PubMed - indexed for MEDLINE] 3548. Nihon Rinsho. 2005 Dec;63 Suppl 12:280-4. [Genetic testing and gene-based testing for obesity]. [Article in Japanese] Hotta K(1). Author information: (1)Laboratory for Obesity, Research Group for Disease-causing Mechanism, SNP Research Center, RIKEN. PMID: 16416808 [PubMed - indexed for MEDLINE] 3549. Dermatol Surg. 2005 Nov;31(11 Pt 2):1626-33. Complications of fillers: overview. Duffy DM(1). Author information: (1)Department of Dermatology, University of Southern California, Los Angeles, California, USA. info@drdavidmduffy.com BACKGROUND: Avoiding complications requires thorough training and medical, anatomic, and esthetic common sense. Complications can occur as a function of anatomic location, technique deficiencies, the type of defect treated, identifiable host factors, infectious processes, and allergies as a consequence of intrinsic characteristics of any particular filler. They can also occur in the absence of any identifiable host factors and flawless technique. Complications following temporary fillers often occur soon after augmentation, may resolve spontaneously, and are usually easy to treat. Conversely, complications that occur after using permanent or semipermanent fillers can appear months to years after augmentation and prove very difficult to treat. OBJECTIVE: To analyze and describe complications that have occurred following soft tissue augmentation and to present strategies for avoiding, recognizing, and treating them. METHODS: Protocols and observations derived from a 24-year experience using a wide variety of soft tissue augmenting agents are presented in association with pertinent clinical literature. Characteristic complications associated with specific types of soft tissue augmenting agents are presented in tabular form. CONCLUSION: Tissue fillers offer patients an opportunity for instant gratification with minimum downtime and, in general, an extremely favorable risk-to-benefit ratio. The best way to minimize complications in both your patients and yourself is to avoid them. PMID: 16416648 [PubMed - indexed for MEDLINE] 3550. Diabetes Metab. 2005 Dec;31 Spec No 2:5S27-5S34. Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? Scheen AJ(1). Author information: (1)Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, University of Liège, Liège, Belgium. andre.scheen@chu.ulg.ac.be Elderly people are more glucose intolerant and insulin resistant than young individuals, and many of them will develop type 2 diabetes. It remains, however, controversial whether this decrease in function is due to an inevitable consequence of "biological aging" or due to environmental or lifestyle variables. Indeed, increased adiposity/altered fat distribution, decreased fat free mass/abnormal muscle composition, poor dietary habits and physical inactivity all contribute to reduce insulin sensitivity. Insulin resistance in elderly people appears to predominate in skeletal muscle, whereas hepatic glucose output seems to be almost unaffected. Several abnormalities in islet beta-cell and insulin secretion were also pointed out in elderly people such as increased amyloid deposition and decreased amylin secretion, impaired insulin secretion pulsatility, decreased insulin sensitivity of pancreatic beta-cells to insulinotropic gut hormones and diminished insulin response to non-glucose stimuli such as arginine. Controversial results were reported concerning the effects of aging on absolute insulin secretion in response to oral or intravenous glucose. However, insulin secretion appears to decrease with age, with significantly diminished beta-cell sensitivity and acute insulin response to glucose, provided it is analyzed relative to concomitant decreased insulin sensitivity. Thus, there is an interplay between decreased insulin secretion and increased insulin resistance that largely explains the abnormal glucose metabolism seen in elderly. Weight loss, especially reduction of abdominal adiposity, and increased physical activity may contribute to improve insulin sensitivity and glucose tolerance, and prevent the development of type 2 diabetes in elderly people. PMID: 16415763 [PubMed - indexed for MEDLINE] 3551. J Cosmet Laser Ther. 2005 Dec;7(3-4):147-54. Cellulite: Is there a role for injectables? Rotunda AM(1), Avram MM, Avram AS. Author information: (1)Department of Dermatology, University of Southern California Keck School of Medicine, Bennett Surgery Center, Santa Monica, CA 90404, USA. arotunda@hotmail.com BACKGROUND: Cellulite describes the cutaneous dimpling of the thighs, buttocks, and hips that is seen predominately in women. Current evidence suggests that structural differences in fat architecture between the sexes account for its appearance. Mesotherapy, a method of delivering medication locally with the use of numerous cutaneous injections, has recently become a popular method to purportedly treat the condition. METHODS: An overview of cellulite and adipocyte physiology, with a literature review and appraisal of compounds commonly used in mesotherapy. RESULTS: Experimental studies using individual mesotherapy ingredients for other conditions suggest a number of mechanisms, including lipolysis, disrupting connective tissue and augmenting circulation, which may theoretically improve cellulite. Peer-reviewed studies have not evaluated whether these effects translate clinically. CONCLUSIONS: Until further studies are performed, patients considering mesotherapy for cellulite must be aware that the substances currently being injected to treat this cosmetically disturbing, but medically benign, condition have not been thoroughly evaluated for safety or efficacy. PMID: 16414902 [PubMed - indexed for MEDLINE] 3552. Clin Sci (Lond). 2006 Feb;110(2):143-52. Neuroendocrine and metabolic effects of adipocyte-derived hormones. Jackson MB(1), Ahima RS. Author information: (1)Division of Endocrinology, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Obesity is characterized by an increase in adipose tissue mass. Contrary to the previous view of adipose tissue as simply an inert tissue devoted to energy storage, studies over the past decade have shown that adipose tissue is actively involved in regulating physiological processes and participates in disease. Adipose tissue secretes factors that exert local and systemic effects. Leptin, pro-inflammatory cytokines, resistin and proteins involved in haemodynamic regulation and coagulation are increased in obesity while adiponectin is reduced. The production of active corticosteroids is also increased in obesity. There is now growing evidence that adipocyte secretory factors regulate energy homoeostasis, as well as cardiovascular and immune systems. Some adipocyte hormones, most notably leptin, act in the brain to influence the neuroendocrine axis and energy balance, whereas adiponectin and resistin exert opposing effects on glucose and lipids. Understanding the actions of adipocyte hormones will provide novel insights into the pathophysiology and treatment of obesity. PMID: 16411891 [PubMed - indexed for MEDLINE] 3553. Nihon Koshu Eisei Zasshi. 2005 Nov;52(11):934-42. Metabolic syndrome from the view point of public health: with special reference to nonalcoholic fatty liver disease. Watanabe T(1), Murata C, Watanabe Y. Author information: (1)Department of Community Health, Tokai University School of Medicine, Kanagawa, Japan. tewatana@is.icc.u-tokai.ac.jp Changes in human behavior and lifestyle over the last century have resulted in a dramatic increase in the incidence of obesity, type 2 diabetes, and the metabolic syndrome. Differences in the reported overall prevalence of the metabolic syndrome, which is generally in the range of 10-30% depend on the diagnostic criteria and subjects of the study. Recently, Japanese criteria for diagnosis of the metabolic syndrome were defined. With these criteria, presence of visceral obesity is essential for the diagnosis and is simply determined by measurement of waist circumference. Reflecting a dramatic increase in the incidence of obesity and type 2 diabetes, the incidence of the metabolic syndrome is increasing in Japan as well as in Western countries, regardless of the criteria applied. Recently, the number of workers with elevated liver enzymes, in whom virus hepatitis, alcoholic liver disease, drug induced hepatitis, autoimmune hepatitis, and iron overload were ruled out as causal agents, has also be found to be increasing at workplace health checkups. Most of such workers have components of the metabolic syndrome and the presence of steatosis in the liver, this pathologic condition now being termed nonalcoholic fatty liver disease (NAFLD). In this review, we describe the relationship between NAFLD and the metabolic syndrome. PMID: 16408478 [PubMed - indexed for MEDLINE] 3554. Nihon Rinsho. 2006 Jan;64(1):45-9. [Effects of aging on insulin resistance and fat accumulation]. [Article in Japanese] Ohara T(1). Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine. Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and a risk factor for cardiovascular disease. Although the relationship between aging and insulin resistance has been well shown, precise mechanism of age-related insulin resistance still remain unknown. Insulin action may deteriorate with age mediated through accumulation of abdominal fat rather than aging per se. Recently it has been reported that intramyocellular lipid content and hepatic lipid content which are related to insulin resistance are increased in elderly. Alternation of fat distribution by aging may be related to age-related insulin resistance. PMID: 16408446 [PubMed - indexed for MEDLINE] 3555. Nihon Rinsho. 2006 Jan;64(1):2-5. [Adipocytokines and diabetes in the elderly]. [Article in Japanese] Hibuse T(1), Funahashi T. Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University. PMID: 16408439 [PubMed - indexed for MEDLINE] 3556. Curr Opin Lipidol. 2006 Feb;17(1):22-7. The use of fatty acid biomarkers to reflect dietary intake. Baylin A(1), Campos H. Author information: (1)Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. PURPOSE OF REVIEW: This review compares fatty acid biomarkers to assess compliance in dietary intervention trials with their application in epidemiological studies. RECENT FINDINGS: Although many studies have used fatty acid biomarkers to assess compliance in short-term dietary intervention trials and habitual diets in observational studies, there is little information on the reliability and comparability of these measures. In this review, we summarize the usefulness and limitations of fatty acid biomarkers in clinical and epidemiological studies. As there are very few recent publications in this area, a complete literature review is provided. SUMMARY: Several options are available for the biological assessment of dietary fatty acids. The type of study (short or long-term), the metabolic characteristics and expected variability in the fatty acids of interest are major considerations when determining which tissues reflect a better measure of true intake. Certain fatty acids may not be suitable to assess differences in intake under non-isocaloric conditions and when trying to identify small differences. Serum cholesterol ester is the most suitable serum fraction to assess short-term dietary compliance, but given the multiple factors that affect response, the quantification of compliance should be interpreted with caution. Adipose tissue is the biomarker of choice for long-term intake, but a preferred blood constituent (plasma versus erythrocytes) is difficult to establish given the data available to date. Future studies should explore the use of whole blood as an alternative choice to measure fatty acid intake in epidemiological studies. PMID: 16407712 [PubMed - indexed for MEDLINE] 3557. Medicina (Kaunas). 2005;41(12):989-1001. [Peptides regulating food intake and body weight]. [Article in Lithuanian] Stasiūniene N(1), Praskevicius A. Author information: (1)Department of Biochemistry, Kaunas University of Medicine, Kaunas, Lithuania. stasiune@med.kmu.lt Regulation of food intake and body weight depends on direct and feedback signals from adipose tissue, alimentary canal and pancreas to the hypothalamus nuclei, where hunger and satiety centers are. During the last decade a few signaling molecules of peptide origin were discovered, which play an important role in the regulation of energy intake and energy expenditure as well as in obesity. So, adipocytes synthesize and express leptin, the product of Ob gene, a regulator of long-term food intake, in amounts proportional to the fat amount, while alimentary canal hormones are regulators of short-term food intake (from meal to meal). Some peptides decrease food intake as they promote satiety (anorexigenic signals), other peptides, contrary, increase food intake as they induce appetite (orexigenic signals). Disturbed equilibrium between the anorexigenic and orexigenic factors manifests as food intake disorders, increase in body weight and obesity or decrease in body weight, i.e. cachexia. PMID: 16401955 [PubMed - indexed for MEDLINE] 3558. J Midwifery Womens Health. 2006 Jan-Feb;51(1):26-34. Environmental contaminants in breast milk. Nickerson K(1). Author information: (1)knickrox@yahoo.com Toxic environmental contaminants can be transferred from mother to infant via breastfeeding. Persistent organic pollutants (POPs) are a family of lipophilic stable chemicals that bioaccumulate in adipose tissue and create a lasting toxic body burden. Breastfeeding provides a significant source of exposure to POPs early in human life, the effects of which are unknown, and is the subject of a growing body of research. Despite the possibility of harm from environmental contaminants in breast milk, breastfeeding is still recommended as the best infant feeding method. This article reviews what is known about POPs in breast milk and their effect on infant development to inform clinicians about the issue, provide recommendations for practice, and promote environmental and public health policies that reduce human exposure to harmful pollutants. PMID: 16399607 [PubMed - indexed for MEDLINE] 3559. Postgrad Med J. 2006 Jan;82(963):2-8. Malnutrition and ageing. Hickson M(1). Author information: (1)Nutrition and Dietetic Department, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. mhickson@hhnt.nhs.uk This article aims to provide an overview of the problems that exist in relation to malnutrition and the elderly population. The changes that occur in body composition during ageing are described and how this may affect disease risk. The possible metabolic processes behind weight loss are discussed and the numerous factors that affect nutritional status in the older age group are described. Prevention of malnutrition in this group is important and so the roles of nutrition screening and assessment are examined. PMCID: PMC2563720 PMID: 16397072 [PubMed - indexed for MEDLINE] 3560. Nat Clin Pract Cardiovasc Med. 2006 Jan;3(1):35-42. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed adipocytokines. Among adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases. PMID: 16391616 [PubMed - indexed for MEDLINE] 3561. J Mol Med (Berl). 2006 Feb;84(2):112-21. Epub 2005 Dec 31. Human genetics of adiponectin in the metabolic syndrome. Yang WS(1), Chuang LM. Author information: (1)Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.. Adiponectin, an adipose-derived plasma protein, has been well established to be an important biomarker for metabolic syndrome and its complications after exhausted studies in humans. Animal and cell culture experiments also support most claims from human observations of its roles in the metabolic syndrome. Reproducible results of human genetic studies of diverse ethnic origin and by different investigators may provide the evidence for its causative roles in the pathogenesis of the metabolic syndrome and further insight into the genetic constitutions of the metabolic syndrome. Some of the common polymorphisms in the promoter region, exon and intron 2, and the rare nonsynonymous mutations in exon 3 of the human adiponectin gene were repeatedly shown in many studies from many different ethnic populations to associate with the phenotypes related to body weight, glucose metabolism, insulin sensitivity, and risk of type 2 diabetes mellitus and coronary artery disease. The association of adiponectin genetic variations with dyslipidemia and blood pressure was less explored. The common polymorphisms and rare mutations of the human adiponectin gene itself were demonstrated to associate with differential expression of adiponectin at the plasma protein level and mRNA level in adipose tissue. The PPARgamma2 Pro12Ala variants were also shown to influence insulin sensitivity in interaction with adiponectin genotype or to influence plasma adiponectin levels. However, the results were not consistent. Three genome-wide scans for the loci that regulate plasma adiponectin concentration suggest further exploration on chromosomes 5, 9, 14, 15, and 18 is required. These human genetic studies on adiponectin and the metabolic syndrome strongly suggest that adiponectin is one of the causative factors in its pathogenesis and provide significant insights into the genetic makeup of the metabolic syndrome. Extension from these studies may accelerate the discovery of new molecular targets for future therapeutic interventions. PMID: 16389553 [PubMed - indexed for MEDLINE] 3562. Biotechnol Genet Eng Rev. 2006;23:291-308. Adipose-derived mesenchymal cells (AMCs): a promising future for skeletal tissue engineering. Xu Y(1), Malladi P, Wagner DR, Tataria M, Chiou M, Sylvester KG, Longaker MT. Author information: (1)Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford University, Stanford, CA 94305-5148, USA. PMID: 22530513 [PubMed - indexed for MEDLINE] 3563. Int J Obes (Lond). 2005 Sep;29 Suppl 2:S97-100. Adipose tissue and metabolic effects: new insight into measurements. Pietrobelli A(1), Boner AL, Tatò L. Author information: (1)Pediatric Unit, Verona University Medical School, Verona, Italy. angpie@tin.it BACKGROUND: Epidemiologic evidence supports the theory that the relation between obesity and disease risk begins early in life, and those risk factors for disease track, or remain at a similar level, with advancing age, growth, and development. The fat tissue, once considered as a depot for energy substrate, is a metabolically active tissue. The fat cells produce agents that regulate a host of physiological processes directly related to carbohydrate and fat metabolism and the development of cardiovascular disease and type 2 diabetes. AIM: To discuss fat tissue, and fat distribution in relation to body composition measurements, with particular emphasis on imaging techniques (ie, dual energy X-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI)) and its relationship with metabolic and cardiovascular heath variables mediated by the metabolic characteristics of the adipose tissue. DISCUSSION: In sum, the medical and physiological health complications of childhood obesity are well documented. Imaging methods are considered the most accurate means available for in vivo quantification at the tissue-organ level and the methods of choice for calibration of field methods designed to measure adipose tissue. PMID: 16385759 [PubMed - indexed for MEDLINE] 3564. Gac Med Mex. 2005 Nov-Dec;141(6):505-12. [Adipocitokines, adipose tissue and its relationship with immune system cells]. [Article in Spanish] Sánchez-Muñoz F(1), García-Macedo R, Alarcón-Aguilar F, Cruz M. Author information: (1)Unidad de Investigacíon Médica en Bioquímica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, D. F., México. fausto22@yahoo.com Adipokines or adipocytokines are the proteins secreted by the adipose tissue. These bioactive molecules include proteins that modify insulin sensitivity (acylation-stimulating protein (ASP), TNF-alpha IL-6, resistin, leptin and adiponectin), and proteins that have known effects on vascularity (angiotensinogen and the plasminogen inhibitor protein PAI-I). Several studies have found a close relationship between adipocytes and immune cells as a consequence of evolutionary mechanisms that favor metabolic adaptation and survival under adverse conditions. It is known that adipokines contribute to the inflammation and insulin resistance present in obese individuals. The aim of this review is to analyze current information related to the physiology of the adipose tissue, with a special emphasis on the secretion of adipokines and their role in inflammation. We recommend that therapies addressing the treatment of obesity related disorders should focus on modifying the inflammatory process that originates in the adipose tissue. PMID: 16381506 [PubMed - indexed for MEDLINE] 3565. Circulation. 2006 Feb 14;113(6):898-918. Epub 2005 Dec 27. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH; American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity is becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Health service use and medical costs associated with obesity and related diseases have risen dramatically and are expected to continue to rise. Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, in addition to as-yet-unrecognized mechanisms. On the whole, overweight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death because of their impact on the cardiovascular system. The pathophysiology of these entities that are linked to obesity will be discussed. However, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. In this statement, we review the available evidence of the impact of obesity on CVD with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system. PMID: 16380542 [PubMed - indexed for MEDLINE] 3566. Int J Biochem Cell Biol. 2006;38(5-6):804-19. Epub 2005 Dec 9. Contribution of adipocyte-derived factors to beta-cell dysfunction in diabetes. Zhao YF(1), Feng DD, Chen C. Author information: (1)Department of Physiology, The Fourth Military Medical University, Xi'an, China. In addition to serving as an energy reservoir, the adipocyte has been characterized as an endocrine cell, secreting many bioactive factors which influence energy homeostasis. Being overweight, with excessive adipose tissue, is considered to be part of the pathogenesis of type 2 diabetes. Insulin resistance and beta-cell dysfunction are two major pathophysiological changes seen in type 2 diabetes. In addition to inducing insulin resistance in insulin-responsive tissues, adipocyte-derived factors play an important role in the pathogenesis of beta-cell dysfunction. Leptin, free fatty acids, adiponectin, tumor necrosis factor-alpha and interleukin-6 are all produced and secreted by adipocytes, and may directly influence aspects of beta-cell function, including insulin synthesis and secretion, insulin cell survival and apoptosis. During the progression from normal weight to obesity and on to overt diabetes, the adipocyte-derived factors contribute to the occurrence and development of beta-cell dysfunction and type 2 diabetes. PMID: 16378747 [PubMed - indexed for MEDLINE] 3567. J Am Coll Nutr. 2005 Dec;24(6 Suppl):537S-46S. The role of dairy foods in weight management. Zemel MB(1). Author information: (1)The University of Tennessee, 1215 W. Cumberland Ave, Room 229, Knoxville, TN 37996-1920, USA. mzemel@utk.edu Dietary calcium appears to play a pivotal role in the regulation of energy metabolism and obesity risk. High calcium diets attenuate body fat accumulation and weight gain during periods of over-consumption of an energy-dense diet and to increase fat breakdown and preserve metabolism during caloric restriction, thereby markedly accelerating weight and fat loss. This effect is mediated primarily by circulating calcitriol, which regulates adipocyte intracellular Ca(2+). Studies of human adipocyte metabolism demonstrate a key role for intracellular Ca(2+) in regulating lipid metabolism and triglyceride storage, with increased intracellular Ca(2+) resulting in stimulation of lipogenic gene expression and lipogenesis and suppression of lipolysis, resulting in adipocyte lipid filling and increased adiposity. Moreover, the increased calcitriol produced in response to low calcium diets stimulates adipocyte Ca(2+) influx and, consequently, promotes adiposity, while higher calcium diets inhibit lipogenesis, promote lipolysis, lipid oxidation and thermogenesis and inhibit diet-induced obesity in mice. Notably, dairy sources of calcium exert markedly greater effects in attenuating weight and fat gain and accelerating fat loss. This augmented effect of dairy products versus supplemental calcium has been localized, in part, to the whey fraction of dairy and is likely due to additional bioactive compounds, such as angiotensin converting enzyme (ACE) inhibitors in dairy, as well as the rich concentration of branched chain amino acids, which act synergistically with calcium to attenuate adiposity; however, these compounds do not fully account for the observed effects, as whey has significantly greater bioactivity than found in these compounds. These concepts are confirmed by epidemiological data as well as recent clinical trials which demonstrate that diets which include at least three daily servings of dairy products result in significant reductions in body fat mass in obese humans in the absence of caloric restriction and markedly accelerates the weight and body fat loss secondary to caloric restriction compared to low dairy diets. These data indicate an important role for dairy products in both the ability to maintain a healthy weight and the management of overweight and obesity. PMID: 16373953 [PubMed - indexed for MEDLINE] 3568. Physiol Rev. 2006 Jan;86(1):205-43. Skeletal muscle lipid metabolism in exercise and insulin resistance. Kiens B(1). Author information: (1)Copenhagen Muscle Research Centre, Dept. of Human Physiology, Institute of Exercise and Sports Sciences, University of Copenhagen, 13 Universitetsparken, DK-2100 Copenhagen, Denmark. bkiens@aki.ku.dk Lipids as fuel for energy provision originate from different sources: albumin-bound long-chain fatty acids (LCFA) in the blood plasma, circulating very-low-density lipoproteins-triacylglycerols (VLDL-TG), fatty acids from triacylglycerol located in the muscle cell (IMTG), and possibly fatty acids liberated from adipose tissue adhering to the muscle cells. The regulation of utilization of the different lipid sources in skeletal muscle during exercise is reviewed, and the influence of diet, training, and gender is discussed. Major points deliberated are the methods utilized to measure uptake and oxidation of LCFA during exercise in humans. The role of the various lipid-binding proteins in transmembrane and cytosolic transport of lipids is considered as well as regulation of lipid entry into the mitochondria, focusing on the putative role of AMP-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), and carnitine during exercise. The possible contribution to fuel provision during exercise of circulating VLDL-TG as well as the role of IMTG is discussed from a methodological point of view. The contribution of IMTG for energy provision may not be large, covering approximately 10% of total energy provision during fasting exercise in male subjects, whereas in females, IMTG may cover a larger proportion of energy delivery. Molecular mechanisms involved in breakdown of IMTG during exercise are also considered focusing on hormone-sensitive lipase (HSL). Finally, the role of lipids in development of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed. PMID: 16371598 [PubMed - indexed for MEDLINE] 3569. J Endocrinol Invest. 2005 Oct;28(9):849-52. Ghrelin and the metabolic balance. Ukkola O(1). Author information: (1)Department of Internal Medicine and Biocenter Oulu, University of Oulu, Finland. olavi.ukkola@oulu.fi Several studies have provided evidence that ghrelin is involved in the regulation of metabolic balance. Recent data provide evidence that when studying the effects of ghrelin on energy balance, differential influences of the acylated and non-acylated forms of the peptide must be considered. Although the correlation between the two forms is good, they may be different hormones with opposite actions with non-acylated ghrelin being able to antagonize some of the effects of the acylated form. Future studies will reveal which of the two forms of ghrelin, the acylated or non-acylated forms, dominates and determines the net influence on energy balance. PMID: 16370569 [PubMed - indexed for MEDLINE] 3570. Mol Genet Metab. 2006 Apr;87(4):289-302. Epub 2005 Dec 20. Laminopathies: multisystem dystrophy syndromes. Jacob KN(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, 75390-9052, USA. Erratum in Mol Genet Metab. 2006 Aug;88(4):391. Laminopathies are a heterogeneous group of genetic disorders due to abnormalities in type A lamins and can manifest varied clinical features affecting many organs including the skeletal and cardiac muscle, adipose tissue, nervous system, cutaneous tissue, and bone. Mutations in the gene encoding lamins A and C (LMNA) cause primary laminopathies, including various types of lipodystrophies, muscular dystrophies and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies, and restrictive dermopathy. The secondary laminopathies are due to mutations in ZMPSTE24 gene which encodes for a zinc metalloproteinase involved in processing of prelamin A into mature lamin A and cause mandibuloacral dysplasia and restrictive dermopathy. Skin fibroblast cells from many patients with laminopathies show a range of abnormal nuclear morphology including bleb formation, honeycombing, and presence of multi-lobulated nuclei. The mechanisms by which mutations in LMNA gene cause multisystem dystrophy are an active area of current investigation. Further studies are needed to understand the underlying mechanisms of marked pleiotropy in laminopathies. PMID: 16364671 [PubMed - indexed for MEDLINE] 3571. Blood Purif. 2006;24(1):51-5. Association between inflammation and malnutrition as risk factors of cardiovascular disease. Kaysen GA(1). Author information: (1)Division of Nephrology, Department of Medicine, University of California, Davis, CA 95616, USA. gakaysen@ucdavis.edu Cardiovascular disease is the leading cause of death among dialysis patients. The relative risk of mortality increases as serum albumin concentration and body mass index decline. While these are generally associated with nutritional status, inflammation causes sarcopenia and decreased albumin concentration by reducing synthesis of proteins and increasing their catabolic rate. While inflammation can arise from atherosclerotic blood vessels, systemic inflammation from any source can alter the vascular endothelium and plasma protein composition in ways that promotes vascular injury. High-density lipoprotein synthesis is decreased and the high-density lipoprotein present is less capable of reducing inflammation. Activation of neutrophils favors lipoprotein oxidation. Surprisingly, while obesity is associated with cytokine production in patients without renal failure, as well as among dialysis patients, increased body mass index, whether reflecting muscle mass or adipose tissue, is associated with a decline in mortality rates. Copyright 2006 S. Karger AG, Basel. PMID: 16361841 [PubMed - indexed for MEDLINE] 3572. Cell. 2005 Dec 16;123(6):993-9. The many faces of PPARgamma. Lehrke M(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. In an era marked by the increasing prevalence of obesity, diabetes, and cardiovascular disease, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a transcriptional regulator of metabolism whose activity can be modulated by direct binding of small molecules. As the master regulator of fat-cell formation, PPARgamma is required for the accumulation of adipose tissue and hence contributes to obesity. Yet PPARgamma ligands are clinically effective antidiabetic drugs, although side effects limit their utility. Can PPARgamma be targeted with greater benefit and with less risk to patients? The answer depends upon the basic biology of PPARgamma, and the possibility of selectively modulating the activity of this nuclear receptor in a tissue- and target-gene-specific manner. PMID: 16360030 [PubMed - indexed for MEDLINE] 3573. J Dairy Sci. 2006 Jan;89(1):1-14. Invited review: Methods to determine body fat reserves in the dairy cow with special regard to ultrasonographic measurement of backfat thickness. Schröder UJ(1), Staufenbiel R. Author information: (1)Klinik für Klauentiere, Freie Universität Berlin, D-14163 Berlin, Germany. schroeder.ulf@vetmed.fu-berlin.de As the dairy cow uses body energy reserves in early lactation, body condition scoring has become an integral part of dairy herd management. Several methods based on visual and tactile evaluation have been developed. Problems caused by the subjectivity of these techniques have been reported. Alternative approaches to predict energy reserves or energy balance in dairy cattle include metabolic profiling and measurement of live weight, heart girth, or skinfold thickness. A less common method to assess fat reserves in body tissues is measuring backfat thickness (BFT) by using ultrasound. An ultrasound technique has been established to predict carcass quality in beef cattle. A new aspect is the application of ultrasound as a monitoring tool in dairy herd management where another location has to be evaluated. This technique has been validated by relating BFT to total body fat (TBF) content and carcass BFT. Backfat thickness also has been related to other methods of body condition scoring. Target values for the development of BFT throughout lactation are available. The relationship between BFT and TBF content is highly significant although biased by multiple factors. A change in BFT of 1 mm equates to approximately 5 kg of TBF content. Measuring BFT by ultrasound is of added value compared with other body condition scoring systems because it is objective and precise. Changes in body condition can be detected and evaluated properly. PMID: 16357263 [PubMed - indexed for MEDLINE] 3574. Am J Med Sci. 2005 Dec;330(6):290-4. The key role of insulin resistance in the cardiometabolic syndrome. Gill H(1), Mugo M, Whaley-Connell A, Stump C, Sowers JR. Author information: (1)Department of Internal Medicine, School of Medicine, University of Missouri-Columbia, Harry S. Truman VA Medical Center, Columbia, Missouri 65212, USA. Insulin resistance is invariably present in patients with the cardiometabolic syndrome and is thought to play a key role in its pathogenesis. It represents a complex interaction of maladaptive characteristics related to impaired insulin action at target organs and external factors such as genetics and environment. It is likely that the molecular factors that underlie insulin resistance and resultant hyperinsulinemia contribute to many of the clinical components of the cardiometabolic syndrome, although the precise associations remain poorly understood. Abnormalities of various adipocytokines (particularly reduced circulating levels of adiponectin and leptin) resistance may also play a role in the genesis of insulin resistance. Genetic factors are an important determinant of insulin sensitivity. Effective management of the cardiometabolic syndrome will ultimately depend on our understanding of the underlying molecular mechanisms of key components of this disorder, such as insulin resistance. PMID: 16355013 [PubMed - indexed for MEDLINE] 3575. Am J Med Sci. 2005 Dec;330(6):280-9. Fat as an endocrine organ: relationship to the metabolic syndrome. Hutley L(1), Prins JB. Author information: (1)Centre for Diabetes and Endocrine Research, University of Queensland, Australia. Obesity and the metabolic syndrome have both reached pandemic proportions. Together they have the potential to impact on the incidence and severity of cardiovascular pathologies, with grave implications for worldwide health care systems. The metabolic syndrome is characterized by visceral obesity, insulin resistance, hypertension, chronic inflammation, and thrombotic disorders contributing to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Obesity is a key component in development of the metabolic syndrome and it is becoming increasingly clear that a central factor in this is the production by adipose cells of bioactive substances that directly influence insulin sensitivity and vascular injury. In this paper, we review advances in the understanding of biologically active molecules collectively referred to as "adipokines" and how dysregulated production of these factors in obese states mediates the pathogenesis of obesity associated metabolic syndrome. PMID: 16355012 [PubMed - indexed for MEDLINE] 3576. Am J Med Sci. 2005 Dec;330(6):269-72. Definition of the metabolic syndrome: current proposals and controversies. Reisin E(1), Alpert MA. Author information: (1)Louisiana State University Health Science Center, Department of Medicine, Section of Nephrology, New Orleans, Louisiana 70112-2822, USA. EReisin@lsuhsc.edu Metabolic syndrome includes a clustering of metabolic derangements that cause affected subjects to have an increased risk for developing diabetes, cardiovascular disease, and, according to recent epidemiologic studies, chronic kidney disease. The present review discusses four definitions of metabolic syndrome published by different national and international committees. In an effort to bridge the differences existent in those classifications, a unified definition that recognizes the increased biologic activity of the upper visceral fatty tissue and the strong association of abdominal obesity as a leading part of metabolic syndrome is proposed herein. The diagnosis of metabolic syndrome is reserved for pre-diabetic patients who share the risk of becoming diabetic or developing cardiovascular or chronic kidney disease. PMID: 16355010 [PubMed - indexed for MEDLINE] 3577. Am J Med Sci. 2005 Dec;330(6):264-8. Metabolic syndrome: historical perspectives. Leslie BR(1). Author information: (1)Department of Medicine, Section of Nephrology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. blesli@lsuhsc.edu The metabolic syndrome is an aggregation of biochemical and physical conditions that presage the development of atherosclerotic cardiovascular disease. The history of the metabolic syndrome is rooted in the recognition of adipose tissue as a heterogeneous, biologically active organ, as well as in the concepts of insulin resistance and its consequences. Establishment of the metabolic syndrome as a disease entity has been hindered by non-uniform criteria for its diagnosis. PMID: 16355009 [PubMed - indexed for MEDLINE] 3578. Nephrology (Carlton). 2005 Dec;10(6):599-605. Should we quantify insulin resistance in patients with renal disease? Shen Y(1), Peake PW, Kelly JJ. Author information: (1)Department of Nephrology, Prince of Wales Hospital, Randwick, Australia. Comment in Nephrology (Carlton). 2005 Dec;10(6):597-8. Cardiovascular disease is a major cause of morbidity and mortality in dialysis patients. Vascular disease develops before the initiation of dialysis, and it is now recognized that chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Death from cardiovascular disease is a more common endpoint of CKD than progression to dialysis. There are multiple mechanisms that contribute to the increased vascular risk of CKD, one of which is the presence of insulin resistance (IR). CKD is characterised by many features of the metabolic syndrome, and features of IR are also observed in dialysis and transplant patients. IR may be quantified by several different methods. One such method is homeostatic model assessment (HOMA) technique, which derives a measurement of IR from fasting plasma glucose and insulin concentrations. The HOMA index has been demonstrated to be an independent predictor of survival in dialysis patients. CKD is characterised by a chronic inflammatory response and abnormalities in the production and regulation of adipose tissue derived proteins, which may contribute to the development of IR. There are a range of interventions including diet and exercise programmes or medications that may influence IR; however, the impact of these interventions in the context of CKD has not been systematically evaluated. PMID: 16354245 [PubMed - indexed for MEDLINE] 3579. AAPS J. 2005 Oct 26;7(3):E686-92. Microdialysis of large molecules. Clough GF(1). Author information: (1)Infection, Inflammation and Repair Research Division, School of Medicine, University of Southampton, UK. G.F.Clough@soton.ac.uk Microdialysis has been used in many tissues, including skin, brain, adipose tissue, muscle, kidney, and gastrointestinal tract, to recover low-molecular mass endogenous mediators, metabolites, and xenobiotics from the interstitial space. Recently, molecules of larger molecular mass, such as plasma proteins, cytokines, growth factors, and neuropeptides, have also been recovered successfully using larger-pore membranes. Microdialysis recovery of large molecules offers the opportunity to identify patterns of protein expression in a variety of tissue spaces and to evaluate clinically useful biomarkers of disease. From this may develop a better understanding of the disease process and its diagnosis and more targeted approaches to therapy. PMCID: PMC2751271 PMID: 16353945 [PubMed - indexed for MEDLINE] 3580. Bosn J Basic Med Sci. 2005 Nov;5(4):30-4. Obesity biological and psychological aspect. Fiseković S(1). Author information: (1)Department of Psychiatry, University of Sarajevo Medical Center, Bosnia and Herzegovina. There is no unique pattern to deal with obesity unless is presented as complex of biological and psychological factors. A lot of studies deal with only one side of it. This work shows both sides and discusses about all relevant factors, which are involved in pathogenesis of obesity. This is only way for finding better approaches for treatment and understandings for this issue. PMID: 16351595 [PubMed - indexed for MEDLINE] 3581. Endokrynol Pol. 2005 May-Jun;56(3):314-21. [Physiological significance of estrogens in men--breakthrough in endocrinology]. [Article in Polish] Kula K(1), Slowikowska-Hilczer J, Walczak-Jedrzejowska R, Kula P, Oszukowska E, Marchlewska K, Wranicz JK. Author information: (1)Department of Andrology and Endocrinology of Fertility, Institute of Endocrinology, Medical University, Lódź. kkula@csk.am.lodz.pl Estradiol (E2) is traditionally recognised as the female sex hormone. It has been believed for 40 years, that E2 didn't exert any influence or caused impairment of the gonadal function in men. The main source of E2 in men is adipose tissue and the brain. E2 is also produced in adrenals, liver, mammary glands, hair and in male gonad. Daily production and the level of E2 in the blood in men are higher than those in postmenopausal women. At the end of the 80-ties we were first reporting that during sexual maturation E2 can be the important hormonal signal for the initiation of spermatogenesis. The traditional view about unimportant or inhibitory role of E2 in male physiology was finally refuted thanks to discovering estrogen receptors in males. In the 90-ties, transgenic mice with the lack of estrogen receptor (ER) or gene encoding enzyme aromatase, that enable the conversion of testosterone into E2, were also produced. Observations of men with inherited mutations of these genes, considerably extended our knowledge about E2 in men in stroma bones formation, inhibition of their growing, lipids metabolism and sexual maturation, the effects that were attributed to testosterone action until today. New data also points at important role of estrogens and ER in the function of the cardio-vascular system and in counteracting coronary disease in men. PMID: 16350725 [PubMed - indexed for MEDLINE] 3582. Curr Opin Nephrol Hypertens. 2006 Jan;15(1):8-13. The tissue renin-angiotensin system and intracellular signalling. Fleming I(1), Kohlstedt K, Busse R. Author information: (1)Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. fleming@em.uni-frankfurt.de PURPOSE OF REVIEW: The renin-angiotensin system is not what it was, or for that matter not necessarily where we thought it should be. For example, there is a novel angiotensin I-metabolizing enzyme that generates angiotensin 1-7 rather than angiotensin II. Moreover, we are slowly realizing the importance of local rather than circulating angiotensin II. RECENT FINDINGS: Rather than concentrating on the systemic renin-angiotensin system, recent work has concentrated on elucidating the consequences of increasing angiotensin II production within specific organs, such as the heart and vasculature, as well as in the pancreas and in adipose tissue. Inhibition of angiotensin II production either using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers not only reverses remodelling but also increases tissue insulin sensitivity. Targeting the renin-angiotensin system clinically delays the onset of type 2 diabetes, but the mechanisms involved are not clearly understood. Moreover, at least one other angiotensin-converting enzyme homologue (ACE2) plays a significant role in the regulation of heart and kidney function, and as it generates angiotensin 1-7 from angiotensin I, it is proposed to counteract the detrimental effects associated with the activation of the classic renin-angiotensin system. SUMMARY: There is a need to re-evaluate the role(s) played by the molecular components of the "extended" local renin-angiotensin system and their role in vascular disease and type 2 diabetes. PMID: 16340660 [PubMed - indexed for MEDLINE] 3583. J Physiol Pharmacol. 2005 Dec;56 Suppl 6:5-25. Neuro-hormonal control of food intake: basic mechanisms and clinical implications. Konturek PC(1), Konturek JW, Cześnikiewicz-Guzik M, Brzozowski T, Sito E, Konturek SJ. Author information: (1)Department of Physiology, Jagiellonian University Medical College, Cracow, Poland. Obesity is one of the most common metabolic diseases and the greatest threats of the health because of possibility of numerous complications. In order to design effective drugs or apply the helpful surgical procedure it is essential to understand physiology of appetite control and pathophysiology of obesity. According to the first law of thermodynamics, the energy input in the form of food, equals energy expenditure through exercise, basal metabolism, thermogenesis and fat biosynthesis. The control of body weight actually concerns the control of adipose tissue with the key role of hypothalamus, possessing several neuronal centers such as that in lateral hypothalamic nuclei considered to be "hunger" center and in ventromedial nuclei serving as the "satiety" center. In addition, paraventricular and arcuate hypothalamic nuclei (ARC) are the sites where multiple hormones, released from the gut and adipose tissue, converge to regulate food intake and energy expenditure. There are two distinct types of neurons in ARC that are important in control of food intake; (1) preopiomelanocortin (POMC) neurons activated by an orexigenic hormones and releasing alpha-melanocyte-stimulating hormone (alpha-MSH) in satiety center and (2) neurons activated by orexigenic peptides such as ghrelin that release the substances including neuropeptide Y (NPY) and Agouti-Related Peptide (AgRP) in hunger center. ARC integrates neural (mostly vagal) and humoral inputs such as enteropeptides including orexigenic (ghrelin and orexins) and an orexigenic peptides (cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin and others) that exert a physiological role in regulating appetite and satiety. The peripherally (gut, adipose tissue) and centrally expressed modulators of appetitive behavior act through specific receptors in the afferent (mostly vagal) nerves and hypothalamic neurons implicated in adiposity signaling and regulation of food intake. PMID: 16340035 [PubMed - indexed for MEDLINE] 3584. Am J Physiol Endocrinol Metab. 2006 Jan;290(1):E1-E8. Hexosamines, insulin resistance, and the complications of diabetes: current status. Buse MG(1). Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA. busemg@musc.edu The hexosamine biosynthesis pathway (HBP) is a relatively minor branch of glycolysis. Fructose 6-phosphate is converted to glucosamine 6-phosphate, catalyzed by the first and rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT). The major end product is UDP-N-acetylglucosamine (UDP-GlcNAc). Along with other amino sugars generated by HBP, it provides essential building blocks for glycosyl side chains, of proteins and lipids. UDP-GlcNAc regulates flux through HBP by regulating GFAT activity and is the obligatory substrate of O-GlcNAc transferase. The latter is a cytosolic and nuclear enzyme that catalyzes a reversible, posttranslational protein modification, transferring GlcNAc in O-linkage (O-GlcNAc) to specific serine/threonine residues of proteins. The metabolic effects of increased flux through HBP are thought to be mediated by increasing O-GlcNAcylation. Several investigators proposed that HBP functions as a cellular nutrient sensor and plays a role in the development of insulin resistance and the vascular complications of diabetes. Increased flux through HBP is required and sufficient for some of the metabolic effects of sustained, increased glucose flux, which promotes the complications of diabetes, e.g., diminished expression of sarcoplasmic reticulum Ca(2+)-ATPase in cardiomyocytes and induction of TGF-beta and plasminogen activator inhibitor-1 in vascular smooth muscle cells, mesangial cells, and aortic endothelial cells. The mechanism was consistent with enhanced O-GlcNAcylation of certain transcription factors. The role of HBP in the development of insulin resistance has been controversial. There are numerous papers showing a correlation between increased flux through HBP and insulin resistance; however, the causal relationship has not been established. More recent experiments in mice overexpressing GFAT in muscle and adipose tissue or exclusively in fat cells suggest that the latter develop in vivo insulin resistance via cross talk between fat cells and muscle. Although the relationship between HBP and insulin resistance may be quite complex, it clearly deserves further study in concert with its role in the complications of diabetes. PMCID: PMC1343508 PMID: 16339923 [PubMed - indexed for MEDLINE] 3585. Int J Epidemiol. 2006 Feb;35(1):83-92. Epub 2005 Dec 8. What aspects of body fat are particularly hazardous and how do we measure them? Snijder MB(1), van Dam RM, Visser M, Seidell JC. Author information: (1)Institute of Health Sciences, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, The Netherlands. marieke.snijder@falw.vu.nl PMID: 16339600 [PubMed - indexed for MEDLINE] 3586. Clin Sci (Lond). 2006 Jan;110(1):1-9. The adipocyte life cycle hypothesis. Smith J(1), Al-Amri M, Dorairaj P, Sniderman A. Author information: (1)The Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. The adipocyte life cycle hypothesis states that the metabolic properties of an adipocyte vary predictably during its life cycle: that as an adipocyte matures, it accumulates triacylglycerol (triglyceride) and becomes larger; that the rates of triacylglycerol synthesis and lipolysis are matched within adipocytes and that larger adipocytes, in general, have greater rates of triacylglycerol synthesis and, concurrently, greater rates of lipolysis and, therefore, larger adipocytes have greater rates of transmembrane fatty acid flux; and that the secretion of cytokines can also be related to adipocyte size with larger adipocytes having a more unfavourable profile of cytokine secretion than smaller adipocytes. Adipocyte location is an important modifier of this relationship and the favoured sites of adipocyte proliferation are a function of gender and the position within the life cycle of the organism at which proliferation occurs. The adipocyte life cycle hypothesis posits that the metabolic consequences of obesity depend on whether expansion of adipose tissue is achieved primarily by an increase in adipocyte number or adipocyte size. This hypothesis may explain a variety of previously unanswered clinical puzzles such as the vulnerability of many peoples from South East Asia to the adverse metabolic consequences of obesity. PMID: 16336200 [PubMed - indexed for MEDLINE] 3587. Presse Med. 2005 Sep 10;34(15):1087-94. [Lipid disorders in patients with HIV-induced diseases]. [Article in French] Chanu B(1), Valensi P. Author information: (1)Service d'endocrinologie, de diabétologie et de nutrition, Hôpital Jean Verdier, Bondy (93). bchanu@jvr.aphp.fr Before the availability of protease inhibitors, elevated triglyceride levels were frequently observed in patients with advanced-stage HIV infection. Since the addition of protease inhibitors to combination treatments, metabolic side effects (alterations in distribution of adipose tissue and metabolic disorders combining dyslipidemia, insulin-resistance and glucose intolerance) have been observed in HIV-positive patients receiving these treatments. Reverse transcriptase nucleoside inhibitors also provoke metabolic disorders. Dyslipidemia is defined by an increase in triglyceride levels of varying and sometimes major intensity, either isolated or combined with a more moderate increase in LDL-cholesterol, while HDL-cholesterol levels may decrease or remain unchanged. These metabolic alterations are potentially atherogenic and may explain these patients' increased risk of cardiovascular disorders. Their mechanism is complex and not yet clearly elucidated. The infection, the improvement in patients' general health and immune status, and individual predisposing factors are probably involved. Treatment probably plays a major role, since the different drugs in these two classes show effects of clearly different intensity. In vitro and ex vivo studies suggest that protease inhibitors alter adipocyte differentiation and induce insulin resistance. Reverse transcriptase nucleoside inhibitors modify adipocyte metabolism too, promoting tissue atrophy. Endocrine factors (cortisol and growth hormones) are also likely to have a role in this hypertrophy of adipose, especially visceral, tissue. These metabolic abnormalities result mainly from the effects of the antiretroviral drugs, notably protease inhibitors, on the hepatic lipid metabolism and on tissue sensitivity to insulin. Lipodystrophy contributes to these abnormalities, as does the reduction in cytokine secretion by adipose tissue. Management of these metabolic disorders is based primarily on a change in the drug regimen (administration of the least deleterious combinations), followed by standard dietary measures and, when necessary, lipid-lowering agents. PMID: 16334888 [PubMed - indexed for MEDLINE] 3588. Diab Vasc Dis Res. 2005 Oct;2(3):105-12. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Reaven G(1). Author information: (1)Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. greaven@cvmed.stanford.edu The ability of insulin to mediate glucose disposal varies more than six-fold in an apparently healthy population, and approximately one third of the most insulin-resistant of these individuals are at increased risk to develop cardiovascular disease. Differences in degree of adiposity account for approximately 25% of this variability, and another 25% varies as a function of level of physical fitness. The more overweight/obese the person, the more likely they are to be insulin-resistant and at increased risk of cardiovascular disease, but substantial numbers of overweight/obese individuals remain insulin-sensitive, and not all insulin-resistant persons are obese. Of greater clinical relevance is evidence that the metabolic benefit and decrease in risk of cardiovascular disease following weight loss occurs primarily in those overweight/obese individuals that are also insulin-resistant. The relationship between insulin resistance and overall obesity, as assessed by measurement of body mass index, is essentially the same as the relationship between insulin action and abdominal obesity as quantified by determining waist circumference. Finally, there appears to be a comparable relationship between insulin-mediated glucose disposal and amount of visceral fat, subcutaneous fat, and total fat as quantified by various imaging techniques, and the magnitude of these relationships is no greater than that between insulin action and simple measure of body mass index. PMID: 16334591 [PubMed - indexed for MEDLINE] 3589. Presse Med. 2005 Dec 3;34(21):1646-53. [Corticotropic axis and chronic stress in abdominal obesity and metabolic syndrome]. [Article in French] Boullu-Ciocca S(1), Verger P, Bocquier A, Oliver C. Author information: (1)Service d'endocrinologie, des maladies métaboliques et de la nutrition, Hôpital Nord, Assistance Publique des Hôpitaux de Marseille, Marseille (13). Several indicators of corticotropic axis hyperactivity have been observed in common abdominal obesity, which is clinically similar to the obesity found in Cushing's syndrome. Corticotropic axis hyperactivity may be involved in the development and metabolic and cardiovascular complications of abdominal obesity. Several mechanisms may be responsible for this hormonal dysregulation: genetic, lifestyle, and nutritional factors, and chronic stress. We note the necessity of methodologically-impeccable clinical studies for an objective evaluation of the role of stress in obesity. PMID: 16327705 [PubMed - indexed for MEDLINE] 3590. Rev Clin Esp. 2005 Nov;205(11):556-64. [Regenerative medicine with adult stem cells]. [Article in Spanish] Valdés Chavarri M(1), Pascual Figal D, Prósper Cardoso F, Moreno Montañés J, García Olmos D, Barcia Albacar JA. Author information: (1)Hospital Universitario Virgen de la Arrixaca, Murcia. vadeschivarri@vadeschivarri.e.telefonica.net The present state of clinical regenerative medicine with adult stem cells in the cardiology, digestive, corneal and neurological fields are reviewed. From the cardiology point of view, there is clinical experience with bone marrow stem cells and peripheral blood cells and with skeletal myoblasts. At present, the adult stem cells (bone marrow hematopoietic or mesenchymal) constitute the best option for the regeneration of heart tissue, the clinical studies showing favorable results without ethical or safety problems. Most of the studies with skeletal myoblasts have also been demonstrated to significantly contribute to improve heart function, above all, the systolic one. However they have the disadvantage that has not been totally clarified that they induce malignant ventricular arrhythmias. In either case, the clinical studies are in the initial phase and new studies, above all randomized, are necessary. In the digestive field, there is the pioneer experience of the Hospital La Paz on the use of stem cells from abdominal fat in the treatment of fistulous condition of patients with Crohn's disease. In ophthalmology, the limbal corneal transplant is a recognized practice, using cells from the contralateral eye when the damage is in a single eye and cells from a donor when the damage is bilateral. Finally, in the neurological field, different zones of the adult mammal brain where there are stem cells have been identified: the hippocampus, subventricular zone, olfactory bulb and periependymal zone of the spinal cord. On the other hand, neurons may be obtained from adult stem cells from other tissues, such as the bone marrow or adipose tissue, which means a practically unendable source of neural precursors, either by direct implant after their selection or after their in vitro culture. However, most of the experimentation is animal up to now, clinical trails on safety in amyotrophic lateral sclerosis are now being initiated. PMID: 16324529 [PubMed - indexed for MEDLINE] 3591. Orv Hetil. 2005 Oct 23;146(43):2199-207. [Insulin resistance: the adipose tissue in the focus]. [Article in Hungarian] Urich E(1). Author information: (1)GlaxoSmithKline Kft. Insulin resistance is defined as a state of subnormal biological response to normal quantity of insulin. It is the central pathogenetic factor of type 2 diabetes and the more complex clinical entity of metabolic syndrome. Its clinical significance is the potential of increasing cardiovascular risk at a considerable level. In the background of insulin resistance alterations of the adipose tissue can be observed which means abdominal obesity in most of the cases, however paradoxically it also causes metabolic disturbances characteristic of metabolic syndrome in certain lipodystrophic diseases. Several similarities can be observed between metabolic syndrome and Cushing's syndrome. Current article discusses the explanation of these issues, the pathophysiologic link between adipose tissue and insulin resistance. It also reviews the therapeutic aspects of insulin resistance emphasizing the role of thiazolidinedione type drugs having recently joined the therapeutic palette. PMID: 16323566 [PubMed - indexed for MEDLINE] 3592. Berl Munch Tierarztl Wochenschr. 2005 Nov-Dec;118(11-12):509-20. [Aspects of prenatal development of muscle and adipose tissue: principles, regulation, and influence of maternal nutrition]. [Article in German] Kalbe C(1), Rehfeldt C. Author information: (1)Forschungsbereich Muskelbiologie und Wachstum, Forschungsinstitut für die Biologie landwirtschaftlicher Nutztiere, Dummerstorf. During pregnancy the developing embryo/foetus is completely dependent on the supply with nutrients and the removal of metabolic by-products through the maternal organism. Therefore, each lasting inadequate nutrient supply may have serious consequences for foetal development. As a kind of "nutritional programming" resulting adaptive changes may be maintained until or manifested at adult age. Intrauterine growth retardation (IUGR) may cause problems in animal health and result in poor animal performance. The relationships between prenatal development and the postnatal phenotypic appearance of muscle and fat are insufficiently investigated. The present paper provides selected aspects of the prenatal development of skeletal muscle (myogenesis) and adipose tissue (adipogenesis), refers to the importance of interactions between both tissues and is focussed on the influence of maternal nutrition on these processes. PMID: 16318276 [PubMed - indexed for MEDLINE] 3593. Eur J Cancer. 2006 Jan;42(1):31-41. Epub 2005 Nov 28. Prevention and treatment of cancer cachexia: new insights into an old problem. Muscaritoli M(1), Bossola M, Aversa Z, Bellantone R, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, University 'La Sapienza', Viale dell'Universita 37, 00185 Rome, Italy. maurizio.muscaritoli@uniroma1.it Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most therapeutic strategies to CC have proven to be only partially effective . The inhibition of catabolic processes in muscle has been attempted pharmacologically with encouraging results in animal models. However, data in the clinical setting are still scanty and contradictory. Stimulation of muscle anabolism could represent a promising and valid therapeutic alternative for cancer-related muscle wasting. This goal may be currently achieved with the conventional, short-acting and adverse side effect-rich anabolic steroids. Insulin-like growth factor-1 (IGF-1) plays a critical role in muscle homeostasis, hypertrophy and regeneration. IGF-1 overexpression at the muscular level by gene therapy reverses muscle hypotrophy secondary to catabolic conditions and induces muscle hypertrophy increasing muscle mass and strength. This allows the speculation that this approach could also prove effective in modulating cancer-induced muscle wasting, while avoiding the potentially hazardous side effects of systemic IGF-1 administration. The present review will focus on the potential biochemical and molecular targets of CC therapy, and will define the rationale for a novel, gene therapy-based approach. PMID: 16314085 [PubMed - indexed for MEDLINE] 3594. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):649-63. Link between obesity and type 2 diabetes. Golay A(1), Ybarra J. Author information: (1)Service of Therapeutic Education for Diabetes, Obesity and Chronic Diseases, Geneva University Hospital, 24 rue Micheli-du-Crest, Switzerland. alain.golay@hcuge.ch The relationship between obesity and diabetes is of such interdependence that the term 'diabesity' has been coined. The passage from obesity to diabetes is made by a progressive defect in insulin secretion coupled with a progressive rise in insulin resistance. Both insulin resistance and defective insulin secretion appear very prematurely in obese patients, and both worsen similarly towards diabetes. Thus, the classic 'hyperbolic relationship' between insulin resistance and insulin secretion and the 'glucose allostasis concept' remain prevailing concepts in this particular field of knowledge. An increase in overall fatness, preferentially of visceral as well as ectopic fat depots, is specifically associated with insulin resistance. The accumulation of intramyocellular lipids may be due to reduced lipid oxidation capacity. The ability to lose weight is related to the capacity to oxidize fat. Thus, a relative defect in fat oxidation capacity is responsible for energy economy and hampered weight loss. PMID: 16311223 [PubMed - indexed for MEDLINE] 3595. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):637-47. White adipose tissue and cardiovascular disease. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital and Osaka University, 5-3-20 Nakanoshima, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Adipocytes have recently been shown to secrete a variety of bioactive substances called 'adipocytokines', and have been recognized as endocrine cells. Tumour necrosis factor (TNF)-alphaalpha, plasminogen activator inhibitor-1 (PAI-1) and heparin-binding epidermal-growth-factor-like growth factor (HBEGF) are among these adipocytokines, and they contribute to the development of vascular diseases. Visfatin is a visceral fat-specific protein that may be related to the development of obesity-related diseases such as diabetes mellitus and cardiovascular disease. In contrast, adiponectin, an adipose-tissue-specific collagen-like protein, has recently been reported as an important anti-atherogenic and anti-diabetic protein. Adipocytokine secretion may be regulated dynamically by the nutritional state. Visceral fat accumulation leads to dysfunction of adipocytes (including hypersecretion of TNF-alphaalpha, PAI-1 and HBEGF, and hyposecretion of adiponectin), which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, including adiponectin, is discussed with respect to cardiovascular disease. PMID: 16311222 [PubMed - indexed for MEDLINE] 3596. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):605-23. Transgenic animal models for the study of adipose tissue biology. Blüher M(1). Author information: (1)Department of Internal Medicine II, University of Köln, Germany. matthias.blueher@uk-koeln.de The traditional view of adipose tissue as a passive energy reservoir has changed. Adipose tissue is a complex, highly active metabolic and endocrine organ. With obesity as an increasingly important public health threat, a major development in the understanding of adipose tissue biology has come with observations in different biological spheres including whole-body physiology and application of transgenic animal models. Scientific progress has been made with the identification of several genes in spontaneous monogenic animal models of obesity, and in understanding the molecular mechanisms underlying phenotypes of altered body weight, adiposity and fat distribution by creating transgenic and knockout animal models. Mouse phenotypes resulting from inactivation or overexpression of molecules responsible for the regulation of adipose tissue metabolism have led to novel concepts in the understanding of adipocyte biology and development of obesity. This review presents an overview of transgenic animal models for the study of adipose tissue biology. PMID: 16311220 [PubMed - indexed for MEDLINE] 3597. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):589-603. Nutrition-/diet-induced changes in gene expression in white adipose tissue. Al-Hasani H(1), Joost HG. Author information: (1)German Institute for Human Nutrition, Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany. al-hasani@mail.dife.de Nutrients regulate metabolic fluxes and homeostasis through transcriptional and translational control of enzyme concentrations and allosteric modulation of enzyme activity. Dietary omega-3 polyunsaturated fatty acids (PUFAs) have been shown to exert a variety of beneficial health effects such as reducing adiposity and increasing insulin sensitivity in rodents. It is now clear that PUFAs regulate fundamental adipose cell and liver functions through modulation of activity and abundance of key transcription factors that act as nutrient sensors, including peroxisome proliferator-activated receptors (PPARalpha/delta/gamma), sterol regulatory element binding proteins (SREBP-1/2), and liver X receptors (LXRalpha/beta). However, in the state of obesity, where adipose tissue shows elevated storage of triglycerides, many lipogenic genes that are essential for adipose cell function including PPARgamma, SREBP-1c, CCAAT-enhancer binding protein alpha and stearoyl-CoA desaturase-1 are downregulated, apparently due to desensitization of the very same crucial nutrient sensors. This chapter will summarize recent studies of PUFA- and obesity-induced changes in gene expression in white adipose tissue. PMID: 16311219 [PubMed - indexed for MEDLINE] 3598. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):577-87. Insulin-like growth factor I, growth hormone and insulin in white adipose tissue. Blüher S(1), Kratzsch J, Kiess W. Author information: (1)Hospital for Children and Adolescents, University of Leipzig, Oststrasse 21-25, Germany. Maturation of adipose tissue results from both the expansion of mature adipocytes and the formation of new adipocytes from adipocyte precursor cells. A variety of hormones related to adipogenesis have been identified recently. Both growth hormone (GH) and insulin-like growth factor I (IGF-I) are of major significance in adipocyte differentiation. IGF-I has been suggested to be a major regulator of cell proliferation, differentiation and metabolism, thus regulating, among other biological processes, adipose tissue growth and differentiation of pre-adipocytes into adipocytes. GH exerts its effects by increasing the pool of adipocyte precursor cells capable of differentiating into mature adipocytes. In addition, GH seems to have the potential to reduce the volume of mature adipocytes, thus inhibiting the expansion of adipose tissue and reducing body fat. This chapter gives an overview of studies that have investigated the roles of insulin, GH and IGF-I in adipogenesis. PMID: 16311218 [PubMed - indexed for MEDLINE] 3599. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):567-75. Mineralocorticoid-stimulating activity of adipose tissue. Lamounier-Zepter V(1), Ehrhart-Bornstein M, Bornstein SR. Author information: (1)Department of Endocrinology, Diabetes and Metabolism, University Medical Centre, University of Dresden, Germany. Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different investigators, suggesting that an abnormal secretion of aldosterone in obesity contributes to the development of arterial hypertension in obese subjects. The mechanisms proposed to explain this abnormal aldosterone production mainly involve the adipose renin-angiotensin system, an indirect effect of increased fatty acids, and direct adrenal stimulation by adipocyte secretory products. Indeed, adipose mineralocorticoid-stimulating activity was recently observed in isolated human adipocytes, suggesting a hitherto unknown direct involvement of adipose tissue in the regulation of blood pressure in obesity. PMID: 16311217 [PubMed - indexed for MEDLINE] 3600. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):547-66. Adipose tissue: a regulator of inflammation. Juge-Aubry CE(1), Henrichot E, Meier CA. Author information: (1)Endocrine Unit, Department of Internal Medicine, University Hospital of Geneva, Switzerland. Adipose tissue is a highly active organ. In addition to storing calories as triglycerides, it also secretes a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. Intriguingly, many, if not most, of these adipose-derived proteins have dual actions; cytokines have both immunomodulatory functions and act as systemic or auto-/paracrine regulators of metabolism, while proteins such as leptin and adiponectin are regulators of both metabolism and inflammation. The production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications. PMID: 16311216 [PubMed - indexed for MEDLINE] 3601. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):525-46. Adipocytokines: leptin--the classical, resistin--the controversical, adiponectin--the promising, and more to come. Koerner A(1), Kratzsch J, Kiess W. Author information: (1)University Hospital for Children and Adolescents, University of Leipzig, Oststrasse 21-25, Germany. antje.boettner@medizin.unileipzig.de With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to affect several aspects in the pathogenesis of obesity-related diseases. The cloning of the ob gene is consistent with this concept and suggests that body fat content in adult rodents is regulated by a negative feedback loop centred in the hypothalamus. In recent years, a number of additional signalling molecules secreted by adipose tissue have been discovered, commonly referred to as 'adipocytokines'. Among these, adiponectin is perhaps the most interesting and promising compound for the clinician since it has profound protective actions in the pathogenesis of diabetes and cardiovascular disease. Adiponectin is low in obese subjects and, in particular, insulin-resistant patients. In contrast, resistin seems to be of greater relevance in relation to the immune stress response than in the regulation of glucose homeostasis. However, inflammatory processes have recently been connected with the development of atherosclerosis. Finally, little is known regarding the clinical relevance of visfatin. Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This report aims to review some of the recent topics of adipocytokine research that may be of particular importance. PMID: 16311215 [PubMed - indexed for MEDLINE] 3602. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):501-23. Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies. Gurnell M(1). Author information: (1)Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, UK. mg299@mole.bio.cam.ac.uk In recent years, the thiazolidinediones (e.g. rosiglitazone, pioglitazone) have emerged as an exciting novel class of therapeutic agent for the treatment of type 2 diabetes mellitus and the human metabolic syndrome. At first glance, the use of these high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, that promote adipogenesis, to treat a group of disorders that typically have their origins in obesity seems counter-intuitive. However, to view PPARgamma simply as a regulator of fat mass, and adipocytes themselves as passive vessels for energy storage, is to ignore an extensive body of data that speaks of the diverse roles of both this receptor and adipose tissue in the maintenance of normal metabolic homeostasis. This article highlights the important clinical and laboratory observations made in human subjects harbouring genetic variations in PPARgamma that have confirmed its pivotal role in the regulation of adipocyte endocrine function, and thus our metabolic response to the environment. PMID: 16311214 [PubMed - indexed for MEDLINE] 3603. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):483-99. Adipogenesis: cellular and molecular aspects. Fève B(1). Author information: (1)INSERM U693, Faculté de Médecine de Bicêtre, 63 rue Gabriel Péri, 94270 Le Kremlin-Bicêtre, France. bfeve@free.fr Obesity and lipoatrophy are major risks for insulin resistance, non-insulin-dependent diabetes and cardiovascular disease. In the past three decades, significant advances have been made in delineating the key transcription factors of adipogenesis, as well as extracellular effectors and intracellular signalling pathways that regulate fat cell formation. This review focuses on in vitro models of adipocyte differentiation, and on the balance between pro- and anti-adipogenic factors that drive the adipocyte differentiation process. Full understanding of the mechanisms of adipose tissue differentiation represents a major issue to develop a comprehensive strategy to prevent and treat obesity. PMID: 16311213 [PubMed - indexed for MEDLINE] 3604. Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):471-82. Human fat cell lipolysis: biochemistry, regulation and clinical role. Arner P(1). Author information: (1)Department of Medicine M63, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. peter.arner@medhs.ki.se Release of fatty acids (FAs) from adipose tissue through lipolysis in fat cells is a key event in many processes. FAs are not only energy substrates but also signalling molecules and substrates for lipoprotein production by the liver. Fat cells consist of>95% triglycerides that are hydrolysed during lipolysis to glycerol and FAs. The major rate-limiting factor for lipolysis is hormone-sensitive lipase, but additional lipases such as adipose tissue triglyceride lipase may also play a role. The regulation of human fat cell lipolysis is, in many ways, species unique. Only catecholamines, insulin and natriuretic peptides have pronounced acute effects. Catecholamines influence lipolysis through four different adrenoceptor subtypes, in contrast to rodents where only one subtype (beta(3)) is of major importance. There are regional variations in adipocyte lipolysis leading to more release of FAs from the visceral than subcutaneous adipose tissue during hormone stimulation (insulin, catecholamines). Since, only visceral fat is linked to the liver (by the portal vein), alterations in visceral adipocyte tissue lipolysis have direct effects on the liver through portal FA release. The regional variations in lipolysis are further enhanced in obesity and polycystic ovarian syndrome, and are of importance for dyslipidaemia, hyperinsulinaemia and glucose intolerance in these conditions. There is a marked elevation of circulating FA levels among the obese, which may be due to enhanced production of tumour necrosis factor alpha in adipose tissue. This cytokine stimulates lipolysis through so-called MAP kinases. Pharmacological agents in clinical practice such as nicotinic acid and glitazones exert lipid-lowering and glucose-lowering effects, respectively, by decreasing FA output from the adipose tissue. This review covers the biochemistry, regulation and clinical aspects of human fat cell lipolysis. PMID: 16311212 [PubMed - indexed for MEDLINE] 3605. Trends Endocrinol Metab. 2006 Jan-Feb;17(1):26-32. Epub 2005 Nov 23. Adipose tissue as source and target for novel therapies. Klein J(1), Perwitz N, Kraus D, Fasshauer M. Author information: (1)Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. j.klein@uni-luebeck.de The physiology of adipose tissue has a key role in the pathogenesis of the metabolic syndrome and related cardiovascular disorders. Three main functions of adipocytes have been proposed to explain this role: the secretion of adipocyte-derived hormones (so-called adipokines), energy dissipation/thermogenesis, and energy storage. There is mounting evidence that this repertoire of actions and reactions contributes to whole-body glucose and energy homeostasis, the control of blood pressure, immune-system function, haemostasis and atherosclerosis. In this article we highlight the most recent examples of adipocyte-based therapies and discuss future pharmacological options for exploiting this triad of adipocyte functions. PMID: 16309918 [PubMed - indexed for MEDLINE] 3606. Diab Vasc Dis Res. 2005 May;2(2):54-60. The application of proteomics to diabetes. Scott EM(1), Carter AM, Findlay JB. Author information: (1)Academic Unit of Molecular Vascular Medicine, The LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. e.m.scott@leeds.ac.uk Poteomics is the investigation of all the proteins and their various modifications making up a system, be that a cell, tissue or organism. The techniques involved in proteomics allow the global screening of complex samples of proteins and provide qualitative and quantitative evidence of altered protein expression. This lends itself to the investigation of the molecular mechanisms underpinning disease processes and the effects of treatment. This review describes the main techniques of proteomics and how they have begun to be applied to diabetes research. PMID: 16305059 [PubMed - indexed for MEDLINE] 3607. Ginecol Obstet Mex. 2005 Jul;73(7):371-7. [Recent concepts in gestational diabetes' etiopathogenesis]. [Article in Spanish] Hernández Valencia M(1), Zárate A. Author information: (1)Unidad de investigación médica en enfermedades endocrinas, Hospital de Especialidades, Centro Médico Nacional, Instituto Mexicano del Seguro Social, México, DF. mhernandezvalencia@prodigy.net.mx Changes in insulin action cause maternal adaptation to fetal nutrient demand. Insulin resistance generates a greater production of insulin to compensate this resistance; however, there could be failure of pancreatic beta-cells to compensate by adequate insulin secretion. Factors linked to the development of gestational diabetes are: increased concentrations of placental growth hormone; peptides produced by adipose tissue, which show predictive value for the development of insulin resistance; adverse effects of intrauterine food restriction; autoimmunity induced by the consumption of some nutrients in early neonatal life; viral infections in children, which could damage pancreatic islets and become incapable of responding to metabolic overload such as pregnancy. PMID: 16304960 [PubMed - indexed for MEDLINE] 3608. Int J Obes (Lond). 2006 Mar;30(3):400-18. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Vincent HK(1), Taylor AG. Author information: (1)The Center for the Study of Complementary and Alternative Therapies, CSCAT, University of Virginia, Charlottesville, 22908-0905, USA. hkv5d@virginia.edu OBJECTIVE: Oxidative stress may be the unifying mechanism underlying the development of comorbidities in obesity. Evidence suggests that a clustering of sources of oxidative stress exists in obesity: hyperglycemia, hyperleptinemia, increased tissue lipid levels, inadequate antioxidant defenses, increased rates of free radical formation, enzymatic sources within the endothelium, and chronic inflammation. METHOD: This review provides a summary of the available evidence on systemic oxidative stress in humans and specific metabolic pathways by which obesity may elevate systemic oxidant stress. The authors suggest possible methods of reducing oxidative stress such as antioxidant supplementation, caloric restriction and/or physical activity and surgical intervention to combat free radicals and reduce adipose tissue. RESULTS: Obesity is associated with oxidative stress and can be reduced with weight loss (regardless of exercise or surgery induced weight loss), caloric restriction or antioxidant rich diets. CONCLUSION: Oxidative stress levels are elevated in human obesity, and these levels are modifiable with various lifestyle modifications and surgical interventions. PMID: 16302012 [PubMed - indexed for MEDLINE] 3609. Tidsskr Nor Laegeforen. 2005 Nov 17;125(22):3098-100. [Brominated flame retardants may cause brain injuries in the fetus and the newborn]. [Article in Norwegian] Gundersen Y(1), Vaagenes P, Reistad T, Opstad PK. Author information: (1)Forsvarets forskningsinstitutt, Avdeling for beskyttelse, 2027 Kjeller. yngvar.gundersen@ffi.no BACKGROUND: Brominated flame retardants are incorporated into an ever-increasing number of ordinary consumer goods, which has lead to pollution of the environment, wildlife, food of animal origin, and human blood, adipose tissue, and mother's milk. This group of chemicals has a striking structural similarity with the thyroid hormones and may constitute a potential health risk by interfering with thyroid hormone homeostasis. MATERIAL AND METHODS: We focus on these features and discuss possible clinical consequences, on the basis of Medline searches and our own experience. RESULTS: The thyroid hormones are essential for normal brain development. Disruption of the hormonal balance may lead to serious and permanent defects of neurological functioning. Brominated flame retardants may interfere with thyroid synthesis, transport, receptor binding, and elimination. The clinical consequences have so far not been firmly established, but results from animal studies suggest that even subtle disturbances of thyroid homeostasis during pregnancy may have serious implications for the developing brain. INTERPRETATION: Numerous scientific reports confirm the neurotoxic potential of these chemicals. The foetus and newborn are especially vulnerable. PMID: 16299563 [PubMed - indexed for MEDLINE] 3610. Biosci Rep. 2005 Jun-Aug;25(3-4):251-69. Neonatal programming of body weight regulation and energetic metabolism. de Moura EG(1), Passos MC. Author information: (1)Dept. Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brasil. egmoura@uerj.br Programming is an epigenetic phenomena by which nutritional, hormonal, physical psychological and other stressful events acting in a critical period of life, such as gestation and lactation, modifies in a prolonged way certain physiological functions. This process was preserved by natural selection as an important adaptive tool for survival of organisms living in nutritional impaired areas. So, malnutrition during gestation and lactation turns on different genes that provide the organism with a thrifty phenotype. In the case of an abundant supply of nutrients after this period, those organisms that were adapted to a low metabolic waste and higher energy utilization will be in a higher risk of developing metabolic diseases, such as obesity, hyperlipidemia, diabetes mellitus and hypertension. The kind of malnutrition, duration and intensity are important for the type of programming obtained. We discuss some of the hormonal and metabolic changes that occur in gestation or lactation, when malnutrition is applied to the mothers and their offspring. Some of these changes, such as an increase of maternal triiodothyronine (T(3)), leptin and glucocorticoids (GC) and decrease in prolactin are by itself potential programming factors. Most of these hormones can be transfer through the milk that has other important macronutrients composition changes in malnourished dams. We discuss the programming effects of some of these hormones upon body weight and composition, leptin, thyroid and adrenal functions, and their effects on liver, muscle and adipose tissue metabolism and the consequences on thermogenesis. PMID: 16283556 [PubMed - indexed for MEDLINE] 3611. Biosci Rep. 2005 Jun-Aug;25(3-4):227-49. Thermoregulation: what role for UCPs in mammals and birds? Mozo J(1), Emre Y, Bouillaud F, Ricquier D, Criscuolo F. Author information: (1)Faculté de Médecine Necker-Enfants Malades, CNRS-UPR 9078, 156 rue de Vaugirard, 75730, Paris, Cedex 15, France. Mammals and birds are endotherms and respond to cold exposure by the means of regulatory thermogenesis, either shivering or non-shivering. In this latter case, waste of cell energy as heat can be achieved by uncoupling of mitochondrial respiration. Uncoupling proteins, which belong to the mitochondrial carrier family, are able to transport protons and thus may assume a thermogenic function. The mammalian UCP1 physiological function is now well understood and gives to the brown adipose tissue the capacity for heat generation. But is it really the case for its more recently discovered isoforms UCP2 and UCP3? Additionally, whereas more and more evidence suggests that non-shivering also exists in birds, is the avian UCP also involved in response to cold exposure? In this review, we consider the latest advances in the field of UCP biology and present putative functions for UCP1 homologues. PMID: 16283555 [PubMed - indexed for MEDLINE] 3612. Biosci Rep. 2005 Jun-Aug;25(3-4):191-208. Adaptive activation of thyroid hormone and energy expenditure. Bianco AC(1), Maia AL, da Silva WS, Christoffolete MA. Author information: (1)Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM Bldg. #643, Massachusetts, Boston, MA 02115, USA. abianco@partners.org The mechanisms by which thyroid hormone accelerates energy expenditure are poorly understood. In the brown adipose tissue (BAT), activation of thyroid hormone by type 2 iodothyronine deiodinase (D2) has been known to play a role in adaptive energy expenditure during cold exposure in human newborns and other small mammals. Although BAT is not present in significant amounts in normal adult humans, recent studies have found substantial amounts of D2 in skeletal muscle, a metabolically relevant tissue in humans. This article reviews current biological knowledge about D2 and adaptive T3 production and their roles in energy expenditure. PMID: 16283553 [PubMed - indexed for MEDLINE] 3613. Biosci Rep. 2005 Jun-Aug;25(3-4):149-80. Control and regulatory mechanisms associated with thermogenesis in flying insects and birds. Loli D(1), Bicudo JE. Author information: (1)Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil. Most insects and birds are able to fly. The chitin made exoskeleton of insects poses them several constraints, and this is one the reasons they are in general small sized animals. On the other hand, because birds possess an endoskeleton made of bones they may grow much larger when compared to insects. The two taxa are quite different with regards to their general "design" platform, in particular with respect to their respiratory and circulatory systems. However, because they fly, they may share in common several traits, namely those associated with the control and regulatory mechanisms governing thermogenesis. High core temperatures are essential for animal flight irrespective of the taxa they belong to. Birds and insects have thus evolved mechanisms which allowed them to control and regulate high rates of heat fluxes. This article discusses possible convergent thermogenic control and regulatory mechanisms associated with flight in insects and birds. PMID: 16283551 [PubMed - indexed for MEDLINE] 3614. Biosci Rep. 2005 Jun-Aug;25(3-4):129-48. Thyroid hormone and the energetic cost of keeping body temperature. Silva JE(1). Author information: (1)Department of Medicine, Division of Endocrinology, Jewish General Hospital, McGill University, Montreal, Canada. PMID: 16283550 [PubMed - indexed for MEDLINE] 3615. Nat Clin Pract Gastroenterol Hepatol. 2005 Jun;2(6):273-80. Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in nonalcoholic fatty liver disease. Schäffler A(1), Schölmerich J, Büchler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Germany. Comment in Nat Clin Pract Gastroenterol Hepatol. 2005 Jun;2(6):245. There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines. PMID: 16265231 [PubMed - indexed for MEDLINE] 3616. Nat Clin Pract Gastroenterol Hepatol. 2005 Feb;2(2):103-11. Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in intestinal and mesenteric diseases. Schäffler A(1), Schölmerich J, Büchler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de Adipose tissue has long been regarded as a passive type of connective tissue that stores energy as triglycerides and releases energy as free fatty acids, however, this point of view has now changed. The wide variety of products expressed and secreted by adipose tissue, such as adiponectin, leptin, and resistin, mean that the total adipose tissue mass can be defined as a real endocrine organ. The anatomic, metabolic and biochemical characteristics of visceral adipose tissue make it interesting in the context of intestinal and mesenteric diseases. These characteristics include increased lipolysis, venous drainage via the portal vein and local glucocorticoid excess owing to the specific expression of 11-beta-hydroxysteroid-dehydrogenase type 1. In this review, the role of the visceral adipose tissue and its secretory products in intestinal and mesenteric diseases is systematically reviewed, with special focus on 'creeping fat' in Crohn's disease and mesenteric panniculitis. PMID: 16265128 [PubMed - indexed for MEDLINE] 3617. Nat Clin Pract Gastroenterol Hepatol. 2005 Jan;2(1):46-53. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. Sanyal AJ(1). Author information: (1)Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA. ajsanyal@hsc.vcu.edu Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death. PMID: 16265100 [PubMed - indexed for MEDLINE] 3618. Nat Clin Pract Oncol. 2005 Mar;2(3):158-65. Therapy insight: Cancer anorexia-cachexia syndrome--when all you can eat is yourself. Laviano A(1), Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Author information: (1)Department of Clinical Medicine, University La Sapienza, Rome, Italy. alessandro.laviano@uniroma1.it Tumor growth is associated with profound metabolic and neurochemical alterations, which can lead to the onset of anorexia-cachexia syndrome. Anorexia is defined as the loss of the desire to eat, while cachexia results from progressive wasting of skeletal muscle mass--and to a lesser extent adipose tissue--occurring even before weight loss becomes apparent. Cancer anorexia-cachexia syndrome is highly prevalent among cancer patients, has a large impact on morbidity and mortality, and impinges on patient quality of life. However, its clinical relevance is frequently overlooked, and treatments are usually only attempted during advanced stages of the disease. The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumor-derived factors have a significant role, thereby representing a suitable therapeutic target. Energy expenditure in anorexia is frequently increased while energy intake is decreased, which further exacerbates the progressive deterioration of nutritional status. The optimal therapeutic approach to anorectic-cachectic cancer patients should be based on both changes in dietary habits, achieved via nutritional counseling; and drug therapy, aimed at interfering with cytokine expression or activity. Our improved understanding of the influence a tumor has on the host's metabolism is advancing new therapeutic approaches, which are likely to result in better preservation of nutritional status if started concurrently with specific antineoplastic treatment. PMID: 16264909 [PubMed - indexed for MEDLINE] 3619. Reproduction. 2005 Nov;130(5):583-97. Adipokines: implications for female fertility and obesity. Mitchell M(1), Armstrong DT, Robker RL, Norman RJ. Author information: (1)Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, Australia, 5011. Obesity is associated with a diverse set of metabolic disorders, and has reproductive consequences that are complex and not well understood. The adipose tissue-produced leptin has dominated the literature with regards to female fertility complications, but it is pertinent to explore the likely role of other adipokines--adiponectin and resistin--as our understanding of their biological functions emerge. Leptin influences the developing embryo, the functioning of the ovary and the endometrium, interacts with the release and activity of gonadotrophins and the hormones that control their synthesis. In this review such biological actions and potential roles of the adipokines leptin, adiponectin and resistin are explored in relation to female fertility and the complexity of the obese metabolic state. PMID: 16264089 [PubMed - indexed for MEDLINE] 3620. Appetite. 2006 Jan;46(1):26-30. Epub 2005 Nov 2. Stress response and binge eating disorder. Gluck ME(1). Author information: (1)New York Obesity Research Center, Departments of Medicine, St Luke's/Roosevelt Hospital Center, Columbia University-College of Physicians and Surgeons, New York, NY 10025, USA. marci513@aol.com In clinical practice, obese patients report stress as a primary trigger for binge eating. However, the biological mechanism underlying this relationship is poorly understood. This paper presents, a theoretical overview of how cortisol secretion, a major component of the stress response, could play a role in binge eating, given that exogenous glucocorticoids can lead to obesity by increasing food intake. I will discuss findings from recent studies demonstrating links between laboratory stress, cortisol, food intake and abdominal fat in humans. Cortisol is elevated following laboratory stressors in women with anorexia nervosa (AN), bulimia nervosa (BN), and obesity, but has not been widely studied in women with binge eating disorder (BED). Additionally, I will review recent findings demonstrating a greater cortisol response to stress in obese women with BED compared to non-BED. PMID: 16260065 [PubMed - indexed for MEDLINE] 3621. J Nutr. 2005 Nov;135(11):2499-502. Comparative aspects of lipid metabolism: impact on contemporary research and use of animal models. Bergen WG(1), Mersmann HJ. Author information: (1)Program in Cellular and Molecular Biosciences, Department of Animal Sciences, Auburn University, AL 36849, USA. bergewg@auburn.edu The emerging obesity crisis and consequent concerns for corrective measures and appropriate public policy have stimulated research into causes, prevention, remediation, and health consequences of obesity and associated maladies. Such research areas include eating behavior, appetite control, and food intake regulation as well as the regulation of lipid metabolism, cardiovascular function, endocrine function, and dyslipidemia states utilizing various animal models and cell culture systems. Although the liver has a central role in lipid/fatty acid synthesis and glucose is the precursor for de novo fatty acid synthesis in rodents and humans, in many other species, adipose tissues are the primary sites of lipogenesis. In addition, many species utilize acetic acid as a precursor for fatty acid synthesis. This fundamental difference in the site of fatty acid synthesis and the pattern of consequent lipid trafficking influences overall animal lipid metabolism and the role of regulatory hormones and transcription factors. Researchers utilizing various animal species in targeted biomedical research should be aware of these species differences when interpreting their data. In addition, many animal species are used for food production, recreational, and companion purposes. Understanding the lipid metabolism regulatory mechanisms of such species from a comparative perspective is important for the proper nutrition and health of these animals. PMID: 16251600 [PubMed - indexed for MEDLINE] 3622. Curr Med Chem Cardiovasc Hematol Agents. 2005 Oct;3(4):377-81. Clinical determination of the severity of metabolic syndrome: preheparin lipoprotein lipase mass as a new marker of metabolic syndrome. Miyashita Y(1), Shirai K. Author information: (1)Internal Medicine of Sakura Hospital, School of Medicine, Toho University, 564-1 Shimoshizu, Sakura-City, Chiba, 285-0841, Japan. mumon@sf6.so-net.ne.jp The severity of metabolic syndrome depends on the degree of insulin resistance. However, currently there is no adequate clinical marker for quantitative analysis of insulin resistance. A small quantity of lipoprotein lipase (LPL) protein, which is an inactive form and commonly called 'preheparin LPL mass', exists in serum and is detected by a sensitive immunoassay system. Recent studies have reported the clinical significance of serum preheparin LPL mass levels in various aspects. For example, preheparin LPL mass is negatively related to serum triglyceride and positively related to HDL-cholesterol, is low in type 2 diabetes mellitus, is increased by administration of insulin sensitizer, and shows an inverse relationship with visceral adiposity. Furthermore, preheparin LPL mass level is significantly lower in patients with coronary atherosclerosis compared to patients with no lesion, and correlates negatively with the severity of these lesions. From these reports, preheparin LPL mass may be considered to be the most important quantitative indicator of insulin resistance of the whole body. PMID: 16250868 [PubMed - indexed for MEDLINE] 3623. Hepatology. 2005 Nov;42(5):987-1000. Insulin resistance: a metabolic pathway to chronic liver disease. Bugianesi E(1), McCullough AJ, Marchesini G. Author information: (1)Gastroenterology Department, University of Turin, Turin, Italy. Comment in Hepatology. 2006 May;43(5):1168; author reply 1168-9. Insulin resistance (IR) is the pathophysiological hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. We review the definition of IR, the methods for the quantitative assessment of insulin action, the pathophysiology of IR, and the role of IR in the pathogenesis of chronic liver disease. Increased free fatty acid flux from adipose tissue to nonadipose organs, a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a proinflammatory state, which may be limited to the liver or more extensively expressed throughout the body. IR is the common characteristic of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscles, pancreas, kidney, heart, and immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances IR and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome, and the risk of progressive liver disease should not be underestimated in individuals with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing IR in the liver (metformin) and in the periphery (thiazolidinediones) are discussed. PMID: 16250043 [PubMed - indexed for MEDLINE] 3624. J Clin Endocrinol Metab. 2006 Jan;91(1):248-55. Epub 2005 Oct 25. Activation of phospholipase A2 is associated with generation of placental lipid signals and fetal obesity. Varastehpour A(1), Radaelli T, Minium J, Ortega H, Herrera E, Catalano P, Hauguel-de Mouzon S. Author information: (1)Department of Reproductive Biology, Shwartz Center for Nutrition and Metabolism, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109, USA. CONTEXT: Obesity and diabetes during pregnancy are associated with increased insulin resistance and higher neonatal adiposity. In turn, insulin resistance triggers inflammatory pathways with accumulation of placental cytokines. OBJECTIVE: To determine placental signals that translate into development of excess adipose tissue, we investigated the role of phospholipases A2 (PLA2) as targets of inflammatory mediators. SETTING: The study was conducted at Case Western Reserve University, Department of Reproductive Biology. SUBJECTS: Volunteers gave informed written consent in accordance with the Institutional Review Board guidelines. Placenta and cord blood samples were obtained at the time of elective cesarean section in 15 term pregnancies. INTERVENTION: Neonatal anthropometric measurements were performed within 48 h of delivery. Placentas were grouped based on neonatal percentage body fat as obese (body fat > or = 16%) and lean control (body fat < or = 8%). MAIN OUTCOME MEASURES: The primary outcomes were placenta PLA2 expression and fatty acid concentration. RESULTS: Expression of PLA2G2A and PLA2G5, the main placenta phospholipases, was greater (P < 0.05) in placenta of obese compared with control neonates and was associated with increased 20:3 and 20:5 omega-3 polyunsaturated fatty acids. TNF-alpha and leptin content was increased 3-fold in placenta of obese neonates. TNF-alpha and leptin both induced a time-dependent activation of PLA2G2 and PLA2G5 in placental cells. CONCLUSION: Accumulation of omega-3 fatty acids through secretory PLA2 activation is associated with high neonatal adiposity. We propose that the generation of placental lipid mediators through TNF-alpha and leptin stimulation represents a key mechanism to favor excess fetal fat accretion. PMID: 16249288 [PubMed - indexed for MEDLINE] 3625. Biochem Soc Trans. 2005 Nov;33(Pt 5):1078-81. Signalling role of adipose tissue: adipokines and inflammation in obesity. Trayhurn P(1), Wood IS. Author information: (1)Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences, University of Liverpool, Duncan Building, Liverpool L69 3GA, UK. p.trayhurn@liverpool.ac.uk White adipose tissue (WAT) is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. A number of adipokines, including leptin, adiponectin, tumour necrosis factor alpha, IL-1beta (interleukin 1beta), IL-6, monocyte chemotactic protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands (adiponectin, which has anti-inflammatory action is an exception). The elevated production of inflammation-related adipokines is increasingly considered to be important in the development of diseases linked to obesity, particularly Type II diabetes and the metabolic syndrome. WAT is involved in extensive cross-talk with other organs and multiple metabolic systems through the various adipokines. PMID: 16246049 [PubMed - indexed for MEDLINE] 3626. Biochem Soc Trans. 2005 Nov;33(Pt 5):1073-7. Diseases of adipose tissue: genetic and acquired lipodystrophies. Capeau J(1), Magré J, Lascols O, Caron M, Béréziat V, Vigouroux C, Bastard JP. Author information: (1)INSERM U680, Saint-Antoine Faculty of Medicine, Université Pierre et Marie Curie (UPMC), Paris, France. capeau@st-antoine.inserm.fr Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition and major metabolic alterations with insulin resistance leading to diabetic complications and increased cardiovascular and hepatic risk. Genetic forms of lipodystrophies are rare. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis. The Dunnigan syndrome [FPLD2 (familial partial lipodystrophy of the Dunnigan type)] is due to mutations in LMNA encoding the lamin A/C, belonging to the complex group of laminopathies that could comprise muscular and cardiac dystrophies, neuropathies and syndromes of premature aging. Some FPLDs are linked to loss-of-function mutations in the PPAR-gamma gene (peroxisome-proliferator-activated receptor gamma; FPLD3) with severe metabolic alterations but a less severe lipodystrophy compared with FPLD2. The metabolic syndrome, acquired, represents the most common form of lipodystrophy. HIV-infected patients often present lipodystrophies, mainly related to side effects of antiretroviral drugs together with insulin resistance and metabolic alterations. Such syndromes help to understand the mechanisms involved in insulin resistance resulting from altered fat repartition and could benefit from insulin-sensitizing effects of lifestyle modifications or of specific medications. PMID: 16246048 [PubMed - indexed for MEDLINE] 3627. Biochem Soc Trans. 2005 Nov;33(Pt 5):1059-62. Regulation of lipid metabolism via angiopoietin-like proteins. Kersten S(1). Author information: (1)Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, PO BOX 8129, 6700 EV, Wageningen, The Netherlands. sander.kersten@wur.nl Regulation of mammalian energy metabolism is an intricate process involving numerous hormones, transcription factors and signal transduction cascades. Much of the regulation occurs via secreted factors that relay information from one organ to another. One group of secreted factors that recently emerged as having a major impact on lipid and possibly glucose metabolism are the ANGPTLs (angiopoietin-like proteins). This includes ANGPTL3, ANGPTL4/FIAF (fasting-induced adipose factor), and ANGPTL6/AGF (angiopoietin-related growth factor). Although the receptors for these proteins have yet to be identified, it is nevertheless increasingly clear that these proteins have important effects on plasma triacylglycerol clearance, adipose tissue lipolysis, and adiposity. This review summarizes contemporary data on ANGPTLs with emphasis on the connection with energy metabolism. PMID: 16246045 [PubMed - indexed for MEDLINE] 3628. Biochem Soc Trans. 2005 Nov;33(Pt 5):1053-8. Mouse models of PPAR-gamma deficiency: dissecting PPAR-gamma's role in metabolic homoeostasis. Gray SL(1), Dalla Nora E, Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Box 232, Addenbrooke's Hospital, Level 4, Cambridge CB2 2QR, UK. The identification of humans with mutations in PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-gamma regulates metabolic processes. Ablation of PPAR-gamma in vivo is lethal and thus dissection of PPAR-gamma function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-gamma impairment and are useful to elucidate how PPAR-gamma regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-gamma in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-gamma regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-gamma increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-gamma, some murine models suggest PPAR-gamma expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-gamma that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-gamma have provided useful in vivo systems to dissect the function of PPAR-gamma, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-gamma in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome. PMID: 16246044 [PubMed - indexed for MEDLINE] 3629. Biochem Soc Trans. 2005 Nov;33(Pt 5):1049-52. Adipose tissue changes in obesity. Coppack SW(1). Author information: (1)Barts and The London, Queen Mary's School of Medicine and Dentistry, Queen Mary, University of London, London E1 2AT, UK. s.w.coppack@qmul.ac.uk This review gives a broad description of some of the changes in adipose tissue seen in obesity. There are multiple changes in adipose tissue in obesity: histological, neural and vascular, relating to lipid and carbohydrate metabolism and to adipose tissue's endocrine functions. Some may originate from a simple physical expansion of cell size and number. It is unclear which are the most important either in terms of intermediary metabolism or of contributing to the co-morbidities of obesity. Important questions for the future include the reversibility of obesity-related changes and indeed whether the changes differ between depots and species. Recent studies examining physiological regulation within adipose tissue demonstrate it to be relatively unresponsive to changes in everyday life. PMID: 16246043 [PubMed - indexed for MEDLINE] 3630. Biochem Soc Trans. 2005 Nov;33(Pt 5):1045-8. Adipose tissue function in the insulin-resistance syndrome. Karpe F(1), Tan GD. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK. fredrik.karpe@ocdem.ox.ac.uk Insulin resistance is often seen as a consequence of obesity and there are several possible links between adipose tissue function and insulin resistance determined in other organs such as skeletal muscle or liver. One such link is the regulation of NEFA (non-esterified fatty acid) delivery to the rest of the body. Simplistically, an expanded adipose tissue mass delivers more NEFA to the systemic circulation and these fatty acids compete for substrate utilization in skeletal muscle, which in turn reduces glucose utilization. This increases blood glucose concentration and provides the stimulus for increased insulin secretion and hyperinsulinaemia is a key feature of the insulin-resistance syndrome. However, there is abundant evidence that adipose tissue is exquisitely insulin sensitive and hyperinsulinaemia may therefore lead to a constant lipolytic inhibition in adipose tissue. Consequently, the main function of adipose tissue, to rapidly switch between fat uptake and fat release, will be hampered. Adipose tissue blood flow is the conveyor of signals and substrates to and from the adipose tissue. In healthy people adipose tissue blood flow is much enhanced by food intake, whereas in insulin-resistant subjects this response is blunted. This is another facet of unresponsiveness of adipose tissue in the insulin-resistance syndrome. PMID: 16246042 [PubMed - indexed for MEDLINE] 3631. J Nephrol. 2005 Jul-Aug;18(4):464-8. Leptin in end stage renal disease (ESRD): a link between fat mass, bone and the cardiovascular system. Mallamaci F(1), Tripepi G, Zoccali C. Author information: (1)CNR-IBIM, Institute of Biomedicine, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension and Division of Nephrology, Reggio Calabria - Italy. Adipose tissue is now considered an important system operating strictly in concert with other systems. The adipocyte is the main producer of two pleiotropic compounds, leptin and adiponectin, modulating inflammation and having multiple effects in disparate organs including the cardiovascular and the central nervous system. Leptin has disparate influences on various physiologic and organ systems including glucose homeostasis, hematopoiesis and the reproductive and cardiovascular systems and is a crucial hormone for the regulation of food intake and body weight. Peripherally, leptin modulates insulin sensitivity and high leptin triggers insulin resistance and vice versa. Obesity, a situation where circulating leptin attains very high levels is accompanied by increased bone mass, a phenomenon which may depend on direct stimulation of osteoblasts by leptin. However in animal models the stimulating effect of leptin on the osteoblast is counterbalanced by a strong inhibitor effect on bone formation in the central nervous system. Two recent studies reported an inverse link between leptin, bone mass and PTH in dialysis patients suggesting that leptin may be implicated in low bone turnover in these patients, likely by a mechanism involving the central nervous system. Leptin induces vascular calcifications in vitro. In uremic man leptin is unrelated to valvular calcifications but predicts incident cardiovascular events in overweight and obese dialysis patients. Leptin seems to be a relevant player in the emerging connection between bone and cardiovascular alterations in patients with end stage renal disease. PMID: 16245256 [PubMed - indexed for MEDLINE] 3632. Placenta. 2006 Aug;27(8):794-8. Epub 2005 Oct 20. The placenta cytokine network and inflammatory signals. Hauguel-de Mouzon S(1), Guerre-Millo M. Author information: (1)Department of Reproductive Biology, Schwartz Center for Metabolism and Nutrition, Case Western Reserve University, Metro Health Medical Center, 2550 Metrohealth Drive, Cleveland, OH 44109, USA. shdemouzon@metrohealth.org Throughout its entire lifespan, the placenta is able to produce as well as respond to a variety of inflammatory stimuli. Many signaling molecules and concurrent pathways responsible for the propagation of an inflammatory response have been identified in placental cells. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines and inflammatory molecules. Two aspects of the progression of an immune response have been particularly investigated: the highly regulated process of invasion and implantation and, the induction of preterm labor associated with infections. With the progression of pregnancy, the physiological role of most placental cytokines is more uncertain. Many placental cytokines are similar to adipose tissue derived cytokines. One possibility is that they contribute to the low grade systemic inflammation developing during the third trimester of pregnancy. The prevalent hypothesis is that activation of some inflammatory pathways is necessary to induce maternal insulin resistance which is required for the progression of normal gestation. As an integrative organ, the placenta may relay or enhance the contribution made by the cells of the adipose tissue and immune system in non-pregnant individuals. In pregnancy complicated with obesity or diabetes mellitus, continuous adverse stimulus is associated with dysregulation of metabolic, vascular and inflammatory pathways supported by increased circulating concentration of inflammatory molecules. It is believed that maternal adipose tissue and placental cells both contribute to the inflammatory situation by releasing common molecules. For example, the accumulation of leptin and TNF-alpha is associated with an increased production for markers of inflammation, fibrotic response, vascular remodeling and proteins facilitating lipid storage within the placenta. PMID: 16242770 [PubMed - indexed for MEDLINE] 3633. Gut. 2006 Feb;55(2):285-91. Epub 2005 Oct 20. Influence of obesity on the risk of developing colon cancer. Frezza EE(1), Wachtel MS, Chiriva-Internati M. Author information: (1)Department of Surgery, Division of General Surgery, Texas Tech University Health Sciences Center, MOP Building, Suite 380, 3502 9th St, Lubbock, Texas 79415, USA. eldo.frezza@ttuhsc.edu Comment in Gut. 2007 Jul;56(7):1034-5. Obesity is a risk factor for many diseases. Thirty per cent of Americans are viewed as super obese; therefore, we need to find a solution. We already know about the diseases associated with obesity such as high blood pressure, diabetes, sleep apnoea, etc. Lately, there has been an increased interest in understanding if cancer is related to obesity. In this paper, we review the incidence of colon cancer and obesity. Insulin is the best established biochemical mediator between obesity and colon cancer. Hyperinsulinaemia, such as occurs in type II diabetes, is important in the pathogenesis of colon cancer. All adipose tissue is not equal. Visceral abdominal fat has been identified as the essential fat depot for pathogenetic theories that relate obesity and colon cancer. The genders differ as regards to how the relationship between obesity and colon cancer has been evaluated. Obesity imposes a greater risk of colon cancer for men of all ages and for premenopausal women than it does for postmenopausal women. Regular exercise reduces the risk of developing colon cancer and the risk of death from colon cancer should it develop. We believe that a combination of waist circumference (WC) and body mass index (BMI) measurements is recommended to assess the obesity related risk of developing colon cancer. Radiographic assessments of visceral abdominal fat may eventually prove to be the best means of assessing a patient's obesity related risk of developing colon cancer. Although WC is better established as a measure of obesity than BMI, the evidence for colon cancer risk is not secure on this point; combining BMI and WC measurements would appear, at present, to be the wisest approach for colon cancer risk assessment. Doctors who wish to decrease their patients' risk of dying of colon cancer should advise weight loss and exercise. Conversely, physicians and public health authorities should consider both exercise and obesity when designing colon cancer screening protocols. Morphometric cut offs should be adjusted, if possible, for age, sex, ethnicity, and height. PMCID: PMC1856517 PMID: 16239255 [PubMed - indexed for MEDLINE] 3634. Physiol Res. 2006;55(3):233-44. Epub 2005 Oct 17. Adipocytokines and cancer. Housa D(1), Housová J, Vernerová Z, Haluzík M. Author information: (1)Third Department of Medicine, First Faculty of Medicine, Charles University, U Nemocnice 1, 128 00 Prague 2, Czech Republic. mhalu@lf1.cuni.cz Adipose tissue-produced hormones significantly affect the metabolism of lipids and carbohydrates as well as numerous other processes in human body. It is generally accepted that endocrine dysfunction of adipose tissue may represent one of the causal links between obesity and insulin resistance/diabetes. Epidemiological studies underlined that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Multiple recent studies have indicated that some of adipose tissue-derived hormones may significantly influence the growth and proliferation of tumorous stroma and malignant cells within. Here we review current knowledge about possible relationship of leptin and adiponectin to the etiopathogenesis of different malignant tumors. Most of the studies indicated that while leptin may potentiate the growth of cancer cells in vitro, adiponectin appears to have an opposite effect. Further studies are necessary to decide whether obesity-induced endocrine dysfunction of adipose tissue can directly influence carcinogenesis in different tissues and organs. PMID: 16238454 [PubMed - indexed for MEDLINE] 3635. Keio J Med. 2005 Sep;54(3):132-41. Multipotential differentiation of adipose tissue-derived stem cells. Strem BM(1), Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Author information: (1)Cytori Therapeutics, Inc., San Diego, CA 92121, USA. Tissue engineering offers considerable promise in the repair or replacement of diseased and/or damaged tissues. The cellular component of this regenerative approach will play a key role in bringing these tissue engineered constructs from the laboratory bench to the clinical bedside. However, the ideal source of cells still remains unclear and may differ depending upon the application. Current research for many applications is focused on the use of adult stem cells. The properties of adult stem cells that make them well-suited for regenerative medicine are (1) ease of harvest for autologous transplantation, (2) high proliferation rates for ex vivo expansion and (3) multilineage differentiation capacity. This review will highlight the use of adipose tissue as a reservoir of adult stem cells and draw conclusions based upon comparisons with bone marrow stromal cells. PMID: 16237275 [PubMed - indexed for MEDLINE] 3636. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2005;11(3):187-90. [Adiponectin as an adipose tissue hormone and its role in the metabolic syndrome and cardiovascular disease]. [Article in Polish] Pańkowska E(1), Szalecki M. Author information: (1)Klinika Diabetologii Dieciecej i Wad Wrodzonych AM w Warszawie, Warszawa. epankowska@interia.pl Adiponectin, is a novel hormone secreted by the adipose tissue. This active protein plays a role in the regulation of whole body energy homeostasis. It enhances insulin sensitivity and has antiatherogenic properties, reduces hepatic glucose production, and diminishes gluconeogenesis. Adiponectin accelerates the oxidation process of fatty acids in muscle cells, reduces triglycerides plasma concentration. In addition, plasma adiponectin levels negatively correlated with BMI and fat content. Numerous analyses have indicated that hypoadiponectinemia is a consequence of the development of obesity in childhood. The adiponectin secretion in newborn children is higher than in older, an child small for gestational age has lower plasma concentration of this protein. Clinical studies suggest that adiponectin deficiency associates with gestational diabetes in women. However, serum adiponectin levels in type 1 diabetes have not been elucidated, probably factors other than glucose and insulin play a significant role in adiponectin secretion in type 1 diabetes. PMID: 16232373 [PubMed - indexed for MEDLINE] 3637. Clin Otolaryngol. 2005 Oct;30(5):405-8. Dissemination of fat in CSF: a common finding following translabyrinthine acoustic neuroma surgery*. Ray J(1), D'Souza AR, Chavda SV, Walsh AR, Irving RM. Author information: (1)Department of Otolaryngology, University Hospital Birmingham, Edgbaston, Birmingham, UK. jaydip@bigfoot.com OBJECTIVES: Following translabyrinthine craniotomy the temporal bone defect is commonly obliterated using a free autologous fat graft. In this series the dura was put back in place but not closed primarily. As the fat graft remains in direct contact with the cerebro spinal fluid (CSF) there is potential for dispersal of fat within the CSF space. This paper aims to determine the frequency of such CSF fat dissemination and its clinical significance. DESIGN: A retrospective review of translabyrinthine acoustic neuroma removal with free fat autograft obliteration of the temporal bone defect between the years 1997 and 2000. SETTING: Tertiary referral oto-neurosurgical centre. Postoperative magnetic resonance (MR) imaging. PARTICIPANTS: All translabyrinthine patients who had postoperative MR imaging were included. Twenty-six cases were identified. Age range was 13-70 years. Fourteen were male patients. MAIN OUTCOME MEASURES: Evidence of CSF fat dissemination on MR and patients' clinical findings. RESULTS: Twenty-two of the 26 scans (85%) demonstrated evidence of fat dissemination into the subarachnoid CSF spaces in the form of microemboli. The cerebellopontine angle was the most common site involved. No evidence of ventricular dilation or any other abnormality was noted. There was no relationship between the presence or extent of fat microembolization and the patients' clinical course. CONCLUSIONS: This study suggests that free fat placed in temporal bone defects commonly migrate into the subarachnoid space and subsequently move around in these spaces. This is not associated with any complications such as hydrocephalus, meningitis or prolonged postoperative headache. PMID: 16232242 [PubMed - indexed for MEDLINE] 3638. Clin Exp Immunol. 2005 Nov;142(2):216-28. The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes. Mills SC(1), Windsor AC, Knight SC. Author information: (1)Antigen Presentation Research Group, Imperial College London, UK. n-3 Polyunsaturated fatty acids (PUFAs) are recognized as having an anti-inflammatory effect, which is initiated and propagated via a number of mechanisms involving the cells of the immune system. These include: eicosanoid profiles, membrane fluidity and lipid rafts, signal transduction, gene expression and antigen presentation. The wide-range of mechanisms of action of n-3 PUFAs offer a number of potential therapeutic tools with which to treat inflammatory diseases. In this review we discuss the molecular, animal model and clinical evidence for manipulation of the immune profile by n-3 PUFAs with respect to inflammatory bowel disease. In addition to providing a potential therapy for inflammatory bowel disease there is also recent evidence that abnormalities in fatty acid profiles, both in the plasma phospholipid membrane and in perinodal adipose tissue, may be a key component in the multi-factorial aetiology of inflammatory bowel disease. Such abnormalities are likely to be the result of a genetic susceptibility to the changing ratios of n-3 : n-6 fatty acids in the western diet. Evidence that the fatty acid components of perinodal adipose are fuelling the pro- or anti-inflammatory bias of the immune response is also reviewed. PMCID: PMC1809520 PMID: 16232207 [PubMed - indexed for MEDLINE] 3639. J Child Neurol. 2005 Aug;20(8):637-43. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. Sarnat HB(1), Flores-Sarnat L. Author information: (1)Department of Pediatrics (Neurology), University of Calgary, Faculty of Medicine, Alberta Children's Hospital, Calgary, AB, Canada. harvey.sarnat@calgaryhealthregion.ca Neural crest cells are first recognized at the lateral margin of the neural placode shortly after gastrulation, although they are not committed to their diverse fates until later. After dorsal closure of the neural tube, neural crest cells separate and migrate throughout the embryo to form many structures of ectodermal origin (eg, dorsal root and autonomic ganglia, peripheral nerve sheaths) and mesodermal origin (eg, blood vessels, melanocytes, adipose tissue, membranous bone, connective tissue, most of the ocular globe). Terminal differentiation occurs after migration is complete. Three regions of the neural tube generate neural crest: rhombencephalon, mesencephalon, and prosencephalon, each with a different migratory pattern. The most important genes promoting neural crest differentiation and migration are those with a dorsalizing influence in the vertical axis of the neural tube (eg, PAX3, BMP4, ZIC2), some segmentation genes (eg, WNT1), genes that inhibit neural crest (eg, EGR2), and neural crest-specific differentiating genes (eg, SLUG, SOX10). In the neurocutaneous syndromes, diverse features result from abnormal neural crest differentiation, providing a more encompassing embryologic basis for these disorders than the traditional view that these syndromes are somehow related to skin and brain because both are ectodermal derivatives. Abnormal angiogenesis, areas of abnormal pigmentation that sometimes follow the lines of Blashko, nerve sheath proliferations, disorders of chromaffin tissue, lipomes and benign and malignant tumors are frequent features. Many defective genes in neurocutaneous syndromes have an additional function as tumor suppressors. Interactions between genes associated with these disorders and others essential to neural crest formation, migration, and differentiation, are a likely molecular genetic basis for these diseases. The craniofacial abnormalities associated with many cerebral malformations and cutaneous lesions in some neurocutaneous syndromes emphasize an important inductive role of the neural tube in the development of non-neural tissues, mediated through neural crest. PMID: 16225807 [PubMed - indexed for MEDLINE] 3640. Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:64-70. Review article: hepatic steatosis and insulin resistance. Lonardo A(1), Lombardini S, Ricchi M, Scaglioni F, Loria P. Author information: (1)Unità Operativa Medicina I Gastroenterologia, Ospedale Civile di Modena, Modena, Italy. a.lonardo@libero.it Hepatic steatosis may be both an adaptive phenomenon and an example of lipotoxicity. Its prevalence ranks in the same order of magnitude of insulin resistance in the general population. Studies support the finding that hepatic steatosis is secondary to insulin resistance and not vice versa. A steatotic liver will further contribute to the development of insulin resistance through impaired clearance of insulin from the portal blood, creating a vicious cycle. Insulin resistance is the leading force in the pathogenesis and natural history of non-alcoholic fatty liver disease. Dysfunction of energetic homeostasis and the interaction of adiponectin, leptin and tumour necrosis factor-alpha are key events in the pathogenesis of steatosis and insulin resistance. Insulin resistance represents the frame within which hepatic and extrahepatic non-alcoholic fatty liver disease-related clinical manifestations are to be anticipated and interpreted. PMID: 16225477 [PubMed - indexed for MEDLINE] 3641. Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:44-7. Review article: the pathogenesis of fibrosis in non-alcoholic steatohepatitis. Marra F(1), Aleffi S, Bertolani C, Petrai I, Vizzutti F. Author information: (1)Dipartimento di Medicina Interna, University of Florence, Florence, Italy. f.marra@dmi.unifi.it Non-alcoholic steatohepatitis has been recognized as a significant cause of end-stage liver disease and hepatic decompensation. Despite the growing interest in this condition, the molecular mechanisms underlying the development of fibrosis in this setting are only partially understood. In this article, the cellular and molecular basis of fibrosis in chronic liver disease are briefly outlined. In addition, mechanisms specifically operating in the context of fatty liver and steatohepatitis are examined, including: insulin resistance, oxidative stress, and inflammation. Finally, recent developments indicating the possible contribution of cytokines derived from adipose tissue (adipokines) to liver fibrosis is discussed. PMID: 16225472 [PubMed - indexed for MEDLINE] 3642. Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:3-10. Review article: adipocytokines and insulin resistance. Vettor R(1), Milan G, Rossato M, Federspil G. Author information: (1)Endocrine-metabolic laboratory, Internal Medicine, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy. roberto.vettor@unipd.it Insulin resistance has been implicated as one possible factor that links visceral obesity to unfavourable metabolic and cardiovascular consequences. However, the mechanism whereby adipose tissue causes alterations in insulin action remains unclear. White adipose tissue is secreting several hormones, particularly leptin and adiponectin, and a variety of other protein signals: the adipocytokines. They include proteins involved in the regulation of energy balance, lipid and glucose metabolism as well as angiogenesis, vascular and blood pressure regulation. Visceral obesity and inflammation within white adipose tissue may be a crucial step contributing to the emergence of insulin resistance, type 2 diabetes and atherosclerosis. A growing list of adipocytokines involved in inflammation (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, TGF-beta,) and the acute-phase response (serum amyloid A, PAI-1) have been found to be increased in the metabolic syndrome. It is, however, unclear as to the extent adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and how they may affect the insulin-dependent tissues. This review describes the role of the currently known adipocytokines and hormones released by adipose tissue in generating the insulin resistance state and the chronic inflammatory profile which frequently goes together with visceral obesity. PMID: 16225463 [PubMed - indexed for MEDLINE] 3643. J Dairy Res. 2005 Nov;72(4):460-9. Lipid metabolism during lactation: a review of adipose tissue-liver interactions and the development of fatty liver. Vernon RG(1). Author information: (1)Hannah Research Institute, Ayr, KA6 5HL, UK. r.vernon@hannah.ac.uk Fatty acids are the major source of energy for most tissues during periods of negative energy balance; however, fatty acids can, in some circumstances, have pathological effects. Fatty acids are stored as triacylglycerols (TAG), mostly in the various adipose tissue depots of the body. However, if blood unesterified fatty acid (NEFA) levels are elevated for prolonged periods, as may occur during lactation or obesity, TAG can accumulate in other tissues including liver and muscle cells (myocytes), and this can have pathological consequences such as the development of ketosis (Grummer, 1993; Drackley et al. 2001) or type 2 diabetes (Boden & Shulman, 2002; McGarry, 2002). PMID: 16223462 [PubMed - indexed for MEDLINE] 3644. Semin Vasc Med. 2002 Feb;2(1):45-57. The insulin resistance syndrome: mechanisms of clustering of cardiovascular risk. Chan JC(1), Tong PC, Critchley JA. Author information: (1)Departmentof Medicine Therapeutics,Prince of Wales Hospital,TheChinese University of Hong Kong Shatin, Hong Kong. j.chan@cuhk.edu.hk For more than a decade, insulin resistance has been proposed as the key linking factor for the metabolic syndrome disease cluster of glucose intolerance, hypertension, dyslipidemia, obesity, and cardiovascular disease. Although most of the epidemiological, experimental, and clinical evidence still support the role of insulin resistance as an important component of this multifaceted syndrome, there is evidence amassing that a neurohormonal mechanism, including an endocrine role for adipocytes, probably plays a more fundamental role. This is supported by the strong associations between obesity, especially central adiposity, and all components of the metabolic syndrome, in contrast to the inconsistent relationships between blood pressure and markers of insulin resistance. However, much of the effect of visceral fat on cardiovascular risk factors is mediated through the metabolic actions of free fatty acids (FFA) on insulin resistance, thus resolving any obesity versus insulin resistance controversy. In addition to the roles of obesity and FFA in the development of insulin resistance syndrome, the high prevalence rates of this disease cluster among subjects from low socioeconomic groups as well as from developing countries have led to alternative hypotheses to better our understanding of the contributory roles of socioeconomic, in utero, and genetic factors in this syndrome. More recently, the pathogenetic roles of iron overload and liver dysfunction have also been re-examined. In this article, the various hypotheses which have been put forward to explain the diverse clinical manifestations of the metabolic or insulin resistance syndrome are summarized and put into perspective. While there is clinical and experimental evidence to support many of these independent pathways, alternative statistical methods such as factor analysis or structural equation modeling may be needed to unravel the complex nature of these interacting pathways. Finally, these hypotheses, if proven, will add new dimensions to our current strategies and emphasize the need to focus on behavioral and socioeconomic interventions in addition to the use of pharmacological therapy in our attempt to control this epidemic disease of modern societies. PMID: 16222595 [PubMed - indexed for MEDLINE] 3645. Curr Opin Gastroenterol. 2005 Nov;21(6):702-7. Role of inflammation in nonalcoholic steatohepatitis. Choi S(1), Diehl AM. Author information: (1)Department of Medicine, Duke University, Durham, NC 27705, USA. PURPOSE OF REVIEW: Products of hepatic macrophages and lymphocytes are acknowledged regulators of liver injury and repair. Recent studies have identified inflammatory modulators from sources within and outside the liver that are critical to the pathogenesis and progression of chronic liver diseases, including nonalcoholic fatty liver disease. This review will focus on these developments to clarify how inflammatory mediators from adipose tissue and the liver interact to mediate the pathogenesis of nonalcoholic fatty liver disease. RECENT FINDINGS: Hepatic steatosis and steatohepatitis are extremely prevalent in obese individuals with the metabolic syndrome. The metabolic syndrome results from abnormal production of various adipose-derived and liver-derived factors that modulate energy substrate flux to coordinate tissue anabolism and catabolism. Individuals with the metabolic syndrome produce a relative excess of proinflammatory factors. Some factors inhibit hepatic fat disposal and promote lipid accumulation within hepatocytes. The latter induces sustained hepatic generation of proinflammatory cytokines, particularly when the hepatic innate immune system becomes Th-1 polarized. Although chronic inflammation induces production of various profibrogenic factors, progression to latter stages of nonalcoholic fatty liver disease is relatively unusual in individuals with the metabolic syndrome. This may reflect requirements for additional factors that become abundant only in individuals who have additional defects in hepatic innate immunity. SUMMARY: Obesity and the metabolic syndrome represent chronic inflammatory states and are associated with nonalcoholic fatty liver disease. Liver injury that ensues is dictated by metabolic and immunomodulatory factors that are produced by adipose tissue and within the liver. PMID: 16220049 [PubMed - indexed for MEDLINE] 3646. Plast Reconstr Surg. 2005 Oct;116(5):1453-60. The potential of adipose-derived adult stem cells as a source of neuronal progenitor cells. Kokai LE(1), Rubin JP, Marra KG. Author information: (1)Division of Plastic and Reconstructive Surgery, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. Adipose-derived adult stem cells are a population of mesenchymal stem cells extracted from discarded adipose tissue. Many have reported the differentiation of adipose-derived stem cells into chondrocytes, myocytes, osteoblasts, and, most recently, neural progenitor cells. This article covers the current state of the potential of the differentiation of adipose-derived stem cells into neuronal cells and an overview of their potential as adult stem therapies for neurological disorders. It has been reported that adipose-derived stem cells are capable of undergoing neuronal differentiation using protocols similar to that of Woodbury et al., which reported the differentiation of bone marrow stromal cells specifically into neurons. However, the transdifferentiation of bone marrow stromal cells into neuronal cells has recently fallen under intense criticism, which will likely place the plasticity of adipose-derived stem cells under scrutiny as well. To date, no group has produced evidence that adipose-derived stem cells are capable of differentiating to mature, functional neuronal cells in vitro. However, recent in vivo studies with adipose-derived stem cells are promising. PMID: 16217495 [PubMed - indexed for MEDLINE] 3647. J Nutr Biochem. 2006 Jan;17(1):1-13. Epub 2005 Sep 8. Effects of dietary polyunsaturated n-3 fatty acids on dyslipidemia and insulin resistance in rodents and humans. A review. Lombardo YB(1), Chicco AG. Author information: (1)Department of Biochemistry, School of Biochemistry, University of Litoral, Santa Fe 3000, Argentina. ylombard@fbcb.unl.edu.ar For many years, clinical and animal studies on polyunsaturated n-3 fatty acids (PUFAs), especially those from marine oil, eicosapentaenoic acid (20:5,n-3) and docosahexaenoic acid (22:6,n-3), have reported the impact of their beneficial effects on both health and diseases. Among other things, they regulate lipid levels, cardiovascular and immune functions as well as insulin action. Polyunsaturated fatty acids are vital components of the phospholipids of membrane cells and serve as important mediators of the nuclear events governing the specific gene expression involved in lipid and glucose metabolism and adipogenesis. Besides, dietary n-3 PUFAs seem to play an important protecting role against the adverse symptoms of the Plurimetabolic syndrome. This review highlights some recent advances in the understanding of metabolic and molecular mechanisms concerning the effect of dietary PUFAs (fish oil) and focuses on the prevention and/or improvement of dyslipidemia, insulin resistance, impaired glucose homeostasis, diabetes and obesity in experimental animal models, with some extension to humans. PMID: 16214332 [PubMed - indexed for MEDLINE] 3648. Drug Discov Today. 2005 Sep 15;10(18):1219-30. Keynote review: the adipocyte as a drug discovery target. Nawrocki AR(1), Scherer PE. Author information: (1)Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. The adipocyte has pleiotropic functions beyond the storage of energy in times of nutrient abundance. Considerable efforts in adipocyte biology within the past ten years have emphasized the important role of adipose tissue in processes as diverse as energy metabolism, inflammation and cancer. Adipocytes are able to communicate with the brain and peripheral tissues implementing metabolic signals such as satiety, food intake and energy expenditure. Despite its huge pharmacological potential, only a small number of clinical applications interfere directly with adipocyte physiology. Here, we want to highlight various areas of adipocyte physiology that have not yet been explored pharmacologically and emphasize some of the limitations associated with these pharmacotherapies. PMID: 16213414 [PubMed - indexed for MEDLINE] 3649. Panminerva Med. 2005 Jun;47(2):75-80. Endothelium and inflammation. Piro M(1), Giubilato G, Pinnelli M, Giordano Sciacca P, Biasucci LM. Author information: (1)Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy. During the past decade, our understanding of the pathophysiology of coronary heart disease (CAD) has undergone a remarkable evolution. To date atherosclerosis is considered an inflammatory disease, whose the endothelial dysfunction represents an early key event. When the arterial endothelium encounters certain bacterial products or risk factors, such as dyslipidemia, vasoconstrictor hormones involved in hypertension, the products of glycoxidation associated with hyperglycemia, or proinflammatory cytokines derived from excess adipose tissue, these cells increase the expression of adhesion molecules that promote the sticking of blood leukocytes to the inner surface of the arterial wall. Once in the arterial intima these cells communicate with endothelium and smooth muscle cells, under the influence of mediators of inflammation and immunity, such as the cytokines and complements components, prostanoids and leukotrienes. Thus, the activated endothelium promotes the development of the atherosclerotic disease process, i.e., vascular inflammation and thrombosis by producing vasoconstrictor substances, by inducing the expression of adhesive receptors for leukocytes and platelets, the production of tissue factor and endothelin, and by increasing the production of the plasminogen activator inhibitor-1. Emerging data support the concept that assessment of endothelial vasomotion may be a useful biomarker for atherosclerotic vascular disease. PMID: 16210992 [PubMed - indexed for MEDLINE] 3650. Nutr Clin Pract. 2005 Feb;20(1):13-6. Low-carbohydrate diets, con: the mythical phoenix or credible science? Kushner RF(1). Author information: (1)Northwestern University Feinberg School of Medicine, Wellness Institute, Northwestern Memorial Hospital, Chicago, Illinois, USA. rkushner@nmh.org Low-carbohydrate diets are based on an alternative theory of obesity where dietary carbohydrate, particularly unprocessed sugars, causes hyperinsulinemia, leading to insulin resistance, obesity, and cardiovascular disease. In this model, carbohydrate is viewed as a "metabolic poison" and therefore is limited in the diet. This article systematically reviews and refutes the 6 major physiologic claims made by proponents of low-carbohydrate diets. Any benefits or advantages resulting from these diets must therefore be derived from factors other than those stated by the alternative theory. PMID: 16207642 [PubMed - indexed for MEDLINE] 3651. Curr Opin Clin Nutr Metab Care. 2005 Nov;8(6):624-9. Air-displacement plethysmography: here to stay. Fields DA(1), Higgins PB, Radley D. Author information: (1)Department of Pediatrics, University of Oklahoma Health Science Center, Children's Medical Research Institute's Metabolic Research Center, Oklahoma City, Oklahoma 73104, USA. dfields@ouhsc.edu PURPOSE OF REVIEW: Air-displacement plethysmography holds promise as an alternative to more traditional body composition techniques, although our understanding of air-displacement plethysmography is less than complete. Specifically, factors that influence its validity and application in certain populations, for example children, the obese, and athletes, must be better understood. This review will summarize recent findings on the validity and precision of air-displacement plethysmography and will focus primarily on papers published since 2004, with particular attention on its use in infants. RECENT FINDINGS: The most significant recent findings in the air-displacement plethysmography literature are mechanistic in nature specifically dealing with measurement issues such as heat, moisture, clothing, and recently, inter-device variability. SUMMARY: It is important to recognize that air-displacement plethysmography can be a practical instrument in the evaluation of body composition in a wide range of populations. Therefore, based on the body of literature that has emerged, air-displacement plethysmography appears to be a suitable and reliable instrument in the assessment of body composition. Of particular interest is its use in pediatric and obese individuals, areas requiring further study. Research is also needed to help us better understand sources of measurement error. PMID: 16205463 [PubMed - indexed for MEDLINE] 3652. Curr Opin Clin Nutr Metab Care. 2005 Nov;8(6):618-23. Body mass index and body fatness in childhood. Freedman DS(1), Ogden CL, Berenson GS, Horlick M. Author information: (1)Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention K-26, Atlanta, Georgia 30341-3717, USA. dfreedman@cdc.gov PURPOSE OF REVIEW: The prevalence of overweight, as assessed by a high body mass index (kg/m), has greatly increased among children and adolescents over the last three decades. Because body mass index is a measure of excess weight rather than excess body fatness, it is important to understand the ability of a high level to identify children who truly have excess adiposity. This review covers the measurement and classification of overweight and obesity, the expression of body composition data, and the relation of body mass index to adiposity. RECENT FINDINGS: Although adiposity has typically been expressed as percentage body fat, the use of the fat mass index (fat mass/height) and the fat-free mass index (fat-free mass/height) may provide more information. For example, body mass index differences among relatively thin children have been found to largely reflect differences in fat-free mass index, whereas differences among relatively heavy children are primarily due to differences in fat mass index. In addition, the ability of overweight to identify obese children is greatly influenced by the cutpoints selected for body mass index and adiposity. The use of inappropriate cutpoints, rather than the limitations of body mass index, may account for the frequently reported finding that many obese children are not overweight. SUMMARY: The use of fat mass index and fat-free mass index in expressing body composition data allows one to easily assess the contribution of each to body mass index. If appropriate cutpoints are used, a high body mass index level is a moderately sensitive and a very specific indicator of excess adiposity among children. PMID: 16205462 [PubMed - indexed for MEDLINE] 3653. Curr Opin Clin Nutr Metab Care. 2005 Nov;8(6):607-12. Early adiposity rebound: review of papers linking this to subsequent obesity in children and adults. Taylor RW(1), Grant AM, Goulding A, Williams SM. Author information: (1)Department of Human Nutrition, University of Otago, Dunedin, New Zealand. PURPOSE OF REVIEW: Improving our understanding of factors driving fat gain in young children should increase our ability to manage the rising problem of obesity. Accordingly, studies associating timing of adiposity rebound with later obesity are reviewed. RECENT FINDINGS: Investigations in many countries have confirmed that early adiposity rebound increases risk of high blood pressure and obesity in young adults. The magnitude of the effect can be substantial (>3 body mass index units at 18-21 years) for those undergoing early (<5 years of age) compared with late (>7 years of age) rebound. Early rebound is also associated with impaired glucose tolerance and diabetes in adulthood. Because adiposity rebound is determined using serial measurements of body mass index, the actual changes in body composition occurring during this time are obscured. Recent data show that changing body mass index during adiposity rebound is due to higher than average deposition of weight rather than slowing of the rate of height gain. Moreover, this increased weight gain occurs because of rapid deposition of fat rather than lean tissue, with early rebounders gaining fat mass at almost three times the rate of late rebounders. SUMMARY: Future work is needed to identify reasons for early adiposity rebound. Because high physical activity and low inactivity are associated with lower body fat during the period of adiposity rebound, studies should be undertaken to see whether stepping up activity can slow fat gain, delay the onset of adiposity rebound and lower adult obesity. PMID: 16205460 [PubMed - indexed for MEDLINE] 3654. Curr Opin Clin Nutr Metab Care. 2005 Nov;8(6):602-6. Body composition measurement in severe obesity. Das SK(1). Author information: (1)Energy Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. sai.das@tufts.edu PURPOSE OF REVIEW: Severe obesity is accompanied by large increases in fat mass and alterations in the composition of fat free mass, in particular total body water and its extracellular compartment. The physical size limitations imposed by severe obesity, and variations in body composition from that of normal weight, pose tremendous challenges to the measurement of body composition. This review focuses on some of the methodological and practical issues associated with the use of common body composition methods, and identifies available published information on feasible methods for use in the severely obese. RECENT FINDINGS: There is little published research regarding what body composition methods can be used with confidence in the severely obese populations. A simple three-compartment model combining measurements of body density by air displacement plethysmography and total body water by bio-electrical impedance can provide measurements of percentage body fat in the severely obese that are comparable with a traditional, highly technical three-compartment model requiring facilities such as isotope ratio mass spectrometry along with a substantial technical expertise. SUMMARY: This review highlights some of the basic challenges faced by researchers and clinicians when conducting body composition assessments in severely obese patients. A simple three-compartment model that is accurate and easy to perform appears to be promising for use in this population. Further research is needed, however, on this and other feasible methods of body composition assessment in a diverse group of severely obese people. PMID: 16205459 [PubMed - indexed for MEDLINE] 3655. Curr Opin Clin Nutr Metab Care. 2005 Nov;8(6):595-601. Pediatric obesity phenotyping by magnetic resonance methods. Shen W(1), Liu H, Punyanitya M, Chen J, Heymsfield SB. Author information: (1)New York Obesity Research Center, St. Luke's-Roosevelt Hospital, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10025, USA. ws2003@columbia.edu PURPOSE OF REVIEW: Accurate measurement of adiposity in obese children is required for characterizing the condition's phenotype, severity, and treatment effects in vivo. Non-invasive and safe, magnetic resonance imaging and spectroscopy provide an important new approach for characterizing key aspects of pediatric obesity. This review focuses on recent advances in non-invasive magnetic resonance imaging and spectroscopy for quantifying total body and regional adiposity, mapping adipose tissue distribution, and evaluating selected metabolic disturbances in children. The aim is to provide an investigator-focused overview of magnetic resonance methods for use in the study of pediatric body composition and metabolism. RECENT FINDINGS: Whole body axial images can be rapidly acquired on most clinical magnetic resonance imaging scanners. The images can then be semi-automatically segmented into subcutaneous, visceral, and intramuscular adipose tissue. Specific pediatric studies of errors related to slice gap and number are available. The acquisition of scans in healthy and premature infants is now feasible with recent technological advances. Spectroscopic, Dixon, and other approaches can be used to quantify the lipid content of liver, skeletal muscle, and other organs. Protocol selection is based on factors such as subject age and cost. Particular attention should be directed towards identification of landmarks in growth studies. Recent advances promise to reduce the requirement of subjects to remain motionless for relatively long periods. SUMMARY: Magnetic resonance imaging and spectroscopy are safe, practical, and widely available methods for phenotyping adiposity in children that open new opportunities for metabolism and nutritional research. PMCID: PMC1894644 PMID: 16205458 [PubMed - indexed for MEDLINE] 3656. IUBMB Life. 2005 Sep;57(9):631-8. Animal models of complex diseases: an initial strategy. Britton SL(1), Koch LG. Author information: (1)Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan 48109, USA. brittons@med.umich.edu We speculated that the rise in atmospheric oxygen from 2 billion years ago was so integral for the evolution of biocomplexity that it must also associate strongly with complex diseases. As a remote test of this idea, we hypothesized that lines contrasting for disease and health would emerge from artificial selection for low and high aerobic treadmill running capacity. Eleven generations of selection in rats produced lines that differed by 347% in running capacity. The low line demonstrated health risk factors including higher visceral adiposity, blood pressure, insulin, and triglycerides. The high line was superior for VO2max, economy of running, heart function, and nitric oxide-induced vascular dilation. PMID: 16203682 [PubMed - indexed for MEDLINE] 3657. J Am Acad Dermatol. 2005 Oct;53(4):671-83. Subcutaneous fat in normal and diseased states: 2. Anatomy and physiology of white and brown adipose tissue. Avram AS(1), Avram MM, James WD. Author information: (1)asaderm@aol.com White and brown adipose tissues, both present to some degree in all mammals, represent counter actors in energy metabolism. One of the primary functions of white adipocytes is to store excess energy as lipid, which is then mobilized to other tissues in response to metabolic needs that arise in times of food shortage. White adipocyte physiology can be grouped into 3 main categories with potentially overlapping mechanisms: lipid metabolism, glucose metabolism, and endocrine functions. Brown adipocytes, on the other hand, use accumulated lipid from food primarily as a source for chemical energy that can then be released from the cell in the form of heat. Recently, new discoveries about the significance of brown fat have sparked interest in this organ as a potential tool in the fight against obesity in adult humans. A basic overview of the anatomy and physiology of adipose tissue, with particular emphasis on the differences between white and brown fat, is presented. PMID: 16198791 [PubMed - indexed for MEDLINE] 3658. J Am Acad Dermatol. 2005 Oct;53(4):663-70. Subcutaneous fat in normal and diseased states: 1. Introduction. Avram MM(1), Avram AS, James WD. Author information: (1)Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA. In recent years, our understanding of adipose tissue physiology and function has undergone an enormous transformation. Once considered a passive storage receptacle with a fixed number of cells and limited purpose, adipose tissue is now recognized as a complicated organ with important endocrine and metabolic functions. It is now known that both increased and decreased adipose tissue mass, as seen in obesity, anorexia, and lipodystrophy, have profound effects on multiple body systems, including immune, reproductive, and hematopoietic. The study of adipose tissue, therefore, is important not only for those who treat obesity, lipoatrophy, and their associated metabolic and endocrine derangements, but also for those dermatologists who specialize in the medical and surgical treatment of disorders within the body's largest adipose tissue subdivision, the subcutaneous fat. This introductory article is the first in a series about adipose tissue in normal and diseased states. PMID: 16198790 [PubMed - indexed for MEDLINE] 3659. Biol Neonate. 2006;89(2):109-19. Epub 2005 Sep 29. Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system. Garbrecht MR(1), Klein JM, Schmidt TJ, Snyder JM. Author information: (1)Department of Anatomy and Cell Biology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, 52242, USA. It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11beta-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species. PMID: 16195667 [PubMed - indexed for MEDLINE] 3660. Diabetologia. 2005 Nov;48(11):2203-5. Resistin: yet another adipokine tells us that men are not mice. Arner P(1). Author information: (1)Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden. peter.arner@medhs.ki.se Comment on Diabetologia. 2005 Nov;48(11):2330-3. PMID: 16193286 [PubMed - indexed for MEDLINE] 3661. Int J Impot Res. 2007 Jan-Feb;19(1):2-24. Epub 2005 Sep 29. Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Seftel A(1). Author information: (1)Department of Urology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH 44106-5046, USA. adseftel@aol.com Male hypogonadism is associated with potentially distressing adverse effects on diverse organs and tissues. These include sexual dysfunction, particularly diminished libido, as well as mood disturbances, reduced lean body mass, and increased adipose-tissue mass. A wide range of effective and well-tolerated options exists. These include relatively noninvasive therapies, such as testosterone (T) gels and T patches; slightly more invasive treatments, such as the T buccal system; and invasive therapies, such as intramuscular T injections and subcutaneous depot implants (T pellets). Testosterone replacement therapy (TRT) can be individualized to enhance patient health and well-being. Screening and ongoing monitoring are necessary to ensure both the efficacy and safety of TRT, particularly prostate safety. Investigational agents, including selective androgen receptor modulators, may offer new pharmacodynamic and/or pharmacokinetic properties that enhance outcomes of TRT. PMID: 16193074 [PubMed - indexed for MEDLINE] 3662. Curr Opin Investig Drugs. 2005 Sep;6(9):887-94. Cardiovascular disease and PPARdelta: targeting the risk factors. Muscat GE(1), Dressel U. Author information: (1)Institute for Molecular Bioscience, Division of Molecular Genetics and Development, University of Queensland, St Lucia, QLD 4072, Australia. g.muscat@imb.uq.edu.au Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease. PMID: 16187688 [PubMed - indexed for MEDLINE] 3663. Birth Defects Res C Embryo Today. 2005 Sep;75(3):193-9. Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity. Budge H(1), Gnanalingham MG, Gardner DS, Mostyn A, Stephenson T, Symonds ME. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, United Kingdom. As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all. Copyright (c) 2005 Wiley-Liss, Inc. PMID: 16187315 [PubMed - indexed for MEDLINE] 3664. Nat Clin Pract Cardiovasc Med. 2005 Oct;2(10):536-43. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Iacobellis G(1), Corradi D, Sharma AM. Author information: (1)Department of Medicine, Cardiovascular Obesity Research and Management, Michael G deGroote School of Medicine, Hamilton, Ontario, Canada. gianluca.iaco@tin.it A growing amount of evidence suggests that regional fat distribution plays an important part in the development of an unfavorable metabolic and cardiovascular risk profile. Epicardial fat is a metabolically active organ that generates various bioactive molecules, which might significantly affect cardiac function. This small, visceral fat depot is now recognized as a rich source of free fatty acids and a number of bioactive molecules, such as adiponectin, resistin and inflammatory cytokines, which could affect the coronary artery response. The observed increases in concentrations of inflammatory factors in patients who have undergone coronary artery bypass grafting remain to be confirmed in healthy individuals. Furthermore, epicardial adipose mass might reflect intra-abdominal visceral fat. Therefore, we propose that echocardiographic assessment of this tissue could serve as a reliable marker of visceral adiposity. Epicardial adipose tissue is also clinically related to left ventricular mass and other features of the metabolic syndrome, such as concentrations of LDL cholesterol, fasting insulin and adiponectin, and arterial blood pressure. Echocardiographic assessment of epicardial fat could be a simple and practical tool for cardiovascular risk stratification in clinical practice and research. In this paper, we briefly review the rapidly emerging evidence pointing to a specific role of epicardial adipose tissue both as a cardiac risk marker and as a potentially active player in the development of cardiac pathology. PMID: 16186852 [PubMed - indexed for MEDLINE] 3665. Arq Bras Endocrinol Metabol. 2005 Apr;49(2):196-204. Epub 2005 Sep 12. [Visceral obesity, hypertension and cardio-renal risk: a review]. [Article in Portuguese] Rosa EC(1), Zanella MT, Ribeiro AB, Kohlmann Junior O. Author information: (1)Disciplina de Nefrologia, Setor de Hipertensão e Diabetes, Universidade Federal de São Paulo, São Paulo, SP. eduardocantoni@uol.com.br Great part of obesity adversity is due to its cardiovascular/coronary risk, particularly present in obese with visceral adiposity distribution. Visceral fat deposition is known to be associated with a greater prevalence of metabolic, neurohormonal, inflammatory and hemodynamic disorders, which together will be implicated in microvascular and target organ involvement, particularly to the cardio-renal axis. In this aspect, beyond its classical association with coronary disease, visceral obesity has been associated with left ventricular hypertrophy and microalbuminuria, which are known cardiac and nephrologic risk factors. So, therapeutic tools for obese patients, specially for those with hypertension, must accomplish the risk stratification based on body fat distribution, which will allow a more adequate therapy in terms of risk factors control as well as target organ damage monitoring. PMID: 16184247 [PubMed - indexed for MEDLINE] 3666. Physiol Rev. 2005 Oct;85(4):1131-58. Hormonal regulation of food intake. Stanley S(1), Wynne K, McGowan B, Bloom S. Author information: (1)Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Our knowledge of the physiological systems controlling energy homeostasis has increased dramatically over the last decade. The roles of peripheral signals from adipose tissue, pancreas, and the gastrointestinal tract reflecting short- and long-term nutritional status are now being described. Such signals influence central circuits in the hypothalamus, brain stem, and limbic system to modulate neuropeptide release and hence food intake and energy expenditure. This review discusses the peripheral hormones and central neuronal pathways that contribute to control of appetite. PMID: 16183909 [PubMed - indexed for MEDLINE] 3667. Cell Signal. 2006 Apr;18(4):401-8. Epub 2005 Sep 22. Signalling mechanisms regulating lipolysis. Carmen GY(1), Víctor SM. Author information: (1)Department of Medical Biochemistry and Molecular Biology, School of Medicine. Investigation Unit, Virgen Macarena University Hospital, Av. Sanchez Pizjuan 4, Seville 41009, Spain. Adipose tissue plays an important role providing energy to other tissues and functioning as an energy reserve organ. The energy supply is produced by triglycerides stored in a large vacuole representing approximately 95% of adipocyte volume. In the fasting period, triglyceride hydrolysis produces glycerol and free fatty acids which are important oxidative fuels for other tissues such as liver, skeletal muscle, kidney and myocardium. Hormone-sensitive lipase (HSL) is the enzyme that hydrolyzes intracellular triacylglycerol and diacylglycerol, and is one of the key molecules controlling lipolysis. Hormones and physiological factors such as dieting, physical exercise and ageing regulate intensively the release of glycerol and free fatty acids from adipocytes. One of the best known mechanisms that activate lipolysis in the adipocyte is the cAMP dependent pathway. cAMP production is modulated by hormone receptors coupled to Gs/Gi family of GTP binding proteins, such as beta-adrenergic receptors, whereas cAMP degradation is controlled by modulation of phosphodiesterase activity, increased by insulin receptor signalling. cAMP activates PKA which activates HSL by promoting its phosphorylation. Hormonal control of lipolysis can also be achieved by receptors coupled G proteins of the Gq family, through molecular mechanisms that involve PKC and MAPK, which are currently under investigation. cGMP and PKG have also been found to activate lipolysis in adipocytes. In this review we have compiled data from literature reporting both the classical and the alternative mechanisms of lipolysis. PMID: 16182514 [PubMed - indexed for MEDLINE] 3668. Ann Med. 2005;37(5):347-56. Fat in the liver and insulin resistance. Yki-Järvinen H(1). Author information: (1)Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland. ykijarvi@cc.helsinki.fi Insulin resistance in humans is not always accompanied by obesity, since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART- (highly-active antiretroviral therapy)-associated lipodystrophy. Both obese and lipodystrophic patients, however, have an increase in the amount of fat hidden in the liver. Liver fat content can be accurately quantified non-invasively by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin concentrations and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. An increase in liver fat content has been shown to predict type 2 diabetes, independently of other cardiovascular risk factors. This is easily explained by the fact that the liver, once fatty, overproduces most of the known cardiovascular risk factors such as very low density lipoprotein (VLDL), glucose, C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), fibrinogen and coagulation factors. The causes of inter-individual variation in liver fat content, independent of obesity, are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin-resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss and by a low as compared to a high fat diet. In addition, treatment of both lipodystrophic and type 2 diabetic patients with peroxisome proliferators activator receptor-gamma (PPARgamma) agonists, but not metformin, decreases liver fat and markedly increases adiponectin levels. The fatty liver may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease. PMID: 16179270 [PubMed - indexed for MEDLINE] 3669. Curr Med Chem. 2005;12(19):2215-25. Novel treatments for obesity and osteoporosis: targeting apoptotic pathways in adipocytes. Nelson-Dooley C(1), Della-Fera MA, Hamrick M, Baile CA. Author information: (1)Departments of Animal and Dairy Sciences, University of Georgia, Athens, GA, USA. Obesity and osteoporosis have grave consequences for human health, quality of life, and even the efficiency of the labor force and economy. However, these pathologies share a common cell progenitor, revealing a surprising target for drug research and development. Recent findings show that high adipocyte count in bone marrow is directly related to bone loss, as fat cells replace osteoblasts (or bone-forming cells). The objective of this review is to examine the importance of adipocyte apoptosis in the treatment of obesity and/or osteoporosis, with special emphasis on natural products as promising leads for drug development. We have induced in vivo adipocyte apoptosis, using leptin, ciliary neurotrophic factor (CNTF), beta adrenergic agonists and conjugated linoleic acid (CLA) in rodents. The results of leptin treatments on rats are suppressed food intake, reduced body weight, reduced body fat, adipocyte apoptosis, and elevated energy expenditure. Further, leptin treatment of leptin-deficient (ob/ob) mice increases endosteal bone formation and bone mineral density. Adipocyte apoptosis has also been induced in vitro using tumor necrosis factor-alpha (TNF-alpha), (-)-epigallocatechin gallate (EGCG) from Camellia sinensis and ajoene, from Allium sativum. Natural products have potential for inducing apoptosis of adipose tissue, inhibiting bone marrow adipogenesis and increasing the expression of osteogenic factors in bone, thereby yielding effective treatments for obesity and osteoporosis. PMID: 16178781 [PubMed - indexed for MEDLINE] 3670. Acta Paediatr Suppl. 2005 Jun;94(448):40-1. Appetite regulation and energy balance. Erlanson-Albertsson C(1). Author information: (1)Department of Experimental Medicine, University of Lund, Lund, Sweden. charlotte.erlanson-albertsson@med.lu.se The decision to begin eating or to stop eating is a complex process. Hunger is primarily driven by hunger signals, like ghrelin and neuropeptide Y, originating from the gastrointestinal tract and from the hypothalamus. The hunger signals stimulate the seeking of food and the eating, being activating for the body and mind. Thirty minutes after the start of eating, satiety signals arise from the intestinal tract and, in between meals, from the adipose tissue and liver. Satiety signals are sedative and arrest the processing of food in the intestine, hence leading to termination of eating. One problem with overeating today is the ready access to palatable food, such as sucrose and fat. The palatable food works by weakening the satiety signals and activating the hunger signals. The reward system with endogenous opiates may also be activated.CONCLUSIONS: Food and drinks rich in sucrose and fat should be given in a restricted way to children, since there is no biological control feedback to regulate the intake of such products. PMID: 16175806 [PubMed - indexed for MEDLINE] 3671. Hepatology. 2005 Oct;42(4):755-8. Fat is an immuno-regulatory issue. Jones DE. Comment on Hepatology. 2005 Oct;42(4):880-5. PMID: 16175616 [PubMed - indexed for MEDLINE] 3672. Horm Metab Res. 2005 Sep;37(9):550-4. Towards comprehension of the physiological role of UCP3. Hesselink MK(1), Schrauwen P. Author information: (1)Department of Movement Sciences, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, The Netherlands. matthijs.hesselink@bw.unimaas.nl Thyroid hormones have long been known to stimulate energy expenditure partly via loss of metabolic efficiency. The mechanism underlying the loss in metabolic efficiency observed, however, is not yet understood. An important candidate gene responsible for thyroid hormone induced thermogenesis was identified in 1997 with the discovery of skeletal muscle-uncoupling protein 3 (UCP3), a protein with approximately 60 % homology to the brown adipose tissue uncoupling protein 1 (UCP1). This short review summarizes our presentation held at the 'Thyroid and Sports' meeting; it does not aim to provide a concise overview of the available literature at this topic. Although induction of the UCP3 gene and increased protein expression during hyperthyroidism has been shown, there are no convincing data that increased UCP3 levels account for the increase in thermogenesis in the hyperthyroid state in humans. In contrast to cell and animal studies using ectopic overexpression of UCP3 as a model, induction of UCP3 in humans does not result in any apparent mitochondrial uncoupling. Hence, the primary physiological role of UCP3 may not be mitochondrial uncoupling, but uncoupling may occur as a side effect of a more pivotal role played by UCP3. Recently, UCP3 has been hypothesized to export fatty acid anions and/or lipid peroxides away from the mitochondrial matrix to prevent mitochondria from the harmful effects of peroxidized lipids. The present review aims to provide an overview of studies testing the feasibility of this unconventional function of UCP3. PMID: 16175492 [PubMed - indexed for MEDLINE] 3673. Horm Metab Res. 2005 Sep;37(9):545-9. Cold adaptation and thyroid hormone metabolism. Laurberg P(1), Andersen S, Karmisholt J. Author information: (1)Department of Endocrinology and Medicine, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. laurberg@aas.nja.dk Resting oxygen consumption and energy expenditure is sensitive to slight alterations in thyroid function. This means that timing and magnitude of cold adaptation would to some extent depend on thyroid function. Local thyroid hormone metabolism is important for energy expenditure and dissipation of heat in special tissues. Recruitment of brown adipocytes and upregulation of uncoupling protein 1 in mitochondria depends on high tissue T3 concentrations. Most of this T3 is derived from local 5' deiodination of T4. Brown fat is vital for cold exposed mice and rats, and may be important for temperature adaptation in human neonates. The role of thyroid hormone metabolism in adult human cold adaptation has not been finally clarified. Hypothetically, cold exposure may enhance T3 production by deiodination of T4 in skeletal muscle, which may enhance heat production in muscle via a change in muscle fiber type. Another hypothetical possibility is recruitment of brown adipocytes embedded in white adipose tissue in human adults. Understanding cold adaptation in human adults may lead to development of new drugs against obesity. PMID: 16175491 [PubMed - indexed for MEDLINE] 3674. Horm Metab Res. 2005 Sep;37(9):538-44. Thyroid hormones, cytokines, physical training and metabolic control. Steinacker JM(1), Brkic M, Simsch C, Nething K, Kresz A, Prokopchuk O, Liu Y. Author information: (1)Sektion Sport- und Rehabilitationsmedizin, Medizinische Klinik, Universität Ulm, Ulm, Germany. juergen.steinacker@medizin.uni-ulm.de During the acute training response, peripheral cellular mechanisms are mainly metabolostatic to achieve energy supply. During prolonged training, glycogen deficiency occurs; this is associated with increased expression of local cytokines, and decreased insulin secretion and beta-adrenergic stimulation and lipolysis in adipose tissue which looses energy. This is indicated by decrease of adipocyte hormone leptin, which has inhibitory effects on excitatory hypothalamic neurons. Leptin, insulin, and cytokines such as interleukin 6 (IL-6) contribute to the metabolic error signal to the hypothalamus which result in decrease of hypothalamic release hormones and sympathoadrenergic stimulation. Thyroid stimulating hormone (TSH) is correlated to the metabolic hormones leptin and insulin, and may be used as indicator of metabolic control. Because the hypothalamus integrates various error signals (metabolic, hormonal, sensory afferents, and central stimuli), the pituitary's releasing hormones represent the functional status of an athlete. Long-term overtraining will lead to downregulation of hypothalamic hormonal and sympathoadrenergic responses, catabolism, and fatigue. These changes contribute to myopathy with predominant expression of slow muscle fiber type and inadequacy in performance. Thyroid hormones are closely involved in the training response and metabolic control. PMID: 16175490 [PubMed - indexed for MEDLINE] 3675. Horm Metab Res. 2005 Sep;37(9):533-7. Leptin TRH and ghrelin: influence on energy homeostasis at rest and during exercise. Popovic V(1), Duntas LH. Author information: (1)Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center, Belgrade, Serbia. popver@eunet.yu The hypothalamus has long been recognized as a major site in the central nervous system (CNS) where a spectrum of internal and external environmental information is integrated for energy homeostasis. The isolation and sequencing of leptin in the mid 90 s, together with the demonstration of leptin administration's ability to correct the obesity syndrome in leptin-deficient ob/ob mice and humans by suppressing food intake and weight gain in laboratory rodents, confirmed the hypothesized existence of a direct humoral signal from adipose tissue to the hypothalamus, thus integrating the energy-related signals. In the 80 s, neuropeptide Y (NPY) was identified as a potent appetite-stimulating neuropeptide produced, released and acting locally within the hypothalamus. This is recognized as a major physiological appetite transducer and central neurochemical substrate receiving, interpreting and processing incoming information on energy status. More recently, ghrelin, produced in the stomach and released into the general circulation, has drawn attention as the other limb of the feedback circuit that stimulates appetite at NPY network level. Prolonged fasting suppresses serum leptin, while suppressing TSH secretion. Intervention with leptin replacement can prevent fasting-induced changes in TSH, suggesting that leptin regulates TSH. Low leptin levels in sportsmen and sportswomen as well as in recreational runners are consistent with reduction in body fat, but are also influenced by the presence of low insulin, hypothyroxemia, and elevated cortisol levels. These metabolic adaptations to chronic energy deficits indicate a role in leptin regulation. A study within the general population found that activity levels and leptin were significantly negatively associated in both sexes. Circulating ghrelin levels, however, do not change during energy expenditure. PMID: 16175489 [PubMed - indexed for MEDLINE] 3676. Health Care Food Nutr Focus. 2005 Oct;22(10):10-1. Exercise can help control body changes during menopause. Smith KR(1). Author information: (1)Institute for Natural Resources. PMID: 16175071 [PubMed - indexed for MEDLINE] 3677. Physiology (Bethesda). 2005 Oct;20:340-8. Molecular pathways leading to cancer cachexia. Tisdale MJ(1). Author information: (1)Cancer Biochemistry, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom. m.j.tisdale@aston.ac.uk Loss of body weight in cancer patients strongly influences morbidity and mortality. Recent studies have suggested that both tumor and host factors play a major role in tissue catabolism in cachexia, leading to upregulation of degradative pathways in both skeletal muscle and adipose tissue. PMID: 16174873 [PubMed - indexed for MEDLINE] 3678. Minerva Med. 2005 Apr;96(2):65-75. Focus on leptin, a pleiotropic hormone. Fietta P(1). Author information: (1)Rheumatic Disease and Internal Medicine Unit Osteo-Articular Department, Hospital of Parma, Parma, Italy. farnese15@libero.it Leptin, the product of the obese gene located on human chromosome 7 (7q31.3), is a cytokine-type hormone mainly secreted by the white adipose tissue and in a lesser extent by placenta, skeletal muscle, gastric mucosa, mammary and salivary glands. Leptin, released by the adipocytes into the bloodstream in positive correlation to the fat mass, plays a key role in the body weight control. Indeed, it suppresses the appetite and increases the metabolic rate, primarily acting through central pathways. Conversely, during starvation leptinemia rapidly falls, leading to a reduction of the energy expenditure and allowing a longer survival. Recently, pleiotropic effects of leptin have been identified, consisting in modulation of several processes, such as thermogenesis, reproduction, hemostasis, angiogenesis, hematopoiesis, osteogenesis, chondrogenesis, neuroendocrine and immune functions, as well as arterial pressure control. Leptin has been also suggested as neuroendocrinologic marker of hypervigilant state. Ultimately, it may be the signal that integrates metabolic, vascular, neuroendocrine, immune and behavioural responses. In this paper, the more recent information on leptin is reviewed and summarized. PMID: 16172576 [PubMed - indexed for MEDLINE] 3679. Front Horm Res. 2005;33:185-95. Growth hormone and body composition. Mersebach H(1), Feldt-Rasmussen U. Author information: (1)Department of Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark. mersebach@rh.dk PMID: 16166762 [PubMed - indexed for MEDLINE] 3680. Front Horm Res. 2005;33:103-20. Consequences of growth hormone deficiency for intermediary metabolism and effects of replacement. Nørrelund H(1). Author information: (1)Medical Department M, Aarhus University Hospital, Aarhus Sygehus, Aarhus, Denmark. helenenorrelund@dadlnet.dk PMID: 16166758 [PubMed - indexed for MEDLINE] 3681. Exp Gerontol. 2005 Nov;40(11):894-9. Epub 2005 Sep 12. Regulation of glycolysis-role of insulin. Wu C(1), Khan SA, Lange AJ. Author information: (1)Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. PMID: 16157461 [PubMed - indexed for MEDLINE] 3682. Curr Opin Biotechnol. 2005 Oct;16(5):503-9. Advancing cartilage tissue engineering: the application of stem cell technology. Raghunath J(1), Salacinski HJ, Sales KM, Butler PE, Seifalian AM. Author information: (1)Biomaterials and Tissue Engineering Centre (BTEC), Academic Division of Surgical and Interventional sciences, University College London, London, UK. The treatment of cartilage pathology and trauma face the challenges of poor regenerative potential and inferior repair. Nevertheless, recent advances in tissue engineering indicate that adult stem cells could provide a source of chondrocytes for tissue engineering that the isolation of mature chondrocytes has failed to achieve. Various adjuncts to their propagation and differentiation have been explored, such as biomaterials, bioreactors and growth hormones. To date, all tissue engineered cartilage has been significantly mechanically inferior to its natural counterparts and further problems in vivo relate to poor integration and deterioration of tissue quality over time. However, adult stem cells--with their high rate of proliferation and ease of isolation--are expected to greatly further the development and usefulness of tissue engineered cartilage. PMID: 16153817 [PubMed - indexed for MEDLINE] 3683. Rev Endocr Metab Disord. 2005 Aug;6(3):173-82. Growth hormone during development. Osafo J(1), Wei Y, Kenth G, Goodyer CG. Author information: (1)Department of Pediatrics, McGill University, Montreal, Quebec, Canada. PMID: 16151621 [PubMed - indexed for MEDLINE] 3684. Endocrinology. 2005 Dec;146(12):5071-8. Epub 2005 Sep 8. Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners. Ishiki M(1), Klip A. Author information: (1)Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. Glucose transporter (GLUT) 4 is the major glucose transporter of muscle and adipose cells, exquisitely regulated by insulin through posttranslational events. Twenty years after the seminal observations that GLUT4 levels rapidly rise at the plasma membrane (PM) and drop in endomembranes in response to an acute insulin challenge, we are still mapping the intracellular traffic of the transporter and the regulatory events that insulin unleashes. Newly synthesized GLUT4 enters an insulin-responsive compartment aided by GGA2 (an Arf-binding protein). In cultured adipocytes and myocytes, GLUT4 concentrates in a perinuclear pole through participation of microtubules and the EHD1 Eps15 homology domain-containing protein 1. In the absence of stimuli, GLUT4 distributes between recycling endosomes and the insulin-responsive compartment. A handful of proteins that bind to GLUT4 appear to regulate its half-life (e.g. Ubc9) and tethering within endomembranes (e.g. TUG). Insulin-derived signals promote not only GLUT4 mobilization toward the PM but also its traffic between endosomal compartments and internalization from the PM. Class IA phosphatidylinositol (PI) 3-kinase plays a pivotal role at several steps of GLUT4 mobilization. The PI 3-kinase --> atypical PKC and --> Akt/PKB --> AS160 signaling cascades are major regulators of GLUT4 exocytosis aided by small GTPases. At the cell periphery, GLUT4-containing vesicles tether, dock, and fuse with the PM assisted by the exocyst complex followed by engagement of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex [with vesicle-associated membrane protein (VAMP)2 as the vesicular (v)-SNARE and soluble NSF-attachment protein (SNAP)23 and syntaxin4 as target (t)-SNAREs] regulated by the accessory proteins Munc18c, Synip and Tomosyn. Vesicle tethering and fusion are regulated by insulin through input from class IA PI 3-kinase. PMID: 16150904 [PubMed - indexed for MEDLINE] 3685. Best Pract Res Clin Endocrinol Metab. 2005 Sep;19(3):391-403. Metabolic fluxes in skeletal muscle in relation to obesity and insulin resistance. Blaak EE(1). Author information: (1)Department of Human Biology, Nutrition Research Centre, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. e.blaak@hb.unimaas.nl The present article addresses the hypothesis that inefficient skeletal muscle lipid utilization may relate to the development of obesity and insulin resistance. In practice, there is evidence of impaired muscle fatty acid utilization in the obese state, and studies indicate that differences in muscle fatty acid oxidative capacity might play a role in the pathogenesis of obesity. The link between obesity and insulin resistance has been recognized for many years. There is accumulating evidence that a disturbed muscle fat oxidative capacity results in the accumulation of the lipid intermediates diacylglycerol and Fatty acid acyl coenzyme A (CoA), which may interfere with insulin signaling and result in an inhibition of insulin-mediated glucose uptake. Underlying mechanisms for disturbed fatty acid handling may relate to impaired adipose tissue lipolysis, abnormal muscle fatty acid uptake and a reduced ability to oxidize fat. Many of these abnormalities have been reported both in the obese and the type 2 diabetic state. The role of obesity per se in these disturbances is an important question that needs to be addressed. PMID: 16150382 [PubMed - indexed for MEDLINE] 3686. Am J Dermatopathol. 2005 Oct;27(5):418-21. Cutaneous angiomyolipomas are HMB45 negative, not associated with tuberous sclerosis, and should be considered as angioleiomyomas with fat. Beer TW(1). Author information: (1)Cutaneous Pathology, Nedlands, Australia. twb@lycos.com Angiomyolipomas are uncommon tumors in the skin. Neoplasms with the same name are more typically associated with a renal location, many in the context of tuberous sclerosis. Three cases of cutaneous angiomyolipoma are reported, which were all HMB45 negative and not associated with tuberous sclerosis. This is the first series of such tumors to be stained with HMB45. The presence of fat in histologically similar cutaneous angioleiomyomas has been previously documented and a review of 40 archival cases revealed fat in 1 case. The author proposes that cutaneous angiomyolipomas should be termed angioleiomyoma with fat to avoid confusion with unrelated non-cutaneous angiomyolipomas that are HMB45 negative and require investigation for tuberous sclerosis. PMID: 16148412 [PubMed - indexed for MEDLINE] 3687. World Rev Nutr Diet. 2005;94:158-65. Omega-6/omega-3 polyunsaturated fatty acids ratio and breast cancer. Bougnoux P(1), Maillard V, Chajes V. Author information: (1)Nutrition, Growth and Cancer, INSERM EMI-U 0211, University Francois- Rabelais, Tours, France. bougboux@med.univ-tours.fr PMID: 16145262 [PubMed - indexed for MEDLINE] 3688. J Nutr. 2005 Sep;135(9):2271-3. Arachidonic acid and ischemic heart disease. Hjelte LE(1), Nilsson A. Author information: (1)Department of Pediatrics, Karolinska University Hospital Huddinge, B59, S-11486 Stockholm, Sweden. PMID: 16140910 [PubMed - indexed for MEDLINE] 3689. Adv Exp Med Biol. 2005;569:95-108. Experimental models for studying perinatal lipid metabolism. Long-term effects of perinatal undernutrition. Herrera E(1), López-Soldado I, Limones M, Amusquivar E, Ramos MP. Author information: (1)Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU, E-28668, Madrid, Spain. By using different experimental designs in the rat we have been able to answer several unanswered questions on the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first was to demonstrate the importance of maternal body fat accumulation during the first half of pregnancy, since undernutrition in this critical period when fetal growth is slow, impedes fat depot accumulation and not only restrains intrauterine development but has long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect of decreasing body weight, even though food intake is kept normal from the weaning period. Our findings also show that a diet rich in n-3 fatty acids during pregnancy and lactation has adverse effects on offspring development, but cross fostered experiments showed that this effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a n-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake or altered dietary fatty acid composition, or both, were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a n-3 fatty acid-rich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition, have major effects on postnatal development and affect glucose/insulin relationships in adult rats. PMID: 16137112 [PubMed - indexed for MEDLINE] 3690. Adv Exp Med Biol. 2005;569:64-8. Longterm effects of pre- and postnatal exposure to low and high dietary protein levels. Evidence from epidemiological studies and controlled animal experiments. Metges CC(1). Author information: (1)Research Institute for the Biology of Farm Animals, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany. The purpose of this short review is to summarize the available evidence from observational studies and rodent models for an association between maternal protein intake, birth weight, pre- and post-weaning body mass gain and adult body fatness in the offspring. PMID: 16137109 [PubMed - indexed for MEDLINE] 3691. Adv Exp Med Biol. 2005;569:35-9. Rate of growth in early life: a predictor of later health? Rolland-Cachera MF(1). Author information: (1)INSERM Unit 557, ISTNA-CNAM, 2 rue Conté, 75003 Paris, France. The purpose of this review is to describe the studies which investigate the association between early growth pattern and future metabolic risks. Childhood obesity is increasing but other growth parameters are also changing. There is a trend of earlier maturation and increasing height. The increase in height from one generation to the next occurs mainly in the first years of life. Rapid growth in early life (rapid weight and length gain, early adiposity rebound) is associated with various health risks in later life (obesity, cancer, cardiovascular diseases, diabetes). Pattern of growth rather than absolute level of fatness seams to be of most importance. PMID: 16137104 [PubMed - indexed for MEDLINE] 3692. Thyroid. 2005 Aug;15(8):823-34. The roles of the iodothyronine deiodinases in mammalian development. Galton VA(1). Author information: (1)Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. val.galton@dartmouth.edu The thyroid hormones (TH) are essential for normal development in vertebrate species. This review considers the roles that the three deiodinases, types 1, 2 and 3 (D1, D2, and D3), play in regulating intracellular levels of TH during this critical period. The focus is on rodents and humans with emphasis on brain development. There is little evidence to suggest that the D1 plays a significant role in development and this is substantiated by the absence of any obvious developmental impairment in a D1-deficient mouse model. There is, however, compelling indirect evidence pertaining to the importance of the D2 in development, particularly with respect to that of the brain. However, surprisingly, a D2-deficient mouse model exhibits a very mild phenotype. This, together with the fact that D2 activity is increased in hypothyroidism, suggests that this deiodinase may be of greater importance in development when supplies of thyroxine are limited. The D3 is clearly essential for development in the euthyroid mammal. Information, both indirect and that obtained from a D3-deficient mouse model, strongly suggests that its presence in placenta, uterus and some fetal tissues are critical for limiting exposure of fetal tissues to inappropriate levels of TH. PMID: 16131325 [PubMed - indexed for MEDLINE] 3693. Klin Lab Diagn. 2005 Jul;(7):17-20, 37-8. [Leptin and its effect on energy metabolism (a review of literature)]. [Article in Russian] Selivanova AV. PMID: 16127991 [PubMed - indexed for MEDLINE] 3694. Crit Rev Biochem Mol Biol. 2005 Jul-Aug;40(4):229-42. Adipose development: from stem cell to adipocyte. Otto TC(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cell culture models have been developed to study commitment and subsequent differentiation of preadipocytes into adipocytes. Bone morphogenetic protein 4 commits mesenchymal stem cells to the adipose lineage. Other factors, including Wnt signaling, cell density, and cell shape, play a role in lineage commitment. Following commitment to the adipose lineage, growth-arrested preadipocytes can differentiate to adipocytes by treatment with insulin-like growth factor 1, glucocorticoid and an agent that increases cAMP level. This process is characterized by a rapid and transient increase in CCAAT/enhancer binding protein (C/EBP) beta and synchronous re-entry into the cell cycle. Acquisition of DNA-binding by C/EBPbeta occurs after the transcription factor becomes phosphorylated. The cells enter a growth-arrested state and begin terminal differentiation. C/EBPalpha, peroxisome proliferator-activated receptor gamma, and adipocyte determination, and differentiation-dependent factor 1 coordinate the expression of genes that create and maintain the adipocyte phenotype. PMID: 16126487 [PubMed - indexed for MEDLINE] 3695. Exp Gerontol. 2005 Nov;40(11):878-83. Epub 2005 Aug 25. Extended longevity and insulin signaling in adipose tissue. Klöting N(1), Blüher M. Author information: (1)Department of Internal Medicine III, University of Leipzig, Leipzig, Germany. Caloric restriction and leanness have been shown to increase longevity in organisms ranging from yeast to mammals. Adipose tissue seems to be a pivotal organ in the aging process and in determination of lifespan. We have recently shown that fat-specific disruption of the insulin receptor gene is sufficient to increase lifespan in FIRKO mice, suggesting that reduced adiposity, even in the presence of normal or increased food intake, can extend lifespan. The model also suggests a special role for the insulin-signaling pathway in adipose tissue in the longevity process. Reduced fat mass has an impact on the duration of life in several other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends lifespan. Furthermore, sirtuin1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking lifespan to adipose tissue. In the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. The effect of reduced adipose tissue mass on lifespan could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis. PMID: 16125891 [PubMed - indexed for MEDLINE] 3696. J Pharm Pharm Sci. 2005 Aug 5;8(2):259-71. Emerging pharmacological approaches to the treatment of obesity. Wasan KM(1), Looije NA. Author information: (1)Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Kwasan@unixg.ubc.ca The obesity epidemic has been recognized by the World Health Organization (WHO) as one of the top 10 global health problems. Worldwide, more than one billion adults are overweight and over 300 million are obese. The majority of developed countries, including the United States, Canada and England are experiencing dramatic increases in obesity. Obesity is a condition associated with the accumulation of excessive body fat resulting from chronic imbalance of energy whereby the intake of energy exceeds expenditure. The excess body fat predisposes an obese individual to chronic diseases, such as coronary heart disease, type 2 diabetes and diseases of the gall bladder and cancer. The high incidence of obesity and the lack of safe pharmaceutical agents have fuelled an increase in anti-obesity drug-related research. Although a number of pharmacological approaches have been investigated in recent years, few safe, therapeutically effective products have been developed. This commentary focuses on emerging pharmacological approaches targeted for the treatment of obesity. PMID: 16124937 [PubMed - indexed for MEDLINE] 3697. Diabetes Care. 2005 Sep;28(9):2326-8. Counterpoint: visceral adiposity is not causally related to insulin resistance. Miles JM(1), Jensen MD. Author information: (1)Endocrine Research Unit, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota 55905, USA. miles.john@mayo.edu Comment on Diabetes Care. 2005 Sep;28(9):2322-5. PMID: 16123513 [PubMed - indexed for MEDLINE] 3698. Diabetes Care. 2005 Sep;28(9):2322-5. Point: visceral adiposity is causally related to insulin resistance. Lebovitz HE(1), Banerji MA. Author information: (1)Division of Endocrinology, Department of Medicine, State University of New York Health Science Center at Brooklyn, USA. hlebovitz@attglobal.net Comment in Diabetes Care. 2005 Sep;28(9):2326-8. PMID: 16123512 [PubMed - indexed for MEDLINE] 3699. Bull Cancer. 2005 Jul;92(7):697-707. [Dietary fatty acids and cancer: potential cellular and molecular mechanisms]. [Article in French] Bardon S(1), Benelli C, Bernard-Gallon D, Blottière H, Demarquoy J, Duée PH, Forest C. Author information: (1)Laboratoire de nutrition et sécurité alimentaire INRA CRJ, Domaine de Vilvert, 78352 Jouy-en-Josas Cedex. duee@paris.inra.fr Experimental evidence indicates that n-3 fatty acids, especially the long-chain polyunsaturated fatty acids, unlike n-6 fatty acids could prevent cancer development. This survey shows that fatty acids could act through several mechanisms including the production of reactive oxygen species, the modulation of gene expression and signal transduction pathways, or the eicosanoid biosynthesis. Human genetics has underlined several polymorphisms in genes identified as possible targets of fatty acids which suggests that the link between nutritional intake and cancer prevention, especially the eventual anti-carcinogenic effects of n-3 fatty acids, depends on the genetic background. Further studies are needed to evaluate the effects of fatty acids on angiogenesis which represents a marker of a poor prognosis in cancer. Finally, the use of genomic technologies combined with nutritional strategies could provide a more understanding of the effects of n-3 fatty acid intake on cancer prevention. PMID: 16123008 [PubMed - indexed for MEDLINE] 3700. Bull Cancer. 2005 Jul;92(7):658-69. [Unsaturated fatty acids intake and breast cancer risk: epidemiological data review]. [Article in French] Thiébaut AC(1), Chajès V, Clavel-Chapelon F, Gerber M. Author information: (1)Equipe E3N-EPIC, Inserm, Institut Gustave Roussy, 39, rue Camille-Desmoulins, 94805 Villejuif Cedex. The relationship between fatty acids and breast cancer has been debated for long, because of the high frequency of breast cancer and the contradictory results from the numerous studies devoted to this issue. The present review includes case-control and prospective studies, according to specified methodological criteria, which estimated the exposure to monounsaturated fatty acids (MUFA) and n-6 and n-3 polyunsaturated fatty acids (PUFA) using dietary questionnaires or markers (plasma, erythrocytes, adipose tissue). The relationship between MUFA intake and breast cancer risk seems to depend on the contributing food : neutral or beneficial for vegetable oil, rather deleterious for animal products. Contrary to data from animal experiments, human studies do not show an increase of breast cancer risk with n-6 PUFA intake. Estimating the risk associated with alpha-linolenic acid appears difficult due to the incompleteness of food composition tables and studies on biomarkers remain few. The same applies to long-chain n-3 PUFA despite the suggestion of a decrease in risk, in agreement with animal studies. However, it is difficult in human to disentangle the effect of nutrient intake from that of contributing foods or even nutritional profile. PMID: 16123005 [PubMed - indexed for MEDLINE] 3701. Curr Opin Mol Ther. 2005 Aug;7(4):300-5. Adipose-derived mesenchymal cells as a potential cell source for skeletal regeneration. Xu Y(1), Malladi P, Wagner DR, Longaker MT. Author information: (1)Stanford University School of Medicine, Department of Surgery, 257 Campus Drive, Stanford, CA 94305-5148, USA. Recent studies suggest that adipose tissue contains pluripotent cells that are similar to those derived from other tissues, such as bone marrow. Mesenchymal cells isolated from adipose tissue are capable of differentiating along osteogenic, chondrogenic, myogenic, adipogenic and possibly neuronal lineages. Current knowledge of adipose-derived mesenchymal cells is reviewed, with a particular focus on efforts to direct these cells towards bone formation. Cell-based therapies using adipose tissue are anticipated to be of great clinical interest for skeletal tissue repair and regeneration. PMID: 16121695 [PubMed - indexed for MEDLINE] 3702. Br J Dermatol. 2005 Sep;153(3):657-60. Calcifying panniculitis following subcutaneous injections of nadroparin-calcium in a patient with osteomalacia. Campanelli A(1), Kaya G, Masouyé I, Borradori L. Author information: (1)Department of Dermatology, University Hospital of Geneva, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. alexandre.campanelli@hcuge.ch Calcifying panniculitis is a rare form of calcinosis cutis belonging to the spectrum of calciphylaxis that has almost invariably been described in patients with severe renal disturbances. We report a patient with osteomalacia without chronic renal failure, who developed calcifying panniculitis following subcutaneous administration of nadroparin-calcium. Light microscopy studies of biopsy specimens revealed multiple foci of microcalcification within the adipose lobules, in the interadipocyte spaces, in connective tissue septa and in the media of small arteries in the subcutis. The patient had an elevated level of intact parathyroid hormone, whereas the calcium-phosphorus product was normal. The lesions slowly resolved upon discontinuation of nadroparin. We conclude that calcifying panniculitis is a rare complication associated with the subcutaneous administration of nadroparin-calcium that may rarely also occur in the absence of renal disturbances. Low molecular weight calcium-containing heparins should probably be used with caution in the presence of hyperparathyroidism. PMID: 16120161 [PubMed - indexed for MEDLINE] 3703. Hepatology. 2005 Sep;42(3):530-2. Adiponectin and alcoholic fatty liver: Is it, after all, about what you eat? Anania FA. Comment on Hepatology. 2005 Sep;42(3):568-77. PMID: 16116627 [PubMed - indexed for MEDLINE] 3704. Inflamm Bowel Dis. 2005 Sep;11(9):847-55. The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel disease. Karmiris K(1), Koutroubakis IE, Kouroumalis EA. Author information: (1)Department of Gastroenterology, University Hospital of Heraklion, Crete, Greece. Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD. PMID: 16116320 [PubMed - indexed for MEDLINE] 3705. Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1173-81. Mitochondrial uncoupling proteins in the central nervous system. Kim-Han JS(1), Dugan LL. Author information: (1)Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. Mitochondrial uncoupling proteins (UCPs), a subfamily of the mitochondrial transporter family, are related by sequence homology to UCP1. This protein, which is located in the inner mitochondrial membrane, dissipates the proton gradient between the intermembrane space and the mitochondrial matrix to uncouple electron transport from ATP synthesis. UCP1 (thermogenin) was first discovered in brown adipose tissue and is responsible for non-shivering thermogenesis. Expression of mRNA for three other UCP isoforms, UCP2, UCP4, and BMCP1/UCP5, has been found at high levels in brain. However, the physiological function(s) of UCPs in the brain have not been determined, although it has recently been postulated that UCPs regulate free radical flux from mitochondria by physiologically modulating mitochondrial membrane potential. In the CNS, this hypothesis has been studied primarily for UCP2. UCP2 message has been shown to be up-regulated in the CNS by stress signals such as kainate administration or ischemia, and overexpression of UCP2 has been reported to be neuroprotective against oxidative stress in vivo and in vitro, although the exact mechanism has not been fully established. In this review, studies on UCPs in the nervous system will be reviewed, and the potential roles of these intriguing proteins in acute and chronic diseases of the nervous system will be discussed. PMID: 16115020 [PubMed - indexed for MEDLINE] 3706. Asian Cardiovasc Thorac Ann. 2005 Sep;13(3):287-96. Cellular cardiomyoplasty for myocardial regeneration. Chachques JC(1), Salanson-Lajos C, Lajos P, Shafy A, Alshamry A, Carpentier A. Author information: (1)Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, Paris 75015, France. j.chachques@brs.ap-hop-paris.fr The evolving challenge of managing patients with congestive heart failure is the need to develop new therapeutic strategies. The cellular, molecular, and genetic approaches investigated aim to reinforce the weak, failing heart muscle while restoring its functional potential. This approach is principally cellular therapy (i.e. cellular cardiomyoplasty), the preferred therapeutic choice because of its clinical applicability and regenerative capacity. Different stem cells: bone marrow cells, skeletal and smooth muscle cells, vascular endothelial cells, mesothelial cells, adipose tissue stroma cells, dental stem cells, and embryonic and fetal cells, have been proposed for regenerative medicine and biology. Stem cell mobilization with G-CSF cytokine was also proposed as a single therapy for myocardial infarction. We investigated the association of cell therapy with electrostimulation (dynamic cellular cardiomyoplasty), the use of autologous human serum for cell cultures, and a new catheter for simultaneous infarct detection and cell delivery. Our team conducted cell-based myogenic and angiogenic clinical trials for chronic ischemic heart disease. Cellular cardiomyoplasty constitutes a new approach for myocardial regeneration; the ultimate goal is to avoid the progression of ventricular remodeling and heart failure for patients presenting with ischemic and non-ischemic cardiomyopathies. PMID: 16113008 [PubMed - indexed for MEDLINE] 3707. Scand J Clin Lab Invest Suppl. 2005;240:30-40. Insulin resistance and inflammation in the early phase of type 2 diabetes: potential for therapeutic intervention. Schernthaner GH(1), Schernthaner G. Author information: (1)Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Austria. Prospective studies of prediabetic subjects have shown that obesity and its duration are major risk factors for type 2 diabetes. Longitudinal studies are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. Inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The adipose tissue has been recognized as an important source of metabolically active secretory products (adipocytokines), free fatty acids, leptin, TNF-alpha, Iinterleucin-6, plasminogen activator inhibitor-1, adiponectin and resistin. Prevention of insulin resistance by weight loss, diet and exercise is very effective in reducing the progression from glucose intolerance to type 2 diabetes in obese subjects. Since insulin resistance is a key disturbance in early type 2 diabetes additional drug treatment with insulin-sensitizing drugs might be helpful to reduce the progression to both beta-cell failure and macrovascular late complications. The PROACTIVE study will determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes. PMID: 16112958 [PubMed - indexed for MEDLINE] 3708. Pharmacol Rev. 2005 Sep;57(3):359-83. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Bulun SE(1), Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S. Author information: (1)Division of Reproductive Biology Research, Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA. s-bulun@northwestern.edu A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues. PMID: 16109840 [PubMed - indexed for MEDLINE] 3709. Brief Funct Genomic Proteomic. 2005 Jul;4(2):95-111. Dissecting the role of cocaine- and amphetamine-regulated transcript (CART) in the control of appetite. Murphy KG(1). Author information: (1)Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. k.g.murphy@imperial.ac.uk Cocaine- and amphetamine-regulated transcript (CART) codes for a neuropeptide system with a number of biological roles. The high conservation of CART across species suggests that it has an important role in mammalian physiology. CART is widely expressed in the central nervous system and the periphery, but is particularly concentrated in the hypothalamus. CART peptides, particularly CART (55-102), appear to have an important function in the regulation of energy homeostasis. This review aims to dissect the role of CART in appetite and energy expenditure. CART interacts with a number of central appetite circuits. Hypothalamic CART expression is regulated by a number of peripheral factors, including the adipose hormone leptin. Intracerebroventricular administration of CART (55-102) reduces appetite and stimulates energy expenditure. Hypothalamic CART may also play an orexigenic role under specific circumstances, however, as injection of CART (55-102) into specific hypothalamic nuclei increases food intake. PMID: 16102267 [PubMed - indexed for MEDLINE] 3710. Nihon Rinsho. 2005 Aug;63(8):1485-91. [The metabolic syndrome and insulin resistance]. [Article in Japanese] Kotani K(1), Kaku K. Author information: (1)Endocrinology and Diabetes Division, Kawasaki Medical School. The frequency of cardiovascular disease associated with metabolic disorder is increasing rapidly worldwide. The metabolic syndrome, a concurrence of glucose intolerance, obesity, dyslipidemia, and hypertension that are risk factors for atherosclerosis, accounts for a large proportion of cardiovascular morbidity and mortality. Exceeding energy intake coupled with high fat diet, sedentary lifestyle, and multiple genetic factors interact to produce the metabolic syndrome, and insulin resistance and visceral adiposity have been suggested to be the common pathophysiological basis of the metabolic syndrome. Adiposity is correlated with altered production of so-called adipocytokines that play a role on the atherosclerotic angiopathy. At the cellular level, excess insulin is involved in VLDL-triglycerides production, decreased HDL, and various elements of atherogenesis. Detecting the metabolic syndrome and implementing preventive lifestyle interventions--diet education, physical activity, and weight control--is a high clinical priority. PMID: 16101244 [PubMed - indexed for MEDLINE] 3711. Ital J Anat Embryol. 2005;110(2 Suppl 1):97-102. The "interfascial" veins of the lower limbs. Caggiati A(1). Author information: (1)Department of Anatomy, Faculty of Medicine, University of Rome La Sapienza, Rome, Italy. alberto.caggiati@uniroma1.it The veins of the lower limb are commonly divided in deep and superficial ones according to their position with respect to the Muscular Fascia (MF). Anatomical textbooks affirm that all superficial veins are thin walled vessels that run in a yielding layer of fat. Accordingly, no differences between saphenous Veins (SVs) and their tributaries (TVs) are reported by physiologists and pathophysiologists. On the contrary, the SVs do not correspond to the classic anatomic, physiologic and clinical descriptions of the "superficial" veins. In fact, the SVs: 1) are not superficial because they course between the SF and the MF; 2) they are not thin vessels, being their wall thick and rich in muscular cells; 3) they actively contribute to the complex mechanisms of venous return from the lower limbs; and finally, 4) they are quite resistant to hypertension and usually afflicted with limited varicose changes. As a consequence, the SVs should not be longer considered "real" superficial veins and the venous bed of the lower limb would be better represented by a three-layered model. PMID: 16101026 [PubMed - indexed for MEDLINE] 3712. Trends Endocrinol Metab. 2005 Sep;16(7):307-13. Central actions of adipocyte hormones. Ahima RS(1). Author information: (1)University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu Adipose tissue secretes a variety of proteins with important roles in metabolism, reproduction, immunity and cardiovascular function. The endocrine function of adipose tissue, especially that of leptin, is linked to energy storage and thus might provide insights into obesity and other diseases associated with energy imbalance. This review highlights the current understanding of the actions of leptin in the brain, with particular emphasis on transport across the blood-brain barrier, signal transduction, neuropeptide targets and roles during fasting and obesity. Moreover, data pertaining to the potential central effects of adiponectin, cytokines and resistin on energy homeostasis, glucose and lipid metabolism are discussed. PMID: 16098759 [PubMed - indexed for MEDLINE] 3713. Presse Med. 2005 Jun 18;34(11):820-4. [The link between molecules produced by the adipose tissue, obesity and atherothrombosis]. [Article in French] Alessi MC(1), Frère C, Juhan-Vague I. Author information: (1)Laboratoire hématologie, 27 bd Jean Moulin, Faculté de Médecine Timone, 13385 Marseille 05. Christine.Alessi@medecine.univ-mrs.fr Obesity is associated with increased risk of cardiovascular morbidity. Biologically active molecules produced by adipose tissue constitute a critical link between obesity and cardiovascular complications. Adipose tissue has recently been recognized to be an important endocrine organ that controls energy metabolism. It also secretes adipocytokines, which can modify vascular responses, and antifibrinolytics, including plasminogen activator inhibitor 1, which favors fibrin accumulation, and proinflammatory cytokines, which facilitate the inflammatory response. Here we review new advances in our understanding of the mechanisms linking the endocrine activity of adipose tissue to vascular risk. PMID: 16097387 [PubMed - indexed for MEDLINE] 3714. Can J Physiol Pharmacol. 2005 Jul;83(7):529-39. Potential application for mesenchymal stem cells in the treatment of cardiovascular diseases. Bunnell BA(1), Deng W, Robinson CM, Waldron PR, Bivalacqua TJ, Baber SR, Hyman AL, Kadowitz PJ. Author information: (1)Department of Pharmacology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Stem cells isolated from various sources have been shown to vary in their differentiation capacity or pluripotentiality. Two groups of stem cells, embryonic and adult stem cells, may be capable of differentiating into any desired tissue or cell type, which offers hope for the development of therapeutic applications for a large number of disorders. However, major limitations with the use of embryonic stem cells for human disease have led researchers to focus on adult stem cells as therapeutic agents. Investigators have begun to examine postnatal sources of pluripotent stem cells, such as bone marrow stroma or adipose tissue, as sources of mesenchymal stem cells. The following review focuses on recent research on the use of stem cells for the treatment of cardiovascular and pulmonary diseases and the future application of mesenchymal stem cells for the treatment of a variety of cardiovascular disorders. PMID: 16091779 [PubMed - indexed for MEDLINE] 3715. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Jun;5(2):219-26. Myocardial insulin resistance and cardiac complications of diabetes. Abel ED(1). Author information: (1)Program in Human Molecular Biology and Genetics, and Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT 84112, USA. dale.abel@hmbg.utah.edu Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes. PMID: 16089356 [PubMed - indexed for MEDLINE] 3716. Int J Biochem Cell Biol. 2005 Nov;37(11):2254-9. Obesity: the role of hypothalamic AMP-activated protein kinase in body weight regulation. Lee WJ(1), Koh EH, Won JC, Kim MS, Park JY, Lee KU. Author information: (1)Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Song-Pa P.O. Box 145, Seoul 138-600, Republic of Korea. Obesity is rapidly increasing and is of great public health concern worldwide. Although there have been remarkable developments in obesity research over the past 10 years, the molecular mechanism of obesity is still not completely understood. Body weight results from the balance between food intake and energy expenditure. Recent studies have found that hypothalamic AMP-activated protein kinase plays a key role in regulating these processes. Leptin, insulin, glucose and alpha-lipoic acid have been shown to reduce food intake by lowering hypothalamic AMP-activated protein kinase activity, whereas ghrelin and glucose depletion increase food intake by increasing hypothalamic AMP-activated protein kinase activity. In addition, this enzyme plays a role in the central regulation of energy expenditure. These findings indicate that hypothalamic AMP-activated protein kinase is an important signal molecule, which integrates nutritional and hormonal signals and modulates feeding behavior and energy expenditure. PMID: 16085448 [PubMed - indexed for MEDLINE] 3717. Facial Plast Surg Clin North Am. 2005 Aug;13(3):393-9. Experience with percutaneous suspension of the malar fat pad for midface rejuvenation. Laferriere KA(1), Castellano RD. Author information: (1)Fremont Avenue Medical Building, 1965 S. Fremont, Suite 1990, Springfield, MO 65804, USA. Repositioning of the ptotic malar fat pad represents a key element of midface rejuvenation. Traditional face-lifting techniques have been minimally effective in correcting the midface changes commonly seen in aging. Many candidates, especially younger patients, desire procedures that have rapid recovery times with reduced risk and the absence of visible incisions. Percutaneous suspension of the malar fat pad to reposition it in a more youthful position is a minimally invasive technique producing a long lasting elevation that would be a welcomed addition to midface rejuvenation. PMID: 16085285 [PubMed - indexed for MEDLINE] 3718. Expert Opin Ther Targets. 2005 Aug;9(4):861-73. Peroxisome proliferator-activated receptor beta/delta as a therapeutic target for metabolic diseases. Bedu E(1), Wahli W, Desvergne B. Author information: (1)Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland. The peroxisome proliferator-activated receptor (PPAR) family comprises three distinct isotypes: PPARalpha, PPARbeta/delta and PPARgamma. PPARs are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. Until recently, the characterisation of the important role of PPARalpha in fatty acid oxidation and of PPARgamma in lipid storage contrasted with the sparse information concerning PPARbeta/delta. However, evidence is now emerging for a role of PPARbeta/delta in tissue repair and energy homeostasis. Experiments with tissue-specific overexpression of PPARbeta/delta or treatment of mice with selective PPARbeta/delta agonists demonstrated that activation of PPARbeta/delta in vivo increases lipid catabolism in skeletal muscle, heart and adipose tissue and improves the serum lipid profile and insulin sensitivity in several animal models. PPARbeta/delta activation also prevents the development of obesity and improves cholesterol homeostasis in obesity-prone mouse models. These new insights into PPARbeta/delta functions suggest that targeting PPARbeta/delta may be helpful for treating disorders associated with the metabolic syndrome. Although these perspectives are promising, several independent and contradictory reports raise concerns about the safety of PPARbeta/delta ligands with respect to tumourigenic activity in the gut. Thus, it appears that further exploration of PPARbeta/delta functions is necessary to better define its potential as a therapeutic target. PMID: 16083348 [PubMed - indexed for MEDLINE] 3719. Curr Opin Clin Nutr Metab Care. 2005 Sep;8(5):523-8. Relationship between body composition changes and changes in physical function and metabolic risk factors in aging. St-Onge MP(1). Author information: (1)Department of Nutrition Sciences, Division of Physiology and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35226-3360, USA. mpstonge@uab.edu PURPOSE OF REVIEW: Several body composition changes are known to occur with aging. The purpose of this review is to evaluate recent literature examining body composition changes with aging and how these relate to changes in physical function and metabolic risk. RECENT FINDINGS: Cross-sectional and longitudinal studies have observed increases in fat mass and decreases in muscle mass or lean tissue mass in older adults, often in the absence of differences or changes in body weight. Cross-sectional studies have also reported increases in intramyocellular lipid and liver fat in older versus younger adults and related changes in body composition with changes in physical function and metabolic risk, but few longitudinal data are available. Furthermore, most longitudinal studies lack precise methods of assessing body fat distribution and muscle and organ quality, resulting in a lack of detailed and precise information on body composition changes with aging and their relationship to health. SUMMARY: Research to date has outlined a need for more detailed body composition measurements of aging adults. Absence of change in a total body compartment may mask a change in subcompartments that may impact health. Furthermore, intervention studies to determine ways to maintain body composition are consistent with healthy living throughout the aging process. PMID: 16079623 [PubMed - indexed for MEDLINE] 3720. J Cell Sci. 2005 Aug 1;118(Pt 15):3225-32. More than just water channels: unexpected cellular roles of aquaporins. Verkman AS(1). Author information: (1)Department of Medicine, Cardiovascular Research Institute, Room 1246, Box 0521 University of California San Francisco, San Francisco, CA 94143-0521, USA. verkman@itsa.ucsf.edu Aquaporins (AQPs) are membrane proteins that transport water and, in some cases, also small solutes such as glycerol. AQPs are expressed in many fluid-transporting tissues, such as kidney tubules and glandular epithelia, as well as in non-fluid-transporting tissues, such as epidermis, adipose tissue and astroglia. Their classical role in facilitating trans-epithelial fluid transport is well understood, as in the urinary concentrating mechanism and gland fluid secretion. AQPs are also involved in swelling of tissues under stress, as in the injured cornea and the brain in stroke, tumor and infection. Recent analysis of AQP-knockout mice has revealed unexpected cellular roles of AQPs. AQPs facilitate cell migration, as manifested by reduced tumor angiogenesis in AQP1-knockout mice, by a mechanism that might involve facilitated water transport in lamellipodia of migrating cells. AQPs that transport both glycerol and water regulate glycerol content in epidermis and fat, and consequently skin hydration/biosynthesis and fat metabolism. AQPs might also be involved in neural signal transduction, cell volume regulation and organellar physiology. The many roles of AQPs could be exploited for clinical benefit; for example, treatments that modulate AQP expression/function could be used as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer. PMID: 16079275 [PubMed - indexed for MEDLINE] 3721. Medicina (B Aires). 2005;65(2):163-9. [Role of uncoupling proteins UCP1, UCP2 and UCP3 in energy balance, type 2 diabetes and obesity. Synergism with the thyroid]. [Article in Spanish] Zaninovich AA(1). Author information: (1)Centro de Investigaciones Tiroideas (CONICET), Centro de Medicina Nuclear, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires. azaninovich@sinectis.com.ar Accumulation of fat in the tissues results from the balance between energy intake and expenditure. The thyroid hormones have long been known to be the main regulators of basal metabolism through its stimulation of oxygen consumption in cells. The discovery of brown adipose tissue (BAT) and its unique activity of heat production and dissipation through the action of uncoupling protein-1 (UCP1) during cold stress, showed the relevance of this tissue for energy expenditure in lower mammals. UCP1 is only expressed in BAT through the synergistic action of norepinephrine (NE) and thyroid hormones in animals exposed to cold and to a lesser degree after meals. The uncoupling protein-2 (UCP2) is found in many tissues and exerts dual effects: it protects cells function from damage caused by reactive oxygen species (ROS). On the other hand, the uncoupling induced by UCP2 in mitochondria of pancreatic beta cells decreases ATP synthesis and impairs insulin secretion in response to glucose. Hyperlipidemia also prevents insulin secretion through a similar pathway, leading to hyperglycemia. The uncoupling protein-3 is found mostly in skeletal muscle and BAT and its absence did not alter heat production or body temperature. This protein would export fatty acids ouside the mitochondrial matrix for combustion in tissues where fat is the main fuel. In humans, the uncoupling proteins may not play a leading role in energy regulation. However, intensive studies on these and other factors influencing energy expenditure, appetite and glucose metabolism are taken place worldwide and may soon provide more clues on the mechanisms regulating energy balance and their use in the prevention or treatment of human obesity and diabetes type 2. PMID: 16075814 [PubMed - indexed for MEDLINE] 3722. Adv Gerontol. 2005;16:51-64. [Hormones of adipose tissue (adipocytokines): ontogenetic and oncologic aspects]. [Article in Russian] Berstein LM. Being an important component of body composition, adipose tissue accepts a lot of hormonal signals and, besides, is able to produce hormone-like peptides, named adipokines or adipocytokines, and participate in the metabolism of steroid hormones. Endocrine properties of adipose tissue are dependent of its volume, morphology (size and number of adipocytes), fat topography (visceral and subcutaneous fat), characteristics of distinct fat depot (including mammary fat), some features of genome, etc. Certain characteristics of the adipose organ are formed and then realized in pre- and postnatal life (pregnancy and fetal programming), in duration of puberty, after menopause and with aging. Adipocyte and non-adipocyte compartments of adipose tissue are involved into reactions of immunity/inflammation and into development of glucose intolerance and insulin resistance. The latter are peculiar for obesity and lipodystrophy, which in their turn are associated with a number of main chronic non-communicable diseases limiting the human life span. The balance among adipocytokines (adipocytokine net or lattice) with distinct properties (TNF-alpha, leptin and adiponectin as an examples) and between adipocytokines and steroid-producing capacity of adipose tissue is an important variable representing a basis for the modification of cardiovascular and oncological morbidity risk as well as a target for geroprotection and cancer prevention. PMID: 16075677 [PubMed - indexed for MEDLINE] 3723. Atheroscler Suppl. 2005 Sep;6(3):15-9. Does statin monotherapy address the multiple lipid abnormalities in type 2 diabetes? Shepherd J(1). Author information: (1)Department of Biochemistry, Royal Infirmary, Glasgow G4 OSF, Scotland, UK. jshepherd@gri-biochem.org.uk Lipid abnormalities, which are common in type 2 diabetes, predispose to a greatly increased risk of coronary heart disease. This characteristic dyslipidaemia includes decreased concentrations of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and a small, dense, atherogenic form of low-density lipoprotein cholesterol (LDL-C). Insulin resistance and obesity, which is commonly present in type 2 diabetes, act in concert to disrupt normal lipoprotein metabolism; reverse cholesterol transport in particular. The proatherogenic changes, which result from this process include enrichment of very-low-density lipoprotein with cholesteryl esters and enrichment of LDL with triglycerides. Results from both the Pravastatin Pooling Project and the Heart Protection Study demonstrate that, although people with diabetes obtain the same relative risk reduction with statin therapy, the absolute benefit derived is much lower than for comparable individuals without diabetes. In order to achieve improved outcomes in diabetes patients, it will be important to address other abnormalities in their lipid profiles, including elevated triglycerides and low HDL-C. PMID: 16046280 [PubMed - indexed for MEDLINE] 3724. Obes Rev. 2005 Aug;6(3):247-58. Conjugated linoleic acid evokes de-lipidation through the regulation of genes controlling lipid metabolism in adipose and liver tissue. House RL(1), Cassady JP, Eisen EJ, McIntosh MK, Odle J. Author information: (1)Department of Animal Science & Functional Genomics Program, North Carolina State University, Raleigh, NC 27695, USA. Conjugated linoleic acid (CLA) is a unique lipid that elicits dramatic reductions in adiposity in several animal models when included at < or = 1% of the diet. Despite a flurry of investigations, the precise mechanisms by which conjugated linoleic acid elicits its dramatic effects in adipose tissue and liver are still largely unknown. In vivo and in vitro analyses of physiological modifications imparted by conjugated linoleic acid on protein and gene expression suggest that conjugated linoleic acid exerts its de-lipidating effects by modulating energy expenditure, apoptosis, fatty acid oxidation, lipolysis, stromal vascular cell differentiation and lipogenesis. The purpose of this review shall be to examine the recent advances and insights into conjugated linoleic acid's effects on obesity and lipid metabolism, specifically focused on changes in gene expression and physiology of liver and adipose tissue. PMID: 16045640 [PubMed - indexed for MEDLINE] 3725. Respir Physiol Neurobiol. 2005 Jul 28;147(2-3):289-98. Genetic determinants of upper airway structures that predispose to obstructive sleep apnea. Schwab RJ(1). Author information: (1)Center for Sleep and Respiratory Neurobiology, Pulmonary, Allergy and Critical Care Division, Dept. of Medicine, University of Pennsylvania Medical Center, 893 Maloney Building, 3600 Spruce St., Philadelphia, PA 19104-4283, USA. rschwab@mail.med.upenn.edu Genetic factors are thought to play an important role in human development. Recent data indicate that obstructive sleep apnea may have a genetic basis. Sleep apnea is a very common disorder with significant cardiovascular and neurophysiologic morbidity. The pathogenesis of sleep apnea is related to a reduction in the size of the upper airway. The reduction in airway size is secondary to increased adipose tissue (enlargement of the parapharyngeal fat pads), alterations in craniofacial structure (reduction in mandibular size) and enlargement of the surrounding soft tissue structures (tongue, lateral pharyngeal walls). Genetic factors are one of the factors that have been proposed to mediate the size of each of these anatomic risk factors for sleep apnea. Recent evidence is accumulating about the genetic loci for these structural risk factors that predispose to the development of obstructive sleep apnea. PMID: 16043425 [PubMed - indexed for MEDLINE] 3726. J Endocrinol Invest. 2005;28(3 Suppl):56-64. Androgens and body composition in the aging male. Moretti C(1), Frajese GV, Guccione L, Wannenes F, De Martino MU, Fabbri A, Frajese G. Author information: (1)Unit of Endocrinology, University of Roma Tor Vergata, AFaR Fatebenefratelli Hospital San Giovanni Calibita, Isola Tiberina, Italy. moretti@med.unitoma2.it The relevant age-related changes in male body composition are mainly related to the progressive decrease in the level of circulating anabolic hormones, among which testosterone (T) is rather important. Its decline, between the ages of 35 and 75, is associated to a loss of muscle mass and fibers number, a doubling of fat mass and a decrease in bone mineral density by 0.3% per yr after age 35; thus the relationship between age-related changes in body composition and T bioactivity reflects an important endocrine aspect of the aging male. The assessment of human body composition and in particular the evaluation of fat tissue and its distribution, is currently standardized by the use of dual-energy x-ray absorpiometry (DXA). In the present paper we review the mechanisms through which testosterone may inhibit adipogenesis, restore the myogenic programme enhancing the protein turnover at muscle level and maintain bone mineral density in elderly men. PMID: 16042362 [PubMed - indexed for MEDLINE] 3727. Neuropeptides. 2005 Aug;39(4):363-7. Hypothesis paper Brain talks with fat--evidence for a hypothalamic-pituitary-adipose axis? Schäffler A(1), Binart N, Schölmerich J, Büchler C. Author information: (1)Department of Internal Medicine I, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de The adipose tissue signals to the brain via its secretory products. However, it is unknown whether the brain itself can directly contact the fat tissue. In order to test this hypothesis, the adipocytic expression of receptors for pituitary hormones and hypothalamic peptides was investigated. Besides FSH- and LH-receptors, adipocytes do express the specific receptors for ACTH, TSH, GH, prolactin, oxytocin and the three receptor subtypes for vasopressin. Thus, the adipose tissue might no longer be regarded as an inert and steady tissue but as a fast acting player downstream of and under the control of the brain. Based on this, the potential existence and clinical impact of a hypothalamic-pituitary-adipose axis should further be investigated. PMID: 16040119 [PubMed - indexed for MEDLINE] 3728. Trends Cardiovasc Med. 2005 Apr;15(3):81-5. PPARgamma: a critical determinant of body fat distribution in humans and mice. Tsai YS(1), Maeda N. Author information: (1)Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, 27599, USA. Evidence emerging from studies of humans and mice has indicated peroxisome proliferator-activated receptor gamma (PPARgamma) to be not only a key factor for adipogenesis but also a critical determinant of body fat distribution. Whereas genetically reduced PPARgamma activity in adipose tissue leads to reduction of total fat mass in humans and in mice, mutations in the ligand-binding domain of PPARgamma cause abnormal body fat distributions. It is less clear from mutation analysis how PPARgamma is involved in metabolic disturbances such as insulin resistance and its cardiovascular complications. Nevertheless, similarities and differences in the phenotypes associated with PPARgamma mutations in humans and in mouse models provide opportunities to dissect relationships between body fat distribution and its metabolic complications. PMID: 16039966 [PubMed - indexed for MEDLINE] 3729. Endothelium. 2005 Jan-Apr;12(1-2):73-9. Leptin, fetal nutrition, and long-term outcomes for adult hypertension. Symonds ME(1), Budge H, Stephenson T, Gardner DS. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham, United Kingdom. Michael.Symonds@nottingham.ac.uk One factor contributing to later hypertension, particularly in response to nutritional challenges is excess fat deposition around the kidney. In this review we discuss the hypothesis that these adverse conditions can be entrained by exposure of the conceptus to maternal nutrient restriction in early pregnancy. To this end we have shown in sheep that maternal nutrient restriction coincident with the time of embryogenesis and placental growth results in an early increase in fetal fat mass around the kidney that persists into later life. This is accompanied by an increase in leptin mRNA abundance and growth factor sensitivity. These adaptations occur in conjunction with reduced maternal plasma cortisol, thyroid hormones and leptin concentrations over the period of nutrient restriction. Some, but not all of these effects on fat development are accompanied by long term cardiovascular adaptations. As young adults, offspring from mothers nutrient restricted between early to mid gestation exhibit a leftward resetting, and blunting, of the cardiovascular baroreflex that appears to be mediated centrally through altered regional angiotensinogen II activity. At the same time, fat mass remains raised in nutrient restricted offspring. These animals demonstrate a marked increase in plasma leptin following sympathetic stimulation which is not observed in controls that indicates resetting of adipocyte sensitivity to stress. In conclusion, global nutrient restriction confined to the periods of embryonic and placental development therefore, programmes adult physiology, which may enhance predisposition to later disease given the appropriate environmental stimuli. PMID: 16036318 [PubMed - indexed for MEDLINE] 3730. Int J Clin Pract Suppl. 2004 Oct;(143):9-21. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. DeFronzo RA(1). Author information: (1)Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA. albarado@uthscsa.edu Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition. PMID: 16035392 [PubMed - indexed for MEDLINE] 3731. Rev Med Liege. 2005 May-Jun;60(5-6):374-82. [Obesity and type 2 diabetes]. [Article in French] Rorive M(1), Letiexhe MR, Scheen AJ, Ziegler O. Author information: (1)Université de Liège, Centre de l'Obésité, CHU Ourthe-Amblève, Esneux et Service de Diabétologie, Nutrition et Maladies métaboliques, CHU Sart Tilman, Liège. Obesity is an epidemic disease associated with numerous cardiovascular risk factors as diabetes mellitus, dyslipidemia, hypertension. Insulin resistance seems to be an important promoter for the development of most of these abnormalities. Besides genetic background, obesity, especially abdominal adiposity, is by far the most important factor for the development of type 2 diabetes. The treatment of a diabetic obese subject begins with diet and regular physical activity, eventually with a psychological support. In case of failure of such lifestyle approach alone, addition of drug therapy should be considered. It may include pharmacological agents able to promote weight loss (orlistat, sibutramine, possibly rimonabant) and/or antihyperglycaemic compounds capable of reducing insulin resistance (metformin, glitazones, acarbose). In case of severe/morbid obesity complicated with type 2 diabetes not well controlled with medical means, bariatric surgery is the only treatment that can induce an important and sustained weight loss, associated with marked improvement of metabolic control and amelioration of overall prognosis. PMID: 16035297 [PubMed - indexed for MEDLINE] 3732. Rev Med Liege. 2005 May-Jun;60(5-6):369-73. [Adipocytokines: link between obesity, type 2 diabetes and atherosclerosis]. [Article in French] Paquot N(1), Tappy L. Author information: (1)Service de Diabétologie, Nutrition et Maladies Métaboliques, CHU Sart-Tilman, 4000 Liège. Adipose tissue, in addition to the storage of lipids function for lipids, plays active roles in normal metabolic homeostasis and in the development of several diseases, such as type 2 diabetes, dyslipaemia and atherosclerosis. These roles are mediated by adipocytokines, factors secreted by adipose tissue. These include tumor necrosis factors (TNF)-alpha, leptin, resistin, adiponectin or visfatin. Adipocytokines act in an autocrine, paracrine and endocrine manner. Adiponectin is a peculiar adipocytokine because in contrast to the markedly increased levels of leptin, resistin or TNF-alpha in obesity, its level is negatively correlated with body mass index, and is decreased in presence of insulin resistance and in type 2 diabetes. Adiponectin may play a crucial role in the development of diabetes mellitus and high adiponectin levels should protect against impairment of glucose metabolism. Moreover, adipocytokines are involved in the pathogenesis of vascular diseases and may represent a link between obesity, diabetes, inflammation and atherosclerosis. Weight loss, exercise and some antidiabetic drugs also influence plasma adipocytokines levels. For instance, thiazolidinediones treatment in patients with type 2 diabetes resulted in an increased in plasma adiponectin levels and a decrease in circulating TNF-alpha concentrations. PMID: 16035296 [PubMed - indexed for MEDLINE] 3733. Rev Med Liege. 2005 May-Jun;60(5-6):361-8. [Etiopathogenesis and pathophysiology of type 2 diabetes]. [Article in French] Féry F(1), Paquot N. Author information: (1)Service d'Endocrinologie, Hôpital Erasme, Université Libre de Bruxelles. Etiopathogenesis of type 2 diabetes is complex and still partially unknown. Its etiology is determined by the interaction of genetic and environmental factors. The genetic contribution is important, but has a polygenic origin. Obesity, especially when fat mass is preferably located in the abdomen, is the main predisposing factor for type 2 diabetes, and almost 80% of diabetic patients are overweight or obese. The diabetogenic effect of obesity is due to the capacity of excessive fat mass to induce or aggravate insulin resistance. Increasing lack of physical activity is also a contributing factor as it increases insulin resistance. As far as pathophysiology is concerned, the development of type 2 diabetes results from the coexistence of abnormalities of insulin secretion and insulin action. Insulin secretory dysfunction, whose underlying mechanism remains poorly understood, is characterized by a relative defect in circulating insulin levels of variable severity. Resistance to insulin action is located in the liver (increased hepatic glucose production), in the skeletal muscle (decreased muscular glucose uptake) and in the adipose tissue (exaggerated lipolysis with elevated plasma free fatty acids). Changes in life-style habits (weight reduction, regular physical activity) are able to prevent or delay the development of type 2 diabetes. PMID: 16035295 [PubMed - indexed for MEDLINE] 3734. Curr Diab Rep. 2005 Aug;5(4):278-81. Adiponectin and human pregnancy. Mazaki-Tovi S(1), Kanety H, Sivan E. Author information: (1)Department of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel-Hashomer 52621, Israel. Adiponectin is an adipose tissue-derived plasma protein that is involved in regulation of insulin resistance and glucose hemostasis. Human pregnancy is characterized by an increase in insulin resistance. Therefore, it is only natural that the role of adiponectin, a modulator of insulin resistance, is subject to investigation during gestation. Furthermore, conditions associated with increased insulin resistance, such as gestational diabetes and preeclampsia, may be influenced by this hormone. Adiponectin, a key modulator of insulin action and glucose metabolism, both known to regulate fetal growth, is a plausible candidate for regulation of intrauterine fetal development. In this review, we summarize the recent studies describing the relationship between adiponectin, pregnancy, and fetal growth. PMID: 16033679 [PubMed - indexed for MEDLINE] 3735. Int J Obes (Lond). 2005 Oct;29(10):1175-83. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Ceddia RB(1). Author information: (1)Department of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. roceddia@yorku.ca In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed. PMID: 16030519 [PubMed - indexed for MEDLINE] 3736. Acta Physiol Scand. 2005 Aug;184(4):295-307. A role for suppressed skeletal muscle thermogenesis in pathways from weight fluctuations to the insulin resistance syndrome. Dulloo AG(1). Author information: (1)Division of Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland. abdul.dulloo@unifr.ch An impressive body of epidemiological evidence suggests that a history of large perturbations in body weight earlier in life, independently of excess weight, is a risk factor for later development of insulin-related complications, namely central obesity, type 2 diabetes and cardiovascular disease. Such an increased risk has been reported in men and women who in young adulthood experienced weight fluctuations that involved weight recovery after weight loss caused by disease, famine or voluntary 'yoyo' dieting, and is particularly strong when the weight fluctuations occurred much earlier in life and are characterized by catch-up growth after foetal and/or neonatal growth retardation. As the phase of weight recovery/catch-up growth is associated with both hyperinsulinaemia and an accelerated rate for recovering fat mass (i.e. catch-up fat), the questions arise as to whether, why and how processes that regulate catch-up fat might predispose to hyperinsulinaemia and to insulin-related diseases. In addressing these issues, this paper first reviews evidence for the existence of an adipose-specific control of thermogenesis, whose suppression contributes to the phenomenon of catch-up fat during weight recovery/catch-up growth. It subsequently concentrates upon recent findings suggesting that: (i) such suppression of thermogenesis directed at catch-up fat is accompanied by a redistribution of glucose from skeletal muscle to white adipose tissue, and (ii) substrate cycling between de novo lipogenesis and lipid oxidation can operate as a thermogenic effector in skeletal muscle in response to signalling interactions between leptin and insulin - two key 'adiposity' hormones implicated in the peripheral control of substrate metabolism. These new findings are integrated into the proposal that, in its 'evolutionary adaptive' role to spare glucose for rapid rebuilding of the fat stores, suppressed thermogenesis in skeletal muscle - via inhibition of substrate cycling between de novo lipogenesis and lipid oxidation - confers to the phase of weight recovery/catch-up growth its high sensitivity towards the development of insulin resistance and hyperinsulinaemia, and hence towards diseases that are clustered around the insulin resistance syndrome. PMID: 16026421 [PubMed - indexed for MEDLINE] 3737. Acta Physiol Scand. 2005 Aug;184(4):285-93. Endocrine and signalling role of adipose tissue: new perspectives on fat. Trayhurn P(1). Author information: (1)Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences, University of Liverpool, Liverpool, UK. p.trayhurn@liverpool.ac.uk White adipose tissue (WAT) is now recognized as a major endocrine and secretory organ, releasing a wide range of protein factors and signals termed adipokines - in addition to fatty acids and other lipid moieties. A paradigm shift came with the discovery of leptin, a pleiotropic hormone which is a critical signal to the hypothalamus in the control of appetite and energy balance. A number of adipokines, including adiponectin, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor-1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of mild inflammation, and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands; a notable exception is adiponectin, with its anti-inflammatory action, the levels of which fall. WAT may be the main site of inflammation in obesity, increased circulating levels of inflammatory markers reflecting spillover from an 'inflamed' tissue, leading to the obesity-associated pathologies of type 2 diabetes and the metabolic syndrome. From the wide range of adipokines now identified, it is evident that WAT is highly integrated into overall physiological regulation, involving extensive crosstalk with other organs and multiple metabolic systems. Whether major changes in adipokine production in obesity, particularly of those factors linked to inflammation, are unique to this condition, or are a feature of all situations in which there are substantial increases in adipose mass (such as pregnancy, and pre-hibernatory and pre-migratory fattening) requires consideration. PMID: 16026420 [PubMed - indexed for MEDLINE] 3738. Acta Physiol Scand. 2005 Aug;184(4):265-83. Thyroid hormones as molecular determinants of thermogenesis. Silvestri E(1), Schiavo L, Lombardi A, Goglia F. Author information: (1)Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Benevento, Italy. Thyroid hormones (TH) are major modulators of energy metabolism and thermogenesis. It is generally believed that 3,5,3'-triiodo-l-thyronine (T3) is the only active form of TH, and that most of its effects are mediated by nuclear T3 receptors, which chiefly affect the transcription of target genes. Some of these genes encode for the proteins involved in energy metabolism. However, a growing volume of evidence now indicates that other iodothyronines may be biologically active. Several mechanisms have been proposed to explain the calorigenic effect of TH, but none has received universal acceptance. Cold acclimation/exposure and altered nutritional status are physiological conditions in which a modulation of energy expenditure is particularly important. TH seem to be deeply involved in this modulation, and this article will review some aspects of their possible influence in these conditions. PMID: 16026419 [PubMed - indexed for MEDLINE] 3739. Acta Physiol Scand. 2005 Aug;184(4):255-64. Pituitary and autonomic responses to cold exposures in man. Leppäluoto J(1), Pääkkönen T, Korhonen I, Hassi J. Author information: (1)Department of Physiology and Centre for Arctic Medicine, University of Oulu, Oulun yliopisto, Finland. juhani.leppaluoto@oulu.fi This review presents hormonal responses to various cold exposures and their calorigenic effects in man and some animals. Previous studies in rats have shown that cold exposures activate the hypothalamic-pituitary-thyroid axis. Increased thyroid hormone concentrations lead to heat production via general stimulation of metabolism (obligatory thermogenesis) and possibly via activation of thyroid hormone receptors and uncoupling protein 1 (UCP 1) and deiodinase enzyme genes in the brown adipose tissue (BAT). In human subjects long-term cold exposures do not seem to activate the pituitary-thyroid axis, but rather accelerate the elimination of triiodothyronine (T3), leading to low serum concentrations of free T3 hormone. In corollary to this a hypothyreotic condition with increased serum thyroid-stimulating hormone and impaired mood and cognitive performance can be observed after long-term cold exposures such as wintering. During cold exposures the sympathetic nerve system is activated and noradrenaline is released to blood circulation and to BAT, where it leads to production of cAMP, lipolysis and free fatty acids. Free fatty acids open the mitochondrial proton channel protein in BAT. Protons enter the mitochondria and inhibit ATP synthesis (uncoupling). By this way energy is transformed into heat (facultatory or adaptive thermogenesis). In adult human subjects the amount of BAT is small and adaptive thermogenesis (non-shivering thermogenesis) has a smaller role. UCP 1 with other uncoupling proteins may have other functions in the control of body weight, sugar balance and formation of reactive oxygen species. PMID: 16026418 [PubMed - indexed for MEDLINE] 3740. Curr Drug Targets. 2005 Jun;6(4):525-9. Adipokines: therapeutic targets for metabolic syndrome. Kobayashi K(1). Author information: (1)Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan. nihisak@intmed3.med.kyushu-u.ac.jp For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFalpha, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome. PMID: 16026271 [PubMed - indexed for MEDLINE] 3741. Perit Dial Int. 2005 Jul-Aug;25(4):340-2. Adipokines in chronic kidney disease--fat tissue gives nephrologists a message. Heimbürger O(1), Stenvinkel P. Author information: (1)Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden. olof.heimburger@klinvet.ki.se Comment on Perit Dial Int. 2005 Jul-Aug;25(4):357-61. PMID: 16022088 [PubMed - indexed for MEDLINE] 3742. J Appl Physiol (1985). 2005 Aug;99(2):757-64. Fat as an endocrine organ: influence of exercise. Berggren JR(1), Hulver MW, Houmard JA. Author information: (1)Human Performance Laboratory and Department of Exercise and Sport Science, 363 Ward Sports Medicine Bldg., East Carolina University, Greenville, NC 27858, USA. berggrenj@mail.ecu.edu The prevalence of diabetes and obesity continues to increase. It is therefore important to identify the pathophysiology underlying these disorders. An inability of insulin to stimulate glucose uptake, i.e., insulin resistance, appears to be a common link between diabetes and obesity. The identification of various adipocyte-secreted cytokines (adipocytokines) that influence satiety, energy balance, and insulin sensitivity provide a novel target for the treatment of these disorders. Adipocytokines are differentially expressed with obesity and diabetes, making them a strong candidate for linking insulin resistance to these pathological conditions. This review explores the role of adipocytokines in insulin action and examines the effect of exercise training on adipocytokine content. PMID: 16020439 [PubMed - indexed for MEDLINE] 3743. J Cosmet Laser Ther. 2004 Dec;6(4):181-5. Cellulite: a review of its physiology and treatment. Avram MM(1). Author information: (1)Division of Dermatology, David Geffen School of Medicine, UCLA Medical Center, Los Angeles, CA, USA. mavram@mednet.ucla.edu Cellulite affects 85-98% of post-pubertal females of all races. While not a pathologic condition, it remains an issue of cosmetic concern to a great number of individuals. Despite its high prevalence, there have been few scientific investigations into the physiology of cellulite. There have only been a few dozen peer-reviewed articles devoted to cellulite in the medical literature in the past 30 years. There is no definitive explanation for its presentation. This greatly complicates the ability to treat or improve it. The four leading hypotheses that purport to explain the physiology of cellulite include: sexually dimorphic skin architecture, altered connective tissue septae, vascular changes and inflammatory factors. Treatment modalities can be divided into four main categories: attenuation of aggravating factors, physical and mechanical methods, pharmacological agents and laser. There are no truly effective treatments for cellulite. PMID: 16020201 [PubMed - indexed for MEDLINE] 3744. Ann Med. 2005;37(4):270-5. The endocannabinoid system and the treatment of obesity. Pagotto U(1), Vicennati V, Pasquali R. Author information: (1)Endocrinology Unit and Center for Applied Biomedical Research, Dept. of Internal Medicine and Gastroenterology, S. Orsola-Malpighi General Hospital, Bologna, Italy. The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors. PMID: 16019725 [PubMed - indexed for MEDLINE] 3745. Gynecol Endocrinol. 2005 Apr;20(4):227-35. Role of postmenopausal hormone replacement therapy on body fat gain and leptin levels. Augoulea A(1), Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. Author information: (1)Second Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, Greece. During menopause women tend to gain body fat. The increase in adiposity seems to be a consequence of the decline in endogenous estrogens and the reduced energy expenditure. The role of post-menopausal hormone replacement therapy (pHT) in modulating visceral obesity is controversial. Some studies have shown that pHT has no effect on body weight while in other studies pHT increased body weight. Leptin is an adipocyte-derived hormone and its levels reflect the amount of adipose tissue. Obesity is associated with elevated serum leptin levels. The effect of pHT on leptin levels is also controversial. In some studies pHT increased leptin levels while other studies have not confirmed this increasing effect. The major problem encountered during administration of hormone therapy seems to be the timing of pHT initiation which is a strong confounder on the effect of pHT on leptin levels in postmenopausal women. PMID: 16019366 [PubMed - indexed for MEDLINE] 3746. J Intern Med. 2005 Aug;258(2):94-114. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. Carlson LA(1). Author information: (1)King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden. lars.a.carlson@bredband.net Nicotinic acid has, like the Roman God Janus, two faces. One is the vitamin. The other is the broad-spectrum lipid drug. The Canadian pathologist Rudolf Altschul discovered 50 years ago that nicotinic acid in gram doses lowered plasma levels of cholesterol. From the point of view of treatment of the dyslipidaemias that are risk factors for clinical atherosclerosis nicotinic acid is a miracle drug. It lowers the levels of all atherogenic lipoproteins--VLDL and LDL with subclasses as well as Lp(a)--and in addition it raises more than any other drug the levels of the protective HDL lipoproteins. Trials have shown that treatment with nicotinic acid reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The new combination treatment with statin-lowering LDL and nicotinic acid-raising HDL is reviewed. A basic effect of nicotinic acid is the inhibition of fat-mobilizing lipolysis in adipose tissue leading to a lowering of plasma free fatty acids, which has many metabolic implications which are reviewed. The very recent discovery of a nicotinic acid receptor and the finding that the drug stimulates the expression of the ABCA 1 membrane cholesterol transporter have paved the way for exciting and promising new 50 years in the history of nicotinic acid. PMID: 16018787 [PubMed - indexed for MEDLINE] 3747. Am J Physiol Regul Integr Comp Physiol. 2005 Aug;289(2):R297-R298. White adipose tissue grafts--keeping in contact. Trayhurn P. Comment on Am J Physiol Regul Integr Comp Physiol. 2005 Aug;289(2):R380-R388. PMID: 16014445 [PubMed - indexed for MEDLINE] 3748. J Clin Psychiatry. 2005 Jul;66(7):900-6. Diabetes mellitus among outpatients receiving clozapine: prevalence and clinical-demographic correlates. Lamberti JS(1), Costea GO, Olson D, Crilly JF, Maharaj K, Tu X, Groman A, Dietz MB, Bushey MP, Olivares T, Wiener K. Author information: (1)Department of Psychiatry, University of Rochester Medical Center, Rochester, NY 14642, USA. steve_lamberti@urmc.rochester.edu BACKGROUND: Treatment with antipsychotic drugs has been associated with increased risk for developing diabetes mellitus. Recent consensus statements suggest that clozapine may pose an especially high risk. The purpose of this study is to examine the prevalence and clinical-demographic correlates of diabetes among outpatients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder receiving clozapine. METHOD: One hundred one outpatients receiving clozapine at the University of Rochester Department of Psychiatry, Rochester, N.Y., were evaluated between September 2002 and September 2003. Demographic data were collected from medical records, and body mass index (BMI) and body fat measurements were conducted. Diagnosis of diabetes was established through review of medical records and fasting blood glucose testing. Associations between clinical and demographic variables and diabetes were examined using t tests, Fisher exact tests, and logistic regression. RESULTS: Mean (SD) age of patients was 40.4 (9.5) years, and 79% were white. Mean (SD) dose and duration of clozapine treatment were 426 (164) mg/day and 5.7 (3.6) years, respectively. Point prevalence of diabetes was 25.7%. Mean (SD) BMI was 32.6 (8.0) kg/m(2), and mean (SD) body fat was 34.0% (11.0%). Logistic regression revealed significant associations between diabetes and nonwhite race/ethnicity and family history of diabetes (p = .02 and .002, respectively). No significant associations were found between diabetes prevalence and BMI or body fat. CONCLUSION: Patients receiving clozapine are at substantial risk for developing diabetes, although the level of risk relative to other antipsychotic medications has not been fully determined. Clinicians should monitor all severely mentally ill patients receiving antipsychotic drugs for diabetes, with closer monitoring of patients with established demographic risk factors. PMID: 16013906 [PubMed - indexed for MEDLINE] 3749. Curr Opin Otolaryngol Head Neck Surg. 2005 Aug;13(4):248-54. Eyelid rejuvenation: a marriage of old and new. Weiss DD(1), Carraway JH. Author information: (1)Plastic and Cosmetic Surgery Center of Eastern Virginia Medical School, 5589 Greenwich Road, Virginia Beach, VA 23455, USA. weissdd@evms.edu PURPOSE OF REVIEW: Lower lid anatomy and the subtleties of this region have been studied extensively in the past. The variations that are found in the lower eyelid can lead to complications if the surgeon does not have a complete understanding. Lower lid blepharoplasty techniques have progressed over the past from simple skin excisions to midface and lower eyelid repositioning. With these modifications, our understanding of the anatomy and the function of the lower eyelid improve. This review highlights the findings of lower eyelid anatomy and rejuvenating techniques reported over the past year. RECENT FINDINGS: Over this past year anatomic studies have been performed focusing on the aging eye and midface in both Asians and non-Asians. Controversial work has been presented using an injectable (phosphatidylcholine) to ablate fat in the lower eyelids. A myriad of articles have discussed various options for combined midface and lower eyelid rejuvenation. The age-old argument of transconjunctival vs skin muscle techniques has been presented. More recent debates over fat volumetric preservation continue. Finally, a highlight of this year was a retrospective study looking at a conservative approach to blepharoplasty. SUMMARY: This has been a year of confirmation of old techniques and anatomic findings and a year of increasing complexity in midface lower eyelid rejuvenation. What is clear is that no one technique is ideal for every patient. A basic understanding of lower eyelid anatomy, preoperative evaluation, and a grasp of the multiple techniques will allow us to formulate a treatment algorithm that can be safe and effective for our patients. PMID: 16012250 [PubMed - indexed for MEDLINE] 3750. HIV Med. 2005 Jul;6(4):245-52. Body shape and composition in HIV-infected women: an urban cohort. Karmon SL(1), Moore RD, Dobs AS, Keruly J, Barnett S, Cofrancesco J Jr. Author information: (1)Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. OBJECTIVES: Alterations in body shape and composition are associated with HIV/AIDS. Wasting remains prevalent; increasingly, lipodystrophy is reported. Obesity is also epidemic in the USA. In this study, we sought to characterize the body changes reported by women attending a US urban clinic, and to evaluate contributing factors using inexpensive methods that are readily available in clinical practice. METHODS: In an urban Maryland clinic, a cross-section of HIV-infected women were evaluated by self report, anthropomorphic measurements, bioelectric impedance analysis (BIA) and chart review; they were categorized as no change, lipodystrophy, weight loss/wasting or weight gain/obesity. RESULTS: One hundred and sixty-one women were evaluated: 144 (89%) were African-American; 100 (62%) had used intravenous drugs and 40 (25%) were actively injecting drugs, while 39 (24%) smoked crack. Ninety-five (59%) were on highly active antiretroviral therapy (HAART) for a median period of 11.7 months [interquartile range (IQR)=4.5-24.2]. Since starting current HAART or in the previous year, 12 (7.4%) reported lipodystrophy changes, 85 (52.8%) weight gain, 27 (16.8%) overall weight loss, and 37 (23.0%) no change. Lipodystrophy was associated with higher CD4 percentage (P=0.03), lower frequency of crack use (P=0.04) and higher educational level (P=0.03). Weight loss correlated with longer duration of infection (P=0.01), select BIA results and increased rate of crack use (P=0.005). Weight gain was associated with higher fat mass (P=0.005), higher peak viral load (P=0.02), and lower rate of intravenous drug use (P=0.03). CONCLUSIONS: Self-reported changes in body shape were common. Obesity and complications of illicit drug use were more prevalent than lipodystrophy in this inner-city population of HIV-positive women. PMID: 16011529 [PubMed - indexed for MEDLINE] 3751. Annu Rev Nutr. 2005;25:499-522. Drosophila nutrigenomics can provide clues to human gene-nutrient interactions. Ruden DM(1), De Luca M, Garfinkel MD, Bynum KL, Lu X. Author information: (1)Department of Environmental Health Sciences, University of Alabama at Birmingham, Alabama 35294, USA. douglasr@uab.edu Nutrigenomics refers to the complex effects of the nutritional environment on the genome, epigenome, and proteome of an organism. The diverse tissue- and organ-specific effects of diet include gene expression patterns, organization of the chromatin, and protein post-translational modifications. Long-term effects of diet range from obesity and associated diseases such as diabetes and cardiovascular disease to increased or decreased longevity. Furthermore, the diet of the mother can potentially have long-term health impacts on the children, possibly through inherited diet-induced chromatin alterations. Drosophila is a unique and ideal model organism for conducting nutrigenomics research for numerous reasons. Drosophila, yeast, and Caenorhabditis elegans all have sophisticated genetics as well as sequenced genomes, and researchers working with all three organisms have made valuable discoveries in nutrigenomics. However, unlike yeast and C. elegans, Drosophila has adipose-like tissues and a lipid transport system, making it a closer model to humans. This review summarizes what has already been learned in Drosophila nutrigenomics (with an emphasis on lipids and sterols), critically evaluates the data, and discusses fruitful areas for future research. PMID: 16011476 [PubMed - indexed for MEDLINE] 3752. Annu Rev Nutr. 2005;25:469-97. Annual lipid cycles in hibernators: integration of physiology and behavior. Dark J(1). Author information: (1)Department of Psychology, University of California, Berkeley, California 94720-1650, USA. johndark@berkeley.edu Mammalian hibernation is a temporary suspension of euthermia allowing endotherms to undergo reversible hypothermia and generate a marked savings in energy expenditure. In most fat-storing hibernator species, seasonal changes in food intake, triacylglycerol deposition, metabolism, and reproductive development are controlled by a circannual clock. In ground-dwelling sciurid rodents (ground squirrels and marmots), for example, energy intake increases during a summer body mass gain phase, and toward the end of this phase metabolic rate also begins to decrease, resulting in a profound increase in lipid deposition as fat. Increased activity of lipogenic hormones and enzymes correspond with this increase. The hibernation mass loss phase begins after the body mass peak in the fall and ends in spring. During this phase, stored lipids are slowly utilized in a programmed manner by undergoing deep torpor or hibernation during which the hypothalamic setpoint for body temperature is typically reduced to just above 0 degrees C. Throughout the hibernation season, bouts of deep torpor are punctuated by periodic arousals in which brown adipose tissue thermogenesis plays a critical role. Lipid oxidation nearly exclusively fuels deep torpor and most of the rewarming process. The fatty acid composition of stored lipids can affect the depth and duration of deep torpor, and saturated fatty acids may be preferentially used during hibernation, whereas polyunsaturated fatty acids may be preferentially retained. Female and underweight male hibernators terminate hibernation in spring when aboveground food becomes available; in contrast, heavier males with sufficient lipid reserves spontaneously terminate hibernation several weeks before females and independent of food availability. Mating occurs shortly after emergence from hibernation, and the lipid cycle begins again with the completion of reproduction. Lipid deposition and mobilization, temperature regulation, reproduction, and circannual timing are intimately interdependent. The unique manner in which they are controlled during the annual cycle, especially lipid reserves, makes hibernators valuable and promising models for research into the mechanisms underlying these processes in all mammals. PMID: 16011475 [PubMed - indexed for MEDLINE] 3753. J Acquir Immune Defic Syndr. 2005 Aug 1;39(4):395-400. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. Lichtenstein KA(1). Author information: (1)University of Colorado Infectious Disease Group Practice, Denver, 80262, USA. didc.kal@juno.com Lipodystrophy syndrome comprises several conditions (lipoatrophy; lipohypertrophy; mixed syndrome, often associated with dyslipidemia; and insulin resistance). These conditions, though sometimes occurring together, may occur independently, suggesting a complex, multifactorial cause. To elucidate the relative contribution of risk factors of drug, disease, and host to fat redistribution, large epidemiologic studies using multivariate analysis were reviewed. In studies assessing lipoatrophy, the most common statistically significant risk factors were use of specific nucleoside analogues, increasing age, presence of markers of disease severity (CD4/HIV RNA), duration of therapy, and white race. In studies assessing lipohypertrophy, the most common statistically significant risk factors were duration of therapy, markers of disease severity, and protease inhibitor use. The pathogenesis of these disorders is complex, but recent hypotheses and evidence suggest that impairment to adipocyte differentiation, impairment of adipokine regulation, unopposed production of proinflammatory cytokines, dysregulation of 11-beta-hydroxysteroid dehydrogenase, and mitochondrial toxicity may play a role. PMID: 16010159 [PubMed - indexed for MEDLINE] 3754. Exerc Sport Sci Rev. 2005 Jul;33(3):150-4. Skeletal muscle lipid and its association with insulin resistance: what is the role for exercise? Goodpaster BH(1), Brown NF. Author information: (1)Division of Endocrinology and Metabolism, University of Pittsburgh Department of Medicine, Montefiore Hospital, Pittsburgh, PA 15213, USA. bgood@pitt.edu Skeletal muscle lipid content has been associated with insulin resistance and type 2 diabetes. However, intramuscular triglycerides can also be a fuel source for healthy muscle during exercise. The balance between storage and use of muscle triglycerides is likely a key to the interaction between dysregulated fat and glucose metabolism by healthy and insulin resistant muscle. PMID: 16006823 [PubMed - indexed for MEDLINE] 3755. J Pharmacol Sci. 2005 Jul;98(3):225-31. Epub 2005 Jul 9. Transcriptional regulation of neuronal genes and its effect on neural functions: transcriptional regulation of neuropeptide Y gene by leptin and its effect on feeding. Higuchi H(1), Hasegawa A, Yamaguchi T. Author information: (1)Division of Pharmacology, Department of Molecular Genetics and Signal Transduction Research, Niigata University, Japan. hhiguchi@med.niigata-u.ac.jp Leptin is an adipose tissue-derived secretory hormone that suppresses appetite by inhibition of neuropepeptide Y (NPY) gene expression in arcuate nucleus (ARC) in the hypothalamus. To investigate the transcriptional regulation of NPY gene by leptin, we carried out a luciferase assay using NPY gene promotor plasmid (NPY-luc) in NPY expressing cells such as N18TG2, NG108-15, and PC12 cells. In these cells, the NPY gene was transactivated by leptin through activation of leptin receptor. Leptin-induced transactivation was mediated through the 221-bp region of the NPY gene promotor, which possesses two putative STAT3 binding sites. To investigate the mechanism of in vivo suppression of NPY gene transcription in ARC by leptin, the effect of SOCS members on the leptin-induced transactivation of NPY gene was studied. In vivo SOCS2 and SOCS3 mRNAs were induced in mouse hypothalamus by leptin. Although leptin (125 ng/ml) induced significant increase in NPY gene transcriptional activity in mock-transfected cells, the leptin-induced NPY gene transcriptional activity was completely abolished in SOCS3-transfected cells. SOCS3 also suppressed the basal NPY gene transcription. These finding suggested that leptin inhibits NPY gene transcription in the hypothalamus in vivo and SOCS3 is a negative regulator of the NPY gene. PMID: 16006740 [PubMed - indexed for MEDLINE] 3756. Trends Mol Med. 2005 Aug;11(8):344-7. Visfatin: the missing link between intra-abdominal obesity and diabetes? Sethi JK(1), Vidal-Puig A. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, UK. Human obesity-related diabetes and the accompanying metabolic disorders have been specifically linked to increased visceral adipose tissue mass. Understanding the differences in biology of the two human fat depots (visceral and subcutaneous) might hold the key to therapeutic strategies aimed at reducing obesity-induced insulin resistance and alleviating symptoms of the metabolic syndrome. Visfatin (pre-B-cell colony-enhancing factor, PBEF) is a novel adipokine that appears to be preferentially produced by visceral adipose tissue and has insulin-mimetic actions. Could this molecule hold the key to future treatments for type 1 and 2 diabetes? This article discusses the pros and cons of visfatin action and how it might affect future therapeutic strategies. PMCID: PMC4303999 PMID: 16005682 [PubMed - indexed for MEDLINE] 3757. Clin Chim Acta. 2005 Dec;362(1-2):1-11. Epub 2005 Jul 7. Leptin as a new diagnostic tool in chronic heart failure. Schulze PC(1), Kratzsch J. Author information: (1)Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA. pcschulze@rics.bwh.harvard.edu Leptin, the product of the ob-gene, regulates cellular homeostasis and glycemic control. While initially described as an adipocyte-derived protein with expression and secretion restricted to adipose tissue, recent reports have shown local expression of leptin in several tissues including the skeletal muscle, heart, vessels and brain. Leptin acts through the different isoforms of its receptor which are ubiquitously expressed and can be detected in endothelium, vascular smooth muscle and myocardium. In addition to its metabolic effects, leptin has distinct effects in the cardiovascular system leading to increased production of proinflammatory cytokines and oxidative stress, vascular remodeling and neointima formation as well as cardiomyocyte hypertrophy. Notably, recent clinical studies have linked serum levels of leptin to the occurrence of cardiovascular events such as myocardial infarction and stroke suggesting that leptin promotes pro-atherogenic vascular mechanisms. In contrast, less is known about the role and effects of leptin in the setting of chronic heart failure. We here review the current knowledge on cardiovascular effects of leptin and discuss its potential as a new therapeutic tool in chronic heart failure. PMID: 16005450 [PubMed - indexed for MEDLINE] 3758. Peptides. 2005 Oct;26(10):1782-7. Roles for melanocortins and leptin in adipose tissue apoptosis and fat deposition. Della-Fera MA(1), Baile CA. Author information: (1)Department of Animal and Dairy Science, University of Georgia, 444 Animal Science Complex, Athens, GA 30602-2771, USA. Leptin has a wide range of effects on physiological functions related to the regulation of body energy balance. Many of leptin's effects are mediated through neuropeptide-containing neurons and neuropeptide receptors in the hypothalamus. The melanocortin system includes both agonist (alpha-melanocyte stimulating hormone, alphaMSH) and antagonist peptides (agouti related peptide, AGRP). Increased melanocortin receptor stimulation following leptin administration plays an important role in leptin-induced hypophagia and increased sympathetic nervous system activity and is partly responsible for leptin-induced weight loss. However, melanocortins do not appear to mediate some of the more striking centrally-mediated effects of leptin on adipose tissue, including adipose tissue apoptosis, that lead to the extensive depletion of fat. PMID: 16002187 [PubMed - indexed for MEDLINE] 3759. Nutrition. 2005 Sep;21(9):969-76. Waist circumference criteria for the diagnosis of abdominal obesity are not applicable uniformly to all populations and ethnic groups. Misra A(1), Wasir JS, Vikram NK. Author information: (1)Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. anoopmisra@metabolicresearchindia.com Determination of cutoff points of waist circumference is of paramount importance for prevention, optimum management, and prognostication of obesity, the metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. Heterogeneity of composition of abdominal tissues, in particular adipose tissue and skeletal muscle, and their location-specific and changing relations with metabolic factors and cardiovascular risk factors in different ethnic groups do not allow a simple definition of abdominal obesity that could be applied uniformly. In particular, Asians appear to have higher morbidity at lower cutoff points for waist circumference than do white Caucasians. International health agencies that deal with obesity (World Health Organization, International Obesity Task Force) should take cognizance of these data and consider formulating new cutoff points for waist circumference to define abdominal obesity for Asian populations. PMID: 15993041 [PubMed - indexed for MEDLINE] 3760. Med Sci Monit. 2005 Jul;11(7):RA221-8. Epub 2005 Jun 29. Systemic effects of cancer: role of multiple proteases and their toxic peptide products. Rubin H(1). Author information: (1)Department of Molecular and Cell Biology, Life Sciences Addition, University of California, Berkeley, CA 94720-3200, USA. hrubin@uclink4.berkeley.edu Cachexia, or the loss of skeletal muscle, adipose tissue and immunological competence, is a common systemic condition in advanced cases of cancer, and is a frequent cause of death. There have been many reports that small peptides isolated from tumors induce systemic effects correlated with cachexia upon injection into mice or addition to cell cultures. Only recently has evidence been presented for the origin of these peptides from the large increase in proteolytic enzymes found in tumors. Additional evidence is presented here for a major role of tumor peptides in producing effects associated with cachexia. Such peptides of low molecular weight were found to produce lipolysis in adipose tissue. Fibrinogen degradation products from the plasma of cancer patients and other chronic diseases suppress activation of the immune response. Some proteases of the cathepsin class occur in high concentration at the surface of transformed cells where the pH is low enough to allow digestion of pericellular proteins; other cathepsins elevated in tumors are highly active at physiological pH. Cathepsin L is the major excreted protein of cultured cells transformed by viruses or chemicals and is likely to form toxic peptides by digestion of extracellular proteins. Even normal liver and skeletal muscle of some cancer patients and tumor-bearing animals exhibit significant increases in cathepsins and components of the ubiquitin-proteasesome pathway which would add to circulating peptides. These observations argue for a central role of multiple proteases and their proteolytic products in producing the debilitating systemic effects of cancer. PMID: 15990698 [PubMed - indexed for MEDLINE] 3761. Curr Opin Lipidol. 2005 Aug;16(4):409-15. Adipose tissue fatty acid metabolism and cardiovascular disease. Frayn KN(1), Fielding BA, Karpe F. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK. keith.frayn@oxlip.ox.ac.uk PURPOSE OF REVIEW: Fatty acid and triacylglycerol metabolism in adipose tissue may be involved in the generation of risk factors for cardiovascular disease and type 2 diabetes. Pharmaceutical companies are targeting adipocyte metabolism in their search for drugs for treating, or reducing the risk of, these conditions. We review new developments in adipose tissue fatty acid metabolism and how that might relate to cardiovascular disease. RECENT FINDINGS: Fatty acid release from human adipose tissue is oscillatory, with a period of about 12 min. Remarkably, oscillatory fatty acid release is also seen in isolated adipocytes. Further evidence has emerged that not all adipose depots are equal, and that lower-body adipose tissue may exert protective effects against cardiovascular disease. There have been a number of developments in the area of fatty acid handling by adipocytes. Fatty acid binding proteins are clearly important in regulating fatty acid metabolism, with striking protection against atherosclerosis in mice deficient in both the binding proteins expressed in adipocytes. The demonstration that adipocytes lacking hormone-sensitive lipase still display lipolysis has led to the identification of novel lipases that may play crucial roles in adipose tissue fatty acid metabolism. Further evidence has accrued of the interaction between hormone-sensitive lipase and perilipin, the protein that coats the adipocyte lipid droplet. SUMMARY: Recent developments in our understanding of adipose tissue fatty acid metabolism open up the possibility of new pharmaceutical targets. However, interference with adipose tissue fatty acid metabolism is not to be undertaken lightly and needs a clear understanding of the normal role of adipocyte lipolysis. PMID: 15990589 [PubMed - indexed for MEDLINE] 3762. Expert Opin Emerg Drugs. 2002 May;7(1):165-74. Insulin-sensitising agents: beyond thiazolidinediones. Perry CG(1), Petrie JR. Author information: (1)Department of Medicine, University of Glasgow, Royal Infirmary, Glasgow, G31 2ER, United Kingdom. colin@fulcrum.u-net.com The global prevalence of Type 2 diabetes mellitus is increasing rapidly, at least in part as a function of obesity. The results of the United Kingdom Prospective Diabetes Study emphasise the importance of developing safe, efficacious new agents for the treatment of Type 2 diabetes. The pharmaceutical industry has recently focused on strategies to improve insulin resistance, particularly modulation of PPAR-gamma. Here we review current thinking on the mechanism of action of these agents, and consider future directions that may arise as a result of increasing understanding of the biology of these receptors and of insulin action. Studies of thiazolidinedione action in adipose tissue have revealed several novel adipocyte-derived hormones that may also be future pharmacological targets for increasing insulin sensitivity. The role of other hormones, such as cortisol and dehydroepiandrosterone, are also discussed in a therapeutic context, as are other novel approaches to the pharmacological management of patients with insulin resistance and Type 2 diabetes. PMID: 15989542 [PubMed] 3763. Ann Endocrinol (Paris). 2005 Jun;66(3):270-8. [Laminopathies: lipodystrophies, insulin resistance, syndromes of accelerated ageing... and others]. [Article in French] Vigouroux C(1). Author information: (1)Faculté de médecine Saint-Antoine, Université Pierre et Marie Curie, INSERM U680, 27, rue Chaligny, 75 571 Paris Cedex 12. vigouroux@st-antoine.inserm.fr Laminopathies are a group of diseases due to mutations of type A-lamins, a group of proteins lining the inner aspect of cell nuclei. These diseases illustrate the complexity of the genotype-phenotype relationship characteristic of same genetic diseases. Since the discovery of the causal role of LMNA gene mutations in the genesis of Emery Dreifuss muscular dystrophy in 1999, no less than eight other diseases have been associated with mutations of this same gene! The tissue-specific nature of the clinical manifestations, contrasting with the ubiquitous expression of these proteins, has incited much research concerning the physiological role of lamins, considered to be much broader than the structural function initially put forward. Certain laminopathies, which combine insulin resistance, android distribution of adipose tissue, dyslipidemia, early atherosclerosis, and hepatic steatosis, appear very similar though more severe to the frequent dysmetabolism syndrome. The relationships of laminopathies with accelerated aging syndrome, Hutchinson-Gilford progeria, or progeroid syndromes, which are also related to A/C lamin anomalies, could provide new avenues of research on the pathogenesis of the metabolic syndrome. In addition, clinicians have to be aware of atypical and milder forms of laminopathies, that require specific investigations and molecular screening of relatives allowing an adequate medical management. PMID: 15988390 [PubMed - indexed for MEDLINE] 3764. Gan To Kagaku Ryoho. 2005 Jun;32(6):743-9. [Recent development in research and management of cancer anorexia-cachexia syndrome]. [Article in Japanese] Inui A(1). Author information: (1)Dept. of Social and Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan. Cachexia is among the most debilitating and life-threatening aspects of cancer, and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be done by persistent inhibition of feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide-all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. Communication among physicians and other health care professionals provides the patient with a multidisciplinary approach to care. The patient record will be an excellent resource to document a plan of care and patient responses to treatment. Psychological distress and psychiatric disorders are common among cancer patients. These problems are also as common among the family members of people with cancer. The use of psychological and behavioral interventions in cancer is increasing, and recent studies have suggested that some of these techniques may affect quality of life and, perhaps, survival rates. Evaluations of relaxation, hypnosis, and short-term group psychotherapy have suggested some benefit with regard to anorexia and fatigue, although the population most likely to benefit from these interventions has not yet been determined. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life. PMID: 15984510 [PubMed - indexed for MEDLINE] 3765. Clin Chim Acta. 2005 Oct;360(1-2):9-26. Mechanisms of endothelial dysfunction in obesity. Avogaro A(1), de Kreutzenberg SV. Author information: (1)Metabolic Diseases--Department of Clinical and Experimental Medicine, University of Padova, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy. angelo.avogaro@unipd.it Obesity is a chronic disease, whose incidence is alarmingly growing, affecting not only adults but also children and adolescents. It is associated with severe metabolic abnormalities and increased cardiovascular morbidity and mortality. Adipose tissue secretes a great number of hormones and cytokines that not only regulate substrate metabolism but may deeply and negatively influence endothelial physiology, a condition which may lead to the formation of the atherosclerotic plaque. In this review, the physiology of the endothelium is summarised and the mechanisms by which obesity, through the secretory products of adipose tissue, influences endothelial function are explained. A short description of methodological approaches to diagnose endothelial dysfunction is presented. The possible pathogenetic links between obesity and cardiovascular disease, mediated by oxidative stress, inflammation and endothelial dysfunction are described as well. PMID: 15982646 [PubMed - indexed for MEDLINE] 3766. Can J Appl Physiol. 2005 Apr;30(2):233-45. Effects of different types of exercise on body composition and fat distribution in HIV-infected patients: a brief review. Malita FM(1), Karelis AD, Toma E, Rabasa-Lhoret R. Author information: (1)Département de Nutrition, Faculté de Médicine, Université de Montréal, Pavillon Liliane de Stewart, 2405 Côte Ste Catherine, Montréal, Quebec H3C 3J7. HIV infection and its treatment is associated with unfavourable metabolic and morphological abnormalities. These metabolic abnormalities, particularly alterations in body composition and fat distribution, may increase the risk for cardiovascular and metabolic complications, as well as reduce functional independence and lower self-esteem. Thus there is an urgent need to develop interventions intended to manage secondary side effects of HIV or antiretroviral therapy-related complications. In poly-treated patients, nonpharmacological interventions are a logical first step. Exercise training in particular may help alleviate some of the metabolic adverse effects associated with antiretroviral therapy by favourably altering body composition and patterns of body fat distribution. Studies have shown that exercise training, particularly aerobic training, can help reduce total body and visceral fat, as well as normalizing lipid profiles in HIV-infected patients. The results for resistance training, however, are less conclusive. Knowledge of the use of resistance and aerobic training and its attendant effects on insulin resistance and adipocytokines may represent an effective nonpharmacologic means for treating metabolic complications of HIV-infected persons who are receiving appropriate antiretroviral therapy. In this brief review we examine the effects of aerobic and resistance training on body composition, body fat distribution, and selected metabolic outcomes. PMID: 15981790 [PubMed - indexed for MEDLINE] 3767. Diabetes Metab Res Rev. 2005 Nov-Dec;21(6):487-94. Is insulin resistance caused by defects in insulin's target cells or by a stressed mind? Burén J(1), Eriksson JW. Author information: (1)Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden. jonas.buren@medicin.umu.se The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits. Copyright (c) 2005 John Wiley & Sons, Ltd. PMID: 15977304 [PubMed - indexed for MEDLINE] 3768. Am J Epidemiol. 2005 Jul 15;162(2):101-14. Epub 2005 Jun 22. Genetics of leptin and obesity: a HuGE review. Paracchini V(1), Pedotti P, Taioli E. Author information: (1)Unit of Molecular and Genetic Epidemiology, Fondazione Policlinico IRCCS, Milan, Italy. Leptin is an important regulator of the mass of adipose tissue and of body weight; it operates by inhibiting food intake and stimulating energy expenditure. Some polymorphic genes involved in the regulation of leptin-the leptin gene (LEP A19G), the leptin receptor gene (LEPR Q223R, K109R, and K656N), and the peroxisome proliferator-activated receptor-gamma gene (PPARG P12A and C161T)--have been investigated as possible factors associated with obesity. Allelic frequencies of these polymorphisms show ethnic variation. The authors performed a meta-analysis of the available data on the association between these polymorphisms and obesity based on case-control studies. Odds ratios and 95% confidence intervals for obesity associated with leptin polymorphisms were calculated by using both fixed- and random-effects models. Results suggest no evidence of association between the genes under study and obesity. The lack of association could be due to the complex pathogenesis of obesity, which involves a number of genetic and environmental factors. Large studies including testing of multiple genes in both obese and lean subjects, with epidemiologic data on dietary habits in different ethnic groups, are necessary to better understand the role of leptin in regulating weight in human populations. PMID: 15972940 [PubMed - indexed for MEDLINE] 3769. Nutr Rev. 2005 May;63(5):166-70. The mechanism and regulation of fat mobilization from adipose tissue: desnutrin, a newly discovered lipolytic enzyme. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, USA. A new member of a family of proteins functioning in the regulation of lipolysis in adipose tissue has been discovered and named "desnutrin." Desnutrin is transiently induced by fasting and decreased by re-feeding. A close homolog, termed adiponutrin, has the opposite expression pattern, being induced by feeding and disappearing upon fasting. Desnutrin functions by acting as the first enzyme in lipolysis, hydrolyzing triglycerides to diglycerides, whereas the well-known hormone-sensitive lipase takes the diglycerides to monoglycerides and on to free fatty acids. PMID: 15971411 [PubMed - indexed for MEDLINE] 3770. Reprod Biomed Online. 2005 Jun;10(6):713-20. Genetics of polycystic ovarian syndrome. Fratantonio E(1), Vicari E, Pafumi C, Calogero AE. Author information: (1)Section of Andrology and Internal Medicine, Department of Biomedical Sciences, University of Catania, Catania, Italy. Polycystic ovarian syndrome (PCOS) is a reproductive system disorder characterized by irregular menses, anovulation, clinical and/or biochemical signs of hyperandrogenism (hirsutism and/or acne), ovarian micropolycystic appearance and metabolic abnormalities, such as hyperinsulinaemia and obesity. The aetiopathogenesis of this syndrome is not well known. Several pathogenetic hypotheses have been proposed to explain the full array of symptoms and signs, but with elusive results. A genetic abnormality causing PCOS is supported by the observation that different members of the same family are often affected, and about half of the sisters of PCOS women have elevated serum testosterone concentrations. Therefore, the presence of gene abnormalities in women with PCOS has been widely explored in the attempt to establish whether their mutations or polymorphisms may cause PCOS. The main genes evaluated are those involved in steroidogenesis, steroid hormone effects, gonadotrophin release regulation and action, insulin secretion and action, and adipose tissue metabolism. Despite the vast body of literature produced, none of the genes evaluated seems to play a key role in PCOS pathogenesis. It is likely that PCOS may represent the final outcome of different, deeply inter-related genetic abnormalities that influence each other and perpetuate the syndrome. PMID: 15969998 [PubMed - indexed for MEDLINE] 3771. Semin Vasc Med. 2005 Feb;5(1):48-55. Visceral fat as a determinant of fibrinolysis and hemostasis. Mertens I(1), Van Gaal LF. Author information: (1)Department of Diabetology, Metabolism and Clinical Nutrition, Faculty of Medicine, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium. An increased amount of deep abdominal visceral fat has generally been accepted as an important cardiovascular risk factor, and disturbances in hemostasis and fibrinolysis have been suggested to play a role. Fibrinogen and von Willebrand factor, representatives of the hemostatic system, and plasminogen activator inhibitor 1 (PAI-1), as the most important inhibitor of the fibrinolytic system, have been associated with visceral obesity, with the most convincing evidence found for the involvement of PAI-1. The association with fibrinogen and von Willebrand factor has been suggested to be merely a reflection of the association with inflammation and endothelial dysfunction. The fact that PAI-1 is secreted by adipose tissue has attracted much attention. The increase of PAI-1 in visceral obesity could be because visceral adipose tissue produces more PAI-1 compared with subcutaneous abdominal adipose tissue. The contribution of other cell types such as hepatocytes or endothelial cells is probably more important, with stimulation of PAI-1 production by different components of the metabolic syndrome. PAI-1 secretion by adipose tissue has been suggested to have a more local effect, playing a role in tissue remodeling during the development of obesity. PMID: 15968580 [PubMed - indexed for MEDLINE] 3772. Semin Vasc Med. 2005 Feb;5(1):34-9. Adipocytokines and metabolic syndrome. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Osaka University, Osaka, Japan. Recently, adipocytes have been shown to be endocrine cells that secrete a variety of bioactive substances-the so-called adipocytokines. Among adipocytokines, tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as already known organs, and they contribute to the development of vascular diseases. Visfatin is a very recently discovered visceral fat-specific protein that may be related to the development of obesity-related diseases such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, also a newfound adipose tissue-specific collagen-like protein, has been noted recently as an important antiatherogenic as well as antidiabetic protein. The function of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysfunction of adipocytes including oversecretion of tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor, as well as hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, including adiponectin, is discussed with respect to atherosclerosis. PMID: 15968578 [PubMed - indexed for MEDLINE] 3773. Semin Vasc Med. 2005 Feb;5(1):15-24. Human leptin: an adipocyte hormone with weight-regulatory and endocrine functions. Considine RV(1). Author information: (1)Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. Leptin is synthesized and secreted primarily by adipocytes, and is present in serum in direct proportion to the amount of adipose tissue. The primary role of leptin is to provide to the central nervous system a signal of energy intake and energy stores in the body so that the hypothalamus can efficiently maintain a stable body weight. The receptor for leptin in the hypothalamus signals by activation of an associated janus kinase which phosphorylates signal transducer and activator of transcription (STAT) proteins that regulate neuronal gene expression. Genetic mutations in leptin and its receptor can result in obesity in both rodents and humans, supporting a central role for leptin in the regulation of body weight. Leptin has also been implicated in a variety of physiological processes other than body weight homeostasis. Many of these functions are mediated through the central nervous system; however, the presence of leptin receptors in tissues throughout the body suggests that leptin can also have direct effects on cells and tissues. Serum leptin levels have been associated with cardiovascular risk factors after correction for adiposity. Leptin can promote platelet aggregation, which requires expression of functional leptin receptors on the platelet. Leptin-induced increases in sympathetic nerve activity have been suggested to contribute to hypertension, and leptin has been observed to increase oxidative stress in cultured endothelial cells. Many of these pathophysiologic effects of leptin on the vasculature are most likely of importance when leptin levels are elevated in obese subjects due to resistance to the weight-reducing effects of the hormone. An improved understanding of the effects of leptin on the vasculature will provide valuable insight into the relationship between obesity and cardiovascular disease. PMID: 15968576 [PubMed - indexed for MEDLINE] 3774. Pol Arch Med Wewn. 2004 Dec;112(6):1521-5. [Inflammation of fat tissue--panniculitis. The clinical study--part I. The clinical picture of panniculitis and pathogenetic hypotheses]. [Article in Polish] Zimmnermann-Górska I(1), Tuchocka-Piotrowska A, Puszczewicz M. Author information: (1)Katedra i Klinika Reumatologiczno-Rehabilitacyjna i Chorób Wewnetrznych AM, im. K. Marcinkowskiego, Poznaniu. PMID: 15962619 [PubMed - indexed for MEDLINE] 3775. Pol Arch Med Wewn. 2004 Dec;112(6):1513-9. [Adiponectin--common link in the pathogenesis of metabolic disorders and cardiovascular diseases?]. [Article in Polish] Michalewska-Włudarczyk A(1), Tendera M. Author information: (1)III Klinika Kardiologii Sl. AM, Katowicach. Erratum in Pol Arch Med Wewn. 2005 Mar;113(3):301. PMID: 15962618 [PubMed - indexed for MEDLINE] 3776. Proc Nutr Soc. 2005 May;64(2):263-7. The management of short-term intestinal failure in obese patients. Powell-Tuck J(1). Author information: (1)St. Bartholomew's and the Royal London Hospital Medical College, Queen Mary University of London, UK. J-Powell-Tuck@qmul.ac.uk The prevalence of obesity in the general population is high and it is inevitable that artificial feeding will be needed from time to time in the obese patient, particularly in the critical care setting. Against a background of generous endogenous stores of energy as adipose tissue and the ability of obese individuals to survive starvation longer than non-obese individuals, emphasis is placed on preserving lean body mass and optimizing physiological function. Insulin resistance is typical of the obese individual and is exacerbated by stress; overfeeding is dangerous, particularly if it results in hyperglycaemia. Refeeding syndrome also has to be avoided. Weight may be difficult to measure and lean body mass difficult to assess. Calculation of energy requirements is therefore problematic in practice in the obese individual and there is substantial evidence from controlled clinical trials of the safety of feeding at or below resting energy expenditure. If this approach is taken it is wise to provide a more generous than normal protein intake and to beware of patients with a very high baseline urinary N excretion. PMID: 15960871 [PubMed - indexed for MEDLINE] 3777. Proc Nutr Soc. 2005 May;64(2):213-6. Peptide YY, appetite and food intake. le Roux CW(1), Bloom SR. Author information: (1)Department of Metabolic Medicine, Imperial College London, W12 0NN, UK. Obesity is taking on pandemic proportions. The laws of thermodynamics, however, remain unchanged, as energy will be stored if less energy is expended than consumed; the storage is usually in the form of adipose tissue. Several neural, humeral and psychological factors control the complex process known as appetite. Recently, a close evolutionary relationship between the gut and brain has become apparent. The gut hormones regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. Peptide YY (PYY) is a thirty-six amino acid peptide related to neuropeptide Y (NPY) and is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 h. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake. PMID: 15960866 [PubMed - indexed for MEDLINE] 3778. Proc Nutr Soc. 2005 May;64(2):163-9. Secretory factors from human adipose tissue and their functional role. Hauner H(1). Author information: (1)Else Kröner-Fresenius-Centre for Nutritional Medicine of the Technical University of Munich, Klinikum Rechts der Isar, Germany. hans.hauner@lrz.tum.de Obesity is characterized by an expanded adipose tissue mass. Recent data suggest that adipose tissue is a multi-functional organ rather than simply a passive storage site for excess energy. It has been clearly demonstrated that human adipose tissue produces a variety of secretory factors that exert multiple effects at both the local and the systemic level. To date, >100 products, covering a broad range of protein families as well as many fatty acids and prostaglandins, have been reported to be secreted by adipose tissue. The source of these secreted factors is not only mature fat cells but also poorly-identified cells present in the stromal-vascular fraction including macrophages. Secreted factors of particular interest include many cytokines or chemokines, such as TNF-alpha, IL-6, IL-8, as well as plasminogen activator inhibitor-1, angiotensin-II, leptin, and adiponectin. In the obese state the expression and secretion of these factors is disturbed. With the exception of adiponectin, most circulating factors are elevated. From this perspective, obesity can be described as a pro-inflammatory condition. In addition, regional differences in adipose expression of many of these factors have been found. There is now growing evidence that many secretory factors play an important role in the pathophysiology of the metabolic and cardiovascular complications of obesity. The question arising from these observations is how the secretory pattern of adipose tissue can be modified by dietary and pharmacological measures to reduce the health risks of obesity. PMID: 15960861 [PubMed - indexed for MEDLINE] 3779. Birth Defects Res A Clin Mol Teratol. 2005 Jul;73(7):481-4. Fetal nicotinic overload, blunted sympathetic responsivity, and obesity. Levin ED(1). Author information: (1)Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. edlevin@duke.edu PMID: 15959889 [PubMed - indexed for MEDLINE] 3780. Birth Defects Res A Clin Mol Teratol. 2005 Jul;73(7):470-1. Overview of clinical perspectives and mechanisms of obesity. Collins S(1). Author information: (1)CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA. scollins@ciit.org PMID: 15959883 [PubMed - indexed for MEDLINE] 3781. Ann Endocrinol (Paris). 2005 Apr;66(2 Pt 2):1S81-90. [Kidney and glitazones]. [Article in French] Deray G(1), Izzedine H, Launay-Vacher V, Bagnis C. Author information: (1)Service de Néphrologie, Groupe Hospitalier Pitié-Salpêtrière, F-75651 Paris Cedex 13, France. gilbert.deray@psl.ap-hop-paris.fr PPARgamma nuclear receptors are mainly expressed in adipose tissue. However, they are also expressed in renal glomerular tissue and in vascular walls, thus participating through various and complex mechanisms, to glomerular and vascular sclerosis and to nephropathy development and progression. Studies carried out with glitazones, pharmacological agonists of nuclear receptor PPARgamma, in experimental models, either in vitro, or in vivo in animal models, have demonstrated their favourable effects on arterial blood pressure and on prevention and/or progression of diabetic nephropathy. The few clinical studies conducted in type 2 diabetic patients to assess these effects, are also in favor of a beneficial effect of glitazones on blood pressure and nephropathy in these patients. Thus, it appears extremely important and fully justified to conduct specific studies in patients with type 2 diabetes, with the aim to establish and to better characterize these effects in various clinical conditions (antihypertensive effect in treated hypertensive patients according to the class of antihypertensive agents used, prevention of diabetic nephropathy and/or effect on its progression, renal protection, etc.). Some adverse events, although with a low incidence, may be associated with glitazone use (weight gain, peripheral oedema, fluid retention, etc.), and may limit their use in some patients. It is clearly important to better understand the pathophysiological mechanisms of these effects and their possible long term consequences. Finally, it is important to emphasize the easiness to use glitazones in patients with renal insufficiency, without the need to adjust the drug regimen. PMID: 15959407 [PubMed - indexed for MEDLINE] 3782. Ann Endocrinol (Paris). 2005 Apr;66(2 Pt 3):2S7-10. [Development of adipose tissue and dietary lipids: from basic science to medicine]. [Article in French] Ailhaud G(1). Author information: (1)Institut de Recherches Signalisation, Biologie du Développement et Cancer, Centre de Biochimie (UMR 6543 CNRS), UNSA, Faculté des Sciences, Nice, France. ailhaud@unice.fr Professor Gérard Ailhaud was awarded the 2005 Institut Roche de l'Obésité Prize, for his studies on adipocyte biology and the differential role of dietary lipids in the increasing prevalence of overweight and obesity. With his colleagues, he demonstrated that natural fatty acids play an hormonal role by favouring the differentiation of preadipocytes into adipocytes, showed the potent adipogenic role of arachidonic acid (C20:4, n-6) and depicted the signaling pathways involved in this process. More recently, his research has underscored the importance of the composition of dietary fats during the gestation/suckling period, i.e. an excess of the essential polyunsaturated fatty acids of the n-6 series, in the hypertrophic/hyperplasic development of adipose tissue which has been associated over the last decades with the increasing prevalence of childhood obesity. The main findings of his studies are summarised in this review. PMID: 15959391 [PubMed - indexed for MEDLINE] 3783. Diabetes Obes Metab. 2005 Jul;7(4):301-6. Visceral fat and respiratory complications. Busetto L(1), Sergi G. Author information: (1)Department of Medical and Surgical Sciences, University of Padova, Padova, Italy. luca.busetto@unipd.it PMID: 15955115 [PubMed - indexed for MEDLINE] 3784. Annu Rev Biochem. 2005;74:515-34. Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Dowell P(1), Hu Z, Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dowellp@jhmi.edu Because energy balance is important for survival, a system is required to monitor energy status and to make appropriate adjustments in energy intake and energy expenditure. In higher animals, a centrally located system has evolved to accomplish this task. When caloric intake exceeds expenditure, the surplus is channeled into energy storage pathways, primarily the synthesis of fatty acids, which are converted into fat and stored in adipose tissue. Thus, metabolic flux through the pathway of fatty acid synthesis, located in the lipogenic tissues, reflects the "energy status" of the animal. The enzymatic machinery of this pathway is also expressed in the brain, notably the hypothalamus. In the hypothalamus, intermediates in this pathway appear to serve as energy sensors that signal higher brain centers to produce appropriate responses, e.g., altered food intake and energy expenditure. PMID: 15952896 [PubMed - indexed for MEDLINE] 3785. Seikagaku. 2005 May;77(5):440-3. [Regulation of skeletal muscle mass and adipose tissue mass by follistatin and follistatin-related gene (FLRG) and development of novel polypeptides as medical drugs]. [Article in Japanese] Tsuchita K(1). Author information: (1)Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Sciences, Fujita Health University, Kutsukate-cho, Toyoake, Japan. PMID: 15952337 [PubMed - indexed for MEDLINE] 3786. Biochim Biophys Acta. 2005 May 30;1740(2):313-7. Epub 2004 Dec 8. Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes. Luquet S(1), Gaudel C, Holst D, Lopez-Soriano J, Jehl-Pietri C, Fredenrich A, Grimaldi PA. Author information: (1)Inserm U636, Centre de Biochimie, UFR Sciences, Université de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice, France. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARalpha, activated by polyunsaturated fatty acids and fibrates, is implicated in regulation of lipid metabolism, lipoprotein synthesis and metabolism and inflammatory response in liver and other tissues. PPARgamma plays important roles in regulation of proliferation and differentiation of several cell types, including adipose cells. Its activation by thiazolidinediones results in insulin sensibilization and antidiabetic action. Until recently, the physiological functions of PPARdelta remain elusive. The utilization of specific agonists and of appropriate cellular and animal models revealed that PPARdelta has an important role in metabolic adaptation of several tissues to environmental changes. Treatment of obese animals by specific PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. The nuclear receptor appeared to be implicated in the regulation of fatty acid burning capacities of skeletal muscle and adipose tissue by controlling the expression of genes involved in fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also implicated in the adaptive metabolic response of skeletal muscle to endurance exercise by controlling the number of oxidative myofibers. Given the results obtained with animal models, PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue. PMID: 15949697 [PubMed - indexed for MEDLINE] 3787. Biochim Biophys Acta. 2005 May 30;1740(2):293-304. Epub 2005 Feb 22. PPARgamma in the control of brown adipocyte differentiation. Nedergaard J(1), Petrovic N, Lindgren EM, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se The effects of fatty acids and retinoic acid (carotene) on brown adipose tissue differentiation are mediated by activation of the transcription factors PPARgamma and PPARalpha in combination with RXR. There is good support for the idea that activated PPARgamma promotes adipogenesis also in brown adipose tissue. However, the issue is more complex concerning the full differentiation to the brown adipocyte phenotype, particularly the expression of the brown-fat-specific marker UCP1. The effect of norepinephrine on PPARgamma gene expression, at least in-vitro, is negative, PPARgamma-ablated brown adipose tissue can express UCP1, and PGC-1alpha coactivates other transcription factors (including PPARalpha); thus, the significance of PPARgamma for the physiological control of UCP1 gene expression is not settled. However, importantly, the effects of PPAR agonists demonstrate the existence of a pathway for brown adipose tissue recruitment that is not dependent on chronic adrenergic stimulation and may be active in recruitment conditions such as prenatal and prehibernation recruitment. The ability of chronic PPARgamma agonist treatment to promote the occurrence of brown-fat features in white adipose tissue-like depots implies a role in anti-obesity treatment, but this will only be effective if the extra thermogenic capacity is activated by adrenergic stimulation. PMID: 15949696 [PubMed - indexed for MEDLINE] 3788. Biochim Biophys Acta. 2005 May 30;1740(2):287-92. Epub 2004 Dec 8. Fatty acids and expression of adipokines. Drevon CA(1). Author information: (1)Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. c.a.drevon@basalmed.uio.no Adipose tissue has been recognised as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermic insulator. In mammals, the adipose organ is localised in several depots including white as well as brown adipose tissues. The largest depots are found subcutaneously and in the abdominal region. Several secretory proteins are synthesised in adipose tissue including leptin, resistin, adiponectin, tumor necrosis factor (TNFalpha), angiotensinogen, adipsin, acylation-stimulating protein, retinol-binding protein (RBP), interleukin (IL)-1b, IL-6, IL-8, IL-10, plasminogen activator inhibitor-1 (PAI-1), fasting-induced adipose factor, fibrinogen-angiopoietin-related protein, metallothionein, tissue factor (TF), complement C3, fibronectin, haptoglobin, entactin/nidogen, collagen VI alpha 3, pigment epithelium-derived factor (PEDF), hippocampal cholinergic neurostimulating peptide (HCNP), neutrophil gelatinase-associated lipocalin (NGAL) and adiponutrin. Fatty acids may influence the expression of adipokines like leptin, resistin or adiponectin directly by interaction with transcription factors, or indirectly via unknown mechanisms possibly linked to fatty acid oxidation, synthesis or storage. Because fatty acids are the main components of adipose tissue, it is of essential interest to clarify the biological effects of different types of fatty acids on the expression of relevant adipokines. PMID: 15949695 [PubMed - indexed for MEDLINE] 3789. Biochim Biophys Acta. 2005 May 30;1740(2):266-86. Epub 2005 Mar 22. Regulation of adipocyte differentiation and function by polyunsaturated fatty acids. Madsen L(1), Petersen RK, Kristiansen K. Author information: (1)Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. A diet enriched in PUFAs, in particular of the n-3 family, decreases adipose tissue mass and suppresses development of obesity in rodents. Although several nuclear hormone receptors are identified as PUFA targets, the precise molecular mechanisms underlying the effects of PUFAs still remain to be elucidated. Here we review research aimed at elucidating molecular mechanisms governing the effects of PUFAs on the differentiation and function of white fat cells. This review focuses on dietary PUFAs as signaling molecules, with special emphasis on agonistic and antagonistic effects on transcription factors currently implicated as key players in adipocyte differentiation and function, including peroxisome proliferator activated receptors (PPARs) (alpha, beta and gamma), sterol regulatory element binding proteins (SREBPs) and liver X receptors (LXRs). We review evidence that dietary n-3 PUFAs decrease adipose tissue mass and suppress the development of obesity in rodents by targeting a set of key regulatory transcription factors involved in both adipogensis and lipid homeostasis in mature adipocytes. The same set of factors are targeted by PUFAs of the n-6 family, but the cellular/physiological responses are dependent on the experimental setting as n-6 PUFAs may exert either an anti- or a proadipogenic effect. Feeding status and hormonal background may therefore be of particular importance in determining the physiological effects of PUFAs of the n-6 family. PMID: 15949694 [PubMed - indexed for MEDLINE] 3790. Congest Heart Fail. 2005 May-Jun;11(3):163-6. Gender and its effect in cardiovascular pharmacotherapeutics: recent considerations. Sica DA(1), Wood M, Hess M. Author information: (1)Departments of Medicine and Pharmacology, Section of Clinical Pharmacology and Hypertension, Division of Nephrology; Virginia Commonwealth University Health System, Richmond, VA 23298, USA. dsica@hsc.vcu.edu Gender differences in drug pharmacokinetics and pharmacodynamics have been recognized for some time. This issue has generally been ignored in clinical practice, despite there being ample evidence to suggest that gender can influence multiple aspects of pharmacokinetics. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, the amount of drug-binding proteins, gender-specific changes in the available amount of P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and differences in renal blood flow are several factors that may have some bearing on sex-related differences in pharmacokinetics. Furthermore, female-specific issues such as pregnancy, menopause, oral contraceptive use, and menstruation may independently influence drug metabolism and serve as confounders to the interpretation of gender differences in drug handling or effect. While gender-related pharmacodynamic data are limited, evidence suggests that women are more prone to the development of torsade de pointes from proarrhythmic drugs such as quinidine or d-sotalol and have an increased cardiovascular risk with the use of digoxin. The specific risk:benefit ratio for individual cardiovascular medications should be more routinely considered in the context of gender. PMID: 15947543 [PubMed - indexed for MEDLINE] 3791. Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):17-30. Adipose tissue and the immune system. Pond CM(1). Author information: (1)Department of Biological Sciences, The Open University, Milton Keynes MK7 6AA, UK. C.M.Pond@open.ac.uk Adipocytes anatomically associated with lymph nodes (and omental milky spots) have many special properties including fatty acid composition and the control of lipolysis that equip them to interact locally with lymphoid cells. Lymph node lymphocytes and tissue dendritic cells acquire their fatty acids from the contiguous adipocytes. Lymph node-derived dendritic cells suppress lipolysis in perinodal adipocytes but those that permeate the adipose tissue stimulate lipolysis, especially after minor, local immune stimulation. Inflammation alters the composition of fatty acids incorporated into dendritic cells, and that of node-containing adipose tissue, counteracting the effects of dietary lipids. Thus these specialised adipocytes partially emancipate the immune system from fluctuations in the abundance and composition of dietary lipids. Prolonged, low-level immune stimulation induces the local formation of more adipocytes, especially adjacent to the inflamed lymph node. This mechanism may contribute to hypertrophy of the mesentery and omentum in chronic inflammatory diseases such as HIV-infection, and in smokers. Paracrine interactions between adipose and lymphoid tissues are enhanced by diets rich in n-6 fatty acids and attentuated by fish oils. The latter improve immune function and body conformation in animals and people. The partitioning of adipose tissue in many depots, some specialised for local, paracrine interactions with other tissues, is a fundamental feature of mammals. PMID: 15946832 [PubMed - indexed for MEDLINE] 3792. Eur Rev Med Pharmacol Sci. 2005 Mar-Apr;9(2):75-92. Physiological endocrine control of energy homeostasis and postprandial blood glucose levels. Gagliardino JJ(1). Author information: (1)CENEXA--Center of Experimental and Applied Endocrinology (National University of La Plata, National Research Council, PAHO/WHO Collaborating Center) School of Medical Sciences, La Plata, Argentina. The aim of this review is to analyze the different components and the feedback mechanisms involved in the normal control of energy homeostasis and postprandial blood glucose levels. Such control involves exogenous and endogenous factors: while the former include quantity and quality of food intake, the latter involve the balance of glucose intestinal absorption (postprandial period), glucose production and release by the liver and its consumption by peripheral tissues. Adequate secretion and peripheral metabolic effects of insulin play a key role in the control of both processes. Insulin secretion is controlled by the level of circulating substrates and by gastrointestinal hormones. The mechanism for the immediate control of blood glucose levels is modulated by energy homeostasis, with the participation of the above mentioned hormones and others produced at the classical endocrine system and adipose tissue, whose actions integrate at the central nervous system. The alteration of such delicate mechanism of control causes diseases such as diabetes; therefore, identification of the multiple components of this mechanism and comprehension of its normal function would facilitate the selection of effective strategies for diabetes prevention and treatment. PMID: 15945497 [PubMed - indexed for MEDLINE] 3793. Biomed Khim. 2005 Mar-Apr;51(2):107-17. [Achievements in molecular genetics studies of diabetes mellitus]. [Article in Russian] Pankov IuA. Tissue specific insulin receptor knockout mice have been employed to study the features of non-insulin-dependent diabetes mellitus (NIDDM) at Research Division, Joslin Diabetes Center, Boston, Massachusetts. The muscle insulin receptor knockout (MIRKO) mice display muscle insulin resistance but do not develop hyperinsulinemia or diabetes. White adipose tissue of MIRKO mice have increased the sensitivity to insulin and its glucose uptake is dramatically elevated that activates fat accumulation and induces obesity which results from an increase in adipocyte number (hyperplasia) of the same size as well as individual cells in the control mice. MIRKO mouse adipose tissue increased secretion of adiponectin that increases the insulin sensitivity and do not alter the leptin production. The liver insulin receptor knockout (LIRKO) mice develop a syndrome like NIDDM with hyperinsulinemia and hyperglycemia, decreased liver size and its function since insulin is an important liver growth factor but they do not suffer with fat accumulation The fat tissue insulin receptor knockout (FIRKO) mice become lean with the 50-60% reduction of fat masses. FIRKO mouse remains resistant to obesity with age and as a result it has high insulin sensitivity and normal glucose tolerance. They eat normal amount of food, increase the longevity of life and decrease the mortality. The beta-cell insulin receptor knockout in combination with the insulin receptor substrates 1 or 2 or both knockouts mice develop beta-cell insensitivity to insulin and the insensitivity to the stimulation of insulin secretion by glucose. The animals show the alterations of beta-cell growth and 20% of experimental mice develop II type diabetes. The brain insulin receptor knockout (BIRKO) mice are obese and insulin resistant. They have increased appetite, hyperinsulinemia, hypertrigliceridemia, and decreased responses of neurons to epinephrine. The endothelial cell insulin receptor knockout mice have the normal levels of insulin and glucose in the circulation, and the normal or decreased blood pressure. They look healthy but have decreased level of the vascular endothelial growth factor in blood which may prevent the development of retinopathy as NIDDM complication. PMID: 15945346 [PubMed - indexed for MEDLINE] 3794. Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):65-75. The effect of PPARgamma ligands on the adipose tissue in insulin resistance. Hammarstedt A(1), Andersson CX, Rotter Sopasakis V, Smith U. Author information: (1)The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45, Göteborg, Sweden. Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue. PMID: 15936183 [PubMed - indexed for MEDLINE] 3795. Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):9-15. The adipose organ. Cinti S(1). Author information: (1)University of Ancona, Italy, European Union. cinti@univpm.it In mammals, the adipose tissues are contained in a multi-depot organ: the adipose organ. It consists of several subcutaneous and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while many are white and correspond to white adipose tissue. The organ is rich of vessels and parenchymal nerve fibers, but their density is higher in the brown areas. White areas contain a variable amount of brown adipocytes and their number varies with age, strain and environmental conditions. All adipocytes of the adipose organ express a specific adrenoceptor: ss3AR. Recent data have stressed the plasticity of the adipose organ in adult animals, and in parallel with the cytological variations there are also vascular as well as neural variations. Of note, treatment of genetically and diet induced obese rats with ss3 adrenoceptor agonists ameliorate their pathological condition and this is accompanied by the appearance of brown adipocytes in white areas of the adipose organ. This drug-induced modification of the anatomy of the organ is also obtained by the treatment with PPARgamma agonists in rats and dogs. We have previously shown that the transformation of white adipose tissue into brown adipose tissue in rats treated with ss3 adrenoceptor agonists is due to a direct transformation of differentiated unilocular adipocytes (transdifferentiation). We recently also showed that the absence of ss3 adrenoceptors strongly depress this type of plasticity in the adipose organ. All together these experiments strongly suggest the possibility to modulate the plasticity of the adipose organ with therapeutic implications for obesity and related disorders. PMID: 15936182 [PubMed - indexed for MEDLINE] 3796. Brain Behav Immun. 2005 Sep;19(5):371-6. Muscle-derived interleukin-6--a possible link between skeletal muscle, adipose tissue, liver, and brain. Pedersen BK(1), Febbraio M. Author information: (1)Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Denmark. bkp@rh.dk Accumulating evidence exists that regular exercise offers protection against chronic disorders such as cardiovascular diseases, type 2 diabetes, dementia, and depression. Although acute and chronic exercise has numerous consequences, it is still discussed how contracting skeletal muscles mediate metabolic and physiological effects of benefits on health. For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus,' 'the work factor' or 'the exercise factor.' In other terms, the big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Recently, we identified that muscle fibers produce and release the cytokine IL-6 into the circulation during exercise. We further proposed that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines.' In line with that adipokines have been suggested as a term, which is restricted to cover cytokines and other peptides which are produced and secreted by adipocytes, we suggest that the term "myokines" should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se. Myokines may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments. Here, we review the literature on muscle- and brain-derived IL-6. We further suggest that myokines may also provide an explanation as to how regular muscle activity influences mood, performance, and cognitive function. PMID: 15935612 [PubMed - indexed for MEDLINE] 3797. Expert Opin Ther Targets. 2005 Apr;9(2):245-51. Adiponectin: a key fat-derived molecule regulating inflammation. Tilg H(1), Wolf AM. Author information: (1)Division of Gastroenterology and Hepatology, Department of Medicine, University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. herbert.tilg@uibk.ac.at Adiponectin is the abundant adipocyte-derived protein with well-established anti-atherogenic and insulin-sensitising properties. Besides these well characterised biological functions, recent evidence supports a strong anti-inflammatory function. Whereas initial studies demonstrated that adiponectin suppresses the production of the potent pro-inflammatory cytokine TNF-alpha, current studies showed that this adipokine also induces various anti-inflammatory cytokines, such as IL-10 or -1 receptor antagonists. These effects are paralleled by various other immune-regulatory properties, such as specific effects on endothelial cell functions. These in vitro effects are directly translated into various animal models of inflammation, demonstrating a potent anti-inflammatory effect for adiponectin. Thiazolidinediones selectively upregulate peroxisome-proliferator-activated receptor-gamma, leading to increased tissue and serum concentrations of adiponectin. Adiponectin has emerged as a key mediator regulating and affecting the balance between fat and inflammation. Therefore, either adiponectin itself or its inducing agents, such as thiazolidinediones, might be of key therapeutic interest in the near future far beyond diseases being associated with insulin resistance. PMID: 15934913 [PubMed - indexed for MEDLINE] 3798. Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):440-4. Sympathetic and parasympathetic innervation of adipose tissue: metabolic implications. Romijn JA(1), Fliers E. Author information: (1)Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands. j.a.romijn@lumc.nl PURPOSE OF REVIEW: Adipose tissue is of fundamental importance for the integrative physiology of the body by serving metabolic and endocrine functions. The purpose of this review is to evaluate the functions of the autonomic innervation of adipose tissue. RECENT FINDINGS: Different lines of evidence from studies on the sympathetic or parasympathetic innervation of adipose tissue have indicated that the autonomic nervous system modulates the fundamental properties of adipose tissue function and biology at the cellular and molecular level. This is reflected in the modulation of lipolysis/lipogenesis, local insulin sensitivity of glucose and fatty acid uptake, the expression levels of several adipokines in adipose tissue, and the modulation of fat cell number. In general, the function of the sympathetic nervous system can be described in terms of catabolism, whereas the function of the parasympathetic system can be described as anabolic. SUMMARY: Innervation by autonomic nerves modulates glucose and fat metabolism in adipose tissue. It is very tempting to speculate on the effects of shifts in the balance between sympathetic and parasympathetic activity in adipose tissue in (patho)physiological conditions, such as lipodystrophy, type 2 diabetes mellitus, dyslipidemia and other insulin-resistant states. PMID: 15930971 [PubMed - indexed for MEDLINE] 3799. Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):431-9. Effects of weight loss and calorie restriction on carbohydrate metabolism. Manco M(1), Mingrone G. Author information: (1)Department of Internal Medicine and Clinical Science, Catholic University, Rome, Italy. melania.manco@rm.unicatt.it PURPOSE OF REVIEW: This article provides an overview of the most recent molecular and clinical outcomes of studies that investigate the effect of weight loss and calorie restriction on carbohydrate metabolism, obtained either by dieting or bariatric surgery. It will focus on aspects of carbohydrate metabolism related to insulin action. The discussion begins by describing attempts to restrain calories by shifting the macronutrient balance from carbohydrates to a higher protein and fat content. The topics covered include insulin secretion and resistance, glucose homeostasis and allostasis, changes in the secretive patterns of adipose tissue and the entero-insular axis. RECENT FINDINGS: Any improvement in glucose homeostasis, insulin sensitivity and secretion after a low-carbohydrate high-fat diet is still unproved. However, the restriction of dietary carbohydrate seems to reduce glycogenolysis and endogenous glucose production in type 2 diabetes mellitus, thus inducing the amelioration of plasma glucose levels, ultimately resulting in a reduction in the glycated haemoglobin concentration. The increased endogenous glucose production caused by enhanced gluconeogenesis and glycogenolysis, reduced insulin sensitivity, mainly caused by acquired defects of glucose transport and phosphorylation, and the impairment of insulin secretion all together contribute to maintain a chronic status of hyperglycaemia. Weight loss and calorie restriction restore glucose homeostasis and produce changes in the secretive activities of adipose tissue and the entero-insular axis. SUMMARY: Weight loss and calorie restriction partly explain the positive changes of glucose disposal. The multistep interaction of several factors at sites of insulin action, insulin secretion, adipose tissue and the entero-insular axis needs further investigation. PMID: 15930970 [PubMed - indexed for MEDLINE] 3800. Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):347-54. Role of macrophage tissue infiltration in metabolic diseases. Bouloumié A(1), Curat CA, Sengenès C, Lolmède K, Miranville A, Busse R. Author information: (1)Institute of Cardiovascular Physiology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. bouloumie@zphys1.uni-frankfurt.de PURPOSE OF REVIEW: White adipose tissue is necessary for optimal energy homeostasis and the excessive development of fat mass is clearly associated with the metabolic syndrome. The fact that adipocytes secrete a number of specific factors or 'adipokines' has forced a reassessment of the involvement of adipose tissue in a wide range of physiological and pathophysiological processes. Obesity has recently been described as a 'low-grade' inflammatory condition, a state proposed to represent a common determinator in the genesis of obesity-associated pathologies, i.e. diabetes and atherosclerosis. RECENT FINDINGS: Recent reports of an increase in the number of macrophages that infiltrate the fat mass in obese individuals led to the suggestion that adipose tissue itself is a source and site of inflammation. SUMMARY: This review summarizes recent data on the characterization of the macrophage population in fat tissue. Their origin, fate and activation will be considered. The potential involvement of adipose tissue macrophages in the development of insulin resistance and vascular pathologies, as well as in the control of adipose tissue growth and metabolism, will be examined. PMID: 15930956 [PubMed - indexed for MEDLINE] 3801. Domest Anim Endocrinol. 2005 Jul;29(1):186-92. Epub 2005 Apr 7. Leptin: a metabolic signal affecting central regulation of reproduction in the pig. Barb CR(1), Hausman GJ, Czaja K. Author information: (1)USDA/ARS, Animal Physiology Research Unit, Russell Research Center, P.O. Box 5677, Athens, GA 30604, USA. rbarb@saa.ars.usda.gov The discovery of the obesity gene and its product, leptin, it is now possible to examine the relationship between body fat and the neuroendocrine axis. A minimum percentage of body fat may be linked to onset of puberty and weaning-to-estrus interval in the pig. Adipose tissue is no longer considered as only a depot to store excess energy in the form of fat. Recent findings demonstrate that numerous genes, i.e., relaxin, interleukins and other cytokines and biologically active substances such as leptin, insulin-like growth factor-I (IGF-I), IGF-II and Agouti protein are produced by porcine adipose tissue, which could have a profound effect on appetite and the reproductive axis. Hypothalamic neurons are transsynaptically connected to porcine adipose tissue and may regulate adipose tissue function. In the pig nutritional signals such as leptin are detected by the central nervous system (CNS) and translated by the neuroendocrine system into signals, which regulate appetite, hypothalamic gonadotropin-releasing hormone (GnRH) release and subsequent luteinizing hormone (LH) secretion. Furthermore, leptin directly affects LH secretion from the pituitary gland independent of CNS input. Changes in body weight or nutritional status are characterized by altered adipocyte function a reduction in adipose tissue leptin expression, serum leptin concentrations and a concurrent decrease in LH secretion. During pubertal development serum leptin levels, hypothalamic leptin receptor mRNA and estrogen-induced leptin gene expression in fat increased with age and adiposity in the pig and this occurred at the time of expected puberty. In the lactating sow serum and milk leptin concentrations were positively correlated with backfat thickness and level of dietary energy fed during gestation as well as feed consumption. Although, these results identify leptin as a putative signal that links metabolic status and neuroendocrine control of reproduction, other adipocyte protein products may play an important role in regulating the reproductive axis in the pig. PMID: 15927773 [PubMed - indexed for MEDLINE] 3802. Domest Anim Endocrinol. 2005 Jul;29(1):78-87. Epub 2005 Feb 23. Potential involvement of mammalian and avian uncoupling proteins in the thermogenic effect of thyroid hormones. Collin A(1), Cassy S, Buyse J, Decuypere E, Damon M. Author information: (1)Unité de Recherches Avicoles, Institut National de la Recherche Agronomique, 37380 Nouzilly, France. collin@tours.inra.fr Thyroid hormones (THs) have long been known to be involved in the control of thermoregulation in birds and mammals. In particular, they are reported to play a role in the regulation of heat production. The underlying mechanisms could be the stimulation of the nuclear and mitochondrial transcription of several genes involved in energy metabolism and/or a direct action on the activity of components of the mitochondrial respiratory chain. Attention has recently been focussed on a subfamily of mitochondrial anion carriers called uncoupling proteins (UCPs). These proteins are suspected to be involved in a partial dissipation of the mitochondrial proton electrochemical gradient that would uncouple phosphorylations from oxidations and hence produce heat. However, the involvement of uncoupling mechanisms in thermogenesis and particularly in the thermogenic effect of TH is still unclear. The thermogenic role of UCP1, specifically expressed in brown adipose tissue, and its regulation by TH in rodents is quite well recognised, but the involvement in heat production of its mammalian homologues UCP2, ubiquitously expressed, and UCP3, muscle and adipose tissue-specific, as well as the role of the muscular avian UCP (avUCP), are to be further investigated. The expression of the UCP2 and UCP3 genes was shown to be enhanced by TH in muscle of several rodent species, and to be increased in situations where thermogenesis is stimulated, whereas results are more contrasted in pig. There is now increasing evidence that the physiological role of the mammalian UCP3 and UCP2 is rather related to lipid oxidation and/or prevention of reactive oxygen species accumulation than to heat production by uncoupling. The expression of avUCP was also recently demonstrated to be strongly regulated by thyroid status in chicken, and overexpressed in experimental conditions favouring high triiodothyronine concentrations and thermogenesis. However, its real uncoupling activity and contribution to thermogenesis remain to be established. PMID: 15927767 [PubMed - indexed for MEDLINE] 3803. Int J Obes (Lond). 2005 Sep;29(9):1011-29. Health consequences of obesity in the elderly: a review of four unresolved questions. Zamboni M(1), Mazzali G, Zoico E, Harris TB, Meigs JB, Di Francesco V, Fantin F, Bissoli L, Bosello O. Author information: (1)Division of Geriatric Medicine, University of Verona, Verona, Italy. mauro.zamboni@univr.it Obesity prevalence is growing progressively even among older age groups. Controversy exists about the potential harms of obesity in the elderly. Debate persists about the relation between obesity in old age and total or disease-specific mortality, the definition of obesity in the elderly, its clinical relevance, and about the need for its treatment. Knowledge of age-related body composition and fat distribution changes will help us to better understand the relationships between obesity, morbidity and mortality in the elderly. Review of the literature supports that central fat and relative loss of fat-free mass may become relatively more important than BMI in determining the health risk associated with obesity in older ages. Weight gain or fat redistribution in older age may still confer adverse health risks (for earlier mortality, comorbidities conferring independent adverse health risks, or for functional decline). Evaluation of comorbidity and weight history should be performed in the elderly in order to generate a comprehensive assessment of the potential adverse health effects of overweight or obesity. The risks of obesity in the elderly have been underestimated by a number of confounders such as survival effect, competing mortalities, relatively shortened life expectancy in older persons, smoking, weight change and unintentional weight loss. Identification of elderly subjects with sarcopenic obesity is probably clinically relevant, but the definition of sarcopenic obesity, the benefits of its clinical identification, as well as its relation to clinical consequences require further study. Studies on the effect of voluntary weight loss in the elderly are scarce, but they suggest that even small amounts of weight loss (between 5-10% of initial body weight) may be beneficial. In older as well as in younger adults, voluntary weight loss may help to prevent the adverse health consequences of obesity. PMID: 15925957 [PubMed - indexed for MEDLINE] 3804. Arch Med Res. 2005 May-Jun;36(3):232-40. Regulation of plasma triglycerides in insulin resistance and diabetes. Ginsberg HN(1), Zhang YL, Hernandez-Ono A. Author information: (1)College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. hng1@columbia.edu Increased plasma levels of triglycerides (TG) in very low density lipoproteins (VLDL) are not only common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus (T2DM) but are the central pathophysiologic feature of the abnormal lipid profile. Overproduction of VLDL leads to increased plasma levels of TG which, via an exchange process mediated by cholesterol ester transfer protein (CETP), results in low levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I, and the generation of small, dense, cholesterol ester depleted low density lipoproteins (LDL). Increased assembly and secretion of VLDL by the liver results from the complex, post-transcriptional regulation of apolipoprotein B (apoB) metabolism in the liver. In the presence of low levels of hepatic TG and cholesterol, much of the constitutively synthesized apoB is degraded by both proteasomal and non-proteasomal pathways. When excess TG, and to a lesser extent, cholesterol, are present, and in the presence of active microsomal triglycerides transfer protein, apoB is targeted for secretion. The major sources of TG in the liver: uptake of fatty acids (FA) released by lipolysis of adipose tissue TG, uptake of TGFA in VLDL and chylomicrons remnants, and hepatic de novo lipogenesis (the synthesis of FA from glucose) are all abnormally increased in insulin resistance. Treatment of the dyslipidemia in insulin resistant individuals and patients with T2DM has been successful in reducing cardiovascular disease; LDL cholesterol, TG, and HDL cholesterol are all appropriate targets for therapy when diet, exercise, and weight loss do not achieve goals. PMID: 15925013 [PubMed - indexed for MEDLINE] 3805. Cell Mol Life Sci. 2005 Jun;62(12):1359-62. Newly discovered endocrine functions of white adipose tissue: possible relevance in obesity-related diseases. Krug AW(1), Ehrhart-Bornstein M. Author information: (1)Department of Medicine, Carl Gustav Carus University Hospital, University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany. During recent years our view of adipose tissue has been revolutionized. White adipose tissue (WAT) is no longer seen as mere energy store or provider of thermal and mechanical insulation. Neglect of WAT has been overcome by surprising discoveries in recent years, changing the view of this tissue towards a highly endocrine organ that is involved in a wide variety of physiological and pathophysiological processes. In this brief article we will focus on new developments in adipocyte and WAT biology. The appreciation of WAT as an endocrine organ will provide the basis for new and promising perspectives in the management of obesity and obesity-related diseases including diabetes, mellitus type II and arterial hypertension. PMID: 15924267 [PubMed - indexed for MEDLINE] 3806. Circ Res. 2005 May 27;96(10):1042-52. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Yu YH(1), Ginsberg HN. Author information: (1)Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. hng1@columbia.edu For many years adipose tissue was viewed as the site where excess energy was stored, in the form of triglycerides (TGs), and where that energy, when needed elsewhere in the body, was released in the form of fatty acids (FAs). Recently, it has become clear that when the regulation of the storage and release of energy by adipose tissue is impaired, plasma FA levels become elevated and excessive metabolism of FA, including storage of TGs, occurs in nonadipose tissues. Most recently, work by several laboratories has made it clear that in addition to FA, adipose tissue communicates with the rest of the body by synthesizing and releasing a host of secreted molecules, collectively designated as adipokines. Several recent reviews have described how these molecules, along with FA, significantly effect total body glucose metabolism and insulin sensitivity. Relatively little attention has been paid to the effects of adipokines on lipid metabolism. In this review, we will describe, in detail, the effects of molecules secreted by adipose tissue, including FA, leptin, adiponectin, resistin, TNF-alpha, IL-6, and apolipoproteins, on lipid homeostasis in several nonadipose tissues, including liver, skeletal muscle, and pancreatic beta cells. PMID: 15920027 [PubMed - indexed for MEDLINE] 3807. Crit Rev Biochem Mol Biol. 2005 May-Jun;40(3):129-54. Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C. Chakravarty K(1), Cassuto H, Reshef L, Hanson RW. Author information: (1)Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4935, USA. Transcription of the gene for PEPCK-C occurs in a number of mammalian tissues, with highest expression occurring in the liver, kidney cortex, and white and brown adipose tissue. Several hormones and other factors, including glucagon, epinephrine, insulin, glucocorticoids and metabolic acidosis, control this process in three responsive tissues, liver, adipose tissue, and kidney cortex. Expression of the gene in these three tissues in regulated in a different manner, responding to the specific physiological role of the tissue. The PEPCK-C gene promoter has been extensively studied and a number of regulatory regions identified that bind key transcription factors and render the gene responsive to hormonal and dietary stimuli. This review will focus on the control of transcription for the gene, with special emphasis on our current understanding of the transcription factors that are involved in the response of PEPCK-C gene in specific tissues. We have also reviewed the biological function of PEPCK-C in each of the tissues discussed in this review, in order to place the control of PEPCK-C gene transcription in the appropriate physiological context. Because of its extraordinary importance in mammalian metabolism and its broad pattern of tissue-specific expression, the PEPCK-C gene has become a model for studying the biological basis of the control of gene transcription. PMID: 15917397 [PubMed - indexed for MEDLINE] 3808. J Surg Res. 2005 Jun 1;126(1):121-9. Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. Kougias P(1), Chai H, Lin PH, Yao Q, Lumsden AB, Chen C. Author information: (1)Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. Adipose tissue has recently emerged as an active endocrine organ that secretes a variety of metabolically important substances, collectively called adipocytokines or adipokines. In this review we summarize the effects of the adipokines leptin, adiponectin, and resistin on the vasculature and their potential role for pathogenesis of vascular disease. Leptin is associated with arterial wall thickness, decreased vessel distensibility, and elevated C reactive protein (CRP) levels. Leptin possesses procoagulant and antifibrinolytic properties, and it promotes thrombus and atheroma formation, probably through the leptin receptors by promoting vascular inflammation, proliferation, and calcification, and by increasing oxidative stress. Research for development of pharmacologic antagonism for the leptin receptor is currently under way. Adiponectin inhibits the expression of the adhesion molecules ICAM-1, VCAM-1, and P selectin. Therefore, it interferes with monocyte adherence to endothelial cells and their subsequent migration to the subendothelial space, one of the initial events in the development of atherosclerosis. Adiponectin also inhibits the transformation of macrophages to foam cells in vitro and decreases their phagocytic activity. Resistin, discovered in 2001, represents the newest of the adipokines and was named for its ability to promote insulin resistance. Resistin increases the expression of the adhesion molecules VCAM-1 and ICAM-1, up-regulates the monocyte chemoattractant chemokine-1, and promotes endothelial cell activation via ET-1 release. Although many aspects of its function need further clarification, it appears that resistin will add significantly to our knowledge of the pathophysiology of vascular disease and the metabolic syndrome. PMID: 15916985 [PubMed - indexed for MEDLINE] 3809. Eur J Hum Genet. 2005 Sep;13(9):1033-9. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Geneviève D(1), Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P, Boustani-Samara D, Pinto G, Ozilou C, Abeguilé G, Munnich A, Romana S, Raoul O, Cormier-Daire V, Vekemans M. Author information: (1)Département de Génétique, Hôpital Necker Enfants Malades, Paris, France. gendav@club-internet.fr Deletions of the long arm of chromosome 20 are rare. Here, we report on two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and post-natal growth retardation, intractable feeding difficulties, abnormal subcutaneous adipose tissue, similar facial dysmorphism, psychomotor retardation and hypotonia. Standard cytogenetic studies were normal, but high-resolution chromosomes analysis showed the presence of a chromosome (20)(q13.2-q13.3) interstitial deletion. Karyotypes of both parents were normal. Molecular studies using FISH and microsatellite polymorphic markers showed that the deletion was of paternal origin and was approximatively 4.5 Mb in size. A review of other reported patients with similar deletions of the long arm of chromosome 20 shows that the observed phenotype might be explained in the light of the GNAS imprinted locus in particular by the absence of the Gnasxl paternally imprinted gene and the TFA2PC gene in the deleted genetic interval. PMID: 15915160 [PubMed - indexed for MEDLINE] 3810. Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):59-63. LXR is crucial in lipid metabolism. Ulven SM(1), Dalen KT, Gustafsson JA, Nebb HI. Author information: (1)Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046 Blindern, N-0316 Oslo, Norway. Liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily and are activated by oxysterols and intermediates in the cholesterol synthetic pathway. The pivotal role of LXRs in the metabolic conversion of cholesterol to bile acids is well established. Analysis of gene expression in LXRalpha and LXRbeta deficient mice have confirmed that LXR regulates a number of target genes involved in both cholesterol and fatty acid metabolism in liver, macrophages and intestine. The observation that LXRalpha is responsive to fatty acids and is expressed in metabolic tissues suggests that it also plays a general role in lipid metabolism. Adipose tissue is the main storage site for fat in the body and plays a crucial role in overall lipid handling. Both LXRalpha and LXRbeta are expressed and activated by endogenous and synthetic ligands, which lead to lipid accumulation into adipocytes. This indicates an important regulatory role of LXR in several metabolic signaling pathways in the adipose tissue, such as glucose uptake and de novo fatty acid synthesis. Here, we review recent studies that provide new insights into the mechanisms by which LXRs act to influence fatty acid synthesis in liver and adipose tissue. PMID: 15913974 [PubMed - indexed for MEDLINE] 3811. Orthopade. 2005 Jul;34(7):645-51. [Obesity and osteoporosis]. [Article in German] Friebe H(1), Peters A. Author information: (1)Reha-Klinik Aukammtal, Wiesbaden. h.friebe@rmkliniken.de Atherosclerosis is a chronic inflammatory disease associated with an elevation of inflammatory markers such as CRP -- a robust predictor of cardiovascular events. Inflammation also plays a pivotal role in the pathogenesis of osteoporosis. IL-6 proved to be the most important predictor of bone loss in the proximal femur. Adipocyte-produced inflammatory cytokines are the pathogenetic link between obesity and its metabolic consequences. The different components of the metabolic syndrome are at the same time well-established risk factors for osteoporosis. Physical training, weight loss, and a Mediterranean-style diet all have a proven cytokine-lowering effect. Contrary to muscle mass, adipose tissue if at all contributes only marginally to the preservation of bone. As a consequence, increasing lean body mass while reducing fat mass seems to be the most effective way to prevent both atherosclerosis and osteoporosis. PMID: 15912326 [PubMed - indexed for MEDLINE] 3812. Diabet Med. 2005 Jun;22(6):674-82. Molecular mechanisms of insulin resistance. Schinner S(1), Scherbaum WA, Bornstein SR, Barthel A. Author information: (1)Klinik für Endokrinologie, Diabetologie und Rheumatologie, Universitäts Klinikum Düsseldorf, Düsseldorf, Germany. Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with Type 2 diabetes the resistance of fat, muscle and liver to insulin is the central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and Type 2 diabetes is still largely unknown. However, recent studies have contributed to a deeper understanding of the molecular mechanisms underlying this process. In this review we therefore summarize the current developments in understanding the pathophysiological process of insulin resistance and Type 2 diabetes. Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)-2, the protein kinase B (PKB)-beta isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in-vivo. Furthermore, we have now increasing evidence that the adipose tissue not only produces free fatty acids that contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. The identification of the molecular pathophysiological mechanisms of insulin resistance and Type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and Type 2 diabetes. PMID: 15910615 [PubMed - indexed for MEDLINE] 3813. Physiol Res. 2006;55(2):115-22. Epub 2005 May 24. PPAR-alpha and insulin sensitivity. Haluzík MM(1), Haluzík M. Author information: (1)Third Department of Medicine, First Faculty of Medicine, Charles University and University Hospital, U nemocnice 1, 128 08, Praha 2, Czech Republic. mhalu@lf1.cuni.cz Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear receptor superfamily of ligand-activated transcription factors. PPAR-alpha, first of its three subtypes (alpha, beta, gamma) has traditionally been considered an important regulator of lipid metabolism while its role in the regulation of insulin sensitivity has not been recognized until recently. Here we summarize the experimental and clinical studies focusing on the role of PPAR- alpha in the regulation of insulin sensitivity. In most of the experimental studies the activation of PPAR-alpha in rodents leads to improvement of insulin sensitivity by multiple mechanisms including improvement of insulin signaling due to a decrease of ectopic lipids in non-adipose tissues and decrease of circulating fatty acids and triglycerides. In contrast, the effect of PPAR-alpha agonist in humans is much less pronounced probably due to a lower expression of PPAR-alpha relative to rodents and possibly other mechanisms. Further clinical studies using more potent PPAR-alpha agonists on a larger population need to be performed to evaluate the possible role of PPAR- alpha in the regulation of insulin sensitivity in humans. PMID: 15910175 [PubMed - indexed for MEDLINE] 3814. Nutr Neurosci. 2005 Feb;8(1):7-20. The brain-adipose axis: a review of involvement of molecules. Shimizu H(1), Mori M. Author information: (1)Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. Many molecules are involved in the regulation of feeding behavior, and they and their receptors are located in the brain hypothalamus and adipocytes. On the basis of evidence suggesting an association between the brain and adipose tissue, we propose the concept of the brain-adipose axis. This model consists of (l) the expression of endogenous molecules and/or their receptors in the hypothalamus and peripheral adipose tissue, (2) the function of these molecules as appetite regulators in the brain, (3) their existence in the general circulation as secreted proteins and (4) the physiological affects of these molecules on fat cell size and number. These molecules can be divided into two anorexigenic and orexigenic classes. In adipose tissue, all orexigenic molecules possess adipogenic activity, and almost all anorexigenic molecules suppress fat cell proliferation. Although the manner, in which they present in the circulating blood connect the brain and peripheral adipocytes, remains to be well-organized, these observations suggest the positive feedback axis affecting molecules in the hypothalamus and adipose tissue. Analysis of the disturbance and dysregulation of this axis might promote the development of new anti-obesity drugs useful in treating the metabolic syndrome. PMID: 15909763 [PubMed - indexed for MEDLINE] 3815. Nutr Neurosci. 2005 Feb;8(1):1-5. Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity. Popovic V(1), Duntas LH. Author information: (1)Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center, Belgrade, Serbia, Yugoslavia. popver@eunet.yu Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways. PMID: 15909762 [PubMed - indexed for MEDLINE] 3816. Ann Plast Surg. 2005 Jun;54(6):651-6. The cellular plasticity of human adipocytes. Tholpady SS(1), Aojanepong C, Llull R, Jeong JH, Mason AC, Futrell JW, Ogle RC, Katz AJ. Author information: (1)Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA. Little is known regarding the biology of fat considering its extensive use clinically in soft tissue implantation. Free-fat transfer is problematic the result of graft site volume loss, appearing histologically as the replacement of mature adipocytes with a fibroblast-like infiltrate. We hypothesize that these histologic changes reflect a dedifferentiation of ischemic mature adipocytes instead of, or in addition to, a more traditional response. To explore this hypothesis, we studied the in vitro morphologic changes of cultured mature human adipocytes isolated from liposuctioned adipose tissue. Most adipocytes over time lost significant amounts of intracellular lipid. Ultimately, these cells lost all lipid, appeared fibroblastic, and proliferated to confluence. Adipogenic induction of such dedifferentiated adipocytes resulted in reaccumulation of intracellular lipid. This study demonstrates that mature adipocytes can be cultured from human liposuctioned fat, they can dedifferentiate into fibroblastic cells, and the fibroblast-like cells can be expanded and turned into lipid-synthesizing adipocytes. Exploration of this cellular plasticity might ultimately yield important insights into free-fat transfer and novel tissue-engineering strategies. PMID: 15900154 [PubMed - indexed for MEDLINE] 3817. Endocr Rev. 2005 May;26(3):439-51. Adiponectin and adiponectin receptors. Kadowaki T(1), Yamauchi T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kadowaki-3im@h.u-tokyo.ac.jp Metabolic syndrome is thought to result from obesity and obesity-linked insulin resistance. Obesity in adulthood is characterized by adipocyte hypertrophy. Adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active "adipokines."Heterozygous peroxisome proliferator-activated receptor-gamma knockout mice were protected from high-fat diet induced obesity, adipocyte hypertrophy, and insulin resistance. Systematic gene profiling analysis of these mice revealed that adiponectin/Acrp30 was overexpressed. Functional analyses including generation of adiponectin transgenic or knockout mice have revealed that adiponectin serves as an insulin-sensitizing adipokine. In fact, obesity-linked down-regulation of adiponectin was a mechanism whereby obesity could cause insulin resistance and diabetes. Recently, we have cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell-surface receptor family. We showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMP-activated protein kinase, peroxisome proliferator-activated receptor-alpha ligand activities, and glucose uptake and fatty-acid oxidation by adiponectin. Obesity decreased expression levels of AdipoR1/R2, thereby reducing adiponectin sensitivity, which finally leads to insulin resistance, the so-called "vicious cycle." Most recently, we showed that osmotin, which is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists. Adiponectin receptor agonists and adiponectin sensitizers should serve as versatile treatment strategies for obesity-linked diseases such as diabetes and metabolic syndrome. PMID: 15897298 [PubMed - indexed for MEDLINE] 3818. Sports Med. 2005;35(5):393-412. Interactions of metabolic hormones, adipose tissue and exercise. McMurray RG(1), Hackney AC. Author information: (1)University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-8700, USA. exphys@email.unc.edu Physiological and psychological systems work together to determine energy intake and output, and thus maintain adipose tissue. In addition, adipose tissue secretes leptin and cytokines, which induces satiety and has been linked to catecholamines, cortisol, insulin, human growth hormone, thyroid hormones, gonadotropin and lipolysis. Thus, adipose tissue is acted upon by a number of physiological stimuli, including hormones, and simultaneously, is an active component in the regulation of its own lipid content. All of the hormones mentioned above are associated with each other and respond to exercise and exercise training. Thus, exercise is one of the major links between the hormonal modulators of energy intake and output. It appears that the sympathetic nervous system and the catecholamines are key components facilitating the lipolytic activity during exercise. These two neuroendocrine factors directly affect adipose metabolism and metabolic hormones that influence adipose metabolism. Acute low- and moderate-intensity exercise causes hormonal changes that facilitate lipolytic activity. Exercise training reduces these hormonal responses, but the sensitivity to these hormones increases so that lipolysis may be facilitated. Large amounts of adipose tissue blunt the metabolic hormonal responses to exercise, but the sensitivity of these hormones is increased; thus maintaining normal lipolytic activity. Although the physiological role of the endocrine system during exercise and training is significant, other training effects may have as great, or greater influence on lipolytic activity in adipose tissue. PMID: 15896089 [PubMed - indexed for MEDLINE] 3819. Curr Mol Med. 2005 May;5(3):333-9. Insulin resistance in type 2 diabetes -- role of the adipokines. Arner P(1). Author information: (1)Department of Medicine at Karolinska Institutet, SE-141 86 Stockholm, Sweden. peter.arner@medhs.ki.se The role of adipocytes as protein secreting cells has been known for almost 15 years. Most of these proteins have known biological activity and are called adipokines. However, only a few of the adipokines have been shown to regulate insulin sensitivity. The latter effects are direct or indirect. The adipokines regulating insulin sensitivity are tumor necrosis factor alpha, adiponectin, interleukin-6, resistin and leptin. This review examines the mechanism how these adipokines influence insulin sensitivity, how the adipocyte production of the adipokines is regulated and if genetic variance in the genes encoding for adipokines is important for the development of type 2 diabetes mellitus. PMID: 15892652 [PubMed - indexed for MEDLINE] 3820. Curr Mol Med. 2005 May;5(3):297-308. Type 2 diabetes as a lipid disorder. Taskinen MR(1). Author information: (1)Department of Medicine, University of Helsinki, Finland. Marja-Riitta.Taskinen@helsinki.fi Diabetic dyslipidemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The recognition that the elevation of large VLDL 1 particles initiates a sequence of events that leads to the formation of small dense LDL and HDL species has focused the assembly of VLDL particles on the spotlight as a potential culprit of dyslipidemia. Notably dyslipidemia is associated with insulin resistance, visceral obesity and liver fat content. Insulin resistance is associated with excessive flux of substrates for VLDL assembly to the liver as well as the upregulation of the machinery generating large VLDL particles in excess. The regulation of different molecular steps in this cascade of events are complex and so far poorly understood. The disordered crosstalk between adipose tissue and the liver results in an imbalance of the machinery that orchestrates the regulation of VLDL production. A number of studies indicates that adipocytokines in particular adiponectin may be a seminal player in the regulation of fat metabolism in the liver. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidemia. PMID: 15892649 [PubMed - indexed for MEDLINE] 3821. Curr Mol Med. 2005 May;5(3):287-95. The fatty liver and insulin resistance. Yki-Järvinen H(1), Westerbacka J. Author information: (1)Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki Finland. ykijarvi@cc.helsinki.fi Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease. PMID: 15892648 [PubMed - indexed for MEDLINE] 3822. Curr Opin Lipidol. 2005 Jun;16(3):333-40. Lipolysis: pathway under construction. Zechner R(1), Strauss JG, Haemmerle G, Lass A, Zimmermann R. Author information: (1)Institute of Molecular Biosciences, Karl-Franzens University Graz, Graz, Austria. rudolf.zechner@uni-graz.at PURPOSE OF REVIEW: The lipolytic catabolism of stored fat in adipose tissue supplies tissues with fatty acids as metabolites and energy substrates during times of food deprivation. This review focuses on the function of recently discovered enzymes in adipose tissue lipolysis and fatty acid mobilization. RECENT FINDINGS: The characterization of hormone-sensitive lipase-deficient mice provided compelling evidence that hormone-sensitive lipase is not uniquely responsible for the hydrolysis of triacylglycerols and diacylglycerols of stored fat. Recently, three different laboratories independently discovered a novel enzyme that also acts in this capacity. We named the enzyme 'adipose triglyceride lipase' in accordance with its predominant expression in adipose tissue, its high substrate specificity for triacylglycerols, and its function in the lipolytic mobilization of fatty acids. Two other research groups showed that adipose triglyceride lipase (named desnutrin and Ca-independent phospholipase A2zeta, respectively) is regulated by the nutritional status and that it might exert acyl-transacylase activity in addition to its activity as triacylglycerol hydrolase. Adipose triglyceride lipase represents a novel type of 'patatin domain-containing' triacylglycerol hydrolase that is more closely related to plant lipases than to other known mammalian metabolic triacylglycerol hydrolases. SUMMARY: Although the regulation of adipose triglyceride lipase and its physiological function remain to be determined in mouse lines that lack or overexpress the enzyme, present data permit the conclusion that adipose triglyceride lipase is involved in the cellular mobilization of fatty acids, and they require a revision of the concept that hormone-sensitive lipase is the only enzyme involved in the lipolysis of adipose tissue triglycerides. PMID: 15891395 [PubMed - indexed for MEDLINE] 3823. Circ Res. 2005 May 13;96(9):939-49. Adipose tissue, inflammation, and cardiovascular disease. Berg AH(1), Scherer PE. Author information: (1)Department of Cell Biology, Bronx, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Comment in Circ Res. 2006 Mar 17;98(5):e49. Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. Circulating mediators of inflammation participate in the mechanisms of vascular insult and atheromatous change, and many of these inflammatory proteins are secreted directly from adipocytes and adipose tissue-derived macrophages. Several factors linking obesity with an increased cardiovascular risk have been identified. The adipocyte-specific secretory protein adiponectin is a particularly promising candidate in this context. Its levels are decreased in obesity. Adiponectin may mediate some of its demonstrated cardioprotective effects through its anti-inflammatory properties. In addition to decreased expression of beneficial adipokines, secretion of a host of inflammatory factors from visceral adipose tissue may contribute to the increased cardiovascular risk associated with obesity. The cardioprotective effects of many of the most popular drug regimens corroborate these conclusions, demonstrating that along with improvements in other therapeutic end points, they mediate improvements in systemic inflammation. In some cases, these improvements are attributable to direct suppression of inflammatory signaling in adipocytes. The targeted suppression of various proinflammatory cascades in adipocytes specifically represents an exciting new therapeutic opportunity for the cardiovascular disease area. PMID: 15890981 [PubMed - indexed for MEDLINE] 3824. Expert Rev Cardiovasc Ther. 2005 May;3(3):465-71. Adiponectin: linking the metabolic syndrome to its cardiovascular consequences. Rabin KR(1), Kamari Y, Avni I, Grossman E, Sharabi Y. Author information: (1)The C Sheba Medical Center, Tel Hashomer, 52621, Israel. Obesity and its related disorders, glucose intolerance, hypertension and hyperlipidemia, collectively named the metabolic syndrome, result in substantial cardiovascular morbidity and mortality. Recent data point to several underlying regulatory mechanisms through which obesity links these various outcomes. Adipose tissue is now understood to function not merely as a passive energy storage depot but as an active endocrine organ, producing a variety of bioactive substances termed adipocytokines. Adiponectin, an adipocytokine first described as the most abundant protein produced by adipocytes, appears to serve as a central regulatory protein in many of the physiologic pathways controlling lipid and carbohydrate metabolism, and to mediate various vascular processes. Adiponectin displays both anti-inflammatory and antiatherogenic properties. Unlike other adipocytokines, its levels are paradoxically decreased in obesity and insulin-resistance states including metabolic syndrome and diabetes, as well as hypertension and coronary artery disease. This review will detail the relationship of adiponectin to various features of obesity and insulin-resistance syndromes, as well as its relationship to the cardiovascular complications of these disorders. PMID: 15889974 [PubMed - indexed for MEDLINE] 3825. Expert Rev Cardiovasc Ther. 2005 May;3(3):393-404. Adiposopathy, metabolic syndrome, quantum physics, general relativity, chaos and the Theory of Everything. Bays H(1). Author information: (1)L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. HBaysMD@aol.com Excessive fat (adiposity) and dysfunctional fat (adiposopathy) constitute the most common worldwide epidemics of our time -- and perhaps of all time. Ongoing efforts to explain how the micro (adipocyte) and macro (body organ) biologic systems interact through function and dysfunction in promoting Type 2 diabetes mellitus, hypertension and dyslipidemia are not unlike the mechanistic and philosophical thinking processes involved in reconciling the micro (quantum physics) and macro (general relativity) theories in physics. Currently, the term metabolic syndrome refers to a constellation of consequences often associated with excess body fat and is an attempt to unify the associations known to exist between the four fundamental metabolic diseases of obesity, hyperglycemia (including Type 2 diabetes mellitus), hypertension and dyslipidemia. However, the association of adiposity with these metabolic disorders is not absolute and the metabolic syndrome does not describe underlying causality, nor does the metabolic syndrome necessarily reflect any reasonably related pathophysiologic process. Just as with quantum physics, general relativity and the four fundamental forces of the universe, the lack of an adequate unifying theory of micro causality and macro consequence is unsatisfying, and in medicine, impairs the development of agents that may globally improve both obesity and obesity-related metabolic disease. Emerging scientific and clinical evidence strongly supports the novel concept that it is not adiposity alone, but rather it is adiposopathy that is the underlying cause of most cases of Type 2 diabetes mellitus, hypertension and dyslipidemia. Adiposopathy is a plausible Theory of Everything for mankind's greatest metabolic epidemics. PMID: 15889967 [PubMed - indexed for MEDLINE] 3826. Orthod Craniofac Res. 2005 May;8(2):54-9. Stem cells in craniofacial and dental tissue engineering. Risbud MV(1), Shapiro IM. Author information: (1)Graduate Program in Tissue Engineering and Regenerative Medicine, Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA. makarand.risbud@jefferson.edu Mesenchymal stem cells (MSC) have been identified in a variety of adult tissues as a population of pluripotential self-renewing cells. Based on their adherence and colony forming properties, a small number of MSC can be isolated from most mesenchymal tissues as well as bone marrow. In the presence of one or more growth factors, these cells commit to lineages that lead to the formation of bone, cartilage, muscle, tendon and adipose tissue; recent studies indicate that stem cells for cementum, dentine and the periodontal ligament also exist. All of these cells can be expanded in vitro, and, embedded in a scaffold, inserted into defects to promote healing and tissue replacement. Increased understanding of the molecular mechanism directing lineage specification and morphogenesis is providing a rational approach for the regeneration of craniofacial tissues and oral structures. PMID: 15888117 [PubMed - indexed for MEDLINE] 3827. Med Sci (Paris). 2005 May;21(5):507-11. [A role of PPARgamma in reproduction?]. [Article in French] Froment P(1), Gizard F, Staels B, Dupont J, Monget P. Author information: (1)LMBC, Department for Molecular Biomedical Research, VIB, Technologiepark 927, B-9052 Gand (Zwijnaarde), Belgique. pascalf@dmbr.ugent.be Synthetic molecules of the glitazone family are currently used in the treatment of type II diabetes. Glitazones also improve secondary pathologies that are frequently associated with insulin resistance such as the polycystic ovary syndrome (PCOS). Glitazones bind to the peroxysome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor which is highly expressed in adipose tissue. PPARgamma also binds natural ligands such as long-chain fatty acids. Recently, several groups have shown that PPARgamma is also highly expressed in ovarian granulosa cells, and that glitazones are able to modulate in vitro granulosa cell proliferation and steroidogenesis in several species. These recent data raise new questions concerning the underlying mechanism of the effect of glitazones on PCOS. One might hypothesize, as for other << glucophage >> molecules such as metformin, that it is the general improvement of glucose metabolism and insulin sensitivity by glitazones which indirectly, and via an unknown mechanism, ameliorates ovarian functionality. The data discussed here suggest now an alternative possibility, that glitazones act directly at the ovarian level. Moreover, PPARgamma also seems to play a key role in the maturation of the placenta. In particular, inactivation of PPARgamma in mice is lethal, since the foetus is unable to develop because of alterations of placental maturation. In women, the activation of PPARgamma in placenta leads to an increase of placental hormone secretion. Overall, these results raise some questions about the role of natural ligands of PPARgamma such as long chain fatty acids on female fertility and the interactions between energy metabolism and reproduction in general. PMID: 15885201 [PubMed - indexed for MEDLINE] 3828. Am J Hypertens. 2005 May;18(5 Pt 1):731-7. The association of heart failure with insulin resistance and the development of type 2 diabetes. Kostis JB(1), Sanders M. Author information: (1)Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903-0019, USA. kostis@umdnj.edu Heart failure (HF) is associated with a significant risk for either concurrently having diabetes or subsequently developing diabetes. Medications that block the sympathetic nervous system (SNS) have been shown to improve clinical outcomes in patients with chronic HF but may be associated with the development of new-onset diabetes. Depending on the receptor specificity of the individual agent, beta-blockers have different effects on glucose and lipid metabolism as well as on the risk for developing new-onset diabetes. Although SNS modulation with beta-blockade reduces mortality in patients with chronic HF, certain beta-blockers may actually worsen glucose and lipid metabolism and increase the risk for new-onset diabetes. The use of vasodilating beta-blockers, on the other hand, has not produced these harmful metabolic effects. PMID: 15882558 [PubMed - indexed for MEDLINE] 3829. Med Clin (Barc). 2005 May 7;124(17):668-77. [Pathogenesis of primary nonalcoholic fatty liver disease]. [Article in Spanish] Moreno Sánchez D(1). Author information: (1)Sección de Aparato Digestivo, Hospital General de Móstoles, Móstoles, Madrid, España. dmorenosanchez@sepd.es The challenges of growing prevalence and evident trend to progressive damage of primary nonalcoholic fatty liver disease confront a poorly understood pathogenesis. It appears to develop in two steps. First, a high adipocyte protein production in the context of a silent inflammatory background causes insulin resistance in adipose tissue. It leads both to lipolysis, with increase of the circulating and hepatic uptake of free fatty acids, and hyperinsulinemia. Within hepatocytes, the subsequent lipogenesis, together with a decreased secretion of lipoproteins, induces an accumulation of excessive hepatic triglycerides (steatosis), impliying some oxidative damage, but it remain balanced by uncoupling protein upregulation and antioxidant systems activation. Second, a more forceful fat catabolism by beta and omega oxidation results in respiratory chain hyperactivity with overproduction of free radicals and reactive oxygen species that exceed the antioxidant capacity. These agents lead to hepatocellular injury and necrosis, inflammatory infiltration and fibrosis (steatohepatitis) through induction of Fas ligand and cytokines (tumor necrosis factor alpha, transforming growth factor beta, interleukin-8), and lipid peroxidation and by-products (malondialdehyde and 4-hydroxynonenal). Other mechanisms (hepatic iron, Kupffer cells dysfunction or endotoxemia) play uncertain roles. PMID: 15882516 [PubMed - indexed for MEDLINE] 3830. J Am Board Fam Pract. 2005 May-Jun;18(3):205-10. Dietary calcium intake and obesity. Schrager S(1). Author information: (1)Department of Family Medicine, University of Wisconsin-Madison, Madison, WI 53715, USA. sbschrag@wisc.edu Obesity is increasing in the United States in epidemic proportions. Epidemiologic data suggest that people with high calcium intake have a lower prevalence of overweight, obesity, and insulin resistance syndrome. Studies in transgenic mice have demonstrated that calcium influences adipocyte metabolism. High calcium intake depresses levels of parathyroid hormone and 1,25-hydroxy vitamin D. These decreased hormone levels cause decreases in intracellular calcium, thereby inhibiting lipogenesis and stimulating lipolysis. High dietary calcium intakes also increases excretion of fecal fat and may increase core body temperature. Calcium from dairy products seems to have more of an impact than calcium from dietary supplements. Primary care providers should include recommendations about adequate calcium intake in standard dietary counseling about weight management. PMID: 15879568 [PubMed - indexed for MEDLINE] 3831. Proc Nutr Soc. 2005 Feb;64(1):53-64. Brain-adipose tissue cross talk. Bartness TJ(1), Kay Song C, Shi H, Bowers RR, Foster MT. Author information: (1)Department of Biology, Neurobiology & Behavior Program, Center for Behavioral Neuroscience, Georgia State University, Atlanta, 30302-4010, USA. bartness@gsu.edu While investigating the reversible seasonal obesity of Siberian hamsters, direct sympathetic nervous system (SNS) postganglionic innervation of white adipose tissue (WAT) has been demonstrated using anterograde and retrograde tract tracers. The primary function of this innervation is lipid mobilization. The brain SNS outflow to WAT has been defined using the pseudorabies virus (PRV), a retrograde transneuronal tract tracer. These PRV-labelled SNS outflow neurons are extensively co-localized with melanocortin-4 receptor mRNA, which, combined with functional data, suggests their involvement in lipolysis. The SNS innervation of WAT also regulates fat cell number, as noradrenaline inhibits and WAT denervation stimulates fat cell proliferation in vitro and in vivo respectively. The sensory innervation of WAT has been demonstrated by retrograde tract tracing, electrophysiological recording and labelling of the sensory-associated neuropeptide calcitonin gene-related peptide in WAT. Local injections of the sensory nerve neurotoxin capsaicin into WAT selectively destroy this innervation. Just as surgical removal of WAT pads triggers compensatory increases in lipid accretion by non-excised WAT depots, capsaicin-induced sensory denervation triggers increases in lipid accretion of non-capsaicin-injected WAT depots, suggesting that these nerves convey information about body fat levels to the brain. Finally, parasympathetic nervous system innervation of WAT has been suggested, but the recent finding of no WAT immunoreactivity for the possible parasympathetic marker vesicular acetylcholine transporter (VAChT) argues against this claim. Collectively, these data suggest several roles for efferent and afferent neural innervation of WAT in body fat regulation. PMID: 15877923 [PubMed - indexed for MEDLINE] 3832. Proc Nutr Soc. 2005 Feb;64(1):47-52. Respiration uncoupling and metabolism in the control of energy expenditure. Ricquier D(1). Author information: (1)Centre National de la Recherche Scientifique Unit 9078, Faculty of Medicine Necker-Enfants Malades, Paris, France. Metabolic energy expenditure negatively regulates energy balance. Metabolic and catabolic pathways contribute to energy expenditure. Catabolic pathways split C-containing molecules into small molecules and generate reduced coenzymes and ATP. For a given amount of substrate, any increase in energy expenditure requires either increased ATP hydrolysis or decreased ATP synthesis. In skeletal muscles substrate utilisation is coupled to ATP production, whereas ATP hydrolysis is activated during physical exercise and increases energy expenditure. In brown adipose tissue activation of cells during exposure to cold increases substrate utilisation in such a way that glucose and fatty acid oxidation detach from the orthodox coupling to ATP synthesis and result in thermogenesis. The unique mechanism of uncoupling respiration that occurs in brown adipocyte mitochondria represents an attractive strategy for promoting energy expenditure and decreasing the fat content of the body. Moreover, ectopic expression of brown fat uncoupling protein (UCP) 1 in mouse skeletal muscle and induction of UCP1 in mouse or human white adipocytes promote fatty acid oxidation and resistance to obesity. In normal conditions UCP2 and UCP3 do not seem to contribute substantially to energy expenditure. Whether the induction of UCP1, the induction of other UCP or chemical mild uncoupling represent promising strategies for attenuating nutrient efficiency and counteracting obesity should be considered. PMID: 15877922 [PubMed - indexed for MEDLINE] 3833. Proc Nutr Soc. 2005 Feb;64(1):39-46. Central regulation of energy balance: inputs, outputs and leptin resistance. Arch JR(1). Author information: (1)Clore Laboratory, University of Buckingham, UK. jon.arch@buckingham.ac.uk The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects. PMID: 15877921 [PubMed - indexed for MEDLINE] 3834. Proc Nutr Soc. 2005 Feb;64(1):15-22. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Singhal A(1). Author information: (1)MRC Childhood Nutrition Research Centre, Institute of Child Health, London, UK. a.singhal@ich.ucl.ac.uk Atherosclerotic CVD is the most common cause of death in the West. Yet, its pathogenesis and early development are only partially understood. Central to the early atherosclerotic process is impairment of vascular endothelial function. Endothelial dysfunction can be measured non-invasively and is evident in children before clinical manifestations of atherosclerosis in adulthood. Factors in early life, such as conventional cardiovascular risk factors, or programming by perinatal growth and nutrition strongly affect endothelial function and hence the development of atherosclerosis and CVD. For instance, low birth weight and faster growth early in infancy have a detrimental effect on vascular structure and function. Childhood obesity, a key independent risk factor for CVD, also adversely affects early vascular health. Obesity is associated with endothelial dysfunction and greater arterial stiffness from as early as the first decade of life, while weight loss is beneficial. This effect on vascular function is probably mediated in part by low-grade inflammation and insulin resistance associated with obesity or by the production by adipose tissue of cytokine-like molecules, collectively termed adipokines. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis. The present review focuses on the early origins of endothelial dysfunction, emphasising the role of obesity. It also considers the mechanisms by which obesity impairs endothelial function, understanding of which will be important to further scientific knowledge and to improve public health. PMID: 15877918 [PubMed - indexed for MEDLINE] 3835. Proc Nutr Soc. 2005 Feb;64(1):7-13. Obesity and metabolic disease: is adipose tissue the culprit? Frayn KN(1). Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK. keith.frayn@oxlip.ox.ac.uk Obesity is a risk factor for the development of type 2 diabetes and CVD. Is adipose tissue the culprit in the relationship between obesity and metabolic disease? It is certainly possible to argue that adipose tissue function is disturbed in obesity in such a way that adverse consequences may follow. For instance, lipolysis is down regulated, the sensitivity of lipolysis to insulin is reduced and there are disturbances in the regulation of adipose tissue blood flow. However, when examined critically these changes can be seen as adaptations to the increased adipose tissue mass, making the situation better rather than worse. In terms of the many peptide and other factors now known to be secreted from adipose tissue, it is easier to argue that adipose tissue is the culprit. However, for no single 'adipokine' is there as yet unequivocal evidence of a link between adipose tissue secretion and adverse metabolic events in other tissues. The best documented of these adipokines in relation to insulin resistance is adiponectin. Here, unusually, adiponectin confers insulin sensitivity, and its secretion is down regulated in obesity. It could be again that adipose tissue has down regulated its function in an attempt to compensate for its increased mass, although certainly that down-regulation is too extreme. On balance, it is clear that adipose tissue is a link in the chain of events leading to metabolic disease, but in many respects it is an innocent intermediary trying to deal with the consequences of positive energy balance, the real culprit. PMID: 15877917 [PubMed - indexed for MEDLINE] 3836. Br J Nutr. 2005 Apr;93 Suppl 1:S163-8. Effects of inulin-type fructans on lipid metabolism in man and in animal models. Beylot M(1). Author information: (1)Inserm U 499, Faculté RTH Laennec, Lyon, France. beylot@laennec.univ-lyon1.fr Studies in rodents show that inulin and oligofructose can reduce the plasma levels of cholesterol and triacylglycerols (TG). In addition, they can oppose TG accumulation in liver and have favourable effects on hepatic steatosis. The hypotriglyceridaemic effect is due to a reduction in hepatic re-esterification of fatty acids, but mainly in the expression and activity of liver lipogenesis, resulting in lower hepatic secretion rate of TG. This repression of lipogenesis is not observed in adipose tissue. The effect on liver lipogenesis can be explained by reduced insulin/glucose levels or by a selective exposure of the liver to increased amounts of propionic acid produced in the large intestine during fermentation of non-digestible carbohydrates. The decrease in plasma cholesterol could also be due to inhibition of cholesterol synthesis by propionic acid or to modifications in the bile acid metabolism. Studies in man yield more conflicting results with a decrease or no effects on plasma lipid levels, and, when a decrease is observed, more marked effects on TG than on cholesterol and more consistent action of inulin than of oligofructose. Besides the difference in the dose of inulin or oligofructose used, differences in metabolic status could play a role in this discrepancy between man and animals since reduction in plasma TG is observed in man mainly in a situation of increased liver lipogenesis (high-carbohydrate diet, obesity, hypertriglyceridaemia). The effects on plasma cholesterol appear also more marked in hyperlipidaemic subjects than in healthy controls, suggesting that inulin and oligofructose have beneficial effects in these types of subjects. PMID: 15877890 [PubMed - indexed for MEDLINE] 3837. Minerva Endocrinol. 2005 Mar;30(1):37-46. 11Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target. Tomlinson JW(1). Author information: (1)Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. J.W.Tomlinson@bham.ac.uk Patients with cortisol excess, Cushing's syndrome, develop a classical phenotype characterized by central obesity, hypertension, and increased cardiovascular mortality. Whilst this observation points to the importance of glucocorticoids, circulating cortisol excess is rare and does not explain the pathogenesis of many common conditions. At a tissue specific level, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally regenerates active cortisol from inactive cortisone amplifying glucocorticoid receptor activation in the context of normal circulating cortisol levels. Increased 11beta-HSD1 activity and expression have been implicated in the pathogenesis of many common conditions including, obesity, insulin resistance, the metabolic syndrome, polycystic ovarian syndrome, osteoporosis and glaucoma. Furthermore, selective 11beta-HSD1 inhibition has been proposed as a novel therapeutic strategy in many of these conditions. Here we review the role of 11beta-HSD1 in human disease and discuss the impact of selective 11beta-HSD1 inhibition. PMID: 15877012 [PubMed - indexed for MEDLINE] 3838. Domest Anim Endocrinol. 2005 Jul;29(1):3-22. Epub 2005 Apr 7. Leptin expression in ruminants: nutritional and physiological regulations in relation with energy metabolism. Chilliard Y(1), Delavaud C, Bonnet M. Author information: (1)Herbivore Research Unit, Adipose Tissue and Milk Lipids Group, INRA-Theix, 63122 Saint-Genès-Champanelle, France. Yves.Chilliard@clermont.inra.fr Leptin, mainly produced in adipose tissue (AT), is a protein involved in the central and/or peripheral regulation of body homeostasis, energy intake, storage and expenditure, fertility and immune functions. Its role is well documented in rodent and human species, but less in ruminants. This review is focused on some intrinsic and extrinsic factors which regulate adipose tissue leptin gene expression and leptinemia in cattle, sheep, goat and camel: age, physiological status (particularly pregnancy and lactation) in interaction with long-term (adiposity) and short-term effects of feeding level, energy intake and balance, diet composition, specific nutrients and hormones (insulin, glucose and fatty acids), and seasonal non-dietary factors such as photoperiod. Body fatness strongly regulates leptin and its responses to other factors. For example, leptinemia is higher after underfeeding or during lactation in fat than in lean animals. Physiological status per se also modulates leptin expression, with lactation down-regulating leptinemia, even when energy balance (EB) is positive. These results suggest that leptin could be a link between nutritional history and physiological regulations, which integrates the animal's requirements (e.g., for a pregnancy-lactation cycle), predictable food availability (e.g., due to seasonal variations) and potential for survival (e.g., body fatness level). Reaching permissive leptin thresholds should be necessary for pubertal or postpartum reproductive activity. In addition to the understanding of leptin yield regulation, these data are helpful to understand the physiological significance of changes in leptin secretion and leptin effects, and how husbandry strategies could integrate the adaptative capacities of ruminant species to their environment. PMID: 15876510 [PubMed - indexed for MEDLINE] 3839. Ned Tijdschr Geneeskd. 2005 Apr 16;149(16):871-6. [Tissue-specific changes in cortisol metabolism and their potential role in the metabolic syndrome]. [Article in Dutch] Kerstens MN(1), Wolffenbuttel BH, Dullaart RP. Author information: (1)Universitair Medisch Centrum Groningen, afd. Endocrinologie, Postbus 30.001, 9700 RB Groningen. m.n.kerstens@int.umcg.nl Comment in Ned Tijdschr Geneeskd. 2005 Apr 16;149(16):855-8. The intracellular enzyme IIbeta-hydroxysteroid dehydrogenase (IIbetaHSD) catalyses the interconversion between the biologically-active cortisol and inactive cortisone. There are two distinct isozymes: IIbetaHSD type I behaves predominantly as a reductase in vivo and activates cortisone into cortisol, whereas IIbetaHSD type 2 functions as a dehydrogenase and inactivates cortisol into cortisone. At tissue level, IIbetaHSD type I amplifies the effect ofglucocorticoids, whereby free cortisol is generated from the relative excess of circulating free cortisone. Both animal and human studies have demonstrated that alterations in IIbetaHSD type I activity in adipose tissue and liver are associated with the metabolic syndrome, thus possibly reflecting a tissue-specific (omental) Cushing's syndrome. Pharmacological inhibition of IIbettaHSD type I activity provides an interesting mechanism for the development of novel therapeutic agents for type-2 diabetes mellitus. PMID: 15868991 [PubMed - indexed for MEDLINE] 3840. Acta Diabetol. 2005 Apr;42 Suppl 1:S3-8. Obesity, hypertension and insulin resistance. Sharma AM(1), Chetty VT. Author information: (1)Department of Medicine, McMasterUniversity, Hamilton General Hospital, 237 Barton Street, East Hamilton, Ontario L8L 2X2, Canada. sharma@ccc.mcmaster.ca Being overweight or obese has become highly prevalent in Western countries and are rapidly reaching epidemic proportions in the developing world. Obesity-related disorders, such as hypertension and diabetes, are also increasing at an alarming rate. The relationship between obesity, hypertension and insulin resistance is well recognised, but the molecular mechanisms involved remain relatively poorly understood. Adipose tissue plays a key role in the pathogenesis of the metabolic syndrome. It serves as an important source of pro-inflammatory molecules, including leptin, tumour necrosis factor alpha, angiotensin II and interleukin-6, as well as anti-inflammatory molecules, such as adiponectin. Knowledge of how these adipose tissue-derived factors influence metabolic and cardiovascular disease has recently expanded. Leptin is now considered to play a key role in the elevation of sympathetic activity commonly found in obese, hypertensive patients, and decreased secretion of adiponectin appears to be an important predictor of diabetes. The ectopic storage of excess fat in skeletal muscle, liver or pancreas, due to the decreased capacity of adipose tissue to scavenge excess calories, may also play a role in the development of insulin resistance and type 2 diabetes. Overall, continuing research into the relationship between adipose-tissue biology and metabolic abnormalities may lead to a better understanding of the molecular mechanisms underlying the relationship between obesity and cardiovascular disease, and ultimately provide alternative treatments for the control of potentially life-threatening conditions. PMID: 15868117 [PubMed - indexed for MEDLINE] 3841. J Allergy Clin Immunol. 2005 May;115(5):911-9; quiz 920. Adipose tissue, adipokines, and inflammation. Fantuzzi G(1). Author information: (1)Department of Human Nutrition, University of Illinois at Chicago, USA. giamila@uic.edu White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified. PMID: 15867843 [PubMed - indexed for MEDLINE] 3842. Laryngoscope. 2005 May;115(5):791-5. HIV-associated cervicodorsal lipodystrophy: etiology and management. Gold DR(1), Annino DJ Jr. Author information: (1)Department of Otolaryngology-Head and Neck Surgery, TUFTS University School of Medicine, Boston, Massachusetts, USA. OBJECTIVES: To familiarize the otolaryngologist with the evaluation and management of cervicodorsal manifestations of lipodystrophy in patients who have been treated with HIV protease inhibitor medications. In addition, to share the benefits obtainable with ultrasonic tumescent liposuction treatment. STUDY DESIGN: Retrospective chart review of patients presenting to the senior author with symptomatic hypertrophic cervicodorsal fat pad attributable to HIV infection and HIV protease inhibitor use. RESULTS: Eight patients presented for evaluation of hypertrophic cervicodorsal fat pads between January 1, 2002 and December 31, 2004. All patients had been on protease inhibitors in the past and had minimal resolution after discontinuing offending agent. Most common presenting problems include disfigurement, limited range of upper extremity and neck motion, neck and back discomfort, and difficulty with sleep including sleep-study-confirmed obstructive sleep apnea. Five of eight patients underwent ultrasonic tumescent liposuction. Three patients had satisfactory improvement of symptoms after the first surgery, whereas the other two required additional operative sessions. No complications of hematoma, seroma, infection, prolonged pain, or re-accumulation of fat pad were encountered. The primary obstacle in the three nonoperative patients was insurance denial on the basis of deemed lack of established necessity. CONCLUSIONS: Cervicodorsal lipodystrophy is a well-recognized outcome of prolonged HIV infection and side effect of certain HIV medications. Patients may present with both esthetic and functional issues related to the excess tissue. Although cessation of associated medications may halt further progression, this alone does resolve the symptoms. Ultrasonic tumescent liposuction is shown in this study to be a well-suited modality for reduction of this fibrous adipose tissue. Multiple sessions may be necessary to achieve satisfactory results because of the tenacity of the tissue. It is important for the otolaryngologist to be familiar with the head and neck issues relevant to this disorder and its treatment. PMID: 15867641 [PubMed - indexed for MEDLINE] 3843. Diabetologia. 2005 Jun;48(6):1038-50. Epub 2005 Apr 30. An immune origin of type 2 diabetes? Kolb H(1), Mandrup-Poulsen T. Author information: (1)German Diabetes Center, Leibniz-Institute at the University of Düsseldorf, Düsseldorf, Germany. hkolb@uni-duesseldorf.de Erratum in Diabetologia. 2005 Aug;48(8):1677. Subclinical, low-grade systemic inflammation has been observed in patients with type 2 diabetes and in those at increased risk of the disease. This may be more than an epiphenomenon. Alleles of genes encoding immune/inflammatory mediators are associated with the disease, and the two major environmental factors the contribute to the risk of type 2 diabetes-diet and physical activity-have a direct impact on levels of systemic immune mediators. In animal models, targeting of immune genes enhanced or suppressed the development of obesity or diabetes. Obesity is associated with the infiltration and proinflammatory activity of macrophages in adipose tissue, and immune mediators may be important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and beta cell dysfunction or death. Intervention studies targeting these pathways would help to determine the contribution of an activated innate immune system to the development of type 2 diabetes. PMID: 15864529 [PubMed - indexed for MEDLINE] 3844. Trends Endocrinol Metab. 2005 May-Jun;16(4):190-7. Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance. Ranke MB(1). Author information: (1)Paediatric Endocrinology Section, University Children's Hospital, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. michael.ranke@med.uni-tuebingen.de Insulin-like growth factor I (IGF-I) has many potential therapeutic uses because of its varied effects--growth promotion, insulin-like influence on glucose metabolism, and neuroprotection resulting from cell-proliferative and antiapoptotic properties--but they have not been investigated systematically in clinical situations. The growth-promoting effect of recombinant human IGF-I (rhIGF-I) in the extensively studied growth hormone insensitivity syndrome (GHIS; Laron syndrome) signifies an endocrine role for the GH-IGF system. The metabolism of (adult) patients with severe insulin resistance is improved by rhIGF-I, which--together with insulin therapy--also improves metabolic control in type 1 and 2 diabetes. Further studies on IGF-I metabolic effects and growing understanding of the IGF-I-IGF-binding protein system could open new therapeutic avenues. PMID: 15860416 [PubMed - indexed for MEDLINE] 3845. Pol Merkur Lekarski. 2005 Jan;18(103):101-4. [Nitric oxide in physiology and pathology of metabolism]. [Article in Polish] Olszanecka-Glinianowicz M(1), Zahorska-Markiewicz B, Zurakowski A, Glinianowicz M. Author information: (1)Katedra Patofizjologii Slaskiej Akademii Medycznej w Katowicach. magols@esculap.pl Adipose tissue generates many bioactive substances, which may exert autocrine, paracrine and endocrine effects. Recent studies have revealed, that one of these substances is nitric oxide. There are observed increased expressions of synthases NO (eNOS and iNOS) in adipose tissue in obesity. It seems that these increased expression NOS is reflected by increased serum concentration of NO in obese subjects. The review of the current literature on role of nitric oxide in physiology and pathology metabolism is presented in this paper. PMID: 15859560 [PubMed - indexed for MEDLINE] 3846. Nat Neurosci. 2005 May;8(5):585-9. Endocannabinoid control of food intake and energy balance. Di Marzo V(1), Matias I. Author information: (1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy. vdimarzo@icmib.na.cnr.it Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes. PMID: 15856067 [PubMed - indexed for MEDLINE] 3847. Nat Neurosci. 2005 May;8(5):571-8. Anatomy and regulation of the central melanocortin system. Cone RD(1). Author information: (1)Vollum Institute and the Center for the Study of Weight Regulation, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. cone@ohsu.edu The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems. PMID: 15856065 [PubMed - indexed for MEDLINE] 3848. Nat Neurosci. 2005 May;8(5):566-70. Molecular and anatomical determinants of central leptin resistance. Münzberg H(1), Myers MG Jr. Author information: (1)Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. The increasing incidence of obesity in developed nations is an ever-growing challenge to health care, promoting diabetes and other diseases. The hormone leptin, which is derived from adipose tissue, regulates feeding and energy expenditure. Most forms of obesity are associated with diminished responsiveness to the appetite-suppressing effects of leptin. Here we review the mechanisms by which leptin activates intracellular signals, the roles of these signals in leptin action in vivo, and mechanisms that may attenuate leptin signaling, limiting its action in obese individuals. We highlight data regarding the expression of SOCS3 (a potential mediator of leptin resistance) in the arcuate nucleus of the hypothalamus. PMID: 15856064 [PubMed - indexed for MEDLINE] 3849. Expert Rev Cardiovasc Ther. 2005 Mar;3(2):231-41. Lifestyle modification and endothelial function in obese subjects. Hamdy O(1). Author information: (1)Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA. Osama.Hamdy@joslin.harvard.edu The metabolic syndrome is a cluster of metabolic and vascular abnormalities that include central obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, dyslipidemia, hypercoagulability and an increased risk of coronary and cerebral vascular disease. These metabolic and vascular abnormalities are the main cause of cardiovascular mortality in western societies. Endothelial dysfunction, an early step in the development of atherosclerosis, has been reported in obese nondiabetic individuals and in patients with Type 2 diabetes. It has also been observed in individuals at high risk for Type 2 diabetes, including those with impaired glucose tolerance and the normoglycemic first-degree relatives of Type 2 diabetic patients. Recent evidence points to adipocytes as a complex and active endocrine tissue whose secretory products, including free fatty acids and several cytokines (i.e., leptin, adiponectin, tissue necrosis factor-alpha, interleukin-6, and resistin) play a major role in the regulation of human metabolic and vascular biology. These adipocytokines have been claimed to be the missing link between insulin resistance and cardiovascular disease. Interventions designed to improve endothelial and/or adipose-tissue functions may reduce cardiovascular events in obese individuals with either the metabolic syndrome or Type 2 diabetes. Lifestyle modification in the form of caloric restriction and increased physical activity are the most common modalities used for treating those individuals at risk and is unanimously agreed to be the initial step in managing Type 2 diabetes. Several recent studies have demonstrated favorable impacts of lifestyle modifications in improving endothelial function and insulin sensitivity, in addition to altering serum levels of adipocytokines and possibly reducing cardiovascular events. This review discusses current knowledge of the role of lifestyle modifications in ameliorating cardiovascular risk in obese subjects with either the metabolic syndrome or Type 2 diabetes. PMID: 15853597 [PubMed - indexed for MEDLINE] 3850. CMAJ. 2005 Apr 26;172(9):1199-209. Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training. Nicklas BJ(1), You T, Pahor M. Author information: (1)Sticht Center on Aging, Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. bnicklas@wfubmc.edu Comment in CMAJ. 2005 Oct 25;173(9):1066. Persistent low-grade inflammation, as indicated by higher circulating levels of inflammatory mediators such as C-reactive protein, interleukin-6 and tumour necrosis factor-alpha, is a strong risk factor for several chronic diseases. There are data indicating that decreasing energy intake and increasing physical activity may be effective therapies for reducing overall inflammation. Evidence is strong that circulating levels of inflammatory markers are elevated with total and abdominal obesity, possibly owing to a higher secretion rate of cytokines by adipose tissue in obese people. Moreover, very-low-energy dietary weight loss reduces both circulating markers of inflammation and adipose-tissue cytokine production. Data from several large population-based cohorts show an inverse association between markers of systemic inflammation and physical activity or fitness status; small-scale intervention studies support that exercise training diminishes inflammation. Dietary weight loss plus exercise is likely more effective than weight reduction alone in reducing inflammation. To date, data from randomized, controlled trails designed to definitively test the effects of weight loss or exercise training, or both, on inflammation are limited. Future studies are required to define the amount of weight loss needed for clinically meaningful reductions of inflammation; in addition, fully powered and controlled studies are necessary to clarify the effect of exercise training on chronic, systemic inflammation. PMCID: PMC557073 PMID: 15851714 [PubMed - indexed for MEDLINE] 3851. Nutr Clin Care. 2005 Jan-Mar;8(1):31-6. The role of nutrition in fat deposition and fat atrophy in patients with HIV. Dong KR(1), Hendricks KM. Author information: (1)Nutrition/infection Unit, Department of Public Health and Family Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. kimberly.dong@tufts.edu HIV-associated body shape changes and metabolic abnormalities, called HIV-associated lipodystrophy, are being seen with increased frequency. These issues may be associated with an increased risk of other diseases, such as cardiovascular disease, or with poor adherence to antiretroviral medications. Diet may be useful in the prevention and treatment of lipodystrophy and is a cost-effective and non-toxic intervention. At present, there are limited data on nutrition and HIV-related body shape changes. The purpose of this article is to review the roles that diet may play in the development and treatment of fat deposition and fat atrophy. PMID: 15850232 [PubMed - indexed for MEDLINE] 3852. Clin Med. 2005 Mar-Apr;5(2):142-6. Tissue-specific Cushing's syndrome uncovers a new target in treating the metabolic syndrome--11beta-hydroxysteroid dehydrogenase type 1. Stewart PM(1). Author information: (1)Division of Medical Sciences, Institute of Biomedical Research, Medical School, University of Birmingham. PMID: 15847006 [PubMed - indexed for MEDLINE] 3853. Nihon Rinsho. 2005 Apr;63(4):665-71. [The roles of PPARs in digestive diseases]. [Article in Japanese] Nakajima A(1), Yoneda M, Takahashi H, Fujisawa N, Wada K. Author information: (1)Gastroenterology Division, Yokohama City University. Peroxisome proliferator-activated receptor gamma (PPARgamma), one of the nuclear receptors, is expressed at high levels in adipose tissue and is related to adipocyte differentiation and insulin sensitivity. PPARgamma is also expressed at high levels in digestive organs, especially in the colon epithelium. The physiological and pathological roles of PPARgamma in the gastrointestinal tract have been investigated and recognized as an endogenous regulator of innate immunity, inflammation, and cell proliferation. PPARgamma ligands have recently been reported to improve the condition of patients with non-alcoholic steatohepatitis (NASH). Thus, PPARgamma ligands are indeed potential benefit candidates for various digestive diseases. In this review, we will focus on the current knowledge and new insights of the roles of PPARgamma in digestive diseases, especially in (1) inflammatory bowel disease (IBD), (2) colon cancer, and (3) NASH. PMID: 15828235 [PubMed - indexed for MEDLINE] 3854. Postepy Biochem. 2004;50(3):256-71. [Secretory function of adipose tissue]. [Article in Polish] Kochan Z(1), Karbowska J. Author information: (1)Katedra Biochemii, Akademia Medyczna w Gdańsku, 80-211 Gdańsk. kochanz@amg.gda.pl PMID: 15822755 [PubMed - indexed for MEDLINE] 3855. Cardiovasc Res. 2005 May 1;66(2):276-85. Epub 2004 Dec 8. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Yamamoto K(1), Takeshita K, Kojima T, Takamatsu J, Saito H. Author information: (1)Department of Transfusion Medicine, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya 466-8550, Japan. kojiy@med.nagoya-u.ac.jp Thrombotic cardiovascular diseases increase in incidence in the elderly, a tendency dependent on the age-related changes in vascular and hemostatic systems that include platelets, coagulation, and fibrinolytic factors as well as in the endothelium. The hypercoagulability of and advanced sclerotic changes in the vascular wall may contribute to the increased incidence of thrombosis in the elderly. One of the important key genes for aging-associated thrombosis is plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of fibrinolysis. The expression of PAI-1 is not only elevated in the elderly but also significantly induced in a variety of pathologies associated with the process of aging. These conditions include obesity, insulin resistance, emotional stress, immune responses, and vascular sclerosis/remodeling. Several cytokines and hormones, including tumor necrosis factor-alpha, transforming growth factor-beta, angiotensin II, and insulin, positively regulate the gene expression of PAI-1. The recent epidemic in obesity with aging in the industrialized society may heighten the risk for thrombotic cardiovascular disease because adipose tissue is a primary source of PAI-1 and cytokines. Emotional or psychosocial stress and inflammation also cause the elevated expression of PAI-1 in an age-specific pattern. Thus, PAI-1 could play a key role in the progression of cardiovascular aging by promoting thrombosis and vascular (athero)sclerosis. Further studies on the genetic mechanism of aging-associated PAI-1 induction will be necessary to define the basis for cardiovascular aging in relation to thrombosis. PMID: 15820196 [PubMed - indexed for MEDLINE] 3856. Rev Med Liege. 2005 Feb;60(2):89-95. [PPAR-gamma receptors, new therapeutic target in metabolic and cardiovascular diseases]. [Article in French] Scheen AJ(1), Paquot N. Author information: (1)Université de Liege. PPARs ("Peroxisome Proliferator-Activated Receptors") belong to a superfamily of nuclear receptors with several isoforms, among which PPAR-alpha mainly located in the liver and PPAR-gamma mainly located in the adipose tissue. These receptors are considered as major pharmacological targets since the discovery of their activation by specific agonists, which lead to various favourable metabolic effects. Improvement of lipid profile by fibrates is explained by the activation of liver PPAR-alpha receptors. However, PPAR-gamma receptors have focused most fundamental and clinical research in recent years after the demonstration of their activation by thiazolidinediones (pioglitazone, rosiglitazone), a new class of antidiabetic agents. Beyond their effects on insulin sensitivity, glitazones exert pleiotropic effects that may result in cardiovascular protection in high risk patients. It has been recently demonstrated that certain angiotensin AT1 receptor blockers (sartans) can also exert a partial agonist activity on PPAR-gamma. Among the molecules of this class, telmisartan appears to exert this effect at the lower concentrations. Thus, PPAR-y, as common pharmacological target, may, at least partially, explain some of the effects observed with both thiazolidinediones and inhibitors of the renin-angiotensin system, in particular the improvement in insulin sensitivity (in particular via an increase in adiponectin levels), the protection against type 2 diabetes, the reduction in arterial blood pressure and the prevention of cardiovascular complications. There is currently a major interest from the pharmaceutical industry in the development of new molecules able to activate both PPAR-alpha and PPAR-gamma. PMID: 15819371 [PubMed - indexed for MEDLINE] 3857. J Endocrinol. 2005 Apr;185(1):1-9. Role of the RIP140 corepressor in ovulation and adipose biology. Steel JH(1), White R, Parker MG. Author information: (1)Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Du Cane Road, London W12 0NN, UK. j.steel@imperial.ac.uk RIP140 is a ligand-dependent corepressor for most, if not all, nuclear receptors. It is expressed widely in many different tissues, but the phenotype of mice devoid of RIP140 indicates that it plays a crucial role in the ovary and in adipose biology. Ovarian expression of RIP140 is cell-type-specific during follicular development and it is essential for oocyte release during ovulation, but not for luteinization of mature ovarian follicles. In adipose tissue, RIP140 is essential for normal fat accumulation and RIP140-null mice show decreased lipid storage even on a high-fat diet, with upregulation of mitochondrial uncoupling protein (UCP1) in some fat depots. Thus RIP140 plays a crucial role in female fertility and in energy homeostasis, and could be a target for infertility treatment, new contraceptive strategies or prevention of obesity. PMID: 15817822 [PubMed - indexed for MEDLINE] 3858. IUBMB Life. 2004 Oct;56(10):595-600. Insulin regulation of fatty acid synthase gene transcription: roles of USF and SREBP-1c. Griffin MJ(1), Sul HS. Author information: (1)Department of Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA 94720, USA. The transcriptional regulation of lipogenesis is a highly coordinated process occurring in concert with transcriptional as well as post-transcriptional regulation of enzymes involved in glycolysis and gluconeogenesis. Fatty acid synthase (FAS) plays a central role in de novo lipogenesis by converting acetyl-CoA and malonyl-CoA into the final end product, palmitate, which can subsequently be esterified into triacylglycerols and then stored in adipose tissue. Ultimately, this helps to prevent buildup of excess glucose in other types of cells and tissues, the effects of which can be readily observed in the pathophysiology of disease states such as Type-11 diabetes and obesity. Thus, elucidating the transcriptional mechanisms of lipogenic enzyme genes is important for understanding the normal regulation of lipogenesis and ultimately the dysregulation that may occur in certain metabolic disease. In this review, we discuss advances in our understanding of the regulation of lipogenesis at the genetic level, with a special emphasis on the common cis- and trans-acting factors involved in regulation of FAS. Two transcription factors, Upstream Stimulatory Factor (USF) and Sterol Regulatory Element Binding Protein-lc (SREBP-lc), seem to play a dominant and possibly cooperative role in regulating FAS transcription. PMID: 15814457 [PubMed - indexed for MEDLINE] 3859. Curr Atheroscler Rep. 2005 May;7(3):196-203. Genetic lipoprotein disorders and coronary atherosclerosis. Alawadhi M(1), Thanassoulis G, Marcil M, Genest J. Author information: (1)Division of Cardiology Research, MUHC-Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada. Familial lipoprotein disorders are seen frequently in subjects with premature coronary artery disease. The genetic basis for several dyslipoproteinemias has been elucidated in the past two decades. The majority of lipoprotein disorders result from a combination of polygenic predisposition and poor lifestyle habits, including physical inactivity, increased visceral adipose tissue, increased caloric intake, and cigarette smoking. Monogenic disorders are seen in approximately 5% of premature coronary artery disease cases, and this prevalence is higher in populations with the Founder effect. Unraveling the genetic basis of many lipoprotein disorders has allowed fundamental discoveries in molecular cellular physiology and has paved the way for novel therapeutic approaches. PMID: 15811253 [PubMed - indexed for MEDLINE] 3860. Clin Exp Pharmacol Physiol. 2005 Apr;32(4):302-7. Active role for the vasculature in the delivery of insulin to skeletal muscle. Vincent MA(1), Clerk LH, Rattigan S, Clark MG, Barrett EJ. Author information: (1)Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. 1. In the 80+ years since insulin's discovery, an enormous amount of literature has accumulated relating to its actions on body fat, glucose and protein metabolism. In particular, skeletal muscle has been extensively studied because of its major role as a site of insulin-mediated glucose disposal. Liver and adipose tissue are two other extensively studied sites of insulin action. Much less investigation has been directed towards delineating insulin's actions on cells other than myocytes, adipocytes and hepatocytes. 2. Over the past 5-10 years it has become increasingly evident that insulin exerts important actions on vascular cells. Here, we review evidence that insulin's action within muscle may be very much regulated by its ability to transit the vasculature to access the interstitial fluid (and hence the myocyte insulin receptor). Surprisingly little is known regarding the regulation of vascular events that first bring insulin to the capillary endothelium within muscle, whence presumably it transits from the vascular to the interstitial space. Recent studies suggest that insulin can increase blood flow and also influence the distribution of blood flow within skeletal muscle, potentially therefore regulating its own delivery to the capillary endothelium. Beyond insulin's ability to access the vascular lumen within skeletal muscle microvasculature lies the issue of its passing the endothelial barrier. Even less is known about the processes involved in insulin's actual transit across the endothelium. Available data do not clearly indicate whether this is a saturable, receptor-mediated process or a passive-diffusion pathway. Also, whether insulin in any manner regulates its own transit across the endothelium or its clearance via the lymphatic system is entirely unknown. 3. The aim of the present review is to identify areas where knowledge is deficient and highlight hypotheses which may lead to a better understanding of the coordinated relationship between insulin's vascular actions within muscle and its metabolic actions in that tissue. Even so, there is now sufficient evidence to indicate that insulin's vascular action within skeletal muscle is a major regulatory locus for its insulin mediated glucose disposal. PMID: 15810996 [PubMed - indexed for MEDLINE] 3861. Pediatr Nephrol. 2005 Jun;20(6):701-6. Epub 2005 Apr 5. Alterations of leptin and ghrelin serum concentrations in renal disease: simple epiphenomena? Dötsch J, Nüsken K, Schroth M, Rascher W, Meissner U. The hypothesis that alterations of serum concentrations of the anorexigenic adipose tissue-derived hormone leptin or the orexigenic peptide ghrelin might help to regain appetite and fight malnutrition in patients with chronic renal failure cannot be confirmed at present. For the future, however, strategies interfering with signal transduction of these peptides in the hypothalamus might be more promising and should be investigated and further developed. PMID: 15809831 [PubMed - indexed for MEDLINE] 3862. Forum Nutr. 2003;56:299-301. Validity of body composition methods across ethnic population groups. Deurenberg P(1), Deurenberg-Yap M. Author information: (1)Wageningen University, The Netherlands. padeu@singnet.com.sg Body composition methods can be classified into direct, indirect and doubly indirect methods. In vivo direct methods use neutron activation analysis to get information on body composition. Indirect methods rely on rules and constants derived from direct methods. Most basic research, especially the development of rules and models has been done in Caucasian subjects in Europe or USA. The critical use of more advanced body composition methodologies in various ethnic groups has shown that assumptions may differ between ethnic groups, an example being the assumption of constant density of the fat free mass. Indirect or predictive methods rely on statistical relationships between body parameters and components of body composition. Subcutaneous fat patterning differs among ethnic groups, and this may have consequences for the validity of body fat predicted from skinfold thickness. Relative leg length and relative arm length also differ between ethnic groups. As a result the body mass index (weight/height squared, BMI), often used as surrogate for body fat percent, and formulas based on bioelectrical impedance measurement show different validity among ethnic groups. Less information is available about the validity of indicators for body fat distribution. There are indications that the relationship between the amount of visceral adipose tissue and waist circumference or waist-hip circumference ratio also differs among ethnic groups. Ethnic differences in body composition rules and constants are important and challenging to investigate, especially in relation to overweight and obesity. PMID: 15806909 [PubMed - indexed for MEDLINE] 3863. Diabetes Metab. 2005 Feb;31(1):23-7. PPAR delta: an uncompletely known nuclear receptor. Fredenrich A(1), Grimaldi PA. Author information: (1)INSERM, U 636, Centre de Biochimie, UFR Sciences, Parc Valrose, Université de Nice-Sophia-Antipolis, Nice, F-06108 France. fredenrich.a@chu-nice.fr Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, alpha, gamma, and B/delta. Roles of PPAR alpha and PPARgamma are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARdelta are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARdelta using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARdelta play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, alpha and gamma, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding delta agonists (for all that their safety will be established) to the already available alpha and gamma agonists. PMID: 15803109 [PubMed - indexed for MEDLINE] 3864. Nihon Naika Gakkai Zasshi. 2005 Feb 20;94 Suppl:40-4. [Molecular mechanism in life style diseases]. [Article in Japanese] Matsuzawa Y. PMID: 15796054 [PubMed - indexed for MEDLINE] 3865. Diabetes. 2005 Apr;54(4):917-27. A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes? Tataranni PA(1), Ortega E. Author information: (1)Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA. antonio.tataranni@sanofi-aventis.com There is growing support for the hypothesis that obesity is an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance. Experimental studies in animals and evidence from prospective and longitudinal studies in humans are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. However, the exact chain of molecular events linking overnutrition, activation of the innate immune system, and impairment of insulin signaling in peripheral tissues remains incompletely understood. Notwithstanding this limitation, treating the underlying subclinical inflammation may constitute a novel approach to prevention and/or treatment of type 2 diabetes. PMID: 15793228 [PubMed - indexed for MEDLINE] 3866. Exp Biol Med (Maywood). 2005 Apr;230(4):225-34. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Fride E(1), Bregman T, Kirkham TC. Author information: (1)Department of Behavioral Sciences, College of Judea and Samaria, Ariel, Israel. fride@research.yosh.ac.il The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB1 receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB1 receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB1 receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause. PMID: 15792943 [PubMed - indexed for MEDLINE] 3867. Science. 2005 Mar 25;307(5717):1909-14. The gut and energy balance: visceral allies in the obesity wars. Badman MK(1), Flier JS. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Finard 202, 330 Brookline Avenue, Boston, MA 02215, USA. In addition to digesting and assimilating nutrients, the intestine and associated visceral organs play a key sensing and signaling role in the physiology of energy homeostasis. The gut, the pancreatic islets of Langerhans, elements in the portal vasculature, and even visceral adipose tissue communicate with the controllers of energy balance in the brain by means of neural and endocrine pathways. Signals reflecting energy stores, recent nutritional state, and other parameters are integrated in the central nervous system, particularly in the hypothalamus, to coordinate energy intake and expenditure. Our understanding of regulatory neural circuits and the signaling molecules that influence them has progressed rapidly, particularly after the discovery of the adipocyte hormone leptin. These discoveries have led to exploration of novel routes for obesity control, some of which involve gut-derived pathways. PMID: 15790843 [PubMed - indexed for MEDLINE] 3868. Rev Environ Contam Toxicol. 2005;184:1-57. Organohalogen contaminants in delphinoid cetaceans. Houde M(1), Hoekstra PF, Solomon KR, Muir DC. Author information: (1)University of Guelph, Department of Environmental Biology, Guelph, Ontario NIG 2WI, Canada. This chapter reviews the global distribution, biotransformation, accumulation patterns, and mechanisms of action and the potential impacts of persistent organohalogen contaminants (PHCs) on physiological systems of cetaceans with emphasis on delphinoids. Methods used to study PHCs in stranded and free-living cetaceans are discussed, and concentrations of PHCs of stranded, hunted, by-catch, and free-ranging delphinoids are summarized. Overall, the highest concentrations of PHC contamination were found in delphinoids from industrialized areas of the Northern Hemisphere compared to the Southern Hemisphere. Nonetheless, PHCs are also found in marine mammal tissues from the Southern Hemisphere and in remote regions such as the Arctic, reflecting the global distribution and contamination of PHCs in the marine ecosystem. PMID: 15790172 [PubMed - indexed for MEDLINE] 3869. Biochem Soc Trans. 2005 Apr;33(Pt 2):354-7. Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Björnholm M(1), Zierath JR. Author information: (1)Department of Surgical Sciences, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden. Type II diabetes is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue and liver and pancreatic beta-cell defects. Since the skeletal muscle accounts for approx. 75% of whole body insulin-stimulated glucose uptake, defects in this tissue play a major role in the impaired glucose homoeostasis in Type II diabetic patients. Thus identifying defective steps in this process may reveal attractive targets for drug development to combat insulin resistance and Type II diabetes. This review will describe the effects of insulin on glucose transport and other metabolic events in skeletal muscle that are mediated by intracellular signalling cascades. Evidence for impaired activation of the insulin receptor signalling cascade and defective glucose transporter 4 translocation in the skeletal muscle from Type II diabetic patients will be presented. Through the identification of the intracellular defects in insulin action that control glucose homoeostasis, a better understanding of the disease pathogenesis can be gained and strategies for intervention may be developed. PMID: 15787605 [PubMed - indexed for MEDLINE] 3870. Int J Gynecol Pathol. 2005 Apr;24(2):196-200. Lipomatous variant of angiomyofibroblastoma: report of two cases and review of the literature. Cao D(1), Srodon M, Montgomery EA, Kurman RJ. Author information: (1)Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA. Angiomyofibroblastoma (AMF) is a rare, benign, mesenchymal tumor occurring mainly in the female genital tract. Some cases contain scattered mature adipocytes, but the lipomatous variant in which mature adipose tissue is prominent or striking is rare. Only five cases have been reported in the English literature. We report two more such cases that were composed of 70 to 80% and 30 to 40% adipose tissue, respectively. Immunohistochemical analysis showed that the tumor cells were positive for estrogen receptor, progesterone receptor, vimentin, and Bcl-2, and negative for cytokeratin AE1/1, EMA, and CD117. Tumor cells in the first case were positive for CD34 but not desmin and muscle-specific actin. The opposite expression profile of these three markers was observed in tumor cells in the second case: positive for desmin and muscle-specific actin and negative for CD34. Rare cells were positive for S-100 in adipose-rich areas in the first case. Our findings indicate that the tumor cells in the lipomatous variant have similar immunoprofile to those of usual AMF and support the concept that the lipomatous variant probably represents an extreme end of a wide spectrum of differentiation in AMF. PMID: 15782077 [PubMed - indexed for MEDLINE] 3871. Anesth Analg. 2005 Apr;100(4):1020-33. Illustrations of inhaled anesthetic uptake, including intertissue diffusion to and from fat. Eger EI 2nd(1), Saidman LJ. Author information: (1)Department of Anesthesia and Perioperative Care, S-455, University of California, San Francisco, CA 94143-0464, USA. egere@anesthesia.ucsf.edu Although several mathematical and computer simulations of inhaled anesthetic pharmacokinetics have been devised, their complexity sometimes limits an intuitive appreciation of the interactions produced by the determinants of kinetics. In this essay, we illustrate the factors that govern inhaled anesthetic pharmacokinetics with drawings that consider delivery of anesthetic by ventilation to the lungs and dispersion of the anesthetic to tissue depots by the circulation. The illustrations incorporate the effects of both blood flow and blood solubility as determinants of the extent of dispersion. They incorporate tissue volume and solubility as determinants of the capacity of the tissue depots. Capacity to hold (take up) anesthetic is depicted by areas representing specific tissues, and the extent of anesthetic movement is depicted by the length and breadth of arrows to and from the areas depicting capacity. The illustrations incorporate increasingly important elements to kinetics, such as obesity. Obesity increases the depots available for storage of anesthetic, including anesthetic that reaches fat by intertissue diffusion. Such anesthetic returns to the circulation to delay recovery in healthy and obese patients, particularly with more soluble anesthetics. However, the increased anesthetic in fat occurs at a lower partial pressure and thus might not influence emergence materially. We hope that these illustrations will allow anesthesia practitioners to appreciate the interactions of the factors that govern inhaled anesthetic pharmacokinetics. PMID: 15781517 [PubMed - indexed for MEDLINE] 3872. Curr Opin Pharmacol. 2005 Apr;5(2):122-8. Adipose tissue as an active endocrine organ: recent advances. Gimeno RE(1), Klaman LD. Author information: (1)Department of Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, MA 02140, USA. rgimeno@wyeth.com Adipose tissue secretes a variety of factors in a manner dependent upon its metabolic state. These factors are derived from adipocyte or non-adipocyte fractions, and include proteins, metabolites and hormones. Obesity is a major risk factor for type 2 diabetes and cardiovascular disease, and adipocyte-derived factors might contribute to or ameliorate obesity-associated pathologies such as insulin resistance, dyslipidemia, vascular dysfunction and a chronic inflammatory and prothrombotic state. PMID: 15780819 [PubMed - indexed for MEDLINE] 3873. Nihon Rinsho. 2005 Feb;63 Suppl 2:417-20. [The cutoff point of visceral fat area as a goal for improving risk factors of arteriosclerosis in patients with glucose intolerance]. [Article in Japanese] Nagano M(1), Sasaki H, Kumagai S. Author information: (1)Graduate School of Human-Environment Studies, Kyushu University. PMID: 15779415 [PubMed - indexed for MEDLINE] 3874. Nihon Rinsho. 2005 Feb;63 Suppl 2:324-8. [Glucocorticoid-induced diabetes]. [Article in Japanese] Ogawa Y(1), Tomotsune K, Suda T. Author information: (1)Third Department of Internal Medicine, Hirosaki University School of Medicine. PMID: 15779396 [PubMed - indexed for MEDLINE] 3875. Nihon Rinsho. 2005 Feb;63 Suppl 2:269-73. [Hyperuricemia as a unique marker for metabolic syndrome]. [Article in Japanese] Nakajima H(1). Author information: (1)Department of Clinical Laboratory, Osaka Medical Center for Cancer and Cardiovascular Diseases. PMID: 15779385 [PubMed - indexed for MEDLINE] 3876. Nihon Rinsho. 2005 Feb;63 Suppl 2:264-8. [Obesity and the metabolic syndrome]. [Article in Japanese] Masuzaki H(1), Nakao K. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. PMID: 15779384 [PubMed - indexed for MEDLINE] 3877. Nihon Rinsho. 2005 Feb;63 Suppl 2:246-9. [Significance of visceral fat syndrome in pathogenesis of impaired glucose tolerance]. [Article in Japanese] Nakamura T(1). Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. PMID: 15779380 [PubMed - indexed for MEDLINE] 3878. Mini Rev Med Chem. 2005 Mar;5(3):269-78. The brown adipose cell: a unique model for understanding the molecular mechanism of insulin resistance. Valverde AM(1), Benito M. Author information: (1)Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular II, Centro Mixto CSIC/UCM, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain. valverde@farm.ucm.es Type 2 diabetes mellitus (NIDDM) is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signaling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue (BAT) and pinpoints the role of BAT in the control of glucose homeostasis. PMID: 15777261 [PubMed - indexed for MEDLINE] 3879. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Mar;5(1):1-10. Effects of endocrine disruptors on developmental and reproductive functions. Brevini TA(1), Zanetto SB, Cillo F. Author information: (1)Department of Anatomy of Domestic Animals, School of Veterinary Medicine, University of Milano, Italy. tiziana.brevini@unimi.it Endocrine disruptors (EDs) are exogenous environmental molecules that may affect the synthesis, secretion, transport, metabolism, binding, action, and catabolism of natural hormones in the body. EDs may thus interact with the endocrine system of animals and humans and can exert this effect even when present in minute amounts. EDs have adverse impacts on a number of developmental functions in wildlife and humans. Critical periods of urogenital tract and nervous system development in-utero and during early post-natal life are especially sensitive to hormonal disruption. Furthermore a wide range of hormone-dependent organs (pituitary gland, hypothalamus, reproductive tract) are targets of EDs disrupting effects in adult subjects, possibly resulting in cell transformation and cancer. At present about 60 chemicals have been identified and characterized as EDs and belong to three main groups: (a) synthetic compounds utilized in industry, agriculture and consumer products; (b) synthetic molecules used as pharmaceutical drugs and (c) natural chemicals found in human and animal food (phytoestrogens). In the present review we will give special attention to the family of Polychlorinated biphenyls (also indicated as PCBs) because of their persistence in the environment, ability to concentrate up the food chain, continued detection in environmental matrices, and ability to be stored in the adipose tissue of animals as well as humans. The detrimental effects of these compounds, and of EDs more in general, on health and reproduction will be discussed, presenting experimental data aimed at understanding the molecular mechanisms involved in their action. PMID: 15777200 [PubMed - indexed for MEDLINE] 3880. Vestn Ross Akad Med Nauk. 2005;(2):44-8. [The role of leptin and its peptide mediators in neurophysiology]. [Article in Russian] Pankov IuA. The adipocyte hormone leptin binds to its receptors in hypothalamic neurons and decreases appetite and food consumption. Its effect on appetite is mediated by melanocortines (MC) that are derivative of proopiomelanocortin (POMK) and their receptor (MC4-R). The knock-out of POMC gene or MC4-R gene causes obesity in animals. However, the growth of the animals intensifies and their reproductive function does not cease. The paper covers consequences of mutations in genes responsible for leptin regulation of various functions. PMID: 15776967 [PubMed - indexed for MEDLINE] 3881. Novartis Found Symp. 2005;264:81-90; discussion 90-97, 227-30. Genetics of laminopathies. Ben Yaou R(1), Muchir A, Arimura T, Massart C, Demay L, Richard P, Bonne G. Author information: (1)Inserm U582, Institut de Myologie, Batiment Babinski, Groupe Hospitalier Pitié-Salpe'triire, 47, Boulevard de l'Hôpital, Paris, France. Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy. PMID: 15773749 [PubMed - indexed for MEDLINE] 3882. Exp Clin Endocrinol Diabetes. 2005 Feb;113(2):67-79. Adipocytokines: fat-derived humoral mediators of metabolic homeostasis. Staiger H(1), Häring HU. Author information: (1)Department of Endocrinology, Metabolism, and Pathobiochemistry, Medical Clinic Tübingen, Eberhard-Karls-University, Tübingen, Germany. The metabolic syndrome currently reaches epidemic proportions in the Western industrialized world. Its hallmarks obesity, type 2 diabetes mellitus, and atherosclerosis are closely associated, and we are just beginning to understand the reasons for this relationship: adipose tissue-derived proteohormones (adipocytokines), under normal weight conditions, guarantee homeostasis of glucose and lipid metabolism, but their dysregulated production in the obese state promotes insulin resistance, inflammation, as well as atherosclerotic events. This review will focus on the current understanding of the adipocytokines' molecular role in metabolism and metabolic disease. PMID: 15772897 [PubMed - indexed for MEDLINE] 3883. J Appl Physiol (1985). 2005 Apr;98(4):1154-62. The anti-inflammatory effect of exercise. Petersen AM(1), Pedersen BK. Author information: (1)Dept. of Infectious Diseases, Rigshospitalet, Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases. PMID: 15772055 [PubMed - indexed for MEDLINE] 3884. Cell Mol Life Sci. 2005 Mar;62(6):708-16. Regulation of food intake by oleoylethanolamide. Lo Verme J(1), Gaetani S, Fu J, Oveisi F, Burton K, Piomelli D. Author information: (1)Department of Pharmacology, University of California, Irvine, California, 92697-4260, USA. Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In the present article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPAR-alpha. Finally, we discuss the possible role of OEA as a peripheral satiety hormone. PMID: 15770421 [PubMed - indexed for MEDLINE] 3885. Cell Mol Life Sci. 2005 Mar;62(6):642-52. Leptin receptor action and mechanisms of leptin resistance. Münzberg H(1), Björnholm M, Bates SH, Myers MG Jr. Author information: (1)Division of Metabolism, Endocrinology and Diabetes, Departments of Internal Medicine and Molecular and Physiology, University of Michigan Medical School, 1150 W. Medical Center Dr., 4301 MSRB 3, Box 0638, Ann Arbor, Michigan, 48109-0638, USA. The adipose tissue-derived hormone leptin regulates energy balance and neuroendocrine function. Resistance to the appetite-suppressing effects of leptin is associated with common forms of obesity. Here, we review the mechanisms by which leptin activates intracellular signals and the roles that these signals play in leptin action in vivo. Furthermore, we discuss potential mechanisms of leptin resistance, specifically focusing on data regarding the neuroanatomical locus of leptin resistance and potential mechanisms by which expression of the suppressor of cytokine signaling-3 may impair leptin action. PMID: 15770417 [PubMed - indexed for MEDLINE] 3886. Curr Opin Lipidol. 2005 Apr;16(2):173-8. Fatty acid transport proteins and insulin resistance. Fisher RM(1), Gertow K. Author information: (1)Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. rachel.fisher@medks.ki.se PURPOSE OF REVIEW: Disturbed fatty acid metabolism and homeostasis is associated with insulin resistance. The aim of this review, therefore, is to summarize recent developments relating to the relevance and importance of the fatty acid transport proteins (FATPs) in the aetiology of insulin resistance. In particular, the potential differences between the six members of the FATP family will be considered. RECENT FINDINGS: FATP1 knockout mice failed to develop insulin resistance associated with lipid infusion or a high-fat diet, as wild-type mice did. FATP1-mediated fatty acid uptake may cause intramuscular lipid accumulation leading to insulin resistance in muscle if the fatty acids are not oxidized. While mouse models demonstrated an absolute requirement for FATP4 for survival, they provided no direct evidence for a role of FATP4 in insulin resistance. However, expression of FATP4 in human adipose tissue was increased in obesity (independent of genetic factors). While other members of the FATP family have important roles in fatty acid metabolism, they have not been clearly linked to insulin resistance. FATP-mediated fatty acid uptake may be driven by intrinsic acyl-CoA synthase activity. SUMMARY: Any role in the development of insulin resistance is likely to be different for each member of the FATP family. So far, both FATP1 and FATP4 have been associated with parameters related to insulin resistance. Whether increased FATP-mediated fatty acid uptake is beneficial or detrimental may be dependent on the tissue in question and on the subsequent fate of the fatty acids. These issues remain to be resolved. PMID: 15767857 [PubMed - indexed for MEDLINE] 3887. Drugs. 2004;64 Suppl 2:19-41. Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis. van Oostrom AJ(1), van Wijk J, Cabezas MC. Author information: (1)Departments of Internal Medicine and Endocrinology, University Medical Centre Utrecht, The Netherlands. Atherosclerosis is the major cause of death in the world. Fasting and postprandial hyperlipidaemia are important risk factors for coronary heart disease (CHD). Recent developments have undoubtedly indicated that inflammation is pathophysiologically closely linked to atherogenesis and its clinical consequences. Inflammatory markers such as C-reactive protein (CRP), leucocyte count and complement component 3 (C3) have been linked to CHD and to hyperlipidaemia and several other CHD risk factors. Increases in these markers may result from activation of endothelial cells (CRP, leucocytes, C3), disturbances in adipose tissue fatty acid metabolism (CRP, C3), or from direct effects of CHD risk factors (leucocytes). It has been shown that lipoproteins, triglycerides, fatty acids and glucose can activate endothelial cells, most probably as a result of the production of reactive oxygen species. Similar mechanisms may also lead to leucocyte activation. Increases in triglycerides, fatty acids and glucose are common disturbances in the metabolic syndrome and are most prominent in the postprandial phase. People are in a postprandial state most of the day, and this phase is proatherogenic. Inhibition of the activation of leucocytes, endothelial cells, or both, is an interesting target for intervention, as activation is obligatory for adherence of leucocytes to the endothelium, thereby initiating atherogenesis. Potential interventions include the use of unsaturated long-chain fatty acids, polyphenols, antioxidants, angiotensin converting enzyme inhibitors and high-dose aspirin, which have direct anti-inflammatory and antiatherogenic effects. Furthermore, peroxisome proliferator activating receptor gamma (PPARgamma) agonists and statins have similar properties, which are in part independent of their lipid-lowering effects. PMID: 15765889 [PubMed - indexed for MEDLINE] 3888. J Endocrinol Invest. 2004 Nov;27(10):982-91. Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. Giannini S(1), Serio M, Galli A. Author information: (1)Endocrinology Unit, Department of Clinical Pathophysiology, University of Florence, Italy. s.giannini@dfc.unifi.it Thiazolidinediones (TZD) [Troglitazone (TRO), Pioglitazone (PGZ), Rosiglitazone, (RGZ)] are a novel class of antidiabetic drugs for patients with Type-2 diabetes mellitus (T2DM) able to decrease blood glucose, working through a reduction of insulin resistance. The family of TZD exerts its effect specifically bound to peroxisome proliferator-activated receptor y (PPARy). This is a member of the nuclear hormone receptor superfamily of ligand-dependent transcription factors, together with PPARalpha and deltabeta. Although PPARgamma is essentially expressed in adipose tissue, it has also been found in endothelial cells, macrophages, vascular smooth muscle cells, glomerular mesangial cells, hepatic stellate cells and in several cancer cell lines. In these cells, the PPARgamma activation by TZD determines modulatory effects on growth factor release, production of cytokine, cell proliferation and migration, extracellular matrix remodeling and control on cell cycle progression and differentiation. In addition, TZD have been shown to have a potent antioxidant effect. This review, taking a quick look beyond the antidiabetic activity of PPARgamma, shows the dramatic ranging of medical implications that the use of TZD could have modulating the PPARgamma activity in several diseases with a strong social impact, such as insulin resistance syndrome, chronic inflammation, atherosclerosis and cancer. PMID: 15762051 [PubMed - indexed for MEDLINE] 3889. J Endocrinol Invest. 2004 Nov;27(10):969-74. Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 and pathogenesis of the metabolic syndrome. Putignano P(1), Pecori Giraldi F, Cavagnini F. Author information: (1)University of Milan, Istituto Scientifico Ospedale San Luca, Milan, Italy. Glucocorticoids are important regulators of glucose, lipid and protein metabolism, acting mainly in the liver, adipose tissue and muscle. Chronic glucocorticoid excess is associated with clinical features, such as insulin resistance, visceral obesity, hypertension, and dyslipidemia, which also represent the classical hallmarks of the metabolic syndrome. Elevenbeta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), a key intracellular enzyme which catalyses the conversion of inactive cortisone to active cortisol, has been implicated in the development of the metabolic syndrome. The shift of this reaction towards cortisol generation may lead to tissutal overexposure to glucocorticoids even with normal circulating cortisol levels. The most robust evidence in support of a pathogenetic role of this enzyme in the development of the metabolic syndrome has been reported in experimental animals, whereas results of human studies are less convincing with several case control and cross-sectional studies showing an association between with 11beta-HSD-1 setpoint and individual features of the metabolic syndrome. However, recent data suggest a tissue-specific rather than systemic alteration of this shuttle, with down-regulation in liver but up-regulation in adipose tissue and skeletal muscle of obese subjects. New techniques based on direct tissutal estimates of cortisol/cortisone ratios are clearly needed to precisely assess the role of enzyme in all target tissues. If confirmed, these results would prompt the development of selective and tissue-specific 11beta-HSD-1 inhibitors to decrease insulin resistance and treat the metabolic syndrome, thus contrasting the harmful effects of glucocorticoid excess in peripheral tissues. PMID: 15762049 [PubMed - indexed for MEDLINE] 3890. Arq Bras Endocrinol Metabol. 2004 Dec;48(6):803-11. Epub 2005 Mar 8. [Visceral, subcutaneous or intramuscular fat: where is the problem?]. [Article in Portuguese] Hermsdorff HH(1), Monteiro JB. Author information: (1)Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, MG. The adipose tissue is a dynamic organ that secrets several factors, denominated adipokines. They are associated, directly or indirectly, in a process that contributes to atherosclerosis, hypertension, insulinic resistance and diabetes type 2, dyslipidemias, presenting the link between adiposity, metabolic syndrome and cardiovascular diseases. In the obesity, body fat depots are increased, presenting eventual elevation in the adipokines expression and secretion. The different fat depots, visceral, abdominal subcutaneous, gluteal-femoral subcutaneous and intramuscular adipose tissue, have different metabolic and endocrine degrees, interfering, therefore, with specific form in the process associated with body adiposity in obese and diabetics subjects. The present study seeks to discuss the endocrine and metabolic role of each adipose tissue compartment, by way to assess their contribution to the complications linked to obesity. PMID: 15761553 [PubMed - indexed for MEDLINE] 3891. Drug News Perspect. 2005 Jan-Feb;18(1):5-11. Biphasic expression of lipin suggests dual roles in adipocyte development. Phan J(1), Peterfy M, Reue K. Author information: (1)Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90073, USA. The identification of gene mutations that cause lipodystrophies, conditions characterized by a lack of normal adipose tissue, has revealed new proteins that play a role in adipocyte biology. Lipin is one such protein identified in a lipodystrophic mouse strain and found to be critical for normal adipocyte differentiation. Interestingly, lipin displays a biphasic expression pattern in adipocytes, with peaks of expression at two points during adipogenesis--a transient induction in preadipocytes prior to expression of peroxisome proliferator-activated receptor gamma, and a second wave of expression in mature adipocytes. Thus, lipin appears to have critical roles in both adipocyte differentiation and in the function of mature adipocytes. PMID: 15753971 [PubMed - indexed for MEDLINE] 3892. Endocrinol Metab Clin North Am. 2005 Mar;34(1):49-62. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Reaven GM(1). Author information: (1)Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford Medical Center, Stanford, CA 94305, USA. greaven@cvmed.stanford.edu The ability of insulin to stimulate glucose disposal varies sixfold to eightfold among apparently healthy individuals. The only way that insulin-resistant persons can prevent the development of type 2 diabetes is by secreting the increased amount of insulin that is necessary to compensate for the resistance to insulin action. The greater the magnitude of muscle and adipose tissue insulin resistance, the more insulin must be secreted to maintain normal or near-normal glucose tolerance. Although compensatory hyperinsulinemia may prevent the development of fasting hyperglycemia in insulin-resistant individuals, the price paid is the untoward physiologic effects of increased circulating insulin concentrations on tissues that retain normal insulin sensitivity. This article focused on the interplay between insulin resistance at the level of the muscle and adipose tissue and normal hepatic insulin sensitivity; this leads to the atherogenic lipoprotein profile that is characteristic of insulin-resistant individuals. It would be inappropriate to minimize the importance of differential insulin sensitivity in the genesis of the changes in lipoprotein metabolism that increase CVD risk in insulin-resistant persons. It would be equally remiss not to emphasize that differential tissue insulin resistance also is necessary to explain why insulin-resistant/hyperinsulinemic individuals are more likely to develop the clinical syndromes (with the exception of type 2 diabetes mellitus) that are listed in Box 1. PMID: 15752921 [PubMed - indexed for MEDLINE] 3893. J Immunol. 2005 Mar 15;174(6):3137-42. Leptin in immunology. Matarese G(1), Moschos S, Mantzoros CS. Author information: (1)Gruppo di ImmunoEndocrinologia, Istituto di Endocrinologia e Oncologia Sperimenttale, Consiglio Nazionale delle Ricerche, Naples, Italy. Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses. PMID: 15749839 [PubMed - indexed for MEDLINE] 3894. Curr Hypertens Rep. 2005 Apr;7(2):96-102. Advanced-glycation end products in insulin-resistant states. Soldatos G(1), Cooper ME, Jandeleit-Dahm KA. Author information: (1)Baker Heart Research Institute, Commercial Road, Melbourne 3181, Victoria, Australia. Insulin resistance is a central component of a number of clinical conditions, including the metabolic syndrome, diabetes, and hypertension. There is emerging evidence that the consequent hyperinsulinemia and visceral adiposity may be directly responsible for the excess cardiovascular morbidity and mortality seen in these conditions. Advanced-glycation end products, a chemically diverse group of compounds found in higher levels in insulin-resistant states, have also been shown to adversely affect endothelial function as well as activate numerous intracellular signaling pathways implicated in the atherosclerotic pathway. In this review, we summarize the factors thought to be important in both the initiation and exacerbation of the insulin-resistant state, and directly examine the potential role of advanced-glycation end products in this process. PMID: 15748532 [PubMed - indexed for MEDLINE] 3895. Prog Urol. 2004 Nov;14(5):689-701. [Action of androgens on fat distribution and metabolic balance]. [Article in French] Tostain J(1), Heim M, Rossi D. Author information: (1)Service de médecine interne et gériatrie, CHU de Marseille. PMID: 15747618 [PubMed - indexed for MEDLINE] 3896. MMW Fortschr Med. 2005 Jan 27;147(4):41-3. [Secretory activity of the adipocytes and comorbidities of obesity]. [Article in German] Skurk T(1), Hauner H. Author information: (1)Else-Kröner-Fresenius-Zentrum für Ernährungsmedizin, TU München. thomas.skurk@wzw.tum.de Fatty tissue synthesizes and secretes a wide range of products that may be directly involved in the pathogenesis of the complications associated with obesity. These so-called adipokines may trigger or sustain a chronic inflammatory process. By manipulating the secretory function of fat cells, it might in future be possible to prevent the development of the metabolic and cardiovascular complications of obesity. Current data already suggest that weight reduction and certain substances with an anti-inflammatory action reduce the risk for the metabolic and cardiovascular complications of obesity. To date, however, the evidence available is only indirect, and is insufficient to definitively establish causal relationships between certain secretory products of adipocytes and the comorbidities of adiposity. Further clinical studies are needed. PMID: 15745341 [PubMed - indexed for MEDLINE] 3897. Treat Endocrinol. 2004;3(1):11-8. Leptin as a potential treatment for obesity: progress to date. Bell-Anderson KS(1), Bryson JM. Author information: (1)Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, NSW, Australia. kim@usyd.edu.au Despite significant reductions in the consumption of dietary fat, the prevalence of obesity is steadily rising in western civilization. Of particular concern is the recent epidemic of childhood obesity, which is expected to increase the incidence of obesity-related disorders. The obese gene (ob) protein product leptin is a hormone that is secreted from adipocytes and functions to suppress appetite and increase energy expenditure. Leptin is an attractive candidate for the treatment of obesity as it is an endogenous protein and has been demonstrated to have potent effects on bodyweight and adiposity in rodents. Whereas leptin has been successfully used in the treatment of leptin-deficient obese patients, trials in hyperleptinemic obese patients have yielded variable results. Long-acting leptins have been tried but with no greater success. Other strategies including the use of leptin analogs and other factors that bypass normal leptin delivery systems are being developed. Identifying the mechanisms at the molecular level by which leptin functions will create new avenues for pharmaceutical targeting to simulate the intracellular effects of leptin. PMID: 15743109 [PubMed - indexed for MEDLINE] 3898. Biochimie. 2005 Jan;87(1):117-23. Transcriptomics applied to obesity and caloric restriction. Viguerie N(1), Poitou C, Cancello R, Stich V, Clément K, Langin D. Author information: (1)Unité de Recherches sur les Obésités Inserm UPS U586, Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France. viguenat@toulouse.inserm.fr Caloric restriction still remains the most efficient way to promote weight loss. Deciphering the molecular basis of adaptation to energy restriction is critical for the tailoring of new therapeutic strategies. This review focuses on the recent input of gene profiling on adipose tissue in obesity pathogenesis and on the new insights on adaptations occurring during very low caloric diet (VLCD) in humans. Hypocaloric diets improve a wide range of metabolic parameters including lipolytic efficiency, insulin sensitivity, and inflammatory profile. In the subcutaneous white adipose tissue (scWAT) the VLCD induced a decrease in the mRNA levels for the antilipolytic alpha2-adrenergic receptor associated with changes in catecholamine-induced adipocyte lipolytic capacity. The improvement in insulin sensitivity was not associated with a change in subcutaneous adipose tissue adiponectin gene expression or in its plasma level, suggesting that adiponectin is not involved in the regulation of VLCD-induced improvement of insulin sensitivity and that there is a small contribution of subcutaneous adipose tissue to plasma adiponectin levels. Pangenomic microarray studies in human scWAT revealed that a panel of inflammatory markers and acute phase reactants were over expressed in obese compared to lean subjects. Caloric restriction improved the inflammatory profile of obese subjects through a decrease of pro-inflammatory factors and an increase of anti-inflammatory molecules. These genes were mostly expressed in the stroma vascular fraction of the adipose tissue. Specific cell-type isolation and immunohistochemistry demonstrated that monocyte/macrophage lineage cells were responsible for the expression of both mRNA and protein inflammatory markers. The acute phase proteins serum amyloid A was highly expressed in mature adipocytes from obese subjects. Caloric restriction decreased both serum amyloid mRNA and circulating levels. Obesity now clearly appears as chronic low-grade inflammation state. Modulation of the inflammatory pathways may represent new therapeutic targets for the treatment of obesity-related complications. PMID: 15733746 [PubMed - indexed for MEDLINE] 3899. Biochimie. 2005 Jan;87(1):73-9. Development of conjugated linoleic acid (CLA)-mediated lipoatrophic syndrome in the mouse. Poirier H(1), Niot I, Clément L, Guerre-Millo M, Besnard P. Author information: (1)Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA), UMR 5170 CNRS-CESG/1214INRA/Université de Bourgogne, F-21000 Dijon, France. Conjugated linoleic acids (CLA) are positional and geometric dienoic isomers of linoleic acid. Dietary CLA supplementation leads to a drop in fat mass in various species, including in humans. The t10,c12-CLA isomer is responsible for this anti-obesity effect. The reduction of fat mass is especially dramatic in the mouse, in which it is associated with severe hyperinsulinemia, insulin resistance and massive liver steatosis. The origin of these adverse side effects and putative chronology of events leading to CLA-mediated lipoatrophic syndrome are presented and discussed in this review. PMID: 15733740 [PubMed - indexed for MEDLINE] 3900. Biochimie. 2005 Jan;87(1):65-71. HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo. Lagathu C(1), Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, Caron M, Bastard JP. Author information: (1)Inserm U.680 and IFR65, Université Pierre et Marie Curie, Faculté de Médecine Saint-Antoine, 27, rue Chaligny, 75571 Paris cedex 12, France. HIV-1-infected patients on antiretroviral therapy frequently develop a lipodystrophy syndrome, characterized by peripheral lipoatrophy and visceral fat redistribution associated with metabolic alterations including dyslipidemia and insulin resistance. Its pathophysiology remains unclear but the antiretroviral treatment, associating protease inhibitors (PIs) and nucleoside analogue inhibitors of the viral reverse transcriptase (NRTIs), plays a major role. Some antiretroviral molecules inhibit differentiation and induce insulin resistance and apoptosis in adipose cells both in vitro and in vivo. In vitro, PIs and NRTIs increase the expression and secretion of pro-inflammatory cytokines such as TNF alpha, IL-6 and L-1beta, which are involved in altered adipocyte functions and decrease that of adiponectin, a positive modulator of insulin sensitivity. Similar alterations are observed in fat and serum from HIV-1-infected lipodystrophic patients under antiviral treatment associating PIs and NRTIs. Altered adipokine secretion could result from patients' exposure to PIs and NRTIs and lead to altered adipocyte differentiation, insulin resistance and apoptosis, ultimately resulting in lipoatrophy. These disorders probably result in a decreased secretion of adiponectin and an increased release of free fatty acids by insulin-resistant adipose tissue. Therefore, they could be involved in whole body insulin resistance and metabolic alterations in lipodystrophic HIV-1-infected patients. PMID: 15733739 [PubMed - indexed for MEDLINE] 3901. Biochimie. 2005 Jan;87(1):51-6. The role of MAPKs in adipocyte differentiation and obesity. Bost F(1), Aouadi M, Caron L, Binétruy B. Author information: (1)Inserm U568, Université de Nice Sophia-Antipolis, Faculté de Médecine, Avenue de Valombrose, 06107 Nice cedex, France. bost@unice.fr The ERK, p38 and JNK mitogen activated protein kinases (MAPKs) are intracellular signalling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. MAPKs are activated by a large variety of stimuli and one of their major functions is to connect cell surface receptors to transcription factors in the nucleus, which consequently triggers long-term cellular responses. This review focuses on their in vitro and in vivo roles in adipocyte differentiation and obesity. Hyperplasia of adipose tissue is a critical event for the development of obesity. Several studies have analysed the role of MAPKs in vitro in adipocyte differentiation of preadipocyte established cell lines. In the case of ERK, although the first data appeared contradictory, a consensus scenario arises: ERK would be necessary to initiate the preadipocyte into the differentiation process and, thereafter, this signal transduction pathway needs to be shut-off to proceed with adipocyte maturation. The limitation of these cellular models is that only terminal adipocyte differentiation can be analysed, eluding the early proliferative steps of adipogenesis. New insights are now emerging by investigations conducted either in vitro with the use of embryonic stem (ES) cells or in vivo with mice where these genes are invalidated. These studies not only confirm and/or precise the various functions of MAPKs in adipogenesis but, importantly, reveal unsuspected roles, for example JNK in obesity or ERK in adipogenesis of ES cells, and, for a given pathway, assign specific functions to each isoform. It appears now that a fine tuning of the MAPKs regulates both normal and pathological adipogenesis. The precise understanding of the cascade of these molecular events and the way to regulate them will be certainly crucial in order to efficiently fight obesity. PMID: 15733737 [PubMed - indexed for MEDLINE] 3902. Biochimie. 2005 Jan;87(1):27-32. Proposed involvement of adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase in the metabolic syndrome. Cadoudal T(1), Leroyer S, Reis AF, Tordjman J, Durant S, Fouque F, Collinet M, Quette J, Chauvet G, Beale E, Velho G, Antoine B, Benelli C, Forest C. Author information: (1)Inserm UMR-S 530; Université Paris5, Centre Universitaire, U.F.R. Biomédicale, 45, rue des Saints-Pères, 75006 Paris, France. Elevated concentration of plasma non-esterified fatty acids (NEFA) is now recognized as a key factor in the onset of insulin-resistance and type 2 diabetes mellitus. During fasting, circulating NEFAs arise from white adipose tissue (WAT) as a consequence of lipolysis from stored triacylglycerols. However, a significant part of these FAs (30-70%) is re-esterified within the adipocyte, so that a recycling occurs and net FA output is much less than << true >> lipolysis. Indeed, a balance between two antagonistic processes, lipolysis and FA re-esterification, controls the rate of net FA release from WAT. During fasting, re-esterification requires glyceroneogenesis defined as the de novo synthesis of glycerol-3-P from pyruvate, lactate or certain amino acids. The key enzyme in this process is the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C; EC 4.1.1.32). Recent advance has stressed the role of glyceroneogenesis and of PEPCK-C in FA release from WAT. Results indicate that glyceroneogenesis is indeed important to lipid homeostasis and that a disregulation in this pathway may have profound pathophysiological effects. The present review focuses on the regulation of glyceroneogenesis and of PEPCK-C gene expression and activity by FAs, retinoic acids, glucocorticoids and the hypolipidemic class of drugs, thiazolidinediones. PMID: 15733733 [PubMed - indexed for MEDLINE] 3903. Biochimie. 2005 Jan;87(1):21-5. The role of the orphan nuclear receptor Rev-Erb alpha in adipocyte differentiation and function. Laitinen S(1), Fontaine C, Fruchart JC, Staels B. Author information: (1)UR545 Inserm, Institut Pasteur de Lille, and Faculté de Pharmacie, Université de Lille II, 1, rue du Pr Calmette, 59019 Lille, France. Lipid and carbohydrate homeostasis in higher organisms is governed by an integrated system that has a capacity to rapidly respond to metabolic changes. Numerous signals reciprocally convey information about body fat status from the periphery to central nervous system in the attempt to maintain body weight nearly stable throughout life. The role of adipocyte in energy homeostasis extends its function as a simple energy storage cell. Indeed, adipose tissue not only secretes fatty acids, but is also an active endocrine and paracrine organ due to the production of secreted proteins and lipid indicators collectively called adipokines. These observations have spurred interest in the identification of the transcriptional and other regulatory pathways of adipocyte differentiation. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) (NR1C3) and members of the CCAAT enhancer-binding protein (C/EBP) family are central mediators controlling adipocyte differentiation and function. Rev-erb alpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene. Rev-erb alpha acts as a negative regulator of transcription binding to the same response element than another orphan nuclear receptor, ROR alpha. Rev-erb alpha is highly expressed in adipose tissue, skeletal muscle, heart, liver and brain. Rev-erb alpha expression increases during adipocyte differentiation of 3T3-L1 cells and is induced by PPAR gamma activation in both 3T3-L1 cells in vitro and in rat adipose tissue in vivo via a direct repeat (DR2) in the Rev-erb alpha promoter. Ectopic expression of Rev-erb alpha potentiates the adipocyte differentiation in 3T3-L1 cells. Recent results in vascular smooth muscle cells (VSMCs) indicate that Rev-erb alpha also controls inflammation by regulating NF-kappa B responsive genes, such as IL-6 and COX-2. Future studies on a potential role of Rev-erb alpha on glucose homeostasis and/or inflammation control are thus warranted. PMID: 15733732 [PubMed - indexed for MEDLINE] 3904. Biochimie. 2005 Jan;87(1):9-13. PPAR gamma, 10 years later. Lazar MA(1). Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6149, USA. lazar@mail.med.upenn.edu It is now over 10 years since the discovery of peroxisome proliferator activated receptor gamma (PPAR gamma) and its unique role in adipogenesis. The subsequent identification of PPAR gamma as the target of insulin sensitizing drugs certified this ligand-regulated transcription factor as an exciting link between adipocyte biology and peripheral insulin resistance. Here, I summarize the great progress that has been made over the past decade in elucidating the biology of PPAR gamma and its role in adipogenesis and glucose metabolism. Prospects for future research leading to new therapies for obesity and diabetes are also discussed. PMID: 15733730 [PubMed - indexed for MEDLINE] 3905. Biochimie. 2005 Jan;87(1):5-8. Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment? Grimaldi PA(1). Author information: (1)Inserm U636, Centre de Biochimie, UFR Sciences, Université de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice, France. grimaldi@unice.fr Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in both developmental and metabolic functions. There are activated by fatty acids, fatty acid metabolites, and synthetic compounds marketed for their lipid-lowering and antidiabetic actions. It was clearly established that activation of PPAR alpha and PPAR gamma, by fibrates and thiazolidinediones, respectively, impair metabolic disorders. The implication of the third member of the PPAR family, PPAR delta, remained evasive until recently. These past few years, it has been demonstrated that treatment with PPAR delta agonists normalizes blood lipids, reduces insulin resistance and adiposity in rodent and primate. Utilization of both cellular and animal models revealed that the nuclear receptor plays a central role in the control of fatty acid burning in adipose tissue and skeletal muscle. Furthermore, PPAR delta appeared to be important for adaptive response of skeletal muscle to environmental changes, such as physical exercise. PMID: 15733729 [PubMed - indexed for MEDLINE] 3906. Acta Med Austriaca. 2004;31(4):130-2. [The metabolic syndrome: epidemiology and diagnosis]. [Article in German] Hoppichler F(1). Author information: (1)Salzburg Institute for Preventive Cardiology and Nutrition, Salzburg, Osterreich. Friedrich.Hoppichler@bbsalz.at There has been a tremendous increase in overweight and obesity in industrialized countries. Because of its comorbidities obesity is defined as a disease. The abdominal fat distribution is associated with insulin resistance and with a number of cardiovascular risk factors; all of them are included in the metabolic syndrome. The metabolic syndrome can easily be defined by clinical symptoms and laboratory results, which are defined in the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (AP III). Abdominal obesity is characterised by a waist circumference of over 102 cm for men and over 88 cm for women, plasma triglycerides >150 mg/dL, a low HDL cholesterol level (<40 mg/dL for men, <50 mg/dL for women), a blood pressure of over 130/85 mm Hg and an abnormal fasting glucose value >110 mg/dL. PMID: 15732248 [PubMed - indexed for MEDLINE] 3907. Acta Med Austriaca. 2004;31(4):112-4. [Endocrinologie and obesity]. [Article in German] Maier C(1), Luger A. Author information: (1)Klinische Abteilung für Endokrinologie und Stoffwechsel, Universitätsklinik fur Innere Medizin III, Medizinische Universität Wien, Osterreich. The endocrine system plays a central role in the regulation of body weight and fat distribution. The influence of thyroid hormones, growth hormone, cortisol und sex steroids on body weight are described with a focus on hyper- and hypofunction of these systems. In addition, sequelae of therapeutic interventions aiming to restore homeostasis in dysfunction are discussed. Finally, neuroendocrine control of appetite and syndromes that are consequences of disturbed neuroendocrine control of food intake are described. PMID: 15732244 [PubMed - indexed for MEDLINE] 3908. Acta Med Austriaca. 2004;31(4):98-111. [The adipose tissue as an endocrine organ]. [Article in German] Szendrödi J(1), Roden M. Author information: (1)Klinische Abteilung für Endokrinologie und Stoffwechsel, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Wien, Osterreich. The adipose tissue stores excess energy but also produces a series of substances including cytokines (adipocytokines) which participate in regulatory processes. The physiologic and pathophysiologic relevance of these factors has only recently been described in more detail. Defects in adiponectin as well as overproduction of free fatty acids play an important role in the development of insulin resistance typical for obesity. Rare forms of obesity or lipodystrophy can now be explained by defects in the leptin system. The contribution of adipose tissue and its cytokines to the relationship between inflammation and the metabolic syndrome is currently under investigation. PMID: 15732243 [PubMed - indexed for MEDLINE] 3909. Vitam Horm. 2005;70:309-32. Novel roles for acylation stimulating protein/C3adesArg: a review of recent in vitro and in vivo evidence. Maslowska M(1), Wang HW, Cianflone K. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada. Recent experimental evidence is shedding more light on the physiological actions of acylation-stimulating protein (ASP)/C3adesArg. The role of ASP in regulating lipid metabolism has primarily focused on its participation in the stimulation of triglyceride synthesis (TGS) and glucose transport. Although there is no doubt that ASP, an adipocyte-produced hormone, plays a key physiological role, accumulating evidence suggests that the effects of ASP go beyond its acute effects on lipid metabolism. In this review, we present novel findings of ASP/C3adesArg effects on preadipocyte differentiation. In 3T3-L1 and 3T3-F442A cells, ASP can substitute for insulin and enhance differentiation as measured by intracellular lipid droplet accumulation, clonal expansion, and increased expression of differentiation markers. Specifically, ASP increased basal TGS by 250% after 9 days differentiation, with similar effects induced by insulin. With ASP treatment, expression of C/EBPdelta was up-regulated early in differentiation (day 2) and decreased thereafter. Expression of PPARgamma and late markers of differentiation, such as adipsin and diacylglycerol acyltransferase-1, were also increased. Effects on clonal expansion were indicated by a twofold increase in [(3)H] thymidine incorporation in 3T3-L1 cells compared to treatment with IBMX + DX alone. Further, the effects of ASP extended beyond adipose tissue to endocrine effects on hormone secretion of insulin (pancreatic cells); cytokines TNFalpha, IL-1beta, and IL-6 (myeloid cells); prolactin, growth hormone, and adrenocorticotropin (pituitary cells). Finally, the potential implication of C5L2, the newly discovered ASP receptor, and its expression profile in various tissues are discussed relative to ASP function. PMID: 15727809 [PubMed - indexed for MEDLINE] 3910. Magnes Res. 2004 Dec;17(4):314-26. Importance of magnesium depletion with hypofunction of the biological clock in the pathophysiology of headhaches with photophobia, sudden infant death and some clinical forms of multiple sclerosis. Durlach J(1), Pagès N, Bac P, Bara M, Guiet-Bara A. Author information: (1)Université Pierre et Marie Curie, Paris VI, 75252 Paris Cedex 05, France. jean.durlach@wanadoo.fr Mg depletion is a type of Mg deficit due to a dysregulation of the Mg status. It cannot be corrected through nutritional supplementation only, but requires the most specific correction of the dysregulating mechanism. Among those, Biological Clock (BC) dysrhythmias are to be considered. The aim of this study is to analyze the clinical forms of Mg depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary with homeostatic response [reactive Photophobia (Pphi] to light neurostimulating effects [Nervous Hyper Excitability (NHE)]. The symptomatology is mainly diurnal and observed during fair weather (Spring,Summer). The elective marker of hBC is represented by a decrease in melatonin and in its metabolites in various fluids. The clinical forms of NHE due to Mg depletion with hBC are central and peripheral. The central forms associate anxiety, headaches and dyssomnia. The peripheral manifestations are neuromuscular: photosensitive epilepsia mainly. Three chronopathological forms of Mg depletion with hBC have been highlighted: 1. Headaches with Pphi: mainly migraine; 2. Sudden Infant Death Syndrome (SIDS); 3. Multiple Sclerosis (MS).- Headaches with Pphi, migraine particularly. These cephalalgias are diurnal with Pphi and are aggravated during the fair seasons (particularly during midnight sun-summer). Migraine is their typical form with its dishabituation to visual stimuli and its occipital cortex hyperexcitability. Comorbidity with anxiety is frequent. In 2/3 of the cases, it appears first.- SIDS might be linked to an impaired maturation of both photoendocrine system and brown adipose tissue. MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons. They have been underestimated because they disagree with the dogma of the << latitude gradient >>, presently questioned. Comorbidities with anxiety and migraine are frequent.hBC may be treated by using darkness therapy with a balanced Mg status. Absolute light deprivation should only be used only in acute indications and is time-limited. Partial substitutive therapy and chromatotherapy have not been validated yet and are still uncertain. PMID: 15726907 [PubMed - indexed for MEDLINE] 3911. Lipids. 2004 Nov;39(11):1077-83. Mechanisms of regulation of gene expression by fatty acids. Nakamura MT(1), Cheon Y, Li Y, Nara TY. Author information: (1)Department of Food Science and Human Nutrition and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. mtnakamu@uiuc.edu Fatty acids (FA) regulate the expression of genes involved in lipid and energy metabolism. In particular, two transcription factors, sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator activated receptor alpha (PPARalpha), have emerged as key mediators of gene regulation by FA. SREBP-1c induces a set of lipogenic enzymes in liver. Polyunsaturated fatty acids (PUFA), but not saturated or monounsaturated FA, suppress the induction of lipogenic genes by inhibiting the expression and processing of SREBP-1c. This unique effect of PUFA suggests that SREBP-1c may regulate the synthesis of unsaturated FA for incorporation into glycerolipids and cholesteryl esters. PPARalpha plays an essential role in metabolic adaptation to fasting by inducing the genes for mitochondrial and peroxisomal FA oxidation as well as those for ketogenesis in mitochondria. FA released from adipose tissue during fasting are considered as ligands of PPARalpha. Dietary PUFA, except for 18:2 n-6, are likely to induce FA oxidation enzymes via PPARalpha as a "feed-forward " mechanism. PPARalpha is also required for regulating the synthesis of highly unsaturated FA, indicating pleiotropic functions of PPARalpha in the regulation of lipid metabolic pathways. It is yet to be determined whether FA regulate other transcription factors such as liver-X receptor, hepatocyte nuclear factor 4, and carbohydrate response element binding protein. PMID: 15726822 [PubMed - indexed for MEDLINE] 3912. J Pharmacol Sci. 2005 Feb;97(2):164-70. Epub 2005 Feb 11. Nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor gamma, CREB-binding protein, and adiponectin. Tsuchida A(1), Yamauchi T, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, USA. Obesity is defined as increased mass of adipose tissue, conferring a higher risk of cardiovascular and metabolic disorders such as diabetes, hyperlipidemia, and coronary heart disease. To investigate the role of transcriptional factors, which are involved in adipocytes differentiation and adiposity, we have generated peroxisome proliferator-activated receptor (PPAR) gamma or CREB-binding protein (CBP)-deficient mice by gene targeting. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Heterozygous CBP-deficient mice showed increased insulin sensitivity and were completely protected from body weight gain induced by a high-fat diet. PPARgamma or CBP deficiency results in increased effects of hormones such as adiponectin and leptin. Adiponectin was decreased in obesity and lipoatrophy, and replenishment of adiponectin ameliorated insulin resistance. Moreover, adiponectin-deficient mice showed insulin resistance and atherogenic phenotype. Finally, cDNA encoding adiponectin receptors (AdipoR1/R2) have been identified by expression cloning. The expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyperinsulinemia models, and it is correlated with adiponectin sensitivity. These results facilitate the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and propose the molecular targets for anti-diabetic and anti-atherogenic drugs. PMID: 15725703 [PubMed - indexed for MEDLINE] 3913. Orv Hetil. 2005 Jan 9;146(2):51-5. [Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome]. [Article in Hungarian] Góth M(1), Hubina E, Korbonits M. Author information: (1)Országos Gyógyintézeti Központ, Belgyógyászati Osztály, Endokrinológiai Szakprofil, Budapest. goth@ogyik.hu The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities. PMID: 15724952 [PubMed - indexed for MEDLINE] 3914. Curr Drug Targets. 2005 Feb;6(1):57-62. Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Safford KM(1), Rice HE. Author information: (1)Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA. saffo002@mc.duke.edu There is growing evidence to suggest that reservoirs of stem cells may reside in several types of adult tissue. These cells may retain the potential to transdifferentiate from one phenotype to another, presenting exciting possibilities for cellular therapies. Recent discoveries in the area of neural differentiation are particularly exciting given the limited capacity of neural tissue for intrinsic repair and regeneration. Adult adipose tissue is a rich source of mesenchymal stem cells, providing an abundant and accessible source of adult stem cells. These cells have been termed adipose derived stem cells (ASC). The characterization of these ASCs has defined a population similar to marrow-derived and skeletal muscle-derived stem cells. The success seen in differentiating ASC into various mesenchymal lineages has generated interest in using ASC for neuronal differentiation. Initial in vitro studies characterized the morphology and protein expression of ASC after exposure to neural induction agents. Additional in vitro data suggests the possibility that ASCs are capable of neuronal activity. Progress in the in vitro characterization of ASCs has led to in vivo modeling to determine the survival, migration, and engraftment of transplanted ASCs. While work to define the mechanisms behind the transdifferentiation of ASCs continues, their application to neurological diseases and injuries should also progress. The subject of this review is the capacity of adipose derived stem cells (ASC) for neural transdifferentiation and their application to the treatment of various neurologic disorders. PMID: 15720213 [PubMed - indexed for MEDLINE] 3915. Int J Obes (Lond). 2005 Mar;29 Suppl 1:S13-6. Regulation of PPARgamma activity during adipogenesis. Farmer SR(1). Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. farmer@biochem.bumc.bu.edu Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulating an array of diverse functions in a variety of cell types including regulation of genes associated with growth and differentiation. Its most notable function is to regulate development of adipose tissue, which involves coordinating expression of many hundreds of genes responsible for establishment of the mature adipocyte phenotype. Our recent studies have demonstrated a role for MEK/ERK signaling and CCAAT/enhancer binding proteins (C/EBP)beta in regulating expression of PPARgamma during adipogenesis. Furthermore, we have shown that cAMP-dependent signaling along with C/EBPbeta leads to the stimulation of PPARgamma activity by mechanisms that probably involve production of PPARgamma ligands. Additionally, we have recently demonstrated that phosphorylation of C/EBPbeta at a consensus ERK/GSK3 site is required for the PPARgamma-associated expression of adiponectin during the terminal stages of adipogenesis. GSK3beta also influences PPARgamma activity by regulating the turnover and subcellular localization of beta-catenin, a potent transcriptional activator of Wnt signaling. In fact, we have recently shown a crosstalk between PPARgamma and beta-catenin signaling. Specifically, activation of PPARgamma induces the degradation of beta-catenin during preadipocyte differentiation by mechanisms that require GSK3beta and the proteasome. In contrast, expression of a GSK3beta-phosphorylation-defective beta-catenin renders beta-catenin resistant to the degradatory action of PPARgamma. Interestingly, expression of the mutant beta-catenin blocks expression of adiponectin and C/EBPalpha in response to the activation of PPARgamma. PMID: 15711576 [PubMed - indexed for MEDLINE] 3916. Int J Obes (Lond). 2005 Mar;29 Suppl 1:S10-2. Atypical transcriptional regulators and cofactors of PPARgamma. Miard S(1), Fajas L. Author information: (1)INSERM, U540, Equipe Avenir, Metabolism and Cancer Laboratory, Montpellier, France. Regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) activity is the result of several events. The first control level is the regulation of the expression of PPARgamma. Examples of this regulation, during adipogenesis, is the transactivation of the PPARgamma promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARgamma expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARgamma transcription during clonal expansion, whereas E2F4 represses PPARgamma expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARgamma expression. A second regulatory level of PPARgamma action is interaction with cofactors. We will focus our attention on the atypical PPARgamma modulators. We have described an interaction between PPARgamma and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARgamma and upon the phosphorylation status of RB. The interaction between PPARgamma and RB decreases the transcriptional activity of PPARgamma through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARgamma. PMID: 15711575 [PubMed - indexed for MEDLINE] 3917. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2005 Jan;19(1):78-81. [Adipose tissues and wound healing]. [Article in Chinese] Cheng B(1), Fu X, Sheng Z. Author information: (1)The Key Research Laboratory of Wound Repair of PLA, 304th Clinical Department, General Hospital of PLA, Beijing 100037, P R China. OBJECTIVE: To study the relationship between the adipose tissues and cutaneous morphogenesis on wound healing. METHODS: Adipose tissues' participation in regulation of food intake, energy expenditure, fuel metabolism, and a variety of other physiological processes was reviewed in the latest literature. The wound healing was regulated by endocrine, paracrine, and adipocyte-derived molecules. RESULTS: Several factors secreted by adipose tissues (leptin, cytokines, growth factors, lipids, metallothioneins, ect) regulated wound healing. CONCLUSION: Adipose tissues may play a vital role in the process of wound healing. Further understanding of the complex interaction between adipose cells and cutaneous morphogenesis is essential to explore the mechanism of wound healing. PMID: 15704851 [PubMed - indexed for MEDLINE] 3918. Cesk Fysiol. 2004;53(4):167-75. [Tumor necrosis factor alfa (TNFalpha) and insulin resistance]. [Article in Czech] Gwozdziewiczová S(1), Lichnovská R, Hrebícek J. Author information: (1)Ustav fyziologie, Lékarská fakulta Univerzity Palackého v Olomouci. simgwozd@tunw.upol.cz Obesity and diabetes mellitus type 2 belong among the most frequent illnesses and are categorized among the dominant risk factors for cardiovascular disease in all developed countries. There is a causal relation between insulin resistance and the origin of these risk factors of the cardiovascular morbidity and mortality. Numerous studies have attemted to identify the mechanisms linking obesity with insulin resistance and type 2 diabetes. Numbers of factors have been suggested as having a role in pathogenesis of obesity-related insulin resistance. One of these factors is tumor necrosis factor alfa (TNFalpha). PMID: 15704741 [PubMed - indexed for MEDLINE] 3919. Int J Sports Med. 2005 Feb;26 Suppl 1:S28-37. Measurement of substrate oxidation during exercise by means of gas exchange measurements. Jeukendrup AE(1), Wallis GA. Author information: (1)School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, UK. a.e.jeukendrup@bham.ac.uk Measures of substrate oxidation have traditionally been calculated from indirect calorimetry measurements using stoichiometric equations. Although this has proven to be a solid technique and it has become one of the standard techniques to measure whole body substrate metabolism, there are also several limitations that have to be considered. When indirect calorimetry is used during exercise most of the assumptions on which the method is based hold true although changes in the size of the bicarbonate pool at higher exercise intensities may invalidate the calculations of carbohydrate and fat oxidation. Most of the existing equations are based on stoichiometric equations of glucose oxidation and the oxidation of a triacylglycerol that is representative of human adipose tissue. However, in many exercise conditions, glycogen and not glucose is the predominant carbohydrate substrate. Therefore we propose slightly modified equations for the calculation of carbohydrate and fat oxidation for use during low to high intensity exercise. Studies that investigated fat oxidation over a wide range of intensities and that determined the exercise intensity at which fat oxidation is maximal have provided useful insights in the variation in fat oxidation between individuals and in the factors that affect fat oxidation. Fat oxidation during exercise can be influenced by exercise intensity and duration, diet, exercise training, exercise mode and gender. Although a number of important factors regulating fat oxidation have been identified, it is apparent that a considerable degree of inter-subject variability in substrate utilization persists and cannot be explained by the aforementioned factors. Future research should investigate the causes of the large inter-individual differences in fat metabolism between individuals and their links with various disease states. PMID: 15702454 [PubMed - indexed for MEDLINE] 3920. Growth Horm IGF Res. 2005 Feb;15(1):19-27. Are the metabolic effects of GH and IGF-I separable? Mauras N(1), Haymond MW. Author information: (1)Division of Endocrinology, The Department of Pediatrics at the Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207, USA. nmauras@nemours.org IGF-I mediates some, but not all of the metabolic actions of GH and it has both GH-like and insulin-like actions in vivo. GH and IGF-I both have a net anabolic effect in man enhancing whole body protein synthesis over a period of weeks and perhaps months. Both hormones favorably improve body composition in GH deficient subjects with an increase in lean body mass and decreased adiposity. This is also observed when IGF-I is given to patients with GH-receptor mutations. These compounds, however, have divergent effects on carbohydrate metabolism. A potent glucose lowering effect is typically observed after IGF-I administration, with improved insulin sensitivity with marked lowering of circulating insulin concentrations, whereas GH therapy is associated with mild compensatory hyperinsulinemia, a reflection of relative insulin resistance. The latter observation makes IGF-I a potentially more convenient anabolic agent to use in conditions where carbohydrate metabolism is more likely to be impaired. GH increases lipolysis as a direct effect of GH on the adipocyte, as well as lipid oxidation by increasing substrate availability. However IGF-I increases lipid oxidation only when given chronically, most likely as a result of chronic insulinopenia. These compounds have been tried in a variety of catabolic conditions in man and both hormones have been effective in reducing the protein wasting effects of glucocorticosteroids and mitigate some of the catabolic effects of severe hypogonadism in males. A comparison of these and other effects of these hormones is provided in this brief review. Subsequent studies are still needed to fully elucidate the safety and efficacy of IGF-I for use in humans. PMID: 15701568 [PubMed - indexed for MEDLINE] 3921. Am J Physiol Regul Integr Comp Physiol. 2005 Mar;288(3):R557-60. BAT control shows the way: medullary raphe/parapyramidal neurons and sympathetic regulation of brown adipose tissue. Blessing WW. Comment on Am J Physiol Regul Integr Comp Physiol. 2005 Mar;288(3):R723-32. PMID: 15699359 [PubMed - indexed for MEDLINE] 3922. J Long Term Eff Med Implants. 2004;14(6):455-65. Biomaterials for use in frontal sinus obliteration. D'Addario M(1), Haug RH, Talwar RM. Author information: (1)University of Kentucky, College of Dentistry, Lexington, KY 40536-0297, USA. Although fractures of the frontal sinus are infrequent (2-15% of victims of facial trauma), because of their proximity to the brain and eyes, the consequences of their management may have a significant impact on the patient. For frontal sinus injuries that affect the nasofrontal ducts or posterior wall, obliteration is indicated. Although frontal sinus surgery has been documented since 1750, a consensus as to the best material for obliteration has not been achieved. The particular autogenous and alloplastic materials for use in frontal sinus obliteration will be the focus of this review, with particular attention paid to assessing their physical properties, advantages, disadvantages, and complications. While numerous new alloplastic materials show promise for frontal sinus obliteration, autogenous fat remains the most popular and most frequently used material with the longest history of use, and it is versatile and reliable. PMID: 15698374 [PubMed - indexed for MEDLINE] 3923. Drug News Perspect. 2004 Dec;17(10):661-9. Peroxisome proliferator-activated receptors as attractive antiobesity targets. Zhang F(1), Lavan B, Gregoire FM. Author information: (1)Department of Insulin Resistance Biology, Metabolex, Inc., Hayward, California 94545, USA. The peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are a group of ligand-activated transcription factors that function as lipid sensors and govern numerous biological processes, including energy metabolism, cell proliferation, differentiation and inflammation. It has been known for some time that both PPAR alpha and PPAR gamma play a role in lipid metabolism. Antidiabetic drugs of the thiazolidinedione (TZD) class are potent and selective activators of PPAR gamma known to promote adipocyte differentiation and lipid storage. Lipid-lowering agents of the fibrate class activate PPAR alpha. Until recently, the function of PPAR delta remained elusive, but recent progress has shown that PPAR delta plays a key role in lipid metabolism, as it regulates serum lipid profiles and fatty acid beta oxidation in muscle and adipose tissue. This suggests that PPAR delta agonists may play a beneficial role in the treatment of lipid disorders, in particular obesity. This review will highlight key new findings in PPAR delta biology and discuss the recent evidence linking PPAR alpha and PPAR gamma to adipose tissue biology and the development of obesity. PMID: 15696231 [PubMed - indexed for MEDLINE] 3924. Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):290-7. Adipose tissue and atherothrombosis. Alessi MC(1), Lijnen HR, Bastelica D, Juhan-Vague I. Author information: (1)Laboratoire d'ématologie, INSERM UMR626, UFR de Médecine, Université de la Méditerranée, Marseille, France. Marie-Christine.Alessi@medecine.univ-mrs.fr Obesity is associated with increased cardiovascular mortality and morbidity mainly through insulin resistance. Dysregulation of protein secretion by adipose tissue is involved in obesity-related diseases. Adipose tissue contributes to create a subinflammatory status which could explain the disturbances in the haemostatic and fibrinolytic systems observed in obesity. Elevated plasma levels of PAI-1 demonstrated the strongest association with the degree of insulin resistance and could be an underlying mechanism for the thrombotic tendency and the progression of atherothrombosis during obesity. The effect of PAI-1 was examined on adipose tissue growth in several mouse models as well as on adipocyte differentiation in vitro. Most of the data indicate that PAI-1 can effectively modulate weight gain and may be a potential therapeutic target for controlling cardiovascular morbidity in obese subjects. PMID: 15692231 [PubMed - indexed for MEDLINE] 3925. Endocr Rev. 2005 Feb;26(1):114-46. Endocrine control of body composition in infancy, childhood, and puberty. Veldhuis JD(1), Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M, Mauras N, Bowers CY. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA. veldhuis.johannes@mayo.edu Body composition exhibits marked variations across the early human lifetime. The precise physiological mechanisms that drive such developmental adaptations are difficult to establish. This clinical challenge reflects an array of potentially confounding factors, such as marked intersubject differences in tissue compartments; the incremental nature of longitudinal intrasubject variations in body composition; technical limitations in quantitating the unobserved mass of mineral, fat, water, and muscle ad seriatim; and the multifold contributions of genetic, dietary, environmental, hormonal, nutritional, and behavioral signals to physical and sexual maturation. From an endocrine perspective (reviewed here), gonadal sex steroids and GH/IGF-I constitute prime determinants of evolving body composition. The present critical review examines hormonal regulation of body composition in infancy, childhood, and puberty. PMID: 15689575 [PubMed - indexed for MEDLINE] 3926. J Endocrinol. 2005 Feb;184(2):291-318. Appetite control. Wynne K(1), Stanley S, McGowan B, Bloom S. Author information: (1)Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity. PMID: 15684339 [PubMed - indexed for MEDLINE] 3927. Curr Atheroscler Rep. 2005 Feb;7(1):58-62. Adipocytokines: emerging therapeutic targets. Matsuzawa Y(1). Author information: (1)Sumitomo Hospital, Kita-Ku, Osaka 530-0005, Japan. matsuzawa-yuji@sumitomo-hp.or.jp Recently, adipocytes have been shown to be recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. Among adipocytokines, adiponectin, a newly found adipose tissue-specific collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein. The function of adipocytes might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysfunction of adipocytes and results in the development of a variety of metabolic and circulatory diseases through the abnormal secretion of adipocytokines. In this review, the importance of adipocytokines, including adiponectin, is discussed with respect to atherosclerosis. PMID: 15683604 [PubMed - indexed for MEDLINE] 3928. Nutr Neurosci. 2004 Aug;7(4):195-200. Adiponectin: novelties in metabolism and hormonal regulation. Duntas LH(1), Popovic V, Panotopoulos G. Author information: (1)Evgenidion Hospital, University of Athens, 11528 Athens, Greece. ledunt@otenet.gr Adiponectin is a protein secreted exclusively by white adipose tissues and is abundantly present in human plasma. Adiponectin was found decreased in obese and diabetes mellitus type 2 patients and increased with weight reduction. A negative correlation between circulating adiponectin levels and body mass index and insulin resistance has been demonstrated. Plasma adiponectin concentrations were found lower in diabetes mellitus type 2 patients with coronary artery disease. Moreover, studies in aortic endothelial cells revealed that the protein exerts a dose-dependent decrease of the surface expression of vascular adhesion molecules and cytokine production from macrophages, suggesting the implication of adiponectin in atherosclerosis and inflammation. Weight loss and treatment with thiazolidinediones stimulate endogenous adiponectin production. Peripheral administration of adiponectin leads to reduction of visceral adiposity and increase of free fatty acid oxidation and insulin resistance. Furthermore, it enhances the expression of uncoupling proteins and sympathetic nerve activity in adipose tissues. Experimental studies in mice have shown that intraperitoneal administration of adiponectin lowers plasma glucose. These data show adiponectin to be an important factor in the issue of obesity and its associated disorders, and indicate a potential future utilization of adiponectin as a drug in the treatment of metabolic syndrome. PMID: 15682645 [PubMed - indexed for MEDLINE] 3929. Trends Pharmacol Sci. 2005 Feb;26(2):88-93. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Villarroya F(1), Domingo P, Giralt M. Author information: (1)Department of Biochemistry and Molecular Biology, University of Barcelona, Spain. fvillaroya@ub.edu The lipodystrophy syndrome and associated metabolic alterations are the most prevalent adverse effects in HIV-infected patients taking highly active anti-retroviral therapy (HAART). This syndrome involves profound disturbances in adipose tissue. The toxic effect of nucleoside reverse transcriptase inhibitors on mitochondrial function is a major contributor to the lipodystrophy syndrome. Although adipocytes were not expected to be preferential targets of mitochondrial toxicity, recent re-evaluation of the role of mitochondria in white adipocytes helps to explain the molecular basis of HAART-associated lipodystrophy. Adipocytes are a source of paracrine and endocrine signals that influence adipocyte biology and systemic metabolism. Mitochondrial disturbances elicited by HAART result in an abnormal perception of the bioenergetic status by adipocytes, thus leading to enhancement of catalytic pathways and apoptosis in peripheral adipose tissue, alterations in the differentiation of brown versus white adipocytes, and the release of hormonal signals that lead to systemic metabolic disturbances. PMID: 15681026 [PubMed - indexed for MEDLINE] 3930. Ginecol Obstet Mex. 2005 Feb;73(2):99-104. [Leptin and its influence on the main gynecoobstetric diseases]. [Article in Spanish] Vadillo Buenfil M(1), Vela Ojeda J, Galindo Rodríguez G, Salazar Exaire D. Author information: (1)Unidad de Investigación en Epidemiología, Clínica y Departamento Clínico de Endocrinología, Hospital de Especialidades Antonio Fraga Mouret, Centro Médico La Raza, IMSS, México, DF. mvadillo_2000@yahoo.com.mx Leptin is a protein hormone synthesized and secreted by adipose tissue and also probably in other organs and systems in human body. It has multiple functions such as to regulate feed intake and energy balance, gonadal regulation, action in the hypothalamo-pituitary-gonadal axis, regulates the metabolism of the fetal-placental unit in the pregnancy, fertility and reproductive systems, actions in the endometrium, mammary gland with corresponding influences on important physiologic processes such as menstruation, pregnancy and lactation. In the gynecologic surgery the serum leptin concentration is also modified. The knowledge of serum leptin concentration in the oncological diseases is going-up. Leptin is modified in the choriocarcinoma, Meigs' syndrome and other tumors. A better understanding of regulatory mechanisms will have direct clinical significance, as leptin has been proposed to impact on those causes of human perinatal morbidity and mortality that are associated with abnormalities of fetal maturity and development, general concept growth, trophoblast endocrinology, and placental sufficiency. Further investigations in this area will be necessary to improve new knowledge and a better understanding of the actions about this hormone. PMID: 21961344 [PubMed - indexed for MEDLINE] 3931. J Nippon Med Sch. 2004 Dec;71(6):360-70. Fetal and neonatal thermoregulation. Asakura H(1). Author information: (1)Department of Obstetrics and Gynecology, Nippon Medical School Second Hospital, Kanagawa 211-8533, Japan. morgen@nms.ac.jp The metabolic rate of the fetus per tissue weight is relatively high when compared to that of an adult. Moreover, heat is transferred to the fetus via the placenta and the uterus, resulting in a 0.3 degrees C to 0.5 degrees C higher temperature than that of the mother. Therefore, fetal temperature is maternally dependent until birth. At birth, the neonate rapidly cools in response to the relatively cold extrauterine environment. Thus, the neonatal temperature rapidly drops soon after birth. In order to survive, the neonate must accelerate heat production via nonshivering thermogenesis (NST), which is coupled to lypolysis in brown adipose tissue. Heat is produced by uncoupling ATP synthesis via the oxidation of fatty acids in the mitochondria, utilizing uncoupled protein. Thermogenesis must begin shortly after birth and continue for several hours. Since thermogenesis requires adequate oxygenation, a distressed neonate with hypoxemia cannot produce an adequate amount of heat to increase its temperature. In contrast to the neonate, the fetus cannot produce extra heat production. This is because the fetus is exposed to inhibitors to NST, which are produced in the placenta and then enter the fetal circulation. The important inhibitors include adenosine and prostaglandin E2, both of which have strong anti-lypolytic actions. The inhibitors play an important role in the metabolic adaptation of a physiological hypoxic fetus because NST requires adequate oxygenation. Furthermore, the presence of NST inhibitors allows the fetus to accumulate an adequate amount of brown adipose tissue before birth. The umbilical circulation transfers 85% of the heat produced by the fetus to the maternal circulation. The remaining 15% is dissipated through the fetal skin to the amnion, and is then transferred through the uterine wall to the maternal abdomen. As long as fetal heat production and loss are appropriately balanced, the temperature differential between the fetus and the mother remains constant (heat clump). However, when the umbilical circulation is occluded for any reason, the fetal temperature will rise in relation to the extent of the occlusion. The fetal temperature may elevate to the hyperthermic range in cases of acute cord occlusion; if this occurs, fetal growth, including brain development, may be impacted. Experimentally induced cord occlusion, which is recognized as a significant cause of brain damage, results in a rapid elevation of body temperature; however, the brain temperature tends to remain constant. This is considered to be a cerebral thermoregulatory adaptation to hypoxemia, which has the physiologic advantage of protecting the fetus from hyperthermia, a condition that predisposes the fetus to hypoxic injury (cerebral hypometabolism). A number of thermoregularatory mechanisms are in place to maintain normal fetal and neonatal growth. Data has primarily been collected from animal studies; aside from the strict thermal control provided in the newborn nursery, little information exists concerning these mechanisms in the human fetus and neonate. Probably further information on thermoregulation is necessary specially to improve perinatal management for hypoxic fetuses. PMID: 15673956 [PubMed - indexed for MEDLINE] 3932. Nutr Hosp. 2004 Nov-Dec;19(6):319-24. [Obesity and the immune system]. [Article in Spanish] Muñoz M(1), Mazure RA, Culebras JM. Author information: (1)Facultad de Medicina. Universidad de Málaga. With an increased prevalence of obesity in developed countries, associated chronic diseases rise in a parallel way. Morbidity secondary to overweight and obesity include type 2 diabetes, dislipemia, hypertension, heart disease, cerebrovascular disease, cholelithiasis, osteoarthritis, heart insufficiency, sleep apnoea, menstrual changes, sterility and psychological alterations. There is also a greater susceptibility to suffer some types of cancer, infections, greater risk of bacteremia and a prolonged time of wound healing after surgical operations. All these factors indicate that obesity exerts negative effects upon the immune system. Immune changes found in obesity and their possible interrelations are described in this article. Changes produced during obesity affect both humoral and cellular immunity. It is known that adipose tissue, together with its role as energy reserve in form of triglycerides, has important endocrine functions, producing several hormones and other signal molecules. Immune response can be deeply affected by obesity, playing leptin an important role. Properties of leptin, alterations of leptin levels in different situations and its changes with different medical and surgical therapies for obesity are described in this article. PMID: 15672646 [PubMed - indexed for MEDLINE] 3933. Diabetes Metab. 2004 Dec;30(6):498-505. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Scheen AJ(1). Author information: (1)Department of Medicine, Division of Diabetes, Nutrition and Metabolic Disorders, CHU Sart Tilman (B35), B-4000 Liège 1, Belgium. Andre.scheen@chu.ulg.ac.be The inhibition of the renin-angiotensin system (RAS) with either angiotensin converting enzyme inhibitors (ACEIs) or AT1 angiotensin receptor blockers (ARBs) consistently and significantly reduces the incidence of type 2 diabetes in patients with hypertension or congestive heart failure. The mechanisms underlying this protective effect appear to be complex and may involve an improvement of both insulin sensitivity and insulin secretion. These two effects may result, at least in part, from the well known effects of these pharmacological agents on the vascular system on the one hand, on the ionic balance on the other hand. Indeed, the vasodilation induced by ACEIs or ARBs could improve the blood circulation in skeletal muscles, thus favouring peripheral insulin action, but also in the pancreas, thus promoting insulin secretion. Preserving cellular potassium and magnesium pools by blocking the aldosterone effects could also improve both cellular insulin action and insulin secretion. However, besides these classical effects, new mechanisms have been recently suggested. A direct effect of the inhibition of angiotensin and/or of the enhancement of bradykinin on various steps of the insulin cascade signalling has been described as well an increase in GLUT4 glucose transporters after RAS inhibition. Furthermore, it has been demonstrated that angiotensin II inhibits adipogenic differentiation of human adipocytes via A1 receptors and, therefore, it has been hypothesised that RAS blockade may prevent diabetes by promoting the recruitment and differentiation of adipocytes. Finally, some lipophilic ARBs appear to induce PPAR-gamma activity in the adipose tissue. Hence, the protection against type 2 diabetes observed after RAS inhibition may be partially linked to a thiazolidinedione-like effect. In conclusion, numerous physiological and biochemical mechanisms could explain the protective effect of RAS inhibition against the development of type 2 diabetes in individuals with arterial hypertension or congestive heart failure. What might be the main mechanism in the overall protection effect of ACEIs or ARBs remains an open question. PMID: 15671919 [PubMed - indexed for MEDLINE] 3934. Alcohol. 2004 Aug;34(1):81-7. Obesity and alcoholic liver disease. Diehl AM(1). Author information: (1)Johns Hopkins University, Baltimore, MD 21205, USA. diehl004@mc.duke.edu Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index-based guidelines for "safe" alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators. PMID: 15670669 [PubMed - indexed for MEDLINE] 3935. Aging Male. 2004 Sep;7(3):236-57. Progesterone: the forgotten hormone in men? Oettel M, Mukhopadhyay AK. 'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches. PMID: 15669543 [PubMed - indexed for MEDLINE] 3936. Eur J Clin Invest. 2005 Feb;35(2):82-92; discussion 80. Peroxisome proliferator-activated receptor gamma: the more the merrier? Argmann CA(1), Cock TA, Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 1 rue Laurent Fries, F-67404 Illkirch, France. The consequence of activating the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), which coordinates adipocyte differentiation, validates the concept, 'you are what you eat'. Excessive caloric intake leads to fat formation if the energy from these nutrients is not expended. However, this evolutionary adaptation to store energy in fat, which can be released under the form of fatty acids, potent PPARgamma agonists, has become a disadvantage in today's affluent society as it results in numerous metabolic imbalances, collectively known as the metabolic syndrome. With the surge of human and genetic studies on PPARgamma function, the limitations to the benefits of PPARgamma signalling have been realized. It is now evident that the most effective strategy for resetting the balance of this thrifty gene is through its modulation rather than full activation, with the goal to improve glucose homeostasis while preventing adipogenesis. Finally, as more PPARgamma targeted pathways are revealed such as bone homeostasis, atherosclerosis and longevity, it is most certain that the PPARgamma thrifty gene hypothesis will evolve to incorporate these. PMID: 15667578 [PubMed - indexed for MEDLINE] 3937. Curr Diab Rep. 2005 Feb;5(1):70-5. The evolving role of inflammation in obesity and the metabolic syndrome. Lee YH(1), Pratley RE. Author information: (1)Diabetes and Metabolism Translational Medicine Unit, Division of Endocrinology and Metabolism, Department of Medicine, University of Vermont College of Medicine, FAHC/UHC--Arnold 3412, One South Prospect Street, Burlington, VT 05401, USA. ylee@uvm.edu Advances in adipose tissue biology over the past 10 years have led to an improved understanding of the mechanisms linking obesity with the metabolic syndrome and other complications. Obesity is characterized by a chronic, systemic low-grade state of inflammation. Biomarkers of inflammation, such as the leukocyte count, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and C-reactive protein, are increased in obesity, associated with insulin resistance, and predict the development of type 2 diabetes and cardiovascular disease. It is now clear that the adipocyte is an active participant in the generation of the inflammatory state in obesity. Adipocytes secrete a variety of cytokines, including IL-6 and TNF-alpha, that promote inflammation. Moreover, recent studies suggest that obesity is associated with an increase in adipose tissue macrophages, which also participate in the inflammatory process through the elaboration of cytokines. An improved understanding of the role of adipose tissue in the activation of inflammatory pathways may suggest novel treatment and prevention strategies aimed at reducing obesity-associated morbidities and mortality. PMID: 15663921 [PubMed - indexed for MEDLINE] 3938. Curr Opin Crit Care. 2005 Feb;11(1):1-9. Is loaded breathing an inflammatory stimulus? Vassilakopoulos T(1), Roussos C, Zakynthinos S. Author information: (1)Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, Greece. tvassil@med.uoa.gr PURPOSE OF REVIEW: To summarize recent data indicating that loaded breathing generates an inflammatory response. RECENT FINDINGS: Loaded breathing initiates an inflammatory response consisting of elevation of plasma cytokines and recruitment and activation of lymphocyte subpopulations. These cytokines do not originate from monocytes but are instead produced within the diaphragm secondary to the increased muscle activation. Oxidative stress is a major stimulus for the cytokine induction secondary to loaded breathing. The production of cytokines within the diaphragm may mediate the diaphragm muscle fiber injury that occurs with strenuous contractions, or contribute to the expected repair process. These cytokines may also compromise diaphragmatic contractility or contribute to the development of muscle cachexia. They may also have systemic effects, mobilizing glucose from the liver and free fatty acids from the adipose tissue to the strenuously working respiratory muscles. At the same time, they stimulate the hypothalamic-pituitary-adrenal axis, leading to the production of adrenocorticotropic hormone and beta-endorphins. The adrenocorticotropic hormone response may represent an attempt of the organism to reduce the injury occurring in the respiratory muscles through the production of glucocorticoids and the induction of the acute-phase response proteins. The beta-endorphin response would decrease the activation of the respiratory muscles and change the pattern of breathing, which becomes more rapid and shallow, possibly in an attempt to reduce and/or prevent further injury to the respiratory muscles. SUMMARY: Loaded breathing is an immune challenge for the body, initiating an inflammatory response. Further studies are needed to elucidate the role of this response in the development of ventilatory failure. PMID: 15659939 [PubMed - indexed for MEDLINE] 3939. Nihon Naika Gakkai Zasshi. 2004 Dec 10;93(12):2543-51. [Sleep apnea syndrome in elderly patients]. [Article in Japanese] Tatsumi K, Kuriyama T. PMID: 15658483 [PubMed - indexed for MEDLINE] 3940. Ann Hepatol. 2004 Oct-Dec;3(4):137-45. Microarrays, antiobesity and the liver. Castro-Chávez F(1). Author information: (1)Departamento de Biología Molecular en Medicina, Hospital Civil de Belén, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, México. fdocc@yahoo.com In this review, the microarray technology and especially oligonucleotide arrays are exemplified with a practical example taken from the perilipin-/- mice and using the dChip software, available for non-lucrative purposes. It was found that the liver of perilipin-/- mice was healthy and normal, even under high-fat diet when compared with the results published for the scd1-/- mice, which under high-fat diets had a darker liver, suggestive of hepatic steatosis. Scd1 is required for the biosynthesis of monounsaturated fatty acids and plays a key role in the hepatic synthesis of triglycerides and of very-low-density lipoproteins. Both models of obesity resistance share many similar phenotypic antiobesity features, however, the perilipin-/- mice had a significant downregulation of stearoyl CoA desaturases scd1 and scd2 in its white adipose tissue, but a normal level of both genes inside the liver, even under high-fat diet. Here, different microarray methodologies are discussed, and also some of the most recent discoveries and perspectives regarding the use of microarrays, with an emphasis on obesity gene expression, and a personal remark on my findings of increased expression for hemoglobin transcripts and other hemo related genes (hemo-like), and for leukocyte like (leuko-like) genes inside the white adipose tissue of the perilipin-/- mice. In conclusion, microarrays have much to offer in comparative studies such as those in antiobesity, and also they are methodologies adequate for new astounding molecular discoveries [free full text of this article Online]. PMCID: PMC3651835 PMID: 15657555 [PubMed - indexed for MEDLINE] 3941. Horm Metab Res. 2004 Nov-Dec;36(11-12):859-66. GIP as a potential therapeutic agent? Meier JJ(1), Nauck MA. Author information: (1)Larry Hillblom Islet Research Center, UCLA School of Medicine, Los Angeles, CA 90095, USA. jmeier@mednet.ucla.eu Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity. PMID: 15655720 [PubMed - indexed for MEDLINE] 3942. Horm Metab Res. 2004 Nov-Dec;36(11-12):771-4. Physiology of GIP--a lesson from GIP receptor knockout mice. Yamada Y(1), Seino Y. Author information: (1)Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. yamada@metab.kuhp.kyoto-u.ac.jp A much greater insulin response is observed after oral glucose load than after intravenous injection of glucose. The hormonal factor(s) implicated as transmitters of signals from the gut to pancreatic beta-cells was referred to incretin; gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (GIP) is identified as one of the incretins. GIP exerts its effects by binding to its specific receptor, the GIP receptor, which is expressed in various tissues including pancreatic islets, adipose tissue, and brain. However, the physiological role of GIP has been generally thought to stimulate insulin secretion from pancreatic beta-cells, and the other actions of GIP have received little attention. We have bred and characterized mice with a targeted mutation of the GIP receptor gene. From these studies, we now know that GIP not only mediates early insulin secretion by acting on pancreatic beta-cells, but also links overnutrition to obesity by acting on adipocytes. PMID: 15655707 [PubMed - indexed for MEDLINE] 3943. Acta Physiol Scand. 2005 Jan;183(1):59-73. The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance. Valverde AM(1), Benito M, Lorenzo M. Author information: (1)Instituto de Bioquimica. Centro Mixto CSIC/UCM, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain. Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signalling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of glucose homeostasis. Brown adipocytes are target cells for insulin and IGF-I action, especially during late foetal development when insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K)/Akt. Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and protein kinase C zeta. Tumour necrosis factor (TNF-alpha) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS-2. Activation of stress kinases and phosphatases by this cytokine contribute to insulin resistance. Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor gamma, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. Rosiglitazone ameliorates insulin resistance provoked by TNF-alpha, completely restoring insulin-stimulated glucose uptake in parallel to the insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating insulin action, as well as for the mechanism by which rosiglitazone increase insulin sensitivity under situations that mimic insulin resistance. PMID: 15654920 [PubMed - indexed for MEDLINE] 3944. Acta Physiol Scand. 2005 Jan;183(1):13-30. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Giorgino F(1), Laviola L, Eriksson JW. Author information: (1)Medicina Interna, Endocrinologia e Malattie Metaboliche, Dipartimento dell'Emergenza e dei Trapianti di Organi, Università degli Studi di Bari, Piazza Giulio Cesare, 11, 1-70124 Bari, Italy. Adipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot-related differences in the protein content of fat-produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots. PMID: 15654917 [PubMed - indexed for MEDLINE] 3945. Pediatr Radiol. 2005 Feb;35(2):141-54. Epub 2004 Nov 16. 18F-FDG-avid sites mimicking active disease in pediatric Hodgkin's. Kaste SC(1), Howard SC, McCarville EB, Krasin MJ, Kogos PG, Hudson MM. Author information: (1)St. Jude Children's Research Hospital, Department of Radiological Sciences, University of Tennessee College of Medicine, 332 N. Lauderdale, Memphis, TN 38105, USA. sue.kaste@stjude.org About 1,700 children in the United States are diagnosed yearly with lymphomas; Hodgkin's disease accounts for approximately half of these cases, or 6% of all childhood cancers. Contemporary therapy allows for the achievement of remission in the majority of cases. The fusion of positron emission tomography (PET) with CT provides the most accurate imaging method for disease characterization and treatment response. However, experience with 18F-FDG PET-CT is limited in pediatric Hodgkin's disease. Numerous non-oncologic processes can mimic recurrent or residual tumor. This pictorial addresses mimickers of disease such as uptake in normal structures, infections, transforming germinal canters and effects of therapy on normal tissues. It is essential for radiologists to be familiar with these findings in order to stage disease activity and therapeutic response accurately. PMID: 15654605 [PubMed - indexed for MEDLINE] 3946. Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2031-41. Epub 2005 Jan 14. Adipokines: molecular links between obesity and atheroslcerosis. Lau DC(1), Dhillon B, Yan H, Szmitko PE, Verma S. Author information: (1)Department of Medicine, Julia McFarlane Diabetes Research Center, University of Calgary, Calgary, Canada. Atherosclerotic disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment, and prevention. The increasing epidemic of obesity, insulin resistance, and diabetes will likely add to this burden. Increasingly, it is becoming apparent that adipose tissue is an active endocrine and paracrine organ that releases several bioactive mediators that influence not only body weight homeostasis but also inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, and atherosclerosis. The cellular mechanisms linking obesity and atherosclerosis are complex and have not been fully elucidated. This review summarizes the experimental and clinical evidence on how excess body fat influences cardiovascular health through multiple yet converging pathways. The role of adipose tissue in the development of obesity-linked insulin resistance, metabolic syndrome, and diabetes will be reviewed, including an examination of the molecular links between obesity and atherosclerosis, namely, the effects of fat-derived adipokines. Finally, we will discuss how these new insights may provide us with innovative therapeutic strategies to improve cardiovascular health. PMID: 15653761 [PubMed - indexed for MEDLINE] 3947. Vnitr Lek. 2004 Nov;50(11):852-7. [An ultrasensitive C-reactive protein assay--a new parameter in cardiovascular risk]. [Article in Czech] Dvoráková A(1), Poledne R. Author information: (1)Centrum experimentálního výzkumu srdce a cév, Laborator pro výzkum aterosklerózy Institutu klinické a experimentální mediciny, Praha. Comment in Vnitr Lek. 2004 Nov;50(11):809-11. Vnitr Lek. 2004 Nov;50(11):807-9. Elevated C-reactive protein concentration, measured by an ultrasensitive method (hsCRP), has been proved to be a risk factor for atherosclerosis progression and its complications (myocardial infarction and stroke) in otherwise healthy men and women. In patients with already diagnosed atherosclerotic disease elevated concentration of hsCRP predicts prognosis. There are multiple causes of elevated hsCRP concentration: metabolic changes (e.g. as a part of metabolic syndrome), genetic background and chronic infections. Proinflammatory effect of adipose tissue in obese individuals seems to play an important role, hsCRP levels correlate with markers of abdominal obesity. Elevated hsCRP concentrations can be lowered both pharmacologically and by a lifestyle change. This review covers current knowledge of pathophysiology of elevated hsCRP concentration and possible use of this method in clinical medicine. PMID: 15648966 [PubMed - indexed for MEDLINE] 3948. J Ren Nutr. 2005 Jan;15(1):131-6. Adipose tissue and its relation to inflammation: the role of adipokines. Axelsson J(1), Heimbürger O, Lindholm B, Stenvinkel P. Author information: (1)Division of Renal Medicine, Department of Clinical Science, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. An activated inflammatory response is a common feature of end-stage renal disease (ESRD) patients and predicts outcome. Although various factors related to the dialysis procedure may contribute to inflammation in ESRD, a number of nondialysis-related factors also are of importance. Adipose tissue is a complex organ with functions far beyond the mere storage of energy and secretes a number of proinflammatory adipokines, such as leptin, resistin, tumor necrosis factor-alpha and interleukin-6, as well as one anti-inflammatory adipokine, adiponectin. It has been proposed that adipose tissue may be a significant contributor to increased systemic inflammation in nonrenal patients. In this review, we put forward the hypothesis that a reduction of renal mass will contribute to retention of proinflammatory adipokines, thus generating adipokine imbalance. Such an imbalance may, via effects on the central nervous system and the vasculature, contribute to wasting, atherosclerosis, and insulin resistance--all common features of ESRD. PMID: 15648022 [PubMed - indexed for MEDLINE] 3949. J Ren Nutr. 2005 Jan;15(1):125-30. Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients. Zoccali C(1), Tripepi G, Cambareri F, Catalano F, Finocchiaro P, Cutrupi S, Pizzini P, Testa A, Spoto B, Panuccio V, Enia G, Mallamaci F. Author information: (1)Consiglio Nazionale Ricerche-Istituto BIo Medicina Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell'Ipertensione Arteriosa, Reggio Calabria, Italy. carmine.zoccali@tin.it From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD. PMID: 15648021 [PubMed - indexed for MEDLINE] 3950. J Ren Nutr. 2005 Jan;15(1):111-5. Metabolic effects of ghrelin and its potential implications in uremia. Barazzoni R(1), Zanetti M, Biolo G, Guarnieri G. Author information: (1)Clinica Medica, DSCMT, University of Trieste, Trieste, Italy. barazzon@units.it Ghrelin is a recently described hormone secreted by the stomach. Ghrelin administration in ad-libitum-fed rodents was shown to increase appetite as well as body weight and body fat content, showing metabolic effects of ghrelin in vivo and suggesting its involvement in the pathogenesis of obesity. However, plasma ghrelin concentration was shown to be inversely correlated with body weight and body fat in people and rodents. Increased plasma ghrelin concentration was also reported during diet-induced weight loss and in malnourished states. These findings suggest that circulating ghrelin is regulated by nutritional state and body fat with a feedback mechanism opposing changes in body composition, with a potential key adaptive role during calorie restriction. Plasma ghrelin concentration was shown to be increased in advanced renal failure and hemodialysis patients. The known metabolic effects of ghrelin and the potential implications of hyperghrelinemia in kidney disease will be discussed in this article. PMID: 15648018 [PubMed - indexed for MEDLINE] 3951. Gac Med Mex. 2004 Jul-Aug;140 Suppl 2:S33-40. [Obesity and steatohepatitis. Histologic aspects]. [Article in Spanish] Pichardo-Bahena R(1), Paz-Gómez FJ, Estrada-Villaseñor EG. Author information: (1)Departamento de Anatomía Patológica de Medica Sur. rpichardo@medicasur.org.mx The traditional concept of adipose tissue as a passive reservoir for energy storage is no longer valid because it has been demonstrated that adipose tissue is a complex, essential, and highly active metabolic and endocrine organ that not only responds to afferent signals from traditional hormone systems and the central nervous system (CNS), but also expresses and secretes factors with important endocrine functions. These factors include leptin and other cytokines. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by adverse metabolic consequences of both adipose tissue excess and deficiency. Adipose tissue excess, particularly in visceral compartment, is associated with insulin resistance, hyperglycemia, dyslipidemia, hypertension, and prothrombotic and proinflammatory states. Liver is one of the principal targets of lipid-associated damage by mechanisms that involve apoptosis activation by source of tumoral necrosis factor-alpha and caspase activation and liberation of oxygen-reactive species by oxidative stress and enzymatic chains such as P450, CYP2E1, and CYP3A4, resulting in a continuum involving non alcohol-related fatty liver, non-alcoholic steatohepatitis with or without fibrosis, and liver cirrhosis. This work presents an overview of endocrine functions of adipose tissue and its influence on mechanisms of liver damage. PMID: 15641470 [PubMed - indexed for MEDLINE] 3952. Arq Bras Endocrinol Metabol. 2004 Jun;48(3):337-44. Epub 2004 Aug 26. [UCP-3: regulation of genic expression on skeletal muscle and possible role on body weight control]. [Article in Portuguese] Depieri TZ(1), Pinto RR, Catarin JK, de Carli MC, Garcia Júnior JR. Author information: (1)Pró-Reitoria de Pesquisa e Pós-Graduação, UNOESTE, Presidente Prudente, SP. Uncoupling proteins constitute a subgroup of mitochondrial carrier proteins that are located in the inner mitochondrial membrane. By dissipating proton gradients, they act to uncouple respiration from oxidative phosphorylation and convert fuel to heat. Four homologous UCP isoforms have been identified. UCP-1, the first UCP to be described, is found exclusively in brown adipose tissue, UCP-2 in several tissues, UCP-3 in human skeletal muscle and rat brown adipose tissue and skeletal muscle, whereas UCP-4 is expressed in the brain. Expression of UCP-3 in the skeletal muscle and the brown adipose tissue may place these tissues as important mediators for adaptative thermogenesis. However, the role of UCP-3 in energy expenditure and as a cause of obesity has been controversial. There are evidences that UCP-3 can be regulated by energy substrates as fatty acids and glucose, by entering the muscle and stimulating UCP-3 to increase energy expenditure. Our aim in this review was to describe and discuss the available information on UCP-3 regulation and its possible relation with body weight control. PMID: 15640895 [PubMed - indexed for MEDLINE] 3953. Gait Posture. 2005 Feb;21(2):212-25. Human movement analysis using stereophotogrammetry. Part 3. Soft tissue artifact assessment and compensation. Leardini A(1), Chiari L, Della Croce U, Cappozzo A. Author information: (1)Laboratorio di Analisi del Movimento, Centro di Ricerca Codivilla-Putti, Istituti Ortopedici Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy. leardini@ior.it When using optoelectronic stereophotogrammetry, skin deformation and displacement causes marker movement with respect to the underlying bone. This movement represents an artifact, which affects the estimation of the skeletal system kinematics, and is regarded as the most critical source of error in human movement analysis. A comprehensive review of the state-of-the-art for assessment, minimization and compensation of the soft tissue artifact (STA) is provided. It has been shown that STA is greater than the instrumental error associated with stereophotogrammetry, has a frequency content similar to the actual bone movement, is task dependent and not reproducible among subjects and, of lower limb segments, is greatest at the thigh. It has been shown that in in vivo experiments only motion about the flexion/extension axis of the hip, knees and ankles can be determined reliably. Motion about other axes at those joints should be regarded with much more caution as this artifact produces spurious effects with magnitudes comparable to the amount of motion actually occurring in those joints. Techniques designed to minimize the contribution of and compensate for the effects of this artifact can be divided up into those which model the skin surface and those which include joint motion constraints. Despite the numerous solutions proposed, the objective of reliable estimation of 3D skeletal system kinematics using skin markers has not yet been satisfactorily achieved and greatly limits the contribution of human movement analysis to clinical practice and biomechanical research. For STA to be compensated for effectively, it is here suggested that either its subject-specific pattern is assessed by ad hoc exercises or it is characterized from a large series of measurements on different subject populations. Alternatively, inclusion of joint constraints into a more general STA minimization approach may provide an acceptable solution. PMID: 15639400 [PubMed - indexed for MEDLINE] 3954. Rev Med Interne. 2005 Jan;26(1):54-7. [The glitazones]. [Article in French] Halimi S(1). Author information: (1)Département d'urologie, néphrologie et endocrinologie, UF diabétologie 11 A, centre hospitalier universitaire de Grenoble, BP 217, 38043 Grenoble cedex 09, France. shalimi@chu-grenoble.fr INTRODUCTION: Type 2 diabetes mellitus is one of the biggest public health problem, responsible of major complications. The treatment of hyperglycaemia has been based on lifestyle changes, diet and physical exercise, and oral antidiabetic drugs for reducing the microangiopathic complications and the high cardiovascular risk of these patients. For decades we used sulfonylureas, metformin and alpha glucosidases inhibitors. However these drugs have no effect on muscle insulin resistance, high levels of free fatty acids, lipotoxicity and progressive pancreatic beta-cell loss. EXEGESIS: Thiazolidine-diones or glitazones are the pharmacological ligands of peroxisome proliferator activated receptor gamma mainly expressed in the white adipose tissue. New adipocytes are recruited with, finally, a decrease of free fatty acids, of some cytokines, of muscle and liver insulin resistance. The hypoglycaemic effect is moderate but more pronounced in association with other oral antidiabetic drugs. Long-term studies will possibly confirm the beneficial effects on the beta-cell loss and some cardiovascular parameters in type 2 diabetes and the metabolic syndrome. CONCLUSION: Glitazones enrich the treatment of type 2 diabetes allowing new and synergistic combinations for more precocious and efficient strategies. Moreover their action on peroxisome proliferator activated receptor opens on new therapeutics for cancer, immunology, rheumatology, and infection. PMID: 15639326 [PubMed - indexed for MEDLINE] 3955. Med Sci (Paris). 2005 Jan;21(1):49-54. [PGC-1alpha, a transcriptional coactivator involved in metabolism]. [Article in French] Tiraby C(1), Langin D. Author information: (1)Unité de recherches sur les obésités, Inserm UPS U.586, Institut Louis-Bugnard, CHU de Rangueil, 1, avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France. Transcriptional coactivators can be important targets for physiologic regulation. PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells. PGC-1alpha could be a target for antiobesity or diabetes drugs. The aim of this article was to summarize the molecular mechanisms and biological programs controlled by the transcriptional coactivator PGC-1alpha. PMID: 15639020 [PubMed - indexed for MEDLINE] 3956. Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E287-91. PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. Kintscher U(1), Law RE. Author information: (1)Center for Cardiovascular Research, Institut für Pharmakologie und Toxikologie, Campus Charité-Mitte, Charité-Universitätsmedizin Berlin, Hessische Strasse 3/4, 10115 Berlin, Germany. ulrich.kintscher@charite.de Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARgamma activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARgamma function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARgamma in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARgamma in those tissues. In those studies, adipose PPARgamma has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPARgamma protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPARgamma guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPARgamma-deficient mice, the data in muscle-specific PPARgamma(-/-) mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPARgamma system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPARgamma knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization. PMID: 15637349 [PubMed - indexed for MEDLINE] 3957. J Am Coll Nutr. 2004 Dec;23(6):694S-700S. New data on the importance of gestational Mg deficiency. Durlach J(1). Author information: (1)International Society for the Development of Research on Magnesium, Pierre et Marie Curie University, Paris, France. Jean.Durlach@wanadoo.fr Chronic primary Mg deficiency is frequent. About 20% of the population consumes less than two-thirds of the RDA for Mg. Women, particularly, have low intakes. For example, in France, 23% of women and 18% of men have inadequate intakes. Mg deficiency during pregnancy can induce maternal, fetal, and pediatric consequences that might last throughout life. Studies of gestational Mg deficiency in animals show that Mg deficiency may have marked effects on parturition and postuterine involution. It has interfered with fetal growth and development, and caused morbidity from hematological effects and disturbances in temperature regulation, to teratogenic effects. Emphasis, here, is on effects of chronic clinical gestational Mg deficiency as it affects the infant. Premature labor, contributed to by uterine hyperexcitability caused by chronic maternal Mg deficiency, that can be intensified by stress, gives rise to preterm birth. If the only cause of uterine overactivity is Mg deficiency, its supplementation constitutes nontoxic tocolytic treatment, as an adjuvant treatment, that is devoid of toxicity and enhances efficacy and safety of tocolytic drugs such as beta-2 mimetics. Evidence is considered that Mg deficiency or Mg depletion can contribute to the Sudden Infant Death Syndrome (SIDS). SIDS may be a fetal consequence of maternal Mg deficiency through impaired control of Brown Adipose Tissue (BAT) thermoregulation mechanisms leading to a modified temperature set point. SIDS can result from dysthermias: hypo- or hyperthermic forms. Possibly, simple nutritional Mg supplements might be preventive. Various stresses in an infant can transform simple Mg deficiency into Mg depletion. For example, lying prone can be stressful for the baby, as can parental smoking. The role of chronopathological stress appears to be often neglected, as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to impaired maturation of both the photoneuroendocrine system and BAT. Prophylaxis of this form of SIDS should include atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. Consequences of maternal primary Mg deficiency have been inadequately studied. To determine ultimate outcomes of gestational Mg deficiency in infants, a long-term multicenter placebo-controlled prospective study should undertaken on effects of maternal nutritional Mg supplementation on lethality/morbidity in fetus, neonates, infants, children and adults, not only during pregnancy and the baby's first year, but throughout life. PMID: 15637217 [PubMed - indexed for MEDLINE] 3958. Proc West Pharmacol Soc. 2004;47:30-2. Pharmaceutical reversal of insulin resistance. Lautt WW(1), Macedo MP, Sadri P, Legare DJ, Reid MA, Guarino MP. Author information: (1)Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. wlautt@cc.umanitoba.ca Insulin action is approximately doubled following a meal. The mechanism of postprandial insulin sensitization is dependent on hepatic parasympathetic nerves regulated by the prandial status. The nerves provide a permissive signal to the liver that allows insulin to cause the release of a putative hepatic insulin sensitizing substance (HISS) that selectively stimulates glucose uptake into skeletal muscle but not liver or adipose tissue. The parasympathetic signal has several steps identified in the regulatory pathway; acetylcholine acts on muscarinic receptors leading to activation of nitric oxide synthase and generation of HISS. The meal-induced insulin (MIS) sensitization requires hepatic GSH, which decreases with fasting and several disease states. Interfering with the MIS process results in severe insulin resistance with the response to insulin being reduced by approximately 50% to levels seen in the fasted state. A wide range of conditions have been shown to be associated with insulin resistance attributed to lack of the MIS process including insulin resistance; in chronic liver disease produced by chemical damage or bile duct ligation, hepatic denervation, sucrose fed rats, aging, spontaneously hypertensive rats, fetal alcohol exposed adult offspring, spontaneously insulin resistant rats, animals with pharmacological blockade of hepatic muscarinic receptors, NO synthase, cyclooxygenase, hepatic cGMP, and hepatic GSH levels. Pharmaceutical reversal of insulin resistance has been shown in several models using a variety of approaches including mimicking or potentiating the parasympathetic signal using cholinergic agonists, NO donors, cholinesterase antagonists, phosphodiesterase antagonists, and replenishment of hepatic GSH levels. These compounds are being evaluated for therapeutic application by our international academic/industry collaborative team. The MIS process has now been demonstrated in mice, rats, guinea pigs, cats, dogs, and humans, and has been demonstrated by independent laboratories. PMID: 15633605 [PubMed - indexed for MEDLINE] 3959. Clin Calcium. 2005 Jan;15(1):87-93. [Active absorbable algal calcium (AAACa) changes calcium paradigm]. [Article in Japanese] Fujita T(1). Author information: (1)Katsuragi Hospital, Japan. Active Absorbable Algal Calcium (AAA Ca) is made by submaximally (800 degrees ) heating cleaned oyster shell under reduced pressure and mixing it with similarly heated seaweed (Cystophyllum fusiforme). AAA Ca, the best absorbed from the intestine than other available calcium compounds, consequently most efficiently suppresses parathyroid hormone secretion, increases bone mineral density and decreases vertebral fracture. Aging is associated with calcium deficiency, mostly because of the decreased biosynthesis of 1,25 (OH)2 vitamin D in the kidney. Parathyroid hormone consequently increases, contributing to various diseases associated with aging such as osteoporosis or decrease of calcium in the bone, as well as hypertension, arteriosclerosis, Alzheimer's disease and osteoarthritis due to paradoxical increase of calcium in vascular walls, brain, cartilage and intracellular compartment of many kinds of cells. Mild calcium deficiency is hard to detect despite these serious consequences because of the remarkable constancy of blood calcium concentration maintained by elaborate homeostatic control. Only by successfully counteracting calcium deficiency by AAA Ca with outstanding absorbability, the phenomenon of calcium paradox becomes a recognizable reality within our reach. PMID: 15632477 [PubMed - indexed for MEDLINE] 3960. Semin Vasc Med. 2004 Aug;4(3):229-40. Diagnostic criteria in relation to the pathogenesis of familial combined hyperlipidemia. de Graaf J(1), van der Vleuten G, Stalenhoef AF. Author information: (1)Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands. Familial combined hyperlipidemia (FCH) is the most common inherited hyperlipidemia in humans, affecting 1 to 3% of the adult population and up to 20% of patients with premature myocardial infarction. FCH is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender; however, the diagnosis of FCH based on these diagnostic criteria is inconsistent in 26% of the subjects over a five-year period, emphasizing the need for re-evaluation of the diagnostic criteria for FCH. Recently, a nomogram was developed based on absolute apolipoprotein B levels in combination with triglyceride and total cholesterol levels adjusted for both age and gender to simply and accurately diagnose FCH. When percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established based on hypertriglyceridemia (> 1.5 mmol/l) and hyperapoB (> 1200 mg/l). Standardized and simple diagnostic criteria are necessary to further delineate the pathogenesis of FCH. Several metabolic pathways have been suggested to be important in causing the FCH phenotype including hepatic VLDL overproduction either with or without impaired clearance of triglyceride-rich lipoproteins from plasma. The presence of insulin resistance and obesity in FCH patients further contribute to the expression of the lipidphenotype. A disturbed adipose tissue metabolism that results in an increased plasma free fatty acid pool may be the culprit in the pathogenesis of FCH. PMID: 15630632 [PubMed - indexed for MEDLINE] 3961. Can J Appl Physiol. 2004 Dec;29(6):808-29. Metabolic syndrome, a cardiovascular disease risk factor: role of adipocytokines and impact of diet and physical activity. Robinson LE(1), Graham TE. Author information: (1)Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. The metabolic syndrome comprises an array of cardiovascular disease (CVD) risk factors such as abdominal obesity, dyslipidemia, hypertension, and glucose intolerance. Insulin resistance and/or increased abdominal (visceral) obesity have been suggested as potential etiological factors. More recently, increasing evidence has associated insulin resistance and subclinical inflammation involving cytokines derived from adipose tissue, or adipocytokines. Despite the fact that precise mechanisms have yet to be established, there is a significant role for both diet and physical activity to improve the many factors associated with the metabolic syndrome, including modulation of various adipocytokines. Although both diet and physical activity have been studied for their ability to modify cytokines in more traditional inflammatory conditions, such as rheumatoid arthritis, they have been less studied in relation to inflammation as an underlying cause of the metabolic syndrome and/or CVD. A more thorough understanding of the clustering of metabolic abnormalities and their underlying etiology will help to define diet and physical activity guidelines for preventing and treating the metabolic syndrome, an important aspect of CVD prevention. This paper will address potential underlying causes of the metabolic syndrome, with a focus on the putative mechanistic role of adipocytokines, and will discuss the impact of diet and physical activity on the metabolic syndrome. PMID: 15630152 [PubMed - indexed for MEDLINE] 3962. Diabetes Technol Ther. 2004 Oct;6(5):732-49. Can you be large and not obese? The distinction between body weight, body fat, and abdominal fat in occupational standards. Friedl KE(1). Author information: (1)U.S. Army Research Institute of Environmental Medicine, Natick, Massachusetts 01760-5007, USA. karl.friedl@us.army.mil Weight control is an important early intervention in diabetes, but the nature of the association between weight and disordered metabolism has been confused because fat mass and its distribution are only partly associated with increasing body size. Weight, fat, and regional fat placement, specifically in the abdominal site, may each have distinctly different associations with diabetes risk. Abdominal circumference may be the common marker of poor fitness habits and of increased risk for metabolic diseases such as diabetes. This is an important question for public health policy as well as for occupational standards such as those of the military, which are intended to promote fitness for military missions and include strength and aerobic capacity, as well as military appearance considerations. U.S. soldiers are heavier than ever before, reflecting both increased muscle and fat components. They also have better health care than ever before and are required to exercise regularly, and even the oldest soldiers are required to remain below body fat limits that are more stringent than the current median values of the U.S. population over age 40. The body fat standards assessed by circumference-based equations are 20-26% and 30-36%, for various age groups of men and women, respectively, and the upper limits align with threshold values of waist circumference recommended in national health goals. The basis and effects of the Army standards are presented in this paper. U.S. Army body fat standards may offer practical and reasonable health guidelines suitable for all active Americans that might help stem the increasing prevalence of obesity that is predicted to increase the prevalence of Type 2 diabetes. PMID: 15628823 [PubMed - indexed for MEDLINE] 3963. Physiol Behav. 2004 Dec 30;83(4):659-71. Is the control of fat ingestion sexually differentiated? Geary N(1). Author information: (1)EW Bourne Laboratory, Weill Medical College of Cornell University, White Plains, NY 10506, USA. nori.geary@inw.argl.ethz.ch Sexual differentiation is a fundamental aspect of human physiology [Wizemann TM, Pardue M-L, editors. Exploring the biological contributions to human health: does sex matter? Washington DC, National Academy Press, 2001]. Therefore, this review considers whether the physiological control of eating, as related to dietary fat, is sexually differentiated. The effects of dietary fat are considered from the perspective of stimuli controlling eating that arise from oral, gastric, intestinal, hepatic, and adipose sites. The data reviewed provide substantial support for hypothesis that many such controls of fat ingestion are sexually differentiated in both humans and laboratory animals. Because as yet little is established definitively, however, the apparently most promising questions and methodologies for future work are emphasized. PMID: 15621072 [PubMed - indexed for MEDLINE] 3964. Physiol Behav. 2004 Dec 30;83(4):653-8. The new concept of adipose tissue function. Hauner H(1). Author information: (1)Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany. hauner@wzw.tum.de PMID: 15621071 [PubMed - indexed for MEDLINE] 3965. Ageing Res Rev. 2005 Jan;4(1):55-65. Epub 2004 Dec 8. Lessons learned from gene expression profile studies of aging and caloric restriction. Park SK(1), Prolla TA. Author information: (1)Department of Genetics and Medical Genetics, University of Wisconsin, 5302B Genetics building, 445 Henry Mall, Madison, WI 53706, USA. To examine molecular events associated with aging and its retardation by caloric restriction (CR), we have employed high-density oligonucleotide microarrays to define transcriptional patterns in mouse tissues, including skeletal muscle, brain, heart, and adipose. Aging results in a differential gene expression pattern specific to each tissue, and most alterations can be completely or partially prevented by CR. Transcriptional patterns of tissues from calorie-restricted animals suggest that CR retards the aging process by reducing endogenous damage and by inducing metabolic shifts associated with specific transcriptional profiles. These studies demonstrate that DNA microarrays can be used in aging research to generate panels of hundreds of transcriptional biomarkers, providing a new tool to measure biological age on a tissue-specific basis and to evaluate interventions designed to mimic the effects of CR. PMID: 15619470 [PubMed - indexed for MEDLINE] 3966. Ned Tijdschr Geneeskd. 2004 Nov 27;148(48):2379-82. [The value and limitations of the body mass index (BMI) in the assessment of the health risks of overweight and obesity]. [Article in Dutch] Kok P(1), Seidell JC, Meinders AE. Author information: (1)Leids Universitair Medisch Centrum, afd. Algemene Interne Geneeskunde, Postbus 9600, 2300 RC, Leiden. p.kok@lumc.nl --The Body Mass Index (BMI) is used as a measure of overweight and obesity. In epidemiological studies age, sex and ethnic background all have to be taken into consideration, particularly when determining the health risk caused by the amount of body fat. --Caution should be observed when using the BMI as a measure for interpreting overweight and obesity as body composition can be highly variable yet have the same BMI. Therefore, BMI is not a reliable measurement of body composition in individuals particularly in older and younger people. --Excess body fat in the visceral depot poses a separate health risk. The BMI does not give any insight into regional body fat distribution. Waist circumference is a valid index of visceral fat accumulation and can therefore be used as an indicator of health risks associated with visceral obesity. PMID: 15615272 [PubMed - indexed for MEDLINE] 3967. Rev Invest Clin. 2004 May-Jun;56(3):351-67. [Peroxisome proliferator-activated receptors (PPARs) in obesity and insulin resistance development]. [Article in Spanish] Alemán G(1), Torres N, Tovar AR. Author information: (1)Departamento de Fisiología de la Nutrición, Area de Nutriología Molecular, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF. Comment in Rev Invest Clin. 2004 Sep-Oct;56(5):686-7. The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear transcription factors that belong to the steroid receptor superfamily. PPARs family includes PPARalpha, PPARbeta/delta, PPARgamma1 and PPARgamma2. PPARs form an heterodimer with the 9-cis retinoic acid receptor (RXR) and bind to response elements present in target genes activated by these transcription factors. PPARs control the expression of genes involved in fatty acid synthesis, oxidation and storage. PPARs are present in most tissues, where PPARalpha is most abundant in liver and skeletal muscle, whereas PPARgamma is found mainly in adipose tissue. Natural ligands for PPARs are polyunsaturated fatty acids (PUFAs) and some eicosanoids, however they are also activated by compounds such as fibrates and thiazolidinediones (TZDs). In this review is shown the different PPARs isoforms, identification, and regulation of their expression and activity. Also shows which are the natural ligands, and the chemical compounds that activate PPARs. Finally, it shows the target genes activated by the different isoforms of PPARs, the metabolic integration between the different PPAR isoforms to maintain a balance between fatty acid synthesis and oxidation and the association with the development of obesity and insulin resistance. Also shows information about the nutritional requirements of PUFAs that are the main natural ligands of PPARs. PMID: 15612519 [PubMed - indexed for MEDLINE] 3968. Eur Arch Otorhinolaryngol. 2004 Nov;261(10):560-1. Epub 2004 Apr 29. Technical considerations in fat augmentation for patients with glottic insufficiency. Hsiung MW. PMID: 15609111 [PubMed - indexed for MEDLINE] 3969. Semin Liver Dis. 2004 Nov;24(4):371-9. Effects of weight loss surgeries on liver disease. Blackburn GL(1), Mun EC. Author information: (1)Division of Nutrition Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. gblackbu@bidmc.harvard.edu Obesity is the single most significant risk factor for the development of nonalcoholic fatty liver disease (NAFLD) in children and adults. NALFD is estimated to occur in 30 to 100% of obese adults, and in approximately 53% of obese children. The majority of obese patients have ultrasonographic evidence of fatty liver; 30% have histologically documented nonalcoholic steatohepatitis (NASH). Up to 25% of patients with NASH may progress to cirrhosis. In the United States, an estimated 65% of adults are overweight and 31% are obese. Between 2001 and 2002, the number of people with severe obesity, who are more than 100 pounds overweight, rose to nearly 11 million. Since 1970, levels of childhood and teen overweight have climbed to approximately 16% in those aged 6 to 19 years. Recent findings indicate that key features of NAFLD and NASH improve or resolve dramatically with weight loss. This article discusses weight loss surgeries and their effects on liver disease. PMID: 15605305 [PubMed - indexed for MEDLINE] 3970. Obes Res. 2004 Nov;12 Suppl 2:124S-9S. Carbohydrates and increases in obesity: does the type of carbohydrate make a difference? Wylie-Rosett J(1), Segal-Isaacson CJ, Segal-Isaacson A. Author information: (1)Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA. jwrosett@aecom.yu.edu With the prevalence of obesity increasing in the U.S. and elsewhere, the place of carbohydrates in the diet has recently been under closer examination. This has led to the development of methods for analyzing the effects of dietary carbohydrate. Primary among these methods is the glycemic index, a measure of a food's effect on blood glucose levels, which was initially designed as a method for determining suitable carbohydrates for people with diabetes. However, the glycemic index does not address other metabolic issues related to excess sugar consumption. Prominent among these issues is the use of low glycemic index sweeteners, particularly fructose, which is increasingly present in processed food. Fructose is associated with increased adiposity, which may result from its effects on hormones associated with satiety. Other methods of determining "good" carbohydrates have also been developed. The common theme among them is increased nonstarchy vegetables and higher-fiber legumes. PMID: 15601960 [PubMed - indexed for MEDLINE] 3971. Obes Res. 2004 Nov;12 Suppl 2:88S-101S. The obesity pandemic: where have we been and where are we going? Roth J(1), Qiang X, Marbán SL, Redelt H, Lowell BC. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. jroth@lij.edu Obesity, a new pandemic, is associated with an increased risk of death, morbidity, and accelerated aging. The multiple therapeutic modalities used to promote weight loss are outlined with caution, especially for patients who are very young or old. Except for very rare single gene defects, the inheritance of obesity is complex and still poorly understood, despite active investigations. Recent advances that have shed light on the pathophysiology of obesity are the recognition that 1) excess fat is deposited in liver, muscle, and pancreatic islets; 2) fat tissue secretes a large number of active signaling molecules including leptin, adiponectin, and resistin, as well as free fatty acids; and 3) activated macrophages colonize the adipose tissue. Other candidates for key roles in the causes and consequences of obesity include 1) metabolic programming, where food acts as a developmental regulator; 2) the constellation of defects known as the "metabolic syndrome;" 3) cortisol overproduction in the adipose tissue; and especially, 4) insulin resistance. The possible etiologies of insulin resistance include cytokine excess, elevated free fatty acids, and hyperinsulinemia itself, as with transgenic overproduction of insulin in mice. PMID: 15601956 [PubMed - indexed for MEDLINE] 3972. Pediatr Diabetes. 2004 Dec;5(4):219-26. Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes. Goodpaster BH(1), Wolf D. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. In addition to obesity, many factors, including the distribution of body fat, contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Lipid contained within skeletal muscle as triglyceride is a parameter of regional fat accumulation thought to be an important link among obesity, insulin resistance, and type 2 diabetes, even in the pediatric population. Intramuscular triglycerides can also be a fuel source for healthy muscle during periods of physical activity. Thus, the balance between storage and efficient utilization of muscle triglycerides is likely a key to a better understanding of the interaction between dysregulated fat and glucose metabolism by muscle in both adults and children. This review examines the evidence that muscle lipid accumulation is linked with insulin resistance and type 2 diabetes of both adults and children. In addition, we explore the potential mechanisms for muscle lipid accumulation as well as the effects of weight loss and physical activity on muscle lipid. Further defining the links between muscle lipid accumulation and insulin action should help develop more effective strategies to prevent or treat type 2 diabetes and other obesity-associated disorders. PMID: 15601366 [PubMed - indexed for MEDLINE] 3973. Neurosci Res. 2005 Jan;51(1):1-8. Sympathetic premotor neurons mediating thermoregulatory functions. Nakamura K(1), Matsumura K, Kobayashi S, Kaneko T. Author information: (1)Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. kazu@mbs.med.kyoto-u.ac.jp The sympathetic nervous system controls various homeostatic conditions, such as blood circulation, body temperature, and energy expenditure, through the regulation of diverse peripheral effector organs. In this system, sympathetic premotor neurons play a crucial role by mediating efferent signals from higher autonomic centers directly to sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord. The medulla oblongata is thought to subsume many sympathetic premotor neurons, and the rostral ventrolateral medulla (RVLM) has been established to contain the sympathetic premotor neurons responsible for cardiovascular control. Although premotor neurons controlling other effector organs than the cardiovascular system have been largely unknown, recent accumulating findings have suggested that medullary raphe regions including the raphe pallidus and raphe magnus nuclei are candidates for the pools of excitatory sympathetic premotor neurons involved in thermoregulation. Further recently, excitatory premotor neurons controlling the thermoregulatory effector organs, brown adipose tissue and tail, have been identified with expression of vesicular glutamate transporter (VGLUT)3, whereas those for cardiovascular control were characterized with VGLUT2 expression. The VGLUT3-expressing premotor neurons would mediate thermoregulation including fever induction, and could be also involved in the control of energy metabolism. PMID: 15596234 [PubMed - indexed for MEDLINE] 3974. Trends Cardiovasc Med. 2004 Nov;14(8):318-22. Endothelial progenitor cells functional characterization. Urbich C(1), Dimmeler S. Author information: (1)Division of Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany. Increasing evidence suggests that circulating progenitor cells contribute to postnatal neovascularization. These cells home to sites of ischemia, adopt an endothelial phenotype, and contribute to new blood vessel formation. Hence, the identity of the circulating cells that contribute to neovascularization is not entirely clear. Bone-marrow-derived hematopoietic progenitor cells can give rise to endothelial cells and contribute to endothelial recovery and new capillary formation after ischemia. However, nonhematopoietic stem cells within the bone marrow and adipose-tissue-derived cells, as well as cardiac and neural progenitor cells, also differentiate to endothelial cells. Progenitor cells from the different sources may be useful to augment therapeutic vascularization. The present review article summarizes the different subtypes of (endothelial) progenitor cells that can give rise to endothelial cells, enhance neovascularization, and may be suitable for therapeutic neovascularization. PMID: 15596109 [PubMed - indexed for MEDLINE] 3975. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S58-65. Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases. Montani JP(1), Carroll JF, Dwyer TM, Antic V, Yang Z, Dulloo AG. Author information: (1)Department of Medicine/Division of Physiology, University of Fribourg, Switzerland. jean-pierre.montani@unifr.ch In humans and most animal models, the development of obesity leads not only to increased fat depots in classical adipose tissue locations but also to significant lipid deposits within and around other tissues and organs, a phenomenon known as ectopic fat storage. The purpose of this review is to explore the possible locations of ectopic fat in key target-organs of cardiovascular control (heart, blood vessels and kidneys) and to propose how ectopic fat storage can play a role in the pathogenesis of cardiovascular diseases associated with obesity. In animals fed a high-fat diet, cardiac fat depots within and around the heart impair both systolic and diastolic functions, and may in the long-term promote heart failure. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete vascular relaxing factors, proatherogenic cytokines and smooth muscle cell growth factors. Furthermore, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Taken together, ectopic fat storage in key target-organs of cardiovascular control may impair their functions, contributing to the increased prevalence of cardiovascular diseases in obese subjects. PMID: 15592488 [PubMed - indexed for MEDLINE] 3976. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S45-52. Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance. Asensio C(1), Muzzin P, Rohner-Jeanrenaud F. Author information: (1)Laboratory of Metabolism, Department of Internal Medicine, Department of Cell Biology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland. Glucocorticoids are important hormones in the regulation of metabolic homeostasis. We infused normal rats with dexamethasone given intracerebroventricularly (i.c.v.) for 3 days. This resulted in hyperphagia, hyperinsulinemia, and marked insulin resistance. Similar metabolic defects were observed following i.c.v. infusion of neuropeptide Y (NPY) in normal rats. As central dexamethasone infusion enhanced NPY content in the arcuate nucleus, it suggested that its metabolic effects are mediated by NPY. Moreover, due to the lack of effects observed in vagotomized animals, activation of the parasympathetic nervous system by central dexamethasone infusion is proposed. Glucocorticoid action is known to involve prereceptor metabolism by enzymes such as 11beta-HSD-1 that converts inactive into active glucocorticoids. Mice overexpressing 11beta-HSD-1 in adipose tissue were shown to be obese and insulin resistant. We recently observed that adipose tissue 11beta-HSD-1 mRNA expression is increased at the onset of high-fat diet-induced obesity and positively correlated with the degree of hyperglycemia. In human obesity, increased adipose tissue 11beta-HSD-1 expression and activity were also reported. Resistin is a new adipose tissue-secreted hormone shown to play a role in glucose homeostasis by increasing hepatic glucose production and inhibiting muscle and adipose tissue glucose utilization. We observed increased adipose tissue resistin expression in the early phase of high-fat diet-induced obesity as well as decreased resistin expression in response to leptin. A positive correlation between glycemia and adipose tissue resistin expression further suggested a role of this hormone in the development of insulin resistance. The melanocortin system is another important player in the regulation of energy balance. Peripheral administration of a melanocortin agonist decreased food intake and body weight and favored lipid oxidation, effects that were more marked in obese than in lean rats. It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11beta-HSD-1, thereby decreasing or enhancing glucose metabolism. PMID: 15592486 [PubMed - indexed for MEDLINE] 3977. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S38-44. Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores. Rossmeisl M(1), Flachs P, Brauner P, Sponarova J, Matejkova O, Prazak T, Ruzickova J, Bardova K, Kuda O, Kopecky J. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. As indicated by in vitro studies, both lipogenesis and lipolysis in adipocytes depend on the cellular ATP levels. Ectopic expression of mitochondrial uncoupling protein 1 (UCP1) in the white adipose tissue of the aP2-Ucp1 transgenic mice reduced obesity induced by genetic or dietary manipulations. Furthermore, respiratory uncoupling lowered the cellular energy charge in adipocytes, while the synthesis of fatty acids (FA) was inhibited and their oxidation increased. Importantly, the complex metabolic changes triggered by ectopic UCP1 were associated with the activation of AMP-activated protein kinase (AMPK), a metabolic master switch, in adipocytes. Effects of several typical treatments that reduce adiposity, such as administration of leptin, beta-adrenoceptor agonists, bezafibrate, dietary n-3 polyunsaturated FA or fasting, can be compared with a phenotype of the aP2-Ucp1 mice. These situations generally lead to the upregulation of mitochondrial UCPs and suppression of the cellular energy charge and FA synthesis in adipocytes. On the other hand, FA oxidation is increased. Moreover, it has been shown that AMPK in adipocytes can be activated by adipocyte-derived hormones leptin and adiponectin, and also by insulin-sensitizes thiazolidinediones. Thus, it is evident that metabolism of adipose tissue itself is important for the control of body fat content and that the cellular energy charge and AMPK are involved in the control of lipid metabolism in adipocytes. The reciprocal link between synthesis and oxidation of FA in adipocytes represents a prospective target for the new treatment strategies aimed at reducing obesity. PMID: 15592485 [PubMed - indexed for MEDLINE] 3978. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S3-S11. Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis. Schutz Y(1). Author information: (1)Department of Physiology, Faculty of Medicine and Biology, University of Lausanne, Lausanne, Switzerland. Yves.Schutz@unil.ch The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes. PMID: 15592484 [PubMed - indexed for MEDLINE] 3979. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S22-8. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Lelliott C(1), Vidal-Puig AJ. Author information: (1)Department of Clinical Biochemistry and Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. Obesity and type 2 diabetes mellitus are the major noncommunicable public health problem of the 21st century. The best strategy to tackle this problem is to develop strategies to prevent/treat obesity. However, it is becoming clear that despite successful research identifying weight regulatory pathways, the development of the obesity epidemic is outpacing scientific progress. The lack of success controlling the obesity epidemic in an aging population will result in another subsequent uncontrolled epidemic of complications. Our research focuses on the mechanisms causing lipotoxicity aiming to identify suitable strategies to prevent or at least retard the development of the metabolic syndrome. Previous work using transgenic and knockout mouse models has shown an interplay between white adipose tissue and skeletal muscle linking fatty acid (FA) synthesis with reciprocal effects on FA oxidation. Work from our lab and others suggests that defective adipose tissue is a key link between obesity, insulin resistance and type 2 diabetes mellitus by promoting the development of lipotoxicity in peripheral tissues. We propose a series of models to describe the process by which the adipose tissue could react to an energy-rich environment and responds depending on genetic and physiological factors, impacting on the functions of other peripheral tissues. We suggest that by examining hypotheses that encompass multiple organs and the partitioning of energy between these organs, a suitable strategy can be devised for the treatment of chronic obesity. PMID: 15592482 [PubMed - indexed for MEDLINE] 3980. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S12-21. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Heilbronn L(1), Smith SR, Ravussin E. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA, USA. BACKGROUND: It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues. OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. (A) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (B) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes. PMID: 15592481 [PubMed - indexed for MEDLINE] 3981. Horm Res. 2004;62 Suppl 4:23-30. Long-term challenges in growth hormone treatment. Leal Cerro A(1). Author information: (1)Department of Endocrinology, Hospital Universitario Virgen del Rocio, Hospital General, Sevilla, Spain. alfonso.leal.sspa@juntadeandalucia.es Growth hormone deficiency (GHD) is defined biochemically as a response to hypoglycaemia with a peak GH concentration of less than 5 microg/l. The 'GHD syndrome' is a range of psychological and physical symptoms that are associated with GHD, which include increased central adiposity, decreased bone mineral density, abnormal lipid profiles, decreased cardiovascular performance, reduced lean body mass (LBM), social isolation, depressed mood and increased anxiety. Importantly, the combination of physical and psychological problems can often result in a reduced quality of life. A number of trials have shown that GH replacement therapy can lead to a substantial improvement in GHD associated symptoms. Following up to 12 months of treatment with GH, LBM increased, left ventricular systolic function improved and the mean volume of adipose tissue fell. After only 4 months of treatment, a rise in exercise capacity was recorded, and after 2 years' treatment, isokinetic and isometric muscle strength had normalized in proximal muscle groups. Feelings of well-being and vitality also improved significantly. However, studies on the effects of treatment on insulin sensitivity in GH-deficient patients have had conflicting results. In this paper, we will discuss the long-term consequences of GHD and the effects of GH replacement therapy. PMID: 15591763 [PubMed - indexed for MEDLINE] 3982. Biochimie. 2004 Nov;86(11):833-7. Roles of peroxisome proliferator-activated receptor delta (PPARdelta) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome. Luquet S(1), Lopez-Soriano J, Holst D, Gaudel C, Jehl-Pietri C, Fredenrich A, Grimaldi PA. Author information: (1)Inserm U636, Centre de Biochimie, UFR Sciences, Université de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice, France. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARalpha and PPARgamma are the most extensively examined and characterized, mainly because they are activated by marketed hypolipidemic and insulin sensitizer compounds, such as fibrates and thiazolidinediones. It has been established that the third member of the family, PPARdelta is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARdelta agonists and of appropriate cellular and animal models revealed that PPARdelta plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. Activation of the nuclear receptor promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also involved in the adaptive metabolic responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations strongly suggest that PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity. PMID: 15589693 [PubMed - indexed for MEDLINE] 3983. Stem Cells Dev. 2004 Oct;13(5):463-72. Mesenchymal stem cells in autoimmune disease. El-Badri NS(1), Maheshwari A, Sanberg PR. Author information: (1)Center for Excellence for Aging and Brain Repair, Department of Neurosurgery, College of Medicine, University of South Florida, Tampa, FL 33612, USA. ndajani@hsc.usf.edu Autoimmune diseases afflict more than 3% of the U.S. population. Current therapy for mild to moderate cases is symptomatic, however advanced cases suffer high morbidity and mortality. Advanced patients have benefited from stem cell therapy in the form of bone marrow transplantation in conjunction with high-dose cytotoxic therapy. Broader application of stem cell therapy requires better understanding of how adult stem cells affect development and foster treatment of autoimmune pathologies, and of better ways to manipulate the host immune responses. While extensive research documents the role of hematopoietic stem cells (HSCs) in autoimmune disease, few studies have addressed if and how mesenchymal stem cells (MSCs) contribute to their etiopathology. Recent characterization of MSCs and their role in hematopoiesis and immune modulation suggest that their potential for cell therapy extends beyond their traditional accessory function in HSC engraftment. MSCs contribute significantly to tissue restructuring and immune functioning, in addition to facilitating durable, long-lasting stem cell engraftment. MSCs are relatively easy to obtain and expand in in vitro cultures, rendering them a prime candidate for genetic manipulations for stem cell therapy. They have the potential to differentiate into multiple lineages such as osteoblasts, adipose tissue, cartilage, tendon, and stromal cells. The role of MSCs for autoimmune disease therapy could thus be based both on immune function modulation and contribution to hematopoiesis. In this review, we examine the biology of MSCs, and their potential for cell therapy of autoimmune disease. PMID: 15588504 [PubMed - indexed for MEDLINE] 3984. Tidsskr Nor Laegeforen. 2004 Dec 2;124(23):3051-4. [Can linoleic acids in conjugated CLA products reduce overweight problems?]. [Article in Norwegian] Haugen M(1), Alexander J. Author information: (1)Avdeling for naeringsmiddeltoksikologi, Divisjon for miljømedisin, Nasjonalt folkehelseinstitutt, Postboks 4404 Nydalen, 0403 Oslo. margaretha.haugen@fhi.no Comment in Tidsskr Nor Laegeforen. 2005 Apr 21;125(8):1047; author reply 1047-8. BACKGROUND: CLA (conjugated linoleic acid) supplements are advertised as a way to reduce weight and to obtain a "better balance between fat and muscle". What evidence is there for these health claims, and is CLA supplementation safe and without adverse effects? MATERIAL AND METHODS: This review is based on peer-reviewed scientific publications. RESULTS: Large doses of CLA supplements in rodents reduce fat mass and increases muscle mass, but the results from 13 randomised, placebo-controlled clinical studies do not support these findings with regard to humans. However, results from both animal and human studies indicate that the CLA isomer 10-trans,12-cis may have a negative impact on carbohydrate and lipid metabolism by inducing insulin resistance and hyperlipidaemia. Studies of CLA supplementation to lactating women have revealed lower fat content in their milk. Furthermore, the cordial blood concentration of CLA in women has been shown to correlate negatively with both gestational length and birth weight. CONCLUSION: Even if reduced weight and fat mass has been observed in animal models following CLA supplementation, the basis is, at best, weak for such claims in humans. Provided that the fat mass reducing effect of CLA is mediated through PPARgamma, this may result in adverse metabolic effects. PMID: 15586185 [PubMed - indexed for MEDLINE] 3985. Dimens Crit Care Nurs. 2004 Nov-Dec;23(6):237-43. The biochemical basis of metabolism in cancer cachexia. Tijerina AJ(1). Author information: (1)Air Force Research Laboratory/Human Effects Directorate, USA. Amanda.Tijerina@brooks.af.mil Cancer cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass. It is the most common side effect of malignancy occurring in approximately one-half of untreated cancer patients. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of carbohydrate, lipid, and protein metabolism. This leads to a shorter survival time and a decreased response to therapy. Cachexia is often found before any signs or symptoms of the cancer. An uncertainty with cachexia is whether nutritional support is feeding the patient or the tumor. Often, cachexia is not responsive to simple nutritional interventions. Furthermore, appetite stimulants, cytokine inhibitors, and Cori cycle inhibitors have been used to treat cancer cachexia. PMID: 15586034 [PubMed - indexed for MEDLINE] 3986. Exp Gerontol. 2004 Nov-Dec;39(11-12):1761-4. IGF-1 signaling and aging. Holzenberger M(1), Kappeler L, De Magalhaes Filho C. Author information: (1)Inserm U515, Hôpital Saint-Antoine, 75571 Paris 12, France. holzenberger@st-antoine.inserm.fr We briefly compare calorie restriction, GHRH-R and Pit-1 mutants with knockout phenotypes of GH receptor, IGF-1 receptor and p66Shc, to make some general conclusions. Growth, fertility and longevity phenotypes may dissociate in some of these mutants, and we try to interpret this. Follows a short discussion on the importance of genetic background for aging studies in mice. We then evoke studies in C. elegans showing that lifespan may be regulated in a non-cell-autonomous fashion, and that the nervous system could play a central role therein. Recent findings on DILP-2 regulation in Drosophila transpose this hypothesis of endocrine lifespan regulation to insects. Work in mice shows that inactivation of the insulin receptor specifically in the adipose tissue is sufficient to increase the mouse lifespan. In summary, exciting findings obtained in very different model organisms are rapidly converging and suggest that animal lifespan may be subject to endocrine regulation. Interestingly, the hypothalamus centralizes many age related hormonal regulations and at the same time participates in the integration of numerous nutritional signals, such that one could ask whether the hypothalamus may be at the crossroads of metabolic and endocrine lifespan regulation. PMID: 15582293 [PubMed - indexed for MEDLINE] 3987. Curr Med Chem Anticancer Agents. 2004 Nov;4(6):523-34. Aromatase inhibitors: a new paradigm in breast cancer treatment. Narashimamurthy J(1), Rao AR, Sastry GN. Author information: (1)Medicinal Chemistry Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal -506 009, Andhra Pradesh, India. Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects. PMID: 15579017 [PubMed - indexed for MEDLINE] 3988. Comb Chem High Throughput Screen. 2004 Nov;7(7):653-9. Synthetic molecules that modulate transcription and differentiation: hints for future drug discovery. Uesugi M(1). Author information: (1)The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. muesugi@bcm.tmc.edu Regulation of gene transcription and cell differentiation often induces drastic phenotypes in living organisms. External, precise control over these processes through small organic molecules represents a challenge in chemistry and biology. Our laboratory has been discovering small organic molecules that modulate transcription or differentiation and using them as a tool to understand biological phenomena. This personal perspective summarizes our contributions to chemical biology and chemical genetics in the fields of gene transcription and cell differentiation. Our case studies may foreshadow the promise and the challenge of future drug discovery. PMID: 15578927 [PubMed - indexed for MEDLINE] 3989. Yakugaku Zasshi. 2004 Dec;124(12):893-908. [Identification of muscle-type carnitine palmitoyltransferase I and characterization of its gene structure]. [Article in Japanese] Yamazaki N(1). Author information: (1)Faculty of Pharmaceutical Sciences, University of Tokushima, Tokushima 770-8505, Japan. To characterize energy metabolism in brown adipose tissue (BAT), differential screening of a cDNA library of rat BAT with a cDNA probe of rat white adipose tissue was carried out. We isolated one novel cDNA clone encoding a protein of 88.2 kDa consisting of 772 amino acids. The deduced amino acid sequence showed the highest homology (62.6%) with that of rat liver carnitine palmitoyltransferase I (CPTI). The transcript corresponding to this cDNA was abundantly expressed not only in BAT but also in the heart and skeletal muscle. CPTI is a protein necessary for the beta-oxidation of long-chain fatty acids in mammalian mitochondria, and it has been suggested that at least two isoforms, the liver type and muscle (M-CPTI) type, exist. Based on these observations, we concluded that the novel cDNA clone isolated from rat BAT encodes M-CPTI. Isolation and characterization of a genomic DNA clone revealed that the gene for human M-CPTI consists of two 5'-noncoding exons, 18 coding exons, and one 3'-noncoding exon spanning approximately 10 kbp, and a gene encoding choline/ethanolamine kinase-beta (CK/EK-beta) was located about 300 bp upstream from the M-CPTI gene with the same strand direction. Furthermore, we found atypical transcripts containing exons of both CK/EK-beta and M-CPTI genes in humans and rodents. The physiologic role(s) of these transcripts is still unknown. However, it is interesting that such transcripts are produced from two tightly arranged and functionally unrelated genes in mammalian tissues. PMID: 15577262 [PubMed - indexed for MEDLINE] 3990. Sports Med. 2004;34(15):1051-76. Effects of exercise on the fatty-acid composition of blood and tissue lipids. Nikolaidis MG(1), Mougios V. Author information: (1)Department of Physical Education and Sport Science, Aristotle University of Thessaloniki, Thessaloniki, 541 24 Thessaloniki, Greece. This article reviews the effects of acute and chronic exercise on the fatty-acid composition of animal and human tissues (plasma, skeletal muscle, heart, adipose tissue, liver, artery and erythrocytes), as reported in 68 studies spanning four decades. The most consistently observed effect has been an increase in the relative amount of unsaturated, especially monounsaturated, non-esterified fatty acids in plasma of both animals and humans after acute exercise. Chronic exercise seems to increase the proportion of polyunsaturated fatty acids and omega6 fatty acids, while decreasing the proportion of monounsaturated fatty acids in animal and human adipose tissue. Additionally, chronic exercise seems to decrease the relative amount of unsaturated fatty acids in liver lipids of animals and humans. There is no consensus regarding the effect of exercise on the fatty-acid composition of lipids in any other tissue. In general, the effects of exercise are independent of nutrition and, regarding skeletal muscle, muscle fibre type. The available literature shows that, in addition to modifying the concentrations of animal and human tissue lipids, exercise also changes their fatty-acid profile. Unfortunately, the available studies are so much divided among exercise models, species and biological samples that a cohesive picture of the plasticity of the fatty-acid pattern of most tissues toward exercise has not emerged. Future studies should focus on determining the fatty-acid profile of separate lipid classes (rather than total lipids) in separate subcellular fractions (rather than whole tissues), examining tissues and organs on which no data are available and exploring the mechanisms of the exercise-induced changes in fatty-acid composition. PMID: 15575795 [PubMed - indexed for MEDLINE] 3991. Eur Respir J. 2004 Dec;24(6):1033-43. The immune response to resistive breathing. Vassilakopoulos T(1), Roussos C, Zakynthinos S. Author information: (1)Critical Care Dept, Evangelismos Hospital, 45-47 Ipsilandou Str, GR-10675 Athens, Greece. tvassil@med.uoa.gr Comment in Eur Respir J. 2005 Jun;25(6):1128-9; author reply 1129-30. Resistive breathing is an "immune challenge" for the body, initiating an inflammatory response consisting of an elevation of plasma cytokines, and the recruitment and activation of lymphocyte subpopulations. These cytokines do not originate from monocytes, but are, instead, produced within the diaphragm, secondary to the increased muscle activation. Oxidative stress is a major stimulus for the cytokine induction, secondary to resistive breathing. The production of cytokines within the diaphragm may be mediating the diaphragm muscle fibre injury that occurs with strenuous contractions, or contributing towards the expected repair process. These cytokines may also compromise diaphragmatic contractility or contribute towards the development of muscle cachexia. They may also have systemic effects, mobilising glucose from the liver and free fatty acid from the adipose tissue to the strenuously working respiratory muscles. At the same time, they stimulate the hypothalamic-pituitary-adrenal axis, leading to production of adrenocorticotropin and beta-endorphins. The adrenocorticotropin response may represent an attempt of the organism to reduce the injury occurring in the respiratory muscles via the production of glucocorticoids and the induction of the acute phase-response proteins. The beta-endorphin response would decrease the activation of the respiratory muscles and change the pattern of breathing, which becomes more rapid and shallow, possibly in an attempt to reduce and/or prevent further injury to the respiratory muscles. PMID: 15572550 [PubMed - indexed for MEDLINE] 3992. Sports Med. 2004;34(14):955-65. Lipid-induced insulin resistance in the liver: role of exercise. Katsanos CS(1). Author information: (1)Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, USA. cskatsan@utmb.edu Hepatic lipid accumulation may be a result of one or several of the following factors: increased delivery of adipose tissue or dietary fatty acids to the liver, increased de novo synthesis of fatty acids in the liver, decreased rate of hepatic fatty-acid oxidation, or decreased rate in the exit of fatty acids from the liver in the form of triglycerides. Delivery of fatty acids to the liver appears to be the most potent mechanism for hepatic lipid accumulation. Hepatic lipid accumulation is linked to the development of hepatic insulin resistance, which is demonstrated by the impaired suppression of hepatic glucose output by insulin. Current evidence suggests that defects associated with the molecular mechanisms responsible for the propagation of the insulin signal in the liver cells are responsible for the impaired insulin effect and that these defects can develop secondary to lipid accumulation in the liver. Hepatic lipid accumulation appears to affect the activity of phosphatidylinositol 3-kinase, which has a central role in mediating the insulin action in hepatocytes. Generally, exercise has been shown to enhance the insulin action in the liver. Although an exercise-related mechanistic link between attenuation in hepatic lipid accumulation and enhancement in insulin action in the liver has not been described yet, the benefits of exercise on hepatic insulin action may relate to the potential effects of exercise on regulating/preventing hepatic lipid accumulation. However, direct effects of exercise on insulin action in the liver, independent of any effects on hepatic lipid metabolism, cannot currently be excluded. Further research is needed to evaluate the relative importance of exercise in the treatment of hepatic insulin resistance, specifically as it relates to lipid accumulation in the liver. PMID: 15571427 [PubMed - indexed for MEDLINE] 3993. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):482-6. Epub 2004 Nov 29. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Chen HC(1), Farese RV Jr. Author information: (1)Department of Medical Sciences, Amgen Inc, Thousand Oaks, USA. Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metabolism result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not observed in mice with partial DGAT1 deficiency. These findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes. PMID: 15569818 [PubMed - indexed for MEDLINE] 3994. Annu Rev Genet. 2004;38:553-85. Genomic imprinting and kinship: how good is the evidence? Haig D(1). Author information: (1)Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. dhaig@oeb.harvard.edu The kinship theory of genomic imprinting proposes that parent-specific gene expression evolves at a locus because a gene's level of expression in one individual has fitness effects on other individuals who have different probabilities of carrying the maternal and paternal alleles of the individual in which the gene is expressed. Therefore, natural selection favors different levels of expression depending on an allele's sex-of-origin in the previous generation. This review considers the strength of evidence in support of this hypothesis for imprinted genes in four "clusters," associated with the imprinted loci Igf2, Igf2r, callipyge, and Gnas. The clusters associated with Igf2 and Igf2r both contain paternally expressed transcripts that act as enhancers of prenatal growth and maternally expressed transcripts that act as inhibitors of prenatal growth. This is consistent with predictions of the kinship theory. However, the clusters also contain imprinted genes whose phenotypes as yet remain unexplained by the theory. The principal effects of imprinted genes in the callipyge and Gnas clusters appear to involve lipid and energy metabolism. The kinship theory predicts that maternally expressed transcripts will favor higher levels of nonshivering thermogenesis (NST) in brown adipose tissue (BAT) of animals that huddle for warmth as offspring. The phenotypes of reciprocal heterozygotes for Gnas knockouts provide provisional support for this hypothesis, as does some evidence from other imprinted genes (albeit more tentatively). The diverse effects of imprinted genes on the development of white adipose tissue (WAT) have so far defied a unifying hypothesis in terms of the kinship theory. PMID: 15568986 [PubMed - indexed for MEDLINE] 3995. Exp Biol Med (Maywood). 2004 Dec;229(11):1127-35. Role of estrogens in adipocyte development and function. Cooke PS(1), Naaz A. Author information: (1)Department of Veterinary Biosciences, University of Illinois, 2001 S. Lincoln Ave., Urbana, IL 61802, USA. p-cooke@uiuc.edu Estrogen has historically been viewed as a major regulator of adipose tissue in adult females, but recent work has indicated that estrogen's role in adipose biology may be broader than initially appreciated and has also provided important insights into the mechanism of estrogen effects on adipose tissue. Estrogen has direct effects on adipocytes to inhibit lipogenesis and may also have direct effects on other cellular constituents of adipose tissue, as well as metabolic effects on other target organs that can regulate adipose tissue. Estrogen has central effects on food consumption and energy expenditure that contribute to its overall inhibitory effects on adipose deposition. Estrogen also plays an important role in regulating adipose deposition in males and recently has been shown to be an important factor in the determination of adipocyte number, indicating that it regulates key developmental events in adipogenesis. Although critical questions still remain in our understanding of the overall role of estrogen in adipose tissue, it is clear that estrogen plays a more important role in adipose tissue than originally realized and that it is a major regulator of adipose tissue in both sexes during development and adulthood. PMID: 15564439 [PubMed - indexed for MEDLINE] 3996. Best Pract Res Clin Gastroenterol. 2004 Dec;18(6):1167-75. Risk of gastrointestinal malignancies and mechanisms of cancer development with obesity and its treatment. Freeman HJ(1). Author information: (1)Department of Medicine (Gastroenterology), University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 1W5, Canada. hugfree@shaw.ca Gastrointestinal malignancies may be associated with obesity, defined specifically by increased body-mass index, and based largely on environmental factors rather than genetics. In particular, there seems to be a definite increase in the incidence of both oesophageal and colorectal cancer. Mechanisms associated with obesity include a particular metabolic state characterized by hyperinsulinemia, or insulin resistance, along with elevated serum leptin. Leptin is derived from adipocytes and appears to play a role in the regulation of ghrelin, a peptide derived from the stomach and small intestine that stimulates appetite and weight gain. In addition to these metabolic changes, there are other anatomical alterations that may indirectly predispose to cancer, including the predisposition of obesity to gastroesophageal reflux and, possibly, oesophageal cancer. Other mechanisms may involve adipocyte-derived cytokines, or adipokines, that may serve as signalling devices in the pathogenesis of cancer. Finally, pharmacologic and surgical avenues available for treatment of obesity, including lipase inhibitors and gastric or jejuno-ileal bypass procedures may set the stage for subsequent gastric or intestinal tract cancer. PMID: 15561645 [PubMed - indexed for MEDLINE] 3997. Clin Nutr. 2004 Dec;23(6):1256-66. Acute and "chronic" phase reaction-a mother of disease. Bengmark S(1). Author information: (1)Department of Surgery and Liver Institute, UCL, London, UK. The world is increasingly threatened by a global epidemic of chronic diseases. Almost half of the global morbidity and almost two thirds of global mortality is due to these diseases-approximately 35 million die each year from chronic diseases. And they continue to increase. Increasing evidence suggest that these diseases are associated with lifestyle, stress, lack of physical exercise, over-consumption of calorie-condensed foods rich in saturated fat, sugar and starch, but also under-consumption of antioxidant-rich fruits and vegetables. As a result the function of the innate immune system is severe impaired. This review discusses the changes induced in response to mental and physical stress and their association with the subsequent development of metabolic syndrome, and its association with various chronic diseases. The endothelial cells and their function appears to be of great importance, and the function of their cellular membranes of special importance to the function of the underlying cells; their ability to obtain nutrients and antioxidants and to eliminate waste products. The abdominal adipocytes seen to play a key role, as they have the ability to in stressful situations release much of proinflammatory cytokines, PAI-1 and free fatty acids compared to elsewhere in the body. The load on the liver of these various substances in often of greater magnitude than the liver can handle. Some of the most common chronic diseases and their potential association with acute and "chronic" phase response, and with metabolic syndrome are discussed separately. The need for studies with lifestyle modifications is especially emphasized. PMID: 15556248 [PubMed - indexed for MEDLINE] 3998. Curr Drug Targets CNS Neurol Disord. 2004 Oct;3(5):431-9. Metabolic syndrome targets. Smith SR(1). Author information: (1)Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. smithsr@pbrc.edu The metabolic syndrome is a cluster of easy-to-measure clinical phenotypes that serve as markers for increased risk for CVD and diabetes. There is no universal agreement as to the underlying pathophysiology of the metabolic syndrome. At its core, the metabolic syndrome is the result of energy excess; therefore treating obesity is a good strategy to reverse the clinical features of the metabolic syndrome. Hypertension is a special case, may not be part of the core pathophysiology of the metabolic syndrome, and will not be discussed. After a brief review of recent developments in the pathophysiology of the metabolic syndrome, this review will concentrate on peripheral targets in the following categories: ectopic fat and fat oxidation, intrinsic defects in substrate switching and mitochondrial biogenesis, lipolysis and lipid turnover, adipose tissue as an endocrine organ, nutrient / energy sensing systems, and inflammation. The advantages and pitfalls of these targets will be discussed with an eye towards the relevant literature. PMID: 15544449 [PubMed - indexed for MEDLINE] 3999. Curr Drug Targets CNS Neurol Disord. 2004 Oct;3(5):411-30. Lipid metabolism and nutrient partitioning strategies. Morris AM(1), Calsbeek DJ, Eckel RH. Author information: (1)Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045, USA. The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task. PMID: 15544448 [PubMed - indexed for MEDLINE] 4000. Curr Drug Targets CNS Neurol Disord. 2004 Oct;3(5):389-409. Exercise in a pill: feasibility of energy expenditure targets. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, Microbiology and Immunology, Faculyt of Medicine, University of Ottawa, 451 Smyth Road, Ottawa ON K1H 8M5, Canada. jhhagen@uottawa.ca The possibility of developing a pill to increase energy expenditure is explored by examining the metabolic processes involved. Such a pill should be targeted at organ systems involved in facultative thermogenesis. In rodents, these are brown adipose tissue (BAT) and skeletal muscle. Since BAT-mediated thermogenesis is not available in adult humans, emphasis here is on skeletal muscle. A hypothesis is presented based on three known facts: (1) plasticity of skeletal muscle, with interconversion of fiber types that differ in their fuel efficiency; (2) presence of thyroxine 5'-deiodinase type 2 (TD2) in human skeletal muscle; (3) gradual increase in thermogenesis that occurs during rehabilitation after starvation, probably in muscle. A low capacity thermogenic system, muscle efficiency thermogenesis (MET), is proposed to occur as adipose stores refill during the transition from famine to feasting to obesity. This system involves increased activity of TD2 and a T3-induced increase in proportion of type II fibers, less efficient at rest and during activity. The protective effect of this system is probably overwhelmed by long-term eating in excess of energy needs. Better understanding of the complex remodeling of differentiated muscle fibers in the conversions proposed and of the regulation of TD2 activity in human skeletal muscle may reveal targets for increasing energy expenditure in humans. In addition, the possibility of exploiting the plasticity of the adipose organ, with conversion of white adipocytes in white adipose tissue to atypical brown adipocytes and increasing thermogenesis in them is considered as another potential target for increasing energy expenditure in humans. PMID: 15544447 [PubMed - indexed for MEDLINE] 4001. Physiol Res. 2005;54(2):133-40. Adiponectin, an adipocyte-derived protein. Nedvídková J(1), Smitka K, Kopský V, Hainer V. Author information: (1)Institute of Endocrinology, First Faculty of Medicine, Charles University, Národní 8, 11694 Prague 1, Czech Republic. jnedvidkova@endo.cz Adipose tissue is a hormonally active tissue, producing adipocytokines which may influence activity of other tissues. Adiponectin, abundantly present in the plasma increases insulin sensitivity by stimulating fatty acid oxidation, decreases plasma triglycerides and improves glucose metabolism. Adiponectin levels are inversely related to the degree of adiposity. Anorexia nervosa and type 1 diabetes are associated with increased plasma adiponectin levels and higher insulin sensitivity. Decreased plasma adiponectin levels were reported in insulin-resistant states, such as obesity and type 2 diabetes and in patients with coronary artery disease. Activity of adiponectin is associated with leptin, resistin and with steroid and thyroid hormones, glucocorticoids, NO and others. Adiponectin suppresses expression of extracellular matrix adhesive proteins in endothelial cells and atherosclerosis potentiating cytokines. Anti-atherogenic and anti-inflammatory properties of adiponectin and the ability to stimulate insulin sensitivity have made adiponectin an important object for physiological and pathophysiological studies with the aim of potential therapeutic applications. PMID: 15544426 [PubMed - indexed for MEDLINE] 4002. Int J Obes Relat Metab Disord. 2004 Nov;28 Suppl 3:S21-8. Epidemiology of childhood obesity--methodological aspects and guidelines: what is new? Wang Y(1). Author information: (1)Department of Human Nutrition, Division of Epidemiology and Biostatistics, University of Illinois, Chicago, IL 60612, USA. youfwang@uic.edu INTRODUCTION: It is still a matter of debate as to how to define obesity in young people, although a growing consensus is to use body mass index (BMI) cutoffs to classify obesity in children and adolescents. OBJECTIVE: This article provides a brief overview of issues related to the assessment of obesity in children and adolescents. RESULTS: At present, BMI is probably the best choice among available measures. BMI can be easily assessed at low cost, and has a strong association with body fatness and health risks. However, as an indirect measure of adipose tissue, BMI has a number of limitations. Cole et al published a set of sex- and age-specific BMI cutoffs, which had been developed based on data collected in six countries, and the reference has been recommended for international use. Recently, several researchers have raised concerns regarding this international reference. It has been argued that population-specific standards should be used due to biological differences between populations. CONCLUSION: BMI is a valid and feasible indirect measure of body fatness, but it suffers from a number of limitations. More efforts are needed to develop valid classifications of childhood obesity. PMID: 15543215 [PubMed - indexed for MEDLINE] 4003. Trends Endocrinol Metab. 2004 Dec;15(10):488-99. The electrophysiology of feeding circuits. Jobst EE(1), Enriori PJ, Cowley MA. Author information: (1)Division of Neuroscience, Oregon National Primate Research Center, Oregon Health Sciences University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. Obesity is quickly becoming one of the most common and debilitating disorders of the developed world. More than 60% of American adults are now overweight or obese, predisposing them to a host of chronic diseases. To understand the etiology of obesity, and to discover new therapies for obesity, we must understand the components of energy balance. In simple terms, energy intake (feeding) must equal energy expenditure (physical activity, basal metabolism and adaptive thermogenesis) for body weight homeostasis. To maintain homeostasis, neurocircuitry must sense both immediate nutritional status and the amount of energy stored in adipose tissue, and must be able to provide appropriate output to balance energy intake and energy expenditure. The brain receives various signals that carry information about nutritional and metabolic status including neuropeptide PYY(3-36), ghrelin, cholecystokinin, leptin, glucose and insulin. Circulating satiety signals access the brain either by "leakage" across circumventricular organs or transport across the blood-brain barrier. Signals can also activate sensory vagal terminals that innervate the whole gastrointestinal tract. PMID: 15541648 [PubMed - indexed for MEDLINE] 4004. Am J Hypertens. 2004 Nov;17(11 Pt 2):16S-20S; quiz A2-4. The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications. Cooper ME(1). Author information: (1)Danielle Alberti Memorial Centre for Diabetes Complications, Wynn Domain Baker Heart Research Institute, Melbourne, Australia. mark.cooper@baker.edu.au Clinical trials have demonstrated the benefit of blood pressure (BP) reduction in reducing the risk of cardiovascular and renal complications in patients with diabetes mellitus. Incorporation of agents that inhibit the renin-angiotensin-aldosterone system (RAAS) into antihypertensive regimens has been shown to provide reductions in renal and cardiovascular events that are mediated by both BP-dependent and -independent mechanisms. Recent studies exploring these potential mechanisms have demonstrated a direct role of angiotensin II (ATII) in the pathology of the vasculature and other sites of end-organ injury. In animal models of diabetes, inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 (AT(1)) receptor blockade has been shown to prevent atherosclerosis, an effect that was independent of BP reduction. In addition to its direct effects on the vasculature, ATII also has direct detrimental effects on end organs, including the kidney and the heart, which lead to the development of proteinuria and left ventricular hypertrophy (LVH), respectively. Left ventricular hypertrophy has been shown to be predictive of cardiovascular and renal events, and the benefits of RAAS inhibition with angiotensin receptor blocker therapy are accompanied by a reduction in LVH. In addition to preventing the cardiovascular and renal complications of diabetes, the RAAS blockade has also been shown, in several large randomized clinical trials, to inhibit new onset of diabetes. Recent studies have revealed that many tissues, including pancreatic islets and adipose tissue, have a local RAAS. In the diabetic rat model (Zucker diabetic fatty rats), pancreatic islets exhibit an increased intraislet expression of ACE and AT(1) as well as increased intraislet fibrosis, apoptosis, and oxidative stress. The local RAAS also appears to play a role in the function of the adipocyte. Angiotensin II inhibits adipocyte differentiation, potentially decreasing the storage capacity of adipose tissue. The reduced capacity of adipose tissue to store fatty acids may cause their accumulation in other tissues, leading to insulin resistance and development of diabetes. Collectively, these studies demonstrate that ATII has direct effects on multiple tissues, and inhibition of ATII action in these tissues may be responsible for many of the clinical benefits observed with RAAS inhibition. PMID: 15539106 [PubMed - indexed for MEDLINE] 4005. MLO Med Lab Obs. 2004 Oct;36(10):20, 22-5. The chemical pathology of insulin resistance and the metabolic syndrome. Harris NS(1), Winter WE. Author information: (1)Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA. In this review, we have examined the phenomenon of insulin resistance, a central manifestation of the metabolic syndrome. While it is by no means clear-cut, many new and exciting hypotheses have been proposed to explain this puzzling and enigmatic phenomenon. These studies have also led to a new way of looking at adipose tissue--it is no longer a passive repository of fat. It now actually appears to be a very active endocrine organ. A disturbance in this endocrine function helps contribute to the metabolic syndrome. PMID: 15536804 [PubMed - indexed for MEDLINE] 4006. Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):629-33. Leptin and energy expenditure. Hukshorn CJ(1), Saris WH. Author information: (1)Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Human Biology, Maastricht University, Maastricht, The Netherlands. c.hukshorn@hb.unimaas.nl PURPOSE OF REVIEW: A fundamental advance in our understanding of endocrine control of energy balance and body weight came with the discovery of the adipocyte-derived hormone leptin. The leptin pathway appeared to be the long-sought peripheral signal pathway from the adipose tissue to the brain involved in the regulation of feeding and energy balance. RECENT FINDINGS: Initially, leptin was considered to function as the long-sought antiobesity hormone. According to this hypothesis, rising concentrations of leptin with increasing adiposity would generate a signal to reduce food intake and increase energy expenditure in order to limit further weight gain. However, widespread resistance to the proposed antiobesity action of leptin is observed in humans, which might reflect the fact that the inability to store energy efficiently at times of abundance is evolutionarily disadvantageous. According to this alternative view, falling leptin concentrations observed during fasting act as a peripheral signal of starvation, which serves to conserve energy in the face of limited reserves. However, leptin administration failed to blunt the changes in energy expenditure during severe energy restrictions in several clinical studies. In addition, leptin therapy in several different human low-leptin states failed to affect energy expenditure in recent studies. SUMMARY: Increasing evidence from human studies suggests that leptin predominantly influences the human energy balance through appetite but appears not to be involved in regulating energy expenditure. None of the expected factors such as resting metabolic rate, total diurnal energy expenditure or dietary induced thermogenesis was related to blood leptin concentrations. PMID: 15534430 [PubMed - indexed for MEDLINE] 4007. Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):623-8. Metabolic consequences of overfeeding in humans. Tappy L(1). Author information: (1)Department of Physiology and Division of Endocrinology, Diabetes and Metabolism, Lausanne University Faculty of Biology and Medicine, Lausanne, Switzerland. luc.tappy@physiol.unil.ch PURPOSE OF REVIEW: Overfeeding leads to obesity and metabolic disorders, including impaired glucose homeostasis, lipid disorders, and hepatic steatosis. The consequences of standardized overfeeding on body weight have shown, however, considerable interindividual variability, which suggests that it also leads to adaptative changes in energy expenditure, in some individuals at least. The present review is mainly focused on the recent developments regarding the effects of overfeeding on energy expenditure. RECENT FINDINGS: Individuals who gain the less body weight during overfeeding are those who experience a greater increase in total energy expenditure. This increase in energy expenditure has been attributed to stimulation of nonexercise physical activity. Recent developments regarding adaptative increases in physical activity are critically reviewed. Overfeeding also alters the pathways used for carbohydrate storage after a glucose load, by increasing de-novo lipogenesis in the liver and adipose tissue at the expense of glycogen storage. The sympathetic nervous system is a good candidate for energy expenditure increase during overfeeding. The increases in energy expenditure observed during acute stimulation of the sympathetic nervous system were however found to be unaltered by short-term overfeeding. SUMMARY: The mechanisms by which some individuals protect themselves against body weight gain remain poorly understood. Nonvoluntary physical activity may allow one to increase energy expenditure during overfeeding, and may therefore constitute a regulatory factor in body weight control. The biological determinant of spontaneous, nonvoluntary physical activity, however, remains to be investigated. PMID: 15534429 [PubMed - indexed for MEDLINE] 4008. Trends Pharmacol Sci. 2004 Dec;25(12):647-53. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Gollasch M(1), Dubrovska G. Author information: (1)LSU Health Sciences Center, Physiology, 1901 Perdido Street, Box P7-3, New Orleans, LA 70112-1393, USA. mgolla@lsuhsc.edu Recent studies propose a paracrine role for periadventitial adipose tissue in the regulation of vascular tone. This regulation depends on the anatomical integrity of the periadventitial adipose tissue and involves adipocyte-derived relaxing factor (ADRF). Although the nature of ADRF is largely unknown, it is released by periadventitial adipocytes and induces vasorelaxation by opening K+ channels in the plasma membrane of smooth muscle cells. Alterations in the paracrine role of periadventitial adipose tissue might have a role in vascular dysfunction in hypertension and metabolic disease. Therefore, understanding alterations in ADRF release and the K+ channels involved will help further our understanding of the increased cardiovascular risk and development of chronic vascular disease in obesity. Furthermore, ADRF and perhaps its putative targets might represent exciting new targets for the development of drugs to treat cardiovascular disorders. PMID: 15530643 [PubMed - indexed for MEDLINE] 4009. Rom J Intern Med. 2004;42(2):237-45. Metabolic syndrome--practical approach. Hâncu N(1), Roman G, Nită C, Negrean M. Author information: (1)Iuliu Hatieganu University of Medicine and Pharmacy Clinical Center of Diabetes, Nutrition, Metabolic Diseases, Cluj-Napoca, Romania. diabet@insin.hearticj.ro The diagnosis of metabolic syndrome is based on identification of the following parameters: abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, fasting glycemia, as recommended by ATP III. In order to simplify the clinical practice, at least two parameters should be screened for. The most frequent couple, easy to be determined in practice, is hypertensive waist, followed by hypertriglyceridemic waist, hypertensive dyslipidemia, dysglycemic dyslipidemia and hypertensive dysglycemia. Based on these couples the next step would be to identify the triads that diagnose the metabolic syndrome. A global assessment of cardiovascular risk should be made. Suggested method is to apply the Framingham Score. Therapeutic intervention is structured according to levels of cardiovascular risk. Clinical management is structured on THEME Programs (therapy, education, monitoring, evaluation), applied to all risk factors. PMID: 15529614 [PubMed - indexed for MEDLINE] 4010. Rom J Intern Med. 2003;41(1):27-33. The endothelial dysfunction in diabetes mellitus. Pănuş C(1), Moţa M, Vladu D, Vanghelie L, Răducanu CL. Author information: (1)University of Medicine and Pharmacy, Craiova, Romania. The vascular chronic complications are the main cause of morbidity and mortality in patients with diabetes mellitus. Nowadays it is well known the fact that the arteriosclerosis is initiated by the injury of the vascular endothelium and that the normal endothelial cells are producing a number of vasoactive factors. Thus, the vascular endothelium was considered an inert "lining" layer, but today is seen as a complex organ, with paracrin and autocrin function, which provides a "first line" physiological defence against atherosclerosis. Impaired endothelial function occurs in people with diabetes as a result of associated conditions (e.g. hyperglycemia, hypertension, dyslipidemia), or as an effect of hyperglycemia itself (e.g. cytokines, free fatty acids, AGES). The presence of endothelial dysfunction in non diabetic insulin resistant subjects suggests that metabolic and vascular abnormalities are tightly related at a fundamental level. Recent evidence suggests that insulin signalling for glucose transport in classical target tissues (muscle and adipose tissue) and upregulation of NO production in the endothelium utilises the same postreceptor pathway. This pathway involves the enzyme P13 kinase. Knowledge of the molecular mechanisms involved in the pathogenesis of endothelial dysfunction may ultimately result in novel approaches to the treatment and prevention of cardiovascular disease in people with diabetes mellitus. PMID: 15529582 [PubMed - indexed for MEDLINE] 4011. Pol Arch Med Wewn. 2004 Jul;112(1):865-72. [Obesity. The role of recently discovered hormones in the regulation of energy balance]. [Article in Polish] Czerwińska E(1), Marcinowska-Suchowierska E. Author information: (1)Klinika Medycyny Rodzinnej i Chorób Wewnetrznych Centrum Medycznego Kształcenia Podyplomowego w Warszawie. PMID: 15526850 [PubMed - indexed for MEDLINE] 4012. Rom J Intern Med. 2003;41(2):103-11. Hypertension in obese patients: a dysmetabolic hypertension with a possible adipocyte dysfunction mechanism. Blaj S(1), Stanciu S, Jurcut C, Ciobîcă L. Author information: (1)Internal Medicine I Department, Central Clinical Military Hospital 88, Mircea Vulcanescu Str., Bucharest, Romania. Large longitudinal studies showed the epidemiological link between obesity and hypertension. During last years, multiple possible mechanisms involved in this association were identified. Adipose tissue has an important role in the genesis of hypertension in obese patients through several pathways: insulin resistance, leptin, renin-angiotensin-aldosteron system and mediators of inflammation (TNF-alpha, IL-6). Adipocyte may be the major player in the development of insulin resistance and hypertension, elements of the metabolic syndrome, responsible for the cardiovascular complications. PMID: 15526495 [PubMed - indexed for MEDLINE] 4013. Cell Mol Life Sci. 2004 Oct;61(19-20):2485-96. An update on the biology and physiology of resistin. Adeghate E(1). Author information: (1)Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. eadeghate@uaeu.ac.ae. Resistin is a newly discovered adipocyte hormone. It is related to resistin-like molecules alpha, beta and gamma in structure and function. Resistin is produced by white and brown adipose tissues but has also has been identified in several other tissues, including the hypothalamus, pituitary and adrenal glands, pancreas, gastrointestinal tract, myocytes, spleen, white blood cells and plasma. The tissue level of resistin is decreased by insulin, cytokines such as tumour necrosis factor alpha, endothelin-1 and increased by growth and gonadal hormones, hyperglycaemia, male gender and some proinflammatory cytokines, such as interleukin-6 and lipopolysaccharide. Resistin antagonizes insulin action, and it is downregulated by rosiglitazone and peroxisome proliferator-activated receptor gamma agonists. Since evidence of a direct link between resistin genotype and human diabetes is still weak, more molecular, physiological and clinical studies are needed to determine the role of resistin in the aetiology of type 2 diabetes. PMID: 15526156 [PubMed - indexed for MEDLINE] 4014. Diabetes Metab. 2004 Sep;30(4):294-309. Metabolism of lipids in human white adipocyte. Large V(1), Peroni O, Letexier D, Ray H, Beylot M. Author information: (1)INSERM 499, Faculté de médecine Laennec, rue Paradin, 69372 Lyon. large@laennec.univ-lyon1.fr Adipose tissue is considered as the body's largest storage organ for energy in the form of triacylglycerols, which are mobilized through lipolysis process, to provide fuel to other organs and to deliver substrates to liver for gluconeogenesis (glycerol) and lipoprotein synthesis (free fatty acids). The release of glycerol and free fatty acids from human adipose tissue is mainly dependent on hormone-sensitive lipase which is intensively regulated by hormones and agents, such as insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). A special attention is paid to the recently discovered perilipins which could regulate the activity of the lipase hormono-sensible. Most of the plasma triacylglycerols are provided by dietary lipids, secreted from the intestine in the form of chylomicron or from the liver in the form of VLDL. Released into circulation as non-esterified fatty acids by lipoprotein lipase, those are taken up by adipose tissue via specific plasma fatty acid transporters (CD36, FATP, FABPpm) and used for triacylglycerol synthesis. A small part of triacylglycerols is synthesized into adipocytes from carbohydrates (lipogenesis) but its regulation is still debated in human. Physiological factors such as dieting/fasting regulate all these metabolic pathways, which are also modified in pathological conditions e.g. obesity. PMID: 15525872 [PubMed - indexed for MEDLINE] 4015. Trends Endocrinol Metab. 2004 Nov;15(9):425-31. Effective treatments for insulin resistance: trim the fat and douse the fire. Evans JL(1), Youngren JF, Goldfine ID. Author information: (1)Medical Research Institute, San Francisco, CA 94107, USA. jevansphd@earthlink.net Currently, only limited treatments are available for insulin resistance, a major cause of type 2 diabetes (T2D) and the metabolic syndrome. Combined innovative pharmaceutical and non-pharmaceutical strategies are needed. Obesity, a major cause of insulin resistance in T2D, can be treated relatively safely with modern bariatric surgery. Exercise training to increase VO(2max) is an important non-pharmaceutical approach to decrease insulin resistance. The thiazolidinediones are useful in treating insulin resistance, but newer agents with broader specificity might be more efficacious without deleterious side effects. Recently oxidative stress has been implicated in insulin resistance. One antioxidant that is safe and appears effective is alpha-lipoic acid. Thus, combinations of surgery, exercise training, insulin sensitizers and antioxidants will probably constitute future insulin resistance management. PMID: 15519889 [PubMed - indexed for MEDLINE] 4016. Trends Endocrinol Metab. 2004 Nov;15(9):418-24. 11beta-hydroxysteroid dehydrogenase type 1 as a modulator of glucocorticoid action: from metabolism to memory. Seckl JR(1), Walker BR. Author information: (1)Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK. J.Seckl@ed.ac.uk Increases in plasma cortisol and glucocorticoid pharmacotherapy cause myriad adverse effects from obesity and diabetes to impairments in memory. The common metabolic syndrome phenotypically resembles the rare disorder Cushing's syndrome, but plasma cortisol levels are usually normal. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the regeneration of active glucocorticoids (cortisol and corticosterone) from inert 11-keto forms in specific tissues, notably liver, adipose and brain. Recent work shows that obese humans and rodents have increased 11beta-HSD1 activity selectively in adipose tissue. By locally amplifying glucocorticoid action, this increase in activity might explain the Cushing's syndrome/metabolic syndrome paradox. Indeed, mice deficient in 11beta-HSD1 resist both the metabolic syndrome that develops with dietary obesity and glucocorticoid-associated cognitive impairments that develop with ageing. The ongoing development of selective 11beta-HSD1 inhibitors affords the opportunity to explore a new approach to some major common disorders. PMID: 15519888 [PubMed - indexed for MEDLINE] 4017. Domest Anim Endocrinol. 2004 Nov;27(4):303-31. Intercellular signaling between adipose tissue and muscle tissue. Kokta TA(1), Dodson MV, Gertler A, Hill RA. Author information: (1)Department of Animal and Veterinary Science, University of Idaho, 311 Agricultural Biotechnology Building, P.O. Box 442330, Moscow, ID 83844-2330, USA. Adipose and muscle tissues undergo regulated growth and differentiation processes that are modulated by a wide range of factors. The interactions between myogenic cells and adipocytes play a significant role in growth and development, including the rate and extent of myogenesis, muscle growth, adipogenesis, lipogenesis/lipolysis, and in the utilization of energy substrates. Important hormones and growth factors involved in the regulation of these processes include glucocorticoids, insulin-like growth factors, various cytokines, insulin, and leptin. Interactions among these axes have important implications in their influence on relative fat and lean deposition and the efficiency of energy utilization in growth and development. As research progresses to better clarify the interactions among adipose tissue depots and muscle of different fiber types, pathways will become better understood, ultimately leading to the optimized management of fat and lean growth in domestic livestock species. This review will focus on elements of intercellular signaling, using data from cell culture studies to illustrate specific examples of signaling pathways between cells. PMID: 15519037 [PubMed - indexed for MEDLINE] 4018. Ann Chir Plast Esthet. 2004 Oct;49(5):426-36. [The effect of different factors on the survival of transplanted adipocytes]. [Article in French] Mojallal A(1), Foyatier JL. Author information: (1)Service de chirurgie plastique et des grands brûlés, centre hospitalier Saint-Joseph-Saint-Luc, 20, quai Claude-Bernard 69007, Lyon, France. alimojallal@yahoo.fr Most authors supported the theory of adipocyte survival. The viability of these cells has been demonstrated by various experimental clinical, radiological and biochemical studies. After a review of the literature, the authors report the various factors, which influence the survival of the transplanted adipocytes. These factors are presented according to their chronology in the operative procedure. The techniques used are very diverse. The reference technique chosen is that described by Coleman (Lipostructure). The following factors are studied: type of anaesthesia, infiltration, donor site of adipose tissue, method of harvesting, method of refining adipose tissue, anabolic complements, receiving site, reinjection technique, number of grafting sessions, freezing of adipose tissue and complementary postoperative treatments. It seems imperative that each phase of the operative procedure should be carried out without damage to the adipocytes, in particular their harvesting, refining and reinjection. All the other factors studied require comparative analysis in order to demonstrate their true importance. This opens up various directions of research aiming to improve the survival of the transplanted adipocytes. PMID: 15518943 [PubMed - indexed for MEDLINE] 4019. Ann Chir Plast Esthet. 2004 Oct;49(5):419-25. [Historical review of the use of adipose tissue transfer in plastic and reconstructive surgery]. [Article in French] Mojallal A(1), Foyatier JL. Author information: (1)Service de chirurgie plastique et des grands brûlés, centre hospitalier Saint-Joseph-Saint-Luc, 20, quai Claude-Bernard 69007 Lyon, France. alimojallal@yahoo.fr Use of adipose tissue transfer in plastic and reconstructive surgery is not new, and has been the subject of numerous studies. Transfer of autologous adipose tissue was reported for the first time at the end of the 19th century. Ideas and techniques have greatly changed during the last century. Adipocyte transfer has attracted renewed interest in recent years, due in particular to the development of Lipostructure by Coleman, who introduced a procedure based on strict methodology and the use of specific material. The history of adipose tissue transfer is retraced through the works of various authors and briefly recounted by highlighting the major landmarks of its advance. The evolution of ideas and techniques can be divided into three periods. The period before the introduction of lipoaspiration was termed "open surgery", when adipose tissue was harvested by surgical excision. The next period is that following the discovery of lipoaspiration, called the "unrefined" period, during which adipose tissue was obtained by aspiration and reinjected without preparation. During the third period, following the works of Coleman, the adipose tissue now undergoes non-traumatic refinement before grafting; this period is called "non-traumatic refined". Various studies have shown that this technique causes little damage to the cells and have demonstrated survival of the tissue transferred. Discovery of the developmental capacities of the various lineages from a mesodermal stem cell, and in vitro culture of these cells, opens up new research perspectives and clinical applications. From this precursor cell, adipocytes, osteoblasts, chondrocytes, myocytes and neurone-like cells can be developed. The future of autologous reconstruction appears promising. PMID: 15518942 [PubMed - indexed for MEDLINE] 4020. Ann Chir Plast Esthet. 2004 Oct;49(5):409-18. [Adipose tissue, plastic and reconstructive surgery: come back to sources]. [Article in French] Casteilla L(1), Charrière G, Laharrague P, Cousin B, Planat-Benard V, Péricaud L, Chavoin JP. Author information: (1)UMR 5018 CNRS UPS, IFR31, TSA 50032, IFR31, Bat. L1, CHU de Rangueil, 1, avenue Poulhès, 31059 Toulouse 09, France. casteil@toulouse.inserm.fr The adipose tissue represents a large amount of adult tissue. For long time, it was considered as a filling tissue and used in plastic and reconstructive surgery. It was always studied for its main involvement in energy metabolism and energy disorders as diabetes and obesity. More recently, its endocrine functions emerged and thus play a key role in many physiological functions as inflammation and immunity. The presence of preadipocytes throughout life was demonstrated using primary culture technology from cells derived from adipose tissue. In recent papers, cells derived from adipose tissue were used for haematopoiesis, vascularisation or skeletal muscle recovery. Differentiation into functional cardiomyocytes, osteoblasts and neural cells was obtained in vitro. These spectacular data, the fact that adipose tissue is easy to sample and the possibility to create cell or tissue banks open numerous and promising perspectives in regenerative medicine. PMID: 15518941 [PubMed - indexed for MEDLINE] 4021. Biol Pharm Bull. 2004 Nov;27(11):1707-16. Identification of muscle-type carnitine palmitoyltransferase I and characterization of its atypical gene structure. Yamazaki N(1). Author information: (1)Faculty of Pharmaceutical Sciences, University of Tokushima, Japan. yamazaki@ph.tokushima-u.ac.jp To characterize energy metabolism in rat brown adipose tissue (BAT), we carried out differential screening of a cDNA library of BAT with a cDNA probe of white adipose tissue and isolated one novel cDNA clone. It contained a single open-reading frame of 2316 bases, which encodes a protein of 88.2 kDa. The predicted amino acid sequence showed the highest homology (62.6%) with that of carnitine palmitoyltransferase I (CPTI) from rat liver. The transcript corresponding to this cDNA was found to be abundantly expressed not only in BAT but also in heart and skeletal muscle. CPTI is known to be a protein necessary for the beta-oxidation of long-chain fatty acids in mammalian mitochondria, and it has been suggested that at least two isoforms, the liver type and muscle type, exist. From these observations, a cDNA clone isolated from rat BAT was concluded to be encoding muscle-type CPTI (M-CPTI). Characterization of a genomic DNA clone revealed that the gene for human M-CPTI consists of two 5'-noncoding exons, 18 coding exons, and one 3'-noncoding exon spanning approximately 10 kbp, and a gene encoding choline/ethanolamine kinase-beta (CK/EK-beta) was located only about 300 bp upstream from the M-CPTI gene with the same strand direction. Furthermore, we found that unordinary transcripts containing exons of both CK/EK-beta and M-CPTI genes exist in human and rodent tissues. Although the physiologic role(s) of these transcripts is still unknown, it is interesting that such transcripts are produced from two tightly arranged and functionally unrelated genes. PMID: 15516711 [PubMed - indexed for MEDLINE] 4022. Nihon Ronen Igakkai Zasshi. 2004 Sep;41(5):460-7. [Pathogenesis and treatment of cancer anorexia-cachexia, with special emphasis on aged patients]. [Article in Japanese] Inui A(1). Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine. Cachexia is among the most debilitating and life-threatening aspects of cancer and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be caused by persistent inhibition of the feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life. PMID: 15515719 [PubMed - indexed for MEDLINE] 4023. Drugs Today (Barc). 2004 Jul;40(7):633-43. Rosiglitazone maleate/metformin hydrochloride: a new formulation therapy for type 2 diabetes. Cox SL(1). Author information: (1)Medical Information Department, Prous Science, 08025 Barcelona, Spain. support@prous.com Many patients with type 2 diabetes require treatment with more than one antihyperglycemic drug to achieve optimal glycemic control. The thiazolidinediones are a novel class of oral antihyperglycemic drugs that improve glycemic control primarily by increasing peripheral insulin resistance and sensitizing the skeletal muscle, liver and adipose tissue to the actions of insulin, in addition to improving beta-cell function. One of the many features of the thiazolidinedione class of drugs is their synergism with other antihyperglycemic drugs that have a different mechanism of action. The combination of metformin hydrochloride, a biguanide that enhances glucose uptake in peripheral tissues and reduces hepatic gluconeogenesis, with rosiglitazone maleate, one of the newly available members of the thiazolidinedione family, offers a rational therapeutic approach to the treatment of type 2 diabetes. In patients whose type 2 diabetes is inadequately controlled with metformin monotherapy, the addition of rosiglitazone significantly improves glycemic control, insulin sensitivity and beta-cell function, compared with either drug alone. In addition, this combination therapy has beneficial effects on other cardiovascular risk factors. Rosiglitazone maleate/metformin hydrochloride combination therapy is well tolerated in patients with type 2 diabetes and has a favorable safety profile. This review summarizes the available evidence on the clinical efficacy and safety of rosiglitazone maleate and metformin hydrochloride combination therapy in patients with type 2 diabetes. PMID: 15510236 [PubMed - indexed for MEDLINE] 4024. Nutr Rev. 2004 Oct;62(10):389-94. Insulin resistance and obesity: resistin, a hormone secreted by adipose tissue. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, USA. A newly discovered hormone named adipocyte-secreted factor, or resistin, is secreted by adipocytes in mice. Expression of resistin is low during food deprivation and in diabetes, and increased greatly during refeeding and insulin treatment. It is found in serum in mice and humans, and is greatly increased in obesity. Resistin inhibits adipocyte differentiation and may function as a feedback regulator of adipogenesis. Administration of resistin to mice resulted in increased glucose production and blood glucose levels. Therefore, resistin also functions as a regulator of glucose homeostasis and a physiologic antagonist to hepatic insulin action. PMID: 15508908 [PubMed - indexed for MEDLINE] 4025. Biochem Soc Trans. 2004 Dec;32(Pt 6):999-1002. Dietary lipids and gene expression. Roche HM(1). Author information: (1)Nutrigenomics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Ireland. hmroche@tcd.ie Nutrition is a key environmental factor that is particularly involved in the pathogenesis and progression of several polygenic, diet-related diseases. Nutrigenomics refers to the interaction between nutrition and the human genome. Dietary fatty acids interact with multiple nutrient-sensitive transcription factors. This explains the molecular basis of some of the health effects associated with altered dietary fatty acid composition. The metabolic syndrome is a very common condition, characterized by insulin resistance, abdominal obesity, dyslipidaemia and hypertension. It often precedes Type 2 diabetes mellitus, and is associated with a greater risk of cardiovascular disease. Several lines of evidence suggest that the interaction between nutrient-derived metabolic stressors and pro-inflammatory signals play an important role in the aetiology of insulin resistance and the development of the metabolic syndrome. This paper will address the interaction between several nutrient-sensitive transcription factors, including SREBP (sterol-regulatory-element-binding protein) and NFkappaB (nuclear factor kappaB), demonstrating how this interaction may be altered with dietary fatty acid interventions. PMID: 15506946 [PubMed - indexed for MEDLINE] 4026. Nihon Rinsho. 2004 Sep;62 Suppl 9:256-9. [Adrenomedullin in adipose tissue]. [Article in Japanese] Arai H(1). Author information: (1)Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. PMID: 15506381 [PubMed - indexed for MEDLINE] 4027. Niger Postgrad Med J. 2004 Sep;11(3):207-11. The use of buccal fat pad in oral reconstruction - a review. Adeyemo WL(1), Ladeinde AL, Ogunlewe MO, Bamgbose BO. Author information: (1)Oral and Maxillofacial Surgery Department , School of Dental Sciences, College of Medicine, University of Lagos, P.M.B.12003, Lagos, Nigeria. AIM: The aim of this article is to review the applications of the buccal fat pad (BFP) in oral reconstruction, 25 years after its first use as a pedicled flap. MATERIALS AND METHODS: A computerized literature search was conducted for articles published from 1977-2002. Mesh phrases used in the search were: buccal fat pad, buccal fat pad and oral reconstruction. RESULTS: A total of 43 articles were selected for the review based on the criteria for the study. Thirty of these articles were clinical articles, 8 were anatomic studies, 2 were review articles, 1 was an experimental study and 2 discussion articles. Only 9 clinical articles were published prior to 1990, and between 1990 and 2002, a total of 21 clinical articles were published. Various application of BFP in oral reconstruction include closure of surgical defects following tumor excision, repair of surgical defects following excision of leukoplakia and submucous fibrosis, closure of primary and secondary palatal clefts, coverage of maxillary and mandibular bone grafts and lining of sinus surface of maxillary sinus bone graft in sinus lift procedure for maxillary augmentation. CONCLUSIONS: The easy mobilisation of the BFP and its excellent blood supply and minimal donor site morbidity makes it an ideal flap. The main advantages of BFP are ease of harvesting, simplicity, versatility, low rate of complications as well as quick surgical technique. The operation can be performed in one incision, affecting neither appearance nor function of the area. PMID: 15505652 [PubMed - indexed for MEDLINE] 4028. J Am Soc Nephrol. 2004 Nov;15(11):2792-800. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. Wisse BE(1). Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington 98104-2499, USA. bewisse@u.washington.edu The metabolic effects of obesity have made this highly prevalent disease one of the most common risk factors for diabetes, hypertension, and atherosclerosis, the leading causes of end-stage renal failure. However, obesity per se, as defined by body mass index, is less predictive of the development of these diseases than is the presence of a constellation of obesity-related abnormalities now known as the metabolic syndrome. Recognition of this syndrome, which can readily be identified in clinical settings using defined threshold values for waist circumference, BP, fasting glucose, and dyslipidemia, allows for earlier intervention in these high-risk patients. Systemic insulin resistance has been implicated as one possible factor that links visceral obesity to adverse metabolic consequences; however, the mechanism whereby adipose tissue causes alterations in insulin sensitivity remains unclear. Infection and inflammation are commonly associated with insulin resistance, and visceral obesity is associated with a chronic, low-grade inflammatory state, suggesting that inflammation may be a potential mechanism whereby obesity leads to insulin resistance. Moreover, adipose tissue is now recognized as an immune organ that secretes numerous immunomodulatory factors and seems to be a significant source of inflammatory signals known to cause insulin resistance. Therefore, inflammation within white adipose tissue may be a crucial step contributing to the emergence of many of the pathologic features that characterize the metabolic syndrome and result in diabetes and atherosclerosis. This review describes the role of proinflammatory cytokines and hormones released by adipose tissue in generating the chronic inflammatory profile associated with visceral obesity. PMID: 15504932 [PubMed - indexed for MEDLINE] 4029. Nutr Rev. 2004 Sep;62(9):333-9. Polyunsaturated fatty acid regulation of gene expression. Sampath H(1), Ntambi JM. Author information: (1)Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, USA. Polyunsaturated fatty acids (PUFAs), specifically the n-3 series, have been implicated in the prevention of various human diseases, including obesity, diabetes, coronary heart disease and stroke, and inflammatory and neurologic diseases. PUFAs function mainly by altering membrane lipid composition, cellular metabolism, signal transduction, and regulation of gene expression. PUFAs regulate the expression of genes in various tissues, including the liver, heart, adipose tissue, and brain. The role of transcription factors such as SREBP1c and nuclear receptors such as PPAR-alpha, HNF-4alpha, and LXRalpha in mediating the nuclear effects of PUFAs are addressed. PMID: 15497766 [PubMed - indexed for MEDLINE] 4030. J Pathol. 2004 Nov;204(4):478-88. Laminopathies. Broers JL(1), Hutchison CJ, Ramaekers FC. Author information: (1)Department of Molecular Cell Biology, Research Institutes CARIM, GROW, and EURON, University of Maastricht, The Netherlands. Nuclear lamins form a fibrous nucleoskeletal network of intermediate-sized filaments that underlies the inner nuclear membrane. It associates with this membrane through interactions with specific integral nuclear membrane proteins, while within this flattened lamin lattice the nuclear pore complexes are embedded. Next to this peripheral network, the lamins can form intranuclear structures. The lamins are the evolutionary progenitors of the cytoplasmic intermediate filament proteins and have profound influences on nuclear structure and function. These influences require that lamins have dynamic properties and dual identities as structural building blocks on the one hand, and transcription regulators on the other. Which of these identities underlies the laminopathies, a myriad of genetic diseases caused by mutations in lamins or lamin-associated proteins, is a topic of intense debate. Copyright (c) 2004 Pathological Society of Great Britain and Ireland. PMID: 15495262 [PubMed - indexed for MEDLINE] 4031. J Psychiatry Neurosci. 2004 Sep;29(5):364-82. Mother to infant or infant to mother? Reciprocal regulation of responsiveness to stress in rodents and the implications for humans. Walker CD(1), Deschamps S, Proulx K, Tu M, Salzman C, Woodside B, Lupien S, Gallo-Payet N, Richard D. Author information: (1)Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Douglas Hospital Research Centre, 6875 Lasalle Blvd, Montréal QC H4H IR3, Canada. waldom@douglas.mcgill.ca Optimal early development in most species is dependent upon a stable relationship between the mother and her infant. The research described here focuses on the reciprocal nature of this dyad in rodents and humans, with respect to the regulation of responsiveness to stress in both mother and offspring. Dietary influences are critical not only to regulate infant growth but also to modulate the response of the neuroendocrine system to stress and, possibly, to influence some aspects of brain development. In particular, we discuss the role of leptin, a protein produced in the adipose tissue and present in maternal milk, that reduces responses to stress in the infant. We suggest that leptin acts on both central (hypothalamus and hippocampus) and peripheral (pituitary, adrenal gland) targets in the infant to reduce exposure to glucocorticoids and enhance hippocampal development during a sensitive period of brain development. There is also evidence to support the reverse regulatory influence, in which maternal state is profoundly affected by stimulation from the young. During the period of lactation, mothers exhibit lower neuroendocrine and behavioural responses to several types of stressors, except possibly those representing a threat to the infant. This ability to "filter" relevant from irrelevant stimuli while caring for their young might be viewed as adaptive for the mother-infant dyad, and the inability to filter adequately stressful stimuli could at least in part be associated with the development of postpartum depression. PMCID: PMC518866 PMID: 15486606 [PubMed - indexed for MEDLINE] 4032. Rev Endocr Metab Disord. 2004 Dec;5(4):303-9. The physiological role of triacylglycerol hydrolase in lipid metabolism. Gilham D(1), Lehner R. Author information: (1)Department of Pediatrics, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, 328 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2. PMID: 15486462 [PubMed - indexed for MEDLINE] 4033. Neuropathology. 2004 Sep;24(3):159-71. Human neural stem cells genetically modified for brain repair in neurological disorders. Kim SU(1). Author information: (1)Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea. sukim@ajou.ac.kr Existence of multipotent neural stem cells (NSC) has been known in developing or adult mammalian CNS, including humans. NSC have the capacity to grow indefinitely and have multipotent potential to differentiate into three major cell types of CNS, neurons, astrocytes and oligodendrocytes. Stable clonal lines of human NSC have recently been generated from the human fetal telencephalon using a retroviral vector encoding v-myc. One of the NSC lines, HB1.F3, carries normal human karyotype of 46XX and has the ability to self-renew, differentiate into cells of neuronal and glial lineages, and integrate into the damaged CNS loci upon transplantation into the brain of animal models of Parkinson disease, HD, stroke and mucopolysaccharidosis. F3 human NSC were genetically engineered to produce L-dihydroxyphenylalanine (L-DOPA) by double transfection with cDNA for tyrosine hydroxylase and guanosine triphosphate cylohydrolase-1, and transplantation of these cells in the brain of Parkinson disease model rats led to L-DOPA production and functional recovery. Proactively transplanted F3 human NSC in rat striatum, supported the survival of host striatal neurons against neuronal injury caused by 3-nitropro-pionic acid in rat model of HD. Intravenously introduced through the tail vein, F3 human NSC were found to migrate into ischemic lesion sites, differentiate into neurons and glial cells, and improve functional deficits in rat stroke models. These results indicate that human NSC should be an ideal vehicle for cell replacement and gene transfer therapy for patients with neurological diseases. In addition to immortalized human NSC, immortalized human bone marrow mesenchymal stem cell lines have been generated from human embryonic bone marrow issues with retroviral vectors encording v-myc or teromerase gene. These immortalized cell lines of human bone marrow mesenchymal stem cells differentiated into neurons/glial cells, bone, cartilage and adipose tissue when they were grown in selective inducing media. There is further need for investigation into the neurogenic potential of the human bone marrow stem cell lines and their utility in animal models of neurological diseases. PMID: 15484694 [PubMed - indexed for MEDLINE] 4034. Pathol Int. 2004 Oct;54(10):751-8. Uterine lipoleiomyoma: a histopathological review of 17 cases. Aung T(1), Goto M, Nomoto M, Kitajima S, Douchi T, Yoshinaga M, Yonezawa S. Author information: (1)Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. Lipoleiomyoma is a rare uterine tumor. The exact frequency and proliferation activity are not yet known. This study aims to know the frequency and evaluate the relation with renal angiomyolipoma. Lipoleiomyoma cases were immunohistochemically stained by antibodies for Ki-67, melanoma specific antigen HMB45, S-100 protein, and alpha smooth muscle actin (alpha-SMA). Frequency of uterine lipoleiomyoma among uterine myomatous tumor was 17/4904 (0.35%) in the Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School database (1983-2003). Patients ranged from 45 to 74 years of age, and 10 cases were associated with leiomyoma. Six of 17 (35%) cases showed areas with renal angiomyolipoma-like vessels and atypical cellular features. Immunostaining was available in 12 cases. By Ki-67 labeling index, both muscle (average 1.38%) and fat (average 1.17%) portions of the tumor had greater proliferation than normal myometrium (average 0.76%), which suggests that fat portions of the tumor are proliferating adipose tissue rather than fatty degeneration of muscular counterpart. HMB45 antigen, which is positive in renal angiomyolipoma, was negative in three uterine cases having angiomyolipoma-like vessels (3/12). However, HMB45 antigen was positive in spindle-shaped tumor cells of three cases (3/12) which lacked angiomyolipoma-like vessels. Presence of angiomyolipoma-like blood vessels in these tumors is not an uncommon feature. However, the diagnosis of uterine angiomyolipoma should not be based on the result of HMB45 antigen immunoreactivity alone. PMID: 15482564 [PubMed - indexed for MEDLINE] 4035. Drug Discov Today. 2004 Oct 15;9(20):874-80. Pharmaceutical approaches to the treatment of obesity. Jandacek RJ(1), Woods SC. Author information: (1)Department of Pathology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA. The recent increase in pharmaceutical companies' efforts toward the treatment of obesity reflects recognition of the related health risks, the growth of knowledge about mechanisms that control energy balance, and the potential market for new compounds. The current patent literature gives a picture of the targets that are available for pharmaceutical intervention; these include signals of satiety and signals related to fat storage that act in the hypothalamus. The regulation of energy use and storage in adipocytes and the reduction of intestinal absorption of energy are also pharmaceutical focus areas. The multiplicity of targets illustrates not only the many potential approaches to the treatment of obesity but also the complexity and redundancy of the processes that regulate energy storage in the body. PMID: 15475320 [PubMed - indexed for MEDLINE] 4036. Br J Nutr. 2004 Sep;92(3):347-55. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Trayhurn P(1), Wood IS. Author information: (1)Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences, University of Liverpool, UK. p.trayhurn@liverpool.ac.uk White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1. PMID: 15469638 [PubMed - indexed for MEDLINE] 4037. Diagn Cytopathol. 2004 Nov;31(5):300-6. Improved detection of amyloid in fat pad aspiration: an evaluation of Congo red stain by fluorescent microscopy. Giorgadze TA(1), Shiina N, Baloch ZW, Tomaszewski JE, Gupta PK. Author information: (1)Department of Pathology and Laboratory Medicine, Cytopathology and Cytometry Section, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. tamar_giorgadze@yahoo.com Amyloid fat pad aspiration specimens for cases with a clinical suspicion of amyloid typically are stained with Congo red and examined by brightfield microscopy. Congophilia with apple-green birefringence by polarization microscopy (PM) is considered diagnostic for amyloid. Examination of Congo red-stained slides by fluorescent microscopy (FM) is considered by some to be a more sensitive detection method. In this study, we assessed the utility of this technique in cytopathology archival slides from abdominal fat pad aspirations previously stained with Congo red dye. Seventy-eight cases of abdominal fat pad aspirations collected during the last 5 yr and stained with the Congo red procedure were obtained from archival files. Additionally, 20 adipose tissue material slides prepared from the surgical pathology specimens were examined as controls. One representative smear was examined in each case using FM equipped with rhodamine excitation/absorption (540/570 nm) filters. Relevant clinical information was obtained in all cases. Twelve cases (15.4%) of the 78 fat pad aspiration cases were reported originally as positive by Congo red stain using polarization and apple-green birefringence as diagnostic criteria. On review, four cases were deemed unsatisfactory. By FM examination 29 of the 74 (39.2%) cases were reclassified as positive for amyloid. The results were confirmed by immunohistochemical stain for amyloid P protein and electron microscopy. A number of similar distinct fluorescence and immunohistochemical patterns were recognized in the positive cases. Minimally weak fluorescence in the adipose tissue was observed in the control cases. The use of FM in Congo red-stained fat pad smears can improve the detection of amyloid in cytology preparations. PMID: 15468138 [PubMed - indexed for MEDLINE] 4038. Cardiovasc Radiat Med. 2004 Apr-Jun;5(2):97-103. Peroxisome proliferator-activated receptor gamma: its role in metabolic syndrome. Pakala R(1), Kuchulakanti P, Rha SW, Cheneau E, Baffour R, Waksman R. Author information: (1)Cardiovascular Research Institute, Washington Hospital Center, 110 Irving Street NW, Suite 4B-1, Washington, DC 20010, USA. Here we review PPARgamma function in relation to human adipogenesis, insulin sensitization, lipid metabolism, blood pressure regulation and prothrombotic state to perhaps provide justification for this nuclear receptor remaining a key therapeutic target for the continuing development of agents to treat human metabolic syndrome. PMID: 15464947 [PubMed - indexed for MEDLINE] 4039. Curr Cancer Drug Targets. 2004 Sep;4(6):531-42. Mammaglobin-based strategies for treatment of breast cancer. Goedegebuure PS(1), Watson MA, Viehl CT, Fleming TP. Author information: (1)Department of Surgery, Washington Univesity School of Medicine, St. Louis, MO 63110, USA. goedegep@wustl.edu Mammaglobin is a gene that is expressed almost exclusively in the normal breast epithelium and human breast cancer. It is a member of the secretoglobin gene family and forms a heterodimer with lipophilin B. We have focused on the tissue-specificity of mammaglobin as a potential mechanism for the specific killing of breast cancer cells. By elucidating the promoter region of mammaglobin, we hope to utilize this site as a method for turning on the apoptosis inducer gene, Bax, in breast cancer cells. The Bax gene will only be expressed at levels necessary to induce apoptosis in mammaglobin positive cells. This would include > 80% of all breast cancers and some normal breast epithelium. This type of targeted killing could be conceptualized as a biochemical mastectomy, that is, genetic ablation of breast tumor cells and perhaps non-malignant breast epithelium while preserving the adipose and stromal components of the breast. Work is also being done to address the binding specificity of the secreted mamaglobin protein. There is early evidence that the mammaglobin heterodimer may in fact bind to breast and breast cancer cells. If this finding is validated, this creates the possibility that mammaglobin can be tagged with radioisotope or toxin, so that binding of the tagged-mammaglobin complex results in the specific killing of that breast cancer cell. Finally, mammaglobin is being explored as a target for immune-based interventions. In vitro studies have demonstrated that T cell-mediated immune responses can be induced against mammaglobin-derived peptides expressed by MHC molecules on tumor cells and antigen-presenting cells. Copyright 2004 Bentham Science Publishers Ltd. PMID: 15462037 [PubMed - indexed for MEDLINE] 4040. Obes Rev. 2004 Nov;5(4):197-216. Direct effects of sex steroid hormones on adipose tissues and obesity. Mayes JS(1), Watson GH. Author information: (1)Center for Health Sciences, Oklahoma State University, Tulsa, OK 74107-1898, USA. Sex steroid hormones are involved in the metabolism, accumulation and distribution of adipose tissues. It is now known that oestrogen receptor, progesterone receptor and androgen receptor exist in adipose tissues, so their actions could be direct. Sex steroid hormones carry out their function in adipose tissues by both genomic and nongenomic mechanisms. In the genomic mechanism, the sex steroid hormone binds to its receptor and the steroid-receptor complex regulates the transcription of given genes. Leptin and lipoprotein lipase are two key proteins in adipose tissues that are regulated by transcriptional control with sex steroid hormones. In the nongenomic mechanism, the sex steroid hormone binds to its receptor in the plasma membrane, and second messengers are formed. This involves both the cAMP cascade and the phosphoinositide cascade. Activation of the cAMP cascade by sex steroid hormones would activate hormone-sensitive lipase leading to lipolysis in adipose tissues. In the phosphoinositide cascade, diacylglycerol and inositol 1,4,5-trisphosphate are formed as second messengers ultimately causing the activation of protein kinase C. Their activation appears to be involved in the control of preadipocyte proliferation and differentiation. In the presence of sex steroid hormones, a normal distribution of body fat exists, but with a decrease in sex steroid hormones, as occurs with ageing or gonadectomy, there is a tendency to increase central obesity, a major risk for cardiovascular disease, type 2 diabetes and certain cancers. Because sex steroid hormones regulate the amount and distribution of adipose tissues, they or adipose tissue-specific selective receptor modulators might be used to ameliorate obesity. In fact, hormone replacement therapy in postmenopausal women and testosterone replacement therapy in older men appear to reduce the degree of central obesity. However, these therapies have numerous side effects limiting their use, and selective receptor modulators of sex steroid hormones are needed that are more specific for adipose tissues with fewer side effects. PMID: 15458395 [PubMed - indexed for MEDLINE] 4041. Obes Rev. 2004 Nov;5(4):189-96. Adipose tissue: new therapeutic targets from molecular and genetic studies--IASO Stock Conference 2003 report. Farmer SR(1), Auwerx J. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. This review highlights the presentations and discussions held during the 2003 Stock Conference in Lisbon focussed on the identification of new therapeutic targets for the treatment of obesity and identified through molecular and genetic studies. Transcription factors and their cofactors, signalling pathways and new insights provided by cellular and genetic studies were discussed as potential new avenues to modulate adipocyte formation and function. PMID: 15458394 [PubMed - indexed for MEDLINE] 4042. Obes Rev. 2004 Nov;5(4):177-81. Aetiology of obesity: a striving after wind? Rosmond R(1). Author information: (1)Lundvägen, Sävedalen, Sweden. rolandrosmond@hotmail.com The current global epidemic of obesity is fuelled by a constant, unidirectional adverse effect on energy balance that exceeds the adaptive capacity of the system. The individual response to this environmental pressure is under the control of a variety of genes, which not only interacts with environmental factors but also with one another. Since the discovery that adipocytes may produce and secrete hormones, the adipose tissue has taken on increasing importance in the regulation of energy balance. Indeed, the pathogenesis of obesity, once regarded as so obvious and simple, is becoming one of the most complex in medical practice. From a clinical perspective, obesity is associated with a remarkably broad spectrum of health complications and, over the years, obesity-related mortality has consistently increased. From a theoretical viewpoint, the growing complexity of factors affecting the liability to obesity, the inconsistency of scientific results, the lack of consensus among scientists, and so forth, obstruct our efforts to unravel the aetiology of obesity. Is the field of obesity research merely a striving after wind, and nothing more? PMID: 15458392 [PubMed - indexed for MEDLINE] 4043. Free Radic Biol Med. 2004 Nov 1;37(9):1499-507. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Videla LA(1), Rodrigo R, Araya J, Poniachik J. Author information: (1)Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Chile. lvidela@med.uchile.cl Human nonalcoholic fatty liver disease (NAFLD) associated with obesity is characterized by depletion of hepatic n-3 long-chain polyunsaturated fatty acids (LCPUFA), with lower LCPUFA product/precursor ratios and higher 18:1n-9 trans levels in adipose tissue, both in patients with steatosis and in those with steatohepatitis. These changes point to modification of gene expression, with decreased fatty acid oxidation and triacylglycerol export and enhanced lipid synthesis, thereby leading to fat accumulation in the liver. Changes in oxidative stress-related parameters indicate a moderate enhancement in the pro-oxidant status of the liver in steatosis, which is further exacerbated in steatohepatitis. It is proposed that oxidative stress plays a dual role in NAFLD by contributing to steatosis due to higher peroxidation of LCPUFA, in addition to defective fatty acid desaturation and diet imbalance, and by promoting progression of steatosis to steatohepatitis, features that might involve changes in the activity of transcriptional mediators. PMID: 15454290 [PubMed - indexed for MEDLINE] 4044. Domest Anim Endocrinol. 2004 Oct;27(3):241-55. Regulation of development and metabolism of adipose tissue by growth hormone and the insulin-like growth factor system. Louveau I(1), Gondret F. Author information: (1)Institut National de la Recherche Agronomique, Unité Mixte de Recherches sur le Veau et le Porc, 35590 Saint Gilles, France. Isabelle.Louveau@rennes.inra.fr White adipose tissue plays a key role in the regulation of the energy balance of vertebrates. This tissue is also now recognized to secrete a variety of factors such as leptin, which is thought to be involved in the modulation of adipose mass. Unlike other tissues, adipose tissue mass has considerable capacity to expand. The review deals primarily on the regulation of development and metabolism of adipose tissue by growth hormone (GH) and the insulin-like growth factor (IGF) system, with a special focus on the pig. The anti-insulin effects of GH are well-documented in pigs as in other species. In vitro exposure of adipose precursor cells to GH leads to a decrease in differentiation of those cells in pigs, in contrast to data obtained in murine cell lines. In vivo treatment and prolonged in vitro incubation of adipose tissue or isolated adipocytes with GH result in a decrease in glucose transport and lipogenesis, especially at the level of the fatty acid synthase gene, resulting in a reduction of the lipid content and adipose tissue mass. The mechanism by which GH antagonizes insulin stimulation of lipogenesis is still unresolved, as it is not mediated by protein kinase A, protein kinase C and Janus kinase-2 at the signaling level, or upstream stimulatory factor 1 or sterol regulatory element binding protein-1 at the transcriptional level. GH is apparently the main regulator of IGF-I mRNA expression in adipose tissue, however, the effects of IGF-I on this tissue are rather unclear. PMID: 15451072 [PubMed - indexed for MEDLINE] 4045. Pediatr Diabetes. 2004 Sep;5(3):147-53. Long-term metabolic consequences of being born small for gestational age. Levy-Marchal C(1), Jaquet D. Author information: (1)INSERM U457, Robert Debré Hospital, Paris, France. clairelm@rdebre.inserm.fr Comment in Pediatr Diabetes. 2004 Sep;5(3):113-6. This review highlights the evidence of linking small for gestational age (SGA) with metabolic/cardiovascular disturbances (dysmetabolic syndrome) in later life. The metabolic and cardiovascular complications associated with in utero undernutrition have been identified during the past 10 yr. Reduced fetal growth is independently associated with an increased risk of the development of cardiovascular diseases, the insulin-resistance syndrome, or one of its components: hypertension, dyslipidemia, impaired glucose tolerance, or type 2 diabetes. All of them appear to result from the initial development of insulin-resistance which appears as a key component underlying the metabolic complications. Although the mechanism remains unclear, there is some evidence that argues in favor of an active contribution of the adipose tissue in the emergence of insulin-resistance associated with in utero undernutrition, but this hypothesis remains to be further documented. From a broader point of view, several hypotheses have been proposed over the past 10 yr to understand this unexpected association. Each of them points to either a detrimental fetal environment or genetic susceptibilities or interactions between these two components as playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains at the moment the most attractive. PMID: 15450010 [PubMed - indexed for MEDLINE] 4046. J Cell Biochem. 2004 Nov 15;93(5):871-7. Tumor-host interactions. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Birmingham, B4 7ET, United Kingdom. m.j.tisdale@aston.ac.uk A number of malignant tumors interact with the host to cause a syndrome of cachexia, characterized by extensive loss of adipose tissue and skeletal muscle mass, but with preservation of proteins in visceral tissues. Although anorexia is frequently present, the body composition changes in cancer cachexia cannot be explained by nutritional deprivation alone. Loss of skeletal muscle mass is a result of depression in protein synthesis and an increase in protein degradation. The main degradative pathway that has been found to have increased expression and activity in the skeletal muscle of cachectic patients is the ubiquitin-proteasome proteolytic pathway. Cachexia-inducing tumors produce catabolic factors such as proteolysis-inducing factor (PIF), a 24 kDa sulfated glycoprotein, which inhibit protein synthesis and stimulate degradation of intracellular proteins in skeletal muscle by inducing an increased expression of regulatory components of the ubiquitin-proteasome proteolytic pathway. While the oligosaccharide chains in PIF are required to initiate protein degradation the central polypeptide core may act as a growth and survival factor. Only cachexia-inducing tumors are capable of elaborating fully glycosylated PIF, and the selectivity of production possibly rests with the acquisition of the necessary glycosylating enzymes, rather than expressing the gene for the polypeptide core. Loss of adipose tissue is probably the result of an increase in catabolism rather than a defect in anabolism. A lipid mobilizing factor (LMF), identical with the plasma protein Zn-alpha2-glycoprotein (ZAG) is found in the urine of cachectic cancer patients and is produced by tumors causing a decrease in carcass lipid. LMF causes triglyceride hydrolysis in adipose tissue through a cyclic AMP-mediated process by interaction with a beta3-adrenoreceptor. Thus, by producing circulating factors certain malignant tumors are able to interfere with host metabolism even without metastasis to that particular site. (c) 2004 Wiley-Liss, Inc. PMID: 15449322 [PubMed - indexed for MEDLINE] 4047. Med Res Rev. 2005 Jan;25(1):49-65. Cross-talk between skeletal muscle and adipose tissue: a link with obesity? Argilés JM(1), López-Soriano J, Almendro V, Busquets S, López-Soriano FJ. Author information: (1)Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. Since the discovery of leptin, the adipocyte and its products have been the subject of intensive research. Thus, it has been demonstrated that adipose tissue plays a central role in energy homeostasis, behaving as an endocrine organ that expresses molecules involved in regulation of metabolism; alterations in the expression or activity of those molecules have a fundamental role in pathologies such as obesity and insulin resistance. However, little is known about the role played by another tissue, skeletal muscle, which may have similar functions regarding metabolism control. Indeed, some molecules expressed in this tissue have recently been shown to modulate adipose metabolism. The present review considers the metabolic interrelationships and cross-talk of signals derived from both skeletal muscle and adipose tissue. It is suggested that cytokines derived from both tissues may have an important role in maintaining an adequate ratio of skeletal muscle to fat and thus may play an important role in the control of body weight. IL-15 (a cytokine highly-expressed in skeletal muscle), TNF-alpha, and leptin could play a decisive role in the suggested "conversation" between adipose tissue and skeletal muscle. 2004 Wiley Periodicals, Inc. PMID: 15389734 [PubMed - indexed for MEDLINE] 4048. Nutr Rev. 2004 Jul;62(7 Pt 2):S134-9. Early malnutrition and metabolic abnormalities later in life. González-Barranco J(1), Ríos-Torres JM. Author information: (1)Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Medícas y Nutrición Salvador Subirán, México City, México, Vasco de Quiroga no. 15, Col. Sección XVI, Deleg. Tlalpan, 14000, México, DF. Early malnutrition has been significantly associated with chronic diseases later in life. The finding of metabolic abnormalities in individuals with malnutrition in fetal life and early in postnatal life may have important public health implications in developing countries, although only a few studies have examined the relationship between body weight at the first year of life and later metabolic abnormalities. We assessed the effects of malnutrition during the first year of life (independent of birth weight) on several metabolic parameters in young men. The areas under the curves of glucose and insulin were significantly higher in 52 individuals with a history of malnutrition during the first year of life (cases) than in controls. An insulin sensitivity index was derived and was lower in cases than in controls. In cases, the insulin sensitivity index worsened as body mass index (BMI) increased within the normal range of BMI. A euglycemic insulin clamp as well as an abdominal CT scan were performed in 26 cases and 27 controls. Higher levels of abdominal adipose tissue were more detrimental to insulin sensitivity in previously malnourished individuals. This study suggests that metabolic programming early in life is not restricted to intrauterine growth. We conclude that early malnutrition in extrauterine life independent of birth weight has an adverse effect on insulin sensitivity, glucose tolerance, and lipid profile in young men. This appears to worsen as body mass index increases, even within "normal" limits. PMID: 15387479 [PubMed - indexed for MEDLINE] 4049. Nutr Rev. 2004 Jul;62(7 Pt 2):S127-33. Long-term effects of early malnutrition on body weight regulation. Sawaya AL(1), Martins PA, Grillo LP, Florêncio TT. Author information: (1)Departamento de Fisiologia, Disciplina de Neurofisiologia e Fisiologia Endócrina, Universidade Federal de São Paulo, Rua Botucatu 862, 2nd floor, São Paulo, Capital, Brazil, CEP: 04023-060. Malnutrition is still highly prevalent in developing countries. Studies have shown an increase in the number of obese individuals in very poor urban communities. This review shows a co-existence between malnutrition and obesity in households of slums in Brazil and a higher prevalence of stunted/overweight or obese individuals (30%) in comparison with stunted/underweight (16%). These conditions are associated with important metabolic changes. Results from stunted children showed higher susceptibility to the effects of higher fats diets, lower fat oxidation, higher central fat, and higher body fat gain. A model to explain how early malnutrition alters energy balance in adults is outlined. In the presence of a relative food intake insufficiency, a higher cortisol:insulin ratio, associated with lower levels of IGF-1 will lead to lower muscle gain and linear growth, impaired lypolysis and fat oxidation. When these hormonal changes are combined with a higher fat/carbohydrate and/or marked decreased in physical activity, obesity with short stature will occur. PMID: 15387478 [PubMed - indexed for MEDLINE] 4050. Nutr Rev. 2004 Jul;62(7 Pt 2):S120-6. The epidemiology of central fat distribution in relation to disease. Pi-Sunyer FX(1). Author information: (1)Obesity Research Center, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, NY 10025, USA. Comment in Nutr Rev. 2004 Nov;62(11):448. The effect of fat distribution on disease risk is a subject of great interest. Central fat has been measured anthropometrically, by computed tomography, and by magnetic resonance imaging. Both cross-sectional and longitudinal studies have related central fat to type 2 diabetes mellitus and cardiovascular disease, independent of body mass index. The mechanism may relate to increased lipolysis causing the liver to increase glucose and very low density lipoprotein output, while muscle uses less. This leads to a rise in blood glucose and triglycerides, a drop in HDL cholesterol, and an increase in small, dense LDL particles. There is also an increase in blood pressure and inflammatory markers. Certain populations put on excess fat more centrally than others. These include Asian populations. It is likely that with better differentiation of abdominal fat into visceral and subcutaneous depots, clearer data will accrue on their impact on disease risk. PMID: 15387477 [PubMed - indexed for MEDLINE] 4051. Nutr Rev. 2004 Jul;62(7 Pt 2):S112-9. Influence of lactation on body weight regulation. Lederman SA(1). Author information: (1)Columbia Center for Children's Environmental Health, 100 Haven Avenue, Suite 25F, New York, NY 10032, USA. Maternal weight homeostasis during lactation depends on the management of energy resources. Studies indicate that regulatory processes allow for successful lactation in varied conditions of food availability. These processes involve mobilizing fat, increasing food intake, reducing energy expenditure, and changing the composition or volume of milk. Changes in energy efficiency do not seem important. Early in lactation, fat mobilization appears to be physiologic and gradual, even when food is readily available. Later in lactation, dietary intake may decline even though that allows continued loss of body fat when fat has already lowered. Where increasing dietary intake is less possible, or dietary restriction is imposed, reductions in energy expenditure seem to take precedence over an increase in the rate of fat mobilization. The findings reviewed indicate that for lactation to play a major role in the reduction of body fat in the postpartum period, women have to breastfeed fully for a substantial period. PMID: 15387476 [PubMed - indexed for MEDLINE] 4052. Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):3-14. Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage. Raz I(1), Eldor R, Cernea S, Shafrir E. Author information: (1)Department of Medicine, Diabetes Center, Hadassah University Hospital, Jerusalem 91120, Israel. ntv502@netvision.net.il We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARgamma, or PPARgammaalpha agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening. Copyright (c) 2004 John Wiley & Sons, Ltd. PMID: 15386813 [PubMed - indexed for MEDLINE] 4053. Br J Nutr. 2004 Aug;92 Suppl 1:S47-57. Peripheral and central signals in the control of eating in normal, obese and binge-eating human subjects. Hellström PM(1), Geliebter A, Näslund E, Schmidt PT, Yahav EK, Hashim SA, Yeomans MR. Author information: (1)Department of Gastroenterology and Hepatology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. The worldwide increase in the incidence of obesity is a consequence of a positive energy balance, with energy intake exceeding expenditure. The signalling systems that underlie appetite control are complex, and the present review highlights our current understanding of key components of these systems. The pattern of eating in obesity ranges from over-eating associated with binge-eating disorder to the absence of binge-eating. The present review also examines evidence of defects in signalling that differentiate these sub-types. The signalling network underlying hunger, satiety and metabolic status includes the hormonal signals leptin and insulin from energy stores, and cholecystokinin, glucagon-like peptide-1, ghrelin and peptide YY3-36 from the gastrointestinal tract, as well as neuronal influences via the vagus nerve from the digestive tract. This information is routed to specific nuclei of the hypothalamus and brain stem, such as the arcuate nucleus and the solitary tract nucleus respectively, which in turn activate distinct neuronal networks. Of the numerous neuropeptides in the brain, neuropeptide Y, agouti gene-related peptide and orexin stimulate appetite, while melanocortins and alpha-melanocortin-stimulating hormone are involved in satiety. Of the many gastrointestinal peptides, ghrelin is the only appetite-stimulating hormone, whereas cholecystokinin, glucagon-like peptide-1 and peptide YY3-36 promote satiety. Adipose tissue provides signals about energy storage levels to the brain through leptin, adiponectin and resistin. Binge-eating has been related to a dysfunction in the ghrelin signalling system. Moreover, changes in gastric capacity are observed, and as gastric capacity is increased, so satiety signals arising from gastric and post-gastric cues are reduced. Understanding the host of neuropeptides and peptide hormones through which hunger and satiety operate should lead to novel therapeutic approaches for obesity; potential therapeutic strategies are highlighted. PMID: 15384323 [PubMed - indexed for MEDLINE] 4054. Rev Med Univ Navarra. 2004 Apr-Jun;48(2):49-54. [Obesity and inflammation]. [Article in Spanish] Recasens M(1), Ricart W, Fernández-Real JM. Author information: (1)Unidad de Diabetes, Endocrinología y Nutrición, Hospital Universitari de Girona, Doctor Josep Trueta. The adipose tissue produces a vast number of molecules called adipokines such as leptin, tumoral necrosis factor (TNFalpha), interleukins and adiponectin. Many of the metabolic disturbances associated with obesity and the metabolic syndrome may be due to citokine production by adipocytes. The adipose tissue increases the soluble fractions of TNFalpha leading to a rise in its biological activity. The activation of TNFalpha system causes insulin resistance through different mechanisms such as defects in receptor fosforilation and reduction in insulin-sensitive glucose transporters. TNFalpha is also involved in the pathophysiology of hypertension and dyslipidaemia associated with obesity and insulin resistance. More than one third of interleukin-6 (IL-6) concentrations come from the adipocytes. It has been demonstrated a role for IL-6 in the development of hyperlipidemia, diabetes and hypertension. In contrast to the rest of adipokines, adiponectin is reduced in obesity, diabetes or cardiovascular disease. Adiponectin improves insulin resistance, dyslipidaemia and adhesion to endothelial cells protecting from atherosclerosis development. Thus, adipokines have an important role in the pathophysiology of metabolic syndrome by different mechanisms involving metabolic and vascular effects. PMID: 15382613 [PubMed - indexed for MEDLINE] 4055. Clin Nutr. 2004 Oct;23(5):963-74. Adiponectin, the missing link in insulin resistance and obesity. Gil-Campos M(1), Cañete RR, Gil A. Author information: (1)Unit of Paediatric Endocrinology, University Hospital Reina Sofia, Avda. Menendez Pidal, 14004 Cordoba, Spain. Obesity and insulin resistance have been recognised as leading causes of major health issues, particularly diabetes type 2 and metabolic syndrome. Although obesity, defined as excess body fat, is frequently accompanied by insulin resistance, diabetes, metabolic syndrome and cardiovascular diseases, the molecular basis for the link between obesity and those diseases has not yet been clarified. Adipose tissue expresses various secretory proteins, including leptin, tumour necrosis factor-alpha and adiponectin, which may be involved in the regulation of energy expenditure, lipid metabolism and insulin resistance. The aim of this study is to provide an overview of the metabolic alterations occurring in insulin resistance as well as to review the biological roles of adiponectin, particularly in the regulation of fatty acid oxidation and insulin action. Adiponectin is the most abundant gene product in adipose tissue and accounts for 0.01% of total plasma protein. Plasma adiponectin level is decreased in obesity, both in children and adults, and it is negatively associated to plasma insulin and positively associated to plasma triglycerides. Low levels of adiponectin decreases fatty acid oxidation in muscle. Recent data have demonstrated that adiponectin effects are mediated by the interaction with muscle and hepatic receptors through activation of AMP kinase, the cellular "fuel gauge", which in turn inhibits acetyl CoA carboxylase and increases fatty acid beta-oxidation. Since there is no available recombinant adiponectin for human use, its direct effects on human metabolism remain unknown, but this hormone appears to be promising in the treatment of obesity an related metabolic disorders. PMID: 15380884 [PubMed - indexed for MEDLINE] 4056. J Dairy Sci. 2004 Oct;87(10):3105-24. Invited review: pathology, etiology, prevention, and treatment of fatty liver in dairy cows. Bobe G(1), Young JW, Beitz DC. Author information: (1)Nutritional Physiology Group, Department of Animal Science, Iowa State University, Ames 50011-3150, USA. Fatty liver (i.e., hepatic lipidosis) is a major metabolic disorder of many dairy cows in early lactation and is associated with decreased health status and reproductive performance. In severe cases, milk production and feed intake are decreased. Therefore, a practical preventative or an efficacious treatment of fatty liver could save millions of dollars yearly in treatment, replacement, and production losses for dairy farmers. Fatty liver develops when the hepatic uptake of lipids exceeds the oxidation and secretion of lipids by the liver, which usually is preceded by high concentrations of plasma NEFA mobilized from adipose tissue. Excess lipids are stored as triacylglycerol in the liver and are associated with decreased metabolic functions of the liver. Liver can be categorized into normal liver or mild, moderate, or severe fatty liver; the latter can be subdivided further into nonencephalopathic severe fatty liver and hepatic encephalopathy. Insufficient or unbalanced dietary intake, obesity, and elevated estrogen concentrations are involved in the etiology of fatty liver, which is associated with greater incidence of dystocia, diseases, infections, and inflammations. Because even mild fatty liver is associated with decreased health status and reproductive performance of dairy cows, prevention of fatty liver by supplying cows with sufficient nutrients and a clean and health-promoting environment in the peripartal period would reduce production losses of cows more than would any treatment of fatty liver. This, however, might not be enough for cows that are obese or do not eat well, had calving difficulties or twins, have metabolic or infectious diseases, or are in severe negative energy balance because of high milk production immediately after calving. Potential and commonly used preventatives, as well as treatments, are discussed in the review. Currently, detection of fatty liver is possible only by minor surgery. Ultrasonic techniques offer a potential tool to noninvasively detect fatty liver. Future gene-array and proteomic studies may provide means to detect early molecular events in the etiology of fatty liver plus their connection with immune function and reproductive performance so that more effective treatments and preventatives of fatty liver can be developed. Such advances hopefully will make fatty liver a problem of the past. PMID: 15377589 [PubMed - indexed for MEDLINE] 4057. Rev Invest Clin. 2004 Mar-Apr;56(2):193-208. [Metabolic abnormalities in patients with HIV infection]. [Article in Spanish] Rodríguez-Carranza SI(1), Aguilar-Salinas CA. Author information: (1)Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF. Highly active antiretroviral therapy (HAART) decreased the mortality of patients with HIV infection, but its effects on the metabolism of lipoproteins, carbohydrates and adipose tissue are a common cause for seeking treatment. Our purpose is to present the current knowledge available regarding the epidemiology, pathophysiology, diagnosis and treatment of these conditions. A discussion about the limitations of the current evidence is included. HIV-related dyslipidemia is multifactorial. Prior to the treatment, hypertriglyceridemia is found frequently, usually with low cholesterol and HDL cholesterol levels. Antiretroviral agents, especially some protease inhibitors, have adverse effects on plasma lipids. Nutritional recovery and lipodistrophy exacerbate the lipid abnormalities. Hypertriglyceridemia (usually moderate to severe) and moderate hypercholesterolemia (< 300 mg/dL) are the most common end-results. Subcutaneous fat of the face and limbs decreases and it is deposited in the neck and in the abdomen. The diagnosis and treatment of these conditions are controversial due to the lack of appropriate evidence. The metabolic complications of HAART could be a leading cause of mortality in the near future. Thus, longitudinal studies, including subjects from several ethnic groups are needed to identify the main factors involved in the pathophysiology and to assess several therapeutical and preventive strategies. Collaboration between HIV specialists and other health professionals (i.e. endocrinologists) will be required to accomplish these goals. PMID: 15377073 [PubMed - indexed for MEDLINE] 4058. Proc Nutr Soc. 2004 Aug;63(3):405-12. Prenatal programming of postnatal obesity: fetal nutrition and the regulation of leptin synthesis and secretion before birth. McMillen IC(1), Muhlhausler BS, Duffield JA, Yuen BS. Author information: (1)Discipline of Physiology, School of Molecular and Biomedical Sciences, University of Adelaide, SA 5005, Australia. caroline.mcmillen@adelaide.edu.au Exposure to either an increased or decreased level of intrauterine nutrition can result in an increase in adiposity and in circulating leptin concentrations in later life. In animals such as the sheep and pig in which fat is deposited before birth, leptin is synthesised in fetal adipose tissue and is present in the fetal circulation throughout late gestation. In the sheep a moderate increase or decrease in the level of maternal nutrition does not alter fetal plasma leptin concentrations, but there is evidence that chronic fetal hyperglycaemia and hyperinsulinaemia increase fetal fat mass and leptin synthesis within fetal fat depots. Importantly, there is a positive relationship between the relative mass of the 'unilocular' component of fetal perirenal and interscapular adipose tissue and circulating fetal leptin concentrations in the sheep. Thus, as in the neonate and adult, circulating leptin concentrations may be a signal of fat mass in fetal life. There is also evidence that leptin can act to regulate the lipid storage, leptin synthetic capacity and potential thermogenic functions of fat before birth. Thus, leptin may act as a signal of energy supply and have a 'lipostatic' role before birth. Future studies are clearly required to determine whether the intrauterine and early postnatal nutrient environment programme the endocrine feedback loop between adipose tissue and the central and peripheral neuroendocrine systems that regulate energy balance, resulting in an enhanced risk of obesity in adult life. PMID: 15373950 [PubMed - indexed for MEDLINE] 4059. Proc Nutr Soc. 2004 Aug;63(3):397-403. Timing of nutrient restriction and programming of fetal adipose tissue development. Symonds ME(1), Pearce S, Bispham J, Gardner DS, Stephenson T. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK. Michael.Symonds@nottingham.ac.uk It is apparent from epidemiological studies that the timing of maternal nutrient restriction has a major influence on outcome in terms of predisposing the resulting offspring to adult obesity. The present review will consider the extent to which maternal age, parity and nutritional restriction at defined stages of gestation can have important effects on fat deposition and endocrine sensitivity of adipose tissue in the offspring. For example, in 1-year-old sheep the offspring of juvenile mothers have substantially reduced fat deposition compared with those born to adult mothers. Offspring of primiparous adult mothers, however, show increased adiposity compared with those born to multiparous mothers. These offspring of multiparous ewes show retained abundance of the brown adipose tissue-specific uncoupling protein 1 at 1 month of age. A stimulated rate of metabolism in brown fat of these offspring may act to reduce adipose tissue deposition in later life. In terms of defined windows of development that can programme adipose tissue growth, maternal nutrient restriction targetted over the period of maximal placental growth results in increased adiposity at term in conjunction with enhanced abundance of mRNA for the insulin-like growth factor-I and -II receptors. In contrast, nutrient restriction in late gestation, coincident with the period of maximal fetal growth, has no major effect on adiposity but results in greater abundance of specific mitochondrial proteins, i.e. voltage-dependent anion channel and/or uncoupling protein 2. These adaptations may increase the predisposal of these offspring to adult obesity. Increasing maternal nutrition in late gestation, however, can result in proportionately less fetal adipose tissue deposition in conjunction with enhanced abundance of uncoupling protein 1. PMID: 15373949 [PubMed - indexed for MEDLINE] 4060. Proc Nutr Soc. 2004 Aug;63(3):387-96. Obesity epidemic in India: intrauterine origins? Yajnik CS(1). Author information: (1)Diabetes Unit, Edward Memorial Hospital & Research Center, Pune, India. diabetes@vsnl.com The epidemic of 'obesity' in India is not appreciated because BMI underestimates the adiposity of Indians. Specific adiposity measurements are necessary for recognition of the adiposity of 'thin' Indians. The origin of this adiposity is only beginning to be understood. In addition to a possible genetic predisposition, intrauterine 'programming' might be responsible, although in the 'thrifty phenotype' hypothesis the adiposity of the 'thin' fetus has not been appreciated. Dutch men who faced 'winter hunger' during the first trimester of their in utero life have become more obese as adults. Low birth weight predicts central obesity in some studies, including studies in urban children. It has also been shown that small and thin Indian newborns (weight 2.7 kg and ponderal index 2.4 kg/m3) have poor muscle and visceral mass but higher adiposity for a given weight compared with white Caucasian babies. This body composition is influenced by maternal adiposity before pregnancy and by aspects of maternal nutritional intake and circulating nutrient concentrations during pregnancy. There are no strong paternal determinants of adiposity at birth. Adiposity may be an integral part of the orchestrated adjustments made to support 'brain preservation' during intrauterine growth, because brain tissue is predominantly fat. Increased nutrition in the face of a genetic predisposition or multigenerational undernutrition increases maternal insulin resistance in late pregnancy and promotes fetal adiposity even in absence of marked hyperglycaemia. Further research is necessary to define the role of specific nutrients and metabolites in the intrauterine processes promoting adiposity before maternal interventions to curtail the epidemic of obesity and diabetes are planned. PMID: 15373948 [PubMed - indexed for MEDLINE] 4061. Mov Disord. 2004 Sep;19(9):1109-11. Persistent abnormal shoulder elevation after accessory nerve injury and differential diagnosis with post-traumatic focal shoulder-elevation dystonia: report of a case and literature review. Cossu G(1), Melis M, Melis G, Ferrigno P, Molari A. Author information: (1)Department of Neuroscience, A.O.B. S. Michele General Hospital, Via Peretti, 09100 Cagliari Sardinia, Italy. giovannicossu@aob.it We report on a patient with persistent abnormal shoulder posture associated with isolated neurogenic hypertrophy of the trapezius muscle due to accessory nerve injury. The patient complained of marked difficulty in shoulder elevation and abduction. Over 6-month treatment with botulinum toxin, there was a complete resolution. PMID: 15372608 [PubMed - indexed for MEDLINE] 4062. Wien Med Wochenschr. 2004 Jul;154(13-14):300-4. [Pathogenesis of obesity]. [Article in German] Lechleitner M(1). Author information: (1)Universitätsklinik für Innere Medizin, Innsbruck, Osterreich. monika.lechleitner@uibk.ac.at During the last years various studies have been able to offer an insight into the regulation of appetite, satiety and energy balance, as well as adipocyte differentiation and the role of adipose tissue as an endocrine organ. These mechanisms add new aspects to the pathogenesis of obesity, but also to the development of weight-reducing medications. Life-style factors, including reduced physical exercise and a high calorie intake, are responsible for the increase in obesity in industrialized countries. As a result of twin and adoption studies, the genetic influence on the development of obesity is estimated to be 30-70%. As regards the common form of obesity, more than 70 gene loci have been described as possible candidate genes. These comprise genes involved in central nervous regulation systems, including leptin, the leptinreceptor, POMC, MCR-4, as well as energy expenditure and adipocyte differentiation such as beta-adrenergic receptors, UCPs, and the nuclear receptor PPARy. The common form of obesity seems to be mainly due to an interaction between genetic disposition and environmental factors. PMID: 15368950 [PubMed - indexed for MEDLINE] 4063. Circulation. 2004 Sep 14;110(11):1507-12. Renin-angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Prasad A(1), Quyyumi AA. Author information: (1)Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn, USA. PMID: 15364819 [PubMed - indexed for MEDLINE] 4064. Drug Discov Today. 2004 Sep 15;9(18):785-94. Target discovery in metabolic disease. Dohrmann CE(1). Author information: (1)DeveloGen AG, Rudolf-Wissell Strasse 28, 37079 Goettingen, Germany. dohrmann@develogen.com The prevalence of metabolic diseases is taking on epidemic proportions and poses a serious threat to human health. Current treatment options have proven insufficient to cope with obesity and diabetes because they rarely restore normal metabolism and thus leave patients exposed to life-threatening complications. Successful management of these diseases depends on novel, improved therapeutic strategies targeting early intervention in disease progression. Discovery of novel metabolic disease targets has been hampered by the complexity of contributing environmental and genetic factors, as well as the need for potent but safe treatments suitable for chronic diseases. Genomic approaches are excellent tools to manage genetic complexity and have been applied successfully to identify candidate target genes that will lead to the development of novel therapies for metabolic diseases. PMID: 15364066 [PubMed - indexed for MEDLINE] 4065. Nestle Nutr Workshop Ser Clin Perform Programme. 2004;9:77-88; discussion 88-92. The metabolic syndrome as a clinical problem. Kopelman P(1). Author information: (1)Department of Clinical Medicine, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK. PMID: 15361680 [PubMed - indexed for MEDLINE] 4066. J Appl Physiol (1985). 2004 Oct;97(4):1170-87. Use of intramuscular triacylglycerol as a substrate source during exercise in humans. van Loon LJ(1). Author information: (1)Nutrition Research Institute Maastricht (NUTRIM Dept. of Human Biology, Maastricht Univ., PO Box 616, 6200 MD Maastricht, The Netherlands. l.vanloon@hb.unimaas.nl Fat and carbohydrate are the principal substrates that fuel aerobic ATP synthesis in skeletal muscle. Most endogenous fat is stored as triacylglycerol in subcutaneous and deep visceral adipose tissue. Smaller quantities of triacylglycerol are deposited as lipid droplets inside skeletal muscle fibers. The potential role of intramyocellular triacylglycerol (IMTG) as a substrate source during exercise in humans has recently regained much of its interest because of the proposed functional relationship between IMTG accumulation and the development of skeletal muscle insulin resistance. Exercise likely represents an effective means to prevent excess IMTG accretion by stimulating its rate of oxidation. However, there is much controversy on the actual contribution of the IMTG pool as a substrate source during exercise. The apparent discrepancy in the literature likely stems from methodological difficulties that have been associated with the methods used to estimate IMTG oxidation during exercise. However, recent studies using stable isotope methodology, 1H-magnetic resonance spectroscopy, and electron and/or immunofluorescence microscopy all support the contention that the IMTG pool can function as an important substrate source during exercise. Although more research is warranted, IMTG mobilization and/or oxidation during exercise seem to be largely determined by exercise intensity, exercise duration, macronutrient composition of the diet, training status, gender, and/or age. In addition, indirect evidence suggests that the capacity to mobilize and/or oxidize IMTG is substantially impaired in an obese and/or Type 2 diabetic state. As we now become aware that skeletal muscle has an enormous capacity to oxidize IMTG stores during exercise, more research is warranted to develop combined exercise, nutritional, and/or pharmacological interventions to effectively stimulate IMTG oxidation in sedentary, obese, and/or Type 2 diabetes patients. PMID: 15358749 [PubMed - indexed for MEDLINE] 4067. Int J Obes Relat Metab Disord. 2004 Nov;28(11):1357-64. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Skurk T(1), Hauner H. Author information: (1)Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany. Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease.. PMID: 15356668 [PubMed - indexed for MEDLINE] 4068. N Engl J Med. 2004 Sep 9;351(11):1106-18. Thiazolidinediones. Yki-Järvinen H(1). Author information: (1)Division of Diabetes, Department of Medicine, University of Helsinki, Finland. ykijarvi@cc.helsinki.fi Comment in N Engl J Med. 2005 Jan 13;352(2):205-7; author reply 205-7. N Engl J Med. 2005 Jan 13;352(2):205-7; author reply 205-7. N Engl J Med. 2005 Jan 13;352(2):205-7; author reply 205-7. PMID: 15356308 [PubMed - indexed for MEDLINE] 4069. J Clin Endocrinol Metab. 2004 Sep;89(9):4206-10. Regional adiposity and insulin resistance. Garg A(1). Author information: (1)University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052, USA. abhimanyu.garg@utsouthwestern.edu PMID: 15356007 [PubMed - indexed for MEDLINE] 4070. Trends Mol Med. 2004 Sep;10(9):434-9. CIDE-A, a novel link between brown adipose tissue and obesity. Lin SC(1), Li P. Author information: (1)Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. PMID: 15350895 [PubMed - indexed for MEDLINE] 4071. Am J Obstet Gynecol. 2004 Aug;191(2):669-74. Obesity: physiologic changes and challenges during laparoscopy. Lamvu G(1), Zolnoun D, Boggess J, Steege JF. Author information: (1)Department of Obstetrics and Gynecology, Division of Advanced Laparoscopy and Gynecologic Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. glamvu@med.unc.edu OBJECTIVE: The purpose of this report was to describe the evidence for the benefits of laparoscopic surgery in obese patients, to review the physiologic abnormalities that are associated with obesity, and to explore surgical techniques that will enable surgeons to perform laparoscopy successfully in obese patients. STUDY DESIGN: This article is a review of the available literature on obesity, the physiologic changes that occur in obese patients, and the impact of these changes on laparoscopy outcomes. RESULTS: Obesity is associated with sudden death and a wide range of morbid conditions such as hypertension, atherosclerosis, angina, chronic obstructive disease, and diabetes mellitus. Recent studies have demonstrated that obese patients who undergo laparoscopy have shorter hospital stays, less postoperative pain, and fewer wound infections when compared with obese patients who undergo laparotomy. Laparoscopy patients also have fewer postoperative ileus and fevers. CONCLUSION: With thorough preparation and careful preoperative evaluation, laparoscopy can be performed safely and is the preferred surgical method in obese patients. PMID: 15343262 [PubMed - indexed for MEDLINE] 4072. J Am Geriatr Soc. 2004 Sep;52(9):1582-3. Metabolic improvement and abdominal fat redistribution in Werner syndrome by pioglitazone. Yokote K, Honjo S, Kobayashi K, Fujimoto M, Kawamura H, Mori S, Saito Y. PMID: 15341572 [PubMed - indexed for MEDLINE] 4073. J Support Oncol. 2003 Sep-Oct;1(3):159-68. Pathogenesis of cancer cachexia. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham, United Kingdom. m.j.tisdale@aston.ac.uk Cachexia is a progressive wasting syndrome characterized by extensive loss of adipose tissue and skeletal muscle. It occurs in about half of all cancer patients. While anorexia also may be present, the energy deficit alone does not explain the pathogenesis of cachexia. The presence of an acute phase response (APR) has been linked to accelerated weight loss and a shortened survival time. The APR is thought to be initiated by cytokines such as interleukin (IL)-6 and IL-8, production of which is induced by a tumor factor, proteolysis inducing factor (PIF). Cachectic cancer patients also show an increased expression of uncoupling protein-3 in muscle, which may act as an energy sink, increasing energy expenditure. Loss of adipose tissue appears to be due to an increase in degradation of triglycerides, rather than a decrease in synthesis. One candidate for this effect is a tumor lipid mobilizing factor, which stimulates lipolysis directly through a cyclic AMP-mediated process via interaction with a beta3-adrenergic receptor. Loss of skeletal muscle arises from both a depression in protein synthesis and an increase in protein degradation. The major proteolytic pathway involved in intracellular protein breakdown in cachectic muscle is the ATP-ubiquitin-dependent proteolytic pathway. Both PIF and tumor necrosis factor-alpha, but not other cytokines, can induce expression of the key regulatory components of this pathway. Eicosapentaenoic acid, found in oily fish, effectively attenuates protein degradation in cachectic muscle by inhibiting the increased proteasome expression and can stabilize body weight in cachectic cancer patients. PMID: 15334872 [PubMed - indexed for MEDLINE] 4074. Drug News Perspect. 2004 Jun;17(5):293-8. The role of adipocytokines in adipocyte-related pathological processes. Youn BS(1), Min SS, Park KS, Lee HW, Yu R, Kwon BS. Author information: (1)KOMED Institute for Life Science, Korea University, Seoul, Korea. It is becoming clear that adipose tissue is not merely a storage for excess energy but that it secretes a number of biologically active soluble factors collectively termed adipocytokines that control glucose and fatty acid metabolism. Of these adipocytokines, adiponectin and resistin have been the objects of intensive research, as they are implicated in obesity and diabetes-related diseases. In this review, we summarize recent advances in understanding the roles of adiponectin and resistin in the causation of metabolic diseases and consider the prospects for treating metabolic disorders by targeting these two adipocytokines. (c) 2004 Prous Science. All rights reserved. PMID: 15334178 [PubMed - indexed for MEDLINE] 4075. Diabetes Care. 2004 Sep;27(9):2253-9. Lipids and glucose in type 2 diabetes: what is the cause and effect? Boden G(1), Laakso M. Author information: (1)Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140, USA. bodengh@tuhs.temple.edu Comment in Diabetes Care. 2005 Apr;28(4):985-6; author reply 986-7. PMID: 15333497 [PubMed - indexed for MEDLINE] 4076. Med Sci (Paris). 2004 Jun-Jul;20(6-7):651-62. [Cell transplantation in heart failure management]. [Article in French] Vilquin JT(1), Marolleau JP. Author information: (1)Inserm U.582, Institut de Myologie, Groupe hospitalier Pitié-Salpêtrière, Bâtiment Babinski, 75651 Paris Cedex 13, France. jt.vilquin@myologie.chups.jussieu.fr Heart failure is becoming a major issue for public health in western countries and the effect of currently available therapies is limited. Therefore cell transplantation was developed as an alternative strategy to improve cardiac structure and function. This review describes the multiple cell types and clinical trials considered for use in this indication. Most studies have been developed in models of post-ischemic heart failure. The transplantation of fetal or neonatal cardiomyocytes has proven to be functionally successful, but ethical as well as immunological and technical reasons make their clinical use limited. Recent reports, however, suggested that adult autologous cardiomyocytes could be prepared from stem cells present in various tissues (bone marrow, vessels, adult heart itself, adipose tissue). Alternatively, endothelial progenitors originating from bone marrow or peripheral blood could promote the neoangiogenesis within the scar tissue. Hematopietic stem cells prepared from bone marrow or peripheral blood have been proposed but their differentiation ability seems limited. Finally, the transplantation of skeletal muscle cells (myoblasts) in the infarcted area improved myocardial function, in correlation with the development of skeletal muscle tissue in various animal models. The latter results paved the way for the development of a first phase I clinical trial of myoblast transplantation in patients with severe post-ischemic heart failure. It required the scale-up of human cell production according to good manufacturing procedures, started in june 2000 in Paris and was terminated in november 2001, and was followed by several others. The results were encouraging and prompted the onset of a blinded, multicentric phase II clinical trial for skeletal muscle cells transplantation. Meanwhile, phase I clinical trials also evaluate the safeness and efficacy of various cell types originating from the bone marrow or the peripheral blood. However, potential side effects related to the biological properties of the cells or the delivery procedures are being reported. High quality clinical trials supported by strong pre-clinical data will help to evaluate the role of cell therapy as a potential treatment for heart failure. PMID: 15329815 [PubMed - indexed for MEDLINE] 4077. Ann Clin Psychiatry. 2004 Apr-Jun;16(2):75-85. Atypical antipsychotic induced weight gain: pathophysiology and management. Ananth J(1), Venkatesh R, Burgoyne K, Gadasalli R, Binford R, Gunatilake S. Author information: (1)University of California, Los Angeles and Harbor-UCLA Medical Center, Torrance, California 90509, USA. jananth@rei.edu There is compelling evidence that patients with schizophrenia are prone to gain weight. In addition, atypical antipsychotic (AAP) drugs also induce weight gain. All antipsychotic drugs produce weight gain but the potential varies. Many studies overwhelmingly confirm that AAP drugs produce substantially more weight gain in comparison to conventional antipsychotic drugs. Clozapine and olanzapine have the most weight inducing potential. Even ziprasidone, which is considered to be weight neutral, and aripiprazole a dopamine modulator produce weight gain in some. The pathophysiology of weight gain is complicated. Many neurohormones, neuropeptides, gut hormones, as well as adipose tissue and hair root derived hormones interact with environmental factors to produce weight gain. Management of weight gain is a difficult problem. Basic to treatment is an understanding of the etiology. Drug induced obesity provides a unique opportunity to psychiatrists to understand this clinically important problem. In the absence of this knowledge, prevention is the best hope. Education, diet control and simple behavioral measures may prevent excessive weight gain. In those with weight gain, treatment can be attempted with pharmacotherapy with careful monitoring of the side effects. PMID: 15328901 [PubMed - indexed for MEDLINE] 4078. Can J Appl Physiol. 2004 Aug;29(4):504-23. Muscle oxygenation trends during dynamic exercise measured by near infrared spectroscopy. Bhambhani YN(1). Author information: (1)Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada. During the last decade, NIRS has been used extensively to evaluate the changes in muscle oxygenation and blood volume during a variety of exercise modes. The important findings from this research are as follows: (a) There is a strong correlation between the lactate (ventilatory) threshold during incremental cycle exercise and the exaggerated reduction in muscle oxygenation measured by NIRS. (b) The delay in steady-state oxygen uptake during constant work rate exercise at intensities above the lactate/ventilatory threshold is closely related to changes in muscle oxygenation measured by NIRS. (c) The degree of muscle deoxygenation at the same absolute oxygen uptake is significantly lower in older persons compared younger persons; however, these changes are negated when muscle oxygenation is expressed relative to maximal oxygen uptake values. (d) There is no significant difference between the rate of biceps brachii and vastus lateralis deoxygenation during arm cranking and leg cycling exercise, respectively, in males and females. (e) Muscle deoxygenation trends recorded during short duration, high-intensity exercise such as the Wingate test indicate that there is a substantial degree of aerobic metabolism during such exercise. Recent studies that have used NIRS at multiple sites, such as brain and muscle tissue, provide useful information pertaining to the regional changes in oxygen availability in these tissues during dynamic exercise. PMID: 15328597 [PubMed - indexed for MEDLINE] 4079. Congenit Anom (Kyoto). 2004 Sep;44(3):111-24. Tissue regeneration based on tissue engineering technology. Tabata Y(1). Author information: (1)Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. yasuhiko@frontier.kyoto-u.ac.jp Recent development of biomedical engineering as well as basic biology and medicine has enabled us to induce cell-based regeneration of body tissue to self-repair defective tissue or substitute biological functions of damaged organs. For successful tissue regeneration, it is indispensable to give cells an environment suitable for regeneration induction. Tissue engineering is a newly emerging biomedical technology for creating an environment for tissue regeneration with various biomaterials. The paper presented here overviews recent research data on tissue regeneration based on tissue engineering, and briefly explains the key technology of tissue engineering. PMID: 15327480 [PubMed - indexed for MEDLINE] 4080. Clin Sci (Lond). 2004 Dec;107(6):519-32. The role of insulin and the adipocytokines in regulation of vascular endothelial function. Ritchie SA(1), Ewart MA, Perry CG, Connell JM, Salt IP. Author information: (1)Henry Wellcome Laboratory of Cell Biology, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. Vascular integrity in the healthy endothelium is maintained through the release of a variety of paracrine factors such as NO (nitric oxide). Endothelial dysfunction, characterized by reduced NO bioavailability, is associated with obesity, insulin resistance and Type II diabetes. Insulin has been demonstrated to have direct effects on the endothelium to increase NO bioavailability. Therefore altered insulin signalling in the endothelium represents a candidate mechanism underlying the association between insulin resistance and endothelial dysfunction. In recent years, it has become apparent that insulin sensitivity is regulated by the adipocytokines, a group of bioactive proteins secreted by adipose tissue. Secretion of adipocytokines is altered in obese individuals and there is increasing evidence that the adipocytokines have direct effects on the vascular endothelium. A number of current antidiabetic strategies have been demonstrated to have beneficial effects on endothelial function and to alter adipocytokine concentrations in addition to their effects on glucose homoeostasis. In this review we will explore the notion that the association between insulin resistance and endothelial dysfunction is accounted for by adipocytokine action on the endothelium. In addition, we examine the effects of weight loss, exercise and antidiabetic drugs on adipocytokine availability and endothelial function. PMID: 15324298 [PubMed - indexed for MEDLINE] 4081. Curr Vasc Pharmacol. 2003 Mar;1(1):11-7. Lipoprotein lipase and atherosclerosis. Tsutsumi K(1). Author information: (1)Research and Development, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima 772-8601, Japan. tutumikz@otsukakj.co.jp Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoprotein such as very low density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and decrease in high density lipoprotein (HDL) cholesterol. The increase in plasma TG and decrease in HDL cholesterol are risk factors of coronary heart disease. However, whether LPL directly or indirectly promotes or protects against atherosclerosis remains unclear as two contrary views exist in this regard: one where LPL promotes atherosclerosis and one where LPL protects against atherosclerosis. Many studies have been carried out to investigate whether LPL is an anti-atherogenic or atherogenic enzyme by using animals with genetic defects or with an excess of this enzyme. From these studies, much evidence has been acquired showing that LPL is an anti-atherogenic enzyme. We hypothesized that elevating LPL activity would cause a reduction of plasma TG and increase in HDL cholesterol, resulting in protection against the development of atherosclerosis. To test this hypothesis, we studied the effects of the LPL activator NO-1886 in animals. NO-1886 has been shown to increase LPL mRNA in adipose tissue and myocardium, and increase LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 has also been shown to decrease plasma TG levels accompanied by a concomitant rise in HDL cholesterol. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortae. The results of multiple regression analysis in these studies suggest that the increase in plasma HDL cholesterol and the decrease in TG protect against atherosclerosis. We have determined in our studies that the atherogenic lipid profile is changed to an anti-atherogenic lipid profile by increasing LPL activity, resulting in protection against the development of atherosclerosis. Therefore, we believe that high activity of LPL is anti-atherogenic, whereas a low activity of LPL is atherogenic. PMID: 15320848 [PubMed - indexed for MEDLINE] 4082. Curr Med Chem Cardiovasc Hematol Agents. 2004 Jul;2(3):197-208. The adipose tissue as a source of vasoactive factors. Frühbeck G(1). Author information: (1)Department of Endocrinology, Clinica Universitaria de Navarra and Metabolic Research Laboratory, University of Navarra, Pamplona, Spain. gfruhbeck@unav.es Obesity is associated with increased incidence of cardiovascular mortality. However, the mechanisms that link increased fat mass with hypercholesterolemia, hypertension, endothelial dysfunction and coronary heart disease have not been fully elucidated. Unravelling the diverse neuroendocrine systems, which regulate energy balance and body fat has been a long-standing challenge in biology, with obesity as an increasingly important public health focus. Until recently, the adipocyte has been considered only a passive tissue for the storage of excess energy in the form of fat. However, there is now compelling evidence that adipocytes act as endocrine, secretory cells. It has been shown that several hormones, growth factors and cytokines are actually expressed in white adipose tissue. In a dynamic view of the adipocyte a wide range of signals emanates from white adipose tissue such as tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and their respective soluble receptors. White adipose tissue also secretes important regulators of lipoprotein metabolism like lipoprotein lipase (LPL), apolipoprotein E (apoE) and cholesteryl ester transfer protein (CETP). The increasing number of products secreted by adipocytes also includes leptin, estrogen, angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), tissue factor and transforming growth factor-beta (TGF-beta). Nitric oxide synthase (NOS) has been also reported to be expressed in white adipose tissue. Acylation stimulating protein (ASP), adipophilin, adipoQ, adipsin, monobutyrin, agouti protein and factors related to pro-inflammatory and immune processes have also been shown to be released by white adipocytes. Since blood vessels express receptors for most of the adipocyte-derived factors, adipose tissue seems to play a key role in cardiovascular physiology through the existence of a network of local and systemic signals. The current knowledge in this field will be reviewed in the broader perspective of cardiovascular physiology and pathophysiology. PMID: 15320786 [PubMed - indexed for MEDLINE] 4083. Curr Pharm Des. 2004;10(22):2779-86. Pleiotropic actions of PPAR gamma activators thiazolidinediones in cardiovascular diseases. Takano H(1), Hasegawa H, Zou Y, Komuro I. Author information: (1)Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily and form heterodimers with retinoid X receptor. To date, three PPARs isoforms have been isolated and termed alpha, beta (or delta), and gamma. Although PPAR gamma is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, it has been recently demonstrated that PPAR gamma is present in a variety of cell types. Synthetic antidiabetic thiazolidinediones (TZDs) and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), are well-known as ligands for PPAR gamma. After it has been reported that activation of PPAR gamma suppresses production of proinflammatory cytokines in activated macrophages, medical interest in PPAR gamma have grown and a huge research effort has been concentrated. PPAR gamma, is currently known to be implicated in various human chronic diseases such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimer's disease. Moreover, PPAR gamma ligands have potent tumor modulatory effects against colorectal, prostate, and breast cancers. Recent studies suggest that TZDs not only ameliorate insulin sensitivity but also have pleiotropic effects on many tissues and cell types. Although activation of PPAR gamma seems to have beneficial effects on atherosclerosis and heart failure, the mechanisms by which PPAR gamma ligands prevent the development of cardiovascular diseases are not fully understood. This review will focus on the latest developments in the PPAR gamma field and the roles of PPAR gamma-dependent pathway in cardiovascular diseases. PMID: 15320743 [PubMed - indexed for MEDLINE] 4084. Curr Protein Pept Sci. 2004 Aug;5(4):267-73. The peptide hormone angiotensin II: its new functions in tissues and organs. Leung PS(1). Author information: (1)Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. psleung@cuhk.edu.hk The peptide hormone angiotensin II is well established to play an endocrine role in the regulation of blood pressure, fluid and electrolyte homeostasis. In addition to its hemodynamic function, recent studies have shown that numerous tissues and organs contain their own locally generated angiotensin products (angiotensin II, III, IV and Ang 1-7) and they exhibit their respective activities. Such an intrinsic angiotensin-generating system renders to specific tissue function of our body, frequently via the regulatory mechanism of a paracrine, autocrine or intracrine manner. These tissues and organs include, to name but a few, the brain, bone marrow, adipose, epididymis, carotid body, liver, and pancreas. This local system has been shown to be responsive to various stimuli of physiological and pathophysiological importance. Moreover, the locally generated angiotensin peptides have multiple and novel actions including cell growth, anti-proliferation, apoptosis, reactive oxygen species generation, hormonal secretion, pro-inflammatory, and pro-fibrogenic actions, as well as vasoconstriction and vasodilatation. Notwithstanding the emerging roles of angiotensin II in various tissues and organs, the physiological significance and ultimately the clinical relevance remain largely undefined. Future target for these new functions by making use of specific renin-angiotensin system inhibitors, such as the angiotensin-converting enzyme and angiotensin II receptor blockers either in mono-therapy or in combination, could be of clinical importance. The current review is to focus on some of the new functions arising from the locally formed angiotensin II in tissues and organs, with particular attention to its emerging roles in the liver and the pancreas. PMID: 15320733 [PubMed - indexed for MEDLINE] 4085. Magnes Res. 2004 Jun;17(2):116-25. New data on the importance of gestational Mg deficiency. Durlach J(1), Pagès N, Bac P, Bara M, Guiet-Bara A. Author information: (1)Pierre et Marie Curie University (UPMC), F-75252 Paris, Cédex 05, France. Jean.Durlach@wanadoo.fr Chronic primary Mg deficiency is frequent. Around 20% of the population consumes less than two-thirds of the RDA for Mg, in both genders and in women particularly: for example, in France, 23% of women and 18% of men. Primary Mg deficiency may occur in fertile women. Gestational Mg deficiency is able to induce maternal, fetal, and pediatric consequences which might last throughout life. Experimental studies of gestational Mg deficiency show that Mg deficiency during pregnancy may have marked effects on the processes of parturition and of postuterine involution. It may interfere with fetal growth and development from teratogenic effects to morbidity: i.e. hematological effects and disturbances in temperature regulation. Clinical studies on the consequences of maternal primary Mg deficiency in women have been insufficiently investigated. To check the validity of the role of this frequent gestational Mg deficiency, the protocol of a long term multicentric placebo controlled prospective study on the effects of maternal nutritional Mg supplementation on lethality and morbidity in fetus, neonates, infants, children and adults should be carried out not only during pregnancy and the first year of life, but throughout life. Two clinical forms of chronic gestational Mg deficiency in women have been stressed: Premature labor when chronic maternal Mg deficiency is involved in uterine hyperexcitability, Sudden Infant Death Syndrome (SIDS) when it is caused by either simple Mg deficiency or various forms of Mg depletion. Nutritional Mg treatment of premature labor. If gestational Mg deficiency is the only cause for uterine overactivity, nutritional Mg supplementation constitutes the etiopathogenic atoxic tocolytic treatment. But although it is an adjuvant factor in premature labor, it is only a useful accessory treatment, devoid of toxicity but which increases the effectiveness and safety of the associated tocolytic drugs such as beta-2 mimetics. SIDS due to gestational Mg deficit: Mg deficiency or various forms of Mg depletion. SIDS may be caused by the fetal consequences of maternal Mg deficiency through an impaired control of Brown Adipose Tissue (BAT) thermoregulation, mechanisms leading to a modified temperature set point. SIDS may result from dysthermias: hypo- or hyperthermic forms. A possible prevention could rest on simple maternal nutritional Mg supplementation. Various stresses in pregnant women or in the infant may transform a simple Mg deficiency into Mg depletion: stress in baby care such as bedding in prone position, environmental factors such as parental smoking, but the role of chronopathological stress particularly appears to be too often neglected as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to an impaired maturation of both the photoneuroendocrine system and BAT. A preventive treatment of this form of SIDS should associate atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. The place of Mg therapy for the infant and of MT, L Tryptophan and taurine is uncertain for the moment. PMID: 15319145 [PubMed - indexed for MEDLINE] 4086. J Cell Biol. 2004 Aug 16;166(4):447-53. Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. Imanishi Y(1), Gerke V, Palczewski K. Author information: (1)Department of Ophthalmology, University of Washington, Box 356485, Seattle, WA 98195-6485, USA. Lipid bodies form autonomous intracellular structures in many model cells and in some cells of specific tissue origin. They contain hydrophobic substances, a set of structural proteins such as perilipin or adipose differentiation-related protein, enzymes implicated in lipid metabolism, and proteins that participate in signaling and membrane trafficking. Retinosomes, particles reminiscent of lipid bodies, have been identified in retinal pigment epithelium as distinct structures compartmentalizing a metabolic intermediate involved in regeneration of the visual chromophore. These observations suggest that lipid bodies, including retinosomes, carry out specific functions that go beyond those of mere lipid storage organelles. PMCID: PMC1360213 PMID: 15314061 [PubMed - indexed for MEDLINE] 4087. Int J Biochem Cell Biol. 2004 Nov;36(11):2098-104. The brown adipocyte: update on its metabolic role. Sell H(1), Deshaies Y, Richard D. Author information: (1)Department of Anatomy and Physiology, School of Medicine, Laval Hospital Research Center and D. B. Brown Obesity Research Chair, Laval University, Pavillon Ferdinand-Vandry, Local 3217, Quebec City, Que., Canada G1K 7P4. Brown adipocytes are multilocular lipid storage cells that play a crucial role in non-shivering thermogenesis. These cells are located in brown adipose tissue (BAT) depots which are found in abundance in small mammals as well as in newborns of larger mammals, including humans. Brown adipocytes comprise a very large number of mitochondria packed with cristae and are densely innervated by the sympathetic nervous system (SNS). Sympathetic nerve endings release noradrenaline (NA) in the proximity of brown fat cells, where noradrenaline activates G-protein-coupled beta-adrenergic receptors (AR) and by doing so initiates a cascade of metabolic events culminating in the activation of uncoupling protein 1 (UCP1). Uncoupling protein 1 is a unique feature of brown adipocytes that allows for the generation of heat upon sympathetic nervous system stimulation. It is found in the inner membrane of the mitochondrion, where uncoupling protein 1 uncouples the oxidation of fuel from adenosine triphosphate (ATP) production. The expression of uncoupling protein 1 is strongly induced by cold exposure, revealing the importance of this uncoupling protein in thermoregulation. The thermoregulatory role of uncoupling protein 1 has been emphasized in uncoupling protein 1-deficient mice, whose resistance to cold is impaired. Uncoupling protein 1 expression is modulated by diet and metabolic hormones such as leptin and glucocorticoids, which suggests that the protein is a player in energy balance regulation. PMID: 15313455 [PubMed - indexed for MEDLINE] 4088. Biorheology. 2004;41(3-4):389-99. Adipose-derived adult stem cells for cartilage tissue engineering. Guilak F(1), Awad HA, Fermor B, Leddy HA, Gimble JM. Author information: (1)Departments of Surgery and Biomedical Engineering, Duke University Medical Center, Durham, NC 27710, USA. guilak@duke.edu Tissue engineering is a promising therapeutic approach that uses combinations of implanted cells, biomaterial scaffolds, and biologically active molecules to repair or regenerate damaged or diseased tissues. Many diverse and increasingly complex approaches are being developed to repair articular cartilage, with the underlying premise that cells introduced exogenously play a necessary role in the success of engineered tissue replacements. A major consideration that remains in this field is the identification and characterization of appropriate sources of cells for tissue-engineered repair of cartilage. In particular, there has been significant emphasis on the use of undifferentiated progenitor cells, or "stem" cells that can be expanded in culture and differentiated into a variety of different cell types. Recent studies have identified the presence of an abundant source of stem cells in subcutaneous adipose tissue. These cells, termed adipose-derived adult stem (ADAS) cells, show characteristics of multipotent adult stem cells, similar to those of bone marrow derived mesenchymal stem cells (MSCs), and under appropriate culture conditions, synthesize cartilage-specific matrix proteins that are assembled in a cartilaginous extracellular matrix. The growth and chondrogenic differentiation of ADAS cells is strongly influenced by factors in the biochemical as well as biophysical environment of the cells. Furthermore, there is strong evidence that the interaction between the cells, the extracellular biomaterial substrate, and growth factors regulate ADAS cell differentiation and tissue growth. Overall, ADAS cells show significant promise for the development of functional tissue replacements for various tissues of the musculoskeletal system. PMID: 15299271 [PubMed - indexed for MEDLINE] 4089. Proc Nutr Soc. 2004 May;63(2):381-5. Metabolic and hormonal interactions between muscle and adipose tissue. Tomas E(1), Kelly M, Xiang X, Tsao TS, Keller C, Keller P, Luo Z, Lodish H, Saha AK, Unger R, Ruderman NB. Author information: (1)Department of Medicine, Physiology and Biophysics, Diabetes Unit, Boston University Medical Center, Boston, MA, USA. From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues. Deficiencies of leptin or leptin receptor, adiponectin and IL-6 are associated with obesity, insulin resistance and a propensity to type 2 diabetes. In addition, a lack of adiponectin has been linked to atherosclerosis. Whether this pathology reflects a deficient activation of AMP-activated protein kinase in peripheral tissues remains to be determined. Finally, recent studies have suggested that skeletal muscle may also function as an endocrine organ when it releases the cytokine IL-6 into the circulation during sustained exercise. Interestingly, one of the apparent effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. Thus, hormonal communications exist between the adipocyte and muscle that could enable them to talk to each other. The physiological relevance of this cross talk clearly warrants further study. PMID: 15294059 [PubMed - indexed for MEDLINE] 4090. Proc Nutr Soc. 2004 May;63(2):375-80. The molecular mechanism linking muscle fat accumulation to insulin resistance. Hulver MW(1), Dohm GL. Author information: (1)Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA. Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport. PMID: 15294058 [PubMed - indexed for MEDLINE] 4091. Proc Nutr Soc. 2004 May;63(2):369-74. Physiological regulation of NEFA availability: lipolysis pathway. Stich V(1), Berlan M. Author information: (1)Franco-Czech Laboratory for Clinical Research of Obesity, Third Faculty of Medicine, Charles University, Prague, Czech Republic. vladimir.stich@lf3.cuni.cz Plasma NEFA are an important energy substrate and, furthermore, play a key role in the induction of insulin resistance in the body. The availability of NEFA is determined predominantly by their mobilization from adipose tissue triacylglycerol stores by the process of lipolysis. Adipose tissue lipolysis in man is regulated by a number of hormonal and paracrine and/or autocrine signals. The main hormonal signals may be represented by catecholamines, insulin, growth hormone, natriuretic peptides and some adipocytokines. The absolute levels and relative importance and contribution of these signals vary in different physiological situations, with diet and physical exercise being the main physiological variables that affect the hormonal signalling. Thus, modulations in hormonal signals induce an increase in NEFA mobilization in the post-absorptive state and during an acute bout of exercise, and suppress NEFA mobilization in the postprandial state. In addition, hormonal regulation is modified by long-term interventions in energy balance, such as dietary restriction and/or physical training, and is disturbed in some pathological states, such as obesity or diabetes. The question that remains is whether disturbances in lipolysis regulation in obese and diabetic subjects may be 'corrected' by the long-term interventions in diet and physical activity. PMID: 15294057 [PubMed - indexed for MEDLINE] 4092. Proc Nutr Soc. 2004 May;63(2):363-8. Metabolic flexibility. Storlien L(1), Oakes ND, Kelley DE. Author information: (1)AstraZeneca R&D, Pepparedsleden 3, Mölndal 431 83, Sweden. leonard.storlien@astrazeneca.com Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires 'a clear capacity to utilize lipid and carbohydrate fuels and to transition between them' (Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed 'metabolic flexibility'. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term 'metabolic syndrome'. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained. PMID: 15294056 [PubMed - indexed for MEDLINE] 4093. Proc Nutr Soc. 2004 May;63(2):323-30. Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus. Blaak EE(1). Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E.Blaak@HB.Unimaas.nl The present article addresses the hypothesis that disturbances in skeletal muscle fatty acid handling in abdominal obesity and type 2 diabetes mellitus may play a role in the aetiology of increased adipose tissue stores, increased triacylglycerol storage in skeletal muscle and skeletal muscle insulin resistance. The uptake and/or oxidation of fatty acids have been shown to be impaired during post-absorptive conditions in abdominally-obese subjects and/or subjects with type 2 diabetes. Also, human studies have shown that muscle of subjects that are (abdominally) obese and/or have type 2 diabetes is characterized by an inability to increase fatty acid uptake and/or fatty acid oxidation during beta-adrenergic stimulation and exercise. This disturbance in fat oxidation may promote, on one hand, the development of increased adipose tissue stores and obesity. On the other hand, fatty acids that are taken up by muscle and not oxidized may increase triacylglycerol storage in muscle, which has been associated with skeletal-muscle insulin resistance. Disturbances in the capacity to increase fat oxidation during post-absorptive conditions, beta-adrenergic stimulation and exercise in subjects who are obese and/or have type 2 diabetes persist after weight reduction, indicating that the diminished fat oxidation may be a primary factor leading to the obese and/or insulin-resistant state rather than an adaptational response. Clearly, the precise sequence of events leading to an increased adiposity and insulin resistance in obesity and type 2 diabetes mellitus is not yet fully understood. PMID: 15294050 [PubMed - indexed for MEDLINE] 4094. Proc Nutr Soc. 2004 May;63(2):309-14. Regulation and role of hormone-sensitive lipase in rat skeletal muscle. Donsmark M(1), Langfort J, Holm C, Ploug T, Galbo H. Author information: (1)Copenhagen Muscle Research Centre, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark. mdonsmark@mfi.ku.dk Intramyocellular triacylglycerol (TG) is an important energy store, and the energy content of this depot is higher than the energy content of the muscle glycogen depot. It has recently been shown that the mobilization of fatty acids from this TG pool may be regulated by the neutral lipase hormone-sensitive lipase (HSL). This enzyme is known to be rate limiting for intracellular TG hydrolysis in adipose tissue. The presence of HSL has been demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying. The content of HSL varies between fibre types, being higher in oxidative fibres than in glycolytic fibres. When analysed under conditions optimal for HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by the presence of anti-HSL antibody during analysis. Moreover, immunoprecipitation with affinity-purified anti-HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via beta-adrenergic activation of cAMP-dependent protein kinase (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser(563), Ser(659) and Ser(660). Contraction probably also enhances muscle HSL activity by phosphorylation, because the contraction-induced increase in HSL activity is elevated by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal-regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle the activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction-induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser(600). Hence, phosphorylation of different sites may explain the finding that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases contraction-mediated HSL activation but diminishes adrenaline-mediated HSL activation in muscle. In conclusion, HSL is present in skeletal muscle and can be activated by phosphorylation in response to both adrenaline and muscle contractions. Training increases contraction-mediated HSL activation, but decreases adrenaline-mediated HSL activation in muscle. PMID: 15294048 [PubMed - indexed for MEDLINE] 4095. Proc Nutr Soc. 2004 May;63(2):263-7. The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Pedersen BK(1), Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Wolsk-Petersen E, Febbraio M. Author information: (1)Copenhagen Muscle Research Centre, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. bkp@rh.dk For most of the last century, researchers have searched for a muscle contraction-induced factor that mediates some of the exercise effects in other tissues such as the liver and the adipose tissue. It has been called the 'work stimulus', the 'work factor' or the 'exercise factor'. In the search for such a factor, a cytokine, IL-6, was found to be produced by contracting muscles and released into the blood. It has been demonstrated that IL-6 has many biological roles such as: (1) induction of lipolysis; (2) suppression of TNF production; (3) stimulation of cortisol production. The IL-6 gene is rapidly activated during exercise, and the activation of this gene is further enhanced when muscle glycogen content is low. In addition, carbohydrate supplementation during exercise has been shown to inhibit the release of IL-6 from contracting muscle. Thus, it is suggested that muscle-derived IL-6 fulfils the criteria of an exercise factor and that such classes of cytokines could be termed 'myokines'. PMID: 15294041 [PubMed - indexed for MEDLINE] 4096. Proc Nutr Soc. 2004 May;63(2):189-97. Physical activity and health, novel concepts and new targets: report from the 12th Conference of the International Research Group on the Biochemistry of Exercise. Hesselink MK(1), van Baak MA. Author information: (1)Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. matthijs.hesselink@bw.unimaas.nl The present paper is the introductory paper to a series of brief reviews representing the proceedings of a recent conference on 'The biochemical basis for the health effects of exercise' organized by the International Research Group on the Biochemistry of Exercise in conjunction with the Nutrition Society. Here the aim is to briefly review and highlight the main innovations presented during this meeting. The following topics were covered during the meeting: exercise signalling pathways controlling fuel oxidation during and after exercise; the fatty acid transporters of skeletal muscle; mechanisms involved in exercise-induced mitochondrial biogenesis in skeletal muscle; new methodologies and insights in the regulation of fat metabolism during exercise; muscle hypertrophy: the signals of insulin, amino acids and exercise; adipose tissue-liver-muscle interactions leading to insulin resistance. In these symposia state-of-the-art knowledge on how physical exercise exerts its effects on health was presented. The fast-growing number of identified pathways and processes involved in the health effects of physical exercise, which were discussed during the meeting, will help to develop tailored physical-activity regimens in the prevention of inactivity-induced deterioration of health. PMID: 15294029 [PubMed - indexed for MEDLINE] 4097. Nutr Rev. 2004 Jun;62(6 Pt 1):253-5. Tissue-specific knockout defines peroxisome proliferator-activated receptor gamma function in muscle and liver. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720-3104, USA. Although the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed mostly in adipose tissue, it also occurs in skeletal muscle and liver. Mice lacking a functional PPARgamma gene, specifically in muscle, showed increased adiposity with reduced caloric intake, resulting from shunting of lipid to the liver. This result suggested a function for muscle PPARgamma in the up-regulation of muscle lipid metabolism. A study in lipoatrophic mice--that were also defective in the liver PPARgamma gene--suggested that liver PPARgamma functions in the uptake and clearance of fat in that organ. However, PPARgamma in liver has an antidiabetic role, whereas muscle PPARgamma was found to have no part in opposing diabetes. PMID: 15291399 [PubMed - indexed for MEDLINE] 4098. Curr Pharm Des. 2004;10(17):2021-39. A(1) adenosine receptor agonists: medicinal chemistry and therapeutic potential. Hutchinson SA(1), Scammells PJ. Author information: (1)Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia. Adenosine receptors are widely distributed in the body and modulate numerous physiological processes. Four receptor subtypes (termed A(1), A(2A), A(2B) and A(3)) have been identified based on their pharmacological profile and cloning. Activation of the A(1) adenosine receptors produces a number of effects including a reduction in heart rate and atrial contractility, the attenuation of the stimulatory actions of catecholamines on the heart as well as a reduction of lipolysis in adipose tissue. As a result, A(1)AR agonists have been targeted as anti-arrhythmic and cardioprotective agents. This review discusses the synthesis, structure-activity relationships and therapeutic potential of A(1)AR agonists. PMID: 15279543 [PubMed - indexed for MEDLINE] 4099. Eur J Clin Nutr. 2004 Dec;58(12):1559-70. Effect of placental function on fatty acid requirements during pregnancy. Haggarty P(1). Author information: (1)Rowett Research Institute, Aberdeen, UK. p.haggarty@abdn.ac.uk The fetus has an absolute requirement for the n-3/n-6 fatty acids and docosahexaenoic acid (22:6 n-3; DHA) in particular is essential for the development of the brain and retina. Most of the fat deposition in the fetus occurs in the last 10 weeks of pregnancy. The likely rate of DHA utilisation during late pregnancy cannot be met from dietary sources alone in a significant proportion of mothers. De novo synthesis makes up some of the shortfall but the available evidence suggests that the maternal adipose tissue makes a significant contribution to placental transport to the fetus. The placenta plays a crucial role in mobilising the maternal adipose tissue and actively concentrating and channelling the important n-3/n-6 fatty acids to the fetus via multiple mechanisms including selective uptake by the syncytiotrophoblast, intracellular metabolic channelling, and selective export to the fetal circulation. These mechanisms protect the fetus against low long-chain polyunsaturated fatty acid (LCPUFA) intakes in the last trimester of pregnancy and have the effect of reducing the maternal dietary requirement for preformed DHA at this time. As a result of these adaptations, small changes in the composition of the habitual maternal diet before pregnancy are likely to be more effective in improving LCPUFA delivery to the fetus than large dietary changes in late pregnancy. There is little evidence that DHA intake/status in the second half of pregnancy affects visual and cognitive function in the offspring, but more studies are needed, particularly in children born to vegetarian and vegan and mothers who may have very low intakes of DHA. PMID: 15266306 [PubMed - indexed for MEDLINE] 4100. Clin Chem. 2004 Sep;50(9):1511-25. Epub 2004 Jul 20. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Meier U(1), Gressner AM. Author information: (1)Institute of Clinical Chemistry and Pathobiochemistry, Rhenish-Westphalian Technical University, University Hospital Aachen, Pauwelsstrasse 30, D-52074, Germany. umeier@ukaachen.de BACKGROUND: Recent studies point to the adipose tissue as a highly active endocrine organ secreting a range of hormones. Leptin, ghrelin, adiponectin, and resistin are considered to take part in the regulation of energy metabolism. APPROACH: This review summarizes recent knowledge on leptin and its receptor and on ghrelin, adiponectin, and resistin, and emphasizes their roles in pathobiochemistry and clinical chemistry. CONTENT: Leptin, adiponectin, and resistin are produced by the adipose tissue. The protein leptin, a satiety hormone, regulates appetite and energy balance of the body. Adiponectin could suppress the development of atherosclerosis and liver fibrosis and might play a role as an antiinflammatory hormone. Increased resistin concentrations might cause insulin resistance and thus could link obesity with type II diabetes. Ghrelin is produced in the stomach. In addition to its role in long-term regulation of energy metabolism, it is involved in the short-term regulation of feeding. These hormones have important roles in energy homeostasis, glucose and lipid metabolism, reproduction, cardiovascular function, and immunity. They directly influence other organ systems, including the brain, liver, and skeletal muscle, and are significantly regulated by nutritional status. This newly discovered secretory function has extended the biological relevance of adipose tissue, which is no longer considered as only an energy storage site. SUMMARY: The functional roles, structures, synthesis, analytical aspects, and clinical significance of leptin, ghrelin, adiponectin, and resistin are summarized. PMID: 15265818 [PubMed - indexed for MEDLINE] 4101. J Vet Med A Physiol Pathol Clin Med. 2004 May;51(4):157-66. Role of leptin in farm animals: a review. Mácajová M(1), Lamosová D, Zeman M. Author information: (1)Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Moyzesova 61, 900 28 Ivanka pri Dunaji, Slovakia. mariana.macajova@savba.sk The discovery of hormone leptin has led to better understanding of the energy balance control. In addition to its effects on food intake and energy expenditure, leptin has now been implicated as a mediator of diverse physiological functions. Recently, leptin has been cloned in several domestic species. The sequence similarity suggests a common function or mechanism of this peptide hormone across species. Leptin receptors are expressed in most of tissues, which is consistent with the multiplicity of leptin functions. The main goal of this review was to summarize knowledge about effect of leptin on physiology of farm animals. Experiments point to a stimulatory action of leptin on growth hormone (GH) secretion, normal growth and development of the brain. Surprisingly, leptin is synthesized at a high rate in placenta and may function as a growth factor for fetus, signalling the nutritional status from the mother to her offspring. Maturation of reproductive system can be stimulated by leptin administration. Morphological and hormonal changes, consistent with a major role of leptin in the reproductive system, have also been described, including the stimulation of the release of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin. Leptin has a substantial effect on food intake and feeding behaviour in animals. Administration of leptin reduces food intake. Its level decrease within hours after initiation of fasting. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which was the molecule evolved. PMID: 15265171 [PubMed - indexed for MEDLINE] 4102. Best Pract Res Clin Endocrinol Metab. 2004 Sep;18(3):349-62. Androgens and the ageing male. Swerdloff RS(1), Wang C. Author information: (1)Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA Harbor-UCLA Medical Center and Research Institute, Box 446, 1000 West Carson Street, Torrance, CA 90509-2910, USA. swerdloff@gcrc.rei.edu Serum testosterone levels peak in early adulthood in men and fall progressively with age. Since sex hormone binding globulin increases with age, the unbound forms of testosterone (free and bioavailable testosterone) fall more steeply than total testosterone levels. Serum testosterone levels below the normal range for young healthy adult males provide chemical evidence of androgen deficiency independent of the age of the patient. When accompanied by signs or symptoms that are compatible with androgen deficiency, treatment with testosterone should be considered in older men without evidence of prostate or breast cancer. While such therapy for younger hypogonadal men has shown benefit on libido, mood, muscle mass, muscle strength, bone mineral density and haematocrit, similar benefits in older men have not been as adequately assessed. While there is no convincing evidence that testosterone treatment in older men will increase the risk of cardiovascular or prostate cancer, long-term, well-controlled studies are lacking and needed. Treatment options for older men include injectable, transdermal and transbuccal testosterone preparations. Copyright 2004 Elsevier Ltd. PMID: 15261842 [PubMed - indexed for MEDLINE] 4103. Journ Annu Diabetol Hotel Dieu. 2004:29-37. [Adipose tissue cytokines and insulin resistance]. [Article in French] Bastard JP(1), Lagathu C, Maachi M, Kim M, Vigouroux C, Caron M, Vidal H, Capeau J. Author information: (1)INSERM U402, Faculté de Médecine Saint-Antoine et Service de Biochimie et Hormonologie, Hôpital Tenon, Université Pierre et Marie Curie, Paris. PMID: 15259303 [PubMed - indexed for MEDLINE] 4104. Minerva Endocrinol. 2004 Jun;29(2):47-54. Obesity and the metabolic syndrome. Vega GL(1). Author information: (1)Department of Clinical Nutrition, University of Texas, Southwestern Medical Center, Dallas, TX, USA. gloria.vega@utsouthwestern.edu The metabolic syndrome is a cluster of risk factors for coronary heart disease that seemingly have an underlying metabolic causation. Central obesity is the centerpiece of the metabolic alterations. Accordingly, increased abdominal adiposity contributes to dyslipidemia, hyperglycemia, and hypertension. In about 20% of the cases with metabolic syndrome, there is also beta-cell dysfunction that leads to the clinical manifestation of diabetes mellitus. Recent evidence suggests that increased obesity is also associated with inflammation. The role of adipose tissue in the causation of metabolic alterations that lead to the clinical manifestation of the metabolic syndrome has become a focus of active research. Adipose tissue not only secretes non-esterified fatty acids that contribute to atherogenic dyslipidemia, steatosis and lipotoxicity. This organ is also an active endocrine and paracrine system. It can secrete pro-inflammatory factors, pro-insulin resistance factors, and other cytokines and hormones that can contribute to hypertension and impaired fibrinolysis. Therefore, the metabolic alterations commonly associated with increased central obesity of the metabolic syndrome are pro-atherogenic partly because the metabolites are proinflammatory. PMID: 15257255 [PubMed - indexed for MEDLINE] 4105. Radiographics. 2004 Jul-Aug;24(4):1051-68. Radiologic manifestations of Proteus syndrome. Jamis-Dow CA(1), Turner J, Biesecker LG, Choyke PL. Author information: (1)Department of Radiology, Georgetown University Hospital, Washington, DC, USA. Proteus syndrome is a sporadic disorder named for its highly variable manifestations. The disease causes tissue overgrowth in a mosaic pattern and may affect tissues derived from any germinal layer. The disease process is not usually apparent at birth but develops rapidly in childhood. Common manifestations include macrodactyly, vertebral abnormalities, asymmetric limb overgrowth and length discrepancy, hyperostosis, abnormal and asymmetric fat distribution, asymmetric muscle development, connective-tissue nevi, and vascular malformations. The features of Proteus syndrome indicate that the condition may be caused by a somatic alteration in a gene, but no specific genetic mutation has yet been identified. Therefore, the diagnosis and management of the disease depend heavily on clinical evaluation and imaging. Although the manifestations of Proteus syndrome are highly variable, accurate diagnosis is possible if standard diagnostic criteria are followed and if disease features are assessed in comparison with those found in similar syndromes. Copyright RSNA, 2004 PMID: 15256628 [PubMed - indexed for MEDLINE] 4106. J Addict Dis. 2004;23(3):5-21. Overlapping and interactive pathways regulating appetite and craving. Kalra SP(1), Kalra PS. Author information: (1)Department of Neuroscience, University of Florida McKnight Brain Institute, PO Box 100244, Gainesville, FL 32610-0244, USA. skalra@ufbi.ufl.edu Multidisciplinary research in recent years has delineated the hypothalamic hardcore wiring that encodes appetitive drive. The appetite regulating network (ARN) consisting of distinct orexigenic and anorexigenic circuitries operates in the arcuate nucleus-paraventricular nucleus axis of the hypothalamus to propagate and relay the appetitive drive, and is subject to modulation by excitatory and inhibitory messages from the lateral hypothalamus and ventromedial nucleus, respectively. Reciprocal afferent humoral signals, comprised of anorexigenic leptin from white adipose tissue and orexigenic ghrelin from stomach, to the ARN integrate the moment-to-moment regulation of energy homeostasis. Various loci in the ARN and afferent hormonal feedback circuitry in the rodent brain are important for food craving elicited by drugs of abuse. This convergence of neurochemical and hormonal signaling has now paved the way to address the fundamental question of whether cellular and molecular events that underlie the appetitive drive in response to diminished energy stores in the body are akin to drug craving during withdrawal in humans. PMID: 15256341 [PubMed - indexed for MEDLINE] 4107. Annu Rev Biomed Eng. 2004;6:109-30. Breast tissue engineering. Patrick CW(1). Author information: (1)Laboratory of Reparative Biology & Bioengineering, Department of Plastic Surgery, The University of Texas M.D. Anderson Cancer Center and The University of Texas Center for Biomedical Engineering, Houston, Texas 77030, USA. cpatrick@mdanderson.org Tissue engineering has the potential to redefine rehabilitation for the breast cancer patient by providing a translatable strategy that restores the postmastectomy breast mound while concomitantly obviating limitations realized with contemporary reconstructive surgery procedures. The engineering design goal is to provide a sufficient volume of viable fat tissue based on a patient's own cells such that deficits in breast volume can be abrogated. To be sure, adipose tissue engineering is in its infancy, but tremendous strides have been made. Numerous studies attest to the feasibility of adipose tissue engineering. The field is now poised to challenge barriers to clinical translation that are germane to most tissue engineering applications, namely scale-up, large animal model development, and vascularization. The innovative and rapid progress of adipose engineering to date, as well as opportunities for its future growth, is presented. PMID: 15255764 [PubMed - indexed for MEDLINE] 4108. Int J Obes Relat Metab Disord. 2004 Aug;28(8):941-55. Conjugated linoleic acid and obesity control: efficacy and mechanisms. Wang YW(1), Jones PJ. Author information: (1)School of Dietetics and Human Nutrition, Macdonald Campus, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada. Obesity is associated with high blood cholesterol and high risk for developing diabetes and cardiovascular disease. Therefore, management of body weight and obesity are increasingly considered as an important approach to maintaining healthy cholesterol profiles and reducing cardiovascular risk. The present review addresses the effects of conjugated linoleic acid (CLA) on fat deposition, body weight and composition, safety, as well as mechanisms involved in animals and humans. Animal studies have shown promising effects of CLA on body weight and fat deposition. The majority of the animal studies have been conducted using CLA mixtures that contained approximately equal amounts of trans-10, cis-12 (t10c12) and cis-9, trans-11 (c9t11) isomers. Results of a few studies in mice fed CLA mixtures with different ratios of c9t11 and t10c12 isomers have indicated that the t10c12 isomer CLA may be the active form of CLA affecting weight gain and fat deposition. Inductions of leptin reduction and insulin resistance are the adverse effects of CLA observed in only mice. In pigs, the effects of CLA on weight gain and fat deposition are inconsistent, and no adverse effects of CLA have been reported. A number of human studies suggest that CLA supplementation has no effect on body weight and insulin sensitivity. Although it is suggested that the t10c12 CLA is the antiadipogenic isomer of CLA in humans, the effects of CLA on fat deposition are marginal and more equivocal as compared to results observed in animal studies. Mechanisms through which CLA reduces body weight and fat deposition remain to be fully understood. Proposed antiobesity mechanisms of CLA include decreased energy/food intake and increased energy expenditure, decreased preadipocyte differentiation and proliferation, decreased lipogenesis, and increased lipolysis and fat oxidation. In summary, CLA reduces weight gain and fat deposition in rodents, while produces less significant and inconsistent effects on body weight and composition in pigs and humans. New studies are required to examine isomer-specific effects and mechanisms of CLA in animals and humans using purified individual CLA isomers. PMID: 15254484 [PubMed - indexed for MEDLINE] 4109. Ann N Y Acad Sci. 2004 Jun;1019:436-8. Reproductive switch and aging: the case of leptin change in dietary restriction. Koochmeshgi J(1). Author information: (1)National Research Center for Genetic Engineering and Biotechnology, P. O. Box 14155-6343, Tehran, Iran. jkoochmeshgi@yahoo.co.uk We have proposed that normal food intake is geared toward optimizing the internal milieu for reproduction, despite some components of this milieu being detrimental to health. In dietary restriction, the animal is prevented from eating enough to attain or maintain reproductive capacity and this particular milieu does not materialize. Life extension occurs as a by-product. This idea provides a framework for exploring biomolecular changes in dietary restriction and their relevance to aging. Leptin is a case in point: here, a decrease in leptin level in dietary restriction is explored in the light of leptin's role in the complex signaling system of reproductive switch. PMID: 15247061 [PubMed - indexed for MEDLINE] 4110. Obes Rev. 2004 Aug;5(3):145-51. Obesity as a disease: no lightweight matter. Conway B(1), Rene A. Author information: (1)Department of Epidemiology, The University of North Texas School of Public Health, 3500 Camp Bowie Boulevard, EAD-709B, Fort Worth, TX 76107, USA. baqiyyah@yahoo.com The epidemic rise in obesity has fuelled the current debate over its classification as a disease. Contrary to just being a medical condition or risk factor for other diseases, obesity is a complex disease of multifaceted aetiology, with its own disabling capacities, pathophysiologies and comorbidities. It meets the medical definition of disease in that it is a physiological dysfunction of the human organism with environmental, genetic and endocrinological aetiologies. It is a response to environmental stimuli, genetic predisposition and abnormalities, and has a characteristic set of signs and symptoms with consistent anatomical alterations. Excess adipose tissue increases the work of the heart and leads to anatomical changes in this organ. It alters pulmonary, endocrine and immunological functions, all with adverse effects on health. Some of the complications of obesity include cardiovascular disease, non-insulin-dependent diabetes mellitus, obstructive pulmonary disease, arthritis and cancer. Given the excess mortality, substantial morbidity and the economic toll of obesity, this is a disease that warrants serious attention by the medical community. Obesity's status and acceptance as a disease is pivotal in determining its treatment, reimbursement for treatment and the development of widespread interventions. PMID: 15245383 [PubMed - indexed for MEDLINE] 4111. Menopause. 2004 Jul-Aug;11(4):484-94. Preventing clinically evident coronary heart disease in the postmenopausal woman. Welty FK(1). Author information: (1)Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. fwelty@caregroup.harvard.edu OBJECTIVE: This review summarizes data on the prevalent coronary heart disease risk factors of postmenopausal women and the pharmacologic and nonpharmacologic therapies available for preventing or treating them. DESIGN: Medline searches from 1966 on were used to identify manuscripts for coronary heart disease risk factor information, lipid levels as predictors of cardiovascular disease in women, non-pharmacologic therapies, side effects of statins, and lipid-lowering trials that included women and had myocardial infarction or coronary heart disease death as endpoints. RESULTS: Dyslipidemias that occur with menopause are particularly atherogenic and tend to cluster with other metabolic and nonmetabolic risk factors. Estrogen therapy, with or without progestogen, can no longer be recommended for primary or secondary prevention of cardiovascular disease in postmenopausal women. Statins have been effective in reducing cardiovascular-related morbidity and mortality and should be first-line therapy for lipid-lowering. CONCLUSIONS: A considerable number of women look to obstetricians-gynecologists for primary care. For postmenopausal women especially, primary care must include management of risk factors for coronary heart disease. Estrogen or estrogen plus progestin should be used only for symptomatic hot flashes and at the lowest dose possible. Statins should be first-line therapy in preventive strategies for lipid-lowering. PMID: 15243287 [PubMed - indexed for MEDLINE] 4112. Mol Endocrinol. 2004 Sep;18(9):2123-31. Epub 2004 Jul 8. Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Collins S(1), Cao W, Robidoux J. Author information: (1)CIIT Centers for Health Research, Six Davis Drive, Research Triangle Park, North Carolina 27709, USA. scollins@ciit.org. The three beta AR (beta-adrenergic receptor) subtypes (beta(1)AR, beta(2)AR, and beta(3)AR) are members of the large family of G protein-coupled receptors, each of which is coupled to G alpha s and increases in intracellular cAMP levels. In white adipose tissues, catecholamine activation of the beta ARs leads to the mobilization of stored fatty acids and regulates release of several adipokines, whereas in brown adipose tissue they stimulate the specialized process of adaptive nonshivering thermogenesis. Noteworthy, in most models of obesity the beta AR system is dysfunctional, and its ability to stimulate lipolysis and thermogenesis are both impaired. Nevertheless, selective agonists for the beta(3)AR, a subtype that is found predominantly in adipocytes, have been able to prevent or reverse obesity and accompanying insulin resistance in animal models. Whether this is a viable therapeutic option for human obesity is much debated with regard to the existence of brown adipocytes in humans or their ability to be recruited. Nevertheless, probing the physiological changes in adrenoceptor function in rodent obesity, as well as the process by which beta(3)AR agonists promote a thermogenic shift in fuel use, have yielded unexpected new insights into beta AR signaling and adipocyte physiology. These include the recent discovery of an essential role of p38 MAPK in mediating adaptive thermogenesis, as well as the accessory role of the ERK MAPK pathway for the control of lipolysis. Because these metabolic events were traditionally ascribed solely to the cAMP/protein kinase A system, the integration of these signaling mechanisms may pose new therapeutic directions in the quest to counter the obesity epidemic in our midst. PMID: 15243132 [PubMed - indexed for MEDLINE] 4113. Bull Cancer. 2004 Apr;91(4):317-23. [From cytogenetics to cytogenomics of adipose tissue tumors: 2. Malignant adipose tissue tumors]. [Article in French] Pedeutour F(1), Maire G, Sirvent N; Groupe francophone de cytogénétique oncologique. Author information: (1)Laboratoire de génétique, Hôpital de l'Archet, CHU de Nice, 151, route de Saint-Antoine-de-Ginestière, BP 3079, 06202 Nice cedex 3. pedeutour@unice.fr Malignant adipose tissue tumors, also called liposarcomas, are the most common sarcoma of adult life. They may be hard to distinguish from benign adipose tissue tumors as well as from other types of sarcomas. Well-differentiated liposarcomas and myxoid liposarcomas are the two histological subtypes that have been best characterized at the genetic level. The defining genetic features of well-differentiated liposarcoma cells are supernumerary circular ("ring") and giant linear rod chromosomes. These rings and giant chromosomes contain amplification of the 12q14-15 region, including the MDM2 gene, associated with coamplification of various other chromosomal regions. In addition, they most often lack alpha-satellite centromeric sequences. The detection of MDM2 amplification is a valuable tool for the differential diagnosis between well-differentiated liposarcomas and lipomas. Dedifferentiated liposarcomas usually present with patterns of MDM2 amplification similar to those observed in well-differentiated liposarcomas. In addition, recent CGH-array studies suggest that co-amplification of MDM2 with the 6q23-25 region might be a specific feature. Myxoid and round-cell liposarcomas are characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. A rare variant translocation t(12;22) that fuses DDIT3 with EWS has also been described. The genetics of pleomorphic liposarcoma is still obscure. Pleomorphic liposarcomas show complex karyotypes with many numerical and structural chromosomal aberrations. To date, no specific molecular abnormality has been identified. PMID: 15242313 [PubMed - indexed for MEDLINE] 4114. Horm Metab Res. 2004 Jun;36(6):376-80. Mechanisms of obesity-related hypertension. Lamounier-Zepter V(1), Bornstein SR, Ehrhart-Bornstein M. Author information: (1)Department of Endocrinology, University Medical Center, Heinrich Heine University, Düsseldorf, Germany. Valeria.Lamounier-Zepter@uni-duesseldorf.de Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension and cardiovascular disease. Although the importance of obesity as a cause of hypertension is well established, the molecular basis of the relationship between obesity and increased blood pressure remains poorly understood. This brief review examines the association between obesity and hypertension along with the mechanisms proposed to explain this association, while presenting evidence of a direct causal effect of adipose tissue in the development of hypertension through the involvement of the adrenal cortex. PMID: 15241727 [PubMed - indexed for MEDLINE] 4115. Horm Metab Res. 2004 Jun;36(6):365-9. Hypothalamic regulation of adiposity: the role of 11beta-hydroxysteroid dehydrogenase type 1. Hochberg Z(1), Friedberg M, Yaniv L, Bader T, Tiosano D. Author information: (1)Division of Endocrinology, Meyer Children's Hospital, PO Box 9602, Rambam Medical Center, Haifa 31096, Israel. z_hochberg@rambam.health.gov.il Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11beta-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11beta-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11beta-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11beta-HSD-1 activity and induce lipolysis. Tumor necrosis factor-alpha and interleukin-1beta upregulate 11beta-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through beta-adrenergic upregulation and alpha-adrenergic downregulation of 11beta-HSD-1 activity. Inhibition of 11beta-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool. PMID: 15241725 [PubMed - indexed for MEDLINE] 4116. J Endocrinol Invest. 2004 Apr;27(4):400-3. Is there a role of ghrelin in preventing catabolism? Janssen JA(1), van der Lely AJ, Lamberts SW. Author information: (1)Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. j.a.m.j.l.janssen@erasmusmc.nl Catabolism is a metabolic process in which muscle and fat cell tissues are broken down in their constituent parts to provide nutrients and energy for the body. Whilst undoubtedly a potent stimulator of GH secretion in pharmacological doses, at present no clear physiological role for ghrelin in the regulation of GH secretion has been identified in man. In addition to its GH-releasing properties, ghrelin stimulates food intake and adipogenesis. The role of ghrelin has been extensively studied in three human models of catabolism: anorexia nervosa, cardiac cachexia and cancer cachexia. In this review we discuss the role of ghrelin in the etiology and treatment of catabolism using these three human models of catabolism. In the presence of clear catabolism in all the three conditions plasma total ghrelin levels are increased, suggesting that ghrelin does not increase food intake and/or anabolism in these circumstances. In addition, it is at present unknown whether administration of additional ghrelin in these conditions may reduce (or attenuate) the development of cachexia. In conclusion, the anabolic effects of ghrelin in man have still to be demonstrated. PMID: 15233563 [PubMed - indexed for MEDLINE] 4117. Przegl Lek. 2004;61(2):109-14. [Adiponectin--adipocytokine with a broad clinical spectrum]. [Article in Polish] Szopa M(1), Malczewska-Malec M, Wybrańska I, Kieć-Wilk B, Bodzioch M, Trzos M, Dembińska-Kieć A. Author information: (1)Zakład Biochemii Klinicznej, Collegium Medicum Uniwersytet Jagielloński, Kraków. Adiponectin (also called AdipoQ, gelatin-binding protein 28, Acrp30) is a novel adipocytokine with important metabolic effects. It is physiologically released from adipose tissue and circulates in serum as a hexamer and larger multimeric structure of high molecular weight. Serum level of the protein correlates with systemic insulin sensitivity. Recently adiponectin receptors AdipoR1 and AdipoR2 have been discovered by expression cloning. AdipoR1 is abundantly expressed in skeletal muscles, whereas AdipoR2 is predominantly expressed in the liver. Marked expression of mRNA for AdipoR1 and AdipoR2 has been lately reported in pancreatic beta cells. Both of the receptors activate AMPK and PPAR alpha metabolic pathways leading to an increase in fatty acid oxidation, glucose uptake and a decreased rate of gluconeogenesis, thus enhancing insulin sensitivity. Moreover effects of adiponectin mimic many metabolic actions of insulin such as augmenting blood flow and glucose disposal in NO-dependent manner. The precise mechanism of regulation of plasma adiponectin level is unknown. Recently the mechanism of transcriptional activation of adiponectin gene via PPAR gamma was described. Its level seems to be decreased by TNFalfa and beta-adrenergic agonists. Furthermore there is increasing evidence that some genetic variants in the adiponectin gene may be associated with its ethnical differences in level as well as its likely clinical consequences. Hipoadiponectynemia is associated with obesity, metabolic syndrome, diabetes type 2, cardiovascular disease, lipodystrophy in AIDS. In patients with chronic renal failure, anorexia nervosa plasma adlponectin level is increased. Weight loss and therapy with thlazolidinediones are proved to enhance endogenous adlponectin production in humans. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and antiatherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, especially in individuals with low plasma levels of adiponectin. PMID: 15230153 [PubMed - indexed for MEDLINE] 4118. Mutat Res. 2004 Jul 13;551(1-2):199-211. Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response. Carlsen H(1), Alexander G, Austenaa LM, Ebihara K, Blomhoff R. Author information: (1)Department of Nutrition, Faculty of Medicine, University of Oslo, P.O. Box 1046 Blindern, N-0316 Oslo, Norway. A wide range of environmental stress and human disorders involves inappropriate regulation of NF-kappaB, including cancers and numerous inflammatory conditions. We have developed transgenic mice that express luciferase under the control of NF-kappaB, enabling real-time non-invasive imaging of NF-kappaB activity in intact animals. We show that, in the absence of stimulation, strong, intrinsic luminescence is evident in lymph nodes in the neck region, thymus, and Peyer's patches. Treating mice with stressors, such as TNF-alpha, IL-1alpha, or lipopolysaccharide (LPS) increases the luminescence in a tissue-specific manner, with the strongest activity observable in the skin, lungs, spleen, Peyer's patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue exhibit less intense activities. Exposure of the skin to a low dose of UV-B radiation increases luminescence in the exposed areas. In ocular experiments, LPS- and TNF-alpha injected NF-kappaB-luciferase transgenic mice exhibit a 20-40-fold increase in lens NF-kappaB activity, similar to other LPS- and TNF-alpha-responsive organs. Peak NF-kappaB activity occurs 6h after injection of TNF-alpha and 12h after injection of LPS. Peak activities occur, respectively, 3 and 6h later than that in other tissues. Mice exposed to 360J/m(2) of UV-B exhibit a 16-fold increase in NF-kappaB activity 6h after exposure, characteristically similar to TNF-alpha-exposed mice. Thus, in NF-kappaB-luciferase transgenic mice, NF-kappaB activity also occurs in lens epithelial tissue and is activated when the intact mouse is exposed to classical stressors. Furthermore, as revealed by real-time non-invasive imaging, induction of chronic inflammation resembling rheumatoid arthritis produces strong NF-kappaB activity in the affected joints. Finally, we have used the model to demonstrate NF-kappaB regulation by manipulating the Vitamin A status in mice. NF-kappaB activity is elevated in mice fed a Vitamin A deficient (VAD) diet, and suppressed by surplus doses of retinoic acid (RA). We thus demonstrate the development and use of a versatile model for monitoring NF-kappaB activation both in tissue homogenates and in intact animals after the use of classical activators, during disease progression and after dietary intervention. PMID: 15225593 [PubMed - indexed for MEDLINE] 4119. Clin Sci (Lond). 2004 Sep;107(3):233-49. Lipoprotein transport in the metabolic syndrome: pathophysiological and interventional studies employing stable isotopy and modelling methods. Chan DC(1), Barrett PH, Watts GF. Author information: (1)Lipoprotein Research Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6847. Comment on Clin Sci (Lond). 2004 Sep;107(3):221-32. The accompanying review in this issue of Clinical Science [Chan, Barrett and Watts (2004) Clin. Sci. 107, 221-232] presented an overview of lipoprotein physiology and the methodologies for stable isotope kinetic studies. The present review focuses on our understanding of the dysregulation and therapeutic regulation of lipoprotein transport in the metabolic syndrome based on the application of stable isotope and modelling methods. Dysregulation of lipoprotein metabolism in metabolic syndrome may be due to a combination of overproduction of VLDL [very-LDL (low-density lipoprotein)]-apo (apolipoprotein) B-100, decreased catabolism of apoB-containing particles and increased catabolism of HDL (high-density lipoprotein)-apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, that collectively increases the flux of fatty acids from adipose tissue to the liver, the accumulation of fat in the liver and skeletal muscle, the hepatic secretion of VLDL-triacylglycerols and the remodelling of both LDL (low-density lipoprotein) and HDL particles in the circulation. These lipoprotein defects are also related to perturbations in both lipolytic enzymes and lipid transfer proteins. Our knowledge of the pathophysiology of lipoprotein metabolism in the metabolic syndrome is well complemented by extensive cell biological data. Nutritional modifications may favourably alter lipoprotein transport in the metabolic syndrome by collectively decreasing the hepatic secretion of VLDL-apoB and the catabolism of HDL-apoA-I, as well as by potentially increasing the clearance of LDL-apoB. Several pharmacological treatments, such as statins, fibrates or fish oils, can also correct the dyslipidaemia by diverse kinetic mechanisms of action, including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. The complementary mechanisms of action of lifestyle and drug therapies support the use of combination regimens in treating dyslipoproteinaemia in subjects with the metabolic syndrome. PMID: 15225143 [PubMed - indexed for MEDLINE] 4120. Ann Med. 2004;36(4):252-61. The role of acyl-CoA:diacylglycerol acyltransferase (DGAT) in energy metabolism. Yu YH(1), Ginsberg HN. Author information: (1)Department of Medicine, Columbia University College of Physicians and Surgeons, New York, USA. yy102@columbia.edu Acyl-CoA:diacylglycerol acyltransferase (DGAT, EC2.3.1.20), a key enzyme in triglyceride (TG) biosynthesis, not only participates in lipid metabolism but also influences metabolic pathways of other fuel molecules. Changes in the expression and/or activity levels of DGAT may lead to changes in systemic insulin sensitivity and energy homeostasis. The synthetic role of DGAT in adipose tissue, the liver, and the intestine, sites where endogenous levels of DGAT activity and TG synthesis are high, is relatively clear. Less clear is whether DGAT plays a mediating or preventive role in the development of ectopic lipotoxicity in tissues such as muscle and the pancreas, when their supply of free fatty acids (FFAs) exceeds their needs. Future studies with tissue-specific overexpression and/or knockout in these animal models would be expected to shed additional light on these issues. PMID: 15224651 [PubMed - indexed for MEDLINE] 4121. Cell Mol Life Sci. 2004 Jul;61(13):1633-51. Triacylglycerol hydrolase: role in intracellular lipid metabolism. Dolinsky VW(1), Gilham D, Alam M, Vance DE, Lehner R. Author information: (1)Department of Pediatrics, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, 328 Heritage Medical Research Centre, Edmonton, Alberta 94143-0414, Canada. Recent scientific advances have revealed the identity of several enzymes involved in the synthesis, storage and catabolism of intracellular neutral lipid storage droplets. An enzyme that hydrolyzes stored triacylglycerol (TG), triacylglycerol hydrolase (TGH), was purified from porcine, human and murine liver microsomes. In rodents, TGH is highly expressed in liver as well as heart, kidney, small intestine and adipose tissues, while in humans TGH is mainly expressed in the liver, adipose and small intestine. TGH localizes to the endoplasmic reticulum and lipid droplets. The TGH genes are located within a cluster of carboxylesterase genes on human and mouse chromosomes 16 and 8, respectively. TGH hydrolyzes stored TG, and in the liver, the lipolytic products are made available for VLDL-TG synthesis. Inhibition of TGH activity also inhibits TG and apolipoprotein B secretion by primary hepatocytes. A role for TGH in basal TG lipolysis in adipocytes has been proposed. TGH expression and activity is both developmentally and hormonally regulated. A model for the function of TGH is presented and discussed with respect to tissue specific functions. PMID: 15224187 [PubMed - indexed for MEDLINE] 4122. Diabetes Metab. 2004 Jun;30(3):215-27. Adiposity signals, genetic and body weight regulation in humans. Cancello R(1), Tounian A, Poitou Ch, Clément K. Author information: (1)EA3502, et INSERM Avenir, Laboratoire de nutrition, Service de nutrition Hôtel Dieu, 1 place du Parvis Notre-Dame, 75181 Paris Cedex 04, France. Numerous signals convey information about body fat status from the periphery to the brain areas that control energy homeostasis so that, throughout life, body weight remains nearly stable. These signals mainly originate, either from the adipose tissue, like leptin and to a lesser extent interleukin 6, or from the pancreas, like insulin and amylin. These factors circulate in proportion to body fat mass and they are referred to as "adiposity signals". It is well established, at least for leptin and insulin, that they enter the brain from the plasma where they induce/repress a network of important neuropeptide regulators of energy intake and expenditure. Beside these endocrine signals, a growing amount of literature show data relative to adipocyte-derived molecules, most of them belonging to the cytokine family, like IL6, TNFalpha, IL8, IL10 whose secretion also correlates with body fat mass and that may locally regulate fat mass expansion. Others, like adiponectin, are negatively correlated with body fat mass. These "adiposity molecules" have already been involved in insulin resistance associated with obesity and inflammatory process. They may participate to a complex inter organ dialogue. In this review, we will synthesize data relative to the role played by insulin, leptin and amylin, either alone or through a cross talk, in "energy level sensing" at the brain level. Furthermore, we will develop how "adiposity molecules" through their paracrin and/or autocrin action may contribute to maintain fat mass expansion, therefore representing new adiposity molecules per se. Lastly, since any distortion in the metabolic circuitry of energy homeostasis is susceptible to lead to a pathological status like obesity, the impact of known genetic polymorphisms in genes encoding the adiposity signals will be discussed. PMID: 15223973 [PubMed - indexed for MEDLINE] 4123. Eur J Nutr. 2004 Jun;43 Suppl 2:II7-II46. PASSCLAIM--body weight regulation, insulin sensitivity and diabetes risk. Riccardi G(1), Aggett P, Brighenti F, Delzenne N, Frayn K, Nieuwenhuizen A, Pannemans D, Theis S, Tuijtelaars S, Vessby B. Author information: (1)Università degli Studi di Napoli, Federico II, Dip. di Medicina Clinica e Sperimentale, Via Sergio Pansini 5, 80131, Napoli, Italy. BACKGROUND: Insulin sensitivity is a key function in human metabolism because it has a crucial role in the development of disease that are increasingly common in modern society. Impaired insulin sensitivity is an important determinant of type 2 diabetes; moreover, it has been proposed as an independent risk factor for cardiovascular disease. Thus, reduced insulin sensitivity is strongly associated with the metabolic syndrome, which represents a cluster of metabolic abnormalities and cardiovascular risk factor. Insulin sensitivity can be modulated by different environmental factors, including dietary habits. Obesity, especially if associated with abdominal adiposity, impairs insulin-sensitivity while physical activity can improve it; however, the composition of the habitual diet is clearly an important regulator of this function. AIM: To evaluate methodologies and markers that can be used to substantiate existing and potential claims of beneficial effects of foods on relevant functions connected with body fat deposition, insulin sensitivity and blood glucose regulation. RESULTS: We have reviewed the scientific basis for existing and potential claims, based not only on modifications of the target functions (body fat deposition, insulin sensitivity and blood glucose regulation) but also on modifications of other relevant associated functions (energy intake, energy expenditure, fat storage and oxidation, lipotoxicity, body fat composition, inflammation, oxidative stress, vascular function, glucose production and utilization). In this context we have identified a number of markers and evaluated appropriate method to measure and validate them. CONCLUSIONS: Relevant functions contributing to overweight, the metabolic syndrome and diabetes have been identified. The evidence reviewed indicates that in this field the link between nutrition, biological responses and diseases is clearly established. Therefore, there is a strong potential to develop functional food science. The major gap in the evidence continues to be the lack of diet based intervention trials of sufficient duration to be relevant for affecting the natural history of these conditions. PMID: 15221353 [PubMed - indexed for MEDLINE] 4124. Arch Pathol Lab Med. 2004 Jul;128(7):797-800. Intrascrotal lipoblastoma with a complex karyotype: a case report and review of the literature. Somers GR(1), Teshima I, Nasr A, Cook A, Khoury AE, Taylor GP. Author information: (1)Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada. gino.somers@sickkids.ca Lipoblastoma is a tumor of adipose tissue that usually occurs in young children. Most lipoblastomas occur on the extremities, trunk, and head and neck, and most have rearrangements of the 8q region. We describe a lipoblastoma in a 12-month-old boy who presented with a rapidly enlarging scrotal mass. Electron microscopy revealed features consistent with immature adipocytes, and cytogenetic analysis revealed the following karyotype: 57,XY,+4,+6,+7,der(8)t(8;12) (q22;q13), +der(8)t(8;12) (q22;q13), +9,+10,+12,-16,+17,+der(18)t(8;18)(q22;q23),+19,+20. Interestingly, the breakpoint on chromosome 12 (q13) is the same as that seen in lipoblastomas. To our knowledge, this is the first reported case of such a complex karyotype in lipoblastoma and adds to the expanding list of karyotypic abnormalities seen in such tumors. PMID: 15214818 [PubMed - indexed for MEDLINE] 4125. Nutrition. 2004 Jul-Aug;20(7-8):716-27. Optimizing fat oxidation through exercise and diet. Achten J(1), Jeukendrup AE. Author information: (1)School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom. jachten@bham.ac.uk Interventions aimed at increasing fat metabolism could potentially reduce the symptoms of metabolic diseases such as obesity and type 2 diabetes and may have tremendous clinical relevance. Hence, an understanding of the factors that increase or decrease fat oxidation is important. Exercise intensity and duration are important determinants of fat oxidation. Fat oxidation rates increase from low to moderate intensities and then decrease when the intensity becomes high. Maximal rates of fat oxidation have been shown to be reached at intensities between 59% and 64% of maximum oxygen consumption in trained individuals and between 47% and 52% of maximum oxygen consumption in a large sample of the general population. The mode of exercise can also affect fat oxidation, with fat oxidation being higher during running than cycling. Endurance training induces a multitude of adaptations that result in increased fat oxidation. The duration and intensity of exercise training required to induce changes in fat oxidation is currently unknown. Ingestion of carbohydrate in the hours before or on commencement of exercise reduces the rate of fat oxidation significantly compared with fasted conditions, whereas fasting longer than 6 h optimizes fat oxidation. Fat oxidation rates have been shown to decrease after ingestion of high-fat diets, partly as a result of decreased glycogen stores and partly because of adaptations at the muscle level. PMID: 15212756 [PubMed - indexed for MEDLINE] 4126. CNS Spectr. 2004 Jul;9(7):523-9. Leptin functioning in eating disorders. Monteleone P(1), DiLieto A, Castaldo E, Maj M. Author information: (1)Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. monteri@tin.it Leptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN. PMID: 15208512 [PubMed - indexed for MEDLINE] 4127. Curr Opin Nephrol Hypertens. 2004 Jul;13(4):451-8. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Frey FJ(1), Odermatt A, Frey BM. Author information: (1)Department of Nephrology and Hypertension, Inselspital, University of Berne, Switzerland. felix.frey@insel.ch PURPOSE OF REVIEW: Traditionally, the mineralocorticoid receptor was thought to be activated by the mineralocorticoid hormone aldosterone, and to exhibit its main action on epithelia by promoting renal sodium retention, potassium excretion and inducing hypertension upon excessive activation. Recently, evidence appeared that mineralocorticoid receptors are expressed in nonepithelial cells and activated by endogenous glucocorticoids including cortisol. Therefore, the prereceptor regulation of cortisol access to the mineralocorticoid receptors by 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSDs), a mechanism absent in most nonepithelial cells, appears to be relevant for disease states with cortisol-induced mineralocorticoid action. The present review focuses on direct and indirect effects attributable to mineralocorticoid receptor activation by glucocorticoids. RECENT FINDINGS: The determination of the intracellular topology of 11beta-HSD1, facing the endoplasmic reticulum lumen, and 11beta-HSD2, facing the cytoplasm, suggests that 11beta-HSD1 acts as a prereceptor mechanism in the local activation of glucocorticoid receptors, whereas 11beta-HSD2 controls mineralocorticoid receptors by interacting with the receptor in the absence of aldosterone. Downregulation of 11beta-HSD2 was observed with various stimuli including hypoxia, shear stress, angiotensin II and tumor necrosis factor alpha. The corresponding signal transcription pathways and some relevant transcription factors have been identified. Renal sodium retention in liver cirrhosis, nephrotic syndrome and hypoxia have been linked to 11beta-HSD2 reduced activity. Overexpression of 11beta-HSD1 specifically in adipose tissue in mice caused central obesity, a metabolic syndrome and hypertension due to increased intracellular cortisol concentrations. Peroxisome proliferator-activated receptor gamma agonists reduce 11beta-HSD1 activity and diminish the intracellular availability of cortisol, an effect accompanied by a decline in blood pressure. Three individuals with loss-of-function mutations of peroxisome proliferator-activated receptor gamma developed early hypertension. A potential mechanism might be glucocorticoid dependent mineralocorticoid receptor-mediated downregulation of endothelial nitric oxide synthase. SUMMARY: Recently, mineralocorticoid receptor antagonists have been used in the randomized aldactone evaluation study (RALES) with spironolactone, the eplerenone post-AMI heart failure efficacy and survival study (EPHESUS), and in severe and postmyocardial infarct heart failure, respectively. These investigations cannot be understood on the basis of the present physiological knowledge and underscore the relevance of focusing on mineralocorticoid receptor activation by ligands other than aldosterone. PMID: 15199296 [PubMed - indexed for MEDLINE] 4128. Cell Cycle. 2004 Jun;3(6):774-8. Epub 2004 Jun 15. Novel function of the retinoblastoma protein in fat: regulation of white versus brown adipocyte differentiation. Hansen JB(1), te Riele H, Kristiansen K. Author information: (1)The Netherlands Cancer Institute, Division of Molecular Biology, The Netherlands. The differentiation of white and brown fat cells is controlled by a similar set of transcription factors, including PPARgamma and C/EBPalpha. However, despite many similarities between the two types of fat cells, they carry out essentially opposite functions in vivo, with white adipocytes being the major energy store and brown adipocytes being potent energy-dissipaters through thermogenesis. Yet, little is known about factors differentially regulating the formation of white and brown fat cells. Members of the retinoblastoma protein family (pRB, p107, p130) have been implicated in the regulation of adipocyte differentiation, and expression and phosphorylation of the three retinoblastoma family proteins oscillate in a characteristic manner during differentiation of the white preadipocyte cell line 3T3-L1. We have recently demonstrated a surprising function of the retinoblastoma protein in the regulation of white versus brown adipocyte differentiation in vitro and possibly in vivo. Here we summarize the current knowledge on the retinoblastoma protein in fat cells, with particular emphasis on its potential role in adipocyte lineage commitment and differentiation. PMID: 15197340 [PubMed - indexed for MEDLINE] 4129. FEBS Lett. 2004 Jun 18;568(1-3):4-9. Links between fatty acids and expression of UCP2 and UCP3 mRNAs. Thompson MP(1), Kim D. Author information: (1)Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand. mary.thompson@stonebow.otago.ac.nz Physiological and pathological states that are associated with elevated plasma fatty acids (FAs) increase uncoupling protein 2 (UCP2) mRNA in white adipose tissue and UCP3 mRNA in skeletal muscle and heart. A direct effect of unsaturated fatty acids from all classes has been shown in various cultured cells. There is evidence that FAs could induce expression of UCPs by acting as ligands for peroxisome proliferator-activated receptors, influencing the function of sterol responsive element binding protein or activating 5'-AMP-activated protein kinase. Oleic acid has been shown to stimulate the activity of the promoter regions of UCP2 and UCP3 genes and the FA responsive regions are beginning to be characterised. PMID: 15196910 [PubMed - indexed for MEDLINE] 4130. Clin Exp Hypertens. 2004 May;26(4):387-98. Adipose tissue as an endocrine organ? A review of recent data related to cardiovascular complications of endocrine dysfunctions. Pantanetti P(1), Garrapa GG, Mantero F, Boscaro M, Faloia E, Venarucci D. Author information: (1)Clinica di Endocrinologia, Istituto di Medicina Clinica, Università Politecnica delle Marche, Ancona, Italy. Clinical and experimental data obtained in the last few years have modified the concept of adipose tissue as one solely directed at energy storage and release. The adipose tissue is a target organ for glucocorticoids and several studies have been carried out on the function of hypothalamic-pituitary-adrenal axis in obese subjects without conclusive results. A recent and innovative finding is that adipose tissue can produce cortisol from its inactive precursor, cortisone. The identification of leptin, a hormone synthesised by fat tissue, has ushered in the modern view of this tissue as a true endocrine organ. Leptin is produced primarily by subcutaneous and to a lesser extent by visceral adipose tissue, and has a central role in controlling body weight and, especially in regulating fat stores. Leptin is also involved in several complex functions, including physiological processes associated with puberty. Another hormone of fat tissue is angiotensinogen, which is produced in larger amounts by visceral than subcutaneous fat. Human and animals adipose tissue express a whole renin-angiotensin system (RAS). Angiotensin II, the final effector of this system is probably produced locally by adipose tissue. The function of adipose RAS is not well known. RAS can participate together with other hormones and substances, in adipocyte differentiation and fat tissue growth, but could be also involved in the pathogenesis of complications of obesity including arterial hypertension. PMID: 15195692 [PubMed - indexed for MEDLINE] 4131. Curr Opin Clin Nutr Metab Care. 2004 Jul;7(4):451-7. Role of myostatin in metabolism. Gonzalez-Cadavid NF(1), Bhasin S. Author information: (1)Division of Endocrinology, Department of Internal Medicine, Charles R. Drew University, Los Angeles, CA, USA. ncadavid@ucla.edu PURPOSE OF REVIEW: To review papers on myostatin published in 2003 and early 2004. Myostatin is a negative regulator of skeletal muscle mass produced in this tissue. Inactivating mutations of the myostatin gene or interaction of myostatin protein with follistatin and other inhibitory proteins induce a hypermuscular phenotype in cattle and mice; this is assumed to result from inhibition of muscle cell proliferation and DNA and protein synthesis (antianabolic effects). Myostatin also controls muscle mass in other animals, and appears to affect adipose tissue mass. RECENT FINDINGS: New protein interactions inhibiting myostatin that lead to double muscling, as well as the induction of hypermuscularity with myostatin antibodies, or the generation of a myostatin conditional knockout mouse, have been reported. Conversely, a transgenic mouse over-expressing myostatin and exhibiting reduced muscle mass in a gender-specific process has been obtained. In addition, novel inactivating mutations in the myostatin gene and genetic loci regulating myostatin effects, and the characterization of the myostatin gene and its effects on metabolism in fish and chicken have been described. Finally, the regulation of myostatin levels by growth hormone, glucorticoids, anabolic agents, nutritional status and exercise, the characterization of myostatin signaling pathways, and the clarification of myostatin effects on cell replication and differentiation, are other important recent findings. SUMMARY: These studies suggest that proteins and drugs that inactivate myostatin, or interfere with its binding to its receptor, may be useful for the therapy of wasting and degenerative muscle diseases and for the food industry. Other promising approaches may derive from new insights into the biochemical cascade that mediates myostatin effects, and into the role of myostatin in the regulation of fat metabolism and of heart and muscle regeneration after injury. PMID: 15192449 [PubMed - indexed for MEDLINE] 4132. Curr Opin Clin Nutr Metab Care. 2004 Jul;7(4):377-81. Roles of peroxisome proliferator-activated receptor delta in skeletal muscle function and adaptation. Fredenrich A(1), Grimaldi PA. Author information: (1)Inserm U636, Centre de Biochimie, Parc Valrose, Université de Nice-Sophia Antipolis, 06108 Nice, France. PURPOSE OF THE REVIEW: Peroxisome proliferator-activated receptors mediate the transcriptional effects of fatty acids and fatty acid metabolites and regulate many physiological functions including development and metabolism. The roles of peroxisome proliferator-activated receptor alpha and gamma isotypes have been well established, while the functions of the third member of the family, peroxisome proliferator-activated receptor delta, remained unclear until very recently. This review focuses on the physiological functions of the nuclear receptor and especially on its roles in the control of fatty acid metabolism. RECENT FINDINGS: We review very recent data demonstrating that peroxisome proliferator-activated receptor delta plays a central role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue, and also that the nuclear receptor is involved in cholesterol metabolism. SUMMARY: Use of potent and specific peroxisome proliferator-activated receptor delta agonists and appropriate transgenic animal models revealed the importance of this nuclear receptor in regulation of fatty acid catabolism in skeletal muscle and other tissues. It also indicated the potential of peroxisome proliferator-activated receptor delta as a therapeutic target in pathologies such as metabolic syndrome. However, the effects of peroxisome proliferator-activated receptor delta activation in atherosclerosis and the control of cell proliferation remain to be established. PMID: 15192438 [PubMed - indexed for MEDLINE] 4133. Hematol J. 2004;5 Suppl 3:S15-9. Relations between hemostatic variables, insulin resistance and inflammation. Morange PE(1), Alessi MC, Juhan-Vague I. Author information: (1)Hematology Laboratory CHU Timone Insern U626, Faculty of Medicine, Marseille, France. PMID: 15190271 [PubMed - indexed for MEDLINE] 4134. Sci Aging Knowledge Environ. 2004 Jun 9;2004(23):pe25. Inside insulin signaling, communication is key to long life. Antebi A(1). Author information: (1)Max-Planck-Institut fur Molekulare Genetik, Ihnestrasse 73, D-14195 Berlin, Germany. antebi@molgen.mpg.de In a recent Nature paper, Tatar and colleagues show that inhibition of insulin/insulin-like growth factor (IGF) signaling specifically in the adipose tissue of Drosophila melanogaster retards organismal aging, increases resistance to oxidative stress, augments lipid deposition, and restricts insulin signaling in peripheral tissues by a cell-non-autonomous mechanism. Consistent with recent work in the worm, these results suggest that insulin/IGF signaling itself may mediate communication among various tissues to influence organismal longevity. PMID: 15190176 [PubMed - indexed for MEDLINE] 4135. Annu Rev Nutr. 2004;24:55-78. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury. Nagy LE(1). Author information: (1)Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106-4906, USA. len2@po.cwru.edu Alcohol metabolism takes place primarily in the liver. Initial exposures to ethanol have a major impact on the hepatic redox state and intermediary metabolism as a consequence of ethanol metabolism via alcohol dehydrogenase. However, upon continued exposure to ethanol, the progression of liver injury involves ethanol metabolism via CYP2E1 and consequent oxidant stress, as well as potential direct effects of ethanol on membrane proteins that are independent of ethanol metabolism. Multiple organ systems contribute to liver injury, including the innate immune system and adipose tissue. In response to ethanol exposure, specific signal transduction pathways, including NFkappaB and the mitogen-activated protein kinase family members ERK1/2, JNK, and p38, are activated. These complex responses to ethanol exposure translate into activation of nuclear transcription factors and altered gene expression within the liver, leading to the development of steatosis and inflammation in the early stages of alcohol-induced liver injury. PMID: 15189113 [PubMed - indexed for MEDLINE] 4136. Obes Surg. 2004 May;14(5):589-600. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Cottam DR(1), Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, Schauer PR. Author information: (1)Department of Surgery, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA. BACKGROUND: Obesity is a worldwide pandemic that causes a multitude of co-morbid conditions.However, there has been slow progress in understanding the basic pathophysiology that underlies co-morbid conditions associated with obesity. Recently, there has been intense interest in the role of inflammation in obesity. Using the inflammatory hypothesis, many of the mechanisms by which co-morbid conditions are associated with obesity are being elucidated. METHODS: We searched the literature and reviewed all relevant articles. We focused on hormones and cytokines that have been associated with other inflammatory conditions such as sepsis and systemic inflammatory response syndrome. FINDINGS: Angiotensinogen (AGT), transforming growth factor beta (TGFbeta), tumor necrosis factor alpha (TNFalpha), and interleukin six (IL-6) are all elevated in obesity and correlate with several markers of adipocyte mass. These mediators have detrimental effects on hypertension, diabetes, dyslipidemia, thromboembolic phenomena, infections, and cancer. Weight loss results in a reduction of inflammatory mediators and a diminution of the associated co-morbid conditions. CONCLUSIONS: The success of weight loss surgery in treating the complications associated with obesity is most probably related to the reduction of inflammatory mediators. While some aspects of bariatric physiology remain unclear, there appears to be a strong association between obesity and inflammation, thereby rendering obesity a chronic inflammatory state. A clearer understanding of the physiology of obesity will allow physicians who treat the obese to develop better strategies to promote weight loss and improve the well-being of millions of individuals. PMID: 15186624 [PubMed - indexed for MEDLINE] 4137. Lancet. 2004 Jun 5;363(9424):1892-4. The nicotinic acid receptor--a new mechanism for an old drug. Karpe F(1), Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. Fredrik.Karpe@ocdem.ox.ac.uk CONTEXT: Non-esterified fatty acids in plasma originate from adipose tissue. Delivery of fatty acids to the liver provides the substrate for VLDL triglycerides. Insulin-sensitive organs, overburdened by high concentrations of non-esterified fatty acids, may develop resistance to insulin action. In addition, insulin secretion from pancreatic beta-cells may be impaired by long-standing elevation of concentrations of non-esterified fatty acid in plasma. Normally, such concentrations fluctuate over the day depending on the transient suppression of lipolysis from adipose tissue by insulin released after meals. Diurnal concentrations of non-esterified fatty acid are often elevated in obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic acid is the only drug that primarily lowers concentrations of non-esterified fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its analogues, seems to alleviate insulin resistance in the short-term whereas, paradoxically, the long-term effect is often the opposite. Suppression of lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to which this occurs might explain this paradox. STARTING POINT: The exact cellular mechanism by which nicotinic acid exerts its antilipolytic effects has not been known until the recent discovery of a distinct G-protein coupled receptor. Nicotinic acid is a high affinity ligand, but the endogenous ligand is still unknown. Recently, Tina Rubic and colleagues (Biochem Pharmacol 2004; 67: 411-19) proposed a mechanism in which nicotinic acid stimulates cholesterol mobilisation from macrophages, thereby providing a potential link between regression of atherosclerosis and use of nicotinic acid. WHERE NEXT: Research on signalling through the nicotinic acid receptor might give rise to novel and more effective methods to interfere with fatty-acid metabolism, with insulin resistance, hyperlipidaemia, and atherosclerosis as target diseases. PMID: 15183629 [PubMed - indexed for MEDLINE] 4138. Front Neuroendocrinol. 2004 Apr;25(1):27-68. Ghrelin--a hormone with multiple functions. Korbonits M(1), Goldstone AP, Gueorguiev M, Grossman AB. Author information: (1)Department of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, UK. m.korbonits@qmul.ac.uk Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach mucosa but it is also expressed widely in different tissues and therefore may have both endocrine and paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor. In the current review we comprehensively summarize (i) the data available regarding the structure, expression pattern and regulation of ghrelin and its receptor; (ii) the available information regarding the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac and gastrointestinal function, carbohydrate metabolism, adipose and reproductive tissue, cell proliferation and behavioral effects; (iii) experimental and clinical data regarding circulating ghrelin levels observed in various physiological and pathological conditions; and (iv) data on gene variations of ghrelin and its receptor. It is apparent that ghrelin is involved in many more processes than originally envisaged, and in particular appears to have relatively less relevance to growth hormone physiology and more to the regulation of energy fluxes in the organism. Increasing data link ghrelin to the overall control of energy use and flow in situations where there is a limitation of energy sources and ghrelin appears to play a pivotal role in energy homeostasis. Copyright 2004 Elsevier Inc. PMID: 15183037 [PubMed - indexed for MEDLINE] 4139. J Clin Endocrinol Metab. 2004 Jun;89(6):2583-9. Medical consequences of obesity. Bray GA(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. brayga@pbrc.edu Obesity is an epidemic disease that threatens to inundate health care resources by increasing the incidence of diabetes, heart disease, hypertension, and cancer. These effects of obesity result from two factors: the increased mass of adipose tissue and the increased secretion of pathogenetic products from enlarged fat cells. This concept of the pathogenesis of obesity as a disease allows an easy division of disadvantages of obesity into those produced by the mass of fat and those produced by the metabolic effects of fat cells. In the former category are the social disabilities resulting from the stigma associated with obesity, sleep apnea that results in part from increased parapharyngeal fat deposits, and osteoarthritis resulting from the wear and tear on joints from carrying an increased mass of fat. The second category includes the metabolic factors associated with distant effects of products released from enlarged fat cells. The insulin-resistant state that is so common in obesity probably reflects the effects of increased release of fatty acids from fat cells that are then stored in the liver or muscle. When the secretory capacity of the pancreas is overwhelmed by battling insulin resistance, diabetes develops. The strong association of increased fat, especially visceral fat, with diabetes makes this consequence particularly ominous for health care costs. The release of cytokines, particularly IL-6, from the fat cell may stimulate the proinflammatory state that characterizes obesity. The increased secretion of prothrombin activator inhibitor-1 from fat cells may play a role in the procoagulant state of obesity and, along with changes in endothelial function, may be responsible for the increased risk of cardiovascular disease and hypertension. For cancer, the production of estrogens by the enlarged stromal mass plays a role in the risk for breast cancer. Increased cytokine release may play a role in other forms of proliferative growth. The combined effect of these pathogenetic consequences of increased fat stores is an increased risk of shortened life expectancy. PMID: 15181027 [PubMed - indexed for MEDLINE] 4140. J Clin Endocrinol Metab. 2004 Jun;89(6):2576-82. The gut and regulation of body weight. Wynne K(1), Stanley S, Bloom S. Author information: (1)Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom. Signals generated by the gastrointestinal tract are able to regulate appetite and influence body weight. Ghrelin is an orexigenic peptide produced by the stomach. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Signals from the gut and adipose tissue are integrated in the central nervous system to provide energy homeostasis. Knowledge of the body's control of appetite is important because we strive to combat obesity in man. PMID: 15181026 [PubMed - indexed for MEDLINE] 4141. J Clin Endocrinol Metab. 2004 Jun;89(6):2563-8. Adiponectin: A novel adipokine linking adipocytes and vascular function. Goldstein BJ(1), Scalia R. Author information: (1)Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. barry.goldstein@jefferson.edu Cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with obesity and type 2 diabetes mellitus, and recent work has elucidated several potential mechanisms by which increased adiposity enhances cardiovascular risk. Excess adipose tissue, especially in certain compartments, leads to reduced insulin sensitivity in metabolically responsive tissues, which is frequently associated with a set of cardiovascular risk factors, including hyperinsulinemia, hypertension, dyslipidemia, and glucose intolerance. Increasing attention has also been paid to the direct vascular effects of plasma proteins that originate from adipose tissue, especially adiponectin, which exhibits potent antiinflammatory and antiatherosclerotic effects. This brief review will summarize recent work on the vascular actions of adiponectin, which complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism. Adiponectin is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk. PMID: 15181024 [PubMed - indexed for MEDLINE] 4142. J Clin Endocrinol Metab. 2004 Jun;89(6):2548-56. Adipose tissue as an endocrine organ. Kershaw EE(1), Flier JS. Author information: (1)Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ekershaw@bidmc.harvard.edu Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue. PMID: 15181022 [PubMed - indexed for MEDLINE] 4143. Int J Surg Pathol. 2004 Apr;12(2):151-3. Myoid hamartomas of the breast: report of 3 cases and review of the literature. Filho OG(1), Gordan AN, Mello Rde A, Neto CS, Heinke T. Author information: (1)Department of Pathology, Universidade Federal de São Paulo/Escola Paulista de Medicina, São Paulo, Brazil. Hamartomas were first described by Albrecht in 1904, who defined them as tumor-like malformations in which there was abnormal blending of the normal components of an organ. The myoid hamartoma is a rare benign lesion of the breast and has an uncertain origin, possibly in the walls of the blood vessels, muscularis mammillae of the areolae, and mainly in myoepithelium. We report 3 cases of myoid hamartomas of the breast, with the clinical, radiologic, and histopathological findings, and review the literature. The 3 lesions showed normal breast ducts and lobules, entrapped by a muscular stroma and some foci of mature adipose tissue. The muscular origin of part of the stroma was confirmed by strong reactiveness with smooth-muscle actin. PMID: 15173923 [PubMed - indexed for MEDLINE] 4144. Hypertension. 2004 Jul;44(1):12-9. Epub 2004 Jun 1. Is there a rationale for angiotensin blockade in the management of obesity hypertension? Sharma AM(1). Author information: (1)McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, ON, Canada. sharma@ccc.mcmaster.ca Obesity, currently affecting >20% of the adult population in most Western countries, is a major risk factor for the development of hypertension. Hypertension in obese patients is, in the majority of instances, further complicated by the concomitant presence of dyslipidemia and insulin resistance. The latter is reflected by derangement of glucose homeostasis, ranging from hyperinsulinemia to frank type 2 diabetes. Hypertension in obese patients is also associated with an increased risk for left ventricular hypertrophy, endothelial dysfunction, renal hyperfiltration, microalbuminuria, and elevated markers of inflammation. Sodium retention, volume expansion, and increased cardiac output are common findings in obese individuals. These changes are largely attributable to increased activity of the sympathetic nervous system and insufficient suppression of the renin-angiotensin system. Recent data show increased expression of angiotensin II-forming enzymes in adipose tissue, and increased activity of the renin-angiotensin system has recently been implicated in the development of insulin resistance and type 2 diabetes. Accordingly, antihypertensive agents that block the renin-angiotensin system might be a beneficial strategy for treatment of obesity-related hypertension. Both angiotensin-converting enzyme inhibitors and angiotensin type-1 receptor blockers have been associated with favorable metabolic properties and end-organ protection in addition to their antihypertensive effects. Data from ongoing large trials will provide an indication of the protective and preventive effects of these treatment strategies while offering insights into the mechanisms linking obesity, hypertension, and other facets of the metabolic syndrome. PMID: 15173127 [PubMed - indexed for MEDLINE] 4145. Neurosci Biobehav Rev. 2004 Apr;28(2):143-80. The selfish brain: competition for energy resources. Peters A(1), Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL. Author information: (1)Department of Internal Medicine, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany. achim.peters@uni-luebeck.de The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier, has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term 'allocation' refers to the allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary-adrenal (LHPA) system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a 'glutamate command' signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress, traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine system. Disorders in the 'energy on demand' process or the LHPA-system can influence the allocation of energy and in so doing alter the body mass of the organism. In summary, the presented model includes a newly discovered 'principle of balance' of how pairs of high and low-affinity receptors can originate setpoints in biological systems. In this 'Selfish Brain Theory', the neocortex and limbic system play a central role in the pathogenesis of diseases such as anorexia nervosa and obesity. Copyright 2004 Elsevier Ltd. PMID: 15172762 [PubMed - indexed for MEDLINE] 4146. Langenbecks Arch Surg. 2004 Aug;389(4):299-305. Epub 2004 May 28. Cancer cachexia. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, B4 7ET, Birmingham, UK. m.j.tisdale@aston.ac.uk CAUSATIVE FACTORS: Nutritional supplementation or pharmacological manipulation of appetite are unable to control the muscle atrophy seen in cancer cachexia. This suggests that tumour and/or host factors might be responsible for the depression in protein synthesis and the increase in protein degradation. An increased expression of the ubiquitin-proteasome proteolytic pathway is responsible for the increased degradation of myofibrillar proteins in skeletal muscle, and this may be due to tumour factors, such as proteolysis-inducing factor (PIF), or host factors such as tumour necrosis factor-alpha (TNF-alpha). In humans loss of adipose tissue is due to an increase in lipolysis rather than a decrease in synthesis, and this may be due to tumour factors such as lipid-mobilising factor (LMF) or TNF-alpha, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL). Levels of mRNA for HSL are elevated twofold in adipose tissue of cancer patients, while there are no changes in lipoprotein lipase (LPL), involved in extraction of fatty acids from plasma lipoproteins for storage. TREATMENT FOR CACHEXIA: This has concentrated on increasing food intake, although that alone is unable to reverse the metabolic changes. Agents interfering with TNF-alpha have not been very successful to date, although more research is required in that area. The only agent tested clinically that is able to interfere with the action of PIF is eicosapentaenoic acid (EPA). EPA attenuates protein degradation in skeletal muscle by preventing the increased expression of the ubiquitin-proteasome pathway, but has no effect on protein synthesis. When used alone EPA prevents further wasting in cachectic patients, and, when it is combined with an energy- and protein-dense nutritional supplement, weight gain is seen, which is totally lean body mass. These results suggest that mechanistic studies into the causes of cancer cachexia will allow appropriate therapeutic intervention. PMID: 15168125 [PubMed - indexed for MEDLINE] 4147. Curr Opin Lipidol. 2004 Jun;15(3):303-7. New insights into inhibitors of adipogenesis. Harp JB(1). Author information: (1)Department of Nutrition and Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. PURPOSE OF REVIEW: Adipose tissue is a dynamic organ that changes mass throughout life in response to the metabolic needs of the animal. In the past three decades, significant advances have been made in delineating key extracellular and intracellular stimulators of fat cell formation or adipogenesis. In this review, the author focuses on new findings of specific inhibitors of adipogenesis. Understanding the balance between positive and negative regulators of adipogenesis has important health-related implications for anti-obesity medical therapy and lipodystrophy. RECENT FINDINGS: Adipogenesis is a highly regulated process requiring coordinated expression and activation of two main groups of adipogenic transcription factors, CCAAT/enhancer binding proteins and peroxisome proliferators activated receptor gamma. In response to hormonal and nutrient stimuli, the increased expression and activation of these transcription factors induce the expression of adipocyte-specific genes. More recently, several groups have identified extracellular inhibitors of adipocyte formation, including cytokines, lipid molecules, genistein, and protease inhibitors. Intracellular signaling molecules, which negatively regulate adipogenesis, include Pref-1, Foxo1, Foxa2, SMAD-3, WNT-10b, GATA-2 and GATA-3. SUMMARY: The prevalence of obesity is increasing in the United States and in other westernized societies. Understanding the mechanisms of excessive energy storage in adipose tissue is necessary to develop a comprehensive strategy to prevent and treat obesity. One potential, but unrealized, approach to obesity treatment is to target excessive adipose tissue enlargement. A number of promising extra- and intracellular inhibitors of fat cell formation have been identified, but the modulation of adipose tissue mass may have both advantageous and deleterious health effects. PMID: 15166786 [PubMed - indexed for MEDLINE] 4148. Curr Opin Lipidol. 2004 Jun;15(3):297-302. Regulation of insulin sensitivity by adipose tissue-derived hormones and inflammatory cytokines. Ruan H(1), Lodish HF. Author information: (1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Rm 601, Cambridge, MA 02142, USA. PURPOSE OF REVIEW: The aim of this review is to assess the role of adipose tissue-derived hormones and inflammatory cytokines in the pathogenesis of obesity-linked type II diabetes, with a special focus on articles published between December 2002 and December 2003. RECENT FINDINGS: Insulin resistance is widely recognized as a fundamental defect seen in obesity and type II diabetes. Although the molecular mechanisms triggering the development of insulin resistance remain elusive, recent studies have suggested that adipose tissue and adipose tissue-derived hormones and inflammatory cytokines play essential roles in the overall insulin sensitivity in vivo. Dysfunctions of adipose tissue can lead to systemic insulin resistance. SUMMARY: Understanding the regulation of the metabolic and secretory functions of adipose tissue, as well as its subsequent impact on overall insulin sensitivity, is becoming increasingly important given the therapeutic potential of targeting the root causes of insulin resistance in the treatment of type 2 diabetes and its associated complications, such as cardiovascular and cerebrovascular diseases. PMID: 15166785 [PubMed - indexed for MEDLINE] 4149. Int Arch Allergy Immunol. 2004 Jun;134 Suppl 1:30-6. Peroxisome proliferator-activated receptor gamma regulates eosinophil functions: a new therapeutic target for allergic airway inflammation. Ueki S(1), Matsuwaki Y, Kayaba H, Oyamada H, Kanda A, Usami A, Saito N, Chihara J. Author information: (1)Department of Clinical and Laboratory Medicine, Akita University School of Medicine, Akita, Japan. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates lipid metabolism and glucose homeostasis. PPARgamma is not only highly expressed in adipose tissue but also in cells involved in the immune system, and it exerts anti-inflammatory activities. We showed that eosinophils, a major inflammatory cell in allergic inflammation, express PPARgamma. PPARgamma negatively modulates eosinophil functions, such as survival, chemotaxis, antibody-dependent cellular cytotoxicity and degranulation. Recently, three independent groups have demonstrated that PPARgamma agonists inhibit airway inflammation in an animal model of asthma. This evidence suggests that PPARgamma agonists may be a new therapeutic modality for the treatment of allergic diseases including asthma. Copyright 2004 S. Karger AG, Basel PMID: 15166481 [PubMed - indexed for MEDLINE] 4150. Trends Pharmacol Sci. 2004 Jun;25(6):331-6. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Rangwala SM(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. The peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been the focus of intense research during the past decade because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. Recent advances include the discovery of novel genes that are regulated by PPAR-gamma, which helps explain how activation of this adipocyte-predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPAR-gamma ligands, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis. The net result of the pleiotropic effects of PPAR-gamma ligands is improvement of insulin sensitivity, although undesired side-effects limit the utility of this therapy. It might be possible to dissociate the anti-diabetic and adverse effects through selective modulation of PPAR-gamma activity. PMID: 15165749 [PubMed - indexed for MEDLINE] 4151. J Clin Laser Med Surg. 2004 Apr;22(2):141-50. Photobiological basis and clinical role of low-intensity lasers in biology and medicine. Reddy GK(1). Author information: (1)Department of Physical Therapy and Rehabilitation Sciences, University of Kansas Medical Center, Kansas City, Kansas, USA. kreddy_usa@yahoo.com The purpose of this article is to provide a comprehensive review on the clinical role of low intensity laser therapy (laser photostimulation) in biology and medicine. Studies on wound healing and pain relief are highlighted to show the clinical efficacy of laser therapy. Controversies about the use of low intensity laser as a therapeutic modality for wound healing and pain relief are presented and a brief explanation is provided to overcome these controversies. The importance of standard parameters is emphasized for the applications of low intensity lasers in biology and medicine. A justification has been made to warrant further research on the use of low intensity laser as a therapeutic modality. Although the therapeutic applications of low intensity laser are imminent, the heterogeneity in treatment protocols and study design calls for a vigilant interpretation of the findings. PMID: 15165389 [PubMed - indexed for MEDLINE] 4152. J Endocrinol Invest. 2004 Mar;27(3):211-5. Inducing Graves' ophthalmopathy. Ludgate M(1), Baker G. Author information: (1)Department of Medicine, University of Wales, College of Medicine, Heath Park, Cardiff, UK. ludgate@cf.ac.uk The majority of patients with Graves' disease (GD) have some degree of ocular involvement and this requires surgical or medical intervention in about 5% of cases. There are autoimmune and inflammatory processes operating in Graves' ophthalmopathy (GO), which together induce glycosaminoglycan production, edema and adipogenesis resulting in an increase in the volume of the orbital contents. GO is a heterogeneous disorder, i.e.: 1) whilst usually associated with hyperthyroidism it may occur in euthyroid (and even hypothyroid) patients; 2) expansion of orbital tissues may be due to 'big-fat' or 'big muscles'. The heterogeneity is further exemplified by the spectrum of protocols which have succeeded in inducing aspects of the disease both in animal models and in humans including: 1) Production of severe hypothyroidism in guinea pigs by thyroidectomy and administration of pituitary extract (TSH); 2) Induction of T cells autoreactive to the thyrotropin receptor (TSHR) in mice; 3) Depletion of regulatory T cells in humans susceptible to autoimmunity; 4) Modulation of adipose tissue metabolism in mice and men. In addition, identical induction protocols result in different pathological features depending on the environment, e.g. TSHR primed T cells produce thyroiditis and ocular pathology in BALBc mice in Brussels but thyroid stimulating antibodies accompanied by elevated thyroxine in these animals (from the same supplier) in Cardiff. Thus, experiences in the induction of GO have confirmed the polygenic, multifactorial nature of the disorder and highlight the importance of careful disease classification to promote further progress in understanding. PMID: 15164995 [PubMed - indexed for MEDLINE] 4153. Ann Endocrinol (Paris). 2004 Feb;65(1 Suppl):S36-43. [Adiponectin: from adipocyte to skeletal muscle]. [Article in French] Ferré P(1). Author information: (1)INSERM U465, Centre de Recherches Biomédicales des Cordeliers, F-75270 Paris Cedex 06. pferre@bhdc.jussieu.fr Insulin resistance is characterized by a peripheral resistance to insulin-mediated glucose uptake, and an hepatic resistance of glucose production to insulin. Insulin resistance in skeletal muscle is of a particular importance, and could be the consequence of an increase in intracellular and circulating fatty acids and triglycerides. Adipose tIssue plays an important role to regulate mobilization and release of fatty acids. Adipose tIssue is an endocrine organ which secretes several factors, including adiponectin. Adiponectin improves insulin sensitivity in skeletal muscle and liver, through a stimulation of fatty acid oxidation and glucose utilization. Thiazolidinediones enhance adiponectin expression and synthesis through PPARgamma, although the precise mechanism remains controversial. AMP-activated protein kinase (AMPK) is the main adiponectin target. Adiponectin, clearly, is a major modulator of glucose and lipid metabolism in insulin-sensitive tIssue and/or regulator of insulin-sensitivity, in obese and/or glucose intolerant subjects, as well as in type 2 diabetes mellitus. Recent works and the links between insulin resistance, adipose tIssue, adiponectin and its PPARgamma-enhanced secretion are reviewed in this paper. PMID: 15163922 [PubMed - indexed for MEDLINE] 4154. Am J Clin Nutr. 2004 Jun;79(6 Suppl):1153S-1158S. Dietary conjugated linoleic acid and body composition. Wang Y(1), Jones PJ. Author information: (1)School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada. Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. The major dietary source of CLA for humans is ruminant meats, such as beef and lamb, and dairy products, such as milk and cheese. The major isomer of CLA in natural food is cis-9,trans-11 (c9,t11). The commercial preparations contain approximately equal amounts of c9,t11 and trans-10,cis-12 (t10,c12) isomers. Studies have shown that CLA, specifically the t10,c12-isomer, can reduce fat tissue deposition and body lipid content but appears to induce insulin resistance and fatty liver and spleen in various animals. A few human studies suggest that CLA supplementation has no effect on body weight and could reduce body fat to a much lesser extent than in animals. To draw conclusions on this form of dietary supplementation and to ultimately make appropriate recommendations, further human studies are required. The postulated antiobesity mechanisms of CLA include decreased energy and food intakes, decreased lipogenesis, and increased energy expenditure, lipolysis, and fat oxidation. This review addresses recent studies of the effects of CLA on lipid metabolism, fat deposition, and body composition in both animals and humans as well as the mechanisms surrounding these effects. PMID: 15159250 [PubMed - indexed for MEDLINE] 4155. Physiol Behav. 2004 Apr;81(2):289-317. Energy balance and reproduction. Schneider JE(1). Author information: (1)Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA. js0v@lehigh.edu The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Thus, it is difficult to understand the physiology of energy balance without understanding its link to reproductive success. The metabolic sensory stimuli, hormonal mediators and modulators, and central neuropeptides that control reproduction also influence energy balance. In general, those that increase ingestive behavior inhibit reproductive processes, with a few exceptions. Reproductive processes, including the hypothalamic-pituitary-gonadal (HPG) system and the mechanisms that control sex behavior are most proximally sensitive to the availability of oxidizable metabolic fuels. The role of hormones, such as insulin and leptin, are not understood, but there are two possible ways they might control food intake and reproduction. They either mediate the effects of energy metabolism on reproduction or they modulate the availability of metabolic fuels in the brain or periphery. This review examines the neural pathways from fuel detectors to the central effector system emphasizing the following points: first, metabolic stimuli can directly influence the effector systems independently from the hormones that bind to these central effector systems. For example, in some cases, excess energy storage in adipose tissue causes deficits in the pool of oxidizable fuels available for the reproductive system. Thus, in such cases, reproduction is inhibited despite a high body fat content and high plasma concentrations of hormones that are thought to stimulate reproductive processes. The deficit in fuels creates a primary sensory stimulus that is inhibitory to the reproductive system, despite high concentrations of hormones, such as insulin and leptin. Second, hormones might influence the central effector systems [including gonadotropin-releasing hormone (GnRH) secretion and sex behavior] indirectly by modulating the metabolic stimulus. Third, the critical neural circuitry involves extrahypothalamic sites, such as the caudal brain stem, and projections from the brain stem to the forebrain. Catecholamines, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) are probably involved. Fourth, the metabolic stimuli and chemical messengers affect the motivation to engage in ingestive and sex behaviors instead of, or in addition to, affecting the ability to perform these behaviors. Finally, it is important to study these metabolic events and chemical messengers in a wider variety of species under natural or seminatural circumstances. Copyright 2004 Elsevier Inc. PMID: 15159173 [PubMed - indexed for MEDLINE] 4156. Physiol Behav. 2004 Apr;81(2):243-8. Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics. Collins S(1), Martin TL, Surwit RS, Robidoux J. Author information: (1)Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA. colli008@mc.duke.edu The development of the metabolic syndrome in an increasing percentage of the populations of Western societies, particularly in the United States, requires valid models for establishing basic biochemical changes and performing preclinical studies on potential drug targets. The C57BL/6J mouse has become an important model for understanding the interplay between genetic background and environmental challenges such as high-fat/high-calorie diets that predispose to the development of the metabolic syndrome. This review highlights metabolic and signal transduction features that are altered during the course of disease progression, many of which mirror the human situation. Copyright 2004 Elsevier Inc. PMID: 15159170 [PubMed - indexed for MEDLINE] 4157. Physiol Behav. 2004 Apr;81(2):223-41. Leptin signaling. Ahima RS(1), Osei SY. Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Pennsylvania School of Medicine, 415 Curie Boulevard, 764 Clinical Research Building, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu The discovery of leptin was a major breakthrough in our understanding of the role of adipose tissue as a storage and secretory organ. Leptin was initially thought to act mainly to prevent obesity; however, studies have demonstrated profound effects of leptin in the response to fasting, regulation of neuroendocrine and immune systems, hematopoiesis, bone and brain development. This review will focus on the signaling pathways which mediate these diverse effects of leptin in the brain and other physiologic systems. Copyright 2004 Elsevier Inc. PMID: 15159169 [PubMed - indexed for MEDLINE] 4158. Endocrinol Metab Clin North Am. 2004 Jun;33(2):431-53, table of contents. Metabolic syndrome: an appraisal of the pro-inflammatory and procoagulant status. Devaraj S(1), Rosenson RS, Jialal I. Author information: (1)Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4365 Second Avenue, Room 3000, Sacramento CA 95817, USA. Inflammation and hypercoagulability predispose to atherothrombosis and seem to be important features of the metabolic syndrome. The most convincing evidence is the association with increased levels of C-reactive protein. The hemostatic abnormality that has been most consistently associated with insulin resistance is an elevated plasminogen activator inhibitor-1 level. In contrast, markers of hypercoagulability have been associated inconsistently with hyperinsulinemia and glucose intolerance. Fibrinogen clusters with inflammatory factors, which suggests involvement of adipose tissue-generated inflammatory cytokines. Elevated von Willebrand's factor and factor VIII levels aggregate with indicators of endothelial injury,whereas vitamin K-dependent coagulation proteins correlate with triglyceride levels. PMID: 15158528 [PubMed - indexed for MEDLINE] 4159. Endocrinol Metab Clin North Am. 2004 Jun;33(2):305-31. Lipodystrophies: rare disorders causing metabolic syndrome. Garg A(1), Misra A. Author information: (1)Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052, USA. Recent advances in the understanding of the molecular basis of genetic lipodystrophies have promoted understanding of how adipose tissue disorders can cause the metabolic syndrome and its complications. These discoveries hold promise for elucidating pathways and mechanisms by which common disorders of obesity cause metabolic complications. Novel therapeutic approaches for patients with lipodystrophies also may have implications for treatment of the metabolic syndrome in patients with regional adiposity. This article reviews these recent advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or other bases of various types of lipodystrophies. PMID: 15158521 [PubMed - indexed for MEDLINE] 4160. Clin Lab Med. 2004 Mar;24(1):217-34. Adipocyte biology and adipocytokines. Haque WA(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Adipose tissue actively participates in regulation of food intake, energy expenditure, fuel metabolism, and a variety of other physiologic processes through its endocrine, paracrine, and autocrine secretory products (Table 4). Abnormal synthesis of these secretory products may be related to the pathogenesis of insulin resistance and its complications in patients who have adipose tissue disorders, such as obesity and lipodvstrophies. PMID: 15157564 [PubMed - indexed for MEDLINE] 4161. Duodecim. 2004;120(7):799-805. [Nuclear lamins and their diseases]. [Article in Finnish] Taimen P(1), Kalimo H, Kallajoki M. Author information: (1)Turun yliopisto, kliinis-teoreettinen laitos, patologia MediCity-tutkimuslaboratorio Tykistökatu 6 A, 4. kerros 20520 Turku. pekka.taimen@utu.fi PMID: 15154299 [PubMed - indexed for MEDLINE] 4162. Expert Rev Cardiovasc Ther. 2004 Mar;2(2):213-28. Treatment of metabolic syndrome. Wagh A(1), Stone NJ. Author information: (1)Departments of Endocrinology and Cardiology, Feinberg School of Medicine, Northwestern University, 211 E Chicago Avenue, 1050 Chicago, Il 60611, USA. The metabolic syndrome is intended to identify patients who have increased risk of diabetes and/or a cardiac event due to the deleterious effects of weight gain, sedentary lifestyle, and/or an atherogenic diet. The National Cholesterol Education Program's Adult Treatment Panel III definition uses easily measured clinical findings of increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. The authors also note that other definitions of metabolic syndrome focus more on insulin resistance and its key role in this syndrome. This review focuses on how treatment might affect each of the five components. Abdominal obesity can be treated with a variety of lower calorie diets along with regular exercise. Indeed, all of the five components of the metabolic syndrome are improved by even modest amounts of weight loss achieved with diet and exercise. For those with impaired fasting glucose tolerance, there is good evidence that a high fiber, low saturated fat diet with increased daily exercise can reduce the incidence of diabetes by almost 60%. Of note, subjects who exercise the most, gain the most benefit. Metformin has also been shown to be helpful in these subjects. Thiazolidinedione drugs may prove useful, but further studies are needed. Although intensified therapeutic lifestyle change will help the abnormal lipid profile, some patients may require drug therapy. This review also discusses the use of statins, fibrates, and niacin. Likewise, while hypertension in the metabolic syndrome benefits from therapeutic lifestyle change, physicians should also consider angiotensin converting enzyme inhibitor drugs or angiotensin receptor blockers, due to their effects on preventing complications of diabetes, such as progression of diabetic nephropathy and due to their effects on regression of left ventricular hypertrophy. Aspirin should be considered in those with at least a 10% risk of a coronary event over 10 years. Finally, three related conditions, nonalcoholic fatty liver disease, polycystic ovary syndrome and protease inhibitor associated lipodystrophy improve with therapeutic lifestyle change. Although metformin is shown to be useful with polycystic ovary syndrome, the data supporting drug therapy for the other syndromes is less convincing. More robust studies are needed before any firm recommendations can be made. PMID: 15151470 [PubMed - indexed for MEDLINE] 4163. Expert Rev Cardiovasc Ther. 2004 Mar;2(2):193-201. Impact of bariatric surgery on cardiac structure, function and clinical manifestations in morbid obesity. Poirier P(1), Martin J, Marceau P, Biron S, Marceau S. Author information: (1)Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie, Laval Hospital, 2725 Chemin Sainte-Foy, Sainte-Foy, Québec, G1V 4G5, Canada. Paul.Poirier@crhl.ulaval.ca Obesity results from the excessive accumulation of fat. Risk of premature death is doubled compared to nonobese individuals, and risk of death from cardiovascular disease is increased fivefold. In patients with morbid obesity, a variety of adaptations and alterations in cardiac structure and function occur in the individual, as an excess amount of adipose tissue accumulates. The high long-term failure rate of diet intervention is well acknowledged by the clinician. Surgery for severe obesity has evolved during the last 40 years. Many surgical techniques have been described and abandoned. Nevertheless, numerous different techniques are still in use today. Weight loss has beneficial impacts on functional and structural cardiac status and will be reviewed in this report. PMID: 15151468 [PubMed - indexed for MEDLINE] 4164. Clin Chim Acta. 2004 Jun;344(1-2):1-12. Adiponectin and atherosclerotic disease. Shimada K(1), Miyazaki T, Daida H. Author information: (1)Department of Cardiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-k, Tokyo 113-8421, Japan. shimakaz@med.juntendo.ac.jp Adiponectin has been identified as one of the "adipocytokines" that are derived only from adipose tissue, and are abundantly present in circulating blood. Adiponectin has protective actions in the initiation and progression of atherosclerosis through anti-inflammatory and anti-atherogenic effects. Adiponectin levels are decreased in obesity, type 2 diabetes, and patients with coronary artery disease (CAD). Adiponectin levels were negatively correlated with the CRP levels in patients with CAD. Adiponectin plays a crucial role in the association between obesity, type 2 diabetes, and insulin resistance. Mechanisms explaining the relationship between adiponectin and insulin resistance suggest that adiponectin and tumor necrosis factor (TNF)-alpha inhibited each other's expression and production in adipocytes. Thiazolidinediones, which are insulin-sensitizing agents, increased the production of adiponectin through directly enhancing its gene expression. The C-terminal globular domain of adiponectin may play a central role in the protective effects against atherosclerosis. Adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) are expressed ubiquitously in most organs, especially in skeletal muscle in AdipoR1, and liver in AdipoR2. With the prospect of future basic and clinical research on the molecular structure-receptor relationship, adiponectin could become a promising target for future investigations in reducing the morbidity and mortality of atherosclerotic disease. Copyright 2004 Elsevier B.V. PMID: 15149866 [PubMed - indexed for MEDLINE] 4165. Clin Ter. 2004 Jan;155(1):29-31. [Leptin and hypothalamus-hypophysis-thyroid axis]. [Article in Italian] Riccioni G(1), Menna V, Lambo MS, Della Vecchia R, Di Ilio C, De Lorenzo A, D'Orazio N. Author information: (1)Human Nutrition, Departement of Biomedical Sciences, University "G. D' Annunzio", Chieti, Italy. griccioni@hotmail.com The leptin system is a major regulator of food intake and metabolic rate. The leptin, an adipose tissue hormone whose plasma levels reflect energy stores, plays an important rule in the pathogenesis of such eating disorders like bulimia and anorexia. Thyroid hormones are major regulators of energy homeostasis. It is possible that leptin and thyroid hormone exert their actions on thermogenesis and energy metabolism via the same common effector patways. Leptin influences feedback regulation of the hypotalamic TRH-secreting neurons by thyroid hormone. Low serum levels of thyroid hormones reflect a dysfunction of the hypotalamic-pituitary-thyroid (HPT) and hypotalamic-pituitary-adrenal (HPA) axis in patients with nervosa anorexia. Neuroendocrine effects of leptin include effects on the HPT and HPA axis. The aim of this work is to evaluated the interactions between leptina and HPT axis on the basis of recent published works and reviews in literature. PMID: 15147079 [PubMed - indexed for MEDLINE] 4166. Bull Acad Natl Med. 2003;187(7):1357-63; discussion 1364-6. [Adipose tissue: new aspects]. [Article in French] Dugail I(1). Author information: (1)INSERM U465, 15 rue de l'Ecole de médecine, 75006 Paris. During the last past years, obesity had become a major public health problem, and new aspects of fat cells biology have been unraveled. First, since the discovery of leptin, the adipocytes has been recognized as true endocrine cells secreting a variety of factors in a regulated manner. The role of these factors on the development of obesity-associated metabolic complications is becoming increasingly clear. Also, the process of fat cell differentiation has been uncovered, leading to the possibility of efficient targeting protein expression in adipose tissue. Finally, lines of transgenic mice have been created, some of which are totally resistant to obesity. These models led to the identification of new potential adipose targets for the treatment of obesity. PMID: 15146609 [PubMed - indexed for MEDLINE] 4167. Bull Acad Natl Med. 2003;187(7):1343-52; discussion 1352-5. [Natural history of obesity]. [Article in French] Basdevant A(1). Author information: (1)Service de Nutrition, Hôtel-Dieu, Université Paris 6, 75181 Paris. Obesity is a chronic disease. At the initial phase, behavioral and environmental factors play a key role in the constitution of adipose tissue excess. Progressively biological alterations of adipose tissue metabolism lead to some degree of irreversibility of the disease and contribute to the development of its metabolic and cardio-vascular complications. PMID: 15146608 [PubMed - indexed for MEDLINE] 4168. Bull Acad Natl Med. 2003;187(7):1225-43; discussion 1244-7. [Physiology of somatotropic axis: interest of gene inactivation experiments]. [Article in French] Le Bouc Y(1), Gicquel C, Holzenberger M. Author information: (1)Hôpital d'Enfants Armand-Trousseau 75571 Paris, 26 Avenue du Docteur Arnold Netter. Research into the somatotropic axis (growth hormone, insulin-like growth factors) has received renewed attention in the last few years, owing to techniques for genetic modification in the mouse, essentially transgenesis, and gene inactivation. The results, compared with phenotypic and molecular data for various pathological conditions, e.g. short stature, have increased our understanding of the function of the various parameters of the somatotropic axis, especially those of the insulin-like growth factor (IGF) system. During fetal development, IGF-II (which is subject to imprinting) and IGF-I are essential for increases in height and weight and for development of the various organs, adipose tissue in particular. The action of these two IGF is mediated by the IGF type 1 receptor. Total inactivation of the IGF-I gene, the paternal allele of the IGF-II gene or the IGF type 1 receptor gene leads to growth retardation resulting in mouse fetuses weighing only 60%, 60% and 45% of their wild-type controls. Combinations of these inactivations have shown that IGF-II also exerts its effects by interacting with another, as yet uncharacterized receptor. Moreover, inactivation of the IGF-I gene specifically in the liver, organ which normally maintains the high IGF-I concentrations in the blood (endocrine action), has no effect on growth, demonstrating that local IGF-I plays an auto/paracrine role in the periphery, under the direct influence of growth hormone (GH). However, endocrine IGF-I plays an important role in metabolism and cellular proliferation, and its function in mitosis may favor the development of cancer in the breast, colon and prostate. Mice with homozygous inactivation of the IGF type 1 receptor gene are not viable after birth. Partial and conditional inactivation have made it possible to study the physiology of these factors in adult animals. In contrast to IGF-II, the IGF type 1 receptor is, like IGF-I, involved in postnatal growth regulation. Lack of IGF type 1 receptor or of IGF-I affects both height and weight, and shows that this receptor is particularly involved in promoting pubertal growth. The activated receptor acts differently and specifically in each tissue. Finally, the IGF type 1 receptor has recently been implicated in the control of lifespan: a 50% decrease in the number of receptors increased the lifespan of these mice by 26%. This increase displayed sexual dimorphism, being greater for females (33%) than for males (16%). Invalidations combining different properties--specificities according to tissue, development stage or inducibility by an exogenous product--will facilitate fine dissection of the roles of the various ubiquitous actors in the IGF system. PMID: 15146601 [PubMed - indexed for MEDLINE] 4169. Endocrine. 2004 Mar-Apr;23(2-3):183-8. Bone and fat: old questions, new insights. Gimble JM(1), Nuttall ME. Author information: (1)Pennington Biomedical Research Center, LSU, 6400 Perkins Rd, Baton Rouge, LA,70808, USA. gimblejm@pbrc.edu Until recently, adipose tissue was considered to serve only as a triglyceride reservoir and was relegated to a passive endocrine role. With the discovery of leptin and other adipokines, adipose tissue is now recognized as an active participant in systemic metabolism. This review focuses on the complex relationship existing between adipose tissue and bone metabolism and differentiation. It explores the paradigms that have shaped the past decade's research and what these findings forecast for the future. Particular attention is given to the multipotent adult stem cell populations that reside within bone and fat. These adult stem cells have critical importance to the emerging field of tissue engineering and regenerative medicine. Copyright 2004 Humana Press Inc. PMID: 15146099 [PubMed - indexed for MEDLINE] 4170. Cancer Causes Control. 2004 May;15(4):367-86. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Astorg P(1). Author information: (1)UMR U557 INSERM/INRA/CNAM Epidémiologie Nutritionnelle, Institut Scientifique et Technique de la Nutrition et de l'Alimentation, Conservatoire National des Arts et Métiers, 5 rue du Vertbois, 75003 Paris, France. pierre.astorg@cnam.fr OBJECTIVE: This study reviews epidemiological and experimental works dealing with the effects of dietary n -6 or n -3 polyunsaturated fatty acids (PUFA) on prostate cancer (PCa) development and PCa risk. METHODS: Systematic literature searches were made using Medline. The epidemiological studies reviewed (ecological, case-control, cohorts, and nested case-control) were those having tested the association of PCa risk with the dietary intake or the blood or adipose tissue levels of PUFA ( n -6 PUFA, n -3 PUFA, long-chain n -3 PUFA, linoleic acid, alpha -linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid), and with the dietary intake of fish and seafood. Experimental studies dealing with the effects of PUFA on PCa development in animal models or with PCa cell growth in vitro were also reviewed, as well as studies on the mechanisms of the effects of PUFA on PCa. RESULTS: There is no or little evidence of an association of linoleic or arachidonic acids with PCa risk. Most epidemiological studies failed to find an association of PCa risk with fish or long-chain n -3 PUFA intake, but two recent cohort studies did find an inverse association of fish consumption with the risk of the latest stages of PCa. alpha -linolenic acid intake was associated with an increase of PCa risk in a majority of epidemiological studies, but other studies did not find this association. Experimental work in vitro and in vivo, as well as mechanistic studies, support a protective effect of long-chain n -3 PUFA on PCa, but data on the effects of linoleic and alpha -linolenic acids are scarce. CONCLUSIONS: Long-chain n -3 PUFA from fish are possible promising nutrients for the dietary prevention of PCa, but to-date with little epidemiological support. In contrast, studies suggest that alpha -linolenic acid intake might be a risk factor. New work, both epidemiological and experimental, is awaited to clarify these results. PMID: 15141138 [PubMed - indexed for MEDLINE] 4171. Curr Opin Pharmacol. 2004 Jun;4(3):281-9. The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Nawrocki AR(1), Scherer PE. Author information: (1)Department of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. Adipose tissue has evolved as a complex organ with functions far beyond the mere storage of energy. Chronic oversupply of calories, common to Western-style diets, frequently goes hand-in-hand with an altered secretion pattern of adipokines and elevated plasma free fatty acid levels, known to modulate insulin sensitivity in skeletal muscle. Intramyocellular accumulation of lipids directly attenuates insulin signaling within myocytes via distinct kinases. Obesity is also accompanied by an enhanced basal inflammatory tone, originating from adipocytes and adipose tissue-associated macrophages. In addition, adipocytes accumulate within the skeletal muscle and exert direct paracrine effects on muscle insulin sensitivity. PMID: 15140421 [PubMed - indexed for MEDLINE] 4172. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):127-36. Expression and function of the human mineralocorticoid receptor: lessons from transgenic mouse models. Le Menuet D(1), Viengchareun S, Muffat-Joly M, Zennaro MC, Lombès M. Author information: (1)Inserm U478, 16 rue Henri Huchard, Faculté de Médecine Xavier Bichat, 75870 Paris cedex 18, France. The human mineralocorticoid receptor (hMR), a ligand-dependent transcription factor (NR3C2) which belongs to the nuclear receptor superfamily, mediates most of the known effects of aldosterone. Beside its involvement in the regulation of sodium balance and the control of blood pressure, aldosterone-hMR tandem also exerts important regulatory functions on the cardiovascular and central nervous systems. To study the molecular mechanisms involved in the tissue-specific expression of hMR and explore its functional implication in pathophysiology, transgenic mouse models have been generated using both targeted oncogenesis and MR overexpression. We have previously demonstrated that the transcription of hMR is directed by two alternative promoters, P1 and P2, which correspond to the 5'-flanking regions of the untranslated exons 1alpha and 1beta of the hMR gene, respectively. Utilization of P1 and P2 to drive expression of the SV40 large T antigen (TAg) in transgenic mice led us (i) to determine distinct tissue-specific patterns of promoter usage; (ii) to identify novel sites of MR expression including brown adipose tissue, thus providing a new functional link between aldosterone and energy homeostasis; (iii) to generate original immortalized cell lines derived from numerous aldosterone-sensitive tissues most notably distal nephron, brown fat, skin, liver, lung, brain, heart, blood vessels and inner ear. These differentiated cell lines represent suitable models to further explore cell-specific mineralocorticoid responses and cross-talk with other signaling pathways. Generation of transgenic mice in which hMR expression was directed by P1 promoter demonstrated the importance of MR in the cardiac and renal function. Morphological and functional alterations of the renal tubule were observed with basal decreased sodium/potassium ratio exacerbated under sodium depletion. Hypokinetic dilated cardiomyopathies were associated with tachycardia, arrhythmia but normal arterial blood pressure emphasizing the direct role of MR on cardiomyocyte function. Taken together, transgenic animal models constitute valuable experimental systems to gain new insights into the widespread and pleiotropic in vivo functions of MR. PMID: 15134811 [PubMed - indexed for MEDLINE] 4173. Curr Opin Investig Drugs. 2004 Apr;5(4):411-8. Inhibition of glycerol-3-phosphate acyltransferase as a potential treatment for insulin resistance and type 2 diabetes. Thuresson ER(1). Author information: (1)Biovitrum AB, Department of Biology, Strandbergsgatan 49, S-1 1276 Stockholm, Sweden. Eva.Rupp-Thuresson@biovitrum.com This review focuses on the potential of glycerol-3-phosphate acyltransferase (GPAT) inhibition as a strategy to treat insulin resistance, one of the characteristics of obesity and type 2 diabetes. Inhibition of GPAT, which catalyzes the first and committed step in triacylglyceride synthesis, has the potential to reduce accumulation of ectopic fat in insulin-sensitive organs such as the liver and skeletal muscle. Such an accumulation of fat has been shown to be correlated with insulin resistance. Thus, its reduction by pharmacological treatment is an attractive strategy to treat type 2 diabetes. Potential methods to identify inhibitors for acyltransferases suitable for treatment of human diseases are described. PMID: 15134282 [PubMed - indexed for MEDLINE] 4174. Antivir Ther. 2004 Apr;9(2):161-77. Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Gougeon ML(1), Pénicaud L, Fromenty B, Leclercq P, Viard JP, Capeau J. Author information: (1)Unité d'Immunité Anti-virale, Biothérapie et Vaccins, Département de Medecine Moleculaire, Institut Pasteur, Paris, France. mlgougeo@pasteur.fr The recent clinical use of potent HIV-1 drugs, including nucleoside reverse transcriptase inhibitors (NRTIs) and non-peptidic viral protease inhibitors (PIs), and their combinations, termed highly active antiretroviral therapy (HAART), has dramatically reduced the infection-related mortality of AIDS patients, but it is associated with severe metabolic adverse events such as lipodystrophy syndrome, dyslipidaemia, insulin resistance and diabetes mellitus. The aetiology of this syndrome and metabolic alterations appear to be multifactorial, including HIV drug inhibitory effects on adipocyte differentiation, alteration of mitochondrial functions in adipocytes and altered leptin, adiponectin and cytokine expression in adipose tissue of patients. Adipose tissue may thus be a central regulator in disorganized lipid metabolism and insulin resistance associated with antiretroviral therapy, and we propose in this review to explore how adipose tissue may be a target, but also an actor, in the aetiopathogenesis of the lipodystrophy syndrome. PMID: 15134178 [PubMed - indexed for MEDLINE] 4175. Curr Diab Rep. 2004 Jun;4(3):219-23. Diabetes in African Americans: unique pathophysiologic features. Banerji MA(1). Author information: (1)SUNY Health Science Center, 450 Clarkson Avenue, Box 123, Brooklyn, NY 11203, USA. mbanerji@downstate.edu Type 2 diabetes is an increasing public health problem among African Americans, especially children. Several features make type 2 diabetes among African Americans unique. First, African-American adults with type 2 diabetes, or Flatbush diabetes, present with diabetic ketoacidosis. Patients are insulin resistant with acute, severe defects in insulin secretion and no islet cell autoantibodies. Following treatment, some insulin secretory capacity is recovered and ketoacidosis generally does not recur. The second is remission in African Americans with type 2 diabetes. Recovery of glucose homeostasis, accompanied by recovery of beta-cell function, follows intensive glycemic regulation. Finally, among African Americans with diabetes who are not obese, normal insulin sensitivity is not uncommon. Such individuals do not have the increased cardiovascular risk of insulin-resistant individuals. Differences in visceral, not subcutaneous, adipose tissue volume appear to determine insulin sensitivity. Understanding the unique physiologic and clinical features of African Americans is critical in designing appropriate treatment strategies. PMID: 15132889 [PubMed - indexed for MEDLINE] 4176. J Nutr Health Aging. 2004;8(3):163-74. Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing. Bourre JM(1). Author information: (1)INSERM Research Director. Unit U26 Neuro-pharmaco-nutrition. Hopital Fernand Widal, 200 rue du Faubourg Saint Denis. 75745 Paris cedex 10. jean-marie.bourre@fwidal.inserm.fr Among various organs, in the brain, the fatty acids most extensively studied are omega-3 fatty acids. Alpha-linolenic acid (18:3omega3) deficiency alters the structure and function of membranes and induces minor cerebral dysfunctions, as demonstrated in animal models and subsequently in human infants. Even though the brain is materially an organ like any other, that is to say elaborated from substances present in the diet (sometimes exclusively), for long it was not accepted that food can have an influence on brain structure, and thus on its function. Lipids, and especially omega-3 fatty acids, provided the first coherent experimental demonstration of the effect of diet (nutrients) on the structure and function of the brain. In fact the brain, after adipose tissue, is the organ richest in lipids, whose only role is to participate in membrane structure. First it was shown that the differentiation and functioning of cultured brain cells requires not only alpha-linolenic acid (the major component of the omega-3, omega3 family), but also the very long omega-3 and omega-6 carbon chains (1). It was then demonstrated that alpha-linolenic acid deficiency alters the course of brain development, perturbs the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (2). This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioural upset (3). Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Recent results have shown that dietary alpha-linolenic acid deficiency induces more marked abnormalities in certain cerebral structures than in others, as the frontal cortex and pituitary gland are more severely affected. These selective lesions are accompanied by behavioural disorders more particularly affecting certain tests (habituation, adaptation to new situations). Biochemical and behavioural abnormalities are partially reversed by a dietary phospholipid supplement, especially omega-3-rich egg yolk extracts or pig brain. A dose-effect study showed that animal phospholipids are more effective than plant phospholipids to reverse the consequences of alpha-linolenic acid deficiency, partly because they provide very long preformed chains. Alpha-linolenic acid deficiency decreases the perception of pleasure, by slightly altering the efficacy of sensory organs and by affecting certain cerebral structures. Age-related impairment of hearing, vision and smell is due to both decreased efficacy of the parts of the brain concerned and disorders of sensory receptors, particularly of the inner ear or retina. For example, a given level of perception of a sweet taste requires a larger quantity of sugar in subjects with alpha-linolenic acid deficiency. In view of occidental eating habits, as omega-6 fatty acid deficiency has never been observed, its impact on the brain has not been studied. In contrast, omega-9 fatty acid deficiency, specifically oleic acid deficiency, induces a reduction of this fatty acid in many tissues, except the brain (but the sciatic nerve is affected). This fatty acid is therefore not synthesized in sufficient quantities, at least during pregnancy-lactation, implying a need for dietary intake. It must be remembered that organization of the neurons is almost complete several weeks before birth, and that these neurons remain for the subject's life time. Consequently, any disturbance of these neurons, an alteration of their connections, and impaired turnover of their constituents at any stage of life, will tend to accelerate ageing. The enzymatic activities of sytivities of synthesis of long-chain polyunsaturated fatty acids from linoleic and alpha-linolenic acids are very limited in the brain: this organ therefore depends on an exogenous supply. Consequently, fatty acids that are essential for the brain are arachidonic acid and cervonic acid, derived from the diet, unless they are synthesized by the liver from linoleic acid and alpha-linolenic acid. The age-related reduction of hepatic desaturase activities (which participate in the synthesis of long chains, together with elongases) can impair turnover of cerebral membranes. In many structures, especially in the frontal cortex, a reduction of cervonic and arachidonic acids is observed during ageing, predominantly associated with a reduction of phosphatidylethanolamines (mainly in the form of plasmalogens). Peroxisomal oxidation of polyunsaturated fatty acids decreases in the brain during ageing, participating in decreased turnover of membrane fatty acids, which are also less effectively protected against peroxidation by free radicals. PMID: 15129302 [PubMed - indexed for MEDLINE] 4177. Curr Hypertens Rep. 2004 Jun;6(3):241-6. The global epidemic of obesity: are we becoming more sympathetic? Davy KP(1). Author information: (1)Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, 215 War Memorial Hall (0351), Blacksburg, VA 24061, USA. kdavy@vt.edu The relationship between obesity and sympathetic nervous system (SNS) behavior has been controversial. Existing paradigms have been opposed in their views of the directional changes in SNS activity in obesity. In addition, limitations of previous approaches to assess SNS activity have produced inconsistent findings. However, the use of state-of-the-art neurochemical and neurophysiologic techniques has improved our current understanding of this issue. There is regional heterogeneity in the SNS activation associated with obesity, with the renal and skeletal muscle circulations, but not the heart, being targets for SNS activation. Abdominal visceral fat appears to be an important depot linking obesity and skeletal muscle SNS activation. The impact of this depot on SNS activity to the kidney or other regions is unknown. Future studies are needed to address this issue as well as the mechanisms and consequences of SNS activation in visceral obesity. PMID: 15128479 [PubMed - indexed for MEDLINE] 4178. Sheng Li Ke Xue Jin Zhan. 2004 Jan;35(1):7-12. [Adipocyte differentiation and its regulation]. [Article in Chinese] Zhang CB(1). Author information: (1)College of Life Sciences, Peking University, Beijing 100871. Fat tissue and adipocytes have been exclusively investigated in the past two decades, especially in the last ten years, due to the following two reasons. Firstly, more and more studies showed that fat tissue is not only an organ for energy storage, but also an endocrine one that can secret many kinds of hormones or hormone-like peptides. Secondly, the established preadipocyte cell lines have been providing powerful tools for the in vitro research of adipocyte differentiation, because these immortal cell lines authentically represent, to a great extend, the in vivo situations of these cells and can be induced to differentiate into mature adipose cells with proper hormones. It has been demonstrated that there exists close relations between adipocyte differentiation and many physiological or pathological processes including saccharide and fat metabolism, energy balance, obesity, diabetes, hyperlipidemia and breast cancer. It is very important to make known the differentiation mechanisms of preadipocyte into adipocyte for understanding the above mentioned diseases and for screening anti-obesity and anti-diabetes drugs. PMID: 15127590 [PubMed - indexed for MEDLINE] 4179. Spinal Cord. 2004 May;42(5):313-6. Lumbar spinal angiolipomas: report of two cases and review of the literature. Rocchi G(1), Caroli E, Frati A, Cimatti M, Savlati M. Author information: (1)Department of Neurological Sciences, Neurosurgery, University of Rome La Sapienza, Italy. STUDY DESIGN: Case report and review of the literature. OBJECTIVES: To describe two patients with angiolipoma in the ventral aspect of the lumbar epidural space, to discuss the clinical, radiologic, and surgical features of these lesions, and to review previously reported cases. SETTING: Rome, Italy. METHODS: Two cases, a 60-year-old man and a 54-year-old woman presented with lumbar-sciatic pain but with no abnormal neurological signs. Investigation (CT and MRI) demonstrated lumbar tumours. RESULTS: Laminectomy and excision of the tumors were performed, and symptoms improved immediately. CONCLUSIONS: Magnetic resonance imaging with suppression fat sequences allows the recognition of these lesions. The prognosis after surgical removal of spinal angiolipoma is favorable. PMID: 15123997 [PubMed - indexed for MEDLINE] 4180. Ann Endocrinol (Paris). 2004 Feb;65(1):51-9. Mouse models of insulin resistance and type 2 diabetes. Postic C(1), Mauvais-Jarvis F, Girard J. Author information: (1)Département d'Endocrinologie, Institut Cochin, INSERM U567, CNRS UMR8104 Université Paris V René Descartes, 24, rue du Faubourg Saint Jacques, 75014 Paris, France. postic@cochin.inserm.fr PMID: 15122092 [PubMed - indexed for MEDLINE] 4181. Ann Endocrinol (Paris). 2004 Feb;65(1):43-8. Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. Tanti JF(1), Gual P, Grémeaux T, Gonzalez T, Barrès R, Le Marchand-Brustel Y. Author information: (1)INSERM Unité U 568, Faculty of Medicine, avenue de Valombrose, 06107 Nice Cedex 02, France. tanti@unice.fr Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes. PMID: 15122091 [PubMed - indexed for MEDLINE] 4182. Atheroscler Suppl. 2004 May;5(2):19-24. Insights from apoB: from better diagnosis & therapy to the Medusa Hypothesis. Sniderman A(1), Williams K, Haffner S, Sattar N. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Center, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada. allan.sniderman@muhc.mcgill.ca This article will review six of the most important insights that have come from the measurement of apolipoprotein B (apoB). Amongst these are critical clinical advances, which include better definition of those at high risk of vascular disease and better definition of the adequacy of statin therapy. There are also major advances in our understanding of the fundamental processes that interact to cause vascular disease. These include a more precise understanding of the determinants of lipoprotein levels and lipoprotein composition in plasma and, even more importantly, an appreciation of the pivotal role excess fatty acid intake and impaired fatty acid trapping by adipose tissue play in the generation of the complex risk profile that is so common in patients with coronary disease. We have designated the constellation of hypertriglyceridemic (hyperTg) hyperapoB, dysglycemia, and elevated levels of markers of prothrombosis and inflammation--all of which are traceable to adipose tissue dysfunction--as the Medusa Hypothesis. The Medusa Hypothesis puts forward a common pathophysiology for the complex and biologically diverse array of factors that have been associated with vascular disease. PMID: 15121031 [PubMed - indexed for MEDLINE] 4183. Physiol Res. 2004;53 Suppl 1:S199-211. Mitochondrial uncoupling proteins--facts and fantasies. Jezek P(1), Zácková M, Růzicka M, Skobisová E, Jabůrek M. Author information: (1)Department of Membrane Transport Biophysics, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. jezek@biomed.cas.cz Instead of a comprehensive review, we describe the basic undisputed facts and a modest contribution of our group to the fascinating area of the research on mitochondrial uncoupling proteins. After defining the terms uncoupling, leak, protein-mediated uncoupling, we discuss the assumption that due to their low abundance the novel mitochondrial uncoupling proteins (UCP2 to UCP5) can provide only a mild uncoupling, i.e. can decrease the proton motive force by several mV only. Contrary to this, the highly thermogenic role of UCP1 in brown adipose tissue is not given only by its high content (approximately 5 % of mitochondrial proteins) but also by the low ATP synthase content and high capacity respiratory chain. Fatty acid cycling mechanism as a plausible explanation for the protonophoretic function of all UCPs and some other mitochondrial carriers is described together with the experiments supporting it. The phylogenesis of all UCPs, estimated UCP2 content in several tissues, and details of UCP2 activation are described on the basis of our experiments. Functional activation of UCP2 is proposed to decrease reactive oxygen species (ROS) production. Moreover, reaction products of lipoperoxidation such as cleaved hydroperoxy-fatty acids and hydroxy-fatty acid can activate UCP2 and promote feedback down-regulation of mitochondrial ROS production. PMID: 15119950 [PubMed - indexed for MEDLINE] 4184. Physiol Res. 2004;53 Suppl 1:S141-52. Biochemistry of transmembrane signaling mediated by trimeric G proteins. Svoboda P(1), Teisinger J, Novotný J, Bourová L, Drmota T, Hejnová L, Moravcová Z, Lisý V, Rudajev V, Stöhr J, Vokurková A, Svandová I, Durchánková D. Author information: (1)Department of Membrane Receptors, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. svobodap@biomed.cas.cz Many extracellular signals are at the cell surface received by specific receptors, which upon activation transduce information to the appropriate cellular effector molecules via trimeric G proteins. The G protein-mediated cascades ultimately lead to the highly refined regulation of systems such as sensory perception, cell growth, and hormonal regulation. Transmembrane signaling may be seriously deranged in various pathophysiological conditions. Over the last two decades the major experimental effort of our group has been devoted to better understanding the molecular mechanisms underlying transmembrane signaling regulated by G proteins and to the closely related process of desensitization of hormone response. This review provides general information about the basic principles of G protein-regulated transmembrane signaling as well as about our contribution to the current progress in the field. PMID: 15119945 [PubMed - indexed for MEDLINE] 4185. Med Clin (Barc). 2004 Apr 17;122(14):542-51. [Obesity studies in candidate genes]. [Article in Spanish] Ochoa Mdel C(1), Martí A, Martínez JA. Author information: (1)Departamento de Fisiología y Nutrición, Universidad de Navarra, Pamplona, Spain. There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions. PMID: 15117649 [PubMed - indexed for MEDLINE] 4186. Diabetologia. 2004 May;47(5):770-81. Epub 2004 Apr 28. Control of glycaemia: from molecules to men. Minkowski Lecture 2003. Stumvoll M(1). Author information: (1)3rd Medical Department, University of Leipzig, Philipp-Rosenthal-Str. 27, 04301 Leipzig, Germany. michael.stumvoll@medizin.uni-leipzig.de Regulation of glycaemia represents a fundamental biological principle, and its failure underlies Type 2 diabetes. The complex aetiology of Type 2 diabetes, which probably involves a medley of molecular mechanisms, requires dissection out of diabetes-associated subphenotypes, such as the non-obese with increased liver fat or the obese with low plasma adiponectin. The concepts of the hyperbolic relationship of insulin secretion and insulin sensitivity with glucose allostasis help us to establish the pathophysiological framework within which such mechanisms must operate. The translation of burgeoning new basic science findings into a physiological and clinical context calls for novel and imaginative clinical experimental tools. For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-gamma [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. These include procedures as diverse as isotope dilution for turnover studies (e.g. glycerol turnover as a proxy for lipolysis), conventional and modified clamp procedures, association studies of functionally relevant single nucleotide polymorphisms in candidate genes (e.g. IRS-1 and PPAR gamma), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. A concerted effort by scientists from many disciplines (genetics and cell biology, physiology and epidemiology) will be required to bridge the growing gap between basic scientific concepts of biological modifiers of glycaemia and concepts that are truly relevant for human Type 2 diabetes. PMID: 15114471 [PubMed - indexed for MEDLINE] 4187. Am J Clin Nutr. 2004 May;79(5):907S-912S. Role of calcium and dairy products in energy partitioning and weight management. Zemel MB(1). Author information: (1)University of Tennessee Nutrition Institute, 1215 West Cumberland Avenue, Room 229, Knoxville, TN 37996-1920, USA. mzemel@itk.edu Dietary calcium plays a pivotal role in the regulation of energy metabolism because high-calcium diets attenuate adipocyte lipid accretion and weight gain during the overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, which thereby markedly accelerates weight loss. Intracellular Ca(2+) plays a key regulatory role in adipocyte lipid metabolism and triacylglycerol storage; increased intracellular Ca(2+) results in the stimulation of lipogenic gene expression and lipogenesis and the suppression of lipolysis, which results in increased lipid filling and increased adiposity. Moreover, the increased calcitriol produced in response to low-calcium diets stimulates adipocyte Ca(2+) influx and, consequently, promotes adiposity, whereas higher-calcium diets inhibit lipogenesis, inhibit diet-induced obesity in mice, and promote lipolysis, lipid oxidation, and thermogenesis. Notably, dairy sources of calcium markedly attenuate weight and fat gain and accelerate fat loss to a greater degree than do supplemental sources of calcium. This augmented effect of dairy products relative to supplemental calcium is likely due to additional bioactive compounds, including the angiotensin-converting enzyme inhibitors and the rich concentration of branched-chain amino acids in whey, which act synergistically with calcium to attenuate adiposity. These concepts are confirmed by epidemiologic data and recent clinical trials, which indicate that diets that include > or =3 daily servings of dairy products result in significant reductions in adipose tissue mass in obese humans in the absence of caloric restriction and markedly accelerate weight and body fat loss secondary to caloric restriction compared with diets low in dairy products. These data indicate an important role for dairy products in both the prevention and treatment of obesity. PMID: 15113738 [PubMed - indexed for MEDLINE] 4188. Ann Pharm Fr. 2004 Mar;62(2):87-91. [New insights into adipose cell biology]. [Article in French] Dugail I(1). Author information: (1)INSERM U465, Nutrition, Métabolisme, Obésité, 15, rue de l'Ecole de Médecine, F75006 Paris. During the last past Years, obesity had become a major public health problem, and new aspects of fat cells biology have been unraveled. First, since the discovery of leptin, adipocytes have been recognized as true endocrine cells secreting a variety of factors in a regulated manner. The role of these factors on the development of obesity-associated metabolic complications is becoming increasingly clear. Also, the process of fat cell differentiation has been uncovered, leading to the possibility of efficient targeting protein expression in adipose tIssue. Finally, lines of transgenic mice have been created, some of which are totally resistant to obesity. These models led to the identification of new potential adipose targets for the treatment of obesity. PMID: 15107725 [PubMed - indexed for MEDLINE] 4189. Ann Pharm Fr. 2004 Mar;62(2):80-6. [Natural course of obesities]. [Article in French] Basdevant A(1). Author information: (1)Service de Nutrition, Hôtel Dieu, F75181 Paris Cedex 04. Obesity is a chronic disease. At the initial phase, behavioral and environmental factors play a key role in the constitution of adipose tIssue excess. Progressively biological alterations of adipose tIssue metabolism lead to some degree of irreversibility of the disease and contribute to the development of its metabolic and cardio-vascular complications. PMID: 15107724 [PubMed - indexed for MEDLINE] 4190. Sports Med. 2004;34(5):317-27. Macronutrient considerations for the sport of bodybuilding. Lambert CP(1), Frank LL, Evans WJ. Author information: (1)Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Center on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. LambertCharlesP@uams.edu Participants in the sport of bodybuilding are judged by appearance rather than performance. In this respect, increased muscle size and definition are critical elements of success. The purpose of this review is to evaluate the literature and provide recommendations regarding macronutrient intake during both 'off-season' and 'pre-contest' phases. Body builders attempt to increase muscle mass during the off-season (no competitive events), which may be the great majority of the year. During the off-season, it is advantageous for the bodybuilder to be in positive energy balance so that extra energy is available for muscle anabolism. Additionally, during the off-season, adequate protein must be available to provide amino acids for protein synthesis. For 6-12 weeks prior to competition, body builders attempt to retain muscle mass and reduce body fat to very low levels. During the pre-contest phase, the bodybuilder should be in negative energy balance so that body fat can be oxidised. Furthermore, during the pre-contest phase, protein intake must be adequate to maintain muscle mass. There is evidence that a relatively high protein intake (approximately 30% of energy intake) will reduce lean mass loss relative to a lower protein intake (approximately 15% of energy intake) during energy restriction. The higher protein intake will also provide a relatively large thermic effect that may aid in reducing body fat. In both the off-season and pre-contest phases, adequate dietary carbohydrate should be ingested (55-60% of total energy intake) so that training intensity can be maintained. Excess dietary saturated fat can exacerbate coronary artery disease; however, low-fat diets result in a reduction in circulating testosterone. Thus, we suggest dietary fats comprise 15-20% of the body builders' off-season and pre-contest diets. Consumption of protein/amino acids and carbohydrate immediately before and after training sessions may augment protein synthesis, muscle glycogen resynthesis and reduce protein degradation. The optimal rate of carbohydrate ingested immediately after a training session should be 1.2 g/kg/hour at 30-minute intervals for 4 hours and the carbohydrate should be of high glycaemic index. In summary, the composition of diets for body builders should be 55-60% carbohydrate, 25-30% protein and 15-20% of fat, for both the off-season and pre-contest phases. During the off-season the diet should be slightly hyperenergetic (approximately 15% increase in energy intake) and during the pre-contest phase the diet should be hypoenergetic (approximately 15% decrease in energy intake). PMID: 15107010 [PubMed - indexed for MEDLINE] 4191. J Lipid Res. 2004 Jul;45(7):1169-96. Epub 2004 Apr 21. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. Khovidhunkit W(1), Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis. PMID: 15102878 [PubMed - indexed for MEDLINE] 4192. Obes Rev. 2004 May;5 Suppl 1:4-104. Obesity in children and young people: a crisis in public health. Lobstein T(1), Baur L, Uauy R; IASO International Obesity TaskForce. Author information: (1)IASO International Obesity TaskForce, 231 North Gower Street, London NW1 2NS, UK. Childhood@iotf.org Comment in Obes Rev. 2004 May;5 Suppl 1:1-3. Obes Rev. 2004 May;5(2):91-2. PMID: 15096099 [PubMed - indexed for MEDLINE] 4193. Rev Med Suisse Romande. 2004 Mar;124(3):171-5. [Adipose tissue: a real endocrine gland synthesizing hormones and cytokines: clinical implications]. [Article in French] Martin-Du Pan RC, Giusti V. Adipose tissue (AT) is not considered anymore as a passive depot for storing excess energy in the form of triglycerides but as an active organ secreting several hormones or adipokines. With the exception of adiponectin the serum levels of adipokines are increased in obesity. Leptin regulates food intake, reproductive and immune system. Adiponectin decreases insulin resistance and has antiinflammatory properties. On the contrary, resisting, tumor necrosis factor and Interleukin-6 are diabetogenic and induce inflammatory reactions. It is believed that atherosclerosis is due to the inflammation induced by oxydized LDL-cholesterol in vessels. Abdominal obesity is associated with increased incidence of metabolic disorders and insulin resistance. The role of adipokines in these disorders is described as well as their role in the antidiabetic effect of thiazo-linedinediones. AT contains also enzymes responsible for the aromatization of androstenedione into estrone, which could explain an increase of breast and uterus cancer in obese people. PMID: 15095664 [PubMed - indexed for MEDLINE] 4194. Diabetologia. 2004 May;47(5):767-9. Epub 2004 Apr 17. Is "Cushing's disease of the omentum" an affliction of mouse and men? Walker BR(1). Author information: (1)Endocrinology Unit, University of Edinburgh, Western General Hospital, EH4 2XU, Edinburgh, UK, B.Walker@ed.ac.uk Comment on Diabetologia. 2004 May;47(5):833-6. PMID: 15095042 [PubMed - indexed for MEDLINE] 4195. Curr Opin Clin Nutr Metab Care. 2004 Jan;7(1):11-4. Monitoring body fat in the elderly: application of air-displacement plethysmography. Fields DA(1), Hunter GR. Author information: (1)Department of Health and Sport Sciences, University of Oklahoma, 1401 Asp Avenue, Room 104, Norman, OK 73019, USA. dafieldsd@ou.edu PURPOSE OF REVIEW: This review will focus chiefly on recently published studies utilizing air-displacement plethysmography (i.e. BOD POD) in geriatric populations. This innovative technology has been available commercially since 1995. As the test procedure is relatively easy to perform and quick, it may provide an improvement in body composition testing, especially in older individuals with poor ambulation and health. RECENT FINDINGS: This review will explain in a concise and detailed manner the underlying principles of air-displacement plethysmography specifically related to the BOD POD. Second, it will review the studies using this new technology in comparison with more commonly used techniques (hydrostatic weighing, dual energy X-ray absorptiometry, deuterium oxide, multi-compartmental models) for body composition analysis in geriatric populations. Third, it will provide a direction for future studies. SUMMARY: A review of the current body of literature in which air-displacement plethysmography was used is beginning to emerge with a clear picture. Although this technique is still new, it appears that air-displacement plethysmography is a valid and reliable alternative to more traditional body composition techniques, as indicated by small mean differences between techniques. This has special implications in a geriatric population because traditional techniques are difficult to perform in individuals with joint pain, ambulation issues, and overall poor health. PMID: 15090897 [PubMed - indexed for MEDLINE] 4196. Curr Opin Investig Drugs. 2004 Mar;5(3):283-9. Acetyl-CoA carboxylase inhibition for the treatment of metabolic syndrome. Harwood HJ Jr(1). Author information: (1)Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc, Eastern Point Road, Groton, CT 06340, USA. h_james_harwood@groton.pfizer.com Metabolic syndrome is defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinemia, atherogenic dyslipidemia, hypertension and hypercoagulability) that together increase the risk of developing coronary heart disease and type 2 diabetes. Inhibition of acetyl-CoA carboxylase (ACC), which results in inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect a multitude of cardiovascular risk factors associated with metabolic syndrome. ACC exists as two tissue-specific isozymes, ACC1 present in lipogenic tissues (liver and adipose) and ACC2 present in oxidative tissues (liver, heart and skeletal muscle). Studies in both ACC2 knockout mice and animals administered isozyme-nonselective ACC inhibitors have demonstrated the utility of treating metabolic syndrome through this modality. An isozyme-non-selective ACC inhibitor may potentially provide the optimal therapeutic for beneficially affecting metabolic syndrome. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition. While demonstrating clinical efficacy of an ACC inhibitor should be relatively straightforward, the heterogeneity of the patient population and the absence of established guidelines regarding approval endpoints for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries. PMID: 15083594 [PubMed - indexed for MEDLINE] 4197. Semin Reprod Med. 2004 Feb;22(1):11-23. Aromatase: biologic relevance of tissue-specific expression. Simpson ER(1). Author information: (1)Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia. Aromatase p450 (p450arom) catalyzes the formation of estrogen in several human tissues under the control of alternatively used promoters. Each promoter is regulated by a distinct signaling pathway in a tissue- and hormone-specific manner. This article reviews these regulatory mechanisms in the ovary, adipose tissue, placenta, bone, brain, and various malignant cells. Moreover, the physiological and pathologic impacts of local estrogen biosynthesis in contrast to circulating estrogen or estrogen-responsive human tissues are discussed. PMID: 15083377 [PubMed - indexed for MEDLINE] 4198. Semin Reprod Med. 2004 Feb;22(1):5-9. Organization of the human aromatase p450 (CYP19) gene. Bulun SE(1), Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S. Author information: (1)Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois 60611, USA. The human CYP19 (p450arom) gene is located in the 21.2 region on the long arm of chromosome 15 (15q21.2). This gene spans a region that consists of a 30 kb coding region and a 93 kb regulatory region ( approximately 123 kb total length). Its regulatory region contains at least 10 distinct promoters regulated in a tissue- or signaling pathway-specific manner. The Human Genome Project data published in 2000 enabled us to accurately align these promoters within the 93 kb regulatory region of the p450arom gene. Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences. In most vertebrates, p450arom expression is under the control of gonad- and brain-specific promoters. In humans, however, there are at least eight additional promoters that were apparently recruited throughout evolution, possibly via alterations in DNA. A critical mechanism that permits the use of such a large number of promoters seems to be the extremely promiscuous nature of the common splice acceptor site because, with activation of each promoter, an untranslated first exon is spliced onto this common junction immediately upstream of the translation start site in the coding region. These partially tissue-specific promoters are used in the gonads, bone, brain, vascular tissue, adipose tissue, skin, fetal liver, and placenta for estrogen biosynthesis necessary for human physiology. Ovary and testis use promoter II, which is located immediately upstream of the coding region. The adipose tissue in general, including adipose tissue of the disease-free breast, on the other hand, maintains low levels of aromatase expression primarily via promoter I.4, which lies 73 kb upstream of the common coding region. Promoters I.3 and II are used only minimally in normal breast adipose tissue. Promoter II and I.3 activities in breast cancer tissue, however, are strikingly increased. Additionally, the endothelial-type promoter I.7 is also upregulated in breast cancer. Therefore, breast tumor tissue takes advantage of four promoters (II, I.3, I.7, and I.4) for aromatase expression and estrogen production. The sum of p450arom mRNA species arising from these four promoters contributes significantly to elevated levels of total p450arom mRNA in breast cancer in contrast to the normal breast that uses promoter I.4. Because each mRNA species contains the identical coding region regardless of the variable untranslated first exon, the encoded protein functions as the aromatase enzyme in each case. PMID: 15083376 [PubMed - indexed for MEDLINE] 4199. Vet J. 2004 May;167(3):242-57. Technologies for the control of fat and lean deposition in livestock. Sillence MN(1). Author information: (1)School of Agriculture, Charles Sturt University, Locked Bag 588, Wagga Wagga, NSW 2678, Australia. msillence@csu.edu.au Comment in Vet J. 2004 May;167(3):217-8. When the ratio of lean to fat deposition is improved, so is feed conversion efficiency. Net benefits may include lower production costs, better product quality, less excretion of nitrogenous wastes into the environment, decreased grazing pressure on fragile landscapes, and reduced pressure on world feed supplies. However, finding a way to achieve these goals that is reliable, affordable, and acceptable to the majority of consumers has proved to be a major challenge. Since the European Union banned hormonal growth promoters (HGPs) 15 years ago, countries such as Australia and the United States have licensed new products for livestock production, including bovine growth hormone (GH), porcine and equine GH, and the beta-agonist ractopamine. There has also been considerable research into refining these products, as well as developing new technologies. Opportunities to improve beta-agonists include lessening their effects on meat toughness, reducing adverse effects on treated animals, and prolonging their duration of action. In the last regard, the combined use of a beta-agonist with GH, which upregulates beta-adrenoceptors, can produce an outstanding improvement in carcass composition and feed efficiency. Insulin-like growth factor-1 (IGF-1) mediates many of the actions of GH, but has proved to be of more use as a growth reporter/selection marker in pigs, than as a viable treatment. However, a niche for this product could exist in the manipulation of neonatal growth, causing a life-long change in lean:fat ratio. Another significant advance in endocrinology is the discovery of hormones secreted by muscle and fat cells, that regulate feed intake, energy metabolism, and body composition. Leptin, adiponectin and myostatin were discovered through the study of genetically obese, or double-muscled animals. Through genetic manipulation, there is potential to exploit these findings in a range of livestock species, although the production of transgenic animals is still hampered by the poor level of control over gene expression, and faces an uphill battle over consumer acceptance. There are several alternatives to HGPs and transgenics, that are more likely to gain world-wide acceptance. Genetic selection can be enhanced by using markers for polymorphic genes that control fat and lean, such as thyroglobulin, or the callipyge gene. Feed additives of natural origin, such as betaine, chromium and conjugated linoleic acid, can improve the fat:lean ratio under specific circumstances. Additionally, 'production vaccines' have been developed, which alter the neuro-endocrine system by causing an auto-immune response. Thus, antibodies have been used to neutralise growth-limiting factors, prolong the half-life of anabolic hormones, or activate hormone receptors directly. Unfortunately, none of these technologies is sufficiently well advanced yet to rival the use of exogenous HGPs in terms of efficacy and reliability. Therefore, further research is needed to find ways to control fat and lean deposition with due consideration of industry needs, animal welfare and consumer requirements. PMID: 15080873 [PubMed - indexed for MEDLINE] 4200. Curr Opin Nephrol Hypertens. 2004 May;13(3):325-32. Impact of the renin-angiotensin system on lipid and carbohydrate metabolism. Strazzullo P(1), Galletti F. Author information: (1)Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy. straazzul@unina.it PURPOSE OF REVIEW: This review is intended to provide an update of the impact of the renin-angiotensin system on lipid and carbohydrate metabolism and of its relationship with adipose-tissue and skeletal muscle activities. RECENT FINDINGS: The components of the renin-angiotensin system are fully represented in the adipose tissue and appear to be upregulated in obesity--a condition associated with enhanced circulating angiotensinogen levels. The local renin-angiotensin system plays a role in adipocyte differentiation and possibly in body-fat accumulation. In humans, angiotensin II produced by mature adipocytes appears to inhibit the differentiation of adipocyte precursors, thus decreasing the percentage of small insulin-sensitive adipocytes. In turn, the lipid-storage capacity of adipose tissue could become reduced and triglycerides might accumulate in liver and skeletal muscle, contributing to insulin resistance. Randomized controlled trials indicating that pharmacological renin-angiotensin system blockade improves insulin sensitivity and reduces the risk of type 2 diabetes are in keeping with this possibility. The local renin-angiotensin system in skeletal muscle may affect exercise performance and the individual response to different types of muscular performance. The concept that the local renin-angiotensin system plays a role in body-fat storage and in lipid and carbohydrate metabolism is further supported by genetic studies showing that susceptibility to weight gain and possibly insulin resistance is greater in individuals carrying certain renin-angiotensin system allelic variants associated with alterations in systemic and local angiotensinogen levels and angiotensin-converting enzyme activity. SUMMARY: In summary, the aforementioned data imply that the renin-angiotensin system plays a substantial role in obesity, insulin resistance and the associated increase in blood pressure. PMID: 15073492 [PubMed - indexed for MEDLINE] 4201. Proc Nutr Soc. 2004 Feb;63(1):153-60. Lipid metabolism in women. Williams CM(1). Author information: (1)Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, Reading RG6 6AP, UK. c.m.williams@reading.ac.uk Differences in whole-body lipid metabolism between men and women are indicated by lower-body fat accumulation in women but more marked accumulation of fat in the intra-abdominal visceral fat depots of men. Circulating blood lipid concentrations also show gender-related differences. These differences are most marked in premenopausal women, in whom total cholesterol, LDL-cholesterol and triacylglycerol concentrations are lower and HDL-cholesterol concentration is higher than in men. Tendency to accumulate body fat in intra-abdominal fat stores is linked to increased risk of CVD, metabolic syndrome, diabetes and other insulin-resistant states. Differential regional regulation of adipose tissue lipolysis and lipogenesis must underlie gender-related differences in the tendency to accumulate fat in specific fat depots. However, empirical data to support current hypotheses remain limited at the present time because of the demanding and specialist nature of the methods used to study adipose tissue metabolism in human subjects. In vitro and in vivo data show greater lipolytic sensitivity of abdominal subcutaneous fat and lesser lipolytic sensitivity of femoral and gluteal subcutaneous fat in women than in men. These differences appear to be due to fewer inhibitory alpha adrenergic receptors in abdominal regions and greater alpha adrenergic receptors in gluteal and femoral regions in women than in men. There do not appear to be major gender-related differences in rates of fatty acid uptake (lipogenesis) in different subcutaneous adipose tissue regions. In visceral fat rates of both lipolysis and lipogenesis appear to be greater in men than in women; higher rates of lipolysis may be due to fewer alpha adrenergic receptors in this fat depot in men. Fatty acid uptake into this depot in the postprandial period is approximately 7-fold higher in men than in women. Triacylglycerol concentrations appear to be a stronger cardiovascular risk factor in women than in men, with particular implications for cardiovascular risk in diabetic women. The increased triacylglycerol concentrations observed in women taking hormone-replacement therapy (HRT) may explain the paradoxical findings of increased rates of CVD in women taking HRT that have been reported from recent primary and secondary prevention trials of HRT. PMID: 15070445 [PubMed - indexed for MEDLINE] 4202. Am J Physiol Regul Integr Comp Physiol. 2004 May;286(5):R803-13. Obesity and hypertension: two epidemics or one? Davy KP(1), Hall JE. Author information: (1)Dept. of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. kdavy@vt.edu The association between obesity and hypertension is well documented, although the exact nature of this relation remains unclear. Sympathetic nervous and renin-angiotensin-aldosterone system activation appear to play an important role in the sodium and water retention, rightward shift in the pressure-natriuresis, and blood pressure elevation observed in obese individuals. Visceral obesity and the ectopic deposition of adipose tissue may be important in the activation of these systems and in the target organ damage that ensues. Weight loss is critical in the effective management of obesity hypertension and the accompanying target organ damage, although recidivism rates are high. However, prevention of weight gain should be the major priority for combating hypertension and its consequences in the future. The present review will provide an overview of our understanding of the etiology, pathophysiology, and treatment of obesity hypertension. Our focus is on the state of knowledge in humans. The potential role of abdominal obesity is considered throughout our review. We refer to relevant animal literature for supportive evidence and where little or no data in humans are available. PMID: 15068965 [PubMed - indexed for MEDLINE] 4203. Curr Atheroscler Rep. 2004 May;6(3):180-5. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Louet JF(1), LeMay C, Mauvais-Jarvis F. Author information: (1)Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, 520B, Houston, TX 77030, USA. There is increasing evidence both in humans and rodents linking the endogenous estrogen 17b-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic b-cell function/survival and insulin secretion in conditions of oxidative stress. PMID: 15068742 [PubMed - indexed for MEDLINE] 4204. Acta Clin Belg. 2003 Nov-Dec;58(6):335-41. Pathophysiology of type 2 diabetes. Scheen AJ(1). Author information: (1)Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, Liège, Belgium. andre.scheen@chu.ulg.ac.be Type 2 diabetes mellitus is a heterogeneous syndrome characterized by abnormalities in carbohydrate and fat metabolism. The causes of type 2 diabetes are multi-factorial and include both genetic and environmental elements that affect beta-cell function and tissue (muscle, liver, adipose tissue, pancreas) insulin sensitivity. Although there is considerable debate as to the relative contributions of beta-cell dysfunction and reduced insulin sensitivity to the pathogenesis of diabetes, it is generally agreed that both these factors play important roles. However, the mechanisms controlling the interplay of these two impairments are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes. A majority of individuals suffering from type 2 diabetes are obese, with central visceral adiposity. Therefore, the adipose tissue should play a crucial role in the pathogenesis of type 2 diabetes. Although the predominant paradigm used to explain this link is the portal/visceral hypothesis giving a key role in elevated non-esterified fatty acid concentrations, two new emerging paradigms are the ectopic fat storage syndrome (deposition of triglycerides in muscle, liver and pancreatic cells) and the adipose tissue as endocrine organ hypothesis (secretion of various adipocytokins, i.e. leptin, TNF-alpha, resistin, adiponectin, implicated in insulin resistance and possibly beta-cell dysfunction). These two paradigms constitute the framework for the study of the interplay between insulin resistance and beta-cell dysfunction in type 2 diabetes as well as between our obesogenic environment and diabetes risk in the next decade. PMID: 15068125 [PubMed - indexed for MEDLINE] 4205. Med Sci (Paris). 2004 Mar;20(3):339-45. [What is the role of endothelin system?]. [Article in French] Pinet F(1). Author information: (1)Inserm U.508-IPL, 1, rue du Professeur Calmette, 59019 Lille Cedex, France. florence.pinet@pasteur-lille.fr Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (" big endothelins") which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system. PMID: 15067580 [PubMed - indexed for MEDLINE] 4206. J Atheroscler Thromb. 2004;11(1):1-5. Pre-heparin lipoprotein lipase mass. Kobayashi J(1). Author information: (1)Department of Lifestyle-related Disease, Kanazawa University Graduate School of Medical Science, Takara-machi, Japan. junji@med.kanazawa-u.ac.jp Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing the hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, the clinical significance of measuring LPL mass without heparin injection has been increasingly studied. In earlier studies, it was shown that this marker was utilized to classify type 1 hyperlipoproteinemia, which is an extremely rare metabolic disorder. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma LPL mass has significant relationships with serum lipid and lipoproteins, visceral fat area, and even a marker for acute inflammation, although this might be a metabolic surrogate marker which does not appear to be involved in catalyzing the hydrolysis of TG in TG-rich lipoproteins. We suggest that pre-heparin LPL mass in plasma or sera provides us with useful and important information on the pathophysiology of metabolic disorders or acute inflammation despite its simplicity from a practical point of view. PMID: 15067192 [PubMed - indexed for MEDLINE] 4207. Atherosclerosis. 2004 Apr;173(2):157-69. The aging male: testosterone deficiency and testosterone replacement. An up-date. Alexandersen P(1), Christiansen C. Author information: (1)CCBR, Ballerup Byvej 222, DK-2750 Ballerup, Denmark. pa@ccbr.dk The significance of the age-related decline of androgens remains unclear in terms of cardiovascular risk, mood and cognition, and prostatic health. Although much research has been undertaken in this area and men's health has received still more attention in the latest years, there are no data based on randomized controlled clinical studies in aging men investigating the long-term effects of androgen replacement therapy on various aspects of the cardiovascular system, the immune system, body composition, and the brain. In men receiving long-term androgen replacement therapy, the safety aspects regarding the prostate are also an area of clinical importance. In this paper we present an up-dated review of the experimental and clinical evidence of androgen deficiency and androgen replacement therapy on carbohydrate metabolism, on coagulation and fibrinolysis, inflammatory effects, effects on lipoprotein metabolism, direct arterial effects, effects on body composition, effects on cognitive function and mood, and prostatic effects. The evidence clearly shows that data for the most part are conflicting, with only very few randomized studies available. PMID: 15064089 [PubMed - indexed for MEDLINE] 4208. Mech Ageing Dev. 2004 Apr;125(4):337-8. Cidea, brown fat and obesity. Li P(1). Author information: (1)Department of Biology, Hong Kong University of Science and Technology, Kowloon, Hong Kong. bolipeng@ust.hk PMID: 15063110 [PubMed - indexed for MEDLINE] 4209. Mech Ageing Dev. 2004 Apr;125(4):297-304. Effects of testosterone on body composition of the aging male. Mudali S(1), Dobs AS. Author information: (1)Johns Hopkins University School of Medicine, Baltimore, MD 21208, USA. The aging process is accompanied by significant changes in body composition characterized by decreased fat free mass and increased and redistributed fat mass. Muscle loss results from the atrophy of muscle fibers and decreased synthesis of muscle proteins. Increased number of adipocytes and fat accumulation in non-adipose tissue leads to adiposity. These changes can impose functional limitations and increase morbidity. In men, declining testosterone levels that occur with aging can be a contributing factor to these changes. Studies in hypogonadal men have shown that testosterone replacement is effective in increasing muscle mass and strength and decreasing fat mass. The molecular mechanisms of testosterone's influence on muscle and adipose are not fully elucidated. However, testosterone appears to stimulate IGF-1 expression directly and indirectly leading to increased muscle protein synthesis and growth. It may also counter the inhibitory effects of myostatin, cytokines, and glucocorticoids. The predominant effects of testosterone on fat mass are increased lipolysis and decreased adipogenesis. Current evidence suggests that testosterone replacement may be effective in reversing age-dependent body composition changes and associated morbidity. However, hypogonadism must be diagnosed carefully, and therapy should be monitored regularly in order to avoid the adverse effects associated with testosterone supplementation. PMID: 15063106 [PubMed - indexed for MEDLINE] 4210. Mol Cell Endocrinol. 2003 Dec 31;213(1):1-11. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Bassett JH(1), Harvey CB, Williams GR. Author information: (1)Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Triiodothyronine (T3) classically regulates gene expression by binding to high-affinity thyroid hormone receptors (TR) that recognize specific response elements in the promoters of T3-target genes and activate or repress transcription in response to hormone. However, a number of thyroid hormone effects occur rapidly and are unaffected by inhibitors of transcription and translation, suggesting that thyroid hormones may also mediate non-genomic actions. Such actions have been described in many tissues and cell types, including brown adipose tissue, the heart and pituitary. The site of non-genomic hormone action has been localized to the plasma membrane, cytoplasm and cellular organelles. These non-genomic actions include the regulation of ion channels, oxidative phosphorylation and mitochondrial gene transcription and involve the generation of intracellular secondary messengers and induction of [Ca(2+)](I), cyclic AMP or protein kinase signalling cascades. These observations have been interpreted to imply the presence of a specific, membrane associated, TR isoform or an unrelated high affinity membrane receptor for thyroid hormone. The recent identification of a progestin membrane receptor and the sub cellular targeted nuclear receptor isoforms ER46, mtRXR, mtPPAR, p28 and p46, has highlighted the potential importance of non-genomic actions of steroid hormones. Here we compare these recently identified receptors with the genomic, non-genomic and mitochondrial actions of thyroid hormones and consider their implications. PMID: 15062569 [PubMed - indexed for MEDLINE] 4211. Int J Biochem Cell Biol. 2004 May;36(5):753-8. Hepatocytes: critical for glucose homeostasis. Klover PJ(1), Mooney RA. Author information: (1)Graduate Program in Biochemistry, University of Rochester Medical Center, NY, USA. Maintaining blood glucose levels within a narrow range is a critical physiological function requiring multiple metabolic pathways and involving several cell types, including a prominent role for hepatocytes. Under hormonal control, hepatocytes can respond to either feeding or fasting conditions by storing or producing glucose as necessary. In the fasting state, the effects of glucagon avoid hypoglycemia by stimulating glucogenesis and glycogenolysis and initiating hepatic glucose release. Postprandially, insulin prevents hyperglycemia, in part, by suppressing hepatic gluconeogenesis and glycogenolysis and facilitating hepatic glycogen synthesis. Both transcriptional regulation of rate limiting enzymes and modulation of enzyme activity through phosphorylation and allosteric regulation are involved. Type 2 diabetes mellitus is the most common serious metabolic condition in the world, and results from a subnormal response of tissues to insulin (insulin resistance) and a failure of the insulin-secreting beta cells to compensate. In type 2 diabetes, glucose is overproduced by the hepatocyte and is ineffectively metabolized by other organs. Impairments in the insulin signal transduction pathway appear to be critical lesions contributing to insulin resistance and type 2 diabetes. PMID: 15061128 [PubMed - indexed for MEDLINE] 4212. Curr Drug Targets. 2004 Apr;5(3):309-23. Treating obesity: pharmacology of energy expenditure. Clapham JC(1). Author information: (1)Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden. john.clapham@astrazeneca.com The pharmacological treatment options for obesity are currently very limited but the prevalence of the disease is increasing rapidly. Obesity has many serious sequelae, the most common of which is type-2-diabetes. The benefits of weight loss on health are established but the major impediment to weight loss treatments is maintenance of weight lost over the long term. The reduced- or post-obese individual undergoes physiological changes that are geared towards energy storage and weight regain. One of the physiological changes is a reduced capacity to oxidise fatty acids pushing them through pathways of triacylglycerol synthesis. In this review, some of the past drug treatments aimed at increasing energy expenditure, such as dinitrophenol and ephedrine. are discussed. Current, or nearly current therapies such as sibutramine and rimonabant are also discussed in the context of increased energy expenditure. The main part of the review focuses on future prospects with discussion around a selection of targets with potential in energy expenditure that lie in pathways with AMP-kinase at their centre and ending at the mitochondrion. PMID: 15058315 [PubMed - indexed for MEDLINE] 4213. Curr Drug Targets. 2004 Apr;5(3):241-50. Adipose tissue as a regulator of energy balance. Klaus S(1). Author information: (1)German Institute of Human Nutrition in Potsdam (DIfE), Arthur-Scheunert Allee 114-116, 14558 Bergholz-Rehbrücke, Germany. Klaus@mail.dife.de Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines. These consist of polypeptides but also non-protein factors and are metabolically active molecules belonging to different functional categories like immunity (complement factors, haptoglobin), endocrine function (leptin, sex steroids, various growth factors), metabolic function (fatty acids, adiponectin, resistin), and cardiovascular function (angiotensinogen, PAI-1). Recent advances using genomic and proteomic approaches have identified numerous new adipocyte secreted factors whose function remain to be established. Too little as well as too much adipose tissue leads to metabolic disturbances like insulin resistance. Visceral obesity is especially strongly correlated with the development of diabetes, hypertension and cardio-vascular disease. Thermogenesis in brown adipose tissue is a means to dissipate excess energy, but in adult humans brown fat is very scarce and probably not functional. However, human white adipose tissue contains mesenchymal stem cells, and if these could be stimulated to differentiate into brown adipocytes, increased energy expenditure in white fat could help to shift energy balance towards a more negative state. PMID: 15058310 [PubMed - indexed for MEDLINE] 4214. Nihon Yakurigaku Zasshi. 2004 Apr;123(4):281-7. [A new system using NMR technology for measurement of body composition in experimental animals]. [Article in Japanese] Suzuki J(1), Furutoh K, Nishikibe M. Author information: (1)Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. jun-suzuki@merck.com Measurement of body composition (fat mass) is an important item in pathophysiological and pharmacological studies using small animals (mice) in the fields of obesity and diabetes. The existing methods are, however, difficult, time consuming, and require a shielding facility. Now a novel system using nuclear magnetic resonance (NMR) technique was developed for measurement of body composition in small animals (mice) that provides noninvasive and rapid measurement without anesthetics; we introduced and evaluated this system and tried another application of this system. First, we validated this system using canola oil, soft tissues (adipose and skeletal muscle), and various kinds of rodent chows. Accuracy, precision, and reproducibility of this system were demonstrated to be equal to those in standard chemical methods. A strong positive correlation (y=x) between the results of NMR and chemical methods was found. Secondly, we evaluated accuracy and assay range of the NMR method using live mice that were fasted overnight or fed high fat diet (HFD). In fasted mice, a small but quantitative decrease of fat mass (5.1% from 9.1%) was detected. Total decrease of fat and lean mass (5.0 g) in fasted mice was equivalent to the decrease of body weight (5.0 g). In mice fed the HFD, increase of fat mass with relative decrease of lean mass were qualitatively detected in a time-dependent manner. We would like to emphasize that operation of the system was actually easy and measurements were accomplished in a short time (1 minute). Thirdly, we tried to use the NMR system for determination of hepatic fat contents using mice fasted or treated with a PPARgamma agonist; our results showed a quantitative increase in fat by fasting or in decrease in fat by the drug treatment. The changes of fat contents determined by the NMR method were well correlated with the changes in triglyceride and total cholesterol values obtained by the biochemical assays. In conclusion, body composition data acquired by the new NMR system are equivalent in accuracy and precision to classical chemical methods. The NMR analysis is simple, fast, and does not require anesthesia for acquisition of data, which are remarkable advantages compared to the existing methods. This system is expected to contribute to drug discovery and appropriate evaluation in the fields of obesity and diabetes. PMID: 15056944 [PubMed - indexed for MEDLINE] 4215. Biochem Cell Biol. 2004 Feb;82(1):170-90. Diabetes, lipids, and adipocyte secretagogues. Faraj M(1), Lu HL, Cianflone K. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada. That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism. PMID: 15052336 [PubMed - indexed for MEDLINE] 4216. J Intern Med. 2004 Apr;255(4):448-56. Hypofibrinolysis in the insulin resistance syndrome: implication in cardiovascular diseases. Mavri A(1), Alessi MC, Juhan-Vague I. Author information: (1)Laboratory of Hematology, CHU Timone, Marseille, France. Insulin resistance syndrome (IRS) is associated with increased cardiovascular morbidity and mortality. IRS is becoming one of the major health problems as its prevalence grows rapidly. Accelerated atherothrombotic process in the IRS is attributed to metabolic abnormalities, inflammation and to impaired fibrinolysis due to increased plasma plasminogen activator inhibitor type 1 (PAI-1) levels. Proinflammatory cytokines may have an important role in PAI-1 overexpression, particularly in the adipose tissue. Studies in genetically modified mice indicate that PAI-1 might be involved in the aetiopathogenesis of obesity. Modifying PAI-1 expression by PAI-1 inhibitors may open a new field of research and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes. PMID: 15049879 [PubMed - indexed for MEDLINE] 4217. Ann Biol Clin (Paris). 2004 Jan-Feb;62(1):25-31. [Insulin resistance and adipose tissue gene expression in humans]. [Article in French] Bastard JP(1). Author information: (1)Service de biochimie et hormonologie, Hôpital Tenon, 4, rue de la Chine, 75970 Paris. jean-philippe.bastard@tnn.ap-hop-paris.fr Obesity is a risk factor for type 2 diabetes and cardiovascular diseases. The hypothesis that cytokines could play a role in the pathophysiology of obesity and insulin resistance is suggested in the last few years. We showed a positive correlation between circulating interleukin (IL-6) levels and obesity and insulin resistance suggesting that IL-6 could be involved in insulin resistance in humans. We showed a decrease of both circulating and adipose tissue IL-6 levels in non-diabetic obese subjects after a very low calorie diet program inducing weight loss. This suggests that adipose tissue could be involved in the regulation of circulating IL-6 levels in these subjects. Adipose tissue is also involved in lipodystrophies particularly in HIV patients on antiviral therapy. We showed an alteration of the SREBP-1 transcription step in subcutaneous abdominal adipose tissue from HIV patients. We found an inverse correlation between circulating adiponectin levels and both insulin resistance and cardiovascular risk factors such as CRP levels and apolipoprotein B/A1 ratio. These findings suggest that adipose tissue is involved in insulin resistance in humans particularly via adipocytokine secretion. Copyright John Libbey Eurotext 20003. PMID: 15047487 [PubMed - indexed for MEDLINE] 4218. Horm Behav. 2004 Mar;45(3):173-80. The energetics of immunity: a neuroendocrine link between energy balance and immune function. Demas GE(1). Author information: (1)Department of Biology, Indiana University, Bloomington, IN 47405, USA. gdemas@bio.indiana.edu PMID: 15047012 [PubMed - indexed for MEDLINE] 4219. Trends Endocrinol Metab. 2004 Apr;15(3):129-35. Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Beale EG(1), Hammer RE, Antoine B, Forest C. Author information: (1)Department of Cell Biology and Biochemistry, Stop 6540, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. elmus.beale@ttuhsc.edu Erratum in Trends Endocrinol Metab. 2004 Jul;15(5):192. ). Genetics and diet interact to cause type 2 diabetes mellitus and obesity. PCK1 has been implicated as one of many genes associated with type 2 diabetes mellitus. The common assumption is that mutations in PCK1 lead to excessive glucose production through hepatic gluconeogenesis. However, there is an alternative explanation, wherein mutations at the PCK1 locus could selectively affect PCK1 expression in adipose tissue. The result would be changes in glyceroneogenesis that would affect the storage and release of fatty acids. Here, we present the novel hypothesis that a variety of phenotypes could arise from mutations of the various tissue-specific control elements of PCK1. We also suggest specific quantitative metabolic traits that would accompany mutations that selectively affect PCK1 expression in adipose tissue. PMID: 15046742 [PubMed - indexed for MEDLINE] 4220. Physiol Res. 2004;53(2):123-9. Adiponectin and its role in the obesity-induced insulin resistance and related complications. Haluzík M(1), Parízková J, Haluzík MM. Author information: (1)Third Department of Medicine, First Faculty of Medicine, Charles University, U nemocnice 1, 128 08, Praha 2, Czech Republic. mhalu@lf1.cuni.cz It is now generally accepted that adipose tissue acts as an endocrine organ producing a number of substances with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adiponectin is a recently discovered protein produced exclusively by adipocytes. A number of studies have shown that obesity, insulin resistance and atherosclerosis are accompanied by decreased adiponectin levels and that adiponectin replacement under experimental settings is able to diminish both insulin resistance and atherosclerosis. The aim of this review is to summarize the current knowledge about the physiology and pathophysiology of adiponectin and to discuss its potential in the treatment of insulin resistance and atherosclerosis. PMID: 15046547 [PubMed - indexed for MEDLINE] 4221. Dig Liver Dis. 2004 Mar;36(3):165-73. Non-alcoholic fatty liver and insulin resistance: a cause-effect relationship? Bugianesi E(1), Zannoni C, Vanni E, Marzocchi R, Marchesini G. Author information: (1)Gastroenterology Department, University of Turin, Turin, Italy. The role of insulin resistance in non-alcoholic fatty liver disease is suggested by laboratory data (hyperinsulinemia and decreased sensitivity to endogenous and exogenous insulin). The clinical association with features of the metabolic syndrome, particularly in the most aggressive stages of the disease, further confirms a causative role. Fat accumulation in the liver may stem either from genetic defects, primarily responsible for insulin resistance, or excessive calorie intake and visceral obesity, and is mediated by adipocytokines (leptin, adiponectin, tumour necrosis factor-alpha). Progression of fatty liver to steatohepatitis may be the result of an imbalance between pro-inflammatory and anti-inflammatory cytokines, triggering the formation of reactive oxygen species and intrahepatic lipid peroxidation. This process may also be promoted or accelerated by pro-oxidant xenobiotics or environmental factors. Insulin resistance provides a target for specific treatment of non-alcoholic fatty liver, and insulin-sensitising agents (metformin or thiazolidinediones) as well as lifestyle changes to reduce visceral adiposity are the most promising therapeutic options. Future trials need to be performed in order to test the long-term effectiveness of these treatments on the basis of clinically relevant histological outcomes. PMID: 15046183 [PubMed - indexed for MEDLINE] 4222. Scand J Med Sci Sports. 2004 Apr;14(2):74-99. Fat metabolism in exercise--with special reference to training and growth hormone administration. Lange KH(1). Author information: (1)Sports Medicine Research Unit, Bispebjerg Hospital, Copenhagen, Denmark. klange@dadlnet.dk Comment in Scand J Med Sci Sports. 2004 Apr;14(2):72-3. Despite abundance of fat, exclusive dependency on fat oxidation can only sustain a metabolic rate corresponding to 50-60% of VO(2max) in humans. This puzzling finding has been subject to intense research for many years. Lately, it has gained renewed interest as a consequence of increased obesity and physical inactivity imposed by Western lifestyle. Why are humans so poor at metabolizing fat? Can fat metabolism be manipulated by exercise, training, diet and hormones? And why is fat stored in specialized adipose tissue and not just as lipid droplets inside muscle cells? In the present review, human fat metabolism is discussed in relation to how human fat metabolism is designed. Limitations in this design are explored and examples of different designs for fat metabolism from animal physiology are included to illustrate these limitations. Various means of manipulating fat metabolism are discussed with special emphasis on exercise, training, growth hormone (GH) physiology and GH administration. It is concluded that fat stores, non-esterified fatty acids (NEFAs) availability and enzymes for fat oxidation can be increased substantially. However, it is almost impossible to increase fat oxidation during endurance exercise at higher intensities. It seems that, for some reason, the human being is far from optimally designed for fat oxidation during exercise. Acute GH administration has several unexpected effects on fat and carbohydrate metabolism during aerobic exercise, and future research in this area is likely to provide valuable information with respect to GH physiology and the regulation of fat and carbohydrate metabolism during aerobic exercise. PMID: 15043630 [PubMed - indexed for MEDLINE] 4223. Rev Endocr Metab Disord. 2004 May;5(2):143-9. New insights into the integrated physiology of insulin action. Kitamura Y(1), Accili D. Author information: (1)Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA. PMID: 15041790 [PubMed - indexed for MEDLINE] 4224. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):361-72. Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Horrocks LA(1), Farooqui AA. Author information: (1)Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA. horrocks.2@osu.edu The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease. PMID: 15041028 [PubMed - indexed for MEDLINE] 4225. Vnitr Lek. 2003 Dec;49(12):894-9. [Pathogenesis of insulin resistance]. [Article in Czech] Skrha J(1). Author information: (1)III. interní klinika 1. lékarské fakulty UK a VFN, Praha. Insulin resistance characterized by a decreased biological response to insulin is caused by genetic and exogenous factors influencing the target tissues for insulin, like the muscle, adipose tissue and the liver. A hyperbolic relationship was found between insulin secretion and insulin action. The insulin hypersecretion caused by short-time B-cell stimulation with free fatty acids is associated with hyperinsulinemia and worsening of insulin resistance. On the contrary, longtime exposure of B-cells by free fatty acids is followed by a decreased secretion and thus by hypoinsulinemia. Triglyceride infiltration of the muscle tissue and B-cells further worsens the insulin resistance and impairs the insulin secretion. Lipotoxicity worsens the whole metabolic disorder including the glucose tolerance and causes apoptosis of the islet cells. Free fatty acids are causative factor in the pathogenesis of insulin resistance as well as of Type 2 diabetes. PMID: 15040151 [PubMed - indexed for MEDLINE] 4226. Pediatr Dev Pathol. 2004 May-Jun;7(3):262-7. Epub 2004 Mar 25. Intrathyroidal branchial cleft-like cyst with heterotopic salivary gland-type tissue. Park JY(1), Kim GY, Suh YL. Author information: (1)Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. Erratum in Pediatr Dev Pathol. 2004 Nov-Dec;7(6):672. A rare case is described of intrathyroidal branchial cleft-like cyst associated with unusual heterotopic tissues including the salivary gland type tissue, fat, and cartilage. This coexistence in the thyroid gland has not been described previously, to our knowledge. The patient was a 7-year-old girl with a growing mass in the left lateral neck. The ultrasonography revealed a cystic lesion in the left thyroid. Histologically, the cyst was lined by squamous or respiratory-type epithelium resting on the fibrous tissue containing lymphoid tissues with follicle formation and solid cell nests (SCNs). This cyst was intimately associated with heterotopic tissues including lobules of well-differentiated seromucinous salivary glands, mature fat tissue, and islands of the cartilage. This association of branchial cleft-like cyst with SCNs and unusual heterotopic tissues in the normal thyroid suggests a possible origin from the SCN as ultimobranchial vestigial structures. PMID: 15037945 [PubMed - indexed for MEDLINE] 4227. J Anim Sci. 2004 Mar;82(3):935-41. The adipocyte as an endocrine cell. Miner JL(1). Author information: (1)Department of Animal Science, University of Nebraska, Lincoln 68583-0908, USA. jminer1@unl.edu Communication between adipose and other tissues has been hypothesized since at least the 1940s to be bidirectional. Despite this expectation, early progress was largely limited to adipose tissue's role in metabolism and storage of fatty acids, its development, and its response to endocrine and neural cues. However, efforts of the last decade have identified several molecules that are secreted from adipocytes, apparently for the purpose of signaling to other tissues. Cloning of the mouse obesity gene in 1994 is perhaps the most famous impetus for recognition that adipocytes are active in the regulation of multiple body functions. The product of this gene, leptin, has since been found to inhibit feeding, enhance energy expenditure, and stimulate gonadotropes. Evidence for the roles of other adipocyte-derived signals is being generated. Resistin is a protein that can cause whole-body insulin resistance. Its expression is correlated with body fatness and is inhibited by thiazolidinediones, perhaps mediating the association of type 2 diabetes with obesity, and the effectiveness of these drugs. Resistin and a related molecule, RELM alpha, can also inhibit differentiation of preadipocytes. Adiponectin/Acrp30 secretion from adipocytes is diminished in obese states. This protein can enhance use of fatty acids in lean tissues, inhibit glucose production by liver, and consequently decrease both blood glucose and BW. Adiponectin may also be responsible for the effectiveness of thiazolidinediones, given that these drugs promote adiponectin secretion. Secretion of complement proteins has been observed in adipocytes, and these interact to generate a signal called acylation-stimulating protein, which can promote triacylglycerol synthesis. These signals seem to be largely unique to adipocytes. Other signals are derived from adipose tissue, and it is unlikely that all the adipocyte's endocrine signals have been identified. Certainly, there is much to learn about how these signals function; however, it is clear that these biomedical research discoveries comprise a useful model for our study of growth and development in livestock. PMID: 15032452 [PubMed - indexed for MEDLINE] 4228. J Anim Sci. 2004 Mar;82(3):925-34. Adipose tissue angiogenesis. Hausman GJ(1), Richardson RL. Author information: (1)USDA-ARS, Richard B. Russell Agricultural Research Center, Animal Physiology Research Unit, Athens, GA 30605-2720, USA. ghausman@saa.ars.usda.gov A review of adipose tissue angiogenesis includes the morphological and cytochemical development of adipose tissue vasculature and the concept of primitive fat organs. Spatial and temporal relationships between fetal vascular and fat cell development are discussed, including depot- and genetic-dependent arteriolar differentiation. The relationship between connective tissue deposition and elaboration of adipose tissue vasculature is discussed with respect to regulating adipocyte development in a depot-dependent manner. In vitro studies indicated that depot-dependent vascular traits may be attributable to intrinsic growth characteristics of adipose tissue endothelial cells. These studies indicate that adipogenesis may be regulated by factors that drive angiogenesis. Fundamental aspects of angiogenesis, including basement membrane breakdown, vasculogenesis, angiogenic remodeling, vessel stabilization, and vascular permeability were reviewed. Critical angiogenic factors include vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins (Ang), ephrins, matrix metalloproteinases, and the plasminogen enzymatic system. Vascular endothelial growth factor is the most critical factor because it initiates the formation of immature vessels and disruption of a single VEGF allele leads to embryonic lethality in mice. Expression of VEGF is influenced by hypoxia, insulin, growth factors, and several cytokines. Angiogenic factors secreted and/or produced by adipocytes or preadipocytes are discussed. Vascular endothelial growth factor expression and secretion by adipocytes is regulated by insulin and hypoxia, and is associated with adipose tissue accretion. Vascular endothelial growth factor accounts for most of the angiogenic activity of adipose tissue. The proposed role of leptin as an adipogenic factor is reviewed with respect to efficacy on various aspects of angiogenesis relative to other angiogenic factors. The VEGF and leptin genes are both hypoxia inducible, but potential links between VEGF and leptin gene expression have not been examined. Finally, several studies including a study of mice treated with antiangiogenic factors indicate that adipose tissue accretion can be controlled through the vasculature per se. PMID: 15032451 [PubMed - indexed for MEDLINE] 4229. J Anim Sci. 2004 Mar;82(3):916-24. Role of fatty acids in adipocyte growth and development. Azain MJ(1). Author information: (1)Animal and Dairy Science Department, University of Georgia, Athens 30602, USA. mazain@arches.uga.edu Fat is typically added to diets as a source of energy. The alternative aspects considered here are the use of specific fats to alter the fatty acid profile of adipose tissue toward creation of value-added products and the potential for individual fatty acids to alter gene expression and control adipose tissue development. Emphasis is placed on the omega-3 fatty acids, such as those found in fish oil, and on CLA. The most common association of fatty acids with adipose tissue is related to their storage as triglycerides in mature adipocytes and the consequences of excess accumulation in obesity. Fatty acids and their derivatives also can have hormone-like effects and have been be shown to regulate gene expression in preadipocytes, which ultimately effects their proliferation and differentiation. Long-chain, saturated, and polyunsaturated fatty acids have been shown to regulate transcription factors, such as CCAAT/enhancer binding protein, peroxisome proliferator activated receptor, and other adipose-specific genes, very early in adipocyte development. These effects have the potential to affect fat cell number at maturity. Specifically, there is evidence that the fatty acids in fish oil, such as docosahexaenoic and eicosopentaenoic acids, and fatty acids in the CLA series, decrease preadipocyte proliferation in cell lines and reduce adiposity in rodents. There is little direct evidence of the ability of fatty acids to manipulate adipocyte development in non-rodent species. The genetic, nutritional, and pharmacological manipulation of adipose tissue in meat animals has long been of interest to animal scientists. An understanding of the ability of fatty acids to regulate factors such as adipocyte size and number, particularly in meat animals, would be of great interest. The evidence for regulatory roles of fatty acids in development from rodent and in vitro studies and their potential application to meat animals are reviewed. PMID: 15032450 [PubMed - indexed for MEDLINE] 4230. J Anim Sci. 2004 Mar;82(3):905-15. Adipogenesis: usefulness of in vitro and in vivo experimental models. Novakofski J(1). Author information: (1)Department of Animal Sciences, University of Illinois, Urbana 61801, USA. Jnova@uiuc.edu The use of experimental models is the foundation of experimental biology, so it is important to know how much the models can tell us about actual animals. Inconsistent or contradictory results from in vitro models are often associated with the perception that a particular model or results are somehow wrong and therefore cannot tell us anything important about how an animal works. In fact, in vitro conditions do not create new biology. Differences between in vitro and in vivo behavior can only result from the actual cellular repertoire, which provides a powerful tool to uncover new information. Adipose tissue research provides a useful context for examining this issue because the regulation of adipose growth and metabolism has important economic implications for livestock production. Examples are discussed in which either excess skepticism or narrow interpretation of results slowed progress toward our current understanding of adipose biology. Similarly, contemporary examples using genomics are used to suggest that large inconsistencies are still apparent with in vitro methods. Careful consideration of these inconsistencies may provide new insights. PMID: 15032449 [PubMed - indexed for MEDLINE] 4231. Diabetes Metab. 2004 Feb;30(1):13-9. Adipose tissue and adipokines: for better or worse. Guerre-Millo M(1). Author information: (1)U 465 INSERM, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 15, rue de l'Ecole de Médecine, 75006 Paris, France. mguerre@bhdc.jussieu.fr It is now recognized that the white adipose tIssue (WAT) produces a variety of bioactive peptIdes, collectively termed "adipokines". Alteration of WAT mass in obesity or lipoatrophy, affects the production of most adipose secreted factors. Since both conditions are associated with multiple metabolic disorders and increased risk of cardiovascular diseases, the Idea has emerged that WAT could be instrumental in these complications, by virtue of its secreted factors. Several adipokines are increased in the obese state and have been implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (ASP, TNFalpha, IL-6, resistin). Conversely, leptin and adiponectin both exert an insulin-sensitizing effect, at least in part, by favoring tIssue fatty-acId oxIdation through activation of AMP-activated kinase. In obesity, insulin resistance has been linked to leptin resistance and decreased plasma adiponectin. In lipoatrophic mice, where leptin and adiponectin circulating levels are low, administration of the two adipokines synergistically reverses insulin resistance. Leptin and adiponectin also have distinct properties: leptin, as a long-term integrative signal of energy store and adiponectin, as a potent anti-atherogenic agent. The thiazolIdinedione anti-diabetic drugs increase endogenous adiponectin production in rodents and humans, supporting the Idea that the development of new drugs targeting adipokines might represent a promising therapeutic approach to protect obese patients from insulin resistance and atherosclerosis. PMID: 15029093 [PubMed - indexed for MEDLINE] 4232. Mol Cell Endocrinol. 2004 Feb 27;215(1-2):45-54. 11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Wake DJ(1), Walker BR. Author information: (1)Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, 2nd Floor Out Patients Building, Edinburgh EH4 2XU, UK. 11 beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing's syndrome. Transgenic mice over-expressing 11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected from these metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has been achieved in liver with carbenoxolone, which enhances hepatic insulin sensitivity. Newer selective 11HSD1 inhibitors are in development, which may achieve reduced cortisol action in adipose tissue and confer therapeutic benefit in obese patients. PMID: 15026174 [PubMed - indexed for MEDLINE] 4233. Mol Cell Endocrinol. 2004 Feb 27;215(1-2):39-44. Regulation of aromatase expression by the nuclear receptor LRH-1 in adipose tissue. Clyne CD(1), Kovacic A, Speed CJ, Zhou J, Pezzi V, Simpson ER. Author information: (1)Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Vic. 3168, Australia. colin.clyne@med.monash.edu.au Aromatase is the enzyme responsible for estrogen production, and is the product of the CYP19 gene. This gene is under the control of many tissue-specific promoters, each of which is regulated by different cohorts of factors. In normal breast adipose tissue, relatively low levels of aromatase are expressed via the action of the adipose specific promoter I.4. Breast tumor-derived factors such as prostaglandin E(2) (PGE(2)) strongly stimulate aromatase expression via an alternative promoter, promoter II, leading to increased estrogenic drive and tumor growth. Understanding the mechanisms that regulate promoter II activity in tumorous breast may therefore identify new targets for breast cancer drug discovery. The current study describes the role of the orphan nuclear receptor LRH-1 and its co-regulators in modulating aromatase expression in breast adipose tissue. PMID: 15026173 [PubMed - indexed for MEDLINE] 4234. Curr Med Res Opin. 2004 Mar;20(3):295-304. Obesity as the core of the metabolic syndrome and the management of coronary heart disease. Shirai K(1). Author information: (1)Center for Diabetes, Endocrinology and Metabolism, Sakura Hospital, Toho University, Shimoshizu, Japan. kshira@kb3.so-net.ne.jp The global burden of coronary heart disease (CHD) has led to the introduction of international guidelines to minimize the morbidity and mortality that result from this condition. These guidelines recognize the contribution of multiple risk factors to the development of CHD and advocate a multifaceted approach to treatment. Obesity, particularly visceral adiposity, contributes to the clustering of many other risk factors, such as hypertension, insulin resistance/type 2 diabetes and dyslipidemia, within individual patients. The molecular mechanisms underlying the metabolic abnormalities induced by visceral adiposity have yet to be fully elucidated; however, adipocytokines such as adiponectin, tumor necrosis factor-alpha and resistin seem to play an important role in this process. Obesity is a major modifiable CHD risk factor, and the benefits of weight loss are numerous, leading to improvements in several co-morbidities. Guidelines advocate lifestyle changes to correct excess bodyweight and improve the CHD risk factor profile. In addition, pharmacologic therapy is recommended for the management of other risk factors, such as hypertension and dyslipidemia, which may not be adequately controlled by lifestyle changes alone. Lowering low-density lipoprotein cholesterol (LDL-C) levels is the primary target for drug therapy for CHD prevention, and statins are first-line lipid-modifying therapy. The introduction of more efficacious statins with favorable effects on the lipid profile will optimize the control of dyslipidemia. Combining these new treatments with lifestyle changes and drug therapies for managing other CHD risk factors, as part of a multifaceted approach to treatment, will have benefits for CHD prevention. PMID: 15025838 [PubMed - indexed for MEDLINE] 4235. J Nutr Biochem. 2004 Mar;15(3):130-41. Obesity and post-prandial lipid metabolism. Feast or famine? Martins IJ(1), Redgrave TG. Author information: (1)Centre for Human Genetics, Edith Cowan University, Joondalup Drive, Joondalup, Perth 6027, Australia. imartins@cyllene.uwa.edu.au Both in Western countries and in third world countries there is an increasing incidence of obesity. Obesity per se or insulin resistance associated with obesity may increase cardiovascular risk factors including dyslipidemia, hypertension and Type 2 diabetes. Over the past decade the understanding has increased of specific mediators in the hypothalamus that are involved in regulating food intake and body weight. In obese humans fasting plasma lipids can be normal but postprandial lipid metabolism is abnormal with an accumulation of triglyceride-rich remnant lipoproteins. In viscerally obese men chylomicron remnant catabolism was markedly decreased when compared with lean individuals. The decreased clearance of chylomicron remnants in viscerally obese subjects may be explained by competition between chylomicron remnants and the increased hepatic production of VLDL for clearance by low density lipoprotein receptors. Increased food intake in rodent models of obesity was shown to be associated with a delay in the catabolism of remnant lipoprotein particles. Prevention of hyperphagia was found to correct the impairment in the metabolism of remnant lipoproteins. Under fasting and food restricted conditions the improvement of remnant metabolism was associated with an increased oxidation of remnant lipids as determined by a novel stable isotope breath test. Anti-obesity and lipid lowering drugs have been used for the treatment of obesity. Inhibitors of cholesterol synthesis inhibitors (statins) have been shown to be effective in treating dyslipidemia. Inhibition of cholesterol synthesis with Atorvastatin was shown to improve chylomicron metabolism by increasing chylomicron remnant catabolism in obese subjects as assessed by the newly developed stable isotope breath test. PMID: 15023394 [PubMed - indexed for MEDLINE] 4236. News Physiol Sci. 2004 Apr;19:67-74. Central pathways controlling brown adipose tissue thermogenesis. Morrison SF(1). Author information: (1)Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon 97006. Heat production in brown adipose tissue contributes to cold defense, to stress-induced increases in body temperature, and to energy balance. Elucidating the functional organization of the central network controlling the sympathetic outflow to brown adipose tissue could provide a framework for understanding how dysregulation of thermogenesis contributes to hyperthermia and to obesity. PMID: 15016906 [PubMed - indexed for MEDLINE] 4237. Semin Neonatol. 2004 Feb;9(1):67-74. Long-term metabolic consequences of being born small for gestational age. Levy-Marchal C(1), Jaquet D, Czernichow P. Author information: (1)INSERM Unit 457, Robert Debré Hospital, 75019 Paris, France. clairelm@inserm.fr This article reviews the evidence for fetal and early origins of type 2 diabetes, insulin resistance, dyslipidaemia and obesity. Particular emphasis is given to the role of adipose tissue in catch-up growth and long-term metabolic complications following restricted fetal growth. To date, several pathways have been proposed to explain the development of insulin resistance following restricted fetal growth, but no precise mechanisms have been demonstrated. It appears that early postnatal growth may also be a critical step. PMID: 15013477 [PubMed - indexed for MEDLINE] 4238. Int J Biochem Cell Biol. 2004 Apr;36(4):658-66. Adult stem cell therapy for the heart. Fraser JK(1), Schreiber RE, Zuk PA, Hedrick MH. Author information: (1)MacroPore Biosurgery Inc., San Diego, CA 92121, USA. The purpose of this review is to summarize current data leading to and arising from recent clinical application of cellular therapy for acute myocardial infarct (heart attack) and congestive heart failure. We specifically focus on use of adult stem cells and compare and contrast bone marrow and adipose tissue; two different sources from which stem cells can be harvested in substantial numbers with limited morbidity. Cellular therapy is the latest in a series of strategies applied in an effort to prevent or mitigate the progressive and otherwise irreversible loss of cardiac function that frequently follows a heart attack. Unlike surgical, pharmacologic, and gene transfer approaches, cellular therapy has the potential to restore cardiac function by providing cells capable of regenerating damaged myocardium and/or myocardial function. Skeletal muscle myoblast expansion and transfer allows delivery of cells with contractile function, albeit without any evidence of cardiomyogenesis or electrical coupling to remaining healthy myocardium. Delivery of endothelial progenitor cells (EPCs) which drive reperfusion of infarct zone tissues is also promising, although this mechanism is directed at halting ongoing degeneration rather than initiating a regenerative process. By contrast, demonstration of the ability of adult stem cells to undergo cardiomyocyte differentiation both in vitro and in vivo suggests a potential for regenerative medicine. This potential is being examined in early clinical studies. PMID: 15010330 [PubMed - indexed for MEDLINE] 4239. Int J Biochem Cell Biol. 2004 Apr;36(4):568-84. Mesenchymal stem cells: clinical applications and biological characterization. Barry FP(1), Murphy JM. Author information: (1)Osiris Therapeutics Inc., 2001 Aliceanna Street, Baltimore, MD 21231, USA. fbarry@osiristx.com Mesenchymal stem cells (MSCs) have been isolated from bone marrow, periosteum, trabecular bone, adipose tissue, synovium, skeletal muscle and deciduous teeth. These cells have the capacity to differentiate into cells of connective tissue lineages, including bone, fat, cartilage and muscle. A great deal has been learned in recent years about the isolation and characterization of MSCs, and control of their differentiation. These cells have generated a great deal of interest because of their potential use in regenerative medicine and tissue engineering and there are some dramatic examples, derived from both pre-clinical and clinical studies, that illustrate their therapeutic value. This review summarizes recent findings regarding the potential clinical use of MSCs in cardiovascular, neural and orthopaedic applications. As new methods are developed, there are several aspects to the implanted cell-host interaction that need to be addressed before we can fully understand the underlying mechanisms. These include the host immune response to implanted cells, the homing mechanisms that guide delivered cells to a site of injury and the differentiation in vivo of implanted cells under the influence of local signals. PMID: 15010324 [PubMed - indexed for MEDLINE] 4240. Praxis (Bern 1994). 2004 Feb 4;93(6):188-92. [Injectable therapy for urinary incontinence: a review]. [Article in German] Kuhn A(1), Gelman W, Kuhn P. Author information: (1)Frauenklinik, Inselspital Bern. Trans- or periurethral bladder neck injections are minimal invasive therapies for stress urinary incontinence which can be performed under local anaesthetic as an outpatient procedure. So far the best documented substance is collagen of bovine origin but other substances as silicone, autologous fat, chondrocytes and ethylenevinylalcohol are available. Success rates are between 60 and 80% with deteriorating long term results of approximately 30% requiring reinjection usually after 18 to 24 months. PMID: 15008014 [PubMed - indexed for MEDLINE] 4241. J Med Invest. 2004 Feb;51(1-2):20-8. Identification of possible protein machinery involved in the thermogenic function of brown adipose tissue. Kajimoto K(1), Yamazaki N, Kataoka M, Terada H, Shinohara Y. Author information: (1)Institute for Genome Research, The University of Tokushima, Tokushima, Japan. Brown adipose tissue (BAT) is believed to function by dissipating excess energy in mammals. It is very important to understand the energy metabolism held in BAT since disorder of its energy-dissipating function may cause obesity or lifestyle-related diseases such as hypertension and diabetes. This function in BAT is mainly attributable to uncoupling protein (UCP), specifically expressed in its mitochondria. This protein consumes excess energy as heat by dissipating the H+ gradient across the inner mitochondrial membrane that is utilized as a driving force for ATP synthesis. In this review article, in addition to providing a brief introduction to the functional properties of BAT and UCP, we also describe and discuss properties of cultured brown adipocytes and the results of our exploratory studies on protein components involved in the energy-dissipating function in BAT. PMID: 15000252 [PubMed - indexed for MEDLINE] 4242. Med Sci (Paris). 2004 Feb;20(2):219-24. [How to reach the right size?]. [Article in French] Roisin-Bouffay C(1), Gomer RH. Author information: (1)Centre d'immunologie de Marseille-Luminy, CNRS-Inserm-Université de la Méditerranée, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. roisin@ciml.univ-mrs.fr Very little is known about how the size of an organism, or a specific tissue in an organism, is regulated. Coordinating and regulating the size of tissues is necessary for proper development, wound healing, and regeneration. Defects in a tissue-size regulation mechanism could lead to birth defects or cancer. In addition, there is a strong psychological aspect to some areas of tissue size regulation, as many cosmetic surgery procedures involve enlarging or reducing the size of some body parts. This review addresses the little bit that we know about size regulation. A key concept is that the size of a tissue is the size of the component cells multiplied by the number of those cells. This breaks the size regulation problem down to two parts. The size of cells can be regulated by nutrient sensing and secreted factors, and may have an upper limit due to an upper limit of a genome's ability to produce mRNA's and thus proteins. To regulate the number of cells in a tissue, there are several simple theoretical models involving secreted factors. In one case, the cells can secrete a characteristic factor and the concentration of the factor will increase with the number of cells secreting it, allowing the tissue to sense its own size. In another scenario, a specific cell secretes a limited amount of a factor necessary for the survival of a target population, and this then limits the size of the target population. There are currently several examples of secreted factors that regulate tissue size, including myostatin, which regulates the amount of muscles, leptin, which regulates adipose tissue, and growth hormone and insulin-like growth factors which regulate total mass. In addition, there are factors such as the <> found in Dictyostelium that regulate the breakup of a tissue into sub-groups. A better understanding of how these factors regulate size will hopefully allow us to develop new therapeutic procedures to treat birth defects or diseases that affect tissue size. PMID: 14997443 [PubMed - indexed for MEDLINE] 4243. Sheng Li Ke Xue Jin Zhan. 2003 Oct;34(4):309-13. [Research advancement of adipocytokine adiponectin]. [Article in Chinese] Xiao FY(1), Lu FE. Author information: (1)Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030. The Adiponectin, an adipocytokine, is a plasma protein produced and secreted exclusively by adipose tissues. Adiponectin has important effects on angiocardiopathy, obesity and type 2 diabetes. In addition, adiponectin has certain roles in inflammation and hematopoiesis. Primarily results from adiponectin treatment of type 2 diabetes and some metabolism diseases suggest that adiponectin may serve as a potential and novel medicine. PMID: 14992011 [PubMed - indexed for MEDLINE] 4244. Expert Rev Mol Med. 2002 Dec 2;4(24):1-14. Pre- and early postnatal nongenetic determinants of type 2 diabetes. Ozanne SE(1), Hales CN. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QR, UK. Epidemiological studies have revealed strong and internationally reproducible links between early growth restriction and subsequent risk of developing type 2 diabetes and the metabolic syndrome (glucose intolerance, hypertension and hypertriglyceridaemia). This effect can exist independently of genetic factors. There is also direct evidence that poor maternal nutrition and maternal smoking cause both a reduction in birthweight and subsequent loss of glucose tolerance. High rates of growth in childhood may add to these effects. The 'thrifty phenotype' hypothesis attempts to explain these associations in terms of an altered programming of growth and metabolism that aids survival both pre- and postnatally. Type 2 diabetes is envisaged as a consequence of a clash of this programming with adult obesity. Tests of this hypothesis in animal models have shown that both the metabolic syndrome and type 2 diabetes can result from early growth restriction in rats consequent upon rat dams being fed a reduced protein, isocaloric diet (in which the protein is replaced by an equal quantity of nonprotein energy). A variety of other models of early growth restriction in rats lead to a similar phenotype. Several structural and gene expression changes have been shown in many tissues, including pancreas, liver, kidney, muscle and adipose tissue. Changes in gene expression include those concerned with hormone receptors, signalling and glycolytic enzymes. Many important questions remain for future research. PMID: 14987383 [PubMed - indexed for MEDLINE] 4245. Am J Clin Nutr. 2004 Mar;79(3):352-61. Effect of conjugated linoleic acid on body composition and plasma lipids in humans: an overview of the literature. Terpstra AH(1). Author information: (1)Department of Laboratory Animal Science, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands. a.h.m.terpstra@las.vet.uu.nl Studies in mice have indicated that feeding diets containing 0.5-1% conjugated linoleic acid (CLA) considerably reduces body fat. These findings have attracted much interest because of the potential use of CLA as a tool to promote weight loss in humans. Several CLA studies in humans have now been published, and the objective of the present review was to give an overview of these experiments. Most of the studies were done in free-living subjects and were not strictly controlled for nutrient and energy intakes. None of the studies found a significant reduction in body weight, and only 2 studies showed a significant but relatively small body fat-lowering effect. Some studies suggested that CLA may have a tendency to increase lean body mass. Furthermore, there are indications from animal studies that CLA may have effects on plasma lipids. However, only one study in humans showed a significant HDL-cholesterol-lowering effect of CLA; in all the other studies, there were no significant effects on plasma total, LDL-, and HDL-cholesterol concentrations or on plasma triacylglycerol concentrations. Thus, the results of the studies in humans indicate that the effect of CLA on body fat is considerably less than that anticipated from mice studies and that CLA has no major effect on plasma lipids. PMID: 14985207 [PubMed - indexed for MEDLINE] 4246. Obes Res. 2004 Feb;12(2):180-6. A novel pathway to the manifestations of metabolic syndrome. Sonnenberg GE(1), Krakower GR, Kissebah AH. Author information: (1)Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. gsonnen@mcw.edu Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappa B activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome. PMID: 14981209 [PubMed - indexed for MEDLINE] 4247. Rev Med Liege. 2003 Dec;58(12):734-40. [Body mass changes at menopause: impact of therapeutic strategies]. [Article in French] van den Brûle F(1), Gaspard U. Author information: (1)Service de Gynécologie, CHU Sart Tilman Liège. Weight gain constitutes a worry for perimenopausal patients. Current understanding of the problem indicates that age constitutes the most important factor, whereas menopause contributes to the development of android obesity. Hygyenodietetic counseling allows to reduce or even prevent these problems. Finally, hormone replacement therapy does not induce weight gain: it rather contributes to reduce central adipose deposition and improves the risk profile of menopausal patients, in relation to the nature and metabolic profile of the prescribed molecules. PMID: 14978847 [PubMed - indexed for MEDLINE] 4248. J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):251-8. Biology of aromatase in the mammary gland. Simpson ER(1). Author information: (1)Prince Henry's Institute of Medical Research, Clayton Vic, Australia. evan.simpson@med.monash.edu.au While the ovaries are the principal source of systemic estrogen in the premenopausal nonpregnant woman, other sites of estrogen biosynthesis are present throughout the body and these become the major sources of estrogen beyond menopause. These sites include the mesenchymal cells of the adipose tissue and skin, osteoblasts, and perhaps chondrocytes in bone, vascular endothelial and aortic smooth muscle cells, as well as a number of sites in the brain including the medial preoptic/anterior hypothalamus, the medial basal hypothalamus and the amygdala. These extragonadal sites of estrogen biosynthesis possess several fundamental features which differ from those of the ovaries. Principally, the estrogen synthesized within these compartments is probably only biologically active at a local tissue level in a paracrine or 'intracrine' fashion. Thus the total amount of estrogen synthesized by these extragonadal sites may be small, but the local tissue concentrations achieved are probably quite high, and exert significant biological influence locally. Thus these sources of estrogen play an important but hitherto largely unrecognized, physiological and pathophysiological role. PMID: 14973387 [PubMed - indexed for MEDLINE] 4249. Curr Hypertens Rep. 2004 Feb;6(1):66-73. Metabolic syndrome X: an inflammatory condition? Das UN(1). Author information: (1)Reflexis Systems, Inc., 1420 Providence Highway, Suite #266, Norwood, MA 02062, USA. undas@efasciences Obesity, atherosclerosis, insulin resistance and hyperinsulinemia, hyperlipidemia, essential hypertension, type 2 diabetes mellitus, and coronary heart disease (CHD) are the components of metabolic syndrome X and are associated with elevated plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, which are markers of inflammation. This suggests that metabolic syndrome X is a low-grade, systemic, inflammatory condition. Hence, instituting anti-inflammatory measures might be beneficial in preventing or halting the progress of metabolic syndrome X in high-risk populations. PMID: 14972097 [PubMed - indexed for MEDLINE] 4250. Diabetes Self Manag. 2003 Nov-Dec;20(6):100-1, 103-4. Getting to know ketones. Weil RM(1). Author information: (1)St. Luke's-Roosevelt Hospital Center, New York City, USA. PMID: 14971344 [PubMed - indexed for MEDLINE] 4251. Obes Rev. 2004 Feb;5(1):21-6. Fatty acid composition of fats is an early determinant of childhood obesity: a short review and an opinion. Ailhaud G(1), Guesnet P. Author information: (1)Institut de Recherche Signalisation, Biologie du Développement et Cancer, Centre de Biochimie, Faculté des Sciences, Parc Valrose, Nice, France. ailhaud@unice.fr The importance of dietary fat in human obesity remains a controversial issue as the prevalence of overweight and obesity has increased despite no dramatic change in the amount of ingested fats over the past few decades. However, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. In this review, we summarize experimental evidence which supports polyunsaturated fatty acids of the omega6 series as being potent promoters of both adipogenesis in vitro and adipose tissue development in vivo during the gestation/lactation period. This conclusion is also supported by epidemiological data from infant studies as well as by the assessment of the fatty acid composition of mature breast milk and formula milk. It is proposed that unnoticed changes in fatty acid composition of ingested fats over the last decades have been important determinants in the increasing prevalence of childhood overweight and obesity. PMID: 14969504 [PubMed - indexed for MEDLINE] 4252. Obes Rev. 2004 Feb;5(1):13-9. Caloric restriction, body fat and ageing in experimental models. Das M(1), Gabriely I, Barzilai N. Author information: (1)Institute for Ageing Research, Diabetes Research and Training Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Caloric restriction in animal models delays many age-related pathological conditions. Ageing rats have characteristically increased body weight, fat mass and a specific body fat distribution. This report will focus on the potential cause-effect relationship between increased fat mass and accelerated ageing. In humans, increased fat mass (obesity), and in particular increases in abdominal obesity as a result of deposition of visceral fat, are associated with the metabolic syndrome of ageing. This syndrome is associated with hyperinsulinaemia, dyslipidaemia, type 2 diabetes mellitus, atherosclerosis, hypercoagulability and hypertension. Fat tissue, however, plays a major role by secreting multiple metabolically active factors, which are potentially responsible for the development of insulin resistance. This article will review various experimental models (in animals) used to prevent insulin resistance of ageing by decreasing fat mass, and in particular, decreasing visceral fat. We suggest that this decrease in fat mass and its beneficial repercussions observed in ageing animal models may apply also to human ageing and its related pathology. PMID: 14969503 [PubMed - indexed for MEDLINE] 4253. Obes Rev. 2004 Feb;5(1):3-12. Role of candidate genes in the responses to long-term overfeeding: review of findings. Ukkola O(1), Bouchard C. Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808-4124, USA. Comment in Obes Rev. 2004 Feb;5(1):1-2. An overfeeding experiment conducted with 12 pairs of young male identical twins revealed that genetic factors were likely to play an important role in the response to caloric affluence. Significant intrapair resemblance was observed for the overfeeding-induced changes in body weight, fat mass, abdominal fat, fasting insulin, fasting cholesterol and triglycerides. In an attempt to define the molecular basis of these genotype-energy balance interaction effects, a panel of candidate genes has been investigated. Among the most significant findings, an adipsin polymorphism was associated with increases in body weight, total fat mass and subcutaneous fat in response to overfeeding. In addition, the beta2 adrenergic receptor gene Gln27Glu polymorphism showed a strong association with the gains in body weight and subcutaneous fat. Only a few markers were related to abdominal fat changes and, among them, the adipsin Hinc II polymorphism was associated with both computed tomography (CT)-measured abdominal visceral and total fat. The changes in insulin parameters brought about by long-term overfeeding were influenced most consistently by leptin receptor (LEPR) Gln223Arg and insulin-like growth factor-II Apa I polymorphisms. The LEPR Gln223Arg variant was also associated with the changes in plasma total triglycerides and high-density lipoprotein cholesterol concentrations. Further research with larger sample sizes should make it possible to identify the specific contributions of DNA sequence variations at multiple candidate gene loci in the complex response to chronic positive energy balance. PMID: 14969502 [PubMed - indexed for MEDLINE] 4254. Ann Biomed Eng. 2004 Jan;32(1):136-47. Genetic modification of stem cells to enhance bone repair. Gamradt SC(1), Lieberman JR. Author information: (1)Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Orthopaedic surgeons are often faced with difficult bone loss problems. Conventional bone grafting is usually accomplished with autogenous iliac crest bone graft that provides osteogenic cells, osteoinductive growth factors, and an osteoconductive matrix. Cadaveric bone allograft and bone graft substitutes are inferior to autogenous bone graft because they fail to supply osteogenic cells or a significant amount of osteoinductive growth factors. Recombinant growth factors such as bone morphogenetic protein-2 and osteogenic protein-1 are currently in clinical use but these proteins require supraphysiologic dosing and considerable expense while failing to provide a sustained osteoinductive signal at the implantation site. Mesenchymal stem cells capable of differentiating into mesodermal tissues have been isolated and expanded in culture from several different sources including bone marrow, adipose tissue, and muscle. In the presence of appropriate growth factors these cells can differentiate into osteoblast lineage cells that will form bone in vitro and in vivo. Recent attention has focused on genetic modification of mesenchymal stem cells to both produce and respond to osteogenic growth factors with the goal of developing a tissue engineering strategy for bone repair. This review examines the current potential and limitations of these cellular systems for bone repair. PMID: 14964729 [PubMed - indexed for MEDLINE] 4255. J Endocrinol Invest. 2003 Sep;26(9):855-60. Growth, body composition and hormonal axes in children and adolescents. Rogol AD(1). Author information: (1)University of Virginia, Charlottesville, Virginia, USA. arogol@cstone.net Growth and physical maturation are dynamic processes that encompass a broad range of cellular and somatic changes. Most investigators who study growth have focused on linear growth (change in height over time), but alterations in the relative body proportions, body composition, and the regional distribution of body fat (upper body vs lower body, axial vs appendicular, and sc vs deep visceral) are essential elements for growth and sexual maturation. In fact, cardiovascular risk assessment in the adult relies heavily on the regional distribution of body fat. The antecedents for the adult pattern of fat are clearly present in the adolescent, if not the younger child. Standards for each of these parameters have been developed for multiple ethnic and racial populations and aid materially in the identification of children with normal growth and physical development, variations within the broad normal (physiological) range, and those with clearly pathological growth patterns. PMID: 14964438 [PubMed - indexed for MEDLINE] 4256. J Endocrinol Invest. 2003 Sep;26(9):814-22. Regulation of body composition by androgens. Bhasin S(1). Author information: (1)UCLA School of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA. sbhasin@ucla.edu Human body can be viewed simplistically as being composed of fat-free and fat mass. With more sophisticated techniques, body composition can be broken down into fat mass, skeletal muscle mass, nonmuscle lean mass, visceral mass and bone mineral content. Similarly, it is possible to obtain estimates of total body water and intracellular and extracellular water contents. Regardless of the model of body composition assessment, it is evident that androgens are important determinants of body composition; there is no body compartment that is not directly or indirectly affected by androgens. The effects of androgens on skeletal muscle mass have received the greatest attention in recent literature; however, growing body of evidence suggests that androgens also regulate fat mass, bone mineral content, nonmuscle soft tissues and body water. PMID: 14964432 [PubMed - indexed for MEDLINE] 4257. AIDS Read. 2003 Dec;13(12 Suppl):S5-13. Current concepts of metabolic abnormalities in HIV patients: focus on lipodystrophy. Kolter DP(1). Author information: (1)Gastrointestinal Division, St. Luke's-Roosevelt Hospital Center, New York, USA. HIV infection is associated with a number of metabolic abnormalities, including lipodystrophy, a difficult-to-define disorder whose characteristics include hyperlipidemia, insulin resistance, and fat redistribution. Current data suggest that lipodystrophy is caused by multiple factors. Dual-nucleoside reverse transcriptase inhibitor therapy combined with protease inhibitor therapy has been shown to increase the risk of metabolic abnormalities, but susceptibility independent of drug effects has also been shown. While many of the treatments for the broad range of signs and symptoms of lipodystrophy bring about improvements in patient status, none have been demonstrated to bring about a return to baseline levels. PMID: 14959694 [PubMed - indexed for MEDLINE] 4258. Exp Clin Endocrinol Diabetes. 2004 Jan;112(1):2-9. Hormonal and nutritional regulation of adipose tissue mitochondrial development and function in the newborn. Mostyn A(1), Pearce S, Stephenson T, Symonds ME. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham, United Kingdom. Growth, development, and maturation of adipose tissue in the fetus can determine both survival at birth as well as having longer term consequences for adult disease. The mitochondrial proteins uncoupling protein (UCP) 1, voltage dependent anion channel (VDAC), and cytochrome c have an important role in cellular energy regulation. Activity of these proteins is particularly important during the transition from fetal to neonatal life when cellular energy requirements are at near maximal rates. The regulation of these proteins by endocrine factors is highly complex and may be dependent on both fetal number and maternal nutrition. The cytokine hormones leptin and prolactin have well established functions in energy regulation and lactation respectively. However, recent data proposes a role in regulation of mitochondrial proteins, particularly UCP1, and thermogenesis. Cortisol is an adrenal hormone with a critical role in fetal tissue maturation, especially the lung. It has now been shown to influence the abundance of UCP1 in the fetus, a role that may in part be regulated by the metabolically active thyroid hormone triiodothyronine. A greater understanding of the regulation of mitochondrial proteins within adipose tissue by endocrine and nutritional factors is likely to be important in preventing neonatal morbidity and mortality. It could also add substantially to our understanding of pathological conditions such as obesity and non-insulin dependent diabetes. PMID: 14758565 [PubMed - indexed for MEDLINE] 4259. Int J Obes Relat Metab Disord. 2004 Apr;28(4):500-2. Uncoupling proteins: gender dependence and their relation to body weight control. Rodríguez AM(1), Palou A. Author information: (1)Departament de Biologia Fonamental i Ciències de la Salut, Ed. Guillem Colom, Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Universitat de les Illes Balears, Palma de Mallorca, Spain. amrodriguez@uib.es Members of the uncoupling protein (UCP) family have different purported functions, which can be either directly or indirectly related to the control of body weight. In this sense, most studies on this topic have been carried out using male subjects, although different works with males and females have shown important sex-associated differences in the regulation of these proteins; for instance, sex differences have been shown in the cold-, diet- and overweight-induced expression of brown adipose tissue UCP1 and also in the correlation of muscle UCP3 with overweight. In these kinds of studies, models of obesity such as cafeteria diet feeding and postcafeteria have been very useful. Moreover, sex hormones have been shown to modulate UCP1 expression in brown adipocytes in vitro. All these sex-dependent differences, as well as sex differences in body weight gain under a hypercaloric diet, could be related to the different respective biological functions of males and females, taking into account the fact that the gender effect in future studies on obesity could be of interest. PMID: 14758347 [PubMed - indexed for MEDLINE] 4260. EMBO Rep. 2004 Feb;5(2):142-7. Peroxisome proliferator-activated receptor-gamma: too much of a good thing causes harm. Cock TA(1), Houten SM, Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) helps to translate 'what you eat' into 'what you are' because it allows dietary fatty acids (PPARgamma ligands) to modulate gene transcription. Treatments for diabetes include PPARgamma activators, as they sensitize the body to insulin. Our understanding of PPARgamma function has recently been enhanced by a flurry of human and mouse genetic studies, and the characterization of new PPARgamma ligands. This insight has led us to propose that modulating PPARgamma activity, rather than activating it, might be the most effective strategy for treating metabolic disorders, as this will improve glucose homeostasis while preventing adipogenesis. PMCID: PMC1298993 PMID: 14755307 [PubMed - indexed for MEDLINE] 4261. Ann Pharmacother. 2004 Mar;38(3):448-57. Epub 2004 Jan 30. Pharmacologic therapy for HIV-associated lipodystrophy. Benavides S(1), Nahata MC. Author information: (1)College of Pharmacy, Ohio State University, Columbus, OH 43210, USA. OBJECTIVE: To evaluate the efficacy and safety of pharmacologic therapy in the treatment of HIV-associated lipodystrophy, with a focus on the treatment of fat redistribution. Drug therapies that have been shown to be beneficial in other forms of lipodystrophy and are currently being evaluated in HIV-associated lipodystrophy are also discussed. DATA SOURCES: A MEDLINE search was conducted from 1996 to February 2003. Bibliographies of all articles were reviewed and pertinent articles were included. Abstracts from major meetings in 2002 and 2003 were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All published studies were included in the review. DATA SYNTHESIS: Lipodystrophy has become more prevalent in patients with HIV. Lipodystrophy consists of adipose redistribution and metabolic abnormalities including dyslipidemia and insulin resistance. Treatment of lipodystrophy has been directed at either decreasing the amount of visceral adipose tissue (VAT), dorsocervical adipose tissue (commonly known as buffalo hump) and/or increase subcutaneous adipose tissue (SAT). Recombinant human growth hormone (rhGH) decreases VAT and buffalo hump, although it has been associated with a high frequency of adverse effects. Metformin and the thiazolidinediones have favorable metabolic effects, but were not found to be effective in correcting body compositional changes associated with lipodystrophy. Anabolic steroids and l-carnitine are not effective in the treatment of lipodystrophy. CONCLUSIONS: No drug therapy exists to fully ameliorate or correct the cosmetic changes of HIV-associated lipodystrophy. Clinicians must weigh the benefits and risks of each agent and individualize treatment for each patient. PMID: 14755064 [PubMed - indexed for MEDLINE] 4262. Recent Prog Horm Res. 2004;59:359-93. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. Seckl JR(1), Morton NM, Chapman KE, Walker BR. Author information: (1)Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome. PMID: 14749510 [PubMed - indexed for MEDLINE] 4263. Recent Prog Horm Res. 2004;59:267-85. Insulin and leptin as adiposity signals. Benoit SC(1), Clegg DJ, Seeley RJ, Woods SC. Author information: (1)Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA. There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simultaneously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropeptide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits. PMID: 14749506 [PubMed - indexed for MEDLINE] 4264. Recent Prog Horm Res. 2004;59:245-66. The use of animal models to dissect the biology of leptin. Chehab FF(1), Qiu J, Ogus S. Author information: (1)Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USA. Our understanding of the effects of leptin have stemmed mainly from animal studies, which continue to leave important clues of its roles in physiology, metabolism, neuroscience, and cell signaling. Since its discovery, leptin has been linked to various pathways, either directly at its primary site of action in the hypothalamus, or indirectly via downstream effector pathways such as in adipocytes and muscle. Leptin's importance is exemplified by the lack of redundant backup mechanisms, since leptin-deficient mice are obese, diabetic, and sterile. Investigations uncovering the pleiotropic actions of leptin were unfolded mainly from rodent models. Thus, this chapter focuses on these studies and, more specifically, on those findings recently brought forward by transgenic mice overexpressing leptin. The vast amount of biology that has been ascribed to leptin encompasses effects on food intake, insulin sensitivity, adiposity, thermogenesis, reproduction, immunity, and bone regulation. Mechanisms underlying leptin's action revolve essentially around neural pathways but also encompass to a lesser extent peripheral mechanisms. The roles of leptin along these axes are reviewed, with particular emphasis on pathways and phenotypes generated by transgenic hyperleptinemia. An evolutionary significance of hyperleptinemia in association with development of leptin resistance is suggested as a protective armament against some of the detrimental effects caused by hyperleptinemia in transgenic mice overexpressing leptin. PMID: 14749505 [PubMed - indexed for MEDLINE] 4265. Recent Prog Horm Res. 2004;59:169-205. Hypertension and obesity. Aneja A(1), El-Atat F, McFarlane SI, Sowers JR. Author information: (1)Department of Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA. Obesity is a common problem in much of the western world today in that is linked directly with several disease processes, notably, hypertension. It is becoming clear that the adipocyte is not merely an inert organ for storage of energy but that it also secretes a host of factors that interact with each other and may result in elevated blood pressure. Of particular importance is the putative role of leptin in the causation of hypertension via an activation of the sympathetic nervous system and a direct effect on the kidneys, resulting in increased sodium reabsorption leading to hypertension. Obesity per se may have structural effects on the kidneys that may perpetuate hypertension, leading to an increased incidence of end-stage renal disease that results in further hypertension. Adipose tissue may elaborate angiotensin from its own local renin-angiotensin system. The distribution of body fat is considered important in the genesis of the obesity-hypertension syndrome, with a predominantly central distribution being particularly ominous. Weight loss is the cornerstone in the management of the obesity-hypertension syndrome. It may be achieved with diet, exercise, medications, and a combination of these measures. Anti-obesity medications that are currently undergoing clinical trials may play a promising role in the management of obesity and may also result in lowering of blood pressure. Antihypertensives are considered important components in the holistic approach to the management of this complex problem. PMID: 14749502 [PubMed - indexed for MEDLINE] 4266. Diabetes. 2004 Feb;53 Suppl 1:S152-8. Leptin effects on pancreatic beta-cell gene expression and function. Seufert J(1). Author information: (1)Division of Metabolism, Medizinische Poliklinik, University of Wuerzburg, Wuerzburg, Germany. j.seufert@mail.uni-wuerzburg.de The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic beta-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop-the so-called "adipo-insular axis." Multiple signal transduction pathways are involved in leptin signaling in pancreatic beta-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic beta-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance." This leptin resistance at the level of the pancreatic beta-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients. PMID: 14749281 [PubMed - indexed for MEDLINE] 4267. Diabetes. 2004 Feb;53 Suppl 1:S143-51. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Havel PJ(1). Author information: (1)Department of Nutrition, University of California, Davis, Davis, California 95616, USA. pjhavel@ucdavis.edu Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones-leptin, acylation stimulating protein (ASP), and adiponectin-with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity. Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-gamma and may contribute to increased insulin sensitivity. Adiponectin and leptin cotreatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase-induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status. These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance. PMID: 14749280 [PubMed - indexed for MEDLINE] 4268. Diabetes. 2004 Feb;53 Suppl 1:S60-5. Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells. Kim HI(1), Ahn YH. Author information: (1)Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea. Type 2 diabetes develops in the context of both insulin resistance and beta-cell failure. Thiazolidinediones are a class of antidiabetic agents that are known to improve insulin sensitivity in various animal models of diabetes. The improved insulin sensitivity may be achieved either by systemic insulin sensitization or by direct action of peroxisome proliferator-activated receptor (PPAR)-gamma on the transcription of genes involved in glucose disposal. Evidence supporting the direct action of PPAR-gamma on glucose metabolism is observed in the genes involved in insulin-stimulated glucose disposal. We already showed that GLUT2 and beta-glucokinase were directly activated by PPAR-gamma. Recently, we have identified and characterized the functional PPAR response element in the GLUT2 and liver type glucokinase (LGK) promoter of the liver. It is well known that adipose tissue plays a crucial role in antidiabetic action of PPAR-gamma. In addition, PPAR-gamma can directly affect liver and pancreatic beta-cells to improve glucose homeostasis. PMID: 14749267 [PubMed - indexed for MEDLINE] 4269. Diabetes. 2004 Feb;53 Suppl 1:S43-50. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Ferré P(1). Author information: (1)INSERM Unit 465, Cordeliers Biomedical Research Center, Paris, France. pferre@bhdc.jussieu.fr Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. Three isoforms (alpha, delta, and gamma) have been described. They act on DNA response elements as heterodimers with the nuclear retinoic acid receptor. Their natural activating ligands are fatty acids and lipid-derived substrates. PPAR-alpha is present in liver, heart, and, to a lesser extent, skeletal muscle. When activated, it promotes fatty acid oxidation, ketone body synthesis, and glucose sparing. Fibrates, which are used as hypolipidemic drugs, are ligands of PPAR-alpha. PPAR-delta is ubiquitous and could also favor fatty acid oxidation in tissues in which PPAR-alpha is absent or less expressed. PPAR-gamma is expressed in adipose tissue, lower intestine, and cells involved in immunity. Activation of PPAR-gamma induces the differentiation of preadipocytes into adipocytes and stimulates triglyceride storage. Thiazolidinediones are compounds used as hypoglycemic, muscle insulin-sensitizing agents in type 2 diabetes. Unexpectedly, they are activators of PPAR-gamma. Their action on muscle insulin sensitivity may be secondary to the lowering of circulating lipids on PPAR-gamma activation and to the secretion by adipocytes of insulin-sensitizing hormones such as adiponectin, all promoting glucose utilization. The PPARs are thus major regulators of lipid and glucose metabolism, allowing adaptation to the prevailing nutritional environment. PMID: 14749265 [PubMed - indexed for MEDLINE] 4270. Biochem Soc Trans. 2004 Feb;32(Pt 1):103-6. Adipocyte cholesterol balance in obesity. Le Lay S(1), Ferré P, Dugail I. Author information: (1)INSERM U 465, Institut Biomedical des Cordeliers, 15, rue de l'école de médecine, 75006 Paris, France. Adipose tissue is specialized in the storage of energy in the form of triacylglycerol. Within the fat cell, triacylglycerols are found in a well-defined structural compartment called the lipid droplet, which occupies the vast majority of the fat cell volume. However, many other lipids are present in the lipid droplet. These include sterols, carotenoids, cholecalciferol and lipophilic toxic pollutants of the environment such as dioxins and tocopherols. The topic of this article is the role of fat cell cholesterol in adipose tissue physiology and its potential implication in pathological states such as obesity. PMID: 14748723 [PubMed - indexed for MEDLINE] 4271. Medicine (Baltimore). 2004 Jan;83(1):18-34. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Misra A(1), Peethambaram A, Garg A. Author information: (1)Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 75390-9052, USA. We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities in 35 patients with acquired partial lipodystrophy (APL) seen by us over 8 years, and also review 220 cases of APL described in the literature. Based on the review and our experience, we propose that the essential diagnostic criterion for APL is the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. Analysis of the pooled data revealed that female patients were affected approximately 4 times more often than males. The median age of the onset of lipodystrophy was 7 years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Approximately 83% of APL patients had low complement (C) 3 levels and the presence of polyclonal immunoglobulin C3 nephritic factor. Twenty-two percent of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of approximately 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 +/- 10.3 yr vs 7.7 +/- 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02). The pathogenesis of fat loss and MPGN in patients with APL remains unclear, but activation of an alternate complement pathway has been implicated. Treating the cosmetic disfigurement by surgical procedures has yielded inconsistent results. The use of thiazolidinediones to treat fat loss in patients with APL remains anecdotal. Prognosis is mainly determined by renal insufficiency due to MPGN. PMID: 14747765 [PubMed - indexed for MEDLINE] 4272. Diabetes. 2004 Feb;53(2):276-84. Chronic sympathetic activation: consequence and cause of age-associated obesity? Seals DR(1), Bell C. Author information: (1)Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA. seals@colorado.edu Primary aging in adult humans is associated with a progressive, tonic activation of the peripheral sympathetic nervous system (SNS). The purpose of this SNS activation and its physiological impact are, however, unknown. We hypothesize that the chronic stimulation of the SNS with aging is driven in part by a progressive accumulation of body fat. This "error" is sensed by the central nervous system via increases in adiposity-sensitive humoral signals (e.g., leptin, insulin) that cross the blood-brain barrier, activate subcortical areas involved in the regulation of energy balance (e.g., ventromedial hypothalamus), and stimulate SNS outflow to peripheral tissues. The SNS activation is intended to increase beta-adrenergic thermogenesis in order to expend excess energy as heat rather than by storage of fat. Recent evidence, however, indicates that these adjustments are not effective in augmenting energy expenditure with aging. Indeed, older sedentary adults demonstrate reduced, not increased, beta-adrenergic stimulation of metabolic rate because of reduced tissue responsiveness, presumably mediated by SNS-induced impairment of beta-adrenergic signaling. As a result, age-associated SNS activation, initiated as a consequence of accumulating adiposity with the intent of preventing further fat storage, ironically, may in time evolve into a potential mechanism contributing to the development of obesity with aging. PMID: 14747276 [PubMed - indexed for MEDLINE] 4273. Annu Rev Pharmacol Toxicol. 2004;44:297-323. Beta-adrenergic receptors and regulation of energy expenditure: a family affair. Robidoux J(1), Martin TL, Collins S. Author information: (1)Departments of Pharmacology, Psychiatry, and Behavioral Sciences, and The Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, North Carolina 27710, USA. robid001@mc.duke.edu The family of adrenergic receptors (ARs) expressed in adipocytes includes three sibling betaARs and two alphaAR cousins. Together they profoundly influence the mobilization of stored fatty acids, secretion of fat-cell derived hormones, and the specialized process of nonshivering thermogenesis in brown adipose tissue. The two types of fat cells that compose adipose tissue, brown and white, are structurally and functionally distinct. Studies on the mechanisms by which individual betaAR regulates these cell-specific functions have recently uncovered new signal transduction cascades involved in processes traditionally ascribed to adenylyl cyclase/cAMP/protein kinase A system. They illustrate how betaAR signaling can orchestrate a coordinated set of intracellular responses for fine control of metabolic balance. PMID: 14744248 [PubMed - indexed for MEDLINE] 4274. Biochimie. 2003 Dec;85(12):1199-205. Glyceroneogenesis revisited. Hanson RW(1), Reshef L. Author information: (1)Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-3945, USA. rwh@po.cwru.edu Glyceroneogenesis is the synthesis of 3-glycerol phosphate by an abbreviated version of gluconeogenesis. The research that led to the discovery of glyceroneogenesis in white adipose tissue is presented. This pathway is active during fasting in white and brown adipose tissue and in the liver as part of the triglyceride/fatty acid cycle. Glyceroneogenesis is critical for the extensive recycling of free fatty acid (FFA) back to triglyceride that occurs in mammals, including humans, after lipolysis, when up to 65% of the fatty acids are re-esterified back to triglyceride. The rate-limiting enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK-C). Transcription of this gene is induced in adipose tissue and liver during fasting. Ablation of expression of the gene for PEPCK-C in white adipose tissue of mice results in lipodsytrophy, while overexpression of the gene for this enzyme in adipose tissue causes obesity. The critical role of glyceroneogenesis in diabetes was suggested by experiments in which the gene for PEPCK-C is induced in white adipose tissue by rosiglitazone, a drug used to control diabetes in humans. This was accompanied by a marked decrease in FFA release from adipose tissue due to an induction in glyceroneogenesis in the tissue. Since the chronic release of FFA by adipose tissue is a critical factor in the development Type 2 diabetes, it is likely that rosiglitazone acts in part by stimulating transcription of the gene for PEPCK-C, thereby increasing rate of glyceroneogenesis and lowering the rate of FFA release from adipose tissue. PMID: 14739071 [PubMed - indexed for MEDLINE] 4275. Obes Surg. 2003 Dec;13(6):954-64. Measuring outcomes following bariatric surgery: weight loss parameters, improvement in co-morbid conditions, change in quality of life and patient satisfaction. Ballantyne GH(1). Author information: (1)Hackensack University Medical Center, Hackensack, NJ, USA. ghb@lapsurgery.com Restrictive and particularly malabsorptive bariatric operations achieve significant sustained weight loss. Results from different operations have been difficult to compare. The aims of this review are: 1) to indicate the limitations of outcomes reported as weight-related parameters; 2) to document some of the patient characteristics that impact weight loss; 3) to assess the literature documenting improvement in obesity-related medical conditions; and 4) to review studies that quantitate changes in health-related quality of life (QoL). Weight-related parameters such as body mass index and % excess weight inconsistently correlate with body fat. Direct determination of body fat with bioelectric impedance may offer more reliable outcome parameters. Patient characteristics such as gender, age, weight, body mass index, ethnicity, race and socioeconomic status affect weight loss following bariatric operations. Improvements in co-morbid conditions are poorly documented in many studies. Standardized instruments that assess health-related QoL have shown differing values. SF-36 has given inconsistent results following bariatric operations. Both BAROS and IWQoL-Lite have demonstrated significant improvements after surgery. Bariatric surgeons have rarely used patient satisfaction as an outcome parameter. This review suggests that bariatric operations should be judged by change in fat mass or fat mass index, improvement in obesity-related medical conditions, change in health-related QoL as judged by standardized instruments, and level of patient satisfaction. In addition, surgeons should characterize their study population and report outcomes for sub-populations. PMID: 14738691 [PubMed - indexed for MEDLINE] 4276. Postepy Hig Med Dosw. 2003;57(5):579-91. [Role of adiponectin--a protein secreted by adipose tissue in preventing atherosclerosis]. [Article in Polish] Karbowska J(1), Brzeziński M, Kochan Z. Author information: (1)Katedra Biochemii Akademii Medycznej w Gdańsku. Adiponectin is an adipocyte-specific secretory protein, which seems to play a protective role in different models of vascular injury. Adiponectin infiltrates in the subendothelial space of injured vascular walls and suppresses the expression of adhesion molecules on endothelial cells, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. Adiponectin also suppresses lipid accumulation in macrophages and macrophage-to-foam cell transformation. The ability of adiponectin to act as an anti-inflammatory and anti-atherogenic factor has made this novel adipocytokine a promising therapeutic tool for the future. PMID: 14737971 [PubMed - indexed for MEDLINE] 4277. Clin Endocrinol (Oxf). 2004 Feb;60(2):153-60. Appetite regulation: from the gut to the hypothalamus. Neary NM(1), Goldstone AP, Bloom SR. Author information: (1)Department of Metabolic Medicine, Faculty of Medicine, Imperial College of Science Technology and Medicine, Hammersmith Campus, London, UK. PMID: 14725674 [PubMed - indexed for MEDLINE] 4278. Int J Obes Relat Metab Disord. 2004 Feb;28(2):327-9. Uncoupling proteins: gender-dependence and their relation to body weight control. Rodríguez AM(1), Palou A. Author information: (1)Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Palma de Mallorca, Spain. amrodriguez@uib.es The members of the uncoupling protein family have different purported functions, which can be either directly or indirectly related to the control of body weight. In this sense, a great part of the studies carried out on this topic have been made using male subjects, although different works with male and female subjects have shown important sex-associated differences in the regulation of these proteins; for instance, sex differences have been shown in the cold-, diet- and overweight-induced expression of brown adipose tissue UCP1 and also in the correlation of muscle UCP3 with overweight. In these kinds of studies, models of obesity such as the cafeteria diet feeding and postcafeteria have been very useful. Moreover, sex hormones have been shown to modulate UCP1 expression in brown adipocytes in vitro. All of these sex-dependent differences, as well as sex differences in body weight gain under a hypercaloric diet, could be related to the different respective biological functions of male and female subjects and taking into account the gender effect in future studies on obesity could be of interest. PMID: 14724666 [PubMed - indexed for MEDLINE] 4279. Semin Dial. 2004 Jan-Feb;17(1):44-52. Eating behavior disorders in uremia: a question of balance in appetite regulation. Aguilera A(1), Codoceo R, Bajo MA, Iglesias P, Diéz JJ, Barril G, Cigarrán S, Alvarez V, Celadilla O, Fernández-Perpén A, Montero A, Selgas R. Author information: (1)Servicio de Nefrología, Hospitales Universitarios de la Princesa y la Paz, Madrid, Spain. Eating and appetite disorders are frequent complications of the uremic syndrome which contribute to malnutrition in dialysis patients. The data suggest that uremic anorexia may occur with or without abdominal and visceral fat accumulation despite a lower food intake. This form of obesity (i.e., with low food intake and malnutrition) is more common in dialysis patients than obesity with high food intake. This article reviews the current knowledge regarding mechanisms responsible for appetite regulation in normal conditions and in uremic patients. Anorexia in dialysis patients has been historically considered as a sign of uremic toxicity due to "inadequate" dialysis as judged by uncertain means ("middle molecule" accumulation, Kt/V, "peak-concentration hypothesis," and others). We propose the tryptophan-serotonin hypothesis, based on a uremia-induced disorder in patients' amino acid profile--low concentrations of large neutral and branched-chain amino acids with high tryptophan levels. A high rate of tryptophan transport across the blood-brain barrier increases the synthesis of serotonin, a major appetite inhibitor. Inflammation may also play a role in the genesis of anorexia and malnutrition. For example, silent infection with Helicobacter pylori may be a source of cytokines with cachectic action; its eradication improves appetite and nutrition. The evaluation of appetite should take into account cultural and social aspects. Uremic patients showed a universal trend to carbohydrate preference and red meat refusal compared to healthy people. In contrast, white meat was less problematic. Uremic patients also have a remarkable attraction for citrics and strong flavors in general. Eating preferences or refusals have been related to the predominance of some appetite peptide modulators. High levels of cholecystokinin (CCK) (a powerful anorexigen) are associated with early satiety for carbohydrates and neuropeptide Y (NPY) (an orexigen) with repeated food intake. Obesity and elevated body mass index often falsely suggest a good nutritional status. In uremic patients (a hyperinsulinemia state), disorders in the regulation of fat distribution (insulin, leptin, insulin-like growth factor [IGF]-1, fatty acids, and disorders in receptors for insulin, lipoprotein lipase, mitochondrial uncoupling protein-2, and beta 3 adrenoreceptors) may cause abdominal fat accumulation without an increase in appetite. Finally, appetite regulation in uremia is highly complex. Disorders in adipose tissue, gastrointestinal and neuropeptides, retained or hyperproduced inflammatory end products, and central nervous system changes may all play a role. Uremic anorexia may be explained by a hypothalamic hyperserotoninergic state derived from a high concentration of tryptophan and low branched-chain amino acids. PMID: 14717811 [PubMed - indexed for MEDLINE] 4280. Physiol Rev. 2004 Jan;84(1):277-359. Brown adipose tissue: function and physiological significance. Cannon B(1), Nedergaard J. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden. The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogenesis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings. PMID: 14715917 [PubMed - indexed for MEDLINE] 4281. Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):644-9. Epub 2004 Jan 8. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. den Boer M(1), Voshol PJ, Kuipers F, Havekes LM, Romijn JA. Author information: (1)TNO Prevention and Health, Gaubius Laboratory Leiden, Leiden, The Netherlands. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance, and type 2 diabetes mellitus. Recently, attention has been focused on the excessive accumulation of triglycerides (TG) in the liver as part of this syndrome. In this review, important principles of the pathophysiological involvement of the liver in the metabolic syndrome obtained in rodent models are summarized. We focus on non-alcoholic causes of steatosis, because the animal experiments we refer to did not include alcohol as an experimental condition. In general, there is continuous cycling and redistribution of non-oxidized fatty acids between different organs. The amount of TG in an intrinsically normal liver is not fixed but can readily be increased by nutritional, metabolic, and endocrine interactions involving TG/free fatty acid (FFA) partitioning and TG/FFA metabolism. Several lines of evidence indicate that hepatic TG accumulation is also a causative factor involved in hepatic insulin resistance. Complex interactions between endocrine, metabolic, and transcriptional pathways are involved in TG-induced hepatic insulin resistance. Therefore, the liver participates passively and actively in the metabolic derangements of the metabolic syndrome. We speculate that similar mechanisms may also be involved in human pathophysiology. PMID: 14715643 [PubMed - indexed for MEDLINE] 4282. Endocrinol Metab Clin North Am. 2003 Dec;32(4):895-914. Obesity and endocrine disease. Kokkoris P(1), Pi-Sunyer FX. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Hellenic Air Force General Hospital, 3 P. Kanelopoulou Street, Athens 11525, Greece. pakokkoris@hotmail.com Several endocrine abnormalities are reported in obesity. Some of these abnormalities are considered as causative factors for the development of obesity, whereas others are considered to be secondary effects of obesity and usually are restored after weight loss. Thyroid hormones usually are normal in obesity, with the exception of T3 which is elevated. Prolactin is normal but prolactin response to different stimuli is blunted. GH is low and GH response to stimuli is blunted. IGF-I levels are normal or elevated. Cortisol, ACTH, and urine free cortisol levels are usually normal; however, a hyperresponsiveness of the HPA axis with increased cortisol and ACTH response to stimulatory tests is observed in centrally obese individuals. Total testosterone and SHBG levels are low, but free testosterone levels are usually normal in obese men. LH and FSH levels usually are normal and estrogens are elevated. Norepinephrine levels are elevated, whereas epinephrine levels are low or normal. Aldosterone levels are elevated but renin activity is usually normal. Parathyroid hormone levels are elevated with normal serum calcium levels and increased urine calcium levels. Monogenic mutations that result in severe obesity have been described in several individuals. Also, several endocrine diseases have obesity as one their clinical manifestations. Hypothyroidism, Cushing's syndrome, GH and testosterone deficiency, polycystic ovarian syndrome, insulinoma, hypothalamic lesions, and genetic syndromes often present with obesity. In most of these conditions, appropriate treatment of the primary disease results in weight loss. In addition, the fat cell has been found to be an endocrine organ that produces several peptides that are bioactive and participate in the regulation of adipocyte function. PMID: 14711067 [PubMed - indexed for MEDLINE] 4283. Endocrinol Metab Clin North Am. 2003 Dec;32(4):823-54. Obesity and hypertension. El-Atat F(1), Aneja A, Mcfarlane S, Sowers J. Author information: (1)Division of Cardiovascular Diseases, Department of Medicine, State University of New York Health Science Center and Veteran Affairs Hospital, 450 Clarkson Avenue, Brooklyn, NY 11201, USA. This article has discussed some of the mechanisms involved in the causal relation between obesity and hypertension. Obesity causes a constellation of maladaptive disorders that individually and synergistically contribute to hypertension, among other cardiovascular morbidities. Well-designed population-based studies are needed to assess the individual contribution of each of these disorders to the development of hypertension. In addition, because the control of obesity may eliminate 48% of the hypertension in whites and 28% in blacks, this article has offered an up-to-date on the management of this problem. It is hoped that this article will help scientists formulate a thorough understanding of obesity hypertension and form the basis for more research in this field, which has a huge impact on human life. PMID: 14711064 [PubMed - indexed for MEDLINE] 4284. Curr Top Dev Biol. 2003;58:137-60. Differentiation potential of adipose derived adult stem (ADAS) cells. Gimble JM(1), Guilak F. Author information: (1)Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA. gimblejm@pbrc.edu PMID: 14711015 [PubMed - indexed for MEDLINE] 4285. Biol Psychiatry. 2004 Jan 1;55(1):1-9. Association of depression with medical illness: does cortisol play a role? Brown ES(1), Varghese FP, McEwen BS. Author information: (1)Psychoneuroendocrine Research Program, Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8849, USA. Elevated cortisol in a subset of depressed patients is an enduring and well-replicated finding. Much interest has focused on the possible effects of depression on the hippocampus; however, an emerging body of evidence suggests an association between depression and non-central nervous system illnesses. In this review, data on the effects of depression on the brain and other organ systems sensitive to elevated cortisol are discussed. From searches of the MEDLINE, PSYCHINFO, and Current Contents databases, and other sources, articles were found specifically related to depression and physical changes or medical conditions associated with corticosteroid excess in patients with Cushing's disease, including cognitive impairment, hippocampal atrophy, increased waist-to-hip ratio, bone loss, hypertension, diabetes, peptic ulcers, and hyperlipidemia. Data are strongest for a relationship between elevated cortisol and depression, hippocampal atrophy, cognitive impairment, abdominal obesity, and loss of bone density. Some evidence suggests an association between depression and hypertension, peptic ulcers, and diabetes. Depression does not appear to be associated with hyperlipidemia. The data provide some support for similar health effects in depressed patients and patients with Cushing's disease or the metabolic syndrome; however, additional studies are needed relating systemic effects of depression to cortisol. Limitations of the current literature, treatment implications, and possible directions for future research are discussed. PMID: 14706419 [PubMed - indexed for MEDLINE] 4286. Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S25-8. Adipose tissue, insulin action and vascular disease: inflammatory signals. Yudkin JS(1). Author information: (1)Diabetes and Cardiovascular Risk Academic Unit, University College London, London, UK. j.yudkin@ucl.ac.uk Insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly an excess of central fat. Many of the features that have been ascribed to the metabolic or insulin-resistance syndrome are also more commonly found in obese subjects. These phenotypes include diabetic dyslipidaemia, elevation of levels of plasminogen activator inhibitor-1, microalbuminuria and endothelial dysfunction. More recently, features of acute-phase activation and low-grade inflammation, including elevated levels of fibrinogen, C-reactive protein and interleukin-6, have been associated with (central) obesity. Adipose tissue generation of cytokines has been shown in vitro and in vivo, and a number of novel cytokine-like molecules, collectively termed adipocytokines, have been identified as adipocyte products. While several of these, such as tumour necrosis factor-alpha, may act predominantly in autocrine or paracrine fashion, others are released into the systemic circulation, acting as signalling molecules to remote tissues, including liver, skeletal muscle and endothelium. A clearer understanding of adipose tissue signalling, and its contribution to the state of low-grade inflammation of obesity, will require physiological, as well as cellular and molecular, studies. PMID: 14704740 [PubMed - indexed for MEDLINE] 4287. Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S17-21. Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Moller DE(1), Berger JP. Author information: (1)Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA. david_moller@merck.com Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor isoforms with key roles in the regulation of lipid and glucose metabolism. Synthetic ligands for PPAR gamma (and PPAR alpha) have effects of promoting insulin sensitization in the context of obesity. Recent evidence suggests that activation of PPAR delta might produce similar effects. Both PPAR gamma and PPAR alpha have also been shown to produce selected anti-inflammatory effects and to reduce the progression of atherosclerosis in animals (alpha and gamma) or in humans (alpha). Mechanisms underlying insulin-sensitizing effects are complex. For PPAR gamma, direct effects on adipose tissue lipid metabolism with secondary benefits in liver and/or muscle (lipid levels and insulin signaling) have been implicated. For PPAR alpha, accelerated lipid catabolism may contribute to reduced muscle or liver 'steatosis'. Anti-inflammatory mechanisms as contributors to the beneficial metabolic effects of PPAR activation are also worth considering for the following reasons: (1) obesity and insulin resistance are associated with a proinflammatory milieu. (2) PPAR gamma has clear effects to oppose the effects of tumor necrosis factor-alpha (TNFalpha) in adipocytes. (3) effects of PPAR ligands on cytokine-mediated signaling (eg via NF-kappa B) may be expected to enhance insulin action. (4) Adipose production of several molecules that are implicated as markers or mediators of inflammation is reduced. (5) In humans, treatment with either PPAR alpha or PPAR gamma agonists has been shown to reduce circulating levels of proteins that serve as markers of inflammation. (6) Adiponectin, a fat-derived circulating factor that has been implicated as having anti-inflammatory activity, is induced by PPAR gamma agonism. PMID: 14704738 [PubMed - indexed for MEDLINE] 4288. Pituitary. 2003 Sep;6(2):97-102. Effects of growth hormone and prolactin on adipose tissue development and function. Flint DJ(1), Binart N, Kopchick J, Kelly P. Author information: (1)Hannah Research Institute, Ayr KA6 5HL, UK. flintd@hri.sari.ac.uk GH and PRL are both implicated in adipose tissue development. Whilst direct effects of GH have been clearly demonstrated, direct effects of PRL have been subject to considerable debate. Recent studies have however provided compelling evidence for PRL receptors on adipocytes and in vitro effects on leptin and lipoprotein lipase activity have been demonstrated. Quantitatively however these effects of PRL are less significant than those of GH and the most pronounced effects of PRL on adipose tissue are indirect, for example, during lactation, when prolactin drives milk synthesis which results in a homeorhetic shift towards lipid mobilization from adipose tissue to support milk production. GH also exhibits such homeorhetic effects, most notably in ruminants, but also clearly has direct, insulin-antagonistic, metabolic effects. The roles of GH and PRL on adipocyte proliferation and differentiation have also been controversial, with GH stimulating adipocyte differentiation in vitro in cell lines whilst stimulating proliferation and inhibiting differentiation of primary cell cultures. Examination of adipose tissue development in PRLRko and GHRko mice has revealed roles for both hormones. PRLRko mice show impaired development of both internal and subcutaneous adipose tissue due to decreased numbers of adipocytes. In contrast, GHRko mice exhibit major decreases in the number of internal (parametrial) adipocytes whereas subcutaneous adipocytes develop almost normally. This leads to major changes in the sites of adipose tissue accretion and bears interesting parallels with the adipose tissue redistribution which occurs in HIV-induced lipodystrophy. Such individuals exhibit a central obesity which can be partially corrected by GH treatment. However, recent studies suggest that this may be a physiological response in which adipose tissue sites containing lymphoid tissue (such as mesenteric) show preservation of adipose tissue perhaps to support augmented immune responses. PMID: 14703019 [PubMed - indexed for MEDLINE] 4289. J Am Diet Assoc. 2004 Jan;104(1):86-9. Obesity and the Metabolic Syndrome: implications for dietetics practitioners. Bray GA(1), Champagne CM. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA, USA. brayga@pbrc.edu The Metabolic Syndrome encompasses a set of laboratory and physical findings, including central adiposity, insulin resistance, hypertension, high triglycerides, and low HDL-cholesterol and several abnormalities in clotting and inflammatory markers. Using the definition provided by the Adult Treatment Panel III of the National Cholesterol Education Program, 24% of adult Americans have the Metabolic Syndrome. Central location of fat and release of fatty acids and cytokines from enlarged fat cells located in the intra-abdominal fat tissue provide the major agents that incite this syndrome. From a practical point of view, identifying dietary and lifestyle factors, including low levels of physical activity, are important in designing a diet and exercise program that can help individuals with the Metabolic Syndrome to reduce the associated detrimental health consequences. PMID: 14702589 [PubMed - indexed for MEDLINE] 4290. Prog Brain Res. 2004;146:279-89. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease? Chaldakov GN(1), Fiore M, Stankulov IS, Manni L, Hristova MG, Antonelli A, Ghenev PI, Aloe L. Author information: (1)Division of Cell Biology, Department of Forensic Medicine, Medical University, Varna, Bulgaria. The development of atherosclerotic cardiovascular disease is a common comorbidity in patients with the metabolic syndrome, a concurrence of cardiovascular risk factors in one individual. While multiple growth factors and adipokines are identified in atherosclerotic lesions, as well as neurotrophins implicated in both cardiac ischemia and lipid and glucose metabolism, the potential role of neurotrophins in human coronary atherosclerosis and in the metabolic syndrome still remains to be elucidated. Here we describe and discuss our results that represent a novel attempt to study the cardiovascular and metabolic biology of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and mast cells (MC). The local amount of NGF, the immunolocalization of p75 neurotrophin receptor (p75NTR) and the number of MC were correlatively examined in coronary vascular wall and in the surrounding subepicardial adipose tissue, obtained from autopsy cases in humans with advanced coronary atherosclerosis. We also analyzed the plasma levels of NGF, BDNF and leptin and the number of MC in biopsies from abdominal subcutaneous adipose tissue in patients with a severe form of the metabolic syndrome. The results demonstrate that NGF levels are decreased in atherosclerotic coronary vascular tissue but increased in the subepicardial adipose tissue, whereas both tissues express a greater number of MC and a stronger p75NTR immunoreactivity, compared to controls. Metabolic syndrome patients display a significant hyponeurotrophinemia and an increased number of adipose MC; the later correlates with elevated plasma leptin levels. In effect, we provide the first evidence for (i) an altered presence of NGF, p75NTR and MC in both coronary vascular and subepicardial adipose tissue in human coronary atherosclerosis, and (ii) a significant decrease in plasma NGF and BDNF levels and an elevated amount of plasma leptin and adipose MC in metabolic syndrome patients. Together our findings suggest that neuroimmune mediators such as NGF, BDNF, leptin and MC may be involved in the development of cardiovascular disease and related disorders. PMID: 14699970 [PubMed - indexed for MEDLINE] 4291. Ann Surg Oncol. 2004 Jan;11(1):78-84. Atypical lipomatous tumor/well-differentiated liposarcoma of the extremity and trunk wall: importance of histological subtype with treatment recommendations. Kooby DA(1), Antonescu CR, Brennan MF, Singer S. Author information: (1)Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. BACKGROUND: This study defines the behavior and classification of atypical lipomatous tumors (ALT) and well-differentiated liposarcomas (WDLS) of the extremity and trunk. METHODS: A total of 91 well-differentiated lipomatous tumors of the extremity and trunk were identified from a soft tissue tumor database between July 1982 and June 2001. A soft tissue pathologist, blinded to prior diagnosis and clinical outcome, reviewed histology. Those composed predominantly of mature adipose tissue with scattered atypical stromal cells and scant lipoblasts or fibrosis were ALTs. Tumors with lipoblasts but <25% fibrosis were termed lipoma-like WDLS, and those with >/=25% fibrosis were identified as sclerosing WDLS. Clinical factors were analyzed to assess effects on local recurrence-free survival (LRFS). RESULTS: Histological review identified 34 ALTs and 57 WDLSs. Of the WDLSs, 29 were lipoma-like and 28 were sclerosing. Five-year and 10-year LRFS were 100% +/- 0% and 78% +/- 9%, respectively. Factors evaluated were age, sex, tumor site, tumor size, histology, presentation status, margin status, and adjuvant radiotherapy. Positive resection margins and sclerosing histology were associated with reduced LRFS. Dedifferentiation was observed in three tumors (3%). CONCLUSIONS: Lipoma-like WDLSs and ALTs share similar histological features and favorable behavior. Margin-positive sclerosing WDLSs have a 10-year LRFS of only 17% and should undergo function-preserving re-excision when possible, or adjuvant radiotherapy. PMID: 14699038 [PubMed - indexed for MEDLINE] 4292. Nutrition. 2004 Jan;20(1):127-33. Genetic architecture of ingestive behavior in humans. Faith MS(1), Keller KL. Author information: (1)Weight and Eating Disorders Program, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. mfaith@mail.med.upenn.edu PMID: 14698027 [PubMed - indexed for MEDLINE] 4293. Nutrition. 2004 Jan;20(1):115-20. Gene expression profiling of adipose tissue: individual, depot-dependent, and sex-dependent variabilities. Klaus S(1), Keijer J. Author information: (1)German Institute of Human Nutrition in Potsdam, Bergholz-Rehbrücke, Germany. klaus@mail.dife.de PMID: 14698025 [PubMed - indexed for MEDLINE] 4294. Nutrition. 2004 Jan;20(1):14-25. Application of genomic technologies: DNA microarrays and metabolic profiling of obesity in the hypothalamus and in subcutaneous fat. Middleton FA(1), Ramos EJ, Xu Y, Diab H, Zhao X, Das UN, Meguid M. Author information: (1)Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA. middletf@upstate.edu PMID: 14698009 [PubMed - indexed for MEDLINE] 4295. Neurotoxicology. 2004 Jan;25(1-2):325-35. Selective inhibitors of membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues. Kinemuchi H(1), Sugimoto H, Obata T, Satoh N, Ueda S. Author information: (1)Laboratory of Enzyme Pharmacology, Senshu University at Ishinomaki, Ishinomaki 986-8580, Japan. kinemuti@isenshu-u.ac.jp Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) is a group of enzymes highly sensitive to inhibition by semicarbazide. This high sensitivity distinguishes these enzymes from monoamine oxidase (MAO). Various mammalian tissues contain membrane-bound SSAO which metabolizes only the primary monoamines. Vascular and non-vascular smooth muscle cells have particularly high SSAO activity, but recently the enzyme activity has also been found in non-vascular smooth muscle cells. The substrate specificity of SSAO shows considerable species-related variations. A variety of compounds inhibiting MAO activity has also been identified as SSAO inhibitors. Among inhibitors, there is no specific SSAO inhibitor so far tested. Many studies reinforce the conclusion that inhibitory properties of some compounds against MAO activities has been markedly differed from their properties as SSAO inhibitors. 2-bromoethylamine has been recently developed with a potent, selective and suicide SSAO inhibitor without any inhibitory effect on MAO activity Using this inhibitor, it is possible to study the role of the enzyme in mammalian tissues. As physiological role the increased concentrations of SSAO, especially in blood plasma, have been found in diabetic patients and experimental animals. This enzyme was found to be associated with translocation of the glucose transporter GLUT 4 into the adipose cell surface and involved in the signaling of glucose uptake. Recent studies showed that vascular SSAO metabolizes endogenous primary amines, allylamine, methylamine and aminoacetone, to the corresponding cytotoxic aldehydes. These aldehydes have been linked to the ability of diabetic complications such as neuropathy, retinopathy and nephropathy. Overproduction of such toxic aldehydes produced by increased SSAO activity was proposed to be potentially hazardous in diabetic complications. Thus, reduction or inhibition of SSAO may be beneficial in these pathological conditions. Clearly species-related differences in properties of SSAO must be taken into account in this respect, particularly when assessing if SSAO inhibition may have great application in human. PMID: 14697907 [PubMed - indexed for MEDLINE] 4296. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):21-6. Salt-inducible kinase in steroidogenesis and adipogenesis. Okamoto M(1), Takemori H, Katoh Y. Author information: (1)Laboratories for Biomolecular Networks, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan. mokamoto@mr-mbio.med.osaka-u.ac.jp The salt-inducible kinases (SIKs) are a family of related serine-threonine kinases. In cultured adrenocortical cells, SIK1 is rapidly but transiently induced by adrenocorticotropin (ACTH) treatment, suggesting that it contributes to ACTH-mediated induction of steroidogenic enzymes. However, ACTH treatment of Y1 mouse adrenocortical cells stimulates a rapid translocation of SIK1 from the nucleus to the cytoplasm, and SIK1 represses the transcription of a steroidogenic enzyme by inhibiting the action of cAMP-responsive elements in the promoter. These studies suggest that SIK1 has a role in the fine tuning of steroidogenic enzyme production during the initial phase of steroidogenesis. SIK2 is found in adipocytes and phosphorylates a specific serine residue in insulin receptor substrate-1. This finding, along with the fact that its expression is raised in the white adipose tissue of mice with type 2 diabetes mellitus, suggests that SIK2 might be involved in metabolic regulation in adipose tissue. Thus, members of the SIK family are emerging as important modulators of key processes such as steroid hormone biosynthesis by the adrenal cortex and insulin signaling in adipocytes. PMID: 14693422 [PubMed - indexed for MEDLINE] 4297. Proc Nutr Soc. 2003 Aug;62(3):753-60. Fatty acid metabolism in obesity and type 2 diabetes mellitus. Blaak EE(1). Author information: (1)Dept of Human Biology, Nutrition Research Centre, Maastricht University, PO Box 6166200, MD Maastricht, The Netherlands. E.Blaak@HB.Unimaas.nl Disturbances in pathways of lipolysis and fatty acid handling are of importance in the aetiology of obesity and type 2 diabetes mellitus. There is evidence that a lowered catecholamine-mediated lipolytic response may play a role in the development and maintenance of increased adipose tissue stores. Increased adipose tissue stores, a disturbed insulin-mediated regulation of lipolysis and subnormal skeletal muscle non-esterified fatty acid (NEFA) uptake under conditions of high lipolytic rate may increase circulating NEFA concentrations, which may promote insulin resistance and cardiovascular complications. In addition, a disturbance of NEFA uptake by adipose tissue postprandially is also a critical determinant of plasma NEFA concentration. Furthermore, evidence is increasing that insulin-resistant muscle is characterised by a lowered ability to oxidise fatty acids. A dysbalance between fatty acid uptake and fatty acid oxidation may in turn be a factor promoting accumulation of lipid intermediates and triacylglycerols within skeletal muscle, which is strongly associated with skeletal muscle insulin resistance. The present review describes the reported disturbances in pathways of lipolysis and skeletal muscle fatty acid handling, and discusses underlying mechanisms and metabolic consequences of these disturbances. PMID: 14692611 [PubMed - indexed for MEDLINE] 4298. Proc Nutr Soc. 2003 Aug;62(3):621-34. Physical activity and resting metabolic rate. Speakman JR(1), Selman C. Author information: (1)Aberdeen Centre for Energy Regulation and Obesity, Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen AB21 9SB, UK. J.speakman@abdn.ac.uk The direct effects of physical activity interventions on energy expenditure are relatively small when placed in the context of total daily energy demands. Hence, the suggestion has been made that exercise produces energetic benefits in other components of the daily energy budget, thus generating a net effect on energy balance much greater than the direct energy cost of the exercise alone. Resting metabolic rate (RMR) is the largest component of the daily energy budget in most human societies and, therefore, any increases in RMR in response to exercise interventions are potentially of great importance. Animal studies have generally shown that single exercise events and longer-term training produce increases in RMR. This effect is observed in longer-term interventions despite parallel decreases in body mass and fat mass. Flight is an exception, as both single flights and long-term flight training induce reductions in RMR. Studies in animals that measure the effect of voluntary exercise regimens on RMR are less commonly performed and do not show the same response as that to forced exercise. In particular, they indicate that exercise does not induce elevations in RMR. Many studies of human subjects indicate a short-term elevation in RMR in response to single exercise events (generally termed the excess post-exercise O2 consumption; EPOC). This EPOC appears to have two phases, one lasting < 2 h and a smaller much more prolonged effect lasting up to 48 h. Many studies have shown that long-term training increases RMR, but many other studies have failed to find such effects. Data concerning long-term effects of training are potentially confounded by some studies not leaving sufficient time after the last exercise bout for the termination of the long-term EPOC. Long-term effects of training include increases in RMR due to increases in lean muscle mass. Extreme interventions, however, may induce reductions in RMR, in spite of the increased lean tissue mass, similar to the changes observed in animals in response to flight. PMID: 14692598 [PubMed - indexed for MEDLINE] 4299. Exerc Immunol Rev. 2003;9:34-9. Signaling pathways for IL-6 within skeletal muscle. Febbraio MA(1). Author information: (1)Skeletal Muscle Research Laboratory, School of Medical Sciences, RMIT University, PO Box 71, Bundoora 3083, Victoria, Australia. mark.febbraio@rmit.edu.au Over the past 5 years it has become apparent that cytokines are produced by myocytes in the absence of any markers of inflammation. Specifically, the gene encoding for the cytokine interleukin (IL)-6 is present in skeletal muscle and is induced by muscle contraction and, in some circumstances by insulin. In turn, IL-6 protein is produced throughout the myocyte and released into the circulation where it acts in an "endocrine like" manner to activate processes designed to maintain metabolic homeostasis. Hence, it has become apparent that IL-6 may be a factor that is coupled to genes involved in metabolic processes both within skeletal muscle and adipose tissue. Relatively less is known regarding the upstream factors that induce the transcription of IL-6. However, it is clear that IL-6 production is activated by intracellular calcium levels, mitogen-activated protein kinases, reduced glycogen availability and other cytokines such as IL-1 beta. This review will briefly discuss the signaling pathways involved in IL-6 gene transcription. PMID: 14686092 [PubMed - indexed for MEDLINE] 4300. J Am Coll Nutr. 2003 Dec;22(6):487-93. Insulin clearance in obesity. Valera Mora ME(1), Scarfone A, Calvani M, Greco AV, Mingrone G. Author information: (1)Institute of Internal Medicine, Catholic University of Rome, Largo Agostino Gemelli 8, 00168 Rome, Italy. valeramora@virgilio.it Insulin uptake and degradation is a complex and not yet completely understood process involving not only insulin sensitive tissues. The most important degradative system is insulin degrading enzyme which is a highly conserved metalloendopeptidase requiring Zn(++) for its proteolytic action, although protein disulfide isomerase and cathepsin D are also involved in insulin metabolism. The liver and the kidney are the principal sites for insulin clearance. In obese subjects with hyperinsulinemia and high levels of free fatty acids, insulin hepatic clearance is impaired, while the glomerular filtration rate, renal plasma flow and albumin excretion are increased, suggesting a state of renal vasodilatation leading to an abnormally transmitted arterial pressure to the glomerular capillaries through a dilated afferent arteriole. Insulin can be cleared also by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes which contain insulin receptors and internalization and regulation mechanism for insulin metabolism. PMID: 14684753 [PubMed - indexed for MEDLINE] 4301. Curr Drug Targets Immune Endocr Metabol Disord. 2003 Dec;3(4):255-62. Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)--a promising drug target for the treatment of metabolic syndrome. Masuzaki H(1), Flier JS. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, 02215, USA. Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing-s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARgamma agonists and LXRalpha agonists significantly reduce 11beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11beta-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11beta-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome. PMID: 14683456 [PubMed - indexed for MEDLINE] 4302. Endocr Res. 2003 Nov;29(4):411-8. Cortisol metabolism and visceral obesity: role of 11beta-hydroxysteroid dehydrogenase type I enzyme and reduced co-factor NADPH. Agarwal AK(1). Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. anil.agarwal@utsouthwestern.edu Several factors including genetic and environmental play a role in the development of obesity and the metabolic syndrome. The transgenic mouse overexpressing 11beta-hydroxysteroid dehydrogenase (11beta-HSD) develops visceral obesity. However, it remains unclear how a ubiquitously expressed 11beta-HSD1 enzyme affects adipose tissue so much that it would lead to obesity. In this commentary we explore the possibility that increased intracellular availability of reduced co-factor, NADPH, could exacerbate the enzymatic activity. PMID: 14682470 [PubMed - indexed for MEDLINE] 4303. Breast Cancer Res. 2004;6(1):1-11. Epub 2003 Aug 19. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Fata JE(1), Werb Z, Bissell MJ. Author information: (1)Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. jefata@lbl.gov A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions. PMCID: PMC314442 PMID: 14680479 [PubMed - indexed for MEDLINE] 4304. Rinsho Byori. 2003 Nov;51(11):1090-5. [Adipocytokines and life style-related disease]. [Article in Japanese] Shimomura I(1). Author information: (1)Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Graduate School of Medicine, Osaka University, Suita 565-0871. The adipose tissue produces and secretes many bioactive substances, which we conceptualized as Adipocytokines (Nature Medicine 1996). Adiponectin is a novel adipocytokine, which we identified by screening the adipose-specific genes from human fat. Adiponectin is a secreted protein, the concentration of which reaches as high as 5-15 micrograms/ml in human plasma. Adiponectin mRNA is expressed exclusively in adipose tissues. The adiponectin mRNAs and its plasma levels are reduced in obesity, type 2 diabetes and atherosclerosis. Hyperinsulinemic euglycemic clamp studies in humans and monkeys, and several recent studies from others revealed that adiponectin is an insulin-sensitizing hormone. Furthermore, adiponectin exhibited anti-atherogenic moieties, decreasing the attachment of monocytes to endothelial cells through inhibiting the expression levels of adhesion molecules. It reduced the lipid accumulation in macrophages through reducing the expression of scavenger receptor, and inhibited the cytokine-stimulated proliferation of smooth muscle cells. The genetic mutation of the adiponectin gene accompanying hypoadiponectinemia was strongly associated with the incidence of type 2 diabetes and atherosclerosis in Japanese subjects. Hypoadiponectinemia was the strongest predictor for the development of type 2 diabetes in humans. Adiponectin knockout mice exhibited diet-induced diabetes and severer atherosclerotic response by vascular injury. Adiponectin supplement reversed the insulin resistance syndrome including diabetes and atherosclerotic change in the knockout mice. We conclude that "Hypoadiponectinemia" stands upstream of the pathophysiology of metabolic syndrome, hence, can be a direct target of drug intervention to tackle life style-related disease rampant in developed countries. PMID: 14679787 [PubMed - indexed for MEDLINE] 4305. Am J Med. 2003 Dec 8;115 Suppl 8A:42S-48S. Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Fonseca V(1). Author information: (1)Department of Medicine, Section of Endocrinology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA. Treatment of diabetes mellitus with medications, including insulin, sulfonylureas, and thiazolidinediones (TZDs), often leads to weight gain through a variety of mechanisms. Weight gain can have adverse consequences for patients with type 2 diabetes, many of whom are overweight or obese, because obesity is linked to insulin resistance and other medical consequences such as cardiovascular disease. TZDs improve glycemic control and insulin sensitivity in patients with type 2 diabetes, despite their potential to cause weight gain. Studies have attempted to elucidate the mechanisms behind the apparent paradox of TZDs improving insulin sensitivity while causing weight gain. Data indicate that with TZD treatment, there is a favorable shift in fat distribution from visceral to subcutaneous adipose depots that is associated with improvements in hepatic and peripheral tissue sensitivity to insulin. Although weight gain may occur with TZD therapy, it is not inevitable. A weight-management program combining a low-calorie, low-sodium diet with education and behavior modification has been shown to be effective in patients with type 2 diabetes being treated with TZDs. Further research is needed to define the optimal dietary modifications that can be used universally in TZD-treated patients to minimize weight gain while effectively treating insulin resistance and hyperglycemia. PMID: 14678865 [PubMed - indexed for MEDLINE] 4306. Am J Med. 2003 Dec 8;115 Suppl 8A:37S-41S. Obesity as a cardiovascular risk factor. Sowers JR(1). Author information: (1)Department of Internal Medicine, University of Missouri-Columbia and H. S. Truman VAMC, Columbia, Missouri 65212, USA. The prevalence of overweight and obesity continues to increase rapidly in the United States, with more than half of all adults currently overweight or obese. In general, people become obese because of a combination of inherited genes and a lifestyle consisting of low levels of physical activity and consumption of excess calories. Obesity, especially the central or visceral type, is a predisposing factor for the development of type 2 diabetes mellitus, hypertension, and cardiovascular disease (CVD). Obesity and type 2 diabetes are associated with insulin resistance. The relation among obesity, insulin resistance, and CVD appears to develop at a relatively young age. Central obesity is linked with hyperinsulinemia, insulin resistance, dyslipidemia, and proinflammatory and prothrombotic clinical states. Adipose tissue synthesizes and secretes biologically active molecules that may affect CVD risk factors. These chemical messengers include adiponectin, resistin, leptin, plasminogen activator inhibitor-1, tumor necrosis factor-alpha, and interleukin-6. In overweight and obese individuals, weight loss may improve insulin sensitivity, leading to reduction in risk factors for CVD and, consequently, the potential for cardiovascular events. Agents that improve insulin sensitivity, such as the thiazolidinediones, have been shown to reduce visceral obesity. Decreases in visceral adipose tissue contribute to improvements in insulin sensitivity and blood pressure, and weight loss reduces serum levels of triglycerides and low-density lipoprotein cholesterol while increasing serum levels of high-density lipoprotein cholesterol. Reduction of risk factors suggests that the development of cardiovascular disease will be reduced by the improvement of insulin sensitivity and weight loss. PMID: 14678864 [PubMed - indexed for MEDLINE] 4307. Nutr Rev. 2003 Nov;61(11):387-90. The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. The metabolic function of the nuclear receptor peroxisome proliferator-activated receptor delta (PPAR(delta)) has been established by transfer of the PPAR(delta) gene into adipose tissue of mice in vivo and into adipocytes in culture. Investigators found that PPAR(delta) activation by such transfer leads to up-regulation of energy expenditure by fatty acid oxidation. PPAR(delta) activation also results in lowered serum triglyceride and free fatty acid levels and decreased lipid accumulation. In vivo activation of PPAR(delta) in adipose tissue protects against obesity and fatty liver in mice fed a high-calorie diet. PPAR(delta) also activates the heat-producing uncoupling enzymes in brown adipose tissue (UCP1 and 3) and muscle (UCP2). PMID: 14677574 [PubMed - indexed for MEDLINE] 4308. Horm Res. 2003;60 Suppl 3:56-9. Importance of adipocytokines in obesity-related diseases. Matsuzawa Y(1), Shimomura I, Kihara S, Funahashi T. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp To elucidate the biological characteristics of adipose tissue, we analyzed the gene expression profile of visceral and subcutaneous fat. Unexpectedly, adipose tissue, especially visceral fat, expressed a variety of genes for secretory proteins. About 30% of the genes expressed in visceral adipose tissue encoded secretory proteins and most were biologically active molecules, which we called adipocytokines. We found plasminogen activator inhibitor type 1 and heparin binding EGF-like growth factor. Production of these atherogenic adipocytokines was shown to increase with the accumulation of visceral fat, which may be one of the mechanisms of vascular disease in visceral obesity. We found a unique and novel collagen-like protein, adiponectin, encoded by the most abundantly expressed gene in adipose tissue, termed APM1 (adipose most abundant gene transcript-1). Plasma levels of adiponectin ranged from 0.3 to approximately 3 mg/dl but were decreased in patients with visceral obesity, type 2 diabetes and coronary artery disease (CAD). Screening for mutations in the adiponectin gene revealed that patients carrying a missense mutation showed markedly decreased plasma levels of adiponectin and had CAD. These data suggest that hypoadiponectinemia may be considered an important risk factor for CAD. Cell biology studies revealed that adiponectin has a potent inhibitory effect on the expression of adhesion molecules in endothelial cells and an inhibitory effect on the expression in macrophages. In order to confirm these antidiabetic and antiatherogenic functions of adiponectin, we developed adiponectin knockout mice. Adiponectin knockout mice showed severe insulin resistance and impaired glucose metabolism when fed a high-fat, high-sucrose diet. Knockout mice also developed intimal thickening in response to endothelial injury. Copyright 2003 S. Karger AG, Basel PMID: 14671398 [PubMed - indexed for MEDLINE] 4309. Horm Res. 2003;60 Suppl 3:51-5. Peroxisome proliferator-activated receptor-gamma and insulin action: insights from human genetics. Chatterjee VK(1). Author information: (1)Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. kkcl@mole.bio.cam.ac.uk Peroxisome proliferator-activated receptor-gamma (PPARgamma), an orphan nuclear receptor, mediates adipocyte differentiation and is the cellular target for the thiazolidinedione group of insulin-sensitizing antidiabetic agents. We screened this receptor gene in a cohort of subjects with severe insulin resistance and have identified heterozygous missense mutations in several individuals from three families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild type PPARgamma action in a dominant-negative manner. The clinical phenotype of patients includes partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Factors which contribute to the severe insulin resistance in affected individuals include diminished body fat mass, impaired lipid flux in adipose tissue and reduced circulating levels of adiponectin. In a large kindred of five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARGAMMA; and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A). The frameshift PPARgamma mutant exhibits complete loss of function with no dominant-negative activity; the PPP1R3A truncation mutant is mislocalized intracellularly. Individuals harbouring either gene defect alone have normal circulating insulin levels, but a combination of both genetic abnormalities co-segregates with severe insulin resistance. Copyright 2003 S. Karger AG, Basel PMID: 14671397 [PubMed - indexed for MEDLINE] 4310. Biochem Pharmacol. 2004 Jan 1;67(1):1-15. Mitochondrial biogenesis as a cellular signaling framework. Nisoli E(1), Clementi E, Moncada S, Carruba MO. Author information: (1)Center for Study and Research on Obesity, Department of Preclinical Sciences, LITA Vialba, Luigi Sacco Hospital, University of Milan, via G.B. Grassi 74, 20157, Milan, Italy. enzo.nisoli@unimi.it Erratum in Biochem Pharmacol. 2004 Feb 15;67(4):803. The identification, more than 50 years ago, of mitochondria as the site of oxidative energy metabolism has prompted studies that have unraveled the complexity of the numerous biosynthetic and degradative reactions, fundamental to cell function, carried out by these organelles. These activities depend on a distinctive mitochondrial structure, with different enzymes and reactions localized in discrete membranes and aqueous compartments. The characteristic mitochondrial structural organization is the product of both synthesis of macromolecules within the mitochondria and the import of proteins and lipids synthesized outside the organelle. Synthesis and import of mitochondrial components are required for mitochondrial proliferation, but rather than producing new organelles, these processes may facilitate the growth of pre-existing mitochondria. Recent evidence indicates that these events are regulated in a complex way by several agonists and environmental conditions, through activation of specific transcription factors and signaling pathways. Some of these are now being elucidated. Generation of nitric oxide (NO) appears to be a novel player in this scenario, possibly acting as a unifying molecular switch to trigger the whole mitochondriogenic process. PMID: 14667924 [PubMed - indexed for MEDLINE] 4311. Am J Physiol Gastrointest Liver Physiol. 2004 Jan;286(1):G7-13. Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake. Woods SC(1). Author information: (1)Dept. of Psychiatry, Univ. of Cincinnati, Cincinnati, OH 45267, USA. steve.woods@psychiatry.uc.edu An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases meal size has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GI tract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors. PMID: 14665437 [PubMed - indexed for MEDLINE] 4312. Vet Clin North Am Small Anim Pract. 2003 Nov;33(6):1317-34. New insights into the physiology and treatment of acquired myelodysplastic syndromes and aplastic pancytopenia. Weiss DJ(1). Author information: (1)Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA. weiss005@umn.edu MDS are a diverse group of primary and secondary bone marrow disorders that are characterized by cytopenias in blood, prominent dysplastic features in blood or bone marrow, and normal or hypercellular bone marrow. MDS in cats are typically associated with FeLV infection. Dogs with MDS-RC and MDS-Er seem to respond to erythropoietin administration and have prolonged survival. Dogs with MDS-EB respond poorly to present treatments, and survival is short. Prognosis and probability of progression to acute myelogenous leukemia can be predicted based on the percentage of myeloblasts in bone marrow. Several experimental therapeutic modalities in human beings have been described that may be useful in treating MDS-EB in dogs and cats. Aplastic pancytopenia is a relatively rare disorder in dogs and cats. Causes include Ehrlichia spp, Parvovirus, and FeLV infections; sepsis; chronic renal failure; drug and toxin exposure; and idiopathic causes. Diagnosis is based on identification of multiple cytopenias in the blood and hypoplastic/aplastic bone marrow, with the marrow space replaced by adipose tissue. Treatment and outcome are dependent on determining the underlying cause of the bone marrow failure. PMID: 14664201 [PubMed - indexed for MEDLINE] 4313. Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R14-5. Regulation of body fat content? Wade GN. Comment on Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R61-70. PMID: 14660470 [PubMed - indexed for MEDLINE] 4314. J Endocrinol. 2003 Dec;179(3):293-9. Endocrine and nutritional regulation of fetal adipose tissue development. Symonds ME(1), Mostyn A, Pearce S, Budge H, Stephenson T. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK. Michael.Symonds@nottingham.ac.uk In the fetus, adipose tIssue comprises both brown and white adipocytes for which brown fat is characterised as possessing the unique uncoupling protein (UCP)1. The dual characteristics of fetal fat reflect its critical role at birth in providing lipid that is mobilised rapidly following activation of UCP1 upon cold exposure to the extra-uterine environment. A key stage in the maturation of fetal fat is the gradual rise in the abundance of UCP1. For species with a mature hypothalamic-pituitary axis at birth there is a gradual increase in the amount and activity of UCP1 during late gestation, in conjunction with an increase in the plasma concentrations of catecholamines, thyroid hormones, cortisol, leptin and prolactin. These may act individually, or in combination, to promote UCP1 expression and, following the post-partum surge in each hormone, UCP1 abundance attains maximal amounts. Adipose tIssue grows in the fetus at a much lower rate than in the postnatal period. However, its growth is under marked nutritional constraints and, in contrast to many other fetal organs that are unaffected by nutritional manipulation, fat mass can be significantly altered by changes in maternal and, therefore, fetal nutrition. Fat deposition in the fetus is enhanced during late gestation following a previous period of nutrient restriction up to mid gestation. This is accompanied by increased mRNA abundance for the receptors of IGF-I and IGF-II. In contrast, increasing maternal nutrition in late gestation results in less adipose tIssue deposition but enhanced UCP1 abundance. The pronounced nutritional sensitivity of fetal adipose tIssue to both increased and decreased maternal nutrition may explain why the consequences of an adverse nutritional environment persist into later life. PMID: 14656200 [PubMed - indexed for MEDLINE] 4315. Pediatr Diabetes. 2003 Mar;4(1):32-7. Adiponectin/Acrp30, an adipocyte-specific secretory factor: physiological relevance during development. Iyengar P(1), Scherer PE. Author information: (1)Department of Cell Biology, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Adiponectin/Acrp30 is a fat cell-specific secretory product. The convergence of results from epidemiological, pharmacological and genetic studies over the last 2 yr has highlighted the important role that this multimeric protein complex plays in the context of insulin sensitivity. While the exact mechanism of action has not been elucidated, it is clear that adiponectin has insulin-sensitizing effects on both liver and muscle. The important role that adipose tissue plays in energy homeostasis as a storage compartment for triglycerides has been appreciated for a long time. The identification of leptin as a key hormone involved in central control of energy metabolism suggested that adipocytes also use polypeptide hormones to influence metabolic processes at distant sites. The recent progress made towards the characterization of the physiological role of adiponectin highlights the important role of adipose tissue as an endocrine organ and its central role in the fine-tuning of hepatic and muscle insulin responsiveness. PMID: 14655522 [PubMed - indexed for MEDLINE] 4316. Pediatr Diabetes. 2003 Jun;4(2):101-9. Leptin: obesity, diabetes and other peripheral effects--a review. Moran O(1), Phillip M. Author information: (1)Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202. There is an increasing epidemic of obesity in the Western and developing world that has not spared children and, hence, is of great concern. Obesity presents numerous physiological and psychosocial problems for the child. Childhood obesity not only increases the risk of obesity in adulthood, it is associated with type 2 diabetes mellitus; is the leading cause of pediatric hypertension; increases the risk of coronary heart disease; and increases stress on the weight-bearing joints. Social and psychological problems are also significant consequences of obesity in children, with lowering of self-esteem and its effects on relationships with peers. Obesity is clearly associated with increased levels of the recently discovered hormone, leptin. Leptin, secreted from adipocytes, is involved in the regulation of food intake, energy expenditure, and energy balance in humans. This review focuses on the hormone, leptin, in an effort to document some of its many local and systemic effects on the body and, specifically, its potential role in obesity-induced diabetes. PMID: 14655266 [PubMed - indexed for MEDLINE] 4317. Diabetologia. 2004 Jan;47(1):1-11. Epub 2003 Dec 3. 11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes. Stulnig TM(1), Waldhäusl W. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Thomas.Stulnig@akh-wien.ac.at Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11beta-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11beta-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11beta-HSD1 activity. PMID: 14652720 [PubMed - indexed for MEDLINE] 4318. Atherosclerosis. 2003 Nov;171(1):1-13. Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives. Chapman MJ(1). Author information: (1)National Institute for Health and Medical Research (INSERM), Unit 551, Pavillon Benjamim Delessert, Hôpital de la Pitié, 83 Bd de l'hôpital, 75651 Paris Cedex 13, France. chapman@infobiogen.fr OBJECTIVES: To explore the therapeutic potential of fibrates to attenuate premature atherosclerosis and cardiovascular disease in the atherogenic dyslipidemias typical of Type II diabetes, Metabolic Syndrome, and the Type IIB (mixed) lipid phenotype; such dyslipidemias frequently feature peripheral insulinoresistance. BACKGROUND: Recent epidemiological data reveal that a marked increase in the prevalence of Type II diabetes, obesity and the Metabolic Syndrome has occurred on a worldwide scale. Dyslipidemia is an integral component of the metabolic perturbations which characterise these disorders, and is intimately associated with premature atherosclerosis and elevated cardiovascular risk. The atherogenic dyslipidemias of Type II diabetes, the Metabolic Syndrome and mixed (IIB) hyperlipidemia feature moderate to marked elevation of triglyceride-rich lipoproteins, low HDL-C cholesterol levels, and a dense LDL phenotype; equally, they feature an inflammatory state. Fibrates, agonists of PPARalpha, act to modulate the expression of key genes of lipid transport and metabolism in organs such as the liver and adipose tissue; equally, they exert pleiotropic, anti-inflammatory effects downregulating expression of genes encoding acute phase proteins and inflammatory cytokines. By inducing elevation of HDL-C levels, reduction in triglyceride-rich lipoproteins and a shift in the dense LDL phenotype to receptor-active, buoyant LDL, and by diminishing the inflammatory state, fibrates act to attenuate the atherosclerotic burden in atherogenic dyslipidemia. Such actions translate into significant clinical benefit as demonstrated by the reduction in cardiovascular morbi-mortality observed in both primary and secondary intervention trials (VA-HIT, Helsinki Heart Study, SENDCAP, DAIS, BECAIT). CONCLUSIONS: Fibrate therapy represents a cost effective approach to the clinical management of a wide spectrum of atherogenic dyslipidemias involving low HDL-C and elevated TGRL levels, and which include Type II diabetes and the Metabolic Syndrome. Optimised clinical application of these lipid modulating, anti-inflammatory drugs in these disorders in the context of either monotherapy or in combination with low dose statin is, therefore, warranted. PMID: 14642400 [PubMed - indexed for MEDLINE] 4319. Biochem Soc Trans. 2003 Dec;31(Pt 6):1161-4. Extending the glucose/fatty acid cycle: a glucose/adipose tissue cycle. Guerre-Millo M(1). Author information: (1)U 465 INSERM, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, 75006 Paris, France. mguerre@bhdc.jussieu.fr It is now recognized that the WAT (white adipose tissue) produces a variety of bioactive peptides, collectively termed "adipokines". Alteration of WAT mass in obesity or lipoatrophy affects the production of most adipose secreted factors. Since both conditions are associated with insulin resistance, the idea has emerged that certain adipokines might influence insulin action. Among these, tumour necrosis factor alpha, interleukin-6 and resistin are increased in the obese state and interfere negatively with insulin-mediated processes. Conversely, leptin and adiponectin exert an insulin-sensitizing effect, at least in part by favouring tissue fatty-acid oxidation through AMP-activated kinase activation. Obesity-induced insulin resistance has been linked to leptin resistance and decreased plasma adiponectin, while administration of leptin and adiponectin normalizes plasma levels in lipoatrophic mice and reverses insulin resistance. Thiazolidinedione anti-diabetic agents increase endogenous adiponectin production in rodents and humans, supporting the idea that drugs targeting adipokines might represent a new therapeutic approach to sensitize peripheral tissues to insulin. PMID: 14641017 [PubMed - indexed for MEDLINE] 4320. Biochem Soc Trans. 2003 Dec;31(Pt 6):1152-6. Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Le Marchand-Brustel Y(1), Gual P, Grémeaux T, Gonzalez T, Barrès R, Tanti JF. Author information: (1)INSERM Unité U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 02, France. lemarcha@unice.fr Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes. PMID: 14641015 [PubMed - indexed for MEDLINE] 4321. Biochem Soc Trans. 2003 Dec;31(Pt 6):1125-9. Fatty acid recycling in adipocytes: a role for glyceroneogenesis and phosphoenolpyruvate carboxykinase. Forest C(1), Tordjman J, Glorian M, Duplus E, Chauvet G, Quette J, Beale EG, Antoine B. Author information: (1)UMR-S 530 Inserm-Université René Descartes, Centre Universitaire-U.F.R. Biomédicale, 45 rue des Saints-Pères, 75006 Paris, France. claude.forest@biomedicale.univ-paris5.fr FA (fatty acid) recycling in adipose tissue appears to be an important pathway for regulating FA release into the blood during fasting. Re-esterification requires G3P (glycerol 3-phosphate), which cannot be synthesized from glucose because glycolysis is much reduced under such circumstances. In addition, G3P can scarcely originate from glycerol since glycerol kinase has a very low activity in white adipose tissue. It was shown about 35 years ago that a metabolic pathway named glyceroneogenesis, which allows G3P synthesis from non-carbohydrate precursors like pyruvate, lactate or amino acids, is activated during fasting. The major enzyme in this pathway was shown to be PEPCK-C [cytosolic phosphoenolpyruvate carboxykinase (GTP); EC 4.1.1.32]. The present review analyses the mechanisms by which a series of hormones and nutrients affect PEPCK-C gene transcription and glyceroneogenesis and describes evidence for dysregulation of this pathway in type 2 diabetes. PMID: 14641009 [PubMed - indexed for MEDLINE] 4322. Biochem Soc Trans. 2003 Dec;31(Pt 6):1120-4. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Holm C(1). Author information: (1)Department of Cell and Molecular Biology, Section for Molecular Signalling, Lund University, Lund, Sweden. cecilia.holm@medkem.lu.se HSL (hormone-sensitive lipase) is a key enzyme in the mobilization of fatty acids from acylglycerols in adipocytes as well as non-adipocytes. In adipocytes, catecholamines stimulate lipolysis mainly through PKA (protein kinase A)-mediated phosphorylation of HSL and perilipin, a protein coating the lipid droplet. The anti-lipolytic action of insulin is mediated mainly via lowered cAMP levels, accomplished through activation of phosphodiesterase 3B. Phosphorylation of HSL by PKA occurs at three sites, the serines 563, 659 and 660, both in vitro and in primary rat adipocytes. Phosphorylation of Ser-659 and -660 is required for in vitro activation as well as translocation from the cytosol to the lipid droplet, whereas the role of the third PKA site remains elusive. Adipocytes isolated from homozygous HSL-null mice, generated in our laboratory, exhibit completely blunted catecholamine-induced glycerol release and reduced fatty acid release, suggesting the presence of additional, although not necessarily hormone-activatable, triacylglycerol lipase(s). Basal hyperinsulinaemia, release of exaggerated amounts of insulin during glucose challenges and retarded glucose disposal during insulin tolerance tests suggest that HSL-null mice are insulin resistant. Liver, adipose tissue and skeletal muscle appear all to be sites of impaired insulin sensitivity in HSL-null mice. PMID: 14641008 [PubMed - indexed for MEDLINE] 4323. Expert Opin Ther Targets. 2003 Dec;7(6):771-83. 11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease. Walker BR(1), Seckl JR. Author information: (1)University of Edinburgh, Endocrinology Unit, Western General Hospital, Edinburgh EH4 2XU, UK. B.Walker@ed.ac.uk 11beta-hydroxysteroid dehydrogenase Type 1 (11HSD1) catalyses regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues. Inhibition of 11HSD1 has been proposed as a novel strategy to lower intracellular glucocorticoid concentrations, without affecting circulating glucocorticoid levels and their responsiveness to stress. Increased 11HSD1 activity may be pathogenic, for example, in adipose tissue in obesity. Experiments in transgenic mice and using prototype inhibitors in humans show benefits of 11HSD1 inhibition in liver, adipose and brain tissue in treating features of the metabolic syndrome and cognitive dysfunction with ageing. The clinical development of potent selective 11HSD1 inhibitors is now a high priority. PMID: 14640912 [PubMed - indexed for MEDLINE] 4324. Nutr Metab Cardiovasc Dis. 2003 Aug;13(4):244-9. Role of the natriuretic peptide system in lipogenesis/lipolysis. Dessì-Fulgheri P(1), Sarzani R, Rappelli A. Author information: (1)Clinica di Medicina Interna, Azienda Ospedaliera Umberto I, Via Conca, 60020 Ancona, Italy. dessi@unian.it AIM: There is recent evidence that the natriuretic peptide (NP) system promotes adipose tissue lipolysis in primates. This effect is mediated by the interaction of NP with its active receptors through guanylyl cyclase activation and cGMP production. This review will briefly focus on the new aspects of NP pathophysiology in man. DATA SYNTHESIS: NP receptors have been described in rodent adipocytes, and the expression of their mRNA is found in human adipose tissue together with high level of ANP binding sites. In isolated fat cells, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were able to stimulate lipolysis as much as isoproterenol, a non-selective beta-adrenergic receptor agonist, whereas C-type natriuretic peptide (CNP) had the lowest lipolytic effect. The potent lipolytic effect of NP has also been confirmed in samples of abdominal adipose tissue from healthy subjects. The potency order of the lipolytic effect (ANP > BNP > CNP) and ANP-induced cGMP production supported the presence of type A natriuretic peptide receptor in human fat cells. The effect of NP on lipid metabolism is confirmed by the fact that intravenous ANP infusion is followed by plasma NEFA and glycerol concentration increase (reflecting lipid mobilisation). CONCLUSIONS: The NP system seems to play an important role in lipid metabolism, possibly affecting the pathophysiology of obesity and obesity-related disorders, such hypertension. Further studies, however, are needed to completely establish the mechanisms involved in NP-induced lipolysis and the real relevance of this new pathway specific of primates. PMID: 14650358 [PubMed - indexed for MEDLINE] 4325. J Child Neurol. 2003 Oct;18(10):725-9. Encephalocraniocutaneous lipomatosis: neurologic manifestations. Lasierra R(1), Valencia I, Carapeto FJ, Ventura P, Samper MP, Rodríguez G, Pérez-González JM, Legido A. Author information: (1)Department of Radiology, Hospital Clínico Universitario Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, Spain. We report a new case of encephalocraniocutaneous lipomatosis, a rare neurocutaneous syndrome of unknown etiology with involvement of tissues arising from the mesoderm and ectoderm: skin, eye, adipose tissue, and brain. We also review the neurologic manifestations of the syndrome, the most frequent of which include seizures, ventricular enlargement, calcifications, mental retardation, and cerebellopontine angle tumor. Our patient had an extensive extradural spinal cord lipomatous lesion, emphasizing the importance of screening for spinal abnormalities in asymptomatic patients with this condition. PMID: 14649557 [PubMed - indexed for MEDLINE] 4326. Obes Rev. 2003 Nov;4(4):257-90. Physical inactivity, excess adiposity and premature mortality. Katzmarzyk PT(1), Janssen I, Ardern CI. Author information: (1)School of Physical and Health Education, Queen's University, Kingston, ON, Canada. katzmarz@post.queensu.ca The purpose of this report is to review the evidence that physical inactivity and excess adiposity are related to an increased risk of all-cause mortality, and to better identify the independent contributions of each to all-cause mortality rates. A variance-based method of meta-analysis was used to summarize the relationships from available studies. The summary relative risk of all-cause mortality for physical activity from the 55 analyses (31 studies) that included an index of adiposity as a covariate was 0.80 [95% confidence interval (CI) 0.78-0.821, whereas it was 0.82 [95% CI 0.80-0.84] for the 44 analyses (26 studies) that did not include an index of adiposity. Thus, physically active individuals have a lower risk of mortality by comparison to physically inactive peers, independent of level of adiposity. The summary relative risk of all-cause mortality for an elevated body mass index (BMI) from the 25 analyses (13 studies) that included physical activity as a covariate was 1.23 [95% CI 1.18-1.29], and it was 1.24 [95% CI 1.21-1.28] for the 81 analyses (36 studies) that did not include physical activity as a covariate. Studies that used a measure of adiposity other than the BMI show similar relationships with mortality, and stratified analyses indicate that both physical inactivity and adiposity are important determinants of mortality risk. PMID: 14649376 [PubMed - indexed for MEDLINE] 4327. Aesthetic Plast Surg. 2003 Sep-Oct;27(5):397-402. Epub 2003 Dec 4. A new paradigm for the aging Asian face. Shirakabe Y(1), Suzuki Y, Lam SM. Author information: (1)Sapho Clinic, Tokyo, Japan. sapho@io.ocn.ne.jp Traditionally, Asians have been thought to age more gracefully than Caucasians. The resistance to aging in the Asian patient was credited to the thicker dermis of Asian skin that contains greater collagen and the darker pigment that protects against photoaging. Although these statements are true, the authors propose a new paradigm that explains how the illusion of Asian youthfulness may be understood. The "baby model" purports that the Asian face has many attributes similar to an infant, including a wider and rounder face, higher eyebrow, fuller upper lid, lower nasal bridge, flatter midface, apparently more protuberant lips, and more receded chin. These commonalities between the infant and the Asian compel the viewer to perceive the Asian face as more youthful. However, the Asian face is subjected to a greater amount of gravitational force due to weaker skeletal support, heavier soft tissue, larger amount of malar fat, thicker skin, and a weaker chin. Facial rejuvenative surgery should always be cognizant of the propensity of the Asian skin to unfavorable healing, need for greater tissue suspension, and more conspicuous temporal alopecia. Asian aesthetics that differ and converge with Western ideals are reviewed so that the Western surgeon in particular can comprehend the Asian conception of youthful beauty. PMID: 14648062 [PubMed - indexed for MEDLINE] 4328. Ann N Y Acad Sci. 2003 Nov;997:64-76. The role of leptin in female adolescence. Apter D(1). Author information: (1)The Sexual Health Clinic, Family Federation of Finland, PO Box 849, 00101 Helsinki, Finland. dan.apter@vaestoliitto.fi Leptin, the ob gene product, is related to the onset of puberty in animal models, but its role in human puberty is still rather undefined. In prepubertal girls and boys, leptin concentrations increase slowly with age and body-fat mass. In boys, this increase is interrupted in early puberty, when testosterone and lean body mass increase. In girls, leptin, along with the body-fat mass, continue to increase during puberty. Plasma leptin concentrations are significantly correlated with fat mass at all Tanner stages in males and females. The diurnal variation of leptin concentrations seen in adults is apparent for all age groups with no significant changes in the pattern across puberty. Leptin is bound in blood by a high-affinity binding protein identical with the soluble leptin receptor (sOB-R). In the first year of life, the concentration of sOB-R is high, and then a continuous decline of sOB-R follows until midpuberty. The therapeutic response to leptin treatment in a child with leptin deficiency confirms the importance of leptin in the regulation of body weight in humans, and establishes an important role for this hormone in the regulation of appetite. Still no evidence is available that would indicate leptin is a primary signal that initiates the onset of human puberty. Instead, it may act in a permissive way as one of several metabolic factors to allow pubertal maturation to proceed and later reproduction to occur. PMID: 14644811 [PubMed - indexed for MEDLINE] 4329. Ann N Y Acad Sci. 2003 Nov;997:56-63. Interactions of leptin, GH, and cortisol in normal children. Ghizzoni L(1), Mastorakos G. Author information: (1)Department of Pediatrics, University of Parma, Parma, Italy. lughizzo@ipruniv.cce.unipr.it Leptin is the product of the ob gene located in humans on chromosome 7q31.3. It is a 16-kDa protein named after the Greek "leptos," meaning lean, to indicate the function that this adipocyte-secreted protein was thought to have. Since its discovery, in fact, most of the research focused on the role of leptin in body-weight regulation, aiming to elucidate the pathophysiology of human obesity. However, more and more data show that leptin is not only important in the regulation of food intake and energy balance, but it also functions as a neuroendocrine hormone. It is involved in glucose metabolism, as well as in normal sexual maturation and reproduction, and interacts with the hypothalamic-pituitary-adrenal (HPA) and the growth hormone (GH) axes. PMID: 14644810 [PubMed - indexed for MEDLINE] 4330. Trends Endocrinol Metab. 2003 Dec;14(10):439-41. Conversion from white to brown adipocytes: a strategy for the control of fat mass? Tiraby C(1), Langin D. Author information: (1)Unité de Recherches sur les Obésités, Institut National de la Santé et de la Recherche Médicale (Inserm) Unité 586, Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France. Understanding the mechanisms governing the acquisition of white and brown adipocyte phenotypes might have implications for the physiopathology of, and therapeutic strategies for obesity. Peroxisome proliferator-activated recetor gamma (PPARgamma) and its coactivators, PGC-1alpha and SRC-1, influence brown adipocyte metabolism and development. Ectopic expression of PGC-1alpha induces the expression of brown adipocyte genes in human white adipocytes. The changes in gene expression promote stimulation of fatty acid oxidation. There is now evidence to support the concept of an alteration in energy balance through a conversion of white to brown adipose tissue. PMID: 14643055 [PubMed - indexed for MEDLINE] 4331. Reprod Suppl. 2003;61:415-27. Mechanisms linking nutrition and reproduction in postpartum cows. Lucy MC(1). Author information: (1)164 Animal Sciences Research Center, University of Missouri, Columbia, MO 65211, USA. LucyM@missouri.edu The reproductive physiology of postpartum cows is different from that of heifers because of the combined effects of the past pregnancy and lactation. Neither lactation nor pregnancy has a major effect on postpartum fertility when calving is free from disease and lactation is moderate. Postpartum beef cows in good body condition have conception rates nearly equivalent to those of virgin heifers once their uteri are involuted and they initiate ovarian cycles. However, cows will experience infertility when nutrient requirements for maintenance and lactation exceed nutrient intake (postpartum beef cows) or when nutrients are specifically partitioned toward lactation (postpartum dairy cows). The subsequent loss of body fat that occurs in either case has effects on a variety of reproductive processes and reproduction becomes less efficient. The mechanisms that lead to abnormal reproduction in nutritionally compromised postpartum cattle have been investigated intensively. Much of the effort has focused on the nature of the signal (endocrine or otherwise) that controls pituitary secretion of LH and FSH, the response of the ovary to LH and FSH, and other ovarian effects that are independent of gonadotrophins. Reproductive studies in ruminants have tended toward studies of follicular development and this focus relates back to solving the problem of anoestrus. Less work has been done on the effects of nutrition on the early embryo, the health of which may be predetermined by factors affecting the oocyte within the preovulatory follicle. Few studies have examined the effect of nutrition on uterine function in postpartum cattle. Solutions to postpartum reproduction will probably arise from a variety of approaches that include traditional physiology as well as more modern genomic and proteomic technologies. PMID: 14635952 [PubMed - indexed for MEDLINE] 4332. Rev Med Liege. 2003 Sep;58(9):554-8. [Adiponectin: a new adipocytokine]. [Article in French] Lebas E(1), Paquot N, Scheen AJ. Author information: (1)Service de Diabétologie, Nutrition et Maladies métaboliques, Département de Médecine, CHU Sart Tilman, Liège. Adipose tissue is not simply a store of excess energy, but also secretes a variety of proteins into circulating blood that influence systemic metabolism. These include tumor necrosis factor (TNF-alpha), plasminogen activator inhibitor type 1 (PAI-1), leptin, resistine and adiponectin. These are collectively known as adipocytokines. Adiponectin (also referred to as AdipoQ, Acrp 30, apM1 or GBP28) is a novel adipose-specific protein. A recent genome study mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome on chromosome 3q27, where the adiponectin gene is located. Adiponectin is a peculiar adipocytokine because in contrast to the markedly increased levels of many others, as leptin or TNF-alpha, its level is reduced in obesity and type 2 diabetes. The administration of thiazolidinediones, which are synthetic PPARs-gamma ligands, significantly increases the plasma adiponectin concentrations, an effect that could improve insulin sensitivity. Thus, the administration of adiponectin may provide a novel treatment modality for insulin resistance and type 2 diabetes. PMID: 14626649 [PubMed - indexed for MEDLINE] 4333. Curr Opin Lipidol. 2003 Dec;14(6):561-6. Obesity, adiponectin and vascular inflammatory disease. Ouchi N(1), Kihara S, Funahashi T, Matsuzawa Y, Walsh K. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. ouchi@imed2.med.osaka-u.ac.jp PURPOSE OF REVIEW: Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as adipocytokines, and that dysregulation of adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic adipocytokine, and vascular inflammation. RECENT FINDINGS: Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. SUMMARY: Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease. PMID: 14624132 [PubMed - indexed for MEDLINE] 4334. Curr Opin Lipidol. 2003 Dec;14(6):549-53. The metabolic syndrome and type 2 diabetes: role of the adipocyte. McPherson R, Jones PH. PMID: 14624130 [PubMed - indexed for MEDLINE] 4335. J Steroid Biochem Mol Biol. 2003 Sep;86(3-5):501-7. Aromatase and cyclooxygenases: enzymes in breast cancer. Brueggemeier RW(1), Richards JA, Petrel TA. Author information: (1)Division of Medical Chemistry & Pharmacognosy, OSU Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210-1291, USA. brueggemeier.1@osu.edu Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C19 androgens to C18 estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin PGE2 increases intracellular cAMP levels and stimulates estrogen biosynthesis, and previous studies in our laboratories have shown a strong linear association between aromatase (CYP19) expression and expression of the cyclooxygenases (COX-1 and COX-2) in breast cancer specimens. To further investigate the pathways regulating COX and CYP19 gene expression, studies were performed in normal breast stromal cells, in breast cancer cells from patients, and in breast cancer cell lines using selective pharmacological agents. Enhanced COX enzyme levels results in increased production of prostaglandins, such as PGE2. This prostaglandin increased aromatase activity in breast stromal cells, and studies with selective agonists and antagonists showed that this regulation of signaling pathways occurs through the EP1 and EP2 receptor subtypes. COX-2 gene expression was enhanced in breast cancer cell lines by ligands for the various peroxisome proliferator-activated receptors (PPARs), and differential regulation was observed between hormone-dependent and -independent breast cancer cells. Thus, the regulation of both enzymes in breast cancer involves complex paracrine interactions, resulting in significant consequences on the pathogenesis of breast cancer. PMID: 14623550 [PubMed - indexed for MEDLINE] 4336. J Steroid Biochem Mol Biol. 2003 Sep;86(3-5):225-30. Sources of estrogen and their importance. Simpson ER(1). Author information: (1)Monash Medical Center, Prince Henry's Institute of Medical Research, PO Box 5152, Clayton 3168, Vic, Australia. evan.simpson@med.monash.edu.au In premenopausal women, the ovaries are the principle source of estradiol, which functions as a circulating hormone to act on distal target tissues. However, in postmenopausal women when the ovaries cease to produce estrogen, and in men, this is no longer the case, because estradiol is no longer solely an endocrine factor. Instead, it is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. These sites include the mesenchymal cells of adipose tissue including that of the breast, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Thus, circulating levels of estrogens in postmenopausal women and in men are not the drivers of estrogen action, they are reactive rather than proactive. This is because in these cases circulating estrogen originates in the extragonadal sites where it acts locally, and if it escapes local metabolism then it enters the circulation. Therefore, circulating levels reflect rather than direct estrogen action in postmenopausal women and in men. Tissue-specific regulation of CYP19 expression is achieved through the use of distinct promoters, each of which is regulated by different hormonal factors and second messenger signaling pathways. Thus, in the ovary, CYP19 expression is regulated by FSH which acts through cyclic AMP via the proximal promoter II, whereas in placenta the distal promoter I.1 regulates CYP19 expression in response to retinoids. In adipose tissue and bone by contrast, another distal promoter--promoter I.4--drives CYP19 expression under the control of glucocorticoids, class 1 cytokines and TNFalpha. The importance of this unique aspect of the tissue-specific regulation of aromatase expression lies in the fact that the low circulating levels of estrogens which are observed in postmenopausal women have little bearing on the concentrations of estrogen in, for example, a breast tumor, which can reach levels at least one order of magnitude greater than those present in the circulation, due to local synthesis within the breast. Thus, the estrogen which is responsible for breast cancer development, for the maintenance of bone mineralization and for the maintenance of cognitive function is not circulating estrogen but rather that which is produced locally at these specific sites within the breast, bone and brain. In breast adipose of breast cancer patients, aromatase activity and CYP19 expression are elevated. This occurs in response to tumor-derived factors such as prostaglandin E2 produced by breast tumor fibroblasts and epithelium as well as infiltrating macrophages. This increased CYP19 expression is associated with a switch in promoter usage from the normal adipose-specific promoter I.4 to the cyclic AMP responsive promoter, promoter II. Since these two promoters are regulated by different cohorts of transcription factors and coactivators, it follows that the differential regulation of CYP19 expression via alternative promoters in disease-free and cancerous breast adipose tissue may permit the development of selective aromatase modulators (SAMs) that target the aberrant overexpression of aromatase in cancerous breast, whilst sparing estrogen synthesis in other sites such as normal adipose tissue, bone and brain. PMID: 14623515 [PubMed - indexed for MEDLINE] 4337. J Steroid Biochem Mol Biol. 2003 Sep;86(3-5):219-24. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. Bulun SE(1), Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. Author information: (1)Department of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, 820 S Wood St M/C 808, Chicago, IL 60612, USA. sbulun@uic.edu The human CYP19 (P450arom) gene is located in the chromosome 15q21.2 region and is comprised of a 30 kb coding region and a 93 kb regulatory region. The Internet-based Human Genome Project data enabled us to elucidate its complex organization. The unusually large regulatory region contains 10 tissue-specific promoters that are alternatively used in various cell types. Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences. In most mammals, P450arom expression is under the control of gonad- and brain-specific promoters. In the human, however, there are at least eight additional promoters that seemed to have been recruited throughout the evolution possibly via alterations in DNA. One of the key mechanisms that permit the recruitment of such a large number of promoters seems to be the extremely promiscuous nature of the common splice acceptor site, since activation of each promoter gives rise splicing of an untranslated first exon onto this common junction immediately upstream of the translation start site in the coding region. These partially tissue-specific promoters are used in the gonads, bone, brain, vascular tissue, adipose tissue, skin, fetal liver and placenta for physiologic estrogen biosynthesis. The most recently characterized promoter (I.7) was cloned by analyzing P450arom mRNA in breast cancer tissue. This TATA-less promoter accounts for the transcription of 29-54% of P450arom mRNAs in breast cancer tissues and contains endothelial-type cis-acting elements that interact with endothelial-type transcription factors, e.g. GATA-2. We hypothesize that this promoter may upregulate aromatase expression in vascular endothelial cells. The in vivo cellular distribution and physiologic roles of promoter I.7 in healthy tissues, however, are not known. The gonads use the proximally located promoter II. The normal breast adipose tissue, on the other hand, maintains low levels of aromatase expression primarily via promoter I.4 that lies 73 kb upstream of the common coding region. Promoters I.3 and II are used only minimally in normal breast adipose tissue. Promoters II and I.3 activities in the breast cancer, however, are strikingly increased. Additionally, the endothelial-type promoter I.7 is also upregulated in breast cancer. Thus, it appears that the prototype estrogen-dependent malignancy breast cancer takes advantage of four promoters (II, I.3, I.7 and I.4) for aromatase expression. The sum of P450arom mRNA species arising from these four promoters markedly increase total P450arom mRNA levels in breast cancer compared with the normal breast. PMID: 14623514 [PubMed - indexed for MEDLINE] 4338. Eur J Pharmacol. 2003 Nov 7;480(1-3):31-42. Neuroendocrinology of insulin resistance: metabolic and endocrine aspects of adiposity. van Dijk G(1), de Vries K, Benthem L, Nyakas C, Buwalda B, Scheurink AJ. Author information: (1)Department of Neuroendocrinology, University of Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands. g.van.dijk@biol.rug.nl Abdominal obesity is a major risk factor to attract the insulin resistance syndrome. It is proposed that abdominal obesity exposes the liver to elevated levels of free fatty acids, which activate a neuroendocrine reflex, leading to increased circulating levels of glucocorticoids. Besides directly attenuating peripheral insulin signaling, glucocorticoids oppose the activity of central nervous regulatory systems that stimulate insulin action. Among the factors that promote insulin action is leptin. Leptin regulates peripheral fuel partitioning and insulin action mainly through hypothalamic neuronal networks, which in turn, regulate endocrine activity of adipose tissue in a way comparable to thiazolidinediones. These are a class of insulin-sensitizing drugs, which exert their antidiabetic effects through the gamma isoform of peroxisome proliferator-activated receptor (PPAR-gamma). Since glucocorticoids oppose leptin action at several levels of control (including the central nervous system, CNS), it is argued that subjects easily develop obesity and associated metabolic disorders. PMID: 14623348 [PubMed - indexed for MEDLINE] 4339. J Neuroendocrinol. 2003 Nov;15(11):1005-10. White adipose tissue: getting nervous. Fliers E(1), Kreier F, Voshol PJ, Havekes LM, Sauerwein HP, Kalsbeek A, Buijs RM, Romijn JA. Author information: (1)Academic Medical Center of the University of Amsterdam, Department of Endocrinology and Metabolism, Amsterdam, The Netherlands. e.fliers@amc.uva.nl Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes. PMID: 14622429 [PubMed - indexed for MEDLINE] 4340. Clin Plast Surg. 2003 Oct;30(4):547-58, viii. Progress in adipose tissue construct development. Beahm EK(1), Walton RL, Patrick CW Jr. Author information: (1)Department of Plastic Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 443, Houston, TX 77030, USA. Although the field of tissue engineering has been the focus of a great deal of promise and study, only recently has significant attention been given to the engineering of soft tissues. The applicability of an engineered adipose construct as a basic science model and a reconstructive tool is unquestioned; yet, there have been limitations in previous work, specifically issues of construct size and maintenance over time. This article briefly overviews the pivotal factors necessary for adipocyte growth and differentiation, optimal scaffolds for the engineering of soft tissues, and a means of providing vascular support for these highly demanding cells. Clinical science and bioengineering concepts that may provide the foundation toward the successful in vivo engineering of an adipose tissue construct that maintains its complex three-dimensional shape over time are critically reviewed. PMID: 14621302 [PubMed - indexed for MEDLINE] 4341. Vopr Pitan. 2003;72(5):29-33. [The principles of using anthropometry in the clinical estimation of a nutritional status]. [Article in Russian] Petukhov AB, Deriabin VE. In paper the procedure and principles of carrying out of anthropometric measurements permitting to the practical doctor in clinical and out-patient conditions to supervise behind changes of volume muscle and bodies composition, and also total body water in subjects at carrying of a medical nutrition. Usage of integral parameters on the basis of anthropometric measurements allows effectively to inspect a status of nutrition of the able-bodied and in car patients. PMID: 14619613 [PubMed - indexed for MEDLINE] 4342. Acta Diabetol. 2003 Oct;40 Suppl 1:S154-7. Body composition in disease: what can we measure and how can we measure it? Van Loan MD(1). Author information: (1)US Department of Agriculture Western Human Nutrition Research Center, University of California, Davis, CA 95616, USA. mvanloan@whnrc.usda.gov This manuscript presents a brief overview of the topic of body composition in disease. The purpose of this paper is threefold: (1). to present examples of diseases in which body composition assessment might provide valuable information to physicians and other clinical personnel in patient care; (2). provide basic information on the types of methodologies available for various aspects of body composition assessment; and (3). give a brief review of some of the research literature available on the topic of body composition use in disease. Materials in this paper should not be interpreted as providing all the relevant information in this area of research, but the paper does represent a limited overview of the topic. PMID: 14618459 [PubMed - indexed for MEDLINE] 4343. Acta Diabetol. 2003 Oct;40 Suppl 1:S45-50. Advances in the application of imaging methods in applied and clinical physiology. Ross R(1). Author information: (1)School of Physical and Health Education, Department of Medicine, Queen's University, K7L 3N6, Kingston, Ontario, Canada. rossr@post.queensu.ca Application of computed tomography (CT) and magnetic resonance imaging (MRI) represents one of the most important advances in the history of human body composition research. Independently, these methods have been used to significantly advance our understanding of the complex relationships between human body composition and disease. They are the methods of choice for calibration of field methods designed to measure adipose tissue and skeletal muscle in vivo, and are the only procedures available for measurement of internal tissues and organs. More recently, both methods have been employed to measure the quality of various tissues including skeletal muscle and hepatic tissue. These recent advances in the use of CT and MRI in body composition research are discussed with a focus on clinical applications. PMID: 14618432 [PubMed - indexed for MEDLINE] 4344. Panminerva Med. 2003 Sep;45(3):189-95. Is visceral obesity a physiological adaptation to stress? Drapeau V(1), Therrien F, Richard D, Tremblay A. Author information: (1)Division of Kinesiology, Laval University, Ste-Foy, Québec, Canada. angelo.tremblay@kin.msp.ulaval.ca Visceral obesity represents an important risk factor associated with hypertension, diabetes and cardiovascular diseases. Since this condition is associated with a disruption of the functioning of the HPA axis, stress-induced HPA axis activation has been identified to play an important role in this preferential body fat accumulation. HPA axis activation increases cortisol (corticosterone) production which has been shown to exert hyperphagic and antithermogenic effects. Since abdominal adipose tissue has more cells per mass units, higher blood flow and more glucocorticoid receptors, glucocorticoids affect abdominal fat to a greater extent than subcutaneous adipose tissue. Cushing's syndrome in humans is the best evidence showing a link between hypercortisolemia and accumulation of central fat. The Hervey's hypothesis which suggests that fat cells take up and catabolize glucocorticoids is one of the possible regulatory effect that supports the adaptive role of visceral fat in response to stress. This is also supported by other evidence showing that abdominal obesity is associated with an increased cortisol clearance. Hormonal and enzymatic changes have been implicated in this preferential body fat accumulation in response to stress. Specific genetic background may also accentuate this visceral fat accumulation in some individuals exposed to stress. Alternatively, obesity could also be a source of stress promoting the visceral fat accumulation since visceral fat is able to release cytokines which stimulate the HPA axis. Even if the available literature does not permit to establish clearly which comes first, it suggests that visceral obesity could represent a non optimal physiological adaptation to stress. In this context, visceral obesity treatment should focus on stress management and weight loss strategies in order to stop this vicious circle. PMID: 14618117 [PubMed - indexed for MEDLINE] 4345. N Engl J Med. 2003 Nov 13;349(20):1966-7. Nerves, fat, and insulin resistance. Boden G(1), Hoeldtke RD. Author information: (1)Department of Medicine, Temple University Hospital, Philadelphia, USA. PMID: 14614173 [PubMed - indexed for MEDLINE] 4346. Expert Opin Emerg Drugs. 2003 May;8(1):217-37. Emerging antiobesity drugs. Spanswick D(1), Lee K. Author information: (1)Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK/NeuroSolutions Ltd, Warwick BioVentures, Coventry CV4 7AL, UK. The healthcare burden that the obesity epidemic now poses in highly significant, in part due to increased risk of secondary chronic diseases such as hypertension. A lack of physical activity and high fat diets are major factors contributing to this condition. However, increasingly apparent is the genetic predisposition of individuals and ethnic groups to obesity. Present treatment strategies are currently inadequate and unlikely to have a major effect on the future prevalence of obesity. To slow the obesity epidemic, the source needs to be tackled now through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. This article will describe current and emerging treatments for obesity and review the recent advances in research that may provide the antiobesity treatments of the future. Research into obesity has escalated at considerable pace, catalysed by the discovery of the obese gene product leptin. Leptin is secreted by adipose tissue and acts via specific receptors in the brain to engage central neural pathways involved in regulating energy homeostasis. Since this discovery, numerous significant advances have been made in our understanding of how the brain integrates and responds to central and peripheral signals involved in maintaining energy homeostasis, and how disruption of these signalling mechanisms can manifest as obesity. As a consequence of these findings, numerous potential sites for therapeutic intervention into this condition have and are materializing. The aim of this review is to highlight current treatment strategies for obesity, recent advances in our understanding of the central neural control of energy balance, and what the authors consider to be the most promising targets for the development of novel antiobesity drugs in the future. Thus, the review focuses on leptin, neuropeptide Y, melanocortin and ghrelin signalling at the level of the CNS, and strategies targeting the sympathetic innervation of fat cells at the periphery. PMID: 14610923 [PubMed - indexed for MEDLINE] 4347. Endocrine. 2003 Oct;22(1):49-56. Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin. Kalra SP(1), Kalra PS. Author information: (1)Department of Neuroscience, McKnight Brain Institute, PO Box 100244, University of Florida, Gainesville, FL 32610-0244, USA. skalra@ufbi.ufl.edu Neuropeptide Y (NPY), a 36-amino-acid neuropeptide is the most potent physiological appetite transducer known. Episodic NPY neurosecretion in hypothalamic target sites is temporally linked with onset of the daily feeding pattern. Upregulation of NPY signaling in the arcuate nucleus-paraventricular nucleus (ARC-PVN) neural axis is responsible for the hyperphagia evoked by dieting, fasting, hormonal and genetic factors, and disruption in intrahypothalamic signaling. Clusters of NPY-producing neurons in the ARC that coexpress gamma- amino butyric acid and agouti-related peptide, and those in the brain stem (BS) that coexpress catecholamines and galanin, participate in disparate manners to regulate appetitive behavior. NPY receptors, Y1, Y2, and Y5, expressed by various components of the NPY network, mediate NPY-induced feeding. Imbalance in NPY signaling due either to high or low abundance of NPY at target sites elicits hyperphagia leading to increased fat accretion and obesity. Recent studies show that intermittent, feedback action of opposing afferent hormonal signals-leptin from adipose tissue and ghrelin from stomach-regulate the episodic secretion of orexigenic NPY in the PVN-ARC. Apparently, the hypothalamic NPY network is the primary common pathway intimately involved in genesis of appetite- stimulating impulses. PMID: 14610298 [PubMed - indexed for MEDLINE] 4348. Exp Biol Med (Maywood). 2003 Nov;228(10):1175-80. Gender differences in the control of energy homeostasis. Woods SC(1), Gotoh K, Clegg DJ. Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267, USA. steve.woods@psychiatry.uc.edu The world is experiencing an epidemic of obesity and its concomitant health problems. One implication is that the normally robust negative feedback system that controls energy homeostasis must be responding to different inputs than in the past. In this review we discuss the influence of gender on the efficacy of adiposity hormones as they interact with food intake control systems in the brain. Specifically, the levels of insulin and leptin in the blood are correlated with body fat, insulin being related mainly to visceral fat and leptin to subcutaneous fat. Since females carry more fat subcutaneously and males carry more fat viscerally, leptin correlates better with total body fat in females and insulin correlates better in males. High visceral fat and plasma insulin are also risk factors for the complications of obesity, including type-2 diabetes, cardiovascular problems, and certain cancers, and these are more prevalent in males. Consistent with these systemic differences, the brains of females are more sensitive to the catabolic actions of low doses of leptin whereas the brains of males are more sensitive to the catabolic action of low doses of insulin. The implications of this are discussed. PMID: 14610257 [PubMed - indexed for MEDLINE] 4349. Exp Biol Med (Maywood). 2003 Nov;228(10):1106-10. Anti-obesity actions of mastication driven by histamine neurons in rats. Sakata T(1), Yoshimatsu H, Masaki T, Tsuda K. Author information: (1)Department of Nutritional Sciences, Faculty of Nutritional Sciences, Nakamura Gakuen University, Fukuoka, 814-0198 Japan. sakata@oita-med.ac.jp Implications of mastication in energy intake and expenditure regulated by histamine (HA) neurons were investigated in rats. Depletion of neuronal HA from the mesencephalic trigeminal sensory nucleus (Me5) reduced eating speed, but that from a satiety center of the ventromedial hypothalamus (VMH) increased both meal size and its duration leaving eating speed unaffected. Turnover of neuronal HA in the Me5 was elevated at the early phase of feeding and that in the VMH was at the later phase. This elevated turnover was abolished by gastric intubations of an isocaloric liquid diet or an equivolume of water. Mastication-induced activation of HA neurons suppressed physiological food intake through H1-receptor in the hypothalamic paraventricular nucleus (PVN) and the VMH. On the other hand, the HA neurons activation accelerated lipolysis particularly in the visceral adipose tissues and up-regulated mRNA expression of uncoupling protein family through sympathetic efferent nerve. Mastication thus plays an important role as a potent input signal to activate HA neurons. Our recent findings have evidently shown how tightly and elegantly HA neurons are concordant with leptin signaling system through a negative feedback loop. PMID: 14610247 [PubMed - indexed for MEDLINE] 4350. J Muscle Res Cell Motil. 2003;24(2-3):113-9. Searching for the exercise factor: is IL-6 a candidate? Pedersen BK(1), Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B. Author information: (1)The Copenhagen Muscle Research Centre, Copenhagen, Denmark. bkp@rh.dk For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus', 'the work factor' or 'the exercise factor'. In other terms, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Here we discuss the possibility that interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-alpha-production and may thereby inhibit TNF-alpha-induced insulin resistance and atherosclerosis development. We propose that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines'. PMID: 14609022 [PubMed - indexed for MEDLINE] 4351. Eur J Appl Physiol. 2004 Apr;91(4):382-91. Epub 2003 Nov 8. New aspects of the hormone and cytokine response to training. Steinacker JM(1), Lormes W, Reissnecker S, Liu Y. Author information: (1)Sektion Sport- und Rehabilitationsmedizin, Abt. Innere Medizin II, Medizinische Klinik und Poliklinik, Universität Ulm, 89070 Ulm, Germany. juergen.steinacker@medizin.uni-ulm.de Exercise training is associated with peripheral-cellular and central-cerebral processes, hormonal-neuronal regulation and transmission mechanisms. During the acute training response, peripheral cellular mechanisms are mainly metabolostatic to achieve energy supply and involve associated cytokine and hormonal reactions. Glycogen deficiency is associated with increased expression of local cytokines (interleukin-6, IL-6), decreased expression of glucose transporters, increased cortisol and decreased insulin secretion and beta-adrenergic stimulation. A nutrient-sensing signal of adipose tissue may be represented by leptin which, as for insulin, IL-6 and insulin-like growth-factor I (IGF-I), has profound effects on the hypothalamus and is involved in the metabolic hormonal regulation of exercise and training. Muscle damage and repair processes may involve the expression of inflammatory cytokines (e.g. tumour necrosis factor-alpha, TNF-alpha) and of stress proteins (e.g. heat shock protein 72). During overreaching and overtraining, a myopathy-like state is observed in skeletal muscle with depressed turnover of contractile proteins (e.g. in fast-type glycolytic fibres with a concomitant increase in slow type myosins). These alterations are influenced by exercise-induced hypercortisolism, and by decreased somatotropic hormones (e.g. IGF-I). The hypothalamus integrates various error signals (metabolic, hormonal, sensory afferents and central stimuli) and therefore pituitary releasing hormones represent the functional status of an athlete and long-term hypothalamic hormonal and sympathoadrenal downregulation are some of the prominent hormonal signs of prolonged overtraining and performance incompetence syndrome. PMID: 14608461 [PubMed - indexed for MEDLINE] 4352. Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1151-60. Role of caveolin and caveolae in insulin signaling and diabetes. Cohen AW(1), Combs TP, Scherer PE, Lisanti MP. Author information: (1)Department of Molecular Pharmacology, Albert Einstein Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. Caveolae are specialized membrane microdomains present within the plasma membrane of the vast majority of cell types. They have a unique composition in that they are highly enriched in cholesterol, sphingolipids, and their coat proteins the caveolins (-1, -2, and -3). In recent years it has been recognized that caveolae act as signaling platforms, serving as a concentrating point for numerous signaling molecules, as well as regulating flux through many distinct signaling cascades. Although caveolae are found in a variety of cell types, they are most abundant in adipose tissue. This fact has led to the intense study of the function of these organelles in adipocytes. It has now become apparent that effective insulin signaling in the adipocyte may be strictly dependent on localization of at least two insulin-responsive elements to caveolae (insulin receptor and GLUT4), as well as on a direct functional interaction between caveolin-1 and the insulin receptor. We present a critical discussion of these recent findings. PMID: 14607781 [PubMed - indexed for MEDLINE] 4353. Diabetologia. 2003 Dec;46(12):1594-603. Epub 2003 Nov 6. Regulation of adipocytokines and insulin resistance. Fasshauer M(1), Paschke R. Author information: (1)Department of Internal Medicine III, University of Leipzig, Leipzig, Germany. It has long been known that obesity and insulin resistance are linked. Recently, it has been shown that adipocytes secrete several proteins including tumour necrosis factor-alpha, interleukin-6, resistin, and adiponectin. Since several of these so-called adipocytokines influence insulin sensitivity and glucose metabolism profoundly, they might provide a molecular link between increased adiposity and impaired insulin sensitivity. Thiazolidinediones which decrease insulin resistance and are used in the treatment of Type 2 diabetes seem to mediate part of their insulin-sensitising effects via modulation of adipocytokine expression. Furthermore, hormones such as beta-adrenergic agonists, insulin, glucocorticoids, and growth hormone might impair insulin sensitivity at least in part via up-regulation or down-regulation of adipocytokine synthesis. We summarise the current knowledge on how major adipocyte-secreted proteins are regulated by hormones and drugs influencing insulin sensitivity and discuss its implications for insulin resistance and obesity. PMID: 14605806 [PubMed - indexed for MEDLINE] 4354. Nephrol Dial Transplant. 2003 Dec;18(12):2471-4. After all those fat years: renal consequences of obesity. Wolf G(1). Author information: (1)Department of Medicine, Division of Nephrology, Rheumatology and Osteology, University of Hamburg, University Hospital Eppendorf, Pavilion N26, Martinistrasse 52, D-20246 Hamburg, Germany. Wolf@uke.uni-hamburg.de Comment in Nephrol Dial Transplant. 2004 Jul;19(7):1934. PMID: 14605265 [PubMed - indexed for MEDLINE] 4355. Rev Med Interne. 2003 Nov;24(11):730-7. [Pathogenesis of type 2 diabetes mellitus]. [Article in French] Guillausseau PJ(1), Laloi-Michelin M. Author information: (1)Service de médecine interne B, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris 10, France. pierre-jean.guillausseau@lrb.ap-hop-paris.fr "Common" type 2 diabetes mellitus is a multifactorial disease. Hyperglycemia is related to a decrease in glucose peripheral uptake, and to an increase in hepatic glucose production, due to reduced insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including loss of basal pulsatility, lack of early phase of insulin secretion after intravenous glucose administration, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. These genetically determined abnormalities appear early in the course of the disease. Insulin resistance affects muscle, liver, and adipose tissue. For the same plasma insulin levels, peripheral glucose uptake and hepatic glucose production suppressibility are lower in diabetic patients than in controls. It results from aging of the population and from "western" lifestyle, with progressive increase in mean body weight, due to excess in energy intake, decreased energy expenses and low physical activity level.NEW ASPECTS: The role of beta-cell dysfunction, as well as the interplay between insulin secretory defect and insulin resistance are now better understood. In subjects with normal beta-cell function, increase in insulin needs secondary to insulin resistance is compensated by an increase in insulin secretion adjusted to maintain plasma glucose levels to normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate for increased needs is responsible for a progressive elevation in plasma glucose levels, then for overt type 2 diabetes. This adaptative phenomenon is called beta-cell compensation of insulin resistance. The lack of compensation is responsible for type 2 diabetes. When permanent hyperglycemia is present, progressive insulin secretory failure with time ensues, due to glucotoxicity and to lipotoxicity. PERSPECTIVES: Simple changes in lifestyle, such regular moderate physical activity, and control of body weight, should permit to avoid the explosion in prevalence of type 2 diabetes. This has been evidenced by the results of prospective studies aiming at preventing conversion from impaired glucose tolerance to diabetes. In patients with permanent hyperglycemia not controlled by lifestyle changes, metabolic defects are the targets of specific therapy intervention with antidiabetic oral agents, such as insulin secretagogues, insulin sensitizers, and inhibitors of hepatic glucose production. PMID: 14604750 [PubMed - indexed for MEDLINE] 4356. Clin Chem Lab Med. 2003 Sep;41(9):1266-78. Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine. Dominiczak MH(1). Author information: (1)Department of Biochemistry, Gartnavel General Hospital, Glasgow, UK. m.h.dominiczak@clinmed.gla.ac.uk This article provides an overview of the role of metabolite toxicity, low-grade inflammation and disturbed cellular signaling in obesity, glucose intolerance and diabetes. It also highlights links between this continuum of deteriorating glucose tolerance and atherosclerosis. Obesity, diabetes mellitus, and cardiovascular disease are all related to diet and to the level of physical activity. They have reached epidemic proportions worldwide. Glucose intolerance and diabetes increase the risk of atherosclerotic events. Moreover, obesity, and glucose intolerance or diabetes, are components of the metabolic syndrome, which also imparts an increased cardiovascular risk. There is increasing recognition that common mechanisms contribute to diabetes and cardiovascular disease. Following increased calorie intake and/or decreased physical activity, fuel metabolism generates excess of 'toxic' metabolites, particularly glucose and fatty acids. Homeostasis is affected by the endocrine output from the adipose tissue. Reactive oxygen species are generated, creating oxidative stress, which exerts major effects on signaling pathways, further affecting cellular metabolism and triggering low-grade inflammatory reaction. This perspective on the diabetic syndrome has been reflected in the approach to its treatment, which integrates maintenance of glycemic control with primary and secondary cardiovascular prevention. Laboratory medicine should support diabetes care with an integrated package of tests which, in addition to glycemic control, enable assessment and monitoring of the risk of microvascular complications as well as cardiovascular disease. PMID: 14598880 [PubMed - indexed for MEDLINE] 4357. Med Sci (Paris). 2003 Aug-Sep;19(8-9):860-3. [Gluco-incretin hormones in insulin secretion and diabetes]. [Article in French] Thorens B(1). Author information: (1)Institut de Physiologie, 27, rue du Bugnon, 1005 Lausanne, Suisse. Bernard.Thorens@ipharm.unil.ch Nutrient ingestion triggers a complex hormonal response aimed at stimulating glucose utilization in liver, muscle and adipose tissue to minimize the raise in blood glucose levels. Insulin secretion by pancreatic beta cells plays a major role in this response. Although the beta cell secretory response is mainly controlled by blood glucose levels, gut hormones secreted in response to food intake have an important role in potentiating glucose-stimulated insulin secretion. These gluco-incretin hormones are GLP-1 (glucagon-like peptide-1) and GIP (gluco-dependent insulinotropic polypeptide). Their action on pancreatic beta cells depends on binding to specific G-coupled receptors linked to activation of the adenylyl cyclase pathway. In addition to their effect on insulin secretion both hormones also stimulate insulin production at the transcriptional and translational level and positively regulate beta cell mass. Because the glucose-dependent insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide is now developed as a novel therapeutic drug for this disease. PMID: 14593618 [PubMed - indexed for MEDLINE] 4358. Med Sci (Paris). 2003 Aug-Sep;19(8-9):834-9. [Insulin signaling: mechanisms altered in insulin resistance]. [Article in French] Capeau J(1). Author information: (1)Inserm U.402, Hôpital Tenon, Faculté de médecine Saint-Antoine, Université Pierre-et-Marie-Curie, 27, rue Chaligny, 75571 Paris Cedex 12, Paris, France. capeau@st-antoine.inserm.fr Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome. PMID: 14593614 [PubMed - indexed for MEDLINE] 4359. Med Sci (Paris). 2003 Aug-Sep;19(8-9):809-17. [Adipocytokins, obesity and development of type 2 diabetes]. [Article in French] Lacquemant C(1), Vasseur F, Leprêtre F, Froguel P. Author information: (1)Hammersmith Genome Centre, Imperial College, Londres, Royaume-Uni. Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin. PMID: 14593611 [PubMed - indexed for MEDLINE] 4360. Dtsch Med Wochenschr. 2003 Oct 31;128(44):2319-23. [Visceral adipose tissue and metabolic syndrome]. [Article in German] Blüher M(1), Paschke R. Author information: (1)Medizinische Klinik und Poliklinik III, und Nachwuchsgruppe N03, IZKF Leipzig, Universität Leipzig. PMID: 14593576 [PubMed - indexed for MEDLINE] 4361. Trends Endocrinol Metab. 2003 Nov;14(9):398-403. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Unger RH(1). Author information: (1)University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA. roger.unger@UTSouthwestern.edu Approximately two-thirds of the US population are overweight, which means that insulin resistance is probably the most common metabolic abnormality in the USA. I propose three novel concepts concerning the causes and consequences of insulin resistance that challenge current thinking. First, there is the evidence that resistance to insulin-stimulated glucose metabolism is not a primary event in obesity, but is secondary to lipid accumulation resulting from full responsiveness to insulin-stimulated lipogenic activity. Second, resistance to insulin-stimulated glucose metabolism, now considered detrimental to health, might be a protective mechanism that reduces lipid-induced damage to tissue by excluding glucose from cells, thus decreasing glucose-derived lipogenesis. Third, I suggest that lipid-induced insulin resistance and the accompanying metabolic syndrome are secondary to leptin resistance, resulting in breakdown in the normal partitioning of surplus lipids in the adipocyte compartment. PMID: 14580758 [PubMed - indexed for MEDLINE] 4362. Curr Opin Chem Biol. 2003 Oct;7(5):648-54. Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis. Griffin JL(1). Author information: (1)Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. jlg40@mole.bio.cam.ac.uk Global profiling tools are required to fully understand the impact of genetic modifications and toxicological interventions on the network of transcripts, proteins and metabolites found within a cell, tissue or organism. High-resolution 1H NMR spectroscopy in conjunction with statistical pattern recognition is one such technique, referred to as metabonomics or metabolomics, which is increasingly being used to globally profile metabolites. This review examines analytical advances in NMR spectroscopy that have aided this development including high-resolution magic angle spinning NMR spectroscopy, cryogenically cooled probes and high-through put systems. This has allowed the approach to identify genetically modified yeast strains and distinguish both disease presence and severity in coronary heart disease. PMID: 14580571 [PubMed - indexed for MEDLINE] 4363. J Nippon Med Sch. 2003 Oct;70(5):428-31. [Versatility of adipose tissue as a source of stem cells]. [Article in Japanese] Mizuno H(1). Author information: (1)Department of Plastic and Reconstructive Surgery, Nippon Medical School, Japan. hiromzn@attglobal.net The stem cells are promising for future cell-based therapy such as tissue engineering or regenerative medicine. Although Embryonic Stem Cells (ESCs) are theoretically highly beneficial, there are various limitations on their use posed by cell regulations and ethical considerations. Therefore, adult stem cells are considered to be highly available with neither ethical nor immunoreactive considerations as long as they are of autologous tissue origin. Much of work has focused on the Mesenchymal Stem Cells (MSCs) isolated from bone marrow stroma, which have been shown to possess adipogenic, osteogenic, chondrogenic, myogenic and neurogenic potential in vitro. However bone marrow procurement is severely painful for patients and the harvested cells yields low number. Our preliminary studies have identified a putative stem cell population isolated from human adipose tissue. This cell population, termed Processed Lipoaspirate Cells (PLA Cells), is found to differentiate into adipogenic, osteogenic, chondrogenic and myogenic lineage in vitro in lineage-specific culture media. In addition to these findings, our recent data shows that PLA cells can be induced to differentiate into neural precursors, which are of an ectodermal origin. Furthermore, PLA cells express multiple CD marker antigens similar to those observed on MSCs. Finally, some of PLA clonal cells have capabilities of differentiate into adipogenic, osteogenic and chondrogenic lineage. These findings suggest that human PLA have a mesodermal stem cell population. Since human adipose tissue is ubiquitous, easily obtainable in large quantity under local anesthesia with little patient discomfort, it may be an alternative stem cell source for mesenchymal tissue regeneration and engineering. PMID: 14578945 [PubMed - indexed for MEDLINE] 4364. Cytotherapy. 2003;5(5):362-9. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Gimble J(1), Guilak F. Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA. Adipose tissue is an abundant, accessible, and replenishable source of adult stem cells that can be isolated from liposuction waste tissue by collagenase digestion and differential centrifugation. These adipose-derived adult stem (ADAS) cells are multipotent, differentiating along the adipocyte, chondrocyte, myocyte, neuronal, and osteoblast lineages, and can serve in other capacities, such as providing hematopoietic support and gene transfer. ADAS cells have potential applications for the repair and regeneration of acute and chronically damaged tissues. Additional pre-clinical safety and efficacy studies will be needed before the promise of these cells can be fully realized. PMID: 14578098 [PubMed - indexed for MEDLINE] 4365. Pathol Biol (Paris). 2003 Jul;51(5):244-7. [The adipocyte in the history of slimming agents]. [Article in French] Franchi J(1), Pellicier F, André P, Schnebert S. Author information: (1)Laboratoires R&D-LVMH branche parfums et cosmétiques, 45804 Saint-de-Braye, France. jfranchi@diormail.com Nowadays, in industrialised societies, it is fashionable for women to be slim. However, throughout history, this has not always been the case, especially as "cellulite" (cellulitis) was full of typically feminine symbols. The ideal feminine silhouette has changed with the rhythm of cultures. Cellulitis is an inappropriate term used by women to describe curves which they judge to be too plump and not very aesthetic, mostly around the thighs and hips. This lipodystrophy of the adipose tissue represents approximately 25% of a woman's body weight. It is clinically characterised by an "orange peel" skin surface, which is a result of the excessive development of the volume of the adipocytes organised in lobules within the walls of the unstretchable conjunctive tissue. This phenomenon is associated with an insufficiency of the venous tonus and an increase in the capillary permeability, which both contribute to an increase in the infiltration of water in the tissue. In reality, the understanding of cellulite has truly progressed with research based on adipocyte functions. An adipocyte is a metabolically active cell which plays a central role in the control of the energetic balance of the organism. In order to assume this role, it possesses all the enzymatic equipment necessary for synthesis (lipogenesis) and for triglyceride storage, mobilisation and liberation as free fatty acids (lipolysis). During these last few years, as well as this role as an energetic reserve which manages lipogenesis/lipolysis balance, the adipocyte has acquired the status of an endocrine and paracrine cell through the identification of numerous secreted factors. When we look back at the history of slimming products launched on the market since the 1980's, we can notice the role of the adipocyte tool and understand its functions in the choice of active ingredients, the development of complementary actions, the importance of the texture, the evolution of methods used to evaluate the efficacy on human volunteers and of course, we must not forget the women satisfaction and the power of seduction through words. PMID: 14567186 [PubMed - indexed for MEDLINE] 4366. Prim Care. 2003 Jun;30(2):249-65. Evaluation of body composition: practical guidelines. Gallagher D(1), Song MY. Author information: (1)Department of Medicine, Institute of Human Nutrition, Body Composition Unit, Obesity Research Center, College of Physicians and Surgeons, Columbia University, St. Luke's-Roosevelt Hospital, New York, NY 10025, USA. dg108@columbia.edu The measurement of body composition in the truest sense allows for the estimation of body tissues, organs, and their distributions in living persons without inflicting harm. It is important to recognize that there is no single measurement method that is error-free. Furthermore, bias can be introduced if a measurement method makes assumptions related to body composition proportions and characteristics that are inaccurate across different populations. Some methodologic concerns include hydration of fat-free body mass changes with age and differences across ethnic groups [73]; the density of fat-free body mass changes with age and differences between men and women [74, 75]; total body potassium decreases with age [73] and fatness [76] and differences between African Americans and Caucasians [77]; the mass of skeletal muscle differences across race group [63]; and VAT differences across sex [78] and race [67, 79, 80] groups, independent of total adiposity. These between-group differences influence the absolute accuracy of methods for estimating fatness or FFM that involve the two-compartment model approach. The clinical significance of the body compartment to be measured should be determined before a measurement method is selected, because the more advanced techniques are less accessible and more costly. PMID: 14567146 [PubMed - indexed for MEDLINE] 4367. Drugs Today (Barc). 2003 Aug;39(8):609-32. Therapeutic significance of peroxisome proliferator-activated receptor modulators in diabetes. Ram VJ(1). Author information: (1)Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India. vjiram@yahoo.com Peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, identified and encoded by different genes: PPARalpha, PPARdelta and PPARgamma. Each subtype of PPAR appears to be differently expressed in a tissue-specific manner due to its binding to a specific consensus DNA sequence of peroxisome proliferator response elements (PPREs). PPARalpha plays a significant role in the regulation of nutrient metabolism, including fatty acid oxidation, gluconeogenesis and amino acid metabolism. PPARdelta is expressed ubiquitously and has been found to be effective in controlling dyslipidemia and cardiovascular diseases, while PPARgamma isotype is mainly expressed in adipose tissue where it stimulates adipogenesis and lipogenesis. Thus PPARs have emerged as potential molecular targets for the design and synthesis of a different class of compounds, considering the conformation of receptors for the treatment of human metabolic disorders. This review concerns the therapeutic importance of PPARs in diabetes drug development. PMID: 14566384 [PubMed - indexed for MEDLINE] 4368. Curr Drug Targets Inflamm Allergy. 2002 Sep;1(3):243-8. Peroxisome proliferator-activated receptors and the control of inflammation. Cabrero A(1), Laguna JC, Vázquez M. Author information: (1)Unitat de Farmacologia, Departament de Farmacologia i Química Terapeùtica, Facultat de Farmàcia, Universitat de Barcelona, Spain. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. This subfamily consists of three isotypes, alpha (NR1C1), gamma (NR1C3), and beta/delta (NRC1C2) with a differential tissue distribution. PPARalpha is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle. PPARbeta is ubiquitously expressed, and PPARgamma has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts. Furthermore, PPARalpha and gamma isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages/foam cells. PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes. In addition to fatty acids, several synthetic compounds, such as fibrates and thiazolidinediones, bind and activate PPARalpha and PPARgamma, respectively. In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR). Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses. The first evidence of the involvement of PPARs in the control of inflammation came from the PPARalpha null mice, which showed a prolonged inflammatory response. PPARalpha activation results in the repression of NF-kappaB signaling and inflammatory cytokine production in different cell-types. A role for PPARgamma in inflammation has also been reported in monocyte/macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNFalpha, interleukin 6 and 1beta), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPARgamma. All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases. PMID: 14561188 [PubMed - indexed for MEDLINE] 4369. Nutrition. 2003 Oct;19(10):891-900. Effect of endurance training on muscle fat metabolism during prolonged exercise: agreements and disagreements. Smekal G(1), von Duvillard SP, Pokan R, Tschan H, Baron R, Hofmann P, Wonisch M, Bachl N. Author information: (1)Institute of Sports Sciences, Department of Sport Physiology, University of Vienna, Vienna, Austria. gerhard.smekal@univie.ac.at PMID: 14559327 [PubMed - indexed for MEDLINE] 4370. J Mol Med (Berl). 2004 Jan;82(1):12-20. Epub 2003 Oct 14. The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective. Bates SH(1), Myers MG. Author information: (1)Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA. The hormone leptin is secreted by adipose tissue in proportion to fat mass to signal the repletion of body energy stores to the neuroendocrine system. Leptin acts on neurons in the hypothalamus and elsewhere in the brain to decrease appetite and regulate the activity of the thyroid, adrenal, growth, gonadal, and lactational axes. Conversely, absence of leptin signaling initiates the neuroendocrine starvation response. Leptin mediates these effects by activating the long form (LRb) of its receptor. One LRb signal, STAT3, has recently been shown to play a critical role in the regulation of body weight and some elements of neuroendocrine function (thyroid, adrenal, lactation), although the participation of STAT3 in the gonadal and growth axes is negligible. We discuss these findings in the context of the hypothalamic neuroendocrine system as it is presently understood. PMID: 14557860 [PubMed - indexed for MEDLINE] 4371. Int J Obes Relat Metab Disord. 2004 Feb;28(2):336-9. Genetic basis of congenital generalized lipodystrophy. Agarwal AK(1), Barnes RI, Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, 75390, USA. Anil.Agarwal@UTSouthwestern.edu Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL. PMID: 14557833 [PubMed - indexed for MEDLINE] 4372. Curr Opin Clin Nutr Metab Care. 2003 Nov;6(6):621-9. Peripheral signals in the control of satiety and hunger. Drazen DL(1), Woods SC. Author information: (1)Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, MSB G059, Cincinnati, OH 45267-0559, USA. debbie.drazen@uc.edu PURPOSE OF REVIEW: Food intake is critical for survival and is a complex behavior with multiple levels of control. Short-term, meal-related signals arise from many sources including the gastrointestinal tract, the environment, and higher centers in the brain. As described in this review, inputs from the gastrointestinal tract can exert potent effects on meal initiation, meal termination, and meal frequency. The complex array of signals generated from the gastrointestinal system and from adipose tissue, which participate in the regulation of food intake, and specifically how these signals relate to satiety and hunger, is the focus of this review. RECENT FINDINGS: Literature on the role of the well-studied gastrointestinal peptide, cholecystokinin, in satiety, in addition to its interaction with long-term adiposity signals in mediating food intake will be reviewed. In addition, literature on the gastrointestinal hormones glucagon-like-peptide 1, apolipoprotein A-IV and peptide YY, and how they may act to regulate satiety, is described. Finally, the newly discovered hormone, ghrelin, and how it relates to meal initiation and hunger is discussed. SUMMARY: A better understanding of these systems and how they relate to body adiposity will prove to have important clinical applications. The available data suggest that interventions directed at multiple targets in the energy homeostasis system may be necessary to achieve and maintain weight loss. PMID: 14557791 [PubMed - indexed for MEDLINE] 4373. Bull Acad Natl Med. 2003;187(1):69-82; discussion 83-4. [From fibrinogen to fibrin and its dissolution]. [Article in French] Juhan-Vague I(1), Hans M. Author information: (1)Laboratoire d'Hématologie, CHU Timone, INSERM EPI 9936-13385 Marseille. Fibrinogen is a protein synthesised by the liver. It is converted by thrombin to an insoluble fibrin network to induce, together with platelet aggregates, haemostasis in response to rupture of endothelium. This change includes several steps and implied factor XIII. Molecular properties of fibrin are responsible for its important role in hemostasis which goes beyond the one of a simple final inert product of coagulation. In fact, fibrin regulates thrombin and factor XIII activities and its own destruction also called fibrinolysis. The multiple domains of fibrinogen and fibrin confer a role not only in haemostasis but also in wound healing, cellular migration and proliferation, due to interactions with endothelial cells, leukocytes and components of the extracellular matrix. Fibrin must be removed once its haemostatic role has been reached. The fibrinolytic process takes place in the vessel lumen. It is strongly regulated by the plasma concentration of an inhibitor called plasminogen activator inhibitor-1 (PAI-1) which synthesis strongly increases in obese insulin resistant and diabetic patients. Data from animal models show that increased PAI-1 production represents a prothrombotic state. Fibrinolysis plays also a role in tissue remodeling (vascular wall, placenta, adipose tissue....) by degrading the extracellular matrix, by activating growth factors or modifying cellular adhesion and migration properties. It has been proposed that PAI-1 in excess could be directly responsible for the development of atherothrombosis in insulin resistant subjects. Moreover recent results from transgenic mice indicate that PAI-1 in excess interferes also with weight gain. These data point out the importance of the haemostatic system in the extra vascular phenomenon of tissue remodeling. PMID: 14556455 [PubMed - indexed for MEDLINE] 4374. Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):29-33. Epub 2003 Oct 9. Adiponectin and metabolic syndrome. Matsuzawa Y(1), Funahashi T, Kihara S, Shimomura I. Author information: (1)Department of Internal Medicine and Molecular Science, Osaka University Graduate School, Sumitomo Hospital, Osaka, Japan. matsuzawa-yuji@sumitomo-hp.or.jp In this review article, the crucial roles of adipocytes in the development of so-called metabolic syndrome and vascular disease are reviewed, focusing on adipocyte-derived bioactive substances, adipocytokines. Recent progress in adipocyte biology shows that adipocytes are not merely energy-storing cells but that they secrete a variety of hormones cytokines, growth factors, and other bioactive substances. To search for novel adipocytokines by the large-scale random sequence analysis of expressed genes in adipocytes, we identified an adipose-specific collagen-like molecule, adiponectin. This novel adipocytokine has plural biofunctions, such as antidiabetic, antiatherosclerotic, and antiinflammatory functions. Adiponectin plasma levels decrease with the accumulation of visceral adipose tissue. In this review, we discuss the link of adiponectin to visceral adiposity, insulin resistance, and vascular diseases. PMID: 14551151 [PubMed - indexed for MEDLINE] 4375. Keio J Med. 2003 Sep;52(3):198-203. Functional genetic dissection of nuclear receptor signalling in obesity, diabetes and liver regeneration using spatiotemporally controlled somatic mutagenesis in the mouse. Imai T(1). Author information: (1)Department of Physiological Genetics of Nuclear Signalling, IGBMC, Illkirch, France. imai@igbmc.u-strasbg.fr The mouse is an excellent animal model for defining human diseases. The null allele mutations (knockouts, KO) have already provided valuable information about their functions, but have also revealed major complications and difficulties: (1) an early embryonic lethality, (2) temporal effect (developmental stage or adult stage), (3) functional redundancy and (4) spatio-effect (cell-autonomous or non-autonomous). To overcome these limitations, spatio-temporally controlled somatic mutagenesis, Cre-ER(T)/LoxP system, was established. The nuclear receptors (NRs) play central roles in development, organogenesis, metabolism and energy homeostasis through their ability to transduce hormonal signals into modulation of gene activity. Obesity, excess energy storage in adipose tissue, has a strong link to diabetes. Among NRs, retinoid X receptor alpha (RXRalpha)-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers can mediate adipocyte differentiation and obesity which has been demonstrated with in vitro cell culture systems and RXR- and PPARgamma-specific ligand studies. Therefore an adipocyte-specific temporally controlled somatic mutagenesis system was established and analysed. Furthermore, the functional roles of NRs to control liver regeneration were also studied with similar system in hepatocytes. PMID: 14529153 [PubMed - indexed for MEDLINE] 4376. Comp Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):17-26. Survival of the fattest: fat babies were the key to evolution of the large human brain. Cunnane SC(1), Crawford MA. Author information: (1)Department of Nutritional Sciences, University of Toronto, M5S 3E2, Toronto, Canada. s.cunnane@utoronto.ca In the past 2 million years, the hominid lineage leading to modern humans evolved significantly larger and more sophisticated brains than other primates. We propose that the modern human brain was a product of having first evolved fat babies. Hence, the fattest (infants) became, mentally, the fittest adults. Human babies have brains and body fat each contributing to 11-14% of body weight, a situation which appears to be unique amongst terrestrial animals. Body fat in human babies provides three forms of insurance for brain development that are not available to other land-based species: (1) a large fuel store in the form of fatty acids in triglycerides; (2) the fatty acid precursors to ketone bodies which are key substrates for brain lipid synthesis; and (3) a store of long chain polyunsaturated fatty acids, particularly docosahexaenoic acid, needed for normal brain development. The triple combination of high fuel demands, inability to import cholesterol or saturated fatty acids, and dependence on docosahexaenoic acid puts the mammalian brain in a uniquely difficult situation compared with other organs and makes its expansion in early humans all the more remarkable. We believe that fresh- and salt-water shorelines provided a uniquely rich, abundant and accessible food supply, and the only viable environment for evolving both body fat and larger brains in human infants. PMID: 14527626 [PubMed - indexed for MEDLINE] 4377. Anat Sci Int. 2003 Sep;78(3):123-38. Hypothalamic neuronal networks and feeding-related peptides involved in the regulation of feeding. Funahashi H(1), Takenoya F, Guan JL, Kageyama H, Yada T, Shioda S. Author information: (1)Department of Anatomy, Showa University School of Medicine, Tokyo, Japan. The hypothalamus is a region of the brain that plays a critical role in feeding regulation. It has been revealed by various physiological experiments that the feeding-regulating center is confined to the ventromedial hypothalamus, lateral hypothalamus (LH) and arcuate nucleus (ARC). Many kinds of neurons in these areas of the hypothalamus express factors such as melanin-concentrating hormone (MCH), neuropeptide Y (NPY), proopiomelanocortin (POMC), orexin (OX) and ghrelin, which have been implicated in feeding regulation. In tissues of the periphery, two critical factors involved in feeding regulation, leptin and ghrelin, have been identified. Both hormone peptides are secreted mainly from adipose and stomach tissue, respectively, and are considered to function via their receptors mainly through several hypothalamic nuclei that play important roles in the regulation of appetite. The present review looks mainly at the functional significance of feeding-regulation factors, such as those described above, and the humoral and neuronal interactions among these compounds in the hypothalamus by drawing on published reports of morphological and physiological analyses. Immunohistochemical and in situ hybridization experiments indicate that both leptin and ghrelin receptors are distributed in the hypothalamus and that there are reciprocal interactions between MCH and OX neurons in the LH. Morphological and physiological studies on single living cells isolated from fresh rat hypothalamus or with receptor agonist and antagonist combined with immunohistochemisry clearly demonstrate that both leptin and OX reciprocally regulate NPY- and POMC-containing neurons in the ARC and that ghrelin may regulate feeding status independently through direct OX and NPY pathways. In this way, cross-talking systems in the hypothalamus play a role in determining feeding states. PMID: 14527127 [PubMed - indexed for MEDLINE] 4378. J Nutr. 2003 Oct;133(10):3041-6. Conjugated linoleic acid in humans: regulation of adiposity and insulin sensitivity. Brown JM(1), McIntosh MK. Author information: (1)Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402-6170, USA. Conjugated linoleic acid (CLA) isomers, a group of positional and geometric isomers of linoleic acid [18:2(n-6)], have been studied extensively due to their ability to modulate cancer, atherosclerosis, obesity, immune function and diabetes in a variety of experimental models. The purpose of this review was to examine CLA's isomer-specific regulation of adiposity and insulin sensitivity in humans and in cultures of human adipocytes. It has been clearly demonstrated that specific CLA isomers or a crude mixture of CLA isomers prevent the development of obesity in certain rodent and pig models. This has been attributed mainly to trans-10, cis-12 CLA, both in vivo and in vitro. However, CLA's ability to modulate human obesity remains controversial because data from clinical trials using mixed isomers are conflicting. In support of some studies in humans, our group demonstrated that trans-10, cis-12 CLA prevents triglyceride (TG) accumulation in primary cultures of differentiating human preadipocytes. In contrast, cis-9, trans-11 CLA increases TG content. Closer examination has revealed that CLA's antiadipogenic actions are due, at least in part, to regulation of glucose and fatty acid uptake and metabolism. This review presents our current understanding of potential isomer-specific mechanisms by which CLA reduces human adiposity and insulin sensitivity. PMCID: PMC1307498 PMID: 14519781 [PubMed - indexed for MEDLINE] 4379. Expert Opin Biol Ther. 2003 Oct;3(7):1061-70. The therapeutic potential of interleukin-6 in treating obesity. Wallenius K(1), Jansson JO, Wallenius V. Author information: (1)Research Center for Endocrinology and Metabolism (RCEM), Endocrine Division, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, Sweden. ville.wallenius@medic.gu.se Interleukin (IL)-6 is a multifunctional immune-modulating cytokine that has been suggested to have important functions in glucose and lipid metabolism. It is secreted from adipose tissue during resting conditions and from muscle during strenuous exercise. Recently, the authors reported that mice deficient of IL-6 develop mature-onset obesity, which was reversed by IL-6 replacement. The IL-6-deficient mice had increased glucose levels and decreased glucose tolerance, and blood lipids were increased in females. Furthermore, it was found that intracerebroventricular (ICV) IL-6 treatment acutely increased energy expenditure in rats and led to loss of fat mass following prolonged treatment, without causing symptoms of sickness behaviour or increased levels of acute-phase reactants. Thus, these data indicate a role for IL-6 in the regulation of energy homeostasis in rodents. In humans, several single nucleotide polymorphisms in the IL-6 gene promoter are known, one of which (174 C) is associated with reduced IL-6 transcription as well as decreased basal metabolic rate and insulin sensitivity in healthy male subjects. Furthermore, it was found that IL-6 levels in cerebrospinal fluid in obese humans were inversely correlated with more severe obesity, suggesting that severe obesity is coupled to a relative central IL-6 deficiency. Taken together, these data suggest that endogenous IL-6 has antiobesity effects and, therefore, it is possible that low endogenous IL-6 production contributes to obesity in humans. PMID: 14519071 [PubMed - indexed for MEDLINE] 4380. Antivir Ther. 2003 Aug;8(4):261-3. Mitochondria and lipodystrophy: where are we now? Gerschenson M. Comment on Antivir Ther. 2003 Aug;8(4):333-8. Antivir Ther. 2003 Aug;8(4):315-21. Antivir Ther. 2003 Aug;8(4):323-31. PMID: 14518694 [PubMed - indexed for MEDLINE] 4381. Trends Endocrinol Metab. 2003 Oct;14(8):386-92. Fatty acid mobilization from adipose tissue during exercise. Horowitz JF(1). Author information: (1)Division of Kinesiology, The University of Michigan, Ann Arbor, MI 48109-2214, USA. jeffhoro@umich.edu By far the largest energy reserve in the human body is adipose tissue triglycerides, and these reserves are an important source of fuel during prolonged endurance exercise. To use this rich source of potential energy during exercise, adipose tissue triglycerides must first be hydrolyzed and the resultant fatty acids delivered to the working muscles. The aims of this review are to describe how exercise alters lipid mobilization from adipose tissue, to identify alternative sources of lipids and to discuss some of the key factors regulating fatty acid mobilization, uptake and oxidation during exercise. The impact of understanding factors involved in the coordinated regulation of lipid mobilization and oxidation during exercise goes far beyond its relevance for endurance exercise performance. A better understanding of the regulation of these processes will facilitate the development of more effective treatment modalities for obesity-related metabolic disorders. PMID: 14516937 [PubMed - indexed for MEDLINE] 4382. Semin Oncol. 2003 Aug;30(4 Suppl 14):3-11. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Miller WR(1). Author information: (1)University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK. The natural history of breast cancer is closely linked with estrogens. These hormones influence both risk to the disease and growth of many established tumors. Consequently, measures that either inhibit the synthesis or block the mechanism of action of estrogens are attractive strategies for therapeutic intervention. This is particularly true in postmenopausal women in whom hormone responsiveness is common and estrogen synthesis is primarily sited peripherally in adipose tissue, muscle and breast tissue, rather than in the ovaries as in premenopausal women. In terms of inhibiting production, the most specific effects are best achieved by blocking the last step in biosynthesis, the conversion of androgens to estrogens by the heme-containing enzyme, aromatase. Two major classes of aromatase inhibitors have been developed and are currently in clinical use. Type I steroidal drugs include formestane and exemestane; they are androgen substrate analogues that bind competitively but irreversibly to the enzyme and have been marketed as "inactivators." Type II nonsteroidal inhibitors such as anastrozole and letrozole are triazoles; they bind reversibly to the enzyme and fit into the substrate binding site, such that azole nitrogens interact with the heme prosthetic group. This type of association provides exquisite potency for and specificity against the aromatase enzyme. These agents represent several generations of development, with each step in the evolution producing an increase in both potency and specificity. The latest aromatase inhibitors are drugs of immense potential that will undoubtedly play a major role in the management of postmenopausal women with hormone-dependent breast cancer. They also represent tools by which to elucidate the roles of both aromatase and estrogen in the development and growth of breast cancer. PMID: 14513432 [PubMed - indexed for MEDLINE] 4383. Diabetes Technol Ther. 2003;5(4):589-98. A model for transport of glucose in adipose tissue to a microdialysis probe. Schoonen AJ(1), Wientjes KJ. Author information: (1)Department of Biomonitoring and Sensoring, University Center of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.j.m.schoonen@farm.rug.nl A model is presented, describing diffusion of solutes (as glucose) through adipose tissue. The model is based on the well-known extraction equation for diffusion across capillary walls or across the membrane of microdialysis probes, but adapted for use in adipose tissue. Arguments are presented for a simple scheme in which the mean capillary concentration of a solute (i.e., glucose) is substituted for the interstitial fluid solute concentration in the extraction equation, as the driving force for diffusion of glucose from capillary to cell or from capillary to a microdialysis probe. The model is discussed by evaluating the results of previous studies by our group and others on the equilibrium concentration of glucose in a microdialysis probe, as well as the effect of insertion on recovery of glucose by the probe and the time it takes for glucose in adipose tissue to diffuse to the probe. The results of these studies are in good agreement with the predictions derived from the model: The equilibrium concentration of glucose in the microdialysis probe is equal to the capillary glucose concentration. Insertion effects can be explained by a lower glucose concentration around the probe because of inflammation (12-18 h) and by a slow increase in the number of functioning capillaries around the probe due to wound healing (4-6 days). Transport time of glucose from capillaries to a microdialysis probe is not more than a few seconds. Reported delay times in the literature are probably caused by an uneven distribution of blood glucose after a glucose challenge. PMID: 14511413 [PubMed - indexed for MEDLINE] 4384. Proc Nutr Soc. 2003 May;62(2):521-8. Body composition in childhood: effects of normal growth and disease. Wells JC(1). Author information: (1)MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. J.Wells@ich.ucl.ac.uk Body composition in children is of increasing interest within the contexts of childhood obesity, clinical management of patients and nutritional programming as a pathway to adult disease. Energy imbalance appears to be common in many disease states; however, body composition is not routinely measured in patients. Traditionally, clinical interest has focused on growth or nutritional status, whereas more recent studies have quantified fat mass and lean mass. The human body changes in proportions and chemical composition during childhood and adolescence. Most of the weight gain comprises lean mass rather than fat. In general, interest has focused on percentage fat, and less attention has been paid to the way in which lean mass varies within and between individuals. In the general population secular trends in BMI have been widely reported, indicating increasing levels of childhood obesity, which have been linked to reduced physical activity. However, lower activity levels may potentially lead not only to increased fatness, but also to reduced lean mass. This issue merits further investigation. Diseases have multiple effects on body composition and may influence fat-free mass and/or fat mass. In some diseases both components change in the same direction, whereas in other diseases, the changes are contradictory and may be concealed by relatively normal weight. Improved techniques are required for clinical evaluations. Both higher fatness and reduced lean mass may represent pathways to an increased risk of adult disease. PMID: 14506900 [PubMed - indexed for MEDLINE] 4385. Proc Nutr Soc. 2003 May;62(2):447-53. n-3 Polyunsaturated fatty acids, inflammation and obesity-related disease. Browning LM(1). Author information: (1)MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK. Lucy.Browning@mrc-hnr.cam.ac.uk Obese individuals are at increased risk from a range of metabolic diseases, including insulin resistance, dyslipidaemia and hypertension. Adipose tissue is an important endocrine organ, secreting a range of inflammatory mediators, including tumour necrosis factor alpha and interleukin 6. Circulating concentrations of these cytokines are increased in obesity and may contribute to the pathogenesis of metabolic diseases. The present review considers the evidence linking inflammation and obesity-related disease. The data show that an inflammatory phenotype, measured by serum sialic acid concentration, identifies individuals with insulin resistance, dyslipidaemia and hypertension. Serum sialic acid concentration increases progressively in obese individuals with none, one or multiple features of the metabolic syndrome, independent of BMI. Supplementation with long-chain n-3 polyunsaturated fatty acids has shown anti-inflammatory effects in studies of both healthy populations and in models of chronic inflammatory conditions. The effect on insulin sensitivity has been varied, with both positive and negative effects. This variability may relate to the metabolic characteristics of the study population; individuals with high background inflammation may derive greater benefits from n-3 polyunsaturated fatty acid supplements, suggesting a possible interaction between diet and phenotype. Future research is needed to fully evaluate the role of anti-inflammatory strategies in the dietary management of obesity. PMID: 14506893 [PubMed - indexed for MEDLINE] 4386. Proc Nutr Soc. 2003 May;62(2):421-7. Prolactin, prolactin receptor and uncoupling proteins during fetal and neonatal development. Pearce S(1), Mostyn A, Alves-Guerra MC, Pecqueur C, Miroux B, Webb R, Stephenson T, Symond ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK. mgxsp@nottingham.ac.uk Uncoupling proteins (UCP) 1 and 2 are members of the subfamily of inner mitochondrial membrane carriers. UCP1 is specific to brown adipose tissue (BAT), where it is responsible for the rapid production of heat at birth. In fetal sheep UCP1 is first detectable at approximately 90 d of gestation; its abundance increases with gestational age and peaks at the time of birth. The mRNA and protein for both the long and short form of the prolactin (PRL) receptor (PRLR) are also highly abundant in BAT. Enhanced PRLR abundance in late gestation is associated with an increase in the abundance of UCP1. This relationship between PRLR and UCP is not only present in BAT. Similar findings are now reported in the pregnant ovine uterus, where PRLR abundance reaches a maximum just before that of UCP2. However, the role of PRLR in BAT remains undetermined. Rat studies have shown that PRL administration throughout pregnancy results in offspring with increased UCP1 at birth. Studies in newborn lambs have shown that administration of PRL (2 mg/d) causes an acute response, increasing colonic temperature in the first hour by 1 degrees. This increased colonic temperature is maintained for the first 24h of life, in conjunction with enhanced lipolysis. After 7 d of treatment there is no difference in the abundance of UCP1 but an increase in UCP1 activity; this effect may be mediated by an increase in lipolysis. Taken together these findings suggest that PRL could be an important endocrine factor during pregnancy and early postnatal life. PMID: 14506890 [PubMed - indexed for MEDLINE] 4387. Proc Nutr Soc. 2003 May;62(2):319-28. Conjugated linoleic acid and its effects on animal products and health in single-stomached animals. Azain MJ(1). Author information: (1)Animal and Dairy Science Department, University of Georgia, Athens, Georgia 30602, USA. mazain@arches.uga.edu Conjugated linoleic acids (CLA) have been shown to have anti-carcinogenic, anti-obesity, anti-atherogenic and immunomodulatory functions. The basis for these effects has not been fully explained, but probably involves effects of CLA on eicosanoid metabolism, cytokine production and/or gene expression. The predominant isomer (85-90%) in the natural sources of CLA has the cis-9, trans-11 configuration. As interest in CLA grew and synthetic forms became available, the number of studies examining the effects of dietary CLA in rodents, human subjects and livestock has increased greatly. In the late 1990s the observation that CLA had anti-obesity effects was reported. Subsequently, it was determined that this effect in mice could be attributed to the trans-10, cis-12 isomer that, along with the cis-9, trans-11 isomer, predominates in the synthetic forms of CLA. The anti-obesity response varies in magnitude depending on species, and has not been consistent in non-rodents. In general, the response is greatest in mice and less or absent in other species. The basis for this lack of consistency is not clear and is unlikely to be accounted for by differences in the source of CLA. In the pig variation in body fat of animals may account for differences in responsiveness. There is no direct evidence of an anti-carcinogenic effect of CLA in human subjects or livestock. Indirect evidence from in vitro studies with cell lines, as well as epidemiological studies, suggest that CLA may be relevant as a natural anti-carcinogen. The immunomodulatory effects of CLA may have application in livestock production as an alternative to the use of feed antibiotics, or as a means of improving the response to vaccination and conferring disease resistance. The recent literature on the effects of CLA, with emphasis on its anti-obesity effects, is reviewed. PMID: 14506879 [PubMed - indexed for MEDLINE] 4388. Cell Mol Life Sci. 2003 Aug;60(8):1607-12. Intermediate filaments: novel assembly models and exciting new functions for nuclear lamins. Herrmann H(1), Foisner R. Author information: (1)German Cancer Research Center (DKFZ), Division of Cell Biology, Technology Park 3, 1.308, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany, h.herrmann@dkfz.de Intermediate filament (IF) proteins constitute a highly diverse family of fibrous proteins in metazoans, which assemble into 10-nm-thick filaments in the cytoplasm and the nucleus. Novel recent insights into the in vitro assembly mechanism have revealed principal differences in the formation of cytoplasmic and nuclear filaments. Moreover, the past years have seen dramatic developments for the nuclear specific IF proteins, the lamins. While in the past lamins have been assumed to form only a structural scaffold at the nuclear periphery, their discovery in the nuclear interior, the identification of novel lamin-binding proteins and the functional disruption of lamin structures have brought to light essential functions for lamins in fundamental cellular events such as chromatin organization, DNA replication and RNA transcription. Furthermore, mutations in lamins and lamin-binding proteins have been demonstrated to cause various different human diseases, affecting muscle, heart, neuronal, adipose and bone tissue or leading to premature ageing. However, the molecular basis of these diseases is just beginning to emerge. PMID: 14504651 [PubMed - indexed for MEDLINE] 4389. Diabetes Metab. 2003 Sep;29(4 Pt 2):6S53-61. Potential contribution of metformin to the management of cardiovascular disease risk in patients with abdominal obesity, the metabolic syndrome and type 2 diabetes. Després JP(1). Author information: (1)Québec Heart Institute, Laval Hospital Research Center, Québec Lipid Research Center, CHUL Research Center (CHUQ), and Department of Food Sciences and Nutrition, Laval University, Ste-Foy, Québec, Canada. jean-pierre.despres@crhl.ulaval.ca With an evolving landscape of a growing number of obese and/or type 2 diabetic patients in our affluent population, the metabolic syndrome has become a major issue because of its impact on cardiovascular disease risk. In this regard, although it is appropriate to aim at a better glycaemic control in type 2 diabetic patients, hyperglycaemia does not appear to be the main culprit responsible for the markedly increased cardiovascular disease risk in this population. Rather, studies have suggested that a cluster of metabolic abnormalities, which includes an atherogenic dyslipidaemic state, an impaired glucose/insulin homeostasis, and a pro-thrombotic and inflammatory profile, substantially increases the risk of coronary heart disease in type 2 diabetic patients in a manner which is partly independent of glycaemic control. These results imply that in order to reduce the risk of atherosclerotic macrovascular disease in type 2 diabetic patients, physicians need not only to focus on a better glycaemic control but also to improve the features of the metabolic syndrome. As a consequence, in order to evaluate the clinical benefits of pharmacotherapy in type 2 diabetic patients, we need to quantify the impact of any pharmacological intervention beyond glucose control. In this context, metformin has been shown to not only contribute to a better glycaemic control but also to induce some weight loss (especially in the visceral depot) which may contribute to the improvement of the features of the metabolic syndrome. Thus, metformin treatment may represent a relevant element of an integrated lifestyle modification-pharmacotherapy to prevent not only type 2 diabetes but also cardiovascular disease. PMID: 14502101 [PubMed - indexed for MEDLINE] 4390. Diabetes Metab. 2003 Sep;29(4 Pt 2):6S28-35. Reducing insulin resistance with metformin: the evidence today. Giannarelli R(1), Aragona M, Coppelli A, Del Prato S. Author information: (1)Department of Endocrinology and Metabolism, Section of Diabetes, School of Medicine, University of Pisa, Italy. Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study. PMID: 14502098 [PubMed - indexed for MEDLINE] 4391. Nihon Yakurigaku Zasshi. 2003 Oct;122(4):294-300. [The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism]. [Article in Japanese] Kamon J(1), Yamauchi T, Terauchi Y, Kubota N, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan. Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome. PMID: 14501164 [PubMed - indexed for MEDLINE] 4392. Endocrinology. 2003 Dec;144(12):5166-71. Epub 2003 Sep 18. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Ruderman NB(1), Saha AK, Kraegen EW. Author information: (1)D.Phil., Diabetes Unit, Boston Medical Center, 650 Albany Street, X825, Boston, Massachusetts 02118, USA. nruderman@medicine.bu.edu. An increasing body of evidence has linked AMP-activated protein kinase (AMPK) and malonyl coenzyme A (CoA) to the regulation of energy balance. Thus, factors that activate AMPK and decrease the concentration of malonyl CoA in peripheral tissues, such as exercise, decrease triglyceride accumulation in the adipocyte and other cells. The data reviewed here suggest that this is related to the fact that these factors concurrently increase fatty acid oxidation, decrease the esterification of fatty acids to form glycerolipids, and, by mechanisms still unknown, increase energy expenditure. Malonyl CoA contributes to these events because it is an allosteric inhibitor of carnitine palmitoyltransferase, the enzyme that controls the transfer of long-chain fatty acyl CoA from the cytosol to the mitochondria, where they are oxidized. AMPK activation in turn increases fatty acid oxidation (by effects on enzymes that govern malonyl CoA synthesis and possibly its degradation) and inhibits triglyceride synthesis. It also increases the expression of uncoupling proteins and the transcriptional regulator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1alpha), which could possibly increase energy expenditure. Recent studies suggest that the ability of leptin, adiponectin, 5'-aminoimidazole 4-carboxamide riboside (AICAR), adrenergic agonists, and metformin to diminish adiposity may be mediated, at least in part, by AMPK activation in peripheral tissues. In addition, preliminary studies suggest that malonyl CoA and AMPK take part in fuel-sensing and signaling mechanisms in the hypothalamus that could regulate food intake and energy expenditure. PMID: 14500570 [PubMed - indexed for MEDLINE] 4393. Pathophysiol Haemost Thromb. 2002 Sep-Dec;32(5-6):269-73. The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. Juhan-Vague I(1), Morange PE, Alessi MC. Author information: (1)Lab. Haematology, CHU Timone, Inserm EPI 99 36, Marseille, France. ijuhan@ap-hm.fr The insulin resistance syndrome (IRS) with obesity is large-word wide-spread and represents a strong risk factor for vascular disease. Atherothrombotic complications in IRS are partly attributed to a dysregulation of hemostasis inducing a prothrombotic state which includes endothelial activation, hyperactivity of platelets, hypercoagulability and hypofibrinolysis. This latter, due to elevated PAI-1 levels, is a core feature of the IRS. Most of the prothrombotic modifications can be reversed by loosing weight. Low grade inflammation with prolonged cytokines mediated acute phase reaction is actually considered as strongly related to the IRS and is involved in the dysregulation of hemostasis. TNF pathway and TGFb play an important role in the regulation of PAI-1 synthesis in the adipose tissue and the liver with steatosis. Interestingly, modulation of PAI-1 expression in adipose tissue influences adipose tissue growth, increasing once more the spectrum of the non hemostatic functions of coagulation/fibrinolysis parameters. PMID: 13679655 [PubMed - indexed for MEDLINE] 4394. Nutr Rev. 2003 Aug;61(8):290-2. Adiponectin: a regulator of energy homeostasis. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720-3104, USA. Adiponectin, a protein produced exclusively in adipose tissue, occurs in serum in relatively high concentration. Its concentration is decreased in obese and in type 2 diabetic humans. When administered to mice, it enhances insulin sensitivity and glucose tolerance, and appears to increase free fatty acid oxidation in muscle. Adiponectin is likely to be involved in the regulation of energy homeostasis. PMID: 13677592 [PubMed - indexed for MEDLINE] 4395. Z Gastroenterol. 2003 Sep;41(9):929-36. [Appetite regulation by ghrelin - a novel neuro-endocrine gastric peptide hormone in the gut-brain-axis]. [Article in German] Hagemann D(1), Meier JJ, Gallwitz B, Schmidt WE. Author information: (1)Medizinische Klinik I, St.-Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Germany. Dirk.Hagemann@ruhr-uni-bochum.de Ghrelin a novel peptide consisting of 28 amino acids was first identified in the stomach in 1999. It is mainly produced in endocrine cells of the human gastric mucosa, but it was also found in several other tissues e. g. in the pituitary, the hypothalamus and the pancreas. The functional receptor belongs to the family of the 7-transmembrane G-protein receptors and is predominantly detected in the pituitary and at lower levels in hypothalamic nuclei, the stomach, heart, lungs, kidneys, gut, the adipose and many other tissues. According to the widespread distribution of the peptide and its receptor, ghrelin has multiple biological effects: it stimulates the release of growth hormone in the pituitary and induces a rise in the serum concentration of ACTH, cortisol, catecholamines and prolactin. Ghrelin causes an increase of food intake and body weight by stimulating the production of neuropeptide Y (NPY) and agouti-related protein (AGP) in the nucleus arcuatus. It further leads to elevated concentrations of plasma glucose. A physiological antagonism between ghrelin and GLP-1 in the hypothalamic regulation of appetite is being discussed. The basic serum level of ghrelin depends on the state of nutrition and is negatively correlated with the body-mass-index. It shows a certain pattern of variation before and after food intake with a preprandial increase and a postprandial decrease. Ghrelin modulates gastric acid secretion and the gastrointestinal motility via vagal cholinergic pathways. The discovery of ghrelin definitely contributes to the understanding of the growth-hormone secretion and of the regulation of appetite and food intake. PMID: 13130331 [PubMed - indexed for MEDLINE] 4396. Br J Nutr. 2003 Oct;90(4):735-41. Gastric leptin: a putative role in the short-term regulation of food intake. Picó C(1), Oliver P, Sánchez J, Palou A. Author information: (1)Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma de Mallorca, Spain. The discovery of the production of leptin by the stomach, in addition to its production by adipose tissue, has initiated new investigation into the possible role of this protein in the digestive physiology, in particular in the short-term control of energy balance. Leptin has been identified in the lower half of the stomach glands both in the pepsinogen granules of chief cells and in the granules of a specific endocrine cell type, suggesting that leptin action is exerted by both exocrine and endocrine pathways. Gastric leptin is sensitive to the nutritional state, being rapidly mobilized in response to food intake following fasting, or after the administration of satiety factors; this suggests a role for this protein in the short-term regulation of feeding, acting in collaboration with satiety peptides such as cholecystokinin. Leptin, produced by gastric cells and by adipocytes, could act on both acute and chronic regulation of feeding behaviour respectively, giving information to the brain on the availability of external (food) and internal (fat depots) energy resources, thus participating in short- and long-term satiation. PMID: 13129441 [PubMed - indexed for MEDLINE] 4397. Am J Cardiol. 2003 Aug 18;92(4A):27J-33J. Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Ayyobi AF(1), Brunzell JD. Author information: (1)Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Washington 98195, USA. Metabolic abnormalities associated with the metabolic syndrome are also present in patients with type 2 diabetes mellitus and in those with familial combined hyperlipidemia (FCHL). These abnormalities include central obesity, insulin resistance with hyperinsulinemia, hypertension, increased plasma triglycerides, and decreased high-density lipoprotein cholesterol levels. Other characteristics associated with FCHL include the presence of small, dense low-density lipoprotein cholesterol and increased apolipoprotein B. Patients with these abnormalities are at an increased risk for premature coronary artery disease. Treatment of the dyslipidemia associated with type 2 diabetes and FCHL with a combination of a statin and a thiazolidinedione or niacin offers the most comprehensive modality to correct the various lipid abnormalities. PMID: 12957324 [PubMed - indexed for MEDLINE] 4398. Am J Cardiol. 2003 Aug 18;92(4A):3J-9J. The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Hsueh WA(1), Law R. Author information: (1)Division of Endocrinology, Diabetes, and Hypertension, University of California-Los Angeles School of Medicine, Los Angeles, California 90095-7073, USA. whsueh@mednet.ucla.edu Recent evidence suggests that progression of insulin resistance parallels progression of atherosclerosis. Fat plays an integral role in the development of type 2 diabetes and vascular injury. The balance of adipose-derived substances, including free fatty acids, tumor necrosis factor-alpha, leptin, adiponectin, and plasminogen activator inhibitor-1, determine both insulin action and the state of vascular inflammation. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands promote the balance of these substances to enhance insulin-mediated glucose uptake and decrease inflammation. PPAR-gamma ligands reverse the major defect of the insulin resistance syndrome and have important effects that inhibit atherosclerosis, improve endothelial cell function, and attenuate inflammation. Although more research is needed, data suggest that PPAR-gamma ligands may prevent the progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis. PMID: 12957321 [PubMed - indexed for MEDLINE] 4399. Horm Res. 2003;60(Suppl 1):36-45. Puberty and body composition. Siervogel RM(1), Demerath EW, Schubert C, Remsberg KE, Chumlea WC, Sun S, Czerwinski SA, Towne B. Author information: (1)Department of Community Health, Wright State University School of Medicine, Dayton, OH 45420, USA. roger.siervogel@wright.edu Body composition during puberty is a marker of metabolic changes that occur during this period of growth and maturation, and, thus, holds key information regarding current and future health. During puberty, the main components of body composition (total body fat, lean body mass, bone mineral content) all increase, but considerable sexual dimorphism exists. Methods for measuring body composition (e.g. densitometry and dual-energy X-ray absorptiometry) and degree of maturity will be discussed in this review. Components of body composition show age-to-age correlations (i.e. 'tracking'), especially from adolescence onwards. Furthermore, adipose tissue is endocrinologically active and is centrally involved in the interaction between adipocytokines, insulin and sex-steroid hormones, and thus influences cardiovascular and metabolic disease processes. In conclusion, pubertal body composition is important, not only for the assessment of contemporaneous nutritional status, but also for being linked directly to the possible onset of chronic disease later in life and is, therefore, useful for disease risk assessment and intervention early in life. Copyright 2003 S. Karger AG, Basel PMID: 12955016 [PubMed - indexed for MEDLINE] 4400. Nurs Stand. 2003 Aug 20-26;17(49):37-44. The metabolic syndrome. Marks V(1). Author information: (1)University of Surrey. Prevention of disease rather than its alleviation or cure has always been the aim of healthcare professionals. While this goal has been achieved for many infectious diseases through improvements in hygiene and vaccination, as well as for acute deficiency diseases such as scurvy, less progress has been made with chronic diseases. These are increasing as the population ages. Chief among the chronic diseases on the increase are: Type 2 diabetes. Hypertension and cardiovascular disease, which are responsible for over 40 per cent of all deaths in the UK (DoH 1999). Obesity, which is a major cause of morbidity and predisposes to diabetes, cardiovascular disease and other chronic illnesses. Cancer. This article describes the nature, aetiology and prevention of the metabolic syndrome. Although not a disease, the metabolic syndrome is like smoking in that it strongly predisposes to disease and is preventable. PMID: 12953375 [PubMed - indexed for MEDLINE] 4401. Am J Clin Pathol. 2003 Jun;119 Suppl:S94-9. Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake. Soderberg BL(1), Salem RO, Best CA, Cluette-Brown JE, Laposata M. Author information: (1)Division of Laboratory Medicine, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Fatty acid ethyl esters (FAEEs) are nonoxidative ethanol metabolites that have been implicated as mediators of alcohol-induced organ damage. FAEEs are detectable in the blood after ethanol ingestion, and on that basis represent markers of ethanol intake. FAEEs have also been quantitated in human liver and adipose tissue and have been shown to be postmortem markers of premortem ethanol intake. A substantial difference in FAEE concentration was found in liver and adipose tissue of patients with detectable blood ethanol at the time of autopsy vs those with no detectable blood ethanol, who were either chronic alcoholics or social drinkers. Most currently available diagnostic markers for chronic alcoholism have limited clinical utility. Data in this report demonstrate that the amount or type of FAEEs can be used to differentiate a chronic alcoholic from an episodic heavy drinker (binage drinker) at or near peak blood ethanol concentrations and approximately 24 hours after discontinuation of ethanol. Thus, FAEEs are markers of ethanol intake in blood and tissues and can be useful in distinguishing chronic alcoholics from binge drinkers. PMID: 12951847 [PubMed - indexed for MEDLINE] 4402. Clin Biochem. 2003 Sep;36(6):413-20. Emergence of the metabolic syndrome in childhood: an epidemiological overview and mechanistic link to dyslipidemia. Kohen-Avramoglu R(1), Theriault A, Adeli K. Author information: (1)Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Insulin resistance and type 2 diabetes are rapidly emerging as major disorders of childhood and adolescence. This appears to be closely linked to a rapid rise in the prevalence of obesity in the pediatric population. The development of insulin resistance appears to lead to a "metabolic syndrome" which includes a number of major complications such as dyslipidemia and hypertension. Childhood metabolic syndrome promotes the development of premature atherosclerosis and significantly increases cardiovascular disease risk early in life. The mechanisms linking obesity, insulin resistance, and metabolic dyslipidemia are not fully understood. This review will attempt to discuss some of the key mechanistic issues surrounding insulin resistance and its association with metabolic dyslipidemia. Most of the recent progress in this field has come from the use of genetic and diet-induced animal models of insulin resistance. New data from these animal studies particularly the fructose-fed hamster, a model of metabolic syndrome and dyslipidemia, will be reviewed. Evidence from both animal and human studies suggest a key role for insulin sensitive tissues such as adipose tissue, liver, and intestine in the development of an insulin resistant state and its associated lipid and lipoprotein disorders. The critical interaction of metabolic signals among these tissues appears to govern the transition from an insulin sensitive to an insulin resistant state that underlies dyslipidemic conditions. PMID: 12951167 [PubMed - indexed for MEDLINE] 4403. Cytokine Growth Factor Rev. 2003 Oct;14(5):447-55. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Ruan H(1), Lodish HF. Author information: (1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Room 601, Cambridge, MA 02142, USA. Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-alpha on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-kappaB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-alpha to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-alpha and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-kappaB, in the treatment of type 2 diabetes. PMID: 12948526 [PubMed - indexed for MEDLINE] 4404. Neth J Med. 2003 Jun;61(6):194-212. Adipose tissue as an endocrine organ: impact on insulin resistance. Jazet IM(1), Pijl H, Meinders AE. Author information: (1)Department of General Internal Medicine (C1-r-45), Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. i.m.jazet@lumc.nl It is well known that obesity is associated with insulin resistance and an increased risk for type 2 diabetes mellitus. Formerly it was postulated that increased lipolysis and consequently free fatty acid (FFA) production, from with triglycerides overloaded fat cells, would disrupt glucose homeostasis via Randle's hypothesis. Lipodystrophy, however, also leads to insulin resistance. Recently it has become clear that adipose tissue functions as an endocrine organ and secretes numerous proteins in response to a variety of stimuli. These secreted proteins exert a pleiotropic effect. The proteins that are involved in glucose and fat metabolism and hence can influence insulin resistance are discussed in this paper. They include leptin, resistin, adiponectin, acylation-stimulating protein, tumour necrosis factor-alpha and interleukin-6. The stimuli for production and the site and mechanism of action in relation to insulin resistance will be discussed. None of these proteins are, however, without controversy with regard to their mechanism of action. Furthermore, some of these proteins may influence each other via common signalling pathways. A theory is presented to link the interrelationship between these adipocyte secretory products and their effect on insulin resistance. PMID: 12948164 [PubMed - indexed for MEDLINE] 4405. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):415-21. 11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy. Rabbitt EH(1), Gittoes NJ, Stewart PM, Hewison M. Author information: (1)Department of Endocrinology, Division of Medical Sciences, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11beta-HSD1 and 2) have well-defined roles in the tissue-specific metabolism of glucocorticoids which underpin key endocrine mechanisms such as adipocyte differentiation (11beta-HSD1) and mineralocorticoid action (11beta-HSD2). However, in recent studies we have shown that the effects of 11beta-HSD1 and 2 are not restricted to distinct tissue-specific hormonal functions. Studies of normal fetal and adult tissues, as well as their tumor equivalents, have shown a further dichotomy in 11beta-HSD expression and activity. Specifically, most normal glucocorticoid receptor (GR)-rich tissues such as adipose tissue, bone, and pituitary cells express 11beta-HSD1, whereas their fetal equivalents and tumors express 11beta-HSD2. We have therefore postulated that the ability of 11beta-HSD1 to generate cortisol acts as an autocrine anti-proliferative, pro-differentiation stimulus in normal adult tissues. In contrast, the cortisol-inactivating properties of 11beta-HSD2 lead to pro-proliferative effects, particularly in tumors. This proposal is supported by experiments in vitro which have demonstrated divergent effects of 11beta-HSD1 and 2 on cell proliferation. Current studies are aimed at (1) characterizing the underlying mechanisms for a "switch" in 11beta-HSD isozyme expression in tumors; (2) defining the molecular targets for glucocorticoids as regulators of cell proliferation; (3) evaluating the potential for targeting glucocorticoid metabolism as therapy for some cancers. These and other issues are discussed in the present review. PMID: 12943730 [PubMed - indexed for MEDLINE] 4406. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):95-9. Androgen receptor functions from reverse genetic models. Matsumoto T(1), Takeyama K, Sato T, Kato S. Author information: (1)Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. The androgen receptor (AR) is a ligand-dependent transcription factor involved in the regulation of many different physiological processes. AR dysfunction causes a diverse range of clinical conditions, including testicular feminization mutation (Tfm) syndrome, prostate cancer, and motor neuron disease (Kennedy's disease). However, due to lack of genetic models, the molecular basis of the AR in these disorders remains largely unknown. Using a conditional targeting technique based on the Cre-loxP system, we successfully generated null AR mutant (ARKO) mice. ARKO males exhibited normal healthy growth, but showed typical Tfm abnormalities. Hormonal assay of ARKO males revealed that while serum androgen levels were very low, estrogen levels were normal. Another hallmark of ARKO males was late-onset obesity, with marked accumulation of white adipose tissue. To clarify the role of human AR (hAR) mutants with expanded polyQ stretches as observed in neurodegenerative disease, we also established a Drosophila model in which either wild-type or polyQ-expanded hAR were ectopically expressed. Although no overt phenotype was detected in adult fly-eye neurons expressing mutant hAR, the ingestion of androgen caused marked neurodegeneration. PMID: 12943692 [PubMed - indexed for MEDLINE] 4407. Cell Mol Life Sci. 2003 Jul;60(7):1311-21. Vitamin A and the regulation of fat reserves. Bonet ML(1), Ribot J, Felipe F, Palou A. Author information: (1)Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Cra. Valldemossa Km 7.5, 07071 Palma de Mallorca, Spain. Beyond their classical nutritional roles, nutrients modify gene expression and function in target cells and, by so doing, affect many fundamental biological processes. An emerging example, which is the focus of this review, is the involvement of vitamin A in the regulation of the level and functioning of body fat reserves. Retinoic acid, the carboxylic acid form of vitamin A, is a transcriptional activator of the genes encoding uncoupling proteins, and results in animals indicate that whole body thermogenic capacity is related to the vitamin A status. Retinoic acid also influences adipocyte differentiation and survival, with high doses inhibiting and low doses promoting adipogenesis of preadipose cells in culture. Moreover, vitamin A status can influence the development and function of adipose tissues in whole animals, with a low vitamin A status favouring increased fat deposition. PMID: 12943220 [PubMed - indexed for MEDLINE] 4408. Clin Infect Dis. 2003;37 Suppl 2:S142-9. Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression. Bhasin S(1). Author information: (1)Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine Science, University of California-Los Angeles School of Medicine, 90059, USA. sbhasin@ucla.edu In spite of the widespread belief that testosterone supplementation increases the risk of atherosclerotic heart disease, evidence to support this premise is lacking. Although supraphysiological doses of testosterone, such as those used by athletes and recreational body builders, decrease plasma high-density lipoprotein (HDL) cholesterol concentrations, replacement doses of testosterone have had only a modest or no effect on plasma HDL in placebo-controlled trials. In epidemiological studies, serum total and free testosterone concentrations have been inversely correlated with intra-abdominal fat mass, risk of coronary artery disease, and type 2 diabetes mellitus. Testosterone administration to middle-aged men is associated with decreased visceral fat and glucose concentrations and increased insulin sensitivity. Testosterone infusion increases coronary blood flow. Similarly, testosterone replacement retards atherogenesis in experimental models of atherosclerosis. However, the long-term risks and benefits of testosterone administration in human immunodeficiency virus-infected men with fat redistribution syndrome have not been studied in randomized clinical trials. PMID: 12942389 [PubMed - indexed for MEDLINE] 4409. Clin Infect Dis. 2003;37 Suppl 2:S43-6. Difficulties in understanding the metabolic complications of acquired immune deficiency syndrome. Grunfeld C(1), Tien P. Author information: (1)Department of Veterans Affairs Medical Center, and University of California, San Francisco 94121, USA. With the introduction of combination antiretroviral therapy, changes in fat distribution and serum metabolites were reported. These included increased central fat ("buffalo hump," abdominal, and visceral); decreased peripheral fat (in the face, legs, and arms); increased levels of triglycerides, low-density lipoprotein and total cholesterol, glucose, and insulin; and low levels of high-density lipoprotein cholesterol. Many of these changes predict increased atherosclerosis. It has been proposed that these findings are part of a single syndrome, much like metabolic syndrome. Our data indicate that many of these changes are independent. Some changes are antiretroviral drug (but not necessarily class)-specific, some represent the restoration to health, and others are due to effects of the host response to human immunodeficiency virus itself. PMID: 12942373 [PubMed - indexed for MEDLINE] 4410. Clin Invest Med. 2003 Aug;26(4):167-78. The molecular genetics of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Ahmad F(1). Author information: (1)Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Mass 02115, USA. fahmad@genetics.med.harvard.edu Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD or ARVC) is an inherited disorder characterized by replacement of the right ventricular myocardium by adipose and fibrous tissue and associated with sudden cardiac death. This disorder may be as prevalent as 6 in 10 000 and causes 12.5%-25% of sudden death events in the young. Nine genetic loci associated with this disease have been ascertained, and mutations in genes at 3 loci have been discovered. These genetic studies have shed light on some of the pathogenetic mechanisms. Mutations in genes encoding desmoplakin and plakoglobin suggest that altered integrity at cardiac myocyte cell-cell junctions may promote myocyte degeneration and death, with the repair process consisting of replacement of myocardium by adipose and fibrous tissue. Mutations in the gene encoding the cardiac ryanodine receptor suggest that cytoplasmic calcium overloading may lead to arrhythmias characteristic of ARVD, and perhaps also the structural changes. Many of the remaining questions concerning the pathogenesis of ARVD can be answered only by the mapping and identification of other genes associated with this disease. PMID: 12934820 [PubMed - indexed for MEDLINE] 4411. Endocrinology. 2003 Sep;144(9):3765-73. Minireview: The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Rajala MW(1), Scherer PE. Author information: (1)Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Adipose tissue evolved to efficiently store energy for times of caloric restriction. The large caloric excess common in many Western diets has negated the need for this thrifty function, leaving adipose tissue ill-equipped to handle this increased load. An excess of adipose tissue increases risk for a number of conditions including coronary artery disease, hypertension, dyslipidemias, type 2 diabetes, and even cancer. Indeed, the ability of the adipocyte to function properly when engorged with lipid can lead to lipid accumulation in other tissues, reducing their ability to function and respond normally. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, is gaining appreciation. The normal balance of these adipose tissue secretory proteins is perturbed in obesity. Paradoxically, the lack of normal adipose tissue, as seen in cases of lipodystrophy and lipoatrophy, is also associated with pathologic sequelae similar to what is seen with obesity. The pathologic findings associated with lack of adipose tissue, largely due to inability to properly store lipids, may also be due to a lack of adipokines. In this review, we highlight the role of adipose tissue as an endocrine organ focusing on some of the recent advances in the identification and pharmacological characterization of adipokines as well as their regulation in the context of obesity and insulin-resistant states. PMID: 12933646 [PubMed - indexed for MEDLINE] 4412. J Nippon Med Sch. 2003 Aug;70(4):300-6. Mesengenic potential and future clinical perspective of human processed lipoaspirate cells. Mizuno H(1), Hyakusoku H. Author information: (1)Department of Plastic and Reconstructive Surgery, Nippon Medical School, Tokyo, Japan. hiromzn@attglobal.net The use of stem cells is promising for future cell-based therapy such as tissue regeneration and engineering. Although Embryonic Stem Cells (ESCs) are theoretically highly beneficial, there are some potential limitations of cell regulations and ethical consideration. Mesenchymal Stem Cells (MSCs) isolated from bone marrow stroma have been shown to possess adipogenic, osteogenic, chondrogenic, myogenic and neurogenic potential in vitro. However, bone marrow procurement is severely painful for donors and often requires general anesthesia. Moreover, only small numbers of cells can be harvested. We previously hypothesized that human adipose tissue obtained from liposuction procedures also contains the same cell population as MSCs, because adipose tissue is mesenchymal in origin, like bone marrow stroma. Subsequent studies revealed that: (1) cell population (which we termed Processed Lipoaspirate [PLA] cells), observed by indirect immunofluorescence study of adipose tissue, consist of cells of mesenchymal origin that have little contamination with endothelial cells, smooth muscle cells and pericytes; (2) these PLA cells exhibit low levels of cell senescence even after multiple passage, as demonstrated by beta-galactosidase staining assay; and (3) PLA cells can differentiate into adipogenic, osteogenic, chondrogenic and myogenic cells in vitro in lineage-specific culture media. These findings suggest that human PLA might have a mesodermal stem cell population. Since human adipose tissue is plentiful, easily harvested in large quantity under local anesthesia with little patient discomfort, it may be an alternative stem cell source for mesenchymal tissue regeneration and engineering. This review highlights our previous research work on PLA cells and future clinical perspectives, particularly in the field of plastic and reconstructive surgery. PMID: 12928709 [PubMed - indexed for MEDLINE] 4413. Int J Occup Med Environ Health. 2003;16(2):113-24. Estrogens and organochlorine xenoestrogens and breast cancer risk. Starek A(1). Author information: (1)Department of Biochemical Toxicology, Collegium Medicum, Jagiellonian University, Kraków, Poland. mfstarek@cyf-kr.edu.pl Breast cancer is responsible for considerable morbidity and the majority of female deaths in industrialized countries. In the etiology of breast cancer many endogenous and exogenous risk factors have been discussed. It is estimated that about 40% of all cancers in women are hormonally mediated. Both estrogens and androgens play critical roles in the development of breast cancer, which has been confirmed by numerous epidemiologic data on the levels of serum and urine hormons in populations at low and high risk, as well as by case-control and cohort studies. Estrogen carcinogenesis is attributed to receptor-mediated growth and proliferation of breast epithelial cells and to DNA impairment caused by activated estrogen metabolites, e.g., catechol estrogens and free radicals. In the last decade, the organochlorine chemicals, which include pesticides, polychlorinated biphenyl congeners and other representatives of the dioxin family, have been regarded as xenoestrogens. These chemicals are capable of modulating hormonally regulated processes and inducing changes in growth factors that may be responsible for carcinogenic effect. Many case-control studies have shown the distinct association between breast adipose tissue concentrations of several organochlorine xenoestrogens and breast cancer risk. Also in some studies, the women with breast cancer had higher organochlorine levels in serum as compared with controls. PMID: 12921380 [PubMed - indexed for MEDLINE] 4414. Clin Endocrinol (Oxf). 2003 Sep;59(3):267-77. PPARgamma and metabolism: insights from the study of human genetic variants. Gurnell M(1). Author information: (1)Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. mg299@mole.bio.cam.ac.uk Diabetes, obesity, atherosclerosis and cancer are the principal contributors to morbidity and mortality in Western society. Emerging evidence indicates that a nuclear receptor, the peroxisome proliferator-activated receptor gamma (PPARgamma), plays a role in these pathological processes. Furthermore, modulation of receptor action in these diseases may be of therapeutic value, as exemplified by the recent introduction of the thiazolidinediones, a novel class of insulin-sensitizing agent for the treatment of type 2 diabetes mellitus. The availability of such high-affinity ligands has facilitated the study of signalling pathways through which PPARgamma regulates metabolic processes; these analyses have been complemented by the study of human subjects harbouring (naturally occurring) mutations and polymorphisms within the receptor. The latter have provided unique genetic evidence for a link between PPARgamma and mammalian glucose homeostasis, lipid metabolism and regulation of fat mass. This review highlights recent studies which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the consequences of inherited variation in the human receptor gene. PMID: 12919147 [PubMed - indexed for MEDLINE] 4415. Growth Horm IGF Res. 2003 Aug;13 Suppl A:S63-71. Androgen effects on body composition. Bhasin S(1), Woodhouse L, Storer TW. Author information: (1)Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA. sbhasin@ucla.edu Androgens are known to have a role in the body fat, muscle size, muscle performance and physical function differences seen between hypogonadal and eugonadal men. The results of investigations into effects of testosterone on body composition, fat metabolism and muscle anabolism are reviewed here. Testosterone dose-response relationships are presented in studies of the effects of physiologic and supraphysiologic doses with and without exercise in young hypogonadal men, older men with low testosterone levels and in chronic illness states. PMID: 12914730 [PubMed - indexed for MEDLINE] 4416. Growth Horm IGF Res. 2003 Aug;13 Suppl A:S28-32. On the site and mechanism of action of the anti-obesity effects of interleukin-6. Jansson JO(1), Wallenius K, Wernstedt I, Ohlsson C, Dickson SL, Wallenius V. Author information: (1)Division of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden. JOJ@medic.gu.se We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus. PMID: 12914723 [PubMed - indexed for MEDLINE] 4417. J Dairy Sci. 2003 Jul;86(7):2369-72. Short communication: Tissue distribution of leptin and leptin receptor mRNA in the bovine. Chelikani PK(1), Glimm DR, Kennelly JJ. Author information: (1)Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada T6G 2P5. Detection of leptin and leptin receptor mRNA in various tissues is crucial to an understanding of leptin physiology in dairy cattle. We report here evidence of leptin receptor gene expression in central and peripheral tissues of the bovine by reverse transcription and polymerase chain reaction analysis. Leptin mRNA was detectable in mammary parenchyma and in adipose tissue with similar transcript abundance among the subcutaneous, pericardial, perirenal, and mesenteric adipose depots. The mRNA for the long-form of the leptin receptor, Ob-Rb, was detectable in all four adipose depots, mammary parenchyma, semintendinosus muscle, liver, adrenal cortex, spleen, kidney, testis, mesenteric lymph node, lung, aorta, abomasum, duodenum, jejunum, ileum, hypothalamus, pituitary, brain stem, cerebral cortex, cerebellar cortex, pons, and pineal gland. The mRNA for the short form of the leptin receptor, Ob-Ra, was detectable in the liver, adrenal cortex, spleen, pituitary, and brain stem, but not in the other tissues surveyed. The wide spectrum of tissues expressing the leptin receptor gene reveals that leptin may have multiple physiological functions in the bovine. PMID: 12906054 [PubMed - indexed for MEDLINE] 4418. Diabetologia. 2003 Sep;46(9):1179-89. Epub 2003 Aug 7. Cyclic nucleotide phosphodiesterases in pancreatic islets. Pyne NJ(1), Furman BL. Author information: (1)Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, Scotland. Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes. PMID: 12904862 [PubMed - indexed for MEDLINE] 4419. J Physiol Biochem. 2003 Mar;59(1):51-60. Adipose tissue as an endocrine organ: role of leptin and adiponectin in the pathogenesis of cardiovascular diseases. Fortuño A(1), Rodríguez A, Gómez-Ambrosi J, Frühbeck G, Díez J. Author information: (1)Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, 31008 Pamplona, Spain. afortuno@unav.es Obesity, the most common nutritional disorder in industrial countries, is associated with increased cardiovascular mortality and morbidity. Nevertheless, the molecular basis linking obesity with cardiovascular disturbances have not yet been fully clarified. Recent advances in the biology of adipose tissue indicate that it is not simply an energy storage organ, but also a secretory organ, producing a variety of bioactive substances, including leptin and adiponectin, that may influence the function as well as the structural integrity of the cardiovascular system. Leptin, besides being a satiety signal for the central nervous system and to be related to insulin and glucose metabolism, may also play an important role in regulating vascular tone because of the widespread distribution of functional receptors in the vascular cells. On the other hand, the more recently discovered protein, adiponectin, seems to play a protective role in experimental models of vascular injury, in probable relation to its ability to suppress the attachment of monocytes to endothelial cells, which is an early event in the atherosclerotic process. There is already considerable evidence linking altered production of some adipocyte hormones with the cardiovascular complications of obesity. Therefore, the knowledge of alterations in the endocrine function of adipose tissue may help to further understand the high cardiovascular risk associated with obesity. PMID: 12903905 [PubMed - indexed for MEDLINE] 4420. Med Pregl. 2003 Mar-Apr;56(3-4):142-5. [Development and differentiation of adipose tissue]. [Article in Croatian] Ivković-Lazar T(1). Author information: (1)Institut za interne bolesti, Klinika za endokrinologiju, dijabetes i bolesti metabolizma, Klinicki centar Novi Sad. INTRODUCTION: For years adipose tissue has been considered inert, serving only as a depot of energy surplus. However, there have been recent changes, undoubtedly due to advancement of methods for studying the morphology and metabolic activities of adipose tissue (microdialysis and adipose tissue catheterization). In normal-weight subjects, adipose tissue makes 10-12% with males and 15-20% with females. About 80% of adipose tissue is located under the skin, and the rest envelops the internal organs. With humans there are white and brown adipose tissues, which is predominant with infants and small children. HISTOLOGIC CHARACTERISTICS: From a histological point of view, it is a special form of reticular connective tissue, which contains adipocytes with netlike structure. Human adipose tissue has four types of adrenergic receptors with different topographic dispositions, which manifest different metabolic activity of adipocytes of particular body organs. Changes in adipose tissue are associated with the process of adipocyte differentiation. Critical moments for this process are last months of pregnancy, the first six months of infancy and then puberty. However, the differentiation process may also begin during maturity. Namely, as size of adipocytes can increase to a certain limit, this process can be activated after reaching a "critical" adipocyte volume. The differentiation process is affected by a number of hormones (insulin, glucagon, corticosteroids, somatotropin (STH), thyroid gland hormones, prolactin, testosterone), but also by some other substances (fatty acids, prostaglandins, liposoluble vitamins, butyrate, aspirin, indomethacin, metylxanthine, etc.). PMID: 12899078 [PubMed - indexed for MEDLINE] 4421. Sports Med. 2003;33(10):709-26. Abdominal adipose tissue distribution and metabolic risk. Wong S(1), Janssen I, Ross R. Author information: (1)School of Physical and Health Education, Queen's University, Kingston, Ontario, Canada. It is now established that waist circumference remains a significant predictor of disease and metabolic risk independent of obesity measured by body mass index. These observations are reinforced by a large body of evidence implicating abdominal obesity measured by imaging modalities in the pathogenesis of numerous metabolic risk factors. However, the extent to which abdominal subcutaneous or visceral adipose tissue (AT) independently contribute to the established association between abdominal obesity and metabolic risk remains a subject of considerable research. Discrepancies in the literature may be partially explained by methodological issues, as currently there is no accepted definition for either visceral or abdominal subcutaneous AT. Accordingly, there is confusion concerning how best to measure these depots in metabolic and descriptive studies. Further, despite numerous studies linking abdominal AT depots with metabolic risk factors, the underlying mechanisms remain unclear. The primary purpose of this review is to examine the independent contribution of visceral and abdominal subcutaneous AT to the aetiology of obesity-related health risk. We begin by considering specific methodological issues with respect to the current classification of abdominal AT as measured by imaging methods. When necessary, we present original data to reinforce important concepts not suitably addressed in the literature. We conclude with a consideration of proposed mechanisms that may link abdominal adiposity and metabolic risk. PMID: 12895129 [PubMed - indexed for MEDLINE] 4422. Arch Tierernahr. 2003 Apr;57(2):137-50. Conceptual paper for modelling protein and lipid accretion in different body parts of growing and fattening pigs. Halas V(1), Babinszky L, Verstegen MW. Author information: (1)Department of Animal Nutrition, University of Kaposvár, Faculty of Animal Science, Kaposvár, Hungary. The objective of this review is to outline those parts of modelling approaches in pig production which are not highly developed: these are the partitioning of protein and lipid accretion in different anatomical body parts. The authors introduce present models with a critical evaluation and draw some conclusions for further developments. Based on present knowledge this paper demonstrates the process of protein and fat accretion in different body compartments in pigs and influencing factors. A further aim is to assist in the conceptual development of a new pig model, which is more detailed, precise and accurate than currently available models. Exsisting models are generally deficient with regard to the translation of lipid and protein gain into lean and fatty tissue. Only assumed values for this translation have been used so far and the concepts underlying these values are not well understood. Therefore, it may be appropriate to develop a compartimental model to predict protein and fat deposition in growing and fattening pigs. With this new approach the model can supply sufficiently the changing consumer demands regarding to the possibility of meat quality prediction. PMID: 12894755 [PubMed - indexed for MEDLINE] 4423. Trends Endocrinol Metab. 2003 Aug;14(6):289-96. Sex hormones and male health: effects on components of the frailty syndrome. Muller M(1), Grobbee DE, Thijssen JH, van den Beld AW, van der Schouw YT. Author information: (1)Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, D01.335, 3508 GA Utrecht, The Netherlands. t.h.muller@jc.azu.nl Physicians are seeing an increasing number of older male patients with chronic diseases and conditions. However, the potential relevance of low levels of circulating endogenous androgens in connection with these diseases and conditions is generally poorly understood. Research findings have suggested that androgens play a distinct role in bone metabolism, body composition such as muscle and fat mass and fat distribution, cognitive functioning, mood and well being. The aim of this paper is to summarize the currently available data on the association between endogenous androgens and the intermediate or clinically manifest indicators of chronic conditions in men that might contribute to the phenomenon "frailty". The evidence that reductions in endogenous androgens play a role in age-related health problems is circumstantial. Therefore, large-scale randomized trials are needed to establish whether aging males with low serum androgen levels benefit from androgen supplementation. PMID: 12890594 [PubMed - indexed for MEDLINE] 4424. Can J Vet Res. 2003 Jul;67(3):161-8. Nursing sickness in the mink--a metabolic mystery or a familiar foe? Rouvinen-Watt K(1). Author information: (1)Nova Scotia Agricultural College, Department of Plant and Animal Sciences, P.O. Box 550, Truro, Nova Scotia B2N 5E3. krouvinen@nsac.ns.ca Nursing sickness, the largest single cause of mortality in adult female mink (Mustela vison), is an example of a metabolic disorder, which develops when the demands for lactation require extensive mobilization of body energy reserves. The condition is characterized by progressive weight loss, emaciation, and dehydration with high concentrations of glucose and insulin in the blood. Morbidity due to nursing sickness can be as high as 15% with mortality around 8%, but the incidence is known to vary from year to year. Stress has been shown to trigger the onset of the disease and old females and females with large litters are most often affected. Increasing demand for gluconeogenesis from amino acids due to heavy milk production may be a predisposing factor. Glucose metabolism is inextricably linked to that of protein and fats. In obesity (or lipodystrophy), the ability of adipose tissue to buffer the daily influx of nutrients is overwhelmed (or absent), interfering with insulin-mediated glucose disposal and leading to insulin resistance. Polyunsaturated fatty acids of the n-3 family play an important role in modulating insulin signalling and glucose uptake by peripheral tissue. The increasing demand on these fatty acids for milk fat synthesis towards late lactation may result in deficiency in the lactating female, thus impairing glucose disposal. It is suggested that the underlying cause of mink nursing sickness is the development of acquired insulin resistance with 3 contributing key elements: obesity (or lipodystrophy), n-3 fatty acid deficiency, and high protein oxidation rate. It is recommended that mink breeder females be kept in moderate body condition during fall and winter to avoid fattening or emaciation. A dietary n-3 fatty acid supplement during the lactation period may be beneficial for improved glycemic control. Lowering of dietary protein reduces (oxidative) stress and improves water balance in the nursing females and may, therefore, prevent the development and help in the management of nursing sickness. It is also surmised that other, thus far unexplained, metabolic disorders seen in male and female mink may be related to acquired insulin resistance. PMCID: PMC227047 PMID: 12889720 [PubMed - indexed for MEDLINE] 4425. Chir Main. 2003 Jun;22(3):125-30. ["Square sail" flap in median nerve lesions at the wrist. Anatomical elements and review of twenty operated cases]. [Article in French] Pagliei A(1), Tulli A, Rocchi L. Author information: (1)Sezione di chirurgia della mano, istituto di clinica ortopedica, università cattolica del Sacro Cuore, Via G. Moscati, 33, 00168 Roma, Italia. INTRODUCTION: Following an anatomical study on the vascular supply of the upper limb, we propose a new adipo-fascial flap at the wrist. The fat pad of pronator quadratus lies over the muscle and is vascularised by a recurrent branch arising from the anastomotic "cross-road" of the anterior interosseous, radial and ulnar arteries, at the radio-carpal joint. The peripheral extensions of the adipose tissue have to be anchored to the palmar fascia of the muscle in order to hoist the flap as a "square sail". The flap is then distally rotated in order to cover the traumatized median nerve segment at the wrist, for 2.5-3 cm of length. METHODS: The authors present a review of the clinical applications (1995-2001) on painful neuromas of the median nerve at the wrist, where traumatic and iatrogenic injuries frequently occur. The surgical procedure consists of external neurolysis followed by coverage of the nerve using this vascularised flap. RESULTS: The results confirm the usefulness of vascularised fat flaps in creating an optimal perineural environment in terms of biological and mechanical quality. The advantage offered by this particular local flap is that it can be speedily raised. Because of its limited length the flap is only able to cover the median nerve at the level of the carpal tunnel: its indications are therefore very selective but not rare, due to the frequency of median nerve injuries at this level. DISCUSSION: Clinical results were very satisfactory: in the twenty cases reviewed, resolution of the symptoms of algodystrophy and causalgia was consistently observed, sometimes to an extraordinary degree, and associated with an improvement in the neurological deficit. PMID: 12889266 [PubMed - indexed for MEDLINE] 4426. Cad Saude Publica. 2003;19 Suppl 1:S7-19. Epub 2003 Jul 21. [Treatment of obesity: the need to target attention on high-risk patients characterized by abdominal obesity]. [Article in Spanish] Scarsella C(1), Després JP. Author information: (1)Quebec Heart Institute, Saint-Foy, Quebec, Canada. Abdominal obesity is associated with metabolic abnormalities, increasing the risk of type 2 diabetes and coronary artery disease (CAD). The Quebec Cardiovascular Survey demonstrated that the atherogenic metabolic triad (AMT) present in abdominally obese (AO) males increases the risk of CAD 20-fold over the course of 5 years. An early detection algorithm was developed to identify individuals presenting these atherogenic abnormalities. It was found that the association of large waist circumference (WC) and moderate hypertriglyceridemia (the "hypertriglyceridemic waist", or HW) could adequately identify a significant portion of individuals with the AMT. It is important to note that even in the absence of classic risk factors, abdominally obese patients can present increased risk of CAD if they have HW. Finally, it has been suggested that the risk of developing an acute coronary syndrome in AO patients is not always related to the degree of coronary stenosis, and the patient s atherothrombotic/inflammatory profile should be taken into account in evaluating risk. Stabilization of the atherosclerotic plaque would become a legitimate therapeutic objective, and more feasible for prevention of CAD, in AO patients. PMID: 12886431 [PubMed - indexed for MEDLINE] 4427. Przegl Lek. 2003;60(1):40-2. [Resistine--a new hormone secreted by adipose tissue (adipose tissue in insulin resistance)]. [Article in Polish] Kochan Z(1), Karbowska J. Author information: (1)Katedra Biochemii Akademia Medyczna w Gdańsku, 80-211 Gdańsk, ul. Debinki 1. Obesity is an important risk factor for the development of insulin resistance and type 2 diabetes. The molecular mechanism linking obesity to insulin resistance is, however, unclear. Recently, a new circulating hormone resistine, which is expressed in adipose tissue, has been identified. Resistine has been shown to antagonize insulin action. Resistine levels are increased in diet-induced obesity as well as in genetic models of obesity and insulin resistance. Furthermore, resistine gene expression is markedly downregulated by treatment with anti-diabetic drugs called thiazolidinediones, that improve target-tissue sensitivity to insulin. It has been found that in human abdominal adipose tissue, which is thought to be a main risk factor for insulin resistance, amount of resistine mRNA is higher than in other fat depots. Resistine, therefore, may play a role in the pathogenesis of obesity-related insulin resistance. PMID: 12884646 [PubMed - indexed for MEDLINE] 4428. Przegl Lek. 2003;60(1):35-9. [Leptin--the metabolic signal from adipose tissue]. [Article in Polish] Kulik-Rechberger B(1). Author information: (1)Zakład Propedeutyki Pediatrii AM 20-093 Lublin, ul. Chodźki 2. Leptin is a hormone that is released mainly by adipocytes. One of the roles of leptin in animals is regulation of the energy balance by decreasing food intake and increasing energy expenditure. Beyond this function, it influences sexual and reproductive system development. Much evidence suggests that leptin plays the same roles in human beings. It is also believed that this hormone takes part in the regulation of hematopoietic, endocrine (other than reproductive) and sympathetic system functioning, and is involved in pathogenesis of arterial hypertension and diabetes. This brief overview focuses on the history of leptin discovery, regulation of circulating leptin levels, and physiological role (scientifically proved and being under research). The use of recombinant leptin in patients with obesity is mentioned. PMID: 12884645 [PubMed - indexed for MEDLINE] 4429. Expert Opin Biol Ther. 2003 Aug;3(5):705-13. Adipose tissue-derived therapeutics. Gimble JM(1). Author information: (1)Artecel Sciences, Inc., Brightleaf Square, 905 West Main Street, Box 44, Suite 25-B, Durham, NC 27701, USA. Jeffrey.M.Gimble.77@alum.dartmouth.org Human adipose tissue provides a uniquely abundant and accessible source of adult stem cells for applications in tissue engineering and regenerative medicine. The adult stem cells are isolated by collagenase digestion, differential centrifugation and subsequent adherence to a plasticware surface. Based on their immunophenotype, the cells are relatively homogeneous, with shared expression of integrin beta(1), the hyaluronate receptor, and the tetraspan protein CD9, among other markers. In response to chemical, hormonal or structural stimuli, the adipose-derived adult stem (ADAS) cells can differentiate along multiple lineage pathways, including adipocytes, chondrocytes, myocytes, neurons and osteoblasts. The cells can be transduced with viral vectors and have potential utility as gene delivery vehicles. Further studies will facilitate the clinical and commercial development of ADAS cells. First, it will be necessary to develop closed system bioreactors for the large-scale manufacture of ADAS cells. Second, methods that improve the vascularisation of in vivo implants will allow transplantation of larger engineered tissues. Finally, experiments must investigate the feasibility of transplanting allogeneic, as compared to autologous, ADAS cells for therapeutic applications. Based on the promising findings from adipose-derived and other adult stem cells to date, it is likely that future studies will address these challenges. PMID: 12880371 [PubMed - indexed for MEDLINE] 4430. Nihon Rinsho. 2003 Jul;61(7):1145-53. [Significance of renin-angiotensin system in diabetes mellitus with hypertension]. [Article in Japanese] Itoh H(1). Author information: (1)Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. Diabetes mellitus and hypertension frequently occur in the same individual, based upon 'insulin resistance', which is caused by obesity and impairment of secretion of several adipocyte-derived hormones(adipocytokines), including leptin and adiponectin. Insulin resistance and activation of tissue renin-angiotensin system mutually affect each other to promote diabetes mellitus/hypertension and their complications. Especially, renin-angiotensin system in the adipose tissue modulate adipocyte differentiation and adipose tissue mass. Vascular renin-angiotensin system causes endothelial dysfunction and promotes inflammatory process to accelerate atherosclerosis. Blockade of renin-angiotensin system is reasonable for prevention and suppression of diabetes mellitus/hypertension and their complications. PMID: 12877076 [PubMed - indexed for MEDLINE] 4431. J Nutr Biochem. 2003 Jun;14(6):298-305. Niacin and cholesterol: role in cardiovascular disease (review). Ganji SH(1), Kamanna VS, Kashyap ML. Author information: (1)Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California, USA. Niacin has been widely used as a pharmacologic agent to regulate abnormalities in plasma lipid and lipoprotein metabolism and in the treatment of atherosclerotic cardiovascular disease. Although the use of niacin in the treatment of dyslipidemia has been reported as early as 1955, only recent studies have yielded an understanding about the cellular and molecular mechanism of action of niacin on lipid and lipoprotein metabolism. In brief, the beneficial effect of niacin to reduce triglycerides and apolipoprotein-B containing lipoproteins (e.g., VLDL and LDL) are mainly through: a) decreasing fatty acid mobilization from adipose tissue triglyceride stores, and b) inhibiting hepatocyte diacylglycerol acyltransferase and triglyceride synthesis leading to increased intracellular apo B degradation and subsequent decreased secretion of VLDL and LDL particles. The mechanism of action of niacin to raise HDL is by decreasing the fractional catabolic rate of HDL-apo AI without affecting the synthetic rates. Additionally, niacin selectively increases the plasma levels of Lp-AI (HDL subfraction without apo AII), a cardioprotective subfraction of HDL in patients with low HDL. Using human hepatocytes (Hep G2 cells) as an in vitro model system, recent studies indicate that niacin selectively inhibits the uptake/removal of HDL-apo AI (but not HDL-cholesterol ester) by hepatocytes, thereby increasing the capacity of retained HDL-apo AI to augment cholesterol efflux through reverse cholesterol transport pathway. The studies discussed in this review provide evidence to extend the role of niacin as a lipid-lowering drug beyond its role as a vitamin. PMID: 12873710 [PubMed - indexed for MEDLINE] 4432. J Thromb Haemost. 2003 Jul;1(7):1575-9. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. Juhan-Vague I(1), Alessi MC, Mavri A, Morange PE. Author information: (1)Laboratory of Hematology, CHU Timone, Inserm Epi 99-36, Marseille, France. ijuhan@ap-hm.fr Elevated plasma plasminogen activator inhibitor-1 (PAI-1) level is a core feature of insulin-resistance syndrome (IRS). Atherothrombotic complications in IRS are partly attributed to impaired fibrinolysis caused by increased plasma PAI-1 levels. Although the etiology of IRS is far from being explained, the clustering of inflammation, adipose tissue accumulation and insulin resistance suggests an etiopathological link. Proinflammatory cytokines might regulate PAI-1 expression in IRS; however, more studies are needed to confirm this complex mechanism in humans. Furthermore, modifying PAI-1 expression by PAI-1 inhibitors provides a new challenge and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes. PMID: 12871293 [PubMed - indexed for MEDLINE] 4433. AIDS. 2003 Apr;17 Suppl 1:S149-54. Clinical impact of HIV-related lipodystrophy and metabolic abnormalities on cardiovascular disease. Behrens GM(1), Meyer-Olson D, Stoll M, Schmidt RE. Author information: (1)Department of Clinical Immunology, Hannover Medical School, Hannover, Germany. Behrens@wehi.edu.au Metabolic complications and altered fat distribution associated with HIV infection and antiretroviral therapy may lead to accelerated coronary artery disease (CAD). The high prevalence of multiple cardiovascular risk factors in a significant number of HIV patients is a cause for concern in both patients and physicians. Non-invasive strategies to measure subclinical CAD have been inconclusive. Long-term studies are underway to determine cardiac event rates, intervention strategies and consequences for the clinical management of HIV disease. In the present paper, we summarize the most prevalent risk factors in individuals with HIV infection receiving highly active antiretroviral therapy by focusing on the clinical implications of metabolic abnormalities and HIV-related lipodystrophy on CAD. PMID: 12870541 [PubMed - indexed for MEDLINE] 4434. Journ Annu Diabetol Hotel Dieu. 2003:147-58. [Antiretroviral treatment for HIV and adipose tissue]. [Article in French] Caron M(1), Bastard JP, Auclair M, Vigouroux C, Capeau J. Author information: (1)Inserm U402, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, Paris, France. PMID: 12868307 [PubMed - indexed for MEDLINE] 4435. Journ Annu Diabetol Hotel Dieu. 2003:99-109. [Diabetes and genetic and acquired lipodystrophy syndrome]. [Article in French] Capeau J(1), Magré J, Vigouroux C, Caron M, Maachi M, Dubosclard E, Lascols O, Bastard JP. Author information: (1)Service de Biochimie et Hormonologie, Hôpital Tenon, Unité INSERM 402, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, Paris, France. PMID: 12868305 [PubMed - indexed for MEDLINE] 4436. Journ Annu Diabetol Hotel Dieu. 2003:37-52. [Apollinaire Bouchardat prize 2003. Glycemic equilibrium and glucose detection]. [Article in French] Burcelin R(1). Author information: (1)UMR 5018, CNRS-UP5, CHU Rangueil, Toulouse, France. PMID: 12868300 [PubMed - indexed for MEDLINE] 4437. Curr Diab Rep. 2003 Aug;3(4):293-8. Adipokines, inflammation, and the endothelium in diabetes. Aldhahi W(1), Hamdy O. Author information: (1)Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. waleed.aldhahi@joslin.harvard.edu Cytokines are biologically active low molecular weight proteins that possess several endocrine and metabolic functions and are known products of the immune system and inflammation. Several of these cytokines were shown to be independent risk factors for cerebrovascular and coronary artery disease. Because visceral and subcutaneous adipose tissues are the major sources of cytokines (adipokines), increased adipose tissue mass is associated with alteration in adipokine production (eg, overexpression of tumor necrosis factor-a, interleukin-6, plasminogen activator inhibitor-1, and underexpression of adiponectin in adipose tissue). The proinflammatory status associated with these changes provides a potential link between insulin resistance and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and in type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-a, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. PMID: 12866991 [PubMed - indexed for MEDLINE] 4438. Acta Physiol Scand. 2003 Aug;178(4):435-42. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Ruderman NB(1), Park H, Kaushik VK, Dean D, Constant S, Prentki M, Saha AK. Author information: (1)Diabetes Unit, Section of Endocrinology and Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA. An increasing body of evidence has revealed that activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-activated protein kinase increases fatty acid oxidation by lowering the concentration of malonyl coenzyme A (CoA), an inhibitor of carnitine palmitoyl transferase 1. Studies carried out primarily in skeletal muscle suggest that AMPK modulates the concentration of malonyl CoA by concurrently phosphorylating and inhibiting acetyl CoA carboxylase (ACC), the rate limiting enzyme in malonyl CoA synthesis, and phosphorylating and activating malonyl CoA decarboxylase (MCD), an enzyme involved in its degradation. We have recently observed that AMPK and MCD activities are increased and ACC activity diminished in skeletal muscle, liver and, surprisingly, in adipose tissue 30 min following exercise (treadmill run) in normal rats. In liver and adipose tissue these changes were associated with a decrease in the activity of glycerol-3-phosphate acyltransferase (GPAT), which catalyses the first committed reaction in glycerolipid synthesis and, which like ACC, is phosphorylated and inhibited by AMPK. Similar changes in ACC, MCD and GPAT were observed following the administration of 5-aminoimidazole 4-carboxamide-riboside (AICAR), further indicating that the exercise-induced alterations in these enzymes were AMPK-mediated.CONCLUSIONS: (1) AMPK plays a major role in regulating lipid metabolism in multiple tissues following exercise. (2) The net effect of its activation is to increase fatty acid oxidation and diminish glycerolipid synthesis. (3) The relevance of these findings to the regulation of muscle glycogen repletion in the post-exercise state and to the demonstrated ability of AMPK activation to decrease adiposity and increase insulin sensitivity in rodents remains to be determined. PMID: 12864749 [PubMed - indexed for MEDLINE] 4439. Acta Physiol Scand. 2003 Aug;178(4):405-12. The role of uncoupling proteins in the regulation of metabolism. Erlanson-Albertsson C(1). Author information: (1)Department of Cell and Molecular Biology, Medical Faculty, University of Lund, Lund, Sweden. Investigations of variations in metabolic efficiency and thermogenesis have a short and turbulent history. In small animals, non-shivering thermogenesis and diet-induced thermogenesis have a great impact on overall body weight, and the question is whether mechanisms to waste energy have evolved also in human energy metabolism. The candidate molecules for this adaptive thermogenesis are the uncoupling proteins. This is a newly discovered family of proteins, consisting of at least five proteins, namely UCP1, UCP2, UCP3, UCP4 and UCP5. Although a role for UCP1 in thermogenesis is unequivocal, the physiological function of the newer uncoupling proteins is as yet unclear. UCP1 is present in brown adipose tissue and has a well-documented role in cold-induced thermogenesis. The targeted disruption of the UCP1-gene rendered animals that were cold sensitive, but not obese. UCP2 mRNA has a ubiquitous distribution in tissue, namely, in skeletal muscle, white and brown adipose tissue, the gastro-intestinal tract, the lung and the spleen. By targeting the UCP2-gene there was no effect on whole body energy metabolism, but instead, a reduced ability to protect against free-radical oxygen species. UCP2 has also been shown to act as a negative regulator for insulin secretion. UCP3 is present in skeletal muscle. Targeted disruption of the UCP3-gene gave no effect on whole body energy metabolism, but showed the mitochondria in muscle to be more coupled. In conclusion, the uncoupling proteins may be important in various specific ways, as protectors of free radical oxygen species and as regulators of ATP-dependent processes. PMID: 12864746 [PubMed - indexed for MEDLINE] 4440. Acta Physiol Scand. 2003 Aug;178(4):397-403. Hormone-sensitive lipase in skeletal muscle: regulatory mechanisms. Langfort J(1), Donsmark M, Ploug T, Holm C, Galbo H. Author information: (1)Copenhagen Muscle Research Centre, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark. AIM: The enzymatic regulation of intramuscular triacylglycerol (TG) breakdown has until recently not been well understood. Our aim was to elucidate the role of hormone-sensitive lipase (HSL), which controls TG breakdown in adipose tissue. METHODS: Isolated rat muscle as well as exercising humans were studied. RESULTS: The presence of HSL was demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying. The content of HSL varies between fibre types, being higher in oxidative than in glycolytic fibres. Analysed under conditions optimal for HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by presence of anti-HSL antibody during analysis. Moreover, immunoprecipitation with affinity-purified anti-HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via beta-adrenergic activation of protein kinase A (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser563, Ser659 and Ser660. Contraction probably also enhances muscle-HSL activity by phosphorylation, because the contraction-induced increase in HSL activity is increased by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction-induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser600. So, phosphorylation of different sites may explain that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases the contraction-mediated, but diminishes the adrenaline mediated HSL activation in muscle. CONCLUSION: The existence and regulation of HSL in skeletal muscle indicate a role of HSL in muscle TG metabolism. PMID: 12864745 [PubMed - indexed for MEDLINE] 4441. Acta Physiol Scand. 2003 Aug;178(4):357-65. Energy translocation across cell membranes and membrane models. Pownall HJ(1), Hamilton JA. Author information: (1)Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Fatty acid transport is an important process in cellular energy distribution and storage in both normal and pathological states, especially obesity-linked type 2 diabetes mellitus. Fatty acid transport has been studied by the complementary approaches of cell biology and biophysics. According to the latter approach, specific proteins that enhance the uptake and storage of fatty acids are posited as fatty acid translocases, which facilitate fatty acid movement from the outer to inner leaflets of the plasma membrane. According to biophysical studies conducted in vitro, fatty acid translocation occurs by a rapid diffusive process that does not require a protein. Herein, we critically review these two mechanisms and their importance in the regulation of fatty acid uptake in vivo. PMID: 12864740 [PubMed - indexed for MEDLINE] 4442. Drugs Today (Barc). 2003 May;39(5):347-57. The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy. Takano H(1), Hasegawa H, Nagai T, Komuro I. Author information: (1)Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. komuro-tky@umin.ac.jp Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARs have three isoforms, alpha, beta (or delta) and gamma. It has been conceived that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), have been identified as ligands for PPARgamma. Following demonstration that PPARgamma is present in a variety of cell types, further study of PPARgamma has been conducted. Although activation of PPARgamma appears to have beneficial effects on atherosclerosis and heart failure, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular diseases. Recent evidence suggests that some benefit from the antidiabetic agents known as thiazolidinediones may occur through PPARgamma-independent mechanisms. In this review, we report on the latest developments concerning the study of PPARs and summarize the roles of the PPARgamma-dependent pathway in cardiovascular diseases. (c) 2003 Prous Science. All rights reserved. PMID: 12861348 [PubMed - indexed for MEDLINE] 4443. Int J Obes Relat Metab Disord. 2003 Aug;27(8):875-88. Integrative physiology of human adipose tissue. Frayn KN(1), Karpe F, Fielding BA, Macdonald IA, Coppack SW. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK. keith.frayn@oxlip.ox.ac.uk Adipose tissue is now recognised as a highly active metabolic and endocrine organ. Great strides have been made in uncovering the multiple functions of the adipocyte in cellular and molecular detail, but it is essential to remember that adipose tissue normally operates as a structured whole. Its functions are regulated by multiple external influences such as autonomic nervous system activity, the rate of blood flow and the delivery of a complex mix of substrates and hormones in the plasma. Attempting to understand how all these factors converge and regulate adipose tissue function is a prime example of integrative physiology. Adipose tissue metabolism is extremely dynamic, and the supply of and removal of substrates in the blood is acutely regulated according to the nutritional state. Adipose tissue possesses the ability to a very large extent to modulate its own metabolic activities, including differentiation of new adipocytes and production of blood vessels as necessary to accommodate increasing fat stores. At the same time, adipocytes signal to other tissues to regulate their energy metabolism in accordance with the body's nutritional state. Ultimately adipocyte fat stores have to match the body's overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the body's energy status, and points once again to the need for an integrative view of adipose tissue function. PMID: 12861227 [PubMed - indexed for MEDLINE] 4444. J Intern Med. 2003 Aug;254(2):114-25. Genotype, obesity and cardiovascular disease--has technical and social advancement outstripped evolution? Zimmet P(1), Thomas CR. Author information: (1)International Diabetes Institute, Caulfield, Victoria, Australia. pzimmet@idi.org.au Comment in J Intern Med. 2004 Jul;256(1):86-8. Teleologically, our ancestors were highly adapted hunter-gatherers. In recent history, the environment in which Homo sapiens exists has altered drastically and humans are exposed to environments for which the hunter-gatherer genotype is ill-suited. The adoption of a sedentary Western lifestyle, and the case of obtaining food of a high calorific content imposed upon a thrifty genotype, have resulted in the current global epidemic of obesity, Type 2 diabetes and the Metabolic Syndrome. The ramification of this epidemic is that cardiovascular disease is becoming a global healthcare problem, which will have its greatest impact on the developing nations. A global strategy is required to reduce the impact of the Western lifestyle on the health of developing nations and prevent obesity and Type 2 diabetes. Such an approach needs to be culturally sensitive, integrated, and multidisciplinary and involve a range of interventions that work at the individual and community levels. If lifestyle measures fail, then pharmacological intervention may be necessary. For this, novel agents such as dual PPARalpha/gamma agonists may be the therapy of the future. PMID: 12859692 [PubMed - indexed for MEDLINE] 4445. Cold Spring Harb Symp Quant Biol. 2002;67:417-27. Vascular endothelium in tissue remodeling: implications for heart failure. Dallabrida SM(1), Rupnick MA. Author information: (1)Children's Hospital, Division of Surgical Research, Boston, Massachusetts 02115, USA. PMID: 12858567 [PubMed - indexed for MEDLINE] 4446. Pflugers Arch. 2004 Feb;447(5):722-7. Epub 2003 Jul 11. A current review of fatty acid transport proteins (SLC27). Stahl A(1). Author information: (1)Research Institute, Palo Alto Medical Foundation, Ames Bldg., 795 El Camino Real, Palo Alto, CA 94301, USA. AStahl@Stanford.edu Long-chain fatty acids (LCFAs) are not only important metabolites but contribute to many cellular functions including activation of protein kinase C (PKC) isoforms and nuclear transcription factors such as peroxisome proliferator-activated receptors (PPAPs). To assert their diverse effects LCFAs have first to traverse the plasma membrane, a process that can occur either through diffusion or be mediated by proteins. Considerable evidence has accumulated to show that in addition to a diffusional component, the intestine, heart, adipose tissue, and the liver express a saturable and specific LCFA transport system. Identifying the postulated fatty acid transporters is of considerable importance, since both increased and decreased fatty acid uptake have been implicated in diseases such as type-2 diabetes and acute liver failure. Fatty acid transport proteins (FATPs/solute carrier family 27) are integral transmembrane proteins that enhance the uptake of long-chain and very long chain fatty acids into cells. In humans FATPs comprise a family of six highly homologous proteins, hsFATP1-6, which are found in all fatty acid-utilizing tissues of the body. This review will focus on a brief discussion of FATP expression patterns, regulation, structure, and mechanism of transport. PMID: 12856180 [PubMed - indexed for MEDLINE] 4447. Ann N Y Acad Sci. 2003 Jun;994:258-66. The role of the melanocortin-3 receptor in cachexia. Marks D(1), Cone RD. Author information: (1)Department of Pediatric Endocrinology, Oregon Health and Sciences University, Portland, Oregon 97239, USA. marksd@ohsu.edu Cachexia refers to a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of chronic diseases and is an important determinant of mortality. In this paper, we provide evidence that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. We have also demonstrated that blockade of the melanocortin-3 receptor (MC3-R) leads to enhanced disease-associated cachexia. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem. PMID: 12851324 [PubMed - indexed for MEDLINE] 4448. Cardiovasc Drug Rev. 2003 Summer;21(2):133-42. Lipoprotein lipase activator NO-1886. Yin W(1), Tsutsumi K. Author information: (1)Department of Biochemistry and Molecular Biology, Medical School, Nanhua University, Hengyang 421001, China. wdy20012001@yahoo.com Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins such as very low-density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO-1886. NO-1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL-C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO-1886 or other possible LPL activating agents are potentially beneficial for the treatment of hypertriglyceridemia, hypo-HDL cholesterolemia, and protection from atherosclerosis. PMID: 12847564 [PubMed - indexed for MEDLINE] 4449. Curr Opin Lipidol. 2003 Jun;14(3):289-97. Letting lipids go: hormone-sensitive lipase. Haemmerle G(1), Zimmermann R, Zechner R. Author information: (1)Institute of Molecular Biology, Karl-Franzens University, Graz, Autria. PURPOSE OF REVIEW: Despite their pathophysiological importance, the molecular mechanisms and enzymatic components of lipid mobilization from intracellular storage compartments are insufficiently understood. The aim of this review is to evaluate the role of hormone-sensitive lipase in this process. RECENT FINDINGS: Hormone-sensitive lipase exhibits a broad specificity for lipid substrates such as triglycerides, diglycerides, cholesteryl esters, and retinyl esters and the enzyme is in a wide variety of tissues. The high enzyme activity in adipose tissue was considered rate-limiting in the degradation of stored triglycerides. This view of a single enzyme controlling the catabolism of stored fat was challenged by recent findings that in hormone-sensitive lipase deficient mice adipose tissue triglycerides were still hydrolyzed and that these animals were leaner than normal mice. These results indicated that in adipose tissue hormone-sensitive lipase cooperates with other yet unidentified lipases to control the mobilization of fatty acids from cellular depots and that this process is coordinately regulated with lipid synthesis. Induced mutant mouse lines that overexpress or lack hormone-sensitive lipase also provided evidence that hormone-sensitive lipase-mediated cholesteryl ester hydrolysis is involved in steroid-hormone production in adrenals and affects testis function. Finally, hormone-sensitive lipase deficiency in mice results in a lipoprotein profile characterized by low triglyceride and VLDL levels and increased HDL cholesterol concentrations. SUMMARY: The 'anti-atherosclerotic' plasma lipoprotein profile and the fact that hormone-sensitive lipase deficient animals become lean identifies the inhibition of hormone-sensitive lipase as a potential target for the treatment of lipid disorders and obesity. PMID: 12840660 [PubMed - indexed for MEDLINE] 4450. Biochem J. 2003 Oct 1;375(Pt 1):1-16. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Rutter GA(1), Da Silva Xavier G, Leclerc I. Author information: (1)Henry Wellcome Laboratories of Integrated Cell Signalling and Department of Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, UK. g.a.rutter@bris.ac.uk AMPK (5'-AMP-activated protein kinase) is emerging as a metabolic master switch, by which cells in both mammals and lower organisms sense and decode changes in energy status. Changes in AMPK activity have been shown to regulate glucose transport in muscle and glucose production by the liver. Moreover, AMPK appears to be a key regulator of at least one transcription factor linked to a monogenic form of diabetes mellitus. As a result, considerable efforts are now under way to explore the usefulness of AMPK as a therapeutic target for other forms of this disease. Here we review this topic, and discuss new findings which suggest that AMPK may play roles in regulating insulin release and the survival of pancreatic islet beta-cells, and nutrient sensing by the brain. PMCID: PMC1223661 PMID: 12839490 [PubMed - indexed for MEDLINE] 4451. Med Sci (Paris). 2003 Apr;19(4):473-6. [Glucocorticoids, 11 beta-hydroxysteroid dehydrogenase type 1, and visceral obesity]. [Article in French] Paulmyer-Lacroix O(1), Boullu-Ciocca S, Oliver C, Dutour A, Grino M. Author information: (1)Laboratoire des Interactions fonctionnelles en Neuroendocrinologie, UFR de Médecine secteur Nord, Institut Jean Roche, Université de la Méditerranée, boulevard Pierre Dramard, 13916 Marseille, France. Glucocorticoids are implicated as a pathophysiological mediator of obesity and its accompanying metabolic and cardiovascular complications. Obese patients exhibit normal circulating cortisol levels, related to increased glucocorticoid production and degradation. However, it has been demonstrated that local production of active cortisol from inactive cortisone driven by 11 beta-hydroxysteroid dehydrogenase type 1 is exaggerated in adipose tissue of obese subjects. Such local hypercortisolism may be responsible for increased adipocyte differentiation and enhanced secretion of free fatty acids and other substances involved in the metabolic and cardiovascular complications observed in obesity. PMID: 12836221 [PubMed - indexed for MEDLINE] 4452. J Nutr Biochem. 2003 May;14(5):251-8. Functional properties of whey, whey components, and essential amino acids: mechanisms underlying health benefits for active people (review). Ha E(1), Zemel MB. Author information: (1)Functional Ingredients Research, Inc, Twin Falls, Idaho, USA. Whey proteins and amino acid supplements have a strong position in the sports nutrition market based on the purported quality of proteins and amino acids they provide. Recent studies employing stable isotope methodology demonstrate the ability of whey proteins or amino acid mixtures of similar composition to promote whole body and muscle protein synthesis. Other developing avenues of research explore health benefits of whey that extend beyond protein and basic nutrition. Many bioactive components derived from whey are under study for their ability to offer specific health benefits. These functions are being investigated predominantly in tissue culture systems and animal models. The capacity of these compounds to modulate adiposity, and to enhance immune function and anti-oxidant activity presents new applications potentially suited to the needs of those individuals with active lifestyles. This paper will review the recent literature that describes functional properties of essential amino acids, whey proteins, whey-derived minerals and other compounds and the mechanisms by which they may confer benefits to active people in the context that exercise is a form of metabolic stress. The response to this stress can be positive, as with the accretion of more muscle and improved functionality or greater strength. However, overall benefits may be compromised if immune function or general health is challenged in response to the stress. From a mechanistic standpoint, whey proteins, their composite amino acids, and/or associated compounds may be able to provide substrate and bioactive components to extend the overall benefits of physical activity. PMID: 12832028 [PubMed - indexed for MEDLINE] 4453. Expert Opin Investig Drugs. 2003 Jul;12(7):1179-87. Thiazolidinediones -- some recent developments. Stumvoll M(1). Author information: (1)Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-karls-Universität, Tübingen, Germany. michael.stumvoll@med.uni-tuebingen.de The role of thiazolidinediones (currently rosiglitazone and pioglitazone) in the treatment of Type 2 diabetes is firmly established. The mechanism of action involves binding to the peroxisome proliferator-activated receptor-gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also other cell types such as endothelial cells, macrophages and monocytes, vascular smooth muscle cells and colonic epithelium. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g., increased free fatty acids, decreased adiponectin) in a way that results in net improvement of insulin sensitivity (i.e., in muscle and liver). A direct or indirect effect on AMP-dependent protein kinase may also be involved. Prevention of lipid accumulation in tissues critical to glycaemia such as visceral adipocytes, liver, muscle and beta-cells at the expense of lipids accumulating at the less harmful subcutaneous site may be central to their net metabolic effect. The sustained beneficial effect of troglitazone on beta-cell function in women with previous gestational diabetes in addition to the insulin-sensitising properties point to an important role of this class of drugs in the prevention of Type 2 diabetes. Original safety concerns based on animal and in vitro studies (e.g., fatty bone marrow transformation, colonic cancer, adipogenic transdifferentiation of blood cells) remain theoretical issues but become less pressing practically with prolonged uneventful clinical use. Hepatotoxicity for troglitazone and fluid retention, which can aggravate pre-existing heart failure, are the most important side effects. In summary, with the thiazolidinediones, a novel concept for the treatment of insulin resistance and possibly preservation of beta-cell function is available that could become effective in the prevention of Type 2 diabetes. Moreover, their anti-inflammatory properties also make them interesting in the prevention and treatment of atherosclerosis and possibly other inflammatory conditions (e.g., inflammatory bowel disease). Long-term data will be necessary for a final risk-benefit assessment of these substances. PMID: 12831352 [PubMed - indexed for MEDLINE] 4454. Nutr Rev. 2003 May;61(5 Pt 2):S88-94. Glycemic carbohydrates consumed with amino acids or protein right after exercise enhance muscle formation. Suzuki M(1). Author information: (1)School of Sport Sciences, University of Waseda, Tokorozawa, Saitama, Japan 359-1192. This review shows the importance of high-glycemic carbohydrates consumed together with protein in enhancing the exercise-induced muscle formation relative to timing of intake. Insulin, which increases in blood after glycemic carbohydrate ingestion, seems to effectively stimulate protein synthesis and inhibit protein degradation right after exercise rather than later. This presents a new aspect in nutrition: the importance of intake timing in addition to the composition and amount of nutrients. PMID: 12828198 [PubMed - indexed for MEDLINE] 4455. Am J Surg Pathol. 2003 Jul;27(7):969-77. Adenomatoid tumor of the adrenal gland: a clinicopathologic study of five cases and review of the literature. Isotalo PA(1), Keeney GL, Sebo TJ, Riehle DL, Cheville JC. Author information: (1)Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. We report the clinicopathologic, immunophenotypic, DNA ploidy, and MIB-1 proliferative findings of five adenomatoid tumors of the adrenal gland. All patients were male, and tumors were incidental radiologic, surgical, or autopsy findings. Mean patient age at diagnosis was 41 years (range 31-64 years). The tumors ranged from 1.2 to 3.5 cm (mean 2.8 cm; median 3.2 cm) in greatest dimension, and all originated within the adrenal gland. The tumors were composed of anastomosing variably sized tubules lined by epithelioid as well as flattened cells. Signet-ring-like cells were present in all cases. The previously described histologic patterns of adenomatoid tumor, adenoid, angiomatoid, cystic, and solid, were observed, and each tumor contained multiple histologic patterns. In three of five cases, there was extra-adrenal extension of tumor into periadrenal adipose tissue. All adenomatoid tumors infiltrated the adrenal cortex, and in four cases the adrenal medulla was involved. All tumors exhibited strong immunoreactivity for calretinin, cytokeratins AE1/AE3, and CAM 5.2, cytokeratin 7, and vimentin. Tumors showed weak and focal immunoreactivity for cytokeratin 5/cytokeratin 6 and were negative for CD15, CD31, CD34, cytokeratin 20, MOC31, and polyclonal carcinoembryonic antigen. Ploidy analysis using Feulgen-stained sections and image analysis showed that three tumors were diploid and two were tetraploid. Tumors exhibited low MIB-1 proliferative activity, ranging from 0.2% to 2.7% (mean 1.6%). In three cases with clinical follow-up, no recurrence or metastases occurred. Adrenal gland adenomatoid tumors are morphologically and immunophenotypically identical to adenomatoid tumors of the genital tract and appear benign. PMID: 12826889 [PubMed - indexed for MEDLINE] 4456. Trends Endocrinol Metab. 2003 Jul;14(5):214-21. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Agarwal AK(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes. PMID: 12826327 [PubMed - indexed for MEDLINE] 4457. Trends Pharmacol Sci. 2003 Jun;24(6):276-83. Do regional differences in adipocyte biology provide new pathophysiological insights? Lafontan M(1), Berlan M. Author information: (1)Unité de Recherches sur les Obésités-Unité INSERM 586, Institut Louis Bugnard, Université Paul Sabatier, CHU Rangueil, 31403 Toulouse cedex 4, France. Max.Lafontan@toulouse.inserm.fr Obesity is an increasing health problem in many countries. Striking differences exist in the magnitude of the impact of different obesities on comorbidities. Individuals with peripheral obesity ('pears') possess fat distributed subcutaneously in gluteofemoral areas and the lower part of the abdomen, and are at little risk of metabolic complications. Conversely, individuals with upper-body obesity ('apples') accumulate fat in subcutaneous and visceral deposits and are more prone to metabolic and cardiovascular problems, particularly when visceral fat deposits are abundant. In this article, whether the different risk factors for obesity of 'apples' and 'pears' are largely related to the heterogeneity of function and responsiveness of the adipocytes from visceral and subcutaneous deposits is questioned. Possible pharmacological approaches to the treatment of obesity and related diseases are also considered. PMID: 12823953 [PubMed - indexed for MEDLINE] 4458. Int J Obes Relat Metab Disord. 2003 Jul;27(7):755-77. The influence of birthweight and intrauterine environment on adiposity and fat distribution in later life. Rogers I(1); EURO-BLCS Study Group. Author information: (1)Unit of Paediatric and Perinatal Epidemiology, Division of Child Health, University of Bristol, Bristol, UK. Imogen.Rodgers@bristol.ac.uk OBJECTIVE: To review the literature on the association between birthweight and body mass index (BMI) and obesity in later life. METHODS: Included in the review were papers appearing in Medline since 1966 and identified using the search terms obesity, body fat, waist, body constitution, birthweight and birth weight. Further papers were identified by examining bibliographies. RESULTS: There is good evidence that there is an association between birthweight and subsequent BMI and overweight in young adults and children, which is linear and positive in some studies and J- or U-shaped in others. The evidence is less strong for middle-aged subjects. Studies that have assessed lean body mass (LBM) and fat body mass have tended to find that birthweight is positively associated with LBM and negatively associated with relative adiposity. This suggests that the association between birthweight and BMI/overweight does not necessarily reflect increased adiposity at higher birthweights. On controlling for current body mass there is fairly consistent evidence of a negative association between birthweight and a central pattern of fat distribution as measured by central:peripheral skinfold ratios. It has been suggested that the prenatal period is a 'critical' period for the development of adiposity, but it is unclear how far associations between birthweight and subsequent body habitus are genetic in origin and how far they result from intrauterine 'programming'. Two lines of evidence would suggest that the association is predominantly genetic. Studies of monozygotic twins have found environmentally determined differences in birthweight to be unrelated to subsequent BMI, and the association between birthweight and BMI is substantially reduced on controlling for parental BMI. However, some evidence of an influence of intrauterine environment on later obesity comes from studies of subjects who were exposed in utero to the effects of diabetes, famine conditions or smoking. CONCLUSIONS: The reasons for the positive association between birthweight and BMI remain unclear. More studies including accurate measurement of body composition are needed to assess how far this relation is accounted for by changes in fat mass or by changes in lean mass. Studies with accurate measures of parental BMI would also be useful in assessing the importance of this confounder. PMID: 12821960 [PubMed - indexed for MEDLINE] 4459. Apoptosis. 2003 Aug;8(4):327-35. Leptin-induced adipose apoptosis: Implications for body weight regulation. Gullicksen PS(1), Della-Fera MA, Baile CA. Author information: (1)Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602, USA. Great strides have been made in understanding the genetics of body weight regulation, in part due to the study of rodent models of obesity that are characterized by mutations affecting leptin or its receptors. Leptin, produced in adipose tissue, acts both centrally and peripherally to orchestrate complex metabolic and behavioral changes that increase loss of adipose tissue, including suppressing food intake and increasing thermogenesis. In addition, recent evidence indicates that leptin acts centrally to trigger an apoptotic process resulting in adipocyte deletion. Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following leptin treatments. This review summarizes the major aspects of leptin-induced adipose tissue apoptosis, including some of the newest findings about possible mechanisms of action. PMID: 12815275 [PubMed - indexed for MEDLINE] 4460. J Cell Biol. 2003 Jun 23;161(6):1011-2. Epub 2003 Jun 16. Lipolysis: more than just a lipase. Birnbaum MJ(1). Author information: (1)Morris J. Birnbaum, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 415 Curie Blvd., Room 322 CRB, Philadelphia, PA 19104, USA. birnbaum@mail.med.upenn.edu Comment on J Cell Biol. 2003 Jun 23;161(6):1093-103. Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it has long been recognized that cyclic AMP represents the critical second messenger and hormone-sensitive lipase (HSL)**Abbreviations used in this paper: ADRP, adipocyte differentiation-related protein; HSL, hormone-sensitive lipase; PKA, protein kinase A; TAG, triacylglycerol. the rate-determining enzyme for lipolysis, simple activation of the enzyme has failed to account for the robust augmentation of fatty release in response to physiological agonists. In this issue, Sztalryd et al. (2003) provide convincing support to the notion that the subcellular compartmentalization of lipase also regulates lipolysis, and, more importantly, that proteins other than HSL are localized to the lipid droplet and are indispensable for its optimal hydrolysis. PMCID: PMC2172981 PMID: 12810703 [PubMed - indexed for MEDLINE] 4461. Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):469-75. Cold-induced metabolism. van Marken Lichtenbelt WD(1), Daanen HA. Author information: (1)Department of Human Biology, Maastricht University, Maastricht, The Netherlands. PURPOSE OF REVIEW: Cold response can be insulative (drop in peripheral temperature) or metabolic (increase in energy expenditure). Nonshivering thermogenesis by sympathetic, norepinephrine-induced mitochondrial heat production in brown adipose tissue is a well known component of this metabolic response in infants and several animal species. In adult humans, however, its role is less clear. Here we explore recent findings on the role and variability of nonshivering thermogenesis in adults. RECENT FINDINGS: Large individual differences exist in mild cold response with respect to the relative contribution of the insulative response and the metabolic (nonshivering) response. In search for the possible explanations of this variation, recent studies on potential mechanisms of nonshivering thermogenesis in humans are presented. Emphasis is given to the role of uncoupling proteins, mitochondrial ATP-synthase, and calcium cycling. The potential contribution of human skeletal muscle to nonshivering thermogenesis is discussed. The differences in nonshivering thermogenesis can partly be attributed to factors such as age, gender, physical fitness, adaptation, and diet. There are indications that genetic variation affect cold response. SUMMARY: The implications of the observed large individual variation in cold response is that a low metabolic response to cold can partly explain increased risk to develop obesity. Both the effect of environmental factors and genetic factors on nonshivering thermogenesis require more well controlled studies. With extended knowledge on these factors it can be ascertained if a pharmacological regimen is possible which would mimic the effects of chronic cold or elevated catecholamine levels, without attendant side effects. PMID: 12806223 [PubMed - indexed for MEDLINE] 4462. Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):387-93. Body composition measurements: interpretation finally made easy for clinical use. Kyle UG(1), Piccoli A, Pichard C. Author information: (1)Department of Clinical Nutrition, Geneva University Hospital, Geneva, Switzerland. PURPOSE OF REVIEW: This review presents the latest clinical applications of bioelectrical impedance analysis. It discusses the evaluation of nutritional status by using fat-free mass and body fat, percentiles of fat-free mass and body fat, height-normalized fat-free mass and body fat mass indices and a resistance/reactance vector graph. RECENT FINDINGS: Fat-free mass and body fat can be used to evaluate nutritional status by comparing individuals or groups of individuals with themselves or with reference values. Percentile distributions are also useful in determining whether individuals or groups fall within the population range. Percentile ranks can also be used to define nutritional depletion and obesity. The use of the fat-free mass and body fat mass indices has the advantage of compensating for differences in body height. The use of low, normal, high and very high fat-free mass and body fat mass indices ranges that correspond to underweight, normal, overweight and obese body mass index categories further aid in the nutritional assessment process. With vector bioelectrical impedance analysis, an individual impedance vector is compared with the 50, 75, and 95% tolerance ellipses calculated in the reference, healthy population, allowing evaluation in any clinical condition. More accurate estimates of conventional bioelectrical impedance analysis equations might be obtained in individuals with a normal impedance vector. SUMMARY: The assessment of fat-free mass and body fat provides valuable information about changes in body composition with weight gain or loss and physical activity, and during ageing. The use of percentiles and height-normalized fat-free mass and body fat permit the classification of patients as under or overnourished. PMID: 12806211 [PubMed - indexed for MEDLINE] 4463. Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):377-81. Effect of thyroid hormone on gene expression. Viguerie N(1), Langin D. Author information: (1)French Institute of Health and Medical Research, Toulouse University Hospitals, Toulouse, France. PURPOSE OF REVIEW: Thyroid hormones are key regulators of development and metabolism that modulate transcription via nuclear receptors. Although the molecular actions of thyroid hormones have been thoroughly studied, their pleiotropic effects are mediated by complex changes in expression of numerous, but still largely unknown, target genes. This review summarizes the recent advances in the characterization of target genes in different organs. RECENT FINDINGS: New patterns of gene expression regulation have been described in tissues with known physiological actions of thyroid hormone, that is brain, liver, skeletal and cardiac muscles, and brown and white adipose tissues. The studies have benefited from the numerous transgenic models with altered thyroid hormone receptor expression and the application of DNA microarray technology to mouse and human tissues. SUMMARY: Data on thyroid hormone-mediated control of gene expression and on the roles of the different thyroid hormone receptor isoforms bring new clues to our understanding of the molecular mechanisms of thyroid hormone action in physiological situations and, most importantly, in diseases associated with alterations of the thyroid status. PMID: 12806209 [PubMed - indexed for MEDLINE] 4464. ScientificWorldJournal. 2001 May 1;1:188-9. Signaling pathway puts the break on fat cell formation. MacDougald OA(1). Author information: (1)Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622, USA. macdouga@umich.edu Obesity is approaching epidemic proportions in the western industrialized world, and is also becoming a major problem among young people in eastern and developing countries. Unfortunately, excess fat or adipose tissue is associated with a wide array of health problems, including increased incidence of type II diabetes, cardiovascular disease, hypertension, sleep apnea, and skeletomuscular problems. Obesity is the second leading cause of death from "unnecessary" causes in the U.S. (after smoking), and costs individuals and society billions of dollars worldwide to treat. Despite common wisdom that "one just needs to eat less and exercise more" and a multi-billion-dollar diet industry, epidemiological data indicate that the incidence of obesity will continue to rise. This alarming trend is, in part, due to the unprecedented availability of energy-dense foods and an increasingly sedentary lifestyle. These environmental factors may be complicated in some individuals by an unfavorable genetic predisposition. Pharmaceutical companies lead active research programs to identify drugs that target weight control centers in the body and which may help individuals control their weight; however, no satisfactory magic bullet to fight obesity has yet come through the pipeline. PMID: 12805664 [PubMed - indexed for MEDLINE] 4465. Ann Plast Surg. 2003 Mar;50(3):244-8; discussion 248. Clinical analysis of malar fat pad re-elevation. de la Torre JI(1), Rosenberg LZ, De Cordier BC, Gardner PM, Fix RJ, Vasconez LO. Author information: (1)The University of Alabama at Birmingham, Division of Plastic Surgery and The Center for Advanced Surgical Aesthetics, Birmingham, AL, USA. jorge.delatorre@ccc.uab.edu Primary suture suspension of the malar fat pad has been described as a safe and simple component of global facial rejuvenation. This review evaluates the efficacy and indications for re-elevation of the malar fat pad elevation. A retrospective review of the medical records of patients who underwent malar fat pad elevation was performed between 1994 and 2000. Of 472 procedures, 14 involved re-elevation of the malar fat pad. These cases were examined for complications, risks, and results. Secondary midface elevation was performed using a subcutaneous approach to the malar fat pad through a pre-hairline incision and vertical suspension of the malar fat pad to the temporoparietal fascia. The indications for re-elevation of the malar fat pad included nasolabial asymmetry, malar fat pad malposition, and malar fat pad asymmetry. Primary elevation of the malar fat was performed in 472 patients. Fourteen of these patients had suboptimal results that necessitated re-elevation of their malar fat pads. Their average age was 57.5 years. Of the 14 malar fat pad elevations, 12 included SMAS procedures, nine were combined with platysmal plication/submental lipectomy, six with forehead lift, and three with eyelid procedures. The average interval between original malar fat pad elevation and the re-elevation was 40 months. Average follow-up was 15 months. Complications were seen in five patients, with the most significant being persistent eye irritation. Two patients had some minimal scar hypertrophy, which was self-limiting. Minor preauricular skin slough developed in one patient. Restoration of the youthful position of the deep structures in patients with a previous mid-facelift was successfully achieved by re-elevating the malar fat pad in a vertical direction. Re-elevation of the malar fat pad demonstrated effective and reliable long-term results. It is appropriate in the small number of patients who require revision or improvement of midface rejuvenation using the malar fat pad suspension technique. PMID: 12800899 [PubMed - indexed for MEDLINE] 4466. Physiol Biochem Zool. 2003 Mar-Apr;76(2):165-79. The role of energy availability in Mammalian hibernation: a cost-benefit approach. Humphries MM(1), Thomas DW, Kramer DL. Author information: (1)Department of Biology, McGill University, 1205 Avenue Docteur Penfield, Montreal, Quebec H3A 1B1, Canada. humphries@nrs.mcgill.ca Hibernation is widely regarded as an adaptation to seasonal energy shortage, but the actual influence of energy availability on hibernation patterns is rarely considered. Here we review literature on the costs and benefits of torpor expression to examine the influence that energy may have on hibernation patterns. We first establish that the dichotomy between food- and fat-storing hibernators coincides with differences in diet rather than body size and show that small or large species pursuing either strategy have considerable potential scope in the amount of torpor needed to survive winter. Torpor expression provides substantial energy savings, which increase the chance of surviving a period of food shortage and emerging with residual energy for early spring reproduction. However, all hibernating mammals periodically arouse to normal body temperatures during hibernation. The function of these arousals has long been speculated to involve recovery from physiological costs accumulated during metabolic depression, and recent physiological studies indicate these costs may include oxidative stress, reduced immunocompetence, and perhaps neuronal tissue damage. Using an optimality approach, we suggest that trade-offs between the benefits of energy conservation and the physiological costs of metabolic depression can explain both why hibernators periodically arouse from torpor and why they should use available energy to minimize the depth and duration of their torpor bouts. On the basis of these trade-offs, we derive a series of testable predictions concerning the relationship between energy availability and torpor expression. We conclude by reviewing the empirical support for these predictions and suggesting new avenues for research on the role of energy availability in mammalian hibernation. PMID: 12794670 [PubMed - indexed for MEDLINE] 4467. Int J Clin Pract Suppl. 2003 Mar;(134):18-27. The relationship of obesity to the metabolic syndrome. Lebovitz HE(1). Author information: (1)State University of New York Health Science at Brooklyn, New York, USA. Obese patients with the metabolic syndrome generally have a visceral (apple-shaped) fat distribution and are at an increased risk of macrovascular disease, while those with peripheral (pear-shaped) obesity tend not to have metabolic abnormalities and are at less risk. This difference appears to be related to the differing metabolic functions (and secretory products) of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as the fact that VAT drains directly into the liver. Thus, it appears that increased VAT, but not SAT, is associated with both hepatic and peripheral biochemical abnormalities leading to insulin resistance and the associated metabolic syndrome. Insulin resistance is associated with VAT products, such as free fatty acids and their metabolites, as well as cytokines, such as tumour necrosis factor alpha (TNF-alpha). These factors may activate components of the inflammatory pathway such as nuclear factor kappa-B (NFkappaB), and inhibit insulin signalling. Insulin resistance is further associated with decreased levels of another tissue product, adiponectin. The incidence and prevalence of obesity is increasing at an unprecedented rate. The classic treatment of obesity is weight loss via lifestyle modification. However, prevention of obesity comorbidity can also be achieved by modifying the mechanisms by which obesity causes these comorbid conditions. For instance, it is now known that the peroxisome proliferator-activated receptor (PPAR) family of transcriptional regulators are crucial in regulating adipose tissue development and metabolism; this helps explain why compounds with PPARgamma agonist activity, e.g. thiazolidinediones, increase insulin action through their effects in regulating adipose tissue metabolism. PMID: 12793594 [PubMed - indexed for MEDLINE] 4468. Int J Clin Pract Suppl. 2003 Mar;(134):10-7. Inflammation, the metabolic syndrome and cardiovascular risk. Tracy RP(1). Author information: (1)University of Vermont College of Medicine, Burlington, Vermont, USA. Over the past ten years it has become clear that cardiovascular disease (CVD) and atherosclerosis have a 'microinflammatory' component and are often associated with low levels of inflammatory markers that are in the upper part of the 'normal' range. In particular, diseases that predispose to CVD, such as the metabolic syndrome and type 2 diabetes, appear to have a very strong inflammatory component. While the inflammatory process is very complicated, single measures, such as C-reactive protein (CRP) or fibrinogen, have clear benefits as they summarise many different parts of the inflammatory process and are easy to apply. However, it is important to remember that the process of inflammation includes coagulation, fibrinolysis, complement activation, antioxidation, immune response and hormonal regulation through the hypothalamic-pituitary-adrenal axis. Furthermore, genetic variation, differences in exposure to environmental influences and the mass of inflammation-producing tissue (e.g. adipose tissue) can all influence responses. Thus, the relationship between atherosclerosis, the metabolic syndrome and inflammation is extraordinarily complex. Inflammatory markers such as CRP exhibit strong CVD-risk prediction that is consistent across sexes and a number of different populations. They reflect risk not only for 'vulnerable plaque' and myocardial infarction (MI) but also for other cardiovascular diseases. In fact, inflammation is associated with several, if not all, of the chronic diseases of old age, and it is now clear that there are important links between inflammation and general metabolism. For instance, visceral adiposity exerts a major influence on inflammation status. Medications that affect atherosclerosis appear to do so at least in part by influencing inflammation (for instance, the emerging pleiotropic effects of statins), and this has far-reaching ramifications for chronic diseases of old age and their treatment. PMID: 12793593 [PubMed - indexed for MEDLINE] 4469. Int J Clin Pract Suppl. 2003 Mar;(134):3-9. Metabolic syndrome: multiple candidate genes, multiple environmental factors--multiple syndromes? Nestel P(1). Author information: (1)Baker Medical Research Institute, Melbourne, Australia. Key elements of the metabolic syndrome include the development of insulin resistance, glucose intolerance, dyslipidaemia and hypertension, which lead to multiple effects on lipoprotein metabolism and vascular functions and, ultimately an increased risk of cardiovascular disease. There are probably multiple presentations of the metabolic syndrome, and these depend on the interplay of genetic variation and environmental factors. In particular, polymorphisms in genes that are expressed in adipose tissue may play a crucial role in the development of the metabolic syndrome. Elucidation of the aetiology of metabolic syndrome(s) will therefore play an important role in developing strategies to reduce adverse outcome. It is probable that pharmacological therapy will be needed for many patients with the metabolic syndrome to help reduce the risk of future cardiovascular events. PMID: 12793592 [PubMed - indexed for MEDLINE] 4470. J Biol Chem. 2003 Sep 5;278(36):33609-12. Epub 2003 Jun 4. Tissue-specific ablation of the GLUT4 glucose transporter or the insulin receptor challenges assumptions about insulin action and glucose homeostasis. Minokoshi Y(1), Kahn CR, Kahn BB. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA. PMID: 12788932 [PubMed - indexed for MEDLINE] 4471. J Biol Chem. 2003 Aug 15;278(33):30413-6. Epub 2003 Jun 4. Glyceroneogenesis and the triglyceride/fatty acid cycle. Reshef L(1), Olswang Y, Cassuto H, Blum B, Croniger CM, Kalhan SC, Tilghman SM, Hanson RW. Author information: (1)Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. PMID: 12788931 [PubMed - indexed for MEDLINE] 4472. J Biol Chem. 2003 Aug 1;278(31):28359-62. Epub 2003 Jun 4. In vivo mutagenesis of the insulin receptor. Okamoto H(1), Accili D. Author information: (1)Department of Medicine and Institute of Human Nutrition, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA. Mice bearing targeted gene mutations that affect insulin receptor (Insr) function have contributed important new information on the pathogenesis of type 2 diabetes. Whereas complete Insr ablation is lethal, conditional mutagenesis in selected tissues has more limited consequences on metabolism. Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic beta-cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. These studies are consistent with an oligogenic inheritance, in which synergistic interactions among few alleles may account for the genetic susceptibility to diabetes. In addition to mutant alleles conferring an increased risk of diabetes, these studies have uncovered mutations that protect against insulin resistance, thus providing proof-of-principle for the notion that certain alleles may confer resistance to diabetes. PMID: 12788928 [PubMed - indexed for MEDLINE] 4473. J Clin Endocrinol Metab. 2003 Jun;88(6):2412-21. The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. Gurnell M(1), Savage DB, Chatterjee VK, O'Rahilly S. Author information: (1)Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom. By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gamma gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome. PMID: 12788836 [PubMed - indexed for MEDLINE] 4474. Biochem Pharmacol. 2003 Jun 15;65(12):1917-21. Mitochondrial uncoupling protein 2 in the central nervous system: neuromodulator and neuroprotector. Horvath TL(1), Diano S, Barnstable C. Author information: (1)Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, FMB 339, New Haven, CT 06520, USA. tamas.horvath@yale.edu Uncoupling proteins (UCPs) are localized in the inner membrane of the mitochondria in diverse tissues and decrease mitochondrial membrane potential. The first of these proteins, UCP1, was discovered in brown adipose tissue, where it has a well-described role in thermogenesis. The functional significance of other UCPs, including UCP2, is less well understood. Here we summarize the recent advancements on the role of UCP2 in the brain and portray this uncoupler as an important player in normal neuronal function as well as a key cell death-suppressing device. These previously unknown functions of UCPs offer new avenues not only for the better understanding of these proteins but also for the furthering of our knowledge on the central nervous system in healthy and disease states. PMID: 12787871 [PubMed - indexed for MEDLINE] 4475. J Cardiopulm Rehabil. 2003 May-Jun;23(3):161-9. Waist circumference, visceral obesity, and cardiovascular risk. Poirier P(1), Després JP. Author information: (1)Institut Universitaire de Cardiologie et de Pneumologie, Hopital Laval, Sainte-Foy, Quebec, Canada. PMID: 12782898 [PubMed - indexed for MEDLINE] 4476. Mol Cell Endocrinol. 2003 May 30;203(1-2):1-12. The functional roles of 11 beta-HSD1: vascular tissue, testis and brain. Morris DJ(1), Brem AS, Ge R, Jellinck PH, Sakai RR, Hardy MP. Author information: (1)Department of Pathology and Laboratory Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA. dmorris@lifespan.org Glucocorticoid hormones bind both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) exerting a broad spectrum of actions in various tissues. The concentrations of glucocorticoid hormones in the target cells are regulated by 11 beta-hydroxysteroid dehydrogenases, type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2). 11 beta-HSD2 is a unidirectional dehydrogenase, which inactivates biologically active glucocorticoid into inert metabolite, while 11 beta-HSD1 is a bi-directional oxidoreductase, which either inactivates biologically active glucocorticoid or activates inert metabolite into active forms. GRs and MRs are present in various tissues and mediate a broad spectrum of physiological actions. The co-existence of 11 beta-HSD1 with these two types of receptors plays an important role in regulation of glucocorticoid actions. This review examines the roles of 11 beta-HSD1 in vascular tissues, testis, brain and other tissues such as placental, retinal and adipose tissues. PMID: 12782398 [PubMed - indexed for MEDLINE] 4477. Horm Metab Res. 2003 Apr;35(4):204-10. New insights into how adipocytes sense their triglyceride stores. Is cholesterol a signal? Dugail I(1), Le Lay S, Varret M, Le Liepvre X, Dagher G, Ferré P. Author information: (1)INSERM U 465, Institut Biomedical des Cordeliers, Paris, France. idugail@bhdc.jussieu.fr In recent years, our view of adipose tissue has evolved from a passive sink for energy storage to an active tissue producing multiple molecules acting on various tissues in different aspects of energy homeostasis. The production of adipose-derived secretory products is tightly regulated as a function of adipocyte lipid accumulation, but the mechanisms by which fat cells are able to sense the levels of their triglyceride stores still remains largely unknown. This paper reviews new insights into this question taking cholesterol as a potential intracellular signaling molecule. PMID: 12778362 [PubMed - indexed for MEDLINE] 4478. Curr Mol Med. 2003 Jun;3(4):325-40. Molecular and genetic mechanisms of obesity: implications for future management. Liu YJ(1), Araujo S, Recker RR, Deng HW. Author information: (1)Osteoporosis Research Center, Creighton University, 601 N. 30th St., Suite 6787, Omaha, NE 68131, USA. Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed. PMID: 12776988 [PubMed - indexed for MEDLINE] 4479. J Endocrinol. 2003 Jun;177(3):351-5. Tumour necrosis factor alpha: a key regulator of adipose tissue mass. Warne JP(1). Author information: (1)Department of Neuroendocrinology, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. james.warne@imperial.ac.uk In addition to its established role in the immune system, tumour necrosis factor alpha (TNFalpha) exerts complex regulatory actions on adipose tissue. TNFalpha is produced in and secreted by the adipocyte and thus is in a position to exert a paracrine and/or autocrine role within adipose tissue. TNFalpha affects many aspects of adipocyte function, from adipocyte development to lipid metabolism. Bringing together all of these diverse actions, TNFalpha appears to play a general role in reducing adipose tissue mass. Dysregulation of TNFalpha production and/or action could be one facet in the development of cachexia and obesity, as well as associated metabolic disorders such as insulin resistance. PMID: 12773114 [PubMed - indexed for MEDLINE] 4480. Curr Pharm Des. 2003;9(17):1411-8. The insulin-sensitizing role of the fat derived hormone adiponectin. Heilbronn LK(1), Smith SR, Ravussin E. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. Adiponectin is an insulin-sensitizing hormone whose blood concentration is reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin in rodents increases glucose uptake and increases fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole body insulin resistance. The exact receptor and signaling systems are unknown, however, recent studies suggest adiponectin activates AMPK, a putative master metabolic regulator. Thus, excitement surrounds the potential for adiponectin, or a homologue of adiponectin, as pharamacotherapy agents for patients suffering from the metabolic syndrome and more particularly for individuals with insulin resistance and type 2 diabetes. PMID: 12769732 [PubMed - indexed for MEDLINE] 4481. Curr Pharm Des. 2003;9(17):1397-410. Acylation stimulating protein and triacylglycerol synthesis: potential drug targets? Cianflone K(1). Author information: (1)McGill Unit for the Prevention of Cardiovascular Disease, McGill University Health Centre, Montreal, Quebec, Canada. katherine.cianflone@mcgill.ca Triacylglycerol storage in adipose tissue is mediated by a host of transporters, enzymes and binding proteins. Additionally, several hormones (both autocrine and endocrine) are known to interact with cell surface receptors and modulate triacylglycerol synthesis (such as acylation stimulating protein, ASP). The many proteins involved contribute to the robustness of the system and, in most cases, deletion of a single gene is not deleterious and adipose tissue is preserved. On the other hand, this does not mean that gene disruption is not without effect, and in fact often results in a leaner, and presumably "healthier" mouse. These insights provide valuable indications for potential drug tools to delay and/or reverse obesity. In this review we examine the potential of ASP as a candidate target. ASP deficiency in mice decreases adipose tissue mass, increases insulin sensitivity and energy expenditure even in obese ob/ob mice, suggesting that partial interference of ASP action could be advantageous. ASP interacts with a specific cell surface receptor present in adipose tissue and certain structural components, such as the tightly folded core region, are implicated in activity. We propose that interference of the ASP-receptor interaction using an antagonist offers future prospect for an anti-obesity target. PMID: 12769731 [PubMed - indexed for MEDLINE] 4482. Curr Pharm Des. 2003;9(17):1383-95. Ghrelin as a potential anti-obesity target. Horvath TL(1), Castañeda T, Tang-Christensen M, Pagotto U, Tschöp MH. Author information: (1)Dept. of Ob/Gyn, Yale University School of Medicine, New Haven, CT, USA. In order to develop an effective pharmacological treatment for obesity, an endogenous factor that promotes a positive energy balance by increasing appetite and decreasing fat oxidation could represent the drug target scientists have been looking for. The recently discovered gastric endocrine agent ghrelin, which appears to be the only potent hunger-inducing factor to naturally circulate in our blood stream, was discovered in 1999. Since then the acylated peptide hormone ghrelin has evolved from an endogenous growth hormone secretagogue to a regulator of energy balance to a pleiotropic hormone with multiple sources, numerous target tissues and most likely several physiological functions. Although neither the exact mechanism of action by which ghrelin increases food intake and adiposity is known, nor the putatively differential effects of brain-derived and stomach-derived ghrelin on energy homeostasis have been determined, blocking or neutralizing ghrelin action still seems one of the more reasonable pharmacological approaches to reverse a chronically positive energy balance. However, based on growing experience with compounds targeting the neuroendocrine regulation of energy balance, it is quite possible that a ghrelin antagonist will either fail to cure obesity due to the existence of compensatory mechanisms or undesired effects might reveal the true biological function of ghrelin (e.g. cardiovascular mechanisms, anti-proliferative effects, reproduction). PMID: 12769730 [PubMed - indexed for MEDLINE] 4483. Curr Diab Rep. 2003 Jun;3(3):207-13. Adiponectin: systemic contributor to insulin sensitivity. Pajvani UB(1), Scherer PE. Author information: (1)Department of Cell Biology and Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Adipocyte-specific secreted molecules, termed adipokines, have dispelled the notion of adipose tissue as an inert storage depot for lipids, and highlighted its role as an active endocrine organ that monitors and alters whole-body metabolism and maintains energy homeostasis. One of these adipokines, adiponectin (also known as Acrp30, AdipoQ, and GBP28), has gained significant attention recently as a mediator of insulin sensitivity. Many clinical reports and genetic studies over the past few years demonstrate decreased circulating levels of this hormone in metabolic dysfunction, such as obesity and insulin resistance, in both humans and animal models. Pharmacologic adiponectin treatments in rodents increase insulin sensitivity, although the primary site and detailed mechanism of action is yet to be determined. The phenotypes of adiponectin-deficient and transgenic adiponectin-overproducing animal models underscore the role of adiponectin in the maintenance of glucose and lipid homeostasis. PMID: 12762967 [PubMed - indexed for MEDLINE] 4484. Curr Diab Rep. 2003 Jun;3(3):201-6. Surgical removal of visceral adipose tissue: effects on insulin action. Gabriely I(1), Barzilai N. Author information: (1)Institute for Aging Research, Belfer Building #701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus. PMID: 12762966 [PubMed - indexed for MEDLINE] 4485. Curr Diab Rep. 2001 Aug;1(1):71-7. Maternal factors that determine neonatal size and body fat. Catalano PM(1), Kirwan JP. Author information: (1)Department of Reproductive Biology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. pcatalano@metrohealth.org These data are a review of previously published data. Initially, body composition was estimated in 186 neonates. Fat- free mass (FFM), which constituted 86% of birth weight, accounted for 83% of the variance in birth weight; fat mass (FM), which constituted 14% of birth weight, accounted for 46% of the variance in birth weight. Male neonates were an average of 175 g heavier than females. FFM was greater among males compared with females (P = 0.0001). Using stepwise logistic regression, 29% of the variance in birth weight, 30% in FFM, and 17% in FM was accounted for. Independent variables included maternal height, pregravid weight, weight gain during pregnancy, education, parity, paternal height and weight, neonatal sex, and gestational age. Including maternal insulin sensitivity explained 48% of the variance in birth weight, 53% in FFM, and 46% in FM. There was a positive correlation between weight gain and birth weight in control subjects but a negative correlation in subjects with gestational diabetes mellitus. Lastly, the roles of insulin, insulin-like growth factors, and leptin were examined in relation to fetoplacental growth and body composition. The assessment of fetal/neonatal body composition may improve the understanding of the effect of differential factors on fetal growth. Factors associated with accretion of fetal adipose tissue in late gestation are less well understood compared with birth weight and FFM. Additional studies of maternal glucose and lipid metabolism are needed to better evaluate fetal growth. PMID: 12762960 [PubMed - indexed for MEDLINE] 4486. Sports Med. 2003;33(7):473-82. Plasma leptin and exercise: recent findings. Hulver MW(1), Houmard JA. Author information: (1)Department of Physiology, East Carolina University, Greenville, North Carolina, USA. hulverm@mail.ecu.edu It is established that plasma leptin is associated with satiety and that leptin stimulates lipid metabolism, and increases energy expenditure. These effects implicate leptin as a major regulator of energy homeostasis, which may serve to limit excess energy storage. As plasma leptin concentrations are tightly coupled with fat mass in humans, decreases in adipose mass with weight loss coincide with decreased concentrations of circulating leptin. However, due to many confounding factors, the effects of exercise on circulating leptin are less clear. The data from investigations examining single exercise bouts suggest that serum leptin concentrations are unaltered by short duration (41 minutes or less), non-exhaustive exercise, but may be affected by short duration, exhaustive exercise. More convincingly, studies investigating long duration exercise bouts indicate that serum leptin concentrations are reduced with exercise durations ranging from one to multiple hours. These findings raise speculation that exercise-associated reductions in leptin may be due to alterations in nutrient availability or nutrient flux at the level of the adipocytes, the primary site of leptin production and secretion. Thus, one purpose of this review is to discuss the effects of exercise on circulating leptin concentrations with special emphasis on studies that have examined single exercise bouts that are associated with high levels of energy expenditure and energy deficit. In addition, a 'nutrient sensing pathway' (the hexosamine biosynthetic pathway), which regulates leptin gene expression, will be discussed as a possible mechanism by which exercise-induced energy deficit may modulate serum leptin concentrations. PMID: 12762824 [PubMed - indexed for MEDLINE] 4487. Usp Fiziol Nauk. 2003 Apr-Jun;34(2):3-20. [Leptin--a new hormone in endocrinology]. [Article in Russian] Pankov IuA(1). Author information: (1)Endocrynology Research Centre, RAMN, Moscow. Research of recent years has fundamentally revised modern endocrinology. Many organs and tissue that have never before been treated as endocrinal or involved in production of various hormones, became such. In particular, adipose tissue secreting to blood an important hormone--leptin--became the study object of particular interest. PMID: 12754787 [PubMed - indexed for MEDLINE] 4488. IUBMB Life. 2003 Feb;55(2):67-70. Anti-retroviral protease inhibitors--'a two edged sword?'. Germinario RJ(1). Author information: (1)Lady Davis Institute for Medical Research, S.M.B.D. Jewish General Hospital, Montreal, Quebec, Canada. ralph.germinario@mcgill.ca The use of anti-retroviral protease inhibitors in combination with nucleoside analog or non nucleoside reverse transcriptase inhibitors (HAART) has led to dramatic decreases in the mortality seen with HIV infected patients. In concert with these treatment regimens, especially with the inclusion of the anti-retroviral protease inhibitors (PI), a complex series of metabolic complications occurred. These included alterations of fat and carbohydrate metabolism. In some patients, one could observe either lipoatrophy (fat wasting) as well as lipohypertrophy (fat deposition) or both. The problem is that the lack of a case definition of the altered fat metabolism confuses diagnoses. In vitro, interference with fat cell differentiation has been demonstrated by PI. Further, in vitro studies demonstrate that indinavir, a PI currently used in HIV treatment, can interact with the insulin responsive glucose transporter (GLUT4). The activity of the GLUT4 is inhibited by indinavir and eventual insulin resistance has been shown (i.e. in vivo and in vitro). Also, controversy exists regarding insulin signaling in fat cells. Finally, the relationships between hyperlipidemia and/or lipolysis and altered carbohydrate metabolism (i.e. mild glucose intolerance, insulin resistance) suggest an association with cardiovascular risk in protease treated patients (Metabolic Syndrome X). In short, while multiple problems exist, no one mechanism can account for the changes observed. PMID: 12749688 [PubMed - indexed for MEDLINE] 4489. Nihon Naika Gakkai Zasshi. 2003 Apr 10;92(4):629-34. [Current topics in endocrinology: blood vessels and bones]. [Article in Japanese] Koshiyama H. PMID: 12746964 [PubMed - indexed for MEDLINE] 4490. Endocrinology. 2003 Jun;144(6):2195-200. Minireview: adiposity, inflammation, and atherogenesis. Lyon CJ(1), Law RE, Hsueh WA. Author information: (1)Division of Endocrinology, Diabetes, and Hypertension, University of California at Los Angeles, Los Angeles, California 90095-7073, USA. Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown regulate, directly or indirectly, a number of the processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Several adipokines are preferentially expressed in visceral adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Not surprisingly, approaches that reduce adipose tissue depots, including surgical fat removal, exercise, and reduced caloric intake, improve proinflammatory adipokine levels and reduce the severity of their resultant pathologies. Systemic adipokine levels can also be favorably altered by treatment with several of the existing drug classes used to treat insulin resistance, hypertension, and hypercholesterolemia. Greater understanding of adipokine regulation, however, should result in the design of improved treatment strategies to control disease states associated with increase adiposity, an important outcome in view of the growing worldwide epidemic of obesity. PMID: 12746274 [PubMed - indexed for MEDLINE] 4491. Drugs Today (Barc). 2003 Apr;39(4):287-95. The role of uncoupling protein 2 in the development of type 2 diabetes. Langin D(1). Author information: (1)Institut Louis Bugnard, Unite Recherches sur les Obesites INSERM U586, Toulouse, France. Uncoupling proteins (UCP) are carriers expressed in the mitochondrial inner membrane that uncouple oxygen consumption by the respiratory chain from ATP synthesis. UCP2 is a member of the multigenic UCP family that is expressed in a wide range of tissues and organs. Possible functions of UCP2 include control of ATP synthesis, regulation of fatty acid metabolism and control of reactive oxygen species production. UCP2 expression in tissues involved in lipid and energy metabolism and mapping of the gene to a region linked to obesity and hyperinsulinemia prompted studies on the involvement of UCP2 in metabolic disorders, and especially in type 2 diabetes. In human adipose tissue and skeletal muscle, UCP2 expression is increased during fasting. The carrier was shown to be under the control of fatty acids and thyroid hormones in vivo. An upregulation has been observed in the liver during high-fat feeding and obesity. However, data in UCP2 gene knockout mice do not support a role for UCP2 in steatohepatitis. The most compelling metabolic role of UCP2 comes from studies in pancreatic beta cells. Overexpression in isolated pancreatic islets results in decreased ATP content and blunted glucose-stimulated insulin secretion. UCP2-deficient mice show an increased ATP level and an enhanced insulin secretion. Lack of UCP2 dramatically improves insulin secretion and decreases hyperglycemia in leptin-deficient mice. The role of UCP2 in the control of insulin secretion constitutes, to date, the most pertinent path to investigate in a therapeutic perspective. Prous Science 2003. All rights reserved. PMID: 12743644 [PubMed - indexed for MEDLINE] 4492. Prog Retin Eye Res. 2003 Jul;22(4):545-62. Functions of insulin and insulin receptor signaling in retina: possible implications for diabetic retinopathy. Reiter CE(1), Gardner TW. Author information: (1)Department of Cellular and Molecular Physiology, The Ulerich Ophthalmology Research Center, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033 USA. Insulin action regulates the metabolic functions of the classically insulin-responsive tissues: liver, adipose, and skeletal muscle. Evidence also suggests that insulin acts on neural tissue and can modulate neural metabolism, synapse activity, and feeding behaviors. Insulin receptors are expressed on both the vasculature and neurons of the retina, but their functions are not completely defined. Insulin action stimulates neuronal development, differentiation, growth, and survival, rather than stimulating nutrient metabolism, e.g., glucose uptake as in skeletal muscle. Insulin receptors from retinal neurons and blood vessels share many similar properties with insulin receptors from other peripheral tissues, and retinal neurons express numerous proteins that are attributed to the insulin signaling cascade as in other tissues. However, undefined neuron-specific signals downstream of the insulin receptor are likely to also exist. This review compares retinal insulin action to that of peripheral tissues, and demonstrates that the retina is an insulin-sensitive tissue. The review also addresses the hypothesis that dysfunctional insulin receptor signaling in the retina contributes to cell dysfunction and death in retinal diseases. PMID: 12742394 [PubMed - indexed for MEDLINE] 4493. J Cardiovasc Electrophysiol. 2003 Apr;14(4):422-30. Pericardial anatomy for the interventional electrophysiologist. D'Avila A(1), Scanavacca M, Sosa E, Ruskin JN, Reddy VY. Author information: (1)Cardiac Arrhythmia Service, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts 02114, USA. Investigators are beginning to exploit the pericardial space for a number of cardiovascular applications, including catheter ablation of cardiac arrhythmias, cardiovascular drug therapy, and cardiac pacing. This review explores the anatomy of the pericardial space and the anatomic variants that may be encountered in this novel approach to the heart. PMID: 12741718 [PubMed - indexed for MEDLINE] 4494. Proc Nutr Soc. 2003 Feb;62(1):25-9. Whole grain consumption and weight gain: a review of the epidemiological evidence, potential mechanisms and opportunities for future research. Koh-Banerjee P(1), Rimm EB. Author information: (1)Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. pkoh@hsph.harvard.edu The epidemiological data that directly examine whole grain v. refined grain intake in relation to weight gain are sparse. However, recently reported studies offer insight into the potential role that whole grains may play in body-weight regulation due to the effects that the components of whole grains have on hormonal factors, satiety and satiation. In both clinical trials and observational studies the intake of whole-grain foods was inversely associated with plasma biomarkers of obesity, including insulin, C-peptide and leptin concentrations. Whole-grain foods tend to have low glycaemic index values, resulting in lower postprandial glucose responses and insulin demand. High insulin levels may promote obesity by altering adipose tissue physiology and by enhancing appetite. The fibre content of whole grains may also affect the secretion of gut hormones, independent of glycaemic response, that may act as satiety factors. Future studies may examine whether whole grain intake is directly related to body weight, and whether the associations are primarily driven by components of the grain, including dietary fibre, bran or germ. PMID: 12740053 [PubMed - indexed for MEDLINE] 4495. Lipids. 2003 Feb;38(2):139-46. Role of dietary calcium and dairy products in modulating adiposity. Zemel MB(1). Author information: (1)Department of Nutrition, The University of Tennessee, Nutrition Institute, Knoxville, Tennessee 37996, USA. mzemel@utk.edu Dietary calcium plays a pivotal role in the regulation of energy metabolism. High-calcium diets attenuate adipocyte lipid accretion and weight gain during overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Our studies of the agouti gene demonstrate a key role for intracellular Ca2+ in regulating adipocyte lipid metabolism and TG storage. Increased intracellular Ca2+ resulting in stimulation of lipogenic gene expression, and lipogenesis and suppression of lipolysis resulting in adipocyte lipid filling and increased adiposity. Moreover, we recently demonstrated that the increased calcitriol produced in response to low-calcium diets stimulates adipocyte Ca2+ influx and, consequently, promotes adiposity. Accordingly, suppressing calcitriol levels by increasing dietary calcium is an attractive target for obesity intervention. In support of this concept, transgenic mice expressing the agouti gene specifically in adipocytes (a human-like pattern) respond to low-calcium diets with accelerated weight gain and fat accretion, whereas high-calcium diets markedly inhibit lipogenesis, accelerate lipolysis, increase thermogenesis, and suppress fat accretion and weight gain in animals maintained at identical caloric intakes. Further, low-calcium diets impede body fat loss, whereas high-calcium diets markedly accelerate fat loss in transgenic mice subjected to caloric restriction. Dairy sources of calcium exert markedly greater effects in attenuating weight and fat gain and accelerating fat loss. This augmented effect of dairy products is likely due to additional bioactive compounds in dairy that act synergistically with calcium to attenuate adiposity. These concepts are confirmed by both epidemiological and clinical data, which demonstrate that increasing dietary calcium results in significant reductions in adipose tissue mass in obese humans in the absence of caloric restriction and markedly accelerates the weight and body fat loss secondary to caloric restriction, whereas dairy products exert significantly greater effects. These data indicate an important role for dairy products in both the prevention and treatment of obesity. PMID: 12733746 [PubMed - indexed for MEDLINE] 4496. Ann Endocrinol (Paris). 2002 Dec;63(6 Pt 2):S7-14. [To burn or to store]. [Article in French] Ricquier D(1). Author information: (1)CNRS-UPR 9078, Institut de Recherche Necker-Enfants Malades 9, rue Jules-Hetzel-92190 Meudon. ricquier@infobiogen.fr Energy exists as organic molecules and heat in living organisms. In adult mammals, body weight and fat content remain unchanged if energy intake is strictly equivalent to energy expenditure. In other words, regulation of body weight requires energy of foods to be entirely dissipated as heat. Imbalance between ingested energy and thermogenesis induces obesity or thinness. Alterations of food intake or energy expenditure represent the two causes of body weight disturbance. It is accepted that individuals differ in food efficiency i.e. ability to metabolize foods and store fat or totally burn nutrients. Mechanisms of food efficiency and futile cycles are presented. I started my research work analysing thermogenic mechanism in brown adipose tissue. Actually, in addition to white adipose tissue which is the major type of adipose tissue, mammals own another type of adipose tissue referred to as brown adipose tissue. This later tissue is an activatable thermogenic organ which oxidizes fatty acids and releases heat in blood stream. Brown fat is activated during exposure to the cold (in rodents), at birth, and during arousal in hibernators. My initial work helped to characterize a mitochondrial protein named uncoupling protein or UCP which is responsible for activation of fatty acid oxidation and heat production in brown adipocytes. Actually, in most cells, fifty per cent of oxidation energy is recovered as ATP in mitochondria through the process of coupling of respiration to ADP phosphorylation. In contrast to mitochondria of most tissues, brown adipocyte mitochondria can escape the obligatorily coupling of respiration and waste almost ninety per cent of respiration energy as thermogenesis. UCP characterization and its molecular cloning as well as antibodies obtention were used to better understand cellular thermogenesis. Brown adipocytes were identified in babies and adult patients with pheochromocytoma. More recently, research on the brown fat UCP helped us to identify UCP2, a UCP homolog present in most human and animal tissues. A family of UCPs exist in animals and plants. These UCPs may function as mitochondrial uncouplers. However, the ancient function of the UCPs may be rather associated to adaptation to oxygen and control of free radicals than to thermogenesis. Further studies of UCPs will improve the knowledge of mitochondrial metabolism and substrate oxidation. In other respects, analysis of molecular mechanisms controlling respiration uncoupling may contribute to new strategies of treatment of metabolic disorders such as obesity. PMID: 12733325 [PubMed - indexed for MEDLINE] 4497. Przegl Lek. 2002;59(12):1024-7. [Leptin and thyroid hormones]. [Article in Polish] Kotulska A(1), Kucharz EJ. Author information: (1)Katedra i Klinika Chorób Wewnetrznych i Reumatologii, Slaskiej Akademii Medycznej, 40-635 Katowice, ul. Ziołowa 45/47. Leptin, a satiety hormone is a protein produced by the adipose tissue that regulates appetite and energetic balance of the body. Results of investigations of serum leptin in patients with hyperthyroidism or hypothyroidism are controversial. Influence of thyroid hormones on leptin secretion is complex and partially unrecognized. PMID: 12731381 [PubMed - indexed for MEDLINE] 4498. J Nutr. 2003 May;133(5 Suppl 2):1674S-1683S. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. Catalano PM(1), Kirwan JP, Haugel-de Mouzon S, King J. Author information: (1)Department of Reproductive Biology, Schwartz Center for Metabolism and Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, OH 44109, USA. pcatalano@metrohealth.org Gestational diabetes and obesity are the common metabolic abnormalities occurring during pregnancy. Decreased maternal pregravid insulin sensitivity (insulin resistance) coupled with an inadequate insulin response are the pathophysiological mechanisms underlying the development of gestational diabetes. Insulin-regulated carbohydrate, lipid and protein metabolism are all affected to a variable degree. Decreased maternal insulin sensitivity in women with gestational diabetes may increase nutrient availability to the fetus, possibly accounting for an increased risk of fetal overgrowth and adiposity. Epidemiological studies from Europe show an increased risk of the insulin resistance syndrome in adults who were low birth weight at delivery. However, in the United States over the past 20 y there has been a significant 33% increase in the incidence of type 2 diabetes, which has been associated with a parallel increase in obesity. All age groups have been affected but the most dramatic increases have occurred in adolescents. The relationship between decreased maternal insulin sensitivity and fetal overgrowth particularly in obese women and women with gestational diabetes may help explain the increased incidence of adolescent obesity and related glucose intolerance in the offspring of these women. In this review, we address 1) the pathophysiology of gestational diabetes, 2) the changes in maternal insulin sensitivity during pregnancy that effect maternal accretion of adipose tissue and energy expenditure, 3) the influence of maternal metabolic environment on fetal growth, 4) the life-long effect of being born at either extreme of the birth weight continuum and 5) micronutrients and decreased insulin sensitivity during pregnancy. PMID: 12730484 [PubMed - indexed for MEDLINE] 4499. J Clin Endocrinol Metab. 2003 May;88(5):1961-76. Clinical review 159: Human immunodeficiency virus/highly active antiretroviral therapy-associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies. Leow MK(1), Addy CL, Mantzoros CS. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. PMID: 12727939 [PubMed - indexed for MEDLINE] 4500. J Clin Endocrinol Metab. 2003 May;88(5):1939-46. Clinical review 157: Pathophysiology of Graves' ophthalmopathy: the cycle of disease. Bahn RS(1). Author information: (1)Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota 55905, USA. bahn.rebecca@mayo.edu PMID: 12727937 [PubMed - indexed for MEDLINE] 4501. Minerva Endocrinol. 2003 Jun;28(2):155-67. Neuroendocrine regulation of feeding. Vettor R(1), Fabris R, Pagano C, Federspil G. Author information: (1)Department of Medical and Surgical Sciences, University of Padua, Padua, Italy. roberto.vettor@unipd.it Eating behavior is a complex phenomenon, resulting from the interaction in the hypothalamus and other brain regions, of many factors, including olfactory, visual, emotional and higher cognitive inputs, as well as several nutritional signals coming from the periphery. These signals modulate the expression of neurotransmitters and neuropeptides with orexigenic and anorexigenic activity. Observations performed more than 5 decades ago with brain lesioning and stimulation experiments led to the proposal of the dual centre hypothesis in the central control of energy balance. On the basis of these studies the "satiety centre" was located in the ventromedial hypothalamic nucleus, since lesions of this region caused overfeeding, while its electrical stimulation suppressed eating. On the contrary, lesioning or stimulation of the lateral hypothalamus elicited the opposite set of responses, thus leading to the conclusion that this area represented the "feeding centre". The subsequent expansion of our knowledge of specific neuronal subpopulations involved in energy homeostasis has replaced the notion of specific "centres" controlling energy balance with that of discrete neuronal pathways fully integrated in a more complex neuronal network. This review will focus on the central and peripheral factors thought to be involved in the neuroendocrine control of feeding behavior. PMID: 12717345 [PubMed - indexed for MEDLINE] 4502. Paediatr Drugs. 2003;5(5):291-9. Insulin resistance syndrome in children : pathophysiology and potential management strategies. Decsi T(1), Molnár D. Author information: (1)Department of Paediatrics, University of Pécs, Pécs, Hungary. tamas.decsi@oak.pte.hu The simultaneous presence of various cardiovascular risk factors in the same individual is not rare, even in the pediatric age group. The clustering of risk factors can be termed insulin resistance syndrome (IRS) because of the putative central role of tissue insulin insensitivity in the background of the inter-related metabolic disturbances. Fasting hyperinsulinemia, impaired glucose tolerance, dyslipidemia, and hypertension are considered to represent the basic abnormalities of IRS. The most prevalent related disturbances are increased plasma levels of plasminogen activator inhibitor-1, fibrinogen, uric acid, homocysteine, and C-reactive protein, as well as visceral adiposity, microalbuminuria, disturbed essential fatty acid metabolism, low availability of lipid-soluble antioxidant vitamins, and enhanced expression of tumor necrosis factor-alpha in adipose tissues. Certain genetic abnormalities have been associated with IRS, but explain only a small part of the variability in insulin resistance. The exact prevalence of IRS in children remains to be defined; it was found to be 9% in one survey among children with obesity seeking medical attention. Modification of lifestyle, i.e. reduction of energy intake and enhancement of physical activity, are unquestionable prerequisites for long-term success in the management of IRS. In at least two randomized controlled studies, metformin proved to be clinically effective in increasing insulin sensitivity in hyperinsulinemic, nondiabetic adolescents. Thiazolidinediones have been successfully tested for the treatment of insulin resistance in adults, but not in children as yet. Prevention of the development of IRS in children is obviously of great significance for the health status of the community. However, the efficacy of various preventive approaches should be investigated further in carefully designed controlled trials. PMID: 12716216 [PubMed - indexed for MEDLINE] 4503. Natl Med J India. 2003 Jan-Feb;16(1):3-7. Body composition and the metabolic syndrome in Asian Indians: a saga of multiple adversities. Misra A. PMID: 12715948 [PubMed - indexed for MEDLINE] 4504. Arch Physiol Biochem. 2003 Feb;111(1):45-52. Maternal nutrient restriction during placental growth, programming of fetal adiposity and juvenile blood pressure control. Symonds ME(1), Gopalakrishnan G, Bispham J, Pearce S, Dandrea J, Mostyn A, Ramsay MM, Stephenson T. Author information: (1)School of Human Development, University Hospital, Nottingham, UK. Michael.Symonds@nottingham.ac.uk Comment in Arch Physiol Biochem. 2003 Feb;111(1):3-7. Epidemiological and experimental studies have demonstrated that maternal undernutrition during pregnancy is associated with abnormal placental growth. In sheep, maternal nutrient restriction over the period of rapid placental growth (30-80 days) restricts placentome growth. Then following adequate nutrition up to term (147 days), placental mass is greater in association with a higher total abundance of the predominant placental glucose transporter-1. The resulting lambs are larger at birth, have heavier kidneys with an increased expression of the glucocorticoid-responsive type 1 angiotensin II receptor. Near to term, these fetuses possess more adipose tissue, the endocrine sensitivity of which is markedly enhanced. For example, the abundance of mRNA for 11beta-hydroxysteroid dehydrogenase type 1, which catalyses the conversion of cortisone to bio-active cortisol is increased. This is associated with a higher abundance of both leptin and glucocorticoid receptor mRNA. At 6 months of age, the juvenile offspring of nutrient restricted ewes have lower resting blood pressure that was positively correlated with plasma cortisol concentration, suggesting their blood pressure could be more strongly driven by circulating cortisol. These offspring also exhibited a greater pressor response to vasoconstrictor challenges, but showed no difference in vasodilatory response. At this age, the kidney weight was similar between groups, but the abundance of cytochrome c in kidney mitochondria was enhanced in lambs born to nutrient restricted ewes that could indicate increased mitochondrial activity. Reduced maternal nutrition during the period of rapid placental growth may therefore contribute to hypertension in later life through physiological and vascular adaptations during fetal life. PMID: 12715274 [PubMed - indexed for MEDLINE] 4505. Trends Endocrinol Metab. 2003 May-Jun;14(4):169-75. Novel targets and therapeutic strategies for type 2 diabetes. Morral N(1). Author information: (1)Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. nuria.morral@mssm.edu The number of people diagnosed with type 2 diabetes mellitus (T2DM) is increasing at an alarming rate in western societies and has become a major health concern. During the past decade, studies using transgenic animals, gene transfer and pharmacological agents have yielded many data that have helped understand the molecular alterations characteristic of T2DM. This has opened the possibility for the development of potentially more-effective therapies, mainly focused on attenuating hepatic glucose production, enhancing glucose-dependent insulin secretion, enhancing the insulin signal transduction pathway, inhibiting lipolysis from the adipose tissue and promoting fatty acid oxidation. PMID: 12714277 [PubMed - indexed for MEDLINE] 4506. Nutrition. 2003 May;19(5):457-66. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Misra A(1), Vikram NK. Author information: (1)Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. anoopmisra@hotmail.com OBJECTIVES: To highlight the clinical and metabolic correlates of abdominal obesity and various abdominal adipose tissue depots. METHODS: We researched the topic using the search terms abdominal obesity, central obesity, visceral obesity, regional obesity, and subcutaneous adipose tissue from MEDLINE (National Library of Medicine, Bethesda, MD), PubMed (National Library of Medicine, Bethesda, MD), Current Contents (Institute for Scientific Information, Thomson Scientific, Philadelphia, PA), and using manual search for the cited references. RESULTS: Abdominal obesity contributes significantly to the metabolic perturbations and cardiovascular risk in human beings. Abdominal adipose tissue depots (intraabdominal and subcutaneous [deep subcutaneous, posterior subcutaneous]) are metabolically active and appear to be important for the pathogenesis of insulin resistance, dyslipidemia, glucose intolerance, hypertension, hypercoagulable state, and cardiovascular risk. Adipocyte anatomy (size), physiology (growth, catecholamine sensitivity, lipolysis, insulin action), and biochemistry (leptin, plasminogen activator inhibitor-1, cytokines, renin-angiotensin system) are reported to be relatively site-specific, highlighting unique roles of regional adipose tissue depots. CONCLUSIONS: Several physiological and metabolic parameters are site-specific in abdominal adipose tissue. The epidemiological, clinical, and prognostic significance and relative importance of the regional adipose tissue depots, however, remain to be ascertained. PMID: 12714101 [PubMed - indexed for MEDLINE] 4507. Wei Sheng Yan Jiu. 1999 Sep 30;28(5):318-20. [Leptin and the feedback regulation of body weight]. [Article in Chinese] Wang X(1), Ye G, Sun J. Author information: (1)Institute of Child and Adolescent Health, Beijing Medical University, Beijing 100083, China. Body weight may be controlled by a negative feedback loop. Recent studies have identified that the ob gene product, leptin, apparently and exclusively expressed in adipose tissue, is a part of the negative feedback loop. Leptin is proposed to act as an afferent signal in the negative feedback loop to hypothalamus that limiting food-intake, controlling energy homeostasis and regulating the mass of adipose tissue. The dificiency of or resistance to leptin causes severe obesity. PMID: 12712709 [PubMed - indexed for MEDLINE] 4508. Novartis Found Symp. 2003;249:86-96; discussion 96-102, 170-4, 239-41. Mesenchymal stem cell therapy in joint disease. Barry FP(1). Author information: (1)Osiris Therapeutics Inc., 2001 Aliceanns Street, Baltimore, MD 21231, USA. Mesenchymal stem cells have the capacity to differentiate into a variety of connective tissue cells including bone, cartilage, tendon, muscle and adipose tissue. These multipotent cells have been isolated from bone marrow and from other adult tissues including skeletal muscle, fat and synovium. Because of their multipotentiality and capacity for self renewal adult stem cells may represent units of active regeneration of tissues damaged as a result of trauma or disease. In certain degenerative diseases such as osteoarthritis (OA) stem cells are depleted, and have reduced proliferative capacity and reduced ability to differentiate. The delivery of stem cells to these individuals may therefore enhance repair or inhibit the progressive destruction of the joint. We have developed methods for the delivery of mesenchymal stem cell preparations taken from bone marrow to the injured knee joint. This treatment has the potential to stimulate regeneration of cartilage and retard the progressive destruction of the joint that typically occurs following injury. PMID: 12708651 [PubMed - indexed for MEDLINE] 4509. Eur Rev Med Pharmacol Sci. 2002 Mar-Jun;6(2-3):27-32. Pathophysiology of obesity-induced insulin resistance and type 2 diabetes mellitus. Tataranni PA. Erratum in Eur Rev Med Pharmacol Sci. 2003 May-Jun;7(3):74. PMID: 12708607 [PubMed - indexed for MEDLINE] 4510. Cell. 2003 Apr 18;113(2):144-5. Muscle or fat? Rho bridges the GAP. Saltiel AR(1). Author information: (1)Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. Comment on Cell. 2003 Apr 18;113(2):147-58. Mesenchymal stem cells can differentiate into muscle or fat cells, depending on the exposure to growth factors. The Rho GTPase appears to play a crucial role in this decision of cellular fate, promoting myogenesis and inhibiting adipogenesis. PMID: 12705863 [PubMed - indexed for MEDLINE] 4511. Int J Occup Med Environ Health. 2003;16(1):7-20. Global surveillance of DDT and DDE levels in human tissues. Jaga K(1), Dharmani C. Author information: (1)Montrose Research Corporation, VA Hudson Valley Health Care System, Montrose, New York, USA. KUSHIK_JAGA@NYMC.edu Corrected and republished in Int J Occup Med Environ Health. 2006;19(1):83. The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) was initially introduced for control of vector-borne discases It was banned in the United States by the Environmental Protection Agency in 1972 because of potential harmful effects on humans, wildlife and the environment. Since it is a potential human carcinogen, the United Nations Environmental Program (UNEP) has recently restricted the use of DDT in developing countries until alternative methods of vector control are sought. DDT and its metabolite, dichlorodiphenyltrichloroethylene (DDE) are lipid soluble, and bioaccumulate more in human adipose tissue, than breast milk and serum. This article is a review of DDT and DDE levels in human tissues from different countries in the world. Data on p,p'-DDT and p,p'-DDE levels in human adipose tissue, breast milk and serum were selected from more recent literature. It was discovered that countries in Africa, Asia, and Latin America with more recent exposure to DDT and DDE have higher levels in human tissue than in Europe and the United States. The global concern for DDT and DDE is the environmental spread and persistence in the food chain. Hypothetically, there is a potential risk of harmful effects of DDT and DDE to human health. UNEP has cautiously taken action to protect human health, the environment and the earth from further destruction by persistent organic pollutants. Further exposure to DDT should be prevented to achieve this goal. PMID: 12705713 [PubMed - indexed for MEDLINE] 4512. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5384-9. Epub 2003 Apr 17. Cancer cachexia: its correlations and causes. Rubin H(1). Author information: (1)Department of Molecular and Cell Biology, Life Sciences Addition, University of California, Berkeley, CA 94720-3200, USA. hrubin@uclink4.berkeley.edu Cancer cachexia involves the loss of weight, mainly in skeletal muscle and adipose tissue, that is not caused simply by anorexia. The syndrome includes anemia and immunosuppression along with a number of biochemical changes indicating systemic effects of the cancer. It is a major factor in morbidity and mortality from cancer. For 30 years beginning in 1948, a large number of studies reported isolation from many tumors of a heterogeneous group of small peptides, generally labeled toxohormone, that caused various correlates of cachexia shortly after injection into mice. Interest in toxohormone-like peptides then fell off for diverse reasons that had little to do with their clinical significance and was shifted to cytokines, ILs, and ectopic hormones with catabolic consequences that were sporadically found in tumors. At the same time, evidence was accumulating for an important role of pericellular proteases in driving progressive stages of neoplastic development. A central part of that evidence was the inhibition of transformation-related changes by protease inhibitors, particularly the combination present in fetal bovine serum, which fully suppressed the expression of the transformed phenotype in discrete foci of chicken embryo fibroblasts (CEF) infected by Rous sarcoma virus against a confluent background of uninfected CEF. In contrast, CEF cultures heavily infected with Rous sarcoma virus in the same medium underwent pervasive transformation, which was correlated with the release of low molecular weight cytotoxic substances. Reevaluation of all of the evidence supports a central role for proteolytically generated peptides derived from tumors in producing cancer cachexia. PMCID: PMC154354 PMID: 12702753 [PubMed - indexed for MEDLINE] 4513. Front Biosci. 2003 May 1;8:s401-9. Regulation of GLUT4 expression in vivo and in vitro. Olson AL(1), Knight JB. Author information: (1)Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA. ann-olson@ouhsc.edu The GLUT4 gene is subject to complex tissue-specific and metabolic regulation that has a profound impact on insulin-mediated glucose disposal. The regulation of this gene is of special clinical interest because insulin-mediated glucose homeostasis is highly sensitive to the levels of GLUT4 protein in muscle and adipose tissue. For this reason, the mechanisms of regulated expression of the GLUT4 gene have been intensively studied over the past decade. Understanding the transcriptional mechanisms that underlie the regulated expression of this highly differentiated gene have been slow to emerge, due to the paucity of suitable model systems available for detailed investigation. The development of transgenic mouse models to understand the mechanisms of transcriptional regulation has greatly enhanced our understanding of this gene. Information gained about the regulation of the GLUT4 gene has provided insight into mechanisms by which complex gene regulation occurs through a small number of cis-acting regulatory elements. PMID: 12700047 [PubMed - indexed for MEDLINE] 4514. Reprod Suppl. 2002;59:115-29. Potential signals mediating the maintenance of reproductive activity during the non-breeding season of the mare. Fitzgerald BP(1), Reedy SE, Sessions DR, Powell DM, McManus CJ. Author information: (1)Department of Veterinary Science, Maxwell Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA. bfitz@pop.uky.edu The seasonal nature of reproductive activity in mares is widely accepted and considerable attention has focused on the mechanisms that lead to the initiation of the breeding season. In contrast, considerably less information is available about the termination of the breeding season. It is interesting to note that each winter a sub-population of mares continues to undergo oestrous cyclicity during the non-breeding season. Continuation of reproductive activity during the winter occurs most frequently in mares that maintain a non-pregnant condition in successive years. The maintenance of a non-pregnant condition in successive years leads to an increase in the percentage of total body fat and it has been proposed that the degree of adiposity may be a determinant of reproductive activity during the winter months. To investigate this hypothesis we have manipulated fat stores by either pharmacological treatments or feed restriction. The studies described in this review demonstrate that manipulation of body fat during the autumn months fails to modify the mechanisms that lead to anoestrus or the proportion of mares that continues to show oestrous cyclicity during the winter months. On the basis of these and related studies two hypotheses are presented that may serve as a template for future work. The first hypothesis proposes that one aspect of the long-term regulation of seasonal reproductive rhythms in mares, specifically anoestrus, may reflect recognition of the availability of metabolic fuels before perception of a change in photoperiod. Alternatively, energy availability may need to reach a critical value before a presumptive inhibitory daylength signal initiates termination of the breeding season. This review describes previous and current studies that have led to development of these proposals. PMID: 12698977 [PubMed - indexed for MEDLINE] 4515. Cas Lek Cesk. 2003 Feb;142(2):80-3. [Recently discovered hormones with a role in energy homeostasis]. [Article in Czech] Krykorková I(1), Nedvídková J. Author information: (1)Prírodovĕdecká fakulta UK, Endokrinologický ústav, Praha. ivana.krykorkova@email.cz Adipocytal hormones resistin and adiponectin and gastric peptide ghrelin are recently discovered hormones, which are considered to take part in energy metabolism regulation. Resistin is expressed in adipose tissue only and its increased levels could cause insulin resistance and thus link obesity with type 2 diabetes. Adiponectin, as well as resistin, are products of genes, expressed in adipose tissue. Adiponectin could prevent development of aterosclerosis and it could play a role in anti-inflammatory reactions. Ghrelin is produced mainly in the stomach. Beside its role in long-term regulation of energy metabolism, it is involved in the short-term regulation of feeding. Main roles of resistin, adiponectin and ghrelin are summarised in the presented overview. PMID: 12698533 [PubMed - indexed for MEDLINE] 4516. G Ital Med Lav Ergon. 2003 Jan-Mar;25(1):61-7. [Polychlorobiphenyls: reference values]. [Article in Italian] Pavan I(1), Baroffio C, Passini V, Bilei T, Pira E, Minoia C. Author information: (1)Dipartimento di Traumatologia Ortopedia e Medicina del Lavoro Università di Torino. The purpose of this work is to compare the PCB values in blood, serum and adipose tissue of non-exposed people over the last twenty years of scientific literature in order to establish whether the determination of single congeners is better then the evaluation of the total PCB amount moreover an analytical strategy useful to define a reference value for non-exposed Italian population has been evaluated. In the literature very variable results were found for the determination of total PCBs in blood, in serum or adipose tissue. We suggest to determine only the amount of the most toxic congeners of PCBs (28, 52, 77, 101, 118, 126, 138, 153, 169, 180) by using the HRGC/ECD as analytical technique. PMID: 12696486 [PubMed - indexed for MEDLINE] 4517. Nihon Shokakibyo Gakkai Zasshi. 2003 Mar;100(3):298-305. [Molecular mechanisms and clinical implications for the regulatory feedback loop of feeding and body adiposity]. [Article in Japanese] Inui A(1). Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine. PMID: 12696170 [PubMed - indexed for MEDLINE] 4518. Kidney Int Suppl. 2003 May;(84):S65-8. Adipose tissue as a source of inflammatory cytokines in health and disease: focus on end-stage renal disease. Zoccali C(1), Mallamaci F, Tripepi G. Author information: (1)Laboratorio di Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell'Ipertensione Arteriosa, Istituto di Biomedicina, Reggio Calabria, Italy. Carmine.zoccali@tin.it Adipose tissue is a necessary survival characteristic of species that do not have constant access to food. TNF-alpha is a very fundamental "internal regulator" (intra-system) of adipose tissue metabolism, and IL-6 and IL-1 beta are relevant control factors, as well. Leptin and IL-6, but not TNF-alpha, appear to be the major signals linking adipose tissue to the systemic immunologic response. In ESRD, it has been coherently observed that acute-phase reactants like CRP and serum amyloid A are independently associated to atherosclerosis, death, and cardiovascular complications. Leptin is inversely related with plasma creatinine, suggesting that reduced renal clearance is a primary factor responsible for hyperleptinemia in ESRD. On the other hand, this adipose tissue hormone behaves as an inverse acute-phase reactant (i.e., it decreases during spontaneous episodes of the acute-phase response). Dialysis patients with hyperleptinemia have more severe degrees of insulin resistance but further studies are required to see whether leptin plays a role in insulin resistance in these patients. The most abundant protein synthesized in the adipose tissue, adiponectin, is inversely related to metabolic risk factors like glucose, triglycerides, insulin, and HDL cholesterol in uremic patients, suggesting that this cytokine is a protective factor for the cardiovascular system. Accordingly, plasma adiponectin is an independent, inverse predictor of incident cardiovascular events in dialysis patients. PMID: 12694312 [PubMed - indexed for MEDLINE] 4519. Proc Nutr Soc. 2002 Nov;61(4):489-96. Recent advances in the physiology of eating. French S(1), Castiglione K. Author information: (1)Masterfoods (a division of Mars UK Ltd), Dundee Road, Slough SL1 4JX, UK. Stephen.French@eu.effem.com Since the discovery of the protein product of the ob/ob gene, leptin, knowledge of the neurochemical pathways involved in the regulation of feeding has increased enormously. Our understanding of the mechanisms regulating food intake in man has also progressed greatly over a similar time span. Previous research into the regulation of food intake has largely proceeded through a reductionist approach, defining ever-smaller components of these mechanisms. This research strategy has been very productive and instructive, and has yielded a great deal of information on the specific putative components linking energy status and food intake. However, to fully understand the regulation of feeding it is important that these components are systematically reconstructed to investigate relevant interactions. In the present review recent data relating to interactions between systems proposed to be involved in feeding regulation will be highlighted. The review will be directed predominantly (but not exclusively) towards the regulation of human feeding. PMID: 12691178 [PubMed - indexed for MEDLINE] 4520. Proc Nutr Soc. 2002 Nov;61(4):473-87. Does body mass play a role in the regulation of food intake? Speakman JR(1), Stubbs RJ, Mercer JG. Author information: (1)Aberdeen Centre for Energy Regulation and Obesity, Division of Appetite and Energy Balance, Rowett Research Institute, Aberdeen AB21 9SB, UK. J.Speakman@rri.sari.ac.uk It is widely believed that body fatness (and hence total body mass) is regulated by a lipostatic feedback system. This system is suggested to involve at least one peripheral signalling compound, which signals to the brain the current size of body fat stores. In the brain the level of the signal is compared with a desirable target level, and food intake and energy expenditure are then regulated to effect changes in the size of body fat stores. There is considerable support for this theory at several different levels of investigation. Patterns of body-mass change in subjects forced into energy imbalance seem to demonstrate homeostasis, and long-term changes in body mass are minor compared with the potential changes that might result from energy imbalance. Molecular studies of signalling compounds have suggested a putative lipostatic signal (leptin) and a complex network of downstream processing events in the brain, polymorphisms of which lead to disruption of body-mass regulation. This network of neuropeptides provides a rich seam of potential pharmaceutical targets for the control of obesity. Despite this consistent explanation for the observed phenomena at several different levels of enquiry, there are alternative explanations. In the present paper we explore the possibility that the existence of lipostatic regulation of body fatness is an illusion generated by the links between body mass and energy expenditure and responses to energy imbalance that are independent of body mass. Using computer-based models of temporal patterns in energy balance we show that common patterns of change in body mass following perturbation can be adequately explained by this 'non-lipostatic' model. This model has some important implications for the interpretations that we place on the molecular events in the brain, and ultimately in the search for pharmaceutical agents for alleviation of obesity. PMID: 12691177 [PubMed - indexed for MEDLINE] 4521. Proc Nutr Soc. 2002 Nov;61(4):441-6. Mapping quantitative trait loci and identification of genes that control fatness in poultry. Burt DW(1), Hocking PM. Author information: (1)Department of Genomics and Bioinformatics, Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, UK. Dave.Burt@bbsrc.ac.uk Chicken genomics has benefited from the rapid technological advances in the genomics of model organisms and man. A number of resources and approaches are now well established, in the chicken, including genetic markers and maps (both genetic and physical), quantitative trait loci mapping, comparative mapping, expressed sequence tag and bacterial artificial chromosome resources, and physical mapping. In addition, the next phase of gene discovery, functional genomics, is underway. Progress in mapping quantitative trait loci for growth and fatness traits will be discussed, as an application of these new technologies and approaches in the study of avian physiology and genetics. PMID: 12691173 [PubMed - indexed for MEDLINE] 4522. Obes Res. 2003 Apr;11(4):496-506. Fetal origins of obesity. Oken E(1), Gillman MW. Author information: (1)Department of Ambulatory Care and Prevention, Harvard Medical School/Harvard Pilgrim Health Care, Boston, Massachusetts, USA. emily_oken@harvardpilgrim.org The worldwide epidemic of obesity continues unabated. Obesity is notoriously difficult to treat, and, thus, prevention is critical. A new paradigm for prevention, which evolved from the notion that environmental factors in utero may influence lifelong health, has emerged in recent years. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and BMI attained in later life. Although the data are limited by lack of information on potential confounders, these associations seem robust. Possible mechanisms include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, and pancreatic structure and function. Additionally, lower birth weight seems to be associated with later risk for central obesity, which also confers increased cardiovascular risk. This association may be mediated through changes in the hypothalamic pituitary axis, insulin secretion and sensing, and vascular responsiveness. The combination of lower birth weight and higher attained BMI is most strongly associated with later disease risk. We are faced with the seeming paradox of increased adiposity at both ends of the birth weight spectrum-higher BMI with higher birth weight and increased central obesity with lower birth weight. Future research on molecular genetics, intrauterine growth, growth trajectories after birth, and relationships of fat and lean mass will elucidate relationships between early life experiences and later body proportions. Prevention of obesity starting in childhood is critical and can have lifelong, perhaps multigenerational, impact. PMID: 12690076 [PubMed - indexed for MEDLINE] 4523. Prog Lipid Res. 2003 Jul;42(4):257-88. Selective mobilization of fatty acids from adipose tissue triacylglycerols. Raclot T(1). Author information: (1)Centre d'Ecologie et de Physiologie Energétiques, CNRS UPR 9010, associé à l'Université Louis Pasteur, 23 rue Becquerel, 67087 Strasbourg Cedex 2, France. thierry.raclot@c-strasbourg.fr Adipose tissue triacylglycerols represent the main storage of a wide spectrum of fatty acids differing by molecular structure. The release of individual fatty acids from adipose tissue is selective according to carbon chain length and unsaturation degree in vitro and in vivo in animal studies and also in humans. The mechanism of selective fatty acid mobilization from white fat cells is not known. Lipolysis is widely reported to work at a lipid-water interface where only small amounts of substrate are available. A preferential hydrolysis of a small triacylglycerol fraction enriched in certain triacylglycerol molecular species at the lipid-water interface and enzymological properties of hormone-sensitive lipase could explain the selective mobilization of fatty acids from fat cells. This selectivity could affect the individual fatty acid supply to tissues. PMID: 12689620 [PubMed - indexed for MEDLINE] 4524. Diabetologia. 2003 Mar;46(3):433-40. Epub 2003 Mar 14. Diabetes: mellitus or lipidus? Shafrir E(1), Raz I. Author information: (1)Department of Medicine, Diabetes Research Centre, Hadassah University Hospital, Ein Kerem, Jerusalem, 91120 Israel. shafrir@md.huji.ac.il Comment in Diabetologia. 2003 Nov;46(11):1586-7; author reply 1587. PMID: 12687345 [PubMed - indexed for MEDLINE] 4525. J Clin Endocrinol Metab. 2003 Apr;88(4):1417-27. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. Goran MI(1), Ball GD, Cruz ML. Author information: (1)Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. goran@usc.edu Overweight/obesity continues to increase in children and adolescents, and annual obesity-related hospital costs in 6-17 yr olds have reached 127 million dollars per year. Overweight children and adolescents are now being diagnosed with impaired glucose tolerance and type 2 diabetes, and they show early signs of the insulin resistance syndrome and cardiovascular risk. Several risk factors have been identified as contributors to the development of type 2 diabetes and cardiovascular risk in youth. These factors include increased body fat and abdominal fat, insulin resistance, ethnicity (with greater risk in African-American, Hispanic, and Native American children), and onset of puberty. There is no clear explanation of how these factors increase risk, but they appear to act in an additive fashion. We hypothesize that the constellation of these risk factors may be especially problematic during the critical period of adolescent development, especially in individuals who may have compromised beta-cell function and an inability to compensate for severe insulin resistance. Therefore, the purpose of this paper is to review the pathophysiology of type 2 diabetes and cardiovascular risk in obese children and adolescents. PMID: 12679416 [PubMed - indexed for MEDLINE] 4526. Curr Pharm Des. 2003;9(12):1023-31. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Chaldakov GN(1), Stankulov IS, Hristova M, Ghenev PI. Author information: (1)Division of Cell Biology, Department of Forensic Medicine, Medical University, BG-9002 Varna, Bulgaria. chaldakov@yahoo.com In recent years, the simple paradigm of adipose tissue as merely a fat store is rapidly evolving into a complex paradigm of this tissue as multipotential secretory organ, partitioned into a few large depots, including visceral and subcutaneous location, and many small depots, associated with a variety of organs in the human body. The major secretory compartment of adipose tissue consists of adipocytes, fibroblasts, and mast cells. These cells, using endocrine, paracrine and autocrine pathways, secrete multiple bioactive molecules, conceptualized as adipokines or adipocytokines. This review examines current information in adipobiology of various diseases besides obesity and related diseases such as type 2 diabetes, metabolic syndrome, and cardiovascular disease. Finally, we emphasize the possibilities for adipokine-targeted pharmacology in adiponectin (Acrp30, apM1, AdipoQ, GBP28), angiotensin II, estrogens, nerve growth factor, tumor necrosis factor-alpha, and also adipose mast cells. PMID: 12678860 [PubMed - indexed for MEDLINE] 4527. Int J Biochem Cell Biol. 2003 Jun;35(6):807-25. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Engeli S(1), Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiéra F, Sharma AM. Author information: (1)HELIOS Klinikum Berlin, Franz Volhard Clinic--Charité, Department of Nephrology and Hypertension, Humboldt University of Berlin, Wiltberg Strasse 50, Berlin 13125, Germany. engeli@fvk.charite-buch.de Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome. PMID: 12676168 [PubMed - indexed for MEDLINE] 4528. Diabet Med. 2003 Apr;20(4):255-68. Pathophysiological implications of insulin resistance on vascular endothelial function. Wheatcroft SB(1), Williams IL, Shah AM, Kearney MT. Author information: (1)Department of Cardiology, Guy's, King's & St Thomas' School of Medicine, King's College, London, UK. stephen.wheatcroft@kcl.ac.uk BACKGROUND: Insulin resistance is a key component of the insulin resistance syndrome and is a crucially important metabolic abnormality in Type 2 diabetes. Insulin-resistant individuals are at significantly increased risk of cardiovascular disease, although the underlying mechanisms remain incompletely understood. The endothelium is thought to play a critical role in maintaining vascular homeostasis, a process dependent on the balance between the production of nitric oxide, superoxide and other vasoactive substances. Endothelial dysfunction has been demonstrated in insulin-resistant states in animals and humans and may represent an important early event in the development of atherosclerosis. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signalling pathways common to both insulin action and nitric oxide production. Other potential unifying links include the roles of oxidant stress, endothelin, the renin angiotensin system and the secretion of hormones and cytokines by adipose tissue. Lifestyle measures and drug therapies which improve insulin sensitivity and ameliorate endothelial dysfunction may be important in delaying the progression to overt cardiovascular disease in at risk individuals. METHODS: We conducted a literature search using Medline, restricted to articles published in the English language between 1966 and the present, and reviewed bibliographies of relevant articles. An initial search strategy employing combinations of the MeSH terms: insulin resistance; endothelium, vascular; insulin; nitric oxide or hyperinsulinaemia produced over 300 references. Focused searches using keywords relevant to the molecular aspects of endothelial function and insulin signalling, and lifestyle or pharmacological interventions relevant to insulin resistance or endothelial function, produced over 300 further references. Abstracts of all references were screened before selecting those relevant to this review. PMID: 12675638 [PubMed - indexed for MEDLINE] 4529. Trends Endocrinol Metab. 2003 Apr;14(3):137-45. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Arner P(1). Author information: (1)Dept of Medicine, CME M63, Huddinge University Hospital, Stockholm, Sweden. peter.arner@medhs.ki.se Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and beta-cell dysfunction, including tumour necrosis factor alpha (TNF-alpha), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor gamma, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve beta-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-alpha and FFAs. PMID: 12670740 [PubMed - indexed for MEDLINE] 4530. Lik Sprava. 2002;(8):36-9. [Adipose tissue as an endocrine organ: role in pathogenesis of ischemic heart disease and insulin independent diabetes mellitus]. [Article in Ukrainian] Lapchyns'ka II, Stefaniuk MF. Obesity is a risk factor for cardiovascular morbidity and mortality. The present review of the modern literature is devoted to the problem of regarding the adipose tissue as not only a repository of energy supplies but an active endocrine organ as well whose activity exerts a definite effect on the function of many bodily systems. Specific emphasis is directed toward aspects of the function of certain secretory proteins involved in the process of the arterial pressure regulation and/or organs injuring. PMID: 12669536 [PubMed - indexed for MEDLINE] 4531. J Investig Med. 2003 Feb;51 Suppl 1:S12-7. Managing risk in normal volunteers participating in metabolic studies. Jensen MD(1), Siverling C. Author information: (1)Endocrine Research Unit, Mayo Clinic & Foundation, Joseph 5-194, 200 First Street SW, Rochester, MN 55905, USA. jensen.michael@mayo.edu BACKGROUND: Much emphasis has been placed on the risks volunteers face when participating in research studies, but little has been said about how to mitigate against such risks. METHODS: We review our experiences in over 15 years of managing risk in metabolic studies and the results of an intervention study designed to reduce the risk of femoral artery and femoral vein catheterization. RESULTS: Assessing the causes of adverse events and the context of a research study allowed us to design educational processes that reduced the incidence of adverse events. CONCLUSIONS: Although risk is inherent in any research study, approaching the risk issues in a manner designed to minimize the risk is possible. Ongoing efforts to further reduce risk in the context of research studies can benefit both the volunteers and the scientific community. PMID: 12664949 [PubMed - indexed for MEDLINE] 4532. Br J Sports Med. 2003 Apr;37(2):100-5. Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes? Rennie MJ(1). Author information: (1)Faculty of Life Sciences, Old Medical School, University of Dundee, Scotland, UK. m.j.rennie@dundee.ac.uk This review examines the evidence that growth hormone has metabolic effects in adult human beings. The conclusion is that growth hormone does indeed have powerful effects on fat and carbohydrate metabolism, and in particular promotes the metabolic use of adipose tissue triacylglycerol. However, there is no proof that net protein retention is promoted in adults, except possibly of connective tissue. The overexaggeration of the effects of growth hormone in muscle building is effectively promoting its abuse and thereby encouraging athletes and elderly men to expose themselves to increased risk of disease for little benefit. PMCID: PMC1724606 PMID: 12663349 [PubMed - indexed for MEDLINE] 4533. Horm Metab Res. 2002 Nov-Dec;34(11-12):764-6. Aortic carboxypeptidase-like protein (ACLP): what is a protein with a name like that doing in adipose tissue? Sorisky A(1), Gagnon A, Abaiian K. Author information: (1)Departments of Medicine and Biochemistry, Microbiology & Immunology, Ottawa Health Research Institute, Ottawa Hospital, University of Ottawa, Canada. PMID: 12660896 [PubMed - indexed for MEDLINE] 4534. Horm Metab Res. 2002 Nov-Dec;34(11-12):746-51. The functional consequences of 11beta-hydroxysteroid dehydrogenase expression in adipose tissue. Tomlinson JW(1), Stewart PM. Author information: (1)Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. Clinical observations have highlighted the link between glucocorticoids and obesity. While exogenous glucocorticoids in excess predispose to the development of central obesity, we have focused on cortisol metabolism within human adipose tissue. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inter-converts the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1, the only isoform expressed in adipose tissue, acts predominantly as an oxoreductase to generate cortisol. Expression is higher in omental compared to subcutaneous preadipocytes and activity and expression are potently regulated by growth factors and cytokines. Mice over-expressing 11beta-HSD1 specifically within adipocytes develop central obesity. However, the situation is less clear in humans. Globally, there appears to be inhibition of the enzyme, but expression in human obesity is still not fully characterized; its functional role in adipocyte biology remains to be elucidated. In vitro, 11beta-HSD1 appears to function in promoting adipocyte differentiation and limiting preadipocyte proliferation, but the impact of these effects in vivo upon the regulation of fat mass remains to be defined. Clinical studies utilizing selective 11beta-HSD1 inhibitors may help to answer this question. PMID: 12660893 [PubMed - indexed for MEDLINE] 4535. Horm Metab Res. 2002 Nov-Dec;34(11-12):737-45. Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Bélanger C(1), Luu-The V, Dupont P, Tchernof A. Author information: (1)Molecular Endocrinology and Oncology Research Center, Quebec, Canada. The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes. PMID: 12660892 [PubMed - indexed for MEDLINE] 4536. Horm Metab Res. 2002 Nov-Dec;34(11-12):731-6. Sex steroid biosynthesis in white adipose tissue. Meseguer A(1), Puche C, Cabero A. Author information: (1)Centre d'Investigacions en Bioquímica i Biologia Molecular, Hospital Universitari Vall d'Hebron, Barcelona, Spain. meseguer@hg.vhebron.es PMID: 12660891 [PubMed - indexed for MEDLINE] 4537. Horm Metab Res. 2002 Nov-Dec;34(11-12):664-70. Pref-1 and ADSF/resistin: two secreted factors inhibiting adipose tissue development. Villena JA(1), Kim KH, Sul HS. Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, USA. Adipose tissue is the source of a wide array of factors of great biological significance that are involved in many aspects of organism physiology, including appetite control and peripheral metabolism. Here, we describe two secreted factors from adipose tissue that inhibit adipogenesis. Pref-1 is a preadipocyte secreted factor synthesized as a transmembrane protein that undergoes proteolitic cleavage to generate two distinct soluble forms. In vitro assays have demonstrated that only the large soluble form of Pref-1 is biologically active and inhibits adipocyte differentiation. In vivo, mice lacking Pref-1 expression show accelerated fat deposition, perinatal mortality and growth retardation as well as distinct skeletal malformations, highlighting the importance of Pref-1 during mouse development in addition to its role in adipose tissue development. ADSF/resistin is secreted by adipocytes and inhibits adipose cells differentiation in vitro. Its function is still unclear, but its expression and high circulating levels have been associated with an impairment of insulin action. The findings show that Pref-1 and possibly ADSF/resistin secretion control fat cell differentiation and adipose tissue development. PMID: 12660879 [PubMed - indexed for MEDLINE] 4538. Horm Metab Res. 2002 Nov-Dec;34(11-12):616-21. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Wajchenberg BL(1), Giannella-Neto D, da Silva ME, Santos RF. Author information: (1)Endocrine Service (Diabetes), Medical Investigation Laboratories, Hospital das Clinicas, São Paulo, SP, Brazil. Visceral adipose tissue (VAT) imaged by computed tomography (CT) or magnetic resonance imaging (MRI) is associated with the metabolic syndrome features, being morphologically and functionally different from subcutaneous adipose tissue (SAT). Insulin effect is lower and catecholamine effect higher in visceral adipose tissue, with its metabolites and its secretions draining through portal system, partially at least, to the liver. Thus, visceral cells transfer and release fatty acids more extensively, have increased glucocorticoid and reduced thiazolidinedione responses, produce more angiotensinogen, interleukin-6 and plasminogen activator inhibitor-1, and secrete less leptin and adiponectin than SAT. Furthermore, there are regional differences in the intrinsic characteristics of the preadipocytes, with those of SAT presenting greater differentiation and fat cell gene expression but less apoptosis than that of VAT. All features contribute to the morbidity associated with increased VAT. To evaluate the relationship between VAT and components of the metabolic syndrome, 55 non-diabetic women, 11 lean (VAT < 68 cm 2) and 44 obese were studied. The obese with VAT within the normal range (VAT < or = 68 cm 2) had higher BMI, WHR, BP and resistance to FFA suppression during oGTT in comparison to the lean controls. The obese with VAT > 68 cm 2 compared to those with VAT < or = 68 cm 2 had similar body mass index (BMI) but significantly higher in vivo homeostasis model assessment for insulin resistance (HOMA IR ) results and triglycerides. By pooling all data, correlation analysis indicated that VAT contributes more to insulin resistance (HOMA IR ) than SAT does, but not when insulin-suppressed plasma free fatty acids during oral glucose tolerance test as an index of insulin resistance are taken into consideration. PMID: 12660870 [PubMed - indexed for MEDLINE] 4539. Horm Metab Res. 2002 Nov-Dec;34(11-12):607-15. Completing the loop: neuron-adipocyte interactions and the control of energy homeostasis. Turtzo LC(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. lturtzo@jhmi.edu Control of energy homeostasis requires communication between the brain and adipose tissue. The sympathetic nervous system plays an integral role in relaying information during this process. Recent investigations indicate that the contributions of the sympathetic nervous system to the regulation of adipose tissue are greater than initially appreciated. A recently developed co-culture system provides evidence that a local feedback loop may exist between sympathetic neurons and adipose tissue. The co-culture approach may prove useful in further investigations of the interaction between sympathetic neurons and adipocytes, and might be adapted to study interactions between other types of neurons and adipose tissue. PMID: 12660869 [PubMed - indexed for MEDLINE] 4540. Am J Phys Anthropol. 2002;Suppl 35:159-84. Critical periods in human growth and their relationship to diseases of aging. Cameron N(1), Demerath EW. Author information: (1)Department of Human Sciences, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK. N.Cameron@lboro.ac.uk It has long been recognized that there are "critical periods" during mammalian development when exposure to specific environmental stimuli are required in order to elicit the normal development of particular anatomical structures or their normal functioning. The responses of the organism to these stimuli depend on a specific level of anatomical maturation and a state of rapid anatomical and/or functional change. This discussion of critical periods in growth is not confined to the classic definition of a narrow time frame of development during which a particular environmental threshold or limit must exist for normal growth and function to ensue. Using both auxological and epidemiological approaches, we suggest a lifespan perspective which encompasses accumulating and interacting risks that are manifest from prenatal life onward. By understanding the process of growth development, and by scrutinizing the growth process, early variations that lead to later disease can be identified. Here we review a significant amount of the evidence that links exposure during growth to later morbidity and mortality. The fetus appears to respond to insults during the prenatal period through the process of "programming," which has short-term survival advantages but may have a long-term disadvantage in that it is associated with cardiovascular disease, hypertension, type II diabetes, and later obesity. Low birth weight combined with rapid postnatal growth during infancy also appears to be associated, for instance, with later childhood and adult sequelae in terms of glucose tolerance and obesity. Independent of birth weight, the timing of adiposity rebound during mid-childhood also predicts later obesity. The timing, magnitude, and duration of adolescent growth and maturationare associated with critical body composition changes, including the normal acquisition of body fat and bone mineralization. In particular, the acquisition of appropriate peak bone mass is critical in determining the later risk of osteoporosis. A putative causal mechanism linking early growth variation to later chronic disease risk through telomeric attrition is discussed. The obligatory loss of telomeric DNA with each cell division serves as a mitotic clock and marks the rate of growth and repair processes in the cell. Although much more work is required, existing studies support the notion that telomere shortening is not only a clock of cellular division, but also marks relative growth rate, as well as contributing to common degenerative processes of aging through its impact on cellular senescence. PMID: 12653312 [PubMed - indexed for MEDLINE] 4541. J Soc Biol. 2002;196(4):339-48. [Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane]. [Article in French] Sauviat MP(1), Pages N. Author information: (1)Laboratoire d'Optique et Biosciences, INSERM U 451-CNRS UMR 7645-X ENSTA, Ecole Polytechnique, 91128 Palaiseau, France. martin-pierre.sauviat@polytechnique.fr The goal of the present review is to collect information concerning membrane effects induced by lindane intoxication, a y isomer of hexachiorocyclohexane (gamma-HCH) that has been largely used as an insecticide and disinfectant in agriculture and entered also in the composition of some lotions, creams and shampoos used against parasites (lice and scabies). Absorbed through respiratory, digestive or transcutaneous pathways, lindane accumulates within lipid rich tissues. Lindane accumulation depends on the duration of the exposure and affects tissues in the following order: adipose tissues > brain > kidney > muscle > lungs > heart > liver > blood. Whatever the mode of lindane absorption, it accumulates in blood and is distributed throughout the body. It may affect human health by exerting systemic, immunologic, teratogenic, and/or cancerogenic effects. The symptoms of lindane intoxication are different according to the mode of intoxication, acute or chronic. The absorption of high doses of gamma-HCH is particularly toxic for the central nervous system and for the female and male reproduction apparatus in mammals where lindane is considered as an endocrine disruptor. Lindane is highly lipophilic and incorporates into biological membranes according to the following sequence: mitochondria > sarcoplasmic reticulum > myelin > brain microsomes > erythrocytes. Lindane exerts a stimulating action on synaptic transmission and inhibits the chloride current activated by gamma-amino butyric acid (GABA) of many muscular and nervous preparations by interacting with the receptors GABA-chloride channel complex. It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered energetic metabolism of hepatic mitochondria and the inositol-phosphate synthesis in neuronal cells. However, lindane does not compete with the IP3 receptor. Lindane produces a Ca2+ influx in mice peritoneal macrophage cells responsible for the Ca2+ induced Ca2+ release produced by phospholipase C via IP3 pathway and resulting in a maintained increase of the free cytosolic Ca2+ concentration. Lindane decreased the membrane erythrocyte and cerebral cell concentration of phosphatidyl inositol PI, PIP and PIP2 in rats repetitively exposed to lindane for 3 or 6 months. Lindane induces oxidative stress; it modifies the activity of the scavenger enzymes. This effect is involved in the inhibition of intercellular gap junctions. Modifications of the electrocardiogram (ECG), sinusal rhythm alteration and negative and dysphasic variations of T wave, similar to those produced by hyperkaliemia, have been reported after lindane absorption. During acute lindane poisoning, the activities of serum transaminases (SGOT, SGTP), and lactate deshydrogenase (LDH) increase. Lindane produces histological alterations of cardiac tissues and a cardio-vascular dystrophy (contracture, degenerescence and necrosis) mainly in the left ventricular wall and a hypertrophy of the left ventricle. Chronic application of residual doses of lindane shortened the action potential duration in rat papillary muscle. These effects were similar to those induced by hyperthyroidism. Lindane increases the triiodothyronine (T3) serum level in hyperthyroid rats. T3 plays an important role in the postnatal development of the rat ventricle by increasing the density of potassium channels which contribute to action potential shortening during the development. Thyroid hormones influence the regulation and the expression of messengers ARN which encode different potassium channels involved in action potential repolarization (Kvl.2; Kvl.4; Kvl.5; Kv2.1; Kv4; HCN2). The thyrotropine-releasing hormone (TRH) modulates the HERG-type rapid delayed potassium channel (IKr) encoded by the human gene ether-a-go-go in rat anterior pituitary cells GH3/B6. This channel is involved in the cardiac long QT syndrome. TRH modifies the current kinetics of human HERG potassium channel co-expressed in Xenopus oocytes with the TRH receptor, whose activity is modulated via the protein kinase C pathway linked to a G protein-coupled receptor and is regulated by changes in the PIP2 concentration in the membrane. IKr channels regulation is also dependent on sexual hormones. In conclusion, lindane affects the excitable membranes and the cardio circulatory system. These alterations (may) represent a potential risk for human health. PMID: 12645305 [PubMed - indexed for MEDLINE] 4542. Pharmacol Res. 2003 Apr;47(4):263-8. Differentiation of embryonic stem cells for pharmacological studies on adipose cells. Phillips BW(1), Vernochet C, Dani C. Author information: (1)Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre de Biochimie, 06108 Nice Cedex 2, France. The ongoing global explosion in the incidence of obesity has focused attention on the development of adipose cells. Severe obesity is the result of an increase in fat cell size in combination with increased fat cell number. New fat cells arise from a pre-existing pool of adipose stem cells that are present irrespective of age. The development of established preadipocyte cell lines has facilitated the study of different steps leading to terminal differentiation. However, these systems are limited for studying early events of differentiation as they represent cells which are already determined for the adipogenic lineage. In vitro differentiation of mouse embryonic stem (ES) cells towards the adipogenic lineage provides an alternative source of adipocytes for study in tissue culture and offers the possibility to investigate regulation of the first steps of adipose cell development. In this review, we describe the sequential requirement of retinoic acid and PPARgamma during adipogenesis in ES cells. Stimulation of ES cells with synthetic retinoids which are selective ligands of the retinoic acid receptor isotypes allowed the investigation of the contribution of the different retinoic receptors on the RA-dependent differentiation. The effects of thiazolidinediones, a new class of pharmacological agents used for the treatment of type 2 diabetes, and of statins, drugs used in therapy for lowering cholesterol, on the differentiation of ES cells into adipocytes or osteoblasts are described. Finally, we propose a model in which PPARgamma plays a key role in the decision of stem cells to undergo differentiation into adipocytes or osteoblasts, two closely related lineages. PMID: 12644382 [PubMed - indexed for MEDLINE] 4543. Curr Diab Rep. 2002 Apr;2(2):179-85. The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. Celi FS(1), Shuldiner AR. Author information: (1)University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition, 660 West Redwood Street, Room 494, Baltimore, MD 21201, USA. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which upon activation with various natural and synthetic ligands, stimulates the transcription of genes responsible for growth and differentiation of adipocytes. Furthermore, PPAR gamma is the receptor for the insulin-sensitizing thiazolidinediones, which are commonly used for the treatment of type 2 diabetes. Rare inactivating mutations of the gene encoding PPAR gamma are associated with insulin resistance type 2 diabetes, and hypertension, whereas a rare gain of function mutation causes extreme obesity. A common polymorphism (Pro12Ala) of the adipose tissue-specific gamma 2 isoform is associated with increased insulin sensitivity and decreased risk of developing type 2 diabetes. These findings indicate a central role of PPAR gamma in fat cell biology and in the pathophysiology of obesity, diabetes, and insulin resistance. PMID: 12643137 [PubMed - indexed for MEDLINE] 4544. Curr Diab Rep. 2002 Apr;2(2):116-24. HIV-associated lipodystrophy: description, pathogenesis, and molecular pathways. Mallon PW(1), Carr A, Cooper DA. Author information: (1)National Centre in HIV Epidemiology and Clinical Research, St. Vincent's Hospital Medical Centre, 376 Victoria Street, Sydney NSW 2010, Australia. pmallon@nchecr.unsw.edu.au HIV-infected individuals taking antiretroviral medications may experience changes in body shape and metabolism, commonly known as HIV-associated lipodystrophy (HIVLD). In vitro and in vivo research have revealed numerous effects of both protease inhibitors and nucleoside reverse transcriptase inhibitors on the function of various organs--most importantly adipose tissue, liver, and muscle. The metabolic abnormalities could result in an increased risk of cardiovascular disease in this vulnerable and relatively young population. Treatment strategies, normally successful in the general population, have generally been less effective in this group of people, in which the detrimental effects of the antiretroviral medications are ongoing. PMID: 12643131 [PubMed - indexed for MEDLINE] 4545. Curr Diab Rep. 2002 Feb;2(1):77-82. The effect of in-utero undernutrition on the insulin resistance syndrome. Jaquet D(1), Leger J, Czernichow P, Levy-Marchal C. Author information: (1)INSERM Unité 457, Hôpital Robert Debré, Paris 75019, France. djacquet@infobiogen.fr The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk for the development of cardiovascular diseases, the insulin resistance syndrome and its components: hypertension, dyslipidemia, impaired glucose tolerance, and type 2 diabetes. All appear to result from the initial development of insulin resistance that seems to be a key component underlying this association. Several hypotheses have been proposed over the past 10 years to understand this unexpected association. Each of them points to either a detrimental fetal environment or genetic susceptibilities or interactions between these two components as playing a critical role in this context. The hypothesis that this association could be the consequence of genetic/environmental interactions remains at the moment the most attractive. Although the mechanism remains unclear, there is also some evidence that adipose tissue plays a role in the emergence of insulin resistance associated with in-utero undernutrition. PMID: 12643126 [PubMed - indexed for MEDLINE] 4546. Curr Hypertens Rep. 2003 Apr;5(2):117-21. Insulin resistance in HIV-related lipodystrophy. Mikhail N(1). Author information: (1)Endocrinology Division, Olive View - UCLA Medical Center, 14445 Olive View Drive, Sylmar, CA 91342, USA. nasser.mikhail@gte.net Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-a in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome. PMID: 12642010 [PubMed - indexed for MEDLINE] 4547. Tidsskr Nor Laegeforen. 2003 Feb 6;123(3):311-4. [The importance of adipose tissue for development of obesity and diabetes mellitus type 2]. [Article in Norwegian] Hollung K(1), Reseland JE, Ranheim T, Haugen F, Drevon CA. Author information: (1)Institutt for ernaeringsforskning Universitetet i Oslo Postboks 1046 Blindern 0316 Oslo. PMID: 12640896 [PubMed - indexed for MEDLINE] 4548. Medicine (Baltimore). 2003 Mar;82(2):129-46. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Misra A(1), Garg A. Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75390, USA. We present clinical descriptions, metabolic features, and patterns of body fat loss of 16 patients with acquired generalized lipodystrophy (AGL) seen by us over the last 10 years. In addition, we review 63 cases of AGL reported in the literature. Based on these data, we propose new diagnostic criteria for AGL, the essential criterion being selective loss of body fat from large regions of the body occurring after birth. We also propose a subclassification of AGL into 3 varieties, type 1, the panniculitis variety; type 2, the autoimmune disease variety; and type 3, the idiopathic variety, which affect nearly 25%, 25%, and 50% of patients, respectively. Most of the patients presented in childhood and adolescence. Females were affected approximately 3 times more than males. Subcutaneous fat loss was severe and usually affected the face, trunk, abdomen, and extremities. In some patients, fat loss also involved the palms and soles and intraabdominal region; however, the bone marrow and retroorbital fat were preserved in all patients. Clinically, patients may have voracious appetite, fatigue, and acanthosis nigricans. Hepatomegaly was common, mostly due to hepatic steatosis. Most AGL patients had fasting and/or postprandial hyperinsulinemia, diabetes mellitus, hypertriglyceridemia, and low serum levels of high-density lipoprotein cholesterol, leptin, and adiponectin. Diabetes mellitus and hypertriglyceridemia were less prevalent in the panniculitis variety compared with the idiopathic and autoimmune varieties. The management of AGL includes cosmetic surgery for loss of fat. Severe hypertriglyceridemia should be treated with a very low-fat diet and omega-3 polyunsaturated fatty acid supplementation from fish oils. Management of diabetes is difficult and may necessitate insulin therapy in large doses. Insulin sensitizers such as metformin and thiazolidinediones have been used, although their long-term efficacy and safety remain unknown. Subcutaneous administration of recombinant leptin in AGL patients with hypoleptinemia effectively improves hyperglycemia, hypertriglyceridemia, and hepatic steatosis. Leptin therapy, however, remains investigational. Fibrates alone or in combination with statins may be used to treat hypertriglyceridemia. PMID: 12640189 [PubMed - indexed for MEDLINE] 4549. Joint Bone Spine. 2003 Feb;70(1):18-21. Leptin: a potential mediator for protective effects of fat mass on bone tissue. Thomas T(1). Author information: (1)Inserm E9901, Saint-Etienne University Hospital, Saint-Etienne, France. thierry.thomas@univ-st-etienne.fr Body weight is among the most powerful predictors of bone status, and adipose tissue plays a substantial role in weight-related protective effects on bone. An understanding of the mechanisms underlying the relation between adipose tissue and bone may open up new perspectives for treatment. Leptin, which is known to regulate appetite and energy expenditures, may also contribute to mediate the effects of fat mass on bone. Although reported data are somewhat conflicting, there is some evidence that leptin may decrease bone formation via a central nervous effect and may stimulate both bone formation and bone resorption via direct peripheral effects on stromal precursor cells. The net result of these central and peripheral effects may depend on serum leptin levels and blood-brain barrier permeability, of which the first increase and the second decrease as obesity develops. Further work is needed to improve our understanding of these effects. PMID: 12639613 [PubMed - indexed for MEDLINE] 4550. Public Health Nutr. 2002 Dec;5(6A):865-71. Biomarkers and the measurement of fatty acids. Arab L(1), Akbar J. Author information: (1)Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, USA. Lenore@unc.edu OBJECTIVE: To review the various biomarkers of dietary intakes of fatty adds in human populations, their measurement, limitations and analytical considerations. DESIGN: Review of the literature. RESULTS: Although there is no good biomarker of intake of total fat, a number of alternatives exist for assessing the intakes of exogenously produced fatty acids that are consumed. Adipose tissue, erythrocyte membrane concentrations and serum or plasma levels can reflect prior intakes over the past few hours to the past few years. The concentrations of individual fatty acids in these media generally reflect relative levels, and are influenced by a number of factors. Although relatively expensive to analyse, a single analysis by gas chromatography or high-performance liquid chromatography provides information on multiple fatty acids, and is superior to attempting to measure specific fatty acids using traditional dietary assessment methods. CONCLUSIONS: Biomarkers of fatty acids that reflect long-term intake are available for nutritional epidemiology purposes. Analytical methods have become very accurate and able to detect and quantify smaller families, such as trans-fatty acids. PMID: 12638594 [PubMed - indexed for MEDLINE] 4551. Horm Res. 2003;59 Suppl 1:131-7. Born small for gestational age: increased risk of type 2 diabetes, hypertension and hyperlipidaemia in adulthood. Jaquet D(1), Czernichow P. Author information: (1)INSERM Unité 457, Hôspital Robert Debré, Paris, France. The metabolic and cardiovascular complications associated with reduced fetal growth have been identified in the past 10 years. These include cardiovascular disease and the insulin resistance syndrome, comprising dyslipidaemia and impaired glucose tolerance or type 2 diabetes, and they appear to result from the initial development of insulin resistance. Although the mechanism underlying the development of insulin resistance associated with reduced fetal growth remains unclear, there is some evidence that adipose tissue plays a key role. Over the past decade, several hypotheses have been proposed to explain this unexpected association. Each points to either a detrimental fetal environment, genetic susceptibility or an interaction between the two. Although yet to be confirmed, the hypothesis suggesting that the association could be the consequence of genetic-environmental interactions is at present the most attractive. PMID: 12638526 [PubMed - indexed for MEDLINE] 4552. Diabetologia. 2003 Jan;46(1):3-19. Epub 2003 Jan 11. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Kahn SE(1). Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington, USA. Comment in Diabetologia. 2003 Dec;46(12):1707. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes. PMID: 12637977 [PubMed - indexed for MEDLINE] 4553. Curr Mol Med. 2003 Mar;3(2):107-25. Insulin resistance and type 2 diabetes--an adipocentric view. Cederberg A(1), Enerbäck S. Author information: (1)Medical Genetics, Department of Medical Biochemistry, Göteborg University, Box 440, SE-405 30 Göteborg, Sweden. anna.cederberg@medgen.gu.se As a result of selecting triglycerides as the major vehicle for storing superfluous energy, evolution came up with a specialized cell type, the adipocyte, equipped to handle triglycerides and its potentially toxic metabolites--fatty acids. For the first time in history large human populations are subjected a wealth of cheap, accessible and palatable calories. This has created a situation, on a large scale not previously encountered, in which the capacity to store triglycerides in adipocytes is an important determinant of human health. Too few adipocytes (e.g. lipodystrophia) or a situation in which all adipocytes are filled, to their maximum capacity (e.g. severe obesity), will create very similar and unfavorable metabolic situations in which ectopic triglyceride stores will appear in tissues like liver and muscle. This review sets out to discuss the adipocyte and its role in metabolism as well as the consequences of a metabolic situation, in which the adipocyte has lost its fat storing monopoly. PMID: 12630558 [PubMed - indexed for MEDLINE] 4554. J Sports Med Phys Fitness. 2003 Mar;43(1):1-13. The use of near infrared spectroscopy in sports medicine. Quaresima V(1), Lepanto R, Ferrari M. Author information: (1)Department of Biomedical Sciences and Technologies, University of L'Aquila, L'Aquila, Italy. vale@univaq.it In the last 15 years the study of the human muscle energetics in sports medicine underwent a radical change thanks to the progressive introduction of non-invasive techniques, including near infrared (NIR) spectroscopy (NIRS). NIR light (700-1000 nm) penetrates skin, subcutaneous fat and underlying muscle, and is either absorbed (by oxy- and deoxy-haemoglobin) or scattered within the tissue. NIRS is a non-invasive and relatively low cost optical technique that is becoming a widely used instrument for measuring muscle O(2) saturation and changes in haemoglobin volume. Muscle O(2) saturation represents a dynamic balance between O(2) supply and O(2) consumption in the small vessels such as the capillary, arteriolar and venular bed. NIRS offers the advantage of being less restrictive than (31)P-magnetic resonance spectroscopy with regard to muscle performance and more comfortable and suitable for the monitoring, with high temporal resolution (up to 10 Hz), of multiple muscle groups. The aim of this review is to summarise the NIRS instrumentation and the measurable parameters, the role of NIRS in muscle exercise physiology, and the applications in sports medicine. The advantages and the problems of NIRS measurements, in resting and exercising skeletal muscles, are reported. The results of several studies suggest that NIRS is a powerful tool for being applied successfully in sports medicine. NIRS can objectively evaluate muscle oxidative metabolism in athletes and its modifications following potential therapeutic strategies and specific training programs. PMID: 12629456 [PubMed - indexed for MEDLINE] 4555. Curr Womens Health Rep. 2003 Apr;3(2):110-5. Cardiovascular consequences of obesity. Okerberg K(1), Hamilton Dougherty A. Author information: (1)Division of Cardiology, University of Texas-Houston, 77030, USA. Obesity is a problem of epidemic proportions that is associated with adverse cardiovascular outcomes. The long-term efficacy of currently available treatments is limited, and therapeutic benefits might paradoxically be achieved only at the expense of other serious adverse cardiovascular consequences. Owing to these limitations, new paradigms in the management of obesity are being explored, including expanded surgical and pharmacologic therapies. Recent discoveries in the pathogenesis of obesity, including the discovery of leptin, might lead to new treatment options. Leptin dysregulation within the central nervous system or in peripheral adipose tissue has a putative role in the pathogenesis of obesity. Furthermore, important differences exist between men and women in regard to leptin levels; these discrepancies might ultimately impact the therapeutic approach in a gender-specific manner. The goals of obesity therapy and the appropriate therapeutic endpoints are being evaluated to maximize the efficacy of therapy and improve cardiovascular outcomes, while diminishing the risk of adverse cardiovascular complications. PMID: 12628080 [PubMed - indexed for MEDLINE] 4556. Gynecol Endocrinol. 2002 Dec;16(6):479-91. Effects of sex steroid hormones and menopause on serum leptin concentrations. Di Carlo C(1), Tommaselli GA, Nappi C. Author information: (1)Department of Obstetrics and Gynecology, University of Naples 'Federico II', Naples, Italy. Leptin is a protein secreted by adipocytes; its circulating levels are correlated to fat mass and it acts on the hypothalamic centers regulating body weight. Leptin may also play an important role in regulating reproductive function. Indeed, ob/ob mice, lacking leptin due to a genetic mutation, are obese and infertile; administration of recombinant leptin to these animals reduces body weight and restores fertility. A sexual dimorphism in serum leptin levels has also been observed, with higher concentrations in women. Studies in vitro seem to indicate that estrogens stimulate leptin secretion, while in vivo studies are extremely discordant. In humans, several studies showed increased, unmodified and decreased leptin levels after the menopause. Furthermore, hormonal replacement therapy (HRT) after the menopause was reported to result in unmodified, increased or decreased leptin levels. It is likely that the effects of postmenopausal hypoestrogenism on leptin levels are masked by the postmenopausal changes in body composition. Indeed, after menopause, there is an increase in body weight, body mass index (BMI) and fat mass with a centralization of fat distribution. Administration of HRT may stop these changes and even restore a premenopausal pattern, leading then to decreased leptin levels. PMID: 12626035 [PubMed - indexed for MEDLINE] 4557. J Neuroendocrinol. 2003 Apr;15(4):409-14. Leptin and seasonal mammals. Rousseau K(1), Atcha Z, Loudon AS. Author information: (1)School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK. Seasonal mammals commonly exhibit robust annual cycles of adiposity, food intake and energy metabolism. These cycles are driven by changes in the external daylength signal, which generates a diurnal melatonin profile and acts on neuroendocrine pathways. The white adipose tissue hormone leptin reflects overall adiposity in seasonal mammals, and consequently undergoes significant seasonal fluctuations in secretion. The seasonally breeding Siberian (Djungarian) hamster is a convenient laboratory model to study the effect of a seasonal time-keeping clock on energy metabolism, appetite regulation and the control of adiposity. We have shown that administration of exogenous leptin at physiological doses induces significant loss of adipose tissue for short-day housed winter-like hamsters in which endogenous adipose tissue and leptin concentrations are already low. By contrast, long-day housed hamsters with high adipose tissue reserves are refractory to the effects of leptin. This phenomenon of seasonal leptin resistance appears to be a general feature of other seasonally breeding mammals, and may reflect the operation of an annual timer controlling leptin uptake and/or action on central nervous system signal transduction pathways. The mobilization of fat by leptin in short-day housed hamsters is not associated with changes in expression in either anorexic or anabolic peptides expressed in leptin-receptor rich structures in the arcuate region of the hypothalamus, and suggests that leptin may target other structures. These data contrast with studies, which show that homeostatic mechanisms in response to feed-restriction induce changes in hypothalamic peptides in a similar manner to nonphotoperiodic species. Thus, the long-term seasonal regulation of body weight set point and leptin feedback may operate through separate pathways to those responsible for acute responses to food restriction. PMID: 12622842 [PubMed - indexed for MEDLINE] 4558. Rocz Panstw Zakl Hig. 2002;53(3):293-305. [Flame retardants--use and hazards for human]. [Article in Polish] Góralczyk K(1), Struciński P, Czaja K, Hernik A, Ludwicki JK. Author information: (1)Zakład Toksykologii Srodowiskowej Państwowy Zakład Higieny 00-791 Warszawa, ul. Chocimska 24. Flame retardants (FRs) are chemicals which added to materials during or after manufacture, inhibit or even suppress the combustion process due to their thermal stability. Large quantities of FRs are added to the plastic material (resins) in variety of electrical and electronic appliances including television and computer casing. The other uses of these compounds include production of building materials, upholstered furniture, textiles, wall covering, carpets, hydraulic fluids as well as vehicles and aircraft. Taking into account the chemical structure, there are five main groups of FRs: brominated, chlorinated, phosphorous-containing, nitrogen-containing (i.e. melamines) and inorganic compounds. Halogenated compounds, especially polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, due to their lipophilic characteristics and persistence have become ubiquitous environmental contaminants. There are indications that PBDEs may affect hormone function acting as endocrine disruption and may be toxic for developing brain. These compounds have been associated with non-Hodgkin's lymphoma in humans, a variety of cancers in rodents and disruption of thyroid hormones balance. Similarly to other persistent halogenated compounds they are also able to affect the xenobiotic metabolizing enzymes activity. PBDEs are now found as residues in sediments, wildlife and human (milk, serum adipose tissue) samples. The predominant congeners in environmental samples, including human specimens are two congeners: 47 and 99. Currently, the estimated daily intake of PBDEs by adult humans is equal 51 ng x day-1 while by breast-fed infants equals 110 ng x day-1. PMID: 12621885 [PubMed - indexed for MEDLINE] 4559. Otol Neurotol. 2003 Mar;24(2):158-64. Adipose graft: an original option in myringoplasty. Ayache S(1), Braccini F, Facon F, Thomassin JM. Author information: (1)Otorhinolaryngology and Cervical and Facial Surgery Federation, La Timone Hospital, Marseille Cedex, France. Comment in Otol Neurotol. 2005 May;26(3):554-5. OBJECTIVE: To describe the fat graft as a reconstructive material in myringoplasty. METHOD: In a review of 45 patients conducted between 1993 and 1999, the authors analyzed their patients' outcomes after having myringoplasties with fat graft. Median follow-up was 2.5 years (range, 6 mo-6 yr). RESULTS: We achieved a success rate of 91.1%. Different features of the patient and the tympanic perforation were studied to demonstrate their role in the quality of the surgical closing. A review of the literature was done to compare our results with the results of other series using this type of graft as well as with studies of the temporalis fascia as a graft material. CONCLUSION: The high reliability of the fat graft and the technical simplicity of this procedure in anterior perforations, especially with the use of intraoperative endoscopy, make it an attractive technique. PMID: 12621327 [PubMed - indexed for MEDLINE] 4560. Ginekol Pol. 2002 Oct;73(10):870-6. [The role of leptin in human reproduction]. [Article in Polish] Grabiec M(1), Szymański W. Author information: (1)Katedry i Kliniki Połoznictwa i Chorób Kobiecych AM w Bydgoszczy. The article reviews the current literature about leptin, a hormone produced mainly in the adipose tissue, in terms of its role in reproduction. The structure of leptin, its biological activity as well as its influence on secretion of their hormones has been discussed. The leptin concentrations during the ovulatory cycle, pregnancy puerperium and assisted reproduction have been presented. It has been suggested that leptin may have an advantageous effect not only on oocyte and zygote development in the early stages, but also on the process of implantation and therefore its evaluation may be useful for the clinical determination of embryo quality in IVF-ET program. PMID: 12619324 [PubMed - indexed for MEDLINE] 4561. Lipids. 2002 Dec;37(12):1113-23. What is the role of alpha-linolenic acid for mammals? Sinclair AJ(1), Attar-Bashi NM, Li D. Author information: (1)Department of Food Science, RMIT University, Melbourne, Victoria, 3001, Australia. andrew.sinclair@rmit.edu.au This review examines the data pertaining to an important and often underrated EFA, alpha-linolenic acid (ALA). It examines its sources, metabolism, and biological effects in various population studies, in vitro, animal, and human intervention studies. The main role of ALA was assumed to be as a precursor to the longer-chain n-3 PUFA, EPA and DHA, and particularly for supplying DHA for neural tissue. This paper reveals that the major metabolic route of ALA metabolism is beta-oxidation. Furthermore, ALA accumulates in specific sites in the body of mammals (carcass, adipose, and skin), and only a small proportion of the fed ALA is converted to DHA. There is some evidence that ALA may be involved with skin and fur function. There is continuing debate regarding whether ALA has actions of its own in relation to the cardiovascular system and neural function. Cardiovascular disease and cancer are two of the major burdens of disease in the 21st century, and emerging evidence suggests that diets containing ALA are associated with reductions in total deaths and sudden cardiac death. There may be aspects of the action and, more importantly, the metabolism of ALA that need to be elucidated, and these will help us understand the biological effects of this compound better. Additionally, we must not forget that ALA is part of the whole diet and should be seen in this context, not in isolation. PMID: 12617463 [PubMed - indexed for MEDLINE] 4562. J Diabetes Complications. 2003 Mar-Apr;17(2):108-13. Leptin: metabolic control and regulation. Sandoval DA(1), Davis SN. Author information: (1)Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University, Nashville, TN, USA. darleen.sandoval@vanderbilt.edu Leptin, a protein released from adipose tissue, is being recognized to play an integral role in endocrine regulation of metabolism. While it is clearly evident that leptin is decreased during caloric restriction, the response of leptin to other types of stress has been plagued by conflicting data. With hypoglycemia stress, the literature may conflict because experimentally hypoglycemia is induced with infusion of insulin, an endocrine factor that can increase leptin levels. With exercise, leptin's response may depend on duration and intensity of exercise. While it has been clearly shown that the sympathetic nervous system (SNS) inhibits leptin secretion in a variety of experimental modes, the hypothalamic-pituitary-adrenal (HPA) axis may stimulate leptin secretion. This creates a paradox of leptin regulation during stress since both systems are activated with stress. If the SNS inhibition overrides the HPA axis' activation of leptin secretion, leptin's role during stress may be to allow a shifting of fuel consumption towards carbohydrate utilization. In type 1 diabetes mellitus, autonomic dysfunction may prevent the fall in leptin during stress. Although obesity is associated with type 2 diabetes mellitus, patients may have decreased leptin levels, especially when glucose is poorly controlled. This may contribute to further obesity and worsening of the disease. The purpose of this review to is critically analyze the literature regarding the impact of different types of stress on leptin secretion, the function of leptin during stress, and the role of leptin in the pathophysiology of diabetes. PMID: 12614978 [PubMed - indexed for MEDLINE] 4563. Dermatol Surg. 2003 Mar;29(3):235-40. Multiple symmetric lipomatosis: Korean experience. Lee HW(1), Kim TH, Cho JW, Ryu BY, Kim HK, Choi CS. Author information: (1)Department of General Surgery, College of Medicine, Hallym University, Chunchon, Korea. leehw@hallym.or.kr BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disorder that is characterized by abnormal adipose tissue growth mainly at the neck, abdominal wall, back, shoulder girdle, and arms. A suggested mechanism for accumulation of adipose tissue is a defect in the lipolytic pathway of fat cell. OBJECTIVE: To evaluate the clinical, morphologic, and biochemical findings in Korean patients. METHOD: A total of 32 patients with MSL were evaluated retrospectively. Ten patients were seen at our hospital. The remaining 22 patients from literature were reviewed. Biochemical analyses and neurologic studies were performed. RESULTS: All cases were a sporadic form of MSL. The age of onset ranged from 26 to 70 years (mean of 49.4 years). The male-to-female ratio was 31:1. All but two patients were alcoholics with a daily intake of more than 80 g of alcohol for at least 10 years. In metabolic studies of 17 patients, a Fredrickson type IIb or IV hyperlipoproteinemia was found in three patients. High-density lipoprotein cholesterol values were higher in three patients. A glucose tolerance test was abnormal in five patients. A high prevalence of neurologic abnormalities was observed. Clinical signs of peripheral neuropathy were present in 11 of 13 patients. Central nervous system involvement was found clinically in 3 of 13 patients. CONCLUSION: The surgical removal of the fatty tissue and abstinence from alcohol are essential for relieving the patients from functional impairment. Not only metabolic studies of lipid abnormalities but also a complete neurologic examination were required in order to improve the quality of life in MSL patients. PMID: 12614415 [PubMed - indexed for MEDLINE] 4564. Eur J Endocrinol. 2003 Mar;148(3):293-300. The role of the novel adipocyte-derived hormone adiponectin in human disease. Díez JJ(1), Iglesias P. Author information: (1)Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain. mibarsd@infomed.es Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose tIssue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, and that circulates in human plasma at high levels. It is one of the physiologically active polypeptides secreted by adipose tIssue, whose multiple functions have started to be understood in the last few Years.A reduction in adiponectin expression is associated with insulin resistance in some animal models. Administration of adiponectin has been accompanied by a reduction in plasma glucose and an increase in insulin sensitivity. In addition, thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of the peroxisome proliferator-activated receptor-gamma, increase plasma adiponectin and mRNA levels in mice. On the other hand, this adipocyte protein seems to play a protective role in experimental models of vascular injury. In humans, adiponectin levels are inversely related to the degree of adiposity and positively associated with insulin sensitivity both in healthy subjects and in diabetic patients. Plasma adiponectin levels have been reported to be decreased in some insulin-resistant states, such as obesity and type 2 diabetes mellitus, and also in patients with coronary artery disease. On the contrary, chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased plasma adiponectin levels. Concentrations of plasma adiponectin have been shown to correlate negatively with glucose, insulin, triglyceride levels and body mass index, and positively with high-density lipoprotein-cholesterol levels and insulin-stimulated glucose disposal. Weight loss and therapy with thiazolidinediones increased endogenous adiponectin production in humans. Adiponectin increases insulin sensitivity by increasing tIssue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. In view of these data, it is possible that hypoadiponectinemia may play a role in the development of atherosclerotic vascular disease. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and anti-atherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, with potential applications in states associated with low plasma adiponectin levels. PMID: 12611609 [PubMed - indexed for MEDLINE] 4565. Reproduction. 2003 Mar;125(3):313-25. The impact of endocrine disruptors on oocyte competence. Pocar P(1), Brevini TA, Fischer B, Gandolfi F. Author information: (1)Department of Anatomy and Cell Biology, Martin Luther University, Halle (Saale) Germany. To date, approximately 60 chemicals have been identified as endocrine disruptors: exogenous agents that interfere with various aspects of natural hormone physiology. The potential reproductive and health hazards of these environmental chemicals have recently generated concern among the scientific community, policy makers and general public. The present review presents and discusses the available evidence that environmental chemicals are causing ovarian toxicity in various species, with particular attention to farm animals. The impact of chronic exposure to endocrine disruptors via food and drinking water cannot be neglected when studying fertility problems in these species. This review focuses attention on the superfamily of organochlorine chemicals, persistent organic pollutants (POPs), because of their persistence in the environment, ability to concentrate up the food chain, continued detection in environmental matrices and ability to be stored in the adipose tissue of animals and humans. Published data clearly indicate that POPs disrupt mammalian oocyte maturation and follicle physiology in every species studied so far, including farm animals. However, as most of the data available still derive from experiments performed on laboratory species or in vitro models, great care should be taken when extrapolations to other species or environmental situations are attempted. PMID: 12611595 [PubMed - indexed for MEDLINE] 4566. Acta Physiol Scand. 2003 Mar;177(3):351-7. Sympathetic control of white adipose tissue in lean and obese humans. Dodt C(1), Lönnroth P, Wellhöner JP, Fehm HL, Elam M. Author information: (1)Department of Internal Medicine I, University of Lübeck, Germany. AIM: To induce lipolysis, catecholamines could reach the adipocyte via the blood stream after being released from the adrenal medulla or, alternatively, via neuronal release in the vicinity of the fat cell. Sympatho-neuronal effects on fat tissue lipolysis have been demonstrated in experimental animal models. However, the role of sympathetic nerves in the control of lipolysis in human white adipose tissue, which is sparsely innervated, has not been clarified. CONCLUSION: The present review summarizes evidence for a direct neuronal influence on lipolysis in humans. PMID: 12609006 [PubMed - indexed for MEDLINE] 4567. Acta Physiol Scand. 2003 Mar;177(3):345-9. A leptin-sympathetic-leptin feedback loop: potential implications for regulation of arterial pressure and body fat. Mark AL(1), Rahmouni K, Correia M, Haynes WG. Author information: (1)Specialized Center of Research in Hypertension Genetics, the Department of Internal Medicine, Lucille A Carver College of Medicine, and the Veterans Administration Medical Center, Iowa City, IA 52242-1101, USA. AIM: This manuscript briefly reviews evidence and potential implications of a leptin-sympathetic-leptin feedback loop. RESULTS: Leptin increases sympathetic nerve activity to brown adipose tissue, kidney and other tissues. This action has implications for regulation of arterial pressure. In turn, there is evidence that sympathoadrenal stimulation inhibits leptin mRNA expression and secretion from white adipose tissue through beta adrenergic mechanisms. CONCLUSION: This sympathetic modulation of leptin expression has potential implications for regulation of body fat. PMID: 12609005 [PubMed - indexed for MEDLINE] 4568. Acta Physiol Scand. 2003 Mar;177(3):337-43. Sympathetic nerve activity in metabolic control--some basic concepts. Fagius J(1). Author information: (1)Department of Neurology, University Hospital, Uppsala, Sweden. A role for the sympathetic nervous system in hypertension has been looked for in relation to the 'metabolic syndrome' with associations between body weight, insulin sensitivity and hypertension. By use of microneurography human sympathetic responses to hypoglycaemia, normoglycaemic hyperinsulinaemia and food intake have been studied. A strong but differentiated influence of insulin-induced hypoglycaemia comprises increase in muscle sympathetic nerve activity (MSNA) and the sudomotor part of skin sympathetic nerve activity (SSNA), whereas vasoconstrictor SSNA is inhibited. Responses to infusion of 2-deoxy-D-glucose are identical, suggesting central nervous system glucopenia and not insulin to be the causative factor. Insulin infusion during normoglycaemia evokes a moderate increase in MSNA; SSNA and blood pressure does not change. After glucose ingestion MSNA displays a sustained increase, which is only partly elicited by insulin. A significant albeit weaker increase occurs after pure protein or fat meals, and after glucose ingestion in C-peptide-negative diabetic patients, with no insulin secretion. In healthy elderly people the MSNA response to food intake is weak, because of a high outflow already at rest; this is suggested to explain postprandial hypotension in the elderly, a paradoxical mechanism behind clinical autonomic failure. A pathophysiological role of MSNA in the metabolic syndrome with hypertension has been speculated. An association between obesity and elevated level of MSNA at rest is established; observed relationships to chronic insulin levels and hypertension are less unanimous. The adipose tissue regulating hormone leptin has become one focus of interest in ongoing attempts to elucidate a possible role of the human sympathetic nervous system in the 'metabolic syndrome' and hypertension. PMID: 12609004 [PubMed - indexed for MEDLINE] 4569. Obes Rev. 2003 Feb;4(1):43-55. Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Goossens GH(1), Blaak EE, van Baak MA. Author information: (1)Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. g.goossens@hb.unimaas.nl Angiotensin II (Ang II), acting on the AT1 and AT2 receptors in mammalian cells, is the vasoactive component of the renin-angiotensin system (RAS). Several components of the RAS have been demonstrated in different tissues, including adipose tissue. Although the effects of Ang II on metabolism have not been studied widely, it is intriguing to assume that components of the RAS produced by adipocytes may play an autocrine, a paracrine and/or an endocrine role in the pathophysiology of obesity and provide a potential pathway through which obesity leads to hypertension and type 2 diabetes mellitus. In the first part of this review, we will describe the production of Ang II, the different receptors through which Ang II exerts its effects and summarize the concomitant intracellular signalling cascades. Thereafter, potential Ang II-induced mechanisms, which may be associated with obesity and obesity-related disorders, will be considered. Finally, we will focus on the different pharmaceutical agents that interfere with the RAS and highlight the possible implications of these drugs in the treatment of obesity-related disorders. PMID: 12608526 [PubMed - indexed for MEDLINE] 4570. Obes Rev. 2003 Feb;4(1):17-24. Energy balance and pollution by organochlorines and polychlorinated biphenyls. Pelletier C(1), Imbeault P, Tremblay A. Author information: (1)Division of Kinesiology, PEPS, Laval University, Ste-Foy, Québec, Canada. Organochlorines are fat-soluble chemical compounds resistant to degradation, so they are stored in the adipose tissue of practically every organism on the planet, including humans. Accumulation of these compounds in the body seems to be related to fat mass, obese individuals having a higher plasma organochlorine concentration than lean subjects. During body weight loss, lipid mobilization and a decrease in fat mass result in increased concentrations of organochlorines in plasma and adipose tissue. Organochlorines may have adverse health effects. For example, they have been associated with altered immune and thyroid functions and with some types of cancer. As these compounds may reach their target organs whilst in the circulation, their increase in plasma during weight loss might be associated with some physiological changes occurring during weight loss. Relationships have indeed been reported among weight loss-induced increase in plasma organochlorine concentration and decreased triiodothyronine (T3) concentration, resting metabolic rate, and skeletal muscle markers for fat oxidation. Although further studies are needed to assess the causality of these relationships, they raise concern about some potential undesirable effects of weight loss. Indeed, the effects of organochlorines on energy balance could complicate body weight loss and even favour weight regain. These notions lend support for weight-loss strategies favouring a moderate weight loss, which would reduce risks for cardiovascular diseases, diabetes and hypertension, without resulting in a substantial release of organochlorines. PMID: 12608524 [PubMed - indexed for MEDLINE] 4571. Expert Opin Investig Drugs. 2003 Mar;12(3):373-8. The therapeutic potential of leptin. Proietto J(1), Thorburn AW. Author information: (1)Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia. Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood-brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action. PMID: 12605561 [PubMed - indexed for MEDLINE] 4572. Med Sci Monit. 2003 Feb;9(2):RA55-61. Adiponectin and resistin--new hormones of white adipose tissue. Bełtowski J(1). Author information: (1)Department of Pathophysiology, Lublin Medical University, Lublin, Poland. patfiz@asklepois.am.lublin.pl Comment in Med Sci Monit. 2003 Nov;9(11):LE26. Adiponectin and resistin are recently described secretory products of adipose tissue. Adiponectin is secreted by fat cells and circulates in the blood. Plasma adiponectin concentration is reduced in obese animals and humans and in patients with type 2 diabetes mellitus. Adiponectin stimulates fatty acids oxidation, decreases plasma triglycerides, and improves glucose metabolism by increasing insulin sensitivity. In addition, adiponectin inhibits the inflammatory process and possibly atherogenesis by suppressing the migration of monocytes/macrophages and their transformation into foam cells. Plasma adiponectin is lower in patients with ischemic heart disease than in body mass index-matched healthy individuals. Hypoadiponectinemia may contribute to insulin resistance and accelerated atherogenesis associated with obesity. Resistin/FIZZ3 is a member of the newly discovered cysteine-reach secretory protein family, referred to as 'resistin-like molecules' (RELM) or 'found in inflammatory zone' (FIZZ), together with FIZZ1/RELMalpha and FIZZ2/RELMbeta. Each of these has unique tissue distribution. Both resistin and FIZZ1/RELMalpha are expressed in adipose tissue. Initial studies in rodents suggested that resistin is upregulated in obesity and may be involved in the development of insulin resistance. Later studies failed to confirm this hypothesis and demonstrated reduced resistin expression in adipose tissue of obese animals. In human adipose tissue resistin is detectable at a very low level, and there is no relationship between resistin expression and obesity. Although the role of resistin in linking human obesity with type 2 diabetes is thus questionable, this protein is detected in peripheral blood monocytes, PMID: 12601307 [PubMed - indexed for MEDLINE] 4573. Cancer Detect Prev. 2003;27(1):55-66. Specific fatty acids and human colorectal cancer: an overview. Nkondjock A(1), Shatenstein B, Maisonneuve P, Ghadirian P. Author information: (1)Département de Nutrition, Faculté de Médecine, Université de Montréal, Montreal, Canada. BACKGROUND: Evidence suggests that dietary fats are associated with risk of colorectal cancer. The effect of fats depends not only on the quantity, but also on their composition in specific fatty acids. Moreover, fats are peroxidizable, and peroxidation products as well as antioxidants play a role in the pathogenic process of colorectal cancer. METHODS: The published literature was reviewed for the relationship between dietary intake or concentration of specific fatty acids in adipose tissue, erythrocytes, plasma or feces in relation to colorectal cancer. RESULTS: Increased concentrations of short-chain fatty acids (SCFAs) and eicosanopentaenoic acid (EPA) seem to protect against colorectal cancer. Increased concentrations of medium-chain fatty acids (MCFAs) and arachidonic acid (AA) might be associated with increased risk. Long-chain saturated fatty acids (LCSFAs) seem unrelated to colorectal cancer, while the associations between monounsaturated fatty acids (MUFAs), trans fatty acids, polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), omega-3/omega-6 ratio and colorectal cancer are unconvincing. CONCLUSIONS: It is suggested that the substitution of food with high MCFAs and AA content by a SCFAs- and EPA-rich diet may contribute to reduced risk of colorectal cancer. Copyright 2003 International Society for Preventive Oncology PMID: 12600418 [PubMed - indexed for MEDLINE] 4574. Curr Opin Nephrol Hypertens. 2003 Mar;12(2):195-200. Obesity-associated hypertension and kidney disease. Hall JE(1), Kuo JJ, da Silva AA, de Paula RB, Liu J, Tallam L. Author information: (1)Department of Physiology and Biophysics and Center of Excellence in Cardiovascular-Renal Research, Jackson, Mississippi, USA. jehall@physiology.umsmed.edu PURPOSE OF REVIEW: The worldwide prevalence of obesity and its associated metabolic and cardiovascular disorders has risen dramatically during the past two decades. Our objective is to review the mechanisms that link obesity with hypertension and altered kidney function. RECENT FINDINGS: Current evidence suggests that excess weight gain may be responsible for 65-75% of the risk for essential hypertension. Abnormal renal pressure natriuresis, due initially to increased renal tubular sodium reabsorption, is a key factor linking obesity with hypertension. Obesity increases renal sodium reabsorption by activating the renin-angiotensin and sympathetic nervous systems, and by altering intrarenal physical forces. Adipose tissue functions as an endocrine organ, secreting hormones/cytokines (e.g. leptin) that may activate the sympathetic nervous system and alter kidney function. Excess visceral adipose tissue may physically compress the kidneys, increasing intrarenal pressures and tubular reabsorption. Sustained obesity eventually causes structural changes in the kidneys and loss of nephron function, further increasing arterial pressure and leading to severe renal disease in some cases. SUMMARY: Despite considerable progress in understanding the pathophysiology of obesity, there are still no specific guidelines for the treatment of obesity hypertension other than weight reduction. Special considerations for obese hypertensive patients, in addition to controlling blood pressure, are correcting the metabolic abnormalities and protecting the kidneys from injury. This remains an important area for further research, especially in view of the current 'epidemic' of obesity in most industrialized countries. PMID: 12589181 [PubMed - indexed for MEDLINE] 4575. Int J Obes Relat Metab Disord. 2003 Feb;27(2):147-61. PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? Larsen TM(1), Toubro S, Astrup A. Author information: (1)Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Copenhagen, Denmark. tml@kvl.dk The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARgamma in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARgamma seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARgamma-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these 'adipogenic compounds' is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes. PMID: 12586994 [PubMed - indexed for MEDLINE] 4576. Obes Res. 2003 Feb;11(2):170-5. Effects of growth hormone administration in human obesity. Shadid S(1), Jensen MD. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. OBJECTIVE: To summarize the reports in the literature regarding the effect of growth hormone (GH) treatment of obesity. RESEARCH METHODS AND PROCEDURES: Clinical trials of GH treatment of obese adults were reviewed and summarized. Specifically, information regarding the effects of GH on body fat and body fat distribution, glucose tolerance/insulin resistance, and adverse consequences of treatment were recorded. RESULTS: GH administered together with hypocaloric diets did not enhance fat loss or preserve lean tissue mass. No studies provided strong evidence for an independent beneficial effect of GH on visceral adiposity. In all but one study, glucose tolerance during GH treatment suffered relative to placebo. CONCLUSION: The bulk of studies indicate little or no beneficial effects of GH treatment of obesity despite the low serum GH concentrations associated with obesity. PMID: 12582210 [PubMed - indexed for MEDLINE] 4577. Obes Res. 2003 Feb;11(2):167-9. PDK4: A factor in fatness? Sugden MC. PMID: 12582209 [PubMed - indexed for MEDLINE] 4578. Sci STKE. 2003 Feb 11;2003(169):PE7. Leptin--a critical body weight signal and a "master" hormone? Trayhurn P(1). Author information: (1)Liverpool Centre for Nutritional Genomics, Neuroendocrine and Obesity Biology Unit, Department of Medicine, University of Liverpool, University Clinical Departments, Liverpool L69 3GA, UK. p.trayhurn@liverpool.ac.uk Leptin, initially identified as a hormone produced by white fat that acted as a satiety signal, has since been found to be synthesized in various tissues and to subserve diverse functions, including regulation of blood glucose concentrations and blood vessel growth, and signaling to the reproductive and immune systems. Recent research suggests that leptin, acting through the sympathetic nervous system, may also regulate bone density. Trayhurn discusses this research in the context of the established bidirectional interaction between leptin and the sympathetic nervous system, and the need to elucidate a unifying theme with which to make sense of leptin's myriad, seemingly quite disparate, functions. PMID: 12582201 [PubMed - indexed for MEDLINE] 4579. Am J Physiol Regul Integr Comp Physiol. 2003 Mar;284(3):R639-51. Cardiovascular effects of leptin and orexins. Shirasaka T(1), Takasaki M, Kannan H. Author information: (1)Department of Anesthesiology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Leptin, the product of the ob gene, is a satiety factor secreted mainly in adipose tissue and is part of a signaling mechanism regulating the content of body fat. It acts on leptin receptors, most of which are located in the hypothalamus, a region of the brain known to control body homeostasis. The fastest and strongest hypothalamic response to leptin in ob/ob mice occurs in the paraventricular nucleus, which is involved in neuroendocrine and autonomic functions. On the other hand, orexins (orexin-A and -B) or hypocretins (hypocretin-1 and -2) were recently discovered in the hypothalamus, in which a number of neuropeptides are known to stimulate or suppress food intake. These substances are considered important for the regulation of appetite and energy homeostasis. Orexins were initially thought to function in the hypothalamic regulation of feeding behavior, but orexin-containing fibers and their receptors are also distributed in parts of the brain closely associated with the regulation of cardiovascular and autonomic functions. Functional studies have shown that these peptides are involved in cardiovascular and sympathetic regulation. The objective of this article is to summarize evidence on the effects of leptin and orexins on cardiovascular function in vivo and in vitro and to discuss the pathophysiological relevance of these peptides and possible interactions. PMID: 12571072 [PubMed - indexed for MEDLINE] 4580. Curr Top Med Chem. 2003;3(4):369-85. Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Dhalla AK(1), Shryock JC, Shreeniwas R, Belardinelli L. Author information: (1)Department of Drug Research and Pharmacological Sciences, CV Therapeutics Inc. Palo Alto, CA 94304, USA. Adenosine's diverse physiological functions are mediated by four subtypes of receptors (A(1), A(2A), A(2B) and A(3)). The A(1) adenosine receptor pharmacology and therapeutic application of ligands for this receptor are the subjects of this review. A(1) receptors are present on the surface of cells in organs throughout the body. Actions mediated by A(1) receptors include slowing of heart rate and AV nodal conduction, reduction of atrial contractility, attenuation of the stimulatory actions of catecholamines on beta-adrenergic receptors, reduction of lipolysis in adipose tissue, reduction of urine formation, and inhibition of neuronal activity. Although adenosine analogs with high efficacy, affinity, and selectivity for the A(1) receptor are available, the ubiquitous distribution and wide range of physiological actions mediated by A(1) receptors are obstacles to development of therapeutic agents that activate these receptors. However, it may be possible to exploit the high A(1) "receptor reserve" for some actions of adenosine by use of weak (partial) agonists to target these actions while avoiding others for which receptor reserve is low. The presence of high receptor reserves for the anti-arrhythmic and anti-lipolytic actions of adenosine suggests that partial A(1) agonists could be used as anti-arrhythmic and anti-lipolytic agents. In addition, allosteric enhancers of the binding of adenosine to A(1) receptors could be used therapeutically to potentiate desirable effects of endogenous adenosine. Antagonists of the A(1) receptor can increase urine formation, and because they do not decrease renal blood flow, are particularly useful to maintain glomerular filtration in patients having edema secondary to reduced cardiac function. PMID: 12570756 [PubMed - indexed for MEDLINE] 4581. Cytotherapy. 2002;4(6):509-10. Adipose tissue: challenging the marrow monopoly. Fraser JK(1). Author information: (1)David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. PMID: 12568984 [PubMed - indexed for MEDLINE] 4582. Br J Nutr. 2003 Jan;89(1):3-9. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Wood IS(1), Trayhurn P. Author information: (1)Liverpool Centre for Nutritional Genomics, Neuroendocrine & Obesity Biology Unit, Department of Medicine, UK. iswood@liverpool.ac.uk The number of known glucose transporters has expanded considerably over the past 2 years. At least three, and up to six, Na+-dependent glucose transporters (SGLT1-SGLT6; gene name SLC5A) have been identified. Similarly, thirteen members of the family of facilitative sugar transporters (GLUT1-GLUT12 and HMIT; gene name SLC2A) are now recognised. These various transporters exhibit different substrate specificities, kinetic properties and tissue expression profiles. The number of distinct gene products, together with the presence of several different transporters in certain tissues and cells (for example, GLUT1, GLUT4, GLUT5, GLUT8, GLUT12 and HMIT in white adipose tissue), indicates that glucose delivery into cells is a process of considerable complexity. PMID: 12568659 [PubMed - indexed for MEDLINE] 4583. J Assoc Physicians India. 2002 Oct;50:1303-11. Cellular and molecular biology of adiposity and adipogenesis. Lele RD(1). Author information: (1)Lilavati Hospital and Research Centre, Mumbai. PMID: 12568218 [PubMed - indexed for MEDLINE] 4584. Horm Res. 2003;59(1):1-6. Low birth weight: effect on insulin sensitivity and lipid metabolism. Jaquet D(1), Léger J, Lévy-Marchal C, Czernichow P. Author information: (1)INSERM Unité 457, Hôpital Robert Debré, Paris, France. The metabolic and cardiovascular complications associated with reduced fetal growth have been identified during the past 10 years. These complications that encompass cardiovascular diseases and insulin resistance syndrome consist of dyslipidemia, impaired glucose tolerance or type 2 diabetes and appear to result from the initial development of insulin resistance. The association of reduced fetal growth with the other parameters of the syndrome X appear less constant than with insulin resistance and the expression and/or the age of onset seem to depend on the degree of genetic predisposition of the population. Although the mechanisms underlying the development of the insulin resistance associated with reduced fetal growth remain unclear, some evidence argues in favor of a key role of the adipose tissue. Several hypotheses have been proposed over the past 10 years to understand this unexpected association. Each of them points to either a detrimental fetal environment or genetic susceptibilities or interactions between these two components as playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains at the moment the most attractive. Copyright 2003 S. Karger AG, Basel PMID: 12566728 [PubMed - indexed for MEDLINE] 4585. Horm Res. 2003;59 Suppl 1:77-84. Type 2 diabetes mellitus in children and adolescents: a review from a European perspective. Kiess W(1), Böttner A, Raile K, Kapellen T, Müller G, Galler A, Paschke R, Wabitsch M. Author information: (1)Hospital for Children and Adolescents, University of Leipzig, Germany. kiw@medizin.uni-leipzig.de Changes in food consumption and exercise are fueling a worldwide increase in obesity in children and adolescents. As a consequence of this dramatic development, an increasing rate of type 2 diabetes mellitus has been recorded in children and adolescents in the USA and, more recently, in many countries around the world. Both genetic and environmental factors contribute to the pathogenesis of type 2 diabetes. Lower susceptibility in white Caucasians and higher susceptibility in Asians, Hispanics and blacks have been noted. There is a high hidden prevalence and a lack of exact data on the epidemiology of the disease in Europe: in Germany only 70 patients below the age of 15 years were identified in the systematic, nationwide DPV (Diabetessoftware für prospektive Verlaufsdokumentation) diabetes survey, but our calculations suggest that more than 5000 young people in Germany at present would meet the diagnostic criteria of type 2 diabetes. In Australasia, the prevalence of type 2 diabetes is reportedly high in some ethnic groups and again is linked very closely to the obesity epidemic. No uniform and evidence-based treatment strategy is available: many groups use metformin, exercise programmes and nutritional education as a comprehensive approach to treat type 2 diabetes in childhood and adolescence. The lack of clear epidemiological data and a strong need for accepted treatment strategies point to the key role of preventive programmes. Prevention of obesity will help to counteract the emerging worldwide epidemic of type 2 diabetes in youth. Preventive programmes should focus on exercise training and reducing sedentary behaviour such as television viewing, encouraging healthy nutrition and supporting general education programmes since shorter school education is clearly associated with higher rates of obesity and hence the susceptibility of an individual to acquire type 2 diabetes. Copyright 2003 S. Karger AG, Basel PMID: 12566725 [PubMed - indexed for MEDLINE] 4586. Am J Med. 2002 Dec 30;113 Suppl 9B:47S-59S. Dietary fat is not a major determinant of body fat. Willett WC(1), Leibel RL. Author information: (1)Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. The percentage of energy from fat in diets has been thought to be an important determinant of body fat, and several mechanisms have been proposed. Comparisons of diets and the prevalence of obesity between affluent and poor countries have been used to support this relationship, but these contrasts are seriously confounded by differences in physical activity and food availability. Within areas of similar economic development, regional intake of fat and prevalence of obesity have not been positively correlated. Randomized trials are the preferable method to evaluate the effect of dietary fat on adiposity and are feasible because the number of subjects needed is not large. In short-term trials, a modest reduction in body weight is typically seen in individuals randomized to diets with a lower percentage of calories from fat. However, compensatory mechanisms appear to operate, because in randomized trials lasting >or=1 year, fat consumption within the range of 18% to 40% of energy appears to have little if any effect on body fatness. The weighted mean difference was -0.25 kg overall and +1.8 kg (i.e., less weight loss on the low-fat diets) for trials with a control group that received a comparable intensity intervention. Moreover, within the United States, a substantial decline in the percentage of energy from fat during the last 2 decades has corresponded with a massive increase in the prevalence of obesity. Diets high in fat do not appear to be the primary cause of the high prevalence of excess body fat in our society, and reductions in fat will not be a solution. PMID: 12566139 [PubMed - indexed for MEDLINE] 4587. Am J Med. 2002 Dec 30;113 Suppl 9B:41S-46S. Low-fat diets are preferred. Jéquier E(1), Bray GA. Author information: (1)Institute of Physiology, University of Lausanne, Lausanne, Switzerland. This short review summarizes 4 main reasons for which low-fat diets are preferred to limit excessive weight gain: (1) For metabolic reasons, fat intake does not measurably stimulate fat oxidation; dietary fat above energy requirements is stored in adipose tissue. (2) Diets that are high in fat or are energy dense have a weak satiating effect and promote a passive overconsumption of energy relative to need. (3) A recent meta-analysis on the effect on body weight loss of low-fat diets followed for >2 months showed a significant weight difference of 3.3 kg between the diet and the control groups. A low-fat diet may also be beneficial in helping maintain weight loss. (4) Low-fat diets are also advocated to lower the risk of coronary heart disease and certain forms of cancer. There is no evidence showing that the small physiologic reduction of plasma highdensity lipoprotein cholesterol levels with a low-fat diet is detrimental. PMID: 12566138 [PubMed - indexed for MEDLINE] 4588. J Physiol. 2003 Feb 15;547(Pt 1):5-10. Epub 2002 Aug 2. The dangerous road of catch-up growth. Hales CN(1), Ozanne SE. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK. cnh1000@cam.ac.uk Many epidemiological studies have now shown a strongly increased risk of developing type 2 diabetes and the metabolic syndrome in adults who as neonates showed signs of poor early (fetal and early postnatal) growth. The thrifty phenotype hypothesis was proposed to provide a conceptual and experimentally testable basis of these relationships. We have used protein restriction of rat dams, as a means to test this hypothesis. In vivo and in vitro studies of the growth-restricted offspring of such pregnancies have provided findings showing remarkable parallels with the human conditions. Permanent changes in the expression of regulatory proteins in liver, muscle and adipose tissue provide at least part of the explanation of the changes observed and offer potential markers for testing in the human context. These studies have also raised the question as to whether 'catch up' growth following early growth retardation may add to the risks posed by this early handicap. Male rats growth-retarded during fetal life and cross-fostered shortly after birth to normal lactating dams reach normal body and organ weights by weaning but have a reduced longevity. This finding raises the possibility that catch up growth, whilst potentially beneficial in the short term, may be detrimental to long-term survival. Human epidemiological studies may point in the same direction. Work by others on other models of early growth restriction have produced similar, although more limited, data. These findings raise the interesting possibility that the response to fetal stress, be it nutritional or other, may evoke a somewhat restricted and uniform pattern of adaptive response. PMCID: PMC2342634 PMID: 12562946 [PubMed - indexed for MEDLINE] 4589. Dermatol Surg. 2003 Feb;29(2):165-7; discussion 167. Breast enlargement observed after power liposuction: a retrospective review. Yun PL(1), Bruck M, Felsenfeld L, Katz BE. Author information: (1)College of Physicians and Surgeons, Columbia University, New York, New York, USA. Comment in Dermatol Surg. 2003 Nov;29(11):1162. BACKGROUND: After undergoing power liposuction to various body areas, a significant number of subjects reported an increase in their breast size that occurred spontaneously several months after their procedure. OBJECTIVE: To establish the incidence of breast enlargement among subjects who underwent power liposuction and to identify variables that are associated with the phenomenon. METHODS: A retrospective chart review and patient interview were performed from among 73 subjects who had undergone power liposuction at our center. Variables such as age, original weight, volume of aspirated fat, estrogen supplements, amount of weight loss or gain, and body areas aspirated were compared between those who experienced breast enlargement and those who did not. RESULTS: Thirty-four percent of the subjects (25 of 73) reported an increase in breast size. Of this group, 32% (8 of 25) reported an increase in cup size of one or more. Variables associated with the cohort who experienced breast enlargement included larger volume of fat aspiration and liposuction in the abdomen and hip location. CONCLUSION: Breast enlargement was observed in 34% of the subjects after power liposuction either in the form of a larger bra cup size or a subjective feeling of increased fullness. We hypothesize that an altered androgen to estrogen ratio after liposuction may be responsible for this change. PMID: 12562347 [PubMed - indexed for MEDLINE] 4590. Ann Cardiol Angeiol (Paris). 2000 Feb;49(1):37-47. [Etiopathogenesis of arrhythmogenic right ventricular dysplasia]. [Article in French] Fontaine G(1), Mallat Z, Fornes P, Fontaliran F, Frank R. Author information: (1)Hôpital Jean Rostand, 39, rue Jean Le Galleu, 94200 Ivry-sur-Seine, France. Arhythmogenic right ventricular dysplasia (ARVD) is a genetically determined cardiomyopathy with a dominant transmission mode and variable penetrance. Transdifferenciation of cardiomyocytes into adipocytes is likely to explain massive replacement of right ventricular and to a lesser extent left ventricular myocardium by adipose tissue. This phenomenon starts in the mediomural layers and extends into the epicardium. It can occur in the fetus, however youth and young adults are more frequently involved. Apoptosis defined as a programmed cell death, is likely to enhance adipogenesis and tiny fibrosis production. Inflammation can be superimposed on the genetically determined substrate and usually involves both ventricles. Myocarditis can be acute or chronic with interstitial or scar fibrosis, or active chronic. In some cases, left ventricular involvement can be as important as right ventricle, characterizing biventricular dysplasia. In Naxos disease, ARVD is associated with an ectodermic dysplasia. The transmission mode is recessive. PMID: 12555319 [PubMed - indexed for MEDLINE] 4591. Eur J Obstet Gynecol Reprod Biol. 2003 Feb 10;106(2):118-24. The role of leptin in fertility. Goumenou AG(1), Matalliotakis IM, Koumantakis GE, Panidis DK. Author information: (1)Department of Obstetrics and Gynecology, University of Crete, P.O. Box 1393, 714-9 Heraklion, Crete, Greece. The relationship between metabolism and reproduction remains a mystery in female endocrinology. Such substances as insulin, amino acids and IGFBP-I have been proposed as signals of body mass fat on the genital axis. Today this role is claimed by leptin, a protein hormone decoded from the obesity gene and is secreted exclusively from adipose tissue. This hormone acts on the central nervous system (CNS) to result in the suppression of food intake and increase in energy consumption. What is more, it also influences the capacity for reproduction. This paper reports findings with regard to the factors influencing the secretion of leptin and identification of the leptin's hormonal receptors. Particular emphasis was placed on the relationship between secretion of leptin and disturbances in menstruation, the anticipated role of this hormone in the pathogenesis of the polycystic ovarian syndrome (PCOS) and its effects on the reproductive capacity. PMID: 12551775 [PubMed - indexed for MEDLINE] 4592. Prog Lipid Res. 2003 Mar;42(2):81-92. Effects of HIV protease inhibitor therapy on lipid metabolism. Hui DY(1). Author information: (1)Department of Pathology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA. huidy@email.uc.edu Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection. PMID: 12547652 [PubMed - indexed for MEDLINE] 4593. Curr Opin Lipidol. 2003 Feb;14(1):29-33. Diacylglycerol on lipid metabolism. Tada N(1), Yoshida H. Author information: (1)Department of General Medicine, Jikei University School of Medicine, Chiba, Japan. n-tada27@jikei.ac.jp PURPOSE OF REVIEW: Diacylglycerol is an intermediate product of triacylglycerol hydrolysis and comprises up to 10% of glycerides in plant-derived edible fats and oils. Recent developments in oil chemistry have led to the availability of a novel diacylglycerol oil for clinical studies. Recent research has shown that the oil containing 70% of unusual 1,3- species has metabolic characteristics distinct from those of triacylglycerol of similar fatty acid composition. This review summarizes recent research in humans and experimental animals into the metabolic effects and possible mechanisms of action of this oil. RECENT FINDINGS: Consumption of the oil affects lipid metabolism including lowering of plasma triacylglcerol, decreases postprandial lipemia and reduces body fat mass, compared with triacylglcerol. As the fatty acids of the two oils are similar, the metabolic differences reside in their structural differences. SUMMARY: It is still uncertain whether longer term consumption of the diacylglycerol oil will lead to persistent and consistent reductions in plasma triacylglycerol and body fat. However future studies may demonstrate a role in managing aspects of the metabolic syndrome. PMID: 12544658 [PubMed - indexed for MEDLINE] 4594. Pediatr Infect Dis J. 2003 Jan;22(1):77-84. Metabolic complications of antiretroviral therapy in children. Leonard EG(1), McComsey GA. Author information: (1)Division of Pediatric Infectious Diseases, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA. Survival in HIV-infected children has greatly improved with the introduction of highly active antiretroviral therapy. Children are more vulnerable than adults to metabolic side effects of therapy because of its potential impact on growth and the children's likely greater cumulative exposure. This review summarizes the epidemiology and management of lipodystrophy, dyslipidemia, insulin resistance, hyperlactatemia, osteopenia and growth failure in HIV-infected children. PMID: 12544413 [PubMed - indexed for MEDLINE] 4595. Ann N Y Acad Sci. 2002 Dec;979:143-58; discussion 188-96. The molecular control of adipogenesis, with special reference to lymphatic pathology. Rosen ED(1). Author information: (1)Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. erosen@caregroup.harvard.edu Adipogenesis is the process by which mature fat cells are formed from pre-adipocytes. Adipogenesis has come under increasing scrutiny not only because the availability of reliable in vitro models makes it an attractive choice for developmental studies, but also because adipocytes are increasingly recognized as major players in a variety of physiological and pathophysiological states, such as obesity and type 2 diabetes. Adipocytes develop from mesenchymal stem cell precursors that are characterized by multipotency. Under the influence of various cues, these cells become committed to the adipocyte lineage. Further hormonal stimulation recruits these pre-adipocytes to accumulate lipid, express fat-specific markers, and become sensitive to the metabolic effects of insulin. A complex transcriptional cascade regulates this process, involving several distinct classes of transcription factor. In particular, the role of the nuclear hormone receptor PPARgamma will be discussed, along with bZip family members C/EBPalpha, C/EBPbeta, and C/EBPdelta. The relationship of adipose depots to the lymphatic system will also be discussed. PMID: 12543724 [PubMed - indexed for MEDLINE] 4596. Biochim Biophys Acta. 2003 Jan 31;1609(2):127-43. Critical review of acylation-stimulating protein physiology in humans and rodents. Cianflone K(1), Xia Z, Chen LY. Author information: (1)McGill University, Cardiology, H7.30, Royal Victoria Hospital, 687 Pine Ave West, Montreal, Quebec, Canada H3A 1A1. katherine.cianflone@mcgill.ca In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans. PMID: 12543373 [PubMed - indexed for MEDLINE] 4597. Am J Clin Nutr. 2003 Feb;77(2):281-7. Calcium intake and adiposity. Parikh SJ(1), Yanovski JA. Author information: (1)Unit on Growth and Obesity, Developmental Endocrinology Branch, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD 20892-1862, USA. pariks@mail.nih.gov Limited epidemiologic and experimental data support the possibility that dietary calcium intake plays a role in human body weight regulation. The aim of this review was to present the data from human studies that link calcium and dairy intake to body weight, describe the existing evidence for an effect of calcium intake on body weight from animal models of obesity, present evidence of a role for intracellular calcium in the regulation of lipogenesis and lipolysis, elucidate the potential suggested relation between dietary calcium intake and intracellular calcium concentrations, and outline the effects of calcium supplementation on dietary fat absorption. We suggest that these data support the need for large, population based clinical trials to assess the effects of supplemental calcium and other components of dairy products on human body weight. PMID: 12540383 [PubMed - indexed for MEDLINE] 4598. Reprod Nutr Dev. 2002 Sep-Oct;42(5):399-413. Mammary leptin synthesis, milk leptin and their putative physiological roles. Bonnet M(1), Delavaud C, Laud K, Gourdou I, Leroux C, Djiane J, Chilliard Y. Author information: (1)Unité de Recherche sur les Herbivores, Equipe Tissu Adipeux et Lipides du Lait, INRA, 63122 Saint-Genès-Champanelle, France. This paper reviews data on mammary leptin and leptin receptor gene expression as well as on blood and milk leptin levels during the pregnancy-lactation cycle in humans, rodents and ruminants, with the aim of better understanding milk leptin origin and functions. The few published papers report that leptin may be produced by different cell types in the mammary tissue, and may act as a paracrine factor on mammary epithelial cell proliferation, differentiation and/or apoptosis via adipose-epithelial and/or myoepithelial-epithelial cellular interactions. In addition to leptin synthesis, epithelial cells may transfer leptin from the blood, and these two mechanisms may account for the presence of leptin in the milk. The respective parts of these two processes remain to be determined, as well as the true milk leptin levels. Indeed, reported concentrations for milk leptin vary strongly according to species and mainly according to the milk fractions and the assay methods used. If leptin levels in milk (and specially colostrum) are found to be significant, this hormone could be involved in neonate physiology. PMID: 12537253 [PubMed - indexed for MEDLINE] 4599. Semin Thromb Hemost. 2002 Dec;28(6):555-68. Aging and thrombosis. Wilkerson WR(1), Sane DC. Author information: (1)Department of Internal Medicine, Section of Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1045, USA. Advanced age is associated with a dramatic increase in the rates of venous and arterial thrombotic events. Increases in fibrinogen, factors VIII and IX, and other coagulation proteins, without a proportional increase in anticoagulant factors, likely contribute to this risk. Recent studies have delineated a role for genomic elements in controlling age-related expression of some coagulation proteins. Enhanced platelet activity as well as molecular and anatomic changes in the vessel wall also contribute to the thrombotic propensity. Advanced age is associated with elevated interleukin-6 (IL-6) and C-reactive protein levels, indicating an inflammatory state that may be an important stimulus for thrombus formation in the elderly. Despite evidence of a prothrombotic state, many elderly people do not experience clinical thrombotic events. It is possible that the increase in coagulation proteins and activation markers conveys a survival advantage, such as inhibiting tumor angiogenesis. The recent epidemic in obesity may heighten thrombotic risks in the elderly because adipose tissue is an important source of inflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1). As the population ages, further studies will be warranted to define the mechanisms for thrombosis in the elderly. PMID: 12536349 [PubMed - indexed for MEDLINE] 4600. Drugs Today (Barc). 2002 Feb;38(2):113-33. Matrices for tissue-engineered skin. Hutmacher DW(1), Vanscheidt W. Author information: (1)Division of Bioengineering, Faculty of Mechanical Engineering, Department of Orthopaedic Surgery, Faculty of Medicine, National University of Singapore, Singapore. Academic, clinical and industrial efforts are increasingly being directed toward the use of molecular- and cell-based therapies for diagnosis and treatment of a great number and broad variety of pathologies and injuries. Hence, tissue engineering is, next to genetic engineering, widely heralded as the healthcare technology heir of the revolutionary advances in life sciences. In a cost-controlled healthcare environment, only those technologies capable of providing a major enhancement to quality of life and a reduction in expenditure will be driven forward. Skin tissue engineering concepts based on the application of a scaffold/cell construct represent a treatment concept with the clear potential to meet this criterion. Several important issues concerning the research and product strategy (e.g., choice of matrix of natural or synthetic polymer origin and the use of autogenic versus allogenic cells) remain to be fully resolved. However, there is little doubt that wound regeneration via modern tissue engineering strategies will present significant therapeutic benefits when compared with existing treatments. This paper reviews the biography and future research directions of matrices used in skin tissue engineering. PMID: 12532189 [PubMed - indexed for MEDLINE] 4601. Obes Res. 2003 Jan;11(1):2-4. Measuring activity of the autonomic nervous system in humans. Hirsch J, Mackintosh RM. PMID: 12529478 [PubMed - indexed for MEDLINE] 4602. Ann Endocrinol (Paris). 2002 Dec;63(6 Pt 1):511-23. [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)]. [Article in French] Dubois M(1), Vantyghem MC, Schoonjans K, Pattou F. Author information: (1)ERIM 0106, Thérapie Cellulaire du Diabète, Faculté de Médecine, 1, place de Verdun, 59045 Lille Cedex. Thiazolidinediones (TZDs) form a new class of oral antidiabetic agents. They improve insulin sensitivity and reduce glycemia, lipidemia and insulinemia in patients with type 2 diabetes. Their mechanism is original, since they activate the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), altering the expression of genes involved in glucose and lipid homeostasis. Stimulating PPARgamma improves insulin sensitivity via several mechanisms: 1) it raises the expression of GLUT4 glucose transporter; 2) it regulates release of adipocyte-derived signaling factors that affect insulin sensitivity in muscle, and 3) it contributes to a turn-over in adipose tissue, inducing the production of smaller, more insulin sensitive adipocytes. TZDs also affect free fatty acids (FFA) lipotoxicity on islets, improving pancreatic B-cell function. In addition, triglycerides and FFA levels are lowered by TZDs. Two TZDs, rosiglitazone and pioglitazone, have recently obtained the European commercial licence, but their use is restricted to the association with metformin or sulfonylureas. At the moment, they are indicated in type 2 diabetes but could be of interest in a broader array of diseases related to insulin resistance. As for side effects, rosiglitazone and pioglitazone may cause increased plasma volume, edema and dose-related weight gain. TZDs offer an attractive option in the treatment of type 2 diabetes, though it may be too soon to determine if they prevent vascular complications, as do other oral antidiabetic agents. An important issue for the future will be to assess the influence of weight gain in the long time. PMID: 12527853 [PubMed - indexed for MEDLINE] 4603. Exp Physiol. 2003 Jan;88(1):141-8. Cold-induced recruitment of brown adipose tissue thermogenesis. Klingenspor M(1). Author information: (1)Animal Physiology, Department of Biology, Philipps-University, Marburg, Germany. klingens@mailer.uni-marburg.de Non-shivering thermogenesis in brown adipose tissue is the main mechanism for thermoregulatory heat production in small mammals and newborns. During cold acclimation the sympathetic innervation triggers the recruitment of brown adipose tissue by hyperplasia, which involves the proliferation and differentiation of precursor cells, and by hypertrophy of mature brown adipocytes. Mitochondrial biogenesis and increased synthesis of the uncoupling protein 1 (UCP-1) are hallmarks of the thermogenic recruitment process. The severalfold increase of mitochondrial protein content during cold acclimation recruits a large capacity for oxidative phosphorylation. However, UCP-1 increases proton leakage across the inner membrane of brown adipocyte mitochondria and thereby dissipates proton motive force as heat instead of ATP synthesis. During recent years considerable progress has been achieved in the analysis of transcriptional mechanisms controlling Ucp1 gene expression. However, so far only little is known about the molecular basis of cold-induced mitochondrial biogenesis in brown adipose tissue. PMID: 12525862 [PubMed - indexed for MEDLINE] 4604. J Am Diet Assoc. 2003 Jan;103(1):86-96. The effect of fiber-rich carbohydrates on features of Syndrome X. Davy BM(1), Melby CL. Author information: (1)Department of Medicine, The University of Mississippi Medical Center, Jackson 39216, USA. There has been much debate among nutritionists and scientists regarding the optimal dietary approach for the treatment of the Insulin Resistance Syndrome, also called Syndrome X. This condition, which may affect as many as 47 million individuals in the United States, significantly increases risk of coronary heart disease and stroke. Major health organizations have historically recommended high-carbohydrate, low-fat (HCLF) diets to reduce chronic disease risk. However, there is evidence that a high intake of carbohydrates may adversely affect one or more of the abnormalities associated with this syndrome. Studies in this area have often had limitations. For example, some studies showing adverse effects of an HCLF diet have not taken into account the dietary fiber content of the diet. This article describes abnormalities often associated with Syndrome X, reviews the beneficial effects of fiber-rich carbohydrates, discusses the effect of fiber-rich carbohydrates on features of this syndrome, and concludes with applications of these findings for those involved in treating individuals with features of this disorder. This review indicates that an HCLF dietary pattern such as that used in the DASH trial, with a level of dietary fiber consistent with the recommendations of the American Dietetic Association (eg, 20-35g/day), containing from 3 to 10 g soluble fiber/day, may be beneficial for treating those with Syndrome X. PMID: 12525799 [PubMed - indexed for MEDLINE] 4605. Adv Parasitol. 2002;52:1-154. The ecology of fish parasites with particular reference to helminth parasites and their salmonid fish hosts in Welsh rivers: a review of some of the central questions. Thomas JD(1). Author information: (1)School of Biological Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK. Ecological studies carried out in Welsh rivers on the feeding behaviour of salmonid fish, their helminth parasites and intermediate hosts in the early 1950s and in 1998 have been used as a basis to review the literature dealing with the following questions. First, how are the helminth populations dispersed in space-time? Second, to what extent are the distributional patterns and the life history strategies of the parasites influenced by physicochemical factors? Third, to what extent are populations of helmith parasites in salmonid fish influenced by host characteristics including the genome, sex, age, size, social position and Feeding behaviour? Fourth, are the populations of parasites regulated in a density-dependent manner? Fifth, do the parasites influence the survival and wellbeing of their salmonid hosts and the evolution of sex? Sixth, to what extent is the parasite community influenced by environmental changes including those of an anthropogenic nature and can the parasites be used as bioindicators of pollution? As with most parasites the helminth species found were highly overdispersed thus making it necessary to undertake a log10 (1 + x) conversion for statistical analyses. Statistical analyses confirm that the genome, age and sex of salmonid fish hosts, the station and seasonal change in radiation levels were significant factors in predicting the number of parasites. The evidence given supports the hypothesis that the feeding behaviour and habitat selection by the host fish, their position in the social hierarchy and the overdispersed nature of the transmission sites are the key factors in causing differences in the parasitic fauna related to host species, age, size and sex. Differences in the helminth parasite community related to station can be explained on the basis of differences in water types, sediments and chemistry. Although the evidence presented is in accord with the consensus view that temperature is correlated with seasonal changes in the abundance of many species of helminth parasites, it is argued that it may not be the direct causative mechanism. It is postulated that the life history strategy that results in a decline in abundance of the more vulnerable adult parasites in the gut of the salmonid hosts during the summer has arisen as a result of evolutionary pressures. At this time, the gut environment is particularly inhospitable because of the temperature-related enhancement of the host's immune mechanism and the increased gut turnover rate. In contrast, the larval stages in the immunologically and metabolically more benign intermediate host would be under less intensive selective pressures. It is postulated therefore that evolutionary pressures have caused the parasites to leave the definitive host and concentrate their reproductive efforts in the intermediate hosts during the warmer months. Evidence is given in support of the hypothesis that the parasite populations are regulated in a density-dependent manner and that the regulatory mechanisms may involve the host's immune mechanisms and intraspecies competition and interspecies competition of an exploitative or interference nature. Quantitative studies using 'K' factor analysis and biochemical research to elucidate the nature of the interference mechanisms are required to test this hypothesis. The absence of age-related resistance indicates an old and stable relationship in which the immunosuppressive and immunoavoidance mechanisms of the parasites and hosts, respectively, are in balance. This indicates that the introduction of novel parasites or new genetic strains of host fish could result in harmful epidemics. Despite causing tissue damage, there was no evidence of parasite-induced mortality among the salmonids in the Teifi. This finding is in accord with the generally accepted view that most freshwaters are not troubled by parasite problems. although parasites are present in abundance. In fact, parasite abundance in the salmonid fish in the Teifi was positively correlated with the condition factor and the adipose index. Two testable hypotheses were advanced to explain these observations. First, the more dominant well-conditioned fish in the hierarchy are more likely to acquire parasites because they ingest more food items and spend more time in sheltered habitats with depositing sediments where transmission mainly occurs. Second, the parasites may release factors that stimulate the host's immune and endocrinological systems to produce factors that enhance somatic growth and inhibit reproduction of the host. This benign relationship is considered to be indicative of long-term coevolution. The sex of the fish had a significant influence on the abundance of the parasites in total and also on particular species with the bias in all cases being in favour of the female fish. This review shows that sex bias in parasitism is generally not strong and that male bias in parasitism is not a general rule. Taken as a whole, the results fail to support most of the predictions based on the Hamilton-Zuk and the immunocompetence hypotheses. Possible hypotheses to explain why parasitism tends to be higher in female than in male trout include testosterone immunosuppression, corticosteroid-based immune suppression and differences between the size and behaviour of the sexes. However, the latter two hypotheses have more credence, although testosterone levels are higher in female than male trout. Between the early 1950s and 1998 there has been a marked decline in the prevalence, abundance and diversity of the helminth parasite communities in salmonid fish as well as their intermediate hosts. Possible reasons for these declines include heavy metal pollution, increased acidity and habitat degradation linked to changes in land use. It is concluded that although helminth parasites can provide supplementary information on pollution. the use of biotic indices based on the Biological monitoring working party (BMWP) or River invertebrate prediction and classification system (RIVPACS) methods are preferable. However, as these methods were designed to measure the impact of organic pollution they lack the sensitivity for measuring metal pollution. It is advocated therefore that new biomonitoring methods should be developed to measure the impact of heavy metal pollution using biotic indices based on the sampling of the susceptible invertebrate communities inhabiting depositing sediments in the transmission sites of helminth parasites. PMID: 12521260 [PubMed - indexed for MEDLINE] 4606. Annu Rev Physiol. 2003;65:261-311. Epub 2002 May 1. Nuclear receptors and the control of metabolism. Francis GA(1), Fayard E, Picard F, Auwerx J. Author information: (1)CIHR Group on Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders. PMID: 12518001 [PubMed - indexed for MEDLINE] 4607. Minerva Endocrinol. 2002 Dec;27(4):299-311. A transgenic model to determine the physiological role of liver-derived insulin-like growth factor I. Sjögren K(1), Jansson JO, Isaksson OG, Ohlsson C. Author information: (1)Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden. Insulin-like growth factor-I (IGF-I) has important growth promoting and metabolic effects and is expressed in virtually every tissue of the body. The highest expression is found in the liver but the physiological role of liver-derived IGF-I is unknown. It has been difficult to separate the endocrine effects of liver-derived IGF-I from the autocrine/paracrine effects of locally produced IGF-I in peripheral tissues. Therefore, we have developed a mouse model with a liver-specific inducible deletion of the IGF-I gene. The liver-IGF-I deficient mouse have dramatically reduced (>80%) serum IGF-I levels, demonstrating that the major part of serum IGF-I is liver-derived. Surprisingly, liver-IGF-I deficient mice demonstrate a normal appendicular skeletal growth up to at least 12 months of age despite the dramatic decrease in circulating IGF-I levels, indicating that liver-derived IGF-I is not required for appendicular skeletal growth. However, the adult axial skeletal growth is clearly reduced in the liver-IGF-I deficient mice. Furthermore, the amount of cortical bone is reduced due to decreased radial growth of the cortical bone while the amount of trabecular bone is unchanged in the liver-IGF-I deficient mice. The decreased levels of circulating IGF-I are associated with increased serum levels of growth hormone (GH), indicating a role for liver-derived IGF-I in the negative feedback regulation of GH secretion. Measurements of factors regulating GH-secretion in the pituitary and in the hypothalamus revealed an increased expression of growth hormone releasing hormone (GHRH) and growth hormone secretagogue (GHS) receptors in the pituitary of liver-IGF-I deficient mice. This in turn results in an increased sensitivity to systemically administered GHRH and GHS, demonstrating that the regulatory action of liver-derived IGF-I on GH secretion is at the pituitary rather than at the hypothalamic level. The liver is an important metabolic organ and liver-IGF-I deficient mice are markedly hyperinsulinemic and yet normoglycemic, consistent with an adequately compensated insulin resistance. Interestingly, liver-IGF-I deficient mice display a reduced age-dependent fat mass accumulation compared with control mice. In conclusion, liver-derived IGF-I is important for carbohydrate- and lipid-metabolism and for the regulation of GH-secretion at the pituitary level. Furthermore, it regulates adult axial skeletal growth and cortical radial growth while it is not required for appendicular skeletal growth. PMID: 12511852 [PubMed - indexed for MEDLINE] 4608. J Endocrinol Invest. 2002 Nov;25(10):899-904. Coagulation and fibrinolysis abnormalities in obesity. De Pergola G(1), Pannacciulli N. Author information: (1)Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari, Bari, Italy. g.depergola@endo.uniba.it Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile. PMID: 12508953 [PubMed - indexed for MEDLINE] 4609. J Endocrinol Invest. 2002 Nov;25(10):893-8. Adrenal and gonadal function in obesity. Pasquali R(1), Vicennati V, Gambineri A. Author information: (1)Endocrinology Unit, Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. rpasqual@almadns.unibo.it Obesity is associated with multiple alterations of the endocrine systems, including abnormal circulating blood hormone concentrations, due to changes in their pattern of secretion and/or metabolism, altered hormone transport, and/or action at the level of target tissues. There is evidence that alterations of endocrine systems regulating sex hormones and corticosteroids may play a crucial role in the development of obesity, particularly the abdominal phenotype. Obese women are characterized by a condition of sc"functional hyperandrogenism", whereas in males, obesity is associated with reduced T levels and decreased LH secretory pattern from the pituitary. In addition, in both sexes a dysregulation of the hypothalamic-pituitary-adrenal axis has been reported, including both neuroendocrine and peripheral alterations, finally leading to inappropriately higher than normal exposure to F of peripheral tissues, particularly the visceral adipose tissue. By these mechanisms, it can be hypothesized that both visceral fat enlargement and alterations of insulin action and associated metabolic disturbances may develop, therefore predisposing abdominally obese individuals to Type 2 diabetes and cardiovascular disease. PMID: 12508952 [PubMed - indexed for MEDLINE] 4610. J Endocrinol Invest. 2002 Nov;25(10):884-92. Establishing body composition in obesity. Pietrobelli A(1), Heymsfield SB. Author information: (1)Pediatric Unit, Verona University Medical School, Verona, Italy. angpie@tin.it The field of human body composition research is reaching a mature stage in its development. Quantifying the main body components is integral to the study of growth, as the assessment of human physical characteristics is important both in anthropological and medical fields. This article will focus on body composition methodology. Specifically, our attention is aimed at estimates of body fatness. An overview is first provided of the five-level model of body composition as it relates to measures of fatness. We then provide general concepts related to techniques for estimating body composition. Finally, we briefly discuss the measurement of adipose tissue distribution. PMID: 12508951 [PubMed - indexed for MEDLINE] 4611. J Endocrinol Invest. 2002 Nov;25(10):876-83. Metabolic impact of body fat distribution. Gasteyger C(1), Tremblay A. Author information: (1)Division of Kinesiology, Faculty of Medicine, Laval University, Ste-Foy, Québec, Canada. Many studies have shown that fat distribution influences metabolism independently of the effects of total body fat stores. The accumulation of fat in the abdominal area, particularly in the visceral fat compartment, seems to be associated with an increased risk to display complications such as insulin resistance, diabetes, dyslipidemias and atherosclerosis. As reviewed in this paper, the mechanisms explaining this impact of fat distribution is not clearly established, although evidence suggests that free-fatty acids, leptin, TNF-alpha, PPAR-gamma, and F are directly or indirectly involved in this process. Despite a lot of research has yet to be performed to mechanistically characterize the impact of visceral fat on the metabolic profile, there is enough consensus in the literature about its effect to justify its consideration in a clinical setting. In this regard, the use of waist circumference as a clinical marker of variations in visceral fat is highly relevant and should be encouraged. This review also presents an evolutionary perspective according to which body fat gain would have been and may still remain an adaptation that helps to deal with stress and inflammation. PMID: 12508950 [PubMed - indexed for MEDLINE] 4612. J Endocrinol Invest. 2002 Nov;25(10):867-75. Lessons in obesity from transgenic animals. Arch JR(1). Author information: (1)Clore Laboratory, University of Buckingham, Buckingham, UK. jon.arch@buckingham.ac.uk Many genetic manipulations have created models of obesity, leanness or resistance to dietary obesity in mice, often providing insights into molecular mechanisms that affect energy balance, and new targets for anti-obesity drugs. Since many genes can affect energy balance in mice, polymorphisms in many genes may also contribute to obesity in humans, and there may be many causes of primary leptin resistance. Secondary leptin resistance (due to high leptin levels) can be investigated by combining the ob mutation with other obesity genes. Some transgenic mice have failed to display the expected phenotype, or have even been obese when leanness was expected. Compensatory changes in the expression of other genes during development, or opposing influences of the gene on energy balance, especially in global knockout mice, may offer explanations for such findings. Obesity has been separated from insulin resistance in some transgenic strains, providing new insights into the mechanisms that usually link these phenotypes. It has also been shown that in some transgenic mice, obesity develops without hyperphagia, or leanness without hypophagia, demonstrating that generalised physiological explanations for obesity in individual humans may be inappropriate. Possibly the most important transgenic model of obesity so far created is the Type 1 11beta-hydroxysteroid dehydrogenase over-expressing mouse, since this models the metabolic syndrome in humans. The perspectives into obesity offered by transgenic mouse models should assist clinical researchers in the design and interpretation of their studies in human obesity. PMID: 12508949 [PubMed - indexed for MEDLINE] 4613. J Endocrinol Invest. 2002 Nov;25(10):855-61. Adipose tissue hormones. Guerre-Millo M(1). Author information: (1)Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France. mguerre@bhdc.jussieu.fr It is now widely accepted that white adipose tissue (WAT) secretes a number of peptide hormones, including leptin, several cytokines, adipsin and acylation-stimulating protein (ASP), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), adiponectin, resistin etc., and also produces steroids hormones. This newly discovered secretory function has shifted our view of WAT, which is no longer considered only an energy storage tissue but a major endocrine organ, at the heart of a complex network influencing energy homeostasis, glucose and lipid metabolism, vascular homeostasis, immune response and even reproduction. Virtually all known adipose secreted proteins are dysregulated when the WAT mass is markedly altered, either increased in the obese state or decreased in lipoatrophy. This strongly implicates adipose-secreted products in the ethiopathology and/or complications of both obesity and cachexia. This review discusses the physiological relevance of adipose secretion by focusing on protein and steroid hormones. Regulation of WAT secretion by the major regulatory factors impinging on the adipocytes, i.e. insulin, glucocorticoids, catecholamines and thiazolidinediones (TZD) will be addressed. The rationale for therapeutic strategies aimed at compensating adverse effects resulting from overproduction or lack of a specific adipose secretory product will be discussed. PMID: 12508947 [PubMed - indexed for MEDLINE] 4614. J Endocrinol Invest. 2002 Nov;25(10):823-35. Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ. Cinti S(1). Author information: (1)Institute of Normal Human Morphology, Faculty of Medicine, University of Ancona, Ancona, Italy. cinti@popcsi.unian.it In mammals, the adipose organ is a multi-depot organ made of two tissue types, the white and brown adipose tissues, which collaborate in partitioning the energy contained in lipids between thermogenesis and the other metabolic functions. It consists of several sc and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while many are white and correspond to white adipose tissue. White areas contain a variable amount of brown adipocytes and their number varies with age, strain and environmental conditions. Brown and white adipocyte are morphologically different. At light microscopy level, brown adipocytes have cytoplasmic lipids arranged as numerous small droplets (multilocularity), while white adipocytes have cytoplasmic lipids arranged in a unique vacuole (unilocularity). Ultrastructurally, brown adipocytes have numerous big mitochondria packed with cristae and containing the thermogenic uncoupling protein 1 (UCP1). In vivo and in vitro studies have shown that the differentiation process of brown and white adipocytes shows distinctive features. Nevertheless, the origin of the adipocyte precursor is still unknown. Recent data have stressed the plasticity of the adipose organ in adult animals. Indeed, under peculiar conditions fully differentiated, white adipocytes can transdifferentiate into brown adipocytes, and viceversa. The ability of the adipose organ to interconvert its main cytotypes in order to meet changing metabolic needs is highly pertinent to the physiopathology of obesity and related to therapeutic strategies. PMID: 12508945 [PubMed - indexed for MEDLINE] 4615. J Exp Zool A Comp Exp Biol. 2003 Jan 1;295(1):99-110. Paracrine interactions of mammalian adipose tissue. Pond CM(1). Author information: (1)Department of Biological Sciences, The Open University, Milton Keynes, MK7 6AA, United Kingdom. C.M.Pond@open.ac.uk Adipose tissue develops in and/or around most lymphoid tissues in mammals and birds. Early reports of this widespread association and hypotheses for its functional basis were long ignored in the planning of in vitro studies and the interpretation of in vivo results. Biochemical studies on rodent tissues reveal many site-specific properties of adipocytes anatomically associated with lymph nodes and omental milky spots that equip them to interact locally with lymphoid cells. The paracrine interactions are strongest for the most readily activated lymph nodes and are modulated by dietary lipids. Perinodal adipocytes contribute less than those in the large nodeless depots to whole-body lipid supplies during fasting. Observations on wild animals show that perinodal adipose tissue is selectively conserved even in starvation but does not enlarge greatly in natural obesity. Such paracrine provisioning of peripheral immune responses improves their efficiency and emancipates activated lymphocytes from competition with other tissues for blood-borne nutrients. The relationship is found in extant protherians and metatherians, so it almost certainly arose early in the evolution of mammals, possibly as part of the metabolic reorganisation associated with homeothermy, viviparity, and lactation. Prolonged disruption to paracrine interactions between lymphoid and adipose tissue may contribute to the HIV-associated adipose redistribution syndrome, causing selective hypertrophy of the mesentery, omentum, and other adipose depots that contain much activated lymphoid tissue. Skeletal and cardiac muscle may also have paracrine relationships with anatomically associated adipose tissue, but interactions between contiguous tissues have not been demonstrated directly. Copyright 2003 Wiley-Liss, Inc. PMID: 12506408 [PubMed - indexed for MEDLINE] 4616. J Diabetes Complications. 2003 Jan-Feb;17(1):39-58. The impact of ethnicity on type 2 diabetes. Abate N(1), Chandalia M. Author information: (1)Center for Human Nutrition, UT Southwestern Medical Center at Dallas, USA. nicola.abate@utsouthwestern.edu The rapid increase of diabetes prevalence in the US population and across all westernized world has been associated with environmental changes that promote obesity. Although dietary factors, such as total caloric intake, relative excess of dietary saturated fats content and lack of fibers, together with reduced level of physical activity clearly determine the main features of the "obesogenic" environment typical of "western" societies, the impact of lifestyle factors on obesity and diabetes appears to differ in various ethnic groups. Although ethnic-related differences in lifestyle factors may account for some of the predisposition to obesity and diabetes of various ethnic groups, genetic factors may play a more determinant role. These observations pose important public health questions in regard to strategies for treatment and prevention of diabetes both within the multiethnic US population and in the population of origin of various ethnicities. The elucidation of the pathophysiologic mechanisms responsible for the heterogeneous relationship between obesity and type 2 diabetes in various ethnicities may give important contributions to better understand the complex mechanisms involved in the development of this disease. This review examines epidemiological and pathophysiological aspects of the interaction between environment and ethnic predisposition to type 2 diabetes. PMID: 12505756 [PubMed - indexed for MEDLINE] 4617. Med Sci Monit. 2002 Dec;8(12):RA282-92. Leptin--from a signal of adiposity to a hormonal mediator in peripheral tissues. Baratta M(1). Author information: (1)Department of Veterinary Morphophysiology, University of Turin, Italy. baratta@veter.unito.it The biology of leptin has been studied most extensively in the central nervous system for the regulation of food intake and energy balance. In recent years, a growing number of publications have reported several activities of this adipose-secreted protein in different organs. These effects appear to be independent of the regulation of food intake or at least not directly correlated to it, but rather related to the hormonal regulation of these particular tissues. Thus leptin is now also considered to be a hormonal factor that informs several hormonal circuits and biological peripheral functions of the nutrition status of the organism. Different systems are involved in leptin activity, such as the pituitary, male and female reproductive organs, the mammary gland, the immune system, the gut, the kidney and the lung. Functional leptin receptors and/or leptin protein have been shown to be expressed in these tissues. Furthermore, interesting interactions have been reported with classical hormones involved in the regulation of activities in such organs. These observations give more detailed evidence of the relationship between nutrition and tissue differentiation in peripheral sites, possibly mediated by classical hormonal circuits. This work aims to review the most important functional findings on leptin's effects in these peripheral sites, and potential future studies are suggested, based on currently available data. PMID: 12503048 [PubMed - indexed for MEDLINE] 4618. Theriogenology. 2003 Jan 1;59(1):95-106. Development of efficient strategies for the production of genetically modified pigs. Nagashima H(1), Fujimura T, Takahagi Y, Kurome M, Wako N, Ochiai T, Esaki R, Kano K, Saito S, Okabe M, Murakami H. Author information: (1)Laboratory of Developmental Engineering, Department of Life Science, School of Agriculture, Meiji University, Kawasaki, Japan. hnagas@isc.meiji.ac.jp Although pronuclear DNA micro-injection has long been the most reliable method to produce transgenic pigs, the efficiency of production of transgenic offspring is generally plagued by 1% of the DNA-injected embryos. Therefore, a problem with this method is the need for large numbers of pronuclear stage embryos. One great advancement would be the use of in vitro-matured (IVM) oocytes for the purpose of transgenic pig production. High developmental competence of IVM oocytes was proven by transfer of parthenogenetic IVM oocytes. A combined method of sperm vectors with the IVM of oocytes would make the production of transgenic pigs remarkably feasible. Rate of blastocyst formation following intracytoplasmic sperm injection (ICSI) by frozen sperm was over 20%, and transgene was expressed in approximately 50% of blastocysts generated. Somatic cell nuclear transfer would enable more efficient and sophisticated genetic modification of the pig. Simultaneous comparison between two nuclear transfer methods by electro-fusion and intracytoplasmic injection revealed clear differences in the pattern of nuclear remodeling and development of the reconstructed embryos. To specify the donor cell type that allows efficient genetic modification and easy reprogramming or to establish such cell lines is a critical issue in pig cloning. We tested pre-adipocytes from the subcutaneous adipose tissue of adult pigs for nuclear transfer. Cell cycle synchronization by differentiation induction is unique to the pre-adipocytes. Frequency of apoptosis was low in the cells synchronized by differentiation induction compared with other synchronization methods, including serum starvation, confluency, and chemical treatment. It would be of great worth if cryopreserved clone embryos were available. We have demonstrated that cryopreservation of in vitro-produced porcine embryos as well as clone blastocysts is possible by our unique method. Copyright 2002 Elsevier Science Inc. PMID: 12499021 [PubMed - indexed for MEDLINE] 4619. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1531-43. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Kaaks R(1), Lukanova A, Kurzer MS. Author information: (1)Hormones and Cancer Group, International Agency for Research on Cancer, 69372 Lyon, France. kaaks@iarc.fr Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism. PMID: 12496040 [PubMed - indexed for MEDLINE] 4620. Trends Cell Biol. 2002 Dec;12(12):591-8. The nuclear lamina and inherited disease. Worman HJ(1), Courvalin JC. Author information: (1)Dept of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. hjw14@columbia.edu Inherited disorders of the nuclear lamina present some of the most intriguing puzzles in cell biology. Mutations in lamin A and lamin C - nuclear intermediate filament proteins that are expressed in nearly all somatic cells - cause tissue-specific diseases that affect striated muscle, adipose tissue and peripheral nerve or skeletal development. Recent studies provide clues about how different mutations in these proteins cause either muscle disease or partial lipodystrophy. Although the precise pathogenic mechanisms are currently unknown, the involvement of lamins in several different disorders shows that research on the nuclear lamina will shed light on common human pathologies. PMID: 12495848 [PubMed - indexed for MEDLINE] 4621. Trends Immunol. 2003 Jan;24(1):13-8. Paracrine relationships between adipose and lymphoid tissues: implications for the mechanism of HIV-associated adipose redistribution syndrome. Pond CM(1). Author information: (1)Department of Biological Sciences, The Open University, Milton Keynes MK7 6AA, UK. c.m.pond@open.ac.uk The adipocytes anatomically associated with lymph nodes and omental milky spots have site-specific properties that equip them to interact locally with lymphoid cells. Paracine provisioning of peripheral immune responses improves their efficiency and emancipates activated lymphocytes from competition with other tissues for blood-borne nutrients. Prolonged disruption to such paracine interactions might contribute to the HIV-associated adipose redistribution syndrome, causing selective hypertrophy of the mesentery, omentum and other lymphoid tissue-containing adipose depots, while nodeless depots atrophy. PMID: 12495719 [PubMed - indexed for MEDLINE] 4622. Asia Pac J Clin Nutr. 2002;11 Suppl 3:S642-52. Benefits of exercise and dietary measures to optimize shifts in body composition with age. Fiatarone Singh MA(1). Author information: (1)School of Exercise and Sport Science, University of Sydney, Lidcombe, New South Wales, Australia. m.singh@cchs.usyd.edu.au Ageing is associated with changes in body composition, including an increase and redistribution of adipose tissue and a decrease in muscle and bone mass, beginning as early as the fourth decade of life. These changes have significant implications for the health and functioning of the individual because of their associations with chronic disease expression and severity, as well as geriatric syndromes such as mobility impairment, falls, frailty and functional decline. Therefore, understanding the preventive and therapeutic options for optimizing body composition in old age is central to the care of patients in mid-life and beyond. Pharmacological interventions are currently available for maintaining or improving bone mass, and much current interest is focused on anabolic agents that will preserve or restore muscle mass, as well as those that can potentially limit adipose tissue deposition. However, in this brief review, non-pharmacological modulation of body composition through appropriate dietary intake and physical activity patterns, will be discussed. There is sufficient evidence currently to suggest that a substantial portion of what have been considered 'age-related' changes in muscle, fat and bone are in fact related either to excess energy consumption, decreased energy expenditure in physical activity, or both factors in combination. In addition, selective underconsumption of certain macro- or micronutrients contributes to losses of muscle and bone mass. Each of the three compartments will be considered in turn, with recommendations for optimizing the size of these body tissue stores in early adulthood, and minimizing undesirable changes typically seen in middle and old age. PMID: 12492658 [PubMed - indexed for MEDLINE] 4623. Obes Res. 2002 Dec;10 Suppl 2:97S-104S. The obesity epidemic: pathophysiology and consequences of obesity. Pi-Sunyer FX(1). Author information: (1)Division of Endocrinology, Diabetes, and Nutrition, New York Obesity Research Center, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York 10025, USA. fxp1@columbia.edu Obesity has reached epidemic proportions in the United States: more than 20% of adults are clinically obese as defined by a body mass index of 30 kg/m(2) or higher, and an additional 30% are overweight. Environmental, behavioral, and genetic factors have been shown to contribute to the development of obesity. Elevated body mass index, particularly caused by abdominal or upper-body obesity, has been associated with a number of diseases and metabolic abnormalities, many of which have high morbidity and mortality. These include hyperinsulinemia, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, coronary heart disease, gallbladder disease, and certain malignancies. This underscores the importance of identifying people at risk for obesity and its related disease states. PMID: 12490658 [PubMed - indexed for MEDLINE] 4624. Am J Health Syst Pharm. 2002 Dec 1;59 Suppl 9:S9-13. Treating dual defects in diabetes: insulin resistance and insulin secretion. Bohannon NJ(1). Author information: (1)Baylor College of Medicine, Houston, TX, USA. sugarnancy@pol.net The therapeutic goals in patients with type 2 diabetes mellitus and the mechanisms of insulin resistance and secretion are discussed. Sulfonylureas improve glycemic control, restore the acute insulin response, and help improve beta-cell function in the short term. Meglitinides and phenylalanine derivatives and alpha-glucosidase inhibitors may be useful for elderly patients and others with normal fasting blood glucose levels and postprandial hyperglycemia, but they are less effective in achieving goal HbA1c levels in patients with marked fasting hyperglycemia. Metformin and thiazolidinediones act on hepatic, muscle, and adipose tissue through different mechanisms to improve glycemic control, beta-cell function, and the lipid profile. Thiazolidinediones have a greater impact on free fatty acids than metformin. They may have an additive effect with sulfonylureas, metformin, or insulin in improving glycemic control and the lipid profile. Many patients require combination therapy with one or more insulin sensitizers and an insulin secretagogue to achieve therapeutic goals. Insulin therapy should be initiated in patients in whom an HbA1c level less than 7.0% cannot be maintained with other therapies. This is vital in preventing diabetes complications. Insulin sensitizers should be continued during insulin therapy to reduce insulin resistance and treat the insulin resistance syndrome. Therapeutic goals for patients with type 2 diabetes mellitus include improvement in glycemic control and prevention of diabetes complications. Elevated levels of fasting blood glucose should be addressed before postprandial levels to reduce HbA1c levels and glucotoxicity to the beta cell. Dyslipidemia, hypertension, and hypercoagulability should be treated to minimize the increased cardiovascular risk seen in people with diabetes, which is responsible for the majority of deaths. PMID: 12489381 [PubMed - indexed for MEDLINE] 4625. Ann N Y Acad Sci. 2002 Nov;973:17-25. The effects of peroxisome proliferators on global lipid homeostasis and the possible significance of these effects to other responses to these xenobiotics: an hypothesis. Xie Y(1), Yang Q, DePierre JW. Author information: (1)Unit for Biochemical Toxicology, Department of Biochemistry Biophysics, Wallenberg Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. yi@dbb.su.se Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid metabolism via activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Recent studies have revealed that PPs also exert considerable influence on certain extrahepatic tissues, including adipose tissue and lymphoid organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and splenocytes and alteration of fatty acid uptake into and release from adipose tissue might be consequences of the hypolipidemic effect of PPs involving both PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the cholesterol content of circulating low-density lipoprotein (LDL), which is the major supply of this steroid to most peripheral tissues. In addition, PPs increase serum levels of high-density lipoprotein (HDL), which extracts cholesterol from peripheral tissues and returns it to the liver, thereby further decreasing the cholesterol content of peripheral tissues. This net flux of cholesterol from extrahepatic tissues to the liver represents a change in global lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could result in loss of cholesterol and other lipids from peripheral tissues (e.g., adipose tissue, thymus, and spleen), especially from plasma membrane caveolae, which might perturb normal cellular signaling and result in tissue atrophy. On the other hand, the increased hepatic cholesterol content in the hepatocyte plasma membrane might actually enhance signaling, playing a role in the liver hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In conclusion, it is important to consider the systemic effects of PPs, rather than to focus on the liver alone. PMID: 12485828 [PubMed - indexed for MEDLINE] 4626. IARC Sci Publ. 2002;156:337-41. n-3 fatty acids and breast cancer. Bougnoux P(1), Maillard V, Ferrari P, Jourdan ML, Chajès V. Author information: (1)INSERM EMI 02-11, Université François-Rabelais, Tours, France. PMID: 12484201 [PubMed - indexed for MEDLINE] 4627. Curr Drug Targets Immune Endocr Metabol Disord. 2001 Nov;1(3):265-75. Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. Goldstein BJ(1). Author information: (1)Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 19107-6799, USA. Barry.Goldstein@mail.tju.edu Resistance to the cellular action of insulin, a fundamental pathophysiological defect accompanying the worldwide epidemic of obesity, is closely associated with the development of type 2 diabetes mellitus and the set of cardiovascular risk factors that constitute the "metabolic" syndrome. The development of novel pharmaceutical agents that help ameliorate insulin resistance will be potentially important not only for the prevention and treatment of diabetes, but also in reducing its associated cardiovascular risk profile. Studies on the cellular role of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves as a key negative regulator of the tyrosine phosphorylation cascade integral to the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide have provided crucial "proof-of-concept" data to show that eradicating or reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of over-nutrition and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cellular studies suggesting that PTPIB may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors that may serve as a novel type of "insulin sensitizer" in the management of type 2 diabetes and the cardiovascular / metabolic syndrome. PMID: 12477292 [PubMed - indexed for MEDLINE] 4628. Curr Drug Targets Immune Endocr Metabol Disord. 2002 Jul;2(2):119-27. Targeting the AMP-activated protein kinase for the treatment of type 2 diabetes. Musi N(1), Goodyear LJ. Author information: (1)Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Womens's Hospital, Harvard Medical School, Boston, MA, USA. The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated in response to conditions of cellular stress such as muscle contraction and hypoxia. In skeletal muscle, activation of AMPK leads to increased glucose uptake, enhanced insulin sensitivity and oxidation of fatty acids. In the liver, AMPK activation causes an increase in fatty acid oxidation and inhibition of glucose production. These effects on glucose and fat metabolism make AMPK an important pharmacological target for the treatment of type 2 diabetes. Studies done in animal models of type 2 diabetes have shown that pharmacological activation of AMPK with the compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) decreases blood glucose and insulin concentrations. While strong efforts are underway in order to identify novel AMPK-activating compounds, the safety of chronic pharmacological activation of AMPK remains to be determined. PMID: 12476786 [PubMed - indexed for MEDLINE] 4629. Diabetes. 2002 Dec;51 Suppl 3:S414-20. Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion. Eto K(1), Yamashita T, Matsui J, Terauchi Y, Noda M, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Triacylglyceride (TG) accumulation in pancreatic beta-cells is associated with impaired insulin secretion, which is called lipotoxicity. To gain a better understanding of the pathophysiology of lipotoxicity, we generated three models of dysregulated fatty acid metabolism in beta-cells. The overexpression of sterol regulatory element binding protein-1c induced lipogenic genes and TG accumulation. Under these conditions, we observed a decrease in glucose oxidation and upregulation of uncoupling protein-2, which might be causally related to the decreased glucose-stimulated insulin secretion. The overexpression of AMP-activated protein kinase was accompanied by decreased lipogenesis, increased fatty acid oxidation, and decreased glucose oxidation; insulin secretions to glucose and depolarization stimuli were decreased, probably because of the decrease in glucose oxidation and cellular insulin content. It was notable that the secretory response to palmitate was blunted, which would suggest a role of the fatty acid synthesis pathway, but not its oxidative pathway in palmitate-stimulated insulin secretion. Finally, we studied islets of PPAR-gamma(+/-) mice that had increased insulin sensitivity and low TG content in white adipose tissue, skeletal muscle, and liver. On a high-fat diet, glucose-stimulated insulin secretion was decreased in association with increased TG content in the islets, which might be mediated through the elevated serum free fatty acid levels and their passive transport into beta-cells. These results revealed some aspects about the mechanisms by which alterations of fatty acid metabolism affect beta-cell functions. PMID: 12475784 [PubMed - indexed for MEDLINE] 4630. Expert Opin Pharmacother. 2002 Dec;3(12):1711-8. Pharmacological management of obesity. Hanif MW(1), Kumar S. Author information: (1)Birmingham Heartlands Hospital, Bordsley Green East, Birmingham B9 5SS, UK. Obesity is a major chronic health problem in adults. It is a complex, multifactorial disorder characterised by excess accumulation of adipose tissue. It is associated with a number of complications including cardiovascular disease, hypertension, type 2 diabetes, dyslipidaemia and cancer. A weight loss in the order of 5-10% is associated with clinically meaningful reductions with respect to all comorbidities. Diet and exercise has been the cornerstone of weight management therapy, but this approach has limitations, especially for weight maintenance. Previous drugs used in obesity had serious side effects including valvular heart disease. However, recent drugs like orlistat and sibutramine have been rigorously tested and proven safe. Orlistat, a lipase inhibitor, inhibits absorption of dietary fat by approximately 30%. Taken with a hypocaloric diet, it produces and maintains clinically meaningful weight loss. Sibutramine is a centrally-acting agent which enhances satiety and thermogenesis by inhibiting serotonin and noradrenaline re-uptake. It is appropriate for patients who are unable to lose weight by lifestyle modification. PMID: 12472368 [PubMed - indexed for MEDLINE] 4631. Annu Rev Physiol. 2003;65:333-47. Epub 2002 May 1. The physiology of cellular liporegulation. Unger RH(1). Author information: (1)Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA. Roger.Unger@utsouthwestern.edu Here we explore the physiologic role of leptin as a liporegulatory hormone responsible for maintaining intracellular homeostasis in the face of wide variations in caloric intake. Normally, rats can tolerate a 60% fat diet because 96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is congenitally absent or inactive, even on a normal diet, unutilized dietary fat is deposited in nonadipose tissues, causing dysfunction (lipotoxicity) and possible cell death (lipoapoptosis). We theorize that in diet-induced obesity, acquired leptin resistance may also develop as the result of increase in certain leptin resistance factors. Acquired leptin resistance occurs in aging, obesity, Cushing's syndrome, and acquired lipodystrophy, and preliminary evidence suggests that ectopic lipid deposition is increased. We speculate that the metabolic syndrome may be the human equivalent of the lipotoxic syndrome of rodents. PMID: 12471167 [PubMed - indexed for MEDLINE] 4632. J Adolesc Health. 2002 Dec;31(6 Suppl):192-200. Growth at puberty. Rogol AD(1), Roemmich JN, Clark PA. Author information: (1)Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA. arogol@cstone.net Somatic growth and maturation are influenced by a number of factors that act independently or in concert to modify an individual's genetic potential. The secular trend in height and adolescent development is further evidence for the significant influence of environmental factors on an individual's genetic potential for linear growth. Nutrition, including energy and specific nutrient intake, is a major determinant of growth. Paramount to normal growth is the general health and well-being of an individual; in fact, normal growth is a strong testament to the overall good health of a child. More recently the effect of physical activity and fitness on linear growth, especially among teenage athletes, has become a topic of interest. Puberty is a dynamic period of development marked by rapid changes in body size, shape, and composition, all of which are sexually dimorphic. One of the hallmarks of puberty is the adolescent growth spurt. Body compositional changes, including the regional distribution of body fat, are especially large during the pubertal transition and markedly sexually dimorphic. The hormonal regulation of the growth spurt and the alterations in body composition depend on the release of the gonadotropins, leptin, the sex-steroids, and growth hormone. It is very likely that interactions among these hormonal axes are more important than their main effects, and that alterations in body composition and the regional distribution of body fat actually are signals to alter the neuroendocrine and peripheral hormone axes. These processes are merely magnified during pubertal development but likely are pivotal all along the way from fetal growth to the aging process. PMID: 12470915 [PubMed - indexed for MEDLINE] 4633. Best Pract Res Clin Endocrinol Metab. 2002 Dec;16(4):667-78. Substrate oxidation, obesity and exercise training. Blaak EE(1), Saris WH. Author information: (1)Department of Human Biology, Nutrition Research Centre, Maastricht University, The Netherlands. Regular physical exercise is of the utmost importance in the treatment of obesity because exercise is one of the factors determining long-term weight maintenance in weight reduction programmes and because exercise has been associated with a reduced risk for developing type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an impaired utilization of fat as a fuel during post-absorptive conditions, during beta-adrenergic stimulation and possibly during exercise, although the latter data are controversial. One of the underlying mechanisms for the positive effect of exercise training in obesity may be related to its effects on fat utilization because exercise training has been shown to increase basal fat oxidation and exercise fat oxidation in lean volunteers. Data on the effect of aerobic exercise training on exercise fat oxidation are controversial, whereas the available data indicate that exercise training may not be able to increase resting fat oxidation or 24-hour fat oxidation in obese subjects. Because disturbed muscle fat oxidation may be a primary event in the aetiology of obesity it is of the utmost importance to obtain more information on how and whether exercise training may be able to compensate for these impairments. PMID: 12468414 [PubMed - indexed for MEDLINE] 4634. Best Pract Res Clin Endocrinol Metab. 2002 Dec;16(4):653-66. Peripheral metabolic actions of leptin. Muoio DM(1), Lynis Dohm G. Author information: (1)Duke University Medical Center, Box 3327, Durham, NC 27710, USA. The adipocyte-derived hormone, leptin, regulates food intake and systemic fuel metabolism; ob /ob mice, which lack functional leptin, exhibit an obesity syndrome that is similar to morbid obesity in humans. Leptin receptors are expressed most abundantly in the brain but are also present in several peripheral tissues. The role of leptin in controlling energy homeostasis has thus far focused on brain receptors and neuroendocrine pathways that regulate feeding behaviour and sympathetic nervous system activity. This chapter focuses on mounting evidence that leptin's effects on energy balance are also mediated by direct peripheral actions on key metabolic organs such as skeletal muscle, liver, pancreas and adipose tissue. Strong evidence indicates that peripheral leptin receptors regulate cellular lipid balance, favouring beta-oxidation over triacylglycerol storage. There are data to indicate that peripheral leptin also modulates glucose metabolism and insulin action; however, its precise role in controlling gluco-regulatory pathways remains uncertain and requires further investigation. PMID: 12468413 [PubMed - indexed for MEDLINE] 4635. Best Pract Res Clin Endocrinol Metab. 2002 Dec;16(4):639-51. Adipose tissue as an endocrine organ. Prins JB(1). Author information: (1)Princess Alexandra Hospital, Ipswich Rd, Woolloongabba 4102, Australia. Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested. PMID: 12468412 [PubMed - indexed for MEDLINE] 4636. Int J Adolesc Med Health. 2002 Jul-Sep;14(3):193-7. The importance of the measurement of the circumference of arm, arm muscle area and skinfold thickness during puberty. Derman O(1), Yalcin SS, Kanbur NO, Kinik E. Author information: (1)Adolescent Unit, Department of Pediatrics, Hacettepe University, Faculty of Medicine, Ankara, Turkey. oderman@hacettepe.edu.tr Several methods are available to study lean and adipose tissue component of the upper arm, but the use of a specific technique is mostly determined by time and financial expense. Besides, anthropometric techniques (arm muscle area, mid-arm circumference and the triceps skinfold thickness), which are the most practical, simple, inexpensive and noninvasive, x-ray, ultrasound scanning, computed tomography (CT), or magnetic resonance images (MRI) are also used to determine separate measures of muscles, adipose tissue, and bone area. These radiographic methods are expensive and suitable only for research studies. This short review will try to stress the importance of the measurement of the circumference of arm, arm muscle area and skinfold thickness during puberty and adolescence. PMID: 12467194 [PubMed - indexed for MEDLINE] 4637. J Allergy Clin Immunol. 2002 Dec;110(6 Suppl):S313-7. beta-Agonists and metabolism. Philipson LH(1). Author information: (1)Department of Medicine, University of Chicago, Chicago, IL 60637, USA. l-philipson@uchicago.edu This review presents recent concepts of how beta-agonists affect glucose homeostasis by modulating insulin secretion, liver metabolism, and uptake of glucose into muscle, with attention to the influence of hypoglycemia on beta-agonist sensitivity and the effects of beta(3)-adrenergic receptor (beta(3)AR) polymorphisms on adipocyte metabolism. Specific beta(2)-agonist effects on the pancreatic beta cell result in increased insulin secretion, yet other mechanisms, such as increased glucagon secretion and hepatic effects, cause an overall increase in serum glucose and an apparent decrease in insulin sensitivity. Human studies confirm the presence of beta(2)ARs on pancreatic beta cells. Intensive treatment of diabetes mellitus with insulin, especially in type 1 diabetes, has led to increased incidence of hypoglycemia. Repeated episodes of hypoglycemia lead to unawareness of neuroglycopenia, a major limitation to intensive treatment. Hypoglycemic unawareness is associated with reduced beta-agonist sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can restore beta-agonist sensitivity and improve detection of hypoglycemia. beta-agonists have also been employed to prevent hypoglycemia. beta-agonists can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. While beta(1)ARs and beta(2)ARs mediate many of these actions, it is likely that beta(3)ARs in the adipocyte membrane also play an important role. Specific beta(3)AR subtypes have been associated with obesity and the metabolic syndrome. PMID: 12464941 [PubMed - indexed for MEDLINE] 4638. Curr Drug Targets Infect Disord. 2002 Mar;2(1):1-8. Investigating the cellular targets of HIV protease inhibitors: implications for metabolic disorders and improvements in drug therapy. Murata H(1), Hruz PW, Mueckler M. Author information: (1)Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. The use of HIV protease inhibitors (PIs) may be associated with serious adverse side effects that include fat tissue redistribution, hyperlipidemia, and insulin resistance. The etiology of this toxic metabolic syndrome (commonly referred to as 'HIV lipodystrophy syndrome') remains to be elucidated. The interpretation of available clinical data on this subject is complicated in part by the pervasiveness of potential confounding factors that cannot be easily eliminated or adequately controlled. Numerous investigators have examined the effects of PIs on cellular processes in model systems amenable to extensive experimental manipulations; the present review primarily focuses on these efforts. The ultimate goal is the unambiguous identification of discrete cellular targets being surreptitiously impacted by PIs. SREBP and Glut4 are discussed as candidate target molecules in this context. The identification of cellular factors interacting with PIs represents a necessary first step in devising rational strategies for improvement in drug therapy. PMID: 12462148 [PubMed - indexed for MEDLINE] 4639. Clin Endocrinol (Oxf). 2002 Dec;57(6):701-11. Leptin and the skeleton. Whipple T(1), Sharkey N, Demers L, Williams N. Author information: (1)Department of Kinesiology, The Pennsylvania State University, University Park, USA. tjw208@psu.edu PMID: 12460318 [PubMed - indexed for MEDLINE] 4640. Int J Obes Relat Metab Disord. 2002 Dec;26 Suppl 4:S34-7. Metabolic benefits associated with sibutramine therapy. Krejs GJ(1). Author information: (1)Karl-Franzens University, Graz, Austria. guenter.krejs@uni-graz.at Sibutramine-induced weight loss and weight maintenance lead to clinically relevant reductions in risk factors associated with the metabolic syndrome. Treatment with the drug decreases visceral fat, improves lipid levels, decreases glycosylated haemoglobin and decreases uric acid concentrations. Sibutramine is effective in achieving weight loss in patients with type 2 diabetes but weight loss occurs more slowly than in non-diabetic patients. The criteria for predicting response to treatment in uncomplicated patients may not be appropriate to those with type 2 diabetes. Furthermore, it is important to set realistic goals for weight loss in type 2 diabetes to avoid the risk of denying effective treatment to patients. PMID: 12457298 [PubMed - indexed for MEDLINE] 4641. Int J Obes Relat Metab Disord. 2002 Dec;26 Suppl 4:S8-S10. Understanding the physiology of obesity: review of recent developments in obesity research. Woods SC(1), Seeley RJ. Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. steve.woods@psychiatry.uc.edu Knowledge of the genetic and regulatory factors that influence energy homeostasis is advancing rapidly. There is increased understanding of the molecular signals that reach the brain with information regarding the current state of energy balance, how those signals are detected by the brain, and key neuronal systems important in translating the information into efferent responses. The identification of molecules that control food intake has generated new targets for drug development in the treatment of obesity. In view of the complexities of the energy control system, therapeutic strategies that target only one site are likely to be less effective than those targeting two or more sites. PMID: 12457292 [PubMed - indexed for MEDLINE] 4642. Int J Obes Relat Metab Disord. 2002 Dec;26 Suppl 4:S5-7. Adipose tissue: a mediator of cardiovascular risk. Sharma AM(1). Author information: (1)Department of Medicine, McMaster University, Hamilton, Ontario, Canada. sharma@ccc.mcmaster.ca Two key findings regarding the cardiovascular risks associated with obesity have emerged in recent years: one relates to the importance of visceral obesity as a risk factor for cardiovascular disease, and the other to the recognition that adipose tissue can be regarded as a large endocrine organ that directly contributes to cardiovascular risk by secreting a number of molecules known to modulate vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system. Therefore, abdominal fat deposition, which is characterized by increase in waist circumference, should be the target of clinical intervention in obese individuals. PMID: 12457291 [PubMed - indexed for MEDLINE] 4643. Diabetes Care. 2002 Dec;25(12):2342-9. Adiposity and diabetes. Bloomgarden ZT(1). Author information: (1)Diabetes Center, Mount Sinai School of Medicine, New York, New York, USA. PMID: 12453983 [PubMed - indexed for MEDLINE] 4644. Obes Res. 2002 Nov;10 Suppl 1:14S-21S. Adiposity and fat distribution outcome measures: assessment and clinical implications. Aronne LJ(1), Segal KR. Author information: (1)Weill Medical College of Cornell University, 1165 York Avenue, New York, NY 10021, USA. ljaronne@med.cornell.edu PMID: 12446853 [PubMed - indexed for MEDLINE] 4645. Can J Appl Physiol. 2002 Aug;27(4):396-414. Application of simple anthropometry in the assessment of health risk: implications for the Canadian Physical Activity, Fitness and Lifestyle Appraisal. Janssen I(1), Heymsfield SB, Ross R. Author information: (1)School of Physical and Health Education, Queen's University, Kingston, ON. Incremental improvements in our knowledge of the associations between human body composition and disease have been facilitated by advances in research technology. Magnetic resonance imaging and computerized tomography are among the technological advances that have helped unravel the mechanisms that link body composition and disease. However, because the use of these methods in large-scale studies and field settings is impractical, the potential relationships between body composition and health risk rely on the use of anthropometric tools. Indeed, the application of simple anthropometry to identify relationships between body composition and health risk in clinical practice is no less valuable than the use of advanced technologies to gain insight into the mechanistic links between body composition and disease in the laboratory. Accordingly, the purpose of this review is to summarize current knowledge regarding the ability of anthropometry to predict health risk and to act as surrogate measures of total and abdominal fat distribution. Because the ultimate objective is to make recommendations for revision to the Healthy Body Composition section of the Canadian Physical Activity, Fitness and Lifestyle Appraisal (CPAFLA) manual, we focus on those anthropometric methods specific to CPAFLA. Consistent with this objective, when necessary we present original data to reinforce important concepts not suitably addressed in the literature. PMID: 12442353 [PubMed - indexed for MEDLINE] 4646. Biochem Soc Trans. 2002 Nov;30(Pt 6):1086-90. Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Smith SA(1). Author information: (1)Metabolic Scientific Strategy, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. stephen_a_smith@gsk.com Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of ligand-activated nuclear transcription factors. Three PPAR subtypes, PPARalpha, PPARdelta (PPARbeta) and PPARgamma, have been described in mammals. The tissue distribution of PPARs is heterogeneous: PPARalpha is highly expressed in liver and skeletal muscle, PPARgamma is preferentially expressed in adipose tissues, and PPARdelta is expressed in most cell types with relative abundance. Unlike most receptors, PPARs show low ligand specificity, being activated by many long-chain saturated and unsaturated fatty acids, or by eicosanoids. PPARs are transcriptionally active as heterodimeric complexes with the retinoid X receptor and bind to specific recognition sequences in the regulatory region of target genes. Many PPAR-regulated genes encode proteins that regulate fatty acid oxidation and storage. Elucidation of the biological functions of PPARs has been aided by the development of PPAR-null mice and the identification of humans bearing PPAR mutations, together with the discovery of synthetic small-molecule ligands that selectively activate individual PPAR subtypes. Using these genetic and pharmacological approaches, it has been shown that PPARalpha predominantly regulates pathways of fatty acid oxidation, whereas PPARgamma modifies fatty acid synthesis and storage in adipose tissues. By reducing systemic fatty acid availability, thiazolidinedione PPARgamma activators regulate glucose metabolism and are now used clinically in the treatment of Type II diabetes. In summary, PPARs play a central role in the mechanisms that balance fatty acid oxidation and storage in the face of fluctuations of dietary fat intake and energy expenditure. PMID: 12440979 [PubMed - indexed for MEDLINE] 4647. J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. Schambelan M(1), Benson CA, Carr A, Currier JS, Dubé MP, Gerber JG, Grinspoon SK, Grunfeld C, Kotler DP, Mulligan K, Powderly WG, Saag MS; International AIDS Society-USA. Author information: (1)University of California San Francisco, San Francisco General Hospital, San Francisco, California, USA. morrie@sfghgcrc.ucsf.edu OBJECTIVE: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV-1 infection and potent antiretroviral therapy, but limited data are available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. PARTICIPANTS: A 12-member panel representing international expertise in HIV-1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society-USA, a not-for-profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society-USA; the panel members are not compensated for their participation. EVIDENCE: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. PROCESS: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. CONCLUSIONS: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV-1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long-term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long-term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the risk-benefit ratio of antiretroviral therapies. PMID: 12439201 [PubMed - indexed for MEDLINE] 4648. J Mol Med (Berl). 2002 Nov;80(11):696-702. Epub 2002 Sep 10. Adiponectin: a link between excess adiposity and associated comorbidities? Ukkola O(1), Santaniemi M. Author information: (1)Department of Internal Medicine and Biocenter Oulu, University of Oulu, Kajaanintie 50/P.O. Box 5000, 90220 Oulu, Finland. olavi.ukkola@oulu.fi Adiponectin is a novel polypeptide that is highly specific to adipose tissue. In contrast to other adipocytokines, adiponectin levels are decreased in obesity and associated comorbidities, such as type 2 diabetes. Decreased expression of adiponectin is correlated with insulin resistance. It has been suggested that several agents, such as tumor necrosis factor alpha, could mediate their effects on insulin metabolism through modulating adiponectin secretion from adipocytes. The mechanisms for the development of atherosclerotic vascular disease in obese individuals are largely unknown. Several findings support the interesting hypothesis that adiponectin could be a link between obesity and related atherosclerosis. First, adiponectin levels are lower in patients with coronary artery disease. Second, adiponectin modulates endothelial function and has an inhibitory effect on vascular smooth muscle cell proliferation. Moreover, adiponectin is accumulated more preferably to the injured vascular wall than intact vessels and has been shown to suppress macrophage-to-foam cell transformation. Adiponectin may also be involved in the modulation of inflammation. Thiazolidinediones, antiatherogenic and other effects have been explained by their direct enhancing effect on adiponectin. In conclusion, adiponectin has anti-inflammatory and antiatherogeneic effects as well as multiple beneficial effects on metabolism. Therefore it is not a surprise that adiponectin therapy has been tested in animal models of obesity, and it has been shown to ameliorate hyperglycemia and hyperinsulinemia without inducing weight gain or even inducing weight loss in some studies. Unlike agents that exert their effects centrally, adiponectin's effects seem to be peripherally mediated. The evidence of an association between adiponectin and the metabolic and cardiovascular complications of obesity is growing all the time. PMID: 12436346 [PubMed - indexed for MEDLINE] 4649. Diabetologia. 2002 Nov;45(11):1475-83. Epub 2002 Oct 18. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Khan AH(1), Pessin JE. Author information: (1)Department of Physiology and Biophysics, University of Iowa, Iowa City 52242, USA. Insulin-stimulated glucose uptake in adipose tissue and striated muscle is critical for reducing post-prandial blood glucose concentrations and the dysregulation of this process is one hallmark of Type II (non-insulin-dependent) diabetes mellitus. It has been well established that the insulin-stimulated redistribution of the insulin responsive glucose transporter, GLUT-4, from intracellular storage sites to the plasma membrane depends on the production of phosphoinositide 3,4,5 trisphosphate by the Class IA Phosphatidylinositol 3' kinase. Recent discoveries however, have shown the presence of a second insulin signalling pathway leading to GLUT-4 translocation, a pathway dependent on insulin receptor signalling emanating from caveolae or lipid rafts at the plasma membrane. This pathway begins with the phosphorylation of the adaptor protein Cbl by the insulin receptor, and results in the activation of a small GTP binding protein, TC10, a member of the Rho family. TC10 is able to modulate actin structure in 3T3L1 adipocytes, and its overexpression inhibits insulin-stimulated GLUT-4 translocation, an inhibition completely dependent on localization of TC10 to the caveolae or lipid rafts. The spatial compartmentalization of insulin signalling from caveolae or lipid rafts provides a novel signalling pathway that functions in concert with general signalling mechanisms in the control of actin dynamics regulating insulin-dependent GLUT-4 translocation. PMID: 12436329 [PubMed - indexed for MEDLINE] 4650. Trends Endocrinol Metab. 2002 Dec;13(10):444-51. Role of Akt/protein kinase B in metabolism. Whiteman EL(1), Cho H, Birnbaum MJ. Author information: (1)Dept Medicine and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 415 Curie Blvd, 322 Clinical Research Building, Philadelphia, PA 19104, USA. Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein kinase B) has been recognized as being remarkably well conserved across a broad range of species and involved in a diverse array of cellular processes. Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiologically important target tissues. Refining our understanding of those pivotal molecular components that normally coordinate insulin action throughout the body is essential for a full understanding of insulin resistance in diabetes mellitus and ultimately the successful treatment of this disease. PMID: 12431841 [PubMed - indexed for MEDLINE] 4651. Am J Med. 2002 Oct 28;113 Suppl 6A:3S-11S. Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. LeRoith D(1). Author information: (1)Clinical Endocrinology Branch of the National Institutes of Health, Bethesda, Maryland, USA. leroith@comcast.net Defects in insulin action and insulin secretion are both present in type 2 diabetes, and both are believed to be genetically predetermined. In the absence of a defect in beta-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations such as the Pima Indians of Arizona. However, loss of beta-cell function leads eventually to the postprandial and fasting hyperglycemia that characterizes type 2 diabetes. This progression occurs despite initially effective antidiabetic therapies, a situation clearly demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high-calorie foods, lack of exercise, weight gain), the increased insulin requirements imposed by insulin resistance, and toxicities from hyperglycemia and elevated free fatty acids may all contribute to beta-cell deterioration. Free fatty acids, resistin, and tumor necrosis factor (TNF)-alpha potentially worsen the insulin resistance. beta-Cell dysfunction resulting from glucose toxicity and lipotoxicity is potentially reversible with restoration of metabolic control. Therefore, attention to these toxicities may delay the deterioration of beta-cell function and suggest new approaches to the management of type 2 diabetes. PMID: 12431757 [PubMed - indexed for MEDLINE] 4652. Nihon Rinsho. 2002 Oct;60 Suppl 10:673-80. [Glucose metabolism in adipose tissue]. [Article in Japanese] Inoue A(1), Tobe K, Suzuki R, Kadowaki T. Author information: (1)Department of Internal Medicine, Graduate School of Medicine, University of Tokyo. PMID: 12430302 [PubMed - indexed for MEDLINE] 4653. Int J Oncol. 2002 Dec;21(6):1285-92. Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Rose DP(1), Gilhooly EM, Nixon DW. Author information: (1)American Health Foundation, Valhalla, NY 10595, USA. Leptin is a hormone with multiple biological actions which is produced predominantly by adipose tissue; in humans, plasma levels correlate with total body fat, and particularly high concentrations occur in obese women. Several actions of leptin, including the stimulation of normal and tumor cell growth, migration and invasion, and enhancement of angiogenesis, suggest that this hormone can promote an aggressive breast cancer phenotype which can be estrogen-independent. This effect may involve activation of the transcription factor NFkappaB. Leptin can also induce aromatase activity, with the potential for the promotion of estrogen production from androstenedione in adipose tissue, and hence the stimulation of estrogen-dependent breast cancer progression. On this basis, we hypothesize that leptin, perhaps in association with insulin, the plasma concentrations of which correlate with those of leptin, has an important role in the known adverse effect of obesity on breast cancer. PMID: 12429979 [PubMed - indexed for MEDLINE] 4654. Tanpakushitsu Kakusan Koso. 2002 Nov;47(14):1896-903. [Significance of adipocytokine, fat-derived hormones, in metabolic syndrome]. [Article in Japanese] Shimomura I(1), Funahashi T, Matsuzawa Y. Author information: (1)ichi@fbs.osaka-u.ac.jp PMID: 12428373 [PubMed - indexed for MEDLINE] 4655. Semin Reprod Med. 2002 Aug;20(3):277-84. The essential role of the aromatase/p450arom. Meinhardt U(1), Mullis PE. Author information: (1)Department of Pediatrics, Pediatric Endocrinology/Diabetology and Metabolism, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland. Aromatase (P450arom) catalyzes the conversion of testosterone to estradiol, androstenedione to estrone, and 16a-hydroxylated dehydroepiandrosterone to estriol. P450arom is encoded by the human CYP19 gene (15q21.1) spanning about 123 kb with a coding region of 9 exons (about 30 kb, exon II to exon X). Although there are a number of alternative first exons and nine different transcriptional start sides with individual promoters that permit tissue-specific regulation of expression, the protein expressed in these various tissue sites (placenta, adipose tissue, brain, bone, ovary, etc.) always remains the same. As not only androgens but also estrogens are of importance particularly in male pubertal development including bone changes, which were classically considered androgen dependent, the features of the aromatase deficiency syndrome in affected boys and girls as well as adult males and females are discussed. There is growing awareness that androgens and estrogens have general metabolic roles that reach far beyond reproductive processes. For instance, estrogen has a significant impact on carbohydrate and lipid metabolism, vascular function, and arteriosclerosis. In addition, extragonadal estrogen biosynthesis plays an important but often underestimated physiological and pathophysiological role, for example, in breast cancer and endometriosis. Based on that knowledge, progress has been made as far as treatment and follow-up of this disorder are concerned. PMID: 12428207 [PubMed - indexed for MEDLINE] 4656. Microsc Res Tech. 2002 Nov 15;59(4):317-24. Anti-aging effects of caloric restriction: Involvement of neuroendocrine adaptation by peripheral signaling. Chiba T(1), Yamaza H, Higami Y, Shimokawa I. Author information: (1)Department of Respiratory and Digestive Medicine, Nagasaki University School of Medicine, Nagasaki City 852-8523, Japan. takuya@net.nagasaki-u.ac.jp Many hormonal signals from peripheral tissues contribute to the regulation of energy homeostasis and food intake. These regulators including leptin, insulin, and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in hypothalamic nuclei. The anti-aging effects of caloric restriction have been explained from an evolutional viewpoint of the adaptive response of the neuroendocrine and metabolic response systems to maximize survival during periods of food shortage. In organisms, excess energy is stored in adipose tissues as a triglyceride preparation for such survival situations. Adipose tissue has recently been recognized as an endocrine organ, and leptin, as secreted by adipocyte, seems to be an especially important factor for the adaptive response to fasting and neuroendocrine alterations under caloric restriction. In this review, we discuss the potential involvement of neuroendocrine modulators in longevity and the anti-aging effects of caloric restriction. Copyright 2002 Wiley-Liss, Inc. PMID: 12424795 [PubMed - indexed for MEDLINE] 4657. Med Res Rev. 2003 Jan;23(1):1-14. Practice and principles of pharmacodynamic determination of HISS-dependent and HISS-independent insulin action: methods to quantitate mechanisms of insulin resistance. Lautt WW(1). Author information: (1)Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, A210-753 Mcdermot Avenue, Winnipeg, Manitoba, Canada, R3E 0T6. wlautt@cc.umanitoba.ca Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50-60% of the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS-dependent and HISS-independent insulin action. Copyright 2002 Wiley Periodicals, Inc. PMID: 12424750 [PubMed - indexed for MEDLINE] 4658. Lancet. 2002 Nov 2;360(9343):1410-8. Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Dubuquoy L(1), Dharancy S, Nutten S, Pettersson S, Auwerx J, Desreumaux P. Author information: (1)Equipe Propre INSERM 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, Centre Hospitalier Universitaire, Lille, France. The peroxisome proliferator-activated receptor gamma (PPARgamma) and its partner the retinoid X receptor (RXR) are two nuclear receptors that are expressed mainly in adipose tissue and which have a role in lipid metabolism and insulin sensitisation. New sites of PPARgamma/RXR expression have been described, especially in the intestinal tract, pancreas, and liver. Concomitantly, new functions have been attributed to this heterodimer in regulation of inflammation, by its inhibition of nuclear factor (NF)-kappaB and via stress-kinase pathways. These new sites and functions of PPARgamma/RXR have led to novel ideas about pathophysiology of different inflammatory digestive diseases and to development of innovative treatment strategies with PPARgamma activators. PMID: 12424006 [PubMed - indexed for MEDLINE] 4659. Anat Sci Int. 2002 Sep;77(3):149-60. Melanin-concentrating hormone neuron system: the Wide Web that controls the feeding. Kawano H(1), Honma S, Honma A, Horie M, Kawano Y, Hayashi S. Author information: (1)Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan. hkawano@tmin.ac.jp Recent evidence indicates that the hypothalamic control system of food intake involves many feeding-related neuropeptides. Melanin-concentrating hormone (MCH), one of a group of potent orexigenic peptides, is exclusively produced in neurons of the lateral hypothalamic area that give off fibers to the widespread brain regions. The receptor of MCH was recently identified to be localized in cell bodies and dendritic processes of particular neurons throughout the brain, in close spatial relation to MCH fibers. Leptin, an anorectic hormone secreted from the adipose tissue, acts on the specific receptor present on its target neurons in the brain, and suppresses the expression of both MCH and its receptor. Leptin receptor and STAT3, a transcription factor mediating the leptin signaling, are distributed in the widespread brain regions including the cerebral neocortex, hippocampal formation and lower brainstem as well as the hypothalamus where MCH fibers and the MCH receptor are abundantly present. These findings suggest that MCH exerts the effect through its specific receptor distributed throughout the brain and that the function of MCH is influenced by the condition of peripheral energy balance via leptin, the leptin receptor and STAT3, not only in the hypothalamus, but also in other brain regions. In the brain, MCH might be involved in various feeding-related functions, such as appetite, food-searching behavior, eating muscle movement, and control of energy balance, depending upon the physiological role of each region. PMID: 12422407 [PubMed - indexed for MEDLINE] 4660. Ned Tijdschr Geneeskd. 2002 Oct 19;146(42):1976-9. [Adipose tissue: an innervated endocrine gland]. [Article in Dutch] Fliers E(1), Romijn JA, Sauerwein HP, Kalsbeek A, Kreier F, Buijs RM. Author information: (1)Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Endocrinologie en Metabolisme, Meibergdreef 9, 1105 AZ Amsterdam. e.fliers@amc.uva.nl Until recently, adipose tissue was considered to function as a passive store of triglycerides and therefore of calories. Fascinating research over the past ten years has altered this traditional perspective. Adipose tissue has been shown to produce hormones. Leptin was discovered in 1994; one of its main functions is to adapt the organism to starvation. Sympathetic nerve fibres were shown to innervate adipose tissue and to facilitate lipolysis leading to the release of glycerol and free fatty acids. In addition, parasympathetic innervation of adipose tissue was recently demonstrated, with anabolic effects. Different sets of autonomic neurons in the brain stem appear to innervate either the abdominal or the subcutaneous fat compartment. This may be the anatomical substrate for the hitherto unexplained regulation of body fat distribution (subcutaneous versus intra-abdominal). Moreover, fat distribution under physiological conditions (sex steroids, glucocorticoids) and pathological conditions (e.g., AIDS lipodystrophy, Cushing syndrome) might be mediated via the central nervous system. The developments in this research area have the potential to increase our insights into the pathogenesis of metabolic disorders such as hypertriglyceridaemia and type-2 diabetes mellitus. PMID: 12420422 [PubMed - indexed for MEDLINE] 4661. Am J Cardiol. 2002 Oct 17;90(8A):30i-47i. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. Kwiterovich PO Jr(1). Author information: (1)Lipid Research Atherosclerosis Division, Departments of Pediatrics and Medicine, the Johns Hopkins University School of Medicine, University Lipid Clinic, Baltimore, Maryland 21205, USA. pkwitero@jhmi.edu Traditional risk factors for coronary artery disease (CAD) predict about 50% of the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined emerging risk factors for CAD, including small, dense low-density lipoprotein (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and low high-density lipoprotein (HDL). An increased number of small, dense LDL particles is often missed when the LDL cholesterol level is normal or borderline elevated. Small, dense LDL particles are present in families with premature CAD and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic syndrome, as defined by ATP III, incorporates a number of the components of these syndromes, including insulin resistance and intra-abdominal fat. Subclinical inflammation and elevated procoagulants also appear to be part of this atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by the liver and increased secretion of large, apolipoprotein (apo) B-100-containing VLDL is the primary metabolic characteristic of most of these patients. The TG in VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate-density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed further, resulting in the generation of LDL. The cholesterol esters in LDL are exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL. Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty acid trapping and retention by adipose tissue may result from a primary defect in the incorporation of free fatty acids into TGs. Alternatively, insulin resistance may promote reduced retention of free fatty acids by adipocytes. Both these abnormalities lead to increased levels of free fatty acids in plasma, increased flux of free fatty acids back to the liver, enhanced production of TGs, decreased proteolysis of apo B-100, and increased VLDL production. Decreased removal of postprandial TGs often accompanies these metabolic abnormalities. Genes regulating the expression of the major players in this metabolic cascade, such as LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the expression of small, dense LDL but these are not the major defects. New candidates for major gene effects have been identified on chromosome 1. Regardless of their fundamental causes, small, dense LDL (compared with normal LDL) particles have a prolonged residence time in plasma, are more susceptible to oxidation because of decreased interaction with the LDL receptor, and enter the arterial wall more easily, where they are retained more readily. Small, dense LDL promotes endothelial dysfunction and enhanced production of procoagulants by endothelial cells. Both in animal models of atherosclerosis and in most human epidemiologic studies and clinical trials, small, dense LDL (particularly when present in increased numbers) appears more atherogenic than normal LDL. Treatment of patients with small, dense LDL particles (particularly when accompanied by low HDL and hypertriglyceridemia) often requires the use of combined lipid-altering drugs to decrease the number of particles and to convert them to larger, more buoyant LDL. The next critical step in further reduction of CAD will be the correct diagnosis and treatment of patients with small, dense LDL and the dyslipidemia that accompanies it. PMID: 12419479 [PubMed - indexed for MEDLINE] 4662. Mt Sinai J Med. 2002 Oct;69(5):280-90. Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology. Bergman RN(1). Author information: (1)Department of Physiology and Biophysics, Center for Diabetes Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. The molecular revolution in biology is providing an exponentially increasing body of data regarding subcellular events in normal and pathological conditions. The task of integrating even a small part of this deluge of information is a formidable challenge. Many integrative regulatory principles are still unknown. The present article argues that important principles may be discovered by the repetitive experimental testing of simple isomorphic computer or mathematical models of biological regulation. The system regulating the blood glucose is used as an example. Implicit in a minimal model, postulated more than 20 years ago, were specific but untested assumptions. These assumptions, which were tested over the ensuing decades, have enriched our understanding of metabolic regulation and the causes of diabetes. Currently accepted concepts emerging from modeling include: (a) the importance of sluggish insulin transport across the capillary endothelium in stimulation of glucose uptake; (b) the single gateway concept, that insulin transport across endothelium of adipose tissue suppresses free fatty acids, which act in turn to reduce endogenous glucose production by the liver; (c) the importance of the single gateway mechanism in the metabolic syndrome, whereby increased fat in the abdominal compartment relates to insulin resistance and risk for type 2 diabetes; and (d) the hyperbolic relationship between insulin action and insulin secretion, which provides an accurate prediction of diabetes risk. It is hoped that the experience with the metabolic system will provide a metaphor for other regulatory systems less subjected to critical quantitative analysis. Such analysis may well lead to analogous conceptual understanding of other important integrated biological systems, and provide approaches for early intervention in the pathogenic process of other chronic and devastating diseases. PMID: 12415321 [PubMed - indexed for MEDLINE] 4663. Nat Rev Cancer. 2002 Nov;2(11):862-71. Cachexia in cancer patients. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK. m.j.tisdale@aston.ac.uk PMID: 12415256 [PubMed - indexed for MEDLINE] 4664. FASEB J. 2002 Nov;16(13):1695-6. Glyceroneogenesis comes of age. Beale EG(1), Hammer RE, Antoine B, Forest C. Author information: (1)Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA. elmus.beale@ttuhsc.edu Glyceroneogenesis is a generally ignored metabolic pathway that occurs in adipose tissues and liver of mammalian species. This short review highlights a series of recent discoveries showing that glyceroneogenesis is important in lipid homeostasis. PMID: 12409311 [PubMed - indexed for MEDLINE] 4665. Best Pract Res Clin Gastroenterol. 2002 Oct;16(5):709-31. The metabolic abnormalities associated with non-alcoholic fatty liver disease. Haque M(1), Sanyal AJ. Author information: (1)Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, MCV Box 980711, Richmond, VA 23298-0711, USA. Non-alcoholic fatty liver disease (NAFLD) is a common disorder in the Western hemisphere. It encompasses two histological lesions: fatty liver and steatohepatitis. A large body of literature indicates that insulin resistance is a key pathophysiological abnormality in patients with NAFLD. Insulin resistance results from a complex interplay between the major targets of insulin action, i.e. muscle, adipose tissue and liver, versus the ability of the pancreatic islet beta cells to compensate for insulin resistance by increasing insulin production. The metabolic and clinical profile associated with insulin resistance is thus defined by the factors that produce and maintain insulin resistance and the effects of decreased insulin sensitivity on various insulin-dependent pathways. The major metabolic defects associated with insulin resistance are increased peripheral lipolysis, increased hepatic glucose output due to increased gluconeogenesis and increased lipid oxidation. This is associated with an oxidative stress in the liver that may be compounded by additional pathophysiological abnormalities. While much work remains to be done, the current understanding of the pathogenesis of NAFLD provides direction for both future investigation and development of therapeutic trials. PMID: 12406441 [PubMed - indexed for MEDLINE] 4666. Diabetes Obes Metab. 2002 Nov;4(6):356-61. Adipose depot-specific effects of PPAR gamma agonists: a consequence of differential expression of PPAR gamma in adipose tissue depots? Montague CT(1). Author information: (1)AstraZeneca Pharmaceuticals, Macclesfield, UK. Carl.Montague@astrazeneca.com PMID: 12406031 [PubMed - indexed for MEDLINE] 4667. Nutr Rev. 2002 Oct;60(10 Pt 2):S39-46; discussion S68-84, 85-7. Leptin and reproduction. Chehab FF(1), Qiu J, Mounzih K, Ewart-Toland A, Ogus S. Author information: (1)Department of Laboratory Medicine, University of California, San Francisco 94143-0134, USA. Leptin, a hormone secreted from adipose tissue, plays an important role in reproductive physiology. It has been shown to stimulate the reproductive system by rescuing the sterility of leptin-deficient mice and advancing the onset of puberty in normal mice. Although leptin is not critical for the biology of pregnancy in mice, its ability to reduce food intake is blunted in mid-gestation suggesting that late pregnancy may be a leptin-resistant state. Modifier genes originating from the Balb/cJ genetic background profoundly alter the sterile-obese phenotype of ob/ob mice by reducing their obesity and stimulating their reproductive system despite the absence of leptin. The mechanism of leptin's action on the reproductive system remains to be determined but is likely to be mediated by multiple factors. PMID: 12403083 [PubMed - indexed for MEDLINE] 4668. FEBS Lett. 2002 Oct 30;531(1):81-7. Dynamics of plasma membrane microdomains and cross-talk to the insulin signalling cascade. Müller G(1). Author information: (1)Aventis Pharma Germany, DG Metabolic Diseases, Industrial Park Höchst, Bldg. H825, 65926, Frankfurt am Main, Germany. guenter.mueller@aventis.com The critical role of the heterogeneous nature of cellular plasma membranes in transmembrane signal transduction has become increasingly appreciated during the past decade. Areas of relatively disordered, loosely packed phospholipids are disrupted by hydrophobic detergent/carbonate-insoluble glycolipid-enriched raft microdomains (DIGs) of highly ordered (glyco)sphingolipids and cholesterol. DIGs exhibit low buoyant density and are often enriched in glycosylphosphatidylinositol-anchored plasma membrane proteins (GPI proteins), dually acylated signalling proteins, such as non-receptor tyrosine kinases (NRTKs), and caveolin. At least two types of DIGs, hcDIGs and lcDIGs, can be discriminated on basis of higher and lower content, respectively, of these typical DIGs components. In quiescent differentiated cells, GPI proteins and NRTKs are mainly associated with hcDIGs, however, in adipose cells certain insulin-mimetic stimuli trigger redistribution of subsets of GPI proteins and NRTKs from hcDIGs to lcDIGs. Presumably, these stimuli induce displacement of GPI proteins from a GPI receptor located at hcDIGs whereas simultaneously NRTKs dissociate from a complex with caveolin located at hcDIGs, too. NRTKs are thereby activated and, in turn, modulate intracellular signalling pathways, such as stimulation of metabolic insulin signalling in insulin-sensitive cells. The apparent dynamics of DIGs may provide a target mechanism for regulating the activity of lipid-modified signalling proteins by small drug molecules, as exemplified by the sulfonylurea, glimepiride, which lowers blood glucose in an insulin-independent fashion, in part. PMID: 12401208 [PubMed - indexed for MEDLINE] 4669. Endocrinology. 2002 Nov;143(11):4161-4. Leptin-central or peripheral to the regulation of bone metabolism? Khosla S. Comment on Endocrinology. 2002 Nov;143(11):4304-9. PMID: 12399407 [PubMed - indexed for MEDLINE] 4670. Steroids. 2002 Nov;67(12):979-83. Regulation of estrogen synthesis in postmenopausal women. Purohit A(1), Reed MJ. Author information: (1)Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St Mary's Hospital, W2 1NY, London, UK. The decrease in ovarian estrogen production that occurs at the menopause may lead to an increase in peripheral aromatase activity. While estrogens can have beneficial effects on some body tissues, such as bone and the cardiovascular system, they also have a crucial role in supporting the growth and development of breast tumors. A number of factors, including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)), which can stimulate aromatase activity, have now been identified. As plasma concentrations of some cytokines increase at the menopause, this may account for the increased peripheral aromatase activity that is detected in older women. Macrophages and lymphocytes which infiltrate breast tissue are now thought to be an important source of cytokines that can stimulate aromatase activity in this tissue. Studies, we have recently carried out, have suggested that the endogenous estrogen metabolite, 2-methoxy-estradiol, may be able to modulate the ability of cytokines and PGE(2) to stimulate aromatase activity. Understanding the role of endogenous estrogen metabolites in regulating estrogen synthesis may give rise to new strategies for the prevention or treatment of breast cancer. PMID: 12398994 [PubMed - indexed for MEDLINE] 4671. Diabetes Metab Res Rev. 2002 Sep-Oct;18(5):345-56. An adipocentric view of signaling and intracellular trafficking. Mora S(1), Pessin JE. Author information: (1)Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, USA. Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-alpha, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter. Copyright 2002 John Wiley & Sons, Ltd. PMID: 12397577 [PubMed - indexed for MEDLINE] 4672. Nihon Rinsho. 2002 Sep;60 Suppl 9:685-90. [Indices of body weight and body fat distribution]. [Article in Japanese] Honda M(1), Asano T. Author information: (1)Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo. PMID: 12387070 [PubMed - indexed for MEDLINE] 4673. Nihon Rinsho. 2002 Sep;60 Suppl 9:409-15. [Insulin sensitizer drugs--review]. [Article in Japanese] Yamanouchi T(1). Author information: (1)Department of Internal Medicine, School of Medicine, University of Teikyo. PMID: 12387026 [PubMed - indexed for MEDLINE] 4674. Nihon Rinsho. 2002 Sep;60 Suppl 9:291-6. [Adverse effects and management of insulin therapy]. [Article in Japanese] Takahashi H(1). Author information: (1)Minami Akatsuka Clinic. PMID: 12387008 [PubMed - indexed for MEDLINE] 4675. Nihon Rinsho. 2002 Sep;60 Suppl 9:261-6. [Mechanisms of improvement of insulin resistance by exercise treatment]. [Article in Japanese] Yamanouchi K(1). Author information: (1)Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetology, Aichi Medical University School of Medicine. PMID: 12387003 [PubMed - indexed for MEDLINE] 4676. Respir Physiol Neurobiol. 2002 Oct 23;133(1-2):3-10; discussion 1-2. The pyrophysiology and sexuality of dragons. Georgy ST(1), Widdicombe JG. Author information: (1)Department of Physiology, St. George's Hospital Medical School, London SW17 0RE, UK. To examine the means whereby dragons produce fire and steam, we have studied a related species, the desert-lizard Lacerta pyrophorus. Morphological studies showed that there were in the snout three distinctive features: (1) a dorsal swelling in the pharynx, the Organ of Feuerwerk, consisting of brown adipose tissue with an extensive sympathetic innervation; (2) greatly enlarged lachrymonasal ducts, the Ducts of Kwentsch; and (3) asbestos deposits in the nasal skin, the Bestos Bodies. Physiological studies show that the Organ of Feuerwerk can, when the animal is excited, produce extremely high temperatures. We discuss how these mechanisms can produce steam and fire, and how the snout is protected. We also discuss and offer a solution to the problem of how, since dragons are invariably male, the species can be propagated. PMID: 12385726 [PubMed - indexed for MEDLINE] 4677. Crit Rev Clin Lab Sci. 2002 Sep;39(4-5):499-525. Leptin and the adipocyte endocrine system. Diamond FB Jr(1), Eichler DC. Author information: (1)Department of Pediatrics, University of South Florida, College of Medicine, Tampa 33612, USA. Although adipose tissue has long been considered to be metabolically passive and primarily responsible for energy storage, recent scientific advances have dramatically altered our understanding of the function of this ubiquitous tissue. The fat cell is a transducer of energy supply for the changing metabolic needs of the body, modulating glucose homeostasis, hypothalamic function, sympathetic output, vascular tone, immune response, and reproduction. Through endocrine/autocrine and paracrine actions, adipocyte-derived molecules defend the body during periods of energy deficit and stress. With the development of obesity, maladaptive responses to adipose excess result in pathologic states of inflammation, coagulopathy, and altered insulin sensitivity. PMID: 12385504 [PubMed - indexed for MEDLINE] 4678. Horm Metab Res. 2002 Sep;34(9):469-74. Adiponectin--its role in metabolism and beyond. Stefan N(1), Stumvoll M. Author information: (1)Clinical Nutrition and Metabolism Section, NIDDK, NIH, Phoenix, Arizona 85016, USA. Adiponectin is a recently identified adipose tissue-derived protein (adipocytokine) with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation. Adiponectin expression and/or secretion is increased by insulin like growth factor-1 and ionomycin, and decreased by tumor necrosis factor-alpha, glucocorticoids, beta-adrenergic agonists and cAMP. Data for insulin are somewhat inconclusive. Moreover, adiponectin expression and secretion are increased by activators of peroxisome proliferator-activated receptor (PPAR)-gamma. Besides inhibiting inflammatory pathways, recombinant adiponectin increases insulin sensitivity and improves glucose tolerance in various animal models. This insulin-sensitizing effect appears to be mostly attributable to enhanced suppression of glucose production, but beneficial effects on muscle cannot be excluded. In humans, plasma adiponectin concentrations exceed those of any other hormone by a thousand times; they decrease with obesity and are positively associated with whole-body insulin sensitivity. Therefore, low adiponectin may contribute to the decrease in whole-body insulin sensitivity that accompanies obesity. Furthermore, there is increasing evidence that genetic variants in the adiponectin gene itself and/or in genes encoding adiponectin-regulatory proteins--such as PPAR-gamma--may be associated with hypoadiponectinemia, insulin resistance and type 2 diabetes. This suggests that adiponectin may reflect PPAR-gamma activity in vivo. Finally, reversal or alleviation of hypoadiponectinemia may represent a target for development of drugs improving insulin sensitivity and glucose tolerance. PMID: 12384822 [PubMed - indexed for MEDLINE] 4679. Curr Cardiol Rep. 2002 Nov;4(6):514-21. Insulin resistance, diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions. Raji A(1), Plutzky J. Author information: (1)Cardiovascular Division/Department of Medicine, Brigham and Women's Hospital, 221 Longwood Avenue, LMRC 307, Boston, MA 02115, USA. The insulin resistance syndrome, a cluster of metabolic abnormalities involving dyslipidemia, hypertension, diabetes, impaired glucose tolerance, and hypercoagulability, carries an increased risk of atherosclerosis. Although interventions targeting elements of this syndrome have dramatically reduced cardiovascular risk, the impact of glucose-lowering has been more disappointing. Thiazolidinediones (TZDs) are a new class of insulin-sensitizing agents that activate the nuclear receptor peroxisome proliferator-activated receptor-g. TZDs may improve not only glucose levels but also other metabolic parameters associated with insulin resistance. The TZD data are reviewed, with a focus on their potential cardiovascular effects. PMID: 12379175 [PubMed - indexed for MEDLINE] 4680. J Psychosom Res. 2002 Oct;53(4):865-71. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Tsigos C(1), Chrousos GP. Author information: (1)Hellenic National Diabetes Center, Athens, Greece. The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli. PMID: 12377295 [PubMed - indexed for MEDLINE] 4681. Endocrine. 2002 Jul;18(2):105-19. The endocrine system in diabetes mellitus. Alrefai H(1), Allababidi H, Levy S, Levy J. Author information: (1)Division of Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201, USA. The pathophysiology of diabetes mellitus is complex and not fully understood. However, it emerges as an abnormal metabolic condition associated with a systemic damage to the vascular bed. Cumulative evidence also reveals that the endocrine system is not intact in patients with diabetes mellitus. It is not clear whether the changes observed in the endocrine system represent a primary defect or reflect the effects of the impaired insulin action and abnormal carbohydrate and lipid metabolism on the hormonal milieu. Review of the literature reveals that the function of the entire endocrine system including the functions of hormones from the hypothalamus, pituitary, adrenal, thyroid, parathyroid, the vitamin D system, the gonads, and the endocrine function of the adipose tissue, is impaired. Good metabolic control and insulin treatment may reverse some of these abnormalities. It remains unanswered as to what extent these changes in the endocrine system contribute to the vascular pathologies observed in individuals affected by diabetes mellitus and whether part of the abnormalities observed in the endocrine system reflect a basic cellular defect in the diabetic syndrome. PMID: 12374457 [PubMed - indexed for MEDLINE] 4682. Eur J Pediatr. 2002 Oct;161 Suppl 1:S65-9. Epub 2002 Jul 13. Disturbed lipid metabolism in glycogen storage disease type 1. Bandsma RH(1), Smit GP, Kuipers F. Author information: (1)Centre for Liver, Digestive and Metabolic Diseases, Room Y2117, CMCIV, University Hospital Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen The Netherlands. R.H.J.Bandsma@med.rug.nl Glycogen storage disease type 1 (GSD1) is an inborn error of metabolism caused by deficiency of glucose-6-phosphatase, the enzyme catalysing the conversion of glucose-6-phosphate (G6P) to glucose. GSD1 is associated with severe hyperlipidaemia and hepatic steatosis. The underlying mechanisms responsible for these abnormalities in lipid metabolism are only partly known. This review summarises data available on hyperlipidaemia and steatosis in GSD1 and postulates new hypotheses for unresolved issues. Evidence indicates that lipid clearance from the blood compartment is decreased in GSD1. Furthermore, in two GSD1a patients synthesis of palmitate, an indicator of de novo lipogenesis, and cholesterol were found to be increased 40-fold and 7-fold, respectively. Elevated hepatic G6P levels may play a regulatory role in lipid synthesis via activation of transcription of lipogenic genes. In addition, accelerated glycolysis will supply acetyl-CoA molecules required for lipogenesis. It is as yet unclear whether hepatic secretion of lipids in the form of very low density lipoprotein-triglycerides (VLDL-TG) is altered in GSD1 patients: we recently found unaffected VLDL-TG secretion rates in an acute animal model of GSD1b. Hepatic steatosis, which is invariably present in GSD1 is probably mainly caused by an increased free fatty acid flux from adipose tissue to the liver and, to a limited extent, by increased de novo lipogenesis.CONCLUSION: future studies, using novel stable isotope methodologies, are warranted to further clarify the disturbances in lipid and lipoprotein metabolism in glycogen storage disease type 1 and the role of glucose-6-phosphate herein. PMID: 12373575 [PubMed - indexed for MEDLINE] 4683. Toxic Rep Ser. 2002 Sep;(73):1-23, A1-C6. NTP Technical Report on the metabolism, toxicity and predicted carcinogenicity of diazoaminobenzene (CAS No. 136-35-6). Ress NB(1); National Toxicology Program. Author information: (1)National Toxicology Program, U.S. Department of Health and Human Services, PHS/NIH, Washington, DC, USA. Diazoaminobenzene is used as an intermediate, complexing agent, and polymer additive. It is also an impurity in certain color additives used in cosmetics, food products, and pharmaceuticals. Diazoaminobenzene was selected for metabolism and toxicity studies based on the potential for worker exposure from its use in laboratories, positive Salmonella typhimurium gene mutation data, its presence as an impurity in foods and cosmetics, and the lack of adequate toxicity data. Several structural analogues and presumed metabolites of diazoaminobenzene are carcinogenic, providing evidence for the possible carcinogenicity of diazoaminobenzene. The chemical structure of diazoaminobenzene suggested that it would be metabolized into aniline and benzene; therefore, metabolism and disposition studies were performed in male and female F344/N rats and male B6C3F1 mice administered a single oral, dermal, or intravenous dose of diazoaminobenzene. Electron spin resonance (ESR) studies were conducted to assess the possible formation of a phenyl radical from the reduction of diazoaminobenzene by components of the cytochrome P450 mixed-function oxidase (P450) system in microsomes or by gut microflora in anaerobic cecal incubations. Bile duct-cannulated male F344/N rats were administered diazoaminobenzene and 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) for in vivo determination of the DMPO-phenyl radical. 16-Day toxicity studies were performed to identify target organs of diazoaminobenzene following dermal application to male and female F344/N rats and B6C3F1 mice. In the disposition and metabolism studies, oral doses of 20 mg/kg to male and female rats and male mice were readily absorbed and excreted mainly in the urine, with exhalation of volatile organics accounting for about 1% of the dose. The only volatile metabolite detected in the breath was benzene, and all the metabolites in the urine were those previously shown to result from the metabolism of benzene and aniline in rats and mice. While dermal doses to rats and mice (2 and 20 mg/cm2) were only slightly absorbed, benzene and aniline metabolites were nonetheless detected in the urine. High circulating levels of benzene, aniline, and their metabolites were detected in the blood of rats administered 20 mg/kg diazoaminobenzene as early as 15 minutes after exposure. At 24 hours after dosing, diazoaminobenzene was detected at low levels (<1%) in the adipose tissue, blood, kidney, liver, muscle, skin, and spleen. Metabolites of benzene and aniline were also formed in an in vitro study using human liver slices. In the ESR spin-trapping experiments, the ESR spectrum of the DMPO-phenyl radical was detected when diazoaminobenzene was incubated with microsomes or P450 reductase, DMPO, and NADPH, or when incubated with cecal contents and DMPO. The DMPO-phenyl radical spectrum was not attenuated by the P450 inhibitor, 1-aminobenzotriazole, or carbon monoxide suggesting that P450s were not required. In in vivo experiments in which rats were administered diazoaminobenzene and DMPO, the DMPO-phenyl radical adduct was detected in bile within 1 hour after treatment. In the 16-day toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice received dermal applications of 0, 12.5, 25, 50, 100, or 200 mg diazoaminobenzene/kg body weight. Animals were evaluated for absolute and relative organ weights, for hematological effects, and for gross and microscopic lesions. No mortality occurred in rats. However, most male mice exposed to concentrations of 50 mg/kg or greater and female mice exposed to 200 mg/kg died. Body weights of male and female rats and female mice were less than those of the vehicle controls. Similar chemical-related toxicities were observed in both species. Clinical pathology data indicated a chemical-related methemoglobinemia and Heinz body formation in male and female rats and mice. Analysis of organ weights indicated possible chemical-related effects in the thymus, heart, spleen, kidney, and liver of rats and/or mice. Increases in the incidences of several skin lesionseral skin lesions, including hyperplasia of the epidermis and hair follicles, and inflammation in rats and mice and ulceration in female mice were observed. Other nonneoplastic lesions that were considered to be related to diazoaminobenzene administration were atrophy of the thymus, mandibular and/or mesenteric lymph nodes, and white pulp of the spleen, as well as splenic hematopoietic cell proliferation in rats and mice. In mice, there were increased incidences of atrial thrombosis, and necrosis was observed in the renal tubules and liver. Diazoaminobenzene was mutagenic in S. typhimurium strains TA98, TA100, and TA1537 with induced rat or hamster liver S9 enzymes; no activity was noted in strain TA1535, with or without S9. In vivo, two gavage administrations of either diazoaminobenzene or benzene induced highly significant increases in micronucleated polychromatic erythrocytes in bone marrow of male B6C3F1 mice at all doses tested. Diazoaminobenzene is metabolized to the known carcinogens benzene and aniline. Further evidence of this metabolism is that some toxic effects associated with aniline (methemoglobinemia) and benzene (atrophy of the lymphoid tissue) were identified. Based on these results, it is predicted that diazoaminobenzene is a carcinogen. PMID: 12370695 [PubMed - indexed for MEDLINE] 4684. Clin Sports Med. 2002 Jul;21(3):335-47, vii. Sources of anterior knee pain. Biedert RM(1), Sanchis-Alfonso V. Author information: (1)Orthopaedic Surgery and Sport Traumatology, Institute of Sport Sciences, Magglingen, Switzerland. The anterior part of the knee consists mainly of structures belonging to the patellofemoral joint, which includes a variety of tissues, such as cartilage, subchondral bone, synovial plicae, infrapatellar fat pad, retinacula, capsule, and tendons. Each of these structures, alone or in combination, can be a source of anterior knee pain. Unphysiologic load or changed metabolic activities can lead to structural failure with loss of homeostatic conditions. PMID: 12365231 [PubMed - indexed for MEDLINE] 4685. J Lipid Res. 2002 Oct;43(10):1585-94. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. Kraemer FB(1), Shen WJ. Author information: (1)Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA. fbk@stanford.edu Hormone-sensitive lipase (HSL) is an intracellular neutral lipase that is capable of hydrolyzing triacylglycerols, diacylglycerols, monoacylglycerols, and cholesteryl esters, as well as other lipid and water soluble substrates. HSL activity is regulated post-translationally by phosphorylation and also by pretranslational mechanisms. The enzyme is highly expressed in adipose tissue and steroidogenic tissues, with lower amounts expressed in cardiac and skeletal muscle, macrophages, and islets. Studies of the structure of HSL have identified several amino acids and regions of the molecule that are critical for enzymatic activity and regulation of HSL. This has led to important insights into its function, including the interaction of HSL with other intracellular proteins, such as adipocyte lipid binding protein. Accumulating evidence has defined important functions for HSL in normal physiology, affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action; however, direct links between abnormal expression or genetic variations of HSL and human disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, await further clarification. The published reports examining the regulation, and function of HSL in normal physiology and disease are reviewed in this paper. PMID: 12364542 [PubMed - indexed for MEDLINE] 4686. Biol Res Nurs. 2002 Jul;4(1):43-53. The case for an immunologic cause of obesity. Rogge MM(1). Author information: (1)Indiana University School of Nursing, Indianapolis, IN 46202, USA. mmrogge@iupui.edu The most pressing public health problem at the start of the century is the mounting prevalence of obesity. Acknowledging an interplay between genetics and the environment in the development of obesity, most experts still attribute the rising trend toward obesity to the ready availability offood and an increasingly sedentary lifestyle. With a growing body of evidence demonstrating strong links between adipose tissue and the immune system, there is good reason to ask whether the cause of the current obesity epidemic might be a less obvious disorder of immune function, perhaps even the consequence of infection. The interplay between preadipocytes and adipocytes and the immune system is examined, and recommendations for further research are offered. PMID: 12363281 [PubMed - indexed for MEDLINE] 4687. Curr Atheroscler Rep. 2002 Nov;4(6):448-53. Obesity and cardiovascular disease. Poirier P(1), Eckel RH. Author information: (1)Institut Universitaire de Cardiologie et de Pneumologie, Hôspital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, Québec G1V 4G5, Canada. Obesity is a major contributor to the prevalence of cardiovascular disease in the developed world, and yet has only recently been afforded the same level of attention as other risk factors of coronary artery disease. Obesity is a chronic metabolic disorder associated with cardiovascular disease and increased morbidity and mortality. It is apparent that a variety of adaptations/alterations in cardiac structure and function occur as excessive adipose tissue accumulates, even in the absence of comorbidities. Shifts toward a less physically demanding lifestyle are observed today throughout different populations, and this scourge associated with obesity implicates a corresponding increase in the number of individuals afflicted with the metabolic syndrome, which defines the obese patient as being "at risk." Adipose tissue is not simply a passive storehouse for fat, but an endocrine organ that is capable of synthesizing and releasing into the bloodstream a variety of molecules that may impact unfavorably the risk factor profile of a patient. Indeed, obesity may affect atherosclerosis through unrecognized variables and risk factors for coronary artery disease such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, and the prothrombotic state. By favorably modifying lipids, decreasing blood pressure, and decreasing levels of glycemia, proinflammatory cytokines, and adhesion molecules, weight loss may prevent the progression of atherosclerosis or the occurrence of acute coronary syndrome events in the obese high-risk population. PMID: 12361492 [PubMed - indexed for MEDLINE] 4688. J Pharm Pharmacol. 2002 Sep;54(9):1237-45. Prediction of the volume of distribution of a drug: which tissue-plasma partition coefficients are needed? Björkman S(1). Author information: (1)Hospital Pharmacy, Malmö University Hospital, Sweden. Sven.Bjorkman@Apoteket.Se The aim of this study was to identify the tissue-plasma partition coefficients (Kp) needed for an initial prediction of the volume of distribution at steady state (Vd(ss)) of a drug in humans. Values of Kp were collected from the literature. Only Kp values plausibly representing true steady state distribution were accepted, and data had to be available for muscle, fat, skin and at least five other organs. The apparent volume of distribution of a drug in an organ/tissue (Vapp) was calculated as Kp multiplied by the volume of the organ/tissue, and the Vd(ss) as the sum of all available Vapp values. The percentage contribution of each Vapp to the Vd(ss) was estimated. In addition, linear regressions were calculated between Kp values of all drugs in a specific organ/tissue and Kp in muscle or fat. Finally, the Vd(ss) was re-calculated using (for basic drugs) the Kp in fat to calculate Vapp in fat and lungs and the Kp in muscle for the Vapp of all other organs/tissues. The two sets of estimates of Vd(ss) were compared by linear regression. The same calculations were performed for acidic drugs, except that muscle Kp was used also forthe lungs. Distribution to fat and muscle accounted for 84% (61-91%) (median and range) of the total estimated Vd(ss) of the basic drugs (n = 17). The regressions between Kp in organs/tissues and muscle Kp were statistically significant except in the case of liver. For acidic drugs (n = 18), distribution to fat and muscle accounted for 65% (42-92%) of Vd(ss), and the regressions of Kp were significant for all organs/tissues except kidney and bone. For both types of drugs, correlations between organ/tissue Kp values and Kp in fat were generally worse. There were excellent linear correlations between Vd(ss) calculated by means of only two Kp values and the originally calculated Vd(ss) (r2> or = 0.99 for both basic and acidic drugs; slopes were notsignificantly different from unity). Thus, initial estimation of the Vd(ss) of a new drug can normally be based on only two Kp values, those of muscle and fat. The muscle Kp can be used to represent all lean tissues, including the residual "carcass", with the exception that fat Kp can be used for distribution of basic drugs to lungs. PMID: 12356278 [PubMed - indexed for MEDLINE] 4689. Curr Opin Lipidol. 2002 Oct;13(5):471-81. Lipoprotein lipase: the regulation of tissue specific expression and its role in lipid and energy metabolism. Preiss-Landl K(1), Zimmermann R, Hämmerle G, Zechner R. Author information: (1)Institute of Molecular Bioloogy, Biochemistry and Microbiology, Karl-Frasnzens-University, Graz, Heinrichstrasse 31a, A-8010 Graz, Austria. PURPOSE OF REVIEW: The aim of this review is to summarize and discuss recent advances in the understanding of the physiological role of lipoprotein lipase in lipid and energy metabolism. RECENT FINDINGS: Studies on the transcriptional and the posttranscriptional level of lipoprotein lipase expression have provided new insights into the complex mechanisms that are involved in the regulation of the enzyme. Additionally a large body of evidence from both human studies and animal models suggests that the level of lipoprotein lipase expression in a given tissue is the rate limiting process for the uptake of triglyceride derived fatty acids. Imbalances in the partitioning of fatty acids among peripheral tissues have major metabolic consequences. For example, in mice both decreased lipoprotein lipase activities in adipose tissue and increased activity in muscle are associated with resistance to obesity; lack of lipoprotein lipase activity in macrophages is correlated with a decreased susceptibility to develop atherosclerotic lesions and overexpression of the enzyme in muscle is associated with increased blood glucose levels and insulin resistance. SUMMARY: Considering the central role of lipoprotein lipase in energy metabolism it is a reasonable goal to discover and develop new drugs that affect the tissue specific expression pattern of the enzyme. PMID: 12352010 [PubMed - indexed for MEDLINE] 4690. JAMA. 2002 Oct 2;288(13):1622-31. Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: plausible mechanisms for improving cardiovascular health. Stewart KJ(1). Author information: (1)Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. kstewart@mail.jhmi.edu The coexistence of type 2 diabetes and hypertension is especially damaging to cardiovascular health. Most trials of exercise training for these conditions have focused on glycemic control and blood pressure reduction. Less is known about the effects of exercise on the cardiovascular consequences of diabetes and hypertension. This article reviews the available evidence and plausible mechanisms by which exercise training may improve the cardiovascular health of persons with type 2 diabetes and hypertension and provides practical guidelines for exercise prescription. A MEDLINE search was performed for January 1985 to June 2002. Bibliographies from relevant articles, professional society clinical practice guidelines, and books were also reviewed. Because few large, randomized trials exist on these topics, meta-analyses, smaller trials, nonrandomized trials, and animal studies were also considered. Data quality was determined by publication in peer-reviewed journals or professional society literature. Type 2 diabetes and hypertension result in abnormalities in central and peripheral parameters of cardiovascular structure and function. Evidence for an exercise training benefit is strongest for improvements in endothelial vasodilator function and left ventricular diastolic function. The data for exercise training's improvement of arterial stiffness and system inflammation and reduction of left ventricular mass are less robust. However, this assertion is based more on a lack of randomized controlled trials rather than data to the contrary. Exercise training also reduces total and abdominal fat. These changes in body composition mediate improvements in insulin sensitivity and blood pressure and may improve endothelial vasodilator function. The current evidence, albeit not fully confirmed in randomized trials, suggests that the benefits of exercise training go beyond the recognized benefits of glycemic control and blood pressure reduction. PMID: 12350193 [PubMed - indexed for MEDLINE] 4691. Hepatology. 2002 Oct;36(4 Pt 1):781-91. Epidemiology of the American Indians' burden and its likely genetic origins. Carey MC(1), Paigen B. Author information: (1)Department of Medicine, Harvard Medical School and Digestive Diseases Center, Gastroenterology Division, Brigham and Women's Hospital, Boston, MA 02115, USA. mccarey@rics.bwh.harvard.edu Erratum in Hepatology 2002 Dec;36(6):1559. Comment in Hepatology. 2003 Apr;37(4):947-8; author reply 948-9. It was not known until recently whether the endemic of cholesterol gallstones among certain southwestern American Indian tribes was unique among this ethnic group. With use of ultrasonography of the gallbladder and standard diagnostic criteria, gallstones are now found in epidemic proportions in 13 diverse American Indian tribes and communities living in Arizona, Oklahoma, and the Dakotas. We speculate that this predisposition is polygenic involving "thrifty" genes that conferred survival advantages when Paleo-Indians migrated from present-day Siberia to the Americas during the last Great Ice Age approximately 50,000 to 10,000 years ago. A reasonable hypothesis is that functioning of these genes promoted more efficient calorie utilization and storage in the form of adipose tissue. Beneficial results would have been operative during the isolation of Paleo-Indians in the Bering Strait land bridge (Beringia) when thrifty genes would have ensured sufficient fat reserves for survival of prolonged winters, successful pregnancy outcomes, and extended lactation periods. The authors' conjoint work on genetics of experimental cholesterol cholelithiasis in inbred mice promises help in pinpointing orthologous genetic loci (LITH genes) in the human genome. Moreover, the shared environments and homogeneity of American Indian tribes and communities should facilitate discovery of the ensembles of their common and rarer cholesterol gallstone genes. It is anticipated that knowledge of expression, polymorphisms, and functionality of LITH genes will help resolve the molecular mechanisms of this complex heterogeneous trait and thereby provide targets for novel therapies to prevent cholesterol cholelithiasis worldwide. PMID: 12297824 [PubMed - indexed for MEDLINE] 4692. Diabetologia. 2002 Sep;45(9):1211-23. Epub 2002 Jul 5. Thiazolidinediones: metabolic actions in vitro. Fürnsinn C(1), Waldhäusl W. Author information: (1)Department of Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Austria. clemens.fuernsinn@akh-wien.ac.at To unravel the molecular mechanisms and the causal chain of how thiazolidinediones (TZDs) affect glucose homeostasis, it is helpful to analyse their direct influence on isolated specimens of fat, muscle, and liver in vitro. Studies on isolated adipocytes have shown that the nuclear peroxisome proliferator-activated receptor-gamma (PPAR gamma) is an important molecular target for TZDs, through which they trigger adipocyte differentiation and adipose tissue remodelling. It is not clear, however, if the activation of PPAR gamma in adipose tissue is the cause of all the metabolic actions of TZDs. Based on in vitro studies, two hypotheses have been developed. The first emphasizes PPAR gamma-mediated actions on adipose tissue, suggesting that insulin sensitization of skeletal muscle and liver is triggered indirectly by changes in circulating concentrations of adipocyte-derived non-esterified fatty acids and peptide hormones. The second states that TZDs improve glucose homeostasis independently from adipose tissue actions by the direct interaction with muscle and liver. This hypothesis is supported by direct TZD actions on fuel metabolism of skeletal muscle and liver in vitro, which seem to be independent from PPAR gamma signalling. Major progress has been made in understanding the mechanisms involved in the effects of TZDs on adipose tissue but the causal chain responsible for their antihyperglycaemic action is still not clear. The involvement of other molecular targets in addition to PPAR gamma, of adipocyte-derived messengers, and of direct interaction with skeletal muscle and liver have yet to be clarified. PMID: 12242453 [PubMed - indexed for MEDLINE] 4693. Diabetologia. 2002 Sep;45(9):1201-10. Epub 2002 Jul 24. Adipose tissue as a buffer for daily lipid flux. Frayn KN(1). Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE, UK. keith.frayn@oxlip.ox.ac.uk Insulin resistance occurs in obesity and Type II (non-insulin-dependent) diabetes mellitus, but it is also a prominent feature of lipodystrophy. Adipose tissue could play a crucial part in buffering the flux of fatty acids in the circulation in the postprandial period, analogous to the roles of the liver and skeletal muscle in buffering postprandial glucose fluxes. Adipose tissue provides its buffering action by suppressing the release of non-esterified fatty acids into the circulation and by increasing triacylglycerol clearance. In particular, the pathway of 'fatty acid trapping' (adipocyte uptake of fatty acids liberated from plasma triacylglycerol by lipoprotein lipase) could play a key part in the buffering process. If this buffering action is impaired, then extra-adipose tissues are exposed to excessive fluxes of lipid fuels and could accumulate these in the form of triacylglycerol, leading to insulin resistance. These tissues will include liver, skeletal muscle and the pancreatic beta cell, where the long term effect is to impair insulin secretion. Adipose tissue buffering of lipid fluxes is impaired in obesity through defects in the ability of adipose tissue to respond rapidly to the dynamic situation that occurs after meals. It is also impaired in lipodystrophy because there is not sufficient adipose tissue to provide the necessary buffering capacity. Thus, the phenotype, at least with regard to insulin resistance, is similar with both excess and deficiency of adipose tissue. Furthermore, this concept could provide a framework for understanding the action of the thiazolidinedione insulin-sensitizing agents. PMID: 12242452 [PubMed - indexed for MEDLINE] 4694. Verh K Acad Geneeskd Belg. 2002;64(3):167-87; discussion 187-8. Endocrinology in intensive care medicine: new insights and therapeutic consequences. Van den Berghe G(1). Author information: (1)Department of Intensive Care Medicine, University Hospital Gasthuisberg-KULeuven, Herestraat 39, B-3000 Leuven. Sepsis, excessive inflammation, multiple organ failure and weakness prolong the need for intensive care in critically ill patients. Furthermore, the risk of death is high in the prolonged critically ill patient (20% after two weeks and 30% after 3 weeks). In prolonged critical illness, protein hypercatabolism and relative preservation of adipose tissue with fatty infiltration of vital organ systems is present. In view of the crucial role of the hypothalamus-pituitary axis for metabolic homeostasis, we have studied this endocrine organ in the context of critical illness. The initial "adaptive" neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function. In the chronic phase of critical illness, a uniformly reduced pulsatile secretion of anterior pituitary hormones has been observed, whereby impaired function of target organs. A reduced availability of thyrotropin (TSH)-releasing hormone (TRH), gonadotropin (LH)-releasing hormone (GnRH), the endogenous ligand of the growth hormone (GH)-releasing peptide (GHRP) receptor (ghrelin) and, in very long-stay critically ill men also of GH-releasing hormone (GHRH), inferrentially appears involved. Pulsatile secretion of GH, TSH and LH can be re-amplified by relevant combinations of releasing factors which also substantially increases circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine (T4), triiodothyronine (T3) and testosterone. Anabolism is only evoked when GH-secretagogues, TRH and GnRH are administered together whereas the effect of single hormone treatment is minor and accompanied by side effects. A remarkable observation was that a high serum concentration of IGF-binding protein 1 predicts death in the ICU. This observation challenged the classical dogma of adaptive hyperglycemia during critical illness. In a large prospective randomized clinical study (1548 patients), we showed that ICU mortality was reduced by 42% with strict normalization of glycemia using exogenous insulin infusion (N Engl J Med 2001). This was due to prevention of typical ICU complications such as sepsis, multiple organ failure and need for prolonged invasive organ support and intensive care. We conclude that the new concept of reduced stimulation of pituitary function in prolonged critically ill patients opens new therapeutic perspectives to reverse the paradoxical 'wasting syndrome' but that maintenance of strict normoglycemia with insulin is crucial to also increase the chances of survival of these patients. PMID: 12238241 [PubMed - indexed for MEDLINE] 4695. Nihon Rinsho. 2002 Jul;60 Suppl 7:746-51. [Glucose intolerance in visceral fat syndrome]. [Article in Japanese] Matsuzawa Y(1). Author information: (1)Department of Internal Medicine and Molecular Science, Osaka University Graduate School. PMID: 12238130 [PubMed - indexed for MEDLINE] 4696. Nihon Rinsho. 2002 Jul;60 Suppl 7:583-92. [Adiponectin as a key molecule of the metabolic syndrome]. [Article in Japanese] Funahashi T(1), Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine. PMID: 12238103 [PubMed - indexed for MEDLINE] 4697. Nihon Rinsho. 2002 Jul;60 Suppl 7:565-70. [Beta 3 adrenergic receptor]. [Article in Japanese] Kogure A(1), Yoshida T. Author information: (1)Department of Endocrinology, Diabetes and Metabolism, Kyoto Prefectural University of Medicine. PMID: 12238099 [PubMed - indexed for MEDLINE] 4698. Nihon Rinsho. 2002 Jul;60 Suppl 7:286-90. [The effect of estrogen on adiposity and metabolism]. [Article in Japanese] Osuga J(1). Author information: (1)Department of Metabolic Disease, Faculty of Medicine, University of Tokyo. PMID: 12238062 [PubMed - indexed for MEDLINE] 4699. Nihon Rinsho. 2002 Jul;60 Suppl 7:280-5. [Glucocorticoid]. [Article in Japanese] Tsuchida Y(1), Miyachi Y, Tsuchida Y. Author information: (1)First Department of Internal Medicine, School of Medicine, Toho University. PMID: 12238061 [PubMed - indexed for MEDLINE] 4700. Nihon Rinsho. 2002 Jul;60 Suppl 7:228-33. [Insulin action: its variety and diversity]. [Article in Japanese] Ogawa W(1), Kasuga M. Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine. PMID: 12238052 [PubMed - indexed for MEDLINE] 4701. Am J Cardiol. 2002 Sep 5;90(5A):3G-10G. Insulin resistance as the core defect in type 2 diabetes mellitus. Goldstein BJ(1). Author information: (1)Department of Medicine, Division of Endocrinology, Diabetes, and Metabolic Disease, Jefferson Medical College, Jefferson Alumni Hall Suite 349, 1020 Locust Street, Philadelphia, PA 19107, USA. barry.goldstein@mail.tju.edu Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension. Obesity, especially visceral adiposity, is negatively correlated with insulin sensitivity. The release of free fatty acids from adipocytes can block insulin-signaling pathways and lead to insulin resistance. In addition, recently identified adipocyte-specific chemical messengers, the adipocytokines, such as tumor necrosis factor-alpha, adiponectin, and resistin, appear to modulate the underlying insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or type 2 diabetes can result. The thiazolidinediones are potent peroxisome proliferator-activated receptor-gamma agonists and directly improve insulin resistance and glycemic control in patients with type 2 diabetes. Increasing evidence supports the early use of thiazolidinediones for preventing, delaying, or treating diabetes by improving insulin sensitivity and beta-cell insulin secretion. PMID: 12231073 [PubMed - indexed for MEDLINE] 4702. Pediatrics. 1998 Mar;101(3 Pt 2):539-49. Development of eating behaviors among children and adolescents. Birch LL(1), Fisher JO. Author information: (1)Department of Human Development and Family Studies, Pennsylvania State University, University Park, USA. The prevalence of obesity among children is high and is increasing. We know that obesity runs in families, with children of obese parents at greater risk of developing obesity than children of thin parents. Research on genetic factors in obesity has provided us with estimates of the proportion of the variance in a population accounted for by genetic factors. However, this research does not provide information regarding individual development. To design effective preventive interventions, research is needed to delineate how genetics and environmental factors interact in the etiology of childhood obesity. Addressing this question is especially challenging because parents provide both genes and environment for children. An enormous amount of learning about food and eating occurs during the transition from the exclusive milk diet of infancy to the omnivore's diet consumed by early childhood. This early learning is constrained by children's genetic predispositions, which include the unlearned preference for sweet tastes, salty tastes, and the rejection of sour and bitter tastes. Children also are predisposed to reject new foods and to learn associations between foods' flavors and the postingestive consequences of eating. Evidence suggests that children can respond to the energy density of the diet and that although intake at individual meals is erratic, 24-hour energy intake is relatively well regulated. There are individual differences in the regulation of energy intake as early as the preschool period. These individual differences in self-regulation are associated with differences in child-feeding practices and with children's adiposity. This suggests that child-feeding practices have the potential to affect children's energy balance via altering patterns of intake. Initial evidence indicates that imposition of stringent parental controls can potentiate preferences for high-fat, energy-dense foods, limit children's acceptance of a variety of foods, and disrupt children's regulation of energy intake by altering children's responsiveness to internal cues of hunger and satiety. This can occur when well-intended but concerned parents assume that children need help in determining what, when, and how much to eat and when parents impose child-feeding practices that provide children with few opportunities for self-control. Implications of these findings for preventive interventions are discussed. PMID: 12224660 [PubMed - indexed for MEDLINE] 4703. Pediatrics. 1998 Mar;101(3 Pt 2):525-39. The physiology of body weight regulation: relevance to the etiology of obesity in children. Rosenbaum M(1), Leibel RL. Author information: (1)Tufts University School of Medicine and the Floating Hospital, Boston, Massachusetts, USA. The prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. Recent studies of the physiology and molecular genetics of obesity in humans have provided evidence that body weight (fat) is regulated. Some of the genes encoding the molecular components of this regulatory system have been isolated from rodents. The increasing prevalence of obesity in the United States apparently represents the interaction of these genes with an environment that encourages a sedentary lifestyle and consumption of calories. The rapid increase in the prevalence of obesity emphasizes the role of environmental factors, because genetic changes could not occur at this rate. Thus, understanding of the relevant genes and how their effects are mediated by environment and development should lead to more effective prophylaxis and therapy of obesity. Although no clear environmental factors have been identified as causative of obesity, the rapid increases in the prevalence of obesity and the seeming voluntary immutability of adult body fatness can be taken as tacit evidence that the pediatric environment can be altered in a way that affects adult body weight. PMID: 12224659 [PubMed - indexed for MEDLINE] 4704. Pediatrics. 1998 Mar;101(3 Pt 2):505-18. Measurement issues related to studies of childhood obesity: assessment of body composition, body fat distribution, physical activity, and food intake. Goran MI(1). Author information: (1)Department of Nutrition Sciences, University of Alabama at Birmingham, USA. This article reviews the current status of various methodologies used in obesity and nutrition research in children, with particular emphasis on identifying priorities for research needs. The focus of the article is 1) to review methodologic aspects involved with measurement of body composition, body-fat distribution, energy expenditure and substrate use, physical activity, and food intake in children; and 2) to present an inventory of research priorities. PMID: 12224657 [PubMed - indexed for MEDLINE] 4705. Trends Mol Med. 2002 Sep;8(9):442-7. Adipogenesis and fat-cell function in obesity and diabetes. Camp HS(1), Ren D, Leff T. Author information: (1)Department of Molecular Sciences and Technology, Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA. heidi.camp@pfizer.com Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects in any part of this system can lead to metabolic disorders, such as diabetes and obesity. Adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues. Here, we review new advances in our understanding of adipogenesis and fat-cell function, primarily from the perspective of the transcription factor peroxisome proliferator-activated receptor gamma. PMID: 12223316 [PubMed - indexed for MEDLINE] 4706. Biochim Biophys Acta. 2002 Sep 19;1572(2-3):285-93. Galectins and cancer. Danguy A(1), Camby I, Kiss R. Author information: (1)Laboratory of Histopathology, CP 620, Faculty of Medicine, Université Libre de Bruxelles, 808 Route de Lennik, B-1070, Brussels, Belgium. adanguy@ulb.ac.be The galectins are a family of proteins that are distributed widely in all living organisms. All of them share galactose-specificity. At present, 14 members of the family are characterized in mammals. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, RNA splicing, and tumor metastasis. Although efforts have mostly focused on the possible function of galectins in tumor development and invasiveness, their precise role in this field is still debated. This review discusses the recent way in which the expression of galectins and galectin-binding sites may affect the behavior of a variety of human neoplastic tissues. PMID: 12223276 [PubMed - indexed for MEDLINE] 4707. Med Sci Sports Exerc. 2002 Sep;34(9):1477-84. Regulation of skeletal muscle fat oxidation during exercise in humans. Spriet LL(1). Author information: (1)Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1. lspriet@uoguelph.ca Fat and carbohydrate are the major energy substrates during aerobic exercise in well-fed humans. The regulation of fat metabolism during exercise has not been as thoroughly studied as carbohydrate metabolism, especially in human skeletal muscle. Traditionally, it was believed that the regulation of skeletal muscle fat metabolism was mainly at the level of the delivery of free fatty acids to the muscle (adipose tissue lipolysis) and transport of the long chain fatty acids into the mitochondria. It is now known that the transport of fatty acids into the muscle cell and the regulation of muscle triacylglycerol lipase activity are also important sites of regulation. New lines of research are currently underway examining the regulation of fat metabolism in skeletal muscle at the level of fat transport across the sarcolemmal and mitochondrial membranes and regulation of TG lipase activity in both rodent and human models. A major goal of this research is to determine the regulatory signals that control the up-regulation of fat metabolism during the transition from rest to low and moderate aerobic exercise (30-65% (.)VO(2max)) and the down-regulation that occurs when exercising at intense aerobic exercise (approximately 85% (.)VO(2max)). Although it is expected that the signals that activate carbohydrate metabolism during exercise (Ca and free ADP, AMP, and P(i)) would also play a role in fat metabolism, this has not been demonstrated to date. PMID: 12218742 [PubMed - indexed for MEDLINE] 4708. J R Soc Med. 2002;95 Suppl 42:46-53. Metabolic pathogenesis of familial combined hyperlipidaemia with emphasis on insulin resistance, adipose tissue metabolism and free fatty acids. de Graaf J(1), Veerkamp MJ, Stalenhoef AF. Author information: (1)Department of Medicine, Division of General Internal Medicine 541, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. j.degraaf@aig.azn.nl PMCID: PMC1308945 PMID: 12216327 [PubMed - indexed for MEDLINE] 4709. J R Soc Med. 2002;95 Suppl 42:39-45. Ectopic fat accumulation: an important cause of insulin resistance in humans. Yki-Järvinen H(1). Author information: (1)Department of Medicine, Division of Diabetes, University of Helsinki, PO Box 340, FIN-00029 HUCH, Helsinki, Finland. ykijarvi@helsinki.fi PMCID: PMC1308944 PMID: 12216326 [PubMed - indexed for MEDLINE] 4710. J R Soc Med. 2002;95 Suppl 42:33-8. Correction of dysfunctional fatty acid metabolism using peroxisome proliferator activated receptor gamma agonists. Oakes ND(1), Ljung B, Camejo G. Author information: (1)AstraZeneca R&D Mölndal, S-431 82 Mölndal, Sweden. Nick.Oakes@astrazeneca.com PMCID: PMC1308943 PMID: 12216325 [PubMed - indexed for MEDLINE] 4711. J R Soc Med. 2002;95 Suppl 42:3-7. Adipose tissue and fatty acid metabolism in humans. Jensen MD(1). Author information: (1)Endocrine Research Unit, 5-194 Joseph, Mayo Clinic, Rochester, MN 55905, USA. jensen.michael@mayo.edu It is now clear that there are major regional differences in adipose tissue function as regards the uptake and release of fatty acids. Visceral adiposity is a good predictor of abnormal regulation of adipose tissue fuel export, but it is not the source of excess systemic FFA in humans. Regional differences in adipose tissue uptake of fatty acids may be an important determinant of body fat distribution, which in turn appears to predict abnormalities of fatty acid metabolism. PMCID: PMC1308942 PMID: 12216324 [PubMed - indexed for MEDLINE] 4712. Nervenarzt. 2002 Sep;73(9):897-902. [Leptin and psychiatric disorders]. [Article in German] Pollmächer T(1). Author information: (1)Max-Planck-Institut für Psychiatrie, München, Germany. As early as the beginning of the 20th century, changes in appetite and weight were recognized as important symptoms of severe psychiatric disorders. Particularly in the last decade, understanding of the regulation of appetite and weight has made major progress. In this context, the discovery of the adipose tissue hormone leptin, which signals the size of the peripheral fat stores to the CNS, was crucial. In addition, leptin is also involved in a number of CNS networks regulating behavior and thus of great importance for the pathophysiology of psychiatric disorders. Apart from sexual behavior, those networks include motor activity, sleep, and cognition. Moreover, leptin seems to be involved in the development and maturation of the brain. The present paper summarizes current studies which suggest that, in psychiatric disorders, leptin could be of importance not only for disease-associated or drug-related changes in appetite and weight but also for alterations in behavior and cognition. PMID: 12215885 [PubMed - indexed for MEDLINE] 4713. Rev Endocr Metab Disord. 2002 Sep;3(3):225-30. Estrogens. Ackerman GE(1), Carr BR. Author information: (1)Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA. PMID: 12215717 [PubMed - indexed for MEDLINE] 4714. Bull Cancer. 2002 Jul-Aug;89(7-8):689-95. [From cytogenetics to cytogenomics of adipose tissue tumors: 1. Benign adipose tissue tumors]. [Article in French] Pedeutour F(1), Foa C. Author information: (1)Laboratoire de génétique, Hôpital de l'Archet, 151, route de Saint-Antoine-de-Ginestière, BP 3079, 06202 Nice Cedex 3, France. pedeutou@unice.fr Benign lipomatous tumors are characterized at the genetic level by different types of chromosomal abnormalities. A rearrangement of the HMGIC (HMGA2) gene, localized in 12q15 and coding for an architectural non-histone DNA protein, is observed in a majority of solitary superficial lipomas. Alterations of HMGIC are often resulting from reciprocal translocations, such as t(3;12)(q27-28;q15) that fuses LPP with HMGIC, but a variety of chromosomal anomalies, such as deletions, inversions or insertions are also observed. Rearrangements of chromosomal regions 6p21-22, 13q, 11q13, 12q13 or others are described in approximately one third of superficial lipoma cases with abnormal karyotypes. The genes involved in these alterations remain to be determined. Lipoblastomas are pediatric neoplasms that are characterized by rearrangements of PLAG1, located in 8q11-12 whereas hibernomas, that resemble brown fat, are associated with 11q13 rearrangements together with often complex chromosomal alterations. Deletions of 13q and 16q have been identified in spindle cell lipomas. A t(11;16)(q13;p12-13) have been described in the two published karyotypes of chondroid lipomas. The chromosomal features of other rare benign lipomatous tumors, the differential diagnosis of which is occasionally difficult, such as infiltrating intra-muscular lipomas, organic deep-seated lipomas, or angiomyolipomas, myolipomas, myxolipomas are still poorly defined. Although the genetic characterization of benign lipomatous tumors has been dramatically in progress over the last ten years, many aspects remain obscure and warrant future investigations for a better comprehension of underlying molecular mechanisms. PMID: 12206982 [PubMed - indexed for MEDLINE] 4715. J Bone Miner Res. 2002 Sep;17(9):1563-9. Is leptin the link between fat and bone mass? Thomas T(1), Burguera B. Author information: (1)INSERM E9901, University Hospital of Saint-Etienne, France. Recently, leptin has emerged as a potential candidate responsible for protective effects of fat on bone tissue. However, it remains difficult to draw a clear picture of leptin effects on bone metabolism because published data are sometimes conflicting or apparently contradictory. Beyond differences in models or experimental procedures, it is tempting to hypothesize that leptin exerts dual effects depending on bone tissue, skeletal maturity, and/or signaling pathway. Early in life, leptin could stimulate bone growth and bone size through direct angiogenic and osteogenic effects on stromal precursor cells. Later, it may decrease bone remodeling in the mature skeleton, when trabecular bone turnover is high, by stimulating osteoprotegerin (OPG) expression. Leptin negative effects on bone formation effected through central nervous system pathway could counterbalance these peripheral and positive effects, the latter being predominant when the blood-brain barrier permeability decreases or the serum leptin level rises above a certain threshold. Thus, the sex-dependent specificity of the relationship between leptin and bone mineral density (BMD) in human studies could be, at least in part, caused by serum leptin levels that are two- to threefold higher in women than in men, independent of adiposity. Although these hypotheses remain highly speculative and require further investigations, existing studies consistently support the role of leptin as a link between fat and bone. PMID: 12211425 [PubMed - indexed for MEDLINE] 4716. Neurosci Biobehav Rev. 2002 Jun;26(4):485-98. The temporal organization of ingestive behaviour and its interaction with regulation of energy balance. Strubbe JH(1), van Dijk G. Author information: (1)Division of Neuroendocrinology, Department of Animal Physiology, School of Cognitive and Behavioural Neurosciences, University of Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands. j.h.strubbe@biol.rug.ac.nl Body weight of man and animals is under homeostatic control mediated by the adjustment of food intake. It is discussed in this review that besides signals reporting energy deficits, optimized programs of body clocks take part in feeding behaviour as well. Circadian light- and food-entrainable clocks determine anticipatory adaptive behavioural and physiological mechanisms, promoting or inhibiting food intake. In fact these clocks form the constraints within which the homeostatic regulation of feeding behaviour is operating. Therefore, a strong interaction between circadian and homeostatic regulation must occur. In this homeostatic control, a wide variety of regulatory negative feedback mechanisms, or satiety signals, play a dominant role. In this respect several gut hormones and body temperature function as 'short-term' satiety factors and determine meal sizes and intermeal intervals. Leptin, secreted by fat cells in proportion to the size of adipose tissue mass, is probably an important determinant of the 'long-term' regulation of feeding behaviour by setting the motivational background level for feeding behaviour. Thus, initiation or termination of meals at any particular point in time, depends on the resultant of all satiety signals and on constraints imposed by circadian light- and food-entrainable oscillators. PMID: 12204194 [PubMed - indexed for MEDLINE] 4717. Am J Hum Biol. 2002 Sep-Oct;14(5):584-602. Comparative and evolutionary dimensions of the energetics of human pregnancy and lactation. Dufour DL(1), Sauther ML. Author information: (1)Department of Anthropology, University of Colorado, Boulder, Colorado 80309-0233, USA. darna.dufour@colorado.edu The purpose of this article is to compare the energetics of reproduction for human and other primates in order to evaluate the extent to which human reproductive energetics are distinct from other primates and other large-bodied placental mammals. The article also evaluates the energetics of human and primate gestation and lactation using data from a variety of different populations living under different environmental circumstances. Energetics refers to energy intake and expenditure, and changes in body fat stores. Human and nonhuman primates have longer periods of gestation and lactation and slower prenatal and postnatal growth than other mammals of similar size. This reduces daily maternal energy costs. The development of sizable fat stores is not unique to humans, but fat stores are typically greater in human females and may play a greater role in reproduction. The strategies used to meet the energy costs of pregnancy vary among populations of humans and nonhuman primates and among humans interindividual variability is high. In pregnancy, some increase energy intake but others apparently do not. Increases in metabolic efficiency are evident in some human populations, whereas decreases in physical activity occur, but are not seen in all human or primate populations. Lactation is more energetically costly on a daily basis among humans and nonhuman primates, but has not been as well studied. It appears that both nonhuman and human primates tend to increase energy intake to meet in part the cost of lactation. They also use other strategies such as relying on body tissue stores, reductions in physical activity, and/or increases in metabolic efficiency to meet the remainder of the cost. It is also clear that human females in different populations and different women in the same population use a different combination of strategies to meet the cost of lactation. Copyright 2002 Wiley-Liss, Inc. PMID: 12203813 [PubMed - indexed for MEDLINE] 4718. Am J Hum Biol. 2002 Sep-Oct;14(5):566-83. Neandertal cold adaptation: physiological and energetic factors. Steegmann AT Jr(1), Cerny FJ, Holliday TW. Author information: (1)Department of Anthropology, 380 MFAC, SUNY Buffalo, Buffalo, New York 14261, USA. atsjr@acsu.buffalo.edu European Neandertals employed a complex set of physiological cold defenses, homologous to those seen in contemporary humans and nonhuman primates. While Neandertal morphological patterns, such as foreshortened extremities and low relative surface-area, may have explained some of the variance in cold resistance, it is suggested the adaptive package was strongly dependent on a rich array of physiological defenses. A summary of the environmental cold conditions in which the Neandertals lived is presented, and a comparative ethnographic model from Tierra del Fuego is used. Muscle and subcutaneous fat are excellent "passive" insulators. Neandertals were quite muscular, but it is unlikely that they could maintain enough superficial body fat to offer much cold protection. A major, high-energy metabolic adaptation facilitated by modest amounts of highly thermogenic brown adipose tissue (BAT) is proposed. In addition, Neandertals would have been protected by general mammalian cold defenses based on systemic vasoconstriction and intensified by acclimatization, aerobic fitness, and localized cold--induced vasodilation. However, these defenses are energetically expensive. Based on contemporary data from circumpolar peoples, it is estimated that Neandertals required 3,360 to 4,480 kcal per day to support strenuous winter foraging and cold resistance costs. Several specific genetic cold adaptations are also proposed--heat shock protein (actually, stress shock protein), an ACP*1 locus somatic growth factor, and a specialized calcium metabolism not as yet understood. Copyright 2002 Wiley-Liss, Inc. PMID: 12203812 [PubMed - indexed for MEDLINE] 4719. Gastroenterology. 2002 Sep;123(3):882-932. AGA technical review on obesity. Klein S(1), Wadden T, Sugerman HJ. Author information: (1)Department of Internal Medicine and Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA. Erratum in Gastroenterology 2002 Nov;123(5):1752. PMID: 12198715 [PubMed - indexed for MEDLINE] 4720. Curr Opin Rheumatol. 2002 Sep;14(5):566-70. Panniculitis and lipodystrophy. Eberhard BA(1), Ilowite NT. Author information: (1)Schneider Children's Hospital, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA. aeberhar@lij.edu Panniculitis and lipodystrophy are rare disorders of subcutaneous tissue. Recently the incidence of lipodystrophy has been increasing secondary to its appearance in patients with HIV. In this population, the lipodystrophy appears to be a direct consequence of drug therapy. A review of the available literature regarding pathogenesis and treatment options is discussed. The diagnosis of panniculitis has been hampered by problems. The recent literature has concentrated on ways of improving pathologic diagnostic yields, and new aids in diagnosis are presented. PMID: 12192256 [PubMed - indexed for MEDLINE] 4721. Exp Biol Med (Maywood). 2002 Sep;227(8):587-600. Determinants affecting physical activity levels in animal models. Tou JC(1), Wade CE. Collaborators: Wade CE(1). Author information: (1)Lockheed Martin Engineering and Sciences, and National Aeronautics and Space Administration (NASA) Ames Research Center, Life Sciences Division, NASA Ames Research Center, Moffett Field, California 94035, USA. Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play an underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multifactorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked, making it difficult to determine whether a single, combination, or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to the ventral medial hypothalamus, and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population. PMID: 12192100 [PubMed - indexed for MEDLINE] 4722. Toxicol Pathol. 2002 Jul-Aug;30(4):420-6. Vascular effects of GI262570X (PPAR-gamma agonist) in the brown adipose tissue of Han Wistar rats: a review of 1-month, 13-week, 27-week and 2-year oral toxicity studies. Elangbam CS(1), Brodie TA, Brown HR, Nold JB, Raczniak TJ, Tyler RD, Lightfoot RM, Wall HG. Author information: (1)Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA. cse63957@gsk.com We describe and discuss microscopic findings in the brown adipose tissue (BAT) blood vessels of Han Wistar rats treated with GI262570X, a peroxisome proliferator-activated receptor-gamma agonist (PPAR-gamma agonist) by oral gavage for 28 days, 13 weeks, 27 weeks, and 2 years. Review of these studies revealed a consistent vascular change, consisting of multifocal fatty infiltration in the BAT of treated rats. A similar vascular change was not seen in other vessels or organs. Microscopically, fatty infiltration was characterized primarily by round, clear vacuoles within the tunica media and/or tunica adventitia of small and medium-sized arteries and arterioles. Occasionally, these vacuoles had peripherally located nuclei and morphologically resembled adipocytes, suggesting a well-characterized PPAR effect (ie, differentiation of stem cells or preadipocytes into mature adipocytes). However, administration of GI262570X up to 2 years failed to induce more severe or progressive lesions in the blood vessels of rat BAT and, in particular, did not result in induction of any atherosclerotic-like lesions or foam cell infiltration. At the longer exposure, there was an apparent reduction of severity and/or incidence, indicating a possible adaptive response. These results suggest that the possibility of generating atherosclerotic-like lesions through prolonged treatment of GI262570X (PPAR-gamma agonist) is highly unlikely in rats. PMID: 12187934 [PubMed - indexed for MEDLINE] 4723. Arq Bras Cardiol. 2002 Jun;78(6):618-30. [The adipose tissue in the genesis of hypertension and atherosclerotic cardiovascular disease. An emerging concept]. [Article in Portuguese] Barroso SG(1), Abreu VG, Francischetti EA. Author information: (1)Clínica de Hipertensão e Obesidade, Laboratório de Fisiopatologia Clínica e Experimental, Clinex e Faculdade de Ciências Médicas da UERJ. PMID: 12185864 [PubMed - indexed for MEDLINE] 4724. Klin Med (Mosk). 2002;80(7):9-14. [Endocrine function of fat tissue. Problems of obesity treatment]. [Article in Russian] Tereshchenko IV. PMID: 12181826 [PubMed - indexed for MEDLINE] 4725. Am J Clin Dermatol. 2002;3(7):497-506. Dermatological complications of obesity. García Hidalgo L(1). Author information: (1)Department of Dermatology, Salvador Zubiran National Nutrition Institute, Mexico City, Mexico. lindagh@avantel.net Obesity is a health problem of considerable magnitude in the Western world. Dermatological changes have been reported in patients with obesity, including: acanthosis nigricans and skin tags (due to insulin resistance); hyperandrogenism; striae due to over extension; stasis pigmentation due to peripheral vascular disease; lymphedema; pathologies associated with augmented folds; morphologic changes in the foot anatomy due to excess load; and complications that may arise from hospitalization. Acanthosis nigricans plaques can be managed by improved control of hyperinsulinemia; the vitamin D3 analog calcipitriol has also been shown to be effective. Skin tags can be removed by snipping with curved scissors, by cryotherapy or by electrodesiccation. Hyperandrogenism, a result of increased production of endogenous androgens due to increased volumes of adipose tissue (which synthesizes testosterone) and hyperinsulinemia (which increases the production of ovarian androgens) needs to be carefully assessed to ensure disorders such as virilizing tumors and congenital adrenal hyperplasia are treated appropriately. Treatment of hyperandrogenism should be centred on controlling insulin levels; weight loss, oral contraceptive and antiandrogenic therapies are also possible treatment options. The etiology of striae distensae, also known as stretch marks, is yet to be defined and treatment options are unsatisfactory at present; striae rubra and alba have been treated with a pulsed dye laser with marginal success. The relationship between obesity and varicose veins is controversial; symptoms are best prevented by the use of elastic stockings. Itching and inflammation associated with stasis pigmentation, the result of red blood cells escaping into the tissues, can be treated with corticosteroids. Lymphedema is associated with dilatation of tissue channels, reduced tissue oxygenation and provides a culture medium for bacterial growth. Lymphedema treatment is directed towards reducing the limb girth and weight, and the prevention of infection. Intertrigo is caused by friction between skin surfaces, combined with moisture and warmth, resulting in infection. This infection, most commonly candidiasis, is best treated with topical antifungal agents; systemic antifungal therapy may be required in some patients. Excess load on the feet can result in morphological changes that require careful diagnosis; insoles may offer some symptom relief while control of obesity is achieved. Obesity-related dermatoses associated with hospitalization, such as pressure ulcers, diminished wound healing, dermatoses secondary to respiratory conditions, and incontinence, must all be carefully managed with an emphasis on prevention where possible. Recognition and control of the dermatological complications of obesity play an important role in diminishing the morbidity of obesity. PMID: 12180897 [PubMed - indexed for MEDLINE] 4726. Exp Gerontol. 2002 Jun;37(6):757-67. Adipogenesis and aging: does aging make fat go MAD? Kirkland JL(1), Tchkonia T, Pirtskhalava T, Han J, Karagiannides I. Author information: (1)Geriatrics Section, Departments of Medicine and Biochemistry, Boston University, 88 East Newton Street, F435, Boston, MA 02118, USA. kirkland@bu.edu In advanced old age, fat depot size declines while lipid is redistributed to muscle, bone marrow, and other tissues. Decreased fat depot size is related to reduced fat cell size and function and impaired differentiation of preadipocytes into fat cells. Reduced differentiation-dependent gene expression results from decreased abundance of the adipogenic transcription factors, CCAAT/enhancer binding alpha (C/EBPalpha) and peroxisome proliferator activated receptor gamma (PPARgamma). Increased expression of anti-adipogenic C/EBP family members contributes, perhaps due to cellular stress response pathway activation with aging. Hence, dysfunctional adipocyte-like cells appear in adipose tissue that are smaller and less insulin responsive than fully differentiated fat cells. Adipogenesis can be restored by overexpressing adipogenic transcription factors in preadipocytes from old animals. Redistribution of lipid to extra-adipose sites with aging could result from loss of lipid storage capacity in fat depots, altered fatty acid handling resulting in lipid accumulation, dysdifferentiation of mesenchymal precursors, such as muscle satellite cells and osteoblast precursors, into a partial adipocyte phenotype, or a combination of these mechanisms. Thus, accumulation of mesenchymal adipocyte-like default (MAD) cells in fat depots, muscle, bone marrow, and elsewhere is a potentially reversible process that could contribute to maldistribution of fat in old age. PMID: 12175476 [PubMed - indexed for MEDLINE] 4727. Int J Obes Relat Metab Disord. 2002 Sep;26 Suppl 2:S46-57. Pathways from weight fluctuations to metabolic diseases: focus on maladaptive thermogenesis during catch-up fat. Dulloo AG(1), Jacquet J, Montani JP. Author information: (1)Department of Medicine/Physiology, University of Fribourg, Switzerland. abdul.dulloo@unifr.ch It has long been known that obesity is a high risk factor for cardiovascular diseases. In more recent years, the analysis of several large epidemiological databases has also revealed that, independently of excess weight, large fluctuations in body weight at some point earlier in life represent an independent risk factor for type 2 diabetes and hypertension-two major contributors to cardiovascular diseases. High cardiovascular morbidity and mortality have indeed been reported in men and women who in young adulthood experienced weight fluctuations (involving the recovery of body weight after weight loss due to disease, famine or voluntary slimming), or when weight fluctuations occurred much earlier in life and involved catch-up growth after fetal or neonatal growth retardation. This paper addresses the pathways from weight fluctuations to chronic metabolic diseases by focusing on the phenomenon of accelerated fat recovery (ie catch-up fat) after weight loss or growth retardation. Arguments are put forward that, during catch-up growth or weight recovery on our modern refined foods, the mechanisms of adaptive thermogenesis that regulate catch-up fat are pushed beyond the limits for which they were meant to operate and turn maladaptive. The consequences are enhanced susceptibilities towards skeletal muscle insulin resistance and overactive sympathetic activity, both of which are major contributors to the pathogenesis of chronic metabolic diseases. Since weight fluctuation earlier in life (independently of excess weight later in life) is an independent risk factor for metabolic diseases, the mechanisms by which body fat is acquired would seem to be at least as important as the consequences of excess fat per se in the pathogenesis of diabetes, hypertension and cardiovascular diseases. PMID: 12174328 [PubMed - indexed for MEDLINE] 4728. Int J Obes Relat Metab Disord. 2002 Sep;26 Suppl 2:S18-27. Molecular pathways to obesity. Hofbauer KG(1). Author information: (1)Chair for Applied Pharmacology, Biozentrum/Pharmazentrum, University of Basel, Switzerland. karl.hofbauer@unibas.ch Obesity results from a chronic imbalance between energy intake and energy expenditure. Environmental factors, such as the increased availability of high caloric food or the decreased need for physical activity, contribute to its development and their influence is amplified by genetic predisposition. In recent years remarkable progress has been made in the understanding of the pathophysiology of obesity. Although most of the insights into the regulation of energy balance have been obtained in rodent models, the rare clinical cases of monogenic obesity provided evidence for the importance of several of these mechanisms in humans. The identification of leptin as a factor originating from adipose tissue and informing the brain about the status of energy reserves firmly established the concept of long-term regulation of body fat stores. The disappointing therapeutic results with leptin in obese patients could be explained by the fact that during evolution this hormone developed rather as a starvation signal than as an adiposity signal. It is conceivable that the pharmacological interference with mechanisms downstream of leptin, for example with the melanocortin pathway, might be therapeutically more promising. The discovery of new molecular mechanisms involved in the regulation of the differentiation and proliferation of adipocytes and the elucidation of their paracrine and endocrine functions have changed the traditional view of adipose tissue as an inert depot for triglycerides. The identification of new uncoupling proteins could modify the current concepts of the regulation of thermogenesis in humans. The remarkable progress in the identification of novel targets involved in the regualtion of energy balance should have a positive impact on the search for new antiobesity agents. PMID: 12174325 [PubMed - indexed for MEDLINE] 4729. Int J Obes Relat Metab Disord. 2002 Sep;26 Suppl 2:S12-7. Pathways to obesity. Jéquier E(1). Author information: (1)Institute of Physiology, University of Lausanne, Switzerland. eric.jequier@iphysiol.unil.ch The prevalence of obesity is increasing worldwide, which indicates that the primary cause of obesity lies in environmental and behavioural changes rather than in genetic modifications. Among the environmental influences, the percentage of fat energy of the everyday diet and the lack of physical activity are two important factors, which contribute to explain the rising prevalence of obesity. In this review, several lines of evidence are presented to illustrate why dietary fat does affect obesity development. There are four factors which support a link between dietary fat and obesity development:The thermic effect of nutrients, expressed as percentage of their energy content, is 2-3% for lipids, 6-8% for carbohydrates and 25-30% for proteins. This means that the efficiency of nutrient utilization (calculated as 100%-the thermic effect of the nutrient) is higher for fat than for carbohydrate or protein.Postingestive fuel selection favours the oxidation of dietary proteins and carbohydrates, whereas dietary fats are preferentially stored as triacylglycerol in adipose tissue. Alcohol, by inhibiting lipid oxidation, indirectly favours the storage of dietary fats.High-fat diet promotes excessive energy intake by passive overconsumption; the fat-induced appetite control signals are too weak or too delayed to prevent excessive energy intake from a fatty meal. The only proof that dietary fats contribute to weight gain is to test the long-term effect of ad libitum low-fat diets. Most studies on low-fat diets show that they induce a modest weight loss in obese individuals, but their long-term effect from a public health perspective is limited, probably due to a low compliance to the dietary advice. PMID: 12174324 [PubMed - indexed for MEDLINE] 4730. Ann Med. 2002;34(3):217-24. Glitazones: clinical effects and molecular mechanisms. Stumvoll M(1), Häring HU. Author information: (1)Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany. michael.stumvoll@med.uni-tuebingen.de With the thiazolidinediones rosiglitazone and pioglitazone a novel treatment modality for type 2 diabetes has become available in many countries. As monotherapy, fasting blood glucose and glycosylated hemoglobin (HbA1c), on average, can be improved by approximately 40 mg/dl and almost 1%, respectively. In combination with other agents their efficacy is additive. Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPARgamma is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis factor alpha, resistin, adiponectin) in a way that results in net improvement of insulin sensitivity (i.e. in muscle and liver). Nevertheless, a direct molecular effect in skeletal muscle cannot be excluded. Interference with transcription entails a potential for side-effect risk, that cannot definitively be assessed yet. For example, the in-vitro stimulation of adipogenic differentiation may underlie the clinical observation of weight gain. Theoretically, this may turn out to be counterproductive in the long run. However, there is not sufficient evidence from humans at the moment, especially no long-term data, to allow a conclusive statement. The hepatotoxicity observed with troglitazone, on the other hand, does not seem to be PPARgamma-mediated but secondary to toxic metabolites. Based on differences in drug metabolism this problem is relatively unlikely to occur with rosiglitazone or pioglitazone. Unexplained but not unimportant is the propensity for fluid retention. In summary, with the thiazolidinediones a novel concept for the treatment of insulin resistance is available that in theory could also be used for prevention of type 2 diabetes. Long-term data are indispensable for a final risk-benefit assessment of these substances. PMID: 12173692 [PubMed - indexed for MEDLINE] 4731. Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):551-9. Inflammatory status and insulin resistance. Grimble RF(1). Author information: (1)Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton SO16 7PX, UK. rfg1@soton.ac.uk PURPOSE OF REVIEW: The inflammatory response is essential in the response to pathogens. TNF-alpha, IL-1 and IL-6 are key mediators of the response. They initiate metabolic changes to provide nutrients for the immune system, from host tissues. These changes include hyperlipidemia and increased gluconeogenesis. Insulin resistance and disordering of lipid metabolism occur in obesity, diabetes mellitus, atherosclerosis. This review examines recent research that links inflammation to insulin insensitivity. RECENT FINDINGS: Population studies show a strong association between indices of inflammation, and abnormal lipid and carbohydrate metabolism, obesity and atherosclerosis. TNF-alpha is produced, by cells of the immune system and by adipocytes. It may provide the link between inflammation and insulin sensitivity. TNF-alpha results in insulin insensitivity, indirectly by stimulating stress hormone production and directly by sustained induction of SOCS-3 which decreases insulin-induced insulin receptor substrate 1 (IRS1) tyrosine phosphorylation and its association with the p85, regulatory subunit of phosphatidylinositol-3 kinase; and by negative regulation of PPAR gamma. Adipose tissue produces both TNF-alpha and leptin. Production of the latter relates positively to adipose tissue mass and through its actions on immune function exerts a pro-inflammatory influence. SUMMARY: Recent studies on diseases which involve insulin insensitivity (e.g. obesity, type 2 diabetes and atherosclerosis) also show increased cytokine production and markers of inflammation. Evidence at present favours chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation. PMID: 12172480 [PubMed - indexed for MEDLINE] 4732. Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):481-7. Measuring body fat distribution and content in humans. Goodpaster BH(1). Author information: (1)Division of Endocrinology and Metabolism, University of Pittsburgh Department of Medicine, Montefiore Hospital, Pittsburgh, Pennsylvania 15213, USA. bgood@pitt.edu PURPOSE OF REVIEW: In this review methods to measure the content and distribution of body fat or adipose tissue in humans are examined. The review particularly emphasizes methods to characterize regional fat distribution and ectopic fat (fat contained within other tissues) including specific applications and implications of region-specific or tissue-specific fat content. RECENT FINDINGS: Recent novel applications of body composition methods, including in-vivo imaging modalities, magnetic resonance spectroscopy techniques, and direct measurement of extracted tissue have advanced our understanding of many health related issues including obesity, type 2 diabetes mellitus, progressive muscle weakness in aging and lipodystrophy. In particular, the accumulation of lipid within muscle and liver has received increased attention because of its association with metabolic dysregulation or impaired muscle function. SUMMARY: Methods to quantify total body fat content in humans have provided considerable insight into obesity and related disorders, the aging process and its associated changes in function, and response to intervention. However, these methods have typically not been able to identify fat contained within specific regions of the body or within specific tissue. Direct quantification of fat distribution and fat within tissue in humans have been accomplished through in-vivo imaging techniques as well as invasive histological and biochemical approaches, and have advanced our understanding of many structure-function relationships. Further queries about human health and disease will undoubtedly lead to refinement of these methods and innovation of new body composition methodologies. PMID: 12172470 [PubMed - indexed for MEDLINE] 4733. Curr Pharm Des. 2002;8(21):1917-28. Mesenchymal stem cells for bone gene therapy and tissue engineering. Pelled G(1), G T, Aslan H, Gazit Z, Gazit D. Author information: (1)Skeletal Biotech. Lab., Hebrew University-Hadassah Medical and Gene Therapy Center, P.O. Box 12272, Jerusalem, Israel. Mesenchymal Stem Cells (MSCs) are adult stem cells that constitute a variety of adult tissues. MSCs maintain self-renewal ability with the ability to give rise to different mesenchymal cells, and are therefore responsible in part, for the regenerative capacity of mesenchymal tissues. MSCs throughout a variety of species were found to be able to differentiate to several mesenchymal tissues including: bone, cartilage, stroma, adipose, connective tissue, muscle and tendon. MSCs are relatively easily isolated from the bone marrow and expanded in vitro. It was found that MSCs play an important role in bone physiology and hematopoiesis, and in part participate in the pathophysiology related to bone diseases, mainly osteoporosis. MSCs were widely used in experimental studies in vivo, and were shown to form mesenchymal tissues. These discovered features have made MSCs good candidates for the development of various therapeutic modalities aimed to regenerate mesenchymal tissues, mainly bone. The more important approaches currently utilizing MSCs are gene therapy and tissue engineering. Both exploit the current knowledge in molecular biology and biomaterial science in order to direct MSCs to differentiate in vivo to desired lineages and tissues. Better understanding of the molecular mechanism directing the differentiation of MSCs, will eventually allow us to properly manipulate MSCs both in vivo and ex vivo to allow the regeneration of complex tissues and organs. PMID: 12171527 [PubMed - indexed for MEDLINE] 4734. J Am Diet Assoc. 2002 Aug;102(8):1119-25. Affect of serum leptin on nutritional status in renal disease. Norton PA(1). Author information: (1)Clinical Computing Inc, Cincinnati, OH 45203, USA. Protein-energy malnutrition is a major comorbid condition in persons with renal disease. A variety of interventions have been implemented to supplement protein and energy intake in malnourished patients with renal disease, but the prevalence of protein-energy malnutrition remains high. Leptin, a hormone secreted by adipose tissue, decreases food intake via neuroendocrine systems in the hypothalamus in persons with normal renal function. Serum leptin levels are elevated in patients with chronic renal insufficiency and end-stage renal disease, and experimental evidence suggests a possible role for leptin in the development of protein-energy malnutrition in this population. Release of leptin from adipocytes may be stimulated by cytokines mediating the inflammatory response, which is frequently pronounced in patients with end-stage renal disease receiving hemodialysis and peritoneal dialysis. This article provides an overview of research conducted on serum leptin levels in different stages of renal disease, and the relationship among serum leptin, body composition, biochemical indexes, and markers of inflammation in persons with end-stage renal disease. Effects of intradialytic parenteral nutrition and anabolic factors on leptin levels and nutritional status are briefly reviewed. PMID: 12171457 [PubMed - indexed for MEDLINE] 4735. Obes Rev. 2002 Aug;3(3):217-24. The lifecycle effects of nutrition and body size on adult adiposity, diabetes and cardiovascular disease. Yajnik CS(1). Author information: (1)Diabetes Unit, KEM Hospital Research Centre, Rasta Peth, Pune, India. diabetes@vsnl.com This study was undertaken to review the links between maternal nutrition, offspring's birth weight and the propensity to early insulin resistance and high diabetes rates in Indian adults. Studies included a comparison of maternal size and nutrition with birth weights in Pune, India, and Southampton, UK. In Pune, the growth, insulin resistance and blood pressure of four-year-old children were assessed. Adults >40 years of age, who were resident in rural areas, were compared with adults living in urban areas for size, glucose handling, lipid status and blood pressure. Newly diagnosed diabetic adults living in urban areas were also monitored. Height, weight, head, waist and hip circumferences, skin-fold measurements and blood pressure were routinely measured. Fasting glucose, insulin, total and high-density lipoprotein cholesterol and triglycerides were linked to the glucose and insulin responses during glucose tolerance tests. Cytokine levels were measured in plasma samples of urban and rural adults. Indian babies were lighter, thinner, shorter and had a relatively lower lean tissue mass than the Caucasian babies. However, the subcutaneous fat measurements of these babies were comparable to those of the white Caucasian babies. The Indian mothers were small, but relatively fat mothers produced larger babies. Maternal intake of green vegetables, fruit and milk, and their circulating folate and vitamin C levels, predicted larger fetal size. Rapid childhood growth promoted insulin resistance and higher blood pressure. Rural adults were thin, with a 4% prevalence of diabetes and a 14% prevalence of hypertension, but the risks increased within the normal body mass index (BMI) range. Type 2 diabetes was common in urban adults younger than 35 years of age. Although the average BMI was 23.9 kg m(-2), central obesity and thin limbs were noteworthy. Levels of interleukin-6 and tumour necrosis factor-a were markedly increased in urban dwellers. Hence, there is evidence of a remarkably powerful, intergenerational effect on body size and total and central adiposity. Indians are highly susceptible to insulin resistance and cardiovascular risks, with babies being born small but relatively fat. Insulin resistance is amplified by rapid childhood growth. Dietary factors seem to have profound long-term metabolic influences in pregnancy. Overcrowding with infections and central obesity may amplify cytokine-induced insulin resistance and early diabetes in Indian adults with a low BMI. PMID: 12164475 [PubMed - indexed for MEDLINE] 4736. Obes Rev. 2002 Aug;3(3):209-15. Elevated body fat percentage and cardiovascular risks at low body mass index levels among Singaporean Chinese, Malays and Indians. Deurenberg-Yap M(1), Chew SK, Deurenberg P. Author information: (1)Research and Information Management, Health Promotion Board, Singapore. Mabel_YAP@hpb.gov.sg The aim of this study was to investigate the relationship between body mass index (BMI) and body fat percentage (BF%) in Singaporean Chinese, Malays and Indians, and to determine the risk for selected comorbidities at various BMI categories and abdominal fat distributions, as assessed by waist circumference (WC). The study was a cross-sectional (population) design. In total, 4723 subjects participated in the National Health Survey of 1998 in which the risks were investigated. A selected subsample of 291 subjects participated in a detailed body composition study, where weight, height and WC were measured, as were blood pressure, total and high-density lipoprotein (HDL) cholesterol, serum triglycerides and fasting glucose. In the subsample, BF% was determined by means of a chemical four-compartment model. At any given BF% the BMI of Singaporeans was about 3 kg m(-2) lower than that of Caucasians. There were slight differences in the BF%/BMI relationship between the three ethnic groups. For all the ethnic groups, it was found that at low categories of BMI (between 22 and 24 kg m(-2)) and WC (between 75 and 80cm for women and between 80 and 85 cm for men), the absolute risks for having at least one of the aforementioned risk factors were high, ranging from 41 to 81%. At these same categories the relative risks were significantly higher compared to the reference category, odds ratios ranging from 1.97-4.38. These categories of BMI and WC were all far below the cut-off values of BMI and WC as currently recommended by the World Health Organization (WHO). The data from the current study, which includes evidence that not only risk factors, but also BF% are elevated at low BMI values, presents a strong case for lowering the BMI cut-off value for overweight and obesity among Singaporeans, from 25 kg m(-2) and 30 kg m(-2) to 23 kg m(-2) and 27 kg m(-2), respectively. PMID: 12164474 [PubMed - indexed for MEDLINE] 4737. Obes Rev. 2002 Aug;3(3):141-6. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Deurenberg P(1), Deurenberg-Yap M, Guricci S. Author information: (1)Wageningen University, The Netherlands. padeu@singnet.com.sg The objective was to study the relationship between body mass index (BMI) and body fat per cent (BF%) in different population groups of Asians. The study design was a literature overview with special attention to recent Asian data. Specific information is provided on Indonesians (Malays and Chinese ancestry), Singaporean Chinese, Malays and Indians, and Hong Kong Chinese. The BMI was calculated from weight and height and the BF% was determined by deuterium oxide dilution, a chemical-for-compartment model, or dual-energy X-ray absorptiometry. All Asian populations studied had a higher BF% at a lower BMI compared to Caucasians. Generally, for the same BMI their BF% was 3-5% points higher compared to Caucasians. For the same BF% their BMI was 3-4 units lower compared to Caucasians. The high BF% at low BMI can be partly explained by differences in body build, i.e. differences in trunk-to-leg-length ratio and differences in slenderness. Differences in muscularity may also contribute to the different BF%/BMI relationship. Hence, the relationship between BF% and BMI is ethnic-specific. For comparisons of obesity prevalence between ethnic groups, universal BMI cut-off points are not appropriate. PMID: 12164465 [PubMed - indexed for MEDLINE] 4738. Arch Histol Cytol. 2002 Jun;65(2):109-26. Collagen fibers, reticular fibers and elastic fibers. A comprehensive understanding from a morphological viewpoint. Ushiki T(1). Author information: (1)Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Japan. t-ushiki@med.niigata-u.ac.jp Fibrous components of the extracellular matrix are light-microscopically classified into three types of fibers: collagen, reticular and elastic. The present study reviews the ultrastructure of these fibrous components as based on our previous studies by light, electron, and atomic force microscopy. Collagen fibers present a cord- or tape-shape 1-20 microm wide and run a wavy course in tissues. These fibers consist of closely packed thin collagen fibrils (30-100 nm thick in ordinary tissues of mammals), and exhibit splitting and joining in altering the number of the fibrils to form a three-dimensional network as a whole. Individual collagen fibrils (i.e., unit fibrils) in collagen fibers have a characteristic D-banding pattern whose length is ranges from 64 to 67 nm, depending on tissues and organs. During fibrogenesis, collagen fibrils are considered to be produced by fusing short and thin fibrils with tapered ends. Reticular fibers are usually observed as a delicate meshwork of fine fibrils stained black by the silver impregnation method. They usually underlie the epithelium and cover the surface of such cells of muscle cells, adipose cells and Schwann cells. Electronmicroscopically, reticular fibers are observed as individual collagen fibrils or a small bundle of the fibrils, although the diameter of the fibrils is thin (about 30 nm) and uniform. Reticular fibers are continuous with collagen fibers through the exchange of these collagen fibrils. In silver-impregnated specimens, individual fibrils in reticular fibers are densely coated with coarse metal particles, probably due to the high content of glycoproteins around the fibrils. Elastic fibers and laminae are composed of microfibrils and elastin components. Observations of the extracted elastin have revealed that elastin components are comprised of elastin fibrils about 0.1-0.2 microm thick. Elastic fibers and laminae are continuous with networks and/or bundles of microfibrils (or oxytalan fibers), and form an elastic network specific to individual tissues. The fibrous components of the extracellular matrix are thereby morphologically categorized into two systems: the collagen fibrillar system as a supporting framework of tissues and cells, and the microfibrilelastin system for uniformly distributing stress to maintain the resilience adapted to local tissue requirements. PMID: 12164335 [PubMed - indexed for MEDLINE] 4739. Int J Cardiol. 2002 Sep;85(1):125-32. Regulation of lipolysis: natriuretic peptides and the development of cachexia. Kalra PR(1), Tigas S. Author information: (1)Clinical Cardiology, National Heart and Lung Institute, London, UK. p.kalra@ic.ac.uk The development of cachexia is commonly seen in many pathological states and is associated with a markedly impaired prognosis. Loss of fat tissue appears to be of particular pathophysiological importance in this setting. Lipolysis is closely regulated in health; the major established pathways involving catecholamines (stimulation of lipolysis) and insulin (inhibition of lipolysis). The wasting process in cachexia is associated with marked metabolic dysfunction, and loss of this tight regulatory control. Natriuretic peptides are a family of related peptides with important vasodilatory, natriuretic and diuretic properties. It has recently been shown that natriuretic peptides are also potent stimuli for lipolysis in humans. In this respect, atrial and brain natriuretic peptide appear to have the greatest lipolytic effect, and are similar in potency to catecholamines. Elevated levels of circulating natriuretic peptides are found in several pathological states, and generally reflect disease severity. This article will provide a concise review of the regulation of lipolysis in humans, concentrating on the role of the natriuretic peptides. The relevance of natriuretic peptides to the development of cachexia will be discussed. PMID: 12163217 [PubMed - indexed for MEDLINE] 4740. Mol Cell Endocrinol. 2002 Jul 31;193(1-2):7-12. Effect of estrogen deficiency in the male: the ArKO mouse model. Murata Y(1), Robertson KM, Jones ME, Simpson ER. Author information: (1)Prince Henry's Institute of Medical Research, 246 Clayton Road, Clayton, Vic. 3168, Australia. yoko.murata@med.monash.edu.au Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is present in the mouse gonads, brain, adipose tissue and bone. Depletion of endogenous estrogens in the aromatase deficient mouse (ArKO) caused by the targeted disruption of the Cyp19 gene resulted in an impairment of sexual behaviour and an age-dependent disruption of spermatogenesis. This disruption occurred during early spermiogenesis, due possibly to increased number of apoptotic round spermatids. Development of obesity was associated with ageing, decrease in lean mass, hypercholesterolemia, hyperleptinemia, and insulin resistance and hepatic steatosis. However, it was not correlated with hyperphagia but to decreased physically-active behaviour. ArKO mice also developed osteoporosis. Thus, studies using the ArKO mice model has led to several insights into the multiple roles played by estrogens in the development and maintenance of fertility, sexual behaviour, lipid metabolism and bone remodelling. Copyright 2002 Elsevier Science Ireland Ltd. PMID: 12160996 [PubMed - indexed for MEDLINE] 4741. J Med Dent Sci. 1999 Dec;46(4):139-43. Utilization of the concentric circle model in clinical nursing: a review. Kazuma K(1). Author information: (1)Department of Adult Nursing II, School of Allied Health Sciences, Tokyo Medical and Dental University, Japan. In this article, I review applications of the concentric circle model in clinical nursing. The concentric circle model is based on the cross-sectional shape of the body extremities at several points, and can be used in the areas of both kinesiology and nutritional science. This model makes it possible to calculate the cross-sectional area of muscles from measurement of the circumference of the extremities and the thickness of adipose (fatty) tissue. Then, changes in muscle strength or nutritional status can be inferred or assessed from these data. This model requires only simple and non-invasive measurements, and this is a significant and essential characteristic for its use by nurses, both in clinical and research applications. PMID: 12160251 [PubMed - indexed for MEDLINE] 4742. Nat Rev Genet. 2002 Aug;3(8):589-600. Genetic approaches to studying energy balance: perception and integration. Barsh GS(1), Schwartz MW. Author information: (1)[1] Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA. gbarsh@pmgm2.stanford.edu PMID: 12154382 [PubMed - indexed for MEDLINE] 4743. FASEB J. 2002 Aug;16(10):1163-76. Analysis of paradoxical observations on the association between leptin and insulin resistance. Ceddia RB(1), Koistinen HA, Zierath JR, Sweeney G. Author information: (1)Department of Biology, York University, Toronto, Canada. Obesity is commonly associated with the development of insulin resistance and diabetes in humans and rodents. Insulin resistance and diabetes are observed in lipoatrophic individuals or rodent models of lipoatrophy. Here we focus on the role of leptin, the product of the obesity (ob) gene, in the development of insulin resistance and diabetes associated with obesity and lipoatrophy. We review the reported effects of leptin on whole body glucose metabolism and compare and contrast these with direct effects on skeletal muscle, fat and liver. This summary of paradoxical observations on the effects of leptin on glucose homeostasis and the ability of leptin to induce or improve insulin resistance suggests that a complex interplay exists between direct peripheral and centrally mediated effects of the hormone. Evidence suggesting that leptin acts as a mediator of insulin release from pancreatic beta cells is reviewed. Finally, intracellular signaling mechanisms stimulated by both leptin and insulin are discussed, with potential points of cross-talk suggested. PMID: 12153984 [PubMed - indexed for MEDLINE] 4744. Przegl Lek. 2002;59(2):115-7. [Agouti protein--the role in contemporary medicine]. [Article in Polish] Zdrojewicz Z(1), Wontor D. Author information: (1)Katedra i Klinika Endokrynologii i Diabetologii, Akademii Medycznej, 50-369 Wrocław, Wybrzeze L. Pasteura 4. Nowadays a lot of researches are carried out of agouti protein's activity, since a lot of its functions in the field of physiology and its role in pathogenesis of some diseases are not definitely specified. The study presents the latest reports on agouti protein. The authors have shown researches into agouti's structure, activity and clinical meaning. The research particularly concentrates on issues connected with adipose tissue, obesity, skin pigmentation and action of central nervous system. PMID: 12152248 [PubMed - indexed for MEDLINE] 4745. Curr Opin Cardiol. 2002 Jul;17(4):355-9. Emerging concepts in the pathophysiology and treatment of obesity-associated hypertension. Engeli S(1), Sharma AM. Author information: (1)Franz Volhard Clinic, Helios Klinikum Buch-Charité, Medical Faculty of the Humboldt University Berlin, Germany. The dramatic increase in the prevalence of obesity is a global phenomenon associated with increased risk of the development of cardiovascular and renal disease. Changes in renal structure and function that occur early in the development of obesity may lead to urine outflow obstruction and increased intrarenal pressure, mechanisms sufficient to shift the pressure-natriuresis relation to higher blood pressure levels. Another important alteration that may lead to hypertension with obesity is the increase in sympathetic nervous system activity. Several studies point to higher leptin levels associated with hypertension in humans, and animal data now convincingly suggest that leptin has direct central effects that increase sympathetic outflow to the kidneys, associated with increases in blood pressure. Although understanding of the pathophysiology of obesity-associated hypertension has made substantial progress during the past years, treatment of obese hypertensives remains largely empirical and clearly deserves to be addressed in larger randomized, controlled trials. PMID: 12151869 [PubMed - indexed for MEDLINE] 4746. J Endocrinol Invest. 2002 Jul-Aug;25(7):646-9. Obesity, cytokines and endothelial dysfunction: a link for the raised cardiovascular risk associated with visceral obesity. Esposito K(1), Nicoletti G, Giugliano D. Author information: (1)Center for Obesity Management, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. katherine.esposito@unina2.it PMID: 12150343 [PubMed - indexed for MEDLINE] 4747. Sleep. 2002 Aug 1;25(5):499-506. Gender and obstructive sleep apnea syndrome, part 2: mechanisms. Kapsimalis F(1), Kryger MH. Author information: (1)Respiratory Medicine Department, Thriasio General Hospital of Elefsina, Athens, Greece. Epidemiologic studies have reported that obstructive sleep apnea syndrome (OSAS) is a common disorder affecting about four percent of adult males and two percent of adult females. This difference in OSAS prevalence suggests that the female gender may reduce the risk of sleep breathing disorders in adults. We review several interrelated factors that may explain the differences in risk related to gender. These include differences in obesity and the distribution of adipose tissue, upper-airway anatomy, upper-airway muscle function, control of ventilation, the effect of sex hormones and leptin. The gender related protective effect decreases in females who are postmenopausal and not on hormone replacement therapy. PMID: 12150315 [PubMed - indexed for MEDLINE] 4748. Exp Clin Endocrinol Diabetes. 2002 Aug;110(5):199-211. The neuroendocrine control of glucose allocation. Peters A(1), Schweiger U, Frühwald-Schultes B, Born J, Fehm HL. Author information: (1)Medical Clinic 1, Medical University of Luebeck, Germany. achim.peters@medinf.mu-luebeck.de Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes. PMID: 12148083 [PubMed - indexed for MEDLINE] 4749. Diabet Med. 2002 Aug;19(8):619-27. Neuropeptides and appetite control. Wilding JP(1). Author information: (1)Clinical Sciences Centre, University Hospital Aintree, Longmoor lane, Liverpool L9 7AL, Liverpool, UK. j.p.h.wilding@liv.ac.uk Obesity is important in the aetiology of type 2 diabetes, and presents a major barrier to its successful prevention and management. Obesity develops when energy intake exceeds energy expenditure over time. A complex system has evolved to maintain energy homeostasis, but this is biased towards weight gain. Meal size is controlled by a series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin whereas others may initiate meals, such as the recently discovered hormone, ghrelin. Other hormones such as insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act at several central nervous system (CNS) sites but the pathways converge on the hypothalamus, which contains a large number of peptide and other neurotransmitters that influence food intake. As energy deficit is most likely to compromise survival, it is not surprising that the most powerful of these pathways are those that increase food intake and decrease energy expenditure when stores are depleted. When energy stores are low, production of leptin from adipose tissue, and thus circulating leptin concentrations fall, leading to increased production of hypothalamic neurotransmitters that strongly increase food intake, such as neuropeptide Y (NPY), galanin and agouti-related protein (AGRP) and decreased levels of alpha-melanocyte-stimulating hormone (alpha-MSH), cocaine and amphetamine-regulated transcript (CART) and neurotensin that reduce food intake and increase energy expenditure. The finding that mutations in leptin and POMC lead to severe early onset obesity in humans has highlighted the importance of these peptides in humans. This new understanding may eventually lead to new treatments for obesity that will be of particular benefit in the prevention and treatment of type 2 diabetes. PMID: 12147141 [PubMed - indexed for MEDLINE] 4750. Diabetes. 2002 Aug;51(8):2341-7. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Stumvoll M(1), Häring H. Author information: (1)University Hospital, Department of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-Universität, Tübingen, Germany. michael.stumvoll@med.uni-tuebingen.de Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-gamma2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of >75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR-gamma2 is predominantly expressed. Moderate reduction in transcriptional activity of PPAR-gamma as a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor-alpha, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced beta-cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR-gamma2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes. PMID: 12145143 [PubMed - indexed for MEDLINE] 4751. Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S42-5. Obesity and immunocompetence. Lamas O(1), Marti A, Martínez JA. Author information: (1)Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain. The increasing worldwide prevalence of obesity is a major health problem since excessive body weight constitutes a risk factor in a number of chronic diseases. It has been reported that obese individuals are more susceptible to infection than lean subjects; however, the underlying factors are not fully understood. Limited and often controversial information exists comparing immunocompetence in obese and nonobese subjects as well as the cellular and molecular mechanisms involved, although much evidence supports a link between adipose tissue metabolism and immunocompetent cell functions. The complexity and heterogeneity of nutritional status and immune system interactions require an integral study of the immunocompetent cells, their subsets and products, as well as specific and non-specific inducer/regulatory systems in situations of human obesity. Additional research is needed to determine the clinical implications of these alterations on immunity and whether various interventions such as weight loss, exercise or nutrient supplementation could help to ameliorate them. PMID: 12142961 [PubMed - indexed for MEDLINE] 4752. Aust Dent J. 2002 Jun;47(2):99-105. Reconstructive techniques for the repair of oral and maxillofacial oncological procedures: what are they, how do they work and what do they look like? Chandu A(1), Bridgeman AM, Smith AC, Flood SJ. Author information: (1)Oral and Maxillofacial Surgery, Austin and Repatriation Medical Centre, Heidelberg, Victoria. BACKGROUND: There are many different ways to reconstruct the oral and maxillofacial region post tumour ablation. In the past, the resection of oral tumours had been associated with significant disfigurement and loss of function. Modern techniques aim to restore function and improve cosmetics. This paper aims to describe the techniques used in patients treated at the Austin and Repatriation Medical Centre and to answer the more common questions associated with reconstructive techniques. METHODS: A review of techniques of oral reconstruction used by our unit over the last nine years and a review of the literature. RESULTS: Various techniques of reconstruction gained from our experience in treating patients with oral cancer are documented. There are a variety of techniques including grafts, local flaps, regional flaps and free vascularized flaps. Metallic implants such as osseointegrated dental implants may also be used for dental rehabilitation. CONCLUSIONS: There are many different methods of reconstruction in patients who have had resection for oral tumours. It is important for general dental practitioners who may be involved with the care of such patients to have an understanding of the modern techniques of reconstruction that may be used. PMID: 12139281 [PubMed - indexed for MEDLINE] 4753. Regul Pept. 2002 Jul 15;107(1-3):1-13. Gastric inhibitory polypeptide: the neglected incretin revisited. Meier JJ(1), Nauck MA, Schmidt WE, Gallwitz B. Author information: (1)Medizinische Klinik I, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Gudrunstrasse 56, 44791, Bochum, Germany. After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings. PMID: 12137960 [PubMed - indexed for MEDLINE] 4754. J Soc Biol. 2002;196(1):47-52. [Role of the peroxisome proliferator-activated receptors (PPARS) in the regulation of lipids and inflammation control]. [Article in French] Bocher V(1), Chinetti G, Fruchart JC, Staels B. Author information: (1)UR 545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, 1, rue Calmette, 59019 Lille et Faculté de Pharmacie, Université de Lille II, 59006 Lille, France. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPAR alpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPAR alpha furthermore mediates the action of the hypolipidemic drugs of the fibrate class on plasma lipoprotein metabolism. PPAR gamma is predominantly expressed in intestine and adipose tissue. PPAR gamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs play a role in inflammation control. PPAR activators inhibit the activation of inflammatory response genes by negatively interfering with the NF-kappa B and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte-macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis. PMID: 12134632 [PubMed - indexed for MEDLINE] 4755. Int J Biochem Cell Biol. 2002 Oct;34(10):1190-206. Possible physiological roles of mitochondrial uncoupling proteins--UCPn. Jezek P(1). Author information: (1)Department of Membrane Transport Biophysics No. 375, Institute of Physiology, Academy of Sciences, Vídenská 1083, Prague 4, Czech Republic. jezek@biomed.cas.cz Five mitochondrial uncoupling proteins exist in the human gemone: UCP2, expressed ubiquitously; UCP1, exclusively in brown adipose tissue (BAT); UCP3, predominantly in muscle; UCP4 and BMCP (UCP5), in brain. UCP4 is the ancestral prototype from which the other UCPn diverged. Findings on the level of organism and reconstituted recombinant proteins demonstrated that UCPn exhibit a protonophoric function, documented by overexpression in mice, L6 myotubes, INS1 cells, muscle, and yeast. In a few cases (yeast), this protonophoric function was correlated with elevated fatty acid (FA) levels. Reconstituted UCPn exhibited nucleotide-sensitive FA induced H(+) uniport. Two mechanisms, local buffering or FA cycling were suggested as an explanation. A basic UCPn role with mild uncoupling is to accelerate metabolism and reduce reactive oxygen species. UCP2 (UCP3) roles were inferred from transcriptional up-regulation mediated by FAs via peroxisome proliferator-activated receptors, cytokines, leptin signalling via hypothalamic pathway, and by thyroide and beta2 adrenergic stimulation. The latter indicated a role in catecholamine-induced thermogenesis in skeletal muscle. UCP2 (UCP3) may contribute to body weight regulation, although obesity was not induced in knockout (KO) mice. An obesity reduction in middle-aged humans was associated with the less common allele of -866 G/A polymorphism in the ucp2 gene promoter enhancing the exon 8 insertion: deletion transcript ratio. Up-regulated UCP2 transcription by pyrogenic cytokines (tumour necrosis factor alpha (TNFalpha)) suggested a role in fever. UCP2 could induce type 2 diabetes as developed from obesity due to up-regulated UCP2 transcription by FAs in pancreatic beta-cells. UCPn might be pro-apoptotic as well as anti-apoptotic, depending on transcriptional and biochemical regulation. Copyright 2002 Elsevier Science Ltd. PMID: 12127570 [PubMed - indexed for MEDLINE] 4756. Clin Pharmacokinet. 2002;41(9):615-37. Distribution of cyclosporin in organ transplant recipients. Akhlaghi F(1), Trull AK. Author information: (1)College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA. fatemeh@uri.edu Cyclosporin is an immunosuppressive agent with a narrow therapeutic index. The total concentration of cyclosporin in blood is usually monitored to guide dosage adjustment and to compensate for substantial interindividual and intraindividual variability in cyclosporin pharmacokinetics. Cyclosporin is a highly lipophilic molecule and widely distributes into blood, plasma and tissue components. It mainly accumulates in fat-rich organs, including adipose tissue and liver. In blood, it binds to erythrocytes in a saturable fashion that is dependent on haematocrit, temperature and the concentration of plasma proteins. In plasma, it binds primarily to lipoproteins, including high-density, low-density and very-low-density lipoprotein, and, to a lesser extent, albumin. The unbound fraction of cyclosporin in plasma (CsA(fu)) expressed as a percentage is approximately 2%. It has been shown that both the pharmacokinetic and pharmacodynamic properties of cyclosporin are related to its binding characteristics in plasma. Furthermore, there is some evidence to indicate that the unbound concentration of cyclosporin (CsA(U)) has a closer association with both kidney and heart allograft rejection than the total (bound + unbound) concentration. However, the measurement of CsA(fu) is inherently complex and cannot easily be performed in a clinical setting. Mathematical models that calculate CsA(fu), and hence CsA(U), from the concentration of plasma lipoproteins may be a more practical option, and should provide a more accurate correlate of effectiveness and toxicity of this drug in transplant recipients than do conventional monitoring procedures. In conclusion, the distribution characteristics of cyclosporin in blood, plasma and various tissues are clinically important. Further investigations are needed to verify whether determination of CsA(U) improves the clinical management of transplant recipients. PMID: 12126456 [PubMed - indexed for MEDLINE] 4757. Nutr Metab Cardiovasc Dis. 2002 Feb;12(1):36-41. High-density lipoprotein metabolism in familial hypercholesterolaemia: significance, mechanisms, therapy. Watts GF(1), Barrett PH. Author information: (1)University Department of Medicine, University of Western Australia, West Australian Heart Research Institute, Royal Perth Hospital, Perth, Australia. gfwatts@cyllene.uwa.edu.au AIM: To assess the significance, mechanisms and therapy of impaired high-density lipoprotein (HDL) metabolism in patients with heterozygous familial hypercholesterolaemia (FH). METHODS: Review of epidemiological, metabolic and clinical literature with synthetic analysis of data referring to HDL. PRINCIPAL FINDINGS AND SYNTHESIS: Low HDL is a powerful risk factor for coronary artery disease (CAD) in FH. Low HDL in FH is a metabolic sequel of insulin resistance, which is the central feature of the visceral accumulation of adipose tissue acquired in later life. Insulin resistance increases hepatic secretion of triglycerides that subsequently results in remodelling of holo-HDL particles and enhanced catabolism of apolipoprotein A-I. Gene-gene and gene-environment interactions may contribute to the pathogenesis of low HDL in FH. Low HDL may also point to other cardiovascular risk factors, such as hyper-remnantaemia, increased small dense low-density lipoproteins (LDL), procoagulopathy and vascular insulin resistance. Visceral obesity should be vigorously identified and treated in FH. Judicious addition of fish oils, niacin and fibrates to a statin may be required to optimise HDL metabolism. Extracorporeal removal of LDL cholesterol should aim not to extract HDL from plasma. CONCLUSIONS: With the increasing incidence of obesity in the community, the metabolic syndrome will overmanifest in patients with FH. Impaired HDL metabolism is an important consequence of this syndrome for FH patients, because it will per se or in collusion with other associated risk factors accelerate the progression of atherosclerosis and CAD. Dysregulation of HDL metabolism principally results from hepatic insulin resistance and remodelling of HDL particles. Obesity should be prevented and aggressively treated in FH and use of a safe combination drug regimen considered to correct the dysmetabolism of HDL in these patients. PMID: 12125229 [PubMed - indexed for MEDLINE] 4758. Cardiovasc Res. 2002 Aug 1;55(2):261-9. The pivotal role of lipoprotein lipase in atherosclerosis. Mead JR(1), Ramji DP. Author information: (1)Cardiff School of Biosciences, Cardiff University, Museum Avenue, P.O. Box 911, CF10 3US, Cardiff, UK. PMID: 12123765 [PubMed - indexed for MEDLINE] 4759. Obes Rev. 2002 May;3(2):113-22. Metabolically active components of fat-free mass and resting energy expenditure in humans: recent lessons from imaging technologies. Müller MJ(1), Bosy-Westphal A, Kutzner D, Heller M. Author information: (1)Institut für Humanernährung und Lebensmittelkunde, Agrar- und Ernährungswissenschaftliche Fakultät, Christian-Albrechts-Universität zu Kiel, Düsternbrooker Weg 17-19, D-24105 Kiel, Germany. mmueller@nutrfoodsc.uni-kiel.de Imaging technologies, i.e. magnetic resonance imaging (MRI), computer tomography (CT) and dual-energy X-ray absorptiometry (DEXA), are precise and accurate techniques used to study lean body mass and adipose tissue distribution. CT and MRI can also be used to assess metabolically active components of fat-free mass (FFM). (Throughout this article, metabolic activity is defined with respect to oxidative metabolism.) To date a total of 116 in vivo measurements of organ masses (OM), in combination with the measurement of resting energy expenditure (REE), have been reported. These data suggest that MRI- or CT-derived OM explains part (approximately 5-10%) of the interindividual variance in REE. The data also suggest that REE can be reconstructed from detailed body composition analysis. Calculating REE from the sum of individual OM multiplied by a constant organ tissue-respiration rate showed a high correlation between calculated and measured REE, with only small and non-significant differences of 83-96 kJ d-1. In addition to CT- and MRI-derived OM, data are available of 244 obese and non-obese subjects regarding the association between regional components of lean body mass (LBM, assessed by DEXA) and REE. These results suggest that measurement of LBM distribution also provides the opportunity to adjust for the non-linearity of REE on body mass. Assessment of metabolically active components of FFM or LBM may also add to our understanding of malnutrition-, obesity- and disease states-related variance in REE. There is need for (1) standardization of imaging technology in body composition research; (2) reference data on detailed body composition, also including more recent autopsy data; (3) reducing the number of assumptions in model-based predictions; and (4) a combination of imaging technologies with in vivo measurements of individual OM respiration. PMID: 12120418 [PubMed - indexed for MEDLINE] 4760. Nat Rev Drug Discov. 2002 Apr;1(4):276-86. Obesity therapy: altering the energy intake-and-expenditure balance sheet. Crowley VE(1), Yeo GS, O'Rahilly S. Author information: (1)University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, UK. Obesity is associated with numerous health complications, which range from non-fatal debilitating conditions such as osteoarthritis, to life-threatening chronic diseases such as coronary heart disease, diabetes and certain cancers. The psychological consequences of obesity can range from lowered self-esteem to clinical depression. Despite the high prevalence of obesity and the many advances in our understanding of how it develops, current therapies have persistently failed to achieve long-term success. This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure. PMID: 12120279 [PubMed - indexed for MEDLINE] 4761. Obes Rev. 2001 Nov;2(4):239-54. The biology of white adipocyte proliferation. Hausman DB(1), DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ. Author information: (1)Department of Foods and Nutrition, 263 Dawson Hall, University of Georgia, Athens, GA 30602, USA. dhausman@arches.uga.edu Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated. PMID: 12119995 [PubMed - indexed for MEDLINE] 4762. Obes Rev. 2001 Nov;2(4):231-8. The influence of obesity on hyperandrogenism and infertility in the female. Diamanti-Kandarakis E(1), Bergiele A. Author information: (1)Endocrine Section, 1st Department of Internal Medicine, Laiko General Hospital, Athens University, Athens, Greece. akandara@otenet.gr Although a critical mass of adipose tissue is essential for the normal development of female reproductive function, obesity has been shown to produce menstrual disturbances and subfertility. The severity of obesity and the distribution of fat tissue are important factors that influence the female reproductive system. The pathogenetic mechanistic links between them aren't clearly elucidated. Obese women, especially those with upper body obesity, have insulin resistance and hyperinsulinaemia, hyperandrogenaemia, increased peripheral aromatization of androgens to oestrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased growth hormone (GH) and insulin like growth factor binding proteins (IGFBPs), increased leptin levels and altered neuroregulation of the hypothalamic-pituitary-gonadal axis. These have been considered as some of the links in the sequence of events of the disrupted ovulatory process. The mechanisms of these actions and their influence on female reproductive function are discussed below. PMID: 12119994 [PubMed - indexed for MEDLINE] 4763. Obes Rev. 2000 Oct;1(2):73-86. The mechanism of effect of growth hormone on preadipocyte and adipocyte function. Nam SY(1), Lobie PE. Author information: (1)Department of Internal Medicine, Yongdong Severance Hospital, Yonsei University College of Medicine, Dogok-dong 146-92, Kangnam-Ku, Seoul 135-270, Korea. Growth hormone (GH) is not only the major regulator of postnatal somatic growth but also exerts profound effects on body composition through a combination of anabolic, lipolytic and antinatriuretic actions. GH enhancement of the lipolytic activity of adipose tissue in combination with a reduction of triglyceride accumulation via inhibition of lipoprotein lipase activity appears to be the major mechanism by which GH results in a reduction of the total fat mass. Recently, much progress has been made in understanding the molecular mechanism by which GH affects cellular function. This review provides a brief discourse and summary of the mechanism of effects of GH on preadipocyte/adipocyte function. It is intended to provide a functional understanding of the mechanism of action of GH as it relates to adipogenesis and adipocyte function. PMID: 12119989 [PubMed - indexed for MEDLINE] 4764. Obes Rev. 2000 Oct;1(2):61-72. The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research. Del Mar Gonzalez-Barroso M(1), Ricquier D, Cassard-Doulcier AM. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Développement, CNRS, 9 rue Jules Hetzel, 92190 Meudon, France. Energy expenditure through brown adipose tissue thermogenesis contributes either to maintenance of body temperature in a cold environment or to wasted food energy, i.e. cold-induced or diet-induced thermogenesis. Both mechanisms are due to a specific and unique protein: the uncoupling protein-1. Uncoupling protein-1 is exclusively expressed in mitochondria of brown adipocytes where it uncouples respiration from ATP synthesis, dissipating the proton gradient as heat. In humans, although uncoupling protein-1 can be detected, the inability to quantify brown adipose tissue makes it difficult to argue for a role for uncoupling protein-1 in thermogenesis and energy expenditure. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans. Understanding the mechanisms which regulate transcription and expression of the human UCP1 gene will facilitate the identification of molecules able to increase the levels of this protein in order to modulate energy expenditure in adult humans. PMID: 12119988 [PubMed - indexed for MEDLINE] 4765. Obes Rev. 2001 May;2(2):131-40. Obesity and immune function relationships. Martí A(1), Marcos A, Martínez JA. Author information: (1)Department of Physiology and Nutrition, University of Navarra, C/Irunlarrea s/n 31080 Pamplona, Navarra, Spain. The immunological processes involved in the collaborative defence of organisms are affected by nutritional status. Thus, a positive chronic imbalance between energy intake and expenditure leads to situations of obesity, which may influence unspecific and specific immune responses mediated by humoral and cell mediated mechanisms. Furthermore, several lines of evidence have supported a link between adipose tissue and immunocompetent cells. This interaction is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. However, limited and often controversial information exist comparing immunity in obese and non-obese subjects as well as about the cellular and molecular mechanisms implicated. In general terms, clinical and epidemiological data support the evidence that the incidence and severity of specific types of infectious illnesses are higher in obese persons as compared to lean individuals together with the occurrence of poor antibody responses to antigens in overweight subjects. Leptin might play a key role in linking nutritional status with T-cell function. The complexities and heterogeneity of the host defences concerning the immune response in different nutritional circumstances affecting the energy balance require an integral study of the immunocompetent cells, their subsets and products as well as specific and unspecific inducer/regulator systems. In this context, more research is needed to clarify the clinical implications of the alterations induced by obesity on the immune function. PMID: 12119664 [PubMed - indexed for MEDLINE] 4766. Obes Rev. 2000 May;1(1):47-56. Visceral obesity and metabolic syndrome. Bosello O(1), Zamboni M. Author information: (1)Department of Biomedical and Surgical Sciences, University of Verona, Piazza Stefani, 1-37126, Verona, Italy. bosello@borgotrento.univr.it There is increasing evidence for the existence of a condition consisting of a cluster of metabolic disorders which include insulin resistance, alterations in glucose and lipid metabolism, increased blood pressure and visceral obesity. The metabolic syndrome is now the favoured definition of the cluster. Each single component of the cluster increases the cardiovascular risk, but the combination of factors is much more important. Insulin resistance is the most frequently associated factor to the singular components of the syndrome: most authors believe that it may be the common aetiological factor. However, visceral obesity seems to be the main driving factor by means of the increased production of free fatty acids whose activity, in turn, might interfere with the action of insulin. Some questions exist about the syndrome because of the frequent lack in the cluster of one of the factors. This does not mean that the missing factor does not belong to the syndrome, but only that it is not yet clinically evident. Weight gain has been shown to be a strong predictor of the metabolic syndrome. This aspect gives strength to treatment and prevention because it means that losing weight or stopping weight increase might reduce the risk of a future appearance of a factor that is still not evident. Interventions to treat visceral obesity by means of losing weight seem to be the most efficacious way to treat the metabolic syndrome thus improving the most widespread cardiovascular risk factor in western countries. PMID: 12119645 [PubMed - indexed for MEDLINE] 4767. Obes Rev. 2000 May;1(1):27-35. Obesity: a disease or a biological adaptation? Tremblay A(1), Doucet E. Author information: (1)Department of Social and Preventive Medicine, Division of Kinesiology, Laval University, Ste-Foy, Québec, Canada. angelo.tremblay@kin.msp.ulaval.ca The increase in obesity prevalence is problematic as this condition is associated with health complications such as diabetes and cardiovascular diseases, more particularly when the excess body fat is stored in the deep abdominal region. On the other hand, obesity facilitates the maintenance of body homeostasis probably because of an increased hormonal gradient which favours the regulation of energy balance, to give but one example. The regulation potential of excess body fat is particularly apparent in the reduced-obese state where a reduction of energy expenditure, fat oxidation and some immune system markers, as well as an increase in appetite, stress vulnerability and circulating and adipose tissue organochlorines have been observed. These constitute another category of risk factors which can certainly favour the accumulation of body fat to reestablish body homeostasis on other fronts. Under such conditions, obesity is perceived by the physiologist as a necessary biological adaptation rather than a disease. For health professionals, this emphasizes the importance to seek a reasonable compromise between the favourable reduction of risk to develop metabolic complications by body weight loss and the physiological vulnerability which is also generated by such an intervention. PMID: 12119642 [PubMed - indexed for MEDLINE] 4768. Ann N Y Acad Sci. 2002 Jun;968:75-95. The essential role of RI alpha in the maintenance of regulated PKA activity. Amieux PS(1), McKnight GS. Author information: (1)Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA. pamieux@u.washington.edu Cloning of the individual regulatory (R) and catalytic (C) subunits of the cAMP-dependent protein kinase (PKA) and expression of these subunits in cell culture have provided mechanistic answers about the rules for PKA holoenzyme assembly. One of the central findings of these studies is the essential role of the RI alpha regulatory subunit in maintaining the catalytic subunit under cAMP control. The role of RI alpha as the key compensatory regulatory subunit in this enzyme family was confirmed by gene knockouts of the three other regulatory subunits in mice. In each case, RI alpha has demonstrated the capacity for significant compensatory regulation of PKA activity in tissues where the other regulatory subunits are expressed, including brain, brown and white adipose tissue, skeletal muscle, and sperm. The essential requirement of the RI alpha regulatory subunit in maintaining cAMP control of PKA activity was further corroborated by the knockout of RI alpha in mice, which results in early embryonic lethality due to failed cardiac morphogenesis. Closer examination of RI alpha knockout embryos at even earlier stages of development revealed profound deficits in the morphogenesis of the mesodermal embryonic germ layer, which gives rise to essential structures including the embryonic heart tube. Failure of the mesodermal germ layer in RI alpha knockout embryos can be rescued by crossing RI alpha knockout mice to C alpha knockout mice, supporting the conclusion that inappropriately regulated PKA catalytic subunit activity is responsible for the phenotype. Isolation of primary embryonic fibroblasts from RI alpha knockout embryos reveals profound alterations in the actin-based cytoskeleton, which may account for the failure in mesoderm morphogenesis at gastrulation. PMID: 12119269 [PubMed - indexed for MEDLINE] 4769. J Exp Biol. 2002 Aug;205(Pt 15):2275-85. UCP2 and UCP3 in muscle controlling body metabolism. Schrauwen P(1), Hesselink M. Author information: (1)Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Department of Human Biology, Maastricht University, The Netherlands. p.schrauwen@hb.unimaas.nl The uncoupling protein-1 (UCP1) homologues UCP2 and UCP3 are able to uncouple ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting energy metabolism efficiency. In contrast to UCP1, which plays an important role in adaptive thermogenesis, UCP2 and UCP3 do not have a primary role in the regulation of energy metabolism. UCP2, which is expressed in a wide variety of tissues, including white adipose tissue, skeletal muscle and tissues of the immune system, has been suggested to affect the production of reactive oxygen species. UCP2 has also been suggested to regulate the [ATP]/[ADP] ratio and was recently shown to influence insulin secretion in the beta-cells of the pancreas. UCP3, in contrast, is expressed predominantly in skeletal muscle and has been associated with whole-body energy metabolism. However, the primary function of UCP3 is not the regulation of energy metabolism. For example, fasting, a condition attenuating energy expenditure, upregulates UCP3 expression. Moreover, UCP3-knockout mice have a normal metabolic rate. The exact function of UCP3 therefore remains to be elucidated, but putative roles for UCP3 include involvement in the regulation of ROS, in mitochondrial fatty acid transport and in the regulation of glucose metabolism in skeletal muscle. Whatever the primary function of these novel uncoupling proteins, a secondary effect via uncoupling might allow them to influence (but not to regulate) energy metabolism, which would be consistent with the observations from linkage and association studies. Therefore, UCP2 and UCP3 remain interesting targets for pharmacological upregulation in the treatment of obesity and diabetes. PMID: 12110661 [PubMed - indexed for MEDLINE] 4770. J Exp Biol. 2002 Aug;205(Pt 15):2267-73. Adaptive thermogenesis in hummingbirds. Bicudo JE(1), Bianco AC, Vianna CR. Author information: (1)Department of Physiology, Biosciences Institute, University of São Paulo, SP, Brazil. jebicudo@usp.br The occurrence of non-shivering thermogenesis in birds has long been a controversial issue. Although birds are endothermic vertebrates, sharing with mammals (placental mammals and marsupials) a common ancestor, they do not possess brown adipose tissue or a similar type of tissue, unlike their mammalian counterparts. Some bird species are, however, able to withstand very low ambient temperatures (-70 degrees C) or undergo periods of heterothermia, and there is now good experimental evidence showing that non-shivering thermogenesis may indeed occur in birds under such conditions. The skeletal muscles of birds, particularly the flight muscles, occupy a significant fraction (approximately 30 %) of the total body mass, and recent results have shown that they are likely to be the main sites for non-shivering thermogenesis. The precise mechanisms involved in adaptive thermogenesis in birds are still not fully understood. The translocation of Ca(2+) between intracellular compartments and the cystosol mediated by the sarcoplasmic reticulum Ca(2+)-ATPase, uncoupled from ATP synthesis, is one mechanism whereby chemi-osmotic energy can be converted into heat, and it has been proposed as one of the possible mechanisms underlying non-shivering thermogenesis in birds on the basis of data obtained mainly from ducklings acclimatized to cold conditions. The recent characterization of an uncoupling protein homolog in avian skeletal muscle and the expression of its mRNA at different stages of the torpor/rewarming cycle of hummingbirds indicate that it has the potential to function as an uncoupling protein and could play a thermogenic role during rewarming in these birds. PMID: 12110660 [PubMed - indexed for MEDLINE] 4771. Curr Opin Clin Nutr Metab Care. 2002 Jul;5(4):427-33. Body composition: what's new? Kyle UG(1), Genton L, Pichard C. Author information: (1)Clinical Nutrition, Geneva University Hospital, 1211 Geneva 14, Switzerland. PURPOSE OF REVIEW: Body mass index has been shown to be an imprecise measurement of fat-free and fat mass, and provides no information if weight changes occur as a result of a decrease in fat-free mass or an increase in fat mass. RECENT FINDINGS: Non-invasive body composition methods (i.e. bioelectrical impedance analysis, air displacement plethysmography) can now be used to monitor fat-free and fat mass with weight gain and loss, and during aging. This review discusses body composition measurements in terms of ethnic differences, physical activity, and age, and the limitations of bedside techniques in obesity and abnormal hydration status. SUMMARY: An assessment of the fat-free and fat mass provides valuable information about changes in body composition with weight gain or loss and physical activity, and during aging. Non-invasive bedside techniques can now be used to evaluate the nutritional status of healthy and ill individuals. PMID: 12107379 [PubMed - indexed for MEDLINE] 4772. Curr Opin Clin Nutr Metab Care. 2002 Jul;5(4):419-26. Peripheral mechanisms involved with catabolism. Langhans W(1). Author information: (1)Institute of Animal Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland. wolfgang.langhans@inw.agrl.ethz.ch PURPOSE OF REVIEW: This review summarizes recent developments concerning the mechanisms of skeletal muscle and adipose tissue breakdown, which are a hallmark of cachexia during many diseases. Current knowledge on the hypermetabolism which often contributes to cachexia is also considered. RECENT FINDINGS: Recent studies have identified interactions between Ca2+, proinflammatory cytokines (in particular tumor necrosis factor-alpha) and the activation of transcription factors (e.g. nuclear factor-kappaB) in the stimulation of major proteolytic pathways in cachexia. Progress has also been made in explaining the inhibiting effects of several drugs on protein breakdown. Advances in our understanding of the mechanisms of adipose tissue catabolism in cachexia include demonstrations that (1) tumor necrosis factor-alpha, in addition to its direct lipolytic effect, promotes adipose tissue breakdown by inhibiting adipocyte differentiation and increasing adipocyte apoptosis, (2) interleukin-6 has a lipolytic effect, and (3) chemokines are expressed by adipocytes and interact with tumor necrosis factor-alpha to cause lipolysis. Concerning the hypermetabolism in cachexia, new evidence supports previous theories that uncoupling protein-2 and 3 are primarily involved in the generation of reactive oxygen species and in the control of fatty acid flux across the mitochondrial membrane, respectively. Furthermore, the cytokine-induced transcriptional coactivator-1 for the peroxysome proliferator-activated receptor-gamma was recently identified as a contributor to hypermetabolism. SUMMARY: These new insights into major catabolic pathways during cachexia provide a focus for future studies in this area and may help to develop promising therapeutic approaches. PMID: 12107378 [PubMed - indexed for MEDLINE] 4773. Curr Opin Clin Nutr Metab Care. 2002 Jul;5(4):407-18. Central mechanisms involved with catabolism. Nandi J(1), Meguid MM, Inui A, Xu Y, Makarenko IG, Tada T, Chen C. Author information: (1)Department of Medicine, Gastroenterology Division, University Hospital, SUNY Upstate Medical University, Syracuse, NY 13210, USA. PURPOSE OF REVIEW: Catabolism conjures up an end-metabolic process in which muscle and fat tissue are broken down into their constituent parts to provide nutrients for the body, secondary to a noxious stimulus that prevents the organism from adequately nourishing itself. However, catabolism is a primary event, initiated in the brain in response to perceived or real stresses or noxious stimuli, which has a secondary effect of inhibiting food intake and consequently the break down of skeletal muscle and adipose tissues to provide nutrients for the body to survive. RECENT FINDINGS: This is achieved via a cascade of neurohormonal monoaminergic and peptidergic mediators in the central nervous system, invoking the cortex, the limbic system and the hypothalamus. Among the most detailed mediators studied are corticotropin-releasing factor and serotonin which, via the hypothalamic-pituitary-adrenal axis and the sympathetic and parasympathetic nervous system, stimulate catecholamines and cortisol and inhibit anabolic hormones, insulin, leptin, ghrelin, including neuropeptide Y and other neuropeptides, among them the paracrine-acting cytokines. Simultaneously, there occurs stimulation of the counter-regulatory hormones cortisol, glucagon and the melanocortin family of neuropeptides. SUMMARY: The net effect is anorexia, with the inhibition of food intake, body weight loss, delayed gastric emptying and functions, the stimulation of gluconeogenesis, glycogenolysis and ketogenesis as sources of metabolic fuel, which if unabated leads ultimately to cachexia. The use of antagonists and the removal of stress or noxious stimuli experimentally test different pathways of this dynamic metabolic picture. Several studies have demonstrated important progress towards our understanding of the central mechanisms involved in anorexia and weight loss, which we summarize in this review. PMID: 12107377 [PubMed - indexed for MEDLINE] 4774. Curr Opin Clin Nutr Metab Care. 2002 Jul;5(4):401-5. Biochemical mechanisms of cellular catabolism. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK. m.j.tisdale@aston.ac.uk PURPOSE OF REVIEW: To provide an in-depth analysis of current developments concerning biochemical mechanisms of cellular catabolism. There have been a number of important developments in this area over the past 12 months, particularly with respect to protein catabolism. RECENT FINDINGS: Protein degradation in a range of catabolic conditions is mediated primarily through the ubiquitin-proteasome proteolytic pathway. Glucocorticoids have been suggested to activate this system in sepsis, while in cancer cachexia a tumour-produced sulphated glycoprotein, proteolysis-inducing factor, induces protein catabolism in skeletal muscle by increasing expression of proteasome subunits and the ubiquitin carrier protein, E2(14k). Apoptosis may also be important in the loss of muscle protein during the early stage of cachexia. Induction of proteasome expression by glucocorticoids appears to be a direct result of the downregulation of the activity of nuclear factor kappaB, while proteolysis-inducing factor acts through 15-hydroxyeicosatetraenoic acid as an intracellular transducer. SUMMARY: Formation of 15-hydroxyeicosatetraenoic acid is inhibited by eicosapentaenoic acid, which has been shown to attenuate the development of weight loss in patients with pancreatic cancer. When eicosapentaenoic acid is combined with an energy dense nutritional supplement, there is an increase in body weight of cachectic cancer patients through an increase in lean body mass. Eicosapentaenoic acid also prevents protein catabolism and activation of the ubiquitin-proteasome proteolytic pathway during acute starvation in mice, suggesting a similar pathway is involved. Thus eicosapentaenoic acid may be effective in the treatment of protein catabolism in conditions other than cancer. PMID: 12107376 [PubMed - indexed for MEDLINE] 4775. Curr Opin Clin Nutr Metab Care. 2002 Jul;5(4):385-9. Angiotensinogen, adipocyte differentiation and fat mass enlargement. Ailhaud G(1), Teboul M, Massiera F. Author information: (1)Institute of Signaling, Developmental Biology and Cancer Research, Centre de Biochimie (UMR 6543 CNRS), Laboratory Biology of Adipose Tissue Development, Faculté des Sciences, Parc Valrose, Nice, France. ailhaud@unice.fr PURPOSE OF REVIEW: Angiotensinogen and components of the renin-angiotensin system are expressed in adipose tissue of rodents and humans, but the role of generated angiotensin II has remained intriguing. Moreover, the functional importance of angiotensin II receptor subtypes in preadipocytes and adipocytes still remains a controversial subject. RECENT FINDINGS: Recent findings in transgenic mice have emphasized the upregulation of angiotensinogen expression by glucocorticoids. Furthermore, angiotensinogen products, that is angiotensin II and possibly angiotensin II-related products, have been found to act locally in modulating adipose tissue growth in an autocrine/paracrine manner. Cellularity measurements show that fat mass enlargement is associated with adipocyte hypertrophy, consistent with the upregulation of the fatty acid synthetase gene by angiotensin II depicted at the molecular level. Together, these findings suggest a mechanism by which transient or chronic overexpression of angiotensinogen in adipose tissue favors lipogenesis in adipocytes and leads to a 'vicious' circle whereby adipose tissue development is further increased. SUMMARY: Additional studies are warranted to characterize angiotensin II-related receptors, if any, and to clarify the role played by angiotensin II receptor subtypes and metabolites in various metabolic aspects of white adipose tissue. PMID: 12107373 [PubMed - indexed for MEDLINE] 4776. J Clin Endocrinol Metab. 2002 Jul;87(7):3019-22. Hepatic steatosis, insulin resistance, and adipose tissue disorders. Garg A, Misra A. Comment on J Clin Endocrinol Metab. 2002 Jul;87(7):3023-8. PMID: 12107193 [PubMed - indexed for MEDLINE] 4777. Breast J. 2002 Jul-Aug;8(4):234-43. Pathology of the breast associated with HIV/AIDS. Pantanowitz L(1), Connolly JL. Author information: (1)Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. lpantanowitz@hotmail.com Breast pathology that is characteristic of patients infected with human immunodeficiency virus (HIV) has not been addressed in the literature. HIV may directly and indirectly affect the glandular, mesenchymal, and intramammary lymphoid tissue in seropositive patients. Likely infections in this setting include tuberculous mastitis and pyogenic abscesses that may lead to fatal septicemia. Benign stromal changes include gynecomastia, adipose tissue deposition as part of the fat maldistribution syndrome, and pseudoangiomatous stromal hyperplasia. Breast carcinoma in HIV-infected patients occurs at a relatively early age, with increased bilateral disease, unusual histology, and early metastatic spread with a poor outcome. However, the link between breast cancer and HIV remains controversial. Kaposi's sarcoma and non-Hodgkin's lymphoma may also be localized to the breast in patients with acquired immunodeficiency syndrome (AIDS). This article reviews benign and malignant breast diseases that are likely to be encountered in patients with HIV/AIDS. PMID: 12100117 [PubMed - indexed for MEDLINE] 4778. Clin Endocrinol (Oxf). 2002 Jul;57(1):1-9. Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Mauvais-Jarvis F(1), Kulkarni RN, Kahn CR. Author information: (1)Department of Endocrinology and Diabetes, Saint-Louis Hospital and University of Paris VII Medical School, France. FMauvais_jarvis@aol.com OBJECTIVE: The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion. DESIGN: Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance. RESULTS: Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity. PMID: 12100063 [PubMed - indexed for MEDLINE] 4779. Invest New Drugs. 2002 May;20(2):195-200. Peroxisome proliferator-activated receptor gamma (PPargamma) as a novel target for prostate cancer. Smith MR(1), Kantoff PW. Author information: (1)Massachusetts General Hospital, Boston 02114, USA. smith.matthew@mgh.harvard.edu Peroxisome proliferator activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARgamma is expressed at high levels in adipose tissue and plays a central role in adipocyte differentiation. Recent studies have implicated PPARgamma in the pathogenesis of several human malignancies. Here we review the evidence that PPARgamma contributes to prostate carcinogenesis and the potential for PPARgamma as a novel therapeutic target for prostate cancer. PMID: 12099579 [PubMed - indexed for MEDLINE] 4780. Semin Perinatol. 2002 Jun;26(3):190-5. Identification of fetal growth abnormalities in diabetes mellitus. Jaffe R(1). Author information: (1)Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, NY 10019, USA. rjaffemd@aol.com Gestational diabetes complicates 3% to 5% of all pregnancies. Shoulder dystocia and fetal injuries are associated with macrosomia, a complication often encountered in diabetic pregnancies. The route of delivery is often planned in advance and based on estimated fetal weight. Fetuses of diabetic mothers are prone to macrosomia due to increased subcutaneous adipose tissue deposits, and perinatal complications are more frequent in these fetuses. For this reason, particular effort should be directed toward the diagnosis of fetal growth abnormalities in fetuses of diabetic mothers. There are numerous formulas for estimating fetal weight, and they are all error prone. An effort should be made to follow these high-risk pregnancies in a longitudinal fashion to detect any developing growth abnormality as early as possible. Whether macrosomia or intrauterine growth restriction, early detection and careful planning of mode and time of delivery is the foundation of successful lowering of perinatal morbidity and mortality. PMID: 12099308 [PubMed - indexed for MEDLINE] 4781. Nat Rev Immunol. 2002 Jun;2(6):417-26. No one is naive: the significance of heterologous T-cell immunity. Welsh RM(1), Selin LK. Author information: (1)Department of Pathology, University of Massachusetts Medical School, Worcester 01655, USA. Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host's history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified. Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection. PMID: 12093008 [PubMed - indexed for MEDLINE] 4782. J Pediatr Endocrinol Metab. 2002 May;15 Suppl 2:751-7. Exercise, diet, and childhood obesity: the GH-IGF-I connection. Nemet D(1), Cooper DM. Author information: (1)Center for the Study of Health Effects of Exercise in Children, University of California, Irvine, College of Medicine, Orange 92868, USA. dcooper@uci.edu The recent "obesity epidemic" among children and adolescents is a major public health concern. The mechanisms responsible for the increased incidence of childhood obesity are not yet well understood. The absence of a clear mechanism makes treating the obese child or adolescent a difficult task, and standardized therapeutic approaches simply do not yet exist. Metabolic derangements associated with obesity may contribute to the difficulty in treatment. Observed abnormalities in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis in obese adults and the impact of exercise on the GH-IGF-I system are of particular relevance to the growing obese child. In this review, we focus on the interacting mechanisms of diet and exercise through specific hormonal mediators and their contribution to the current obesity epidemic. An improved understanding of these mechanisms may be helpful in creating effective treatment programs for children with obesity. PMID: 12092690 [PubMed - indexed for MEDLINE] 4783. Minerva Endocrinol. 2002 Sep;27(3):181-91. [PAI-1, the primary plasmatic inhibitor of fibrinolysis. Physiopathologic role and molecular mechanisms]. [Article in Italian] Banfi C(1), Mussoni L, Tremoli E. Author information: (1)Dipartimento di Scienze Farmacologiche, Università degli Studi, Milan, Italy. Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in blood. PAI-1 is known to contribute to thrombus formation and to the development and the clinical course of acute and chronic cardiovascular diseases. Plasma levels of PAI-1 are regulated on a genetic basis but, more important, is the dependence on a series of other atherosclerotic risk factors like hypertriglyceridemia, diabetes and insulin resistance. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. At least in vitro, insulin is a potent inducer of PAI-1 synthesis by human hepatic cells, and, we have recently disentangled the molecular mechanisms responsible for enhanced PAI-1 gene expression by insulin. However, clinical data fail to support a direct acute contribution of insulin in regulating circulating PAI-1 levels. Recently, it has been proposed that adipose tissue could be responsible for the elevated plasma PAI-1 level observed in insulin resistance. It now seems reasonable to view PAI-1 as one of the factors contributing to the complex gene-environment interactions involved in the formation and dissolution of thrombi. PMID: 12091793 [PubMed - indexed for MEDLINE] 4784. Prev Cardiol. 2002 Summer;5(3):138-44. Genetics and blood pressure response to exercise, and its interactions with adiposity. Rankinen T(1), Bouchard C. Author information: (1)Pennington Biomedical Research Center, Human Genomics Laboratory, Baton Rouge, LA 70808-4124, USA. Regular aerobic exercise has the potential to induce several beneficial health effects, including a decrease in blood pressure level, especially in hypertensive patients and in subjects with high-normal blood pressure. However, it is also well documented that some people show more pronounced blood pressure responses to endurance training than others, despite identical training programs and similar initial blood pressure levels. This kind of variation is an example of normal biologic diversity and most likely originates from interactions with genetic factors. Data from genetic epidemiologic studies indicate that there is a genetic component that affects both resting blood pressure and blood pressure responses to acute exercise. Evidence from molecular genetic studies is scarce, but the first reports suggest that DNA sequence variation in the hypertension candidate genes, such as angiotensinogen, also modify blood pressure responses to endurance training. The current knowledge regarding the role of genetic factors in the modification of blood pressure responses to endurance training will be summarized and discussed. Copyright 2002 CHF, Inc. PMID: 12091756 [PubMed - indexed for MEDLINE] 4785. Semin Reprod Med. 2002 May;20(2):123-30. Leptin in relation to growth and developmental processes in the fetus. Christou H(1), Serdy S, Mantzoros CS. Author information: (1)Division of Newborn Medicine, Children's Hospital, Boston, Massachusetts, USA. Leptin, a 16-kilodalton protein secreted by the adipose tissue in proportion to the amount of energy stored in adipose tissue, conveys to the hypothalamus information on energy homeostasis and regulates reproductive function. In addition, there is accumulating evidence that leptin produced by placental or fetal tissues acts through specific leptin receptors to regulate fetal growth and development. Although leptin levels are correlated with insulin and insulin-like growth factor (IGF)-1 levels, observational studies in humans indicate that its effects on fetal growth are independent of these axes and of adiposity. The extent to which leptin per se mediates the fetal growth and developmental abnormalities associated with disease states such as diabetes, hypoxia, or preeclampsia remains to be fully clarified by future studies in humans. It is hoped that clarification of these mechanisms may provide novel therapeutic approaches. PMID: 12087497 [PubMed - indexed for MEDLINE] 4786. Semin Reprod Med. 2002 May;20(2):113-22. Leptin: roles and regulation in primate pregnancy. Henson MC(1), Castracane VD. Author information: (1)Department of Obstetrics and Gynecology, and the Tulane National Primate Research Center, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA. Leptin, a hormone produced by adipose tissue and the placenta, is enhanced in the maternal circulation throughout pregnancy in both the human and the baboon ( Papio sp.), a proven nonhuman primate model for the study of human pregnancy. The presence of both leptin and its receptor in the fetus implies a role for the polypeptide as a regulator of in utero development, although localization in the placental trophoblast may relate to autocrine and/or paracrine regulatory functions in this important endocrine tissue. Although regulatory mechanisms remain incompletely defined, it has been suggested that cross talk occurs between the fetus, placenta, and maternal adipose stores. Placental estrogen, which is present in increasing concentrations with advancing gestation, is suggested to influence leptin synthesis in a tissue- and cell type-specific fashion. In this capacity, cellular hypoxia, diabetes, and preeclampsia are conditions that appear to be intimately linked to leptin dynamics. A better understanding of regulatory mechanisms will have direct clinical significance, as leptin has been proposed to impact on those causes of human perinatal morbidity and mortality that are associated with anomalies of fetal maturity and development, general conceptus growth, trophoblast endocrinology, and placental sufficiency. PMID: 12087496 [PubMed - indexed for MEDLINE] 4787. J Biol Chem. 2002 Aug 23;277(34):30409-12. Epub 2002 Jun 26. The key role of anaplerosis and cataplerosis for citric acid cycle function. Owen OE(1), Kalhan SC, Hanson RW. Author information: (1)Department of Pediatrics, Case Western Reserve University School of Medicine, Robert Schwartz M.D. Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, OH 44109, USA. oeowen@comcast.net PMID: 12087111 [PubMed - indexed for MEDLINE] 4788. Rev Pneumol Clin. 2002 Apr;58(2):117-20. [Anesthesia and obesity]. [Article in French] Valette S(1), Cohendy R. Author information: (1)Département Anesthésie-Douleur, CHU de Nîmes, 30029 Nîmes Cedex 9, France. Problems encountered during anesthesia procedures in obese subjects is related to the level of overweight. Obesity multiplies the effect of general anesthesia on the respiratory function and increases the postoperative risk of cardiovascular disorders and deep vein thrombosis. The pharmacokinetic behavior of most general anesthesia drugs is affected by the mass of adipose tissue producing a prolonged less predictable effect. Control of airway permeability and continence is also a major problem with predictable or unpredictable difficulties with endotracheal intubation. Locoregional anesthesia, which avoids the intubation problem, is difficult to implement and does not provide satisfactory results in all cases. The preoperative work-up should assess the consequences of obesity, particularly concerning the respiratory, cardiovascular, and metabolic systems. A proper work-up allows the anesthesist to provide the obese subject with well-informed information on the risk and benefit of proposed options. PMID: 12082451 [PubMed - indexed for MEDLINE] 4789. Rev Pneumol Clin. 2002 Apr;58(2):63-70. [Obesity: epidemiology, pathophysiology and extra-respiratory complications]. [Article in French] Oppert JM(1). Author information: (1)Service de Médecine et Nutrition, Hôtel-Dieu (AP-HP), 1, place du Parvis-Notre-Dame, 75181 Paris Cedex 04, France. jean-michel.oppert@htd.ap-ap-hop-paris.fr Obesity is the most common nutritional disease in industrialized countries and constitutes an important public health issue. Strictly speaking, obesity is an excess of adipose tissue. In practice, body mass index (BMI)=weight (kg)/height (m)(2) is used to determine the degree of excess body weight in a patient. A BMI >=30 kg/m(2), which is associated with significantly higher morbidity and mortality, is generally used as a threshold value for obesity. Despite this measurement, obesity includes a very wide range of variable symptoms. Development of obesity is a multifactorial phenomenon implicating biological, genetic, behavioral, and environmental factors whose interaction and inter-association vary from individual to individual. There are many extra-respiratory complications of obesity which may be somatic (cardiovascular, mechanic, metabolic.), psychological, or social. Abdominal adipose tissue plays an important role in metabolic and vascular complications of obesity independently of the degree of corpulence. As an introduction, we discuss here the definitions concerned as well as the epidemiology, basic pathophysiological mechanisms, and extra-respiratory complications of adult obesity. PMID: 12082444 [PubMed - indexed for MEDLINE] 4790. Clin Hemorheol Microcirc. 2002;26(2):63-79. Hormones, metabolism and body composition as major determinants of blood rheology: potential pathophysiological meaning. Brun JF(1). Author information: (1)Service Central de Physiologie Clinique, Centre d' Exploration et de Réadaption des Anomalies du Métabolisme Musculaire, France. drjfbrun.@aol.com The rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status and plasma protein pattern are well known to exert a major influence. The oxidative stress induced by increased free radicals production decreases red cell deformability. Among circulating substances, the divalent cations magnesium and zinc improve red cell deformability probably via calcium antagonistic effects. Some metabolites like lactate or ketone bodies decrease red cell deformability, although the former has apparently the opposite effect in highly trained individuals. Endothelium-derived factors such as nitric oxide (NO) and several arachidonic acid derivatives modulate both RBC and white cell mechanics. Endothelium regulates also blood rheology via the release of PAI-1 which governs plasma fibrinogen levels. However, endothelium is not the only organ involved in the regulation of blood rheology: the kidney (by releasing erythropoietin which is a major "viscoregulatory" factor), the endocrine pancreas (via the action of insulin and glucagon on red cells), the adrenal gland (norepinephrine) and the endocrine heart (atrial natriuretic peptide) are also likely to exert important effects. Recently, increasing evidence is accumulating for a role of two other endocrine tissues in the regulation of blood rheology: the adipose tissue (free fatty acids, PAI-1, IL-6, leptin) and the pituitary gland (growth hormone-somatomedin axis, including the somatomedin carrier protein IGFBP1). These organs provide a link between body composition and hemorheology, since GH and somatomedins are major regulators of the body content in fat and water while the endocrine activity of fat mass is apparently proportional to its size. These mechanisms explain to some extent why many situations, either physiological (diet, exercise) or pathological (diabetes, uremia) are associated with marked changes in blood rheology that may in turn modify micro and macrocirculatory hemodynamics and the distribution of O(2) and fuels to tissues. PMID: 12082254 [PubMed - indexed for MEDLINE] 4791. Hum Fertil (Camb). 2002 May;5(2):67-71. Polycystic ovary syndrome and fat distribution: the central issue? Lord J(1), Wilkin T. Author information: (1)South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon PL6 8DH, UK. This review discusses the role of central obesity in polycystic ovary syndrome. There is increasing evidence that intraabdominal or visceral fat is either causative or a very early effect of polycystic ovary syndrome. The clinical implications of this are discussed. The simplest technique for assessing visceral fat and monitoring treatment is to measure waist circumference rather than waist:hip ratio or body weight. Weight loss is an effective treatment even where there is only a very modest reduction. The key element in lifestyle modification is regular exercise. PMID: 12082210 [PubMed - indexed for MEDLINE] 4792. Am J Clin Nutr. 2002 Jul;76(1):281S-5S. Glycemic index and obesity. Brand-Miller JC(1), Holt SH, Pawlak DB, McMillan J. Author information: (1)Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, NSW, Australia. j.brandmiller@biochem.usyd.edu.au Although weight loss can be achieved by any means of energy restriction, current dietary guidelines have not prevented weight regain or population-level increases in obesity and overweight. Many high-carbohydrate, low-fat diets may be counterproductive to weight control because they markedly increase postprandial hyperglycemia and hyperinsulinemia. Many high-carbohydrate foods common to Western diets produce a high glycemic response [high-glycemic-index (GI) foods], promoting postprandial carbohydrate oxidation at the expense of fat oxidation, thus altering fuel partitioning in a way that may be conducive to body fat gain. In contrast, diets based on low-fat foods that produce a low glycemic response (low-GI foods) may enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity. This hypothesis is supported by several intervention studies in humans in which energy-restricted diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods. Long-term studies in animal models have also shown that diets based on high-GI starches promote weight gain, visceral adiposity, and higher concentrations of lipogenic enzymes than do isoenergetic, macronutrientcontrolled, low-GI-starch diets. In a study of healthy pregnant women, a high-GI diet was associated with greater weight at term than was a nutrient-balanced, low-GI diet. In a study of diet and complications of type 1 diabetes, the GI of the overall diet was an independent predictor of waist circumference in men. These findings provide the scientific rationale to justify randomized, controlled, multicenter intervention studies comparing the effects of conventional and low-GI diets on weight control. PMID: 12081852 [PubMed - indexed for MEDLINE] 4793. Int J Obes Relat Metab Disord. 2002 Jul;26(7):897-904. Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance--is insulin resistance initiated in the adipose tissue? Smith U(1). Author information: (1)The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. ulf.smith@medic.gu.se This review postulates and presents recent evidence that insulin resistance is initiated in the adipose tissue and also suggests that the adipose tissue may play a pivotal role in the induction of insulin resistance in the muscles and the liver. Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. However, insulin-stimulated glucose transport and glycogen synthesis are markedly reduced. Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. In addition, GLUT4 expression is markedly reduced in these cells, similar to what is seen in diabetic cells. The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. It is proposed that insulin resistance and/or its effectors is initiated in fat cells and that this may secondarily encompass other target tissues for insulin, including the impaired glucose transport in the muscles. PMID: 12080441 [PubMed - indexed for MEDLINE] 4794. Ann N Y Acad Sci. 2002 Jun;967:398-402. Uncoupling proteins, leptin, and obesity: an updated review. Giacobino JP(1). Author information: (1)Département de Biochimie Médicale, C. M. U., 1211 Geneva 4, Switzerland. jean-paul.giacobino@medicine.unige.ch The hypothesis that the novel uncoupling protein UCP3 is thermogenic and/or thermoregulatory is discussed. In vitro, ex vivo, and in vivo models are presented. The beta(3)-adrenoceptors are crucial for the appearance of UCP1-expressing cells in the white adipose tissue. These cells might differ from classical brown adipocytes. Besides its well-known effect on brown adipose tissue UCP1, leptin might stimulate indirectly muscle UCP3 expression. PMID: 12079867 [PubMed - indexed for MEDLINE] 4795. Ann N Y Acad Sci. 2002 Jun;967:379-88. Leptin signaling, adiposity, and energy balance. Jéquier E(1). Author information: (1)Institute of Physiology, University of Lausanne, Switzerland. Eric.Jequier@iphysiol.unil.ch A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake. PMID: 12079865 [PubMed - indexed for MEDLINE] 4796. Ann N Y Acad Sci. 2002 Jun;967:363-78. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ravussin E(1), Smith SR. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808-4124, USA. ravusse@pbrc.edu It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type 2 diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free fatty acid flux and inhibition of insulin action via Randle's effect in insulin-sensitive tissues. Recent data do not entirely support this hypothesis. As such, two new paradigms have emerged that may explain the established links between adiposity and disease. (A) Three lines of evidence support the ectopic fat storage syndrome. First, failure to develop adequate adipose tissue mass in either mice or humans, also known as lipodystrophy, results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle, and the pancreatic insulin-secreting beta cell. Second, most obese patients also shunt lipid into the skeletal muscle, the liver, and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver correlates highly with insulin resistance. Third, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and thus to accommodate an increased energy influx. Taken together, these three observations support the acquired lipodystrophy hypothesis as a link between adiposity and insulin resistance. (B) The endocrine paradigm developed in parallel with the ectopic fat storage syndrome hypothesis. Adipose tissue secretes a variety of endocrine hormones, such as leptin, interleukin-6, angiotensin II, adiponectin (also called ACRP30 and adipoQ), and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. These two new paradigms provide a framework to advance our understanding of the pathophysiology of the insulin-resistance syndrome. PMID: 12079864 [PubMed - indexed for MEDLINE] 4797. Ann N Y Acad Sci. 2002 Jun;967:135-45. Skeletal muscle triglycerides: an aspect of regional adiposity and insulin resistance. Kelley DE(1). Author information: (1)Department of Medicine, Montefiore University Hospital, University of Pittsburgh, Pennsylvania 15213, USA. kelley@msx.dept-med.pitt.edu The composition and biochemistry of skeletal muscle are altered in obesity and type 2 diabetes mellitus (DM) as compared to nonobese individuals. In health, skeletal muscle has a clear capacity to utilize both carbohydrate and lipid fuels and to transition between these in response to hormonal, chiefly insulin, and substrate signals. This metabolic flexibility is key for the major role that skeletal muscle can have in overall fuel balance. In obesity and type 2 DM, there is a loss of this plasticity and, instead, there is metabolic inflexibility. Rates of lipid oxidation do not suppress effectively in response to insulin, but neither do rates of lipid oxidation effectively increase during the transition to fasting conditions. An important morphological characteristic of skeletal muscle in obesity and type 2 DM is an increased content of triglyceride. The accretion of fat within muscle tissues appears to strongly correlate with insulin resistance and may not be simply a passive process, paralleling fat storage in other tissues. Instead, and of particular metabolic interest, a concept is emerging that biochemical characteristics of skeletal muscle in obese individuals dispose to fat accumulation in muscle. An effort to modify skeletal muscle in individuals with obesity and type 2 DM so that the capacity for fat oxidation and metabolic flexibility is improved should be among the goals of treatment for these disorders. PMID: 12079843 [PubMed - indexed for MEDLINE] 4798. Ann N Y Acad Sci. 2002 Jun;967:102-11. Transgenic mice overexpressing the rate-limiting enzyme for hexosamine synthesis in skeletal muscle or adipose tissue exhibit total body insulin resistance. Cooksey RC(1), McClain DA. Author information: (1)VA Medical Center and Department of Medicine, University of Utah, Salt Lake City 84132, USA. High concentrations of glucose induce insulin resistance and impair insulin secretion in a manner that mirrors type 2 diabetes, a phenomenon known as glucose toxicity. High concentrations of hexosamines mimic these effects, leading to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase, GFA) in muscle and fat results in insulin resistance and hyperleptinemia. GFA overexpression targeted to liver results in hyperlipidemia and to the beta cell in increased insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype". The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes. PMID: 12079840 [PubMed - indexed for MEDLINE] 4799. Ann N Y Acad Sci. 2002 Jun;967:88-101. Modulation of lipid metabolism by energy status of adipocytes: implications for insulin sensitivity. Kopecký J(1), Flachs P, Bardová K, Brauner P, Prazák T, Sponarová J. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. kopecky@biomed.cas.cz It is becoming evident that insulin resistance of white adipose tissue is a major factor underlying the cardiovascular risk of obesity. Impaired fat storage rather than altered glucose metabolism in adipocytes probably contributes to development of insulin resistance in muscle and other tissues, in particular via increased delivery of nonesterified fatty acids into circulation. Lipid metabolism of adipose tissue is affected by the energy status of fat cells. In vitro experiments indicated the dependence of both lipogenesis and lipolysis on ATP levels in adipocytes. Thus, respiratory uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to the control of lipid metabolism, adiposity, and insulin sensitivity. This notion is supported by the expression of UCPs in adipocytes, for example, UCP2, UCP5, as well as some protonophoric anion transporters, and by induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. A negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in the aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by respiratory uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white, but not brown fat. Probably due to depression of the ATP/ADP ratio, both fatty acid synthesis and lipolytic action of norepinephrine in adipocytes of transgenic mice were relatively low. Expression of regulatory G-proteins, which are essential for both catecholamine and insulin signaling in adipocytes, was also altered by ectopic UCP1. These results support the role of protonophoric proteins in adipocytes in the control of adiposity and insulin sensitivity. Antidiabetic effects of thiazolidinediones, fibrates, beta(3)-adrenoreceptor agonists, dietary n-3 PUFAs, and leptin may be explained at least partially by their effects on the energy and hence also the lipid metabolism of fat cells. PMID: 12079839 [PubMed - indexed for MEDLINE] 4800. Ann N Y Acad Sci. 2002 Jun;967:80-7. Adiposity and the development of diabetes in mouse genetic models. Kozak LP(1), Rossmeisl M. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. kozaklp@pbrc.edu While it is certain from the analysis of transgenic models of lipodystrophy that a critical mass of adipose tissue is necessary to prevent the development of diabetes, the reasons why diabetes develops in one obese individual and not in another need to be further investigated. This is also one of the major questions associated with the current obesity epidemic and the development of the metabolic syndrome. The severe lipodystrophic models do not really address this big problem. In this presentation, we point out that models exist among inbred strains of mice that can contribute towards finding answers to the diabetes found in the metabolic syndrome. The differences responsible for the phenotypic variations are undoubtedly multifactorial and involve many genes, but there are powerful genetic resources to investigate these problems. PMID: 12079838 [PubMed - indexed for MEDLINE] 4801. Ann N Y Acad Sci. 2002 Jun;967:52-65. Insulin stimulation of hepatic triacylglycerol secretion in the insulin-replete state: implications for the etiology of peripheral insulin resistance. Zammit VA(1). Author information: (1)Cell Biochemistry, Hannah Research Institute, Ayr KA6 5HL, Scotland, United Kingdom. zammitv@hri.sari.ac.uk Observations on humans, on rats in vivo, and on isolated perfused rat livers indicate that insulin stimulates hepatic very-low-density lipoprotein (VLDL)-TAG secretion when the liver is chronically exposed to the hormone. They suggest that frequent stimulation of insulin secretion throughout the diurnal cycle may result in a chronic stimulation of VLDL secretion and increased delivery of acyl moieties to the periphery, particularly to muscle, the most important site of insulin-sensitive glucose disposal. If acyl groups are provided in excess of the oxidative needs of the tissue, this may lead to induction of insulin resistance, irrespective of whether obesity is established concomitantly. Dietary factors that stimulate hepatic VLDL secretion may have the same effect and contribute to the induction of a vicious spiral leading to the development of the full-blown Metabolic Syndrome and its pathological consequences, including type-2 diabetes, stroke, and cardiovascular disease. PMID: 12079835 [PubMed - indexed for MEDLINE] 4802. Ann N Y Acad Sci. 2002 Jun;967:28-33. PPARgamma, an X-ceptor for Xs. Koutnikova H(1), Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, F-67404 Illkirch, France. Evidence from both human genetic studies and characterization of peroxisome proliferator-activated receptor gamma (PPARgamma) knockout mice suggested that the prime function of PPARgamma is fat formation and that its role in insulin sensitization might be secondary to this function. The thrifty function of PPARgamma was most likely evolutionary beneficial, but might in "times of plenty" contribute to the pathogenesis of disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, often commonly referred to as "syndrome X". This role of PPARgamma in these diseases also questions the eventual therapeutic benefits of pure PPARgamma activation, which is associated with an increase in adipose tissue mass. We characterized a new chemical class of PPARgamma agonists, that is, FMOC-l-leucine (FLL). FLL induces a different conformation of PPARgamma relative to classical PPARgamma ligands. Mass spectrometry indicates that two molecules of FLL bind to a single PPARgamma molecule, making its mode of receptor interaction distinctive. FLL recruits a different set of coactivators and activates PPARgamma with a lower potency, but a similar maximal efficacy, relative to known PPARgamma ligands. In contrast, FLL is a more effective insulin sensitizer than current PPARgamma agonists, an effect potentially linked to its weak adipogenic activity. These data make a strong point for potential therapeutic benefits of PPARgamma modulation rather than activation. PMID: 12079832 [PubMed - indexed for MEDLINE] 4803. Otolaryngol Head Neck Surg. 2002 May;126(5):512-7. Hydroxyapatite cement cranioplasty in translabyrinthine acoustic neuroma surgery. Arriaga MA(1), Chen DA. Author information: (1)Pittsburgh Ear Associates, Allegheny General Hospital Hearing and Balance Center, PA 15212, USA. OBJECTIVES: Hydroxyapatite cement cranioplasty (HAC) after translabyrinthine resection of acoustic neuroma is a promising new technique for wound reconstruction. This study reviews the efficacy of HAC for the prevention of cerebrospinal fluid (CSF) leakage and the long-term wound outcomes of HAC versus abdominal fat graft (AFG) reconstruction. METHODS: This retrospective study of l08 consecutive acoustic neuromas operated on by Pittsburgh Ear Associates uses chart review, telephone interview, and mail questionnaire data. Fifty-four patients received AFG dural repair, and 54 patients received HAC. RESULTS: Seven AFG patients (12.5%) had CSF leaks versus 2 (3.7%) of the overall group of 54 HAC patients. However, none (0%) of the 47 HAC patients had CSF leakage with current HAC techniques. HAC also produced significantly less postauricular wound depression and superior cosmetic results in comparison with AFG. Although HAC patients experienced less postoperative discomfort, wound complications requiring medical or surgical intervention were extremely uncommon in both groups. CONCLUSION: HAC offers significant CSF leakage control and long-term cosmetic and comfort advantages over AFG alone. We recommend HAC as the standard closure technique for translabyrinthine acoustic neuroma surgery. PMID: 12075225 [PubMed - indexed for MEDLINE] 4804. Clin Biochem. 2002 May;35(3):171-7. The molecular basis of genetic lipodystrophies. Bhayana S(1), Hegele RA. Author information: (1)Robarts Research Institute, London, Ontario, Canada. OBJECTIVES: Hyperinsulinemia is often associated with a cluster of metabolic abnormalities, which usually presents before the onset of frank diabetes. Lipodystrophy syndromes are frequently associated with hyperinsulinemia and may act as models for insulin resistance. Lipodystrophy is characterized in broad terms by loss of subcutaneous adipose tissue. Despite heterogeneous causes, which include both genetic and acquired forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes. RESULTS: Recently, the molecular basis of two genetic forms of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD; MIM 151660) and Berardinelli-Seip complete lipodystrophy (BSCL; MIM 269700) have been reported. There is evidence for genetic heterogeneity for both types of lipodystrophy. In addition, murine models of lipodystrophy have provided key insights into alterations of metabolic pathways in lipodystrophy. CONCLUSIONS: Delineation of the human molecular genetic basis of two distinct forms of inherited lipodystrophy may have relevance for the common insulin resistance syndrome and for acquired lipodystrophy syndromes. PMID: 12074822 [PubMed - indexed for MEDLINE] 4805. Proc Nutr Soc. 2001 Nov;60(4):527-37. Lactation and gestation in dairy cows: flexibility avoids nutritional extremes. Knight CH(1). Author information: (1)Hannah Research Institute, Ayr, UK. knightc@hri.sari.ac.uk The modern dairy cow has been selectively bred to produce large amounts of milk. Partly as a result, food consumption is considerably less than milk energy output in early lactation. It is only at 2 months or more postpartum that intake increases to the point where positive energy balance is regained, the initial production being achieved by a substantial mobilisation of body reserves. These reserves are laid down before parturition, but it is certainly not the case that the pregnant cow will accumulate adipose tissue recklessly; in the last third of pregnancy well-fed cows in good body condition exhibit reduced, not increased, appetite. There is a fine balancing act to perform. Excessive body condition at parturition quickly leads to metabolic problems such as ketosis, but cows who subsequently become too thin have increased risk of metabolic diseases such as mastitis and lameness. The biological mechanisms regulating output of milk are reasonably well understood, those controlling appetite less well so, and there has been little attempt at systematic integration of the two. The transition from pregnancy to lactation represents a major challenge to homeostasis, made more complicated in multiparous cows by the fact that much of gestation is concurrent with lactation. Herein lies the potential for nutritionally-entrained flexibility. In the wild, concurrent pregnancy and lactation only occur when nutritional conditions are favourable. If conditions are poor, rebreeding will be delayed and lactation will continue, at an energetically-sustainable level, for much longer than its 'normal' duration. In this way the twin energetic burdens of pregnancy and lactation are separated, and extremes are avoided. Given the increasing public concern about stresses suffered by intensively-managed dairy cows, this case may be one where commercial dairying could learn useful lessons from nature. PMID: 12069406 [PubMed - indexed for MEDLINE] 4806. J Reprod Immunol. 2002 May-Jun;55(1-2):21-33. Mechanisms of excessive estrogen formation in endometriosis. Bulun SE(1), Gurates B, Fang Z, Tamura M, Sebastian S, Zhou J, Amin S, Yang S. Author information: (1)Department of Obstetrics and Gynecology, University of Illinois at Chicago, 820 S. Wood St. M/C 808, Chicago, IL 60612, USA. sbulun@uic.edu Estrogen is produced in a number of human tissues including the ovary, placenta and extraglandular sites such as adipose tissue, skin and the brain. Aromatase is the key enzyme that regulates estrogen formation in these tissues. Aromatase activity is not detectable in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis and is stimulated by PGE(2). This results in local production of estrogen, which induces PGE(2) formation and establishes a positive feedback cycle. Another abnormality in endometriosis, i.e. deficient 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE(2) in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor. PMID: 12062819 [PubMed - indexed for MEDLINE] 4807. Vnitr Lek. 2002 Apr;48(4):349-52. [Obesity and disorders of the menstrual cycle]. [Article in Slovak] Lazúrová I(1), Dravecká I. Author information: (1)II. interná klinika Lekárskej fakulty UPJS a FNsP Kosice, Slovenská republika. Obesity, the result of combined genetic and environmental factors, is in recent decades one of the most frequent diseases and is encountered mainly in Europe and North America. In women it is associated with the risk of several diseases, such as diabetes mellitus, osteoarthritis, cardiovascular diseases, sleep apnoea syndromee, breast cancer, cancer of the uterus and also with impairment of reproductive functions. Already during the last century some observations confirmed that a very low or very high body weight is more frequently associated with disorders of the menstrual cycle (MC), infertility and poor reproductive capacity. However only during the last decades the pathophysiological and molecular mechanisms of this relationship were gradually elucidated. The main factors which influences the menstrual cycle in obesity are: impaired estrogen metabolism, changes in the concentration of sex hormone binding globulin, hyperinsulinaemia, and probably also leptin levels. PMID: 12061186 [PubMed - indexed for MEDLINE] 4808. Annu Rev Nutr. 2002;22:505-31. Epub 2002 Apr 4. Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action. Belury MA(1). Author information: (1)Department of Molecular Medicine, Northwest Hospital, 21720 23rd Drive SE, Bothell, Washington 98021, USA. Belury@u.washington.edu Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health. PMID: 12055356 [PubMed - indexed for MEDLINE] 4809. Annu Rev Nutr. 2002;22:383-415. Epub 2002 Apr 4. Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. Hajri T(1), Abumrad NA. Author information: (1)Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York, 11794-8661, USA. thajri@dualphy.pnb.sunysb.edu Long-chain fatty acids are an important constituent of the diet and they contribute to a multitude of cellular pathways and functions. Uptake of long-chain fatty acids across plasma membranes is the first step in fatty acid utilization, and recent evidence supports an important regulatory role for this process. Although uptake of fatty acids involves two components, passive diffusion through the lipid bilayer and protein-facilitated transfer, the latter component appears to play the major role in mediating uptake by key tissues. Identification of several proteins as fatty acid transporters, and emerging evidence from genetically altered animal models for some of these proteins, has contributed significant insight towards understanding the limiting role of transport in the regulation of fatty acid utilization. We are also beginning to better appreciate how disturbances in fatty acid utilization influence general metabolism and contribute to metabolic pathology. PMID: 12055351 [PubMed - indexed for MEDLINE] 4810. Annu Rev Nutr. 2002;22:325-46. Epub 2002 Jan 4. Muscle triglyceride and insulin resistance. Kelley DE(1), Goodpaster BH, Storlien L. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. Kelley@msx.dept-med.pitt.edu Skeletal muscle contains the majority of the body's glycogen stores and a similar amount of readily accessible energy as intramyocellular triglyceride (imTG). While a number of factors have been considered to contribute to the pathogenesis of insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM), this review will focus on the potential role of skeletal muscle triglyceride content. In obesity and type 2 DM, there is an increased content of lipid within and around muscle fibers. Changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, almost certainly contribute to accumulation of imTG and to the pathogenesis of both obesity and type 2 DM. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in type 2 DM and obesity, skeletal muscle manifests inflexibility in the transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle appears to be related to the accumulation of imTG and is an important aspect of IR of skeletal muscle in obesity and type 2 DM. PMID: 12055349 [PubMed - indexed for MEDLINE] 4811. Annu Rev Nutr. 2002;22:167-97. Epub 2002 Jan 4. PPAR(gamma) and glucose homeostasis. Picard F(1), Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, B.P. 163, F-67404 Illkirch, C.U. de Strasbourg, France. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor involved in the control of metabolism. Research on PPARgamma is oriented towards understanding its role in insulin sensitization, which was inspired by the discovery that antidiabetic agents, the thiazolidinediones, were agonists for PPARgamma. PPARgamma stimulation improves glucose tolerance and insulin sensitivity in type 2 diabetic patients and in animal models of insulin resistance through mechanisms that are incompletely understood. Upon activation, PPARgamma heterodimerizes with retinoid X receptor, recruits specific cofactors, and binds to responsive DNA elements, thereby stimulating the transcription of target genes. Because PPARgamma is highly enriched in adipose tissue and because of its major role in adipocyte differentiation, it is thought that the effects of PPARgamma in adipose tissue are crucial to explain its role in insulin sensitization, but recent studies have highlighted the contribution of other tissues as well. Although relatively potent for their insulin-sensitizing action, currently marketed PPARgamma activators have some important undesirable side effects. These concerns led to the discovery of new ligands with potent antidiabetic properties but devoid of certain of these side effects. Data from human genetic studies and from PPARgamma heterozygous knockout mice indicate that a reduction in PPARgamma activity could paradoxically improve insulin sensitivity. These findings suggest that modulation of PPARgamma activity by partial agonists or compounds that affect cofactor recruitment might hold promise for the treatment of insulin resistance. PMID: 12055342 [PubMed - indexed for MEDLINE] 4812. Annu Rev Nutr. 2002;22:1-17. Epub 2002 Jan 4. Body composition of the male and female reference infants. Fomon SJ(1), Nelson SE. Author information: (1)Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242-1083, USA. samfomon@aol.com During infancy, especially early infancy, a substantial proportion of the requirements for energy and specific nutrients are those needed for growth. Knowledge of the body composition of a reference infant (body size and chemical composition at the 50th centile for age) permits an estimate of the growth needs of the infant. In this communication, we review efforts from the 1960s to the present at defining the composition of the male and female reference infants. We and others have demonstrated that accumulation of fat is remarkably rapid during the first 4 or 6 months of life. As a percentage of fat-free mass, water decreases throughout infancy whereas protein and minerals increase. However, the quantitative nature of these changes remains uncertain. After identifying the areas in which further data are needed, we conclude that the single most important area for further work is determining the relation of "bone mineral content" determined by dual energy X-ray absorptiometry to the osseous mineral content of the infant. PMID: 12055335 [PubMed - indexed for MEDLINE] 4813. Biochem Biophys Res Commun. 2002 May 17;293(4):1145-52. The role of uncoupling proteins in pathophysiological states. Argilés JM(1), Busquets S, López-Soriano FJ. Author information: (1)Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. argiles@porthos.bio.ub.es Until very recently, the uncoupling protein-1 (UCP1), present only in brown adipose tissue (BAT), was considered to be the only mitochondrial carrier protein that stimulated heat production by dissipating the proton gradient generated during respiration across the inner mitochondrial membrane and therefore uncoupling respiration from ATP synthesis. Recently, new uncoupling proteins, UCP2, UCP3, and UCP4, and brain mitochondrial carrier protein-1 (BMCP-1) have been described in mammalian tissues. The present review deals with the possible role of these proteins in different pathological conditions involving alterations in energy balance such as obesity or cachexia. In conclusion, the emergence of the UCP family has altered the approaches to bioenergetics and stressed the importance of uncoupling respiration in different pathophysiological conditions. An extensive qualitative and quantitative characterization of the new members of the UCP family in mammalian tissues will allow a better understanding of the molecular and regulatory mechanisms of thermogenesis and energy metabolism. At this point, we hope that the knowledge presented in the present review will not only stimulate a debate about the role of the UCP family in disease but also lead to applications beneficial for human health. (c) 2002 Elsevier Science (USA). PMID: 12054495 [PubMed - indexed for MEDLINE] 4814. Rev Invest Clin. 2002 Mar-Apr;54(2):161-5. [Leptin]. [Article in Spanish] Sabath Silva EF(1). Author information: (1)esabath@yahoo.com Leptin is a hormone secreted by adipocytes, stomach and placenta. Age, sex, puberty onset and food intake are the most important physiological factors that determines leptin concentration. It has been shown that leptin secretion is regulated by other hormones such as insulin, glucocorticoids and sex steroids. Leptin has an important role in hungry and satiety regulation as well as in normal sexual maturation. There have been some studies in obese subjects showing promising results with leptin administration. PMID: 12053815 [PubMed - indexed for MEDLINE] 4815. Horm Res. 2002;57(5-6):145-52. The aromatase cytochrome P-450 and its clinical impact. Meinhardt U(1), Mullis PE. Author information: (1)University Children's Hospital, Inselspital, Bern, Switzerland. Cytochrome P-450 aromatase (P450arom), the key enzyme for estrogen biosynthesis, is encoded by a single gene, namely the CYP19 gene, localized on 15q21.2. The human CYP19 gene spans about 123 kb with a coding region of 9 exons (about 30 kb, exon II-exon X). Although there are a number of alternative first exons and nine different transcriptional start sides with individual promoters that permit tissue-specific regulation of expression, the protein expressed in these various tissue sites (placenta, adipose tissue, brain, bone, ovary, etc.) is the same regardless of the promoter used. P450arom catalyzes the conversion of testosterone to estradiol, of androstenedione to estrone, and of 16alpha-hydroxylated dehydroepiandrosterone to estriol. As not only androgens but also estrogens are of importance, particularly in the male pubertal development, including bone changes which were classically considered mostly androgen dependent, the features of the aromatase deficiency syndrome in affected boys and girls as well as adult males and females are discussed. There is growing awareness that androgens and estrogens have general metabolic roles that reach far beyond reproductive processes. For instance, estrogen has a significant impact on carbohydrate and lipid metabolism, vascular function, and arteriosclerosis. In addition, extragonadal estrogen biosynthesis plays an important but often underestimated physiological and pathophysiological role, for example in breast cancer and endometriosis. Based on that knowledge, progress has been made as far as treatment and follow-up of these disorders are concerned. In addition, there is a focus on the treatment of children suffering from a lack of P450arom activity. Copyright 2002 S. Karger AG, Basel PMID: 12053085 [PubMed - indexed for MEDLINE] 4816. Curr Pharm Des. 2002;8(14):1199-227. The impact of fatty acid oxidation on energy utilization: targets and therapy. Bebernitz GR(1), Schuster HF. Author information: (1)Novartis Pharmaceuticals Corporation, Novartis Institute for Biomedical Research, Metabolic and Cardiovascular Diseases Department, Summit, NJ 07901, USA. greg.bebernitz@pharma.novartis.com Utilization of fat as a long-term energy storage vehicle is crucial for the maintenance of cellular metabolism and is under intricate and many times redundant control mechanisms. Aberrations in the control of energy metabolism is apparent in diseases such as diabetes and obesity and is evident early on in patients with impaired glucose tolerance. Insulin resistance has been observed at the level of muscle, liver and adipose tissue. Hyperglycemia is the hallmark of diabetes and is characterized by decreased glucose disposal and increased glucose production, driven by enhanced and uncontrolled fatty acid oxidation (FAO). Mechanisms aimed at limiting the availability of substrates or the activity of processes involved in FAO should provide an immediate reduction in undesired glucose production in these individuals. Numerous targets are available which influence directly the metabolism of fat, including limiting availability of substrate to FAO, inhibiting oxidation of the fatty acid per se, and uncoupling the energy obtained during the oxidation of the fatty acid. These include antilipolytic agents which limit the availability of substrate, FAO inhibitors which limit fatty acid transport (carnitine palmitoyl transferase, CoA sequestration), FAO per se (beta oxidation), and agents which uncouple the energy of FAO (uncoupling proteins, beta3 agonists). These other targets which affect fatty acid metabolism indirectly will be discussed in this review with 184 references. PMID: 12052217 [PubMed - indexed for MEDLINE] 4817. RCM Midwives J. 2002 May;5(5):193-5. Pregnancy as a cause of obesity--myth or reality? Soltani H(1), Fraser R. Author information: (1)Maternity and Gynaecology Audit and Research Department, Derby City General Hospital. PMID: 12046195 [PubMed - indexed for MEDLINE] 4818. Curr Opin Lipidol. 2002 Jun;13(3):295-304. Metabolic effects of thia fatty acids. Berge RK(1), Skorve J, Tronstad KJ, Berge K, Gudbrandsen OA, Grav H. Author information: (1)Department of Clinical Biochemistry, Haukeland Hospital, University of Bergen, Norway. rolf.berge@ikb.uib.no Thia substituted fatty acids are saturated fatty acids which are modified by insertion of a sulfur atom at specific positions in the carbon backbone. During the last few years pleiotropic effects of the 3-thia fatty acid tetradecylthioacetic acid have been revealed. The biological responses to tetradecylthioacetic acid include mitochondrial proliferation, increased catabolism of fatty acids, antiadiposity, improvement in insulin sensitivity, antioxidant properties, reduced proliferation and induction of apoptosis in rapidly proliferating cells, cell differentiation and antiinflammatory action. These biological responses indicate that tetradecylthioacetic acid changes the plasma profile from atherogenic to cardioprotective. As a pan-peroxisome proliferator-activated receptor ligand, tetradecylthioacetic acid regulates the adipose tissue mass and the expression of lipid metabolizing enzymes, particularly those involved in catabolic pathways. In contrast, circumstantial evidences suggest that peroxisome proliferator-activated receptor-independent metabolic pathways may be of importance for the antioxidant, antiproliferative and antiinflammatory action of tetradecylthioacetic acid. PMID: 12045400 [PubMed - indexed for MEDLINE] 4819. Curr Opin Lipidol. 2002 Jun;13(3):241-5. New factors in the regulation of adipose differentiation and metabolism. Holst D(1), Grimaldi PA. Author information: (1)Institute of Signaling, Developmental Biology and Cancer, Center for Biochemistry, UFR Sciences, Parc Valrose, Nice, France. Obesity and lipoatrophy are major risks for insulin resistance, type 2 diabetes and cardiovascular diseases. The molecular links between adipocyte dysfunction and metabolic disorders were elusive until the discovery that adipose tissue operates as an endocrine organ and releases factors targeting a wide range of organs. This article attempts to review the more recent advances from research on the transcriptional control of adipogenesis and on new adipocyte-secreted proteins that have been proposed as molecular links between adipose tissue and insulin resistance. PMID: 12045392 [PubMed - indexed for MEDLINE] 4820. Med J Aust. 2002 Apr 15;176(8):381-6. Thiazolidinediones and type 2 diabetes: new drugs for an old disease. O'Moore-Sullivan TM(1), Prins JB. Author information: (1)Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD. tomoore@medicine.pa.uq.edu.au Erratum in Med J Aust 2002 Oct 7;177(7):396. Thiazolidinediones are a new class of drugs for the treatment of type 2 diabetes, and act by improving insulin sensitivity in adipose tissue, liver and skeletal muscle. Rosiglitazone and pioglitazone are registered for use in monotherapy, and in combination with sulfonylureas and metformin. Pioglitazone is also licensed for use in combination with insulin. There is level II evidence that in patients with inadequate glycaemic control both drugs reduce the level of HbA1c and fasting plasma glucose (FPG) when used as monotherapy and in combination with sulfonylurea or metformin or insulin; and both drugs increase levels of HDL and LDL and lower free fatty acid levels, but only pioglitazone significantly lowers triglyceride levels. Both drugs lower fasting insulin and C-peptide levels. In monotherapy, they may be slightly less potent at reducing the level of HbA1c than sulfonylureas or metformin. The maximal effect of these agents may not be seen for 6-14 weeks after commencement. Both drugs are well tolerated but liver function must be checked at baseline every second month for the first year, and periodically thereafter. The drugs are currently contraindicated in patients with moderate to severe liver dysfunction and alanine aminotransferase levels more than 2.5 times normal, New York Heart Association III-IV cardiac status, pregnancy, lactation and in children. The main side effects include weight gain, oedema, and mild dilutional anaemia. PMID: 12041635 [PubMed - indexed for MEDLINE] 4821. Int J Obes Relat Metab Disord. 2002 Jun;26(6):747-53. Upper abdominal obesity, insulin resistance and breast cancer risk. Stoll BA(1). Author information: (1)Oncology Department, St Thomas' Hospital, London, UK. PURPOSE: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. MECHANISMS: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. CONCLUSION: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations. PMID: 12037643 [PubMed - indexed for MEDLINE] 4822. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 2):1S41-4. [Glitazones and weight gain]. [Article in French] Scheen A(1). Author information: (1)Service de Diabétologie, Nutrition et Maladies métaboliques, Département de Médecine, CHU Sart Tilman, B-4000 Liège, Belgique. PMID: 12037507 [PubMed - indexed for MEDLINE] 4823. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 2):1S19-22. [PPARgamma and insulin resistance]. [Article in French] Girard J(1). Author information: (1)Endocrinologie et Métabolisme, Faculté de Médecine Cochin, F - 75014 Paris, France. The thiazolidinediones (TZD), a new class of oral antidiabetic agent, act by improving insulin sensitivity. TZD correct hyperglycemia and hyperinsulinism in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorbtive glycemia and insulinemia. Glucose clamp studies have clearly shown a 30% improvement of insulin-induced glucose utilisation in skeletal muscle. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator-Activated Receptor). PPARgamma is a transcription factor which, after heterodimerisation with the retinoid receptor (RXR), binds to specific response elements of a number of target genes, and control their transcription. How TZD, with their principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin and skeletal muscles contain only a limited amount of PPARgamma! This is the paradox to which we attempt to answer. PMID: 12037503 [PubMed - indexed for MEDLINE] 4824. Exp Biol Med (Maywood). 2002 Jun;227(6):363-76. Seasonal changes in adiposity: the roles of the photoperiod, melatonin and other hormones, and sympathetic nervous system. Bartness TJ(1), Demas GE, Song CK. Author information: (1)Department of Biology and of Psychology, Neurobiology and Behavior Program, Georgia State University, Atlanta, Georgia 30303, USA. bartness@gsu.edu It appears advantageous for many non-human animals to store energy body fat extensively and efficiently because their food supply is more labile and less abundant than in their human counterparts. The level of adiposity in many of these species often shows predictable increases and decreases with changes in the season. These cyclic changes in seasonal adiposity in some species are triggered by changes in the photoperiod that are faithfully transduced into a biochemical signal through the nightly secretion of melatonin (MEL) via the pineal gland. Here, we focus primarily on the findings from the most commonly studied species showing seasonal changes in adiposity-Siberian and Syrian hamsters. The data to date are not compelling for a direct effect of MEL on white adipose tissue (WAT) and brown adipose tissue (BAT) despite some recent data to the contrary. Thus far, none of the possible hormonal intermediaries for the effects of MEL on seasonal adiposity appear likely as a mechanism by which MEL affects the photoperiodic control of body fat levels indirectly. We also provide evidence pointing toward the sympathetic nervous system as a likely mediator of the effects of MEL on short day-induced body fat decreases in Siberian hamsters through increases in sympathetic drive on WAT and BAT. We speculate that decreases in the SNS drive to these tissues may underlie the photoperiod-induced seasonal increases in body fat of species such as Syrian hamsters. Clearly, we need to deepen our understanding of seasonal adiposity, although, to our knowledge, this is the only form of environmentally induced changes in body fat where the key elements of its external trigger have been identified and can be traced to and through their transduction into a physiological stimulus that ultimately affects identified responses of white adipocyte physiology and cellularity. Finally, the comparative physiological approach to the study of seasonal adiposity seems likely to continue to yield significant insights into the mechanisms underlying this phenomenon and for understanding obesity and its reversal in general. PMID: 12037125 [PubMed - indexed for MEDLINE] 4825. Pharmacoeconomics. 2002;20 Suppl 1:1-9. New solutions for type 2 diabetes mellitus: the role of pioglitazone. Grossman LD(1). Author information: (1)Associate Vice President, Clinical Research, Eli Lilly, Canada. GROSSMAN_LOREN@LILLY.COM Type 2 diabetes mellitus remains a significant burden to the Canadian healthcare system. Over 2 million Canadians have diabetes, with 85 to 90% having type 2 diabetes. Insulin resistance is a major pathophysiological mechanism in the development of type 2 diabetes. Insulin resistance can be defined as an impaired biological response to the metabolic and/or mitogenic effects of either exogenous or endogenous insulin. As a consequence of insulin resistance, type 2 diabetes is characterised by decreased glucose transport and utilisation at the level of muscle and adipose tissue and increased glucose production by the liver. The traditional oral agents used to treat type 2 diabetes clearly do not address the underlying insulin resistance responsible for the development of diabetes. Thiazolidinediones (TZDs) represent a relatively new class of oral hypoglycaemic medications that have been shown to reverse some of the metabolic processes believed responsible for the development of insulin resistance and, ultimately, type 2 diabetes. Research has demonstrated that TZDs activate peroxisome proliferator activator receptors, in particular, the gamma-receptor isoform. Pioglitazone is a TZD that reduces plasma glucose levels by increasing peripheral glucose utilisation and decreasing hepatic glucose production. Clinical studies with pioglitazone have demonstrated the following: absolute reductions in glycosylated haemoglobin of 0.8 to 2.6%; reductions in fasting plasma glucose of 1.7 to 4.4 mmol/L; an increase in high density lipoprotein cholesterol of 8.7 to 12.6%; and a decrease in triglycerides of 18.2 to 26.0%, with no significant effects on low density lipoprotein or total cholesterol. PMID: 12036379 [PubMed - indexed for MEDLINE] 4826. J Lipid Res. 2002 Jun;43(6):835-60. Understanding adipose tissue development from transgenic animal models. Valet P(1), Tavernier G, Castan-Laurell I, Saulnier-Blache JS, Langin D. Author information: (1)INSERM Unit 317, Louis Bugnard Institute, Paul Sabatier University, Bldg. L3, Rangueil University Hospital, 31403 Toulouse Cedex 4, France. valet@toulouse.inserm.fr The World Health Organization has recognized obesity as a health problem of pandemic proportions. Recent work led to major breakthroughs in the understanding of the molecular basis of adipose tissue development with the cloning and characterization of numerous genes involved in fat cell differentiation and metabolism. Transgenesis has proved very useful in establishing the physiological roles of these genes. Here we review transgenic models made to study adipose tissue's metabolic and trophic responses. Genetic modifications unexpectedly associated to alterations of adipose tissue development are also examined because of their potential involvement in obesity and energy balance regulation. After a description of the methodologies commonly used, we review the data obtained on transcription factors, metabolism, signal transduction, secreted products, and models of lipodystrophy. An overview of such integrative studies leads to a better understanding of the physiology of adipose tissue development. Alterations in expression levels of proteins involved at different steps of a regulatory pathway highlight the complementary roles of genes in the regulation of adipose tissue development. However, lack of phenotypes also illustrates the capacity of animals to set up adaptive mechanisms. PMID: 12032159 [PubMed - indexed for MEDLINE] 4827. Nutr Rev. 2002 May;60(5 Pt 1):148-51. Glucocorticoids in adipocytes stimulate visceral obesity. Wolf G(1). Author information: (1)Department of Nutritional Sciences and Toxicology, University of California, Berkeley 94720-3104, USA. The enzyme 11beta hydroxysteroid dehydrogenase-1 (11beta HSD-1) regenerates active glucocorticoids from inactive glucocorticoids. When over-expressed in adipose tissue, this enzyme was shown to promote increased visceral adipose levels. The resulting visceral obesity was associated with insulin-resistant diabetes and dyslipidemia. Increased adipocyte 11beta HSD-1 is a possible cause of visceral obesity in humans. PMID: 12030279 [PubMed - indexed for MEDLINE] 4828. Eur J Clin Invest. 2002 Jun;32 Suppl 3:24-34. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Greenberg AS(1), McDaniel ML. Author information: (1)Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University and the Division of Endocrinology, Tupper Research Institute, New England Medical Center, Boston MA, USA. A combination of insulin resistance and pancreatic beta-cell dysfunction underlies most cases of type 2 diabetes. While the interplay of these two impairments is believed to be important in the development and progression of type 2 diabetes, the mechanisms involved are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) have deleterious effects on both glucose homeostasis and beta-cell function, and can disrupt insulin signalling pathways in both pancreatic beta cells and liver and adipose tissue. The anti-inflammatory activity of the thiazolidinedione anti-diabetic agents is potentially beneficial, given the possible role of pro-inflammatory cytokines in linking insulin resistance with beta-cell dysfunction. PMID: 12028372 [PubMed - indexed for MEDLINE] 4829. Eur J Clin Invest. 2002 Jun;32 Suppl 3:3-13. Molecular insights into insulin action and secretion. Rhodes CJ(1), White MF. Author information: (1)Pacific Northwest Research Institute & Department of Pharmacology, University of Washington, 720 Broadway, Seattle, WA 98122, USA. Tightly co-ordinated control of both insulin action and secretion is required in order to maintain glucose homeostasis. Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. beta-cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and beta-cell mass. While signalling molecules play important roles in insulin action and secretion under normal circumstances, abnormal insulin signalling in muscle, adipose tissue, liver and pancreas leads to insulin resistance and beta-cell dysfunction. In particular, the signalling protein IRS-2 may have a central role in linking these abnormalities, although other factors are likely to be involved. PMID: 12028370 [PubMed - indexed for MEDLINE] 4830. Adv Exp Med Biol. 2002;503:17-25. The milky way: from mammary gland to milk to newborn--Macy-Gyorgy Award presentation (1999). Hamosh M(1). Author information: (1)Georgetown University Medical Center, Department of Pediatrics, Washington, DC 20007, USA. phamosh@excite.com PMID: 12026017 [PubMed - indexed for MEDLINE] 4831. Biochem Soc Trans. 2002 Apr;30(2):270-5. Adipose tissue, the immune system and exercise fatigue: how activated lymphocytes compete for lipids. Pond CM(1). Author information: (1)Department of Biological Sciences, The Open University, Milton Keynes, MK7 6AA, U.K. C.M.Pond@open.ac.uk Adipose depots that contain lymph nodes, and probably intermuscular fat in skeletal and cardiac muscle, are specialized to provision adjacent tissue in a paracrine mode. Perinodal adipocytes respond selectively to various cytokines and incorporate proportionately more polyunsaturated fatty acids. Lipolysis in the adipocytes of node-containing depots can be stimulated via inflammation of the enclosed lymph nodes. Repeated immune stimulation elicits properties characteristic of perinodal adipocytes in those elsewhere in the same depot, and hours later in other node-containing depots, but not in nodeless depots. Such site-specific properties of adipose tissue enable partitioning of dietary and metabolic supplies of fatty acids between competing tissues. Local interactions emancipate the peripheral immune system from competing with other tissues for lipids during immune responses, and may be especially important during periods of high demand, such as strenuous exercise. Biopsies of subcutaneous adipose tissue from sites remote from lymph nodes do not adequately represent the composition of fatty acids available to the immune system in situ, and perhaps that supplied to other tissues. Intermuscular fat in skeletal and cardiac muscle may also indicate paracrine relationships between adipocytes and "end-user" tissues. The concept of paracrine interactions between certain adipocytes and "user" tissue may account for the widespread contiguity between these tissues in vivo. PMID: 12023863 [PubMed - indexed for MEDLINE] 4832. J Pediatr Endocrinol Metab. 2002 Apr;15 Suppl 1:487-92. Insulin resistance in childhood obesity. Caprio S(1). Author information: (1)Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510, USA. Sonia.Caprio@Yale.edu The prevalence of childhood obesity is on the rise in the USA. Approximately 20% of children and adolescents are overweight, as defined by a body mass index (BMI) greater than the 85th percentile. We describe a series of studies that has elucidated the impact of both childhood and adolescent obesity on glucose and lipid metabolism in vivo. We used magnetic resonance imaging to quantify the abdominal, visceral and subcutaneous fat depots, together with the insulin and glucose clamping techniques, to assess alterations in insulin action and secretion early in the course of obesity. PMID: 12017221 [PubMed - indexed for MEDLINE] 4833. Cells Tissues Organs. 2002;171(1):90-5. Human mesenchymal stem cells: insights from a surrogate in vivo assay system. MacKenzie TC(1), Flake AW. Author information: (1)The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, Pa. 19104, USA. Mesenchymal stem cells (MSC) are multipotent cells that have been isolated from the bone marrow of multiple species that can be induced to differentiate into at least bone, cartilage, and adipose tissue in vitro. Using a model of in utero cellular transplantation in which human MSC are transplanted into fetal lambs, we have shown that MSC can engraft in multiple tissues and persist for over one year. Furthermore, these cells can differentiate into cardiac and skeletal myocytes, bone marrow stromal cells, adipocytes, thymic epithelial cells, and chondrocytes. These observations lend support to the potential utility of MSC for cellular and/or gene therapy in the treatment of a variety of congenital or acquired diseases such as osteogenesis imperfecta, muscular dystrophy, lysosomal storage diseases, and for enhancement of bone marrow transplantation. Copyright 2002 S. Karger AG, Basel PMID: 12021494 [PubMed - indexed for MEDLINE] 4834. News Physiol Sci. 2002 Jun;17:99-104. Cross talk between adipose tissue cells: impact on pathophysiology. Schling P(1), Löffler G. Author information: (1)Institut für Biochemie, Genetik und Mikrobiologie, Universität Regensburg, 93053 Regensburg, Germany. The metabolic functionality of adipose tissue is intimately dependent on local communication between various cell types. It influences not only the equilibrium between lipogenesis and lipolysis but also between hypertrophic and hyperplastic growth, thereby determining the role adipose tissue plays in the insulin resistance syndrome. PMID: 12021379 [PubMed - indexed for MEDLINE] 4835. Klin Padiatr. 2002 May-Jun;214(3):99-103. [Lipodystrophies]. [Article in German] Fischer-Posovszky P(1), Debatin KM, Wabitsch M. Author information: (1)Universitätskinderklinik und Poliklinik, Ulm, Germany. The lipodystrophy syndromes are rare disorders characterized by the loss of adipose tissue. The loss of fat tissue can have genetic, immune, or infectious/drug-associated causes. With the extent of fat loss metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver increase in severity. Lipodystrophies can be divided into two subtypes: familial and acquired. Causative mutations have recently been identified in one form of familial lipodystrophy as well as in one form of acquired lipodystrophy. Several mouse models might help understanding the development of these syndrome. In this review article, the recently introduced classification of lipodystrophy syndromes is presented as well as new insights into pathogenesis and therapeutic strategies. PMID: 12015640 [PubMed - indexed for MEDLINE] 4836. Ann Med. 2002;34(1):5-18. The role of leptin in reproduction: experimental and clinical aspects. Baldelli R(1), Dieguez C, Casanueva FF. Author information: (1)Department of Medicine, Santiago de Compostela University and Complejo Hospitalario Universitario de Santiago, Spain. The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and future treatment as well as our understanding of energy homeostasis in man. In addition to its relevant role as a metabolic adaptor to overweight and fasting states, new and previously unsuspected neuroendocrinological roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation and appears as a permissive factor for puberty. In particular, various sets of data suggest that leptin may serve as a signal to the central nervous system (CNS) with information on the critical amount of adipose tissue stores that is necessary for gonadotropin-releasing hormone (GnRH) secretion and pubertal activation of the hypothalamic-pituitary-gonadal axis. Leptin also acts at the periphery, directly on the ovary and testis where it may control steroidogenesis, although the exact role of intragonadal action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated. Furthermore, relevant gender-based differences in leptin levels exist, with higher levels in women, even at birth, and which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the menstrual cycle, with a regulatory role exerted at hypothalamic, pituitary and gonadal levels, and with severe changes in pregnancy and postpartum. Moreover, leptin is present in both human and commercial milk, and may play a role in the adaptive responses of the newborn. PMID: 12014435 [PubMed - indexed for MEDLINE] 4837. Eur J Pharmacol. 2002 Apr 12;440(2-3):255-68. Galanin/GALP and galanin receptors: role in central control of feeding, body weight/obesity and reproduction? Gundlach AL(1). Author information: (1)Howard Florey Institute of Experimental Physiology and Medicine, and Department of Medicine, Austin and Repatriation Medical Centre, The University of Melbourne, Victoria, 3010, Australia. a.gundlach@hfi.unimelb.edu.au Scientific and commercial pharmacological interest in the role of galanin and galanin receptors in the regulation of food intake, energy balance, and obesity has waned recently, following initial enthusiasm during the 1980-1990s. It has been replaced by efforts to understand the role of newly discovered peptide systems such as the hypocretin/orexins, melanocortins and cocaine- and amphetamine-regulated transcript (CART) and their relationship to the important hormones, leptin and insulin. Thus, while numerous studies have revealed the ability of galanin to stimulate food intake via actions at sites within the hypothalamus, and shown reliable changes in hypothalamic galanin synthesis in response to food ingestion; findings including the lack of a 'body weight/obesity' phenotype in galanin transgenic mouse strains and a lack of agonists/antagonists for galanin receptor subtypes have probably served to reduce enthusiasm. However, as more is learnt about the general and galanin-related neurochemistry of brain pathways involved in feeding, metabolism and body weight control, the potential importance of galanin systems is again in focus. Studies of the newly discovered galanin family peptide, 'galanin-like peptide' (GALP), highlight the likely role of galanin peptides and receptors in the physiological coupling of body weight, adiposity and reproductive function. GALP is produced by a discrete population of neurons within the basomedial arcuate nucleus (and median eminence) that send projections to the anterior paraventricular nucleus and that make close contacts with leutinizing hormone-releasing hormone (LHRH) neurons in basal forebrain. Furthermore, GALP neurons express leptin receptors and respond to leptin treatment by increasing their expression of GALP mRNA. Centrally administered GALP activates LHRH-immunoreactive neurons and increases plasma LH levels. These findings suggest a direct stimulatory action of endogenous GALP on gonadotropin secretion via actions within the hypothalamus/basal forebrain, with leptin actions linking this system to body adipose levels. PMID: 12007540 [PubMed - indexed for MEDLINE] 4838. Eur J Pharmacol. 2002 Apr 12;440(2-3):223-34. Peroxisome proliferator activated receptors and obesity. Kersten S(1). Author information: (1)Nutrition, Metabolism and Genomics Group, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands. sander.kersten@staff.nutepi.wau.nl The peroxisome proliferator activated receptors (PPARs) are a group of ligand-activated transcription factors that govern numerous biological processes, including energy metabolism, cell proliferation, and inflammation. Three different PPAR isotypes can be distinguished: alpha, beta and gamma. PPARalpha is mainly present in liver where it has an important role in the regulation of nutrient metabolism, including fatty acid oxidation, gluconeogenesis, and amino acid metabolism. It mediates the effects of fibrates, which are drugs used in the treatment of hyperlipidemia, on DNA transcription. Little is still known about PPARbeta. The PPARgamma isotype is mainly expressed in adipose tissue where it stimulates adipogenesis and lipogenesis. It is the target of a group of anti-diabetic drugs called thiazolidinediones. As PPARs have a very important role in the regulation of energy metabolism, and as their activity can be modulated by drugs, there is an increasing interest in the potential connection between PPARs and obesity. In this article, the diverse pieces of evidence that have linked PPARs with obesity are reviewed. Furthermore, the association between PPARs and type 2 diabetes is discussed. PMID: 12007538 [PubMed - indexed for MEDLINE] 4839. Eur J Pharmacol. 2002 Apr 12;440(2-3):213-21. ACRP30, a new hormone controlling fat and glucose metabolism. Tsao TS(1), Lodish HF, Fruebis J. Author information: (1)Whitehead Institute for Biomedical Research, Cambridge, MA 02142-1479, USA. Adipocyte complement-related protein of 30 kDa (ACRP30) is a secreted serum protein expressed exclusively in differentiated adipocytes. Recent studies have indicated that its expression and serum levels are reduced in humans and animals with obesity and insulin resistance. Metabolic studies have demonstrated a role for ACRP30 in the regulation of glucose and lipid homeostasis. This review will describe the current literature on the biochemistry of ACRP30 and its physiological functions. We will also discuss issues that are relevant to the directions of future research. PMID: 12007537 [PubMed - indexed for MEDLINE] 4840. Eur J Pharmacol. 2002 Apr 12;440(2-3):159-72. Ups and downs for neuropeptides in body weight homeostasis: pharmacological potential of cocaine amphetamine regulated transcript and pre-proglucagon-derived peptides. Larsen PJ(1), Vrang N, Tang-Christensen M, Jensen PB, Hay-Schmidt A, Rømer J, Bjerre-Knudsen L, Kristensen P. Author information: (1)Laboratory of Obesity Research, Center for Clinical and Basic Research, Ballerup Byvej 222, 2750, Denmark. pjl@ccbr.dk Although most humans experience an underlying upwards drift of the body-weight set-point, body weight appears tightly regulated throughout life. The present review describes the structural basis of the adipostat and hypothesise, which components may constitute available targets for pharmacotherapy of excess body weight. Hypothalamic neurones constitute the major components of the body weight homeostasis maintaining device. Together with neurones of the nucleus of the solitary tract, neurones of the hypothalamic arcuate nucleus constitute the sensory components of the adipostat. The arcuate nucleus neurones respond to circulating levels of leptin and insulin, both of which reflect the levels of energy stored as triacylglycerol in adipocytes. The arcuate nucleus projects heavily to the hypothalamic paraventricular nucleus. Neurones of the hypothalamic paraventricular nucleus are hypothesised to constitute, at least partly, the adipostat motor pattern generator, which upon stimulation activates either net anabolic or catabolic physiological responses. The overall sensitivity of the adipostat is influenced by gain setting neurones hypothesised to be located in the dorsomedial hypothalamic nucleus and lateral hypothalamic area. Cocaine amphetamine regulated transcript (CART) peptides and pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are catabolic neurotransmitters synthesised in neurones of the arcuate nucleus and the nucleus of the solitary tract, respectively. The present review summarises the available evidence that both families of peptides constitute endogenous transmitters mediating satiety and touch upon potential pharmacological exploitation of this knowledge. PMID: 12007533 [PubMed - indexed for MEDLINE] 4841. Eur J Pharmacol. 2002 Apr 12;440(2-3):99-107. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. Arch JR(1). Author information: (1)GlaxoSmithKline, New Fontiers Science Park-North, Coldharbour Road, Harlow, Essex CM19 5AD, UK. jon.arch@buckingham.ac.uk beta(3)-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. beta(3)-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, beta(3)-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify beta(3)-adrenoceptor agonist drugs because the pharmacology of both beta(3)- and beta(1)-adrenoceptors can vary; near absolute selectivity is needed to avoid beta(1/2)-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. beta(3)-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling. PMID: 12007528 [PubMed - indexed for MEDLINE] 4842. Usp Fiziol Nauk. 2002 Apr-Jun;33(2):3-16. [Neuroimmunoendocrinology of the fat tissue]. [Article in Russian] Akmaev IG(1), Sergeev VG. Author information: (1)Russian Endokrinology Research Center, Moscow. Recent information concerning the white fat tissue allows considering it as endocrine system involved in the neuro-immune-endocrine interactions in regulating various aspects of homeostasis. The contribution presented sums up the latest evidence of adipocyte secreting hormones (leptine and resistine), cytokine (TNF alpha), as well as shedlight on mechanisms, involved in control of energy metabolism, immune reactions and food intake monitoring. PMID: 12004575 [PubMed - indexed for MEDLINE] 4843. Usp Fiziol Nauk. 2002 Apr-Jun;33(2):17-29. [Brown fat tissue in humans]. [Article in Russian] Medvedev LN(1), Elsukova EI. Author information: (1)Pedagogical University, Krasnoyarsk. Brown adipose tissue (BAT) is universally present in mammals. Thermal production in such tissue is physiologically important for maintaining temperature homeostasis and regulation of body mass in small-size homoiotherms. At present it is clearly established that unlike other large mammals, brown adipose in man and primates is retained throughout the whole postnatal othogenesis. Therefore, BAT appears as a possible effector of pharmacogenetic protection from human excessive adiposis. Systematic reserach of various functioning aspects of this unique organ of mammals were started abroad as early as 1960-es, and are actively developing at present. Domestic research of energy circulation physiology and of thermoregulation developed mostly outside the brown adipose tissue. Therefore, the principal objective of this publication is to draw attention of experimental and clinical researches to an intriguing aspect of the issue of energy circulation in humans--the issue of brown adipose functioning. PMID: 12004574 [PubMed - indexed for MEDLINE] 4844. Proc Nutr Soc. 2002 Feb;61(1):131-6. The paradox of improved antiretroviral therapy in HIV: potential for nutritional modulation? Ware LJ(1), Wootton SA, Morlese JM, Gazzard BG, Jackson AA. Author information: (1)Institute of Human Nutrition, Southampton General Hospital, UK. lware@shsint.co.uk Chronic infection with HIV type 1 is associated with alterations in macronutrient metabolism, specifically elevated plasma lipids, glucose and reduced insulin sensitivity. These alterations are most severe in patients at the later stages of AIDS, indicating a relationship with disease progression. Recently, a metabolic syndrome, termed lipodystrophy, has been described in successfully-treated HIV patients in whom the altered macronutrient metabolism of HIV infection appears to be amplified markedly, with concurrent alterations in adipose tissue patterning. This syndrome presents a paradox, as before the development of highly-active antiretroviral therapy (HAART) the most severe perturbations in metabolism were observed in the sickest patients. Now, the patients that respond well to therapy are showing metabolic perturbations much greater than those seen before. The implications of this syndrome are that, whilst life expectancy may be increased by reducing viral load, there are concomitant increases in the risk of cardiovascular disease, diabetes and pancreatitis within this patient population. The aetiology of the syndrome remains unclear. In a collaborative trial with the Chelsea and Westminster Hospital in London we have used stable-isotope-labelled fatty acids to examine the hypothesis that treatment with HAART causes a delayed clearance of dietary lipid from the circulation, resulting in the retention of lipid within plasma and the downstream changes in insulin and glucose homeostasis. This hypothesis would indicate a role for low-fat diets, exercise and drugs that reduce plasma lipid or insulin resistance, in modulating the response to antiretroviral therapy in HIV infection. PMID: 12002787 [PubMed - indexed for MEDLINE] 4845. J Am Coll Nutr. 2002 Apr;21(2):146S-151S. Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications. Zemel MB(1). Author information: (1)The University of Tennessee, Knoxville 37996, USA. mzemel@utk.edu Dietary calcium plays a pivotal role in the regulation of energy metabolism; high calcium diets attenuate adipocyte lipid accretion and weight gain during periods of overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Intracellular Ca2+ has a key role in regulating adipocyte lipid metabolism and triglyceride storage, with increased intracellular Ca2+ resulting in stimulation of lipogenic gene expression and lipogenesis, suppression of lipolysis, and increased lipid filling and adiposity. Moreover, we have recently demonstrated that the increased calcitriol released in response to low calcium diets stimulates Ca2+ influx in human adipocytes and thereby promotes adiposity. Accordingly, suppressing calcitriol levels by increasing dietary calcium is an attractive target for the prevention and management of obesity. In support of this concept, transgenic mice expressing the agouti gene specifically in adipocytes (a human-like pattern) respond to low calcium diets with accelerated weight gain and fat accretion, while high calcium diets markedly inhibit lipogenesis, accelerate lipolysis, increase thermogenesis and suppress fat accretion and weight gain in animals maintained at identical caloric intakes. Further, low calcium diets impede body fat loss, while high calcium diets markedly accelerate fat loss in transgenic mice subjected to caloric restriction. These findings are further supported by clinical and epidemiological data demonstrating a profound reduction in the odds of being obese associated with increasing dietary calcium intake. Notably, dairy sources of calcium exert a significantly greater anti-obesity effect than supplemental sources in each of these studies, possibly due to the effects of other bioactive compounds, such as the angiotensin converting enzyme inhibitor found in milk, on adipocyte metabolism, indicating an important role for dairy products in the control of obesity. PMID: 11999543 [PubMed - indexed for MEDLINE] 4846. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):117-20. Neuronal pathways regulating food intake and body adiposity. Schwartz MW(1). Author information: (1)University of Washington and Harborview Medical Center Division of Endocrinology, 325 9th Avenue Seattle, WA 98104, USA. PMID: 11994673 [PubMed - indexed for MEDLINE] 4847. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):114-6. Regulation of gene expression in human skeletal muscle and adipose tissue. Vidal H(1). Author information: (1)INSERM U.449, Faculté de Médecine R Laennec, 69372 Lyon Cedex 08, France. PMID: 11994672 [PubMed - indexed for MEDLINE] 4848. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):91-5. Angiogenesis in adipose tissue. Bouloumié A(1), Lolmède K, Sengenès C, Galitzky J, Lafontan M. Author information: (1)INSERM U317, Faculté de médecine, 37, allées Jules Guesde, 31073 Toulouse, France. PMID: 11994668 [PubMed - indexed for MEDLINE] 4849. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):83-5. Autocrine/paracrine effectors of adipogenesis. Ailhaud G(1). Author information: (1)Laboratoire Biologie du Développement du Tissu Adipeux , Centre de Biochimie (UMR 6543 CNRS), UNSA, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France. PMID: 11994666 [PubMed - indexed for MEDLINE] 4850. Ugeskr Laeger. 2002 Apr 15;164(16):2130-5. [Insulin resistance: organ manifestations and cellular mechanisms]. [Article in Danish] Beck-Nielsen H(1). Author information: (1)Endokrinologisk afdeling, Odense Universitetetshospital, DK-5000 Odense C. Insulin resistance is an important issue in the understanding of the metabolic syndrome. Clinical insulin resistance is usually defined by reduced insulin-mediated uptake of glucose in skeletal muscle. However, new studies have shown that liver and fat cells may also develop insulin resistance in subjects with the metabolic syndrome, specifically when these subjects are hyperglycaemic. New investigations also indicate that the endothelial cell itself can be insulin-resistant, reduced blood flow and increased peripheral resistance as the outcome. Insulin resistance may not only induce hyperglycaemia, but also dyslipidaemia (increased plasma levels of free fatty acids and triglyceride, and reduced plasma HDL levels) and arterial hypertension. All these variables may provoke arteriosclerosis and ischaemic heart disease. Specifically, abdominal adiposity seems to be responsible for insulin resistance in subjects with the metabolic syndrome. The mechanism could be intracellular accumulation of acyl CoA and triglyceride. However, an increased production of peptides from the adipose tissue, such as TNF alpha and reduced production of adiponectine may also play a role. The mechanism by which FFA and triglyceride, together with the peptides mentioned, may induce insulin resistance at a cellular level, resulting in reduced glucose transport and intracellular glucose processing, is still being discussed. A change in the insulin signalling cascade is one possibility, but the results so far have been contradictory. Another possibility is, of course, that the cellular accumulation of acyl CoA itself intervenes with gene expression and with phosphorylation of proteins. PMID: 11989054 [PubMed - indexed for MEDLINE] 4851. J Womens Health Gend Based Med. 2002 Apr;11(3):225-37. The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. D'Eon T(1), Braun B. Author information: (1)Department of Exercise Science, University of Massachusetts, Amherst 01003, USA. OBJECTIVE: Compared with men, women use more fat and less carbohydrate to fuel exercise at the same relative intensity. Circulating levels of estrogen and progesterone are likely to play an important role in explaining this gender difference in exercise substrate utilization. METHODS: Studies, mainly using animal models, have shown that estrogen increases fatty acid availability (lipolysis) and decreases carbohydrate availability and uptake. Studies conducted in humans corroborate the reduction in carbohydrate turnover and oxidation in the presence of estrogen, but the impact on fatty acid availability and utilization is less clear. RESULTS: The effect of circulating estrogen may be mediated, at least in part, by changes in the sensitivity of stored carbohydrate and lipids to mobilization in response to epinephrine. The role of progesterone in metabolic regulation during exercise has not been systematically studied in humans. CONCLUSIONS: Understanding the role of the ovarian hormones in fat and carbohydrate metabolism during exercise may have practical applications in terms of understanding the metabolic consequences of amenorrhea, menopause, and hormone replacement therapy (HRT). PMID: 11988133 [PubMed - indexed for MEDLINE] 4852. J Gastrointest Surg. 2001 Sep-Oct;5(5):556-67. The gut and food intake: an update for surgeons. Näslund E(1), Hellström PM, Kral JG. Author information: (1)Division of Surgery, Karolinska Institutet Danderyd Hospital, SE-182 88 Danderyd, Sweden. Erik.Naslund@kir.ds.sll.se Food intake is the simplest and most obvious measure of gastrointestinal function, yet it rarely receives more than cursory attention from surgeons. In this review we cover recent findings on relationships between gut function and appetite regulation mediated via neuropeptides influenced by afferent and efferent vagal activity. Evidence from the new discipline known as neurogastroenterology elucidates gastric and intestinal signals involved in the elicitation of hunger, satiety, and aversion. Discovery of the adipose-tissue-derived hormone, leptin, has energized the field of metabolism spawning increasing numbers of publications related to interactions between leptin and insulin release and glucose disposal, as well as appetitive behavior. Peptides such as cholecystokinin (CCK), the proglucagon-derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), and the recently identified powerful intake-stimulating molecule, orexin, are examples of potential targets for drug development and studies of surgical pathophysiology. A major conclusion of this work is that the considerable redundancy and overlap between mediators of caloric intake subserving survival of the species, while beneficial after foregut surgery, contribute to the complexity of treating the global epidemic of obesity. Possibly knowledge derived from basic research in neurogastroenterology can translate into advances in surgical treatment of obesity. PMID: 11986008 [PubMed - indexed for MEDLINE] 4853. Reprod Suppl. 2001;58:1-15. Nutritional regulators of the hypothalamic-pituitary axis in pigs. Barb CR(1), Kraeling RR, Rampacek GB. Author information: (1)Animal Physiology Research Unit, USDA/ARS, Richard B. Russell Agriculture Research Center, PO Box 5677, Athens, GA 30604, USA. rbarb@saa.ars.usda.gov Nutritional signals are detected by the central nervous system (CNS) and translated by the neuroendocrine system into signals that alter secretion of LH and growth hormone (GH). Furthermore, these signals directly affect the activity of the pituitary gland independently of CNS input. Insulin-like growth factor I (IGF-I), insulin, leptin and specific metabolites, such as glucose and free fatty acids (FFA), are potential signals of the metabolic status to the brain-pituitary axis. Intravenous injection of a lipid emulsion or glucose suppressed the GH and LH response to GH releasing hormone (GHRH) and GnRH, respectively. Insulin and IGF-I regulation of LH and GH secretion occur at the pituitary gland. Feed deprivation for 24 h suppressed leptin secretion without affecting LH or GH secretion, whereas central administration of leptin resulted in a decrease in feed intake and an increase in GH secretion. Oestrogen-induced leptin gene expression in adipose tissue increased with age and adiposity in pigs. Leptin stimulated GnRH release from hypothalamic tissue in vitro. These results identify putative signals that link metabolic status and neuroendocrine control of growth and reproduction by altering endocrine function during periods of fasting, feed restriction and lactation. PMID: 11980182 [PubMed - indexed for MEDLINE] 4854. Placenta. 2002 Apr;23 Suppl A:S80-6. Role of leptin in pregnancy--a review. Sagawa N(1), Yura S, Itoh H, Mise H, Kakui K, Korita D, Takemura M, Nuamah MA, Ogawa Y, Masuzaki H, Nakao K, Fujii S. Author information: (1)Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. fetus@kuhp.kyoto-u.ac.jp Leptin is an adipocyte-derived hormone that decreases food intake and body weight via its receptor in the hypothalamus. In rodents, it also modulates glucose metabolism by increasing insulin sensitivity. We previously reported that leptin is produced by human placental trophoblasts. We also revealed that leptin gene expression in the placenta was augmented in severe pre-eclampsia, and suggested that placental hypoxia may play a role in this augmentation. Maternal plasma leptin levels correlated well with mean blood pressure, but not with body mass index. Plasma leptin levels in pre-eclamptic women with IUGR were higher than those without IUGR (P< 0.05). We further examined the effects of hyperleptinemia on the course of pregnancy by using transgenic mice (Tg) overexpressing leptin. In pregnant Tg mice, food intake was significantly less than non-Tg, and the fetal body weights were reduced to approximately 70 per cent of those of non-Tg. Resistin is a novel adipocyte-derived hormone that decreases insulin sensitivity and increases plasma glucose concentration, thus contributing the development of obesity-related type II diabetes mellitus. We recently found that resistin gene is expressed in the human placenta as well as adipose tissue. In this review, possible roles of placental leptin and resistin are discussed. Copyright 2002 IFPA and Elsevier Science Ltd. PMID: 11978063 [PubMed - indexed for MEDLINE] 4855. Placenta. 2002 Apr;23 Suppl A:S28-38. Placental regulation of fatty acid delivery and its effect on fetal growth--a review. Haggarty P(1). Author information: (1)Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK. p.haggarty@abdn.ac.uk More than 90 per cent of the fat deposition in the fetus occurs in the last 10 weeks of pregnancy during which it increases exponentially to reach a rate of accretion of around 7 g/day close to term. All of the n -3 and n -6 fatty acid structure acquired by the fetus has to cross the placenta and fetal blood is enriched in long chain polyunsaturated fatty acids (LCPUFA) relative to the maternal supply. The placenta may regulate its own fatty acid substrate supply via the action of placental leptin on maternal adipose tissue. Fatty acids cross the microvillous and basal membranes by simple diffusion and via the action of membrane bound and cytosolic fatty acid binding proteins (FABPs). The direction and magnitude of fatty acid flux is mainly dictated by the relative abundance of available binding sites. The fatty acid mix delivered to the fetus is largely determined by the fatty acid composition of the maternal blood although the placenta is able to preferentially transfer the important PUFA to the fetus as a result of selective uptake by the syncytiotrophoblast, intracellular metabolic channelling of individual fatty acids, and selective export to the fetal circulation. Placental FABP polymorphisms may affect these processes. There is little evidence to suggest that placental delivery of fatty acids limits normal fetal growth although the importance of the in utero supply may be to support post-natal development as most of the LCPUFA accumulated by the fetus is stored in the adipose tissue for use in early post-natal life. Copyright 2002 IFPA and Elsevier Science Ltd. PMID: 11978057 [PubMed - indexed for MEDLINE] 4856. Placenta. 2002 Apr;23 Suppl A:S9-19. Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development--a review. Herrera E(1). Author information: (1)Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU, Ctra. Boadilla del Monte km 5,300, E-28668 Boadilla del Monte (Madrid), Spain. During pregnancy, the mother adapts her metabolism to support the continuous draining of substrates by the fetus. Her increase in net body weight (free of the conceptus) corresponds to the accumulation of fat depots during the first two-thirds of gestation, switching to an accelerated breakdown of these during the last trimester. Under fasting conditions, adipose tissue lipolytic activity is highly enhanced, and its products, free fatty acids (FFA) and glycerol, are mainly driven to maternal liver, where FFA are converted to ketone bodies and glycerol to glucose, which easily cross the placenta and sustain fetal metabolism. Lipolytic products reaching maternal liver are also used for triglyceride synthesis that are released in turn to the circulation, where together with an enhanced transfer of triglycerides among the different lipoprotein fractions, and a decrease in extrahepatic lipoprotein lipase activity, increase the content of triglycerides in all the lipoprotein fractions. Long chain polyunsaturated fatty acids (LCPUFA) circulate in maternal plasma associated to lipoprotein triglycerides, and in a minor proportion in the form of FFA. Despite the lack of a direct placental transfer of triglycerides, diffusion of their fatty acids to the fetus is ensured by means of lipoprotein receptors, lipoprotein lipase activity and intracellular lipase activities in the placenta. Maternal plasma FFA are also an important source of LCPUFA to the fetus, and their placental uptake occurs via a selective process of facilitated membrane translocation involving a plasma membrane fatty acid-binding protein. This mechanism together with a selective cellular metabolism determine the actual rate of placental transfer and its selectivity, resulting even in an enrichment of certain LCPUFA in fetal circulation as compared to maternal. The degree to which the fetus is capable of fatty acid desaturation and elongation is not clear, although both term and preterm infants can synthesize LCPUFA from parental essential fatty acids. Nutritional status of the mother during gestation is related to fetal growth, and excessive dietary intake of certain LCPUFA has inhibitory effects on Delta-5- and Delta-6-desaturases. This inhibition causes major declines in arachidonic acid levels, as directly found in pregnant and lactating rats fed a fish oil-rich diet as compared to olive oil. An excess in dietary PUFA may also enhance peroxidation and reduce antioxidant capacity. Thus, since benefit to risks of modifying maternal fat intake in pregnancy and lactation are not yet completely established, additional studies are needed before recommendations to increase LCPUFA intake in pregnancy are made. Copyright 2002 IFPA and Elsevier Science Ltd. PMID: 11978055 [PubMed - indexed for MEDLINE] 4857. Diabetes Metab. 2002 Apr;28(2):85-92. Molecular mechanisms of insulin-stimulated glucose uptake in adipocytes. Ducluzeau PH(1), Fletcher LM, Vidal H, Laville M, Tavaré JM. Author information: (1)Department of Biochemistry, School of Medical Sciences, University of Bristol, BS8 1TD, UK. ph.ducluzeau@chu-lyon.fr The stimulation of muscle and adipose tissue glucose metabolism, which is ultimately responsible for bringing about post-absorptive blood glucose clearance, is the primary clinically relevant action of insulin. Insulin acts on many steps of glucose metabolism, but one of the most important effects is its ability to increase the rate of cellular glucose transport. This results from the translocation of the insulin-responsive transporter isoform, GLUT4, from intra-cellular vesicular storage sites to the plasma membrane. In adipocytes, a substantial amount of cellular GLUT4 is located in a specific highly insulin-responsive storage pool, termed GLUT4 Storage Vesicles (GSVs). GLUT4 can also translocate to the plasma membrane from the recycling endosomal pool which also additionally contains the GLUT1 isoform of glucose transporter and the transferrin receptor. In this article we review the molecular mechanism by which insulin stimulates GLUT4 translocation in adipose cells, including the nature of the signaling pathways involved and the role of the cytoskeleton. PMID: 11976560 [PubMed - indexed for MEDLINE] 4858. Climacteric. 2002 Mar;5(1):15-25. Defining 'relative' androgen deficiency in aging men: how should testosterone be measured and what are the relationships between androgen levels and physical, sexual and emotional health? Haren MT(1), Morley JE, Chapman IM, O'Loughlin PD, Wittert GA. Author information: (1)Department of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. In men, bioavailable and free testosterone levels decline by about 1.0 and 1.2% per year, respectively, after the age of 40. The definition of clinically relevant androgen deficiency in the aging male remains uncertain. Clinical features common to both aging and androgen deficiency include decreased muscle mass and strength, and increased fatigue, increased fat mass, loss of libido, erectile dysfunction, impaired cognitive function and depression. It is, however, difficult to separate the effect on plasma testosterone of concomitant disease, compared with the effects of a decrease in testosterone levels alone. Testosterone supplementation has been shown to be effective in improving many of the clinical features of androgen deficiency in the older male, and is safe, at least in the short term. The maximum benefit occurs in those men with the lowest testosterone levels. PMID: 11974555 [PubMed - indexed for MEDLINE] 4859. J Appl Physiol (1985). 2002 May;92(5):2187-98. Uncoupling proteins and thermoregulation. Argyropoulos G(1), Harper ME. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. argyrog@pbrc.edu Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs. PMID: 11960973 [PubMed - indexed for MEDLINE] 4860. Eur J Clin Nutr. 2002 Mar;56(3):181-91. Fatty acid analysis of wild ruminant tissues: evolutionary implications for reducing diet-related chronic disease. Cordain L(1), Watkins BA, Florant GL, Kelher M, Rogers L, Li Y. Author information: (1)Department of Health and Exercise Sciences, Colorado State University, Fort Collins, Colorado 80523, USA. cordain@cahs.colostate.edu HYPOTHESES: Consumption of wild ruminant fat represented the primary lipid source for pre-agricultural humans. Hence, the lipid composition of these animals' tissues may provide insight into dietary requirements that offer protection from chronic disease in modern humans. METHOD: We examined the lipid composition of muscle, brain, marrow and subcutaneous adipose tissue (AT) from 17 elk (Cervus elaphus), 15 mule deer (Odocoileus hemionus), and 17 antelope (Antilicapra americana) and contrasted them to wild African ruminants and pasture and grain-fed cattle. RESULTS: Muscle fatty acid (FA) was similar among North American species with polyunsaturated fatty acids/saturated fatty acids (P/S) values from 0.80 to 1.09 and n-6/n-3 FA from 2.32 to 2.60. Marrow FA was similar among North American species with high levels (59.3-67.0%) of monounsaturated FA; a low P/S (0.24-0.33), and an n-6/n-3 of 2.24-2.88. Brain had the lowest n-6/n-3 (1.20-1.29), the highest concentration of 22:6 n-3 (elk, 8.90%; deer, 9.62%; antelope, 9.25%) and a P/S of 0.69. AT had the lowest P/S (0.05-0.09) and n-6/n-3 (2.25-2.96). Conjugated linoleic acid (CLA) isomers were found in marrow of antelope (1.5%), elk (1.0%) and deer (1.0%), in AT (deer, 0.3%; antelope, 0.3%) in muscle (antelope, 0.4%; elk, trace), but not in brain. CONCLUSIONS: Literature comparisons showed tissue lipids of North American and African ruminants were similar to pasture-fed cattle, but dissimilar to grain-fed cattle. The lipid composition of wild ruminant tissues may serve as a model for dietary lipid recommendations in treating and preventing chronic disease. PMID: 11960292 [PubMed - indexed for MEDLINE] 4861. Neurochem Res. 2002 Apr;27(4):263-8. Semicarbazide-sensitive amine oxidase (SSAO) in the brain. Obata T(1). Author information: (1)Department of Pharmacology, Oita Medical University, Hasama, Japan. tobata@oita-med.ac.jp Semicarbazide-sensitive amine oxidase (SSAO) is widely distributed in almost tissues. However, its presence in brain microvessels is still controversial. The affinity of SSAO towards benzylamine (Bz) is considerably higher than that of monoamine oxidase (MAO). SSAO plays a role in the toxicity of several environmental and endogenous amines. SSAO-mediated production of toxic aldehydes has been proposed to be related to pathophysiological conditions. The most potent of inhibition of SSAO in monkey brain was observed by tricyclic antidepressant drug imipramine, as compared to tetracyclic drug maprotiline or non-cyclic drug nomifensine. An endogenous SSAO modulator in rat brain cytosol after immobilization stress (IMMO) was found and that this inhibitor could be induced by IMMO. SSAO activity in rat brain might be regulated by the level of this inhibitor. Semicarbazide, a SSAO inhibitor, enhances the formation of .OH products of efflux/oxidation due to 1-methyl-4-phenylpyridinium ion (MPP+). The precise physiological functions of SSAO could play an important role in the control of energy balance in adipose tissue. SSAO could play an important role in the regulation of adipocyte homeostasis. PMID: 11958526 [PubMed - indexed for MEDLINE] 4862. Thyroid. 2002 Mar;12(3):193-5. Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Bahn RS(1). Author information: (1)Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA. bahn.rebecca@mayo.edu The TSH receptor (TSHR) is the autoantigen responsible for the hyperthyroidism of Graves' disease. However, whether this receptor plays a role in the development of Graves' ophthalmopathy (GO) is unclear. Expression of TSHr is augmented in orbital tissues from patients with GO, and in newly differentiated adipocytes derived from precursor cells within the orbit. Our recent studies suggest that interleukin-6 (IL-6), a cytokine elevated in the circulation of Graves' patients, stimulates TSHr expression in vitro in orbital preadipocyte fibroblasts. This cytokine might play a role in the pathogenesis of GO by stimulating TSHr expression within the fatty connective tissues of the orbit, allowing the receptor to act there as an autoantigen. Whether IL-6 also stimulates adipogenesis in the orbit is unclear at present, but such an effect could contribute to the increased volume of orbital adipose/connective tissue characteristic of this condition. Other cytokines, including IFN-gamma and TGF-beta, inhibit TSHr expression and adipogenesis by orbital fibroblasts, effects that would seem to favor disease remission. The initiation and subsequent clinical severity of GO may therefore be influenced by competing inhibitory and stimulatory cytokine effects occurring simultaneously within the orbit. Some of these may impact the expression of TSHr, the putative orbital autoantigen in this condition. PMID: 11952038 [PubMed - indexed for MEDLINE] 4863. Bioessays. 2002 Apr;24(4):382-8. Novel adipocyte lines from brown fat: a model system for the study of differentiation, energy metabolism, and insulin action. Klein J(1), Fasshauer M, Klein HH, Benito M, Kahn CR. Author information: (1)Department of Internal Medicine I, Medical University of Lübeck, Germany. johannes.klein@medinf.mu-luebeck.de Adipose tissue has emerged as an important endocrine regulator of glucose metabolism and energy homeostasis. By virtue of the mitochondrial protein uncoupling protein-1 (UCP-1), brown fat additionally plays a unique role in thermoregulation. Interest has focused on this tissue not only as a target for pharmacotherapy of obesity and insulin resistance but also as an endocrine tissue with leptin secretion and high insulin sensitivity. Most studies of adipocytes have been limited either to primary cell culture or to a small number of established cell lines. Recently, we have generated immortalized brown adipocyte cell lines from single newborn mice of different knockout mouse models. These cell lines retain the main characteristics of primary cells including UCP-1 expression. They display sensitive and diverse metabolic responses to insulin and adrenergic stimulation and have proven to be useful in the characterization of UCP regulation and the role of key insulin signaling elements for insulin action. Here, we outline common approaches to the generation of adipose tissue cell lines. Furthermore, we propose that the novel technique of generating brown adipocyte lines from a single newborn mouse will be instrumental in gaining further insight into the role of a broad range of signaling molecules in adipose tissue biology and in the pathogenesis of insulin resistance. Copyright 2002 Wiley Periodicals, Inc. PMID: 11948624 [PubMed - indexed for MEDLINE] 4864. Endocr Rev. 2002 Apr;23(2):201-29. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Lewis GF(1), Carpentier A, Adeli K, Giacca A. Author information: (1)Department of Medicine, Division of Endocrinology, University of Toronto, Canada M5G 2C4. gary.lewis@uhn.on.ca The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes. PMID: 11943743 [PubMed - indexed for MEDLINE] 4865. Urology. 2002 Apr;59(4 Suppl 1):41-50. Is obesity a risk factor for prostate cancer, and does it even matter? A hypothesis and different perspective. Moyad MA(1). Author information: (1)Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0330, USA. moyad@umich.edu Measurement of obesity is not as simple as its definition. Currently, several methods of measuring obesity are used in clinical studies. Skinfold thickness, crude weight, lean body mass (LBM), body mass index (BMI), and waist-to-hip ratio (WHR) are some of the more popular methods, but each contains its inherent strengths and flaws. In general, the results of the largest studies on prostate cancer and obesity have not been conclusive. One of the largest studies found an inverse relation to prostate cancer in the youngest age groups. The age and duration of obesity or any rapid changes in weight gain, along with other unhealthy exposures, may have some relation to prostate cancer incidence and mortality. Early intrinsic or extrinsic exposure to estrogen or estrogenlike compounds may provide a protective effect. The timing and duration of a higher estrogen and/or lower testosterone exposure may have a beneficial or detrimental impact on the prognosis of an established prostate tumor. Negative exposures over time such as low levels of sex hormone-binding globulin (SHBG), a greater exposure to growth factors, elevated insulin levels, greater sympathetic activity, higher cholesterol levels, immune system dysfunction, inadequate diets, smoking status, and other factors may be associated with an increased risk of prostate cancer and other diseases. Obesity may also be associated with other cancers for similar and different reasons. For example, morbidity and mortality from postmenopausal breast cancer, colon, kidney, and other cancers are potentially associated with obesity. Other comorbidities such as cataracts, coronary heart disease, diabetes, erectile dysfunction, hypertension, and others are also associated with obesity. The 2 largest prospective studies on BMI and overall mortality have also demonstrated the substantial negative impact of excess weight on society. Prostate cancer risk and obesity need further research to establish if a true association exists, but at this time, does it really matter? Overall, the profound adverse effect of being obese on general health is dramatic, and this is what clinicians and patients need to remember. PMID: 11937435 [PubMed - indexed for MEDLINE] 4866. World Rev Nutr Diet. 2001;88:155-62. Studies on the role of dietary diacylglycerols in human nutrition. Watanabe H(1), Nagao T, Yasukawa T, Shimasaki H. Author information: (1)Biological Science Laboratories, Kao Corporation, Tochigi, Japan. 306945@kastanet.kao.co.jp PMID: 11935948 [PubMed - indexed for MEDLINE] 4867. World Rev Nutr Diet. 2001;88:148-54. Dietary fat subtypes and obesity. Storlien LH(1), Huang XF, Lin S, Xin X, Wang HQ, Else PL. Author information: (1)Metabolic Research Centre, University of Wollongong, NSW, Australia. leonard.storlien@astrazeneca.com PMID: 11935947 [PubMed - indexed for MEDLINE] 4868. Diabetologia. 2002 Feb;45(2):174-87. Uncoupling protein-2: evidence for its function as a metabolic regulator. Saleh MC(1), Wheeler MB, Chan CB. Author information: (1)Department of Anatomy and Physiology, University of Prince Edward Island, Charlottetown, PE I, Canada. Comment in Diabetologia. 2003 Jan;46(1):132-3; author reply 133-4. Uncoupling protein-2, discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as carriers. The function(s) of uncoupling protein-2 have not yet been definitively described. However, mounting evidence suggests that uncoupling protein-2 could act in multiple tissues as a regulator of lipid metabolism. A role as a modulator of reactive oxygen species as a defence against infection is also postulated. In this review, a brief overview of the general and specific properties of uncoupling protein-2 is given and evidence for metabolic and immune regulatory functions is summarized. Uncoupling protein-2 could have particular importance in the regulation of lipid metabolism in adipose tissue and skeletal muscle. In addition, its ability to inhibit insulin secretion could also promote fat utilization over storage. Inhibition by uncoupling protein-2 of reactive oxygen species formation in macrophages and other tissues could have implications for regulation of immune function. The possibility of functions of uncoupling protein-2 in other tissues such as the brain are beginning to emerge. PMID: 11935148 [PubMed - indexed for MEDLINE] 4869. Sports Med. 2002;32(5):297-307. Blood lipids and lipoproteins in child and adolescent athletes. Eisenmann JC(1). Author information: (1)Division of Kinesiology and Health, Pediatric Health and Performance Laboratory, University of Wyoming, Laramie, Wyoming 82070, USA. eisenman@uwyo.edu The purpose of this review is to describe the age- and gender-associated variation in blood lipids of young athletes and examine the association between training status, peak oxygen consumption (VO(2peak)), and body fatness with blood lipids in young athletes. Results from cross-sectional studies suggest similar levels of total cholesterol (TC), lower levels of triglycerides (TG) and low-density lipoprotein-cholesterol (LDL-C), and higher levels of high-density lipoprotein-cholesterol (HDL-C) in young athletes compared with controls. Longitudinal data show that the age- and gender-associated variation in blood lipids in young distance runners is similar to youth in the general population; TC and LDL-C remain stable, HDL-C declines during adolescence (especially in males), and TG increases with age. Considerable heterogeneity exists in the blood lipids of young athletes, including dyslipidaemic values. Age, sexual maturity status, training status, VO(2peak) and body fatness are determinants of blood lipids in young athletes. VO(2peak) is a significant predictor of HDL-C independent of body fatness. Further research is warranted to examine: the prevalence rates of dyslipidaemia in various sport groups; and the complex interactions of genes, biological maturation, exercise training, dietary intake and composition, skeletal muscle and adipose tissue properties on lipoprotein metabolism in young athletes. PMID: 11929357 [PubMed - indexed for MEDLINE] 4870. Drugs. 2002;62(6):915-44. Pharmacological approaches for the treatment of obesity. Fernández-López JA(1), Remesar X, Foz M, Alemany M. Author information: (1)Centre Especial de Recerca en Nutrició i Ciència dels Aliments, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. The high incidence of obesity, its multifactorial nature, the complexity and lack of knowledge of the bodyweight control system, and the scarcity of adequate therapeutics have fuelled anti-obesity drug development during a considerable number of years. Irrespective of the efforts invested by researchers and companies, few products have reached a minimum level of effectiveness, and even fewer are available in medical practice. As a consequence of anti-obesity research, our knowledge of the bodyweight control system increased but, despite this, the pharmacological approaches to the treatment of obesity have not resulted yet in effective drugs. This review provides a panoramic of the multiple different approaches developed to obtain workable drugs. These approaches, however, rely in only four main lines of action: control of energy intake, mainly through modification of appetite;control of energy expenditure, essentially through the increase of thermogenesis;control of the availability of substrates to cells and tissues through hormonal and other metabolic factors controlling the fate of the available energy substrates; andcontrol of fat reserves through modulation of lipogenesis and lipolysis in white adipose tissue. A large proportion of current research is centred on neuropeptidic control of appetite, followed by the development of drugs controlling thermogenic mechanisms and analysis of the factors controlling adipocyte growth and fat storage. The adipocyte is also a fundamental source of metabolic signals, signals that can be intercepted, modulated and used to force the brain to adjust the mass of fat with the physiological means available. The large variety of different approaches used in the search for effective anti-obesity drugs show both the deep involvement of researchers on this field and the large amount of resources devoted to this problem by pharmaceutical companies. Future trends in anti-obesity drug research follow closely the approaches outlined; however, the increasing mass of information on the molecular basis of bodyweight control and obesity will in the end prevail in our search for effective and harmless anti-obesity drugs. PMID: 11929339 [PubMed - indexed for MEDLINE] 4871. Nutr Neurosci. 2002 Feb;5(1):1-11. Uncoupling proteins--a new family of proteins with unknown function. Erlanson-Albertsson C(1). Author information: (1)Department of Cell and Molecular Biology, Medical Faculty, University of Lund, Sweden. charlotte.erlanson-albertsson@medkem.lu.se Uncoupling proteins are inner mitochondrial membrane proteins, which dissipate the proton gradient, releasing the stored energy as heat. Five proteins have been cloned, named UCP1, UCP2, UCP3, UCP4 and UCP5/BMCP1. These proteins are structurally related but differ in tissue expression. UCP1 is expressed uniquely in the brown adipose tissue, while UCP2 is widely distributed, UCP3 is mainly restricted to skeletal muscle and UCP4 and UCP5/BMCP1 expressed in the brain. The properties and regulation of the uncoupling proteins and their exact function has been the focus of an intense research during recent years. This review briefly summarizes the actual knowledge of the properties and function of this new family of proteins. While UCP1 has a clear role in energy homeostasis, the newcomers UCP2-UCP5 may have more delicate physiological importance acting as free radical oxygen scavengers and in the regulation of ATP-dependent processes, such as secretion. PMID: 11929192 [PubMed - indexed for MEDLINE] 4872. Nutr Hosp. 2002 Feb;17 Suppl 1:42-8. [Leptin in the regulation of energy balance]. [Article in Spanish] Bulló Bonet M(1). Author information: (1)Unidad de Nutrición Humana, Facultad de Medicina y Ciencias de la Salud de Reus, Universitat Rovira i Virgili, Sant Llorenç, 21, 43201 Reus. mbullo@fmcs.urv.es Leptin, identified in 1994 as a substance synthesized in adipose tissue in amounts that are proportional to the magnitude of fat reserves, has been described as an important factor in the regulation of the body's energy homeostasis as it is capable of inhibiting intake, stimulating energy expenditure and regulating other peripheral metabolic processes involved in the control of the spread of body fat (secretion of insulin, lipolysis, glucose transport). Nonetheless, leptin is a pleotropic substance also involved in fertility, inflammation and angiogenesis processes, among others. Although these actions have been well defined in certain animal models of obesity, the role played by leptin in humans is less clear since, at least at the hypothalamic level, there seems to be considerable resistance to the effects of this hormone. The trials which administered recombinant leptin to humans recently have not provided sufficiently hopeful results as the weight reductions obtained have not been greater than those achieved with other drugs currently available on the market and its subcutaneous administration has led to some undesirable side effects. In any case, the results obtained must be treated with caution, with further trials being needed on the biological activity of leptin in humans in order to determine the clinical repercussions of the administration of this hormone. PMID: 11928535 [PubMed - indexed for MEDLINE] 4873. Comp Biochem Physiol B Biochem Mol Biol. 2002 Apr;131(4):653-73. Brain-specific lipids from marine, lacustrine, or terrestrial food resources: potential impact on early African Homo sapiens. Broadhurst CL(1), Wang Y, Crawford MA, Cunnane SC, Parkington JE, Schmidt WF. Author information: (1)US Department of Agriculture, Environmental Chemistry Laboratory, Agricultural Research Service, Beltsville, MD 20705, USA. The polyunsaturated fatty acid (PUFA) composition of the mammalian central nervous system is almost wholly composed of two long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA) and arachidonic acid (AA). PUFA are dietarily essential, thus normal infant/neonatal brain, intellectual growth and development cannot be accomplished if they are deficient during pregnancy and lactation. Uniquely in the human species, the fetal brain consumes 70% of the energy delivered to it by mother. DHA and AA are needed to construct placental and fetal tissues for cell membrane growth, structure and function. Contemporary evidence shows that the maternal circulation is depleted of AA and DHA during fetal growth. Sustaining normal adult human brain function also requires LC-PUFA.Homo sapiens is unlikely to have evolved a large, complex, metabolically expensive brain in an environment which did not provide abundant dietary LC-PUFA. Conversion of 18-carbon PUFA from vegetation to AA and DHA is considered quantitatively insufficient due to a combination of high rates of PUFA oxidation for energy, inefficient and rate limited enzymatic conversion and substrate recycling. The littoral marine and lacustrine food chains provide consistently greater amounts of pre-formed LC-PUFA than the terrestrial food chain. Dietary levels of DHA are 2.5-100 fold higher for equivalent weights of marine fish or shellfish vs. lean or fat terrestrial meats. Mammalian brain tissue and bird egg yolks, especially from marine birds, are the richest terrestrial sources of LC-PUFA. However, land animal adipose fats have been linked to vascular disease and mental ill-health, whereas marine lipids have been demonstrated to be protective. At South African Capesites, large shell middens and fish remains are associated with evidence for some of the earliest modern humans. Cape sites dating from 100 to 18 kya cluster within 200 km of the present coast. Evidence of early H. sapiens is also found around the Rift Valley lakes and up the Nile Corridor into the Middle East; in some cases there is an association with the use of littoral resources. Exploitation of river, estuarine, stranded and spawning fish, shellfish and sea bird nestlings and eggs by Homo could have provided essential dietary LC-PUFA for men, women, and children without requiring organized hunting/fishing, or sophisticated social behavior. It is however, predictable from the present evidence that exploitation of this food resource would have provided the advantage in multi-generational brain development which would have made possible the advent of H. sapiens. Restriction to land based foods as postulated by the savannah and other hypotheses would have led to degeneration of the brain and vascular system as happened without exception in all other land based apes and mammals as they evolved larger bodies. PMID: 11923081 [PubMed - indexed for MEDLINE] 4874. Diabetes Metab Res Rev. 2002 Mar-Apr;18 Suppl 2:S10-5. The mode of action of thiazolidinediones. Hauner H(1). Author information: (1)Diabetes Research Institute, Heinrich-Heine University, Düsseldorf, Germany. hauner@dfi.uni-duesseldorf.de The thiazolidinediones (TZDs) or 'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. TZD-induced activation of PPAR gamma alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR gamma is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-alpha (TNF-alpha), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full 'insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease. Copyright 2002 John Wiley & Sons, Ltd. PMID: 11921433 [PubMed - indexed for MEDLINE] 4875. Diabetes Metab Res Rev. 2002 Mar-Apr;18 Suppl 2:S5-9. Insulin resistance in type 2 diabetes: role of fatty acids. Arner P(1). Author information: (1)Karolinska Institute, Huddinge Hospital, Huddinge, Sweden. Peter.Arner@medhs.ki.se Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high 'portal' FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or 'glitazones' has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs. Copyright 2002 John Wiley & Sons, Ltd. PMID: 11921432 [PubMed - indexed for MEDLINE] 4876. Environ Mol Mutagen. 2002;39(2-3):143-9. Mutagens in human breast lipid and milk: the search for environmental agents that initiate breast cancer. Phillips DH(1), Martin FL, Williams JA, Wheat LM, Nolan L, Cole KJ, Grover PL. Author information: (1)Institute of Cancer Research, Haddow Laboratory, Sutton, Surrey, United Kingdom. davidp@icr.ac.uk Epidemiological studies indicate the involvement of environmental factors in the etiology of breast cancer, but have not provided clear indications of the nature of the agents responsible. Several environmental carcinogens are known to induce mammary tumors in rodents, and the abundance of adipose tissue in the human breast suggests that the epithelial cells, from which breast tumors commonly arise, could be exposed to lipid-soluble carcinogens sequestered by the adipose tissue. In this report we review our studies in which we have examined human mammary lipid, obtained from elective reduction mammoplasties from healthy donors, and human milk from healthy mothers, for the presence of components with genotoxic activity in several in vitro assays. A significant proportion of lipid extracts induced mutations in bacteria and micronuclei in mammalian cells. They also caused DNA damage, detected as single-strand breaks in the alkaline single-cell gel electrophoresis (comet) assay, in both the MCL-5 cell line and in primary cultures of human mammary epithelial cells. Genotoxic activity was also found in a significant proportion of extracts of human breast milk. Viable cells recovered from milk samples showed evidence of DNA damage and were susceptible to comet formation by genotoxic agents in vitro. Genotoxic activity was found to be less prevalent in milk samples from countries of lower breast cancer incidence (the Far East) compared with that in samples from the UK. The agents responsible for the activity in milk appear to be moderately polar lipophilic compounds and of low molecular weight. Identification of these agents and their sources may hold clues to the origins of breast cancer. Copyright 2002 Wiley-Liss, Inc. PMID: 11921182 [PubMed - indexed for MEDLINE] 4877. Int J Sport Nutr Exerc Metab. 2001 Dec;11 Suppl:S86-91. Effect of aging on glucose and lipid metabolism during endurance exercise. Mittendorfer B(1), Klein S. Author information: (1)Center for Human Nutrition and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Endurance exercise increases the use of endogenous fuels to provide energy for working muscles. Elderly subjects oxidize more glucose and less fat during moderate intensity exercise. This shift in substrate use is presumably caused by age-related changes in skeletal muscle, including decreased skeletal muscle respiratory capacity, because adipose tissue lipolysis and plasma fatty acid availability are not rate limiting. Endurance training in elderly subjects increases muscle respiratory capacity, decreases glucose production and oxidation, and increases fat oxidation thereby correcting or compensating for the alterations in substrate oxidation associated with aging. PMID: 11915933 [PubMed - indexed for MEDLINE] 4878. Int J Sport Nutr Exerc Metab. 2001 Dec;11 Suppl:S78-85. Insulin action, training, and aging. Dela F(1), Holten M, Jensen CM. Author information: (1)Copenhagen Muscle Research Centre, Department of Medical Physiology, University of Copenhagen, Denmark. PMID: 11915932 [PubMed - indexed for MEDLINE] 4879. Climacteric. 1998 Sep;1(3):229-42. How significant are environmental estrogens to women? Cassidy A(1), Milligan S. Author information: (1)Centre for Nutrition and Food Safety, School of Biological Sciences, University of Surrey, London, UK. Women are exposed to xenobiotic estrogens at least to the same extent as men. These estrogenic chemicals are either from plant material in the diet (phytoestrogens) or from industrial sources. Mainly industrially derived environmental estrogens may accumulate within the food chain and persist in human adipose tissue. In contrast, phytoestrogens do not bioaccumulate and are rapidly excreted in urine. The phytoestrogens probably represent the source of most extensive exposure for humans. Epidemiological evidence suggests that diets rich in phytoestrogens are associated with reduced incidences of cardiovascular disease, breast cancer, prostate cancer and osteoporosis. The numerous bioactivities (other than just estrogenicity) of phytoestrogens and related dietary compounds make it difficult to single out the mechanisms mediating such protective effects. The possibility that the newly discovered estrogen receptor beta may be an important modulator of phytoestrogen action is opening up new lines of research. While the evidence suggests that phytoestrogens may be of positive relevance to postmenopausal women, indications that exposure of women to industrially derived xenobiotic estrogens provides risks to health remain unproven. Further work is necessary to clarify the relative importance of 'xenobiotic' estrogens to human health, but it must be emphasized that the estrogenic potency of all the xenobiotic estrogens is very low compared with that of endogenous estrogens. PMID: 11907947 [PubMed - indexed for MEDLINE] 4880. Int J Dev Biol. 2002 Jan;46(1):105-14. PPAR expression and function during vertebrate development. Michalik L(1), Desvergne B, Dreyer C, Gavillet M, Laurini RN, Wahli W. Author information: (1)Institut de Biologie Animale, Université de Lausanne, Switzerland. The peroxisome proliferator activated receptors (PPARs) are ligand activated receptors which belong to the nuclear hormone receptor family. As with other members of this superfamily, it is thought that the ability of PPAR to bind to a ligand was acquired during metazoan evolution. Three different PPAR isotypes (PPARalpha, PPARbeta, also called 6, and PPARgamma) have been identified in various species. Upon binding to an activator, these receptors stimulate the expression of target genes implicated in important metabolic pathways. The present article is a review of PPAR expression and involvement in some aspects of Xenopus laevis and rodent embryonic development. PPARalpha and beta are ubiquitously expressed in Xenopus early embryos but become more tissue restricted later in development. In rodents, PPARalpha, PPARbeta and PPARgamma show specific time- and tissue-dependent patterns of expression during fetal development and in the adult animals. PPARs are implicated in several aspects of tissue differentiation and rodent development, such as differentiation of the adipose tissue, brain, placenta and skin. Particular attention is given to studies undertaken by us and others on the implication of PPARalpha and beta in rodent epidermal differentiation. PMID: 11902671 [PubMed - indexed for MEDLINE] 4881. J Steroid Biochem Mol Biol. 2002 Feb;80(2):203-12. Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells. Richards JA(1), Petrel TA, Brueggemeier RW. Author information: (1)Ohio State Biochemistry Program, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C(19) androgens to C(18) estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin PGE(2) increases intracellular cAMP levels and stimulates estrogen biosynthesis, and our recent studies have shown a strong linear association between CYP19 expression and the sum of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression in breast cancer specimens. Knowledge of the signaling pathways that regulate the expression and enzyme activity of aromatase and cyclooxygenases (COXs) in stromal and epithelial breast cells will aid in understanding the interrelationships of these two enzyme systems and potentially identify novel targets for regulation. The effects of epidermal growth factor (EGF), transforming growth factor-beta (TGFbeta), and tetradecanoyl phorbol acetate (TPA) on aromatase and COXs were studied in primary cultures of normal human adipose stromal cells and in cell cultures of normal immortalized human breast epithelial cells MCF-10F, estrogen-responsive human breast cancer cells MCF-7, and estrogen-unresponsive human breast cancer cells MDA-MB-231. Levels of the constitutive COX isozyme, COX-1, were not altered by the various treatments in the cell systems studied. In breast adenocarcinoma cells, EGF and TGFbeta did not alter COX-2 levels at 24h, while TPA induced COX-2 levels by 75% in MDA-MB-231 cells. EGF and TPA in MCF-7 cells significantly increased aromatase activity while TGFbeta did not. In contrast to MCF-7 cells, TGFbeta and TPA significantly increased activity in MDA-MB-231 cells, while only a modest increase with EGF was observed. Untreated normal adipose stromal cells exhibited high basal levels of COX-1 but low to undetectable levels of COX-2. A dramatic induction of COX-2 was observed in the adipose stromal cells by EGF, TGFbeta, and TPA. Aromatase enzyme activity in normal adipose stromal cells was significantly increased by EGF, TGFbeta and TPA after 24h of treatment. In summary, the results of this investigation on the effects of several paracrine and/or autocrine signaling pathways in the regulation of expression of aromatase, COX-1, and COX-2 in breast cells has identified more complex relationships. Overall, elevated levels of these factors in the breast cancer tissue microenvironment can result in increased aromatase activity (and subsequent increased estrogen biosynthesis) via autocrine mechanisms in breast epithelial cells and via paracrine mechanisms in breast stromal cells. Furthermore, increased secretion of prostaglandins such as PGE(2) from constitutive COX-1 and inducible COX-2 isozymes present in epithelial and stromal cell compartments will result in both autocrine and paracrine actions to increase aromatase expression in the tissues. PMID: 11897504 [PubMed - indexed for MEDLINE] 4882. Comp Biochem Physiol A Mol Integr Physiol. 2002 Apr;131(4):733-9. Facultative and obligatory thermogenesis in young birds: a cautionary note. Hohtola E(1). Author information: (1)University of Oulu, Department of Biology, P.O. Box 3000, FIN-90014, Oulu, Finland. esa.hohtola@oulu.fi A brief overview on thermogenic mechanisms in young precocial birds is given. While shivering thermogenesis is well documented in these birds, evidence for a facultative non-shivering component of heat production, comparable to that found in the brown adipose tissue of mammals, is ambiguous. One reason for this is the confusion between thermoregulatory and obligatory thermogenesis. In particular, the existence of a thermogenic reaction, even a futile one, does not by itself constitute proof of true thermoregulatory non-shivering thermogenesis. More probably, such a reaction is another obligatory component of heat production. Heat increment of feeding and motor activity are classical examples of such mechanisms. Thermogenesis arising from such mechanisms can often be adaptively used by the thermoregulatory systems in young birds, as well as in adults. PMID: 11897184 [PubMed - indexed for MEDLINE] 4883. Br J Nutr. 2002 Jan;87 Suppl 1:S111-9. Nutrition and HIV infection. Salomon J(1), De TP, Melchior JC. Author information: (1)Department of Infectious Diseases and Internal Medicine, Raymond Poincaré University Hospital, Garches, France. jerome.salomon@rpc.ap-hop-paris Infection by the human immunodeficiency virus (HIV) is characterized by progressive destruction of the immune system, which leads to recurrent opportunistic infections and malignancies, progressive debilitation and death. Malnutrition is one major complication of HIV infection and is recognized as a significant prognostic factor in advanced disease. Malnutrition is multifactorial and poorly treated during the course of HIV. Even if a standardized approach to the management of active weight loss has not been well established, early nutritional intervention is important in HIV infected patients to maximize gain of lean body mass. From early in the era of highly active antiretroviral therapy (HAART), an initial decreased incidence of malnutrition was noted only in western countries while a variety of changes in the distribution of body fat and associated metabolic abnormalities have been recognized under the banner of lipodystrophy. PMID: 11895147 [PubMed - indexed for MEDLINE] 4884. Nutr Metab Cardiovasc Dis. 2001 Aug;11(4 Suppl):118-21. Study of the regulation by nutrients of the expression of genes involved in lipogenesis and obesity in humans and animals. Delzenne N(1), Ferré P, Beylot M, Daubioul C, Declercq B, Diraison F, Dugail I, Foufelle F, Foretz M, Mace K, Reimer R, Palmer G, Rutter G, Tavare J, Van Loo J, Vidal H. Author information: (1)Unité de Pharmacocinétique, Metabolisme, Nutrition et Toxicologie, School of Pharmacy, Université Catholique de Louvain, MD/FARM/PMNT 7369 Avenue Emmanuel Mounier, 73 B-1200 Brussels, Belgium. Delzenne@pmnt.ucl.ac.be Dietary digestible carbohydrates are able to modulate lipogenesis, by modifying the expression of genes coding for key lipogenic enzymes, like fatty acid synthase. The overall objective of the Nutrigene project (FAIR-CT97-3011) was to study the efficiency of various carbohydrates to modulate the lipogenic capacity and relevant gene expression in rat and human species (control and obese subjects) and to understand the underlying molecular mechanisms involved in the regulation of lipogenic genes by carbohydrates. Key cellular mediators (namely SREBP-1c and 2, AMP activated protein kinase, cholesterol content) of the regulation of lipogenic gene expression by glucose and/or insulin were identified and constitute new putative targets in the development of plurimetabolic syndrome associated with obesity. In humans, hepatic lipogenesis and triglyceride synthesis, assessed in vivo by the use of stable isotopes, was promoted by a high-carbohydrate diet in non obese subjects, and in non alcoholic steatotic patients, but was not modified in the adipose tissue of obese subjects. Non digestible/fermentable carbohydrates, such as fructans, were shown to decrease hepatic lipogenesis in non obese rats, and to lessen hepatic steatosis and body weight in obese Zucker rats. If confirmed in obese humans, this would allow the development of functional food able to counteract the metabolic disturbances linked to obesity. PMID: 11894744 [PubMed - indexed for MEDLINE] 4885. Trends Endocrinol Metab. 2002 Apr;13(3):122-8. Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans. Kamat A(1), Hinshelwood MM, Murry BA, Mendelson CR. Author information: (1)Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9038, USA. In humans, aromatase P450, which catalyses conversion of C(19)-steroids to estrogens, is expressed in several tissues, including gonads, brain, adipose tissue, skin and placenta, and is encoded by a single-copy gene (CYP19); however, this does not hold true for all species. The human gene is approximately 130 kb and its expression is regulated, in part, by tissue-specific promoters and by alternative splicing mechanisms. Using transgenic mouse technology, it was observed that ovary-, adipose tissue- and placenta-specific expression of human CYP19 is directed by relatively small segments of DNA within 500 bp upstream of each of the tissue-specific first exons. Thus, the use of alternative promoters allows greater versatility in tissue-specific regulation of CYP19 expression. Characterization and identification of transcription factors and crucial cis-acting elements within genomic regions that direct tissue-specific expression will contribute to improved understanding of the regulation of CYP19 expression in the tissues that synthesize estrogens under both physiological and pathophysiological conditions. PMID: 11893526 [PubMed - indexed for MEDLINE] 4886. Am J Med. 2002 Mar;112(4):305-11. Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes. Oliver MF(1). Author information: (1)Cardiovascular Research Division, University of Edinburgh, Edinburgh, United Kingdom. The mechanisms leading to ventricular fibrillation that occur during acute myocardial ischemia are ill understood. Whether primary ventricular fibrillation is due to a transient imbalance of electrolytes, an alteration of membrane permeability, electrical re-entry phenomena, or other factors, one overriding influence is the development of regional myocardial energy crises. Acute alteration in the balance of substrate supply may lead, during greatly reduced blood flow, to instability of myocardial electrical conduction with the development of re-entry circuits. An immediate response to the angor animi and initial symptoms of an acute coronary syndrome is a rapid and marked increase in catecholamine release, which leads to adipose tissue lipolysis with an acute increase in plasma free fatty acid concentrations, suppression of insulin activity, and a reduction in glucose uptake by the myocardium. The utilization of free fatty acids instead of glucose by the ischemic myocardium could precipitate regional oxygen or energy crises. Prevention therefore should focus on minimizing the catecholamine response and providing the myocardium with an optimum supply of energy substrates. Since catecholamines are inotropic, the aim should be to redress the imbalance of substrate availability by controlling adipose lipolysis with reduction of plasma free fatty acid concentrations, increasing the availability of glucose, or both. Other approaches include inhibition of acylcarnitine transport and manipulation of fatty acid intermediaries. To combat primary ventricular fibrillation, preventive treatment must be established within 6 to 10 hours of the onset of ischemia. There is already experimental and clinical evidence that antilipolytic drugs decrease the incidence of ventricular fibrillation, but their potential has not been explored extensively. PMID: 11893370 [PubMed - indexed for MEDLINE] 4887. Cell Biochem Biophys. 2001;35(2):191-209. Signal integration and the specificity of insulin action. Kanzaki M(1), Pessin JE. Author information: (1)Department of Physiology & Biophysics, The University of Iowa, Iowa City 52242, USA. Insulin is a potent metabolic hormone essential for the maintenance of normal circulating blood glucose level in mammals. The physiologic control of glucose homeostasis results from a balance between hepatic glucose release (glycogenolysis and gluconeogenesis) and dietary glucose absorption versus skeletal muscle and adipose tissue glucose uptake and disposal. Disruption of this delicate balance either through defects in insulin secretion, liver glucose output, or peripheral tissue glucose uptake results in pathophysiological states of insulin resistance and diabetes. In particular, glucose transport into skeletal muscle and adipose tissue is the rate-limiting step in glucose metabolism and reduction in the efficiency of this process (insulin resistance) is one of the earliest predictors for the development of Type II diabetes. Importantly, recent studies have directly implicated an impairment in insulin receptor signal transduction as the prime mechanism for peripheral tissue insulin resistance. In this review, we have focused on recent developments in our understanding of the molecular mechanisms and signal transduction pathways that insulin utilizes to specifically regulate glucose uptake. The detailed understanding of these events will provide a conceptual framework for the development of new therapeutic targets to treat this chronic and debilitating disease process. PMID: 11892791 [PubMed - indexed for MEDLINE] 4888. Semin Nephrol. 2002 Mar;22(2):148-53. Genetics of Cd36 and the hypertension metabolic syndrome. Pravenec M(1), Kurtz TW. Author information: (1)Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic; and the Department of Laboratory Medicine, University of California, San Francisco, CA. Although genetic mapping of quantitative trait loci (QTL) for complex traits related to hypertension is relatively straightforward, the identification of QTL at the molecular level has proven far more difficult. By combining techniques of gene mapping and gene expression profiling with studies in congenic and transgenic strains, a specific molecular defect in the Cd36 fatty acid transporter has been identified that contributes to the pathogenesis of 2 complex traits in the spontaneously hypertensive rat (SHR), namely, insulin resistance and disordered fatty acid metabolism. After mapping QTL linked to insulin resistance and dyslipidemia to the telomeric region of SHR chromosome 4, gene expression studies were used to identify candidate genes within the target chromosome segment that were differentially expressed in white adipose tissue between SHR congenic strains. This led to the identification of a major mutation in the SHR gene encoding Cd36, a fatty acid transporter involved in the transmembrane transport of long-chain fatty acids. The role for mutant Cd36 in the pathogenesis of insulin resistance and dyslipidemia was confirmed by rescuing the abnormal metabolic phenotypes through transgenic expression of wild-type Cd36 on the SHR background. These findings show that a primary defect in fatty acid transport can promote disordered carbohydrate metabolism in the SHR and show the power of advanced genome technologies for identifying QTL at the molecular level. Copyright 2002, Elsevier Science (USA). All rights reserved. PMID: 11891508 [PubMed - indexed for MEDLINE] 4889. Nutr Metab Cardiovasc Dis. 2001 Oct;11(5):354-9. Impact of obesity in primary hyperlipidemias. Carmena R(1), Ascaso JF, Real JT. Author information: (1)Department of Medicine, Endocrinology Service, Hospítal Cliníco Universitario, University of Valencia, Valencia, Spain. Obesity is frequently associated with high plasma triglyceride and reduced plasma high-density lipoprotein (HDL)-cholesterol (HDL-C) levels, and an increased concentration of apoB-carrying lipoproteins. The effects of obesity on lipid metabolism are mainly mediated by insulin resistance and, as central (visceral) obesity significantly increases insulin resistance, it aggravates these lipid changes. We have reviewed the impact of obesity on lipid metabolism in different types of primary hyperlipidemias. Obesity is not common in primary (familial and polygenic) hypercholesterolemias, and insulin resistance is infrequent; various investigators have found no or only a weak association between plasma cholesterol concentrations and insulin levels. On the other hand, in familial hypertriglyceridemia (type IV) and familial combined hyperlipidemia (FCH), obesity and insulin resistance are common and, when present, contribute to a further deterioration in the lipid profile. Weight loss in most of these patients is accompanied by a significant decrease in plasma triglyceride levels and an increase in HDL-C. Reviewing the data published by our group, we show that insulin resistance is an important component of the metabolic derangement in FCH subjects; high fasting plasma free fatty acids and triglycerides levels correlate to insulin resistance, thus linking this abnormality to lipid metabolism. A high waist/hip ratio (indicating visceral fat deposits) exacerbates insulin resistance, but this is also present in lean FCH subjects. Furthermore, insulin resistance is associated with a higher prevalence of coronary heart disease in this group of subjects. PMID: 11887432 [PubMed - indexed for MEDLINE] 4890. Curr Hypertens Rep. 2002 Apr;4(2):119-25. Cardiovascular and sympathetic effects of leptin. Rahmouni K(1), Haynes WG, Mark AL. Author information: (1)SCOR Hypertension Genetics and Department of Internal Medicine, University of Iowa, 524 MRC, Iowa City, IA 52242, USA. kamal-rahmouni@uiowa.edu Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders. PMID: 11884267 [PubMed - indexed for MEDLINE] 4891. J Nutr. 2002 Mar;132(3):329-32. Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity. St-Onge MP(1), Jones PJ. Author information: (1)School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9. Medium chain fatty acids (MCFA) are readily oxidized in the liver. Animal and human studies have shown that the fast rate of oxidation of MCFA leads to greater energy expenditure (EE). Most animal studies have also demonstrated that the greater EE with MCFA relative to long-chain fatty acids (LCFA) results in less body weight gain and decreased size of fat depots after several months of consumption. Furthermore, both animal and human trials suggest a greater satiating effect of medium-chain triglycerides (MCT) compared with long-chain triglycerides (LCT). The aim of this review is to evaluate existing data describing the effects of MCT on EE and satiety and determine their potential efficacy as agents in the treatment of human obesity. Animal studies are summarized and human trials more systematically evaluated because the primary focus of this article is to examine the effects of MCT on human energy metabolism and satiety. Hormones including cholescytokinin, peptide YY, gastric inhibitory peptide, neurotensin and pancreatic polypeptide have been proposed to be involved in the mechanism by which MCT may induce satiety; however, the exact mechanisms have not been established. From the literature reviewed, we conclude that MCT increase energy expenditure, may result in faster satiety and facilitate weight control when included in the diet as a replacement for fats containing LCT. PMID: 11880549 [PubMed - indexed for MEDLINE] 4892. Sex Transm Infect. 2002 Feb;78(1):64-6. Does increased aromatase activity in adipose fibroblasts cause low sexual desire in patients with HIV lipodystrophy? Goldmeier D(1), Scullard G, Kapembwa M, Lamba H, Frize G. Author information: (1)Jefferiss Wing, St Mary's Hospital, London W2 1NY, UK. There is evidence from our own unit and other workers that many patients who have lipodystrophy on HAART given for HIV disease also have raised oestrogen levels and complain of low sexual desire. This hypothesis paper discusses a possible pathological mechanism for these changes--an increase in the number of fibroblasts and macrophages present in lipoatrophic areas that could convert testosterone to oestrogen by intracellular aromatisation. This process is known to be enhanced by increased levels of tumour necrosis factor, interleukin 6 (IL-6), and hydroxycorticosteroids present in many patients with HIV lipodystrophy. Treatment options are discussed, including aromatase inhibitors and testosterone. PMCID: PMC1763708 PMID: 11872865 [PubMed - indexed for MEDLINE] 4893. J Diabetes Complications. 2002 Jan-Feb;16(1):108-14. Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease. Takano H(1), Komuro I. Author information: (1)Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to a nuclear receptor superfamily. PPARs have three isoforms: alpha, beta (or delta), and gamma. It is known that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones (TZDs) and the natural prostaglandin D2 (PGD2) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been identified as ligands for PPARgamma. Furthermore, it has become apparent that PPARs are present both in a variety of different cell types and in atherosclerotic lesions and the studies about PPARgamma have been extended. Although activation of PPARgamma appears to have protective effects on atherosclerosis, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular disease. Recent evidence suggests that some benefit from antidiabetic agents, TZDs, may occur independent of increased insulin sensitivity. In this article, we review the latest developments in the PPAR field and summarize the roles of PPARgamma and the actions of PPARgamma ligands in the cardiovascular system. PMID: 11872377 [PubMed - indexed for MEDLINE] 4894. Domest Anim Endocrinol. 2001 Nov;21(4):319-27. Chicken leptin: properties and actions. Taouis M(1), Dridi S, Cassy S, Benomar Y, Raver N, Rideau N, Picard M, Williams J, Gertler A. Author information: (1)Station de Recherches Avicoles, Institut National de la Recherche Agronomique, 37380, Nouzilly, France. taouis@tours.inra.fr Chicken leptin cDNA shows a high homology to mammalian homologous, with an expression localized in the liver and adipose tissue. It is noteworthy, that the hepatic expression is most likely associated with the primary role that this organ plays in lipogenic activity in avian species. As in mammals, chicken leptin expression is regulated by hormonal and nutritional status. This regulation is tissue-specific and with a high sensitivity in the liver compared to adipose tissue. The blood leptin levels are regulated by the nutritional state with high levels in the fed state compared to the fasted state. The recombinant chicken leptin markedly inhibits food intake as reported in mammals, suggesting the presence of an hypothalamic leptin receptor. The chicken leptin receptor has been identified and all functional motifs are highly conserved compared to mammalian homologous. Chicken leptin receptor is expressed in the hypothalamus but also in other tissues such as pancreas, where leptin inhibits insulin secretion and thus may have a key role in regulating nutrient utilization in this species. PMID: 11872323 [PubMed - indexed for MEDLINE] 4895. Domest Anim Endocrinol. 2001 Nov;21(4):297-317. Biology of leptin in the pig. Barb CR(1), Hausman GJ, Houseknecht KL. Author information: (1)USDA-ARS, Animal Physiology Unit, Russell Research Center, P. O. Box 5677, Athens, GA 30604-5677, USA. rbarb@saa.ars.usda.gov The recently discovered protein, leptin, which is secreted by fat cells in response to changes in body weight or energy, has been implicated in regulation of feed intake, energy expenditure and the neuroendocrine axis in rodents and humans. Leptin was first identified as the gene product found deficient in the obese ob/ob mouse. Administration of leptin to ob/ob mice led to improved reproduction as well as reduced feed intake and weight loss. The porcine leptin receptor has been cloned and is a member of the class 1 cytokine family of receptors. Leptin has been implicated in the regulation of immune function and the anorexia associated with disease. The leptin receptor is localized in the brain and pituitary of the pig. The leptin response to acute inflammation is uncoupled from anorexia and is differentially regulated among swine genotypes. In vitro studies demonstrated that the leptin gene is expressed by porcine preadipocytes and leptin gene expression is highly dependent on dexamethasone induced preadipocyte differentiation. Hormonally driven preadipocyte recruitment and subsequent fat cell size may regulate leptin gene expression in the pig. Expression of CCAAT-enhancer binding proteinalpha (C/EBPalpha) mediates insulin dependent preadipocyte leptin gene expression during lipid accretion. In contrast, insulin independent leptin gene expression may be maintained by C/EBPalpha auto-activation and phosphorylation/dephosphorylation. Adipogenic hormones may increase adipose tissue leptin gene expression in the fetus indirectly by inducing preadipocyte recruitment and subsequent differentiation. Central administration of leptin to pigs suppressed feed intake and stimulated growth hormone (GH) secretion. Serum leptin concentrations increased with age and estradiol-induced leptin mRNA expression in fat was age and weight dependent in prepuberal gilts. This occurred at the time of expected puberty in intact contemporaries and was associated with greater LH secretion. Further work demonstrated that leptin acts directly on pituitary cells to enhance LH and GH secretion, and brain tissue to stimulate gonadotropin releasing hormone secretion. Thus, development of nutritional schemes and (or) gene therapy to manipulate leptin secretion will lead to practical methods of controlling appetite, growth and reproduction in farm animals, thereby increasing efficiency of lean meat production. PMID: 11872322 [PubMed - indexed for MEDLINE] 4896. Domest Anim Endocrinol. 2001 Nov;21(4):271-95. Leptin in ruminants. Gene expression in adipose tissue and mammary gland, and regulation of plasma concentration. Chilliard Y(1), Bonnet M, Delavaud C, Faulconnier Y, Leroux C, Djiane J, Bocquier F. Author information: (1)Herbivore Research Unit, Adipose Tissue and Milk Lipids Group, INRA - Theix, 63122, Saint-Genès-Champanelle, France. Yves.Chilliard@clermont.inra.fr This paper reviews data on leptin gene expression in adipose tissue (AT) and mammary gland of adult ruminants, as well as on plasma leptin variations, according to genetic, physiological, nutritional and environmental factors. AT leptin mRNA level was higher in sheep and goat subcutaneous than visceral tissues, and the opposite was observed in cattle; it was higher in fat than in lean selection line in sheep; it was decreased by undernutrition and increased by refeeding in cattle and sheep, and not changed by adding soybeans to the diet of lactating goats; it was increased by injection of NPY to sheep, and by GH treatment of growing sheep and cattle. Insulin and glucocorticoids in vitro increased AT leptin mRNA in cattle, and leptin production in sheep. Long daylength increased AT lipogenic activities and leptin mRNA, as well as plasma leptin in sheep. Mammary tissue leptin mRNA level was high during early pregnancy and was lower but still expressed during late pregnancy and lactation in sheep. Leptin was present in sheep mammary adipocytes, epithelial and myoepithelial cells during early pregnancy, late pregnancy and lactation, respectively. Plasma leptin in cattle and sheep was first studied thanks to a commercial "multi-species" kit. It was positively related to body fatness and energy balance or feeding level, and decreased by beta-agonist injection. The recent development of specific RIA for ruminant leptin enabled more quantitative study of changes in plasma leptin concentration, which were explained for 35--50% by body fatness and for 15--20% by feeding level. The response of plasma leptin to meal intake was related positively to glycemia, and negatively to plasma 3-hydroxybutyrate. The putative physiological roles of changes in leptin gene expression are discussed in relation with published data on leptin receptors in several body tissues, and on in vivo or in vitro effects of leptin treatment. PMID: 11872321 [PubMed - indexed for MEDLINE] 4897. Domest Anim Endocrinol. 2001 Nov;21(4):251-70. Leptin: a possible metabolic signal affecting reproduction. Spicer LJ(1). Author information: (1)Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma 74078, USA. igf1Leo@okstate.edu Since its discovery in 1994, leptin, a protein hormone synthesized and secreted by adipose tissue, has been shown to regulate feed intake in several species including sheep and pigs. Although a nimiety of information exists regarding the physiological role of leptin in rodents and humans, the regulation and action of leptin in domestic animals is less certain. Emerging evidence in several species indicates that leptin may also affect the hypothalamo-pituitary-gonadal axis. Leptin receptor mRNA is present in the anterior pituitary and hypothalamus of several species, including sheep. In rats, effects of leptin on GnRH, LH and FSH secretion have been inconsistent, with leptin exhibiting both stimulatory and inhibitory action in vivo and in vitro. Evidence to support direct action of leptin at the level of the gonad indicates that the leptin receptor and its mRNA are present in ovarian tissue of several species, including cattle. These leptin receptors are functional, since leptin inhibits insulin-induced steroidogenesis of both granulosa and thecal cells of cattle in vitro. Leptin receptor mRNA is also found in the testes of rodents. As with the ovary, these receptors are functional, at least in rats, since leptin inhibits hCG-induced testosterone secretion by Leydig cells in vitro. During pregnancy, placental production of leptin may be a major contributor to the increase in maternal leptin in primates but not rodents. However, in both primates and rodents, leptin receptors exist in placental tissues and may regulate metabolism of the fetal-placental unit. As specific leptin immunoassays are developed for domestic animals, in vivo associations may then be made among leptin, body energy stores, dietary energy intake and reproductive function. This may lead to a more definitive role of leptin in domestic animal reproduction. PMID: 11872320 [PubMed - indexed for MEDLINE] 4898. Domest Anim Endocrinol. 2001 Nov;21(4):215-50. Leptin and the regulation of food intake, energy homeostasis and immunity with special focus on periparturient ruminants. Ingvartsen KL(1), Boisclair YR. Author information: (1)Danish Institute of Agricultural Sciences, Department of Animal Health and Welfare, Research Centre Foulum, DK-8830, Tjele, Denmark. KlausL.Ingvartsen@agrsci.dk The biology of leptin has been studied most extensively in rodents and in humans. Leptin is involved in the regulation of food intake, energy homeostasis and immunity. Leptin is primarily produced in white adipose tissue and acts via a family of membrane bound receptors, including an isoform with a long intracellular domain (OB-Rb), and many isoforms with short intracellular domains (Ob-Rs). OB-Rb is predominantly expressed in the hypothalamic regions involved in the regulation of food intake and energy homeostasis. The other isoforms are distributed ubiquitously and are found in most peripheral tissues in far greater abundance than OB-Rb. The effects of leptin on food intake and energy homeostasis are central and are mediated via a network of orexigenic neuropeptides (neuropeptide Y, galanin, galanin-like peptide, melanin-concentrating hormone, orexins, agouti-related peptide) and anorexigenic neuropeptides (corticotropin-releasing hormone, pro-opiomelanocortin, alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript). In addition, leptin acts directly on immune cells to stimulate hematopoesis, T-cell immunity, phagocytosis, cytokine production, and to attenuate susceptibility to infectious insults. Emerging data in ruminants suggest that leptin is dynamically regulated by many factors and physiological states. Thus, leptin is secreted in a pulsatile fashion, but without a marked diurnal rhythm. A positive relationship between adiposity and plasma leptin concentration exists in growing and lactating ruminants. The concentration of plasma leptin increases during pregnancy, starts to decline 1--2 wk before parturition, and reaches a nadir in early lactation. The reduction of plasma leptin at parturition is likely to promote centrally mediated adaptations required in periods of energy deficit, but could have negative effects on immune cell function. Future research is needed in ruminants to address the roles played by leptin and the central nervous system in orchestrating metabolism during the periparturient period and during infectious diseases. PMID: 11872319 [PubMed - indexed for MEDLINE] 4899. Domest Anim Endocrinol. 2001 Nov;21(4):197-214. Signals of adiposity. Vernon RG(1), Denis RG, Sørensen A. Author information: (1)Hannah Research Institute, Ayr KA6 5HL, Scotland, UK. vernonr@hri.sari.ac.uk Adipose tissue, a reserve of energy, has played an essential role in mammalian evolution. Adipose tissue differs from other tissues in that its mass has considerable capacity to expand, which while beneficial in decreasing the risk of starvation, increases the risk of predation. Adipose tissue mass is thus under tight control in nondomestic species. Adipose tissue secretes a variety of factors, some of which (leptin, tumor necrosis factor (TNF) alpha, resistin) are thought to be involved in modulation of adipose mass. Leptin has a variety of functions, primarily targetting the hypothalamus where it acts to decrease appetite and increase energy expenditure. Leptin is also involved in the adaptations to fasting, and leptin is also required for normal reproductive and immune function. TNF alpha and resistin appear to have key paracrine roles, attenuating the anabolic effects of insulin on adipose tissue metabolism. PMID: 11872318 [PubMed - indexed for MEDLINE] 4900. Fertil Steril. 2002 Mar;77(3):433-44. Leptin and reproduction: a review. Moschos S(1), Chan JL, Mantzoros CS. Author information: (1)Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. OBJECTIVE: To review recent advances in understanding the role of leptin in the physiology and pathophysiology of reproduction, with a focus on relevant clinical situations. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Leptin, an adipocyte hormone important in regulating energy homeostasis, interacts with the reproductive axis at multiple sites, with stimulatory effects at the hypothalamus and pituitary and inhibitory actions at the gonads. More recently, leptin has been shown to play a role in other target reproductive organs, such as the endometrium, placenta, and mammary gland, with corresponding influences on important physiologic processes such as menstruation, pregnancy, and lactation. As a marker of whether nutritional stores are adequate, leptin may act in concert with gonadotropins and the growth hormone axis to initiate the complex process of puberty. Conditions in which nutritional status is suboptimal, such as eating disorders, exercise-induced amenorrhea, and functional hypothalamic amenorrhea, are associated with low serum leptin levels; and conditions with excess energy stores or metabolic disturbances, such as obesity and polycystic ovarian syndrome, often have elevated serum or follicular fluid leptin levels, raising the possibility that relative leptin deficiency or resistance may be at least partly responsible for the reproductive abnormalities that occur with these conditions. CONCLUSION(S): Leptin may act as the critical link between adipose tissue and the reproductive system, indicating whether adequate energy reserves are present for normal reproductive function. Future interventional studies involving leptin administration are expected to further clarify this role of leptin and may provide new therapeutic options for the reproductive dysfunction associated with states of relative leptin deficiency or resistance. PMID: 11872190 [PubMed - indexed for MEDLINE] 4901. J Lipid Res. 2002 Feb;43(2):177-86. PPARadigms and PPARadoxes: expanding roles for PPARgamma in the control of lipid metabolism. Walczak R(1), Tontonoz P. Author information: (1)Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095-1662, USA. The nuclear receptor PPARgamma is a central regulator of adipose tissue development and an important modulator of gene expression in a number of specialized cell types including adipocytes, epithelial cells, and macrophages. PPARgamma signaling pathways impact both cellular and systemic lipid metabolism and have links to obesity, diabetes, and cardiovascular disease. The ability to activate this receptor with small molecule ligands has made PPARgamma an attractive target for intervention in human metabolic disease. As our understanding of PPARgamma biology has expanded, so has the therapeutic potential of PPARgamma ligands. Recent studies have provided insight into the paradoxical relationship between PPARgamma and metabolic disease and established new paradigms for the control of lipid metabolism. This review focuses on recent advances in PPARgamma biology in the areas of adipocyte differentiation, insulin resistance, and atherosclerosis. PMID: 11861659 [PubMed - indexed for MEDLINE] 4902. Curr Opin Nephrol Hypertens. 2002 Mar;11(2):191-5. Peroxisome proliferator-activated receptor-gamma in the renal mesangium. Hsueh WA(1), Nicholas SB. Author information: (1)UCLA School of Medicine, Los Angeles, California 90095, USA. whsueh@mednet.ucla.edu The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are expressed in a variety of tissues, including the liver (PPARalpha), adipose tissue, vascular smooth muscle, the heart, skeletal muscle, and the kidney (PPARgamma). PPARdelta is expressed ubiquitously. The receptors function as transcription factors to regulate the expression of genes involved in lipid metabolism, cell growth and migration as well as insulin-mediated skeletal muscle glucose uptake. Although the mechanisms by which all these actions occur have not been completely worked out, ligands to these receptors function to improve lipid metabolism, insulin sensitivity, endothelial dysfunction and urinary albumin excretion in patients with diabetes. Thus PPARs appear to have enormous implications for the management of cardiovascular disease. PMID: 11856912 [PubMed - indexed for MEDLINE] 4903. Trends Endocrinol Metab. 2002 Mar;13(2):84-9. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Berg AH(1), Combs TP, Scherer PE. Author information: (1)Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. In recent years, we have learned that adipocytes are not merely inert storage depots for triglycerides but rather highly active cells with potent autocrine, paracrine and endocrine functions. Adipose tissue secretes a large number of physiologically active polypeptides. Although leptin remains one of the best-studied examples of an adipocyte-specific secretory factor, recent reports describe potent physiological activities for another adipocyte-specific secreted protein, adipocyte complement-related protein of 30 kDa (Acrp30). Full-length versions of Acrp30 or its proteolytic fragments decrease the postprandial rise of plasma free fatty acids and improve postabsorptive insulin-mediated suppression of hepatic glucose output. A strong correlation between plasma Acrp30 levels and systemic insulin sensitivity is well established and the protein has putative anti-atherogenic properties that are relevant for the prevention of formation of atherosclerotic plaques. The current challenge is to understand the molecular mechanisms through which the protein exerts its multiple functions. PMID: 11854024 [PubMed - indexed for MEDLINE] 4904. Minerva Med. 2002 Feb;93(1):41-57. Mitochondrial uncoupling proteins in human physiology and disease. Hagen T(1), Vidal-Puig A. Author information: (1)The Wolfson Institute for Biomedical Research, University College London, London, UK. Uncoupling proteins are mitochondrial carrier proteins that catalyse a regulated proton leak across the inner mitochondrial membrane, diverting free energy from ATP synthesis by the mitochondrial F0F1-ATP synthase to the production of heat. Uncoupling protein 1 (UCP1), which is exclusively expressed in brown adipose tissue, is the mediator of thermogenesis in response to beta-adrenergic stimulation. Using gene a knockout mouse model, UCP1 has been shown to be required for cold acclimation. Two homologues of UCP1, UCP2 and UCP3, have been identified recently and show a much wider tissue distribution. UCP2 and UCP3 have been postulated to play a role in the regulation of cold acclimation, energy expenditure and diet-induced thermogenesis in humans, who, in contrast to rodents, have very little brown fat in adult life. However, evidence is accumulating that thermogenesis and regulation of body weight may not be the physiological functions of UCP2 and UCP3. For instance, mice deficient for UCP2 or UCP3 are not cold-intolerant and do not develop obesity. Alternative functions were suggested, primarily based on findings in UCP2 and UCP3 gene knockout mice. Both UCP2- and UCP3-deficient mice were found to overproduce reactive oxygen species and UCP2-deficient mice to hypersecrete insulin. Thus, the UCP1 homologues may play a role in regulating mitochondrial production of reactive oxygen species and b-cell function. In this review, we discuss the role of UCP1, UCP2 and UCP3 in human physiology and disease, primarily based on findings from the various animal models that have been generated. PMID: 11850613 [PubMed - indexed for MEDLINE] 4905. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):19-25. Role of aromatase in endometrial disease. Bulun SE(1), Yang S, Fang Z, Gurates B, Tamura M, Zhou J, Sebastian S. Author information: (1)Department of Obstetrics and Gynecology, University of Illinois at Chicago, 820 S. Wood St. M/C 808, Chicago, IL 60612, USA. sbulun@uic.edu Aromatase is the key enzyme for estrogen biosynthesis. It is normally expressed in the human ovary, skin, adipose tissue and brain. Aromatase activity is not detectable in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis and is stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, i.e. deficient 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of post-menopausal endometriosis using an aromatase inhibitor. PMID: 11850203 [PubMed - indexed for MEDLINE] 4906. Phys Med Biol. 2002 Feb 7;47(3):491-505. L-shell x-ray fluorescence measurements of lead in bone: theoretical considerations. Todd AC(1). Author information: (1)Department of Community and Preventive Medicine, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA. andrew.todd@mssm.edu This paper reviews several theoretical considerations pertinent to the use of lead L-shell x-rays for the in vivo measurement of lead in bone: the method of correcting for attenuation, the contributions to the measurement uncertainty, interferences, the depth of bone sampled and the signal strength. Both the predicted bone lead concentration and the measurement uncertainty therein are influenced by the choice of linear attenuation coefficient with which to correct for overlying tissue. Measurement uncertainty is also influenced by inter-individual variability in body composition, methodological uncertainty in the ultrasound measurement of overlying tissue thickness and discrepancy between the site of LXRF and the site of ultrasound measurement. Interference with the Pb Lalpha x-rays by As Kalpha has been overstated and is probably negligible, interference from lead in non-bone tissues may not be. The depth of bone from which the signal is obtained and a crude estimate of signal strength are calculated for different bone compositions for both K and L x-ray fluorescence. PMID: 11848124 [PubMed - indexed for MEDLINE] 4907. Curr Opin Clin Nutr Metab Care. 2002 Mar;5(2):185-8. Microdialysis in the intensive care unit: a novel tool for clinical investigation or monitoring? Binnert C(1), Tappy L. Author information: (1)Institute of Physiology, University of Lausanne, Lausanne, Switzerland. Microdialysis is a minimally invasive tool that allows us to gain insight into metabolism at the tissue level. In human investigations, it can be safely performed in the brain (neurosurgical patients), skeletal muscle and adipose tissue. Basically, the technique allows interstitial concentrations of small solutes to be evaluated. Several limitations of the method and possible ways to circumvent them are indicated. Recent technical developments are reviewed. At present, this method is rarely used in metabolic monitoring of critically ill patients, but its potential applications are highlighted. PMID: 11844986 [PubMed - indexed for MEDLINE] 4908. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S73-7. Interoceptive and integrative contributions of forebrain and brainstem to energy balance control. Grill HJ(1), Kaplan JM. Author information: (1)Graduate Groups of Psychology and Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. grill@cattell.psych.upenn.edu An anatomically distributed model of energy balance control contrasts with the widely held hypothalamic center model. The distributionist model is recommended by the observations that the caudal brainstem contains critical interoceptive, integrative and neurochemical mediating functions. A prominent example of interoceptive function is sensitivity to the adipose tissue-derived hormone, leptin. To complement the well established focus on hypothalamic leptin receptors (Ob-Rb), we describe an extensive distribution of Ob-Rb in the brainstem. These receptors, moreover, are functionally relevant given the intake suppressive effects of fourth-intracerebroventricular (i.c.v) and brainstem intraparenchymal (in dorsal vagal complex) delivery. A wide variety of intake relevant peptides receptors are found in hypothalamus, but these receptors are also widely distributed in the caudal brainstem. As an example of the functional relevance of these neurochemical mediators, we describe ingestive effects of ligands for melanocortin 3/4 and corticotrophin-releasing hormone receptors obtained with brainstem ventricular and parenchymal (dorsal vagal complex and parabrachial nucleus) delivery. It is clear that responses obtained from hypothalamic treatments can arise independently from stimulation of caudal brainstem receptors. We have used the chronic decerebrate preparation to ask whether the brainstem contains integrative substrates sufficient to mediate behavioral responses to variations in physiological state. The experiments reveal that the brainstem is indeed sufficient for the integration of taste and gastrointestinal signals that co-determine the size of meals in the short term. Decerebrate rats, however, do not respond to food deprivation or to reductions in the number of daily feeding opportunities. These results suggest that the brainstem in neural isolation from forebrain influence is not sufficient for ingestive response to systemic/metabolic signals that affect intake over the long term. The relative contribution of brainstem and forebrain substrates to long-term intake and body weight control in the neurologically intact animal, remains unclear. The data reviewed support a distributed anatomical model of energy balance and recommend increased attention to specific responses (behavioral, autonomic and endocrine) that are mediated by local (brainstem or forebrain) interoceptive and integrative processes, and those requiring bi-directional interactions. PMID: 11840220 [PubMed - indexed for MEDLINE] 4909. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S56-62. The NPY/AgRP neuron and energy homeostasis. Morton GJ(1), Schwartz MW. Author information: (1)Department of Medicine, Harborview Medical Center and University of Washington, Seattle, Washington 98104, USA. Kennedy hypothesized nearly 50 y ago that negative feedback regulation of body fat stores involves hormones that circulate in proportion to adiposity and enter the brain, where they exert inhibitory effects on food intake and energy balance. Recent studies implicate leptin and insulin as 'adiposity signals' to the brain that promote negative energy balance in two ways: by inhibiting 'anabolic' hypothalamic neuronal circuits that stimulate food intake and promote weight gain, and by activating 'catabolic' pathways that reduce food intake and body weight. Chief among candidate 'anabolic' effector pathways is the NPY/AgRP neuron, found only in the hypothalamic arcuate nucleus. These neurons make peptides that potently stimulate food intake not only by increasing neuropeptide Y (NPY) signaling, but by reducing melanocortin signaling via the release of agouti-related peptide (AgRP), an endogenous melanocortin 3/4 receptor antagonist. Since NPY/AgRP neurons express receptors for leptin and insulin and are inhibited by these hormones, they are activated by a decrease of leptin or insulin signaling. Fasting, uncontrolled diabetes, and genetic leptin deficiency are examples of conditions in which food intake increases via a mechanism hypothesized to involve NPY/AgRP neurons. Data are reviewed which illustrate the role of these neurons in adaptive and maladaptive states characterized by hyperphagia and weight gain. PMID: 11840217 [PubMed - indexed for MEDLINE] 4910. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S35-8. Insulin as an adiposity signal. Woods SC(1), Seeley RJ. Author information: (1)Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. steve.woods@psychiatry.uc.edu Insulin is now well established as an adiposity signal that acts in the brain to influence energy homeostasis. It is secreted in direct proportion to adiposity; it enters the brain from the blood, and it interacts with neurons in the ventral hypothalamus. Experimental manipulation of brain insulin causes predictable changes of food intake and body weight. Because insulin shares many properties with other adiposity signals, especially leptin, in this regard, it is important to recognize the similarities and differences in the signal each conveys to the brain in order to design effective therapeutic approaches to treat pathologies of eating and body weight. PMID: 11840212 [PubMed - indexed for MEDLINE] 4911. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S22-9. An adipose-specific control of thermogenesis in body weight regulation. Dulloo AG(1), Jacquet J. Author information: (1)Institute of Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland. abdul.dulloo@unifr.ch Much of our understanding about 'adaptive thermogenesis' as a control system in mammalian weight regulation derives from studies of experimental starvation and overfeeding, and these have served to characterize its functional role as an 'attenuator' of energy imbalance. By applying a system-analysis approach in evaluating data on the energetics of starvation and refeeding, evidence is presented here in support of the hypothesis that there are in fact two distinct control systems underlying adaptive thermogenesis. In one of them, the efferent limb is primarily under the control of the sympathetic nervous system (SNS), whose functional state is dictated by overlapping or interacting signals arising from a variety of environmental stresses, including food deprivation, deficiency of essential nutrients, excess energy intake and exposure to cold or to infections; it is hence referred to as the non-specific control of thermogenesis, and is likely to occur primarily in organs/tissues with a high specific metabolic rate (eg liver, kidneys, brown fat). The other is independent of the functional state of the SNS and is dictated solely by signals arising from the state of depletion of the adipose tissue fat stores; it is hence referred to as the adipose-specific control of thermogenesis, and is postulated to occur primarily in the skeletal muscle. While suppression of this adipose-specific thermogenesis during both starvation and refeeding leads to energy conservation, the energy spared during refeeding is directed specifically at the replenishment of the fat stores, so that it functions as an 'accelerator' of fat recovery. These two distinct control systems for adaptive thermogenesis have been incorporated in a compartmental model of body weight and body composition regulation. This is used to provide a mechanistic explanation as to how, during weight recovery, they can operate simultaneously but in opposite directions--with activation of thermogenesis under non-specific control being energy-dissipating, while suppression of thermogenesis under adipose-specific control being energy-conserving--and could hence explain the paradox of a high efficiency of fat recovery co-existing with an overall state of enhanced thermogenesis and hypermetabolism. Elucidating the components of the adipose-specific control of thermogenesis (ie its sensors, signals and effector mechanisms) will have important implications for our understanding of body composition regulation, and hence for the development of more effective strategies in the management of cachexia and obesity. PMID: 11840210 [PubMed - indexed for MEDLINE] 4912. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S4-6. Clinical implications of the ponderostat concept: view from the chair. Tremblay A(1). Author information: (1)Division of Kinesiology, Laval University, Ste-Foy Québec, Canada. angelo.tremblay@kin.msp.ulaval.ca PMID: 11840206 [PubMed - indexed for MEDLINE] 4913. J Pediatr Endocrinol Metab. 2001;14 Suppl 6:1445-51. Prader-Willi syndrome: how does growth hormone affect body composition and physical function? Carrel AL(1), Allen DB. Author information: (1)Department of Pediatrics, University of Wisconsin Children 's Hospital, Madison 53792, USA. alcarrel@facstaff.wisc.edu Children with Prader-Willi syndrome (PWS) display diminished growth, reduced muscle mass (lean body mass), and increased adipose tissue-body composition abnormalities resembling those seen in growth hormone (GH) deficiency. Diminished GH responses to various provocative agents, low insulin-like growth factor-I levels, and the presence of other hypothalamic dysfunction support the presence of true GH deficiency (GHD) in many children with PWS. GH treatment in these children decreases body fat, and increases linear growth, muscle mass, fat utilization and energy expenditure. Strength and agility are also improved. These improvements are most dramatic during the first year of GH therapy, and prolonged treatment still does not 'normalize' these parameters. The metabolic effects, including changes in physical strength and agility, may be the most important features for this particular pediatric population. These observations support a contribution of GHD to disabilities of children with PWS, and a clinically significant benefit of GH treatment. PMID: 11837498 [PubMed - indexed for MEDLINE] 4914. J Pediatr Endocrinol Metab. 2001;14 Suppl 6:1417-29. How the brain regulates food intake and body weight: the role of leptin. Baskin DG(1), Blevins JE, Schwartz MW. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, USA. baskindg@u.washington.edu The brain plays a key role in the regulation of energy homeostasis, balancing food intake and energy expenditure to maintain adipose tissue mass. A widely accepted model proposes that energy homeostasis is modulated by hormones that circulate in the blood in proportion to adipose tissue mass. A major candidate 'adiposity signal' to the brain is the adipocyte hormone, leptin; this inhibits neuropeptide circuits that promote anabolic metabolism, and stimulates those that promote catabolic metabolism. It is hypothesized that leptin-responsive circuits in the hypothalamus project to caudal brainstem neuronal groups that integrate satiety signals converging on the brain from the stomach and intestine following ingestion of food. Leptin signaling to the brainstem via hypothalamic pathways potentially increases the brain's motor and autonomic responses to satiety signals, leading to smaller individual meals, reduced cumulative food intake, and a lower body weight. This mechanism explains how leptin deficiency or defects in the brain's processing of leptin signaling can result in a sustained increase in food intake and obesity. PMID: 11837495 [PubMed - indexed for MEDLINE] 4915. Pigment Cell Res. 2002 Feb;15(1):10-8. Agouti: from mouse to man, from skin to fat. Voisey J(1), van Daal A. Author information: (1)Co-operative Research Centre for Diagnostics, Queensland University of Technology, Brisbane, Australia. The agouti protein regulates pigmentation in the mouse hair follicle producing a black hair with a subapical yellow band. Its effect on pigmentation is achieved by antagonizing the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (Mc1r), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). Dominant mutations in the non-coding region of mouse agouti cause yellow coat colour and ectopic expression also results in obesity, type 11 diabetes, increased somatic growth and tumourigenesis. At least some of these pleiotropic effects can be explained by antagonism of other members of the melanocortin receptor family by agouti protein. The yellow coat colour is the result of agouti chronically antagonizing the binding of alpha-MSH to Mc1r and the obese phenotype results from agouti protein antagonizing the binding of alpha-MSH to Mc3r and/or Mc4r. Despite the existence of a highly homologous agouti protein in humans, agouti signal protein (ASIP), its role has yet to be defined. However it is known that human ASIP is expressed at highest levels in adipose tissue where it may antagonize one of the melanocortin receptors. The conserved nature of the agouti protein combined with the diverse phenotypic effects of agouti mutations in mouse and the different expression patterns of human and mouse agouti, suggest ASIP may play a role in human energy homeostasis and possibly human pigmentation. PMID: 11837451 [PubMed - indexed for MEDLINE] 4916. Lipids. 2001 Dec;36(12):1289-305. Factors affecting the storage and excretion of toxic lipophilic xenobiotics. Jandacek RJ(1), Tso P. Author information: (1)The University of Cincinnati, Department of Pathology, Ohio 45267, USA. ronald.jandacek@uc.edu Lipophilic toxins have been introduced into the environment both as functional compounds, such as pesticides, and as industrial waste from incineration or the manufacture of electrical transformer components. Among these substances are compounds that are carcinogenic and that affect the endocrine system. Accidental high exposures of humans to some lipophilic toxins have produced overt disease symptoms including chloracne and altered liver function. These toxic materials have been the recent focus of international effort to reduce or eliminate classes of halogenated hydrocarbons from the environment. Evidence of the widespread distribution of lipophilic toxins in the biosphere has been obtained by analyses of human tissues and human milk. The principal route of entry of lipophilic toxins into humans is through the food chain, and most of them are stored in adipose tissue. A common route of excretion is in bile, but there is also evidence of nonbiliary excretion into the intestine. Enterohepatic circulation of many of these compounds slows their removal from the body. Substances that interrupt the enterohepatic circulation of compounds that enter the intestine by the biliary and nonbiliary routes increase the rate of their removal from the body and reduce their storage half-lives. Reduction in body fat, along with these dietary substances that interrupt enterohepatic circulation, further enhances the excretion rate. Areas for further research include optimizing regimens for body burden reductions, understanding the nature of nonbiliary excretion, and following the effects of tissue redistribution during loss of body fat. PMID: 11834080 [PubMed - indexed for MEDLINE] 4917. J Soc Biol. 2001;195(3):243-8. [Regulation of carbohydrate metabolism by insulin: role of transcription factor SREBP-1c in the hepatic transcriptional effects of the hormone]. [Article in French] Foufelle F(1), Ferré P. Author information: (1)Unité INSERM 465, Centre de Recherches Biomédicales des Cordeliers, Université Paris 6, 15, rue de l'Ecole de Médecine, 75270 Paris. A number of tissues such as the brain must be continuously provided with glucose to meet their energy demand. In contrast, carbohydrate absorption during meals is a discontinuous process. Thus, we must store glucose when its is provided, release it or spare it when it is less abundant. Insulin, secreted by the pancreatic beta-cell is a key hormone in the adaptations of metabolic pathways linked to glucose homeostasis. It inhibits hepatic glucose production, promotes glucose storage in the liver and glucose uptake and storage in muscles and adipose tissues. This is achieved through the modifications of the activity of existing proteins (enzymes, transporters) but also through the regulation of gene expression. In the liver, when the diet is rich in carbohydrates, insulin is secreted and stimulates the expression of genes involved in glucose utilization (glucokinase, L-pyruvate kinase, lipogenic enzymes) and inhibits genes involved in glucose production (phosphenolpyruvate carboxykinase). The mechanisms by which insulin controls the expression of these genes were poorly understood. Recently, the transcription factor Sterol Regulatory Element Binding Protein-1c (SREBP-1c) has been proposed as a key mediator of insulin transcriptional effects. Insulin increases the synthesis and nuclear abundance of this factor which when overexpressed in the liver mimics the effects of insulin on insulin-sensitive genes. This suggests that SREBP-1c could be involved in pathologies such as type 2 diabetes, obesity and more generally in insulin resistance syndromes. PMID: 11833461 [PubMed - indexed for MEDLINE] 4918. Nutrition. 2002 Jan;18(1):66-70. Dual-energy X-ray absorptiometry and body composition: differences between devices and comparison with reference methods. Genton L(1), Hans D, Kyle UG, Pichard C. Author information: (1)Geneva University Hospital, Geneva, Switzerland. PMID: 11827768 [PubMed - indexed for MEDLINE] 4919. Ned Tijdschr Geneeskd. 2002 Jan 19;146(3):103-9. [Free fatty acids: mediators of insulin resistance and atherosclerosis]. [Article in Dutch] Castro Cabezas M(1), Erkelens DW, van Dijk H. Author information: (1)Afd. Vasculaire Geneeskunde, Universitair Medisch Centrum Utrecht, Postbus 85.500, 3508 GA Utrecht. m.castrocabezas@azu.nl Free fatty acids (FFAs) are involved in the transportation of energy; in the postprandial phase to the peripheral tissues and in the postabsorptive phase from the adipose tissue to the liver. In the postprandial phase, FFAs are mainly derived from hydrolysis of triglyceride-rich particles like chylomicrons and very low-density lipoproteins (VLDL). The flux of FFAs is directed to peripheral cells such as adipocytes and muscle cells. In the postabsorptive period, FFAs are transported to the liver after being released from intracellular storage in the adipocytes. Complement component 3 (C3) plays an important role in the uptake of free fatty acids by the peripheral cells and their esterification to triglycerides. Since C3 is also involved in the pathogenesis of the insulin resistance syndrome, and since a deviant FFA metabolism with an increased FFA flux to the liver may induce insulin resistance, it is hypothesized that C3 may form the missing link between FFA metabolism and insulin resistance. In addition, recent studies have increasingly indicated that atherosclerosis is in fact an inflammation-based process involving complement-dependent responses, in which FFAs seem to play a role in the complement-dependent pathway. It has recently become apparent that FFAs have a regulatory function in the transcription of DNA, in relation to lipoprotein metabolism. This is where PPAR-gamma and PPAR-alpha agonists ('glitazones' and fibrates respectively) are active (PPAR is an abbreviation for peroxisome proliferation activating receptor). Glitazons may play an important role in the treatment of insulin resistance and related disorders. Acquiring more knowledge about the relationship between complement and FFA metabolism may increase our understanding of these processes and provide openings for the development of new antiatherogenic strategies. PMID: 11826668 [PubMed - indexed for MEDLINE] 4920. Expert Opin Pharmacother. 2001 Oct;2(10):1615-22. Perspectives in the therapeutic use of leptin. Salvador J(1), Gomez-Ambrosi J, Frühbeck G. Author information: (1)Department of Endocrinology, University Clinic of Navarra and Metabolic Research, University of Navarra, Pamplona, Spain. jsalvador@unav.es The cloning and characterisation of the protein encoded by the ob gene, called leptin, has represented an enormous advance in the knowledge we have at the present time on the control of appetite and the regulation of body weight. Animal experiments have shown that this adipocyte-derived hormone informs the hypothalamus about the magnitude of fat stores and induces changes in eating behaviour and thermogenesis directed to maintain nutritional homeostasis. Besides the CNS and adipose tissue, other tissues like the gonads, adrenals, pancreas, blood vessels, immune cells and bone are also targets for leptin action, setting the basis for the pleiotropic character of leptin. In contrast to ob(-)/ob(-) mice, which have leptin deficiency, obese patients usually exhibit hyperleptinaemia due to leptin resistance of uncertain aetiology. Patients with congenital leptin deficiency show a dramatic response to recombinant leptin therapy in terms of body weight and fat reduction. However, in contrast to animals, no thermogenic effect has been demonstrated in humans treated with leptin. Leptin-resistant obese subjects display a heterogeneous response to leptin treatment, though some patients achieve a significant weight loss when receiving high doses. New formulations are being tried with different success rates. Before leptin can play a role in the treatment of obesity, more studies are needed to discover which is the adequate dose, which the best route and form of administration and how we can select the patients who will benefit from this particular therapy. The development of new leptin analogues with high penetrating capacity to cross the blood-brain barrier and the investigation of other approaches to overcome the leptin resistance are awaited. Future applications of leptin may be directed to the treatment of infertility, wound healing and bone remodelling among others. PMID: 11825304 [PubMed - indexed for MEDLINE] 4921. Pituitary. 2001 Jan-Apr;4(1-2):93-9. Leptin, reproduction and sex steroids. Casabiell X(1), Piñeiro V, Vega F, De La Cruz LF, Diéguez C, Casanueva FF. Author information: (1)Department of Physiology, Complejo Hospitalario Universitario de Santiago, University of Santiago de Compostela, Spain. xcasab@lugo.usc.es Leptin is a hormone secreted mainly by the adipose cells with a primary role in the regulation of body weight by establishing a feedback loop between the energy reserves and the hypothalamic centers that control food intake. Recent data suggest that, in addition, leptin interacts with other endocrine systems to provide critical information about the size of the fat stores, acting as a permissive factor that allows the triggering of energy-demanding situations, as the onset of puberty and the reproduction, only when the size of the fuel reserve is large enough to guarantee its success. In addition, leptin appears to play a role during pregnancy and lactation, as it is produced by the placenta and is present in maternal milk. The fact that leptin levels are always higher in females, even after correcting for body fat content, suggests that the interaction between the adipose tissue and the reproductive system is modulated in a different way in males and females by androgenic and estrogenic hormones. In fact, adipose tissue samples taken from male donors are completely refractory in vitro to the action of both estrogens and androgens. On the contrary, dihydrotestosterone, androstenedione and dehydroepiandrosterone-S are potent inhibitors of leptin secretion, while estradiol induces a strong stimulation in adipose tissue taken from women. Testosterone is devoid of activity in either gender. PMID: 11824514 [PubMed - indexed for MEDLINE] 4922. Pituitary. 2001 Jan-Apr;4(1-2):33-47. Leptin and leptin receptor in anterior pituitary function. Lloyd RV(1), Jin L, Tsumanuma I, Vidal S, Kovacs K, Horvath E, Scheithauer BW, Couce ME, Burguera B. Author information: (1)Department of Laboratory Medicine and Pathology, Mayo Foundation, Rochester, MN 55905, USA. Leptin is a 16 kDa protein that exerts important effects on the regulation of food intake and energy expenditure by interacting with the leptin receptor in the brain and in many other tissues. Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland. Many studies have implicated leptin in anterior pituitary function including the observation that homozygous mutations of the leptin receptor gene led to morbid obesity, lack of pubertal development and decreased GH and TSH secretion. In addition, leptin functions as a neuroendocrine hormone and regulates many metabolic activities. Leptin also interacts with and regulates the hypothalamic-pituitary-adrenal, the hypothalamic-pituitary-thyroid and the hypothalamic-pituitary-gonadal axes. All of the anterior pituitary cell types express the leptin receptor. However, leptin has been localized in specific subtypes of anterior pituitary cells indicating cell type-specific production of leptin in the anterior pituitary. Subcellular localization of leptin indicates co-storage with secretory granules and implicates hypothalamic releasing hormones in leptin secretion from anterior pituitary hormone cells. Leptin signal transduction in the anterior pituitary has been shown to involve the janus protein-tyrosine kinase (JAK)/signal transducer and activation of transcription (STAT) as well as suppressor of cytokine signalling (SOCS). These proteins are activated by tyrosine-phosphorylation in anterior pituitary cells. The various steps in pituitary leptin signal transduction remain to be elucidated. PMID: 11824506 [PubMed - indexed for MEDLINE] 4923. Pituitary. 2001 Jan-Apr;4(1-2):111-6. Influence of cortisol status on leptin secretion. Leal-Cerro A(1), Soto A, Martínez MA, Dieguez C, Casanueva FF. Author information: (1)Department of Endocrinology, H. U. Virgen del Rocío, Sevilla, Spain. aleal@hvr.sas.cica.es The discovery of the adipocyte-produced hormone leptin has changed the field of obesity research and our understanding of energy homeostasis. It is now accepted that leptin is the afferent loop informing the hypothalamus about the states of fat stores, with hypothalamic efferents regulating appetite and energy expenditure. I addition, leptin has a role as a metabolic adaptator in overweight and fasting states. New and previously unsuspected neuroendocrine roles have emerged for leptin. Leptin participates in the expression of CRH in the hypothalamus, interacts at the adrenal level with ACTH, and is regulated by glucocorticoids. Since leptin and cortisol show an inverse circadian rhythm, it has suggested that a regulatory feedback is present. However glucocorticoids appears to play a modulatory, but not essential roles in generating leptin diurnal rhythm. Glucocortiocids act directly on the adipose tissue and increase leptin synthesis and secretion in humans. Leptin levels are markedly increased in Cushing's syndrome patients and in other pseudo-Cushing's syndrome states. Glucocorticoids appears to act as a key modulator of body weight and food intake, promoting leptin secretion by adipocytes, limiting central leptin induced effects and favoring those of the NPY. Furthermore the modulatory role of glucocorticoids could be altered in obesity, but the precise mode of action remains to be established. The relevance of this finding merits further studies. PMID: 11824503 [PubMed - indexed for MEDLINE] 4924. Annu Rev Med. 2002;53:319-36. Lipotoxic diseases. Unger RH(1). Author information: (1)Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA. roger.unger@utsouthwestern.edu I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic beta-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as beta-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents. PMID: 11818477 [PubMed - indexed for MEDLINE] 4925. J Endocrinol Invest. 2001 Dec;24(11):897-913. Control of energy metabolism by iodothyronines. Lanni A(1), Moreno M, Lombardi A, de Lange P, Goglia F. Author information: (1)Department of Life Sciences, Second University of Naples, Caserta, Italy. One of the most widely recognized effects of thyroid hormones (TH) in adult mammals is their influence over energy metabolism. In the past, this has received much attention but, possibly because of the complex mode of action of thyroid hormones, no universally accepted mechanism to explain this effect has been put forward so far. Significant advances in our understanding of the biochemical processes involved in the actions of TH have been made in the last three decades and now it seems clear that TH can act through both nuclear-mediated and extranuclear-mediated pathways. TH increase energy expenditure, partly by reducing metabolic efficiency, with control of specific genes at the transcriptional level, being is thought to be the major molecular mechanism. However, both the number and the identity of the thyroid-hormone-controlled genes remain unknown, as do their relative contributions. The recent discovery of uncoupling proteins (UCPs) (in addition to UCP1 in brown adipose tissue) in almost all tissues in animals, including humans, has opened new perspectives on the understanding of the mechanisms involved in the regulation of energy metabolism by thyroid hormones. Other approaches have included the various attempts made to attribute changes in respiratory activity to a direct influence of thyroid hormones over the mitochondrial energy-transduction apparatus. In addition, an increasing number of studies has revealed that TH active in the regulation of energy metabolism include not only T3, but also other iodothyronines present in the biological fluids, such as 3,5-diiodothyronine (3,5-T2). This, in turn, may make it possible to explain some of the effects exerted by TH on energy metabolism that cannot easily be attributed to T3. PMID: 11817716 [PubMed - indexed for MEDLINE] 4926. Nephrol Dial Transplant. 2002 Feb;17(2):191-5. The adipose tissue--a novel endocrine organ of interest to the nephrologist. Wiecek A, Kokot F, Chudek J, Adamczak M. PMID: 11812861 [PubMed - indexed for MEDLINE] 4927. Klin Med (Mosk). 2001;79(11):8-12. [Digestive and regulatory effects of chyme lipolytic activity]. [Article in Russian] Korot'ko GF. PMID: 11811118 [PubMed - indexed for MEDLINE] 4928. Nihon Rinsho. 2002 Jan;60(1):154-60. [The tailor-made diet therapy to improve obesity]. [Article in Japanese] Takakura Y(1), Yoshida T. Author information: (1)First Department of Internal Medicine, Kyoto Prefectural University of Medicine. As the white adipose tissue, especially abdominal fat is an endocrine organ secreting adipocytokines, which induce insulin resistance, hypertension, and arteriosclerotic diseases, reduction of the abdominal fat is important. But effect of the diet therapy differs in each individual, because of the difference of energy expenditure. Since the relationship between the missense mutation (Trp64Arg) of the beta 3-adrenergic receptor (beta 3-AR) gene and low energy expenditure in the obese Pima Indians was made clear, gene polymorphisms that mediate body weight are reported one after another. We also reported that one third of Japanese have the Trp64Arg mutation of beta 3-AR gene, which may produce obesity or difficulties in weight loss. Here we introduce the obesity-related genes, and report the importance of Tailor-made diet therapy based on molecular genetics to improve obesity. PMID: 11808327 [PubMed - indexed for MEDLINE] 4929. Laryngoscope. 2001 Dec;111(12):2157-61. Lipoinjection augmentation of the soft palate for velopharyngeal stress incompetence. Klotz DA(1), Howard J, Hengerer AS, Slupchynskj O. Author information: (1)Division of Otolaryngology, University of Rochester Medical Center, Rochester, New York 14642, USA. OBJECTIVES/HYPOTHESIS: Velopharyngeal stress incompetence in professional musicians is an uncommon but potentially career-ending problem. Pharyngeal flaps, V-Y palatal pushback procedures, Teflon or collagen injection of the posterior pharyngeal wall, and speech therapy have all been used to address this problem. The ideal procedure for this subset of patients with velopharyngeal incompetence (VPI) with high-pressure, mild VPI would be one that combines low morbidity and an expedient recovery for the busy musician. We describe an approach of endoscopically assisted autologous lipoinjection of the soft palate. STUDY DESIGN: A retrospective review of our experience treating high-pressure stress VPI in two professional musicians. METHODS: Literature review and retrospective chart review. RESULTS: Two musicians underwent autologous lipoinjection of the soft palate for stress VPI. Patients resumed full play within 2 weeks of the operation with no serious complications. There has been no recurrence of the VPI after 18 and 12 months of follow-up, respectively. CONCLUSIONS: Velopharyngeal stress incompetence in musicians is an uncommon disorder. Velopharyngeal incompetence in these patients may not present as in a typical manner with hypernasality but may go undiagnosed for years mistakenly rationalized as a declining performance ability rather than a curable structural problem. The performance demands of professional musicians necessitate a timely solution to their VPI. More precise and limited contouring of palatal bulk can be achieved through the lipoinjection technique than compared with traditional palatal V-Y pushback or a standard pharyngeal flap. Lipoinjection of the palate can be performed as an outpatient procedure with only minor discomfort and an expedient recovery for the career musician. PMID: 11802016 [PubMed - indexed for MEDLINE] 4930. IUBMB Life. 2001 Sep-Nov;52(3-5):175-9. Uncoupling proteins--how do they work and how are they regulated. Klingenberg M(1). Author information: (1)Institute of Physical Biochemistry, University of Munich, Germany. klingenberg@pbm.med.uni-muenchen.de Uncoupling proteins (UCPs) are regulated H+ transporters and a subfamily of the mitochondrial carrier family. Whereas UCP1 in brown adipose tissue has a well-defined role in thermogenesis, the roles of other UCPs are still tentative, such as in control of immune response, oxygen radical formation, and insulin secretion. The popular overexpression in yeast did not yield a functional form of UCP3 and possibly of other UCPs in mitochondria with the exception of UCP1. Whereas UCP1 can be isolated in native form, the isolation of other native UCPs from tissues or from overexpression in yeast failed. UCPs (UCP1, 2, and 3) expressed in E. coli as inclusion bodies can be reconstituted to yield H+ transport only in the presence of CoQ requiring fatty acids as native UCP1. The rates are similar to native UCP1 and are inhibited by low nucleotide concentrations. Native UCP1 is activated by endogenous CoQ. Differences between UCPs may reside in the regulation, such as by the ATP/ADP ratio in accordance with the specific cellular requirements. PMID: 11798030 [PubMed - indexed for MEDLINE] 4931. Curr Opin Lipidol. 2002 Feb;13(1):51-9. Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Havel PJ(1). Author information: (1)Department of Nutrition, University of California, Davis, California 95616, USA. pjhavel@ucdavis.edu Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation-stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptin's critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin-induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation-stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation-stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation-stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin-resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma; an action may contribute to the insulin-sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance. PMID: 11790963 [PubMed - indexed for MEDLINE] 4932. Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):25-30. Perspectives on body composition. Forbes GB(1). Author information: (1)University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 777, Rochester, NY 14642, USA. Gilbert_Forbes@URMC.Rochester.edu Comment in Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):1-3. Herein modern body composition techniques are described, and the uses to which they are put are set forth. They have increased our knowledge of the human growth process as well as the effects of disease, hormones, and nutrition. In essence they provide for a bloodless dissection of the human body. PMID: 11790945 [PubMed - indexed for MEDLINE] 4933. Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):11-7. Insulin resistance in the elderly--the focus enlarges. Kinney JM(1). Author information: (1)Columbia University, College of Physicians and Surgeons, NY, USA. PMID: 11790943 [PubMed - indexed for MEDLINE] 4934. Adv Exp Med Biol. 2001;501:397-401. Long-chain polyunsaturated fatty acids (LC-PUFA) during early development: contribution of milk LC-PUFA to accretion rates varies among organs. Hamosh M(1), Henderson TR, Kemper MA, Orr NM, Gil A, Hamosh P. Author information: (1)Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA. Long-chain polyunsaturated fatty acids (LC-PUFA) accretion (essential for growth and neural development) was studied from late fetal throughout weaning age in the ferret, a species with maternal LC-PUFA sufficiency during pregnancy and lactation. The data show that a) accretion rate of LC-PUFA is rapid during early postnatal development, b) milk LC-PUFA decrease during lactation, c) adipose tissue LC-PUFA level is directly related to milk LC-PUFA level, while accretion in brain and liver exceeds dietary intake, d) accretion of arachidonic acid occurs earlier than docosahexaenoic acid, suggesting earlier development of n6-fatty acid endogenous synthesis. PMID: 11787708 [PubMed - indexed for MEDLINE] 4935. Ann Endocrinol (Paris). 2001 Sep;62(4 Pt 2):S7-17. [Lipid metabolism in adipose tissue: adrenergic control of the adipocyte and mobilization if the lipids]. [Article in French] Lafontan M(1). Author information: (1)Unité INSERM 317, Institut Louis-Bugnard, Université Paul-Sabatier, CHU Rangueil F-31403 Toulouse. lafontan@rangueil.inserm.fr PMID: 11787372 [PubMed - indexed for MEDLINE] 4936. Horm Res. 2001;56 Suppl 1:82-5. Physiological principles of endocrine replacement: estrogen. Burger HG(1). Author information: (1)Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton Road, Clayton 3168 Victoria, Australia. henry.burger@med.monash.edu.au The major biologically active circulating estrogen in both males and females is estradiol (E(2)). Circulating E(2) is a product of the ovarian granulosa cell and the testicular Leydig cell. Its gonadal formation is dependent on A-ring aromatization of its immediate precursor, testosterone, by a particular isoform of the enzyme aromatase, which also catalyses the conversion of the much weaker androgen, androstenedione, to the weak estrogen, estrone. E(2) is also formed in non-gonadal tissues, such as adipose tissue, liver, muscle and brain. Only adipose tissue makes significant extra-gonadal contributions to circulating estrogen. Loss of ovarian function during reproductive life, as a result of loss of gonadotropin secretion (secondary hypogonadism) or as a result of premature ovarian failure (generally defined as cessation of ovarian function prior to age 40), results in loss of the majority of circulating E(2) and of luteal progesterone. Loss of ovarian function at the menopause likewise results in a 90% loss of circulating E(2). The consequences of loss of ovarian function during reproductive life may be severe. Symptoms include hot flushes, night sweats, vaginal dryness and dyspareunia, loss of libido, loss of bone mass with subsequent osteoporosis and abnormalities of cardiovascular function, including a substantial increase in the risk of ischemic heart disease. Various regimens of estrogen replacement have been employed, aiming to eliminate symptoms, restore well-being and avert the consequences of estrogen depletion. The commonly adopted form of replacement is with the low-dose oral contraceptive pill for reasons of convenience, cost, efficacy, general freedom from side effects and the psychological advantage that many of the patient's peer group are also "taking the pill". An often neglected aspect of hormone therapy in the reproductive age group is the therapeutic use of testosterone. The application of such principles to the postmenopausal period is more problematic, as there is a common perception that the menopause is a normal physiological occurrence and that it is therefore not physiological to offer hormone therapy at that time. The pragmatic approach is to recommend standard therapy with estrogen and progestogen for the management of menopausal symptoms and to recommend longer term hormone replacement in the light of the individual's needs and current data with regard to efficacy for protection from osteoporosis and cardiovascular disease. Copyright 2001 S. Karger AG, Basel PMID: 11786692 [PubMed - indexed for MEDLINE] 4937. Horm Res. 2001;56 Suppl 1:1-6. Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. Stewart PM(1), Toogood AA, Tomlinson JW. Author information: (1)Department of Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. p.m.stewart@bham.ac.uk In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11beta-HSD type 2 (11beta-HSD2) inactivates F to E in the kidney, whilst 11beta-HSD type 1 (11beta-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11beta-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11beta-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11beta-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11beta-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing's syndrome--notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11beta-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11beta-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone - levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11beta-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11beta-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11beta-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach. Copyright 2001 S. Karger AG, Basel PMID: 11786677 [PubMed - indexed for MEDLINE] 4938. Mol Membr Biol. 2001 Oct-Dec;18(4):237-45. Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane (review). Thurmond DC(1), Pessin JE. Author information: (1)Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indianapolis 46202, USA. The GLUT4 facilitative glucose transporter protein is primarily expressed in muscle and adipose tissue and accounts for the majority of post-prandial glucose uptake. In the basal or non-stimulated state, GLUT4 is localized to intracellular membrane compartments sequestered away from circulating glucose. However, in response to agonist stimulation, there is a marked redistribution of the GLUT4 protein to the cell surface membrane providing a transport route for the uptake of glucose. This GLUT4 translocation can be divided into four general steps: (i) GLUT4 vesicle trafficking out of the storage pool, (ii) docking just below the cell surface, (iii) priming via the interactions of the SNARE proteins present on the vesicular and plasma membranes, and (iv) fusion of the GLUT4 vesicle with the plasma membrane. This review focuses on recent advances made in identification and characterization of the molecular events and protein interactions involved in these steps of insulin-stimulated GLUT4 translocation. PMID: 11780752 [PubMed - indexed for MEDLINE] 4939. Theriogenology. 2002 Jan 1;57(1):73-86. Leptin regulation of reproductive function and fertility. Smith GD(1), Jackson LM, Foster DL. Author information: (1)Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109-0617, USA. smithgd@umich.edu Leptin, a 16-KD protein secreted primarily by adipose tissue, was first discovered in the search for a satiety signal. When administered into the brain, leptin depresses appetite. Interestingly, hyperphagic, obese, transgenic mice with leptin deficiency were noted to be reproductively incompetent, and administration of leptin restored their fertility. These pivotal observations led to numerous studies on the site of action of leptin within the hypothalamo-hypophyseal-gonadal axis, and a variety of models have been used ranging from the prepubertal condition to fasting suppression of reproductive hormones. The preponderance of studies thus far has focused on how leptin serves as a metabolic signal of energy balance within the neuroendocrine system, particularly as a regulator of GnRH/LH secretion. Less research has been conducted with other components of the reproductive system, but local effects of leptin have been demonstrated in the gonads where hyperleptinemia suppresses steroidogenesis and potentially affects gamete maturation. This presentation will review the major concepts for the role of leptin in the modulation of fertility and will consider the potential use of leptin in assisted reproductive technology and embryo transfer. PMID: 11775982 [PubMed - indexed for MEDLINE] 4940. Am J Kidney Dis. 2002 Jan;39(1):1-11. Leptin and renal disease. Wolf G(1), Chen S, Han DC, Ziyadeh FN. Author information: (1)Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Germany. Leptin is a small peptide hormone that is mainly, but not exclusively, produced in adipose tissue. The circulating leptin concentration therefore directly reflects the amount of body fat. Leptin was identified through positional cloning of the obese (ob) gene, which is mutated in the massively obese ob/ob mouse, and it has a pivotal role in regulating food intake and energy expenditure. It binds to the so-called long receptor (Ob-Rb) in the hypothalamus and regulates food intake through the release of other neurotransmitters. Moreover, leptin exerts several other important metabolic effects on peripheral tissue, including modification of insulin action, induction of angiogenesis, and modulation of the immune system. As a small peptide, leptin is cleared principally by the kidney. Not surprisingly, serum leptin concentrations are increased in patients with chronic renal failure and those undergoing maintenance dialysis. Whether the hyperleptinemia of chronic renal failure contributes to some uremic manifestations, such as anorexia and weight loss, requires additional investigation. The kidney expresses abundant concentrations of the truncated isoform of the leptin receptor Ob-Ra, but only a small amount of the full-length receptor Ob-Rb. We recently discovered that leptin has direct effects on renal pathophysiological characteristics. Both cultured glomerular endothelial cells and mesangial cells obtained from the diabetic db/db mouse possess the Ob-Ra receptor, but whether biological effects of leptin are transduced through this receptor remains unknown. In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta1 (TGF-beta1) synthesis, and type IV collagen production. Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor, but not TGF-beta1, and stimulates glucose transport and type I collagen production through signal transduction pathways involving phosphatidylinositol-3-kinase. These data suggest that leptin triggers a paracrine interaction in which glomerular endothelial cells secrete TGF-beta, to which sensitized mesangial cells may respond. Both cell types increase their expression of extracellular matrix in response to leptin. Infusion of leptin into normal rats for 3 weeks fosters the development of focal glomerulosclerosis and proteinuria. Additional previously described direct and indirect effects of leptin on the kidney include natriuresis, increased sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is not only a site of leptin metabolism, but also a target organ for leptin action in pathophysiological states. Copyright 2002 by the National Kidney Foundation, Inc. PMID: 11774095 [PubMed - indexed for MEDLINE] 4941. Expert Opin Investig Drugs. 2001 Sep;10(9):1677-86. Therapeutic potential of bone morphogenetic proteins. Azari K(1), Doll BA, Sfeir C, Mu Y, Hollinger JO. Author information: (1)Bone Tissue Engineering Center, Carnegie Mellon University, 125 Smith Hall, 5000 Forbes Avenue, Pittsburgh, PA 15213, USA. kodiazari@yahoo.com Recently, there has been substantial progress in the area of bone morphogenetic protein (BMP) research. This review serves as an up-to-date summary of the history of BMPs, the mechanisms of BMP signalling and the role of BMPs in adipose, kidney, liver, bone and nervous system. The potential of BMPs as therapeutic agents will also be discussed. PMID: 11772277 [PubMed - indexed for MEDLINE] 4942. Climacteric. 2001 Dec;4(4):273-83. Menopausal obesity--myth or fact? Milewicz A(1), Tworowska U, Demissie M. Author information: (1)Department of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland. Obesity, particularly with central fat distribution, and mortality from all causes are directly related in middle-aged women. Many studies have shown that women in their mid-life tend to gain weight, with a shift to visceral fat distribution. The etiology of perimenopausal obesity is not fully known, and it remains unclear whether excessive weight gain and changes in fat distribution at menopausal age result from climacteric changes or are related to the process of aging of the individual and/or to changing life-style factors. Obesity may have a genetic background. It is well established that an excessive amount of energy intake and too small an energy expenditure is crucial for the development of obesity. Diet composition also plays a role in the pathogenesis of obesity. Neuropeptides appear to be one of the factors that control food intake and nutrient balance. The aging process in women is associated with progressive declines in the levels of many hormones including estrogens, dehydroepiandrosterone (DHEA) and growth hormone-insulin-like growth factor I (GH-IGF-I). These endocrine perturbations may result in altered body composition and weight gain. Obesity in postmenopausal women is accompanied by many metabolic disturbances leading to increased mortality. PMID: 11770183 [PubMed - indexed for MEDLINE] 4943. Semin Urol Oncol. 2001 Nov;19(4):270-9. Obesity, interrelated mechanisms, and exposures and kidney cancer. Moyad MA(1). Author information: (1)Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109-0330, USA. Obesity has been shown to increase the risk or be associated with numerous conditions from cardiovascular disease and type II diabetes to erectile dysfunction and osteoarthritis. Obesity may also be associated with numerous cancers, and kidney cancer or renal-cell cancer (RCC) may have one of the strongest correlations to obesity compared with cancer at any other site. Almost every epidemiologic investigation has demonstrated an association that tends to affect women more than men, but both genders are impacted. In general, past studies suggest that with increasing weight, a threshold point exists whereby a certain range of body mass index dramatically changes risk. Men and women at the most extreme ends of obesity tend to have the highest risk or only risk in past studies. Individuals at the more extreme ends of obesity may be affected by an almost indefinite number of mechanisms and exposures that could determine incidence and possibly prognosis. For example, higher estrogen levels, elevated insulin levels, a greater concentration of growth factors in adipose tissue, hypertension, cholesterol metabolism abnormalities, and immune malfunction are just some of the potential mechanisms that may increase kidney cancer risk. Obese individuals may also have lower serum levels of vitamin D and engage in less physical activity. Smoking or genetic predisposition to RCC may synergistically contribute to the effect of obesity on risk. The potential mechanisms and associations are numerous and complex. Regardless of the actual cancer risk now and in the future, the overall effect of obesity on general health is clear, and this should be kept in mind in the discussion between health professional and patient. PMID: 11769879 [PubMed - indexed for MEDLINE] 4944. Przegl Lek. 2001;58(7-8):788-91. [The role of beta 3-adrenergic receptors in the human organism]. [Article in Polish] Zdrojewicz Z(1), Sztuka-Pietkiewicz A. Author information: (1)Katedra i Klinika Endokrynologii i Diabetologii Akademii Medycznej we Wrocławiu. Beta 3-adrenergic receptors (beta 3 ARs) are important structures in the human body but the role they play is not yet very clear. Stimulation of beta 3 AR in adipose tissue causes greater energy expenditure and increases thermogenesis and lipolysis. Mutation of the gene coding beta 3 AR in position 64 with thymidine instead of cytosine leads to the replacement of tryptophan (Trp 64) with arginine (Arg 64) and may be the cause of greater increase in body mass and the decrease in basic metabolism. The data however, is differentiated in populations and cannot be conclusive. The connection has been discovered between the state of the beta 3 ARs and the blood lipid concentration (also differing in populations). In some patients beta 3 AR mutation is correlated with high arterial diastolic pressure, increased incidence of noninsulin-dependent diabetes in younger, increased insulin resistance and diabetes in pregnant. beta 3-AR agonists might be used in treatment of many diseases, which obviously demands further investigations. PMID: 11769388 [PubMed - indexed for MEDLINE] 4945. Semin Diagn Pathol. 2001 Nov;18(4):286-93. The genetics of lipomatous tumors. Rubin BP(1), Dal Cin P. Author information: (1)Department of Pathology, University of Washington Medical Center, Seattle, USA. The current classification of lipomatous neoplasms has been validated by the identification of characteristic cytogenetic and molecular genetic profiles associated with various neoplasms within the family of lipomatous tumors. The review describes characteristic cytogenetic and molecular genetic profiles and discusses their significance. The clinicopathologic features of these tumors, which are described elsewhere, will not be included in this review. PMID: 11757869 [PubMed - indexed for MEDLINE] 4946. Curr Opin Pharmacol. 2001 Dec;1(6):613-9. Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice. Mueller SO(1), Korach KS. Author information: (1)Merck KGaA, Institute of Toxicology, Darmstadt, Germany. stefan.o.mueller@merck.de The estrogen receptors ERalpha and ERbeta are the main mediators of estrogen action and estrogens play an important role in a variety of aspects of physiology besides their well acknowledged function in reproduction. In vivo and in vitro studies indicate that the estrogen receptors are mechanistically implicated in endocrine-related diseases. Recent studies with estrogen receptor knockout mice have helped to unravel the role of the estrogen receptors in brain degeneration, osteoporosis, cardiovascular diseases and obesity. PMID: 11757817 [PubMed - indexed for MEDLINE] 4947. Pol Merkur Lekarski. 2001 Aug;11(62):187-90. [Testosterone and dehydroepiandrosterone deficiency, general adiposity and visceral obesity during normal male aging]. [Article in Polish] Medraś M(1), Jankowska EA. Author information: (1)Katedra i Klinika Endokrynologii i Diabetologii Akademii Medycznej we Wrocławiu. Both clinical observations and in vitro studies reveal that sex steroids are essential factors affecting body fat accumulation and distribution of healthy men. An excessive adiposity and visceral obesity are frequently accompanied by an adrenal and gonadal andropenia among men aged 50 and over. The relationships between an age-related increase in BMI and WHR values and an altered androgen-estrogen activity in the course of normal male aging have not been firmly established, as not all studies have thus far produced consistent results. The effects of androgen substitutive therapy (testosterone and dehydroepiandrosterone) in elderly men suggest the possible relationship between androgens and male visceral adiposity; unfortunately the results of available studies on that issue are also not consistent. Therefore, nowadays there is an urgent need to comprehensively establish the androgen contribution in the pathogenesis of male visceral obesity. PMID: 11757227 [PubMed - indexed for MEDLINE] 4948. Trends Endocrinol Metab. 2002 Jan-Feb;13(1):18-23. Resistin and obesity-associated insulin resistance. Steppan CM(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes, and Metabolism, Depts of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania Medical Center, Philadelphia, PA 19104-6149, USA. Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity. These include leptin, tumor necrosis factor alpha, Acrp30/adiponectin/adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor gamma, a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans. PMID: 11750858 [PubMed - indexed for MEDLINE] 4949. Endocr Pract. 2001 Nov-Dec;7(6):430-7. Syndrome of lipodystrophy, hyperlipidemia, insulin resistance, and diabetes in treated patients with human immunodeficiency virus infection. Graber AL(1). Author information: (1)Division of Endocrinology and Diabetes, Vanderbilt University School of Medicine, Vanderbilt Medical Center, 2558 TVC, Nashville, TN 37232, USA. Comment in Endocr Pract. 2001 Nov-Dec;7(6):480-4. OBJECTIVE: To describe the syndrome of lipodystrophy, hyperlipidemia, insulin resistance, and diabetes in patients with human immunodeficiency virus (HIV) infection treated with protease inhibitor drugs. METHODS: This is a case series of patients referred from an infectious disease clinic to a diabetes-endocrinology clinic in an academic medical center because of severe metabolic problems that occurred during the course of otherwise-successful treatment of HIV infection. The clinical course, abnormalities on physical examination, laboratory data, and complications are described and analyzed. The pathogenesis of the syndrome is discussed and compared with that of type 2 diabetes, lipoatrophic diabetes, and mouse models of lipodystrophy. RESULTS: In six male patients receiving antiretroviral therapy for HIV infection, a syndrome of lipoatrophy of the face, legs, and buttocks, hyperlipidemia (predominantly hypertriglyceridemia), and type 2 diabetes mellitus was noted. Two patients had pronounced abdominal obesity, in contrast to their thin extremities. Five of the six patients were receiving protease inhibitor drugs, which have been thought to contribute to metabolic abnormalities. In two patients, ischemic heart disease had developed. CONCLUSION: Protease inhibitors frequently cause insulin resistance and lipoatrophy in subcutaneous adipose tissue. These abnormalities are associated with visceral adiposity, hyperlipidemia, diabetes, and cardiovascular consequences and represent an important and unsolved problem in the treatment of HIV-infected patients. PMID: 11747278 [PubMed - indexed for MEDLINE] 4950. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):363-73. Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms. Sesti G(1), Federici M, Lauro D, Sbraccia P, Lauro R. Author information: (1)University of Catanzaro-Magna, Graecia, Italy. sesti@uniroma2.it Type 2 diabetes is a heterogeneous and polygenic disorder resulting from interaction of genetic factors with environmental influences. Numerous candidate genes for insulin signaling proteins have been screened, but no single major susceptibility gene for type 2 diabetes has been identified. Due to its pivotal role in insulin action, the insulin receptor was considered a plausible candidate gene. The insulin receptor exists in two isoforms differing by the absence (Ex11(-)) or presence (Ex11(+)) of a 12 amino acid sequence in the COOH-terminus of the alpha-subunit, as a consequence of alternative splicing of exon 11. The Ex11(-) binds insulin with two-fold higher affinity than the Ex11(+). This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. Some, but not all, studies have reported that expression of the low-affinity Ex11(+) is increased in target tissues from type 2 diabetic patients, thus suggesting that alterations in abundance of the two isoforms might contribute to insulin resistance. Insulin and type 1 IGF receptors have been shown to form hybrid receptors in tissues co-expressing both molecules. Hybrid receptors bind IGF-I, but not insulin, with high affinity, and behave as IGF-I holoreceptors, rather than insulin receptors, in terms of receptor autophosphorylation, and hormone internalization. It has been shown that the abundance of hybrid receptors is increased in skeletal muscle and adipose tissue from type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations in the insulin receptor gene have been identified in studies which examined an appropriately sized population of patients with type 2 diabetes. The prevalence of mutations in the insulin receptor gene ranged from 0.4%-7.8%. This review will focus on the structural and functional heterogeneity of the insulin receptor, and will discuss the pathogenetic role of insulin receptor variant forms and polymorphisms in the development of the common form of type 2 diabetes. Copyright 2001 John Wiley & Sons, Ltd. PMID: 11747141 [PubMed - indexed for MEDLINE] 4951. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):347-62. Human obesity: an evolutionary approach to understanding our bulging waistline. Lev-Ran A(1). Author information: (1)Maccabi Health Services, Petah-Tikva, Israel. levr@internet-zahav.net The unique worldwide spread of the human species and the remarkably long post-reproductive survival show that our genome permits excellent adaptation to vastly different environments. Moreover, the main scourges of later age, namely malignant growths and atherosclerosis, appear in humans later than in shorter-living animals. In recent years, excess weight and obesity have become mass phenomena with a pronounced upward trend in all developed countries. However, despite the detrimental effects of being overweight, these populations live longer than ever, which in part may be explained by the availability of better medical treatment. The prevalence and predicted further spread of obesity can be understood in the light of evolution. In all animal species energy metabolism is asymmetric with energy accumulation ('thrifty genotype') being the necessary condition of survival during hard times. For humans, which are no different to other animals in this respect, this genetic programming was necessary for survival because during the course of history, including the recorded history in the more developed Middle East, Europe or China, there was never a long period of uninterrupted food abundance, whereas famines were regular and frequent. Therefore fat accumulation, when food was available, meant survival at times of shortage, while the possible detrimental effects of overindulgence in food and being overweight expressed in unrealistically old age were irrelevant. It is the central, mostly intra-abdominal fat (in both humans and animals) that is more medically important than the subcutaneous truncal fat, and the accumulation of both types of fat is conditioned by high food consumption; therefore it is a historic novelty for human populations. In contrast, lower-body fat in human females is unique in the animal kingdom: it is much less metabolically active, it is of much lower pathologic significance than central fat, and it is programmed to be mobilized mostly during pregnancy and lactation. In view of all this, norms of desired weight should be based on hard mortality and morbidity statistics and not on theoretical, esthetic or fashion considerations. By this criterion, the upper limit of desirable weight is likely to be body mass index (BMI) 27 or 28, but specified for different populations (sex, race, ethnic origin); moreover, with aging, the detrimental effects of obesity diminish and finally disappear. Risks of other pathologies related to obesity (e.g. diabetes, hypertension and coronary disease) are also population-specific. However, total fatness, measured by BMI, is insufficiently sensitive as a risk factor, and fat distribution (upper-body versus low-body type, as reflected by waist circumference and waist:hip ratio) plays at least as prominent a role. Therefore the detailed norms, not yet available, should take into account both general obesity and fat distribution and be specific for different populations. Since long-term weight loss in adults is rarely achievable, public health measures should be aggressively directed at the prevention of obesity from childhood. Copyright 2001 John Wiley & Sons, Ltd. PMID: 11747140 [PubMed - indexed for MEDLINE] 4952. Bioessays. 2001 Dec;23(12):1095-9. Leptin signaling pathways in the central nervous system: interactions between neuropeptide Y and melanocortins. Rahmouni K(1), Haynes WG. Author information: (1)Department of Internal Medicine, University of Iowa, Iowa City 52242, USA. No other hormone has drawn more attention than leptin in recent studies on the control of appetite, body weight and obesity. This hormone is produced by adipose tissue and enters the brain via a saturable specific transport mechanism. Leptin acts in the hypothalamus to modulate food intake and heat production as well as several other neuroendocrine pathways. The mechanisms through which leptin exerts its central nervous effects are now better understood. Proopiomelanocortin- and neuropeptide Y-containing neurons in the hypothalamus have emerged as potent candidate mediators of leptin action. These two neuropeptides have been shown to exert opposing effects using different pathways. Recently, Cowley et al. (2001) described a new circuit in the regulation of neuronal activity by leptin with an interaction between these two pathways. These data add complexity to the mechanisms by which leptin achieves its effects in the central nervous system, but they also offer potential mechanisms to explain the phenomenon of leptin resistance observed in obesity. Copyright 2001 John Wiley & Sons, Inc. PMID: 11746228 [PubMed - indexed for MEDLINE] 4953. Exp Biol Med (Maywood). 2001 Dec;226(11):997-1002. Adipocyte differentiation: from fibroblast to endocrine cell. Gregoire FM(1). Author information: (1)Metabolex, Hayward, California 94549, USA. fmgregoire@metabolex.com Recent advances regarding the biology of adipose tissue have demonstrated that white adipose tissue (WAT) plays a central role in the regulation of energy balance and acts as a secretory/endocrine organ that mediates numerous physiological and pathological processes. Dysregulation of WAT mass causes obesity or lipoatrophy, two disorders associated with life-threatening pathologies, including cardiovascular diseases and diabetes. Alterations in WAT mass result from changes in adipocyte size and/or number. Change in adipocyte number is achieved through a complex interplay between proliferation and differentiation of preadipocytes. Adipocyte differentiation or adipogenesis is a highly controlled process that has been extensively studied for the last 25 years. In vitro preadipocyte culture systems that recapitulate most of the critical aspects of fat cell formation in vivo have allowed a meticulous dissection of the cellular and molecular events involved in the adipogenesis process. The adipogenic transcription factors peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer binding protein-alpha play a key role in the complex transcriptional cascade that occurs during adipogenesis. Hormonal and nutritional signaling affects adipocyte differentiation in a positive or negative manner, and components involved in cell-cell or cell-matrix interactions are also pivotal in regulating the differentiation process. This knowledge provides a basis for understanding the physiological and pathophysiological mechanisms that underlie adipose tissue formation and for the development of novel and sound therapeutic approaches to treat obesity and its related diseases. PMID: 11743135 [PubMed - indexed for MEDLINE] 4954. Exp Biol Med (Maywood). 2001 Dec;226(11):982-90. Adrenoceptors, uncoupling proteins, and energy expenditure. Collins S(1), Cao W, Daniel KW, Dixon TM, Medvedev AV, Onuma H, Surwit R. Author information: (1)Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. colli008@mc.duke.edu Interest in the biology of adipose tissue has undergone a revival in recent years with the discovery of a host of genes that contribute to the regulation of satiety and metabolic rate. The catecholamines have long been known to be key modulators of adipose tissue lipolysis and the hydrolysis of triglyceride energy stores. However, more recent efforts to understand the role of individual adrenergic receptor subtypes expressed in adipocytes and their signal transduction pathways have revealed a complexity not previously appreciated. Combined with this interest in the modulation of adipocyte metabolism is a renewed focus upon brown adipose tissue and the mechanisms of whole body thermogenesis in general. The discovery of novel homologs of the brown fat uncoupling protein (UCP) such as UCP2 and UCP3 has provoked intensive study of these mitochondrial proteins and the role that they play in fuel metabolism. The story of the novel UCPs has proven to be intriguing and still incompletely understood. Here, we review the status of adipose tissue from inert storage depot to endocrine organ, interesting signal transduction pathways triggered by beta-adrenergic receptors in adipocytes, the potential of these receptors for discriminating and coordinated metabolic regulation, and current views on the role of UCP2 and UCP3 based on physiological studies and gene knockout models. PMID: 11743133 [PubMed - indexed for MEDLINE] 4955. Comp Biochem Physiol C Toxicol Pharmacol. 2001 Dec;130(4):435-45. Somatotropic regulation of fish growth and adiposity: growth hormone (GH) and somatolactin (SL) relationship. Company R(1), Astola A, Pendón C, Valdivia MM, Pérez-Sánchez J. Author information: (1)Instituto de Acuicultura de Torre de la Sal (CSIC), 12595 Ribera de Cabanes, Castellón, Spain. Growth hormone (GH) and insulin-like growth factors (IGFs) play a major role in fish development and metabolism, and several studies have allowed discernment of a complex and tissue-specific collection of salmonid IGF-I transcripts (Ea-4, Ea-3, Ea-2, Ea-1), which are the result of the alternative splicing of the E-domain region. However, the pattern of IGF-I expression is different in non-salmonid fish, and only one or two transcripts (Ea-4, Ea-2) have been detected in hepatic and extrahepatic tissues of common carp, barramundi, black sea bream and gilthead sea bream. Despite this, when comparisons are made within Mediterranean fish species (European sea bass, common dentex and gilthead sea bream), plasma IGF-I levels are consistent with fish species differences in growth rates. Changes of growth rates, and plasma IGF-I and GH levels are also found in response to changes in diet composition and ration size, which may serve to assess the suitability of feeding regimes in aquaculture practice. Regulation of plasma somatolactin (SL) levels is also examined in gilthead sea bream, and the resulting plasma SL profile differs from that of GH. Thus, in contrast to GH, plasma SL levels augment with the increase of ration size and fish size (advancement of age). A transient increase in plasma SL levels is also found in short-term fasted fish, and this fish peptide may act as an anti-obesity hormone helping to expedite growth-reproductive processes following replenishment of fat stores, and/or mediate the adaptation to fasting until the lipolytic action of GH and/or other endocrine factors is fully accomplished. This agrees with the known increase of plasma SL levels during acute stress and exhaustive exercise. However, a causal link between SL and energy mobilisation (lipid metabolism) remains to be established, and further research is needed to determine the extent to which SL and GH act in a complementary manner to make available metabolic fuels and to regulate body fat mass and feeding behaviour. PMID: 11738631 [PubMed - indexed for MEDLINE] 4956. Clin Biochem. 2001 Oct;34(7):519-29. Sterol regulatory element-binding proteins and reactive oxygen species: potential role in highly-active antiretroviral therapy (HAART)-associated lipodystrophy. Nerurkar PV(1), Shikuma CM, Nerurkar VR. Author information: (1)Retrovirology Research Laboratory, Leahi Hospital, Honolulu, Hawaii 96816, USA. pneururka@pbrc.hawaii.edu OBJECTIVES: To summarize the existing pathophysiological concepts and to hypothesize new mechanisms involving sterol regulatory element-binding proteins (SREBP) and reactive oxygen species (ROS), in highly-active antiretroviral therapy (HAART)-associated lipodystrophy. CONCLUSIONS: The widespread use of HAART has dramatically reduced AIDS-related deaths in the developed world. Unfortunately, long-term HAART has been associated with a unique and unexpected syndrome of lipodystrophy manifested by fat wasting in the subcutaneous adipose tissue of the face and extremities, and accumulation of fat in the viscera and neck, often accompanied by hyperlipidemia and insulin resistance. Despite intensive study of this syndrome over the past three years, the pathophysiologic mechanism(s) underlying HAART-associated lipodystrophy syndrome remains elusive. A continued attempt to elucidate pathophysiological mechanisms involved in HAART-associated lipodystrophy remains critically important to improving the treatment strategies for this epidemic condition. In this review, we suggest two new hypotheses that may explain the pathogenesis and pathophysiology of HAART-associated lipodystrophy that warrant further investigations. First, we hypothesize that upregulation and/or increase in the mature form of SREBP-1 caused by HAART may lead to perturbations in synergistic regulation of genes involved in maintenance of cholesterol homeostasis and synthesis of fatty acids, that may explain the accumulation of fat which is a hallmark of this syndrome. Second, we hypothesize that the generation of reactive oxygen species in adipocytes may be an early and critical event in HAART-associated toxicity leading to cell death, partially explaining the mechanism underlying lipoatrophy. PMID: 11738387 [PubMed - indexed for MEDLINE] 4957. Sports Med. 2001;31(14):965-83. Brain microdialysis in exercise research. Meeusen R(1), Piacentini MF, De Meirleir K. Author information: (1)Department of Human Physiology and Sports Medicine, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Belgium. rmeeusen@vub.ac.be During the last 5 to 10 years, the microdialysis technique has been used to explore neurotransmitter release during exercise. Microdialysis can collect virtually any substance from the brains of freely moving animals with a limited amount of tissue trauma. It allows the measurement of local neurotransmitter release in combination with ongoing behavioural changes such as exercise. Several groups examined the effect of treadmill running on extracellular neurotransmitter levels. Microdialysis probes were implanted in different brain areas to monitor diverse aspects of locomotion (striatum, hippocampus, nucleus accumbens, frontal cortex, spinal cord), food reward (hypothalamus, hippocampus, cerebral cortex), thermoregulation (hypothalamus). Some studies combined microdialysis with running on a treadmill to evaluate motor deficit and improvement following dopaminergic grafts in 6-hydroxydopamine lesioned rats, or combined proton nuclear magnetic resonance spectroscopy and cortical microdialysis to observe intra- plus extracellular brain glucose variations. This method allows us to understand neurotransmitter systems underlying normal physiological function and behaviour. Because of the growing interest in exercise and brain functioning, it should be possible to investigate increasingly subtle behavioural and physiological changes within the central nervous system. There is now compelling evidence that regular physical activity is associated with significant physiological, psychological and social benefits in the general population. In contrast with our knowledge about the peripheral adaptations to exercise, studies relating exercise to brain neurotransmitter levels are scarce. It is of interest to examine the effect of short and long term exercise on neurotransmitter release, since movement initiation and control of locomotion have been shown to be related to striatal neurotransmitter function, and one of the possible therapeutic modalities in movement, and mental disorders is exercise therapy. Until very recently most experimental studies on brain chemistry were conducted with postmortem tissue. However, in part because of shortcomings with postmortem methods, and in part because of the desire to be able to directly relate neurochemistry to behaviour, there has been considerable interest in the development of 'in vivo' neurochemical methods. Because total tissue levels may easily mask small but important neurochemical changes related to activity, it is important to sample directly in the extracellular compartment of nervous tissue in living animals. Since the chemical interplay between cells occurs in the extracellular fluid, there was a need to access this compartment in the intact brain of living and freely moving animals. Estimation of the transmitter content in this compartment is believed to be directly related to the concentration at the site where these compounds are functionally released: in the synaptic cleft. As measurements in the synapse are not yet possible, in vivo measurements in the extracellular fluid appear to provide the most directly relevant information currently available. This article provides an overview of the in vivo microdialysis technique as a method for measuring in the extracellular space, and its application in exercise science. Although this technique has been used in different tissues such as brain, adipose tissue, spinal cord and muscle, in animals as well as humans, we will focus on the use of this in vivo method in brain tissue. Recently two excellent reviews on the application of microdialysis in human experiments especially in subcutaneous tissue have been published, and we refer the interested reader to these articles. PMID: 11735681 [PubMed - indexed for MEDLINE] 4958. Metabolism. 2001 Dec;50(12):1499-504. Are there persons who are obese, but metabolically healthy? Sims EA(1). Author information: (1)Endocrinology, Diabetes, and Metabolism Unit, Department of Medicine, College of Medicine, University of Vermont, Burlington VT, USA. Erratum in Metabolism 2002 Apr;51(4):536. The aim of this article was to review the evidence for a metabolically normal subset of the obese and its implications for clinical and research work. The methods included literature review and correspondence with authors. Since 1947, when Vague described a relation between distribution of body fat and the risk factors for cardiovascular disease, much evidence has suggested that early onset of the obesity, hyperplasia of normal adipocytes, and normal quantities of visceral abdominal fat may be associated with a favorable metabolic response in obese subjects. Analyses in 1973 by Keyes and later by Reuben Andres in 1980 suggested that obesity for some was not a risk factor and might even be an asset. Recently, in the study by Bonora et al of the relation between insulin resistance and the 4 main disorders of the metabolic syndrome in the Bruneck epidemiologic study, a subgroup of obese individuals with a normal metabolic response was evident. In a current study by Brochu et al of an obese metabolically normal subgroup of postmenopausal women, visceral abdominal fat estimated by computed tomography (CT) scan and age of onset were significant variables. The obese, metabolically normal subgroup (OBMN) must be taken into consideration in both clinical and research work. Persons with OBMN and their parents may be wrongly blamed because of the obesity. Attempts at weight loss may be counterproductive. The criteria for selection of obese research subjects may favor inclusion of an OBMN subset, which may invalidate statistical analysis. Findings suggesting the OBMN subset include family members with uncomplicated obesity, early onset of the obesity, fasting plasma insulin within normal range, and normal distribution of the excess fat. Hormonal, genetic studies, and prospective studies will help to clarify the significance and underlying mechanisms of this subset. Copyright 2001 by W.B. Saunders Company PMID: 11735101 [PubMed - indexed for MEDLINE] 4959. J Toxicol Environ Health A. 2001 Nov 23;64(6):453-64. Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. Haddad S(1), Restieri C, Krishnan K. Author information: (1)Groupe de Recherche en Toxicologie Humaine (TOXHUM), Faculté de Médecine, Université de Montréal, Quebec, Canada. The pharmacokinetics and tissue dose of chemicals may differ among individuals of a population, particularly between adults and children. The adult-children differences in pharmacokinetics arise from age-related changes in the physiological, biochemical, and physicochemical determinants of uptake and disposition of chemicals. The objectives of this study were to review the published literature to assemble data on the human body weight and organ weights as a function of age (specifically between birth and 18 yr old) and to analyze these data, in order to develop regression equations for calculating body weight and organ weights of children using age as the dependent function. The specific organs/tissues for which the data on age-related weight were obtained and analyzed include blood, adipose tissues, liver, lungs, brains, heart, kidneys, spleen, the reproductive organs (male: prostate gland, seminal vesicle, testes, and epididymis; female: ovaries, uterus, and uterine tubes), glands (adrenal, pituitary, thymus, pancreas, and thyroid), bone marrow (total and red), intestinal tract, stomach, muscle, skin (epidermis and dermis), and skeleton. In both male and female children, the sum of these organs is systematically lower than the body weight, and this discrepancy may be resolved with the additional availability and consideration of data on hypodermis weight. The equations and data on body weight and organ weights presented in this article should be useful for constructing age-specific, physiologically based pharmacokinetic models for children. PMID: 11732696 [PubMed - indexed for MEDLINE] 4960. Curr Drug Targets. 2001 Dec;2(4):353-70. Pharmacology of appetite suppression: implication for the treatment of obesity. Halford JC(1). Author information: (1)Department of Psychology, University of Liverpool, UK. j.c.g.halford@liverpool.ac.uk Given the current global epidemic of obesity there is a demand for new anti-obesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as 'appetite suppressants' with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with life style changes and dietary intervention may be critical in dealing with the rising world epidemic of obesity. PMID: 11732637 [PubMed - indexed for MEDLINE] 4961. J Gerontol A Biol Sci Med Sci. 2001 Oct;56 Spec No 2:7-12. Physical activity and parameters of aging: a physiological perspective. Westerterp KR(1), Meijer EP. Author information: (1)Department of Human Biology, Maastricht University, The Netherlands. K.Westerterp@HB.Unimaas.NL Increasing age is associated with a decline in fat-free mass. The question is whether age-related changes in body composition can be delayed by an active life style. This analysis includes data where physical activity was assessed with doubly labeled water and body composition with hydrodensitometry or isotope dilution. Subjects were 136 women and 180 men over 20 years, who were tested in Maastricht University between 1983 and 1998. Increasing age was associated with lower activity levels and lower fat-free mass. After controlling for age there was no longer any association between physical activity and fat-free mass. A few exercise intervention studies showed that elderly subjects compensate for exercise training by a decline in spontaneous physical activity, in contrast to younger subjects. Although no effect of habitual activity level on changes in body composition are observed, training has a positive effect on muscle function. Elderly subjects with relatively high levels of physical activity are not different from those with low activity levels, as far as fat-free mass and fat mass are concerned. However, training might delay the age-induced impairment of personal mobility associated with a reduction in physical activity. PMID: 11730240 [PubMed - indexed for MEDLINE] 4962. Ann Med. 2001 Nov;33(8):556-61. Regulation of adipocyte differentiation. Koutnikova H(1), Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, Université Louis Pasteur, Illkirch, CU de Strasbourg, France. Once multipotent mesenchymal cells become committed to the adipoblast lineage, adipogenesis, the process of preadipocytes differentiation into adipocytes is initiated. This process starts with a phase of exponential growth of adipoblasts. Following confluence of these adipoblasts, the cells enter into a cell cycle arrest, they re-enter the cell cycle and pass through a limited number of cell divisions, and finally differentiate into fully mature adipocytes. Adipogenesis is controlled by a complex cross-talk between positive and negative regulators, such as hormonal and nutritional stimuli, that change the activity of a selected set of transcription factors. Regulation of adipogenesis is crucial to keep the body energy balance because a limited amount of adipose tissue, lipodystrophy, or an excess of adipose tissue, such as occurs in obesity, lead to profound metabolic dysfunctions and disease. PMID: 11730163 [PubMed - indexed for MEDLINE] 4963. Ann Med. 2001 Nov;33(8):547-55. Gene expression in visceral and subcutaneous adipose tissues. Vidal H(1). Author information: (1)INSERM U-449, Faculty of Mèdicine R Laennec, University of Lyon, France. vidal@laennec.univ-lyon1.fr A large body of evidence demonstrates depot-specific differences in the expression of genes coding important functional proteins in adipocytes. This may contribute to the well-known specific functional properties of the adipocytes from intra-abdominal and subcutaneous regions. This review will focus on the main findings regarding the regional differences in adipocyte gene expression in humans. These genes encode proteins belonging to three different functional groups: the metabolic enzyme and related signalling proteins, the adipogenic factors, and, finally, the products of adipocytes. PMID: 11730162 [PubMed - indexed for MEDLINE] 4964. Ann Med. 2001 Nov;33(8):534-41. Health consequences of visceral obesity. Després JP(1). Author information: (1)Québec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Canada. despres@crchul.ulaval.ca Visceral obesity is associated with metabolic abnormalities that increase the risk of type 2 diabetes and coronary heart disease. Obese patients with a substantial accumulation of visceral adipose tissue are characterized by higher insulinaemic and glycaemic responses during an oral glucose challenge as well as by a deteriorated plasma lipoprotein-lipid profile compared with individuals with normal body weights or obese subjects with low levels of visceral adipose tissue. Results of the Quebec Cardiovascular Study have shown that the cluster of metabolic disturbances observed among subjects with visceral obesity (hyperinsulinaemia, hyperapolipoprotein B and small, dense low-density lipoprotein (LDL) particles) is associated with a 20-fold increase in the risk of coronary heart disease in a sample of middle-aged men followed over 5 years. Therefore, we have developed a simple screening approach in order to help physicians and health professionals identify at low cost individuals who would be characterized by this cluster of atherogenic abnormalities. We found that the simultaneous presence of an elevated waist girth combined with moderate hypertriglyceridaemia ('hypertriglyceridaemic waist') could adequately identify a large proportion (approximately 80%) of carriers of the above triad of atherogenic metabolic abnormalities (hyperinsulinaemia, hyperapolipoprotein B and small, dense LDL particles). Finally, there is evidence suggesting that the risk of an acute coronary syndrome in these viscerally obese patients may not always be related to the extent of coronary artery stenosis, providing further support to the notion that additional markers of thrombosis/inflammation should be considered. Thus, the stabilization of the atherosclerotic plaque, rather than its regression may even become a more legitimate and feasible therapeutic objective for the management of the coronary heart disease risk in the viscerally obese patient. Although these notions are based on a plausible metabolic rationale, randomized trials with proper end-points will be needed to determine the clinical benefits associated with the management of visceral obesity and related metabolic complications. PMID: 11730160 [PubMed - indexed for MEDLINE] 4965. Nihon Yakurigaku Zasshi. 2001 Nov;118(5):327-33. [Mitochondrial uncoupling protein as a target of pharmacotherapy for obesity]. [Article in Japanese] Saito M(1), Ohashi A. Author information: (1)Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. saito@vetmed.hokudai.ac.jp Uncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the beta-adrenergic action of norepinephrine. Since the beta 3-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on beta 1- and beta 2-adrenoceptos. Therefore, beta 3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effective anti-obesity tool. PMID: 11729636 [PubMed - indexed for MEDLINE] 4966. Nihon Yakurigaku Zasshi. 2001 Nov;118(5):321-6. [PPAR gamma agonist and antagonist]. [Article in Japanese] Kadowaki T(1). Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. kadowaki-3im@h.u-tokyo.ac.jp Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPAR gamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPAR gamma activity observed in heterozygous PPAR gamma-deficient mice or the Pro 12 Ala polymorphism in human PPAR gamma has been shown to prevent insulin resistance and obesity induced by a high-fat (HF) diet. We investigated whether functional antagonism toward PPAR gamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that moderate reduction of PPAR gamma with an RXR antagonist or a PPAR gamma antagonist decreases triglyceride (TG) content in white adipose tissue, skeletal muscle and liver. These inhibitors potentiate leptin's effects and stimulated adiponectin levels, which increases fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, severe reduction of PPAR gamma by treatment of heterozygous PPAR gamma-deficient mice with an RXR antagonist or a PPAR gamma antagonist depletes white adipose tissue and markedly decreases leptin and adiponectin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggest that appropriate functional antagonism of PPAR gamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes. PMID: 11729635 [PubMed - indexed for MEDLINE] 4967. Nihon Yakurigaku Zasshi. 2001 Nov;118(5):315-20. [Beta 3-adrenergic receptor agonists--past, present and future]. [Article in Japanese] Takakura Y(1), Yoshida T. Author information: (1)Department of Medicine, Fukuchiyama City Hospital, Department of Endocrinology, Diabetes and Metabolism, Kyoto Prefectural University of Medicine, Kyoto, Japan. beta 3-Adrenergic receptors (beta 3-AR) play an important role in the thermogenesis in brown adipose tissue and lipolysis in white adipose tissue. beta 3-AR agonists developed in the early stages produced marked weight reduction and an anti-diabetic effect in rats and mice, but did not in humans, because of the difference in the chemical structure of the beta 3-AR. In 1995, a naturally occurring variant (Trp64Arg) of the human beta 3-AR gene was shown to be correlated with obesity and insulin resistance in Pima Indians. Moreover, the fact that white adipocytes produce various hormones and cytokines that cause life-style-related disease was recently made clear. Because the reduction of the visceral fat is thought to be important to prevent these diseases, the expectations for the human beta 3-AR agonist having a novel anti-obesity effect are rising. Some interesting findings were recently reported with beta 3-AR agonists: the difference of the lipolysis was dependent on the existence of the Trp64Arg mutation and the up-regulation effect of the UCP1 and beta 3-ARs themselves in the adipose tissue and skeletal muscle. Therefore, we introduce informations (past, present and future) on beta 3-AR agonists in this paper. PMID: 11729634 [PubMed - indexed for MEDLINE] 4968. FASEB J. 2001 Dec;15(14):2565-71. Leptin regulation of the immune response and the immunodeficiency of malnutrition. Faggioni R(1), Feingold KR, Grunfeld C. Author information: (1)Department of Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, 94121, USA. faggioni@amgen.com Leptin is a 16 kDa protein mainly produced by adipose tissue in proportion to adipose tissue mass. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to playing a role in energy regulation, leptin also regulates endocrine and immune functions. Both the structure of leptin and that of its receptor suggest that leptin might be classified as a cytokine. The secondary structure of leptin has similarities to the long-chain helical cytokines family, which includes interleukin 6 (IL-6), IL-11, CNTF, and LIF, and the leptin receptor is homologous to the gp-130 signal-transducing subunit of the IL-6-type cytokine receptors. Leptin plays a role in innate and acquired immunity. Leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation. More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production. Leptin deficiency also causes a defect in hematopoiesis. Leptin regulates T cells responses, polarizing Th cells toward a Th1 phenotype. Low leptin levels occurring during starvation mediate the neuroendocrine and immune dysfunction of starvation. PMID: 11726531 [PubMed - indexed for MEDLINE] 4969. Biosci Rep. 2001 Apr;21(2):195-200. The discovery of an uncoupling mitochondrial protein in plants. Vercesi AE(1). Author information: (1)Departamento de Patologia Clinica, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas, SP, Brazil. anibal@unicamp.br This paper describes peculiar properties of plant mitochondria and summarizes the experiments that led to the discovery of an uncoupling protein in these mitochondria. Recent advances in the study of the biochemical and physiological properties as well as on genes encoding plant uncoupling proteins are described in articles by Borecky et al., Jezek et al., and Jarmuszkiewicz et al. in this issue. PMID: 11725868 [PubMed - indexed for MEDLINE] 4970. Rev Endocr Metab Disord. 2001 Oct;2(4):395-401. Does brown adipose tissue (BAT) have a role in the physiology or treatment of human obesity? Himms-Hagen J(1). Author information: (1)Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. jhhagen@uottawa.ca PMID: 11725726 [PubMed - indexed for MEDLINE] 4971. Rev Endocr Metab Disord. 2001 Oct;2(4):357-63. Regulation of leptin production. Considine RV(1). Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana, USA. rconsidi@iupui.edu Fat mass is the primary determinant of serum leptin in humans with energy intake and gender also having significant effects. Gender influences leptin production through the reproductive hormones. Glucose metabolism links food intake to leptin production and hexosamine biosynthesis appears to play a significant role in this process. Catecholamines inhibit leptin production and the sympathetic nervous system has been proposed to be the efferent arm of the leptin signal transduction pathway between adipose tissue and the central nervous system. Additional regulators of leptin production include glucocorticoids, cytokines and agonists of PPAR gamma. In addition to adipose tissue, leptin is produced in several other places including placenta, bone marrow, stomach, muscle and perhaps brain, thus increasing the number of potential regulatory roles for this hormone. Future work will be needed to fully elucidate the mechanisms regulating leptin synthesis/release in each tissue as well as its regulatory functions. PMID: 11725722 [PubMed - indexed for MEDLINE] 4972. Rev Endocr Metab Disord. 2001 Oct;2(4):349-55. Molecular mechanisms of adipocyte differentiation. Tong Q(1), Hotamisligil GS. Author information: (1)Division of Biological Sciences, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. PMID: 11725721 [PubMed - indexed for MEDLINE] 4973. J Clin Hypertens (Greenwich). 2001 Nov-Dec;3(6):362-7. Obesity, body fat distribution, and ambulatory blood pressure in children and adolescents. Lurbe E(1), Alvarez V, Redon J. Author information: (1)Pediatric Nephrology Unit, Department of Pediatrics, Hospital General, University of Valencia, Valencia, Spain. Obesity is a common disease with an ever-increasing prevalence and usually with late-onset consequences. If acquired during childhood, it tracks into adult life to some extent, and since the relationship between obesity and hypertension is well established in adults, obese children appear to be at particularly high risk of becoming hypertensive adults. In the authors' study, obese children seemed to have significantly higher casual and ambulatory blood pressure than nonobese children, except for nighttime diastolic blood pressure. The health effects of obesity may depend on the anatomic distribution of body fat, which in turn may be a better indicator of endocrinologic imbalance, environmental stress, or genetic factors than is fatness per se. Subjects with a higher waist-to-hip ratio or a larger waist, as an estimate of central obesity, tend to have higher blood pressure values even during childhood. Prevention of the onset of obesity in early life may be important to reducing the risk of coronary heart disease in later life. PMID: 11723358 [PubMed - indexed for MEDLINE] 4974. Am J Hypertens. 2001 Nov;14(11 Pt 2):304S-309S. Sympathetic nervous system and insulin resistance: from obesity to diabetes. Esler M(1), Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Author information: (1)Baker Medical Research Institute, Melbourne, Australia. murray.esler@baker.edu.au As the world faces an obesity "epidemic," the mechanisms by which overweight is translated into insulin resistance, hypertension, and diabetes need to be better understood. Although the processes of transition remain uncertain, overactivity of the sympathetic nervous system appears pivotal. In obesity, there is stimulation of sympathetic outflow to the kidneys, evident in increased rates of spillover of noradrenaline into the renal veins, and to skeletal muscle vasculature, demonstrated with microneurography. The cause is unclear, but possibly involves the stimulatory action of leptin released from adipose tissue, or from within the brain, for which there is recent evidence in human obesity. The high renal sympathetic tone contributes to hypertension development by stimulating renin secretion and through promoting renal tubular reabsorption of sodium. Neurally mediated skeletal muscle vasoconstriction reduces glucose delivery and uptake in muscle. Impairment of glucose uptake by skeletal muscle is a hallmark of insulin resistance syndromes. Pharmacologic sympathetic nervous suppression within the central nervous system with imidazoline receptor-binding agents such as rilmenidine is a logical therapeutic approach for lowering blood pressure (BP) in patients with essential hypertension, in whom sympathetic activity is often increased. In addition, drugs of this class appear to have the capacity to favorably modify insulin sensitivity, which has particular relevance in the treatment of hypertensive diabetic patients. In the hypertension accompanying maturity onset obesity, with recent recommendations from advisory bodies setting lower goal BP, and with these lower targets often being reached only with combinations of antihypertensive agents, it is advisable that all drugs used in combination therapy have a favorable or at least a neutral effect on insulin resistance. PMID: 11721888 [PubMed - indexed for MEDLINE] 4975. Medicina (B Aires). 2001;61(5 Pt 1):597-602. [Thyroid hormones, obesity and brown adipose tissue thermogenesis]. [Article in Spanish] Zaninovich AA(1). Author information: (1)Centro de Investigaciones de la Glándula Tiroides (CONICET), Centro de Medicina Nuclear, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires, Argentina. azaninovich@sinectis.com.ar Brown adipose tissue (BAT) is the main site for hormone-dependent (non-shivering) thermogenesis in response to cold in lower mammals. The hypothalamus controls the cold-induced BAT activation by stimulating the sympathetic nerves and the secretion of norepinephrine (NE) in BAT. Mediated by beta-3 noradrenergic receptor and in the presence of triiodothyronine (T3), NE promotes the synthesis of the uncoupling protein 1 (UCP1). UCP1 is a 32 kDa protein located in the inner membrane of BAT mitochondria, where it dissipates the proton gradient created by oxidations in the mitochondria. UCP1 functions as a proton translocator, substituting for another translocator, the ATP synthetase. The uncoupling of oxidations and phosphorylations and the inhibition of ATP synthesis lead to dissipation as heat of all energy produced in the respiratory chain. The supply of adequate amounts of T3 is ensured by the cold-induced enhancement of the enzyme 5'-deiodinase type II activity, which deiodinates thyroxine (T4) to T3. The absence of T3 blocks UCP1 synthesis, leading to hypothermia. BAT has a limited significance in humans, except in the newborn, where it serves for a rapid acclimation to ambient temperature. The study of BAT physiology will provide more insight into the mechanisms regulating energy balance and body weight in humans, thus contributing to prevent and treat human obesity. PMID: 11721329 [PubMed - indexed for MEDLINE] 4976. Nihon Rinsho. 2001 Nov;59(11):2117-26. [The desirable insulin preparations from the viewpoint of insulin secretory dynamics]. [Article in Japanese] Kawamori R(1). Author information: (1)Department of Medicine, Metabolism & Endocrinology, Juntendo University School of Medicine. Glucose fluxes are deteriorated in type 1 and type 2 diabetic patients. The mechanisms why hepatic glucose production, muscle and adipose tissue glucose uptake, and hepatic glucose uptake after meal intake are regulated with subcutaneous insulin administration, should be clarified. Insulin analogues, either stable long-acting insulin or rapidly absorbed regular insulin are now under developed. PMID: 11712395 [PubMed - indexed for MEDLINE] 4977. Nihon Rinsho. 2001 Nov;59(11):2102-8. [Insulin sensitizer drugs, thiazolidinediones: current state and prospect]. [Article in Japanese] Kuzuya T(1). Author information: (1)Aino Institute for Aging Research, Jichi Medical School. Type 2 diabetes is characterized by decreased secretion of insulin and insulin resistance. Thiazolidinediones are drugs to ameliorate insulin resistance. At present, only pioglitazone is available in Japan. The first drug of this category, troglitazone, has been withdrawn from market because of its liver toxicity in a few patients. The decrease in fasting plasma glucose begins within 2 weeks and reaches the nadir in 8-12 weeks. Plasma insulin levels usually decrease together with plasma glucose. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients. The efficacy is higher in patients with obesity, high insulin levels and in aged people and females. The mechanism is thought to be mediated by activation of a nuclear receptor, PPAR-gamma, which is most abundantly expressed in the adipose tissue. Current concept is that, when PPAR-gamma is activated by these drugs, the number of small adipocytes is increased to replace large adipocytes, thereby decreasing the release of TNF-alpha and FFA from adipose tissue. However, there seems to be a complex relationship between the activity of PPAR-gamma and insulin sensitivity. The effect of these new category drugs should be monitored carefully on a long-term basis. PMID: 11712393 [PubMed - indexed for MEDLINE] 4978. Folia Med Cracov. 2001;42(1-2):83-93. [The role of leptin in metabolic regulation]. [Article in Polish] Zurowski D(1), Koprowska B, Thor PJ. Author information: (1)Katedra Patofizjologii Collegium Medicum UJ ul. Czysta 18, 31-121 Kraków. Leptin discovery--the hormone derived from adipose tissue became a challenging event in understanding food intake and energy balance regulation. Leptin serum level correlates with fat stores and reacts according to changes in energy balance. Although leptin is thought of as a factor preventing obesity, in most of the cases obesity develops in association with increase in serum leptin level which indicates leptin resistance. It may be possible that the primary role of leptin is to mediate the signal for the switch between the starved and fed state. There is a lot of evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine, immune and reproductive function. PMID: 11712329 [PubMed - indexed for MEDLINE] 4979. Asia Pac J Clin Nutr. 2001;10(2):85-9. Cardiovascular risk in the Asia-Pacific region from a nutrition and metabolic point of view: abdominal obesity. Gill TP(1). Author information: (1)International Obesity TaskForce, University of Sydney, Australia. tim.gill@iotf.org The level of obesity within the Pacific Islands is extremely high and so is the prevalence of weight-related morbidity and mortality. In contrast, the level of obesity, as defined by the standard WHO classification, remains relatively low in most Asian countries, yet rates of obesity-related disease, such as diabetes and cardiovascular disease are increasing rapidly. Many Asian races appear to be susceptible to the development of excessive abdominal fatness, even at low levels of body mass index (BMI). In addition, the health consequences of weight gain appear to occur at much lower levels of BMI and are more intense than in those of European origin. The exact reasons for these ethnic variations in the development of coronary heart disease (CHD) remain unclear. It is likely that genetic differences contribute to this variation in CHD risk, but different dietary and physical activity patterns may also play a role. The advent of modernisation has resulted in marked changes in the level of physical activity and the food supply available throughout the Asia-Pacific region. There has been a shift towards higher intakes of fats (particularly animal fats and vegetable oils) and sugars. Urbanisation and occupational restructuring have reduced daily physical activity levels. As a result, the population mean BMI and consequent illness is increasing in many countries within the region. Recent studies have shown that infants who were undernourished in utero and then born small have a greater risk of developing abdominal obesity and related morbidity as adults. As undernutrition coexists with overnutrition throughout the Asia-Pacific, focusing efforts to improve nutrition during pregnancy will need to be combined with programs to prevent weight gain in adults if CHD and other chronic diseases are to be effectively tackled in the region. PMID: 11710363 [PubMed - indexed for MEDLINE] 4980. Asia Pac J Clin Nutr. 2001;10(2):82-4. Cardiovascular risk in the Asia-Pacific region from a nutrition and metabolic point of view: visceral obesity. Sullivan DR(1). Author information: (1)Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia. davids@bioc.rpa.cs.nsw.gov.au The association between abdominal obesity and an increased risk of cardiovascular disease (CVD) is now well recognized. Both problems are becoming more prevalent within the Asia-Pacific region, but there are substantial differences within and between countries. The strength of the temporal relationship between obesity and CVD in the region has led to the suggestion that obesity is the driving force behind the continuing epidemic of CVD. This raises the question as to whether there are any special aspects to the Asia-Pacific epidemic of obesity and resultant problems as a result of genetic or developmental factors. It is clear that the experience of central obesity and its cardiovascular consequences in western society cannot be directly transposed to all countries in the region. Issues such as smoking, alcohol use and inactivity may carry different implications. The Asia-Pacific region has started from low baseline prevalence of both obesity and CVD. but this implies that the potential for major problems in the future is particularly severe. PMID: 11710362 [PubMed - indexed for MEDLINE] 4981. Biochem Soc Trans. 2001 Nov;29(Pt 6):791-7. Mitochondrial uncoupling and lipid metabolism in adipocytes. Kopecký J(1), Rossmeisl M, Flachs P, Bardová K, Brauner P. Author information: (1)Department of Adipose Tissue Biology and Center for Integrated Genomics, Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic. kopecky@biomed.cas.cz Metabolism of white adipose tissue is involved in the control of body fat content. In vitro experiments indicated a dependence of lipogenesis on mitochondrial ATP production, as well as a reciprocal link between hormonal effects on metabolism and energetics of adipocytes. Therefore, mitochondrial uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to control of lipid metabolism and adiposity. This is supported by the expression of protonophoric proteins in adipocytes, e.g. uncoupling proteins (UCPs) 2 and 5, and some anion transporters, and induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. Negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by mitochondrial uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white but not in brown fat. Probably due to depression of ATP/ADP ratio in white fat of transgenic mice, both fatty acid synthesis and lipolytic action of noradrenaline in adipocytes were relatively low. These results support the role of protonophoric proteins in adipocytes in the control of adiposity. The main function of these proteins in white fat may be modulation of lipogenesis and intracellular hormone signalling. Augmentation of energy expenditure may be of relatively small importance, in accordance with the low oxidative capacity of white adipocytes. PMID: 11709076 [PubMed - indexed for MEDLINE] 4982. Biochem Soc Trans. 2001 Nov;29(Pt 6):785-91. Uncoupling protein 3 and fatty acid metabolism. Dulloo AG(1), Samec S, Seydoux J. Author information: (1)Institute of Physiology, Department of Medicine, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland. abdul.dulloo@unifr.ch A role for uncoupling protein (UCP) 3 in fatty acid metabolism is reviewed within the context of our proposal, first put forward in 1998, that this homologue of UCP1 may be involved in the regulation of lipids as fuel substrate rather than in the mediation of thermogenesis. Since then, the demonstrations of muscle-type differences in UCP3 gene regulation in response to dietary manipulations (starvation, high-fat feeding) or to pharmacological interferences with the flux of lipid substrates between adipose-tissue stores and skeletal-muscle mitochondrial oxidation are all in accord with this proposed role for UCP3 in regulating lipids as fuel substrate. However, given the current limitations of gene-knockout technology for evaluating/interpreting the functional importance of genes encoding mitochondrial membrane proteins, the transition from 'associative' to 'cause-and-effect' evidence for a physiological role of UCP3 in regulating fatty acid metabolism will have to await the development of assays that are sensitive to changes in UCP3 activity. Furthermore, in evaluating the physiological regulators of UCP3, the available evidence points to the existence of adipose-derived factor(s) which, independently of circulating levels of free fatty acids, initiates events leading to the transcription of genes encoding UCP3 and key enzymes of lipid oxidation in the fast glycolytic or fast oxidative-glycolytic muscles, i.e. in the bulk of the skeletal-muscle mass. It is proposed that in tissues where UCP3 co-exists with UCP2 (skeletal muscle, brown adipose tissue, heart) they may act in concert in the overall regulation of lipid oxidation, concomitant to the prevention of lipid-induced oxidative damage. PMID: 11709075 [PubMed - indexed for MEDLINE] 4983. Biochem Soc Trans. 2001 Nov;29(Pt 6):756-63. Life without UCP1: mitochondrial, cellular and organismal characteristics of the UCP1-ablated mice. Nedergaard J(1), Golozoubova V, Matthias A, Shabalina I, Ohba K, Ohlson K, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se Mice devoid of the original uncoupling protein UCP1 have provided opportunities to delineate UCP1 function in a series of biochemical and physiological contexts. The isolated brown-fat mitochondria from such mice are fully coupled (without the addition of GDP), but still exhibit a depressed capacity for ATP synthesis. However, they only show a 2-fold decrease in sensitivity to the de-energizing effect of free fatty acids, compared with UCP1-containing mitochondria, whereas they possess a (UCP1-independent) 50-fold higher sensitivity than liver mitochondria; the fatty acid sensitivities in wild-type and UCP1-deficient mitochondria may, however, be of different natures. Despite the fact that brown-fat cells from UCP1-ablated mice cannot produce heat when stimulated by noradrenaline ('norepinephrine') or fatty acids, UCP1-ablated mice can be induced to tolerate extended cold exposure, but the heat then fully results from shivering thermogenesis. Recruitable or adaptive (by cold acclimation or adaptation to a cafeteria diet) adrenergically-stimulated thermogenesis does not exist in the UCP1-ablated animals, demonstrating the unique ability of UCP1 to mediate recruitable non-shivering thermogenesis. In addition to information on the function of UCP1, the UCP1-ablated mice can be used to gain information concerning the function of the UCP1 homologues. Thus whereas an uncoupling function of the UCP1 homologues cannot be excluded, UCP1-ablated animals clearly lack any ability to recruit any UCP1 homologue to functionally replace the loss of thermogenesis resulting from UCP1. UCP1 (thermogenin) thus remains the only protein the activity of which can be recruited for the purpose of facultative thermogenesis. PMID: 11709070 [PubMed - indexed for MEDLINE] 4984. Biochem Soc Trans. 2001 Nov;29(Pt 6):751-5. A history of UCP1. Nicholls DG(1). Author information: (1)Buck Institute for Age Research, Redwood Boulevard, Novato, CA 94945, USA. dnicholls@buckinstitute.org Interest in the enormous thermogenic capacity of brown adipose tissue (BAT) began in the 1960s and focused on BAT mitochondria (BATM), which when prepared by conventional techniques respired rapidly but displayed no respiratory control. Two apparently distinct treatments, fatty acid removal and purine nucleotide addition, induced respiratory control. In 1972, we found that BATM were highly permeant to halides and protons, and that albumin decreased the proton conductance while purine nucleotides decreased both. Devising techniques to quantify the proton leak in respiring mitochondria we found a nucleotide-sensitive conductance pathway whose 'break-point', the protonmotive force at which conductance suddenly increased, could be subtly modulated by free fatty acids. The nucleotide-binding site on the outer face of the inner membrane was characterized and identified by photoaffinity labelling as a 32 kDa 'uncoupling protein', now UCP1. Studies with intact brown adipocytes generated the currently accepted model, namely that fatty acids liberated by beta3-adrenergic receptor activation act as both self-regulating second messengers for UCP1 and substrates for fatty acid activation and oxidation. Fatty acid concentration increases at the outset of thermogenesis, binding to UCP1 lowers the protonmotive force below that giving respiratory control and rapid thermogenesis proceeds. At the termination of receptor activation oxidation of residual fatty acid 'recouples' the mitochondria. The challenge with the novel UCPs is to demonstrate a similar coherent mechanism. PMID: 11709069 [PubMed - indexed for MEDLINE] 4985. Eat Weight Disord. 2001 Sep;6(3 Suppl):4-8. The adipose organ: endocrine aspects and insights from transgenic models. Cinti S(1). Author information: (1)Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Via Tronto 10/A, 60020 Ancona, Italy. PMID: 11706507 [PubMed - indexed for MEDLINE] 4986. Eat Weight Disord. 2001 Sep;6(3 Suppl):22-7. Control and function of the GH-IGF-I axis in obesity. Pombo M(1), Maccario M, Seoane LM, Tovar S, Micic D, Ghigo E, Casanueva FF, Dieguez C. Author information: (1)Department of Paediatrics, University of Santiago, Santiago de Compostela, Spain. PMID: 11706504 [PubMed - indexed for MEDLINE] 4987. Eat Weight Disord. 2001 Sep;6(3 Suppl):1-3. Obesity: a new paradigm in endocrinology. Vettor R(1). Author information: (1)Department of Medical and Surgical Sciences, University of Padua, Padua, Italy. PMID: 11706502 [PubMed - indexed for MEDLINE] 4988. Curr Opin Clin Nutr Metab Care. 2001 Nov;4(6):515-20. Effects of ovarian hormones on exercise metabolism. Campbell SE(1), Febbraio MA. Author information: (1)Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada. Growing evidence suggests that the ovarian hormones have major effects on lipid and carbohydrate metabolism, and may also play a major role in up-stream molecular signaling mechanisms for regulating substrate metabolism. It appears that the absence of estrogen can impair glucose uptake during exercise. In contrast, progesterone not only impairs contraction-mediated glucose uptake when solely administered, but impairs glucose uptake when physiological concentrations of both estrogen and progesterone are administered. Likewise, progesterone administered to rodents for 14 days decreases glucose transporter (GLUT) 4 protein content in skeletal muscle and adipose tissue. Furthermore removing the ovaries decreases the activity of key oxidative enzymes while estrogen treatment restores the activity of these enzymes. It appears, therefore, that estrogen increases the metabolic capacity for both carbohydrate and lipid metabolism, perhaps increasing the overall metabolic flexibility of skeletal muscle. Conversely, progesterone negates both these effects, and could therefore result in a state of relative metabolic inflexibility, similar to that observed in the metabolic syndrome. PMID: 11706286 [PubMed - indexed for MEDLINE] 4989. Curr Opin Clin Nutr Metab Care. 2001 Nov;4(6):503-8. The influence of aging and sex on skeletal muscle mass and strength. Doherty TJ(1). Author information: (1)Department of Physical Medicine and Rehabilitation, Faculty of Medicine and Dentistry, University of Western Ontario, London, Canada. tim.doherty@lhsc.on.ca This brief review examines the influence of aging on skeletal muscle mass and strength and specifically highlights sex-related differences. It is well established that aging is associated with a significant decline in muscle strength that becomes functionally important by the seventh decade of life. Age-related strength losses are mainly secondary to decline in skeletal muscle mass in men and women. While women may experience earlier strength losses than men, overall, age associated decreases in strength are similar when controlling for muscle mass. Although men may experience greater losses of total muscle mass, recent evidence, however, points toward greater declines in muscle quality in older women. The implications and potential mechanisms for these differences are discussed. PMID: 11706284 [PubMed - indexed for MEDLINE] 4990. Curr Opin Clin Nutr Metab Care. 2001 Nov;4(6):499-502. Gender differences in fat metabolism. Blaak E(1). Author information: (1)Department of Human Biology, Nutrition Research Centre, Maastricht University, The Netherlands. E.Blaak@HB.Unimaas.nl Women generally have a higher percentage of body fat than men. Also, women store more fat in the gluteal-femoral region, whereas men store more fat in the visceral (abdominal) depot. This review focuses on differences in regional fatty acid storage, mobilization and oxidation that may contribute to gender-related differences in body fat distribution. There are pronounced regional differences in the regulation of regional fatty acid metabolism between men and women. Firstly, there is evidence that in vivo, catecholamine mediated leg free fatty acid release is lower in women than in men, whereas free fatty acid release from the upper body depots is comparable. These data correspond to in-vitro adipose tissue biopsy data, which indicate a more pronounced difference in catecholamine mediated lipolysis between upper body and lower body fat depots in women than in men. Secondly, free fatty acid release by the upper body subcutaneous fat depots is higher in men than in women, indicating a higher resistance to the antilipolytic effect of meal ingestion in the upper body fat depots in men. Thirdly, there are indications that basal fat oxidation (adjusted for fat free mass) is lower in females as compared to males, thereby contributing to a higher fat storage in women. Finally, postprandial fat storage may be higher in subcutaneous adipose tissue in women than in men, whereas storage in visceral adipose tissue has been hypothesized to be higher in men. All the above differences may play a role in the variation in net regional fat storage between men and women, but the number of in-vivo studies on gender-related differences in fatty acid metabolism is very limited and most findings require confirmation. Furthermore, there is abundant evidence that the proportion of energy derived from fat during exercise is higher in women than in men. With respect to total body fat, this finding seems counterintuitive, as percentage body fat is increased in women. Further studies are necessary to investigate the significance of differences in exercise-induced fat oxidation on 24-h fat balance. PMID: 11706283 [PubMed - indexed for MEDLINE] 4991. Rev Endocr Metab Disord. 2000 Jan;1(1-2):87-95. Pathogenesis of ophthalmopathy in autoimmune thyroid disease. Heufelder AE(1). Author information: (1)Department of Internal Medicine, Division of Gastroenterology, Endocrinology and Metabolism, Philipps-University, Baldingerstrasse, 35033 Marburg, Germany. What causes GO is still a mystery, but the disease process results from a complex interplay of genetic and environmental factors. Genes such as those for HLA genes may determine a patient's susceptibility to the disease and its severity, but environmental factors, often unknown, may determine its course. Once established, the chronic inflammatory process within the orbital tissues appears to take on a momentum of its own. Given our current state of knowledge, the following working scheme for the pathogenesis of GO can be proposed (Fig. 1): On the background of a permissive immunogenetic milieu, circulating T cells in patients with GD, directed against certain antigens on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the orbital space. Of the cell types residing in these tissues, preadipocytes and fibroblasts, most likely act as target and effector cells of the orbital immune process, respectively. This includes preadipocyte fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically different from those located in the orbital connective tissue. Orbital preadipocyte fibroblasts may be stimulated by unknown circulating or locally produced factors to differentiate into mature adipocytes that express increased levels of TSHr. How autoreactive T cells escape deletion and control by the immune system and come to be directed against a self-antigen presented by cells residing in the thyroid gland and extrathyroidal locations, is still unknown. Proliferation and expansion of autoreactive T cell clones may be due to mimicry of a host antigen by a microorganism, but this remains speculative. T cell recruitment into the orbital tissues is facilitated by certain chemokines and cytokines, which help to attract T cells by stimulating the expression of certain adhesion molecules (e.g., ICAM-1, VCAM-1, CD44) in vascular endothelium and connective tissue cells. These adhesion receptors are known to also play an important costimulatory role by activating T cells and facilitating antigen recognition, which amplifies the cellular immune process. Analysis of variable region genes of T cell antigen receptors in orbital T cells of patients with active GO has revealed their restricted TcR V gene usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur early in the evolution of GO. T cells and macrophages populating the orbital space are known to synthesize and release a [figure: see text] number of cytokines (most likely a Th1-type spectrum) into the surrounding tissue. Cytokines, oxygen free radicals and fibrogenic growth factors, released both from infiltrating inflammatory and residential cells, act upon orbital preadipocytes in a paracrine and autocrine manner to stimulate adipogenesis, fibroblast proliferation, glycosaminoglycan synthesis, and the expression of immunomodulatory molecules. Smoking, a well-known aggravating factor in GO, may aggravate tissue hypoxia and exert important immunomodulatory effects. The long held hypothesis of a thyroid cross-reactive antigen within the orbital tissues has recently gained significant support by an animal model of GO, and by in vitro and ex vivo studies. If confirmed in immunological studies, these data may well explain the localized infiltration of the orbital tissues by autoreactive lymphocytes that share intriguing molecular features with intrathyroidal lymphocytes. Local release of particular cytokines, TSHr-directed antibodies, or other factors might further enhance adipogenesis, glycosaminoglycan synthesis and expression of immunomodulatory proteins within the orbit. Other factors, including inflammatory cytokines, might act as counterbalancing inhibitors of these effects. However, if the net effect of these changes is to increase the volume of the fatty connective tissues within the orbit, then proptosis, extraocular muscle dysfunction, and periorbital congestion will ensue. Whether this hypothetical sequence of events will finally explain the involvement of the orbit in GD is unknown. Future studies will be aimed at identifying factors that might modulate adipogenesis in orbital cells and clarifying the link between adipogenesis and TSHr expression in the orbit. Taken together, a number of important details in the complex pathogenesis of GO have been resolved in recent years, but many challenges are still ahead. Elucidation of the primary antigen and how it is recognized by the immune system will be key issues. PMID: 11704996 [PubMed - indexed for MEDLINE] 4992. Diabetes Obes Metab. 2001 Oct;3(5):299-310. Adipocyte apoptosis in the regulation of body fat mass by leptin. Della-Fera MA(1), Qian H, Baile CA. Author information: (1)Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA. PMID: 11703419 [PubMed - indexed for MEDLINE] 4993. Physiol Res. 2001;50(5):443-59. The role of leptin in human physiology and pathophysiology. Janeckova R(1). Author information: (1)Institute of Endocrinology, Prague, Czech Republic. drjaneckova@hotmail.com This review focuses on current knowledge of leptin biology and the role of leptin in various physiological and pathophysiological states. Leptin is involved in the regulation of body weight. Serum leptin can probably be considered as one of the best biological markers reflecting total body fat in both animals and humans. Obesity in man is accompanied by increased circulating leptin concentrations. Gender differences clearly exist. Leptin is not only correlated to a series of endocrine parameters such as insulin, glucocorticoids, thyroid hormones, testosterone, but it also seems to be involved in mediating some endocrine mechanisms (onset of puberty, insulin secretion) and diseases (obesity, polycystic ovary syndrome). It has also been suggested that leptin can act as a growth factor in the fetus and the neonate. PMID: 11702849 [PubMed - indexed for MEDLINE] 4994. Receptors Channels. 2001;7(4):249-58. PPAR gamma/RXR as a molecular target for diabetes. Lenhard JM(1). Author information: (1)Department of Metabolic Diseases, GlaxoSmithKline Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat. Novel therapies that improve insulin action include ligands that bind and activate the nuclear receptors peroxisome proliferator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR). PPAR gamma/RXR form heterodimers that regulate transcription of genes involved in insulin action, adipocyte differentiation, lipid metabolism and inflammation. PPAR gamma activators include prostanoids, fatty acids, thiazolidinediones and N-(2-benzoylphenyl)tyrosine analogues. RXR ligands include naturally occurring retinoic acid and synthetic rexinoids. Selective ligands for these receptors improve metabolic abnormalities associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia, insulin resistance and other cardiovascular risk factors. Although adipose tissue mediates some of the effects of PPAR gamma/RXR ligands, other tissues also regulate the effects of these receptors. The activity of the PPAR gamma/RXR heterodimer is influenced by posttranslational modifications, receptor turnover, polymorphisms, splice variants, coactivators and corepressors. This article reviews recent developments in research on these receptors, with particular emphasis on metabolic effects, ligand selectivity, structure and regulation of the PPAR gamma/RXR heterodimer. PMID: 11697231 [PubMed - indexed for MEDLINE] 4995. Exerc Sport Sci Rev. 2001 Oct;29(4):149-54. Endocrine regulation of exercise substrate utilization in women compared to men. Braun B(1), Horton T. Author information: (1)Department of Exercise Science, University of Massachusetts, Amherst 01003, USA. bbraun@excsci.umass.edu During low to moderate intensity exercise, women utilize proportionally more lipid and less carbohydrate compared to men. Estrogen and progesterone may have direct effects on these differences by increasing lipolysis and/or constraining glucose production and utilization. Furthermore, sex steroids may have indirect effects through interactions with other hormones, especially catecholamines. PMID: 11688786 [PubMed - indexed for MEDLINE] 4996. Nutrition. 2001 Oct;17(10):799-805. Vitamin E kinetics and the function of tocopherol regulatory proteins. Blatt DH(1), Leonard SW, Traber MG. Author information: (1)Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA. Plasma and tissue alpha-tocopherol concentrations are remarkably stable, which suggests that they are regulated. alpha-Tocopherol transfer protein, tocopherol-associated protein, and tocopherol-binding protein bind alpha-tocopherol. These proteins might function as tocopherol regulatory proteins, although only tocopherol transfer protein has been shown to influence plasma and tissue alpha-tocopherol concentrations. Tissue alpha-tocopherol concentrations likely depend on tocopherol regulatory protein function and tissue lipid content, vitamin E uptake and efflux, oxidative stress, and interactions between vitamin E and other antioxidants. Pharmacokinetic models often divide tissues into rapidly perfused, slowly perfused, and very slowly perfused compartments. Tissue vitamin E concentrations might equilibrate more rapidly in tissues with greater perfusion, greater vitamin E uptake, increased amounts or activities of tocopherol regulatory protein, and lower lipid contents. The rate at which tissue concentrations approach equilibrium, however, does not predict the final equilibrium concentrations because of redistribution among tissues. Redistribution of vitamin E to adipose tissue from other tissues may be significant. Intracellular trafficking of vitamin E might occur in conjunction with membrane recycling because membrane constituents rapidly recycle between the plasma membrane and intracellular endocytic compartments. Thus, tocopherol regulatory proteins may modulate rather than directly regulate vitamin E tissue distribution and intracellular trafficking. PMID: 11684383 [PubMed - indexed for MEDLINE] 4997. Nutrition. 2001 Oct;17(10):789-92. Porcine growth hormone: a central metabolic hormone involved in the regulation of adipose tissue growth. Etherton TD(1). Author information: (1)Department of Dairy and Animal Science, The Pennsylvania State University, 324 W.L.Henning Building, University Park, PA 16802, USA. tetherton@psu.edu During the past 20 y, much has been learned about how porcine growth hormone (pGH) affects growth and nutrient partitioning in growing pigs. Our contemporary understanding of the biology of pGH has as its roots the seminal studies conducted by Larry Machlin. His studies and many subsequent reports by other investigators have established that treatment of growing pigs with pGH markedly stimulates muscle growth and, concurrently, reduces fat deposition. In growing pigs, maximally effective doses of pGH increase average daily gain as much as 10% to 20%, improve feed efficiency 15% to 30%, decrease adipose tissue mass and lipid accretion rates by as much as 50% to 80%, and concurrently increase protein deposition by 50%. These effects are associated with a decrease in feed intake of approximately 10% to 15%. These responses occur because pGH has a wide array of biological effects that modulate nutrient partitioning between adipose tissue and skeletal muscle. The decrease in adipose tissue growth is due to a reduction in lipogenesis that is the consequence of pGH blunting the effects of many insulin-dependent events. This article provides an overview of some of the biological effects pGH has in adipose tissue and discusses what is known about the underlying mechanisms that account for these effects. PMID: 11684380 [PubMed - indexed for MEDLINE] 4998. Proc Nutr Soc. 2001 Aug;60(3):375-80. Adipose tissue and the insulin resistance syndrome. Frayn KN(1). Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, UK. keith.frayn@oxlip.ox.ac.uk Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation. Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are 'full up' and resisting further fat storage. Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been 'absorbed' by adipose tissue. This situation leads to fat deposition in other tissues. Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in 'buffering' the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx. PMID: 11681812 [PubMed - indexed for MEDLINE] 4999. Proc Nutr Soc. 2001 Aug;60(3):365-74. Long-term changes in adipose tissue in human disease. Pond CM(1). Author information: (1)Department of Biological Sciences, The Open University, Milton Keynes, UK. C.M.Pond@open.ac.uk Redistribution of white adipose tissue is a long-term symptom of several chronic diseases. Although the roles of adipocytes in acute illness have been thoroughly studied, how or why short-term responses of adipose tissue to disease sometimes produce long-term redistribution, and the causal relationship between the anatomical changes and the associated metabolic syndromes are poorly understood. The present paper reviews explanations for the redistribution of adipose tissue after infection with HIV, and in Crohn's disease; both conditions that share the peculiarity of selective expansion of certain adipose depots while others are depleted. HIV adipose tissue redistribution syndrome (HARS) develops gradually after several months of infection with the HIV both in untreated patients and in those taking protease inhibitors and nucleoside reverse transcriptase inhibitors. Some current theories about the causes of HARS are critically assessed, and reasons presented for implicating local interactions between the immune system and perinodal adipocytes. Some evolutionary aspects of conspicuous long-term changes in the distribution of human adipose tissue are discussed. Adipose tissue acts as a social signal, indicating dietary history and previous exposure to pathogens. A distinctive symptom of Crohn's disease is selective enlargement of the mesenteric adipose tissue near the diseased lymph nodes and intestine. Perinodal adipocytes have site-specific properties not found in adipocytes from nodeless depots, such as perirenal and epididymal, that may equip them to interact locally with lymph-node lymphoid cells, making polyunsaturated fatty acids selectively and rapidly available to activated immune cells. Studies of the time course of activation of perinodal adipocytes via the lymph nodes they enclose indicate that prolonged or frequent stimulation recruits more adipocytes to control by immune cells, which may lead to selective enlargement of node-containing depots. These concepts suggest hypotheses about HARS and the anomalous development of mesenteric adipose tissue in Crohn's disease that could form the basis for further investigations. PMID: 11681811 [PubMed - indexed for MEDLINE] 5000. Proc Nutr Soc. 2001 Aug;60(3):357-64. The sympathetic nervous system in white adipose tissue regulation. Rayner DV(1). Author information: (1)Molecular Physiology Group, Rowett Research Institute, Bucksburn, Aberdeen, UK. dvr@rri.sari.ac.uk Sympathetic stimulation has long been recognized to mobilise fatty acids from white adipose tissue. However, it is now apparent that adipose tissue is not only concerned with energy storage as fat, but is a major endocrine and secretory organ. This change has resulted from the identification of leptin as a hormone of energy balance secreted by white adipose tissue. The sympathetic system is a key regulator of leptin production in white fat. Sympathomimetic amines, cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease ob gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and ob gene expression, and it is postulated that the sympathetic system has a tonic inhibitory action on leptin synthesis. In rodents this action is through stimulation of, beta3-adrenoceptors. The adrenal medulla (as opposed to the direct sympathetic innervation) has been thought to play only a minor role in the catecholaminergic regulation of white adipose tissue. However, in rodents responses of the leptin system to adrenergic blockade vary with the method used. Changes in leptin and ob gene expression are considerably less using methods of blockade that only effect the terminal adrenergic innervation, rather than medullary secretions as well. Stimulation of the leptin system increases sympathetic activity and hence metabolic activity in many tissues. As well as leptin, other (but not all) secretions from white adipose tissue are subject to sympathetic regulation. In obesity the sympathetic sensitivity of adipose tissue is reduced and this factor may underlie the dysregulation of leptin production and other adipose tissue secretions. PMID: 11681810 [PubMed - indexed for MEDLINE] 5001. Proc Nutr Soc. 2001 Aug;60(3):349-56. Pro-inflammatory cytokines and adipose tissue. Coppack SW(1). Author information: (1)Academic Medical Unit, St Bartholomew's and The Royal London School of Medicine, Whitechapel, UK. s.w.coppack@mds.qmw.ac.uk Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body. PMID: 11681809 [PubMed - indexed for MEDLINE] 5002. Proc Nutr Soc. 2001 Aug;60(3):341-7. Plasminogen activator inhibitor-1 and haemostasis in obesity. Mutch NJ(1), Wilson HM, Booth NA. Author information: (1)Institute of Medical Sciences, University of Aberdeen, UK. The connection between obesity and disordered haemostasis is well established, but incompletely understood. There is a strong link between inhibition of fibrinolysis and obesity, and elevation of the plasma inhibitor, plasminogen activator inhibitor-1 (PAI-1), is regarded as a central factor. Here we explore the increased risk of atherothrombotic disorders in obese subjects, and the evidence for metabolic and genetic causes. There is a clear relationship between plasma PAI-1 and obesity, and adipose tissue synthesises PAI-1, as has been shown in mouse and rat models, and more recently in human material. This tissue also produces several effector molecules that can up regulate PAI-1. These molecules include transforming growth factor beta, tumour necrosis factor alpha, angiotensin II and interleukin 6, all of which up regulate PAI-1 in various cell types. The issue of whether adipose tissue directly contributes to plasma PAI-1, or whether it primarily contributes indirectly, its products stimulating other cells to produce PAI-1 that feeds into the plasma pool, is not yet resolved. Finally, we briefly examine other proteins of haemostasis that are products of adipose tissue. Further studies are needed to define the regulation of these proteins, in adipose tissue itself and in other cells influenced by its products, in order to extend recent insights into the links between obesity and haemostasis. PMID: 11681808 [PubMed - indexed for MEDLINE] 5003. Proc Nutr Soc. 2001 Aug;60(3):329-39. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Trayhurn P(1), Beattie JH. Author information: (1)Institute for Nutrition Research, University of Oslo, Blindern, Norway. p_trayhurn@altavista.com The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage. PMID: 11681807 [PubMed - indexed for MEDLINE] 5004. Mol Membr Biol. 2001 Jul-Sep;18(3):205-11. GLUT4: a key player regulating glucose homeostasis? Insights from transgenic and knockout mice (review). Wallberg-Henriksson H(1), Zierath JR. Author information: (1)Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. Studies in which GLUT4 has been overexpressed in transgenic mice provide definitive evidence that glucose transport is rate limiting for muscle glucose disposal. Transgenic overexpression of GLUT4 selectively in skeletal muscle results in increased whole body glucose uptake and improves glucose homeostasis. These studies strengthen the hypothesis that the level of muscle GLUT4 affects the rate of whole body glucose disposal, and underscore the importance of GLUT4 in skeletal muscle for maintaining whole body glucose homeostasis. Studies in which GLUT4 has been ablated or 'knocked-out' provide proof that GLUT4 is the primary effector for mediating glucose transport in skeletal muscle and adipose tissue. Genetic ablation of GLUT4 results in impaired insulin tolerance and defects in glucose metabolism in skeletal muscle and adipose tissue. Because impaired muscle glucose transport leads to reduced whole body glucose uptake and hyperglycaemia, understanding the molecular regulation of glucose transport in skeletal muscle is important to develop effective strategies to prevent or reduce the incidence of Type II diabetes mellitus. In patients with Type II diabetes mellitus, reduced glucose transport in skeletal muscle is a major factor responsible for reduced whole body glucose uptake. Overexpression of GLUT4 in skeletal muscle improves glucose homeostasis in animal models of diabetes mellitus and protects against the development of diabetes mellitus. Thus, GLUT4 is an attractive target for pharmacological intervention strategies to control glucose homeostasis. This review will focus on the current understanding of the role of GLUT4 in regulating cellular glucose uptake and whole body glucose homeostasis. PMID: 11681787 [PubMed - indexed for MEDLINE] 5005. Proc Nutr Soc. 2001 May;60(2):187-94. The role of leptin in the transition from fetus to neonate. Mostyn A(1), Keisler DH, Webb R, Stephenson T, Symonds ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham, UK. mgxam2@nottingham.ac.uk Leptin is a 16 kDa hormone which has been shown to have a major physiological role in the control of energy balance. Leptin is produced primarily in white adipose tissue, although there is evidence for its production in brown adipose tissue (BAT) and the placenta. BAT is critically important for the initiation of non-shivering thermogenesis in the newborn through the BAT-specific uncoupling protein (UCP), UCPI. This factor is particularly important in lambs in which levels of UCP1 peak at birth, concomitant with a rapid decline in plasma leptin levels. Our studies have examined the effect of acute and chronic administration of leptin to neonatal lambs, investigating effects on colonic temperature, UCP1 and thermogenic potential of BAT. Administration of leptin in sequential physiological doses of 10, 100 and 100 microg to neonatal lambs caused a modest increase in colonic temperature which was not observed in weight-matched vehicle-treated controls. This increase in colonic temperature was not mediated by an increase in either abundance or thermogenic potential of UCPI, as previously shown in adult rodents. UCP1 mRNA levels were 30 % lower in leptin-treated lambs, which is also contradictory to findings in adult rodents. Leptin treatment resulted in a dose-dependent rise in plasma leptin, with levels at the end of the study being almost twenty times greater in leptin-treated animals. To determine whether these findings in neonatal lambs were transient due to the complex milieu of hormones present after birth, we examined the effect of chronic leptin treatment over 6 d. Pairs of lambs were treated daily, from the second to seventh day of life with 100 microg leptin or vehicle. Colonic temperatures of leptin- and vehicle-treated animals remained similar throughout the study. UCP1 abundance was significantly lower in the leptin-treated animals, suggesting that the drop in UCP1 mRNA seen in the previous study had been translated to protein levels. In conclusion, the decline in plasma leptin levels at birth may be a signal to initiate enteral feeding. In lambs, the rapid loss of UCP1 mRNA, which occurs within the first few days of life, appears to be accelerated by leptin administration, possibly stimulating the development of white adipose tissue and generation of body heat through mechanisms other than non-shivering thermogenesis by UCP1 in BAT. PMID: 11681634 [PubMed - indexed for MEDLINE] 5006. J Neuroendocrinol. 2001 Oct;13(10):913-21. The role of leptin in the regulation of energy balance and adiposity. van Dijk G(1). Author information: (1)Department of Animal Physiology, Division Neuroendocrinology, School of Behavioural and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands. g.van.dijk@biol.rug.nl Since its discovery, leptin (a 167-amino acid product of the OB gene) has quickly moved to the forefront as an important hormone for regulation of energy balance. It closes a feedback loop from adipose tissue to hypothalamic neuropeptide-containing neural circuitry involved in regulation of food intake and neuroendocrine/autonomic outflow. While increased central leptin signalling reduces adiposity via a reduction in food intake, it also has remarkable metabolic effects that promote leanness, independent of food intake. These include: (i) increased energy expenditure, (ii) in-place degradation of fat, and (iii) increased thermogenesis. Hypothalamic neurones that synthesize corticotropin releasing hormone and melanocortins (i.e. alpha-melanocyte-stimulating hormone and agouti-related protein) are likely effector pathways that mediate the anorexigenic and metabolic effects of leptin. Activation of sympathetic outflow (via neuropeptidergic effector pathways of central leptin) to a number of tissues that store fat might be an important mechanism through which these peripheral metabolic effects are elicited. It is proposed that these peripheral metabolic effects contribute to the satiating properties of leptin. PMID: 11679060 [PubMed - indexed for MEDLINE] 5007. Clin Endocrinol (Oxf). 2001 Oct;55(4):437-8. Resistin: a new link between obesity and insulin resistance? Vidal-Puig A(1), O'Rahilly S. Author information: (1)University of Cambridge, Departments of Medicine and Clinical Biochemistry, Cambridge, UK. PMID: 11678824 [PubMed - indexed for MEDLINE] 5008. J Am Diet Assoc. 2001 Oct;101(10):1175-80. The fat redistribution syndrome in patients infected with HIV: measurements of body shape abnormalities. Gerrior J(1), Kantaros J, Coakley E, Albrecht M, Wanke C. Author information: (1)Department of Community Health, Tufts University School of Medicine, Boston, MA 02111, USA. OBJECTIVE: To describe the body shape changes in the syndrome of fat redistribution or lipodystrophy seen in patients infected with HIV. DESIGN: An objective description of patients with HIV with fat redistribution syndrome. Body-height, weight, shape, and composition were measured by anthropometrics and biolectrical impedance analysis by a single observer. Clinical data were collected by chart review. SUBJECTS/SETTING: Thirty-nine patients with HIV receiving primary HIV care at a university hospital-affiliated infectious disease clinic who presented with complaints of body shape changes or who were referred by their primary care providers for body shape changes. ANALYSIS: Descriptive statistics were performed. RESULTS: Four of the 39 patients (10%) had not used protease inhibitor therapy. HIV status (by clinical presentation, CD4 and VL) varied widely. Laboratory abnormalities were moderate. Percent body fat differed widely when measured by bioelectrical impedance analysis and anthropometry (23% vs 13%). The mean body mass index was 25.6 kg/m2 for men and 25.8 kg/m2 for women. The mean waist/hip ratio was above normal, at 1.02. The mean mid-arm circumference and triceps skinfolds were below national standards for both men (30.4 cm and 8.1 mm, respectively) and women (26.7 cm and 7.5 mm, respectively). Nine patients (23%) had an increased dorso-cervical pad. Seventeen patients returned for follow-up measurements at 3 months; no significant differences were found between baseline and follow-up measurements. CONCLUSIONS: The waist/hip ratio, mid-arm and mid-thigh circumference, and triceps skinfolds were useful measures to define and follow the fat redistribution syndrome in patients with HIV. These body composition changes were not transitory in this short follow-up period. PMID: 11678488 [PubMed - indexed for MEDLINE] 5009. FASEB J. 2001 Oct;15(12):2099-111. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. Sesti G(1), Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Author information: (1)Department of Experimental and Clinical Medicine, University of Catanzaro-Magna Graecia, 88100 Catanzaro, Italy. sesti@unicz.it Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling and play a central role in maintaining basic cellular functions such as growth, survival, and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues to the functional differences among these related molecules, suggesting they play different and specific roles in vivo. The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. By contrast, IRS-3 and IRS-4 genes appear to play a redundant role in the IRS signaling system. Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly-->Arg972 substitution of IRS-1, interacting with environmental factors, seems to have a pathogenic role in the development of type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to type 2 diabetes. PMID: 11641236 [PubMed - indexed for MEDLINE] 5010. J Am Coll Nutr. 2001 Oct;20(5 Suppl):428S-435S; discussion 440S-442S. Calcium modulation of hypertension and obesity: mechanisms and implications. Zemel MB(1). Author information: (1)Department of Nutrition, University of Tennessee, Knoxville, USA. mzemel@utk.edu Regulation of intracellular calcium plays a key role in hypertension and obesity. Dysregulation of calcium homeostasis appears to be a fundamental factor linking these conditions. Regulation of intracellular calcium in key disease-related target tissues by calcitrophic hormones provides the opportunity to modulate disease risk with dietary calcium. Overall, sub-optimal calcium intakes contribute to the etiology of salt-sensitivity and hypertension. High salt diets exert a calciuretic effect, serving to exacerbate the physiological consequences of sub-optimal calcium diets. Among these are increases in 1,25-dihydroxyvitamin D, which increases vascular smooth muscle intracellular calcium, thereby increasing peripheral vascular resistance and blood pressure. Dietary calcium reduces blood pressure in large part via suppression of 1,25-dihydroxyvitamin D, thereby normalizing intracellular calcium. The practical relevance of this approach has been confirmed in the DASH (Dietary Approaches to Stop Hypertension) trial, which demonstrated that increasing low-fat dairy product and fruit and vegetable consumption exerted profound blood pressure-lowering effects. The magnitude of this effect among hypertensives was comparable to that typically found in pharmacological trials of mild hypertension. 1,25-dihydroxyvitamin D also stimulates calcium influx in human adipocytes, resulting in stimulation of lipogenesis, inhibition of lipolysis and expansion of triglyceride stores. Accordingly, suppression of 1,25-dihydroxyvitamin D by dietary calcium has been identified as a target, which may contribute to the prevention and management of obesity. Indeed, laboratory, clinical and population data all indicate a significant anti-obesity effect of dietary calcium, although large-scale prospective clinical trials have not yet been conducted to definitively demonstrate the scope of this effect. Thus, available evidence indicates that increasing dietary calcium intakes may result in reductions in fat mass as well as in blood pressure. PMID: 11603653 [PubMed - indexed for MEDLINE] 5011. J Physiol. 2001 Oct 15;536(Pt 2):329-37. Muscle-derived interleukin-6: possible biological effects. Pedersen BK(1), Steensberg A, Schjerling P. Author information: (1)The Copenhagen Muscle Research Centre, University of Copenhagen, Denmark. bkp@rh.dk Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor alpha. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis. PMCID: PMC2278876 PMID: 11600669 [PubMed - indexed for MEDLINE] 5012. Int J Clin Pract Suppl. 2001 Sep;(121):8-12. Insulin resistance and its impact on the approach to therapy of type 2 diabetes. Laakso M(1). Author information: (1)Department of Medicine, University of Kuopio, Finland. Insulin resistance is a core defect in Type 2 diabetes, occurring in peripheral organs (skeletal muscle and adipose tissue) leading to decreased glucose uptake and utilisation and in liver leading to increased hepatic glucose production. As long as the beta-cell can compensate for this by producing more insulin, glucose tolerance remains normal. However, as insulin resistance worsens, the beta-cell starts to fail to compensate leading to impaired glucose tolerance and then frank diabetes. The exact pathophysiology of insulin resistance is not clear but it probably involves a combination of genetic and environmental factors. These factors may result in changes in the number of insulin receptors, their affinity for insulin or a defect in post-receptor signalling or a combination of these. Insulin resistance also affects lipid metabolism such that there is increased production of triglycerides from the liver, which in turn both amplifies insulin resistance and exacerbates atherogenesis. The promotion of atherosclerosis by insulin resistance means that patients with Type 2 diabetes are at particularly high risk of cardiovascular disease. Therefore, treatment of insulin resistance with thiazolidinediones has the potential to offer improvements both in glycaemic control and in cardiovascular events. PMID: 11594246 [PubMed - indexed for MEDLINE] 5013. Int J Clin Pract Suppl. 2001 Sep;(121):13-8. Pioglitazone: mechanism of action. Smith U(1). Author information: (1)Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Göteborg University, Sweden. Thiazolidinediones, such as pioglitazone, are synthetic ligands for peroxisome proliferator-activated receptors (PPARs). They alter the transcription of genes influencing carbohydrate and lipid metabolism, resulting in changed amounts of protein synthesis and, therefore, metabolic changes. Pioglitazone improves glycaemic control in people with Type 2 diabetes by improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha. The results of these interactions include increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance. PMID: 11594239 [PubMed - indexed for MEDLINE] 5014. An Med Interna. 2001 Mar;18(3):152-60. [Leptin: physiological and clinical role]. [Article in Spanish] Botella Carretero JI(1), Lledín Barbancho MD, Valero González MA, Varela Dacosta C. Author information: (1)Servicio de Endocrinología y Nutrición, Hospital Ramón y Cajal, Colmenar km 9,700, 28034 Madrid. Leptin is a protein that has been identified three years ago, but its role, or at least its deficiency, was suspected from 1950. Dickie and coworkers reported the appearance of a mutant rat in one of their colonies with morbid obesity. The genetic defect was autosomal recessive and was manifested early in life. In December 1994, the gen ob was cloned, which stated the first step for the later identification of the gen product leptin, as a protein of 167 aminoacids expressed in adipose tissue. Since then, leptin has been implicated in many neuroendocrine regulatory pathways. The recent research in leptin roles worth an update review, and so its current and future clinical relevance. PMID: 11594183 [PubMed - indexed for MEDLINE] 5015. Nutr Metab Cardiovasc Dis. 2001 Jun;11(3):195-204. Visceral obesity and the metabolic syndrome: effects of weight loss. Busetto L(1). Author information: (1)Department of Medical and Surgical Sciences, University of Padova, Italy. luca.busetto@unipd.it A large body of experimental and epidemiological evidence has established an association between visceral obesity and the metabolic syndrome, which retains its power throughout the spectrum of adiposity and is still clinically meaningful in severe obesity. The association may be due to an overload of liver free fatty acids (FFA) produced by the high lipolytic activity of omental fat. A substantial improvement in all aspects of the metabolic syndrome with only a moderate degree of weight loss has been observed in a large number of randomised controlled studies and can also be obtained in severe obesity, despite the fact that the patients remain obese. The reasons for this apparent dissociation between weight loss and metabolic improvement are not yet clearly understood, but may involve the relationship between visceral fat and metabolic alterations. The results of some studies suggest that the favourable metabolic changes observed in obese patients with weight loss may be directly attributable to a reduction in visceral fat, and other studies have recently shown that a rapid and preferential reduction in visceral fat mass occurs during the first phase of weight loss in morbidly obese patients possibly as a result of sympathetic nervous system activation. It is therefore possible that the apparent dissociation between weight loss and metabolic improvement is partially due to a difference in the responsiveness of visceral and subcutaneous adipose tissue to energy restriction: i.e. the fact that the metabolic profile of patients with visceral obesity may substantially improve after the loss of only a few kilograms of body weight could be related to a greater relative reduction in the amount of visceral rather than other fat. In this respect, the characteristically high rate of visceral fat mobilisation can also be seen as a good target for interventions aimed at reducing cardiovascular risk factors. PMID: 11590996 [PubMed - indexed for MEDLINE] 5016. J Lipid Res. 2001 Oct;42(10):1521-42. Sources of eicosanoid precursor fatty acid pools in tissues. Zhou L(1), Nilsson A. Author information: (1)Gastroenterology Division, Department of Medicine, University Hospital of Lund, BMC B11, Tornavägen 10, 221 85 Lund, Sweden. Tissue arachidonic acid (AA) pools originate from the diet, and from hepatic and extrahepatic desaturation-elongation of dietary linoleic acid (LA). This review summarizes the roles of absorption, transport, and formation of AA in the buildup of tissue AA pools. In humans who ingest 0.2-0.3 g of AA and 10-20 g of LA per day on a Western diet, the formation of AA from LA exceeds the dietary supply of AA. A number of factors favor the partitioning of AA to tissue phospholipids rather than adipose tissue and plasma triglycerides. The characteristics of AA transport with lipoproteins are discussed with focus on the role of lipoprotein lipase, lecithin:cholesterol acyltransferase, hepatic lipase, and the scavenger receptor BI and LDL receptors in tissue uptake of AA. Liver-derived 2-acyl-lysophosphatidylcholine and plasma free AA are two important sources of AA for extrahepatic tissues which exhibit a low rate of uptake of lipoprotein AA. Desaturation-elongation of LA to produce AA occurs both in liver and in extrahepatic tissues, plasma free LA being an important substrate particularly during fasting. The AA preference of the reacylation and transacylation reactions is crucial for the selective retention of AA in phospholipids. PMID: 11590208 [PubMed - indexed for MEDLINE] 5017. Carcinogenesis. 2001 Oct;22(10):1583-91. Role of the high mobility group A proteins in human lipomas. Fedele M(1), Battista S, Manfioletti G, Croce CM, Giancotti V, Fusco A. Author information: (1)Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli, Via Pansini, 5, I-80131 Naples, Italy. The HMGA family is comprised of four proteins: HMGA1a, HMGA1b, HMGA1c and HMGA2. The first three proteins are products of the same gene, HMGA1, generated through an alternative splicing mechanism. The HMGA proteins are involved in the regulation of chromatin structure and HMGA DNA-binding sites have been identified in functional regions of many gene promoters. Rearrangements of the HMGA2 gene have been frequently detected in human benign tumors of mesenchymal origin including lipomas. 12q13-15 chromosomal translocations involving the HMGA2 gene locus, account for these rearrangements. The HMGA proteins have three AT-hook domains and an acidic C-terminal tail. The HMGA2 modifications consist in the loss of the C-terminal tail and fusion with ectopic sequences. A pivotal role of the HMGA2 rearrangements in the process of lipomagenesis is suggested by experiments showing that transgenic mice carrying a truncated HMGA2 gene showed a giant phenotype together with abdominal/pelvic lipomatosis. As HMGA2 null mice showed a great reduction in fat tissue, a positive role of the HMGA2 gene in adipocytic cell proliferation is proposed. More recently, similar alterations of the HMGA1 gene have been described. As the block of the HMGA1 protein synthesis induces an increase in growth rate of the pre-adipocytic cell line 3T3-L1, we suggest a negative role of the HMGA1 proteins in adipocytic cell growth and, therefore, we propose that adipocytic cell growth derives from the balance of the HMGA1 and HMGA2 protein functions. PMID: 11576996 [PubMed - indexed for MEDLINE] 5018. Gynecol Obstet Fertil. 2001 Jul-Aug;29(7-8):534-7. [Placental leptin and pregnancy pathologies]. [Article in French] Hauguel-de Mouzon S(1), Lepercq J. Author information: (1)Institut Cochin de génétique moléculaire, départment d'endocrinologie, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France. Leptin, the protein encoded by the Ob gene, is produced by the white adipose tissue and by the placenta during pregnancy. Placental leptin production makes a substantial contribution to maternal circulating levels during pregnancy which rapidly decrease and return to normal after delivery. Leptin has been detected in fetal plasma as early as week 18 of gestation, and umbilical leptin concentrations are closely related to birth weight. This has led to the hypothesis that fetal fat mass mainly determines fetal circulating leptin. Placental leptin production is increased in choriocarcinoma, preeclampsia and type 1 diabetes. Estrogens, hypoxia and insulin have been suggested as positive regulators of placental leptin production. Maternal leptinemia might act as a sensor of energy balance during pregnancy. The presence of both leptin and leptin receptors in the placenta suggests that leptin can act by autocrine or endocrine pathways in the human placenta. The roles of fetal leptin and consequences of increased placental leptin production in pathological pregnancies have yet to be elucidated. PMID: 11575151 [PubMed - indexed for MEDLINE] 5019. Orv Hetil. 2001 Aug 19;142(33):1781-8. [Diabetes mellitus as a general membrane disease and its consequences]. [Article in Hungarian] Somogyi J(1), Kiss G, Pentek E, Csermely P, Vér A. Author information: (1)Altalános Orvostudományi Kar, Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet, Semmelweis Egyetem, Budapest. The metabolic disturbances and their consequences in diabetes mellitus are well known more or less in details too. However, our knowledge on the diabetic disorders in membrane functions are limited. These damages are connected mostly with the disregulation of the membrane protein syntheses due to deficiency of insulin. In this review the impairments of the Na(+)-pump and the Ca(2+)-transport mechanisms as well as the insulin-dependent glucose transporter GLUT4 will be discussed in diabetes. The capacity of these transporters could be decreased even more than 50 percent in diabetes. This is the reason why using the same dose of cardioactive steroids as if in not diabetic subjects--can cause toxic alterations on the heart in diabetic patients. Insulin regulates not only the expression of some membrane proteins but it can initiate the translocation of the Na(+)-pump and GLUT4 from the intracellular membrane compartments to the plasma membrane in muscle, heart and adipose tissue. Therefore the uptake of K+ and glucose into these tissues will increase significantly under the acute influence of insulin. Untreated diabetic patients generally show hyperkalemia. Forceful treatment with insulin of these subjects often causes severe hypokalemia as a consequence of sudden translocation of the Na(+)-pump. Different Ca(2+)-transport systems are also impaired in diabetes. These changes may result significantly higher free Ca2+ concentration in the cytoplasma of cardiomyocytes. This is one of the most important reason for the Ca2+ overloading and ultimately for heart death. According to authors opinion, beside the dangerous metabolic disorders, general membrane damage and extended disturbances in membrane functions are also very characteristic for diabetes. The acknowledgement of these alterations are very important for the exact planning of the up to date treatment of diabetes. PMID: 11573448 [PubMed - indexed for MEDLINE] 5020. Cardiol Clin. 2001 Aug;19(3):459-70. Exercise in weight management of obesity. Poirier P(1), Després JP. Author information: (1)Department of Pharmacy, Laval University School of Pharmacy, Sainte-Foy, Québec, Canada. Obesity is a chronic metabolic disorder associated with CVD and increased morbidity and mortality. When the BMI is > or = 30 kg/m2, mortality rates from all causes, and especially CVD, are increased by 50% to 100%. There is strong evidence that weight loss in overweight and obese individuals improves risk factors for diabetes and CVD. Additional evidence indicates that weight loss and the associated diuresis reduce blood pressure in both overweight hypertensive and nonhypertensive individuals, reduce serum TG levels, increase high-density lipoprotein cholesterol levels, and may produce some reduction in low-density lipoprotein cholesterol concentrations. Of interest, even if weight loss is minimal, obese individuals showing a good level of cardiorespiratory fitness are at reduced risk for cardiovascular mortality than lean but poorly fit subjects. Insulin and catecholamines have pronounced metabolic effects on human adipose tissue metabolism. Insulin stimulates LPL and inhibits HSL; the opposite is true for catecholamines. There is regional variation in adipocyte TG turnover favoring lipid mobilization in the visceral fat depots and lipid storage in the peripheral subcutaneous sites. The hormonal regulation of adipocyte TG turnover is altered in obesity and is most marked in central obesity. There is resistance to insulin stimulation of LPL; however, LPL activity in fasted obese subjects is increased and remains so following weight reduction. Catecholamine-induced lipolysis is enhanced in visceral fat but decreased in subcutaneous fat. Numerous adaptive responses take place with physical training. These adaptations result in a more efficient system for oxygen transfer to muscle, which is now able to better utilize the unlimited lipid stores instead of the limited carbohydrate reserves available. In addition, the reduced adipose tissue mass represents an important mechanical advantage, allowing better long-term work. Gender differences have been reported in the adaptation of adipose tissue metabolism to aerobic exercise training. Physical training helps counteract the permissive and affluent environment that predisposes reduced-obese subjects to regain weight. An exercise program using weight resistance modalities may also be included safely, and it improved program retention in a multidisciplinary weight management program that was designed for obese children. Thirty to 45 minutes of physical activity of moderate intensity, performed 3 to 5 days a week, should be encouraged. All adults should set a long-term goal to accumulate at least 30 minutes or more of moderate-intensity physical activity on most, and preferably all days. Public health interventions promoting walking are likely to be the most successful. Indeed, walking is unique because of its safety, accessibility, and popularity. It is noteworthy that there is a clear dissociation between the adaptation of cardiorespiratory fitness and the improvements in the metabolic risk profile that can be induced by endurance training programs. It appears that as long as the increase in energy expenditure is sufficient, low-intensity endurance exercise is likely to generate beneficial metabolic effects that would be essentially similar to those produced by high-intensity exercise. The clinician should therefore focus on the improvement of the metabolic profile rather than on weight loss alone. Realistic goals should be set between the clinician and the patient, with a weight loss of approximately of 0.5 to 1 pound per week. It should be kept in mind that since it generally takes years to become overweight or obese, a weight loss pattern of 0.5 or 1 pound per week will require time and perseverance to reach the proposed target. However, the use of physical activity as a method to lose weight seems inversely related to patients' age and BMI and directly related to the level of education. Thus, public health interventions helping these groups to become physically active remain a challenge and further emphasize the importance of the one-on-one interaction between the clinician/health care professional with the obese individual "at risk" of CVD. This notion is critical, as it has been shown that less than half of obese adults have reported being advised to lose weight under the guidance of health care professionals. PMID: 11570117 [PubMed - indexed for MEDLINE] 5021. Journ Annu Diabetol Hotel Dieu. 2001:33-45. [Antidiabetic effect of thiazolidinediones]. [Article in French] Girard J(1). Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS, 9, rue Jules Hetzel, 92190 Meudon. PMID: 11565467 [PubMed - indexed for MEDLINE] 5022. Journ Annu Diabetol Hotel Dieu. 2001:129-43. [Maurice Dérot Prize 2001. The liporegulator system and disease]. [Article in French] Unger RH(1). Author information: (1)Touchstone Center for Diabetes Research, University of Texas, Southwestern Medical School, Dallas, Texas, USA. PMID: 11565455 [PubMed - indexed for MEDLINE] 5023. Journ Annu Diabetol Hotel Dieu. 2001:113-8. [Uncoupling proteins]. [Article in French] Ricquier D(1). Author information: (1)CNRS UPR 9078, 9 rue Jules Hetzel, 92190 Meudon. PMID: 11565453 [PubMed - indexed for MEDLINE] 5024. Endocr Regul. 2001 Jun;35(2):101-14. Effects of exposure to space flight on endocrine regulations in experimental animals. Macho L(1), Kvetnansky R, Fickova M, Popova IA, Grigoriev A. Author information: (1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, 833 06 Bratislava, Slovakia. ueenlaco@savba.sk This minireview summarizes the results of the observations on changes in endocrine functions of rats exposed to space flights for various periods. The results found after space flights are compared with those obtained from rats in acute or repeated restrain stress. A slight increase of plasma catecholamine levels was observed in rats after space flight of longer duration (>14 days), but no changes in catecholamine content in the activity of catecholamine synthesizing enzymes were noted in adrenal medulla and in hypothalamus. The norepinephrine content was, however, decreased in several nuclei selected from hypothalamus of flight rats. Plasma corticosterone levels were increased after space flight and morphological examination of pituitary showed elevated activity of corticotrophs. However, the plasma levels of ACTH were not increased in rats 6 hours after space flight. These changes in plasma hormone levels affected the activity of enzymes involved in metabolism of amino acids in liver and lipolysis in adipose tissue. The plasma levels of testosterone and triiodothyronine were diminished after space flight suggesting the suppression of the thyroid and gonadal activity. Increase of plasma insulin and glucose levels were found in rats after space flight, but the glucagon values were not changed. Comparing these results from flight rats with the animals exposed to acute or repeated stress indicate that long stay in microgravity do not represent very intensive stressogenic stimulus for adrenocortical and sympatho-adrenomedullar systems, and hormone alterations observed after space flight may be due to acute gravitational stress resulting from a return to Earth gravity. Therefore further studies including the inflight animal experiments on a board of International Space Station are necessary for elucidation of the effects of microgravity on endocrine functions. PMID: 11563939 [PubMed - indexed for MEDLINE] 5025. Ann Intern Med. 2001 Sep 18;135(6):447-59. Hypertriglyceridemic hyperapob: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Sniderman AD(1), Scantlebury T, Cianflone K. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, Room H7.22, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. Abnormalities in insulin and glucose metabolism do not seem to entirely account for the high frequency of cardiovascular disease in patients with type 2 diabetes mellitus. An important additional factor may be hypertriglyceridemic hyperapoB, an atherogenic dyslipoproteinemia that is common in these patients. The major features of hypertriglyceridemic hyperapoB are hypertriglyceridemia; low levels of high-density lipoprotein cholesterol; and increased numbers of small, dense low-density lipoprotein (LDL) particles. This article reviews the pathophysiology of this disorder, focusing on the changes in lipoprotein particle number and composition rather than lipoprotein lipid levels. The in vitro and in vivo evidence that small, dense LDL are more atherogenic than normal larger, buoyant LDL is summarized, and the particularly high-risk state conferred by increased numbers of small, dense LDL is delineated. This review demonstrates how abnormalities in the plasma lipoproteins may relate to the effectiveness with which adipose tissue traps and retains fatty acid. The effects of increased fatty acid flux on the hepatic metabolism of lipids and apoB secretion are detailed, and the mechanisms by which fibrates and statins may improve these are described. An understanding of these principles should provide the physician with a more physiologic basis on which to choose appropriate therapy. PMID: 11560458 [PubMed - indexed for MEDLINE] 5026. Pharmacotherapy. 2001 Sep;21(9):1082-99. A review of rosiglitazone in type 2 diabetes mellitus. Werner AL(1), Travaglini MT. Author information: (1)Medical Information Department, GlaxoSmithKline, Philadelphia, Pennsylvania, USA. The thiazolidinedione rosiglitazone maleate works primarily to improve insulin sensitivity in muscle and adipose tissue. It may have additional pharmacologic effects, however, as its main target is peroxisome proliferator-activated receptor-gamma. Data using the homeostasis model assessment and proinsulin:insulin ratio in patients with type 2 diabetes mellitus suggest that rosiglitazone may have the potential to sustain or improve beta-cell function. In these patients the drug reduces fasting plasma glucose, glycosylated hemoglobin, insulin, and C-peptide. In clinical trials, rosiglitazone monotherapy significantly reduced glycosylated hemoglobin by 1.5% compared with placebo and led to significant improvements in glycemic control when given in combination with metformin, sulfonylureas, or insulin. A dosage of 4 mg twice/day significantly reduced fasting plasma glucose levels and produced comparable reductions in glycosylated hemoglobin compared with glyburide. Rosiglitazone has a low risk of gastrointestinal side effects and hypoglycemia, reduced insulin demand, potential sparing effects on beta-cells, and favorable drug interaction profile. Adverse events of clinical significance are edema, anemia, and weight gain. Premarketing data indicate no significant difference in liver enzyme elevations for rosiglitazone, placebo, or active controls. Another drug in the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity and was removed from the market. Therefore, until long-term data are available for rosiglitazone, liver enzyme monitoring is recommended. PMID: 11560198 [PubMed - indexed for MEDLINE] 5027. Ultrasound Obstet Gynecol. 2001 Sep;18(3):268-71. Prenatal ultrasound findings in a fetus with paternal uniparental disomy 14q12-qter. Towner D(1), Yang SP, Shaffer LG. Author information: (1)Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of California Davis, Sacramento, California 95817, USA. drtowner@ucdavis.edu We present the prenatal ultrasound findings in a case of postnatally identified paternal uniparental isodisomy 14q12-qter. Increased nuchal translucency and a large omphalocele were identified at 14 weeks' gestation. Karyotyping revealed a normal male, 46,XY. As gestation advanced, polyhydramnios developed, skeletal abnormalities involving the long bones and chest became evident, hand contractures developed, and the presumed large omphalocele was in part found to be a large ventral hernia, as echogenic adipose tissue could be seen in the abdominal wall near to the cord insertion. Prenatal findings were confirmed after delivery and central nervous system imaging revealed lissencephaly. The combination of an abdominal wall defect with either increased nuchal translucency or skeletal abnormalities should prompt an investigation for uniparental disomy 14 even if the karyotype is normal. PMID: 11555459 [PubMed - indexed for MEDLINE] 5028. Dermatol Surg. 2001 Sep;27(9):819-26. Fat transfer techniques: the effect of harvest and transfer methods on adipocyte viability and review of the literature. Shiffman MA, Mirrafati S. BACKGROUND: Autologous fat transplantation is an excellent tool for filling defects and augmenting tissue. The literature provides a variety of reports with varying degrees of success or failure. The procedure is operator dependent and relies on the techniques of harvesting, cleansing, and reinjection. OBJECTIVE: To evaluate various retrieval and reinjection techniques to see their effect on the viability of the fat cells. METHODS: Fat was removed from five patients utilizing various cannulas, needles, suction pressures, and centrifugation for collection and reinjection. Preoperative external ultrasound and massage were evaluated as well as the use of the ratchet gun for injection. The fat was routinely cleansed of blood and tumescent solution products by means of washing with normal saline and then decanting repeatedly until the infranatant solution was clear. RESULTS: Histologic examination of the fat cells showed the central core of fat and edges of the core had 98-100% intact cells (presumably viable) in every specimen except when -700 mmHg vacuum was used for fat collection where cell damage was greater than 10% and when preoperative massage was performed where cell damage was 30%. Preoperative external ultrasound did not appear to damage the fat cell but did disrupt some of the fibrous tissue holding the fat cells in large bundles. CONCLUSION: The variety of techniques used to collect, clean, and reinject fat do not damage the fat cells except for the collection of fat at -700 mmHg vacuum. External ultrasound, preoperatively, does not destroy fat cells but produces smaller bundles of fat. The ratchet gun does not result in increased fat cell loss. Preoperative massage causes 30% cell loss and deformation of 80% of the remaining cells. PMID: 11553171 [PubMed - indexed for MEDLINE] 5029. J Cardiovasc Risk. 2001 Aug;8(4):187-94. PPARS in inflammation, atherosclerosis and thrombosis. Duez H(1), Fruchart JC, Staels B. Author information: (1)UR545 INSERM, Départment d'Athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille, France. Comment in J Cardiovasc Risk. 2001 Aug;8(4):185-6. PPARs are transcription factors which regulate lipid and lipoprotein metabolism, glucose homeostasis and cellular differentiation. PPARalpha enhances fatty acid oxidation whereas PPARgamma promotes adipogenesis and fatty acid storage in adipose tissue. Both PPARalpha and PPARgamma improve glucose homeostasis. PPARalpha and PPARgamma are activated by the pharmacological agents fibrates and glitazones respectively, and by natural fatty acid derivatives, including inflammation mediators. PPARs are expressed in the different cell types of human atherosclerotic lesions where they regulate the expression of genes involved in the inflammatory response and lipid homeostasis. PPARs modulate the recruitment and adhesion of leukocytes and monocytes to the atherosclerotic lesion. PPARs furthermore control macrophage lipid homeostasis through their action on scavenger receptors and by regulating genes involved in the first steps of the reverse cholesterol transport pathway. Finally, PPARs regulate genes controlling thrombogenicity associated with plaque rupture. These observations suggest that PPARs modulate atherosclerosis development by acting at both metabolic and vascular levels. This review will essentially focus on the functions of PPARalpha and PPARgamma in immunoregulation, vascular inflammation and thrombosis associated to atherosclerosis. PMID: 11550996 [PubMed - indexed for MEDLINE] 5030. Diabetes Metab Res Rev. 2001 Jul-Aug;17(4):273-84. Prostaglandylinositol cyclic phosphate (cPIP): a novel second messenger of insulin action. Comparative analysis of two kinds of "insulin mediators". Shashkin PN(1), Wasner HK, Ortmeyer HK, Hansen BC. Author information: (1)Obesity and Diabetes Research Center, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. pshashkin@hotmail.com Insulin induces a broad spectrum of effects over a wide time interval. It also stimulates the phosphorylation of some cellular proteins, while decreasing the state of phosphorylation of others. These observations indicate the presence of different, but not necessarily mutually exclusive, pathways of insulin action. One well-known pathway represents a phosphorylation cascade initiated by the tyrosine kinase activity of the insulin receptor followed by involvement of different MAP-kinases. Another pathway suggests the existence of low molecular weight insulin mediators whose synthesis and/or release is initiated by insulin. Comparable analysis of two kinds of insulin mediators, namely inositolphosphoglycans and prostaglandylinositol cyclic phosphate (cPIP), has been carried out. It has been shown that the expression of a number of enzymes, such as phospholipase A(2), phospholipase C, cyclo-oxygenase and IRS-1-like enzyme, could regulate the biosynthesis of cPIP in both normal and diabetes-related conditions. Data on the activity of a key enzyme of cPIP biosynthesis termed cPIP synthase (IRS-1-like enzyme) in various monkey tissues before and twice during an euglycemic hyperinsulinemic clamp have been presented. It has been concluded that in vivo insulin increases cPIP synthase activity in both liver and subcutaneous adipose tissue of lean normal monkeys. It has been also suggested that abnormal production of cPIP could be related to several pathologies including glucocorticoid-induced insulin resistance and diabetic embryopathy. Further studies on cPIP and other types of insulin mediators are necessary to aid our understanding of insulin action. Copyright 2001 John Wiley & Sons, Ltd. PMID: 11544611 [PubMed - indexed for MEDLINE] 5031. Mutat Res. 2001 Oct 1;482(1-2):77-82. Genetic susceptibility and environmental estrogen-like compounds. Kristensen VN(1), Kure EH, Erikstein B, Harada N, Børresen-Dale A. Author information: (1)Department of Genetics, Institute of Cancer Research, The Norwegian Radium Hospital, Montebello 0310, Oslo, Norway. nedelcheva.vessela@dnr.uio.no Environmental chemicals with estrogenic activities have been suggested to be able to interact with the endocrine system. Endogenous estrogen is synthesized in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and minor quantities in peripheral tissue. These cells, as well as breast tissue, express all the necessary enzymes for this synthesis, CYP17, CYP11a, CYP19, 17-beta-hydroxysteroid hydrogenase, steroid sulfatase as well as enzymes further hydroxylating estradiol, such as CYP1A1, CYP3A4, CYP1B1, catechol-o-methyltransferase (COMT). Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer. PMID: 11535251 [PubMed - indexed for MEDLINE] 5032. FASEB J. 2001 Sep;15(11):1996-2006. Rationale for the existence of additional adipostatic hormones. Frühbeck G(1), Gómez-Ambrosi J. Author information: (1)Metabolic Research Laboratory, University of Navarra, 31008-Pamplona, Spain. gfruhbeck@unav.es Parabiosis studies with obese rodents demonstrated that circulating factors are involved in the long-term control of food intake and energy balance. More than 40 years ago it was hypothesized that rats made obese by hypothalamic or dietary means, as well as genetically obese fa/fa rats and db/db mice, produce a circulating factor that either inhibits food intake or acts metabolically to reduce the fat content of non-obese ad libitum-fed partners. However, none of these obese rodents showed a significant change in weight when parabiosed to a normal animal. It was therefore postulated that these obese rodents produced a circulating lipostatic factor but were unable to respond to it. In contrast, genetically obese ob/ob mice were thought to be deficient in the circulating signal, as they lost weight when parabiosed to lean or obese db/db mice. The discovery of leptin suggested that the circulating lipostatic signal had been identified. However, a closer look at the outcome of the parabiotic studies reveals that leptin alone does not explain all of the findings of the parabiotic experiments. Another (or more than one) as yet unidentified factor(s) may be involved in energy balance regulation. The evidence for the existence of further leptin-like hormones comes from observations in which the direct effect of leptin has been eliminated or can be excluded. PMID: 11532980 [PubMed - indexed for MEDLINE] 5033. Growth Horm IGF Res. 2001 Jun;11 Suppl A:S97-102. Visceral obesity and the role of the somatotropic axis in the development of metabolic complications. Franco C(1), Bengtsson BA, Johannsson G. Author information: (1)Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden. celina.franco@sahlgrenska.se It is well recognized that aberrant fat localization such as visceral obesity rather than total body fat mass is a major risk factor for cardiovascular disease and type 2 diabetes mellitus. During recent decades, several studies have described a range of metabolic disturbances associated with abdominal obesity, including glucose intolerance, hyperinsulinaemia, insulin resistance, hypertension and dyslipoproteinaemia, now widely known as the metabolic syndrome. Several abnormalities in the hypothalamic-pituitary axis have been described associated with visceral obesity, suggesting a central neuroendocrine dysregulation including increased cortisol concentration and impaired gonadotropin and growth hormone (GH) secretion. Some steps in the chain of events in this theory still remain unclear, however, although these findings have introduced new therapeutic possibilities. These include therapy with sex steroids in both viscerally obese men and women, and several attempts to use GH to treat the endocrine abnormalities present in visceral obesity. The results of these studies are promising, but the therapies are still not recommended for general use. PMID: 11527097 [PubMed - indexed for MEDLINE] 5034. Growth Horm IGF Res. 2001 Jun;11 Suppl A:S91-5. Activation of the hypothalamic-pituitary-adrenal axis in obesity: cause or consequence? Walker BR(1). Author information: (1)Department of Medical Sciences, Western General Hospital, University of Edinburgh, UK. Brian.Walker@ed.ac.uk Cortisol secretion rate is increased in obesity, but plasma cortisol levels are not consistently elevated. This suggests that the principal abnormality in obesity may relate to enhanced peripheral metabolism. Recent studies have identified enhanced inactivation of cortisol by 5alpha-reductase, and impaired regeneration of cortisol in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), as possible mediators of this increased cortisol clearance rate in obesity. Most intriguingly, the changes in 11beta-HSD1 are tissue-specific, and generation of cortisol from inactive cortisone appears to be increased in adipose tissue in obesity. Selective inhibition of 11beta-HSD1 provides a novel therapeutic target for lowering intra-adipose cortisol concentrations and effect, without inducing other adverse effects of cortisol deficiency. PMID: 11527096 [PubMed - indexed for MEDLINE] 5035. Growth Horm IGF Res. 2001 Jun;11 Suppl A:S85-9. The role of leptin and hypothalamic neuropeptides in energy homeostasis: update on leptin in obesity. Mantzoros CS(1). Author information: (1)Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. cmantzor@caregroup.harvard.edu Leptin is an adipocyte-secreted hormone the serum levels of which reflect the amount of energy stored in adipose tissue as well as short-term energy imbalance. Serum levels of many cytokines and hormones also influence circulating leptin levels. Leptin binding to specific receptors in the hypothalamus results in altered expression of orexigenic and anorexigenic neuropeptides that regulate neuroendocrine function and energy homeostasis, and recent experimental evidence suggests that leptin plays an important role in the pathogenesis of obesity and eating disorders. Research that followed the discovery of leptin is significantly broadening our understanding of the mechanisms underlying energy homeostasis, the elucidation of which is expected to result soon in the development of new therapeutic approaches for obesity and eating disorders. PMID: 11527094 [PubMed - indexed for MEDLINE] 5036. Seikagaku. 2001 Jul;73(7):525-35. [FGFs as multifunctional signaling molecules: diversity of structure and function]. [Article in Japanese] Itoh N(1). Author information: (1)Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8501. PMID: 11521283 [PubMed - indexed for MEDLINE] 5037. Br J Nutr. 2001 Aug;86(2):119-22. DNA hybridization arrays: a powerful technology for nutritional and obesity research. Moreno-Aliaga MJ(1), Marti A, García-Foncillas J, Alfredo Martínez J. Author information: (1)Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain. PMID: 11519524 [PubMed - indexed for MEDLINE] 5038. J Am Acad Dermatol. 2001 Sep;45(3 Suppl):S116-24. Estrogen production and action. Nelson LR(1), Bulun SE. Author information: (1)Department of Obstetrics and Gynecology, University of Illinois at Chicago, 60612, USA. lrnelson@uic.edu Estradiol production is most commonly thought of as an endocrine product of the ovary; however, there are many tissues that have the capacity to synthesize estrogens from androgen and to use estrogen in a paracrine or intracrine fashion. In addition, other organs such as the adipose tissue can contribute significantly to the circulating pool of estrogens. There is increasing evidence that in both men and women extraglandular production of C(18) steroids from C(19) precursors is important in normal physiology as well as in pathophysiologic states. The enzyme aromatase is found in a number of human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin fibroblasts, bone, and the brain, and it locally catalyzes the conversion of C(19) steroids to estrogens. Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age. Sufficient circulating levels of the biologically active estrogen estradiol can be produced as a result of extraglandular aromatization of androstenedione to estrone that is subsequently reduced to estradiol in peripheral tissues to cause uterine bleeding and endometrial hyperplasia and cancer in obese anovulatory or postmenopausal women. Extraglandular aromatase expression in adipose tissue and skin (via increasing circulating levels of estradiol) and bone (via increasing local estrogen concentrations) is of paramount importance in slowing the rate of postmenopausal bone loss. Moreover, excessive or inappropriate aromatase expression was demonstrated in adipose fibroblasts surrounding a breast carcinoma, endometriosis-derived stromal cells, and stromal cells in endometrial cancer, giving rise to increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will promote the growth of these steroid-responsive tissues. Finally, local estrogen biosynthesis by aromatase activity in the brain may be important in the regulation of various cognitive and hypothalamic functions. The regulation of aromatase expression in human cells via alternatively used promoters, which can be activated or inhibited by various hormones, increases the complexity of estrogen biosynthesis in the human body. Aromatase expression is under the control of the classically located proximal promoter II in the ovary and a far distal promoter I.1 (40 kilobases upstream of the translation initiation site) in the placenta. In skin, the promoter is I.4. In adipose tissue, 2 other promoters (I.4 and I.3) located between I.1 and II are used in addition to the ovarian-type promoter II. In addition, promoter use in adipose fibroblasts switches between promoters II/I.3 and I.4 upon treatments of these cells with PGE(2) versus glucocorticoids plus cytokines. Moreover, the presence of a carcinoma in breast adipose tissue also causes a switch of promoter use from I.4 to II/I.3. Thus there can be complex mechanisms that regulate the extraglandular production of estrogen in a tissue-specific and state-specific fashion. PMID: 11511861 [PubMed - indexed for MEDLINE] 5039. Mech Ageing Dev. 2001 Sep 30;122(14):1565-76. The role of fat cell derived peptides in age-related metabolic alterations. Gabriely I(1), Barzilai N. Author information: (1)Department of Medicine, Diabetes Research and Training Center, Belfer Bld. #701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Aging in humans is associated with alterations in body fat distribution and a parallel gradual increase in the prevalence of atherosclerotic cardiovascular disease, as well as mortality of all causes. Because of nutrient cost, availability, and the sedentary life-style, half of the western world population has fat mass in excess of 30% of the body weight that weighs 3-4 times more than the fat mass of lean subjects. Recent discoveries of various hormones, cytokines and complement factors secreted by adipose cells opened a new avenue of research, looking at the role of these fat derived peptides in different conditions. We will focus here on the potential role of fat tissue in different physiological and physiopathological conditions associated with age-related metabolism and risk factors for diseases. We will also exemplify how body fat capacity, distribution and function can be directly linked, and may play a central role in energy metabolism and homeostasis, atherosclerosis, and possibly in the defense against cancer. We hypothesize that biological pathways involved in nutrient regulation in fat tissue may be important in inducing longevity in calorie restricted animals. PMID: 11511397 [PubMed - indexed for MEDLINE] 5040. Nestle Nutr Workshop Ser Clin Perform Programme. 2001;5:93-112; discussion 112-5. Neuropeptides and the control of energy homeostasis. Woods SC(1), Rushing PA, Seeley RJ. Author information: (1)Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. PMID: 11510449 [PubMed - indexed for MEDLINE] 5041. Cas Lek Cesk. 2001 Jun 5;140(13):387-91. [Uncoupling proteins]. [Article in Czech] Mikulová R(1), Hainer V. Author information: (1)Centrum pro diagnostiku a lécbu obezity III. interní kliniky 1. LF UK a VFN, Praha. mikulova@email.cz Uncoupling proteins are located in the inner mitochondria membrane. Their name is derived from their function: they uncouple oxidative procesess of the respiratory chain from ATP synthesis. Hitherto several members of the family have been described, the best known being UCP1. UCP1 can be expressed exclusively in brown adipose tissue and it is responsible for the heat production. In humans the brown fat disappears during the early childhood. In adults another members of the UCP family can be found--UCP2 and UCP3. It is widely accepted that these proteins affect lipid metabolism and energy expenditure. They are intensively studied owing to their possible use in the therapy of obesity. However, their physiological function has not been yet fully established. PMID: 11507948 [PubMed - indexed for MEDLINE] 5042. Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R683-98. Differential control of sympathetic outflow. Morrison SF(1). Author information: (1)Department of Physiology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, Illinois 60611, USA. s-morrison2@northwestern.edu With advances in experimental techniques, the early views of the sympathetic nervous system as a monolithic effector activated globally in situations requiring a rapid and aggressive response to life-threatening danger have been eclipsed by an organizational model featuring an extensive array of functionally specific output channels that can be simultaneously activated or inhibited in combinations that result in the patterns of autonomic activity supporting behavior and mediating homeostatic reflexes. With this perspective, the defense response is but one of the many activational states of the central autonomic network. This review summarizes evidence for the existence of tissue-specific sympathetic output pathways, which are likely to include distinct populations of premotor neurons whose target specificity could be assessed using the functional fingerprints developed from characterizations of postganglionic efferents to known targets. The differential responses in sympathetic outflows to stimulation of reflex inputs suggest that the circuits regulating the activity of sympathetic premotor neurons must have parallel access to groups of premotor neurons controlling different functions but that these connections vary in their ability to influence different sympathetic outputs. Understanding the structural and physiological substrates antecedent to premotor neurons that mediate the differential control of sympathetic outflows, including those to noncardiovascular targets, represents a challenge to our current technical and analytic approaches. PMID: 11506981 [PubMed - indexed for MEDLINE] 5043. Rev Prat. 2001 Jun 30;51(12 Suppl):S36-41. [Lipid metabolism and exercise]. [Article in French] Lacour JR(1). Author information: (1)Laboratoire de physiologie de l'exercice, EA 645 Faculté de médecine Lyon-Sud F-69921 Oullins. lacour@univ-lyon1.fr A high level of physical activity is associated with a lower cardiovascular risk in adult and elderly subjects. Several mechanisms are involved. Physical activity induces an increase in energy output. The contribution of fats to muscle energy metabolism increases with exercise duration. It decreases with exercise intensity. EPOC contributes by about 10% to the total energy cost of exercise. This supplementary energy expenditure is principally covered with fat oxidation, this being related to GH release. Part of energy expended during intermittent exercise is supplied by fat oxidation. The used lipids are taken from the muscular triacylglycerol stores and from the circulating FFA and lipoprotein triacylglycerols. Hydrolysis of triacylglycerols is achieved by LPL. Endurance training induces an increased contribution from fat to the exercise energy need. This results from increased muscle capillary density, enhanced activity of LPL and of the enzymes controlling beta-oxydation. The increased energy expenditure results in a reduced fat mass, which accounts for a decreased plasma triacylglycerol level. Endurance activity requiring approximately an expenditure of 60 kJ.kg-1 per week usually produces favourable lipoprotein changes. Level of post-prandial lipemia is lowered. These alterations disappear within the first two days of recovery. PMID: 11505866 [PubMed - indexed for MEDLINE] 5044. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Aug;92(2):194-201. MDM2+/CDK4+/p53+ oral liposarcoma: case report and review of the literature. Nikitakis NG(1), Lopes MA, Pazoki AE, Ord RA, Sauk JJ. Author information: (1)Oral and Maxi;;ofacial Pathology, Dental School, University of Maryland, Baltimore 21201-1586, USA. nin001@dental.umaryland.edu Although liposarcoma is one of the most common soft tissue sarcomas, its location in the oral cavity is very rare. To our knowledge, only 43 cases of liposarcoma originating in the oral tissues have been reported in the English-language literature. In this article, we report a case of well-differentiated liposarcoma affecting the cheek of a 28-year-old man and review the oral liposarcoma literature. Immunohistochemical analysis of the tumor revealed an MDM2+/CDK4+/p53+ immunophenotype that is consistent with the immunohistochemical profile of well-differentiated liposarcoma originating in other areas of the body. Quantitative polymerase chain reaction analysis of the DNA levels of the MDM2 (human homologue of the murine double-minute type 2), CDK4 (cyclin-dependent kinase 4), and SAS (sarcoma amplified sequence), genes was performed, revealing only SAS gene amplification. The possibility of misdiagnosis of oral liposarcoma because of its sometimes inconspicuous clinical and microscopic features is emphasized. Careful pathologic examination of liposarcoma is essential for discrimination from benign adipose tissue neoplasms and for precise histologic classification, both of major prognostic significance. Possible implications of molecular and cytogenetic analysis for unraveling the pathogenesis and determining the prognosis of liposarcoma are discussed. PMID: 11505267 [PubMed - indexed for MEDLINE] 5045. Br J Nutr. 2001 Aug;86(2):123-39. Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered. Dulloo AG(1), Samec S. Author information: (1)Institute of Physiology, Department of Medicine, University of Fribourg, Rue du Musée 5, Fribourg, Switzerland. abdul.dulloo@unifr.ch During the past few years, there have been two major developments, if not revolutions, in the field of energy balance and weight regulation. The first at the molecular level, which was catalysed by developments in DNA screening technology together with the mapping of the human genome, has been the tremendous advances made in the identification of molecules that play a role in the control of food intake and metabolic rate. The second, at the systemic level, which centered upon the use of modern technologies or more robust analytical techniques for assessing human energy expenditure in response to starvation and overfeeding, has been the publication of several papers providing strong evidence that adaptive thermogenesis plays a much more important role in the regulation of body weight and body composition than previously thought. Within these same few years, several new members of the mitochondrial carrier protein family have been identified in a variety of tissues and organs. All apparently possess uncoupling properties in genetically-modified systems, with two of them (uncoupling protein (UCP) 2 and UCP3) being expressed in adipose tissues and skeletal muscles, which are generally recognised as important sites for variations in thermogenesis and/or in substrate oxidation. Considered as breakthrough discoveries, the cloning of these genes has generated considerable optimism for rapid advances in our molecular understanding of adaptive thermogenesis, and for the identification of new targets for pharmacological management of obesity and cachexia. The present paper traces first, from a historical perspective, the landmark events in the field of thermogenesis that led to the identification of these genes encoding candidate UCP, and then addresses the controversies and on-going debate about their physiological importance in adaptive thermogenesis, in lipid oxidation or in oxidative stress. The general conclusion is that UCP2 and UCP3 may have distinct primary functions, with UCP3 implicated in regulating the flux of lipid substrates across the mitochondria and UCP2 in the control of mitochondrial generation of reactive oxygen species. The distinct functions of these two UCP1 homologues have been incorporated in a conceptual model to illustrate how UCP2 and UCP3 may act in concert in the overall regulation of lipid oxidation concomitant to the prevention of lipid-induced oxidative damage. PMID: 11502224 [PubMed - indexed for MEDLINE] 5046. Anat Rec. 2001 Aug 1;263(4):361-6. Tissue engineering strategies for adipose tissue repair. Patrick CW Jr(1). Author information: (1)Laboratory of Reparative Biology & Bioengineering, Department of Plastic Surgery, The University of Texas M.D. Anderson Cancer Center and University of Texas Center for Biomedical Engineering, Houston, Texas 77030, USA. cpatrick@mdanderson.org Tissue engineering is a relatively young field that combines engineering, clinical science, and life sciences to, in part, repair or regrow tissues. Adipose tissue has recently become a focus area for tissue engineering, encouraged by the large number of reconstructive, cosmetic, and correctional indications that could be addressed with clinically translatable adipose tissue engineering strategies. This review discusses the three aspects of an adipose construct, namely cell types, scaffold, and microenvironment, and presents current tissue engineering strategies under pursuit. Copyright 2001 Wiley-Liss, Inc. PMID: 11500812 [PubMed - indexed for MEDLINE] 5047. J Nutr. 2001 Aug;131(8):2078-81. Please pass the chips: genomic insights into obesity and diabetes. Nadler ST(1), Attie AD. Author information: (1)Departments of Biochemistry and Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA. Type 2 diabetes mellitus is an increasingly common disorder of carbohydrate and lipid metabolism. Approximately 16 million individuals in the United States have diabetes, and 800,000 new cases are identified each year. Two important characteristics of this disease are insulin resistance, the failure of peripheral tissues, including liver, muscle, and adipose tissue, to respond to physiologic doses of insulin, and failure of pancreatic beta-cells to properly secrete insulin in response to elevated blood glucose levels. Obesity is a significant risk factor for the development of type 2 diabetes mellitus. Recent observations of extremely lean, lipoatrophic models have revealed a similar predisposition to developing diabetes. Although it may seem paradoxical that both increased adiposity and severely reduced fat mass cause diabetes, a common pathophysiologic process in fat may be responsible for the predisposition to develop hyperglycemia in both conditions. This review will focus on the important role of adipose tissue dysfunction in the pathogenesis of diabetes, and on insights gained through the application of microarray technology to analyze adipocyte gene expression. PMID: 11481397 [PubMed - indexed for MEDLINE] 5048. J Mol Neurosci. 2001 Apr-Jun;16(2-3):117-21; discussion 151-7. Role of CD36 in membrane transport and utilization of long-chain fatty acids by different tissues. Coburn CT(1), Hajri T, Ibrahimi A, Abumrad NA. Author information: (1)Department of Physiology, State University of New York at Stony Brook, 11794-8661, USA. The transmembrane glycoprotein CD36 has been identified in isolated cell studies as a putative transporter of long-chain fatty acids. To examine the physiological role of CD36, we studied FA uptake and metabolism by tissues of CD36 null mice after injection with two fatty acid analogs. Compared to controls, uptake was substantially reduced (50-80%) in heart, skeletal muscle, and adipose tissues of null mice. The reduction in uptake was associated with a large decrease in fatty acid incorporation into triglycerides, which could be accounted for by an accumulation of diacylglycerides. Thus CD36 facilitates a major fraction of fatty acid uptake by myocardial, skeletal muscle, and adipose tissues, where it is highly expressed. Its role in other tissues where its expression is low and cell-specific could not be determined in these studies. PMID: 11478366 [PubMed - indexed for MEDLINE] 5049. Gan To Kagaku Ryoho. 2001 Jul;28(7):883-91. [Molecular and cellular biological analysis on cancer cachexia syndrome]. [Article in Japanese] Mukaiyama T(1). Author information: (1)Department of Palliative Medicine and Medical Oncology, Tokyo Metropolitan Toshima General Hospital, 33-1 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan. About half of patients with cancer will suffer from wasting syndrome, called cancer cachexia, which shows abnormality of homeostasis, nutrition, endocrine function, metabolism, immunity et al. This syndrome is characterized with anorexia and weight loss caused by degradation of skeletal muscle and adipose tissue. Progressive weight loss is responsible not only for a poor quality of life and poor response to anti-cancer drug, but also shorter survival time comparing patient without weight loss. Various factors have been found as mediators of this syndrome base on the development of immunology, biochemistry and molecular and cellular biology. These include several cytokines, proteolysis-inducing factor (PIF), lipid-mobilizing factor (LMF), apoptosis-inducing factor and another factors. Recentry, molecular biological analysis makes clear more detail mechanisms of cancer cachexia syndrome, for example, ubiqutin/proteasome pathway, activation of nuclear transcriptional factors and others. These progresses will contribute not only to establish new treatment but also to carry out "order-made palliative oncology" using DNA-chip and/or Protein-chip in near future. PMID: 11478136 [PubMed - indexed for MEDLINE] 5050. Sports Med. 2001;31(8):583-9. Plasma leptin and exercise: recent findings. Hickey MS(1), Calsbeek DJ. Author information: (1)Department of Health and Exercise Science, Colorado State University, Fort Collins 80523, USA. hickey@cahs.colostate.edu The cloning of murine and human obese genes in 1994, and the subsequent identification that the product of the obese gene, leptin, is secreted from adipose tissue, stimulated a tremendous amount of interdisciplinary interest in adipose tissue endocrinology and the potential role of this tissue in the regulation of energy balance. Exercise, with concomitant changes in fuel flux, systemic hormone levels and energy expenditure, may contribute to the regulation of plasma leptin levels and presumably, leptin action. The initial work characterising the leptin-exercise relationship was equivocal. Cross-sectional studies provided some mixed evidence regarding the relationship between aerobic capacity or habitual physical activity and plasma leptin. In contrast, studies on acute bouts of exercise and exercise training interventions have, with few exceptions, suggested that exercise does not alter systemic leptin independent of changes in fat mass. In general, these studies did not carefully control for energy balance, and sampled only a single fasting plasma leptin level. Two recent studies utilising experimental designs in which energy balance was controlled and 24-hour profiles of plasma leptin were determined have provided the most compelling evidence to date of the interaction between exercise, energy balance and systemic leptin in humans. These studies provide a clear explanation for the apparent lack of an acute effect of exercise on systemic leptin and underscore the importance of clearly defining the balance between energy intake and energy expenditure when studying the physiology of leptin. The aim of this brief review is to provide an overview of the interaction between energy expenditure during physical activity and systemic leptin level. Special emphasis will be placed on those studies in which energy intake/balance was carefully controlled. PMID: 11475320 [PubMed - indexed for MEDLINE] 5051. Best Pract Res Clin Endocrinol Metab. 2001 Mar;15(1):111-22. Steroid metabolism in metabolic syndrome X. Walker BR(1). Author information: (1)The University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, Scotland, EH4 2XU, UK. Preceding chapters in this volume describe relatively rare conditions associated with qualitative rather than quantitative changes in enzymes involved in steroid synthesis and metabolism. In this chapter, several examples show how more subtle variations in activities of the same enzymes may be important in the pathophysiology of common diseases of complex aetiology. This chapter reviews evidence for deranged steroid metabolism in patients with the 'insulin resistance syndrome'. In summary, patients with essential hypertension may have subtle 11beta-hydroxylase or 11beta-hydroxysteroid dehydrogenase type 2 deficiency resulting in mild mineralocorticoid excess. Patients with obesity, and/or associated hirsutism or hyperglycaemia, have evidence of altered peripheral metabolism of androgens (increased 5alpha-reductase) and glucocorticoids (altered 11beta-hydroxysteroid dehydrogenase type 1, resulting in enhanced cortisol levels in adipose tissue). Some of these changes in steroid metabolism lend themselves to therapeutic manipulation which may provide novel strategies to reduce cardiovascular risk. PMID: 11469814 [PubMed - indexed for MEDLINE] 5052. Int J Obes Relat Metab Disord. 2001 May;25 Suppl 1:S29-34. Regulation of appetite: role of leptin in signalling systems for drive and satiety. Blundell JE(1), Goodson S, Halford JC. Author information: (1)PsychoBiology Group, School of Psychology, Department of Psychology, University of Leeds, Leeds LS2 9JT, UK. j.e.blundell@psychology.leeds.ac.uk BACKGROUND: The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores. ANALYSIS: This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes. CONCLUSION: It is proposed that leptin modulates the drive signals arising from the metabolic demand for energy but also shows some properties of a post-prandial satiety signal. PMID: 11466583 [PubMed - indexed for MEDLINE] 5053. Int J Obes Relat Metab Disord. 2001 May;25 Suppl 1:S26-8. Biology of leptin--its implications and consequences for the treatment of obesity. Trayhurn P(1). Author information: (1)Molecular Physiology Group, Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, Scotland, UK. paul.trayhurn@basalmed.uio.no The fundamental biology of leptin and the leptin system is summarised. The hormone is produced in several organs, but primarily white adipose tissue, and is subject to acute regulation, particularly by the sympathetic nervous system. Leptin receptors are widely distributed, both centrally and peripherally, and there are several neuroendocrine targets. Although leptin is a key hormone in the regulation of energy balance, the biological effects of the hormone are extensive. Increasing leptin levels is unlikely to be an effective strategy for the treatment of obesity-except in those limited number of cases where there is a genuine deficiency of the hormone (eg in individuals with mutations of the leptin gene). PMID: 11466582 [PubMed - indexed for MEDLINE] 5054. J Mol Endocrinol. 2001 Aug;27(1):1-9. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. Fajas L(1), Debril MB, Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, 67404 Illkirch, France. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds inducing peroxisome proliferation. PPAR-gamma, the best characterized of the PPARs, plays a crucial role in adipogenesis and insulin sensitization. Furthermore, PPAR-gamma has been reported to affect cell proliferation/differentiation pathways in various malignancies. We discuss in the present review recent advances in the understanding of the function of PPAR-gamma in both cell proliferation and adipocyte differentiation. PMID: 11463572 [PubMed - indexed for MEDLINE] 5055. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S202-14. Nutritional regulation of lipid metabolism in human adipose tissue. Coppack SW(1), Patel JN, Lawrence VJ. Author information: (1)St. Bartholomew's & The Royal London School of Medicine, Whitechapel, London, United Kingdom. s.w.coppack@mds.qmw.ac.vk Pfeiffer and colleagues years ago pointed out that different distributions and amounts of adipose tissue are associated with abnormalities of lipolysis and lipoprotein metabolism. Adipose tissue has several crucial roles including (i) mobilization from stores of fatty acids as an energy source, (ii) catabolism of lipoproteins such as very-low-density lipoprotein and (iii) synthesis and release of hormonal signals such as leptin and interleukin-6. These adipose tissue actions are crucially regulated by nutrition. The review considers the existence of metabolic pathways and modes of regulation within adipose tissue, and how such metabolic activity can be quantitated in humans. Nutrition can influence adipose tissue at several 'levels'. Firstly the level of obesity or malnutrition has important effects on many aspects of adipose tissue metabolism. Secondly short-term overfeeding, underfeeding and exercise have major impacts on adipose tissue behaviour. Lastly, specific nutrients are capable of regulating adipose tissue metabolism. Recently there have been considerable advances in understanding adipose tissue metabolism and in particular its regulation. This review discusses the behaviour of adipose tissue under various nutritional conditions. There is then a review of recent work examining the ways in which nutritional influences act via intra-cellular mechanisms, insulin and the sympathetic innervation of adipose tissue. PMID: 11460571 [PubMed - indexed for MEDLINE] 5056. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S122-34. Integration of biochemical and physiologic effects of insulin on glucose metabolism. Newsholme EA(1), Dimitriadis G. Author information: (1)Merton College, Oxford, United Kingdom. The major effects of insulin on tissues are: (1) Carbohydrate metabolism: (a) It increases the rate of transport of glucose across the cell membrane in adipose tissue and muscle, (b) it increases the rate of glycolysis in muscle and adipose tissue, (c) it stimulates the rate of glycogen synthesis in a number of tissues, including adipose tissue, muscle, and liver. It also decreases the rate of glycogen breakdown in muscle and liver, (d) it inhibits the rate of glycogenolysis and gluconeogenesis in the liver. (2) Lipid metabolism: (a) It decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level, (b) it stimulates fatty acid and triacylglycerol synthesis in tissues, although only to a minor extent in humans, (c) it increases the rate of very-low-density lipoprotein formation in the liver, (d) it increases the uptake of triglyceride from the blood into adipose tissue and muscle, (e) it decreases the rate of fatty acid oxidation in muscle and liver, (f) it increases the rate of cholesterol synthesis in liver. (3) Protein metabolism: (a) It increases the rate of transport of some amino acids into tissues, (b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other tissues, (c) it decreases the rate of protein degradation in muscle (and perhaps other tissues), (d) it decreases the rate of urea formation.--These insulin effects serve to encourage the synthesis of carbohydrate, fat and protein. PMID: 11460564 [PubMed - indexed for MEDLINE] 5057. Exp Clin Endocrinol Diabetes. 2001;109(4):S516-26. Triglycerides, fatty acids and insulin resistance--hyperinsulinemia. Kraegen EW(1), Cooney GJ, Ye J, Thompson AL. Author information: (1)Garvan Institute of Medical Research, St Vincent's Hospital. Sydney NSW, Australia. e.kraegen@garvan.org.au There is now much interest in the mechanisms by which altered lipid metabolism might contribute to insulin resistance as is found in Syndrome X or in Type II diabetes. This review considers recent evidence obtained in animal models and its relevance to humans, and also likely mechanisms and strategies for the onset and amelioration of insulin resistance. A key tissue for development of insulin resistance is skeletal muscle. Animal models of Syndrome X (eg high fat fed rat) exhibit excess accumulation of muscle triglyceride coincident with development of insulin resistance. This seems to also occur in humans and several studies demonstrate increased muscle triglyceride content in insulin resistant states. Recently magnetic resonance spectroscopy has been used to demonstrate that at least some of the lipid accumulation is inside the muscle cell (myocyte). Factors leading to this accumulation are not clear, but it could derive from elevated circulating free fatty acids, basal or postprandial triglycerides, or reduced muscle fatty acid oxidation. Supporting a link with adipose tissue metabolism, there appears to be a close association of muscle and whole body insulin resistance with the degree of abdominal obesity. While causal relationships are still to be clearly established, there are now quite plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic Randle glucose-fatty acid cycle. In animal models, dietary changes or prior exercise which reduce muscle lipid accumulation also improve insulin sensitivity. It is likely that cytosolic accumulation of the active form of lipid in muscle, the long chain fatty acyl CoAs, is involved, leading to altered insulin signalling or enzyme activities (eg glycogen synthase) either directly or via chronic activation of mediators such as protein kinase C. Unless there is significant weight loss, short or medium term dietary manipulation does not alter insulin sensitivity as much in humans as in rodent models, and there is considerable interest in pharmacological intervention. Studies using PPARgamma receptor agonists, the thiazolidinediones, have supported the principle that reduced muscle lipid accumulation is associated with increased insulin sensitivity. Other potent systemic lipid-lowering agents such as PPARalpha receptor agonists (eg fibrates) or antilipolytic agents (eg nicotinic acid analogues) might improve insulin sensitivity but further work is needed, particularly to clarify implications for muscle metabolism. In conclusion, evidence is growing that excess muscle and liver lipid accumulation causes or exacerbates insulin resistance in Syndrome X and in Type II diabetes; development of strategies to prevent this seem very worthwhile. PMID: 11453039 [PubMed - indexed for MEDLINE] 5058. Diabetes Metab. 2001 Apr;27(2 Pt 2):279-85. [Thiazolidinediones: clinical data and perspectives]. [Article in French] Blicklé JF(1). Author information: (1)Service de Médecine Interne, Diabétologie et Maladies Métaboliques Hôpitaux Universitaires de Strasbourg, Cedex, France. Jean-Frederic.Blickle@chru-strasbourg.fr This brief review realizes a synthesis of the main clinical studies of the three thiazolidinediones (TZDs) which have been launched elsewhere, troglitazone, rosiglitazone and pioglitazone. At optimal dose, the three molecules have a similar effect, although slightly weaker for the first, on the fasting plasma glucose and HbA1c levels. They exhibit identical activity, or even higher for troglitazone, in combination with sulfonylureas, metformine and insulin. On the contrary, the three TZDs seem to differentiate according to their effects on lipid metabolism. While rosiglitazone only moderately and inconstantly reduces plasma triglycerides, troglitazone and pioglitazone decreases them by 15 to 25%. LDL-cholesterol levels are almost unaffected by pioglitazone while they increase by 6 to 8% with troglitazone and by more than 10% with rosiglitazone. On the other hand, HDL-cholesterol strongly increases with rosiglitazone and pioglitazone and only slightly on troglitazone. Besides these metabolic effects, TZDs have several properties which could be of therapeutical interest, particularly a possible beta cell protective effect. Except for the severe problems of hepatotoxicity which appear specific to troglitazone and have led to its withdrawal, TZDs are well tolerated. They share as major undesirable effects a risk of peripheral oedema, of anemia due to plasma volume expansion and of weight gain due to the development of subcutaneous adipose tissue. Until now, the European Product licence of rosiglitazone and pioglitazone is limited to the combination with metformin in case of failure of a monotherapy with metformin in obese type 2 diabetic patients and to the combination with a sulphonylurea only in case of intolerance or contra-indication to metformin in type 2 diabetics insufficiently controlled by sulphonylurea therapy at maximal tolerated dose. These indications will probably be enlarged to earlier treatments when long term study results will be available. PMID: 11452222 [PubMed - indexed for MEDLINE] 5059. Diabetes Metab. 2001 Apr;27(2 Pt 2):271-8. [Mechanisms of action of thiazolidinediones]. [Article in French] Girard J(1). Author information: (1)Centre de Recherche sur l'Endocrinologie, Moleculaire et le developpement, UPR 524 CNRS, 9, rue Jules Hetzel, 92190 Meudon, France. The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma. PMID: 11452221 [PubMed - indexed for MEDLINE] 5060. Diabetes Metab. 2001 Apr;27(2 Pt 2):261-70. [Macronutrients, fat mass, fatty acid flux and insulin sensitivity]. [Article in French] Ziegler O(1), Quilliot D, Guerci B, Drouin P. Author information: (1)Service de Diabétologiem Maladies Métaboliques et Nutrition, Centre Hospitalier Universitaire de Nancy, 54201 Toul Cedex, France. o.ziegler@chu-nancy.fr Obesity and visceral or upper body fat distribution, have a major impact on insulin sensitivity. There is strong evidence to suggest that free fatty acids (FFA) contribute to the pathogenesis of insulin resistance and the metabolic syndrome. Increased FFA release from adipose tissue or failure of FFA using tissues to remove them normally, lead to increased triglycerides (TG) and FFA fluxes. Increased delivery of FFA to muscle reduces muscle glucose uptake and utilisation by substrate competition or direct inhibition of glucose transport. Insulin resistance has been correlated with the size of intramuscular TG store. Intracellular TG have been involved in beta cell failure the so called lipotoxicity phenomena. The rate of FFA to the liver is a major determinant of hepatic TG secretion. So the regulation of FFA distribution between FFA using tissues and the partition of FFA between storage and oxidation could be involved in the developpment of insulin resistance. The dietary macronutrients could play a role in nutrient partitioning but their role in the etiology of insulin resistance is poorly understood due to a paucity of credible intervention studies in humans. However deleterious effects of saturated fatty acids on insulin action and the beneficial effects of polyunsaturated fatty acids (PUFAs) could be suspected from animal studies, and from epidemiological or clinical studies in humans. A very high intake of sucrose or fructose could be deleterious but low glycemic index foods, and fibers could have protective effects. Weight loss can induce marked improvement in insulin resistance, but weight maintenance is also required to keep long term good metabolic results. PMID: 11452220 [PubMed - indexed for MEDLINE] 5061. Diabetes Metab. 2001 Apr;27(2 Pt 2):247-53. [Insulin resistance: why is it important to treat?]. [Article in French] Reaven GM(1). Author information: (1)Professor of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. The ability of insulin to stimulate muscle glucose disposal and inhibit adipose tissue lipolysis is impaired in patients with type 2 diabetes. The progression from normal glucose tolerance and/or impaired glucose tolerance to type 2 diabetes only occurs when insulin secretory function declines to a degree that circulating insulin concentrations are no longer able to overcome muscle and adipose tissue insulin resistance. Although, ambient plasma insulin concentrations are not sufficiently high to maintain euglycaemia in patients with type 2 diabetes, absolute plasma insulin concentrations in these individuals are as high, if not higher, than in nondiabetic subjects. Since the plasma concentrations of insulin, or free fatty acids (FFAs), or both, are elevated in patients with type 2 diabetes secondary to muscle and adipose tissue insulin resistance, hypertriglyceridaemia is common in these individuals. Improvement in glycaemic control with insulin or insulin secretagogues is achieved by raising plasma insulin concentrations to a level high enough to overcome the insulin resistance. This is not the case with thiazolidinediones (TZDs): glycaemic control is associated with lower plasma insulin concentration. Compounds that improve insulin sensitivity and lead to lower glucose and insulin concentrations may have unique clinical benefit in the treatment of patients with type 2 diabetes. PMID: 11452218 [PubMed - indexed for MEDLINE] 5062. Diabetes Metab. 2001 Apr;27(2 Pt 2):239-45. [Insulin sensitivity and polycystic ovarian syndrome]. [Article in French] Bringer J(1), Raingeard I, Renard E, Grigorescu F, Lefebvre P. Author information: (1)Service des Maladies Endocriniennes, Hôpital Lapeyronie, 34295 Montpellier Cedex 5, France. Insulinresistance, commonly associated with polycystic ovarian syndrome (PCOS), raises many unresolved debates about its prevalence, mechanism and true pathological role. Low insulin sensibility may have multiple origins among them genetic molecular defects in pathways of cellular insulin effects. A weight gain and android distribution of fat mass may reveal or increase insulin resistance and hyperinsulinemia. The preexisting unbalanced ovarian steroidogenesis secondary to abnormalities in gene coding for enzymes of P450C17 alpha might be the necessary support facilitating the stimulatory effect of hyperinsulinemia or other factors (LH, IGF1) on ovarian androgens. In practice, the phycisian has to know how to evaluate and to treat insulin resistance in view of its implication in dysovulation and, later on, metabolic and cardiovascular risks. Nutritional education and regular physical exercice are the necessary approaches. The efficacy and indications of metformin and thiazolidinediones have to be further evaluated. PMID: 11452217 [PubMed - indexed for MEDLINE] 5063. Diabetes Metab. 2001 Apr;27(2 Pt 2):223-7. [Insulin sensitiviy and lipids]. [Article in French] Vergès B(1). Author information: (1)Service Endocrinologie, Diabétologie et Maladies métaboliques C.H.U. Dijon, France. bruno.verges@chu-eijon.fr Insulin plays a central role in regulation of lipid metabolism, with different sites of action. In the adipose tissue, insulin inhibits lipolysis via an inhibition of the lipase, leading to reduce the flux of free fatty acids into the circulation. Insulin inhibits the VLDL production by the liver. Insulin is a potent activator of the lipoprotein lipase, promoting the catabolism of triglyceride-rich lipoproteins (Chylomicrons, VLDL). insulin promotes the clearance of LDL. Indeed, insulin stimulates apoB/E receptor (LDL-receptor) activity and enhances LDL degradation via the LDL-receptor pathway. Insulin also plays an important role in HDL metabolism since it activates LCAT activity, it reduces PLTP activity and modulates the hepatic triglyceride lipase activity. Because of the key role of insulin in lipid metabolism, we can easily understand that all diseases with impaired insulin action, such as insulin resistance or diabetes mellitus, will be characterized by important lipid abnormalities, which are important factors responsible for the increased cardiovascular risk in the patients. PMID: 11452214 [PubMed - indexed for MEDLINE] 5064. Przegl Lek. 2001;58(1):25-7. [Aging and so called "youth hormones". Potential influence of exercise training]. [Article in Polish] Kostka T(1). Author information: (1)Katedra Medycyny Społecznej i Zapobiegawczej Zakład Medycyny Zapobiegawczej AM 90-402 Łódź, Zachodnia 81/83. Plasma levels of dehydroepiandrosterone sulphate (DHEAS), insulin-like growth factor-I (IGF-I), and testosterone decline with ageing. These hormones share some biological activities which counteract the aging processes: increase in fat-free mass, decrease of adipose tissue and globally increased fitness and well being. It seems that lower levels of these hormones may reflect partially lower physical activity and fitness of older subjects. If further longitudinal studies confirm this, regular participation in exercise training would become a useful alternative to hormone replacement therapy. PMID: 11450151 [PubMed - indexed for MEDLINE] 5065. Przegl Lek. 2001;58(1):20-4. [Glucose homeostasis in children. I. Regulation of blood glucose]. [Article in Polish] Otto Buczkowska E(1), Szirer G, Jarosz-Chobot P. Author information: (1)Ośrodek Diabetologiczny Dzieci i Młodziezy w Gliwicach. em.buczkowski@pro.onet.pl The amount of glucose in the circulation depends on its absorption from the intestine, uptake by and release from the liver and uptake by peripheral tissues. Insulin and glucagon together control the metabolities required by peripheral tissues and both are involved in maintaining glucose homeostasis. Insulin is considered to be an anabolic hormone in that it promotes the synthesis of protein, lipid and glycogen. The key target tissues for insulin are liver, muscles and adipose tissue. Glucagon acts largely to increase catabolic processes. Between meals or during fast, the most tightly regulated process is the release of glucose from the liver. During fasting glucose is produced from glycogen and is formed by enzymes on the gluconeogenic pathway. Fetal metabolism is directed to ensure anabolism with formation of glycogen, fat and protein. Glucogen is stored in the liver and serves as the immediate source of new glucose during first few hours after birth. Glucose is the most important substrate for brain metabolism. Due to the large size of neonatal brain in relation to body weight cerebral glucose consumption is particularly high. Postnatal hormonal changes have a central role in regulating glucose mobilization through glycogenolysis and gluconeogenesis. The initial glucagon surge is the key adaptive change which triggers the switch to glucose production. The control of insulin and glucagon secretion is of fundamental importance during first hours after birth. Children have a decreased tolerance to starvation when compared with adults, they are more prone to develop hypoglycaemia after short fasting. The faster rate in the fall of blood glucose and gluconeogenic substrates and rapid rate of ketogenesis are characteristic features of fasting adaptation in children. PMID: 11450150 [PubMed - indexed for MEDLINE] 5066. Panminerva Med. 2001 Jun;43(2):123-33. Breast cancer and obesity. La Guardia M(1), Giammanco M. Author information: (1)Institute of Physiology and Human Nutrition, University of Palermo, Palermo, Italy. Epidemiological evidence links breast cancer, a typical endocrine-related tumor, with western lifestyle, in particular eating habits. Yet, it's necessary to distinguish premenopausal from postmenopausal breast cancer. Visceral obesity and body weight gain are considered responsible for the increased risk of postmenopausal breast cancer. In fact, the mammary gland is sensitive to the level of circulating estrogens, visceral obesity is usually associated with higher levels of free steroid hormones, and the adipose tissue performs important endocrine function (clearance and aromatisation of androgens, regulation of free testoterone/DHEAS molar ratio). Before menopause, ovarian polycystosis is often seen with android obesity, and breast cancer risk could arise; however, as visceral obesity is generally less frequent, genetic factors are more important than nutritional ones. Furthermore, variations have been recorded in the secretion of insulin and insulin-like growth factors, involved in the genesis of the breast cancer. High body weight and male fat distribution negatively influence prognosis of breast cancer, too; this association is linked with the presence of estrogen and progesterone receptors in tumoral cells. Links between diet quality and breast cancer risk are shown: increased use of saturated fats and animal proteins, and a consequently decreased use of vegetables, legumes and fruit, constituting the so-called Mediterranean diet, are considered responsible for the increased risk of breast cancer. Lower fat and alcohol ingestion, the use of dietary fibre and a higher use of complex carbohydrates could reduce breast cancer risk. Finally, starting from the results of our previous animal researches, we suggest using a tryptophan devoid diet for a few days for premenopausal women with male obesity and alterations to the menstrual cycle. PMID: 11449184 [PubMed - indexed for MEDLINE] 5067. Exp Biol Med (Maywood). 2001 Feb;226(2):78-84. Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Himms-Hagen J(1), Harper ME. Author information: (1)Department of Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ontario, Canada. jhhagen@uottawa.ca This hypothesis proposes a physiological role for uncoupling protein-3 (UCP3) in the export of fatty acid anions from muscle and brown adipose tissue (BAT) mitochondria when fatty acids are the predominant substrate being used. It proposes that excess acyl CoA within the mitochondria is hydrolyzed by a mitochondrial acyl CoA thioesterase, yielding fatty acid anion and CoASH. The fatty acid anion is exported to the cytosol by being carried across the inner mitochondrial membrane by UCP3. The CoASH is conserved within the mitochondrion to participate in other reactions for which it is needed during fatty acid oxidation in the beta-oxidation cycle and in the tricarboxylic acid cycle. The export of the fatty acid anion thus permits continued rapid fatty acid oxidation in the face of an oversupply. The hypothesis provides a logical explanation for the observed up-regulation of gene expression for UCP3 in muscle when there is a switch to fatty acid oxidation, as during fasting, and in BAT when fatty acid oxidation is stimulated, as during exposure to cold. It provides a plausible physiological role for UCP3 as a transporter protein, not as an uncoupling protein. PMID: 11446442 [PubMed - indexed for MEDLINE] 5068. Can J Appl Physiol. 2001 Jun;26(3):273-90. Contribution of visceral obesity to the insulin resistance syndrome. Lemieux S(1). Author information: (1)Department of Food Science and Nutrition and Lipid Research Centre, Laval University, Ste-Foy, Québec, Canada. A high visceral adipose tissue accumulation has been associated with many metabolic perturbations typical of the insulin resistance syndrome, such as dyslipidemia, impaired glucose-insulin homeostasis, hypertension and impaired fibrinolysis. It has been documented that male gender aging, and a hyperglycemic state are conditions that increase the likelihood of displaying features of the insulin resistance syndrome. Accordingly, studies have demonstrated that the variation in visceral adipose tissue accumulation explains a significant proportion of the gender differences in the metabolic risk profile. Age-related differences in metabolic components of the insulin resistance syndrome have also been shown to be partly explained by the concomitant increase in visceral adipose tissue accumulation found with age. Studies have suggested that a high visceral adipose tissue accumulation contributes significantly to the deterioration in the plasma lipid-lipoprotein profile found in hyperglycemic subjects. Finally, it appears that the clustering of metabolic alterations of the insulin resistance syndrome is more pronounced in obese subjects with high levels of visceral fat that in those with a lower visceral adipose tissue accumulation. PMID: 11441231 [PubMed - indexed for MEDLINE] 5069. Diabetologia. 2001 Jun;44(6):659-73. Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Idris I(1), Gray S, Donnelly R. Author information: (1)School of Medical and Surgical Sciences, University of Nottingham, Royal Infirmary, Derby, UK. Comment in Diabetologia. 2001 Jun;44(6):657-8. Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca2+/phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the beta-selective inhibitor LY333531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits. PMID: 11440359 [PubMed - indexed for MEDLINE] 5070. J Nutr. 2001 Jul;131(7):2062-6. Does dietary protein in early life affect the development of adiposity in mammals? Metges CC(1). Author information: (1)Deutsches Institut für Ernährungsforschung, D-14558, Bergholz-Rehbrücke, Germany. metges@www.dife.de This article examines the proposition that dietary protein in pre- and early postnatal life influences the development of adiposity in later life. In rodents, low protein intake during gestation can result in low birth weight and subsequently leads to various metabolic disturbances in adulthood, such as high blood pressure, impaired glucose tolerance and insulin resistance. The few controlled studies conducted in animals suggest that high protein or energy intake during gestation leads to low birth weights. Observational studies in humans have been inconclusive in establishing a relationship between dietary protein intake in pregnancy and effects on birth weight and adiposity of the offspring later in life. There is only weak epidemiological evidence linking high protein intake during early childhood and the development of obesity. By contrast, studies in domestic animals have found that higher levels of protein intake are often associated with lower rates of fat accretion. Additional studies are proposed to explore claims linking protein nutrition in early life to the postnatal development of obesity and disease in humans. PMID: 11435530 [PubMed - indexed for MEDLINE] 5071. Reprod Nutr Dev. 2001 Mar-Apr;41(2):109-18. Lipids in monogastric animal meat. Mourot J(1), Hermier D. Author information: (1)Unité Mixte de Recherche sur le Veau et le Porc, INRA, Saint-Gilles, France. mourot@st-gilles.rennes.inra.fr Meat from monogastric animals, essentially pigs and poultry, is from afar the most consumed of all meats. Meat products from every species have their own characteristics. For a long time, pig meat has been presented as a fatty meat because of the importance of subcutaneous adipose tissue. Actually, when the visible fat is separated, this meat is rather poor in lipids: pieces eaten as fresh meat and without transformation, such as roasts, contain less then 2% total lipids. Poultry meat has always had a reputation of leanness because of its low content in intramuscular lipids. In addition, adipose tissues, localised in the abdominal cavity, are easily separable. The progress in genetics and a better knowledge of dietary needs has allowed to improve growth performances, to increase muscle weight and, in the pig, to strongly decrease carcass adiposity. However, strong contradictions appear between transformers and nutritionists, especially concerning the pig: the former wish to have meat with adipose tissues containing a high percentage of saturated fatty acids and the latter wish meat with more unsaturated fatty acids. The consumer, however, regrets the pigs of yesteryear or the poultry bred on farmyard that had tastier meat. At the same time, however, they request meat with a low fat content, which is paradoxical. PMID: 11434515 [PubMed - indexed for MEDLINE] 5072. Int J Hyg Environ Health. 2001 May;203(4):293-9. Evaluation of health risks caused by musk ketone. Schmeiser HH(1), Gminski R, Mersch-Sundermann V. Author information: (1)Institute of Microbiology and Hygiene, Faculty of Clinical Medicine Mannheim, University of Heidelberg, P.O. Box 100023, D-68135 Mannheim, Germany. Among the nitro musks, musk ketone (MK) as a synthetic compound with a typical musk odor is widely used in cosmetics. In the European Community the total amount used in fragrances has been reported to be 110 tons/a. Additionally, relevant amounts of MK are used in Indian joss sticks. As a result of its inherently low biodegradability MK has been detected in the aquatic environment (surface water, sediments, edible fish). Moreover, it has been shown that MK concentrates in human fatty tissue and breast milk, indicating that humans are constantly exposed. Several studies provided convincing evidence of lack of a genotoxic potential for MK. However, MK was identified as a strong inducer of phase I enzymes in rodents and a cogenotoxicant in vitro in human derived cells in rather low doses, suggesting that exposure to MK might increase the susceptibility to health hazards caused by carcinogens in humans. PMID: 11434209 [PubMed - indexed for MEDLINE] 5073. J Radiol. 2001 Feb;82(2):127-35. [Normal bone marrow: dynamic aspects in magnetic resonance imaging]. [Article in French] Vande Berg BC(1), Malghem J, Lecouvet FE, Maldague B. Author information: (1)Département d'imagerie médicale, Cliniques universitaires Saint Luc, Université catholique de Louvain, 10, avenue Hippocrate, 1200-Bruxelles, Belgique. vandeberg@rdgn.ucl.ac.be The bone marrow is a complex organ that contains fat and nonfat cells, the proportion of which varies greatly with age and in the different bones of the skeleton. Magnetic resonance imaging provides information on the composition of the medullary cavity of any given bone and on the distribution of red and yellow marrow in the skeleton. The wide spectrum of appearances of the normal bone marrow at MR imaging will be reviewed. The purpose of this paper is to determine the MR appearance of the bone marrow, to illustrate the phenomenon of marrow conversion and to familiarize the readers with the complex parameters that interfere with the MR appearance of normal bone marrow. PMID: 11428207 [PubMed - indexed for MEDLINE] 5074. Med Sci Sports Exerc. 2001 Jun;33(6 Suppl):S611-21; discussion S640-1. Health effects resulting from exercise versus those from body fat loss. Williams PT(1). Author information: (1)Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. PTWilliams@LBL.gov OBJECTIVE: The purpose of this review was to assess whether body weight confounds the relationships between physical activity and its health benefits. METHODS: The review includes 80 reports from population-based studies (Evidence Category C) of physical activity or fitness and cardiovascular disease (CVD) or coronary heart disease (CHD). RESULTS: Eleven of 64 reports on activity found no relationship between physical activity and disease. Of the remaining 53 reports, 11 did not address the possible confounding effects of body weight, nine cited reasons that weight differences should not explain their observed associations, and 33 statistically adjusted for weight (as required). Only three of these changed their associations from significant to nonsignificant when adjusted. Ten of 16 reports on cardiorespiratory fitness and CHD or CVD used statistical adjustment, and none of these changed their findings to nonsignificant. Population studies show that vigorously active individuals also have higher high-density lipoprotein (HDL)-cholesterol concentration, a major risk factor for CHD and CVD, than sedentary individuals when statistically adjusted for weight. In contrast, intervention studies, which relate dynamic changes in weight and HDL, suggest that adjustment for weight loss largely eliminates the increase in HDL-cholesterol in sedentary men who begin exercising vigorously. Adjusting the cross-sectional HDL-cholesterol differences for the dynamic effects of weight loss eliminates most of the HDL-cholesterol difference between active and sedentary men. CONCLUSION: Population studies show that the lower incidence of CHD and CVD and higher HDL of fit, active individuals are not because of lean, healthy individuals choosing to be active (i.e., self-selection bias). Nevertheless, metabolic processed associated weight loss may be primarily responsible for the HDL differences between active and sedentary men, and possibly also their differences in CHD and CVD. PMID: 11427786 [PubMed - indexed for MEDLINE] 5075. Med Sci Sports Exerc. 2001 Jun;33(6 Suppl):S521-7; discussion S528-9. Physical activity, total and regional obesity: dose-response considerations. Ross R(1), Janssen I. Author information: (1)School of Physical and Health Education, Queen's University, Ontario, Canada. rossr@post.queensu.ca PURPOSE: This review was undertaken to determine whether exercise-induced weight loss was associated with corresponding reductions in total, abdominal, and visceral fat in a dose-response manner. METHODS: A literature search (MEDLINE, 1966--2000) was performed using appropriate keywords to identify studies that consider the influence of exercise-induced weight loss on total and/or abdominal fat. The reference lists of those studies identified were cross-referenced for additional studies. RESULTS: Total fat. Review of available evidence suggested that studies evaluating the utility of physical activity as a means of obesity reduction could be subdivided into two categories based on study duration. Short-term studies (< or = 16 wk, N = 20) were characterized by exercise programs that increased energy expenditure by values double (2200 vs 1100 kcal.wk-1) that of long-term studies (> or = 26 wk, N = 11). Accordingly, short-term studies report reductions in body weight (-0.18 vs -0.06 kg x wk(-1)) and total fat (-0.21 vs -0.06 kg x wk(-1)) that are threefold higher than those reported in long-term studies. Moreover, with respect to dose-response issues, the evidence from short-term studies suggest that exercise-induced weight loss is positively related to reductions in total fat in a dose-response manner. No such relationship was observed when the results from long-term studies were examined. Abdominal fat. Limited evidence suggests that exercise-induced weight loss is associated with reductions in abdominal obesity as measured by waist circumference or imaging methods; however, at present there is insufficient evidence to determine a dose-response relationship between physical activity, and abdominal or visceral fat. CONCLUSION: In response to well-controlled, short-term trials, increasing physical activity expressed as energy expended per week is positively related to reductions in total adiposity in a dose-response manner. Although physical activity is associated with reduction in abdominal and visceral fat, there is insufficient evidence to determine a dose-response relationship. PMID: 11427779 [PubMed - indexed for MEDLINE] 5076. Reproduction. 2001 May;121(5):685-95. Mammalian aromatases. Conley A(1), Hinshelwood M. Author information: (1)Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. ajconley@ucdavis.edu Aromatase is the enzyme complex that catalyses the synthesis of oestrogens from androgens, and therefore it has unique potential to influence the physiological balance between the sex steroid hormones. Both aromatase cytochrome P450 (P450arom) and NADPH-cytochrome P450 reductase (reductase), the two essential components of the enzyme complex, are highly conserved among mammals and vertebrates. Aromatase expression occurs in the gonads and brain, and is essential for reproductive development and fertility. Of interest are the complex mechanisms involving alternative promoter utilization that have evolved to control tissue-specific expression in these tissues. In addition, in a number of species, including humans, expression of aromatase has a broader tissue distribution, including placenta, adipose and bone. The relevance of oestrogen synthesis and possibly androgen metabolism in these peripheral sites of expression is now becoming clear from studies in P450arom knockout (ArKO) mice and from genetic defects recognized recently in both men and women. Important species differences in the physiological roles of aromatase expression are also likely to emerge, despite the highly conserved nature of the enzyme system. The identification of functionally distinct, tissue-specific isozymes of P450arom in at least one mammal, pigs, and several species of fish indicates that there are additional subtle, but physiologically significant, species-specific roles for aromatase. Comparative studies of mammalian and other vertebrate aromatases will expand understanding of the role played by this ancient enzyme system in the evolution of reproduction and the adaptive influence of oestrogen synthesis on general health and well being. PMID: 11427156 [PubMed - indexed for MEDLINE] 5077. Toxicol Pathol. 2001 Mar-Apr;29(2):224-31. Peroxisome proliferator-activated receptors in atherosclerosis and inflammation--an update. Elangbam CS(1), Tyler RD, Lightfoot RM. Author information: (1)Department of Pathology and GlaxoWellcome Inc, Research Triangle Park, North Carolina 27709, USA. cse63957@GlaxoWellcome.com Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor subfamily of transcription factors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation, and atherosclerosis. Three PPARs, namely alpha, delta, and gamma have been identified with distinct tissue distribution patterns and metabolic functions. PPAR-alpha is predominantly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle, and vascular endothelial cells and is involved in the control of lipoprotein metabolism, fatty acid oxidation, and the cellular uptake of fatty acids. PPAR-gamma is highly expressed in brown and white adipose tissues and, to lesser extent, in large intestine, retina, and some parts of the immune system, and plays a critical role in adipocyte differentiation and fat deposition. PPAR-delta shows a widespread tissue distribution but its regulation and functions are not yet known. Considerable evidence indicates that PPARs (PPAR-alpha and PPAR-gamma) have beneficial effects in inflammatory diseases, including atherosclerosis, through regulation of cytokine production, adhesion molecule expression on the endothelial cells, fibrinolysis, and modulation of monocyte-derived macrophages. In this review, the general and specific roles of the PPAR isotypes and their implications in the control of vascular inflammation and atherosclerosis are discussed. PMID: 11421489 [PubMed - indexed for MEDLINE] 5078. Herz. 2001 May;26(3):178-84. [Molecular principles of obesity]. [Article in German] Hamann A(1), Münzberg H, Algenstaedt P, Tafel J. Author information: (1)Abteilung Innere Medizin I, Medizinische Klinik und Poliklinik der Universität Heidelberg. andreas_hamann@med.uni-heidelberg.de BACKGROUND: The deposition of excess amounts of energy in adipose tissue is enhanced by high-fat diets and lack of physical activity. Furthermore, the existence of a specific genetic predisposition towards the development of obesity becomes evident by marked interindividual differences in the response to caloric oversupply. GENETIC DEFECTS AND HORMONES: In recent years, numerous genes and genetic defects with importance for human obesity were identified, especially through studies in animal models. The adipocyte-derived hormone leptin and its hypothalamic receptor play a premier role, as they interact with a network of proteins and neuropeptides within the regulation of food intake and energy expenditure. CONCLUSION: The search for the key molecular mechanisms in the pathogenesis of obesity will not only improve our understanding of energy metabolism, but may ultimately also lead to the development of new treatment strategies for obese patients. PMID: 11413797 [PubMed - indexed for MEDLINE] 5079. Cesk Fysiol. 2001 May;50(2):57-63. [Effect of nutrition on adipose tissue metabolism in humans]. [Article in Czech] Suljkovicoyá H(1), Viguerie N, Kunesová M, Millet L, Avizou S, Hejnová J, Hainer V, Barbe P, Vecka M, Tvrzická E, Langin D, Stich V. Author information: (1)Centrum preventivního lékarství 3. LF UK. Lipolysis in adipose tissue and balance between energy intake and expenditure are involved in the regulation of adipose tissue mass. Several recent findings suggest that alterations in the regulation of lipolysis and/or energy balance might contribute to the development of obesity. Hormone-sensitive lipase and uncoupling proteins play important role in regulation of lipolysis in adipose tissue as well as in the regulation of energy balance of various tissues. Mechanisms of the control of expression of genes coding synthesis of these proteins are poorly known. A brief overview of the present knowledge of the effects of nutritional intervention on the regulation of lipolysis in adipose tissue and on the expression of genes of hormone-sensitive lipase and that of uncoupling proteins is given in this article. Results of the authors' studies on the effect of calorie restriction on gene expression in adipose tissue are presented. PMID: 11409350 [PubMed - indexed for MEDLINE] 5080. Prog Lipid Res. 2001 Jul;40(4):269-81. The roles of PPARs in adipocyte differentiation. Grimaldi PA(1). Author information: (1)INSERM U470, Centre de Biochimie, University of Nice-Sophia Antipolis, Parc Valrose, 06108 Cedex, Nice, France. grimaldi@unice.fr Adipose tissue development takes place primarily around birth but adipose cell number can increase throughout life in response to nutritional changes. At the molecular level, adipogenesis is the result of transcriptional remodeling that leads to activation of a considerable number of genes. Several transcription factors act cooperatively and sequentially in this process. This article attempts to review the roles of peroxisome proliferator-activated receptors gamma and delta in the control of preadipocyte proliferation and differentiation during adipose tissue development or during the adaptive response of adipose tissue mass to high-fat feeding. PMID: 11412892 [PubMed - indexed for MEDLINE] 5081. Nihon Yakurigaku Zasshi. 2001 May;117(5):319-27. [Physiological and pharmacological function of PPARs]. [Article in Japanese] Takahashi N(1), Kawada T. Author information: (1)Research Project for Obesity and Lipid Metabolism Regulation, Bio-oriented Research Advancement Institution (BRAIN), Tokyo 105-0001, Japan. The finding of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, thyroxine, vitamin D and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains. In mammals, the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes by separate genes: PPAR alpha, PPAR delta (also referred to as hNUC1 or PPAR beta), and PPAR gamma. PPARs have been associated with several distinct biological programs. PPARs function as a heterodimer with the retinoid X receptor. This complex binds to sequences termed direct repeat-1 response element in enhancer sites of regulated genes and activates transcription upon ligand and coactivator binding. Three different PPAR subtypes have specific roles in different organs. PPAR alpha, mainly expressed in liver, plays an important role in fatty acid metabolism. PPAR gamma predominantly is expressed in adipose cells. PPAR delta displays a high level of expression in lipid-metabolizing organs such as small intestine, heart and adipose tissue. Naturally occurring and synthetic molecules (anti-hyperlipidemia and diabetic drugs) that are ligands for these nuclear receptors control transcriptional activity of PPARs. We believe that the pharmacological and genomic researches on PPAR will develop powerful tools for prevention and medical care against common diseases. PMID: 11411341 [PubMed - indexed for MEDLINE] 5082. Mol Cell Endocrinol. 2001 Jun 10;178(1-2):147-54. The role of estrogen and estrogen receptor-alpha in male adipose tissue. Cooke PS(1), Heine PA, Taylor JA, Lubahn DB. Author information: (1)Department of Veterinary Biosciences, University of Illinois, 2001 S. Lincoln Avenue, Urbana, IL 61802, USA. p-cooke@uiuc.edu Males and females both express estrogen receptor (ER) in white adipose tissue (WAT), and estrogens appear to play an important role in regulating WAT in females. However, the role of ER in male WAT was unclear. In this review, we describe our work, which used wild type (WT) and ERalpha-knockout (alphaERKO) male and female mice to determine the role of ERalpha in regulating WAT and brown adipose tissue (BAT). There were progressive increases in WAT with advancing age in alphaERKO compared with WT males; weights of various WAT depots in alphaERKO males were increased by more than 100% compared with WT controls during adulthood. Conversely, BAT weight was similar in alphaERKO and WT males at all ages. Adipocyte areas and numbers were also increased in WAT from alphaERKO compared with WT males. Compared with WT controls, alphaERKO females also had increases in WAT. The alphaERKO mice also had insulin resistance and impaired glucose tolerance, similar to humans lacking ERalpha or aromatase. The obesity in alphaERKO males appeared to involve decreased energy expenditure rather than hyperphagia. In summary, ERalpha absence causes adipocyte hyperplasia and hypertrophy in WAT, but not BAT, and is accompanied by insulin resistance and glucose intolerance in both males and females. These results are the first evidence that the estrogen/ERalpha signaling system is critical in female and male WAT deposition, and may have clinical implications. PMID: 11403904 [PubMed - indexed for MEDLINE] 5083. Horm Res. 2001;55 Suppl 1:42-5. Long-term effects of childhood obesity on morbidity and mortality. Maffeis C(1), Tatò L. Author information: (1)Department of Pediatrics, University of Verona, Italy. maffeis@borgoroma.univr.it Obesity tracks from childhood into adulthood, and the persistence of obesity rises with age among obese children. Early onset obesity was suggested as a risk factor for morbidity and mortality later in life. In both sexes, rates of diabetes, coronary heart disease, atherosclerosis, hip fracture and gout were increased in those who were overweight as adolescents. Especially in females, obesity at late adolescence was associated with several and relevant psychosocial consequences in adulthood. Finally, a higher mortality risk for all causes of death, especially atherosclerotic cerebrovascular disease and colorectal cancer, was demonstrated in males but not in females who were overweight during high school years. Although the persistence of excess adiposity from childhood to adulthood is a morbidity risk factor, it is not known if total body fat or body fat distribution is the main factor responsible. In particular, a specific role for the intra-abdominal adipose tissue (IAAT) in childhood, independently from that of total body fat, on morbidity risk in adulthood was not demonstrated yet. The association between childhood obesity and adult morbidity and mortality strongly suggests that a more effective prevention and treatment of childhood obesity should be pursued. Copyright 2001 S. Karger AG, Basel. PMID: 11408761 [PubMed - indexed for MEDLINE] 5084. Horm Res. 2001;55 Suppl 1:11-6. Hormonal control of growth hormone secretion. Pombo M(1), Pombo CM, Garcia A, Caminos E, Gualillo O, Alvarez CV, Casanueva FF, Dieguez C. Author information: (1)Department of Pediatrics, Faculty of Medicine, University of Santiago, Santiago de Compostela, Spain. Growth hormone secretion by the somatotroph cells depends upon the interaction between hypothalamic regulatory peptides, target gland hormones and a variety of growth factors acting in a paracrine or autocrine fashion. This review will be focused on recent data regarding the mechanism by which growth hormone-releasing hormone (GHRH) influences somatotroph cell function and the physiological role played by Ghrelin and leptin in the regulation of growth hormone (GH) secretion. It is well established that binding of GHRH to its receptor leads to activation of protein kinase A (PKA). More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Whether somatotroph adenomas, either with or without a GS-alpha mutation, have alterations in some of the components of the activation of the MAP kinase pathway remains to be known. The recent isolation of Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, can be considered a landmark in the GH field, which opens up the possibility of gaining greater insight into our understanding of the mechanisms involved in the regulation of GH secretion and somatic growth. Indeed, preliminary evidences indicate that this peptide exerts a marked stimulatory effect on plasma GH levels in both rats and humans. Finally, it is well known that GH secretion is markedly influenced by nutritional status. Leptin has emerged as an important adipose tissue-generated signal that is involved in the regulation of GH secretion, thus providing an integrated regulatory system of growth and metabolism. Although the effects of leptin on GH secretion in humans remain to be clarified, indirect evidences indicate that it may play an inhibitory role. Copyright 2001 S. Karger AG, Basel. PMID: 11408755 [PubMed - indexed for MEDLINE] 5085. J Biol Rhythms. 2001 Jun;16(3):196-204. SCN efferents to peripheral tissues: implications for biological rhythms. Bartness TJ(1), Song CK, Demas GE. Author information: (1)Department of Biology, Center for Behavioral Neuroscience, Georgia State University, Atlanta 30303-3083, USA. bartness@gsu.edu The suprachiasmatic nucleus (SCN) is the principal generator of circadian rhythms and is part of an entrainment system that synchronizes the animal with its environment. Here, we review the possible communication of timing information from the SCN to peripheral tissues involved in regulating fundamental physiological functions as revealed using a viral, transneuronal tract tracer, the pseudorabies virus (PRV). The sympathetic nervous system innervation of the pineal gland and the sympathetic outflow from brain to white adipose tissue were the first demonstrations of SCN-peripheral tissue connections. The inclusion of the SCN as part of these and other circuits was the result of lengthened postviral injection times compared with those used previously. Subsequently, the SCN has been found to be part of the sympathetic outflow from the brain to brown adipose tissue, thyroid gland, kidney, bladder, spleen, adrenal medulla, and perhaps the adrenal cortex. The SCN also is involved in the parasympathetic nervous system innervation of the thyroid, liver, pancreas, and submandibular gland. Individual SCN neurons appear connected to more than one autonomic circuit involving both sympathetic and parasympathetic innervation of a single tissue, or sympathetic innervation of two different peripheral tissues. Collectively, the results of these PRV studies require an expansion of the traditional roles of the SCN to include the autonomic innervation of peripheral tissues and perhaps the modulation of neuroendocrine systems traditionally thought to be controlled solely by hypothalamic stimulating/inhibiting factors. PMID: 11407779 [PubMed - indexed for MEDLINE] 5086. Ugeskr Laeger. 2001 May 21;163(21):2913-7. [Fatty tissue as a secretory organ. Significance for obesity-related diseases]. [Article in Danish] Richelsen B(1), Bruun JM, Pedersen SB. Author information: (1)Arhus Universitetshospital, Arhus Amtssygehus, medicinsk endokrinologisk afdeling C. br@aas.auh.dk Adipose tissue is not only a passive storage organ for excessed energy intake, it is also able to produce and release several substances with local (autocrine) and systemic (endocrine) actions. An up-to-date review of our knowledge in this area is given here. Several of the compounds deriving from adipose tissue have been shown to play a role in obesity-related health complications. The production of cytokines (TNF-alpha, IL-6, IL-8) is implicated in the development of insulin resistance and atherosclerosis. All elements in the renin-angiotensin system are produced in adipose tissue, which is thus related to hypertension. The production of PAI-1 could be related to enhanced thrombogenesis. The release of the compounds described is generally higher from adipocytes in the visceral depot, which could explain the close association between this depot and health complications. PMID: 11402968 [PubMed - indexed for MEDLINE] 5087. Pol Merkur Lekarski. 2001 Mar;10(57):180-4. [Lipid metabolism. I. Role of insulin in lipid metabolism]. [Article in Polish] Otto-Buczkowska E(1), Jarosz-Chobot P. Author information: (1)Ośrodek Diabetologiczny Dzieci i Młodziezy Gliwice, Klinika Endokrynologii i Diabetologii Dzieci Sl. AM w Katowicach. The triacylglyceroles that comprise the bulk of lipids in the diet are hydrolyzed to free fatty acids, monoacylglyceroles and glycerol in the intestinal tract. During absorption through the intestinal tract mucosa, triacylglyceroles are resynthesized from free fatty acids, and glycerol-3-phosphate is formed in the intestinal mucose. these globules, called chylomicrons, pass through the liver and adipose tissue, they are reduced in size by an enzyme, lipoprotein lipase (LPL). In the postabsorptive period, free fatty acids and glycerol are released from adipocytes by neural and hormonal stimulation. The free fatty acids can be burned by almost all tissues of the body except the brain. They are burned in the mitochondria by a process of b-oxidation to acetyl-CoA, which can then enter the citrate acid cycle for conversion to CO2, adenosine triphosphate, and water. When excessive quantities of glucose are ingested, the glucose can be converted to a storage form, triacylglycerol. Fatty acids are synthesized by a series of reactions in which acetyl-CoA and malonylo-CoA residues sequentially condense until the fatty acid chain is completed. The fatty acids are then combined with glycerol-3-phosphate, generated in the liver, to form the neutral triacylglyceroles. The insulin has effects on both the synthetic (estrification) and breakdown (lipolysis) pathways. The promotion of triacylglycerol storage in fat is one of the most important of the actions of insulin. PMID: 11398523 [PubMed - indexed for MEDLINE] 5088. Nihon Rinsho. 2001 May;59(5):973-7. [Treatment of hypertension in the patients with obesity]. [Article in Japanese] Hano T(1), Nishio I. Author information: (1)Department of Cardiology, Wakayama Medical School. Obesity is often accompanied with hypertension and increases cardiovascular events. Japanese new guideline on identification of obesity includes a modified BMI categories and a method of detection of visceral fat obesity in Japanese. Hyper-insulinemia and leptin released from adipose tissue play an important role in the development of hypertension in obese patients. Insulin and leptin increase sympathetic tone which results in sodium retention and hyper-responsiveness of blood vessels. As leptin has also a direct vasodilative and diuretic action, its effect on blood pressure is bidirectional. Life style modification, especially diet and physical exercise are important to obtain the body weight loss and the improvement of insulin resistance. Dynamic exercise at the level of fifty percent of max VO2 for 30 to 60 minutes over three times a week should be recommended for hypertensive patients with obesity. ACE inhibitors improve the hypersympathetic tone and impaired insulin sensitivity in obese patients. Calcium antagonist is also useful for these patients. PMID: 11392001 [PubMed - indexed for MEDLINE] 5089. Vopr Onkol. 2001;47(2):182-6. [Aromatase and breast cancer]. [Article in Russian] Miller WR(1), Howie F, Mason I. Author information: (1)University of Edinburgh, Edinburgh, Great Britain. Aromatase activity may be detected using in vitro and in vivo techniques in most breast cancers and mammary adipose tissue. This activity makes a variable contribution to endogenous estrogens within the breast and in many cases represents the major source of these hormones. Such local biosynthesis may maintain the growth of some hormone-dependent tumors. The factors which regulate aromatase activity within the breast are not defined but are likely to include growth factors and cytokines which may be produced by breast tissues so that autocrine and paracrine loops may exist. Estrogen biosynthesis within the breast, like other peripheral systems, appears sensitive to classical aromatase inhibitors and the new generation of drugs are capable of profoundly blocking the activity and markedly reducing endogenous estrogen levels; in turn these endocrine effects are translated in dramatic anti-tumor influences in hormone-dependent breast cancer. PMID: 11383454 [PubMed - indexed for MEDLINE] 5090. Vopr Onkol. 2001;47(2):156-9. [Genetic polymorphism and variability of steroid hormone metabolism: connection with risk of developing breast neoplasms]. [Article in Russian] Kristensen VN, Harada N, Kristensen T, Borresen-Dale AL. Endogenous estradiol is synthesized in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and in minor quantities in peripheral tissue. These cells, as well as breast cancer tissue, express all the necessary enzymes for this synthesis: CYP17, CYP11a, CYP19, hydroxysteroid hydrogenase, steroid sulphatase as well as enzymes further hydroxylating estradiol such as CYP1A1, CYP3A4, CYP1B1. Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer. PMID: 11383450 [PubMed - indexed for MEDLINE] 5091. Nutr Metab Cardiovasc Dis. 2001 Feb;11(1):70-5. Mitochondrial uncoupling proteins (UCPs) and obesity. Crowley V(1), Vidal-Puig AJ. Author information: (1)Departments of Medicine and Clinical Biochemistry, University of Cambridge, Level 4, Box 232, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, UK. Obesity is now regarded as major public health problem worldwide. Research into this condition has been increasingly focussed on elucidating the cellular and molecular mechanisms regulating mammalian energy intake and expenditure. It is widely acknowledged that the brown adipose tissue (BAT) mitochondrial uncoupling protein (UCP1) plays a pivotal role in adaptive thermogenic responses. Two homologues of UCP1 (UCP2 and UCP3) have recently been identified and population-based genetic studies have linked them with basal metabolic rate, while in vitro studies report that both have proton transport activity and may thus be involved in regulation of energy homeostasis and hence obesity. However, evidence from genetically modified animal models indicates that UCP2 and UCP3 have no specific physiological thermogenic function in vivo, though they may still be useful therapeutic targets for obesity. Furthermore, their role in modulating levels of reactive oxygen species and glucose homeostasis is also being investigated. PMID: 11383327 [PubMed - indexed for MEDLINE] 5092. Nutr Metab Cardiovasc Dis. 2001 Feb;11(1):64-9. PPAR gamma: an essential role in metabolic control. Fajas L(1), Debril MB, Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP, Illkirch, France. The peroxisome proliferator-activated receptor gamma is a nuclear hormone receptor playing a crucial role in adipogenesis and insulin sensitization. Prostaglandin J2 derivatives and the antidiabetic thiazolidinediones are its respective natural and synthetic ligands. The RXR/PPAR gamma heterodimer has also been reported to have important immunomodulatory activities and its pleiotropic functions suggest wide-ranging medical implications. PMID: 11383325 [PubMed - indexed for MEDLINE] 5093. Cancer Control. 2001 May-Jun;8(3):239-51. Genetic and molecular abnormalities in tumors of the bone and soft tissues. Letson GD(1), Muro-Cacho CA. Author information: (1)Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa 33612, USA. BACKGROUND: Malignant transformation requires the accumulation of multiple genetic alterations such as chromosomal abnormalities, oncogene activation, loss of tumor suppressor genes, or abnormalities in genes that control DNA repair and genomic instability. Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult histologic classification and strong genetic predisposition. This article provides a comprehensive review of the cytogenetic abnormalities observed in bone and soft-tissue tumors, emphasizing known downstream molecular changes that may play a role in oncogenesis. METHODS: The database of the National Library of Medicine was searched for literature relating to genetic and molecular mechanisms in sarcomas in general and in each of the main tumor entities. RESULTS: Recent techniques in chromosome analysis and molecular cytogenetics have improved our ability to characterize genetic changes in mesenchymal tumors. Some changes are so characteristic as to be virtually pathognomonic of particular histologic types, while others are complex, difficult to characterize, and of unknown relevance to pathogenesis. The implications to the cell of some of these abnormalities are now being recognized. CONCLUSIONS: The study of sarcomas will benefit from the information derived from genetic studies and translational research. The human genome project and new methodologies, such as computer-based DNA microarray, may help in the histogenetic classification of sarcomas and in the identification of molecular targets for therapy. PMID: 11378650 [PubMed - indexed for MEDLINE] 5094. Nutrition. 2001 May;17(5):438-42. Cancer anorexia and cachexia. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Birmingham, United Kingdom. Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP-dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin-proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia. PMID: 11377146 [PubMed - indexed for MEDLINE] 5095. J Endocrinol. 2001 Jun;169(3):453-9. Peroxisome proliferator-activated receptors in inflammation control. Delerive P(1), Fruchart JC, Staels B. Author information: (1)U325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, 1 rue Professeur Calmette, 59019 Lille, France. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARalpha is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARgamma is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARalpha and PPARgamma respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARalpha controls intra- and extracellular lipid metabolisms whereas PPARgamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs also modulate the inflammatory response. PPAR activators have been shown to exert anti-inflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases. PMID: 11375115 [PubMed - indexed for MEDLINE] 5096. Z Kardiol. 2001;90 Suppl 3:125-32. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall. Chinetti G(1), Fruchart JC, Staels B. Author information: (1)U 325 Inserm, Institut Pasteur de Lille 1, rue Calmette BP245, 59019 Lille, France. bart.staels@pasteur-lille.fr Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPAR alpha is highly expressed in liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPAR gamma is predominantly expressed in intestine and adipose tissue, where it triggers adipocyte differentiation and promotes lipid storage. Recently, the expression of PPAR alpha and PPAR gamma was also reported in cells of the vascular wall, such as monocyte/macrophages, endothelial and smooth muscle cells. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. Furthermore, fatty acid-derivatives and eicosanoids are natural PPAR ligands: PPAR alpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPAR gamma ligand, as well as some components of oxidized LDL, such as 9- and 13-HODE. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control and, by consequence, in related diseases such as atherosclerosis. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNF alpha and metalloproteases) by negatively interfering with the NF-kappa B, STAT and AP-1 signalling pathways in cells of the vascular wall. Furthermore, PPARs may also control lipid metabolism in the cells of the atherosclerotic plaque. In addition, different clinical trials (such as the LOCAT, BECAIT and VA-HIT) as well as animal studies indicate that PPAR activators may have anti-atherogenic properties by reducing the progression of atherosclerotic lesions. In this review, we summarize the evidence indicating that PPAR alpha and PPAR gamma directly modulate vessel wall functions, and its consequences in the control of cardiovascular disease. PMID: 11374025 [PubMed - indexed for MEDLINE] 5097. Biochem Soc Trans. 2001 May;29(Pt 2):80-5. Fetal and neonatal adipose maturation: a primary site of cytokine and cytokine-receptor action. Stephenson T(1), Budge H, Mostyn A, Pearce S, Webb R, Symonds ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, U.K. During late gestation, the maturation of fetal adipose tissue is geared towards the synthesis of high levels of uncoupling protein 1 (UCP1), which is unique to brown adipose tissue. At birth, rapid activation of UCP1 ensures a large increase in heat production. These adaptations are nutritionally sensitive, and may be mediated in part by rapid changes in prolactin and leptin secretion after birth. Restriction of maternal nutrition reduces adipose tissue deposition, with no effect on UCP1. Increased maternal food intake results in increases in levels of UCP1 and the short form of the prolactin receptor, but in a decrease in adipose tissue content per kg of fetus. The ontogeny of the long and short forms of the prolactin receptor follows that of UCP1, to peak at birth. Then, during postnatal life, UCP1 disappears in parallel with the loss of prolactin receptors. Treatment of neonatal lambs with prolactin increases body temperature and the thermogenic potential of brown adipose tissue. In contrast, acute leptin treatment results in maintenance of colonic temperature, but chronic leptin treatment accelerates UCP1 loss. Increasing our understanding of the interaction between prolactin and leptin during perinatal development may enable the establishment of strategies aimed at maximizing adipose tissue development in order to promote metabolic adaptation to the extra-uterine environment. PMID: 11356132 [PubMed - indexed for MEDLINE] 5098. Biochem Soc Trans. 2001 May;29(Pt 2):72-5. Regional differences in protein production by human adipose tissue. Arner P(1). Author information: (1)Department of Medicine, CME M63, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden. peter.arner@medhs.ki.se Human adipose tissue has an important protein secretory function. Cytokines, hormones, prohormones and enzymes are secreted from fat cells and act in an endocrine or paracrine fashion. The production of several of these proteins is affected by obesity; normally there is an increase in the obese state. Protein production is, as a metabolic activity, subject to regional variations. In particular, the production of leptin, angiotensinogen, interleukin-6 and plasmin activator inhibitor-1 differs between subcutaneous and visceral adipose tissue sites, but no regional differences have been reported in the production of tumour necrosis factor alpha. It is possible that regional variations in protein production by adipose tissue are of importance in some of the endocrine and metabolic disturbances seen in various forms of obesity, such as visceral and upper-body obesity. PMID: 11356130 [PubMed - indexed for MEDLINE] 5099. Biochem Soc Trans. 2001 May;29(Pt 2):33-7. Cytokines and cytokine receptors in fetal growth and development. Symonds ME(1), Mostyn A, Stephenson T. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, U.K. Michael.Symonds@nottingham.ac.uk The cytokine receptors for growth hormone (GH), prolactin and leptin have a critical role in regulating embryo, placental and/or fetal development, which is dependent on stage of gestation and species. GH and prolactin receptors are detectable from conception, and alterations in the maternal hormonal environment may impact on placental growth from this early stage of gestation. Leptin is critical for conception, but its role in fetal growth remains elusive. During late gestation, when fetal growth accelerates and organ maturation occurs, prolactin and insulin-like growth factor-I may have interactive roles in regulating the growth of specific tissues, including adipose tissue. Prolactin, leptin and GH all have specific effects on fetal and neonatal energy balance, which are mediated in part through promoting lipolysis and/or enhancing the expression of uncoupling proteins. An increased understanding of these interactions is likely to have important implications for a number of potentially pathological conditions, including infection, obesity and hypertension. PMID: 11356122 [PubMed - indexed for MEDLINE] 5100. Curr Opin Lipidol. 2001 Jun;12(3):321-7. Leptin and its role in lipid metabolism. Hynes GR(1), Jones PJ. Author information: (1)School of Dietetics and Human Nutrition, McGill University, Ste Anne de Bellevue, Quebec, Canada. Since the discovery of leptin in 1994, a considerable amount of research has focused on leptin as a central regulator of body weight. In the animal model, research has demonstrated leptin action through hypothalamic centres altering both satiety and energy expenditure. In contrast to animal studies, it is unlikely that leptin functioning in the human system exerts such a profound role in body weight regulation. Human studies suggest that leptin levels are strongly correlated with both percentage fat mass and body mass index, in accordance with the proposed 'lipostatic theory'. Current research suggests the existence of a unique inter-relationship between dietary fat, leptin expression and leptin action within the peripheral system. More specifically, it has been demonstrated that polyunsaturated fatty acid (PUFA) intake influences adipose tissue expression of leptin, and of several lipogenic enzymes and transcription factors. In addition, leptin stimulates triglyceride depletion in white adipose tissue without increasing free fatty acid release, thus favouring fatty acids versus glucose as a fuel source. Recent studies suggest that the reduction in adipose hypertrophy observed with n-3 PUFA-containing fish oil feeding might involve a leptin-specific process. A large amount of evidence supports direct functioning of leptin in peripheral lipid metabolism in vivo and in vitro. It is possible that PUFAs will maintain an efficient level of circulating leptin, thus preventing leptin insensitivity and weight gain. There has been much recent progress in clinical leptin research, from energy expenditure to leptin analogue efficacy; the purpose of the present review is to summarize our current understanding of leptin functioning. PMID: 11353336 [PubMed - indexed for MEDLINE] 5101. Curr Opin Lipidol. 2001 Jun;12(3):275-9. Living up to a name: the role of the VLDL receptor in lipid metabolism. Tacken PJ(1), Hofker MH, Havekes LM, van Dijk KW. Author information: (1)Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. The VLDL receptor (VLDLR) is a member of the LDL receptor family. The VLDLR was hypothesized to mediate fatty acid entry into peripheral tissues, on the basis of its expression in tissues that are active in fatty acid metabolism and its capacity to bind apolipoprotein-E-rich VLDL in vitro. This hypothesis initially proved difficult to confirm, because VLDLR-knockout mice were reported to display normal plasma lipid levels. Moreover, studies in VLDLR-knockout mice that were also deficient in a second LDL receptor family member, the apolipoprotein E receptor 2, indicated a role for the VLDLR in neuronal migration during brain development. However, in accordance with what the term VLDLR suggests, recent studies using VLDLR-deficient and transgenic mice have provided compelling evidence that the VLDLR does indeed play a role in VLDL-triglyceride metabolism, and that it is important for triglyceride storage in the adipocyte. PMID: 11353330 [PubMed - indexed for MEDLINE] 5102. Nihon Rinsho. 2001 Feb;59 Suppl 2:520-4. [The clinical significance and the assessment of fat distribution]. [Article in Japanese] Takahashi M(1). Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. PMID: 11351642 [PubMed - indexed for MEDLINE] 5103. Nihon Rinsho. 2001 Feb;59 Suppl 2:504-8. [Adipocytes as endocrine organ--adipocytokines and lipid metabolism]. [Article in Japanese] Takahashi M(1). Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. PMID: 11351639 [PubMed - indexed for MEDLINE] 5104. Nihon Rinsho. 2001 Feb;59 Suppl 2:498-503. [The physiological role of beta 3 adrenergic receptor in adipose tissue]. [Article in Japanese] Togo M(1), Hashimoto Y. Author information: (1)Department of Diabetes and Metabolism, Faculty of Medicine, University of Tokyo. PMID: 11351637 [PubMed - indexed for MEDLINE] 5105. Nihon Rinsho. 2001 Feb;59 Suppl 2:489-97. [The mechanisms by which PPAR gamma regulates fat storage and insulin sensitivity]. [Article in Japanese] Yamauchi T(1), Hara K, Miki H, Kadowaki T. Author information: (1)Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo. PMID: 11351636 [PubMed - indexed for MEDLINE] 5106. Nihon Rinsho. 2001 Feb;59 Suppl 2:483-8. [Molecular mechanism of energy regulation in adipose tissues]. [Article in Japanese] Kishida K(1), Kuriyama H, Funahashi T, Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. PMID: 11351635 [PubMed - indexed for MEDLINE] 5107. Nihon Rinsho. 2001 Feb;59 Suppl 2:421-5. [Role of catecholamines on the regulation of lipid metabolism]. [Article in Japanese] Kawasaki E(1), Eguchi K. Author information: (1)First Department of Internal Medicine, Nagasaki University School of Medicine. PMID: 11351622 [PubMed - indexed for MEDLINE] 5108. Nihon Rinsho. 2001 Feb;59 Suppl 2:259-63. [SREBP1 and fatty acid metabolism]. [Article in Japanese] Sato R(1). Author information: (1)Department of Applied Biological Chemistry, University of Tokyo. PMID: 11351585 [PubMed - indexed for MEDLINE] 5109. Nihon Rinsho. 2001 Feb;59 Suppl 2:21-8. [Triacylglycerol, diacylglycerol, monoacylglycerol]. [Article in Japanese] Shimakata T(1). Author information: (1)Department of Biochemistry, Kawasaki Medical School. PMID: 11351576 [PubMed - indexed for MEDLINE] 5110. Nihon Rinsho. 2001 Feb;59 Suppl 2:205-8. [Hormone sensitive lipase]. [Article in Japanese] Takahashi A(1). Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Tsukuba. PMID: 11351574 [PubMed - indexed for MEDLINE] 5111. Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E827-47. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Frühbeck G(1), Gómez-Ambrosi J, Muruzábal FJ, Burrell MA. Author information: (1)Department of Endocrinology, Clínica Universitaria de Navarra, 31008 Pamplona, Spain. The ability to ensure continuous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-alpha, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. PMID: 11350765 [PubMed - indexed for MEDLINE] 5112. J Nutr Sci Vitaminol (Tokyo). 2001 Feb;47(1):1-12. Biochemical and physiological characteristics of fat cell. Kawada T(1), Takahashi N, Fushiki T. Author information: (1)Laboratory of Nutrition Chemistry, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan. fat@kais.kyoto-u.ac.jp Since animals are under constant threat of starvation, storage of energy sources inside the body is essential for various activities. Therefore, animals exhibit highly sophisticated mechanisms for storing energy inside their bodies in adipose tissue. However, in humans it has been clarified that fat cell (adipocyte, which comprises adipose tissues) differentiation and the extent of subsequent fat accumulation (hypertrophy of cells) are closely associated with the occurrence and advancement of various diseases resulting from obesity. Moreover, progress in biochemical studies with respect to adipocyte in recent years has rapidly clarified new functions and differentiation mechanisms of adipocytes. Interesting points, in particular, are the function of white adipocytes as "secreting cells" and the molecular mechanism of adipocyte differentiation via the nuclear receptors. Consequently, adipose tissue is being targeted to prevent or treat many common diseases. This paper summarizes recent knowledge on characteristics, differentiation and proliferation of adipocytes and the mechanisms by which adipocytes are regulated. PMID: 11349884 [PubMed - indexed for MEDLINE] 5113. Transplantation. 2001 Apr 15;71(7):892-5. Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation. Cauble MS(1), Gilroy R, Sorrell MF, Mailliard ME, Sudan DL, Anderson JC, Wisecarver JL, Balakrishnan S, Larsen JL. Author information: (1)Department of Internal Medicine, University of Nebraska Medical Center, Omaha 63198-3020, USA. BACKGROUND: Lipoatrophic diabetes is an insulin resistance syndrome characterized by the complete or partial lack of adipose tissue and disturbances in lipid and glucose metabolism. Nonalcoholic steatohepatitis (NASH) is a well-described change in liver pathology consisting of steatosis, hepatitis, and fibrosis that can be associated with lipoatrophic diabetes. RESULTS: This article describes the first reported case of lipoatrophic diabetes with NASH leading to liver failure and liver transplantation. Before transplantation, the patient required 600-700 U of insulin/day. After transplantation, a dramatic decline in her insulin requirements was observed, despite corticosteroids. Eighteen months after transplantation, her glycemic control worsened, and she developed recurrent NASH on serial liver biopsies. CONCLUSIONS: NASH associated with lipoatrophic diabetes can recur after liver transplantation, and in this case, was accompanied by increased insulin requirements. These results suggest that the development of NASH itself may contribute to the insulin resistance observed in lipoatrophic diabetes. PMID: 11349722 [PubMed - indexed for MEDLINE] 5114. Diabetes Care. 2001 May;24(5):933-41. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Kelley DE(1), Goodpaster BH. Author information: (1)Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA. Recent evidence derived from four independent methods indicates that an excess triglyceride storage within skeletal muscle is linked to insulin resistance. Potential mechanisms for this association include apparent defects in fatty acid metabolism that are centered at the mitochondria in obesity and in type 2 diabetes. Specifically, defects in the pathways for fatty acid oxidation during postabsorptive conditions are prominent, leading to diminished use of fatty acids and increased esterification and storage of lipid within skeletal muscle. These impairments in fatty acid metabolism during fasting conditions may be related to a metabolic inflexibility in insulin resistance that is not limited to defects in glucose metabolism during insulin-stimulated conditions. Thus, there is substantial evidence implicating perturbations in fatty acid metabolism during accumulation of skeletal muscle triglyceride and in the pathogenesis of insulin resistance. Weight loss by caloric restriction improves insulin sensitivity, but the effects on fatty acid metabolism are less conspicuous. Nevertheless, weight loss decreases the content of triglyceride within skeletal muscle, perhaps contributing to the improvement in Insulin action with weight loss. Alterations in skeletal muscle substrate metabolism provide insight into the link between skeletal muscle triglyceride accumulation and insulin resistance, and they may lead to more appropriate therapies to improve glucose and fatty acid metabolism in obesity and in type 2 diabetes. PMID: 11347757 [PubMed - indexed for MEDLINE] 5115. Nihon Rinsho. 2001 Mar;59 Suppl 3:549-54. [Catabolic substance in human adipose tissue]. [Article in Japanese] Asano T(1). Author information: (1)Asano Institute of Preventive Medicine. PMID: 11347129 [PubMed - indexed for MEDLINE] 5116. World J Surg. 2001 Apr;25(4):516-22. Epub 2001 Apr 11. Whole organ transplantation and glucose regulation. Wideman L(1), Elahi D, Hanks J. Author information: (1)Department of Exercise and Sports Medicine, University of North Carolina-Greensboro, 100 Spring Garden, Greensboro, North Carolina 27412, USA. Pancreas transplantation has gained clinical acceptance since its initial application more than 30 years ago. A constellation of surgical, pharmacologic, and metabolic alterations occur with transplantation, particularly if pancreatic transplantation is performed in addition to renal transplantation in a uremic diabetic. Increasingly sophisticated studies have allowed analysis of the performance of the transplanted organ and have enhanced our basic understanding of insulin's complex interplay in peripheral glucoregulatory processes. PMID: 11344406 [PubMed - indexed for MEDLINE] 5117. World J Surg. 2001 Apr;25(4):461-7. Epub 2001 Apr 11. Overview of glucose regulation. Tirone TA(1), Brunicardi FC. Author information: (1)Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6550 Fannin, Suite 1661, Houston, Texas 77030, USA. Glucose homeokinesis is a remarkable process that provides glucose to the body for energy and a constant source of glucose to the brain while preventing hyperglycemia. The latter leads to excessive glycosylation of proteins, changing their structure and function and eventually affecting every organ system in the body. Despite a variable diet of feast and famine throughout the day, the body maintains strict blood glucose levels through a remarkable network between the pancreas, liver, adipose tissue, muscle, and brain. These interactions and both glucose production and utilization are discussed. Glucose production is governed by the liver, which can generate free glucose from hepatic glycogen stores and de novo through gluconeogenesis. Specific glucose transporters found on every cell of the body administer glucose utilization. Each transporter works with a different serum glucose level. The mechanism of these transporters and the specific glucose cycles are discussed. The purpose of this article is to review glucose regulation; it serves as a reference for the other presentations of this symposium. PMID: 11344399 [PubMed - indexed for MEDLINE] 5118. Trends Pharmacol Sci. 2001 May;22(5):247-54. Pharmacotherapy of obesity: targets and perspectives. Chiesi M(1), Huppertz C, Hofbauer KG. Author information: (1)Cardiovascular and Metabolic Diseases Research, Novartis Pharma AG, CH 4002 Basel, Switzerland. The search for anti-obesity agents has become one of the most exciting areas in drug discovery. Subsequent to an enormous increase in the number of possible molecular targets, the focus has shifted from target identification to target validation. Because important biological functions such as the regulation of energy intake and expenditure are controlled by complex systems, an improved understanding of pathophysiology is a prerequisite for the selection of successful development candidates for the treatment of obesity. Although most of the information on the regulation of energy balance has been obtained from rodents, various monogenic forms of human obesity provide clinical proof of concept for some of these mechanisms. However, it is still not known which are the most promising clinical approaches to lowering body weight and subsequently reducing morbidity and mortality. PMID: 11339976 [PubMed - indexed for MEDLINE] 5119. J Hypertens. 2001 Mar;19(3 Pt 2):523-8. Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). Landsberg L(1). Author information: (1)Northwestern University Medical School, Chicago, Illinois, USA. LLandsbe@nmh.org Thus, the evidence summarized here supports an important role for insulin and the sympathetic nervous system in the pathogenesis of obesity-related hypertension. Is it possible that insulin-mediated sympathetic stimulation contributes a pro-hypertensive effect in non-obese as well? It seems possible in young borderline hypertensives where sympathetically mediated thermogenic mechanisms are potent enough to compensate for the increased caloric intake, thereby enabling these young hypertensives to avoid obesity. This is consistent with an observation made in the original Framingham cohort that not only did obesity predict the eventual development of hypertension, but hypertension, as well, predicted the eventual development of obesity. A reasonable interpretation of these data suggests that as subjects age and the effectiveness of thermogenic mechanisms wanes, obesity might develop as a consequence of increased caloric intake no longer effectively buffered by the increased SNS activity. It is important to note that the mechanisms described here exert a pro-hypertensive effect and cannot properly be considered to 'cause' hypertension. Hypertension is rarely the consequence of a single mechanism. It is also true, as pointed out convincingly by Julius and his colleagues, that enhanced sympathetic activity, as a primary factor, can be associated with both hypertension, insulin resistance and, possibly, obesity [39]. And, finally, it should be noted that the mechanism described here is not the only mechanism linking obesity and hypertension. A rapidly emerging body of evidence indicates that leptin, the polypeptide product of the ob/ob gene secreted from adipose tissue, exerts potent central neural effects on both appetite and sympathetic activity. Leptin levels, elevated in obese humans, have the potential to increase both sympathetic activity and blood pressure [40-43]. A more comprehensive summary of the relationships between hypertension and obesity may, therefore, involve insulin and leptin, as well as the SNS, as represented in the schema presented in Figure 7. Both leptin and insulin may, therefore, be considered as compensatory mechanisms recruited to restore energy balance, with the SNS as one of the effector arms. Viewed in this way, obesity-related hypertension is inextricably linked to the metabolic economy of the obese. PMID: 11327624 [PubMed - indexed for MEDLINE] 5120. Ann Med. 2001 Mar;33(2):79-90. Clustering of metabolic abnormalities in obese individuals: the role of genetic factors. Ukkola O(1), Bouchard C. Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808-4124, USA. The objective of this paper is to review the current evidence in support of genetic factors underlying the clustering of components of the metabolic syndrome in obese individuals. It has become clear that individual features of the metabolic syndrome are partially determined by familial factors some of which are unique to a given component and others that are shared among several features. A few candidate genes, encoding proteins of glucose, insulin and lipid metabolism, lipolytic cascade, fatty acid intestinal absorption, glucocorticoid metabolism, haemostasis and blood pressure, have been associated with a clustering of metabolic abnormalities, although the functional significance of these associations remains to be established. Furthermore, genetic polymorphisms, such as those detected at several lipoprotein metabolism loci, can modulate the relationships between different components of the metabolic syndrome. An overfeeding study conducted on identical twins has demonstrated that genetic factors play an important role in the responsiveness to changing energy balance conditions. Leptin receptor, beta2 adrenergic receptor and glucocorticoid receptor gene polymorphisms have been associated with an augmented clustering of metabolic abnormalities in response to overfeeding. Gene-gene interaction effects between markers of the alpha2A, beta2 and beta3 adrenergic receptor genes on components of the metabolic syndrome have been described. Genetic factors also seem to modify the responsiveness of metabolic syndrome features to endurance training. A growing understanding of the genetic architecture of the metabolic syndrome may help in the prevention of this condition. The reduction of excess body fat, the most common clinical feature among the cluster of metabolic abnormalities, should be the focus of the prevention and treatment of the metabolic syndrome. PMID: 11327119 [PubMed - indexed for MEDLINE] 5121. J Mol Med (Berl). 2001;79(1):8-20. Regulation of leptin production: sympathetic nervous system interactions. Rayner DV(1), Trayhurn P. Author information: (1)Rowett Research Institute, Bucksburn, Aberdeen, Scotland, UK. dvr@rri.sari.ac.uk Leptin is secreted primarily from white adipose tissue and stimulates long-form OB-Rb receptors in the hypothalamus to decrease food intake and increase energy expenditure. A variety of neuropeptides are involved in these responses, including neuropeptide Y, agouti-related protein, the prepro-melanocortin system and cocaine- and amphetamine-regulated transcript. OB-Rb receptors (and other receptor isoforms) are also found in peripheral tissues. Leptin is now known to have a wide range of peripheral actions and is involved in activating the immune system, haematopoiesis, angiogenesis and as a growth factor, as well as being a regulator of many cellular functions. The identification of leptin has led to reappraisal of the role of white adipose tissue from being an organ concerned primarily with energy storage as fat to an understanding that it is also a major endocrine and secretory organ. While the importance of the sympathetic nervous system in mobilising fatty acids from adipose tissue has long been known, it has become apparent that the sympathetic system is a key regulator of leptin production in white adipose tissue as well. Sympathomimetic amines and cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease leptin gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and leptin gene expression, and it is possible that the sympathetic system has a tonic inhibitory action on leptin synthesis. Apart from the few instances where leptin is absent, leptin levels are increased in obesity, while the sympathetic sensitivity of adipose tissue is reduced, consistent with the high leptin levels that are seen. The dysregulation of energy balance leading to obesity may partly involve a decrease in leptin sensitivity, or the leptin system may be set to have maximal effects at low leptin levels. PMID: 11327106 [PubMed - indexed for MEDLINE] 5122. J Mol Med (Berl). 2001;79(1):30-47. The pleiotropic functions of peroxisome proliferator-activated receptor gamma. Debril MB(1), Renaud JP, Fajas L, Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, Parc d'Innovation, CNRS, INSERM, ULP, Illkirch, France. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds that induce peroxisome proliferation. PPARgamma is the best characterized of the PPARs. The heterodimer of PPARgamma with the retinoid X receptor (RXR) plays a crucial role in adipogenesis and insulin sensitization. The RXR/PPARgamma heterodimer furthermore has been reported to have important immunomodulatory activities and to affect cell proliferation/differentiation pathways in various malignancies. PPARgamma is activated by a number of naturally occurring fatty acid derivatives and by several synthetic compounds, including the thiazolidinediones and L-tyrosine-based insulin sensitizers. This review gives an overview of the pleiotropic functions of PPARgamma and discusses the wide-ranging medical implications that modulation of PPARgamma activity might have for various diseases, ranging from obesity and type 2 diabetes to cancer and inflammation. PMID: 11327101 [PubMed - indexed for MEDLINE] 5123. J Mol Med (Berl). 2001;79(1):21-9. The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. Engeli S(1), Sharma AM. Author information: (1)Department of Nephrology and Hypertension, Franz-Volhard-Klinik, Universitätsklinikum Charité, Humboldt Universität, Berlin, Germany. Excessive accumulation of adipose tissue is associated with profound alterations in the cardiovascular system. including an increase in systemic blood pressure. It now appears clear that a central feature of obesity-associated hypertension is related to changes in sodium handling that may result from abnormalities in sympathetic nervous system activity, the renin-angiotensin-aldosterone system, natriuretic peptides, and kidney function. In this paper we review the role of these factors in the development of obesity-associated hypertension, thereby focusing on the potential role of adipose tissue in these alterations. PMID: 11327100 [PubMed - indexed for MEDLINE] 5124. Prostaglandins Other Lipid Mediat. 2001 Apr;64(1-4):1-10. Lysophosphatidic acid synthesis and release. Pagès C(1), Simon MF, Valet P, Saulnier-Blache JS. Author information: (1)INSERM U317, Institut Louis Bugnard, Université Paul Sabatier, CHU Rangueil, Toulouse, France. Lysophosphatidic acid (LPA) is a bioactive phospholipid controlling numerous cellular responses through the activation of specific G-protein coupled transmembrane receptors. LPA is present in several biological fluids (serum, plasma, aqueous humor) and can be secreted by several cell types (platelets, fibroblasts, adipocytes, cancer cells). Whereas, multiple pathways of synthesis and degradation of LPA have been described, their relative contribution in extracellular secretion and biodisponibility is still a matter of debate. The first part of the present review is devoted to the description of the different enzymes involved in LPA synthesis (acyltransferases, phospholipases, kinases) and degradation (lysophospholipases, lipid-phosphatases), as well as to the molecules involved in LPA transport (albumin, fatty acid binding proteins, gelsolin, lipoproteins). In a second part, the different physio-pathological situations (aggregation, cancer, injuries) associated with LPA production, as well as the potential role played by LPA in genesis of certain diseases (cancer, obesity, arteriosclerosis) are listed and analyzed. PMID: 11324699 [PubMed - indexed for MEDLINE] 5125. Crit Rev Biomed Eng. 2001;29(1):77-97. Technical aspects of electromagnetic hyperthermia in medicine. Gel'vich EA(1), Mazokhin VN. Author information: (1)Istok State Research and Manufacturing Enterprise, Fryazino, Moscow Province, Russia. This article considers the fundamental advantages of electromagnetic hyperthermia over different techniques for heating the human being's body. It also presents basic parameters that characterize hyperthermia and electromagnetic techniques for heating biological tissues. Apart from that, engineering solutions directed at providing effective hyperthermia are outlined. PMID: 11321649 [PubMed - indexed for MEDLINE] 5126. Tohoku J Exp Med. 2001 Feb;193(2):79-114. Adrenomedullin from a pheochromocytoma to the eye: implications of the adrenomedullin research for endocrinology in the 21st century. Takahashi K(1). Author information: (1)Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan. ktaka-md@mail.cc.tohoku.ac.jp In the last several decades, the concept of "endocrinology" has been greatly changed. One major change was due to the discovery of peptide hormones secreted by the organs that were not "classical" endocrine organs. For example, corticotropin-releasing hormone and many neuropeptides are secreted by the neurons, atrial natriuretic peptide by the heart, endothelin-1 by the vascular endothelial cells, and leptin by the adipose tissues. Now, the brain, heart, vascular tissue and adipose tissue can be considered to be endocrine organs. Cardiovascular diseases and obesity are therefore important targets of the endocrine research. Adrenomedullin is a potent vasodilator peptide consisting of 52 amino acids. It was originally discovered from a human pheochromocytoma, and belongs to the calcitonin gene-related peptide (CGRP) family. Adrenomedullin is produced and secreted by various types of cells, for example, vascular endothelial and smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, neurons, glial cells, and retinal pigment epithelial cells. Such ubiquitous expression has not been observed in other neuropeptides, including neuropeptide Y and CGRP. Expression of adrenomedullin is induced by hypoxia and proinflammatory cytokines. In addition to vasodilator actions, this peptide has central inhibitory actions on water drinking and salt appetite, effects on the secretion of some hormones and cytokines, inotropic actions and effects on cell growth and apoptosis. Adrenomedullin is produced by various non-endocrine tumors, as well as endocrine tumors, and acts as a growth stimulatory factor for the tumor cells. Adrenomedullin seems to be involved in the pathophysiology of many diseases, including ischemic heart diseases, inflammatory diseases, tumors, and even eye diseases. The adrenomedullin research implies that "the neuroendocrine system" exists in much broader types of cells than previously thought, and that the endocrine research is able to contribute to the understanding of the pathophysiology of many diseases. PMID: 11318031 [PubMed - indexed for MEDLINE] 5127. Nutr Rev. 2001 Feb;59(2):56-7. The uncoupling proteins UCP2 and UCP3 in skeletal muscle. Wolf G(1). Author information: (1)Department of Nutritional Sciences, University of California, Berkeley, 94720-3104, USA. The uncoupling protein UCP1 aids the production of heat by uncoupling respiration from oxidative phosphorylation in brown fat of rodents. UCP1 is down-regulated during starvation to conserve energy. Levels of other uncoupling proteins named UCP2 and UCP3, which are present in skeletal muscle, increase during starvation without changing heat production. Transgenic mice ectopically over-expressing UCP3 lost weight and had less adipose tissue than controls, although they were hyperphagic. It was proposed that muscle UCP3 regulated fat oxidation rather than thermogenesis. PMID: 11310777 [PubMed - indexed for MEDLINE] 5128. Am J Med Sci. 2001 Apr;321(4):215-24. Obesity and coronary heart disease. Alexander JK(1). Author information: (1)Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. Obesity is commonly cited as a risk factor for the development of coronary heart disease (CHD). Epidemiologic studies tend to support this contention, particularly those focusing on patients with central obesity. Such studies however, are imprecise and prone to misclassification bias. Angiographic and post mortem studies have demonstrated little or no correlation of total fat mass and coronary atherosclerosis except in those with abdominal obesity. There is a strong association of obesity, particularly central obesity, and traditional risk factors for CHD such as hypertension, type II diabetes mellitus, and dyslipidemia. There may also be an association between obesity and several nontraditional risk factors such as hyperhomocystinemia, elevated Lp(a) levels and factors that increase thrombogenesis. Obesity may also alter endothelial function. Weight loss, although associated with favorable modification of multiple risk factors for CHD, has not been shown to independently and definitively reduce CHD risk. PMID: 11307863 [PubMed - indexed for MEDLINE] 5129. Ned Tijdschr Geneeskd. 2001 Mar 24;145(12):572-4. [From gene to disease; leptin and obesity]. [Article in Dutch] Pijl H(1), Meinders AE. Author information: (1)Leids Universitair Medisch Centrum, afd. Algemene Interne Geneeskunde, Postbus 9600, 2300 RC Leiden. h.pijl@lumc.nl Homozygous mutations of the ob gene, encoding leptin, are associated with severe obesity, hyperphagia and insulin resistance in humans. Leptin conveys a signal from adipose tissue to hypothalamic nuclei that integrate whole body fuel metabolism, informing those nuclei about the magnitude of fuel reserves. In the absence of leptin, the brain perceives energy availability as insufficient and therefore activates powerful mechanisms to restore fuel depots. If leptin synthesis or signal transduction is perturbed in the presence of food, a severely obese phenotype ensues. PMID: 11293996 [PubMed - indexed for MEDLINE] 5130. Methods Mol Biol. 2001;155:89-96. Glycogen synthase activity in adipose tissue. Methods for freeze-clamping and assay. Ortmeyer HK(1). Author information: (1)Obesity and Diabetes Research Center, University of Maryland School of Medicine, Baltimore, MD, USA. PMID: 11293087 [PubMed - indexed for MEDLINE] 5131. Methods Mol Biol. 2001;155:83-8. Quantification of lipid-related mRNAs by reverse transcription-competitive polymerase chain reaction in human white adipose tissue biopsies. Vidal H(1). Author information: (1)Faculté de Médecine Laennec, INSERM U-449 Lyon, France. PMID: 11293086 [PubMed - indexed for MEDLINE] 5132. Methods Mol Biol. 2001;155:305-21. Measurements of white adipose tissue metabolism by microdialysis technique. Barbe P(1), Darimont C, Saint-Marc P, Galitzky J. Author information: (1)Service d'Endocrinologie-Nutrition and INSERM U-317, Hôpital Rangueil, Toulouse, France. PMID: 11293081 [PubMed - indexed for MEDLINE] 5133. Methods Mol Biol. 2001;155:295-303. Respiratory and thermogenic capacities of cells and mitochondria from brown and white adipose tissue. Cannon B(1), Nedergaard J. Author information: (1)Arrhenius Laboratories F3, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. PMID: 11293080 [PubMed - indexed for MEDLINE] 5134. Methods Mol Biol. 2001;155:281-93. Measurement of adipose tissue blood flow. Bülow J(1). Author information: (1)Department of Clinical Physiology, Bispebjerg Hospital, Copenhagen, Denmark. PMID: 11293079 [PubMed - indexed for MEDLINE] 5135. Methods Mol Biol. 2001;155:269-79. Assessment of white adipose tissue metabolism by measurement of arteriovenous differences. Frayn KN(1), Coppack SW. Author information: (1)Oxford Lipid Metabolism Group, University of Oxford, Oxford, UK. PMID: 11293078 [PubMed - indexed for MEDLINE] 5136. Methods Mol Biol. 2001;155:21-51. Morphologic techniques for the study of brown adipose tissue and white adipose tissue. Cinti S(1), Zingaretti MC, Cancello R, Ceresi E, Ferrara P. Author information: (1)Institute of Normal Human Morphology-Anatomy, School of Medicine, University of Ancona, Ancona, Italy. PMID: 11293073 [PubMed - indexed for MEDLINE] 5137. Methods Mol Biol. 2001;155:193-6. Metabolite and ion fluxes and ion channels in brown and white adipocytes. Nedergaard J(1). Author information: (1)Arrhenius Laboratories F3, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. PMID: 11293071 [PubMed - indexed for MEDLINE] 5138. Methods Mol Biol. 2001;155:121-7. Assays of lipogenic enzymes. Bazin R(1), Ferré P. Author information: (1)Institut Biomédical des Cordeliers, INSERM U-465, Paris, France. PMID: 11293064 [PubMed - indexed for MEDLINE] 5139. Trends Mol Med. 2001 Mar;7(3):121-6. Molecular basis of partial lipodystrophy and prospects for therapy. Hegele RA(1). Author information: (1)Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8. robert.hegele@rri.on.ca Lipodystrophy is characterized by altered partition of adipose tissue. Despite heterogeneous causes, which include genetic, autoimmune and drug-induced forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes. The mechanisms underlying the insulin resistance are unknown. One form of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD) was shown to result from mutations in the LMNA gene, which encodes nuclear lamins A and C. Although the relationship between the mutations in the nuclear envelope and insulin resistance is unclear at present, these findings might eventually be shown to have relevance for the common insulin resistance syndrome and for drug-associated lipodystrophies. PMID: 11286783 [PubMed - indexed for MEDLINE] 5140. Nutr Rev. 2001 Jan;59(1 Pt 1):1-9. The insulin resistance epidemic in India: fetal origins, later lifestyle, or both? Yajnik CS(1). Author information: (1)Diabetes Unit, King Edward Memorial Hospital & Research Center, Rasta Peth, Pune, India. In India there is a rapidly escalating epidemic of insulin resistance syndrome (diabetes and coronary heart disease). Contribution of genes and environment is under debate. Small size at birth coupled with subsequent obesity increases risk for insulin resistance syndrome in later life. The tendency of Indians to have higher body fat and central adiposity compared with other races may be programmed in utero. The adipose tissue releases not only fatty acids but also a number of proinflammatory cytokines, which increase insulin resistance and cause endothelial dysfunction. Crowding, infections, and environmental pollution in Indian cities may increase cardiovascular risk by stimulating fat cells. Prevention of diabetes and coronary heart disease in India will have to be approached throughout the life cycle. PMID: 11281246 [PubMed - indexed for MEDLINE] 5141. Med Wieku Rozwoj. 2001 Jan-Mar;5(1):17-26. [The role of leptin in human obesity]. Szymczak E(1), Laskowska-Klita T. Author information: (1)Zaklad Biochemii i Diagnostyki Laboratoryjnej, Instytut Matki i Dziecka, Kasprzaka 17a, 01-211, Warszawa, Poland. The mechanism involved in body mass regulation in humans includes genetic, environmental, and behavioural factors. Human obesity is usually associated with a positive energy balance. Genetic studies in obese mice have revealed the Ob. gene, its products leptin and the leptin receptor to be important factors in the regulation of both appetite and energy expenditure. Leptin is a 16-kilodaltons adipocyte-derived hormone -which circulates in the serum as the free and bound forms. The leptin serum level reflects the amount of energy stored in adipose tissue. Leptin acts through the leptin receptor, -which belongs to the cytokine - receptor family. In rodents as well as in humans, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia, and reduced energy expenditure. Recent studies have demonstrated that Ob. gene expression is increased in human obesity. However, mutations of Ob. gene present in the mouse are rare in the human population. PMID: 11276500 [PubMed - indexed for MEDLINE] 5142. Curr Hypertens Rep. 2001 Apr;3(2):152-6. New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Sharma AM(1), Engeli S, Pischon T. Author information: (1)Department of Nephrology and Hypertension, Franz-Volhard-Klinik, Universitätsklinikum Charité, Humboldt-University zu Berlin, Wiltbergstr. 50, 13125 Berlin, Federal Republic of Germany. sharma@fvk.berlin.de Hypertension develops in almost 60% of obese individuals. Apart from the recent observation of obesity-associated structural changes in kidney structure that may lead to enhanced tubular sodium reabsorbtion, reports of paracrine and hormonal factors derived from adipose tissue have prompted speculations about the role of adipose tissue in the pathophysiology of obesity-induced hypertension. We summarize recent data on leptin's sympathoexcitatory actions, the possible influence of adipose tissue on atrial natriuretic peptide levels, and the formation of vasoactive substances, such as angiotensin II and nonesterified fatty acids, by adipocytes. The mechanisms discussed herein may contribute to the typical findings in obesity-induced hypertension, including volume expansion, sodium retention, enhanced sympathetic nervous system activity, increased activity of the systemic renin-angiotensin system, low atrial natriuretic peptide levels, and disturbed glucose and insulin metabolism. Together, these data strengthen the hypothesis that adipose tissue is potentially a major regulator of cardiovascular-renal function. PMID: 11276398 [PubMed - indexed for MEDLINE] 5143. AIDS. 2001 Feb 16;15(3):413-5. Mitochondrial toxicity hypothesis for lipoatrophy: a refutation. Moyle G(1). Author information: (1)Chelsea and Westminster Hospital, London, UK. Comment in AIDS. 2001 Jul 27;15(11):1450-2. PMID: 11273222 [PubMed - indexed for MEDLINE] 5144. J Clin Pathol. 2001 Jan;54(1):1-3. Leptin: of mice and men? Bowles L(1), Kopelman P. Author information: (1)Department of Diabetes and Metabolic Medicine, St Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Turner Street, London E1 2AD, UK. A major advance in the understanding of the control of appetite, food intake, and energy expenditure came with the discovery of leptin. Leptin concentrations correlate with adipose tissue mass, and leptin acts via the central nervous system (CNS) to reduce food intake and increase energy expenditure. A variety of different neurotransmitters have been implicated in mediating the CNS effects of leptin. In humans, leptin deficiency is unlikely to be a major cause of obesity. Most humans are not leptin deficient, but have a leptin concentration raised in proportion to their fat mass. A recent clinical trial looking at the use of recombinant leptin in treating human obesity has resulted in only variable amounts of weight loss. The role of leptin extends beyond the control of food intake and energy expenditure. Leptin reverses many of the physiological responses to starvation. It is suggested that the main role of leptin might be in response to food deprivation and not in obesity. PMCID: PMC1731273 PMID: 11271782 [PubMed - indexed for MEDLINE] 5145. Nihon Rinsho. 2001 Mar;59(3):515-20. [Mechanisms of cancer-induced anorexia]. [Article in Japanese] Noguchi Y(1), Yoshikawa T. Author information: (1)Department of Surgery, Yokohama City Kowan Hospital. Possible mediators of anorexia-cachesia syndrome are hormones, cytokines, and leptin at the peripheral tissues, and neuropeptides, cytokines, and hormones in the hypothalamus. Insulin resistance and relative hyper-glucagonemia might stimulate anorexia. Interleukin(IL)-6, and tumor necrosis factor(TNF)-alpha as well as IL-1 and leukemia inhibitory factor(LIF) are some of those cytokines. Although leptin in the adipose tissue is an attractive addition, changes in the tumor-bearing state does not support its active role in the induction of anorexia. Newer neuropeptides related with anorexia and oxygenia have been found in the hypothalamus. Hypothalamic neuropeptide Y(NPY) and ciliary neurotropic factor(CNTF) are some of those promising mediators. Although current trend has been progestational drugs, newer drugs such as anticytokines, anabolic agents, and neuropeptide agonists/antagonists are now under investigations. PMID: 11268601 [PubMed - indexed for MEDLINE] 5146. Nihon Rinsho. 2001 Mar;59(3):481-6. [Molecular mechanism in the development of the complications associated with obesity--the physiological and pathological role of adipocytokines]. [Article in Japanese] Hotta K(1), Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. Visceral fat accumulation often accompanies various complications, such as insulin resistance, hypertension, dyslipidemia and atherosclerosis. Adipose tissue has been found to secrete various biologically active adipocytokines including free fatty acids. Accumulation of visceral fat increases the portal free fatty acids concentration to cause insulin resistance and dyslipidemia. Tumor necrosis alpha (TNF alpha) deteriorates insulin resistance in obesity. The levels of plasminogen activator inhibitor(PAI)-1 increase and plasma adiponectin concentration decreases in obesity leading to the development of vascular disease. The finding of genes specifically expressed in visceral fat and new adipocytokines should facilitate clarification of the mechanism for the development and complications of visceral fat accumulation. PMID: 11268596 [PubMed - indexed for MEDLINE] 5147. Nihon Rinsho. 2001 Mar;59(3):472-80. [Pathology and significance of leptin resistance in obesity]. [Article in Japanese] Hidaka S(1), Ogawa Y, Ebihara K, Shintani M, Abe M, Miyanaga F, Nakao K. Author information: (1)Department of Clinical Science and Medicine, Kyoto University Graduate School of Medicine. Leptin, the protein product of the ob gene, is predominantly secreted from white adipose tissue, and acts on the brain to regulate food intake, energy expenditure, and neuroendocrine function. Obese rodent and humans are mostly associated with high circulating leptin levels. These findings have led to the conclusion that obese individuals are relatively insensitive to endogenous leptin termed 'leptin resistance'. The potential sites for leptin resistance include the blood-brain-barrier transport system and the leptin signaling mechanism in leptin-responsive neurons in the hypothalamus. In this review, we describe leptin, leptin receptor, and potential hypothesis of leptin resistance. PMID: 11268595 [PubMed - indexed for MEDLINE] 5148. Nihon Rinsho. 2001 Mar;59(3):456-65. [Distorted control of feeding behavior induced by abnormally regulated peripheral energy metabolism]. [Article in Japanese] Yoshimatsu H(1), Sakata T. Author information: (1)Department of Internal Medicine 1, School of Medicine, Oita Medical University. To regulate feeding behavior and energy metabolism, a variety of neuronal and hormonal messages are integrated by glucose sensing system located in peripheral organ and central nervous system. Among them, a hepatoportal glucose sensor plays a major role in perception of peripheral humoral information such as brain-gut peptides and cytokines. These signals are transmitted to the hypothalamus through the hepatic afferent vagus nerve and the nucleus of the solitary tract. Recent molecular approaches using knock out or transgenic mice have indicated important effects of peripheral energy metabolism on feeding control. Particularly, fatty acid metabolism in the liver and functions of uncoupling protein family in the brown adipose tissue and the muscle play an essential role as detector for energy storage, and in turn may be contributable to regulation of feeding behavior. PMID: 11268593 [PubMed - indexed for MEDLINE] 5149. Nihon Rinsho. 2001 Mar;59(3):437-42. [The relationship between beta 3-adrenoceptor and regulation of body fat mass, and food intake]. [Article in Japanese] Yoshida T(1), Takakura Y, Sakane N. Author information: (1)First Department of Internal Medicine, Kyoto Prefectural University of Medicine. beta 3-adrenoceptor(beta 3-AR) plays important roles in thermogenesis of brown adipose tissue(BAT) and lypolysis of white adipose tissue(WAT). Anti-obesity effect of beta 3-agonists is reported, and the Trp64Arg point mutation of the human beta 3-AR gene is associated with abdominal obesity. beta 3-agonist decreases food intake in rat and mice, and its effect is confirmed by both direct infusions to the brain and peripheral injections. Stimulated thermogenesis of BAT increases glucose utilization, then 'glucose dip' signals meal initiation. Risen core temperature leads to meal termination. But, because of decreased ability for thermogenesis, meal size increases in many obese animal models. Further investigations are being carried out to make these problems clear. PMID: 11268590 [PubMed - indexed for MEDLINE] 5150. Nihon Rinsho. 2001 Mar;59(3):421-6. [Role of leptin and its receptor in the regulation of appetite and body fat]. [Article in Japanese] Shimizu H(1), Mori M. Author information: (1)First Department of Internal Medicine, Gunma University School of Medicine. The role of leptin and its receptor on the regulation of appetite and body fat was summarized. Leptin directly exerts its anorexigenic effects on arcuate nucleus via proopiomelanocortin and neuropeptide Y neurons. The anorexia and sympathetic nerve activation result in the reduction of body fat. But physiological concentrations of leptin could not reduce body fat in obese people, while genetic loss of central leptin effects induces obesity in children. Melanin concentrating hormone, orexin, and corticotropin-releasing hormone may be directly regulated by leptin. Serotonergic neurons may be separate from leptin effects. Phosphorylation of 985- and 1138-tyrosine of long-form leptin receptor activates SHP-2 and STAT3, respectively. Soluble leptin receptor concentrations in serum are negatively correlated with BMI. Clinical usefulness of leptin is now in progress. PMID: 11268587 [PubMed - indexed for MEDLINE] 5151. Ann N Y Acad Sci. 2000;917:647-57. Cytokines, leptin, and the hypothalamo-pituitary-adrenal axis. Gaillard RC(1), Spinedi E, Chautard T, Pralong FP. Author information: (1)Division of Endocrinology, Diabetology and Metabolism, Department of Medicine, University Hospital (CHUV), CH-1011 Lausanne, Switzerland. Rolf-Christian.Gaillard@chuv.hospvd.ch The endocrine and immune systems are linked via an elaborated communication system constituted by an array of cytokines and neuropeptides which interact to modulate the integrated response of an organism to infection. Weight loss and anorexia, probably secondary to cytokine release, frequently accompany infection, but leptin could also play a role. Like cytokines, leptin serves as a peripheral messenger to convey signals to the brain. Expression of leptin is stimulated by glucocorticoids, endotoxins, and cytokines; on the other hand, leptin seems to inhibit the activation of the hypothalmo-pituitary-adrenal (HPA) axis. Indeed leptin exerts a direct, dose-dependent inhibition of stimulated cortisol secretion by normal human and rat adrenal cells in vitro. These effects are mediated by the long isoform of the leptin receptor, because its transcript is expressed in the adrenal tissue. In addition we investigated the role played by the glucocorticoids in the development of tolerance of the hypothalamo-corticotropic, immune and adipose system responses to repeated endotoxin administration. Unlike that of the corticotropic axis, tolerance of the immune and adipose systems is at least partially glucocorticoid-independent. This crosstalk between the endocrine, immune, and adipose systems may be of prime importance to homeostasis in pathophysiological events occurring during infection. PMID: 11268393 [PubMed - indexed for MEDLINE] 5152. Pharmacogenomics. 2000 May;1(2):179-85. Human adipocyte proteomics--a complementary way of looking at fat. Halvorsen YD(1), Wilkison WO, Briggs MR. Author information: (1)Zen-Bio Inc, Research Triangle Park, NC 27709, USA. yuan-di@zen-bio.com PMID: 11256589 [PubMed - indexed for MEDLINE] 5153. Dtsch Med Wochenschr. 2001 Mar 2;126(9):241-6. [Some may feel hot: significance of thermogenesis for energy metabolism and the treatment of obesity]. [Article in German] Hamann A(1), Münzberg H, Tafel J, Ziegler R. Author information: (1)Abteilung Innere Medizin I, Medizinische Klinik und Poliklinik, Universität Heidelberg. andreas_hamann@med.uni-heidelberg.de PMID: 11256039 [PubMed - indexed for MEDLINE] 5154. Am J Physiol Endocrinol Metab. 2001 Apr;280(4):E549-53. Adverse metabolic consequences of HIV protease inhibitor therapy: the search for a central mechanism. Hruz PW(1), Murata H, Mueckler M. Author information: (1)Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Although the clinical introduction of human immunodeficiency virus (HIV) protease inhibitors (PIs) has resulted in a dramatic decline in HIV-related morbidity and mortality, it is now recognized that PI therapy is associated with serious adverse metabolic effects, including peripheral lipoatrophy, increased visceral fat, hyperlipidemia, and insulin resistance. Despite increasing awareness of this metabolic syndrome, the etiology of these side effects remains obscure. This review critically examines current mechanistic hypotheses in the context of the available experimental data. To date, a single unifying explanation for this syndrome has not been confirmed. As data accumulate, it is becoming clear that PIs lack precision in their cellular targets and it is likely that many of the side effects of these drugs are due to inhibition of a number of unrelated molecules. PMID: 11254460 [PubMed - indexed for MEDLINE] 5155. Endocrinology. 2001 Apr;142(4):1371-6. Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Seckl JR(1), Walker BR. Author information: (1)Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. J.Seckl@ed.ac.uk 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) catalyze the interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11beta-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11beta-HSD type 1 has, until recently, been little understood. 11beta-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11beta-HSD1 acts as a predominant 11beta-reductase in many intact cells, whole organs, and in vivo. This reaction direction locally regenerates active glucocorticoids within expressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reaction direction are not fully understood, insights to its biological importance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11beta-HSD1 effectively amplifies glucocorticoid action at least in the liver, adipose tissue, and the brain. Inhibition of 11beta-HSD1 represents a potential target for therapy of disorders that might be ameliorated by local reduction of glucocorticoid action, including type 2 diabetes, obesity, and age-related cognitive dysfunction. PMID: 11250914 [PubMed - indexed for MEDLINE] 5156. Environ Health Perspect. 2001 Mar;109 Suppl 1:35-47. Pesticides and breast cancer risk: a review of DDT, DDE, and dieldrin. Snedeker SM(1). Author information: (1)Program on Breast Cancer and Environmental Risk Factors in New York State, Cornell University, Ithaca, New York 14853, USA. sms31@cornell.edu Established risk factors for breast cancer explain breast cancer risk only partially. Hence, there has been interest in evaluating what role environmental chemicals, especially those with evidence of being hormonally active agents, play in breast cancer risk. Organochlorine pesticides have received the most attention because of their persistence in the environment, ability to concentrate up the food chain, continued detection in the food supply and breast milk, and ability to be stored in the adipose tissue of animals and humans. Although several early descriptive studies and a cohort study identified a strong positive association with breast cancer risk and adipose or blood levels of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and/or its metabolite dichlorodiphenyldichloroethylene (DDE), most of the more recent case--control and nested case--control studies have not supported this association. In this review I discuss these findings and explore how exposure to different forms of DDT with varying estrogenicities may have affected the results of these studies. I also address how other factors influence the interpretation of the studies on DDT, DDE, and breast cancer risk. These include the effect of analytic methods, dietary factors, menopausal status, use of different types of control populations, lactation history, estrogen receptor status, ethnic/racial subgroups, breast tumor characteristics, and polymorphisms. I also discuss the emerging research on whether serum levels of the persistent organochlorine insecticide dieldrin are related to breast cancer risk in Danish and American women. Further research needs are also identified. PMCID: PMC1240541 PMID: 11250804 [PubMed - indexed for MEDLINE] 5157. Horm Metab Res. 2000 Nov-Dec;32(11-12):526-36. Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women. Tchernof A(1), Després JP. Author information: (1)Molecular Endocrinology Laboratory and Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Québec, Canada. Andre.tchernof@crchul.ulaval.ca Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk. PMID: 11246820 [PubMed - indexed for MEDLINE] 5158. Horm Metab Res. 2000 Nov-Dec;32(11-12):504-8. Fat cell function and fibrinolysis. Alessi MC(1), Morange P, Juhan-Vague I. Author information: (1)Laboratory of Hematology, Faculty of Medicine, CHU Timone, Marseille, France. Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and may be the principal regulator of plasminogen activation in vivo. PAI-1 levels are elevated in insulin-resistant subjects and are associated with an increased risk of atherothrombosis. After adjustment for metabolic parameters, increased PAI-1 levels were no longer considered as a cardiovascular risk factor. The mechanisms underlying the strong association between PAI-1 levels and the metabolic disturbances found in insulin resistance are still not understood. Several studies have suggested that visceral adipose tissue may be a major source of PAl-1. Accordingly, adipose tissue PAI-1 production particularly that from visceral fat, was found to be elevated in obese human subjects. Within human adipose tissue, stromal cells appear to be the main cells involved in PAI-1 synthesis. This review discusses the potential mechanisms linking adipose tissue to plasma PAI-1 levels such as the intervention of cytokines (TNFalpha and TGFbeta), free fatty acids and hormones (insulin and glucocorticoids). Moreover alteration of adipose tissue cellular composition induced by the modulation of PAI-1 expression opens a novel field of interest. PMID: 11246816 [PubMed - indexed for MEDLINE] 5159. Horm Metab Res. 2000 Nov-Dec;32(11-12):485-99. Role of adipose tissue for cardiovascular-renal regulation in health and disease. Engeli S(1), Sharma AM. Author information: (1)Franz-Volhard-Klinik at the Max-Delbrück-Center for Molecular Medicine, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Germany. Obesity is associated with profound alterations of the cardiovascular system including an increase in systemic blood pressure. Several vasoactive factors, including non-esterified fatty acids, angiotensin II, prostaglandins, and nitric oxide are known to be produced by adipose tissue, and are therefore of particular interest regarding their potential role for the regulation of vascular tone and structure. In addition, central nervous system actions of the adipose tissue-derived hormone leptin may contribute to increased sympathetic nervous system activity that is typically found in obesity. Enhanced leptin-driven renal sympathetic out-flow, in combination with low atrial natriuretic peptide plasma levels possibly due to over-expression of the natriuretic peptide clearance receptor in adipocytes, may enhance sodium retention and volume expansion, both key features in the pathophysiology of obesity-associated hypertension. In this review, we discuss these and other possible contributions of adipose tissue to the regulation of cardiovascular-renal function and speculate on the role of adipose tissue for the development of obesity-associated hypertension. PMID: 11246814 [PubMed - indexed for MEDLINE] 5160. Horm Metab Res. 2000 Nov-Dec;32(11-12):468-74. TSH receptor in adipose cells. Sorisky A(1), Bell A, Gagnon A. Author information: (1)Department of Medicine, Loeb Health Research Institute, Ottawa Hospital, University of Ottawa, ON, Canada. asorisky@Lri.ca Although there have been reports supporting the presence of the TSH receptor (TSHR) in human adipose tissue, these findings are still not universally accepted. Contributing to the controversy is a paucity of data about the physiological role the TSH receptor might play in adipose cells. In addition to mature lipid-filled adipocytes, adipose tissue also harbors a pool of specialized, fibroblast-like preadipocytes within the stromal-vascular compartment. Upon appropriate induction, preadipocytes can either differentiate into adipocytes or undergo apoptosis. Since TSHR has been detected in preadipocytes and adipocytes, its potential impact on adipose tissue function may relate to differentiation stage-specific cellular properties. PMID: 11246811 [PubMed - indexed for MEDLINE] 5161. Horm Metab Res. 2000 Nov-Dec;32(11-12):453-67. The endocrine function of the fat cell-regulation by the sympathetic nervous system. Lawrence VJ(1), Coppack SW. Author information: (1)Department of Diabetes and Metabolic Medicine, St. Bartholomews and the Royal London School of Medicine and Dentistry, UK. v.j.lawrence@mds.qmw.ac.uk The landmark discovery of leptin established beyond question the fact that adipose tissue is a crucial active regulator of body weight, an endocrine organ in its own right and part of a feedback circuit possessing both afferent and efferent loops. This is in addition to its more established roles as a receiver of incoming endocrine signals and modulator of circulating hormones such as sex steroids. Since this discovery, much has been learned about the role of leptin in the afferent loop of the hypothalamic regulation of body weight and indeed about some of the neuro-endocrine circuitry involved in the regulation of appetite and weight. Much less, however, is known about the efferent limb of the circuit, specifically relating to how the hypothalamus is able to influence adipocyte behaviour and how this link may itself be influenced by endocrine and paracrine signals, both acting on and emanating from adipocytes themselves, acting at multiple levels. This review will focus on the role of the sympathetic nervous system (SNS) and adreno-medullary system in relation to the regulation of adipose tissue physiology and endocrine function. The evidence in support of the hypothesis that the SNS is a crucial mediator of the efferent loop of this feedback circuit will be considered. PMID: 11246810 [PubMed - indexed for MEDLINE] 5162. Horm Metab Res. 2000 Nov-Dec;32(11-12):443-52. Millennium fat-cell lipolysis reveals unsuspected novel tracks. Langin D(1), Lucas S, Lafontan M. Author information: (1)INSERM unit 317, Institut Louis Bugnard, H pital Rangueil, Université Paul Sabatier, Toulouse, France. langin@rangueil.inserm.fr Adipose tissue lipolysis, i.e., the catabolic process leading to the breakdown of triglycerides into fatty acids and glycerol, is often considered as a simple and well-understood metabolic pathway. However, progress on the hormonal regulation and molecular mechanism of fat-cell lipolysis is opening new avenues and points to a number of unanswered questions. Recent studies on the lipolytic beta- and antilipolytic alpha2-adrenergic control of lipolysis has allowed a better understanding of the relative contribution of the two types of receptors and provide strong evidence for the in vivo implication of alpha2-adrenoceptors in the physiological control of subcutaneous adipose-tissue lipolysis. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. The molecular details of the lipolytic reaction are not fully understood. Translocation of hormone-sensitive lipase, the rate-limiting enzyme of lipolysis, to the lipid droplet seems to be an important step during lipolytic activation. Reorganization of the lipid droplet coating by perilipins may also facilitate the access of the enzyme. Unexpectedly, hormone-sensitive lipase-deficient mice are not obese and show residual adipose-tissue lipolysis, which suggests the existence of another triglyceride lipase. Whether the expression of this uncharacterized neutral lipase is compensatory for the lack of hormone-sensitive lipase is an important question yet to be resolved. In humans, alterations of hormone-sensitive lipase expression are associated with changes in lipolysis in various physiological and pathological states. Genetic studies show that beta2-adrenoceptor and hormone-sensitive lipase genes may participate in the polygenic background of obesity. PMID: 11246809 [PubMed - indexed for MEDLINE] 5163. Endocr Pract. 2000 Jul-Aug;6(4):318-23. Amyloid goiter: report of two cases and review of the literature. Goldsmith JD(1), Lai ML, Daniele GM, Tomaszewski JE, LiVolsi VA. Author information: (1)Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA. OBJECTIVE: To describe two recent cases of amyloid goiter that occurred in two patients with a history of diffuse enlargement of the thyroid gland, progressing over several years' time. METHODS: We reviewed the medical histories as well as the histologic, immunohistochemical, and electron microscopic findings in these patients. RESULTS: Assessment of the clinical records of a 59-year-old man and a 64-year-old woman revealed histories that included chronic psoriasiform arthritis and asthma in conjunction with chronic obstructive pneumonia and bronchiectasis. In both cases, total thyroidectomy was performed. On histologic examination of both thyroid glands, the appearance was characterized by moderate to severe distortion of the normal thyroid architecture by amyloid in a perifollicular distribution and focally abundant interfollicular adipose tissue. In both cases, the amyloid stained intensely positive with Congo red, which bleached after treatment with potassium permanganate. Immunohistochemical staining patterns were consistent with AA amyloid, and electron microscopy showed nonbranching 9-nm fibrils consistent with amyloid. CONCLUSION: The diagnosis of amyloid goiter should be suspected in patients with a diffusely enlarging thyroid gland and an appropriate clinical history. PMID: 11242609 [PubMed - indexed for MEDLINE] 5164. Br J Nutr. 2000 Dec;84 Suppl 2:S223-7. Peroxisome proliferator-activated receptor gamma, the ultimate liaison between fat and transcription. Rocchi S(1), Auwerx J. Author information: (1)Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP, BP 163, F-67404 Illkirch cedex, C.U. de Strasbourg, France. The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes. PMID: 11242474 [PubMed - indexed for MEDLINE] 5165. Br J Nutr. 2000 Nov;84 Suppl 1:S47-53. Occurrence and biochemical characteristics of natural bioactive substances in bovine milk lipids. Molkentin J(1). Author information: (1)Institute for Chemistry and Physics, Federal Dairy Research Centre, Kiel, Germany. molkentin@bafm.de Bovine milk lipids (BML) contain a number of bioactive substances with positive as well as negative properties, mainly in the class of fatty acids. Besides trans fatty acids (TFA), conjugated linoleic acids (CLA) are of particular interest. Apart from ruminant meat products the main source of CLA in food are BML. Although TFA as well as saturated fatty acids (12:0-16:0) are thought to be positively correlated with atherosclerosis and coronary heart disease, CLA are considered antiatherogenic. Further, CLA are reported to reduce adipose fat and to have anticarcinogenic properties. The varying CLA and TFA contents of lipids from milk and dairy products are positively correlated with one another. However, TFA are also negatively correlated with 12:0-16:0 in BML. Anticarcinogenic effects are also ascribed to butyric acid as well as to some phospholipids and ether lipids present in BML. Moreover, the essential fatty acids 18:2n-6 and 18:3n-3 are found in BML which are involved in a variety of biochemical processes and thus have numerous functions in human metabolism. Contents of the individual bioactive components of BML are summarised taking into account also seasonal variations. The total content of bioactive substances in BML is approximately 75 % but their overall impact on human health considering benefits and drawbacks is difficult to assess. PMID: 11242446 [PubMed - indexed for MEDLINE] 5166. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):19-26. Age-related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians. Barbieri M(1), Rizzo MR, Manzella D, Paolisso G. Author information: (1)Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, I-80138 Naples, Italy. It is widely known that advancing age is associated with impaired glucose handling. A unifying hypothesis explaining the relationship between aging and insulin resistance might encompass four main pathways, namely: (a) anthropometric changes (relative and absolute increase in body fat combined with a decline in fat free mass) which could be the anatomic substrate for explaining the reduction in active metabolic tissue; (b) environmental causes, mainly diet style and physical activity; (c) neuro-hormonal variations [decline in plasma dehydroepandrosterone sulphate (DHEAS) and IGF-1]; and finally (d) the rise in oxidative stress. Indeed previous studies have also investigated the occurrence and the degree of insulin resistance in healthy centenarians. Such data demonstrated that age-related insulin resistance is not an obligatory finding in the elderly and that healthy centenarians have a preserved insulin action compared to aged subjects. Why insulin action is preserved in centenarians is still not known. Nevertheless, a possible approach to the question is to outline the centenarians' anthropometric, endocrine and metabolic characteristics in order to design a clinical picture of such metabolic "successful aging". According to the remodeling theory of age, the preserved insulin action in centenarians might be the net result of the continuous adaptation of the body to the deleterious changes that occur over time. Nevertheless, only future longitudinal studies specifically designed to investigate the relationship between extreme old age and degree of insulin sensitivity will provide a conclusive answer with regard to the pathophysiology of adaptive metabolic changes occurring in the elderly. Copyright 2001 John Wiley & Sons, Ltd. PMID: 11241888 [PubMed - indexed for MEDLINE] 5167. Biochim Biophys Acta. 2001 Mar 1;1504(1):159-72. Mitochondrial efficiency: lessons learned from transgenic mice. Harper ME(1), Himms-Hagen J. Author information: (1)Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ont., Canada K1H 8M5. mharper@uottawa.ca Metabolic research has, like most areas of research in the life sciences, been affected dramatically by the application of transgenic technologies. Within the specific area of bioenergetics it has been thought that transgenic approaches in mice would provide definitive proof for some longstanding metabolic theories and assumptions. Here we review a number of transgenic approaches that have been used in mice to address theories of mitochondrial efficiency. The focus is largely on genes that affect the coupling of energy substrate oxidation to ATP synthesis, and thus, mice in which the uncoupling protein (Ucp) genes are modified are discussed extensively. Transgenic approaches have indeed provided proof-of-concept in some instances, but in many other instances they have yielded results that are in contrast to initial hypotheses. Many studies have also shown that genetic background can affect phenotypic outcomes, and that the upregulated expression of genes that are related to the modified gene often complicates the interpretation of findings. PMID: 11239492 [PubMed - indexed for MEDLINE] 5168. Biochim Biophys Acta. 2001 Mar 1;1504(1):128-43. Uncoupling proteins: the issues from a biochemist point of view. Klingenberg M(1), Echtay KS. Author information: (1)Institut für Physiologische Chemie der Universität München, Schillerstrasse 44, D-80336 Munich, Germany. klingenberg@pbm.med.uni-muenchen.de The functional characteristics of uncoupling proteins (UCP) are reviewed, with the main focus on the results with isolated and reconstituted proteins. UCP1 from brown adipose tissue, the paradigm of the UCP subfamily, is treated in more detail. The issues addressed are the role and mechanism of fatty acids, the nucleotide binding, the regulation by pH and the identification by mutagenesis of residues involved in these functions. The transport and regulatory functions of UCP2 and 3 are reviewed in comparison to UCP1. The inconsistencies of a proposed nucleotide insensitive H(+) transport by these UCPs as concluded from the expression in yeast and Escherichia coli are elucidated. In both expression system UCP 2 and 3 are not in or cannot be converted to a functionally native state and thus also for these UCPs a nucleotide regulated H (+) transport is postulated. PMID: 11239490 [PubMed - indexed for MEDLINE] 5169. Biochim Biophys Acta. 2001 Mar 1;1504(1):120-7. Mitochondrial proton leak: a role for uncoupling proteins 2 and 3? Porter RK(1). Author information: (1)Department of Biochemistry, Trinity College Dublin, Dublin 2, Ireland. rkporter@tcd.ie In mitochondria ATP synthesis is not perfectly coupled to oxygen consumption due to proton leak across the mitochondrial inner membrane. Quantitative studies have shown that proton leak contributes to approximately 25% of the resting oxygen consumption of mammals. Proton leak plays a role in accounting for differences in basal metabolic rate. Thyroid studies, body mass studies, phylogenic studies and obesity studies have all shown that increased mass-specific metabolic rate is linked to increased mitochondrial proton leak. The mechanism of the proton leak is unclear. Evidence suggests that proton leak occurs by a non-specific diffusion process across the mitochondrial inner membrane. However, the high degree of sequence homology of the recently cloned uncoupling proteins UCP 2 and UCP 3 to brown adipose tissue UCP 1, and their extensive tissue distribution, suggest that these novel uncoupling proteins play a role in proton leak. Early indications from reconstitution experiments and several in vitro expression studies suggest that the novel uncoupling proteins uncouple mitochondria. Furthermore, mice overexpressing UCP 3 certainly show a phenotype consistent with increased metabolism. The evidence for a role for these novel UCPs in mitochondrial proton leak is reviewed. PMID: 11239489 [PubMed - indexed for MEDLINE] 5170. Biochim Biophys Acta. 2001 Mar 1;1504(1):107-19. Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. Bouillaud F(1), Couplan E, Pecqueur C, Ricquier D. Author information: (1)CEREMOD, C.N.R.S., UPR 9078, 9 rue Jules Hetzel, 92190 Meudon, France. bouillau@infobiogen.fr PMID: 11239488 [PubMed - indexed for MEDLINE] 5171. Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Nedergaard J(1), Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se The uniqueness of UCP1 (as compared to UCP2/UCP3) is evident from expression analysis and ablation studies. UCP1 expression is positively correlated with metabolic inefficiency, being increased by cold acclimation (in adults or perinatally) and overfeeding, and reduced in fasting and genetic obesity. Such a simple relationship is not observable for UCP2/UCP3. Studies with UCP1-ablated animals substantiate the unique role of UCP1: the phenomenon of adaptive adrenergic non-shivering thermogenesis in the intact animal is fully dependent on the presence of UCP1, and so is any kind of cold acclimation-recruited non-shivering thermogenesis; thus UCP2/UCP3 (or any other proteins or metabolic processes) cannot substitute for UCP1 physiologically, irrespective of their demonstrated ability to show uncoupling in reconstituted systems or when ectopically expressed. Norepinephrine-induced thermogenesis in brown-fat cells is absolutely dependent on UCP1, as is the uncoupled state and the recoupling by purine nucleotides in isolated brown-fat mitochondria. Although very high UCP2/UCP3 mRNA levels are observed in brown adipose tissue of UCP1-ablated mice, there is no indication that the isolated brown-fat mitochondria are uncoupled; thus, high expression of UCP2/UCP3 does not necessarily confer to the mitochondria of a tissue a propensity for being innately uncoupled. Whereas the thermogenic effect of fatty acids in brown-fat cells is fully UCP1-dependent, this is not the case in brown-fat mitochondria; this adds complexity to the issues concerning the mechanisms of UCP1 function and the pathway from beta(3)-adrenoceptor stimulation to UCP1 activation and thermogenesis. In addition to amino acid sequences conserved in all UCPs as part of the tripartite structure, all UCPs contain certain residues associated with nucleotide binding. However, conserved amongst all UCP1s so far sequenced, and without parallel in all UCP2/UCP3, are two sequences: 144SHLHGIKP and the C-terminal sequence RQTVDC(A/T)T; these sequences may therefore be essential for the unique thermogenic function of UCP1. The level of UCP1 in the organism is basically regulated at the transcriptional level (physiologically probably mainly through the beta(3)-adrenoceptor/CREB pathway), with influences from UCP1 mRNA stability and from the delay caused by translation. It is concluded that UCP1 is unique amongst the uncoupling proteins and is the only protein able to mediate adaptive non-shivering thermogenesis and the ensuing metabolic inefficiency. PMID: 11239487 [PubMed - indexed for MEDLINE] 5172. Biochim Biophys Acta. 2001 Mar 1;1504(1):70-81. Physiological regulation of the transport activity in the uncoupling proteins UCP1 and UCP2. Rial E(1), González-Barroso MM. Author information: (1)Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006 Madrid, Spain. rial@cib.csic.es Brown fat is a thermogenic organ that allows newborns and small mammals to maintain a stable body temperature when exposed to cold. The heat generation capacity is based on the uncoupling of respiration from ATP synthesis mediated by the uncoupling protein UCP1. The first studies on the properties of these mitochondria revealed that fatty acid removal was an absolute prerequisite for respiratory control. Thus fatty acids, that are substrate for oxidation, were proposed as regulators of respiration. However, their ability to uncouple all types of mitochondria and the demonstration that several mitochondrial carriers catalyze the translocation of the fatty acid anion have made them unlikely candidates for a specific role in brown fat. Nevertheless, data strongly argue for a physiological function. First, fatty acids mimic the noradrenaline effects on adipocytes. Second, there exists a precise correlation between fatty acid sensitivity and the levels of UCP1. Finally, fatty acids increase the conductance by facilitating proton translocation, a mechanism that is distinct from the fatty acid uncoupling mediated by other mitochondrial carriers. The regulation of UCP1 and UCP2 by retinoids and the lack of effects of fatty acids on UCP2 or UCP3 are starting to set differences among the new uncoupling proteins. PMID: 11239486 [PubMed - indexed for MEDLINE] 5173. J Nutr. 2001 Mar;131(3):903S-906S. The role of fat depletion in the biological benefits of caloric restriction. Barzilai N(1), Gabriely I. Author information: (1)Department of Medicine, Division of Geriatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. barzilai@aecom.yu.edu One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in substantial decrease in fat mass, the role of fat in life extension was considered minimal. Indeed, in the fields of obesity and diabetes, the amount of fat has been directly implicated in the metabolic consequences. Since it became apparent that fat is a massive endocrine tissue, some of its roles have been recently revised. Many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors and substrates that are produced in fat. Most of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to a decrease in adipose cells and their products. If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate substrates and proteins may be explored and manipulated in searching for the most powerful adipose-dependent signals that modulate life expectancy. PMID: 11238783 [PubMed - indexed for MEDLINE] 5174. J Nutr. 2001 Mar;131(3):861S-865S. Role of leucine in the regulation of mTOR by amino acids: revelations from structure-activity studies. Lynch CJ(1). Author information: (1)Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. clynch@psu.edu In this study an overview is presented of the mTOR signaling pathway and its regulation by amino acids, particularly L-leucine. Our laboratory is studying amino acid regulation of mTOR in adipocytes. Potential roles for mTOR in adipocytes that were previously posited include hypertrophic growth, leptin secretion, protein synthesis and adipose tissue morphogenesis. A current area of interest in the field is how amino acids regulate mTOR and which amino acids are regulatory. Revelations concerning mechanism and recognition are emerging from different laboratories that examined the structural requirements for stimulation and inhibition of the mTOR signaling pathway by leucine and amino acid analogs. In adipocytes and some other cell types, leucine appears to be the main regulatory amino acid. However, this is not uniformly the case. In those cells where mTOR is regulated by several amino acids, there is evidence that the mechanism of mTOR activation may be different from cells where mainly leucine is regulatory. Furthermore, in tissues where leucine regulates mTOR, the possible existence of different tissue-specific leucine recognition sites may be indicated. PMID: 11238775 [PubMed - indexed for MEDLINE] 5175. J Clin Endocrinol Metab. 2001 Mar;86(3):980-3. Is fat intake a risk factor for fat gain in children? Jéquier E(1). Author information: (1)Institute of Physiology, University of Lausanne, 1005 Lausanne, Switzerland. PMID: 11238472 [PubMed - indexed for MEDLINE] 5176. Am J Clin Nutr. 2001 Mar;73(3):511-6. The importance of clinical research: the role of thermogenesis in human obesity. Schoeller DA(1). Author information: (1)Nutritional Sciences, The University of Wisconsin-Madison, WI 53706, USA. dschoell@nutrisci.wisc.edu The hypothesis that human obesity is caused by deficient thermogenesis has been proposed by many investigators throughout the 20th century. Supporting evidence was obtained from epidemiologic studies of dietary intake, animal models with aberrant brown adipose tissue (BAT) function, and genetic studies of human polymorphisms of genes involved in BAT function. Supporting evidence was also obtained from clinical studies of the thermogenic effect of meals, but these measures capture only a short portion of the day and may miss some of the thermogenic effect. To capture the effects throughout the day and to move the studies out of the metabolic ward, investigators have used the doubly labeled water (DLW) method to measure total daily energy expenditure. DLW studies have not supported the above hypothesis. Increases in total energy expenditure (TEE) during overfeeding have been small (0.9 +/- 0.8 MJ/d) and account for an average of only 18 +/- 18% of the excess energy intake. Most of this increase is in the resting metabolic rate. Moreover, these studies showed little variation in the changes in resting metabolic rate or in thermogenesis from meals during overfeeding. Instead, the component that is most variable and that accounts for the variability in weight gain during overfeeding is the energy expended in physical activity. This component of TEE deserves greater attention in future studies. These studies of thermogenesis have shown the importance of clinical research as part of a comprehensive approach to understanding the etiology of human obesity. PMID: 11237925 [PubMed - indexed for MEDLINE] 5177. Recent Prog Horm Res. 2001;56:309-28. The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Collins S(1), Surwit RS. Author information: (1)Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA. The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed. PMID: 11237219 [PubMed - indexed for MEDLINE] 5178. Recent Prog Horm Res. 2001;56:265-94. Insulin resistance and its treatment by thiazolidinediones. Lebovitz HE(1), Banerji MA. Author information: (1)State University of New York, Health Science Center at Brooklyn, 11203, USA. Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistance is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glucose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormalities involving body fat distribution, lipid metabolism, thrombosis and fibrinolysis, blood pressure regulation, and endothelial cell function. This cluster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. It is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, if so, what might it be? Several promising hypotheses have been proposed. There are some data to support the hypothesis that fetal malnutrition imprints on metabolic regulatory processes that, in later adult life, predispose to the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic and environmental components. Among the biochemical mediators that are likely to be responsible for the interference with insulin's effects on intermediary metabolism are free fatty acids and other products from adipose tissue. Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby blocking the ability of these molecules to be tyrosine phosphorylated and initiate the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed to treat type 2 diabetic patients. These drugs act as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Following their binding to the receptor, the heterodimer molecule that contains the binding site is activated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metabolism. These genes are either activated or inhibited. Specifically, the thiazolidinediones improve insulin action and decrease insulin resistance. The exact mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insulin-resistant patients and they appear to change the body distribution of adipose tissue. Treatment of insulin-resistant type 2 diabetic patients with thiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome. PMID: 11237217 [PubMed - indexed for MEDLINE] 5179. Recent Prog Horm Res. 2001;56:175-93. Intracellular organization of insulin signaling and GLUT4 translocation. Watson RT(1), Pessin JE. Author information: (1)Department of Physiology & Biophysics, The University of Iowa, Iowa City 52242, USA. Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscle and adipose. Currently, there are five established functional facilitative glucose transporter isoforms (GLUT1-4 and GLUTX1), with GLUT5 being a fructose transporter. GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neurons. GLUT2 is a low-affinity (high Km) glucose transporter present in liver, intestine, kidney, and pancreatic beta cells. This transporter functions as part of the glucose sensor system in beta cells and in the basolateral transport of intestinal epithelial cells that absorb glucose from the diet. A new facilitative glucose transporter protein, GLUTX1, has been identified and appears to be important in early blastocyst development. The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted to striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized to the cell surface membrane, GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell's interior under basal conditions. As postprandial glucose levels rise, the subsequent increase in circulating insulin activates intracellular signaling cascades that ultimately result in the translocation of the GLUT4 storage compartments to the plasma membrane. Importantly, this process is readily reversible such that when circulating insulin levels decline, GLUT4 transporters are removed from the plasma membrane by endocytosis and are recycled back to their intracellular storage compartments. Therefore, by establishing an internal membrane compartment as the default localization for the GLUT4 transporters, insulin-responsive tissues are poised to respond rapidly and efficiently to fluctuations in circulating insulin levels. Unfortunately, the complexity of these regulatory processes provides numerous potential targets that may be defective and eventually result in peripheral tissue insulin resistance and possibly diabetes. As such, understanding the molecular details of GLUT4 expression, GLUT4 vesicle compartment biogenesis, GLUT4 sequestration, vesicle trafficking, and fusion with the plasma membrane has become a major focus for many laboratories. This chapter will focus on recently elucidated insulin signal transduction pathways and GLUT4 vesicle trafficking components that are necessary for insulin-stimulated glucose uptake and GLUT4 translocation in adipocytes. PMID: 11237212 [PubMed - indexed for MEDLINE] 5180. Mutagenesis. 2001 Mar;16(2):155-61. Genotoxins and the initiation of sporadic breast cancer. Martin FL(1). Author information: (1)Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey SM2 5NG, UK. flmartin@icr.ac.uk Breast cancer is the most frequently diagnosed female malignancy world-wide. The aetiology of the majority of cases remains obscure and the only genotoxin as yet known to initiate breast cancer is ionizing radiation. High penetrance susceptibility genes probably account for no more than 5-10% of cases. The breast, which consists of 70-90% adipose tissue, has a unique morphological structure. Dispersed within it are the functional elements that are lined with cancer-susceptible epithelial cells. Numerous dietary and/or environmental fat-soluble compounds are known to be rodent mammary carcinogens. Extracts of lipid obtained following collagenase digestion of elective reduction mammoplasty tissues from UK resident women showed activity in short-term genotoxicity assays in 40% of cases. More active lipid extracts tended to come from donors whose human mammary epithelial cells (HMECs) exhibited pre-existing DNA single-strand breaks (SSBs). Lipid extracts also induced morphological transformation of mammalian cells in vitro. To increase cohort size, extracts of UK breast milk were examined for genotoxicity and similar activity profiles were observed. Viable cells, a large percentage of which were HMECs, were recovered from breast milk and examined for pre-existing SSBs and for the ability of the donor's own milk extract to induce SSBs. Again, donors whose untreated cells contained the most SSBs tended to yield genotoxic breast milk extracts. Breast milk cells were also able to activate rodent mammary carcinogens to DNA-damaging species. These studies provide good evidence for in vivo exposure of HMECs to genotoxic agents years before the peak in occurrence of sporadic breast cancer. Work is in progress to characterize these agents and to determine their possible role in breast cancer aetiology. PMID: 11230559 [PubMed - indexed for MEDLINE] 5181. Antioxid Redox Signal. 2000 Fall;2(3):405-12. Mechanisms of vitamin E regulation: research over the past decade and focus on the future. Parks E(1), Traber MG. Author information: (1)Department of Food Science and Nutrition, University of Minnesota, Twin Cities, St Paul 55108-6099, USA. ejparks@tc.umn.edu This paper discusses the developments in human vitamin E research since 1990. New methodologies such as the use of stable isotopes, advances in vitamin E measurements, and isolation and cloning of specific alpha-tocopherol binding proteins have facilitated investigation of alpha-tocopherol absorption, metabolism, and transport in humans in vivo. Changes in food production in the United States and dietary intake impacted vitamin E availability and intake. Epidemiologic and therapeutic studies have pointed to its role in disease prevention and in healing processes. Specific molecular functions of alpha-tocopherol have been the most recent and surprising new findings and are an important area for future experimentation. Given the aging of the American population and the potential role for alpha-tocopherol in preventive medicine, the study of the molecular functions of vitamin E promises to provide some of the most exciting discoveries of the next decade. PMID: 11229354 [PubMed - indexed for MEDLINE] 5182. Rev Med Chil. 2000 Dec;128(12):1354-60. [Obesity and fatty acids in the etiology of insulin resistance]. [Article in Spanish] Galgani J(1), Díaz E. Author information: (1)Laboratorio de Metabolismo Energético e Isótopos Estables, INTA-Universidad de Chile, Av Macul 5540, Santiago de Chile. Fatty acids, obesity and insulin resistance relationship are discussed. In the last decades fatty acids (FA) have been implicated in the etiology of insulin resistance. Initially, this process was related to FA inhibitory effects on glucose uptake mediated by the FA oxidation metabolites. This mechanism known as the Randle cycle has been presently discarded based on recent evidence for FA effects on glucose metabolism. Now is known that cytosolic lipid content and FA molecular structure determines higher or lower storage and oxidation capacity. Another factor is given by Tumor Necrosis Factor-alpha, which is overexpressed in animal and human obesity, producing insulin signaling and glucose uptake inhibition. This paper discuss the role played by FA and obesity on insulin resistance, mainly in relation to FA effects on glucose metabolism in the liver, muscle and adipose tissues. In the obesity condition adipose tissue releases higher levels of free FA which in turn stimulates hepatic glucose production. Adipose tissue also, increase TNF-alpha secretion impairing glucose utilization and insulin signaling. In muscle, cytosolic lipid content activate a Protein Kinase that inhibits the insulin signaling and reduce GLUT-4 translocation. The study of cellular and metabolic changes associated to weight gain and its relationship with insulin resistance etiology are encouraged. PMID: 11227245 [PubMed - indexed for MEDLINE] 5183. Diabetes Obes Metab. 2000 Jun;2(3):121-9. Metabolic consequences of weight loss on glucose metabolism and insulin action in type 2 diabetes. Williams KV(1), Kelley DE. Author information: (1)The Department of Medicine, University of Pittsburgh, PA 15261, USA. kelley@med1.dept-med.pitt.edu PMID: 11220547 [PubMed - indexed for MEDLINE] 5184. Diabetes Obes Metab. 1999 May;1 Suppl 1:S8-16. The relation between insulin resistance and cardiovascular complications of the insulin resistance syndrome. Rett K(1). Author information: (1)Medizinische Klinik und Poliklinik, Universitätsklinikum Tübingen, Germany. knrett@med.uni-Tuebingen.de It has been known for years that cardiovascular disease frequently precedes the development of type 2 diabetes, and that atherosclerosis might not be a complication of type 2 diabetes, but rather the consequence of common genetic and environmental factors (the common soil' hypothesis). The insulin resistance syndrome (IRS) is a cluster of closely associated and interdependent abnormalities, including insulin resistance, hyperinsulinaemia, android fat distribution, progressive glucose intolerance, dyslipidaemia (increased triglycerides, decreased HDL, increased small dense LDL), increased prothrombotic and antifibrinolytic factors, and hypertension. Many of these abnormalities are risk factors for type 2 diabetes, and most of them explain the predilection for atherosclerosis to occur in conjunction with IRS. Insulin resistance is a key feature of IRS, and has been suggested to be the common pathophysiological basis of atherosclerosis and type 2 diabetes. The term 'insulin resistance' denotes resistance to insulin-mediated glucose uptake into skeletal muscle, which can be measured by the glucose clamp technique. There are, however, other less understood sites of abnormal insulin action that may also be relevant in IRS. These include liver, adipose, and kidney tissue, and systems such as muscle perfusion, antilipolysis, lipoprotein lipase activity, and cation transport. The development of clinical cardiovascular end-points in a patient with insulin resistance is complex, as it includes the degree of the defect, its associated abnormalities, its consequences, and the ability to compensate for the underlying defect. It is therefore more appropriate to consider the different facets and risk factors of IRS in aggregate, rather than seeking 'independent' effects. Accordingly, treatment of insulin resistance per se has not yet been shown to reduce the incidence of cardiovascular complications. At the cellular level, excess insulin is involved in various elements of atherogenesis. It interacts with cytokines and growth factors in a cross talk among vascular wall cells and a variety of mediators that play a role in the establishment of atheroma. Excess insulin also plays an important role in concert with lipoproteins when they exhibit an abnormal pattern and become modified by oxidation and glycation. It is therefore currently hoped that the introduction of a new class of insulin-sensitizing agents, the thiazolidinediones, may attenuate these processes. The thiazolidinediones act through ligand activation of a nuclear transcription factor, the peroxisomal proliferator-activated receptor-gamma (PPARgamma). Although this receptor was initially linked to lipid and glucose metabolism, recent data suggest that PPARgamma is also involved in the differentiation of mononuclear phagocytes, their inflammatory reactions, and macrophage conversion to foam cells. Thus, PPARgamma ligands may also be important regulators of monocyte/ macrophage gene expression during atherogenesis. PMID: 11220289 [PubMed - indexed for MEDLINE] 5185. Cell Mol Life Sci. 1999 Dec;56(11-12):945-70. Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin. Müller G(1), Frick W. Author information: (1)Hoechst Marion Roussel Deutschland GmbH, DG Metabolic Diseases and Medicinal Chemistry, Frankfurt am Main, Germany. Guenter.Mueller@hmrag.com In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy. PMID: 11212327 [PubMed - indexed for MEDLINE] 5186. Cell Mol Life Sci. 1999 Oct 30;56(5-6):538-42. Role of pathways for signal transducers and activators of transcription, and mitogen-activated protein kinase in adipocyte differentiation. Aubert J(1), Belmonte N, Dani C. Author information: (1)Laboratoire de Biologie du Développement du Tissu Adipeux, Centre de Biochimie, UMR 6543 CNRS, Nice, France. Members of the signal transducer and activator of transcription (STAT) family and the mitogen-activated protein kinase (MAPK) cascade play a major role in the regulation of cell growth and differentiation. This review concentrates on the role played by these pathways in the development of adipose cells. STATs are activated by both positive and negative modulators of adipocyte differentiation leading to the hypothesis that the STAT pathway may function in adipogenesis. The role of the p42/p44 MAPK pathway in adipocyte differentiation has recently been the subject of contradictory reports. Several molecular mechanisms are proposed to explain the opposing effects of MAPK activation in the programme of adipose cell differentiation. PMID: 11212303 [PubMed - indexed for MEDLINE] 5187. Exerc Sport Sci Rev. 2001;29(1):42-6. Regulation of lipid mobilization and oxidation during exercise in obesity. Horowitz JF(1). Author information: (1)Division of Kinesiology, University of Michigan, Ann Arbor, Michigan, USA. jeffhoro@umich.edu Regulation of lipid mobilization and oxidation during exercise in obesity. Exerc. Sport Sci. Rev. Vol. 29, No. 1, pp 42-46, 2001. Obesity is associated with metabolic disorders that may be related to alterations in lipid mobilization and oxidation. Although exercise is essential for successful weight management, the regulation of fatty acid metabolism during exercise in obesity is unclear. This review discusses factors that regulate fat metabolism during exercise and the effects of endurance training on these responses. PMID: 11210447 [PubMed - indexed for MEDLINE] 5188. Ann Med. 2000 Dec;32 Suppl 1:78-84. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Juhan-Vague I(1), Alessi MC, Morange PE. Author information: (1)Laboratory of Hematology, Faculty of Medicine, CHU Timone, Marseille, France. ijuhan@mail.ap-hm.fr Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in vivo. Circulating PAI-1 levels are elevated in patients with coronary heart disease and may play an important role in the development of atherothrombosis by decreasing fibrin degradation. Increased PAI-1 expression can also directly influence vessel wall remodelling. Prospective cohort studies have underlined the association between increased plasma PAI-1 levels and the risk of coronary events, but the predictive capacity of PAI-1 disappeared after adjustments for insulin resistance markers. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. Recently, production of PAI-1 by adipose tissue, in particular by fat from omentum, has been evidenced, and it has been proposed that it could be responsible for the elevated plasma PAI-1 level observed in insulin resistance. The role of stroma cells, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta as possible enhancers of PAI-1 synthesis are presently emphasized. Glucocorticoids and insulin may also be implicated. Moreover, a weak genetic control of plasma PAI-1 concentration has been described in patients with high plasma levels of PAI-1. The role of PAI-1 in the development of adipose tissue metabolism is important to consider as PAI-1 -/- mice submitted to a high-fat diet showed changes in cell composition of adipose tissue and in plasma insulin and triglyceride levels. PMID: 11209987 [PubMed - indexed for MEDLINE] 5189. Natl Med J India. 2000 Nov-Dec;13(6):311-2. Further insight into the thrifty phenotype. Unnikrishnan AG(1), Sahay RK, Reddy DV, Singh SK. Author information: (1)Department of Endocrinology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh. PMID: 11209487 [PubMed - indexed for MEDLINE] 5190. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1431-7. Estrogen treatment and estrogen suppression: metabolic effects in adolescence. Mauras N(1), Hayes V, O'Brien KO. Author information: (1)Nemours Children's Clinic and Research Programs, Jacksonville, Florida 32211, USA. nmauras@nemours.org The metabolic consequences of reaching full reproductive maturity in humans involve not only growth hormone (GH) and insulin-like growth factor-I, but also the collaborative interaction of the gonadal sex steroids. Estrogen is critical for completing linear growth. It also inhibits bone resorption, decreases plasma lipid levels and serves as an antiatherosclerotic agent. Our studies show that, in low doses, estrogen increases GH production, increases calcium absorption and decreases bone turnover; however, unlike testosterone, estrogen has no effects as a protein-anabolic agent, at least at the whole body level. Studies of selective estrogen suppression, achieved using a potent aromatase inhibitor, show that estrogen is the main regulator of the gonadotropin axis. In boys, selective aromatase blockade may have a role in delaying epiphyseal fusion. Large placebo-controlled trials will be required to study this effect further. PMID: 11202220 [PubMed - indexed for MEDLINE] 5191. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1353-8. Evidence-based approach to growth hormone replacement therapy in adults, with special emphasis on body composition. Conceicao FL(1), Jørgensen JO, Vahl N, Nørrelund H, Christiansen JS. Author information: (1)Medical Department M, Aarhus Kommunehospital, Aarhus University Hospital, Denmark. In the past decade, a large number of controlled clinical trials have reported positive effects of growth hormone (GH) replacement therapy in GH-deficient adults. The majority of these studies have been carried out in accordance with the guidelines for Good Clinical Practice. The data thus accumulated offer a solid baseline for practicing evidence-based medicine within this area of endocrinology. PMID: 11202209 [PubMed - indexed for MEDLINE] 5192. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1321-6. What happens when growth hormone is discontinued at completion of growth? Metabolic aspects. Johannsson G(1). Author information: (1)Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden. Gudmundur.Johannsson@medic.gu.se Continuing growth hormone (GH) replacement therapy in patients with childhood-onset GH deficiency (GHD) that persists into adulthood is an emerging issue. The prospective, long-term metabolic consequences of discontinuing GH therapy in adolescent patients with childhood-onset GHD and short stature have only recently been reported. These studies demonstrate that serum concentrations of total cholesterol, low-density lipoprotein-cholesterol and apolipoprotein B are higher in adolescents in whom severe GHD continues into adulthood. Upon discontinuation of GH therapy, serum concentrations of high-density lipoprotein-cholesterol have been found to decrease in patients with severe GHD and increase in patients regarded as GH sufficient when retested for GHD. Furthermore, total body fat and truncal fat mass increase after discontinuation of GH in both these patient groups, but more markedly in the patients with severe GHD. In adolescents with severe GHD persisting into adulthood, the discontinuation of GH therapy produces, over a period of 2 years, the accumulation of important cardiovascular risk factors that are associated with GHD in adults. Continuing replacement therapy into adulthood should therefore be considered. PMID: 11202204 [PubMed - indexed for MEDLINE] 5193. Nihon Rinsho. 2001 Jan;59(1):188-94. [Life style-related disease]. [Article in Japanese] Matsuzawa Y(1). Author information: (1)Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine. Diabetes mellitus, hyperlipidemia, hypertension and atherosclerotic diseases have recently defined as typical life style-related diseases. A common background of these life style-related diseases is overnutrition and its consequence, obesity. Recent advances in the biology of adipose tissue have revealed that adipose is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Through a systematic search of active genes in adipose tissue, we found that adipose tissue, especially visceral fat expressed numerous genes for secretory proteins. Among them, plasminogen activator inhibitor-1(PAI-1) was over expressed in the visceral fat in an animal model of obesity. Plasma level of PAI-1 was closely correlated with visceral adiposity in human. Thus, PAI-1 secreted from visceral fat may play an important role in vascular disease in visceral obesity. Adiponectin, a novel adipose-specific gene product, is abundantly presented in human plasma. This molecule has been shown to have protective roles against atherosclerotic vascular changes and its plasma level is negatively correlated with visceral adiposity. In conclusion, dysregulated secretion of these adipose-specific secretory proteins(adipocytokines) may have important roles in the development of life style-related diseases, especially atherosclerotic diseases. PMID: 11197854 [PubMed - indexed for MEDLINE] 5194. AIDS Read. 2000 Dec;10(12):688-91. HAART-associated body habitus and metabolic changes, Part 2. Liss M(1), Boyle BA. Author information: (1)Department of International Medicine and Infectious Disease, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, USA. PMID: 11189733 [PubMed - indexed for MEDLINE] 5195. Traffic. 2001 Jan;2(1):2-11. GLUT4--at the cross roads between membrane trafficking and signal transduction. Simpson F(1), Whitehead JP, James DE. Author information: (1)Institute for Molecular Biosciences and the Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia. GLUT4 is a mammalian facilitative glucose transporter that is highly expressed in adipose tissue and striated muscle. In response to insulin, GLUT4 moves from intracellular storage areas to the plasma membrane, thus increasing cellular glucose uptake. While the verification of this 'translocation hypothesis' (Cushman SW, Wardzala LJ. J Biol Chem 1980;255: 4758-4762 and Suzuki K, Kono T. Proc Natl Acad Sci 1980;77: 2542-2545) has increased our understanding of insulin-regulated glucose transport, a number of fundamental questions remain unanswered. Where is GLUT4 stored within the basal cell? How does GLUT4 move to the cell surface and what mechanism does insulin employ to accelerate this process? Ultimately we require a convergence of trafficking studies with research in signal transduction. However, despite more than 30 years of intensive research we have still not reached this point. The problem is complex, involving at least two separate signal transduction pathways which feed into what appears to be a very dynamic sorting process. Below we discuss some of these complexities and highlight new data that are bringing us closer to the resolution of these questions. PMID: 11208163 [PubMed - indexed for MEDLINE] 5196. Can J Appl Physiol. 2001 Feb;26(1):102-22. Skeletal muscle mass and aging: regional and whole-body measurement methods. [Article in English, French] Lee RC(1), Wang ZM, Heymsfield SB. Author information: (1)Obesity Research Center, Department of Medicine, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA. Skeletal muscle is a large compartment that can now be quantified using research and clinically applicable regional and whole-body methods. The most important advances are the two imaging methods, computed tomography (CT) and magnetic resonance imaging (MRI). Both CT and MRI can serve as regional and whole-body reference methods when evaluating other approaches for estimating skeletal muscle mass. Imaging methods also afford the opportunity to quantify both anatomic skeletal muscle and the smaller adipose-tissue free skeletal muscle component. Other available methods for estimating skeletal muscle, either regional or at the whole body level, include dual-energy x-ray absorptiometry, in vivo neutron activation analysis-whole body counting, anthropometry, ultrasound, bioimpedance analysis, and urinary metabolite markers. Each method is reviewed in the context of the aging process, cost, availability, practicality, and desired accuracy. New insights should be possible when skeletal muscle mass, measured using these methods, is combined with other descriptors of muscle biochemical and mechanical function. PMID: 11173672 [PubMed - indexed for MEDLINE] 5197. Trends Endocrinol Metab. 2001 Mar;12(2):65-72. Leptin in reproduction. Caprio M(1), Fabbrini E, Isidori AM, Aversa A, Fabbri A. Author information: (1)Cattedra di Andrologia, Dipartimento di Fisiopatologia Medica, Università La Sapienza, 00100 Rome, Italy. In mammals, the function of the reproductive system is dependent on the availability of energy in the environment. It is well established that acute modifications of energy balance modulate the hypothalamic-pituitary-gonadal axis. In several species, fasting and caloric restriction have been shown to cause the suppression of pulsatile luteinizing hormone secretion, via an inhibition of the gonadotropin-releasing hormone pulse generator. Such a mechanism probably prevents energy being wasted for reproduction. By contrast, excessive energy storage and obesity interfere with the correct regulation of the reproductive axis. The identification of leptin and leptin receptors, along with studies performed in animal models of leptin deficiency and resistance, has focused attention on the role of this molecule in reproduction, and disclosed new aspects of the relationship between energy stores, adipose tissue and reproductive function. Here, we discuss the central and peripheral effects of leptin on reproductive tissues, and try to fit a complex reality into a simplified model. In particular, the roles of leptin in reproduction at different anatomical levels and in various clinical and experimental settings are discussed. PMID: 11167124 [PubMed - indexed for MEDLINE] 5198. Neurosci Biobehav Rev. 2001 Jan;25(1):15-28. The regulation of total body fat: lessons learned from lipectomy studies. Mauer MM(1), Harris RB, Bartness TJ. Author information: (1)Department of Biology and the Neurobiology and Behavior Program, Georgia State University, University Plaza, Atlanta, GA 30303-3083, USA. Surgical removal of body fat (partial lipectomy) is a means of directly reducing fat such that metabolic and behavioral responses can be readily attributed to the lipid deficit. If total body fat is regulated, then lipectomy should trigger compensatory increases in nonexcised white adipose tissue (WAT) mass and/or regrowth at excision sites. Many species, including laboratory rats and mice, show lipectomy-induced compensatory recovery of body fat. Those animals exhibiting naturally occurring annual adiposity cycles, such as ground squirrels and hamsters, do so most impressively reaching seasonally appropriate body fat levels indistinguishable from controls. Reparation of the lipid deficit occurs without an increase in food intake, and generally through enlargement of non-excised WAT mass, rather than regrowth of excised WAT. A body fat regulatory system involving humoral and sensory neural inputs to the brain as well as sympathetic neural outputs from brain to adipose tissue is presented. Collectively, the lipectomy model appears useful for testing mechanisms controlling adiposity, or individual depot growth, and offers insight into how lipid stores fluctuate naturally. PMID: 11166075 [PubMed - indexed for MEDLINE] 5199. Annu Rev Med. 2001;52:339-51. Effects of neuropeptides and leptin on nutrient partitioning: dysregulations in obesity. Jeanrenaud B(1), Rohner-Jeanrenaud F. Author information: (1)Geneva University, Chemin des Piverts 6, 1226 Geneva, Switzerland. jeanrenaud.bf@vtx.ch Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity. PMID: 11160783 [PubMed - indexed for MEDLINE] 5200. J Nutr. 2001 Feb;131(2):354S-60S. Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as explanations for metabolic diversity. Kahn SE(1), Prigeon RL, Schwartz RS, Fujimoto WY, Knopp RH, Brunzell JD, Porte D Jr. Author information: (1)Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Department of Veterans Affairs, Puget Sound Health Care, Seattle, WA 98108, USA. skahn@u.washington.edu Studies of metabolic processes have been enhanced by our understanding of the relationships among obesity, body fat distribution, insulin sensitivity and islet beta-cell function. Thus, we have learned that although insulin resistance is usually associated with obesity, even lean subjects can be insulin resistant due to the accumulation of visceral fat. Insulin sensitivity and beta-cell function are also intimately linked. The hyperbolic relationship between these two parameters explains why insulin-resistant individuals have markedly enhanced insulin responses, whereas subjects who are insulin sensitive exhibit very low responses. Failure to take into account this relationship will lead to erroneous conclusions. By accounting for this important interaction, it has been clearly demonstrated that subjects at high risk of developing type 2 diabetes (older individuals, women with a history of gestational diabetes or polycystic ovary syndrome, subjects with impaired glucose tolerance and first-degree relatives of individuals with type 2 diabetes) have impaired beta-cell function. Furthermore, the progression from normal glucose tolerance to impaired glucose tolerance and type 2 diabetes is associated with declining insulin secretion. PMID: 11160560 [PubMed - indexed for MEDLINE] 5201. Clin Exp Pharmacol Physiol. 2001 Jan-Feb;28(1-2):115-9. Neuroanatomical specificity of the circuits controlling sympathetic outflow to different targets. Sved AF(1), Cano G, Card JP. Author information: (1)Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260, USA. sved@bns.pitt.edu 1. Despite the emerging framework that central neural pathways controlling the activity of the sympathetic nervous system are capable of producing highly selective responses, the specific neural pathways governing different sympathetic outflows are poorly understood. 2. Anatomical studies suggest that five brain areas, namely the rostral ventrolateral medulla, the rostral ventromedial medulla, the caudal raphe nuclei, the region containing the A5 noradrenergic neurons and the paraventricular hypothalamic nucleus, provide dominant supraspinal innervation of sympathetic preganglionic neurons. 3. The anatomical parcellation of different functions within and among these cell groups is uncertain. However, recent studies using transynaptic retrograde labelling of neural pathways connected to various sympathetic targets suggest that the circuits controlling these different targets may be partially distinct. Similarly, anatomical studies relying on stimulus-evoked expression of immediate early genes, such as c-fos, suggest that different sympathetic responses may be controlled by distinct, neural circuits. 4. Thus, although many similarities exist in the anatomical circuits innervating different sympathetic targets, possibly supporting the orchestration of global sympathetic responses, differences are also discernible. PMID: 11153526 [PubMed - indexed for MEDLINE] 5202. Ann Endocrinol (Paris). 2000 Dec;61 Suppl 6:56-69. [Lipid mobilization and energy metabolism: impact of molecular and cellular approaches on the treatment of obesity]. [Article in French] Lafontan M(1), Berlan M, Galitzky J. Author information: (1)Unité INSERM 317, Université Paul Sabatier, Institut Louis Bugnard, CHU Rangueil, 31403 Toulouse cedex 4. lafontan@rangueil.inserm.fr There is strong evidence that reduced sympathetic nervous system (SNS) activity is involved in the etiology of obesity in several animal models of obesity. In humans the situation is more complex but humans with low SNS activity, reduced beta-adrenergic sensitivity, reduced lipid mobilizing efficacy of catecholamines have lowered energy expenditure and are at greater risk of obesity. The SNS with its effect on food intake, lipid mobilization and energy expenditure has a major potential as a target for novel pharmacotherapies in weight reducing strategies. Extended cellular and molecular knowledge about the nature, the distribution and the role of the adrenergic receptors (beta(1)-, beta(2)-, beta(3)-, alpha(2)- and alpha(1)-) existing in tissue effectors involved in the control of lipid mobilization (adipose tissue) and energy expenditure (brown adipose tissue, skeletal muscle) has opened new pathways for pharmacological strategies. In this manuscript, after a summary of current knowledge on the regulation of lipid mobilization and energy expenditure in humans, we briefly review the putative targets and the most recent attempts to develop agents acting at various adrenergic receptor types in SNS effectors or on SNS activity. These include major questions about putative utilization of beta(3)-agonists, alpha(2)-antagonists and beta-antagonists in pharmacotherapy and/or prevention of obesity in humans. PMID: 11148337 [PubMed - indexed for MEDLINE] 5203. Ann Endocrinol (Paris). 2000 Dec;61 Suppl 6:31-38. [Risk factors associated with obesity: a metabolic perspective]. [Article in French] Després JP(1), Pascot A, Lemieux I. Author information: (1)Institut de cardiologie de Québec, Centre de recherche de l'Hôpital Laval, Pavillon Mallet, 2e étage, 2725, chemin Sainte-Foy, Sainte-Foy (Québec), GIV 4G5. jean-pierre.depres@crchul.ulaval.ca Obesity, especially visceral obesity, is associated with a cluster of metabolic complications increasing the risk of type 2 diabetes and coronary heart disease. It has been shown that obese patients characterized by a high accumulation of visceral adipose tissue have increased glycemic and insulinemic responses to an oral glucose load compared to normal weight individuals or to obese individuals with a low accumulation of visceral adipose tissue. Viscerally obese patients are also characterized by an unfavourable plasma lipid profile which includes elevated triglyceride and apolipoprotein B concentrations, reduced HDL-cholesterol levels as well as an increased proportion of small, dense LDL particles. Such alterations in the lipid profile are often observed even in the absence of elevated LDL-cholesterol concentrations. Our work has clearly shown that this cluster of metabolic abnormalities found among viscerally obese patients was associated with a substantial increase in coronary heart disease risk. Our work has also shown that the "metabolic triad" of non-traditional risk factors (hyperinsulinemia, elevated apolipoprotein B levels, increased proportion of small, dense LDL particles) was associated with a 20-fold increase in the risk of coronary heart disease. In this regard, we have been interested in developing simple tools which would allow clinicians to identify at an early stage and at low cost individuals who would be carriers of the atherogenic metabolic triad. We have noted that the measurement and interpretation of waist circumference and of fasting plasma triglyceride levels could allow the identification of a high proportion of carriers of the metabolic triad. Indeed, less than 10% of men with a waist circumference below 90 cm and triglyceride concentrations below 2 mmol/l were characterized by the features of the metabolic triad. However, more than 80% of individuals with a waist circumference above 90 cm and triglyceride levels above 2 mmol/l were carriers of the metabolic triad. Finally, an elevated visceral adipose tissue accumulation has also been associated with a thrombogenic and a pro-inflammatory metabolic profile which would be predictive of an unstable atherosclerotic plaque. Therefore, the stabilisation of the atherosclerotic plaque may represent a legitimate therapeutic objective to reduce the risk of coronary heart disease among patients with visceral obesity. It is proposed that a rather modest weight loss (approximately 10%) could contribute to substantially improve the risk profile of these patients. PMID: 11148334 [PubMed - indexed for MEDLINE] 5204. Ann Endocrinol (Paris). 2000 Dec;61 Suppl 6:24-30. [Genetics of human obesity: results from genetic epidemiology studies]. [Article in French] Pérusse L(1). Author information: (1)Division de Kinésiologie, Département de médecine sociale et préventive, PEPS, Université Laval, Sainte-Foy, PQ, G1K 7P4 Canada. Louis.Perusse@kin.msp.ulaval.ca Obesity is a complex disease resulting from the interaction between a variety of genetic and environmental factors. Research conducted over the past 20 years in the field of genetic epidemiology has contributed to increase our understanding of the genetic basis of obesity. It is now clearly established that overweight and obesity aggregate in families. Studies have shown that the prevalence of obesity is 2 to 8 times higher in families of obese individuals than in the population at large and that the familial risk increases with the severity of obesity. The heritability of the various obesity phenotypes varies considerably depending on the phenotype under study, the nature of familial data and the methods used to compute heritability estimates. Heritability estimates tend to be highest when derived from twin studies (50% à 80%) while they are the lowest when derived from adoption studies (10% à 30%). Several studies have reported the presence of major gene effects for body mass index, body fat and abdominal visceral fat. Finally, there is increasing evidence that shared genetic factors could play a role in determining the covariation between obesity and its major co-morbidities, including blood pressure, insulin resistance, diabetes and dyslipidemia. This genetic covariation is however moderate and accounts for a smaller percentage of the variance compared to the genetic effects reported for each of the phenotypes studied independently. PMID: 11148333 [PubMed - indexed for MEDLINE] 5205. Ann Endocrinol (Paris). 2000 Dec;61 Suppl 6:12-23. [Physiopathology of obesity. Dietary factors, and regulation of the energy balance]. [Article in French] Ziegler O(1), Quilliot D, Guerci B. Author information: (1)Diabétologie, Maladies Métaboliques et Nutrition, Centre Hospitalier Universitaire de Nancy, Hôpital Jeanne d'Arc, 54201 Toul. o.ziegler@chu-nancy.fr Energy balance and macronutrient balance are the cornerstones upon which any theories of obesity must be built. Obesity can only occur when energy intake remains higher than energy expenditure for an extended period of time. However the macronutrient composition of the diet can also affect energy balance. Fat is a key nutrient because it is poorly regulated at both the level of consumption and oxidation. Psychological and behavioural profiles of obese subjects are clearly important because they can affect food choice and eating patterns. The role of eating frequency and circadian distribution of food is still debated. Eating disorders could be implicated in the development of obesity, but it is uncertain whether obesity is a direct result or a cause of the eating disorder. There are strong evidence to suggest that dietary restraint is associated with loss of dietary control and excessive eating. Early stages of fat storage involve expansion of existing adipocytes (hypertrophy) and later stages involve the recruitment of new adipocytes (hyperplasia). The mechanisms controlling the transformation of preadipocyte could also involve specific dietary components such as polyunsaturated fatty acids or proteins. The age of adiposity rebound, that is a risk factor for later obesity has been found significantly younger in children consuming a high protein diet. These factors could be involved during early infancy or even in utero, according to the hypothesis of fetal programming of adult diseases. There is a need for more longitudinal studies on the role of macronutrient composition, food choice or eating disorders, especially among children, teenagers and young adults. PMID: 11148332 [PubMed - indexed for MEDLINE] 5206. Mol Med. 2000 Nov;6(11):907-33. The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl. Müller G(1). Author information: (1)Aventis Pharma Germany, Frankfurt. Guenter.Mueller@aventis.com The hypoglycemic sulfonylurea drugs cause reduction of blood glucose predominantly via stimulation of insulin release from pancreatic beta cells. In addition, during long-term treatment, an insulin-independent blood glucose-decreasing mechanism is assumed to operate. This may include insulin-sensitizing and insulin-mimetic activity in muscle and adipose tissue. This review summarizes our current knowledge about the putative modes of action of the sulfonylurea compound, Amaryl, in pancreatic beta cells and, in particular, peripheral target cells that form the molecular basis for its characteristic pharmacological and clinical profile. The analysis was performed in comparison with the conventional and the "golden standard" sulfonylurea, glibenclamide. I conclude: (I) The blood glucose decrease provoked by Amaryl can be explained by a combination of stimulation of insulin release from the pancreas and direct enhancement, as well as potentiation of the insulin response of glucose utilization in peripheral tissues only. (II) The underlying molecular mechanisms seemed to rely on beta cells on a sulfonylurea receptor protein, SURX, associated with the ATP-sensitive potassium channel (K(ATP)) and different from SUR1 for glibenclamide, and in muscle and adipose cells on: (a) the increased production of diacylglycerol and activation of protein kinase C; (b) the enhanced expression of glucose transporter isoforms; and (c) the insulin receptor-independent activation of the insulin receptor substrate/phosphatidylinositol-3-kinase pathway. (III) The latter mechanism involved a nonreceptor tyrosine kinase and a number of components, such as caveolin and glycosylphosphatidylinositol structures, which are assembled in caveolae/detergent-insoluble glycolipid-enriched rafts of the target cell plasma membrane. Since hyperinsulinism and permanent K(ATP) closure are supposed to negatively affect the pathogenesis and therapy of non-insulin-dependent diabetes mellitus, the demonstrated higher insulin-independent blood glucose-lowering activity of Amaryl may be therapeutically relevant. PMCID: PMC1949923 PMID: 11147570 [PubMed - indexed for MEDLINE] 5207. J Nutr. 2000 Dec;130(12):3132S-3133S. Genetic studies of brown adipocyte induction. Kozak LP(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. We seek to discover an effective method for utilizing thermogenesis to reduce the caloric load in obese individuals. Experimental evidence indicates that nonshivering thermogenesis is the most effective cellular and biochemical mechanism known for reducing excessive adiposity. In this presentation, we describe our experiments aimed at understanding how nonshivering thermogenesis can be induced. In addition, these experiments have led to a genetic approach for the identification of variant genes that coordinate the expression of pathways of gene transcription that are associated with brown adipocyte induction. PMID: 11110889 [PubMed - indexed for MEDLINE] 5208. J Nutr. 2000 Dec;130(12):3127S-3131S. Regulation of leptin production in humans. Fried SK(1), Ricci MR, Russell CD, Laferrère B. Author information: (1)Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA. Serum levels of the adipocyte hormone leptin are increased in proportion to body fat stores as a result of increased production in enlarged fat cells from obese subjects. In vitro studies indicate that insulin and glucocorticoids work directly on adipose tissue to upregulate in a synergistic manner leptin mRNA levels and rates of leptin secretion in human adipose tissue over the long term. Thus, the increased leptin expression observed in obesity could result from the chronic hyperinsulinemia and increased cortisol turnover. Superimposed upon the long-term regulation, nutritional status can influence serum leptin over the short term, independent of adiposity. Fasting leads to a gradual decline in serum leptin that is probably attributable to the decline in insulin and the ability of catecholamines to decrease leptin expression, as observed in both in vivo and in vitro studies. In addition, increases in serum leptin occur approximately 4-7 h after meals. Increasing evidence indicates that insulin, in concert with permissive effects of cortisol, can increase serum leptin over this time frame and likely contributes to meal-induced increases in serum leptin. Further research is required to elucidate the cellular and molecular mechanisms underlying short- and long-term nutritional and hormonal regulation of leptin production and secretion. PMID: 11110887 [PubMed - indexed for MEDLINE] 5209. J Nutr. 2000 Dec;130(12):3122S-3126S. Adipocyte differentiation and gene expression. Ntambi JM(1), Young-Cheul K. Author information: (1)Departments of Biochemistry and Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI 53706, USA. The major function of adipocytes is to store triacylglycerol in periods of energy excess and to mobilize this energy during times of deprivation. The short-term control of these lipogenic and lipolytic processes is carefully modulated by hormonal signals from the bloodstream, which provide an inventory of the body's metabolic state. Long-term changes in fat storage needs are accomplished by altering both the size and number of fat cells within the body because terminally differentiated adipocytes cannot divide. Alterations in the number of fat cells within the body must be accomplished by the differentiation of preadipocytes, which act as the renewable source of adipocytes. Our understanding of the events that occur during preadipocyte differentiation has advanced considerably in the last few years and has relied mainly on the use of tissue culture models of adipogenesis. This article will discuss the various models used for studying the preadipocyte differentiation process, with the mouse 3T3-L1 cell culture line described in detail. We focus on those genetic events that link effectors to induction of adipocyte gene expression. PMID: 11110885 [PubMed - indexed for MEDLINE] 5210. J Nutr. 2000 Dec;130(12):3116S-3121S. Hormonal signaling and transcriptional control of adipocyte differentiation. Morrison RF(1), Farmer SR. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. Recent advances regarding the biology of adipose tissue have identified the adipocyte as an important mediator in many physiologic and pathologic processes regarding energy metabolism. Consideration for a central role of adipose tissue in the development of obesity, cardiovascular disease and noninsulin-dependent diabetes mellitus has resulted in new incentives toward understanding the complexities of adipocyte differentiation. Current knowledge of this process includes a cascade of transcriptional events that culminate in the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha). These prominent adipogenic transcription factors have been shown to regulate, directly or indirectly, the gene expression necessary for the development of the mature adipocyte. Hormonal and nutritional signaling that impinges on these trans-acting factors provides a molecular link between lipids and lipid-related compounds and the gene expression important for glucose and lipid homeostasis. Knowledge concerning the transcriptional events mediating adipocyte differentiation provides a basis for understanding the physiologic processes associated with adipose tissue as well as for the development of therapeutic interventions in obesity and its related disorders. PMID: 11110883 [PubMed - indexed for MEDLINE] 5211. J Nutr. 2000 Dec;130(12):3110S-3115S. Secretory, endocrine and autocrine/paracrine function of the adipocyte. Kim S(1), Moustaid-Moussa N. Author information: (1)Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1900, USA. Obesity is a major public health problem in Western countries, and >55% of adult Americans are overweight or obese. A major contributor to the epidemic of obesity is the current environment, which is characterized by increased availability of high energy foods and decreased physical activity. Several studies also demonstrated that genetic susceptibility contributes to obesity in some populations. Obesity research has focused primarily on the role of the hypothalamus in neuroendocrine regulation of food intake. However, a growing number of studies support a potential contribution of adipose tissue, via its newly discovered secretory function, to the pathogenesis of obesity and co-morbid conditions including cardiovascular disease, diabetes and hypertension. This paper will review the role of four factors secreted by adipose tissue (leptin, agouti, angiotensin II and prostaglandins) and their functions in the regulation of energy balance and whole-body homeostasis. Several other peptide and nonpeptide substances are secreted from adipose tissue; their function and regulation have been documented extensively. PMID: 11110881 [PubMed - indexed for MEDLINE] 5212. Endocr Rev. 2000 Dec;21(6):697-738. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Wajchenberg BL(1). Author information: (1)Endocrine Service, Hospital das Clinicas of The University of São Paulo Medical School, São Paulo, Brazil. Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented. PMID: 11133069 [PubMed - indexed for MEDLINE] 5213. Curr Opin Obstet Gynecol. 2000 Dec;12(6):501-5. Leptin and pregnancy outcome. Kratzsch J(1), Höckel M, Kiess W. Author information: (1)Institute of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Germany. Kraj@medizin.uni-leipzig.de Leptin, a recently discovered hormone that is involved in the regulation of body weight, appears to be one of the hormonal factors that signal the body's readiness for sexual maturation and reproduction to the brain. The present review focuses on clinical and experimental studies that describe the roles of maternal and foetal leptin as predictive factors for the physiological and pathophysiological development of the foetus during pregnancy, assisted reproduction and neonatal life. Through evaluating alterations of maternal serum leptin levels, a physiological hyperleptinaemia has been observed to occur, particularly during the second and third trimesters of pregnancy, which is not associated with a decreased food intake or reduced metabolic activity in the pregnant women. This state of leptin resistance is comparable to the condition in obesity. In contrast, hypoleptinaemia is suggested to be an indicator for the cessation of pregnancy, either naturally at term or as a result of pathology at any time during gestation. Thus, an appropriate maternal leptin level seems to be a prerequisite for a normal pregnancy. The main source of foetal leptin is the still immature foetal adipose tissue. As intrauterine growth has been found to be independently associated with cord blood leptin level, it has been suggested that leptin plays a role as a regulator of foetal growth. During assisted reproduction cycles leptin levels in the follicular fluid of patients may be also of predictive value, with low levels predicting therapeutic failure. Finally, the relevance of leptin to postnatal development is reviewed; leptin may be important for regulation of satiety and peripheral metabolism. In summary, leptin appears to be an important permissive factor that is involved in female reproduction. PMID: 11128413 [PubMed - indexed for MEDLINE] 5214. Zentralbl Gynakol. 2000;122(11):549-55. [The significance of leptin for reproduction]. [Article in German] Nawroth F(1), Foth D, Schmidt T, Römer T. Author information: (1)Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universität zu Köln. Frank.Nawroth@medizin.uni-koeln.de Leptin is mainly synthesized by adipocytes and might represent the connecting link between fatty tissue and brain. In reference to reproduction, leptin resistance could play a role particularly in the pathogenesis of the PCO syndrome. However, there exists at present contradictory data on this, so that further clarification is necessary. Leptin interacts with the steroid synthesis to a degree not yet precisely clarified and possesses receptors in numerous tissues, which suggests extensive local and endocrine effects. Its exact significance for the initiation of puberty still remains unknown. The same is true for first data regarding leptin and endometriosis and the interpretation of hyperleptinemia during pregnancy. It is clear that this protein mediates between fatty tissue and the reproductive function. However, the detailed physiologic and pathophysiologic role of leptin in reproduction can only be clarified through further extensive studies. To date there is not yet a practical importance for the measurement of leptin in routine work in reproductive medicine. PMID: 11127767 [PubMed - indexed for MEDLINE] 5215. Am J Med. 2000 Feb;108(2):143-52. Lipodystrophies. Garg A(1). Author information: (1)Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA. The lipodystrophies are rare disorders characterized by selective but variable loss of adipose tissue. Metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver, increase in severity with the extent of fat loss. The lipodystrophies can be classified into two major types: familial and acquired. The main subtypes of familial lipodystrophies are congenital generalized lipodystrophy, an autosomal recessive disorder characterized by near complete lack of metabolically active adipose tissue from birth, and familial partial lipodystrophy, Dunnigan type, an autosomal dominant disorder characterized by loss of subcutaneous fat from the extremities at puberty and excess fat accumulation in the face and neck. Recently, a gene for congenital generalized lipodystrophy was localized to chromosome 9q34, and a gene for familial partial lipodystrophy, Dunnigan type, to chromosome 1q21-22; the genes, however, remain to be identified. Patients with acquired generalized lipodystrophy have generalized loss of subcutaneous fat, but those with acquired partial lipodystrophy have fat loss limited to the face, trunk, and upper extremities. Both varieties occur approximately three times more often in women, begin during childhood, and have underlying autoimmunity. Patients infected with the human immunodeficiency virus (HIV) who are receiving therapy that includes HIV-1 protease inhibitors have been reported to develop a lipodystrophy characterized by loss of subcutaneous fat from the extremities and face but excess fat deposition in the neck and trunk. Localized lipodystrophies can be caused by drugs, pressure, panniculitis, or unknown mechanisms. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia. PMID: 11126308 [PubMed - indexed for MEDLINE] 5216. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S8-10. Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Spiegelman BM(1), Puigserver P, Wu Z. Author information: (1)Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. Bruce_Spiegelman@dfci.harvard.edu There has been a great deal of recent progress in our understanding of the transcriptional control of adipogenesis. Current data suggest that fat cell differentiation involves an interplay between the C/EBP family of transcription factors and PPARgamma. The thermogenic program of brown fat cells may also include a contribution from a new coactivator, PGC-1. Recent data suggests that this coactivator is responsible for activation of thermogenesis and oxidative metabolism in both brown fat and muscle. The PGC-1 dependent program includes both mitochondrial biogenesis and tissue-specific expression of uncoupling proteins. PMID: 11126248 [PubMed - indexed for MEDLINE] 5217. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S67-70. Insulin signaling in the adipocyte. Summers SA(1), Whiteman EL, Birnbaum MJ. Author information: (1)Howard Hughes Medical Institute, University of Pennsylvania Medical School, Philadelphia 19104-6148, USA. Mammalian adipose tissue serves a number of functions, including storage of nutrients for periods of fasting and control of organismal metabolism. Critical to these functions is the capacity of the fat cell to respond to insulin with a significant increase in glucose uptake. It is now generally recognized that the major site of action of insulin in this tissue is the mobilization of a pool of latent, intracellular transport proteins. Nonetheless, the precise signaling pathways which mediate the insulin-stimulated increase in glucose transport remain uncertain. In recent years, the serine/threonine protein kinase Akt/PKB has emerged as an important candidate signaling molecule. Considerable current effort is being directed at trying to definitively establish whether Akt/PKB is an important intermediate in insulin signaling to glucose transport in muscle and fat. PMID: 11126246 [PubMed - indexed for MEDLINE] 5218. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S63-6. The regulation of body fat distribution and the modulation of insulin action. Cases JA(1), Barzilai N. Author information: (1)Division of Endocrinology and the Diabetes Research and Training Center, Albert Einstein College of Medicine, New York 10461, USA. Body fat distribution may determine insulin resistance and its metabolic syndrome in humans, independent of obesity. Surgical removal of visceral fat (VF) in obese rats was associated with decreased leptin plasma levels and its gene expression in subcutaneous fat (SC). Chronic leptin treatment to rats decreased VF specifically supporting the role of leptin in determining fat distribution. Surgical removal of selected VF provided direct evidence of improved in vivo insulin action on hepatic glucose production (HGP) by over 2-fold vs sham-operated control. The impact of decreased VF on improved in vivo insulin action was further supported by obtaining similar decreases in VF by treating rats with leptin (Lep), beta3-aderenoreceptor agonist, or by severe caloric restriction (CR). All these three interventions improved insulin action on the modulation of HGP and were mostly attributed to preservation of hepatic glycogen stores. Because free fatty acids (FFA) plasma levels were unchanged, this effect may not be mediated portally by substrates. Improved peripheral insulin sensitivity and glycogen synthesis was demonstrated only in Lep. These data suggest that VF is a major determinant of hepatic insulin action. In obese rats, the ability of leptin to prevent visceral adiposity and its own expression is attenuated. Thus, the failure of leptin to regulate fat distribution and its own secretion suggest that 'leptin resistance' may be a pathologic feature in obesity. PMID: 11126245 [PubMed - indexed for MEDLINE] 5219. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S57-62. Hunting for human obesity genes? Look in the adipose tissue! Arner P(1). Author information: (1)Karolinska Institute, Department of Medicine, Huddinge Hospital, Stockholm, Sweden. Peter.ARner@medhs.ki.se Over-eating and physical inactivity in combination with genetic factors play the most important roles in the development of over weight in humans. The common genetic components behind excess accumulation of body fat are so far unknown. Studies of candidate genes indicate that most of the genes that associate with obesity control important functions of adipose tissue as well. Furthermore, structural variations in these genes may alter adipose tissue function in a way that promotes obesity. The genes which both are functional in human adipose tissue and associate with obesity are: hormone sensitive lipase, beta2 and beta3-adrenoceptors, tumor necrosis factor alpha, low density lipoprotein receptor, uncoupling protein-1 and peroxisome proliferator activated receptor gamma-2. Other genes are mostly important for obesity among women (for example beta2 -and beta3-adrenoceptors, low density lipoprotein receptor and tumor necrosis factor alpha). Some of these genes may promote obesity by gene-gene interactions (for example beta3-adrenoceptors and uncoupling protein-1) or gene-environmental interactions (for example beta2-adrenoceptors and physical activity). Few genes with no known function in adipose tissue have shown a firm association with excess body fat. The latter suggests that the important human obesity genes also control adipose tissue function. Therefore it might be of value to focus the further hunt for obesity genes on the fat tissue. PMID: 11126244 [PubMed - indexed for MEDLINE] 5220. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S53-6. The role of lipoprotein lipase in adipose tissue development and metabolism. Zechner R(1), Strauss J, Frank S, Wagner E, Hofmann W, Kratky D, Hiden M, Levak-Frank S. Author information: (1)Institute of Molecular Biology, Biochemistry and Microbiology, University of Graz, Austria. rudolf.zechner@kfunigraz.ac.at Lipoprotein lipase (LPL) is essential for the hydrolysis and distribution of triglyceride-rich lipoprotein-associated fatty acids among extrahepatic tissues. Additionally, the enzyme facilitates several non-lipolysis associated functions including the cellular uptake of whole lipoprotein particles and lipophilic vitamins. The tissue-specific variations of LPL expression have been implicated in the pathogenesis of various lipid disorders, obesity and atherosclerosis. Transgenic technology provided the means to study the physiological response to the overexpression or absence of the enzyme in adipose tissue, muscle and macrophages. The effects of varying LPL expression in adipose tissue and muscle are summarized in this article. PMID: 11126243 [PubMed - indexed for MEDLINE] 5221. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S47-52. Recent developments on lipolysis regulation in humans and discovery of a new lipolytic pathway. Lafontan M(1), Sengenes C, Galitzky J, Berlan M, De Glisezinski I, Crampes F, Stich V, Langin D, Barbe P, Rivière D. Author information: (1)Unité INSERM 317, Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France. lafontan@rangueil.inserm.fr In man, the major hormones controlling the lipolytic function are insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). Catecholamines are of major importance for the regulation of lipid mobilization in human adipose tissue and for the increase of non-esterified fatty acid supply to the working muscle. In vitro studies have shown that there are differences in the catecholaminergic control of fat cells from various fat deposits and a number of physiological and pathological alterations of catecholamine-induced lipolysis have been reported. Lipolytic resistance to catecholamines has been reported in subcutaneous adipose tissue, the major fat depot in obese subjects. Multiple alterations in catecholamine signal transduction pathways have been reported. In situ microdialysis allows a physiological exploration of adipose tissue biology. Recent data obtained on the catecholaminergic regulation of lipolysis and lipid mobilization, using microdialysis in humans, will be analysed. A potent lipolytic and lipomobilizing effect of atrial natriuretic peptide has recently been discovered; the mechanisms of action and physiological relevance will also be discussed. PMID: 11126242 [PubMed - indexed for MEDLINE] 5222. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S41-4. Adipose-derived stromal cells--their utility and potential in bone formation. Halvorsen YC(1), Wilkison WO, Gimble JM. Author information: (1)Zen-Bio Inc, Research Triangle Park, North Carolina 27709, USA. yuan-di@zen-bio.com Many organs contain connective tissue or stromal cells and these cells play important roles in growth, development and tissue repair. Subcutaneous adipose tissue represents an accessible reservoir for the isolation of human stromal cells. Ex vivo, the adipose tissue-derived human stromal cells can be expanded more than 100-fold. These primary cultures respond to adipogenic agonists by accumulating lipid and expressing adipocyte specific proteins, including leptin and the peroxisome proliferator-activated receptor gamma (PPARgamma). In contrast, when the adipose tissue-derived stromal cells are exposed to osteogenic factors, they display osteoblastic gene markers and mineralize their extracellular matrix. This work demonstrates that subcutaneous adipose tissue is a readily available source of multipotential stromal cells. It is possible that these cells will be used clinically to treat a broad range of orthopedic, rheumatologic and periodontal disorders. PMID: 11126240 [PubMed - indexed for MEDLINE] 5223. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S36-40. Nitric oxide: a new player in the modulation of energy metabolism. Kapur S(1), Picard F, Perreault M, Deshaies Y, Marette A. Author information: (1)Department of Physiology, Centre de Recherche sur le Métabolisme Energétique, Laval University Hospital Research Center, Québec, Canada. Nitric oxide (NO) is a key messenger molecule in several cell types. NO formation is catalyzed by a family of NO synthases (NOS) that use L-arginine as a substrate. Rat adipose tissue expresses the inducible, macrophage-type, nitric oxide (NO) synthase isoform (iNOS). Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) markedly increases the expression and activity of iNOS in both white and brown adipose tissues, as well as in skeletal muscle. iNOS induction can be reproduced in vitro by treatment of cultured white or brown adipocytes or L6 myocytes with LPS and inflammatory cytokines (TNFalpha, IFNgamma). The physiological role of NO in adipose tissues and skeletal muscle is still obscure. Recent evidence suggests that NO may be implicated in the regulation of energy metabolism. Using both pharmacological and genetic models of iNOS invalidation, we have recently begun to uncover a role for NO in the modulation of glucose transport and lipoprotein hydrolysis. These studies support the emerging concept that NO may fulfill the dual role of modulating energy metabolism in both physiological and pathological conditions as well as contributing to local immune defense during inflammatory processes. PMID: 11126239 [PubMed - indexed for MEDLINE] 5224. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S33-5. Angiotensinogen, angiotensin II and adipose tissue development. Ailhaud G(1), Fukamizu A, Massiera F, Negrel R, Saint-Marc P, Teboul M. Author information: (1)Laboratoire Biologie du Développement du Tissu Adipeux, Centre de Biochimie (UMR 6543 CNRS), UNSA, Nice, France. ailhaud@unice.fr Adipose tissue is an important source of angiotensinogen (AGT). Recent evidence shows that a local renin-angiotensinogen system (RAS) is present in human adipose tissue and may act as a distinct system from plasma RAS. In obese patients, the involvement of angiotensin II (angII) as a consequence of increased plasma AGT secreted from adipose tissue has been proposed in the development of hypertension. Another role of AGT via angII in the development of adipose tissue is supported by the following: (i) in vitro, angII stimulates the production and release of prostacyclin from adipocytes, which in turn promotes the differentiation of precursor cells into adipocytes; (ii) ex vivo and in vivo, both angII and (carba)prostacyclin promote the formation of new fat cells; and (iii) AGT -/- mice exhibit a slowing down of adipose tissue development, as compared to wild-type mice. Altogether the data are consistent with an autocrine/paracrine mechanism implicating AGT, angII and prostacyclin in adipose tissue development. PMID: 11126238 [PubMed - indexed for MEDLINE] 5225. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S3-7. Adipose cell apoptosis: death in the energy depot. Sorisky A(1), Magun R, Gagnon AM. Author information: (1)Department of Medicine and Biochemistry, Microbiology and Immunology, Loeb Health Research Institute at the Ottawa Hospital, University of Ottawa, Canada. asorisky@Lri.ca Apoptosis is critical for mammalian tissue homeostasis, and its disruption has been linked to a wide variety of disorders, including cancer, neurodegenerative disease, autoimmune disease and diabetes. This review will focus on recent investigations that have begun to address the potential role of apoptosis in adipose tissue growth. Evidence for apoptosis occurring in mature adipocytes has been obtained through the use of in vitro cell culture models as well as in vivo studies in rodents and humans. Preadipocytes, fibroblast-like adipocyte precursor cells, can also undergo apoptotic cell death. As they differentiate, preadipocytes acquire a relative resistance to apoptosis. The levels of the cell survival proteins Bcl-2 and neuronal apoptosis inhibitory protein (NAIP) have been observed to increase during adipogenesis. Further research on the effect of apoptosis on adipose tissue cellularity should clarify its influence on adipose tissue mass and distribution. PMID: 11126237 [PubMed - indexed for MEDLINE] 5226. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S23-7. Molecular mechanisms of insulin resistance and the role of the adipocyte. Hotamisligil GS(1). Author information: (1)School of Public Health, Harvard University, Boston, Massachusetts 02115, USA. ghotamis@hsph.harvard.edu Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity. PMID: 11126235 [PubMed - indexed for MEDLINE] 5227. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S15-9. Function of pref-1 as an inhibitor of adipocyte differentiation. Sul HS(1), Smas C, Mei B, Zhou L. Author information: (1)Department of Nutritional Sciences, University of California, Berkeley 94720, USA. hsul@nature.berkeley.edu During conversion of preadipocytes to adipocytes, growth arrest and subsequent activation of adipocyte genes by the transcription factors, C/EBPalpha and PPARgamma, lead to adipogenesis. During differentiation, these cells not only start expressing those genes necessary for adipocyte function, but also undergo changes in morphology to become rounded lipid filled adipocytes. Various factors in cell-cell communication or cell-matrix interaction may govern whether preadipocytes are kept in an undifferentiated state or undergo differentiation. In an attempt to identify molecules that play critical roles in the conversion of preadipocytes to adipocytes, we cloned by differential screening several regulatory molecules, including pref-1. Pref-1 is an inhibitor of adipocyte differentiation and is synthesized as a plasma membrane protein containing 6 EGF-repeats in the extracellular domain. Pref-1 is highly expressed in 3T3-L1 preadipocytes, but is not detectable in mature fat cells. Dexamethasone, a component of standard differentiation agents, inhibits pref-1 transcription and thereby promotes adipogenesis. Downregulation of pref-1 is required for adipose conversion and constitutive expression of pref-1 inhibits adipogenesis. Conversely, decreasing pref-1 levels by antisense pref-1 transfection greatly enhances adipogenesis. The ectodomain of pref-1 is cleaved to generate a biologically active 50kDa soluble form. There are four major forms of membrane pref-1 resulting from alternate splicing. Two of these forms which have a deletion that includes the putative processing site proximal to the membrane do not produce a biologically active soluble form. This indicates that alternate splicing may determine the range of action, juxtacrine or paracrine, of pref-1. PMID: 11126233 [PubMed - indexed for MEDLINE] 5228. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S11-4. A-ZIP/F-1 mice lacking white fat: a model for understanding lipoatrophic diabetes. Reitman ML(1), Gavrilova O. Author information: (1)Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892-1770, USA. mlr@helix.nih.gov The A-ZIP/F-1 mouse is lacking virtually all white adipose tissue. Like humans with extensive deficiencies of adipose tissue, the A-ZIP/F-1 mice develop a severe form of insulin resistant diabetes. We have studied the physiology of the A-ZIP/F-1 mice. Their adaptation to fasting is notable for its rapidity and the use of torpor, a hibernation-like state, to minimize energy needs. Transplantation of adipose tissue reversed the metabolic manifestations in the mice, demonstrating that the lack of adipose tissue is the cause of the insulin resistance. Leptin replacement is not very effective in reversing the diabetes of the A-ZIP/F-1 mice, which contrasts with its efficacy in the aP2-SREBP-lc mouse. PMID: 11126232 [PubMed - indexed for MEDLINE] 5229. Curr Atheroscler Rep. 2000 Sep;2(5):390-6. Mouse models of lipodystrophy. Reue K(1), Péterfy M. Author information: (1)Department of Medicine, University of California, Los Angeles, 11301 Wilshire Blvd., Building 113, Room 312, Los Angeles, CA 90073, USA. reuek@ucla.edu Lipodystrophies are a group of heterogeneous diseases characterized by the loss of adipose tissue and by abnormalities of carbohydrate and lipid metabolism, including insulin resistance, diabetes, and hyperlipidemia. In this review, we describe several mouse models that recapitulate various aspects of the lipodystrophy syndrome, offering insights into the etiology of this condition and potential therapeutic approaches. Studies on these mice suggest that adipose is the primary tissue affected in lipodystrophy, and that secondary leptin deficiency may be responsible for the associated insulin resistance. PMID: 11122770 [PubMed - indexed for MEDLINE] 5230. Adv Drug Deliv Rev. 2000 Dec 15;45(2-3):189-216. Microdialysis in peripheral tissues. de la Peña A(1), Liu P, Derendorf H. Author information: (1)100494 College of Pharmacy, University of Florida, Gainesville, FL 32610-0494, USA. The objective of this review is to survey the recent literature regarding the applications of microdialysis in pharmacokinetic studies and facilitating many other studies in peripheral tissues such as muscle, subcutaneous adipose tissue, heart, lung, etc. It has been reported extensively that microdialysis is a useful technique for monitoring free concentrations of compounds in extracellular fluid (ECF), and it is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses the use of microdialysis technique for ECF sampling in peripheral tissues in animal studies. The second part of the review describes the use of microdialysis for ECF sampling in peripheral tissues in human studies. Microdialysis has been applied extensively to measure both endogenous and exogenous compounds in ECF. Of particular benefit is the fact that microdialysis measures the unbound concentrations in the peripheral tissue fluid which have been shown to be responsible for the pharmacological effects. With the increasing number of applications of microdialysis, it is obvious that this method will have an important place in studying drug pharmacokinetics and pharmacodynamics. PMID: 11108974 [PubMed - indexed for MEDLINE] 5231. J Acquir Immune Defic Syndr. 2000 Oct 1;25(2):130-9. Fat redistribution in indinavir-treated patients with HIV infection: A review of postmarketing cases. Benson JO(1), McGhee K, Coplan P, Grunfeld C, Robertson M, Brodovicz KG, Slater E. Author information: (1)Merck & Company, Inc., West Point, Pennsylvania, USA. joan_benson@merck.com CONTEXT: Fat redistribution (FR) occurring alone or in association with hyperlipidemia has been associated with protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTIs); however, the relationship between FR features, relationship of FR to hyperlipidemia, and pathogenesis of FR is unknown. OBJECTIVE: To characterize the spectrum of FR, assess relationships among FR features, determine trends in occurrence of FR, and determine relationship of FR to hyperlipidemia. DESIGN: Review of postmarketing indinavir reports of FR in Merck & Co. Inc.'s database. SETTING AND PARTICIPANTS: 282 reports of FR among HIV-positive patients taking indinavir submitted through the passive postmarketing system to Merck through February 23, 1998. RESULTS: 282 FR reports were compared across 3 groups: fat accumulation (FA) only, FA with peripheral wasting (FA with PW), and peripheral wasting only (PWO). Of 282 reports, 56% (159 of 282) had FA only, 22% (63 of 282) had FA with PW, and 21% (60 of 282) had PWO. The proportions of reports of PWO was higher in men, whereas the proportion of reports of FA was higher in women. Blood lipids were provided in 93 of 282 reports; were elevated in 69 of 93, and were normal in 24 of 93 reports. Proportions of hyperlipidemia and hypertriglyceridemia reports were significantly higher in the PWO group versus FA only group (p =.024 and.003, respectively) and versus FA with/without PW groups (p =.038 and.005, respectively). Weight gain was more frequently reported in those with FA (100%) or FA with PW (68%), whereas weight loss was usually reported in those with PWO (83%). In all, 98% of patients reporting FR on indinavir for whom a concomitant drug history was available were also taking lamivudine, stavudine, or both. A higher proportion of patients reporting PWO (34 of 60; 56.7%) versus FA (42 of 159; 26.4%) only took both lamivudine and stavudine. CONCLUSIONS: Differences observed from analysis of cases in clinical features, gender, weight change, concomitant medications, and presence of hyperlipidemia among the three groups of FR cases reported to Merck suggests that PWO may be a distinct entity from other features of FR. The data suggest that certain antiretroviral combinations predispose HIV persons to development of FR. PMID: 11103043 [PubMed - indexed for MEDLINE] 5232. Trends Endocrinol Metab. 2000 Dec;11(10):410-6. Lipoatrophy revisited. Reitman ML(1), Arioglu E, Gavrilova O, Taylor SI. Author information: (1)Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8N-250, 10 Center Drive, Bethesda, MD 20892-1770, USA. mlr@helix.nih.gov The lipoatrophy syndromes are a heterogeneous group of syndromes characterized by a paucity of adipose tissue. Severe lipoatrophy is associated with insulin-resistant diabetes mellitus (DM). The loss of adipose tissue can have a genetic, immune, or infectious/drug-associated etiology. Causative mutations have been identified in patients for one form of partial lipoatrophy--Dunnigan-type familial partial lipodystrophy. Experiments using lipoatrophic mice demonstrate that the diabetes results from the lack of fat and that leptin deficiency is a contributing factor. Thiazolidinedione therapy improves metabolic control in lipoatrophic patients; the efficacy of leptin treatment is currently being investigated. PMID: 11091118 [PubMed - indexed for MEDLINE] 5233. Inflamm Res. 2000 Oct;49(10):497-505. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Chinetti G(1), Fruchart JC, Staels B. Author information: (1)U.325 TNSERM, Département d'Athérosclerose, Institut Pasteur de Lille, France. Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease. PMID: 11089900 [PubMed - indexed for MEDLINE] 5234. Nihon Rinsho. 2000 Sep;58 Suppl:151-6. [Development of life fitness check system]. [Article in Japanese] Fukunaga T(1). Author information: (1)Department of Life Sciences, University of Tokyo. PMID: 11085106 [PubMed - indexed for MEDLINE] 5235. Eat Weight Disord. 2000 Sep;5(3):132-42. Anatomy of the adipose organ. Cinti S(1). Author information: (1)Institute of Normal Human Morphology-Anatomy, School of Medicine, University of Ancona, Italy. In rats and mice the adipose organ consists of several subcutaneous and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while most are white and correspond to white adipose tissue. The number of brown adipocytes found in white areas varies with age, strain and environmental conditions. Brown and white adipocyte precursors are morphologically dissimilar. Together with a rich vascular supply, brown areas receive abundant noradrenergic parenchymal innervation. The gross anatomy and histology of the organ vary considerably in different physiological (cold acclimation, warm acclimation, fasting, lactation) and pathological (obesity) conditions, and many important genes, such as leptin and uncoupling protein 1, are also expressed differently in the two cell types. These basic mechanisms should be taken into account when addressing the physiopathology of obesity and its treatment. PMID: 11082792 [PubMed - indexed for MEDLINE] 5236. Eat Weight Disord. 2000 Sep;5(3):116-23. Adipose tissue as an endocrine organ? A review of some recent data. Faloia E(1), Camilloni MA, Giacchetti G, Mantero F. Author information: (1)School of Medicine, University of Ancona, Italy. Recent clinical and experimental data have radically modified the concept of adipose tissue as one solely devoted to energy storage and release. Adipose tissue is a target organ for glucocorticoids. Several studies of the function of the hypothalamic-pituitary-adrenal axis in obese subjects have failed to reach conclusive results. An innovative finding is that adipose tissue produces cortisol from its inactive precursor, cortisone. Identification of leptin, a hormone synthesised by adipose tissue, has ushered in the modern view that it is a true endocrine organ. Leptin is produced by subcutaneous and to a lesser extent by visceral adipose tissue. It has a central role in body weight and especially fat stores regulation, but is also involved in several complex functions, including the physiological processes associated with puberty. Angiotensinogen (AGT), another hormone synthesised in abundance by adipose tissue, is produced in larger amounts by visceral than subcutaneous fat. In addition, in man and animals adipose tissue appears to possess the whole renin-angiotensin system (RAS), suggesting that angiotensin II, the final effector of the system, is locally produced. The function of adipose RAS is not well known; besides participating, together with other hormones and substances, in adipocyte differentiation and fat tissue growth, it could be involved in the pathogenesis of the complications of obesity. All these findings have opened interesting prospects and are expected to yield further stimulating insights into the physiopathology of the adipose organ. PMID: 11082790 [PubMed - indexed for MEDLINE] 5237. Reprod Nutr Dev. 2000 Jul-Aug;40(4):325-58. The adipose conversion process: regulation by extracellular and intracellular factors. Boone C(1), Mourot J, Grégoire F, Remacle C. Author information: (1)Unité Mixte de Recherche sur le Veau et le Porc, INRA, Saint-Gilles, France. boone@st-gilles.rennes.inra.fr White adipose tissue regulates lipid metabolism and acts as a secretory organ. Because of its importance for human health and animal production, many studies have attempted to better understand its development at the cellular and molecular levels by culturing preadipose cells in vitro. This synthesis article describes our current knowledge, acquired by this approach, concerning the regulation of the different steps of the adipocyte differentiation program by extracellular (hormones, cytokines, growth factors, retinoids and fatty acids) and intracellular agents (second messengers and transcription factors). The discrepant effects that have been observed for some of these factors are also discussed. This information is very important in the perspective of a better control of fat deposits in human and breeding species. PMID: 11081662 [PubMed - indexed for MEDLINE] 5238. J Physiol. 2000 Nov 15;529 Pt 1:3-10. Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. Ricquier D(1), Bouillaud F. Author information: (1)Centre de recherche sur l'Endocrinologie Moleculaire et le Developpement, Centre National de la Recherche Scientifique, Meudon 92190, France. ricquier@infobiogen.fr The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regulated uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in the inner mitochondrial membrane referred to as uncoupling protein-1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1's role in cold-induced thermogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent cloning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic diseases and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid-rich diet in obesity-resistant mice suggested that UCP2 is involved in diet-induced thermogenesis. A strong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are known or supposed to participate in basal and regulatory thermogenesis, but their exact biochemical and physiological functions have yet to be elucidated. UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an important role for the UCPs in the control of production of free radicals by mitochondria, and in response to oxidants. PMCID: PMC2270181 PMID: 11080246 [PubMed - indexed for MEDLINE] 5239. Eur J Nutr. 2000 Aug;39(4):127-44. Obesity: molecular bases of a multifactorial problem. Palou A(1), Serra F, Bonet ML, Picó C. Author information: (1)Departament de Biologia Fonamental i Ciències de la Salut, Bioquímica i Biologia Molecular, Universitat de les Illes Balears, Palma de Mallorca, Spain. dbfapoO@ps.uib.es Obesity could well become the most common health problem of the 21st century. There are more opportunities to consume large quantities of food: big portions of tasty, varied food, at reasonable prices, are available everywhere. Moreover, our bodies are better adapted to combat weight loss than to combat weight gain, since for thousands of years our species evolved in circumstances where nutrients were in short supply. The response of each individual to diet and other environmental factors varies considerably, depending on the characteristics of his/her body weight control mechanisms. The differentiating element in the future, especially as regards the dietary and pharmacological control of obesity, will be knowledge of an individual's possible response depending on his/her genetic background. Obesity can occur as a result of genetic or acquired changes in three main types of biochemical processes, which are the main focus of this review: a)feeding control, which determines the sensations of satiety and hunger through processes that depend on an interplay between internal signals (notably leptin) and environmental factors; b) energy efficiency, in particular the activation of thermogenesis mediated by uncoupling proteins (UCPs) that makes it possible to dissipate part of the energy contained in food as heat instead of accumulating it as fat, and c) adipogenesis, the process by which cells specialised in fat storage (adipocytes) are formed, which is controlled by an interplay of transcription factors, including members of the C/EBP, PPARgamma and ADD families. The knowledge of a growing number of genes and molecules implicated in these three types of processes and of their metabolic relationships is leading toward a molecular understanding of the body weight regulatory system, and is paving the way for new methods of obesity control, especially pharmacological but also nutritional and possibly involving genetic intervention. PMID: 11079733 [PubMed - indexed for MEDLINE] 5240. Life Sci. 2000 Oct 6;67(20):2405-16. Troglitazone and related compounds: therapeutic potential beyond diabetes. Fujiwara T(1), Horikoshi H. Author information: (1)Pharmacology and Molecular Biol. Res. Labs., Sankyo. Co. Ltd., Tokyo, Japan. Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "insulin resistance syndrome" which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor. Although PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARgamma activation by PPARgamma agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes. PMID: 11065164 [PubMed - indexed for MEDLINE] 5241. Adv Exp Med Biol. 2000;478:307-25. Exposition to and health effects of residues in human milk. Przyrembel H(1), Heinrich-Hirsch B, Vieth B. Author information: (1)Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany. A great variety of drugs, cosmetics, food ingredients as well as environmental contaminants are secreted with human milk as a result of actual exposure or the accumulated body burden of the mother. Of great concern and least amenable to short-term intervention are persistent substances in the environment with long half-lives in the body due to their lipophilic properties and minimal degradation. Polyhalogenated aromatic hydrocarbons, namely organochlorine pesticides, polychlorinated biphenyls (PCB) and polychlorinated dibenzodioxins (PCDD) and dibenzofurans (PCDF) are fetotoxic, neurotoxic, immunotoxic, some are promoting carcinogens and/or interfere with hormonal receptors. They pass the placenta and equilibrate among the lipid compartments of the body including breast milk lipids. Transplacental exposure is more relevant with regard to physical development and cognitive functioning of the child than postnatal exposure via breastmilk. Restrictions for production, use and release have been successful in decreasing exposure as shown by a downward trend of their contents both in human milk and serum lipids for the last 15 to 20 years. It is difficult to evaluate the potentially late effects of the exposure via breastmilk which is 10 to 100 times higher in industrialised countries than the tolerable daily intake (TDI) of 1 to 4 toxic equivalents (WHO-TEQ) pg/kg/day established in 1998 by WHO for dioxins and dioxin-like PCBs but which lasts for 0.6% of the expected life span only. Carefully conducted long-term follow-up of cohorts with defined exposure levels, with consideration of numerous biological and psychological parameters, is expected to provide the answer. PMID: 11065082 [PubMed - indexed for MEDLINE] 5242. Expert Opin Investig Drugs. 2000 Jun;9(6):1347-61. Insulin sensitiser drugs. Murphy E(1), Nolan JJ. Author information: (1)Metabolic Research Unit, Department of Endocrinology, St. James's Hospital, Dublin, Ireland. elmurphy@indigo.ie Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease. PMID: 11060747 [PubMed - indexed for MEDLINE] 5243. Surg Today. 2000;30(10):937-41. Insulinoma occurring in association with fatty replacement of unknown etiology in the pancreas: report of a case. Eriguchi N(1), Aoyagi S, Hara M, Imayama H, Okuda K, Hashino K, Kanazawa N, Tamae T, Fukuda S, Jimi A. Author information: (1)Department of Surgery, Kurume University School of Medicine, Japan. A 66-year-old woman with a 10-year-history of diabetes mellitus was admitted to our hospital for investigation of several recent attacks of hypoglycemia. Her fasting blood glucose level was very low, at 30-40 mg/dl, and abdominal ultrasonography and computed tomography revealed a tumor in the pancreatic tail with fatty changes. Endoscopic retrograde cholangiopancreatography revealed absence of the main pancreatic duct from the body to tail of the pancreas. Abdominal angiography showed a hypervascular tumor stain in the pancreas, and percutaneous transhepatic portal vein sampling demonstrated a step-up of immunoreactive insulin levels in the splenic vein. Based on these clinical findings, we made a preoperative diagnosis of an insulinoma accompanied by fatty changes in the pancreatic body and tail. During laparotomy for the insulinoma, fat tissue was identified in the anatomic location of the pancreatic body and tail, and resected. Pathological examination of the resected specimen revealed a number of Langerhans islets in the adipose tissue, and an islet cell tumor with fatty replacement of the pancreatic tissue around the tumor. The insulinoma was found not to have caused obstruction of the main pancreatic duct. We present herein a rare case of an insulinoma that developed in the pancreas, and was associated with fatty replacement of unknown etiology. PMID: 11059738 [PubMed - indexed for MEDLINE] 5244. Biol Reprod. 2000 Nov;63(5):1219-28. Leptin in pregnancy. Henson MC(1), Castracane VD. Author information: (1)Departments of Obstetrics and Gynecology, Physiology, and Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA. michael.henson@tulane.edu Leptin is a polypeptide hormone that aids in the regulation of body weight and energy homeostasis and is linked to a variety of reproductive processes in both animals and humans. Thus, leptin may help regulate ovarian development and steroidogenesis and serve as either a primary signal initiating puberty or as a permissive regulator of sexual maturation. Perhaps significantly, peripheral leptin concentrations, adjusted for adiposity, are dramatically higher in females than in males throughout life. During primate pregnancy, maternal levels that arise from adipose stores and perhaps the placenta increase with advancing gestational age. Proposed physiological roles for leptin in pregnancy include the regulation of conceptus growth and development, fetal/placental angiogenesis, embryonic hematopoiesis, and hormone biosynthesis within the maternal-fetoplacental unit. The specific localization of both leptin and its receptor in the syncytiotrophoblast implies autocrine and/or paracrine relationships in this endocrinologically active tissue. Interactions of leptin with mechanisms regulating pre-eclampsia and maternal diabetes have also been suggested. Collectively, therefore, reports suggest that a better understanding of the regulation of leptin and its role(s) throughout gestation may eventually impact those causes of human perinatal morbidity and mortality that are exacerbated by intrauterine growth retardation, macrosomia, placental insufficiency, or prematurity. PMID: 11058523 [PubMed - indexed for MEDLINE] 5245. Nutrition. 2000 Oct;16(10):1013-4. Metabolic abnormalities in cachexia and anorexia. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK. m.j.tisdale@aston.ac.uk An increased glucose requirement by many solid tumors produces an increased metabolic demand on the liver, resulting in an increased energy expenditure. In addition, several cytokines and tumor catabolic products have been suggested as being responsible for the depletion of adipose tissue and skeletal-muscle mass in cachexia. A sulphated glycoprotein of molecular mass 24 kDa, produced by cachexia-inducing tumors and present in the urine of cancer patients actively losing weight, has been shown to be capable of inducing direct muscle catabolism in vitro and a state of cachexia in vivo, with specific loss of the non-fat carcass mass. In vitro studies have shown the bioactivity of this proteolysis-inducing factor to be attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid. Preliminary clinical studies have shown that eicosapentaenoic acid stabilizes body weight and protein and fat reserves in patients with pancreatic carcinoma. Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer. PMID: 11054609 [PubMed - indexed for MEDLINE] 5246. Nutrition. 2000 Oct;16(10):996-1005. Anorexia of infection: current prospects. Langhans W(1). Author information: (1)Institute of Animal Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. wolfgang.langhans@inw.agrl.ethz.ch The anorexia of infection is part of the host's acute phase response (APR). Despite being beneficial in the beginning, long lasting anorexia delays recovery and is ultimately deleterious. Microbial products such as bacterial cell wall compounds (e.g., lipopolysaccharides and peptidoglycans), microbial nucleic acids (e. g., bacterial DNA and viral double-stranded RNA), and viral glycoproteins trigger the APR and presumably also the anorexia during infections. Microbial products stimulate the production of proinflammatory cytokines (e.g., interleukins [ILs], tumor necrosis factor-alpha, interferons), which serve as endogenous mediators. Several microbial products and cytokines reduce food intake after parenteral administration, suggesting a role of these substances in the anorexia during infection. Microbial products are mainly released and cytokines are produced in the periphery during most infections; they might inhibit feeding through neural and humoral pathways activated by their peripheral actions. Activation of peripheral afferents by locally produced cytokines is involved in several cytokine effects, but is not crucial for the anorectic effect of microbial products and IL-1beta. Cytokines increase leptin expression in the adipose tissue, and leptin may contribute to, but is also not essential for, the anorectic effects of microbial products and cytokines. In addition, a direct action of cytokines and microbial products on the central nervous system (CNS) is presumably involved in the anorexia during infection. Cytokines can reach CNS receptors through circumventricular organs and through active or passive transport mechanisms or they can act through receptors on endothelial cells of the brain vasculature and stimulate the release of subsequent mediators such as eicosanoids. De novo CNS cytokine synthesis occurs in response to peripheral infections, but its role in the accompanying anorexia is still open to discussion. Central mediators of the anorexia during infection appear to be neurochemicals involved in the normal control of feeding, such as serotonin, dopamine, histamine, corticotropin releasing factor, neuropeptide Y, and alpha-melanocyte-stimulating hormone. Reciprocal, synergistic, and antagonistic interactions between various pleiotropic cytokines, and between cytokines and neurochemicals, form a complex network that mediates the anorexia during infection. Current knowledge on the mechanisms involved suggests some therapeutic options for treatment. Substances that block common key steps in cytokine synthesis or cytokine action, or inhibitors of eicosanoid synthesis, may hold more promise than attempts to antagonize specific cytokines. To target the neurochemical mediation of the anorexia during infection may be even more efficient. Future research should address these neurochemical mechanisms and the cytokine actions at the blood-brain barrier. Further unanswered questions concern the modulation of the anorexia during infection by gender and nutritional state. PMID: 11054606 [PubMed - indexed for MEDLINE] 5247. Nutrition. 2000 Oct;16(10):967-75. Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. York DA(1), Singer L, Thomas S, Bray GA. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. yorkda@pbrc.edu The effects of topiramate on food intake and body composition were investigated in rats fed a high-fat diet and compared with rats that were pair fed or treated with D-fenfluramine. Topiramate (40 mg. kg. d for 80 d) reduced body-weight gain in a manner similar to that of pair-fed rats and D-fenfluramine-treated rats. The reduction in body fat accounted for all the weight reduction after topiramate treatment but not after pair feeding or D-fenfluramine treatment. Topiramate reduced food intake acutely and increased metabolic rate. There were also significant reductions in leptin, insulin, and corticosterone. In the hypothalamus, topiramate increased mRNA for neuropeptide Y, reduced mRNA for neuropeptide-Y Y1 and Y5 receptors, corticotropin-releasing hormone (CRH), and type II glucocorticoid receptors but had no effect on mRNA levels for the short or long form of the leptin receptor. In peripheral tissues, topiramate reduced leptin mRNA in adipose tissue, had no effect on uncoupling protein 1 mRNA in brown adipose tissue but had tissue-selective effects on uncoupling proteins 2 and 3 mRNA levels in white and brown adipose tissues and muscle. In conclusion, topiramate is an effective inhibitor of weight gain in rats on a high-fat diet, but the mechanism through which the change in energy balance is achieved is unclear. PMID: 11054603 [PubMed - indexed for MEDLINE] 5248. Nutrition. 2000 Oct;16(10):961-6. Influence of topiramate in the regulation of energy balance. Richard D(1), Ferland J, Lalonde J, Samson P, Deshaies Y. Author information: (1)Centre de recherche de l'hôpital Laval et Centre de recherche sur le Métabolisme énergétique de l'Université Laval, Faculté de Médecine, Université Laval, Québec, Canada. denis.richard@phs.ulaval.ca Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from D-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague-Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated. Copyright1999 ASCRS and ESCRS PMID: 11054602 [PubMed - indexed for MEDLINE] 5249. Nutrition. 2000 Oct;16(10):916-23. Neuropeptides and obesity. Beck B(1). Author information: (1)INSERM U.308 Mécanismes de Régulation du Comportement Alimentaire, Nancy, France. bernard.beck@nancy.inserm.fr This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by alpha-melanocyte-stimulating hormone (alpha-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc. ). The pathways used by all of these neuromodulators include numerous brain areas, but some interest has returned to the classic ones such as the ventromedial and lateral hypothalamic areas because of the recent discovery of some peptides (orexins and melanin-concentrating hormone for the lateral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalamus). All of these pathways are redundant and function in a coordinated manner and sometimes by the novel expression of a peptide in an unusual area. The importance of such a phenomenon in obesity remains to be determined. Even if single-gene mutations are exceptions in human obesity, the study of genetic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develop new drug treatments for obesity that have to be associated with drastic changes in lifestyle (feeding, work habits, and physical activity) for a complete efficiency. PMID: 11054597 [PubMed - indexed for MEDLINE] 5250. Nutrition. 2000 Oct;16(10):903-8. The autonomic nervous system, adipose tissue plasticity, and energy balance. Pénicaud L(1), Cousin B, Leloup C, Lorsignol A, Casteilla L. Author information: (1)UMR 5018 CNRS-UPS, Toulouse, France. penicaud@rangueil.inserm.fr In most mammals, two types of adipose tissue, white and brown, are present. Both are able to store energy in the form of triacylglycerols and to hydrolyze them into free fatty acids and glycerol. Whereas white adipose tissue can provide lipids as substrates for other tissues according to the needs of the organism, brown adipose tissue will use fatty acids for heat production. Over the long term, white fat mass reflects the net balance between energy expenditure and energy intake. Even though these two parameters are highly variable during the life of an individual, most adult subjects remain relatively constant in body weight throughout their lives. This observation suggests that appetite, energy expenditure, and basal metabolic rate are linked. An important characteristic of the adipose tissue is its enormous plasticity for volume and cell-number variations and an apparent change in phenotype between the brown and white adipose tissues. The present review focuses on the cellular mechanisms participating in the plasticity of adipose tissues and their regulation by the autonomic nervous system. There is compelling evidence with regard to the importance of the nervous system in the regulation of adipose tissue mass, either brown or white, by acting on the metabolic pathways and on the plasticity (proliferation, differentiation, transdifferentiation, apoptosis) of these tissues. A better comprehension of the different mechanisms involved in the feedback loop linking the brain and these two types of adipose tissue will lead to a better understanding of the pathophysiology of various disorders including obesity, cachexia, anorexia, and type II diabetes mellitus. PMID: 11054595 [PubMed - indexed for MEDLINE] 5251. Nutrition. 2000 Oct;16(10):894-902. Adiposity signals and the control of energy homeostasis. Woods SC(1), Seeley RJ. Author information: (1)Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA. steve.woods@psychiatry.uc.edu Recent technologic innovations have enabled probing the workings of individual cells and even molecules. As a result, our knowledge of the biological controls over eating and the regulation of body adiposity is increasing at a rapid pace. We review the evidence that food intake is controlled by separate but interacting groups of molecular signals. One group, termed satiety signals, are proportional to what is being consumed and help to determine meal size. Cholecystokinin is the best known of these, and its premeal administration causes a dose-dependent reduction of meal size. In and of itself, however, cholecystokinin (and other satiety signals) has little impact on body-fat stores. The second group, termed adiposity signals, circulate in proportion to body adiposity and enter the brain, where they interact with satiety signals in the brainstem and hypothalamus. Insulin and leptin are the best known of these adiposity signals, and the administration of either into the brain causes a dose-dependent reduction of both food intake and body weight. Within the brain, parallel but opposing pathways originating in the hypothalamic arcuate nuclei integrate adiposity signals with satiety signals. Those with a net anabolic effect increase food intake and reduce energy expenditure and are represented (among many such signals) by neuropeptide Y; those with a net catabolic effect decrease food intake and energy expenditure and are represented by brain melanocortins. This complex regulatory mechanism allows individuals to adapt their feeding schedule to idiosyncratic environmental constraints, eating whenever it is desirable or possible. Body-weight regulation occurs as adiposity signals alter the efficacy of meal-generated satiety signals. PMID: 11054594 [PubMed - indexed for MEDLINE] 5252. J Nutr. 2000 Nov;130(11):2623-5. The biology of somatotropin in adipose tissue growth and nutrient partitioning. Etherton TD(1). Author information: (1)Department of Dairy and Animal Science, The Pennsylvania State University, University Park, PA 16802, USA. During the past 20 years, much has been learned about how porcine somatotropin (pST) affects growth and nutrient partitioning in growing pigs. The development of techniques to produce large quantities of recombinantly derived pST enabled numerous long-term studies to be conducted in which the effects of daily pST administration could be evaluated. Collectively, these studies established that treatment of growing pigs with pST markedly stimulated muscle growth and, concurrently, reduced fat deposition. In growing pigs, maximally effective doses of pST increase average daily gain as much as 10-20%, improve feed efficiency 15-30%, decrease adipose tissue mass and lipid accretion rates by as much as 50-80% and concurrently increase protein deposition by 50%. These effects are associated with a decrease in feed intake of approximately 10-15%. These responses occur because pST has a wide array of biological effects that modulate nutrient partitioning between adipose tissue and skeletal muscle. The decrease in adipose tissue growth is due to a reduction in lipogenesis that is the consequence of pST blunting the effects of many insulin-dependent events. With respect to fatty acid synthase (FAS), a pace-setting enzyme in the lipogenic pathway, enzyme activity is markedly reduced by pST. This is the result of a pST-mediated decrease in FAS mRNA levels that occurs because FAS gene transcription is decreased. The consequence of the decrease in lipid synthesis is that adipocyte hypertrophy is impaired and, hence, tissue growth. This review will provide an overview of some of the biological effects of pST in adipose tissue and will discuss what is known about the underlying mechanisms that account for these effects. PMID: 11053496 [PubMed - indexed for MEDLINE] 5253. Z Orthop Ihre Grenzgeb. 1999 Jul-Aug;137(4):376-8. [Synovial hemangioma within Hoffa's fat pad as the cause of anterior knee pain. 2 cases within a family and review of the literature]. [Article in German] Petersen W(1), Rafii M, Ellwanger S, Laprell H. Author information: (1)Lubinusklinik, Christian-Albrechts-Universität zu Kiel. An 18 years old man and his younger sister suffered from anterior knee pain. Cause is a soft tissue tumor located within Hoffa's fat pad however in both cases. The tumor has been excised and the histological examination demonstrated the diagnosis synovial hemangioma. A literature search shows that synovial hemangiomas are rare soft tissue tumors. They mainly involve the knee joint. Mean age is the second decade of life and most authors observed severe degenerative changes in the involved knee joint. There are no reports about familiar accumulation within the literature. Familiar accumulation of synovial hemangiomas however have been described for cerebral, skin and hepatic manifestations but not for synovial hemangiomas. PMID: 11051028 [PubMed - indexed for MEDLINE] 5254. Sports Med. 2000 Oct;30(4):249-68. Strength training in the elderly: effects on risk factors for age-related diseases. Hurley BF(1), Roth SM. Author information: (1)Department of Kinesiology, College of Health & Human Performance, University of Maryland, College Park 20742, USA. bh24@umail.umd.edu Strength training (ST) is considered a promising intervention for reversing the loss of muscle function and the deterioration of muscle structure that is associated with advanced age. This reversal is thought to result in improvements in functional abilities and health status in the elderly by increasing muscle mass, strength and power and by increasing bone mineral density (BMD). In the past couple of decades, many studies have examined the effects of ST on risk factors for age-related diseases or disabilities. Collectively, these studies indicate that ST in the elderly: (i) is an effective intervention against sarcopenia because it produces substantial increases in the strength, mass, power and quality of skeletal muscle; (ii) can increase endurance performance; (iii) normalises blood pressure in those with high normal values; (iv) reduces insulin resistance; (v) decreases both total and intra-abdominal fat; (vi) increases resting metabolic rate in older men; (vii) prevents the loss of BMD with age; (viii) reduces risk factors for falls; and (ix) may reduce pain and improve function in those with osteoarthritis in the knee region. However, contrary to popular belief, ST does not increase maximal oxygen uptake beyond normal variations, improve lipoprotein or lipid profiles, or improve flexibility in the elderly. PMID: 11048773 [PubMed - indexed for MEDLINE] 5255. Biochemistry (Mosc). 2000 Sep;65(9):991-1005. Fatty acids as uncouplers of oxidative phosphorylation. Samartsev VN(1). Author information: (1)Mari State University, Yoshkar-Ola, 424000, Russia. This review summarizes data on the uncoupling effect of fatty acids on oxidative phosphorylation in mitochondria of various animal and plant tissues. PMID: 11042489 [PubMed - indexed for MEDLINE] 5256. Trends Endocrinol Metab. 2000 Nov;11(9):356-61. GLUT4 and company: SNAREing roles in insulin-regulated glucose uptake. Cheatham B(1). Author information: (1)Research Division of Joslin Diabetes Center and the Department of Medicine, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA. Bentley.Cheatham@joslin.harvard.edu The primary physiological role of insulin is in glucose homeostasis. This is accomplished through the inhibition of gluconeogenesis in the liver and the stimulation of glucose uptake into insulin-sensitive tissues, such as adipose tissue, skeletal muscle and cardiac muscle. The ability of insulin to stimulate glucose uptake relies on a complex signaling cascade that leads to the translocation of glucose transporter protein 4 (GLUT4) from an intracellular compartment to the plasma membrane, which results in increased glucose uptake. Defects in the ability of insulin to regulate this key metabolic event can lead to insulin resistance and non-insulin-dependent type 2 diabetes mellitus (T2DM). To design effective treatments for diabetes, there have been major efforts to understand the insulin-regulated mechanisms that govern glucose uptake. These have involved defining the components of the insulin signaling network and identifying the molecular machinery that is used to translocate GLUT4. PMID: 11042465 [PubMed - indexed for MEDLINE] 5257. Eur J Clin Nutr. 2000 Jun;54 Suppl 3:S121-5. Lipid metabolism in the elderly. Toth MJ(1), Tchernof A. Author information: (1)Department of Medicine, University of Vermont, Burlington 05405, USA. mtoth@zoo.uvm.edu Adiposity increases with age. The size of the adipose tissue mass is determined by the balance between the recruitment of lipid substrates (ie free fatty acids) from adipose tissue and their subsequent oxidation by respiring tissues. Thus, change in the liberation of free fatty acids from adipocytes, the capacity of respiring tissue to oxidize free fatty acids or a combination of both may contribute to the age-related increase in body fat. This review focuses on studies that have examined the effect of age on free fatty acid release and the capacity of respiring tissues to oxidize fat. In vitro studies have shown that hormonal and pharmacological stimulation of lipolysis diminished with age. Despite this cellular defect, however, in vivo studies suggest that fatty acids are recruited from adipose tissue in excess of the energy demands of the body in older individuals. The capacity of respiring tissues, in particular skeletal muscle, to oxidize fat declines with age. The age-related decrease in fat oxidation is related to a reduction in both the quantity and oxidative capacity of respiring tissue. Taken together, these results suggest that an age-related decrease in the capacity of respiring tissues to oxidize fat, rather than decreased free fatty acid release, is a more likely determinant of lipid imbalance and the age-related increase in adiposity. Interventions designed to increase the mass or oxidative capacity of respiring tissue, therefore, may be effective in counteracting the age-related reduction in fat oxidation. PMID: 11041083 [PubMed - indexed for MEDLINE] 5258. Eur J Clin Nutr. 2000 Jun;54 Suppl 3:S48-53. Fat and protein redistribution with aging: metabolic considerations. Beaufrère B(1), Morio B. Author information: (1)Laboratoire de Nutrition Humaine, Université d'Auvergne/INRA and CRNH Auvergne, Clermont Ferrand, France. beaufrer@clermont.inra.fr Aging is associated with a redistribution of both fat and lean tissue within the body. Intra-abdominal fat (IAF) accumulates more rapidly than total fat while the loss of lean body mass is mostly due to sarcopenia. Increase of visceral fat plays a major role in the pathogenesis of insulin resistance, which leads to type II diabetes and also to cardiovascular diseases. This review is focussed on the relationships that exist between the accumulation of IAF and insulin resistance during aging. The various methods available for assessing IAF are briefly reviewed; imaging techniques are the only reference methods, and their availability is limited. Insulin resistance that appears with aging is caused by accumulation of IAF, rather than by aging per se. Studies done in type II diabetic patients suggest that the metabolic link between increased IAF and insulin resistance could well be the increased availability and/or oxidation of free fatty acids. Physical inactivity certainly enhances both IAF accumulation and, more directly, insulin resistance. Independent and significant effects of menopause or of sarcopenia on insulin resistance remain to be established. The influence of hormonal changes, reduced fatty acid utilization, and resistance to leptin on IAF accumulation are also discussed. Although it is difficult to determine the independent influence of each of these factors, IAF accumulation seems to be a central and important determinant of cardiovascular risk. The last part of this review is devoted to protein metabolism and focused on the preservation of protein metabolism in the liver during aging. PMID: 11041075 [PubMed - indexed for MEDLINE] 5259. Eur J Clin Nutr. 2000 Jun;54 Suppl 3:S33-9. Body weight and weight change and their health implications for the elderly. Seidell JC(1), Visscher TL. Author information: (1)Department of Chronic Diseases Epidemiology, National Institute of Public Health, Bilthoven, The Netherlands. j.seidell@rivm.nl After the age of 60 y, body weight on average tends to decrease. The contribution of fat mass to this weight loss is relatively small, but fat tends to be redistributed with advancing age toward more abdominal (particularly visceral) fat. Anthropometric data are relatively poor indicators of these aging processes. This may be one of the explanations why the relationship between high body mass index and mortality is less pronounced in older than in younger people. Reduced lipolysis in the visceral fat depot with aging is among potential explanations why increased visceral fat seems to be less harmful in elderly subjects compared to young adults. Even though the relative contribution of increased fat mass to mortality may be less pronounced in elderly people, the impact on disability and functional limitations is found to be important from both a clinical and a public health point of view. At the other end of the scale studies have shown that low body mass index and weight loss in the elderly are both strong predictors of subsequent mortality. This cannot be explained by effects of smoking and early mortality after baseline. There are only few systematic studies comparing the predictive validity of different anthropometric data for mortality. One recent prospective study showed that a high waist circumference (in nonsmoking men) may be a better predictor of all-cause mortality than high body mass index and waist/hip ratio. Low BMI was a better predictor of mortality than low waist circumference. In conclusion changes in body composition and fat distribution with aging are poorly captured by standard anthropometric data. Low lean body mass is probably better reflected by low BMI, whereas increased (abdominal) fatness is better reflected by increased waist circumference. PMID: 11041073 [PubMed - indexed for MEDLINE] 5260. Medsurg Nurs. 2000 Aug;9(4):183-8. Pickwickian syndrome: the challenge of severe sleep apnea. Marchiondo K(1). Author information: (1)Department of Nursing Science, Lincoln University, Jefferson City, MO, USA. Pickwickian syndrome is a severe form of sleep apnea in obese persons which involves mechanical impairment of ventilation resulting in greatly compromised gas exchange. Manifestations of the syndrome are associated with deposits of adipose tissue around the abdomen and diaphragm and are completely reversible with weight loss. Since sleep apnea is now recognized as a significant chronic health problem, nurses in intensive care, medical-surgical, and home care settings are increasingly challenged to provide competent assessment, care, and rehabilitation of affected individuals. PMID: 11040660 [PubMed - indexed for MEDLINE] 5261. J Leukoc Biol. 2000 Oct;68(4):437-46. Leptin in the regulation of immunity, inflammation, and hematopoiesis. Fantuzzi G(1), Faggioni R. Author information: (1)Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. Giamila.Fantuzzi@UCHSC.edu Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis. PMID: 11037963 [PubMed - indexed for MEDLINE] 5262. Neuropathology. 2000 Sep;20 Suppl:S25-9. Nasu-Hakola disease: a review of its leukoencephalopathic and membranolipodystrophic features. Tanaka J(1). Author information: (1)Division of Neuropathology, Jikei University School of Medicine, Tokyo, Japan. jtanaka@jikei.ac.jp The clinicopathological features of Nasu-Hakola disease are described by reviewing previously reported cases and adding consideration to newly disclosed evidence. This disease is an autosomal recessive disorder characterized by membranocystic lipodystrophy in the skeletal system and sclerosing leukoencephalopathy in the nervous system. The leukoencephalopathic alterations are demyelinization of the cerebral white matter, associated with conspicuous fibrillary gliosis and preservation of the subcortical arcuate fibers. Sudanophilic granules are focally scattered in the perivascular space or widely infiltrated in the affected white matter, and some neuronal loss with deposits of calcospherites is encountered in the basal ganglia and also in the thalamus. Spheroid formation with an increased number of neurofilaments in the neuronal axon is considered a possible pathogenesis, and a primary vascular mechanism is also suggested. Interestingly, most of the reported cases of Nasu-Hakola disease are from Japan and Finland which suggests heredofamilial background as a cause. PMID: 11037183 [PubMed - indexed for MEDLINE] 5263. Annu Rev Cell Dev Biol. 2000;16:145-71. Molecular regulation of adipogenesis. Rosen ED(1), Spiegelman BM. Author information: (1)Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. edrosen@massmed.org Adipogenesis, or the development of fat cells from preadipocytes, has been one of the most intensely studied models of cellular differentiation. In part this has been because of the availability of in vitro models that faithfully recapitulate most of the critical aspects of fat cell formation in vivo. More recently, studies of adipogenesis have proceeded with the hope that manipulation of this process in humans might one day lead to a reduction in the burden of obesity and diabetes. This review explores some of the highlights of a large and burgeoning literature devoted to understanding adipogenesis at the molecular level. The hormonal and transcriptional control of adipogenesis is reviewed, as well as studies on a less well known type of fat cell, the brown adipocyte. Emphasis is placed, where possible, on in vivo studies with the hope that the results discussed may one day shed light on basic questions of cellular growth and differentiation in addition to possible benefits in human health. PMID: 11031233 [PubMed - indexed for MEDLINE] 5264. Ther Umsch. 2000 Aug;57(8):511-5. [Principles of dietary treatment of obesity]. [Article in German] Ditschuneit HH(1). Author information: (1)Abteilung für Gastroenterologie, Endokrinologie, Ernährungswissenschaften und Stoffwechsel, Universitätsklinikum Ulm. herwig.ditschuneit@medizin.uni-ulm.de One of the first steps in a clinical approach to any obese subject should be focused on the reduction and/or normalization of any potential or existing metabolic abnormality. Overeating and/or unbalanced food intake remains the major element in the origin and maintenance of obesity. The reduction of energy intake is the basis of successful weight loss. In obese subjects there are huge amounts of energy stored, mainly in the adipose tissue, which are mobilized according to the size and duration of an energy deficit. Considerable studies have been devoted to finding the optimal dietary approach that would promote rapid weight loss while maximizing the depletion of adipose tissue and conserving body protein. During fasting adipose tissue lipolysis rate increases and liberated unesterified fatty acids are oxidized in muscle and liver. The liver produces ketones which are oxidized in muscle and brain. The energy need of the brain is not sufficiently covered by ketone oxidation, therefore additional glucose must be provided. The liver produces glucose by gluconeogenesis using amino acids from muscle protein. Because of limited protein sources, protein must be given during energy restricted diet. Besides protein also vitamins, minerals, trace elements, fiber, and linoleic acid must be substituted during fasting and during treatment with very low calorie diets. Meal replacements are helpful to fulfil all the requirements. There is consensus that the first step in dietary treatment is an energy restricted diet with a calorie deficit of at least 600 Kcal/day, but more than 800 Kcal/day must be provided, with all essential nutrients. Observing the regulations, weight reduction with appropriate diet plans improves metabolic disturbances. PMID: 11026088 [PubMed - indexed for MEDLINE] 5265. Ther Umsch. 2000 Aug;57(8):488-92. [Adipose tissue and obesity]. [Article in German] Kather H(1). Author information: (1)Klinisches Institut für Herzinfarktforschung, Medizinischen Universitätsklinik, Heidelberg. Adipose tissue is not simply a storage depot. Adipocytes secrete hormones, growth factors and cytokines, such as leptin and TNF-alpha, as well as proteins that are related to the immune system and vascular functions. Through this network of endocrine, paracrine, and autocrine signals fat cells participate in the regulation of energy homeostasis, host defense and reproduction, and may also contribute to the development of pathological states, such as insulin resistance. Adipose tissue is confined to distinct depots. In Cushing's disease or following treatment of AIDS, certain adipose depots enlarge whereas others shrink, suggesting the existence of site-specific differences in fat cell function. Increases in adipocyte number occur via replication of preadipocytes, a process that is not restricted to infancy but occurs throughout life. In contrast to still widely-held beliefs, mature fat cells can be eliminated by dedifferentiation or apoptosis. PPAR-gamma, a transcription factor that is activated by fatty acids and prostaglandins, plays a central role in adipose conversion of preadipocytes and appears to participate in controlling the size of mature fat cells as well. PMID: 11026084 [PubMed - indexed for MEDLINE] 5266. Domest Anim Endocrinol. 2000 Aug;19(2):63-74. Effects of underfeeding during the weaning period on growth, metabolism, and hormonal adjustments in the piglet. Le Dividich J(1), Sève B. Author information: (1)Institut National de la Recherche Agronomique, Unité Mixte de Recherches sur le Veau et le Porc, F-35590, Saint Gilles, France. didi@st-gilles.rennes.inra.fr PMID: 11025186 [PubMed - indexed for MEDLINE] 5267. Regul Pept. 2000 Aug 25;92(1-3):51-6. Leptin: a possible link between food intake, energy expenditure, and reproductive function. Magni P(1), Motta M, Martini L. Author information: (1)Istituto di Endocrinologia, Università degli Studi di Milano, Milan, Italy. paolo.magni.unimi.it Several regulatory substances participate in the regulation of both food intake/energy metabolism and reproduction in mammals. Most of these neuropeptides originate and act in the central nervous system, mainly at specific hypothalamic areas. Leptin represents a signal integrating all these functions, but originating from the periphery (adipose tissue) and carrying information mainly to central structures. Observations in rodent models of leptin deficiency have suggested that leptin participates in the control of reproduction, in conjunction with that of food intake and energy expenditure. Indeed, leptin administration resulted in the restoration of normal body weight, food intake, and fertility in the ob mouse, lacking circulating leptin. Specific targets of leptin in the hypothalamus are neurons expressing neuropeptide Y, proopiomelanocortin and gonadotropin-releasing hormone, but the presence of leptin receptors in peripheral reproductive structures suggests that leptin might also act at these sites. Human obesity is often associated with reproductive disturbances. The situation in humans is more complex than in the animal models of leptin deficit and the presence of leptin resistance in these subjects is suggested. In conclusion, leptin fits many requirements for a molecule linking the regulation of energy balance and the control of reproduction. PMID: 11024565 [PubMed - indexed for MEDLINE] 5268. Vet Clin North Am Food Anim Pract. 2000 Jul;16(2):215-30, v. Ruminant adaptation to negative energy balance. Influences on the etiology of ketosis and fatty liver. Herdt TH(1). Author information: (1)Nutrition Section, Michigan State University, East Lansing, USA. herdt@pilot.msu.edu Ketosis and fatty liver occur when physiologic mechanisms for the adaptation to negative energy balance fail. Failure of hepatic gluconeogenesis to supply adequate glucose for lactation and body needs may be one cause of ketosis; however, poor feedback control of nonesterified fatty acid release from adipose tissue is another likely cause of ketosis and fatty liver. The types of ketosis resulting from these two metabolic lesions may require different therapeutic and prophylactic approaches. PMID: 11022337 [PubMed - indexed for MEDLINE] 5269. Clin Pharmacokinet. 2000 Sep;39(3):215-31. Effects of obesity on pharmacokinetics implications for drug therapy. Cheymol G(1). Author information: (1)Department of Pharmacology, Faculty of Medicine Saint-Antoine, Paris, France. Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations. PMID: 11020136 [PubMed - indexed for MEDLINE] 5270. J Mol Endocrinol. 2000 Oct;25(2):149-56. Role of aromatase in sex steroid action. Simpson ER(1). Author information: (1)Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia. PMID: 11013343 [PubMed - indexed for MEDLINE] 5271. Biochem Pharmacol. 2000 Oct 15;60(8):1245-50. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Neve BP(1), Fruchart JC, Staels B. Author information: (1)Département d'Athérosclérose, U.325 INSERM, Institut Pasteur de Lille, France. Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well. PMID: 11007963 [PubMed - indexed for MEDLINE] 5272. Biochem Pharmacol. 2000 Oct 15;60(8):1027-32. Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases. Latruffe N(1), Cherkaoui Malki M, Nicolas-Frances V, Clemencet MC, Jannin B, Berlot JP. Author information: (1)LBMC, University of Burgundy, 21000 Dijon, France. latruffe@u-bourgogne.fr The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPAR alpha, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPAR beta/delta, which is not very well known yet, appears to be more specifically activated by fatty acids. PPAR gamma (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411-418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPAR alpha is mainly expressed in liver and kidney, while PPAR beta/delta is almost constitutively expressed. In contrast, PPAR gamma is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRalpha (9-cis-retinoic acid receptor alpha) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPAR alpha in the regulation of peroxisomal fatty acid beta-oxidation is presented. In relation to this, we showed that PPAR alpha activates peroxisomal beta-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183-186, 1995). Moreover, rat liver PPAR alpha regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001-1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316-321, 1995). From all these findings, PPAR alpha and kinases appear to play an important role in lipid homeostasis. PMID: 11007938 [PubMed - indexed for MEDLINE] 5273. Proc Nutr Soc. 2000 Aug;59(3):397-404. Signalling in body-weight homeostasis: neuroendocrine efferent signals. Webber J(1), Macdonald IA. Author information: (1)School of Medical and Surgical Sciences, University of Nottingham, Queen's Medical Centre, UK. jonathan.webber@nottingham.ac.uk Whilst a number of neuroendocrine afferent signals are implicated in body-weight homeostasis, the major efferent pathway is the sympathetic nervous system (SNS), which affects both energy expenditure and substrate utilization. Thyroid hormones and their interactions with the SNS may also have a role to play. Some of the variability in resting energy expenditure can be explained by differences in SNS activity, and beta-blockade can reduce energy expenditure and diet-induced thermogenesis in Caucasians. Excess energy intake leads to SNS activation and increased diet-induced thermogenesis. A relationship has also been demonstrated between spontaneous physical activity and SNS activity. In many animal models the SNS activates brown adipose tissue thermogenesis, hence increasing diet-induced thermogenesis and dissipating excess energy as heat. This effect is mediated via beta3-adrenoceptors and activation of an uncoupling protein unique to brown adipose tissue. Homologous proteins have been identified in human tissues and may play a role in human energy expenditure. How the SNS is implicated in this process is unclear at present. beta3-Adrenoceptor polymorphism has been associated both with lower resting energy expenditure in some populations and with reduced autonomic nervous system activity. SNS effects on substrate cycling may also play a role. In the development of obesity the effects of the SNS in promoting lipolysis and fat oxidation are likely to be at least as important as its effects on thermogenesis. beta-Blockade has relatively small effects on energy expenditure, but more pronounced effects on reducing lipid oxidation, so tending to favour fat storage and weight gain. Low lipid oxidation is a risk factor for weight gain, and there is some evidence that low basal sympathetic nerve activity in muscle is associated with this process. Overall, the relationship between SNS activity and obesity is complex, with evidence of low SNS activity occurring in some, but not all, studies. PMID: 10997655 [PubMed - indexed for MEDLINE] 5274. Proc Nutr Soc. 2000 Aug;59(3):373-84. Afferent signals regulating food intake. Bray GA(1). Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808, USA. BrayGA@pbrc.edu Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. beta-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development. PMID: 10997653 [PubMed - indexed for MEDLINE] 5275. Proc Nutr Soc. 2000 Aug;59(3):359-71. Role of adipose tissue in body-weight regulation: mechanisms regulating leptin production and energy balance. Havel PJ(1). Author information: (1)Department of Nutrition, University of California, Davis 95616, USA. pjhavel@ucdavis.edu Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor alpha, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity. PMID: 10997652 [PubMed - indexed for MEDLINE] 5276. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S109-12. Thyroid and lipid metabolism. Pucci E(1), Chiovato L, Pinchera A. Author information: (1)Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del lavoro, Universita' di Pisa, Italy. a.pinchera@endoc.med.unipi.it Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With specific regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is influenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esterified fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia. PMID: 10997623 [PubMed - indexed for MEDLINE] 5277. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S100-3. Regulation of somatotroph cell function by the adipose tissue. Dieguez C(1), Carro E, Seoane LM, Garcia M, Camina JP, Senaris R, Popovic V, Casanueva FF. Author information: (1)Department of Physiology, Faculty of Medicine, University of Santiago, Santiago de Compostela, Spain. fscadiago@uscmail.usc.es Obese subjects exhibit a marked decrease in plasma growth hormone (GH) levels. However, the mechanisms by which increased adiposity leads to an impairment of GH secretion are poorly understood. Recent evidence suggests that the adipose tissue can markedly influence GH secretion via two different signals, namely free fatty acids (FFA) and leptin. FFA appear to inhibit GH secretion mainly by acting directly at pituitary level. Interestingly, reduction in circulating FFA levels in obese subjects led to a marked increase in GH responses to different GH secretagogues. This indicates that FFA exert a tonic inhibitory effect that contributes to blunted GH secretion in obese subjects. Recent data have shown that leptin is a metabolic signal that regulates GH secretion, since the administration of leptin antiserum to adult rats led to a marked decrease in spontaneous GH secretion. However, leptin prevents,the inhibitory effect exerted by fasting on plasma GH levels. The effect of leptin in adult rats appears to be exerted at hypothalamic level by regulating growth hormone releasing hormone (GHRH), somatostatin and neuropeptide Y (NPY)-producing neurones. In addition, during fetal life or following the development of pituitary tumors, leptin can also act directly at the anterior pituitary. PMID: 10997621 [PubMed - indexed for MEDLINE] 5278. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S86-8. Endocrine regulation of uncoupling proteins and energy expenditure. Ricquier D(1), Miroux B, Larose M, Cassard-Doulcier AM, Bouillaud F. Author information: (1)Centre National de la Recherche Scientifique-Unité 9078, Meudon, France. ricquier@infobiogen.fr Regulatory thermogenesis occurs upon exposure to the cold or during food intake. Among a variety of mechanisms leading to heat production, uncoupling of respiration in brown adipocyte mitochondria appears to be a major contributor to resistance to the cold in rodents. This uncoupling mechanism is due to the activity of uncoupling protein-1 (UCP-1), a specific carrier present in the inner membrane of mitochondria. The recent identification of UCP-2 and UCP-3, two homologues of the brown fat UCP, suggested that respiration uncoupling could contribute to thermogenesis in most tissues. Activity and expression of the three UCP's are stimulated by several neuromediators and hormones such as noradrenaline, tri-iodothyronine and leptin. PMID: 10997617 [PubMed - indexed for MEDLINE] 5279. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S59-63. The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. De Pergola G(1). Author information: (1)Istituto di Clinica Medica, Endocrinologia e Malattie Metaboliche dell'Universita di Bari, Policlinico di Bari, Italy. depergio@iqsnet.it Testosterone (T) and dehydroepiandrosterone (DHEA) are fat-reducing hormones, even though they exert this effect by different mechanisms. In particular, T inhibits lipid uptake and lipoprotein-lipase (LDL) activity in adipocytes, and stimulates lipolysis by increasing the number of lipolytic beta-adrenergic receptors. An indirect sign of these effects is the decrease of adipocyte leptin production. Lastly, T inhibits differentiation of adipocyte precursor cells. Concerning DHEA, this hormone does not seen to have any of T effects; however, DHEA stimulates resting metabolic rate (RMR) and lipid oxidation, and enhances glucose disposal, by increasing the expression of GLUT-1 and GLUT-4 on fat cell plasma membrane. The insulin-like effect of DHEA would be associated to a decrease of plasma insulin concentrations and, thus, to an increase of the molar ratio between lipolytic hormones and insulin. Noteworthy, the fat-reducing effect of both T and DHEA seems to be more evident at the level of visceral adipose tissue. PMID: 10997611 [PubMed - indexed for MEDLINE] 5280. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S56-8. Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: epidemiological and clinical correlation. Haffner SM(1). Author information: (1)Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7873, USA. Increased androgenicity as assessed by increased testosterone and decreased SHBG is strongly associated with an unfavorable body fat distribution and increased glucose and insulin concentrations and insulin resistance in both pre- and postmenopausal women. However, the temporal direction of the association between androgens and insulin is uncertain. In men, the association between SHBG and insulin levels is much weaker and is probably inverse. PMID: 10997610 [PubMed - indexed for MEDLINE] 5281. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S50-5. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Chrousos GP(1). Author information: (1)Pediatric Endocrinology Section, PREB, NICHD, National Institutes of Health, Bethesda, MD 20892, USA. George_Chrousos@nih.gov The stress system coordinates the adaptive response of the organism to real or perceived stressors. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine/ autonomic (LC/NE) systems and their peripheral effectors, the hypothalamic-pituitary-adrenal (HPA) axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. Thus, CRH and the LC/NE system stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the amygdala, which are responsible for the generation of fear. Hypothalamic CRH plays an important role in inhibiting gonadotropin-releasing hormone secretion during stress, while via somatostatin it also inhibits growth hormone, thyrotropin-releasing hormone and thyrotropin secretion, suppressing thus reproduction, growth and thyroid function. Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone and thyrotropin secretion and make the target tissues of sex steroids and growth factors resistant to these substances. In addition, glucocorticoids stimulate hepatic gluconeogenesis, and inhibit or potentiate insulin actions on skeletal muscle and adipose tissue respectively, ultimately promoting visceral adiposity and the metabolic syndrome. Glucocorticoids also have direct effects on the bone, inhibiting osteoblastic activity and causing osteoporosis. Obese subjects with psychiatric manifestations ranging from those of melancholic depression to anxiety with perception of 'uncontrollable' stress, frequently have mild hypercortisolism, while carefully screened obese subjects with no such manifestations are eucortisolemic. The former may have stress-induced glucocorticoid-mediated visceral obesity and metabolic syndrome manifestations, which in the extreme may be called a pseudo-Cushing state that needs to be differentiated from frank Cushing syndrome. Stress-induced hypercortisolism and visceral obesity and their cardiovascular and other sequelae increase the all-cause mortality risk of affected subjects by 2-3-fold and curtail their life expectancy by several years. PMID: 10997609 [PubMed - indexed for MEDLINE] 5282. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S47-9. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Pasquali R(1), Vicennati V. Author information: (1)Department of Internal Medicine and Gastroenterology, S Orsola-Malpighi Hospital, University of Bologna, Italy. rpasqual@almadns.unibo.it Subjects with abdominal obesity are characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to a condition of 'functional hypercortisolism'. This appears to be the result of two distinct mechanisms. The first, which appears to be central in origin, is characterized by altered ACTH pulsatile secretory dynamics and by hyper-responsiveness of the HPA axis to different neuropeptides and acute or chronic stress events and, possibly, to selected dietary factors. The other appears to be located in the periphery, specifically the liver and visceral adipose tissue, and is characterized by supranormal cortisol production, whose paracrine and systemic effects remain unclear. It is suggested that increased exposure to cortisol of the body may play a fundamental role not only in the development of increased fat in abdominal/visceral depots, but also in determining all metabolic abnormalities closely related to the abdominal obesity phenotype. PMID: 10997608 [PubMed - indexed for MEDLINE] 5283. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S36-9. The corticotropin-releasing hormone system in the regulation of energy balance in obesity. Richard D(1), Huang Q, Timofeeva E. Author information: (1)Centre de recherche sur le métabolisme énergétique, and Départment d'anatomie et de physiologie, Faculté de médecine, Université Laval, Québec, Canada. denis.richard@phs.ulaval.ca The view that energy balance is regulated has gained acceptance in recent years. An important role in this regulation is played by brain circuitries involved in the control of energy intake (food intake) and energy expenditure (thermogenesis) that are capable of integrating peripheral signals, produced by perturbations of adipose tissue mass, into messages to effectors of food intake and energy expenditure, so as to prevent substantial variations in the level of energy reserves. More than one neurosystem has been reported to genuinely participate in the regulation of energy balance. Among them is the corticotropin-releasing hormone (CRH) system. This system, with its numerous clusters of brain neurons, its closely related peptide urocortin, its two receptor types and its binding protein, all generally widely distributed throughout the brain, forms a network of neuronal pathways capable of interacting with the circuitries controlling food intake and energy expenditure. In addition, CRH and urocortin's anorectic and thermogenic actions appear to be coordinated to optimize energy losses. Finally, the CRH system seems to demonstrate a certain degree of plasticity in obesity and in response to food deprivation that is consistent with its action on food intake and thermogenesis. The observations have been made that food deprivation and obesity can blunt the expression of the CRH type 2alpha receptor in the ventromedial hypothalamic nucleus and can induce the expression of the CRH-binding protein (a CRH-inactivating protein) in brain areas involved in the anorectic and thermogenic actions of CRH. PMID: 10997606 [PubMed - indexed for MEDLINE] 5284. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S32-5. Relationship between regional fat distribution and insulin resistance. Bonora E(1). Author information: (1)Division of Endocrinology and Metabolic Diseases, University of Verona Medical School, Italy. malmetab@borgotrento.univr.it Visceral fat is a strong predictor of insulin resistance in obese subjects, but not in normal weight individuals, suggesting that this association might occur only beyond a certain threshold of visceral fat amount. Unlike subcutaneous fat, increased visceral fat is associated with increased hepatic glucose production and reduced glucose disposal. This association is independent of the methodology used to assess insulin sensitivity in humans. This article reviews all relevant data coming from epidemiological, clinical and interventional (weight loss) studies and studies obtained in identical twins. PMID: 10997605 [PubMed - indexed for MEDLINE] 5285. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S22-4. Substrate competition and insulin action in animal models. Vettor R(1), Lombardi AM, Fabris R, Serra R, Pagano C, Macor C, Federspil G. Author information: (1)Department of Medical and Surgical Sciences, University of Padova, Italy. rvettor@ux1.unipd.it Increased basal plasma FFA and lactate concentrations are often present in obesity and may deeply affect insulin action. The inhibition of glucose transport or phosphorylation is thought to be involved in this phenomenon, but the molecular mechanisms on the basis are still unknown. In our laboratory we observed that a chronic infusion of Intralipid plus heparin in rats significantly decreased the insulin dependent-glucose uptake, as well as GLUT4 gene expression in muscular tissue. On the other hand it has been shown that an enhanced plasma lactate concentration may increase insulin secretion and hepatic insulin clearance. Moreover we observed that chronic hyperlactatemia in rats is able to decrease glucose uptake in muscles, while reducing GLUT4 mRNA and protein in the same tissues. In obesity, lactate and FFA overproduction from visceral fat may therefore play a synergic role in reducing insulin sensitivity. PMID: 10997602 [PubMed - indexed for MEDLINE] 5286. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S18-21. Hormones and body composition in humans: clinical studies. Armellini F(1), Zamboni M, Bosello O. Author information: (1)Division of Geriatrics, Hospital of Valdagno, Italy. farmel@tin.it Leptin in relation to body fat and hormonal regulation of body fat distribution will be treated. Leptin circulating levels are strongly related to the percentage of body fat and in women leptin values are always twofold those observed in men. A role of androgens has been suggested to explain this gender difference. Insulin resistance may contribute to the wide variation in leptin levels. Leptin levels and insulin resistance are increased at the end of pregnancy and normalize after delivery. Furthermore, insulin resistance is associated with elevated plasma leptin levels independent of body fat mass and leptin levels are significantly related to insulin sensitivity independent of BMI. Energy restriction can strongly influence leptin levels, overcoming the effects of body composition changes. The shift from a state of triglycerides storage to a state of release could down-regulate leptin production. Triglyceride flux at the intra-abdominal level depends on the balance between insulin and corticosteroids, which have liposynthetic activity, and between sexual and growth hormones, which have lipolytic activity. Both hormonal and body composition change with ageing, primarily due to a decrease in lipolytic activity, with consequent prevalence of liposynthesis and visceral fat accumulation. Enlargement of intra-abdominal adipose cells is more gradual in men and more abrupt in women after menopause. PMID: 10997601 [PubMed - indexed for MEDLINE] 5287. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S4-7. Hormonal regulation of energy partitioning. Rohner-Jeanrenaud F(1). Author information: (1)Division of Endocrinology and Diabetology, Hôpital cantonal Universitaire de Genève, Geneva, Switzerland. F.Rohner-Jeanrenaud@hcuge.ch A loop system exists between hypothalamic neuropeptide Y (NPY) and peripheral adipose tissue leptin to maintain normal body homeostasis. When hypothalamic NPY levels are increased by fasting or by intracerebroventricular (i.c.v.) infusion, food intake and body weight increase. NPY has genuine hormono-metabolic effects. It increases insulin and corticosterone secretion relative to controls. These hormonal changes, acting singly or combined, favor adipose tissue lipogenic activity, while producing muscle insulin resistance. They also promote leptin release from adipose tissue. When infused i.c.v. to normal rats to mimic its central effects, leptin decreases NPY levels, thus food intake and body weight. Leptin i.c.v. has also genuine hormono-metabolic effects. It decreases insulinemia and adipose tissue storage ability, enhancing glucose disposal. Leptin increases the expression of uncoupling proteins (UCP-1, -2, -3) and thus energy dissipation. Leptin-induced changes favor oxidation at the expense of storage. Circadian fluctuations of NPY and leptin levels maintain normal body homeostasis. In animal obesity, defective hypothalamic leptin receptor activation prevent leptin from acting, with resulting obesity, insulin and leptin resistance. PMID: 10997599 [PubMed - indexed for MEDLINE] 5288. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S1-3. Adipose tissue as an endocrine organ. Ailhaud G(1). Author information: (1)Laboratoire de Biologie du Développement du Tissu Adipeux, Centre de Biochimie, UNSA, Faculté des Sciences, Nice, France. ailhaud@unice.fr The objective is to present a brief overview of peptide and non-peptide factors secreted from adipocytes and to describe some studies on the postulated role of the locally active triad angiotensinogen/angiotensinII/ prostacyclin in the development/enlargement of adipose tissue mass and increased blood pressure. In addition to the role of adipose tissue as an endocrine organ, the results emphasize the autocrine/paracrine mechanisms which are postulated to play a role in adipose tissue development and enlargement. PMID: 10997598 [PubMed - indexed for MEDLINE] 5289. Med Clin (Barc). 2000 Jul 1;115(5):185-9. [An increased proinflammatory activity is inherent in insulin resistance]. [Article in Spanish] Fernández-Real JM(1), Ricart W. Author information: (1)Unidad de Diabetes, Endocrinología y Nutrición (UDEN), Hospital Universitario de Girona Dr. Josep Trueta. endocrino@htrueta.scs.es PMID: 10996876 [PubMed - indexed for MEDLINE] 5290. Trends Endocrinol Metab. 2000 Oct;11(8):327-32. Adipose tissue as an endocrine organ. Ahima RS(1), Flier JS. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 764 CRB, 415 Curie Blvd, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu The discovery of leptin in the mid-1990s has focused attention on the role of proteins secreted by adipose tissue. Leptin has profound effects on appetite and energy balance, and is also involved in the regulation of neuroendocrine and immune function. Sex steroid and glucocorticoid metabolism in adipose tissue has been implicated as a determinant of body fat distribution and cardiovascular risk. Other adipose products, for example, proinflammatory cytokines, complement factors and components of the coagulation/fibrinolytic cascade, may mediate the metabolic and cardiovascular complications associated with obesity. PMID: 10996528 [PubMed - indexed for MEDLINE] 5291. Growth Horm IGF Res. 1998 Apr;8 Suppl B:93-6. Theoretical considerations in estimating the growth hormone axis in adults. Garcia-Mayor RV(1), Leal-Cerro A, Perez FR, Menendez C, Micic D, Pombo M, Dieguez C, Casanueva FF. Author information: (1)Division of Endocrinology, Hospital Xeral, Vigo, Spain. PMID: 10990140 [PubMed - indexed for MEDLINE] 5292. Growth Horm IGF Res. 1998 Apr;8 Suppl B:19-23. Effects of growth hormone treatment on visceral adipose tissue. Brummer RJ(1). Author information: (1)Department of Internal Medicine, University Hospital Maastricht, The Netherlands. It is now evident that an increased amount of intra-abdominal (visceral) adipose tissue is associated with an impaired metabolic profile, increasing the risk of CVD and NIDDM. Visceral obesity also appears to be associated with impaired GH action. GH replacement therapy in patients with GHD, or GH treatment of viscerally obese individuals, is able to induce a profound reduction in the amount of visceral adipose tissue and to improve the metabolic profile. PMID: 10990132 [PubMed - indexed for MEDLINE] 5293. Growth Horm IGF Res. 1998 Apr;8 Suppl B:15-7. Hormonal regulation of visceral adipose tissue. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's University Hospital, Göteborg, Sweden. PMID: 10990131 [PubMed - indexed for MEDLINE] 5294. Growth Horm IGF Res. 1998 Apr;8 Suppl B:1-8. Visceral obesity and the risk of ischaemic heart disease: insights from the Québec Cardiovascular Study. Lamarche B(1), Lemieux S, Dagenais GR, Després JP. Author information: (1)Lipid Research Center, CHUL Research Center, Québec, Canada. There is no doubt that visceral obesity increases the susceptibility to IHD, emphasizing the need to consider this condition in the risk management of IHD. The use of CT or MRI as clinical tools to assess visceral adipose tissue accumulation does not appear to be justified, however, mostly because of the costs of the procedures and the limited availability of the necessary apparatus. The waist:hip ratio has been used extensively as an indicator of body fat distribution. However, it has been shown that the waist:hip ratio is less accurate than the waist circumference alone or the sagittal diameter in predicting visceral adipose tissue accumulation, particularly when monitoring changes in visceral adipose tissue mass over time.79 Also, the prediction of visceral adipose tissue levels by the waist circumference alone, as opposed to the waist:hip ratio, does not appear to be affected by gender or by the degree of obesity.80 For these reasons we have proposed that the waist circumference should be systematically measured in managing the risk of IHD. It is a simple and inexpensive measurement to perform, while providing potentially critical information on the risk profile of both men and women.80 We believe that identification of viscerally obese patients, a high-risk population for IHD, should be considered as a critical step in the risk management of IHD. PMID: 10990129 [PubMed - indexed for MEDLINE] 5295. Curr Hypertens Rep. 2000 Jun;2(3):311-8. Interaction between leptin and sympathetic nervous system in hypertension. Haynes WG(1). Author information: (1)Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Leptin is a protein produced by adipose tissue that acts in the central nervous system (CNS) to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback loop that maintains stable adipose tissue mass. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Leptin also increases sympathetic nerve activity to tissues not usually considered thermogenic, including the kidney, hindlimb, and adrenal gland. Chronic systemic CNS administration of leptin increases arterial pressure and heart rate in conscious animals. However, leptin has additional cardiovascular actions that may act to oppose sympathetically mediated vasoconstriction. These actions include natriuresis, insulin sensitization, endothelium-dependent dilatation, and angiogenesis. Thus, the overall effect of leptin on arterial pressure has been unclear. Recent studies have demonstrated that leptin-deficient ob/ob obese mice have lower arterial pressure than lean controls with normal leptin levels. These studies suggest that leptin contributes physiologically to maintenance of arterial pressure. Leptin expression and plasma leptin concentrations are elevated in obese humans. Abnormalities in the generation or actions of leptin may, therefore, have implications for the sympathetic, cardiovascular, and renal changes associated with obesity. PMID: 10981165 [PubMed - indexed for MEDLINE] 5296. Curr Gastroenterol Rep. 2000 Aug;2(4):331-6. Nutritional effects of alcoholism. Falck-Ytter Y(1), McCullough AJ. Author information: (1)Robert Schwartz Center for Metabolism and Nutrition, Division of Gastroenterology, MetroHealth Medical Center, Cleveland, OH, USA. Alcohol is the most frequently used drug worldwide and remains a socially acceptable hepatotoxin. Although the toxic effects of alcohol on various organs (liver, pancreas, heart, and intestine) are well recognized, the role of alcohol in overall energy and protein metabolism is less well understood. In particular, the efficiency of alcohol as a source of calories and as a substrate for energy production appears to be influenced by the amount of both alcohol and fat consumption as well as by gender. The relationship between alcohol intake and body weight is complex, but it is a clinical dilemma with important nutritional implications for weight management in addition to specific organ toxicity. PMID: 10981033 [PubMed - indexed for MEDLINE] 5297. Curr Cardiol Rep. 1999 Jul;1(2):119-24. Fibrinolytic function and coronary risk. Juhan-Vague I(1), Morange P, Christine Alessi M. Author information: (1)Laboratoire d'Hématologie, CHU Timone, 13385 Marseille, France. Plasminogen activation potential in the blood is controlled by an equilibrium between plasminogen activators, mainly tissue-type plasminogen activator (t-PA), and inhibitors, mainly plasminogen activator inhibitor (PAI)-1. In cardiovascular practice, imbalance of this fibrinolytic potential is encountered primarily in the insulin-resistance syndrome. This syndrome leads to increased plasma PAI-1 and t-PA antigen levels (reflecting inactive t-PA/PAI-1 complexes) with a consequent decrease in fibrinolytic activity. Increased plasma PAI-1 and t-PA antigen both are predictive of myocardial infarction. The prognostic value of PAI-1 disappears after adjustments for insulin resistance markers, whereas the prognostic value of t-PA antigen disappears after simultaneous adjustments for insulin resistance and inflammation markers, suggesting an additive role of inflammation in inducing plasma fibrinolytic markers. Recently the production of PAI-1 by adipose tissue, in particular by tissue from the omentum, has been shown. PAI-1 produced in this way could be an important contributor to the elevated plasma PAI-1 levels observed in insulin-resistant patients. These results support the notion that PAI-1 may be a link between obesity, insulin resistance, and cardiovascular disease. Genetic control of PAI-1 expression has also been shown, involving a -675 4G/5G polymorphism, the 4G/4G genotype being associated with higher plasma PAI-1 levels; its proper influence on the development of myocardial infarction is still debated. PMID: 10980830 [PubMed - indexed for MEDLINE] 5298. J Pediatr Endocrinol Metab. 2000 Jul;13 Suppl 1:717-22. Body fat mass, leptin and puberty. Kiess W(1), Müller G, Galler A, Reich A, Deutscher J, Klammt J, Kratzsch J. Author information: (1)Children's Hospital, University of Leipzig, Germany. kiw@server3.medizin.uni-leipzig.de Leptin, the ob gene product, provides a molecular basis for the lipostatic theory of the regulation of energy balance. Leptin circulates as a monomeric 16 kDa protein in rodent and human plasma and is also bound to leptin binding proteins that may form large high molecular weight complexes. Initial models of leptin action included leptin-deficient ob/ob mice and leptin-insensitive db/db mice. Peripheral or central administration of leptin reduced body weight, adiposity, and food intake in ob/ob mice but not in db/db mice. In ob/ob mice leptin treatment restored fertility. Leptin interacts with many messenger molecules in the brain. For example, leptin suppresses neuropeptide Y (NPY) expression in the arcuate nucleus. Increased NPY activity has an inhibitory effect on the gonadotropin axis and represents a direct mechanism for inhibiting sexual maturation and reproductive function in conditions of food restriction and/or energy expenditure. By modulating the hypothalamo-pituitary-gonadal axis both directly and indirectly, leptin may thus serve as the signal from fat to the brain about the adequacy of fat stores for pubertal development and reproduction. Normal leptin secretion is necessary for normal reproductive function to proceed and leptin may be a signal allowing for the point of initiation of and progression toward puberty. PMID: 10969914 [PubMed - indexed for MEDLINE] 5299. Med Clin (Barc). 2000 Jun 17;115(3):103-10. [Genetic studies of obesity in humans]. [Article in Spanish] Macho Azcárate T(1), Martí del Moral A, Martínez Hernández JA. Author information: (1)Departamento de Fisiología y Nutrición, Universidad de Navarra, Pamplona. PMID: 10965486 [PubMed - indexed for MEDLINE] 5300. J Am Coll Nutr. 2000 Aug;19(4):487S-493S. Changes in body composition with conjugated linoleic acid. DeLany JP(1), West DB. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. delanyjp@pbrc.edu Conjugated linoleic acid has been shown to reduce body fat accumulation in several animal models. We have conducted several studies in AKR/J mice showing that CLA reduces body fat accumulation whether animals are fed a high-fat or low-fat diet, with no effect on food intake. One mechanism by which CLA reduces body fat is by increased energy expenditure, which is observed within one week of CLA feeding and is sustained for at least six weeks. The increased energy expenditure is sufficient to account for the decreased fat accumulation. Increased uncoupling protein gene expression does not appear to be involved in the increased energy expenditure. We have observed increased fat oxidation but no decrease in de novo fat biosynthesis with CLA feeding. We have also observed increased liver weights and plasma insulin levels with higher doses of CLA. In all of the studies we have conducted to date we have used a CLA preparation that contains several isomers, primarily c9,t11 and t10,c12. It was assumed that the active form was c9,t11, as CLA was identified as an anticarcinogenic compound from cooked beef, of which the c9,t11 form accounts for 60% to 80% of the CLA. Most of the studies conducted so far must be repeated using the purified isomers in order to determine which isomers are responsible for each of the identified actions of CLA. PMID: 10963469 [PubMed - indexed for MEDLINE] 5301. Mayo Clin Proc. 2000 Jan;75 Suppl:S65-8; discussion S68-9. Androgen effect on body composition and fat metabolism. Jensen MD(1). Author information: (1)Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic Rochester, Minn., USA. Recognizing the adverse metabolic effects of predominantly visceral body fat distribution associated with low testosterone levels, researchers have investigated the effects of androgen treatment on body fat distribution in men. This presentation reviews the results of research on acute and longer-term effects of treatment with testosterone and dihydrotestosterone. Methods for investigating these results, including measurement of lipoprotein lipase activity and of radiolabeled fat uptake and turnover, are described and discussed. PMID: 10959220 [PubMed - indexed for MEDLINE] 5302. Med Pregl. 2000 Jan-Feb;53(1-2):45-50. [Clinical importance and pathogenic mechanisms of insulin resistance in chronic renal insufficiency (part I): insulin resistance in patients with chronic renal insufficiency]. [Article in Croatian] Rasić-Milutinović Z(1), Perunicić-Peković G. Author information: (1)Odeljenje za endokrinologiju, Klinicko-bolnicki centar Zemun/Beograd. INTRODUCTION: This paper presents new investigations of abnormal insulin action in patients with chronic renal failure. Reduced tissue sensitivity to insulin action and the effects of the impairments on carbohydrate, protein and lipid metabolism have important pathophysiological implications in the genesis of the uremic syndrome. We analyzed confounding factors of reduced insulin sensitivity and potential sites of insulin resistance. INSULIN RESISTANCE IN HUMANS: Insulin resistance is associated with a number of metabolic and vascular abnormalities known as "syndrome X" or metabolic syndrome. Other features include obesity, particularly truncal distribution, glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM), hypertension, a specific dyslipidemia with raised triglyceride concentrations and a high low-density lipoprotein: high-density lipoprotein ratio, and hyperuricemia. These features, are all associated with accelerated atherogenesis and cardiovascular disease, the main cause of premature mortality. Some genetic (mutations affecting postreceptor signalling pathways) and environmental factors that could contribute to insulin resistance are discussed. INSULIN RESISTANCE IN CHRONIC RENAL FAILURE: The most prominent metabolic disturbance in uremic patients is insulin resistance due to a post-receptor defect. Insulin secretion is also impared, because the pancreatic beta-cell response to hyperglycemia is blunted. Insulin clearance by renal and extrarenal mechanisms is reduced. POSSIBLE SITES OF INSULIN RESISTANCE IN TERMINAL RENAL FAILURE: Increase in hepatic glucose production or impaired hepatic glucose uptake were overestimated. Impaired glucose uptake by peripheral tissues, primarily muscle and adipose tissue, has been extensively studied, and there is abundant evidence in patients with chronic renal failure. Decrease in renal glucose production would lead to a decrease in glucose appearance in circulation and decrease of insulin sensitivity. CONCLUSION: Cellular basis for insulin resistance in uremic patients is, however, unknown. It is now recognized that insulin-stimulated glucose transport in skeletal muscles and in other peripheral tissues is reduced. Although the majority of uremic patients are insulin resistant and about half of them are glucose intolerant, they are rarely diabetics. But, there are clinical implications of abnormal insulin metabolism in uremia. Cardiovascular complications are the most important consequences and significant cause of mortality in these patients. PMID: 10953550 [PubMed - indexed for MEDLINE] 5303. J Clin Invest. 2000 Aug;106(4):473-81. Obesity and insulin resistance. Kahn BB(1), Flier JS. Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. bkahn@caregroup.harvard.edu PMCID: PMC380258 PMID: 10953022 [PubMed - indexed for MEDLINE] 5304. Vnitr Lek. 1999 Oct;45(10):614-7. [The paradox of insulin resistance]. [Article in Czech] Kubát K(1). Author information: (1)Internal I MN, Litomĕrice. Insulin resistance (IR) is a phenomenon which associates several serious "diseases of civilization" within the framework of Reaven's metabolic syndrome. In the submitted paper the authors describe the so-called "paradox of insulin resistance"--a paradoxical finding of inadequate insulin action under laboratory induced conditions while under "common" conditions the finding is reversed. Diabetes mellitus type 2 (with obesity) is characterized by excessive filling of cells by energetically rich substances. A low energy output, inadequate physical activity in these subjects leads to the development of regulatory mechanisms, which restrict further nutrient (glucose) uptake from blood into cells. During subsequent stages of the disease the excessive glucose uptake by adipose tissue cells and muscle is ensured by the high concentration gradient, hyperglycaemia and hyperinsulinaemia. Induction of "comparable" conditions in clamp studies leads to paradoxical results. During relative hypoglycaemia and hypoinsulinaemia (as compared with normal conditions) the tissues of the diabetic patient, due to regulatory mechanisms, take up a smaller amount of glucose than tissues of non-diabetic subjects (although under normal conditions the glucose uptake is higher). This phenomenon is called "Paradox of insulin resistance". In a major proportion of patients IR can be induced by mere maintenance of hyperinsulinaemia, it can be minimalized by reducing the nutrient intake and by increasing physical exertion. Differentiation of patients where IR is a secondary, regulatory phenomenon is one of the basic tasks of the physician. Only patients who suffer from primary disorders of insulin function, primary IR and true insulin deficiency should be treated by administration of hyperinsulinaemia inducing drugs. It is questionable how suitable it is to administer these drugs to patients who suffer from a life-style disorder and are threatened by complications associated with hyperinsulinism. PMID: 10951872 [PubMed - indexed for MEDLINE] 5305. Proc Nutr Soc. 2000 May;59(2):325-30. The acquisition of obesity: insights from cellular and genetic research. Wabitsch M(1). Author information: (1)Department of Pediatrics, University of Ulm, Germany. martin.wabitsch@medizin.uni-ulm.de The acquisition of increased adipose tissue mass in man occurs during prolonged periods of positive energy balance. Normally, energy homeostasis in children and adults is regulated strictly and the energy stores are kept within the defined age-dependent physiological range. Susceptibility to definitive increases in the level of energy balance during times of reduced energy consumption or increased energy intake, leading to changes in body composition and/or changes in relative body weight, seems to be genetically determined. Although at present much information on the regulation of energy homeostasis and related unfavourable factors exists from animal studies, knowledge of the regulation of energy balance in human subjects is still insufficient. Some evidence on relevant factors involved in the regulation of energy balance in man has been obtained from epidemiological data, as well as from studies of patients with rare monogenetic forms of obesity. In the present article a special focus will be put on the regulation of body energy stores at the level of the adipose tissue, with emphasis on the regulation of human adipocyte differentiation. In addition to the currently intensive scientific interest in the central regulation of energy homeostasis in man, there is sufficient evidence to support the idea that the acquisition of an increased adipose tissue mass is also dependent on the susceptibility of pre-adipocytes to proliferate, to differentiate or to enter into apoptosis. PMID: 10946802 [PubMed - indexed for MEDLINE] 5306. Proc Nutr Soc. 2000 May;59(2):187-91. Assessment of individual fatty acid intake. Cantwell MM(1). Author information: (1)Department of Biological Sciences, Dublin Institute of Technology, Republic of Ireland. cantwemm@yahoo.com Dietary assessment of individual fatty acid intake is difficult due to a number of limitations. Information regarding the type, quantity and brand-name of fat used in cooking and at the table is required. In addition, margarine manufacturers may change the component oils used for reasons of cost, which changes the fatty acid composition of their products from season-to-season. Independent markers of fatty acid intake are required, therefore, to compensate for these limitations. Adipose tissue concentrations have been used as a measure of habitual intake of fatty acid groups and individual fatty acids in numerous studies. Saturated (SFA) and monounsaturated fatty acids (MUFA) are generally poorly correlated with adipose tissue concentrations, which can be explained partly by endogenous synthesis. In general, adipose tissue concentrations of exogenously-produced fatty acids (n-3 and n-6 polyunsaturated fatty acids (PUFA)) are well correlated with estimates of habitual intake. Correlations between dietary trans unsaturated fatty acids (TUFA) and adipose tissue concentrations vary between countries, which may be due to differences in dietary sources. Correlations may be affected by differences in bioavailability or selective retention of fatty acids in certain tissue lipids. PMID: 10946786 [PubMed - indexed for MEDLINE] 5307. Yakugaku Zasshi. 2000 Aug;120(8):657-66. [Identification and characterization of hexokinase isozyme predominantly expressed in malignant tumor cells]. [Article in Japanese] Shinohara Y(1). Author information: (1)Faculty of Pharmaceutical Sciences, University of Tokushima, Japan. Tumor cells show a higher glycolytic rate than normal cells. Of glycolytic enzymes, the activity of hexokinase, known as a rate limiting enzyme in glycolysis, is amazingly high in malignant tumor cells. In mammals, four isozymes of hexokinase are expressed but the question which isozyme is responsible for the high hexokinase activity observed in tumor cells was not yet clearly answered. By Northern blot analysis, we found that the type II isozyme, which is only slightly expressed in normal heart, muscle and adipose tissue, was remarkably expressed in malignant tumor cells. We next tried to understand how the expression of type II hexokinase gene is regulated in tumor cells. For this purpose, we first isolated the type II hexokinase gene and characterized its structural features. We further investigated the regulatory mechanisms of the expression of type II hexokinase in tumor cells. Results indicate the potential involvement of a serum responsive factor in the regulation of the expression of type II hexokinase in tumor cells. In addition to the remarkable expression, binding of the type II hexokinase to mitochondria is another characteristic of tumor cells, however, the physiological meaning of hexokinase binding to mitochondria was not yet fully understood. Our results clearly showed that the mitochondria-bound hexokinase utilize mitochondrially generated ATP more preferentially under normal conditions. However, when the rate of extramitochondrial ATP generating system (glycolysis) exceed that of mitochondrial ATP generating system (oxidative phosphorylation), the mitochondria-bound hexokinase utilize extramitochondrial ATP. This result indicates that the hexokinase binding enables a cross talk between oxidative phosphorylation and glycolysis. PMID: 10946615 [PubMed - indexed for MEDLINE] 5308. Diabetes Metab. 2000 Jun;26 Suppl 3:42-5. [Mechanisms for weight gain during blood glucose normalization]. [Article in French] Laville M(1), Andreelli F. Author information: (1)Service d'Endocrinologie, Diabétologie, Nutrition Hôpital Edouard Herriot, Lyon. Secondary failure to dietary and maximal oral treatment leads to insulin therapy in type 2 diabetic patients. However, weight gain is a frequent side effect of insulin therapy in these patients. Mechanisms for this weight gain are complex. Insulin 1) reduces glycosuria and its caloric expenditure; 2) stimulates the stockage of fatty acids into triglycerides in adipose tissue, thus favoring an increase in adipose mass; 3) yields a positive nitrogen balance through an inhibition of muscle proteolysis, thus favoring an increase in lean mass. Most studies report an average 6 kg weight gain during the first year following the initiation of insulin therapy in type 2 diabetic patients. Analysing body composition variations shows that weight gain results both from an increase in fat mass (mean 63%) and an increase in lean mass (mean 37%). Preexisting obesity does not influence this weight gain. Finally, the 10 year-follow up of UKPDS showed a beneficial effect of insulin therapy on microangiopathy prevention, without increasing cardiovascular mortality as compared with type 2 diabetic patients on oral treatment. Thus, while weight gain seems mandatory, it should not refrain from initiating insulin therapy in poorly controlled type 2 diabetic patients, as its expected beneficial effects on the prevention of microangiopathy seem well established. PMID: 10945152 [PubMed - indexed for MEDLINE] 5309. Diabetes Metab. 2000 Jun;26 Suppl 3:10-2. [Metabolic difference between visceral fat and subcutaneous abdominal fat]. [Article in French] Björntorp P(1). Author information: (1)Department of Head and Lung Disease, University of Goteborg, Sahlgrenska Hospital, Sweden. Obesity stands as a public health issue. Obesity prevalence is increasing throughout every industrialized country. Android obesity is linked with an increased cardiovascular mortality and with type 2 diabetes mellitis, thus calling for an early management of this disease. Several studies showed a significant association between an android fat distribution and an increased cortisol secretion, raising the still debated question of a causal relationship between the development of android obesity and hypercorticism. Moreover, android obese subjects exhibit reduced plasma testosterone and growth hormone levels, meaning complex hormonal abnormalities in these subjects. Current hypotheses suggest that android fat distribution depends on the association of these hormonal abnormalities. Android obese patients have supranormal free fatty acid plasma concentrations. Visceral fat tissue, through its portal drainage, could be an important source for free fatty acids that may exert complex metabolic effects: involvement in hepatic lipogenesis, increase in hepatic neoglucogenic flux, reduction in insulin metabolic clearance and involvement in peripheral insulin resistance through a competition mechanism described by Randle. Technics in vitro (isolated adipocytes) and in vivo in human (labelled fatty acid flux) showed that visceral fatty acid flux was increased in obese patients and subcutaneous adipose tissue, as opposed to common opinion, was also involved in free fatty acid pool in obese patients. Thus, visceral obesity and diabetes could be linked through an enhanced fatty acid availability from adipose tissues (visceral and subcutaneous) in otherwise genetically type 2 diabetes-prone individuals. PMID: 10945144 [PubMed - indexed for MEDLINE] 5310. Nihon Rinsho. 2000 Aug;58(8):1693-7. [Future direction of therapies for sleep related breathing disorders]. [Article in Japanese] Okabe S(1). Author information: (1)First Department of Internal Medicine, Tohoku University, School of Medicine. There are several mechanisms by which pharmacologic agents might improve sleep related breathing disorders. Upper airway muscle atony during sleep and fat deposition on the upper airway walls are critical in the pathogenesis of upper airway obstruction. As central neuromediators that regulate upper airway muscle activity, serotonin, gamma amino-butyric acid and thyrotropin releasing hormone are reviewed. Although agonists or antagonists of these mediators changed the upper airway muscle activity, no agents have successfully improved sleep related breathing disorders. Leptin is a protein produced by adipose tissue that interacts with receptors in the hypothalamus to inhibit eating. Leptin might have therapeutic potential for obesity-related breathing disorders related to a relative deficiency in leptin, or a leptin resistance. PMID: 10944937 [PubMed - indexed for MEDLINE] 5311. Nihon Rinsho. 2000 Aug;58(8):1632-6. [Leptin and stress protein (heat shock protein 72: HSP72) in patients with obstructive sleep apnea-hypopnea syndrome]. [Article in Japanese] Chin K(1). Author information: (1)Department of Physical Therapeutics, Kyoto University Hospital of Medicine. Leptin is a circulating hormone that is expressed abundantly and specifically in adipose tissue. Leptin induces a complex response involving control of body weight, energy expenditure and fat distribution. It is difficult for patients with obstructive sleep apnea-hypopnea syndrome to reduce and maintain their weights. Therefore, it is important to understand the circadian rhythms and regulation of serum leptin levels in order to control the body weight of obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. Heat shock protein(HSP) 72 is generally known to be a stress-inducible isoform that is barely detectable under unstressed conditions but which is rapidly synthesized during or after stress. Recent data suggest that OSAHS may have significant effects on the serum leptin levels and HSP72 levels in peripheral blood mononuclear cells(PBMC) of patients with OSAHS. PMID: 10944925 [PubMed - indexed for MEDLINE] 5312. Annu Rev Nutr. 2000;20:535-59. Transcriptional control of adipogenesis. Rangwala SM(1), Lazar MA. Author information: (1)Departments of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. The major transcriptional factors involved in the adipogenic process include proteins belonging to the CCAAT/enhancer binding protein family, peroxisome proliferator-activated receptor gamma, and adipocyte determination and differentiation dependent factor 1, also known as sterol regulatory element-binding protein 1. This process has been characterized with the aid of cell lines that represent various stages in the path of adipocyte commitment, ranging from pluripotent mesodermal fibroblasts to preadipocytes. Molecular analyses have led to a cascade model for adipogenesis based on timed expression of CCAAT/enhancer-binding proteins and peroxisome proliferator-activated receptor gamma. Gene targeting and transgenic-mouse technologies, which allow the manipulation of endogenous genes for these transcription factors, have also contributed to the understanding of adipogenesis. This review aims to integrate this information to gain an understanding of the transcriptional regulation of fat cell formation. PMID: 10940345 [PubMed - indexed for MEDLINE] 5313. Annu Rev Nutr. 2000;20:365-93. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Holm C(1), Osterlund T, Laurell H, Contreras JA. Author information: (1)Department of Cell and Molecular Biology, Section for Molecular Signalling, Lund University, Lund, Sweden. Cecilia.Holm@medkem.lu.se Hormone-sensitive lipase, the rate-limiting enzyme of intracellular TG hydrolysis, is a major determinant of fatty acid mobilization in adipose tissue as well as other tissues. It plays a pivotal role in lipid metabolism, overall energy homeostasis, and, presumably, cellular events involving fatty acid signaling. Detailed knowledge about its structure and regulation may provide information regarding the pathogenesis of such human diseases as obesity and diabetes and may generate concepts for new treatments of these diseases. The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general. A summary of the current knowledge regarding regulation of expression, potential involvement in lipid disorders, and role in tissues other than adipose tissue is also provided. PMID: 10940339 [PubMed - indexed for MEDLINE] 5314. Annu Rev Nutr. 2000;20:339-63. Mitochondrial uncoupling proteins in energy expenditure. Kozak LP(1), Harper ME. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. kozaklp@pbrc.edu Four recently discovered homologues of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP1) vary from 29% to 58% in their similarity to UCP1. Although these homologues share important structural features with UCP1 and like UCP1 can reduce the mitochondrial membrane potential when expressed in yeast, there is no clear evidence that they can function thermogenically in vivo. On the other hand, evidence continues to accumulate indicating that the up-regulation of Ucp1 reduces excessive adiposity. PMID: 10940338 [PubMed - indexed for MEDLINE] 5315. Annu Rev Nutr. 2000;20:77-103. Physiological and nutritional regulation of enzymes of triacylglycerol synthesis. Coleman RA(1), Lewin TM, Muoio DM. Author information: (1)Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. rcoleman@sph.unc.edu Although triacylglycerol stores play the critical role in an organism's ability to withstand fuel deprivation and are strongly associated with such disorders as diabetes, obesity, and atherosclerotic heart disease, information concerning the enzymes of triacylglycerol synthesis, their regulation by hormones, nutrients, and physiological conditions, their mechanisms of action, and the roles of specific isoforms has been limited by a lack of cloned cDNAs and purified proteins. Fortunately, molecular tools for several key enzymes in the synthetic pathway are becoming available. This review summarizes recent studies of these enzymes, their regulation under varying physiological conditions, their purported roles in synthesis of triacylglycerol and related glycerolipids, the possible functions of different isoenzymes, and the evidence for specialized cellular pools of triacylglycerol and glycerolipid intermediates. PMID: 10940327 [PubMed - indexed for MEDLINE] 5316. Annu Rev Nutr. 2000;20:45-75. Leptin--much more than a satiety signal. Harris RB(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. harrisrb@pbrc.edu Much attention has focused on the effects of leptin as a central satiety agent. There is now a significant amount of evidence that leptin is active in the periphery. This review focuses on the ability of leptin to modify insulin sensitivity, tissue metabolism, stress responses, and reproductive function. Leptin's effect on several of these systems is mediated via the hypothalamic-pituitary axis. Therefore, although in vitro studies provide evidence for direct effects on specific tissues and metabolic pathways, it is essential to consider the interactions between leptin and other regulatory factors in vivo. Little is known about the regulation of peripheral receptor expression or the production of binding proteins. Both of these factors determine the bioactivity of circulating leptin and have the potential to induce a peripheral resistance to leptin, similar to the central "leptin resistance" observed in obese subjects. Future research will clarify which of the endocrine and metabolic actions of peripheral leptin are of physiological relevance and which should be considered a pharmacological manipulation. PMID: 10940326 [PubMed - indexed for MEDLINE] 5317. Comp Biochem Physiol A Mol Integr Physiol. 2000 Jun;126(2):153-9. History of polar whaling: insights into the physiology of the great whales. Castellini M(1). Author information: (1)Institute of Marine Science, University of Alaska, Fairbanks 99775, USA. mikec@ims.uaf.edu The sheer size and pelagic nature of the great whales has effectively precluded detailed studies of most of their physiological processes. The vast majority of all data for these species have come from anatomical studies conducted on specimens that were caught in commercial and native whaling operations. In both the polar regions, an incredible number of whales were hunted, but anatomical studies were not usually conducted until relatively recent times. However, the anatomical data that do exist provide a valuable insight into some of the physiological demands placed on the animals by their marine habitat. These include information on blubber and nutrition; baleen and feeding ecology; contaminant chemistry and tissue samples; diving chemistry and acoustics. Taken together, these anatomical data provide the only substantial information on how these animals dive and hunt. Recent breakthroughs in chemical techniques however, are providing even greater details on function (for example, fatty acid signature methods). Coupled with advanced methods for tracking these whales at sea (acoustic and satellite), future studies should provide significant new information on the general physiology of these difficult to study species. PMID: 10936757 [PubMed - indexed for MEDLINE] 5318. Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Apr;13(1):121-9. Physical activity and obesity. Tremblay A(1). Author information: (1)Division of Kinesiology, Laval University, Ste-Foy, Quebec, Canada. The regular practice of physical activity promotes metabolic adaptations that facilitate the regulation of energy and fat balance. These effects are important for a better control of body weight in the obese individual and should enable him or her to involve adipose tissue to a lesser extent in this regulation. Physical activity favours a negative energy and fat balance, particularly if activities are prolonged and vigorous. The achievement of a negative energy and fat balance with physical activity also strongly depends on the nutritional context in which it is performed. In the long term, an active lifestyle and low-fat food habits are expected to induce a substantial body weight loss in the obese. This weight loss is progressively attenuated over time, presumably because of the decreased impact of a reduced adipose tissue mass on the regulation of energy and fat balance. For the obese individual complying with an activity programme and healthy food habits, a body weight loss of 10% is a realistic goal before the occurrence of resistance to further loss of body fat. PMID: 10932680 [PubMed - indexed for MEDLINE] 5319. Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Apr;13(1):13-30. The pathogenesis of obesity. Campfield LA(1), Smith FJ. Author information: (1)Center for Human Nutrition, University of Colorado Health Sciences Center, Denver 80262, USA. Obesity is an extremely challenging medical condition because it is a multifactorial disease that lies at the interface between the biology of body energy regulation and an environment (physical and sensory) that has been increasingly characterized as 'hostile to good health'. The deceptively straightforward anthropomorphic definition of obesity is the excessive accumulation of body fat. However, obesity is a chronic disease that is much more than excessive fat. It involves genetic predisposition and metabolic, hormonal and behavioural aspects and results in significant morbidity, reduced quality of life, discrimination and early mortality. The development and maintenance of obesity can be considered to result from the integration, or the accumulation, of small daily errors in energy balance over several months and years. The biological factors involved increase the predisposition toward the expansion of adipose tissue mass together with the consequences of an environment that promotes increased food intake and decreased physical activity. Multiple aetiologies may result in similar degrees of obesity. PMID: 10932674 [PubMed - indexed for MEDLINE] 5320. Curr Opin Clin Nutr Metab Care. 2000 Jul;3(4):275-9. Nutritional and insulin regulation of leptin gene expression. Iritani N(1). Author information: (1)Department of Human and Cultural Studies, Tezukayama Gakuin University, Sakai, Osaka, Japan. iritani@hcs.tezuka-gu.ac.jp The leptin and lipogenic enzyme genes contain the common DNA sequences of binding sites for Sp1 proteins. These sites appear to be responsible for glucose/insulin stimulation and polyunsaturated fatty acid suppression. In rat adipose tissue leptin and lipogenic gene expression is similarly regulated by nutritional manipulation. Interestingly, leptin has the ability to down-regulate lipogenic enzyme expression. PMID: 10929673 [PubMed - indexed for MEDLINE] 5321. Cell Tissue Res. 2000 Jul;301(1):101-24. Hormonal regulation of physiological cell turnover and apoptosis. Medh RD(1), Thompson EB. Author information: (1)Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston 77555-0645, USA. rmedh@utmb.edu Physiological cell turnover plays an important role in maintaining normal tissue function and architecture. This is achieved by the dynamic balance of cellular regeneration and elimination, occurring periodically in tissues such as the uterus and mammary gland, or at constant rates in tissues such as the gastrointestinal tract and adipose tissue. Apoptosis has been identified as the prevalent mode of physiological cell loss in most tissues. Cell turnover is precisely regulated by the interplay of various endocrine and paracrine factors, which modulate tissue and cell-specific responses on proliferation and apoptosis, either directly, or by altering expression and function of key cell proliferative and/or death genes. Although recent studies have provided significant information on specific tissue systems, a clearly defined pathway that mediates cell turnover has not yet emerged for any tissue. Several similarities exist among the various tissues with regard to the intermediates that regulate tissue homeostatis, enabling a better understanding of the general mechanisms involved in the process. Here we review the mechanisms by which hormonal and cytokine factors mediate cell turnover in various tissues, emphasizing common themes and tissue-specific differences. PMCID: PMC2763512 PMID: 10928284 [PubMed - indexed for MEDLINE] 5322. Biochem Biophys Res Commun. 2000 Aug 11;274(3):571-5. Regulation of leptin release by mammalian adipose tissue. Fain JN(1), Bahouth SW. Author information: (1)Department of Biochemistry, University of Tennessee, Memphis, Memphis, Tennessee, 38163, USA. PMID: 10924319 [PubMed - indexed for MEDLINE] 5323. Trends Pharmacol Sci. 2000 Aug;21(8):309-14. Leptin as a regulator of adipose mass and reproduction. Chehab FF(1). Author information: (1)Department of Laboratory Medicine, University of California, 505 Parnassus Avenue, San Francisco, CA 94143-0134, USA. chehab@pangloss.ucsf.EDU Leptin, an adipocyte-derived hormone, informs neuroendocrine pathways about the status of energy stores in adipose tissue. The integration of this peripheral signal in hypothalamic networks results in activation of peripheral metabolic pathways that control energy build-up and expenditure. Firing of the reproductive cascade of hormones at puberty and its regulation in adults is tightly associated with energy metabolism and is thus regulated by leptin. This article provides an update of past and present theories that link nutrition and reproduction in light of new research. PMID: 10918637 [PubMed - indexed for MEDLINE] 5324. Am J Clin Nutr. 2000 Aug;72(2 Suppl):558S-63S. Lipid metabolism during endurance exercise. Horowitz JF(1), Klein S. Author information: (1)Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110-1093, USA. Endogenous triacylglycerols represent an important source of fuel for endurance exercise. Triacylglycerol oxidation increases progressively during exercise; the specific rate is determined by energy requirements of working muscles, fatty acid delivery to muscle mitochondria, and the oxidation of other substrates. The catecholamine response to exercise increases lipolysis of adipose tissue triacylglycerols and, presumably, intramuscular triacylglycerols. In addition, increases in adipose tissue and muscle blood flow decrease fatty acid reesterification and facilitate the delivery of released fatty acids to skeletal muscle. Alterations in fatty acid mobilization and the relative use of adipose and intramuscular triacylglycerols during exercise depend, in large part, on degree of fitness and exercise intensity. Compared with untrained persons exercising at the same absolute intensity, persons who have undergone endurance training have greater fat oxidation during exercise without increased lipolysis. Available evidence suggests that the training-induced increase in fat oxidation is due primarily to increased oxidation of non-plasma-derived fatty acids, perhaps from intramuscular triacylglycerol stores. Fat oxidation is lower in high-intensity exercise than in moderate-intensity exercise, in part because of decreased fatty acid delivery to exercising muscles. Parenteral lipid supplementation during high-intensity exercise increases fat oxidation, but the effect of ingesting long-chain or medium-chain triacylglycerols on substrate metabolism during exercise is less clear. This review discusses the relation between fatty acid mobilization and oxidation during exercise and the effect of endurance training, exercise intensity, and lipid supplementation on these responses. PMID: 10919960 [PubMed - indexed for MEDLINE] 5325. J Mol Endocrinol. 2000 Aug;25(1):35-42. Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. Bulun SE(1), Zeitoun KM, Takayama K, Sasano H. Author information: (1)Departments of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, 820 S. Wood St. M/C 808, Illinois 60612, USA. sbulun@uic.edu Conversion of C(19) steroids to estrogens is catalyzed by aromatase in human ovary, placenta and extraglandular tissues such as adipose tissue, skin and the brain. Aromatase activity is not detectable in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis and is stimulated by prostaglandin E(2) (PGE(2)).( )This results in local production of estrogen, which induces PGE(2) formation and establishes a positive feedback cycle. Another abnormality in endometriosis, i.e. deficient hydroxysteroid dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE(2 )in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor. PMID: 10915216 [PubMed - indexed for MEDLINE] 5326. Biochem J. 2000 Aug 1;349 Pt 3:657-65. Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus. Holness MJ(1), Langdown ML, Sugden MC. Author information: (1)Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Mile End Road, London E1 4NS, U.K. There is increasing epidemiological evidence in humans which associates low birthweight with later metabolic disorders, including insulin resistance and glucose intolerance. There is evidence that nutritional and hormonal factors (e.g. maternal protein restriction, exposure to excess maternal glucocorticoids) markedly influence intra-uterine growth and development. A picture is also emerging of the biochemical and physiological mechanisms that may underlie these effects. This review focuses on recent research directed towards understanding the molecular basis of the relationship between indices of poor early growth and the subsequent development of glucose intolerance and Type 2 diabetes mellitus using animal models that attempt to recreate the process of programming via an adverse intra-uterine or neonatal environment. Emphasis is on the chain of events and potential mechanisms by which adverse adaptations affect pancreatic-beta-cell insulin secretion and the sensitivity to insulin of key metabolic processes, including hepatic glucose production, skeletal-muscle glucose disposal and adipose-tissue lipolysis. Unravelling the molecular details involved in metabolic programming may provide new insights into the pathogenesis of impaired glucoregulation and Type 2 diabetes. PMCID: PMC1221191 PMID: 10903125 [PubMed - indexed for MEDLINE] 5327. Dtsch Med Wochenschr. 2000 Jun 9;125(23):746-8. [Clinical significance of leptin]. [Article in German] Joost HG(1), Becker W. Author information: (1)Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen. joost@rwth-aachen.de PMID: 10902510 [PubMed - indexed for MEDLINE] 5328. Cell Res. 2000 Jun;10(2):81-92. Leptin: a multifunctional hormone. Huang L(1), Li C. Author information: (1)Department of Physiology, The University of Texas Southwestern Medical Center, Dallas 75390-8854, USA. Leptin is the protein product encoded by the obese (ob) gene. It is a circulating hormone produced primarily by the adipose tissue. ob/ob mice with mutations of the gene encoding leptin become morbidly obese, infertile, hyperphagic, hypothermic, and diabetic. Since the cloning of leptin in 1994, our knowledge in body weight regulation and the role played by leptin has increased substantially. We now know that leptin signals through its receptor, OB-R, which is a member of the cytokine receptor superfamily. Leptin serves as an adiposity signal to inform the brain the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Leptin also plays important roles in angiogenesis, immune function, fertility, and bone formation. Humans with mutations in the gene encoding leptin are also morbidly obese and respond to leptin treatment, demonstrating that enhancing or inhibiting leptin's activities in vivo may have potential therapeutic benefits. PMID: 10896170 [PubMed - indexed for MEDLINE] 5329. Ginekol Pol. 1999 Jun;70(6):456-63. [Pathophysiological aspects of adipose tissue development in women]. [Article in Polish] Kanadys WM(1), Oleszczuk J. Author information: (1)Zespołu Opieki Zdrowotnej w Lublinie. The fat cell, the functional entity of adipose tissue, is mainly involved in energy storage and mobilization. The deposition of fat in, and the mobilization of fat from, adipose tissue are precisely controlled by enzyme activities: LPL and HSL. These functions are under control of hormones such as insulin, catecholamines and, to some extent, steroid hormones. The adipocytes have been recently identified as the source of many factors that may act like hormones either in the local environment or at distant sites, are also target cells for many more hormones. Adipose tissue metabolism varies from one region of the body to another. The metabolic activity is the lowest in the subcutaneous gluteofemoral area, followed by the abdominal subcutaneous area, and the highest in the visceral region. The metabolic activity of gluteofemoral fat is activated in lactating mothers. Body fat content changes with female age. Puberty, parity and menopause seems to increase accretion of adipose tissue. Obesity is defined as an increase in body fat content. There is general agreement that obesity develops as an interaction between a genetic susceptibility and environment which is expressed when the subject is exposed to a certain set of environmental conditions. Obesity develops when energy intake exceeds energy expenditure over a prolonged period. Excess body weight is associated with several diseases which can shorten life expectancy. The prevalence of obesity is high and increases steadily. Approximately 20-40% of women are overweight (BMI 25-30 kg/m-2) and 5-20% are obese (BMI > 30 kg/m-2). PMID: 10895289 [PubMed - indexed for MEDLINE] 5330. Horm Res. 2000;53 Suppl 1:87-97. Growth hormone and adipocyte function in obesity. Nam SY(1), Marcus C. Author information: (1)Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. In obesity, growth hormone (GH) secretion is impaired which is considered a consequence rather than a cause of obesity. GH regulates the expression of GH receptor and the synthesis of insulin-like growth factor I (IGF-I) in adipocytes. Although GH hyposecretion in obesity may decrease the generation of IGF-I in each adipocyte, increased amounts of IGF-I and GH-binding protein could be secreted from the excessively enlarged amounts of adipose tissue. This may contribute to the normal/high serum-IGF-I and high GH-binding protein levels in obesity. Hyperinsulinemia and increased GH receptor activity may also affect the GH-IGF-I axis. Favorable effects of GH treatment have been observed in obese children and adults. GH treatment decreases adiposity, reduces triglyceride accumulation by inhibiting lipoprotein lipase and enhances lipolysis both via increased hormone-sensitive lipase activity and via induction of beta adrenoreceptors. GH treatment also has a favorable effect on obesity-associated dyslipidemia, but the effects on insulin sensitivity have been conflicting. Copyright 2000 S. Karger AG, Basel PMID: 10895049 [PubMed - indexed for MEDLINE] 5331. Rev Epidemiol Sante Publique. 2000 Jun;48(3):281-93. [General population exposure to dioxins, human ubiquitous pollutants]. [Article in French] Seta N(1), Arfi C, Momas I. Author information: (1)Laboratoire d'Hygiène et de Santé Publique, UFR des Sciences Pharmaceutiques et Biologiques, 75270 Paris. Cedex 06, France. Nathalie.Seta@pharmacie.univ-paris5.fr This paper gives an overview of the environmental or background exposure of general population to dioxins, polychlorinated dibenzo-para-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), originating from a variety of industrial and thermal processes and recognized as cancerous and toxic substances. The daily consumption of low-level contaminated food, mainly of animal origin, leads to the accumulation of dioxins in the human body. To determine the background exposure, human milk, adipose tissue or blood from many geographical locations (except France) have been used as bioindicators for body burden of dioxins. Human milk also allows the daily intake estimation of dioxins for breast-fed babies. Efforts should be made to minimize or avoid PCDD/PCDF emission in the environment. PMID: 10891788 [PubMed - indexed for MEDLINE] 5332. Br J Nutr. 2000 Mar;83 Suppl 1:S169-72. Can dietary intervention produce long-term reduction in insulin resistance? Mann JI(1). Author information: (1)Department of Human Nutrition, University of Otago, Dunedin, New Zealand. jim.mann@stonebow.otago.ac.nz Insulin sensitivity is potentially enhanced by a range of diet-related changes including reduction of visceral adiposity, a reduction in saturated fatty acids, and possibly a redistribution of the proportions of various unsaturated fatty acids. While there is evidence to suggest that lifestyle changes can reduce the risk of progression of impaired glucose tolerance to type 2 diabetes, there are no clinical trials which have conclusively demonstrated that any measure can reduce insulin resistance in the long term to an extent that can prevent the development of type 2 diabetes and other clinical complications. Evidence concerning the possibilities for reducing visceral adiposity and altering the nature of dietary fat are therefore considered. Attempts to achieve prolonged and substantial weight reduction in adults have not been encouraging, and it may be that preventing further weight gain is the most realistic target in this age group. In childhood the attempts have been more successful. The development of new approaches to achieving behavioural change and an environment which facilitates physical activity and appropriate food choices will be essential for more successful individual and population attempts to facilitate reduction in insulin resistance by weight loss. Changes in the nature of dietary fat appear to be more easily achieved. This is already a component of dietary advice aimed at cardiovascular risk reduction, and should be reinforced now with a view to also achieving a reduction in insulin resistance. PMID: 10889809 [PubMed - indexed for MEDLINE] 5333. Br J Nutr. 2000 Mar;83 Suppl 1:S71-7. Visceral fat and insulin resistance--causative or correlative? Frayn KN(1). Author information: (1)Oxford Lipid Metabolism Group, Radcliffe Infirmary, UK. keith.frayn@oxlip.ox.ac.uk The association between abdominal fat accumulation and risk of chronic diseases, including type II diabetes and coronary heart disease, has long been recognized. Insulin resistance may be a key factor in this link. Many studies have pointed to an association between insulin resistance and intra-abdominal fat accumulation (visceral obesity). However there is no clear proof of a causal link between visceral fat accumulation and insulin resistance. In assessing the probability of a causal link, it is useful to consider potential mechanisms. One such potential causal link is the release of non-esterified fatty acids from visceral fat into the portal vein, so that they have direct effects on hepatic metabolism. Visceral fat has been shown in many studies to exhibit a high rate of lipolysis compared with subcutaneous fat depots. However, if the idea that visceral fat releases fatty acids into the portal vein at a high rate is examined critically, a number of difficulties appear. Not least of these is the fact that continued high rates of lipolysis should lead to the disappearance of the visceral fat depot, unless these high rates of fat mobilization are matched by high rates of fat deposition. There is far less evidence for high rates of fat deposition in visceral adipose tissue, and some contrary evidence. Evidence for high rates of visceral lipolysis in vivo from studies involving catheterization of the portal vein is not strong. If this potential link is discounted, then other reasons for the relationship between visceral fat and insulin resistance must be considered. One is that there is no direct causal link, but both co-correlate with some other variable. A possibility is that this other variable is subcutaneous abdominal fat, which usually outweighs intra-abdominal fat several-fold. Subcutaneous fat probably plays the major role in determining systemic plasma non-esterified fatty acid concentrations, which are relevant in determining insulin resistance. In conclusion, there is at present no proof of a causal link between visceral fat accumulation and insulin resistance, or the associated metabolic syndrome. The possibility of co-correlation with some other factor, such as subcutaneous abdominal fat accumulation, must not be forgotten. PMID: 10889795 [PubMed - indexed for MEDLINE] 5334. Br J Nutr. 2000 Mar;83 Suppl 1:S9-16. Obesity--a genetic disease of adipose tissue? Arner P(1). Author information: (1)Karolinska Institute, Department of Medicine, CME, Huddinge Hospital, Stockholm, Sweden. peter.arner@medhs.ki.se Although the rapid increase in the prevalence of obesity in many countries suggests that environmental factors (mainly overeating and physical inactivity) play the most important role in the development of overweight, it is very likely that genetic factors also contribute. It appears that one major gene in combination with one or several minor genes constitute the genetic components behind excess accumulation of body fat in most obese individuals. However, monogenic obesity has been described in a few families due to changes in leptin, leptin receptor, prohormone convertase, pro-opiomelanocortin or melanocortin-4 receptor. None of the monogenic variants is of great importance for common human obesity; the latter genes are unknown so far. Results from genomic scans suggest that major obesity genes are located on chromosomes 2, 10, 11 and 20. Studies of candidate genes indicate that the minor obesity genes control important functions of adipose tissue, and that structural variance in these genes may alter adipose tissue function in a way that promotes obesity. Such genes are beta 2- and beta 3-adrenoceptors, hormone-sensitive lipase, tumour necrosis factor alpha, uncoupling protein-1, low-density lipoprotein receptor, and peroxisome proliferator activator receptor gamma-2. Some of these genes may promote obesity by gene-gene interactions (for example beta 3-adrenoceptors and uncoupling protein-1) or gene-environment interactions (for example beta 2-adrenoceptors and physical activity). Some are important for obesity only among women (for example beta 2- and beta 3-adrenoceptors, low-density lipoprotein receptor and tumour necrosis factor alpha). Few 'non-adipose' genes have so far shown a firm association to common human obesity, which could suggest that the important genes for the development of excess body fat also control adipose tissue function. PMID: 10889786 [PubMed - indexed for MEDLINE] 5335. AIDS Read. 2000 Jun;10(6):365-9, 371-5. Reversal of cachexia in patients treated with potent antiretroviral therapy. Scevola D(1), Di Matteo A, Uberti F, Minoia G, Poletti F, Faga A. Author information: (1)Institute of Infectious Diseases, IRCCS Policlinico S. Matteo, University of Pavia, Italy. The introduction of HAART has changed the nutritional status of HIV patients. In the pre-protease inhibitor (PI) era, more than 60% of HIV-positive persons presented with protein energy malnutrition (PEM) and vitamin and mineral deficit. This caused progressive physical-metabolic wasting (wasting syndrome/cachexia) and increased susceptibility to opportunistic infections and drug toxicity. PEM was a concurrent cause in 80% of deaths attributed to AIDS. Since 1996, the year in which PIs were introduced, the number of patients dying as a result of AIDS has decreased by two thirds, and cachexia is no longer the AIDS terminal phase in developed countries. But different patterns of nutritional status changes have appeared in association with the use of newer anti-HIV therapies and with longer survival of HIV-infected patients. A new clinical and laboratory syndrome--lipodystrophy syndrome--now affects patients receiving PI-based therapy. This syndrome consists of changes in body shape that are caused by an abnormal redistribution of fat. Fat accumulates in the abdominal area (truncal and visceral obesity), in the axillary pads (bilateral symmetric lipomatosis), and in the dorsocervical pads ("buffalo hump," "bull neck") but decreases in the legs, arms, and nasolabial and cheek pads (peripheral lipodystrophy). Hyperlipidemia and insulin resistance are also frequently present (metabolic syndrome X). Pathogenic mechanisms of lipid and fat tissue disturbances are discussed in this article, and the clinical approach to patient management and therapeutic options for lipodystrophy and lipid dysmetabolism is evaluated. PMID: 10881368 [PubMed - indexed for MEDLINE] 5336. Trends Endocrinol Metab. 2000 Aug;11(6):212-7. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Moller DE(1). Author information: (1)Departments of Molecular Endocrinology and Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA. david_moller@merck.com Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia. PMID: 10878750 [PubMed - indexed for MEDLINE] 5337. Arch Dis Child. 2000 Jul;83(1):31-4. Recent advances in the genetics of severe childhood obesity. Farooqi IS(1), O'Rahilly S. Author information: (1)University Departments of Medicine and Clinical Biochemistry, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. ifarooqi@hgmp.mrc.ac.uk Childhood obesity is becoming a global epidemic. Twin studies suggest a heritability of fat mass, and disorders of energy balance that arise from genetic defects have been identified. In the past three years, five single gene disorders resulting in early onset obesity have been characterised. The discovery of these genetic defects has biological and clinical implications which are greater than the rarity of the individual diseases might suggest. PMCID: PMC1718391 PMID: 10868996 [PubMed - indexed for MEDLINE] 5338. Diabetes Metab Res Rev. 2000 May-Jun;16(3):202-10. Lipid metabolism in the fetus and the newborn. Herrera E(1), Amusquivar E. Author information: (1)Facultad de Ciencias Experimentales y Técnicas, Universidad San Pablo-CEU, E-28668 Madrid, Spain. eherrera@ceu.es During late gestation, although maternal adipose tissue lipolytic activity becomes enhanced, lipolytic products cross the placenta with difficulty. Under fasting conditions, free fatty acids (FFA) are used for ketogenesis by the mother, and ketone bodies are used as fuels and lipogenic substrates by the fetus. Maternal glycerol is preferentially used for glucose synthesis, saving other gluconeogenic substrates, like amino acids, for fetal growth. Placental transfer of triglycerides is null, but essential fatty acids derived from maternal diet, which are transported as triglycerides in lipoproteins, become available to the fetus owing to the presence of both lipoprotein receptors and lipase activities in the placenta. Diabetes in pregnancy promotes lipid transfer to the fetus by increasing the maternal-fetal gradient, which may contribute to an increase in body fat mass in newborns of diabetic women. Deposition of fat stores in the fetus is very low in the rat but high in humans, where body fat accretion occurs essentially during the last trimester of intra-uterine life. This is sustained by the intense placental transfer of glucose and by its use as a lipogenic substrate, as well as by the placental transfer of fatty acids and to their low oxidation activity. During the perinatal period an active ketonemia develops, which is maintained in the suckling newborn by several factors: (i) the high-fat and low-carbohydrate content in milk, (ii) the enhanced lipolytic activity occurring during the first few hours of life, and (iii) both the uptake of circulating triglycerides by the liver due to the induction of lipoprotein lipase (LPL) activity in this organ, and the presence of ketogenic activity in the intestinal mucose. Changes in LPL activity, lipogenesis and lipolysis contribute to the sequential steps of adipocyte hyperplasia and hypertrophia occurring during the extra-uterine white adipose tissue development in rat, and this may be used as a model to extrapolate the intra-uterine adipose tissue development in other species, including humans. Copyright 2000 John Wiley & Sons, Ltd. PMID: 10867720 [PubMed - indexed for MEDLINE] 5339. Diabetes Metab Res Rev. 2000 May-Jun;16(3):192-201. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Bastard JP(1), Piéroni L, Hainque B. Author information: (1)Service de Biochimie et Hormonologie, Hôpital Tenon, Paris, France. jean-philippe.bastard@tnn.ap-hop-paris.fr High plasminogen activator inhibitor 1 (PAI-1) levels are associated with an increased cardiovascular risk of atherothrombosis. Furthermore, increased plasma PAI-1 levels are associated with dyslipidemia, hyperinsulinemia and hypertension. This association between PAI-1 and metabolic components of the Metabolic Syndrome could explain the predisposition of insulin resistant patients to atherothrombosis. Recent studies have suggested that visceral adipose tissue might be the link between elevated plasma PAI-1 and insulin resistance in the Metabolic Syndrome. Indeed, visceral adipose tissue was proposed as a potentially important source of PAI-1 in humans. However, in light of recent studies, visceral adipose tissue appears to be involved in the increase of plasma PAI-1 via the metabolic disorders usually associated with central obesity, rather than directly. High plasma PAI-1 levels are undoubtedly related to insulin resistance, and the mechanisms which could explain such an increase in the Metabolic Syndrome appear to be multi-factorial and remain to be elucidated. These mechanisms may involve several metabolic disorders such as hyperinsulinemia, dyslipidemia, impaired glucose tolerance and hypertension, which would favor PAI-1 synthesis and release from different cell types. Copyright 2000 John Wiley & Sons, Ltd. PMID: 10867719 [PubMed - indexed for MEDLINE] 5340. Diabetes. 2000 Jun;49(6):883-8. The perils of portliness: causes and consequences of visceral adiposity. Montague CT(1), O'Rahilly S. Author information: (1)Cardiovascular and Gastrointestinal Discovery Research Department, AstraZeneca Pharmaceuticals, Macclesfield, UK. carl.montague@astrazeneca.com Although an individual's total fat mass predicts morbidities such as coronary artery disease and diabetes, the anatomical distribution of adipose tissue is a strong and independent predictor of such adverse health outcomes. Thus, obese individuals with most of their fat stored in visceral adipose depots generally suffer greater adverse metabolic consequences than similarly overweight subjects with fat stored predominantly in subcutaneous sites. A fuller understanding of the biology of central obesity will require information regarding the genetic and environmental determinants of human fat topography and of the molecular mechanisms linking visceral adiposity to degenerative metabolic and vascular disease. Here we attempt to summarize the growing body of data relevant to these key areas and, in particular, to illustrate how recent advances in adipocyte biology are providing the basis for new pathophysiological insights. PMID: 10866038 [PubMed - indexed for MEDLINE] 5341. Ann N Y Acad Sci. 2000 May;904:553-7. Sarcopenic obesity: does muscle loss cause fat gain? Lessons from rheumatoid arthritis and osteoarthritis. Roubenoff R(1). Author information: (1)Nutrition, Exercise Physiology, and Sarcopenia (NEPS) Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA. roubenoff@hnrc.tufts.edu PMID: 10865804 [PubMed - indexed for MEDLINE] 5342. Ann N Y Acad Sci. 2000 May;904:502-6. Menopause-related changes in body fat distribution. Toth MJ(1), Tchernof A, Sites CK, Poehlman ET. Author information: (1)Department of Medicine, University of Vermont, Burlington 05405, USA. mtoth@zoo.uvm.ed Menopause-related changes in body fat distribution may partially explain the greater risk of cardiovascular and metabolic disease during the postmenopausal years. To date, however, the effect of the menopause transition on body fat distribution remains unclear. Cross-sectional and longitudinal studies using waist circumference or the waist-to-hip ratio show no effect of menopause on body fat distribution. By contrast, studies using dual-energy X-ray absorptiometry showed increased trunk fat in postmenopausal women. Moreover, studies using computed tomography (CT) and magnetic resonance imaging (MRI) show that postmenopausal women have greater amounts of intra-abdominal fat compared to premenopausal women. Collectively, these studies suggest that the menopause transition is associated with an accumulation of central fat and, in particular, intra-abdominal fat. Whether menopause-related differences in trunk or intra-abdominal fat are independent of age and/or adiposity, however, is unclear. Thus, we recently examined the effect of menopausal status on body composition and abdominal fat distribution in 53 middle-aged, premenopausal women (47 +/- 3 years) and 28 early postmenopausal women (51 +/- 4 years). Postmenopausal women had 36% more trunk fat (p < 0.01), 49% greater intra-abdominal fat area (p < 0.01), and 22% greater subcutaneous abdominal fat area (p < 0.05) than premenopausal women. The menopause-related difference in intra-abdominal fat persisted (p < 0.05) after statistical adjustment for age and fat mass, whereas no differences were noted in trunk or abdominal subcutaneous fat. A similar pattern of differences in trunk, subcutaneous, and intra-abdominal fat was observed in subsamples of pre- and postmenopausal women matched for age or fat mass. Our data and that of others suggest that early postmenopausal status is associated with a preferential increase in intra-abdominal fat that is independent of age and total adiposity. Thus, CT and MRI should be used when examining menopause-related changes in body fat distribution. PMID: 10865795 [PubMed - indexed for MEDLINE] 5343. Ann N Y Acad Sci. 2000 May;904:359-65. Body fat content influences the body composition response to nutrition and exercise. Forbes GB(1). Author information: (1)University of Rochester School of Medicine and Dentistry, New York 14642, USA. In most situations involving a significant change in body weight, both fat-free body mass (FFM) and body fat participate, but the relative contribution of FFM and fat to the total weight change is influenced by the initial body fat content. Overfeeding: In experiments of at least 3-weeks' duration, the weight gain of thin people comprises 60-70% lean tissues, whereas in the obese it is 30-40%. Underfeeding: In humans, there is an inverse curvilinear relationship between initial body fat content and the proportion of weight loss consisting of lean tissue. The same trend holds for animals and birds, including loss during hibernation. Another factor is the magnitude of the energy deficit: as energy intake is reduced, lean tissue makes up an increasing fraction of the total weight loss. Exercise: If individuals lose much weight with exercise, the result is usually some loss of lean tissue as well as fat, and once again the proportion of lean loss to total weight loss is greater in thin people than in those who have larger body fat burdens. Members of twin pairs often differ in weight. In thin individuals, lean accounts for about half of the intrapair weight difference, whereas in the obese it accounts for only one quarter. Body fat content must be taken into account in evaluating body composition changes induced by nutrition and exercise. PMID: 10865771 [PubMed - indexed for MEDLINE] 5344. Ann N Y Acad Sci. 2000 May;904:25-31. Observation of intramyocellular lipids by 1H-magnetic resonance spectroscopy. Boesch C(1), Kreis R. Author information: (1)Department of Clinical Research, University Bern, Switzerland. chris.boesch@insel.ch Magnetic resonance (MR) methods are increasingly being used to investigate the physiology of human muscle. Although MR imaging (MRI) reveals the morphology of muscles in great detail, for example, for determining their volume and fiber orientation, MR spectroscopy (MRS) provides information on the chemical composition of the tissue. Depending on the observed nucleus, MRS allows the observation of high-energy phosphates (31P-MRS), glycogen (13C-MRS), or intramyocellular lipids (1H-MRS), to give only a few examples. 1H-MRS of human skeletal muscle requires special techniques because 1H nuclei in water or adipose tissue are far more concentrated than in any other metabolite of human tissue. The strong signal from water can be suppressed by special prepulses, whereas large signals from fat in adipose tissue can be reduced by carefully selecting the region of interest. Until recently, it was presumed that only a few metabolites would be visible underneath the large resonances of water and subcutaneous fat. Meanwhile, it was clear that 1H-MR spectra of human muscle reveal much metabolic and structural information. The determination of intramyocellular lipids (IMCL) by 1H-MRS was initiated by the observation of two compartments of triacylglycerols with a resonance-frequency shift of approximately 0.2 ppm. The two resonances can be attributed to CH2 protons of lipids in fat cells, and to lipids inside muscle cells (IMCL). 1H-MRS examinations are noninvasive and, therefore, can be repeated many times and with a high temporal resolution. MRS has the potential to replace biopsy to follow-up IMCL levels; however, biopsy still has the advantage that other methods, such as molecular biology, can be applied to the sample. It can be shown that IMCL levels (expressed in mMol/kg wet weight and volume %) are muscle specific and vary with diet and physical activity. In addition, it has been reported that IMCL levels are correlated with insulin sensitivity. A comparison of different methods for assessing IMCL levels, including MRS, chemical analysis, and morphometry, revealed a satisfactory correlation among them and a superior correlation of MRS with the average of the three methods. The observation of IMCL levels by means of 1H-MRS is extremely promising, but several methodological limitations and pitfalls need to be considered. PMID: 10865706 [PubMed - indexed for MEDLINE] 5345. Ann N Y Acad Sci. 2000 May;904:18-24. Composition of skeletal muscle evaluated with computed tomography. Goodpaster BH(1), Thaete FL, Kelley DE. Author information: (1)Department of Medicine, University of Pittsburgh, Pennsylvania 15261, USA. bgood+@pitt.edu Computed tomography (CT) can yield quantitative imaging data from detailed maps of linear attenuation coefficients within tissue. The attenuation characteristics of skeletal muscle and adipose tissue can be quantified in vivo to provide information about the composition of skeletal muscle and the distribution of adipose tissue within muscle. Several studies have taken advantage of this utility to quantify skeletal muscle composition and fatty infiltration of muscle, in particular to quantify the attenuation characteristics of muscle as a marker of its lipid content. In this manner we found that the mean muscle attenuation of skeletal muscle reflects an increase in its fat content in obesity, and that this regional body composition parameter is strongly related to insulin-resistant glucose metabolism. In addition, muscle composition and adipose tissue distribution within muscle may be altered with clinical weight-loss interventions. CT may also provide important information about the changes in muscle mass and composition with aging and disease, which may, in turn, affect the muscle's function. In summary, CT can provide important quantitative data on the composition of muscle, and the distribution of adipose tissue within it, and this may be important in examining the relationships among skeletal muscle metabolism, lipid accumulation within muscle, and muscle function. PMID: 10865705 [PubMed - indexed for MEDLINE] 5346. J Pathol. 2000 Jun;191(2):115-9. Methods for imaging the structure and function of living tissues and cells: 1. Optical coherence tomography. Tadrous PJ(1). Author information: (1)Department of Histopathology, Imperial College School of Medicine, The Hammersmith Hospital, London, UK. pjtadrous@ieee.org This is the first in a series of review articles which aim to present a concise and systematic overview of the principles, limitations, advantages, and uses of some of the more important recently developed techniques capable of imaging living histology. Optical coherence tomography (OCT) is now an established optical biopsy method, imaging 2-3 mm into opaque tissue. It is analogous to optical 'ultrasound' but has an outstanding resolution, being capable of imaging single cells in the intact animal via a surface, intravascular or endoscopic approach. Both two-dimensional (2D) and three-dimensional (3D) image datasets can be acquired and studied over time (4D imaging) in the live animal or human subject without the need to remove tissue or perform any tissue processing or staining. It has been used in ophthalmology, gastrointestinal tract (GI) studies, gynaecological tract investigation, and endovascular imaging, to name but a few areas. A degree of differential tissue contrast information can also be gleaned, since different tissue components give different OCT reflectivity signals such that adipose, muscle, collagen, and elastic components may all be resolved without staining. Continuing developments include faster data acquisition for real-time recording and Doppler OCT for more functional imaging. Copyright 2000 John Wiley & Sons, Ltd. PMID: 10861568 [PubMed - indexed for MEDLINE] 5347. Horm Behav. 2000 Jun;37(4):306-26. Leptin and metabolic control of reproduction. Schneider JE(1), Zhou D, Blum RM. Author information: (1)Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, USA. js0v@lehigh.edu Leptin treatment prevents the effects of fasting on reproductive processes in a variety of species. The mechanisms that underlie these effects have not been elucidated. Progress in this area of research might be facilitated by viewing reproductive processes in relation to mechanisms that maintain fuel homeostasis. Reproduction, food intake, and fuel partitioning can be viewed as homeostatic responses controlled by a sensory system that monitors metabolic signals. These signals are generated by changes in intracellular metabolic fuel availability and oxidation rather than by changes in the amount of body fat or by changes in any aspect of body composition. Leptin might be viewed as either a mediator or as a modulator of the intracellular metabolic signal. Consistent with its purported action as a mediator of the metabolic signal, leptin synthesis and secretion are influenced acutely by changes in metabolic fuel availability, and these changes might lead to changes in reproductive function. The effects of leptin treatment on reproduction are blocked by treatments that inhibit intracellular fuel oxidation. Metabolic signals that inhibit reproduction in leptin-treated animals might act via neural pathways that are independent of leptin's action. Alternatively, both leptin and metabolic inhibitors might interact at the level of intracellular fuel oxidation. In keeping with the possibility that leptin modulates the metabolic signal, leptin treatment increases fuel availability, uptake, and oxidation in particular tissues. Leptin might affect reproduction indirectly by altering fuel oxidation or other peripheral processes such as gastric emptying. Reproductive processes are among the most energetically expensive in the female repertoire. Because leptin increases energy expenditure while simultaneously inhibiting energy intake, it may have limited use as a long-term treatment for infertility. Copyright 2000 Academic Press. PMID: 10860675 [PubMed - indexed for MEDLINE] 5348. Nutr Rev. 2000 May;58(5):145-8. Functional glycerol kinase activity and the possibility of a major role for glyceroneogenesis in mammalian skeletal muscle. Watford M(1). Author information: (1)Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA. According to textbook descriptions of glycerol metabolism, liver and kidney are the only tissues that express significant glycerol kinase activity. Thus esterification of fatty acids to triglycerides in peripheral tissues such as skeletal muscle and adipose tissue is presumed to be dependent on the synthesis of glycerol-3-phosphate from glucose. This report describes exciting new data indicating that, although low, the glycerol kinase activity of skeletal muscle is functional. Interestingly, the results also suggest that neither glycerol nor glucose is the major substrate for the synthesis of muscle triglyceride glycerol. Rather, glyceroneogenesis, the synthesis of glycerol-3-phosphate from lactate, may play an as yet under-appreciated, but quantitatively important, role. PMID: 10860394 [PubMed - indexed for MEDLINE] 5349. Diabetes Care. 2000 Apr;23 Suppl 2:B1-4. The changing lifestyle in the world. Body weight and what else? Sørensen TI(1). Author information: (1)Danish Epidemiology Science Centre, Institute of Preventive Medicine, Copenhagen University Hospital, Denmark. Body weight and the prevalence of obesity are rising so rapidly in many countries that the World Health Organization has recognized that there is a "global epidemic of obesity." The prevalence of type 2 diabetes is rising in parallel. In view of its associated cardiovascular complications, we are facing a severe public health problem. Both obesity and type 2 diabetes have a combined genetic and environmental background, but the epidemic must be due to major changes in the environment. By definition, obesity is a result of a positive energy balance, which usually amounts to a tiny proportion of the total energy turnover. Energy intake, energy expenditure, and energy accumulation (as fat) may all be primarily disturbed. There is a great, and still insufficiently understood, variation in prevalence of obesity and in the rate of change of the prevalence. The prevailing contention is that the epidemic is due to the changes in the society--the so-called modernization--leading to overnutrition and a sedentary life. These factors are likely contributors, but it has been difficult to provide consistent evidence for their effects. In Denmark, a steep rise has taken place in the prevalence of obesity among schoolboys and young men in two phases linked to the birth cohorts of the 1940s and of the mid-1960s and later. This rise suggests that environmental influences operating early in life are involved. In conclusion, a global obesity epidemic is developing, but the causes of the epidemic are not yet clear and more research is needed to establish the grounds for prevention. PMID: 10860183 [PubMed - indexed for MEDLINE] 5350. Prog Drug Res. 2000;54:25-58. Pharmacology of appetite suppression. Halford JC(1), Blundell JE. Author information: (1)Department of Psychology, Eleanor Rathbone Building, University of Liverpool, UK. Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, modulation of appetite may involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with lifestyle changes and dietary intervention may be useful in dealing with the rising world epidemic of obesity. PMID: 10857385 [PubMed - indexed for MEDLINE] 5351. Trends Endocrinol Metab. 2000 Jul;11(5):184-8. The role of local estrogen biosynthesis in males and females. Simpson E(1), Rubin G, Clyne C, Robertson K, O'Donnell L, Jones M, Davis S. Author information: (1)Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia. evan.simpson@med.monash.edu.au Natural (human) and experimental (mouse) models of estrogen insufficiency have revealed hitherto unexpected roles for estrogens in both males and females. In postmenopausal women, and in men, estrogen no longer has a major role as a circulating hormone, but rather it functions locally as a paracrine or even 'intracrine' factor in tissue sites where it is formed. As a consequence, the tissue-specific nature of aromatase production assumes physiological and pathophysiological significance. The availability of circulating precursors is also important in sites where there is no local supply of C19 precursors, particularly in elderly women. The potential clinical significance of these findings in terms of the development of new therapeutic modalities is discussed. PMID: 10856920 [PubMed - indexed for MEDLINE] 5352. Hypertension. 2000 Jun;35(6):1270-7. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Engeli S(1), Negrel R, Sharma AM. Author information: (1)Department of Internal Medicine, Division of Endocrinology and Nephrology, Benjamin Franklin Clinic, Free University of Berlin Germany. The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest. PMID: 10856276 [PubMed - indexed for MEDLINE] 5353. Diabetologia. 2000 May;43(5):533-49. New insights into sympathetic regulation of glucose and fat metabolism. Nonogaki K(1). Author information: (1)Department of Psychiatry, University of California at San Francisco, 94143-0984, USA. The autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that beta-(beta3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and beta3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus. PMID: 10855527 [PubMed - indexed for MEDLINE] 5354. Semin Reprod Endocrinol. 1999;17(4):349-58. Aromatase in aging women. Bulun SE(1), Zeitoun K, Sasano H, Simpson ER. Author information: (1)Department of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago 60612, USA. Cessation of ovarian estrogen secretion is the key event during the climacteric. An enzyme termed aromatase in a number of human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin fibroblasts, bone, and the brain, catalyzes the conversion of C19 steroids to estrogens. Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age. Sufficient circulating levels of the biologically active estrogen, estradiol, can be produced as a result of extraglandular aromatization of androstenedione to estrone, which is subsequently reduced to estradiol in peripheral tissues, to cause uterine bleeding and endometrial hyperplasia and cancer in obese anovulatory or postmenopausal women. Extraglandular aromatase expression in adipose tissue and skin (via increasing circulating levels of estradiol) and bone (via increasing local estrogen concentrations) is of paramount importance in slowing the rate of postmenopausal bone loss. Moreover, excessive or inappropriate aromatase expression was demonstrated in adipose fibroblasts surrounding a breast carcinoma, endometriosis-derived stromal cells, and stromal cells in endometrial cancer and gave rise to increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels promote the growth of these steroid-responsive tissues. Finally, local estrogen biosynthesis by aromatase activity in the brain may be important in the regulation of various cognitive and hypothalamic functions. The regulation of aromatase expression in human cells via alternatively used promoters, which can be activated or inhibited by various hormones, increases the complexity of estrogen biosynthesis in the human body. Aromatase expression is under the control of the classically located proximal promoter II in the ovary and a far distal promoter I.1 (40 kb upstream of the translation initiation site) in the placenta. In adipose tissue, two other promoters (I.4 and I.3) located between I.1 and II are used in addition to the ovarian-type promoter II. To add a further twist, promoter use in adipose fibroblasts switches between promoters II/I.3 and I.4 upon treatment of these cells with prostaglandin E2 (PGE2) versus glucocorticoids plus cytokines. Moreover, the presence of a carcinoma in breast adipose tissue causes a switch of promoter use from I.4 to II/I.3. Molecular and cellular mechanisms responsible for estrogen formation and their physiologic and clinical relevance will be reviewed in this article. PMID: 10851574 [PubMed - indexed for MEDLINE] 5355. Vutr Boles. 1999;31(1):28-32. [Arterial hypertension and obesity--a dangerous combination]. [Article in Bulgarian] Zakharieva S. The combination of obesity with arterial hypertension is frequent finding in clinical practice. In 70% of the males and 61% of the females the high blood pressure is directly connected with obesity. The assumed mechanisms by which obesity leads to arterial hypertension are: insuline resistance; genetic factors (hypothesis for the sparing gene); correlations leptin-neuropeptide Y; fatty tissue as origin of local pressor and depressor humoral factors. The arterial hypertension in obesity is salt-sensible, associated with increased intraglomerular pressure, microalbuminuria and increased risk for cardiovascular complications. The reduction of the body weight is the principal nonmedical mean for treatment of the arterial hypertension. Of the antihypertensive drugs those which are neutral with respect to the carbohydrat and fat metabolism are preferred inhibitors of the converting enzyme, calcium antagonists, selective alpha-1 blockers, central alpha-2 agonist. PMID: 10847146 [PubMed - indexed for MEDLINE] 5356. Med Clin (Barc). 2000 Apr 29;114(16):624-30. [The role of tumor necrosis factor in the control of fat reserve and obesity]. [Article in Spanish] Bulló Bonet M(1), García-Lorda P, Argilés JM, Salas-Salvadó J. Author information: (1)Unidad de Nutrición Humana, Facultad de Medicina, Universidad Rovira i Virgili, Tarragona. PMID: 10846690 [PubMed - indexed for MEDLINE] 5357. Annu Rev Physiol. 2000;62:413-37. Leptin. Ahima RS(1), Flier JS. Author information: (1)Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development. PMID: 10845097 [PubMed - indexed for MEDLINE] 5358. Ann N Y Acad Sci. 1999 Nov 18;892:289-96. Transgenic mice lacking white fat: models for understanding human lipoatrophic diabetes. Reitman ML(1), Mason MM, Moitra J, Gavrilova O, Marcus-Samuels B, Eckhaus M, Vinson C. Author information: (1)Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. mlr@helix.nih.gov The human disease lipoatrophic (or lipodystrophic) diabetes is a rare syndrome in which a deficiency of adipose tissue is associated with Type 2 diabetes. This disease is an interesting contrast to the usual situation in which diabetes is associated with obesity, an excess of fat. Aside from obesity, patients with lipodystrophic diabetes have the other features associated with Metabolic Syndrome X, including hypertension and dyslipidemia. The contrast between diabetes with a lack of fat and diabetes with an excess of fat provides an opportunity to study the mechanisms causing Type 2 diabetes and its complications. Recently, three laboratories have produced transgenic mice that are deficient in white adipose tissue. These mice have insulin resistance and other features of lipoatrophic diabetes, and are a faithful model for the human disease. Here we review the different murine models of fat ablation and compare the murine and human diseases, addressing the questions: Is the lack of fat causative of the diabetes, and if so by what mechanism? How could the other clinical features be explained mechanistically? And finally, what can be gleaned about insight into treatment options? PMID: 10842669 [PubMed - indexed for MEDLINE] 5359. Ann N Y Acad Sci. 1999 Nov 18;892:261-71. Neuroendocrine regulation of nutrient partitioning. Rohner-Jeanrenaud F(1). Author information: (1)Laboratoires de Recherches Métaboliques, Geneva University School of Medicine, Switzerland. Jeanrenaud_Francoise@Lilly.com Leptin is a satiety factor which acts within the hypothalamus to decrease the levels of several neuropeptides stimulating food intake (among them, neuropeptide Y [NPY]), while increasing those that inhibit food intake. These effects of leptin bring about decreased body weight. In vivo, leptin potentiates basal and insulin-stimulated glucose utilization, presumably its oxidation, and decreases fat storage. Leptin increases sympathetic-mediated energy dissipation, and the expression of uncoupling proteins-1, -2, and -3. In peripheral tissues (muscles, adipose, others), leptin decreases triglyceride content by increasing fatty acid oxidation, decreasing the activity/expression of esterification and lipogenic enzymes, and favoring lipolysis. It decreases the lipogenic activity of insulin. Ultimately, leptin depletes fat stores and promotes leanness. NPY, taken as one example of what an orexigenic agent may produce, increases food intake and body weight. It favors fat storage in adipose tissue by stimulating lipogenic activity. It decreases glucose utilization by muscles, making more glucose carbon available for lipogenesis. Effects of NPY result from vagus nerve-mediated hyperinsulinemia and overactivity of the hypothalamo-pituitary-adrenal axis. Thus, NPY favors fat stores, and ultimately obesity. Glucocorticoids are necessary for NPY effects to occur, because central administration of the neuropeptide in adrenalectomized animals is ineffective. Glucocorticoids also have genuine effects when administered centrally to normal rats. They increase the hypothalamic content of NPY and decrease that of CRH. This double neuro-peptidic change stimulates food intake, insulin output, adipose tissue storage ability, decreases the expression of uncoupling proteins-1 and -3, and increases body weight. Body weight homeostasis appears to require a finely tuned regulation of both leptin and glucocorticoids, with their respective opposite effects. PMID: 10842667 [PubMed - indexed for MEDLINE] 5360. Ann N Y Acad Sci. 1999 Nov 18;892:146-54. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Matsuzawa Y(1), Funahashi T, Nakamura T. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. yuji@imed2.med.osaka-u.ac.jp Syndrome X is a clinical syndrome in which multiple risks cluster in an individual, and it is a common basis of vascular disease in the industrial countries. The molecular basis of Syndrome X, however, has not been elucidated. We have analyzed body fat distribution using CT scan and have shown that people who have accumulated intra-abdominal visceral fat frequently have multiple risks and vascular diseases. Thus, "visceral fat syndrome" is a clinical entity compatible with Syndrome X. To clarify the molecular mechanism of the disorders in visceral fat syndrome, we analyzed the expressed genes in adipose tissue by a large-scale random sequencing. Unexpectedly, visceral fat expressed a variety of the genes for secretory proteins including various bioactive substances; we designated them adipocytokines. One of them, plasminogen activator inhibitor-1, was overproduced in accumulated visceral fat and might contribute to the development of vascular disease. We have also cloned a novel adipose-specific gene named adiponectin. Adiponectin is a collagen-like plasma protein which has an inhibitory effect on proliferation of vascular smooth muscle cells; its plasma levels are paradoxically decreased in obesity. Adipocytokines may play important roles in the development of the disorders in Syndrome X. PMID: 10842660 [PubMed - indexed for MEDLINE] 5361. Ann N Y Acad Sci. 1999 Nov 18;892:119-26. Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Smith U(1), Axelsen M, Carvalho E, Eliasson B, Jansson PA, Wesslau C. Author information: (1)Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. ulf.smith@medicine.gu.se Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X. PMID: 10842657 [PubMed - indexed for MEDLINE] 5362. Ann N Y Acad Sci. 1999 Nov 18;892:58-72. Interaction between aging and syndrome X: new insights on the pathophysiology of fat distribution. Barzilai N(1), Gupta G. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA. barzilai@aecom.yu.edu Increased fat mass (FM), and in particular a specific increase in visceral fat (VF), may account for the age-associated decrease in insulin action and the development of Syndrome X. Utilizing chronic caloric restriction (CR) with aging in a rodent model, we dissociated the effects of VF and FM, and demonstrated that the decrease in VF accumulation was sufficient to prevent the marked decrease in hepatic insulin action. This suggests that the typical increase in VF with aging, rather than aging per se, determines hepatic insulin resistance. To directly assess the role of VF, we studied rats after surgical removal of VF or sham operation. Surgical extraction of VF (which accounts for approximately 10% of total fat) improved hepatic insulin action by more than twofold. We studied the role of fat-derived peptides in the regulation of body composition and insulin action. While VF extraction resulted in decreased gene expression for leptin and TNF-alpha in the subcutaneous adipose, administration of leptin selectively decreased visceral fat (approximately 60%), and enhanced the action of insulin on inhibiting hepatic glucose production (approximately 80%). Thus, the cause-effect relationship between the age-related increase in VF and the decrease in hepatic insulin action may involve the failure of leptin to "cross talk" with other fat depots to regulate fat distribution. PMID: 10842652 [PubMed - indexed for MEDLINE] 5363. Am J Clin Nutr. 2000 Jun;71(6 Suppl):1691S-5S; discussion 1696S-7S. Lycopene and cardiovascular disease. Arab L(1), Steck S. Author information: (1)School of Public Health, University of North Carolina, Chapel Hill. Considerable evidence suggests that lycopene, a carotenoid without provitamin A activity found in high concentrations in a small set of plant foods, has significant antioxidant potential in vitro and may play a role in preventing prostate cancer and cardiovascular disease in humans. Tomato products, including ketchup, tomato juice, and pizza sauce, are the richest sources of lycopene in the US diet, accounting for >80% of the total lycopene intake of Americans. Unlike other carotenoids, lycopene is not consistently lower among smokers than among nonsmokers, suggesting that any possible preventive activity is not as an antioxidant. Instead, lycopene may have a cholesterol synthesis-inhibiting effect and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene. The question of whether lycopene helps to prevent cardiovascular disease can only be answered by a trial specifically evaluating its effectiveness in this area. PMID: 10837319 [PubMed - indexed for MEDLINE] 5364. Genes Dev. 2000 Jun 1;14(11):1293-307. Transcriptional regulation of adipogenesis. Rosen ED(1), Walkey CJ, Puigserver P, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 USA. edrosen@massmed.org PMID: 10837022 [PubMed - indexed for MEDLINE] 5365. Proc Nutr Soc. 2000 Feb;59(1):127-34. Adipose tissue metabolism and its role in adaptations to undernutrition in ruminants. Chilliard Y(1), Ferlay A, Faulconnier Y, Bonnet M, Rouel J, Bocquier F. Author information: (1)Adipose Tissue and Milk Lipids Team of the Research Unit on Herbivores, INRA - Theix, 63122 St Genès Champanelle, France. Yves.Chilliard@clermont.inra.fr Changes in the amount and metabolism of adipose tissue (AT) occur in underfed ruminants, and are amplified during lactation, or in fat animals. The fat depot of the tail of some ovine breeds seems to play a particular role in adaptation to undernutrition; this role could be linked to its smaller adipocytes and high sensitivity to the lipolytic effect of catecholamines. Glucocorticoids and growth hormone probably interact to induce teleophoretic changes in the AT responses to adenosine and catecholamines during lactation. Fat mobilization in dry ewes is related both to body fatness and to energy balance. The in vivo beta-adrenergic lipolytic potential is primarily related to energy balance, whereas basal postprandial plasma non-esterified fatty acids (NEFA) are related to body fatness, and preprandial plasma NEFA is the best predictor of the actual body lipid loss. Several mechanisms seem to be aimed at avoiding excessive fat mobilization and/or insuring a return to the body fatness homeostatic set point. As well as providing the underfed animal with fatty acids as oxidative fuels, AT acts as an endocrine gland. The yield of leptin by ruminant AT is positively related to body fatness, decreased by underfeeding, beta-adrenergic stimulation and short day length, and increased by insulin and glucocorticoids. This finding suggests that the leptin chronic (or acute) decrease in lean (or underfed respectively) ruminants is, as in rodents, a signal for endocrine, metabolic and behavioural adaptations aimed at restoring homeostasis. PMID: 10828182 [PubMed - indexed for MEDLINE] 5366. Ann Med. 2000 Apr;32(3):222-32. Separate systems for serotonin and leptin in appetite control. Halford JC(1), Blundell JE. Author information: (1)Department of Psychology, University of Liverpool, UK. j.c.g.halford@liverpool.ac.uk Appetite control involves an integration of the drive signals arising form energy stores in the body with the satiety signals generated by periodic episodes of food consumption. Serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the processes of within-meal satiation and postmeal satiety (5-HT1B and 5-HT2C postsynaptic receptors) which are concerned with the signals arising form the pattern of food intake. Central nervous system (CNS) 5-HT is sensitive to circulating levels of the precursor tryptophan, certain macronutrients and peripheral satiety factors such as cholecystokinin (CCK) and enterostatin. Hypothalamic 5-HT receptor systems inhibit neuropeptide Y (NPY), a potent stimulator of hunger and food intake. In contrast to the linking of 5-HT with the consequences of food ingestion, the hormone leptin (OB protein) is regarded as a signal linking adipose tissue status with a number of key CNS circuits. Leptin itself stimulates CNS leptin receptors (OB-r receptor) which link with pro-opiomelanocortin (POMC)/ MC-4 receptors. The effects of leptin may also be modulated by factors such as the corticotrophin-releasing factor (CRF), cocaine and amphetamine-regulated transcript (CART), orexins and galanin. Very little evidence exists to support any direct link between the actions of 5-HT and leptin, suggesting that they are separate systems. 5-HT is a part of an integrated network for short-acting satiety signals (episodic in nature), and leptin is a hormonal indicator of long-term (tonic) energy reserves. At a conceptual level, these may represent the distinction between 'satiety' and 'drive'. Interestingly, both 5-HT and leptin modulate the action of NPY, which may form a part of a common output pathway for the expression of appetite. PMID: 10821329 [PubMed - indexed for MEDLINE] 5367. J Mammary Gland Biol Neoplasia. 1998 Apr;3(2):109-16. The mammary fat pad. Neville MC, Medina D, Monks J, Hovey RC. Comment on J Mammary Gland Biol Neoplasia. 1998 Apr;3(2):191-200. The mammary fat pad is essential for development of the mammary epithelium, providing signals that mediate ductal morphogenesis and, probably, alveolar differentiation. The "cleared" fat pad is often used as a transplantation site. Considering the crucial role of the fat pad, its properties have received relatively little attention from researchers in the field. Some of the questions whose investigation is pertinent to understanding both normal mammary development and carcinogenesis are outlined in this commentary in the spirit of stimulating enquiry into this important subject. It is clear from a brief perusal of the available literature that until studies are specifically designed to clearly differentiate between functional effects of the fibrous and the adipose stroma, more substantive information about their differential effects on mammary development and tumorigenesis will not be forthcoming. PMID: 10819521 [PubMed - indexed for MEDLINE] 5368. Ann N Y Acad Sci. 2000 Apr;905:159-64. LPA as a paracrine mediator of adipocyte growth and function. Pagès G(1), Girard A, Jeanneton O, Barbe P, Wolf C, Lafontan M, Valet P, Saulnier-Blache JS. Author information: (1)INSERM U317, Institut Louis Bugnard, Université Paul Sabatier, CHU Rangueil, Toulouse, France. Adipogenesis corresponds to the recruitment of new adipocytes in adipose tissue, and results from the proliferation/differentiation of preadipocytes. Production of paracrine and autocrine factors by adipocytes plays an important role in adipogenesis. We recently demonstrated the existence of adipocyte production of lysophosphatidic acid (LPA) both in vitro and in situ. This production is modulated by catecholamines via alpha 2-adrenergic receptors. Adipocyte-LPA present in conditioned media increases the growth of a preadipose cell line in culture. This growth is associated with an activation of mitogen-activated protein kinases, and of the focal adhesion kinase. Because of the close proximity of preadipocytes and adipocytes within adipose tissue, adipocyte-LPA could play an important role in autocrine/paracrine control of adipogenesis. PMID: 10818451 [PubMed - indexed for MEDLINE] 5369. Proc Nutr Soc. 1999 Nov;58(4):973-8. Glycerol production and utilization measured using stable isotopes. Landau BR(1). Author information: (1)Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4951, USA. epc2@po.cwru.edu The rate of appearance of glycerol in the systemic circulation is determined from the enrichment of arterial blood glycerol when labelled glycerol is infused intravenously. This value provides a good measure of whole-body lipolysis during fasting, except that arterial infusion and venous sampling, if feasible, would probably give a higher more-accurate value. Lipolysis occurs primarily in adipose tissue, although other tissues contribute, notably muscle. Measurement is based on the difference in the enrichment of the glycerol entering and leaving the tissue. Lipolysis is underestimated by the extent to which glycerol released by lipolysis does not enter the systemic circulation, as occurs when lipolysis takes place in the non-hepatic tissue of the splanchnic bed. Glycerol released into the systemic circulation is utilized mainly by liver, although kidney and muscle are also major users of glycerol. Measurement of glycerol utilization is based on the amount of labelled glycerol taken up by the tissues. Other tissues probably utilize glycerol to a smaller extent, but in total this represents a significant amount. Most glycerol taken up by liver is converted to glucose. Glucose is probably the major source of glycerol-3-phosphate used in the esterification of fatty acids by adipose tissue. PMID: 10817165 [PubMed - indexed for MEDLINE] 5370. Proc Nutr Soc. 1999 Nov;58(4):919-23. Microdialysis of skeletal muscle at rest. Henriksson J(1). Author information: (1)Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. jan.henriksson@fyfa.ki.se Techniques in human skeletal muscle research are by necessity predominantly 'descriptive'. Microdialysis has raised high expectations that it could meet the demand for a method that allows 'mechanistic' investigations to be performed in human skeletal muscle. In the present review, some views are given on how well the initial expectations on the use of the microdialysis technique in skeletal muscle have been fulfilled, and the areas in which additional work is needed in order to validate microdialysis as an important metabolic technique in this tissue. The microdialysis catheter has been equated to an artificial blood vessel, which is introduced into the tissue. By means of this 'vessel' the concentrations of compounds in the interstitial space can be monitored. The concentration of substances in the collected samples is dependent on the rate of perfusate flow. When perfusate flow is slow enough to allow complete equilibration between interstitial and perfusate fluids, the concentration in the perfusate is maximal and identical to the interstitial concentration. Microdialysis data may be influenced by changes in blood flow, especially in instances where the tissue diffusivity limits the recovery in vivo, i.e. when recovery in vitro is 100%, whereas the recovery in vivo is less than 100%. Microdialysis data indicate that a significant arterial-interstitial glucose concentration gradient exists in skeletal muscle but not in adipose tissue at rest. While the concentrations of glucose and lactate in the dialysate from skeletal muscle are close to the expected values, the glycerol values obtained for muscle are still puzzling. Ethanol added to the perfusate will be cleared by the tissue at a rate that is determined by the nutritive blood flow (the microdialysis ethanol technique). It is concluded that microdialysis of skeletal muscle has become an important technique for mechanistic studies in human metabolism and nutrition. PMID: 10817159 [PubMed - indexed for MEDLINE] 5371. Proc Nutr Soc. 1999 Nov;58(4):913-7. Microdialysis: use in human exercise studies. Amer P(1). Author information: (1)Karolinska Institute, Department of Medicine, Huddinge Hospital, Sweden. Peter.Arner@medhs.ki.se Microdialysis has been used for 25 years to study brain function in vivo. Recently, it has been developed for investigations on peripheral tissues. A microdialysis catheter is an artificial blood vessel system which can be placed in the extracellular space of various tissues such as adipose tissue and skeletal muscle in order to examine these tissues in situ. Molecules are collected from the tissue by the device and their true interstitial concentration can be estimated. Metabolically-active molecules can be delivered to the interstitial space through the microdialysis probe and their action on the tissue can be investigated locally without producing generalized effects. It is also possible to study local tissue blood flow with microdialysis by adding a flow marker (usually ethanol) to the microdialysis solvent. The microdialysis technique is particularly useful for studies of small and water-soluble molecules. A number of important observations on the in vivo regulation of lipolysis, carbohydrate metabolism and blood flow in human skeletal muscle and adipose tissue have been made recently using microdialysis. PMID: 10817158 [PubMed - indexed for MEDLINE] 5372. Proc Nutr Soc. 1999 Nov;58(4):877-86. Macronutrient metabolism of adipose tissue at rest and during exercise: a methodological viewpoint. Frayn KN(1). Author information: (1)Oxford Lipid Metabolism Group, Radcliffe Infirmary, UK. keith.frayn@oxlip.ox.ac.uk The metabolism of white adipose tissue is regulated by many factors, including hormones and substrates delivered in the blood, the activity of the autonomic nervous system and the rate of flow of blood through the tissue. An integrated view of adipose tissue metabolism can only be gained, therefore, from studies in vivo. Of the various techniques available for studying adipose tissue metabolism in vivo, the measurement of arterio-venous differences offers some unique possibilities. In human subjects this technique has been performed mostly by catheterization of the venous drainage of the subcutaneous abdominal depot. Studies using this technique indicate that adipose tissue has an active pattern of metabolism, responding rapidly to meal ingestion by suppressing the release of non-esterified fatty acids, or to exercise with an increase in fat mobilization. Adipose tissue blood flow may also change rapidly in these situations; for instance, it increases markedly after a meal, potentially increasing the delivery of triacylglycerol to the enzyme lipoprotein lipase (EC 3.1.1.34) for hydrolysis. During exercise, there is evidence that adipose tissue blood flow does not increase sufficiently to allow delivery of all the fatty acids released into the systemic circulation. The various adipose tissue depots have their own characteristic metabolic properties, although in human subjects these are difficult to study with the arterio-venous difference technique. A combination of tracer infusion with selective catheterization allows measurements of leg, splanchnic and non-splanchnic upper-body fat mobilization and triacylglycerol clearance. Development of such techniques may open up new possibilities in the future for obtaining an integrated picture of adipose tissue function and its depot-specific variations. PMID: 10817155 [PubMed - indexed for MEDLINE] 5373. Biochem Soc Trans. 2000 Feb;28(2):126-31. Adipocyte studies: systems for investigating effects of growth hormone and other chronically acting hormones. Vernon RG(1). Author information: (1)Hannah Research Institute, Ayr, Scotland, UK. Adipose tissue is very amenable to study in vitro. Collagenase digestion yields free adipocytes which usually respond well to acute stimulation/inhibition by hormones and other factors. Chronic effects of hormones are best studied using explants of adipose tissue which, from some species (e.g. sheep), can be maintained in culture for up to a week without loss of function. Alternatively, preadipocytes can be readily isolated from adipose tissue and induced to proliferate and differentiate in culture, while various adipocyte-like cell-lines have been established, which can be used for chronic studies. Use of these various systems for investigating the mechanisms of action of growth hormone are described. PMID: 10816113 [PubMed - indexed for MEDLINE] 5374. Nutr Rev. 2000 Mar;58(3 Pt 2):S19-21. Effect of aging. Kohrt WM(1). Author information: (1)Department of Internal Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. PMID: 10812931 [PubMed - indexed for MEDLINE] 5375. Pol Merkur Lekarski. 2000 Feb;8(44):109-12. [Leptin and obesity]. [Article in Polish] Miczke A(1), Pupek-Musialik D. Author information: (1)Kliniki Chorób Wewnetrznych Akademii Medycznej w Poznaniu. Obesity is associated with increased incidence of cardiovascular diseases, insulin resistance, dyslipoproteinemia and cancer. The discovery of leptin in 1994 has provided a lot of new information about obesity. Leptin is a 167-amino acid peptide synthetized almost exclusively in adipose tissue. This hormone circulates in blood serum in both free and bound forms. The long isoform of leptin receptor is widely distributed in brain, whereas numerous short forms are also being present in peripheral tissues. Leptin acts by binding to the receptors in hypothalamus and altering a release of several neuropeptides, especially neuropeptide Y, regulating energy intake and expenditure. Apart from signaling energy reserves to the brain, leptin promotes hematopoiesis, influences pubertal development and contributes to the increase in arterial blood pressure. Leptin production regulation in humans is poorly understood, but appears to depend on the total body fat, changes in energy intake and serum level of several hormones. Despite the recent advances in the knowledge of both physiology and pathophysiology of leptin, several many important questions require further studies. PMID: 10808743 [PubMed - indexed for MEDLINE] 5376. Postgrad Med. 2000 May 15;107(6 Suppl Key):11-5. doi: 10.3810/pgm.5.15.2000.suppl4.22. The pathophysiologic defects of type 2 diabetes. Abnormal insulin action and impaired insulin secretion. Kahn SE(1). Author information: (1)Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Medical Center, Seattle, WA 98108, USA. Normal glucose metabolism is dependent on tight interplay among the pancreas, the liver, muscle, and adipose tissue. If this interplay is disturbed by decreased insulin secretion or decreased insulin effectiveness, glucose intolerance and type 2 diabetes ensue. Therapeutic approaches currently available and those under development target the pathophysiologic defects of type 2 diabetes, and treatment must be selected with this in mind, a major goal being to ensure adequate availability of insulin to the tissues. PMID: 19667505 [PubMed - indexed for MEDLINE] 5377. Eur J Clin Nutr. 2000 Mar;54 Suppl 1:S47-51. Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Herrera E(1). Author information: (1)Facultad de Ciencias Experimentales y Técnicas, Universidad San Pablo-CEU, Boadilla del Monte, Madrid, Spain. eherrera@ceu.es During the first two-thirds of gestation, the mother is in an anabolic condition, increasing her fat depots thanks to both hyperphagia and enhanced lipogenesis. During the last third of gestation, the mother switches to a catabolic condition. Glucose is the most abundant nutrient crossing the placenta, which causes maternal hypoglycemia despite an increase in the gluconeogenetic activity. Adipose tissue lipolytic activity becomes enhanced, increasing plasma levels of FFA and glycerol that reach the liver; consequently there is an enhanced production of triglycerides that return to the circulation in the form of very low density lipoproteins (VLDL). Glycerol is also used as a preferential gluconeogenetic substrate, saving other more essential substrates, like amino acids, for the fetus. Under fasting conditions, fatty acids are converted into ketone bodies throughout the beta-oxidation pathway, and these compounds easily cross the placental barrier and are metabolized by the fetus. An enhanced liver production of VLDL-triglycerides together with a decrease in adipose tissue lipoprotein lipase (LPL) and an increase in plasma activity of cholesterol ester transfer protein causes both an intense increment in these lipoproteins and a proportional enrichment of triglycerides in both low and high density lipoproteins. Maternal triglycerides do not cross the placenta, but the presence of LPL and other lipases allows their hydrolysis, releasing fatty acids to the fetus. Under fasting conditions, the maternal liver uses circulating triglycerides as ketogenic substrates. Around parturition there is an induction of LPL activity in the mammary glands, driving circulating triglycerides to this organ for milk synthesis, allowing essential fatty acids derived from the mother's diet to become available to the suckling newborn. PMID: 10805038 [PubMed - indexed for MEDLINE] 5378. Eur J Clin Nutr. 2000 Mar;54 Suppl 1:S1-6. Morphological and physiological changes during growth: an update. Ballabriga A(1). Author information: (1)Autonomous University of Barcelona, Department of Pediatrics, Spain. tberry@alehop.com Skeletal growth and changes in body composition during growth present important variations; body mass index and lean body mass related to age show important gender differences. The process of ossification is developed in two different ways, endochondral and intramembraneous. The former is characterised by the formation of bone from growth cartilage. Intramembraneous ossification is characterised by the formation of bone from a mesenchymal structure, as occurs with the flat bones of the skull. During childhood and adolescence and up to the acquisition of adult stature, two phenomenons are produced simultaneously: the synthesis of new bone from growth cartilage due to the process of endochondral ossification, and modeling-remodeling of previously synthesized bone. Bone growth and mineralisation of its extracellular matrix are simultaneous phenomenons, the final result being the acquisition and maintenance of body bone mass. A positive calcium balance is necessary during adolescence in order to achieve the maximum peak of bone mass and even with the termination of longitudinal growth of bone, the process of mineralisation can last a further 4 years. Childhood and adolescence are the period of life in which the peak of bone mass must be achieved, and if during this time this does not happen there will be a greater risk for the later development of osteoporosis. Regulation of bone mass is a polygenic process and during recent years studies have been centred on the receptor genes of vitamin D and estrogens. A maximum calcium retention during adolescence may influence the achievement of a high peak of bone mass but at a certain level of calcium intake the calcium retention reaches a plateau. The expression of grams of hydroxyapatite per square centimetre has been used clinically, or expressed in volume as g/cm3. From birth until 3 years, the increase represents approximately 30% of the total increase, from 3 years until the beginning of pubertal development the increase is 20%. During pubertal development there is an increase of 30-40% and from the end of growth until the age of 21 years there is an increase of 15-20%. Both prepubertal boys and girls show a progressive increase of leptin levels during the years prior to the onset of puberty and until Tanner's stage 11 and higher levels are observed in girls in this period, possibly in relation to their earlier onset of puberty. This increase of leptin in girls during pubertal development suggests that leptin may be a link between adipose tissue and puberty. PMID: 10805030 [PubMed - indexed for MEDLINE] 5379. Diabetes Metab. 2000 Apr;26(2):98-106. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Luyckx FH(1), Lefebvre PJ, Scheen AJ. Author information: (1)Department of Clinical Chemistry, Department of Medicine, CHU Sart Tilman, Liège, Belgium. Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and importance, and is now considered as one of the commonest liver diseases in western countries. It is frequently associated with severe obesity, especially abdominal adiposity, and is intimately related to various clinical and biological markers of the insulin resistance syndrome. Especially, both the prevalence and the severity of liver steatosis are related to male sex, body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. A substantial weight loss following gastroplasty is accompanied by a marked reduction in the prevalence and the severity of the various biological abnormalities of the metabolic syndrome and, concomitantly, by an important regression of liver steatosis in most obese patients. However, in some patients, this rapid and drastic weight loss may result in a mild increase in inflammatory lesions (hepatitis), despite the regression of steatosis, which might result from the rapid mobilization of fatty acids or cytokines from adipose tissue, especially visceral fat. The intimate relationship between NASH and obesity leads to the concept that NASH may be considered as another disease of affluence, as is the insulin resistance syndrome and perhaps being part of it. PMID: 10804323 [PubMed - indexed for MEDLINE] 5380. Med Clin North Am. 2000 Mar;84(2):363-85, vi. Metabolic complications of obesity. Pathophysiologic considerations. Sheehan MT(1), Jensen MD. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, USA. Given a specific research interest in human fatty acid metabolism, this article focuses primarily on the evidence surrounding the hypothesis that dysregulation of the fuel release function of fat cells (lipolysis) is an important contributing factor to the health hazards of obesity. PMID: 10793647 [PubMed - indexed for MEDLINE] 5381. Acta Clin Belg. 2000 Jan-Feb;55(1):9-15. From obesity to diabetes: why, when and who? Scheen AJ(1). Author information: (1)Département de Médecine, CHU Sart Tilman, Liège, Belgique. Andre.Scheen@chu.ulg.ac.be Obesity is considered as the most important risk factor for type 2 diabetes. We will briefly discuss why does obesity predispose to diabetes, when does diabetes occur in obese subjects and who among obese individuals is particularly prone to develop diabetes. Obesity, especially intraabdominal adiposity, is associated with increased FFA plasma concentrations which exert a major negative effect on insulin sensitivity at both muscular and hepatic sites. Various metabolic, haemodynamic and hormonal theories have been proposed to explain insulin resistance in obese subjects. A specific role of TNF-alpha has been recently suggested. However, besides insulin resistance, defective insulin secretion is a prerequisie for the development of overt type 2 diabetes. Both lipotoxicity and glucotoxicity may initiate and perpetuate a vicious circle responsible for the metabolic deterioration. Diabetes occurs as a late phenomenon in obesity and is preceded by years of impaired glucose tolerance. The progression to diabetes is heralded by an inability of the B cell to maintain its previously high rate of insulin secretion in response to glucose in face of insulin resistance. This propensity to develop type 2 diabetes may be genetically determined and/or triggered by environmental factors. The evolution from obesity to diabetes represents a continuum that progresses through different phases in which defects in both insulin action and insulin secretion play a critical interaction and must be looked at in concert. PMID: 10783502 [PubMed - indexed for MEDLINE] 5382. Clin Chem Lab Med. 2000 Jan;38(1):3-11. Regulation of lipid and lipoprotein metabolism by PPAR activators. Gervois P(1), Torra IP, Fruchart JC, Staels B. Author information: (1)Département d'Athérosclérose, INSERM U.325, Institut Pasteur de Lille et Faculté de Pharmacie, Université de Lille II, France. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARalpha, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and muscle. PPARgamma, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by pharmacological drugs, such as fibrates for PPARalpha and glitazones for PPARgamma. PPARalpha mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARalpha is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPARalpha down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPARalpha activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPARgamma-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better understanding of the mechanism of action of fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs. PMID: 10774955 [PubMed - indexed for MEDLINE] 5383. Ginecol Obstet Mex. 2000 Feb;68:64-9. [Clinical and metabolic effects of oral contraceptives]. [Article in Spanish] Vázquez Hernández L(1), Téllez Martínez J, Hicks Gómez JJ. Author information: (1)Hospital de Ginecología y Obstetricia Luis Castelazo Ayala IMSS, México. The oral contraception most employed, consists in a combination of estrogen and progestin, the main action in the prevention of ovulation through the inhibition of the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). The progestin in combination with estrogen produces an endometrium not receptive to the oocyte implantation and changes tubal, this affects capacitation and acrosomal reaction. Since 1960s up to date the reports made had been established that the OC had been developed adverse effects such as increase concentration of HDL, increase of apolipoprotein B-100, insulin resistance, increase in SHBG, atherogenicity, alteration in the coagulation factors and increase in the risk of venous thromboembolic disease. This work was elaborated with literature search on MEDLINE between 1985 to 1998, with the purpose to search the collateral effects of Oral Contraceptives evaluated by other authors. PMID: 10774107 [PubMed - indexed for MEDLINE] 5384. Tanpakushitsu Kakusan Koso. 2000 Apr;45(6 Suppl):935-40. [Beta 3-adrenergic receptor]. [Article in Japanese] Furutani Y(1), Karasawa T. Author information: (1)Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita, Japan. yasuji-furutani@dainippon-pharm.co.jp PMID: 10771654 [PubMed - indexed for MEDLINE] 5385. Mutat Res. 2000 Apr;462(2-3):323-33. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Kristensen VN(1), Borresen-Dale AL. Author information: (1)Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello 0310, Oslo, Norway. The age-specific incidence rate of breast cancer in women rises until menopause, levels off and then rises again at a much lower rate indicating a possible hormonal influence on the disease risk. A large amount of evidence has implicated hormones and other compounds with oestrogen activity in the pathogenesis of certain endocrine cancers, particularly breast cancer. Widely dispersed hormone-like chemicals, capable of disrupting the endocrine system and interfering with proliferation, have been described. Compounds such as dioxins, some polychlorinated biphenyls and the plastic ingredient bisphenol-A have been shown to interfere with human reproduction and hormonal regulation. The levels of these foreign compounds as well as the levels of endogenous oestradiol may influence the risk of breast cancer. Endogenous oestradiol is synthesised in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and minor quantities in peripheral tissue. These cells, as well as breast cancer tissue, express all the necessary enzymes for this synthesis: CYP17, CYP11a, CYP19, hydroxysteroid hydrogenase, steroid sulphatase as well as enzymes further hydroxylating oestradiol such as CYP1A1, CYP3A4, CYP1B1. Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer. PMID: 10767642 [PubMed - indexed for MEDLINE] 5386. Nature. 2000 Apr 6;404(6778):672-7. Medicinal strategies in the treatment of obesity. Bray GA(1), Tartaglia LA. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. BrayGA@pbrc.edu When prevention fails, medicinal treatment of obesity may become a necessity. Any strategic medicinal development must recognize that obesity is a chronic, stigmatized and costly disease that is increasing in prevalence. Because obesity can rarely be cured, treatment strategies are effective only as long as they are used, and combined therapy may be more effective than monotherapy. For a drug to have significant impact on body weight it must ultimately reduce energy intake, increase energy expenditure, or both. Currently approved drugs for long-term treatment of obesity include sibutramine, which inhibits food intake, and orlistat, which blocks fat digestion. PMID: 10766254 [PubMed - indexed for MEDLINE] 5387. Nature. 2000 Apr 6;404(6778):652-60. Towards a molecular understanding of adaptive thermogenesis. Lowell BB(1), Spiegelman BM. Author information: (1)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. blowell@caregroup.harvard.edu Obesity results when energy intake exceeds energy expenditure. Naturally occurring genetic mutations, as well as ablative lesions, have shown that the brain regulates both aspects of energy balance and that abnormalities in energy expenditure contribute to the development of obesity. Energy can be expended by performing work or producing heat (thermogenesis). Adaptive thermogenesis, or the regulated production of heat, is influenced by environmental temperature and diet. Mitochondria, the organelles that convert food to carbon dioxide, water and ATP, are fundamental in mediating effects on energy dissipation. Recently, there have been significant advances in understanding the molecular regulation of energy expenditure in mitochondria and the mechanisms of transcriptional control of mitochondrial genes. Here we explore these developments in relation to classical physiological views of adaptive thermogenesis. PMID: 10766252 [PubMed - indexed for MEDLINE] 5388. Am J Med. 2000 Apr 17;108 Suppl 6a:9S-14S. The importance of insulin resistance in the pathogenesis of type 2 diabetes mellitus. Fujimoto WY(1). Author information: (1)Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine, Seattle, Washington 98195, USA. wilfuji@u.washington.edu Many patients with type 2 diabetes have hyperglycemia as a result of deficiencies in both insulin secretion and insulin action, that is, beta-cell dysfunction and insulin resistance. Insulin resistance is a state of reduced insulin sensitivity, an inability of insulin to lower plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose utilization in skeletal muscle and adipose tissue. Insulin resistance stems from genetic and environmental causes, and its extent varies considerably among individuals. Studies have shown that enhanced insulin secretion can compensate for insulin resistance and that enhanced insulin sensitivity can mask defects in beta-cell function. However, insulin resistance is essential to the development of the majority of cases of type 2 diabetes. Numerous epidemiologic studies have demonstrated an increase in the prevalence of insulin resistance and type 2 diabetes in various ethnic populations that have migrated from their native lands to more urbanized and westernized regions of the world. Type 2 diabetes has already reached epidemic proportions worldwide. By 2025, an estimated 300 million people will have diabetes, most of whom will inhabit China, India, and the United States. These studies have also demonstrated the complex interrelationship of hyperinsulinemia, obesity (primarily visceral adiposity), and free fatty acids with beta-cell dysfunction, insulin resistance, and the development of type 2 diabetes. Although little can be done to avert a genetic predisposition to type 2 diabetes, normoglycemia can be preserved in individuals who remain insulin sensitive. Lifestyle changes can be implemented and medications can be administered to improve insulin sensitivity, insulin secretion, and glucose utilization and reduce the prevalence of type 2 diabetes. PMID: 10764845 [PubMed - indexed for MEDLINE] 5389. J Cardiopulm Rehabil. 2000 Mar-Apr;20(2):96-108. Obesity, body fat distribution, and coronary artery disease. Brochu M(1), Poehlman ET, Ades PA. Author information: (1)Division of Cardiology, University of Vermont College of Medicine, Burlington, USA. Obesity is an independent risk factor for the development of coronary artery disease (CAD). Obesity also increases risk for CAD indirectly through its association with insulin resistance, hyperlipidemia, and hypertension. An increased accumulation of fat in the intraabdominal cavity, termed visceral adiposity, is highly correlated with an adverse coronary risk profile. In patients at risk for coronary artery disease, the treatment of obesity results in an improved coronary risk profile. The prevalence of obesity is extremely high in coronary populations, yet the effect of weight loss on cardiovascular outcomes in CAD patients has received relatively little attention. Observational studies in the cardiac rehabilitation setting showed that patients who lose weight and exercise show an improvement in coronary risk profile. Further research is needed to better define the clinical effectiveness of weight loss programs and their benefits in coronary patients. PMID: 10763157 [PubMed - indexed for MEDLINE] 5390. Neth J Med. 2000 Mar;56(3):76-9. Neuroendocrine sequelae of visceral fat accumulation: implications for cardiovascular disease and diabetes. Pijl H, Romijn JA, Benthem L, Meinders AE. PMID: 10759017 [PubMed - indexed for MEDLINE] 5391. Diabetes Metab Res Rev. 2000 Mar-Apr;16(2):114-24. Antiobesity pharmacotherapy in the management of type 2 diabetes. Scheen AJ(1), Lefèbvre PJ. Author information: (1)Division of Diabetes, Nutrition and Metabolic Diseases, Department of Medicine, University of Liège, CHU Sart Tilman, B-4000 Liège 1, Belgium. Andre.Scheen@chu.ulg.ac.be Obesity is a well-known risk factor for the development of Type 2 diabetes mellitus. The management of the obese diabetic patient remains a challenge for the clinician but, in any case, weight reduction should be considered as a key objective. In this respect, several antiobesity drugs have demonstrated potential. However, while fenfluramine and dexfenfluramine have been shown to promote weight loss and to directly improve insulin sensitivity, being two mechanisms contributing to better blood glucose control in obese Type 2 diabetic patients, they were recently withdrawn due to safety problems. Sibutramine, a new selective norepinephrine and serotonin reuptake inhibitor, promotes weight loss by decreasing food intake, an effect which leads to a mild improvement (significant in patients losing > or =5% of initial body weight) of blood glucose control in obese diabetic patients. Similarly, orlistat, a selective gastrointestinal lipase inhibitor which increases faecal fat losses, enhances diet-induced weight reduction and improves both blood glucose control and vascular risk profile, especially dyslipidaemia, in obese Type 2 diabetic patients. Further studies are required to better identify good responders to pharmacotherapy and specify the role of antiobesity agents in the overall long-term management of obese subjects with Type 2 diabetes. Other novel pharmacological approaches deserve further consideration, for instance beta-3 agonists aiming to increase energy expenditure, drugs interfering with tumor necrosis factor-alpha (TNF-alpha) or free fatty acid release by the adipose tissue or agents that slow gastric emptying. However, until now, results regarding efficacy and/or safety have been disappointing or preliminary in humans. PMID: 10751751 [PubMed - indexed for MEDLINE] 5392. Curr Opin Lipidol. 2000 Feb;11(1):37-42. Trans fatty acids and cardiovascular disease risk. Lichtenstein AH(1). Author information: (1)Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research, Center on Aging at Tufts University, Boston, MA 02111, USA. lichtenstein@hnrc.tufts.edu Recent studies continue to confirm previous observations that trans fatty acids elevate low density lipoprotein cholesterol levels, and at relatively high intakes decrease high density lipoprotein cholesterol levels. Considerable interest is focused on the potential benefits of trans-free margarines. Both adipose and plasma trans fatty acid levels reflect dietary intake. Current estimates of trans fatty acid intake in developed countries range from 0.5 to 2.6% of energy, contributed to primarily by differences in food availability and preference, and partly by the methodological differences used to calculate the data. PMID: 10750692 [PubMed - indexed for MEDLINE] 5393. Recenti Prog Med. 2000 Feb;91(2):78-85. [Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data]. [Article in Italian] Urso R(1), Croce GF, Tubili C, De Marco M, La Scala P, Luglio D, Narciso P. Author information: (1)IV Divisione Malattie Infettive, IRCCS Lazzaro Spallanzani, Roma. ursor@tin.it HIV-positive patients receiving antiretroviral therapy with HIV-1 protease-inhibitors (PI) frequently show insulin-resistance, impaired glucose tolerance, hypertriglyceridaemia and lipodystrophy (LD). LD has often been reported only after the beginning of PI therapy. Some authors link LD to HIV chronic infection, some others suggest that PIs increase pre-existent disturb. Preliminary data of an observational study drawn in IV day-hospital of Spallanzani Institute in Rome showed hypertriglyceridaemia in 36.4% and hyperglycaemia in 11.2% of patients treated with PI. Carr suggests that such drugs should have this lipid-increasing effect because of their inhibition of low density lipoprotein-receptor-related protein, cytoplasmic retinoic-acid binding protein type 1 and P450 3A cytochrome. This theory doesn't explain why both untreated patients and treated with only reverse transcriptase inhibitors show sometimes the same disorders. According to another hypothesis Tumor necrosis factor-alpha, through inhibition of lipoprotein-lipase, would determine high fat-storage in the adipose tissue. Cardiovascular risk factors have always to be assessed before starting a therapy with PI. Glycaemia, triglyceridaemia, cholesterolaemia have to be performed every three months during the treatment and, if necessary, C-Peptide and insulinaemia too. A treatment with lipid-lowering drugs is always recommended in patients with hypertriglyceridaemia > 500 mg/dl and/or hypercholesterolaemia LDL > 190 mg/dl in two following checks. Fibrates have proven to be effective in reducing hypertriglyceridaemia, but there is no certainty that such therapies could have good effects on the LD itself too. PMID: 10748653 [PubMed - indexed for MEDLINE] 5394. Clin Exp Pharmacol Physiol. 2000 Mar;27(3):225-8. Skeletal muscle metabolism during exercise in humans. Hargreaves M(1). Author information: (1)School of Health Sciences, Deakin University, Burwood, Victoria, Australia. mharg@deakin.edu.au 1. Contracting skeletal muscle is able to use a number of intra- and extramuscular substrates to generate ATP during exercise. These include creatine phosphate (CP), muscle glycogen, blood-borne glucose, lactate and free fatty acids (FFA), derived from either adipose tissue or intramuscular triglyceride stores. 2. During high-intensity short-duration exercise, CP degradation and the breakdown of muscle glycogen to lactate are the major energy yielding pathways, although oxidative metabolism can make a significant contribution. The 'anaerobic' substrates are also important fuels during the transition from rest to steady state exercise. 3. The oxidative metabolism of carbohydrate and lipid supplies most, if not all, of the ATP during prolonged submaximal exercise. Muscle glycogen, blood glucose and FFA are the key fuels. The relative importance of the various substrates for exercise metabolism is primarily determined by exercise intensity and duration, although training status, dietary manipulation and environmental factors can modify the metabolic response to exercise. PMID: 10744352 [PubMed - indexed for MEDLINE] 5395. Seikagaku. 2000 Feb;72(2):117-21. [Regulation of body weight by leptin]. [Article in Japanese] Murakami T(1). Author information: (1)Department of Laboratory Medicine, School of Medicine, University of Tokushima. PMID: 10737104 [PubMed - indexed for MEDLINE] 5396. Hokkaido Igaku Zasshi. 2000 Jan;75(1):9-14. [Insulin resistance syndrome and hypertension]. [Article in Japanese] Shimamoto K(1). Author information: (1)Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. Insulin resistance syndrome is the theory that glucose intolerance, hyperinsulinemia, increased very low density lipoprotein triglyceride level, decreased high density lipoprotein cholesterol level, and hypertension are proposed consequences of insulin resistance. These metabolic disturbances have been shown to increase the risk of coronary artery disease. In this theory, insulin resistance and the resultant hyperinsulinemia are considered to raise blood pressure through 1) sympathetic nervous system activation, 2) renal sodium retention, 3) renin-angiotensin system stimulation, and 4) intracellular calcium accumulation in vascular smooth muscle. Indeed, metabolic disturbance and insulin resistance have been pointed out in essential hypertensives. Leptin is a recently discovered hormone produced by an adipocyte-specific ob gene, that contributes to the regulation of energy balance by informing the hypothalamus of the amount of adipose tissue in the body. As a result, the hypothalamus adjusts food intake, thermogenesis, and energy expenditure appropriately. It was clarified that ob gene expression and plasma leptin level in humans were highly correlated with the body mass index, insulin sensitivity and blood pressure. Thus, leptin could play a role in the pathophysiology of insulin-resistant hypertension. PMID: 10736756 [PubMed - indexed for MEDLINE] 5397. J Nutr. 2000 Apr;130(4):711-4. Uncoupling protein homologs: emerging views of physiological function. Adams SH(1). Author information: (1)Department of Endocrinology, Genentech, Incorporated, South San Francisco, CA 94080, USA. The widespread occurrence of excess weight and related diseases demands that efforts be made to understand energy expenditure from the gene to the whole animal. For some time, it has been understood that mitochondrial oxidation of fuels generates an electrochemical gradient via outward pumping of protons by the electron transport chain. ATP production via F(1)F(0) ATP synthase is then facilitated by the inward flux of protons down the gradient. There is a growing appreciation that a significant portion of the metabolic rate of endotherms is attributable to counteracting "proton leak" (uncoupling), wherein a flux of protons down the electrochemical gradient generates heat independently of ATP production. Proton leak is especially apparent in thermogenic brown adipose tissue, which expresses a tissue-specific uncoupling protein (UCP1). The recent discovery of widely expressed putative UCP1 homologs [UCP2, UCP3, UCP4, UCP5/brain mitochondrial carrier protein-1 (BMCP1)] raised the possibility that innate proton leak and metabolic rate are regulated by UCP1-like proteins. On the basis of current published data, one may not exclude the possibility that UCP homologs influence metabolic rate. PMID: 10736318 [PubMed - indexed for MEDLINE] 5398. Endocr Relat Cancer. 1999 Jun;6(2):149-56. Breast tumor aromatase: functional role and transcriptional regulation. Chen S(1), Zhou D, Okubo T, Kao YC, Yang C. Author information: (1)Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA. Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters - I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRalpha-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRalpha-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function differently in different tissues, as a result of distinct expression patterns of transcription factors. PMID: 10731103 [PubMed - indexed for MEDLINE] 5399. Endocr Relat Cancer. 1999 Jun;6(2):131-7. Local estrogen biosynthesis in males and females. Simpson E(1), Rubin G, Clyne C, Robertson K, O'Donnell L, Davis S, Jones M. Author information: (1)Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. It is now apparent that in men and in postmenopausal women, estrogens have important physiological and pathophysiological roles. However, importantly, these actions are at a local level, namely paracrine, autocrine, and even 'intracrine' rather than endocrine in the classical sense. Thus for example local estrogen biosynthesis in the bones of men plays a hitherto unsuspected role in the maintenance of bone mineralization and in epiphyseal fusion; and in the testes, estrogen is essential for male germ cell development. On the other hand, in postmenopausal women, the mesenchymal cells of the breast are the major source of estrogen responsible for breast cancer development. This realization points to the importance of circulating C19 precursors in the maintenance of adequate estrogen biosynthesis in extragonadal sites and suggests the possibility of new therapies to block estrogen synthesis in a tissue-specific fashion. PMID: 10731101 [PubMed - indexed for MEDLINE] 5400. Respir Physiol. 2000 Feb;119(2-3):163-70. Leptin, obesity, and respiratory function. O'Donnell CP(1), Tankersley CG, Polotsky VP, Schwartz AR, Smith PL. Author information: (1)Department of Medicine, Division of Pulmonary and Critical Care Medicine, Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD, USA. codonnel@welch.jhu.edu Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. The importance of this single peptide is vividly demonstrated by the profound obesity exhibited by the ob/ob mouse (C57BL/6J-Lep(ob)) which is unable to produce functional leptin. The measurement of respiratory function in the ob/ob mouse shows that the profound obesity is associated with impaired respiratory mechanics and depressed respiratory control, particularly during sleep. Longitudinal studies and leptin replacement studies in the ob/ob mouse indicate that leptin may act as both as a growth factor in the lung and as a neurohumoral modulator of central respiratory control mechanisms. Moreover, wildtype mice with diet-induced obesity have normal respiratory function associated with markedly elevated leptin levels. Human obesity, similar to obesity in wildtype mice, also causes an elevation in circulating leptin. However, unlike the tight relationship between obesity and elevated leptin present in an inbred strain of wildtype mice, human obesity is associated with more variable leptin levels for a given degree of adiposity. Thus, the possibility exists that a relative deficiency in leptin, or a leptin resistance, may play a role in obesity-related breathing disorders such as obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA). PMID: 10722859 [PubMed - indexed for MEDLINE] 5401. Toxicol Lett. 2000 Mar 15;112-113:93-101. Geographical differences and time trends of persistent organic pollutants in the Arctic. Muir DC(1), Norstrom RJ. Author information: (1)Environment Canada, National Water Research Institute, Burlington, Canada. derek.muir@cciw.ca Geographical and temporal trends of total PCBs (SigmaPCBs) and hexachlorocyclohexanes (SigmaHCHs) have been examined in polar bear (Ursus maritimus) adipose tissue and ringed seal (Phoca hispida) blubber along a transect from Alaska to Svalbard and northern Norway/western Russia. PCB concentrations in polar bear show a strong west to east trend with higher levels in east Greenland, Svalbard. In ringed seal, highest PCB levels were found at two sites near the Russian coast. SigmaHCHs levels in ringed seals and polar bear show the reverse trend coinciding with much higher levels of SigmaHCHs in seawater in the North American Arctic. Some of these geographical differences may reflect dietary differences especially in the case of PCBs. Levels of SigmaPCBs in polar bears in the eastern Canadian Arctic appear to have increased from the 1970s to the 1980s but are now on the decline. SigmaPCBs and SigmaHCHs levels showed no significant change from the mid-1980s to 1990s in ringed seal blubber from three locations in the eastern Canadian Arctic. PMID: 10720717 [PubMed - indexed for MEDLINE] 5402. Arch Med Res. 1999 Nov-Dec;30(6):459-64. Insulin resistance and type 2 diabetes mellitus: its relationship with the beta 3-adrenergic receptor. García-Rubi E(1), Calles-Escandón J. Author information: (1)Endocrinology, Diabetes, and Metabolism Unit, University of Vermont College of Medicine, Burlington 05405-0068, USA. jcallese@zoo.uvm.edu The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two. PMID: 10714358 [PubMed - indexed for MEDLINE] 5403. J Pediatr Endocrinol Metab. 2000 Feb;13(2):115-33. Regulation of glucose transporters--implications for insulin resistance states. Tirosh A(1), Rudich A, Bashan N. Author information: (1)Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Altered glucose homeostasis in the different diabetic states often results from a combination of insulin deficiency (absolute or relative), and impaired hormone action. The latter involves alterations in the expression and/or function of glucose transporters in insulin responsive peripheral tissues - skeletal muscle and adipose tissue. Since whole body glucose utilization depends mainly on controlled changes in glucose transport in these tissues, this review focuses on the role of glucose transporters in the regulation of insulin-stimulated glucose transport activity. The molecular mechanisms by which several inducers of insulin resistance inhibit insulin action on glucose uptake are also discussed. Better understanding of the complex regulation of glucose transport and transporters will hopefully shed light on potential sites for new pharmaceutical interventions. Several excellent reviews have been published in the past 2 years detailing various aspects which are discussed only briefly in this review. They are mentioned in the text to allow further reading. PMID: 10711656 [PubMed - indexed for MEDLINE] 5404. Rev Reprod. 2000 Jan;5(1):18-24. Placental leptin. Ashworth CJ(1), Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG. Author information: (1)Rowett Research Institute, Bucksburn, Aberdeen, UK. Placental tissues from humans, rodents and farm animals contain leptin and its receptor. Leptin produced by the human placenta has the same size, charge and immunoreactivity as leptin produced by adipose tissue. However, the expression of human placental leptin appears to be regulated by a placenta-specific upstream enhancer. In this review the occurrence of leptin and its receptor in a range of species and placental types is described, and its significance during pregnancy discussed. Placental leptin contributes to the increase in maternal circulating concentrations of leptin during late pregnancy when it is likely to have an endocrine role in regulating maternal energy balance. Placental leptin may have angiogenic and immunomodulatory activities, which affect the placenta in an autocrine or paracrine manner. It also appears to affect fetal growth and development by binding to leptin receptors present in fetal organs. PMID: 10711732 [PubMed - indexed for MEDLINE] 5405. Curr Opin Clin Nutr Metab Care. 1999 Nov;2(6):499-506. Recent advances in conjugated linoleic acid research. Sébédio JL(1), Gnaedig S, Chardigny JM. Author information: (1)Institut National de la Recherche Agronomique, Unite de Nutrition Lipidique, Dijon, France. sebedio@dijon.inra.fr New results on the physiological properties of conjugated linoleic acid have been published by several working groups, especially showing the effects of single conjugated linoleic acid isomers on carcinogenesis and body composition. Recently, other studies have shown that conjugated linoleic acid has an influence on diabetes mellitus, platelet aggregation and the immune system. Conjugated linoleic acid was found to modify prostaglandin metabolism and delta9-desaturase activity and influence apoptosis. Furthermore, improved analytical methods using 13C nuclear magnetic resonance and silver ion high performance liquid chromatography are available to investigate the composition of conjugated linoleic acid mixtures and the exact structure of separated isomers. Also, the synthesis of isolated isomers is described, as published by different authors, in order to determine further the effects of each single conjugated linoleic acid isomer. In addition, new data on the contents of conjugated linoleic acid in foods, human adipose tissue and fluids are given in this review. More data need to be obtained using isolated isomers, with particular emphasis on studies in humans. PMID: 10678680 [PubMed - indexed for MEDLINE] 5406. Curr Opin Clin Nutr Metab Care. 1999 Nov;2(6):453-63. Neutron activation analysis determination of body composition. Kehayias JJ(1), Valtueña S. Author information: (1)USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. kehayias@hnrc.tufts.edu The nutritional status of patients can be evaluated by monitoring changes in body composition, including the depletion of protein and muscle, adipose tissue distribution and changes in hydration status, bone or cell mass. Neutron activation analysis is a unique reference tool for the in-vivo determination of body composition. In this review we describe the recent changes in the field that followed the advent of new portable generators of fast neutrons, capable of performing elemental analysis in the clinical environment. New models were developed based on the partition of the measurable elements of the body. The recent developments help evaluate new treatments for wasting and obesity, in which change in body composition is the main outcome. PMID: 10678673 [PubMed - indexed for MEDLINE] 5407. Nihon Rinsho. 2000 Feb;58(2):411-5. [Obesity, insulin resistance and the implication of thiazolidinediones]. [Article in Japanese] Oguma Y(1), Kataoka K. Author information: (1)Sports Medicine Research Center, Keio University. The mechanism of insulin resistance in obesity is not fully understood. In muscle cells, the number of insulin receptor, the function of glucose transporter 4 and the activity of tyrosine kinase decrease. The rink of body fat accumulation and insulin resistance in muscle is thought through free fatty acid and tumor necrosis factor alpha secreted in adipose tissue. Thiazolidinediones (TZDs) are useful to reduce insulin resistance especially in obesity. TZDs seem to cause small weight gain, but to reduce visceral fat in 12-24 weeks. In longer period, it hasn't been studied very much. There are some unsolved problems. So now, targets of TZDs are obese diabetes failed in other medicines. When using TZDs, be cautious of excess eating and physical inactivity. PMID: 10707567 [PubMed - indexed for MEDLINE] 5408. Nihon Rinsho. 2000 Feb;58(2):405-10. [Diagnostic criteria of insulin resistance and multiple risk factor syndrome]. [Article in Japanese] Hashimoto N(1), Saito Y. Author information: (1)Second Department of Internal Medicine, Chiba University School of Medicine. Multiple risk factor syndrome (MRFS) is a clustering of cardiovascular risk factors, which describes the epidemiological association of glucose intolerance, central obesity, hypertension, increased triglyceride level and decreased HDL-cholesterol, leading to the atherosclerosis. Insulin resistance is diagnosed clinically by fasting hyperinsulinemia, steady state plasma glucose (SSPG) method, insulin tolerance test and glucose clamp study. Visceral fat accumulation is supposed to play a central role in pathogenesis of MRFS and induces risk factors for cardiovascular disease through the increased TNF-alpha expression in adipose tissue and serum FFA level, which cause insulin resistance state. These risk factors should be prevented at early stage by the intervention in obesity, especially visceral fat accumulation. PMID: 10707566 [PubMed - indexed for MEDLINE] 5409. Nihon Rinsho. 2000 Feb;58(2):389-94. [Troglitazone]. [Article in Japanese] Yamanouchi T(1). Author information: (1)Department of Internal Medicine, University of Teikyo. There are good responders to troglitazone in whom sulfonylurea had failed to improve glycemia. The anti-diabetic effect of this agent seems to be partially composed of prolonged action. The action on different adipose tissue depots of troglitazone may be involved in this slow action. Significant decrease in fasting plasma glucose occurred. The effect may be related to reducing nocturnal hepatic glucose output by the drug. The efficacy of troglitazone is dependent on the levels of circulating insulin. Recent reports demonstrate the good therapeutic power of troglitazone in combination with a sulfonylurea or metformin, or insulin. Thus, we got a new approach of oral therapy to patients with type 2 diabetes in sulfonylurea failure before entering the insulin treatment. Because of low frequency of hypoglycemia, we can safely continue to use this drug in patients with euglycemia by the therapy for preventing return to hyperglycemia. PMID: 10707563 [PubMed - indexed for MEDLINE] 5410. Nihon Rinsho. 2000 Feb;58(2):338-43. [Adipocyte function and insulin resistance]. [Article in Japanese] Matsuzawa Y(1). Author information: (1)Department of Internal Medicine and Molecular Science, Osaka University, Faculty of Medicine. The importance of free fatty acids (FFA) and adipocytokines released from adipocytes in the development of insulin resistance is discussed in this review article. FFA may cause insulin resistance through so-called Rundle cycle and may also inhibit glucose uptake by skeletal muscles. Adipocytokines, bioactive substances secreted from adipose tissue may have important roles in occurrence of insulin resistance. For example, TNF-alpha from adipocytes reduces tyrosine kinase activity of the insulin receptor in obesity. A novel collagen-like protein, adiponectin inhibits TNF-alpha induced cell phenomena and its reduction at obesity may be one of molecular mechanism of insulin resistance. PMID: 10707555 [PubMed - indexed for MEDLINE] 5411. Nihon Rinsho. 2000 Feb;58(2):320-6. [Insulin resistance and cytokine, cytokine receptor]. [Article in Japanese] Hamaguchi T(1), Nakajima H, Hanafusa T, Matsuzawa Y. Author information: (1)Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. Insulin resistance is associated with many common diseases including diabetes mellitus, hyperlipidemia and hypertension, and plays an important role for determining their clinical courses. Obesity is a multifactorial syndrome characterized by an excessive adipose tissue accumulation, and is associated with acquired insulin resistance. Adipose tissue, acting as one of the endocrine organs, has been revealed to produce and secrete some bioactive molecules, "adipocytokines", which regulate cell growth and/or metabolic pathways. Tumor necrosis factor(TNF)-alpha is also synthesized by adipocytes, and is involved in the expression of peripheral insulin resistance. This review deals with molecular mechanisms of the TNF/TNF receptor system promoting insulin resistance, and its prevention by the insulin-sensitizing drugs, thiazolidinediones. PMID: 10707552 [PubMed - indexed for MEDLINE] 5412. Nihon Rinsho. 2000 Feb;58(2):310-4. [Insulin resistance and glucose transporter]. [Article in Japanese] Kurokawa K(1), Oka Y. Author information: (1)Third Department of Internal Medicine, Yamaguchi University, School of Medicine. Insulin stimulates glucose transport in muscle and adipose tissue by promoting the appearance of GLUT4, the main glucose transporter isoform in these tissues, on the cell surface. Insulin resistance is instrumental in pathogenesis of type 2 diabetes mellitus and involves decreased glucose transport activity in these tissues. No significant differences are observed between the diabetic and non-diabetic subjects in muscle GLUT4 levels. Polymorphism in the GLUT4 gene, which is very rare, has the same prevalence between subjects with type 2 diabetes mellitus and the non-diabetic subjects. The most likely explanation for the insulin resistance is a defect in insulin signaling pathways or GLUT4 intracellular trafficking pathways. PMID: 10707550 [PubMed - indexed for MEDLINE] 5413. Diabetes Metab. 2000 Feb;26(1):12-20. Body fat distribution, the menopause transition, and hormone replacement therapy. Tchernof A(1), Poehlman ET, Després JP. Author information: (1)Department of Medicine, University of Vermont, Burlington, VT 05401, USA. Retraction in Halimi S, Guillausseau PJ. Diabetes Metab. 2006 Jun;32(3):285. Comment in NIH Guide Grants Contracts. 2005 Mar 25;:NOT-OD-05-040. Endocrine changes resulting from the menopause transition dramatically modify women's hormonal milieu. The consequences of these changes not only lead to cessation of reproduction and accompanying symptoms in women, but also dramatically impact long-term health. Loss of estrogen has been associated with the development of cardiovascular disease. Central distribution and accumulation of adipose tissue, and the concomitant insulin resistant dyslipidemic state have emerged as important components of a cluster of metabolic abnormalities that are strongly related to coronary heart disease. Thus, estrogen deficiency may affect cardiovascular disease risk by mediating changes in body fat distribution. This article is an update of the literature in the area of menopause, hormone replacement therapy, and body fat distribution. Cross-sectional studies using anthropometric measurements of abdominal fat distribution most often failed to detect an effect of the menopause transition that was independent of advancing age and degree of obesity. The use of radiologic techniques such as DEXA and computed tomography, however, led to the conclusion that the menopause transition accelerates the selective deposition of intra-abdominal fat. Available longitudinal data also support an increase in central body fatness occurring with menopause. Most intervention trials on hormone replacement therapy and body fat distribution showed that the treatment prevented the increase in central adiposity that was noted in postmenopausal women receiving no treatment or placebo. These results are supported by retrospective studies that showed a lower WHR in hormone users vs non-users. Mechanisms potentially explaining the menopause-related acceleration in abdominal fat accumulation include changes in regional adipose tissue metabolism in the face of a positive energy imbalance. As some inconsistencies were found among studies, further investigations using longitudinal and intervention designs, as well as more precise methodologies to measure body fat distribution, are needed to clearly establish the effects of menopause and hormone replacement on abdominal body fat distribution and the concomitant increase in cardiovascular disease risk. PMID: 10705099 [PubMed - indexed for MEDLINE] 5414. Arch Pediatr. 2000 Feb;7(2):173-84. [Carbohydrate-deficient blood glycoprotein syndrome]. [Article in French] de Lonlay P(1), Cormier-Daire V, Vuillaumier-Barrot S, Cuer M, Durand G, Munnich A, Saudubray JM, Seta N. Author information: (1)Département de pédiatrie, hôpital Necker-Enfants-Malades, Paris, France. Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly delineated group of inherited multisystemic disorders associated with abnormal glycosylation of a number of serum glycoproteins. Several types have been described on the basis of clinical presentation and biochemical changes of the glycosylation of serum transferrin and attributed to different enzymatic defects; their clinical presentations are fully different and a clinical heterogeneity is observed within a same type of CDGS. Patients with CDGS type la usually present with neurologic (hypotonia, strabismus and cerebellar hypoplasia) and cutaneous (inverted nipples, abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, hepatic, cardiac, renal). However, neurologic and cutaneous symptoms may be absent, so that CDGS must be looked for in case of unexplained organ failure such as isolated liver insufficiency, cardiomyopathy, pericarditis, tubulopathy, nephrotic syndrome, vascular accident or retinitis pigmentosa. Patients with CDGS type Ib present with liver disease, enteropathy and hypoglycemia without neurologic involvement. These patients are successfully treated with oral mannose administration emphasizing the importance of making the diagnosis. Patients with CDGS type Ic present with mild psychomotor retardation and seizures. Patients with CDGS type II have psychomotor retardation association with severe gastrointestinal disorder, dysmorphic features and abnormal electroretinogram. Other types (III, IV) are less clearly defined and the clinical presentation includes convulsive encephalopathy. Biological abnormalities such as mild hepatic cytolysis, hematologic and hormonal abnormalities are consistently observed in CDGS type I, as well as renal hyperechogeneity, leading one to look for this syndrome when they are associated. Until now, only four enzymatic deficiencies have been identified (types Ia, Ib, Ic, II). PMID: 10701064 [PubMed - indexed for MEDLINE] 5415. J Pediatr Endocrinol Metab. 1999 Apr;12 Suppl 1:259-66. Experience with insulin-like growth factor I (IGF-I) treatment of growth hormone insensitivity syndrome (GHIS). Ranke MB(1), Wollmann HA, Savage MO. Author information: (1)Paediatric Endocrinology Section, University Children's Hospital, Tübingen, Germany. PMID: 10698590 [PubMed - indexed for MEDLINE] 5416. Mol Immunol. 1999 Sep-Oct;36(13-14):869-76. A critical evaluation of the putative role of C3adesArg (ASP) in lipid metabolism and hyperapobetalipoproteinemia. Kildsgaard J(1), Zsigmond E, Chan L, Wetsel RA. Author information: (1)University of Texas-Houston Institute of Molecular Medicine for Prevention of Human Diseases, 77030, USA. The acylation stimulating protein, ASP is a small, basic serum protein capable of stimulating triglyceride synthesis in cultured fibroblasts and adipocytes. Sequence analysis of ASP has shown that ASP is identical to C3adesArg the inactive fragment of the complement anaphylatoxin peptide, C3a. It has been proposed that C3adesArg (ASP) can be generated by mature adipocytes secreting the three complement proteins: complement protein C3, factor B and factor D (adipsin). There have also been indications that adipocytes may express a specific C3adesArg (ASP)-receptor that is distinct from the recently cloned C3a-receptor. This suggests that C3adesArg (ASP) acts as an adipocyte autocrine and that it plays a central role in the metabolism of adipose tissue. Based on these observations a hypothesis for the etiology of hyperapobetalipoproteinemia (hyperapoB) has been proposed. Hyperapobetalipoproteinemia (hyperapoB), is a familial lipoprotein disorder characterized by increased hepatic secretion of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) particles. If C3adesArg (ASP) function in the adipose tissue is impaired, a reduced rate of triglyceride synthesis will follow, generating an increased flux of fatty acids to the liver. In response to an increased flow of fatty acids, the liver will increase its production of VLDL particles yielding the phenotype of hyperapoB. This review critically assesses this hypothesis and the potential role of C3adesArg (ASP) as a major determinant for triglyceride synthesis in the light of data collected in vitro and in vivo. PMID: 10698341 [PubMed - indexed for MEDLINE] 5417. J Endocrinol Invest. 2000 Jan;23(1):54-62. Obesity and hypertension. Faloia E(1), Giacchetti G, Mantero F. Author information: (1)Department Internal of Medicine, University of Ancona, Italy. clendo@popcsi.unian.it PMID: 10698053 [PubMed - indexed for MEDLINE] 5418. Lipids. 2000 Jan;35(1):105-11. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Cunnane SC(1), Francescutti V, Brenna JT, Crawford MA. Author information: (1)Department of Nutritional Sciences, University of Toronto, Canada. s.cunnane@utoronto.ca Docosahexaenoate (DHA) has been increasingly recognized as an important fatty acid for neural and visual development during the first 6 mon of life. One important point of controversy that remains is the degree to which adequate levels of DHA can be acquired from endogenous synthesis in infants vs. what should be provided as dietary DHA. We have approached this problem by a retrospective analysis of published body composition data to estimate the actual accumulation of DHA in the human infant brain, liver, adipose tissue, remaining lean tissue, and whole body. Estimating whether infants can synthesize sufficient DHA required comparison to and extrapolation from animal data. Over the first 6 mon of life, DHA accumulates at about 10 mg/d in the whole body of breast-fed infants, with 48% of that amount appearing in the brain. To achieve that rate of accumulation, breast-fed infants need to consume a minimum of 20 mg DHA/d. Virtually all breast milk provides a DHA intake of at least 60 mg/d. Despite a store of about 1,050 mg of DHA in body fat at term birth and an intake of about 390 mg/d alpha-linolenate (alpha-LnA), the brain of formula-fed infants not consuming DHA accumulates half the DHA of the brain of breast-fed infants while the rest of the body actually loses DHA over the first 6 mon of life. No experimental data indicate that formula-fed infants not consuming DHA are able to convert the necessary 5.2% of alpha-LnA intake to DHA to match the DHA accumulation of breast-fed infants. We conclude that dietary DHA should likely be provided during at least the first 6 mon of life. PMID: 10695931 [PubMed - indexed for MEDLINE] 5419. J Reprod Fertil Suppl. 1999;54:425-35. The role of leptin in nutritional status and reproductive function. Keisler DH(1), Daniel JA, Morrison CD. Author information: (1)Department of Animal Science, University of Missouri, Columbia 65211, USA. Infertility associated with suboptimal nutrition is a major concern among livestock producers. Undernourished prepubertal animals will not enter puberty until they are well fed; similarly, adult, normally cyclic females will stop cycling when faced with extreme undernutrition. Work in our laboratory has focused on how body fat (or adiposity) of an animal can communicate to the brain and regulate reproductive competence. In 1994, the discovery in rodents of the obese (ob) gene product leptin, secreted as a hormone from adipocytes, provided a unique opportunity to understand and hence regulate whole body compositional changes. There is now evidence that similar mechanisms are functioning in livestock species in which food intake, body composition, and reproductive performance are of considerable economic importance. Leptin has been reported to be a potent regulator of food intake and reproduction in rodents. There is evidence indicating that at least some of the effects of leptin occur through receptor-mediated regulation of the hypothalamic protein neuropeptide Y (NPY). NPY is a potent stimulator of food intake, is present at high concentrations in feed-restricted cattle and ewes, and is an inhibitor of LH secretion in these livestock species. In our investigations in sheep, we have cloned a partial cDNA corresponding to the ovine long-form leptin receptor, presumably the only fully active form, and have localized the long-form leptin receptor in the ventromedial and arcuate nuclei of the hypothalamus. Leptin receptor mRNA expression was colocalized with NPY mRNA-containing cell bodies in those regions. We have also determined that hypothalamic leptin receptor expression is greater in feed-restricted ewes than in well-fed ewes. These observations provide a foundation for future investigations into the nutritional modulators of reproduction in livestock. PMID: 10692873 [PubMed - indexed for MEDLINE] 5420. Eur J Obstet Gynecol Reprod Biol. 2000 Feb;88(2):121-7. Leptin, the ob gene product, in female health and disease. Schubring C(1), Blum WF, Kratzsch J, Deutscher J, Kiess W. Author information: (1)Evangelisches Krankenhaus, Giessen, Germany. Leptin is a recently discovered hormone which is involved in the regulation of body weight. It provides a molecular basis for the lipostatic theory of the regulation of energy balance. White adipose tissue is the main site of leptin synthesis and there is some evidence of ob gene expression in brown fat. Leptin seems to play a key role in the control of body fat stores by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous system regulation and body energy balance in rodents, primates and humans. Apart from the function of leptin in the central nervous system on the regulation of energy balance, it may well be one of the hormonal factors that signal the body's readiness for sexual maturation and reproduction to the brain. During late pregnancy and at birth when maternal fat stores have been developed leptin levels are high. Leptin could then be a messenger molecule signaling the adequacy of the fat stores for reproduction and maintenance of pregnancy. At later stages of gestation leptin could signal the expansion of fat stores in order to prepare the expectant mother for the energy requirements of full term gestation, labour and lactation. This overview focuses on those topics of leptin research which are of particular interest in reproductive medicine and gynecology. PMID: 10690668 [PubMed - indexed for MEDLINE] 5421. Horm Metab Res. 1999 Dec;31(12):626-31. The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance? Hube F(1), Hauner H. Author information: (1)German Diabetes Research Institute at the Heinrich-Heine University, Düsseldorf. Since evidence has appeared that tumor necrosis factor-alpha (TNF) is involved in the loss of body fat in the course of wasting diseases, a large number of studies have investigated the physiological role of this cytokine in adipose tissue. TNF treatment of several in vitro models of adipogenesis clearly showed that TNF is a potent inhibitor of adipose differentiation. This antiadipogenic property is accompanied by suppression of developmental and metabolic markers of fat cell differentiation, such as peroxisome proliferator-activated receptor (PPAR)-gamma2, lipoprotein lipase (LPL), glycerol-3-phosphate dehydrogenase (GPDH) and GLUT4. Moreover, TNF promotes lipolysis in mature adipocytes and, subsequently, a reversion of the adipocyte phenotype. Recent studies demonstrated that TNF directly interferes with the insulin signaling cascade at early steps and, thus, impairs insulin-stimulated glucose transport. Further progress in understanding the role of TNF in adipose tissue was made when endogenous TNF mRNA expression was demonstrated in adipose tissue. Obesity was found to represent a state of overexpression of the TNF system. Such findings support the hypothesis that TNF is a mediator of obesity-linked insulin resistance. However, this concept is mainly based on animal data and is so far only partially supported by studies in humans. Taken together, the results of a variety of experimental and clinical studies suggest that TNF may act as an important auto/paracrine regulator of fat cell function which serves to limit adipose tissue expansion, probably by inducing insulin resistance which may in turn cause metabolic disturbances. Elucidation of the molecular mechanisms of TNF production and action in adipose tissue may help to find new approaches for the treatment of insulin resistance in humans. PMID: 10668912 [PubMed - indexed for MEDLINE] 5422. Life Sci. 2000;66(2):91-103. GIP biology and fat metabolism. Yip RG(1), Wolfe MM. Author information: (1)Department of Medicine, Boston University School of Medicine, Boston Medical Center, MA 02118, USA. The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), is synthesized and released from the duodenum and proximal jejunum postprandially. Its release depends upon several factors including meal content and pre-existing health status (ie. obesity, diabetes, age, etc.). It was initially discovered and named for its gastric acid inhibitory properties. However, its more physiologically relevant role appears to be as an insulinotropic agent with a stimulatory effect on insulin release and synthesis. Accordingly, it was later renamed glucose-dependent insulinotropic polypeptide because its action on insulin release depends upon an increase in circulating levels of glucose. GIP is considered to be one of the principle incretin factors of the enteroinsular axis. The GIP receptor is a G-protein-coupled receptor belonging to the family of secretin/VIP receptors. GIP receptor mRNA is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex, and brain, suggesting it may have other functions in addition to the ones mentioned above. An overactive enteroinsular axis has been suggested to play a role in the pathogenesis of diabetes and obesity. In addition to stimulating insulin release, GIP has been shown to amplify the effect of insulin on target tissues. In adipose tissue, GIP has been reported to (1) stimulate fatty acid synthesis, (2) enhance insulin-stimulated incorporation of fatty acids into triglycerides, (3) increase insulin receptor affinity, and (4) increase sensitivity of insulin-stimulated glucose transport. In addition, although controversial, lipolytic properties of GIP have been proposed. The mechanism of action of GIP-induced effects on adipocytes is unknown, and it is unclear whether these effects of GIP on adipocytes are direct or indirect. However, there is now evidence that GIP receptors are expressed on adipocytes and that these receptors respond to GIP stimulation. Given the location of its release and the timing of its release, GIP is an ideal anabolic agent and expanding our understanding of its physiology will be needed to determine its exact role in the etiology of diabetes mellitus and obesity. PMID: 10666005 [PubMed - indexed for MEDLINE] 5423. Biomed Pharmacother. 1999 Dec;53(10):462-5. Lipoprotein (a) in android obesity and NIDDM: a new member in 'the metabolic syndrome'. Wassef GN(1). Author information: (1)National Research Center, Endocrine Unit, Heliopolis, Dokki, Cairo, Egypt. The 'metabolic syndrome' is a special clinical entity characterized by upper body segment obesity (android obesity), together with one or more of a constellation of metabolic disorders that includes glucose intolerance, which may amount to frank diabetes mellitus, hypertension, cardiovascular lesions, hyperuricemia, and dyslipidemias (hypercholesterolemia, hypertriglyceridemia and reduced serum HDL). Recently, lipoprotein (Lp) (a) proved to be a new member in this syndrome. Lp(a) has the distinctive feature of containing apolipoprotein (a), which is a glycoprotein linked to apo B100, and has a similarity to plasminogen; it is also structurally related to LDL. Lp(a) is a macromolecular complex which is genetically determined, and has been identified as an independent risk factor for premature coronary artery disease (CAD). It is elevated in diabetic and non-diabetic android obese subjects, and aggravates the atherogenic effect of diabetes mellitus. Lp(a) is poorly influenced either by dietary measures or by hypolipidemic drugs. Unfortunately, few pharmacologic agents, such as niacin, nicotinic acid, sex hormones (estrogen and testosterone), alcohol and neomycin, affect Lp(a). PMID: 10665339 [PubMed - indexed for MEDLINE] 5424. Biomed Pharmacother. 1999 Dec;53(10):455-61. Plasma plasminogen activator inhibitor 1, insulin resistance and android obesity. Bastard JP(1), Piéroni L. Author information: (1)Laboratoire de biochimie, Hôpital Tenon, Paris, France. Plasma plasminogen activator inhibitor 1 (PAI-1) levels are elevated in insulin-resistant subjects and are associated with increased cardiovascular risk of atherothrombosis. Strong association between PAI-1 and the metabolic components of the insulin resistance syndrome is found in clinical studies, suggesting that insulin resistance may regulate circulating PAI-1. However, the mechanisms underlying increased PAI-1 levels in such conditions are still poorly understood. Several studies have been carried out specifically in patients with central or android obesity, a major characteristic of the insulin resistance syndrome, and have suggested that visceral adipose tissue may be the major component of the relationship between android obesity and PAI-1. Accordingly, adipose tissue PAI-1 production was found to be elevated in obese human subjects, particularly in visceral adipose tissue. The genetic background for having high PAI-1 levels in several populations have been looked for and its role appeared to be weaker than that of the metabolic condition. High plasma PAI-1 levels are then clearly related to android obesity and insulin resistance, but the mechanisms whereby PAI-1 increases in plasma in these diseases remain to be determined. PMID: 10665338 [PubMed - indexed for MEDLINE] 5425. Prog Lipid Res. 1999 May;38(3):225-48. Physiological specialisation of adipose tissue. Pond CM(1). Author information: (1)Department of Biology, Open University, Milton Keynes, UK. C.M.Pond@open.ac.uk PMID: 10664794 [PubMed - indexed for MEDLINE] 5426. Neuropeptides. 1999 Oct;33(5):415-24. Interleukins and tumor necrosis factor as inhibitors of food intake. Langhans W(1), Hrupka B. Author information: (1)Institute of Animal Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. wolfgang.langhans@inw.agrl.ethz.ch Cytokines, such as interleukins and tumor necrosis factor-alpha (TNFalpha), are produced in response to immune stimulation and have systemic effects, mediated by the central nervous system (CNS). Interleukins, in particular interleukin [IL]-1beta, and TNFalpha reduce food intake after peripheral and central administration, suggesting that they contribute to the anorexia during various infectious, neoplastic and autoimmune diseases. Because cytokines are mainly produced in the periphery during most of these diseases, IL-1beta and TNFalpha may inhibit feeding indirectly through neural and humoral pathways activated by their peripheral actions. Activation of afferent nerve fibers by locally produced cytokines in the periphery is involved in several cytokine effects, but is not crucial for the anorectic effect of systemic immune stimulation. Cytokines increase OB protein (leptin) expression in the adipose tissue, and leptin may contribute to, but is also not essential for, the anorectic effects of cytokines. Finally, circulating IL-1beta and TNFalpha may act directly on the brain or cytokine synthesis in the brain may contribute to the anorectic effect of systemic immune stimulation. Central mediators of the anorectic effects of cytokines appear to be neurochemicals involved in the normal control of feeding, such as serotonin, corticotropin releasing factor, histamine, alpha-melanocyte stimulating hormone, and neuropeptide Y. The well-documented cytokine production in the gut in relation to feeding and the expression of TNFalpha by adipocytes suggest that IL-1beta and TNFalpha may also play a role in the control of normal feeding and energy balance. All in all, reciprocal, synergistic and antagonistic interactions between various pleiotropic cytokines and between cytokines and neurochemicals form a complex network that mediates the effects of cytokines on feeding and energy balance. Copyright 1999 Harcourt Publishers Ltd. PMID: 10657519 [PubMed - indexed for MEDLINE] 5427. Neuropeptides. 1999 Oct;33(5):339-49. Two important systems in energy homeostasis: melanocortins and melanin-concentrating hormone. Tritos NA(1), Maratos-Flier E. Author information: (1)Joslin Diabetes Center, Boston, MA, 02215, USA. Our understanding of the regulation of appetite and energy balance has advanced significantly over the past decade as several peptides, centrally or peripherally expressed, have been characterized and shown to profoundly influence food intake and energy expenditure. (1)The growing number of putative appetite-regulating neuropeptides includes peptides that are orexigenic (appetite-stimulating) signals and anorectic peptides. Neuropeptide Y (NPY), melanin concentrating hormone (MCH), orexins A and B, galanin, and agouti -related peptide (AgRP) all act to stimulate feeding while alpha-melanocyte stimulating hormone (alphaMSH), corticotropin releasing hormone (CRH), cholecystokinin (CCK), cocaine and amphetamine regulated transcript (CART), neurotensin, glucagon-like peptide 1 (GLP 1), and bombesin have anorectic actions.(1) Leptin, expressed in the periphery in white adipose tissue, acts in the CNS to modulate the expression of several of these hypothalamic peptides.(1) This creates a functional link between the adipose tissue and the brain that translates the information on body fat provided by leptin to input into energy balance regulating processes. In the current review we examine the significant role of the melanocortin system (alphaMSH, agouti and AgRP peptides, and their receptors and mahogany protein) and melanin concentrating hormone in the regulation of energy balance. Copyright 1999 Harcourt Publishers Ltd. PMID: 10657511 [PubMed - indexed for MEDLINE] 5428. Crit Rev Clin Lab Sci. 1999 Dec;36(6):575-655. Physiological roles of the leptin endocrine system: differences between mice and humans. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, ON. jhhagen@uottawa.ca Leptin is a 16-kDa cytokine secreted in humans primarily but not exclusively by adipose tissues. Its concentration in blood is usually proportional to body fat mass, but is higher in women than in men not only because of a different distribution of and greater fat mass in women, but also because testosterone reduces its level in men. Leptin features in different ways during the life span. It is synthesized in the ovary, transported in the oocyte, and made by both fetus and placenta, particularly during the last month of gestation. It is made by the lactating mammary gland and ingested by the newborn infant in its milk. The prime importance of leptin is realized at puberty when it is necessary for progression to a normal adult reproductive status in females. Fasting and chronic undernutrition result in a lower level of leptin in the blood. Lack of leptin results in hunger, ensuring that the individual eat to survive, and also inhibition of reproduction, until such time as food and fat stores are adequate to supply energy for pregnancy and lactation. Thus, leptin is important for survival of the individual and survival of the species. Although an extremely rare genetic absence of leptin induces hyperphagia and obesity in humans, as it does in mice, there appears to be little role for leptin in humans in ensuring that fat stores are not in excess of adequate, that is, in preventing obesity. The mouse differs from humans in many respects, in particular in the far more drastic ways it conserves energy when it very rapidly adapts to lack of food. These include not only suppression of reproduction but also lowering of its body temperature (torpor), suppressing its thyroid function, suppressing its growth, and increasing secretion of stress hormones (from the adrenal). This review concentrates on roles of leptin in human physiology and pathophysiology but also discusses why some observations on actions of leptin in mice are not applicable to humans. PMID: 10656540 [PubMed - indexed for MEDLINE] 5429. Proc Soc Exp Biol Med. 2000 Feb;223(2):128-35. Tumor necrosis factor-alpha-induced insulin resistance in adipocytes. Qi C(1), Pekala PH. Author information: (1)Department of Biochemistry, School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA. Recent studies examining the link between insulin resistance and the development of obesity and noninsulin-dependent diabetes mellitus are consistent with the involvement of tumor necrosis factor-alpha (TNF-alpha) as a central mediator. In insulin resistant obese mouse models, neutralization of TNF-alpha in circulation has been demonstrated to restore insulin-mediated glucose uptake. Adipose tissue has been shown to be a site for synthesis of TNF-alpha, with the degree of adiposity directly correlated with the level of synthesis. Studies conducted on obese human patients have demonstrated a correlation between levels of TNF-alpha, the extent of obesity, as well as the level of hyperinsulinemia observed. Mechanistic studies in cell culture have suggested that TNF-alpha functions to render cells insulin resistant through regulation of the synthesis of the insulin responsive glucose transporter as well as through interference with insulin signaling. This review will address these issues and additionally introduce the reader to the molecular aspects of TNF-alpha, its receptors as well as TNF-alpha-initiated signaling cascades, that are necessary to understand the function of this cytokine in the regulation of adipose tissue metabolism. PMID: 10654615 [PubMed - indexed for MEDLINE] 5430. J Bioenerg Biomembr. 1999 Oct;31(5):517-25. Mitochondrial proton leak and the uncoupling proteins. Stuart JA(1), Brindle KM, Harper JA, Brand MD. Author information: (1)Department of Biochemistry, University of Cambridge, UK. An energetically significant leak of protons occurs across the mitochondrial inner membranes of eukaryotic cells. This seemingly wasteful proton leak accounts for at least 20% of the standard metabolic rate of a rat. There is evidence that it makes a similar contribution to standard metabolic rate in a lizard. Proton conductance of the mitochondrial inner membrane can be considered as having two components: a basal component present in all mitochondria, and an augmentative component, which may occur in tissues of mammals and perhaps of some other animals. The uncoupling protein of brown adipose tissue, UCP1, is a clear example of such an augmentative component. The newly discovered UCP1 homologs, UCP2, UCP3, and brain mitochondrial carrier protein 1 (BMCP1) may participate in the augmentative component of proton leak. However, they do not appear to catalyze the basal leak, as this is observed in mitochondria from cells which apparently lack these proteins. Whereas UCP1 plays an important role in thermogenesis, the evidence that UCP2 and UCP3 do likewise remains equivocal. PMID: 10653479 [PubMed - indexed for MEDLINE] 5431. J Bioenerg Biomembr. 1999 Oct;31(5):507-16. Brown adipose tissue thermogenesis during aging and senescence. McDonald RB(1), Horwitz BA. Author information: (1)Department of Nutrition Division of Biological Sciences, University of California, Davis 95616-8669, USA. rbmcdonald@ucdavis.edu We have found that cold- and norepinephrine-induced brown adipose tissue (BAT) nonshivering thermogenesis (NST) is significantly lower in old male Fischer 344 rats and is associated with the decreased ability of these animals to maintain homeothermy. This decline in BAT thermogenesis is not as great in females. Although the mechanism(s) underlying this gender difference in the age-related decrease in brown fat NST are not completely elucidated, they do not appear to reflect decreased sympathetic neural activity of BAT in the older males vs. females. Rather, our investigations, strongly suggest that the blunted cold-induced heat production of BAT reflects less functional BAT. The fact that the older animals have less functional BAT than do their younger counterparts may predispose them to the accumulation of excess body fat. Our studies have also found that near the end of the natural life of these rats, they enter a state of senescence that can be identified by spontaneous rapid body weight loss, resulting from decreased food intake. In this state, the rats are considerably more susceptible to cold than are comparably aged presenescent (body weight stable) rats of the same chronological age. The greater hypothermia exhibited by the senescent vs. presenescent rats during cold exposure is associated with a significant reduction in the amount of functional brown fat and in the amount of heat each brown fat cell can generate. It is the intent of this review to discuss the findings of these investigations. PMID: 10653478 [PubMed - indexed for MEDLINE] 5432. J Bioenerg Biomembr. 1999 Oct;31(5):493-506. Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control "the benefits of losing control". Diehl AM(1), Hoek JB. Author information: (1)Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA. amdiehl@welchlink.weich.jhu.edu Uncoupling proteins, a subgroup of the mitochondrial anion transporter superfamily, have been identified in prokaryotes, plants, and mammalian cells. Evolutionary conservation of these molecules reflects their importance as regulators of two critical mitochondrial functions, i.e., ATP synthesis and the production of reactive oxygen species (ROS). Although the amino acid sequences of the three mammalian uncoupling proteins, UCP1, UCP2 and UCP3, are very similar, each homolog is the product of a unique gene and important differences have been demonstrated in their tissue-specific expression and regulation. UCP1 and UCP3 appear to be key regulators of energy expenditure, and hence, nonshivering thermogenesis, either in brown adipose tissue (UCP1) or skeletal muscle (UCP3). UCP2 is expressed more ubiquitously, although generally at low levels, in many tissues. There is conflicting evidence about its importance as a regulator of resting metabolic rate. However, evidence suggests that this homolog might modulate the mitochondrial generation of ROS in some cell types, including macrophages and hepatocytes. While the induction of various uncoupling protein homologs provides adaptive advantages, both to the organism (e.g., thermogenesis) and to individual cells (e.g., reduced ROS), increased uncoupling protein activity also increases cellular vulnerability to necrosis by compromising the mitochondrial membrane potential. This narrow "risk-benefit" margin necessitates tight control of uncoupling protein activity in order to preserve cellular viability and much remains to be learned about the regulatory mechanisms involved. PMID: 10653477 [PubMed - indexed for MEDLINE] 5433. J Bioenerg Biomembr. 1999 Oct;31(5):475-91. UCP1: the original uncoupling protein--and perhaps the only one? New perspectives on UCP1, UCP2, and UCP3 in the light of the bioenergetics of the UCP1-ablated mice. Nedergaard J(1), Matthias A, Golozoubova V, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm University, Sweden. The availability of a UCP1-ablated mouse has enabled critical studies of the function of UCP1, UCP2, and UCP3. Concerning UCP1, its presence in brown-fat mitochondria is associated with innate uncoupling, high GDP-binding capacity, and GDP-inhibitable Cl- permeability and uncoupling--but the high fatty acid sensitivity found in these mitochondria is observed even in the absence of UCP1. The absence of UCP1 leads to low cold tolerance but not to obesity. UCP1 ablation also leads to an augmented expression of UCP2 and UCP3 in brown adipose tissue, making this tissue probably the one that boasts the highest expression of these UCPs. However, these very high expression levels are not associated with any inherent uncoupling, or with a specific GDP-binding capacity, or with a GDP-sensitive Cl- permeability, or with any effect of GDP on mitochondrial membrane potential, or with an increased basal metabolism of cells, or with the presence of norepinephrine- or fatty acid-induced thermogenesis in cells, and not with a cold-acclimation recruited, norepinephrine-induced thermogenic response in the intact animal. Therefore, it can be discussed whether any uncoupling effect is associated with UCP2 or UCP3 when they are endogenously expressed and, consequently, whether (loss of) uncoupling (thermogenic) effects of UCP2 or UCP3 can be invoked to explain metabolic phenomena, such as obesity. PMID: 10653476 [PubMed - indexed for MEDLINE] 5434. J Bioenerg Biomembr. 1999 Oct;31(5):467-73. Uncoupling protein 3: its possible biological role and mode of regulation in rodents and humans. Muzzin P(1), Boss O, Giacobino JP. Author information: (1)Department of Medical Biochemistry, University of Geneva, Switzerland. patrick.muzzin@medecine.unige.ch The recently discovered uncoupling protein 3 (UCP3) is highly homologous to the mitochondrial inner membrane protein UCP1, which generates heat by uncoupling the respiratory chain from oxidative phosphorylation. The thermogenic function of UCP1 protects against cold and regulates the energy balance in rodents. We review in vitro studies investigating the uncoupling activity of UCP3 and in vivo studies, which address UCP3 gene expression in brown adipose tissue and skeletal muscle under various metabolic conditions. The data presented are, for the most, consistent with an uncoupling role for UCP3 in regulatory thermogenesis. We also discuss mediators of UCP3 regulation and propose a potential role for intracellular fatty acids in the mechanism of UCP3 modulation. Finally, we hypothesize a role for UCP3 in the metabolic adaptation of the mitochondria to the degradation of fatty acids. PMID: 10653475 [PubMed - indexed for MEDLINE] 5435. J Bioenerg Biomembr. 1999 Oct;31(5):457-66. Fatty acid interaction with mitochondrial uncoupling proteins. Jezek P(1). Author information: (1)Institute of Physiology, Department of Membrane Transport Biophysics, Academy of Sciences of the Czech Republic, Prague. jezek@sun1.biomed.cas.cz The phenomena of fatty acid interaction with mitochondrial integral membrane proteins, namely uncoupling proteins (UCPs), are reviewed to emphasize the fatty acid cycling mechanism that has been suggested to explain the UCP function. Fatty acid-induced uncoupling is suggested to serve in bioenergetic systems, to set the optimum efficiency, and to tune the degree of coupling of oxidative phosphorylation. Fatty acid interaction with the "classic" uncoupling protein (UCP1) from mitochondria of thermogenic brown adipose tissue (BAT) is well known. UCP1 is considered to mediate purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H+ uniport and uncoupling. Experiments supporting this mechanism are also reviewed for plant uncoupling mitochondrial protein (PUMP) and ADP/ATP carrier. The fatty acid cycling mechanism is predicted, as well for the recently discovered uncoupling proteins, UCP2 and UCP3. PMID: 10653474 [PubMed - indexed for MEDLINE] 5436. J Bioenerg Biomembr. 1999 Oct;31(5):431-45. Anion carriers in fatty acid-mediated physiological uncoupling. Skulachev VP(1). Author information: (1)Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia. skulach@head.genebee.msu.su Physiological aspects of uncoupling of oxidation and phosphorylation are reviewed in the context of involvement of mitochondrial anion carriers. It is assumed that the carriers facilitate electrophoretic translation of fatty acid anion, RCOO-, from the inner to the outer leaflet of the mitochondrial membrane, whereas back movement of the protonated fatty acid, RCOOH, from the outer to the inner leaflet represents flip-flop of RCOOH via the phospholipid bilayer of the membrane. The RCOO- transport seems to be catalyzed by the ATP/ADP and aspartate/ glutamate antiporters, dicarboxylate carrier, and uncoupling proteins (UCP1, UCP2, UCP3L, UCP3s, and plant UCP). The fatty acid uncoupling is shown to be involved in the thermoregulatory heat production in animals and plants exposed to cold, as well as in performance of respiratory functions other than ATP synthesis, i.e., formation of useful substances, decomposition of unwanted substances, and antioxidant defense. Moreover, partial uncoupling might take part in optimization of the rate of ATP synthesis in aerobic cells. PMID: 10653472 [PubMed - indexed for MEDLINE] 5437. J Bioenerg Biomembr. 1999 Oct;31(5):419-30. Uncoupling protein--a useful energy dissipator. Klingenberg M(1). Author information: (1)Institute of Physical Biochemistry, University of Munich, Germany. The structure/function relationship in the uncoupling proteins (UCP) is reviewed, stressing UCP from brown adipose tissue (UCP1) since, so far, nearly no biochemistry is known for the UCP variants UCP2, UCP3, and UCP4. The transport for H+ and Cl- and its dependence on fatty acids in reconstituted vesicles is described. The inhibition and binding of nucleotides to UCP1, in particular, the pH dependence and two-stage binding are analyzed. A model for the role of fatty acid in H+ transport is shown. The role of specific residues in UCP1 is analyzed by directed mutagenesis in a yeast expression system. The different regulation by the cellular energy potential of UCP1 versus UCP3 is discussed. PMID: 10653471 [PubMed - indexed for MEDLINE] 5438. J Bioenerg Biomembr. 1999 Oct;31(5):407-18. Contribution to the identification and analysis of the mitochondrial uncoupling proteins. Ricquier D(1), Miroux B, Cassard-Doulcier AM, Lévi-Meyrueis C, Gelly C, Raimbault S, Bouillaud F. Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, Centre National de la Recherche Scientifique-Unit 9078, Meudon, France. ricquier@infobiogen.fr This review is primarily focused on the contribution of our laboratory to study of the mitochondrial uncoupling UCPs. The initial stage was the description of a 32-kDa membranous protein specifically induced in brown adipose tissue mitochondria of cold-adapted rats. This protein was then shown by others to be responsible for brown fat thermogenesis and was referred to as the uncoupling protein-UCP (recently renamed UCP1). cDNA and genomic clones of UCP1 were isolated and used to investigate the topology and functional organization of the protein in the membrane and the mechanisms of control of UCP1 gene transcription. Orientation of the transmembrane fragments was proposed and specific amino acid residues involved in the inhibition of UCP1 by purine nucleotides were identified in recombinant yeast. A potent enhancer mediating the response of the UCP1 gene to retinoids and controlling the specific transcription in brown adipocytes was identified using transgenic mice. More recently, we identified UCP2, an UCP homolog widely expressed in human and rodent tissues we also collaborated to characterize the plant UCP. Although the biochemical activities and physiological roles of the novel UCPs are not well understood, these recent data stimulate research on mitochondrial carriers, mitochondrial bioenergetics, and energy expenditure. PMID: 10653470 [PubMed - indexed for MEDLINE] 5439. J Bioenerg Biomembr. 1999 Oct;31(5):399-406. A history of the first uncoupling protein, UCP1. Nicholls DG(1), Rial E. Author information: (1)Neurosciences Institute, Ninewells Medical School, Dundee University, Scotland. The lack of energy conservation in brown adipose tissue mitochondria when prepared by conventional methods was established in the 1960s and was correlated with the thermogenic function of the tissue. In order to observe energy conservation, two requirements had to be met: the removal of the endogenous fatty acids and the addition of a purine nucleotide. These two factors have been the essential tools that led to the discovery of the energy dissipation pathway, the uncoupling protein UCP1. The activity is regulated by these two ligands. Purine nucleotides bind from the cytosolic side of the protein and inhibit transport. Fatty acids act as seconds messengers of noradrenaline and increase the proton conductance. This review presents a historical perspective of the steps that led to the discovery of UCP1, its regulation, and our current view on its mechanism of transport. PMID: 10653469 [PubMed - indexed for MEDLINE] 5440. Am J Physiol Endocrinol Metab. 2000 Jan;278(1):E1-E14. The adipoinsular axis: effects of leptin on pancreatic beta-cells. Kieffer TJ(1), Habener JF. Author information: (1)Departments of Medicine and Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. The prevalence of obesity and related diabetes mellitus is increasing worldwide. Here we review evidence for the existence of an adipoinsular axis, a dual hormonal feedback loop involving the hormones insulin and leptin produced by pancreatic beta-cells and adipose tissue, respectively. Insulin is adipogenic, increases body fat mass, and stimulates the production and secretion of leptin, the satiety hormone that acts centrally to reduce food intake and increase energy expenditure. Leptin in turn suppresses insulin secretion by both central actions and direct actions on beta-cells. Because plasma levels of leptin are directly proportional to body fat mass, an increase of adiposity increases plasma leptin, thereby curtailing insulin production and further increasing fat mass. We propose that the adipoinsular axis is designed to maintain nutrient balance and that dysregulation of this axis may contribute to obesity and the development of hyperinsulinemia associated with diabetes. PMID: 10644531 [PubMed - indexed for MEDLINE] 5441. Postepy Hig Med Dosw. 1999;53(5):705-15. [Beta-3 adrenergic receptor--structure and role in obesity and metabolic disorders]. [Article in Polish] Wiejak J(1), Wyroba E. Author information: (1)Zakład Biologii Komórki, Instytut Biologii Doświadczalnej im. M. Nenckiego PAN w Warszawie. Structure and essential motifs of beta 3-adrenergic receptor (known previously as atypical beta-AR), which plays a central role in regulation of lipid metabolism have been described. Obesity results from an imbalance between caloric intake and energy expenditure. The consequence of catecholamine activation of beta 3-AR is increased mobilization of fatty acids from triglyceride stores (lipolysis) in brown and white adipose tissue as well as increased fatty acid beta-oxidation and heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg mutation in beta 3-AR gene in obesity and another metabolic disorders have been discussed. PMID: 10645145 [PubMed - indexed for MEDLINE] 5442. Int J Biometeorol. 1999 Nov;43(3):99-109. Human morphology and temperature regulation. Anderson GS(1). Author information: (1)University College of the Fraser Valley, Mission, BC, Canada. andersong@ucfv.bc.ca For nearly a century individuals have believed that there is a link between human morphology and one's thermoregulatory response in adverse environments. Most early research was focussed on the rate of core cooling in a male adult population and the role of subcutaneous adipose tissue, surface area and the surface-area-to-mass ratio in one's ability to withstand varying degrees of cold stress. More recently research has addressed heat tolerance in various populations, exploring the role of subcutaneous adipose tissue, surface area and the surface-area-to-mass ratio in one's ability to maintain thermal equilibrium in warm and hot, dry and humid environments. Since the late 1970s an emphasis has been placed on the role of muscle and muscle perfusion in total-body thermal insulation. Yet, despite the history of research pertaining to human morphology and temperature regulation there is little consensus as to the impact of variations in human morphology on thermoregulatory responses. Individuals differing in body size, shape and composition appear to respond quantitatively differently to variations in both ambient and core temperatures but the interrelations between morphological components and temperature regulation are complex. It is the purpose of this paper to examine the literature pertaining to the impact of variations in muscularity, adipose tissue thickness and patterning, surface area and the surface-area-to-mass ratio on thermoregulation and thermal stability in response to both heat and cold stress. PMID: 10639901 [PubMed - indexed for MEDLINE] 5443. Sud Med Ekspert. 1999 Nov-Dec;42(6):7-9. [Modern concepts of adipocere formation mechanisms]. [Article in Russian] Manulik AF, Shepelev AP, Akopov VI, Staviskiĭ IM. Biochemical parameters of transformation of fresh subcutaneous fat into adipocere have been studied in experiment. Activation of lipid peroxidation is a significant component of the mechanism of adipocere transformation, which is proven by a drastic increase in the level of Schiff's bases in adipocere in comparison with subcutaneous fat. The concentrations of myristic, palmitic, and stearic fatty acids increase during the formation of adipocere, while the content of linoleic acid decreases in comparison with the unchanged human subcutaneous fat. PMID: 10638263 [PubMed - indexed for MEDLINE] 5444. Diabetes Metab Res Rev. 1999 Nov-Dec;15(6):427-41. Neuroendocrine perturbations as a cause of insulin resistance. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, S-413 45 Göteborg, Sweden. Insulin resistance is followed by several prevalent diseases. The most common condition with insulin resistance is obesity, particularly when localized to abdominal, visceral regions. A summary of recent reviews on the pathogenesis of systemic insulin resistance indicates that major factors are decreased insulin effects on muscular glycogen synthase or preceding steps in the insulin signalling cascade, on endogenous glucose production and on circulating free fatty acids (FFA) from adipose tissue lipolysis. Contributions of morphologic changes in muscle and other factors are considered more uncertain. Newly developed methodology has made it possible to determine more precisely the neuroendocrine abnormalities in abdominal obesity including increased cortisol and adrenal androgen secretions. This is probably due to a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback inhibition by central glucocorticoid receptors, associated with molecular genetic defects. Secondly, secretion of gender-specific sex steroid hormones becomes inhibited and the sympathetic nervous system activated. At this stage the HPA axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer elevated. Cortisol counteracts the insulin activation of glycogen synthase in muscle, the insulin inhibition of hepatic glucose production and the insulin inhibition of lipolysis in adipose tissue, leading to the well-established systemic insulin resistance caused by excess cortisol. This is exaggerated by increased free fatty acid mobilization, particularly with a concomitant elevation of the activity of the sympathetic nervous system. Furthermore, capillarization and fiber composition in muscle are changed. These are the identical perturbations responsible for insulin resistance in recent reviews. The diminished sex steroid secretion in abdominal obesity has the same consequences. It is thus clear that insulin resistance may be induced by neuroendocrine abnormalities, such as those seen in abdominal obesity. These endocrine perturbations also direct excess fat to visceral fat depots via mechanisms that are largely known, indicating why abdominal obesity is commonly associated with insulin resistance. This possible background to the most prevalent condition of insulin resistance has been revealed by development of methodology that allows sufficiently sensitive measurements of HPA axis activity. These findings demonstrate the power of neuroendocrine regulations for somatic health. Copyright 1999 John Wiley & Sons, Ltd. PMID: 10634968 [PubMed - indexed for MEDLINE] 5445. Magn Reson Imaging Clin N Am. 1999 Nov;7(4):629-59. Principles of MR image formation and reconstruction. Duerk JL(1). Author information: (1)Department of Radiology, Case Western Reserve University School of Medicine, Ohio, USA. duerk@uhrad.com This article describes a number of concepts that provide insights into the process of MR imaging. The use of shaped, fixed-bandwidth RF pulses and magnetic field gradients is described to provide an understanding of the methods used for slice selection. Variations in the slice-excitation profile are shown as a function of the RF pulse shape used, the truncation method used, and the tip angle. It should be remembered that although the goal is to obtain uniform excitation across the slice, this goal is never achieved in practice, thus necessitating the use of slice gaps in some cases. Excitation, refocusing, and inversion pulses are described. Excitation pulses nutate the spins from the longitudinal axis into the transverse plane, where their magnetization can be detected. Refocusing pulses are used to flip the magnetization through 180 degrees once it is in the transverse plane, so that the influence of magnetic field inhomogeneities is eliminated. Inversion pulses are used to flip the magnetization from the +z to the -z direction in invesrsion-recovery sequences. Radiofrequency pulses can also be used to eliminate either fat or water protons from the images because of the small differences in resonant frequency between these two types of protons. Selective methods based on chemical shift and binomial methods are described. Once the desired magnetization has been tipped into the transverse plane by the slice-selection process, two imaging axes remain to be spatially encoded. One axis is easily encoded by the application of a second magnetic field gradient that establishes a one-to-one mapping between position and frequency during the time that the signal is converted from analog to digital sampling. This frequency-encoding gradient is used in combination with the Fourier transform to determine the location of the precessing magnetization. The second image axis is encoded by a process known as phase encoding. The collected data can be described as the 2D Fourier transform of the object being imaged. Thus, a concept known as k-space is used to describe the image data and its relationship to the imaging gradient waveforms. The article demonstrates how phase encoding selects the row of k-space from which the data will be recorded, and frequency encoding determines the column. The goal of any acquisition strategy is to map k-space completely, and two methods, spiral imaging and echo-planar imaging, are described to demonstrate that the data acquisition path need not be a straight line. PMID: 10631672 [PubMed - indexed for MEDLINE] 5446. Curr Opin Clin Nutr Metab Care. 2001 Jan;4(1):9-13. Anorexia, body composition, and ageing. Morley JE(1). Author information: (1)GRECC, VA Medical Center, St Louis, Missouri, USA. rinckerv@slu.edu Comment in Curr Opin Clin Nutr Metab Care. 2001 Jan;4(1):1-4. Over the lifespan there is a decline in food intake. This has been termed the physiological anorexia of aging. It has many causes, including alterations in the gastrointestinal satiating system, the effect of elevated leptin levels, especially in men, and a variety of changes in central nervous system neurotransmitters. Beyond the age of 70 years body mass declines. This includes both loss of adipose tissue and muscle mass. The loss of muscle mass in older individuals is termed sarcopenia. There is increasing evidence that this is caused, in men, partly by the decline in testosterone. Illness results in an increase of cytokines that produce both anorexia and cause protein wasting. Many of the causes of cachexia in older individuals are treatable. Depression is the most common cause of weight loss in older individuals. Dieting in older individuals is associated with a loss of skeletal tissue as well as fat mass. This can place older individuals at risk of becoming the 'fat frail'. PMID: 11122553 [PubMed - indexed for MEDLINE] 5447. Clin Nutr. 2000 Dec;19(6):379-86. Hunger disease. Elia M(1). Author information: (1)Addenbrooke's Hospital, Cambridge, UK. This paper examines three aspects of hunger disease: the effect of initial fat stores on macronutrient fuel selection during total starvation (no energy) and how it influences survival; the effects of different rates of weight loss on tissue and body function; and the importance of appetite sensations, including hunger, during malnutrition and during enteral and parenteral nutritional support. Long-term starvation studies in humans reveal major differences in fat carbohydrate and protein metabolism between lean and obese subjects, including a 2-4-fold lower contribution of protein oxidation to energy expenditure in obese subjects, which ensures that more of the excess body fat is oxidized. The rate of weight loss, determined by recent dietary intake, can have major effects on tissue and body function, including wound healing, the acute phase protein response, muscle fatigue and psychological/behavioural function in both clinical and non-clinical settings. In depleted states uncomplicated by disease, changes in appetite sensations can result in energy intakes as high as 6000 to 10,000 kcal/day ( 25-42 MJ/day). Long-term enteral tube feeding and parenteral nutrition are associated with frequent disturbances in appetite sensations, and in those able to eat normally they tend to add rather than replace oral intake to an extent that appears to depend on the regimen. It is concluded that 1) differences between lean and obese subjects in macronutrient fuel selection during starvation are adaptive because they optimize survival in both groups of subjects; 2) the rate of weight loss in health and disease has a major effect on certain tissue and body functions, independently of the magnitude of weight loss; and 3) clinically relevant disturbances in appetite sensations are common subjects receiving long-term enteral and parenteral nutrition. The clinical modulation of all these variables would be aided by greater knowledge of the mechanisms involved. Copyright 2000 Harcourt Publishers Ltd. PMID: 11104587 [PubMed - indexed for MEDLINE] 5448. J Cell Biochem. 1999;Suppl 32-33:59-67. Insights into the transcriptional control of adipocyte differentiation. Morrison RF(1), Farmer SR. Author information: (1)Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. The adipocyte is now known to play an active role in many physiological and pathological processes regarding energy metabolism. Consideration of adipose tissue as an endocrine organ that secretes a variety of unrelated bioactive molecules has broadened our appreciation of adipocyte function to exceed the once considered passive role in lipid metabolism. Growing interest in this tissue has lead to significant advances regarding the molecular basis for adipocyte differentiation. Several diverse families of transcription factors are currently under active investigation for their roles in mediating this complex process. Knowledge concerning the sequence of transcriptional events during adipogenesis and the interplay among adipogenic transcription factors provides a basis for understanding the physiological processes associated with adipose tissue as well as for the development of therapeutic intervention of adipocyte related diseases. J. Cell. Biochem. Suppls. 32/33:59-67, 1999. Copyright 1999 Wiley-Liss, Inc. PMID: 10629104 [PubMed - indexed for MEDLINE] 5449. Acta Paediatr Suppl. 1999 Dec;88(433):95-8. The role of leptin in human growth and puberty. Ong KK(1), Ahmed ML, Dunger DB. Author information: (1)Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Headington, UK. Experimental animal studies demonstrate the effects of leptin on appetite, weight gain and metabolism. The biological effects of leptin in human adults are still to be determined, but recent reports show that congenital leptin deficiency leads to hyperphagia and excessive weight gain from early infancy as well as failure of pubertal onset in adolescence. Our recently reported data from two longitudinal cohorts suggest a role for leptin in the normal regulation of childhood weight gain, maturation and the development of secondary sexual features and body composition. Low leptin levels in cord blood closely reflected decreased adiposity at birth and strongly predicted high rates of weight gain in infancy and catch-up growth. In adolescents, leptin levels rose gradually with age prior to puberty, suggesting that a threshold effect may trigger puberty. In girls, low leptin levels at the start of puberty predicted large gains in the percentage of fat mass, perhaps suggesting a role in the preparation for childbearing. PMID: 10626555 [PubMed - indexed for MEDLINE] 5450. Biochem J. 2000 Jan 15;345 Pt 2:161-79. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Ricquier D(1), Bouillaud F. Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement (CEREMOD), Centre National de la recherche Scientifique (CNRS-Unit 9078), 9 rue Jules Hetzel, 92190 Meudon, France. ricquier@infobiogen.fr Animal and plant uncoupling protein (UCP) homologues form a subfamily of mitochondrial carriers that are evolutionarily related and possibly derived from a proton/anion transporter ancestor. The brown adipose tissue (BAT) UCP1 has a marked and strongly regulated uncoupling activity, essential to the maintenance of body temperature in small mammals. UCP homologues identified in plants are induced in a cold environment and may be involved in resistance to chilling. The biochemical activities and biological functions of the recently identified mammalian UCP2 and UCP3 are not well known. However, recent data support a role for these UCPs in State 4 respiration, respiration uncoupling and proton leaks in mitochondria. Moreover, genetic studies suggest that UCP2 and UCP3 play a part in energy expenditure in humans. The UCPs may also be involved in adaptation of cellular metabolism to an excessive supply of substrates in order to regulate the ATP level, the NAD(+)/NADH ratio and various metabolic pathways, and to contain superoxide production. A major goal will be the analysis of mice that either lack the UCP2 or UCP3 gene or overexpress these genes. Other aims will be to investigate the possible roles of UCP2 and UCP3 in response to oxidative stress, lipid peroxidation, inflammatory processes, fever and regulation of temperature in certain specific parts of the body. PMCID: PMC1220743 PMID: 10620491 [PubMed - indexed for MEDLINE] 5451. Am J Clin Nutr. 2000 Jan;71(1 Suppl):367S-72S. Essential fatty acid metabolism and its modification in atopic eczema. Horrobin DF(1). Author information: (1)Laxdale Research, Stirling, Scotland, United Kingdom. admin@laxdale.co.uk Research from the 1930s to the 1950s established that a deficit of n-6 essential fatty acids (EFAs) leads to an inflammatory skin condition in both animals and humans. In a common inherited skin condition, atopic dermatitis (eczema), there was evidence of low blood EFA concentrations and of a therapeutic response to exceptionally high doses of linoleic acid. More recently, it has been established that there is no deficit of linoleic acid in atopic eczema. Concentrations of linoleic acid instead tend to be elevated in blood, milk, and adipose tissue of patients with atopic eczema, whereas concentrations of linoleic acid metabolites are substantially reduced. This suggests reduced conversion of linoleic acid to gamma-linolenic acid (GLA). In most but not all studies, administration of GLA has been found to improve the clinically assessed skin condition, the objectively assessed skin roughness, and the elevated blood catecholamine concentrations of patients with atopic eczema. Atopic eczema may be a minor inherited abnormality of EFA metabolism. PMID: 10617999 [PubMed - indexed for MEDLINE] 5452. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 5:S158-9. Animal model of thyroid-associated orbitopathy. Ludgate M(1). Author information: (1)Department of Medicine, UWCM, Heath Park, Cardiff, UK. Autoimmune responses to the thyrotropin receptor result in Graves' Disease. Evidence is accumulating that the same antigen is implicated in thyroid-associated orbitopathy (TAO) or thyroid eye disease. Progress in the establishment of receptor induced animal models has led to the development of a murine model in which the orbits of affected mice bear striking resemblance to human TAO with disruption of muscle fibres by oedema, accumulation of adipose tissue and infiltration by cells of the immune system. PMID: 10614911 [PubMed - indexed for MEDLINE] 5453. Brain Res. 1999 Nov 27;848(1-2):114-23. Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Baskin DG(1), Figlewicz Lattemann D, Seeley RJ, Woods SC, Porte D Jr, Schwartz MW. Author information: (1)Division of Endocrinology/Metabolism, VA Puget Sound Health Care System Medical Center, Seattle, WA 98108, USA. baskindg@u.washington.edu Insulin and leptin are hypothesized to be 'adiposity signals' for the long-term regulation of body weight by the brain. Accordingly, a change in the plasma levels of leptin or insulin indicates a state of altered energy homeostasis and adiposity, and the brain responds by adjusting food intake to restore adipose tissue mass to a regulated level. The candidate site for the brain's detection of leptin adiposity signaling is the hypothalamic arcuate nucleus, where leptin inhibits expression neuropeptide Y and increases expression of the pro-opiomelanocortin (POMC) precursor of alphaMSH. Insulin also inhibits arcuate nucleus expression of neuropeptide Y but its effects on other hypothalamic signaling systems are not known. Leptin-responsive neurons in the arcuate nucleus are hypothesized to project to the paraventricular nucleus and lateral hypothalamic area where they are proposed to influence the expression of peptides that regulate food intake. Future development of this model will incorporate brain pathways for integration of leptin and insulin adiposity signaling to the hypothalamus with meal-related signals that act in the caudal brainstem. Recent research showing that leptin and insulin enhance the satiety action of peripheral CCK, thereby causing meals to be terminated earlier and reducing cumulative food intake, suggests that hypothalamic pathways that are sensitive to leptin and insulin adiposity signals have anatomical connections with caudal brainstem neurons that respond to meal-related signals and regulate meal size. The recent findings that insulin alters the expression and function of neural transporters for dopamine and norepinephrine indicate that adiposity signals may influence food intake by acting on non-peptide neurotransmitter systems. PMID: 10612703 [PubMed - indexed for MEDLINE] 5454. J Clin Apher. 1999;14(4):181-4. Phytanic acid storage disease (Refsum's disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. Weinstein R(1). Author information: (1)Department of Medicine, Division of Hematology/Oncology, Section of Hematology and Transfusion Medicine, St. Elizabeth's Medical Center of Boston, Tufts University School of Medicine, Boston, MA 02135, USA. bobbw@massmed.org Phytanic acid storage disease (known also as Refsum's Disease) is caused by inherited defects in the metabolic pathway for phytanic acid, a dietary branched-chain fatty acid. Poorly metabolized phytanic acid accumulates in fatty tissues, including myelin sheaths, and in organs including the liver and kidneys. Over time, affected individuals may develop classical diagnostic features of retinitis pigmentosa, cerebellar ataxia, peripheral polyneuropathy and an elevated protein content in the cerebrospinal fluid. Liver, kidney, and heart disease may also develop. Dietary restriction of phytanic acid is useful in preventing acute attacks and arresting the progression of organ impairment, especially in the peripheral nervous system. Therapeutic plasma exchange has been shown to be particularly useful for rapidly lowering plasma phytanic acid levels during acute attacks and may play a significant role as maintenance therapy as well. Copyright 1999 Wiley-Liss, Inc. PMID: 10611628 [PubMed - indexed for MEDLINE] 5455. Public Health Nutr. 1999 Sep;2(3A):383-90. Interaction of physical activity and diet: implications for haemostatic factors. Rauramaa R(1), Väisänen SB. Author information: (1)Kuopio Research Institute of Exercise Medicine, Finland. rainer.rauramaa@messi.uku.fi Regular moderate intensity physical activity and habitual diet providing no more than one third of energy from fats have been recommended for the prevention of atherosclerotic diseases. The background for these guidelines is the key role of plasma lipids. However, the importance of thrombogenesis in acute myocardial infarction has become obvious during the last decade. Hyperlipidaemia and excess of adipose tissue increase platelet aggregability and blood coagulation, and decrease fibrinolysis. Both regular physical activity and dietary fat reduction decrease blood lipids and body fat thereby diminishing the risk of thrombosis. Currently, data on interactions between physical activity and diet on haemostasis are scarce, and the few studies available have not demonstrated additional effects when these two lifestyle modifications have been combined. This paper is restricted only to studies using controlled randomized design. Regular moderate intensity physical activity as well as diet rich in omega-3 fatty acids decrease platelet aggregability. The effects of regular physical activity on plasma fibrinogen remain contradictory, while the impact of diet is even less clear. Plasminogen activator inhibitor-1, a possible link between insulin resistance syndrome and coronary heart disease, may decrease due to physical training or low fat diet. It can be hypothesized that moderation in physical activity and diet carries a more powerful impact on blood coagulation and fibrinolysis than either lifestyle modification alone. Studies focusing on the interactions of regular moderate physical activity and fat-modified diet are needed in efforts to optimize the preventive actions by lifestyle changes. PMID: 10610077 [PubMed - indexed for MEDLINE] 5456. Endocrinol Metab Clin North Am. 1999 Dec;28(4):749-64, viii. Role of leptin during childhood growth and development. Roemmich JN(1), Rogol AD. Author information: (1)Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, USA. Leptin, the product of the ob/ob gene in rodents, regulates energy balance and fertility. Two genetic models, the ob/ob mouse (deletion of leptin protein) and the db/db mouse (deletion of leptin receptor) have markedly augmented research in obesity. Human obesity is more closely linked to leptin resistance than to the absence of leptin. Serum leptin concentrations reflect the size of the subcutaneous fat depot better than total fat mass or abdominal visceral fat. At the initiation of puberty there is a divergence in circulating leptin concentrations between boys and girls. In boys, leptin concentrations increase and then markedly decrease to prepubertal concentration levels. In girls there are only increasing concentrations. The authors believe these patterns are relevant to the markedly different alterations in the regional distribution of body fat that occurs in boys and girls at puberty. PMID: 10609118 [PubMed - indexed for MEDLINE] 5457. Curr Opin Neurobiol. 1999 Dec;9(6):778-83. Hypothalamic control of feeding. Lawrence CB(1), Turnbull AV, Rothwell NJ. Author information: (1)School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK. Our understanding of the hypothalamic control of energy homeostasis has increased greatly since the discovery of leptin, the adipose cell derived protein. Recent studies have identified several new hypothalamic neuropeptides that affect food intake and energy balance. By studying these molecules and their neuronal systems, receptors and interactions, we are beginning to unravel the circuitry between peripheral adipogenic signals and hypothalamic effector pathways. PMID: 10607641 [PubMed - indexed for MEDLINE] 5458. Curr Opin Cell Biol. 1999 Dec;11(6):689-94. Transcriptional activation of adipogenesis. Wu Z(1), Puigserver P, Spiegelman BM. Author information: (1)Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Studies from the past several years have revealed that adipogenesis is controlled by an interplay of transcription factors, including members of the CCAAT/enhancer binding protein family and peroxisome proliferator activated receptor gamma. In addition to providing a new understanding of this aspect of the energy balance systems, these factors provide potential new targets for therapeutic intervention in metabolic diseases, such as obesity and type 2 diabetes mellitus. PMID: 10600710 [PubMed - indexed for MEDLINE] 5459. Int J Biochem Cell Biol. 1999 Nov;31(11):1261-78. The mitochondrial uncoupling protein-2: current status. Fleury C(1), Sanchis D. Author information: (1)CEREMOD CNRS UPR 9078, Meudon, France. cfleury@genetique.uvsq.fr In eukaryotic cells ATP is generated by oxidative phosphorylation, an energetic coupling at the mitochondrial level. The oxidative reactions occurring in the respiratory chain generate an electrochemical proton gradient on both sides of the inner membrane. This gradient is used by the ATPsynthase to phosphorylate ADP into ATP. The coupling between respiration and ADP phosphorylation is only partial in brown adipose tissue (BAT) mitochondria, where the uncoupling protein UCP1 causes a reentry of protons into the matrix and abolishes the electrochemical proton gradient. The liberated energy is then dissipated as heat and ATP synthesis is reduced. This property was for a long time considered as an exception and specific to the non-shivering thermogenesis found in BAT. The recent cloning of new UCPs expressed in other tissues revealed the importance of this kind of regulation of respiratory control in metabolism and energy expenditure. The newly characterised UCPs are potential targets for obesity treatment drugs which could favour energy expenditure and diminish the metabolic efficiency. In 1997, we cloned UCP2 and proposed a role for this new uncoupling protein in diet-induced thermogenesis, obesity, hyperinsulinemia, fever and resting metabolic rate. Currently, an abundant literature deals with UCP2, but its biochemical and physiological functions and regulation remain unclear. The present review reports the status of our knowledge of this mitochondrial carrier in terms of sequence, activity, tissue distribution and regulation of expression. The putative physiological roles of UCP2 will be introduced and discussed. PMID: 10605819 [PubMed - indexed for MEDLINE] 5460. Thromb Haemost. 1999 Aug;82(2):832-6. Regulation of fibrinolysis in the development of atherothrombosis: role of adipose tissue. Juhan-Vague I(1), Alessi MC. Author information: (1)Lab. Haematology, CHU Timone, Marseille, France. PMID: 10605790 [PubMed - indexed for MEDLINE] 5461. Thromb Haemost. 1999 Aug;82(2):742-7. Hemostatic gene expression and vascular disease in obesity: insights from studies of genetically obese mice. Samad F(1), Loskutoff DJ. Author information: (1)Scripps Research Institute, La Jolla, CA 92037, USA. PMID: 10605777 [PubMed - indexed for MEDLINE] 5462. Proc Nutr Soc. 1999 Aug;58(3):633-46. Selectivity of fatty acids on lipid metabolism and gene expression. Raclot T(1), Oudart H. Author information: (1)Centre d'Ecologie et Physiologie Energétiques, UPR 9010 CNRS, l'Université Louis Pasteur, Strasbourg, France. Thierry.Raclot@c-strasbourg.fr Triacylglycerols represent the main form of storage for a wide spectrum of fatty acids. Their utilization first involves mobilization from adipose tissue through lipolysis. The release of individual fatty acids from adipose tissue is selective in vitro and in vivo in animal studies and also in human subjects. Generally, fatty acids are more readily mobilized from fat cells when they are short-chain and unsaturated. This selectivity could affect the storage of individual fatty acids in adipose tissue, and their subsequent supply to tissues. The nature of the dietary fats could affect lipid homeostasis and body fat deposition. Dietary fish oil influences adipose tissue development in a site-specific manner as a function of diet and feeding period. A diet high in n-3 polyunsaturated fatty acids (PUFA) results in a preferential partitioning of ingested energy towards oxidation at the expense of storage. Fatty acids are important mediators of gene expression in the liver. Indeed, genes encoding both glycolytic and lipogenic enzymes and key metabolic enzymes involved in fatty acid oxidation are regulated by dietary PUFA. White adipose tissue could also be a target for PUFA control of gene expression. The treatment of pre-adipose cells by fatty acids induces the expression of numerous genes that encode proteins involved in fatty acid metabolism. The mechanisms of PUFA-mediated repression of gene expression in adipocytes seem to be different, at least partly, from those described in liver. Tissue-specific and site-specific factors are possibly involved in the specific effect of PUFA on gene expression, although other mechanisms cannot be excluded. PMID: 10604197 [PubMed - indexed for MEDLINE] 5463. Proc Nutr Soc. 1999 Aug;58(3):615-9. The long-term consequences of intra-uterine protein malnutrition for glucose metabolism. Ozanne SE(1), Hales CN. Author information: (1)Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, UK. Our initial observations, in epidemiological studies, linking indices of poor early (fetal and infant) growth to the subsequent development of poor glucose tolerance and the insulin resistance syndrome in adult life, have been confirmed in studies in a wide variety of populations around the world. These findings led us 5 years ago to propose the 'thrifty phenotype' hypothesis. Tests of this hypothesis in an animal model in which the pregnant and/or lactating rat dams are fed on an isoenergetic diet containing just under half the normal protein content are consistent with the ideas put forward. They have also allowed us to refine the hypothesis in the light of the new data as follows: (1) the growth of the fetus (and possibly infant) is quantitatively and qualitatively altered by its nutritional environment (which may include maternal diet-dependent changes in maternal hormones); (2) these changes serve to select between the growth rates of different tissues according to priorities which differ between males and females (nutritional thrift) and to alter organ function to constitute a thrifty offspring adapted to survival in poor nutritional circumstances (thrifty phenotype); (3) an individual so constituted suffers adverse consequences in adult life if he/she experiences good or supranormal nutrition; (4) both poor insulin secretion and insulin resistance can result from these adaptive processes; (5) the adverse consequences include loss of glucose tolerance and hypertension. The precise outcome of growth retardation during early life may vary according to the type and timing of the factors responsible for the retardation. It remains to be determined to what extent these potentially adverse effects can be delayed or prevented by a suitable postnatal diet. Experiments in animal models are largely consistent with the concepts proposed from human epidemiological studies. They show that the metabolism of the liver, muscle and adipose tissue may be programmed by maternal nutrition during gestation and lactation. The combination of early growth restriction and subsequent adult obesity reproduced in the rat are the main features of the insulin resistance syndrome. PMID: 10604194 [PubMed - indexed for MEDLINE] 5464. Proc Nutr Soc. 1999 Aug;58(3):593-607. Targets and procedures for altering ruminant meat and milk lipids. Demeyer D(1), Doreau M. Author information: (1)Department of Animal Production, University of Gent, Melle, Belgium. Daniel.Demeyer@mug.ac.uk Beef and dairy products suffer from a negative health image, related to the nature of their lipid fraction. Rumen lipid metabolism involves the presence of saturated lipids in ruminant tissues. Lipolysis, fatty acid biohydrogenation and formation of microbial fatty acids in the rumen and their effects on rumen outflow of fatty acids are discussed. Special emphasis is given to the formation of trans-fatty acids and the possibilities of decreasing biohydrogenation. Small differences in intestinal digestibilities of fatty acids are mentioned, followed by a discussion on transfer of absorbed fatty acids into milk and adipose tissue lipids. The preferential retention of polyunsaturated fatty acids as well as the balance between synthesis and incorporation of fatty acids in tissues is described. Dietary means for the modification of milk fat are listed, with special emphasis on the possibilities for enrichment in polyunsaturated fatty acids and the presence of conjugated linoleic acids. A description of the nature and development of fat depots in beef cattle is followed by a discussion of breed, conformation and feed effects on adipose tissue distribution and fatty acid composition. Special emphasis is given to the very lean Belgian Blue double-muscled breed. The review ends with a consideration of the limits to the modification of ruminant fats, involving considerations of consumer acceptance as well as animal welfare and environmental effects. PMID: 10604192 [PubMed - indexed for MEDLINE] 5465. An Med Interna. 1999 Oct;16(10):530-40. [Leptin in the endocrinology of obesity]. [Article in Spanish] Sanz París A(1), Guallar Labrador AM, Albero Gamboa R. Author information: (1)Servicio de Endocrinología y Nutrición, Hospital Miguel Servet, Zaragoza. The article summarizes the endocrinology axis in relation to leptin in the obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma leptin levels are elevated in Cushing's syndrome and there is a robust leptin secretory responses to dexamethasone. Obesity impacts on reproductive function in man and women. Leptin levels are higher in women than in men and a critical blood leptin level is necessary to trigger reproductive ability in women. The relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. Obesity is associated with a decrease in growth hormone (GH) and reversible with weight loss. The influence of body composition on GH secretion in the obesity may be mediated through leptin, acting as a peripheral signal from adipose tissue. Thyroid dysfunction appear not associated with alterations in serum leptin levels. There is a significant relationship between insulin and leptin, but it is not immediate, since type 2 diabetics show similar leptin levels to those of nondiabetic humans of the same body mass index. PMID: 10603674 [PubMed - indexed for MEDLINE] 5466. Biochim Biophys Acta. 2000 Jan 3;1483(1):37-57. Mobilisation of triacylglycerol stores. Gibbons GF(1), Islam K, Pease RJ. Author information: (1)Metabolic Research Laboratory, Oxford Lipid Metabolism Group, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford, UK. geoff.gibbons@mrl.ox.ac.uk Triacylglycerol (TAG) is an energy dense substance which is stored by several body tissues, principally adipose tissue and the liver. Utilisation of stored TAG as an energy source requires its mobilisation from these depots and transfer into the blood plasma. The means by which TAG is mobilised differs in adipose tissue and liver although the regulation of lipid metabolism in each of these organs is interdependent and synchronised in an integrated manner. This review deals principally with the mechanism of hepatic TAG mobilisation since this is a rapidly expanding area of research and may have important implications for the regulation of plasma very-low-density lipoprotein metabolism. TAG mobilisation plays an important role in fuel selection in non-hepatic tissues such as cardiac muscle and pancreatic islets and these aspects are also reviewed briefly. Finally, studies of certain rare inherited disorders of neutral lipid storage and mobilisation may provide useful information about the normal enzymology of TAG mobilisation in healthy tissues. PMID: 10601694 [PubMed - indexed for MEDLINE] 5467. Clin Nutr. 1999 Oct;18(5):255-7. TNF-alpha and hypermetabolism in chronic obstructive pulmonary disease. Schols AM. Comment on Clin Nutr. 1999 Oct;18(5):269-74. PMID: 10601531 [PubMed - indexed for MEDLINE] 5468. Clin Pharmacokinet. 1999 Oct;37(4):273-87. Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Tang-Liu DD(1), Matsumoto RM, Usansky JI. Author information: (1)Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, California 92612, USA. tang-liu_diane@allergan.com Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis. PMID: 10554045 [PubMed - indexed for MEDLINE] 5469. Surv Ophthalmol. 1999 Sep-Oct;44(2):173-9. Congenital cystic eye: report of two cases and review of the literature. Hayashi N(1), Repka MX, Ueno H, Iliff NT, Green WR. Author information: (1)The Eye Pathology Laboratory, Wilmer Ophthalmological Institute and Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-9248, USA. A 13-month-old boy and a 2-week-old girl, who were considered to be anophthalmic and who later each developed a cystic lesion in the left orbit with protrusion of the lower eyelid, were studied. The fellow eye in case 1 was subsequently found to be microphthalmic with cyst and was normal in case 2. Histopathologic study of each case revealed a cyst lined externally by dense fibrous connective tissue to which skeletal muscle and adipose tissue were attached. The inner aspect of the cyst was lined by neuroglial tissue, possible immature retinal tissue, and cuboidal epithelium. No fully developed ocular structures or microphthalmos were identified. Fourteen cases of congenital cystic eye, including our cases, have been published in the English-language literature since 1964. We discuss and illustrate the findings in our cases and 10 others in which histopathologic findings were reported. Congenital cystic eye, microphthalmos with cyst, and microphthalmos with cystic teratoma should be suspected in patients with a small or unrecognizable eye and an orbital cystic mass that is detected by palpation or visualization. PMID: 10541156 [PubMed - indexed for MEDLINE] 5470. Diabetes Metab. 1999 Nov;25(5):383-92. Adverse metabolic disorders during highly active antiretroviral treatments (HAART) of HIV disease. Vigouroux C(1), Gharakhanian S, Salhi Y, Nguyên TH, Adda N, Rozenbaum W, Capeau J. Author information: (1)Service de Biochimie, Hôpital Rothschild, Paris, France. capeau@st-antoine.inserm.fr Protease inhibitor treatment has dramatically improved rates of morbidity and mortality in HIV-infected patients. However, it has recently been shown that this medication is associated with long-term side effects characterized by metabolic, clinical and biological alterations. These modifications have been described in patients treated with highly active antiretroviral therapy (HAART), including nucleoside analogue reverse transcriptase inhibitors (NRTI) and generally (but not always) protease inhibitors (PI). Clinical alterations are characterised by a body fat redistribution syndrome or lipodystrophy, with peripheral lipoatrophy and/or central fat accumulation. They are often associated with biological alterations, i.e. insulin resistance, hyperglycaemia and dyslipidaemia, which can also be observed alone. The pathophysiology of these alterations is presently unknown. The deleterious effect of PI on adipose tissue could be direct or indirect, and is probably modulated by genetic or environmental factors. NRTI could also be involved because of their mitochondrial toxicity. The purpose of the treatment is to control metabolic disturbances in order to prevent immediate complications such as acute pancreatitis and limit possible cardiovascular and diabetic complications at longer term. Studies are in progress to evaluate the possibility of therapeutic alternatives to PI when major metabolic disturbances are present. PMID: 10592860 [PubMed - indexed for MEDLINE] 5471. Horm Res. 1999;51 Suppl 3:132-40. Body composition as a clinical endpoint in the treatment of growth hormone deficiency. Haymond MW(1), Sunehag AL, Ellis KJ. Author information: (1)Department of Pediatrics, Children's Nutrition Research Center USDA/ARS, Baylor College of Medicine, Houston, Texas, USA. Endpoints in the treatment and management of adults with growth hormone (GH) deficiency (GHD) can be problematic. Changes in body composition with recombinant human GH (rhGH) treatment may be one of the most objective measures that could be applied in judging the effectiveness and long-term efficacy. The relative strengths and weaknesses of measures of body composition and their potential for clinical utility in the setting of rhGH replacement in GHD in adults are discussed. Measurement of changes in body fat, regardless of the method employed, from pretreatment baseline through 2-6 months of treatment may be quite useful in demonstrating the efficacy of rhGH in each patient. Other changes in body composition are compromised by the imprecision of the measurements, shifts in extracellular water, and the small real changes which occur in bone and muscle in the GHD subject. Use of body composition measures of change in fat content as an endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot be implemented on the basis of current data and would require a carefully designed prospective, controlled study. Until such criteria are established and accepted, endocrinologists must continue to manage these patients purely on the basis of their clinical judgment. Copyright 1999 S. Karger AG, Basel PMID: 10592458 [PubMed - indexed for MEDLINE] 5472. Horm Res. 1999;51 Suppl 3:55-63. A role for leptin in sexual maturation and puberty? Kiess W(1), Reich A, Meyer K, Glasow A, Deutscher J, Klammt J, Yang Y, Müller G, Kratzsch J. Author information: (1)Children's Hospital, University of Leipzig, Germany. Leptin, the ob gene product, is involved in the regulation of body weight in rodents, primates and humans. It provides a molecular basis for the lipostatic theory of the regulation of energy balance. White adipose tissue and placenta are the main sites of leptin synthesis. There is also evidence of ob gene expression in brown fat. Leptin seems to play a key role in the control of body fat stores by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous system regulation and body energy balance. Apart from the function of leptin in the central nervous system on the regulation of energy balance, it may well be one of the hormonal factors that signal to the brain the body's readiness for sexual maturation and reproduction. During late pregnancy and at birth when maternal fat stores have been developed, leptin levels are high. During these developmental stages leptin could be a messenger molecule signalling the adequacy of the fat stores for reproduction and maintenance of pregnancy. At later stages of gestation leptin could signal the expansion of fat stores in order to prepare the expectant mother for the energy requirements of full-term gestation, labour and lactation. Leptin serum concentrations change during pubertal development in rodents, primates and humans. In girls, leptin serum concentrations increase dramatically as pubertal development proceeds. The pubertal rise in leptin levels parallels the increase in body fat mass. In contrast, leptin levels increase shortly before and during the early stages of puberty in boys and decline thereafter. Testosterone has been found to suppress leptin synthesis by adipocytes both in vivo and in vitro. The decline of leptin levels in late puberty in boys accompanies increased androgen production during that time and most likely reflects suppression of leptin by testosterone and a decrease in fat mass and relative increase in muscle mass during late puberty in males. This overview focuses on those topics of leptin research which are of particular interest in reproductive and adolescent medicine. Copyright 1999 S. Karger AG, Basel PMID: 10592445 [PubMed - indexed for MEDLINE] 5473. Med Sci Sports Exerc. 1999 Nov;31(11 Suppl):S568-72. Is abdominal fat preferentially reduced in response to exercise-induced weight loss? Ross R(1), Janssen I. Author information: (1)School of Physical and Health Education, Queen's University, Kingston, Ontario, Canada. rossr@post.queensu.ca PURPOSE: It is known that a preferential deposition of fat in the abdominal region is the obesity phenotype that conveys the greatest health risk. Although physical activity is commonly prescribed to reduce obesity, the influence of exercise-induced weight loss on abdominal fat is unclear. This review was undertaken to clarify whether abdominal fat is preferentially reduced consequent to weight loss induced by regular exercise. METHODS: A literature search (Medline, 1966-1998) was performed using appropriate keywords to identify studies reporting changes in both whole body and abdominal fat in response to exercise. RESULTS: At present there are no randomized controlled trails (RCT) wherein it was clear that exercise alone induced weight loss. For the four RCT within which regular exercise was not associated with weight loss, abdominal fat measured by waist circumference was unchanged. A similar trend is observed for the nonrandomized studies. Abdominal obesity as measured by waist circumference is unchanged for those studies reporting no loss in weight or fat; however, a modest reduction (approximately 3 cm) is observed in response to exercise-induced weight loss of about 3 kg. Without exception, these studies were not designed to determine whether abdominal obesity was preferentially reduced. Absent from the literature are RCT that employ imaging techniques (e.g., computerized tomography or magnetic resonance imaging) to determine whether exercise-induced weight loss is associated with reductions in either visceral or abdominal subcutaneous fat. However, the findings from four nonrandomized or controlled studies report that exercise with or without weight loss is associated with reductions in both visceral and subcutaneous fat. CONCLUSION: There is insufficient evidence to determine whether exercise-induced weight loss is associated with reductions in abdominal fat. Clearly there is a need for carefully controlled studies wherein the primary aim is to determine the influence of regular exercise on total and abdominal adiposity. PMID: 10593530 [PubMed - indexed for MEDLINE] 5474. Med Sci Sports Exerc. 1999 Nov;31(11 Suppl):S564-7. Physical activity and weight gain and fat distribution changes with menopause: current evidence and research issues. Astrup A(1). Author information: (1)Research Department of Human Nutrition and LMC, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark. ast@kvl.dk PURPOSE: At the onset of menopause a woman's body weight reaches its maximum. For any given subsequent body weight there is an increase in relative body fat and abdominal fatness with advancing age. The increased body fatness and abdominal fat distribution are associated with a high incidence of cardiovascular disease and certain cancers, particularly breast cancer. The aim of this analysis was to assess the role of physical activity for weight gain and changes in fat distribution occurring with menopause. METHODS: A systematic review based on a Medline search was conducted. RESULTS: According to cross-sectional observational studies postmenopausal women with high levels of physical activity have lower body fat and abdominal fat. Longitudinal studies show that physically active women are less likely to gain body fat and abdominal fat after menopause than sedentary women (Evidence category C). There are very few randomized controlled trials (RCT) comparing exercise with no intervention, and diet with diet plus exercise, and the results do not allow a firm conclusion as to whether physical activity may prevent or limit the gain of total fat and abdominal fat after menopause, or whether it may be effective as part of an obesity treatment program. CONCLUSIONS: There is a need for RCT to evaluate the effect of increased physical activity and fitness as a tool for prevention of the changes in body composition associated with menopause and aging in normal weight women. The efficiency of different programs of exercise training as a treatment option in postmenopausal women with existing overweight and obesity should be investigated. RCT should have the appropriate design and size and use accurate methods to assess exercise compliance, body composition, and intra-abdominal adipose tissue. PMID: 10593529 [PubMed - indexed for MEDLINE] 5475. Cells Tissues Organs. 1999;165(3-4):173-80. Embryonic stem cell-derived adipogenesis. Dani C(1). Author information: (1)Laboratoire de Biologie du Développement du Tissu Adipeux, Centre de Biochimie (UMR 6543 CNRS), Nice, France. dani@unice.fr Key events leading to terminal differentiation of preadipocytes into adipocytes have been characterized in the recent years. However, master genes that commit progression from multipotent mesenchymal stem cell to the adipoblast stage of development have not yet been identified. The use of embryonic stem (ES) cells as a route to study early events in adipogenesis and to characterize factors involved in the decision of stem cells to follow the adipogenic pathway is described in this paper. The capacity of lif-/- and lifr-/- ES cells to undergo adipocyte differentiation is reported as an application of mutant ES cells to study gene function during the development of adipose cells. Copyright 1999 S. Karger AG, Basel PMID: 10592389 [PubMed - indexed for MEDLINE] 5476. Biochem Biophys Res Commun. 1999 Dec 9;266(1):1-4. Regulation of stearoyl-CoA desaturase genes: role in cellular metabolism and preadipocyte differentiation. Kim YC(1), Ntambi JM. Author information: (1)Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 53706, USA. The degree of fatty acid unsaturation in cell membrane lipids determines membrane fluidity, whose alteration has been implicated in a variety of disease states including diabetes, obesity, hypertension, cancer, and neurological and heart diseases. Stearoyl-CoA desaturase (SCD) is a key rate-limiting enzyme in the synthesis of unsaturated fatty acids by insertion of a cis-double bond in the Delta9 position of fatty acid substrates. Palmitate and stearate are the preferred substrates, which are converted to palmitoleate and oleate, respectively. These monounsaturated fatty acids are the major constituents of cellular membrane phospholipids and triacylglycerol stores found in adipose tissue. Two mouse and rat SCD genes (SCD1 and SCD2) have been cloned and characterized. During the differentiation of 3T3-L1 preadipocytes into adipocytes, SCD1 and SCD2 mRNAs are induced concomitant with increased de novo synthesis of palmitoleate and oleate. The physiological significance of expressing the two isoforms in the adipocytes is currently unknown. In this review we discuss the role of the SCD isoforms in metabolism and the recent findings on the differential regulation of mouse SCD genes by the antidiabetic thiazolidinediones (TZDs), during preadipocyte differentiation. Copyright 1999 Academic Press. PMID: 10581155 [PubMed - indexed for MEDLINE] 5477. FEBS Lett. 1999 Nov 26;462(1-2):1-6. Lipoprotein lipase, a key role in atherosclerosis? Mead JR(1), Cryer A, Ramji DP. Author information: (1)Cardiff School of Biosciences, Cardiff University, Museum Avenue, P. O. Box 911, Cardiff, UK. Lipoprotein lipase (LPL) plays a central role in lipid metabolism and transport by catalysing the hydrolysis of triacylglycerol-rich lipoproteins. The importance of LPL expressed by the adipose tissue and muscles in the provision of non-esterified fatty acids and 2-monoacylglycerol for tissue utilisation is well established. However, recent studies on LPL expressed by cells of the vascular wall, particularly macrophages, have identified additional actions of the enzyme that contribute to the promotion of foam cell formation and atherosclerosis. This review deals with the role of LPL in atherosclerosis, and its regulation by mediators that are known to be present in the lesion. PMID: 10580081 [PubMed - indexed for MEDLINE] 5478. Int J Obes Relat Metab Disord. 1999 Nov;23(11):1105-17. Gluttony and thermogenesis revisited. Stock MJ(1). Author information: (1)Department of Physiology, St George's Hospital Medical School, University of London, London SW17 0RE, UK. m.stock@sghm.ac.uk The evolutionary and biological significance of adaptive, homeostatic forms of heat production (thermogenesis) is reviewed. After summarizing the role and selective value of thermogenesis in body temperature regulation (shivering and non-shivering thermogenesis) and the febrile response to infection (fever), the review concentrates on diet-induced thermogenesis (DIT). Animal studies indicate that DIT evolved mainly to deal with nutrient-deficient or unbalanced diets, and re-analysis of twelve overfeeding studies carried out between 1967 and 1999 suggests the same may be so for humans, particularly when dietary protein concentration is varied. This implies that the role of DIT in the regulation of energy balance is secondary to its function in regulating the metabolic supply of essential nutrients. However, individual differences in DIT are much more marked when high- or low-protein diets are overfed, and this could provide a very sensitive method for discriminating between those who are, in metabolic terms, resistant and those who are susceptible to obesity. PMID: 10578199 [PubMed - indexed for MEDLINE] 5479. Drugs. 1999;58 Suppl 1:13-8; discussion 75-82. Visceral obesity and diabetes. Björntorp P(1), Rosmond R. Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, Sweden. Visceral obesity is a strong predictor of type 2 (non-insulin-dependent) diabetes and is associated with insulin resistance. In addition, research has indicated that the accumulation of visceral fat is regulated by endocrine mechanisms. Data suggest that progressive malfunction of the hypothalamic-pituitary-adrenal (HPA) axis, with elevation of levels of cortisol and reductions in levels of sex steroids and growth hormone, is associated with visceral accumulation of fat that contributes to circulating levels of free fatty acids, and that these factors are implicated in the development of insulin resistance. Furthermore, failure of central feedback control of the HPA axis by glucocorticoid receptors (GR) appears to be correlated with polymorphisms near the first exons of the GR gene. The HPA axis disturbances are similar to those seen after prolonged exposure to environmental stress. Psychosocial and socioeconomic factors, alcohol, depressive traits and anxiety are linked to HPA axis abnormalities. PMID: 10576519 [PubMed - indexed for MEDLINE] 5480. J Dairy Sci. 1999 Nov;82(11):2259-73. ADSA Foundation Scholar Award. Biology of dairy cows during the transition period: the final frontier? Drackley JK(1). Author information: (1)Department of Animal Sciences, University of Illinois, Urbana 61801, USA. The transition period, from 3 wk before to 3 wk after parturition, is critically important to health, production, and profitability of dairy cows. Most health disorders occur during this time. Compared with other stages of the lactation cycle, relatively little is known about fundamental biological processes during the transition period. The regulation and coordination of lipid metabolism among adipose tissue, liver, gut, and mammary gland are key components of the adaptations to lactation. Lipid accumulation in liver may contribute to health disorders and decreased milk production. Knowledge of key control points in hepatic metabolism of long-chain fatty acids is lacking, as is an understanding of the metabolic effects of hormones, growth factors, and cytokines that mediate stress. Recent evidence indicates that supplemental fats or restricted intakes before parturition can induce a coordinated set of metabolic changes in metabolism of long-chain fatty acids, including peroxisomal beta-oxidation, perhaps mediated by peroxisome proliferator-activated receptors. Estimates of the mixture of fuels constituting metabolizable energy in cows during the early postpartum period suggest that supply of amino acids and glucogenic compounds may be under proposed optima, whereas ketogenic and lipogenic compounds and long-chain fatty acids may be in excess. Because dietary fat does not suppress body lipid mobilization, during the early postpartum period supplemental fat may further imbalance the mixture of fuels and lead to decreased dry matter intake. Increased understanding of the biology of the transition period should decrease health problems and increase profitability of dairy cows. PMID: 10575597 [PubMed - indexed for MEDLINE] 5481. Diagn Cytopathol. 1999 Dec;21(6):409-12. Fine-needle aspiration cytology of adrenal myelolipoma: case report and review of the literature. Settakorn J(1), Sirivanichai C, Rangdaeng S, Chaiwun B. Author information: (1)Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Adrenal myelolipoma is a rare nonfunctioning tumor consisting histologically of an admixture of adipose tissue and extramedullary hemopoietic elements within the adrenal glands. Less than 300 cases have been reported in the literature and only 15 case reports have described cytological findings of this tumor obtained by fine-needle aspiration (FNA). We report a case of a 48-year-old male who had had anaplastic large cell carcinoma of the right lung. The left adrenal mass was encountered during a staging workup that led to a clinical suspicion of metastatic disease to the adrenal gland. FNA under computed tomography (CT) guidance was performed obtaining cytological material from which diagnosis of myelolipoma was made. The findings reemphasized an important role of FNA in investigation of adrenal mass. The literature on FNA cytology of adrenal myelolipoma is reviewed. Diagn. Cytopathol. 1999;21:409-412. Copyright 1999 Wiley-Liss, Inc. PMID: 10572274 [PubMed - indexed for MEDLINE] 5482. Can J Appl Physiol. 1999 Oct;24(5):393-415. Dietary carbohydrate and its effects on metabolism and substrate stores in sedentary and active individuals. Graham TE(1), Adamo KB. Author information: (1)Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario. This review of carbohydrate (CHO) ingestion and exercise addresses three major issues: (a) how CHO ingestion influences CHO and fat stores, (b) how exercise, by changing CHO stores, alters the responses to CHO or fat ingestion, and (c) the roles of CHO in exercise performance and metabolism. Dietary manipulation is not a simple issue; increasing the dietary content of any specific nutrient alters the entire diet composition. High CHO diets are often low fat diets, hence changing the metabolism and storage of both fat and CHO. Acute CHO ingestion increases CHO oxidation and the "spared" fats are deposited as fat. Chronic high CHO ingestion (without an active lifestyle) leads to muscle becoming insulin-insensitive, adipose tissue processing CHO to fatty acids, and the liver increasing production of VLDL triglycerides. CHO ingestion prior to and during prolonged exercise can increase endurance. It has been suggested that moderate or low glycemic index forms be used prior to and during the exercise, but there is no consensus as to whether it should be a recommendation. The physiological nature of the regulation of CHO stores is poorly understood, but the recent identification of a key enzyme, glycogenin, and two forms of glycogen (pro- and macroglycogen) show promise of a deeper understanding. PMID: 10566104 [PubMed - indexed for MEDLINE] 5483. Curr Opin Clin Nutr Metab Care. 1998 Jul;1(4):323-8. Glucose regulation of gene expression. Foufelle F(1), Girard J, Ferré P. Author information: (1)U465 INSERM, Centre Biomédical des Cordeliers, Paris, France. Regulation of gene expression by nutrients in mammals is an important mechanism allowing them to adapt to the nutritional environment. In-vivo and in-vitro experiments have demonstrated that the transcription of genes coding for lipogenic and glycolytic enzymes in liver and/or adipose tissue is upregulated by glucose. In order for glucose to act as a gene inducer, it must be metabolized. Recent evidence suggests that glucose-6-phosphate is the signal metabolite in the liver. DNA glucose response elements have been characterized and they have in common the presence of two sequences 5'-CACGTG-3' separated by five nucleotides, which bind in vitro a transcription factor of the basic domain, helix-loop-helix, leucine zipper family called USF/MLTF. Experiments concerning the potential role of USF/MLTF in the glucose response have led to opposite results, suggesting that USF/MLTF might not be the only factor involved. Finally, the glucose effect involves a kinase/phosphatase system. The kinase could be the AMP-activated protein kinase, the mammalian analogue of a yeast kinase, or SNF 1 which is important for the derepression of glucose-inhibited genes. PMID: 10565368 [PubMed - indexed for MEDLINE] 5484. Curr Opin Clin Nutr Metab Care. 1998 May;1(3):253-6. New cachexic factors. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Institute, Aston University, Birmingham, UK. Patients with pancreatic cancer show evidence of cachexia at the time of diagnosis, involving not only loss of adipose tissue, but also lean body mass. The shorter survival time of men than women with non-small cell lung cancer has been attributed to their enhanced rate of weight loss. From studies in animal models, various cytokines have been proposed as mediators of the cachectic process, although evidence from human studies is generally lacking. Only serum levels of IL-6 have been found to correlate with the clinical development of cachexia, but this may be a marker for the process rather than the actual mediator, because the direct administration of this cytokine to experimental animals failed to induce cachexia, despite the induction of an acute-phase response. Ciliary neurotrophic factor, a member of the IL-6 superfamily, has, however, been shown to produce loss of muscle mass in experimental animals, although it failed to exert a direct catabolic effect on muscle in vitro. A sulphated glycoprotein found in the urine of patients with cancer cachexia is capable of directly inducing protein catabolism in skeletal muscle by a process involving an increase in prostaglandin E2. Agents capable of attenuating this effect, e.g. eicosapentaenoic acid and ibuprofen, have been shown to stabilize body weight loss in cachectic cancer patients. This pharmacological approach to the treatment of cachexia appears to be more successful than nutritional manipulation. PMID: 10565357 [PubMed - indexed for MEDLINE] 5485. Cell. 1999 Oct 29;99(3):239-42. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Lowell BB(1). Author information: (1)Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachussetts 02115, USA. PMID: 10555139 [PubMed - indexed for MEDLINE] 5486. Przegl Lek. 1999;56(5):362-71. [Menopause and hormone replacement therapy (HRT) in women with diabetes]. [Article in Polish] Cyganek K(1). Author information: (1)Katedry i Kliniki Chorób Metabolicznych CMUJ w Krakowie. This review is based on publications from 1996-1998 concerned research into hormone replacement therapy (HRT) estimated effect on metabolic factors in diabetic women. Coronary heart disease (CHD) and myocardial infarction are the main reasons of death in postmenopausal women. Evidence from many observational studies suggests that estrogen replacement therapy diminishes the mortality of healthy women due to CHD. Diabetes mellitus is an independent risk factor of CHD. The results of research show that estrogen replacement therapy decreases the death risk of myocardial infarction in diabetic women, too. Transdermal estrogens have beneficial effect on carbohydrate metabolism, attenuate glycemic control and decrease insulin resistance. We can observe favourable changes in fat distribution resulting in decreasing abdominal obesity. Diabetic women do not appear to experience as great changes in lipid profile response with HRT as do non-diabetic women. Women with diabetes had proportionally lower hormone-related decrease in total cholesterol and LDL cholesterol levels and increased HDL cholesterol level. The extent to which the beneficial effect of estrogen on lipoproteins is reversed depends on the type and dose of progestin added. Now, using HRT as secondary prevention of CHD in diabetic women, after consideration of an individual risk factor is recommended. We recommend preparations of 17 beta-estradiol administered transdermally and selected gestagens like dydrogesterone, norethisterone, medroxyprogesterone in small dosage. PMID: 10554574 [PubMed - indexed for MEDLINE] 5487. Clin Plast Surg. 1999 Jul;26(3):447-61. The physics of soft tissue fragmentation using ultrasonic frequency vibration of metal probes. Cimino WW(1). Author information: (1)Sound Surgical Technologies LLC, Lafayette, Colorado, USA. The physics of soft tissue fragmentation using ultrasonic frequency vibration of metal probes has been discussed, including a comparison and contrast of ultrasound radiation and ultrasonic surgery and a brief history of ultrasonic surgery. Three theories of interaction and an assessment of power flow have been presented. Many unanswered questions remain concerning the physics of soft tissue fragmentation using ultrasonic frequency vibratory energy. This effort has hopefully contributed to a better understanding of the general principles involved. PMID: 10549443 [PubMed - indexed for MEDLINE] 5488. Curr Biol. 1999 Oct 21;9(20):R767-9. Adaptive thermogenesis: orchestrating mitochondrial biogenesis. Butow RA(1), Bahassi EM. Author information: (1)Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9148, USA. butow@swmed.edu The biogenesis of mitochondria requires products of the nuclear and mitochondrial genomes. Recent studies of adaptive thermogenesis have shown how mitochondrial proliferation and respiratory activity in brown fat and skeletal muscle are directed by the transcriptional coactivator PGC-1. PMID: 10531019 [PubMed - indexed for MEDLINE] 5489. Gerodontology. 1998;15(1):15-24. Exercise and nutritional needs of elderly people: effects on muscle and bone. Evans WJ(1). Author information: (1)Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, USA. evanswilliamj@exchange.uams.edu Advancing age is associated with a remarkable number of changes in body composition. Reductions in lean body mass have been well characterized. This decreased lean body mass occurs primarily as a result of losses in skeletal muscle mass. This age-related loss in muscle mass has been termed sarcopenia. Loss in muscle mass accounts for the age-associated decreases in basal metabolic rate, muscle strength, and activity levels, which, in turn is the cause of the decreased energy requirements of the elderly. In sedentary individuals, the main determinant of energy expenditure is fat-free mass, which declines by about 15% between the third and eighth decade of life. It also appears that declining caloric needs are not matched by an appropriate decline in caloric intake, with the ultimate result an increased body fat content with advancing age. Increased body fatness along with increased abdominal obesity are thought to be directly linked to the greatly increased incidence of Type II diabetes among the elderly. This review will discuss the extent to which regularly performed exercise can effect nutritional needs and functional capacity in the elderly. In addition, some basic guidelines for beginning an exercise program for older men and women, and establishing community-based programs are provided. PMID: 10530167 [PubMed - indexed for MEDLINE] 5490. Domest Anim Endocrinol. 1999 Oct;17(2-3):257-67. Regulation of porcine adipogenesis in vitro, as compared with other species. Boone C(1), Grégoire F, Remacle C. Author information: (1)Laboratoire de Biologie Cellulaire, Unité de Biologie Animale (BANI), Faculté des Sciences, Université Catholique de Louvain, Louvain-la-Neuve, Belgium. Boone@bani.ucl.ac.be In vitro studies, mostly performed on murine cell lines, allowed us to identify the role played by hormonal agents, second-messenger pathways, extracellular matrix proteins, and transcription factors in adipose conversion. Some information has also been reported when studies were conducted on primary cultures that originated from various species. However, because of conflicting results, probably caused, at least in part, by species specificity, developing cultures of preadipose cells from economically important species appeared necessary to better understand and control the animals' fat development. We reviewed our current knowledge concerning the regulation of cultured porcine preadipose cells by hormones, second-messenger pathways, and extracellular matrix proteins. The results clearly demonstrate that such primary cultures are essential to avoid the establishment of hazardous concepts originated from rodent and aneuploid cell lines in particular. PMID: 10527128 [PubMed - indexed for MEDLINE] 5491. Domest Anim Endocrinol. 1999 Oct;17(2-3):245-55. The role of the somatotrophic axis in the metabolism of the chicken. Buyse J(1), Decuypere E. Author information: (1)Laboratory of Physiology and Immunology of Domestic Animals, Faculty of Agricultural and Applied Biological Sciences, Catholic University of Leuven, Heverlee, Belgium. johan.buyse@agr.kuleuven.ac.be As it is for mammalian species, growth hormone (GH) is indispensable for normal growth and development of avian species. In contrast to mammals, exogenous GH administration has little, if any, potential for improving the growth rate and feed efficiency of rapidly growing broilers; it is more likely to do so in older birds. This is at least partly because of age-related changes in tissue GH-binding activity and GH-receptor mRNA expression. The effects of GH on lipid deposition depends on the age of the bird and pattern of GH administration. Pulsatile, but not continuous, GH administration to older broilers seems to reduce fat deposition. As in rats, the bioactivity of GH might also depend on the pulse-induced cyclicity in GH receptors and GH-binding proteins. In chickens, GH is also a very potent lipolytic hormone, but seems to have no diabetogenic effect, which is reported in mammalian species. Both insulin-like growth factors have apparently no growth-promoting effects in normal growing broilers, but seem to have opposite effects on fat deposition. In contrast to GH, both insulin-like growth factors have a marked hypoglycemic effect. Whether all these effects are direct effects, or are mediated by secondary mechanisms, awaits further investigations. PMID: 10527127 [PubMed - indexed for MEDLINE] 5492. Ann Endocrinol (Paris). 1999 Sep;60(3):188-96. [Insulin resistance: therapeutic approaches]. [Article in French] Gin H(1), Rigalleau V. Author information: (1)Service de Nutrition Diabétologie et Maladies Métaboliques Hôpital Haut-Lévêque, USN, Pessac. NIDDM is characterized by a decrease in insulin sensitivity of the liver, the muscles and adipocytes. Diet, exercise and control of excess body weight are the first step of the treatment; they are even able to prevent NIDDM. In this paper the drugs that may improve insulin sensitivity are described with their different specific action on liver, muscles, or adipocytes. Drugs from the thiazolidinedione class act by enhancing the sensitivity to insulin of adipose tissue; they are high-affinity ligands for peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2 being the predominant form expressed in adipocytes) Hepatotoxicity and weight gain are sides effects of thiazolidinedione. Acipimox (a nicotinic acid analogue) is a NEFA lowering drug that suppress lipolysis, but after a few days of utilisation there is a compensatory free fatty acid rise. Recent data on Metformin action on hepatic insulin sensitivity are discussed and combination with Troglitazone is presented. Vanadyl sulfate may also improve insulin sensitivity but there is no long term human studies. PMID: 10520409 [PubMed - indexed for MEDLINE] 5493. Ann Endocrinol (Paris). 1999 Sep;60(3):167-74. [Metabolic and trophic role of catecholamines in the development of white adipose tissue]. [Article in French] Valet P(1), Saulnier-Blache JS. Author information: (1)INSERM U317, CHU Rangueil, Université Paul-Sabatier, Toulouse. The fat cell is of key significance to the physiologist investigating the mechanisms controlling lipid storage, mobilization and utilization as well as other functions of the adipose tissue. Insulin and catecholamines are the major hormonal regulators of lipolysis. Four adrenoceptor subtypes are involved in the adrenergic regulation of fat cell lipolysis. The control of adenylyl cyclase activity involves stimulatory beta 1-, beta 2- and beta 3-adrenergic receptors and inhibitory alpha 2-adrenergic receptors. Their control of lipolysis is subjected to variations according to the anatomical localization of adipose tissue deposits. In humans, lipolysis differs in visceral and subcutaneous deposits. Changes in beta- and alpha 2-adrenoceptor ratios and function have been proposed to explain the lipolytic disturbances. Human and rodent white adipocytes differ dramatically with respect to the balance between alpha 2 and b-adrenergic receptors. Human adipocytes express mainly alpha 2 and few b3-adrenergic receptors while the reverse is true for rodent adipocytes. Preadipocyte alpha 2-adrenergic receptor stimulation initiates proliferation mediated by MAPkinase activation and cytoskeleton re-arrangements. We have generated transgenic mice on a b3-adrenergic receptor gene knock-out background which express human alpha 2-adrenergic receptors selectively in white and brown fat cells by using an adipocyte-specific promoter. No phenotype was noticed in the mice fed with a standard diet, by contrast a large increase in body weight was observed when the animals are fed with a high fat diet. The weight gain concerns fat deposits and is mainly characterized by a large increase in fat cell number. This phenotype is due to an interaction between two genes and the diet since the unique combination of a high fat diet, absence of b3-adrenergic receptors and presence of alpha 2-adrenergic receptors promotes hyperplastic development of fat deposits and increased weight gain. PMID: 10520405 [PubMed - indexed for MEDLINE] 5494. Clin Chim Acta. 1999 Aug;286(1-2):181-90. Cell surface receptors, nuclear receptors and ligands that regulate adipose tissue development. Ailhaud G(1). Author information: (1)Laboratoire de Biologie du Développement du Tissu Adipeux, Centre de Biochimie (UMR 6543 CNRS), UNSA, Faculté des Sciences, Nice, France. ailhaud@unice.fr Our knowledge of adipose tissue development has increased dramatically over the last two decades, through a combination of in vitro studies using cellular models and in vivo studies using mouse models with invalidated target genes. Critical early events of the differentiation programme appear to involve in preadipose cells (i) the entry of fatty acids and the production of fatty acid metabolites as activators/ligands of nuclear peroxisome proliferator-activated receptors (PPARs) and (ii) the very early expression of PPARdelta and CAAT/enhancer binding proteins (C/EBPs) beta and delta. Among fatty acids, prostacyclin produced from arachidonic acid enhances the expression of both C/EBPs through cell surface IP receptor and presumably activates PPARdelta. Together, these transcription factors up-regulate the expression of PPARgamma and C/EBPalpha which lead in turn to the acquisition of the adipocyte phenotype. Altogether, these studies have provided a molecular link between high-fat diets and excess of adipose tissue development through hyperplasia and hypertrophy. PMID: 10511291 [PubMed - indexed for MEDLINE] 5495. Clin Chim Acta. 1999 Aug;286(1-2):163-80. Regulation of Plasma fatty acid metabolism. Saleh J(1), Sniderman AD, Cianflone K. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Montreal, PQ, Canada. Although adipose tissue serves a crucial function in energy storage, excess adipose tissue--that is, obesity--is often associated with diabetes and cardiovascular disease. A common thread in the weave of complications is increased plasma concentrations of fatty acids. In the present review, we have focused on two specific points that relate to obesity: (i) What are the metabolic consequences of increased free fatty acid concentrations? and (ii) What are the physiological factors that are involved in the regulation of fatty acid uptake or release from adipose tissue? We have tried to emphasize new factors that act as hormones on adipose tissue and in so doing regulate the net concentration of circulating free fatty acids. PMID: 10511290 [PubMed - indexed for MEDLINE] 5496. Obes Res. 1999 Sep;7(5):506-14. The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity. Moussa NM(1), Claycombe KJ. Author information: (1)Department of Nutrition and Agricultural Experiment Station, University of Tennessee, Knoxville 37996-1900, USA. moustaid@utk.edu The yellow mouse obesity syndrome is due to dominant mutations at the Agouti locus, which is characterized by obesity, hyperinsulinemia, insulin resistance, hyperglycemia, hyperleptinemia, increased linear growth, and yellow coat color. This syndrome is caused by ectopic expression of Agouti in multiple tissues. Mechanisms of Agouti action in obesity seem to involve, at least in part, competitive melanocortin antagonism. Both central and peripheral effects have been implicated in Agouti-induced obesity. An Agouti-Related Protein (AGRP) has been described recently. It has been shown to be expressed in mice hypothalamus and to act similarly to agouti as a potent antagonist to central melanocortin receptor MC4-R, suggesting that AGRP is an endogenous MC4-R ligand. Mice lacking MC4-R become hyperphagic and develop obesity, implying that agouti may lead to obesity by interfering with MC4-R signaling in the brain and consequently regulating food intake. Furthermore, food intake is inhibited by intracerebroventricular injection of a potent melanocortin agonist and was reversed by administration of an MC4-R antagonist. The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca(2+)-dependent mechanism. Agouti and insulin act in an additive manner to increase lipogenesis. This additive effect of agouti and insulin is demonstrated by the necessity of insulin in eliciting weight gain in transgenic mice expressing agouti specifically in adipose tissue. This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity. The roles of melanocortin receptors or agouti-specific receptor(s) in agouti regulation of adipocyte metabolism and other peripheral effects remain to be determined. In conclusion, both central and peripheral actions of agouti contribute to the yellow mouse obesity syndrome and this action is mediated at least in part by antagonism with melanocortin receptors and/or regulation of intracellular calcium. PMID: 10509609 [PubMed - indexed for MEDLINE] 5497. Int J Androl. 1999 Oct;22(5):300-6. Testosterone replacement therapy in older adult men. Tenover JL(1). Author information: (1)Wesley Woods Center of Emory University, Atlanta, GA 30329, USA. Serum testosterone levels decline slowly with normal ageing in men and, although all men are not destined to become hypogonadal as they age, the prevalence of androgen deficiency in the older male is not insignificant. Over the past several decades, there has been an increasing interest in evaluating whether testosterone therapy (male HRT) might be beneficial for certain older men in preventing or reversing some aspects of ageing. The major androgen target organs of interest with regard to beneficial effects of male HRT include bone, muscle, adipose tissue, the cardiovascular system and the central nervous system (libido and aspects of mood). At the same time, potential adverse effects of male HRT on target organs such as the prostate continue to be evaluated. It is the purpose of this review to summarize the information to date with regard to testosterone replacement therapy in the older man and to discuss areas where more research and clinical information need to be forthcoming. Hormonal replacement therapy (HRT) for post-menopausal women has been studied and discussed for many years. The idea of male HRT, however, is a relatively recent development, with increasing interest in this area occurring only over the past two decades. Reasons for this nascent enthusiasm include burgeoning evidence that testosterone levels decline with normal male ageing (and with age-associated diseases) and an interest in preventing age-related dysfunction and prolonging quality life among an ever increasing population of older adults. The decline in testosterone with age often parallels unfavourable changes in organs upon which androgens act and the goal of male HRT would be to prevent, stabilize or even reverse some of these detrimental target-organ changes. PMID: 10509230 [PubMed - indexed for MEDLINE] 5498. J Lipid Res. 1999 Oct;40(10):1735-46. Monogenic disorders of obesity and body fat distribution. Chen D(1), Garg A. Author information: (1)Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75235-9052, USA. Recently, great progress has been made towards understanding the molecular basis of body fat regulation. Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) gamma2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future. PMID: 10508193 [PubMed - indexed for MEDLINE] 5499. J Emerg Med. 1999 Sep-Oct;17(5):827-32. Epiploic appendagitis: a new diagnosis for the emergency physician. Two case reports and a review. Vinson DR(1). Author information: (1)Department of Emergency Medicine, Madigan Army Medical Center, Tacoma, Washington, USA. Two cases of epiploic appendagitis are presented. One was mistaken for acute appendicitis, the other for acute diverticulitis. In both cases, the correct diagnosis was made in the operating suite. With the aid of contemporary imaging modalities, however, the diagnosis of epiploic appendagitis need no longer hinge on the pathologic specimen but may be established by the emergency physician. As this disorder recently has been demonstrated to be predominantly self-limited, laparotomy no longer is considered necessary. Conservative management has been shown to be safe. The anatomy, pathophysiology, clinical presentation, radiologic evaluation, and emergency management of epiploic appendagitis are reviewed. PMID: 10499697 [PubMed - indexed for MEDLINE] 5500. Cent Eur J Public Health. 1999 Aug;7(3):122-9. Ischaemic heart disease as an effect of obesity-related metabolic disturbances. Indulski JA(1), Lutz W. Author information: (1)Nofer Institute of Occupational Medicine, Lodz, Poland. janus@porta.imp.lodz.pl Obesity results from excessive accumulation of fats in adipose tissue and constitutes one of the essential sources of increased incidence of some diseases harassing the highly industrialized and urbanized societies. Obesity-related metabolic disorders may be associated with the risk of circulatory diseases. The mechanism causing that obesity enhances the incidence of the metabolic disorders have not been explained to the full extent. Hyperinsulinaemia is one of effects of obesity and of the associated presence of excessive blood fatty acid levels. Overloading of the organism with fatty acids changes the function pancreatic beta cells. Insulin resistance and hyperglycaemia caused by high peripheral fatty acid levels trigger increased insulin secretion. Hyperinsulinaemia affects hepatic metabolism so as to make it hyperanabolic. Liver increases triacylglycerol and cholesterol synthesis and raises the rate of very low density lipoproteins (VLDL) secretion to the blood. Increased VLDL concentration contributes to increased LDL and is associated with reduced HDL cholesterol concentrations. Atherogenic dyslipidemia in obese people results, to a large extent, from increased VLDL secretion. Data collected heretofore point to an undoubtedly essential role of the adipose tissue in the pathogenesis of metabolic disorders in obese people. There are many causes of disturbed adipose tissue function which result in high blood fatty acid levels, excessive fat accumulation in other tissues and organs, or both. Another factor which may aggravate the metabolic disorders is the diet. It is worth noting that genetic determinants may cause that some individuals reveal a specified set of factors increasing the risk of ischaemic heart disease. PMID: 10499142 [PubMed - indexed for MEDLINE] 5501. Cancer Res. 1999 Sep 15;59(18):4493-501. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Inui A(1). Author information: (1)Second Department of Internal Medicine, Kobe University School of Medicine, Japan. inui@med.kobe-u.ac.jp Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown. PMID: 10493494 [PubMed - indexed for MEDLINE] 5502. Bratisl Lek Listy. 1999 Jan;100(1):28-35. [Biochemical markers of fibrogenesis in liver diseases]. [Article in Slovak] Szántová M(1), Kupcová V. Author information: (1)III. interná klinika, Lekárskej fakulty, Univerzizy Komenského v Bratislave. Chronic liver disease evaluation is a very complicated process requiring complex assessment of numerous liver functions. In addition to standard methods of investigation we perform biotransformation liver tests for evaluation of microsome enzyme system. Markers of fibrogenesis represent modern noninvasive tests for fibrotic liver process detection in different diseases. The key role in the process of fibrogenesis have the adipose liver cells (ITO cells) producing collagen I, III, IV and lamilin. These cells may be transformed into myofibroblasts-like cells under specific conditions. Kupffer cells and monocytes produce substances stimulating the proliferation and transformation of liver ITO cells as also proteoglycans and hyaluronic acid synthesis. Mediators of this fibrogenetic activity are platelet derived growth factor (PDGF), transforming growth factors alpha and beta, lymphokines and monokines released by T-lymphocytes and macrophages, interleukin 1-alpha and interferon-tau. Acetaldehyde and its metabolites are important stimulators of collagen production by liver fibroblasts. The most often used markers of hepatic fibrogenesis are the following: procollagen III peptide, procollagen IV. type (one of its end carboxypeptide chains is determined-either with 7s collagen or NC1), hyaluronic acid, fibronectin, tenascine and unduline. As the most sensitive markers of fibrinogenesis are considered: hyaluronic acid, laminine, procollagen IV. type. Less often used are enzymes participating in collagen synthesis: prolyl-4-hydroxylase,lysyl-hydroxylase, galactosyl-hydroxylysyl-glucosyl-transferase, monoaminooxidase and N-acetyl-beta-D-glucoseaminidase. Breakdown of collagen is a multienzymatic process, catalysed by collagenases and other proteolytic enzymes. Decreased activity of collagenase is a supporting factor of cirrhosis development. Cirrhosis may be connected also with the levels of inhibitors such as e.g. serum/tissue? inhibitor of metalloproteinase. Biochemical markers of fibrogenesis are useful in regular monitoring of disease development and treatment effectivness and should be an inseparable part of progression assessment in all chronic hepatopathies. (Fig. 3, Ref. 49.) PMID: 10492995 [PubMed - indexed for MEDLINE] 5503. Am J Hum Genet. 1999 Oct;65(4):959-65. STAT5 signaling in sexually dimorphic gene expression and growth patterns. Davey HW(1), Wilkins RJ, Waxman DJ. Author information: (1)AgResearch, Ruakura Research Centre, Hamilton, New Zealand. daveyh@agresearch.cri.nz The past 10 years have seen enormous advances in our understanding of how cytokine signals are mediated intracellularly. Of particular significance was the discovery of a family of seven Signal Transducer and Activators of Transcription (STAT) proteins. Each of these has now been studied in detail, and appropriate gene-disrupted mouse models are available for all except STAT2 (Leonard and O'Shea 1998). Fetal lethality is observed in Stat3-deficient mice, and various immunodeficiencies characterize mice with disrupted Stat1, Stat4, and Stat6 genes, which is consistent with impaired signaling from the specific cytokines that activate each of these proteins. The recent characterization of Stat5-deficient mice has led to several unanticipated findings that point to diverse biological functions for the two STAT5 forms, STAT5a and STAT5b. These include roles for one or both STAT5 forms in the immune system, hematopoiesis, sexually dimorphic growth, mammary development, hair growth, deposition of adipose tissue, and pregnancy. Here we review the hormone- and cytokine-activated signaling pathways in which STAT5 participates and the extensive evidence, from laboratory animals, that these factors are required for sex-specific aspects of development, including control of body size. Finally, we consider human growth disorders that may involve defects in STAT5-dependent signal transduction. PMCID: PMC1288266 PMID: 10486314 [PubMed - indexed for MEDLINE] 5504. Prostaglandins Leukot Essent Fatty Acids. 1999 May-Jun;60(5-6):383-6. Prostacyclin as a critical prostanoid in adipogenesis. Négrel R(1). Author information: (1)Laboratoire de Biologie du Développement du Tissu Adipeux, CNRS UMR 6543, Faculté des Sciences, Université de Nice - Sophia Antipolis Parc Valrose, Nice, France. negrel@unice.fr Adipose cell differentiation from adipoblasts to preadipose and to adipose cells is a multistep process. Terminal differentiation of preadipose cells expressing early markers to adipose cells expressing late and very late markers and accumulating triacylglycerol requires a combination of circulating and locally-produced hormones. Prostacyclin (PGI2), one of the major metabolites of arachidonic acid in adipose tissue, has been shown to exert autocrine and paracrine adipogenic effects in vitro. As discussed herein, multiple arguments support the proposition that PGI2 is a key prostanoid involved in adipogenesis. PMID: 10471126 [PubMed - indexed for MEDLINE] 5505. Can J Appl Physiol. 1999 Aug;24(4):317-36. Leptin and reproduction: is it a critical link between adipose tissue, nutrition, and reproduction? Thong FS(1), Graham TE. Author information: (1)Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario. Exercise-associated reproductive disorders are frequently reported among recreationally active and elite female athletes. Although an association between exercise and menstrual disorders has been established, the mechanism by which exercise disrupts reproductive function remains unknown. Recent findings suggest that low energy availability rather than inadequate body fatness or exercise stress is likely the mechanism by which exercise impinges negatively on the hypothalamic-pituitary-ovarian axis in female athletes. The peripheral signal that informs the neural network of energy availability remains unknown. The identification of the adipocyte-derived ob gene product, leptin, and subsequent findings of its association with reproduction in both rodents and humans, led to speculations that it may be involved in the interactions between nutrition and reproduction. This review article focuses on leptin's role in modulating reproduction, and in particular, as a peripheral signal of nutritional status that integrates adipose tissue, nutrition, and reproduction in female athletes. PMID: 10470449 [PubMed - indexed for MEDLINE] 5506. Proc Nutr Soc. 1999 May;58(2):459-68. Optimal nutrition: vitamin E. Morrissey PA(1), Sheehy PJ. Author information: (1)Department of Nutrition, University College, Cork, Republic of Ireland. p.morrissey@ucc.ie Interest in the role of vitamin E in disease prevention has encouraged the search for reliable indices of vitamin E status. Most studies in human subjects make use of static markers, usually alpha-tocopherol concentrations in plasma or serum. Plasma or serum alpha-tocopherol concentrations of < 11.6, 11.6-16.2, and > 16.2 mumol/l are normally regarded as indicating deficient, low and acceptable vitamin E status respectively, although more recently it has been suggested that the optimal plasma alpha-tocopherol concentration for protection against cardiovascular disease and cancer is > 30 mumol/l at common plasma lipid concentrations in combination with plasma vitamin C concentrations of > 50 mumol/l and > 0.4 mumol beta-carotene/l. Assessment of vitamin E status has also been based on alpha-tocopherol concentrations in erythrocytes, lymphocytes, platelets, lipoproteins, adipose tissue, buccal mucosal cells and LDL, and on alpha-tocopherol: gamma-tocopherol in serum or plasma. Erythrocyte susceptibility to haemolysis or lipid oxidation, breath hydrocarbon exhalation, oxidative resistance of LDL, and alpha-tocopheryl quinone concentrations in cerebrospinal fluid have been used as functional markers of vitamin E status. However, many of these tests tend to be non-specific and poorly standardized. The recognition that vitamin E has important roles in platelet, vascular and immune function in addition to its antioxidant properties may lead to the identification of more specific biomarkers of vitamin E status. PMID: 10466191 [PubMed - indexed for MEDLINE] 5507. Clin Nutr. 1999 Feb;18(1):5-13. Abnormalities in branched-chain amino acid metabolism in cirrhosis: influence of hormonal and nutritional factors and directions for future research. Blonde-Cynober F(1), Aussel C, Cynober L. Author information: (1)Biochem Laboratory Emile Roux Hospital, INSERM U402, CHU St Antoine, Paris, France. Plasma branched-chain amino acid (BCAA) levels are decreased in patients with liver cirrhosis, owing to an increase in BCAA tissue uptake and/or catabolism and a decrease in BCAA production from proteins. Non-specific factors such as malnutrition worsen this picture. Studies of BCAA fluxes and protein turnover in cirrhotic patients have given conflicting results due to patient heterogeneity, differences in method and bias in the expression of results. In well compensated cirrhosis, muscle wasting is moderate and probably due more to decreased protein synthesis than to increased protein catabolism. Hyperinsulinemia has been suggested as the main cause of decreased BCAA levels, by increasing BCAA uptake in muscle and additionally in adipose tissue. However, as depletion of fat stores is frequent in cirrhosis, this effect is certainly quantitatively weak. Also, there is no correlation between state of hyperinsulinemia and decrease in BCAA levels. An effect of cytokines (IL1 and TNF) on muscle BCAA catabolism is a possibility. Until recently, the contribution of the liver to abnormal BCAA metabolism has been underestimated. In cirrhotic liver an increase in liver transamination of branched-chain keto acids (BCKAs) has been suggested and may result from inhibition of liver BCKA dehydrogenase. A modification of protein turnover in cirrhotic liver must be also considered. Lastly, the contribution of non-hepatocyte liver cells, which are activated in cirrhosis, remains to be assessed. Copyright 1999 Harcourt Publishers Ltd. PMID: 10459077 [PubMed - indexed for MEDLINE] 5508. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S72-4. The physiological role of the novel uncoupling proteins: view from the chair. Silva JE(1). Author information: (1)McGill University, Jewish General Hospital, Montreal, Canada. mdsi@musica.mcgill.ca The recently cloned uncoupling proteins -2 and -3 (UCP2, UCP3) cDNAs encode for proteins with 57-59% homology with brown adipose tissue uncoupling protein (UCP1) that can function as uncouplers of phosphorylation. The presentations of this Session of the Symposium were largely based on mRNA measurements, with one study showing that protein concentrations are well predicted by changes in mRNA in human muscles. Overall the observations suggest more complexity than anticipated. These observations are for the moment hard to reconcile with a simple role for these proteins in energy dissipation. Just the marked differences in tissue distribution of the two novel UCPs suggest they have different functions. It is possible that the activity, rather than the concentrations of these proteins, is regulated. The investigation of this possibility will hopefully enlighten us on their physiological role. PMID: 10454130 [PubMed - indexed for MEDLINE] 5509. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S64-7. Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and skeletal muscle in humans. Langin D(1), Larrouy D, Barbe P, Millet L, Viguerie-Bascands N, Andreelli F, Laville M, Vidal H. Author information: (1)Unité INSERM 317, Institut Louis Bugnard, Université Paul Sabatier, Hôpital Rangueil, Toulouse, France. Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) are mitochondrial proteins that may play a role in the control of energy expenditure by uncoupling respiration from ATP synthesis. The present review focuses on data obtained in humans. UCP2 is widely expressed in the body, whereas UCP3 expression is restricted to skeletal muscle. Positive correlations have been reported between UCP2 mRNA concentrations in adipose tissue, UCP3 mRNA concentrations in skeletal muscle, and components of the metabolic rate. Fasting induces an up-regulation of UCP2 and UCP3 mRNA expression. In vivo and in vitro studies suggest that fatty acids could modulate uncoupling protein gene expression. The putative relationship between obesity, energy expenditure and uncoupling protein expression, and the unexpected rise in UCP2 and UCP3 mRNA concentrations during short-term fasting, are discussed in view of the recent data obtained in rodents and cell lines. PMID: 10454128 [PubMed - indexed for MEDLINE] 5510. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S60-3. Effects of dietary deprivation, obesity and exercise on UCP3 mRNA levels. Giacobino JP(1). Author information: (1)Département de Biochimie Médicale, Centre Médical Universitaire, University of Geneva, Switzerland. Uncoupling protein-3 (UCP3) is selectively expressed in skeletal muscle of rodents and humans, and in brown adipose tissue (BAT) of rodents. C2C12 myoblast transfection with UCP3 induced a decrease in mitochondrial membrane potential suggesting that UCP3 behaves as an uncoupler of oxidative phosphorylations. Cold-exposure, food restriction and fasting affect UCP3 mRNA expression differently in BAT, compared to muscle. The effects induced by cold-exposure and fasting in BAT, and by fasting in muscle, might be explained by changes in intracellular free fatty acids (FFA). A single bout of exercise or endurance training, respectively, increases or decreases muscle UCP3 expression. The effects of PPARgamma agonists and leptin on BAT and muscle UCP3 mRNA expression are also discussed. Hypotheses to explain the effects of these modulations are presented. PMID: 10454127 [PubMed - indexed for MEDLINE] 5511. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S51-2. Molecular and genetic aspects of the UCPs: view from the chair. Stock MJ(1). Author information: (1)Department of Physiology, St George's Hospital Medical School, University of London, UK. m.stock@sghms.ac.uk PMID: 10454124 [PubMed - indexed for MEDLINE] 5512. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S38-42. Uncoupling protein-2 (UCP2): molecular and genetic studies. Ricquier D(1). Author information: (1)CEREMOD, CRNS, Meudon, France. ricquier@infobiogen.fr Thermogenesis is associated to oxygen consumption and cellular respiration. This process is coupled to adenosine-diphosphate (ADP) phosphorylation through the existence of a proton gradient across the inner mitochondrial membrane. It was postulated that proton leaks through this membrane would uncouple respiration from adenosine-triphosphate (ATP) synthesis and induce energy dissipation as heat. Such a mechanism was identified in thermogenic brown adipose tissue mitochondria which contain a unique proton carrier referred to as uncoupling protein (UCP). This UCP is activated by fatty acids and its synthesis is positively controlled by retinoids, thyroid hormones, catecholamines and rexinoids. In fact, in most types of cells, respiring mitochondria release heat and the coupling of substrate oxidation to ADP phosphorylation is under 100%. It suggested that the partial coupling of respiration to ADP phosphorylation was due to proton leaks possibly related to the brown fat UCP. This approach led to the identification of UCP2 and UCP3, two homologues of the brown fat UCP (renamed UCP1). UCP2 gene is widely expressed in tissues and cell types, whereas the UCP3 gene is dominantly expressed in skeletal muscles (and brown fat in mice). Recent genetic, biochemical and physiological studies suggest that these novel UCP2 contribute to resting metabolic rate, fat oxidation and may represent new targets for anti-obesity compounds. PMID: 10454120 [PubMed - indexed for MEDLINE] 5513. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S33-7. Mitochondria uncoupling proteins and obesity: molecular and genetic aspects of UCP1. Kozak LP(1), Koza RA. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. kozaklp@mhs.pbrc.edu Genetic variation in brwon fat specific mitochondrial uncoupling protein-1 (UCP1) expression and brown adipocyte morphology, have provided models to test the hypothesis that nonshivering thermogenesis is associated with the regulation of body weight. Genetic manipulation using transgenic animals and gene targeting, has resulted in mice with an over-expression of UCP1. These variant animals consistently show that over-expression of UCP1 reduced adiposity. On the other hand, less agreement is found in models that reduce nonshivering thermogenesis. Inactivation of the UCP1 gene, by gene targeting, does not increase adiposity when compared to control animals; however, a mouse expressing the UCP1-DTA transgene (UCPI-diphtheria toxin A chain), in which there is a modest reduction in the number of brown adipocytes, becomes obese. Other phenotypes of this mouse, the hyperphagia, extreme resistance to leptin administration, retinopathy and high residual content of brown adipocytes, suggest that the effects of the transgene may be more extensive than simply a 60% reduction in the number of brown adipocytes. Ectopic expression of UCP1-DTA in the brain could explain the phenotype of this mouse in a manner more consistent with the results of other models with altered UCP1 and brown adipocyte expression. PMID: 10454119 [PubMed - indexed for MEDLINE] 5514. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S30-2. Biochemical aspects of the uncoupling proteins: view from the chair. Himms-Hagen J(1), Harper ME. Author information: (1)Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Canada. jhhagen@uottawa.ca The discovery of nonshivering thermogenesis (NST) and its location in brown adipose tissue (BAT) in the 1950s to 1970s was soon followed by purification of the first uncoupling protein (UCP1) and later by cloning of the gene for UCP1 in 1985. The properties of UCP1 fully explained the long-known phenomenon of stimulated NST in BAT. An additional four 'uncoupling proteins' have been cloned in the last two years and are in search of phenomena they can explain. The four speakers in this first session of the symposium on uncoupling proteins reviewed biochemical properties of UCP1 and of three of the novel UCPs. Several suggested functions include mediation of the mitochondrial proton leak in tissues other than BAT, therefore a major role in energy expenditure, and protection against reactive oxygen species. Tools, techniques and information not yet available and for which further research is needed are reviewed. PMID: 10454118 [PubMed - indexed for MEDLINE] 5515. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S19-23. UCP1, UCP2 and UCP3: are they true uncouplers of respiration? Bouillaud F(1). Author information: (1)CEREMOD, CNRS, Meudon, France. bouillau@cnrs-bellevue.fr The thermogenesis in brown adipose tissue (BAT) is due to the activity of a mitochondrial uncoupling protein (UCP1). This protein allows the protons pumped by the respiratory chain to re-enter the matrix without ATP synthesis. Therefore respiration is dramatically increased and produces only heat. The discovery of genes showing strong similarities with the UCP1 gene and expressed in other tissues raised the possibility that these proteins participate in the proton leak observed in mitochondria, and therefore participate in the regulation of energy expenditure. The recombinant expression of UCP1, UCP2 and UCP3 in yeast allows the comparison of the coupling state of yeast mitochondria in the presence or absence of these proteins. PMID: 10454116 [PubMed - indexed for MEDLINE] 5516. Int J Obes Relat Metab Disord. 1999 Jun;23 Suppl 6:S4-11. The significance and mechanism of mitochondrial proton conductance. Brand MD(1), Brindle KM, Buckingham JA, Harper JA, Rolfe DF, Stuart JA. Author information: (1)Department of Biochemistry, University of Cambridge, UK. m.d.brand@bioc.cam.ac.uk There is a futile cycle of pump and leak of protons across the mitochondrial inner membrane. The contribution of the proton cycle to standard metabolic rate is significant, particularly in skeletal muscle, and it accounts for 20% or more of the resting respiration of a rat. The mechanism of the proton leak is uncertain: basal proton conductance is not a simple biophysical leak across the unmodified phospholipid bilayer. Equally, the evidence that it is catalysed by homologues of the brown adipose uncoupling protein, UCP1, is weak. The yeast genome contains no clear UCP homologue but yeast mitochondria have normal basal proton conductance. UCP1 catalyses a regulated inducible proton conductance in brown adipose tissue and the possibility remains open that UCP2 and UCP3 have a similar role in other tissues, although this has yet to be demonstrated. PMID: 10454114 [PubMed - indexed for MEDLINE] 5517. Curr Opin Clin Nutr Metab Care. 1999 Mar;2(2):101-4. Human obesity: a sufficient cause. Hirsch J(1). Author information: (1)Rockefeller University, New York, NY 10021-6390, USA. It is sometimes useful to group the causes for any biological event into those that are necessary and those that are sufficient. Our current, partial understanding of human obesity has come through a focus on readily accessible necessary causes. The sufficient causes are likely to be more complex, dealing with the integration of developmental events, behavior and complex biochemical systems. PMID: 10453338 [PubMed - indexed for MEDLINE] 5518. Br J Nutr. 1999 Feb;81(2):87-106. The comparative roles of polyunsaturated fatty acids in pig neonatal development. Leskanich CO(1), Noble RC. Author information: (1)Department of Biochemical Sciences, Scottish Agricultural College, Auchincruive, Ayr, UK. christian_leskanich@sandwich.pfizer.com The present review focuses on the importance of polyunsaturated fatty acid (PUFA) provision for the normal development of the pig neonate. The review describes first the selected fatty acid composition of a range of porcine tissues including nervous tissues, muscle and adipose tissues, reproductive organs and immune-responsive organs and/or cells. The importance of PUFA to the functioning of the immune system of the neonate is considered briefly and is followed by an in-depth consideration of the sources of PUFA for the neonatal pig. The effects of different categories or specific types of fatty acid (i.e. non-essential, linoleic, alpha-linolenic, long-chain n-6 and n-3 PUFA) on various indices of pig neonatal growth are reviewed. The importance of n-3 PUFA supply to the fetal and early neonatal pig is underlined and evidence is presented for more attention to be given to the amounts available from maternal sources. Based on the material reviewed, recommendations are made on the dietary intake of PUFA in the gestating pig. PMID: 10450326 [PubMed - indexed for MEDLINE] 5519. AIDS. 1999 Jul 30;13(11):1287-93. Epidemiological and clinical aspects of the metabolic complications of HIV infection the fat redistribution syndrome. Wanke CA. PMID: 10449280 [PubMed - indexed for MEDLINE] 5520. Diabetologia. 1999 Sep;42(9):1033-49. PPARgamma, the ultimate thrifty gene. Auwerx J(1). Author information: (1)LBRE, Pasteur Institute, Lille, France. The peroxisome proliferator-activated receptor gamma (PPARgamma) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This fast pace in PPARgamma research was triggered by two main discoveries. Firstly, that PPARgamma was shown to have a key role in adipogenesis and be a master controller of the "thrifty gene response" leading to efficient energy storage. Secondly, the discovery that its synthetic ligands, the thiazolidinediones, are promising insulin sensitizing drugs, which are currently being developed for the treatment of Type II (non-insulin-dependent) diabetes mellitus. More recently this nuclear receptor emerged from a role limited to metabolism (diabetes and obesity) to a power player in general transcriptional control of numerous cellular processes, with implications in cell cycle control, carcinogenesis, inflammation, atherosclerosis and immunomodulation. This widened role of PPARgamma will certainly initiate a new flurry of research, which will not only refine our current often partial knowledge of PPARgamma but more importantly also establish that this receptor has a definite role as a primary link adapting cellular, tissue and whole body homeostasis to energy stores. PMID: 10447513 [PubMed - indexed for MEDLINE] 5521. J Endocrinol Invest. 1999;22(5 Suppl):41-6. Growth hormone and the metabolic syndrome. Johannsson G(1), Bengtsson BA. Author information: (1)Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden. The association of several risk factors, obesity, dyslipoproteinemia, hepatic steatosis, insulin resistance and hypertension with Type 2 (non-insulin-dependent) diabetes mellitus and myocardial infarction has long been known and has been termed the "metabolic syndrome". In 1988 Reaven introduced syndrome X as the link between insulin resistance and hypertension. It has been suggested that a critical factor in the association between obesity, Type 2 diabetes and cardiovascular morbidity is the mass of intraabdominal fat. Striking similarities exist between the metabolic syndrome and untreated growth hormone (GH) deficiency in adults. The central findings in both these syndromes are abdominal/visceral obesity and insulin resistance. Other features common to both conditions are premature atherosclerosis and increased mortality from cardiovascular diseases. These similarities indicate that undetectable and low levels of GH may be of importance in the metabolic aberrations observed in both these conditions. Recent investigations have found that abdominal/visceral distribution of adipose tissue is associated with endocrine disturbances including increased activity of the hypothalamic-pituitary-adrenal axis and a blunted secretion of GH and sex steroids. Theoretically, these endocrine perturbations can be a consequence of obesity, but the endocrine aberrations may have causal effects. We studied moderately obese, middle-aged men with a preponderance of abdominal body fat. As a group, they had slight to moderate metabolic changes known to be associated with abdominal/visceral obesity. Nine months of GH treatment reduced their total body fat and resulted in a specific and a marked decrease in both abdominal subcutaneous and visceral adipose tissue. Moreover, insulin sensitivity improved and serum concentrations of total cholesterol and triglyceride decreased. Diastolic blood pressure also decreased. The finding that GH replacement in men with abdominal obesity can diminish the negative metabolic consequences of visceral obesity suggests that low levels of this hormone are of importance for the metabolic aberrations associated with visceral/abdominal obesity. PMID: 10442570 [PubMed - indexed for MEDLINE] 5522. J Endocrinol Invest. 1999;22(5 Suppl):22-6. Regulation of growth hormone secretion by signals produced by the adipose tissue. Pombo M(1), Pombo CM, Astorga R, Cordido F, Popovic V, Garcia-Mayor RV, Dieguez C, Casanueva FF. Author information: (1)Department of Paediatrics, School of Medicine and Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. The neuroregulation of growth hormone (GH) secretion and the state of the adipose tissue reserves are closely related. GH exerts lipolytic actions on the adipose tissue and low body weight enhances secretion of GH while obesity is associated with reduced levels of GH and blocked release of GH when challenged by all stimuli. The mediators of the regulation exerted by the adipose tissue on the GH/insulin-like growth factor-I axis are not fully understood, but in the last few years two relevant factors have emerged--free fatty acids (FFA) and the adipocyte-produced hormone leptin. FFA and GH integrate a classical feedback loop and a rise in FFA blocks GH secretion. This action is rapid, dose-related and exerted at the pituitary level with no evident hypothalamic participation. A pharmacological reduction in FFA enhances secretion of GH and eliminates the GH blockade of obesity and Cushing's syndrome. The discovery of leptin has expanded our knowledge of the way in which the adipose tissue participates in some neuroendocrine actions. Obesity is associated with elevated levels of serum leptin while undernutrition and fasting lead to low leptin. In fasted rats, the pattern of GH pulsatility is eliminated with a near absence of spontaneous peaks, but the administration of leptin by the intracerebroventricular (i.c.v.) route restores the altered pattern. When fed rats receive antileptin antibodies i.c.v the normal pattern is reversed to an absence of pulses, reminiscent of the fasting state. These results are the first demonstration that, at least in experimental animals, leptin is a relevant factor in GH regulation. Leptin has no direct pituitary action and its action at the hypothalamic level appears to be mediated by neuropeptide Y, being the final step in a reduction in the somatostatin tone. On the other hand, the action of GH on leptin levels seems to be tenuous in humans, but in the near future it will be possible to investigate the action of leptin on human GH. As the hypothalamic neuroregulation of GH secretion in humans is unlike that in the rat, a crucial point for elucidation will be the actions, if any, and the mechanisms by which leptin participates in GH regulation in humans, as well as its alterations in disease states. PMID: 10442566 [PubMed - indexed for MEDLINE] 5523. J Endocrinol Invest. 1999;22(5 Suppl):10-5. Effect of growth hormone on adipose tissue and skeletal muscle lipoprotein lipase activity in humans. Richelsen B(1). Author information: (1)Medical Department C, Aarhus Amtssygehus, Aarhus University Hospital, Denmark. br@aas.auh.dk Lipoprotein lipase (LPL) is involved in clearing triglyceride-rich chylomicrons and very-low-density lipoprotein particles from the bloodstream, providing free fatty acids to particular adipose tissue for storage and to skeletal muscle tissue for oxidation and energy production. Although the same gene (chromosome 8p22) encodes LPL, the enzyme activity is regulated in a tissue-specific manner. Dysfunction of the LPL enzyme has been implicated in the pathogenesis of dyslipidemia (high triglyceride and low high-density lipoprotein (HDL) cholesterol), early arteriosclerosis, and the pathogenesis of obesity. Treatment with growth hormone (GH) both in vivo and in vitro results in a pronounced reduction (often up to 50%) of LPL activity in adipose tissue in humans. The specific level of messenger ribonucleic acid, however, is not generally affected by GH treatment in adipose tissue, indicating that the effect of GH is mediated at a post-translational level. The GH-mediated reduction in adipose tissue LPL activity may be involved in the reduction in adipose tissue mass commonly seen after prolonged GH treatment in GH-deficient adults and GH treatment in obese subjects. LPL activity in adipose and skeletal muscle tissue is generally regulated in a reciprocal manner by, for example, fasting, feeding, insulin and epinephrine. A high level of LPL activity, particularly in skeletal muscle tissue, has been found to be associated with a beneficial lipoprotein profile (low triglyceride and high HDL cholesterol). In investigations where obese but otherwise healthy women were treated with GH, and in another study where adults with GH deficiency were treated for 4 months with GH, we found no effects of GH on either skeletal muscle LPL activity nor on skeletal muscle LPL gene expression. In conclusion, GH has a pronounced inhibitory effect on adipose tissue LPL activity, which is mediated at a post-translational level. The GH-induced reduction in adipose tissue mass may be partly mediated by this effect on adipose tissue LPL. GH has no effects on LPL activity in skeletal muscle, which may be related to the fact that GH has no or only minor effects on plasma triglyceride and HDL cholesterol levels. Finally, GH is not, unlike for example insulin and catecholamines, involved in antagonistic regulation of LPL in muscle and adipose tissue. PMID: 10442564 [PubMed - indexed for MEDLINE] 5524. Ther Umsch. 1999 Jul;56(7):408-14. [Exophthalmos--what now?]. [Article in German] Heufelder AE(1), Schworm HD. Author information: (1)Abteilung Gastroenterologie, Philipps-Universität, Marburg. heufeld@mailer.uni-marburg.de Exophthalmos is most commonly due to Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease. The clinical signs and symptoms of GO are the consequences of increased orbital connective and adipose tissue volume, and of interstitial enlargement of extraocular muscles, within the confines of the bony orbits. Diagnosis of GO is usually readily established by obtaining a careful history, detailed clinical examination of the thyroid gland, eyes and orbits, few laboratory tests and ultrasonography of the thyroid gland and the orbital contents. Additional procedures such as computed tomography or magnetic resonance imaging are rarely needed. A team approach (general practitioner, endocrinologist, ophthalmologist) is essential to assure state-of-the-art management of patients with GO, and to properly select the best choices from a still limited range of therapeutic options. PMID: 10434781 [PubMed - indexed for MEDLINE] 5525. N Engl J Med. 1999 Aug 5;341(6):427-34. Guidelines for healthy weight. Willett WC(1), Dietz WH, Colditz GA. Author information: (1)Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Comment in N Engl J Med. 1999 Dec 30;341(27):2097-8. N Engl J Med. 1999 Dec 30;341(27):2097; author reply 2098. N Engl J Med. 1999 Dec 30;341(27):2097; author reply 2098. PMID: 10432328 [PubMed - indexed for MEDLINE] 5526. Hepatogastroenterology. 1999 Jun;46 Suppl 2:1414-7. Role of hepatic, intrahepatic and hepatoenteral nerves in the regulation of carbohydrate metabolism and hemodynamics of the liver and intestine. Jungermann K(1), Stümpel F. Author information: (1)Institut für Biochemie und Molekulare Zellbiologie, Göttingen, Germany. The liver as an effector organ is the major glucose reservoir, the utilization of which is controlled by hormones but also by hepatic sympathetic nerves. The liver as a sensory organ detects a glucose concentration gradient between the hepatic artery and the portal vein by intrahepatic sensory-effector nerves, generating a cholinergic signal for an insulin-dependent net hepatic glucose uptake. The liver senses the insulin concentration by hepatoenteral sensory-effector nerves, generating a cholinergic signal to increase glucose absorption in the intestine and thus its coordinated utilization in liver, muscle and adipose tissue. PMID: 10431702 [PubMed - indexed for MEDLINE] 5527. J Ren Nutr. 1999 Jul;9(3):122-5. Leptin in renal failure. Mantzoros CS(1). Author information: (1)Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Leptin, an adipocyte-derived hormone, signals to the brain information on the amount of energy stored in adipose tissue and regulates energy homeostasis. In addition, leptin has been implicated in the regulation of neuroendocrine function, growth, hematopoiesis, and immune regulation. Plasma leptin is cleared by the kidney, and thus, leptin levels are elevated in hemodialysis patients. Whether the elevated leptin levels in hemodialysis patients contribute to the pathophysiology of the clinical manifestations of renal failure in humans remains to be conclusively shown in the future. PMID: 10431029 [PubMed - indexed for MEDLINE] 5528. Horm Metab Res. 1999 May;31(5):345-50. Leptin sensitive neurons in the hypothalamus. Baskin DG(1), Hahn TM, Schwartz MW. Author information: (1)VA Puget Sound Health Care System, Department of Medicine, University of Washington School of Medicine, Seattle 98108-1597, USA. baskindg@u.washington.edu A major paradigm in the field of obesity research is the existence of an adipose tissue-brain endocrine axis for the regulation of body weight. Leptin, the peptide mediator of this axis, is secreted by adipose cells. It lowers food intake and body weight by acting in the hypothalamus, a region expressing an abundance of leptin receptors and a variety of neuropeptides that influence food intake and energy balance. Among the most promising candidates for leptin-sensitive cells in the hypothalamus are arcuate nucleus neurons that co-express the anabolic neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), and those that express proopiomelanocortin (POMC), the precursor of the catabolic peptide, alphaMSH. These cell types contain mRNA encoding leptin receptors and show changes in neuropeptide gene expression in response to changes in food intake and circulating leptin levels. Decreased leptin signaling in the arcuate nucleus is hypothesized to increase the expression of NPY and AGRP. Levels of leptin receptor mRNA and leptin binding are increased in the arcuate nucleus during fasting, principally in NPY/AGRP neurons. These findings suggest that changes in leptin receptor expression in the arcuate nucleus are inversely associated with changes in leptin signaling, and that the arcuate nucleus is an important target of leptin action in the brain. PMID: 10422733 [PubMed - indexed for MEDLINE] 5529. Dan Med Bull. 1999 Jun;46(3):197-234. On the pathophysiology of late onset non-insulin dependent diabetes mellitus. Current controversies and new insights. Vaag A(1). Author information: (1)Hvidøre Hospital, Klampenborg. The development of late onset non-insulin dependent diabetes mellitus (NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut incretin hormones (defective glucagon like peptide 1 (GLP1) secretion) on the other side. Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a genetic predisposition to NIDDM, higher concordance rates for abnormal glucose tolerance including NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different NIDDM susceptibility genes at the sites of Insulin Receptor Substrate 1 (IRS1), the beta-3 adrenergic receptor, and the sulfonylurea receptor. However, the latter susceptibility genes only explain a minor proportion of NIDDM in the general population, and the quantitative extent to which genetic versus non-genetic factors contribute to NIDDM is presently unsolved. Environmental components include both an early intrauterine component associated with low birth weight, and later postnatal components including low physical activity, high fat diet, and the subsequent development of obesity and elevated plasma and tissue free fatty acid levels. Our finding of lower birth weights in monozygotic twins compared with their non-diabetic genetically identical co-twins excludes the possibility that the association between NIDDM and low birth weight as demonstrated in several studies may solely be explained by a coincidence between a certain gene causing both a low birth weight and an increased risk of NIDDM. Young first degree relatives of patients with NIDDM are characterized by hyperinsulinaemia and peripheral insulin resistance, which in turn may be explained by a decreased insulin activation of the enzyme glycogen synthase in skeletal muscle. Therefore, a defective skeletal muscle glycogen synthase activation may represent an early phenotypic expression of a genetic defect contributing to an increased risk of later development of NIDDM. However, elderly insulin resistant non-diabetic co-twins (64 years old) of twins with overt NIDDM does not--in contrast to their NIDDM co-twins--have a significantly decreased insulin activation of glycogen synthase in skeletal muscle. This demonstrates that the defective muscle glycogen synthase insulin activation has an apparent non-genetic component, and that this key defect of metabolism can be escaped or postponed even in non-diabetic subjects with a presumably 100% genetic predisposition to NIDDM. The insulin activation of glycogen synthase in skeletal muscle is compensated or apparently normalised in NIDDM patients when studied during their ambient fasting hyperglycaemia and a subsequent isoglycaemic (hyperglycaemic) physiologic insulin infusion. This indicates that the prevailing hyperglycaemia in NIDDM subjects compensates for the defective insulin activation of glycogen synthase present in those subjects when studied during eulycaemia. Our data and those of others also indicates that hyperglycaemia in NIDDM compensates for the defects in insulin secretion, the disproportionately elevated hepatic glucose production, and to some extent for the increased lipid oxidation and the decreased glucose oxidation present in NIDDM patients. Accordingly, NIDDM subjects exhibit all of those defects of metabolism when studied during "experimental decompensation" when the ambient hyperglycaemia is normalized by a prior and later withdrawn intravenous insulin infusion. However, shortly after the withdrawal of the intravenous insulin infusion, the plasma glucose concentration increased spontaneously in the NIDDM patients. (ABSTRACT TRUNCATED) PMID: 10421979 [PubMed - indexed for MEDLINE] 5530. Rev Med Univ Navarra. 1998 Apr-Jun;42(2):91-8. [Lipid metabolism and lipogenesis: application of stable isotopes]. [Article in Spanish] Martínez JA(1), Martí A. Author information: (1)Dpto. Fisiología y Nutrición, Universidad de Navarra. Fat metabolism is regulated by several neuroendocrine and nutritional factors, which affect equilibrium between lipogenesis and lipolysis. Lipid utilization and fate in the organism can be assessed by in vivo and in vitro methods by measuring the rate of the different metabolic pathways (dynamic aspects), but also the net balance which may lead to fat accumulation or loss (static aspects). The quantitation of synthesis and breakdown reactions can be performed by using different tracers such as radioactive and stable isotopes. Fatty acid synthesis can be independently measured by the intravenous infusion of 13C acetate and application of the MIDA technique. In brief, this method uses probability analysis to measure the synthesis of biological polymers. It is based on the mathematical principle that the labeling pattern of a polymer synthesized from a stable-isotopically labeled precursor will conform to a predicted binomial or multinomial expansion. Thus, the isotopic enrichment of the precursor pool is calculated from measurements on the product alone. In the case of fatty acid synthesis, the proportions of excess (above natural background abundance) of single-labeled and double labeled (EM1 and EM2 species respectively) are a function of the probability (p) that the precursor subunits were isotopically labeled. Using this value of P for the isotopic enrichment of the acetylCoA pool, the theoretical 13C enrichment in the fatty acid if 100% were newly formed from this acetate pool is calculated. The actual isotopic enrichment is measured by gas chromatography-mass spectrometry (GCMS). This value divided by the theoretical maximum value equals the fraction of the fatty acid that is newly formed (f). The value for f represents dilution of de novo synthesized fatty acid by non-de novo sources. This method requires that newly synthesized (labeled) and preformed (unlabeled) mix in the liver and communicate with plasma VLDL over the period of the isotope infusion. It also assumes that the major de novo fatty acid is only a single fatty acid, with minor elongation and/or desaturation processes. Finally, the infused isotopic acetate should have no physiologically important effect. This methodology can be applied to assess lipogenesis in very different nutritional and physiopathological conditions such as diabetes, AIDS, obesity, etc. PMID: 10420945 [PubMed - indexed for MEDLINE] 5531. Am J Clin Nutr. 1999 Jul;70(1):149S-56S. Relation between visceral fat and disease risk in children and adolescents. Goran MI(1), Gower BA. Author information: (1)Department of Nutrtion Sciences, University of Alabama at Birmingham, 35294-3360, USA. MIG@uab.edu PMID: 10419419 [PubMed - indexed for MEDLINE] 5532. Lipids. 1999;34 Suppl:S205-8. Roles of lipid-activated receptors in the adipogenic action of fatty acids. Grimaldi PA(1). Author information: (1)INSERM U470, Centre de Biochimie, UFR Sciences, Parc Valrose, UNSA, Nice, France. grimaldi@unice.fr PMID: 10419151 [PubMed - indexed for MEDLINE] 5533. Sports Med. 1999 Jun;27(6):347-58. Leucine supplementation and intensive training. Mero A(1). Author information: (1)Department of Biology of Physical Activity, University of Jyväskylä, Finland. mero@maila.jyu.fi Leucine, isoleucine and valine, the branched-chain amino acids (BCAA), make up about one-third of muscle protein. Of these, leucine has been the most thoroughly investigated because its oxidation rate is higher than that of isoleucine or valine. Leucine also stimulates protein synthesis in muscle and is closely associated with the release of gluconeogenic precursors, such as alanine, from muscle. Significant decreases in plasma or serum levels of leucine occur following aerobic (11 to 33%), anaerobic lactic (5 to 8%) and strength exercise (30%) sessions. In skeletal muscle, there is a decrease in leucine level and a reduction in glycogen stores during exhaustive aerobic exercise. Basal fasting serum leucine levels decrease by 20% during 5 weeks of speed and strength training in power-trained athletes on a daily protein intake of 1.26 g/kg bodyweight. The leucine content of protein is assumed to vary between 5 and 10%. There are suggestions that the current recommended dietary intake of leucine be increased from 14 mg/kg bodyweight/day to a minimum of 45 mg/kg bodyweight/day for sedentary individuals, and more for those participating in intensive training in order to optimise rates of whole body protein synthesis. Consumption of BCAA (30 to 35% leucine) before or during endurance exercise may prevent or decrease the net rate of protein degradation, may improve both mental and physical performance and may have a sparing effect on muscle glycogen degradation and depletion of muscle glycogen stores. However, leucine supplementation (200 mg/kg bodyweight) 50 minutes before anaerobic running exercise had no effect on performance. During 5 weeks of strength and speed training, leucine supplementation of 50 mg/kg bodyweight/day, supplementary to a daily protein intake of 1.26 g/kg bodyweight/day, appeared to prevent the decrease in the serum leucine levels in power-trained athletes. According to 1 study, dietary supplementation of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) 3 g/day to humans undertaking intensive resistance training exercise resulted in an increased deposition of fat-free mass and an accompanying increase in strength. Muscle proteolysis was also decreased with HMB, accompanied by lower plasma levels of enzymes indicating muscle damage and an average 50% decrease in plasma essential amino acid levels. Furthermore, BCAA supplementation (76% leucine) in combination with moderate energy restriction has been shown to induce significant and preferential losses of visceral adipose tissue and to allow maintenance of a high level of performance. Caution must be paid when interpreting the limited number of studies in this area since, in many studies, leucine has been supplemented as part of a mixture of BCAA. Consequently, further research into the effects of leucine supplementation alone is needed. PMID: 10418071 [PubMed - indexed for MEDLINE] 5534. Clin Sports Med. 1999 Jul;18(3):485-98. Role of fats in exercise. Types and quality. Turcotte LP(1). Author information: (1)Department of Exercise Science, University of Southern California, Los Angeles, USA. Plasma TGs, FFAs, and muscle TG are oxidizable lipid fuel sources for skeletal muscle metabolism during prolonged exercise. Plasma FFAs are a major fuel oxidized by skeletal muscle, and their rate of use by muscle depends on several factors, including plasma FFA availability, transport from plasma to the mitochondria, and intracellular metabolism. Mobilization of FFAs from adipose tissue is the first committed step in FFA metabolism, and it depends on the rate of adipose tissue lipolysis. Adipose tissue lipolysis increases with exercise duration and exercise intensity up to intensities of approximately 60% to 65%. Evidence suggests that FFAs are transported from plasma to the mitochondria by FFA transporter proteins that include the plasma membrane and cytosolic FABPPM and FABPC. Plasma FFA use can also be regulated at the mitochondrial transport step by changing the activity of carnitine palmitoyltransferase (CPT-1). Although results from biopsy and tracer studies indicate that muscle TG contribute to skeletal muscle oxidative metabolism during exercise, their exact contribution is difficult to ascertain. Evidence shows that muscle TG use depends on exercise intensity, duration, and mode. The contribution of plasma TG to skeletal muscle metabolism is small. The rate of use of plasma TG is dependent on lipoprotein lipase activity, which is correlated with the oxidative capacity of the muscle fibers. Dietary manipulations can modulate substrate use during exercise and can potentially affect exercise performance. High carbohydrate availability before exercise is associated with an increase in blood glucose and plasma insulin concentrations, which can ultimately decrease the rate of adipose tissue lipolysis and the availability of plasma FFAs. Increased glucose flux has also been shown to decrease lipid oxidation by directly inhibiting the transport of FFAs across the mitochondrial membranes. High lipid availability can be changed by short-term or long-term exposure to high-fat diets. Because carbohydrate reserves are diminished with exposure to high-fat diets, improvements in exercise performance have been difficult to measure under these conditions. PMID: 10410836 [PubMed - indexed for MEDLINE] 5535. Biochemistry (Mosc). 1999 Jun;64(6):601-9. Adipose tissue as an endocrine organ regulating growth, puberty, and other physiological functions. Pankov YA(1). Author information: (1)Endocrinology Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia. yuri-pankov@mtu-net.ru There are reports on some patients with clearly manifested specific features of genotype and phenotype similar to those of ob/ob and db/db mice. Three patients from Turkey were described who had a homozygous mutation in the gene of leptin identical to the mutation in C57BL6J ob/ob mice. This mutation is a C --> T substitution in codon 105 of the amino acid sequence of leptin. In mice this mutation generates a stop-codon; in humans it substitutes Arg-105 with Trp. The mutant human leptin cannot be secreted by the cells and thus has no effect on the hypothalamus. Patients with a homozygous mutation of the leptin receptor resulting in the G --> T substitution in the splice donor site of exon 16 were studied in a family of Kabilian origin. Exon 16 was not included in the mature mRNA molecule, and a truncated leptin receptor was synthesized which lacked the transmembrane and intracellular domains; this receptor was unable to transduce the hormonal signal. Both groups of patients suffered from obesity, delayed linear growth, infertility, increased blood insulin level, and other disorders. Leptin influences lipid metabolism by stimulating the expression of the proopiomelanocortin (POMC) gene in melanocortinergic neurons of the hypothalamus. POMC is the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which binds to the melanocortin receptor MC4-R in the brain, decreases appetite, and activates lipid metabolism. Patients with mutations in MC4-R suffered only from obesity, but their growth and puberty were not affected. Thus, leptin apparently stimulates growth and puberty not through its binding to the receptors on melanocortinergic neurons, but through its binding to receptors on other hypothalamic neurons; this effect of leptin is not affected by mutations in the MC4-R gene. PMID: 10395972 [PubMed - indexed for MEDLINE] 5536. J Intern Med. 1999 Jun;245(6):643-52. Leptin and its potential role in human obesity. Lönnqvist F(1), Nordfors L, Schalling M. Author information: (1)Karolinska Institute at the Department of Medicine, Huddinge University Hospital, Sweden. fredrik.a.lonnqvist@sb.com Genetic studies in inbred obese mice have revealed the ob gene, its product leptin and the leptin receptor as important factors in the regulation of both appetite and energy expenditure. Treatment with recombinant leptin has resulted in a marked weight reduction in obese animals with ob gene mutations as well as in normal mice. Also mutations in the Ob receptor gene result in marked obesity in rodents. These data have given hope of new treatment options in obesity. Further support of leptin being involved in regulation of obesity in man comes from the observation that inactivating mutations in the human ob gene lead to profound early onset obesity. However, the role of leptin and its feedback system in man is still only partly revealed. This review focuses on our present knowledge and hypotheses about the leptin pathway in humans and its potential importance in the clinic of obesity. PMID: 10395194 [PubMed - indexed for MEDLINE] 5537. J Intern Med. 1999 Jun;245(6):637-42. Contributions of studies on uncoupling proteins to research on metabolic diseases. Ricquier D(1), Fleury C, Larose M, Sanchis D, Pecqueur C, Raimbault S, Gelly C, Vacher D, Cassard-Doulcier AM, Lévi-Meyrueis C, Champigny O, Miroux B, Bouillaud F. Author information: (1)Centre National de la Recherche Scientifique, Centre de Recherche sur l'Endocrinologie Molećulaire et le Développement, Meudon, France. ricquier@infobiogen.fr The coupling of O2 consumption to ADP phosphorylation in mitochondria is partial. This is particularly obvious in brown adipocyte mitochondria which use a regulated uncoupling mechanism generating heat production from substrate oxidation, and catalysing thermogenesis in rodents or infants in response to cold, and arousing hibernators. In the case of brown adipose tissue, the uncoupling mechanism is related to a specific protein in the inner mitochondrial membrane referred to as UCP1. Although the biological importance of UCP1 in human adults is not demonstrated, genetic analysis of various human cohorts suggested a participation of UCP1 to control of fat content and body weight. Very recently, the cloning of UCP2 and UCP3, two homologues of UCP1, has renewed the field of research on the importance of respiration control in metabolic processes and metabolic diseases. UCP2 is widely expressed in organs, whereas UCP3 is mainly present in muscles. These proteins may explain why the coupling of respiration to ADP phosphorylation is less than perfect. Their biological importance should be studied. They also represent new putative targets for drugs against metabolic diseases such as obesity. PMID: 10395193 [PubMed - indexed for MEDLINE] 5538. J Intern Med. 1999 Jun;245(6):613-9. Genes involved in animal models of obesity and anorexia. Schalling M(1), Johansen J, Nordfors L, Lönnqvist F. Author information: (1)Neurogenetics Unit, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. martin.schalling@cmm.ki.se Pathological deviations in bodyweight is a major increasing health problem in industrialized societies. It is currently unclear what genetic mechanisms are involved in the long-term control of human body-weight and to what extent these genes are involved in pathological deviations of bodyweight control such as anorexia and obesity. Major support for the concept of genetic control of bodyweight has recently emerged from different animal models. A number of new genes have been found during recent years that, when mutated, have a negative effect on bodyweight in animals and sometimes also in man. Although available evidence points toward a multifactorial nature of weight disorders in most human subjects, the single genes isolated in animal models may become powerful tools to elucidate the genetics also in man. In addition, these genes may serve to promote the development of targeted small-drug pharmaceuticals aimed at novel biochemical pathways. Finally, the uncovering of several quantitative trait loci (QTL) influencing body mass, body fat or fat topography in the mouse and rat has now also made it possible to perform studies of polygenically caused obesity in rodents. The role of the Genome Project in developing a complete gene map will greatly facilitate transforming these OTLs to actual molecules involved in the biology of bodyweight. PMID: 10395190 [PubMed - indexed for MEDLINE] 5539. Tidsskr Nor Laegeforen. 1999 May 30;119(14):2024-7. [Leptin--a fatty tissue hormone with many functions]. [Article in Norwegian] Reseland JE(1), Hollung K, Drevon CA. Author information: (1)Institutt for ernaeringsforskning, Universitetet i Oslo. The importance of genetic factors in obesity is under investigation. During the last few years, our understanding of the regulation of body weight in mammals has broadened to include several new proteins based on the cloning of genes from rodent mutants and characterization of their effects on energy stores and metabolism. Since its discovery in 1994, leptin has been acknowledged as an adipocyte-derived signal molecule, able to limit food intake and increase energy expenditure by interacting with specific leptin receptors located in the central nervous system and in peripheral tissues. Leptin is also important for growth, reproduction and neuroendocrine signalling. Although leptin is mainly synthesized in adipocytes, it is also expressed in the placenta, epithelium of the stomach and breast glands and, under certain conditions, in skeletal muscles. The importance of leptin is demonstrated by the discovery of mutations in the genes encoding leptin and its receptor among some subjects with morbid obesity and infertility. Plasma concentration of leptin should be measured in obese infertile adolescents since replacement could be curative among individuals with leptin deficiency. PMID: 10394277 [PubMed - indexed for MEDLINE] 5540. Am J Clin Nutr. 1999 Jul;70(1 Part 2):149S-156S. Relation between visceral fat and disease risk in children and adolescents. Goran MI(1), Gower BA. Author information: (1)Division of Physiology and Metabolism, Department of Nutrition Sciences, University of Alabama at Birmingham. This review examines whether the relations and metabolic parameters necessary for the development of syndrome X are present in children and whether the metabolic complications of obesity in children are explained by excess intraabdominal adipose tissue (IAAT), or visceral fat. Despite the limited use of imaging techniques in research studies, an increasing number of studies reported on IAAT and its relation to disease risk in children and adolescents. For this article we reviewed studies that documented the early accumulation of IAAT in children and adolescents and the factors that contribute to variation in the degree of IAAT accumulation. We also reviewed studies that showed the clinical relevance of IAAT in children and adolescents through significant relations with adverse health effects including dyslipidemia and glucose intolerance in obese and nonobese children and adolescents of different ethnic groups. PMID: 10393163 [PubMed - as supplied by publisher] 5541. Semin Cutan Med Surg. 1999 Jun;18(2):119-28. Recent advances in soft tissue augmentation. Krauss MC(1). Author information: (1)Tufts University School of Medicine; Center for Cosmetic Skin Surgery in the Department of Dermatology, New England Medical Center, Boston, MA 02111, USA. Soft tissue augmentation has become increasingly important as more individuals seek aesthetic improvement without major surgical procedures. The choice of an appropriate subcutaneous implant, whether solid or injectable, requires a thorough understanding of the materials available. This review of the literature addresses autologous fat and dermis transplantation, autologous and allogeneic human collagen, bovine collagen, acellular dermal allograft, hyaluronic acid derivatives, expanded polytetrafluoroethylene, polymethyl-methacrylate microspheres, and other potential biomaterials. The search for the perfect material to eradicate rhytids, smooth scars, and fill traumatic detects continues. New products appear, sometimes with great fanfare, which fail to fulfill the promise of a better alternative to what we use now. For this reason, an in-depth understanding of implant materials is necessary for any physician performing soft-tissue augmentation procedures. PMID: 10385280 [PubMed - indexed for MEDLINE] 5542. FEBS Lett. 1999 May 28;451(3):215-9. Tumour necrosis factor, a key role in obesity? Bulló-Bonet M(1), García-Lorda P, López-Soriano FJ, Argilés JM, Salas-Salvadó J. Author information: (1)Unitat de Nutrició Humana, Facultat de Medicina i Ciències de la Salut de Reus, Universitat Rovira i Virgili, Spain. Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in many metabolic responses in both normal and pathophysiological states. In spite of the fact that this cytokine (also known as "cachectin") has been related to many of the metabolic abnormalities associated with cachexia, recent studies suggest that TNF may also have a central role in obesity modulating energy expenditure, fat deposition and insulin resistance. This review deals with the role of TNF in the control of fat mass and obesity. PMID: 10371192 [PubMed - indexed for MEDLINE] 5543. Int J Obes Relat Metab Disord. 1999 Apr;23 Suppl 3:S64-71. Physical activity, obesity and blood lipids. Hardman AE(1). Author information: (1)Department of Physical Education, Sports Science and Recreation Management, Loughborough University, Leicestershire, UK. PURPOSE: To present the evidence concerning the influence of physical activity on the dyslipidaemia of obesity and overweight. METHODS: Review of a personal library of literature on the interactions of physical activity, lipoprotein metabolism and body fatness. SUMMARY OF FINDINGS: Obesity, in particular abdominal obesity, is associated with dyslipidaemia--specifically elevated plasma concentrations of triacylglycerol (TAG) in the fasted state, an exaggerated postprandial rise in plasma TAG, low concentrations of high density lipoprotein cholesterol (HDL) and possibly a preponderance of small dense low density lipoproteins. Regular physical activity contributes to the avoidance of overweight and hence to the development of dyslipidaemia. Although low levels of body fatness contribute to the high levels of HDL cholesterol and the low levels of TAG in trained people there are other important determinants of these characteristics. In particular, exercise (and probably training, that is regular, frequent exercise over months and years) enhances the metabolic capacity for TAG, possibly through mechanisms involving increased activity of lipoprotein lipase. This, in turn, has effects on other lipoprotein species such that the transport of TAG and cholesterol in the circulation is improved. There is evidence for a dose-response relationship, with for example, higher levels of HDL cholesterol in men and women who expend more energy in exercise. For the majority of healthy, sedentary adults frequent, moderate intensity exercise equivalent to a total gross energy expenditure of about 8.5 MJ per week is probably a sufficient to influence lipoprotein lipids. PMID: 10368005 [PubMed - indexed for MEDLINE] 5544. Int J Obes Relat Metab Disord. 1999 Apr;23 Suppl 3:S11-7. Exercise training and substrate utilisation in obesity. van Baak MA(1). Author information: (1)NUTRIM, Department of Human Biology, Maastricht University, The Netherlands. Together with diet and behavioural modification, regular exercise is one of the key components of programs for the treatment of obesity. It appears to be one of the major factors determining the long-term success of weight loss programs. One of the mechanisms that may underlie this and other beneficial effects of regular exercise is the effect of exercise training on substrate utilisation. Exercise training increases fat oxidation in lean subjects. The capacity to mobilise and oxidise fat has been shown to be impaired in obese and post-obese subjects. Thus, an increase in the capacity for fat oxidation may help to maintain fat and energy balance at a lower fat mass in individuals with a predisposition for obesity. However, in view of the impaired fat oxidation in obese and post-obese individuals the question arises whether exercise training also increases fat oxidation in the obese. Few studies have addressed this question and have investigated the effect of exercise training on substrate utilisation in obesity. Addition of an exercise training program has been shown to prevent the reduction of basal fat oxidation that is associated with diet-induced weight loss in two studies. No effect of additional exercise training on substrate oxidation during exercise was found. In post-obese subjects exercise training caused no change in 24 h substrate oxidation in one study and increased carbohydrate, rather than fat oxidation in another. In obese subjects neither low (40% maximal aerobic fitness (VO2max)) nor high (70% VO2max) intensity training was found to affect resting substrate oxidation. During exercise fractional fat oxidation was increased after low, but not after high intensity training. The question, whether exercise training increases fat oxidation in obese and post-obese as in lean subjects therefore cannot be answered conclusively at this point in time and requires further study. The role of exercise intensity and type of exercise needs to be studied as well. PMID: 10367998 [PubMed - indexed for MEDLINE] 5545. Mol Med Today. 1999 Jun;5(6):250-6. The role of agouti-related protein in regulating body weight. Wilson BD(1), Ollmann MM, Barsh GS. Author information: (1)Stanford University School of Medicine, B275 Beckman Center, Stanford, CA 94305-5428, USA. Erratum in Mol Med Today 1999 Aug;5(8):336. Defects in signaling by leptin, a hormone produced primarily by adipose tissue that informs the brain of the body's energy reserves, result in obesity in mice and humans. However, the majority of obese humans do not have abnormalities in leptin or its receptor but instead exhibit leptin resistance that could result from defects in downstream mediators of leptin action. Recently, two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified. Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders. PMID: 10366820 [PubMed - indexed for MEDLINE] 5546. Eur J Clin Nutr. 1999 Apr;53 Suppl 1:S124-31; discussion S131-5. Pregnancy and lactation in relation to range of acceptable carbohydrate and fat intake. Catalano PM(1). Author information: (1)Department of Reproductive Biology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio 44122, USA. The additional energy requirements of pregnancy are needed for increases in maternal (breast, uterus and adipose) and feto-placental tissue accrued during pregnancy as well as the additional running cost of pregnancy for example increased cardiac output. Based on prospective longitudinal studies, the additional energy requirements of pregnancy range from > 500 MJ in Swedish women to net savings of approximately 50 MJ in women in The Gambia with their usual nutritional intake. In addition to the wide variation in estimated energy expenditure among various ethnic populations, there is as much as a 10-20 fold range in the total energy cost of pregnancy and lactation within relatively homogenous populations. The estimates of energy intake in these studies, however, are generally less than the estimates of total energy expenditure. The discrepancy between energy intake and energy expenditure during pregnancy is most probably due to several factors including decreased maternal activity, unreliable reporting of energy intake and possibly increased metabolic efficiency of basal metabolic rate, thermic effect of foods and physical activity. Based on recent studies, variations in maternal pregravid glucose insulin sensitivity may account for part of the observed variability associated with maternal metabolic adaptations during pregnancy. Decreases in insulin sensitivity have a significant inverse correlation with accretion of adipose tissue in early pregnancy. Likewise, there is a significant inverse correlation between decreases in basal oxygen consumption with increases in endogenous glucose production. The mechanism for these changes remain speculative. Additionally, although serum leptin concentrations increase 66% in early pregnancy and are correlated with maternal fat mass and basal energy expenditure, the increases in serum leptin occur prior to any significant increases in body fat or basal metabolic rate suggesting that pregnancy represents another leptin resistant state. Based on these data, specific recommendations for acceptable carbohydrate and fat intake during pregnancy and lactation are not possible for every woman at this time. Additional prospective studies, evaluating long-term maternal and neonatal outcome are needed before more meaningful nutritional recommendations can be proposed. PMID: 10365990 [PubMed - indexed for MEDLINE] 5547. Eur J Clin Nutr. 1999 Apr;53 Suppl 1:S78-83. Response to and range of acceptable fat intakes in infants and children. Koletzko B(1). Author information: (1)Division of Metabolic Disorders and Nutrition, Dr. von Hannendes Kinderspital, Ludwig-Maximilians-University of Munich, München, Germany. The maximum and minimum fat intakes that are physiologically tolerable by healthy infants and young children are not well defined. The maximum tolerable fat intake appears to be limited by the minimum requirements of protein, carbohydrates and micronutrients. It is unresolved whether or not there is a minimum metabolic requirement of dietary fat, beyond the requirements of essential fatty acids and lipid soluble vitamins and the effects on energy density and an adequate total energy intake. The first postnatal months of the human infant are characterized by a rapid weight gain and extensive fat deposition. Body fat deposition equals 25% of the total energy intake during the first 2 and 16% during the third and fourth months, respectively. The provision of dietary lipids in amounts at least matching the needs for tissue storage and fat oxidation appears to be of advantage for energy balance and physiological growth. Some reports have associated low fat diets with less than 30% of energy as fat with adverse effects on child growth beyond infancy, but it remains unresolved whether these effects were caused by an associated effect on dietary energy density and total intake of energy and other nutrients. Closely supervised, healthy infants from an affluent population grew normally with a diet providing about 30% of the energy as fat from the seventh month of life onwards, but it is not known to what extent adaptive mechanisms such as a reduction of physical activity may have been required. It is not known whether infants and young children stressed by frequent occurrence of diarrhea and infections may adapt to a 30% fat diet as well or not. No evidence is available for a health benefit of a low total fat intake in infancy. In view of the limited available information, further research is required to define optimal fat intakes in early childhood since this question is of major importance for child health. PMID: 10365983 [PubMed - indexed for MEDLINE] 5548. Eur J Clin Nutr. 1999 Apr;53 Suppl 1:S53-65. De novo lipogenesis in humans: metabolic and regulatory aspects. Hellerstein MK(1). Author information: (1)Department of Nutritional Sciences, University of California at Berkeley, 94270-3104, USA. The enzymatic pathway for converting dietary carbohydrate (CHO) into fat, or de novo lipogenesis (DNL), is present in humans, whereas the capacity to convert fats into CHO does not exist. Here, the quantitative importance of DNL in humans is reviewed, focusing on the response to increased intake of dietary CHO. Eucaloric replacement of dietary fat by CHO does not induce hepatic DNL to any substantial degree. Similarly, addition of CHO to a mixed diet does not increase hepatic DNL to quantitatively important levels, as long as CHO energy intake remains less than total energy expenditure (TEE). Instead, dietary CHO replaces fat in the whole-body fuel mixture, even in the post-absorptive state. Body fat is thereby accrued, but the pathway of DNL is not traversed; instead, a coordinated set of metabolic adaptations, including resistance of hepatic glucose production to suppression by insulin, occurs that allows CHO oxidation to increase and match CHO intake. Only when CHO energy intake exceeds TEE does DNL in liver or adipose tissue contribute significantly to the whole-body energy economy. It is concluded that DNL is not the pathway of first resort for added dietary CHO, in humans. Under most dietary conditions, the two major macronutrient energy sources (CHO and fat) are therefore not interconvertible currencies; CHO and fat have independent, though interacting, economies and independent regulation. The metabolic mechanisms and physiologic implications of the functional block between CHO and fat in humans are discussed, but require further investigation. PMID: 10365981 [PubMed - indexed for MEDLINE] 5549. Semin Cell Dev Biol. 1999 Feb;10(1):3-10. Molecular regulation of adipocyte differentiation. Cowherd RM(1), Lyle RE, McGehee RE Jr. Author information: (1)Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, USA. Significant advances have been made recently toward understanding the molecular events that regulate adipocyte differentiation. In vitro models of adipogenesis, such as the 3T3-L1 and F-442A preadipocyte cell lines have proven to be an invaluable resource in elucidating mechanisms of adipocyte differentiation. Subject to modulation by hormonal, dietary, and genetic influences, the differentiation program now appears to be distinctly controlled through the coordinate regulation of transcription factors that predominantly include members of the C/EBP and PPAR families. Increased understanding of these critical factors and how they are regulated will provide insights into adipose tissue development as well as treatment of obesity. PMID: 10355023 [PubMed - indexed for MEDLINE] 5550. Z Arztl Fortbild Qualitatssich. 1999 Apr;93 Suppl 1:35-9. [Pathogenesis of Graves' ophthalmopathy]. [Article in German] Heufelder AE(1). Author information: (1)Medizinisches Klinikum, Klinikum Innenstadt, Ludwig-Maximilians-Universität, München. u7g11av@mail.lrz-muenchen.de Ophthalmopathy, the most frequent extrathyroidal manifestation of Graves' disease, results from an increased volume of the orbital tissues (connective and adipose tissue, interstitial enlargement of extraocular muscles) within the enclosed space of the bony orbits. While the primary antigen is still uncertain, the thyrotropin receptor has recently become a prime candidate because it is expressed both by thyroid epithelial cells and by orbital preadipocyte fibroblasts. Tolerance towards the thyroidal and orbital TSH receptor may be disrupted by bacterial or viral antigens through a "molecular mimicry"-type mechanism. In the context of appropriate costimulatory signals, this would prompt antigen presentation by local dendritic cells and macrophages followed by the recruitment of TSH receptor-specific T cells to the orbital space. As a result, orbital T cells, fibroblasts, adipocytes and perhaps other residential cells would release numerous cytokines, growth factors and inflammatory mediators, many of which act as potent stimulators of glycosaminoglycan accumulation and edema formation. Once initiated, the orbital immune process frequently takes on a momentum of its own, leading to non-specific but nonetheless harmful consequences such as tissue hypoxia, oxygen free radical damage and fibrogenic tissue remodeling. The clinical signs and symptoms of GO reflect the mechanical consequences of increased orbital tissue volume and pressure within the confines of the bony orbits. PMID: 10355048 [PubMed - indexed for MEDLINE] 5551. Semin Cell Dev Biol. 1999 Feb;10(1):31-41. Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Cianflone K(1), Maslowska M, Sniderman AD. Author information: (1)Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University, Montreal, Quebec, Canada. Acylation stimulating protein (ASP) is an adipocyte-derived protein which has potent anabolic effects on human adipose tissue for both glucose and free fatty acid (FFA) storage. Our hypothesis is that: (i) ASP is produced by adipocytes in specific response to stimuli that initiate efficient fat storage; (ii) ASP interacts with a specific adipocyte receptor triggering an intracellular signalling pathway which activates triglyceride synthesis and fat storage; and (iii) that absence (ASP knockout mouse) or excess (in normal or obese mice) of ASP will result in physiological changes of plasma fat clearance and adipose tissue metabolism. The present review focuses on advances in ASP within the last 2 years with particular emphasis on these three aspects of ASP. PMID: 10355026 [PubMed - indexed for MEDLINE] 5552. Semin Cell Dev Biol. 1999 Feb;10(1):19-29. The role of TNF alpha in adipocyte metabolism. Sethi JK(1), Hotamisligil GS. Author information: (1)Division of Biological Sciences, Harvard School of Public Health, Boston, MA 02115, USA. Tumor necrosis factor-alpha (TNF alpha) is a multifunctional cytokine which exerts a myriad of biological actions in different tissues and species. Many of these actions can perturb the normal regulation of energy metabolism. In adipose tissue, in particular, TNF alpha has been demonstrated to regulate or interfere with adipocyte metabolism at numerous sites including transcriptional regulation, glucose and fatty acid metabolism and hormone receptor signaling. The implications of these perturbations in disease states and the current understanding of the molecular mechanisms utilised by TNF alpha are discussed herein. PMID: 10355025 [PubMed - indexed for MEDLINE] 5553. Semin Cell Dev Biol. 1999 Feb;10(1):11-8. An adipocyte-central nervous system regulatory loop in the control of adipose homeostasis. Loftus TM(1). Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Mounting evidence supports a 'lipostatic' model for the regulation of adipose mass. In such a model, signals are generated in the periphery in proportion to adipose mass that act on hypothalamic control centers in the brain to regulate food intake and energy expenditure. Two such signals, leptin and insulin, have been identified and found to dramatically lower food intake and body weight. Several signalling molecules in the effector pathways that mediate the response to these signals in the brain have also been identified. The regulation of these factors and the nature of the adipose-CNS regulatory loop will be discussed. PMID: 10355024 [PubMed - indexed for MEDLINE] 5554. Recenti Prog Med. 1999 Apr;90(4):196-201. [Juvenile obesity: the pathogenetic aspects and therapeutic outlook]. [Article in Italian] Catassi C(1). Author information: (1)Istituto di Clinica Pediatrica, Università, Ancona. catassi@tin.it PMID: 10354731 [PubMed - indexed for MEDLINE] 5555. Br J Dermatol. 1999 Jun;140(6):1161-4. Lipodystrophia centrifugalis abdominalis infantilis in a 4-year-old Caucasian girl: association with partial IgA deficiency and autoantibodies. Müller S(1), Beissert S, Metze D, Luger TA, Bonsmann G. Author information: (1)Department of Dermatology, Westfälische-Wilhelms Universität, Von Esmarch-Str. 56, D-48149 Münster, Germany. We report the third case of lipodystrophia centrifugalis abdominalis outside East Asia. A 4-year-old Caucasian girl developed an area of bluish erythema on the left side of the lower abdomen which spread centrifugally to the umbilical and inguinal areas with depression of the skin resulting from the loss of subcutaneous fat, surrounded by an erythematous border. This unusual skin disease was characterized by clinical and histological examination. Laboratory tests revealed a partial IgA deficiency, antinuclear antibodies and IgG antibodies against gliadin. PMID: 10354090 [PubMed - indexed for MEDLINE] 5556. Proc Nutr Soc. 1999 Feb;58(1):123-31. Preparing for inactivity: how insectivorous bats deposit a fat store for hibernation. Speakman JR(1), Rowland A. Author information: (1)Aberdeen Centre for Energy Regulation and Obesity, Department of Zoology, University of Aberdeen, UK. J.Speakman@abdn.ac.uk During late autumn insectivorous bats must deposit a fat store to cover their energy demands throughout the period of hibernation, yet the density of aerial insects by this time has already declined from its peak in midsummer. Krzanowski (1961) suggested that bats are able to deposit a fat store by manipulating their energy expenditure; specifically by selecting cold roosting locations rather than warm roosts, and depressing their body temperatures during the day roosting period. It was hypothesized that these behavioural changes result in very low daily energy demands, and despite reduced food intake the animals are still able to gain body fat. We made several tests of this hypothesis. First, we explored the thermo-selection behaviour of long-eared bats (Plecotus auritus) in the summer and in the pre-hibernal period. We found that in summer bats preferred temperatures of about 32-35 degrees (about thermoneutral), but in the pre-hibernal period they preferred much colder temperatures of about 10 degrees. Second, using open-flow respirometry we found that in the cold pre-hibernal bats entered torpor for an average of 14 h each day. Compared with bats held at 30 degrees (that did not go torpid), the bats at 7 degrees expended less energy. The extent of saving was sufficient to positively affect their mass balance, despite the fact that bats at lower temperature also had reduced digestive efficiencies. Our findings support the hypothesis that during the pre-hibernal period insectivorous bats manipulate their mass balance primarily by alterations in their energy expenditure, specifically utilizing energy-sparing mechanisms such as torpor. PMID: 10343349 [PubMed - indexed for MEDLINE] 5557. Proc Nutr Soc. 1999 Feb;58(1):99-105. Influence of intense physical activity on energy balance and body fatness. Tremblay A(1), Doucet E. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Québec, Canada. angelo.tremblay@kin.msp.ulaval.ca The reduced contribution of physical activity to daily energy expenditure and the accessibility to high-fat foods have put an excessive burden on energy balance, resulting in an increase in the prevalence of obesity throughout the world. In this context, fat gain can be seen as a natural adaptation to deal with a fattening lifestyle, since the hormonal adaptations that accompany fat gain favour the readjustment of energy expenditure to energy intake. Intense physical activity would also seem to facilitate the regulation of energy balance, since it increases the energy cost of exercise, increases post-exercise energy expenditure and the potential of skeletal muscles to utilize lipids, and also favours a decrease in post-exercise intake. Moreover, the effects of intense exercise seem to be mediated by an activation of sympathetic nervous system activity that seems to be specific to skeletal muscle. It is also important to manipulate macronutrient composition in order to reduce fat intake, because unhealthy food habits can favour overfeeding and thus overcome the energy deficit caused by regular physical activity. Under free-living conditions, the combination of vigorous activity and healthy food practices can amount to a substantial weight loss which is comparable with that of other non-surgical approaches to treat obesity. PMID: 10343346 [PubMed - indexed for MEDLINE] 5558. Ann Med. 1999 Apr;31 Suppl 1:7-12. Nutrition in early life: somatic growth and serum lipids. Boulton TJ(1), Garnett SP, Cowell CT, Baur LA, Magarey AM, Landers MC. Author information: (1)Department of Paediatrics, Nepean Health, Sydney, NSW, Australia. boultot@wahs.health.nsw.gov.au This paper addresses the questions of whether early nutritional experience affects later somatic growth, the growth of the adipose tissue, or the levels of serum lipids among well-nourished children. The analyses are based on data from three prospective studies. Postnatal nutrition and growth: there were differences in growth between breast-fed and formula-fed children. There was no association between linear growth and differences in food energy or macronutrient intake. Birth size and postnatal growth: there was no association between ponderal index (PI) at birth and body mass index (BMI) in the second year. For boys, the PI at 3 and 6 months of age was significantly positively correlated with BMI at the ages of 8 and 15 years, but not for girls. Childhood growth and lipids: there was no association between lipids at the age of 8 years and either birth weight or length, but children who had had a low PI at birth had higher lipid levels at the age 8 years. A positive association was found between serum lipids and abdominal fat and BMI. We conclude that, although early diet may influence growth rate beyond infancy, the evidence for fat patterning resulting from differences in fetal or early postnatal nutrition is still open to question. PMID: 10342494 [PubMed - indexed for MEDLINE] 5559. Int J Obes Relat Metab Disord. 1999 Apr;23(4):329-35. Visceral adipose tissue: a critical review of intervention strategies. Smith SR(1), Zachwieja JJ. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. OBJECTIVE: To review the published literature regarding the effect of caloric restriction, pharmacologic intervention, and exercise to promote the loss of visceral adipose tissue (VAT) DESIGN: A review was conducted of published studies which measured VAT using computed tomography or magnetic resonance imaging before and after caloric restriction, pharmacologic therapy, or exercise. STUDIES REVIEWED: 23 separate studies were reviewed. Men represented 38% and women 63% of the 599 volunteers. There were 17 black volunteers and 30 patients with NIDDM included in these studies. MEASUREMENTS: Data regarding the baseline and change in VAT, body fat, and body weight were collected. RESULTS: Most interventions demonstrated a preferential loss of VAT regardless of the intervention applied. When expressed as percent change in VAT/percent change in body fat, a ratio can be calculated which we call the Selectivity Index (SI). When this index is applied to the literature reviewed, two observations can be made. First, the Selectivity Index is higher when baseline body fat is higher. Second, there is a direct relationship between the Selectivity Index and the baseline visceral fat ratio. These two observations suggest that individuals with greater visceral fat mass, either through an increase in the body weight or the propensity to store fat in the visceral depot, lose more visceral fat when adjusted to the loss of body fat. CONCLUSION: In conclusion, the Selectivity Index is useful to compare the ability of an intervention to specifically target the loss of AT. This simple index can serve as a benchmark for comparing intervention studies to each other. PMID: 10340808 [PubMed - indexed for MEDLINE] 5560. J Anim Sci. 1999 May;77(5):1249-57. The brain-pituitary-adipocyte axis: role of leptin in modulating neuroendocrine function. Barb CR(1). Author information: (1)USDA, ARS, Richard B. Russell Agriculture Research Center, Athens, GA 30604-5677, USA. rbarb@ars.usda.gov The recently discovered protein leptin has a molecular mass of 16 kDa, consists of 146 amino acids, and is synthesized and secreted by adipose tissue. Leptin affects feed intake, the neuroendocrine-axis, and immunological processes. The protein was first identified as the gene product that is deficient in the obese ob/ob mouse. Leptin serves as a circulating signal of nutritional status and plays a pivotal role in regulation of body weight, energy expenditure, growth, and reproduction. PMID: 10340594 [PubMed - indexed for MEDLINE] 5561. Diabetes Metab. 1999 Mar;25(1):11-21. Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. Weyer C(1), Gautier JF, Danforth E Jr. Author information: (1)National Institutes of Health, Phoenix, AZ. cweyer@phx.niddk.nih.gov Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans. PMID: 10335419 [PubMed - indexed for MEDLINE] 5562. Baillieres Clin Endocrinol Metab. 1998 Oct;12(3):441-51. Androgens and abdominal obesity. Mårin P(1), Arver S. Author information: (1)Department of Heart and Lung Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden. Central or visceral obesity is recognized as a main risk factor for cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral obesity, increased blood lipid levels, hypertension and impaired glucose tolerance defines the metabolic syndrome that today is widely recognized as one of the prime factors behind cardiovascular morbidity and mortality. Endocrine disorders such as insulinoma, hypothyroidism and hypercortisolism are known to cause obesity. However, it is only hypercortisolism that is associated with increased abdominal fat accumulation. Recently, new findings have shed light on subtle endocrinopathies that are prevalent in individuals presenting with the metabolic syndrome. Such derangements are of borderline character and often fall within the normal reference range. Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis of the underlying mechanism has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrates that relatively low testosterone levels are a risk factor for development of visceral obesity. The primary event that triggers the initial development of visceral obesity is not known, but it seems plausible that increased activity in the hypothalamus-pituitary-adrenal axis can be of major importance. PMID: 10332565 [PubMed - indexed for MEDLINE] 5563. Mol Cell Biochem. 1999 Feb;192(1-2):63-8. Long chain fatty acids as modulators of gene transcription in preadipose cells. Grimaldi PA(1), Teboul L, Gaillard D, Armengod AV, Amri EZ. Author information: (1)INSERM U 470, Centre de Biochimie, UFR Sciences, Université de Nice-Sophia Antipolis, Nice, France. During the last years, it has been clearly established that long-chain fatty acids act as modulators of gene expression in various tissues, such as adipose tissue, intestine and liver. This transcriptional action of fatty acids explains in part adaptation mechanisms of tissues to nutritional changes and especially to high-fat diets by increasing expression of proteins involved in lipid catabolism in liver and fatty acid uptake and utilization in other tissues. It is now clearly demonstrated that some of these transcriptional effects of fatty acids are mediated by activation of specific nuclear hormone receptors, called peroxisome proliferator-activated receptors (PPARs). These findings will be discussed with a special reference to control of gene expression in preadipocytes and adipose tissue development. PMID: 10331659 [PubMed - indexed for MEDLINE] 5564. J Am Acad Dermatol. 1999 May;40(5 Pt 2):857-61. Primary cutaneous Ki-1(CD30) positive anaplastic large cell lymphoma in childhood. Tomaszewski MM(1), Moad JC, Lupton GP. Author information: (1)Department of Dermatopathology, Armed Forced Institute of Pathology, Washington, District of Columbia 20306-6000, USA. TOMASZEW@afip.osd.mil Comment in J Am Acad Dermatol. 2001 Oct;45(4):638-40. Primary cutaneous Ki-1(CD30) positive anaplastic large cell lymphoma (ALCL) is an unusual tumor in the pediatric population. However, the nodal-based form of the disease compared with other histologic subsets of childhood non-Hodgkin's lymphomas (NHL) more frequently involves skin, soft tissue, and bone. The objective of this article is to determine the histologic and immunologic characteristics of childhood primary cutaneous Ki-1(CD30) positive ALCL and its prognosis. The clinical data, histologic features and immunohistochemical profiles of skin biopsy specimens from 3 children with cutaneous Ki-1(CD30) positive lymphoma were reviewed. A literature search was performed and disclosed information on 5 childhood cases. The 3 patients with primary cutaneous Ki-1(CD30) positive ALCL all presented similarly as rapidly growing masses initially and clinically believed to be infectious/reactive processes. The diagnosis was established on the basis of histopathologic examination and immunohistochemical studies. Histologic sections revealed an extensive infiltrate of tumor cells extending throughout the entire dermis into the subcutaneous fat with frank ulceration in 1 patient. No significant epidermotropism was noted. Tumor cells exhibited striking cellular pleomorphism and a high mitotic rate with numerous atypical mitoses. Inflammatory cells were present in all patients. The tumor cells stained positively for Ki-1 antigen (CD30), epithelial membrane antigen, and for T-cell markers (UCHL-1, CD3). One of 3 cases, however, failed to stain for leukocyte common antigen (LCA). No clinically apparent adenopathy was observed in any of the patients. In all instances the patients developed recurrent disease in the skin at sites separate from the primary location. None of the patients demonstrated any involvement of lymph nodes, bone marrow, or other organ systems. All patients were treated with chemotherapy with good response. Primary cutaneous Ki-1(CD30) positive lymphoma is rare in children and is characterized by recurrences. The prognosis seems to be favorable. PMID: 10321635 [PubMed - indexed for MEDLINE] 5565. Exp Clin Endocrinol Diabetes. 1999;107(2):119-25. Mechanisms of TNF-alpha-induced insulin resistance. Hotamisligil GS(1). Author information: (1)Harvard School of Public Health, Department of Nutrition, Boston, MA 02115, USA. Comment in Exp Clin Endocrinol Diabetes. 1999;107(2):111-2. There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin. PMID: 10320052 [PubMed - indexed for MEDLINE] 5566. Exp Clin Endocrinol Diabetes. 1999;107(2):107-10. Multiple sites of insulin resistance: muscle, liver and adipose tissue. Stumvoll M(1), Jacob S. Author information: (1)Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany. Comment on Exp Clin Endocrinol Diabetes. 1999;107(2):140-7. PMID: 10320049 [PubMed - indexed for MEDLINE] 5567. Med Res Rev. 1999 May;19(3):223-48. The role of cytokines in cancer cachexia. Argilés JM(1), López-Soriano FJ. Author information: (1)Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. argiles@porthos.bio.ub.es A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the metabolic derangements associated with cancer-bearing states. Indeed, these alterations lead to a pathological state known as cancer cachexia which is, unfortunately, one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is characterized by weight loss together with anorexia, weakness, anemia, and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The cachectic patient, in addition to having practically no adipose tissue, is basically subject to an important muscle wastage manifested as an excessive nitrogen loss. The metabolic changes are partially mediated by alterations in circulating hormone concentrations (insulin, glucagon, and glucocorticoids in particular) or in their effectiveness. The present study reviews the involvement of different cytokines in the metabolic and physiological alterations associated with tumor burden and cachexia. Among these cytokines, some can be considered as procachectic (such as tumor necrosis factor-alpha), while others having opposite effects can be named as anticachectic cytokines. It is the balance between these two cytokine types that finally seems to have a key role in cancer cachexia. PMID: 10232651 [PubMed - indexed for MEDLINE] 5568. Harv Womens Health Watch. 1999 Jun;6(10):2-3. Health risks. Body fat. [No authors listed] PMID: 10233807 [PubMed - indexed for MEDLINE] 5569. Vitam Horm. 1999;57:249-324. 11 beta-Hydroxysteroid dehydrogenase. Stewart PM(1), Krozowski ZS. Author information: (1)Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, United Kingdom. In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid. By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression. PMID: 10232052 [PubMed - indexed for MEDLINE] 5570. Intern Med. 1999 Feb;38(2):213-5. The regulation of obese (ob) gene expression by intracellular fatty acid concentration in adipocytes. Kawakami Y(1), Arai T, Okuda Y, Yamashita K. Author information: (1)Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba. PMID: 10225691 [PubMed - indexed for MEDLINE] 5571. Intern Med. 1999 Feb;38(2):210-2. Clinical implication of leptin, the obese gene product. Ogawa Y(1), Masuzaki H, Nakao K. Author information: (1)Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine. PMID: 10225690 [PubMed - indexed for MEDLINE] 5572. Intern Med. 1999 Feb;38(2):207-9. Association between beta3-adrenoreceptor polymorphism with obesity and diabetes in Japan. Yoshida T(1), Sakane N. Author information: (1)The First Department of Internal Medicine, Kyoto Prefectural University of Medicine. PMID: 10225689 [PubMed - indexed for MEDLINE] 5573. Intern Med. 1999 Feb;38(2):202-6. Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Funahashi T(1), Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y. Author information: (1)The Second Department of Internal Medicine, Osaka University Medical School, Suita. Obesity which is defined as accumulation of excess body fat, is a major cause of atherosclerotic vascular disease in industrial countries. Recent advances in the biology of adipose tissue have revealed that adipose tissue is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Through a systematic search of active genes in adipose tissue, we found that adipose tissue, especially visceral fat expressed numerous genes for secretory proteins (about 30% of total genes analyzed). Among them, plasminogen activator-1 (PAI-1), which is a regulator of the fibrinolytic system, was overexpressed in the visceral fat in an animal model of obesity. Plasma levels of PAI-1 were closely correlated with visceral fat adiposity. Thus, PAI-1 secreted from visceral fat may play some role in thrombotic vascular disease in visceral obesity. Adiponectin, a novel adipose-specific gene product, which has a matrix-like structure, is abundantly present in the bloodstream. Dysregulated secretion of adiponectin may be related to vascular disease in obesity. Biologically active molecules secreted from adipose tissue (adipocytokines) may have important roles in the development of atherosclerotic disease in obesity. PMID: 10225688 [PubMed - indexed for MEDLINE] 5574. Intern Med. 1999 Feb;38(2):200-2. Obesity and obstructive sleep apnea syndrome. Chin K(1), Ohi M. Author information: (1)The Department of Physical Therapeutics, Kyoto University Hospital of Medicine. PMID: 10225687 [PubMed - indexed for MEDLINE] 5575. Int J Biochem Cell Biol. 1999 Mar-Apr;31(3-4):395-403. Angiotensin II and extracellular matrix homeostasis. Weber KT(1), Swamynathan SK, Guntaka RV, Sun Y. Author information: (1)Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia, USA. karl_t_weber@muccmail.missouri.edu As a circulating hormone, endocrine properties of angiotensin (Ang) II are integral to circulatory homeostasis. Produced de novo its autocrine/paracrine properties contribute to biologic responses involving various connective tissues (e.g. extracellular matrix, adipose tissue, bone and its marrow). In this brief review, we develop the concept of extracellular matrix homeostasis, a self regulation of cellular composition and structure, wherein fibroblast-derived AngII regulates elaboration of TGF-beta 1, a fibrogenic cytokine responsible for connective tissue formation at normal and pathologic sites of collagen turnover. PMID: 10224666 [PubMed - indexed for MEDLINE] 5576. Physiol Rev. 1999 Apr;79(2):451-80. Regulation of body weight in humans. Jéquier E(1), Tappy L. Author information: (1)Institute of Physiology, University of Lausanne, Lausanne, Switzerland. The mechanisms involved in body weight regulation in humans include genetic, physiological, and behavioral factors. Stability of body weight and body composition requires that energy intake matches energy expenditure and that nutrient balance is achieved. Human obesity is usually associated with high rates of energy expenditure. In adult individuals, protein and carbohydrate stores vary relatively little, whereas adipose tissue mass may change markedly. A feedback regulatory loop with three distinct steps has been recently identified in rodents: 1) a sensor that monitors the size of adipose tissue mass is represented by the amount of leptin synthesized by adipose cells (a protein encoded by the ob gene) which determines the plasma leptin levels; 2) hypothalamic centers, with specific leptin receptors, which receive and integrate the intensity of the signal; and 3) effector systems that influence the two determinants of energy balance, i.e., energy intake and energy expenditure. With the exception of a few very rare cases, the majority of obese human subjects have high plasma leptin levels that are related to the size of their adipose tissue mass. However, the expected regulatory responses (reduction in food intake and increase in energy expenditure) are not observed in obese individuals. Thus obese humans are resistant to the effect of endogenous leptin, despite unaltered hypothalamic leptin receptors. Whether defects in the leptin signaling cascade play a role in the development of human obesity is a field of great actual interest that needs further research. Present evidences suggest that genetic and environmental factors influence eating behavior of people prone to obesity and that diets that are high in fat or energy dense undermine body weight regulation by promoting an overconsumption of energy relative to need. PMID: 10221987 [PubMed - indexed for MEDLINE] 5577. Free Radic Biol Med. 1999 Mar;26(5-6):746-61. Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Palace VP(1), Khaper N, Qin Q, Singal PK. Author information: (1)Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, Winnipeg, Manitoba, Canada. Despite being one of the first vitamins to be discovered, the full range of biological activities for vitamin A remains to be defined. Structurally similar to vitamin A, carotenoids are a group of nearly 600 compounds. Only about 50 of these have provitamin A activity. Recent evidence has shown vitamin A, carotenoids and provitamin A carotenoids can be effective antioxidants for inhibiting the development of heart disease. Vitamin A must be obtained from the diet: green and yellow vegetables, dairy products, fruits and organ meats are some of the richest sources. Within the body, vitamin A can be found as retinol, retinal and retinoic acid. Because all of these forms are toxic at high concentrations, they are bound to proteins in the extracellular fluids and inside cells. Vitamin A is stored primarily as long chain fatty esters and as provitamin carotenoids in the liver, kidney and adipose tissue. The antioxidant activity of vitamin A and carotenoids is conferred by the hydrophobic chain of polyene units that can quench singlet oxygen , neutralize thiyl radicals and combine with and stabilize peroxyl radicals. In general, the longer the polyene chain, the greater the peroxyl radical stabilizing ability. Because of their structures, vitamin A and carotenoids can autoxidize when O2 tension increases, and thus are most effective antioxidants at low oxygen tensions that are typical of physiological levels found in tissues. Overall, the epidemiological evidence suggests that vitamin A and carotenoids are important dietary factors for reducing the incidence of heart disease. Although there is considerable discrepancy in the results from studies in humans regarding this relationship, carefully controlled experimental studies continue to indicate that these compounds are effective for mitigating and defending against many forms of cardiovascular disease. More work, especially concerning the relevance of how tissue concentrations, rather than plasma levels, relate to the progression of tissue damage in heart disease is required. This review assembles information regarding the basic structure and metabolism of vitamin A and carotenoids as related to their antioxidant activities. Epidemiological, intervention trials and experimental evidence about the effectiveness of vitamin A and carotenoids for reducing cardiovascular disease is also reviewed. PMID: 10218665 [PubMed - indexed for MEDLINE] 5578. Ann Intern Med. 1999 Apr 20;130(8):671-80. The role of leptin in human obesity and disease: a review of current evidence. Mantzoros CS(1). Author information: (1)Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. cmantzor@bidmc.harvard.edu PURPOSE: To review recent advances in the pathophysiology and potential clinical applications of leptin, an adipose tissue-derived hormone. DATA SOURCES: A MEDLINE search of the literature on leptin and the bibliographies of relevant papers. STUDY SELECTION: All 1320 publications on leptin. DATA EXTRACTION: All identified articles were reviewed. Cited publications were selected on the basis of study quality and relevance to human obesity and disease. DATA SYNTHESIS: Leptin is a 16-kilodalton adipocyte-derived hormone that circulates in the serum in the free and bound form. Serum levels of leptin reflect the amount of energy stored in adipose tissue. Short-term energy imbalance as well as serum levels of several cytokines and hormones influence circulating leptin levels. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate neuroendocrine function and energy intake and expenditure. Thus, leptin plays an important role in the pathogenesis of obesity and eating disorders and is thought to mediate the neuroendocrine response to food deprivation. Phase I and II trials recently showed that leptin administration to humans is safe, and ongoing phase III trials are assessing the efficacy of leptin as a treatment for obesity and related disorders. Availability of leptin or smaller and more soluble leptin analogues for clinical studies in humans is expected to significantly advance understanding of the mechanisms underlying energy homeostasis in humans. CONCLUSIONS: Leptin is significantly broadening our understanding of the mechanisms underlying neuroendocrine function, body weight, and energy homeostasis. Elucidation of these mechanisms is expected to result in the development of novel therapeutic approaches for obesity and eating disorders. PMID: 10215564 [PubMed - indexed for MEDLINE] 5579. J Basic Clin Physiol Pharmacol. 1998;9(2-4):281-94. Insulin resistance: site of the primary defect or how the current and the emerging therapies work. Kolaczynski JW(1), Caro JF. Author information: (1)Eli Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Insulin resistance is one of the cardinal pathophysiological components of the metabolic syndrome, type 2 diabetes, and frequently co-exists with essential hypertension. Although insulin resistance is defined as inadequate target organ (muscle, liver and fat) responsiveness and/or sensitivity to insulin, the primary defect may be located in the target organs themselves or at their remote controller--the central nervous system. One of the ways of resolving this dilemma is studying the mechanisms of action of drugs that have insulin-sensitizing properties. In this brief review we discuss how the known and potential insulin sensitizers: metformin, appetite suppressants, thiazolidinediones, and the new class of centrally acting antihypertensive drugs, I1-receptor agonists, may work. PMID: 10212839 [PubMed - indexed for MEDLINE] 5580. J Basic Clin Physiol Pharmacol. 1998;9(2-4):153-65. Role of SNARE's in the GLUT4 translocation response to insulin in adipose cells and muscle. St-Denis JF(1), Cushman SW. Author information: (1)Experimental Diabetes, Metabolism, and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jfstd@sickkids.on.ca Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface. This is achieved by differentially modulating GLUT4 exocytosis and endocytosis, between a specialized intracellular compartment and the plasma membrane. Ligands which activate the heterotrimeric GTP-binding proteins Gs and Gi appear to modulate insulin-stimulated glucose transport through effects on the fusion of docked GLUT4-containing vesicles with the plasma membrane. In insulin resistance states, reduced cellular GLUT4 levels in adipose cells fully account for the decreased glucose transport response to insulin in these cells. In contrast, although insulin-stimulated GLUT4 translocation is also impaired in muscle, total cellular levels of GLUT4 are not altered. The defect in muscle has been attributed to a GLUT4 trafficking problem and thus studies of this mechanism could provide clues as to the nature of the impairment. The movement of GLUT4-containing vesicles from an intracellular storage site to the plasma membrane and the fusion of docked GLUT4-containing vesicles with the plasma membrane are conceptually similar to some secretory processes. A general hypothesis called the SNARE hypothesis (soluble NSF attachment protein receptors where NSF stands for N-ethylmaleimide-sensitive fusion protein) postulates that the specificity of secretory vesicle targeting is generated by complexes that form between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's). Several v- and t-SNARE's have been identified in adipose cells and muscle. VAMP2 and VAMP3/cellubrevin (v-SNARE's) have been shown to interact with the t-SNARE's syntaxin 4 and SNAP-23. The cytosolic protein NSF has the characteristic of binding to the v-/t-SNARE complex through its interaction with alpha-SNAP, another soluble factor. Furthermore, recent studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and thus are likely to be involved in the Gs- and Gi-mediated modulation of the glucose transport response to insulin as well. This review summarizes recent advances on the normal mechanism of GLUT4 translocation and discusses how this process could be affected in insulin resistant states such as type II diabetes. PMID: 10212832 [PubMed - indexed for MEDLINE] 5581. Br J Nutr. 1998 Dec;80(6):495-502. Lipoprotein lipase and the disposition of dietary fatty acids. Fielding BA(1), Frayn KN. Author information: (1)Oxford Lipid Metabolism Group, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, UK. Lipoprotein lipase (EC 3.1.1.34; LPL) is a key enzyme regulating the disposal of lipid fuels in the body. It is expressed in a number of peripheral tissues including adipose tissue, skeletal and cardiac muscle and mammary gland. Its role is to hydrolyse triacylglycerol (TG) circulating in the TG-rich lipoprotein particles in order to deliver fatty acids to the tissue. It appears to act preferentially on chylomicron-TG, and therefore may play a particularly important role in regulating the disposition of dietary fatty acids. LPL activity is regulated according to nutritional state in a tissue-specific manner according to the needs of the tissue for fatty acids. For instance, it is highly active in lactating mammary gland; in white adipose tissue it is activated in the fed state and suppressed during fasting, whereas the reverse is true in muscle. Such observations have led to the view of LPL as a metabolic gatekeeper, especially for dietary fatty acids. However, closer inspection of its action in white adipose tissue reveals that this picture is only partially true. Normal fat deposition in adipose tissue can occur in the complete absence of LPL, and conversely, if LPL activity is increased by pharmacological means, increased fat storage does not necessarily follow. LPL appears to act as one member of a series of metabolic steps which are regulated in a highly coordinated manner. In white adipose tissue, it is clear that there is a major locus of control of fatty acid disposition downstream from LPL. This involves regulation of the pathway of fatty acid uptake and esterification, and appears to be regulated by a number of factors including insulin, acylation-stimulating protein and possibly leptin. PMID: 10211047 [PubMed - indexed for MEDLINE] 5582. Ugeskr Laeger. 1999 Mar 22;161(12):1735-8. [Microdialysis. A method for measurement of local tissue metabolism]. [Article in Danish] Nielsen PS(1), Winge K, Petersen LM. Author information: (1)Divisionen for Klinisk og Eksperimentel Mikrodialyse, Referencelaboratoriet, København. Studies of pharmacological, immunological, and biochemical reactions in intact tissues have been hampered by the lack of appropriate techniques. The purpose of the review is to give a short introduction to the microdialysis technique which permits measurement of low molecular weight compounds in the extracellular water compartment in different tissue. Originally developed for use in animal brain, microdialysis is now being applied in humans for both clinical and experimental studies in different tissues, e.g. subcutaneous adipose tissue, brain, skin, and skeletal muscle. This review summarizes theoretical and practical aspects of microdialysis, and describes its main applications in humans. PMID: 10210970 [PubMed - indexed for MEDLINE] 5583. Nihon Rinsho. 1999 Mar;57(3):622-6. [Syndrome X]. [Article in Japanese] Kotake H(1), Oikawa S. Author information: (1)Third Department of Internal Medicine, Tohoku University School of Medicine. Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus(NIDDM). It is also associated with hyperlipidemia, hypertension, obesity and cardiovascular disease. It is the clustor of the risk factors for atherosclerosis and recognized as 'insulin-resistance syndrome' (Syndrome X). Central (abdominal) obesity is much more strongly associated with insulin resistance than overall obesity. The increase of both the influx of free fatty acid to liver and the production of TNF-alpha in adipose tissue may play an important role in mechanism of insulin resistance associated with central obesity. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Exercise training also improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. The new 'glitazones' (thiazolidinediones) is used clinically to improve insulin sensitivity. PMID: 10199144 [PubMed - indexed for MEDLINE] 5584. Am J Clin Nutr. 1999 Apr;69(4):584-96. Model for the regulation of energy balance and adiposity by the central nervous system. Schwartz MW(1), Baskin DG, Kaiyala KJ, Woods SC. Author information: (1)Department of Medicine, University of Washington, Harborview-Medical Center and the VA Puget Sound Health Care System, Seattle 98108, USA. mschwart@u.washington.edu In 1995, we described a new model for adiposity regulation. Since then, data regarding the biology of body weight regulation has accumulated at a remarkable rate and has both modified and strengthened our understanding of this homeostatic system. In this review we integrate new information into a revised model for further understanding this important regulatory process. Our model of energy homeostasis proposes that long-term adiposity-related signals such as insulin and leptin influence the neuronal activity of central effector pathways that serve as controllers of energy balance. PMID: 10197558 [PubMed - indexed for MEDLINE] 5585. Clin Endocrinol (Oxf). 1998 Nov;49(5):551-67. Leptin: in search of role(s) in human physiology and pathophysiology. Mantzoros CS(1), Moschos SJ. Author information: (1)Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. cmantzor@bidmc.harvard.edu PMID: 10197068 [PubMed - indexed for MEDLINE] 5586. Nat Neurosci. 1998 Oct;1(6):445-50. Unraveling the central nervous system pathways underlying responses to leptin. Elmquist JK(1), Maratos-Flier E, Saper CB, Flier JS. Author information: (1)Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. jelmquis@bidmc.harvard.edu Here we summarize recent progress in the biology of leptin, concentrating on its central nervous system (CNS) actions. The product of the ob gene, leptin is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence in rodents and humans causes severe obesity. We consider the physiological mechanisms underlying leptin action, along with several novel hypothalamic neuropeptides that affect food intake and body weight. The molecular causes of several other obesity syndromes are discussed to illuminate how the CNS regulates body weight. We describe neural circuits that are downstream of leptin receptors and propose a model linking populations of leptin-responsive neurons with effector neurons underlying leptin's endocrine, autonomic and behavioral effects. PMID: 10196541 [PubMed - indexed for MEDLINE] 5587. Int J Obes Relat Metab Disord. 1999 Feb;23 Suppl 1:29-36. Clinical endocrinology of human leptin. Van Gaal LF(1), Wauters MA, Mertens IL, Considine RV, De Leeuw IH. Author information: (1)Department of Endocrinology, Metabolism and Clinical Nutrition, University Hospital Antwerp, Belgium. Since the discovery of leptin, a boom of scientific knowledge became available about the OB-protein gene and its role and significance in weight regulation. Both from animal and human research data, serum leptin can probably be considered as one of the best biological markers to reflect total body fat, and this finding is true over a wide range of body mass indexes (BMIs) and in different pathologies: in normal weight, anorexic and obese subjects; in non insulin-dependent diabetes mellitus (NIDDM) patients, PCO women, Prader-Willi children and subjects with hypogonadism and growth hormone deficiency. Gender differences clearly exist, probably related to sex hormone differences, and from fat distribution studies it could be shown that subcutaneous fat is much more related to serum leptin concentrations than visceral fat: also leptin messenger-RNA (m-RNA) expression is significantly higher in subcutaneous fat from human obese subjects. Leptin is not only correlated to a series of endocrine parameters such as insulin, insulin-like growth factor, (IGF) and SHBG, it seems involved as a mediator in some endocrine mechanisms (onset of puberty, insulin secretion, etc) as well. Weight loss will reduce human leptin concentrations, whereas the administration of human recombinant leptin seems to show only limited effects. PMID: 10193859 [PubMed - indexed for MEDLINE] 5588. Int J Obes Relat Metab Disord. 1999 Feb;23 Suppl 1:22-8. Leptin: fundamental aspects. Trayhurn P(1), Hoggard N, Mercer JG, Rayner DV. Author information: (1)Division of Biomedical Science, Rowett Research Institute, Aberdeen, Scotland, UK. The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy. PMID: 10193858 [PubMed - indexed for MEDLINE] 5589. Int J Obes Relat Metab Disord. 1999 Feb;23 Suppl 1:10-3. Catecholamine-induced lipolysis in obesity. Arner P(1). Author information: (1)Department of Medicine, Karolinska Institute at Huddinge University Hospital, Sweden. Catecholamines are the only hormones with pronounced lipolytic action in man. A number of in vivo and in vitro studies suggest that there is lipolytic resistance to catecholamines in subcutaneous adipose tissue, which is the major fat depot in obese subjects. This is due to multiple alterations in catecholamine signal transduction, involving decreased expression and function of beta2-adrenoceptors, increased function of alpha2-adrenoceptors and decreased ability of cyclic monophosphate (AMP) to stimulate hormone sensitive lipase. A sedentary life-style, which usually characterizes obesity, may contribute to the catecholamine resistance. However, hereditary/genetic factors may also be involved. Recently, decreased expression and function of hormone sensitive lipase has been found in subcutaneous adipocytes of non-obese subjects with heredity for obesity. In addition, polymorphisms in the genes for beta2-adrenoceptors, beta3-adrenoceptors and hormone sensitive lipase, associate with obesity. On the other hand, catecholamine-induced lipolysis in visceral adipose tissue is increased in obesity due to increased function of beta3-adrenoceptors (major finding), decreased function of alpha2-adrenoceptors and increased ability of cyclic AMP to stimulate lipolysis. When the findings in different adipose regions are considered together, it appears that there is a redistribution of lipolysis and thereby fatty acid mobilization in obesity, favouring the visceral fat depot. This leads to an increase in the circulating fatty acid levels in the portal vein, which connects visceral fat with the liver. As a consequence, the liver function may be altered leading to hyperinsulinemia, hyperglycemia and dyslipidemia, which usually accompany the obese state. PMID: 10193856 [PubMed - indexed for MEDLINE] 5590. J Gerontol A Biol Sci Med Sci. 1999 Mar;54(3):B89-96; discussion B97-8. Revisiting the role of fat mass in the life extension induced by caloric restriction. Barzilai N(1), Gupta G. Author information: (1)Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA. barzilai@aecom.yu.edu One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in a severalfold decrease in fat mass (FM), the role of fat on life extension was considered to be minimal. Two main reasons accounted for this belief. First, although increased FM is associated with changes in substrate oxidation and in glucose homeostasis, in part through the effects of free fatty acids (FFA) and glycerol, several studies have suggested that longevity is determined independent of FM. Second, CR has systemic effects on a range of functions including neurological, endocrine, reproductive, immunological and antineoplastic, none of which have been historically linked to fat. In the last few years, an explosion of evidence has demonstrated that fat tissue is a very active endocrine gland which secretes a variety of peptides (such as leptin and plasminogen activating inhibitor-1), cytokines (such as tumor necrosis factor), and complement factors (such as D, C3, and B). This is in addition to the presence of substrates, such as glycerol and FFA, which are stored and released by fat cells and are known to have a major role in hepatic and peripheral glucose metabolism. We propose that many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors, and substrates. In fact, all of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to decrease in adipose cells and their products. Other evidence from epidemiological data in human obesity supports the role of fat mass and its body distribution as a risk factor for morbidity and mortality in humans due to impaired glucose metabolism (similar to rodents), for cancer (similar to rodents), and for the development of atherosclerotic vascular disease (in humans). If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate proteins may be explored and manipulated in the search for the most powerful adipose-dependent signals that modulate life expectancy. PMID: 10191831 [PubMed - indexed for MEDLINE] 5591. Diabetes Care. 1999 Apr;22 Suppl 3:C25-30. Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? Yudkin JS(1). Author information: (1)Centre for Diabetes and Cardiovascular Risk, University College London, U.K. Insulin resistance is associated not only with the classic cardiovascular risk factors of hypertension and dyslipidemia, but also with several disorders of coagulation and fibrinolysis. Elevated concentrations of the fibrinolytic inhibitor plasminogen activator inhibitor-1 are associated with insulin resistance. In experimental systems, increased expression and secretion of plasminogen activator inhibitor-1 by hepatocyte and endothelial cell lines can be induced by insulin, proinsulin-like molecules, triglyceride-rich lipoproteins and oxidized LDL, as well as by inducing insulin resistance in isolated hepatocytes. Concentrations of the endothelial cell protein von Willebrand factor are elevated in insulin-resistant states, suggesting that abnormalities of capillary endothelium, as well as those reported for endothelium-dependent vasodilatation, may play a role in the etiology of insulin resistance. Levels of a third coagulation factor, fibrinogen, are elevated in insulin-resistant subjects, an association that suggests a possible role for acute-phase cytokines in the abnormalities of coagulation and endothelial function. It is proposed that the recent observations of secretion of interleukin-6 by adipose tissue, combined with the actions of adipose tissue-expressed tumor necrosis factor-alpha in obesity-induced insulin resistance, could underlie the associations of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. PMID: 10189559 [PubMed - indexed for MEDLINE] 5592. Acta Paediatr Suppl. 1999 Feb;88(428):51-7. Leptin and the genetics of obesity. Clément K(1). Author information: (1)Laboratoire de Nutrition, Hôtel Dieu de Paris, Paris, France. The discovery of the Ob gene and its product, leptin, is a good example of the contribution made by molecular biology to the understanding of mechanisms initially hypothesized from classic physiological studies. Leptin is produced in adipose tissue and acts on the central nervous system to regulate multiple neuroendocrine secretions. In three rare cases of human morbid obesity, the discovery of mutations in the leptin and leptin receptor genes shows that leptin plays a crucial role in the control of weight and several endocrine functions (particularly reproduction). These studies also illustrate the limits of genetics in the investigation of monogenic forms of animal obesity, and the difficulties of linking molecular findings to the pathophysiology of complex diseases, such as human common obesity. Previous searches for mutations in the leptin and leptin receptor genes indicated that these are probably not major genes for common forms of human obesity. This review focuses on the recent molecular findings that have indicated a putative role for the leptin axis in human obesity. PMID: 10102052 [PubMed - indexed for MEDLINE] 5593. Pol Arch Med Wewn. 1998 Aug;100(2):173-9. [Adipocyte--endocrine organ?]. [Article in Polish] Karnafel W(1). Author information: (1)Katedra i Klinika Gastroenterologii i Chorób Przemiany Materii AM w Warszawie. PMID: 10101933 [PubMed - indexed for MEDLINE] 5594. Cell Biochem Biophys. 1999;30(1):89-113. GLUT4 trafficking in insulin-sensitive cells. A morphological review. Martin S(1), Slot JW, James DE. Author information: (1)Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, Australia. In recent years, there have been major advances in the understanding of both the cell biology of vesicle trafficking between intracellular compartments and the molecular targeting signals intrinsic to the trafficking proteins themselves. One system to which these advances have been profitably applied is the regulation of the trafficking of a glucose transporter, GLUT4, from intracellular compartment(s) to the cell surface in response to insulin. The unique nature of the trafficking of GLUT4 and its expression in highly differentiated cells makes this a question of considerable interest to cell biologists. Unraveling the tangled web of molecular events coordinating GLUT4 trafficking will eventually lead to a greater understanding of mammalian glucose metabolism, as well as fundamental cell biological principles related to organelle biogenesis and protein trafficking. PMID: 10099824 [PubMed - indexed for MEDLINE] 5595. Int J Obes Relat Metab Disord. 1999 Jan;23(1):1-6. Retinoids and adipose tissues: metabolism, cell differentiation and gene expression. Villarroya F(1), Giralt M, Iglesias R. Author information: (1)Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Spain. Vitamin A derivatives (retinoids) play a key role in mammalian development and cell differentiation. Isomers of retinoic acid, the main active metabolite of vitamin A, activate retinoid receptors that act as ligand-dependent transcription factors and affect gene expression. White and brown adipose tissues are major sites of storage of vitamin A derivatives and they play an active role in whole body metabolism of retinoids. Moreover, adipose tissues are targets for the action of retinoic acid. In most cases retinoic acid impairs adipocyte differentiation although its final effects on adipose tissue development depend on retinoic acid concentration, isomers availability and expression of retinoid receptor subtypes in the white or brown adipocyte. Retinoic acid (RA) has a specific effect on brown adipose tissue, because it activates transcription of the gene for uncoupling protein-1, responsible for brown fat thermogenesis. PMID: 10094571 [PubMed - indexed for MEDLINE] 5596. Crit Rev Clin Lab Sci. 1999 Feb;36(1):1-34. From preadipocyte to adipocyte: differentiation-directed signals of insulin from the cell surface to the nucleus. Sorisky A(1). Author information: (1)Department of Medicine and Biochemistry, Loeb Research Institute, Ottawa Civic Hospital, University of Ottawa, Ontario, Canada. An alarming rise in obesity, and the accompanying threat of type 2 diabetes mellitus and cardiovascular disease, have attracted worldwide attention. The pathogenic mechanism(s) underlying obesity remains obscure. However, new cellular and molecular insights about the development of adipose tissue, with respect to adipocyte number (hyperplasia) and size (hypertrophy), are occurring at a rapid pace. Specialized fibroblasts (preadipocytes) committed to the adipocyte lineage are present throughout life. Primary cell culture systems and immortalized cell line models of preadipocytes have advanced the study of adipocyte differentiation (adipogenesis). Differentiation-inducing cues are able to trigger a complex network of intracellular signaling pathways in the preadipocyte, allowing signals from cell-surface receptors to reach nuclear transcription factors that regulate the genetic program of adipocyte differentiation. The extracellular matrix environment of the preadipocyte, known to modulate adipogenesis, may act by altering some of these signaling events. PMID: 10094092 [PubMed - indexed for MEDLINE] 5597. Biochem Soc Trans. 1999 Feb;27(2):97-103. Maternal nutrition and endocrine programming of fetal adipose tissue development. Symonds ME(1), Stephenson T. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Queen's Medical Centre, Nottingham, U.K. PMID: 10093715 [PubMed - indexed for MEDLINE] 5598. Biochem Soc Trans. 1999 Feb;27(2):94-7. Programming of hepatic and peripheral tissue insulin sensitivity by maternal protein restriction. Ozanne SE(1). Author information: (1)Department of Clinical Biochemistry, University of Cambridge, U.K. In recent years a great deal of research effort has been directed towards understanding the molecular basis of the relationship between markers of fetal and early growth retardation and the subsequent development of Type 2 diabetes. A lot of this work has focused on the maternal low protein rat model. Like many animal models, it does not perfectly represent the human situation and frank diabetes has not yet been produced. However, this model has yielded much information on potential mechanisms by which changes in insulin sensitivity can occur and has helped in understanding the role of the molecular machinery involved in the signalling of the metabolic actions of insulin. PMID: 10093714 [PubMed - indexed for MEDLINE] 5599. Sports Med. 1999 Feb;27(2):81-96. Exercise metabolism and beta-blocker therapy. An update. Head A(1). Author information: (1)Department of Sport Sciences, Brunel University, Isleworth, England. The rationale for the concurrent prescription of beta-blockers and programmes of exercise is that both medication and physical activity can improve the quality of life of patients with cardiovascular disease. Difficulties arise when drugs reduce either the physical ability or the motivation to exercise. This article focuses on the physiological limitations to prolonged aerobic exercise in patients receiving beta-blockers. Possible limiting factors to exercise while taking beta-blockers include reduction in heart rate and cardiac output, local alterations to blood flow, changes to muscle and liver glycogenolysis, and alterations to adipose and intra-muscular lipolysis. The disadvantages and advantages of nonselective and beta 1-selective drugs are discussed, as well as those of drugs that have beta 2-agonist properties. Particular emphasis is placed upon the beta-blocker-induced attenuation of the normal increase in fat oxidation during prolonged exercise. There are physiological advantages, especially for the physically active individual, in prescribing beta 1-selective rather than nonselective drugs in controlled release, rather than conventional release, form. Additionally, there may be further advantages in prescribing drugs which have partial agonist properties at beta 2 receptors. PMID: 10091273 [PubMed - indexed for MEDLINE] 5600. Baillieres Clin Endocrinol Metab. 1998 Jul;12(2):297-314. Interaction between body composition, leptin and growth hormone status. Casanueva FF(1), Dieguez C. Author information: (1)Department of Medicine, University of Santiago de Compostela, Spain. Administration of growth hormone (GH) induces changes in body composition, namely, increases in both bone and lean mass and a decrease in fatty tissue. However, the contrary issue, i.e. the way in which body composition affects the secretion of GH, is highly controversial. Disease states such as obesity and chronic hypercortisolism are associated with increased adiposity and/or the central distribution of fat. Ageing, characterized by excess adiposity, is also associated with impaired secretion of GH. In these states, both spontaneous and stimulated secretion of GH is severely impeded. At the other extreme, malnutrition and fasting are both associated with increased secretion of GH when confronted with most, if not all, stimuli. As the common factor in all of these situations is the increased or decreased adiposity, or the changes in energy homeostasis, it has been postulated that adipose tissue exerts a relevant role in the control of GH secretion in man. The link between adipose tissue and GH seems to be exerted through at least two signals produced by adipocytes: free fatty acids (FFA) and the recently cloned protein, leptin. An increase in FFA blocks secretion of GH, while a decrease in FFA enhances secretion. Leptin, a hormone whose main role is to regulate the intake of food and energy expenditure, seems to regulate GH secretion by acting at the hypothalamic level. In summary, body composition affects GH secretion by way of the degree of adiposity, and free fatty acids and leptin would appear to be the messages through which adipocytes participate in the regulation of GH secretion. This framework clarifies the metabolic control of GH, a hormone with profound metabolic activities. PMID: 10083898 [PubMed - indexed for MEDLINE] 5601. Nephrologie. 1999;20(1):9-11. [New target tissues for aldosterone]. [Article in French] Lombès M(1), Zennaro MC. Author information: (1)INSERM U 478, Faculté de médecine Xavier Bichat, Paris. mlombes@bichat.inserm.fr PMID: 10081031 [PubMed - indexed for MEDLINE] 5602. Annu Rev Med. 1999;50:17-35. Arrhythmogenic right ventricular dysplasia. Fontaine G(1), Fontaliran F, Hébert JL, Chemla D, Zenati O, Lecarpentier Y, Frank R. Author information: (1)Service de Cardiologie, Hôpital Jean Rostand, Ivry sur Seine, France. Arrhythmogenic right ventricular dysplasia (ARVD) is a new form of cardiomyopathy probably more frequent than commonly reported. It is a rare but important cause of sudden arrhythmic death in young, otherwise healthy persons, as well as a subtle cause of congestive heart failure. It may lead to temporary incapacitation with catastrophic consequences. Proper electrocardiographic criteria, echocardiography, nuclear medicine, or magnetic resonance imaging could identify most of these individuals. With the exception of full-thickness histological examination of the right ventricular free wall, contrast ventriculography remains the most definitive standard for a positive diagnosis. The wide clinical spectrum of arrhythmogenic right ventricular cardiomyopathies/dysplasia appears to be the result of one or possibly two factors: (a) replacement of most of the right ventricular myocardium by fat and (b) genetic susceptibility to environmental agents (myocarditis). Current treatment modalities include drug therapy, catheter or surgical ablative techniques, and modern treatments of congestive heart failure. Heart transplant is exceptional. Implantable defibrillators, used alone or in combination with drug therapy, will probably play an increasing role in ARVD and related cardiomyopathies. PMID: 10073261 [PubMed - indexed for MEDLINE] 5603. J Recept Signal Transduct Res. 1999 Jan-Jul;19(1-4):217-28. From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance. Le Marchand-Brustel Y(1), Tanti JF, Cormont M, Ricort JM, Grémeaux T, Grillo S. Author information: (1)INSERM U 145 Faculty of Medicine, Nice, France. Insulin resistance is commonly associated with obesity in rodents. Using mice made obese with goldthioglucose (GTG-obese mice), we have shown that insulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alteration in the number of the Glut 4 glucose transporter. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation. In order to better understand the abnormalities in glucose transport in insulin resistance, we have studied the pathway leading from the insulin receptor kinase stimulation to the translocation of the Glut 4 containing vesicles. This stimulation involves the activation of PI 3-kinase, which in turns activates protein kinase B. We have then focussed at the mechanism of vesicle exocytosis, and more specifically at the role of the small GTPase Rab4 in this process. We have shown that Rab4 participates, first in the intracellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation. PMID: 10071760 [PubMed - indexed for MEDLINE] 5604. Biol Trace Elem Res. 1998 Winter;66(1-3):331-41. A comparative review of the pharmacokinetics of boric acid in rodents and humans. Murray FJ(1). Author information: (1)Murray & Associates, San Jose, CA 95138, USA. The pharmacokinetics of boric acid (BA) have been studied in animals and humans. Orally administered BA is readily and completely absorbed in rats, rabbits, and humans, as well as other animal species. In animals and humans, absorbed BA appears to be rapidly distributed throughout the body water via passive diffusion. Following administration of BA, the ratio of blood: soft tissue concentrations of boron (B) is approx 1.0 in rats and humans; in contrast, concentrations of B in bone exceed those in blood by a factor of approx 4 in both rats and humans. In rats, adipose tissue concentrations of B are only 20% of the levels found in blood and soft tissues; however, human data on adipose tissue levels are not available. BA does not appear to be metabolized in either animals or humans owing to the excessive energy required to break the B-O bond. BA has an affinity for cis-hydroxy groups, and it has been hypothesized to elicit its biological activity through this mechanism. The elimination kinetics of BA also appear to be similar for rodents and humans. BA is eliminated unchanged in the urine. The kinetics of elimination were evaluated in human volunteers given BA orally or intravenously; the half-life for elimination was essentially the same (approx 21 h) by either route of exposure. In rats, blood and tissue levels of B reached steady-state after 3-4 d of oral administration of BA; assuming first-order kinetics, a half-life of 14-19 h may be calculated. The lack of metabolism of BA eliminates metabolic clearance as a potential source of interspecies variation. Accordingly, in the absence of differences in metabolic clearance, renal clearance is expected to be the major determinant of interspecies variation in pharmacokinetics. Because glomerular filtration rates are slightly higher in rats than in humans, the slight difference in half-lives may be readily explained. The most sensitive toxicity end point for BA appears to be developmental toxicity in rats, with a No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of 55 and 76 mg BA/kg/d, respectively. Mean blood B levels in pregnant rats on gestation day 20 in the pivotal developmental toxicity study were reported to be 1.27 and 1.53 mcg B/g at the NOAEL and LOAEL, respectively. Blood B concentrations in humans are well below these levels. Average blood B levels in the most heavily exposed worker population at a borate mine was 0.24 mcg B/mL, and the estimated daily occupational exposure was equivalent to 160 mg BA/d. Blood B levels in the general population generally range from 0.03 to 0.09 mcg B/mL. These blood B values indicate an ample margin of safety for humans. In summary, the pharmacokinetics of BA in humans and rodents are remarkably similar, and interspecies differences in pharmacokinetics appear to be minimal. PMID: 10050928 [PubMed - indexed for MEDLINE] 5605. J Nephrol. 1998 Nov-Dec;11(6):296-9. The natriuretic peptide system in obesity-related hypertension: new pathophysiological aspects. Dessì-Fulgheri P(1), Sarzani R, Rappelli A. Author information: (1)Istituto di Medicina Clinica, Cattedra di Medicina Interna I University of Ancona, Italy. The association between obesity and hypertension is well known but the pathophysiology of weight-related changes on blood pressure is still a matter of debate. Although obesity-related hypertension is considered to be sodium-sensitive, little attention has been given to a possible pathophysiological role of Atrial Natriuretic Peptides (ANP) and their receptors (NPr) system. Since the early phase of weight loss induced by very-low-calorie diet or fasting is followed by a significant increase in diuresis and natriuresis together with an increase in circulating ANP, we focused our attention on the possible role of adipose tissue in mediating these changes. We first demonstrated that human and rat adipose tissue contain high levels of mRNA specific for both type A (NPr-A), which is biologically active, and type C (NPr-C) which is biologically inactive, receptors. We then demonstrated in the rat that fasting exerts a tissue-specific and gene-specific suppression of NPr-C gene expression in adipose tissue that appears to be accompanied by an increased biological activity of ANP. These experimental observations were confirmed in man studying gene expression of NPr-A and NPr-C in adipose tissue obtained through subcutaneous peri-umbilical needle aspiration in obese and non-obese hypertensive patients. We found that NPr-A: NPr-C mRNA ratio was significantly lower in obese hypertensive patients as compared with non-obese hypertensives. These findings suggest that overxpression of the clearance receptor in the obese may trap more molecules of circulating ANP so reducing their biological activity at renal level. More recent results were obtained in obese hypertensive patients in whom the intravenous bolus injection of ANP (0.6 mg/kg body weight) was performed before and after four days of very-low-calorie diet which induced a weight loss accompanied by a significant reduction of BP and an increase in the urinary excretion of cGMP. The infusion of ANP after low-calorie diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis and natriuresis significantly increased only after caloric restriction and the effects of ANP infusion on BP were more pronounced. Taken together our studies suggest that the abundance of NPr-C in adipose tissue may play a significant role in explaining at least part of the sodium retention characteristic of obesity associated hypertension. PMID: 10048495 [PubMed - indexed for MEDLINE] 5606. Nurse Pract. 1999 Feb;24(2):125-6, 129. Metabolic complications of HIV disease. Swindells S(1). Author information: (1)Department of Internal Medicine, University of Nebraska Medical Center, USA. PMID: 10048085 [PubMed - indexed for MEDLINE] 5607. Obes Res. 1999 Jan;7(1):97-105. Human uncoupling proteins and obesity. Schrauwen P(1), Walder K, Ravussin E. Author information: (1)Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix AZ 85016, USA. Uncoupling protein (UCP) 2 and UCP3 are newly discovered proteins that can uncouple ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting energy metabolism efficiency. In contrast to UCP1, which is only present in brown adipose tissue, UCP2 has a wide tissue distribution, whereas UCP3 is expressed predominantly in skeletal muscle. Some evidence of a role for UCPs in modulating metabolic rate was provided by linkage and association studies. Furthermore, UCP3 gene expression was found to correlate negatively with body mass index and positively with sleeping metabolic rate in Pima Indians. Treatment with thyroid hormone increases expression of the UCP2 and UCP3 genes. Other regulators of UCP2 and UCP3 gene expression are beta3-adrenergic agonists and glucocorticoids. Surprisingly, fasting has a stimulatory effect on UCP2 and UCP3 mRNA levels, possibly explained by the effects of free fatty acid on UCP2 and UCP3 gene expression. PMID: 10023736 [PubMed - indexed for MEDLINE] 5608. Biochemistry (Mosc). 1999 Jan;64(1):1-7. Growth hormone and a partial mediator of its biological action, insulin-like growth factor I. Pankov YA(1). Author information: (1)Institute of Experimental Endocrinology, Endocrine Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia. pankov@microdin.ru This review summarizes data on two hormones, growth hormone (GH) and insulin-like growth factor I (IGF-I). Genes encoding these hormones are actively expressed in various tissues which can synthesize and secrete the corresponding hormones into the intracellular space and blood. Apart from the pituitary, GH gene is also expressed in mammary gland, thymus, spleen, lymph nodes, and blood cells. GH activates expression of the gene of IGF-I and stimulates its secretion by the liver, adipose tissue, thymus, and other tissues. The growth-stimulating effect of GH is mediated (at least partially) by IGF-I, but direct (IGF-I-independent) influence on target tissues is also possible. Genes encoding GH and IGF-I receptors are expressed in all organs and tissues, including various cells of the immune system. GH and IGF-I regulate the function of the immune system via endocrine, paracrine, and autocrine mechanisms. PMID: 9986906 [PubMed - indexed for MEDLINE] 5609. Crit Rev Oncog. 1998;9(2):99-106. Cytokine involvement in cancer anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate on cytokine downregulation and improvement of clinical symptoms. Mantovani G(1), Macciò A, Lai P, Massa E, Ghiani M, Santona MC. Author information: (1)Department of Medical Oncology, University of Cagliari, Italy. The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named the cancer-related anorexia/cachexia syndrome (CACS). Chronic administration of pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) either alone or in combination, is capable of reproducing the different features of CACS. High serum levels of these cytokines have been found in cancer patients, which seem to correlate with progression of the tumor. This paper describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-1, IL-6, and TNF, are present in advanced-stage cancer patients, particularly those with CACS; (2) megestrol acetate (MA) has a beneficial therapeutic effect on CACS symptoms, such as appetite, body weight, and quality-of-life; (3) MA downregulates the synthesis and release of cytokines and relieves the symptoms of CACS; (4) cytokines play a key role in the onset of CACS; (5) medroxyprogesterone acetate (MPA) reduces the in vitro production of cytokines and serotonin (5-hydroxytryptamine, 5-HT) by peripheral blood mononuclear cells (PBMC) of cancer patients; and (6) MA and MPA reduce the cisplatin-induced 5-HT release in vitro from PBMC of cancer patients. Based on these results, a clinical study incorporating MA/MPA in combination with chemotherapy or chemoimmunotherapy may be warranted. PMID: 9973244 [PubMed - indexed for MEDLINE] 5610. Prog Drug Res. 1998;51:33-94. Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities. Turner NC(1), Clapham JC. Author information: (1)SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (N), Harlow, Essex, UK. Impaired glucose tolerance and non-insulin-dependent diabetes (NIDDM) are the pathologic consequence of two co-incident and interacting conditions, namely insulin resistance and relative insulin deficiency. Recognised by the World Health Authority as a global health problem there are at 1995 estimates at least 110 million diagnosed diabetics world wide with at least the same number undiagnosed. Diabetes is the 4th leading cause of death in developed countries and its management exerts a vast economic and social burden. Insulin resistance is established as the characteristic pathologic feature of patients with glucose intolerance and NIDDM describing a state in which insulin stimulated glucose uptake and utilisation in liver, skeletal muscle and adipose tissue is impaired and coupled to impaired suppression of hepatic glucose output. Although the biochemical mechanisms underpinning both defects are becoming better understood, the genetic and molecular causes remain elusive; and whether insulin resistance or relative insulin deficiency represents the primary defect in patients with NIDDM is the matter of some debate. In this article we review the biochemical and molecular nature of the defects in insulin sensitivity and glucose uptake, and discuss some of the potential causative mechanisms. The genetic and environmental basis of insulin resistance is reviewed and presented, and potential therapeutic targets including thiazolidinediones are discussed. PMID: 9949859 [PubMed - indexed for MEDLINE] 5611. Ann N Y Acad Sci. 1998 Nov 20;854:378-93. Combined exercise and dietary intervention to optimize body composition in aging. Singh MA(1). Author information: (1)Jean Mayer USDA Human Nutrition Research Center, Tufts University, Exercise and Nutrition Laboratory, Boston, Massachusetts 02111, USA. mafiat@ibm.net Concomitant losses of skeletal muscle and bone mass along with gradual accretion of adipose tissue typify usual human aging. Recent investigations have attempted to modify these processes with various combinations of dietary and exercise intervention in older adults. Complete nutritional supplements given with weight-lifting exercise have been shown to augment muscle and fat gains in healthy older men, but have merely suppressed habitual dietary intake when administered to frail sedentary elders, and have not altered body composition responses to strength training in this population. Protein supplementation at twice the RDA does not improve skeletal muscle function or increase muscle mass in healthy elderly weight lifters compared to those on a normal diet. Calcium supplementation during one year of aerobic training has an independent beneficial effect on cortical bone density at the femoral neck in postmenopausal women, whereas the exercise is associated with trabecular bone increases in the lumbar vertebrae. Hypocaloric dieting, with or without aerobic exercise, results in losses of weight, fat and lean mass in obese elderly men and women. By contrast, resistance training during hypocaloric dieting augments lean mass while further reducing fat mass. Low protein, isoenergetic diets result in muscle atrophy in older women. Current studies will determine the ability of resistance training to offset these catabolic effects on skeletal muscles of a low-protein (0.6 g/kg/day) diet prescribed for elderly with chronic renal failure. More long-term studies of efficacy and feasibility of diet and exercise combinations are needed in the aged to optimize the potential for healthful shifts in body composition. PMID: 9928446 [PubMed - indexed for MEDLINE] 5612. Ann N Y Acad Sci. 1998 Dec 15;861:74-8. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Heisler LK(1), Chu HM, Tecott LH. Author information: (1)Department of Psychiatry, University of California at San Francisco 94143, USA. Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake. PMID: 9928241 [PubMed - indexed for MEDLINE] 5613. J Med Chem. 1999 Jan 28;42(2):181-201. Pharmacological treatment of obesity: therapeutic strategies. Kordik CP(1), Reitz AB. Author information: (1)Drug Discovery Division, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA. ckordik@prius.jnj.com PMID: 9925722 [PubMed - indexed for MEDLINE] 5614. Int J Biochem Cell Biol. 1998 Dec;30(12):1285-90. Leptin. Prolo P(1), Wong ML, Licinio J. Author information: (1)Unit on Clinical Research, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1284, USA. Leptin is an adipocyte hormone that signals nutritional status to the central nervous system (CNS) and peripheral organs. Leptin is also synthetized in the placenta and in gastrointestinal tract, although its role in these tissues is not yet clear. Circulating concentrations of leptin exhibit pulsatility and circadian rhythmicity. The levels of plasma leptin vary directly with body mass index and percentage body fat, and leptin contributes to the regulation of body weight. Leptin plasma concentrations are also influenced by metabolic hormones, sex, and body energy requirements. Defects in the leptin signaling pathway result in obesity in animal models. Only a few obese humans have been identified with mutations in the leptin gene or in the leptin receptor; however, most cases of obesity in humans are associated with high leptin levels. Thus, in humans obesity may represent a state of leptin resistance. Minute-to-minute fluctuations in peripheral leptin concentrations influence the activity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes, indicating that leptin may be a modulator of reproduction, stress-related endocrine function, and behavior. This suggests potential roles for leptin or its antagonists in the diagnosis, pathophysiology and treatment of several human diseases. PMID: 9924798 [PubMed - indexed for MEDLINE] 5615. J Rheumatol. 1999 Jan;26(1):68-72. Lupus panniculitis: clinical perspectives from a case series. Martens PB(1), Moder KG, Ahmed I. Author information: (1)Department of Dermatology and Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. OBJECTIVE: To review clinical and laboratory features of lupus panniculitis from a large group of patients. METHODS: Retrospective chart review of patients diagnosed with lupus panniculitis at a tertiary medical center from 1976 to 1993. RESULTS: Lupus panniculitis occurred most frequently in adult women. Skin lesions involved proximal extremities, trunk, face, and scalp. Only 4 of 40 patients fulfilled criteria for systemic lupus erythematosus (SLE), and, other than positive antinuclear antibodies, a paucity of other autoantibodies was seen. Average disease duration was 6 years (range 0-38). Treatment with antimalarial agents was undertaken in most cases. Disease related morbidity (disfigurement and disability) was relatively common, but death was rare. CONCLUSION: Lupus panniculitis is a chronic inflammatory disease of subcutaneous adipose tissue that can develop during the course of SLE, although most patients do not develop systemic lupus. PMID: 9918242 [PubMed - indexed for MEDLINE] 5616. Methods Mol Biol. 1999;109:329-35. Techniques for the measurement of lipoprotein lipase messenger RNA. Ranganathan G(1), Kern PA. Author information: (1)Department of Medicine, University of Arkansas School for Medical Sciences, Little Rock, USA. PMID: 9918033 [PubMed - indexed for MEDLINE] 5617. Methods Mol Biol. 1999;109:145-50. Large-scale lipoprotein lipase purification from adipose tissue. Bensadoun A(1), Hsu J, Hughes B. Author information: (1)Department of Biochemistry, Cornell University, Ithaca, NY, USA. PMID: 9918019 [PubMed - indexed for MEDLINE] 5618. Methods Mol Biol. 1999;109:109-21. Hormone-sensitive lipase and neutral cholesteryl ester lipase. Holm C(1), Osterlund T. Author information: (1)Department of Cell and Molecular Biology, Lund University, Sweden. PMID: 9918016 [PubMed - indexed for MEDLINE] 5619. Ann N Y Acad Sci. 1998 Sep 29;856:171-87. Brown adipose tissue. More than an effector of thermogenesis? Cannon B(1), Houstek J, Nedergaard J. Author information: (1)Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, Sweden. barbara.cannon@wgi.su.se Brown adipose tissue (BAT) produces heat by oxidation of fatty acids. This takes place when the tissue is stimulated by norepinephrine; the molecular background for the ability of BAT to produce heat is the tissue-specific mitochondrial protein UCP1. In the classic view of BAT with respect to fever, BAT is an effector organ, producing heat especially during the onset phase of the fever. There is good evidence that BAT thermogenesis is stimulated via a lipopolysaccharide (LPS), interleukin (IL)-1 beta, IL-6, prostaglandin E cascade. Under physiologic conditions of constantly stimulated activity, BAT is expected to be recruited, but in fevers this is only evident in thyroxine fever. However, BAT may be more than merely an effector. There are indications of a correlation between the amount of BAT and the intensity of fevers, and brown adipocytes can indeed produce IL-1 alpha and IL-6. Furthermore, brown adipocytes are directly sensitive to LPS; this LPS sensitivity is augmented in brown adipocytes from IL-1 beta-deficient mice. Thus, BAT may also have a controlling role in thermoregulation. The existence of transgenic mice with ablations of proteins central in fever and in BAT thermogenesis opens up possibilities for identification and elucidation of this putative new role for brown adipose tissue as an endocrine organ involved in the control of fever. PMID: 9917877 [PubMed - indexed for MEDLINE] 5620. J Nutr. 1999 Jan;129(1S Suppl):243S-246S. Wasting in cancer. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, United Kingdom. Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents. PMID: 9915907 [PubMed - indexed for MEDLINE] 5621. J Nutr. 1999 Jan;129(1):5-8. beta-Carotene, carotenoids and the prevention of coronary heart disease. Kritchevsky SB(1). Author information: (1)Department of Preventive Medicine, University of Tennessee, Memphis, Memphis, TN 38105, USA. The importance of low density lipoprotein (LDL) oxidation to the atherosclerotic process has led to the examination of beta-carotene as a possible preventive agent. Several epidemiologic studies show an inverse association between serum/adipose beta-carotene levels and coronary heart disease risk. Randomized clinical trials, however, have not shown any benefit, and perhaps even an adverse effect, of beta-carotene supplementation. A number of possible confounding factors may explain the inconsistency between the trials and epidemiologic evidence. Other carotenoids that are correlated with beta-carotene both in the diet and in the blood might be important factors, as might other plant-derived compounds. Alternatively, low serum carotenoid levels may reflect either increased lipoprotein density or the presence of inflammation, both factors emerging as important novel risk factors for coronary heart disease. Whereas the trial results support no preventive role for beta-carotene, the epidemiologic evidence does generally support the idea that a diet rich in high carotenoid foods is associated with a reduced risk of heart disease. PMID: 9915867 [PubMed - indexed for MEDLINE] 5622. Biofactors. 1998;8(3-4):209-19. The structure and function of the brown fat uncoupling protein UCP1: current status. Rial E(1), González-Barroso MM, Fleury C, Bouillaud F. Author information: (1)Centro de Investigaciones Biológicas, C.S.I.C., Madrid, Spain. rial@fresno.csic.es The uncoupling protein of brown adipose tissue (UCP1) is a transporter that allows the dissipation as heat of the proton gradient generated by the respiratory chain. The discovery of new UCPs in other mammalian tissues and even in plants suggests that the proton permeability of the mitochondrial inner membrane can be regulated and its control is exerted by specialised proteins. The UCP1 is regulated both at the gene and the mitochondrial level to ensure a high thermogenic capacity to the tissue. The members of the mitochondrial transporter family, which includes the UCPs, present two behaviours with carrier and channel transport modes. It has been proposed that this property reflects a functional organization in two domains: a channel and a gating domain. Mounting evidence suggest that the matrix loops contribute to the formation of the gating domain and thus they are determinants to the control of transport activity. PMID: 9914821 [PubMed - indexed for MEDLINE] 5623. Coron Artery Dis. 1998;9(12):799-803. Traversing the menopause: changes in energy expenditure and body composition. Poehlman ET(1), Tchernof A. Author information: (1)Department of Medicine, College of Medicine, University of Vermont, Burlington 05405, USA. Comment in NIH Guide Grants Contracts. 2005 Mar 25;:NOT-OD-05-040. The menopause transition is associated with several physiological changes that may impact women's health outcome. Among the changes associated with the loss of ovarian function is an increased risk of metabolic and cardiovascular disease. The present review focuses on changes in energy expenditure, body composition and body fat distribution during the postmenopausal transition. Previous work indicates that the most important component of total daily expenditure, resting metabolic rate, may be reduced by the menopause, independently of the effects of the normal aging process. This effect is mainly attributable to a decrease in fat-free mass. The energy expenditure associated with physical activity is the most variable component of total daily energy expenditure. However, small changes in this component may have a substantial impact on body composition. Longitudinal data from our laboratory indicate that the menopause transition also leads to significant decreases in physical activity energy expenditure. The changes in body composition that accompany the menopause transition have been studied by several groups and, although some studies suggested increases in body mass index or total body fat mass with the menopause, currently available cross-sectional data preclude a firm conclusion. Nevertheless, results from our longitudinal study showed significant increases in fat mass with the menopause. The accumulation of abdominal fat, which may be a better correlate of the comorbidities associated with obesity, has also been shown to be accelerated by the menopause transition. In this regard, it has been shown that treatment with hormone replacement therapy prevents the increase in the rate of abdominal adipose tissue accumulation that was noted with the menopause. Thus, it appears that the loss of ovarian function induces a reduction in resting metabolic rate, physical activity energy expenditure, fat-free mass, and an increase in fat mass and abdominal adipose tissue accumulation. These modifications probably contribute to the increased risk of cardiovascular disease of postmenopausal women. PMID: 9894924 [PubMed - indexed for MEDLINE] 5624. Biochim Biophys Acta. 1999 Jan 8;1415(2):271-96. Structure and function of the uncoupling protein from brown adipose tissue. Klingenberg M(1), Huang SG. Author information: (1)Institut für Physikalische Biochemie, Universität München, Schillerstrasse 44, D-80336, Munich, Germany. klingenberg@pbm.med.uni-muenchen.de PMID: 9889383 [PubMed - indexed for MEDLINE] 5625. Atherosclerosis. 1998 Dec;141 Suppl 1:S41-6. Non-esterified fatty acid metabolism and postprandial lipaemia. Frayn KN(1). Author information: (1)Oxford Lipid Metabolism Group, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, UK. keith.frayn@oxlip.ox.ac.uk Non-esterified fatty acids (NEFA, or free fatty acids) are an important metabolic fuel. Both the concentration of NEFA and their flux through the circulation vary widely from hour to hour, reflecting nutritional state and physical activity. Inappropriately elevated plasma NEFA concentrations may have a number of adverse effects on both carbohydrate and lipid metabolism. These adverse effects are likely to be most marked in the postprandial period, when NEFA release from adipose tissue is usually suppressed. Although the regulation of NEFA release in the postabsorptive state is well understood in molecular terms, the predominant pathway for release of NEFA in the postprandial state is the action of lipoprotein lipase (LPL) in adipose tissue capillaries on chylomicron-triacylglycerol (TG). Fatty acids released by LPL may either be sequestered in the adipocytes by esterification, or released as NEFA into the plasma. The regulation of this branch-point, which may be of crucial significance for postprandial metabolism, is not well understood. Factors stimulating tissue retention of fatty acids include insulin and acylation stimulating protein. There is considerable indirect evidence that impaired regulation of this step occurs in insulin resistance and other conditions collectively recognised by an elevated concentration of apolipoprotein B (hyper-apo B). Inappropriate release of NEFA in the postprandial period is likely both to reduce the sensitivity of glucose metabolism to insulin and to accentuate postprandial lipaemia. Further study of the regulation of this pathway is much needed. PMID: 9888641 [PubMed - indexed for MEDLINE] 5626. Int J Hematol. 1998 Dec;68(4):371-85. A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders. Yamamoto K(1), Saito H. Author information: (1)First Department of Internal Medicine, Nagoya University School of Medicine, Japan. Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and may be the principal regulator of plasminogen activation in vivo. Abnormal expression of PAI-1 has been reported in various types of human disorders and in animal models for the diseases in relation to thrombosis. For example, plasma PAI-1 activity was elevated in patients with endotoxemia, and a dramatic induction of PAI-1 mRNA was observed in tissues of endotoxin-treated animals, resulting in tissue microthrombosis. It has also been demonstrated that PAI-1 expression levels are increased in the kidneys of mice with glomerulonephritis, in the adipose tissue of obese subjects or mice, and in human atherosclerotic arteries. This PAI-1 induction may be relevant to pathological processes in these diseases because PAI-1 not only regulated fibrin dissolution in vivo but also inhibited degradation of extracellular matrix by reducing plasmin generation. The responsible cells for abnormal expression of PAI-1 have been identified in each tissue under pathological conditions and PAI-1 synthesis appears to be regulated in a tissue-specific manner. These observations suggest that PAI-1 could play an important role in the progression of tissue pathologies in a variety of human diseases by controlling the rate of plasmin formation. PMID: 9885437 [PubMed - indexed for MEDLINE] 5627. Clin Pharmacokinet. 1998 Dec;35(6):437-59. Pharmacokinetic optimisation of antibacterial treatment in patients with cystic fibrosis. Current practice and suggestions for future directions. Touw DJ(1), Vinks AA, Mouton JW, Horrevorts AM. Author information: (1)Department of Pharmacy, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. dj.touw@azvu.nl Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones. PMID: 9884816 [PubMed - indexed for MEDLINE] 5628. Diabetes Metab. 1998 Nov;24(5):409-18. Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Large V(1), Arner P. Author information: (1)INSERM U499, Faculté de médecine, Lyon, France. Adipose tissue is considered as the body's largest storage organ for energy in the form of triglycerides, which are mobilised through the lipolysis process to provide fuel to other organs and to deliver substrates to liver for gluconeogenesis (glycerol) and lipoprotein synthesis (free fatty acids). The release of glycerol and free fatty acids is intensively regulated by hormones and agents. In man, the major hormones are insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). Physiological factors such as dieting, physical exercise and ageing also regulate lipolysis. The lipolytic process is modified in pathological conditions, e.g. obesity (both upper and lower obesity), diabetes (non- and insulin-dependent diabetes mellitus), and dyslipidaemia (in particular, familial combined hyperlipidaemia). The regulation of lipolysis is complex because of the heterogeneity of fat depots (visceral versus subcutaneous), which may contribute to the well-known gender differences in accumulation of fat. Since visceral fat depot is directly drained into the liver and has a high turnover of visceral triglycerides, "portal" free fatty acids seem to be an important pathophysiological factor in common complications of obesity (in particular, metabolic syndrome). New advances in genetic studies indicate that polymorphisms in several genes encoding for proteins that regulate the lipolysis process are important for the development of obesity and its complications. PMID: 9881238 [PubMed - indexed for MEDLINE] 5629. Am J Phys Anthropol. 1998;Suppl 27:177-209. Adipose tissue in human infancy and childhood: an evolutionary perspective. Kuzawa CW(1). Author information: (1)Department of Anthropology, Emory University, Atlanta, Georgia 30322, USA. Humans diverge from most mammals, including nonhuman primates, by depositing significant quantities of body fat in utero and are consequently one of the fattest species on record at birth. While explanations for the fat layer of human neonates have commonly assumed that it serves as insulation to compensate for hairlessness, empirical support for this hypothesis is presently weak. Whether the tissue's abundance at birth and growth changes in adiposity during infancy and childhood might be explained in light of its role as energy buffer has not been assessed, and this possibility is explored through development of a model of fat function and growth centered on two related hypotheses. The first is that the greater adiposity of human neonates is at least partially explainable as an accompaniment of the enlarged human brain, which demands a larger energy reserve to ensure that its obligatory needs are met when the flow of resources from mother or other caretakers is disrupted. The second is that age-related changes in the likelihood of experiencing such disruption have influenced the pattern of investment in the tissue, reflected today in peak adiposity during infancy and a decline to a leaner childhood period. Nutritional disruption is common at birth and until lactation is established, during which time human newborns survive from fats deposited prenatally, suggesting one possible explanation for the early onset of fat deposition. At weaning, the transition from breast milk to supplemental foods and the parallel transition from maternal to endogenous immune protection interact to increase the frequency and impact of nutritional disruption, and this may help explain why newborns devote roughly 70% of growth expenditure to fat deposition during the early postnatal months. Evidence is presented that fat stores are mobilized during infections, hinting at one possible mechanism underlying the association between nutritional status and infectious morbidity and mortality among infants in nutritionally stressed human populations. Consistent with the proposed hypothesis, well-fed infants acquire peak fat reserves by an age of peak prevalence of malnutrition, infectious disease, and fat reserve depletion in less-buffered contexts, and childhood--characterized by minimal investment in the tissue--is a stage of reduced risk of energy stress. The model presented here foregrounds energy storage in adipose tissue as an important life-history strategy and a means to modify mortality risk during the nutritionally turbulent period of infancy. PMID: 9881526 [PubMed - indexed for MEDLINE] 5630. Z Kinder Jugendpsychiatr Psychother. 1998 Dec;26(4):244-52. [Possible pathophysiologic, diagnostic and therapeutic implications of new findings on leptin secretion within the scope of anorexia nervosa]. [Article in German] Wewetzer C(1), Mauer-Mucke K, Ballauff A, Remschmidt H, Hebebrand J. Author information: (1)Klinik für Psychiatrie und Psychotherapie des Kindes- und Jugendalters, Universität Würzburg. OBJECTIVES: Leptin is a hormone synthesized in adipocytes and secreted into the bloodstream. It plays an important role in the regulation of body weight, the adaptation to semi-starvation and in reproductive function. Hence, clinical studies pertaining to anorexia nervosa can serve to further elucidate the functions of this hormone in light of the unique features of this disorder. METHODS: Circulating concentrations of leptin are exceedingly low during the acute stage of anorexia nervosa. Which symptoms result from these diminished concentrations must be clarified. Furthermore, research is required to evaluate whether or not a too rapid weight gain might induce a physiological counter-regulation which would predispose to renewed loss of weight. RESULTS: This review summarizes findings to date pertaining to leptin secretion in patients with anorexia nervosa. In addition, possible diagnostic, pathophysiological and therapeutic implications are discussed. PMID: 9880834 [PubMed - indexed for MEDLINE] 5631. Acta Med Austriaca. 1998;25(4-5):136-7. [Weight loss by increasing energy consumption and thermogenesis]. [Article in German] Ludvik B(1). Author information: (1)Universitätsklinik für Inner Medizin III, Wien. bernhard.ludvik@akh-wien.ac.at Obesity is caused by a chronic imbalance between energy intake and energy expenditure. The increasing incidence of obesity over the last years is partly caused by the decreased physical activity following industrialization. Weight reduction can be achieved by decreasing energy intake and increasing energy expenditure. The fat loss induced by physical activity, however, is relatively small. Exercise helps to prevent the otherwise inevitable loss of muscle during caloric restriction. Due to the low success rate of conventional weight loss programs, the development of drugs to increase thermogenesis is subject to worldwide research. While in animal experiments stimulation of beta-3 adrenergic receptors leads to a significant weight loss, in humans these drugs fail to stimulate energy expenditure probably due to the lack of significant amounts of brown adipose tissue. The recently identified uncoupling proteins (UCP) 2 and 3 dissipate the protone gradient, thereby releasing stored energy as heat. These proteins might therefore act as potential targets for antiobesity drugs. PMID: 9879388 [PubMed - indexed for MEDLINE] 5632. Acta Med Austriaca. 1998;25(4-5):131-2. [Effect of fat distribution on risk]. [Article in German] Toplak H(1). Author information: (1)Ambulanz für Diabetes und Stoffwechsel, Medizinischen Universitätsklinik Graz. hermann.toplak@kfunigraz.ac.at About 10 years ago the WHO defined obesity as a separate disease whereas in Austria until now it is often regarded as a cosmetical problem only. Many diseases like those of joints and spine are correlated to the body weight and the body mass index (BMI), but macrovascular events (cardiovascular and cerebrovascular) and early death are closer associated with the waist to hip ratio (WHR), indicating an abdominal, android fat distribution. This fat distribution tends toward higher insulin levels, dys- and hyperlipidemia and disturbances in glucose metabolism which can in part explain these associations in the light of the metabolic syndrome. In conclusion, there is no healthy overweight, but not all overweight patients share the same risk. PMID: 9879386 [PubMed - indexed for MEDLINE] 5633. Acta Med Austriaca. 1998;25(4-5):129-30. [Evaluating genetics and environment in development of obesity]. [Article in German] Lechleitner M(1), Hoppichler F. Author information: (1)Universitätsklinik für Innere Medizin, Innsbruck. Previous studies with twins had demonstrated that heredity exerts a definite impact on the development of overweight even more than environmental conditions of nutrition. In recent years studies of molecular genetics in imbred obese mice lead to the discovery of the ob-gene coding for the expression of the ob-protein (leptin) in adipose tissue. Mutation of this gene and also of other genes coding for the expression of receptor proteines for leptin were also discovered in obese mice. In humans, however, mutations of the ob-gene were found only in a few families with hereditary obesity obviously as rarities as compared to a huge number of overweight people with high leptin of normal structure in western societies. About the molecular structure of leptin receptors or its possible mutation in obesity are no human results are available at the present time. In this survey further observations about genetics and mutations of transmitters regulating feeding and for energy expenditure are reported. Although all these results come from animals it may be presumed that they will provide an experimental basis for a better understanding of genetic mechanisms leading to obesity in humans and also for future development of drugs interfering with these mechanisms thus offering a chance for medical treatment of obesity. PMID: 9879385 [PubMed - indexed for MEDLINE] 5634. Int J Obes Relat Metab Disord. 1998 Dec;22(12):1145-58. Adipose tissue as an endocrine and paracrine organ. Mohamed-Ali V(1), Pinkney JH, Coppack SW. Author information: (1)Department of Medicine, University College London School of Medicine, Whittington Hospital, UK. The discovery of leptin has imparted great impetus to adipose tissue research by demonstrating a more active role for the adipocyte in energy regulation. Besides leptin, however, the adipose tissue also secretes a large number other signals. Cytokine signals, TNFalpha and IL-6, and components of the alternative pathway of complement influence peripheral fuel storage, mobilization and combustion, as well as energy homeostasis. In addition to the acute regulation of fuel metabolism, adipose tissue also influences steroid conversion and sexual maturation. In this way, adipose tissue is an active endocrine organ, influencing many aspects of fuel metabolism through a network of local and systemic signals, which interact with the established neuroendocrine regulators of adipose tissue. Thus, insulin, catecholamines and anterior pituitary endocrine axes interact at multiple levels with both cytokines and leptin. It may be proposed that the existence of this network of adipose tissue signalling pathways, arranged in an hierarchical fashion, constitutes a metabolic repertoire which enables the organism to adapt to a range of different metabolic challenges, including starvation, reproduction, times of physical activity, stress and infection, as well as short periods of gross energy excess. However, the occurrence of more prolonged periods of energy surplus, leading to obesity, is an unusual state in evolutionary terms, and the adipose tissue signalling repertoire, although sophisticated, adapts poorly to these conditions. Rather, the responses of the adipose tissue endocrine network to obesity are maladaptive, and lay the foundations of metabolic disease. PMID: 9877249 [PubMed - indexed for MEDLINE] 5635. Int J Cancer Suppl. 1998;11:14-6. Identification of risk factors for malnutrition: is there some evidence for predisposition? Vega Franco L(1). Author information: (1)Departamento de Salud Pública, Facultad de Medicina, UNAM, Mexico City, Mexico. Reviewed are reports on factors, identified by risk analysis, involved in the genesis of primary malnutrition in children. Data are compared with the sequence of factors in a flow diagram, based on the natural history of malnutrition, proposed 3 decades ago. Susceptibility to malnutrition is analyzed in light of observations related to inheritance, the ob gene and leptin. PMID: 9876470 [PubMed - indexed for MEDLINE] 5636. J Med Chem. 1998 Dec 31;41(27):5337-52. Leptin, a pleiotropic hormone: physiology, pharmacology, and strategies for discovery of leptin modulators. Dallongeville J(1), Fruchart JC, Auwerx J. Author information: (1)Laboratoire de Biologie des Régulations chez les Eucaryotes, U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, 1 Rue Calmette, 59019 Lille, France. PMID: 9876104 [PubMed - indexed for MEDLINE] 5637. Br J Nutr. 1998 Sep;80(3):219-29. The assembly of triacylglycerol-rich lipoproteins: an essential role for the microsomal triacylglycerol transfer protein. White DA(1), Bennett AJ, Billett MA, Salter AM. Author information: (1)School of Biomedical Sciences, University of Nottingham, UK. david.white@nottingham.ac.uk Raised plasma triacylglycerol is an independent risk factor for cardiovascular disease, and an understanding of factors which regulate the synthesis and degradation of lipoproteins which carry triacylglycerol in the blood may lead to novel approaches to the treatment of hypertriacylglycerolaemia. An active microsomal triacylglycerol transfer protein (MTP) is essential for the assembly of particles which transport triacylglycerol through the circulation. After absorption in the intestine, dietary fat and fat-soluble vitamins are incorporated into chylomicrons in the intestinal epithelial cells, and these lipoproteins reach the bloodstream via the lymphatic system. Patients with the rare genetic disorder, abetalipoproteinaemia, in which MTP activity is absent, present clinically with fat-soluble vitamin and essential fatty acid deficiency, indicating a key role for MTP in the movement of fat into the body. The triacylglycerol-rich lipoprotein found in fasting blood, VLDL, is assembled in the liver by an MTP-dependent process similar to chylomicron assembly, and transports triacylglycerol to extra-hepatic tissues such as adipose tissue and heart. In the absence of MTP activity, VLDL are not synthesized and only extremely low levels of triacylglycerol are present in the blood. Dietary components, including fat, cholesterol and ethanol, can modify the expression of the MTP gene and, hence, MTP activity. The present review summarizes current knowledge of the role of MTP in the assembly and secretion of triacylglycerol-rich lipoproteins, and the regulation of its activity in both animal and cell systems. PMID: 9875061 [PubMed - indexed for MEDLINE] 5638. C R Seances Soc Biol Fil. 1998;192(5):829-41. [From Claude Bernard to the regulatory system between the hypothalamus and the periphery: implications for homeostasis of body weight and obesity]. [Article in French] Jeanrenaud B(1), Cusin I, Rohner-Jeanrenaud F. Author information: (1)Laboratoires de Recherches Métaboliques, Hôpital cantonal universitaire de Genève. bfjean@compuserve.com The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and adipose tissue leptin. NPY, when infused intracerebroventricularly in normal animals produces hyperphagia and hormono-metabolic changes (hyperinsulinemia, hypercorticism) channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by muscles (muscle insulin resistance). Storage in NPY-infused rats is further favored by the observed decrease in the expression of uncoupling proteins. NPY-induced hyperinsulinemia and hypercorticosteronemia also promote leptin over-secretion. Released leptin, acting within the hypothalamus, decreases hypothalamic NPY levels (probably those of other hypothalamic neuropeptides as well), food intake, insulinemia, insulin sensitivity of white adipose tissue, while increasing that of muscles. Leptin acting centrally additionally favors the expression of uncoupling protein 1, 2, and 3, in keeping with an eflect on energy dissipating mechanisms. The respective hormono-metabolic eflects of NPY and leptin maintain a normal body homeostasis. In most obesity syndromes, the functional relationships between NPY and leptin are altered. Due to hypothalamic leptin receptor mutations or dysfunctions, leptin cannot exert its eflects: NPY levels (possibly those of other neuropeptides) remain elevated, maintaining excess storage, insulin as well as leptin resistance. PMID: 9871796 [PubMed - indexed for MEDLINE] 5639. Amino Acids. 1998;14(1-3):87-93. Nitric oxide as a peripheral and central mediator in temperature regulation. Simon E(1). Author information: (1)Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Federal Republic of Germany. In animals including humans nitric oxide (NO) serves as a biological messenger both peripherally at neuroeffector junctions and in the central nervous system where it modulates neuronal activity. Evidence for the involvement of NO in homeostatic control is accumulating also for temperature regulation in homeotherms. In the periphery an auxiliary role in the vasomotor control of convective heat transfer to heat dissipating surfaces and modulation of thermoregulatory heat generation, especially in brown adipose tissue as the site of nonshivering thermogenesis, are discussed as NO actions. At the central level a thermolytic role of NO in thermoregulation as well as in fever is assumed, however, experimental data opposing this view suggest that topical specificity may be important. At the level of single neurons, the observed interrelationships between thermosensitivity and responsiveness to NO are still not consistent enough to reconcile these data with the effects of NO-donors and inhibitors of NO-synthase on temperature regulation. PMID: 9871447 [PubMed - indexed for MEDLINE] 5640. Endocrine. 1998 Oct;9(2):139-41. The thrifty genotype in type 2 diabetes: an unfinished symphony moving to its finale? Joffe B(1), Zimmet P. Author information: (1)Department of Medicine, University of the Witwatersrand Medical School, Johannesburg, South Africa. 014BAR@CHIRON.WITS.AC.ZA The basic premise of the thrifty gene hypothesis is that certain populations may have genes that determine increased fat storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and type 2 diabetes. The concept finds support in a unique animal model (Psammomys obesus) as well as among high type 2 diabetes susceptibility populations, such as North American Indians and South Pacific islanders. However, in some developing communities (e.g., Black South Africans) the thrifty phenotype hypothesis of perinatal malnutrition causing beta-cell dysfunction seems a better explanation, but this remains a contentious issue. Several genes have already been identified as candidates for the thrifty genotype, including those encoding proteins of the insulin-signaling and leptin pathways, as well as intermediary fat metabolism. Particular interest lies in the peroxisome-proliferator activated receptors. An innovative approach might be to focus on the "mirror image" of the thrifty genotype-congenital lipoatrophic diabetes mellitus, whose molecular defect remains enigmatic. We conclude that the genetic basis of the thrifty genotype probably derives from the multiplicative effects of polymorphisms at several sites mentioned above, rather than a single regulatory abnormality. PMID: 9867247 [PubMed - indexed for MEDLINE] 5641. Aten Primaria. 1998 Nov 15;22(8):527-32. [New etiopathogenic aspects of obesity]. [Article in Spanish] Orozco P(1). Author information: (1)ABS Gòtic, Barcelona. PMID: 9866261 [PubMed - indexed for MEDLINE] 5642. Med Pregl. 1998 Sep-Oct;51(9-10):410-4. [Leptin and human reproduction]. [Article in Croatian] Macut D(1), Micić D. Author information: (1)Institut za endokrinologiju, dijabetes i bolesti metabolizma, Klinicki centar Srbije, Beograd. Leptin is a secretory product of adipocytes. It has been suggested that leptin acts as an afferent satiety signal to the brain modulating the expression of the orexigenic hypothalamic peptide, neuropeptide Y (NPY). Therefore leptin can be regarded as a marker of the nutritional status of the body. It was proposed that human obesity may result from a central resistance to leptin due to different pathophysiological mechanisms: saturation of the leptin transport into the cerebrospinal fluid of the obese subjects, abnormalities in the hypothalamic receptor for leptin, or post-receptor transduction mechanisms. It was shown that circulating leptin levels in humans significantly correlate with the body mass index (BMI). Although most studies point to white adipose tissue as a primary source of leptin there is still some uncertainty towards the relative expression of leptin between various body fat compartments. LEPTIN AND ONSET OF PUBERTY: Studies on animal models recognized various metabolic candidates for modulation of GnRH neuronal activity. It was supposed that mild changes in the body's metabolic status can serve to regulate the central drive to the reproductive axis. It is likely that leptin can serve as a "metabolic cue" that transmits signals of those mild metabolic changes towards activation of the GnRH neuronal system at the end of the prepubertal period. On the other side there is a possibility of altered leptin pulsatility during prepubertal period that can consequently influence hypothalamus and GnRH neuronal system. LEPTIN AND SEXUAL DIMORPHISM: Leptin levels in humans are similar in both sexes during the prepubertal period. During puberty leptin has a tendency to decline in boys and to remain constant in girls. Puberty is also characterized with a similar circadian rhythm pattern between sexes whil girls express different pulse characteristics. It seems that sexual dimorphism is established in early phases of human development. There is a possibility of sex steroid influence on such sexual dimorphism. LEPTIN AND REPRODUCTIVE FUNCTION: It was shown that administration of recombinant leptin to ob ob mice could restore fertility in these infertile animals. There is certain difference in leptin levels according to the phase of the menstrual cycle. It was shown that leptin peak is in the luteal phase of the cycle and that correlates to the maximal progesterone level. It is possible that leptin could directly influence ovary and that disruption of such an effect could play a role in menstrual irregularities in both obese and mal nourished women. This could even become a pathophysiological mechanism in women with polycystic ovary syndrome (PCOS). It was supposed that leptin resistance could be involved in infertility impairment of the obese women with PCOS. Leptin increases during pregnancy. Appearance of placenta as a new, nonadipose source of leptin production, increases a possibility of different leptin mRNA expression through gestation. PMID: 9863330 [PubMed - indexed for MEDLINE] 5643. Domest Anim Endocrinol. 1998 Nov;15(6):457-75. Leptin and its receptors: regulators of whole-body energy homeostasis. Houseknecht KL(1), Portocarrero CP. Author information: (1)Department of Animal Sciences, Purdue University, West Lafayette, IN 47907-1151, USA. Leptin is the adipocyte-specific product of the ob gene. Expression of leptin in fully fed animals reflects adipocyte size and body-fat mass. Leptin signals the status of body energy stores to the brain, where signals emanate to regulate food intake and whole-body energy expenditure. The leptin gene was identified in the leptin-deficient, obese ob/ob mouse by positional cloning techniques. Recently, leptin has been cloned in domestic species including pigs, cattle, and chickens. The leptin receptor has at least five splice variants; the long form of the receptor is primarily expressed in the hypothalamus and is thought to be the predominant signaling isoform. Leptin receptors are members of the cytokine family of receptors and signal via janus-activated kinases (JAK)/signal transducers and activators of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways. Mutations in the leptin or leptin receptor genes results in morbid obesity, infertility, and insulin resistance in rodents and humans. Leptin regulates food intake and energy expenditure via central and peripheral mechanisms. Leptin receptors are expressed in most tissues, and in vitro evidence suggests that leptin may have direct effects on some tissues such as adipose tissue, the adrenal cortex, and the pancreatic beta-cell. Leptin is thought to influence whole-body glucose homeostasis and insulin action. Studies are underway to determine the role that leptin plays in the biology of domestic animals. PMID: 9861538 [PubMed - indexed for MEDLINE] 5644. Ugeskr Laeger. 1998 Dec 7;160(50):7246-50. [The auto- and endocrine function of the adipose tissue. Significance for metabolic complications in obesity]. [Article in Danish] Richelsen B(1), Kristensen K, Jensen JD. Author information: (1)Arhus Universitetshospital, Arhus Amtssygehus, medicinsk-endokrinologisk afdeling C. br@aas.auh.dk The present review discusses recent research showing adipose tissue to be highly metabolically active, producing and releasing many different bioactive compounds besides free fatty acids (FFA) such as tumor necrosis factor alpha (TNF alpha), leptin, acetylation stimulating protein (ASP), plasminogen activator inhibitor-1 (PAI-1), cholesterol ester transfer protein (CETP), prostaglandins and oestrogens. Most of these compounds have autocrine effects on the adipose cells and they are presumably involved in the physiological regulation of blood flow, growth and metabolism of the adipose tissue. When the adipose tissue becomes enlarged, as seen in association with obesity, it has now been shown that several of the compounds produced in the adipose tissue (TNF, PAI-1, CETP etc.) may be directly involved in the pathogenesis of some of the complications commonly seen in association with obesity such as insulin resistance, hypertension, enhanced thrombogenesis, and premature atherosclerosis. PMID: 9859722 [PubMed - indexed for MEDLINE] 5645. Gynecol Endocrinol. 1998 Oct;12(5):321-6. Is there a role for leptin in human reproduction? Macut D(1), Micić D, Pralong FP, Bischof P, Campana A. Author information: (1)Institute of Endocrinology, Clinical Center of Serbia, Beograd, Yugoslavia. Leptin is a protein product from the obesity gene (ob gene). It has been shown that leptin significantly correlates with body mass index in humans. In contrast to the obesity of genetically obese (ob/ob) mice, human obesity is not generally caused by gene mutations. It is possible that human obesity results from central leptin resistance. Leptin can serve as a metabolic cue in the neuronal activation of gonadotropin releasing hormone (GnRH) at the end of the prepubertal period. The concentration of leptin is higher in pubertal girls than pubertal boys, and it is supposed that sexual dimorphism might be established in the prepubertal period or even in earlier developmental phases. This dimorphism could be explained by a suppressive action of androgens on leptin. Decreased leptin levels were found in undernourished women of reproductive age, mainly presenting with oligo- or amenorrhea. Leptin concentrations fluctuate according to the phase of the menstrual cycle. It is suggested that the complex relationship of leptin with other hormones, such as insulin, can have etiopathogenetic importance in some enigmatic reproductive disturbances such as the polycystic ovary syndrome. Recent findings of leptin in non-adipose tissue of the placenta could indicate its potential role in developmental physiology and human reproduction. PMID: 9859024 [PubMed - indexed for MEDLINE] 5646. Am J Obstet Gynecol. 1998 Dec;179(6 Pt 2):S94-S100. Understanding the underlying metabolic abnormalities of polycystic ovary syndrome and their implications. Taylor AE(1). Author information: (1)Harvard Medical School and the Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts, USA. Women with polycystic ovary syndrome have an increased rate of obesity, with a propensity toward abdominal deposition of body fat. Independent of obesity, at least half of affected women have insulin resistance. To understand the mechanisms of insulin resistance in polycystic ovary syndrome, it is necessary to understand normal insulin signaling. Women with polycystic ovary syndrome have normal binding of insulin to its receptor but have decreased activation of events downstream of the receptor. This insulin resistance occurs mostly in the peripheral tissues (muscle and fat cells), and results in increased pancreatic insulin secretion to maintain normal glucose levels. Obese women with polycystic ovary syndrome have a relative defect in insulin secretion. At least 20% of obese patients with polycystic ovary syndrome have glucose intolerance or diabetes, versus about 5% of the healthy age-matched population. Obesity and insulin resistance probably increase the risk of cardiovascular disease in women with polycystic ovary syndrome. The metabolic features of polycystic ovary syndrome are important health risk factors and need to be considered seriously, even if the patient seeks treatment for other concerns. PMID: 9855615 [PubMed - indexed for MEDLINE] 5647. Can J Surg. 1998 Dec;41(6):455-8. Lipoblastoma and liposarcoma in children: an analysis of 9 cases and a review of the literature. Miller GG(1), Yanchar NL, Magee JF, Blair GK. Author information: (1)Department of Surgery, University of British Columbia, British Columbia's Children's Hospital, Vancouver. miller@duke,usask.ca OBJECTIVES: To review the experience at a children's hospital of lipoblastoma and liposarcoma and to identify any factors that would differentiate one type of tumour from the other. DESIGN: A retrospective case series. SETTING: British Columbia's Children's Hospital a tertiary-care pediatric centre. PATIENTS: All patients with a pathological diagnosis of lipoblastoma and liposarcoma recorded over 12 years. MAIN OUTCOME MEASURES: The frequency of lipoblastoma and liposarcoma, identified from biopsy specimens of pediatric adipose tumours. The clinical, pathological and cytogenetic variables between lipoblastoma and liposarcoma. RESULTS: One hundred and forty-nine adipose tumours were recorded. Seven (4.7%) were lipoblastomas and 2 (1.3%) were liposarcomas. All tumours presented as asymptomatic, slow-growing, soft-tissue masses. The children with lipoblastoma tended to be younger, but 29% were over 3 years of age. The liposarcoma patients were aged 9 and 14 years. One liposarcoma was of myxoid type and the other was a round cell variant. Karyotypes were reported for 1 lipoblastoma and 1 liposarcoma. The myxoid liposarcoma karyotype was 46,XY,t(12;16)(q13;p11), and the lipoblastoma was reported as 46,XY,der(8)?t(8q;?),+mar. CONCLUSIONS: Lipoblastoma is an unusual childhood neoplasm and liposarcoma is very rare in children. Both tumours may present in a similar fashion, and differentiating them histologically can be difficult. Age cannot be relied upon to accurately predict their behaviour. The tumour karyotype is very helpful in differentiating these neoplasms. PMCID: PMC3949803 PMID: 9854536 [PubMed - indexed for MEDLINE] 5648. Coron Artery Dis. 1998;9(8):503-11. Menopause, central body fatness, and insulin resistance: effects of hormone-replacement therapy. Tchernof A(1), Calles-Escandon J, Sites CK, Poehlman ET. Author information: (1)Clinical Pharmacology and Metabolic Research Unit, University of Vermont, Burlington 05405, USA. In addition to being associated with termination of reproductive life in women, the menopause coincides with an increase in several comorbidities including cardiovascular disease. This increase in the prevalence of cardiovascular disease in the postmenopausal years has been partially attributed to adverse effects of estrogen deficiency on plasma lipid-lipoprotein levels and on the cardiovascular system, although other factors are contributing. Central body fatness and insulin resistance are components of a cluster of metabolic abnormalities which also increases the risk of cardiovascular disease. This review summarizes studies that have examined the effects of the menopause transition and of estrogen-replacement therapy on central body fatness and insulin resistance. Review of cross-sectional studies suggests that the menopause transition is associated with an increase in abdominal and visceral adipose tissue accumulation, as measured either with dual X-ray absorptiometry or computed tomography. These results appear to be independent of the aging process and total body fatness. In general, cross-sectional studies using circumference measurements did not find any significant effect of the menopause. Longitudinal studies also support that accumulation of central body fatness accelerates with menopause. The effects of the menopause on insulin resistance appear to be moderate, if any, although available studies are clearly insufficient to draw firm conclusions. The majority of interventional studies support the notion that hormone-replacement therapy attenuates the accumulation of central fat in postmenopausal women, compared with control or placebo-treated women. Retrospective comparisons of hormone users and nonusers also support a protective effect of hormone replacement on fat distribution. Moderate effects of estrogen therapy were found on insulin resistance in postmenopausal women, although long-term, controlled trials using accurate measurements of insulin sensitivity are lacking. Treatment with progestins exerts moderate deleterious effects on insulin sensitivity, which may be attributable to the partial androgenicity of progestins used. It is concluded that part of the increased incidence of cardiovascular disease in postmenopausal women may be attributable to increased central body fatness. Therapies aiming at preventing these changes in fat distribution such as hormone-replacement therapy, diet or exercise are likely to provide long-term cardiovascular and metabolic benefits for women's health. PMID: 9847982 [PubMed - indexed for MEDLINE] 5649. Coron Artery Dis. 1998;9(8):495-501. Body weight loss and maintenance with physical activity and diet. Doucet E(1), Tremblay A. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. PMID: 9847981 [PubMed - indexed for MEDLINE] 5650. Coron Artery Dis. 1998;9(8):489-94. Abdominal obesity and associated cardiovascular comorbidities in the elderly. Kohrt WM(1). Author information: (1)Washington University School of Medicine, Division of Geriatrics and Gerontology, St Louis, MO 63110, USA. PMID: 9847980 [PubMed - indexed for MEDLINE] 5651. Int J Biochem Cell Biol. 1998 Nov;30(11):1163-8. Mammalian mitochondrial uncoupling proteins. Jezek P(1), Garlid KD. Author information: (1)Department of Membrane Transport Biophysics, Academy of Sciences of the Czech Republic, Prague, Czech Republic. jezek@sun1.biomed.cas.cz The mammalian uncoupling protein (UCP-1) from the gene family of mitochondrial carriers is a dimer of identical 33 kDa subunits, each containing six membrane-spanning alpha-helices. Its expression, restricted to brown fat, occurs upon birth, cold acclimation and overfeeding. UCP-1 dissipates redox energy and thereby provides heat to the animal. Two additional isoforms have recently been discovered, 59% homologous UCP-2, widely expressed (heart, kidney, lung, placenta, lymphocytes, white fat); and UCP-3 (57% homologous), found in brown fat and skeletal muscle. Their physiological roles are unknown, but may include the regulation of body weight and energy balance, muscle nonshivering thermogenesis, fever, and defense against generation of reactive oxygen species. Consequently, great pharmacological potential is expected in revealing their biochemical and hormonal regulators. UCP-1 mediates a purine-nucleotide-sensitive uniport of monovalent unipolar anions, including fatty acids, that lead to fatty acid cycling and uncoupling. UCP-2 and UCP-3 are expected to share a similar mechanism. PMID: 9839442 [PubMed - indexed for MEDLINE] 5652. Indian Heart J. 1998 Jul-Aug;50(4):385-95. Insulin resistance syndrome: current perspective and its relevance in Indians. Misra A(1). Author information: (1)Department of Medicine, All India Institute of Medical Sciences, New Delhi. Comment in Indian Heart J. 1998 Sep-Oct;50(5):574-7. Indian Heart J. 1998 Sep-Oct;50(5):573-4. PMID: 9835197 [PubMed - indexed for MEDLINE] 5653. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Jun;119(3):295-303. Regulation of appetite and body weight in seasonal mammals. Mercer JG(1). Author information: (1)Molecular Neuroendocrinology Unit, Rowett Research Institute, Aberdeen, Scotland, UK. jgm@rri.sari.ac.uk As models of physiological regulation of body weight, adiposity and appetite, seasonal mammals offer unique opportunities for manipulating fundamental regulatory processes that may not be available in the more frequently-studied laboratory rodents. Seasonal weight and intake cycles are anticipatory rather than reactive in nature, being manifest despite the availability of adlibitum supplies of food. They are exhibited despite all other environmental variables being held constant, and are reversible. Appropriate body weight appears to be a sliding set point in many seasonal mammals, which can move in either direction, largely independently of age. While few data are available other than from rats and mice, there appears to be a strong commonality of central neuroendocrine and peripheral signalling systems between seasonal and non-seasonal mammals, although the conditions under which endogenous regulatory pathways are activated may differ significantly between species. Peripheral and central signalling systems implicated in the regulation of appetite and body weight may be modulated during seasonal transitions. Discussion will concentrate on hypothalamic neuropeptides, gastrointestinal satiety peptides, the recently-described peptide, leptin, that is secreted by adipose tissue, and the interactions between these regulatory components. PMID: 9827002 [PubMed - indexed for MEDLINE] 5654. J Mol Med (Berl). 1998 Oct;76(11):764-72. Physiological consequences of beta-adrenergic receptor disruption. Rohrer DK(1). Author information: (1)Department of Molecular Pharmacology, Roche Bioscience, Palo Alto, CA 94304, USA. Activation of beta-adrenergic receptors (beta-ARs) in vivo is an important means by which animals regulate cardiac performance, vascular tone, lipid and carbohydrate metabolism, and behavior. The advent of targeted gene disruption in mice has led to significant advances in our understanding of the role that beta-AR subtypes play in these processes, and this technique has become an important tool for the study of G protein coupled receptors in general. To date, targeted disruption of both beta1- and beta3-ARs in mice has been reported. Mice lacking beta1-ARs are unresponsive to cardiac beta-AR stimulation, suggesting that neither beta2- nor beta3-ARs couple to inotropic or chronotropic responses in the mouse. Conversely, mice lacking beta3-ARs retain at least some adipose beta-AR responsiveness through remaining beta1- and beta2-ARs, suggesting that all three beta-AR subtypes mediate similar functions in this tissue. While these knockout models have been extremely valuable tools for revealing the roles that individual beta-ARs play in whole animal physiology, it is also useful to integrate the results of experiments derived from either transgenic overexpression of beta-ARs or purely pharmacological approaches to the study of beta-AR function in order to create a comprehensive model of beta-AR function in vivo. PMID: 9826121 [PubMed - indexed for MEDLINE] 5655. Dtsch Med Wochenschr. 1998 Oct 30;123(44):1315-6. [Obesity and leptin]. [Article in German] Hauner H(1). Author information: (1)Klinische Abteilung des Diabetes-Forschungsinstituts, Heinrich-Heine-Universität, Düsseldorf. hauner@dfi.uni-duesseldorf.de PMID: 9824967 [PubMed - indexed for MEDLINE] 5656. Proc Soc Exp Biol Med. 1998 Dec;219(3):200-10. Regulation of adipose cell development in utero. Martin RJ(1), Hausman GJ, Hausman DB. Author information: (1)Department of Foods and Nutrition, University of Georgia and Animal Physiology, USDA Russell Research Center, Athens, Georgia 30602, USA. rjmartin@fcs.uga.edu The condition of obesity is impacted by increases in fat cell number, fat cell size, or a combination of the two. It is generally believed that fat cell number is dependent on the age of onset and the degree of obesity. This review provides an update on intrauterine growth of fetal adipose tissue, the earliest period of proliferation onset, and the factors that interact to enhance or suppress development. Fetal adipose tissue development is regulated by the complex interaction of maternal, endocrine, and paracrine influences that initiate specific changes in angiogenesis, adipogenesis, and metabolism. Developmental stages and metabolic processes influenced by specific hormones and paracrine factors have been identified through examination of the offspring of obese and diabetic pregnancies, hormonal manipulation during late pregnancy in animal models, and the use of cell culture. Collectively, the results of the studies cited herein delineate the basis for imprinting or conditioning of fetal preadipocytes at the paracrine/autocrine level and a role of thyroxine, glucocorticoids, and other hormones in fetal adipose tissue development and metabolism. PMID: 9824542 [PubMed - indexed for MEDLINE] 5657. Mol Cell Biochem. 1998 Nov;188(1-2):129-36. Nutritional and endocrine modulation of intracellular calcium: implications in obesity, insulin resistance and hypertension. Zemel MB(1). Author information: (1)Department of Nutrition, University of Tennessee, Knoxville 37996-1900, USA. Regulation of intracellular Ca2+ ([Ca2+]i) plays a key role in obesity, insulin resistance and hypertension, and [Ca2+]i disorders may represent a fundamental factor linking these three conditions. We have shown insulin to be a direct vasodilator, attenuating voltage-gated Ca2+ influx and stimulating Ca(2+)-ATPase transcription via a glucose-6-phosphate response element. These result in a net decrease in [Ca2+]i and thereby decrease vascular resistance, while these effects are blunted in insulin resistance, leading to increased vascular resistance. Consistent with this concept, pharmacological amplification of peripheral insulin sensitivity results in reduced arterial pressure. While insulin regulates [Ca2+]i, Ca2+ also regulates insulin signaling, as increasing [Ca2+]i impairs insulin signaling in some systems, possibly due to Ca2+ inhibition of insulin-regulated dephosphorylation. Finally, in recent studies of the mouse agouti gene, we have also demonstrated increased [Ca2+]i to play a key role in adipocyte lipogenesis, as follows. We have found dominant agouti mutants to exhibit increased [Ca2+]i in most tissues, leading to increased vascular reactivity and insulin resistance in vascular smooth muscle and skeletal muscle cells, respectively. Further, we have found recombinant agouti protein to directly increase [Ca2+]i in a variety of cells, including murine and human adipocytes, and to stimulate both the expression and activity of adipocyte fatty acid synthase and increase triglyceride accumulation in a Ca(2+)-dependent manner. These effects can be mimicked by stimulation of Ca2+ influx and blocked by Ca2+ channel inhibition, while treatment of mice with a Ca2+ antagonist attenuates agouti-induced obesity. Since humans express agouti in adipose tissue, it may similarly exert paracrine effects on [Ca2+]i and thereby stimulate de novo lipogenesis and promote obesity. Thus, Ca2+ signaling represents a target for therapeutic intervention in obesity as well as hypertension and insulin resistance. PMID: 9823018 [PubMed - indexed for MEDLINE] 5658. Eur Heart J. 1998 Oct;19(10):1421-2. Leptin and cardiac cachexia: marker or mediator? Cleland JG, Clark AL. Comment on Eur Heart J. 1998 Oct;19(10):1547-51. PMID: 9820983 [PubMed - indexed for MEDLINE] 5659. Eur J Endocrinol. 1998 Oct;139(4):363-4. PPARgamma: from adipose tissue to the atherosclerotic plaque. Lopez-Liuchi JV(1), Meier CA. Author information: (1)Département de Médecine Interne, Hôpital Universitaire de Genève, Geneva, Switzerland. PMID: 9820610 [PubMed - indexed for MEDLINE] 5660. Curr Opin Obstet Gynecol. 1998 Oct;10(5):361-3. Leptin and the onset of puberty. Edmonds DK. PMID: 9818212 [PubMed - indexed for MEDLINE] 5661. Nihon Naika Gakkai Zasshi. 1998 Sep 10;87(9):1802-5. [Obesity and diseases. 4. Molecular mechanism involved in the onset of arteriosclerosis in obesity]. [Article in Japanese] Funahashi T, Matsuzawa Y. PMID: 9816853 [PubMed - indexed for MEDLINE] 5662. Biol Psychiatry. 1998 Nov 1;44(9):851-64. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Leibowitz SF(1), Alexander JT. Author information: (1)Rockefeller University, New York, NY 10021, USA. Serotonin (5-HT) has been implicated in the control of eating behavior and body weight. Stimulants of this monoamine reduce food intake and weight gain and increase energy expenditure, both in animals and in humans. This article reviews evidence that supports a role for hypothalamic serotonergic receptor mechanisms in the mediation of these effects. A variety of studies in rodents indicate that, at low doses, 5-HT or drugs that enhance the release of this neurotransmitter preferentially inhibit the ingestion of carbohydrate, more than fat or protein. This phenomenon is mediated, in part, by 5-HT receptors located in various medial hypothalamic nuclei. A negative feedback loop exists between the consumption of this macronutrient and the turnover of 5-HT in the hypothalamus. That is, carbohydrate ingestion enhances the synthesis and release of hypothalamic 5-HT, which in turn serves to control the size of carbohydrate-rich meals. A model is described that proposes the involvement of circulating hormones and glucose in this feedback process. These hormones, including insulin, corticosterone, and the adipose tissue-derived hormone, leptin, have impact on serotonergic function as well as satiety. This model further suggests that 5-HT exerts its strongest effect on appetite at the start of the natural feeding cycle, when carbohydrate is normally preferred. Clinical studies provide evidence that is consistent with the proposed model and that implicates 5-HT in disturbances of eating and body weight disorders. PMID: 9807640 [PubMed - indexed for MEDLINE] 5663. Diabetes Metab. 1998 Sep;24(4):376-8. [Leptin and puberty in humans: hypothesis of the critical adipose mass revisited]. [Article in French] Issad T(1), Strobel A, Camoin L, Ozata M, Strosberg AD. Author information: (1)UPR 415 CNRS, ICGM, Paris, France. PMID: 9805652 [PubMed - indexed for MEDLINE] 5664. Diabetes Metab. 1998 Sep;24(4):321-6. Does leptin regulate insulin secretion? Poitout V(1), Rouault C, Guerre-Millo M, Reach G. Author information: (1)Pacific Northwest Research Institute, Seattle, WA 98122, USA. vpoitout@pnrf.org The hormone leptin secreted by adipocytes plays a major role in body weight homeostasis. Its main target is the hypothalamus, but it also affects several peripheral tissues directly. The direct effect of leptin on insulin secretion by pancreatic beta cells has been investigated in several studies, though with controversial results. Interpretation of these data must take into account the animal model and the leptin concentrations used. Experiments carried out on islets from ob/ob mice harbouring a mutation in the leptin gene are not representative of the leptin effect in normal animals because ob/ob islets are very sensitive to the hormone and show altered regulation of insulin secretion. In normal rodent islets, physiological concentrations of leptin seem to inhibit insulin secretion only when the islets are maximally stimulated with high concentrations of glucose associated with secretion potentiators. Several isoforms of the leptin receptor are expressed in pancreatic beta cells. Indirect experimental evidence suggests that leptin signalling in islets requires the long isoform of the receptor. The molecular mechanisms underlying the effect of leptin on insulin secretion are unknown. Our hypothesis is that physiological concentrations of leptin in normal rodents do not affect the direct pathway (coupling a rise in glucose concentration to insulin secretion) but modulate a potentiation of glucose-induced insulin secretion involving cyclic AMP or phospholipase C/protein kinase C activation. PMID: 9805642 [PubMed - indexed for MEDLINE] 5665. Physiol Res. 1998;47(4):215-25. Thiazolidinediones--tools for the research of metabolic syndrome X. Komers R(1), Vrána A. Author information: (1)Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma PMID: 9803467 [PubMed - indexed for MEDLINE] 5666. Reprod Fertil Dev. 1998;10(2):127-37. Energy balance and ovulation: small cages versus natural habitats. Bronson FH(1). Author information: (1)Institute of Reproductive Biology, Department of Zoology, University of Texas at Austin, USA. bronson@mail.utexas.edu In the laboratory, ovulation is suppressed when a mammal is in negative energy balance whether that state is caused by inadequate food intake, excessive locomotor activity or heavy thermoregulatory costs. In this paper, knowledge generated in the laboratory about the link between ovulation and energy balance is examined in relation to the kinds of energetic challenges mammals actually face in natural habitats. When viewed in that context, several conclusions can be drawn. First, females ovulate whenever extant energetic conditions permit unless the process is blocked by non-metabolic stress, social cues or a predictive seasonal cue such as photoperiod. In the latter case, most mammals show at least a seasonal tendency in their reproduction and the majority do not use a predictive cue; they reproduce opportunistically in relation to seasonal variation in the energetic characteristics of their environment. Second, the widely held assumption that a female's fat reserves must exceed a critical level in order that she may ovulate finds no support in the literature dealing with natural populations. Third, the surprisingly rapid responsiveness of the gonadotrophin releasing hormone (GnRH) pulse generator to energetic manipulation probably reflects the study of animals that are in a pure survival mode. Fourth, the complexity of the energetic challenges mammals face in the wild suggests that there are probably multiple metabolic and neural pathways coupling ovulation to energy balance and that these pathways are probably characterized by considerable overlap and redundancy. Thus, fifth, to develop a more realistic overview of these pathways there is a need for experimental designs that present mammals with the kinds of complex challenges they actually face in the wild habitats in which they evolved. PMID: 9801265 [PubMed - indexed for MEDLINE] 5667. Nature. 1998 Oct 22;395(6704):763-70. Leptin and the regulation of body weight in mammals. Friedman JM(1), Halaas JL. Author information: (1)Laboratory of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA. friedj@rockvax.rockefeller.edu The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution. However, the presence of excess adipose tissue can be maladaptive. A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system. Leptin also signals nutritional status to several other physiological systems and modulates their function. Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity. PMID: 9796811 [PubMed - indexed for MEDLINE] 5668. Breast Cancer Res Treat. 1998;49 Suppl 1:S27-32; discussion S33-7. Clinical importance of intratumoral aromatase. Miller WR(1), Mullen P, Telford J, Dixon JM. Author information: (1)Breast Unit, Western General Hospital, Edinburgh, UK. Evidence to support the contention that estrogen biosynthesis in breast cancers is of clinical significance has been sought by relating activity to (i) clinical response to aromatase inhibitors and (ii) tumor concentrations of estrogens. Significant correlations have been reported between the presence/high levels of tumor aromatase in vitro and likelihood of response to aminoglutethimide in patients with advanced breast cancer, but the association is not absolute and it has been more difficult to demonstrate similar relationships in patients with earlier stages of cancers treated with other more potent inhibitors. There are however data to suggest that in vitro measurements of aromatase may not reflect in situ estrogen synthesis. For example mammary adipose tissue fibroblasts preincubated with reversible aromatase inhibitors may paradoxically display elevated in vitro aromatase activity. Similar enhanced in vitro activity may be observed in breast material taken from patients treated neo-adjuvantly with aromatase inhibitors such as aminoglutethamide and letrozole. That this is an artifact of in vitro systems can be demonstrated by performing in situ assessments of aromatase activity in patients before and after treatment with aromatase inhibitors. Thus it can be shown that letrozole markedly inhibits in situ aromatase and reduces tumor levels of estrogens. PMID: 9797015 [PubMed - indexed for MEDLINE] 5669. Diabetologia. 1998 Oct;41(10):1241-8. Is type II diabetes mellitus a disease of the innate immune system? Pickup JC(1), Crook MA. Author information: (1)Department of Chemical Pathology, United Medical School, Guy's Hospital, London, UK. Comment in Diabetologia. 1999 Apr;42(4):497-8. Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, alpha-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. PMID: 9794114 [PubMed - indexed for MEDLINE] 5670. Proc Nutr Soc. 1998 Aug;57(3):477-85. Human and clinical perspectives on leptin. Blum WF(1), Englaro P, Attanasio AM, Kiess W, Rascher W. Author information: (1)University Children's Hospital, Giessen, Germany. Blum_Werner@Lilly.com PMID: 9794007 [PubMed - indexed for MEDLINE] 5671. Proc Nutr Soc. 1998 Aug;57(3):471-5. ob gene mutations and human obesity. Farooqi S(1), Rau H, Whitehead J, O'Rahilly S. Author information: (1)University Department of Medicine, Addenbrooke's Hospital, Cambridge, UK. ifarooqi@hgmp.mrc.ac.uk PMID: 9794006 [PubMed - indexed for MEDLINE] 5672. Proc Nutr Soc. 1998 Aug;57(3):461-70. Leptin production in human adipose tissue. Coppack SW(1), Pinkney JH, Mohamed-Ali V. Author information: (1)Department of Medicine, University College London Medical School, Whittington Campus, Archway Wing, UK. scoppack@med.ucl.ac.uk PMID: 9794005 [PubMed - indexed for MEDLINE] 5673. Proc Nutr Soc. 1998 Aug;57(3):449-53. Peripheral metabolic actions of leptin. Cawthorne MA(1), Morton NM, Pallett AL, Liu YL, Emilsson V. Author information: (1)Clore Laboratory, University of Buckingham, UK. mac@buck.ac.uk PMID: 9794003 [PubMed - indexed for MEDLINE] 5674. Proc Nutr Soc. 1998 Aug;57(3):429-40. Overview: neurobiology of OB protein (leptin). Campfield LA(1), Smith FJ. Author information: (1)Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. L_Arthur.Campfield@Roche.com PMID: 9794001 [PubMed - indexed for MEDLINE] 5675. Proc Nutr Soc. 1998 Aug;57(3):421-7. Leptin and reproduction. Hoggard N(1), Hunter L, Trayhurn P, Williams LM, Mercer JG. Author information: (1)Molecular Physiology Group, Rowett Research Institute, Bucksburn, Aberdeen, UK. nh@rri.sari.ac.uk PMID: 9794000 [PubMed - indexed for MEDLINE] 5676. Proc Nutr Soc. 1998 Aug;57(3):413-9. Regulation of leptin production: a dominant role for the sympathetic nervous system? Trayhurn P(1), Duncan JS, Hoggard N, Rayner DV. Author information: (1)Division of Biomedical Science, Rowett Research Institute, Bucksburn, Aberdeen, UK. pt@rri.sari.ac.uk PMID: 9793999 [PubMed - indexed for MEDLINE] 5677. Proc Nutr Soc. 1998 Aug;57(3):409-11. Leptin: energy regulation and beyond to a hormone with pan-physiological function. Andrews JF(1). Author information: (1)Department of Physiology, Trinity College, Dublin, Republic of Ireland. jandrews@tcd.ie PMID: 9793998 [PubMed - indexed for MEDLINE] 5678. Exp Clin Endocrinol Diabetes. 1998;106 Suppl 2:35-40. Anti-obesity drugs: what does sibutramine offer? An analysis of its potential contribution to obesity treatment. Van Gaal LF(1), Wauters MA, De Leeuw IH. Author information: (1)Department of Endocrinology, Metabolism and Clinical Nutrition, Universitaire Instelling Antwerpen (UA), Universiteitsplein 1, Antwerp, Belgium. Sibutramine is a serotonin and noradrenaline re-uptake inhibitor (SNRI) which induces weight loss via a dual mode of action: enhancing both satiety and energy expenditure. Sibutramine exerts its in vivo effects predominantly via its secondary and primary amine metabolites. Following oral ingestion, sibutramine is well absorbed and undergoes extensive first pass metabolism. Sibutramine produces statistically and clinically significant, dose-related weight loss over the range 5-30 mg once daily; active weight loss occurs for 6 months. Long-term studies of up to 1 year have found that weight loss is maintained with continued sibutramine therapy. Sibutramine-induced weight loss is associated with beneficial changes in obesity-related risk factors, such as serum lipids, uric acid levels, and glycaemic control (in patients with type 2 diabetes). Subcutaneous/visceral fat ratio was found to increase significantly under sibutramine treatment, indicating that relatively more visceral fat than subcutaneous fat is lost. Sibutramine is well tolerated; side-effects are generally mild, non-treatment limiting, and consistent with the known mechanism of action of the drug. Overall, studies have found sibutramine to be an effective weight loss agent with a good safety profile. PMID: 9792480 [PubMed - indexed for MEDLINE] 5679. Am J Physiol. 1998 Nov;275(5 Pt 2):R1399-411. Innervation of mammalian white adipose tissue: implications for the regulation of total body fat. Bartness TJ(1), Bamshad M. Author information: (1)Departments of Psychology, and of Biology, Neuropsychology and Behavioral Neurosciences, Georgia State University, Atlanta, Georgia 30303, USA. We review the extensive physiological and neuroanatomical evidence for the innervation of white adipose tissue (WAT) by the sympathetic nervous system (SNS) as well as what is known about the sensory innervation of this tissue. The SNS innervation of WAT appears to be a part of the general SNS outflow from the central nervous system, consisting of structures and connections throughout the neural axis. The innervation of WAT by the SNS could play a role in the regulation of total body fat in general, most likely plays an important role in regional differences in lipid mobilization specifically, and may have a trophic affect on WAT. The exact nature of the SNS innervation of WAT is not known but it may involve contact with adipocytes and/or their associated vasculature. We hypothesize that the SNS innervation of WAT is an important contributor to the apparent "regulation" of total body fat. PMID: 9791054 [PubMed - indexed for MEDLINE] 5680. Endocr J. 1998 Apr;45 Suppl:S9-13. Using gene knockout and transgenic techniques to study the physiology and pharmacology of beta3-adrenergic receptors. Lowell BB(1). Author information: (1)Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, MA 02215, USA. PMID: 9790223 [PubMed - indexed for MEDLINE] 5681. Genes Dev. 1998 Oct 15;12(20):3145-48. WAT-free mice: diabetes without obesity. McKnight SL(1). Author information: (1)Department of Biochenistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9152 USA. smckni@biochem.swmed.edu PMID: 9867473 [PubMed - indexed for MEDLINE] 5682. Domest Anim Endocrinol. 1998 Sep;15(5):309-19. Immune and endocrine regulation of food intake in sick animals. Johnson RW(1). Author information: (1)Department of Animal Sciences, University of Illinois, Urbana 61801, USA. To understand why sick animals do not eat, investigators have studied how the immune system interacts with the central nervous system (CNS), where motivation to eat is ultimately controlled. The focus has been on the cytokines secreted by activated mononuclear myeloid cells, which include interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Either central or peripheral injection of recombinant IL-1 beta, IL-6, and TNF-alpha reduce food-motivated behavior and food intake in rodents. Moreover, these cytokines and their receptors are present in the endocrine system and brain, and antagonism of this system (i.e., the cytokine network) has been shown to block or abrogate anorexia induced by inflammatory stimuli. Recent studies indicate that the same cytokines act on adipocytes and induce secretion of leptin, a protein whose activity has been neuroanatomically mapped to brain areas involved in regulating food intake and energy expenditure. Therefore, many findings converge to suggest that the reduction of food intake in sick animals is mediated by inflammatory cytokines, which convey a message from the immune system to the endocrine system and CNS. The nature of this interaction is the focus of this short review. PMID: 9785035 [PubMed - indexed for MEDLINE] 5683. Clin Physiol. 1998 Sep;18(5):399-419. Leptin: physiology and pathophysiology. Frühbeck G(1), Jebb SA, Prentice AM. Author information: (1)MRC Dunn Clinical Nutrition Centre, Cambridge, UK. The identification and sequencing of the ob gene and its product, leptin, in late 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. During this time, a considerable body of knowledge regarding leptin's actions has been accumulated and the field continues to expand rapidly. Currently there is particular interest in the interaction of leptin with other peripheral and neural mechanisms to regulate body weight, reproduction and immunological response. In this review, we attempt to place the current state of knowledge about leptin in the broader perspective of physiology, including its structural characteristics, receptors, binding proteins, signalling pathways, regulation of adipose tissue expression and production, secretion patterns, clearance mechanisms and functional effects. In addition, leptin's involvement in the pathophysiology of obesity, anorexia nervosa, diabetes mellitus, polycystic ovary syndrome, acquired immunodeficiency syndrome, cancer, nephropathy, thyroid disease, Cushing's syndrome and growth hormone deficiency will be reviewed. PMID: 9784936 [PubMed - indexed for MEDLINE] 5684. Clin Exp Pharmacol Physiol. 1998 Oct;25(10):776-82. Role of hepatic fatty acid:coenzyme A ligases in the metabolism of xenobiotic carboxylic acids. Knights KM(1). Author information: (1)Department of Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Flinders University of South Australia, Australia. kathie.knights@flinders.edu.au 1. Formation of acyl-coenzymes (Co)A occurs as an obligatory step in the metabolism of a variety of endogenous substrates, including fatty acids. The reaction is catalysed by ATP-dependent acid:CoA ligases (EC 6.2.1.1-2.1.3; AMP forming), classified on the basis of their ability to conjugate saturated fatty acids of differing chain lengths, short (C2-C4), medium (C4-C12) and long (C10-C22). The enzymes are located in various cell compartments (cytosol, smooth endoplasmic reticulum, mitochondria and peroxisomes) and exhibit wide tissue distribution, with highest activity associated with liver and adipose tissue. 2. Formation of acyl-CoA is not unique to endogenous substrates, but also occurs as an obligatory step in the metabolism of some xenobiotic carboxylic acids. The mitochondrial medium-chain CoA ligase is principally associated with metabolism via amino acid conjugation and activates substrates such as benzoic and salicylic acids. Although amino acid conjugation was previously considered an a priori route of metabolism for xenobiotic-CoA, it is now recognized that these highly reactive and potentially toxic intermediates function as alternative substrates in pathways of intermediary metabolism, particularly those associated with lipid biosyntheses. 3. In addition to a role in fatty acid metabolism, the hepatic microsomal and peroxisomal long-chain-CoA-ligases have been implicated in the formation of the acyl-CoA thioesters of a variety of hypolipidaemic and peroxisome proliferating agents (e.g. clofibric acid) and of the R(-)-enantiomers of the commonly used 2-arylpropionic acid non-steroidal anti-inflammatory drugs (e.g. ibuprofen). In vitro kinetic studies using rat hepatic microsomes and peroxisomes have alluded to the possibility of xenobiotic-CoA ligase multiplicity. Although cDNA encoding a long-chain ligase have been isolated from rat and human liver, there is currently no molecular evidence of multiple isoforms. The gene has been localized to chromosome 4 and homology searches have revealed a significant similarity with enzymes of the luciferase family. 4. Increasing recognition that formation of a CoA conjugate increases chemical reactivity of xenobiotic carboxylic acids has led to an awareness that the relative activity, substrate specificity and intracellular location of the xenobiotic-CoA ligases may explain differences in toxicity. 5. Continued characterization of the human xenobiotic-CoA ligases in terms of substrate/inhibitor profiles and regulation, will allow a greater understanding of the role of these enzymes in the metabolism of carboxylic acids. PMID: 9784915 [PubMed - indexed for MEDLINE] 5685. Adv Exp Med Biol. 1998;441:219-28. Hormone-sensitive lipase (HSL) expression and regulation in skeletal muscle. Langfort J(1), Ploug T, Ihlemann J, Enevoldsen LH, Stallknecht B, Saldo M, Kjaer M, Holm C, Galbo H. Author information: (1)Copenhagen Muscle Research Centre, National University Hospital, Denmark. Because the enzymatic regulation of muscle triglyceride metabolism is poorly understood we explored the character and activation of neutral lipase in muscle. Western blotting of isolated rat muscle fibers demonstrated expression of hormone-sensitive lipase (HSL). In incubated soleus muscle epinephrine increased neutral lipase activity by beta-adrenergic mechanisms involving cyclic AMP-dependent protein kinase (PKA). The increase was paralleled by an increase in glycogen phosphorylase activity and could be abolished by antiserum against HSL. Electrical stimulation caused a transient increase in activity of both neutral lipase and glycogen phosphorylase. The increase in lipase activity during contractions was not influenced by sympathectomy or propranolol. Training diminished the epinephrine induced lipase activation in muscle but enhanced the activation as well as the overall concentration of lipase in adipose tissue. In agreement with the in vitro findings, in adrenalectomized patients an increase in muscle neutral lipase activity was found at the end of prolonged exercise only if epinephrine was infused. In accordance with feedforward regulation of substrate mobilization in exercise, our studies have shown that HSL is present in skeletal muscle cells and is stimulated in parallel with glycogen phosphorylase by both epinephrine and contractions. HSL adapts differently to training in muscle compared with adipose tissue. PMID: 9781328 [PubMed - indexed for MEDLINE] 5686. Adv Exp Med Biol. 1998;441:171-9. Regulation of fatty acid delivery in vivo. Frayn KN(1). Author information: (1)Oxford Lipid Metabolism Group, Nuffield Department of Clinical Medicine, University of Oxford, Radcliffe Infirmary, United Kingdom. keith.frayn@oxiip.ox.ac.uk Adipose tissue triacylglycerol (TG) constitutes by far the largest energy store in the body. In order for this TG to be used as a substrate for oxidative metabolism, it has to be exported from adipose tissue and transported to the tissues where it will be used. Following hydrolysis of stored TG, non-esterified fatty acids (NEFA) leave the adipocyte and enter the plasma. Unlike tissues such as skeletal muscle which extract plasma NEFA, in adipose tissue the flow of fatty acids across the cell membrane is bi-directional, outward in times of net fat mobilization such as fasting and exercise, and inward during the postprandial period. Factors regulating NEFA delivery in vivo include hormonal and nervous stimulation of lipolysis, and a variety of factors, local and systemic, which oppose this by suppressing lipolysis. Adipose tissue blood flow (ATBF) is also important. ATBF is increased in states of fat mobilization and fat deposition, although there is evidence that during strenuous exercise the increase in ATBF is not sufficient for export of all the NEFA made available from lipolysis. There are well-documented regional variations in lipolysis. The intra-abdominal depots appear to have the highest rates of TG turnover, the subcutaneous abdominal an intermediate rate, and the gluteal-femoral depots to have relatively sluggish turnover. However, much of the evidence for this derives from studies of isolated adipocytes, and confirmation in vivo is much needed. There are links between abdominal fat deposition and risk of cardiovascular disease which may be mediated through increased fatty acid delivery from abdominal fat depots. The ability of exercise specifically to decrease intra-abdominal fat stores may be yet another health benefit of regular exercise. PMID: 9781324 [PubMed - indexed for MEDLINE] 5687. Adv Exp Med Biol. 1998;441:157-70. Mechanisms regulating adipocyte lipolysis. Carey GB(1). Author information: (1)Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824, USA. Mechanisms regulating adipocyte lipolysis are reviewed in three stages. The first stage examines plasma membrane hormone receptors and G-proteins. The primary regulators of adipose tissue lipolysis, the catecholamines, bind to the alpha 2, beta 1, beta 2, and beta 3 adrenergic receptors. The alpha 2 receptor couples with Gi-proteins to inhibit cyclic AMP formation and lipolysis, while the beta receptors couple with Gs-proteins to stimulate cyclic AMP formation and lipolysis. The beta 1 receptor may mediate low level catecholamine stimulation, while the beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal. The second stage examines the regulation of cyclic AMP, the intracellular messenger that activates protein kinase A. Adenylyl cyclase synthesizes cyclic AMP from ATP and is regulated by the G-proteins. Phosphodiesterase 3B hydrolyzes cyclic AMP to AMP and is activated and phosphorylated by both insulin and the catecholamines norepinephrine and epinephrine. The third stage focuses on the rate-limiting enzyme of lipolysis, hormone-sensitive lipase (HSL). This 82 to 88 kDa protein is regulated by reversible phosphorylation. Protein kinase A activates and phosphorylates the enzyme at 2 sites, and 3 phosphatases have been implicated in HSL dephosphorylation. The translocation of HSL from the cytosol to the lipid droplet in response to lipolytic stimulation may be facilitated by a family of lipid-associated droplets called perilipins that are heavily phosphorylated by protein kinase A and dephosphorylated by insulin. As the mechanisms regulating adipocyte lipolysis continue to be uncovered, we look forward to the challenges of integrating these findings with research at the in situ and in vivo levels. PMID: 9781323 [PubMed - indexed for MEDLINE] 5688. Adv Exp Med Biol. 1998;441:147-56. Fat metabolism in exercise. Wolfe RR(1). Author information: (1)University of Texas Medical Branch Galveston, Shriners Burns Institute Metabolism Unit 77550, USA. Fatty acids are the most abundant source of endogenous energy substrate. They can be mobilized from peripheral adipose tissue and transported via the blood to active muscle. During higher intensity exercise, triglyceride within the muscle can also be hydrolyzed to release fatty acids for subsequent direct oxidation. Control of fatty acid oxidation in exercise can potentially occur via changes in availability, or via changes in the ability of the muscle to oxidize fatty acids. We have performed a series of experiments to distinguish the relative importance of these potential sites of control. The process of lipolysis normally provides free fatty acids (FFA) at a rate in excess of that required to supply resting energy requirements. At the start of low intensity exercise, lipolysis increases further, thereby providing sufficient FFA to provide energy substrates in excess of requirements. However, lipolysis does not increase further as exercise intensity increases, and fatty acid oxidation becomes approximately equal to the total amount of fatty acids available at 65% of VO2 max. When plasma FFA concentration is increased by lipid infusion during exercise at 85% VO2 max, fat oxidation is significantly increased. Taken together, these observations indicate that fatty acid availability can be a determinant of the rate of their oxidation during exercise. However, even when lipid is infused well in excess of requirements during high-intensity exercise, less than half the energy is derived from fat. This is because the muscle itself is a major site of control of the rate of fat oxidation during exercise. We have demonstrated that the mechanism of control of fatty acid oxidation in the muscle is the rate of entry into the mitochondria. We hypothesize that the rate of glycolysis is the predominant regulator of the rate of carbohydrate metabolism in muscle, and that a rapid rate of carbohydrate oxidation caused by mobilization of muscle glycogen during high intensity exercise inhibits fatty acid oxidation by limiting transport into the mitochondria. During low intensity exercise, glycogen breakdown and thus glycolysis is not markedly stimulated, so the increased availability of fatty acids allows their oxidation to serve as the predominant energy source. At higher intensity exercise, stimulation of glycogen breakdown and glycolysis cause increased pyruvate entry into the TCA cycle for oxidation, and as a consequence the inhibition of fatty acid oxidation by limiting their transport into the mitochondria. PMID: 9781322 [PubMed - indexed for MEDLINE] 5689. Adv Exp Med Biol. 1998;441:47-61. Snareing GLUT4 at the plasma membrane in muscle and fat. Hashiramoto M(1), James DE. Author information: (1)Centre for Molecular and Cellular Biology, University of Queensland, St. Lucia, Australia. Explosive advances in the understanding of vesicle trafficking between intracellular compartments have occurred in recent years. These investigations inspired an attractive model for intracellular membrane transport, referred as the SNARE hypothesis. These advances have been profitably applied to one system in muscle and fat; the regulation of intracellular trafficking of the insulin-regulatable facilitative glucose transporter (GLUT4). Investigations in insulin-sensitive cell types revealed a remarkable conservation in the mechanism of vesicular transport between synaptic vesicles in the presynaptic nerve terminal and GLUT4-containing vesicles in muscle and fat. On the other hand, unique players in insulin-regulatable GLUT4 movement have also been clarified during this process. Thus, unveiling the molecular mechanisms regulating insulin-stimulated GLUT4 trafficking will significantly contribute to our understanding of whole body glucose homeostasis as well as the cell biology of protein trafficking, membrane dynamics, and organelle biogenesis. PMID: 9781313 [PubMed - indexed for MEDLINE] 5690. Postepy Hig Med Dosw. 1998;52(4):347-65. [Lipoprotein lipase (LPL) in the pathogenesis of atherosclerosis]. [Article in Polish] Skoczyńska A(1). Author information: (1)Klinika Chorób Wewnetrznych i Zawodowych, Akademii Medycznej we Wrocławiu. The role of lipoprotein lipase (LPL) in the development of atheromatosis is subject of the increased interest for about 20 years, since then Zilversmit observed that LPL activity is found in greater amounts in atherosclerotic than normal arteries. The general action of this enzyme is hydrolysis of triglycerides in triglyceride rich lipoproteins and thus regulation of metabolism of circulating as well antiatherogenic as proatherogenic lipoproteins. The effect of LPL on the biology of arterial wall seems to be atherogenic. The mechanisms of this effect of LPL is 1) augmentation of the adhesion and aggregation of LDL; 2) influence on the oxygen modification of LDL and increased uptake of oxy-LDL by macrophages; 3) dysfunction of endothelial barrier and retention of atherogenic lipoproteins in the arterial wall and 4) the activity of LPL macrophage origin. Possible atherogenic actions of LPL based on in vitro experimental studies are reviewed. PMID: 9780756 [PubMed - indexed for MEDLINE] 5691. Rev Med Interne. 1998 Feb;19(2):108-18. [Hexose transporters in humans: their role in insulin sensitivity of peripheral tissues]. [Article in French] Bastard JP(1), Jardel C, Guerre-Millo M, Hainque B. Author information: (1)Service de biochimie B, hôpital de la Pitié-Salpêtrière, Paris, France. OBJECTIVES AND JUSTIFICATION: To describe facilitated diffusion glucose transporters (GLUT) in humans, and particularly the regulation of GLUT4 expression since it is predominantly responsible for insulin-mediated glucose transport in muscle and adipose tissue, and plays a crucial role in whole-body glucose homeostasis.MAIN POINTS: Numerous studies have shown abnormal expression of GLUT4 in insulin responsive tissues in diabetes mellitus and other insulin resistant states. The recent development of transgenic mice that overexpress GLUT4 in muscle, adipose tissue, or both has also emphasized the importance of GLUT4 in glucose homeostasis. PERSPECTIVES AND PROJECTS: The studies performed in transgenic mice suggest that strategies to increase GLUT4 transporters in insulin responsive tissues may lead to new therapeutic possibilities to improve insulin sensitivity in insulin resistant states such as non-insulin-dependent diabetes mellitus. CONCLUSIONS: Glucose transport is a crucial process in mammals, which needs specific transmembrane hexose transporters. Each transporter is important in the regulation of glucose homeostasis. Advances in the knowledge of both the action and the regulation of the glucose transport system may provide new insights for the development of therapeutic interventions in diseases such as obesity or diabetes mellitus. PMID: 9775125 [PubMed - indexed for MEDLINE] 5692. Journ Annu Diabetol Hotel Dieu. 1998:215-21. [Obesity in NIDDM: relevance of the control of fat mass or its its distribution?]. [Article in French] Després JP(1). Author information: (1)Centre de recherche sur les maladies lipidiques, Sainte-Foy, Québec. PMID: 9773622 [PubMed - indexed for MEDLINE] 5693. Rev Neurol (Paris). 1998 Jun;154(5):379-88. [Functional imaging of human muscle]. [Article in French] Leroy-Willig A(1), Carlier P, Morvan D, Duboc D, Fardeau M. Author information: (1)Institut de Myologie, Groupe Hospitalier Pitié-Salpétrière, Paris. aleroy@myologie.infobiogen.fr Medical imaging is now giving access not only to anatomy but also to functions of organs in the human body. Functional imaging may yield a direct appreciation of the function of a given organ, as is the case when measuring ejection fraction of heart with SPECT. Alternately the approach is indirect. This is the case of cerebral functional imaging, either with PET or NMR, where the perfusion increase induced by neuronal activity is detected. Recent developments of NMR, combining imaging and spectroscopy, allow now to detect modification of physiological parameters induced by muscular activity. Indirect detection of muscle activity is very rich in information alternately requiring invasive techniques. Water shifts resulting from intense exercise are detected either from muscle volume increase or water signal modifications, using simple NMR sequences. Then it is easy to identify which muscle is involved in a given protocol. These water shifts, studied in various muscles and several types of exercise protocols, reflect the perfusion increase induced by exercise, and the contribution of metabolic products such as lactate. In some patients with metabolic myopathies a decreased adaptation of perfusion has been detected. Perfusion measurements, previously performed by using venous occlusion plethysmography or radioactive tracers, now benefit from recently developed MR techniques. Oxygenation of muscle may be measured either by spectroscopy of myoglobin, allowing a time resolution of 1 second, or by spectroscopic imaging allowing a spatial resolution of 1-2 cm in a few minutes. Muscle temperature may be non invasively monitored by diffusion-weighted MR. Direct detection of muscle activity is useful only in those muscles that cannot be directly observed. Ultrafast MR imaging may be used to study vocal cords or oculomotor muscles. More interesting is the measurement of contractility, either in myocardium or skeletal muscle, allowed by MR with spin-tagging. Another contribution of MR to muscle studies is the possibility to quantify muscle cross section and muscle volume, in order to normalize strength or metabolism measurements. Sequences using T1 or T2 differences between muscular and adipose tissue allow to quantify the true muscular volume in patients with neuromuscular disorders. Protocols combining several of these parameters by interleaved NMR measurements of perfusion, phosphorylated metabolites, lactate, myoglobin, now open the way to many comprehensive non-invasive pathophysiological studies. PMID: 9773069 [PubMed - indexed for MEDLINE] 5694. Am J Clin Nutr. 1998 Oct;68(4):761-2. Do circulating leptin concentrations reflect body adiposity or energy flux? Levine AS, Billington CJ. Comment on Am J Clin Nutr. 1998 Oct;68(4):794-801. PMID: 9771850 [PubMed - indexed for MEDLINE] 5695. Pathology. 1998 Aug;30(3):229-36. Neuropeptides, the hypothalamus and obesity: insights into the central control of body weight. Thorburn AW(1), Proietto J. Author information: (1)Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria, Australia. Body weight tends to remain relatively stable for long periods over an adult's lifespan. Dieting can reduce weight by 5-10%, but in most individuals attempts to lose larger amounts of weight are counteracted by a reduction in energy expenditure and an increase in hunger. The fact that body weight appears to be actively defended in this manner suggests that it is homeostatically regulated at a certain "set-point". Such a mechanism is likely to be centrally controlled by the brain since the hypothalamus can sense the amount of adipose tissue stored in the body and can alter both energy intake and expenditure. Over the past four years a number of major advances have reinforced the critical role the brain may play in controlling body weight, and these have greatly enhanced our understanding of this area. Advances have included the identification of several genetic mutations that cause obesity in animal models, examination of the metabolic consequences of such mutations and the development of mice with genetically engineered altered neuropeptide levels. This review summarises what has been recently discovered about the regulation of body weight by the brain and how this may be disrupted in obesity. PMID: 9770185 [PubMed - indexed for MEDLINE] 5696. Recent Prog Horm Res. 1998;53:139-59; discussion 160-1. Cyclic AMP, PKA, and the physiological regulation of adiposity. McKnight GS(1), Cummings DE, Amieux PS, Sikorski MA, Brandon EP, Planas JV, Motamed K, Idzerda RL. Author information: (1)Department of Pharmacology, University of Washington, Seattle 98195-7750, USA. The major regulator of lipolysis in white adipocytes and brown adipocytes is cAMP and the actions of cAMP are mediated by protein kinase A (PKA). Multiple subunits of PKA, including RII beta, R1 alpha, C alpha, and C beta 1, are expressed in fat cells but the major holoenzyme assembled under normal conditions contains RII beta and C alpha. Targeted disruption of the RII beta gene in mice revealed that both white and brown adipocytes are capable of compensating by increasing the level of RI alpha. Nevertheless, the mice display a lean phenotype, have an elevated metabolic rate due to activation and induction of uncoupling protein in brown fat, and are resistant to diet-induced obesity and insulin resistance. Although the metabolic disturbances in white and brown fat tissue may explain most of the phenotypic changes, the loss of neuronal expression of RII beta may also contribute to the alterations in energy balance. Specific neuronal defects have been characterized that prevent the normal changes in gene expression seen with drugs that act through the dopaminergic pathway. The RII beta mutant mouse provides an interesting model of obesity resistance and demonstrates that chronic changes in the PKA signaling system can lead to stable alterations in energy storage and utilization. PMID: 9769707 [PubMed - indexed for MEDLINE] 5697. Prog Lipid Res. 1998 May;37(1):1-32. Transport and transformations of yolk lipids during development of the avian embryo. Speake BK(1), Murray AM, Noble RC. Author information: (1)Department of Biochemistry and Nutrition, Scottish Agricultural College, Ayr, Scotland. PMID: 9764310 [PubMed - indexed for MEDLINE] 5698. Pharm World Sci. 1998 Aug;20(4):149-60. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. Touw DJ(1). Author information: (1)University Hospital Vrije Universiteit, Department of Pharmacy, Amsterdam, The Netherlands. The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight. PMID: 9762727 [PubMed - indexed for MEDLINE] 5699. Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Heal DJ(1), Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Author information: (1)Knoll Pharmaceuticals Research & Development, Nottingham, UK. Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release. PMID: 9758240 [PubMed - indexed for MEDLINE] 5700. Dev Psychobiol. 1998 Sep;33(2):107-23. Thermoregulatory competence and behavioral expression in the young of altricial species--revisited. Blumberg MS(1), Sokoloff G. Author information: (1)Department of Psychology, University of Iowa, Iowa City 52242, USA. The behavioral and physiological thermoregulatory capabilities of newborn and infant mammals have been studied for over half a century. Psychobiologists have noted that the infants of altricial species (e.g., rats) have physical and physiological limitations such that heat loss overwhelms heat production, thus forcing a reliance on behavioral thermoregulation for the maintenance of body temperature. Recent evidence, however, suggests that a modification of this view is justified. Specifically, throughout a range of moderately cold air temperatures, nonshivering thermogenesis by brown adipose tissue contributes significantly to the infant rat's behavioral and physiological adaptations to cold challenge. Given the prominent use of altricial species for the study of infant behavior, increased understanding of the infant's physiological responses to cold and the effect of thermal factors on behavior is warranted. PMID: 9742406 [PubMed - indexed for MEDLINE] 5701. Przegl Lek. 1998;55(5):266-70. [The role of estrogens in hormonal regulation of lipid metabolism in women]. [Article in Polish] Szafran H(1), Smielak-Korombel W. Author information: (1)Oddziału Kardiologii Wojewódzkiego, Szpitala Specjalistycznego, im. G. Narutowicza w Krakowie. In the view of lipid metabolism, adipose tissue and liver are the most important tissues for 17-beta-estradiol, the main estrogen in women's body. The lack of estrogens in women after menopause may cause coronary heart disease. It is considered, that 25 to 50% of positive effect of estrogens which are given to postmenopausal women is connected with their action on lipid metabolism. Blood plasma parameters which characterize lipid metabolism return to their physiological values during estrogens therapy. Estrogens are transferred to adipose tissue cells and liver cells by endocrine and paracrine way. They are also produced in these cells from androgens. In adipocytes 17-beta-estradiol can be stored as its esters with long-chain fatty acids. It was proved that estrogens receptors are present in adipocytes and hepatocytes but their density is much lower than in gonads. On the cellular level estrogens regulate mRNA production for particular proteins among which there are proteins involved in lipid metabolism. In adipose tissue 17-beta-estradiol has a direct effect on lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL). In the case of the first enzyme its synthesis is faster, while the synthesis of the latter is slower. On the other hand, indirect action of estrogens on adipose tissue is connected with the stimulation of the releasing of other hormones which increase HSL activity. To this group of hormones there belong catecholamines, growth hormone (GH) and glucagon. In liver 17-beta-estradiol regulates the rate of synthesis of structural apolipoproteins for VLDL and HDL. 17-beta-estradiol reduces the rate of apoB-100 synthesis, while stimulates apoA-I and apoA-II synthesis. HDL fraction containing apoA-I and apoA-II is necessary for chylomicrons and VLDL degradation as well as direct and indirect cholesterol transport to liver. Moreover, in hepatocytes estrogens stimulate the synthesis of apoC-III, while they decrease the synthesis of hepatic lipase (HL). In conclusion, 17-beta-estradiol by regulating lipid metabolism in adipocytes and hepatocytes modulates the concentration of lipid substances in plasma. The lack of 17-beta-estradiol leads likely to various lipid metabolism disorders in women after menopause. Estrogens therapy in these postmenopausal women may result in the improvement of lipid metabolism. PMID: 9741194 [PubMed - indexed for MEDLINE] 5702. Sports Med. 1998 Jul;26(1):29-42. Lipid metabolism during exercise. Ranallo RF(1), Rhodes EC. Author information: (1)J.M. Buchanan Exercise Science Laboratory, School of Human Kinetics, University of British Columbia, Vancouver, Canada. Fat is an extremely important substrate for muscle contraction, both at rest and during exercise. Triglycerides (TGs), stored in adipose tissue and within muscle fibres, are considered to be the main source of the free fatty acids (FFAs) oxidised during exercise. It is still unclear, however, how the use of these substrates is regulated during exercise. The regulation seems to be multifactorial and includes: (i) dietary and nutritional status; (ii) hormonal milieu; (iii) exercise mode, intensity and duration; and (iv) training status. On the other hand, the mechanism for FFA transport from its storage as triglycerides in adipose tissue and muscle to its place of utilisation in heart, skeletal muscle, kidney and liver is more clearly understood. It has been determined that the plasma FFA turnover rate is sufficiently rapid to account for most of the fat metabolised during low intensity exercise (25 to 40% VO2max). However, an exercise intensity of 65% VO2max results in a slight decrease in the amount of plasma FFA uptake by muscle tissue. Other studies have found that during prolonged exercise, muscle TGs become the predominant source of energy obtained from fat. Furthermore, it is widely documented that endurance activities increase the energy utilisation from fat while sparing carbohydrate sources. For example, during exercise on a cycle ergometer, nonplasma FFAs and plasma FFAs contribute 40%, and carbohydrates 60%, of the total calculated amount of energy expenditure before exercise and vice versa after exercise (60% nonplasma and plasma FFAs and 40% carbohydrates). Although it was many years before it was fully demonstrated, fat is now known to be transported in the blood as FFA bound to the protein carrier albumin. The mobilisation of FFA is primarily a function of sympathetic nervous activity directed towards the adipocytes, or the 'fat pad'. This nervous activity can be direct or may be an effect of circulating catecholamines such as adrenaline (epinephrine). This article summarises the role of fat metabolism during exercise. PMID: 9739539 [PubMed - indexed for MEDLINE] 5703. Curr Opin Lipidol. 1998 Aug;9(4):295-9. Leptin, the hypothalamus and the regulation of adiposity. Harrold JA(1), Cai X, Williams G. Author information: (1)Department of Medicine, University of Liverpool, UK. harrold@liverpool.ac.uk The hypothalamus contains a wealth of peptide and non-peptide neurotransmitters, many of which have been shown experimentally to influence feeding behaviour and energy metabolism. Regulatory activities as complex as these are likely to be controlled by numerous neurotransmitters interacting at a variety of levels. The hierarchy of command of these neuronal circuits is not known, but it is possible that some converge on to a final common pathway, governed by the actions of a single neurotransmitter, through which all other influences ultimately operate. This review will discuss several of the more recently identified neurotransmitters and consider their validity as candidates in the regulation of energy homeostasis. PMID: 9739483 [PubMed - indexed for MEDLINE] 5704. Int J Sport Nutr. 1998 Sep;8(3):285-307. Practical body composition assessment for children, adults, and older adults. Heyward VH(1). Author information: (1)Exercise Science Program, Johnson Center, University of New Mexico, Albuquerque 87131, USA. This paper provides an overview of practical methods for assessing body composition of children, adults, and older adults. Three methods commonly used in field and clinical settings are skinfolds, bioelectrical impedance analysis, and anthropometry. For each method, standardized testing procedures, sources of measurement error, recommendations for technicians, and selected prediction equations for each age category are presented. The skinfold method is appropriate for estimating body fat of children (6-17 years) and body density of adults (18-60 years) from diverse ethnic groups. Likewise, bioimpedance is well suited for estimating the fat-free mass of children (10-19 years) as well as American Indian, black, Hispanic, and white adults. Anthropometric prediction equations that use a combination of circumferences and bony diameters are recommended for older adults (up to 79 years of age), as well as obese men and women. PMID: 9738136 [PubMed - indexed for MEDLINE] 5705. Int J Sport Nutr. 1998 Sep;8(3):241-9. Pyruvate: beyond the marketing hype. Sukala WR(1). Author information: (1)Department of Exercise and Nutritional Sciences, San Diego State University, CA 92182, USA. PMID: 9738134 [PubMed - indexed for MEDLINE] 5706. Reprod Fertil Dev. 1998;10(1):65-72. Disturbance of the reproductive axis induced by negative energy balance. Judd SJ(1). Author information: (1)Department of Medicine, Flinders Medical Centre, Bedford Park, SA, Australia. stephen.judd@flinders.edu.au Animal reproduction is impaired when intake of energy is so restricted that activities essential to life are threatened; this is seen as a homeostatic adjustment that restricts wasteful energy expenditure. Fasting or exercising to a degree requiring considerable energy expenditure has major effects on the hypothalamus, including activation of corticotrophin-releasing factor (CRF) neurons, suppression of thyrotrophin-releasing hormone synthesis, and increased growth hormone secretion; these are associated with increased concentrations of hypothalamic neuropeptide Y mRNA and are corrected by administration of leptin, an adipose-tissue protein with a tertiary structure similar to the cytokine interleukin-2. This response to fasting results from a disordered pattern of activity in the gonadotrophin-releasing hormone (GnRH) pacemaker, characterized by reduced luteinizing hormone pulsatility, particularly during daytime. Animal studies have suggested that the response depends on an intact afferent vagal system from the stomach and the presence of oestrogen. Noradrenergic neurons forming the A2 group increase the activity of CRF neurons that, in turn, inhibit GnRH pulsatility. Reproductive impairment due to fasting is reversed by leptin, and abnormalities of leptin are described in individuals who fast or who develop exercise-induced amenorrhoea. This paper discusses these changes induced by negative energy balance and speculates on the involvement of leptin as a contributor to these abnormalities. PMID: 9727594 [PubMed - indexed for MEDLINE] 5707. Reprod Fertil Dev. 1998;10(1):55-63. Obesity and reproductive disorders: a review. Norman RJ(1), Clark AM. Author information: (1)Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville, SA, Australia. rnorman@medicine.adelaide.edu.au Obesity has significant consequences for the reproductive system, depending upon the amount and distribution of body fat. Epidemiological evidence clearly shows that being overweight contributes to menstrual disorders, infertility, miscarriage, poor pregnancy outcome, impaired fetal well-being and diabetes mellitus. Central adiposity is particularly important in clinical sequelae associated with an increased body mass index. The advent of assisted reproduction highlights the problems of being overweight, and the use of gonadotrophins in ovulation induction and in vitro fertilization is more difficult when the subject is overweight. Weight loss has marked effects on improving the menstrual cycle and promoting spontaneous ovulation and fertility. Results indicate that fertility is improved through exercise and sensible eating patterns when conducted in a group environment. The mechanisms for this are unclear but may be associated with changes in sensitivity to insulin. PMID: 9727593 [PubMed - indexed for MEDLINE] 5708. Reprod Fertil Dev. 1998;10(1):49-53. Obesity: genes, glands or gluttony? Chisholm DJ(1), Samaras K, Markovic T, Carey D, Lapsys N, Campbell LV. Author information: (1)The Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia. Distribution as well as amount of fat has health implications; central abdominal fat seems to be the major contributor to insulin resistance and risk of diabetes, hypertension and cardiovascular disease. Physical activity and diet affect overall adiposity; moreover, exercise specifically reduces visceral fat. The sexes differ in fat distribution; in particular, pre-menopausal women, despite greater overall adiposity, have much less visceral fat than men. There is a strong genetic determination of overall obesity and central abdominal adiposity. Genes regulating obesity (e.g. Ob) could modulate appetite, satiety, metabolic rate or physical activity. Moderate obesity probably results from interaction between genetic predisposition and an environment of abundant calories and reduced physical activity. Single gene mutations are being identified in a few morbidly obese people; however, the common genetic predisposition for obesity may relate to more subtle variations in regulatory controls. Diet and exercise are effective for some, but the response is often disappointing. Definition of pathways controlling appetite, metabolic rate and lipid metabolism may generate improved pharmacological compounds. Education and availability of lower-energy foods may help, but more radical approaches may be needed, such as environmental restructuring to increase physical activity. The problem is great, but failure will mean intolerably increased health costs. PMID: 9727592 [PubMed - indexed for MEDLINE] 5709. Diabetologia. 1998 Aug;41(8):863-81. Obesity, diabetes and the central nervous system. Porte D Jr(1), Seeley RJ, Woods SC, Baskin DG, Figlewicz DP, Schwartz MW. Author information: (1)Department of Medicine, University of Washington, VA Puget Sound Health Care System, Seattle 98108, USA. Comment in Diabetologia. 2000 Jan;43(1):134. PMID: 9726588 [PubMed - indexed for MEDLINE] 5710. Cas Lek Cesk. 1998 Jun 15;137(12):355-8. [Leptin--the key to obesity?]. [Article in Czech] Drbalová K(1). Author information: (1)Endokrinologický ústav, Praha. Obesity is at present one of the most important health risk factors in developed countries. Several studies show significant involvement of genetic factors. A gene called ob is active in the adipose tissue and its product leptin is secreted from adipocytes. Fully functional leptin receptors (encoded by the ob/R gene, also db) have been found in highest numbers in the hypothalamus and therefore it was suggested that it is the leptin plasma level which in forms the brain about total body fat mass and calories intake. Using this pathway it can directly influence a balance between food intake and energy expenditure. The phenotype of ob/ob mutant mice is characterized by severe obesity, NIDDM (non insulin dependent diabetes mellitus), diminished fertility and hypothermia. Db/db mutant mice show a similar phenotype, here the defect lies in the block of leptin receptor downstream signalling. After leptin administration, it was possible to correct the defect only in the ob/ob, but not db/db mice. There is a positive correlation between body mass index and leptin plasma level in humans and no obese patients have been found defective in leptin production or producing or producing ineffective leptin. Human obesity might be connected to a defect of leptin receptor or to its altered signal transduction. Leptin administration is therefore not important in human obesity treatment. PMID: 9721470 [PubMed - indexed for MEDLINE] 5711. Int J Sports Med. 1998 Jul;19(5):293-302. Fat metabolism during exercise: a review--part II: regulation of metabolism and the effects of training. Jeukendrup AE(1), Saris WH, Wagenmakers AJ. Author information: (1)Department of Human Biology, Maastricht University, The Netherlands. This part discusses the complex regulation of fat metabolism. Catecholamines as a stimulator of lipolysis and insulin as a suppressor play very important roles in the regulation of fat oxidation. The interaction of carbohydrate and fat metabolism has been extensively studied in the past decennia but the understanding of this multifactorial regulation is complex and still incompletely understood. In 1963, Randle et al. proposed the glucose-fatty acid cycle as a possible mechanism, and more recently, regulation through malonyl-CoA has been put forward as a possible way to explain shifts in carbohydrate and fat metabolism at rest and during exercise. The exercise intensity affects fat oxidation mainly by increasing lipolysis and fatty acid availability during exercise of low to moderate intensity. At high exercise intensities, both a reduction in fatty acid availability (decreased RaFa) and intramuscular factors reduce fat oxidation. These intramuscular factors are largely unknown. The increased mitochondrial density after training and increased oxidative enzymes may partly explain the increased fatty acid oxidation during exercise as observed after training. However, also supply of fatty acids to the mitochondria may be important. The available evidence suggests that the additional fatty acids oxidized after training are primarily derived from intramuscular triacylglycerols and not from adipose tissue derived fatty acids or circulating triacylglycerols. PMID: 9721051 [PubMed - indexed for MEDLINE] 5712. Chem Phys Lipids. 1998 Jun;93(1-2):149-55. Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase. Scow RO(1), Schultz CJ, Park JW, Blanchette-Mackie EJ. Author information: (1)Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA. rs1j@nih.gov Lipoprotein lipase (LPL) and hepatic lipase (HL), which act on plasma lipoproteins, belong to the same gene family as pancreatic lipase. LPL is synthesized in heart, muscle and adipose tissue, while HL is synthesized primarily in liver. LPL is also synthesized in liver of newborn rodents. The active form of LPL is a dimer, whereas that of HL has not been established. Combined lipase deficiency (CLD) is an autosomal recessive mutation (cld) in mice which impairs post-translational processing of LPL and HL. Cld/cld mice have very low LPL and HL activities (< 5% of normal), yet normal pancreatic lipase activity. They develop massive hypertriglyceridemia and die within 3 days after birth. The CLD mutation allows synthesis, glycosylation and dimerization of LPL, but blocks activation and secretion of the lipase. Thus, dimerization per se does not result in production of active LPL. Immunofluorescence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells. Translocation of Golgi components to ER by treatment with brefeldin A (BFA) enabled synthesis of active LPL in cultured cld/cld brown adipocytes. Thus, production of inactive LPL in cld/cld cells results from inability of the cells to transport LPL from ER. The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase. Immunofluorescence studies located HL mostly outside of cells in liver, liver cell cultures and incubated adrenal tissue of normal and cld/cld mice and mostly inside of cells in liver cell cultures and adrenal tissues treated with monensin (to block secretion of protein). These findings demonstrate synthesis and secretion of HL by both liver and adrenal cells of normal and cld/cld mice. Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals. However, it does not block synthesis or secretion of active pancreatic lipase. Our findings indicate that LPL, HL and pancreatic lipase, although closely related, are processed differently. PMID: 9720257 [PubMed - indexed for MEDLINE] 5713. Crit Rev Eukaryot Gene Expr. 1998;8(2):141-68. Nuclear hormone receptors and adipogenesis. Gimble JM(1), Robinson CE, Clarke SL, Hill MR. Author information: (1)Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA. Adipocytes provide a model cell system for exploring the complexities of nuclear hormone receptor transcriptional regulation. Adipocytes produce lipid and cholesterol metabolites which can serve as activating ligands for many of the classic and "orphan" nuclear hormone receptors. At the same time, nuclear hormone receptors directly control adipocyte commitment. The recently described nuclear hormone receptor coactivators and corepressors provide an additional level of complexity to this system. This review emphasizes available in vitro and in vivo models and discusses them in the context of current controversies and future experimental directions. PMID: 9714895 [PubMed - indexed for MEDLINE] 5714. Proc Soc Exp Biol Med. 1998 Sep;218(4):284-306. The dorsomedial hypothalamic nucleus revisited: 1998 update. Bernardis LL(1), Bellinger LL. Author information: (1)VA Western New York Healthcare System, State University of New York at Buffalo 14215, USA. This article reviews data that have accumulated since the early 1970s on the role of the dorsomedial hypothalamic nucleus (DMN) in neuroendocrine and autonomic homeostasis. Both the ventromedial hypothalamic nucleus (VMN) and the lateral hypothalamic area (LHA) project to the DMN, which in turn projects to the paraventricular nucleus of the hypothalamus (PVN), thus placing the DMN at an important nodal point of neuroendocrine/autonomic circuitries. The DMN is composed of cells and fibers containing neuropeptide Y (NPY), and the nutritional status (starvation-refeeding) is reflected in NPY levels of both VMN and DMN in Sprague-Dawley, Zucker (fa/fa), and corpulent rats (cp/cp JCR:LA). The DMN is involved in the final common pathway of corticotrophin-releasing hormone (CRH) secretion by the PVN, sympathetic nervous system outflow to the adrenal gland, and brown adipose tissue (BAT) thermogenesis. The DMN is also part of a "fear circuitry" regulating cardiovascular responses to stress such as myocardial blood flow and the tachycardia associated with the defense reaction. This appears to be mediated by a gamma amino butyric acid (GABA) mechanism. Although exhibiting reduced ponderal and linear growth and hypophagia and hypodipsia, the rat with DMN lesions (DMNL rat) has normal body composition, anabolic hormone levels, and intermediary metabolism, and it responds normally to numerous endocrine, nutritional, intra- and extracellular thirst and body weight-regulatory challenges. The DMNL rat shows normal efficiency of food utilization, but shows an attenuated response to the feeding-stimulatory effect of insulin. The only other lesion-induced abnormalities are hyperprolactinemia and a disrupted circadian corticosterone rhythm. The hyperprolactinemia in DMNL rats appears to be related to an attenuation of dopamine (DA). Rats with DMNL are capable of mating and can bear offspring, but there is a dramatic effect on litter size and other litter parameters that only improves when one parent is a DMNL rat. Antiaging effects produced by DMNL are evident in the prevention of age-associated microalbuminuria and kidney lesions, as well as, in prevention of the age-related decline in circulating insulin-like growth factor I (IGF-I). Recent evidence suggests that DMN, together with the VMN and the arcuate nucleus (ARC) of the hypothalamus, may be part of the circuitry that is responsive to the feedback signal from adipose tissue by the hormone leptin. The above findings and others suggest that the DMN plays a diverse role in physiological regulatory processes. PMID: 9714072 [PubMed - indexed for MEDLINE] 5715. Vet Radiol Ultrasound. 1998 Jul-Aug;39(4):357-65. Hepatic abscesses in 13 dogs: a review of the ultrasonographic findings, clinical data and therapeutic options. Schwarz LA(1), Penninck DG, Leveille-Webster C. Author information: (1)Department of Surgery, Foster Hospital for Small Animals, Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA. Historical, physical examination, clinicopathologic, radiographic and ultrasonographic findings of 13 dogs with hepatic abscesses were reviewed. Liver abscessation was characterized by number, size, shape, echogenicity and location. Solitary lesions greater than 3 cm were more common than multiple ones. The abscesses were mainly poorly echogenic lesions, often with central cavitation. The shape of the lesion ranged from round to oval or irregular. Enhancement artifact, abdominal effusion, regional lymphadenopathy and hyperechoic perihepatic fat, were identified in several dogs. Ultrasound-guided aspiration was performed in 10 of 13 dogs, and confirmed abscessation with cytologic and microbiologic evaluation. Ultrasound-guided percutaneous drainage of abscesses was performed as an adjunct to medical management in four dogs. PMID: 9710142 [PubMed - indexed for MEDLINE] 5716. Orthop Clin North Am. 1998 Jul;29(3):445-51. Indications, technique, and results of shoulder arthroplasty in osteonecrosis. Hattrup SJ(1). Author information: (1)Department of Orthopedic Surgery, Mayo Clinic-Scottsdale, Arizona, USA. The most common causes of osteonecrosis of the humeral head are steroid use and trauma. Corticosteroids produce osteonecrosis by alterations in fat metabolism, and trauma, by injury to the anterolateral ascending artery. The need for replacement surgery is influenced by stage and extent of the disease, as well as a history of trauma. Results of replacements are superior in steroid-induced osteonecrosis compared to posttraumatic osteonecrosis. PMID: 9706291 [PubMed - indexed for MEDLINE] 5717. Annu Rev Nutr. 1998;18:207-32. Transgenic mice in the analysis of metabolic regulation. Bosch F(1), Pujol A, Valera A. Author information: (1)Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain. fatima.bosch@blues.uab.es In normal animals, the extracellular concentration of glucose is maintained within a very narrow range by the matching of glucose flux into and out of the extracellular space through the tightly coordinated secretion of insulin and glucagon. Functional alterations in beta-cells, liver, or skeletal muscle and adipose tissue may disrupt glucose homeostasis and lead to the development of non-insulin-dependent diabetes mellitus (type 2 diabetes). This review outlines the contribution of these organs and tissues to the control of glucose homeostasis. We discuss new insights obtained through studies of transgenic mice that overexpress or show decreased expression of putative key genes in the regulation of pancreatic beta-cell function, in the control of hepatic glucose uptake and output, and in the regulation of glucose uptake and utilization by skeletal muscle and adipose tissue. PMID: 9706224 [PubMed - indexed for MEDLINE] 5718. Curr Biol. 1998 Jul 16;8(15):R517-20. Adaptive thermogenesis: turning on the heat. Lowell BB(1). Author information: (1)Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. blowell@bidmc.harvard.edu Brown adipocytes play important roles in the regulation of fat storage and body temperature, by virtue of their ability to uncouple mitochondrial fuel oxidation and ATP synthesis. The discovery of a tissue-specific transcriptional coactivator provides new insights into the regulation of thermogenesis by brown adipocytes. PMID: 9705924 [PubMed - indexed for MEDLINE] 5719. Diabetes Care. 1998 Aug;21 Suppl 2:B85-90. Effect of maternal metabolism on fetal growth and body composition. Catalano PM(1), Thomas AJ, Huston LP, Fung CM. Author information: (1)Department of Reproductive Biology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio 44109, USA. pcatalano@metrohealth.org The objective of this work is to examine the various maternal metabolic and parental anthropometric and demographic factors that affect fetal growth and body composition. These data are a review of previously published data evaluating 1) demographic and anthropometric factors associated with fetal growth; 2) differences in male and female neonatal body composition; 3) anthropometric and maternal metabolic factors correlated with neonatal birth weight, fat-free mass, and fat mass using stepwise logistic regression analysis; and 4) the relationship between maternal weight gain and birth weight in women with normal glucose tolerance (control subjects) and gestational diabetes mellitus (GDM). We estimated body composition in 186 neonates using anthropometry. Fat-free mass, which comprised 86% of mean birth weight, accounted for 83% of the variance in birth weight, and fat mass, which comprised only 14% of birth weight, accounted for 46% of the variance in birth weight. Male neonates were, on average, 175 g heavier than females. There was significantly (P = 0.0001) greater fat-free mass in males than in females but no significant difference in fat mass. Using stepwise logistic regression, we accounted for 29% of the variance in birth weight, 30% in fat-free mass, and 17% in fat mass. Independent variables included maternal height, pregravid weight, weight gain during pregnancy, education, parity, paternal height and weight, neonatal sex, and gestational age. Including maternal glucose insulin sensitivity in 16 additional subjects, we explained 48% of the variance in birth weight, 53% in fat-free mass, and 46% in fat mass. There was a positive (P = 0.0007) correlation between weight gain and birth weight in control subjects, but a negative (P = 0.34) correlation in women with GDM. In control subjects, the correlation was strongest in women who were lean before conception and became progressively weaker as pregravid weight for height increased. In women with GDM, there were no significant correlations between maternal weight gain and birth weight, irrespective of pregravid weight for height. The assessment of fetal/neonatal body composition may improve our understanding of the effect of differential factors on fetal growth. Factors associated with accretion of fetal adipose tissue in late gestation are less well understood in comparison with birth weight and fat-free mass. Additional studies of maternal glucose and lipid metabolism are needed to better evaluate fetal growth. PMID: 9704233 [PubMed - indexed for MEDLINE] 5720. Eur J Endocrinol. 1998 Jul;139(1):1-9. The uncoupling proteins, a review. Boss O(1), Muzzin P, Giacobino JP. Author information: (1)Medical Biochemistry, Faculty of Medicine, University of Geneva, Switzerland. PMID: 9703368 [PubMed - indexed for MEDLINE] 5721. Nihon Rinsho. 1998 Jul;56(7):1871-5. [Beta 3 adrenergic receptor polymorphism and obesity]. [Article in Japanese] Yoshida T(1), Umekawa T. Author information: (1)First Department of Internal Medicine, Kyoto Prefectural University of Medicine. The beta 3-adrenoceptor plays a significant role in the control of lipolysis and thermogenesis in the brown adipose tissue of rodents and humans. In human beta 3-adrenoceptor, a Trp to Arg replacement has recently been discovered. This change which occurs at position 64, in the first coding exon, has been correlated with increased weight gain, difficulty in losing weight, insulin resistance syndrome, and worsened diabetic situation. Higher percentages of this mutation are observed in Pima Indians (over 30%) and Japanese (20%). The possible functional mechanism of Trp54Arg is reported using human HEK293 cell line stably expressing the wild type and the [Arg64] beta 3-adrenoceptor type. Beta 3-adrenoceptor agonists available for humans are been also developing. In this paper we describe these points up-to-date. PMID: 9702068 [PubMed - indexed for MEDLINE] 5722. Braz J Med Biol Res. 1998 Jun;31(6):715-22. Pivotal role of leptin in insulin effects. Ceddia RB(1), William WN Jr, Lima FB, Carpinelli AR, Curi R. Author information: (1)Departamento de Educação Física, Centro de Estudos Gerais, Universidade Federal Fluminense, Niterói, Brasil. The OB protein, also known as leptin, is secreted by adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks regulating ingestive behavior and energy balance. The two forms of leptin receptors (long and short forms) have been identified in various peripheral tissues, a fact that makes them possible target sites for a direct action of leptin. It has been shown that the OB protein interferes with insulin secretion from pancreatic islets, reduces insulin-stimulated glucose transport in adipocytes, and increases glucose transport, glycogen synthesis and fatty acid oxidation in skeletal muscle. Under normoglycemic and normoinsulinemic conditions, leptin seems to shift the flux of metabolites from adipose tissue to skeletal muscle. This may function as a peripheral mechanism that helps control body weight and prevents obesity. Data that substantiate this hypothesis are presented in this review. PMID: 9698815 [PubMed - indexed for MEDLINE] 5723. Rev Stomatol Chir Maxillofac. 1998 Jul;99 Suppl 1:38-71. [Recent progress in facial esthetic surgery (excluding endoscopic technics)]. [Article in French] Gola R(1). Author information: (1)Service de Stomatologie, Chirurgie Maxillo-faciale et Plastique de la face, Hôpital Nord, Marseille. Recent advances offer a new approach to cosmetic surgery of the frontal, cervico-facial and orbito-palpebral areas. Conservative frontal lifting procedures displace the entire frontal muscle (without section or resection) over the underlying bone and periosteal planes by raising the galea and the antagonist muscles. This repositioning reduces or eliminate wrinkles by preventing hyperfunction of the frontal muscle. The risk of sensorial or motor nerve lesions is reduced and the forehead and eyelids have a natural appearance. Unlike extensive lifting of the cervico facial areas, physiological conservative cervico-facial lifting maintains the cutanéomusculo-aponeurotic unity which associates the skin with the superficial musculo-aponeurotic system. The procedure limits detachment in the parotido-masseter region. Early results on the lower cheeks and platysmal cords are significant. The absence of cutaneous detachment preserves the natural appearance of the palpebral complex and the orbital fat allowing improved function and a pleasant aspect of the eyelids. This surgery should be widened beyond the orbito-palpebral area and be used in the frontal, jugal and, in certain cases, the endonasal areas. PMID: 9697233 [PubMed - indexed for MEDLINE] 5724. Exerc Sport Sci Rev. 1998;26:191-218. Skeletal muscle lipoprotein lipase: molecular regulation and physiological effects in relation to exercise. Seip RL(1), Semenkovich CF. Author information: (1)Health, Physical Education, and Recreation Department, University of Nebraska, Kearney, USA. LPL directs the body wide distribution of fatty acids derived from circulating triglycerides. This is accomplished by tissue-specific regulation. In adipose tissue, LPLA per gram is higher than in muscle tissue. Eating increases adipose tissue LPLA and may increase blood flow. Exercise greatly increases SM blood flow and LPLA over a longer time frame as compared to the effect of eating on adipose tissue LPLA. The regulation of LPLA occurs at several levels and is better understood in adipose tissue models. In muscle, the study of regulation has been neglected. LPL expression in muscle may be more complex than in adipose tissue owing to the changes in blood flow and metabolism associated with contractile activity, as well as to other factors intrinsic to contraction, such as electrical events and cellular deformation. Sixty to 90 minutes of continuous leg exercise at 60% of VO2 max induces muscle LPL expression, increases LPL mRNA in humans with 4 hours of exercise, and raises immunoreactive mass by 8 hours post-exercise. Within 24 hours, both LPL and mRNA and mass have returned to normal levels. Increased muscle LPL mass following exercise may serve to replenish intramyofibral stores of triglyceride, which are depleted with endurance exercise and are greater in aerobically-trained individuals as compared to untrained individuals. The post-exercise increase in muscle LPL mass coincides with the post-exercise acute fall in circulating triglycerides typically observed in subjects capable of exercising for 60-90 minutes at 60% of VO2 max. The low fasting triglyceride levels often seen in highly trained individuals are due in part to their high levels of muscle LPLA. Both the physiological mediator and the molecular mediator of the exercised-induced induction of muscle LPL expression are known. Hopefully, the next decade will see careful studies aimed at better defining the molecular physiology of LPL expression in muscle. PMID: 9696990 [PubMed - indexed for MEDLINE] 5725. Atherosclerosis. 1998 Apr;137 Suppl:S75-80. PPARgamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Martin G(1), Schoonjans K, Staels B, Auwerx J. Author information: (1)U.325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, France. It is currently thought that the effects of PPARgamma activation on glucose homeostasis may be due to the effect of this nuclear receptor on the production of adipocyte-derived signalling molecules, which affect muscle glucose metabolism. Potential signalling molecules derived from adipocytes and modified by PPARgamma activation include TNFalpha and leptin, which both interfere with glucose homeostasis. In addition to its effects on these proteins, PPARgamma also profoundly affects fatty acid metabolism. Activation of PPARgamma will selectively induce the expression of several genes involved in fatty acid uptake, such as lipoprotein lipase, fatty acid transport protein and acyl-CoA synthetase, in adipose tissue without changing their expression in muscle tissue. This co-ordinate regulation of fatty acid partitioning by PPARgamma results in an adipocyte 'FFA steal' causing a relative depletion of fatty acids in the muscle. Based on the well established interference of muscle fatty acid and glucose metabolism it is hypothesized that reversal of muscle fatty acid accumulation will contribute to the improvement in whole body glucose homeostasis. PMID: 9694545 [PubMed - indexed for MEDLINE] 5726. Biochim Biophys Acta. 1998 Jun 10;1365(1-2):319-27. Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Jezek P(1), Engstová H, Zácková M, Vercesi AE, Costa AD, Arruda P, Garlid KD. Author information: (1)Department of Membrane Transport Biophysics, Academy of Sciences of the Czech Republic, Prague. jezek@sun1.biomed.cas.cz We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optimum efficiency and tune the degree of coupling of oxidative phosphorylation. Uncoupling results from fatty acid cycling, enabled by several phylogenetically specialized proteins and, to a lesser extent, by other mitochondrial carriers. It is suggested that the regulated uncoupling in mammalian mitochondria is provided by uncoupling proteins UCP-1, UCP-2 and UCP-3, whereas in plant mitochondria by PUMP and StUCP, all belonging to the gene family of mitochondrial carriers. UCP-1, and hypothetically UCP-3, serve mostly to provide nonshivering thermogenesis in brown adipose tissue and skeletal muscle, respectively. Fatty acid cycling was documented for UCP-1, PUMP and ADP/ATP carrier, and is predicted also for UCP-2 and UCP-3. UCP-1 mediates a purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H+ uniport and uncoupling. UCP-2 is probably involved in the regulation of body weight and energy balance, in fever, and defense against generation of reactive oxygen species. PUMP has been discovered in potato tubers and immunologically detected in fruits and corn, whereas StUCP has been cloned and sequenced froma a potato gene library. PUMP is supposed to act in the termination of synthetic processes in mature fruits and during the climacteric respiratory rise. PMID: 9693744 [PubMed - indexed for MEDLINE] 5727. Br J Surg. 1998 Jul;85(7):884-90. Metabolic response to severe injury. Hill AG(1), Hill GL. Author information: (1)University Department of Surgery, Auckland Hospital, New Zealand. BACKGROUND: Severe injury is associated with a complex sequence of metabolic events. The accurate quantification of these changes and a developing understanding of their aetiology has been the product of much work by researchers over the past 60 years. An understanding of these phenomena is vital to the practising surgeon because of the plethora of new metabolic modulators threatening to become part of clinical practice. METHODS: This review describes the clinical picture of the metabolic response to severe injury and then outlines modern understanding of the underlying processes. RESULTS AND CONCLUSION: The need for further research before introduction of new technologies is emphasized. PMID: 9692557 [PubMed - indexed for MEDLINE] 5728. Sports Med. 1998 Jun;25(6):369-406. Sex steroid metabolism and menstrual irregularities in the exercising female. A review. De Crée C(1). Author information: (1)Physiology of Exercise Unit, School of Physical Education, Sport and Leisure, Faculty of Health and Community Studies, De Montfort University, Bedford, England. cdecree@dmu.ac.uk This article aims to clarify why, and by which mechanisms, exercise may influence the normal menstrual cycle. Therefore, the vast amount of literature on this subject is reviewed and a critical appraisal of the most widespread hypotheses if offered. The strikingly low body mass which frequently accompanies exercise-related menstrual irregularities (ERMI) has led some authors to develop a hypothesis which postulates that a critical percentage of body fat is essential to trigger normal menstruation. The relevance of any reference to anorexia nervosa to support this view lacks consistency: female athletes differ in many ways from patients with anorexia nervosa, not least in their excellent physical status which is essential to deliver first-class performances. ERMI is not identical to the so-called female athlete triad, a complicated pathology that involves ERMI, premature osteoporosis and disordered eating. ERMI itself does not seem to have any substantial pathological effects as long as attention is paid to preventing osteoporosis or stress fractures which may result from prolonged hypo-estrogenaemia. In the female athlete with ERMI who wishes to conceive, the accompanying subfertility may necessitate a response other than a prompt reduction in training intensity, as this is hardly a first choice for any top athlete. During recent years, a number of prospective studies have greatly contributed to our understanding of the complexity of the mechanisms involved in ERMI. Older hypotheses, such as those considering hyperprolactinaemia as the cornerstone of ERMI, have now been firmly rejected. The present hypotheses emphasise the importance of caloric deficiency and limited energy availability, although they still fail to identify the actual mechanism that causes ERMI. There is, however, evidence that ERMI is produced by a disturbance of the hypothalamic gonadotrophin-releasing hormone oscillator. This disturbance is caused by either an insufficient estrogen or progesterone feedback or by an imbalance of local opioid peptide and catecholamine activities mediated by gamma-aminobutyric acid (GABA), corticotrophin-releasing hormone and insulin-like growth factor-1. More recent experiments have also linked ERMI with changes in steroid metabolism, in particular, an increasing activity of catecholestrogens possibly leading to enhanced intracerebral noradrenaline (norepinephrine) levels that may interfere with normal gonadotrophin release. This article demonstrates that the outcome of the many studies of ERMI is characterised by much controversy and numerous methodological flaws. The importance and complexity of some recent findings necessitate a comprehensive study which links older and newer findings within a critical perspective. PMID: 9680659 [PubMed - indexed for MEDLINE] 5729. Drugs Aging. 1998 Jul;13(1):43-50. Caffeine and the elderly. Massey LK(1). Author information: (1)Washington State University, Spokane, USA. massey@wsu.edu The most common source of dietary caffeine among the elderly is coffee, with consumption averaging about 200 mg/day. Because of the greater proportion of adipose tissue to lean body mass in older humans, and because caffeine is distributed essentially only through lean body mass, a dose of caffeine expressed as mg/kg total bodyweight may result in a higher plasma and tissue concentration in elderly compared with younger individuals. The metabolism of, and physiological responses to, caffeine is similar in elderly and younger individuals. However, there is a limited amount of evidence that responses to caffeine in some physiological systems may be greater in the elderly at doses in the 200 to 300 mg range. Although caffeine consumption increases urinary calcium levels similarly in both younger and older individuals, the preponderance of data suggest that caffeine has a greater impact on calcium metabolism and bone in older people. Evidence also suggests that increasing age is associated with increasing sensitivity to the pressor effects of caffeine. Caffeine appears to affect metabolic and neurological responses similarly in both young and elderly individuals, when differences in baseline performance are taken into account. PMID: 9679208 [PubMed - indexed for MEDLINE] 5730. Physiol Rev. 1998 Jul;78(3):783-809. Understanding adipocyte differentiation. Gregoire FM(1), Smas CM, Sul HS. Author information: (1)Department of Nutritional Sciences, University of California, Berkeley, USA. The adipocyte plays a critical role in energy balance. Adipose tissue growth involves an increase in adipocyte size and the formation of new adipocytes from precursor cells. For the last 20 years, the cellular and molecular mechanisms of adipocyte differentiation have been extensively studied using preadipocyte culture systems. Committed preadipocytes undergo growth arrest and subsequent terminal differentiation into adipocytes. This is accompanied by a dramatic increase in expression of adipocyte genes including adipocyte fatty acid binding protein and lipid-metabolizing enzymes. Characterization of regulatory regions of adipose-specific genes has led to the identification of the transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein (C/EBP), which play a key role in the complex transcriptional cascade during adipocyte differentiation. Growth and differentiation of preadipocytes is controlled by communication between individual cells or between cells and the extracellular environment. Various hormones and growth factors that affect adipocyte differentiation in a positive or negative manner have been identified. In addition, components involved in cell-cell or cell-matrix interactions such as preadipocyte factor-1 and extracellular matrix proteins are also pivotal in regulating the differentiation process. Identification of these molecules has yielded clues to the biochemical pathways that ultimately result in transcriptional activation via PPAR-gamma and C/EBP. Studies on the regulation of the these transcription factors and the mode of action of various agents that influence adipocyte differentiation will reveal the physiological and pathophysiological mechanisms underlying adipose tissue development. PMID: 9674695 [PubMed - indexed for MEDLINE] 5731. Arch Tierernahr. 1998;51(2-3):177-85. Hormonal and neuroendocrine regulation of energy balance--the role of leptin. Trayhurn P(1), Hoggard N, Mercer JG, Rayner DV. Author information: (1)Molecular Physiology, Rowett Research Institute, Aberdeen, Scotland, U.K. p.trayhurn@rri.sari.ac.uk A new dimension to the regulation of energy balance has come from the identification of the ob (obese) gene and its protein product, leptin. Leptin is produced primarily in white adipose tissue, but synthesis also occurs in brown fat and the placenta. Several physiological functions have been described for leptin the inhibition of food intake, the stimulation/maintenance of energy expenditure, as a signal of energy reserves to the reproductive system, and as a factor in haematopoiesis. The production of leptin by white fat is influenced by a number of factors, including insulin and glucocorticoids (which are stimulatory), and fasting, cold exposure and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production is envisaged for the sympathetic nervous system, operating through beta 3-adrenoceptors. The leptin receptor gene is expressed in a wide range of tissues, and several splice variants are evident. A long form variant (Ob-Rb) with an intracellular signalling domain is found particularly in the hypothalamus. Leptin exerts its central effects through neuropeptide Y, and through the glucagon-like peptide-1 and melanocortin systems, but it may also interact with other neuroendocrine pathways. The role and function of the leptin system in agricultural animals has not been established, but it offers a potential new target for the manipulation of body fat. PMID: 9672715 [PubMed - indexed for MEDLINE] 5732. Horm Metab Res. 1998 May;30(5):231-5. The interaction between leptin and the hypothalamic-pituitary-thyroid axis. Orban Z(1), Bornstein SR, Chrousos GP. Author information: (1)Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892-1862, USA. orbanz@cc1.nichd.nih.gov The description of the adipose tissue hormone leptin has led to important discoveries. Leptin plays a role not only in the regulation of metabolic efficiency, energy expenditure, food intake and adiposity, but also contributes greatly to the adaptation of the organism to starvation. Much of the literature has focused on the physiologic roles of leptin-driven processes as diverse as feeding behavior, body weight, defense to starvation and reproduction. The following discussion summarizes knowledge that has accumulated regarding the interaction between leptin and the hypothalamic-pituitary-thyroid axis. PMID: 9660078 [PubMed - indexed for MEDLINE] 5733. Int J Sports Med. 1998 May;19(4):231-44. Fat metabolism during exercise: a review. Part I: fatty acid mobilization and muscle metabolism. Jeukendrup AE(1), Saris WH, Wagenmakers AJ. Author information: (1)Nutrition Research Center, Department of Human Biology, Maastricht University, The Netherlands. This is the first part in a series of three articles about fat metabolism during exercise. In this part the mobilization of fatty acids and their metabolism will be discussed as well as the possible limiting steps of fat oxidation. It is known for a long time that fatty acids are an important fuel for contracting muscle. After lipolysis, fatty acids from adipose tissue have to be transported through the blood to the muscle. Fatty acids derived from circulating TG may also be used as a fuel but are believed to be less important during exercise. In the muscle the IMTG stores may also provide fatty acids for oxidation after stimulation of hormone sensitive lipase. In the muscle cell, fatty acids will be transported by carrier proteins (FABP), and after activation, fatty acyl CoA have to cross the mitochondrial membrane through the carnitine palmytoyl transferase system, after which the acyl CoA will be degraded to acetyl CoA for oxidation. The two steps that are most likely to limit fat oxidation are fatty acid mobilization from adipose tissue and transport of fatty acids into the mitochondria along with mitochondrial density and the muscles capacity to oxidize fatty acids. PMID: 9657362 [PubMed - indexed for MEDLINE] 5734. Nutr Rev. 1998 Jun;56(6):185-9. Uncoupling proteins: beyond brown adipose tissue. Freake HC(1). Author information: (1)Department of Nutritional Sciences, University of Connecticut, Storrs 06269-4017, USA. Uncoupling protein, originally described in the inner mitochondrial membrane of brown adipose tissue, permits the oxidation of fuels without the generation of adenosine triphosphate (ATP). Closely related proteins have now been found in many other tissues and shown to be regulated by thyroid hormones and dietary factors. These uncoupling proteins may play a significant role in energy expenditure, with implications for the development of human obesity. PMID: 9656731 [PubMed - indexed for MEDLINE] 5735. Magn Reson Imaging Clin N Am. 1998 Aug;6(3):473-95. Normal bone marrow: signal characteristics and fatty conversion. Babyn PS(1), Ranson M, McCarville ME. Author information: (1)Department of Radiology, The Hospital for Sick Children, Toronto, Ontario, Canada. Understanding the dynamic MR appearance of normal bone marrow during childhood is essential. This article reviews normal bone marrow structure and development, especially the process of fatty conversion, laying the cornerstone for accurate interpretation of marrow MR imaging. PMID: 9654581 [PubMed - indexed for MEDLINE] 5736. Trends Pharmacol Sci. 1998 May;19(5):164-6. On the presence of a putative fourth beta-adrenoceptor in human adipose tissue. Galitzky J, Langin D, Montastruc JL, Lafontan M, Berlan M. Comment on Trends Pharmacol Sci. 1996 Oct;17(10):373-81. PMID: 9652187 [PubMed - indexed for MEDLINE] 5737. Pediatrics. 1998 Jul;102(1):e4. Childhood obesity, adipose tissue distribution, and the pediatric practitioner. Slyper AH(1). Author information: (1)Medical College of Wisconsin, Milwaukee, Wisconsin, USA. The prevalence of pediatric obesity is increasing in the United States. Sequelae from pediatric obesity are increasingly being seen, and long-term complications can be anticipated. Obesity is the most common cause of abnormal growth acceleration in childhood. Obesity in females is associated with an early onset of puberty and early menarche. Puberty is now occurring earlier in females than in the past, and this is probably related either directly or indirectly to the population increase in body weight. The effect of obesity on male pubertal maturation is more variable, and obesity can lead to both early and delayed puberty. Pubertal gynecomastia is a common problem in the obese male. Many of the complications of obesity seen in adults appear to be related to increased accumulation of visceral fat. It has been proposed that subcutaneous fat may be protective against the adverse effects of visceral fat. Males typically accumulate fat in the upper segment of the body, both subcutaneously and intraabdominally. In females, adiposity is usually subcutaneous and is found particularly over the thighs, although visceral fat deposition also occurs. Gender-related patterns of fat deposition become established during puberty and show significant familial associations. There are no reliable means for assessing childhood and adolescent visceral fat other than radiologically. Noninsulin-dependent diabetes is being seen more commonly in the pediatric population. Diabetes and impaired glucose tolerance are noted particularly in obese children with a family history of diabetes. In this situation, a glucose tolerance test may be indicated, even in the presence of fasting normoglycemia. Hypertriglyceridemia and low high-density lipoprotein-cholesterol levels are the primary lipid abnormalities of obesity and are related primarily to the amount of visceral fat. Low-density lipoprotein-cholesterol levels are not typically elevated in simple obesity. The offspring of parents with early coronary disease tend to be obese. Very low-density lipoprotein and intermediate-density lipoprotein particles, which are small in size, may be important in atherogenesis but they cannot be identified in a fasting lipid panel. The propensity to atherogenesis cannot be interpreted readily from a fasting lipid panel, which therefore should be interpreted in conjunction with a family history for coronary risk factors. Hypertriglyceridemia may be indicative of increased visceral fat, familial combined hyperlipidemia, familial dyslipidemic hypertension, impaired glucose tolerance, or diabetes. Almost half of adult females with polycystic ovary syndrome are obese and many have a central distribution of body fat. This condition frequently has its origins in adolescence. It is associated with increased androgen secretion, hirsutism, menstrual abnormalities, and infertility, although these may not be present in every case. Adults with polycystic ovary syndrome adults are hyperlipidemic, have a high incidence of impaired glucose tolerance and noninsulin-dependent diabetes, and are at increased risk for coronary artery disease. Weight reduction and lipid lowering therefore are an important part of therapy. Obstructive sleep apnea with daytime somnolence is a common problem in obese adults. Pediatric studies suggest that obstructive sleep apnea occurs in approximately 17% of obese children and adolescents. Sleep disorders in the obese may be a major cause of learning disability and school failure, although this remains to be confirmed. Symptoms suggestive of a sleep disorder include snoring, restlessness at night with difficulty breathing, arousals and sweating, nocturnal enuresis, and daytime somnolence. Questions to exclude obstructive sleep apnea should be part of the history of all obese children, particularly for the morbidly obese. For many children and adolescents with mild obesity, and particularly for females, one can speculate that obesity may not be a great health risk PMID: 9651456 [PubMed - indexed for MEDLINE] 5738. Biochem Soc Trans. 1998 May;26(2):120-3. Neonatal brown adipose tissue, UCP1 and the novel uncoupling proteins. Ricquier D(1). Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement/Centre National de la Recherche Scientifique, Meudon, France. PMID: 9649731 [PubMed - indexed for MEDLINE] 5739. Contracept Fertil Sex. 1998 May;26(5):372-5. [Influence of weight and distribution of adipose tissue in functional hyperandrogenism]. [Article in French] Pasquali R(1), Vicennati V, Gambineri A. Author information: (1)Département de Médecine Interne et Gastro-entérologie, Hôpital S. Orsola-Malpighi, Bologne, Italie. Approximately half the women with the polycystic ovary syndrome (PCOS) are obese or overweight. Obesity and body fat distribution have independent roles in the development of hyperandrogenism in PCOS. Most obese and normal weight PCOS are insulin resistant and hyperinsulinemic. Moreover, a significant positive correlation exists between the degree of hyperandrogenism and that of hyperinsulinism. The pathogenetic role of obesity may involve different mechanisms, the major one being the hyperinsulemic state, since insulin is capable of stimulating ovarian androgen secretion and controlling androgen metabolism and transport in peripheral tissues. Abdominal body fat distribution in obese women with PCOS amplifies the degree of hyperandrogenism and related clinical symptoms and signs. Both loss of body weight and/or the reduction of the degree of hyperinsuliemia, induced by diet or insulin-sensitizing drugs, have important effects, since they reduce blood androgen levels and can improve ovulation and clinical signs of hyperandrogenism. PMID: 9648381 [PubMed - indexed for MEDLINE] 5740. Curr Opin Lipidol. 1998 Jun;9(3):189-96. Defects of lipoprotein metabolism in familial combined hyperlipidaemia. de Graaf J(1), Stalenhoef AF. Author information: (1)Department of Medicine, University Hospital Nijmegen, The Netherlands. Familial combined hyperlipidaemia is the most common inherited hyperlipidaemia and is found in up to 10% of patients with premature myocardial infarction. The genetic and metabolic bases of the disorder have not yet been defined. This review discusses the important advances in the past year in our understanding of the different metabolic pathways contributing to the pathogenesis of familial combined hyperlipidaemia. PMID: 9645500 [PubMed - indexed for MEDLINE] 5741. Exerc Immunol Rev. 1998;4:77-94. Importance of TNF-alpha and leptin in obesity and insulin resistance: a hypothesis on the impact of physical exercise. Halle M(1), Berg A, Northoff H, Keul J. Author information: (1)Dept. of Rehabilitation, Prevention, and Sports Medicine, Freiburg University Hospital, Germany. Obesity is associated with an increased incidence of insulin resistance, dyslipoproteinemia, and hypercoagulability. In a more recently established hypothesis of body weight control and regulation of metabolism, the adipocyte secretes leptin and locally expresses TNF-alpha, the latter being responsible for the expression of metabolic cardiovascular risk factors. TNF-a mRNA expression and TNF-alpha protein are greatly increased in adipose tissue from obese animals and humans. Elevated TNF-alpha expression induces insulin resistance by downregulating the tyrosine kinase activity of the insulin receptor and decreasing the expression of GLUT-4 glucose transporters. TNF-alpha also reduces lipoprotein lipase activity in white adipocytes, stimulates hepatic lipolysis, and increases plasminogen activator inhibitor-1 content in adipocytes. Moreover, adipocytes secrete leptin, a molecule with a secondary cytokine structure whose concentrations correlate with the amount of fat tissue. Increased leptin levels downregulate appetite and increase sympathetic activity and thermogenesis in the hypothalamus. Diet-induced weight loss reduces adipose TNF-alpha expression and serum leptin levels and is associated with improved insulin sensitivity and lipid metabolism. Although exercise has also been shown to reduce leptin levels, an influence on TNF-a expression in adipocytes or muscle cells has not yet been demonstrated. PMID: 9644096 [PubMed - indexed for MEDLINE] 5742. Reprod Nutr Dev. 1998 Mar-Apr;38(2):131-52. Digestive and metabolic adaptations of ruminants to undernutrition, and consequences on reproduction. Chilliard Y(1), Bocquier F, Doreau M. Author information: (1)Laboratoire sous-nutrition des ruminants, France. chilliar@clermont.inra.fr In response to undernutrition, short- (days) and medium-term (weeks) adaptations are more pronounced for splanchnic organs than for other tissues. For the latter, the long-term response involves a sequential mobilization (fat > muscle > bone) with relative priorities differing among anatomical sites. Among chemical components, the body lipids are extensively used (up to 80%) in underfed animals, while the range of protein utilization is limited (up to 15-20%). The decrease in energy expenditure during undernutrition is mostly due to a short- and medium-term decrease in feeding activity, and in the mass and activity of splanchnic tissues. In the long-term, energy expenditure and tissue masses decrease concomitantly, but there does not appear to be a significant decrease in expenditure per unit tissue weight. Nitrogen losses decrease in response to decline in nitrogen fluxes and also due to sparing by renal activities and sometimes by urea recycling. However, ruminants do not seem to be able to compensate for a low level of intake (below maintenance) by an increase in digestive efficiency. Numerous hormones (insulin, growth hormone, insulin-like growth factor I, catecholamines, thyroid hormones, cortisol, leptin, etc.) are involved in the changes during undernutrition of nutrient fluxes between tissues, either through control of synthesis and/or degradation in peripheral tissues (adipose tissue and muscle), or through hepatic conversions of substrates (gluconeogenesis, ureagenesis and ketogenesis), in order to maintain the constancy of the internal environment (homeostasis) and/or to sustain productive functions (teleophoresis). However, reproductive process may be blocked in underfed animals. PMID: 9638788 [PubMed - indexed for MEDLINE] 5743. Science. 1998 May 29;280(5368):1378-83. Signals that regulate food intake and energy homeostasis. Woods SC(1), Seeley RJ, Porte D Jr, Schwartz MW. Author information: (1)Department of Psychiatry, University of Cincinnati Medical Center, Post Office Box 670559, Cincinnati, OH 45267-0559, USA. swoods@uc.campus.mci.net Feeding behavior is critical for survival. In addition to providing all of the body's macronutrients (carbohydrates, lipids, and proteins) and most micronutrients (minerals and vitamins), feeding behavior is a fundamental aspect of energy homeostasis, the process by which body fuel stored in the form of adipose tissue is held constant over long intervals. For this process to occur, the amount of energy consumed must match precisely the amount of energy expended. This review focuses on the molecular signals that modulate food intake while integrating the body's immediate and long-term energy needs. PMID: 9603721 [PubMed - indexed for MEDLINE] 5744. Science. 1998 May 29;280(5368):1383-7. Strategies and potential molecular targets for obesity treatment. Campfield LA(1), Smith FJ, Burn P. Author information: (1)Department of Metabolic Diseases, Hoffmann-La Roche Incorporated, 340 Kingsland Street, Nutley, NJ 07110, USA. l_arthur.campfield@roche.com Obesity is an increasingly prevalent and important health problem. Although treatment is available, the long-term maintenance of medically significant weight loss (5 to 10 percent of initial body weight) is rare. Since 1995 there has been an explosion of research focused on the regulation of energy balance and fat mass. Characterization of obesity-associated gene products has revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Ideally, these treatments will be viewed as adjuncts to behavioral and lifestyle changes aimed at maintenance of weight loss and improved health. PMID: 9603722 [PubMed - indexed for MEDLINE] 5745. Zentralbl Gynakol. 1998;120(5):235-40. [Obesity and risk of cancer in the woman]. [Article in German] Schindler AE(1). Author information: (1)Zentrum für Frauenheilkunde, Universitätsklinikum Essen. Experimental studies in animals and investigations in human beings have demonstrated that an increase of body fat mass and the increase of the waist/hip-ratio raises the risk of endometrial and breast cancer. There are also indications for an influence on ovarian and colon cancer. These effects by adipose tissue are created by endocrine changes such as an increase of total and free estradiol, changes in progesterone secretion, protein binding concentrations, growth factors and receptor action. Besides the increased risk for cancer there is also an effect on prognosis. PMID: 9629630 [PubMed - indexed for MEDLINE] 5746. Ann N Y Acad Sci. 1998 May 15;839:186-9. Lipolytic effects of beta 1-, beta 2-, and beta 3-adrenergic agonists in white adipose tissue of mammals. Carpéné C(1), Bousquet-Mélou A, Galitzky J, Berlan M, Lafontan M. Author information: (1)INSERM U317, Toulouse, France. PMID: 9629148 [PubMed - indexed for MEDLINE] 5747. J Nutr. 1998 Jun;128(6):923-6. Polyunsaturated fatty acid regulation of gene expression. Sessler AM(1), Ntambi JM. Author information: (1)Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. For the past three decades, polyunsaturated fatty acids (PUFA) have been recognized as important energy sources and membrane components. PUFA also play key roles in many cellular events, such as gene regulation. Most recently, research has focused on identifying the mechanisms by which PUFA modulate gene transcription, mRNA stability and cellular differentiation. It is the purpose of this review to examine the effects of PUFA on gene expression in lipogenic as well as other tissues. Because the (n-3) and (n-6) series of PUFA are intimately involved in gene regulation, they will be the focus of review. The effects of other fatty acid families on gene expression are reviewed elsewhere. PMID: 9614148 [PubMed - indexed for MEDLINE] 5748. Crit Rev Food Sci Nutr. 1998 May;38(4):331-52. The role of muscle proteases and lipases in flavor development during the processing of dry-cured ham. Toldrá F(1), Flores M. Author information: (1)Instituto de Agroquímica y Technología de Alimentos (C.S.I.C.), Valencia, Spain. The processing of dry-cured ham is very complex and involves numerous biochemical reactions that are reviewed in this article. Muscle proteins undergo an intense proteolysis, resulting in a great number of small peptides and high amounts of free amino acids. The enzymes responsible of these changes are proteinases (cathepsins B, D, H, and L and, to a less extent, calpains) and exopeptidases (peptidases and aminopeptidases). Muscle and adipose tissue lipids are also subject to intense lipolysis, generating free fatty acids by the action of lipases that, in a second stage, are transformed to volatiles as a result of oxidation. Sensory profiles of dry-cured ham are strongly affected by these enzymatic reactions. In addition, the activity levels of the muscle enzymes significantly depend on the properties of raw ham, such as age and crossbreeding as well as the process conditions such as temperature, time, water activity, redox potential, and salt content. Thus, the control of the muscle enzyme systems, mainly proteases and lipases, is essential for the standardization of the processing and/or enhancement of flavor quality of dry-cured ham. PMID: 9626490 [PubMed - indexed for MEDLINE] 5749. Semin Oncol. 1998 Apr;25(2 Suppl 6):45-52. Cytokine activity in cancer-related anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate. Mantovani G(1), Macciò A, Lai P, Massa E, Ghiani M, Santona MC. Author information: (1)Department of Medical Oncology, University of Cagliari, Italy. The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named the cancer-related anorexia/cachexia syndrome (CACS). Chronic administration of pro-inflammatory cytokines, including interleukin-I (IL-I), IL-6, and tumor necrosis factor (TNF), either alone or in combination, is capable of reproducing the different features of CACS. High serum levels of these cytokines have been found in cancer patients, which seem to correlate with progression of the tumor. This article describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-I, IL-6, and TNF, are present in advanced-stage cancer patients, particularly those with CACS; (2) megestrol acetate (MA) has a beneficial therapeutic effect on CACS symptoms, such as appetite, body weight, and quality of life; (3) MA downregulates the synthesis and release of cytokines and relieves the symptoms of CACS; (4) cytokines play a key role in the onset of CACS; (5) medroxyprogesterone acetate (MPA) reduces the in vitro production of cytokines and serotonin (5-hydroxytryptamine, 5-HT) by peripheral blood mononuclear cells (PBMC) of cancer patients; and (6) MA and MPA reduce the cisplatin-induced 5-HT release in vitro from PBMC of cancer patients. Based on these results, a clinical study incorporating MA/MPA in combination with chemotherapy or chemoimmunotherapy may be warranted. In addition, it has been recently shown that "oxidative stress" resulting from reactive oxygen species, which can be induced by pro-inflammatory cytokines, is involved in tissue wasting and CACS. These results suggest promising approaches for the prevention and treatment of cytokine-induced CACS based on MA, MPA, and metabolic antioxidants. PMID: 9625383 [PubMed - indexed for MEDLINE] 5750. J Neural Transm Suppl. 1998;52:239-50. Properties and functions of tissue-bound semicarbazide-sensitive amine oxidases in isolated cell preparations and cell cultures. Lyles GA(1), Pino R. Author information: (1)Department of Pharmacology and Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom. The demonstration of semicarbazide-sensitive amine oxidase (SSAO) activity in some freshly-dispersed cell preparations and in particular types of cells grown in culture, provides increasing opportunities for investigating the importance of SSAO in various aspects of cellular function. Assays of benzylamine and methylamine metabolism in homogenates of cultured cells have established clearly that SSAO is expressed in rat and pig vascular (aortic) smooth muscle cells, as well as in rat non-vascular (anococcygeus, trachea) smooth muscle, brown and white adipocytes. However, to date little or no SSAO activity has been detected in cultures of human vascular smooth muscle cells grown from blood vessels (e.g. umbilical artery) known to contain the enzyme, and the reason for this is not yet apparent. However, those cell cultures expressing SSAO are offering useful experimental models for studying biochemical and toxicological consequences upon cellular function which may result from the metabolism of various aromatic and aliphatic amines suggested to be possible physiological and xenobiotic substrates of the enzyme. PMID: 9564623 [PubMed - indexed for MEDLINE] 5751. Thyroid. 1998 May;8(5):411-3. The thyrotropin receptor in thyroid eye disease. Ludgate M(1), Crisp M, Lane C, Costagliola S, Vassart G, Weetman A, Daunerie C, Many MC. Author information: (1)Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom. Thyroid eye disease (TED) has an autoimmune etiology, but the nature of the autoantigen that is the target of the initiating event remains unknown. A number of candidates have been proposed based on Western blotting, library screening, and deduction from sequence similarity. A strong favorite is the thyrotropin receptor (TSHR), which is the target of the thyroid stimulating antibodies (TSAB) of Graves' disease (GD). We have recently demonstrated TSHR transcripts in orbital adipose tissue from a patient with TED by Northern blot, transcripts in normal adipose tissue being at the limit of detection. We have shown that the transcripts are translated into protein by immunohistochemical analysis using two monoclonal antibodies to the TSHR generated by genetic immunization. TSHR immunoreactivity is associated with elongated cells with the appearance of a fibroblast, often adjacent to clusters of adipocytes, in orbital biopsies from patients with TED but not in strabismus or pseudotumor biopsies. In animal studies, we have transferred thyroiditis to naive BALBc and NOD mice, using T cells primed to the human TSHR, either using the receptor expressed as a bacterial fusion protein or by genetic immunization. The BALBc develop a Th2-type response to the receptor, but the NOD a Th1-type with thyrocyte destruction. Orbital pathology, edema, infiltration by mast cells and lymphocytes, and adipose accumulation was also induced in 68% of the BALBc but none of the NOD mice. Together these data indicate that the preadipocyte expresses the TSHR and that a Th2 autoimmune response to the receptor may be an initiating event in TED. PMID: 9623732 [PubMed - indexed for MEDLINE] 5752. Obes Res. 1998 May;6(3):246-54. Effects of the menopause transition on body fatness and body fat distribution. Tchernof A(1), Poehlman ET. Author information: (1)Department of Medicine, University of Vermont, Burlington 05405, USA. Comment in Obes Res. 2005 Jul;13(7):1300. NIH Guide Grants Contracts. 2005 Mar 25;:NOT-OD-05-040. OBJECTIVE: The menopause transition increases cardiovascular and metabolic disease risk, partly because of the adverse effects of estrogen deficiency on the plasma lipid-lipoprotein profile and cardiovascular function. This increased cardiovascular and metabolic disease risk may also be partially mediated by increased body fat, increased intra-abdominal adipose tissue accumulation, or both. The objective of this mini-review is to summarize studies that have investigated the relationships among the menopause transition, body fatness, and body fat distribution. RESEARCH METHODS AND PROCEDURES: A review of cross-sectional and longitudinal studies on menopause that examined body fatness and body fat distribution. RESULTS: Cross-sectional reports show that the menopause transition is related to modest increases in body mass index or total fatness, although not all studies found significant effects. Increased central adiposity appears to be related to menopause, independent of advancing age, but these results are methodology dependent. An independent effect of menopause on central body fatness was noted by the use of techniques such as DEXA or computed tomography, whereas studies using circumference measures showed discrepant results. Longitudinal studies showed that the menopause transition accelerated the increase in central adiposity, although no studies quantified changes in intra-abdominal fat by imaging techniques. DISCUSSION: Thus, additional longitudinal studies using more accurate measures of adiposity are needed to critically examine the effects of the menopause transition on total and central body fatness. Collectively, previous studies suggest that menopause is related to modest increase in total fatness and accelerated accumulation of central body fat that exceeds changes normally attributed to the aging process. These changes may increase the risk for cardiovascular and metabolic disease in aging women. PMID: 9618130 [PubMed - indexed for MEDLINE] 5753. Ann N Y Acad Sci. 1997 Dec 29;833:79-90. The epidemiology of physical activity and cancer. Oliveria SA(1), Christos PJ. Author information: (1)Strang Cancer Prevention Center, New York, New York 10021, USA. soliveria@strang.org Experimental studies in animals and epidemiological studies in human populations support an inverse association between exercise and the development of cancer. Physical activity has been shown to be protective against the development of breast and colon cancer and may also be important for other kinds of cancer such as that of the prostate. The proposed biological mechanisms for the physical activity--cancer association include exercise's effect on immune function, transit time of digestion, hormones, and body fat. There has been little research on physical activity and the effect on progression of cancer, although there are studies to suggest that it may slow the clinical course of the disease. Furthermore, exercise may be beneficial in the treatment of cancer through mood elevation, decreased loss of lean tissue, and increased quality of life. Much is still to be learned about the effect of exercise on cancer. The intensity, duration, frequency, and type of exercise that is relevant need to be clarified. As well, the time period during life when exercise is important has not been determined. It seems reasonable to conclude that exercise, a modifiable risk factor, is beneficial in preventing certain forms of cancer. Public health interventions may hold promise for cancer prevention. PMID: 9616742 [PubMed - indexed for MEDLINE] 5754. Recenti Prog Med. 1998 Apr;89(4):200-7. [Leptin: adipocyte hormone]. [Article in Italian] Castagna L(1), De Gregorio T, Allegra A, Buemi M, Corsonello A, Bonanzinga S, Catanoso M, Ceruso D, Corica F. Author information: (1)Dipartimento di Medicina Interna e Terapia Medica, Università, Messina. The authors reviewed the most recent literature on leptin, a protein produced by adipocytes which exerts its action on hypothalamus, modifying eating behavior and inhibiting the lust for food consumption. This one appeared to be the main, if not the only, physiologic action of leptin. Later leptin has been acknowledged a major role in the homeostasis. The regulation of the synthesis, and the mechanisms by which the protein modulates both food intake and energetic balance have been evaluated, and the hypotheses on the regulatory function exerted by leptin on the homeostasis, by acting on neuroendocrine system, on sexual maturity and fertility, on the sympathetic nervous system, on hemopoiesis and hydroelectrolytic balance have been discussed, some of which being already supported by experimental evidences. PMID: 9612014 [PubMed - indexed for MEDLINE] 5755. Cesk Fysiol. 1997 Dec;46(4):182-8. [Leptin]. [Article in Czech] Nedvídková J(1). Author information: (1)Endokrinologický ústav, Praha. Leptin (ob-protein), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks, that regulate weight and energy homeostasis. Leptin provides a communication link between fat tissue and the brain. Ob protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. Leptin levels have pulsative and diurnal character. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form. On other hand, in obese individuals the majority of leptin circulates in free form presumably bioactive protein, and thus obese subjects are resistant to free leptin. Leptin's resistance is often coupled with insuline resistance postreceptor type. Leptin receptor is product of db genes. Ob-protein receptor belongs to the cytokine superfamily of receptors and has several variants. Leptin-receptor gene is expressed in abundant degree in ovary, uterus, testes, less in hypothalamus, hypophysis, and little in kidney. Leptin stimulates the reproductive endocrine system and may serve as a permissive signal to the reproductive system of normal animals. Ob-gene product, leptin is regulated by feedings patterns and hormones, such as insulin and glucocorticoids. There is assumed that neuropeptide Y (NPY) and melanocyte-stimulating hormone (MSH) and its receptor (MCR) are a critical components of the biological response to leptin levels. MCR in contrast to leptin receptors are coupled with G-transduction system. PMID: 9601742 [PubMed - indexed for MEDLINE] 5756. Eur J Clin Nutr. 1997 Nov;51 Suppl 4:S9-10. Prevention and control of iodine deficiency: a review of a study on the effectiveness of oral iodized oil in Malawi. Furnée CA(1). Author information: (1)Faculty of Economics and Business Administration, Department of Economics (IES), Maastricht, The Netherlands. Unfortunately there will always be groups of people who will not have access to iodized salt as a measure for iodine deficiency control. Iodized oil for oral use may be indispensable for them. The conclusions of a study in Malawi on the effectiveness of oral iodized are that the type of iodized oil, goitre, intestinal parasites, sex, adipose tissue, cassava consumption and seasonality are factors which influence the duration of effectiveness of this prophylaxis measure. The study in Malawi used urinary iodine concentration as a measure for iodine status and a hyperbolic function to describe the pattern of urinary iodine excretion after oral dosing. Cumulative frequency distributions of individually assessed durations of effectiveness very conveniently describe the prevalence rate of iodine deficiency after oral iodized oil administration. They are very useful for identifying factors which influence the effectiveness of oral iodized oil and may thus be a tool for optimizing iodized oil programmes. PMID: 9598786 [PubMed - indexed for MEDLINE] 5757. Int J Biochem Cell Biol. 1998 Jan;30(1):7-11. The uncoupling protein, thermogenin. Palou A(1), Picó C, Bonet ML, Oliver P. Author information: (1)Departament de Biologia Fonamental i Ciêncies de la Salut, Universitat de les Illes Balears, Palma de Mallorca 07071, Spain. The uncoupling protein (UCP) or thermogenin is a 33 kDa inner-membrane mitochondrial protein exclusive to brown adipocytes in mammals that functions as a proton transporter, allowing the dissipation as heat of the proton gradient generated by the respiratory chain and thereby uncoupling oxidative phosphorylation. Thermogenesis (heat production) in brown adipose tissue, which is activated in response to cold exposure or chronic overeating, depends largely on UCP activity. Norepinephrine, released from sympathetic terminals and acting via beta-adrenoceptors and cAMP, is the main positive regulator of both UCP synthesis and activity. Brown fat thermogenesis plays a critical role in thermoregulation and in overall energy balance, at least in rodents. Manipulation of thermogenesis, whether through UCP or through analogous uncoupling proteins, could be an effective strategy against obesity. PMID: 9597749 [PubMed - indexed for MEDLINE] 5758. J R Coll Physicians Lond. 1998 Mar-Apr;32(2):101-4. The fat controller: obesity and leptin. Kumar S(1). Author information: (1)Birmingham Heartlands Hospital. Comment in J R Coll Physicians Lond. 1998 May-Jun;32(3):275-6. PMID: 9597620 [PubMed - indexed for MEDLINE] 5759. Am J Otol. 1998 May;19(3):277-82. Laser stapedotomy minus prosthesis (laser STAMP): a minimally invasive procedure. Silverstein H(1). Author information: (1)The Ear Research Foundation, Sarasota, Florida 34239, USA. OBJECTIVE: To determine whether hearing can be restored using a laser without a prosthesis in patients with minimal otosclerosis. STUDY DESIGN: Retrospective case review of 12 patients with minimal otosclerosis who underwent a laser stapedotomy without prosthesis (laser STAMP) procedure. SETTING: An otology/neurotology tertiary referral center. PATIENTS: Patients were chosen for the procedure if there was a blue footplate with minimal otosclerosis confined to the fissula antefenestram. INTERVENTIONS: Using a hand-held probe (CeramOptic), and the HGM argon laser, the anterior crus of the stapes was vaporized. Next, a linear stapedotomy was made across the anterior one third of the footplate. If otosclerosis is confined to the fissula antefenestram, the stapes becomes completely mobile. The stapedotomy opening is sealed with an adipose tissue graft from the ear lobe. MAIN OUTCOME MEASURES: Pure-tone audiometry with appropriate masking and auditory discrimination testing were performed before surgery, 6 weeks after surgery, and 1 year after surgery. RESULTS: The average air-bone gap was closed to a mean (SD) of 2.6 dB (3.3 dB). The average improvement in air-bone gap was 17.4 dB (7.6 dB). The discrimination scores remained unchanged. Audiometric testing of five cases with 1 year follow-up demonstrates that excellent hearing results are maintained. CONCLUSIONS: In selected cases of minimal otosclerosis confined to the fissula antefenestram, normal mobility of the ossicular chain can be obtained without a prosthesis by vaporizing the anterior crus and making a linear stapedotomy across the anterior one third of the footplate. The advantages of the procedure are that the stapedius tendon and most of the normal stapes remain intact, eliminating hyperacusis. The procedure is less invasive so it reduces inner ear trauma, possible prosthesis problems are avoided, and postoperative barotrauma risk is minimized. Minimal surgery is done for minimal disease. If the stapes refixes at some time in the future, a conventional stapedotomy can still be performed. PMID: 9596174 [PubMed - indexed for MEDLINE] 5760. Prog Nucleic Acid Res Mol Biol. 1998;60:317-45. Regulation of fat synthesis and adipose differentiation. Sul HS(1), Smas CM, Wang D, Chen L. Author information: (1)Department of Nutritional Sciences, University of California, Berkeley 94720-3104, USA. Adipocytes have highly specialized function of accumulating fat as stored energy that can be used during periods of food deprivation. The process of fat synthesis and development of adipose tissue are under hormonal and nutritional control. This review first describes transcription of the two critical enzymes involved in fat synthesis, fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase, is decreased to an undetectable level during fasting. Food intake, especially a high carbohydrate, fat-free diet, subsequent to fasting causes dramatic increase in transcription of these genes. Insulin secretion is increased during feeding, having a positive effect, whereas cAMP, which mediates the effect of glucagon which increases during fasting, has a negative effect on transcription of these genes. Using adipocytes in culture and in transgenic mice that express liciferase driven by the fatty acid synthase promoter, cis-acting and trans-acting factors that may mediate the transcriptional regulation were examined. Upstream stimulatory factors (USFs) that bind to -65 E-box are required for insulin-mediated transcriptional activation of the fatty acid synthase gene. This review next describes how pref-1 is a novel inhibitor of adipose differentiation and is a plasma membrane protein containing six EGF-repeats in the extracellular domain. Pref-1 is highly expressed in 3T3-L1 preadipocytes, but is not detectable in mature fat cells. Down regulation of pref-1 is required for adipose differentiation, and constitutive expression of pref-1 inhibits adipogenesis. Moreover, the ectodomain of pref-1 is cleaved to generate a biologically active 50 kDa soluble form. There are four major forms of membrane pref-1 resulting from alternate splicing, but two of the forms with a larger deletion do not produce biologically active soluble form, indicating that alternate splicing determines the range of action, juxtacrine or paracrine, of the pref-1. PMID: 9594578 [PubMed - indexed for MEDLINE] 5761. Seikagaku. 1998 Mar;70(3):212-6. [Mitochondrial uncoupling protein as a thermogenic molecule]. [Article in Japanese] Saito M(1). Author information: (1)Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University. PMID: 9591466 [PubMed - indexed for MEDLINE] 5762. Wien Klin Wochenschr. 1998 Mar 27;110(6):212-9. [Leptin--an interim evaluation]. [Article in German] Bodner J(1), Ebenbichler CF, Lechleitner M, Ritsch A, Sandhofer A, Gander R, Wolf HJ, Huter O, Patsch JR. Author information: (1)Universitiätsklinik für Innere Medizin, Innsbruck, Osterreich. The discovery of leptin, the product of the obese (ob)-gene, has broadened the horizons of research on energy balance. This hormone, produced and secreted by adipose tissue and some placental cells, finds its way to the hypothalamus, where it binds to the leptin receptors and signals satiety through the neuroendocrine axis. The fact that adipose tissue is not merely a storage depot, but also an important endocrine tissue, has revived the interest in the "lipostatic" theory of body fat regulation and has initiated many research efforts in the field of obesity, anorexia nervosa, bulimia, reproduction and haematology. PMID: 9586146 [PubMed - indexed for MEDLINE] 5763. Proc Nutr Soc. 1998 Feb;57(1):49-54. Use of endogenous carbohydrate and fat as fuels during exercise. Martin WH 3rd(1), Klein S. Author information: (1)Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. PMID: 9571708 [PubMed - indexed for MEDLINE] 5764. Appl Radiat Isot. 1998 May-Jun;49(5-6):429-35. The quality of the body cell mass--1996. Are we ready to measure it? Pierson RN Jr(1), Wang J, Thornton JC, Heymsfield SB. Author information: (1)Nutrition Research Center, St Lukes-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, USA. PMID: 9569511 [PubMed - indexed for MEDLINE] 5765. Obes Res. 1998 Apr;6 Suppl 1:8S-17S. The insulin resistance-dyslipidemic syndrome of visceral obesity: effect on patients' risk. Després JP(1). Author information: (1)Lipid Research Center, CHUL Research Center, Ste-Foy, Québec, Canada. Coronary heart disease (CHD) and type 2 diabetes mellitus represent two highly prevalent conditions in affluent societies. Although a dyslipidemic state is frequently found in type 2 patients with obesity, studies have shown that the high triglyceride, low high-density lipoprotein (HDL) cholesterol dyslipidemia is also found in nondiabetic patients with insulin resistance. Studies that have used imaging techniques to assess the regional distribution of body fat have shown that an excess of visceral adipose tissue, that is, a high accumulation of fat in the abdominal cavity, was associated with a cluster of metabolic disturbances such as insulin resistance, hyperinsulinemia, glucose intolerance, hypertriglyceridemia, elevated apolipoprotein B (apoB) concentrations, small, dense low-density lipoprotein (LDL) particles, as well as low HDL cholesterol levels. Prospective studies such as the Québec Cardiovascular Study have shown that this cluster of metabolic abnormalities commonly found in patients with excess visceral adipose tissue substantially increases the risk of CHD. The high prevalence of visceral obesity in sedentary adult men and postmenopausal women is such that it may represent the most prevalent cause of atherogenic dyslipidemic states associated with CHD in our population. PMID: 9569171 [PubMed - indexed for MEDLINE] 5766. Diabetes. 1998 Apr;47(4):507-14. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Spiegelman BM(1). Author information: (1)Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. bruce_spiegelman@dfci.harvard.edu The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance. PMID: 9568680 [PubMed - indexed for MEDLINE] 5767. Nutr Rev. 1998 Feb;56(2 Pt 2):s38-46; discussion s54-75. Leptin, leptin receptors, and the control of body weight. Friedman JM(1). Author information: (1)Howard Hughes Medical Institute, New York, New York, USA. The assimilation, storage, and disposition of nutrient energy constitute a complex homeostatic system central to the survival of both prokaryotic and eukaryotic organisms. In vertebrates, and especially among land dwelling mammalian species, the ability to store large quantities of energy-dense fuel in the form of adipose tissue triglyceride permits survival during prolonged periods of food deprivation. In order to maintain such fuel stores during times of dietary scarcity or surfeit, some balance between energy intake and expenditure must be achieved. Lesions of the hypothalamus alter body weight suggesting that this brain region regulates nutritional state. These and other studies led to the hypothesis that body weight was regulated by a feedback loop in which peripheral signals reported nutritional information to an integratory center in the brain. However, the identity of these nutrition signals proved elusive. PMID: 9564176 [PubMed - indexed for MEDLINE] 5768. Physiol Rev. 1998 Apr;78(2):339-58. Cold-induced thermoregulation and biological aging. Florez-Duquet M(1), McDonald RB. Author information: (1)Department of Nutrition, University of California, Davis, USA. Aging is associated with diminished cold-induced thermoregulation (CIT). The mechanisms accounting for this phenomenon have yet to be clearly elucidated but most likely reflect a combination of increased heat loss and decreased metabolic heat production. The inability of the aged subject to reduce heat loss during cold exposure is associated with diminished reactive tone of the cutaneous vasculature and, to a lesser degree, alterations in the insulative properties of body fat. Cold-induced metabolic heat production via skeletal muscle shivering thermogenesis and brown adipose tissue nonshivering thermogenesis appears to decline with age. Few investigations have directly linked diminished skeletal muscle shivering thermogenesis with the age-related reduction in cold-induced thermoregulatory capacity. Rather, age-related declines in skeletal muscle mass and metabolic activity are cited as evidence for decreased heat production via shivering. Reduced mass, GDP binding to brown fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue cold-induced nonshivering thermogenic capacity during aging. The age-related reduction in brown fat nonshivering thermogenic capacity most likely reflects altered cellular signal transduction rather than changes in neural and hormonal signaling. The discussion in this review focuses on how alterations in CIT during the life span may offer insight into possible mechanisms of biological aging. Although the preponderance of evidence presented here demonstrates that CIT declines with chronological time, the mechanism reflecting this attenuated function remains to be elucidated. The inability to draw definitive conclusions regarding biological aging and CIT reflects the lack of a clear definition of aging. It is unlikely that the mechanisms accounting for the decline in cold-induced thermoregulation during aging will be determined until biological aging is more precisely defined. PMID: 9562032 [PubMed - indexed for MEDLINE] 5769. Curr Opin Cell Biol. 1998 Apr;10(2):165-73. Transcriptional control of adipogenesis. Fajas L(1), Fruchart JC, Auwerx J. Author information: (1)INSERM U 325, Département d'Athérosclérose, Institut Pasteur, Lille, France. Adipocyte differentiation is coordinatedly regulated by several transcription factors. C/EBP beta, C/EBP delta and ADD-1/SREBP-1 are active early during the differentiation process and induce the expression and/or activity of the peroxisome proliferator activated receptor-gamma (PPAR gamma), the pivotal coordinator of the adipocyte differentiation process. Activated PPAR gamma induces exit from the cell cycle and triggers the expression of adipocyte-specific genes, resulting in increased delivery of energy to the cells. C/EBP alpha, whose expression coincides with the later stages of differentiation, cooperates with PPAR gamma in inducing additional target genes and sustains a high level of PPAR gamma in the mature adipocyte as part of a feedforward loop. Altered activity and/or expression of these transcription factors might underlie the pathogenesis of disorders characterized by increased or decreased adipose tissue depots. PMID: 9561840 [PubMed - indexed for MEDLINE] 5770. Z Ernahrungswiss. 1998;37 Suppl 1:1-7. Obesity after genetic ablation of brown adipose tissue. Hamann A(1), Flier JS, Lowell BB. Author information: (1)Medizinische Kernklinik und Poliklinik, Universität-Krankenhaus Eppendorf, Hamburg, FRG. Brown adipose tissue (BAT) has been proposed to play an important role in the regulation of energy balance. The unique presence of uncoupling protein (UCP) permits BAT to expend calories unrelated to the performance of work with the net result being the generation of heat. The role of BAT in mediating diet-induced thermogenesis had led to the suggestion that BAT activity contributes to metabolic inefficiency and, as such, might provide a cellular and molecular explanation for protection from obesity. In order to directly test this hypothesis, we recently created mice with isolated BAT deficiency by using a suicide DNA transgenic vector in which regulatory elements of the UCP gene were used to drive brown fat specific expression of diptheria toxin A-chain (DTA). Transgenic mice are characterized by reduced energy expenditure and marked obesity, associated with insulin resistance and NIDDM with both receptor and post-receptor components. Feeding of a "Western diet" which derives 41% of its calories from fat leads to a synergistic effect on the development of obesity and its accompanying disorders in transgenics. The results of our studies support a critical role for BAT in the nutritional homeostasis of mice and suggest that the intact thermogenic function of BAT is required for protection from diet induced obesity. Obese UCP-DTA mice have many features in common with obesity as it appears in most humans, and should therefore be a useful model that may aid studies of the pathogenesis and treatment of human obesity, NIDDM and their complications. PMID: 9558722 [PubMed - indexed for MEDLINE] 5771. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404. Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Emilien G(1), Maloteaux JM. Author information: (1)Wyeth Ayerst Research, European CR. and D Department, Paris La Défense, France. Beta-adrenoceptors are members of a large family of hormone and neurotransmitter receptors that initiate their biological function by coupling to GTP-binding regulatory proteins. beta-Adrenoceptors can be subdivided into two main subgroups, designated beta1 and beta2. Atypical beta-adrenoceptors or beta3-adrenoceptors, which are present on adipocytes, have been demonstrated pharmacologically. Their function in adipose tissue is currently being investigated. Beta2-adrenoceptor agonists have played a key role in the treatment of asthma for some 30 years, being used for the relief and prophylaxis of symptoms. There is, however, no evidence that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. In neuropsychiatry, beta-adrenoceptor antagonists have been used for the treatment of acute stress reactions and generalised anxiety, essential tremor and prophylaxis of migraine. In general, they are effective in anxiety disorders if the somatic symptoms are not extreme. For prophylactic treatment of migraine, beta-adrenoceptor antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs of first choice. In cardiology, beta-adrenoceptor antagonists are an important class for the treatment of high blood pressure, arrhythmias and angina pectoris, and for prevention of myocardial infarction. With chronic treatment, they reduce mortality in hypertension and prolong survival in patients with coronary heart disease. PMID: 9551698 [PubMed - indexed for MEDLINE] 5772. Mol Cell Biochem. 1998 Mar;180(1-2):53-7. Metabolic disturbances in diabetic cardiomyopathy. Rodrigues B(1), Cam MC, McNeill JH. Author information: (1)Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada. It has been established that diabetes results in a cardiomyopathy, and increasing evidence suggests that an altered substrate supply and utilization by cardiac myocytes could be the primary injury in the pathogenesis of this specific heart muscle disease. For example, in diabetes, glucose utilization is insignificant, and energy production is shifted almost exclusively towards beta-oxidation of free fatty acids (FFA). FFA's are supplied to cardiac cells from two sources: lipolysis of endogenous cardiac triglyceride (TG) stores, or from exogenous sources in the blood (as free acid bound to albumin or as TG in lipoproteins). The approximate contribution of FFA from exogenous or endogenous sources towards beta-oxidation in the diabetic heart is unknown. In an insulin-deficient state, adipose tissue lipolysis is enhanced, resulting in an elevated circulating FFA. In addition, hydrolysis of the augmented myocardial TG stores could also lead to high tissue FFA. Whatever the source of FFA, their increased utilization may have deleterious effects on myocardial function and includes the abnormally high oxygen requirement during FFA metabolism, the intracellular accumulation of potentially toxic intermediates of FFA, a FFA-induced inhibition of glucose oxidation, and severe morphological changes. Therapies that target these metabolic aberrations in the heart during the early stages of diabetes could potentially delay or impede the progression of more permanent sequelae that could ensue from otherwise uncontrolled derangements in cardiac metabolism. PMID: 9546630 [PubMed - indexed for MEDLINE] 5773. Br J Nutr. 1998 Feb;79(2):117-28. Utilization of lipids during exercise in human subjects: metabolic and dietary constraints. Brouns F(1), van der Vusse GJ. Author information: (1)Department of Human Biology, Nutrition Toxicology and Environment Research Institute, Maastricht, The Netherlands. F.Brouns@hb.unimaas.nl During endurance exercise, skeletal muscle relies mainly on both carbohydrate (CHO) and fat oxidation to cover energy needs. Numerous scientific studies have shown that increasing the exercise intensity leads to a progressive utilization of CHO. The latter will induce a state of glycogen depletion which is generally recognized as being a limiting factor for the continuation of strenuous exercise. Different dietary interventions have been proposed to overcome this limitation. A high-CHO diet during periods of intense training and competition, as well as CHO intake during exercise, are known to maintain a high rate of CHO oxidation and to delay fatigue. However, it has been recognized also that enhancing fatty acid (FA) oxidation during exercise induces a reduced rate of glycogen degradation, resulting in an improved endurance capacity. This is most strikingly observed as a result of frequent endurance exercise which improves a number of factors known to govern the FA flux and the oxidative capacity of skeletal muscle. Such factors are: (1) blood flow and capillarization; (2) lipolysis of triacylglycerol (TAG) in adipose tissue and circulating TAG and transport of FA from blood plasma to the sarcoplasm; (3) availability and rate of hydrolysis of intramuscular TAG; (4) activation of the FA and transport across the mitochondrial membrane; (5) the activity of enzymes in the oxidative pathway; (6) hormonal adaptations, i.e. sensitivity to catecholamines and insulin. The observation that the plasma FA concentration is an important factor in determining the rate of FA oxidation, and that some dietary factors may influence the rate of FA supply to muscle as well as to the mitochondria, has led to a number of dietary interventions with the ultimate goal to enhance FA oxidation and endurance performance. It appears that experimental data are not equivocal that dietary interventions, such as a high-fat diet, medium-chain TAG-fat emulsions and caffeine intake during exercise, as well as L-carnitine supplementation, do significantly enhance FA oxidation during exercise. So far, only regular endurance exercise can be classified as successful in achieving adaptations which enhance FA mobilization and oxidation. PMID: 9536855 [PubMed - indexed for MEDLINE] 5774. Ann Pharmacother. 1998 Mar;32(3):337-48. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Johnson MD(1), Campbell LK, Campbell RK. Author information: (1)College of Pharmacy, Washington State University, Spokane 99204, USA. johnsonm@mail.wsu.edu Comment in Ann Pharmacother. 1998 Oct;32(10):1111. Ann Pharmacother. 1998 Oct;32(10):1111-2. OBJECTIVE: To introduce troglitazone (CS-045, Rezulin), a new oral antidiabetic agent and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE database search was completed to identify relevant articles including reviews, recent studies and abstracts, and data from Parke-Davis. STUDY SELECTION: Due to the small number of published human studies available, some data are derived from animal studies and abstracts of human studies. Studies and abstracts chosen summarize the clinical action of troglitazone in healthy volunteers, in subjects with impaired glucose tolerance, and in patients with diabetes mellitus. Three of the six published human studies used subjects in a placebo-controlled, multicenter, randomized environment (type 2 diabetic patients or obese subjects with insulin resistance). DATA EXTRACTION: All clinical trials available, including unpublished reports, were reviewed. DATA SYNTHESIS: Troglitazone is the first member of a new class of medications, the thiazolidinediones, to be approved for clinical use. Troglitazone increases insulin sensitivity in skeletal muscle and in hepatic and adipose tissue. It has been shown to decrease hepatic glucose output while having no effect on stimulating insulin secretion from the pancreatic beta-cells. Its metabolic effects decrease fasting and postprandial hyperglycemia, insulin concentrations, and triglyceride concentrations, while increasing high-density lipoprotein concentrations. There is some evidence, based on short-term trials, that troglitazone causes only minimal decreases in glycosylated hemoglobin A1C (HbA1C) concentrations. Data suggest that troglitazone decreases impaired glucose tolerance in nondiabetic obese subjects and leads to a reduction in both systolic and diastolic blood pressure in hypertensive type 2 diabetes mellitus patients. Troglitazone has a mild adverse effect profile, with rare instances of abnormal liver function tests. CONCLUSIONS: Troglitazone appears to be a safe, effective, and useful new agent in the treatment of insulin-requiring type 2 diabetes mellitus patients, although its HbA1C-lowering effects have been minimal in short-term trials, and its insulin dosage-reduction activity remains unclear. The Food and Drug Administration has also approved its use as monotherapy and in combination with sulfonylureas for patients with type 2 diabetes. It may have use in the treatment of patients with impaired glucose tolerance, but more clinical experience is needed before definitive conclusions can be made. The role of troglitazone therapy in diabetes mellitus and impaired glucose intolerance will continue to evolve as the results of studies and our clinical experience with this agent become available. PMID: 9533065 [PubMed - indexed for MEDLINE] 5775. Vitam Horm. 1998;54:1-30. Clinical aspects of leptin. Sinha MK(1), Caro JF. Author information: (1)Department of Surgery, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA. Hyperleptinemia is an essential feature of human obesity. Total body fat mass > % body fat > BMI are the best predictors of circulating leptin levels. Although ob gene is differentially expressed in different fat compartments, apart from total body fat, upper or lower body adiposity or visceral fat does not influence basal leptin levels. Similarly, age, basal glucose levels, and ethnicity do not influence circulating leptin levels. Only in insulin-sensitive individuals do basal levels of insulin and leptin correlate positively even after factoring in body fat. Diabetes does not influence leptin secretion in both lean and obese subjects per se. Independent of adiposity, leptin levels are higher in women than in men. This sexual dimorphism is also present in adolescent children. In eating disorders anorexia nervosa and bulimea nervosa, leptin levels are not upregulated but simply reflect BMI and probably body fat. In spite of strong correlation between body fat and leptin levels, there is great heterogeneity in leptin levels at any given index of body fat. About 5% of obese populations can be regarded as "relatively" leptin deficient which could benefit from leptin therapy. Leptin has dual regulation in human physiology. During the periods of weight maintenance, when energy intake and energy output are equal, leptin levels reflect total bodyfat mass. However, in conditions of negative (weight-loss programs) and positive (weight-gain programs) energy balances, the changes in leptin levels function as a sensor of energy imbalance. This latter phenomenon is best illustrated by short-term fasting and overfeeding experiments. Within 24 h of fasting leptin levels decline to approximately 30% of initial basal values. Massive overfeeding over a 12-h period increases leptin levels by approximately 50% of initial basal values. Meal ingestion does not acutely regulate serum leptin levels. A few studies have shown a modest increase in leptin secretion at supraphysiological insulin concentrations 4-6 h following insulin infusion. Under in vitro conditions, insulin stimulates leptin production only after four days in primary cultures of human adipocytes, which is apparently due to its trophic effects and an increased fat-cell size. Similar to other hormones, leptin secretion shows circadian rhythm and oscillatory pattern. The nocturnal rise of leptin secretion is entrained to mealtime probably due to cumulative hyperinsulinemia of the entire day. Like other growth factors and cytokines, leptin binding proteins including soluble leptin receptor are present in human serum. In lean subjects, the majority of leptin circulates in the bound form whereas in obese subjects, the majority of leptin is present in the free form. When free-leptin levels are compared between lean and obese subjects, even more pronounced hyperleptinemia in obesity is observed than that reported by measuring total leptin levels. During short-term fasting, free-leptin levels in lean subjects decrease in much greater proportion than those in obese subjects. In lean subjects with a relatively small energy store and particularly during food deprivation, leptin circulating predominantly in the bound form could be the mechanism to restrict its availability to hypothalamic leptin receptors for inhibiting leptin's effect on food intake and/or energy metabolism. Unlike marked changes in serum leptin, CSF leptin is only modestly increased in obese subjects and the CSF leptin/serum leptin ratio decreases logarithmically with increasing BMI. If CSF leptin levels are any indication of brain interstitial fluid levels, then hypothalami of obese subjects are not exposed to abnormally elevated leptin concentrations. In the presence of normal leptin receptor (functional long form, i.e., OB-Rb) mRNA expression and in the absence of leptin receptor gene mutations, it is logical to assume defective leptin signaling and/or impaired affector system(s) are the likely causes of leptin resistance in PMID: 9529971 [PubMed - indexed for MEDLINE] 5776. Neurosurgery. 1998 Mar;42(3):639-43. Lipomatous glioneurocytoma of the posterior fossa with divergent differentiation: case report. Alleyne CH Jr(1), Hunter S, Olson JJ, Barrow DL. Author information: (1)Department of Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia, USA. OBJECTIVE AND IMPORTANCE: We report a case of a posterior fossa neuroepithelial tumor with unusual clinical presentation, magnetic resonance imaging appearance, and morphological features. CLINICAL PRESENTATION: This 66-year-old man presented with a history of gait ataxia, dizziness, and tinnitus and was found to have a large tumor in the posterior fossa and cerebellopontine angle. INTERVENTION: Gross total excision of the tumor was accomplished. Histologically, the most unique features were macrovesicular accumulations of lipid, giving the tumor (at least focally) an appearance virtually identical to that of mature adipose tissue. Evidence of biphasic neuronal and glial differentiation was noted by immunohistochemistry and electron microscopy. CONCLUSION: A literature review is presented. Diagnostically, this neoplasm seems to fit in a unique group of rarely described, lipomatous neuroectodermal tumors that show divergent neuronal and glial differentiation. PMID: 9526999 [PubMed - indexed for MEDLINE] 5777. Hosp Pract (1995). 1998 Mar 15;33(3):55-9, 62-5, 69-70 passim. The genetics of obesity. Hirsch J(1), Leibel RL. Author information: (1)Rockefeller University, New York, USA. Five genes have been identified, each capable of causing obesity in mice and each with a human homologue. One of them codes for a signal expressed by adipose tissue, and another for the signal's brain receptor. The rest reveal brain pathways probably downstream from the receptor. Together, the genes offer glimpses of an intricate system that defends adipose stores--and in some persons maintains an unhealthful set-point. PMID: 9522833 [PubMed - indexed for MEDLINE] 5778. Diabetes. 1998 Feb;47(2):159-69. Glucagon-like peptides. Drucker DJ(1). Author information: (1)Department of Medicine, the Toronto Hospital, Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada. d.drucker@utoronto.ca Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides. PMID: 9519708 [PubMed - indexed for MEDLINE] 5779. J Air Waste Manag Assoc. 1998 Feb;48(2):157-65. Health impact of polychlorinated dibenzo-p-dioxins: a critical review. Mukerjee D(1). Author information: (1)National Center for Environmental Assessment, United States Environmental Protection Agency, Cincinnati, Ohio, USA. Polychlorinated dibenzo-p-dioxins (PCDDs), commonly known as dioxins, form as unwanted impurities in the manufacturing of chlorophenol and its derivatives--pulp and paper--and in the combustion of municipal, sewage-sludge, hospital, and hazardous waste. Combustion, in presence of a chlorine donor, seems to be a major source of these compounds. High levels of dioxins are also emitted from metallurgical industries including copper smelters, electric furnaces in steel mills, and wire reclamation incinerators. Trace levels are detectable in emissions from motor vehicles using leaded gasoline or diesel fuel, in forest fires, and in residential wood burning. Extremely persistent and widely distributed in the environment, PCDDs have been detected in all three primary and many secondary media. Releases into the air occur mainly from combustor emissions. Atmospheric dispersion, deposition, and subsequent accumulation in the food chain seem to be the major pathways of exposure to the general population. Residues of these chemicals have been detected in soil, sediment, fish, meat, cow's milk, human adipose tissue, and mothers' milk. In general, these chemicals have high lipophilicity. The elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans is approximately 7-11 years. Very little human toxicity data from exposure to PCDDs are available. Health-effect data obtained from occupational settings in humans are based on exposure to chemicals contaminated with TCDD. It produces a spectrum of toxic effects in animals and is one of the most toxic chemicals known. Most of the toxicity data available on TCDD are from high-dose oral exposures to animals. Very few percutaneous and no inhalation exposure data are available in the literature. There is a wide range of difference in sensitivity to PCDD lethality in animals. The signs and symptoms of poisoning with chemicals contaminated with TCDD in humans are analogous to those observed in animals. Dioxin exposures to humans are associated with increased risk of severe skin lesions such as chloracne and hyperpigmentation, altered liver function and lipid metabolism, general weakness associated with drastic weight loss, changes in activities of various liver enzymes, depression of the immune system, and endocrine- and nervous-system abnormalities. It is a potent teratogenic and fetotoxic chemical in animals. A very potent promoter in rat liver carcinogenesis, TCDD also causes cancers of the liver and other organs in animals. Populations occupationally or accidentally exposed to chemicals contaminated with dioxin have increased incidences of soft-tissue sarcoma and non-Hodgkin's lymphoma. No comprehensive studies have been conducted to determine any health impact to the general population from environmental exposure to PCDDs. This paper presents a brief review of relevant animal and human data for projecting any possible health effects from environmental exposures to PCDDs. PMID: 9517323 [PubMed - indexed for MEDLINE] 5780. J Dairy Res. 1998 Feb;65(1):155-73. Body score of dairy cows. Broster WH(1), Broster VJ. Author information: (1)Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth, UK. Body CS measurement, based on a standardized technique leading to a numerical assessment, provides a cheap, easily applied measure of fatness in cattle and hence an immediate absolute appraisal that avoids the problems of live weight. The scale is limited and the divisions are coarse. The nutritional significance of CS/C has received considerable research attention. Higher CS/C is associated with smaller feed intake in early lactation, increased loss of CS, increased fat content of milk, especially when the general content is low, and slightly reduced milk protein content. Evidence on the effect of CS/C on subsequent MY is conflicting: some experiments have shown a benefit from increased CS/C but others have not. This outcome may depend on the plane of nutrition after calving. CS/C values > 3.25 have led to small decreases in MY. During lactation, CS responds to change in plane of nutrition in parallel with MY, milk protein content, and live weight. Some but not all the available evidence indicates that the fall in CS in early lactation may be limited physiologically, and subsequent recovery of body reserves may be characterized by a compensatory partition of nutrients to body as well as a response to increased plane of nutrition relative to requirements for milk production. Further investigation is required regarding application of CS to mid to late lactation, particularly partition of nutrients between milk and body, to multiple lactations, to health and fertility, and to CS in relation to the cow potential. PMID: 9513062 [PubMed - indexed for MEDLINE] 5781. Lancet. 1998 Mar 7;351(9104):737-42. Leptin. Auwerx J(1), Staels B. Author information: (1)Laboratoire de Biologie des Régulations chez les Eucaryotes (U325 INSERM), Département d'Athérosclérose, Institut Pasteur, Lille, France. johan.auwerx@paster-lille.fr Leptin (from the Greek leptos=thin) was identified only 3 years ago. It has attracted huge attention both scientifically, with more than 600 publications, and in the media, where this protein has been portrayed as the way to a cure for obesity. Indeed, leptin was first described as an adipocyte-derived signalling factor, which, after interaction with its receptors, induced a complex response including control of bodyweight and energy expenditure. Leptin seems in addition to its role in metabolic control to have important roles in reproduction and neuroendocrine signalling. Human obesity is a complex disorder, with many factors playing a part; the pathophysiology of leptin is not as simple as it seems to be in rodent models of obesity. PMID: 9504534 [PubMed - indexed for MEDLINE] 5782. Curr Opin Lipidol. 1998 Feb;9(1):35-40. Abdominal obesity. Carey DG(1). Author information: (1)Institute of Clinical Nutrition and Metabolism in the Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia. The application of magnetic resonance imaging and computed tomography to obesity research has changed the focus from body mass and skinfold thickness to abdominal fat mass and visceral adiposity. Intra-abdominal fat constitutes less than 20% of total body fat but is a major determinant of fasting and postprandial lipid availability because of its physiological (lipolytic rate and insulin resistance) and anatomical (portal drainage) properties. High levels of serum free fatty acids, as a result of abdominal obesity, cause excessive tissue lipid accumulation and contribute to dyslipidaemia, beta cell dysfunction, and hepatic and peripheral insulin resistance. An individual's risk of non-insulin dependent diabetes mellitus and cardiovascular disease relates closely to the inheritance of central obesity and susceptibility to tissue lipotoxicity. PMID: 9502333 [PubMed - indexed for MEDLINE] 5783. J Nutr. 1998 Feb;128(2 Suppl):381S-385S. Body composition changes during lactation are highly variable among women. Butte NF(1), Hopkinson JM. Author information: (1)USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Changes in body weight and composition in response to the metabolic load imposed by lactation are highly variable among and within diverse populations. In most reports, rates of weight loss did not differ between lactating and nonlactating women. Despite differences in the hormonal milieu between lactating and nonlactating women, only subtle short-term differences were observed in postpartum changes in body composition. Regional patterns of fat deposition and mobilization did not differ between lactating and nonlactating women in most studies. Changes in body composition during lactation are responses to a sequence of complex neuroendocrine and biochemical stimuli that may be significantly modified by environmental factors. Gestational weight gain was the strongest determinant of postpartum weight and fat mass change, which supports the premise that biological mechanisms are aimed at restoring prepregnancy body weight and composition. PMID: 9478031 [PubMed - indexed for MEDLINE] 5784. J Clin Endocrinol Metab. 1998 Mar;83(3):902-10. Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity. Halleux CM(1), Servais I, Reul BA, Detry R, Brichard SM. Author information: (1)Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, Brussels, Belgium. The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhibitory effect was already detectable at 10 nmol/L insulin and was also observed in subcutaneous fat. Although a lowering of intracellular cAMP concentrations is involved in some of the effects of insulin on adipose tissue, this cannot account for the present finding, because the addition of cAMP to the medium also decreased ob mRNA and leptin secretion (regardless of whether dexamethasone was present). In conclusion, glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene and could contribute to the metabolic abnormalities associated with central obesity by para/endocrine actions of hyperleptinemia on adipocytes and liver. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion, and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance. PMID: 9506746 [PubMed - indexed for MEDLINE] 5785. J Clin Endocrinol Metab. 1998 Mar;83(3):847-50. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. Fried SK(1), Bunkin DA, Greenberg AS. Author information: (1)Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey 08903, USA. The purpose of this study was to determine whether human adipocytes from different depots of obese subjects produce interleukin-6 (IL-6) and whether IL-6 release is regulated by glucocorticoids. Fragments of omental and abdominal sc adipose tissue released immunodetectable IL-6 into the medium during acute incubations. Omental adipose tissue released 2-3 times more IL-6 than did sc adipose tissue. Isolated adipocytes prepared from these tissues also released IL-6 (omental > sc), but this accounted for only 10% of the total tissue release. Culture of adipose tissue fragments for 7 days with the glucocorticoid dexamethasone markedly suppressed IL-6 production. These data show for the first time that substantial quantities of IL-6 (up to 75 ng/mL) accumulate in the medium during incubations of both adipocytes and adipose tissue. Although little is known about the effects of IL-6 on adipose tissue, one action is a down-regulation of adipose tissue lipoprotein lipase. The regulated production of this multifunctional cytokine may modulate regional adipose tissue metabolism and may contribute to the recently reported correlation between serum IL-6 and the level of obesity. PMID: 9506738 [PubMed - indexed for MEDLINE] 5786. J Invest Dermatol. 1998 Mar;110(3):238-46. Transcription factors C/EBP alpha, C/EBP beta, and CHOP (Gadd153) expressed during the differentiation program of keratinocytes in vitro and in vivo. Maytin EV(1), Habener JF. Author information: (1)Department of Dermatology, Massachusetts General Hospital, Boston 02114, USA. CCAAT-enhancer binding proteins (C/EBP) are basic region/leucine zipper (bZIP) transcription factors selectively expressed during the differentiation of liver, adipose tissue, blood cells, and the endocrine pancreas. Here we show that C/EBP isoforms are differentially expressed in the skin. BALB/MK keratinocytes incubated in 0.12 mM calcium medium undergo a differentiation program featuring growth-arrest at 24-48 h, keratin K10 gene expression beginning at 24 h, and apoptosis commencing at 48 h. Within this framework, western immunoblot analysis and immunohistochemistry reveal that C/EBP alpha increases 5-fold at 1-2 d and remains elevated, C/EBP beta rises 2-fold at 2-4 d and gradually falls, and CHOP rises 9-fold in the first 24 h then returns rapidly to baseline. Several products of alternative translation are observed in BALB/MK cells, i.e., 42 kDa and 30 kDa forms of C/EBP alpha, and 32 kDa and 20 kDa forms of C/EBP beta. By immunohistologic examination of human, rat, and mouse skin, all three transcription factors are highly expressed within epithelial compartments in a spatially restricted distribution. C/EBP alpha is concentrated in the upper epidermis in a predominantly cytoplasmic location within cells, whereas the highest levels of C/EBP beta and CHOP are seen in the mid-epidermis, mainly within nuclei. High levels of C/EBP beta and CHOP (but not C/EBP alpha) are also observed in hair follicles and sebaceous glands. The identity of these factors in the epidermis is confirmed by western immunoblot analyses. In summary, C/EBP are expressed in a differentiation-associated manner in the skin, and may play an important role in regulating one or more aspects of the epidermal differentiation program. PMID: 9506442 [PubMed - indexed for MEDLINE] 5787. Am J Clin Nutr. 1998 Mar;67(3 Suppl):531S-534S. Diet effects on fatty acid metabolism in lean and obese humans. Jensen MD(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. Jensen.Michael@Mayo.edu The primary role of adipose tissue is to serve as a temporary storage site for energy in the form of nonesterified fatty acids. The regulation of adipose tissue lipolysis, which allows the appropriate delivery of fatty acids to meet the lipid fuel needs of lean tissue, is affected by the amount and the location of fat, as well as by the diet. Excessive accumulation of triacylglycerol fatty acids (obesity) is associated with an increased risk of insulin resistance, diabetes, hyperlipidemia, and hypertension. Some of these abnormalities may be related to dysregulation of fatty acid metabolism. Body fat distribution exerts a major influence on endogenous nonesterified fatty acid metabolism, which may in turn mediate some of the metabolic abnormalities associated with upper-body obesity. The effects of diet on fatty acid metabolism can be dramatic and are not the same in upper-body and lower-body obesity. Different obesity phenotypes may respond differently to low-fat, high-complex-carbohydrate diets, and the response is further modified depending on whether the diet is isoenergetic or restricted in energy. PMID: 9497165 [PubMed - indexed for MEDLINE] 5788. Am J Clin Nutr. 1998 Mar;67(3 Suppl):527S-530S. Effect of lipid oxidation on glucose utilization in humans. Jéquier E(1). Author information: (1)Institute of Physiology, Faculty of Medicine, University of Lausanne, Switzerland. The mechanisms responsible for the competition between glucose and fatty acids as oxidative fuels are not yet completely understood in humans. Maintenance of plasma fatty acid concentrations by means of lipid and heparin infusion during hyperinsulinemic, euglycemic clamps in humans first suppresses glucose oxidation and only later decreases nonoxidative glucose disposal; muscle pyruvate dehydrogenase activity is inhibited when plasma fatty acid concentrations are maintained during hyperinsulinemic, euglycemic clamps. The maintenance of plasma fatty acid concentrations impairs insulin-stimulated muscle glucose uptake only if fatty acid uptake by skeletal muscles is increased. The role of hyperglycemia in glucose-fatty acid competition has recently been emphasized. Fatty acid utilization by muscle is impaired in patients with type 2 diabetes mellitus during fasting hyperglycemia: both lipid oxidation and uptake of plasma fatty acids by skeletal muscle are impaired during postabsorptive conditions. Hyperglycemia indirectly activates pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. The ability of increased glucose availability to stimulate glucose oxidation and reduce lipid oxidation by skeletal muscle can be considered a corollary of the Randle glucose-fatty acid cycle. It can be concluded that within a reasonable range of carbohydrate-to-fat ratios, the addition of fat to a meal does not decrease postprandial carbohydrate oxidation. Furthermore, high-fat meals do not promote fat oxidation leading to fat storage in adipose tissue. PMID: 9497164 [PubMed - indexed for MEDLINE] 5789. Am J Clin Nutr. 1998 Mar;67(3 Suppl):505S-512S. Dietary fat, genetic predisposition, and obesity: lessons from animal models. West DB(1), York B. Author information: (1)Obesity, Diabetes, and Metabolism Section, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808, USA. westdb@mhs.pbrc.edu This review focuses on animal studies that examine the role of dietary fat in obesity. It is evident from animal experiments that the percentage of energy derived from fat in the diet is positively correlated with body fat content. With few exceptions, obesity is induced by high-fat diets in monkeys, dogs, pigs, hamsters, squirrels, rats, and mice. The mechanisms responsible for this correlation between body fat and dietary fat content are not clear. It has been proposed that a high-fat diet produces hyperphagia, which is solely responsible for the increased body fat content. However, several studies in various rodent models showed that increased body fat content still results when the hyperphagia is prevented. This suggests that some metabolic effects of high-fat diets, independent of hyperphagia, may also be contributing to the obesity induced by high-fat diets. It is also clear from animal studies that genetic factors significantly modulate the body's response to diets high in fat-derived energy. In contrast with the animal studies, studies in humans that have examined the relation between dietary fat content and body fat are inconclusive. The limitations of cross-sectional studies, the lack of controlled feeding trials, and the importance of genetic variation in response explain the absence of conclusive evidence. The lessons learned from animal models point to dietary fat as one potentially important component in the etiology of human obesity. Additional comprehensive studies are warranted to determine the role of dietary fat in the etiology of human obesity. PMID: 9497161 [PubMed - indexed for MEDLINE] 5790. Clin Exp Pharmacol Physiol. 1998 Jan;25(1):65-9. Cardiovascular consequences of obesity: role of leptin. Haynes WG(1), Morgan DA, Walsh SA, Sivitz WI, Mark AL. Author information: (1)Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City 52242, USA. william-g-haynes@uiowa.edu 1. Several mechanisms have been implicated in the association between obesity and hypertension, including salt-sensitivity, insulin resistance and sympathetic activation. Obese animals and humans exhibit exaggerated blood pressure responses to increases in salt intake. 2. Although insulin resistance is common in obesity, it is clear that abnormal insulin action is not the sole or sufficient cause of hypertension in obesity. Obesity is associated with increased activity of the sympathetic nervous system. Sympathetic blockade has been reported to attenuate sodium retention and hypertension in experimental models of obesity. 3. The mediators responsible for salt sensitivity, insulin resistance and sympathetic activation in obesity remain unclear. 4. The novel protein hormone leptin is produced almost exclusively by adipose tissue and acts in the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. 5. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, renal and endocrine function. We have shown that leptin increases sympathetic nerve activity to kidney, hindlimb and adrenal gland, in addition to brown adipose tissue. 6. Despite this sympathoexcitatory action, acute systemic administration of leptin does not acutely increase arterial pressure or heart rate in anaesthetized animals. This may reflect opposing antihypertensive actions of leptin. For example, leptin increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin increases systemic insulin sensitivity, even in the absence of weight loss. 7. In conclusion, leptin may act as a mediator linking body adiposity with changes in insulin action, sympathetic neural outflow and renal sodium excretion. Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity. PMID: 9493562 [PubMed - indexed for MEDLINE] 5791. Clin Exp Pharmacol Physiol. 1998 Jan;25(1):58-64. Abnormal kidney function as a cause and a consequence of obesity hypertension. Hall JE(1), Brands MW, Henegar JR, Shek EW. Author information: (1)Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson 39216-4505, USA. jeh@fiona.umsmed.edu 1. Obesity is the most common nutritional disorder in the US and is a major cause of human essential hypertension. Although the precise mechanisms by which obesity raises blood pressure (BP) are not fully understood, there is clear evidence that abnormal kidney function plays a key role in obesity hypertension. 2. Obesity increases tubular reabsorption and this shifts pressure natriuresis towards higher BP. The increased tubular reabsorption is not directly related to hyperinsulinaemia, but is closely linked to activation of the sympathetic and renin-angiotensin systems, and possible changes in intrarenal physical forces caused by medullary compression due to accumulation of adipose tissue around the kidney and increased extracellular matrix within the kidney. 3. Obesity is also associated with marked renal vasodilation and increased glomerular filtration rate, which are compensatory responses that help overcome the increased tubular reabsorption and maintain sodium balance. However, chronic renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli which, along with increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. Because obesity is a primary cause of essential hypertension as well as type II diabetes, there is good reason to believe that obesity may also be the most frequent cause of end-stage renal disease. 4. Future research is needed to determine the mechanisms by which excess weight gain activates the neurohumoral systems and alters renal structure and function. Because of the high prevalence of obesity in most industrialized countries, unravelling these mechanisms will likely provide a better understanding of the pathophysiology of human essential hypertension and chronic renal failure. PMID: 9493561 [PubMed - indexed for MEDLINE] 5792. Clin Exp Pharmacol Physiol. 1998 Feb;25(2):79-87. Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications. Donnelly R(1), Qu X. Author information: (1)Department of Pharmacology, University of Sydney, New South Wales, Australia. richard.donnelly@nottingham.ac.uk 1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development. PMID: 9493493 [PubMed - indexed for MEDLINE] 5793. Proc Nutr Soc. 1997 Nov;56(3):1067-81. Stable isotopes in adipose tissue fatty acids as indicators of diet in arctic foxes (Alopex lagopus). Pond CM(1), Gilmour I. Author information: (1)Department of Biology, Open University, Milton Keynes. PMID: 9483672 [PubMed - indexed for MEDLINE] 5794. Nutr Rev. 1998 Jan;56(1 Pt 1):29-30. Release of stored retinol from adipocytes. Wolf G(1). Author information: (1)Department of Nutritional Sciences, University of California, Berkeley 94720-3104, USA. Adipose tissue is second only to liver as a retinol depot. Retinol is stored there is part as retinyl esters. In cultured mouse adipocytes, a hormone-sensitive lipase hydrolyzes these esters upon cAMP stimulation, with free retinol being released into the medium. PMID: 9481117 [PubMed - indexed for MEDLINE] 5795. Rev Med Liege. 1997 Nov;52(11):703-8. [The adrenergic beta-3 receptor: a role in the genetic predisposition to obesity and diabetes?]. [Article in French] Luyckx F(1), Scheen AJ, Gielen J, Lefèbvre PJ. Author information: (1)Service de Chimie Médicale, Université de Liège. PMID: 9480495 [PubMed - indexed for MEDLINE] 5796. Eur J Med Res. 1997 Nov 28;2(11):457-64. Peroxisome proliferator-activated receptor gamma: A key regulator of adipogenesis and systemic insulin sensitivity. Spiegelman BM(1). Author information: (1)Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Bruce_Spiegelman@dfci.harvard.edu The adipose cell is now known to play a complex role in energy homeostasis, storing energy and signaling to other tissues concerning the state of energy balance. The past several years have seen an explosive increase in our knowledge of the transcriptional basis of adipocyte differentiation. This review describes the role of peroxisome proliferator-activated receptor gamma in this process, and describes how other transcription factors may affect adipogenesis by modulating PPARgamma amount or activity. Furthermore, PPARgamma and other adipogenic transcription factors provide a focus for beginning to understand how various hormones and metabolites influence the development of this tissue in vivo. PMID: 9385114 [PubMed - indexed for MEDLINE] 5797. Poult Sci. 1998 Jan;77(1):118-23. Lysine: Specific effects of lysine on broiler production: comparison with threonine and valine. Leclercq B(1). Author information: (1)INRA, Station de Recherches Avicoles, Nouzilly, France. Lysine exerts specific effects on body composition at dietary levels higher than that required for maximum growth rate, which also results in an improved feed conversion ratio (FCR). As a consequence of these differences, it becomes apparent that there is a hierarchy of requirements. The requirement for maximum gain is lower than that for breast meat (BM) yield, which is lower than the requirement for FCR; and lastly, the requirement for minimum abdominal fat (AF) percentage is the highest of all. Threonine, on the other hand, does not appear to exhibit so pronounced an effect on body composition, whereas, in the case of valine, these effects seem to be absent. These different effects of lysine, threonine, and valine can induce different amino acid requirement profiles according to the criteria used for determining the requirement. Moreover the particular mathematical model being used to calculate amino acid requirements can also influence amino acid requirement profiles. PMID: 9469761 [PubMed - indexed for MEDLINE] 5798. Poult Sci. 1998 Jan;77(1):111-7. Lysine: Making progress in the nutrition of broilers. Gous RM(1). Author information: (1)Department of Animal Science and Poultry Science, University of Natal, Scottsville, South Africa. Genotypes used in the broiler industry have changed significantly in the past 40 yr, and continue to change at the same rate today. Different selection criteria are used by the major breeding companies, leading to widely different genotypes being available to the broiler industry, yet nutritionists have largely ignored these changes when formulating feeds and designing feeding strategies for broilers. The method presently used to formulate feeds for broilers relies on tables of nutrient requirements for different phases in the life of the broiler. These tables do not reflect either the requirements of broilers capable of growing at different rates, or that these strains have different genetically determined degrees of fatness. No further progress can be made with this approach. Progress can be made only by integrating information about the bird, the feed, and the environment into an accurate theory that can then be used in a simulation model to make accurate predictions of feed intake and growth rate for any given bird, in any given state, and in any given environment. With such a model, it is possible to determine the most economical method of feeding broilers under a wide range of economic conditions. The only defensible way in which nutritionists can improve the efficiency of feeding broilers is by the use of simulation modeling. PMID: 9469760 [PubMed - indexed for MEDLINE] 5799. Diabetes Metab. 1997 Nov;23 Suppl 4:16-34. [Interrelation of visceral fat and muscle mass in non insulin-dependent diabetes (type II): practical implications]. [Article in French] Brun JF(1), Bringer J, Raynaud E, Renard E, Orsetti A. Author information: (1)Service d'Endocrinologie, Hôpital Lapeyronie, Montpellier. Insulin resistance, which is found in 85-95% of non-insulin-dependent diabetes mellitus (NIDDM) patients, results from three factors: genetic background (which has been widely investigated), nutritional status (mostly obesity and fat distribution) and exercise. Upper body obesity, which can be found in 85% of these subjects, can increase muscular insulin resistance through several mechanisms, the best known being a free fatty acid-induced decrease in intracellular free CoA/acylCoA that inhibits the stimulatory effect of insulin on glycolysis, glucose transport across cell membrane, and glycogen storage. However, muscle insulin resistance in NIDDM exists before adiposity and is likely to induce it. Actually, muscles of subjects at risk for NIDDM exhibit a very early defect in both glycogen storage ability and free fatty acid oxidation capacity that can impair fuel utilization and increase fat storage. Regular exercise induces muscular metabolic changes which can compensate for those diabetogenic defects and thus prove useful in the management of NIDDM. Moreover, exercise has been shown to prevent subjects at risk for NIDDM from developing overt diabetes. PMID: 9463021 [PubMed - indexed for MEDLINE] 5800. Sports Med. 1998 Jan;25(1):37-62. Quantification of quadriceps and hamstring antagonist activity. Kellis E(1). Author information: (1)Division of Sport and Recreation, University of Northumbria at Newcastle, Newcastle upon Tyne, England. Erratum in Sports Med 1998 Mar;25(3):211. The coactivation of hamstrings and quadriceps, and its relation to knee joint stability and cruciate ligament loading, have been extensively examined over the last decades. The purpose of this review is to present findings on the quantification of antagonist activation around the knee. Coactivation of the quadriceps and hamstrings during many activities has been examined using electromyography (EMG). However, there are several factors that affect antagonist EMG activity, such as the type of muscle action, velocity of the movement, level of effort and angular position. Furthermore, the antagonist EMG can be affected by methodological factors which relate to the data recording, analysis and quantification of the signal. Research has demonstrated that the effect of cross-talk on the hamstrings and quadriceps antagonist EMG depends on electrode size and location, fat layer of the muscles and the technique used to reduce it. There is an inconsistency as to the method used to normalise antagonist EMG depending on the type of movement examined. This makes comparisons between studies difficult and, therefore, further research is recommended. The antagonist function is better represented when the antagonist moment exerted is known; however, the direct measurement of antagonist moments or forces is very difficult. Few studies have used mathematical models to determine the moment or force distribution around the knee, including antagonist forces. This can be attributed to the complexity of the anatomy and function of the knee joint. Despite this, in vivo and in vitro experiments have demonstrated that quadriceps contraction near full extension induces significantly higher anterior shear forces when compared with the forces exerted when the hamstrings act as antagonists, thus indicating the important role of antagonist activity in knee joint stability. However, the magnitude of this contribution to the force distribution around the knee in many activities is unclear. PMID: 9458526 [PubMed - indexed for MEDLINE] 5801. Sports Med. 1998 Jan;25(1):25-35. Exercise in the management of non-insulin-dependent diabetes mellitus. Wallberg-Henriksson H(1), Rincon J, Zierath JR. Author information: (1)Department of Clinical Physiology, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. Erratum in Sports Med 1998 Feb;25(2):130. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) has increased worldwide during the last decades, despite the development of effective drug therapy and improved clinical diagnoses. NIDDM is one of the major causes of disability and death due to the complications accompanying this disease. For the well-being of the patient, and from a public healthcare perspective, the development of effective intervention strategies is essential in order to reduce the incidence of NIDDM and its resulting complications. For the patient, and for society at large, early intervention programmes are beneficial, especially from a cost-benefit perspective. Physical activity exerts pronounced effects on substrate utilisation and insulin sensitivity, which in turn potentially lowers blood glucose and lipid levels. Exercise training also improves many other physiological and metabolic abnormalities that are associated with NIDDM such as lowering body fat, reducing blood pressure and normalising dyslipoproteinaemia. Clearly, regular physical activity plays an important role in the prevention and treatment of NIDDM. Since physical activity has been shown in prospective studies to protect against the development of NIDDM, physical training programmes suitable for individuals at risk for NIDDM should be incorporated into the medical care system to a greater extent. One general determinant in a strategy to develop a preventive programme for NIDDM is to establish a testing programme which includes VO2max determinations for individuals who are at risk of developing NIDDM. Before initiating regular physical training for people with NIDDM, a complete physical examination aimed at identifying any long term complications of diabetes is recommended. All individuals above the age of 35 years should perform an exercise stress test before engaging in an exercise programme which includes moderate to vigorously intense exercise. The stress test will identify individuals with previously undiagnosed ischaemic heart disease and abnormal blood pressure responses. It is important to diagnose proliferative retinopathy, microalbuminuria, peripheral and/or autonomic neuropathy in patients with NIDDM before they participate in an exercise programme. If any diabetic complications are present, the exercise protocol should be modified accordingly. The exercise programme should consist of moderate intensity aerobic exercise. Resistance training and high intensity exercises should only be performed by individuals without proliferative retinopathy or hypertension. Once enrolled in the exercise programme, the patient must be educated with regard to proper footwear and daily foot inspections. Fluid intake is of great importance when exercising for prolonged periods or in warm and humid environments. With the proper motivation and medical supervision, people with NIDDM can enjoy regular physical exercise as a means of enhancing metabolic control and improving insulin sensitivity. PMID: 9458525 [PubMed - indexed for MEDLINE] 5802. Biochem Biophys Res Commun. 1997 Dec 8;241(1):1-6. Regulatory elements in the insulin-responsive glucose transporter (GLUT4) gene. Ezaki O(1). Author information: (1)Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1, Tokyo, Shinjuku-ku, 162, Japan. GLUT4, the insulin responsive-glucose transporter, mediates the rate limiting step of glucose metabolism in skeletal muscle and adipose tissue. GLUT4 expression is up-regulated by exercise training and thyroid hormone treatment and is down-regulated by fasting, streptozotocin-induced diabetes, obesity, high-fat diet, and denervation. Since overexpression of GLUT4 in insulin resistant db/db mice and high-fat diet-fed mice has been observed to dramatically improve glycemic control, increasing GLUT4 expression may be an effective strategy with which to alleviate insulin resistance. This review discusses recent findings on the regulation of the GLUT4 gene and on progress in the identification of regulatory elements in the promoter of the gene. Copyright 1997 Academic Press. PMID: 9405224 [PubMed - indexed for MEDLINE] 5803. Environ Health Perspect. 1997 Nov;105(11):1204-9. Estimating xenobiotic half-lives in humans from rat data: influence of log P. Sarver JG(1), White D, Erhardt P, Bachmann K. Author information: (1)Department of Pharmacology, The University of Toledo, Toledo, OH 43606 USA. The nature of empirical allometric expressions relating dispositional and kinetic parameters for a given xenobiotic across multiple mammalian species is well known. It has also been demonstrated that a simple allometric relationship may be used to predict kinetic parameters for humans based merely on data for multiple xenobiotics from rats. We decided to explore reasons for the variance in the data arising from the latter method. We were particularly interested in learning whether any physicochemical characteristics of xenobiotics might account for outlying data points (i.e., poor prediction of human half-life from rat half-life). We have explored the influence of lipid solubility as reflected by a xenobiotic's log P value because adipose tissue comprises a significantly larger percentage of total body weight in humans than in rats. We used half-life data from the literature for 127 xenobiotics. A data subset of 102 xenobiotics for which we were able to find estimates of log P values, including several with extremely large log P values, was also analyzed. First and second order models, including and excluding log P, were compared. The simplest of these models can be recast as the familiar allometric relationship having the form Y = a(Xb). The remaining models can be seen as extensions of this relationship. Our results suggest that incorporation of log P into the prediction of xenobiotic half-life in humans from rat half-life data is important only for xenobiotics with extremely large log P values such as dioxins and polychlorinated biphenyls. Moreover, a second order model in logarithm of rat half-life accommodates all data points very well, without specifically accounting for log P values. PMCID: PMC1470336 PMID: 9370523 [PubMed - indexed for MEDLINE] 5804. Cancer Epidemiol Biomarkers Prev. 1998 Jan;7(1):65-78. Aromatase inhibitors as potential cancer chemopreventives. Kelloff GJ(1), Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET, Boone CW, Sigman CC. Author information: (1)Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland 20852, USA. Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production. This can be accomplished by inhibiting aromatase, the enzyme that catalyzes the final, rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is of clinical interest for cancer therapy, and selective, potent aromatase inhibitors have been developed. Several of these agents have demonstrated chemopreventive efficacy in animal models. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve as potential chemopreventive agents are the subjects of this review. After background information regarding aromatase is presented, the data for each inhibitor are summarized separately. The discussion focuses on those inhibitors that are clinically available or in clinical trials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane, exemestane, and atamestane. On the basis of results from preclinical studies, aromatase inhibitors may be promising agents for clinical trials in populations at high risk for developing estrogen-dependent cancers. Total suppression of aromatase may have adverse effects, as is evident in postmenopausal women (increased osteoporosis, cardiovascular disease, and urogenital atrophy). However, on the basis of preclinical studies of chemopreventive efficacy and chemotherapeutic applications of aromatase inhibitors showing dose-response efficacy, it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Suppressing local estrogen production may be an alternative strategy, as suggested by the discovery of a unique transcriptional promoter of aromatase gene expression, I.4, in breast adipose tissue. The development of drugs that target this promoter region may be possible. PMID: 9456245 [PubMed - indexed for MEDLINE] 5805. Acta Diabetol. 1997 Dec;34(4):239-44. Glibenclamide: an old drug with a novel mechanism of action? Luzi L(1), Pozza G. Author information: (1)Department of Medicine, San Raphael Scientific Institute, University of Milan, Italy. This review is meant to give to the readers an overview of the pharmacokinetics, pharmacodynamics, mechanism(s) of action and therapeutical indications of the sulfonylurea compound glibenclamide, which is a cardinal drug in the treatment of type 2 diabetes mellitus. Data produced in our own laboratory over the past 15 years will be presented, along with reference to the main literature in the field. As pharmacokinetics is concerned, special emphasis will be placed on the detrimental effect of hyperglycemia in the intestinal absorption of this class of drugs. Both beta-cell and extrapancreatic effects of glibenclamide will be highlighted. The mechanism of action of the drug consists in the inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion. Based on the same mechanism are also the extrapancreatic action of the drug at the liver, skeletal muscle, heart muscle and smooth muscle sites. The newly discovered possible physiological actions of the C-peptide molecule [suggesting a stimulatory effect of C-peptide on the Na+, K+ (ATPase) pump and on diabetic complications], cast a new light on all therapeutic approaches (like sulfonylurea class of compounds and whole pancreas or islet of Langerhans transplantation), which induce/replace both insulin and C-peptide secretion. PMID: 9451465 [PubMed - indexed for MEDLINE] 5806. Biochem Soc Trans. 1997 Nov;25(4):1242-8. Peroxisomal proliferate-activated receptors and the regulation of lipid oxidation and adipogenesis. Smith SA(1). Author information: (1)Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, U.K. PMID: 9449984 [PubMed - indexed for MEDLINE] 5807. Obes Res. 1997 Nov;5(6):650-6. A role for brown adipose tissue in diet-induced thermogenesis. Rothwell NJ(1), Stock MJ. Author information: (1)Department of Physiology, St George's Hospital Medical School, London, UK. Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity. PMID: 9449154 [PubMed - indexed for MEDLINE] 5808. Nihon Rinsho. 1997 Nov;55 Suppl:792-8. [Insulin resistance syndrome, visceral fat syndrome]. [Article in Japanese] Nakamura T(1), Matsuzawa Y. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School. PMID: 9434566 [PubMed - indexed for MEDLINE] 5809. J Pediatr Surg. 1997 Dec;32(12):1771-2. Tumor karyotype differentiates lipoblastoma from liposarcoma. Miller GG(1), Yanchar NL, Magee JF, Blair GK. Author information: (1)Department of Surgery, University of British Columbia, British Columbia's Children's Hospital, Vancouver, Canada. Lipoblastoma is a rare benign pediatric soft tissue tumor that may be difficult to distinguish from a myxoid liposarcoma clinically or histologically. The authors present a case of a progressively growing, locally invasive soft tissue tumor in a child. Tissue culture for cytogenetic study showed a breakpoint in the long arm of chromosome 8. A review of the literature showed seven case reports of lipoblastoma karyotype, six of which had a similar breakpoint in chromosome 8. This distinguishes it from the histologically alike myxoid liposarcoma, the karyotype of which typically contains the clonal anomaly t(12;16)(q13:p11). The authors recommend that when performing a biopsy of a childhood adipose tumor with unusual features, such as progressive or invasive growth, that fresh tissue be submitted for cell culture. The tumor karyotype will, in most cases, aid in differentiating lipoblastoma from myxoid liposarcoma. PMID: 9434024 [PubMed - indexed for MEDLINE] 5810. Dermatol Surg. 1997 Dec;23(12):1177-81. Cellulite. Etiology and purported treatment. Draelos ZD(1), Marenus KD. Author information: (1)Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA. Much research must be undertaken before any of the treatments discussed can be validated as clinically effective. At present, it can be safely stated that there is no topical medication or manipulative process to which advanced cellulite visibly responds in a treatment period of less than 2 months. PMID: 9426662 [PubMed - indexed for MEDLINE] 5811. J Endocrinol. 1997 Nov;155(2):207-9. Role of the agouti gene in obesity. Michaud EJ(1), Mynatt RL, Miltenberger RJ, Klebig ML, Wilkinson JE, Zemel MB, Wilkison WO, Woychik RP. Author information: (1)Life Sciences Division, Oak Ridge National Laboratory, Tennessee 37831, USA. PMID: 9415049 [PubMed - indexed for MEDLINE] 5812. J Endocrinol. 1997 Nov;155(2):187-9. Investigation of human adipose tissue metabolism in vivo. Frayn KN(1), Fielding BA, Summers LK. Author information: (1)Oxford Lipid Metabolism Group, University of Oxford, Radcliffe Infirmary, UK. PMID: 9415043 [PubMed - indexed for MEDLINE] 5813. Med Monatsschr Pharm. 1997 Oct;20(10):264-70. [Progress in obesity research]. [Article in German] Hamann A(1), Matthaei S. Author information: (1)Medizinische Kernklinik und Poliklinik, Universitäts-Krankenhaus Eppendorf, Hamburg. PMID: 9411177 [PubMed - indexed for MEDLINE] 5814. Plast Reconstr Surg. 1997 Nov;100(6):1535-46. Anatomy, pathophysiology, and prevention of senile enophthalmia and associated herniated lower eyelid fat pads. Camirand A(1), Doucet J, Harris J. Author information: (1)Chirurgie Esthétique et Plastique, Montréal, Québec, Canada. Comment in Plast Reconstr Surg. 1998 Sep;102(3):917-8. We describe in detail the anatomy and function of the "Lockwood suspensory ligament" and the interrelated function of the orbital contents responsible for the intraorbital position of the eyeball and fat. With age, or because of genetic disposition, the eyeball descends, reducing the space between it and the floor of the orbit. This will inevitably cause forward projection of the extraconical orbital fat, creating herniated fat pads and resulting in enophthalmia. Based on the volume of the bony orbit and its contents, it is likely that relocating, rather then removing, herniated fat pads will greatly improve and prevent the enophthalmia of aging and give the globe a position and a projection of youth. Based on the results of surgery using the capsulopalpebral flap, it is likely that a descended Lockwood suspensory ligament, rather than a weakened orbital septum, is the cause of herniated fat pads and enophthalmia. We feel neither a weakened orbital septum nor an overabundance of orbital fat nor a shallow orbit is responsible for either of these conditions. We give a detailed description of how to raise the globe, preserve and relocate herniated fat pads, and manage and prevent enophthalmia and obtain a beautiful, youthful looking eye. PMID: 9385969 [PubMed - indexed for MEDLINE] 5815. Hum Reprod. 1997 Oct;12 Suppl 1:26-32. Obesity and reproduction. Bray GA(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Obesity produces a variety of alterations in the reproductive system and, similarly, manipulations of the hypothalamic-pituitary-gonadal axis produce changes in food intake, body weight and fat distribution. In men, the primary effects of obesity are a weight related reduction in testosterone and, with massive overweight, a reduction in free testosterone. In females, the weight-related development of menarche leads to earlier menarche in obese girls than in normal weight girls. One explanation for the relationship of fatness to menarche may be the ob protein (leptin) which is defective in the obese (ob/ob) mouse. Leptin is secreted by adipose tissue in proportion to the quantity of fat and may serve as a signal to the hypothalamus that fat stores are adequate to nourish a conceptus to term. In women, parity affects obesity and obesity in turn affects the regularity of the menstrual cycle. In many experimental animals with obesity, particularly the genetic forms of obesity, there is complete infertility in the females and marked impairment of reproductive function in the males. In animals with hypothalamic lesions, there is a gender effect on the magnitude of weight gain associated with the sexually dimorphic regions in the medial preoptic area. Castration with removal of oestrogen is followed by obesity in female animals and this can be prevented, as can most forms of obesity, by adrenalectomy. The inhibitory effects of oestrogen on food intake may result from suppression of neuropeptide-Y or galanin peptidergic systems in the arcuate nucleus or medial preoptic area. PMID: 9403319 [PubMed - indexed for MEDLINE] 5816. Hum Reprod. 1997 Oct;12 Suppl 1:21-5. Hormonal control of regional fat distribution. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, Sweden. Hormones exert powerful influences on body fat distribution in humans. Studies under fully controlled conditions in vitro have indicated that cortisol and insulin facilitate lipid accumulation by expressing lipoprotein lipase (LPL). Growth hormone (GH) abolishes this and turns metabolism towards lipid mobilization. Testosterone and GH inhibit LPL and stimulate lipolysis markedly. Cortisol effects are mediated via a glucocorticoid receptor, and testosterone effects via an androgen receptor, the density of which appears to be higher in visceral than subcutaneous adipose tissue. The receptor-mediated effects are probably expressed via transcription of appropriate genes. The female sex steroids also regulate adipose tissue metabolism, but apparently not directly in the absence of specific cellular receptors. Oestrogens seem to exert net effects similar to those of testosterone. These results of cellular studies agree well with in-vivo studies of triglyceride uptake and turnover in different adipose tissue regions. Furthermore, clinical entities with characteristic disturbances in hormone levels show the expected redistribution patterns. PMID: 9403318 [PubMed - indexed for MEDLINE] 5817. Hum Reprod. 1997 Oct;12 Suppl 1:1-5. Genetic determinants of regional fat distribution. Bouchard C(1). Author information: (1)Physical Activity Sciences Laboratory, Lavel University, Ste-Foy, Québec, Canada. Upper body fat and abdominal visceral fat are two obesity-related phenotypes of interest because of their relationships with a variety of metabolic complications. The heritability of the amount of upper body fat or the level of upper body fat relative to lower body fat ranges from approximately 30-50% of the phenotype's age, sex and total body fat adjusted variance. On the other hand, familial studies of abdominal visceral fat reveal that the familial transmission reaches > 50% of the age, sex and total body fat adjusted variance. Complex segregation analysis undertaken with a panel of nuclear families indicates that major genes may account for a significant fraction of the variance in upper body fat and abdominal visceral fat. Two intervention studies conducted with pairs of male identical twins have shown that changes in upper body fat and visceral fat are more similar within pairs than between pairs, either in phenotype increments when challenged by chronic overfeeding, or in adipose tissue losses after exposure to long-term negative energy balance conditions. The evidence accumulated to date is sufficient to justify undertaking a search for the specific genes and molecular markers involved in the heterogeneity commonly observed in human fat topography. PMID: 9403316 [PubMed - indexed for MEDLINE] 5818. Nihon Rinsho. 1997 Nov;55 Suppl:822-6. [Pathogenesis of insulin resistance in IGT]. [Article in Japanese] Asakawa H(1), Tokunaga K. Author information: (1)Itami City Hospital. PMID: 9434571 [PubMed - indexed for MEDLINE] 5819. Nihon Rinsho. 1997 Nov;55 Suppl:349-55. [Prediction of the onset of NIDDM in respect to body mass index and body fat distribution]. [Article in Japanese] Nakagawa C(1). Author information: (1)Department of Internal Medicine, Otemae Hospital. PMID: 9434493 [PubMed - indexed for MEDLINE] 5820. J Natl Cancer Inst. 1997 Dec 3;89(23):1763-73. Biology of cachexia. Tisdale MJ. Comment in J Natl Cancer Inst. 1998 Apr 15;90(8):628. J Natl Cancer Inst. 1999 Jun 16;91(12):1077; author reply 1077-8. About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and nutritional supplementation alone is unable to reverse the wasting process. Despite a falling caloric intake, patients with cachexia frequently show an elevated resting energy expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosis factor-apha, interleukins 1 and 6, interferon gamma, and leukemia-inhibitory factor, have been proposed as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably include catabolic factors, which act directly on skeletal muscle and adipose tissue and the presence of which has been associated with the clinical development of cachexia. A polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such catabolic factors and has been shown to stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment of cachexia. PMID: 9392617 [PubMed - indexed for MEDLINE] 5821. J Lipid Res. 1997 Nov;38(11):2173-92. Hepatic uptake of chylomicron remnants. Cooper AD(1). Author information: (1)Research Institute, Palo Alto Medical Foundation, CA 94301, USA. Chylomicrons are formed in the intestine and transport dietary triglyceride to peripheral tissues and cholesterol to the liver. The enzyme lipoprotein lipase, with apolipoprotein (apo)C-II as a co-factor, hydrolyzes chylomicron triglyceride allowing the delivery of free fatty acids to muscle and adipose tissue. As a result, a new particle called a chylomicron remnant is formed. This particle is enriched in cholesteryl ester and fat-soluble vitamins and contains apoB-48 and apoE. It is rapidly removed from the circulation by the liver. ApoE is the moiety required for rapid hepatic removal. Its activity is inhibited by C apolipoproteins, especially apoC-I. Hepatic removal appears to be accomplished by several overlapping mechanisms. The particle must first achieve a size that allows it to be "sieved" through the endothelial fenestre allowing entrance into the space of Disse. Here, it may 1) be removed directly by LDL receptors; 2) acquire additional apoE that is secreted free into the space, and then be removed directly by the LDL receptor-related protein (LRP); or 3) it may be sequestered in the space. Sequestration occurs by binding of apoE to heparan sulfate proteoglycans and/or binding of apoB to hepatic lipase. Sequestered particles may be further metabolized allowing apoE, and lysophospholipid enrichment, followed by transfer to one of the above receptors for hepatic uptake. The above formulation is based upon animal studies. In humans, delayed removal of chylomicron remnants has been documented in diabetes, renal failure, and familial combined hyperlipemia and is the abnormality resulting in type III hyperlipidemia. Case control studies have identified delayed remnant removal as an independent risk factor for atherosclerotic cardiovascular disease. Thus, understanding the further details of the processes, and how it can be regulated in humans, is an important challenge for the future. PMID: 9392416 [PubMed - indexed for MEDLINE] 5822. Curr Opin Genet Dev. 1997 Oct;7(5):603-8. Modulating the transcriptional control of adipogenesis. Loftus TM(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA. tloftus@welchlink.welch.jhu.edu Current evidence indicates that much of the regulation of adipocyte differentiation serves to modulate a common adipogenic transcriptional control pathway, comprising members of the C/EBP and PPAR families. Hormonal regulators have been found to control expression of these factors and to alter their activity through ligand binding, post-transcriptional modification, and protein-protein interactions. PMID: 9388775 [PubMed - indexed for MEDLINE] 5823. Eur J Clin Chem Clin Biochem. 1997 Sep;35(9):647-54. Biological functions of haptoglobin--new pieces to an old puzzle. Dobryszycka W(1). Author information: (1)Department of Biochemistry, Faculty of Pharmacy, Wrocław University of Medicine, Poland. Haptoglobin, an "acute phase" protein, has different functions, which display genetic polymorphism. The complex of haptoglobin with haemoglobin is metabolized in the heptic reticuloendothelial system. Biosynthesis of haptoglobin occurs not only in the liver, but also in adipose tissue and in lung; providing antioxidant and antimicrobial activity. Changes in the measured concentrations of haptoglobin in serum may help to assess the disease status of patients with inflammations, infections, malignancy etc. (increases) as well as in haemolytic conditions (decreases). Haptoglobin plays a role in stimulation of angiogenesis and has highly potent cholesterolcrystallization-promoting activity. Probably the most important biological function of haptoglobin consists in the host defence responses to infection and inflammation, acting as a natural antagonist for receptor-ligand activation of the immune system. PMID: 9352226 [PubMed - indexed for MEDLINE] 5824. Int J Obes Relat Metab Disord. 1997 Sep;21(9):738-46. The beneficial effects of body fat and adipose tissue in humans. Norgan NG(1). Author information: (1)Department of Human Sciences, Loughborough University, Leicester, UK. Body fat and adipose tissue are considered to have beneficial effects when they promote or protect the present and future function. These effects do not occur at absolute amounts or percentages of the body weight but rather they are context specific. Body fat stores are the major energy stores of the body and are important determinants of survival in starvation or undernutrition. Reproduction features highly as a biological function. Humans are alone in having major sex-specific fat stores and patterns of fat distribution and these have been linked with the onset and maintenance of menstruation, with mate selection and sexual signalling, and with favourable pregnancy and lactation outcomes. To survive and reproduce good physical and psychological health are advantageous attributes. Work metabolism, bone health and, possibly immune function and energy balance itself, are related in functionally beneficial ways to fat content and distribution. PMID: 9376885 [PubMed - indexed for MEDLINE] 5825. Int J Obes Relat Metab Disord. 1997 Oct;21(10):839-45. The non-genetic determinants of central adiposity. Samaras K(1), Campbell LV. Author information: (1)Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. Central adiposity carries an increased risk of non-insulin dependent diabetes mellitus (NIDDM), cardiac disease, hypertension and death, and is closely related to insulin resistance. Genetic factors explain a large proportion of the population variance in central adiposity, although the genotypic characteristics remain obscure. Hormonal factors such as endogenous sex steroid levels, the menopause, hormone replacement therapy and cortisol may influence body fat partitioning. The link between dietary factors and central adiposity is controversial, with contradictory results in the literature. Smoking is associated with lower total body fat, but investigations of its influence on central adiposity have also yielded contradictory results. Higher levels of physical activity are associated with lesser amounts of central fat, both cross-sectionally and in intervention studies. Some of the contradictory results regarding putative influences on central adiposity may be due to limitations of some of the anthropometric parameters of central adiposity, such as the waist-hip ratio. Further research is required to clarify the relationships between many of these factors and with both compartments of central adiposity: subcutaneous abdominal and intraabdominal adipose tissue. PMID: 9347401 [PubMed - indexed for MEDLINE] 5826. Int J Obes Relat Metab Disord. 1997 Oct;21(10):831-8. Genetic susceptibility to visceral obesity and related clinical implications. Lemieux S(1). Author information: (1)Lipid Research Center, Laval University Medical Research Center, Québec, Canada. This paper reviews evidence supporting the notion that genetic factors may have an influence on the determination of body fat distribution, particularly emphasizing the genetic susceptibility of visceral adipose tissue (AT) accumulation. The potential contribution of genetic susceptibility to the development of metabolic alterations in visceral obese individuals will also be reviewed. The contribution of genetic factors to the variation in body fat distribution is supported by studies in which racial differences in body fat distribution were reported. These ethnic differences suggest that body fat distribution may be influenced by some components of the genetic background which are shared among individuals of a given race. Furthermore, the familial aggregation and the resemblance between monozygotic twins that have been observed for anthropometric measurements of body fat distribution and for visceral AT accumulation measured by computed tomography, also suggest that genetic factors are involved in the determination of body fat distribution. Genetic susceptibility may also influence the relationship between visceral AT accumulation and the development of metabolic alterations. In this regard, it has been reported that the polymorphism of some genes (for example, the apolipoprotein (apo) E, apo B100 and lipoprotein lipase genes) is altering the relationship between visceral obesity and plasma lipoprotein-lipid levels. In conclusion, results presented in this paper suggest that genetic factors seem to have a significant influence on the propensity to accumulate AT in the visceral depot and that genetic factors also seem to affect the associations commonly reported between visceral obesity and the development of metabolic alterations. PMID: 9347400 [PubMed - indexed for MEDLINE] 5827. Ann N Y Acad Sci. 1997 Sep 20;827:231-45. Pharmacological strategies for reduction of lipid availability. Foley JE(1), Anderson RC, Bell PA, Burkey BF, Deems RO, de Souza C, Dunning BE. Author information: (1)Department of Metabolic Diseases, Sandoz Research Institute, Sandoz Pharmaceutical Corporation, East Hanover, New Jersey 07936, USA. PMID: 9329758 [PubMed - indexed for MEDLINE] 5828. Diabetes Metab. 1997 Sep;23 Suppl 3:16-24. Is leptin the link between obesity and insulin resistance? Girard J(1). Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, Centre National de la Recherche Scientifique, UPR 1511, Meudon, France. girard@bellevue.cnrs-bellevue.fr Leptin is the product of OB gene. This 16 kDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. It has been suggested that leptin could be the link between obesity and diabetes. Recent experiments in rodents have shown that leptin expression in adipocytes is also regulated at short-term by hormones and nutrients. Leptin expression increases after food intake and decreases during fasting and diabetes. Insulin and glucocorticoids increase leptin expression, whereas catecholamines, via beta-adrenergic receptors and cAMP, and long-chain fatty acids (and thiazolidinediones), via PPARy, inhibit leptin expression. Leptin is a cytokine that binds to transmembrane receptors similar to the receptors of cytokine family (type IL-6), and transmit their information inside the cell, after dimerisation. A short-form of leptin receptor (with a cytoplasmic domain of 34 amino residues) has been identified in the choroid plexus. This type of receptor should be used for leptin transport across the blood-brain barrier. Then leptin binds to a long-form of leptin receptor in the hypothalamus (with a cytoplasmic domain of 302 amino residues) and decreases the production of neuropeptide Y, a neuromediator of food intake. The long-form of leptin receptor, transmits its information via the Janus Kinases (JAK) who subsequently phosphorylate transcription factors of the STAT family. Intermediary forms of leptin receptor have been identified in other tissues: liver, heart, skeletal muscles, endocrine pancreas. The role of leptin receptors in these tissues remains obscure, but is of considerable interest. Recent studies have shown that leptin inhibits insulin secretion and have anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to TNF alpha and could participate in the insulin-resistance of obesity and type II diabetes. PMID: 9342538 [PubMed - indexed for MEDLINE] 5829. FASEB J. 1997 Oct;11(12):937-45. Genetics of human obesity: research directions. Bray G(1), Bouchard C. Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808-4124, USA. Rapid strides in understanding the physiology controlling energy or nutrient intake and energy expenditure have complemented the search for the genetic basis of obesity. Several single gene defects are known that produce obesity in animals. All of these have been cloned within the past 4 years, providing a rich new base for understanding obesity. Since obesity is likely to be "multifactorial," a number of laboratories have used the quantitative trait locus (QTL) technique of genome scanning to identify candidate genomic regions and, eventually, genes that may influence body weight and body fat. So far, 18 QTLs have been identified in association with crossbreeding strains of mice or rats with variable susceptibility to obesity. A number of mendelian disorders are known to exist in humans, but no specific genes have yet been identified for them. The potential for inserting new genetic material into mammals has produced numerous transgenic mice with increased or decreased quantities of body fat. These models will provide a continuing source of new insights into obesity. Several areas in the human genome have been linked to the development of obesity. Among the candidate genes with evidence of linkage to body fat are TNF-alpha, adenosine deaminase, and melanocortin-3 receptor. The new insights described above have invigorated the pharmaceutical industry to increase their efforts for new drug development aimed at the growing problem of obesity. PMID: 9337146 [PubMed - indexed for MEDLINE] 5830. Am J Surg Pathol. 1997 Oct;21(10):1131-7. Lipoblastoma/lipoblastomatosis: a clinicopathologic study of 25 tumors. Collins MH(1), Chatten J. Author information: (1)Department of Pathology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. Lipoblastoma/lipoblastomatosis is an uncommon benign adipose tissue tumor of children. Since 1958, 25 of these tumors from 24 patients have been reviewed in the Department of Pathology at The Children's Hospital of Philadelphia. Tumors were resected from 19 boys (79%) and five girls, and 20 patients (84%) were < or =5 years of age at diagnosis. Twenty-three tumors presented as painless superficial soft-tissue masses; one tumor was retroperitoneal and was discovered because of vomiting; one hand tumor was present at birth. Tumors occurred in an extremity (n = 11 patients), the head and neck (n = 5), groin (n = 2), axilla (n = 2), back (n = 1), chest (n = 1), flank (n = 1), labia (n = 1), and retroperitoneum (n = 1). Thirteen tumors occurred on the left side, and five occurred on the right. Lesions measured 1.0-21.0 cm in greatest dimension; 15 of 25 (60%) measured < or =5.0 cm. The largest (retroperitoneal) tumor weighed 450 g. Eleven tumors were discrete lipoblastoma, and 14 had irregular margins (lipoblastomatosis). Microscopically, the tumors displayed adipocytes in different stages of maturation; lobules bordered by septae that were cellular in 11 cases; prominent blood vessels in 19 cases; and myxoid foci in 13 cases. Chart review of 22 patients showed that one tumor recurred 4 years after resection; one tumor recurred after 7 years as fibrolipoma; and one incompletely resected tumor enlarged and at second resection was lipoma. There were no metastases. Three patients also had hemangioma. Juvenile aponeurotic fibroma occurred in one patient near the site of resection of a lipoblastoma 4 years earlier. We conclude that lipoblastoma/lipoblastomatosis behaves benignly, occurs in both superficial and deep sites, occasionally attains large size, may mature, can recur, and may be associated with other benign soft-tissue lesions. Complete surgical excision is the treatment of choice. PMID: 9331284 [PubMed - indexed for MEDLINE] 5831. Hypertension. 1997 Sep;30(3 Pt 2):619-23. Sympathetic and cardiorenal actions of leptin. Haynes WG(1), Sivitz WI, Morgan DA, Walsh SA, Mark AL. Author information: (1)Hypertension Genetics Specialized Center of Research, and Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City 52242, USA. william-g-haynes@uiowa.edu Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity. PMID: 9322991 [PubMed - indexed for MEDLINE] 5832. J Med Genet. 1997 Sep;34(9):753-7. Nasu-Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. Verloes A(1), Maquet P, Sadzot B, Vivario M, Thiry A, Franck G. Author information: (1)Walloon University Centre of Genetics, Sart Tilman University Hospital, Liège, Belgium. PMCID: PMC1051061 PMID: 9321763 [PubMed - indexed for MEDLINE] 5833. Biomed Environ Sci. 1997 Sep;10(2-3):129-35. Selenium and iodine deficiencies and selenoprotein function. Arthur JR(1), Nicol F, Mitchell JH, Beckett GJ. Author information: (1)Division of Biochemical Sciences, Rowett Research Institute, Aberdeen, UK. This paper reviews some recent findings on the interactions between selenium deficiency and iodine deficiency. Both micronutrients can control the levels of selenoprotein mRNAs, particularly in the thyroid and brain. When selenium and iodine supplies are limiting the compensatory mechanisms work to minimise adverse effects on thyroid hormone metabolism and thus neurological development. The mechanisms for regulation of selenoproteins in selenium and iodine deficiency are however very tissue-specific. For example, unlike the brain and thyroid, brown adipose tissue is unable to retain selenoproteins in selenium and iodine deficiency and is therefore at greater risk from injurious effects of the deficiencies. PMID: 9315304 [PubMed - indexed for MEDLINE] 5834. Med Res Rev. 1997 Sep;17(5):499-504. Leptin: an annotated addendum. Remesar X(1), Rafecas I, Fernández-López JA, Alemany M. Author information: (1)Department de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. PMID: 9312591 [PubMed - indexed for MEDLINE] 5835. J Nutr. 1997 Sep;127(9):1917S-1922S. Potential role of TNFalpha and lipoprotein lipase as candidate genes for obesity. Kern PA(1). Author information: (1)Department of Medicine, University of Arkansas for Medical Sciences and John L. McClellan VA Medical Center, Little Rock, AR 72205, USA. To maintain body weight, metabolic efficiency was promoted during evolution; two candidate genes for body weight regulation are lipoprotein lipase (LPL) and tumor necrosis factor-alpha (TNFalpha). Human fat cells do not synthesize lipid, but rely on LPL-mediated plasma triglyceride hydrolysis. Adipose LPL is elevated in obesity. Following weight loss, LPL is elevated further, suggesting attempts to maintain lipid stores during fasting and to replenish lipid stores during refeeding. Muscle LPL is regulated inversely to adipose LPL. Thus, an increased adipose/muscle LPL ratio would partition dietary lipid into adipose tissue and would explain some of the variability in weight gain when humans are exposed to excess calories. Adipose tissue TNFalpha expression is increased in obese rodents and humans and may be important in obesity. When insulin-resistant rodents were injected with anti-TNF binding protein, insulin action improved, suggesting a link between insulin resistance and TNF. TNF is expressed at higher levels in muscle cells of insulin-resistant subjects, and TNF may inhibit LPL expression. Overall, TNF may function to make the subject less obese by inhibiting LPL and rendering the animal more insulin resistant. Obesity has many components, both metabolic and behavioral. However, the metabolic changes resulting from LPL and TNF likely played a role in regulating body adipose tissue during much of human evolution and continue to affect human obesity today. PMID: 9278582 [PubMed - indexed for MEDLINE] 5836. J Nutr. 1997 Sep;127(9):1902S-1907S. The role of the agouti gene in the yellow obese syndrome. Miltenberger RJ(1), Mynatt RL, Wilkinson JE, Woychik RP. Author information: (1)Mammalian Genetics and Development Section, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. The yellow obese syndrome in mice encompasses many pleiotropic effects including yellow fur, maturity-onset obesity, hyperinsulinemia, insulin resistance, hyperglycemia, increased skeletal length and lean body mass, and increased susceptibility to neoplasia. The molecular basis of this syndrome is beginning to be unraveled and may have implications for human obesity and diabetes. Normally, the agouti gene is expressed during the hair-growth cycle in the neonatal skin where it functions as a paracrine regulator of pigmentation. The secreted agouti protein antagonizes the binding of the alpha-melanocyte-stimulating hormone to its receptor (melanocortin 1 receptor) on the surface of hair bulb melanocytes, causing alterations in intracellular cAMP levels. Widespread, ectopic expression of the mouse agouti gene is central to the yellow obese phenotype, as demonstrated by the molecular cloning of several dominant agouti mutations and the ubiquitous expression of the wild-type agouti gene in transgenic mice. Recent experiments have revealed that the hypothalamus and adipose tissue are biologically active target sites for agouti in the yellow obese mutant lines. PMID: 9278579 [PubMed - indexed for MEDLINE] 5837. Med Res Rev. 1997 Sep;17(5):477-98. The metabolic basis of cancer cachexia. Argilés JM(1), Alvarez B, López-Soriano FJ. Author information: (1)Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. argiles@porthos.bio.ub.es PMID: 9276862 [PubMed - indexed for MEDLINE] 5838. Biochim Biophys Acta. 1997 Aug 16;1347(2-3):101-26. Lipid metabolism in the lactating mammary gland. Barber MC(1), Clegg RA, Travers MT, Vernon RG. Author information: (1)Hannah Research Institute, Scotland, UK. PMID: 9295156 [PubMed - indexed for MEDLINE] 5839. Am J Cardiol. 1997 Aug 4;80(3A):41A-49A. Multiple signaling pathways involved in the metabolic effects of insulin. Moule SK(1), Denton RM. Author information: (1)Department of Biochemistry, University of Bristol School of Medical Sciences, UK. The metabolic effects of insulin are initiated by the binding of insulin to the extracellular domain of the insulin receptor within the plasma membrane of muscle and adipose and liver cells. The subsequent activation of the intracellular tyrosine protein kinase activity of the receptor leads to autophosphorylation of the receptor as well as phosphorylation of a number of intracellular proteins. This gives rise to the activation of Ras and phosphatidylinositol 3-kinase and hence to the activation of a number of serine/threanine protein kinases. Many of these kinases appear to be arranged in cascades, including a cascade that results in the activation of mitogen-activated protein kinase and another that may result in the activation of protein kinase B, leading to the inhibition of glycogen synthase kinase-3 and the activation of the 70 kiloDalton ribosomal S6 protein kinase (p70 S6 kinase). We have explored the role of these early events in the the stimulation of glycogen, fatty acid, and protein synthesis by insulin in rat epididymal fat cells. Comparisons have been made between the metabolic effects of insulin and those of epidermal growth factor, since these 2 agents have contrasting effects on p70 S6 kinase and mitogen-activated protein kinase. The effects of wortmannin (which inhibits phosphatidylinositol 3-kinase), and rapamycin (which blocks the activation of p70 S6 kinase) have also been studied. These and other studies indicate that the mitogen-activated protein kinase cascade is probably not important in the acute metabolic effects of insulin, but may have a role in the regulation of gene transcription and hence the more long-term effects of insulin. The short-term metabolic effects of insulin appear to involve at least 3 distinct signaling pathways: (1) those leading to increases in glucose transport and the activation of glycogen synthase, acetyl-CoA carboxylase, eukaryotic initiation factor-2B, and phosphodiesterase, which may involve phosphatidylinositol 3-kinase and protein kinase B; (2) those leading to some of the effects of insulin on protein synthesis (formation of eukaryotic initiation factor-4F complex, S6 phosphorylation, and activation of eukaryotic elongation factor-2), which may involve phosphatidylinositol 3-kinase and p70 S6 kinase; and finally, (3) that leading to the activation of pyruvate dehydrogenase, which is unique in apparently not requiring activation of phosphatidylinositol 3-kinase. PMID: 9293955 [PubMed - indexed for MEDLINE] 5840. Int J Obes Relat Metab Disord. 1997 Aug;21(8):626-31. Visceral fat in relation to health: is it a major culprit or simply an innocent bystander? Seidell JC(1), Bouchard C. Author information: (1)Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and The Environment, Bilthoven, The Netherlands. The aim of this review is to look critically at the widely accepted notion that visceral fat accumulation is the main determinant of obesity related diseases. Most of the epidemiological evidence is based on anthropometric indicators of fatness and fat distribution and their implications for visceral fat accumulation may not be unequivocal. In most cross-sectional studies in which visceral fat is associated with the level of risk factors or presence of disease, no adjustment is made for potential confounders. There are potential confounders at different levels of the causal chains linking visceral fat to health. Firstly, there are aspects of body composition or fat depots associated with visceral fat accumulation such as total body fat or total subcutaneous fat. Total and subcutaneous fat are, by themselves, potentially strong determinants for metabolic disturbances and disease. Secondly, there are behavioural factors (for example smoking, alcohol consumption, physical activity, dietary habits) which have been found to be associated with both the amount of visceral fat and health outcomes. Thirdly, there are hormonal mechanisms (adrenal and gonadal steroids as well as growth hormone) which may affect both the accumulation of visceral fat as well as the development of diseases. Finally, even if associations between visceral fat and risk factors or presence of diseases would be firmly established, the causality of the observed associations may not always be easy to interpret. Prospective studies are needed with appropriate control of potential confounding variables. It is concluded that, based on the current evidence, it is difficult to quantify the independent contribution of visceral fat to the development of a variety of chronic diseases. PMID: 15481760 [PubMed - indexed for MEDLINE] 5841. Int J Obes Relat Metab Disord. 1997 Aug;21(8):619-25. The effects of weight loss treatments on upper and lower body fat. Kopelman PG(1). Author information: (1)St Bartholomew's and The Royal London School of Medicine & Dentistry, Queen Mary and Westfield College, London E1 1BB, UK. The intra-abdominal visceral deposition of adipose tissue, which characterises upper body obesity, is a major contributor to the development of hypertension, glucose intolerance and hyperlipidaemia. Conversely, individuals with lower body obesity may have comparable amounts of adipose tissue but remain relatively free from the metabolic consequences of obesity. This raises an obvious question-are there particular weight reducing treatments which specifically target intra-abdominal fat? In theory, surgical removal of upper body fat should be effective. In reality, neither liposuction nor apronectomy ('tummy tuck') have any beneficial metabolic effects, they simply remove subcutaneous adipose tissue which is often rapidly replaced. Vertical banded gastroplasty and gastric bypass operations may be dramatically effective in improving blood pressure, insulin sensitivity and glucose tolerance. However, these benefits result from a parallel reduction in visceral and total body fat. Studies of body fat distribution in postmenopausal women confirm that the marked decrease in adiposity, following a programme of very low calorie diet and exercise, reflects a comparable reduction in visceral and thigh fat. The reduction in waist circumference after a low fat/exercise programme suggests a similar situation in men. Exercise has an important role in treatment but, once again, the fat loss is generalised. Nevertheless, the improved metabolic parameters seen in exercising obese subjects, independent of weight loss, suggest other beneficial actions. Growth hormone (GH) has a marked lipolytic action. GH replacement treatment for GH deficient adults with pronounced abdominal fat deposition, has been shown to reduce intra-abdominal fat by 47% compared to 27% decrease in abdominal subcutaneous fat. Similar beneficial actions on abdominal fat have been reported following treatment with testosterone in obese men. The potential hazards of such treatments make them unsuitable therapy for obesity. Dexfenfluramine is effective in reducing total body fat but the results from a six month randomised controlled trial indicates that it does not specifically influence changes in waist circumference associated with weight loss. In conclusion, any treatment which reduces total body fat will, by its nature, reduce intra-abdominal visceral fat. There are presently no specific treatments which can be recommended for intra-abdominal fat but increasing knowledge of the biochemical aberrations associated with visceral adiposity may lead to more specific therapies for the future. PMID: 15481759 [PubMed - indexed for MEDLINE] 5842. Eur J Clin Nutr. 1997 Aug;51(8):495-503. Comparison of body composition methods: a literature analysis. Fogelholm M(1), van Marken Lichtenbelt W. Author information: (1)UKK Institute, POB 30, FIN-33501, Tampere, Finland. OBJECTIVE: To examine the comparability of different methods to assess percentage body fat (BF%) against underwater weighing (UWW). DESIGN: A meta-analysis on 54 papers, published in 1985-96, on healthy, adult Caucasians. METHODS: The mean BF% from different studies were treated as single data points. In addition to UWW, the studies included one or more of the following methods: 3- or 4-component model, dual-energy X-ray absorptiometry (DXA), dual-energy photon absorptiometry, isotope dilution, bioimpedance (BIA), skinfolds or near-infrared interactance (NIR). Within each of the methods, the analyses were done separately for different mathematical functions, techniques or instruments. MAIN OUTCOME MEASURES: Bias (mean difference) and error (s.d. of difference) between BF% measured by UWW and the other methods. RESULTS: The 4-component model gave 0.6 (95% confidence interval for the mean, CI: 0.1 to 1.2) BF% higher results than UWW. Also the 3-component model with body density and total body water (+1.4 BF%, 95% CI: +0.3 to +2.6), deuterium dilution (+1.5 BF%, 95% CI: +0.7 to +2.3), DXA by Norland (+7.2 BF%, 95% CI: 2.6 to 11.8) and BIA by Lukaski et al. (+2.0 BF%, 95% CI: 0.2 to 3.8) overestimated BF%, whereas BIA by Valhalla Scientific (-2.6 BF%, 95% CI: -4.5 to -0.6) and skinfold equations by Jackson et al. (-1.20, 95% CI: -2.3 to -0.1) showed a relative underestimation. The mean bias for the skinfold equation by Durnin & Womersley, against UWW, was 0.0 BF% (95% CI: -1.3 to 1.3). The correlation between the size of measurement and the mean difference was significant for only NIR (r = -0.77, P = 0.003). CONCLUSIONS: The difference between any method and UWW is dependent on the study. However, some methods have a systematical tendency for relative over- or underestimation of BF%. PMID: 11248873 [PubMed - indexed for MEDLINE] 5843. Endocrine. 1997 Aug;7(1):1-8. Regulation of circulating leptin in humans. Ahrén B(1), Larsson H, Wilhelmsson C, Näsman B, Olsson T. Author information: (1)Department of Medicine, Lund University, Malmö, Sweden. bo.ahren@medforsk.mas.lu.se PMID: 9449025 [PubMed - indexed for MEDLINE] 5844. Br J Nutr. 1997 Aug;78(2):251-71. Weaning marginally affects glucose transporter (GLUT4) expression in calf muscles and adipose tissues. Hocquette JF(1), Castiglia-Delavaud C, Graulet B, Ferré P, Picard B, Vermorel M. Author information: (1)INRA, Laboratoire Croissance et Métabolismes des Herbivores, Saint-Genès-Champanelle, France. The nutritional regulation of glucose transporter GLUT4 was studied in eight muscles and four adipose tissues from two groups of preruminant (PR) or ruminant (R) calves of similar age (170 d), empty body weight (194 kg) at slaughter, and level of net energy intake from birth onwards. Isocitrate dehydrogenase (EC 1.1.1.41) activity in muscles was not different between PR and R except in masseter muscle from the cheek (+71% in R; P < 0.003), which becomes almost constantly active at weaning for food chewing. Basal and maximally-insulin-stimulated glucose transport rate (GTR) per g tissue wet weight in rectus abdominis muscle were significantly higher in R calves (+31 and 41% respectively; P < 0.05). GLUT4 protein contents did not differ in muscles from PR and R except in masseter (+74% in R; P < 0.05) indicating that the increased GTR in rectus abdominis cannot be accounted for by an enhanced GLUT4 expression. GLUT4 mRNA levels did not differ between the two groups of animals in all muscles suggesting a regulation of GLUT4 at the protein level in masseter. GLUT4 number expressed on a per cell basis was lower in adipose tissue from R calves (-39%; P < 0.05) and higher in internal than in peripheral adipose tissues. In summary, the regulation of GLUT4 in calves at weaning differs markedly from that previously described in rodents (for review, see Girard et al. 1992). Furthermore, significant inter-individual variations were shown for metabolic activities in muscle and for biochemical variables in adipose tissue. PMID: 9301415 [PubMed - indexed for MEDLINE] 5845. Virchows Arch. 1997 Aug;431(2):83-94. The role of cytogenetics in the classification of soft tissue tumours. Dei Tos AP(1), Dal Cin P. Author information: (1)Department of Pathology, City Hospital, Treviso, Italy. Soft tissue tumours represent a heterogeneous group of mesenchymal lesions, and their classification is the subject of continuous debate. Chromosome analysis, molecular cytogenetics and molecular assays may become increasingly useful in diagnosis, and this review summarises advances in the cytogenetic characterisation and classification of soft tissue tumours. Among the group of fibrous lesions, superficial fibromatosis exhibits trisomy 8. This genomic change is also observed in desmoid fibromatosis in association with trisomy 20. Trisomy 11 is the most frequently observed chromosomal aberration in congenital fibrosarcoma. Dermatofibrosarcoma protuberans and giant cell fibroblastoma share a translocation t(17;22), which supports the concept of the existence of a common differentiation pathway. Adipose tissue tumours is the group in which integration of genetics and pathology has been most fruitful. Ordinary lipomas cytogenetically show an abnormal karyotype in about half the cases. Genomic changes of the 11q13 region are observed in hibernoma. Lipoblastoma exhibits a specific 8q rearrangement in 8q11-q13. Loss of material from the region 16q13-qter and 13q deletions are observed in spindle cell/pleomorphic lipomas. The well-differentiated liposarcoma/atypical lipoma group is characterised karyotypically by the presence of one extra ring and/or extra giant chromosome marker. Myxoid and round cell liposarcoma share the same characteristic chromosome change: t(12;16)(q13;p11) in most cases. In the group of smooth muscle lesions most data are derived from uterine leiomyomas, which can be subclassified cytogenetically into seven different types. Half of all leiomyomas are chromosomally normal; the other half have one of six possible consistent chromosome changes. Alveolar rhabdomyosarcoma is characterised cytogenetically by two variant translocations t(2;13)(q35;q14) and t(1;13)(p36;q14). Among tenosynovial tumours, the localised type of giant cell tumour of tendon sheath exhibits two different karyotypic changes. One involves 1p11 in a translocation with chromosome 2 or with another chromosome. A second type involves 16q24. Synovial sarcoma is characterised cytogenetically by a translocation occurring between chromosome 18 and presumably two adjacent loci on the X chromosome. In neural tumours, abnormalities of chromosome 22 have been reported in benign schwannomas and perineuriomas. Malignant peripheral nerve sheath tumours exist in two main forms: sporadic and associated with the NF-1 syndrome. Karyotypes are very complex, but chromosomes 17q and 22q are very often involved. Clear cell sarcoma is characterised cytogenetically and molecularly by a translocation t(12;22)(q13;q12). The Ewing's sarcoma/peripheral neuroectodermal tumour category shows a central karyotypic anomaly represented by the translocation t(11;22). The two variants t(21;22) and t(7;22) are found in some cases. Among cartilaginous lesion, the most frequently described anomaly is the t(9;22)(q22;q12) in extraskeletal myxoid chondrosarcoma. Intra-abdominal desmoplastic small round cell tumour is characterised by a t(11;22)(p13;q12). PMID: 9293889 [PubMed - indexed for MEDLINE] 5846. Mol Aspects Med. 1997 Aug;18(4):247-305. Obesity. Jéquir E(1), Tappy L. Author information: (1)Institute of Physiology, Faculty of Medicine, University of Lausanne, Switzerland. PMID: 9292864 [PubMed - indexed for MEDLINE] 5847. FASEB J. 1997 Aug;11(10):743-51. Journey from cachexia to obesity by TNF. Argilés JM(1), López-Soriano J, Busquets S, López-Soriano FJ. Author information: (1)Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in the physiological and metabolic abnormalities found in cachectic states. Until very recently, it was inconceivable to think of TNF-alpha in obesity. However, recent studies have shown that TNF-alpha can also play a key role in obesity, the cytokine being overexpressed in adipose tissue of obese rodents and humans. The aim of this review is to reconcile the role of TNF-alpha in these two opposite metabolic situations: obesity and cachexia. It is suggested that TNF-alpha may have a key role in the control of body mass in normal weight-controlled situations and that abnormalities in either its production (during cachexia) or action (during obesity) are responsible for the lack of control of body weight. PMID: 9271359 [PubMed - indexed for MEDLINE] 5848. Semin Pediatr Surg. 1997 Aug;6(3):147-55. Masculinizing and feminizing syndromes caused by functioning tumors. Masiakos PT(1), Flynn CE, Donahoe PK. Author information: (1)Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Steroidogenic tumors are derived from cells of male and female reproductive tracts, adrenal glands, central nervous system, and, to a lesser degree, from the liver and pituitary gland. The symptoms caused by these tumors are related to their secretory products. Because enzymatic pathways are shared by both adrenal- and gonadal-derived tissues, and the conversion of some of these steroids occurs in the adipose tissue, positive identification of many lesions cannot be based on peripheral blood hormone levels alone, but require complex protocols to improve diagnostic accuracy. Furthermore, these tumors often are smaller than the size limit of conventional imaging modalities and thus demand more precise imaging techniques. Although diagnosis and localization may be challenging, the rewards of a positive prognosis, with complete reversal of symptoms, are more likely to occur with early detection and treatment. This article is a review of the clinical syndromes associated with pediatric steroidogenic tumors; suggested strategies to facilitate their diagnosis, localization, and treatment are provided. PMID: 9263337 [PubMed - indexed for MEDLINE] 5849. Clin Invest Med. 1997 Aug;20(4):239-44. Obesity research continues to spring leaks. Harper ME(1). Author information: (1)Faculty of Medicine, University of Ottawa, Ont. mharper@uottawa.ca Recent discoveries about the roles of 2 uncoupling proteins are changing the way we view obesity and its treatment. The author is also a coauthor of a recent Nature report that mice deficient in uncoupling protein 1 (UCP1) did not become fat, as anticipated, but lean. She found that the other uncoupling protein (UCP2) was up-regulated in the brown adipose tissue (BAT) of these mice, compensating, at least in part, for the lack of UCP1 and preventing obesity. Researchers have known for 40 years that the function of BAT is heat production. In 1978, researchers discovered UCP1, the protein responsible for this function. Subsequent investigation focused on the role of this protein in staving off obesity in animal models. In the early 1990s, surprising evidence from tissues other than BAT show that 20% to 40% of resting cellular energy expenditure is used to counter a proton leak down the electrochemical gradient across the mitochondrial inner membrane. This leak was found to be related to metabolic rate; the search for the mechanism of the leak led to the discovery of UCP2. Both uncoupling proteins have been found to act as leaks in mitochondrial inner membranes, allowing the dissipation of proton motive force. These findings could lead to new treatments for obesity and non-insulin-dependent diabetes mellitus. PMID: 9258578 [PubMed - indexed for MEDLINE] 5850. J Am Geriatr Soc. 1997 Aug;45(8):959-67. Preadipocyte function and aging: links between age-related changes in cell dynamics and altered fat tissue function. Kirkland JL(1), Dobson DE. Author information: (1)Department of Medicine, Boston University School of Medicine, Massachusetts, USA. OBJECTIVE: To review recent findings about changes with age in the replication and differentiation of preadipocytes, the progenitor cells in fat tissue that are capable of differentiating into fat cells, and to examine possible links between these alterations and age-related changes in fat tissue function. DESIGN: A survey and analysis of recent literature concerning changes in preadipocyte and fat cell function with age. CONCLUSIONS: Intrinsic aging changes in fat cells and preadipocytes as well as in factors extrinsic to fat tissue (such as food intake and absorption and hormonal status) contribute to age-related alterations in fat tissue function and cellularity. Changes with age in preadipocyte number, replicative potential, and capacity for differentiation, which may be linked to aging changes in fat cell size, number, and function, have been identified. The decline in preadipocyte capacity for differentiation and the associated decline in fat cell lipogenic capacity may be particularly important in contributing to the decrease in fat mass and alterations in fat tissue function that occur between middle- and old age. These declines result from blunting of the changes in gene expression that occur during preadipocyte differentiation and may, in turn, be related to altered regulation of particular transcription factors that control the preadipocyte differentiation program and maintenance of fat cell function. PMID: 9256849 [PubMed - indexed for MEDLINE] 5851. Acta Neuropathol. 1997 Aug;94(2):192-6. The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Hague K(1), Lento P, Morgello S, Caro S, Kaufmann H. Author information: (1)Department of Pathology (Division of Neuropathology), Mount Sinai Medical Center, New York, NY 10029, USA. Pure autonomic failure (PAF; also known as idiopathic orthostatic hypotension or Bradbury-Eggleston syndrome) is an uncommon sporadic disorder, characterized by autonomic failure without other neurological deficits and histopathologically by cell loss in intermediolateral columns and sympathetic ganglia. Few postmortem studies of patients with PAF have been reported in the literature, and none have demonstrated Lewy bodies in distal axons, although this has been described as a feature in Parkinson's disease with autonomic failure. We report a patient with PAF who had orthostatic hypotension and urinary symptoms for 15 years prior to death at the age of 63 years. Postmortem findings included typical and atypical Lewy bodies in the substantia nigra, locus ceruleus, substantia innominata, and sympathetic ganglia, as well as in autonomic axons in the epicardial fat, autonomic nerve fascicles in periadrenal adipose tissue, and autonomic nerves in the muscularis of the urinary bladder. Sites of autonomic nerve involvement correlated with clinical symptomatology, and thus were a valuable observation in the complete autopsy. Systemic autopsy results should be reviewed carefully in patients with PAF, as Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies. PMID: 9255396 [PubMed - indexed for MEDLINE] 5852. Curr Opin Lipidol. 1997 Aug;8(4):212-8. Peroxisome proliferator-activated receptor gamma and the control of adipogenesis. Brun RP(1), Kim JB, Hu E, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. The adipose cell is now known to play a complex role in energy homeostasis, storing energy and signaling to other tissues concerning the state of energy balance. The past several years have seen an explosive increase in our knowledge of the transcriptional basis of adipocyte differentiation. This review describes the role of peroxisome proliferator-activated receptor gamma in this process, and describes how other transcription factors may affect adipogenesis by modulating the amount or activity of peroxisome proliferator-activated receptor gamma. Furthermore, peroxisome proliferator-activated receptor gamma and other adipogenic transcription factors provide a focus for beginning to understand how various hormones and metabolites influence the development of this tissue in vivo. PMID: 9253537 [PubMed - indexed for MEDLINE] 5853. Sheng Li Ke Xue Jin Zhan. 1997 Jul;28(3):271-3. [Effect of noradrenaline on brown adipose tissue recruitment]. [Article in Chinese] Gao BB, Han QD. PMID: 11038743 [PubMed - indexed for MEDLINE] 5854. J Mammary Gland Biol Neoplasia. 1997 Jul;2(3):265-78. Adaptations of glucose metabolism during pregnancy and lactation. Bell AW(1), Bauman DE. Author information: (1)Department of Animal Science, Cornell University, Ithaca, New York 14853-4801, USA. awb6@cornell.edu Increased glucose requirements of the gravid uterus during late pregnancy and even greater requirements of the lactating mammary glands necessitate major adjustments in glucose production and utilization in maternal liver, adipose tissue, skeletal muscle, and other tissues. In ruminants, which at all times rely principally on hepatic gluconeogenesis for their glucose supply, hepatic glucose synthesis during late pregnancy and early lactation is increased to accommodate uterine or mammary demands even when the supply of dietary substrate is inadequate. At the same time, glucose utilization by adipose tissue and muscle is reduced. In pregnant animals, these responses are exaggerated by moderate undernutrition and are mediated by reduced tissue sensitivity and responsiveness to insulin, associated with decreased tissue expression of the insulin-responsive facilitative glucose transporter, GLUT4. Peripheral tissue responses to insulin remain severely attenuated during early lactation but recover as the animal progresses through mid lactation. Specific homeorhetic effectors of decreased insulin-mediated glucose metabolism during late pregnancy have yet to be conclusively identified. In contrast, somatotropin is almost certainly a predominant homeorhetic influence during lactation because its exogenous administration causes specific changes in glucose metabolism (and many other functions) of various nonmammary tissues which faithfully mimic normal adaptations to early lactation. PMID: 10882310 [PubMed - indexed for MEDLINE] 5855. J Mammary Gland Biol Neoplasia. 1997 Jul;2(3):231-41. Adaptations of maternal adipose tissue to lactation. Vernon RG(1), Pond CM. Author information: (1)Hannah Research Institute, Ayr, Scotland, United Kingdom. The ability to store substantial amounts of energy as lipid in adipose tissue has allowed development of a variety of strategies in wild animals to meet the considerable metabolic challenge of lactation. The ability to use adipose tissue energy has also been critical for development of the exceptional rates of milk production achieved in the dairy cow. Lactation thus results in profound changes in adipose tissue metabolism, the molecular bases of which are beginning to be resolved in domestic ruminants and laboratory rodents. In addition to its role as an energy store, adipose tissue has a variety of other functions (e.g., modulation of mammary development, appetite, immune system function), some of which are important for lactation. PMID: 10882307 [PubMed - indexed for MEDLINE] 5856. J Mammary Gland Biol Neoplasia. 1997 Jul;2(3):205-30. Lactation in whales and dolphins: evidence of divergence between baleen- and toothed-species. Oftedal OT(1). Author information: (1)Department of Zoological Research, National Zoological Park, Smithsonian Institution, Washington, DC 20008, USA. nzpem031@sivm.si.edu Although it has been more than one hundred years since the first publication on the milks of whales and dolphins (Order Cetacea), information on lactation in these species is scattered and fragmentary. Yet the immense size of some cetaceans, and the recent evidence that another group of marine mammals, the true seals, have remarkable rates of secretion of milk fat and energy, make this group of great comparative interest. In this paper information on lactation patterns, milk composition and lactation performance is reviewed. Two very different patterns are evident. Many of the baleen whales (Suborder Mysticeti) have relatively brief lactations (5-7 months) during which they fast or eat relatively little. At mid-lactation they produce milks relatively low in water (40-53%), high in fat (30-50%), and moderately high in protein (9-15%) and ash (1.2-2.1%). From mammary gland weights and postnatal growth rates, it is predicted that their energy outputs in milk are exceptional, reaching on the order of 4000 MJ/ d in the blue whale. This is possible because pregnant females migrate to feeding grounds where they can ingest and deposit great amounts of energy, building up blubber stores prior to parturition. On the other hand, the toothed whales and dolphins (Suborder Odontoceti) have much more extensive lactations typically lasting 1-3 years, during which the mothers feed. At mid-lactation their milks appear to be higher in water (60-77%) and lower in fat (10-30%) and ash (0.6-1.1%), with similar levels of protein (8-11%). At least some odontocetes resemble primates in terms of low predicted rates of energy output and a long period of dependency of the young. However, these hypotheses are based on small numbers of samples for a relatively small number of species. Much of the available data on milk composition is of rather poor quality; for example, it is not possible to determine if milk composition changes over the course of lactation among odontocetes. Additional research on cetacean mammary glands and their secretions is needed to understand the reproductive strategies of these fascinating animals. PMID: 10882306 [PubMed - indexed for MEDLINE] 5857. Horm Metab Res. 1997 Jul;29(7):344-6. Microdialysis in adipose tissue and skeletal muscle. Lönnroth P(1). Author information: (1)Lundberg Laboratory for Diabetes Research, Göteborg University, Sweden. Peter.Lonnroth@medicine.gu.se Traditionally, investigation of metabolism in peripheral tissues such as the adipose tissue and muscles has been done by indirect measurements on whole body metabolism or in cannulated limbs. The microdialysis technique (1) was first invented and further developed (2) by neurobiologists for regional measurements in the rat brain. During the last ten years the technique has been used in several other organs in laboratory animals and since the first application in man (3) it has become wide spread for clinical investigation of human metabolism as well as for clinical pharmacology research. In this article some methodological aspects will be discussed and a few examples of the application of the technique will be given. PMID: 9288566 [PubMed - indexed for MEDLINE] 5858. Obes Res. 1997 Jul;5(4):360-72. Enterostatin--a peptide regulating fat intake. Erlanson-Albertsson C(1), York D. Author information: (1)Department of Cell and Molecular Biology, University of Lund, Sweden. A high fat intake, together with an inability to match lipid oxidation to fat intake, has been found to be correlated with obesity in humans. This review describes our current understanding of enterostatin, a peptide that selectively reduces fat intake. Enterostatin is formed in the intestine by the cleavage of secreted pancreatic procolipase, the remaining colipase serving as an obligatory cofactor for pancreatic lipase during fat digestion. Enterostatin is also produced in the gastric mucosa and the mucosal epithelia of the small intestine. Procolipase gene transcription and enterostatin release into the gastrointestinal lumen are increased by high-fat diets. After feeding, enterostatin appears in the lymph and circulation. Enterostatin will selectively inhibit fat intake during normal feeding and in experimental paradigms that involve dietary choice. Its anorectic effect has been demonstrated in a number of species. Both peripheral and central sites of action have been proposed. The peripheral mechanism involves an afferent vagal signaling pathway to hypothalamic centers. The central responses are mediated through a pathway that includes both serotonergic and opioidergic components. Chronically, enterostatin reduces fat intake, bodyweight, and body fat. This response may involve multiple metabolic effects of enterostatin, which include a reduction of insulin secretion, an increase in sympathetic drive to brown adipose tissue, and the stimulation of adrenal corticosteroid secretion. A possible pathophysiological role is suggested by studies that have linked low enterostatin production and/or responsiveness to strains of rat that become obese and prefer dietary fat. Humans with obesity also exhibit a lower secretion of pancreatic procolipase after a test meal, compared with persons of normal weight. PMID: 9285845 [PubMed - indexed for MEDLINE] 5859. Proc Nutr Soc. 1997 Jul;56(2):731-7. Lipoprotein lipase (EC 3.1.1.34) targeting of lipoproteins to receptors. Beisiegel U(1), Heeren J. Author information: (1)Medical Clinic, University Hospital Eppendorf, Hamburg, Germany. Summarizing all available data on the role of lipases in targeting lipoproteins to their receptors, we propose the following model: TRL after hydrolysis by LPL have apo E exposed on their surface and might contain one or more molecules of LPL. Both 'apolipoproteins' direct the particles to the cell surface by high-affinity binding to cellular proteoglycans. HL, bound to the surface of hepatocytes can further hydrolyse the particles and together with apo E and LPL mediate the binding to cellular receptors. The most important receptors recognizing these remnants are LRP and VLDLR. The LRP seems to be mainly responsible for the hepatic uptake of remnant lipoproteins, while the VLDLR, mainly located in adipose tissue and muscle, might target the lipoproteins to these tissues for fatty acid delivery. PMID: 9264123 [PubMed - indexed for MEDLINE] 5860. Proc Nutr Soc. 1997 Jul;56(2):713-21. Regulation of the plasma non-esterified fatty acid concentration in the postprandial state. Frayn KN(1), Summers LK, Fielding BA. Author information: (1)Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford. PMID: 9264121 [PubMed - indexed for MEDLINE] 5861. Sports Med. 1997 Jul;24(1):55-64. Effects of diet- and exercise-induced weight loss on visceral adipose tissue in men and women. Ross R(1). Author information: (1)School of Physical and Health Education, Queen's University, Kingston, Ontario, Canada. rossr@post.queensu.ca The effects of diet- and exercise-induced weight loss on visceral adipose tissue (VAT) distribution in both men and women have been reviewed. In general, current knowledge is based on studies that have assessed the influence of diet alone on VAT in obese women. For every kilogram of diet-induced weight loss, the corresponding reduction in VAT expressed in absolute terms is approximately 3 to 4 cm2, and in relative terms is approximately 2 to 3%. Thus, a diet-induced weight loss of approximately 12 kg corresponds to a 30 to 35% reduction in VAT. Two studies that consider the effects of exercise per se on VAT report conflicting results. There appears to be a resistance to VAT reduction in obese women, whereas exercise-induced weight loss is associated with significant reductions in VAT in men. It was also reported that in obese men, reductions in VAT induced by the combination of diet and exercise are not different from those observed in response to diet alone. It is unclear whether the results of these studies reflect a biological truth or are confounded by methodological problems associated with the control of energy intake and expenditure in free-living patients. Evidence suggests that changes in waist circumference and sagittal diameter are well correlated with corresponding changes in VAT. A 1 cm reduction in waist circumference corresponds to a 5 cm2 (4%) reduction in VAT area at the L3 level. Data on the separate effects of diet- and exercise-induced weight loss on VAT from well controlled studies are required to advance current knowledge with respect to the effects of diet and exercise on the adipose tissue depot that conveys the greatest health risk. PMID: 9257410 [PubMed - indexed for MEDLINE] 5862. J Pediatr. 1997 Jul;131(1 Pt 2):S70-4. Is growth hormone good for the heart? Silverman BL(1), Friedlander JR. Author information: (1)Division of Endocrinology, Children's Memorial Hospital, Chicago, IL 60614, USA. Growth hormone (GH), probably acting indirectly through locally produced insulin-like growth factor I, stimulates myocardial hypertrophy and increases myocyte contractility. In experimental models insulin-like growth factor I appears to be a key regulator of ventricular hypertrophy. Many adults with growth hormone deficiency (GHD) have reduced left ventricular mass, a lower ejection fraction, and reduced exercise tolerance. Elevated serum lipid levels, increased visceral fat, and early atheroma formation may contribute to an increased mortality rate from cardiovascular disease in these persons, but GH replacement therapy appears to correct many of these abnormalities. GH excess (acromegaly) results in cardiac hypertrophy that can progress to cardiac failure. Treatment with octreotide at least partially reverses cardiac hypertrophy and dysfunction. GH treatment may induce beneficial cardiac hypertrophy in adults without GHD who have dilated cardiomyopathy. Significant cardiac dysfunction has not been reported in children with GHD who are treated with GH, nor have adverse cardiac effects been reported with GH in short children without GHD, including those with Turner syndrome. We now have extensive experience with the therapeutic use of GH in children with cardiac structural abnormalities (e.g., Turner and Noonan syndromes, congenital heart disease), and such use appears to be safe. Furthermore, cardiac complications of GH in children without cardiac disease are rare. Continued observation to ensure that GH therapy has no long-term effects on cardiac anatomy or function in children is necessary. PMID: 9255233 [PubMed - indexed for MEDLINE] 5863. Toxicol Ind Health. 1997 Jul-Aug;13(4):407-84. Physiological parameter values for physiologically based pharmacokinetic models. Brown RP(1), Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Author information: (1)Risk Science Institute, International Life Sciences Institute Washington, DC, USA. PMID: 9249929 [PubMed - indexed for MEDLINE] 5864. Thromb Haemost. 1997 Jul;78(1):656-60. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Juhan-Vague I(1), Alessi MC. Author information: (1)Laboratory of Hematology, University Hospital Timone, Marseille, France. Circulating (PAI-1) levels are elevated in patients with coronary heart disease and may play an important role in the development of atherothrombosis. Many clinical studies have indicated that the insulin resistance syndrome, which is a situation predisposing to diabetes and ischemic heart disease, may be a major regulator of PAI-1 expression, especially in determining plasma PAI-1 levels. Central obesity is a characteristic of insulin resistance and is a well recognized risk factor for coronary heart disease. Recently the production of PAI-1 by adipose tissue, in particular by tissue from omentum, has been demonstrated and could be an important contributor to the elevated plasma PAI-1 levels observed in insulin resistant patients. Besides the effect of the metabolic status on plasma PAI-1 levels, the role of a genetic control has been emphasized, but according to recent results obtained in a family segregation study, its participation seems limited. Prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between increased plasma PAI-1 levels and the risk of coronary events, but the predictive capacity of PAI-1 disappears after insulin resistance marker adjustments. Taken together these results support the notion that PAI-1 can be a link between obesity, insulin resistance and cardiovascular disease. PMID: 9198234 [PubMed - indexed for MEDLINE] 5865. Thromb Haemost. 1997 Jul;78(1):652-5. The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM. Samad F(1), Loskutoff DJ. Author information: (1)Department of Vascular Biology, Scripps Research Institute, La Jolla, CA 92037, USA. Plasminogen activator inhibitor-1 is elevated in obesity and may be a risk factor for obesity/NIDDM related cardiovascular disease. In spite of this, little is known about the tissue and cellular origin of elevated PAI-1 in obesity or of the mediators and molecular mechanisms that regulate it. We have begun to systematically address these issues using genetically obese (ob/ob, db/db) mice. Plasma PAI-1 levels were 5-fold higher in obese mice compared to their lean counterparts. Subsequent RT-PCR and in situ hybridization studies suggest that the increased plasma PAI-1 originates primarily from the adipocyte in response to chronically elevated levels of tumor necrosis factor-alpha (TNF-alpha), insulin, and transforming growth factor-beta (TGF-beta). Thus, the signals and mechanisms that lead to elevated plasma PAI-1 observed in obesity are complex, and appear to involve interactions between multiple mediators and the adipose tissue itself. PMID: 9198233 [PubMed - indexed for MEDLINE] 5866. N Engl J Med. 1997 Jun 19;336(25):1802-11. Seminars in medicine of the Beth Israel Deaconess Medical Center. Neuroendocrine responses to starvation and weight loss. Schwartz MW(1), Seeley RJ. Author information: (1)Department of Medicine, University of Washington, Harborview Medical Center, Seattle, USA. PMID: 9187072 [PubMed - indexed for MEDLINE] 5867. Eat Weight Disord. 1997 Jun;2(2):61-6. Leptin and obesity in humans. Considine RV(1). Author information: (1)Division of Endocrinology and Metabolism, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. It now appears that leptin is the peripheral signal, hypothesized in the lipostasis theory, that informs the central nervous system how much adipose tissue there is in the body. The ability of the leptin signal to regulate body composition and the amount of body fat has been demonstrated in animals. Furthermore, defects in the ob gene and the leptin receptor lead to the development of obesity in rodents. No such defects have been found in humans although it appears that obese humans are resistant to the action of their endogenous leptin. Further characterization of the hormone and ultimately, the administration of leptin to humans, will be necessary to determine the role of the leptin signal system in the development of obesity in humans. PMID: 14655844 [PubMed - indexed for MEDLINE] 5868. Microcirculation. 1997 Jun;4(2):211-32. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Crandall DL(1), Hausman GJ, Kral JG. Author information: (1)Department of Vascular Biology, Wyeth-Ayerst Research, Princeton, NJ 08543, USA. Adipose tissue microcirculation is unique within the vascular system because of a capacity for this tissue to grow throughout most of adult life. A review of the microcirculation of adipose tissue has included a historical review of the early studies, which served as a foundation for later investigations on this topic, including basic hemodynamic measurements in mammalian adipose tissue. The various methods for measuring blood flow in white and brown adipose tissue are discussed with respect to studies of transport of substrates involved in adipose tissue metabolism. The role of innervation and vascular adrenergic receptors and the effects of diet and exercise on adipose tissue blood flow are also included. An in-depth analysis of the development of adipose tissue microvasculature indicates that angiogenesis often precedes adipogenesis. The clinical effects of hemodynamic adaptations to adipose tissue expansion are discussed in view of an epidemic increase in the prevalence of obesity and its co-morbidities. The recent discovery of sites of nuclear regulation of adipocyte differentiation, together with the identification of growth factors in adipose tissue, is an indication of the progress that is being made in the further understanding of molecular and cellular events that affect adipose tissue growth and, ultimately, adipose tissue microcirculation. PMID: 9219215 [PubMed - indexed for MEDLINE] 5869. FASEB J. 1997 Jun;11(7):544-58. The role of glucose 6-phosphate in the control of glycogen synthase. Villar-Palasí C(1), Guinovart JJ. Author information: (1)Department of Pharmacology, Medical School, University of Virginia, Charlottesville 22908, USA. Elevated blood glucose concentrations result in increased intracellular levels of glucose 6-phosphate in liver, skeletal muscle, and adipose tissue. In liver, blood glucose concentrations are the main factor in control of the synthesis of glycogen; insulin has only a potentiating effect. In skeletal muscle and adipocytes, glucose alone has little effect on the activity of glycogen synthase, the limiting enzyme in glycogen synthesis. However, insulin released as a result of elevated blood glucose stimulates the translocation of specific glucose transporters to the cell membrane, increases the uptake of glucose, and causes the covalent, dephosphorylation-mediated activation of glycogen synthase. We present evidence that elevated intracellular contents of glucose 6-phosphate provoke the activation of glycogen synthase in liver, muscle, and adipose tissue. In addition, glucose 6-phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP-stimulated protein kinase. We show that the stimulated glucose uptake and phosphorylation appear to play a major role in the control by insulin of the enzymes involved in glycogen synthesis. PMID: 9212078 [PubMed - indexed for MEDLINE] 5870. Clin Biochem. 1997 Jun;30(4):301-12. The acylation stimulating protein pathway: clinical implications. Cianflone K(1). Author information: (1)McGill Unit for the Prevention of Cardiovascular Disease, McGill University, Montreal, Quebec, Canada. OBJECTIVES: The present review will focus particularly on acylation stimulating protein (ASP) and its role in adipose tissue. Two issues will be addressed (1) in vitro biochemical characterization of ASP in cell culture studies, and (2) in vivo clinical relevance for normal physiology and in pathological conditions. CONCLUSIONS: Fat is In! There can be no question that in recent years fat tissue has become recognized as more than just a passive storage site. It is a metabolically active tissue that, under normal conditions, allows the efficient clearance of triglyceride and glucose for storage as energy. Under abnormal conditions, adipose tissue dysfunction is associated with obesity, diabetes and coronary heart disease. Adipose tissue function may be controlled by many factors. PMID: 9209788 [PubMed - indexed for MEDLINE] 5871. Toxicol Appl Pharmacol. 1997 Jun;144(2):340-7. Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls. Parham FM(1), Kohn MC, Matthews HB, DeRosa C, Portier CJ. Author information: (1)OAO/National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Physiologically based pharmacokinetic (PBPK) models are useful in describing the distribution, metabolism, and fate of xenobiotics across multiple species. The eventual goal of the present research is to create PBPK models for all 209 polychlorinated biphenyls (PCBs). Key parameters in any PBPK model are the tissue-to-blood partition coefficients. Tissue:blood partition coefficients relate the compound's concentration in a target tissue to its concentration in blood under equilibrium conditions. Data on the adipose:plasma partition coefficients of 24 PCBs were used in a regression analysis to find an expression for the adipose:plasma partition coefficient as a function of molecular structure. Using stepwise regression, it was found that three simple structural descriptors were sufficient to predict adipose:plasma partition coefficients for all 209 PCB congeners. Data on the distribution of PCBs among blood components were used to derive the adipose:blood partition coefficient from the adipose:plasma partition coefficient. The lipid contents of liver, muscle, and skin were used to derive the tissue:blood partition coefficient for those tissues from the adipose:blood partition coefficient. These results allow for the calculation of tissue:blood partition coefficients for liver, skin, muscles, and fat for all 209 PCB congeners. PMID: 9194418 [PubMed - indexed for MEDLINE] 5872. Ann N Y Acad Sci. 1997 May 30;820:97-122. Multiecho approaches to spectroscopic imaging of the brain. Mulkern RV(1), Chao H, Bowers JL, Holtzman D. Author information: (1)Department of Radiology, Children's Hospital, Boston, Massachusetts 02115, USA. mulkern@bwh.harvard.edu Spectroscopic imaging (SI) with nuclear magnetic resonance (NMR) is one of the most powerful tools available for studying brain chemistry in vivo. Both proton (1H) and phosphorus (31P) NMR offer valuable biochemical information that can in principle be mapped throughout the entire brain, thereby enhancing our understanding of brain function. With the exception of protons from tissue water and the triglycerides of adipose tissue, however, nuclei contributing to the NMR signals of living tissue are in relatively small (millimolar) concentrations. The low concentration of metabolite nuclei reduces the overall sensitivity of conventional SI techniques, making high-quality metabolite mapping a lengthy procedure. This problem has led to the development and testing of nonconventional methods for reducing SI scan times, including techniques based on the collection of multiple spin-echoes. The extent to which multiecho methods can be used to decrease SI scan times and maintain high-quality metabolite mapping depends on several factors. These include the spectral transverse relaxation times, the spectral resolution required, and J-coupling interactions. We have discussed these various technical aspects of multiecho SI methods as applied to 1H and 31P spectroscopic imaging of the living brain. PMID: 9237451 [PubMed - indexed for MEDLINE] 5873. Eur J Endocrinol. 1997 May;136(5):461-4. Human leptin: the hormone of adipose tissue. Sinha MK(1). Author information: (1)Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA. PMID: 9186262 [PubMed - indexed for MEDLINE] 5874. J Nutr. 1997 May;127(5 Suppl):943S-947S. Genetic influences on the response of body fat and fat distribution to positive and negative energy balances in human identical twins. Bouchard C(1), Tremblay A. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. This article summarizes a series of intervention studies conducted with pairs of young adult male identical twins and designed to determine whether there is any evidence for genotype x overfeeding or genotype x negative energy balance interaction effects in the changes in body weight, body composition, fat distribution, computerized tomography-assessed abdominal visceral fat, resting metabolic rate and thermic response to a standardized meal of mixed composition brought about by chronic exposure to appropriate experimental treatments. These studies demonstrated that individual differences in response to chronic alterations in energy balance are common. The comparison of the heterogeneity in response between the pairs of twins in contrast to the variance within pairs revealed that members of the same twin pair are significantly more alike than individuals who are not genetically related by descent. The intrapair resemblance in response was particularly strong for the changes in body mass, body composition, subcutaneous fat distribution and abdominal visceral fat. In contrast, the results of two long-term intervention studies showed that variations in resting metabolic rate following exposure to chronic overfeeding or negative energy balance induced by exercise were accounted for primarily by the changes in body mass. Finally, the thermic response to food was not modified by any of the experimental treatments. On the basis of these observations, we conclude that there are individuals at risk of gaining weight and body fat or who are resistant to weight loss. These differences in susceptibility to chronic overfeeding or in sensitivity to negative energy balance seem to be largely explained by genetic factors whose exact nature remains to be determined. PMID: 9164270 [PubMed - indexed for MEDLINE] 5875. J Nutr. 1997 May;127(5 Suppl):940S-942S. Progress in understanding the genetics of obesity. Bray GA(1). Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808, USA. Progress in understanding the genetics of obesity has moved rapidly in the past few years. The genes for all of the single gene defects that produce obesity in experimental animals have now been cloned. The new insights from these models are one spur for the examination of possible links to human obesity. In thinking about the biology of obesity produced by single gene defects, it must be kept in mind that adrenalectomy can prevent the phenotypic expression in all of the single gene models of obesity. Thus, nongenetic components can play a major role in regulating even single gene models of obesity. Transgenic mice have also expanded our understanding of obesity. Transgenic models that both increase and decrease body fat have been published. Of particular interest from the perspective of the physiological control of obesity is the destruction of the uncoupling protein in brown adipose tissue, which is followed by hyperphagia and obesity, suggesting that the sympathetic nervous system is involved in both modulation of food intake and energy storage. Gene mapping using quantitative trait loci and studies of candidate genes have been applied to experimental models of animals with differing susceptibilities to dietary fat and have been applied to the human genome in more detail. PMID: 9164269 [PubMed - indexed for MEDLINE] 5876. J Nutr. 1997 May;127(5 Suppl):805S-808S. Lipoprotein metabolism and fattening in poultry. Hermier D(1). Author information: (1)INRA, Station de Recherches Avicoles, Nouzilly, France. Because de novo fatty acid synthesis in birds takes place mainly in the liver, adipose tissue growth and subsequent fattening depend on the availability of plasma triglycerides, which are transported as components of lipoproteins. In growing birds, VLDL is the major transporter of triglycerides, and attempts to reduce excessive fatness in poultry have involved the control of VLDL metabolism. Lean and fat lines of chickens have been selected on the basis of either their abdominal fat content or plasma VLDL concentration. In both cases, hepatic lipogenesis or LPL activity in adipose tissue did not differ between lean and fat lines, and therefore they did not appear to be limiting factors of susceptibility to fattening. In contrast, hepatic secretion and plasma concentration of VLDL were always higher in fat chickens than in lean chickens. Thus, current methods of selection of broilers against excessive fatness are based on this direct relationship between plasma VLDL and adiposity. When hepatic lipogenesis exceeds the capacity of VLDL secretion, triglycerides accumulate in the liver, causing steatosis. Although fatty liver is associated with reduced egg production and increased mortality in laying hens, hepatic steatosis in overfed ducks and geese is of positive economic value, serving as the basis for "foie-gras" production. The balance between synthesis and secretion of VLDL is therefore the key point that regulates hepatic and extrahepatic fattening in poultry. PMID: 9164241 [PubMed - indexed for MEDLINE] 5877. J Cardiothorac Vasc Anesth. 1997 May;11(3):337-40. Elimination of drugs and toxins during cardiopulmonary bypass. Rosen DA(1), Rosen KR. Author information: (1)Department of Anesthesiology, Robert C. Byrd Health Sciences Center of West Virginia, Morgantown 26506-9134, USA. Cardiopulmonary bypass (CPB) creates a myriad of pharmacological and physiological changes. Some of these changes have been studied in isolated in vitro studies. Integrating an in vitro system into an in vivo process is so complicated that many pharmacological studies simply avoid the bypass period. For the most part, the studies that do examine the bypass period deal with a single drug, reporting how it does or does not produce a predicted concentration on initiation, maintenance and termination of CPB. Based on the isolated results of these studies, this review hypothesizes a model that explains how different substances interact with the CPB system. A summary of the review's findings include the following: 1) drugs with a smaller volume of distribution are more likely to be effected; 2) the pharmacokinetic effects of lipophilic drugs undergo more alterations than hydrophilic drugs; and 3) protein binding minimizes alterations of lipophilic drugs and increase alterations of hydrophilic drugs. PMID: 9161903 [PubMed - indexed for MEDLINE] 5878. Med Sci Sports Exerc. 1997 May;29(5):635-9. Effect of endurance training on fatty acid metabolism during whole body exercise. Martin WH 3rd(1). Author information: (1)Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Endurance exercise training increases fat oxidation during large muscle mass exercise. Although the source of this fat has been thought to be plasma free fatty acids (FFA) released from adipose tissue, the training-induced decrease in lipolytic hormonal responses to exercise is not consistent with this concept. The purpose of this communication is to review findings, from our laboratory indicating that, in young healthy subjects, endurance exercise training reduces plasma FFA turnover and oxidation during moderate intensity prolonged 2-leg cycling while simultaneously enhancing depletion of triglycerides from the active musculature. Evidence is presented that metabolism of intramuscular triglycerides can explain the increase in total fat oxidation observed in the trained state during large muscle mass exercise. However, these results may not be applicable to exercise involving small muscle groups, a distinction that is likely to be important in explaining the apparent conflict between our findings and those from other laboratories where experimental conditions were different. In summary, for large muscle mass exercise up to 2 h in duration, plasma FFA are a less important fuel source in the trained state, and intramuscular triglycerides supply the major portion of the increase in oxidized fatty acids. PMID: 9140900 [PubMed - indexed for MEDLINE] 5879. Cancer Genet Cytogenet. 1997 May;95(1):1-8. Clinical significance of cytogenetic findings in solid tumors. Mitelman F(1), Johansson B, Mandahl N, Mertens F. Author information: (1)Department of Clinical Genetics, University Hospital, Lund, Sweden. Chromosome analysis of solid tumors is becoming an increasingly useful tool to help establish a correct diagnosis and to provide prognostically important information. Characteristic karyotypic patterns in terms of degree of cytogenetic complexity and type of nonrandom abnormalities may help to distinguish neoplasia from a nonneoplastic lesion and to differentiate between a benign and a malignant tumor. More importantly, the presence of a specific or pathognomonic change may confirm or refute a suspected diagnosis, provide an alternative, unsuspected diagnosis, and trace the origin of a metastasis. Presently, specific cytogenetic abnormalities may be of substantial, and sometimes decisive, help in four groups of differential diagnostic dilemmas: (1) Benign vs. malignant epithelial tumors of the kidney, thyroid gland, salivary glands, and ovary; (2) Benign vs. malignant mesenchymal tumors of adipose and muscle tissue; (3) Differentiation between various malignant bone and soft tissue tumors: and (4) Diagnosis of undifferentiated small-cell round-cell tumors. In addition to the diagnostic value, karyotypic findings may provide prognostic information. Thus, the presence of an abnormal clone and/or complex rearrangements is a poor prognostic sign in, e.g., carcinomas of the ovary, prostate, bladder, colon, and pancreas. Furthermore, characteristic cytogenetic aberrations are now known to be valuable prognostic parameters in malignant melanoma, malignant fibrous histiocytoma, germ cell tumors, neuroblastoma, and squamous cell carcinoma of the head and neck region. Many of the correlation analyses are preliminary, but they all point in the same direction, namely that cytogenetic studies will soon play the same essential role in the management of patients with solid tumors as they do today in hematologic oncology. PMID: 9140447 [PubMed - indexed for MEDLINE] 5880. Cas Lek Cesk. 1997 Apr 16;136(8):240-1. [Endocrinology 1995-1996]. [Article in Czech] Schreiber V(1). Author information: (1)Laborator pro endokrinologii a metabolismus 1. LF UK a VFN, Praha. In a brief review of advances in endocrinology in the last two years the author discusses above all the vain expectations of a drug against obesity-the adipose tissue hormone leptin. Its elevated blood level in human obesity indicates that its secretion depends on the mass of adipose tissue and it is not certain whether leptin reduces the food intake in humans. Perhaps resistance to leptin is involved. New receptor diseases were revealed: mutation of LH receptors leads in both sexes to hypogonadism. Mutation of the calcium receptor in parathyroid cells leads to familial hypocalciuric hypercalcaemia or autosomal dominant hypocalcaemia. The complex regulation of the tonus of the vascular wall by endothelins is still the object of interest. Aquaporin is a renal protein which mediates the action of vasopressin. In the sphere of stress evidence is emerging on the participation of CRH in brain activity and the possibility to influence autoimmune inflammations and perhaps even AIDS by interference with the CRH-proopiomelanocortin-ACTH-cortisol system. PMID: 9264867 [PubMed - indexed for MEDLINE] 5881. Ann N Y Acad Sci. 1997 Apr 15;811:350-8; discussion 358-60. Expression of fibrinolytic genes in tissues from human atherosclerotic aneurysms and from obese mice. Samad F(1), Schneiderman J, Loskutoff D. Author information: (1)Scripps Research Institute, Department of Vascular Biology, La Jolla, California 92037, USA. The disturbances in the balance of pro- and antifibrinolytic activity, as observed in AAA and obesity, respectively, have considerable potential for influencing both intra- and extravascular fibrinolytic events and may be causally related to the development of vascular disease. For example, the wall of the aortic atherosclerotic aneurysm seems to host an uneven distribution and imbalanced expression of the various components of the fibrinolytic system. The sites of increased proteolytic activity may contribute to localized neovascularization and promote the rapid breakdown of ECM components, which result in mural weakening and eventual rupture of untreated aortic aneurysms. On the other hand, the disturbance of the normal hemostatic balance observed in obesity appears to result from the elevated expression of PAI-1 by the adipose tissue. Our data strongly suggest that the adipocyte is one of the primary cells in the adipose tissue capable of expressing PAI-1 both in obesity, and in response to cytokines and hormones like TNF-alpha and insulin. Since both TNF-alpha and insulin are known to increase in obesity, the elevated levels of PAI-1 observed in the plasma of obese individuals may result from TNF-alpha and/or insulin induction of PAI-1 in the adipose tissue itself. PMID: 9186610 [PubMed - indexed for MEDLINE] 5882. Mol Cell Endocrinol. 1997 Apr 4;128(1-2):171-7. Obesity, diabetes and functions for proopiomelanocortin-derived peptides. Mountjoy KG(1), Wong J. Author information: (1)Research Centre for Developmental Medicine and Biology, Department of Paediatrics, University of Auckland, New Zealand. Melanocortin peptides (adrenocorticotropin (ACTH), alpha-,beta-, and gamma-melanocyte stimulating hormone (MSH), and fragments thereof) derived from proopiomelanocortin (POMC) have a diverse array of biological activities, many of which have yet to be fully elucidated. The recent cloning of a family of five distinct melanocortin receptors through which these peptides act has provided the tools to further our understanding of melanocortin peptide functions. Early work on melanocortin peptides focused on their roles in pigmentation, adrenocortical function, the immune, central and peripheral nervous systems. Although melanocortin peptides have long been known to affect lipolysis, characterisation of the melanocortin receptors has opened up several lines of evidence for important roles in the development of obesity, insulin resistance and type II diabetes. We present here a review of the current evidence for melanocortin peptides playing such a role, and based on this evidence, a model for melanocortin peptides and their receptors in maintaining energy balance. PMID: 9140088 [PubMed - indexed for MEDLINE] 5883. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):293-8. Aromatase expression and its localization in human breast cancer. Sasano H(1), Ozaki M. Author information: (1)Department of Pathology, Tohoku University School of Medicine, Sendai, Japan. Aromatization or in situ estrogen production by aromatase has been considered to play an important role in the development of human breast carcinoma. In the human breast, aromatase overexpression is observed in the stromal or interstitial cells of the carcinoma, especially at the sites of frank invasion and/or adipose tissue. Transplantation experiments in the nude mouse employing MCF-7 and/or SF-TY human fibroblast cell lines revealed that aromatase activity and expression were much higher in the tumour with MCF-7 and SF-TY than that with MCF-7 alone. Aromatase overexpression in human breast carcinoma tissue is considered to occur as a result of carcinoma-stromal cell interactions, i.e. paracrine communication between stromal and carcinoma cells. Aromatase overexpression is correlated with the malignant phenotype in the human breast, but not with stage, age, clinical stages, clinical course, or proliferative activity of breast carcinoma. Aromatase overexpression may be correlated with development, rather than the biological behaviour of breast malignancy. Aromatase overexpression is not necessarily correlated with expression of 17beta-hydroxysteroid dehydrogenase type 1, which converts estrone to estradiol and estrogen receptor. Different mechanisms may be involved in the regulation of expression of these two important estrogen-metabolizing enzymes and estrogen receptor in human breast cancer. Aromatase overexpression in intratumoral stromal cells was much more frequently detected in male breast cancer than in female counterparts, which confers a growth advantage on cancer cells in a male hormonal environment with low serum estrogen levels. PMID: 9365204 [PubMed - indexed for MEDLINE] 5884. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):281-6. Aromatase in the normal breast and breast cancer. Brodie A(1), Lu Q, Nakamura J. Author information: (1)Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, U.S.A. Adipose tissue and muscle constitute the larger proportion of body mass, and therefore aromatization in these tissues is the major source of circulating estrogens in postmenopausal women. Although plasma estrogen concentrations are very low, levels in breast cancers from postmenopausal patients are reported to be 10-fold higher than in plasma and normal tissue. Whereas studies on aromatase activity in the tumor suggest that estrogen may be produced locally, the significance of this contribution has been questioned. Using immunocytochemistry (ICC) to an anti-aromatase antibody, a relatively strong immunoreaction was detected in tumor epithelial cells as well as in the terminal ductal lobular units (TDLUs) of the normal breast. Aromatase expression was detected in the cytoplasm of tumor epithelial cells and the surrounding stromal cells of over 50% of tumors in a series of 19 breast cancers. In situ hybridization (ISH) to aromatase mRNA confirmed the immunocytochemical result that the epithelial cells are the primary site of estrogen synthesis in the breast and breast cancers. In the 10 tumors which showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 fmol estrogen/mg protein/h (SE), whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 fmol estrogen/mg protein/h (P < 0.05) (SE). The functional significance of tumor aromatase and locally produced estrogens on the growth of tumors was suggested by the correlation between aromatase activity and proliferating cell nuclear antigen (PCNA), a marker of cell proliferation (P < 0.005). Although intratumoral aromatase activity did not correlate with steroid receptors significantly, there was a trend for estrogen receptor (ER)-positive tumors to express aromatase. In addition, proliferation ([3H]-thymidine incorporation into DNA) during histoculture, was increased by both estradiol and testosterone in tumors with high aromatase activity. Our results suggest that some tumors synthesize sufficient estrogen to stimulate their proliferation. It may thus be important to inhibit tumor aromatase as well as to reduce circulating levels of estrogen for effective breast cancer treatment. PMID: 9365202 [PubMed - indexed for MEDLINE] 5885. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):273-80. Gene regulation studies of aromatase expression in breast cancer and adipose stromal cells. Zhou D(1), Zhou C, Chen S. Author information: (1)Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, U.S.A. The expression of aromatase in human breast tumors was studied using the reverse transcription-polymerase chain reaction (RT-PCR) method on 70 breast tissue specimens. An RT-PCR analysis using two oligonucleotide primers derived from exon II of the human aromatase gene revealed that aromatase mRNA was detected in all but three tissue specimens. Furthermore, primer-directed RT-PCR was performed to determine the exon I usage in aromatase mRNA in these breast tumor specimens. The analysis revealed that exons I.3 and PII are the two major exons I present in aromatase mRNA isolated from breast tumors, suggesting that promoters I.3 and II are the major promoters driving aromatase expression in breast cancer and surrounding adipose stromal cells (ASCs). Recently, the regulatory properties of a 696-base pair region that contains promoter II, and is situated immediately upstream of exon II of the human aromatase gene, were investigated. Detailed DNase 1 footprinting analysis, DNA mobility shift assays, and chloramphenicol acetyltransferase (CAT) functional studies of this genomic region were performed and led to the identification of a segment (B1) that could act as a promoter (probably promoter I.3) in adipose stromal and breast cancer cells. The study further revealed that the B1 region could be divided into two domains which were designated RE1 and RE2. RE1 was found to have the promoter activity, and RE2 was found to regulate the promoter activity of RE1, but in different manners in MCF-7 cells (as an example of breast cancer cells) and in ASCs. RE2 was found to function as a positive regulatory element in MCF-7 cells and as a negative regulatory element in ASCs, respectively. It was also found that in several breast cancer cell lines, including MCF-7, the promoter activities of both promoter II and promoter I.3 were found to be suppressed by a negative regulatory element, a silencer, present in the 162 bp fragment which is located upstream from promoter II and downstream from promoter I.3. The precise position of the silencer element (termed S1) was localized by deletion mutation and DNase 1 footprinting analysis, and the silencing activity of S1 on promoter I.3 (in B1 fragment) was confirmed by CAT plasmid transfection experiments. UV crosslinking experiments are being performed to examine the regulatory proteins interacting with the silencer element. These studies serve as the basis for the further characterization of the regulatory mechanism of aromatase expression in human breast cancer and ASCs. PMID: 9365201 [PubMed - indexed for MEDLINE] 5886. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):133-9. Endocrine disorders associated with inappropriately high aromatase expression. Bulun SE(1), Noble LS, Takayama K, Michael MD, Agarwal V, Fisher C, Zhao Y, Hinshelwood MM, Ito Y, Simpson ER. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9051, U.S.A. Bulun@grnctr.swmed.edu Aromatase P450 (P450arom) is responsible for conversion of C19 steroids to estrogens in a number of human tissues, such as the placenta, gonads, adipose tissue, skin and the brain. Aromatase expression in human tissues is regulated by use of alternative promoters in the placenta (promoter I.1), adipose tissue (promoters I.4, I.3 and II) and gonads (promoter II). Aromatase expression is absent in the disease-free adult liver, adrenal and uterine tissues. Excessive or inappropriate aromatase expression in adipose fibroblasts and endometriosis-derived stromal cells, as well as in testicular, hepatic, adrenal and uterine tumors, is associated with abnormally high circulating estrogen levels and/or with increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will in turn promote the growth of hormone-responsive tissues. We recently studied aromatase expression in testicular tumor and adipose tissue samples from prepubertal boys with gynecomastia, in hepatocellular cancer and adrenocortical tumor samples from adult men with gynecomastia, in breast adipose tissue samples proximal to breast tumors, and in endometrial cancer, leiomyoma and endometriosis tissues. Excessive aromatase activity and P450arom transcript levels were found in these tissue samples or in cultured cells derived from these tissues. In these neoplastic or non-neoplastic tissues or cells, the regulation of aromatase expression was studied in terms of alternative promoter use, both in vivo and in response to various hormonal stimuli. Our results were suggestive of a common metabolic abnormality associated with activation of a cyclic AMP-dependent signalling pathway that gives rise to transcriptional transactivation of aromatase expression via promoters I.3 and II in all of the above tissues. This article describes the common pathophysiological and molecular features of excessive aromatase expression in these disease states. PMID: 9365182 [PubMed - indexed for MEDLINE] 5887. Curr Opin Lipidol. 1997 Apr;8(2):89-94. Is familial combined hyperlipidaemia a genetic disorder of adipose tissue? Arner P(1). Author information: (1)Karolinska Institute, Department of Medicine, Huddinge Hospital, Sweden. Familial combined hyperlipidaemia is a common cause of coronary heart disease. Its aetiology is heterogeneous. The genetic and metabolic basis of the disorder has not yet been defined. This review discusses the putative role of adipose tissue in the pathogenesis of familial combined hyperlipidaemia. It is possible that mutations in genes regulating the turnover of lipids in fat cells are involved in the aetiology. PMID: 9183546 [PubMed - indexed for MEDLINE] 5888. Curr Opin Lipidol. 1997 Apr;8(2):77-88. The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism. Zechner R(1). Author information: (1)SFB Biomembrane Research Center, Institute of Medical Biochemistry, Kari-Franzens-University Graz, Austria. The dual function of lipoprotein lipase as a triglyceride hydrolase and a ligand/bridging factor for receptor-mediated lipoprotein uptake implies an important role of the enzyme in the distribution of fatty acids and lipoproteins among extrahepatic tissues. Observations in humans and, more recently, in several induced mutant mouse strains have provided important insights on how fat calories and lipids are partitioned to storage or energy production through the tissue-specific regulation of lipoprotein lipase in adipose tissue and muscle. Imbalances of the tissue-specific expression of lipoprotein lipase were recognized as potentially important effectors of lipoprotein metabolism, energy homeostasis and body weight regulation. PMID: 9183545 [PubMed - indexed for MEDLINE] 5889. Pediatr Clin North Am. 1997 Apr;44(2):339-61. Pediatric obesity. An overview of etiology and treatment. Schonfeld-Warden N(1), Warden CH. Author information: (1)Department of Pediatrics, University of California, Davis, Sacramento, USA. Pediatric obesity is a chronic and growing problem for which new ideas about the biologic basis of obesity offer hope for effective solutions. Prevalence of pediatric and adult obesity is increasing despite a bewildering array of treatment programs and severe psychosocial and economic costs. The definition of obesity as an increase in fat mass, not just an increase in body weight, has profound influence on the understanding and treatment of obesity. In principle, body weight is determined by a balance between energy expenditure and energy intake, but this observation does not by itself explain obesity. There is surprisingly little evidence that the obese overeat and only some evidence that the obese are more sedentary. Understanding of the biologic basis of obesity has grown rapidly in the last few years, especially with the identification of a novel endocrine pathway involving the adipose tissue secreted hormone leptin and the leptin receptor that is expressed in the hypothalamus. Plasma leptin levels are strongly correlated with body fat mass and are regulated by feeding and fasting, insulin, glucocorticoids, and other factors, consistent with the hypothesis that leptin is involved in body weight regulation and may even be a satiety factor (Fig. 2, Table 1). Leptin injections have been shown to reduce body weight of primates, although human clinical trials will not be reported until summer 1997. So many peptides influencing feeding have been described that one or more may have therapeutic potential (Fig. 2, Table 1). Although the complexity of pathways regulating body weight homeostasis slowed the pace of understanding underlying mechanisms, these complexities now offer many possibilities for novel therapeutic interventions (Fig. 2). Obesity is a major risk factor for insulin resistance and diabetes, hypertension, cancer, gallbladder disease, and atherosclerosis. In particular, adults who were obese as children have increased mortality independent of adult weight. Thus, prevention programs for children and adolescents will have long-term benefits. Treatment programs focus on modification of energy intake and expenditure through decreased calorie intake and exercise programs. Behavior-modification programs have been developed to increase effectiveness of these intake and exercise programs. These programs can produce short-term weight loss. Long-term losses are more modest but achieved more successfully in children than in adults. Several drug therapies for obesity treatment recently have been approved for adults that produce sustained 5% to 10% weight losses but experience with their use in children is limited. Identification of the biochemical pathways causing obesity by genetic approaches could provide the theoretic foundation for novel, safe, and effective obesity treatments. The cloning of leptin in 1994 has already led to testing the efficacy of leptin in clinical trials that are now underway. Although novel treatments of obesity are being developed as a result of the new biology of obesity, prevention of obesity remains an important goal. PMID: 9130924 [PubMed - indexed for MEDLINE] 5890. Drugs Aging. 1997 Apr;10(4):278-89. Anticonvulsant therapy in aged patients. Clinical pharmacokinetic considerations. Bernus I(1), Dickinson RG, Hooper WD, Eadie MJ. Author information: (1)Conjoint Endocrine Laboratory, Royal Brisbane Hospital, Queensland, Australia. mortomr@citec.qld.gov.au Alterations in drug disposition that occur with aging are now becoming widely recognised, and there is an increasing number of drugs for which the approach to therapy in elderly patients can be based on pharmacokinetic data. Both healthy aging and comorbid disease can alter the responsiveness of the body to drugs and to their absorption, distribution and elimination. Altered absorption in the elderly has not been documented after oral ingestion of any anticonvulsant drug. Increased adipose tissue in the elderly may raise the apparent volume of distribution (Vd) of lipid-soluble drugs. An increased Vd in the elderly has been shown for diazepam and clobazam, but not midazolam. The data are inconclusive for phenytoin and valproic acid (sodium valproate). The decreased plasma protein binding that often occurs in the elderly has few clinical consequences. The reduced liver function that to occur with aging seems to affect the elimination of drugs that are mainly cleared by oxidative metabolism [e.g. carbamazepine, phenytoin and phenobarbital (phenobarbitone)]. Reduced clearances for methylphenobarbital (methylphenobarbitone), diazepam, midazolam and clobazam occur in elderly men, but not in women. The reduced renal function that is seen in old age affects the disposition of drugs that are eliminated mainly by direct renal excretion. Thus. the clearances of vigabatrin and gabapentin correlate with creatinine clearance. Such considerations may help guide anticonvulsant dosage in the elderly. PMID: 9108988 [PubMed - indexed for MEDLINE] 5891. Internist (Berl). 1997 Mar;38(3):204-13. [Etiology of obesity]. [Article in German] Weck M(1), Fischer S. Author information: (1)Abteilung für Diabetes und Stoffwechselkrankheiten, Klinik Bavaria Kreischa. PMID: 9173041 [PubMed - indexed for MEDLINE] 5892. Proc Nutr Soc. 1997 Mar;56(1B):195-209. Energy expenditure, body composition, and disease risk in children and adolescents. Goran MI(1). Author information: (1)Department of Nutrition Sciences, University of Alabama, Birmingham 35294, USA. Recent methodological advances have led to a tremendous improvement in our ability to measure energy expenditure, body composition and fat distribution in children. The availability of new and improved measurement techniques has greatly enhanced the scope of research studies in children. The key findings from the present review are as follows: total energy expenditure in young children is approximately 25% lower than current recommendations for energy intake and revised recommendations are necessary; reduced energy expenditure, however, does not necessarily explain the greater prevalence of obesity in the population as a whole or in sub-groups at greater risk of obesity; qualitative aspects of physical activity (e.g. time, intensity) may be more important than the energy expenditure of physical activity in the regulation of body composition; for body composition assessment, DXA is emerging as a technique which can substantially improve the accuracy and standardization in children; body fat begins to accumulate in the obese; waist:hip ratio or waist circumference are inadequate markers of intra-abdominal adipose tissue in children and adolescents; finally, the early accumulation of fat in the intra-abdominal region is significantly related to the development of adverse health effects, including dyslipidaemia and glucose intolerance. PMID: 9168532 [PubMed - indexed for MEDLINE] 5893. Proc Nutr Soc. 1997 Mar;56(1A):149-67. Adipose tissue metabolism during lactation: where do we go from here? McNamara JP(1). Author information: (1)Department of Animal Sciences, Washington State University, Pullman 99164-6320, USA. PMID: 9168529 [PubMed - indexed for MEDLINE] 5894. Hepatogastroenterology. 1997 Mar-Apr;44(14):408-10. Retractile mesenteritis: to treat or not to treat. Koornstra JJ(1), van Olffen GH, van Noort G. Author information: (1)Department of Gastroenterology, Medisch Spectrum Twente Hospital, Enschede, Netherlands. Retractile mesenteritis is a rare entity characterized by an inflammatory process of the mesenteric adipose tissue. The disease usually presents with abdominal pain or a palpable abdominal mass. In the majority of cases, the disease is self-limiting and the prognosis is favorable. In this paper we describe a patient who presented with a 7 x 8 cm mass in the left upper abdomen, nausea and pain in the lower back. Symptomatic treatment was given with good result. The literature on different therapeutic intervention is briefly discussed. PMID: 9164510 [PubMed - indexed for MEDLINE] 5895. Nihon Ronen Igakkai Zasshi. 1997 Mar;34(3):171-9. [Causes, diagnosis, and treatment of anemia in the elderly]. [Article in Japanese] Takasaki M(1), Tsurumi N, Konjiki O, Sakurai H, Kanou H, Yanagawa K, Katsunuma H. Author information: (1)Department of Geriatrics, Tokyo Medical College. Healthy elderly people are mildly anemic peripheral blood data on 3,583 healthy elderly people (1,590 men and 1,993 women aged 65 years or older) from among those undergoing medical examinations at our hospital in the 8 years from 1988 to 1995 were compiled into 5-year age groups. For both men and women the mean values of red blood cell count, hemoglobin, and hematocrit were slightly lower among older subjects. The main causes of this apparent reduction may be a decrease in the number of hematopoietic stem cells and regression of the hematopoietic microenvironment. Observation of arteries in specimens of hematopoietic bone marrow obtained from the spines of elderly people showed arteriosclerotic changes such as greater hypertrophy of the media than of the intima, and adventitial fibrous hypertrophy. The number of venous sinuses was low and the amount of adipose tissue was high compared to the bone marrow of younger people. The cell density and the ratio of hematopoietic tissue to fat tended to be lower in older subjects. The number of erythroid burst-forming units formed after 14 days in culture medium containing erythropoietin was 28 +/- 19 in 32 healthy elderly people, which was significantly lower than the number in 30 young people 54 +/- 30, (p < 0.005). The value for erythroid colony-forming units was 170 +/- 67 in eight healthy people, which was much lower than in young people, 276 +/- 54. In the elderly subjects, the plasma iron disappearance time (PIDT/2) was 60-80 min (mean: 71.9 min), which was similar to that in the young, but the percent red cell iron utilization was 67.6%-84.9% (mean: 79.7%), which was slightly lower than in younger people. When the diagnostic criterion for anemia in the elderly was set at a hemoglobin value of 11.0 g/ dl, about 13% of outpatients who came to our Geriatrics department were found to have anemia, and in most of them the anemia had resulted from another disease. In conclusion, anemia in the elderly is likely to be affected by reduction in the function of various organs and by the decreased reserves associated with aging. The causes of anemia are complex and diagnosis is often difficult. The present article gives a general outline of the diagnosis and treatment of common types of primary and secondary anemia in the elderly. PMID: 9155190 [PubMed - indexed for MEDLINE] 5896. Diabetes Metab Rev. 1997 Mar;13(1):3-13. Pathophysiology and molecular mechanisms of visceral fat syndrome: the Japanese experience. Matsuzawa Y(1). Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. PMID: 9134345 [PubMed - indexed for MEDLINE] 5897. Int J Obes Relat Metab Disord. 1997 Mar;21 Suppl 1:S25-9. Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Stock MJ(1). Author information: (1)Department of Physiology, St. George's Hospital Medical School, University of London, UK. Sibutramine is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which causes weight loss in laboratory rodents via effects on both food intake and metabolic rate. Sibutramine's effects are predominantly mediated by two pharmacologically-active metabolites (its primary and secondary amines). Sibutramine and its active metabolites do not cause the release of monoamine neurotransmitters and do not have affinity for their receptors. Sibutramine dose-dependently inhibits 24 h food intake in rats by enhancing the natural physiological process of satiety. Sibutramine also stimulates thermogenesis in rats, producing sustained (> 6 h) increases in oxygen consumption of up to 30%. The thermogenic effect of sibutramine results from central activation of efferent sympathetic activity which, in turn, involves activation of beta 3-adrenoceptors. Sympathetic stimulation of brown adipose tissue via beta 3-adrenoceptors is thought to be the cause of the large, 18 fold increase in brown adipose tissue glucose utilization induced by sibutramine. These dual effects of sibutramine on food intake and thermogenesis explain its anti-obesity effect in animals. PMID: 9130038 [PubMed - indexed for MEDLINE] 5898. Diabetes Metab. 1997 Mar;23 Suppl 2:38-46. Are animal models of diabetes relevant to the study of the genetics of non-insulin-dependent diabetes in humans? Ktorza A(1), Bernard C, Parent V, Penicaud L, Froguel P, Lathrop M, Gauguier D. Author information: (1)Laboratoire de Physiopathologie de la Nutrition, CNRS URA 307, Université Paris 7, France. Although it is well-recognized that non-insulin-dependent diabetes-mellitus (NIDDM) shown a strong genetic component the search for candidate genes has been very difficult since NIDDM is a complex, heterogeneous, multifactorial syndrome resulting from both genetic susceptibility and environmental risk factors. Therefore, the use of inbred animal models is an essential component of genetic investigations in this field. As these lines are genetically homogeneous, it is possible to direct mating for optimal genetic crosses and control environmental factors. Strains with spontaneous NIDDM may be constituted from animals with one or several genetic mutation(s) transmitted generation to generation or selected from non-diabetic outbred animals by repeated breeding. The ob/ob and db/db mice, which are rodent models of NIDDM and obesity, belong to the first category. Recent studies using the positional cloning approach allowed the mapping of ob gene and identification of its product, leptin, which is a protein secreted by white adipose tissue and involved in the control of food intake. The db gene encodes the leptin receptor. The search for genetic linkage was undertaken in polygenic models, especially the Goto-Kakisaki (GK) rat which was obtained by selective breeding of individuals with glucose intolerance from a non-diabetic Wistar rat colony. Though precise definition of sub-phenotypes of glucose tolerance and insulin secretion, the mapping of microsatellite markers and QTL analysis, it has proved possible to identify many independent loci containing genes regulating glucose homeostasis and insulin secretion. In another polygenic model, the OLETF rat, a locus present on chromosome X was identified. Many complementary approaches in different strains may lead to the identification of candidate genes for NIDDM and help direct the search for candidate genes in humans who show synteny relationships with rodents. PMID: 9105782 [PubMed - indexed for MEDLINE] 5899. Eur J Endocrinol. 1997 Mar;136(3):251-64. Regulation of the uncoupling protein gene expression. Silva JE(1), Rabelo R. Author information: (1)Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada. Uncoupling protein (UCP) is essential to the thermogenic function of brown adipose tissue (BAT). The thermogenic role of this protein is due to its capacity to uncouple oxidative phosphorylation in a regulated manner. The thermogenic potential of BAT is determined by its content of UCP. The gene encoding this protein is under complex regulation. Catecholamines, via cAMP, thyroid hormone and retinoic acid, directly stimulate the gene acting upon an upstream (-2.28/-2.49 kb) enhancer sequence, but cAMP may act upon other sequences of the gene as well. CCAAT enhancer binding proteins and peroxisome proliferation activator receptor (PPAR) gamma 2 have also been implicated in the regulation of the gene acting on discrete sequences. While the thyroid hormone response and retinoic acid response elements (TRE and RARE) have been well defined, the cAMP response elements (CRE) remain elusive. The two TREs are 27 bp apart between -2.33 kb and -2.39 kb. The synergism between cAMP and thyroid hormone seems to reside in a 39 bp sequence downstream (-2.28/-2.32 kb). The most important CRE, the RARE, a cell-specific enhancer and a putative PPAR element are all concentrated in a 90 bp regulatory element of great complexity (-2.40/-2.49 kb). Other hormones, such as insulin and glucocorticoids, and IGF-I also modulate the expression of the gene but their effects seem to be largely indirect. Understanding the regulation of the UCP gene expression may facilitate the development of interventions in obesity and related disorders. PMID: 9100546 [PubMed - indexed for MEDLINE] 5900. Pharm Res. 1997 Mar;14(3):267-88. Application of microdialysis in pharmacokinetic studies. Elmquist WF(1), Sawchuk RJ. Author information: (1)Department of Pharmaceutical Sciences, College of Pharmacy University of Nebraska Medical Center, Omaha 68198, USA. The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are being found in a variety of peripheral tissue types, e.g. skin, muscle, adipose, eye, lung, liver, and blood, and these are considered as well. Given the rising interest in this technique, and the ongoing attempts to adapt it to pharmacokinetic studies, it is clear that microdialysis sampling will have an important place in studying drug disposition and metabolism. PMID: 9098867 [PubMed - indexed for MEDLINE] 5901. Bioessays. 1997 Mar;19(3):215-23. Functional differentiation of white and brown adipocytes. Klaus S(1). Author information: (1)Deutsches Institut für Ernährungsforschung (DIfE), Bergholz Rehbrücke, Germany. Adipose tissue plays an important role in mammalian energy equilibrium not only as a lipid-dissipating, i.e. energy-storing, tissue (white adipose tissue), but also as an energy-dissipating one (brown adipose tissue). Brown adipocytes have the ability of facultative heat production due to a unique mitochondrial protein, the uncoupling protein (UCP). Differentiation of white and (to a lesser extent) brown adipocytes has been studied in different cell culture systems, which has led to the identification of external inducers, second messenger pathways and transcription factors involved in adipocyte differentiation. Functional differentiation of white adipocytes implies adipose conversion, whereas in brown adipocytes it insinuates additionally the development of a thermogenic function. This review discusses recent advances in the elucidation of the pathways responsible for, and the molecular bases of, adipose conversion on the one hand and development of the thermogenic properties of brown adipocytes on the other. PMID: 9080771 [PubMed - indexed for MEDLINE] 5902. Int J Obes Relat Metab Disord. 1997 Mar;21(3):250-3. Effects of body fat distribution on body size estimation accuracy among obese women. Rhodes SK(1), O'Neil PM. Author information: (1)Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston 29425-0742, USA. Body fat distribution is a reliable predictor of the health risks of obesity. Abdominal obesity (AO) has been associated with various health complications whereas gluteal-femoral obesity (GFO) appears to be less hazardous. Body size overestimation, a type of body image disturbance, is found in a subset of obese persons.OBJECTIVE: The current study examined body size estimation accuracy as a function of body fat distribution. DESIGN: Cross-sectional, retrospective review of clinical records. SUBJECTS: 101 obese women (Mean age = 39.4) joining a weight loss program. MEASUREMENTS: Subjects provided body size estimates using a live video distortion procedure and were grouped into tertiles (AO; Mixed type obesity (MTO); GFO) on the basis of their waist-to-hip ratios. RESULTS: GFO women had significantly lower body size estimates and felt thinner than did AO or MTO women. In addition, more AO women (20.6% vs GFO: 8.8%) overestimated their body size by more than 15% whereas more GFO women (29.4% vs AO: 5.9%) underestimated their body size by more than 15%. CONCLUSION: Body fat distribution appears to be a mediator in body size estimation accuracy. These findings are discussed in terms of possible differences in perceptual and societal experiences among the groups. PMID: 9080265 [PubMed - indexed for MEDLINE] 5903. Nurse Pract. 1997 Mar;22(3):55-6, 61-6. The perimenopausal hot flash: epidemiology, physiology, and treatment. Shaw CR(1). Author information: (1)Marquette University College of Nursing, Milwaukee, Wis, USA. The "hot flash" (HF), or vasomotor instability, is experienced by 75% of perimenopausal and menopausal women in the United States. The experience for some women is a minor annoyance but for others, the HF is an intensely unpleasant sensation that is disruptive to their lives. The HF is thought to be triggered by a number of external and internal stimuli such as anxiety, stress, ambient high temperatures, caffeine, and alcohol. The thinner woman tends to experience more severe and frequent HFs than the woman with more adipose tissue, probably because of the ability of adipose tissue to transform androstenedione to estrone and estradiol. Smoking history also tends to be associated with the experience of HFs at an earlier age. The etiology of HFs in the decreasing estrogen state is related to the downward resetting of the hypothalamic thermoregulating mechanism, probably by the action of norepinephrine, which is usually modulated by estrogen. The body attempts to dissipate unwanted body heat by vasodilation, thus causing the sensation of the HF. The most successful treatment modalities have been hormone replacement therapy with estrogen and progesterone. Alpha 2-adrenergic blockers have also shown some limited effectiveness. Many alternative therapies such as vitamin E, primrose oil, dong quai, and black cohash have anecdotal support but have not been thoroughly studied. Relaxation, exercise, avoidance of triggering factors, and control of external environment have all been utilized with some success by women. PMID: 9078514 [PubMed - indexed for MEDLINE] 5904. Vnitr Lek. 1997 Feb;43(2):120-4. [Leptin and its biological and clinical significance. Is leptin and insulin resistance in the X-5H hormonal metabolic syndrome a parallel or causally-linked phenomenon?]. [Article in Slovak] Hrnciar J(1). Author information: (1)Interná klinika nemocnice F.D. Roosevelta, Banská Bytstrica. Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors. PMID: 9245068 [PubMed - indexed for MEDLINE] 5905. Biochimie. 1997 Feb-Mar;79(2-3):95-9. The effects of fibrates and thiazolidinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs). Staels B(1), Schoonjans K, Fruchart JC, Auwerx J. Author information: (1)U325 INSERM, Département d'Athérosclérose, Institut Pasteur, Lille, France. The hypolipidemic fibrates and antidiabetic thiazolidinediones display potent triglyceride-lowering activities. Studies on the molecular action mechanisms of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased expression of lipoprotein lipase (LPL) and decreased expression of apolipoprotein (apo) C-III, both key-players in plasma triglyceride metabolism. Fibrates, on the one hand, are PPAR alpha activators, which selectively induce LPL mRNA levels and activity in the liver. Furthermore, hepatic apo C-III mRNA levels and protein production strongly decrease after fibrate treatment. On the other hand, thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect in the liver, but act primarily on adipose tissue, where they induce LPL mRNA levels and activity. The modulation of the expression of the LPL and apo C-III genes in liver and adipose tissue is correlated with the tissue-specific distribution of the respective PPARs (PPAR gamma expression being restricted to adipose tissue, whereas PPAR alpha is expressed predominantly in liver) confirming that fibrates and thiazolidinediones exert their effects primarily through PPAR alpha and PPAR gamma respectively. This distinct tissue-specific transcriptional regulation of genes involved in lipid metabolism by fibrates and thiazolidinediones indicates that research of compounds displaying combined PPAR alpha and PPAR gamma activation potential should lead to the discovery of more potent triglyceride-lowering drugs, which may be of use in the treatment of hypertriglyceridemia. PMID: 9209702 [PubMed - indexed for MEDLINE] 5906. Aging (Milano). 1997 Feb-Apr;9(1-2):57-63. Aging, fat oxidation and exercise. Calles-Escandón J(1), Poehlman ET. Author information: (1)Department of Medicine, University of Vermont, Burlington 05401, USA. Aging is characterized by deleterious changes in body composition and in fat distribution. The mechanisms that determine the aging-associated changes in body composition are not well defined, but the evidence suggests that the loss of fat-free mass is at least partially attributable to physical inactivity. The increase in fat mass may be the result of alterations in fatty acid metabolism. Indeed, fat oxidation is decreased in elderly individuals in several physiological conditions: a) at rest, b) during exercise, and c) in response to meal ingestion (after weight loss). These defects are related in part to loss of fat-free mass, but may also be the consequence of estrogen loss (in women) and/or a decrease in the intrinsic capacity of muscle for fat oxidation, and are amenable to partial correction by exercise training. Special emphasis should be placed in future studies upon the role of steroid hormone in the regulation of fatty acid metabolism in elderly individuals (especially women), as well as therapeutic interventions that may increase the quantity of the fat-free mass and/or fat oxidation. PMID: 9177586 [PubMed - indexed for MEDLINE] 5907. Arterioscler Thromb Vasc Biol. 1997 Feb;17(2):233-8. Regulation of body adiposity and the problem of obesity. Schwartz MW(1), Brunzell JD. Author information: (1)Department of Medicine, University of Washington, Seattle, USA. mschwart@u.washington.edu The hypothesis that body adiposity is homeostatically regulated is the focus of an intensive research effort, and support for this concept is rapidly growing. While generating optimism about the future of obesity treatment, these advances also bear on our current approach to the obese patient. The observation that body adiposity appears to be subject to regulation in obese as well as lean individuals suggests that common forms of obesity may result from a primary disorder of the weight-regulatory system. As a result, voluntary efforts to lower body adiposity activate compensatory responses that limit weight loss and facilitate weight regain. The use of weight-reduction strategies based on caloric restriction, therefore, effectively pits the will of the obese individual against his or her own intrinsic weight-regulatory system. Until more effective approaches to weight reduction are available, we suggest that clinical intervention should focus on patient education and strategies to limit weight gain or modestly lower weight. Since the combination of a low-fat diet with an exercise program appears to reduce the level at which body weight is regulated without active caloric restriction, this approach may be appropriate for many obese individuals. PMID: 9081675 [PubMed - indexed for MEDLINE] 5908. Dan Med Bull. 1997 Feb;44(1):56-69. The glucose-induced thermogenesis in different tissues in man. Simonsen L(1). Author information: (1)Department of Clinical Physiology/Nuclear Medicine, Bispebjerg Hospital, Copenhagen. PMID: 9062764 [PubMed - indexed for MEDLINE] 5909. FEBS Lett. 1997 Jan 27;402(1):9-11. Is leptin an insulin counter-regulatory hormone? Remesar X(1), Rafecas I, Fernández-López JA, Alemany M. Author information: (1)Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. remesar@porthos.bio.ub.es Leptin, the product of the ob gene, controls appetite through the hypothalamus and may affect many other tissues because of the widespread distribution of its receptors. Leptin is synthesized by white adipose tissue (WAT) under conditions of high energy availability and insulin stimulus. Glucocorticoids enhance this synthesis and catecholamines hamper leptin production. Leptin diminishes insulin secretion by the pancreatic beta cells and induces insulin resistance. In fact leptin hampers insulin action on WAT itself in a negative feedback loop. The evidence acquired in studies on diabetics, starvation, refeeding and insulin and glucose clamps supports this interpretation, which may also explain part of the difficulties encountered by the current postulate that links leptin to WAT mass size signalling to the brain. Leptin may be, essentially, a counter-regulatory hormone limiting the insulin drive to store energy in the form of fat, its effects reaching from a decrease in food intake to lower insulin secretion and increased resistance to insulin and lower glucose uptake and fat synthesis by WAT. PMID: 9013847 [PubMed - indexed for MEDLINE] 5910. Horm Res. 1997;48(3):95-102. Gynecomastia: pathomechanisms and treatment strategies. Mathur R(1), Braunstein GD. Author information: (1)Cedars-Sinai Medical Center-UCLA School of Medicine, Los Angeles, California, USA. Gynecomastia is common in adolescents and adults, and reflects an underlying imbalance in hormonal physiology in which there is an increase in estrogen action relative to androgen action at the breast tissue level. Most patients have persistent pubertal gynecomastia or breast glandular enlargement from medications, age-related reduction in testicular function, or idiopathic causes. Gynecomastia must be differentiated from pseudogynecomastia due to increased breast adipose tissue, as well as from breast carcinoma. The evaluation of the causes of gynecomastia can be accomplished through history, physical examination and a few laboratory tests. Painful gynecomastia of recent onset may respond to antiestrogen therapy. Surgical removal is the mainstay for long-standing gynecomastia or glandular enlargement that is unresponsive to medical therapy. PMID: 11546925 [PubMed - indexed for MEDLINE] 5911. Biomed Pharmacother. 1997;51(10):455-60. Metabolic aspects of HIV: associated wasting. Melchior JC(1). Author information: (1)Service de Nutrition, Groupe Hospitalier Bichat-C Bernard, Paris, France. Despite recent progress in the treatment of human immunodeficiency virus (HIV) infection, wasting syndrome (WS) is now one of the major aspects of acquired immunodeficiency syndrome (AIDS). Malnutrition in HIV infected patients is characterised by a predominant loss of body cell mass (BCM), the amount of functional protoplasm in non-adipose tissue. This loss of BCM is correlated with a higher risk of AIDS events and a greater risk of mortality. If anorexia plays a major role in the development of the WS, some abnormalities in the metabolism drive the predominant loss of BCM. In the stable state, the resting energy expenditure (REE) is increased by about 10%. The REE is significantly correlated with the whole body protein turn over as measured by C13 leucine. This particular and only metabolic situation is associated with an increased insulin sensitivity and a high level in de novo hepatic lipogenesis. During periods of secondary infections, patients had a striking average weight loss, resulting from the combination of anorexia and dramatic elevated REE. PMID: 9863505 [PubMed - indexed for MEDLINE] 5912. Postepy Biochem. 1997;43(3):174-82. [Obesity genes]. [Article in Polish] Swierczyński J(1), Kochan Z, Karbowska J. Author information: (1)Katedra i Zakład Biochemii A.M. Debinki I, Gdańsk. PMID: 9558706 [PubMed - indexed for MEDLINE] 5913. Annu Rev Cell Dev Biol. 1997;13:231-59. Adipocyte differentiation and leptin expression. Hwang CS(1), Loftus TM, Mandrup S, Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University Medical School, Baltimore, Maryland 21205, USA. Adipose tissue has long been known to house the largest energy reserves in the animal body. Recent research indicates that in addition to this role, the adipocyte functions as a global regulator of energy metabolism. Adipose tissue is exquisitely sensitive to a variety of endocrine and paracrine signals, e.g. insulin, glucagon, glucocorticoids, and tumor necrosis factor (TNF), that combine to control both the secretion of other regulatory factors and the recruitment and differentiation of new adipocytes. The process of adipocyte differentiation is controlled by a cascade of transcription factors, most notably those of the C/EBP and PPAR families, which combine to regulate each other and to control the expression of adipocyte-specific genes. One such gene, i.e. the obese gene, was recently identified and found to encode a hormone, referred to as leptin, that plays a major role in the regulation of energy intake and expenditure. The hormonal and transcriptional control of adipocyte differentiation is discussed, as is the role of leptin and other factors secreted by the adipocyte that participate in the regulation of adipose homeostasis. PMID: 9442874 [PubMed - indexed for MEDLINE] 5914. Eur Arch Otorhinolaryngol. 1997;254(9-10):410-2. Anatomical considerations of closure of the laryngeal vestibule during swallowing. Reidenbach MM(1). Author information: (1)Department of Anatomy, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. Morphologic correlates of physiologic closure mechanisms of the laryngeal vestibule were investigated in plastinated serial sections of 25 normal adult larynges. The anterior part of the laryngeal vestibule was seen to be bounded by the epiglottis and the thyroepiglottic ligament medially, and by lateral extensions of the periepiglottic adipose tissue laterally. The posterior part of the laryngeal vestibule was bordered by the aryepiglottic folds. Morphologically, the periepiglottic space and the aryepiglottic folds were completely separated by several transversely oriented collagenous fiber layers attached to the thyroid perichondrium laterally. This may suggest a corresponding functional separation, as described previously in the literature. Closure of the anterior part of the laryngeal vestibule during swallowing is probably related to the lowering of the epiglottis, with both depending on pressure exerted onto the periepiglottic adipose tissue. Closure of the posterior part of the laryngeal vestibule is most likely related to closure of the rima glottidis, with both depending on adduction of the arytenoid cartilage. PMID: 9438107 [PubMed - indexed for MEDLINE] 5915. Horm Res. 1997;48 Suppl 5:116-21. Weight regulation, leptin and growth hormone. Considine RV(1). Author information: (1)Indiana University School of Medicine, Department of Medicine, Indianapolis 46202-5111, USA. rconsidi@champion.iupui.edu Leptin, the product of the adipose tissue-specific ob gene, is a newly recognized hormone involved in the regulation of metabolism and body composition. Leptin appears to provide information to the central nervous system on the amount of energy stored in the adipose tissue. Serum leptin levels are highly correlated with body fat mass in adults, children and newborns. Obese individuals have significantly higher circulating leptin than normal, lean subjects. In addition, females have higher serum leptin than males with equivalent fat mass. Although leptin correlates with fat mass, circulating concentrations are altered by extremes in energy intake, such as fasting and overfeeding. Defects in leptin or its receptor in the hypothalamus lead to the development of obesity in several rodent models; however, no such deleterious defects have been identified in humans to date. Taken together, these observations suggest that humans may be resistant to their endogenous leptin levels. Despite this, studies in rodents demonstrating that leptin administration can cause weight loss in both ob/ob mice, and in normal weight controls suggest that leptin may be useful in the treatment of human obesity. This review will summarize the current understanding of leptin and its role in the regulation of body composition. In addition, the interaction of leptin with other metabolic hormones including growth hormone will be discussed. PMID: 9434056 [PubMed - indexed for MEDLINE] 5916. Horm Res. 1997;48 Suppl 5:105-10. Action of growth hormone in adipose tissue. Richelsen B(1). Author information: (1)Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus Amtssygehus, Aarhus C, Denmark. br@aas.arhusamt.dk Growth hormone (GH) has diverse and still not fully elucidated effects on adipose tissue. Both preadipocytes and mature adipocytes possess specific GH receptors. GH may mediate its actions via these receptors, but some effects are indirectly mediated through the GH-mediated secretion of insulin-like growth factor-I (IGF-I). IGF-I may then act back on the adipose tissue in an autocrine/paracrine manner. In primary cultures of adipose precursor cells obtained from human or rat adipose tissue, GH is found to stimulate the proliferation of these immature cells and reduce their differentiation to mature adipocytes. During long-term incubation and in in vivo studies, GH has a pronounced lipolytic effect. Whether this lipolytic effect is a direct effect of GH or more indirectly mediated, for instance, via inhibition of the action of antilipolytic compounds (e.g. adenosine, prostaglandins and insulin) is presently unknown. Finally, GH produces a pronounced inhibition of adipose tissue lipoprotein lipase activity. This enzyme plays a main role for hydrolysing triglycerides in the blood circulation in the adipose tissue and then for triglyceride accumulation in adipose cells. Thus, GH inhibits adipocyte differentiation, reduces triglyceride accumulation and increases lipolyses--all mechanisms which reduce adipose tissue mass. PMID: 9434054 [PubMed - indexed for MEDLINE] 5917. Horm Res. 1997;48 Suppl 5:101-4. Somatopause and adiposity. Jørgensen JO(1), Vahl N, Fisker S, Nørrelund H, Nielsen S, Dall R, Christiansen JS. Author information: (1)Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Denmark. JOJ@afdm.aau.dk Mobilization of lipids is the pivotal action of growth hormone (GH) in both children and adults. The temporal association between declining GH levels and accumulation of body fat with ageing is, therefore, interesting although the cause-effect relationship remains unknown. Recent cross-sectional data suggest that both stimulated and spontaneous GH release is predominantly predicted by the amount of abdominal fat in both men and women. The same study also shows that ageing is associated with an increased metabolic clearance rate and apparent distribution volume, both of which correlate positively with fat mass and negatively with age. Furthermore, the acute lipolytic response to a GH bolus is somewhat lower in older adults (and in women). It is, therefore, proposed that changes in life style and dietary habits, perhaps together with an age-determined reduced lipolytic responsiveness to GH, initiates fat accumulation. The increased fat mass, in turn, inhibits the release and promotes the clearance of GH thus establishing a vicious circle. PMID: 9434053 [PubMed - indexed for MEDLINE] 5918. Horm Res. 1997;48 Suppl 5:93-100. Fat distribution in children and adolescents--the influence of sex and hormones. Cowell CT(1), Briody J, Lloyd-Jones S, Smith C, Moore B, Howman-Giles R. Author information: (1)Robert Vines Growth Centre, Ray Williams Institute of Endocrinology, Diabetes and Metabolism, New Children's Hospital, Parramatta, Australia. Chrisc@NCH.edu.au A significant proportion of the morbidity related to obesity is now recognized to be related to the regional distribution of fat. The advent of dual energy X-ray absorptiometry has facilitated the assessment of body composition in a number of investigations on body fat. From current data, including the authors' own study of trunk and leg fat in 335 children and young adults, it is evident that gender differences for total body fat, percentage of body fat and distribution of fat occur after the pubertal years. Males develop a distribution of fat which favours central deposition of fat irrespective of their total body fat--a distribution that is, unfortunately, associated with a number of adverse implications on health. Furthermore, this tendency to increasing abdominal fat is independent of adipose tissue mass. Hormonal regulators of adipose tissue, including growth hormone which is already known to increase free fatty acids and decrease fat cell mass, need to be studied to account for these gender differences. PMID: 9434052 [PubMed - indexed for MEDLINE] 5919. Horm Res. 1997;48 Suppl 5:88-92. Health consequences of fat distribution. Jensen MD(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, Minn. 55905, USA. Jensen.Michael@mayo.edu Body fat distribution is now recognized as an important predictor of the adverse health consequences of obesity. Upper body obesity, especially with increasing visceral fat, is associated with hypertension, insulin resistance, dyslipidemia, type II diabetes mellitus and premature coronary death. Several lines of evidence suggest that abnormal adipose tissue lipolysis, resulting in elevated free fatty acid (FFA) availability, may contribute to some of the metabolic consequences of upper body obesity. The vast majority of the elevated systemic FFA release appears to come from upper body, non-splanchnic adipose tissue. Thus, dysregulation of upper body, non-splanchnic adipose tissue lipolysis may play an important role in contributing to health consequences of fat distribution. PMID: 9434051 [PubMed - indexed for MEDLINE] 5920. Przegl Lek. 1997;54(5):348-52. [The ob gene product (leptin)--a new hormone of adipose tissue]. [Article in Polish] Robaczyk M(1), Smiarowska M, Krzyzanowska-Swiniarska B. Author information: (1)Oddziału Chorób Wewnetrznych, Szpitala MSW w Szczecinie. Obesity--an important problem in modern societies--is caused by energy balance dysregulation and produces numerous adverse effects on health. Recently a particular attention has been paid to molecular and physiological mechanisms in the development of obesity and to the signalling role of adipose tissue in energy stores maintenance on the hypothalamic level. Leptin, the obese gene product discovered in 1995, may play a key role in the feedback system between adipose tissue and the ventromedial nucleus of the hypothalamus (satiety centre). The level of ob gene expression in adipose tissue and plasma leptin concentrations in humans are highly correlated with BMI. So far no mutations in the ob gene in obese subjects have been reported therefore leptin molecule could be active. Despite markedly increased leptin levels found in obesity its central action decreasing food intake and increasing energy expenditure is hindered. Defective ob protein signalling to the brain may be due to receptor and post-receptor defects. Neuropeptide Y, the hypothalamic neurotransmitter involved in the maintaining of energy homeostasis, is a likely candidate for mediating leptin afferent signals. In adipose tissue, the level of ob mRNA is regulated by insulin and glucocorticoids--hormones responsible for glucose homeostasis as well as for the central regulation of feeding behaviour. Until now the character of interactions between leptin and other hormones that regulate energy balance is not known, neither is the exact nature of leptin hypothalamic receptor defect. Defining of the role of leptin in the regulation of satiety and energy expenditure will undoubtedly contribute to a better understanding of the pathogenesis of obesity and its related metabolic complications and may lead to a new treatment approach to human obesity based on leptin or its analogues. At present research work focuses on leptin receptor studies and on ob gene polymorphism and its expression in feeding disorders including obesity and anorexia nervosa. The ob gene is one of a few genes involved in energy balance, however, very promising one. PMID: 9380811 [PubMed - indexed for MEDLINE] 5921. Horm Res. 1997;48 Suppl 4:2-8. Leptin: the voice of the adipose tissue. Blum WF(1). Author information: (1)Lilly Research Laboratories, Giessen, Germany. BLUM_WERNER@Lilly.com Leptin is a newly discovered hormone that acts as a feedback signal from the adipose tissue. It plays a pivotal role in the modulation of neuronal and hormonal systems involved in the regulation of body weight and reproductive functions. This brief overview focuses on the regulation of circulating leptin levels and leptin in extreme clinical states of body weight, summarizing mainly results from the University of Giessen in collaboration with other groups. Finally, a possible role for leptin is presented. PMID: 9350438 [PubMed - indexed for MEDLINE] 5922. Journ Annu Diabetol Hotel Dieu. 1997:131-48. [OB protein and its receptor: signal transduction between adipose tissue and central nervous system]. [Article in French] Campfield LA(1), Smith FJ, Pénicaud L, Burn P. Author information: (1)Department of Metabolic Diseases, Hoffman-La Roche Inc., Nutley, NJ, USA. PMID: 9296969 [PubMed - indexed for MEDLINE] 5923. Journ Annu Diabetol Hotel Dieu. 1997:125-9. [Secretory function of the adipocyte]. [Article in French] Ailhaud G(1). Author information: (1)Centre de Biochimie (UMR 6543 CNRS), UNSA, Faculté des Sciences, Nice. PMID: 9296968 [PubMed - indexed for MEDLINE] 5924. Br Med Bull. 1997;53(2):322-40. Obesity, non-insulin-dependent diabetes mellitus and the metabolic syndrome. Kopelman PG(1), Albon L. Author information: (1)St Bartholomew's, London, UK. Obesity is characterised by alterations in metabolic function which result from a combination of increasing total body fatness and the regional distribution of adipose tissue. Abdominal visceral obesity is particularly associated with hyperinsulinaemia, increased portal vein free fatty acid concentration, hepatic gluconeogenesis, altered adrenocortical activity and androgen secretion and reduced plasma sex hormone binding globulin levels. These alterations, which are accompanied by changes in visceral adipocyte sensitivity to plasma catecholamine stimulation, enhance further visceral fat deposition and the perpetuation of the metabolic derangements. The characteristic dyslipidaemia associated with upper body obesity and the frequent development of NIDDM are predictable consequences. In contrast to the considerable knowledge about the biochemical background to these alterations, relatively little is understood about the mechanisms through which an individual's ethnic background influences the changes. This chapter reviews these important issues. PMID: 9246839 [PubMed - indexed for MEDLINE] 5925. Br Med Bull. 1997;53(2):238-52. Assessing obesity: classification and epidemiology. Seidell JC(1), Flegal KM. Author information: (1)Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. Obesity is generally defined as a body mass index (BMI) of 30 kg/m2 and higher. Overweight is defined as a BMI between 25 and 30 kg/m2. The prevalence varies considerably between countries, and between regions within countries. It is estimated that more than half of adults aged 35-65 living in Europe are either overweight or obese. Overweight is more common among men than among women but obesity is more common among women. The prevalence of obesity in Europe is probably in the order of 10-20% in men and 15-25% in adult women. In most European countries who have reliable data on time-trends the prevalence of obesity seems to be increasing. In most European countries, obesity is usually inversely associated with socio-economic status, particularly among women. New classifications of overweight may be based on cut-off points for simple anthropometric measures which reflects both total adiposity as well as abdominal fatness. PMID: 9246834 [PubMed - indexed for MEDLINE] 5926. Annu Rev Biochem. 1997;66:581-611. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Hanson RW(1), Reshef L. Author information: (1)Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4936, USA. Phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating the key role played at these sites by the isoforms of CAAT/enhancer binding protein in patterning of PEPCK-C gene expression during the perinatal period. The PEPCK-C gene provides a model for the metabolic control of gene transcription. PMID: 9242918 [PubMed - indexed for MEDLINE] 5927. Annu Rev Nutr. 1997;17:325-52. Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Girard J(1), Ferré P, Foufelle F. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Dévelopement, UPR 1511 CNRS, Meudon, France. Regulation of gene expression by nutrients is an important mechanism in the adaptation of mammals to their nutritional environment. This is especially true for enzymes involved in the storage of energy, such as the lipogenic and glycolytic enzymes in liver and adipose tissue. Transcription of the genes for lipogenic and glycolytic enzymes is stimulated by glucose in adipose tissue, liver, and pancreatic beta-cells. Several lines of evidence suggest that glucose must be metabolized to glucose-6-phosphate to stimulate gene transcription. In adipose tissue, insulin increases the expression of lipogenic enzymes indirectly by stimulating glucose uptake. In the liver, insulin also acts indirectly by stimulating the expression of glucokinase and, hence, by increasing glucose metabolism. Glucose response elements have been characterized for the L-pyruvate kinase and S14 genes. They have in common the presence of a sequence 5'-CACGTG-3', which binds a transcription factor called USF (upstream stimulatory factor). Another glucose response element, which uses a transcription factor named Sp1, has been characterized in the gene for the acetyl-coenzyme A carboxylase. The mechanisms linking glucose-6-phosphate to the glucose-responsive transcription complex are largely unknown. PMID: 9240931 [PubMed - indexed for MEDLINE] 5928. Annu Rev Nutr. 1997;17:127-39. Lipolysis: contribution from regional fat. Jensen MD(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA. jensen.michael@mayo.edu In vitro studies of adipocytes taken from different body fat regions suggest substantial differences in lipolysis between intra-abdominal, lower-body subcutaneous, and abdominal subcutaneous regions. Gender and obesity appear to influence these regional differences. In situ measurements of glycerol release from adipose tissue provided further evidence that regional heterogeneity of lipolysis occurs in humans. In vivo studies of regional free fatty acid (FFA) release have confirmed that adipose tissue lipolysis varies between upper- and lower-body fat. Release of FFA from lower-body adipose tissue is less than that from upper-body adipose tissue in both obese and non-obese men and women. In non-obese men and women, meal ingestion suppresses FFA release from all adipose tissue regions, and adrenergic stimulation activated FFA release from different sites in a gender-specific fashion. Significant regional and gender differences in adipose tissue lipolysis occur in humans, and this could contribute to differences in the health effects of adipose tissue and could theoretically influence body fat distribution. PMID: 9240922 [PubMed - indexed for MEDLINE] 5929. Ann Endocrinol (Paris). 1997;58(2):137-42. Central nervous system and body weight regulation. Rohner-Jeanrenaud E(1), Jeanrenaud B. Author information: (1)Laboratoires de Recherches Métaboliques, Faculty of Medicine, University of Geneva, Switzerland. The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal models. It has strengthened the concept of the importance of the hypothalamus in the etiology of these syndromes. Due to alterations in the regulation of the hypothalamus, e.g. by insulin, by leptin or by decreases in the availability of glucose in specific brain areas, most animal models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypothalamic defect explains why obese rodents are hyperphagic. Increased hypothalamic neuropeptide Y levels produce hyperinsulinemia and hypercorticism, two abnormalities previously reported in obesity, but whose origin is now known to be driven by neuropeptide Y. As hyperinsulinemia favors lipid accretion and muscle insulin resistance, and as hypercorticism favors the occurrence of both high circulating triglyceride levels and muscle insulin resistance, it may be appreciated that most disorders previously reported in obesity can now be explained by high hypothalamic neuropeptide Y levels. Leptin, produced and secreted by adipose tissue, is a potent anorectic agent whose main action is exerted within the hypothalamus in which it has been shown to decrease neuropeptide Y, therefore food intake. Leptin secretion is favored, in particular, by insulin as well as by glucocorticoids. When leptin is administered to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and most metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating levels of leptin are high. This is related to hyperinsulinemia- and hypercorticosteronemia-induced leptin oversecretion, as well as to central leptin receptor dysfunctions preventing normal leptin access to and action within specific brain areas. Under these conditions and to prevent the effects of elevated hypothalamic neuropeptide Y levels, neuropeptide Y antagonists or active leptin agonists must be found. Neuropeptide Y and leptin further underline the existence of functional relationship between the brain (hypothalamus) and the periphery (adipose tissue, muscle). Lack of leptin (mutated leptin gene) or inefficient leptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsulinemia and hypercorticism both producing oversecretion of leptin which, when inefficient, cannot decrease neuropeptide Y: a vicious circle is created which maintains either a "thrifty phenotype" favoring fat depot or overt obesity, depending on the degree of hyperphagia. PMID: 9239233 [PubMed - indexed for MEDLINE] 5930. Ann Endocrinol (Paris). 1997;58(2):129-31. [Hormones and adipocyte development]. [Article in French] Ailhaud G(1). Author information: (1)Centre de Biochimie (UMR6543CNRS), UNSA, Faculté des Sciences, Parc Valrose, Nice. Dormant preadipocytes isolated from adipose tissue are able to differentiate into adipocytes in vitro. A few adipogenic hormones (glucocorticoids or prostacyclin, IGF-I and insulin) are sufficient to trigger the differentiation program. In preadipose and adipose cells, glucocorticoids play a cardinal role by regulating the expression of numerous genes and by increasing the production of prostacyclin which acts as an intracrine/autocrine/paracrine effector. Fatty acids and metabolites (including prostacyclin) enhance adipocyte differentiation via the activation of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs then modulate positively the expression of various lipid-related genes involved in triacylglycerol accumulation. These in vitro observations emphasize the importance of the hypothalamic-pituitary-adrenal axis and provide also a link which may take place in vivo between high-fat diets and the excess of adipose tissue development. PMID: 9239231 [PubMed - indexed for MEDLINE] 5931. Recent Prog Horm Res. 1997;52:359-85; discussion 385-7. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Bergman RN(1). Author information: (1)Department of Physiology and Biophysics, University of Southern California, Los Angeles 90033, USA. Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and cancer. Resistance to insulin's effects on carbohydrate metabolism include diminished actions of insulin to enhance glucose uptake and suppress endogenous glucose production. This chapter introduces new concepts related to the mechanism by which insulin stimulates glucose utilization in vivo and demonstrates that these processes are mechanistically linked to glucose production. Insulin acts rapidly in vitro to stimulate glucose uptake; in contrast, its effects in vivo are relatively slow in the conscious animal or human subject. The explanation for this difference between in vitro and in vivo dynamics is the delay associated with insulin transport across capillary endothelium of insulin-sensitive tissues (primarily muscle). Also, interstitial insulin is attenuated in concentration compared to plasma insulin at basal as well as under hyperinsulinemic conditions (plasma:interstitial ratio, 3:2). The sluggishness of insulin action and the attenuation in insulin concentration can be explained by a model in which transendothelial insulin transport is restricted and interstitial insulin binds to insulin-sensitive cells, where the hormone is internalized and degraded. Whether insulin transport occurs by a hormone-specific mechanism (i.e., via receptors on endothelial cells) was tested by comparing transport at physiological with pharmacological insulin concentrations-evidence supports a nonspecific mechanism of transport across endothelium (i.e., diffusion or transcytosis). Transendothelial transport alters the in vivo patterns of insulin signaling-biphasic plasma insulin after glucose injection is reflected in a simple, rapid increase in interstitial insulin to an elevated concentration. The time course of insulin's effect to suppress endogenous glucose output is a mirror image of its effect to enhance glucose uptake; however, there is no transendothelial barrier to insulin action at the liver. The similarity in action dynamics at periphery and liver was explained by a mechanism in which insulin crosses into peripheral tissue and alters a "second (blood-borne) signal" that, in turn, suppresses liver glucose production. Of various possible alternative candidates for the second signal, declining plasma free fatty acids appear to signal suppression of glucose production. We have proposed the "single gateway hypothesis" to explain insulin's action on carbohydrate metabolism in vivo: insulin crosses the endothelial boundary in skeletal muscle (to stimulate glucose disposal) and traverses the endothelial barrier in adipose tissue to suppress lipolysis. The declining free fatty acids are proposed to be a major factor in the insulin-mediated decline in glucose output. This mechanism can be contrasted with the classical concept that portal insulin controls the liver directly. Recent evidence supports the concept that, under normal levels of glucagonemia, less than 25% of the suppression of hepatic glucose output by insulin is due to a direct effect of insulin via the portal vein and that most of the effect (approximately 75%) is explained by the indirect single gateway mechanism. These results raise the question of whether hepatic insulin resistance in Type 2 diabetes can be explained by insulin resistance at the adipocyte, which causes a failure of reduction of FFA by insulin, leading to overproduction of glucose by the liver. The possible role of the single gateway mechanism in diabetes is under investigation. PMID: 9238859 [PubMed - indexed for MEDLINE] 5932. Recent Prog Horm Res. 1997;52:185-213; discussion 213-4. Aromatase expression in health and disease. Simpson ER(1), Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM, Graham-Lorence S, Sun T, Fisher CR, Qin K, Mendelson CR. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas 75235-9051, USA. Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the delta 4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNF alpha are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast tumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3'-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts- and hence the protein-are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5'-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration. PMID: 9238853 [PubMed - indexed for MEDLINE] 5933. Exerc Sport Sci Rev. 1997;25:271-300. Visceral obesity, insulin resistance, and dyslipidemia: contribution of endurance exercise training to the treatment of the plurimetabolic syndrome. Després JP(1). Author information: (1)Lipid Research Center, Laval University Medical Research Center, Ste-Foy (Quebec), Canada. PMID: 9213095 [PubMed - indexed for MEDLINE] 5934. Exerc Sport Sci Rev. 1997;25:77-103. Effects of endurance exercise on adipose tissue metabolism. Nicklas BJ(1). Author information: (1)Division of Gerontology, University of Maryland School of Medicine, Baltimore, USA. PMID: 9213089 [PubMed - indexed for MEDLINE] 5935. Prog Nucleic Acid Res Mol Biol. 1997;56:83-108. The mitochondrial uncoupling protein: structural and genetic studies. Ricquier D(1), Bouillaud F. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Développement, Centre National de la Recherche Scientifique, Meudon, France. PMID: 9187052 [PubMed - indexed for MEDLINE] 5936. Rev Med Interne. 1997;18(5):396-401. [Lipomatosis induced by corticosteroid therapy]. [Article in French] Humblot S(1), Weber JC, Korganow AS, Hammann B, Pasquali JL, Martin T. Author information: (1)Unité d'immunologie clinique, hôpitaux universitaires de Strasbourg, hôpital Civil, France. Comment in Rev Med Interne. 1997;18(11):908. Steroid-induced lipomatosis usually presents as a localized hypertrophy of the adipose tissue and seems more common than previously thought. Most patients develop this phenomenon after prolonged administration of moderate to high doses of oral corticosteroids. The localizations are numerous and determine the clinical presentation. Often asymptomatic, they can also be revealed by worrying symptoms usually due to a compressive syndrome. The most frequently reported localizations (spinal epidural, retro-orbital, mediastinal) are also the most clinically apparent. The cessation or reduction of steroid therapy, when medically possible, inconsistently results in the decrease or disappearance of the lipomatosis deposits. Computerized tomography or magnetic resonance imaging are the most helpful diagnostic means. Interestingly, these lipomatoses have rarely been reported in patients with Cushing disease. Their pathophysiology remains poorly elucidated and may imply an inhibition of the brown adipose tissue lipolysis. PMID: 9183448 [PubMed - indexed for MEDLINE] 5937. Nutr Rev. 1997 Jan;55(1 Pt 2):S69-73; discussion S74-7. Nutrition and senescence. Rosenberg IH(1). Author information: (1)USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. PMID: 9155228 [PubMed - indexed for MEDLINE] 5938. Curr Top Microbiol Immunol. 1997;220:131-42. TLS-CHOP and the role of RNA-binding proteins in oncogenic transformation. Ron D(1). Author information: (1)Skirball Institute of Biomolecular Medicine, Department of Medicine, New York, NY, USA. PMID: 9103679 [PubMed - indexed for MEDLINE] 5939. Nutrition. 1997 Jan;13(1):1-7. Cancer cachexia: metabolic alterations and clinical manifestations. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom. Progressive wasting is common in many types of cancer and is one of the most important factors leading to the early death of cancer patients. Although anorexia frequently accompanies cachexia it has been difficult to establish a simple cause-and-effect relationship, and nutritional supplementation is not able to effectively reverse the process of cachexia. An increased resting energy expenditure may contribute to weight loss in some cancer patients and may explain the increased oxidation of fat. Futile energy-consuming cycles, such as the Cori cycle, may contribute to the increased energy demand. Unlike starvation, weight loss in cancer arises equally from loss of muscle and fat, and the process is characterized by an increased catabolism of skeletal muscle and a decrease in protein synthesis. Several experimental studies have suggested a role for the cytokines tumor necrosis factor alpha, interleukins-1 and -6, and interferon gamma as mediators of the process of cachexia, although conclusive data supporting a role in human disease are often lacking. Catabolic factors capable of direct breakdown of muscle and adipose tissue appear to be secreted by cachexia-inducing human tumors and may play an active role in the process of tissue degeneration. Pharmacologic intervention using antagonists to cachexia factors may be capable of reversing the wasting process. PMID: 9058439 [PubMed - indexed for MEDLINE] 5940. J Exp Biol. 1997 Jan;200(Pt 2):387-400. Hypometabolic homeostasis in overwintering aquatic amphibians. Boutilier RG(1), Donohoe PH, Tattersall GJ, West TG. Author information: (1)Department of Zoology, University of Cambridge, UK. RGB11@hermes.cam.ac.uk Many amphibians encounter conditions each winter when their body temperature is so low that normal activities are suspended and the animals enter into a state of torpor. In ice-covered ponds or lakes, oxygen levels may also become limiting, thereby forcing animals to endure prolonged periods of severe hypoxia or anoxia. Certain frogs (e.g. Rana temporaria) can dramatically suppress their metabolism in anoxia but are not as tolerant as other facultative vertebrate anaerobes (e.g. turtle, goldfish) of prolonged periods of complete O2 lack. Many overwintering amphibians do, however, tolerate prolonged bouts of severe hypoxia, relying exclusively on cutaneous gas exchange. Rana temporaria overwintering for 2 months in hypoxic water (PO2 approximately 25 mmHg) at 3 degrees C progressively reduce their blood PCO2 to levels characteristic of water-breathing fish. The result is that blood pH rises and presumably facilitates transcutaneous O2 transfer by increasing Hb O2-affinity. Even after months of severe hypoxia, there is no substantial build-up of lactate as the animals continue to rely on cutaneous gas exchange to satisfy the requirements of a suppressed aerobic metabolism. Our recent experiments have shown that the skeletal muscle of frogs oxyconforms in vitro to the amount of O2 available. The cellular basis for the oxyconformation of skeletal muscle is unknown, but the hypothesis driving our continuing experiments theories that metabolic suppression at a cellular level is synonymous with suppressed ion leak across cellular membranes. PMID: 9050248 [PubMed - indexed for MEDLINE] 5941. Eur J Med Res. 1997 Jan;2(1):7-13. Leptin, leptin receptors and the control of body weight. Friedman JM(1). Author information: (1)Howard Hughes Medical Institute, New York, New York, USA. PMID: 9049588 [PubMed - indexed for MEDLINE] 5942. Annu Rev Med. 1997;48:307-16. Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Lowell BB(1), Flier JS. Author information: (1)Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA. blowell@bih.harvard.edu Brown adipose tissue is distinguished by its unique capacity for uncoupled mitochondrial respiration, which is highly regulated by sympathetic nerve activity. Because of this, energy expenditure in brown fat is capable of ranging over many orders of magnitude. The fact that the function of brown adipose tissue is impaired in obese rodents and that transgenic mice with decreased brown fat develop obesity demonstrates the importance of brown fat in maintaining nutritional homeostasis. However, the role of brown fat in humans is less clear. beta 3-Adrenergic receptors are found on brown adipocytes, and treatment with beta 3-selective agonists markedly increases energy expenditure and decreases obesity in rodents. Whether beta 3-selective agonists will be effective anti-obesity agents in humans is presently under investigation. PMID: 9046964 [PubMed - indexed for MEDLINE] 5943. Clin Sci (Lond). 1997 Jan;92(1):3-11. Regulation of adipose cell number in man. Prins JB, O'Rahilly S. 1. Adipose tissue mass is dependent on both the average volume and the number of its constituent adipocytes. Significant alteration in body mass involves alteration in both adipocyte volume and number. 2. Increases in adipocyte number occur via replication and differentiation of preadipocytes, a process which occurs throughout life. Decreases in adipocyte number occur via preadipocyte and adipocyte apoptosis, and possibly adipocyte dedifferentiation. 3. Overall regulation of adipose mass involves endocrine, paracrine and possibly autocrine systems. Hypothalamic centres appear to control appetite, metabolic rate and activity levels in a co-ordinated manner. Within the hypothalamus, known weight regulatory molecules include glucagon-like peptide-1, neuropeptide Y and leptin. Leptin is a major afferent signal from adipose tissue to the hypothalamus, providing information on overall adipose tissue mass. However, the precise means by which the hypothalamus signals to adipose tissue is less well understood. 4. In adipose tissue, known molecular regulators of adipose cell number include insulin, ligands for the peroxisome proliferator activated receptor-gamma, retinoids, corticosteroids and tumour necrosis factor-alpha. The net effect of these and other regulators is to effect a concerted alteration in adipocyte volume and number. This review largely focuses on the control of fat cell acquisition and loss and the influence of these processes on adipose tissue mass and regional distribution. PMID: 9038586 [PubMed - indexed for MEDLINE] 5944. Poult Sci. 1997 Jan;76(1):118-23. Regulators of adipocyte precursor cells. Butterwith SC(1). Author information: (1)Division of Development and Reproduction, Roslin Institute (Edinburgh), Midlothian, United Kingdom. Lean and adipose tissue growth are two of the most important targets for manipulation in commercial livestock. Adipose tissue growth occurs by both hyperplasia and hypertrophy. The processes involved in adipocyte hypertrophy are relatively well understood but much less is known about adipocyte hyperplasia. The mature adipocyte has little capacity for cell division and the hyperplastic capacity of adipose tissue resides in a population of fibroblast-like adipocyte precursor cells. The origin of these cells and the processes involved in their commitment to the adipocyte lineage is not known. Growth factors, in particular the bone morphogenetic proteins (BMP), are likely to be involved in regulating commitment to the adipocyte lineage. In vitro studies have shown that once committed to the adipocyte lineage, the proliferation and differentiation of, adipocyte precursor cells is regulated by a number of different growth factors. A number of these growth factors are expressed in adipocyte precursor cells in vitro and may have an autocrine-paracrine role. Others, such as epidermal growth factor (EGF), are more likely to have an endocrine role. The precise role that each growth factor plays in regulating adipocyte development in vivo is poorly understood. The chick is a useful experimental system with which to study the precise function of growth factors in adipocyte development. PMID: 9037698 [PubMed - indexed for MEDLINE] 5945. FASEB J. 1997 Jan;11(1):29-36. Cytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage. Simpson ER(1), Michael MD, Agarwal VR, Hinshelwood MM, Bulun SE, Zhao Y. Author information: (1)The Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, Dallas 75235-9051, USA. Family 19 of the P450 super family is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization because it involves conversion of the delta4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, because there are numerous untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in the ovary uses a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in the placenta uses a distal promoter located at least 40 kb upstream of the start of transcription that is regulated by retinoids. Other promoters are used in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11, as well as TNF-alpha, are important regulatory factors. A common 3'-splice junction located upstream of the start of translation is used in all of the splicing events involved in the use of these various promoters. Thus, the coding region of the transcripts, and hence the protein, are identical regardless of the tissue site of expression; what differs in a tissue-specific fashion is the 5'-end of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint, as well as for the physiology and pathophysiology of estrogen formation, as will be discussed in this review. PMID: 9034163 [PubMed - indexed for MEDLINE] 5946. J Am Diet Assoc. 1997 Jan;97(1):54-8; quiz 59-60. The new biology of body weight regulation. Schwartz MW(1), Seeley RJ. Author information: (1)Department of Medicine, University of Washington, Seattle, USA. A growing body of evidence suggests that energy balance (the difference between energy intake and expenditure) and body fuel stores in the form of adipose tissue are maintained by the body within a narrow range. This regulation of adiposity is mediated by the secretion of hormonal signals into the circulation in proportion to body adipose stores and their subsequent actions on brain systems that control caloric intake and energy expenditure. As a result, changes in energy balance sufficient to alter fuel stores elicit compensatory changes in energy intake and expenditure that return fat stores to their regulated level. Recent scientific break-through have identified the key components of this physiologic system. These include the circulating signals, leptin (the hormone encoded by the ob gene that is secreted by fat cells) and the pancreatic hormone insulin; and brain peptides such as neuropeptide Y, which is released from nerve terminals in the hypothalamus to elicit changes in feeding behavior and energy expenditure that mediate adaptive changes in energy balance. This article reviews the discovery of leptin and its receptor and discusses the interaction of leptin and insulin with the hypothalamic neuropeptide Y system. These observations provide a basis for understanding how weight lost during a period of negative energy balance (because of the inability to consume and/or store sufficient energy to meet ongoing energy demands) is eventually recovered. As our understanding of this weight-regulatory system increases, new insights into the causes of human obesity are likely to follow. Such insights may yield improvements in the medical and nutrition management of obese patients. PMID: 8990418 [PubMed - indexed for MEDLINE] 5947. Prog Lipid Res. 1996 Dec;35(4):371-85. Short-term regulation of acetyl CoA carboxylase in tissues of higher animals. Allred JB(1), Reilly KE. Author information: (1)Department of Food Science and Technology, Ohio State University, Columbus 43210, USA. PMID: 9246356 [PubMed - indexed for MEDLINE] 5948. Rev Esp Fisiol. 1996 Dec;52(4):255-8. Regulation of energy balance and adiposity: a model with new approaches. Martínez JA(1), Frühbeck G. Author information: (1)Departamento de Fisiología y Nutrición, Universidad de Navarra, Pamplona, Spain. jalfmtz@mail1.cti.unav.es Obesity etiology and treatment have been fraught with disappointment for researchers, because the mechanisms regulating fuel homeostasis and adiposity are incompletely understood. It can now be hypothesized in the light of new evidences that the control of body weight and composition depends upon an axis with three interrelated and self-controlled components: 1) food intake; 2) nutrient turnover and thermogenesis and 3) body fat stores, all of which underly complex feedback mechanisms. This approach considers two of the most relevant recent findings in the field (leptin and beta 3-adrenoceptors), adding new views to previous metabolic models of obesity. This perspective supplies some additional clues to the understanding of body composition regulation as well as the potential involvement of genetic and hypothalamic disorders in the onset of obesity. PMID: 9144847 [PubMed - indexed for MEDLINE] 5949. Cytokine Growth Factor Rev. 1996 Dec;7(4):303-9. Leptin and OB-R: body weight regulation by a cytokine receptor. White DW(1), Tartaglia LA. Author information: (1)Millennium Pharmaceuticals, Cambridge, MA 02139, USA. There has been intense recent interest in the molecules and pathways governing mammalian body weight regulation. Leptin (OB), an ancestral member of the cytokine family, is an adipocyte-secreted circulating hormone exhibiting weight regulatory properties. Recently, the leptin receptor (OB-R) was identified and shown to exhibit sequence homology and functional similarity to members of the class I cytokine receptor family. The mechanisms governing OB-R triggering and signal transduction have begun to be elucidated, providing new insight into the pathways controlling mammalian body weight homeostasis. PMID: 9023054 [PubMed - indexed for MEDLINE] 5950. Horm Metab Res. 1996 Dec;28(12):642-8. The loop system between neuropeptide Y and leptin in normal and obese rodents. Rohner-Jeanrenaud F(1), Cusin I, Sainsbury A, Zakrzewska KE, Jeanrenaud B. Author information: (1)Laboratoires de Recherches Métaboliques, Faculty of Medicine, University of Geneva, Switzerland. Over the years, the work of research laboratories in Baton Rouge (USA), Seattle (USA) and Geneva (Switzerland) have reached analogous conclusions regarding the main etiology of obesity as studied in animals: it largely lies within the brain, notably within the hypothalamus. The hypothalamus is indeed known to modulate food intake and energy partitioning, while the periphery has also been proposed to feed-back on the central nervous system (CNS) to provide information on the state of body energy stores, the two together constituting a loop system connecting the brain to the periphery (1,2,3). This etiologic viewpoint of a pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of one hypothalamic neuropeptide and one peripheral (adipose tissue) hormone, respectively neuropeptide Y (4), and quite particularly, leptin (5). As neuropeptide Y produces hyperphagia (6, 7) and as leptin produces hypophagia in normal animals (8,9,10), the loop system just mentioned was thought to comprise functional relationships, at least between these two factors. Other evidence also suggested that such a loop system was altered in obese animals. PMID: 9013734 [PubMed - indexed for MEDLINE] 5951. Horm Metab Res. 1996 Dec;28(12):633-7. Role of the beta3-adrenoceptor in the control of leptin expression. Giacobino JP(1). Author information: (1)Département de Biochimie Médicale, Centre Médical Universitaire, Genève, Switzerland. The inhibitory effect of beta-adrenoceptor agonists on leptin expression in brown and white adipose tissues is now well documented both in vivo and in vitro. It suggests the existence in vivo of a retroregulatory loop by which leptin inhibits its own expression via the sympathetic nervous system and the beta3-adrenoceptor. The hypothesis that the defect in beta3-adrenoceptor described in the adipose tissue of hereditary obese rodents can contribute to the resistance to leptin and to the increase in leptin expression observed in these animals is discussed. PMID: 9013732 [PubMed - indexed for MEDLINE] 5952. Horm Metab Res. 1996 Dec;28(12):619-32. The OB protein (leptin) pathway--a link between adipose tissue mass and central neural networks. Campfield LA(1), Smith FJ, Burn P. Author information: (1)Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. OB protein (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks that regulate ingestive behavior and energy balance. OB protein provides a communication link from fat tissue and the brain. Rapidly accumulating evidence suggests that OB protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation of the autonomic nervous system. These findings were followed by the identification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found to be expressed in the choroid plexus, the hypothalamus as well as several peripheral tissues. OB-R exists in multiple forms; the two major forms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thought to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated the mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-barrier and enter the brain of mice, rats and humans. The rate of transport can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals. OB protein appears to also play a role in the important neuroendocrine adaptive responses to fasting and in the control of reproduction. Therapeutic approaches to the treatment of obesity based on OB protein ranging from OB protein by injection to OB-R receptor agonists and to upregulation of OB signalling pathways are under intense investigation. PMID: 9013731 [PubMed - indexed for MEDLINE] 5953. Neth J Med. 1996 Dec;49(6):247-52. Leptin. Meinders AE(1), Toornvliet AC, Pijl H. Author information: (1)Department of General Internal Medicine, University Hospital Leiden, Netherlands. A highly conserved protein called 'leptin' was recently discovered to play a role in regulation of the energy balance in humans and rodents. This 167-amino-acid-containing protein is only produced and secreted by mature adipocytes. Absence of the protein in mutant ob/ob mice and resistance to its effects in db/db mice lead to extreme obesity and type II diabetes mellitus. No mutation of the ob-gene encoding for leptin has been found in obese humans so far. ob mRNA in adipocytes and serum leptin levels are positively related to adipose tissue mass. Receptors for leptin have been found in the choroid plexus and hypothalamus. A feedback inhibition of leptin on hypothalamic neuropeptide Y (NY) production is postulated, as hypothalamic NY concentrations are increased in ob/ob mice and NY induces food intake, insulin secretion and autonomic nervous system activity. Insulin increases triglyceride stores in fat cells and could thereby stimulate leptin secretion. The ultimate intracellular pathway within the adipocyte that stimulates or shuts off ob mRNA expression and consequent leptin production and secretion remains to be elucidated. Whether leptin will ever come to play a role in the treatment of human obesity remains an unanswered question at the present time. PMID: 8990865 [PubMed - indexed for MEDLINE] 5954. Endocrinol Metab Clin North Am. 1996 Dec;25(4):921-42. The endocrinology of obesity. Smith SR(1). Author information: (1)Inpatient Metabolic Unit, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, USA. Numerous endocrine alterations are associated with obesity (Table 1). The majority of the alterations are secondary to obesity and must be considered simply associated and potentially in the pathogenesis of the complications of obesity. The discovery of new endocrine peptides such as leptin that signal body fat content will increase our understanding of the regulation of body fat content. As a result, therapies will most certainly be developed that are directly targeted at the alterations in endocrine function. PMID: 8977053 [PubMed - indexed for MEDLINE] 5955. Endocrinol Metab Clin North Am. 1996 Dec;25(4):847-70. Fat cells. Ramsay TG(1). Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, USA. The adipocyte is a metabolically active cell that functions to store energy for times of energy deprivation or enhanced need. Obesity is characterized by increased lipid accumulation and turnover compared with the nonobese state. Both triglyceride synthesis and lipolysis are regulated metabolic processes in the adipocyte. Current research on the metabolic activities of the human adipocyte focus on plasma triglyceride hydrolysis and uptake of fatty acids by LPL, esterification of these fatty acids, and the subsequent triglyceride breakdown by hormone-sensitive lipase in response to stimulation of adrenergic receptors. These topics are discussed in relationship to the development of obesity. PMID: 8977049 [PubMed - indexed for MEDLINE] 5956. Endocrinol Metab Clin North Am. 1996 Dec;25(4):781-800. Lessons from animal models of obesity. York DA(1). Author information: (1)Experimental Obesity Research Program, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, USA. Obesity in animals may result from genetic, dietary, or neuroendocrine perturbations. Study of these models has identified the central systems that regulate food intake and energy expenditure and identified the interdependence of feeding behavior, the autonomic nervous system, and adrenal glucocorticoids in the development of obesity. The animal models of obesity have been influential in showing that adipose tissue is an important secretory tissue. The recent identification of five genes that cause obesity will provide new insight into the physiologic systems that regulate energy balance. PMID: 8977045 [PubMed - indexed for MEDLINE] 5957. Diabetologia. 1996 Dec;39(12):1528-31. New insights into obesity genes. Guerre-Millo M(1), Staels B, Auwerx J. Author information: (1)U 177 INSERM, Institut Biomédical des Cordeliers, Paris, France. PMID: 8960837 [PubMed - indexed for MEDLINE] 5958. Arch Biochem Biophys. 1996 Dec 1;336(1):1-9. Lycopene: a biologically important carotenoid for humans? Stahl W(1), Sies H. Author information: (1)Heinrich-Heine-Universität Düsseldorf, Postfach, Germany. Lycopene is a carotenoid present in human blood (approximately 0.5 micromol/liter plasma), and the tissue levels vary from 1 nmol/g wet wt in adipose tissue to up to 20 nmol/g wet wt in adrenals and testes. Its biological activities include antioxidant activity (singlet oxygen quenching and peroxyl radical scavenging), induction of cell-cell communication, and growth control, but no provitamin A activity. Epidemiological studies suggest protective effects of lycopene on some types of cancer, e.g., prostate cancer. In vitro and in vivo studies on growth of tumor cells support this conclusion. The major sources of lycopene for the human are tomatoes and tomato products, and bioavailability from different food items varies considerably. Lycopene oxidation products have recently been identified in human serum. Suggested health effects of lycopene require further investigation. PMID: 8951028 [PubMed - indexed for MEDLINE] 5959. Laryngoscope. 1996 Dec;106(12 Pt 1):1482-6. Lipoid meningitis due to aseptic necrosis of a free fat graft placed during neurotologic surgery. Hwang PH(1), Jackler RK. Author information: (1)Department of Otolarynology-Head and Neck Surgery and Neurological Surgery, University of California, San Francisco 94117, USA. We present two unusual cases of aseptic postoperative lipoid meningitis resulting from necrosis of a free fat graft placed into a skull base craniotomy defect. Two patients underwent translabyrinthine resection of acoustic neuroma and received abdominal fat grafts to ablate the surgical defect. Both patients presented postoperatively with persistent cerebrospinal fluid (CSF) wound leak and severe headache. Computed tomography demonstrated hydrocephalus and widely dispersed intracranial fat droplets throughout the CSF circulation. Both patients ultimately required CSF diversion for management of persistent communicating hydrocephalus. The clinical and radiographic correlates of lipocephalus and lipoid meningitis are presented, and a review of free fat graft physiology is discussed. PMID: 8948607 [PubMed - indexed for MEDLINE] 5960. Curr Opin Cell Biol. 1996 Dec;8(6):826-32. Adipocyte differentiation: a transcriptional regulatory cascade. Brun RP(1), Kim JB, Hu E, Altiok S, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Regina_Brun@dfci.harvard.edu The adipose cell is now known to play a complex role in energy homeostasis, energy storage and signaling to other tissues concerning the state of energy balance. The past few years have seen an explosive increase in our knowledge of the transcriptional basis of adipocyte differentiation. Factors such as peroxisome proliferator-activated receptor gamma, the CCAAT/enhancer binding protein family members, and adipocyte determination- and differentiation-dependent factor 1 play important regulatory roles in this process. Furthermore, these factors provide a focus for beginning to understand how various hormones and metabolites influence the development of adipose tissue in vivo. PMID: 8939673 [PubMed - indexed for MEDLINE] 5961. Rev Invest Clin. 1996 Nov-Dec;48(6):473-8. Significance of lipid consumption during lactation. Ortíz-Olaya N(1), Flores ME, DeSantiago S. Author information: (1)Unidad de Investigación Médica en Nutrición, Hospital de Pediatría CMN siglo XXI, IMSS, México, D.F. Human milk lipids are the main source of energy to support optimum growth of the breast-fed infant. The content and composition of milk lipids come from three main sources of fatty acids: the diet, mobilization of body fat stores and fatty acid synthesis de novo by the mammary gland. On account of these, the consumption and composition of the lipids from the diet and also the nutritional state, specifically the body fat percentage of the lactating woman, are elements that maintain a close relation with the content and composition of milk lipids which translates into the energy content given to the baby. The evidence suggests that the body fat stores significantly provide the demand imposed by lactation, and under suboptimal nutritional conditions where body fat stores are depleted, dietary lipid consumption is essential. It is necessary to elucidate the physiological regulatory mechanisms involved in the utilization of dietary lipids on milk synthesis. This information will be of great practical value, since it may allow the development of optimum diets for lactating women. PMID: 9028153 [PubMed - indexed for MEDLINE] 5962. Nutrition. 1996 Nov-Dec;12(11-12):749-62. NIH Consensus statement. Bioelectrical impedance analysis in body composition measurement. National Institutes of Health Technology Assessment Conference Statement. December 12-14, 1994. [No authors listed] OBJECTIVE: To provide physicians with a responsible assessment of bioelectrical impedance analysis (BIA) technology for body composition measurement. PARTICIPANTS: A non-Federal, nonadvocate, 13-member panel representing the fields of nutrition, pediatrics, surgery, public health, biomedical engineering, epidemiology, and biostatistics. In addition, 20 experts in nutrition, pediatrics, metabolism, biomedical engineering, physiology, and epidemiology presented data to the panel and a conference audience of 220. EVIDENCE: The literature was searched through Medline and an extensive bibliography of reference was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. ASSESSMENT PROCESS: The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after conference. CONCLUSIONS: BIA provides a reliable estimate of total body water under most conditions. It can be a useful technique for body composition analysis in healthy individuals and in those with a number of chronic conditions such as mild-to-moderate obesity, diabetes mellitus, and other medical conditions in which major disturbances of water distribution are not prominent. BIA values are affected by numerous variables including body position, hydration status, consumption of food and beverages, ambient air and skin temperature, recent physical activity, and conductance of the examining table. Reliable BIA requires standardization and control of these variables. A specific, well-defined procedure for performing routine BIA measurements is not practiced. Therefore, the panel recommends that a committee of appropriate scientific experts and instruments manufacturers be formed with the goal of setting instruments standards and procedural methods. PMID: 8974099 [PubMed - indexed for MEDLINE] 5963. Biochem Soc Trans. 1996 Nov;24(4):1010-4. cGMP-inhibited phosphodiesterases (PDE3 gene family). Degerman E(1), Belfrage P, Manganiello VC. Author information: (1)Department of Cell and Molecular Biology, Lund University, Sweden. PMID: 8968502 [PubMed - indexed for MEDLINE] 5964. Nord Med. 1996 Nov;111(9):300-3. [Leptin--a new weight-loss agent?]. [Article in Danish] Holst JJ(1). Author information: (1)Medicinsk Fysiologisk Institut, Københavns Universitet, Panum-instituttet. The relatively constant level of body fat in the adult mammal is explained by the lipostat theory as follows: A factor is released from adipose tissue in amounts that reflect total body fat content. This factor is then registered by the hypothalamic centres that regulate appetite. The theory has gained particular support from parabiotic experiments in genetically fat mice, amongst whom the so-called ob/ob mice appear to produce too little of the factor, whilst signal transduction to the satiety centre appears to be defective in the so-called db/db mice. The two genetic defects have recently been clarified, and it has been shown that the normal ob gene nodes for a protein called leptin. Leptin is released from adipose tissue, and its plasma concentration reflects total body fat. The normal db-gene codes for a hypothalamic receptor for leptin. These crucial discoveries have greatly supported the correctness of the lipostat theory. At present, extensive investigations of the roles of leptin and the leptin receptor in human adiposity are in progress. PMID: 8966112 [PubMed - indexed for MEDLINE] 5965. Horm Metab Res. 1996 Nov;28(11):573-81. Obesity in children. Environmental and genetic aspects. Guilloume M(1), Björntorp P. Author information: (1)Centre National de Recherche en Nutrition et Santé, Institut d'Hygien et Epidemiologie, Brussels, Belgium. PMID: 8960896 [PubMed - indexed for MEDLINE] 5966. J Mol Med (Berl). 1996 Nov;74(11):639-52. The metabolic consequences of altered glucose transporter expression in transgenic mice. Katz EB(1), Burcelin R, Tsao TS, Stenbit AE, Charron MJ. Author information: (1)Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Glucose transporters are a family of membrane proteins which mediate glucose uptake across the cell membrane. The facilitative glucose transporter proteins are products of unique genes and are expressed in a tissue-specific manner. They are very similar structurally, containing 12 putative membrane spanning domains. Functionally they vary in their affinity for glucose and sensitivity to hormones such as insulin. Glucose homeostasis depends mainly on controlled changes in glucose transport in insulin-responsive tissues such as skeletal muscle and adipose cells where both glucose transporter 1 and glucose transporter 4 are expressed. Glucose transporter 4 is the major glucose transporter in these tissues and translocates from an intracellular vesicle to the cell membrane in response to insulin. Alterations of the level of expression of these glucose transporters should result in changes in insulin sensitivity and modification of whole-body metabolism. To test these hypotheses transgenic mouse models have been generated which overexpress glucose transporters in specific tissues or in the whole body. Glucose transporter 1 and glucose transporter 4 have been overexpressed specifically in skeletal muscle and glucose transporter 4 specifically in adipose tissue. Mice have also been made which overexpress glucose transporter 4 in the whole body. Using homologous recombination technology to disrupt the glucose transporter 4 gene, a "knockout" mouse has been created which expresses no glucose transporter 4. The metabolic consequences of these genetic manipulations on the level of expression of glucose transporters in the mouse are reviewed. The future applications of transgenic mouse technology in creating models which mimic human diseases are also discussed. PMID: 8956150 [PubMed - indexed for MEDLINE] 5967. Bioessays. 1996 Nov;18(11):867-74. Obesity genes and the regulation of body fat content. Weigle DS(1), Kuijper JL. Author information: (1)Department of Medicine, University of Washington School of Medicine, Seattle, USA. Physiological investigation has demonstrated that the central nervous system monitors body composition and adjusts energy intake and expenditure to stabilize total adipose tissue mass. Genetic variations in the signalling molecules involved in this regulatory system account for the heritable component of body fat content. The application of molecular techniques to rodent models of Mendelian obesity has resulted in the characterization of five loci at which mutations produce an abnormal accumulation of body fat. The genes at these loci include agouti, which encodes a molecule that antagonizes the binding of alpha melanocyte-stimulating hormone to its receptor; fat, which encodes carboxypeptidase E; tubby, which encodes a putative phosphodiesterase; obese, which encodes a circulating satiety protein; and diabetes, which encodes the receptor for the obese gene product. A more detailed understanding of the functional interrelationships of these genes should lead to important new insights into the causes and potential therapies for human obesity. PMID: 8939064 [PubMed - indexed for MEDLINE] 5968. Phys Med Biol. 1996 Nov;41(11):2231-49. The dielectric properties of biological tissues: I. Literature survey. Gabriel C(1), Gabriel S, Corthout E. Author information: (1)Physics Department, King's College, Strand, London, UK. The dielectric properties of tissues have been extracted from the literature of the past five decades and presented in a graphical format. The purpose is to assess the current state of knowledge, expose the gaps there are and provide a basis for the evaluation and analysis of corresponding data from an on-going measurement programme. PMID: 8938024 [PubMed - indexed for MEDLINE] 5969. Sports Med. 1996 Nov;22(5):273-81. The importance of fat free mass maintenance in weight loss programmes. Marks BL(1), Rippe JM. Author information: (1)Department of Physical Education, Exercise, and Sport Science, University of North Carolina, Chapel Hill, USA. Obese individuals have excess total body mass, a condition resulting from an overaccumulation of both fat and fat free mass (FFM). Research has been focusing on the need to maintain FFM during weight loss because of its integral role in metabolic rate regulation, preservation of skeletal integrity and maintenance of functional capacity. It has been suggested that FFM loss should compose no more than 30% of total weight loss. Because skeletal muscle in the obese has been shown to consist of an increased amount of low density muscle tissue, impaired strength: size ratio, less capillarisation, decreased mitochondrial density, and consequently impaired work capacity, it may be necessary to stratify FFM into essential and less essential FFM categories. With this categorisation, more specific quantification of FFM loss and maintenance can be made. While FFM influences several physiological functions, it may be that a minimal loss of FFM from the obese state is not only unavoidable, but actually desirable if the loss is in the form of less essential FFM. PMID: 8923645 [PubMed - indexed for MEDLINE] 5970. Cell. 1996 Nov 1;87(3):377-89. Adipogenesis and obesity: rounding out the big picture. Spiegelman BM(1), Flier JS. Author information: (1)Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. PMID: 8898192 [PubMed - indexed for MEDLINE] 5971. Diabetes. 1996 Nov;45(11):1644-54. Lilly lecture 1995. Glucose transport: pivotal step in insulin action. Kahn BB(1). Author information: (1)Department of Medicine at Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts, USA. bkahn@bih.harvard.edu The effect of insulin to acutely stimulate glucose uptake into muscle and adipose tissue is essential for normal glucose homeostasis. The GLUT4 glucose transporter is a major mediator of this action, and insulin recruits GLUT4 from an intracellular pool to the plasma membrane. An important pathologic feature of obesity, NIDDM, and to a lesser extent IDDM is resistance to insulin-stimulated glucose uptake. Investigations of the mechanisms have revealed tissue-specific regulation of GLUT4 with decreased gene expression in adipose cells but not in skeletal muscle. This has led to the hypothesis that alterations in the trafficking of the GLUT4 vesicle or in the exposure or activation of the GLUT4 transporter may cause insulin resistance in skeletal muscle in obesity and diabetes. Exercise training increases GLUT4 expression in muscle in association with enhanced glucose tolerance in vivo. Transgenic mice have been created to investigate other approaches to improve insulin action on glucose transport. Overexpression of GLUT4 in adipocytes of transgenic mice increases the proportion of GLUT4 on the plasma membrane and enhances insulin sensitivity in vivo. Altering insulin signaling by overexpressing p21ras in adipocytes of transgenic mice results in increased GLUT4 on the plasma membrane in the absence of insulin and increases insulin sensitivity in vitro and in vivo. Thus, glucose transport is a pivotal step in whole-body insulin action. Strategies to increase the number of GLUT4 transporters that are functionally inserted in the plasma membrane in muscle and adipocytes may lead to new therapies to treat or prevent NIDDM. PMID: 8866574 [PubMed - indexed for MEDLINE] 5972. Diabetes. 1996 Nov;45(11):1455-62. Leptin: the tale of an obesity gene. Caro JF(1), Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Author information: (1)Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA. carojose@lilly.com PMID: 8866547 [PubMed - indexed for MEDLINE] 5973. Presse Med. 1996 Oct 19;25(31):1453-8. [Acute hemorrhagic pancreatitis]. [Article in French] Varlet C(1), Pourriat JL. Author information: (1)Département d'Anesthésie-Réanimation, CHU Jean Verdier, Bondy. Necrotizing acute pancreatitis is defined as necrosis of the adipose tissue, interstitial tissue and glandular tissue associated with areas of hemorrhage. Several causes are known predominantly biliary lithiasis and alcoholism. Severe consequences due to the release of pancreatic enzymes include activation of inflammation mediators which can lead to multiple organ failure. Although no therapy has been proven to be effective, progress in intensive care has helped reduce mortality. Rapid diagnosis and evaluation of the severity of illness with specific or general scores (Apache II score) are the keys to rapid management using therapies adapted to the degree of organ failure. Indication for surgery must be established in coordination with surgeons and depends both on the clinical course and computed tomography score. PMID: 8958875 [PubMed - indexed for MEDLINE] 5974. Sheng Li Ke Xue Jin Zhan. 1996 Oct;27(4):353-5. [Thermoregulation mechanisms of brown adipose tissue]. [Article in Chinese] Wang ZK, Li QF, Sun RY. PMID: 9772391 [PubMed - indexed for MEDLINE] 5975. Endocr J. 1996 Oct;43 Suppl:S5-11. Management of puberty in growth hormone deficient children. Rogol AD(1). Author information: (1)Department of Pediatrics, University of Virginia Health Sciences Center 22908, USA. At puberty there occur marked increases in gonadotropin, gonadal steroid and GH secretion. An important physiological synergism exists between the gonadal and somatotropic axes to permit the growth spurt and adolescent development; however, epiphyseal maturation is also accelerated leading to cessation of long-bone growth. GH deficiency may be absolute, but often is not and the diagnosis may be complicated by a constellation of physical and hormonal findings that are along a spectrum from low normal GH sufficiency to absent GH secretion. Growth hormone therapy not only accelerates the growth velocity, but also promotes the redistribution of adipose tissue stores to more peripheral sites. Given the remarkable physiological alterations in the activities of the GH and gonadotropin gonadal axes during adolescence in normal children, how should the therapeutic plan for the treatment of prepubertal GH deficiency be altered at puberty? Evidence for efficacy has been reported for each of the following for the treatment of GH deficiency at adolescence: 1) GH alone at the usual dosage (approximately 0.3 mg.kg-1.day-1); 2) Double or triple the amount of GH to mimic the finding of increased GH release at puberty. 3) GH at the usual or moderately increased dose and gonadotropin releasing hormone agonist analog to halt pubertal development. The latter two plans are at present hypotheses that must withstand the rigor of proper controlled trials. The end point is more than merely adult height, because of the significant psychological and skeletal system dysregulation that accompany decrements in the gonadal steroid hormones during adolescence. PMID: 9076336 [PubMed - indexed for MEDLINE] 5976. Nutr Rev. 1996 Oct;54(10):329-31. Insulin-stimulated glucose disposal: does adipose play a role? Frost SC(1). Author information: (1)Department of Biochemistry and Molecular Biology, University of Florida, Gainesville 32610, USA. Although muscle is thought to be a primary assimilator of glucose, adipose may provide a substantial amount of substrate for gluconeogenesis, even in the fed state. PMID: 9063024 [PubMed - indexed for MEDLINE] 5977. Acta Paediatr Suppl. 1996 Oct;417:83-5. Effect of growth hormone treatment in children with craniopharyngioma with reference to the KIGS (Kabi International Growth Study) database. Price DA(1), Jönsson P. Author information: (1)Department of Child Health, Manchester University, Royal Manchester Children's Hospital, UK. In children with craniopharyngioma, poor growth commonly precedes diagnosis, but is observed less frequently than neurological or visual symptoms. A deficiency of growth hormone (GH) is common before, and almost universal after, treatment of the tumour, and is usually treated with GH. However, a minority of these children with GH deficiency (GHD) grow well without GH replacement therapy but exhibit other metabolic effects of GHD that are correctable by GH treatment. This article provides a review of studies in 422 children with craniopharyngioma whose details have been entered into the database of KIGS, the Kabi International Growth Study. The response to GH during the first year of therapy was similar to that seen in children with idiopathic GHD (IGHD). Leg length was relatively greater than sitting height and this disproportion was maintained during treatment. Adiposity increased in some children receiving GH treatment. At the end of GH treatment in 82 patients, there was a median gain in height SD score of 1.51, with evidence of residual growth potential still remaining in the majority. Tumour recurrence occurred in 13.5% of the total group of patients with craniopharyngioma within KIGS, at a median of 3.9 years from diagnosis and 2.3 years from the start of GH therapy. Tumour recurrence was not associated with an impairment in height achieved, but there was a tendency towards greater adiposity in patients in whom recurrence occurred. Adverse events during GH treatment were more frequent in children with craniopharyngioma than in those with IGHD, and headache was commonly reported. The results of these studies suggest that GH treatment is recommended for the treatment of children with craniopharyngioma on the grounds of improved growth velocity, adult height and other GH-dependent metabolic functions, and of the good safety profile of GH in these patients. PMID: 9055921 [PubMed - indexed for MEDLINE] 5978. Clin Endocrinol (Oxf). 1996 Oct;45(4):373-8. Obesity genes. Beales PL(1), Kopelman PG. Author information: (1)Medical Unit, St Bartholomew's School of Medicine and Dentistry, Queen Mary and Westfield College, London, UK. This review highlights the considerable advances in the understanding of the inheritance of fatness and the possible genetic mechanisms. The investigation of animal models confirms the fundamental importance of genes in determining fatness and demonstrates a genetic link between adipocyte function, derangements of steroid metabolism, insulin secretion and hypothalamic regulation. The heterogeneous nature of human obesity makes it unwise to extrapolate directly from the findings in animals but these findings do provide important clues to the situation in man. It is crucial that advances in the knowledge of genes involved in human obesity are paralleled by an understanding of gene-gene interactions and the influence of environmental factors. The rapidly increasing prevalence of obesity in society underlines the paramount influence of the environment. PMID: 8959072 [PubMed - indexed for MEDLINE] 5979. Int J Obes Relat Metab Disord. 1996 Oct;20(10):938-42. Obesity, adiposity, and lengthening of the QT interval: improvement after weight loss. Carella MJ(1), Mantz SL, Rovner DR, Willis PW 3rd, Gossain VV, Bouknight RR, Ferenchick GS. Author information: (1)Department of Medicine, Michigan State University, E. Lansing, USA. OBJECTIVES: To determine the prevalence of QT interval prolongation in patients referred to an outpatient clinic for treatment of obesity; and to describe the change in the QT interval during rapid weight loss with a very-low-calorie diet. DESIGN: Retrospective and prospective review of charts and electrocardiograms. SUBJECTS: Five hundred twenty-two obese patients (411 female, 112 males) with a mean age 44 (18-78 y) and a mean initial weight of 116 kg (63-285 kg) completing 26 weeks of treatment between September, 1989 through to December, 1993. MEASUREMENTS: We reviewed the EKGs of all patients and serially monitored the QTc if greater than 0.44 s or if more than 23 kg was lost during treatment. The QTc interval was calculated with Bazzett's formula using both a manual method and an automated software program. In some patients, body composition was measured by hydrodensitometry. RESULTS: The QTc interval before treatment was 0.42 +/- 0.026 s by manual measurement and 0.41 +/- 0.021 s by automated measurement. Forty-one to 53% of patients showed a QTc interval of greater than 0.42 s and 10-24% demonstrated moderate prolongation (> 0.44 s). In those patients for whom repeat EKG were performed, QTc showed shortening with weight loss by both methods (mean +/- s.e. of 0.42 +/- 0.003 to 0.41 +/- 0.003 s, P < 0.01 manually and 0.41 +/- 0.003 to 0.40 +/- 0.003 s, p < 0.005 by automated program). Analyses were repeated excluding 179 patients with a cardiovascular-related diagnosis or intraventricular block and the results were similar. By regression analysis, gender and fat mass (FM) percentage above normal predicted the QTc. CONCLUSIONS: QT Interval prolongation is common in obesity. For each 50% increase in FM% above normal, there is a 5 ms increase in the QTc above a 'normal' upper limit of 0.40 and 0.38 s in women and men, respectively. Moreover, the QT interval shortens with weight loss. This change may represent an additional benefit of weight loss along with the improvement in other cardiovascular risk factors. PMID: 8910099 [PubMed - indexed for MEDLINE] 5980. Diabetes Metab. 1996 Oct;22(5):305-13. Insulin-resistance syndrome and cardiovascular complications of non-insulin-dependent diabetes mellitus. Fontbonne A(1). Author information: (1)NESC/CPqAM/FIOCRUZ, Coelhos, Recife/PE, Brasil. Although most cohort studies have shown that diabetes is a risk factor for cardiovascular disease, the mechanisms remain unclear. Hyperglycaemia defines this disorder but does not provide the criteria for causality. However, there are new indications for the possible role of a potentially atherogenic and diabetogenic syndrome rooted in insulin resistance, which was first described by Reaven as "syndrome X". In its complete form, this syndrome includes hyperinsulinaemia, glucose intolerance, dyslipidaemia, elevated blood pressure and fibrinolytic impairment. The complex pathophysiological processes leading to the clustering of these abnormalities are still unclear but probably relate to excessive intra-abdominal fat deposits (clinically expressed by upper body fet distribution) and combined insulin resistance and hyper-insulinaemia. The presence of insulin resistance and hyperinsulinaemia in pre-diabetic individuals, and their predictive role in non-insulin dependent diabetes mellitus, has been documented in various ethnic groups, suggesting a two-step process in the natural history of the disease, i.e. "compensated" insulin resistance followed by failure of insulin secretory response leading to a hyperglycaemic (diabetic) phase. In Caucasians at least, in whom the insulin-resistance syndrome includes clear abnormalities in its most potentially atherogenic elements, this natural history suggests that the cardiovascular complications associated with non-insulin dependent diabetes mellitus originate from the initial "pre-diabetic" phase of the disease. Early prevention would theoretically require intervention before hyperglycaemia occurs (or even if it will never occur) for all upper body obese subjects who present with insulin-resistance syndrome. PMID: 8896991 [PubMed - indexed for MEDLINE] 5981. Clin J Sport Med. 1996 Oct;6(4):237-44. Exercise as rehabilitation for cancer patients. Friendenreich CM(1), Courneya KS. Author information: (1)Division of Epidemiology, Prevention and Screening, Alberta Cancer Board, Canada. OBJECTIVE: To review the literature on the association of exercise and rehabilitation among cancer patients in order to stimulate research in this field. DATA SOURCES: Computerized literature search of databases (Medline, Psychlit, Sportdiscus, Cinahl) and manual search of journals done to identify all empirical studies on exercise and rehabilitation of cancer patients ever conducted and published in any language on this topic. STUDY SELECTION: Eleven studies found, of these, two were unpublished conference proceedings and could not be obtained, two were doctoral dissertations and seven were published research studies. Of the nine studies reviewed, four were randomized controlled trials, three were quasi-experimental studies, and two were retrospective studies (case-control and cohort in design). All of the studies examined breast cancer patients only. DATA EXTRACTION: Qualitative review conducted since the studies had heterogeneous study designs including the type and form of exercise intervention or measurement, the data collection methods, and the outcome variables. DATA SYNTHESIS: Overall, exercise resulted in an improvement of the physiologic parameters observed, including increases in functional capacity and lean tissue, decreases in percent body fat, nausea and fatigue. Improvements in psychologic indicators of well-being and quality of life also found. CONCLUSIONS: Exercise appears to improve breast cancer patients physiologic and psychologic well being; however, the research studies reviewed here have numerous methodologic limitations and these results must be considered as preliminary evidence only. To improve knowledge of how exercise may help the rehabilitation of all types of cancer patients, future research studies are needed that use a wider sample of cancer patients, a well-designed randomized controlled design, an exercise intervention that more closely reflects true life circumstances, that is of long duration, that measures numerous physiologic and psychologic changes, and that examines exercise recruitment and adherence problems that may occur. PMID: 8894336 [PubMed - indexed for MEDLINE] 5982. Am J Surg Pathol. 1996 Oct;20(10):1182-9. Combined morphologic and karyotypic study of 59 atypical lipomatous tumors. Evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group). Rosai J(1), Akerman M, Dal Cin P, DeWever I, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rydholm A, Sciot R, Tallini G, Van den Berghe H, Van de Ven W, Vanni R, Willen H. Author information: (1)Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Fifty-nine cases of atypical lipomatous tumors (ALT) of soft tissue (atypical lipomas, well-differentiated liposarcomas) were studied morphologically and cytogenetically as part of an international collaborative study. Forty-nine cases were deeply seated (including retroperitoneum), and 10 were superficial. Clonal chromosomal abnormalities were found in 55 cases (93%). Supernumerary ring or giant marker chromosomes (RGCs), the sole consistent alteration, were found in 37 ALTs (63%). They were more common in tumors that were large (p < 0.001), deeply seated (p < 0.005), that contained lipoblasts (p < 0.05), and that had marked cytologic atypia (p < 0.05). In a relatively short follow-up period (average, 3 years), only three of 59 cases recurred, one resulting in the patient's death. All three cases had RGCs. Also, five of the six cases that underwent dedifferentiation had RGCs, indicating that RGCs are associated not only with low-grade malignant behavior (in the form of local recurrence) but also with the potential for tumor progression. When the karyotypic profile of ALT was compared with that of 233 other types of adipose tissue tumors similarly analyzed by the authors, a statistically highly significant correlation (p < 0.0001) was found between ALT and RGCs. These results support the existence of ALT as a distinct tumor subtype that is different from ordinary lipoma and from spindle or pleomorphic lipoma, albeit histogenetically closely related to them. It also supports the proposed pathogenetic link between ALT and dedifferentiated liposarcoma. The association between chromosomal and morphologic findings indicates the potential role of karyotypic analysis in the differential diagnosis of ALT with ordinary lipoma, spindle or pleomorphic lipoma, hibernoma, and myxoid liposarcoma. PMID: 8827023 [PubMed - indexed for MEDLINE] 5983. Sci Total Environ. 1996 Sep 9;187(3):199-210. Uncertainty in estimated half-lives of PCBS in humans: impact on exposure assessment. Shirai JH(1), Kissel JC. Author information: (1)Delta Toxicology, Seattle, WA 98121, USA. Estimates of the half-lives of PCBs in humans derived from successive body burden measurements are reviewed and found to vary widely whether based on congener-specific or aggregate data. Variability due to differences in physiological processes among individuals and in congener properties is to be expected, but does not appear to be a complete explanation. Very short half-lives (i.e. < 1 year) are unlikely for those congeners most frequently found in human blood because the exposures required to sustain observed body burdens are too large to be easily explained. Very long half-lives ( > 10 years) may be artifacts of confounding by ongoing exposures (a common effect at low body burdens) and are also suspect. The loss of significant quantities of PCBs from the blood of occupationally exposed persons with half-lives of 2-6 years is comparatively well documented (i.e. has been observed in studies with relatively large numbers of subjects and high initial body burdens). Therefore, very long half-lives must be limited to subsets of congeners or of populations if they occur at all. The impact of the use of fixed estimates of half-lives drawn from the tails of the observed range on the evaluation of regulatory standards is shown to be substantial. PMID: 8711465 [PubMed - indexed for MEDLINE] 5984. Br J Surg. 1996 Sep;83(9):1186-96. Sepsis and fat metabolism. Samra JS(1), Summers LK, Frayn KN. Author information: (1)Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, UK. Sepsis is a common surgical problem which can induce profound changes in the plasma concentrations of cytokines and hormones, leading to a catabolic state. Hypertriglyceridaemia and increased fat oxidation are the main features of altered fat metabolism encountered in this state. The endogenous catabolism of sepsis can be reduced by administering exogenous lipid emulsions as a source of metabolic fuel, although the changes in lipid metabolism associated with sepsis may affect the handling of these exogenous lipids. An exciting area for future research is an examination of the ability of lipid emulsions to reduce the morbidity and mortality associated with sepsis by altering immune responses, in addition to limiting catabolism. PMID: 8983604 [PubMed - indexed for MEDLINE] 5985. Leuk Lymphoma. 1996 Sep;22 Suppl 1:129-34. Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders. Peschel C(1), Aulitzky WE, Huber C. Author information: (1)IIIrd Department of Medicine, Johannes Gutenberg University Mainz, Germany. Myeloproliferative disorders (MPD) are characterized by several common clinical and biological features, although at the molecular level, each disease entity exhibits distinct abnormalities. IFN-alpha exerts beneficial therapeutic effects in chronic myelogenous leukemia, polycythemia vera and essential thrombocythemia, resulting in control of hematopoietic hyperplasia and, in a minority of patients, in induction of cytogenetic remission. The mechanism of action of IFN-alpha in MPD is poorly defined. Recently published in vitro findings suggest that IFN-alpha interacts with the regulation of hematopoiesis by multiple ways. Its antiproliferative activity is well known for more than a decade, however, substantial growth inhibition is achieved only at relatively high concentrations. Defective adhesion of hematopoietic progenitor cells in CML to bone marrow stromal cells is corrected by IFN-alpha, which might expose CML progenitors to inhibitory cytokines produced by the bone marrow microenvironment. Recent work from our group demonstrated, that IFN-alpha potently interacts with the production of hematopoietic cytokines in bone marrow stromal cells. Expression of stimulatory cytokines, such as GM-CSF, G-CSF, IL-1 and IL-11 is inhibited by IFN-ct, whereas the production of negative regulators, such as IL-1RA and MIP-1 alpha, is stimulated. The combined action of IFN-alpha on paracrine expression of cytokines suggests an indirect antihematopoietic effect, which might contribute to its clinical activity in MPD. PMID: 8951783 [PubMed - indexed for MEDLINE] 5986. J Endocrinol. 1996 Sep;150 Suppl:S155-64. Obesity and metabolic complications: contribution of dehydroepiandrosterone and other steroid hormones. Tchernof A(1), Labrie F, Bélanger A, Després JP. Author information: (1)Liptd Research Center, Clinical Research Center, Sle foy, Quebec, Canada. Obesity is a heterogeneous condition and not every obese patient is at increased risk of cardiovascular diseases (CVD). It is now well established that the regional distribution of body fat is a critical correlate of the metabolic complications of obesity. Studies that have assessed adipose tissue distribution by imaging techniques such as computed tomography have demonstrated the importance of the intra-abdominal (visceral) fat depot as a marker of a cluster of metabolic abnormalities which include glucose intolerance, insulin resistance, hyper-insulinemia, hypertriglyceridemia, elevated number of apo B-carrying lipoproteins as well as hypoalphalipoproteinemia. Although the association between visceral obesity and metabolic complications can hardly be questioned, it has been suggested that it may not necessarily represent a causal relationship. For instance, concomitant alterations in sex steroid levels have been found in both men and women with abdominal (visceral) obesity which have also been reported to be significantly correlated with the insulin resistant-dyslipidemic state found in abdominal obese subjects. In women, abdominal obesity is associated with increased free testosterone concentrations and reduced sex hormone binding globulin (SHBG) levels, whereas in men this condition is associated with reduced testosterone and adrenal C12 steroid (dehydroepiandrosterone, androstenedione, androstene-3 beta, 17 beta-diol) levels as well as decreased SHBG concentrations. These altered steroid and SHBG; levels have been reported to be independent correlates of the metabolic complications of visceral obesity although they cannot solely account for the increased CVD risk found in these patients. In this regard, intervention studies are clearly warranted to better quantity the respective contribution of excess visceral adipose tissue and of the concomitant alterations in sex steroid levels as modulators of metabolic disturbances increasing CVD risk in obesity. PMID: 8943799 [PubMed - indexed for MEDLINE] 5987. Nihon Geka Gakkai Zasshi. 1996 Sep;97(9):726-32. [Energy substrate metabolism during stress]. [Article in Japanese] Sugimoto H(1). Author information: (1)Department of Traumatology and Critical Care Medicine, Osaka University School of Medicine, Suita, Japan. Energy substrate metabolism during stress is characterized by increased REE (resting energy expenditure), hyperglycemia, hyperlactatemia and protein catabolism. This stress-induced hypermetabolic responses are closely related to increased secretion of neurohormonal and cytokine mediators. The insulin resistance hyperglycemia has been called "stress diabetes" or "surgical diabetes". Glucose disposal has been thought to be impaired in this condition. However, glucose uptake in most tissue is non-insulin mediated. Recent studies showed glucose uptake elevated in sepsis or TNF infusion. Insulin-regulatable glucose transporter (GLUT4) is present only in muscle, heart and adipose tissues. It was demonstrated that insulin binding to membrane receptors in these tissues was intact. This hyperglycemia in stress diabetes results from a postreceptor mechanism. Stress hyperlactatemia is thought to be caused by decreased pyruvate dehydrogenase activity rather than tissue hypoperfusion. Hyperlactatemia may promote gluconeogenesis. Glucose is a essential energy substrate in some tissues such as brain, erythrocyte and leukocyte. Hyperglycemia may be viewed as a beneficial response during stress. PMID: 8940683 [PubMed - indexed for MEDLINE] 5988. Rev Med Brux. 1996 Sep;17(4):240-3. [Surgical treatment of lipodystrophies]. [Article in French] De Mey A(1). Author information: (1)Service de Chirurgie Plastique, Centre Hospitalier Universitaire Brugmann, Bruxelles. Esthetic body contouring has become the most common esthetic surgical procedure since the advent of liposuction. The interest in this surgery led us to focus on the physiology of adipose tissue that behaves differently according to its localisation. Besides, a better knowledge of the anatomy of the subcutaneous tissue has helped us to treat the deep and superficial adipose deposits more effectively. Many technical refinements have been proposed in order to improve the results and decrease the risks. Local infiltration allows us to remove large amounts of fat with a minimal blood loss. Syringe aspiration is less traumatic and avoids the purchase of an expensive suction pump. However, although the technique of suction lipectomy looks simple, this procedure can induce important local complications (contour deformities, skin waves, ...) and general complications (pulmonary embolism, fat embolism, cardio-pulmonary decompensation). A rigorous technique, performed by a well trained surgeon in an adequate medical environment is essential to obtain the best results with suction lipectomy. In order to correct excesses of skin on the abdomen or the thighs after an important weight loss, skin excisions will be necessary. In there cases, the scars are often wide and sometimes difficult to hide. PMID: 8927853 [PubMed - indexed for MEDLINE] 5989. Br J Sports Med. 1996 Sep;30(3):205-8. Effect of altered reproductive function and lowered testosterone levels on bone density in male endurance athletes. Bennell KL(1), Brukner PD, Malcolm SA. Author information: (1)School of Physiotherapy, University of Melbourne, Australia. It is apparent that bone density in male athletes can be reduced without a concomitant decrease in testosterone, suggesting that bone density and testosterone concentrations in the normal range are not closely related in male athletes. Further research is necessary to monitor concurrent changes in bone density and testosterone over a period of time in exercising males. In any case, the effect of exercise on the male reproductive system does not appear as extreme as that which can occur in female athletes, and any impact on bone density is not nearly as evident. These results imply that factors apart from testosterone concentrations must be responsible for the observed osteopenia in some male athletes. Many factors have the potential to adversely affect bone density, independently of alterations in reproductive function. These include low calcium intake, energy deficit, weight loss, psychological stress, and low body fat, all of which may be associated with intense endurance training. Future research investigating skeletal health in male athletes should include a thorough assessment of reproductive function in addition to these other factors. PMCID: PMC1332330 PMID: 8889111 [PubMed - indexed for MEDLINE] 5990. Trends Pharmacol Sci. 1996 Sep;17(9):309-13. Application of in situ microdialysis to measure metabolic and vascular responses in adipose tissue. Lafontan M(1), Arner P. Author information: (1)INSERM Unit 317, Institut Louis Bugnard, Université Paul Sabatier, CHR, Rangueil, Toulouse, France. PMID: 8885693 [PubMed - indexed for MEDLINE] 5991. Br J Clin Pharmacol. 1996 Sep;42(3):291-300. Clinical pharmacology of beta 3-adrenoceptors. Lipworth BJ(1). Author information: (1)Department of Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee, UK. 1. An atypical non beta 1/beta 2-adrenoceptor (AR) subtype (beta 3-AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2. Molecular studies have shown that beta 3-AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall-bladder and colon. In vitro studies with beta 3-AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3. Regulation of beta 3-AR may differ from beta 1/beta 2-AR subtypes in that continuous agonist exposure does not result in receptor down-regulation. 4. A polymorphism of the human beta 3-AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to beta 3-AR stimulation in man. 5. There is accumulating evidence to support a therapeutic role of beta 3-AR agonists in NIDDM because of anti-obesity and anti-diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6. Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a beta 3-AR mediated component to thermogenesis which is dissociated from beta 1/beta 2-mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional beta 3-AR mediating cardiac but not airway responses in humans. An evaluation of beta 3-AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro. PMCID: PMC2042673 PMID: 8877018 [PubMed - indexed for MEDLINE] 5992. Lab Invest. 1996 Sep;75(3):295-306. The contribution of image cytometry and artificial intelligence-related methods of numerical data analysis for adipose tumor histopathologic classification. Goldschmidt D(1), Decaestecker C, Berthe JV, Gordower L, Remmelink M, Danguy A, Pasteels JL, Salmon I, Kiss R. Author information: (1)Department of Plastic Surgery, Erasmus University Hospital, Brussels, Belgium. Thirty-five lipomatous tumors were quantitatively described using 47 variables generated by means of computer-assisted microscope analysis. Of these 47 quantitative variables, 27 were computed on Feulgen-stained specimens (25 on cytologic and 2 on histologic samples) and, of the remaining 20, 8 related to vimentin and S-100 protein immunostaining patterns and the other 12 to the glycohistochemical staining patterns of peanut agglutinin, succinylated wheat germ agglutinin, and concavalin A agglutinin. The 35 lipomatous tumors included 6 atypical lipomas and 8 well differentiated, 5 dedifferentiated, 6 myxoid, and 10 pleomorphic liposarcomas. The actual diagnostic value contributed by each of the 47 variables with respect to the 5 lipomatous tumor groups was determined by means of the decision tree technique, an artificial intelligence-related algorithm that forms part of the supervised learning algorithms. Of the 47 quantitative variables, the decision tree technique retained 8: i.e., 2 tissue architecture-, 2 DNA ploidy level-, 2 morphonuclear-, 1 lectin histochemical-, and 1 vimentin immunostain-related variables. The decision tree technique made use of these 8 variables to set up logical rules that make it possible to identify atypical lipomas from well differentiated liposarcomas, on the one hand, and dedifferentiated liposarcomas from those that are well differentiated and pleomorphic, on the other. Thus, the combination of an artificial intelligence algorithm analyzing quantitative variables generated by means of the computer-assisted microscope analysis of cytologic and histologic samples from lipomatous tumors can be considered an expert system contributing significant diagnostic information to conventional diagnosis. PMID: 8804353 [PubMed - indexed for MEDLINE] 5993. Am J Clin Nutr. 1996 Sep;64(3 Suppl):436S-448S. Why bioelectrical impedance analysis should be used for estimating adiposity. Houtkooper LB(1), Lohman TG, Going SB, Howell WH. Author information: (1)Department of Nutritional Sciences, University of Arizona, Tucson 85721-0033, USA. houtkoop@ag.arizona.edu The whole-body bioelectrical impedance analysis (BIA) approach for estimating adiposity and body fat is based on empirical relations established by many investigators. Properly used, this noninvasive body-composition assessment approach can quickly, easily, and relatively inexpensively provide accurate and reliable estimates of fat-free mass (FFM) and total body water (TBW) in healthy populations. The estimated FFM or TBW values are used to calculate absolute and relative body fat amounts. When different investigators follow the same standard BIA procedures and use the same population and criterion method, similar prediction equations and relatively small prediction errors have been reported for measurement of FFM and TBW (SEE: 1.7-3.0 for FFM and 0.23-1.5 kg for TBW). The BIA approach is most appropriate for estimating adiposity of groups in epidemiologic and field studies but has limited accuracy for estimating body composition in individuals. When used as a simple index (stature2/ resistance), BIA is more sensitive and specific for grading average adiposity in groups than some other anthropometric indexes such as the body mass index. Prediction equations based on BIA have been validated and cross-validated in children, youths, adults, and the elderly, in primarily white populations and, to a limited extent, in Asian, black, and Native American populations. PMID: 8780360 [PubMed - indexed for MEDLINE] 5994. Ugeskr Laeger. 1996 Aug 5;158(32):4505-8. [Leptin--a new way to diet?]. [Article in Danish] Holst JJ(1). Author information: (1)Københavns Universitet, Medicinsk Fysiologisk Institut. The relatively constant level of body fat in the adult mammal is explained by the lipostat theory as follows: A factor is released from adipose tissue in amounts that reflect total body fat content. This factor is then registered by the hypothalamic centres that regulate appetite. The theory has gained particular support from parabiotic experiments in genetically fat mice, amongst whom the so-called ob/ob mice appear to produce too little of the factor, whilst signal transduction to the satiety centre appears to be defective in the so-called db/db mice. The two genetic defects have recently been clarified, and it has been shown that the normal ob gene nodes for a protein called leptin. Leptin is released from adipose tissue, and its plasma concentration reflects total body fat. The normal db-gene codes for a hypothalamic receptor for leptin. These crucial discoveries have greatly supported the correctness of the lipostat theory. At present, extensive investigations of the roles of leptin and the leptin receptor in human adiposity are in progress. PMID: 8759384 [PubMed - indexed for MEDLINE] 5995. Gynecol Endocrinol. 1996 Aug;10(4):285-91. Perimenopausal obesity. Milewicz A(1), Bidzińska B, Sidorowicz A. Author information: (1)Department of Endocrinology, Medical University of Wrocław, Poland. In recent years perimenopausal obesity has attracted much attention, because it affects as many as 60% of women of menopausal age. The severe clinical implications of obesity directed our efforts to establish etiological factors and possible ways of treatment. It is clear that there are numerous conditions that underly perimenopausal obesity. Among these, genetic factors, neuropeptides, adrenergic nervous system activity and hormones play a role. Reproductive hormones are also an important factor, but their influence on adipose tissue is only indirect because there are no receptors for sex steroids in fatty tissue. Reports of hormone replacement therapy in women of postmenopausal age have come to different conclusions, so its influence on the etiology of perimenopausal obesity cannot be completely excluded. However, the potential benefit of this kind of treatment in female patients at menopausal age must always be considered. PMID: 8908531 [PubMed - indexed for MEDLINE] 5996. Curr Opin Lipidol. 1996 Aug;7(4):241-53. Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel? Hopkins PN(1), Hunt SC, Wu LL, Williams GH, Williams RR. Author information: (1)Department of Pathology, University of Utah, Salt Lake City, USA. Rather than a link in a causal chain leading to hypertension, insulin resistance and resultant hyperinsulinemia may be 'spokes on a wheel', with central or visceral obesity as the postulated hub of the wheel. Hypertension, hypertriglyceridemia and high density lipoprotein cholesterol are depicted as other spokes. Newly identified metabolic pathways in adipose tissue or the modulating effects of various predisposing genes may lead to variable expression of various components of the multiple metabolic syndrome in individuals with a predisposition to the collection of visceral fat. PMID: 8883500 [PubMed - indexed for MEDLINE] 5997. Ann Med. 1996 Aug;28(4):371-80. Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Juhan-Vague I(1), Alessi MC, Vague P. Author information: (1)Laboratorie Hématologie, CHU Timone, Marseille, France. Disturbances of the haemostatic system may favour the development of vascular damage and the final occlusion events in the progress of coronary heart disease (CHD). It has been shown recently in epidemiological studies, that increased concentration of several factors, mainly fibrinogen, factor VII, von Willebrand factor (vWF), and the fibrinolytic variables plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA), can be considered as risk factors for CHD. As morbidity and mortality through coronary atherosclerosis are higher in type 2 diabetic patients than in nondiabetic subjects and as insulin resistance represents a situation which favours the development of atherothrombosis, evaluation of the haemostatic factors which are recognized as risk factors may be interesting to consider in these situations. In fact, it has been shown that the fibrinolytic parameters PAI-1 and t-PA antigen are strongly related to the metabolic disorder of insulin resistance, whereas the link with fibrinogen, factor VII, and vWF remains weak. Many cross-sectional studies conducted in different populations have shown that PAI-1 and t-PA antigen (which represents t-PA/PAI-1 complexes) are strongly correlated with insulin, triglyceride, high-density lipoprotein (HDL) cholesterol, body mass index, walst-to-hip ratio and blood pressure, and that the improvement of insulin resistance improves in parallel the metabolic abnormalities and the concentration of the fibrinolytic parameters. Attempts at explaining the elevated PAI-1 and t-PA antigen levels in the insulin resistance syndrome have involved many clinical and in vitro studies, in which the role of insulin, insulin propeptides, very-low-density lipoprotein (VLDL) triglyceride, insulin resistance per se, glucose, and adipose tissue have successively been analysed and the main results of these studies are presented in this review. Due to recent experimental data from animal models of thrombosis, a pathogenic role of decreased fibrinolytic activity or increased PAI-1 levels can be proposed and could play a role in the development of vascular disease in subjects with Type 2 diabetes or insulin resistance. PMID: 8862693 [PubMed - indexed for MEDLINE] 5998. Vopr Med Khim. 1996 Jul-Sep;42(3):179-84. [Are all animal and human organs and tissues endocrine in nature and are they secreting peptide hormones into blood?]. [Article in Russian] Pankov IuA. Endocrinology was born and developed as the science of endocrine glands and the human and animal diseases induced by the gland dysfunctions. The complex of endocrine glands included pituitary, thyroid and parathyroid glands, adrenals, pancreas and gonads. Further, it has been shown that certain brain structures, hypothalamus in particular, are also endocrine organs which secrete in blood a large number of various peptide hormones. Heart secretes in blood the peptide compound natriuretic hormone which regulates the sodium balance. Recent studies have been demonstrated that the adipose tissue cells adipocytes secrete in blood the peptide hormone leptine which stimulates utilization of lipids from the fat deposits in energy metabolism. Leptine is the product obese (ob) gene which is mainly expressed in white adipose tissue. The first natural compound named "hormone" was the peptide "secretin". It is secreted by not a traditional endocrine gland, but by the duodenal cells, and it controls the exosecretory function of the pancreas. The trend allows us to declare that, similarly to adipose tissue, heart and hypothalamus, all other human and animal tissues are probably also endocrine organs and able to secret in blood the peptide hormones still to be identified, which being informative polymers are better adapted to transmit the information than other chemical compounds, and hence, they are most efficient for regulatory functions. PMID: 9139448 [PubMed - indexed for MEDLINE] 5999. Baillieres Clin Endocrinol Metab. 1996 Jul;10(3):337-52. Metabolic actions of growth hormone: direct and indirect. Berneis K(1), Keller U. Author information: (1)Department of Research, Metabolic Unit, Kantonsspital, Basel, Switzerland. GH may exert metabolic effects either directly or indirectly through increased production of IGF-I. GH administration increases circulating IGF-I levels via stimulation of hepatic synthesis and secretion of IGF-I; it may also enhance local IGF-I synthesis, which exerts paracrine or autocrine effects. Figure 2 summarizes the metabolic effects of GH and IGF-I. Administration of GH and IGF-I in adult humans has been demonstrated to enhance protein anabolism. Combined administration of GH and IGF-I was observed to be more anabolic than either IGF-I or GH alone. Evidence is presented that protein accretion results mainly from direct effects of GH on tissues; additional indirect effects via IGF-I production are also likely. Administration of GH has been reported to produce carbohydrate intolerance with elevated plasma insulin levels, resulting from insulin resistance. in contrast, insulin sensitivity increased during administration of IGF-I, which exerts hypoglycaemic effects even with concomitant suppression of insulin secretion. A major direct metabolic effect of GH is to increase fat mobilization and oxidation, and thereby to reduce total body fat; there is no evidence that IGF-I acts directly on adipose tissue in vivo. GH administration results in sodium retention via stimulation of Na-K-ATPase. It is suggested that part of the effects of GH on tubular function (e.g. phosphate reabsorption) are mediated via IGF-I. Energy expenditure may be increased by administration of either GH or relatively high doses of IGF-I. One of the reasons for this phenomenon is an increase in lean body mass; GH may increase energy expenditure additionally be enhancing the production of T3 and by increasing lipid oxidation. PMID: 8853443 [PubMed - indexed for MEDLINE] 6000. Diabet Med. 1996 Jul;13(7):616-24. R.D. Lawrence Lecture 1995 Mrs Sprat's diabetes: some metabolic insights. Coppack SW(1). Author information: (1)UCL Medical School, Whittington Hospital, London, UK. PMID: 8840094 [PubMed - indexed for MEDLINE] 6001. Acta Physiol Scand. 1996 Jul;157(3):359-60. In vitro insulinomimetic [corrected] effects of GLP-1 in liver, muscle and fat. Valverde I(1), Villanueva-Peñacarrillo ML. Author information: (1)Department of Metabolism, Nutrition and Hormones, Fundación Jiménez Díaz, Madrid, Spain. Erratum in Acta Physiol Scand 1996 Nov;158(3):297. PMID: 8830894 [PubMed - indexed for MEDLINE] 6002. Acta Physiol Scand. 1996 Jul;157(3):355-7. Distribution of GLP-1 and PACAP receptors in human tissues. Wei Y(1), Mojsov S. Author information: (1)Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, N.Y. 10021, USA. PMID: 8830893 [PubMed - indexed for MEDLINE] 6003. Forensic Sci Int. 1996 Jun 28;80(1-2):49-61. Investigations on the mechanism of adipocere formation and its relation to other biochemical reactions. Takatori T(1). Author information: (1)Department of Forensic Medicine, Faculty of Medicine, University of Tokyo, Japan. In the adipocere, which is one of the postmortem changes, some specific fatty acids possessing higher melting points, together with soap, play an important role in the formation of adipocere. These fatty acids were shown to be mainly 10-hydroxystearic and 10-hydroxypalmitic acids. Moreover, slight amounts of 10-oxostearic and 10-oxopalmitic acids, which have higher melting points than those of hydroxy fatty acids, exist in the adipocere as well. The substantial adipocere is formed and stabilized by these specific fatty acids together with the soap. The hydroxy fatty acid (OHFA) and oxo fatty acid (OXOFA) are biosynthesized by some bacterial enzymes. Various aerobic and anaerobic bacteria are involved in the formation of adipocere. For example, microbial conversion of various unsaturated fatty acids to 10-OHFA by Micrococcus luteus was investigated. It turned out that 10-OHFA was synthesized only from fatty acids possessing cis-9-unsaturation. It was also shown that 10-OHFAs were converted to the corresponding 10-OXOFAs but the 10-OXO compounds were inactive as substrates. Furthermore, it was found that the enzyme preparations from Flavobacterium meningosepticum solubilized by sonication catalyzed not only hydration of oleic acid to produce 10-hydroxystearic acid, but also dehydrogenation of this product in the presence of deuterium. On the other hand, we found out that there was 10-hydroxy-12-octadecenoic acid (10-OHODA) from linoleic acid in some kinds of adipocere. Recently, 10-epoxy-12-octadecenoic acid (leukotoxin, LTx), which is one of the lipid peroxides, was found not only in rice plants but in polymorphonuclear leukocytes. Since LTx was found in leukocytes related to inflammatory response, interest has been focused on its involvement, not only in the basic mechanism of biological defense, but also on the mechanism of shock as a vasoactive substance. A postmortem change itself is only remotely associated with a phenomenon in a living body. However, 10-OHODA found in adipocere seemed to exist also in polymorphonuclear leukocytes, suggesting that this compound might be closely related to a biological reaction. PMID: 8690322 [PubMed - indexed for MEDLINE] 6004. Biokhimiia. 1996 Jun;61(6):984-92. [ob protein--product of expressing an obesity gene and some aspects of modern-day endocrinology]. [Article in Russian] Pankov IuA. A brief review of the studies on the obese (ob) gene is given. The ob gene is a mouse gene, the mutations of which are associated with altered metabolism and increased lipid deposits in adipose tissue. Recessive ob gene mutations in homozygous mice result in obesity and diabetes mellitus. Both mouse and human ob cDNAs were cloned and sequenced using positional cloning, exon trapping, and PCR. Of ten tested tissues, the ob gene was expressed only in white adipose tissue. The ob gene cDNA has a region of the nucleotide sequence with an opening reading frame and encodes the ob protein consisting of 167 amino acid residues. Mouse and human ob proteins showed a 85% homology. The 145-amino acid peptide termed as leptin and derived from ob protein after cleavage of signal peptide is secreted in the blood and stimulates fat consumption in energy metabolism. The biologically active ob peptide has been obtained by gene engineering methods. Administration of the ob protein to ob/ob mice reduced body weight and abolished symptoms of diabetes. The ob protein lowered body weight also in healthy animals. It was biologically effective both upon parenteral and intravenous administration and also when injected into lateral ventricle of the brain. With a polyclonal antiserum against the peptide the ob protein was shown to be present in human and mouse plasma and mouse adipose tissue. Based on the data obtained, it is postulated that the ob gene protein product leptin, is a hormone, which is secreted by adipocytes in the blood in varying amounts and regulates the mass of adipose tissue by stimulating lipid metabolism. Similarly to adipocytes, many other organs and tissues are presumably endocrine and may secrete peptide hormones in the blood. This considerably extends the scope of endocrinology and makes it necessary to review the existing concepts and views. PMID: 9011250 [PubMed - indexed for MEDLINE] 6005. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:215-22. Body fat and sympathetic nerve activity. Scherrer U(1), Owlya R, Lepori M. Author information: (1)Department of Internal Medicine B, Centre Hospitalier, Universitaire Vaudois, Lausanne, Switzerland. Obesity, a major health problem in industrialized societies, is associated with a high incidence of cardiovascular complications such as hypertension, ischemic heart disease and stroke. However, the underlying mechanism relating obesity and these cardiovascular events is not clear. In lean subjects even slight elevations in plasma insulin concentration exert marked effects on the cardiovascular system, and these effects are directly related to insulin (rather than to insulin-induced stimulation of intermediary metabolism). Moreover, insulin's vascular effects are mediated both by the sympathetic nervous system and the L-arginine nitric oxide pathway. Obesity is characterized by sustained sympathetic activation (possibly related to chronic hyperinsulinemia) and an impaired vasodilator responsiveness to insulin. Although, undoubtedly many factors contribute to the increased incidence of cardiovascular complications in overweight subjects, sympathetic activation could be one important mechanism and either trigger acute events or--possibly in conjunction with an impairment in insulin-induced vasodilation--contribute to sustained elevation of arterial pressure. PMID: 8827943 [PubMed - indexed for MEDLINE] 6006. Dan Med Bull. 1996 Jun;43(3):249-62. Body composition and fat distribution by dual energy X-ray absorptiometry in overweight postmenopausal women. Effect of energy-restriction and exercise. Svendsen OL(1). Author information: (1)Department of Clinical Chemistry, Glostrup Hospital, Ballerup. PMID: 8813454 [PubMed - indexed for MEDLINE] 6007. Acta Paediatr Suppl. 1996 Jun;413:2-28. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Seip M(1), Trygstad O. Author information: (1)Department of Paediatrics, Rikshospitalet, National Hospital, Oslo, Norway. This review is based on longitudinal studies on our seven patients with congenital generalized lipodystrophy, our patient with acquired generalized lipodystrophy, and published papers on these subjects. An inability to store energy in adipose tissue is of pathogenetic importance. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperinsulinaemia, dyslipidaemia. and insulin-resistant diabetes with an anabolic syndrome worsened by a voracious appetite. Clinically, we observed increased height velocity in pre-school age children, and organomegaly with hypertrophic cardiomyopathy, which seems to be lethal in early adulthood: three of our patients died at the ages of 24, 32 and 37 years. The oldest alive, 39 years, suffers from stenocardia. Regarding treatment, it is most important to reduce energy consumption. The congenital form is recessively inherited. The aetiology may be related to insulin receptor or postreceptor mechanisms. Acquired generalized lipodystrophy seems to be an autoimmune disorder with secondary destruction of the adipose organ: the anabolic syndrome with insulin-resistant diabetes is secondary. Our patient died when 24 years old from pneumonia. PMID: 8783769 [PubMed - indexed for MEDLINE] 6008. Int J Sport Nutr. 1996 Jun;6(2):80-92. Physical activity, fat balance, and energy balance. Hill JO(1), Commerford R. Author information: (1)Center for Human Nutrition, University of Colorado Health Sciences Center, Denver 80262, USA. In this paper, we review the impact of physical activity on energy and macronutrient balances. Stability of body weight and body composition depends on reaching a steady-state where the amount and composition of energy ingested are equal to the amount and composition of energy expended. We describe how a person's level of physical activity can have a significant impact on determining the level of body weight and body fatness at which that steady-state is reached. First, physical activity can directly affect both total energy intake and total energy expenditure. Physical activity can also affect fat balance, and it is becoming clear that imbalances in total energy are largely imbalances in fat. High levels of physical activity should help individuals reach fat and energy balances at lower levels of body fatness than would have been achieved at lower levels of physical activity. PMID: 8744781 [PubMed - indexed for MEDLINE] 6009. Am J Surg Pathol. 1996 Jun;20(6):656-64. Medullocytoma (lipidized medulloblastoma). A cerebellar neoplasm of adults with favorable prognosis. Giangaspero F(1), Cenacchi G, Roncaroli F, Rigobello L, Manetto V, Gambacorta M, Allegranza A. Author information: (1)Department of Anatomic Pathology, University of Bologna, Ospedale Bellaria, Italy. Comment in Am J Surg Pathol. 1997 May;21(5):615-6. This study describes three cases of neuroectodermal cerebellar neoplasms occurring in adults, characterized by a monomorphic population of round cells with scanty cytoplasm and focal areas of lipid accumulation. Astrocytic and neuronal differentiation was confirmed in these cells by glial fibrillary acidic protein and synaptophysin immunoreactivity. Electron microscopy performed in two cases showed neuritic processes, synapses, and dense-core granules. Patients included two men and one woman, and the age at diagnosis was 36, 37, and 57 years, respectively. Two patients refused any postoperative treatment. One of these had two surgically removed recurrences after 10 and 11 years and died postoperatively from intracranial hemorrhage. The second had two recurrences after 10 and 15 years and is alive and in good health at the last follow-up. The third patient received postoperative radiotherapy and is alive and well after 2 years. Review of the literature revealed seven cases of cerebellar neoplasms with histological features similar to those observed in our series. These lesions have been considered a variant of medulloblastomas. The age of patients ranged from 42 to 77 years (mean age, 51 years); four were women, 3 men. Follow-up information available in two cases indicates a 5-year survival with surgery alone. These data indicate that these cerebellar neuroectodermal neoplasms have morphologically unique features and indolent biologic behavior that distinguish them from the highly aggressive medulloblastoma; the term medullocytoma for this form is suggested. PMID: 8651344 [PubMed - indexed for MEDLINE] 6010. Experientia. 1996 May 15;52(5):433-9. The regulation of trehalose metabolism in insects. Becker A(1), Schlöder P, Steele JE, Wegener G. Author information: (1)Institut für Zoologie, Johannes-Gutenberg-Universität, Mainz, Germany. Trehalose is a non-reducing disaccharide comprising two glucose molecules. It is present in high concentration as the main haemolymph (blood) sugar in insects. The synthesis of trehalose in the fat body (an organ analogous in function to a combination of liver and adipose tissue in vertebrates) is stimulated by neuropeptides (hypertrehalosaemic hormones), released from the corpora cardiaca, a neurohaemal organ associated with the brain. The peptides cause a decrease in the content of fructose 2,6-biphosphate in fat body cells. Fructose 2,6-biphosphate, acting synergistically with AMP, is a potent activator of the glycolytic enzyme 6-phosphofructokinase-1 and a strong inhibitor of the gluconeogenic enzyme fructose 1,6-biphosphatase. This indicates that fructose 2,6-biphosphate is a key metabolic signal in the regulation of trehalose synthesis in insects. Trehalose is hydrolysed by trehalase (E.C. 3.2.1.28). The activity of this enzyme is regulated in flight muscle, but the mechanism by which this is achieved is unknown. Trehalase from locust flight muscle is a glycoprotein bound to membranes of the microsomal fraction. The enzyme can be activated by detergents in vitro and by short flight intervals in vivo, which indicates that changes in the membrane environment modulate trehalase activity under physiological conditions. PMID: 8706810 [PubMed - indexed for MEDLINE] 6011. Experientia. 1996 May 15;52(5):421-5. Some thoughts on the importance of insulin in the regulation of the blood glucose level. Newsholme EA(1), Dimitriadis G. Author information: (1)Department of Biochemistry, University of Oxford, England. Insulin can influence rates of glucose utilization by muscle and possibly other tissues via both direct and indirect effects. It can control the rate of fatty acid mobilization from adipose tissue and the rate of fatty acid oxidation in muscle, and the latter inhibits glucose utilization and oxidation. Insulin may influence the levels of insulin-like growth factors I and II, both of which have effects on rates of glucose utilization by muscle. The inter-tissue cycle between glucose and lactate-the Cori cycle, which is influenced by insulin-may provide another novel mechanism for control of blood glucose. How far other anti-insulin hormones affect these processes is not clear. PMID: 8641378 [PubMed - indexed for MEDLINE] 6012. Soud Lek. 1996 May;41(2):20-2. Brown adipose tissue. III. Effect of ethanol, nicotine and caffeine exposure. Sidlo J(1), Zaviacic M, Trutzová H. Author information: (1)Institute of Pathology, Comenius University, Bratislava, Slovakia. Brown adipose tissue is known to be the most important organ for generating heat in non-shivering thermogenesis. Process of thermogenesis and thermoregulation may be affected by many drugs. The paper deals with actual literary data of effect of ethanol, nicotine and caffeine on brown adipose tissue, heat production and its regulation in experimental animals and in human. PMID: 9560910 [PubMed - indexed for MEDLINE] 6013. Leuk Lymphoma. 1996 May;21(5-6):399-406. The role of stromal cell heparan sulphate in regulating haemopoiesis. Coombe DR(1). Author information: (1)TVW Telethon Institute for Child Health Research, West Perth, Western Australia. Intimate contact between haemopoietic progenitor cells and elements of the bone marrow stroma is required for progenitor cell proliferation and differentiation. It is believed that the stroma provides particular niches for the development of haemopoietic cells of different lineages. Cytokines, stromal cell surface molecules and molecules of the stromal extracellular matrix all contribute to defining these microenvironmental niches. Data obtained using an in vitro model of haemopoiesis support the view that progenitor cell adhesion to stroma is mediated by multiple receptor-ligand interactions. The possibility of a tethering step, mediated by the engagement of stromal cell heparan sulphate with its ligands on the progenitor cells, preceding stable cell adhesion is discussed. The role of stromal cell heparan sulphate is likely to include cytokine presentation to progenitors as well as the tethering of progenitors to stroma. It is proposed that intracellular signals induced by progenitor cell adhesion to stroma act in association with cytokine induced signals to regulate progenitor cell proliferation and differentiation. PMID: 9172804 [PubMed - indexed for MEDLINE] 6014. Biochem Soc Trans. 1996 May;24(2):565-70. Hormones and the ob gene product (leptin) in the control of energy balance. Trayhurn P(1), Rayner DV. Author information: (1)Division of Biochemical Sciences, Rowett Research Institute, Aberdeen, Scotland, U.K. PMID: 8736804 [PubMed - indexed for MEDLINE] 6015. Biochem Soc Trans. 1996 May;24(2):422-6. Nutritional influences on human adipose-tissue metabolism. Frayn KN(1), Fielding BA, Humphreys SM, Coppack SW. Author information: (1)Oxford Lipid Metabolism Group, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, U.K. PMID: 8736776 [PubMed - indexed for MEDLINE] 6016. Biochem Soc Trans. 1996 May;24(2):418-22. Immunological manipulation of adiposity. Flint DJ(1). Author information: (1)Hannah research Institute, Ayr, Scotland, U.K. PMID: 8736775 [PubMed - indexed for MEDLINE] 6017. Biochem Soc Trans. 1996 May;24(2):412-8. Beta 3-adrenoceptors and the regulation of metabolism in adipose tissues. Arch JR(1), Wilson S. Author information: (1)SmithKline Beecham, Welwyn, Herts, U.K. PMID: 8736774 [PubMed - indexed for MEDLINE] 6018. Biochem Soc Trans. 1996 May;24(2):407-12. Adrenergic regulation of brown adipocyte differentiation. Cannon B(1), Nedergaard J. Author information: (1)Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, Sweden. PMID: 8736773 [PubMed - indexed for MEDLINE] 6019. Biochem Soc Trans. 1996 May;24(2):402-6. Uncoupling protein in brown adipose tissue: molecular differentiation of the adipose tissues. Trayhurn P(1). Author information: (1)Division of Biochemical Sciences, Rowett Research Institute, Bucksburn, Aberdeen, U.K. PMID: 8736772 [PubMed - indexed for MEDLINE] 6020. Biochem Soc Trans. 1996 May;24(2):393-400. Functional interpretation of the organization of mammalian adipose tissue: its relationship to the immune system. Pond CM(1). Author information: (1)Department of Biology, Open University, Milton Keynes, Bucks, U.K. PMID: 8736770 [PubMed - indexed for MEDLINE] 6021. Biochem Soc Trans. 1996 May;24(2):372-8. Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: is glucose 6-phosphate the signalling metabolite? Foufelle F(1), Girard J, Ferré P. Author information: (1)Unité INSERM 342, Höpital Saint-Vincent-de-Paul, Paris, France. PMID: 8736766 [PubMed - indexed for MEDLINE] 6022. Ann N Y Acad Sci. 1996 Apr 30;784:18-26. Estrogen biosynthesis in adipose. Significance in breast cancer development. Simpson ER(1), Zhao Y. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas 75235, USA. PMID: 8651568 [PubMed - indexed for MEDLINE] 6023. J Toxicol Environ Health. 1996 Apr 5;47(5):453-64. Disposition, metabolism, and toxicity of methyl tertiary butyl ether, an oxygenate for reformulated gasoline. Hutcheon DE(1), Arnold JD, ten Hove W, Boyle J 3rd. Author information: (1)Department of Pharmacology and Toxicology, UMDNJ, New Jersey Medical School, Newark 07103, USA. Studies of the toxicology of methyl tertiary butyl ether (MTBE) were reviewed as a possible information base for evaluating the health effects of evaporative emissions from reformulated gasoline (RFG). The major metabolites of the oxidative demethylation of MTBE in vivo were methanol and tertiary butyl alcohol (TBA), whereas formaldehyde and TBA were the principal products of hepatic microsomal oxidation by cytochrome P-450. Pharmacokinetic studies in rats treated with intragastric MTBE in corn oil gave an initial disposition T1/2 for MTBE of 0.32 h. The decline in the serum drug versus time curve for MTBE in rats was accompanied by a progressive increase in serum methanol concentrations to levels more than 50-200 times those of the parent compound. Repeated exposure of MTBE vapor by inhalation in rats resulted in dose-dependent increases in MTBE in the blood, brain, and adipose tissue compartments. Blood concentrations of TBA were also dose dependent and provided an estimate of the total amount of MTBE distributed to peripheral drug metabolizing compartments. Perirenal fat/blood MTBE concentration ratios ranged from 9.7 to 11.6 after 15 wk of intermittent exposure. During an oxyfuels program in Fairbanks, AK, blood levels of occupationally exposed workers were 0.2-31.5 microgram/L MTBE and 1.6 to 72.2 microgram/L TBA with a mean TBA:MTBE blood concentration ratio of 4.2. In patients who received MTBE by percutaneous, transhepatic puncture for the dissolution of cholesterol gallstones, concentrations of MTBE in fat tissue reached 60 and 300 microgram/g at a treatment time when mean blood MTBE was less than 20 microgram/ml. The results of laboratory and clinical studies indicate that metabolites of MTBE may contribute to the nephropathy, neoplasms, and other pathological changes associated with repeated exposure to MTBE in experimental animals. It is concluded that such studies can provide a well-defined database for quantitative safety comparisons and health risk-benefit analyses of MTBE and other oxygenates in RFG. PMID: 8614015 [PubMed - indexed for MEDLINE] 6024. Baillieres Clin Endocrinol Metab. 1996 Apr;10(2):221-47. Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. Holte J(1). Author information: (1)Department of Obstetrics & Gynaecology, Akademiska Hospital, Uppsala, Sweden. Insulin resistance, defined as a diminished effect of a given dose of insulin on glucose homeostasis, is a highly prevalent feature of women with PCOS. Insulin resistance in PCOS is closely associated with an increase in truncal-abdominal fat mass, elevated free fatty acid levels, increased androgens, particularly free testosterone through reduced SHBG levels, and anovulation. The causes for insulin resistance in PCOS are still unknown. One line of evidence suggests that an increase in truncal-abdominal fat mass and subsequently increased free fatty acid levels induce insulin resistance in women with PCOS. Increased effects of corticosteroids and a relative reduction in oestrogen and progesterone seem to be involved in the aberrant body fat distribution. Conversely, there are also results supporting primary, genetic target cell defects as a cause of insulin resistance in PCOS. An explanation for these seemingly contradictory results could be that the group of women with PCOS is heterogeneous with respect to the primary event in carbohydrate/insulin disturbances. Also insulin secretion in PCOS is characterized by heterogeneity. At one end of the spectrum is a large subgroup of mainly obese women with reduced insulin secretion, which appears to result from failure of the beta cells to compensate for insulin resistance in susceptible women, resulting in glucose intolerance and NIDDM. In the insulin-resistant patients with normal glucose tolerance, most of the hyperinsulinaemia is probably due to secondarily increased insulin secretion and decreased insulin degradation. However, a component of the increased first-phase insulin release is not due to measurable insulin resistance. Notably, this is also found in lean women with normal insulin sensitivity, and is not reversed after weight reduction, in contrast to the findings for insulin resistance. The implications of this enhanced insulin release are not fully clear, but it may tentatively be associated with carbohydrate craving and subsequently increased risks for development of obesity and insulin resistance. It may represent a primary disturbance of insulin secretion in PCOS or may be associated with the perturbed steroid balance in anovulation. The insulin-androgen connection in PCOS appears to be amplified by several different mechanisms, notably in both directions, the initiating event probably varying between individuals. Thus insulin increases the biological availability of potent steroids, primarily testosterone, through the suppression of SHBG synthesis. Insulin is also involved as a progonadotrophin in ovarian steroidogenesis, with the possible net result of interfering with ovulation and/or increasing ovarian androgen production in states of hyperinsulinaemia. Conversely, testosterone may indirectly contribute to insulin resistance through facilitating free fatty acid release from abdominal fat, but perhaps also through direct muscular effects at higher serum levels. It seems likely that this constitution, presumably genetic, would provide evolutionary advantages in times of limited nutrition, given the energy-saving effects of insulin resistance. Hypothetically, hyperinsulinaemia (primary) could provide a stimulus to ensure intake of nourishment, but unlimited food supplies could in some cases initiate a vicious 'anabolic' circle, in which several of the proposed amplifying mechanisms between insulin and androgens--in both directions--could take part. PMID: 8773746 [PubMed - indexed for MEDLINE] 6025. J Lipid Res. 1996 Apr;37(4):708-26. The usefulness of dietary medium-chain triglycerides in body weight control: fact or fancy? Bach AC(1), Ingenbleek Y, Frey A. Author information: (1)CEPE, CNRS, Strasbourg, France. Compared to long-chain triglycerides (LCT), medium-chain triglycerides (MCT) display some specific physico-chemical, and biological characteristics. Thus, MCT are currently used in clinical nutrition as energy-yielding substrates, and have been advocated for three decades as a useful mean for body weight reduction. This review encompasses most aspects of MCT metabolism arguing this slimming hypothesis pro and con. Findings in support of the opinion (lower energy density, control of satiety, rapid intrahepatic delivery and oxidation rates, poor adipose tissue incorporation) may be invalidated by counteracting data (stimulation of insulin secretion and of anabolic-related processes, increased de novo fatty acid synthesis, induced hypertriglyceridemia). The balance between these two opposing influences depends on the composition (energy intake, nature of ingredients, MCT/LCT ratio, octanoate/decanoate ratio) and duration of the regimen. Due to the high energy level (around 50%) of MCT necessary to achieve body weight loss, long-term compliance to such slimming regimens is unlikely in human nutrition. PMID: 8732772 [PubMed - indexed for MEDLINE] 6026. Eur J Clin Invest. 1996 Apr;26(4):259-61. Steroid hormones and adipose tissue. Prins JB(1), O'Rahilly S, Chatterjee VK. Author information: (1)Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK. Comment on Eur J Clin Invest. 1996 Apr;26(4):262-9. PMID: 8732481 [PubMed - indexed for MEDLINE] 6027. Int J Obes Relat Metab Disord. 1996 Apr;20(4):291-302. The regulation of adipose tissue distribution in humans. Björntorp P(1). Author information: (1)Department of Heart and Lung Disease, Sahlgren's Hospital, University of Göteborg, Sweden. The regulation of adipose tissue distribution is an important problem in view of the close epidemiological and metabolic associations between centralized fat accumulation and disease. With visceral fat accumulation multiple endocrine perturbations are found, including elevated cortisol and androgens in women, as well as low growth hormone (GH) and, in men, testosterone (T) secretion. These abnormalities probably derive from a hypersensitive hypothalamo-pituitary-adrenal axis, with hyperinsulinemia related to a marked insulin resistance as a consequence. These hormonal changes exert profound effects on adipose tissue metabolism and distribution. At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity, while T, GH and probably estrogens exert opposite effects. The consequences will most likely be more expressed in visceral than subcutaneous adipose tissues because of a higher cellularity, innervation and blood flow. Furthermore, the density of cortisol and androgen receptors seems to be higher in this than other adipose tissue regions. The endocrine perturbations found in visceral obesity with an abundance of the lipid accumulating hormones cortisol and insulin, and a relatively low secretion of the lipid mobilizing sex steroid hormones and GH would therefore be expected to be followed by visceral fat accumulation. The potential significance of local synthesis of steroid hormones in adipose tissue requires more attention. Although studies in vitro are informative when elucidating detailed mechanisms of hormonal interactions, they might not give a true picture of the regional integrated regulation of adipose tissue lipid storage and mobilization. Such information can be obtained by regional measurements of lipid mobilization by free fatty acid turnover or by microdialysis techniques, both showing lower rates of mobilization in leg than in upper body adipose tissues. More detailed information can be obtained by physiological oral administration of triglycerides, labelled with a small amount of oleic acid, followed by measurements of the regional uptake and turn-over of adipose tissue triglycerides. Such studies show lipid uptake in the order omental = retroperitoneal > subcutaneous abdominal > subcutaneous femoral adipose tissues in men, with a similar rank order for half-life of the triglyceride, indicating also a turn-over of triglycerides in that order. T amplifies these differences in men. In premenopausal women subcutaneous abdominal has a higher turnover than femoral adipose tissue. Results of studies in vitro indicate that this difference is diminished at the menopause, and restored by estrogen substitution, suggesting that the functional effects of estrogens in women are similar to those of T in men. The mechanisms are, however, probably indirect because of the apparent absence of specific estrogen and progesterone receptors in human adipose tissue. This interpretation from the studies referred to above fits well with physiological, and clinical conditions with increased visceral fat mass, where the balance between the lipid accumulating hormone couple (cortisol and insulin) and the hormones which prevent lipid accumulation and instead activate lipid mobilization pathways (sex steroid hormones and GH) is shifted to the advantage of the former. Such conditions include Cushing's syndrome, the polycystic ovary syndrome, menopause, aging, GH-deficiency, depression, smoking and excess alcohol intake. With appropriate interventions against hypercortisolemia and substitution of deficient sex steroids and GH, visceral fat mass is decreasing. Based on this evidence from physiological, clinical, interventional observations and detailed studies of mechanisms at cellular and molecular levels it is suggested that the combined endocrine abnormalities in the syndrome of visceral obesity direct storage fat to visceral adipose depots. Therefore, measurements of visceral fat accumulat PMID: 8680455 [PubMed - indexed for MEDLINE] 6028. J Lab Clin Med. 1996 Apr;127(4):328-32. Endocrine regulation of food intake and body weight. Figlewicz DP(1), Schwartz MW, Seeley RJ, Chavez M, Baskin DG, Woods SC, Porte D Jr. Author information: (1)Department of Psychology, University of Washington, Seattle, USA. PMID: 8656034 [PubMed - indexed for MEDLINE] 6029. Ned Tijdschr Geneeskd. 1996 Mar 2;140(9):478-82. [The effect of menopause on risk factors for ischemic diseases]. [Article in Dutch] de Kleijn MJ(1), van der Schouw YT, Banga JD, van der Graaf Y. Author information: (1)Afd. Epidemiologie, Universiteit Utrecht. PMID: 8628434 [PubMed - indexed for MEDLINE] 6030. Nutr Rev. 1996 Mar;54(3):91-3. Leptin: the weight-reducing plasma protein encoded by the obese gene. Wolf G(1). Author information: (1)Department of Nutritional Sciences, University of California at Berkeley 94720, USA. Leptin, the protein encoded by the recently cloned obese gene, has the properties of a hormone released by adipose tissue, regulating appetite and energy expenditure. Injected leptin reduces body weight and food intake in mice, and in obese, diabetic mice (with a mutated obese gene), it also reduces plasma insulin and glucose. Leptin release is stimulated by insulin; leptin appears to act on the hypothalamus by inhibiting the release of the neuropeptide Y. PMID: 8935220 [PubMed - indexed for MEDLINE] 6031. Proc Nutr Soc. 1996 Mar;55(1B):561-9. Influence of thyroid hormones and temperature on adipose tissue development and lung maturation. Symonds ME(1), Clarke L. Author information: (1)School of Animal and Microbial Sciences, University of Reading, Whiteknights. PMID: 8832819 [PubMed - indexed for MEDLINE] 6032. Proc Nutr Soc. 1996 Mar;55(1B):291-305. Nutrient-induced secretion and metabolic effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. Knapper JM(1), Morgan LM, Fletcher JM. Author information: (1)School of Biological Sciences, University of Surrey, Guildford. PMID: 8832801 [PubMed - indexed for MEDLINE] 6033. Proc Nutr Soc. 1996 Mar;55(1B):191-9. Over-expression of GLUT4 selectively in adipose tissue in transgenic mice: implications for nutrient partitioning. Gnudi L(1), Shepherd PR, Kahn BB. Author information: (1)Harvard Thorndike Research Laboratory, Harvard Medical School, Boston, MA, USA. In summary, over-expression of GLUT4 selectively in fat causes increased flux of glucose into adipocytes and leads to increases in either the replication of immature pre-adipocytes or their differentiation into mature adipocytes resulting in an increase in fat cell number. This is the first model in which obesity is accounted for entirely by adipocyte hyperplasia and, therefore, is useful for studying the mechanisms involved in controlling fat cell number in vivo. GLUT4 over-expression in adipocytes of transgenic animals also increased whole- body insulin sensitivity. However, GLUT4 over-expression exclusively in adipocytes did not protect them from insulin resistance in vivo induced by high-fat feeding, in spite of the fact that insulin resistance was prevented at the level of the adipocyte. Interestingly, GLUT4 over-expression in fat protected the animals from developing further obesity when fed on a high-fat diet. It is possible that this failure to increase adiposity further is due to enhanced partitioning of glucose into fat, which may result in decreased glucose supply to muscle. This in turn may cause diversion of lipid to muscle to be oxidized as fatty acid. This diversion of lipid could result in protection against increased fat deposition in adipocytes. Further studies will be required in order to understand the molecular mechanisms by which GLUT4 over-expression in adipose tissues affects nutrient partitioning between muscle and adipose tissue and what the consequences of this are for whole-body fuel metabolism. PMID: 8832791 [PubMed - indexed for MEDLINE] 6034. Proc Nutr Soc. 1996 Mar;55(1B):111-26. Interactions between adipose tissue and the immune system. Pond CM(1). Author information: (1)Department of Biology, Open University, Milton Keynes. PMID: 8832785 [PubMed - indexed for MEDLINE] 6035. Sports Med. 1996 Mar;21(3):191-212. Effects of exercise training on abdominal obesity and related metabolic complications. Buemann B(1), Tremblay A. Author information: (1)Physical Activity Sciences Laboratory, PEPS, Laval University, Ste-Foy, Quebec, Canada. Excessive deposition of visceral adipose tissue is known to predispose to cardiovascular diseases. Considerable epidemiological and experimental evidence suggests that many physiological factors are involved in the aetiology of premature atherosclerosis associated with visceral obesity. Insulin resistance is frequently associated with abdominal obesity, and probably plays an important role in the pathophysiology of hypertriglyceridaemia, low levels of plasma high-density lipoprotein (HDL)-cholesterol, hypertension and reduced fibrinolytic activity. Exercise training may counteract the aberrant metabolic profile associated with abdominal obesity both directly and as a consequence of body fat loss. Exercise may increase insulin sensitivity, favourably alter the plasma lipoprotein profile and improve fibrinolytic activity. Changes in the activity of insulin-sensitive glucose transporters and of skeletal muscle lipoprotein lipase are some of the possible explanations for the increased insulin sensitivity and improved blood lipid profile associated with regular exercise. This review presents physical training as a relevant nonpharmacological tool in the treatment of abdominal obesity and associated metabolic disorders. The impact of regular exercise on the different aspects of the insulin resistance syndrome is discussed. The roles of gender, age and the state of insulin resistance on the metabolic effect of physical training are also considered. PMID: 8776009 [PubMed - indexed for MEDLINE] 6036. Diabetes Care. 1996 Mar;19(3):292-4. Insulin resistance and obesity. The role of fat distribution pattern. Abate N(1). Author information: (1)Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA. abate@crcvax.swmed.edu Comment in Diabetes Care. 1996 Sep;19(9):1033-4. PMID: 8742585 [PubMed - indexed for MEDLINE] 6037. Lipids. 1996 Mar;31 Suppl:S127-30. In vivo 13C nuclear magnetic resonance: applications and current limitations for noninvasive assessment of fatty acid status. Cunnane SC(1), Likhodii SS, Moine G. Author information: (1)Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Canada. As a noninvasive method, in vivo 13C nuclear magnetic resonance has potentially important applications in understanding the metabolism of long chain fatty acids in organs of living humans. At present, this methodology is most advanced for research on glucose utilization. However, the main 13C signals visible in vivo are from fatty acids in adipose tissue and the olefinic signals can be used to noninvasively estimate adipose tissue content and relative dietary intake of polyunsaturates and monounsaturates. The low natural abundance of 13C improves the utility of this isotope for fatty acid tracer studies. Due to excessive signal broadening, uniform 13C-labelling seems to have limited application in in vivo fatty acid studies. Tracer fatty acids with 13C enrichment at a specific carbon position, i.e., [13-13C] gamma-linolenate, appear to be the most useful for in vivo tracer studies. Development of methods permitting resolution of 13C enrichment in structural lipids of lean tissues will be an important breakthrough which may make human tracer studies feasible and worthwhile. PMID: 8729106 [PubMed - indexed for MEDLINE] 6038. Bioorg Khim. 1996 Mar;22(3):228-33. [Leptin--a peptide hormone from adipocytes. Sensation of the 23rd FEBS Meeting]. [Article in Russian] Pankov IuA. Studies of the obese gene are reviewed. Recessive mutations in the ob gene in homozygous state cause excessive weight and diabetes in mice. Cloning and expression of cDNA of the human and mouse ob genes revealed that the ob gene is only expressed in white adipose tissue. cDNA encodes the ob protein that consists of 167 amino acid residues, the homology between the mouse and human ob proteins being 84%. The peptide leptin, secreted into blood, consists of 145 amino acid residues and results from the cleavage of a signal peptide off the ob protein. Leptin was obtained by genetic engineering methods. Its injection into ob/ob mice decreases body weight and eliminates diabetes symptoms. Leptin also decreased body weight of healthy mice by activating the utilization of endogenous lipids in energy metabolism. Leptin was found in human and mouse blood and mouse adipose tissue but not in blood or adipose tissue of ob/ob mice. Based on the results obtained, it was postulated that leptin, a product of the ob gene, is a hormone that is secreted into blood in varying quantities by adipocytes and controls the adipose tissue weight by stimulating lipid metabolism in the organism. PMID: 8687512 [PubMed - indexed for MEDLINE] 6039. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 3:S58-64. Endocrine and paracrine negative regulators of adipose differentiation. Serrero G(1), Lepak N. Author information: (1)W Alton Jones Cell Science Center, Inc, Lake Placid, NY 12946, USA. Obesity which is characterized by an abnormal adipose tissue development is a first degree public health hazard in industrialized countries. One important aspect in the study of adipose tissue development is to investigate the hormonal control of proliferation and differentiation. Any qualitative or quantitative change in these hormones or their receptors can result in abnormalities in the process of proliferation and/or differentiation possibly leading to obesity. Therefore, it is important to identify these factors and investigate their mechanism of action. We have concentrated our efforts in the study of factors triggering differentiation (positive regulators) and also of factors inhibiting differentiation (negative regulators). The present paper provides evidence of the importance of EGF/TGF-alpha and of PGF2 alpha as differentiation inhibitors for adipocyte precursors in primary culture. Data presented here also demonstrate that TGF-alpha is expressed in adipose tissue and that its expression is specifically stimulated by PGF2 alpha, thus suggesting the existence of an amplification mechanism between two differentiation inhibitors within the adipose tissue. The importance of these two types of differentiation inhibitors in the regulation of adipose tissue development is discussed. PMID: 8680479 [PubMed - indexed for MEDLINE] 6040. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 3:S52-7. The possibility of active form of vitamins A and D as suppressors on adipocyte development via ligand-dependent transcriptional regulators. Kawada T(1), Kamei Y, Sugimoto E. Author information: (1)Department of Food Science and Technology, Faculty of Agriculture, Kyoto University, Japan. fat@kais.kyoto-u.ac.jp The study aimed to systematically examine the effects of fat soluble vitamins and their analogs on terminal differentiation of adipocytes on the cellular and molecular aspects. It is well known that fat soluble vitamins especially vitamins A and D inhibit the differentiation of adipocytes in cultured cells. Furthermore, it has been revealed that the low level of dietary fat soluble vitamins, especially vitamin A and carotenoid actively stimulate the development of adipose tissue, namely bovine marbling in vivo. We have shown that the expression of retinoic acid receptor (RAR) alpha and gamma, retinoid X receptor (RXR) alpha and beta, and vitamin D receptor (VDR) mRNA were abundant in rat adipose tissue and 3T3-L1 cells. The autoregulated amplification and reduction of RAR, RXR and VDR mRNA by their own ligands, were observed in 3T3-L1 cells. Finally, we proposed the model of vitamins A and D as suppressors on adipocyte development through retinoid/thyroid/vitamin D/fatty acid-activated/peroxisomal proliferator-activated receptor's subfamily. PMID: 8680478 [PubMed - indexed for MEDLINE] 6041. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 3:S36-42. Signal transduction in brown adipose tissue recruitment: noradrenaline and beyond. Cannon B(1), Jacobsson A, Rehnmark S, Nedergaard J. Author information: (1)Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, Sweden. The classical effect of noradrenaline on brown adipose tissue is stimulation of heat production. However, it is likely that noradrenaline is also the major regulator of proliferation and differentiation. The adrenergic receptors involved include at least beta 1, beta 3, alpha 2 and alpha 1. Heat production is mainly stimulated via beta 3 receptors and cAMP. Cell proliferation is mainly stimulated via beta 1 receptors and cAMP. Cell differentiation is also adrenergically promoted; at least the expression of the gene for the tissue-specific uncoupling protein thermogenin is controlled via beta 3 receptors and cAMP. There is a switch in beta-receptor endowment between young (beta 1) and mature (beta 3) cells. The expression of several transcription factors is also under adrenergic control: c-Fos gene expression depends synergistically on beta- and alpha 1-stimulation mediated via cAMP and [Ca2+]i increases. C/EBP beta gene expression is regulated only via beta-receptors, but the expression of the C/EBP alpha gene shows a switch during differentiation: in young cells, the expression is represented through both beta- and alpha 1-receptors; in mature cells, the expression is stimulated via b-receptors. It is likely that noradrenaline exerts its proliferation- and differentiation-promoting action through alterations in the expression of these or other transcription factors. PMID: 8680475 [PubMed - indexed for MEDLINE] 6042. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 3:S32-5. Beta-adrenergic receptors and G-proteins in the ob/ob mouse. Bégin-Heick N(1). Author information: (1)Department of Biochemistry, University of Ottawa, Canada. The ob/ob mouse white epididymal adipose tissue is endowed with very low lipolytic activity, due to abnormally low adenylyl cyclase activation in response to beta-adrenergic agents. The abundance of the two principal G-proteins that are responsible for the transduction of adenylyl cyclase is also decreased in several tissues of the ob/ob mouse, compared to levels in the lean mouse. By contrast, beta-adrenergic receptor levels appear normal in adipose tissue (Am J Physiol 1992; 263: C121-C129) and are elevated in liver (Am J Physiol 1994; 265: C1664-C1672), suggesting that the diminished abundance of G-proteins was responsible for the low lipolytic activity. We reassessed the relative importance of beta-adrenergic receptors and G-proteins in view of the discovery of the beta 2-adrenergic receptor. The major beta-AR isoform in mouse white adipose tissue is the beta 3-AR and its levels is severely decreased in the obese mouse. This indicates that the lipolytic defect in the ob/ob mouse is due to lack of beta 3-receptor function. Furthermore the extremely high sensitivity of this receptor to the ambient concentrations of GTP, explains the lack of response of adenylyl cyclase activity to the inhibitory effect of GTP in adipose tissue of the ob/ob mouse. PMID: 8680474 [PubMed - indexed for MEDLINE] 6043. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 3:S16-25. Paracrine interactions in adipose tissue development and growth. Lau DC(1), Schillabeer G, Li ZH, Wong KL, Varzaneh FE, Tough SC. Author information: (1)Department of Medicine, University of Ottawa, ON, Canada. PMID: 8680472 [PubMed - indexed for MEDLINE] 6044. Rev Med Liege. 1996 Mar;51(3):254-6. [How I explore... metabolic disorders in menopausal women]. [Article in French] Scheen AJ(1). Author information: (1)Service de Diabétologie, Nutrition et Maladies métaboliques, Université de Liège. PMID: 8668890 [PubMed - indexed for MEDLINE] 6045. Int J Obes Relat Metab Disord. 1996 Mar;20(3):191-9. Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Arch JR(1), Wilson S. Author information: (1)SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK. Jonathan_R_Arch@sbphrd.com beta 3-Adrenoceptor (beta 3-AR) agonists were first identified more than twelve years ago and were found to be remarkably effective in animal models of obesity and Type II (non-insulin dependent) diabetes. Those that have been taken forward to clinical studies have not, however, proved so effective in humans: they have either been of limited efficacy, or their activities have been accompanied by significant side-effects. Reasons for the failure of some beta 3-AR agonists in humans have included a poor pharmacokinetic profile and, possibly, a failure of prodrugs to be metabolised to selective beta 3-AR agonists. A more fundamental problem, however, is that the human and rat beta 3-AR differ pharmacologically, and those compounds that have been evaluated in humans have much lower efficacy at the human than the rat receptor. This problem may be compounded by there being a low number of beta 3-AR relative to beta 1-AR and beta 2-AR in those tissues that mediated thermogenesis in humans, so that low efficacy compounds tend to exhibit mainly beta 1-AR or beta 2-AR-, rather than beta 3-AR-mediated effects, despite their having selective affinity for human beta 3-AR. Nevertheless, studies using CGP 12177, which is an agonist at beta 3-AR but an antagonist at beta 1-AR and beta 2-AR, demonstrate that functional beta 3-AR are present in human adipose tissue. Moreover, the association of a polymorphism in the human beta 3-AR with obesity and diabetes demonstrates that this receptor is relevant to these diseases in humans. Thus the true potential of beta 3-AR agonists in humans can only be evaluated when a compound with good selectivity and efficacy at the human beta 3-AR, coupled with a long duration of action in vivo, has been identified. PMID: 8653138 [PubMed - indexed for MEDLINE] 6046. Int J Obes Relat Metab Disord. 1996 Mar;20 Suppl 2:S1-11. Glycogen levels and obesity. Flatt JP(1). Author information: (1)Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Center, Worcester 01655, USA. Flatt@bangate1.ummed.edu The degree of replenishment of the body's glycogen stores influences the contribution made by glucose and free fatty acids to the fuel mixed oxidized. The expansion of the adipose tissue mass required to promote fat oxidation to rates commensurate on average with fat intake is therefore influenced not only by the diet's fat content, but by glycogen levels as well. It seems possible that recent changes in the food supply and a further decline in physical activity could have led to some increase in the range within which glycogen levels are habitually maintained, and that this could be a cause for the recent increase in the incidence of obesity noted in many countries. PMID: 8646265 [PubMed - indexed for MEDLINE] 6047. Diabetes. 1996 Mar;45(3):273-83. Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Prentki M(1), Corkey BE. Author information: (1)Diabetes and Metabolism Unit, Evans Department of Medicine, Boston University Medical Center, Massachusetts 02118, USA. Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defects is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a "signal of plenty," and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event. PMID: 8593930 [PubMed - indexed for MEDLINE] 6048. Obes Surg. 1996 Feb;6(1):17-27. Drug Distribution in Obesity and following Bariatric Surgery: A Literature Review. Macgregor AM(1), Boggs L. Author information: (1)Department of Surgery, North Florida Regional Medical Center, Gainesville, FL, 32605-4233, USA. BACKGROUND: The pharmacokinetic variables of drug clearance and volume of distribution are usually corrected for body weight or surface area. Only recently have the relationships which exist between body size, physiologic function and pharmacokinetic variables been evaluated in the obese population. These effects are not widely known, and data on this and the effects of bariatric surgical procedures are scantily documented in the surgical literature. METHODS: Literature review. RESULTS: Drugs with a low or moderate affinity for adipose tissue have a moderate increase in the volume of distribution (Vd), and this correlates with the increase in lean body mass (LBM). Highly lipophilic drugs, with some exceptions, show the expected increase in Vd and prolongation of elimination half-life, indicating a marked distribution into adipose tissue. Drug absorption, in general, is slowed by delayed gastric emptying and is normal when gastric emptying is normal or increased. Most drug absorption occurs in the small intestine where duration of drug/mucosal contact is the most important factor. CONCLUSIONS: Drugs whose distribution is restricted to LBM should utilize a loading dose based on ideal body weight (IBW). For those drugs which distribute freely into adipose tissue, the loading dose should be based on total body weight (TBW). Adjustment of the maintenance dose depends on clearance rates. In a few cases dosage adjustment depends on pharmacodynamic data, since drug clearance does not conform to these recommendations, for reasons which remain to be defined. Following bariatric surgery, in the absence of delayed gastric emptying or uncontrolled diarrhea, drug absorption rates are usually comparable to the non-operated patient. PMID: 10731246 [PubMed - as supplied by publisher] 6049. Cesk Patol. 1996 Feb;32(1):45-7. Brown adipose tissue. II. Effect of pathologic and environmental conditions (Review). Sidlo J(1), Zaviacic M, Trutzová H. Author information: (1)Institute of Pathology, Comenius University, Bratislava, Slovakia. Brown adipose tissue is an important source of non-shivering thermogenesis. Its metabolic activity and development are regulated by adrenalin secretion. The greatest amount of brown adipose tissue in humans was observed during the first decade of life. Later it disappears from many sites, but is preserved in the neck and around the kidneys and the adrenal glands. Increased amounts of brown adipose tissue have been reported to occur in association with certain situations and diseases. A review of these literary data is presented. PMID: 9560896 [PubMed - indexed for MEDLINE] 6050. Cesk Patol. 1996 Feb;32(1):41-4. Brown adipose tissue. I. Morphology. (Review). Sidlo J(1), Zaviacic M, Trutzová H. Author information: (1)Insitute of Pathology, Comenius University, Bratislava, Slovakia. Brown adipose tissue appeared in mammals with the development of homeothermy. In consequence of this, their organism became able to maintain constant body temperature independent on the thermal conditions of the surroundings. This tissue-contrary to the white adipose tissue-is distributed only in certain restricted portions of the body. The paper deals with actual literary data of morphology and function of brown adipose tissue. PMID: 9560895 [PubMed - indexed for MEDLINE] 6051. Nutr Rev. 1996 Feb;54(2 Pt 1):41-9. The new obesity genes. Roberts SB(1), Greenberg AS. Author information: (1)Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. Individual susceptibility to obesity is recognized to be influenced significantly by genetic inheritance. Recently, candidate obesity genes have been identified that may contribute to the inheritance of body fat mass and the partitioning of fat between central and peripheral fat depots. In studies of animal models of obesity, the genetic basis for obesity in the obese (Ob/Ob) mouse, the Fat mouse, and the Yellow (Vvy) mouse has been identified. Further research is needed to determine whether abnormalities in these genes contribute to human obesity as well. In studies of humans, sequence variation in at least six genes has been linked to increased body fatness and/or susceptibility to obesity. In addition, five other encoding genes have been linked to a disproportionate storage of fat in the abdominal region. These genes identified in studies of humans are currently thought to be modifying or background genes, each separately conferring a modest increase in susceptibility to fatness. Further research is needed to identify additional candidate genes that confer susceptibility to obesity and to determine the relative importance of each one in a range of human populations with distinct environments. PMID: 9053823 [PubMed - indexed for MEDLINE] 6052. Diabetes Res Clin Pract. 1996 Feb;30 Suppl:25-30. Intra-abdominal fat: is it a major factor in developing diabetes and coronary artery disease? Kissebah AH(1). Author information: (1)Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, USA. Abdominal obesity has emerged as a strong and independent predictor for non-insulin dependent diabetes mellitus (NIDDM). Adiposity located centrally in the abdominal region, and particularly visceral as opposed to subcutaneous fat, is also distinctly associated with hyperlipidemia, compared with generalized distributions of body fat. These lipoprotein abnormalities are characterized by elevated very low density lipoprotein (VLDL) and low density lipoprotein (LDL) levels, small dense LDL with elevated apolipoprotein B levels, and decreased high density lipoprotein2b (HDL2b) levels. This is the same pattern seen in both familial combined hyperlipidemia and NIDDM. The pronounced hyperinsulinemia of upper-body obesity supports the overproduction of VLDL and the increased LDL turnover. We have proposed that an increase in the size of the visceral fat depot is a precursor to the increased lipolysis and elevated free fatty acid (FFA) flux and metabolism and to subsequent overexposure of hepatic and extrahepatic tissues to FFA, which then, in part, promotes aberrations in insulin actions and dynamics. The resultant changes in glucose/insulin homeostasis, lipoprotein metabolism, and vascular events then lead to metabolic morbidities such as glucose intolerance, NIDDM, dyslipidemia, and increased risk for coronary heart disease. PMID: 8964190 [PubMed - indexed for MEDLINE] 6053. Diabetes Metab. 1996 Feb;22(1):15-24. Changes in autonomic nervous system activity and consecutive hyperinsulinaemia: respective roles in the development of obesity in rodents. Pénicaud L(1), Cousin B, Leloup C, Atef N, Casteilla L, Ktorza A. Author information: (1)Laboratoire de Neurobiologie, Plasticité Tissulaire et Métabolisme Energétique, CNRS URA 1937, Université Paul Sabatier, CHU Rangueil, Toulouse, France. The autonomic nervous system plays a major role in metabolism regulation by modulating metabolic pathways directly or indirectly via control of hormone (particularly insulin) secretion in various organs and tissues. In addition, the system modulates the proliferation and differentiation of some cell types. This activity is directly controlled by certain brain areas, particularly those located in the hypothalamus. A feedback loop signals metabolic changes at the periphery to these brain areas. This review focuses on the role of the autonomic nervous system in the activity and plasticity of pancreas and adipose tissues under normal conditions or in obesity, with special attention to the importance of alterations in these functions. PMID: 8697291 [PubMed - indexed for MEDLINE] 6054. J Intern Med. 1996 Feb;239(2):105-10. The android woman--a risky condition. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, Sweden. Normal women produce small amounts of active androgens. When androgen levels are elevated, such as for example in the polycystic ovary syndrome, this is followed by the development of male physical characteristics and muscle mass, structure and function as well as android adipose tissue distribution and function. Psychological features and stress reactions also seem similar to those of men. Such women have an increased risk of developing hypertension, non-insulin-dependent diabetes mellitus and cardiovascular disease. Recent data have shown that these physical, and psychological characteristics, as well as risk of ill health, are also found in the population of women selected at random. Women in the lowest quintiles of levels of sex-hormone-binding globulin--an indicator inversely related to active androgens--are at risk of developing hypertension, non-insulin-dependent diabetes mellitus and cardiovascular mortality. The mechanism probably includes muscular insulin resistance, following a relative androgen excess. It is thus apparent that androgens, even within the highest levels of the nonselected population of women, are powerful predictors of serious disease development. The population at risk might be as large as about 20% of middle-aged women. This is an area of female disease risk which requires more attention in screening and intervention procedures. PMID: 8568477 [PubMed - indexed for MEDLINE] 6055. Diabetes. 1996 Feb;45(2):113-26. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Gerbitz KD(1), Gempel K, Brdiczka D. Author information: (1)Institute of Clinical Chemistry, Academic Hospital Schwabing, München, Germany. Physiologically, a postprandial glucose rise induces metabolic signal sequences that use several steps in common in both the pancreas and peripheral tissues but result in different events due to specialized tissue functions. Glucose transport performed by tissue-specific glucose transporters is, in general, not rate limiting. The next step is phosphorylation of glucose by cell-specific hexokinases. In the beta-cell, glucokinase (or hexokinase IV) is activated upon binding to a pore protein in the outer mitochondrial membrane at contact sites between outer and inner membranes. The same mechanism applies for hexokinase II in skeletal muscle and adipose tissue. The activation of hexokinases depends on a contact site-specific structure of the pore, which is voltage-dependent and influenced by the electric potential of the inner mitochondrial membrane. Mitochondria lacking a membrane potential because of defects in the respiratory chain would thus not be able to increase the glucose-phosphorylating enzyme activity over basal state. Binding and activation of hexokinases to mitochondrial contact sites lead to an acceleration of the formation of both ADP and glucose-6-phosphate (G-6-P). ADP directly enters the mitochondrion and stimulates mitochondrial oxidative phosphorylation. G-6-P is an important intermediate of energy metabolism at the switch position between glycolysis, glycogen synthesis, and the pentose-phosphate shunt. Initiated by blood glucose elevation, mitochondrial oxidative phosphorylation is accelerated in a concerted action coupling glycolysis to mitochondrial metabolism at three different points: first, through NADH transfer to the respiratory chain complex I via the malate/aspartate shuttle; second, by providing FADH2 to complex II through the glycerol-phosphate/dihydroxy-acetone-phosphate cycle; and third, by the action of hexo(gluco)kinases providing ADP for complex V, the ATP synthetase. As cytosolic and mitochondrial isozymes of creatine kinase (CK) are observed in insulinoma cells, the phosphocreatine (CrP) shuttle, working in brain and muscle, may also be involved in signaling glucose-induced insulin secretion in beta-cells. An interplay between the plasma membrane-bound CK and the mitochondrial CK could provide a mechanism to increase ATP locally at the KATP channels, coordinated to the activity of mitochondrial CrP production. Closure of the KATP channels by ATP would lead to an increase of cytosolic and, even more, mitochondrial calcium and finally to insulin secretion. Thus in beta-cells, glucose, via bound glucokinase, stimulates mitochondrial CrP synthesis. The same signaling sequence is used in the opposite direction in muscle during exercise when high ATP turnover increases the creatine level that stimulates mitochondrial ATP synthesis and glucose phosphorylation via hexokinase. Furthermore, this cytosolic/mitochondrial cross-talk is also involved in activation of muscle glycogen synthesis by glucose. The activity of mitochondrially bound hexokinase provides G-6-P and stimulates UTP production through mitochondrial nucleoside diphosphate kinase. Pathophysiologically, there are at least two genetically different forms of diabetes linked to energy metabolism: the first example is one form of maturity-onset diabetes of the young (MODY2), an autosomal dominant disorder caused by point mutations of the glucokinase gene; the second example is several forms of mitochondrial diabetes caused by point and length mutations of the mitochondrial DNA (mtDNA) that encodes several subunits of the respiratory chain complexes. Because the mtDNA is vulnerable and accumulates point and length mutations during aging, it is likely to contribute to the manifestation of some forms of NIDDM.(ABSTRACT TRUNCATED) PMID: 8549853 [PubMed - indexed for MEDLINE] 6056. J Atheroscler Thromb. 1996;3(2):81-9. Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects. Auwerx J(1), Schoonjans K, Fruchart JC, Staels B. Author information: (1)U. 325 INSERM, Département d'Atherosclérose, Institut Pasteur, Lille, France. The molecular mechanism by which hypolipidemic fibrates and antidiabetic thiazolidinediones exert their hypotriglyceridemic action are discussed. Increased activity of lipoprotein lipase (LPL), a key lipolytic enzyme, and decreased levels of apolipoprotein C-III (apo C-III) seem to explain the hypotriglyceridemic effects of compounds. Both fibrates and thiazolidinediones exert their action by activating transcription factors of the peroxisome proliferator activated receptor (PPAR) family, thereby modulating the expression of the LPL and apo C-II genes. First, treatment of rats with PPAR alpha activators, such as fibrates induced LPL mRNA and activity selectively in the liver. In contrast, the thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect on liver, but induce LPL mRNA and activity levels in adipose tissue. In hepatocytes, fibrates, unlike the thiazolidinediones, induce LPL mRNA levels, whereas in preadipocyte cell lines the PPAR gamma ligand induces LPL mRNA levels much quicker and to a higher extent than fibrates. Second, apo C-III mRNA and protein production strongly decrease in livers of fibrate but not thiazolidinedione-treated animals. Fibrates also reduced apo C-III production in primary cultures of rat and human hepatocytes. The modulation of the expression of the LPL and apo C-III genes by either PPAR alpha or gamma activators, correlates with the tissue-specific distribution of the respective PPARs: PPAR gamma expression is restricted to adipose tissues, whereas PPAR alpha is expressed predominantly in liver. In both the LPL and apo C-III genes, sequence elements responsible for the modulation of their expression by activated PPARs have been identified which supports that the transcriptional regulation of these genes by fibrates and thiazolidinediones contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPAR gamma, fibrates exert their effects mainly in the liver via a PPAR alpha-mediated reduction in apo C-III production. This tissue specific transcriptional regulation of genes involved in lipid metabolism by PPAR activators and/or ligands might have important therapeutic implications. PMID: 9226459 [PubMed - indexed for MEDLINE] 6057. Ryoikibetsu Shokogun Shirizu. 1996;(13):524-7. [Deposition of subepicardial fat]. [Article in Japanese] Iwasaka T(1), Koito H. Author information: (1)Second Department of Internal Medicine, Kansai Medical University. PMID: 9117700 [PubMed - indexed for MEDLINE] 6058. Biochem Cell Biol. 1996;74(5):615-22. Of mice and women: the beta 3-adrenergic receptor leptin and obesity. Bégin-Heick N(1). Author information: (1)Department of Biochemistry, Faculty of Medicine, University of Ottawa, Canada. The metabolic response of adipose tissue to stimuli leading to lipid mobilization is important in determining the direction of metabolism and the degree to which adipose tissue can store lipids and release fatty acids in times of need. The lipolytic machinery is controlled by the activity of hormone-sensitive lipase, which in turn is controlled by the cellular levels of cAMP. The production of cAMP is abnormal in the adipose tissue of some animal models of obesity. In the ob/ob mouse, the defective cAMP production has been associated with deficient levels of some of the isoforms of the guanine nucleotide transducing G-proteins and also with the low expression and functionality of the beta 3-adrenergic receptor (beta 3-AR). The recent discovery of the ob gene product leptin calls into question the role of the ob gene in the regulation of the cAMP cascade in adipose tissue. The importance of the beta 3-AR and leptin in regulating human adipose tissue metabolism remains to be clarified. PMID: 9018368 [PubMed - indexed for MEDLINE] 6059. Ciba Found Symp. 1996;201:68-80; discussion 80-9, 188-93. The origins and consequences of obesity. Diabetes. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, University of Göteborg, Sahlgren's Hospital, Sweden. A relationship exists between obesity and non-insulin-dependent diabetes mellitus. Central, abdominal obesity carries a particularly high risk that is most likely associated with enlargement of visceral fat deposits. A multiple endocrine perturbation is associated with visceral obesity. This consists of a hypersensitive hypothalamic-pituitary-adrenal (HPA) axis, with resulting excess of cortisol secretion upon stimulation. Growth hormone levels in both sexes are diminished and testosterone concentrations in men are lower than normal. In women a moderate hyperandrogenism is often present. The elevated sensitivity of the HPA axis may be a primary event, followed by adrenal androgen production in women and by interaction at several levels, with inhibition of both the growth hormone and pituitary-gonadal axes. Together, these endocrine perturbations seem to be able to centralize body fat to visceral depots because of a high density of steroid hormone receptors. The endocrine perturbations are most likely followed by insulin resistance. Elevated cortisol levels, deficiencies in sex-specific steroid hormones and excess androgens result in insulin resistance. The endocrine abnormalities in visceral obesity are followed by insulin resistance, both directly and indirectly via contribution of excess free fatty acids from centralized body fat depots. The hyperactivity of the HPA axis may be due to frequent challenges and it is amplified by a deficient feedback inhibition. A depressive, helplessness reaction to stress may be involved. Such stress factors may be found in socioeconomic and psychosocial handicaps, as suggested by results of population studies. This hypothesis is strongly supported by the reproduction of an identical condition in non-human primates that react with a depressive reaction upon psychosocial types of stressors. The perturbations of the HPA axis may thus be in the centre of the syndrome. Studies of this axis in established non-insulin-dependent diabetes mellitus suggest similar perturbations, but the information is not conclusive. PMID: 9017275 [PubMed - indexed for MEDLINE] 6060. Horm Res. 1996;46(6):249-56. Leptin: genes, concepts and clinical perspective. Considine RV(1), Caro JF. Author information: (1)Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa 19107, USA. Obesity is a complex disease which results from the interaction of multiple genes and the environment. The recently discovered genes for leptin (ob gene) and the leptin receptor appear to play a major regulatory role in body energy balance and adipose tissue deposition. Furthermore, defects in the ob gene and leptin receptor gene have been demonstrated to be the cause of obesity in several rodent models. These observations raise the possibility that human obesity may also be due to defects in the leptin signal system. This review will summarize the current findings on the ob gene, leptin and the leptin receptor in both animals and humans. These observations will be discussed in the context of potential defects in the system and the possibility that these defects result in obesity in humans. PMID: 8982734 [PubMed - indexed for MEDLINE] 6061. Horm Res. 1996;46(4-5):188-91. Growth hormone, insulin-like growth factor-I and lipid metabolism: interactions with sex steroids. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, Sweden. Steroid hormones usually act via specific receptors and the hormone-receptor complex then influences the transcription of genes. These effects are often permissive for the actions of peptide hormones such as insulin and growth hormone (GH). The best known effects are those of cortisol. Since cortisol is always present, the sex steroids often modify cortisol effects. In adipose tissue, lipoprotein lipase (LPL), in the presence of insulin, is expressed via a glucocorticoid receptor, increasing transcription and stabilizing the enzyme. This process is efficiently inhibited by GH via posttranslational effects, and lipolysis is markedly stimulated. Testosterone inhibits LPL expression and, in the presence of GH, markedly increases lipolysis via multiple interactions along the lipolytic cascade. In human adipose tissue, direct effects of estrogen and progesterone cannot be demonstrated, probably because of the apparent absence of specific receptors. These hormones presumably via indirect mechanisms, perhaps by interaction with other hormone receptors. PMID: 8950619 [PubMed - indexed for MEDLINE] 6062. Prog Lipid Res. 1996;35(2):133-53. Phospholipid-rich particles in commercial parenteral fat emulsions. An overview. Bach AC(1), Férézou J, Frey A. Author information: (1)Centre d'Ecologie et Physiologie Energétiques, Strasbourg, France. In parenteral nutrition, the infusion of a fat EMU supplies both concentrated energy and covers the essential fatty acid requirements, the basic objective being to mimic as well as possible the input of chylomicrons into the blood. This objective is well met by the TAGRP of the EMU, which behave as true chylomicrons. However, commercial EMU also contain an excess of emulsifier in the form of PLRP. The number of these PLRP depends directly on the PL/TAG ratio of the EMU. They differ from the TAGRP by their composition (PL vs TAG and PL), their structure (PL in bilayer versus monolayer), and their granulometry (mean diameter 70-100 nm for PL vs 200-500 nm). The metabolic fate of the PLRP is similar in several ways to that of the TAGRP: exchanges of PL with the PL of the different cellular membranes and of the lipoproteins; captation of free CH from these same structures; and enrichment in apolipoproteins. However, because the TAGRP are the preferred substrates of the lipolytic enzymes, their clearance is much more rapid (half-life < 1 h) than that of the PLRP. As the infusion is continued, the PLRP end up accumulating and being transformed into LP-X (free CH/PL = 1; half-life of several days). As soon as the EMU is infused, the PLRP enter into competition with the TAGRP, in the lipolysis process as well as for sites of binding and for catabolism. The sites for catabolism of the two types of PAR are not the same: adipose tissues and muscles utilize the fatty acids and monoacylglycerols released by the lipolysis of the TAGRP; hepatocytes take up their remnants; the RES and the hepatocytes participate in the catabolism of the PLRP and the LP-X. Thus, prolonged infusion of EMU rich in PLRP leads to a hypercholesterolemia, or at least a dyslipoproteinemia, due to elevated LP-X, associated with a depletion of cells in CH, stimulating thus tissue cholesterogenesis. However, parenteral nutrition has evolved towards the utilization of EMU with a low PL/TAG ratio (availability of 30% formula) and less rapid delivery. For these reasons, the hypercholesterolemias that used to be observed with the 10% EMU have become much less spectacular or have even disappeared. It is interesting to note that patients on prolonged TPN, in particular those with a short small intestine, have weak cholesterolemia, reflecting a lowering of HDL and LDL not masked by elevated LP-X. At present, it seems difficult to produce sufficiently stable parenteral EMU devoid of PLRP. Notwithstanding, all the observations made since the introduction of the EMU in TPN are in favour of the use of PLRP-poor EMU. It is clear that the 10% formulas, and generally those with a PL/TAG ratio of 12/100, are ill-advised, especially in patients with a retarded clearance of circulating lipids. PMID: 8944224 [PubMed - indexed for MEDLINE] 6063. Exp Clin Endocrinol Diabetes. 1996;104(4):293-300. Regulation of energy balance by leptin. Hamann A(1), Matthaei S. Author information: (1)Department of Medicine, University of Hamburg, Germany. The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition. PMID: 8886745 [PubMed - indexed for MEDLINE] 6064. Horm Res. 1996;46(2):53-8. Neuropeptide Y, the hypothalamus and the regulation of energy homeostasis. Tomaszuk A(1), Simpson C, Williams G. Author information: (1)Department of Medicine, University of Liverpool, UK. Neuropeptide Y (NPY) neurones in the arcuate nucleus of the rodent hypothalamus may play a key role in responding to reductions in body energy stores with appropriate changes in energy homeostasis, namely an increase in food-seeking behaviour and hyperphagia, together with a reduction in heat production by brown adipose tissue. These adaptive responses are mimicked by the injection of NPY into the main sites of projection of the NPY neurones, and animals that are threatened by energy deficits (e.g. through starvation or insulin-deficient diabetes) show increased activity of these neurones. Genetically obese rodents also show hyperactivity of the NPY neurones, which is inappropriate to their energy needs and may contribute to their hyperphagia, reduced energy expenditure and excessive weight gain. The NPY neurones may be inhibited by insulin and leptin, which may both serve as signals of peripheral fat mass. Ultimately, characterization of the specific "feeding' receptors which mediate NPY's central effects on energy homeostasis may provide opportunities for designing drugs to manipulate and appetite and energy balance in man, notably obesity and the cachexia commonly associated with malignancy and chronic infection. PMID: 8871182 [PubMed - indexed for MEDLINE] 6065. Adv Enzyme Regul. 1996;36:199-226. Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: a review of the potential cellular and molecular mechanisms. Foufelle F(1), Girard J, Ferré P. Author information: (1)Unité INSERM 342, Hôpital Saint-Vincent-de-Paul, Paris, France. Regulation of gene expression by nutrients is an important part of the mechanisms allowing mammals to adapt to their nutritional environment. This is especially true for enzymes involved in the storage of energy such as the lipogenic and glycolytic enzymes in the liver and adipose tissue. We review in the present paper the cellular and molecular mechanisms involved in the regulation of glycolytic and lipogenic enzyme gene expression by glucose. In vivo and in vitro experiments have demonstrated that FAS and ACC gene expression is upregulated by glucose in adipose tissue, FAS, ACC and L-PK expression in the liver and ACC and L-PK expression in a pancreatic beta-cell line. This regulation involves the stimulation of their transcription. In order for glucose to act as a gene inducer, it must be metabolized. In adipose tissue, insulin increases indirectly the expression of FAS and ACC by stimulating glucose metabolism through its well-known effect on glucose transport. In the liver, the action of insulin is also indirect by allowing the expression of glucokinase and hence by increasing glucose metabolism. In the liver, fructose has a potentiating effect on the stimulation of gene expression by glucose through its stimulatory effect on glucokinase activity. Several evidences suggest that glucose-6-phosphate is the signal metabolite: (i) the effect of glucose is mimicked by 2-deoxyglucose (a glucose analogue whose metabolism stops after its phosphorylation by hexokinase) in adipose tissue and beta-cell line but not in the liver in which 2-deoxyglucose-6-phosphate does not accumulate, (ii) intracellular glucose-6-phosphate concentration varies in parallel with ACC, FAS and L-PK mRNA concentrations in liver, adipose tissue and beta-cell line, (iii) in vivo, the kinetics of hexose-phosphate fits with the time-related pattern of gene induction. Glucose response elements have been characterized on three genes, L-PK, S14 (a gene which codes for a protein of unknown function but which is directly related to lipogenesis) and FAS. These glucose response elements have all in common the presence of a sequence 5'-CACGTG-3' which binds a transcription factor of the basic domain, helix-loop-helix, leucine zipper family called USF/MLTF, although the organization of the overall glucose response element probably differs from one gene to another. The mechanisms linking glucose-6-phosphate to the glucose responsive transcription complex are presently largely unknown. PMID: 8869748 [PubMed - indexed for MEDLINE] 6066. Cancer Causes Control. 1996 Jan;7(1):19-32. Nutrition and endometrial cancer. Hill HA(1), Austin H. Author information: (1)Department of Epidemiology, Rollins School of Public Health of Emory University, Atlanta, Georgia 30322, USA. Epidemiologic evidence on the relation between nutrition and endometrial cancer (EC) is reviewed. Obesity is an important determinant of EC, probably because of its effect on the hormonal milieu of both pre- and postmenopausal women. However, epidemiologic studies of body fat distribution and EC are inconsistent, as are the data pertaining to the relation between body fat distribution and sex hormones. Randomized and observational studies of diet and sex hormones indicate that low fat diets may be associated weakly with decreased estrogen levels, and thus a lowering of EC risk. Only ecologic and case-control studies of diet and EC have been reported. These findings as well as the methodologic limitations of these study designs are discussed. Both types of studies implicate fat as a potential risk factor, while the case-control studies suggest that carotene may lower risk of EC. Epidemiologic studies of alcohol and EC also are inconsistent, but generally indicate no association, or a weak protective effect. The role of diet in the etiology of EC is unresolved. The conduct of cohort and intervention studies, which can avoid many of the methodologic shortcomings of ecologic and case-control studies, would improve our understanding of diet and EC. PMID: 8850432 [PubMed - indexed for MEDLINE] 6067. Annu Rev Nutr. 1996;16:523-57. Regulation of hepatic de novo lipogenesis in humans. Hellerstein MK(1), Schwarz JM, Neese RA. Author information: (1)Department of Nutritional Sciences, University of California at Berkeley 94720-3104, USA. The enzymatic pathway for synthesis of fatty acids from acetyl-coenzyme A, or de novo lipogenesis (DNL), is present in human liver and, to a lesser extent, in adipose tissue. Although the molecular and enzymatic regulation of the components for DNL are well characterized, the quantitative importance of the assembled pathway and its physiologic functions have remained uncertain. We review methods that have been used for measuring DNL in vivo, their limitations and the conclusions based on them. Two new methods for direct measurement of DNL in humans are discussed-mass isotopomer distribution analysis (MIDA), a mass spectrometric technique based on combinatorial probabilities, and 2H2O incorporation. Recent findings with these methods in a variety of dietary and hormonal settings are reviewed. In particular, we focus on the question of whether or not surplus carbohydrate energy is converted to fat by the liver in humans. A somewhat surprising model of the response to carbohydrate over-feeding emerges from these studies, with a number of implications for metabolic regulation in health and disease. We close by speculating on potential functions of DNL in physiology and pathophysiology if storage of surplus carbohydrate energy is not an important function of DNL. The availability of techniques for quantifying DNL in vivo should make it possible to resolve these uncertainties regarding its functions and regulation in humans. PMID: 8839937 [PubMed - indexed for MEDLINE] 6068. Annu Rev Nutr. 1996;16:235-56. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Olson AL(1), Pessin JE. Author information: (1)Department of Physiology and Biophysics, University of Iowa, Iowa City 52242, USA. The facilitative transport of glucose across the plasma membranes of mammalian cells is catalyzed by a family of glucose transport proteins (GLUT). Four glucose transport proteins and a fructose transport protein have been identified. These transport proteins have unique tissue distributions and biochemical properties under- lying specific physiologic functions. GLUT1, the first GLUT isoform identified, is expressed at highest levels in the endothelial of barrier tissues such as blood vessels and the blood-brain barrier. GLUT2, found predominantly in liver, intestine, kidney, and pancreatic beta-cells, is a low-affinity glucose transport protein that is part of the glucose sensor in pancreatic beta-cells and facilitates either glucose uptake or efflux from the liver depending on the nutritional state. GLUT3 is the glucose transporter responsible for maintaining an adequate glucose supply to neurons. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues, heart muscles, and skeletal muscles that is responsible for insulin-regulated glucose disposal. PMID: 8839927 [PubMed - indexed for MEDLINE] 6069. Prog Clin Biol Res. 1996;394:41-56. Influence of diet on tumors of hormonal tissues. Rao GN(1). Author information: (1)National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Approximately 20% of all deaths in the United States are due to cancer. Cancers of the hormonal tissues such as breast, uterus, ovary in women and prostate in men account for about 8% and 5% of total mortality and 30% and 11% of cancer mortality in women and men, respectively. Diet is considered to be a major and important environmental factor contributing to cancers of hormonal tissues. Breast, uterus, and ovary cancers in women and prostate cancers in men were positively correlated with high fat consumption, high body weight (body mass), body fat, and obesity. A major mechanism for development of these cancers appears to be mediated through increased levels of hormones, especially estrogens. Adipose tissue is considered to be one of the major sources of extraglandular estrogen, produced by aromatization of androgen precursors. Weight reduction decreases the estrogen levels possibly due to a decrease in body fat, thus decreasing the risk for cancers of the hormonal tissues. Dietary fiber may modify the risk for these cancers by influencing estrogen metabolism, recirculation, and excretion. Vitamin A and its precursors may decrease the risk for prostate cancer. Iodine deficiency may increase the risk for thyroid neoplasms in humans and experimental animals. Tumors of the hormonal tissues are the most common tumors in laboratory rodents, especially rats and mice. Incidences of mammary and anterior pituitary tumors had significant and positive correlation with body weight in rats and mice. Lowering the body weight by either decreased caloric intake or other means (e.g., exercise, increased fiber consumption) markedly lowered the incidences of these tumors in laboratory rodents. Laboratory studies indicated that mammary tumor rates in rats may not depend on the amount of fat consumed per day. The mammary tumor-promoting effect of fat may be due to complex interactions involving energy intake and energy retention (body mass) mediated through paracrine, endocrine, and neurohormonal mechanisms. Dietary protein may influence chemically induced tumors by affecting the metabolism of chemicals through enzyme induction. Thus, environmental factors such as diet are considered to be major and important factors for tumors of the hormonal tissues such as breast, uterus, and ovary in women and prostate in men. Diet and associated body weight are considered to be the major factors for tumors of hormonal tissues such as mammary and pituitary glands in rodents, especially rats. Modification of diet and a decrease in caloric intake may markedly decrease the incidence or delay the development of tumors of hormonal tissues in humans and in experimental animals. PMID: 8778807 [PubMed - indexed for MEDLINE] 6070. Arch Tierernahr. 1996;49(1):63-71. Influence of dietary fatty acid composition and vitamin E on fatty acids and alpha-tocopherol in carp (Cyprinus carpio L.). Schwarz FJ(1). Author information: (1)Institut für Ernährungsphysiologie, Technischen Universität München, Freising-Weihenstephan, Germany. This paper examines the effect of different fatty acid composition, together with varying dietary vitamin E contents on fatty acid composition and tocopherol and tocotrienol contents of carp, and compares with other species of fish and the storage quality of the fish produced. Dietary fatty acid composition affected fatty acid patterns of tissues of carp significantly, but this was correlated with the fat content of the diet. Varying the vitamin E content results in no or only very slight variations in the fatty acid pattern of the tissues. The content of alpha-tocopherol in the tissues was affected significantly by dietary alpha-tocopheryl acetate content and by dietary fat source. There was a negative correlation between (n-3) fatty acids and the storage of alpha-tocopherol, while this was positively correlated with (n-6) fatty acids. The content of alpha-tocopherol in fish affected the stability during storage with the content of malondialdehyde used as a parameter for measuring the extent of fat oxidation. Other relationships, e.g. with sensory qualities and S-containing substances in the edible part of the fish, are discussed. PMID: 8766975 [PubMed - indexed for MEDLINE] 6071. Rev Med Interne. 1996;17(5):391-8. [Refsum disease]. [Article in French] Hochner I(1), Blickle JF, Brogard JM. Author information: (1)Service de médecine interne, HUS, 1, place de l'Hôpital, Strasbourg, France. Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa. PMID: 8763099 [PubMed - indexed for MEDLINE] 6072. Pol Tyg Lek. 1996 Jan;51(1-5):40-5. [The role of muscle, adipose tissue and liver in development of metabolic syndrome]. [Article in Polish] Krotkiewski M(1). Author information: (1)Kliniki Rehabilitacji Medycznej Uniwersytetu w Göteborgu, Szwecja. PMID: 8754301 [PubMed - indexed for MEDLINE] 6073. Exerc Sport Sci Rev. 1996;24:203-31. Effects of acute and chronic exercise on fat metabolism. Martin WH 3rd(1). Author information: (1)Division of Cardiology 111A/JC, John Cochran Hospital, St Louis, Missouri, USA. Fatty acids are an important source of energy for skeletal muscle contraction, particularly during exercise of mild-moderate intensity, prolonged duration, and in the fasting state. Plasma FFA transported from remote adipose tissue stores and triglycerides contained within skeletal muscle fibers are the major sources of these fatty acids. The relative contribution of each source is dependent on the mode, intensity, and duration of exercise and on training status. Plasma FFA oxidation is directly related to the rate of lipolysis in adiopose tissue. The most potent stimulants of the latter are the catecholamines, but a lower plasma insulin concentration during exercise also plays a contributory role. In contrast, intramuscular triglyceride hydrolysis appears to be mediated entirely by beta 2-adrenergic stimulation. Endurance training substantially enhances fatty acid oxidative capacity in skeletal muscle and increases the proportion of energy derived from fatty acid oxidation during exercise. In addition, the sympathoadrenal response to exercise is markedly blunted in the trained state. Studies conducted in our laboratory indicate that plasma FFA and glycerol concentrations and whole body FFA uptake and oxidation are all decreased during moderate-intensity exercise at the same absolute work rate after physical conditioning, probably because of the reduction of sympathoadrenal activity. However, the lipolytic response to catecholamines also is enhanced in trained subjects. Perhaps as a consequence, the magnitude of the decrease in lipolysis and plasma FFA oxidation is less than the decrement in sympathoadrenal activity in the same individuals during exercise in the trained state. Other investigations were conducted in our laboratory to determine the source of the additional fatty acids oxidized in physically conditioned subjects. These studies demonstrated that during moderate-intensity exercise at the same absolute work rate, depletion of triglycerides from within skeletal muscle fibers was twice as great after, as opposed to, before training. Regardless of training status, intramuscular triglyceride use accounted for about 90% of the oxidized fatty acids that were not supplied from adipose tissue via the plasma. Intramuscular triglycerides were the source of virtually all of the additional fatty acids oxidized in the trained state. Both before and after physical conditioning they explained the discrepancy between the rates of plasma FFA and total fat oxidation during moderate-intensity exercise of up to 2 hr in duration. PMID: 8744251 [PubMed - indexed for MEDLINE] 6074. Curr Top Cell Regul. 1996;34:63-100. Type III cyclic nucleotide phosphodiesterases and insulin action. Manganiello VC(1), Degerman E, Taira M, Kono T, Belfrage P. Author information: (1)Laboratory of Cellular Metabolism, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA. PMID: 8646851 [PubMed - indexed for MEDLINE] 6075. Medicine (Baltimore). 1996 Jan;75(1):6-16. The fasciitis-panniculitis syndromes. Clinical and pathologic features. Naschitz JE(1), Boss JH, Misselevich I, Yeshurun D, Rosner I. Author information: (1)Department of Medicine, Bnai-Zion Medical Center, Haifa, Israel. The authors propose to encompass under the designation of "fasciitis-panniculitis syndromes" (FPS) a group of disorders characterized by induration of the skin due to chronic inflammation and fibrosis of the subcutaneous septa and muscular fascia. The prototype of the FPS is eosinophilic fasciitis. Thirty-two consecutive patients with FPS were cared for at the author's hospital during a 10-year period. The association of the FPS with other diseases, clinical presentations, histologic features, and response to treatment were analyzed. Idiopathic FPS, that is, eosinophilic fasciitis, was diagnosed in 14 patients. In the remaining 18 cases, the FPS were ascribed to vascular disorders (n = 6), infections (n = 6), and neoplastic disorders (n = 3), while trauma, insect bites, and Sweet syndrome antedated the FPS in 1 patient each. The lesions had a sleeve-like distribution in 20 patients, plaque-like distribution in 7, and a combined pattern in 5. Skin biopsies revealed lesions in the deep subcutaneous layers with the pathologic triad of septal and fascial fibrosis, chronic inflammatory infiltration, and small-vessel vasculopathy. Spontaneous improvement occurred in 4 cases. Following cimetidine monotherapy, complete remission was achieved in an additional 3 of 5 patients. The concept of the FPS serves to advance our understanding on several fronts: emphasizing the clinical and etiologic diversity; recognizing a stereotypic tissue reaction pattern; highlighting the panniculitis in addition to the fasciitic component; and describing a similar response to drug therapy in different clinical settings. Based on the results of the present series, cimetidine may be recommended as first-line treatment. PMID: 8569470 [PubMed - indexed for MEDLINE] 6076. Ann N Y Acad Sci. 1995 Dec 29;771:665-76. Hypercortisolism and obesity. Peeke PM(1), Chrousos GP. Author information: (1)Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892, USA. Obesity is a multifactorial heterogenous condition. The location of excess fat on the body determines the risk of morbidity and mortality for significant disease. Visceral, or intraabdominal, fat is the fat depot most highly associated with illness and death from cardiocerebrovascular disease and diabetes. Visceral fat is also associated with a quartet of metabolic disturbances. Referred to as the metabolic syndrome, these abnormalities include hypertension, hyperlipidemia, hyperinsulinemia, and insulin resistance. The metabolic syndrome is also present in Cushing's syndrome, which is characterized by primary hypercortisolism as well as profound visceral adiposity and obesity. The interrelationship between hyperactivation or hypersensitivity of the stress axis and disease can be elucidated by an understanding of the effect of excess glucocorticoids upon energy storage and metabolism. The complex interactions of the stress axis upon the growth and reproductive axes, as well as upon the adipose tissue, suggest that chronic stress, whether psychological and/or physical, exerts an intense effect upon body composition, which, in turn, significantly affects the longevity and survival of the organism. PMID: 8597440 [PubMed - indexed for MEDLINE] 6077. Cancer. 1995 Dec 15;76(12):2418-26. Mechanisms mediating cancer cachexia. Toomey D(1), Redmond HP, Bouchier-Hayes D. Author information: (1)Department of Surgical Research, Royal College of Surgeons, Dublin, Ireland. BACKGROUND: Cancer cachexia encompasses a wide range of metabolic, hormonal, and cytokine-related abnormalities that result in a wasting syndrome possibly accounting for up to 30% of cancer-related deaths. METHODS: A literature search was performed to review those pathways of metabolic interference involved in cancer cachexia. RESULTS: An elevated basal metabolic rate and increased energy expenditure combined with systemic catabolism of muscle and adipose tissue are the predominant manifestations of the metabolic and physiologic perturbations noted in this pathologic state. CONCLUSIONS: To date, although some of the cachexia-related metabolic abnormalities have been elucidated, there has been little success in relation to therapeutic manipulation of these pathways. This review evaluates current knowledge relating to cancer cachexia and cautions against generalizations concerning treatment regimens. PMID: 8625066 [PubMed - indexed for MEDLINE] 6078. Thyroid. 1995 Dec;5(6):481-92. Thyroid hormone control of thermogenesis and energy balance. Silva JE(1). Author information: (1)Division of Endocrinology and Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada. The mechanisms whereby thyroid hormone increases heat production have been analyzed with emphasis in more recent developments. Thyroid hormone increases obligatory thermogenesis as a result of the stimulation of numerous metabolic pathways involved in development, remodeling, and delivery of energy to the tissues. In addition, thyroid hormone may specifically stimulate some thermogenic mechanisms selected during evolution of homeotherms (e.g., Na/K-ATPase, Ca2+ cycling in muscle). Thyroid hormone also plays an essential role in facultative thermogenesis interacting with the sympathetic nervous system (SNS) at various levels. Peripherally, thyroid hormone potentiates the effects of the SNS at the level of the adrenergic receptor and adenylyl cyclase complex as well as distal from this point. Synergistic interactions between T3 and cAMP on the regulation of gene expression have been described. Brown adipose tissue (BAT) T4-5'-deiodinase plays a central role in controlling heat production. When this enzyme is stimulated by norepinephrine in the euthyroid and hypothyroid condition, it provides high concentrations of T3 to BAT; inhibition by T4 in hyperthyroidism may limit brown fat thermogenic responses. Also, thyrotoxicosis uniquely reduces the expression of beta 3-adrenergic receptors in brown adipose tissue, and the increased obligatory thermogenesis of this condition, via afferent neural pathways, may reduce the hypothalamic stimulation of brown fat, providing additional mechanisms to limit brown adipose tissue thermogenesis in hyperthyroidism. PMID: 8808101 [PubMed - indexed for MEDLINE] 6079. Obes Res. 1995 Dec;3 Suppl 5:645S-647S. Visceral fat accumulation and cardiovascular disease. Matsuzawa Y(1), Nakamura T, Shimomura I, Kotani K. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. Classification of Obesity. It has been noted that the incidence of metabolic complications among equally obese subjects differs depending on their physique (11) and there has been more scientific assessment in recent years that complications such as diabetes mellitus or hyperlipidemia are related to adipose tissue distribution (5). In 1983, we reported a method for adipose tissue analysis using computed tomography (CT), which enables the analysis of adipose tissue in the body cavity, e.g., abdominal cavity or thoracic cavity, as well as subcutaneous fat (10). Using this method, we found that the patients with accumulation of fat in the abdominal cavity have a higher incidence of complication (1). Based on this finding, we proposed a classification into visceral fat obesity by visceral fat area (V)/subcutaneous fat area (S) ratios obtained from CT cross sectional pictures of the umbilical region. We divided obese subjects at a V/S ratio of 0.4, classifying those with a ratio of 0.4 or more as a visceral fat obesity group and those with V/S ratio of below 0.4 as a subcutaneous fat obesity group. Disorders of glucose and lipid metabolism were more marked in the visceral fat obesity than subcutaneous fat obesity even when sex and age were matched. We also demonstrated that visceral fat obesity is more frequently accompanied by circulatory disorders such as left ventricular enlargement (8) and hypertension than subcutaneous fat obesity (2). PMID: 8653544 [PubMed - indexed for MEDLINE] 6080. Environ Health Perspect. 1995 Dec;103 Suppl 9:7-16. Biomarkers for Great Lakes priority contaminants: halogenated aromatic hydrocarbons. Feeley MM(1). Author information: (1)Bureau of Chemical Safety, Health Canada, Ottawa, Ontario. mfeeley@hpb.hwc.ca One of the major goals of the Great Lakes Action Plan is to actively accumulate and assess toxicological information on persistent toxic substances found in the Great Lakes basin. As part of Health Canada's commitment to this plan, a review of biomarkers for the environmental contaminants polychlorinated biphenyls (PCBs) and polychlorinated dibenzodioxins/dibenzofurans (PCDDs/PCDFs) was conducted. In general, while food consumption was identified as the major source of human exposure to both contaminant groups, certain commodities, such as fish, milk and dairy products, and meat, were found to predominate. Due to the ubiquitous nature of these environmental contaminants and their propensity to bioaccumulate, all humans will have detectable body burdens, which in certain cases can be positively associated with the consumption of particular foods (i.e., PCBs and freshwater fish from the Great Lakes). When dealing with environmental exposure only, relating specific effect biomarkers to contaminant exposure or tissue levels was difficult, due in part to the complex nature of the exposure and the nonspecific nature of the effect. For PCBs, the most likely biomarkers of effect included some form of alteration in lipid metabolism (serum triglyceride/cholesterol levels) and elevation of hepatic-related enzymes, aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT). Cross-species extrapolation also indicates the potential for neurotoxicologic effects to occur in humans. For PCDDs/PCDFs, dermatologic lesions (chloracne) and indications of hepatic enzyme induction have been documented, but primarily due to occupational or high acute accidental exposures. Recent evidence suggests that neonates may represent a potential at-risk population due to relatively high exposure to PCDDs/PCDFs, as with PCBs, during breast feeding as compared to standard adult dietary intake. Future areas of potential benefit for biomarker development include immunologic and endocrine effects, primarily based on biologic plausibility from experimental animal research. PMCID: PMC1518823 PMID: 8635442 [PubMed - indexed for MEDLINE] 6081. Curr Opin Cell Biol. 1995 Dec;7(6):885-90. Regulation of adipose maturation and energy homeostasis. Yeh WC(1), McKnight SL. Author information: (1)Tularik Inc., South San Francisco, USA. The adipose tissue of mammals represents a dynamic organ disseminated throughout the body. It fluctuates in abundance according to the availability of metabolic energy supplies. Mature adipose tissue communicates with the central nervous system via a hormonal circuit that controls satiety. Adipogenesis can be recapitulated in cell culture, thus facilitating molecular biological studies of the regulatory proteins that control this process. Such studies have led to the identification of two families of transcription factors that regulate adipogenesis and mammalian energy homeostasis. PMID: 8608020 [PubMed - indexed for MEDLINE] 6082. Am J Med Sci. 1995 Dec;310 Suppl 1:S72-6. The importance of body fat distribution in early life. Freedman DS(1). Author information: (1)Division of Nutrition, Centers for Disease Control and Prevention, Atlanta, Georgia 30341-3724, USA. It is possible that many of the conflicting findings concerning obesity and cardiovascular disease may be the result of the heterogeneous nature of obesity, adn that only certain subgroups of the obese are at increased risk. Over the last several decades, much attention has focused on the distribution of body fat as an important characteristic in the metabolic and clinical alterations associated with obesity. Several studies have shown that a relative excess of adipose tissue in the upper body, abdominal region, or at various truncal sites is associated with an increased risk of disease; furthermore, these associations are independent of the general level of obesity. This article presents a brief historical overview of the idea of body fat distribution, the measurement techniques that have been used, and the complications associated with an adverse distribution of body fat distribution; particular emphasis is given to studies that have examined fat patterning in early life. Although most investigators recognize that body fat distribution is important in the development of cardiovascular disease, several questions remain. PMID: 7503128 [PubMed - indexed for MEDLINE] 6083. Clin Chem. 1995 Dec;41(12 Pt 2):1804-8. Biomarkers as tools in human health risk assessment. Greim H(1), Csanády G, Filser JG, Kreuzer P, Schwarz L, Wolff T, Werner S. Author information: (1)Institut für Toxikologie, GSF-Forschungszentrum für Umwelt und Gesundheit, GmbH, Oberschleissheim, Germany. Evaluation of occupational or environmental risk due to exposure to chemicals requires sufficient information on the toxic profiles, mechanisms of action, toxicokinetics, dose-response relation, exposure, and the target dose. Usually exposure is estimated by measuring concentrations of the agent in air, food, water, soil, dust, or other media with which a population or an individual is in contact. However, this external exposure is only a rough estimate for the internal exposure (agent dose or its metabolite at the critical target in the organism). Factors of influence are bioavailability of the chemicals, variations in concentrations and routes of exposure, physical activity, and individual variation in rates of metabolism, distribution, and excretion. All these affect the concentration of the toxic agent at the critical target, which is the most precise information for risk assessment. Thus, internal exposure is best measured by determining the concentration of the toxicant or its ultimate metabolite at the critical site in the target organ or by determining adducts with cellular macromolecules such as proteins, amino acids, DNA, or its bases. The latter are easily available in experimental toxicology from animal experiments but only occasionally from humans. For health surveillance such data usually are not available, because they require invasive procedures such as biopsies. Therefore, more accessible body fluids or tissue are used, such as blood, urine, or adipose tissue, or adducts with macromolecules such as albumin or hemoglobin in the blood, DNA adducts in peripheral lymphocytes, or altered DNA bases in urine such as 8-hydroxyguanine. All of these are indicators for exposure, whereas risk can only be estimated if the correlation between their deviations from normal and the dose-response at the critical target is known. PMID: 7497636 [PubMed - indexed for MEDLINE] 6084. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1370S-1376S. Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention. Kohlmeier L(1), Hastings SB. Author information: (1)Department of Nutrition, School of Medicine, University of North Carolina at Chapel Hill 27599-7400, USA. The tremendous chemical potential of the highly conjugated double bonds in carotenoids has driven research into their protective role in cardiovascular disease development. Prevention of low-density-lipoprotein oxidation and reduction of oxidative stress at the plaque formation are popular hypotheses underlying this research. Many epidemiologic studies have examined relations between beta-carotene exposure and cardiovascular disease risk. These studies used different measures to determine carotenoid exposure: semiquantitative food-frequency questionnaires, carotenoid concentrations in serum taken before the onset of disease and analyzed after diagnosis, and carotenoid concentrations in adipose tissue. Although the epidemiologic evidence is consistent with a protective association between beta-carotene and cardiovascular disease, findings from the first single intervention trial conducted in a large free-living population cast doubts on the utility of beta-carotene for all high-risk populations. Beta-Carotene may only represent a marker of dietary behavior conductive to lower risk of cardiovascular disease. Research on other carotenoids is needed. PMID: 7495233 [PubMed - indexed for MEDLINE] 6085. Obes Res. 1995 Nov;3 Suppl 4:613S-616S. Dehydroepiandrosterone and body fat. Clore JN(1). Author information: (1)Department of Internal Medicine, Medical College of Virginia, Richmond 23298, USA. Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant circulating adrenal steroid in man, yet its physiologic role and that of its parent compound DHEA are unknown. Age-related decreases in DHEA in association with increases in obesity, insulin resistance, and atherosclerosis are well known. Recent investigations in lower mammals (which do not secrete DHEA) have suggested that DHEA (or its metabolites) may function as an antiobesity agent in these models of obesity independent of food intake. Proposed mechanisms for the decrease in fat mass and lower weight gain when DHEA is given orally include increases in futile cycling and peroxisomal beta-oxidation and decreases in de novo lipogenesis. Alterations in the availability of reducing equivalents for lipid synthesis do not appear to explain this decrease. Changes in pancreatic insulin secretion or insulin sensitivity may also be responsible for some of these effects. Studies in humans have failed to demonstrate a beneficial effect of DHEA on body composition or energy expenditure at either pharmacologic or physiologic replacement doses for 1-3 months. Administration of DHEA to men or women has also not been shown to alter insulin sensitivity as measured by the minimal model or the euglycemic clamp technique. The effect of DHEA on peroxisomal beta-oxidation and de novo lipogenesis is not known. We conclude that a significant role for DHEA in the pharmacologic treatment of human obesity is unlikely. PMID: 8697065 [PubMed - indexed for MEDLINE] 6086. Proc Nutr Soc. 1995 Nov;54(3):657-64. McCay's hypothesis: undernutrition and longevity. Masoro EJ(1). Author information: (1)Department of Physiology, University of Texas Health Science Center, San Antonio 78284-7756, USA. PMID: 8643703 [PubMed - indexed for MEDLINE] 6087. Berl Munch Tierarztl Wochenschr. 1995 Nov;108(11):427-30. Bovine fat necrosis (Lipomatosis): an overview. el-Sebaie A(1), el-Amrousi S. Author information: (1)Department of Animal Medicine, Assiut University, Faculty of Veterinary Medicine. PMID: 8593136 [PubMed - indexed for MEDLINE] 6088. Cancer Causes Control. 1995 Nov;6(6):551-66. Organochlorine compounds and estrogen-related cancers in women. Adami HO(1), Lipworth L, Titus-Ernstoff L, Hsieh CC, Hanberg A, Ahlborg U, Baron J, Trichopoulos D. Author information: (1)Department of Cancer Epidemiology, Uppsala University, Sweden. The organochlorines, a diverse group of some 15,000 compounds, have been implicated increasingly as being harmful to humans. Some congeners of DDT and PCB elicit very weak estrogenic responses in animals, while the dioxin TCDD and related compounds have antiestrogenic properties. This review summarizes the evidence regarding whether certain organochlorine compounds, usually as persistent food-chain contaminants, increase the risk of breast and endometrial cancers through their estrogenic potential. In humans, neither ecologic data nor occupational studies provide clear support for an association between organochlorine exposure and the occurrence of these cancers. In our summary analysis of occupational exposure, the rate ratio of breast cancer for exposed cf unexposed women was 0.84 (95 percent confidence interval [CI] = 0.50-1.33) for PCBs and 1.08 (CI = 0.68-1.58) for TCDD. Similarly, effect estimates close to unity were found in summary analysis of breast cancer case-control studies regarding levels of DDE and PCB in adipose tissue or serum. In two recent nested case-control studies using stored specimens, the odds ratio per standard deviation increase in serum p,p'-DDE was 1.27 (CI = 0.95-1.69). Although estrogenic effects of certain organochlorine compounds should be easier to detect on the endometrium, we know of no analytic epidemiologic studies of endometrial cancer published to data. We conclude that available data do not indicate that organochlorines will affect the risk of these two cancers in any but the most unusual situation. PMID: 8580305 [PubMed - indexed for MEDLINE] 6089. J Gerontol A Biol Sci Med Sci. 1995 Nov;50 Spec No:78-85. Functional consequences of sarcopenia: effects on thermoregulation. Kenney WL(1), Buskirk ER. Author information: (1)Noll Physiological Research Center, Pennsylvania State University, USA. The loss of skeletal muscle mass with aging (sarcopenia), and related changes in body size and composition, may impact body temperature and thermoregulation in both hot and cold environmental conditions. Sarcopenia alters the thermal properties of the body as a passive system because of differences in water content, and thus specific heat, of muscle and adipose tissue. With respect to active thermoregulation in warm environments, differences in fat-free weight (FFW) can explain more than 80% of the variance in absolute blood volume (BV) among individuals (Allen et al., 1956) and BV, in turn, profoundly influences the cardiovascular responses to exercise and heat stress. For example, a lower BV for a given body weight may explain more than half of the variability in maximal oxygen uptake (VO2max). Thus, as VO2max declines, any absolute task represents a higher relative VO2max (% VO2max) and proportionately greater cardiovascular strain. Because BV is an important determinant of left-ventricular filling pressure, and because older individuals rely more on the Frank-Starling mechanism to increase cardiac output (Q), a lower BV may also be associated with an inability to increase Q appropriately. These effects are particularly important under conditions of heat stress, where a larger increase in Q is necessary to perfuse both skin and active muscle vascular beds. With exposure to cold, age-related changes in body composition affect the insulation provided by the peripheral tissues, especially in the limbs. This results in an increased reliance on peripheral vasoconstriction to minimize heat loss, yet this vasoconstriction is attenuated in older individuals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7493224 [PubMed - indexed for MEDLINE] 6090. J Gerontol A Biol Sci Med Sci. 1995 Nov;50 Spec No:73-7. Sarcopenia in aging humans: the impact of menopause and disease. Poehlman ET(1), Toth MJ, Fishman PS, Vaitkevicius P, Gottlieb SS, Fisher ML, Fonong T. Author information: (1)Department of Medicine, GRECC, Baltimore VA Medical Center, University of Maryland, USA. We examine the association of the menopause transition, congestive heart failure, and Parkinson's disease on body composition and energy expenditure. We present evidence suggesting that the normal menopausal transition is associated with accelerated loss of fat-free mass, a decline in resting metabolic rate, and increased central body fatness. Second, we show that the cardiac cachexia associated with heart failure is partially due to an elevated level of energy expenditure. Despite having a lower quantity of fat-free mass, congestive heart failure patients have a higher resting metabolic rate (approximately 283 kcal/d) for their metabolic size than healthy elderly. The elevated level of resting energy expenditure probably contributes to their unexplained weight loss. Parkinson's patients experience muscular rigidity and tremor which could contribute to inappropriately high levels of energy expenditure and difficulty in maintaining body weight and composition. We examined resting metabolic rate and body composition in eight Parkinson's patients and 34 healthy age-matched controls. Parkinson's patients showed lower levels of fat-free mass (approximately 6 kg), but similar resting metabolic rates (1601 +/- 250 kcal/d) versus healthy controls (1671 +/- 212 kcal/d), suggesting a hypermetabolic state. A re-examination of daily energy needs and the metabolic factors contributing to periods of energy imbalance during the menopausal transition and in several disease states may be a prerequisite to offsetting accelerated sarcopenia. PMID: 7493223 [PubMed - indexed for MEDLINE] 6091. J Gerontol A Biol Sci Med Sci. 1995 Nov;50 Spec No:68-72. Loss of skeletal muscle mass with aging: effect on glucose tolerance. Kohrt WM(1), Holloszy JO. Author information: (1)Washington University School of Medicine, Department of Internal Medicine, St. Louis, USA. It is generally believed that aging results in glucose intolerance. Since skeletal muscle is the major site of glucose uptake following an oral glucose tolerance test (OGTT), it is reasonable to hypothesize that loss of muscle mass with aging causes glucose intolerance. Evidence against this concept comes from extensive data demonstrating the usefulness of the recommended procedures for performing an OGTT. This involves giving 75 g of glucose to all subjects regardless of body weight, and the criteria for categorizing glucose intolerance are the same for all individuals. That this works well, with no evidence that larger people have better glucose tolerance than smaller people, suggests that muscle mass does not usually play a role. Recent studies on humans and rats indicate that aging per se does not result in glucose intolerance. In most of those older people with decreased glucose tolerance, this problem appears to be due to accumulation of abdominal fat with development of insulin resistance. We conclude that the loss of muscle mass with aging does not usually result in glucose intolerance. PMID: 7493222 [PubMed - indexed for MEDLINE] 6092. Am J Clin Nutr. 1995 Nov;62(5 Suppl):1123S-1134S. New model for the regulation of energy balance and adiposity by the central nervous system. Kaiyala KJ(1), Woods SC, Schwartz MW. Author information: (1)Department of Medicine, University of Washington, Seattle, USA. We describe a new model for adiposity regulation in which two distinct classes of peripheral afferent signals modulate neuronal pathways in the brain that control meal initiation, meal termination, and the autonomic outflow influencing the fate of ingested energy. These brain pathways, termed central-effector pathways for the control of energy balance, respond to 1) short-term, situational-, and meal-related signals that are crucial to the size and timing of individual meals, but that are not components of the system serving to regulate adipose stores, and 2) long-term, adiposity-related signals that participate in the negative feedback control of fat stores. Long-term signals, such as the pancreatic hormone insulin, are secreted into the circulation in proportion to energy balance and adipose mass. These signals enter the brain where they influence central-effector pathways, in part by changing the sensitivity of these pathways to short-term signals. Through this mechanism, the central nervous system response to short-term signals is adjusted in proportion to changes in body adiposity, resulting in compensatory changes in food intake and energy expenditure that collectively favor the long-term stability of fat stores. This model provides a comprehensive framework for experimental design and data interpretation in the study of body adiposity regulation. PMID: 7484931 [PubMed - indexed for MEDLINE] 6093. Am J Clin Nutr. 1995 Nov;62(5 Suppl):1067S-1071S. Ethnicity and energy stores. Conway JM(1). Author information: (1)US Department of Agriculture, Beltsville Human Nutrition Research Center, MD 20705-2350, USA. The primary storage form of energy within humans is fat, which accumulates in adipose tissue including the subcutaneous, omental, mesenteric, retroperitoneal, and mammary depots. Although it has been known for some time that the size of these depots varies with sex, age, and physiologic state, it has only recently been suggested that adipose tissue partitioning, and therefore energy storage, may vary among ethnic groups. Indicators of ethnicity include race, place of birth, and culture and traditions. The literature describing energy storage in North American Indians, African Americans, Asian Americans, Mexican Americans, and Pacific Islanders is summarized and data are presented from studies comparing African American and Caucasian (Americans of Northern European descent) obese women. It is proposed that, for the purpose of research, physiologic characteristics and not ethnicity should be the basic factors used to recruit human study volunteers until we obtain mechanisms to discriminate genotype and to relate phenotype to energy storage. PMID: 7484923 [PubMed - indexed for MEDLINE] 6094. Gen Physiol Biophys. 1995 Oct;14(5):383-91. The role of angiotensin II and its receptors in regulation of adipose tissue metabolism and cellularity. Zorad S(1), Fickova M, Zelezna B, Macho L, Kral JG. Author information: (1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia. Angiotensin II exerts its action via at least two distinct receptor subtypes designated AT1 and AT2. AT1 receptors seem to be responsible for most of the known angiotensin II effects while the role of AT2 receptors is not yet clear. Adipocytes of adult rats express exclusively the AT1 subtype. Angiotensin II stimulates prostacyclin release in adult rat adipocytes and in mouse preadipocytes. In the latter prostacyclin release is completely blocked by an AT2 receptor antagonist. Adipocyte angiotensin II receptors seem to be regulated by age and fat mass. Blockade of these receptors by an AT1 antagonist seems to prevent adipose tissue hypertrophy. Moreover, adipose tissue contains all the main components of the renin-angiotensin system such as angiotensinogen, angiotensin converting enzyme, angiotensin II and angiotensin II receptors. Angiotensinogen expression in adipocytes is stimulated by a high fat diet concurrent with enlargement of fat mass, associated with insulin resistance. Angiotensin converting enzyme inhibitors improve insulin sensitivity. Taken together, there is evidence of interaction between insulin and angiotensin II in regulation of adipose tissue metabolism and cellularity. Clarification of these interactions could lead to significant progress in pharmacological treatment of obesity and its comorbidity. PMID: 8786038 [PubMed - indexed for MEDLINE] 6095. Curr Opin Genet Dev. 1995 Oct;5(5):571-6. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Tontonoz P(1), Hu E, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Boston, USA. Peroxisome proliferator activated receptor (PPAR)gamma is an orphan member of the nuclear hormone receptor superfamily and is expressed at high levels specifically in adipose tissue. Recent data suggest that this factor is a central regulator of adipocyte gene expression and differentiation. Fibroblastic cell lines that express PPARgamma ectopically can be induced to differentiate into fat cells by a variety of lipids and lipid-like activators of PPARs, suggesting that this protein may function to link adipogenesis with systemic lipid metabolism. PMID: 8664544 [PubMed - indexed for MEDLINE] 6096. Curr Opin Genet Dev. 1995 Oct;5(5):565-70. C/EBP alpha: a critical regulator of genes governing integrative metabolic processes. Darlington GJ(1), Wang N, Hanson RW. Author information: (1)Baylor College of Medicine, Department of Pathology, Houston, Texas 77030-3498, USA. The role of C/EBPalpha in the developmental expression of a subset of genes governing essential metabolic processes has recently been elucidated using a mutant mouse model that lacks this transcription factor. The mutation results in a failure of the liver and white and brown adipose tissue to develop normal metabolic functions in the immediate perinatal period, including hepatic glycogen synthesis and gluconeogenesis and the synthesis and deposition of triglyceride in adipose tissue. The metabolic alterations are very similar to those of human infants born prior to the third trimester and suggest that many of the medical complications of prematurity are a result of the lack of activation of C/EBPalpha in development. PMID: 8664543 [PubMed - indexed for MEDLINE] 6097. Int J Dev Biol. 1995 Oct;39(5):827-37. Norepinephrine as a morphogen?: its unique interaction with brown adipose tissue. Nedergaard J(1), Herron D, Jacobsson A, Rehnmark S, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm University, Sweden. Norepinephrine is normally considered a neurotransmitter mediating acute metabolic effects in target cells. However, analysis of the regulation of the recruitment process in brown adipose tissue has indicated that norepinephrine may interact with this tissue in such a way that it could be considered a morphogen for this tissue. Besides stimulating the acute thermogenic processes, norepinephrine can induce the expression of tissue-specific proteins such as the uncoupling protein, induce expression of non-tissue specific proteins necessary of the thermogenic processes (e.g. lipoprotein lipase) and repress the expression of non-essential proteins (e.g. subunit c of the ATP-synthase). Upon chronic adrenergic stimulation, the general differentiation state of the tissue is advanced, indicating that the expression of factors with a more general effect on brown adipocyte differentiation is also under adrenergic control. It may even be discussed that norepinephrine may be involved early in the embryonal determination process directing cell clones into this line. The molecular basis for these effects of norepinephrine are only poorly known at present, but adrenergic effects on the expression level of many transcription factors, such as C/EBPalpha, C/EBPbeta, and PPARgamma 2, have been noted. These collective recruitment effects of norepinephrine are well suited to allow the tissue to grow or atrophy in response to the physiological needs of the organism. PMID: 8645567 [PubMed - indexed for MEDLINE] 6098. Baillieres Clin Endocrinol Metab. 1995 Oct;9(4):825-47. Currently available hypolipidaemic drugs and future therapeutic developments. Farmer JA(1), Gotto AM Jr. Author information: (1)Ben Taub General Hospital, Houston, Texas, USA. Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints. PMID: 8593127 [PubMed - indexed for MEDLINE] 6099. Int J Obes Relat Metab Disord. 1995 Oct;19 Suppl 4:S31-40. Integration of the overall response to exercise. Flatt JP(1). Author information: (1)Department of Biochemistry & Molecular Biology, University of Massachusetts Medical Center, Worcester 01655, USA. Physical activity ellicits major perturbations in metabolism during the period of exertion and continues to influence metabolism afterwards as well. The overall effect of these intermittent and extended effects on the balance between energy expenditure and food intake regulation can best be judged by the impact of exercise on the fat mass. Expansion of the adipose tissue mass promotes fat oxidation more than glucose oxidation, but excessive fat accumulation is often necessary to reach the state where fat oxidation becomes commensurate with fat intake. Since the steady-state of weight maintenance is achieved with less body fat in physically active individuals, exercise is a substitute for an enlarged fat mass in bringing about rates of fat oxidation commensurate with fat intake. The increases in energy expenditure induced by expansion of the adipose tissue mass or by physical activity are quantitatively very different. The fact that they are substitutes for each other in relation to body weight maintenance indicates that the critical issue, under conditions where food availability is not a limiting factor, is not overall energy turnover. It appears therefore that it is the effect of exercise on the 24-h RQ that allows the organism to operate with an average RQ as low as the diet's FQ in the presence of less body fat. This also explains why the diet's carbohydrate-to-fat ratio can be an important parameter in shaping the interactions between physical activity and body weight maintenance. PMID: 8581092 [PubMed - indexed for MEDLINE] 6100. Int J Obes Relat Metab Disord. 1995 Oct;19 Suppl 4:S22-30. Role of the endocrine pancreas in control of fuel metabolism by the liver during exercise. Wasserman DH(1), O'Doherty RM, Zinker BA. Author information: (1)Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. The secretions of the pancreas drain into the portal vein just upstream of the liver. This anatomical arrangement is an important component of hepatic function since the pancreatic hormones are key regulators of intermediary metabolism in the liver. In response to moderate-intensity exercise, the secretion of glucagon and insulin from the pancreas generally increase and decrease, respectively. This element of the endocrine response to exercise is critical to the maintenance of glucose homeostasis during exercise. The rise in glucagon and fall in insulin are important for the stimulation of hepatic glycogenolysis. The glucagon response is essential for the exercise-induced increase in gluconeogenesis. In addition, glucagon and insulin are also important to the increase in hepatic fat oxidation during exercise. The fall in insulin enhances the mobilization of NEFA's from adipose tissue and as a result the availability of NEFA's to the liver. The increase in glucagon enhances the oxidation of these NEFA's by stimulating pathways for fat oxidation inside the liver. Hepatic fractional amino acid extraction is increased by glucagon action during exercise. Moreover, the increase in glucagon facilitates the channeling of amino acid carbons to glucose and may play a role in disposal of associated nitrogen. Because of the important roles that glucagon and insulin play, any physiological or pathological condition that affects their secretion or efficacy will impact on the metabolic response to exercise. PMID: 8581091 [PubMed - indexed for MEDLINE] 6101. Int J Obes Relat Metab Disord. 1995 Oct;19 Suppl 4:S18-21. Impact of exercise on adipose tissue metabolism in humans. Arner P(1). Author information: (1)Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden. Mobilization of lipids from adipose tissue during prolonged exercise is of key importance for the supply of energy to the working muscle. During exercise lipid mobilization is mainly stimulated by increased catecholamine production leading to acceleration of the beta-adrenoceptor mediated lipolysis rate in fat cells. This causes breakdown of triglycerides in fat cells to glycerol and free fatty acids, which then are delivered to the blood stream. Decreased insulin production, enhanced adipose tissue blood flow and decreased reesterification of free fatty acids in fat cells contribute to the enhancement of lipid mobilization during strenuous and long-term light exercise. Several additional factors modulate the lipolytic response to exercise as well. Endurance training increases the lipolytic action of catecholamine whereas the opposite occurs during ageing. These alterations are at least in part mediated by changes in the function of the final step in lipolysis activation, the protein kinase-hormone sensitive lipase complex. There are also gender and regional differences in the lipolytic response to exercise. Women mobilize more lipids from the subcutaneous abdominal area than men, whereas a low rate of lipid mobilization from the peripheral subcutaneous areas is observed in either sex. In pathophysiological states, which are associated with catabolism such as fasting and insulin dependent diabetes, there is an enhanced lipolytic response to exercise, because of increased beta-adrenoceptor function. PMID: 8581090 [PubMed - indexed for MEDLINE] 6102. Regul Toxicol Pharmacol. 1995 Oct;22(2):122-42. Progressive application of autoradiography in pharmacokinetic and metabolic studies for the development of new drugs. Shigematsu A(1), Motoji N, Hatori A, Satoh T. Author information: (1)Institute of Whole Body Metabolism, Chiba, Japan. Autoradiographic data of distinctive tissue distributions of 14C atoms obtained by labeling at two different positions of a new drug suggest the metabolic fates of each labeled compound in experimental animals. A more accurate determination of blood-brain barrier (BBB) damage in several regions was indicated by semimicroautoradioluminography, based on no passage of dopamine through the BBB. Autoradioluminography (ARLG) was useful for quantitative validation of whole body autoradiography (WBA) with both ordinal X-ray film and other detectors. In frozen specimens, a good correlation was obtained between the relative radioactivity, photostimulated luminescence (PSL), and liquid scintillation counting (LSC) values in each organ or tissue. However, the correlation was disturbed in lung, brain, bone, and adipose tissue after freeze-drying. In order to be listed in the regulatory items, WBA data must be quantitative as well. The paste-mold method presented here can be used to support WBA data. The thin-layer chromatography (TLC)-ARLG technique and its applications are also presented in this article. A blood concentration-time curve of both the parent compound and its unknown metabolites can be estimated with this technique. PMID: 8577948 [PubMed - indexed for MEDLINE] 6103. Tanpakushitsu Kakusan Koso. 1995 Oct;40(13):1936-41. [Toward the treatment of obesity: role of PPAR gamma in adipogenesis]. [Article in Japanese] Motojima K(1). Author information: (1)Department of Biochemistry, School of Pharmaceutical Sciences, Toho University, Chiba, Japan. PMID: 8524998 [PubMed - indexed for MEDLINE] 6104. Can J Cardiol. 1995 Oct;11 Suppl G:73G-78G. Nutritional regulation of lipoprotein lipase. Olivecrona T(1), Bergö M, Hultin M, Olivecrona G. Author information: (1)Department of Medical Biochemistry and Biophysics, University of Umeå, Sweden. Lipoprotein lipase (LPL) is needed for normal catabolism of triglyceride-rich lipoproteins. In some tissues, notably the adipose tissue, the local LPL activity is an important determinant for how much lipid is taken up. There is regulation of gene expression, but the rapid changes that occur in response to the nutritional state are mediated mainly by post-transcriptional mechanisms. In the fed state, the adipose tissue expresses its full potential for LPL production, as set by the mRNA levels and the rate of protein synthesis. During fasting, LPL activity is suppressed by an unknown post-translational mechanism. In heart, regulation is primarily exerted on the equilibrium between LPL at endothelial sites and LPL in blood, with more endothelial LPL in the fasted state. LPL forms complexes with fatty acids which results in shut-down of lipolysis and detachment of both lipase and lipoproteins from the endothelial site. This provides a molecular coupling device between the cellular metabolic state and the rate of lipoprotein catabolism. There is growing evidence that LPL is a ligand for binding of lipoprotein particles such as chylomicron remnants to cell surfaces and receptors. PMID: 7585297 [PubMed - indexed for MEDLINE] 6105. Physiol Rev. 1995 Oct;75(4):667-88. Insights into cellular energy metabolism from transgenic mice. Koretsky AP(1). Author information: (1)Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. Rapid progress in manipulating the mouse genome now makes it possible to express any cloned gene in virtually any cell type of the mouse. Homologous recombination in embryonic stem cells allows the specific mutation of any gene. These tools are finding widespread application to problems in cell biology and physiology. After a brief description of some of the molecular genetic techniques available for the mouse, the application of transgenic mice to problems in cellular energy metabolism is discussed. The effects of increasing glucose transport on carbohydrate metabolism in muscle and fat are presented. Experiments using a transgenic mouse expressing creatine kinase in liver to understand ATP catabolism and regulation of oxidative phosphorylation are discussed. Finally, mice either lacking or misexpressing different isoforms of creatine kinase have been useful for understanding the detailed role of this important enzyme in cellular energy metabolism. PMID: 7480158 [PubMed - indexed for MEDLINE] 6106. Metabolism. 1995 Oct;44(10 Suppl 4):76-82. Role of insulin and proinsulin in diabetic vascular disease. Wareham NJ(1), Byrne CD, Hales CN. Author information: (1)Department of Community Medicine, University of Cambridge, England. Associations between loss of glucose tolerance, insulin resistance, and ischemic heart disease (IHD) are of great current concern. Considerable controversy and uncertainty relates to the mechanism(s) that underlies these associations. Whilst there is some evidence in prospective studies of an association between hyperinsulinemia and future IHD, it is by no means strong or consistent between different studies. Hypertriglyceridemia is another possible factor involved in the linkage between glucose intolerance and IHD. There is good evidence for an affect of plasma nonesterified fatty acids (NEFA) to increase hepatic output of VLDL. Insulin, contrary to some suggestions, acts to lower plasma VLDL by actions directly on hepatic output and activation of adipose tissue lipoprotein lipase, and indirectly via the hormones affect of lowering plasma NEFA. Glycosylation and oxidation of lipoproteins may enhance their atherogenic potential. It is highly probable that procoagulant changes are also important processes predisposing to IHD. Associations between plasminogen activator inhibitor-1 and insulin, intact and 32,33 split proinsulin hypertriglyceridemia, and insulin resistance have been reported, but a unifying hypothesis explaining these links remains elusive. Epidemiological studies now repeated in a number of centers have shown links between infant mortality and birth weight and risk of IHD, and between birth weight and risk of impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). It has been proposed, therefore, that impairment of fetal and infant growth may underlie the associations between loss of glucose tolerance and risk of IHD. Animal models form the basis of much current research to test this concept. PMID: 7476316 [PubMed - indexed for MEDLINE] 6107. Metabolism. 1995 Oct;44(10 Suppl 4):45-9. The role of growth hormone/insulin-like growth factors in adipocyte differentiation. Wabitsch M(1), Hauner H, Heinze E, Teller WM. Author information: (1)Department of Pediatrics I, University of Ulm, Germany. Growth of the adipose tissue results from both the enlargement of mature adipocytes and the formation of new adipocytes from adipocyte precursor cells. The differentiation process of adipocyte precursor cells is controlled by a variety of hormones. Clinical observations indicate that growth hormone (GH) and insulin-like growth factor I (IGF-I) are able to influence the growth of the adipose organ. Recent in vitro studies using cultures of clonal and primary adipocyte precursor cells have elucidated the role of GH and IGF-I in adipocyte differentiation. From the studies it can be concluded that GH is able to enlarge the pool of adipocyte precursor cells capable of differentiating into mature adipocytes, which occurs under the control of other adipogenic hormones. However, due to its metabolic action, GH is also able to reduce the volume of mature adipocytes and thus the net result of its biological action is aimed at reducing body fat. IGF-I stimulates the differentiation process by inducing critical cell divisions of adipocyte precursor cells necessary for their differentiation. IGF-I, which is known to be regulated by GH and several nutritional factors, may exert its effects in the adipose tissue in an autocrine/paracrine and endocrine way. This review summarizes the results of recent studies investigating the role of GH and IGF-I in adipocyte differentiation. PMID: 7476311 [PubMed - indexed for MEDLINE] 6108. Metabolism. 1995 Oct;44(10 Suppl 4):103-7. Fuel metabolism in growth hormone-deficient adults. Jørgensen JO(1), Møller N, Wolthers T, Møller J, Grøfte T, Vahl N, Fisker S, Orskov H, Christiansen JS. Author information: (1)Department of Internal Medicine (Endocrinology and Diabetes), Aarhus University Hospital, Denmark. Apart from being a stimulator of longitudinal growth, growth hormone (GH) regulates fuel metabolism in children and adults. A halfmark is mobilization of lipids, which involves an inhibition of lipoprotein lipase activity in adipose tissue and activation of the hormone sensitive lipase. Suppression of basal glucose oxidation and resistance to insulin are other important effects. This may cause concern during GH substitution in GH-deficient adults, some of whom may present with insulin resistance due to concomitant abdominal obesity. However, there are data to suggest that the GH-induced reduction in fat mass and increase in lean body mass may offset the insulin antagonistic actions of the hormone. The nitrogen-retaining effects of GH seem to involve a direct stimulation of protein synthesis in addition to secondary effects such as generation of insulin-like growth factor-I (IGF-I), hyperinsulinemia, and promotion of lipolysis. Thus, during periods of substrate affluence, GH acts in concert with insulin and IGF-I to promote protein anabolism. Postabsorptively, GH is primarily lipolytic and thereby indirectly protein-sparing. This effect becomes further accentuated with more prolonged fasting. In that sense, GH is unique by its preservation of protein during both feast and famine. These fuel metabolic effects add merit to the principle of GH substitution in hypopituitary adults. PMID: 7476301 [PubMed - indexed for MEDLINE] 6109. Clin Dermatol. 1995 Sep-Oct;13(5):493-8. Lymphatics and adipose tissue. Ryan TJ(1). Author information: (1)Dermatology Department, Oxford Radcliffe Hospital, United Kingdom. PMID: 8665460 [PubMed - indexed for MEDLINE] 6110. J Anim Sci. 1995 Sep;73(9):2804-19. Regulation of organic nutrient metabolism during transition from late pregnancy to early lactation. Bell AW(1). Author information: (1)Department of Animal Science, Cornell University, Ithaca, NY 14853-4801, USA. Conceptus energy and nitrogen demands in late pregnancy are mostly met by placental uptake of maternal glucose and amino acids. The resulting 30 to 50% increase in maternal requirements for these nutrients is met partly by increased voluntary intake and partly by an array of maternal metabolic adaptations. The latter include increased hepatic gluconeogenesis from endogenous substrates, decreased peripheral tissue glucose utilization, increased fatty acid mobilization from adipose tissue, and, possibly, increased amino acid mobilization from muscle. Within 4 d of parturition, mammary demands for glucose, amino acids, and fatty acids are several-fold those of the pregnant uterus before term. Even unusual postparturient increases in voluntary intake cannot satisfy this increased nutrient demand. Therefore, rates of hepatic gluconeogenesis and adipose fat mobilization are greatly accelerated. Concomitant changes in amino acid metabolism include increased hepatic protein synthesis and, possibly, decreased amino acid catabolism, and increased peripheral mobilization of amino acids. Insulin resistance in adipose tissue and muscle, developed during late pregnancy, continues postpartum; adipose lipolytic responsiveness and sensitivity to adrenergic agents are increased postpartum beyond their levels during late pregnancy. Before parturition, these homeorhetic adjustments may be coordinated with lactogenesis by increased secretion of estradiol and prolactin. Their amplification and reinforcement at and soon after parturition may be regulated mostly by somatotropin. PMID: 8582872 [PubMed - indexed for MEDLINE] 6111. Obes Res. 1995 Sep;3 Suppl 2:187S-194S. Pathophysiology and pathogenesis of visceral fat obesity. Matsuzawa Y(1), Shimomura I, Nakamura T, Keno Y, Kotani K, Tokunaga K. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. Based on the analysis of fat distribution by computed tomography (CT) scans, the classification scheme for obesity should include visceral fat obesity in which fat accumulation is predominant in the intra-abdominal cavity. Obese subjects with visceral fat accumulation more frequently demonstrate impairment of glucose and lipid metabolism than those with subcutaneous fat accumulation. We have shown that visceral fat obesity is present in almost 90% of obese patients with ischemic heart disease. Even in non-obese subjects, visceral fat accumulation is correlated with glucose intolerance, hyperlipidemia and hypertension. Forty percent of non-obese subjects with coronary artery disease (CAD) had increased visceral fat. In non-obese subjects, visceral fat area assessed by abdominal CT at the level of the umbilicus correlates with metabolic risk factors, whereas in obese subjects the visceral fat area to subcutaneous fat area ratio provides a more significant correlation. From clinical and basic investigations, aging, sex hormones, excess intake of sucrose and lack of physical exercise have been suggested to be determinants for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) has been shown to have high activities of both lipogenesis and lipolysis, its accumulation can induce high levels of free fatty acids, a product of lipolysis, in portal circulation which go into the liver. Excess free fatty acids may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. Thus we propose a disease entity, visceral fat syndrome, which may increase susceptibility to atherosclerosis due to multiple risk factors induced by visceral fat accumulation. PMID: 8581775 [PubMed - indexed for MEDLINE] 6112. Obes Res. 1995 Sep;3 Suppl 2:179S-186S. Susceptibility to development of central adiposity among populations. Fujimoto WY(1), Bergstrom RW, Boyko EJ, Leonetti DL, Newell-Morris LL, Wahl PW. Author information: (1)Department of Medicine, University of Washington, Seattle, USA. There is good evidence that central (visceral) adiposity is important in the development of the insulin resistance or metabolic syndrome (obesity, hyperinsulinemia, dyslipidemia, glucose intolerance, hypertension, and coronary heart disease). It is proposed that some non-Caucasian populations are especially susceptible to development of this syndrome, and that lifestyle changes may play important etiologic roles. We postulate that this is due to the presence in these populations of a genetic predisposition to weight gain, perhaps related to a "thrifty" genotype, leading to the concentration of weight gain in visceral fat depots, when there is exposure to conditions associated with westernization. PMID: 8581774 [PubMed - indexed for MEDLINE] 6113. Obes Res. 1995 Sep;3 Suppl 2:173S-178S. Abnormalities of fuel utilization as predisposing to the development of obesity in humans. Schutz Y(1). Author information: (1)Institute of Physiology, Faculty of Medicine, University of Lausanne, Switzerland. A number of recent investigations in man have demonstrated that a low ratio of fat to carbohydrate oxidation (i.e., a high respiratory quotient or RQ) was associated with actual and/or subsequent body weight gain in obese non-diabetic Pima Indians, in American men of various ages and in post-obese European women investigated shortly after the cessation of a hypocaloric diet. It is well known that numerous exogenous and endogenous factors influence the RQ at rest such as: the level of feeding (positive vs. negative energy balance), the composition of food eaten (high vs. low carbohydrate), the size of the glycogen stores, the amount of adipose tissue as well as genetic factors. It should be stressed that some nutritional situations can co-exist during which a low ratio of fat to carbohydrate is observed (i.e., a high RQ) despite weight loss. Furthermore, in most studies mentioned above, the low fat to carbohydrate oxidation ratio explains less than 10% of the variance in weight gain, suggesting that numerous additional factors also play a substantial role in the onset of weight gain. It is concluded that: 1) a low fat to carbohydrate oxidation ratio or an abnormal fat oxidation is difficult to define quantitatively since it is largely influenced by the energy level and the composition of the diet.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8581773 [PubMed - indexed for MEDLINE] 6114. Sports Med. 1995 Sep;20(3):189-98. Thyroid status and exercise tolerance. Cardiovascular and metabolic considerations. McAllister RM(1), Delp MD, Laughlin MH. Author information: (1)Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, USA. Both hypo- and hyperthyroidism are characterised by exercise intolerance. In hypothyroidism, inadequate cardiovascular support appears to be the principal factor involved. Insufficient skeletal muscle blood flow compromises exercise capacity via reduced oxygen delivery, and endurance through decreased delivery of blood-borne substrates. The latter effect results in increased dependence on intramuscular glycogen. Additionally, decreased mobilisation of free fatty acids from adipose tissue and, consequently, lower plasma free fatty acid levels compound the problem of reduced lipid delivery to active skeletal muscle in the hypothyroid state. In contrast, cardiovascular support is enhanced in hyperthyroidism, implicating other factors in exercise tolerance. Greater reliance on muscle glycogen appears to be the primary reason for decreased endurance. Biochemical changes with hyperthyroidism that would favour enhanced flux through glycolysis may account for this dependence on glycogen. Deviations from normal thyroid function, and the ensuing exercise tolerance, require appropriate medical therapy to attain euthyroid status. PMID: 8571001 [PubMed - indexed for MEDLINE] 6115. Am J Clin Pathol. 1995 Sep;104(3):306-12. Amyloid goiter. A clinicopathologic study of 14 cases and review of the literature. Hamed G(1), Heffess CS, Shmookler BM, Wenig BM. Author information: (1)Department of Pathology, Washington Hospital Center, Washington, DC, USA. The authors report the clinicopathologic features of 14 cases of amyloid goiter (AG). Eleven patients were males and three females with ages ranging from 23 to 75 years (median, 54 years). Eight patients had secondary amyloidosis and six had primary amyloidosis. Nine cases were identified at autopsy. In symptomatic patients (n = 5), the clinical presentation included a nontender, rapidly enlarging neck mass with associated dysphagia, dyspnea or hoarseness. Clinical or laboratory evaluation failed to detect evidence of thyroid dysfunction. The histologic appearance of the thyroid predominantly consisted of diffuse amyloid deposition surrounding thyroid follicles. In two cases, a nodular pattern of amyloid deposition was seen resulting in compression and distortion of the follicular architecture. Areas of mature adipose tissue and focal lymphocytic thyroiditis with or without foreign-body type-giant cells were seen in approximately one third of the cases. Confirmation of amyloid was made by the presence of congophilia and apple-green birefringence under polarized-light microscopy. Immunohistochemical evaluation demonstrated the presence of amyloid A immunoreactivity. No Immunoreactivity was seen with calcitonin or thyroglobulin. Fine-needle aspiration may facilitate the diagnosis, as occurred in one the patients. In symptomatic patients, thyroidectomy is warranted to alleviate pressure symptoms. PMID: 7677120 [PubMed - indexed for MEDLINE] 6116. Early Hum Dev. 1995 Aug 18;42(3):169-83. Perinatal thermogenesis. Gunn TR(1), Gluckman PD. Author information: (1)Department of Paediatrics, School of Medicine, University of Auckland, New Zealand. The rapid initiation of thermogenesis is crucial for the survival of newborn infants. At birth the fetus must adapt to cooling, increased oxygenation and separation from the placenta. An experimental approach in the chronically instrumental fetal sheep of 'simulated birth in utero' allowed the evaluation of each of these stimuli sequentially. Cooling stimulated shivering, cardiovascular and endocrine responses but not nonshivering thermogenesis (NST). Ventilation of the cooled fetus with oxygen caused only modest NST which was not altered by an infusion of triiodothyronine. Occluding the umbilical cord was followed by a rapid substantial rise in NST which was maintained until the placental circulation was re-established. Thus the placenta is secreting factors into the fetal circulation which inhibit the ability of the brown adipose tissue to respond to either hormonal or neural stimuli. Placental prostaglandin E2 and probably adenosine are tonic inhibitors of thermogenesis in utero. Effective thermogenesis after birth requires the combination of separation from the placental inhibitors of lipolysis, increased oxygenation from breathing and the stimulation of cutaneous cold receptors. PMID: 7493585 [PubMed - indexed for MEDLINE] 6117. J Hypertens Suppl. 1995 Aug;13(2):S73-6. Risk factors for non-insulin-dependent diabetes mellitus. Haffner SM(1). Author information: (1)Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7873, USA. RISK FACTORS AND PREDICTORS: The risk factors for non-insulin-dependent diabetes mellitus (NIDDM) include age, overall adiposity, an adverse body fat distribution, adverse glucose and insulin concentrations, insulin resistance and lack of physical exercise. The strongest predictors of NIDDM appear to be metabolic factors, including impaired glucose tolerance and insulin resistance.TREATMENT: Pharmacological agents that improve insulin sensitivity are being tested in multicenter clinical trials. In patients with a high risk of NIDDM, it seems prudent to avoid the use of pharmacologic agents that increase insulin resistance. PMID: 8576792 [PubMed - indexed for MEDLINE] 6118. Biochem Soc Trans. 1995 Aug;23(3):611-5. Perilipin: unique proteins associated with intracellular neutral lipid droplets in adipocytes and steroidogenic cells. Londos C(1), Brasaemle DL, Gruia-Gray J, Servetnick DA, Schultz CJ, Levin DM, Kimmel AR. Author information: (1)Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-2715, USA. For several reasons it seems reasonable to suspect that perilipins participate in lipid hydrolysis. First, they are located at the lipid droplet surface, the presumed site of HSL and cholesteryl esterase action. Secondly, they are polyphosphorylated by PKA in concert with lipid hydrolysis. Finally, these proteins appear to be expressed primarily, if not solely, in adipocytes and steroidogenic cells, cells in which lipid hydrolysis is stimulated by cyclic AMP and mediated by HSL or cholesteryl esterase(s), whereas other cells that contain abundant neutral lipid depositions contain no perilipin [13]. Interestingly, these closely related hydrolases share no homology with other mammalian lipases [3]. Although such attributes provide a link between perilipin and lipid hydrolysis, we have no evidence that perilipins participate directly in, or are necessary for, lipid catabolism. The basis for the strong affinity between the perilipins and neutral lipids is unknown. Clearly, lipids and perilipins are tightly linked, as evidenced by selective targeting of epitope-tagged perilipin to lipid droplets and by the paradoxical appearance of lipid droplets in pre-adipocytes transfected with a sense perilipin A construct. Indeed, in differentiating adipocytes the earliest lipid depositions are associated with perilipins, and restriction of perilipin synthesis with anti-sense constructs may impede lipid formation and deposition. It remains to be determined if, in the normal course of events, perilipins are directed toward lipid depositions or if lipids are transported to perilipin foci. Whatever the temporal sequence, the result is that neutral lipids are encased in perilipin-bounded droplets.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8566427 [PubMed - indexed for MEDLINE] 6119. Clin Invest Med. 1995 Aug;18(4):303-11. The mechanism of alpha-glucosidase inhibition in the management of diabetes. Bischoff H(1). Author information: (1)Institute for Cardiovascular and Arteriosclerosis Research, Bayer AG, Wuppertal, Germany. The development of the alpha-glucosidase inhibitor acarbose provides a new approach in the management of diabetes. By competitive and reversible inhibition of intestinal alpha-glucosidases, acarbose delays carbohydrate digestion, prolongs the overall carbohydrate digestion time, and thus reduces the rate of glucose absorption. After oral administration of acarbose, the postprandial rise in blood glucose is dose-dependently decreased, and glucose-induced insulin secretion is attenuated. Because of diminished postprandial hyperglycemia and hyper-insulinemia by acarbose, the triglyceride uptake into adipose tissue, hepatic lipogenesis, and triglyceride content are reduced. Therefore, acarbose treatment not only flattens postprandial glycemia, due to the primary and secondary pharmacodynamic effects, but also ameliorates the metabolic state in general. In diabetic animals, acarbose reduced urinary glucose loss, the blood glucose area under the curve, and prevented the decrease in skeletal muscle GLUT4 glucose transporters. As a consequence of the reduced mean blood glucose area under the curve, the amount of protein nonenzymatically glycated was diminished, as was the formation of advanced glycation end-products (AGEs). The prevention of basement membrane glycation and thickening in various tissues indicated that acarbose treatment of diabetic animals produced beneficial effects against the development of nephropathy, neuropathy, and retinopathy. Thus, the alpha-glucosidase inhibitor acarbose may have the potential to delay or possibly prevent the development of diabetic complications. PMID: 8549017 [PubMed - indexed for MEDLINE] 6120. Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S195-200. Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus. Kashiwagi A(1). Author information: (1)Third Department of Medicine, Shiga University of Medical Science, Japan. A typical clinical feature of patients with fasting hyperglycemia in diabetes is well correlated with accelerated hepatic glucose production which is determined by elevated FFA-induced gluconeogenesis. Therefore, to treat fasting hyperglycemia, inhibition of both FFA release and fatty acid oxidation in the liver may be efficient modalities of treatment. (1) Inhibitor of FFA release: a novel selective adenosine A1 agonist, SDZ WAG 994 is a potent inhibitor of adenosine deaminase-induced lipolysis. Twenty-three-week old, male GK rats showing glucose intolerance were treated with WAG 994 (1000 micrograms/kg body weight) for 16 days. Plasma glucose level at 0 time in WAG group was significantly (P < 0.01) less than that of the control. Both plasma FFA and triglyceride concentrations also decreased by 54% and 74%, respectively (vs. control GK rats). (2) Inhibition of hepatic fatty acid oxidation: beta-aminobetaine (emeriamine) is a water-soluble carnitine analog and inhibition of CPT-1 in isolated hepatocytes is 100 times more sensitive than that in isolated cardiocytes and it suppresses both gluconeogenesis and ketogenesis by 60-80%. However, it may be possible that this drug may induce fat deposition in the liver. An inhibitor of elevated fatty acid release from adipose tissue in concomitant with liver-specific and reversible inhibition of fatty acid oxidation may be an effective agent with hypoglycemic and hypolipidemic action for the treatment of diabetes mellitus. PMID: 8529514 [PubMed - indexed for MEDLINE] 6121. Ann Med. 1995 Aug;27(4):435-8. Differences in lipolysis between human subcutaneous and omental adipose tissues. Arner P(1). Author information: (1)Department of Medicine, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden. Hydrolysis of triglycerides to fatty acids and glycerol in fat cells (lipolysis) is of importance for the control of lipid and carbohydrate metabolism. This process is regulated by several hormones and parahormones acting on cyclic AMP formation or breakdown, which in turn influences the activity of hormone sensitive lipase. The latter enzyme stimulates hydrolysis of triglycerides in fat cells. It is well established through in vivo and in vitro investigations that there are regional variations in the lipolytic activity of human adipose tissue. The rate of lipolysis is low in the subcutaneous femoral/gluteal region, intermediate in the subcutaneous abdominal region and high in the visceral (i.e. omental) region. In non-obese subjects the differences between the subcutaneous and visceral fat depots may be explained by site variations in the function of receptors for insulin, catecholamines and adenosine. The lipolytic beta 1 and beta 2 adrenoceptors, as well as the newly discovered beta 3, are most active in the visceral fat cells. The antilipolytic insulin receptors, alpha 2 adrenoceptors and adenosine receptors are most active in the subcutaneous fat cells. In subjects with upper-body obesity the regional variations in the action of catecholamines on lipolysis are further enhanced. Decreased action of beta 2-adrenergic receptors and increased activity of alpha 2-adrenergic adrenoceptors in combination with defects in hormone sensitive lipase function inhibits the lipolytic effect of catecholamines in subcutaneous fat cells whereas increased activity of beta 3-adrenergic receptors and decreased activity of alpha 2 adrenoceptors augment the lipolytic response in visceral fat cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8519504 [PubMed - indexed for MEDLINE] 6122. Z Lymphol. 1995 Aug;19(1):1-11. [Lipedema]. [Article in German] Herpertz U(1). Author information: (1)Feldbergklinik Dr. Asdonk GmbH. The "Lipedema" or "Fatedema" is conditioned by a slight mechanical obstruction of the small lymphatic vessels by the increasing pressure of the growing fat tissue. This lymphostasis in a normal lymphatic vessel system arises only with women and always symmetrically and conducts to typical complaints. Therapeutically, apart from loss in weight, only lymph drainage therapy is in a position to remove the complaints of edema. PMID: 7571788 [PubMed - indexed for MEDLINE] 6123. Nutr Rev. 1995 Aug;53(8):230-1. A regulatory pathway of thermogenesis in brown fat through retinoic acid. Wolf G(1). Author information: (1)University of California at Berkeley, USA. Thermogenesis in brown adipose tissue is achieved by the enzyme that uncouples the respiratory chain from oxidative phosphorylation. This enzyme is regulated by the sympathetic nervous system and, as recently discovered, by transcriptional regulation through retinoic acid (RA). Thus, RA is involved in heat production and, hence, in the regulation of energy balance. PMID: 7501309 [PubMed - indexed for MEDLINE] 6124. Vnitr Lek. 1995 Aug;41(8):555-9. [Regulation of HDL lipoprotein plasma levels in relation to atherogenesis]. [Article in Czech] Růzek V(1). Author information: (1)Interní klinika FN, Praha-Motol. There is no doubt nowadays on the importance of HDL lipoproteins in atherogenesis. In the submitted review the author presents information on the regulation of HDL lipoprotein plasma levels and their sub-classes. First he deals with metabolic relations, in particular synthesis and catabolism of HDL lipoproteins. He mentions then factors which influence plasma levels of HDL lipoproteins and their sub-classes--external and internal factors. As to internal factors the author discusses genetic predisposition, sex, age, obesity, adipose tissue distribution; as to external factors the effect of diet, exercise, alcohol, smoking and drugs. PMID: 7483341 [PubMed - indexed for MEDLINE] 6125. Dtsch Med Wochenschr. 1995 Jul 7;120(27):971-5. [Through thick and thin: current aspects of obesity research]. [Article in German] Hamann A(1), Matthaei S, Greten H. Author information: (1)Medizinische Kernklinik und Poliklinik, Universitätskrankenhaus Eppendorf, Hamburg. PMID: 7607063 [PubMed - indexed for MEDLINE] 6126. Cell Signal. 1995 Jul;7(5):445-55. Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family). Manganiello VC(1), Taira M, Degerman E, Belfrage P. Author information: (1)Pulmonary/Critical Care Medicine Branch, NHLBI, NIH, MD 20892, USA. Seven different but related cyclic nucleotide phosphodiesterase (PDE) gene families have been identified. Type III cGMP-inhibited (cGI) PDEs, the PDE3 gene family, are found in many tissues. cGI PDEs exhibit a high affinity for both cAMP and cGMP, and are selectively and relatively specifically inhibited by certain agents which augment myocardial contractility, promote smooth muscle relaxation and inhibit platelet aggregation. Adipocyte, platelet, and hepatocyte cGI PDE activities are regulated by cAMP-dependent phosphorylation. Insulin-induced phosphorylation/activation of adipocyte and hepatocyte cGI PDEs is thought to be important in acute regulation of triglyceride and glycogen metabolism by insulin. Two distinct cGI PDE subfamilies, products of distinct but related genes, have been identified. They exhibit the domain structure common to PDEs with a carboxyterminal region, conserved catalytic domain and divergent regulatory domain. In their catalytic domains cGI PDEs contain a 44 amino acid insertion not found in other PDE families. The expression of cGIP1 and cGIP2 mRNAs differs in different rat tissues, suggesting distinct functions for the two cGI PDE subfamilies, i.e., cGIP1 in adipose tissue, liver, testis and cGIP2 in myocardium, platelets and smooth muscle. PMID: 8562305 [PubMed - indexed for MEDLINE] 6127. Obes Res. 1995 Jul;3(4):361-9. Does thermoregulatory feeding occur in newborn infants? A novel view of the role of brown adipose tissue thermogenesis in control of food intake. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, Faculty of Medicine, University of Ottawa, Ontario, Canada. The physiological significance of the extensive deposits of brown adipose tissue (BAT) in newborn human infants has been the subject of much experimentation and discussion. Because of its large thermogenic capacity, its function has usually been viewed as preparing the infant for producing heat in response to cold exposure at birth. Newborn infants are indeed capable of precise thermoregulation for a limited time over a rather limited range of ambient temperatures, from thermoneutrality (32-34 degrees C) down to common "room" temperatures (24-28 degrees C). During such mild "cold-exposure", in response to a decrease in their skin temperature, their sympathetic nervous system activity increases, and they can more than double their resting metabolic rate, principally by thermogenesis in their BAT. This review puts forward an entirely new role for BAT thermogenesis in the cyclic feeding pattern of newborn infants during their first months of life. BAT thermogenesis is proposed to be an integral element in a physiological thermoregulatory feeding control mechanism in which extended periods of very gradual cooling are interspersed with episodes of increased sympathetic nervous system activity, increased heating via BAT thermogenesis, arousal, and feeding. The cry with which the baby attracts its mother's attention is an integral part of the mechanism, as is the nutritive suckling reflex and the behavior of the mother. Initiation of feeding is attributed to a transient dip in blood glucose concentration that is due to stimulation of glucose utilization in the BAT. Termination of feeding is attributed to the high temperature brought about by the stimulated BAT thermogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8521153 [PubMed - indexed for MEDLINE] 6128. Int J Obes Relat Metab Disord. 1995 Jul;19(7):435-42. Techniques for the measurement of white adipose tissue metabolism: a practical guide. Arner P(1). Author information: (1)Karolinska Institute, Department of Medicine, Huddinge Hospital, Sweden. A number of old and new techniques to study various aspects of white adipose tissue metabolism in vivo and in vitro are discussed. It is possible to determine lipolysis rates in vivo with tracer techniques using glycerol or fatty acids labelled with stable or radioactive isotopes. These methods allow the determination of whole body lipolysis rates but are not valuable for the investigations of regional variations in lipolysis. When combined they permit a calculation of the rate of re-esterification of free fatty acids. The vein draining abdominal subcutaneous adipose tissue can be cannulated in humans. By this method substrate turnover can be determined in vivo over the cannulated adipose region. With microdialysis it is possible to study local metabolism in vivo in different adipose tissue regions. At the same time it is possible to locally manipulate the tissue with metabolically active pharmacological substances. A number of in vitro methods to determine glucose transport in isolated fat cells are developed. The most accurate one uses 3-O-methyl glucose as tracer. These methods can be combined with studies of the further metabolism of glucose to lipids, lactate and carbon dioxide using simple (usually radioactive) methods. Lipolysis as well as release and re-esterification of free fatty acids can be investigated in detailed in vitro with sensitive techniques based on luminescence. Finally, triglyceride turnover and partial metabolism of acylglycerols can be investigated in vitro with a double isotope technique. PMID: 8520631 [PubMed - indexed for MEDLINE] 6129. Breast Cancer Res Treat. 1995 Jul;35(1):91-5. Essential fatty acid consumption and risk of breast cancer. Godley PA(1). Author information: (1)Department of Medicine, University of North Carolina, Chapel Hill 27599-7305, USA. Animal and ecological studies of essential fatty acids suggest that omega-3 fatty acids found in fish oils and omega-6 fatty acids found in vegetable oils may be playing a role in the etiology of breast cancer. Essential fatty acids may modulate breast cancer risk by interacting with prostaglandins, which have immunosuppressive and platelet aggregative capabilities. The fatty acid composition of adipose tissue reflects the dietary consumption of essential fatty acids over a period of years. Biochemical techniques have been used in epidemiological studies to accurately estimate fatty acid consumption. However, analytical epidemiology studies that have used biochemical measurements of adipose tissue fatty acid composition, have not supported a relationship between consumption of these essential fatty acids and breast cancer risk. PMID: 7612909 [PubMed - indexed for MEDLINE] 6130. Cell Transplant. 1995 Jul-Aug;4(4):401-10. Endothelial cell transplantation. Williams SK(1). Author information: (1)Department of Surgery, University of Arizona Health Sciences Center, Tucson 85724, USA. Endothelial cells line the lumenal surface of all elements of the vascular system. These cells exhibit numerous metabolic functions necessary for the maintenance of homeostasis. The critical role of endothelium in maintaining normal blood vessel function is exemplified by the poor clinical performance of small diameter polymeric vascular grafts which fail due, in part, to the lack of a functional endothelium on the lumenal surface. Extensive research has explored the potentiality of transplanting endothelial cells onto polymeric vascular grafts to improve graft function. Several critical issues have been explored including the source of endothelial cells for transplantation, the interaction of endothelium with polymers and the healing process of endothelial cell transplanted grafts. The future of endothelial cell transplantation will also include the use of these cells as vehicles for genetic engineering. PMID: 7582571 [PubMed - indexed for MEDLINE] 6131. J Occup Environ Med. 1995 Jul;37(7):856-61. High-density lipoprotein-cholesterol: determining hygienic factors for intervention. Anzalone DA(1), Anzalone FL, Fos PJ. Author information: (1)HRS Monroe County Public Health Unit, Naval Medical Clinic of the United States Navy. Erratum in J Occup Environ Med 1995 Sep;37(9):1121. Current guidelines of the Adult Treatment Panel on High-Density Lipoprotein-Cholesterol (HDL-C) emphasize the protective effect of HDL-C in reducing one's risk for coronary heart disease and recommend that individuals with serum HDL-C levels below 35 mg/dL utilize hygienic means to raise them. A cross-sectional study was performed to examine the relationship of the hygienic factors obesity (measured by percent body fat and body mass index), smoking, and aerobic exercise to HDL-C. The sample, consisting of 1701 male employees of a large aerospace hardware assembly plant, were evaluated by health risk appraisal and anthropometric measurement. Regression analysis revealed a significant negative relationship between body mass index, percent body fat, age, smoking and the level of HDL-C in the blood. Alcohol consumption was directly related to HDL-C, and Whites had a lower HDL-C than all other races combined. Aerobic exercise was not found to be significantly related to HDL-C. A model (multiple R2 = .1136) consisting of age, race, alcohol consumption, smoking, and body mass index fit the data well. These findings justify weight management and smoking cessation interventions for raising HDL-C. However, the role of aerobic exercise was not supported in this study as a means of raising HDL-C. Future studies should use maximum oxygen consumption as a measure of aerobic capacity, which may be a better indicator of aerobic exercise level. The role of medication and genetic and dietary factors in HDL-C management should also be explored. Although findings from this study support smoking cessation and weight management interventions, longitudinal research is needed to determine the most effective strategy for HDL-C management. PMID: 7552471 [PubMed - indexed for MEDLINE] 6132. Behav Brain Res. 1995 Jul-Aug;69(1-2):55-63. Sleep deprivation in the rat by the disk-over-water method. Rechtschaffen A(1), Bergmann BM. Author information: (1)Department of Psychiatry, University of Chicago, IL 60637, USA. Chronic sleep deprivation may be required to reveal the most serious physiological consequences of sleep loss, but it usually requires strong stimulation which can obscure the interpretation of effects. The disk-over-water method permits chronic sleep deprivation of rats with gentle physical stimulation that can be equally applied to yoked control rats. A series of studies with this method has revealed little or no pathology in the control rats. The deprived rats show a reliable syndrome that includes temperature changes (which vary with the sleep stages that are lost); heat seeking behavior; increased food intake; weight loss; increased metabolic rate; increased plasma norepinephrine; decreased plasma thyroxine; an increased triiodothyronine-thyroxine ratio; and an increase of an enzyme which mediates thermogenesis by brown adipose tissue. The temperature changes are attributable to excessive heat loss and an elevated thermoregulatory setpoint, both of which increase thermoregulatory load, and the other changes are interpretable as responses to this increased load. This pattern indicates that sleep serves a thermoregulatory function in the rat. The sleep deprived rats also show stereotypic ulcerative and hyperkeratotic lesions localized to the tail and plantar surfaces of the paws, and they die within a matter of weeks; the mediation of these changes is unresolved. PMID: 7546318 [PubMed - indexed for MEDLINE] 6133. Ann N Y Acad Sci. 1995 Jun 30;758:297-313. Transgenic mouse models of disease: altering adipose tissue function in vivo. Ross SR(1), Graves RA, Choy L, Soleveva V, Spiegelman BM. Author information: (1)Department of Biochemistry, University of Illinois School of Medicine, Chicago 60612, USA. PMID: 7625699 [PubMed - indexed for MEDLINE] 6134. J Nutr. 1995 Jun;125(6 Suppl):1783S-1789S. Proposed mechanisms for the regulation of growth hormone action in poultry: metabolic effects. Vasilatos-Younken R(1). Author information: (1)Department of Poultry Science, Pennsylvania State University, University Park 16802, USA. Growth hormone (GH) administration to nonruminant red meat animals markedly alters carcass composition so that dramatic reductions in adipose tissue accretion and enhancement of lean tissue growth occur. These repartitioning effects of GH in the pig are reported to reflect antagonism of the lipogenic effect of insulin on adipose tissue, the primary site of fatty acid synthesis in this species, so that glucose disposal and utilization by adipose tissue are markedly reduced, and substrate availability to muscle is increased. In poultry, a significant positive response to GH administration is not consistently achieved, and factors such as posthatch period of development and the pattern of tissue exposure to GH are important determinants of the response to GH enhancement. This may relate to the status of target tissue GH receptors that appear subject to down regulation in the adult chicken. Sensitivity of the bird to the appetite-suppressive effects of GH and interaction between this effect and energy intake have recently been demonstrated and need to be further explored. Growth hormone clearly influences hepatic lipogenesis and net lipid deposition in the broiler chicken. However, future research emphasis on the regulation of GH receptor binding activity and gene expression and their relationship to GH action, as well as on newer components of the GH axis such as GH-binding proteins, will help to clarify controlling mechanisms in poultry. PMID: 7782946 [PubMed - indexed for MEDLINE] 6135. J Nutr. 1995 Jun;125(6 Suppl):1777S-1782S. Species variation in mechanisms for modulation of growth by beta-adrenergic receptors. Mersmann HJ(1). Author information: (1)Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Beta-adrenergic agonists have been fed to avian and mammalian species to modulate growth. Such treatment produces increased rate of gain, decreased feed consumption, increased skeletal muscle and decreased fat accretion. There is good evidence for the inhibition of adipose tissue lipogenesis and stimulation of lipolysis as well as stimulation of skeletal muscle protein synthesis and inhibition of degradation. Other effects include increased blood flow and modulation of plasma concentration of various hormones. The degree to which each of these effects is observed varies considerably between experiments. Some of the diversity may be explained by species and/or tissue differences in distribution of beta-adrenergic receptor subtypes, in structure and, consequently, in response of receptors and in the pharmacodynamics of the agonist. In addition, several different agonists have been used, adding further complexity. Oversimplification by extrapolation of research observations across species and agonists may confuse attempts to derive mechanisms for the growth modulation effects of beta-adrenergic agonists in vivo. PMID: 7782945 [PubMed - indexed for MEDLINE] 6136. QJM. 1995 Jun;88(6):391-9. Growth hormone deficiency in adults and its response to growth hormone replacement. Labram EK(1), Wilkin TJ. Author information: (1)Department of Neurosurgery, Derriford Hospital, Plymouth, UK. PMID: 7648230 [PubMed - indexed for MEDLINE] 6137. Curr Opin Lipidol. 1995 Jun;6(3):123-9. Postprandial lipoprotein metabolism and atherosclerosis. Karpe F(1), Hamsten A. Author information: (1)King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden. The metabolism of chylomicrons and their remnants is a highly facilitated route to distribute energy from the diet for storage in adipose tissue or immediate use in the muscles. It has been proposed that chylomicron remnants are atherogenic, and a delayed clearance of chylomicron remnants seems to be associated with compositional abnormalities of other cholesterol-rich lipoproteins. Furthermore, the plasma concentration of chylomicron remnants is very low compared with all other major lipoprotein species. These arguments suggest that the metabolism of chylomicrons may not be directly implicated in atherogenesis, but it may instead enhance the atherogenicity of endogenous lipoproteins. This review critically examines the current literature in this field. PMID: 7648000 [PubMed - indexed for MEDLINE] 6138. Curr Opin Lipidol. 1995 Jun;6(3):117-22. Receptors for triglyceride-rich lipoproteins and their role in lipoprotein metabolism. Beisiegel U(1). Author information: (1)Medical Clinic, University Hospital Eppendorf, Hamburg, Germany. The triglyceride-rich lipoproteins in normal human plasma are VLDL and chylomicrons and their remnants. Several receptors for these lipoproteins have been described, most of them belonging to the LDL receptor family. The LDL receptor itself is able to recognize remnants through apolipoprotein E. However, the LDL receptor-related protein is the actual candidate to be the chylomicron remnant receptor in the liver and the VLDL receptor might be responsible for VLDL catabolism in muscle and adipose tissue. PMID: 7647999 [PubMed - indexed for MEDLINE] 6139. Biosci Rep. 1995 Jun;15(3):117-33. Nobel Lecture. Signal transduction: evolution of an idea. Rodbell M. PMID: 7579038 [PubMed - indexed for MEDLINE] 6140. Semin Perinatol. 1995 Jun;19(3):163-70. The interrelationships of body fat, exercise, and hormonal status and their impact on reproduction and bone health. Ramos RH(1), Warren MP. Author information: (1)Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, NY 10019, USA. PMID: 7570068 [PubMed - indexed for MEDLINE] 6141. Nihon Rinsho. 1995 Jun;53 Suppl:599-603. [Experimental animal models of obesity]. [Article in Japanese] Katoh J(1), Taniguchi H. Author information: (1)Second Department of Internal Medicine, Kobe University School of Medicine. PMID: 7563838 [PubMed - indexed for MEDLINE] 6142. Nihon Rinsho. 1995 Jun;53 Suppl:537-42. [Obesity in the elderly]. [Article in Japanese] Nakano H(1), Sasai K, Suzuki T, Haruyama M, Ohba K, Metori S. Author information: (1)Division of Geriatric Medicine, Nippon Medical School. PMID: 7563818 [PubMed - indexed for MEDLINE] 6143. Nihon Rinsho. 1995 Jun;53 Suppl:371-6. [Obesity associated with distorted function of autonomic nervous system]. [Article in Japanese] Ookuma K(1), Yoshimatsu H, Sakata T. Author information: (1)Department of Internal Medicine I, Oita Medical University. PMID: 7563759 [PubMed - indexed for MEDLINE] 6144. Nihon Rinsho. 1995 Jun;53 Suppl:338-42. [Cerebral circulatory disorder, ischemic cerebrovascular disease in obesity]. [Article in Japanese] Nagatsuka K. PMID: 7563746 [PubMed - indexed for MEDLINE] 6145. Nihon Rinsho. 1995 Jun;53 Suppl:257-61. [Visceral fat obesity]. [Article in Japanese] Tokunaga K(1). Author information: (1)Department of Internal Medicine, Itami City Hospital. PMID: 7563715 [PubMed - indexed for MEDLINE] 6146. Nihon Rinsho. 1995 Jun;53 Suppl:239-46. [Etiology of obesity]. [Article in Japanese] Goto Y(1). Author information: (1)Tohoku Kosei-Nenkin Hospital. PMID: 7563709 [PubMed - indexed for MEDLINE] 6147. Nihon Rinsho. 1995 Jun;53 Suppl:221-6. [Waist to hip circumference ratio]. [Article in Japanese] Abe T(1), Fukunaga T. Author information: (1)Department of Exercise and Sport Science, Faculty of Science, Tokyo Metropolitan University. PMID: 7563704 [PubMed - indexed for MEDLINE] 6148. Nihon Rinsho. 1995 Jun;53 Suppl:133-7. [Characteristics of adipose]. [Article in Japanese] Yamamura M(1), Suzuki S. Author information: (1)Division of Molecular Life Science, School of Medicine, Tokai University. PMID: 7563675 [PubMed - indexed for MEDLINE] 6149. Nihon Rinsho. 1995 Jun;53 Suppl:121-6. [Pathogenesis of visceral fat accumulation]. [Article in Japanese] Keno Y(1), Tokunaga K. Author information: (1)Internal Medicine, Itami City Hospital. PMID: 7563670 [PubMed - indexed for MEDLINE] 6150. Curr Biol. 1995 Jun 1;5(6):618-21. Adipocyte differentiation. When precursors are also regulators. MacDougald OA(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. As well as being the precursors of the triacylglycerols deposited as fat in adipose tissue, long-chain fatty acids are one class of agents that induce the differentiation of preadipocytes to adipocytes. PMID: 7552171 [PubMed - indexed for MEDLINE] 6151. Pharmacol Ther. 1995 Jun;66(3):465-505. Glucose transporter gene expression: regulation of transcription and mRNA stability. McGowan KM(1), Long SD, Pekala PH. Author information: (1)Department of Biochemistry, School of Medicine, East Carolina University, Greenville 27858, USA. The facilitated diffusion of D-glucose across the plasma membrane is carried out by a set of stereospecific transport proteins known as the glucose transporters. These integral membrane proteins are members of a gene family where tissue-specific expression of one or more members will determine in part the net rate of glucose entry into the cell. The regulation of glucose transporter gene expression is a critical feature of cellular homeostasis, as defects in specific transporter expression can lead to profound alterations in cellular physiology. In this review, we provide a brief descriptive background on the family of glucose transporters and examine in depth the regulation of the two transporters expressed in adipose tissue, GLUTI, a basal growth-related transporter and GLUT4, the insulin-responsive glucose transporter. PMID: 7494856 [PubMed - indexed for MEDLINE] 6152. Chem Biol. 1995 May;2(5):261-6. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more.... Wahli W(1), Braissant O, Desvergne B. Author information: (1)Glaxo Institute for Molecular Biology, Geneva, Switzerland. The recent discovery of lipid-activatable transcription factors that regulate the genes controlling lipid metabolism and adipogenesis has provided insight into the way that organisms sense and respond to lipid levels. Identification of the signaling pathways in which these receptors are involved will help us to understand the control of energy balance and the molecular defects underlying its disorders. PMID: 9383428 [PubMed - indexed for MEDLINE] 6153. Biochem Soc Trans. 1995 May;23(2):325-31. Amylin regulation of carbohydrate metabolism. Young A(1), Pittner R, Gedulin B, Vine W, Rink T. Author information: (1)Amylin Pharmaceuticals, San Diego, CA 91901, USA. This review describes how amylin may work in the control of carbohydrate metabolism by actions on gastric emptying and on muscle glycogen metabolism. Amylin, which is co-secreted with insulin from pancreatic beta-cells in response to nutrient stimuli, affects both carbohydrate absorption and carbohydrate disposal. Amylin appears to regulate carbohydrate metabolism as a partner to insulin. Defending fuel stores tends to be hierarchical; plasma glucose is defended first, then muscle glycogen, then liver glycogen, then fat. Fuel stores are replenished by both incorporating ingested nutrient and by translocating nutrient stores among body sites. Lactate may better be regarded as a vector of fuel transfer rather than a 'dead end' in metabolism. Amylin can promote the translocation of lactate from muscle to liver. The amylin effect, illustrated by the simultaneous decrease in muscle glycogen and increase in liver glycogen [53, 56], is similar to the catecholamine effect observed by Cori et al. [57]. Amylin thus may be important in maintaining liver glycogen stores via the Cori cycle and the 'indirect' glycogen synthesis pathway [58,59]. Unlike catecholamines, amylin does not mobilize fat or impede insulin action in adipose tissue [30,35]. It can supply lactate to the liver, and because lactate is a preferred lipogenic substrate [60], may thereby favour fat storage. Amylin may also help to control carbohydrate absorption via an 'entero-insular loop' to ensure that absorption from the gut remains within the regulatory limits for carbohydrate disposal by peripheral tissues. This regulatory system is essential for normal control of plasma glucose and appears to be disrupted in type-1 diabetes, an amylin-deficient state. PMID: 7672355 [PubMed - indexed for MEDLINE] 6154. Int J Eat Disord. 1995 May;17(4):337-45. Refeeding, metabolic rate, and weight gain in anorexia nervosa: a review. Salisbury JJ(1), Levine AS, Crow SJ, Mitchell JE. Author information: (1)West Virginia University, Morgantown, USA. Patients with anorexia nervosa require refeeding to restore normal body weight. A variety of studies have examined the role of metabolic rate in the refeeding of anorectic patients. Several measurement techniques have been used to divide metabolic rate into its components: basal metabolic rate, resting energy expenditure, activity-induced thermogenesis, and dietary-induced thermogenesis. In anorexia nervosa patients several consistent findings are present. First, the number of kilocalories required for weight gain or weight maintenance increases as weight increases. Second, over 50% of the body mass gained in anorectic individuals represents fat tissue. Finally, both a history of bulimic symptoms and a higher premorbid body weight may lead to lower calorie requirements. These findings suggest the need for gradual increase in calories provided throughout treatment; resting energy expenditures may aid the determination of caloric requirements PMID: 7620473 [PubMed - indexed for MEDLINE] 6155. Int J Obes Relat Metab Disord. 1995 May;19 Suppl 1:S76-86. The insulin resistance-dyslipidemic syndrome: contribution of visceral obesity and therapeutic implications. Després JP(1), Lemieux S, Lamarche B, Prud'homme D, Moorjani S, Brun LD, Gagné C, Lupien PJ. Author information: (1)Lipid Research Center, CHUL Research Center, Ste-Foy, Canada. PMID: 7550542 [PubMed - indexed for MEDLINE] 6156. Int J Obes Relat Metab Disord. 1995 May;19 Suppl 1:S34-8. The acylation stimulating protein-adipsin system. Cianflone K(1), Maslowska M, Sniderman A. Author information: (1)McGill Unit for the Prevention of Cardiovascular Disease, McGill University, Montreal, Quebec, Canada. Considerable evidence indicates that obesity, and in particular abdominal obesity, is a risk factor for both heart disease and non-insulin dependent diabetes mellitus. In spite of this, little is known of the regulation of triacylglycerol synthesis in adipose tissue other than by insulin. Acylation stimulating protein (ASP), a human plasma protein, stimulates triacylglycerol synthesis in adipose tissue and is also produced by human adipocytes. ASP may play a physiological role in the regulation of efficiency of adipose tissue fat storage and affect clearance of triglycerides from plasma. PMID: 7550536 [PubMed - indexed for MEDLINE] 6157. Int J Obes Relat Metab Disord. 1995 May;19 Suppl 1:S27-33. Metabolic disruptions in the adipocyte-hepatocyte fatty acid axis as causes of HyperapoB. Sniderman AD(1), Cianflone K. Author information: (1)McGill Unit for the Prevention of Cardiovascular Disease, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada. HyperapoB is the atherogenic dyslipoproteinemia characterized by increased numbers of LDL particles in plasma due to increased secretion of B100 lipoprotein particles by the liver. The lipid phenotype in affected patients is variable but an increased plasma apoB points to the increased LDL particle number. The adipocyte-hepatocyte fatty acid axis refers to the traffic in fatty acids from adipocytes to hepatocytes and back again. Our central thesis is that a reduced rate of adipocyte triglyceride synthesis leads to increased traffic to and fro along this axis. This article outlines the ways in which impaired adipose tissue function leads to increased flux of fatty acids to the liver which leads, in turn, to increased secretion of hepatic B100 particles. The Adipsin-ASP pathway is a newly described biological pathway which appears to play a critical role in regulating adipose tissue triglyceride synthesis. Impaired function of this pathway appears to be the commonest reason for the increased fatty acid traffic in the adipocyte-hepatocyte axis leading to HyperapoB. PMID: 7550535 [PubMed - indexed for MEDLINE] 6158. Int J Obes Relat Metab Disord. 1995 May;19 Suppl 1:S16-21. Alterations in lipoprotein lipase in insulin resistance. Eckel RH(1), Yost TJ, Jensen DR. Author information: (1)Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. PMID: 7550532 [PubMed - indexed for MEDLINE] 6159. Am J Clin Nutr. 1995 Apr;61(4 Suppl):952S-959S. Use and storage of carbohydrate and fat. Flatt JP(1). Author information: (1)Department of Biochemistry, University of Massachusetts Medical Center, Worcester 01655. Starch, sugars, and triglycerides provide the bulk of dietary energy. To preserve homeostasis, most of the glucose and fat absorbed must be stored to be mobilized later at rates appropriate to bring about the oxidation of a fuel mix matching on average the macronutrient distribution in the diet. The body's glycogen stores are so small that regulatory mechanisms capable of efficiently adjusting carbohydrate oxidation to carbohydrate intake have developed through evolution. Fat oxidation is regulated primarily by events pertaining to the body's carbohydrate economy, rather than by fat intake. Adjustment of fat oxidation to intake occurs because cumulative errors in the fat balance lead over time to changes in adipose tissue mass, which can substantially alter free fatty acid concentration, insulin sensitivity, and fat oxidation. Fat intake and habitual glycogen concentrations are important in determining how fat one has to be to oxidize as much fat as one eats. PMID: 7900694 [PubMed - indexed for MEDLINE] 6160. Toxicol Appl Pharmacol. 1995 Apr;131(2):267-76. Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. II. Kinetics of absorption and disposition of PCDDs/PCDFs. Carrier G(1), Brunet RC, Brodeur J. Author information: (1)Département de Médecine du travail et d'Hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada. In the present study, a physiologically based model which describes the absorption and disposition kinetics of PCDDs/PCDFs (globally called PCDXs) in mammalian species, including humans, is developed. The model integrates the distribution model developed in the first article of this series, which described the fractional distribution of total PCDXs between liver and adipose tissues as a function of overall body concentration (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 253-266). In particular it is shown that the liver fraction of the total body burden decreases as overall body concentration decreases. Since elimination is principally through the liver, this leads to lower global elimination rates and longer half-lives of PCDXs. Absorption and disposition kinetics of PCDXs are captured using nonlinear differential equations with anatomically and biochemically relevant input parameters which are readily available. These are solved to predict the fate of PCDXs in liver, adipose tissues, and the body as a whole, as a function of time. Model simulations are in agreement with published data on absorption and disposition kinetics of these substances in rats and in humans. The kinetic profiles are similar for rats and humans, but the varying half-lives differ considerably in both species: weeks with rats, years with humans. For a given body burden, the adipose tissue concentrations vary in an inversely proportional manner to the mass of the adipose tissues; this observation has considerable relevance for interpretation of clinical data for humans. The interest of the proposed model rests upon the fact that it is generalized and broadly applicable: it allows the study of the kinetics of PCDXs for any pattern of exposure from background to highly toxic levels, taking into account variations in time of anatomical and biochemical parameters. PMID: 7716768 [PubMed - indexed for MEDLINE] 6161. Toxicol Appl Pharmacol. 1995 Apr;131(2):253-66. Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues. Carrier G(1), Brunet RC, Brodeur J. Author information: (1)Département de Médecine du travail et d'Hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada. Mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans, globally called PCDXs, are ubiquitously present in the environment. They accumulate in the human organism, especially through uptake from food. In view of their long residence time in the body and their potential adverse health effects for humans, it is therefore important to develop toxicokinetic models capable of predicting their distribution in human tissues. In the present study a physiologically based model which describes the distribution kinetics of PCDXs in various mammalian species is proposed. The approach is both theoretical and empirical. First, a plausible and general dynamical model that takes into account intercellular diffusion, PCDX-receptor and PCDX-protein binding, and PCDX-dependent enzyme induction in the liver is developed. Simplified formulas are proposed to predict the functional dependencies fh(Cb) and f(at)(Cb), which establish the fractions of the total PCDX body burden contained in liver and adipose tissues as a function of overall body concentration at any one moment. These formulas have fewer free parameters that can be determined for various species with the use of already available data. Model simulations are in agreement with published data on the distribution kinetics of PCDXs in rodents and monkeys and clinical data in humans. In rodents and monkeys as well as in humans, the respective relations fh(Cb) and f(at)(Cb) follow a similar nonlinear pattern. These varying distribution functions constitute the basis for a generalized toxicokinetic model of absorption and disposition described in a companion article (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 267-276). PMID: 7716767 [PubMed - indexed for MEDLINE] 6162. Eur J Endocrinol. 1995 Apr;132(4):377-85. Beta 3-adrenoceptor: an update. Giacobino JP(1). Author information: (1)Département de Biochimie médicale, Centre Médical Universitaire, Genève, Switzerland. PMID: 7711872 [PubMed - indexed for MEDLINE] 6163. Diabete Metab. 1995 Apr;21(2):79-88. [Role of free fatty acids in the insulin resistance of non-insulin-dependent diabetes]. [Article in French] Girard J(1). Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS, Moudon, France. Non-insulin-dependent diabetes (NIDDM) is characterized by overproduction of glucose, decreased effects of insulin on glucose utilization and production, and a defect in glucose-induced insulin secretion. NIDDM is also associated with defects in fatty acid metabolism, i.e. enhanced lipolysis and impaired suppression of adipose tissue lipolysis in response to insulin, and increased plasma free fatty acid levels. It has been suggested that the "glucose-fatty acid cycle" is enhanced in NIDDM and could contribute to disturbed glucose homeostasis. Although the use of intralipid + heparin infusion and inhibitors of lipolysis or fatty acid oxidation indicates that the glucose-fatty acid cycle exists both in normal and NIDDM subjects, it does not seem to be the primary cause of distributed glucose homeostasis in lean NIDDM subjects or their first-degree relatives. However, the glucose-fatty acid cycle could contribute to overproduction of glucose (by stimulating gluconeogenesis) and muscle insulin resistance in obese NIDDM subjects. Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels. The role of the glucose-fatty acid cycle in normal subject must be clarified, and its contribution to decreased glucose-induced insulin secretion in NIDDM requires further investigation. PMID: 7621976 [PubMed - indexed for MEDLINE] 6164. Br J Clin Pract. 1995 Mar-Apr;49(2):87-90. The metabolic and cardiovascular consequences of HRT. Stevenson JC(1). Author information: (1)Wynn Department of Metabolic Medicine, National Heart and Lung Institute, London. Hormone replacement therapy comprises natural oestrogen and, when appropriate, progestogen given to postmenopausal women. Population studies have shown that postmenopausal oestrogen administration results in a marked reduction in cardiovascular disease, particularly coronary heart disease, an effect that does not appear to be lost when cyclical progestogen is also included. The way in which the hormones confer this protection has not been fully elucidated, but it includes effects on metabolic processes that contribute to atheroma formation as well as direct effects on the arteries themselves. Oestrogens and progestogens can produce beneficial changes in lipids and lipoproteins, glucose and insulin metabolism, body fat distribution, and coagulation and fibrinolysis. Oestrogen acts directly on blood vessels through both endothelium-dependent and calcium-dependent mechanisms to improve arterial function. More widespread use of HRT could result in a major beneficial impact on cardiovascular disease, the leading cause of death in women. PMID: 7779651 [PubMed - indexed for MEDLINE] 6165. Proc Nutr Soc. 1995 Mar;54(1):49-63. Cellular aspects of fuel mobilization and selection in white adipocytes. Lafontan M(1), Langin D. Author information: (1)Unité INSERM 317, Institut Louis Bugnard, Faculté de Médecine, Université Paul Sabatier, CHU Rangueil, Toulouse, France. PMID: 7568265 [PubMed - indexed for MEDLINE] 6166. Proc Nutr Soc. 1995 Mar;54(1):39-47. Fuel selection in brown adipose tissue. Trayhurn P(1). Author information: (1)Division of Biochemical Sciences, Rowett Research Institute, Bucksburn, Aberdeen. PMID: 7568264 [PubMed - indexed for MEDLINE] 6167. Proc Nutr Soc. 1995 Mar;54(1):177-89. Fuel selection in white adipose tissue. Frayn KN(1), Humphreys SM, Coppack SW. Author information: (1)Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford. PMID: 7568252 [PubMed - indexed for MEDLINE] 6168. Genes Chromosomes Cancer. 1995 Mar;12(3):220-3. Cytogenetic and histologic findings in 17 pulmonary chondroid hamartomas: evidence for a pathogenetic relationship with lipomas and leiomyomas. Fletcher JA(1), Longtine J, Wallace K, Mentzer SJ, Sugarbaker DJ. Author information: (1)Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Pulmonary chondroid hamartomas (PCH) are benign tumors that contain mesenchymal and epithelial components. In this series, we identified clonal chromosome aberrations in mesenchymal cells from 10 of 17 PCH. Chromosome band 12q15 was rearranged most frequently (N = 4), and one case had a t(12;14)(q15;q24) that was identical cytogenetically to the characteristic translocation in uterine leiomyomas. Histologic review revealed diverse mesenchymal populations, including undifferentiated cells, cartilage, adipose tissue, and smooth muscle, in most of the PCH. These findings suggest that PCH result from neoplastic transformation of a primitive mesenchymal cell that differentiates along chondroid, adipose, and smooth muscle pathways. PMID: 7536462 [PubMed - indexed for MEDLINE] 6169. Metabolism. 1995 Feb;44(2 Suppl 2):23-7. Metabolic abnormalities linked to obesity: effects of dexfenfluramine in the corpulent rat. Brindley DN(1), Russell JC. Author information: (1)Department of Biochemistry, University of Alberta, Edmonton, Canada. The JCR:LA-corpulent rat is a useful experimental model for the obese-diabetic-dyslipidemic syndrome that mimics the human condition and exhibits spontaneous development of atherosclerosis and myocardial lesions. A 30-day treatment of 6-month-old rats with dexfenfluramine 1, 2.5, and 5 mg per kilogram decreased body weight through loss of adipose tissue mass. The effect is caused primarily by the ability of dexfenfluramine to reduce food intake. The maximum depression of food intake and greatest weight loss is seen during the first 10 days of treatment in this experimental model; thereafter, body weight stabilizes. However, during this period, there is a marked decrease in serum concentrations of triglycerides, cholesterol, and insulin. Corpulent male rats were also treated from 6 to 37 weeks of age with dexfenfluramine 2.5 mg/kg. This also produces a sustained decrease in body weight and a decrease in circulating insulin concentrations. Preliminary evidence demonstrates a substantial decrease in the incidence of necrotic myocardial lesions produced by ischemic events. This study establishes that dexfenfluramine treatment can decrease the severity of associated risk factors for cardiovascular disease, namely obesity, diabetes, and dyslipidemias. Furthermore, we report the first evidence that long-term treatment with dexfenfluramine can largely prevent the occurrence of myocardial lesions and end-stage cardiovascular disease in this animal model prone to atherosclerosis. PMID: 7869933 [PubMed - indexed for MEDLINE] 6170. Proc Soc Exp Biol Med. 1995 Feb;208(2):159-69. Role of brown adipose tissue thermogenesis in control of thermoregulatory feeding in rats: a new hypothesis that links thermostatic and glucostatic hypotheses for control of food intake. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, University of Ottawa, Ontario, Canada. The hypothesis proposed in this review provides a novel view of both the control of feeding and the function of brown adipose tissue (BAT) thermogenesis. It takes into account the episodic nature of feeding in rats allowed free access to food and the necessity for episodic events in the controlling systems which govern initiation and termination of feeding. A feeding episode is proposed to occur during an episode of increased sympathetic nervous system activity that stimulates BAT thermogenesis and increases body temperature. Two different aspects of stimulated BAT metabolism, namely increased uptake of glucose and increased heat production, evoke initiation and termination of feeding, respectively. Initiation is mediated by a transient dip in blood glucose concentration caused by stimulated glucose utilization in BAT. Feeding continues while both BAT and core temperature continue to rise. Termination is induced by the high level of core temperature brought about by the episode of stimulated BAT thermogenesis. The time between initiation and termination determines the size of the meal and depends on the balance between BAT thermogenesis and heat loss, and thus on ambient temperature. The underlying cause of the episodic stimulation of sympathetic nervous system activity is a decline in core temperature to a level recognized by the hypothalamus as needing a burst of increased heat production. Thus, BAT thermogenesis is important in control of meal size, relating it to thermoregulatory needs. When this function is lost, as in many obese animal models of obesity, the animal loses its ability to remain in energy balance by precisely adjusting its intake in relation to environmental temperature and meal size increases. The hypothesis also predicts that an increase in endogenous heat production that is not due to BAT thermogenesis will prevent the matching of intake to increased expenditure via thermoregulatory feeding. This is seen, for example, in the shivering rat during the early stage of acclimation to cold. Feeding is viewed as the outcome of a thermoregulatory event. Rats do not eat to warm up; they start to eat after they have started to warm up and stop eating once they have warmed up. The phenomenon is termed thermoregulatory feeding, to distinguish it from feeding initiated by other stimuli. PMID: 7831348 [PubMed - indexed for MEDLINE] 6171. Regul Toxicol Pharmacol. 1995 Feb;21(1):108-16. A novel application of a competitive binding model in dioxin risk assessment. Rao VR(1), Unger A. Author information: (1)Quantitative Analysis Division, Science Applications International Corporation, Falls Church, Virginia 22043, USA. The EPA-recommended toxicity equivalence factor (TEF) approach to estimating the lifetime incremental cancer risks for dioxins does not address (a) differences in the severity of toxicity according to the composition of chemical mixture and (b) potentials for modification of tissue-level doses of congeners in mixtures and consequently the cancer risk estimates. Our earlier efforts to model the binding of congeners to the Ah receptor in the low-dose range and to develop quantitative estimates for the formation of fractions of Ah receptor-congener complexes resulted in the definition of a unique parameter, defined as competitive binding ratio (CBR), to adjust tissue-level doses for mixture exposure. We made an effort to incorporate CBR values in the dose-response analysis and risk characterization of congeners in two distinct exposure scenarios. The modified approach to estimating tissue-level doses of congeners in mixtures by the use of a competitive binding model indicated that (a) the Ah receptor affinity is an important criterion in the determination of tissue-level dose of congeners, (b) the TEF doses calculated by using the model algorithms modified the tissue-level doses for congeners in mixture exposures, and (c) the combined lifetime incremental cancer risks for all congeners were generally lower when model algorithms were used in the dose-response analysis. However, the percentage contribution of toxic congeners was significantly higher when model algorithms were used. The percentage contribution of higher congeners with low toxicity was considerably reduced when model algorithms were used.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7784623 [PubMed - indexed for MEDLINE] 6172. Prostaglandins Leukot Essent Fatty Acids. 1995 Feb-Mar;52(2-3):113-5. Fatty acids and adipose cell differentiation. Ailhaud G(1), Amri EZ, Grimaldi PA. Author information: (1)Centre de Biochimie (UMR 134 CNRS), Université de Nice-Sophia Antipolis, Faculté des Sciences, France. Fatty acids are important metabolic substrates for adipose tissue. In preadipose cells, fatty acids are also potent inducers of various genes encoding proteins directly involved in fatty acid metabolism. On a longer-term basis, fatty acids induce the terminal differentiation of preadipose to adipose cells. Fatty acids act primarily at a transcriptional level. A member of the steroid/thyroid hormone receptor superfamily has been identified by cDNA cloning from a mouse Ob1771 preadipose cell library. This receptor is likely the fatty acid-activated receptor implicated in the transcriptional effects of fatty acids in adipose cells. Thus fatty acids appear to play a new role as signal transducing molecules which are involved in adipose cell differentiation. PMID: 7784445 [PubMed - indexed for MEDLINE] 6173. Herz. 1995 Feb;20(1):56-69. [Non-pharmacological therapy of metabolic syndrome]. [Article in German] Wirth A(1). Author information: (1)Teutoburger-Wald-Klinik, Bad Rothenfelde. The metabolic syndrome usually goes along with abdominal obesity: diabetes type II, hypertension, dyslipidemia, and gout are often associated. The common characteristic is the resistance to insulin action. Reasons for the metabolic syndrome are--besides a genetic determination--overnutrition, physical inactivity, and alcohol consumption. Therefore, a causal therapy aims at the elimination of these factors. Consequently, the non-pharmacological therapy of the metabolic syndrome should be emphasized. The most important treatment is the reduction of body weight in the presence of obesity which is relevant for almost 90% of the patients. Body weight can rapidly be diminished by hypocaloric diets. Both, conventional reducing diets or formula diets may be used for weight reduction. Total fasting should not be performed for several reasons. For minor weight reduction or weight maintenance following a period of rapid weight loss with a hypocaloric diet, increased physical activity also lowers weight or prevents relapsing. Aims of therapeutical procedures are the elimination or amelioration of insulin resistance and subsequently the diseases of the metabolic syndrome. Both methods, reducing diet and physical training, act on various factors related to insulin resistance. For example, hypocaloric diets activate thyroxine kinase of the insulin receptor and reduce glucose and insulin in plasma. Physical training reduces not only insulin and glucose in plasma but also free fatty acids in addition and increases capillary density in skeletal muscle. Using the glucose clamp technique, diets and training are equally effective in improving glucose metabolism. Compared to these non-pharmacological methods drugs are less convincing. Since the non-pharmacological treatment implies behavioral changes with regard to nutrition, physical activity and alcohol consumption, simple instructions are not sufficient. Usually long-lasting changes in life style are necessary in order to achieve health improvement. Therefore, health care programs on individual or social basis are required in order to improve nutrition and increase physical activity. However, long-acting effects are difficult to achieve in adults; more promising is the prevention of insulin resistance. PMID: 7713478 [PubMed - indexed for MEDLINE] 6174. Herz. 1995 Feb;20(1):5-15. [Pathophysiology of insulin resistance]. [Article in German] Häring H(1). Author information: (1)Institut für Diabetesforschung München. Insulin resistance of skeletal muscle, liver and fat combined with an abnormality of insulin secretion characterizes Type 2 (non-insulin-dependent) diabetes mellitus. There is increasing evidence that the insulin resistance of the skeletal muscle plays a key role early in the development of Type 2 diabetes. As a consequence recent research efforts have focussed on the characterization of insulin signal transduction elements in the muscle which are candidates for a localization of a defect causing insulin resistance, i.e. the insulin receptor, phosphatases related to insulin action, glycogen synthase and the glucose transporters. In this review we attempt to summarize present knowledge about abnormalities of these systems in skeletal muscle of Type 2 diabetic and pre-diabetic individuals. We try to classify abnormalities as secondary events or as candidates for putative primary molecular defects which might initiate the development of insulin resistance as early as in the "pre-diabetic" state. Insulin resistance is combined with abnormalities of insulin secretion. Compensatory hypersecretion of insulin is typically found in early stages of the development of the "Metabolic Endocrine Syndrome" and the pre-diabetic state. The transition from this pre-diabetic state to the clinically overt Type 2 diabetes is accompanied or even caused by declining insulin secretion. The molecular mechanism causing declining insulin secretion is not understood in detail. Beside genetically determined factors regulatory events might be important. PMID: 7713477 [PubMed - indexed for MEDLINE] 6175. Herz. 1995 Feb;20(1):47-55. [Abdominal obesity and coronary heart disease. Pathophysiology and clinical significance]. [Article in German] Hauner H(1). Author information: (1)Diabetes-Forschungsinstitut an der Heinrich-Heine-Universität Düsseldorf. The relationship between overweight and cardiovascular disease was a matter of debate for many years. Recent studies have demonstrated that obesity defined as body mass index of 30 kg/m2 or higher is associated with an exponential increase of cardiovascular complications. This effect is largely mediated by the induction of established risk factors such as dyslipidemia, hypertension and type 2 diabetes mellitus. Recently, there is growing evidence that the occurrence of most complications of obesity depends not only on the degree of overweight but also on the pattern of body fat distribution. Many data suggest that the anatomical localization of body fat is more important for the risk of developing complications than the adipose tissue mass per se. An abdominal, upper-body type of fat distribution, which can be easily determined by the measurement of waist and hip circumferences (waist/hip ratio = WHR), is also a confirmed risk factor for metabolic disturbances, hypertension and atherosclerosis, independent of body weight. However, the clinical appearance of these disturbances is frequently associated with the development of obesity. This network of metabolic disorders and their vascular complications is termed "metabolic syndrome" or "syndrome X" (Table 2). Abdominal obesity is now known to be closely associated with the metabolic syndrome and is regarded to represent its readily recognizable phenotypic feature. The components of the metabolic syndrome are characterized by varying forms and degrees of insulin resistance. It is assumed that insulin resistance, defined as diminished biological response to the action of insulin, represents the primary defect or at least the common pathogenetic link between these disturbances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7713476 [PubMed - indexed for MEDLINE] 6176. Am J Med. 1995 Jan 16;98(1A):22S-26S. Androgens and women's health: genetic and epidemiologic aspects of lipid metabolism. LaRosa JC(1). Author information: (1)George Washington University Medical Center, Washington, DC. Lipoprotein metabolism may be viewed as a process whereby large, triglyceride-carrying particles from the intestine and liver are broken down into smaller cholesterol-enriched lipoprotein particles. In the process, triglyceride is transported from the intestine and liver to adipose and other storage tissues. Androgen appears to affect lipoprotein metabolism in a number of ways. These include: increasing the activity of lipoprotein lipase and hepatic triglyceride lipase, resulting in higher levels of triglyceride in adipose tissue and a drop in total circulating high-density lipoprotein levels, respectively, and decreasing catabolic removal of low-density lipoproteins from circulating plasma. In pre- and postmenopausal women, androgen progestins in some oral contraceptives, especially the older 19-nortestosterone derivatives such as norgestrel, lower high-density lipoprotein and raise low-density lipoprotein levels. Newer 19-nortestosterone derivatives, such as desogestrel and norgestimate, have a lesser effect on circulating lipoproteins. Nonoral androgenic progestins (e.g., subcutaneous norgestrel) have little effect on circulating lipids, however, which indicates the significance of the "first pass" through the liver for oral agents. The effects of androgens on atherogenesis are largely unexplored, although preliminary studies indicate that they may promote the atherogenic process. PMID: 7825637 [PubMed - indexed for MEDLINE] 6177. J Sports Sci. 1995 Summer;13 Spec No:S83-90. Practical issues in nutrition for athletes. Burke L(1). Author information: (1)Department of Sports Medicine, Australian Institute of Sport, Belconnen, Australia. Many athletes do not achieve sound nutritional practices to optimize their sports performance. Factors include poor nutrition knowledge, dietary extremism, poor practical skills in choosing or preparing meals, and reduced access to food due to a busy lifestyle and frequent travel. Education in nutrition for the athlete needs to be practical, so as to address eating strategies and key food and fluid choices that will help to achieve the goals of sound nutrition. Strategies that can achieve a number of nutritional goals simultaneously are most useful, since athletes often find it difficult to integrate separate issues. Athletes with extreme nutrient requirements, or with nutritional problems, should seek individual assessment and counselling from a sports nutrition expert. PMID: 8897324 [PubMed - indexed for MEDLINE] 6178. Physiol Res. 1995;44(6):353-6. Developmental aspects of lipid metabolism. Koldovský O(1), Dobiásová M, Drahota Z, Hahn P. Author information: (1)Department of Pediatrics, University of Arizona College of Medicine, Tucson, USA. It was confirmed that the main source of energy for growth and development in the neonatal period was fat. Considerable attention was paid to the development of both white adipose tissue (WAT) and brown adipose tissue (BAT) in the rat and human newborn. Cholesterol metabolism during development was studied in the liver, the small intestine and both WAT and BAT. Brown adipose tissue of rats and adipose tissue from human newborns require carnitine for optimum respiration and fatty acid oxidation. Surprisingly, carnitine enhanced lipolysis in human newborn adipose tissue, intravenously-fed newborn patients exhibited a rapid decrease of plasma level of carnitine and its esters, indicating a greater requirement for exogenous carnitine than in adult subjects (52 references). PMID: 8798269 [PubMed - indexed for MEDLINE] 6179. Clin Anat. 1995;8(6):403-6. The buccal pad of fat: a review. Tostevin PM(1), Ellis H. Author information: (1)United Medical and Dental School, Division of Anatomy and Cell Biology, Guy's Hospital, London, England. Within the cheek, wedged between masseter and buccinator, is a biconvex pad of fatty tissue, the corpus adiposum buccae, or buccal fat pad (of Bichat). It contributes significantly to the prominence of the cheek of the newborn infant and is sometimes encountered in surgical procedures in the region of the ramus of the mandible or the maxillary tuberosity. This paper reviews the history of the study of the buccal pad of fat, its anatomical location, blood supply, and comparative anatomy. We have also reviewed the pathology of the buccal pad of fat, including traumatic herniation. The fat pad is of interest surgically as it can be used as a free or pedicled graft to close maxillary defects after excision of tumors. PMID: 8713160 [PubMed - indexed for MEDLINE] 6180. Prog Lipid Res. 1995;34(3):199-217. Fatty acid composition of adipose tissue in humans. Implications for the dietary fat-serum cholesterol-CHD issue. Seidelin KN(1). Author information: (1)Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark. Interest in studies of the fatty acid composition of adipose tissue has arised from the dietary fat-serum cholesterol-CHD issue. The fatty acid composition of depot fat reflects that of the diet. Gas chromatography analysis of subcutaneous adipose tissue yield objective and reliable information of the fatty acid composition of the habitual diet of individuals. A relative linoleic acid deficiency, as depicted by low adipose tissue linoleate levels, has not convincingly been demonstrated to be of importance in the aetiology of atherosclerosis or related disorders. Inverse correlation between n-3 fatty acids and coronary artery disease has been reported. Dietary supplementation of n-3 fatty acids may be of relevance, however the risk of hazardous side-effects do exist. In conclusion, a simple reduction of the total fat content of the diet still seems to be the most important strategy for prevention of atherosclerosis. PMID: 8685239 [PubMed - indexed for MEDLINE] 6181. Jpn J Physiol. 1995;45(6):921-46. Adaptation to heat. Hori S(1). Author information: (1)Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan. PMID: 8676578 [PubMed - indexed for MEDLINE] 6182. Scand J Rheumatol. 1995;24(6):327-9. Diagnosing amyloidosis. Westermark P. Diagnosis of amyloidosis still relies on tissue biopsy for microscopic examination. Biopsy from a symptom-giving organ may be used but more often an easily available tissue which is affected in most forms of systemic amyloidosis is utilized. Rectal biopsy has its place but a fine needle aspiration biopsy of subcutaneous adipose tissue offers a safe and more convenient alternative. With increasing knowledge about the chemical nature, prognosis and treatment of the different systemic amyloidoses there is an increasing demand of exact chemical typing of amyloid deposits. This typing can be performed immunologically on tissue biopsies, e.g. from subcutaneous adipose tissue, by several different methods. The distribution of amyloid in the body and the therapeutic effects can be monitored by scintigraphy after administration of radiolabelled amyloid P-component. PMID: 8610214 [PubMed - indexed for MEDLINE] 6183. Prog Brain Res. 1995;106:323-31. Semicarbazide-sensitive amine oxidases: some biochemical properties and general considerations. Buffoni F(1). Author information: (1)Department of Preclinical and Clinical Pharmacology, University of Florence, Italy. Semicarbazide-sensitive amine oxidases with a high affinity for benzylamine (Bz.SSAO) (E.C.1.4.3.6) have been biochemically described in many mammalian tissues (adipose tissue, lung, heart, blood vessels). The enzymic activity appears to be expressed by mesenchymal cells (fibroblasts, adipocytes, smooth muscles). Although the physiological role of this enzymic activity is still unclear, some possible physiological substrates such as histamine are discussed. Some enzymes of this class (SSAO) have been purified. They share many similarities, among which are that they contain copper and a carbonyl active site. The nature of the organic cofactor of these enzymes is discussed and data are presented which have identified pyridoxal in pig kidney diamine oxidase and in pig plasma benzylamine oxidase by gas chromatography-mass spectrometry. PMID: 8584668 [PubMed - indexed for MEDLINE] 6184. Prog Brain Res. 1995;106:305-21. Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes. Callingham BA(1), Crosbie AE, Rous BA. Author information: (1)Department of Pharmacology, University of Cambridge, UK. The widespread distribution of enzymes classed as semicarbazide-sensitive amine oxidases (SSAO enzymes) throughout a very wide range of eukaryotic as well as prokaryotic organisms encourages the aspirations of those who wish to demonstrate physiological, pathological or pharmacological importance. Such enzymes are found in several tissues of mammals, both freely soluble, as in blood plasma, and membrane-bound, for example, in smooth muscle and adipose tissue. While they are capable of deaminating many amines with the production of an aldehyde and hydrogen peroxide, doubt still surrounds the identity of the most important endogenous substrates for these enzymes. At present, methylamine and aminoacetone appear to head the list of candidates. The possibility that SSAO enzymes can convert amine substrates to highly toxic metabolites is illustrated by the production of acrolein from the xenobiotic amine, allylamine and formaldehyde and methylglyoxal from methylamine and aminoacetone, respectively. Activities of SSAO enzymes may be influenced by physiological changes, such as pregnancy or pathologically by disease states, including diabetes, tumours and burns. Increased deamination of aminoacetone by tissue and plasma SSAO enzymes as a result of its increased production from L-threonine in conditions such as exhaustion, starvation and diabetes mellitus may be harmful. Such dangers could be mitigated either physiologically by a compensatory reduction in SSAO activity or pharmacologically by treatment with inhibitors of SSAO. PMID: 8584667 [PubMed - indexed for MEDLINE] 6185. Prog Brain Res. 1995;106:187-97. Metabolism of agmatine (clonidine-displacing substance) by diamine oxidase and the possible implications for studies of imidazoline receptors. Holt A(1), Baker GB. Author information: (1)Department of Psychiatry, and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Clonidine-displacing substance, thought to be the endogenous ligand for imidazoline receptors, has been identified recently as agmatine (1-amino-4-guanidinobutane). The similarity of this compound's structure to that of the diamine oxidase (DAO) inhibitor, aminoguanidine, led us to investigate the possibility that agmatine might be a substrate for this enzyme. The metabolism of agmatine by purified porcine kidney DAO was measured by a peroxidase-linked colorimetric assay. Agmatine was a substrate for this enzyme and, under the experimental conditions used here, was metabolised at a rate of 0.8 mumol agmatine h-1 (unit DAO activity)-1. In contrast, agmatine was a substrate neither for rat brain monoamine oxidase (MAO) -A or -B, nor for rat brown adipose tissue semicarbazide-sensitive amine oxidase (SSAO). The metabolism of agmatine by DAO was inhibited by aminoguanidine (IC50 14.9 nM) and by the antidepressant, phenelzine (IC50 1.95 microM). These results suggest that administration of DAO inhibitors may increase endogenous agmatine levels and thus alter imidazoline receptor densities. A review of the literature documenting ligand affinities for idazoxan-preferring (I2) imidazoline binding site subtypes and drug affinities for DAO enzymes indicates that some of the I2 sites described elsewhere may correspond to DAO and not to an imidazoline receptor. PMID: 8584654 [PubMed - indexed for MEDLINE] 6186. Fundam Clin Pharmacol. 1995;9(4):324-31. Differential activation of beta 1-, beta 2- and beta 3-adrenoceptors by catecholamines in white and brown adipocytes. Galitzky J(1), Carpéné C, Bousquet-Mélou A, Berlan M, Lafontan M. Author information: (1)Inserm U317, Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, Toulouse France. This review summarizes the experiments performed by various groups to determine how the activation of the different beta-adrenoceptors (beta-ARs) is ordinated when they are present in the same fat cell and involved in the same biological event. When expressed after the transfection of their genes in Chinese hamster ovary cell (CHO cells), beta 1- and beta 2-ARs present a higher affinity for catecholamines than beta 3-ARs. In vitro, the lipolytic effect induced by low concentrations of catecholamines in dog and rat white fat cells is due to the selective activation of beta 1- and/or beta 2-ARs. Higher concentrations only are able to activate beta 3-ARs. Similar results have been obtained in rat brown adipocytes. On the other hand, the lipolytic effect of catecholamines in human and primate adipocytes does not involve a beta 3-AR component whatever the concentration used. In vivo experiments in the dog have also shown that lipomobilization induced by low doses of isoprenaline only involved beta 1- and beta 2-AR activation, this effect being blocked by beta 1-/beta 2-antagonist pretreatment. However, in the same blockade conditions, perfusion of a 10-fold higher dose of isoprenaline revealed a beta 3-AR contribution in the lipomobilizing effect. These data showed that brown and white adipocyte beta 3-ARs possess a lower affinity for catecholamines than beta 1- and beta 2-ARs and are only recruited by high concentrations of the amines.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8566931 [PubMed - indexed for MEDLINE] 6187. Virchows Arch. 1995;427(4):353-63. Lipomatous tumours of soft tissues: an update. Mentzel T(1), Fletcher CD. Author information: (1)Department of Histopathology, St. Thomas's Hospital, London, UK. This review summarizes the clinicopathological features of recently characterized variants of lipomatous tumours of soft tissue, attempts to deal with some difficult conceptual issues relating to adipocytic neoplasms and aims to provide an update on cytogenetic aspects of fatty tumours. Myolipoma is a rare benign neoplasm, occurring most frequently in adults in the deep soft tissue of the abdomen or retroperitoneum, and is composed of irregularly admixed mature adipose and smooth muscle tissues. Chondroid lipoma represents an unusual benign lesion occurring mainly in adult females subcutaneously or in deep soft tissue; it is easily mistaken for myxoid liposarcoma or extraskeletal myxoid chondrosarcoma. Spindle-cell liposarcoma is a variant of well-differentiated liposarcoma quite commonly found in subcutaneous tissue of the shoulder region and upper limbs and is composed of relatively bland-appearing spindle cells mixed with a well-differentiated liposarcomatous component. Recently there has been considerable debate about classification of lipomatous tumours. The term atypical lipoma was proposed for a group of well-differentiated non-metastasizing liposarcomas arising in surgically amenable soft tissues and for deep-seated atypical adipocytic neoplasms that show variation in adipocytic size and atypical stromal cells but lack lipoblasts. However, these neoplasms recur repeatedly and may dedifferentiate and thereby acquire metastatic potential. We use the diagnosis atypical lipoma with caution and propose to use the terms well-differentiated liposarcoma and atypical lipoma interchangeably. The relationship between myxoid and round-cell liposarcoma, which constitutes the morphological spectrum of a single entity, has been clarified but there remain considerable problems in defining likely clinical behaviour. The recent advances in cytogenetic characterization and classification of lipomatous tumours, which is already proving to be of diagnostic importance, are reviewed, and the genetic importance of the distinct chromosomal translocation in myxoid/round cell liposarcoma is briefly discussed. PMID: 8548119 [PubMed - indexed for MEDLINE] 6188. Annu Rev Nutr. 1995;15:133-59. Regulation of glutaminase activity and glutamine metabolism. Curthoys NP(1), Watford M. Author information: (1)Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins 80523, USA. Glutamine is synthesized primarily in skeletal muscle, lungs, and adipose tissue. Plasma glutamine plays an important role as a carrier of nitrogen, carbon, and energy between organs and is used for hepatic urea synthesis, for renal ammoniagenesis, for gluconeogenesis in both liver and kidney, and as a major respiratory fuel for many cells. The catabolism of glutamine is initiated by either of two isoforms of the mitochondrial glutaminase. Liver-type glutaminase is expressed only in periportal hepatocytes of the postnatal liver, where it effectively couples ammonia production with urea synthesis. Kidney-type glutaminase is abundant in kidney, brain, intestine, fetal liver, lymphocytes, and transformed cells, where the resulting ammonia is released without further metabolism. The two isoenzymes have different structural and kinetic properties that contribute to their function and short-term regulation. Although there is a high degree of identity in amino acid sequences, the two glutaminases are the products of different but related genes. The two isoenzymes are also subject to long-term regulation. Hepatic glutaminase is increased during starvation, diabetes, and feeding a high-protein diet, whereas kidney-type glutaminase is increased only in kidney in response to metabolic acidosis. The adaptations in hepatic glutaminase are mediated by changes in the rate of transcription, whereas kidney-type glutaminase is regulated at a posttranscriptional level. PMID: 8527215 [PubMed - indexed for MEDLINE] 6189. Curr Top Pathol. 1995;89:73-94. Characteristic chromosome abnormalities and karyotype profiles in soft tissue tumors. Turc-Carel C(1), Pedeutour F, Durieux E. Author information: (1)Université de Nice, Faculté de Médecine, France. Characteristic chromosome abnormalities and karyotype profiles are emerging for the soft tissue tumors. The notable findings are summarized in the Table 1. Within the broad range of solid tumors, it is certainly the soft tissue tumors in which the most spectacular success has occurred with regard to neoplasia-associated chromosome abnormalities. Cytogenetic studies of soft tissue tumors have been encouraged by the early and growing supporting interest of pathologists and clinicians concerned with soft tissue tumors. However, when one considers the variety of types and subtypes of benign and malignant soft tissue tumors, the number that has been so far characterized by a specific chromosome change is still very small. But, as we attempt to demonstrate in this report, these data should be viewed as paradigms for the importance of cytogenetic investigations in solid tumors. Cytogenetic studies of solid tumors are of more than clinical interest. Cytogenetic studies allow molecular investigations of the chromosomal breakpoints. They allow the search to proceed for genes involved in the chromosomal changes, providing a better knowledge of the malignant transformation process. In addition, the fruits of the combined efforts in cytogenetic and molecular technologies, from which has come "molecular cytogenetics," will let us recognize more conveniently, more quickly and, hopefully, less expensively the well-characterized diagnostic chromosome markers in tumor cells. Thus, we may be able to reach the goal of incorporating cytogenetics into standard diagnostic procedures for solid tumors, as has been achieved with hematological malignancies. Molecular cytogenetics including fluorescent in situ hybridization (FISH) technology promises to bring soft tissue tumor cytogenetics into regular diagnostic armamentaria and concurrently speed research into the basis of soft tissue tumors. PMID: 7882721 [PubMed - indexed for MEDLINE] 6190. Cell Signal. 1995 Jan;7(1):9-15. Why do adipocytes make the beta 3 adrenergic receptor? Granneman JG(1). Author information: (1)Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI 48201, USA. Adipocytes express a mixture of beta-adrenergic receptor subtypes, including the recently characterized beta 3 receptor. The co-expression of these subtypes by fat cells suggest they serve different signalling functions. In this review, the properties of recombinant and natively-expressed beta 3 receptors are detailed and contrasted with those of beta 1 and beta 2 receptors. The beta 3 receptor appears to differ from the other beta receptor subtypes with respect to receptor coupling efficiency, G-protein coupling specificity and regulation by agonist exposure. Lastly, the potential of the beta 3 receptor as a therapeutic target is discussed in view of new data regarding its tissue distribution in humans. PMID: 7756115 [PubMed - indexed for MEDLINE] 6191. Ann Endocrinol (Paris). 1995;56(2):93-5. [Adipose tissue. Hidden aspects]. [Article in French] Ailhaud G(1). Author information: (1)Centre de Biochimie (UMR 134 CNRS), Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose. Adipose differentiation is a sequential process (adipoblasts-->preadipocytes-->adipocytes). Adipogenic factors are only involved in the terminal differentiation of preadipocytes to adipocytes by means of circulating hormones (growth hormone, glucocorticoids, insulin, triiodothyronine) and locally produced hormones (prostacyclin, IGF-I). Fatty acids also behave as hormones and act as transcriptional regulators of lipid-related genes. Once differentiated, adipocytes become secretory cells able to synthetize and release numerous peptide and nonpeptide compounds, suggesting a potential link between excess of adipose tissue mass and various physiopathologic consequences. PMID: 7755345 [PubMed - indexed for MEDLINE] 6192. Ann Endocrinol (Paris). 1995;56(2):101-5. [Grouping of risk factors for cardiovascular diseases in visceral obesity. Therapeutic implications]. [Article in French] Després JP(1), Lesage M, Lemieux S, Prud'Homme D. Author information: (1)Centre de recherche sur les maladies lipidiques, Centre de recherche du CHUL, Ste-Foy, Canada. Obesity is a remarkable heterogeneous condition as shown by the variety of metabolic complications encountered. Imaging techniques with computed tomography have made it possible to quantify adipose tissue deposited within the abdominal cavity (visceral fat) which has been found to be correlated with serum glucose, insulin and lipid levels. Individuals with excessive visceral fat have hypertriglyceridaemia, high apolipoprotein B levels and hypoalphalipoproteinaemia. Several genes could modulate the degree of dyslipidaemia in patients with excessive visceral fat. Consequently, these patients should be managed as a genetically identifiable subgroup at risk of developing metabolic complications of obesity. It would also be justified to focus treatment on mobilizing visceral fat and improving the metabolic syndrome rather than simply on weight loss, an often unrealistic and clinically unjustified objective. PMID: 7755334 [PubMed - indexed for MEDLINE] 6193. Hokkaido Igaku Zasshi. 1995 Jan;70(1):1-8. [Regulation of thermoregulatory thermogenesis]. [Article in Japanese] Kuroshima A(1). Author information: (1)First Department of Physiology, Asahikawa Medical College, Japan. Two modes of heat production exist which are involved in body temperature regulation with decreasing environmental temperature: shivering thermogenesis and more efficient nonshivering thermogenesis (NST). Enhanced NST is mediated by the activated sympathetic nervous activity and increased secretions of hormonal factors such as glucagon through an enhanced lipid utilization. Moreover, cold acclimation causes an increased responsiveness of the organism to these factors. Noradrenaline-induced secretion of glucagon is also enhanced by cold acclimation. Chronic administration of glucagon simulates cold acclimation, resulting in an improved cold tolerance by an increased NST. Brown adipose tissue (BAT) is a major site for nonshivering thermogenesis (NST) during metabolic cold acclimation. Cold acclimation causes a hyperplasia as well as an enhanced metabolic capacity of BAT cell. BAT function is mainly regulated by sympathetic noradrenaline and several hormonal factors such as glucagon. BAT possesses rich blood supply by which its high thermogenic capacity and an efficient transfer of heat are maintained. Noradrenaline and glucagon increases not only heat production, but also blood flow in BAT. Nitric oxide (NO), endothelium-derived relaxing factor, is involved in noradrenaline-, glucagon- and cold-induced increases of blood flow through BAT. Noradrenaline-induced BAT thermogenesis is suggested to be mediated by NO. NO synthase occurs in BAT cell in addition to endothelium of BAT vessel. These findings indicate that NO may be a signalling molecule for an enhanced NST during cold acclimation. Moreover, BAT contributes to adaptation to overfeeding, nonthermal stress and fever by means of producing heat, playing a role as adaptive organ in overall energy metabolism. PMID: 7744360 [PubMed - indexed for MEDLINE] 6194. Diabetologia. 1995 Jan;38(1):3-13. The fourth musketeer--from Alexandre Dumas to Claude Bernard. Reaven GM(1). Author information: (1)Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. Considerations of the pathophysiology of non-insulin dependent diabetes mellitus (NIDDM) usually focus on the respective roles of the so-called triumvirate-beta cell, muscle and liver [1]. Often overlooked in this context is the role of the adipose tissue, and attention is usually addressed to consideration of studies in which isolated adipocytes were used as a surrogate for muscle in studies of insulin action. The goal of this presentation will be to develop a radically different hypothesis, and marshal evidence that it is the loss of normal regulation of adipose tissue that plays the central role in both the hyperglycaemia and the dyslipidaemia that characterizes patients with NIDDM. PMID: 7744226 [PubMed - indexed for MEDLINE] 6195. C R Seances Soc Biol Fil. 1995;189(1):25-41. [Mechanism of insulin action]. [Article in French] Baron V(1), Van Obberghen E. Author information: (1)INSERM U 145, Faculté de Médecine, Nice, France. Insulin is a key hormone regulating glucose homeostasis. Its major target tissues are the liver, the skeletal muscle and the adipose tissue. At the cellular level, insulin activates glucose and amino acids transport, lipid and glycogen metabolism, protein synthesis, and transcription of specific genes. Insulin-induced biological responses are mediated by a specific cell-surface receptor with tyrosine kinase activity. This receptor is a heterotetrameric protein consisting of two extracellular alpha subunits containing the ligand binding site, and two transmembrane beta subunits containing the hormone-sensitive enzymatic activity. The first step following insulin binding consists in receptor autophosphorylation on multiple specific sites and phosphorylation of cellular substrates. We will review the receptor structure, its mechanism of activation, and the autophosphorylation process. Two of the insulin receptor substrates have been identified as IRS-1 and Shc. IRS-1 is phosphorylated at several sites by the insulin receptor, and acts as a docking protein by associating several SH2-containing proteins. One of these proteins is the p85 subunit of P13-kinase which is rapidly stimulated by insulin in adipocytes and skeletal muscle. The phosphorylated IRS-1 also associates Grb2, as does the phosphorylated Shc. This allows recruitment of the preformed complex Grb2-Sos to the plasma membrane. Sos is then capable of stimulating the Ras protein, which in turn activates Raf, the first element of the MAP-kinase cascade. The role of these proteins in insulin signalling will be discussed. PMID: 7648365 [PubMed - indexed for MEDLINE] 6196. Rev Stomatol Chir Maxillofac. 1995;96(3):123-36. [The adipose tissue of the orbit. Anatomic classification, therapeutic deductions]. [Article in French] Gola R(1), Carreau JP, Faissal A. Author information: (1)Service de Stomatologie, Chirurgie maxillo-faciale et Plastique de la face, CHU Nord, Chemin des Bourrely, Marseille. There are two types of adipose tissue in the orbit. The yellow fat and the more abundant white, or orbital fat. Orbital fat cannot be dissociated from the contents of the orbit and plays an important role in ocular physiology and oculomotricity. Orbital fat is essential for aesthetic orbits. Graves' disease and anophthalmia. Adipose tissue in the orbit is particularly important in protecting the ocular globe from lateral wall trauma. PMID: 7644888 [PubMed - indexed for MEDLINE] 6197. Prog Lipid Res. 1995;34(1):53-70. Heterogeneity in adipose tissue metabolism: causes, implications and management of regional adiposity. Abate N(1), Garg A. Author information: (1)Department of Clinical Nutrition, University of Texas Southwestern Medical Center at Dallas 75235-9052, USA. The observation that different patterns of adipose tissue distribution are associated with different metabolic abnormalities, has recently given new impetus to research in obesity. Due to several methodologic problems, however, many aspects of regional excess of adipose tissue are still poorly understood. Among them, the causes and the metabolic consequences of regional adiposity are particularly important. Heterogeneity in adipose tissue distribution may be determined by a combination of genetic and hormonal causes. Both factors may determine differences in metabolism of various adipose tissue compartments primarily by regulating LPL production, storage and release of triacylglycerols, and aromatization of androgens. Furthermore, changes in adipocyte sensitivity to hormones such as, sex steroids, glucocorticoids, insulin and adrenergic hormones may also regulate fat distribution in various adipose tissue compartments. The metabolic heterogeneity of adipose tissue from various compartments, particularly the differences between the "portal" and subcutaneous adipose tissues, may account for several metabolic abnormalities associated with "upper body adiposity". However, no direct evidence is available to confirm this hypothesis. Recent advances in the methodology to study adipose tissue distribution (mainly CT and MRI) may provide the necessary tools to evaluate the true impact of adiposity in various compartments on intermediary metabolism and to identify a "morbid" adipose tissue compartment. These observations may help in designing better therapeutic strategies targeted towards regional adiposity and its metabolic complications. PMID: 7644553 [PubMed - indexed for MEDLINE] 6198. Fundam Clin Pharmacol. 1995;9(2):114-8. Beta 3-adrenoceptors and airways. Martin CA(1), Advenier C. Author information: (1)Université de Rennes I, Laboratoire de Pharmacologie Expérimentale et Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, France. beta 3-adrenoceptors have been identified in a variety of tissues from humans and animals: adipose tissue, gastrointestinal smooth muscle, rat skeletal muscle, bovine skeletal muscle, and human and canine heart. In the airways, the investigation of the beta 3-adrenoceptors came from studies with a series of novel selective agonists. Stimulation of the "atypical" beta-adrenoceptor increases the active transport of albumin across the ferret tracheal epithelium and the ciliary beat frequency of canine bronchial epithelium. Furthermore, it has been demonstrated that beta 3-adrenoceptors agonists selectively inhibited nonadrenergic noncholinergic contractions of guinea-pig bronchi induced by electrical field stimulation or capsaicin. The presence of functional beta 3-adrenoceptors in the bronchial smooth muscle is disputed and seems to be species-related. In isolated canine bronchi, selective agonists induced a relaxation whereas they had no or slight effect in isolated human, guinea-pig and sheep bronchi. Likewise in man, a fall in airway resistance measured by plethysmography, was mediated by beta 2-adrenoceptors, but not beta 3-adrenoceptors. To conclude, an "atypical" or beta 3-adrenoceptor-mediated modulation of bronchomotricity exists, nevertheless strong species specific differences have been reported. PMID: 7628823 [PubMed - indexed for MEDLINE] 6199. Journ Annu Diabetol Hotel Dieu. 1995:129-40. [Autonomic nervous system and development of obesity in the rodent]. [Article in French] Pénicaud L(1), Cousin B, Leloup C, Atef N, Ktorza A. Author information: (1)Laboratoire de Physiopathologie de la Nutrition, CNRS URA 307, Université Paris VII, France. PMID: 7602875 [PubMed - indexed for MEDLINE] 6200. Journ Annu Diabetol Hotel Dieu. 1995:121-8. [Development of insulin resistance in muscle and adipose tissue during obesity in the mouse. Role of phosphatidylinositol 3-kinase]. [Article in French] Le Marchand-Brustel Y(1), Heydrick S, Gautier N, Olichon-Berthe C, Van Obberghen E. Author information: (1)INSERM U145, Faculté de Médecine, Nice. PMID: 7602874 [PubMed - indexed for MEDLINE] 6201. Annu Rev Biochem. 1995;64:345-73. Transcriptional regulation of gene expression during adipocyte differentiation. MacDougald OA(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Cell culture models (e.g. 3T3-L1 cells) have been developed for studying the process of adipocyte differentiation. Differentiation can be induced by adding insulin-like growth factor I, glucocorticoid, fatty acids, and an agent that increases intracellular cAMP level. The adipocyte differentiation program is regulated by transcriptional activators such as CCAAT/enhancer binding protein alpha (C/EBP alpha), peroxisomal proliferator activated receptor gamma 2 (PPAR gamma 2), fatty acid activated receptor (FAAR), and transcriptional repressors such as preadipocyte repressor element binding protein (PRE) and C/EBP undifferentiated protein (CUP). These transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype including the insulin-responsive glucose transporter (GLUT4), stearoyl CoA desaturase 1 (SCD1), and the fatty acid binding protein (422/aP2). PMID: 7574486 [PubMed - indexed for MEDLINE] 6202. Fundam Clin Pharmacol. 1995;9(3):234-9. Beta 3-adrenoceptors in the cardiovascular system. Berlan M(1), Galitzky J, Montastruc JL. Author information: (1)Laboratoire de Pharmacologie Médicale et Clinique, Inserm U 317, Faculté de Médecine, Toulouse, France. Behind the classic beta 1 and beta 2-adrenoceptors, recent molecular and pharmacological studies have described a new receptor, called the beta 3-adrenoceptor, in various mammalian tissues (brown and white adipose tissue, digestive smooth muscle). Few authors have investigated the putative existence of the beta 3-adrenoceptor in the cardiovascular system. This paper reviews the available data. In vitro studies show that beta 3-adrenoceptor agonists (BRL 37344, CGP 12177) induce a relaxation of fragments of rat carotid artery which is not antagonized by propranolol. In dogs, these drugs elicit a decrease in blood pressure due to peripheral vasodilation and an increase in heart rate which is of baroreflex origin. The vasodilating effects are mainly observed in cutaneous and adipose tissue vessels and cannot be explained by any known transductional mechanism. Activation of this vascular beta 3-adrenoceptor requires higher doses of catecholamines than for beta 1- or beta 2-adrenoceptors. In humans, the cardiovascular effects of beta 3-adrenoceptor agonists are explained by the activation of beta 1- or beta 2 (and not beta 3-)-adrenoceptors. These studies suggest the presence of vascular (but not cardiac) beta 3-adrenoceptors in dogs. In other species, including man, the presence of such cardiac beta 3-adrenoceptors remains to be resolved. Their physiological relevance remains unknown. PMID: 7557818 [PubMed - indexed for MEDLINE] 6203. Exerc Sport Sci Rev. 1995;23:411-58. Aging and body composition: biological changes and methodological issues. Going S(1), Williams D, Lohman T. Author information: (1)Department of Exercise and Sports Sciences, University of Arizona, Tucson, USA. There is no doubt that body composition changes with aging. Some general trends have been described, including an increase in body weight and fat mass in middle age followed by a decrease in stature, weight, FFM, and body cell mass at older ages. Losses in muscle, protein, and bone mineral contribute to the decline in FFM; however, the onset and rates of decline remain controversial. Most data are available for men and women < 80 yr and we know relatively little about the normal status and the changes that occur in body composition in elderly men and women. This situation has developed in part because the changes that occur in various body constituents with aging confound the estimation of body composition by traditional techniques. Hence, there is a need for longitudinal reference data in persons 80 yr of age, both to describe the normal status and to develop valid prediction equations for estimating body composition in older men and women in settings outside the laboratory. This should be possible using new technologies and approaches based on multiple component models of body composition. An understanding of the normal changes in body composition with increasing age, the normal variation in these changes, and their health implications is important for the health, nutritional support, and pharmacologic treatment of elderly men and women in the United States. The information is especially important because elderly men and women, in terms of both numbers and health care dollars, represent the most rapidly expanding segment of the U.S. population. PMID: 7556359 [PubMed - indexed for MEDLINE] 6204. Exerc Sport Sci Rev. 1995;23:275-303. Physical activity, body weight, and adiposity: an epidemiologic perspective. DiPietro L(1). Author information: (1)John B. Pierce Laboratory, New Haven, Connecticut, USA. Overweight is a common problem in the United States, especially among minority women and persons of lower socioeconomic status and lower educational attainment. Moreover, the prevalence of reported inactivity may be highest in these same population subgroups. Both overweight and sedentary behavior are important risk factors for chronic disease morbidity and mortality; however, there is encouraging evidence that moderate to higher levels of physical activity may provide protection from certain chronic diseases, even among persons with established risk factors. Several methodological issues preclude the ability to determine accurately the impact of physical activity on body weight and adiposity. These issues include (a) a low prevalence of higher-intensity physical activity in the general population, (b) measurement error with regard to self-reported activity, especially that of lower-intensity, (c) inappropriate time frame of the physical activity assessment, (d) effect modification by age and gender, and (e) failure to adjust for important statistical confounders. Despite these methodological issues, the inverse association between physical activity and weight has been reported in several cross-sectional epidemiologic studies, which consistently report lower body weight, or more favorable distribution of body fat, with higher categorical levels of self-reported physical activity. Directionality of the physical activity and weight relation cannot be determined from these studies, however, and the few longitudinal epidemiologic studies that have assessed the influence of physical activity on the risk of weight gain report inconclusive results. This is possibly because a one-time assessment of physical activity if not adequate in describing the contribution of habitual physical activity on long-term weight maintenance. Therefore, longitudinal population-based studies with multiple assessments of physical activity over long follow-up periods are necessary to determine this relationship. In any case, the evidence suggests that persons concerned with overweight, or especially the prevention of overweight and obesity, should increase their physical activity. Sociodemographic characteristics such as age, gender, educational level, and weight are associated with physical activity patterns and choices. Therefore, these characteristics should be considered by professionals when implementing physical activity interventions for weight control. Walking is accessible to all segments of the U.S. population. Because walking is convenient, low cost, and safe, and can result in weight loss if done regularly for durations of at least 20-30 min, its relative merits should be stressed in weight reduction and maintenance programs. Furthermore, to reduce the morbidity and mortality associated with overweight, obesity, and sedentary behavior, priority for intervention programs should be directed at persons in the most vulnerable sectors of the population. PMID: 7556354 [PubMed - indexed for MEDLINE] 6205. Nihon Rinsho. 1994 Dec;52(12):3292-7. [Nicotinic acid and derivatives for therapy of hyperlipoproteinemia]. [Article in Japanese] Ishikawa T(1). Author information: (1)First Department of Medicine, Defense Medical College. Nicotinic acid and derivatives are effective in numerous forms of hyperlipoproteinemia. Its primary mode of action is to inhibit lipolysis in adipose tissue and to prevent the utilization of free fatty acids for TG-rich lipoprotein synthesis in the liver. Consequently, it decreases the plasma lipoproteins which are considered to be atherogenic--VLDL, LDL and Lp(a), while it increases the antiatherogenic lipoprotein--HDL. A gradual administration of nicotinic acid or derivatives is useful to reduce the side effects such as flushing and itching. In the secondary prevention trials, nicotinic acid therapy with other hypolipidemic drugs asserted protective effects on the development/progression of cardiovascular disease. PMID: 7853725 [PubMed - indexed for MEDLINE] 6206. Nihon Rinsho. 1994 Dec;52(12):3184-90. [VLDL receptor]. [Article in Japanese] Sakai J(1), Yamamoto T. Author information: (1)Department of Molecular Genetics, University of Texas Southwestern Medical Center. The LDL receptor was discovered by Goldstein and Brown in 1974. This discovery has led to dramatic progress toward understanding the mechanisms of cholesterol homeostasis. Recently we have found a second lipoprotein receptor that specifically binds apoE-containing lipoproteins. This new lipoprotein receptor designated VLDL receptor is composed of five functional domains that resemble the LDL receptor. The VLDL mRNA is abundant in heart, muscle and adipose tissue, suggesting that the receptor mediates the uptake of triglyceriderich lipoproteins thereby providing muscle and fat cells with fatty acid. PMID: 7853708 [PubMed - indexed for MEDLINE] 6207. Acta Paediatr Suppl. 1994 Dec;406:60-3; discussion 64. Effects of recombinant human growth hormone on adipose tissue in adults with growth hormone deficiency. Johannsson G(1), Rosén T, Lönn L, Bengtsson BA. Author information: (1)Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden. PMID: 7734813 [PubMed - indexed for MEDLINE] 6208. Acta Paediatr Suppl. 1994 Dec;406:54-8; discussion 59. Effects of growth hormone on lipolysis in humans. Marcus C(1), Margery V, Kamel A, Brönnegård M. Author information: (1)Department of Pediatrics, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden. PMID: 7734812 [PubMed - indexed for MEDLINE] 6209. Acta Paediatr Suppl. 1994 Dec;406:48-53. In vitro effects of growth hormone in adipose tissue. Wabitsch M(1), Hauner H, Heinze E, Teller W. Author information: (1)Department of Pediatrics I, University of Ulm, Germany. PMID: 7734811 [PubMed - indexed for MEDLINE] 6210. J Adolesc Health. 1994 Dec;15(8):619-29. Gender differences in human pharmacokinetics and pharmacodynamics. Fletcher CV(1), Acosta EP, Strykowski JM. Author information: (1)Pediatric AIDS Pharmacology Laboratory, Baylor College of Medicine, Houston, Texas. Gender differences in pharmacokinetics and pharmacodynamics have long been recognized in animals. In humans, however, little attention has been paid to this field despite at least theoretical reasons to believe that gender may be an important variable in the processes of absorption, distribution, metabolism, and excretion. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, amount of drug binding proteins, gender-specific cytochrome P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and renal blood flow are several factors that may contribute to sex-related differences in pharmacokinetics. Clinical investigations have documented greater absorption and subsequent incorporation of iron into erythrocytes, and higher bioavailability of ethanol in females. Women have been shown to have a slower metabolism of mephobarbital and propranolol but an increased biotransformation of methylprednisolone, all three of which are metabolized by enzymes of the cytochrome P450 system. Lastly, the renal excretion of amantadine was inhibited significantly by quinidine and quinine in men but not in women. While gender-specific pharmacodynamic data are meager, evidence also supports the existence of sex-related differences. Women appear to be more prone to develop torsades de points from drugs such as quinidine and procainamide than men. A dimorphism in insulin sensitivity has been demonstrated with males having an enhanced response compared to females. Pharmacokinetic and pharmacodynamic sex-related differences exist and are complex. Future research efforts should be designed to provide more gender-specific information on drug disposition and clinical effect. PMID: 7696281 [PubMed - indexed for MEDLINE] 6211. Ann N Y Acad Sci. 1994 Nov 25;741:1-38. Neuroimmunomodulation. From phenomenology to molecular evidence. Janković BD(1). Author information: (1)Immunology Research Center, Belgrade, Yugoslavia. PMID: 7825795 [PubMed - indexed for MEDLINE] 6212. Biochim Biophys Acta. 1994 Nov 17;1215(1-2):9-32. Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Sparks JD(1), Sparks CE. Author information: (1)Department of Pathology, University of Rochester, School of Medicine and Dentistry, NY 14642. This review has considered a number of observations obtained from studies of insulin in perfused liver, hepatocytes, transformed liver cells and in vivo and each of the experimental systems offers advantages. The evaluation of insulin effects on component lipid synthesis suggests that overall, lipid synthesis is positively influenced by insulin. Short-term high levels of insulin through stimulation of intracellular degradation of freshly translated apo B and effects on synthesis limit the ability of hepatocytes to form and secrete TRL. The intracellular site of apo B degradation may involve membrane-bound apo B, cytoplasmic apo B and apo B which has entered the ER lumen. How insulin favors intracellular apo B degradation is not known. An area of recent investigation is in insulin-stimulated phosphorylation of intracellular substrates such as IRS-1 which activates insulin specific cellular signaling molecules [245]. Candidate molecules to study insulin action on apo B include IRS-1 and SH2-containing signaling molecules. Insulin dysregulation in carbohydrate metabolism occurs in non-insulin-dependent diabetes mellitus due to an imbalance between insulin sensitivity of tissue and pancreatic insulin secretion (reviewed in Refs. [307,308]). Insulin resistance in the liver results in the inability to suppress hepatic glucose production; in muscle, in impaired glucose uptake and oxidation and in adipose tissue, in the inability to suppress release of free FA. This lack of appropriate sensitivity towards insulin action leads to hyperglycemia which in turn stimulates compensatory insulin secretion by the pancreas leading to hyperinsulinemia. Ultimately, there may be failure of the pancreas to fully compensate, hyperglycemia worsens and diabetes develops. The etiology of insulin resistance is being intensively studied for the primary defect may be over secretion of insulin by the pancreas or tissue insulin resistance and both of these defects may be genetically predetermined. We suggest that, in addition to effects in carbohydrate metabolism, insulin resistance in liver results in the inability of first phase insulin to suppress hepatic TRL production which results in hypertriglyceridemia leading to high levels of plasma FA which accentuate insulin resistance in other target organs. As recently reviewed [17,254] the role of insulin as a stimulator of hepatic lipogenesis and TRL production has been long established. Several lines of evidence support that insulin is stimulatory to the production of hepatic TRL in vivo. First, population based studies support a positive relationship between plasma insulin and total TG and VLDL [253]. Second, there is a strong association between chronic hyperinsulinemia and VLDL overproduction [309].(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 7948013 [PubMed - indexed for MEDLINE] 6213. Diabetes. 1994 Nov;43(11):1271-8. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Hotamisligil GS(1), Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Boston, Massachusetts 02115. Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin. PMID: 7926300 [PubMed - indexed for MEDLINE] 6214. Braz J Med Biol Res. 1994 Nov;27(11):2499-519. Carbohydrate-lipid interactions during gestation and their control by insulin. Herrera E(1), Muñoz C, López-Luna P, Ramos P. Author information: (1)Department of Research, Hospital Ramón y Cajal, Madrid, Spain. 1. During the first two thirds of gestation, coinciding with a minimal accretion by the conceptus, the mother is in an anabolic state which is supported by her hyperphagia and the more efficient conservation of exogenous nutrients when she eats. During this phase maternal fat deposits are accumulated thanks to the enhancement in adipose tissue lipogenic and glycerologenic activity. In contrast, in the latter part of gestation, the rapid fetal growth is sustained by the intense transfer of nutrients from maternal circulation. 2. Glucose is quantitatively the most abundant of the several substrates that cross the placenta and despite increased maternal gluconeogenesis this transfer is responsible for the maternal tendency to hypoglycemia. This causes a switch to a net catabolic state which is especially evident in the net breakdown of fat depots. 3. Enhanced release of adipose tissue lipolytic products, free fatty acids (FFA) and glycerol, facilitates the liver synthesis of triglycerides and their later release into circulation associated to very low-density lipoprotein (VLDL). Glycerol is also used as an important gluconeogenic substrate and FFAs are broken down through beta-oxidation for ketone body synthesis. Flow through these pathways becomes increased when food is withheld and this actively contributes to the availability of fuels to the fetus which becomes partially preserved from maternal metabolic insult. Increased liver production of VLDL-triglycerides and decreased extrahepatic lipoprotein lipase contribute to exaggerated maternal hypertriglyceridemia which, besides being a floating metabolic reserve for emergency conditions such as starvation, constitutes an essential substrate for milk synthesis around parturition in preparation for lactation. 4. While the maternal anabolic tendencies found during the first two-thirds of gestation seem to be facilitated by hyperinsulinemia in the presence of a normal responsiveness to the hormone, it is proposed that most of the metabolic changes taking place during the last third of gestation seem to be caused by the insulin-resistant state which is consistently present at this stage, since its reversion caused by sustained exaggerated hyperinsulinemia also reverts several of these metabolic adaptations. PMID: 7549970 [PubMed - indexed for MEDLINE] 6215. Presse Med. 1994 Oct 8;23(30):1393-9. Role of muscle morphology in the development of insulin resistance and metabolic syndrome. Krotkiewski M(1). Author information: (1)Department of Rehabilitation Medicine, Gothenburg University, Sahlgren's Hospital, Sweden. Type IIB muscle fibres are among the most insulin-insensitive muscle fibres and are not adapted to oxidation of fat during muscle work. The first characteristic of this type of muscle fibre most probably reflects or contributes to further development of insulin resistance contribute to further perpetuation of obesity and to the channeling of excess free fatty acids to the liver followed by secondary deterioration of its function. The impaired functioning of the liver is epitomized, among other changes, by impairment of insulin extraction. The increasing hyperinsulinaemia is followed by inhibition of synthesis of specific proteins such as carrier proteins for transporting testosterone (sex hormone binding globulin, SHBG). This results in an increased free testosterone concentration which induces androgenization in women and may further increase insulin insensitivity in abdominal obesity in women. The poor capillarization and changed muscle morphology in spite of great interindividual variety is observed in several pathological conditions characterised by insulin sensitivity (stroke, PCO, hypertension, diabetes, obesity). It is suggested that, in addition to the previous concept of the main role of intraabdominal adipose tissue, even muscles and liver are also important organs contributing to the pathogenesis and development of the metabolic syndrome. PMID: 7831232 [PubMed - indexed for MEDLINE] 6216. Bull Environ Contam Toxicol. 1994 Oct;53(4):501-8. Organochlorine pesticide contaminants in human adipose tissue collected in Ankara (Turkey) 1991-1992. Burgaz S(1), Afkham BL, Karakaya AE. Author information: (1)Gazi University, Faculty of Pharmacy, Department of Toxicology, Ankara, Turkey. PMID: 8000176 [PubMed - indexed for MEDLINE] 6217. Presse Med. 1994 Oct 1;23(29):1353-6. Role of muscle capillarization and morphology in the development of insulin resistance and metabolic syndrome. Krotkiewski M(1). Author information: (1)Department of Rehabilitation Medicine, Gothenburg University, Sahlgren's Hospital, Sweden. PMID: 7984544 [PubMed - indexed for MEDLINE] 6218. Bioessays. 1994 Oct;16(10):745-52. The regulation of the yolk protein genes, a family of sex differentiation genes in Drosophila melanogaster. Bownes M(1). Author information: (1)Division of Biological Sciences, University of Edinburgh, UK. There are many obvious morphological and behavioural differences between male and female Drosophila, whose differing phenotypes are produced by a hierarchy of sex determination genes. These genes have been well characterised at the genetic and molecular level. Similarly, a number of sex-specific differentiation genes have been characterised, such as the chorion and vitelline membrane genes in females and the sex peptide and other accessory gland proteins in males. Despite the depth of these parallel studies, there is only one example of a direct link between the sex determination pathway and the downstream sex differentiation genes, namely the regulation of the female-specific yolk protein genes. The yolk proteins are synthesised in the fat body and ovarian follicle cells of the adult female and are subsequently transported to the oocyte where they are stored for utilization during embryogenesis. The expression of the yolk protein genes is not entirely controlled by the sex determination hierarchy, as several different regulatory pathways must interact to direct their correct sexual, temporal and spatial regulation during development. PMID: 7980478 [PubMed - indexed for MEDLINE] 6219. Physiol Rev. 1994 Oct;74(4):761-811. Regional adiposity and morbidity. Kissebah AH(1), Krakower GR. Author information: (1)Department of Medicine, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin. PMID: 7938225 [PubMed - indexed for MEDLINE] 6220. J Bioenerg Biomembr. 1994 Oct;26(5):537-42. Mitochondrial cation transport: a progress report. Garlid KD(1). Author information: (1)Department of Chemistry, Biochemistry, and Molecular Biology, Oregon Graduate Institute of Science and Technology, Portland 97291-1000. This report summarizes recent work in our laboratory aimed at understanding protein-mediated mitochondrial cation transport. We are studying three distinct cation cycles that contain porters catalyzing influx and efflux of cations between cytosol and mitochondrial matrix. Each of these cation cycles plays a major physiological role in the overall energy economy. The K+ cycle maintains the integrity of the vesicular structure and includes the K+/H+ antiporter, the KATP channel, and K+ leak driven by the high membrane potential. The Ca2+ cycle relays the signals calling for modulation of ATP production and includes the Ca2+ channel, the Na+/Ca2+ antiporter, and the Na+/H+ antiporter. The H+ cycle of brown adipose tissue mitochondria provides heat to hibernating and newborn mammals and consists of the uncoupling protein, which catalyzes regulated H+ influx. PMID: 7896769 [PubMed - indexed for MEDLINE] 6221. Diabetes Res Clin Pract. 1994 Oct;24 Suppl:S111-6. Pathophysiology and pathogenesis of visceral fat obesity. Matsuzawa Y(1), Shimomura I, Nakamura T, Keno Y, Tokunaga K. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. Based on the analysis of fat distribution by CT scanning, we have proposed a classification of obesity: visceral fat obesity, in which fat accumulation is predominant in the intra-abdominal cavity. This type of obesity is more frequently accompanied by disorders of glucose and lipid metabolism, and also with hypertension, than subcutaneous fat obesity. We also showed that almost 90% of obese patients with ischemic heart disease have visceral fat accumulation. From clinical and basic experiments, aging, imbalance of sex hormone, overintake of sucrose and lack of physical exercise have been suggested to be major factors for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) have been show to have high activities of both lipogenesis and lipolysis, its accumulation induces a high content of free fatty acids, a product of lipolysis, in portal circulation which goes into the liver directly. Excess free fatty acid may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. PMID: 7859591 [PubMed - indexed for MEDLINE] 6222. Nutr Rev. 1994 Oct;52(10):356-8. Uptake of retinoids by adipose tissue. Wolf G(1). Author information: (1)Department of Nutritional Sciences, University of California, Berkeley 94720. Adipose tissue was found to contain considerable amounts of retinoids and retinol-binding protein mRNA, particularly in epididymal and perinephric depots. Delivery of retinoids appears to be through the hydrolysis of retinyl esters in postprandial chylomicrons by lipoprotein lipase, with subsequent uptake of retinol by adipocytes. PMID: 7816354 [PubMed - indexed for MEDLINE] 6223. Biochem Pharmacol. 1994 Sep 15;48(6):1059-71. Why are there so many adrenoceptor subtypes? Milligan G(1), Svoboda P, Brown CM. Author information: (1)Department of Biochemistry, University of Glasgow, Scotland, U.K. PMID: 7945399 [PubMed - indexed for MEDLINE] 6224. Obes Res. 1994 Sep;2(5):472-80. Antiobesity and antidiabetic beta-agonists: lessons learned and questions to be answered. Yen TT(1). Author information: (1)Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. In several species of obese animals, a group of phenethanolamine beta-agonists stimulates lipolysis and thermogenesis, resulting in the loss of body fat and weight. Brown adipose tissue is considered to be the major target tissue for the antiobesity activity of these compounds. Independent of this antiobesity activity, some of these compounds are also antidiabetic and increase muscle mass. Based on the pharmacological profile of these compounds, a beta3-receptor was proposed and characterized in mouse, rat, and humans. The beta3-receptor in brown adipose tissue has been suggested to mediate the antiobesity activity of these beta-agonists. Whether this receptor is responsible for the antidiabetic activity and whether there is a linkage between the antiobesity/antidiabetic activity and the nutrient partitioning activity is not clear. Clinical trials with these mixed beta-agonists showed marginal antiobesity effects when caloric intake of subjects was restricted. Insulin sensitivity was also improved in some of the trials designed to test the antidiabetic activity of these compounds. Side effects included tachycardia and tremor. To eliminate these side effects, a second generation of compounds was selected for its agonist activity on rat beta3-receptors. Clinical trials with these compounds have shown little increase of energy expenditure even at high doses. Successful development of an antiobesity and antidiabetic drug from this class of compounds will require the elucidation of the physiological role of the human beta3-receptor and the regulatory mechanism between fuel efficiency and feeding behavior. PMID: 16353599 [PubMed - indexed for MEDLINE] 6225. Diabetologia. 1994 Sep;37 Suppl 2:S170-8. Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM. Jeanrenaud B(1). Author information: (1)Laboratoires de Recherches Métaboliques, Faculty of Medicine, University of Geneva, Switzerland. To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally. PMID: 7821733 [PubMed - indexed for MEDLINE] 6226. J Dairy Sci. 1994 Sep;77(9):2821-36. Metabolic relationships in the supply of nutrients for milk protein synthesis: integrative modeling. Baldwin RL(1), Emery RS, McNamara JP. Author information: (1)Department of Animal Science, University of California, Davis 95616-8521. The objective of research under the NC-185 regional project is to identify the critical chemical transformations in the rumen, digestive tract, gastrointestinal and splanchnic tissues, and adipose and mammary tissues that define patterns of nutrient utilization in lactating dairy cows. This objective includes research on differences in fermentation, digestion, absorption, and tissue utilization of nutrients in sufficiently different situations to permit estimation of parameters defining various nutrient interconversions. The regional project is utilizing dynamic, mechanistic models of metabolism as tools for integrative analyses of experimental data generated by the group. During the early phases of the project emphasized herein, primary emphasis was on development of models of adipose tissue, mammary gland, liver, rumen, and whole animal metabolism. Serious inadequacies exist in the detail and scope of knowledge of rates of chemical transformations across the wide range of milk yields and nutrient intakes found in production situations. Current knowledge, as described in the various equations and parameters in the models, is presented and discussed. Some characteristics of the current models are illustrated, and methods to utilize the models to identify important experiments are discussed. More cooperative efforts are necessary, including experimental designs that focus on quantification of relationships between input and output, physiological mechanisms that alter patterns of nutrient utilization in lactating dairy cows, and yield estimates of the parameters describing the pre- and postabsorptive uses of feed nutrients. PMID: 7814748 [PubMed - indexed for MEDLINE] 6227. Leuk Lymphoma. 1994 Sep;15(1-2):45-9. Interleukin-11. Kobayashi S(1), Teramura M, Oshimi K, Mizoguchi H. Author information: (1)Department of Hematology, Tokyo Women's Medical College, Japan. Interleukin-11 (IL-11), a stromal cell-derived cytokine, has been known to act widely in hematopoietic and non-hematopoietic systems. IL-11 supports the growth of certain types of plasmacytoma and hybridoma cells, acts with interleukin-3 (IL-3) in shortening the Go period of early progenitors. IL-11 supports megakaryocyte colony formation and maturation, and acts as an autocrine growth factor in megakaryoblastic cell lines. In addition, IL-11 stimulates erythrocytopoiesis, enhances antigen-specific antibody responses, induces the synthesis of acute phase proteins, inhibits lipoprotein lipase activity and adipocyte differentiation, and promotes neuronal development. Administration of rhIL-11 to mice resulted in an increase of neutrophils and platelets. The human IL-11 gene is localized at 19q13.3-13.4, and codes 199 amino acids and 23 kDa with no N glycosylation. Its receptor and signal transduction share partially those of interleukin-6 (IL-6). Further analysis of its role in normal and pathological state is necessary to determine the exact function and its application for clinical uses. PMID: 7532057 [PubMed - indexed for MEDLINE] 6228. J Nutr. 1994 Aug;124(8 Suppl):1383S-1391S. Lipid metabolism in adipose tissue during lactation: a model of a metabolic control system. McNamara JP(1). Author information: (1)Department of Animal Sciences and Nutrition Program, Washington State University, Pullman 99164-6320. The flux of energy-yielding compounds through the pathways of lipogenesis, esterification into triglycerides and lipolysis in adipose tissue plays a pivotal role in supplying the demands of lactation and maternal health. The critical importance of these pathways is demonstrated by the number of highly coordinated and redundant metabolic control elements that regulate the enzyme activity in these pathways, including protein and several steroid hormones, catecholamines, and blood concentrations of several nutrients. Control on these pathways is exerted by all of these elements during lactation. Insights have been gained recently into the adaptations of these pathway reactions due to genetic propensity for milk production, stage of lactation, and intake of energy-yielding components such as starch, cellulose and triglycerides. The rates of these pathways vary exponentially with the intakes of key substrates and demands for milk precursors. The parameters of equations describing these pathways are not constant, but vary with genotype and with prolonged changes in nutritional and environmental conditions. Two major regulatory systems are critical to alterations of carbon flux during the entire lactational period. One is the interaction of growth hormone and insulin to control lipogenesis; the other is the counter-regulation by norepinephrine and insulin on cyclic AMP-initiated enzyme phosphorylation to regulate lipolysis. Examples of specific control points having a critical impact on lactational success and that are associated with genetic selection for milk production are the activities of acetyl-CoA carboxylase and hormone sensitive lipase. Further insights into the mechanisms of these adaptations will help us to improve the efficiency of metabolic flux during lactation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8064388 [PubMed - indexed for MEDLINE] 6229. J Nutr. 1994 Aug;124(8 Suppl):1289S-1295S. Dietary regulation of glucose transporter gene expression: tissue specific effects in adipose cells and muscle. Kahn BB(1). Author information: (1)Diabetes Unit, Beth Israel Hospital, Boston, MA. The rapid stimulation of glucose transport into the classic insulin responsive tissues, muscle and adipose cells, is crucial for maintenance of glucose homeostasis in the fed state. Macronutrient content and composition of the diet strongly influence glucose transport into these tissues by altering both the expression of the glucose transporter genes (GLUT1 and GLUT4) and the functional activity of the gene products. Dietary regulation of GLUT1 and GLUT4 is tissue specific. With high fat feeding alterations in transporter expression is much greater in adipose cells than in skeletal muscle. In the unfed state there is a profound down regulation of glucose transporter gene expression in adipose cells while expression of the same transporter genes is increased in skeletal muscle. Thus, tissue specific regulation of glucose transporter expression and function appears to be part of the adaptive response to maintain adequate cellular nutrition in times of altered nutrient availability. PMID: 8064377 [PubMed - indexed for MEDLINE] 6230. Curr Opin Lipidol. 1994 Aug;5(4):274-89. Relation of components of insulin resistance syndrome to coronary disease risk. Després JP(1), Marette A. Author information: (1)Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Quebec, Canada. Insulin resistance, which is a prevalent condition, has been associated with a cluster of metabolic disturbances that increase the risk of non-insulin-dependent diabetes mellitus and cardiovascular diseases. In this review article, the complexity of the etiology of insulin resistance is emphasized as it results from the interaction of genetic and environmental factors. Potential cellular defects underlying insulin resistance are discussed as well as the relation of impaired insulin action to dyslipidaemia and coronary heart disease. PMID: 7981959 [PubMed - indexed for MEDLINE] 6231. Diabetes Care. 1994 Aug;17(8):924-37. Exercise in individuals with IDDM. Wasserman DH(1), Zinman B. Author information: (1)Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. PMID: 7956645 [PubMed - indexed for MEDLINE] 6232. J Nutr. 1994 Aug;124(8 Suppl):1273S-1283S. Pattern and regulation of acetyl-CoA carboxylase gene expression. Kim KH(1), Tae HJ. Author information: (1)Department of Biochemistry, Purdue University, West Lafayette, IN 47907. Acetyl-CoA carboxylase is the rate-limiting enzyme in the biogenesis of long chain fatty acids. There is a single copy of the gene for acetyl-CoA carboxylase per haploid chromosome set. The gene contains two promoters whose primary transcripts are differentially spliced resulting in multiple forms of acetyl-CoA carboxylase mRNA. These mRNA species are different in the 5'-untranslated region, but contain the same coding region. Generation of different forms of the mRNA is tissue specific and controlled by physiological conditions. Two promoters contain an extensive array of cis-elements that perceive changes in the cellular environment signalling repression and induction of long chain fatty acid synthesis. The ability of the gene to respond to various lipogenic signals and the presence of the same coding sequence in all acetyl-CoA carboxylase mRNA species suggest that the biosynthesis of fatty acids required for multiple functions in the cells is primarily regulated at the gene level. PMID: 7914919 [PubMed - indexed for MEDLINE] 6233. Am J Obstet Gynecol. 1994 Jul;171(1):118-25. Energy-sparing strategies to protect human fetal growth. Poppitt SD(1), Prentice AM, Goldberg GR, Whitehead RG. Author information: (1)Dunn Clinical Nutrition Centre, Cambridge, United Kingdom. OBJECTIVES: Our purpose was to test whether energy-sensitive adjustments in gestational metabolism, previously observed in studies of Gambian and British women, are a general phenomenon and to define the nutritional factors that direct them. STUDY DESIGN: Retrospective analysis of data on basal metabolic rate and fat deposition in 360 pregnancies from 10 studies in a wide range of nutritional settings was performed. RESULTS: The energy costs of pregnancy varied widely between different communities: maintenance costs from -45 to +210 MJ, fat deposition from -23 to +267 MJ, and total energy costs from -20 to +523 MJ. Total costs were correlated with prepregnancy fatness (r = 0.80, p < 0.01) and pregnancy weight gain (r = 0.94, p < 0.001). Marginally nourished women conserved energy by suppressing metabolic rate and by gaining little fat. CONCLUSIONS: The energy needs of pregnancy are modulated over a wide range in response to maternal energy status. This may be an important means of protecting fetal growth. PIP: Fetal growth within pregnant women requires energy above and beyond that typically required to maintain normal function in the nonpregnant human female. Many women, however, especially in comparatively poor countries, are undernourished and can not freely secure and consume the additional nutrients which their bodies request. These women still manage to bear children successfully despite the nutritional constraints. The authors previously conducted parallel studies of the energy costs of pregnancy in poor women from a group of rural Gambian villages and in affluent women from Cambridge, United Kingdom. They identified important energy-sparing metabolic strategies which, in response to the energy stresses of pregnancy, help achieve a successful outcome under marginal nutritional conditions. This more recent study was conducted to test whether energy-sensitive adjustments in gestational metabolism observed in the former studies of Gambian and British women are a general phenomenon and to define the nutritional factors which direct them. Data are analyzed from all published studies in which the energy costs of pregnancy have been measured. This covers 360 pregnancies from the Netherlands, Sweden, Scotland, England, the Philippines, Thailand, and the Gambia. It is concluded that the energy needs of pregnancy are modulated over a wide range in response to maternal energy status. Energy costs of pregnancy varied widely between different communities, total costs were correlated with prepregnancy fatness and pregnancy weight gain, and marginally nourished women conserved energy by suppressing metabolic rate and by gaining little fat. PMID: 8030686 [PubMed - indexed for MEDLINE] 6234. Proc Soc Exp Biol Med. 1994 Jul;206(3):185-9. Overexpression of the short form of the growth hormone receptor in 3T3-L1 mouse preadipocytes. Bick T(1), Frick GP, Leonard D, Leonard JL, Goodman HM. Author information: (1)Department of Physiology, University of Massachusetts Medical School, Worchester 01655. In rodents, the gene for the growth hormone receptor (GHR) gives rise to two mRNA transcripts encoding two proteins: a larger membrane spanning receptor (GHRL) and a smaller isoform, GHRs that consists of the extracellular domain and a unique hydrophilic carboxyl terminus. We examined the hypothesis that GHRs may contribute to cellular binding of GH and play a role in growth hormone (GH) signaling. Rat cDNA encoding GHRs was ligated into the mammalian expression vector pcDNA-I/neo and stably transfected into mouse 3T3-L1 preadipocytes which have endogenous GH receptors and, when differentiated into adipocytes, have the biochemical machinery to express the various GH effects. Sixteen of 24 neomycin resistant clones secreted at least twice as much GHRs in the growth medium as cells transfected with the vector alone, and in nine of these, GH binding was increased 2- to 4-fold. The amount of GHRL in extracts of these cells was unchanged, indicating that increased binding could not be accounted for by effects on formation or degradation of GHRL. The transfected cDNA for GHRs directs the synthesis of a 50 kDa protein. Cross-linking of [125I]hGH to transfected 3T3-L1 cells indicated a 3.5-fold increase in a 72 kDa GHRs[125I]hGH complex. In the presence of 10% newborn calf serum, incorporation of [35S]methionine into cellular proteins was similar in transfected clones and control cells. Deprivation of serum for 2 hr decreased protein synthesis by approximately 70% in control cells, but in the transfected cells, protein synthesis was reduced only by approximately 50% or 30% in cells exhibiting 2x or 3x increases in GH binding. In all cells, 1 nM IGF-1 restored protein synthesis to the serum replete level. Similarly, although 3H-2-deoxy-D-glucose (2DG) uptake was comparable in all cells after 2 hr of serum deprivation, 18 hr of serum deprivation decreased uptake by approximately 70% in control cells, but only by approximately 30% in cells with increased GH binding. One nanomolar IGF-1 restored 2DG uptake to levels seen after 2 hr or serum deprivation. IGF-1 had no effect after only 2 hr of serum deprivation. Measurement of IGF-1 secreted into the medium, revealed that clones which overexpress GHRs produce greater amounts of IGF-1 than control cells or transfected clones that failed to overexpress GHRs. We conclude that GHRs contributes to GH binding and may therefore be a functional receptor. In addition, overexpression of GHRs in 3T3-L1 cells altered cell function in the absence of GH. PMID: 8016151 [PubMed - indexed for MEDLINE] 6235. Clin Chem. 1994 Jul;40(7 Pt 2):1405-8. Chlorinated dibenzo-p-dioxins and -furans: problems in analysis of biomarkers. Schlatter C(1). Author information: (1)Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach. Although dioxin concentrations in adipose tissue or blood lipids can suitably be used for toxicological evaluation, such data usually are not yet asked for in the risk assessment process, which is still based mainly on theoretical calculations of possible environmental exposure instead of measured concentrations in humans. The latter is necessary because the substantial kinetic differences between experimental animals and humans observed for dioxins lead to different organ concentrations and distribution patterns. Hence the classical extrapolation method for assessing toxicity on the basis of the administered oral dose is inappropriate. Also, the applied models and theoretical assumptions that often predicted a considerable human exposure by the oral, dermal, or inhalatory route in the case of contaminated soil and dust have not proved to be pertinent, since the actual burdens determined by biomonitoring in people living at heavily contaminated sites did not show markedly increased concentrations. PMID: 8013128 [PubMed - indexed for MEDLINE] 6236. Clin Chem. 1994 Jul;40(7 Pt 2):1368-75. Critical evaluation of current concepts in exposure assessment. Heinzow BG(1), McLean A. Author information: (1)Institute of Environmental Toxicology, Kiel, Germany. The exploitation of natural resources and the improper use and disposal of thousands of chemicals have resulted in environmental pollution and a potential threat to human health on a global scale. Increasing public concern about environmental exposure to and consequent ill health from contaminants demands informed answers based on valid risk assessment. By assessing internal exposure to pollutants, human biomonitoring focuses on early markers of potential risks to prevent serious adverse effects. Exposure assessment may provide a rational basis for risk assessment, with knowledge of the adequacy of limit values; it may also uncover long-term changes in body burdens and thus help identify the sources and transfer pathways of environmental pollutants. The techniques of biological exposure assessment should be incorporated into epidemiological studies if suitable specimens are available, such as exhaled air, blood, urine, breast milk, or adipose or keratinous tissue. Special precautions must be taken in sampling, storage, and analysis if the findings are to be interpreted correctly and reliable conclusions drawn. PMID: 8013121 [PubMed - indexed for MEDLINE] 6237. Baillieres Clin Endocrinol Metab. 1994 Jul;8(3):661-88. Traditional treatment of obesity: does it work? Dyer RG(1). Author information: (1)Department of Medicine, School of Clinical Medical Sciences, Medical School, Newcastle upon Tyne, UK. Obesity is the most important nutritional disorder in the developed world, since up to 10% of the population are obese. The place of physical activity and diet in the aetiology of obesity is discussed. The traditional treatment of obesity includes change in lifestyle, nutritional education and modification and increase in exercise. These changes are important for long-term success. There are a number of other treatment options including anorectic drugs, the use of very low calorie diets and surgical techniques which may have some clinical role. For the extremely obese patient with established complications surgery may be the most appropriate intervention and may be life-saving. Most studies of traditional treatment have demonstrated limited success. The prevention of obesity is therefore of great importance. Large-scale studies have shown that it is possible to modify behaviour and cardiovascular risk factors. The prevention of obesity requires a coordinated approach with targeting of children and their carers. Governmental involvement and legislation is essential. The future holds the promise of more imaginative and coordinated therapies for obesity using the skills of physicians, nutritionists, exercise physiologists and psychologists. Different forms of treatment may be appropriate for different groups of obese patients. PMID: 7980351 [PubMed - indexed for MEDLINE] 6238. Baillieres Clin Endocrinol Metab. 1994 Jul;8(3):629-60. Dyslipidaemia and obesity. Després JP(1). Author information: (1)Lipid Research Center, CHUL Research Center, Ste-Foy, Quebec, Canada. Obesity is frequently associated with a dyslipidaemic state. Several metabolic and epidemiological studies published in the 1980s have, however, emphasized the importance of considering the regional distribution of body fat in the assessment of the health hazards of obesity. The development of imaging techniques such as computed tomography has also allowed it to be established that the fat located in the abdominal cavity, i.e. the visceral adipose tissue, was the critical correlate of the metabolic complications found in abdominal obesity which include insulin resistance and hyperinsulinaemia, glucose intolerance, hypertriglyceridaemia, hypoalphalipoproteinaemia and increased concentrations of dense LDL particles. Furthermore, since several genes are involved in the regulation of plasma lipoprotein-lipid levels and they have been reported to show polymorphism, visceral obesity should be considered as a permissive factor that exacerbates an individual's susceptibility to dyslipidaemia and premature coronary heart disease rather than a primary regulator of the dyslipidaemic state observed in visceral obese patients. Finally, as insulin resistance and the level of visceral adipose tissue are two main correlates of the dyslipidaemic state which characterizes abdominal obesity, treatment should be aimed at reducing visceral fat and improving insulin sensitivity. Prospective studies are clearly warranted to evaluate the potential benefits of such interventions on the incidence of coronary heart disease. PMID: 7980350 [PubMed - indexed for MEDLINE] 6239. Baillieres Clin Endocrinol Metab. 1994 Jul;8(3):549-75. Hormones and obesity. Kopelman PG(1). Author information: (1)London Hospital Medical College, UK. This chapter has reviewed the evidence for obesity being characterized by distinct patterns of hormonal changes related to both the degree of obesity and the distribution of fat tissue. Many of these changes are also seen in subjects with Cushing's and polycystic ovary syndromes, in particular hyperinsulinaemia, alterations in adrenocortical activity and sex steroid secretion and binding. Animal models of obesity provide evidence to suggest the possibility of a primary abnormality of hypothalamic-pituitary function as a basis to corpulence and this cannot be excluded in the human situation. Nevertheless, abdominal distribution of adiposity plays a significant role in establishing a vicious cycle of metabolic events which may perpetuate both the obese state and PCOS. It is of interest that the additive genetic effect for total body fat is about 25% whereas the heritability of subcutaneous truncal-abdominal fat is about 30-35%, and may possibly be higher (Bouchard et al, 1993). Upper body obesity is characterized by large adipose cells with higher LPL activity, elevated basal and stimulated lipolysis but a low antilipolytic effect of insulin. The results from preliminary investigations of potential candidate genes suggest a possible genetic basis to hyperinsulinaemia/insulin resistance found in upper body obesity but further studies of greater numbers are required for confirmation. It is hoped that the findings from such molecular studies will shed additional light on both the genetic background to obesity and the complex hormonal alterations seen at the tissue level. This should provide the confirmation of a unifying theory for the causal factors associated with obesity and related conditions. PMID: 7980347 [PubMed - indexed for MEDLINE] 6240. Probl Endokrinol (Mosk). 1994 Jul-Aug;40(4):65-81. [Growth hormone deficiency in adults. Introduction to the problem]. [Article in Russian] Bengtsson MB. PMID: 7971916 [PubMed - indexed for MEDLINE] 6241. Minerva Pediatr. 1994 Jul-Aug;46(7-8):343-6. [Thrombocytosis and neonatal subcutaneous adiponecrosis]. [Article in Italian] Turba F(1), Bianchi C, Cella D, Rondanini GF. Author information: (1)Divisione di Pediatria e Neonatologia, Regione Lombardia USSL n. 59, Vaprio D'Adda, Milano. The authors report three newborns with subcutaneous fat necrosis, that appeared between the 4th and 21st day of life. The infants, full term of normal weight, presented severe perinatal hypoxia and needed primary resuscitation. Severity and duration of perinatal hypoxia were not related with the time of cutaneous lesion onset. Serum calcium levels were in the higher values of the neonatal normal range. Vitamin D levels were within the normal range and only one patient showed a transient elevation of PTH, suggesting a poor relevance of both these factors in determining serum calcium increase. All patients showed a marked increase of platelets number, before the onset of clinical manifestations. Thrombocytosis could play an important role in the pathogenesis of adipose tissue necrosis, causing lower blood perfusion with relative hypoxia and hypothermia. PMID: 7935252 [PubMed - indexed for MEDLINE] 6242. Diabete Metab. 1994 Jul-Aug;20(4):375-93. Metabolic complications of visceral obesity: contribution to the aetiology of type 2 diabetes and implications for prevention and treatment. Lemieux S(1), Després JP. Author information: (1)Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Québec, Canada. PMID: 7843469 [PubMed - indexed for MEDLINE] 6243. Sports Med. 1994 Jun;17(6):353-7. Body composition assessment in women. Special considerations for athletes. Oppliger RA(1), Cassady SL. Author information: (1)Department of Family Practice, University of Iowa, Iowa City. PMID: 8091045 [PubMed - indexed for MEDLINE] 6244. J Anim Sci. 1994 Jun;72(6):1475-86. A review of probes and robots: implementing new technologies in meat evaluation. Swatland HJ(1), Ananthanarayanan SP, Goldenberg AA. Author information: (1)Department of Animal and Poultry Science, University of Guelph, Ontario, Canada. Changes in function from fat-depth measurement to meat quality measurement, and vice versa, have occurred in the history of electrical and optical meat probes. In the future, robotic systems might use ultrasonics to measure subcutaneous fat depth while at the same time positioning a fiber-optic probe relative to the skeleton to measure meat quality. There is a major distinction between probes that make a measurement at a single site within the carcass and those that produce a vector of measurements as they move through the carcass. Vector measurements were introduced to find subcutaneous fat thickness, but they may be used for meat quality measurements to deal with intra- and intermuscular variation. Replacement of hand-held probes by robots is in progress and could change meat distribution and marketing, perhaps replacing conventional meat grading by lowering the unit cost of grading and improving reliability for consumers. The feasibility of using ultrasonics to find probe measuring sites in the thoraco-lumbar region of pork carcasses has been proven. This requires new types of carcass morphometry data, such as rib angles and curvatures, and intercostal dimensions. PMID: 8071172 [PubMed - indexed for MEDLINE] 6245. Endocrinol Metab Clin North Am. 1994 Jun;23(2):405-27. Obesity and hypertension. Hsueh WA(1), Buchanan TA. Author information: (1)Department of Medicine, University of Southern California Medical Center. Obesity is associated with a spectrum of metabolic and cardiovascular disorders, including hypertension. Both the degree and the distribution of excess adipose tissue impact on the risk of hypertension and associated cardiovascular diseases. The mechanisms that may lead to hypertension in obese individuals include increased SNS activity, insulin resistance and hyperinsulinemia, sodium retention, and enhanced vascular reactivity. These abnormalities are interrelated in a complex fashion, making it difficult to determine which, if any, of them is the primary process leading to elevated blood pressure in obese individuals. Nonetheless, the metabolic abnormalities and hypertension diminish with weight loss and chronic exercise, providing a strong rationale for hypocaloric diets and aerobic exercise in the treatment of obesity-related hypertension. Patients who fail to achieve acceptable blood pressure control with diet and exercise therapy require pharmacologic treatment. Of the available antihypertensive agents, calcium entry blockers, ACE inhibitors, and alpha 1-receptor blockers appear to offer good blood pressure control without worsening--and sometimes while improving--the lipid and carbohydrate abnormalities that often occur in obese patients. New drugs developed to ameliorate insulin resistance show promise as antihypertensive agents as well, and may prove to be ideal in reversing multiple cardiovascular risk factors in obese, hypertensive patients. PMID: 8070430 [PubMed - indexed for MEDLINE] 6246. J Steroid Biochem Mol Biol. 1994 Jun;49(4-6):319-26. Aromatase gene expression in adipose tissue: relationship to breast cancer. Bulun SE(1), Mahendroo MS, Simpson ER. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas 75235. Recent studies have established that concentration gradients of aromatase expression occur within the breast, with the highest levels of expression occurring in sites proximal to a tumor. These variations in aromatase expression correlate with regional differences in the relative proportions of the histologic components of breast adipose tissue, in particular adipocytes and stromal cells, since regions containing the highest numbers of stromal cells are the sites of elevated aromatase transcript levels. Although the initiating events are unknown, it is proposed that, once neoplastic cells start to replicate, tumor growth will be promoted by locally increased estrogen levels. In turn, growth factors produced by the tumor in response to locally increased estrogen levels may further increase aromatase expression in the surrounding adipose tissue. Thus a positive feed-back loop is established in which locally-produced estrogens and tumor-derived growth factors act by paracrine and autocrine mechanisms to sustain the growth and development of the tumor. Further support for this concept is obtained from the observation that aromatase expression in breast adipose is regulated by enhancer elements that appear to respond positively to growth factors, in contrast to expression in granulosa cells, which is inhibited by growth factors. PMID: 8043495 [PubMed - indexed for MEDLINE] 6247. Curr Opin Lipidol. 1994 Jun;5(3):166-74. Fatty acids, hyperinsulinemia, and insulin resistance: which comes first? Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, University of Göteborg, Sweden. The inhibiting effect of insulin on the mobilization of free fatty acids (FFA) from adipose tissue is halted in prevalent conditions with systemic insulin resistance. The nature and cause of this perturbation are unknown, but steroid hormones may be involved. The consequence is the creation or amplification of insulin resistance in muscle and liver. PMID: 7952910 [PubMed - indexed for MEDLINE] 6248. Rev Prat. 1994 Jun 1;44(11):1487-93. [Lipoprotein lipase: a key enzyme of lipid metabolism]. [Article in French] Bruckert E(1), Dejager S. Author information: (1)Unité d'exploration métabolique pour la prévention des maladies cardiovasculaires, hôpital Pitié-Salpêtrière, Paris. Lipoprotein lipase (LPL), a 55 kDa secretory glycoprotein produced in numerous tissues, is a hydrolytic enzyme, rate-limiting for the removal of lipoprotein TG from the circulation. It is activated by apoprotein CII present on TG-rich lipoproteins. It is involved in lipid transfer between lipoproteins, and plays an important role in the formation of HDL. The fate of LPL-derived lypolysis products differs between tissues: for instance, in adipose tissue, LPL-mediated delivery of free fatty acids is rate-limiting for TG storage, whereas in muscle it provides an alternate source of lipid fuel. LPL is regulated by hormones like insulin and nutrients; its activity depends on the metabolic state of the tissue. It has distinct roles in many normal tissues, such as adipocytes or muscles, as well as an important role in atherogenic dyslipidemia and in metabolic diseases including obesity and hypertriglyceridemia. PMID: 7939219 [PubMed - indexed for MEDLINE] 6249. Am J Clin Nutr. 1994 May;59(5):955-9. Critical periods in childhood for the development of obesity. Dietz WH(1). Author information: (1)Division of Pediatric Gastroenterology and Nutrition, New England Medical Center, Boston, MA 02111. Critical periods of development have been well recognized for many behavioral and developmental processes. However, as others have pointed out, such periods have not been widely reported for nutritional diseases. Many observations suggest that two and possibly three critical periods exist for the development of obesity and its complications. These include gestation and early infancy, the period of adiposity rebound that occurs between 5 and 7 y of age, and adolescence. Obesity that begins at these periods appears to increase the risk of persistent obesity and its complications. The mechanisms that account for the increased risk associated with obesity at these ages remain unclear. Nonetheless, the existence of critical periods should serve to focus preventive efforts on these developmental stages. PMID: 8172099 [PubMed - indexed for MEDLINE] 6250. Vet Clin North Am Small Anim Pract. 1994 May;24(3):467-76. Etiopathogenesis of canine hypothyroidism. Kemppainen RJ(1), Clark TP. Author information: (1)Department of Physiology and Pharmacology, Auburn University College of Veterinary Medicine, Alabama. Hypothyroidism in dogs usually results from a progressive destruction of the thyroid, associated with either lymphocytic thyroiditis or idiopathic atrophy. Both syndromes seem to occur with approximately equal frequency. Lymphocytic thyroiditis, which resembles Hashimoto's thyroiditis in humans, is probably an autoimmune disease, and patients often show thyroid autoantibody titers in circulation. By contrast, the pathogenesis of idiopathic atrophy is unclear, and the thyroid seems simply replaced by adipose and connective tissue. PMID: 8053106 [PubMed - indexed for MEDLINE] 6251. Cell Signal. 1994 May;6(4):363-92. Differential recruitment and differential regulation by physiological amines of fat cell beta-1, beta-2 and beta-3 adrenergic receptors expressed in native fat cells and in transfected cell lines. Lafontan M(1). Author information: (1)Unité INSERM 317, Institut Louis Bugnard, Faculté de Médecine, CHU Rangueil, Toulouse, France. PMID: 7946963 [PubMed - indexed for MEDLINE] 6252. Gen Pharmacol. 1994 May;25(3):387-94. 1,3-Dipropyl-8-cyclopentyl xanthine (DPCPX): a useful tool for pharmacologists and physiologists? Coates J(1), Sheehan MJ, Strong P. Author information: (1)Department of Gastrointestinal Pharmacology, Glaxo Group Research Ltd, Ware, Herts, England. There is now ample evidence in the literature to demonstrate the selectivity of action of DPCPX for adenosine A1 vs other adenosine receptor types in tissues derived from a wide range of species. However, care has to be exercised to ensure that its physiochemical properties do not result in the production of quantitatively misleading data. In experiments using canine tissues the still limited data available in the literature clearly and consistently demonstrate that DPCPX has a lower affinity than expected in preparations which would be anticipated to contain A1 receptors. A range of in vitro experiments also demonstrate that DPCPX is not always a "neutral" or "silent" antagonist. The mechanism underlying these additional effects is unclear, but may result from an ability of the compound to disrupt the normal interaction of the A1 receptor with Gi, or may be indicative of a lack of specificity of action. The limited evidence available suggests that the compound retains its selectivity and specificity of action in vivo, and early work indicates that the compound is proving to be a useful tool with which to explore the potential of activation of adenosine A1 receptors as an important mechanism in physiological and pathophysiological processes. PMID: 7926579 [PubMed - indexed for MEDLINE] 6253. Nihon Rinsho. 1994 Apr;52(4):969-73. [Thyrotropin receptor is expressed in non-thyroid tissues]. [Article in Japanese] Endo T(1), Onaya T. Author information: (1)Third Department of Internal Medicine, University of Yamanashi Medical School. We have obtained TSH-R cDNA fragments from rat retro-orbital tissues and adipose tissue as well as FRTL5 cells by polymerase chain reaction methods. Nucleotide sequence of the non-thyroid cDNA was identical to that of the thyroid. Northern blot analysis has revealed that extremely high amount of TSH-R mRNA exist in the adipose tissue. TSH-R peptide antibody produced in rabbit, which stained recombinant TSH-R as 104 and 100 kDa proteins, also recognized the same M.W. bands in the adipose tissue and the retro-orbital tissues. These results suggest that TSH-R is expressed even in non-thyroid tissues. PMID: 8196188 [PubMed - indexed for MEDLINE] 6254. Baillieres Clin Endocrinol Metab. 1994 Apr;8(2):285-304. Hormone-nuclear receptor interactions in health and disease. The iodothyronine deiodinases and 5'-deiodination. Beckett GJ(1), Arthur JR. Author information: (1)University Department of Clinical Biochemistry, Royal Infirmary, Edinburgh, UK. Two types of iodothyronine deiodinase (ID-I and ID-II) catalyse the 5'-deiodination of thyroxine (T4) to produce the biologically active triiodothyronine (T3). Under normal circumstances ID-I in liver and kidney provides the main source of T3 to the circulation, whilst ID-II is largely responsible for local T3 production in the CNS, brown adipose tissue and pituitary. In some circumstances ID-II in brown adipose tissue and ID-I in the thyroid may provide a significant source of plasma T3, and ID-I in the pituitary may be important for local T3 production in this gland. The IDs thus play a pivotal role in controlling the supply of T3 to the nuclear receptors. ID-I is a selenoenzyme and, although ID-II activity is reduced in selenium deficiency, this is a consequence of increased plasma T4 concentration, rather than ID-II activity being directly dependent on selenium. Changes in 5'-deiodination occur in a number of situations such as poor nutrition, illness, iodine and selenium deficiency, and drug therapy. In iodine deficiency these changes appear to have evolved to ensure that the plasma T3 level is maintained and also to provide the brain with a degree of protection from hypothyroxinaemia. Relatively little is known about the importance of selenium deficiency on thyroid function in humans but, in combination with iodine deficiency, selenium deficiency may prove to be a contributing factor in the pathogenesis of myxodematous cretinism. The changes that occur in ID-I and ID-II in illness produce abnormalities in thyroid function tests which, although of no direct clinical significance, may lead to interpretative problems. PMID: 8092974 [PubMed - indexed for MEDLINE] 6255. W V Med J. 1994 Apr;90(4):145-6. Sporadic multiple lipomatosis: a case report and review of the literature. Wilson D(1), Boland J. Author information: (1)Robert C. Byrd Health Sciences Center of WVU, Morgantown. The finding of multiple lipomas, or lipomatosis, can be a marker for several clinical or familial syndromes. Familial multiple lipomatosis is a benign hereditary disorder of adipose regulation associated with hyperlipidemia. Multiple symmetric lipomatosis involves the local infiltration of adipose tissue of the neck, upper torso and mediastinum. This condition is often found in alcoholics and has been associated with diabetes mellitus. An afflicted patient's family history is important both to reveal occult pathology and to help determine the disease's prevalence in the population. In this article, we report the case of a patient with sporadic multiple lipomatosis and provide a brief review of the literature. PMID: 8009872 [PubMed - indexed for MEDLINE] 6256. J Child Neurol. 1994 Apr;9(2):193-201. New insights into the pathogenesis of congenital myopathies. Sarnat HB(1). Author information: (1)Department of Pediatrics, University of Washington School of Medicine, Seattle 98105. Congenital myopathies are developmental disorders of muscle that are best understood in the context of ontogenesis. Segmental amyoplasia results from a defective somite, usually because of lack of induction by the notochord and neural tube; the connective tissue matrix of the muscle is derived from lateral mesoderm and is present, but the myocytes are derived from somitic mesoderm and are replaced by adipose cells. Generalized amyoplasia is due to defective myogenic regulatory genes. X-linked recessive myotubular myopathy is associated with overexpression of vimentin and desmin, fetal intermediate filaments that attach to nuclear, mitochondrial, and inner sarcolemmal membranes and Z-bands of sarcomeres to preserve the morphologic organization of the myotube. Neonatal myotonic dystrophy is a true maturational delay in muscle development. Congenital muscle fiber-type disproportion is a syndrome of multiple etiologies but in some cases is associated with cerebellar hypoplasia and may be the result of abnormal suprasegmental stimulation of the developing motor unit at 20 to 28 weeks' gestation, mediated through bulbospinal pathways but not the corticospinal tract. Maturational delay of muscle in late developmental stages is less specific than in stages before midgestation. The Proteus syndrome is a muscular dysgenesis; abnormal paracrine growth factors and perhaps altered genes that regulate muscle differentiation and growth, such as myoD and myogenin, are the suspected cause. Focal proliferative myositis may be another example of a "paracrine myopathy." PMID: 8006374 [PubMed - indexed for MEDLINE] 6257. Vet Clin North Am Food Anim Pract. 1994 Mar;10(1):69-106. Cold thermoregulation in the newborn calf. Carstens GE(1). Author information: (1)Department of Animal Science, Texas A&M University, College Station. During the fetal to neonatal transition, the newborn calf encounters severe thermolysis due to an abrupt change in thermal environment that is compounded by evaporation of fetal fluids and severe weather conditions. Maintenance of homeothermy during the neonatal period necessitates an acute and sustained thermogenic response by the newborn calf. It is now widely accepted that this thermogenic response is derived from both shivering thermogenesis in muscle tissue and nonshivering thermogenesis in brown adipose tissue (BAT). It is critical that newborn calves possess functional BAT during the neonatal period. This article focuses on the pre- and postnatal factors that influence nonshivering thermogenesis of BAT in the neonatal calf. PMID: 8199923 [PubMed - indexed for MEDLINE] 6258. Proc Soc Exp Biol Med. 1994 Mar;205(3):213-9. Origin of the angiotensin II secreted by cells. Ganong WF(1). Author information: (1)Department of Physiology, University of California, San Francisco 94143-0444. Circulating angiotensin II is unique in that it is formed in the blood by the interaction of circulating proteins. There are in addition many local renin-angiotensin systems in tissues in which angiotensin II is apparently secreted by various types of cells. This brief review considers the possible pathways for synthesis of locally produced angiotensin II in the brain, the anterior pituitary, the testes, the ovaries, the adrenal cortex, the kidneys, the heart, blood vessel walls, and brown and white fat. Synthesis by cells in culture is also reviewed. The possibility that certain cells contain a complete intracellular renin-angiotensin system is not ruled out, but there are problems with this hypothesis. Proteases other than renin may be involved, and there may be different pathways in different tissues. However, it appears that at least in some tissues, angiotensinogen is produced in one population of cells and transported in a paracrine fashion to other renin-containing cells, where it serves as the substrate for production of angiotensin II. PMID: 8171042 [PubMed - indexed for MEDLINE] 6259. FASEB J. 1994 Mar 1;8(3):302-10. Appetite and the regulation of body composition. Weigle DS(1). Author information: (1)Department of Medicine, University of Washington School of Medicine, Harborview Medical Center, Seattle 98104. Stability of body composition requires that energy intake equals energy expenditure when integrated over prolonged periods. As recent human studies have failed to demonstrate active changes in energy expenditure with changes in body composition, it is likely that energy intake is continually adjusted to preserve a constant total adipose tissue mass. If adipose tissue mass is regulated directly, then there must be some input reflecting this quantity to the central nervous system for the purpose of making corrective changes in appetite when total body fat content fluctuates. The nature of this input has been examined in a variety of animal experiments involving induced weight change, lipectomy, plasma transfer from obese or satiated animals to hungry animals, and parabiosis between obese and lean animals. The bulk of evidence suggests that the plasma level of one or more currently unidentified stable circulating molecules increases in proportion to total body fat content and augments the effect of meal-related satiety signals in the central nervous system. The implications of this adipose tissue-related satiety factor for the pathogenesis of obesity, and the possible nature of the factor are discussed. PMID: 8143936 [PubMed - indexed for MEDLINE] 6260. Proc Nutr Soc. 1994 Mar;53(1):113-29. The right weight: body fat, menarche and fertility. Frisch RE(1). Author information: (1)Harvard Center for Population and Development Studies, Cambridge, MA 02138. PMID: 8029220 [PubMed - indexed for MEDLINE] 6261. J Sports Med Phys Fitness. 1994 Mar;34(1):91-8. Physical activity and reduction of health risks: how far are the benefits independent of fat loss? Shephard RJ(1). Author information: (1)School of Physical and Health Education, Faculty of Medicine, University of Toronto, Canada. This paper considers how far the postulated health benefits of exercise are attributable to a decrease of body fat. Some of the well-accepted gains such as a reduction in the risk of ischemic heart disease are seen even when the data are controlled for body mass. However, other responses such as a reduced incidence of some types of cancer and a decrease of waking blood pressure are closely linked to body fat content and associated metabolic disturbances. The medium-term weight loss is relatively similar for an exercise programme and a dietary regimen, but exercise tends to conserve lean tissue. Exercise also has unique beneficial effects upon musculo-skeletal disorders and mood state. Perhaps most importantly, it improves the quality of life, helping to maintain physical abilities and thus independence into extreme old age. Nevertheless, the optimum recommendation for the moderately obese patient is usually to combine a progressive exercise regiment with a moderate restriction of food intake. PMID: 7934018 [PubMed - indexed for MEDLINE] 6262. Am J Clin Nutr. 1994 Feb;59(2 Suppl):439S-445S. Energy metabolism during pregnancy: influence of maternal energy status. King JC(1), Butte NF, Bronstein MN, Kopp LE, Lindquist SA. Author information: (1)Department of Nutritional Sciences, University of California, Berkeley 94720. Additional energy requirements for term pregnancies are traditionally estimated as 1200 kJ/d or 325 MJ. These estimates approximate measured energy costs for well-nourished women, but non-Western populations subsisting on limited diets have much lower expenditures. Based on recent studies of energy expenditure during pregnancy, this paper reviews the 1) association between gestational weight gain and fat gain, 2) the influence of maternal energy status on basal metabolic energy expenditure in late pregnancy, and 3) potential energy metabolism adaptations available to pregnant women and how adaptations vary with energy status. Available data suggest that additional energy requirements during pregnancy vary from 0 to 500 MJ and depend on maternal energy status. If energy supplies are limited, adaptations spare energy for fetal growth; if energy is abundant, energy balance may be achieved in different ways depending on individual behavioral changes in food intake or activity patterns and on adjustments in basal metabolism or fat deposition. PMID: 8304281 [PubMed - indexed for MEDLINE] 6263. J Lipid Res. 1994 Feb;35(2):177-93. In vivo regulation of lipolysis in humans. Coppack SW(1), Jensen MD, Miles JM. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905. Fatty acids are important oxidative fuel for liver, kidney, skeletal muscle, and myocardium. There has been much interest in the role of fatty acids in the pathogenesis of non-insulin-dependent diabetes because they compete with glucose for oxygen and inhibit whole body glucose disposal via the 'Randle cycle,' Control of lipolysis in adipose tissue determines systemic fatty acid supply. A wide range of hormones and other substances have been recognized as regulators of lipolysis, but insulin and catecholamines appear to be the most important. The regulation of lipolysis, in most circumstances, provides a supply of lipid fuel exceeding the rate of lipid oxidation, requiring reesterification to triglyceride of surplus circulating free fatty acids. Thus, free fatty acid supply is usually not matched to the demand for lipid oxidation, and there is no known mechanism for accurately sensing such demand. This lax regulation may be disadvantageous in conditions such as aging, stress, obesity, and diabetes, where the antilipolytic effect of insulin is impaired and lipolysis is therefore increased. In these conditions, the surfeit of fatty acid may impair glucoregulation. In addition, the excess lipolysis may induce hypertriglyceridemia (via increased very low density lipoprotein production) and thus contribute to atherogenesis. Considerable additional research is needed in order to fully understand both normal lipolytic regulation and the abnormalities of lipolysis which accompany pathological conditions. PMID: 8169522 [PubMed - indexed for MEDLINE] 6264. Otolaryngol Clin North Am. 1994 Feb;27(1):13-24. The wound healing response to grafted tissues. Hom DB(1). Author information: (1)University of Minnesota School of Medicine, Minneapolis. When a tissue graft is introduced into a healing wound, the inflammatory and proliferative stages of wound healing are significantly prolonged. This sustained stimulation at the surrounding graft site can develop into chronic inflammation, leading to fibrosis and connective tissue build-up around the graft. Persistence in chronic inflammation surrounding a tissue graft can lead to graft destruction or rejection. Thus, a basic understanding of soft-tissue wound healing in response to grafted tissue is important to optimize the long-term functional results of tissue grafts. PMID: 8159417 [PubMed - indexed for MEDLINE] 6265. FASEB J. 1994 Feb;8(2):174-81. Glucose-6-phosphate dehydrogenase: a "housekeeping" enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. Kletzien RF(1), Harris PK, Foellmi LA. Author information: (1)Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001. The enzyme, glucose-6-phosphate dehydrogenase (G6PDH, EC1.1.1.49), has long been considered and studied as the archetypical X-linked "housekeeping" enzyme that is present in all cells, where it plays the key role in regulating carbon flow through the pentose phosphate pathway. Specifically, the enzyme catalyzes the first reaction in the pathway leading to the production of pentose phosphates and reducing power in the form of NADPH for reductive biosynthesis and maintenance of the redox state of the cell. It was in this latter function that the crucial importance of the enzyme was first appreciated with the description of the human deficiency syndrome. While the gene can be considered to be a constitutively expressed "housekeeping" gene in many tissues, there are several other tissues (liver, adipose, lung, and proliferating cells) wherein modulation of cellular G6PDH activity represents an important component of the integrated response to external stimuli (hormones, growth factors, nutrients, and oxidant stress). In this regard, adaptive regulation of G6PDH has been found to be exerted at transcriptional and posttranscriptional levels. However, the regulation observed is tissue-specific, which elicits the central question of this review, "How can the G6PDH gene be constitutively expressed in some tissues while displaying adaptive regulation in others when there exists a single transcription unit for the gene?" Future studies utilizing cloned genomic fragments of the human and other mammalian G6PDH genes should provide answers to this question. PMID: 8119488 [PubMed - indexed for MEDLINE] 6266. J Clin Endocrinol Metab. 1994 Feb;78(2):277-82. Body composition and spontaneous growth hormone secretion in normal short stature children. Abdenur JE(1), Solans CV, Smith MM, Carman C, Pugliese MT, Lifshitz F. Author information: (1)Department of Pediatrics, Maimonides Medical Center, Brooklyn, New York 11219. This study was designed to compare the relationship of measured and estimated indices of adiposity with the spontaneous GH secretion (SGHS) in 37 normal short stature children. Fifteen of the 37 patients (10 males and 5 females) were pubertal, and 22 (17 males and 5 females) were prepubertal. All patients underwent a review of their medical history, a physical exam, laboratory tests, and a nutritional assessment that included anthropometry and evaluation of body composition by bioelectric impedance. The percentage of body fat and body fat mass index were used as measured indices of adiposity. The weight for height ratio, body mass index, and body mass index z-scores were calculated and used as estimated indices of adiposity. Our results showed that SGHS is greatly influenced by variations in adiposity in normal short stature children, and measured indices of adiposity demonstrated the strongest negative correlation with SGHS. Gender differences were apparent in the degree of adiposity that modified SGHS, and it appears that adiposity altered the amplitude of GH pulses in pubertal patients and the number of pulses in prepubertal children. These results suggest that interpretation of SGHS must take into account body composition and gender in addition to pubertal status. PMID: 8106611 [PubMed - indexed for MEDLINE] 6267. Arch Ital Urol Androl. 1994 Feb;66(1):51-6. [Glucose metabolism and chronic renal insufficiency]. [Article in Italian] Fiorini F(1), Raffa M, Patrone E, Castelluccio A. Author information: (1)Servizi Dialisi, USL 1 Imperiese, Sanremo IM. Chronic renal failure is characterized by abnormalities in glucose metabolism. In fact there are present a normal fasting plasma glucose level )or mild hyperglycemia) in the presence of hyperinsulinemia, blunted decrease in the plasma glucose concentration in response to exogenous insulin administration, and diminished effect of intravenous insulin on glucose uptake in forearm perfusion studies. The glucose intolerance is not the result of reduced insulin secretion, or circulating insulin antagonists, and does not correlate with the coexisting metabolic acidosis. Glucose intolerance exists because the peripheral insulin-sensitive tissue (muscle, adipose tissue, liver) of the patients with chronic renal failure are insulin resistant. However there are two subgroups of uremic patients with regard to glucose tolerance: about half of uremic patients can augment their insulin secretion sufficiently to maintain normal glucose tolerance despite glucose intolerance. In the other half, insulin secretion following glucose loads is not different from normal values, so that glucose intolerance results. The cause of the peripheral insulin resistance remain unclear. Besides deranged renal function can result in the development of hypoglycemia. The most important predisposing mechanism to hypoglycemia is diminished glucose availability due to substrate limitation; the second important mechanism (alcohol, insulin, propranolol, etc.). Finally, in chronic renal failure persistent hyperinsulinemia can contribute hyperlipemia and to high incidence of cardiovascular disease. PMID: 8012426 [PubMed - indexed for MEDLINE] 6268. Genes Chromosomes Cancer. 1994 Feb;9(2):145-7. Band 11q13 is nonrandomly rearranged in hibernomas. Mrózek K(1), Karakousis CP, Bloomfield CD. Author information: (1)Cytogenetics Research Laboratory, Roswell Park Cancer Institute, Buffalo, New York 14263. Cytogenetic study of a short-term culture from a hibernoma, a very rare benign proliferation of the brown fat, demonstrated a four-break translocation t(5;7;11;17)(p14;q11.23;q13.1-13.3;p11.2) as the sole abnormality in all analyzed cells. Complex translocation involving band 11q13 have also been detected in the two other published cases of hibernoma. The consistent finding of 11q13 rearrangements appears to distinguish hibernoma from other benign adipose tissue tumors cytogenetically and suggests that 11q13 changes may play an important role in hibernoma pathogenesis. PMID: 7513546 [PubMed - indexed for MEDLINE] 6269. Wien Med Wochenschr. 1994;144(12-13):286-90. [Physiology and pathophysiology of the metabolism of lipoproteins]. [Article in German] Sandhofer F(1). Author information: (1)I. Medizinischen Abteilung, St. Johanns-Spitals, Salzburg. PHYSIOLOGY: Lipoproteins (LP) are generally classified according to their density. Triglycerides are mainly transported in chylomicrons and very low density LP (VLDL), cholesterol is mainly transported in low density LP (LDL) and high density LP (HDL). The metabolism of LP is controlled by their apolipoproteins, by specific receptors, enzymes, and transfer proteins. Triglycerides and cholesterol from the diet are transported in chylomicrons. The triglycerides are rapidly hydrolyzed by LP-lipase to yield chylomicron remnants. The released free fatty acids are used either for storage in adipose tissue or for oxidation in other tissues. Dietary cholesterol is transported in the chylomicron remnants to the liver. Cholesterol and triglyceride are also synthesized in the liver and then secreted into the blood in the form of VLDL. VLDL triglycerides are metabolized by LP-lipase to intermediate density LP (IDL), which are either taken up by the liver or further catabolized to LDL. LDL are bound and taken up by specific receptors (LDL receptors) in the liver and many other tissues. By this pathway, cholesterol is transported from the liver to peripheral tissues. LDL can be modified by oxidation and then taken up by macrophages in the arterial intima resulting in the formation of foam cells, an important step in atherogenesis. HDL play an important role in reverse cholesterol transport (transport of cholesterol back to the liver, the only site of cholesterol excretion).PATHOPHYSIOLOGY: Various mutations in the LP-lipase gene or in the apo C-II gene result in LP-lipase deficiency. Homozygous carriers of the mutated gene show defective metabolism of chylomicrons and VLDL with extreme hypertriglyceridemia, eruptive xanthomas, hepatosplenomegaly and recurrent bouts of acute pancreatitis. Many mutations in the LDL receptor gene have been described as the primary cause of familial hypercholesterolemia due to LDL receptor deficiency. LDL receptor deficiency results in the accumulation of LDL in the plasma and deposition of LDL cholesterol in tendons and skin (xanthomas) and arteries (atheromas). In homozygotes, coronary heart disease begins in childhood. Familial defective apo B-100 is caused by a mutation in codon 3500 of the apo B gene. LDL with the mutated apo B is not recognized by the LDL receptor and LDL accumulates in the blood. Mutant forms of apo E (apo E-2 and others) are not bound to the LDL(B,E)-receptor resulting in accumulation of chylomicrons and VLDL remnants (beta-VLDL) and IDL. For the manifestation of type III hyperlipemia, additional genetic, hormonal or environmental factors are involved. Cholesterol deposition in macrophages of the arterial intima and skin gives rise to atherosclerosis of coronary and peripheral arteries and xanthomas. The pathogenesis of familial combined hyperlipemia, the most frequent form of primary hyperlipemias, is multifactorial and has not been clarified in detail. PMID: 8650930 [PubMed - indexed for MEDLINE] 6270. FASEB J. 1994 Jan;8(1):72-80. Abnormal A1 adenosine receptor function in genetic obesity. LaNoue KF(1), Martin LF. Author information: (1)Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, College of Medicine, Hershey, Pennsylvania 17033. Obesity is increasingly recognized as an important health problem in developed, industrialized countries. As a large proportion of the variance in individual adiposity is based on genetic factors (1-3), recent efforts have focused on identifying genes involved in regulating the percentage of body fat in a given individual. This effort is helped by the existence of rodent models of genetic obesity. Many strains of mice and at least three rat strains have been identified thus far that exhibit inherited obesity accompanied by a similar set of endocrine abnormalities (4). Although the symptoms of the disease are similar in different strains, different genes appear to be involved in causing the syndrome, as the mutation responsible for the obesity maps to different chromosomal sites in the different strains. Efforts to find the products of the mutated genes over the past 30 years have generally been unsuccessful. However, the available data imply that many obesity mutations may involve genes that code for proteins in a single signal transduction pathway or one particular cascade of covalent modification. Reasonable theories are plentiful about the identity of such a pathway, but current studies in the laboratories of the authors suggest that the A1 adenosine receptor signaling pathway may be involved. Evidence of abnormal A1 receptor function has been obtained from studies of Zucker rats and obese (ob/ob) mice (5-7). These strains are obese because of a single recessive mutation. Measurements of adenylyl cyclase activity and regulation in isolated adipocytes and isolated plasma membranes suggest that the receptor is unusually and tonically active in obese rats. Because signaling from this receptor inhibits lipolysis in white and brown fat, induces insulin resistance in skeletal muscle (8, 9), but increases insulin sensitivity in adipose tissue (10, 11), the possibility arises that the excessive activity of the A1 adenosine receptor may induce obesity. Data from human volunteers are also compatible with the possibility that the activity of the receptor is unusually high in vivo in obese individuals (12). PMID: 8299893 [PubMed - indexed for MEDLINE] 6271. Rev Gastroenterol Mex. 1994 Jan-Mar;59(1):36-45. [Obesity. Its medico-surgical treatment]. [Article in Spanish] Campollo Rivas O(1). Author information: (1)Unidad de Investigación Experimental, Instituto Nacional de la Nutrición Salvador Zubirán, Tlalpan, México, D.F. Obesity has been defined as excessive deposition of body fat tissue that risks the health and survival of the patient. It affects almost 30 per cent of whole population in western societies and it's also becoming a common problem in developing countries as rural areas are slowly decreasing in face of urban growing. In Mexico obesity affects as much as 28 per cent of the population of selected urban areas and the trend seems to follow the incidence in North America. There are genetic, environmental, physiological, psychological, social and cultural factors that determine or influence the presence of obesity in modern societies. To date the most accepted approach to the management of this problem lays on 3 main aspects: diet, exercise and behaviour modification. Pharmacological therapy should be limited to selected cases in which associated clinical risks warrant more urgent intervention. Surgical therapy is indicated for morbid obesity in which there is greater than 70 per cent excess weight. Prevention of obesity should remain one of the top priorities in public health and should take genetic, physiological, environmental, social, psychological, cultural and economic factors into consideration. PMID: 8209151 [PubMed - indexed for MEDLINE] 6272. Langenbecks Arch Chir. 1994;379(2):109-19. [Function of the abdominal wall and development and therapy of hernias (among others: the para-colostomy hernia)]. [Article in German] Stelzner F(1). Author information: (1)Zentrum für Chirurgie, Chirurgische Universitätsklinik Bonn. The peritoneal cavity has a fascial skeleton with musculature that is nearly always active, i.e. it has resting tone activity. During pneumoperitoneum this resting activity increases very markedly. The pelvic floor and its integrated sphincters also have a similar type of spontaneous activity depending on Onuf's nucleus in the spinal cord together with the somatic and autonomic nerves. Hernias such as umbilical hernias develop with disruption of a scar. While in a child the common inguinal hernia develops in an open vaginal processus, in an adult it develops as the result of a congenital muscular defect in the abdominal wall. A femoral hernia develops in a gap through the pressure of the resting activity of the abdominal wall. A paracolostomy hernia develops after an incision in the fascial skeleton and after pull-through of a very adipose sigma-mesosigma. It can often be treated it by pulling a slim colon segment through the innervated rectus muscle incision and closing the gap in the fascial skeleton with a running suture. Incisional or umbilical hernias can be successfully treated by suturing with a continuous nonabsorbable thread. The best therapy for inguinal hernias is suturing of the hyperplastic fascia transversalis and the reconstruction of the muscle sphincter mechanism. Bassini operated on very large hernias with hyperplastic fascia, thereby achieving excellent results. Fascial hyperplasia has been shown to follow the use of tissue expanders. PMID: 8196426 [PubMed - indexed for MEDLINE] 6273. Environ Health Perspect. 1994 Jan;102 Suppl 1:265-74. Polybrominated dibenzo-p-dioxins and dibenzofurans: literature review and health assessment. Mennear JH(1), Lee CC. Author information: (1)Campbell University, School of Pharmacy, Buies Creek, NC 27506. Comment in Environ Health Perspect. 1995 Jan;103(1):13. Polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) occur as trace (ppb) contaminants in brominated flame retardants and are produced during combustion of these chemicals. They are also formed when organics are incinerated in the presence of bromine, e.g., in municipal and industrial incinerators and in internal-combustion engines. Combustion of organics in the presence of both bromine and chlorine results in the formation of mixed (i.e., bromo, bromo/chloro and chloro) halogenated dibenzo-p-dioxins and dibenzofurans (HDDs and HDFs). There are 4600 potential mixed congeners. The biological effects of PBDDs and PBDFs are similar, if not identical, to those of PCDDs and PCDFs. Both groups of compounds induce hepatic aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-o-deethylase (EROD) in rats and cause wasting and thymic atrophy in rats and guinea pigs. Tetrabrominated dinenzo-p-dioxin (TBDD) and dibenzofuran (TBDF) are reproductive toxins in mice and produce skin lesions in the rabbit-ear acnegenic test. The brominated compounds appear to bind to the same cytosolic receptors believed to mediate the toxicities of the chlorinated analogs. When compared on a molar-concentration basis, the brominated compounds are equipotent to the chlorinated analogs. TBDD is absorbed after oral, dermal, or intratracheal administration in rats, stored in the liver and adipose tissue, and eliminated in the feces through biliary excretion. The biological half-lives of the brominated compounds appear to be somewhat shorter than those of the corresponding chlorinated species. The brominated compounds, like their chlorinated congeners, have the potential to cause dermal, hepatic, and gastrointestinal toxicities in humans.(ABSTRACT TRUNCATED AT 250 WORDS) PMCID: PMC1566873 PMID: 8187718 [PubMed - indexed for MEDLINE] 6274. Environ Health Perspect. 1994 Jan;102 Suppl 1:159-71. Chlorinated dioxins and dibenzofurans in human tissue from general populations: a selective review. Schecter A(1), Fürst P, Fürst C, Päpke O, Ball M, Ryan JJ, Hoang DC, Le CD, Hoang TQ, Cuong HQ, et al. Author information: (1)Department of Preventive Medicine, College of Medicine, State University of New York-Health Science Center/Syracuse, Binghamton 13903. During the past decade a considerable amount of data has been generated concerning polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in humans from many geographical locations. To organize these data in a useful fashion for environmental purposes and for consideration of human toxicity, selected portions of our data are presented in a somewhat atypical fashion, by percentage contribution of individual congeners to total PCDD/Fs in human tissue, and to the total dioxin equivalents (TEq). This is done to better characterize congener contributions from environmental contamination in various geographical regions at this time and health-related levels. To present the findings in a global perspective, data from widely different locations are presented including the United States, Germany, Vietnam, the former Soviet Union, Thailand, Cambodia, China, South Africa, and Guam. PMCID: PMC1566889 PMID: 8187705 [PubMed - indexed for MEDLINE] 6275. Environ Health Perspect. 1994 Jan;102 Suppl 1:149-58. Polychlorinated biphenyl levels in the tissues of exposed and nonexposed humans. Schecter A(1), Stanley J, Boggess K, Masuda Y, Mes J, Wolff M, Fürst P, Fürst C, Wilson-Yang K, Chisholm B. Author information: (1)Department of Preventive Medicine, College of Medicine, State University of New York, Health Science Center/Syracuse, Binghamton 13903. Polychlorinated biphenyls (PCBs) are synthetic chemicals, manufactured in volume from about 1929 to the 1970s. Environmental contamination by PCBs has been documented in various substances, including human tissue. PCBs have been measured in human tissue by a variety of analytical methods. PCB levels have been reported as an approximation of total PCB content expressed in terms of a commercial mixture, by identification and quantification of chromatographic peaks, or by qualitative and quantitative characterization of specific congeners. Until recently, the coplanar mono-ortho- and di-ortho substituted PCBs, which are especially toxic and present in significant concentration in humans from industrial countries, had not been measured in human tissues. Examples of various types of commonly used analyses are presented in general population subjects and in persons who experienced special exposure. In this paper, the usefulness of PCB blood determinations following potential exposure is demonstrated, and their application in health studies is illustrated from a number of case studies. Coplanar PCB, mono-ortho-substituted and di-ortho-substituted PCB levels in human blood are presented and compared with polychlorinated dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in the U.S. population. Dioxin toxic equivalents for the two groups of chemicals are calculated and compared. It is found that mono-ortho-substituted and, to a lesser extent, coplanar PCBs, contribute substantially to dioxin toxic equivalents (TEq) in blood from U.S. adults. Because of substantial PCB contribution to dioxin toxic equivalents, total dioxinlike toxicity can only be determined if dioxins, dibenzofurans, and dioxinlike PCBs are measured.(ABSTRACT TRUNCATED AT 400 WORDS) PMCID: PMC1566903 PMID: 8187704 [PubMed - indexed for MEDLINE] 6276. Crit Rev Toxicol. 1994;24(2):87-149. Polychlorinated biphenyls (PCBs): environmental impact, biochemical and toxic responses, and implications for risk assessment. Safe SH(1). Author information: (1)Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466. Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazard and risk assessment of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners in which the TCDD or toxic TEQ = sigma([PCDFi x TEFi]n)+sigma([PCDDi x TEFi]n) equivalent (TEQ) of a mixture is related to the TEFs and concentrations of the individual (i) congeners as indicated in the equation (note: n = the number of congeners). Based on the results of quantitative structure-activity studies, the following TEF values have been estimated by making use of the data available for the coplanar and monoortho coplanar PCBs: 3,3',4,4',5-pentaCB, 0.1; 3,3',4,4',5,5'-hexaCB, 0.05; 3,3',4,4'-tetraCB, 0.01; 2,3,3',4,4'-pentaCB, 0.001; 2,3',4,4',5-pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB, 0.0003; 2,3,3',4,4',5'-hexaCB, 0.0003; 2',3,4,4',5-pentaCB, 0.00005; and 2,3,4,4',5-pentaCB, 0.0002. Application of the TEF approach for the risk assessment of PCBs must be used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs may be both species- and response-dependent because both additive and nonadditive (antagonistic) interactions have been observed with PCB mixtures. In the latter case, the TEF approach would significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data for Aroclor 1260 using the TEF approach suggests that this response is primarily Ah-receptor-independent. Thus, risk assessment of PCB mixtures that uses cancer as the endpoint cannot solely utilize a TEF approach and requires more quantitative information on the individual congeners contributing to the tumor-promoter activity of PCB mixtures. PMID: 8037844 [PubMed - indexed for MEDLINE] 6277. Int J Tissue React. 1994;16(2):59-72. Interactions of anti-inflammatory 2-arylpropionates (profens) with the metabolism of fatty acids: in vitro studies. Mayer JM(1), Roy-De Vos M, Audergon C, Testa B, Etter JC. Author information: (1)School of Pharmacy, University of Lausanne, Switzerland. This review shows conclusively that profens can enter physiological pathways of lipid biochemistry. The first step in this interaction is the formation of an acyl-CoA thioester. These conjugates can lead to the incorporation of the xenobiotic acid into lipids. The resulting hybrid triglycerides have the potential to form long-lasting residues in adipose tissues and to be incorporated into membranes. Furthermore, the acyl-CoA conjugate may also alter lipid biochemistry by inhibiting lipid beta-oxidation either by interfering with the acyl-CoA synthetases or by modifying CoA levels. Thus, the acyl-CoA conjugates of profens intermediates in the inversion of inactive (R)-profens to active (S)-profens can be viewed as pivotal to bioactivation and to pathways of potential toxicity. PMID: 7960502 [PubMed - indexed for MEDLINE] 6278. Breast Cancer Res Treat. 1994;30(1):7-17. The role of aromatase in breast tumors. Reed MJ(1). Author information: (1)Unit of Metabolic Medicine, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK. Aromatization of androstenedione to estrone in peripheral tissues is the major source of estrogen in postmenopausal women. The aromatase enzyme complex, which mediates the conversion of androstenedione to estrone, is present in several tissues, including adipose tissue and normal and malignant breast tissues. Aromatase activity is detectable in 50-60% of breast tumors, but the contribution that tumor aromatase makes to estrogen concentration in tumors and whether the estrogen formed is biologically important remains a controversial matter. Since concentrations of androstenedione are higher in tumors than in blood, and tumor aromatase activity in vivo may be enhanced by growth factors and by cytokines, the contribution of tumor aromatase to tumor estrogen levels may be higher than suggested by the original calculations. Measurements of tumor aromatase, tumor estrone concentrations, and DNA polymerase alpha activity (a marker of cellular proliferation), in samples obtained before and after treatment with the aromatase inhibitor 4-hydroxyandrostenedione, lend some support to a biological role for estrone formed locally. PMID: 7949206 [PubMed - indexed for MEDLINE] 6279. Breast Cancer Res Treat. 1994;30(1):43-55. Aromatase inhibitors--mechanisms for non-steroidal inhibitors. Vanden Bossche HV(1), Moereels H, Koymans LM. Author information: (1)Department of Comparative Biochemistry, Janssen Research Foundation, Beerse, Belgium. The conversion of androgens to estrogens occurs in a variety of cells and tissues, such as ovarian granulosa and testicular cells, placenta, adipose tissue, and various sites of the brain. The extragonadal synthesis of estrogens has great pathophysiological importance. Estrogens produced by, for example, adipose tissue have a role in the pathogenesis of certain forms of breast cancer and endometrial adenocarcinoma. The biosynthesis of estrogens is catalyzed by the aromatase, an enzyme localized in the endoplasmic reticulum that consists of two components: a cytochrome P450 (P450 Arom, P450 19 product of the CYP19 gene) and the NADPH cytochrome P450 reductase. The alignment of the amino acid sequences of human P450 19 with other mammalian P450s shows little sequence similarity, which indicates not only that P450 19 is a unique form of the P450 superfamily but also that the aromatase may be a good target for the development of selective P450 inhibitors. Aminoglutethimide (AG) is the pioneer drug of the reversible competitive nonsteroidal aromatase inhibitors. Since AG is a nonspecific aromatase inhibitor and presents some problems with tolerability, a number of structural analogues have been synthesized. For example, rogletimide is slightly less potent than AG but has the advantage of not inhibiting the cholesterol side-chain cleavage and is devoid of sedative action. Elongation of the ethyl substituent of AG and rogletimide leads to an increase in aromatase inhibition. Further studies led to the discovery of a new generation of much more potent aromatase inhibitors. An example is fadrozole. However, although fadrozole is a poor inhibitor of the cholesterol side-chain cleavage, it suppresses aldosterone release by ACTH-stimulated human adrenocortical cells. More selective aromatase inhibitors are the triazole derivatives. Examples are CGS 20267, CGS 47645, R 76 713, and ICI D1033. R 76 713's aromatase inhibitory effect is largely due to its (+)-S-enantiomer, vorozole. Computer modeling studies of the interaction of vorozole with part of the "I-helix" of P450 19 suggest that the chlorine-substituted phenyl ring of vorozole interacts with the gamma-carbonyl group of Glu-302. Thr-310, which corresponds to the highly conserved Thr-252 in P450 101, interacts with vorozole's triazole ring, and the 1-methyl-benzotriazole moiety binds near Asp-309. PMID: 7949204 [PubMed - indexed for MEDLINE] 6280. Breast Cancer Res Treat. 1994;30(1):19-29. Regulation of aromatase expression in human tissues. Bulun SE(1), Simpson ER. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas 75235-9051. Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell compartments of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom, the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10 out of 15 patients, the highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells vs. adipocytes in these quadrants. These findings suggest that regional differences in the relative proportions of the histologic components give rise to local elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by these locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels. PMID: 7949202 [PubMed - indexed for MEDLINE] 6281. Annu Rev Nutr. 1994;14:187-215. Nutritional mechanisms and temporal control of migratory energy accumulation in birds. Bairlein F(1), Gwinner E. Author information: (1)Institut für Vogelforschung Vogelwarte Helgoland, Wilhelmshaven, Germany. PMID: 7946517 [PubMed - indexed for MEDLINE] 6282. Pharmacol Ther. 1994;61(3):399-411. Molecular events in adipocyte development. Butterwith SC(1). Author information: (1)Agricultural and Food Research Council, Roslin Institute (Edinburgh), Department of Cellular and Molecular Biology, Midlothian, U.K. Adipocyte hyperplasia occurs by the proliferation and differentiation of adipocyte precursor cells or preadipocytes. Although the process of commitment to the adipocyte lineage is poorly understood, a great deal of information has accumulated about the processes and regulatory mechanisms involved in preadipocyte differentiation. The differentiation of preadipocytes is known to be characterized by increased transcription of a number of specific genes. AP-1 and C/EBP binding sites within these genes have been identified as important regulatory sequences. In addition, a specific enhancer sequence has been shown to confer adipose tissue specificity. This article will review the changes in gene transcription that occur during preadipocyte differentiation and how these are regulated. The potential role of autocrine/paracrine acting factors in the proliferation and differentiation of the preadipocyte is also discussed. PMID: 7938180 [PubMed - indexed for MEDLINE] 6283. FASEB J. 1994 Jan;8(1):36-42. Regulation of lipogenic enzyme gene expression by nutrients and hormones. Girard J(1), Perdereau D, Foufelle F, Prip-Buus C, Ferré P. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Développement, C.N.R.S., Meudon-Bellevue, France. In vivo and in vitro experiments strongly support the view that marked increases in the levels of mRNA and in the activities of lipogenic enzymes that occur in liver and white adipose tissue of the rat after weaning to a high-carbohydrate diet are dependent on an increase in plasma glucose and insulin concentrations. An increased glucose metabolism is necessary for the expression of insulin effects on fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) mRNA accumulation in white adipose tissue, as insulin is ineffective in vitro in the absence of glucose. It is suggested that intracellular glucose-6-phosphate could play an important role in the effect of insulin on lipogenic enzyme gene expression in white adipose tissue. Other hormones and substrates could also play a role in the surge of lipogenesis after weaning. The fall in plasma glucagon after weaning to a high-carbohydrate diet could reinforce the insulin-induced accumulation of FAS and ACC mRNA, as this hormone inhibits the accumulation of lipogenic enzyme mRNA in liver and white adipose tissue. The decrease in the dietary supply of fat after weaning to a high-carbohydrate diet could also potentiate the accumulation of FAS and ACC mRNA in liver because long-chain poly-unsaturated fatty acids are potent inhibitors of the expression of the genes encoding liver lipogenic enzymes. A direct effect of fatty acids on a cis-acting element of the lipogenic enzyme genes could be involved, as the regulatory region of FAS gene contains a polyunsaturated fatty acid response element that shares some similarity with the peroxisome proliferator-activated receptor recently described. PMID: 7905448 [PubMed - indexed for MEDLINE] 6284. Int J Fertil Menopausal Stud. 1994;39 Suppl 2:75-83. Aromatase gene expression in adipose tissue: relationship to breast cancer. Simpson ER(1), Mahendroo MS, Nichols JE, Bulun SE. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas. Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell component of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom; the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10/15 patients, highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells versus adipocytes in those quadrants. Such findings suggest that regional differences in the relative proportions of the various histologic components give rise to locally elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by the locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels. PMID: 7874190 [PubMed - indexed for MEDLINE] 6285. World Rev Nutr Diet. 1994;75:35-45. A new look at fatty acids as signal-transducing molecules. Ailhaud GP(1), Abumrad N, Amri EZ, Grimaldi PA. Author information: (1)Centre de Biochimie (UMR 134 CNRS), Université de Nice-Sophia Antipolis, Faculté des Sciences, France. PMID: 7871831 [PubMed - indexed for MEDLINE] 6286. Reprod Nutr Dev. 1994;34(6):569-82. Influence of adiposity (genetic or hormonal) on the metabolism of amino acids and nutritional responses. Leclercq B(1), Sève B. Author information: (1)INRA, Recherches Avicoles, Nouzilly, France. The data published on the modifications of amino-acid metabolism associated with variations of obesity from genetic or hormonal origin have been reviewed. In the first part monogenic models of mice and rats are described. Obesity in humans is analysed in the second part. Lastly, non-ruminant genotypes or hormone-treated ones (chickens and pigs) are reviewed in the third part. Although different mechanisms are probably at the origin of these differences, many similarities can be drawn. Obesity is always associated with: 1) less efficient utilization of dietary amino acid; 2) a high concentration of branched-chain amino acids in plasma; 3) a deviation of carbon from amino acid towards gluconeogenis and lipogenesis; and 4) a less pronounced sensitivity to amino-acid imbalance in the diet. PMID: 7840872 [PubMed - indexed for MEDLINE] 6287. Adv Exp Med Biol. 1994;352:71-84. Animal models for the study of adipose regulation in pregnancy and lactation. Bell AW(1), Bauman DE. Author information: (1)Department of Animal Science, Cornell University, Ithaca, New York 14853. PMID: 7832060 [PubMed - indexed for MEDLINE] 6288. Adv Exp Med Biol. 1994;352:45-70. Cellular mechanisms for the regulation of adipose tissue lipid metabolism in pregnancy and lactation. Williamson DH(1), Lund P. Author information: (1)Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, United Kingdom. PMID: 7832059 [PubMed - indexed for MEDLINE] 6289. Ann Urol (Paris). 1994;28(5):259-64. [Perirenal urinoma]. [Article in French] Rohner S(1), Tuchschmid Y, Graber P. Author information: (1)Département de Chirurgie, Hôpital Cantonal Universitaire de Genève, Suisse. A urinoma is an encapsulated extravasation of urine which can be secondary to trauma or which can occur spontaneously. The essential factors are continued renal function, rupture of the collecting system and distal obstruction. The extravasated urine causes lipolysis and stimulates an intense fibrous reaction which forms a thick wall. This lipolysis may be due to a mass effect as no direct effect of the urine on adipocytes has ever be demonstrated. Early diagnosis by CT scan allows easier treatment: in certain cases, percutaneous drainage alone may be sufficient. PMID: 7825983 [PubMed - indexed for MEDLINE] 6290. Mol Aspects Med. 1994;15 Suppl:s29-36. An updating of the biochemical function of coenzyme Q in mitochondria. Lenaz G(1), Fato R, Castelluccio C, Cavazzoni M, Estornell E, Huertas JF, Pallotti F, Parenti Castelli G, Rauchova H. Author information: (1)Dipartimento di Biochimica Giovanni Moruzzi, Universita' di Bologna, Italy. The apparent Km for coenzyme Q10 in NADH oxidation by coenzyme Q (CoQ)-extracted beef heart mitochondria is close to their CoQ content, whereas both succinate and glycerol-3-phosphate oxidation (the latter measured in hamster brown adipose tissue mitochondria) are almost saturated at physiological CoQ concentration. Attempts to enhance NADH oxidation rate by excess CoQ incorporation in vitro were only partially successful: the reason is in the limited amount of CoQ10 that can be incorporated in monomeric form, as shown by lack of fluorescence quenching of membrane fluorescent probes; at difference with CoQ10, CoQ5 quenches probe fluorescence and likewise enhances NADH oxidation rate above normal. Attempts to enhance the CoQ content in perfused rat liver and in isolated hepatocytes failed to show uptake in the purified mitochondrial fraction. Nevertheless CoQ cellular uptake is able to protect mitochondrial activities. Incubation of hepatocytes with adriamycin induces loss of respiration and mitochondrial potential measured in whole cells by flow cytometry using rhodamine 123 as a probe: concomitant incubation with CoQ10 completely protects both respiration and potential. An experimental study of aging in the rat has shown some decrease of mitochondrial CoQ content in heart, and less in liver and skeletal muscle. In spite of the little change observed, it is reasoned that CoQ administration may be beneficial in the elderly, owing to the increased demand for antioxidants. PMID: 7752842 [PubMed - indexed for MEDLINE] 6291. Adv Nutr Res. 1994;9:257-71. The effect of obesity on postmenopausal bone loss and the risk of osteoporosis. Ribot C(1), Trémollières F, Pouillès JM. Author information: (1)Endocrinology Department, C.H.U. Purpan, Toulouse, France. There are many data indicating that osteoporotic fractures, and particularly hip fractures, are less frequent in obese subjects. Overweight and obese women have a higher bone mass after menopause than women of the same age who are not overweight, and thus in all probability have a slower bone loss. This protective effect appears to be related both to mechanical factors and to estrogen synthesis in adipose tissue. PMID: 7747670 [PubMed - indexed for MEDLINE] 6292. Bone Marrow Transplant. 1994;14 Suppl 4:S71-3. Role of marrow microenvironment in engraftment and maintenance of allogeneic hematopoietic stem cells. Torok-Storb B(1), Holmberg L. Author information: (1)Fred Hutchinson Cancer Research Center, Seattle, WA 98104. Following allogeneic marrow transplantation a competent marrow microenvironment consists of a complex mixture of both donor and host derived cells. Clearly some forms of genetic disparity between donor and host can compromise appropriate interactions and function of these cells. The competency of the microenvironment can also be compromised by viral infections, and the underlying disease process as in rare cases of aplastic anemia. As we come to precisely define each component of the microenvironment, it will become possible to accurately diagnose causes of poor marrow function and develop methods for prevention and treatment. PMID: 7728130 [PubMed - indexed for MEDLINE] 6293. Horm Res. 1994;42(1-2):20-6. Role of insulin-like growth factor II and IGF binding proteins in extrapancreatic tumor hypoglycemia. Zapf J(1). Author information: (1)Department of Internal Medicine, University Hospital, Zürich, Switzerland. Serum from patients with extrapancreatic tumor hypoglycemia (EPTH) contains elevated levels of big (pro) IGF II which disappears after successful removal of the tumor. Nevertheless, total IGF II serum levels are mostly found in the normal range both before and after operation. Why then do these patients become hypoglycemic? Oversecretion of big IGF II leads to suppression of growth hormone (GH). As a consequence, formation of a GH-dependent 150-kD IGF binding protein (BP) complex is impaired which normally carries 70-80% of total serum IGF II and largely restricts its bioavailability. Impaired formation of the 150-kD complex leads to a shift of IGF II to a 50-kD IGFBP complex, resulting in a 30-fold shorter serum half-life of IGF II, increased turnover and enhanced bioavailability. Insulin target organs are thus exposed to an enormous insulin-like potential which is continuously provided by oversecreted big IGF II and causes increased glucose consumption by skeletal muscle, inhibition of hepatic glucose production, inhibition of lipid mobilisation from adipose tissue, and pronounced hypoglycemia. PMID: 7525443 [PubMed - indexed for MEDLINE] 6294. Drugs. 1994;47 Suppl 2:35-41. Hormone replacement therapy and the cardiovascular system. Nonlipid effects. Stevenson JC(1), Crook D, Godsland IF, Collins P, Whitehead MI. Author information: (1)Wynn Institute for Metabolic Research, London, England. Coronary heart disease (CHD) is the leading cause of death in women, and the risk of this disease rises markedly after loss of ovarian function. Hormone replacement therapy (HRT) can reduce the incidence of CHD in postmenopausal women by 50%. HRT causes changes in lipids and lipoproteins, but it is now clear that many other effects of gonadal steroid hormones have important influences on the cardiovascular system. These nonlipid effects include a variety of changes in other metabolic risk factors for CHD, as well as direct arterial effects. Insulin resistance and hyperinsulinaemia may be pivotal disturbances in the pathogenesis of CHD. Estradiol reverses the effects of menopause on glucose and insulin metabolism, resulting in an increase in pancreatic insulin secretion and a decrease in insulin resistance, although other types of estrogen may not do this. Androgenic progestogens may oppose this potentially beneficial effect on insulin resistance. Central obesity is linked with many CHD risk factors, and HRT reverses the increased fat distribution that results from loss of ovarian function at the menopause. HRT may also improve the balance between coagulation and fibrinolysis, resulting in a reduction in arterial thrombosis. Finally, estradiol acts directly on the arterial wall, modifying both endothelium-dependent and calcium-dependent processes. These actions result in improved blood flow and reduced blood pressure and, importantly, have the potential to reduce myocardial ischaemia. PMID: 7517832 [PubMed - indexed for MEDLINE] 6295. Trans Am Clin Climatol Assoc. 1995;106:69-75; discussion 75-6. Obesity-related hypertension and the insulin resistance syndrome. Landsberg L(1). Author information: (1)Northwestern University Medical School, Chicago, Ill 60611, USA. PMCID: PMC2376532 PMID: 7483180 [PubMed - indexed for MEDLINE] 6296. Eur J Biochem. 1993 Dec 15;218(3):785-96. The biochemistry of white and brown adipocytes analysed from a selection of proteins. Ricquier D(1), Cassard-Doulcier AM. Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS-UPR, Meudon, France. PMID: 8281930 [PubMed - indexed for MEDLINE] 6297. J Dermatol Surg Oncol. 1993 Dec;19(12):1074-8. Histology and physiology of tissue expansion. Johnson TM(1), Lowe L, Brown MD, Sullivan MJ, Nelson BR. Author information: (1)Department of Dermatology, University of Michigan, Ann Arbor 48109. BACKGROUND: Tissue expansion is a concept based on the skin's natural ability to stretch in response to an underlying force. OBJECTIVE: The purpose of this article is to review the histological and physiological changes that occur within the soft tissue and underlying structures during tissue expansion. METHODS: An extensive search of the literature reviewing these changes is summarized herein. RESULTS: Conventional tissue expansion may result in epidermal hypertrophy, decreased dermal, muscle, and adipose thickness, and bone resorption. A vascular capsule and angiogenesis provides a highly vascular flap and improves flap viability. Few soft tissue changes occur during rapid tissue expansion. The ability of the skin to increase in surface area during conventional tissue expansion is primarily because of biological tissue creep. Rapid expansion may result from mechanical tissue creep. CONCLUSION: Many soft tissue changes occur during tissue expansion. Most of these changes return to the pre-expansion state over time following discontinuation of the expansion process. PMID: 8282904 [PubMed - indexed for MEDLINE] 6298. J Dairy Sci. 1993 Dec;76(12):3897-931. Dietary fat and adipose tissue metabolism in ruminants, pigs, and rodents: a review. Chilliard Y(1). Author information: (1)Laboratoire Sous-Nutrition des Ruminants, Institut National de la Recherche Agronomique, Saint Genès Champanelle, France. Effects of dietary fat on dairy cows are reviewed. Dietary fat did not affect gain in BW or body condition score after peak lactation but tended to increase BW loss during early lactation and body fat deposition in growing cattle. Dietary fat decreased de novo fatty acid synthesis in adipose tissue. Basal FFA release from adipose tissue in vitro and beta-adrenergic lipolytic responses were increased by protected polyunsaturated fatty acids. Dietary fat increased body fat in growing pigs and decreased BW loss in lactating sows. Dietary fat decreased de novo fatty acid synthesis and basal glycerol release in adipose tissue and tended to increase simultaneously beta-adrenergic lipolytic responses to increased membrane fluidity. Dietary fat increased body fat in rats. Polyunsaturated fatty acids were sometimes less efficient than saturated ones in increasing body fat. Lipoprotein lipase activity in adipose tissue generally decreased. Hepatic fatty acid synthesis was decreased sharply by polyunsaturated fatty acids, and adipose tissue response was less important. beta-Adrenergic-stimulated lipolysis decreased, and fatty acid esterification increased, particularly from saturated fatty acids. A trend toward insulin resistance, which was more marked with saturated fatty acids, occurred in adipose tissue. PMID: 8132894 [PubMed - indexed for MEDLINE] 6299. Int J Obes Relat Metab Disord. 1993 Dec;17 Suppl 3:S78-81; discussion S82. Adrenoceptor subtypes mediating catecholamine-induced thermogenesis in man. Blaak EE(1), Saris WH, van Baak MA. Author information: (1)Department of Human Biology, University of Limburg, Maastricht, The Netherlands. The sympathetic nervous system plays an important role in energy metabolism. This review deals with the type of adrenoceptors involved in catecholamine-induced thermogenesis. In healthy lean males, both beta 1- and beta 2-adrenoceptors are involved in sympathetically-mediated thermogenesis, whereas alpha-adrenoceptors probably do not play an important role. Although there seem to be no firm data to support the involvement of beta 3-adrenoceptors in human energy metabolism, conclusive evidence to exclude a significant role of beta 3-adrenoceptors in man is also lacking. In normal weight man, skeletal muscle is an important site of localization for sympathetically-mediated thermogenesis, but a contribution of other tissues, such as adipose tissue, cannot be excluded. PMID: 8124408 [PubMed - indexed for MEDLINE] 6300. Int J Obes Relat Metab Disord. 1993 Dec;17 Suppl 3:S32-6; discussion S41-2. Dietary composition, substrate balances and body fat in subjects with a predisposition to obesity. Astrup A(1). Author information: (1)Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Copenhagen, Denmark. Ecological, cross-sectional and prospective longitudinal studies show that obesity is positively associated with dietary fat energy percentage and negatively with carbohydrate energy percentage. The relationships are concordant with the concept of separately regulated macronutrient balances and the higher satiating effect of carbohydrate than of fat. Dietary records have suggested that obese subjects tend to consume a diet with a higher fat content than normal weight controls. Due to a carry-over effect of the habitual diet on the next day's substrate use, we were able to show that an obese group of women oxidized 40.2% fat energy while a normal weight group oxidized only 36.0% fat energy, although they all consumed a diet with 30% fat energy. Percentage fat oxidation (24 h) was positively correlated with fat mass, which supports the theory that the expansion of fat stores is a prerequisite to an increase in fat oxidation to match a high dietary fat energy percentage. Post-obese subjects did not differ in 24 h macronutrient balances from a control group when consuming diets with 20 and 30% fat energy. In contrast, they failed to increase the ratio of fat to carbohydrate oxidation appropriately when exposed to a high-fat diet (50% fat energy), which resulted in a positive fat balance and a negative carbohydrate balance. The post-obese subjects seem to have normal insulin sensitivity, and preliminary results suggest that exercise-induced stimulation of lipolysis is normal, while fat oxidation is reduced in spite of higher circulating levels of free fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8124398 [PubMed - indexed for MEDLINE] 6301. Int J Obes Relat Metab Disord. 1993 Dec;17 Suppl 3:S23-7; discussion S41-2. The adjustment of energy expenditure and oxidation to energy intake: the role of carbohydrate and fat balance. Schutz Y(1). Author information: (1)Institute of Physiology, Faculty of Medicine, University of Lausanne, Switzerland. Evidence is accumulating that total body mass and its relative composition influence the rate of fat utilization in man. This effect can be explained by two factors operating in concert: (i) the effect of the size of the tissue mass and (ii) the nature of the fuel mix oxidized, i.e. the proportion of energy derived from fat vs. carbohydrate. In a cross-sectional study of 307 women with increasing degrees of obesity, we observed that the respiratory quotient (RQ) in post-absorptive conditions became progressively lower with increased body fatness, indicating a shift in substrate utilization. However, the RQ is known to be also influenced by the diet commonly ingested by the subjects. A short-term mixed diet overfeeding in lean and obese women has also demonstrated the high sensitivity of RQ to changes in energy balance. Following a one-day overfeeding (2500 kcal/day in excess of the previous 24 h energy expenditure), the magnitude of increase in RQ was identical in lean and obese subjects and the net efficiency of substrate utilization and storage was not influenced by the state of obesity. PMID: 8124396 [PubMed - indexed for MEDLINE] 6302. Int J Obes Relat Metab Disord. 1993 Dec;17 Suppl 3:S18-21; discussion S22. Subcutaneous adipose tissue metabolism studied by local catheterization. Frayn KN(1), Coppack SW, Humphreys SM. Author information: (1)Sheikh Rashid Laboratory, Radcliffe Infirmary, Oxford, UK. Adipose tissue is a metabolically active tissue which plays a key role in regulating the concentrations of circulating lipid fuels. In recent years, two new techniques have become available for the study of human adipose tissue metabolism in vivo: microdialysis, and catheterization of the venous drainage from the subcutaneous abdominal adipose tissue. Blood obtained by the latter method shows all the characteristics expected of adipose tissue drainage. The characteristics of this tissue are quite distinct from those of the superficial (mainly skin) or the deep (mainly muscle) tissues of the forearm. The depot studied appears to be typical of adipose tissue as a whole in terms of non-esterified fatty acid release. In comparison with the microdialysis technique, the arterio-venous difference technique allows easier quantification of substrate uptake and release, and allows the study of hydrophobic molecules (e.g. fatty acids, triacylglycerol). On the other hand, it does not allow the study of more than one depot, nor the local introduction of effectors of metabolism (e.g. adrenergic agents). The two techniques are clearly complementary. PMID: 8124394 [PubMed - indexed for MEDLINE] 6303. Biochim Biophys Acta. 1993 Nov 2;1183(1):41-57. Effect of fatty acids on energy coupling processes in mitochondria. Wojtczak L(1), Schönfeld P. Author information: (1)Nencki Institute of Experimental Biology, Warsaw, Poland. Long-chain fatty acids are natural uncouplers of oxidative phosphorylation in mitochondria. The protonophoric mechanism of this action is due to transbilayer movement of undissociated fatty acid in one direction and the passage of its anion in the opposite direction. The transfer of the dissociated form of fatty acid can be, at least in some kinds of mitochondrion, facilitated by adenine nucleotide translocase. Apart from dissipating the electrochemical proton gradient, long-chain fatty acids decrease the activity of the respiratory chain by mechanism(s) not fully understood. In intact cells and tissues fatty acids operate mostly as excellent respiratory substrates, providing electrons to the respiratory chain. This function masks their potential uncoupling effect which becomes apparent only under special physiological or pathological conditions characterized by unusual fatty acid accumulation. Short- and medium-chain fatty acids do not have protonophoric properties. Nevertheless, they contribute to energy dissipation because of slow intramitochondrial hydrolysis of their activation products, acyl-AMP and acyl-CoA. Long-chain fatty acids increase permeability of mitochondrial membranes to alkali metal cations. This is due to their ionophoric mechanism of action. Regulatory function of fatty acids with respect to specific cation channels has been postulated for the plasma membrane of muscle cells, but not demonstrated in mitochondria. Under cold stress, cold acclimation and arousal from hibernation the uncoupling effect of fatty acids may contribute to increased thermogenesis, especially in the muscle tissue. In brown adipose tissue, the special thermogenic organ of mammals, long-chain fatty acids promote operation of the unique natural uncoupling protein, thermogenin. As anionic amphiphiles, long-chain fatty acids increase the negative surface charge of biomembranes, thus interfering in their enzymic and transporting functions. PMID: 8399375 [PubMed - indexed for MEDLINE] 6304. Diabetes Metab Rev. 1993 Nov;9 Suppl 1:5S-12S. Role of insulin resistance in the pathophysiology of non-insulin dependent diabetes mellitus. Reaven GM(1). Author information: (1)Department of Medicine, Stanford University School of Medicine, Palo Alto, California. PMID: 8299489 [PubMed - indexed for MEDLINE] 6305. Diabetes Metab Rev. 1993 Nov;9 Suppl 1:13S-17S. Epidemiological data on hyperinsulinaemia and vascular disease. Fontbonne A(1). Author information: (1)INSERM U21, National Institute of Health and Medical Research, Villejuif, France. PMID: 8299484 [PubMed - indexed for MEDLINE] 6306. J Anim Sci. 1993 Nov;71(11):3155-63. Nutritional management of replacement beef heifers: a review. Bagley CP(1). Author information: (1)North Mississippi Research and Extension Center, Mississippi State University, Verona 38879. Systems to produce replacement heifers to calve initially at 2 yr of age and at 12-mo intervals thereafter require integrated forage-animal management plans. The process of developing heifers as replacements must begin during the cow-calf production phase. Age and weight at puberty are affected by several factors, including breed of livestock. Generally, breeds of a larger size at maturity are older and heavier when reaching puberty. Heifers that are kept as replacements must be weaned at relatively heavy weights in comparison to their expected mature body size without becoming obese. Excessive adipose tissue in heifers during the preweaning phase may result in reduced subsequent performance of these animals. Several management techniques were reviewed that can be used both pre- and postweaning, including using anthelmintics, anabolic growth implants, and ionophores. Anabolic growth implants can increase heifer rates of gain and increase pelvic size. In addition, there are indications that these implants may alter mammary gland development, which may subsequently increase milk production. Ionophores were shown to increase growth rates, particularly in grazing heifers but more importantly to decrease age at puberty. Age and weight at puberty have been shown to be affected by level of nutrition. It is preferable for heifers to reach puberty one or two estrous cycles before the breeding season, and the breeding season for heifers should begin > or = 21 d before the breeding season of the mature cow herd. This time difference allows for the generally longer postpartum interval for primiparous cows than for multiparous cows. Because of the limited opportunities (every 12 mo) for cows to calve, optimum efficiency must be pursued. PMID: 8270540 [PubMed - indexed for MEDLINE] 6307. J Anim Sci. 1993 Nov;71(11):3138-50. Factors that alter the growth and development of ruminants. Owens FN(1), Dubeski P, Hanson CF. Author information: (1)Department of Animal Science, Oklahoma State University, Stillwater 74078. Growth is defined as an increase in tissue mass. Mass increases by hyperplasia early in life and hypertrophy later in life, although hyperplasia of adipose tissue continues throughout life. The growth curve, being mass or cumulative weight plotted against age, is sigmoid, consisting of a prepubertal accelerating phase plus a postpubertal decelerating phase. Mathematically, this curve can be described as a function of mature mass, fractional growth rate, and age. At a specific fraction of mature mass, body composition seems to be constant, but the degree to which nutrition can alter mature mass is not certain. If mature mass is altered, body composition at any given mass will be altered. Mature mass can be decreased by starvation or protein deficiency early in life. Alternatively, retarding the deposition of fat or the administration of estrogenic compounds may increase mature protein mass. Many of the advances in rate and efficiency of growth and in reduced fat of meat cuts can be explained by increased mature protein mass of ruminants. Animals with higher mature weight require more energy for maintenance and reach puberty later in life, so a larger mature mass is not desirable for the breeding herd. Indeed, smaller replacement heifers would prove economical if reproduction were not decreased. A period of restricted growth and fat deposition (as on pasture) can increase the slaughter weight of small cattle into a more desirable range, presumably through increasing mature protein mass. However, calves with retarded growth often make less efficient feedlot gains than do calves finished immediately after being weaned. For growing large-framed heifers, pasture alone often provides an inadequate energy supply for early puberty, but excessive amounts of supplemental feed can enhance fat deposition in the udder, which subsequently decreases milk production. By manipulating the supply of specific nutrients and hormones, it may prove feasible in the future to reduce fat deposition in specific tissues and to alter mature body protein mass. PMID: 8270538 [PubMed - indexed for MEDLINE] 6308. Mol Cell Biochem. 1993 Nov;127-128:239-53. The role of protein phosphorylation in the regulation of cyclic nucleotide phosphodiesterases. Beltman J(1), Sonnenburg WK, Beavo JA. Author information: (1)Department of Pharmacology, University of Washington, Seattle 98195. The cyclic nucleotide phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the phosphodiesterase. Isozymes of the cGMP-inhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide phosphodiesterases. In particular, the cGMP-inhibited phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased phosphodiesterase activity. PMID: 7935355 [PubMed - indexed for MEDLINE] 6309. Baillieres Clin Endocrinol Metab. 1993 Oct;7(4):785-873. Cellular insulin action and insulin resistance. Garvey WT(1), Birnbaum MJ. Author information: (1)Section of Endocrinology, Indianapolis Veterans Administration Medical Center, IN. PMID: 8304915 [PubMed - indexed for MEDLINE] 6310. J Bioenerg Biomembr. 1993 Oct;25(5):447-57. Dialectics in carrier research: the ADP/ATP carrier and the uncoupling protein. Klingenberg M(1). Author information: (1)Institute for Physical Biochemistry, University of Munich, Germany. A concise review is given of the research in our laboratory on the ADP/ATP carrier (AAC) and the uncoupling protein (UCP). Although homologous proteins, their widely different functions and contrasts are stressed. The pioneer role of research on the AAC, not only for the mitochondrial but also for other carriers, and the present state of their structure-function relationship is reviewed. The function of UCP as a highly regulated H+ carrier is described in contrast to the largely unregulated ADP/ATP exchange in AAC. General principles of carrier catalysis as derived from studies on the AAC and UCP are elucidated. PMID: 8132485 [PubMed - indexed for MEDLINE] 6311. J Bioenerg Biomembr. 1993 Oct;25(5):435-46. The mitochondrial transport protein superfamily. Walker JE(1), Runswick MJ. Author information: (1)Medical Research Council Laboratory of Molecular Biology, Cambridge, U.K. The ADP/ATP, phosphate, and oxoglutarate/malate carrier proteins found in the inner membranes of mitochondria, and the uncoupling protein from mitochondria in mammalian brown adipose tissue, belong to the same protein superfamily. Established members of this superfamily have polypeptide chains approximately 300 amino acids long that consist of three tandem related sequences of about 100 amino acids. The tandem repeats from the different proteins are interrelated, and probably have similar secondary structures. The common features of this superfamily are also present in nine proteins of unknown functions characterized by DNA sequencing in various species, most notably in Caenorhabditis elegans and Saccharomyces cerevisiae. The high level expression in Escherichia coli of the bovine oxoglutarate/malate carrier, and the reconstitution of active carrier from the expressed protein, offers encouragement that the identity of superfamily members of known sequence but unknown function may be uncovered by a similar route. PMID: 8132484 [PubMed - indexed for MEDLINE] 6312. J Clin Psychiatry. 1993 Sep;54 Suppl:50-4; discussion 55-6. Pharmacokinetics of psychotropic drugs in special populations. Rudorfer MV(1). Author information: (1)Division of Clinical and Treatment Research, National Institute of Mental Health, National Institutes of Health, Rockville, MD 20857. Patients treated for psychiatric illness may have a variety of characteristics that alter the pharmacokinetic profiles of psychotropic drugs. Genetic background, age, health status, and personal habits can change the body's ability to absorb, distribute, and metabolize medications. Most psychotropic drugs, with the exception of lithium, are eliminated via biotransformation in the liver rather than renal excretion, and a number of studies have demonstrated distinct phenotypes for hepatic metabolism involving the cytochrome P450 system. "Slow" metabolizers are likely to develop higher plasma concentrations of several different classes of psychotropic drugs, including tricyclic antidepressants. Advancing age reduces renal function but has little effect on hepatic metabolism. Volume of distribution may also be increased in elderly patients because of their greater percentage of adipose tissue. Ethnic background can significantly influence both drug metabolism and the pharmacodynamics of a variety of drugs. Thus, the physician should carefully consider patient characteristics when prescribing psychotropic medications and should engage in therapeutic drug monitoring when there is any doubt about the plasma drug levels that a given dosing regimen will achieve. PMID: 8407858 [PubMed - indexed for MEDLINE] 6313. Clin Sci (Lond). 1993 Sep;85(3):247-56. Assessment of adipose tissue metabolism in man: comparison of Fick and microdialysis techniques. Arner P(1), Bülow J. Author information: (1)Department of Medicine, Huddinge University Hospital, Sweden. PMID: 8403794 [PubMed - indexed for MEDLINE] 6314. Nutrition. 1993 Sep-Oct;9(5):452-9. Abdominal obesity as important component of insulin-resistance syndrome. Després JP(1). Author information: (1)Lipid Research Center, Laval University Medical Research Center, CHUL, Quebec, Canada. The regional distribution of body fat has been identified as a significant risk factor for the development of noninsulin-dependent diabetes mellitus and cardiovascular disease (CVD). Several studies that have investigated the potential associations between topographic features of adipose tissue and indices reflecting carbohydrate and lipid metabolism have reported significant associations between abdominal fat deposition and metabolic complications. The development of computed tomography as a means to precisely measure the amount of subcutaneous and deep adipose tissue at any site of the body has shown that determination of the level of visceral adipose tissue is a critical measurement to perform in the assessment of the health hazards of obesity. Studies that we have conducted in premenopausal women have clearly shown that the level of visceral adipose tissue is the best correlate of lipoprotein ratios used to estimate the risk of CVD. We have also reported that a high level of visceral adipose tissue is associated with a deterioration of glucose tolerance and that the relationship between visceral fat deposition and glucose tolerance remains significant after controlling for the level of total-body fat. Because significant interrelationships were observed between abdominal visceral obesity, insulin resistance, and dyslipoproteinemias in obese women, it is suggested that visceral obesity is an important component of the insulin-resistance syndrome (syndrome X) that has been previously described. This cluster of morphological, hormonal, and metabolic alterations observed in abdominal obesity may have substantial implications for the treatment of this condition. PMID: 8286886 [PubMed - indexed for MEDLINE] 6315. Ann N Y Acad Sci. 1993 Aug 27;692:60-71. Insulin, neuropeptide Y, and food intake. Schwartz MW(1), Figlewicz DP, Woods SC, Porte D Jr, Baskin DG. Author information: (1)Department of Medicine, University of Washington, Seattle 98195. PMID: 8215045 [PubMed - indexed for MEDLINE] 6316. J Am Coll Nutr. 1993 Aug;12(4):363-7. Exercise is not an effective weight loss modality in women. Gleim GW(1). Author information: (1)Nicholas Institute of Sports Medicine & Athletic Trauma, Lenox Hill Hospital, New York, NY 10021. The excess caloric expenditure which results from physical activity should lead to weight loss if caloric expenditure at other times remains constant. Unfortunately, while there is good evidence for such an effect in men, there is little if any evidence for a similar effect in women. Weight loss with exercise does not readily occur in women unless accompanied by caloric restriction. Further, the role of exercise in maintaining resting metabolic rate while dieting has only marginal support. Potential reasons for the ineffectiveness of exercise in inducing weight loss in women include smaller body size and lower aerobic capacity, under-reporting of caloric intake, differences in body fat distribution and sensitivity to catecholamines, a different gonadal hormone milieu, and energy conservation resulting from evolutionary pressures. Nevertheless, regular exercise in women has many beneficial effects on lipids, glucose homeostasis and bone metabolism even if weight loss does not occur. PMID: 8409096 [PubMed - indexed for MEDLINE] 6317. J Am Coll Nutr. 1993 Aug;12(4):349-56. Alcohol and nutrition in postmenopausal women. Gavaler JS(1). Author information: (1)Oklahoma Transplant Institute, Baptist Medical Center, Oklahoma City 73112. The estrogenization of postmenopausal women is of major importance for their health status, particularly with respect to risks of osteoporosis and coronary heart disease. Thus the factors which influence endogenous postmenopausal estrogen levels are receiving increasing attention. There are three major determinants of endogenous estrogen levels; two are well established, while the third is of fairly recent vintage. Two of the three are nutritionally based. A long-recognized nutritional determinant is body fat mass; a newly recognized determinant is that of moderate alcoholic beverage consumption. Another recognized but non-nutritional postmenopausal estrogen determinant is the presence of the ovaries. This review will examine these three determinants of endogenous postmenopausal estrogen levels. Further, data will also be presented to indicate that nationality may be a fourth factor, and may involve a potential nutritional component. Finally, to explore more deeply the nutritional aspects of alcoholic beverage consumption, the effects of phytoestrogen congeners of alcoholic beverages on the estrogenization of postmenopausal women will be reviewed. PMID: 8409094 [PubMed - indexed for MEDLINE] 6318. Clin Pharmacokinet. 1993 Aug;25(2):103-14. Clinical pharmacokinetics of drugs in obesity. An update. Cheymol G(1). Author information: (1)Service of Pharmacology, Saint-Antoine Hospital, Paris, France. Obesity is common enough to constitute a serious medical and public health problem. Drug prescription for obese patients is difficult since dosages based on pharmacokinetic data obtained in normal-weight individuals could induce errors. In obese patients, physiopathological modifications are likely to affect drug tissue distribution and elimination. Body constitution is characterised by a higher percentage of fat and a lower percentage of lean tissue and water. Although the cardiac output and total blood volume are increased, the blood flow per gram of fat is less than in nonobese individuals. Histological hepatic alterations are commonly reported in morbidly obese individuals. A higher glomerular filtration rate is also observed. Most of the pharmacokinetic information concerning obesity deals with distribution. Published data concerning molecules with moderate and weak lipophilicity are homogeneous. In obese compared with normal weight individuals, the total volume of distribution (Vd) is moderately increased (aminoglycosides, caffeine) or similar (H2-blockers, neuromuscular blockers), but the Vd corrected by kilogram of actual bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight. For highly lipophilic drugs, despite this common characteristic, discrepancies in distribution in obesity exist between drugs belonging to different pharmacological classes. Some drugs show a clear augmentation of Vd and elimination half-life (benzodiazepines, carbamazepine, trazodone, verapamil, sufentanil), indicating a marked distribution into adipose tissue. For others, Vd and Vd/kg are decreased (cyclosporin, propranolol), suggesting that factors other than lipid solubility intervene in tissue distribution. As a general trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, and also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Usually CL is identical in obese and nonobese individuals, sometimes it is increased in obesity (enflurane, halothane, prednisolone, some benzodiazepines). With some drugs a significant reduction in CL is observed in obese individuals (methylprednisolone, propranolol). Renal clearance of aminoglycosides and cimetidine increases in obese individuals. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in CL. In some cases (atracurium, prednisolone) dosage adjustment does not follow these recommendations, owing to pharmacodynamic data. PMID: 8403734 [PubMed - indexed for MEDLINE] 6319. Am J Clin Nutr. 1993 Aug;58(2 Suppl):287S-295S. Mechanisms by which somatotropin decreases adipose tissue growth. Etherton TD(1), Louveau I, Sørensen MT, Chaudhuri S. Author information: (1)Department of Dairy and Animal Science, Pennsylvania State University, University Park 16802. When growing pigs are treated daily with recombinantly derived porcine somatotropin (pST) for 30-60 d there is a dose-dependent decrease in lipid accretion. Maximal doses of pST can reduce lipid accretion by as much as 70%. The reduction in lipid accretion occurs because of a marked decrease in glucose transport and lipogenesis that is the result of a pST-dependent decrease in the ability of insulin to stimulate these processes in the adipocyte; lipolysis is not affected. The decrease in insulin sensitivity is not due to a decrease in insulin binding or insulin receptor kinase activity. Little is understood about the somatotropin (ST) intracellular signal pathway(s) that mediate the biological effects of ST. These effects are chronic rather than acute as was previously believed. This pattern likely reflects that ST decreases transcription of important insulin-responsive genes such as the muscle-adipose tissue transporter gene (GLUT4) and key lipogenic enzymes. PMID: 8328402 [PubMed - indexed for MEDLINE] 6320. Proc Nutr Soc. 1993 Aug;52(2):325-33. Influence of the weaning diet on the changes of glucose metabolism and of insulin sensitivity. Girard J(1), Issad T, Maury J, Foufelle F, Postic C, Leturque A, Ferre P. Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS, Meudon-Bellevue, France. PMID: 8234354 [PubMed - indexed for MEDLINE] 6321. Ecotoxicol Environ Saf. 1993 Aug;26(1):45-60. The relevance of fat content in toxicity of lipophilic chemicals to terrestrial animals with special reference to dieldrin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Geyer HJ(1), Scheunert I, Rapp K, Gebefügi I, Steinberg C, Kettrup A. Author information: (1)GSF-Forschungszentrum für Umwelt und Gesundheit, GmbH, München, Germany. Lipophilic chemicals such as chlorinated hydrocarbon insecticides and other persistent chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are fat soluble chemicals and are readily bioconcentrated in animal fat depots. The modifying role of the body fat content in the toxicity of chlorinated cyclodiene insecticides to insects and in the toxicity of TCDD to different mammals was investigated. The single oral acute 30-day LD50 data of TCDD in different mammals are presented and correlated with their total body fat content. A two linear regression equation with log/log values was obtained. It is concluded that the storage of TCDD and other related lipophilic and persistent chemicals in lipids of organisms is, in a sense, a detoxication mechanism by which the compounds are removed from sites of action and/or receptors. Therefore, terrestrial organisms such as insects and mammals with higher total body fat content can accumulate and tolerate higher chlorinated hydrocarbon insecticide and TCDD doses than organisms with lower fat content. The different sensitivity of mammals of various species, strains, body weight, sex, age, etc. to acute toxicity of TCDD and related lipophilic persistent chemicals can mainly be explained by differences in total body fat content. PMID: 7691535 [PubMed - indexed for MEDLINE] 6322. J Lipid Res. 1993 Jul;34(7):1057-91. Fat cell adrenergic receptors and the control of white and brown fat cell function. Lafontan M(1), Berlan M. Author information: (1)Institut National de la Santé et de la Recherche Médicale, INSERM, Unité 317, Institut Louis Bugnard, Faculté de Médecine, CHU Rangueil, Toulouse, France. Five adrenoceptor subtypes are involved in the adrenergic regulation of white and brown fat cell function. The effects on cAMP production and cAMP-related cellular responses are mediated through the control of adenylyl cyclase activity by the stimulatory beta 1-, beta 2-, and beta 3-adrenergic receptors and the inhibitory alpha 2-adrenoceptors. Activation of alpha 1-adrenoceptors stimulates phosphoinositidase C activity leading to inositol 1,4,5-triphosphate and diacylglycerol formation with a consequent mobilization of intracellular Ca2+ stores and protein kinase C activation which trigger cell responsiveness. The balance between the various adrenoceptor subtypes is the point of regulation that determines the final effect of physiological amines on adipocytes in vitro and in vivo. Large species-specific differences exist in brown and white fat cell adrenoceptor distribution and in their relative importance in the control of the fat cell. Functional beta 3-adrenoceptors coexist with beta 1- and beta 2-adrenoceptors in a number of fat cells; they are weakly active in guinea pig, primate, and human fat cells. Physiological hormones and transmitters operate, in fact, through differential recruitment of all these multiple alpha- and beta-adrenoceptors on the basis of their relative affinity for the different subtypes. The affinity of the beta 3-adrenoceptor for catecholamines is less than that of the classical beta 1- and beta 2-adrenoceptors. Conversely, epinephrine and norepinephrine have a higher affinity for the alpha 2-adrenoceptors than for beta 1-, 2-, or 3-adrenoceptors. Antagonistic actions exist between alpha 2- and beta-adrenoceptor-mediated effects in white fat cells while positive cooperation has been revealed between alpha 1- and beta-adrenoceptors in brown fat cells. Homologous down-regulation of beta 1- and beta 2-adrenoceptors is observed after administration of physiological amines and beta-agonists. Conversely, beta 3- and alpha 2-adrenoceptors are much more resistant to agonist-induced desensitization and down-regulation. Heterologous regulation of beta-adrenoceptors was reported with glucocorticoids while sex-steroid hormones were shown to regulate alpha 2-adrenoceptor expression (androgens) and to alter adenylyl cyclase activity (estrogens). PMID: 8371057 [PubMed - indexed for MEDLINE] 6323. J Anim Sci. 1993 Jul;71(7):1957-65. Regulation of fatty acid synthase gene expression: an approach for reducing fat accumulation. Clarke SD(1). Author information: (1)Department of Food Science and Human Nutrition, Colorado State University, Fort Collins 80523. Fatty acid synthase (FAS) catalyzes the last step in the fatty acid biosynthetic pathway. The tissue concentration of FAS, which is affected by a number of hormonal and dietary factors, is a key determinant for the maximal capacity of a tissue to synthesize fatty acids by the de novo pathway. The complete nucleotide sequence of the avian and rat FAS transcripts has been cloned. In addition, a 1.5-kb cDNA that represents the thioesterase domain of the pig FAS protein plus the entire 3'-untranslated region of the transcript was isolated from a porcine liver cDNA library. Using these FAS cDNA tools, FAS mRNA transcripts have been found in most tissues, including adipose, liver, lung, brain, kidney, and small intestine. Moreover, the abundance of FAS mRNA in a tissue determines the rate of FAS protein synthesis, and ultimately the tissue content of FAS protein. In the liver, the rate of FAS gene transcription dictates the level of FAS mRNA, whereas the FAS mRNA content of adipose tissue seems to be determined by factors that affect gene transcription and mRNA stability. Adaptive changes in the abundance of FAS mRNA seem to occur primarily in hepatic and adipose tissues, whereas FAS expression in other tissue types is resistant to nutritional and hormonal manipulations. This review presents the concept that the tissue-specific adaptation in FAS gene expression can be exploited to develop a tissue-specific inhibitor of FAS gene expression and, hence, reduce the tissue capacity for fat accretion through the de novo biosynthetic pathway.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8349524 [PubMed - indexed for MEDLINE] 6324. Clin Endocrinol (Oxf). 1993 Jul;39(1):1-16. The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women. Pasquali R(1), Casimirri F. Author information: (1)Institute of Clinical Medicine 1, University Alma Mater of Bologna, S. Orsola Hospital, Italy. PMID: 8348699 [PubMed - indexed for MEDLINE] 6325. Environ Health Perspect. 1993 Jul;101 Suppl 2:45-52. Nurturing and breast-feeding: exposure to chemicals in breast milk. Somogyi A(1), Beck H. Author information: (1)Max von Pettenkofer-Institut des Bundesgesundheitsamtes, Berlin, Germany. All chemicals that are not normal constituents of human milk should be considered undesirable contaminants. In the present review, the following substances detected in human milk are considered: persistent organochlorine pesticides; polychlorinated biphenyls (PCB); polychlorinated dibenzodioxins (PCDD) and dibenzofurans (PCDF); polybrominated compounds; polycyclic aromatic hydrocarbons (PAH); trace elements; mycotoxins; nitrate, nitrite, nitrosamines; nicotine, caffeine, ethanol; and drugs. The levels of most of these substances found in human milk were within a range that would not constitute health hazards for breast-fed infants. For many of these, there is a comfortable safety margin. This applies also to organochlorine pesticides and PCB, particularly since, as a result of their discontinued use, the levels of these compounds have clearly declined in recent years. On the other hand, the aflatoxin burden mediated through breast milk, at least in certain tropical countries, appears to pose a definite health hazard. Detailed reference are given on the contamination of human milk with PCDD/PCDF which has to be considered as a matter of concern from the viewpoint of preventive public health. Although the low PCDD/PCDF levels found in the adipose tissue of infants indicate that there is no appreciable health risk emanating from these substances for breast-fed infants, appropriate measures to reduce the current rate of their emission into the environment have to be taken. PMCID: PMC1519940 PMID: 8243405 [PubMed - indexed for MEDLINE] 6326. J Anim Sci. 1993 Jul;71(7):1966-77. Effect of metabolism modifiers on lipid metabolism in the pig. Dunshea FR(1). Author information: (1)Department of Agriculture, Victorian Institute of Animal Science, Werribee, Australia. Porcine somatotropin (pST) and certain beta-adrenergic agonists are potent metabolic modifiers that can improve performance in pigs. Pigs treated with either compounds utilize feed more efficiently and are leaner than controls. Comparative slaughter data clearly demonstrate that pST and some beta-agonists stimulate protein deposition. Porcine somatotropin decreases lipid deposition, but this is not the case for all beta-agonists. Somatotropin decreases lipid deposition through decreasing adipose tissue sensitivity to insulin, inhibiting lipogenesis, and perhaps stimulating lipolysis. Although lipolysis is increased during pST treatment of growing pigs, the greatest consequence is decreased lipogenesis. Although under controlled conditions certain beta-agonists stimulate lipolysis and inhibit lipogenesis, the limited metabolic studies suggest that at doses that are most efficacious for enhanced protein deposition, there are limited effects on lipid metabolism. In part, this may be due to desensitization of adipose tissue beta-adrenergic receptors and possibly a consequence of antagonism of beta-receptors. PMID: 8102358 [PubMed - indexed for MEDLINE] 6327. Ann N Y Acad Sci. 1993 Jun 14;683:151-63. Dietary lipids influence insulin action. Clandinin MT(1), Cheema S, Field CJ, Baracos VE. Author information: (1)Nutrition and Metabolism Research Group, University of Alberta, Edmonton, Canada. Insulin binding and insulin responsiveness are altered by dietary fat-induced changes in the fatty acid composition of the adipocyte plasma membrane. Feeding a high P/S diet increased polyunsaturated fatty acid content of major membrane phospholipids of adipocyte plasma membrane in normal and diabetic animals, increased membrane linoleic acid content, and prevented a decrease in arachidonic acid level in diabetic animals. The high P/S diet increased insulin binding in control animals. Animals fed the high P/S diet had significantly higher rates of insulin-stimulated glucose transport and lipogenesis than did animals fed the low P/S diet. Feeding a high P/S diet significantly increased the amount of glucose transported when expressed as a function of the specific amount of insulin bound. To determine if dietary fat-induced alterations in the fatty acid composition of skeletal muscle lipid alter insulin-dependent and basal muscle metabolism, contralateral epitrochlearis and extensor digitorum longus muscles were isolated and incubated in vitro. High levels of dietary omega-3 fatty acids reduced PGE2 and PGF2 alpha synthesis in extensor digitorum longus and epitrochlearis muscle. Insulin increased glucose and amino acid transport; the increase in glucose transport by insulin was significantly greater after consumption of the high omega-3 fatty acid diet. Rats fed high levels of omega-3 fatty acids showed reduced net protein degradation in the presence and absence of insulin due to decreased rates of protein degradation and synthesis. These experiments indicate that high levels of dietary omega-3 fatty acids alter muscle membrane composition, glucose transport, and metabolism of muscle protein. To determine if dietary fatty acids alter the onset of diabetes and insulin binding to liver nuclei in spontaneously diabetic rats, weanling rats were fed chow or semipurified diets containing 20% (w/w) fat of either high or low P/S ratio. Feeding a high P/S diet increased insulin binding to liver nuclei of control and diabetic animals. Although diet did not alter the onset of diabetes, insulin binding to liver nuclei is higher in animals at the onset of diabetes than in highly diabetic animals. Eight-week-old female C57 B 6J lean and ob/ob mice were fed semipurified diets containing 20% (w/w) fat of either high or low P/S ratio to investigate the effect of diet on specific binding of insulin to liver nuclei. Insulin binding was highest in nuclei from lean mice fed a high P/S diet. Specific binding of insulin to nuclei from obese mice was also increased by the high P/S diet, but to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8352437 [PubMed - indexed for MEDLINE] 6328. Prostaglandins. 1993 Jun;45(6):501-7. Cytosolic proteins alter the properties of the prostaglandin E2 receptor in rat epididymal adipocytes. Cohen-Luria R(1), Danon A, Rimon G. Author information: (1)Department of Physiology, Ben Gurion University of Negev, Beer Sheva, Israel. PMID: 8393204 [PubMed - indexed for MEDLINE] 6329. Ann Med. 1993 Jun;25(3):235-41. Transdermal dihydrotestosterone treatment of 'andropause'. de Lignieres B(1). Author information: (1)Département d'endocrinologie et médecine de la reproduction, Hôpital Necker, Paris, France. Male ageing coincides on average with progressive impairment of testicular function. The most striking plasma changes are an increase in sex hormone binding globulin (SHBG) and a decrease in non SHBG-bound testosterone, which is the only testosterone subfraction effectively bioavailable for target tissues. In healthy subjects the bioavailable testosterone declines by approximately 1% per year between 40 and 70 years but a more pronounced decline has been observed in non-healthy groups, especially in high cardiovascular risks groups. Relative androgen deficiency is likely to have unfavourable consequences on muscle, adipose tissue, bone, haematopoiesis, fibrinolysis, insulin sensitivity, central nervous system, mood and sexual function and might be treated by an appropriate androgen supplementation. The potential risk for prostate has been the main reason for limiting indications of such treatment. Testosterone (T) and dihydrotestosterone (DHT) are two potent androgens which have opposite effects regarding aromatase activity, an enzyme present in prostate stroma and suspected to have a pathogenic influence through local oestradiol synthesis. T is the main substrate for aromatase and oestradiol synthesis while DHT is not aromatizable and, at sufficient concentration, decreases T and oestradiol levels. A 1.8 years survey of 37 men aged 55-70 years treated with daily percutaneous DHT treatment suggested that high plasma levels of DHT (> 8.5 nmol/l) effectively induced clinical benefits while slightly but significantly reducing prostate size. Early stages of prostate hypertrophy require synergic stimulation by both DHT and oestradiol, and suppressing oestradiol instead of DHT seems easier and better adapted to the specific situation of aged hypogonadic men.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7687444 [PubMed - indexed for MEDLINE] 6330. Obes Res. 1993 May;1(3):206-22. Visceral obesity: a "civilization syndrome". Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, University of Göteborg, Göteborg, Sweden. Comment in Obes Res. 1993 May;1(3):203-5. The controversial question of the relationship between obesity and disease has been considerably clearer after the demonstration in several prospective, epidemiological studies that the subgroup of central, visceral obesity is particularly prone to develop cardiovascular disease, stroke, and non-insulin dependent diabetes mellitus. Visceral obesity is associated with multiple central endocrine aberrations. The hypothalamo-adrenal axis is apparently sensitive to stimuli, sex steroid hormone secretion blunted, and hyperandrogenicity is found in women. In addition, there seem to be signs of central dysfunctions in the regulation of hemodynamic factors after stress, and growth hormone secretion appears to be particularly blunted. Several of these endocrine abnormalities are associated with insulin resistance, particularly glycogen synthesis in muscle. Fiber composition with low type I/type II ratio might be secondary to the prevailing hyperinsulinemia, but low capillary density in muscle may well be of importance. In combination with elevated turn-over of free fatty acids (FFA) this will probably provide powerful mechanisms whereby insulin resistance is created. Portal FFA, from the highly lipolytic visceral depots may, in addition, affect hepatic metabolism to induce increased gluconeogenesis, production of very low density lipoproteins as well as to perhaps inhibit clearance of insulin. By these mechanisms a Metabolic Syndrome Visceral adipocytes seem to have a high density of several steroid hormone receptors, directing steroid hormone effects particularly to these depots. The net effect of cortisol is apparently a stimulation of lipid storage, with opposing effects of sex steroid hormones which also facilitate lipid mobilization, regulations most often found at the gene transcription level. Growth hormone inhibits cortisol effects on lipid accumulation, and amplifies the lipid mobilizing effects of steroid hormones. The combined perturbations of hormonal secretions will therefore probably direct triglycerides toward visceral depots. Circulatory and nervous regulatory mechanisms require, however, more attention. The multiple central endocrine and nervous aberrations of visceral obesity suggest neuroendocrine dysregulations, and have features characteristic of the hypothalamic arousal seen after certain types of stress, alcohol intake, and smoking. Such factors can be traced to subjects with visceral fat accumulation. Standardized stress, eliciting a "defeat reaction" in primates is followed by an apparently identical syndrome. This integrated picture of the multiple symptoms of visceral obesity is based on epidemiological, clinical, experimental, cellular, and molecular evidence. The ingredients of positive energy balance, including physical inactivity, stress, smoking, and alcohol consumption are frequent features of modern, urbanized society. Visceral obesity may therefore be an expression of a "Civilization Syndrome." PMID: 16350574 [PubMed - indexed for MEDLINE] 6331. J Am Geriatr Soc. 1993 May;41(5):552-9. Regulation of energy expenditure in aging humans. Poehlman ET(1). Author information: (1)Department of Medicine, University of Vermont, Burlington 05405. The regulation of daily energy expenditure and its components in aging humans in considered in this review. Specifically, the effects of age on resting metabolic rate (RMR), the thermic effect of a meal, body composition, and the interaction of these variables with physical activity in both men and women are considered. The possible modulators of the age-related decline in RMR are examined by exploring the influence of alterations in body composition, physical activity, and the sodium-potassium pump. Thereafter, the status of energy requirements in healthy and diseased individuals is examined. New information is presented regarding the use of the doubly-labeled water technique to measure daily energy expenditure and its applicability to the determination of daily energy requirements in free-living older persons. PMID: 8387556 [PubMed - indexed for MEDLINE] 6332. Biochem Soc Trans. 1993 May;21(2):509-13. Regulation of lipoprotein lipase. Olivecrona T(1), Liu G, Hultin M, Bengtsson-Olivecrona G. Author information: (1)Department of Medical Biochemistry and Biophysics, University of Umeå, Sweden. PMID: 8359521 [PubMed - indexed for MEDLINE] 6333. Rev Fr Gynecol Obstet. 1993 May;88(5):291-5. [Relationships between weight and menopause]. [Article in French] Schlienger JL(1), Pradignac A. Author information: (1)Service de Médecine interne, C.H.R.U.-Hôpital de Hautepierre, Strasbourg. Weight gain seen around the time of the menopause justifies a therapeutic action. It seems to be linked more to the effects of age than to the menopause itself. It often causes abdominal obesity which increases vascular risk and predisposes to raised blood pressure. The ability of adipose tissue to concentrate androgens and estrogens probably explains the higher incidence of genital carcinomas in overweight post-menopausal women. Hormone replacement therapy does not seem to have any untoward effects on weight. PMID: 8327816 [PubMed - indexed for MEDLINE] 6334. J Biol Chem. 1993 Apr 5;268(10):6823-6. Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. Spiegelman BM(1), Choy L, Hotamisligil GS, Graves RA, Tontonoz P. Author information: (1)Dana-Farber Cancer Inst., Boston, MA 02115. PMID: 8463205 [PubMed - indexed for MEDLINE] 6335. Nurse Pract. 1993 Apr;18(4):20-2, 25-6, 29. The critical role of exercise in weight control. Grubbs L(1). Author information: (1)Florida State University, Tallahassee. Exercise appears to play a critical role in the loss and maintenance of body weight. Diet alone has met with only temporary success because metabolic rate is decreased with extreme calorie restriction. This decrease persists after the dieting period has ended, often leading to rapid weight regain and the "yo-yo effect." In some instances, exercise alone has been effective for weight loss; however, success varies according to the gender of the subjects and to the type, intensity and duration of the exercise. Exercise programs of low to moderate intensity, long duration and high frequency seem to be most beneficial, with the most popular forms of exercise being walking/jogging, cycling and swimming. The purpose of this article is to explore the differences between diet and exercise, low vs. high intensity, short vs. long duration, and land vs. water exercise as these differences pertain to weight loss, food intake and energy balance. PMID: 8515897 [PubMed - indexed for MEDLINE] 6336. Curr Opin Genet Dev. 1993 Apr;3(2):238-45. Trans-acting factors involved in adipogenic differentiation. Vasseur-Cognet M(1), Lane MD. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205. The differentiation of preadipocytes into adipocytes in culture is accompanied by the coordinate transcriptional activation of adipose-specific genes. Recent studies have identified cis-acting elements that are involved in activating (or derepressing) the transcription of many of these genes during differentiation. The identification of key trans-acting nuclear factors that interact with certain of these elements makes it possible to formulate models for the regulatory network governing the adipogenic differentiation program. PMID: 8504249 [PubMed - indexed for MEDLINE] 6337. Anticancer Drugs. 1993 Apr;4(2):115-25. Cancer cachexia. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Institute, Aston University, Birmingham, UK. Cachexia is a common problem in the clinical management of cancer patients, particularly those with solid tumors. Cachexia is most obviously manifested as weight loss with massive depletion of both adipose tissue and muscle mass, and death is probably due to loss of lean body tissue. Not only is the survival time shorter in patients with cachexia, but the frequency of response to chemotherapy is also significantly reduced. Although anorexia frequently accompanies cachexia, attempts to halt or reverse cachexia by nutritional repletion have not been successful. This suggests that cachexia is due to metabolic abnormalities produced by the tumor in addition to the underlying anorexia. In some patients weight loss is associated with an increased relative energy expenditure possibly through an elevated adrenergic state. Several factors have been postulated as mediators of cancer cachexia and can be divided into two groups. (i) Materials with hormone-like characteristics which result in direct catabolism of host tissues. (ii) Cytokines which cause alterations in host metabolism indirectly. Included in group (i) are the conventional catabolic hormones and a lipid mobilizing factor (LMF) produced by tumors, which causes direct breakdown of adipose tissue. Included in group (ii) are tumor necrosis factor-alpha, interleukin-6, interferon-gamma and leukaemia inhibitory factor. The materials appear to influence adipose tissue indirectly through an inhibition of lipoprotein lipase. Reversal of cachexia has been achieved by two groups of agents. (i) Those stimulating food intake, e.g. megestrol acetate. (ii) Those directly inhibiting the LMF, e.g. eicosapentaenoic acid. While agents in group (i) can cause tumor growth stimulation, those in group (ii) act as tumor growth inhibitors. This latter results suggests that the products of catabolism of host tissues may be important for tumor growth and provides a new avenue for chemotherapeutic intervention. PMID: 8490191 [PubMed - indexed for MEDLINE] 6338. Prog Food Nutr Sci. 1993 Apr-Jun;17(2):89-98. Reproductive functions in obese women. Kumar A(1), Mittal S, Buckshee K, Farooq A. Author information: (1)Department of Physiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi. The prevalence of obesity is increasing in the developed as well as underdeveloped countries. Obesity in women is associated with reproductive disorders. The levels of estrone and androgens are higher in obese women along with a reduction in the levels of sex hormone binding globulin ( SHBG ). The pituitary secretion of hormones is altered either due to a deficient peripheral feedback regulation or a concomitant central defect in the obese. Luteinizing hormone ( LH ) level may increase in some of the obese subjects. The secretion of LH in response to luteinizing hormone releasing hormone ( LHRH or GnRH ), clonidine and naloxone may be altered in obese women. The levels of circulating prolactin may fall along with a delay in the nocturnal surge of the hormone. The secretion of prolactin in response to thyrotropin releasing hormone ( TRH ), insulin-induced hypoglycemia, arginine and chlorpromazine is altered. Similarly growth hormone secretion in response to growth hormone releasing hormone ( GHRH ), clonidine, naloxone and arginine is also altered in obesity. The literature suggests an alteration in the autonomic nervous system activity and the metabolism of carbohydrates and fats in the obese. Steroid hormones could affect the distribution of fat in the various regions of the body, and the distribution of body fat is linked with the severity of hyperandrogenism and metabolic disorders in obese subjects. However, it is heartening to note that many of the endocrinological and reproductive disorders are reversible with weight reduction in the obese subjects. PMID: 8372228 [PubMed - indexed for MEDLINE] 6339. Environ Health Perspect. 1993 Apr;100:259-68. Toxicology, structure-function relationship, and human and environmental health impacts of polychlorinated biphenyls: progress and problems. Safe S(1). Author information: (1)Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station 77843-4466. Polychlorinated biphenyls (PCBs) are industrial compounds that have been detected as contaminants in almost every component of the global ecosystem including the air, water, sediments, fish, and wildlife and human adipose tissue, milk, and serum. PCBs in commercial products and environmental extracts are complex mixtures of isomers and congeners that can now be analyzed on a congener-specific basis using high-resolution gas chromatographic analysis. PCBs are metabolized primarily via mixed-function oxidases into a broad spectrum of metabolites. The results indicate that metabolic activation is not required for PCB toxicity, and the parent hydrocarbons are responsible for most of the biochemical and toxic responses elicited by these compounds. Some of these responses include developmental and reproductive toxicity, dermal toxicity, endocrine effects, hepatotoxicity, carcinogenesis, and the induction of diverse phase I and phase II drug-metabolizing enzymes. Many of the effects observed for the commercial PCBs are similar to those reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Structure-function relationships for PCB congeners have identified two major structural classes of PCBs that elicit "TCDD-like" responses, namely, the coplanar PCBs (e.g., 3,3',4,4'-tetraCB, 3,3'4,4',5-pentaCB and 3,3',4,4',5,5'-hexaCB) and their mono-ortho coplanar derivatives. These compounds competitively bind to the TCDD or aryl hydrocarbon (Ah) receptor and exhibit Ah receptor agonist activity. In addition, other structural classes of PCBs elicit biochemical and toxic responses that are not mediated through the Ah receptor. The shor-term effects of PCBs on occupationally exposed humans appear to be reversible, and no consistent changes in overall mortality and cancer mortality have been reported. Recent studies have demonstrated that some developmental deficits in infants and children correlated with in utero exposure to PCBs; however, the etiologic agent(s) or structural class of PCBs responsible for these effects have not been delineated. In contrast, based on a toxic equivalency factor approach, the reproductive and developmental problems in certain wildlife populations appear to be related to the TCDD-like PCB congeners. PMCID: PMC1519588 PMID: 8354174 [PubMed - indexed for MEDLINE] 6340. J Am Diet Assoc. 1993 Apr;93(4):450-4. Physiologic control of food intake by neural and chemical mechanisms. Norton P(1), Falciglia G, Gist D. Author information: (1)Department of Health and Nutrition Sciences, University of Cincinnati, OH 45221. Physiologic control of eating involves neural and chemical regulators that may have therapeutic applications in weight control. Information on the nature and quantity of ingested and stored nutrients is relayed to the brain via sensory nerve fibers. This information is integrated at specific centers in the brain, then impulses in motor nerve fibers are discharged leading to initiation or termination of eating. Chemical regulators of eating behavior include gastrointestinal peptides released during digestion, absorbed glucose circulating in the plasma, and the hormonal regulators of glucose metabolism (insulin and glucagon). There is, however, considerable interplay between neural and chemical processes in regulation of food intake. Neural mechanisms are evidently mediated by chemical regulators, because neurotransmitters, including serotonin, allow nerve impulses to cross synapses. In addition, some chemical regulators are concentrated at brain centers that are implicated in regulation of eating behavior. Although some gastrointestinal peptides and serotoninergic drugs have been used to treat obesity, the existence of a complex control system with alternate mediators of food intake suggests that a single therapeutic agent is unlikely to be applied universally to suppress overeating. PMID: 8095942 [PubMed - indexed for MEDLINE] 6341. Ann N Y Acad Sci. 1993 Mar 15;676:270-8. Pathophysiology and pathogenesis of visceral fat obesity. Matsuzawa Y(1), Shimomura I, Nakamura T, Keno Y, Tokunaga K. Author information: (1)Second Department of Internal Medicine, Osaka University Medical School, Japan. PMID: 8489138 [PubMed - indexed for MEDLINE] 6342. Ann N Y Acad Sci. 1993 Mar 15;676:253-69. Genetic differences in adipose tissue metabolism and regulation. Greenwood MR(1), Johnson PR. Author information: (1)Department of Nutrition, University of California, Davis 95616. PMID: 8489136 [PubMed - indexed for MEDLINE] 6343. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):321-30. Tissue-specific promoters regulate aromatase cytochrome P450 expression. Simpson ER(1), Mahendroo MS, Means GD, Kilgore MW, Corbin CJ, Mendelson CR. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics/Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9051. In the human, estrogen biosynthesis occurs in several tissue sites, including ovary, placenta, adipose, and brain. Recent work from our laboratory has indicated that tissue-specific expression of aromatase cytochrome P450 (P450arom), the enzyme responsible for estrogen biosynthesis, is determined, in part, by the use of tissue-specific promoters. Thus the expression of P450arom in human ovary appears to utilize a promoter proximal to the translation start-site. This promoter is not utilized in placenta but instead, the promoter used to drive aromatase expression in placenta is at least 40 kb upstream from the translational start-site. In addition, there is a minor promoter used in the expression of a small proportion of placental transcripts which is 9 kb upstream from the start of translation. Transcripts from these promoters are also expressed in other fetal tissues including placenta-related cells such as JEG-3 choriocarcinoma cells, hydatidiform moles, and other fetal tissues such as fetal liver. On the other hand, in adipose tissue expression of P450arom may be achieved by yet another, adipose-specific promoter. The various 5'-untranslated exons unique for expression driven by each of these promoters are spliced into a common intron/exon boundary upstream from the translational start-site. This means that the protein expressed in each of the various tissue-specific sites of estrogen biosynthesis is identical. PMID: 8476746 [PubMed - indexed for MEDLINE] 6344. Minerva Endocrinol. 1993 Mar;18(1):27-35. [Essential obesity: an unresolved clinical problem. Considerations on central appetite stimulants and inhibitors]. [Article in Italian] Lamberto M(1), Mantovan M, Novi RF. Author information: (1)Istituto di Medicina Interna, Università degli Studi di Torino. The recent theories on the etiology of obesity have attributed more importance to the mechanisms of feeding control. The amount of calories taken daily seems to be under the control of a group of substances which stimulate or inhibit the appetite at the hypothalamic level. The hypothalamus is particularly rich in neurotransmitters or neurohormones which are biologically active and represent the connexion between the cells of the upper centers and the hypothalamus and they interfere in the regulation of feeding. The authors pass in review the more recent literature data regarding the main appetite stimulators as well as their site and their mechanism of action. PMID: 7901745 [PubMed - indexed for MEDLINE] 6345. Can Fam Physician. 1993 Feb;39:352-6, 359-63. Photodamaged skin. Update on therapeutic management. Goldhar JN(1), Yong PY. Author information: (1)Mt Sinai Hospital, Toronto. With baby boomers aging, the medical community is ushered into a new era of patient care, that of cosmetic maintenance and rejuvenation. The authors critically review pharmacologic treatments for preventing and treating photodamaged skin. Issues concerning sunscreens, tretinoin, silicone tissue augmentation, fat transplantation, collagen replacement therapy, and chemical exfoliation of the skin are addressed. PMCID: PMC2379729 PMID: 8495125 [PubMed - indexed for MEDLINE] 6346. Endocr Rev. 1993 Feb;14(1):72-93. Genetic and nongenetic determinants of regional fat distribution. Bouchard C(1), Després JP, Mauriège P. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. The role of inherited and nongenetic factors in individual differences observed in the level of sc fat on the trunk and abdominal areas and in the abdominal visceral deposit is reviewed. First, the metabolic and clinical implications of variation in body fat topography are summarized. Second, the results of genetic epidemiology studies on the heritability and other evidence for a role of the genotype in the amount of truncal-abdominal sc fat and abdominal visceral fat are reviewed. Third, the impact of total body fat, age, and gender on regional fat distribution is highlighted. Fourth, adipose tissue lipoprotein lipase activity is considered as a determinant of fat topography, with a discussion of site and gender differences, the effects of steroid hormones, and evidence from genetic epidemiology. Fifth, the contribution of adipose tissue lipolysis is reviewed with an emphasis on the various regulatory factors of the lipolytic pathways including catecholamines, insulin, adenosine, steroids, and other modulators. The role of lipolytic characteristics on fat topography is further assessed by considering changes with age, differences between men and women, effects of excess body fat, and data from heritability studies. Although the study of regional variation of in vitro adipose tissue metabolism has provided valuable information, a better understanding of variation in fat topography and of the role played by adipose tissue in the regulation of whole body carbohydrate and lipid metabolism will likely require extensive in situ and in vivo investigations. Sixth, as enlargement of a specific fat deposit is associated with increases in fat cell size and number, these topics are considered with an emphasis on the role of adipose cell differentiation. Seventh, the importance of blood levels of sex steroids and glucocorticoids for regional fat distribution is discussed. Then, a unifying hypothesis, defined as the hypothalamic arousal and neuroendocrine dysregulation model, is briefly described. Finally, the issue of whether body fat distribution can be altered by caloric restriction or regular exercise is addressed. PMID: 8491156 [PubMed - indexed for MEDLINE] 6347. Vet Parasitol. 1993 Feb;46(1-4):143-58. Pathophysiology of infection with Ostertagia ostertagi in cattle. Fox MT(1). Author information: (1)Department of Veterinary Pathology, Royal Veterinary College, University of London, UK. Infection with the abomasal nematode, Ostertagia ostertagi, is an important cause of impaired productivity in young cattle in temperate parts of the world. Such losses have been associated with marked changes in feed intake, gastrointestinal function, protein, energy and mineral metabolism, and in body composition. The reduction in feed intake is an important factor in the pathogenesis of infection and may account for a large part of the difference in weight gain between ad libitum fed control and infected calves. Despite the obvious importance of inappetance, only recently has an association been made between reduced intake, altered gut motility and elevated levels of certain gastrointestinal hormones, such as gastrin. It has been suggested that the elevated gastrin levels accompanying abomasal parasitism may impair reticulo-ruminal motility and slow down abomasal emptying, leading to a stasis of ingesta and a reduction in feed intake. The rise in blood gastrin levels may also be partly responsible for the marked hyperplasia of the fundic mucosa seen in abomasal infections. Pronounced changes in protein metabolism have also been associated with Ostertagia infection. Radioisotopic studies have demonstrated increased losses of albumin into the gastrointestinal tract which are accompanied by an increase in the rate of synthesis in the liver. Dietary protein breakdown in the abomasum is also likely to be impaired, although there is evidence of a compensatory increase in protein digestion in the lower gut of parasitised calves. Increased losses of albumin are not always accompanied by increases in faecal nitrogen, suggesting that albumin is broken down and recycled as ammonia. Radioisotopic studies in animals with intestinal nematode infections have demonstrated a marked reduction in muscle protein synthesis and an increase in protein synthesis in gastrointestinal tissue. Such changes in the balance of protein synthesis are likely to be brought about by alterations in the balance of certain metabolic hormones. Marked changes in energy metabolism also accompany Ostertagia infection. Parasitised calves exhibit a marked increase in non-esterified fatty acid levels, resulting from the mobilisation of adipose tissue, and a reduction in digestive efficiency of energy, probably associated with the increase in cycling of protein through the gastrointestinal tract and the compensatory increases in protein synthesis. Mineral metabolism may also be affected although relatively little work has been conducted in cattle. Changes in body composition reflect a reduction in deposition of muscle protein and fat, and an increase in bone content and water retention. PMID: 8484207 [PubMed - indexed for MEDLINE] 6348. Clin Chem. 1993 Feb;39(2):317-24. Tissue-specific promoters regulate aromatase cytochrome P450 expression. Simpson ER(1), Mahendroo MS, Means GD, Kilgore MW, Corbin CJ, Mendelson CR. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas 75235-9051. In humans, estrogen biosynthesis occurs in several tissue sites, including ovary, placenta, adipose, and brain. Recent work from our laboratory indicates that tissue-specific expression of aromatase cytochrome P450 (P450arom), the enzyme responsible for estrogen biosynthesis, is determined, in part, by the use of tissue-specific promoters. Thus, the expression of P450arom in human ovary appears to utilize a promoter proximal to the translation start site. This promoter is not utilized in placenta; instead, the promoter used to drive aromatase expression in placenta is > or = 40 kb upstream from the translational start site. In addition, a minor promoter used in the expression of a small proportion of placental transcripts is 9 kb upstream from the start of translation. Transcripts from these promoters are also expressed in other fetal tissues, including placenta-related cells such as JEG-3 choriocarcinoma cells and hydatidiform moles and other fetal tissues such as fetal liver. In adipose tissue, on the other hand, expression of P450arom may be achieved by yet another, adipose-specific promoter. The various 5'-untranslated exons unique for expression driven by each of these promoters are spliced into a common intron/exon boundary upstream from the translational start site. This means that the protein expressed in each of the various tissue-specific sites of estrogen biosynthesis is identical. PMID: 8432022 [PubMed - indexed for MEDLINE] 6349. Int J Obes Relat Metab Disord. 1993 Feb;17 Suppl 1:S3-8. Control systems in the defense of body fat stores. Girardier L(1). Author information: (1)Department of Physiology, Faculty of Medicine, CMU, Geneva, Switzerland. PMID: 8384177 [PubMed - indexed for MEDLINE] 6350. Ann Med. 1993 Feb;25(1):71-6. Dose-response relationships of RU 486. Heikinheimo O(1), Kekkonen R. Author information: (1)Department of Medical Chemistry, University of Helsinki, Finland. Clinical experience has indicated that the effects of RU 486 can be divided into dose-dependent and dose-independent effects. Examples of the dose-dependent effects include the antiglucocorticoid effects of RU 486, whereas pregnancy termination or dilatation of the cervix can be considered dose-independent with the various regimens tested so far. Following oral intake in man, the serum levels of RU 486 are in the micromolar range, and the half-life is approximately 30 hours. The concentrations of RU 486 in myometrial tissue are approximately one-third of those measured in serum. However, due to saturation of alpha 1-acid glycoprotein (AAG), the serum binding protein for RU 486, the serum levels remain similar within the dose range of 100-800 mg of RU 486. The unbound RU 486 is metabolized by two-step demethylation or by hydroxylation. The demethylated and hydroxylated metabolites of RU 486 retain considerable affinities of 9-21% towards the human progesterone receptor, and 45-61% towards the human glucocorticoid receptor (RU 486 = 100%), suggesting a biological role for the metabolites. Rat serum lacks a specific binding protein for RU 486. Even though the levels of RU 486 in rat adipose tissue are 40 times as high as those seen in serum, the concentrations of RU 486 in rat brain are only 28% of the serum levels. This indicates that diffusion of RU 486 into the central nervous system is restricted by the blood-brain barrier. Hence, the dose-dependency of certain centrally mediated effects of RU 486 might be explained by the limited diffusion of RU 486 into hypothalamic/hypophyseal sites, which seem to be reached only after ingestion of high doses of RU 486. However, the peripheral effects of RU 486, such as termination of pregnancy, are mediated via steroid receptors in target tissues. This suggests that similar biological effects can be attained at considerably lower doses than the ones currently in use. PIP: RU-486 has both dose-dependent effects and dose-independent effects. Acute treatment of single doses of at least 400 mg RU-486 increase secretion of adrenocorticotropic hormone. 50-100 mg RU-486 activate the hypothalamo-pituitary-adrenal (HPA) axis. Pregnancy termination and dilatation of the cervix are dose-independent effects. Oral ingestion in humans results in RU-486 serum concentrations in the micromolar range with a half-life of about 30 hours. RU-486 levels in myometrial tissue are about 33% lower than those in the serum. 2-step demethylation or hydroxylation metabolizes unbound R-486. The resulting RU-486 metabolites are able to bond strongly to the human progesterone receptor and to the human glucocorticoid receptor (9-21% and 45-61%, respectively, vs. 100% for RU-486), indicating that the metabolites have a biological role. Research in rats suggests that the blood-brain barrier prevents the diffusion of RU-486 into the central nervous system. Limited diffusion of RU-486 into hypothalamic/hypophyseal sites may account for the dose-dependency of certain centrally mediated effects of RU-486. Oral intake of high doses of RU-486 appears to be the only route to hypothalamic/hypophyseal sites. Steroid receptors in target tissues, e.g., endometrium, mediate RU-486's indirect effects, e.g., pregnancy termination, indicating much lower doses of RU-486 than are now being used can have the same effects. PMID: 8382070 [PubMed - indexed for MEDLINE] 6351. Nihon Naibunpi Gakkai Zasshi. 1993 Jan 20;69(1):9-15. [Thyroid hormone metabolism]. [Article in Japanese] Inada M(1), Nishikawa M. Author information: (1)Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan. Most thyroxine (T4) secreted from the thyroid is deiodinated in peripheral tissues. At least three isozymes are known in iodothyronine deiodinase which catalyzes the conversion of T4 to triiodothyronine (T3) or reverse T3. Type I 5'-deiodinase (5'D-I) exists in most tissues including the liver, kidney and thyroid. Type II 5'-deiodinase (5'D-II) which exists mainly in the brain, pituitary, brown fat and placenta plays an important role in the saturation of intracellular T3 receptor. Type III enzyme (D-III) which deiodinases the five positions of T3 is considered to modulate the T3 content by regulating its degradation. The complementary DNA (cDNA) for the rat and human 5'D-I has recently been cloned. 5'D-I contains a rare amino acid selenocysteine, which is essential for normal deiodinative function in humans as well as rats. On the other hand, 5'D-II, whose molecular weight is much heavier than that of 5'D-I, does not contain selenocysteine and its cDNA has not been sequenced. Little is known about the molecular characteristics of D-III. Further studies are needed to clarify the molecular mechanism by which deiodinase proteins are produced in various circumstances and to investigate the meticulous aspects of metabolic pathways other than deiodination. PMID: 8449246 [PubMed - indexed for MEDLINE] 6352. World Rev Nutr Diet. 1993;72:78-91. Obesity and its treatment by diet and exercise. Parízková J(1). Author information: (1)Biomedical Center, Faculty of Physical Education, 2nd Medical School, Charles University, Prague, Czechoslovakia. PMID: 8506712 [PubMed - indexed for MEDLINE] 6353. Exerc Sport Sci Rev. 1993;21:363-96. Exercise and weight control. Stefanick ML. Several important questions need to be answered to increase the likelihood that exercise will be accepted by the millions in the population who are obese. What is the minimum exercise "dose" (intensity, duration, frequency) and what is the optimal mode to bring about substantial fat weight loss, with minimal loss of lean mass? What is the best nutritional plan to optimize fat utilization during exercise, without impairing performance or loss of lean mass? Which diet and exercise programs maximally increase utilization of centrally deposited fat and how can hyperplastic obesity best be treated? Also of interest is the potential role of resistance exercise for weight loss, and the predictors of weight loss success. For instance, do individuals with gynoid obesity really differ from individuals with android obesity in their utilization and loss of body fat during exercise? The potential advantages of exercise include: stimulation of fat as opposed to carbohydrate oxidation; increased energy use during the exercise itself and in the postexercise period; protection of lean body mass; possible reversal of the diet-induced suppression of BMR; and other health benefits. Among other parameters, the effectiveness of exercise on weight loss may be influenced by the type, intensity, frequency, and duration of exercise bouts and the duration of the training program, the nature of the excess fat stores, i.e., whether the person has obesity characterized by hyperplastic or hypertrophic adipose tissue or central (with large-intra-abdominal depot) or peripheral obesity, the composition and caloric content of the diet, and behavioral aspects that affect adherence to the program. With respect to this latter concern, even if a person has been very successful at weight loss in a metabolic ward or intensive program, he/she must eventually return to the outside world and figure out for himself/herself how to eat real food and/or maintain an activity level that promotes weight maintenance. Because diet and exercise habits are difficult to assess and to quantify in free-living populations, it continues to be difficult to evaluate the success of diet and/or exercise prescriptions for weight loss accurately and we continue to be plagued with questions regarding the effectiveness vs. efficacy of exercise as a means to control body weight. It would seem that the wide range of health benefits derived from regular exercise would justify emphasizing increased activity for inactive people, particularly for obese, sedentary individuals, whether or not ideal body weight or significant weight loss is achieved. PMID: 8504848 [PubMed - indexed for MEDLINE] 6354. Intern Med. 1993 Jan;32(1):42-5. Hereditary lipo-muscular atrophy with joint contracture, skin eruptions and hyper-gamma-globulinemia: a new syndrome. Tanaka M(1), Miyatani N, Yamada S, Miyashita K, Toyoshima I, Sakuma K, Tanaka K, Yuasa T, Miyatake T, Tsubaki T. Author information: (1)Department of Neurology, Niigata University, Japan. We previously reported two siblings with decreased subcutaneous adipose tissue, muscular atrophy, joint contractures, recurrent skin eruptions, hyper-gamma-globulinemia, and reduced natural killer cell activity. Some of their clinical features are similar to those of partial lipodystrophy, but they are distinct in that muscular atrophy, joint contractures and recurrent skin eruptions are not found in patients with partial lipodystrophy. Thirteen other Japanese patients with similar clinical manifestations have been reported. We propose that such cases should be considered a distinct clinical entity. PMID: 8495043 [PubMed - indexed for MEDLINE] 6355. Int Rev Exp Pathol. 1993;34 Pt A:205-14. Review of a novel hematopoietic cytokine, interleukin-11. Quesniaux VF(1), Mayer P, Liehl E, Turner K, Goldman SJ, Fagg B. Author information: (1)Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland. The novel stromal cell factor, IL-11, has been reported to have diverse effects on the lymphopoietic and myeloid/erythroid cells in vitro. These include expansion of T cell-dependent Ig-secreting B cells, proliferation and differentiation of megakaryocytic progenitors and of a variety of myeloid and erythroid precursor cells, and multiplication of pluripotential hematopoietic progenitors. In addition, IL-11 inhibits adipogenesis in vitro. In vivo administration of IL-11 elevated the number of circulating neutrophils and platelets and increased the number of megakaryocytes in the spleens of normal mice. PMID: 8454414 [PubMed - indexed for MEDLINE] 6356. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):89-90. Regulation of gene expression by fatty acids in the adipose cell. Ailhaud G(1). Author information: (1)Centre de Biochimie (UMR 134 CNRS), Universite de Nice-Sophia Antipolis, Nice, France. PMID: 8424127 [PubMed - indexed for MEDLINE] 6357. Biol Cell. 1993;77(1):67-76. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Dreyer C(1), Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W. Author information: (1)Max-Planck-Institut für Entwicklungsbiologie, Abt V für Zellbiologie, Tübingen, Germany. Peroxisome proliferators regulate the transcription of genes by activating ligand-dependent transcription factors, which, due to their structure and function, can be assigned to the superfamily of nuclear hormone receptors. Three such peroxisome proliferator-activated receptors (PPAR alpha, beta, and gamma) have been cloned in Xenopus laevis. Their mRNAs are expressed differentially; xPPAR alpha and beta but not xPPAR gamma are expressed in oocytes and embryos. In the adult, expression of xPPAR alpha and beta appears to be ubiquitous, and xPPAR gamma is mainly observed in adipose tissue and kidney. Immunocytochemical analysis revealed that PPARs are nuclear proteins, and that their cytoplasmic-nuclear translocation is independent of exogenous activators. A target gene of PPARs is the gene encoding acyl-CoA oxidase (ACO), which catalyzes the rate-limiting step in the peroxisomal beta-oxidation of fatty acids. A peroxisome proliferator response element (PPRE), to which PPARs bind, has been identified within the promoter of the ACO gene. Besides the known xenobiotic activators of PPARs, such as hypolipidemic drugs, natural activators have been identified. Polyunsaturated fatty acids at physiological concentrations are efficient activators of PPARs, and 5,8,11,14-eicosatetraynoic acid (ETYA), which is the alkyne homolog of arachidonic acid, is the most potent activator of xPPAR alpha described to date. Taken together, our data suggest that PPARs have an important role in lipid metabolism. PMID: 8390886 [PubMed - indexed for MEDLINE] 6358. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):91-100. Modulation by sex hormones of the membranous transducing system regulating fatty acid mobilization in adipose tissue. Giudicelli Y(1), Dieudonne MN, Lacasa D, Pasquier YN, Pecquery R. Author information: (1)Laboratoire de biochimie, Faculté de Médecine Paris-Ouest, C.H.I. de Poissy, France. This review summarizes recent animal studies performed to determine the possible role played by sex hormones in the sex- and site-related differences characterizing adipocyte lipolytic activity. In both normal female rats and male hamsters, fat cells from deep intra-abdominal sites elicit higher catecholamine-stimulated lipolytic responses than subcutaneous adipocytes. By using ovariectomized rats, it was found that estradiol 'in vivo', while having no effect in subcutaneous cells, promotes catecholamine-stimulated lipolysis in deep intraabdominal adipocytes by increasing their adenylate cyclase catalytic activity. By using castrated hamsters, it was found that both deep intra-abdominal and subcutaneous fat cell lipolytic activities are equally sensitive to testosterone. In these cells, testosterone treatment promotes not only the beta-adrenergic lipolytic responses by increasing both the adenylate cyclase catalytic activity and the Gs alpha level, but also enhances the alpha 2-adrenergic antilipolytic responses through a transcriptional activation of the alpha 2-adrenoceptor expression. These experiments demonstrate that in some, but not all, white adipocytes the adrenergic signal transducing system regulating lipolysis is a target for sex hormones. This finding may have potential importance in the understanding of the mechanisms underlying the sex-related regional specificities of adipose tissue metabolism and distribution. PMID: 8380933 [PubMed - indexed for MEDLINE] 6359. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):105-9. Mechanism of lipid mobilization associated with cancer cachexia: interaction between the polyunsaturated fatty acid, eicosapentaenoic acid, and inhibitory guanine nucleotide-regulatory protein. Tisdale MJ(1). Author information: (1)Pharmaceutical Sciences Institute, Aston University, Birmingham, UK. During a study of the mechanism of cancer cachexia, a debilitating condition in which catabolism of host muscle and adipose tissue occurs, it has been observed that the process can be effectively reversed in vivo by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), but not by other PUFA of either the n-3 or n-6 series. In vitro studies showed that EPA blocked the action of a tumour-produced catabolic factor at the level of the adipocyte, and that the effect of EPA also extended to beta-adrenergic stimuli and polypeptide hormones. Again the effect was specific to EPA and appeared to arise from an inhibition of the elevation of cyclic AMP levels in adipocytes in response to varied stimuli. Using isoprenaline stimulated lipolysis as a model system we have shown that EPA has a direct inhibitory effect on isoprenaline-stimulated adenylate cyclase in isolated plasma membrane fractions with half maximal inhibition at a concentration of 165 microM. The inhibitory effect was specific for EPA and was not shown by docosahexaenoic or arachidonic acids. The inhibitory effect of EPA on adenylate cyclase showed properties similar to hormonal inhibition of the enzyme in that it was (i) GTP-dependent, (ii) non-competitive with isoprenaline, (iii) eliminated following treatment of either adipocytes or plasma membrane fractions with pertussis toxin, which is known to ADP-ribosylate the alpha-subunit of an inhibitory guanine nucleotide-regulatory protein (Gi), thus leading to its inactivation. This suggests that inhibition of cyclic AMP formation by EPA was due, at least in part, to a Gi-mediated inhibition of adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8380931 [PubMed - indexed for MEDLINE] 6360. Annu Rev Nutr. 1993;13:437-61. Effects of exogenous bovine somatotropin on lactation. Bauman DE(1), Vernon RG. Author information: (1)Department of Animal Science, Cornell University, Ithaca, New York 14853. PMID: 8369154 [PubMed - indexed for MEDLINE] 6361. Annu Rev Nutr. 1993;13:337-54. Genetics of obesity. Bouchard C(1), Pérusse L. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. PMID: 8369150 [PubMed - indexed for MEDLINE] 6362. Jpn J Physiol. 1993;43(2):117-39. Brown adipose tissue thermogenesis as physiological strategy for adaptation. Kuroshima A(1). Author information: (1)Department of Physiology I, Asahikawa Medical College, Japan. PMID: 8355416 [PubMed - indexed for MEDLINE] 6363. Horm Res. 1993;40(1-3):5-9. Body fat in GH-deficient children and the effect of treatment. Wabitsch M(1), Heinze E. Author information: (1)Department of Pediatrics I, University of Ulm, FRG. Children with isolated GH deficiency have enlarged fat depots due to increased fat cell volume. The fat cell number is however decreased compared with appropriate controls. Treatment of patients with GH results in a relative loss of body fat and shifts both fat cell number and fat cell volume towards normal. These findings of adipose tissue cellularity in GH-deficient children before and after treatment can be explained by results from in vitro studies indicating that GH exerts a variety of effects on the metabolism of mature fat cells and on the proliferation and differentiation of cultured preadipocytes. Therefore, GH is one of the factors that determines adipose tissue development during childhood. PMID: 8300050 [PubMed - indexed for MEDLINE] 6364. Horm Res. 1993;40(1-3):23-30. The effect of simple obesity on growth and growth hormone. Vanderschueren-Lodeweyckx M(1). Author information: (1)Department of Paediatrics, University of Lausanne, Switzerland. Simple obesity is characterized by a normal or increased growth rate with an acceleration of bone age maturation. When longitudinal growth slows down in the presence of obesity, a hormonal disturbance should be sought. Despite normal growth, simple obesity is characterized by a reduced GH secretion evaluated by standard provocative tests, the administration of GH-releasing hormone or spontaneous 24-hour secretion. In obese children GH secretion may be as low as in poorly growing children with classical GH deficiency. The endocrine abnormalities along the GH axis seem to involve complex mechanisms at the hypothalamic, pituitary and peripheral level. Recent data suggest that simple obesity is associated with an increase in GH clearance and a decrease in GH synthesis and secretion. It is also associated with high insulin and insulin-like growth factor I levels which may interfere in the complex endocrine interactions. In conclusion, simple obesity is characterized by normal growth in the presence of 'hyposomatotropism'. PMID: 8300046 [PubMed - indexed for MEDLINE] 6365. Horm Res. 1993;40(1-3):10-5. Effects of growth hormone on body fat in adults. Gertner JM(1). Author information: (1)Department of Pediatrics, Children's Clinical Research Center, New York Hospital, Cornell Medical Center, NY 10021. The interactions between growth hormone (GH) and adipose tissue can be considered as a cycle: GH is lipolytic and acts to reduce and redistribute body fat; in turn, obesity is characterized by reduced GH output. The effects of GH on adipose tissue have been studied in obese, elderly and nonobese GH-deficient adults and children. In GH-deficient adults GH treatment appears to lead to net loss of fat tissue. However, evidence that GH promotes substantial weight loss in the obese is scanty. GH treatment trials in the elderly show significant increases in lean body mass and smaller decreases in fat mass. Data must be viewed with caution because of the methodological pitfalls inherent in measuring body composition and failure to induce net weight loss in the obese. PMID: 8300043 [PubMed - indexed for MEDLINE] 6366. J Inherit Metab Dis. 1993;16(5):813-20. The carbohydrate-deficient glycoprotein syndromes: an overview. Jaeken J(1), Carchon H. Author information: (1)Department of Pediatrics, University of Leuven, Belgium. The carbohydrate-deficient glycoprotein (CDG) syndromes are a newly recognized family of diseases with autosomal recessive inheritance. The basic defects are probably in the glycosylation pathway (endoplasmic reticulum, Golgi apparatus or post-Golgi). In the present state of our knowledge the central nervous system is always severely affected but nearly all other organs are involved to a variable degree. Like the peroxisomal disorders they also comprise dysmorphic features, the most typical being an abnormal distribution of subcutaneous adipose tissue. A reliable diagnostic test is isoelectric focusing of serum transferrin showing a cathodal shift as a consequence of the partial sialic acid deficiency. Prenatal diagnosis and heterozygote detection are not yet available. These diseases should be differentiated from secondary CDG syndromes such as classical galactosaemia. PMID: 8295395 [PubMed - indexed for MEDLINE] 6367. Horm Res. 1993;39 Suppl 3:81-5. Endocrine-metabolic pattern and adipose tissue distribution. Mårin P(1), Björntorp P. Author information: (1)Department of Heart and Lung Diseases, University of Göteborg, Sweden. The associations between cardiovascular disease (CVD), non-insulin-dependent diabetes mellitus (NIDDM) and abdominal fat distribution are well established. The most important adipose tissue depot in this context is probably the mass of intra-abdominal adipose tissue which has been found to be associated with CVD, NIDDM and their established metabolic risk factors. This type of adipose tissue distribution is also associated with multiple endocrine aberrations, probably comprising an increased responsiveness of the hypothalamo-adrenal axis and a parallel or secondary decreased activity of the hypothalamic-gonadal axis. Epidemiological studies in both men and women indicate that this may be a consequence of psychological stress. Recently, indirect evidence for decreased production of growth hormone in this condition has also been recognized. These multiple and interrelated abnormalities comprise a syndrome where the primary disturbance could be localized to the hypothalamus and the main peripheral consequences would be metabolic effects on the mass and function of intra-abdominal adipose tissue. This in turn, probably by the effects of elevated concentrations of portal free fatty acid levels on the liver, could result in insulin resistance and other metabolic risk factors known to be strongly associated with CVD and NIDDM. PMID: 8262497 [PubMed - indexed for MEDLINE] 6368. Horm Res. 1993;39 Suppl 3:107-11. Syndrome X. Ferrannini E(1). Author information: (1)CNR Institute of Clinical Physiology, University of Pisa, Italy. Using cross-sectional and longitudinal analysis of data from the San Antonio Heart Study, syndrome X (primary insulin resistance syndrome) has been redefined in terms of hyperinsulinaemia combined with changes in glucose tolerance, lipid pattern, blood pressure and body fat distribution. Syndrome X is itself an atherogenic cardiovascular risk factor, which interacts with environmental and genetic factors to lead to the eventual development of the endpoint of cardiovascular disease. PMID: 8262486 [PubMed - indexed for MEDLINE] 6369. Horm Res. 1993;39 Suppl 3:102-6. In vivo metabolic defects in non-insulin-dependent diabetes mellitus. Bonadonna RC(1). Author information: (1)Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa, Italy. In patients with non-insulin-dependent diabetes mellitus (NIDDM) alterations in insulin secretion and insulin action coexist, and create and sustain hyperglycaemia, which results from an imbalance between glucose production and glucose utilization. The target organs for insulin action are the liver (restriction of glucose production), the muscle (acceleration of glucose disposal) and the adipose tissue (inhibition of free fatty acid mobilization). In NIDDM, the liver produces an inordinate amount of glucose, secondary to an acceleration of gluconeogenesis, and is insensitive to the inhibitory action of insulin on glucose production. In NIDDM, skeletal muscle takes up less glucose in response to hyperinsulinaemia. Adipose tissue mobilizes a larger amount of free fatty acid, thereby possibly enhancing glucose production in the liver (Randle's cycle of metabolic competition between free fatty acids and glucose). Thus, the in vivo assessment of insulin action in NIDDM reveals a web of possibly interrelated metabolic defects, which in association with impaired insulin secretion cause a permanent, profound disruption of glucose homoeostasis. PMID: 8262485 [PubMed - indexed for MEDLINE] 6370. Adv Exp Med Biol. 1993;334:269-77. Cellular and molecular factors in adipose tissue growth and obesity. Roncari DA(1), Hamilton BS. Author information: (1)Department of Medicine, Sunnybrook Health Science Centre-University of Toronto, Ontario. Heparin-binding growth factors related to basic fibroblast growth factor are major determinants of the cellular clonal composition of adipose tissue. By providing and maintaining varying complements of preadipocytes in different fat depots, these factors contribute to the varying sizes and functions of different regions, including the hypercellularity in appreciable obesity. Thus, differing levels and activities of the heparin-binding growth factors contribute to variations in depots within the same individual and between individuals, in lean and obese states. In contrast to regional differences in adiposity, which are accounted by factors resident in adipose tissue, we believe that obesity results from a generalized energy overload. According to our concept, there are genetic variations in cytoskeletal activity and thus differing quantities of energy are utilized for biomechanical processes. In a reciprocal relationship, the higher the cytoskeletal activity, the lesser the energy available for chemical energy storage, mainly in the form of triglyceride in adipocytes. At the extreme of "supermassive" obesity, a mutation in a gene related to a cytoskeletal protein would lead to appreciable dampening of cytoskeletal activity, with consequently the greatest quantity of energy remaining available for eventual triglyceride storage. Moreover, the new concept, for which we have have increasing experimental evidence, invokes a hypothalamic-efferent neural-cytoskeletal pathway, which would modulate the activity of the cytoskeleton. PMID: 8249690 [PubMed - indexed for MEDLINE] 6371. Adv Exp Med Biol. 1993;334:259-67. Regulation of adipose tissue lipolysis, importance for the metabolic syndrome. Arner P(1). Author information: (1)Karolinska Institute, Department of Medicine, Huddinge Hospital, Sweden. PMID: 8249689 [PubMed - indexed for MEDLINE] 6372. Reprod Nutr Dev. 1993;33(4):297-323. [Quantitative bibliographic review on the use of anabolic hormones with steroidogenic action in ruminants for meat production. II. Principal mode of action]. [Article in French] Schmidely P(1). Author information: (1)INA-PG, station Nutrition et Alimentation, Paris, France. The hypotheses on the modes of action of hormonal anabolic agents in growing animals have been reviewed in more than 120 recent publications. The mechanisms of action are still not fully understood. Androgens such as testosterone and estrogens such as oestradiol-17 beta (E-17 beta) may act in different ways: firstly, testosterone (and probably also E-17 beta) acts directly on different tissues, and particularly at the level of the muscle cell by binding to a specific receptor. The hormone-receptor complex interacts with the nuclear receptor located in the chromatin and enhances protein synthesis (and probably also protein degradation). Trenbolone acetate (TBA) reduces protein synthesis and to a greater extent protein degradation. This action of TBA could take place via a reduction in the activity of catabolic glucocorticoids, either by a diminution in their secretion, or by displacing them from their receptor, or by reducing the number of receptors. Secondly, an indirect action of anabolic hormones is probable via the modifications in activity of other growth-regulating hormones. Growth hormone and insulin-like growth factor-I concentrations are enhanced by E-17 beta, diethylstilbestrol, zeranol and testosterone but not by TBA. Insulin appears to be indirectly enhanced by estrogens through an increase in growth hormone, whereas androgens reduce insulin levels. Thyroid hormone (tri- and tetra-iodothyronine) activity is reduced by androgens, whereas the action of oestrogens depends on the physiological maturity of the animal. The modes of action of these anabolic hormones are discussed in relation to growth rate and body composition. PMID: 8240677 [PubMed - indexed for MEDLINE] 6373. Kardiologiia. 1993;33(8):7-15. [Primary hypertension--cellular resetting and kidney shifting]. [Article in Russian] Postnov IuV. Developing the idea of the membrane origin of primary hypertension, we proceed from the following: this form of hypertension is based on widespread (i.e., not limited to one type of cells) abnormalities in the ion transport function of the plasma membrane and its structure, leading to changes in the values of several constraints regulated by the plasma membrane (in particular, pHi, Cai2+); plasma membrane alterations apparently have a genomic source and are initiated by a factor whose impact is mediated by the protooncogenes of the genome: the specific functions of the cell are preserved in these conditions by means of a mechanism of cell adaptation, revealed in the example of adipose tissue and called "cell resetting"; the development of cell resetting simultaneously initiates changes in hormone-target relations which manifest themselves, in particular, in augmented corticosteroid secretion (adrenal cortex hypertrophy), in increased activity of the sympathetic nervous system, and in the phenomenon of hyperinsulinemia; considering membrane alterations as the source of primary hypertension, the author proceeds from the assumption of the role of the blood circulation system as an "intermediate link" between two basic systems (effectors) of water-salt homeostasis at the cellular level and at the level of the whole body, i.e., between the cell plasma membrane and the kidney; under conditions of "membrane defect" the functional equilibrium indicated in the previous item occurs at a new level of hormone-target interaction and is achieved via the development of chronic arterial hypertension and the kidney resetting (kidney shifting after Guyton) that prevents water and salt loss.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8121138 [PubMed - indexed for MEDLINE] 6374. Curr Opin Gen Surg. 1993:78-84. Lipid fuel metabolism in health and disease. Miles JM(1). Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. Rates of adipose tissue lipolysis are increased in critically ill patients, thus increasing the systemic supply of free fatty acids. This increase in the availability of free fatty acids is probably mediated by various factors including increases in counterregulatory hormones and tumor necrosis factor alpha. The cytokines tumor necrosis factor and interleukin-1 also promote de novo lipogenesis in the liver and may be responsible for impaired triglyceride removal in peripheral tissues; these effects together contribute to the hypertriglyceridemia often seen in septic states. This hypertriglyceridemia may have a teleologic basis, because triglyceride-rich lipoproteins have been shown to bind and inactivate endotoxin. When present in excess, free fatty acids may be responsible for tissue injury in the cold-stored liver allograft, in ischemic-reperfusion cardiac injury, and in ischemic brain injury. Hypoketonemia commonly occurs in septic states and may be due to the combination of a defect in hepatic ketogenesis and accelerated ketone body uptake by peripheral tissues. Both tumor necrosis factor and interleukin-1 have a hypoketonemic effect in animals. Whether ketone bodies have significant protein-sparing properties remains controversial. PMID: 7584017 [PubMed - indexed for MEDLINE] 6375. EXS. 1993;66:201-11. Nonselective cation channels in brown and white fat cells. Koivisto A(1), Dotzler E, Russ U, Nedergaard J, Siemen D. Author information: (1)Wenner-Gren-Institute, University of Stockholm, Sweden. PMID: 7505651 [PubMed - indexed for MEDLINE] 6376. Presse Med. 1992 Dec 5;21(42):2053-9. [Glucose transporters. Physiology and physiopathology]. [Article in French] Girard J(1), Postic C, Burcelin R, Guillet I, Leturque A. Author information: (1)Centre de Recherche sur l'Endocrinologie moléculaire et le Développement, CNRS, Meudon. Glucose transport is an important step in the regulation of glucose homeostasis. Two types of transport systems are described: active transport accumulates glucose in specific cells, whereas facilitative transport equilibrates blood glucose and intracellular glucose inside all mammalian cells. At the present time, different levels of facilitative transport regulation are known. Facilitative transport is achieved by 5 different isoforms; each isoform has its own characteristics and is subjected to tissue-specific regulation. Alteration of glucose transporters expression may be involved in a physiopathological situation such as diabetes which is characterized by insulin resistance of peripheral tissues and impaired insulin secretion by beta pancreatic cells. Thus, Glut 2 expression is reduced in the beta cells of diabetic rats. The reduction of Glut 2 expression correlates with, and may contribute to the loss of glucose-stimulated insulin secretion. However, Glut 2 expression in liver remains unaltered. The insulin resistance of peripheral tissues may be explained in adipose tissue by a decrease in Glut 4 expression. In skeletal muscle, Glut 4 expression remains constant whatever the physiological or physiopathological situation. PMID: 1294980 [PubMed - indexed for MEDLINE] 6377. Ann Med. 1992 Dec;24(6):465-8. Abdominal obesity and the metabolic syndrome. Björntorp P(1). Author information: (1)Department of Heart and Lung Diseases, Sahlgren's Hospital, Göteborg, Sweden. Abdominal obesity in man is an integrated part of the Metabolic Syndrome, and is associated with a complex neuroendocrine disturbance. Its consequences for the metabolism of the periphery seems to be insulin resistance caused by a combination of a relative hypercortisolaemia and a relative deficiency of sex steroid hormones. This hormonal aberration, in combination with a relative insufficiency of growth hormone secretion, might also direct depot triglycerides to visceral adipose tissues, a consequence at least partly due to varying densities of the specific receptors for these hormones. Visceral fat accumulation may thus be a consequence of the neuroendocrine aberrations, and may amplify the metabolic symptoms via effects on the liver of free fatty acids released in abundance from the lipolytically sensitive enlarged visceral fat depots. The origin of the neuroendocrine disturbance is not known, but epidemiological and cross-sectional information suggest that psychosocial factors are intimately involved. Animal and human studies indicate that the mediating factor(s) may be stress-sensitivity, leading to the neuroendocrine consequences observed. PMID: 1485940 [PubMed - indexed for MEDLINE] 6378. Proc Nutr Soc. 1992 Dec;51(3):441-6. Breeding and transgenesis as means of decreasing adiposity in farm animal species: practice and promise. Griffin HD(1), Cameron ND, Bulfield G. Author information: (1)Department of Cellular and Molecular Biology, AFRC Institute of Animal Physiology and Genetics Research, Edinburgh Research Station, Roslin, Midlothian. PMID: 1480637 [PubMed - indexed for MEDLINE] 6379. Proc Nutr Soc. 1992 Dec;51(3):433-9. Immunological manipulation of adiposity. Flint DJ(1). Author information: (1)Hannah Research Institute, Ayr. Although hormonal regulators of adiposity are available they as yet have not been licensed for use. Withdrawal periods and delivery systems are still potential problems in maximizing their effectiveness. Immunization techniques, on the other hand, suffer none of the problems of withdrawal periods or requirement for frequent injection/implantation. As such they are clearly perceived as safe, economic and should have a positive animal welfare image. They are, however, not without their problems. Active immunization in particular involves an autoimmune response and this is typically difficult to evoke and virtually impossible to regulate. In addition, the fact that antibodies may have immunoneutralizing and immunoenhancing properties may explain the apparently contradictory results obtained in various studies as, for example, in the case of immunization against somatostatin. As our knowledge of immune responsiveness and its control increases, however, the possibilities for immune intervention should increase considerably. We may then be faced with ethical rather than practical limitations as to how far we should manipulate growth and body composition. PMID: 1480636 [PubMed - indexed for MEDLINE] 6380. Proc Nutr Soc. 1992 Dec;51(3):409-18. Effect of diet on human adipose tissue metabolism. Frayn KN(1), Coppack SW, Potts JL. Author information: (1)Oxford Lipid Metabolism Group, Sheikh Rashid Laboratory, Radcliffe Infirmary, Oxford. PMID: 1480635 [PubMed - indexed for MEDLINE] 6381. Proc Nutr Soc. 1992 Dec;51(3):387-95. Influence of diet on the development and regulation of lipogenic enzymes in adipose tissue. Perdereau D(1), Foufelle F, Gouhot B, Ferre P, Girard J. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Développement, CNRS, Meudon-Bellevue, France. PMID: 1480633 [PubMed - indexed for MEDLINE] 6382. Proc Nutr Soc. 1992 Dec;51(3):367-77. An evolutionary and functional view of mammalian adipose tissue. Pond CM(1). Author information: (1)Department of Biology, Open University, Milton Keynes. PMID: 1480631 [PubMed - indexed for MEDLINE] 6383. Proc Nutr Soc. 1992 Dec;51(3):353-65. Why do people get fat: is adipose tissue guilty? Ashwell M(1). Author information: (1)British Nutrition Foundation, London. PMID: 1480630 [PubMed - indexed for MEDLINE] 6384. Proc Nutr Soc. 1992 Dec;51(3):419-31. Manipulation of adiposity by somatotropin and beta-adrenergic agonists: a comparison of their mechanisms of action. Etherton TD(1), Louveau I. Author information: (1)Department of Dairy and Animal Science, Pennsylvania State University, University Park 16802. PMID: 1362272 [PubMed - indexed for MEDLINE] 6385. Int J Obes Relat Metab Disord. 1992 Dec;16 Suppl 4:S19-27. Regional fat distribution--implications for type II diabetes. Björntorp P(1). Author information: (1)Department of Medicine, Sahlgren's Hospital, University of Göteborg, Sweden. Abdominal obesity is closely associated with risk factors for cardiocerebrovascular disease and NIDDM and the precipitation of these diseases. Together, they seem to constitute a metabolic syndrome where hyperinsulinaemia, insulin resistance, hyperlipidaemia, hypertension, visceral fat accumulation, cardiocerebrovascular disease and NIDDM are the individual constituents. The background to this syndrome might be a primary aberration expressing itself as an increased sensitivity of the hypothalamo-adrenal axis, and subsequent inhibition of sex steroid hormone secretions. This in turn will probably be followed by metabolic derangements, primarily peripheral insulin resistance, as well as by visceral fat accumulation by mechanisms which are partially visualized by recent work in the field. Visceral fat accumulation may then amplify the metabolic aberrations via hepatic effects of excessive concentrations of portal FFA, producing hyperproteinaemia, hyperglycaemia, hyperinsulinaemia and, perhaps, hypertension. The background to the central endocrine aberration remains more speculative, but factors leading to increased cortisol production, including specific stress reactions, tobacco smoking and alcohol may turn out to be important. The tentative conclusion provides a hypothesis for further work, and has recently obtained considerable support from further observations in humans in other than the endocrine and metabolic areas, as well as from studies in experimental animal models, where such factors can be studied under fully controlled conditions, which is not possible in humans for ethical reasons. PMID: 1338383 [PubMed - indexed for MEDLINE] 6386. Int J Obes Relat Metab Disord. 1992 Dec;16 Suppl 3:S67-71. Thermogenesis, brown adipose tissue and dexfenfluramine in animal studies. Rothwell NJ(1), Le Feuvre RA. Author information: (1)Department of Physiological Sciences, University of Manchester, UK. D-Fenfluramine is a potent stimulator of thermogenesis in the rat, an action which may contribute to its effects on body weight. The actions of D-fenfluramine appear to control release of endogenous 5-HT which subsequently induces release of eicosanoids and corticotrophin-releasing factor. Peripheral heat production results mainly from sympathetic activation of thermogenesis. PMID: 1338325 [PubMed - indexed for MEDLINE] 6387. Int J Obes Relat Metab Disord. 1992 Dec;16 Suppl 3:S1-4. A retrospective view of obesity. Bray GA(1). Author information: (1)Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808. To gain a perspective on 'obesity in the nineties' requires an understanding of where the field came from during the 1980s. Three main themes seem to characterize much of the research during the 1980s. First there was completion of development of multi-disciplinary treatment programmes utilizing the best behavioural modification, nutrition education, exercise and on occasion pharmacological adjuncts. Most characteristic of all was the widespread use of very low calorie diets which first appeared at the beginning of the decade and peaked at its end. The second major development of the 1980s was the recognition of the importance of fat distribution in addition to total fat as a risk factor for the consequences of obesity. Finally, the 1980s saw the development of serotonin agents and the initial studies with beta adrenergic agonists for the treatment of obesity based on the concepts of nutrient partitioning and reduced sympathetic activity. As we enter the 1990s, three additional themes appear to be in the ascendancy. The first will be the emphasis on molecular mechanisms as an explanation for the genetic diversity of obesity, including fat distribution. The second will be the focus on strategies for prevention of obesity. The third will be the development of newer and more innovative techniques for treating that obesity which we cannot prevent. PMID: 1338316 [PubMed - indexed for MEDLINE] 6388. Int J Obes Relat Metab Disord. 1992 Dec;16 Suppl 2:S43-6. The role of obesity in diabetes. Turner RC(1). Author information: (1)Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, UK. PMID: 1335989 [PubMed - indexed for MEDLINE] 6389. Int J Obes Relat Metab Disord. 1992 Dec;16 Suppl 2:S17-21. A molecular view of adipose tissue. Ailhaud G(1), Grimaldi P, Négrel R. Author information: (1)Centre de Biochimie (UMR 134 CNRS), Université de Nice--Sophia Antipolis, Faculté des Sciences, France. PMID: 1335984 [PubMed - indexed for MEDLINE] 6390. Int J Obes Relat Metab Disord. 1992 Dec;16(12):953-7. Human obesity: a defect in lipid oxidation or in thermogenesis? Tremblay A(1). Author information: (1)Physical Activity Sciences Laboratory, PEPS, Laval University, Ste-Foy, Quebec, Canada. Numerous animal studies have shown that the development of obesity can depend on a decreased sympathetic nervous system activity but it has not been possible to convincingly demonstrate in humans that an excessive accumulation of adipose tissue might also be attributable to this factor. However, results from recent studies suggest that the contribution of the sympathetic nervous system to the development of human obesity may be greater than that generally believed by the scientific community. Indeed, experimental data show that the decrease in lipid oxidation induced by beta adrenergic blockade under free living conditions is substantially higher than the decrease in energy expenditure. Moreover, there are individual variations in the relative capacity to use lipid as an energy substrate under standardized conditions of diet composition. If the contribution of lipid to daily energy expenditure is reduced, there are two options to reach energy balance if physical activity habits are not modified. The first possibility is reduction in the relative lipid content of the diet to match the lipid content of the fuel mix oxidized. The second option is a gain in body weight and fat until the associated increase in the lipid content of the substrate mix is sufficient to re-equilibrate substrate and energy balance. Under high fat diet conditions, this gain in body weight and fat can be large enough to lead to an obese state. As described in this report, an integration of these observations suggests that further research pertaining to the role of sympathetic nervous system activity in human obesity should be focused as much on lipid oxidation as on thermogenesis. PMID: 1335974 [PubMed - indexed for MEDLINE] 6391. FASEB J. 1992 Dec;6(15):3330-7. Cell-specific expression of cytosolic phosphoenolpyruvate carboxykinase in transgenic mice. Beale EG(1), Clouthier DE, Hammer RE. Author information: (1)Department of Cell Biology and Anatomy, Texas Tech University Health Sciences Center, Lubbock 79430. The gene encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is expressed in multiple cell types in diverse tissues including liver, kidney, intestine, and white and brown adipose tissues. It can thus be considered a model system for examining the regulation of cell-specific transcription. The PEPCK gene is transcribed from a single start site, but studies of transgenic mice have revealed that distinct cis-acting elements (and thus different trans-acting factors) regulate PEPCK expression in hepatocytes, renal proximal tubule epithelial cells, and adipocytes. Hepatocytes require elements between -457 and +69 bp; renal proximal tubule epithelia require elements between -363 and +69 bp; and adipocytes require elements between -2086 and -888 bp. An additional element downstream of +69 bp is required to either attenuate PEPCK mRNA levels in liver and fat or increase renal PEPCK mRNA. We hypothesize that the transcription factors C/EBP and DBP are the principal tissue-specific regulators in liver, and that HNF-1 and perhaps C/EBP are important for kidney-specific PEPCK expression. We propose that the putative downstream element is involved in regulating PEPCK mRNA turnover in liver and fat. Finally, we suggest that the fat-specific element is an enhancer that requires a novel adipogenic regulatory factor, ARF6, to function. The long-term objective will be to fine map the cis-acting elements and identify the cognate trans-acting factors that regulate PEPCK in liver, kidney and fat. This information will help elucidate the combinatorial mechanisms that control the cell-specific expression of this complex gene. PMID: 1281456 [PubMed - indexed for MEDLINE] 6392. Prostaglandins Leukot Essent Fatty Acids. 1992 Nov;47(3):171-82. Release and effects of prostaglandins in adipose tissue. Richelsen B(1). Author information: (1)University Clinic of Endocrinology and Internal Medicine, Aarhus Amtssygehus, Denmark. PMID: 1475271 [PubMed - indexed for MEDLINE] 6393. Diabetes Care. 1992 Nov;15(11):1679-89. Interaction of insulin and exercise on glucose transport in muscle. Rodnick KJ(1), Piper RC, Slot JW, James DE. Author information: (1)Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Glucose transport is the rate-limiting step for glucose utilization in muscle. In muscle and adipose tissue, glucose transport is acutely regulated by such factors as insulin and exercise. Translocation of glucose transporters (GLUT4) from an intracellular domain to the cell surface is the major mechanism for this regulation. Using immunocytochemistry, the intracellular distribution of GLUT4 under resting conditions is similar in adipocytes and myocytes. GLUT4 is concentrated in tubulovesicular structures either in the trans-Golgi region or in the cytosol, often close to the cell surface but not on the cell surface. After stimulation, cell surface GLUT4 labeling is increased by as much as 40-fold. GLUT4 is chronically regulated by altered gene expression. Neural and/or contractile activity regulates GLUT4 expression in muscle: 1) GLUT4 levels differ among muscles of different fiber type; 2) GLUT4 levels in muscle are increased with exercise training and decreased with denervation; and 3) cultured muscle cells, which lack an intact nerve supply, express very low levels of GLUT4. GLUT4 expression appears to be regulated in parallel with many oxidative enzymes in muscle, suggesting that there may be a unified developmental program that determines the overall metabolic properties of a particular muscle. Preliminary evidence suggests that impaired GLUT4 expression in muscle is not the primary defect associated with insulin resistance. Nevertheless, it is conceivable that the adaptive increase in muscle GLUT4 that is found with exercise training may have beneficial effects in insulin-resistant states such as non-insulin-dependent diabetes. PMID: 1468301 [PubMed - indexed for MEDLINE] 6394. J Anim Sci. 1992 Nov;70(11):3635-45. Factors that affect drug disposition in food-producing animals during maturation. Schwark WS(1). Author information: (1)Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca 14853. Drugs administered to neonatal food-producing animals (cattle, sheep, goats, swine) may exhibit significantly different pharmacokinetic/disposition characteristics than they do in adult animals of the same species. Undesirable consequences such as suboptimum therapeutic concentrations, toxic effects, and violative tissue residues may result if adult dosage regimens are employed in young animals. Using selected drugs as examples, this paper reviews factors that contribute to differences in drug disposition in newborn vs adult animals. Immaturity of mechanisms involved in drug absorption, especially from gastrointestinal and parenteral sites of administration, and of drug distribution to sites such as plasma proteins, adipose tissue, and fluid compartments are considered. The role of developmental changes in drug biotransformation in the liver and other tissues and the maturation of excretory mechanisms, primarily from the kidney, in the increased rate of drug clearance during maturation is described. Pharmacokinetic studies with specific drugs in the target species are an important approach to establishing rational drug use in immature food-producing animals. PMID: 1459924 [PubMed - indexed for MEDLINE] 6395. Semin Liver Dis. 1992 Nov;12(4):386-96. Hepatic clearance of plasma chylomicron remnants. Cooper AD(1). Author information: (1)Research Institute, Palo Alto Medical Foundation, California 94301. Dietary lipid, following incorporation into chylomicrons, is rapidly removed from the blood by a two-stage process. Most of the triglyceride is taken up by extrahepatic tissue, particularly muscle and adipose tissue. The residual triglyceride and virtually all of the cholesterol ester is removed by the liver through the clearance of a particle called a chylomicron remnant. The remarkable rapidity and specificity of uptake of this particle seems to be due to its acquisition of apoE in the plasma. Uptake is mediated in part by the LDL receptor, the LRP (alpha a-macroglobulin receptor), and perhaps by a sieving mechanism that leads to trapping, but not endocytosis. Uptake is modulated by the type of apoE inherited, the amount of apoC present on the particle, and, perhaps, the phospholipid and fatty acyl chain composition of the particle. The process may be slowed in diabetes and hypothyroidism. The metabolic effects of the particle can be variable, depending on the composition of the diet, and this can affect whole body cholesterol metabolism significantly. Furthermore, even moderately prolonged residence of these particles in the circulation could contribute in a significant way to atherogenesis. Thus, the remnant particle and its uptake by the liver may be important links in determining the dietary contribution to the rate of atherosclerosis. PMID: 1334575 [PubMed - indexed for MEDLINE] 6396. Diabetes. 1992 Oct;41 Suppl 2:97-101. Role of cytokines in inducing hyperlipidemia. Feingold KR(1), Grunfeld C. Author information: (1)Department of Medicine, University of California, San Francisco. Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1526345 [PubMed - indexed for MEDLINE] 6397. Int J Sports Med. 1992 Oct;13 Suppl 1:S191-3. Energy metabolism during cold exposure. Vallerand AL(1), Jacobs I. Author information: (1)Environmental Physiology Section, Defence and Civil Institute of Environmental Medicine, North York, Ontario, Canada. Recent advances on the influence of cold exposure on energy metabolism in animals and humans are summarized. Although the cold-induced enhancements in carbohydrate metabolism have been the focus of numerous studies, it was only recently that pieces of evidence from animal studies have suggested that cold exposure exerts an insulin-like effect on peripheral tissue glucose uptake, which appears to proceed primarily via insulin-independent pathways. Interestingly, this phenomenon was observed in insulin-sensitive tissues of warm- a well as cold-adapted rats. Whereas previous human studies have concentrated on the cold-induced changes in basal levels of hormones and metabolic substrates, recent work from our laboratory has demonstrated that exposure to cold at rest shifts substrate utilization from mainly lipids at thermal neutrality to carbohydrates, representing the main fuel for shivering thermogenesis. Further investigation has revealed that the marked increment in carbohydrate oxidation in cold-exposed humans is derived from a greater utilization of both circulating glucose and intramuscular glycogen. With respect to lipid metabolism, recent studies have shown that the cold-induced increase in lipid oxidation in man is fuelled primarily by the fatty acids released from white adipose tissue triglycerides (TG) and possibly intramuscular TG, not plasma TG. One practical application of this work on energy metabolism in the cold resides in the pharmacological approach to improve cold tolerance, where pharmacological agents that alter energy metabolism and substrate utilization could be used to enhance cold thermogenesis and produce warmer body temperatures. PMID: 1483772 [PubMed - indexed for MEDLINE] 6398. Int J Sports Med. 1992 Oct;13 Suppl 1:S169-72. Mechanisms of adaptation to cold. LeBlanc J(1). Author information: (1)Department of Physiology, Faculty of Medicine, Laval University, Quebec City, Canada. The animal model used the most frequently for understanding the mechanisms of adaptation to cold in humans has been the rat. It has been established that rats kept in the cold for a few weeks stop shivering while preserving a normal internal temperature because of an enhanced thermogenic capacity of the brown adipose tissue (BAT) mediated by the sympathetic nervous system. Studies on groups of humans exposed to cold have shown that shivering is also attenuated but without compensatory increased in heat production possibly because of non-significant contribution of the BAT. However when humans and laboratory animals are exposed repeatedly to short severe cold evidence for adaptation has been described. This adaptation is not metabolic; instead it is related to the phenomenon of habituation. When exposed to a novel stress such as cold, the alarm reaction is initiated as evidenced by the activation of the sympathetic nervous system which opposes the stressing situation. However with time, when it is realized that the normal functioning of the body is not endangered the responses are attenuated and enhanced tolerance is observed. This type of adaptation was observed in Eskimos, fishermen, outdoor workers, etc. PMID: 1483764 [PubMed - indexed for MEDLINE] 6399. Int J Sports Med. 1992 Oct;13 Suppl 1:S114-8. Role of lipids on endurance capacity in man. Guezennec CY(1). Author information: (1)CERMA: CEV, Brétigny sur Orge, France. A man whose weight is near 70 kg has approximately 15 kg of fat as triglycerides in adipose tissue, representing about 140,000 kcal. With such a quantity of stored fat, the question is to know why triglycerides are not the only fuel for exercise. Probably because this fuel cannot sustain maximal rates of exercise. The ability to sustain maximal exercise is dependent on carbohydrate use. The reason for the limited rate at which energy can be derived from fat store is not clear. We can examine successively: 1) The rate of release from adipose tissue. Hydrolysis of the adipose tissue triglyceride is regulated by hormonal and nervous influence. It has recently been shown that 70% of fatty acids released from adipose tissue at rest are reesterified. This value decreases to 25% at the onset of submaximal exercise at 40% of VO2max. One part of the increase in fat oxidation could therefore result from the reduced reesterification. 2) The capacity of transport and muscle extraction. A close correlation has been shown between the increase in FFA concentration and FFA uptake during increased energy expenditure under the effect of exercise. Exercise increases lipoprotein lipase (LPL) activity in muscle. This causes increase in muscle and cardiac FFA uptake and a decrease in LPL activity in adipose tissue. The control of this enzyme is coordinated by hormonal mechanisms resulting from the reduction of insulin and the increase in catecholamines induced by exercise.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1483746 [PubMed - indexed for MEDLINE] 6400. Dan Med Bull. 1992 Oct;39(5):369-90. Magnetic resonance imaging and spectroscopy of the bone marrow in vivo--with special attention to the possibilities for tissue characterization in patients with leukemia. Jensen KE(1). Author information: (1)Department of Magnetic Resonance, Hvidovre Hospital. PMID: 1424814 [PubMed - indexed for MEDLINE] 6401. Free Radic Biol Med. 1992 Oct;13(4):325-40. Brown fat thermogenesis and exercise: two examples of physiological oxidative stress? Barja de Quiroga G(1). Author information: (1)Departamento de Biologia Animal-II (Fisiologia Animal), Facultad de Biología, Universidad Complutense, Madrid, Spain. Both brown fat tissue (BAT) and skeletal muscle experience large increases of oxygen consumption and oxygen radical generation during activation. This, together with the relatively low activities of antioxidant enzymes in these two tissues and the high lipid content and free fatty acid liberation of BAT, can produce a physiological oxidative stress. Increases of in vivo or in vitro (BAT) lipid peroxidation have been described in these tissues after activation. They react to this oxidative stress in an adaptive way after chronic stimulation. Cold acclimation increases antioxidant enzymes, ascorbate, and especially reduced glutathione (GSH) in BAT. There is controversy about the variations of antioxidants in skeletal muscle after acute exercise. Nevertheless, exercise training seems to increase muscle antioxidant enzymes and GSH. Many reports show that vitamin E levels decrease in the muscle and increase in plasma during exercise. Studies of vitamin E deficiency and supplementation strongly suggest that this vitamin is of protective value during exercise. PMID: 1398216 [PubMed - indexed for MEDLINE] 6402. J Steroid Biochem Mol Biol. 1992 Oct;43(5):451-67. Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. Pelletier G(1), Dupont E, Simard J, Luu-The V, Bélanger A, Labrie F. Author information: (1)MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada. Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1390295 [PubMed - indexed for MEDLINE] 6403. Z Arztl Fortbild (Jena). 1992 Sep 25;86(18):891-4. [Obesity--pacemaker of the metabolic syndrome]. [Article in German] Knappe G(1). Author information: (1)Klinik für Innere Medizin Theodor Brugsch, Medizinische Fakultät (Charité), Humboldt-Universität zu Berlin. PMID: 1413907 [PubMed - indexed for MEDLINE] 6404. Presse Med. 1992 Sep 9;21(28):1330-5. [Mode of action of benfluorex. Recent data]. [Article in French] Brindley DN(1). Author information: (1)Department of Biochemistry, University of Alberta, Edmonton, Canada. An increased risk of developing premature atherosclerosis is associated with stress, diabetes, obesity, and hypertension. These conditions are associated with insulin resistance, hyperglycemia, hypertriglyceridemia and hypercholesterolemia. An alternative way of interpreting insulin resistance is to consider that metabolism in this condition would be regulated to a greater extent by stress hormones and in particular by cortisol. Glucocorticoids and fatty acids (which are produced in response to stress) antagonise the actions of insulin in promoting glucose uptake and protein synthesis, in decreasing gluconeogenesis and protein catabolism, and promoting the clearance of intermediate density lipoprotein and low density lipoprotein from the circulation by the liver. They also promote the secretion of very low density lipoprotein thus producing hypertriglyceridemia and hypercholesterolemia. By contrast to this antagonism, cortisol can also facilitate the action of insulin in stimulating the storage of energy via glycogen and fatty acid synthesis and through lipoprotein lipase in adipose tissue. These effects are significant in relation to obesity and to weight gain. An increased control of metabolism by cortisol therefore produces changes in metabolism that are potentially atherogenic and it is associated with insulin resistance and the other risk factors for atherosclerosis. Benfluorex treatment improves insulin sensitivity and has antihyperglycemic and hypolipidemic effects in human beings and in experimental animals. These effects can be observed independently of weight loss, but lowering food intake also produces a metabolic benefit. Long-term treatment with benfluorex can also decrease stress responses in terms of glucocorticoid release and the stimulation of lipolysis probably by its serotoninergic control of the hypothalamic-pituitary-adrenal axis. Such an action provides for an integrated treatment of the obese-diabetic-hyperlipidemic syndrome. Benfluorex produces overall changes in metabolism that tend to normalise the major risk factors associated with premature atherosclerosis. This provides a potential advantage over other therapies for atherosclerosis which may ameliorate a symptom (e.g., hyperlipidemia) without treating the underlying metabolic disturbance that predisposes to atherogenesis. PMID: 1438102 [PubMed - indexed for MEDLINE] 6405. Diabetes. 1992 Sep;41(9):1207-19. Lilly Lecture: syndromes of insulin resistance. From patient to gene and back again. Flier JS(1). Author information: (1)Charles A. Dana Research Institute, Harvard-Thorndike Laboratory, Beth Israel Hospital, Department of Medicine, Brookline, MA 02215. The syndromes of insulin resistance are a group of clinically diverse disorders, and our understanding of their molecular pathogenesis has advanced in parallel with our understanding of the structure of the insulin receptor and the mechanism of insulin action. The most straightforward progress has related to defining the role of both anti-receptor antibodies and mutations in the insulin receptor gene in causing these disorders. Despite this progress, the cause of severe target cell resistance in patients without defects in the receptor locus remains unknown, and we are limited in our ability to relate specific molecular defects in insulin signalling to in vivo phenotypes, such as those relating to growth and development and function of adipose tissue and muscle. Answers to these questions may ultimately be explained by the existence of multiple species of insulin receptors expressed in different tissues, brought about by alternative splicing and receptor hybrids, and by divergent pathways of insulin signalling with different consequences for specific tissues. The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP. Currently, the loci have not been implicated in studies in most patients. Transgenic methodologies will be powerful tools for pursuit of unanswered questions in the field of insulin resistance in coming years. PMID: 1499871 [PubMed - indexed for MEDLINE] 6406. Nutr Rev. 1992 Sep;50(9):267-70. Body weight, fat storage, and alcohol metabolism. Flatt JP(1). Author information: (1)Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester 01655. Ethanol account for a significant fraction of the energy intake of persons consuming even moderate amounts of alcohol. A recent study has shown that although alcohol does not reveal itself as a layer floating at the top of a drink, metabolically it behaves more like oil than sugar. PMID: 1461589 [PubMed - indexed for MEDLINE] 6407. Acta Paediatr Suppl. 1992 Sep;383:62-5; discussion 66. Effects of growth hormone on fat mass and fat distribution. Bengtsson BA(1), Brummer RJ, Edén S, Rosén T, Sjöström L. Author information: (1)Department of Internal Medicine, Sahlgrenska Hospital, Medical Faculty, University of Gothenburg, Sweden. GH has profound effects on the amount and distribution of adipose tissue. GHD in both children and adults is accompanied by an increased amount of adipose tissue and by the abdominal predominance of adipose tissue. In contrast, treatment with GH reduces adipose tissue, and redistributes adipose tissue from abdominal to peripheral depots. PMID: 1458019 [PubMed - indexed for MEDLINE] 6408. Acta Paediatr Suppl. 1992 Sep;383:59-60; discussion 61. Hormonal effects on fat distribution and its relationship to health risk factors. Bjørntorp P(1). Author information: (1)Department of Medicine I, Sahlgrenska Hospital, University of Gothenburg, Sweden. PMID: 1458018 [PubMed - indexed for MEDLINE] 6409. Acta Paediatr Suppl. 1992 Sep;383:47-51; discussion 52. Physiology of the fat cell, with emphasis on the role of growth hormone. Hauner H(1). Author information: (1)Diabetes Research Institute, University of Düsseldorf, Germany. PMID: 1458016 [PubMed - indexed for MEDLINE] 6410. Lancet. 1992 Aug 22;340(8817):469-71. In defence of insulin: a critique of syndrome X. Jarrett RJ(1). Author information: (1)Department of Public Health Medicine, United Medical School, Guy's Hospital, London, UK. Erratum in Lancet. 1993 Jan 30;341(8840):303. Comment in Lancet. 1992 Oct 17;340(8825):973-4. Lancet. 1992 Oct 17;340(8825):973. PMID: 1354794 [PubMed - indexed for MEDLINE] 6411. Mol Cell Biochem. 1992 Aug 18;113(2):151-69. Genetic aspects of susceptibility to obesity and related dyslipidemias. Després JP(1), Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Quebec, Canada. Obesity has a multifactorial origin. However, although environmental variables undoubtedly play a role in the development of obesity, it is now clear that genetic variation is also involved in the determination of an individual's susceptibility to body fat accumulation. In addition, it is also widely accepted that obesity is not a single homogeneous phenotype. It is also heterogeneous regarding its causes and metabolic complications. The regional distribution of body fat appears to be an important correlate of the metabolic complications that have been related to obesity. Due to their higher accumulation of abdominal fat, men are generally more at risk for the metabolic complications of obesity than women whereas some obese women, with large gluteal-femoral adipose depots may have a cosmetic problem which may not necessarily require medical intervention. Several studies have been conducted to understand the mechanisms by which abdominal obesity is related to diabetes, hypertension and cardiovascular disease. It appears that the increased risk of abdominal obesity is the result of complex hormonal and metabolic interactions. Studies in genetic epidemiology have shown that both total body fatness and the regional distribution of body fat have a significant genetic component. Standardized intervention studies using an identical twin design have shown that individuals that have the same genetic background tend to show similar changes in body fat and in plasma lipoprotein levels when exposed to standardized caloric excess or energy restriction. Finally, although abdominal obesity is a significant risk factor for cardiovascular disease, not every abdominal obese subject will experience metabolic complications, suggesting that some obese individuals may be more susceptible than others. Variation in several genes relevant to lipid and lipoprotein metabolism may alter the relation of abdominal obesity to dyslipoproteinemias. Abdominal obesity should therefore be considered as a factor that exacerbates an individual's susceptibility to cardiovascular disease. PMID: 1518506 [PubMed - indexed for MEDLINE] 6412. Proc Nutr Soc. 1992 Aug;51(2):165-72. Maternal and environmental influences on thermoregulation in the neonate. Symonds ME(1), Lomax MA. Author information: (1)Department of Biochemistry and Physiology, School of Animal and Microbial Sciences, University of Reading, Whiteknights. PMID: 1438324 [PubMed - indexed for MEDLINE] 6413. Nihon Rinsho. 1992 Aug;50(8):1833-9. [Function, molecular structure and gene expression of interleukin-11 (IL-11/AGIF)]. [Article in Japanese] Kawashima I, Ohsumi J, Miyadai K, Takiguchi Y. Interleukin-11 (IL-11) is a novel cytokine that was identified in a medium conditioned by the primate bone marrow-derived stromal cell line PU-34. It was originally identified as a growth factor for the IL-6-dependent plasmacytoma cell line T1165. Adipogenesis inhibitory factor (AGIF) was cloned from the human bone marrow-derived cell line KM-102. The AGIF cDNA sequence was revealed to be identical to that of the IL-11 cDNA. AGIF inhibits the process of adipogenesis of the bone marrow-derived preadipocyte cell line H-1/A. Other biological activities of IL-11/AGIF, megakaryocytopoiesis, stem-cell proliferation, hepatic acute phase responses and antigen-specific antibody responses are also summarized. PMID: 1433976 [PubMed - indexed for MEDLINE] 6414. Biochem Soc Trans. 1992 Aug;20(3):659-64. Insulin-activated protein kinases in fat and other cells. Denton RM(1), Tavaré JM, Borthwick A, Dickens M, Diggle TA, Edgell NJ, Heesom KJ, Isaad T, Lynch DF, Moule SK, et al. Author information: (1)Department of Biochemistry, University of Bristol School of Medical Sciences, University Walk, U.K. PMID: 1426609 [PubMed - indexed for MEDLINE] 6415. J Cell Biochem. 1992 Jul;49(3):219-24. Identification of a fat cell enhancer: analysis of requirements for adipose tissue-specific gene expression. Graves RA(1), Tontonoz P, Platt KA, Ross SR, Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute Boston, Massachusetts 02115. The molecular basis for adipose-specific gene expression is not known. To approach the problem of adipocyte gene expression, we have analyzed in detail the capacity of the 5'-flanking region of the adipocyte P2 (aP2) gene to direct cell-type specific gene expression. Although the proximal promoter containing AP-1 and C/EBP binding sites is capable of directing differentiation-dependent gene expression in cultured adipocytes, these constructs are essentially inactive in the tissues of transgenic mice. We found that -5.4 kb of the 5'-flanking region were required to direct heterologous gene (chloramphenicol acetyl transferase; CAT) expression to the adipose tissue of transgenic mice. By deletion analysis, we identified a 520 bp enhancer at -5.4 kb of the aP2 gene. We show that this enhancer can direct high levels of gene expression specifically to the adipose tissue of transgenic mice. This enhancer also functions in a differentiation-dependent manner in cultured adipocytes and cannot be transactivated in preadipocytes by C/EBP. Molecular analysis indicates that several cis- and trans- acting acting elements, though not C/EBP, contribute to the specificity and potency of this enhancer. PMID: 1644859 [PubMed - indexed for MEDLINE] 6416. J Biosoc Sci. 1992 Jul;24(3):367-77. Maternal body composition: methods for measuring short-term changes. Norgan NG(1). Author information: (1)Department of Human Sciences, Loughborough University of Technology, Leicestershire. The measurement of short-term changes in maternal body composition during the post-partum period under field conditions poses many problems: (1) body composition techniques depend on the constancy of the proportions of components or their physical properties and are less suitable for measuring changes; (2) many of the techniques require expensive, technically sophisticated apparatus that is inappropriate to field conditions in many countries; (3) changes in body composition affect some areas of the body more than others so regional as well as whole body approaches are required. The measurements of body weight, triceps and subscapular skinfold thicknesses and upper arm circumference are essential measurements. These can be supplemented with further skinfold thicknesses and circumferences, and possibly body density and body water measurements. There is little to be gained by transforming anthropometric variables into whole body composition indices in these circumstances. PIP: The problems attendant with measurement of maternal body composition shortterm changes during the postpartum period and under field conditions include the requirement for constancy of components, costliness of techniques, and the need for regional and whole body approaches. The in vitro method of measurement includes anatomical dissection and chemical analysis. The in vivo measurement comprises whole body (density, body water, potassium, elemental, and electrical properties assessment), regional (subcutaneous adipose tissue with skinfold, ultrasound, near infrared interactance), cross-sectional areas (skinfolds and circumferences, ultrasound, and computed tomography [CT], volumes (skinfolds, circumferences, lengths, and CT), and estimations (anthropometry). Postpartum changes in body composition include reversal of weight gain induced by pregnancy: 7-8 kg gain in developing countries and 12-14 kg gain in developed countries 2-4 kg of which is fat. 75% of the reduction is adipose tissue and 25% is lean body mass. Choice of methods depends of the purpose, precision of measurement data, cost and availability of instruments (radiography, CT, magnetic resonance imaging, deuterium dilution, bio-impedance meters), and acceptance of the subject (simple, noninvasive procedures). Among these anthropometry scores high on feasibility and desirability, whole techniques requiring elaborate equipment score low. In vivo body composition techniques are best if a 3-compartment model of fat, water, and protein is employed. Thus, anthropometric measurement of weight, height, triceps and subscapular skinfolds, and upper arm circumference is the method of choice. PMID: 1634565 [PubMed - indexed for MEDLINE] 6417. Am J Trop Med Hyg. 1992 Jul;47(1 Pt 2):8-15. Visceral leishmaniasis: a model for infection-induced cachexia. Pearson RD(1), Cox G, Jeronimo SM, Castracane J, Drew JS, Evans T, de Alencar JE. Author information: (1)Department of Medicine, University of Virginia Health Sciences Center, Charlottesville. Parasitic infections and malnutrition coexist in many tropical and subtropical areas. Studies of Leishmania donovani and of experimentally infected Syrian hamsters have provided important insights into the complex interrelationships between malnutrition and this parasitic disease. Malnutrition, which adversely affects cell-mediated immunity, is associated with the development of visceral leishmaniasis (kala-azar) in children living in endemic areas. In turn, L. donovani can cause wasting as well as hepatosplenomegaly, fever, and anemia. Syrian hamsters infected with L. donovani develop a disease that is comparable to that of humans with kala-azar. Weight loss in infected hamsters is associated with splenic macrophage secretion of potentially catabolic cytokines as measured by the D10.G4.1 assay for interleukin-1 and the L929 cytotoxicity assay for tumor necrosis factor/cachectin. Although decreased food intake contributes to wasting in infected hamsters, studies of skeletal muscle function indicate that it is not the sole factor. Leishmania donovani-infected hamsters have also been used to study drugs with the potential to prevent or reverse cachexia. PMID: 1632476 [PubMed - indexed for MEDLINE] 6418. Am J Clin Nutr. 1992 Jul;56(1 Suppl):224S-229S. Factors determining energy expenditure during very-low-calorie diets. Van Gaal LF(1), Vansant GA, De Leeuw IH. Author information: (1)Department of Endocrinology, Metabolism and Clinical Nutrition, University of Antwerp, Belgium. There is an important variability in short- and long-term weight loss success among obese subjects, regardless of the strategy used. It is still unclear whether this variability is a therapy-specific or a patient-specific problem. Changes in energy expenditure are probably a key factor in the phenomena of weight loss or weight regain. Factors influencing resting metabolic rate (RMR) and diet-induced thermogenesis (DIT) in obese patients are considered: age, fat mass, fat-free mass (FFM), sex and thyroid hormones are all related to the components of energy expenditure. Fat distribution estimates [expressed by waist-to-hip ratio (WHR)] seem to be related to DIT rather than to RMR. Short- and long-term effects of very-low-calorie diets (VLCDs) on RMR and DIT were investigated. Short-term weight loss by VLCD induced a significant (P less than 0.001) decrease of FFM with a concomitant decline of RMR values. A nonsignificant decreasing trend exists for thermogenesis. No further decrease of FFM was found after long-term weight loss without differences in RMR/FFM or thermogenesis. Changes in FFM are known to be the major component of changes in RMR, but other factors may be involved. Also some other factors may account for the possible changes in diet-induced thermogenesis during VLCD. Candidates for this include total fat mass, FFM, sex hormones, insulin concentrations, and fat distribution, of which insulin concentrations seem to determine RMR changes to an important extent. Fat distribution patterns per se or changes in WHR seem to account consistently (P less than or equal to 0.05) for changes in DIT during VLCD. PMID: 1615888 [PubMed - indexed for MEDLINE] 6419. Am J Clin Nutr. 1992 Jul;56(1 Suppl):209S-216S. Effects of weight cycling on body composition. Prentice AM(1), Jebb SA, Goldberg GR, Coward WA, Murgatroyd PR, Poppitt SD, Cole TJ. Author information: (1)MRC Dunn Nutrition Unit, Cambridge, UK. Comment in Am J Clin Nutr. 1993 Aug;58(2):243. It is frequently claimed that weight cycling, or "yo-yo" dieting, causes an inappropriate and permanent loss of lean body mass (LBM). Data are presented from a rural African population that undergoes profound weight cycling caused by an annual hungry season. No detrimental effect on LBM was observed. Data are also presented from an 18-wk prospective study of moderately obese British women who underwent three cycles of VLCD-induced weight loss and subsequent relapse. The proportion of weight lost as LBM was no greater than predicted. A review of the published results from experimental weight cycling in small animals also shows a high level of consensus that cycling does not significantly alter body composition. We conclude that, although weight cycling may affect growth of young animals, metabolic efficiency, and health, these effects are not mediated through permanent alterations in body composition. PMID: 1615886 [PubMed - indexed for MEDLINE] 6420. Z Rheumatol. 1992 Jul-Aug;51(4):177-82. [AA-amyloidosis in inflammatory rheumatic diseases. A report of clinical experiences]. [Article in German] Schneider F(1). Author information: (1)Rheumaklinik Oberammergau. A review of the literature on rheumatic diseases with secondary amyloidosis and our diagnostic and therapeutic experiences in 33 own cases were reported. The place of subcutaneous fat biopsy in the diagnosis of secondary amyloidosis was shown included our own results and the corresponding literature. We saw amyloidosis type AA mostly in patients with high disease activity and progressive stage. There is no sure relationship to the duration of the disease. The renal involvement is clinical most significantly and also most frequently. The renal amyloidosis type AA can be influenced therapeutically however only in normal or unimportant restricted renal function. The therapeutic success is not depended on the choice of the long acting antirheumatic drug. The results were discussed in respect with the current literature. PMID: 1414042 [PubMed - indexed for MEDLINE] 6421. Diabetes Care. 1992 Jun;15(6):755-72. Biguanides and NIDDM. Bailey CJ(1). Author information: (1)Department of Pharmaceutical Sciences, Aston University, Birmingham, United Kingdom. The main biguanides, metformin and phenformin, were introduced in 1957 as oral glucose-lowering agents to treat non-insulin-dependent diabetes mellitus (NIDDM). Phenformin was withdrawn in many countries because of an association with lactic acidosis, but metformin does not have the same risk if appropriately prescribed. Metformin is now widely used as a monotherapy and in combination with a sulfonylurea. Unlike sulfonylureas, metformin is not bound to plasma proteins, is not metabolized, and is eliminated rapidly by the kidney. The glucose-lowering effect occurs without stimulation of insulin secretion and results mainly from increased glucose utilization. The presence of insulin is required, and enhancement of insulin action at the postreceptor level occurs in peripheral tissues such as muscle. In peripheral tissues metformin increases insulin-mediated glucose uptake and oxidative metabolism. Metformin also increases glucose utilization by the intestine, primarily via nonoxidative metabolism. The extra lactate produced is largely extracted by the liver and serves as a substrate to sustain gluconeogenesis. This limits the extent to which metformin reduces hepatic glucose production but provides a safeguard against excessive glucose lowering. Because metformin does not cause clinical hypoglycemia, it is actually an antihyperglycemic drug. It does not cause weight gain, it helps combat hypertriglyceridemia, and it has been ascribed some vasoprotective properties. Metformin offers a useful treatment for insulin-resistant overweight NIDDM patients. PMID: 1600835 [PubMed - indexed for MEDLINE] 6422. Clin Chem. 1992 Jun;38(6):793-7. Apolipoprotein A-containing lipoprotein particles: physiological role, quantification, and clinical significance. Fruchart JC(1), Ailhaud G. Author information: (1)INSERM U325, Institut Pasteur, Lille, France. High-density lipoprotein (HDL) particles are made up of two major populations of particles, differing in composition and metabolism. Both contain apolipoprotein (apo) A-I but only one contains apo A-II. Lipoprotein particles that contain only apo A-I (LpA-I particles) can increase cellular cholesterol efflux from cultured cells in vitro. LpA-I:A-II particles, however, do not increase cholesterol efflux. LpA-I:A-II can be determined directly with an enzyme-linked differential antibody immunosorbent assay. LpA-I is determined by differential electroimmunoassay: in the presence of a large excess of anti-apo A-II, LpA-I:A-II particles are retained in one peak, whereas LpA-I migrates grates as a second peak. Both lipoprotein forms of apo A-I-containing particles are present mainly in HDL, but the relative proportion of LpA-I is greater in HDL2 than in HDL3. Concentrations of LpA-I in plasma samples from normolipemic subjects average approximately 10% higher in women than in men. The lower apo A-I concentrations in patients with significant coronary artery disease reflect a decrease in the LpA-I particles. Data obtained in octogenarians also support the possibility that LpA-I might represent the anti-atherogenic fraction of HDL. Moreover, the concentration of LpA-I in children of parents with premature coronary heart disease was lower than that of a control group without any family history of this disease. Nutrients and hypolipidemic drugs seem to affect the two kinds of particles differently. PMID: 1597003 [PubMed - indexed for MEDLINE] 6423. Proc Soc Exp Biol Med. 1992 Jun;200(2):224-7. Tumor necrosis factor, interleukin, and interferon induced changes in lipid metabolism as part of host defense. Grunfeld C(1), Feingold KR. Author information: (1)Department of Medicine, University of California, San Francisco. As the immune response is activated during infection, multiple changes in lipid metabolism, especially increased production of VLDL, occur. Many of the cytokines that mediate the immune response are able to produce such changes in lipid metabolism in vivo. The induction of hypertriglyceridemia or other changes in lipid metabolism during infection do not directly cause the wasting syndrome. It appears that such changes in lipid metabolism may be beneficial to the host, as lipoproteins inactivate a variety of infectious agents. Cytokine-driven hepatic VLDL production during infection most likely represents a part of the acute phase response. The body is thus able to increase serum lipids during infection, or at least maintain triglyceride-rich lipoproteins despite the anorexia of infection. In this manner, the anti-infective, protective effects of lipoproteins are maintained. PMID: 1374564 [PubMed - indexed for MEDLINE] 6424. Can J Sport Sci. 1992 Jun;17(2):83-90. Fat metabolism, exercise, and the cold. Shephard RJ(1). Author information: (1)School of Physical & Health Education, University of Toronto, Ontario. Whereas short-term cold exposure depletes glycogen reserves, repeated and prolonged moderate exercise in a cold environment creates an energy deficit that is satisfied by an increased metabolism of depot fat. Factors contributing to the fat loss include an exercise-induced hypertrophy of lean tissue, a loss of energy through a cold-induced ketonuria, a stimulation of resting metabolism, increases in the energy cost of movement, and a lower yield of energy per litre of oxygen consumed. Biochemical explanations of the enhanced lipolysis include increased catecholamine secretion, altered sensitivity of catecholamine receptors, and decreases of circulating insulin. The enhanced fat loss with combinations of cold and exercise may be helpful in the therapy of obesity, although the response seems less well developed in women than in men. Moreover, there may be other objections to cold exposure in an older obese population. Short-term glycogen depletion has negative implications for the endurance competitor. Cold acclimation, by favoring an insulative response to cold, reduces glycogen depletion; endurance training may supplement this effect by enhancing the activity of fat-metabolizing enzymes. PMID: 1324116 [PubMed - indexed for MEDLINE] 6425. Am J Psychiatry. 1992 May;149(5):587-95. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Yonkers KA(1), Kando JC, Cole JO, Blumenthal S. Author information: (1)Department of Psychiatry, Harvard Medical School, Boston, MA. Comment in Am J Psychiatry. 1993 Apr;150(4):678-9. OBJECTIVE: This review explores the theoretical background for and empirical evidence supporting gender-related differences in pharmacokinetics and pharmacodynamic properties of psychotropic medications. METHOD: The authors reviewed all English-language articles on this topic that involved original research using human subjects. RESULTS: Limited evidence suggests that young women seem to respond better to and require lower doses of antipsychotic agents and benzodiazepines than young men. The administration of exogenous hormones interacts with medications, changing plasma levels and possibly conferring greater risks for toxicity. Young women may have an enhanced response to nontricyclic antidepressants. CONCLUSIONS: Too little basic and clinical research has been conducted on sex differences in therapeutic effects and side effects of psychopharmacological treatments. Addressing these differences as well as similarities will lead to safer and more effective treatment for all patients. PIP: A review of the English-language literature on original research with human subjects concerning sex differences in pharmacokinetics and psychotropic agents was attempted. With respect to absorption and bioavailability, women may secrete less gastric acid, and progesterone in the luteal phase slowed gastric emptying. Drugs with high affinity for adipose tissue (diazepam) would be distributed more in females with a lower ratio of lean body mass to adipose tissue. Yet, over time half-life may be prolonged with higher serum levels in patients with less lean body mass. The 1st-pass metabolism of drugs and later extensive metabolizing for systemic circulation are carried out in the liver. The menstrual cycle also affects gastric motility as dilution via fluid retention results in lower plasma levels. Estrogen may reduce monoamine oxidase activity and progesterone may increase it. Women taking oral contraceptives and diazepam during menstruation become relatively intoxicated. With respect to antipsychotic agents higher fluphenazine levels were found in women, and they required 1/2 the dose of fluspiriline as men. Women improved more after pimozide and chlorpromazine treatment than men. The incidence of severe tardive dyskinesia was higher in postmenopausal women possibly attributable to estrogen loss. Oral contraceptives reduced the clearance of benzodiazepines resulting in slower peak levels of diazepam while being off pills led to impairment of cognitive and psychomotor tasks. Temazepam and oxazepam also cleared more slowly in women. Among antidepressant agents MAO inhibitors produced better results in women than did tricyclic antidepressants. Lithium-induced hypothyroidism predominates in women as does thyroid disease, and possibly rapid-cycling bipolar illness is also linked to this condition. PMID: 1575248 [PubMed - indexed for MEDLINE] 6426. J Clin Invest. 1992 May;89(5):1367-74. Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes. Kahn BB(1). Author information: (1)Charles A. Dana Research Institute, Department of Medicine, Beth Israel Hospital, Boston, Massachusetts 02215. PMCID: PMC443004 PMID: 1569179 [PubMed - indexed for MEDLINE] 6427. Prostaglandins Leukot Essent Fatty Acids. 1992 May;46(1):1-7. Eicosanoids, thermogenesis and thermoregulation. Rothwell NJ(1). Author information: (1)Department of Physiological Sciences, University of Manchester, UK. PMID: 1321446 [PubMed - indexed for MEDLINE] 6428. Schweiz Rundsch Med Prax. 1992 Apr 28;81(18):596-600. [Obesity. Various aspects in daily practice]. [Article in German] Suter PM(1), Gutzwiller F. Author information: (1)Institut für Sozial- und Präventivmedizin, Universität Zürich. Overweight and obesity are the most often encountered disease conditions in general practice. Recent evidence of the importance of fat distribution is discussed. The basic therapeutic approach for the most effective therapy of obesity is probably the combination of a dietary (hypocaloric), a behavioral and a physical activity approach. In this general overview the physiologic background of abdominal obesity and some selected therapeutic implications are discussed. PMID: 1594849 [PubMed - indexed for MEDLINE] 6429. Diabetes Metab Rev. 1992 Apr;8(1):3-7. Some new aspects on adipose tissue development. Ailhaud G(1). Author information: (1)Centre de Biochimie du CNRS (UMR 134), Université de Nice-Sophia Antipolis, U.F.R. Sciences, France. PMID: 1633736 [PubMed - indexed for MEDLINE] 6430. Mil Med. 1992 Apr;157(4):189-92. Fat distribution: its physiological significance, health implications, and its adaptation to exercise training. Vanderburgh PM(1). Author information: (1)Department of Physical Education, United States Military Academy, West Point, NY 10996. Recently, fat distribution has become of clinical interest in assessing one's risk for coronary heart disease (CHD). Investigations have shown stronger relationships between abdominal, or central adiposity, and various well known risk factors for CHD, than peripheral and/or total adiposity. The simple waist-to-hip ratio, shown to be a valid index of such fat distribution, should be considered for use by professionals in military medicine in assessing one's risk for relevant diseases. Consideration must also be made of the role of exercise as an intervention in improving one's fat distribution profile. PMID: 1620380 [PubMed - indexed for MEDLINE] 6431. Sports Med. 1992 Apr;13(4):245-69. Body fat assessment in women. Special considerations. Vogel JA(1), Friedl KE. Author information: (1)Occupational Physiology Division, US Army Research Institute of Environmental Medicine, Natick, Massachusetts. Methods of in vivo body fat estimation are based on simple assumptions about body composition which work reasonably well for men, while estimations in women have been largely extrapolated from the male studies so that women are treated as men with just more of the same fat. Compared to men, fat regulation in women is considerably more elaborate, with more and different sites for storage and a larger proportion of fat distributed to the extremities and in subcutaneous locations. Thus, a ratio of waist-to-hips girth which reflects increasing fatness in men only specifies 2 different extremes of a broader spectrum of possibilities for fat distribution in women. This complicates anthropometric prediction of total fatness and clearly limits the generalisability of any female equations. Anthropometric methods are further confounded by difficulties in the criterion methods against which they are developed. For example, the validity of assumptions about the fractional contributions of bone mineral and body water to fat-free mass and density may not hold through the reproductive cycles. Women athletes involved in weight-bearing or strength training may increase bone mineral content above average values but if they become amenorrhoeic, bone mineral density may fall significantly below average values. Fit premenopausal women distribute fat differently and have a higher bone mineral content than unfit postmenopausal women. Genetic factors which also affect criterion method assumptions in men are superimposed on these additional complications in women. Body fat in female athletes extends across almost the entire range of female fatness, with some of the lowest measurements in distance runners and body builders which fall into the normal male range, but also with some relatively high values in swimmers and strength athletes, which would classify these women as obese by male standards. Thus, total body fat reflects a more complex regulation and has a different meaning to health and performance in women than it does for men. Predictive equations for women athletes should be developed with a view to the specific group and ultimate purpose to which they will be applied. PMID: 1615253 [PubMed - indexed for MEDLINE] 6432. Nutr Rev. 1992 Apr;50(4 ( Pt 2)):12-6. Fat as fuel and metabolic signal. Leibel RL(1). Author information: (1)Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, NY 10021. PMID: 1608559 [PubMed - indexed for MEDLINE] 6433. J Rheumatol Suppl. 1992 Apr;33:49-53. Nutrition and pediatric rheumatic diseases. Hypothesis: cytokines modulate nutritional abnormalities in rheumatic diseases. Ostrov BE(1). Author information: (1)Department of Pediatrics, Hershey Medical Center, PA 17033. Growth abnormalities are common in pediatric rheumatic diseases. Studies suggest that effects of inflammation such as anorexia, and adipose and muscle tissue breakdown contribute to the nutritional and growth aberrations. The effects of the various cytokines produced during inflammation create a vicious cycle of anorexia and increased catabolism, and may be responsible for the nutritional deficits seen. In future, specific treatment with anticytokine monoclonal antibodies may block these effects, minimizing the nutritional consequences of inflammation. PMID: 1593602 [PubMed - indexed for MEDLINE] 6434. FASEB J. 1992 Apr;6(7):2405-12. Lactate production in adipose tissue: a regulated function with extra-adipose implications. DiGirolamo M(1), Newby FD, Lovejoy J. Author information: (1)Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30303. Estimates of the quantitative contribution of adipose tissue to whole-body glucose metabolism, previously reported as 1-3%, have been revised to be on the order of 10-30%. These revised estimates come, in part, from a recognition that adipose tissue uses glucose to produce lactate and pyruvate, in addition to CO2 and triglycerides. Lactate production by adipose tissue is modulated in vitro by changes in glucose, insulin, and epinephrine concentrations. In vivo, lactate production is regulated acutely by the animal's nutritional state (fed or fasted) and chronically by the degree of obesity. A strong positive correlation exists between rat fat cell size and relative conversion of glucose to lactate (r = 0.89, P less than 0.001). Diabetes is also associated with markedly increased lactate production in adipocytes. Fat cells from obese or diabetic rats (or humans) can metabolize to lactate as much as 50-70% of the glucose taken up. From these recent studies, a picture is emerging in which the adipose organ may provide lactate for hepatic gluconeogenesis during fasting, and also lactate for hepatic glycogen synthesis after food ingestion. Modulation of adipocyte lactate production and contribution of adipose tissue lactate to the body's fuel economy in physiological and pathological states are the focus of this review. PMID: 1563593 [PubMed - indexed for MEDLINE] 6435. Metabolism. 1992 Apr;41(4):450-6. Basal metabolic rate, fat-free mass, and body cell mass during energy restriction. Luke A(1), Schoeller DA. Author information: (1)Committee on Human Nutrition, University of Chicago, IL. Basal metabolic rate (BMR) has been reported to decrease during semistarvation and during hypocaloric treatment of obesity. However, it remains controversial whether the decrease is due to change in body composition, or if it represents a downregulation in cellular metabolism. To examine this relationship, we reviewed studies of BMR in children, adolescents, adults, semistarved non-obese, anorexics, and weight-reducing obese. The relationship between BMR and fat-free mass (FFM) of children, lean adolescents, and lean and obese adults consuming sufficient energy could be described by a single line, BMR (MJ/d) = 2.44 + 0.084 FFM (SEE = 0.63, R2 = .80). Obese adolescents demonstrated BMRs greater than predicted and semistarved lean individuals demonstrated BMRs less than predicted by this relationship. Obese individuals demonstrated a reduced BMR during underfeeding, but less so than semistarved lean individuals. The reduction in BMR relative to FFM in semistarved lean individuals could not be explained by disproportionate reductions in body cell mass (BCM). PMID: 1556954 [PubMed - indexed for MEDLINE] 6436. Indian J Biochem Biophys. 1992 Apr;29(2):173-8. Functions of cytochrome c in regulation of electron transfer and protein folding. Ramasarma T(1), Rasheed BK, Vijaya S, Puranam RS, Shivaswamy V, Gaikwad AS, Kurup CK. Author information: (1)Department of Biochemistry, Indian Institute of Science, Bangalore. Cytochrome c, a "mobile electron carrier" of the mitochondrial respiratory chain, also occurs in detectable amounts in the cytosol, and can receive electrons from cytochromes present in endoplasmic reticulum and plasma membranes as well as from superoxide and ascorbate. The pigment was found to dissociate from mitochondrial membranes in liver and kidney when rats were subjected to heat exposure and starvation, respectively. Treating cytochrome c with hydroxylamine gives a partially deaminated product with altered redox properties; decreased stimulation of respiration by deficient mitochondria, increased reduction by superoxide, and complete loss of reducibility by plasma membranes. Mitochondria isolated from brown adipose tissue of cold-exposed rats are found to be sub-saturated with cytochrome c. The ability of cytochrome c to reactivate reduced ribonuclease is now reinterpreted as a molecular chaperone role for the hemoprotein. PMID: 1328035 [PubMed - indexed for MEDLINE] 6437. Lab Anim Sci. 1992 Apr;42(2):132-7. Aging and proliferative homeostasis: modulation by food restriction in rodents. Masoro EJ(1). Author information: (1)Department of Physiology, University of Texas Health Science Center, San Antonio 78284-7756. In rats fed ad libitum, the fat cell number increases with advancing age; the temporal pattern of this increase differs in the perirenal depot compared with the epididymal depot. Restriction of energy intake reduces the number of fat cells in fat depots whether the restriction is started soon after weaning or in adult life. The capacity for diet to modulate fat cell number is maintained through most, if not all, of the life span. Restriction of energy intake delayed death due to neoplasms; restriction of dietary fat or protein without restriction of energy did not have this action. In the case of leukemia/lymphoma, the data indicated that it was the age of occurrence that was delayed by the restriction of energy intake. Because restriction of dietary energy maintains most physiologic systems in a youthful state and retards a broad spectrum of disease processes, the importance of its effects on cellularity and cell proliferation in its anti-aging action remains to be established. PMID: 1318443 [PubMed - indexed for MEDLINE] 6438. Biochim Biophys Acta. 1992 Mar 26;1113(1):71-133. Cardiolipins and biomembrane function. Hoch FL(1). Author information: (1)Department of Internal Medicine, University of Michigan Medical School, Ann Arbor. Evidence is discussed for roles of cardiolipins in oxidative phosphorylation mechanisms that regulate State 4 respiration by returning ejected protons across and over bacterial and mitochondrial membrane phospholipids, and that regulate State 3 respiration through the relative contributions of proteins that transport protons, electrons and/or metabolites. The barrier properties of phospholipid bilayers support and regulate the slow proton leak that is the basis for State 4 respiration. Proton permeability is in the range 10(-3)-10(-4) cm s-1 in mitochondria and in protein-free membranes formed from extracted mitochondrial phospholipids or from stable synthetic phosphatidylcholines or phosphatidylethanolamines. The roles of cardiolipins in proton conductance in model phospholipid membrane systems need to be assessed in view of new findings by Hübner et al. [313]: saturated cardiolipins form bilayers whilst natural highly unsaturated cardiolipins form nonlamellar phases. Mitochondrial cardiolipins apparently participate in bilayers formed by phosphatidylcholines and phosphatidylethanolamines. It is not yet clear if cardiolipins themselves conduct protons back across the membrane according to their degree of fatty acyl saturation, and/or modulate proton conductance by phosphatidylcholines and phosphatidylethanolamines. Mitochondrial cardiolipins, especially those with high 18:2 acyl contents, strongly bind many carrier and enzyme proteins that are involved in oxidative phosphorylation, some of which contribute to regulation of State 3 respiration. The role of cardiolipins in biomembrane protein function has been examined by measuring retained phospholipids and phospholipid binding in purified proteins, and by reconstituting delipidated proteins. The reconstitution criterion for the significance of cardiolipin-protein interactions has been catalytical activity; proton-pumping and multiprotein interactions have yet to be correlated. Some proteins, e.g., cytochrome c oxidase are catalytically active when dimyristoylphosphatidylcholine replaces retained cardiolipins. Cardiolipin-protein interactions orient membrane proteins, matrix proteins, and on the outerface receptors, enzymes, and some leader peptides for import; activate enzymes or keep them inactive unless the inner membrane is disrupted; and modulate formation of nonbilayer HII-phases. The capacity of the proton-exchanging uncoupling protein to accelerate thermogenic respiration in brown adipose tissue mitochondria of cold-adapted animals is not apparently affected by the increased cardiolipin unsaturation; this protein seems to take over the protonophoric role of cardiolipins in other mitochondria. Many in vivo influences that affect proton leakage and carrier rates selectively alter cardiolipins in amount per mitochondrial phospholipids, in fatty acyl composition and perhaps in sidedness; other mitochondrial membrane phospholipids respond less or not at all.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1550861 [PubMed - indexed for MEDLINE] 6439. J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):421-35. Structure and tissue-specific expression of 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues. Labrie F(1), Simard J, Luu-The V, Pelletier G, Bélanger A, Lachance Y, Zhao HF, Labrie C, Breton N, de Launoit Y, et al. Author information: (1)Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Québec, Canada. The enzyme 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase (3 beta-HSD) catalyzes the oxidation and isomerization of 5-ene-3 beta-hydroxypregnene and 5-ene-hydroxyandrostene steroid precursors into the corresponding 4-ene-ketosteroids necessary for the formation of all classes of steroid hormones. We have recently characterized two types of human 3 beta-HSD cDNA clones and the corresponding genes which encode deduced proteins of 371 and 372 amino acids, respectively, and share 93.5% homology. The human 3 beta-HSD genes containing 4 exons were assigned by in situ hybridization to the p11-p13 region of the short arm of chromosome 1. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs as well as that of one type of 3 beta-HSD from bovine and macaque ovary lambda gt11 cDNA libraries which all encode 372 amino acid proteins. The human type I 3 beta-HSD is the almost exclusive mRNA species detected in the placenta and skin, while the human type II is the predominant mRNA species in the adrenals, ovaries and testes. The predicted rat type I and type II 3 beta-HSD proteins expressed in adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and type II as well as rat type I and type II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and these cDNAs encode functional 3 beta-HSD proteins that are capable of converting 3 beta-hydroxy-5-ene-steroids into 3-keto-4-ene derivatives as well as the interconversion of 3 beta-hydroxy and 3-keto-5 alpha-androstane steroids. We have found that the rat type III mRNA species was below the detection limit in intact female liver while, following hypophysectomy, its accumulation increased to 55% of the levels measured in intact or HYPOX male rats, an increase which can be blocked by administration of ovine prolactin (oPRL). In addition, in female rats, treatment with oPRL for 10 days starting 15 days after HYPOX, markedly decreased ovarian 3 beta-HSD mRNA accumulation accompanied by a similar decrease in 3 beta-HSD activity and protein levels. Treatment with the gonadotropin hCG reversed the potent inhibitory effect of oPRL on these parameters and stimulated 3 beta-HSD mRNA levels in ovarian interstitial cells.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1562516 [PubMed - indexed for MEDLINE] 6440. J Nutr. 1992 Mar;122(3 Suppl):806-17. In vitro systems for the analysis of the development of adipose tissue in domestic animals. Ramsay TG(1), Rao SV, Wolverton CK. Author information: (1)Department of Animal Science, Ohio State University, Columbus. In vitro models have been used for many years to assess processes that regulate metabolic activity of adipocytes or that regulate proliferation and differentiation of precursor cells for adipocytes (preadipocytes). The results of these studies have been useful in characterizing the role of various hormones and growth factors in regulating the cellular activities of preadipocytes and adipocytes from domestic animals. Mechanisms that regulate the proliferation and differentiation of the preadipocyte are currently being evaluated with the use of a variety of cell culture systems: matrix suspension, coverslip, micromass, clonal etc. Isolated cell culture of adipose tissue and the tools of molecular biology have allowed direct examination of the effects of potential regulatory hormones of adipogenesis upon gene expression during the development of adipose tissue in domestic animals. Much information has been collected by combining the use of in vivo animal manipulations and in vitro assay techniques to elucidate the mechanisms that affect adipocyte function or formation. The development of in vitro tools to manipulate the development of adipose tissue should result in an increase in our knowledge of the regulation of adipose tissue formation and thus should permit the development of methods to produce leaner and more efficient domestic animals. PMID: 1542052 [PubMed - indexed for MEDLINE] 6441. Mol Cell Biochem. 1992 Feb 12;109(2):119-25. Insulin resistance and hypertension. Lachaal M(1), Jung CY. Author information: (1)Department of Medicine and Biophysical Sciences, State University of New York, Buffalo. PMID: 1625678 [PubMed - indexed for MEDLINE] 6442. Chest. 1992 Feb;101(2):541-9. Mechanisms of obstructive sleep apnea. Hudgel DW(1). Author information: (1)Case Western Reserve University, Cleveland. Comment in Chest. 1994 Jun;105(6):1916-7. This article has reviewed the anatomic, compliance, reflex, and respiratory muscle variables that affect upper airway caliber and abnormalities which may precipitate upper airway collapse during sleep. One or more of these variables may be important in the mechanism of OSA in any given patient. First, anyone with anatomic narrowing of the upper airway is susceptible to OSA. However, we do know if anatomic narrowing of the upper airway is necessary for the development of OSA. Surely, heavy snoring produces pharyngeal trauma and possibly edema or inflammation, which in turn may narrow the upper airway. Submucosal adipose tissue or cervical adipose tissue may compress the airway when the tonic electrical activity of the pharyngeal muscles decreases with sleep onset. Data reviewed support the idea that the upper airway of OSA patients may be more collapsible than the upper airway of nonapneic subjects. Intrinsic tissue abnormalities have not been demonstrated that might be responsible for this collapsibility. Changes in collapsibility found are consistent with, and may be due to, changes in tonic and phasic contraction of upper airway muscles. Abnormalities in reflexes affecting upper airway size surely might exist in OSA. Edema or inflammation of pharyngeal tissues might not only narrow the upper airway but might also impair normal function of the receptors responsible for initiating protective reflexes. We propose the fluctuation between a low- and a high-drive state contributes to upper airway collapse in OSA. With this fluctuation the balance of forces and critical pressure concepts discussed above come into play (Fig 6). By stimulating upper airway inspiratory muscles, CO2 eliminates the hypoapneic, low-drive, high-resistance periods and thereby reduces the number of apneas. In addition, preferential stimulation of upper airway muscle activity dilates the upper airway per se. If the relative value of each of these factors can be determined diagnostically, perhaps therapy can be made more specific. By being more specific, therapy should be more successful than the present practice of prescribing a particular therapy, regardless of the specific mechanism responsible for the OSA in a given patient. PMID: 1735286 [PubMed - indexed for MEDLINE] 6443. J Cell Biochem. 1992 Feb;48(2):122-8. Alterations in glucose transporter expression and function in diabetes: mechanisms for insulin resistance. Kahn BB(1). Author information: (1)Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215. Insulin resistance is a major pathologic feature of human obesity and diabetes. Understanding the fundamental mechanisms underlying this insulin resistance has been advanced by the recent cloning of the genes encoding a family of facilitated diffusion glucose transporters which are expressed in characteristic patterns in mammalian tissues. Two of these transporters, GLUT1 and GLUT4, are present in muscle and adipose cells, tissues in which glucose transport is markedly stimulated by insulin. To understand the mechanisms underlying in vivo insulin resistance, regulation of these transporters is being investigated. Studies reveal divergent changes in the expression of GLUT1 and GLUT4 in a single cell type as well as tissue specific regulation. Importantly, alterations in glucose transport in rodent models of diabetes and in human obesity and diabetes cannot be entirely explained by changes in glucose transporter expression. This suggests that defects in glucose transporter function such as impaired translocation, fusion with the plasma membrane, or activation probably contribute importantly to in vivo insulin resistance. PMID: 1618926 [PubMed - indexed for MEDLINE] 6444. Clin Geriatr Med. 1992 Feb;8(1):127-41. Alcohol and the elderly. Dufour MC(1), Archer L, Gordis E. Author information: (1)National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland. Moderate drinking for the elderly of both genders is no more than one drink per day, where a drink is defined as 12 oz of beer, 5 oz of wine, or 1.5 oz of spirits. Age does not affect the rate of absorption or elimination of alcohol. Lean body mass decreases and adipose tissue increases with age, however, resulting in a corresponding decrease in the volume of total body water. With a smaller volume of distribution, an alcohol dose identical to that administered to a younger individual of the same size and gender will produce a higher blood alcohol concentration in the elderly. Low-dose alcohol stimulates appetite and promoters regular bowel function. In the well-nourished nonalcoholic elderly, the negative impact of alcohol consumption on nutrition is minimal. Alcohol consumption improves mood by increasing feelings of happiness and freedom from care while lessening inhibitions, stress, tension, and depression. Although in the laboratory low-dose alcohol improves certain types of cognitive function in young men, in other types of task performance, alcohol induces impairment, which worsens with age. The effects of alcohol on sleep are primarily detrimental, worsening both insomnia and breathing disturbances during sleep. Although the role of alcohol consumption in mortality from heart disease has not been investigated in the elderly, moderate drinking appears safe. Under some circumstances low-dose alcohol may produce analgesia whereas in others it may worsen pain. The elderly use a significant proportion of both prescription and over-the-counter medication, a large variety of which interact with alcohol. Alcoholic beverage consumption may exacerbate cognitive impairment and dementias of other etiology. Although some studies suggest that moderate use of alcohol by institutionalized senior citizens appears to produce benefits including improved socialization, separation of the effects of the social situation from those specifically attributable to alcohol remains to be accomplished. Older individuals who want to drink, have no medical contraindications, and take no drugs (prescription or over-the-counter) that interact with alcohol, may consider one drink a day to be a prudent level of alcohol consumption. Patients should be counseled to avoid alcohol consumption immediately prior to going to bed in order to avoid sleep disturbances. They also should be cautioned against potential drug-alcohol interactions and told to avoid alcohol ingestion prior to activities such as driving. The decision to recommend a particular level of alcohol consumption in any given patient must, however, be carefully tailored not only to that individual's specific medical needs but to his or her social and environmental circumstances as well. PMID: 1576571 [PubMed - indexed for MEDLINE] 6445. Ann Med. 1992 Feb;24(1):15-8. Abdominal fat distribution and disease: an overview of epidemiological data. Björntorp P(1). Author information: (1)Department of Medicine, University of Göteborg, Sweden. Recent prospective, epidemiological research has demonstrated the power of an increased waist/hip circumference ratio (WHR) to predict both cardiovascular disease (CVD) and non-insulin dependent diabetes mellitus (NIDDM) in men and women. Obesity, defined as an increased total body fat mass, seems to interact synergistically in the development of NIDDM, but not of CVD. Increased WHR with obesity (abdominal obesity) seems to be associated with a cluster of metabolic risk factors, as well as hypertension. This metabolic syndrome is closely linked to visceral fat mass. Increased WHR without obesity may instead be associated with lift style factors such as smoking, alcohol intake, physical inactivity, coagulation abnormalities, psychosocial, psychological and psychiatric factors. Direct observations show, and the risk factor associations further strengthen the assumption, that abdominal (visceral) obesity is more closely associated to NIDDM than CVD, while an increased WHR without obesity may be more closely linked to CVD than NIDDM. It remains to be established to what extent, if any, an increased WHR in lean men, and particularly in lean women, indicates fat distribution. Other components of the WHR measurement might be of more importance in this connection. PMID: 1575956 [PubMed - indexed for MEDLINE] 6446. Biochem Soc Trans. 1992 Feb;20(1):113-8. Non-alpha 2-adrenoceptor idazoxan binding sites; a new target for drug development. Kilpatrick AT(1), Brown CC, Mackinnon AC. Author information: (1)Boots Pharmaceuticals, Nottingham, U.K. PMID: 1353030 [PubMed - indexed for MEDLINE] 6447. Fortschr Med. 1992 Jan 30;110(3):41-2, 45. [Growth hormone therapy in adulthood]. [Article in German] von Werder K(1). Author information: (1)Innere Medizin, Akademisches Lehrkrankenhaus der Freien, Universität Berlin. Only a few controlled studies on replacement therapy with growth hormone (GH) in adults have been published. These studies have demonstrated that GH leads to an increase in muscle mass and a decrease in fatty tissue. In addition, there is an improvement in renal and cardiac function. To date, there has been only a single study demonstrating the efficacy of pharmacotherapy with growth hormone in the elderly. Again, an increase in muscle and bone mass, and a decrease in fat mass, an increase in skin thickness, and an improvement in overall wellbeing was reported. Although these studies do not unequivocally demonstrate the benefit of GH treatment, they are interesting enough to warrant further studies on replacement therapy, and also on pharmacotherapy with growth hormone. PMID: 1607136 [PubMed - indexed for MEDLINE] 6448. Am J Clin Nutr. 1992 Jan;55(1 Suppl):296S-298S. A clinical perspective on peptides and food intake. Hirsch J(1), Leibel RL, Chua SC. Author information: (1)Rockefeller University, New York, New York 10021-6399. Viewed from a clinical perspective, it is difficult to generate enthusiasm for the likelihood of finding a peptide that could be helpful in the treatment of obesity. A deeper understanding of obesity, as will emerge from molecular biology, is more likely to point the way to a useful peptide than further evaluations of the clinical dilemmas posed by obesity. However, a clinical perspective may be useful in pointing the way to a system that needs to be examined by molecular biology and also to inject caution in the evaluation of early findings when peptides are used in treatment. PMID: 1728843 [PubMed - indexed for MEDLINE] 6449. Am J Clin Nutr. 1992 Jan;55(1 Suppl):167S-172S. Metabolic consequences of fenfluramine for the control of body weight. Levitsky DA(1), Troiano R. Author information: (1)Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853. The chronic ingestion of fenfluramine results in a sustained depression in body weight despite the return of ad libitum food intake to normal levels. This chronic suppression of body weight is immediately reversed after discontinuation of the drug treatment. Such a phenomenon indicates that the drug must increase metabolic rate. However, studies in both humans and animals have failed to demonstrate an increase in metabolic rate after the administration of the drug. Instead, fenfluramine appears to potentiate the expenditure of energy whenever increases in energy expenditure occur. Fenfluramine potentiates the thermic effect of food (TEF) both in animals as well as in humans. Moreover, the energy cost of locomotor behavior also appears to be potentiated by this drug. Most importantly from a therapeutic perspective, unlike the anorectic effect of fenfluramine, tolerance does not appear to develop to its ability to potentiate energy expenditure. PMID: 1728828 [PubMed - indexed for MEDLINE] 6450. Neurosci Biobehav Rev. 1992 Summer;16(2):235-72. Metabolic fuels and reproduction in female mammals. Wade GN(1), Schneider JE. Author information: (1)Department of Psychology and Neuroscience, University of Massachusetts, Amherst 01003. A complete reproductive cycle of ovulation, conception, pregnancy, and lactation is one of the most energetically expensive activities that a female mammal can undertake. A reproductive attempt at a time when calories are not sufficiently available can result in a reduced return on the maternal energetic investment or even in the death of the mother and her offspring. Numerous physiological and behavioral mechanisms link reproduction and energy metabolism. Reproductive attempts may be interrupted or deferred when food is scarce or when other physiological processes, such as thermoregulation or fattening, make extraordinary energetic demands. Food deprivation suppresses both ovulation and estrous behavior. The neural mechanisms controlling pulsatile release of gonadotropin-releasing hormone (GnRH) and, consequently, luteinizing hormone secretion and ovarian function appear to respond to minute-to-minute changes in the availability of metabolic fuels. It is not clear whether GnRH-secreting neurons are able to detect the availability of metabolic fuels directly or whether this information is relayed from detectors elsewhere in the brain. Although pregnancy is less affected by fuel availability, both lactational performance and maternal behaviors are highly responsive to the energy supply. When a reproductive attempt is made, changes in hormone secretion have dramatic effects on the partitioning and utilization of metabolic fuels. During ovulatory cycles and pregnancy, the ovarian steroids, estradiol and progesterone, induce coordinated changes in the procurement, ingestion, metabolism, storage, and expenditure of metabolic fuels. Estradiol can act in the brain to alter regulatory behaviors, such as food intake and voluntary exercise, as well as adenohypophyseal and autonomic outputs. At the same time, ovarian hormones act on peripheral tissues such as adipose tissue, muscle, and liver to influence the metabolism, partitioning and storage of metabolic fuels. During lactation, the peptide hormones, prolactin and growth hormone, rather than estradiol and progesterone, are the principal hormones controlling partitioning and utilization of metabolic fuels. The interactions between metabolic fuels and reproduction are reciprocal, redundant, and ubiquitous; both behaviors and physiological processes play vital roles. Although there are species differences in the particular physiological and behavioral mechanisms mediating nutrition-reproduction interactions, two findings are consistent across species: 1) Reproductive physiology and behaviors are sensitive to the availability of oxidizable metabolic fuels. 2) When reproductive attempts are made, ovarian hormones play a major role in the changes in ingestion, partitioning, and utilization of metabolic fuels. PMID: 1630733 [PubMed - indexed for MEDLINE] 6451. Acta Clin Belg Suppl. 1992;14:37-45. Endocrine abnormalities related to total and regional fat mass accumulation. Van Gaal L(1), Vanderkam S, Duysburgh I, De Leeuw I. Author information: (1)Dept. Endocrinology, Metabolism and Clinical Nutrition, Faculty of Medicine, University Hospital, Antwerp, Belgium. PMID: 1604960 [PubMed - indexed for MEDLINE] 6452. Ann Acad Med Singapore. 1992 Jan;21(1):106-13. Lipoprotein metabolism: an overview. Shepherd J(1). Author information: (1)Institute of Pathological Biochemistry, Royal Infirmary, Glasgow, United Kingdom. The major plasma lipids, cholesterol and triglyceride, circulate in association with specific proteins as lipid-protein or lipoprotein complexes. The proteins direct and regulate the metabolism of these complexes in interacting with tissue enzymes and receptors. The metabolic fate of circulating triglyceride is governed by the activity of the enzyme lipoprotein lipase, situated in adipose tissue and skeletal muscle. Cellular demand for cholesterol, on the other hand, is met by activation of a specific receptor which mediates the delivery of sterol-rich lipoproteins to lysosomal degradation in liver and peripheral tissues. In order to prevent excess cholesterol accumulation at the periphery, there is a system of reverse cholesterol transport which involves assimilation and trapping of the sterol in the plasma lipoproteins through the action of the enzyme lecithin: cholesterol acyltransferase. Thereafter, the cholesterol is delivered to the liver, the only organ capable of excreting it in significant amounts. Disturbances in these processes may produce gross changes in the plasma lipid profile, clearly recognisable as hyperlipidaemia. However, it is becoming increasingly clear that a number of inherited traits can subtly perturb the lipoprotein spectrum and increase coronary risk even in subjects whose plasma lipoprotein profile would be considered normal. PMID: 1590643 [PubMed - indexed for MEDLINE] 6453. Diabete Metab. 1992;18(1 Pt 2):145-9. Lipoprotein metabolism in fatty liver dairy cows. Mazur A(1), Ayrault-Jarrier M, Chilliard Y, Rayssiguier Y. Author information: (1)Laboratoire des Maladies Métaboliques, INRA, Theix, Ceyrat, France. High yielding dairy cows undergo a period of energy deficit in early lactation and mobilise body reserves for milk production. During this phase lipid infiltration of the liver takes place as a result of fat mobilization and the degree of accumulation of fat in the liver depends on the level of mobilization of fatty acids from the adipose tissue. The objective of the studies reported was to characterize plasma lipoproteins in dairy cows and to determine whether differences in plasma lipoproteins existed in dairy cows with varied degrees of hepatic lipid infiltration. The physiological mechanism responsible for fatty liver is not fully understood but seems to involve a deficit in the hepatic synthesis and release of lipoproteins as shown by the depressed level and compositional modifications of plasma lipoproteins. Other results indicate a negative correlation between plasma apo B concentration and liver triglyceride content. In studies carried out on fatty liver cows the level of liver apo B mRNA was reported to be lower than in control cows. An impaired synthesis of apo B may result in its decreased availability for lipoprotein formation and in turn results in enhanced triglyceride accumulation in the liver. PMID: 1563549 [PubMed - indexed for MEDLINE] 6454. Annu Rev Physiol. 1992;54:911-30. Mammalian facilitative glucose transporter family: structure and molecular regulation. Pessin JE(1), Bell GI. Author information: (1)Department of Physiology and Biophysics, University of Iowa, Iowa City 52242. PMID: 1562197 [PubMed - indexed for MEDLINE] 6455. Arkh Patol. 1992;54(2):5-10. [Biological manifestations of the tumor necrosis factor effect and its role in the pathogenesis of various diseases]. [Article in Russian] Perskidskiĭ IuV, Barshteĭn IuA. Tumour necrosis factor (TNF) is a polypeptide mediator regulating function of various organs and cells produced by macrophages and lymphocytes due to various stimuli and is responsible for an acute response of the host to the damage. Directly or indirectly the polypeptide modulates biological functions of leucocytes, lymphocytes, macrophages, eosinophils and many other cells and organs as well as different types of metabolism. It is considered now the most important factor of inflammation and cachexia. PMID: 1524503 [PubMed - indexed for MEDLINE] 6456. Annu Rev Nutr. 1992;12:207-33. Cellular and molecular aspects of adipose tissue development. Ailhaud G(1), Grimaldi P, Négrel R. Author information: (1)Centre de Biochimie (CNRS UMR 134), Université de Nice-Sophia Antipolis, Faculté des Sciences, France. Both in animals and humans, before or after birth, angiogenesis appears to be closely coordinated in time and space with the formation of fat cell clusters. Monobutyrin, a novel fat-specific angiogenesis factor, may play a role in this process. The potential to acquire new fat cells appears to be permanent throughout life in both animals and humans, as revealed by in vitro experiments. Considerable evidence now supports the view that BAT and WAT are distinct organs; in addition, the existence of distinct BAT precursor cells is demonstrated by their unique ability to express the UCP gene. In bovine and ovine, the transformation of BAT into WAT is strongly suggested by the rapid disappearance after birth of UCP from the various BAT depots. Despite the initial cell heterogeneity of the stromal-vascular fraction, cultured stromal-vascular cells of adipose tissue are adipose precursor cells that show varying capacities for replication and differentiation, according to age and fat depot. Studies of adipose cell differentiation in vitro correspond to the sequence: adipoblast (unipotential cells)----commitment preadipose cell (preadipocyte)----terminal differentiation immature adipose cell----terminal differentiation mature adipose cell (adipocyte). Cell commitment is triggered by growth arrest and characterized by the expression of early markers (A2COL6/pOb24; clone 5; LPL), whereas only terminal differentiation of preadipocytes requires the presence of various hormones. Multiple signaling pathways have been characterized and shown to cooperate in the process of terminal differentiation. The concept that adipose cells behave as secretory cells is now emerging from in vitro data, since secretion of various proteins (LPL, adipsin, CETP) and important metabolites (fatty acids, monobutyrin, androgens, estrogens, prostaglandins) takes place both constitutively and upon hormonal stimulation. This suggests that adipose tissue participates more directly than previously thought in metabolic activities and energy balance. PMID: 1503804 [PubMed - indexed for MEDLINE] 6457. Horm Metab Res Suppl. 1992;26:90-4. Diabetes mellitus and bone metabolism. Ziegler R(1). Author information: (1)Department of Internal Medicine I, University of Heidelberg, Germany. Whether there is a diabetic osteopathy" or osteopathy in diabetes mellitus", is still unclear. Epidemiological studies show in part discrepant results: bone mass was diminished in some studies, unchanged in others--even more positive trends were reported. Increases in osteoporotic fractures were observed in smaller collectives whereas no general trends for fracturing bones were found in diabetics. There are many in part favouring, in part impairing factors to be taken into consideration: Diabetes mellitus type I is a disease including immune phenomena. As inflammation leads to bone loss (inflammation-mediated osteopenia = IMO), peak bone mass may be influenced by such a process. The lack of insulin-like growth factors may be decisive, too. Complications of diabetes mellitus include hypogonadism--this may be disadvantageous for the skeleton. Diabetic complications like retinopathy, neuropathy, and angiopathy may influence the fracture event independently from bone mass. On the other hand, diabetes mellitus type II may be somehow protected against bone loss: Increased adipose tissue in connection with the frequently seen overweight yields metabolically active steroid hormones, insulin related growth factors may stimulate bone formation (e.g. in Forestier's disease). Older diabetics do not show diminished life expectancy any more due to their regular medical care--whether this includes the risk of bone diseases, is not yet clear. It may be worth to further analyse these "positive" effects seen in bones of type II diabetics because they may be useful in osteoporosis even in non-diabetics. PMID: 1490700 [PubMed - indexed for MEDLINE] 6458. Acta Derm Venereol Suppl (Stockh). 1992;176:77-85. Are disturbances of omega-6-fatty acid metabolism involved in the pathogenesis of atopic dermatitis? Melnik B(1), Plewig G. Author information: (1)Fachbereich für Gesundheitstheorie und Dermatologie, Universität Osnabrück, Germany. Recent evidence indicates that the primary defect in atopic dermatitis (AD) might concern the maturation and differentiation of T cells which infiltrate the skin or are unable to control T cell infiltration of the skin. Unfortunately, there is no information on thymus hormones, T cell differentiation factors or cytokines during early T cell maturation in atopic infants. One of these factors at fault might involve a deficiency of essential long-chain omega-6-fatty acids and E-type prostaglandins which are important for thymic T cell maturation and thymus hormone action. Deficiencies of 6-desaturated omega-6-fatty acids have been observed in plasma phospholipids, epidermal and red cell phospholipids of patients with AD, in umbilical cord plasma lecithin of newborn infants with increased cord blood IgE levels, in cord blood T-cells of 'atopy-at-risk' newborn infants, in atopic monocytes, in adipose tissue lipids of patients with AD, in breast milk lipids of mothers with a history of AD, and in breast milk lipids of mothers of infants with AD. Reduced release of arachidonic acid has been measured in atopic monocytes and platelets. Diminished formation of prostaglandin E2 (PGE2) has been observed in atopic monocytes under stimulated and unstimulated conditions and in inflamed and non-inflamed atopic epidermis. PGE2 is able to suppress interleukin 4-induced IgE synthesis of human non-atopic mononuclear cells in vitro. We have demonstrated a suppressive effect of PGE1 and PGE2 on in vitro IgE synthesis of mononuclear blood cells of patients with AD and respiratory allergies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1476044 [PubMed - indexed for MEDLINE] 6459. Health Psychol. 1992;11 Suppl:10-6. National working conference on smoking and body weight. Task Force 2: Methods of assessment, strategies for research. Henningfield JE, Obarzanek E, Benowitz NL, Hall SM, Klesges RC, Leischow S, Levin ED, Perkins KA, Spring B, Stitzer M, et al. PMID: 1396498 [PubMed - indexed for MEDLINE] 6460. Ciba Found Symp. 1992;167:47-62; discussion 62-7. Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6. Akira S(1), Isshiki H, Nakajima T, Kinoshita S, Nishio Y, Natsuka S, Kishimoto T. Author information: (1)Institute for Molecular and Cellular Biology, Osaka University, Japan. The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6. PMID: 1385054 [PubMed - indexed for MEDLINE] 6461. Curr Top Microbiol Immunol. 1992;177:123-36. Stem cell-stromal cell interactions. Chabannon C(1), Torok-Storb B. Author information: (1)Department of Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98104. PMID: 1379138 [PubMed - indexed for MEDLINE] 6462. Am J Clin Nutr. 1992 Jan;55(1 Suppl):252S-257S. BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Cawthorne MA(1), Sennitt MV, Arch JR, Smith SA. Author information: (1)Diabetes Programme, SmithKline Beecham Pharmaceuticals, Great Burgh, Epsom, Surrey, UK. BRL 35135, via its active deesterified metabolite BRL 37344, is a potent example of a new group of beta-adrenoceptor agonists that stimulate selectively a novel beta adrenoceptor that was originally shown to be present in brown adipose tissue in rodents. BRL 35135 produces a dose-related increase in energy expenditure in rodents and, in genetically obese (ob/ob) mice, a dose of 0.5 mg.kg-1.d-1 has significant antiobesity activity. This weight loss is entirely due to loss of fat; muscle protein is preserved. In studies in nonobese men, BRL 35135 (0.1 mg/kg) increased both resting metabolic rate and the thermic response to a glucose load. BRL 35135 is effective in improving glucose tolerance in genetically obese (ob/ob) mice and obese Zucker (fa/fa) rats at doses that have no significant antiobesity activity. The improved glucose tolerance is the result of significant improvement in insulin sensitivity. In 10-d studies in obese and diabetic patients, BRL 35135 produced improvements in glucose tolerance and insulin sensitivity. PMID: 1345889 [PubMed - indexed for MEDLINE] 6463. Clin Pharmacokinet. 1992;22 Suppl 1:14-23. Pharmacokinetics of temafloxacin after multiple oral administration. Granneman GR(1). Author information: (1)Drug Metabolism Department, Abbott Laboratories, Abbott Park, Illinois. Four multiple dose studies involving 102 healthy volunteers were reviewed to determine the sources of intersubject variability in the pharmacokinetics of temafloxacin. As a result of the preferential distribution of temafloxacin into muscle, liver and kidney compared with adipose tissue, the best anthropometric explanatory variable was found to be lean body mass, rather than total body mass or body surface area. Single dose studies have confirmed that the distribution volume of temafloxacin is smaller in subjects in whom the lean body mass:total body mass ratio is low, notably in females, the elderly, and those with hepatic impairment. Average creatinine clearance for the volunteers included in this analysis was normal (109 +/- 29 ml/min), and renal function was only a marginally significant covariate; however, renal clearance accounts for 60 to 70% of total clearance (CLT) and has been shown to be a major factor in the elderly, as well as in patients with renal or hepatic impairment. Since temafloxacin is partially reabsorbed renally, urine flow rate was found to be a potentially important secondary factor. Overall, the pharmacokinetics of temafloxacin are essentially linear, with steady-state plasma concentrations at trough (Cssmin) and 2h postdose (Css2h) averaging slightly more than 0.5 and 1.0 mg/L per 100mg administered every (q) 12h. For example, mean Cssmin and peak steady-state plasma concentration (Cssmax) values after administration of temafloxacin 600mg q12h were 3.3 +/- 1.1 and 6.2 +/- 1.8 mg/L, respectively. Total apparent clearance (CLT/F) and the terminal elimination half-life (t1/2) averaged 11 L/h (184 ml/min) per 55kg lean body mass and 8.4h, respectively. Considering that the data reviewed came from 4 studies with doses ranging from 100 to 800mg q12h, the intersubject coefficients of variation were low for an orally administered drug, ranging from 15.4% for t1/2, 20.6% for Css2h, 21.2% for CLT/F and 25% for Cssmin. PMID: 1319867 [PubMed - indexed for MEDLINE] 6464. Acta Clin Belg Suppl. 1992;14:3-12. Cellular and molecular biology in the study of the physiopathology of obesity. Remacle C(1), Grégoire F. Author information: (1)University of Louvain, Laboratory of Cell Biology, Louvain-la-Neuve, Belgium. PMID: 1318630 [PubMed - indexed for MEDLINE] 6465. Adv Second Messenger Phosphoprotein Res. 1992;25:147-64. Mechanisms for activation of the rat adipocyte particulate cyclic-GMP-inhibited cyclic AMP phosphodiesterase and its importance in the antilipolytic action of insulin. Manganiello VC(1), Degerman E, Smith CJ, Vasta V, Tornqvist H, Belfrage P. Author information: (1)Laboratory of Cellular Metabolism, NHLBI, National Institutes of Health, Bethesda, Maryland 20892. PMID: 1313257 [PubMed - indexed for MEDLINE] 6466. Clin Sci (Lond). 1992 Jan;82(1):1-8. Insulin resistance, adipose tissue and coronary heart disease. Frayn KN, Coppack SW. PMID: 1310908 [PubMed - indexed for MEDLINE] 6467. Am J Clin Nutr. 1992 Jan;55(1 Suppl):228S-236S. Adrenergic receptor function in fat cells. Arner P(1). Author information: (1)Department of Medicine, Huddinge Hospital, Karolinska Institute, Stockholm. All classical adrenoceptor subtypes are functionally expressed in fat cells. However, only beta 1 adrenoceptors appear to be present in all types of fat cells. There is a substantial adrenoceptor reserve in fat cells; approximately 50% of beta and alpha 2 adrenoceptors are spare receptors. Beta adrenoceptors are subject to intensive regulation. They are regulated by insulin, estrogens, and androgens as well as by thyroid hormones and are altered by nutritional factors, diabetes, autonomic neuropathy, and beta-blocking treatment. Alpha receptors are less sensitive to changes except during infancy, when there are marked developmental alterations in the function of alpha 2 adrenoceptors, and during fasting, when there is a decrease in receptor expression. In addition, beta adrenoceptors but not alpha 2 adrenoceptors are sensitive to homologous desensitization after exposure to agonists. Site variations in the expression and function of beta and alpha 2 adrenoceptors, which in part are situated at the level of gene transcription, may be involved in the development of regional obesity. PMID: 1309480 [PubMed - indexed for MEDLINE] 6468. Ann Med Interne (Paris). 1992;143(7):463-71. [Genetics of human obesity]. [Article in French] Bouchard C(1). Author information: (1)Laboratoire des Sciences de l'Activité Physique (LABSAP-PEPS), Université Laval, Ste-Foy Québec, Canada. PMID: 1300868 [PubMed - indexed for MEDLINE] 6469. Horm Res. 1992;38 Suppl 2:41-3. Growth hormone actions on fat distribution and metabolism. Gertner JM(1). Author information: (1)Department of Pediatrics, Cornell University Medical College, New York, NY. The secretion of growth hormone (GH) and the mass and distribution of body fat are linked through a complex series of interactions. There is increasing evidence that a GH/fat cycle exists and that elements of this cycle may possess regulatory functions. The essential elements of the cycle are: (1) GH-deficient individuals are often obese and lose body fat when they are treated; GH is lipolytic in vitro and causes an acute release of free fatty acids (FFA) when administered in vivo; (3) circulating FFA inhibit the pituitary release of GH by most secretagogues, including growth hormone releasing hormone, and (4) the obese state is characterized by a defect in GH release which can be reversed by weight loss. PMID: 1292980 [PubMed - indexed for MEDLINE] 6470. Acta Med Austriaca. 1992;19(4):96-100. [Insulin resistance]. [Article in German] Waldhäusl W(1). Author information: (1)Klinischen Abteilung für Endokrinologie und Stoffwechselkrankheiten, Medizinischen Universitätsklinik III. Wien. Insulin sensitivity of insulin dependent tissues (muscle, adipose tissue, liver) is subject to a variety of influences. Any change in insulin sensitivity is compensated in healthy subjects by a dynamic change in insulin secretion, which will decrease following a rise in insulin sensitivity and increase if insulin sensitivity is impaired (i.e. during insulin resistance induced by obesity, pregnancy, oral contraceptives, dehydration, saturated fatty acids, fever, drugs, etc.). In contrast to secondary insulin resistance idiopathic insulin resistance in type 2 diabetic individuals is associated with impaired insulin secretion, which thus is unable to overcome impaired insulin sensitivity. Idiopathic insulin resistance in type 2 diabetes is additionally characterized by reduced glucose storage, the basis of which may reside in an insulin receptor defect, in the presence of insulin receptor antibodies, in a postreceptor defect or in the synthesis of abnormal insulin molecules. PMID: 1290322 [PubMed - indexed for MEDLINE] 6471. J Cardiovasc Pharmacol. 1992;20 Suppl 8:S26-8. Abdominal fat distribution and the metabolic syndrome. Björntorp P(1). Author information: (1)Department of Medicine, University of Göteborg, Sahlgren's Hospital, Sweden. Recent studies have indicated that the waist/hip circumference ratio (WHR), an index of abdominal fat distribution, is a risk factor for cardiovascular disease and diabetes, in parallel with other previously established risk factors. Obesity, without taking fat distribution into account, seems to be associated with WHR in its relationship to the metabolic risk factors for these diseases. The important component of the WHR is probably the mass of visceral fat. This cluster of phenomena constitute what has recently been called the metabolic syndrome or syndrome X. Visceral fat mass is probably increased by a multiple endocrine aberration, where steroid hormones are important. This seems to cause insulin resistance by direct effects on the periphery, which may be amplified by the metabolism of the enlarged visceral adipose tissues. PMID: 1283766 [PubMed - indexed for MEDLINE] 6472. J Cardiovasc Pharmacol. 1992;20 Suppl 8:S22-5. Lipoproteins, lipases, and the metabolic cardiovascular syndrome. Blomhoff JP(1). Author information: (1)Medical Department A, National Hospital, Oslo, Norway. High levels of plasma triglycerides and very-low-density lipoproteins and low levels of high-density lipoproteins are consistently found in the metabolic cardiovascular syndrome. These changes are exaggerated postprandially. In the liver, synthesis and secretion of triglyceride-rich particles are increased. In addition, the removal capacity of plasma triglycerides is decreased, due to downregulation of lipoprotein lipase in skeletal muscles by hyperinsulinemia. Resistance to insulin-stimulated glucose uptake is believed to be the main pathogenetic factor. However, increased flux of free fatty acids from abdominally localized adipose tissue must also be considered when discussing pathogenesis. Treatment is primarily nonpharmacological, with diet and increased physical activity. PMID: 1283765 [PubMed - indexed for MEDLINE] 6473. FEBS Lett. 1991 Dec 9;294(3):158-62. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. Skulachev VP(1). Author information: (1)Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, USSR. Free fatty acids, natural uncouplers of oxidative phosphorylation, are shown to differ from artificial ones in that they fail to increase conductance of phospholipid bilayers which are permeable for the protonated form of fatty acids but impermeable for their anionic form. Recent studies have revealed that uncoupling by fatty acids in mitochondria is mediated by the ATP/ADP antiporter and, in brown fat, by thermogenin which is structurally very similar to the antiporter. It is suggested that both the ATP/ADP antiporter and thermogenin facilitate translocation of the fatty anions through the mitochondrial membrane. PMID: 1756853 [PubMed - indexed for MEDLINE] 6474. Proc Nutr Soc. 1991 Dec;50(3):605-18. Interrelationships between obesity and diabetes. Herberg L(1). Author information: (1)Diabetes Research Institute, Heinrich-Heine-University of Düsseldorf, Germany. PMID: 1809969 [PubMed - indexed for MEDLINE] 6475. Diabetes Care. 1991 Dec;14(12):1132-43. Metabolic implications of body fat distribution. Björntorp P(1). Author information: (1)Department of Medicine I, University of Göteborg, Sahlgren's Hospital, Sweden. Insulin resistance is the cornerstone for the development of non-insulin-dependent diabetes mellitus (NIDDM). Free fatty acids (FFAs) cause insulin resistance in muscle and liver and increase hepatic gluconeogenesis and lipoprotein production and perhaps decrease hepatic clearance of insulin. It is suggested that the depressing effect of insulin on circulating FFA concentration is dependent on the fraction derived from visceral adipocytes, which have a low responsiveness to the antilipolytic effect of insulin. Elevated secretion of cortisol and/or testosterone induces insulin resistance in muscle. This also seems to be the case for low testosterone concentrations in men. In addition, cortisol increases hepatic gluconeogenesis. Cortisol and testosterone have "permissive" effect on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus have powerful combined effects, resulting in insulin resistance and increased hepatic gluconeogenesis. All these factors promoting insulin resistance are active in abdominal visceral obesity, which is closely associated with insulin resistance, NIDDM, and the "metabolic syndrome." In addition, the endocrine aberrations may provide a cause for visceral fat accumulation, probably due to regional differences in steroid-hormone-receptor density. In addition to the increased activity along the adrenocorticosteroid axis, there also seem to be signs of increased activity from the central sympathetic nervous system. These are the established endocrine consequences of hypothalamic arousal in the defeat and defense reactions. There is some evidence that suggests an increased prevalence of psychosocial stress factors is associated with visceral distribution of body fat. Therefore, it is hypothesized that such factors might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease. PMID: 1773700 [PubMed - indexed for MEDLINE] 6476. Pharmacol Toxicol. 1991 Dec;69(6):410-5. The use of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) as an unmetabolizable lipophilic model compound. Mühlebach S(1), Wyss PA, Bickel MH. Author information: (1)Department of Pharmacology, Berne, Switzerland. 2,4,5,2',4'5'-Hexachlorobiphenyl (6-CB)--a polychlorinated biphenyl (PCB) congener resistant to metabolism in most species--has become a major residue in the biosphere including human adipose tissue. Its use as a model of unmetabolizable lipophilic compounds and as a tool in toxicokinetics in the last two decades is reviewed. This extremely water-insoluble compound is transported in plasma by albumin and lipoproteins. Binding to these plasma proteins appears to be important for uptake and release processes in different tissues. The redistribution kinetics of 6-CB as well as its pronounced adipose tissue storage and a very slow excretion with the faeces has been established in long-term animal studies. Excretion is strongly influenced by an increasing or diminishing adipose storage compartment size. Other minor pathways of elimination, e.g., via hair, become also important in the absence of metabolism and renal excretion. 6-CB has revealed the possibility of an almost quantitative transfer of the maternal body burden to the offspring via milk. The use of 6-CB in studies with tissue preparations in vitro is providing insight into transport mechanisms of uptake and release. PMID: 1766915 [PubMed - indexed for MEDLINE] 6477. Baillieres Clin Endocrinol Metab. 1991 Dec;5(4):671-87. Growth and differentiation. Lindahl A, Isgaard J, Isaksson O. PMID: 1755811 [PubMed - indexed for MEDLINE] 6478. Diabetes. 1991 Dec;40 Suppl 2:83-8. Intermediary metabolism in pregnancy. First theme of the Freinkel era. Herrera E(1), Lasunción MA, Palacín M, Zorzano A, Bonet B. Author information: (1)Department of Research, Hospital Ramón y Cajal, Madrid, Spain. During the first half of gestation in the rat, maternal net body weight increases rapidly, whereas in the second half of gestation, the mass of maternal structures declines, coincident with the rate of maternal fat accumulation. Enhanced maternal food intake, extrahepatic tissue lipoprotein lipase (LPL) activity, and adipose tissue lipogenesis are responsible for the progressive accumulation of maternal fat. However, during late gestation, decreased fat synthesis in maternal adipose tissue, enhanced lipolytic activity, and decreased LPL activity deplete maternal fat depots. These changes, plus enhanced endogenous production of triglyceride-rich lipoproteins, are also responsible for maternal hypertriglyceridemia. This condition benefits the offspring in two ways: 1) enhanced LPL activity in maternal liver when fasting increases triglyceride consumption for ketone body synthesis, giving the basis for accelerated starvation; and 2) induction of LPL activity in the mammary gland before parturition diverts maternal circulating triglycerides to milk synthesis in preparation for lactation. The magnitude of the maternal-fetal glucose transfer was higher than that of any of the other substrates studied, including alanine, and despite actions to spare glucose, this transfer causes maternal hypoglycemia, which is especially intense in the fasting condition. This increases sympathoadrenal activity in the mother, which may contribute to her active gluconeogenesis. Glycerol was a more efficient glucose precursor than alanine and pyruvate, and whereas glycerol placental transfer is very small, it is proposed that the fetus benefits from this product of adipose tissue lipolysis when it is previously converted into glucose.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1748273 [PubMed - indexed for MEDLINE] 6479. Diabetes. 1991 Dec;40 Suppl 2:18-24. Insulin secretion and insulin resistance in pregnancy and GDM. Implications for diagnosis and management. Kühl C(1). Author information: (1)Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen, Denmark. Glucose tolerance deteriorates in human pregnancy, but approximately 97-98% of all pregnant women retain a normal glucose tolerance, and only 2-3% develop gestational diabetes mellitus (GDM). Both nondiabetic pregnant women and women with GDM exhibit much higher insulin responses to oral or intravenous administration of glucose or amino acids than found in the nonpregnant state, and the insulin responses to a protein-rich meal are also significantly enhanced in pregnancy. Both quantitative and qualitative differences in insulin secretion exist between pregnant women with normal glucose tolerance (NGT) and women with GDM. Insulin responses to oral glucose and protein-rich meals are thus lower in pregnant women with GDM than in women with NGT, despite significantly higher mean plasma glucose concentrations in the women with GDM. Furthermore, peak plasma insulin concentrations occur later in women with GDM than in pregnant control subjects. Finally, a reduced first-phase insulin response to intravenous glucose can be observed in some women with GDM. Impairment of glucose tolerance in pregnancy is not related to a disproportional secretion of proinsulin nor is increased insulin degradation involved. These observations point to pregnancy as a state of peripheral insulin resistance. Because insulin-receptor binding is only slightly changed in pregnancy and not significantly different in pregnant women with NGT and women with GDM, it follows that the insulin resistance is located at the postreceptor level. Insulin-clamp and "minimal model" studies have shown that the whole-body insulin sensitivity is similarly reduced by about two-thirds of nonpregnant values in pregnant women with NGT and women with GDM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1748255 [PubMed - indexed for MEDLINE] 6480. Diabetes. 1991 Dec;40 Suppl 2:175-8. Exercise in the treatment of NIDDM. Applications for GDM? Horton ES(1). Author information: (1)Department of Medicine, University of Vermont College of Medicine, Burlington. Physical training is associated with lower plasma insulin concentrations and increased sensitivity to insulin in skeletal muscle and adipose tissue of individuals with non-insulin-dependent diabetes mellitus (NIDDM). The benefits of exercise to individuals with NIDDM in terms of increased insulin sensitivity could be applied to reversing the insulin resistance associated with gestational diabetes mellitus (GDM). Exercise may also benefit women with GDM by acting as an adjunct to diet in preventing excessive weight gain and preventing or decreasing the severity of hypertension and/or hyperlipidemia during pregnancy. Regular physical exercise should be considered as a potential approach to the prevention and treatment of GDM. PMID: 1748253 [PubMed - indexed for MEDLINE] 6481. FASEB J. 1991 Dec;5(15):3031-6. New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids. Marshall S(1), Garvey WT, Traxinger RR. Author information: (1)Department of Biochemistry, University of Tennessee School of Medicine, Memphis 38164. In primary cultured adipocytes, metabolic substrates such as glucose and amino acids have profound effects on modulating insulin's stimulatory actions on glucose uptake and protein synthesis. Insights into how substrates modulate insulin action were recently obtained when we discovered that the routing of incoming glucose through the hexosamine biosynthesis pathway leads to a refractory state over a period of several hours in which the ability of insulin to stimulate glucose uptake is severely impaired--a state known as insulin resistance. Glutamine:fructose-6-phosphate amidotransferase was found to play a central role in the development of insulin resistance as this enzyme catalyzes the first and rate-limiting step in the formation of hexosamine products. Collectively, these results are consistent with the idea that the hexosamine biosynthesis pathway serves as a glucose sensor coupled to a negative feedback system that can limit the extent of glucose uptake in response to hyperglycemic and hyperinsulinemic conditions. PMID: 1743436 [PubMed - indexed for MEDLINE] 6482. Can J Physiol Pharmacol. 1991 Nov;69(11):1637-47. The 1990 Borden Award Lecture. Dietary regulation of fatty acid and triglyceride metabolism. Herzberg GR(1). Author information: (1)Department of Biochemistry, Memorial University, St. John's, Nfld., Canada. The level of circulating triacylglycerols is determined by the balance between their delivery into the plasma and their removal from it. Plasma triacylglycerols are derived either from dietary fat as chylomicrons or from endogenous hepatic synthesis as very low density lipoproteins. Their removal occurs through the action of lipoprotein lipase after which the fatty acids are either stored in adipose tissue or oxidized, primarily in skeletal muscle and heart. The composition of the diet has been shown to influence many of these processes. Hepatic fatty acid synthesis and triacylglycerol secretion are affected by the quantity and composition of dietary fat, carbohydrate, and protein. Polyunsaturated but not saturated fats reduce hepatic fatty acid synthesis by decreasing the amount of the lipogenic enzymes needed for de novo fatty acid synthesis. Dietary fish oils are particularly effective at reducing both fatty acid synthesis and triacylglycerol secretion and as a result are hypotriacylglycerolemic, particularly in hypertriacylglycerolemic individuals. In addition, dietary fish oils can increase the oxidation of fatty acids and lead to increased activity of lipoprotein lipase in skeletal muscle and heart. It appears that the hypotriacylglycerolemic effect of dietary fish oils is mediated by effects on both synthesis and removal of circulating triacylglycerols. PMID: 1804510 [PubMed - indexed for MEDLINE] 6483. Z Gesamte Inn Med. 1991 Nov;46(16):595-601. [Recent knowledge of the function of glucose transport molecules in cell membranes, of the regulation of their composition and of modification of their activity and changes in concentration in diseases (diabetes mellitus, Tumors)]. [Article in German] Kolb E(1). Author information: (1)Veterinär-Physiologisch-Chemisches Institut, Universität Leipzig. In the outer membrane of animal cells there exist different isoforms of glucose-transporters (GluT), that contain pores for the facilitative intake of glucose. The content of the various forms of GluT in the different cells is influenced by the stage of development and by the plasma-concentration of glucose. In the regulation of the glucose-concentration in the plasma the content of the skeletal musculature and of the adipose tissue in GluT type 4 plays an important role: It is insulin-dependent. In diabetes mellitus the content of the outer membranes of the cells of the mentioned tissues in GluT 4 is - in dependence of the degree of the disturbance - more or less reduced. The binding of insulin to the receptor in the musculature and in adipose tissue stimulates the transport of GluT 4 from the interior of the cells to the outer membrane. Fasting causes an increase in the content of GluT 4 in the musculature and a decrease in the adipose tissue. Tumor-cells have an increased uptake of glucose with the help of GluT. PMID: 1792800 [PubMed - indexed for MEDLINE] 6484. JPEN J Parenter Enteral Nutr. 1991 Nov-Dec;15(6):680-3. Abnormal substrate metabolism and nutritional strategies in cancer management. Rossi-Fanelli F(1), Cascino A, Muscaritoli M. Author information: (1)III Department of Internal Medicine, University La Sapienza, Rome, Italy. Impairment of the nutritional state plays a major role in the morbidity and mortality of cancer patients. However, the opportunity of providing artificial nutritional support to these patients is still debated, because of the concern that energy substrates administered to replete the host may concomitantly stimulate tumor growth. A correct nutritional approach to cancer patients should thus be based on a thorough knowledge of both host and tumor metabolic needs and host-tumor metabolic interactions. Specific modifications of plasma levels of glucogenic, aromatic, sulfur-containing and branched-chain amino acids have been demonstrated in cancer patients, indicating a specific influence of the tumor on amino acid metabolism. Little is known about protein metabolism in neoplastic tissue. Interference with tumor growth has been attempted by deprivation of single amino acids with controversial results. Increased gluconeogenesis and insulin resistance are responsible for the two main abnormalities in carbohydrate metabolism in cancer patients, namely increased glucose turnover and impaired glucose tissue disposal. Lipid metabolism is also affected by the neoplasm: soluble factors such as "lipid-mobilizing factor" lead to increased fat mobilization from adipose tissue; plasma elimination of exogenous triglycerides has also been found to be reduced probably because of a tumor-related decrease in lipoprotein lipase activity. The differences in glucose and fat utilization between tumor and host should be considered in the nutritional approach to cancer patients. Data in this respect are controversial and have been obtained only in experimental animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1766060 [PubMed - indexed for MEDLINE] 6485. J Dairy Sci. 1991 Nov;74(11):4013-21. Acetyl-coenzyme A carboxylase messenger ribonucleic acid metabolism in liver, adipose tissues, and mammary glands during pregnancy and lactation. Ponce-Castañeda MV(1), López-Casillas F, Kim KH. Author information: (1)Department of Biochemistry, Purdue University, West Lafayette, IN 47907. In the rat, the acetyl-coenzyme A carboxylase gene exists as a single copy per haploid chromosome set. However, multiple forms of acetyl-coenzyme A carboxylase mRNA exist, the relative abundance of which varies in a tissue-specific manner under different physiological conditions. In the mammary gland, the major acetyl-coenzyme A carboxylase mRNA species are of the class 2 type, which are products of promoter II. In parametrial white adipose tissue, the main form of species of acetyl-coenzyme A carboxylase is of the class 1 type, which are produced by promoter I. Pregnancy and lactation affect the amounts of these acetyl-coenzyme A carboxylase mRNA. Although the mammary gland acetyl-coenzyme A carboxylase mRNA species increase dramatically upon parturition, the parametrial white adipose tissue forms decrease precipitously at the same time and are not expressed at all during the lactation period. In the liver of these animals, the only form of acetyl-coenzyme A carboxylase mRNA that is expressed is the FL56 form; this form shows a modest decrease during pregnancy that is slowly reversed during lactation. These observations indicate that the changes in lipogenesis that occur during pregnancy and lactation are determined by the transcriptional activity of the acetyl-coenzyme A carboxylase gene. In order to analyze the complex transcriptional activity of this gene in a meaningful way, it is necessary to examine the metabolism of individual isoforms of acetyl-coenzyme A carboxylase mRNA. PMID: 1684590 [PubMed - indexed for MEDLINE] 6486. Diabetes. 1991 Oct;40(10):1223-7. Insulin, prostaglandins, and the pathogenesis of hypertension. Axelrod L(1). Author information: (1)Diabetes Unit, Massachusetts General Hospital, Boston 02114. Hypertension is associated with hyperinsulinemia in the presence or absence of obesity or glucose intolerance. Physiological concentrations of insulin decrease the catecholamine-induced production of prostaglandin I2 (PGI2; prostacyclin) and PGE2, two potent vasodilators, in adipose tissue, one of the largest organs in the body. This finding suggests that hyperinsulinemia increases peripheral vascular resistance and blood pressure by inhibiting the stimulatory effect of adrenergic agonists (and perhaps other agonists) on the production of PGI2 and PGE2 in adipose tissue (and perhaps other tissues). This concept is supported by evidence that PGI2 and PGE2 modulate vascular reactivity in states of health and disease. For example, during insulin deficiency, i.e., in diabetic ketoacidosis, PGI2 and PGE2 production by adipose tissue are increased, and peripheral vascular resistance and blood pressure are decreased. This hypothesis is also supported by evidence that blood flow through rat and human adipose tissue is decreased in obesity and that insulin decreases the blood flow through adipose tissue in nonobese rats. Thus, insulin may regulate PGI2 and PGE2 production by adipose tissue (and possibly other tissues) through a wide range of concentrations with important physiological and clinical consequences. PMID: 1936584 [PubMed - indexed for MEDLINE] 6487. Proc Soc Exp Biol Med. 1991 Oct;198(1):528-38. Genetic obesity: is the defect in the sympathetic nervous system? A review through developmental studies in the preobese Zucker rat. Krief S(1), Bazin R. Author information: (1)INSERM Unité 177, Paris, France. PMID: 1679946 [PubMed - indexed for MEDLINE] 6488. Biochim Biophys Acta. 1991 Sep 24;1094(3):292-9. The actions of cyclic AMP on biosynthetic processes are mediated indirectly by cyclic AMP-dependent protein kinase. Cohen P(1), Hardie DG. Author information: (1)Department of Biochemistry, University of Dundee, U.K. Adrenalin and glucagon inhibit glycogen, fatty acid and cholesterol synthesis by elevation of cyclic AMP, activation of cyclic AMP-dependent protein kinase and increased phosphorylation of the rate-limiting enzymes of these pathways. Here, we review recent evidence which indicates that inhibition of these biosynthetic pathways in muscle, adipose tissue and liver is much more indirect than has previously been supposed. In particular, cyclic AMP-dependent protein kinase does not appear to inhibit glycogen synthase, acetyl-CoA carboxylase and HMG-CoA reductase by phosphorylating them directly. It appears to achieve the same end result by inactivation of the protein phosphatases which dephosphorylate these regulatory enzymes in vivo, although this has only been established definitively in the case of glycogen synthesis. PMID: 1655040 [PubMed - indexed for MEDLINE] 6489. N Engl J Med. 1991 Sep 5;325(10):695-702. Catabolic illness. Strategies for enhancing recovery. Wilmore DW(1). Author information: (1)Department of Surgery, Harvard Medical School, Boston, MA. After injury, infection, extensive chemotherapy, and other critical illnesses, both protein and fat are lost from the body. Although minor alterations in body composition are probably of little clinical importance, losses of body protein of 10 percent or more contribute to morbidity and debility. This catabolic response can be modified and recovery can be accelerated by a variety of approaches. First, the inflammatory response can be reduced; second, specific nutrients can be provided to support the patient's tissue requirements during catabolic illness; and third, growth factors can be used to enhance protein synthesis and tissue repair. These approaches, whether used alone or in combination, will reduce the loss of body protein, which should accelerate recovery, shorten the length of hospitalization, and reduce convalescence. PMID: 1908058 [PubMed - indexed for MEDLINE] 6490. Med Anthropol. 1991 Sep;13(3):215-29. Body composition and longevity: is there a longevous morphotype? Stini WA(1). Author information: (1)Department of Anthropology, University of Arizona, Tucson 85721. Life expectancies are increasing in populations throughout the world. As infectious diseases decline as causes of mortality, certain degenerative diseases including cardiovascular disease and cancer account for an increasing percentage of deaths. As more people survive into old age, the intrinsic limits on the human life span will be reached. It is clear that genetic factors have a strong influence on the life span. It is not clear, however, that there are identifiable longevous body types (morphotypes). For the first time in human history, large numbers of people 80 years old and older are available for study. If there is an association between body form and composition and superior longevity, it should be possible to identify its major aspects. Monitoring changes in body composition throughout the life cycle and the retention of reserves to be drawn upon when disease or trauma threaten life may provide the basis for prediction of the course of life threatening diseases. The unusually high survival of morphotypes classifiable as "moderately obese" casts doubt on standards recommending "ideal weights for height" if the criterion in question is survival. PMID: 1961103 [PubMed - indexed for MEDLINE] 6491. Brain Res Bull. 1991 Sep-Oct;27(3-4):487-91. Transport of fatty acids and monoacylglycerols in white and brown adipose tissues. Scow RO(1), Blanchette-Mackie EJ. Author information: (1)Endocrinology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892. Long chain fatty acids (FA) and 2-monoacylglycerols (MG) are produced by lipoprotein lipase (LPL) from plasma triacylglycerols (TG) in capillaries of adipose tissue and transported to adipocytes for TG synthesis. It is widely proposed FA may be transported in cells by FA-binding protein. Mode of transport of MG has received little attention. Our findings in tissues and model membranes indicate that FA (as 1:1 acid-soaps) and MG can be transported in vivo by lateral movement in an interfacial continuum (IFC) of the outer leaflets of plasma and intracellular membranes of capillary endothelium and adipocytes. We postulate that FA and MG enter the IFC in capillaries and flow in the IFC across endothelium and extracellular space to sites in adipocytes where MG are hydrolyzed by MG-lipase (MGL) to FA and glycerol, and FA are esterified in endoplasmic reticulum or transferred to inner mitochondrial membrane for oxidation. FA and MG produced by hormone-sensitive lipase also enter the IFC. These MG flow in the IFC to sites of MGL activity, and the FA flow in the IFC to capillaries for transport to other tissues by albumin, or to mitochondria for heat production. PMID: 1959050 [PubMed - indexed for MEDLINE] 6492. J Anim Sci. 1991 Sep;69(9):3838-52. Effects of dietary fat on metabolic disorders and reproductive performance of dairy cattle. Grummer RR(1), Carroll DJ. Author information: (1)Dept. of Dairy Sci. University of Wisconsin, Madison 53706. Improved reproductive performance and reduced incidence of metabolic disorders have been postulated to be benefits of feeding supplemental fat to dairy cows. Increased plasma nonesterified fatty acid concentrations during fat supplementation may result from incomplete tissue uptake of fatty acids after lipoprotein lipase hydrolysis of very-low-density lipoprotein triglyceride; however, evidence suggests that net adipose tissue triglyceride hydrolysis may be increased during fat supplementation. Plasma 3-OH-butyrate concentrations remain relatively constant during fat supplementation but may have a tendency to be reduced if fat is supplemented to cows having relatively high basal plasma 3-OH-butyrate concentrations. Because plasma ketone levels usually increase when nonesterified fatty acid concentrations are elevated, it is hypothesized that potential antiketogenic effects of added fat are due to a glucose sparing effect. Supplemental fat does not seem to reduce hepatic lipid infiltration near the time of calving. Potential mechanisms by which supplemental fat may improve reproductive performance include stimulation of prostaglandin F2 a synthesis and secretion and enhanced utilization of blood cholesterol for progesterone synthesis. Days postpartum until first ovulation and luteal function of dairy cattle have been related to energy balance during the first 3 wk postpartum. Energy balance data for early lactation cows fed supplemental fat are not plentiful; however, slight but statistically nonsignificant increases have been observed when feeding fat. Cows fed supplemental fat that experience improved energy balance may begin to cycle sooner because of enhanced follicular growth and development. Applied studies examining the effects of supplemental fat on reproductive performance have provided inconsistent results. PMID: 1938663 [PubMed - indexed for MEDLINE] 6493. J Intern Med. 1991 Sep;230(3):195-201. Visceral fat accumulation: the missing link between psychosocial factors and cardiovascular disease? Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgren's Hospital, University of Göteborg, Sweden. Neuroendocrine responses to psychosocial pressures have been well characterized. The defence reaction is followed by increased activity of the sympathetic nervous system. Essential hypertension might be induced by such mechanisms. The defeat reaction is characterized by increased activity along the corticotropin releasing factor-adrenocorticotropin hormone-cortisol axis, resulting in the inhibition of gonadotropin secretion. Such endocrine disturbances are followed by metabolic aberrations, and probably also by the accumulation of visceral fat. Subjects with abdominal fat accumulation (high waist/hip circumference ratio, WHR) have recently been found to exhibit a number of psychosocial handicaps, together with endocrine aberrations characteristic of the defence and, in particular, the defeat reaction, as well as the associated circulatory and metabolic aberrations. Such abnormalities, including the WHR itself, are established risk factors for cardiovascular disease and diabetes. It is postulated that increased WHR is a symptom of chronic hypothalamic arousal as a result of a defeat reaction to psychosocial pressures. This might lead to the development of disease via circulatory and metabolic derangements. PMID: 1895041 [PubMed - indexed for MEDLINE] 6494. J Nutr. 1991 Sep;121(9):1486-97. Adipose cellularity in Gallus domesticus: investigations to control body composition in growing chickens. Cartwright AL(1). Author information: (1)United States Department of Agriculture, Agricultural Research Service, Georgetown, DE 19947. The domestic chicken, Gallus domesticus, is recognized as an efficient source of lean meat. Genetic selection has resulted in large body size strains that grow rapidly. Concomitant with development of these desirable characteristics is increased abdominal fat deposition and altered body composition. Adipose cellular development in different genetic groups shows that abdominal adipocyte cell number as a proportion of body mass decreases as body size increases, concurrent with increased adiposity. Adipocyte hypertrophy explains a large proportion of the variation in abdominal fat percentage. Growth hormone is correlated with the number and size of abdominal adipocytes across genotype, sex and age. Adipose tissue development and body composition are affected by hormone levels in growing chickens. Possible approaches to modulate fat deposition and adipose cellularity in poultry are reviewed. PMID: 1880626 [PubMed - indexed for MEDLINE] 6495. Magnes Res. 1991 Sep-Dec;4(3-4):137-52. Magnesium and thermoregulation. I. Newborn and infant. Is sudden infant death syndrome a magnesium-dependent disease of the transition from chemical to physical thermoregulation? Durlach J(1), Durlach V, Rayssiguier Y, Ricquier D, Goubern M, Bertin R, Bara M, Guiet-Bara A, Olive G, Mettey R. Author information: (1)SDRM, Hôpital St. Vincent-de-Paul, Paris, France. The sudden infant death syndrome (SIDS) remains a leading cause of death during the first year. The common epidemiological and pathological data which characterize SIDS include the curve for age at death (with 3 months as modal age), the stigmata of early maternal intrauterine injury, the seasonal predominance in winter, and the absence of an adequate cause of death at autopsy. Some data characterize risk factor subgroups: for example low socioeconomic level, environmental pollution, stress, and mistakes in baby care. Symptoms before death may be lacking, they may be common and non-specific, or rarely they may be acute, corresponding to "apparent life-threatening events" (ALTE). SIDS may be a magnesium-dependent disease of the transition from chemical to physical thermoregulation. This theory originates from a synthesis of our present knowledge of SIDS, maternal magnesium status, and thermoregulation in the baby. It is consistent with all the epidemiological and pathological prerequisites characterizing SIDS. It eliminates the hiatus between relatively minor thermal stress and induced lethal thermal stroke. Logical scepticism about the role of an implausible lethal superacute magnesium deficiency is no longer justified with regard to well established chronic marginal magnesium deficiency. Further experimental and clinical research will be interesting, i.e. ex vivo studies on brown adipose tissue (BAT) and magnesium deficiency under various conditions of thermal exposure. But even now the theory leads to three therapeutic consequences: (1) the need to define the importance of magnesium deficiency in diagnosis and treatment of ALTE; (2) an assessment of the use of new techniques of rewarming (i.e. extracorporeal circulation) in hypothermia cases to distinguish cot death from "apparent death"; (3) investigation of the prevention of SIDS with magnesium through a blinded and randomized multicentre prospective cooperative study of magnesium supplementation in pregnant and lactating women, followed not only in the mother, fetus, and neonate at birth, but also through the first year of life. PMID: 1799550 [PubMed - indexed for MEDLINE] 6496. Int J Obes. 1991 Sep;15 Suppl 2:91-9. Expression of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in adipose tissue. Labrie F(1), Simard J, Luu-The V, Trudel C, Martel C, Labrie C, Zhao HF, Rhéaume E, Couet J, Breton N. Author information: (1)MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada. PMID: 1794945 [PubMed - indexed for MEDLINE] 6497. Int J Obes. 1991 Sep;15 Suppl 2:9-18. The genes in the constellation of determinants of regional fat distribution. Bouchard C(1), Després JP, Mauriège P, Marcotte M, Chagnon M, Dionne FT, Bélanger A. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. PMID: 1794944 [PubMed - indexed for MEDLINE] 6498. Int J Obes. 1991 Sep;15 Suppl 2:87-90. Growth and differentiation of regional adipose tissue: molecular and hormonal mechanisms. Ailhaud G(1), Amri E, Bardon S, Barcellini-Couget S, Bertrand B, Catalioto RM, Dani C, Doglio A, Forest C, Gaillard D, et al. Author information: (1)Centre de Biochimie du CNRS, Université de Nice-Sophia Antipolis, France. PMID: 1794943 [PubMed - indexed for MEDLINE] 6499. Int J Obes. 1991 Sep;15 Suppl 2:83-6. Neuroregulation of adipose tissue: molecular and hormonal mechanisms. Rebuffé-Scrive M(1). Author information: (1)Department of Psychology, Yale University, New Haven, CT. PMID: 1794942 [PubMed - indexed for MEDLINE] 6500. Int J Obes. 1991 Sep;15 Suppl 2:45-52. Lipoprotein metabolism in visceral obesity. Després JP(1). Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. PMID: 1794938 [PubMed - indexed for MEDLINE] 6501. Int J Obes. 1991 Sep;15 Suppl 2:31-5. Environmental influences on regional fat distribution. Seidell JC(1). Author information: (1)Department of Human Nutrition, Wageningen University, The Netherlands. PMID: 1794935 [PubMed - indexed for MEDLINE] 6502. Int J Obes. 1991 Sep;15 Suppl 2:127-32. Facilitative glucose transport proteins: structure and regulation of expression in adipose tissue. Bell GI(1), Fukumoto H, Burant CF, Seino S, Sivitz WI, Pessin JE. Author information: (1)Howard Hughes Medical Institute, University of Chicago, Illinois 606037. PMID: 1794933 [PubMed - indexed for MEDLINE] 6503. Int J Obes. 1991 Sep;15 Suppl 2:109-15. Insulin resistance in visceral obesity. Kissebah AH(1). Author information: (1)Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee 53226. PMID: 1794931 [PubMed - indexed for MEDLINE] 6504. Int J Obes. 1991 Sep;15 Suppl 2:101-8. Sex hormone metabolism in upper and lower body obesity. Kirschner MA(1), Samojlik E. Author information: (1)Newark Beth Israel Medical Center/University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark. Morbid obesity has been previously shown to be associated with excessive production and metabolism of a variety of androgens and estrogens. Further, SHBG is lowered, resulting in high levels of 'free' testosterone. We have re-examined these parameters in morbidly obese women with upper vs lower body adipose distribution. Upper body obesity was associated with greater increases in production and clearance of testosterone and dihydrotestosterone compared to lower body obesity. Further, SHBG levels were lower resulting in high serum levels of free T and free E2 in this obesity phenotype. By contrast, lower body obesity was associated with increased peripheral aromatization of androstenedione resulting in higher urinary E1 production rates. The biologic significance of these hormonal differences in obesity phenotypes as well as the potential role of the androgen-estrogen environment in determining body fat distribution is considered. PMID: 1794930 [PubMed - indexed for MEDLINE] 6505. Monatsschr Kinderheilkd. 1991 Aug;139(8):442-9. [Exposure of our children to pesticides, PCB and potentially critical anions]. [Article in German] Teufel M(1), Böhn I, Niessen KH. Author information: (1)Universitäts-Kinderklinik Mannheim. Among environmental pollutants the organohalogens still play an important role since they accumulate in human fat tissue and are secreted with mother's milk during lactation. Fortunately DDT-, HCH- and HCB-levels decreased in breast milk during the last years. In contrast, the PCB concentrations were still three-to five-fold above the permitted limits for cow's milk. Fat tissue of 262 newborns, infants and children was already as severely loaded with organohalogens as human milk. However, children with malignant tumors or congenital malformations did not show elevated concentrations in fat tissue. The significance of the potentially critical anions such as nitrate, nitrite, bromide, sulfate for the health of our children needs further clarification. PMID: 1961213 [PubMed - indexed for MEDLINE] 6506. Regul Toxicol Pharmacol. 1991 Aug;14(1):59-77. Application of biological data in cancer risk estimations of chlordane and heptachlor. Adeshina F(1), Todd EL. Author information: (1)Graduate Program in Environmental Sciences, University of Texas at Dallas, Richardson 75080. Regulatory agencies traditionally use doses associated with ambient concentrations of contaminants in environmental media to estimate lifetime excess cancer risks. This approach is, however, limited by the errors inherent in making several default assumptions such as daily water and food intakes and organ absorption factors. A methodology was developed in this study to estimate daily human doses of chlordane and heptachlor from measured metabolites in adipose tissue. Human biomonitoring data, pharmacodynamic and pharmacokinetic parameters in humans and animals, and selected dose-response data from animal carcinogenicity studies were utilized in this procedure for cancer risk assessment in man. Conversion factors, based on body surface area, were used for animal-to-man extrapolation. Conservative estimates from the Global 82 linearized multistage mathematical model (95% upper confidence limit) associate a 1 x 10(-5) risk probability level to chlordane and heptachlor doses of 1.1 x 10(-4) and 4.0 x 10(-5) mg/kg-day, respectively, via all potential routes of exposure. The unit cancer risks associated with "internal" dose estimates from human adipose tissue concentrations were calculated and compared with U.S. Environmental Protection Agency (1986a, Carcinogenicity Assessment of Chlordane and Heptachlor/Heptachlor Epoxide, EPA-600/6-87-004) unit risks in air and water. The implications and uncertainties associated with the risk estimates were also discussed. PMID: 1947246 [PubMed - indexed for MEDLINE] 6507. Bol Asoc Med P R. 1991 Aug;83(8):354-6. Genetic influences on body composition and regional fat distribution. Bouchard C(1). Author information: (1)Laval University Physical Activity Sciences Laboratory, PEPS Sainte-Foy, Quebec, Canada. It is clear that some people are more at risk of becoming overweight or Type I, II, III or IV obese because of the fact that they store ore mobilize fat more readily than others under identical energy intake, dietary composition and level of physical activity conditions. Much work is needed to elucidate the relative importance of genetic versus nongenetic determinants of overweight and obesity. PMID: 1816790 [PubMed - indexed for MEDLINE] 6508. Curr Opin Cell Biol. 1991 Aug;3(4):702-9. Uniporters and anion antiporters. Hebert DN(1), Carruthers A. Author information: (1)Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Centre, Worcester 01605. The past year has seen a flurry of activity in the area of protein-mediated hexose uniport. Topics of interest covered here include: structure-function studies; the interaction of glucose carriers with glycolytic enzymes; regulation of cell surface glucose-carrier concentrations by insulin and the signalling mechanisms involved; and the role of the glucose-carrier isoform, GLUT2, in pancreatic beta-cell glucose-dependent insulin secretion. Nucleoside uniport and Glu-Asp antiport are also discussed briefly. PMID: 1663376 [PubMed - indexed for MEDLINE] 6509. Nutr Rev. 1991 Jul;49(7):209-10. Postprandial thermogenesis in lactating women. [No authors listed] Postprandial but not basal metabolic rate rises during lactation. The increase shows a positive correlation with nitrogen concentration in milk. PMID: 1945066 [PubMed - indexed for MEDLINE] 6510. Nutrition. 1991 Jul-Aug;7(4):292-4. Obesity: determinants and therapeutic initiatives. Pi-Sunyer FX(1). Author information: (1)St. Luke's/Roosevelt Hospital, Columbia University, New York, New York. Comment in Nutrition. 1992 May-Jun;8(3):198. There are several possible determinants of obesity, including impaired thermogenesis and the differential utilization of fuels in different tissues. Whereas hypometabolism may initiate obesity in some people, once obese, individuals tend to manifest a higher resting metabolic rate because of their greater fat-free mass, exhibit an impaired thermic response to food, and expend more calories than lean individuals for equivalent amounts of activity. As a result, over a 24-h period, obese people generally expend more energy than lean people. A second determinant of obesity is related to fuel utilization and suggests that those predisposed to be obese may have an innate insulin resistance in muscle, leading to decreased uptake, oxidation, and storage of glucose in this tissue. As a result, the glucose is shunted to adipose tissue, where it is stored. With regard to treatment of obesity, emphasis on increased energy expenditure through the inclusion of reasonable amounts of activity is essential. However, this must always be combined with restraint in caloric intake. PMID: 1802223 [PubMed - indexed for MEDLINE] 6511. Nutrition. 1991 Jul-Aug;7(4):287-9. Cellular, metabolic, and clinical consequences of adipose mass enlargement in obesity. DiGirolamo M(1). Author information: (1)Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. When adipose tissue enlarges in obesity, as the result of an imbalance between caloric intake and caloric expenditure, many changes occur in the cellular components of the adipose mass. A combination of increased cell size and number underlies the accretion of the adipose mass, however, only a reduction in cell size is possible with weight loss. Several metabolic abnormalities accompany obesity--most important--hyperinsulinemia, hyperlipidemia, insulin resistance, and carbohydrate intolerance. Clinical consequences of obesity include hypertension, venous insufficiency, gallbladder disease, osteoarthritis, pulmonary and cardiovascular insufficiency, diabetes, and atherosclerotic cardiovascular disease, and all are dependent on the severity and duration of the obesity. Once established, obesity is difficult to correct because of the development of many adaptive mechanisms by which obesity defends itself. PMID: 1802221 [PubMed - indexed for MEDLINE] 6512. Kardiologiia. 1991 Jul;31(7):69-71. [Arteriosclerosis and the adipose tissue: the cause-effect interrelations]. [Article in Russian] Kukharenko SS, Nevokshanov OV, Aleksandrov AA. PMID: 1779524 [PubMed - indexed for MEDLINE] 6513. Gac Med Mex. 1991 Jul-Aug;127(4):359-75. [Hormones and nonendocrine tissues]. [Article in Spanish] Quibrera R(1), Wolpert E, Robles-Díaz G, Herrera-Acosta J, Sandoval-Zárate J, Malacara JM. Author information: (1)Facultad de Medicina, Universidad Autónoma de San Luis Potosí, S.L.P. PMID: 1665130 [PubMed - indexed for MEDLINE] 6514. Med Clin (Barc). 1991 Jun 29;97(5):190-6. [The postnatal development of obesity and other changes in the control of body weight]. [Article in Spanish] Alemany M(1), Remesar X. Author information: (1)Departament de Bioquímica i Fisiologia, Facultat de Biologia, Universitat de Barcelona. PMID: 1921549 [PubMed - indexed for MEDLINE] 6515. Am Fam Physician. 1991 Jun;43(6):2099-108. Obesity: types and treatments. Willard MD(1). Author information: (1)Texas Tech University Health Sciences Center, El Paso. Comment in Am Fam Physician. 1992 Jan;45(1):58, 64, 66. Causes of obesity include a low resting metabolic rate, environmental factors, family behavior patterns, a poorly developed satiety response and reactive eating due to stress or anxiety. Morbid obesity is characterized by an increased number of adipocytes and a degree of irreversibility. Overeating increases the size of adipocytes; however, once adipocytes achieve their maximal size, proliferation is induced and massive, irreversible obesity may result. A syndrome of restrained eating produced by chronic dieting leads to hunger, frustration and rebound overeating. Treatment may be unsuccessful because of the failure to address specific causes of obesity in individual patients and the use of reducing regimens that are not designed to maintain weight loss. Recognition of the diverse clinical forms of obesity and their different etiologies permits treatment regimens to be more specific, increasing the likelihood of success. Even with this approach, treatment failure is common. PMID: 2042552 [PubMed - indexed for MEDLINE] 6516. Endocr Regul. 1991 Jun;25(1-2):63-9. Lipoprotein lipase and fatty acid transport in heart, adipose tissue and mammary gland: immuno and cytochemistry. Blanchette-Mackie EJ(1). Author information: (1)Laboratory of Cellular and Developmental Biology, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892. Lipoprotein lipase acts at the luminal surface of capillaries to hydrolyze chylomicron triacylglycerol to fatty acids that are transferred across the capillary wall to tissue cells for reesterification into cellular triacylglycerol. The distribution of lipoprotein lipase in capillaries and the origin of the lipase was studies with electron microscopic immunocytochemistry in heart. Fatty acids are ampipathic molecules and can be visualized as myelin figures in sections and freeze fracture replicas of tissue. We used this cytochemical technique to study fatty acid transport between capillaries and parenchymal cells in adipose tissue perfused with chylomicrons and in adipose tissue stimulated with isoproterenol to hydrolyze intracellular triacylglycerol with. Morphological results in mammary gland indicate that incorporation of chylomicron fatty acids into milk triacylglycerol occurs via transport of fatty acids in membranes leaflets to sites of reesterification. Fatty acids would leave the membrane leaflet when they are reesterified into triacylglycerol to locate within the hydrocarbon domain of intracellular lipid droplets to be sexcreted into milk. PMID: 1958835 [PubMed - indexed for MEDLINE] 6517. Sports Med. 1991 Jun;11(6):367-81. Physiology of exercise in the cold. Doubt TJ(1). Author information: (1)Hyperbaric Environmental Adaptation Program, Naval Medical Research Institute, Bethesda, Maryland. Recreational and job requirements have increased the incidence in which humans exercise in cold environment. Understanding the physiological responses while exposed to cold entails knowledge of how exercise and cold interact on metabolic, cardiopulmonary, muscle and thermal aspects of human performance. Where possible, distinction are made between responses in cold air and cold water. While there is no consensus for diets most appropriate for working cold exposures, the evidence is strong that adequate amounts of carbohydrate are necessary. Carbohydrate loading appears to be efficacious, as it is for other athletic endeavours. Contrary to conventional wisdom, the combination of exercise and cold exposure does not act synergistically to enhance metabolism of fats. Free fatty acid (FFA) levels are not higher, and may be lower, with exercise in cold air or water when compared to corresponding warmer conditions. Glycerol, a good indicator of lipid mobilisation, is likewise reduced in the cold, suggesting impaired mobilisation from adipose tissue. Catecholamines, which promote lipolysis, are higher during exercise in cold air and water, indicating that the reduced lipid metabolism is not due to a lack of adequate hormonal stimulation. It is proposed that cold-induced vasoconstriction of peripheral adipose tissue may account, in part, for the decrease in lipid mobilisation. The respiratory exchange ratio (RER) is often similar for exercise conducted in warm and cold climates, suggesting FFA utilisation is equivalent between warm and cold exposures. The fractional portion of oxygen consumption (VO2) used for FFA combustion may decrease slightly during exercise in the cold. This decrease may be related to a relative decrease in oxygen delivery (i.e. muscle blood flow) or to impaired lipid mobilisation. Venous glucose is not substantially altered during exercise in the cold, but lactate levels are generally higher than with work in milder conditions. The time lag between production of lactate within the muscle and its release into the venous circulation may be increased by cold exposure. Minute ventilation is substantially increased upon initial exposure to cold, and a relative hyperventilation may persist throughout exercise. With prolonged exercise, though, ventilation may return to values comparable to exercise in warmer conditions. Exercise VO2 is generally higher in the cold, but the difference between warm and cold environments becomes less as workload increases. Increases in oxygen uptake may be due to persistence of shivering during exercise, to an increase in muscle tonus in the absence of overshivering, or to nonshivering thermogenesis. Heart rate is often, but not always, lower during exercise in the cold.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1925184 [PubMed - indexed for MEDLINE] 6518. Trends Biochem Sci. 1991 Jun;16(6):201-2. Adipose tissue metabolism can now be directly studied in vivo. Watford M(1), Fried SK. Author information: (1)Department of Nutritional Sciences, Cook College, Rutgers University, New Brunswick, NJ 08903. PMID: 1891799 [PubMed - indexed for MEDLINE] 6519. Rev Fr Gynecol Obstet. 1991 Jun;86(6):451-4. [Ovarian hormones and cutaneous aging]. [Article in French] de Lignières B(1). Author information: (1)Service Endocrinologie et Médecine de la Reproduction, Hôpital Necker, Paris. The fall-off in ovarian production of estradiol tends to accelerate skin ageing, just as it accelerates bone and vascular ageing. The absence of progesterone increases the impact of the androgens on the sebaceous glands, the body hair and hair on the head. The absence of estradiol slows the mitotic activity of the basal layer ot the epidermis, reduces the synthesis of collagen and probably that of elastic fibers. It contributes to the thickening of the general dermoepidermal junction and the degradation of the mechanical properties, notably of resistance of shocks. General hypoestrogenemia may be spontaneously attenuated by the local synthesis of estradiol in the adipose tissue. Estrogen treatment should be prescribed at a sufficiently high dose to be truly substitutive in order to produce a measureable effect. PMID: 1891674 [PubMed - indexed for MEDLINE] 6520. Q Rev Biol. 1991 Jun;66(2):129-47. Play and energy regulation in mammals. Barber N(1). Author information: (1)Department of Psychology, Bemidji State University, Minnesota 56601. Analysis of ecological constraints on juvenile mammals suggests that energy expended in play behavior does not reduce fitness, but actually increases it. When viewed as a promoter of adaptive energy loss, play can be considered an antipredator strategy. In addition, it may balance a low-protein diet in favor of growth, as well as increase resistance to pathogens and to cold exposure. These short-term benefits result from activation of the sympathetic nervous system (SNS), which is hypothesized to occur during play. SNS activation increases heat production in brown adipose tissue. The energy-regulation approach generates many predictions that are supported in the literature, and others that can be empirically tested. PMID: 1891590 [PubMed - indexed for MEDLINE] 6521. Biol Reprod. 1991 Jun;44(6):945-50. The energetic regulation of ovulation: a realistic role for body fat. Bronson FH(1), Manning JM. Author information: (1)Department of Zoology, University of Texas, Austin 78712. This review weighs the evidence for and against the hypothesis that ovulation is regulated by a critical amount of body fat. The evidence supporting this hypothesis is correlative, and most of it stems from observations made in humans. On balance, the evidence from human studies does not support the hypothesis, however, and the results of animal studies argue strongly against it. In the latter regard, a variety of experimental approaches have been tried in both adult and peripubertal females of several species, and the results almost uniformly show little relationship between fatness and ovulation. There is no doubt that ovulation can be regulated somehow in relation to whole-body energy balance and that fat stores are an important component of energy balance, but there is no reason to accord body fat a direct causal role in regulating ovulation. PMID: 1873394 [PubMed - indexed for MEDLINE] 6522. Dan Med Bull. 1991 Jun;38(3):252-70. Insulin receptor binding and action in human adipocytes. A critical approach to methods, correlations with receptor binding to other cell types, and relations between insulin binding and action. Hjøllund E(1). Author information: (1)Department of Endocrinology and Metabolism, Aarhus Amtssygehus. Since the beginning of the seventies, studies of the cellular mechanisms behind insulin resistance in man have included studies of insulin receptor binding and insulin action in isolated cells. In the first studies, only measurements of insulin binding to circulating blood cells (mononuclear cells and erythrocytes) were possible. In these studies it was thus necessary to anticipate that insulin binding to these cells was representative for binding to target cells for insulin (adipocytes, hepatocytes, muscle cells). Later, studies of the human adipocyte became available. In the isolated human adipocyte it was possible to measure both insulin binding and the action of insulin on glucose transport and on the intracellular glucose processing. Immediately, it was observed that receptor binding to the different cell types was not always comparable. Moreover, the relationship between fat cell insulin binding and action was not always straightforward. Because fat tissue is only responsible for a small fraction of total glucose uptake, it is not possible to know whether changes in insulin binding and action in this tissue is representative for changes in the total organism. In the present review these problems have been elucidated by studies of patients with insulin-dependent and non-insulin-dependent diabetes mellitus. In chapter one, the methods used in the clinical studies are reviewed. The precision (intraassay variability) and reproducibility (intraperson variability) has been measured for all insulin receptor assays. It was found that the earlier used assay for mononuclear cells was improved by using a pure monocyte assay, because precision as well as reproducibility was improved. On the other hand, these values were considerably poorer than those found for the other cell types. The precision was 0.09, 0.04, and 0.04 for monocytes, erythrocytes and adipocytes, respectively. The reproducibility was 0.19, 0.06 and 0.11. In order to be able to measure comparability between insulin binding to the above mentioned cell types and hepatocytes, methods for measurement of insulin binding to these cell types from swine have been developed. These studies showed that insulin binding to swine cells have many similarities to that of human cells whereas several dissimilarities were seen between insulin binding to rat and human cells. Thus, it is surmised that swine cells are more suitable than rat cells concerning insulin receptor binding and action studies.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1868754 [PubMed - indexed for MEDLINE] 6523. Dan Med Bull. 1991 Jun;38(3):228-44. Prostaglandins in adipose tissue--with special reference to triglyceride metabolism. Richelsen B(1). Author information: (1)Department of Endocrinology and Metabolism, Aarhus. PMID: 1868753 [PubMed - indexed for MEDLINE] 6524. FASEB J. 1991 Jun;5(9):2237-42. Molecular studies of the uncoupling protein. Ricquier D(1), Casteilla L, Bouillaud F. Author information: (1)Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS-UPR, Meudon, France. The uncoupling protein (UCP) is a proton/anion transporter found in the inner mitochondrial membrane of brown adipocyte. Although UCP has not been detected in mitochondria from any other tissue, it shares structural and catalytic properties with several other mitochondrial carrier proteins. Although UCP was discovered only recently it is one of the most extensively studied mitochondrial carrier proteins. Many tools useful in research on UCP have been developed such as antibodies and cDNAs corresponding to UCP of several animal species. More recently, the mouse, rat, and human genes encoding for UCP have been isolated and sequenced. The availability of these various tools has led to several significant observations. UCP gene expression is strongly controlled at the level of transcription by signals that are activated after the stimulation of brown adipocytes by norepinephrine. The comparison of UCP gene with the genes encoding the adenine nucleotide translocator revealed the existence of structural and evolutionary homologies. Moreover, in humans the UCP gene and one form of adenine nucleotide translocator gene are located on the same chromosome. Recently, the expression of functional UCP in various heterologous systems was achieved (Xenopus oocytes, CHO cells, yeasts). These data will facilitate studies of the structure/function relationship in UCP (identification of residues involved in H+ transport, Cl- transport, nucleotide binding, mitochondrial targeting...). Another aspect of the present research on UCP is the understanding of mechanisms that control the UCP gene and the differentiated commitment of adipose precursor cells to thermogenic brown adipocytes. The multifaceted aspects of research on UCP make this protein interesting in areas of research as different as studies of ion translocating mechanisms, cellular specificity of gene transcription, control of gene expression by neuromediators, adipocyte differentiation, and the pharmacological treatment of obesity. PMID: 1860614 [PubMed - indexed for MEDLINE] 6525. Rev Prat. 1991 Apr 11;41(11):963-5. [Nutritional requirements of elderly]. [Article in French] Debry G(1). Author information: (1)Université de Nancy, Centre de nutrition humaine. Nutritional requirements of the elderly (more than 70 years old) are not yet well known. The aging-associated changes of the body composition with decrease of height, bodyweight, fat free mass, increase of adipose tissue and the decrease of physical energy expenditure modify the nutritional requirements. Owing the insufficiency of our scientific knowledge the energy and protein requirements of elderly people are assumed by W.H.O. experts as 70 p. 100 of adults' ones. Water, minerals, trace elements and vitamins requirements would be similar to those of adults. The quality of meals and their hedonic properties are important factors for the preservation of appetite. PMID: 2063108 [PubMed - indexed for MEDLINE] 6526. Diabetes. 1991 Apr;40(4):413-22. Lilly lecture 1990. Molecular defects in diabetes mellitus. Bell GI(1). Author information: (1)Howard Hughes Medical Institute, University of Chicago, IL 60637. The application of molecular biology to problems in diabetes mellitus has begun to reveal the underlying molecular defects contributing to the development of hyperglycemia. Islet amyloid represents the most common pathological lesion occurring in the islets of NIDDM subjects. The use of both biochemistry and molecular biology has lead to the identification of the major protein component of human islet amyloid and elucidation of the structure of its precursor. This protein, termed islet amyloid polypeptide, is related to two neuropeptides, calcitonin gene-related peptides 1 and 2, and represents a new beta-cell secretory product whose normal physiological function remains to be determined. The use of molecular biology has also led to a better understanding of the molecular defects contributing to insulin resistance. Characterization of the insulin-receptor gene in patients with extreme forms of insulin resistance has resulted in the identification of mutations that impair its function and lead to tissue resistance to the action of insulin. Molecular biological approaches have also led to a better understanding of the regulation of glucose transport. They have revealed that there is a family of structurally related proteins encoded by distinct genes and expressed in a tissue-specific manner that are responsible for the transport of glucose across the plasma membrane. Moreover, they have shown that specific depletion of the glucose-transporter isoform that mediates insulin-stimulated glucose transport is responsible for decreased transport activity in adipose tissue in insulin-resistant states. PMID: 2010042 [PubMed - indexed for MEDLINE] 6527. Arch Invest Med (Mex). 1991 Apr-Jun;22(2):235-44. 3T3 cells in adipocytic conversion. O'Shea Alvarez MS(1). Author information: (1)Hospital de Especialidades Centro Médico Nacional, Instituto Mexicano del Seguro Social, D.F. 3T3 are murine cells of an established heteroploid cellular line. Some clones of this cellular line, when cultured under adequate conditions differentiate into adipocytes. During the process of differentiation, the cells undergo a change from the elongated fibroblastic shape to a round or oval form and accumulate small drops of lipids within their cytoplasma. These lipid drops fuse into one large drop which displaces the nucleus towards the periphery, giving the cell the aspect of a mature adipocyte of white adipose tissue. The cells not only change their morphology, but they also present important biochemical changes. They show a simultaneous increase in triglyceride synthesis and activity of lipogenic enzymes. There is also an increase in the response of the activity of various hormones and the de novo synthesis of the receptors to such hormones, as insulin and ACTH. During the process of differentiation important changes occur in the synthesis of various proteins, such as actin, tubulin, and other proteins which also make up the cellular cytoskeleton, forming part of the lipid transportation within the adipose cell. The adipocytic differentiation of 3T3 cells depends on adipogenic serum factors used in the supplementary culture medium. These adipogenic factors seem to play an important role in the development of adipose tissue. There are hormones, chemical agents and serum factors which modulate adipocytic differentiation. The clone must be susceptible to adipocytic differentiation, it must reach a quiescent state and find itself in adipogenic conditions for the 3T3 cells to differentiate into adipocytes. It must also carry out an DNA synthesis which is an expression of the new phenotype. The differentiation of 3T3 cells in terminal. The fact that these cells present an adipocytic conversion under physiologic conditions and with adipogenic hormones which exist in the whole animal has been demonstrated. All of these characteristics show that the 3T3 cells may be used as an adequate experimental system to analyze the events which occur during the differentiation and development of adipose tissue. PMID: 1726451 [PubMed - indexed for MEDLINE] 6528. J Anim Sci. 1991 Apr;69(4):1532-50. Protein and energy requirements of animals treated with beta-adrenergic agonists: a discussion. Reeds PJ(1), Mersmann HJ. Author information: (1)USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX. Much recent work has established the efficacy of certain beta-adrenergic agonists in promoting muscle growth. These compounds also lower the deposition of body lipid. Establishing whether treatment of animals with beta-adrenergic agonists alters their metabolism in ways that affect the efficiency of nutrient use will become important if these compounds are to find a place in animal production. Currently the biological basis of amino acid and energy requirements is being reexamined; this paper discusses whether we have sufficient information to conclude that the current dietary recommendations are appropriate for animals receiving beta-adrenergic agonists. When dietary protein is not a primary nutritional limitation to the rate of protein deposition, beta-adrenergic agonists should increase the efficiency with which the existing protein intake is used in growth. Alternatively, diets that supply a higher essential/nonessential amino acid ratio might be desirable. Whether additional nonprotein energy should be fed to these animals remains an open question. On one hand, the compounds increase energy expenditure and probably increase the maintenance energy needs of the recipient animals; on the other, feeding diets of higher energy density may lead to the resumption of undesirably high rates of fat deposition. PMID: 1677000 [PubMed - indexed for MEDLINE] 6529. Fiziol Zh SSSR Im I M Sechenova. 1991 Apr;77(4):1-15. [General energetics and thermoregulation in the homoiothermal organism in ontogeny]. [Article in Russian] Petrova OP, Ivanov KP. PMID: 1664347 [PubMed - indexed for MEDLINE] 6530. Z Gesamte Inn Med. 1991 Apr;46(5):139-44. [Current knowledge of characteristics and effects of alpha and beta tumor necrosis factors (cachectins)]. [Article in German] Kolb E(1). Author information: (1)Veterinär-Physiologisch-Chemisches Institut, Veterinärmedizinischen Fakultät, Universität Leipzig. The tumour necrosis factors (TNF) alpha and beta play a role in the activation of the immune system in bacterial and viral infections as well as in parasitoses and inflammatory processes, respectively. The TNF alpha is formed mainly by activated macrophages and mast cells, the TNF beta is formed by activated T- and B-lymphocytes. The evocation of necroses in certain forms of tumours is done by the furthering of the formation of activated O2-molecules (H2O2, peroxide anions, hydroxyl radicals). In tumour cells with a high activity of glutathione-peroxidase and of Mn peroxide-dismutase the TNF are without any effect. The TNF activate neutrophil and eosinophil granulocytes as well as macrophages. By induction of the formation of an oligoadenylate synthetase in virus-infected cells they inhibit the virus reproduction. In chronic infections and parasitoses they evoke a retrogression of the fatty tissue (cachexia). The division of fibroblasts is stimulated via the activation of the genes c-myc and c-fos. In the same way like interleukin 1 and interferon gamma they cause fever. PMID: 1648848 [PubMed - indexed for MEDLINE] 6531. Ugeskr Laeger. 1991 Mar 25;153(13):908-13. [Health risks of obesity. Significance of the regional distribution of adipose tissue]. [Article in Danish] Richelsen B(1). Author information: (1)Arhus Amtssygehus, medicinsk-endokrinologisk afdeling III. This review concentrates on recent prospective studies concerning evaluation of the health risk of obesity with special reference to the impact of the distribution of the adipose tissue. Analysis of the data indicates that adipose tissue localized to the abdominal region (especially intraabdominal fat) is associated with an enhanced risk profile including elevated levels of triglycerides and insulin, low levels of high density lipoprotein-cholesterol and elevated blood pressure. Abdominal obesity, determined by the waist/hip ratio, was associated with cardiovascular disease, premature death and non-insulin demanding diabetes mellitus. On the other hand, the total fat mass (measured as body mass index) was positively associated only with non-insulin demanding diabetes mellitus. The androgen/estrogen activity seems to be an important factor for determining the topographical localization of the adipose tissue. The great amount of free fatty acids which may be released from the abdominal fat tissue seemed to be of great pathogenetic importance for the metabolic consequences of abdominal obesity. In conclusion, obesity and the abdominal localization of adipose tissue seem to be two separate entities with different pathogenesis and clinical consequences. The abdominal obesity is the type which is predominantly associated with enhanced health risks. These associations may result in an altered strategy of treatment of the obese population. PMID: 2024293 [PubMed - indexed for MEDLINE] 6532. Nutr Rev. 1991 Mar;49(3):84-6. The metabolic basis for the "apple" and the "pear" body habitus. [No authors listed] PMID: 2057144 [PubMed - indexed for MEDLINE] 6533. Nutr Rev. 1991 Mar;49(3):82-4. Dietary fat alters adipocyte membrane lipid composition and cell functions in diabetic and control rats. [No authors listed] PMID: 2057143 [PubMed - indexed for MEDLINE] 6534. Med Sci Sports Exerc. 1991 Mar;23(3):280-4. Diet composition, energy intake, and nutritional status in relation to obesity in men and women. Miller WC(1). Author information: (1)Department of Kinesiology, Indiana University, Bloomington 47405. There are dietary factors besides the total energy value of food that can affect adiposity by disrupting the balance between energy intake and expenditure. The purpose of this paper was to examine how perturbation of these dietary factors that control energy balance affects adiposity. There is a substantial amount of evidence suggesting that obesity is not associated with overeating, but with a high dietary fat-to-carbohydrate intake ratio. Physiological adaptations to energy-reduced dieting facilitate both weight regain and make it more difficult to lose weight during subsequent dieting attempts. Since obesity may be better characterized by diet composition than by energy intake, successful weight-loss programs should include diet compositional changes in their regimes. PMID: 2020264 [PubMed - indexed for MEDLINE] 6535. Arterioscler Thromb. 1991 Mar-Apr;11(2):327-33. Central adipose distribution is related to coronary atherosclerosis. Thompson CJ(1), Ryu JE, Craven TE, Kahl FR, Crouse JR 3rd. Author information: (1)Department of Epidemiology, University of North Carolina, Chapel Hill 27599. A "male" distribution of adipose tissue in women (excess of fat in the abdomen compared with that in the hips; i.e., elevated waist/hip ratio) has been related to symptomatic cardiovascular disease. An elevated waist/hip ratio has also been related to symptomatic cardiovascular and cerebrovascular diseases in men, as well as to risk factors for these diseases and various metabolic conditions. To determine whether adipose distribution was related to coronary atherosclerosis, we performed a case-control study in patients with angiographically documented coronary atherosclerosis (cases) and in angiographically normal hospital and neighborhood controls. The data show that distribution of adiposity as assessed by waist/hip ratio is significantly related to coronary atherosclerosis in both females and males. Waist/hip ratio is significantly greater in female cases compared with either control group; in males, waist/hip ratio is significantly greater in cases compared with asymptomatic neighborhood controls but not compared with patients with normal coronary arteries. These results persist after control for age, plasma concentrations of lipids and lipoproteins, body mass index, history of hypertension, history of diabetes, and smoking status. The connection between the male adipose distribution in females and coronary atherosclerosis partly explains the greater likelihood of symptomatic cardiovascular disease in them. Males with excess deposition of fat in the abdominal region are also likely to experience increased risk. PMID: 1998650 [PubMed - indexed for MEDLINE] 6536. Rev Port Cardiol. 1991 Feb;10(2):155-70. [Lipoproteins]. [Article in Portuguese] Manso C(1). Author information: (1)Instituto de Química Fisiológica, Faculdade de Medicina, Lisboa. The problem of plasma lipid transport between several organs is reviewed. The constitution of plasma lipoproteins is described as well as the importance of enzymes related to them. The problem of lipid transfer proteins is discussed. The origin of atherosclerosis is analyzed in relation to abnormalities of cholesterol metabolism, of its transport and of free radicals generation. PMID: 2059473 [PubMed - indexed for MEDLINE] 6537. J Dairy Sci. 1991 Feb;74(2):706-19. Regulation of adipose tissue metabolism in support of lactation. McNamara JP(1). Author information: (1)Washington State University, Department of Animal Science, Pullman 99164-6320. In the dairy cow, adipose tissue lipid accumulates during pregnancy, and catabolism begins prior to parturition and increases dramatically afterward. After peak lactation, body lipid is replenished. The duration and magnitudes of these adaptations depend on milk energy secretion, net energy intake, genotype, and endocrine environment. Recent research efforts have focused on endocrine, genetic, and biochemical mechanisms underlying metabolic adaptations in cows of high production potential. Adipose tissue lipid synthesis is decreased and lipolysis is increased in early lactation. The magnitude and duration of these adaptations are increased in animals either consuming relatively less energy or producing more milk. Adipose tissue is more responsive to catecholamines in early and midlactation and in animals with higher production. This is more of an increase in maximal response than in sensitivity. In vivo and in vitro rates of adipose tissue lipolysis correlate positively with milk energy secretion, whereas lipid synthesis rates correlate with energy intake. Thus, mammary metabolic activity, within and among lactations, correlates with that in adipose tissue. Likely mechanisms include adaptations in receptors for homeostatic signals and modulation of postreceptor responses. Research is needed into neural, genetic, and hormone regulation of nutrient utilization and body fat use and recovery during lactation. Research should describe mechanistic relationships among nutrients in animals of high production as well as investigate cellular and molecular mechanisms suitable to genetic manipulation. PMID: 2045568 [PubMed - indexed for MEDLINE] 6538. Acta Pathol Jpn. 1991 Feb;41(2):164-9. Atypical lipoleiomyoma of the uterus. Lin M(1), Hanai J. Author information: (1)Second Department of Pathology, Medical School, Osaka University, Japan. A case of uterine atypical lipoleiomyoma in a 55-year-old obese woman is described. Histologically it was composed of atypical smooth muscle tissue and adipose tissue, as proved by immunohistochemical staining and ultrastructural study. Moreover, these studies revealed a transition from tumor smooth muscle cells to lipocytes. The features of this tumor suggest that at least some lipoleiomyomas result from lipomatous metaplasia of leiomyoma. Lipoleiomyoma is a rare lesion of the uterus, and the present tumor with an atypical leiomyomatous appearance is the first reported case of its kind. A review of previous case reports, together with the condition of this patient, revealed that patients with lipoleiomyoma are often overweight and menopausal, and have a high incidence of gallbladder disease. PMID: 2042491 [PubMed - indexed for MEDLINE] 6539. J Dairy Sci. 1991 Feb;74(2):695-705. Adenosine and the control of adrenergic regulation of adipose tissue lipolysis during lactation. Vernon RG(1), Finley E, Watt PW. Author information: (1)Department of Biochemistry and Molecular Biology, Hannah Research Institute, Scotland, UK. Adenosine is a locally active factor that is produced intracellularly and extracellularly in adipose tissue. Adenosine binds to receptors in the plasma membrane of adipocytes; this activates a guanine triphosphate binding protein that inhibits adenylate cyclase activity and, hence, lipolysis. Lactation results in an enhanced responsiveness of adipocytes to beta-agonists, which stimulate lipolysis, and, paradoxically, to adenosine, which inhibits lipolysis. These adaptations are partly due to increases in ligand binding and to changes in postreceptor components of the signal transduction systems. Somatotropin is implicated in the chronic adaptations of the beta-adrenergic system, whereas insulin, somatotropin, glucocorticoids, and at least one unidentified factor have a role in the chronic control of the adenosine system of adipocytes. PMID: 1675224 [PubMed - indexed for MEDLINE] 6540. Science. 1991 Jan 18;251(4991):288-92. CCAAT-enhancer binding protein: a component of a differentiation switch. Umek RM(1), Friedman AD, McKnight SL. Author information: (1)Howard Hughes Research Laboratories, Department of Embryology, Carnegic Institution of Washington, Baltimore, MD 21210. The CCAAT-enhancer binding protein (C/EBP) has now been found to promote the terminal differentiation of adipocytes. During the normal course of adipogenesis, C/EBP expression is restricted to a terminal phase wherein proliferative growth is arrested, and specialized cell phenotype is first manifested. A conditional form of C/EBP was developed, making it feasible to test its capacity to regulate the differentiation of cultured adipocytes. Premature expression of C/EBP in adipoblasts caused a direct cessation of mitotic growth. Moreover, when abetted by the effects of three adipogenic hormones, C/EBP promoted terminal cell differentiation. Since C/EBP is expressed in a variety of tissues, it may have a fundamental role in regulating the balance between cell growth and differentiation in higher animals. PMID: 1987644 [PubMed - indexed for MEDLINE] 6541. Acta Astronaut. 1991;23:117-21. Effect of space flights on plasma hormone levels in man and in experimental animal. Macho L(1), Kvetnansky R, Vigas M, Nemeth S, Popova I, Tigranian RA, Noskov VB, Serova L, Grigoriev IA. Author information: (1)Institute of Experimental Endocrinology, SAS, Bratislava, Czechoslovakia. An important increase of plasma hormone levels like insulin, TSH and aldosterone was observed in human subjects after space flights, however in the changes of plasma content of ACTH, cortisol, adrenaline and noradrenaline the individual variations were observed in relation to number and duration of space flight. For evaluation of the effects of these changes in plasma hormone levels on metabolic processes also the experiments with small animals subjected to space flights on a board of biosatellite of Cosmos series were running. An elevation of plasma levels of corticosterone, adrenaline, noradrenaline and insulin was found in rats after the space flights of duration from 7 to 20 days. It was demonstrated, that the increase of corticosterone in plasma is followed by the activation of enzymes involved in the amino acid metabolism in rat liver (tyrosine aminotransferase, tryptophanpyrolase, alanine aminotransferase and aspartate aminotransferase). After a short recovery period (2 to 6 days) the plasma corticosterone concentration and also the activity of liver enzymes returned to control levels. The exposition of animals to stress stimuli during this revcovery period showed higher response of corticosterone levels in flight rats as compared to intact controls. The increase of plasma catecholamine levels was not followed by elevation of lipolysis in adipose tissue. This is due to lower response of adipose tissue to catecholamine because a decrease of the stimulation of lipolysis by noradrenaline was observed in animals after space flight. The increase of insulin was not followed by adequate decrease of glucose concentration suggesting a disturbances in glucose utilization similarly as in cosmonauts after a long-term space flight. These results showed that changes in plasma hormone levels, observed after space flight, affected the regulation of metabolic processes in tissues. PMID: 11537112 [PubMed - indexed for MEDLINE] 6542. Cell Biol Toxicol. 1991 Jan;7(1):67-94. Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins. Huff JE(1), Salmon AG, Hooper NK, Zeise L. Author information: (1)National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxins (HCDDs) are among the most toxic and carcinogenic of "man-made" chemicals. These "dioxins," as well as many of the other polychlorinated dibenzodioxins (PCDDs) and dibenzofuran (PCDFs) derivatives, are chlorinated aromatic compounds which are chemically stable, insoluble in water, and highly soluble in fats and oils. TCDD acts as a complete carcinogen in several species, causing both common and uncommon tumors at multiple sites. It is a highly potent chemical carcinogen in chronic animal studies, producing carcinogenic effects in laboratory animals with doses as low as 0.001 micrograms/kg/day. In rats, TCDD induces neoplasms in the lung, oral/nasal cavities, thyroid and adrenal glands, and liver. In mice, TCDD induces neoplasms in the liver and subcutaneous tissue, thyroid gland, and thymic lymphomas. In hamsters, it induces squamous cell carcinomas of the facial skin. Tumors of the integumentary system are reported after oral (mice and rats), intraperitoneal (hamsters), and dermal (mice) administration. A mixture of HCDDS (defined as the mixture of the 1,2,3,6,7,8- and 1,2,3,7,8,9 isomers used in the NTP experiments) are potent liver carcinogens in mice and rats. Pharmacokinetic studies in laboratory animals indicate that 50-90% of dietary TCDD is absorbed. It concentrates in adipose tissue and the liver. In mammals, the TCDD present in the liver is slowly redistributed and stored in fatty tissue. Elimination of TCDD occurs via excretion of metabolites in the bile and urine and passively through the gut wall. Metabolism is slow: the biological half-life of TCDD varies from weeks (rodents) to years (humans), and is strongly dependent upon the rate of TCDD metabolism. Many of the toxic effects of TCDD, including teratogenicity, may arise by receptor-mediated mechanisms. The induction of cytochrome P-448 and related enzymes by TCDD occurs by such a mechanism, and is related to the binding of TCDD to the Ah receptor. The specific mechanism(s) by which TCDD exerts its carcinogenic effects is unclear: receptor-binding may be part of the story. The role of the Ah receptor has been indicated in a skin promotion assay. The evidence for mutagenicity is inconclusive. TCDD did not induce lethal mutations, chromosomal aberrations, micronuclei or sister chromatid exchanges in rodents treated in vivo, nor was it mutagenic to bacteria, but it did enhance transformation of mouse C3H 10T1/2 cells by N-methyl-N'-nitro-N-nitrosoguanidine and was mutagenic to mouse lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2054688 [PubMed - indexed for MEDLINE] 6543. Biotherapy. 1991;3(2):143-58. The metabolic effects of tumor necrosis factor and other cytokines. Grunfeld C(1), Feingold KR. Author information: (1)Department of Medicine, University of California, San Francisco. PMID: 2054255 [PubMed - indexed for MEDLINE] 6544. Adv Exp Med Biol. 1991;286:153-72. The physiology of testicular thermoregulation in the light of new anatomical and pathological aspects. Shafik A(1). Author information: (1)Department of Surgery, Faculty of Medicine, Cairo University, Egypt. PMID: 2042497 [PubMed - indexed for MEDLINE] 6545. Biochimie. 1991 Jan;73(1):67-70. Glucose transporters: structure, function, and regulation. Assimacopoulos-Jeannet F(1), Cusin I, Greco-Perotto RM, Terrettaz J, Rohner-Jeanrenaud F, Zarjevski N, Jeanrenaud B. Author information: (1)Laboratories de Recherches Métaboliques, University of Geneva, Switzerland. Glucose is transported into the cell by facilitated diffusion via a family of structurally related proteins, whose expression is tissue-specific. One of these transporters, GLUT4, is expressed specifically in insulin-sensitive tissues. A possible change in the synthesis and/or in the amount of GLUT4 has therefore been studied in situations associated with an increase or a decrease in the effect of insulin on glucose transport. Chronic hyperinsulinemia in rats produces a hyper-response of white adipose tissue to insulin and resistance in skeletal muscle. The hyper-response of white adipose tissue is associated with an increase in GLUT4 mRNA and protein. In contrast, in skeletal muscle, a decrease in GLUT4 mRNA and a decrease (tibialis) or no change (diaphragm) in GLUT4 protein are measured, suggesting a divergent regulation by insulin of glucose transport and transporters in the 2 tissues. In rodents, brown adipose tissue is very sensitive to insulin. The response of this tissue to insulin is decreased in obese insulin-resistant fa/fa rats. Treatment with a beta-adrenergic agonist increases insulin-stimulated glucose transport, GLUT4 protein and mRNA. The data suggest that transporter synthesis can be modulated in vivo by insulin (muscle, white adipose tissue) or by catecholamines (brown adipose tissue). PMID: 2031959 [PubMed - indexed for MEDLINE] 6546. J Int Med Res. 1991 Jan-Feb;19(1):1-18. Cyclosporin A and its metabolites, distribution in blood and tissues. Akagi H(1), Reynolds A, Hjelm M. Author information: (1)Institute of Child Health, Hospital for Sick Children, London, UK. Cyclosporin A (CsA), a non-myelotoxic immunosuppressant, and its metabolites are widely distributed in the body. Highest concentrations of CsA have been detected in the pancreas, adipose tissue and liver, lowest concentrations in brain, muscle, blood and other body fluids. Metabolites are distributed differently to CsA. In addition to lipid partition, intracellular binding to cyclophilin, a peptidyl-prolyl cis-trans isomerase, appears to play a role in its tissue distribution. The temperature dependence of such binding in erythrocytes poses difficulty in serum or plasma measurements. Tissue specific processes may also influence action and toxicity of CsA and its metabolites; thus, a better understanding of the complex distribution pattern of CsA and its metabolites would be important for establishing improved strategies and selection of appropriate specific methodologies for drug monitoring. PMID: 2019311 [PubMed - indexed for MEDLINE] 6547. Clin Sports Med. 1991 Jan;10(1):157-69. Weight control and exercise. Miles DS(1). Author information: (1)Graduate Hospital Human Performance and Sports Medicine Center, Human Performance Division, Wayne, Pennsylvania. Obesity in the United States can truly be called a national epidemic. The associated health risks and diseases present a tremendous drain to the economy. The most effective program to lose and maintain a desirable body weight incorporates a combination of restriction in caloric intake with an increase in caloric expenditure through exercise. A gradual approach of losing 1 or 2 pounds per week has proved to be the most effective. Men should strive to maintain approximately 15% body fat and women 25% body fat. Weight-reduction programs that demonstrate phenomenal weight loss in a short period will not work over the long term and may represent a significant health risk. The ability to lose fat and maintain a desirable body weight is not easy but can be attained through a firm commitment to a healthy life style. PMID: 2015641 [PubMed - indexed for MEDLINE] 6548. J Steroid Biochem Mol Biol. 1991;40(4-6):841-9. Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. Pugeat M(1), Crave JC, Elmidani M, Nicolas MH, Garoscio-Cholet M, Lejeune H, Déchaud H, Tourniaire J. Author information: (1)Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique, Hôpital de l'Antiquaille, France. In humans, the plasma level of sex hormone binding globulin (SHBG) is regulated by several hormones. We have now accumulated evidence that SHBG is also intimately related to nutritional state. However, we do not yet know what specific signal, if any, may be the regulator of SHBG. There is a strong and negative correlation between fasting insulin level and SHBG in obese as in hyperandrogenic women. Under such circumstances, a high fasting insulin level, normal glycemia and a low SHBG level suggest insulin resistance in terms of glucose disposal but not in terms of SHBG inhibition. This is a rather complex situation. It is too early to judge the importance of IGF-I in the regulation of SHBG. But it may turn out that IGF-I is the main regulator of SHBG and that, by interaction with the IGF-I receptors, insulin carries on its inhibitory activity on SHBG. PMID: 1958579 [PubMed - indexed for MEDLINE] 6549. Verh K Acad Geneeskd Belg. 1991;53(4):283-303. Upper body fat predominance: an endocrine and metabolic chaos. Van Gaal L(1). Author information: (1)Universitaire Instelling Antwerpen, Departement Geneeskunde, Wilrijk. PMID: 1950150 [PubMed - indexed for MEDLINE] 6550. Adv Exp Med Biol. 1991;291:99-105. Relationships between the hypothalamus and adipose tissue mass. Roncari DA(1). Author information: (1)Institute of Medical Science, University of Toronto, ON, Canada. The brain, particularly certain nuclei of the hypothalamus and their neural connections, have a major influence on energy balance, through effects on both food intake and energy expenditure. As summarized in Table 1, there are indeed extensive interactions between the hypothalamus and adipose tissue, the predominate site of storage of chemical energy. Structural, and possibly functional, abnormalities of the neural structures facilitate the development of obesity. This review has described four components of the interactive system. Two of these components are still partly conjectural; while we have increasing experimental support, the hypothalamic-pituitary-adipose axis and the hypothalamic-efferent neural-cytoskeletal pathway are the subject of continuing intense investigation. More complete knowledge of the pathophysiology of obesity will, in turn, facilitate prevention and treatment of corpulence, as well as such frequent associations as non-insulin dependent diabetes mellitus. PMID: 1927695 [PubMed - indexed for MEDLINE] 6551. Ann N Y Acad Sci. 1991;628:9-18. Leukemia inhibitory factor: does the cap fit? Gearing DP(1). Author information: (1)Immunex Corporation, Seattle, Washington 98101. PMID: 1906256 [PubMed - indexed for MEDLINE] 6552. Annu Rev Nutr. 1991;11:413-34. The effects of glyceride structure on absorption and metabolism. Small DM(1). Author information: (1)Department of Biophysics, Boston University School of Medicine, Masschusetts 02118-2394. The subtle effects of the stereochemistry of acyl glycerols are apparent from the cited studies. It is not adequate to simply measure the fatty acid composition of dietary lipids or chylomicrons generated from them. To understand the importance of stereospecific acyl glycerols, simplification of the systems is necessary because of the incredible diversity found among dietary triacylglycerols. By feeding simple analogues corresponding to major triacylglycerols found in oils and fats it should be possible to determine the absorption, uptake into the mucosa, resynthesis into chylomicrons, and the stereospecificity that remains. Hydrolysis and uptake of these defined chylomicron triacylglycerols into adipose tissue or muscle could be followed and stereospecificity again determined in depot fats. Finally, the composition of the remnants, particularly the core and surface, and of the bound apoproteins needs to be related to their plasma residence time, hepatic removal, and deposition in nonhepatic tissues such as spleen, bone marrow, and arterial intima. Since increased serum cholesterol and atherogenicity in animals have been related to different dietary fats, some of the effects noted here, that is the retention of certain kinds of remnants in plasma, may lead to increased serum cholesterol and atherogenesis. We must study the metabolism of a few key stereospecific triacylglycerols in more detail to increase our understanding of their effects on hypercholesterolemia and atherogenesis. PMID: 1892708 [PubMed - indexed for MEDLINE] 6553. Reprod Nutr Dev. 1991;31(3):189-203. [Metabolic regulation of ingestion in monogastric animals]. [Article in French] Louis-Sylvestre J(1). Author information: (1)Université P et M Curie, Laboratoire de neurobiologie de la nutrition, Paris, France. Evidence has accumulated over the past 2 decades to show that the regulation of the fat body mass is integrated in the control of food intake. It was suggested long ago that the metabolic stimulation to eat originated from a shortage of available circulating metabolites; particularly, glucose uptake and utilization has been a central feature of many hypotheses since Mayer's glucostatic theory. In the first section of this contribution, evidence is presented that in rats and man a premeal decline in blood glucose concentration is causally related to meal initiation. The origin of the decline and the possible role of "glycemia-sensitive" neurons located in the lateral hypothalamus (LH) as central sensors of this metabolic stimulus to eat are discussed. In the second section, it is suggested that LH energy utilization and ventro-medial hypothalamus (VMH) energy storage reflect metabolic change at the periphery and also determined the neuronal activity which monitors storage or mobilization of fuels into and from stores. Since glucose is a precursor of triglycerides deposited in adipose tissue and since oxidation of fatty acids in peripheral tissues has a glucose-sparing effect, circulating glucose seems a likely candidate for the signal mediating the effect of fat deposits on food intake. PMID: 1878146 [PubMed - indexed for MEDLINE] 6554. Free Radic Res Commun. 1991;14(4):229-46. Absorption, transport and metabolism of vitamin E. Drevon CA(1). Author information: (1)Institute for Nutrition Research, University of Oslo, Norway. Vitamin E includes eight naturally occurring fat-soluble nutrients called tocopherols and dietary intake of vitamin E activity is essential in many species. alpha-Tocopherol has the highest biological activity and the highest molar concentration of lipid soluble antioxidant in man. Deficiency of vitamin E may cause neurological dysfunction, myopathies and diminished erythrocyte life span. alpha-Tocopherol is absorbed via the lymphatic pathway and transported in association with chylomicrons. In plasma alpha-tocopherol is found in all lipoprotein fractions, but mostly associated with apo B-containing lipoproteins in man. In rats approximately 50% of alpha-tocopherol is bound to high density lipoproteins (HDL). After intestinal absorption and transport with chylomicrons alpha-tocopherol is mostly transferred to parenchymal cells of the liver were most of the fat-soluble vitamin is stored. Little vitamin E is stored in the non-parenchymal cells (endothelial, stellate and Kupffer cells). alpha-Tocopherol is secreted in association with very low density lipoprotein (VLDL) from the liver. In the rat about 90% of total body mass of alpha-tocopherol is recovered in the liver, skeletal muscle and adipose tissue. Most alpha-tocopherol is located in the mitochondrial fractions and in the endoplasmic reticulum, whereas little is found in cytosol and peroxisomes. Clinical evidence from heavy drinkers and from experimental work in rats suggests that alcohol may increase oxidation of alpha-tocopherol, causing reduced tissue concentrations of alpha-tocopherol. Increased demand for vitamin E has also been observed in premature babies and patients with malabsorption, but there is little evidence that the well balanced diet of the healthy population would be improved by supplementation with vitamin E. PMID: 1874454 [PubMed - indexed for MEDLINE] 6555. Chin J Physiol. 1991;34(1):27-44. Cellular effects of growth hormone on adipocytes. Goodman HM(1), Gorin E, Schwartz Y, Tai LR, Chipkin SR, Honeyman TW, Frick GP, Yamaguchi H. Author information: (1)Department of Physiology, University of Massachusetts Medical School, Worcester 01655. Erratum in Chin J Physiol 1991;34(2):241. Adipocytes are physiological targets for GH in both growing and nongrowing individuals. In adipocytes that have been deprived of GH for at least 3 h, GH initially produces a response that is characterized by increased metabolism of glucose and inhibition of the lipolytic effects of catecholamines. This insulin-like effect disappears within 2-3 h despite continued stimulation and cannot be elicited again unless cells are deprived of GH for at least 3 h. Despite refractoriness to the insulin-like action of GH, the lipolytic effect of GH is evident at this time. Although termination of the insulin-like response and induction of both refractoriness and lipolysis all depend upon synthesis of RNA and proteins, these 3 effects of GH appear to be neither temporally nor causally related. Scatchard analysis of ligand binding data suggests that these various effects are produced by interaction of GH with a single class of receptors. However, since modification of either the hormone or the carbohydrate moiety of the receptor can selectively attenuate either the insulin-like or the lipolytic response, more than one hormone receptor interaction is likely. Northern analysis indicates the presence of at least 2 alternately spliced mRNA transcripts for the GH receptor, and at least 3 different complexes are seen after GH is covalently crosslinked to intact adipocytes. Refractoriness does not result from changes in either the number or affinity of GH receptors, but may result from increased cytosolic calcium. Although the protein kinase C activator phorbol myristate acetate mimics both the insulin-like and lipolytic actions of GH, increased activity of protein kinase C probably does not mediate either action of GH. The intracellular mediators of the diverse actions of GH are unknown at this time. PMID: 1874033 [PubMed - indexed for MEDLINE] 6556. Proc Soc Exp Biol Med. 1991 Jan;196(1):8-16. The antiobesity effect of dehydroepiandrosterone in rats. Cleary MP(1). Author information: (1)Hormel Institute, University of Minnesota, Austin 55912. Initial studies showed that dehydroepiandrosterone (DHEA) treatment in mice resulted in lower body weight gain. Subsequent studies have shown that DHEA treatment in rats has a similar effect. In adult rodents, weight loss is a consequence of DHEA treatment. In general, these effects are independent of changes in food intake and are accompanied by lower body fat. DHEA treatment has been shown in some circumstances to alter a number of serum factors including glucose, insulin, cholesterol, and triacylglycerol. Recent studies have focused on the effects of DHEA on liver metabolism. Studies have been undertaken to determine whether the antiobesity effect of DHEA is mediated by the previously described inhibition of glucose-6-phosphate dehydrogenase by this steroid. It appears that inhibition of glucose-6-phosphate dehydrogenase in liver is not the initial metabolic response to DHEA but may play a contributing role. Inhibition of glucose-6-phosphate dehydrogenase in adipose tissue may affect differentiation of fat cells. A number of other enzymes involved in lipid and carbohydrate metabolism have also been shown to be altered by DHEA treatment, and several futile cycles involving some of these enzymes have been proposed to play a role in DHEA's antiobesity action. In addition, mitochondrial protein content is elevated by DHEA treatment. There appear to be time-dependent changes due to DHEA treatment on hepatic mitochondrial state three rates of respiration. Studies continue to evaluate the role of alterations in mitochondrial metabolism in DHEA's antiobesity action. PMID: 1824576 [PubMed - indexed for MEDLINE] 6557. Horm Res. 1991;36 Suppl 1:32-5. Effects of growth hormone on glucose metabolism. Møller N(1), Jørgensen JO, Abildgård N, Orskov L, Schmitz O, Christiansen JS. Author information: (1)Medical Department M (Endocrinology and Diabetes), Aarhus Kommunehospital, Denmark. Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp. 1 diabetes or high dose GH treatment) the diabetogenic actions of GH become apparent. In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact beta-cell function these changes are counterbalanced by hyperinsulinemia--such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality ('Reavens syndrome X'). When stimulated with insulin these patients exhibit insulin resistance at the liver, in adipose tissue and in muscle. Few elaborate studies on the effects of GH on glucose metabolism in GH deficient patients have been conducted. These patients are hypersensitive to the actions of insulin on glucose metabolism and there is some evidence that when GH initially is given to such patients in the GH deprived state, paradox insulin-like effects of GH may be observed. Whether this may relate to increased activity of insulin-like growth factors is unsettled. PMID: 1806481 [PubMed - indexed for MEDLINE] 6558. Nutr Cancer. 1991;16(2):79-83. A proposed mechanism for effects of diet on mammary cancer. Carroll KK(1), Parenteau HI. Author information: (1)Department of Biochemistry, University of Western Ontario, London, Canada. Growth and development of mammary glandular parenchyma appear to be strongly influenced by the associated adipose tissue. Because fat is the major form of energy storage in the body, any changes in energy balance will be reflected in the weight of adipose tissue to a greater extent than in body weight as a whole. High-fat diets tend to encourage energy storage and may promote mammary cancer by increasing the amount of adipose tissue in the gland. The intimate association of adipose and glandular tissue would facilitate the transfer of any growth-promoting substances, such as polyunsaturated fatty acids, eicosanoids, estrogens, or other growth factors, from the adipose to the glandular tissue. Conversely, low-fat diets or restriction of food intake may decrease the risk of mammary cancer by reducing the amount of adipose tissue and thus reducing exposure of the glandular tissue to such growth-promoting substances. PMID: 1796011 [PubMed - indexed for MEDLINE] 6559. Ann Fr Anesth Reanim. 1991;10(6):565-79. [Energy substrates in parenteral nutrition]. [Article in French] Raucoules M(1), Ichaï C, Sowka P, Grimaud D. Author information: (1)Départment d'Anesthésie-Réanimation, Hôpital Saint-Roch, Nice. The most appropriate nutriment for total parenteral feeding (TPF) must be nutritionally efficient, safe and easy to use. Glucose is the most used carbohydrate as it has most of these qualities, as well as a high rate of metabolism by all tissues. It has not been clearly demonstrated that the administration of exogenous insulin with glucose improves nitrogen retention. Substitutes for glucose, such as fructose, maltose, galactose or polyols (xylitol, surbitol, glycerol) are not really superior to glucose itself. On the other hand, they have major side-effects. Therefore, they are not much used as energy substrates for TPF, at least not for long term TPF. Intravenous fat emulsions have taken an important place as a source of energy during TPF. Fat emulsions containing long chain triglycerides (LCT) supply essential fatty acids (EFA) (linolenic and linoleic acids), thus preventing EFA deficiency. The metabolism of fat emulsions is influenced by various factors: age, metabolic and nutritional status, the amount of glucose intake, insulin deficiency, sepsis, heparin therapy. Recently, medium chain triglycerides (MCT) have been proposed as an alternative energy source. The latter are cleared more rapidly from the blood, and are therefore less liable to be deposited in the liver and adipose tissue; they are also oxidized more quickly and more completely. MCT are safe to use at a rate of less than 0.12 g.kg-1.h-1 and with a MCT/LCT ratio less than 3 to 1. The simultaneous administration of glucose prevents an acceleration of ketogenesis. MCT/LCT emulsions are a safe and effective source of calories. It is important that those patients for whom such nutriment may be of particular interest should be identified. Fat emulsions associated with glucose seem to be more efficient in terms of nitrogen sparing effect than glucose alone. They also avoid the problems due to the infusion of large amounts of glucose (excessive carbon dioxide production, fatty infiltration of the liver), while there is no EFA deficiency. If the infusion of TPF nutriment must be continuous in intensive care patients, or during the postoperative period, cyclic nocturnal parenteral nutrition over a 12 or 16 hour period may be used in patients who are not in a catabolic state, or only mildly so. This is a safe and efficient method of nutritional support, which reduces the incidence rate of TPF-induced cholestasis. PMID: 1785708 [PubMed - indexed for MEDLINE] 6560. ORL J Otorhinolaryngol Relat Spec. 1991;53(6):342-5. Restoration of hearing with type V tympanoplasty. Montandon P(1), Chatelain C. Author information: (1)Department of Otolaryngology, Cantonal University Hospital, Geneva, Switzerland. Type V tympanoplasty with fenestration of the oval window and protection of the round window in a residual hypotympanic cavity can be considered as the last-chance procedure for rehabilitation of hearing in ears with 'canal wall down' or other conditions. The review of 64 cases suggests that restoration of hearing can be adequate in the majority of cases. PMID: 1784474 [PubMed - indexed for MEDLINE] 6561. Ann Nutr Metab. 1991;35(5):249-52. Biological markers of dietary intake, with emphasis on fatty acids. Katan MB(1), van Birgelen A, Deslypere JP, Penders M, van Staveren WA. Author information: (1)Department of Human Nutrition, Wageningen Agriculture University, The Netherlands. The level of certain polyunsaturated fatty acids in body fluids or tissues can be a valid indicator of their consumption in man. In 59 housewives studied over a 2.5-year period we found a correlation of 0.70 between the intake of linoleic acid, assessed as the mean of nineteen 24-hour recalls, and the level in fat tissue [Van Staveren et al.: Am J Epidemiol 1986; 123:455-465]. In 58 adult men supplemented with fish oil capsules for 1 year, the rise of eicosapentaenoic acid levels in erythrocyte membranes was strongly and specifically related to the rise in intake. We conclude that epidemiological studies of the role of these fatty acids in health and disease could fruitfully employ these markers of dietary intake. PMID: 1776820 [PubMed - indexed for MEDLINE] 6562. Int J Biochem. 1991;23(9):791-801. The uncoupling protein UCP: a membraneous mitochondrial ion carrier exclusively expressed in brown adipose tissue. Klaus S(1), Casteilla L, Bouillaud F, Ricquier D. Author information: (1)Centre de Recherche sur la Nutrition-CNRS, Meudon-Bellevue, France. PMID: 1773883 [PubMed - indexed for MEDLINE] 6563. Adv Exp Med Biol. 1991;293:249-62. Regulation of the glucose transporter in animal models of diabetes. Pessin JE(1), Richardson JM, Sivitz WI. Author information: (1)Department of Physiology & Biophysics, University of Iowa College of Medicine, Iowa City. PMID: 1767734 [PubMed - indexed for MEDLINE] 6564. Dig Dis. 1991;9(5):253-68. Regulation of hunger and satiety in man. Plata-Salamán CR(1). Author information: (1)School of Life and Health Sciences, University of Delaware, Newark. From the perspective presented in this minireview, it is clear that a variety of psychological and physiological factors interact to regulate feeding behavior. The hunger-satiety cycle involves preabsorptive and postabsorptive humoral and neuronal mechanisms. Psychological, social and environmental factors, nutrients and metabolical processes and gastric contractions originate hunger signals. Eating, in turn, activates inhibitory signals to produce satiety. Because of the delay between the swallowing of food and the digestion of food, the satiety mechanism requires a short-term signal to prevent over-eating. This short-term satiety signal is activated by psychological factors (such as sensory-specific satiety), chemical senses (taste and smell) and mechanical factors related to the process of swallowing and gastric distension. The long-term satiety is then activated by the chemoreception of nutrients and peptides by the gastrointestinal system (including the liver), the CNS and by intrinsic CNS mechanisms. The fine regulation of feeding behavior through these mechanisms will ensure the maintenance of normal energy metabolism. It is important to note, however, that despite all the efforts that have gone into the study of peripheral and central mechanisms of ingestive behavior--expressed in thousands of publications related to the anatomy, chemistry and metabolism, physiology and behavioral aspects of feeding--we will lack an understanding of the interactions among signals within a system or among different systems. PMID: 1752065 [PubMed - indexed for MEDLINE] 6565. J Inherit Metab Dis. 1991;14(4):407-20. The role of the liver in metabolic homeostasis: implications for inborn errors of metabolism. van den Berghe G(1). Author information: (1)Laboratory of Physiological Chemistry, International Institute of Cellular and Molecular Pathology, Brussels, Belgium. The mechanisms by which the liver maintains a constant supply of oxidizable substrates, which provide energy to the body as a whole, are reviewed. During feeding, the liver builds up energy stores in the form of glycogen and triglyceride, the latter being exported to adipose tissue. During fasting, it releases glucose and ketone bodies. Glucose is formed by degradation of glycogen and by gluconeogenesis from gluconeogenic amino acids provided by muscle. Ketone bodies are produced from fatty acids, released by adipose tissue, and from ketogenic amino acids. The major signals which control the transition between the fed and the fasted state are glucose, insulin and glucagon. These influence directly or indirectly the enzymes which regulate liver carbohydrate and fatty acid metabolism and thereby orient metabolic fluxes towards either energy storage or substrate release. In the fed state, the liver utilizes the energy generated by glucose oxidation to synthesize triglycerides. In the fasted state it utilizes that produced by beta-oxidation of fatty acids to synthesize glucose. The mechanisms whereby a number of inborn errors of glycogen metabolism, of gluconeogenesis and of ketogenesis cause hypoglycaemia are also briefly overviewed. PMID: 1749209 [PubMed - indexed for MEDLINE] 6566. Ann Endocrinol (Paris). 1991;52(6):467-8. [Binding of apolipoproteins to HDL receptors sites. Role in the efflux of cholesterol]. [Article in French] Ailhaud G(1). Author information: (1)Centre de Biochimie (CNRS UMR 134), Université de Nice-Sophia Antipolis. Cell surface binding sites recognizing artificial or native particles containing human apoAI, apoAII and/or apoAIV have been characterized in mouse Ob1771 adipose cells. These sites appear to be required for the promotion of cholesterol efflux from an intracellular pool. Two apoA-binding proteins of 92 and 80 kDa have been extensively purified from Ob1771 adipose cells. The critical role of both lipoprotein and receptor sites in cholesterol efflux is discussed. PMID: 1668633 [PubMed - indexed for MEDLINE] 6567. Tsitologiia. 1991;33(11):160-5. [The Na+-K+ pump and the thermogenesis of brown fatty tissue]. [Article in Russian] Medvedev LN, Nikol'skaia LE. Mechanisms of participation of Na+K(+)-pump in regulation of the brown adipose tissue are discussed. It is settled that the increase in ATP hydrolysis by Na(+)-K(+)-ATPase is not a dominating factor of thermogenesis activation. It is assumed that the Na(+)-K(+)-pump, through the intracellular K+ concentration, serves a chain relating proliferation and thermogenesis of adipocytes. PMID: 1668046 [PubMed - indexed for MEDLINE] 6568. Adv Exp Med Biol. 1991;293:239-48. Molecular mechanisms involved in the antilipolytic action of insulin: phosphorylation and activation of a particulate adipocyte cAMP phosphodiesterase. Manganiello VC(1), Smith CJ, Degerman E, Vasta V, Tornqvist H, Belfrage P. Author information: (1)Laboratory of Cellular Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. PMID: 1662861 [PubMed - indexed for MEDLINE] 6569. Methods Enzymol. 1991;201:389-98. Classification of protein-serine/threonine phosphatases: identification and quantitation in cell extracts. Cohen P. PMID: 1658556 [PubMed - indexed for MEDLINE] 6570. Int J Biochem. 1991;23(7-8):649-55. Hormone sensitive phosphodiesterase of liver and adipose tissue. Loten EG(1). Author information: (1)Department of Clinical Biochemistry, Medical School, University of Otago, Dunedin, New Zealand. PMID: 1650718 [PubMed - indexed for MEDLINE] 6571. Adv Exp Med Biol. 1991;285:85-92. Binding of apolipoproteins A to adipose cells: role of receptor sites in cholesterol efflux and purification of binding protein(s). Barbaras R(1), Puchois P, Pradines-Figuères A, Steinmetz A, Clavey V, Ghalim N, Fruchart JC, Ailhaud G. Author information: (1)Centre de Biochimie, Parc Valrose, Nice, France. PMID: 1650121 [PubMed - indexed for MEDLINE] 6572. Nord Med. 1991;106(6-7):191-4. [Obesity at the cellular level]. [Article in Swedish] Björntorp P(1). Author information: (1)Medicinska institutionen I, Göteborgs universitet, Sahlgrenska sjukhuset. Adipocytes are capable of thousand-fold variation size. The considerable size-related variation in lipid accumulation and mobilisation is regulated at different levels of adipocyte metabolism. Immediate metabolic effects are mediated via adrenergic and insulin receptors, which in turn are regulated both by the sympathetic nervous system and by a group of superior steroid hormones exerting their effects via specific receptors. The steroid hormone receptor-hormone complexes interact at a genetic level, modifying the direct hormonal effects of insulin and catecholamines. The density of steroid receptors is probably governed both by genetic factors and auto-regulation. Hypothetically, regional differences in adipocyte metabolic function may depend upon genetic differences in the regulation of hormone receptors, which are subject to endocrine secretion patterns, thus determining the distribution of adipose tissue. PMID: 1649448 [PubMed - indexed for MEDLINE] 6573. Biochim Biophys Acta. 1990 Dec 4;1047(3):195-211. Lipid transport function of lipoproteins in flying insects. Van der Horst DJ(1). Author information: (1)Department of Experimental Zoology, University of Utrecht, The Netherlands. PMID: 2252909 [PubMed - indexed for MEDLINE] 6574. Dis Mon. 1990 Dec;36(12):641-731. Metabolic and health complications of obesity. Grundy SM(1), Barnett JP. Author information: (1)Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas. Overnutrition manifested by obesity has emerged as a major health problem in affluent countries. In spite of increased interest in fitness, obesity is on the increase in the United States. This is particularly so among children and adolescents. Although obesity is associated with many risk factors for diseases, the mechanisms whereby it enhances disease risk are not fully understood. Such an understanding is needed to develop strategies for management of these conditions. In this report we suggest that overnutrition produces clinical diseases only in individuals who already possess a metabolic weakness or "defect" in a given system. In the absence of such underlying defects, overnutrition, or obesity, is well tolerated. One of the most common consequences of obesity is dyslipidemia, that is, elevations of very low-density lipoprotein (VLDL) triglycerides and low-density lipoprotein (LDL) cholesterol and low concentrations of high-density lipoprotein (HDL) cholesterol. The major effect of overnutrition on lipoprotein metabolism is to stimulate the production of VLDL. For patients who have an underlying defect in lypolysis of VLDL triglycerides, hypertriglyceridemia will develop in the obese state. For those who have defective clearance of LDL, obesity will accentuate hypercholesterolemia. Both of these effects can be explained by overproduction of VLDL, due to obesity, combined with a genetic defect in clearance of VLDL or LDL. The mechanism whereby obesity causes a lowering of HDL cholesterol is uncertain, although it could enhance removal of HDL by an excess of adipose tissue. Another disease associated with obesity is cholesterol gallstones. The presence of obesity more than doubles the risk for gallstones. Two underlying factors increase the danger for gallstones: a deficiency of hepatic secretion of bile acids and a tendency for formation of cholesterol crystals in bile. Overnutrition promotes the synthesis of whole-body cholesterol, and the only route for excretion of this excess cholesterol is through the biliary tree.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2261844 [PubMed - indexed for MEDLINE] 6575. J Trauma. 1990 Dec;30(12 Suppl):S192-7. Altered Ca2+ homeostasis and functional correlates in hepatocytes and adipocytes in endotoxemia and sepsis. Spitzer JA(1). Author information: (1)Department of Physiology, LSU Medical Center, New Orleans 70112. Decreased cytosolic [Ca2+] and impaired Ca2+ release in response to an IP3 challenge are among perturbations in hepatocyte Ca2+ homeostasis associated with endotoxemia and sepsis. These changes are consistent with the accompanying alterations in appropriate physiologic functions, e.g., activation of glycogen phosphorylase and gluconeogenesis, mediated by [Ca2+]c and defective phosphorylation of relevant enzymes. Attenuation of IP3 binding to the subcellular fractions that are imputed to be targets of IP3 and a decrease in the size of the IP3-sensitive pool of releasable Ca2+ are underlying components of the mechanism of the reduced Ca2+ release upon IP3 stimulation and its metabolic sequelae. ET treatment leads to a significant increase in Ca2+ associated with the cell surface compartment of adipocytes, a reduction in 45Ca2+ uptake by endoplasmic reticulum and higher cytosolic [Ca2+] under basal conditions and upon ACTH stimulation than that observed in cells of control rats. The reduced 45Ca2+ uptake is also manifest in adipocytes of septic rats. Alterations in adipocyte metabolism induced by ET include increased oxidation of glucose to CO2 (an insulin-like effect) and increased lipolysis upon NE and ACTH stimulation. PMID: 2254982 [PubMed - indexed for MEDLINE] 6576. FASEB J. 1990 Dec;4(15):3310-8. Role of set-point theory in regulation of body weight. Harris RB(1). Author information: (1)Kraft General Foods, Inc., Glenview, Illinois 60025. Comment in FASEB J. 1992 Jan 6;6(2):794. FASEB J. 1991 Apr;5(7):2105-6. In adult individuals body weight is maintained at a relatively stable level for long periods. The set-point theory suggests that body weight is regulated at a predetermined, or preferred, level by a feedback control mechanism. Information from the periphery is carried by an affector to a central controller located in the hypothalamus. The controller integrates and transduces the information into an effector signal that modulates food intake or energy expenditure to correct any deviations in body weight from set-point. Evidence for involvement of various factors and physiological systems in the control of food intake and regulation of body weight and fat are reviewed within the context of a control model. Current working hypotheses include roles for nutrients, dietary composition and organoleptic properties, hormones, neural pathways, various brain nuclei, and many neurotransmitters in the regulation of food intake. It is concluded that regulation of body weight in relation to one specific parameter related to energy balance is unrealistic. It seems appropriate to assume that the level at which body weight and body fat content are maintained represents the equilibria achieved by regulation of many parameters. PMID: 2253845 [PubMed - indexed for MEDLINE] 6577. Am Rev Respir Dis. 1990 Dec;142(6 Pt 2):S57-9. The adipocyte: relationships between proliferation and adipose cell differentiation. Ailhaud G(1), Amri E, Bardon S, Barcellini-Couget S, Bertrand B, Catalioto RM, Dani C, Djian P, Doglio A, Forest C, et al. Author information: (1)Centre de Biochimie du CNRS, Laboratoire de Biologie du Développment du Tissu, Adipeux, Faculté des Sciences, Nice, France. The differentiation of adipose precursor cells can be divided into early and late events. Growth arrest at the G1/S boundary triggers the activation of early genes, i.e., pOb24 and lipoprotein lipase; the expression of both genes is primarily regulated at a transcriptional level. The expression of late markers, which lead to terminal differentiation and accumulation of neutral lipids, takes place after a limited number of mitoses of early-marker-expressing cells. Only terminal differentiation requires the presence of growth hormone and triiodothyronine as obligatory hormones and insulin as a modulating hormone, and results in the formation of triacylglycerol-filled, non-dividing cells. It appears that terminal differentiation involves the cyclic AMP pathway, the diacylglycerol pathway, and a third pathway triggered by insulinlike growth factor-I and insulin. It is thus proposed that a combination of mitogenic-adipogenic signals is required to trigger terminal differentiation of preadipose cells. PMID: 2174664 [PubMed - indexed for MEDLINE] 6578. Curr Opin Cell Biol. 1990 Dec;2(6):1043-9. Extracellular factors, signalling pathways and differentiation of adipose precursor cells. Ailhaud G(1). Author information: (1)Centre de Biochimie du CNRS, Université de Nice-Sophia Antipolis UFR Sciences, Parc Valrose, Nice, France. PMID: 2099796 [PubMed - indexed for MEDLINE] 6579. Pathologica. 1990 Nov-Dec;82(1082):593-616. Hypoxic right ventricular cardiomyopathy. A morphological and pathogenetic study on the myocardial atrophy and fatty infiltration. Silvestri F(1), Bussani R. Author information: (1)Institute of Pathological Anatomy and Histology, University of Trieste, Italy. The autopsy report of an asymptomatic, non familial cardiomyopathy with widespread fatty infiltration of the right ventricular wall in two alcoholic subjects, who were also heavy smokers and suffering from a serious laryngeal obstruction, led the Authors to investigate, on the basis of a thorough review of the literature, the possibility that hypoxia, alcoholism and smoke could have caused the development of the cardiac lesion. The presence of myocardial fatty infiltration is explained, under conditions of high-flow hypoxia, by the reduced fatty acid oxidation. The higher tissue levels of fatty acyl-CoA, fatty acyl-carnitine and alpha-glycerophosphate thereby lead to the increased conversion of the FFA into tissue lipids. Under hypoxic conditions there is also an increased polyols synthesis. The reduced conversion of dyacylglycerol into phosphatidic acid causes its tissutal increase and the interaction with fatty acyl-CoA to produce triacylglycerol and CoASH. In alcoholic patients reduced oxidation and increased FFA synthesis is sustained by the altered mitochondrial respiratory control and excess of acetate, with the consequent increase in acetyl-CoA, fatty acyl-CoA and alpha-glycerophosphate concentration. In addition, fatty acid ethyl esters normally absent in the myocardium are formed. The fact that, in hypoxic or alcoholic subjects with cardiomyopathy, an impaired myocardial contractility has been noted as the most relevant haemodynamic factor may be explained by both the reduced energy production following the decrease in aerobic glycolysis and FFA oxidation, and specific genetic changes that lead to both the production of a myosin with lower Ca2 + ATPase activity and a reduced protein (and therefore myofibrillar) synthesis. This fact can result in a severe atrophy of the cardiac myocytes. The lower their contractile activity, the more evident the process of atrophy. The lesion principally affects the right ventricle for both metabolic and anatomical reasons. It has been shown how, under normal conditions, the RV metabolism is suited to a relatively reduced O2 supply situation, with a high lactate dehydrogenase and alpha-hydroxybutiratedehydrogenase activity. It is more likely to be affected therefore whenever there is a chronic state of high-flow hypoxia. While alpha-HBDH allows the RV extensive utilization of ketone bodies as an energy source, its notable increase under hypoxic conditions further increases the synthesis of fatty acids and therefore fatty infiltration of the myocardium. The relatively lower capacity for oxygen extraction and lower tissue perfusion of the RV compared with the left ventricle make an adequate oxygen supply in the case of increased O2 demand even more difficult.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2094833 [PubMed - indexed for MEDLINE] 6580. Mol Cell Biochem. 1990 Oct 15-Nov 8;98(1-2):11-8. Detection, tissue distribution and (sub)cellular localization of fatty acid-binding protein types. Veerkamp JH(1), Paulussen RJ, Peeters RA, Maatman RG, van Moerkerk HT, van Kuppevelt TH. Author information: (1)Department of Biochemistry, University of Nijmegen, The Netherlands. This overview of recent work on FABP types is focussed on their detection and expression in various tissues, their cellular and subcellular distribution and their binding properties. Besides the 3 well-known liver, heart and intestinal types, new types as the adipose tissue, myelin and (rat) renal FABPs have been described. Recent observations suggest the occurrence of more tissue-specific types, e.g. in placenta and adrenals. Heart FABP is widely distributed and present in skeletal muscles, kidney, lung, brain and endothelial cells. The cellular distribution of FABP types appears to be related to the function of the cells in liver, muscle and kidney. The presence of FABP in cellular organelles requires more evidence. The functional significance of the occurrence of more FABP types is unclear, in spite of the observed differences in their ligand-protein interaction. PMID: 2266952 [PubMed - indexed for MEDLINE] 6581. Ginecol Obstet Mex. 1990 Oct;58:277-83. [Pharmacodynamics of synthetic estrogens. Review article]. [Article in Spanish] Sojo-Aranda I(1), Cortés-Gallegos V. Author information: (1)Unidad de Investigación Biomédica, Centro Médico Nacional, IMSS. Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cummulative local effects that could explain some intra and extracellular phenomena. PIP: Some studies of the peripheral concentration and concentration in reproductive tissues of ethinyl estradiol (EE) and mestranol are reviewed. Orally administered EE is observable in the peripheral circulation within 30-60 minutes. A 1970 study of radioactive EE demonstrated that the endometrium and ovaries captured most of the EE, with levels in the uterus and serum much lower. Adipose tissue was found to be important in storing the hormones. Other studies of radioactive mestranol and EE demonstrated that the compounds were deposited in other organs in significant quantities and that the deposits were perhaps irreversible or of very slow release. The ability of estrogens to remain concentrated at the systemic level and not just in reproductive organs may be related to some adverse effects reported in women using oral contraceptives (OCs). Advances in radiochemistry and immunology in the 1960s made it possible to measure steroid hormone levels in different tissues. The capacity of the endometrium to concentrate natural steroids such as 17-beta estradiol and progesterone during the ovulatory menstrual cycle was demonstrated in 1978. A subsequent study showed that the endometrium captured and stored the synthetic estrogen EE in even greater concentrations than the natural estrogen estradiol. A study of the pharmacodynamics of EE in hysterectomized women showed that 24 hours after the 1st dose of 30 mcg the EE was not detected in the peripheral circulation. But the peripheral concentration increased with continuous daily administration of 30 mcg of EE. 27 days after suppression of treatment it was still detectable in the peripheral circulation. Another experiment was designed to measure simultaneously the concentrations of EE in the peripheral circulation and in the endometrial tissue of 36 women terminating use of OCs containing norgestrel and EE after 2-36 months of treatment. The study showed that synthetic estrogen was still observable in the endometrial tissue 1 month after discontinuing OC use. Inexplicably, levels of EE were higher in the circulation in the cycle after treatment than in the final treatment cycle. 5 of the women participated in the study for 3 posttreatment cycles. EE was observed in the circulation 1 month after termination of OC use in 5 women, 2 months after termination in 4 women, and 3 months after termination in 3 women. The persistence of EE in the tissue months after termination of treatment suggests the need for further research and assessment of possible resulting risks. PMID: 2292429 [PubMed - indexed for MEDLINE] 6582. An Esp Pediatr. 1990 Oct;33(4):349-53. [Relationship between sexual maturation and subcutaneous fat]. [Article in Spanish] García Llop LA(1), Ramada Benedito A, Rodríguez-Estecha P. Author information: (1)Centro de Salud, Jaraíz de la Vera, Cáceres. Due to the great variability at the beginnings and the period of the puberty, authors have studied the modifications of the subcutaneous-fat and their relation with the sexual maturating. They have measured the skinfold thickness of biceps, triceps, subscapular and suprailiac in 358 boys from 10 to 15 years old and 424 girls from 8 to 14 years old inrelation to sexual maturating through the stages described by Tanner. It has been found more subcutaneous fat in girls than in boys (p less than 0.05). The boys increase their subcutaneous fat until the stage 3 (except the skinfold triceps) and decrease later (except the skinfold subscapular). In boys, the analysis of varianza, show that the variations are related with the sexual maturating and not with chronologic age. PMID: 2278437 [PubMed - indexed for MEDLINE] 6583. Clin Biochem. 1990 Oct;23(5):343-7. Cellular and secreted lipoprotein lipase revisited. Ailhaud G(1). Author information: (1)Centre de Biochimie du CNRS, Faculté des Sciences, Nice, France. Lipoprotein lipase (LPL) of adipose cells is present only in membrane compartments, mainly in the Golgi apparatus. LPL is a typical secretory protein which appears to be active as a homodimer. The process of LPL synthesis and maturation requires multiple steps. LPL is synthesized in the endoplasmic reticulum as an inactive monomer of Mr 51,000; a high-mannose, inactive monomer of Mr 55,500 is then formed. An active homodimer form, bearing two complex oligosaccharide chains per monomer of Mr 58,000, forms in the Golgi apparatus. This mature form, present in secretory vesicles, can be secreted constitutively or after exposure to heparin. A model is proposed in which LPL is present in secretory vesicles in a potentially active, condensed, or "polymerized" form. This model, which applies to various LPL-containing tissues in different species - including human - would explain the "activation" of LPL. PMID: 2253330 [PubMed - indexed for MEDLINE] 6584. Pediatr Clin North Am. 1990 Oct;37(5):1057-83. Body composition in adolescent athletes. Hergenroeder AC(1), Klish WJ. Author information: (1)Baylor College of Medicine, Houston, Texas. This article has set out to provide basic knowledge about body composition in athletic and nonathletic adolescents and young adults and to provide the practicing physician with methods of making body composition assessment. We suggest the physician approach the adolescent athlete who requests information about body composition in the following way: 1. Calculate the ideal body weight. 2. Estimate the percentage of body fat, realizing the errors associated with each method. If a body composition laboratory is available, use that equipment. In the absence of this equipment, we recommend the equations of Slaughter et al, given earlier. 3. The athlete should be given a range of percentage of body fat values measured in other athletes of the same gender and sport. Health and performance should be monitored as the athlete attempts to achieve or maintain body composition in this range. 4. If the athlete has an interest in altering body composition, then recommend the athlete seek the advice of a professional who has expertise in nutrition and physiology. PMID: 2216555 [PubMed - indexed for MEDLINE] 6585. Int J Sports Med. 1990 Oct;11(5):329-48. The possible involvement of endogenous opioid peptides and catecholestrogens in provoking menstrual irregularities in women athletes. De Crée C(1). Author information: (1)Research Unit of Biomedical and Clinical Kinanthropology, Catholic University of Leuven, Belgium. It is well known that women athletes engaged in strenuous physical exercise and endurance training may develop "athletic menstrual irregularities" (AMI). Although many studies have appeared dealing with the immediate endocrinological and physiological changes in these women, the underlying mechanisms have remained unknown to date. A number of hypotheses have been put forward, the most well-known among them, for example, defending the existence of a critical percent of body fat necessary to trigger or maintain normal menstruation. All these theories have, however, their own, sometimes numerous, methodological inaccuracies and a teleological way of investigation. Spectacular, and perhaps promising new developments concern the possible involvement of endogenous opioid peptides and catecholestrogens in these processes. In basal circumstances beta-endorphin, the most well-known endogenous substance with opiate-like activity, may decrease LH levels by suppressing hypothalamic GnRH. This phenomenon is, however, only observed during the estrogen-dominant late-follicular and mid-luteal phases. As for catecholestrogens, it appears essential to differentiate between, for example, the 2- and 4-hydroxy derivatives of both estrone and estradiol. While some of these catecholestrogens obviously seem to suppress LH levels, others seem to potentiate and induce the LH surge. In any case, similar to beta-endorphin, these activities of catecholestrogens appear to depend upon the essential presence of a sufficiently estrogenic environment. In addition, both endogenous opioid peptides and some of the catecholestrogens appear to be able to suppress prolactin release, probably by interfering with its inhibiting factor dopamine. Other effects of catecholestrogens may include the control of the luteolysis-potent prostaglandin F2 alpha. Although a number of studies have investigated the behaviour of beta-endorphin during and post-exercise, similar studies investigating catecholestrogens as to their relation to physical exercise are almost nonexistent. This, in association with the numerous methodological inaccuracies of various studies, makes it difficult to draw any firm conclusion. As to formulate new hypotheses, the only reasonable suggestion considers the possible existence of a complex feedback system including catecholestrogens and endogenous opioid peptides. Furthermore, recommendations made in this survey may be helpful in designing new, perhaps more firmly supported and appropriate future studies. PMID: 2175732 [PubMed - indexed for MEDLINE] 6586. An Esp Pediatr. 1990 Sep;33(3):237-44. [Estimation of the degree of metabolism-energy maturity in the premature newborn infant: plasma lipid profile and lipid transport systems]. [Article in Spanish] Campoy Folgoso C(1), Bayés García R, Molina Font J. Author information: (1)Departamènto de Pediatría, Facultad de Medicina, Universidad de Granada. The newborn preterm infant loses the opportunity to store energy as triacylglycerides form in the adipose tissue during the last quarter of gestation, so they have a real threat to maintain with exogenous supports only the high energy request, and they have been exposed to an elevated risk for central nervous system damage. Small reserves of substrates and poor metabolic adaptation may make the premature infant more vulnerable to the normal stresses of birth and the early postnatal period. We have studied the changes in plasma lipids profile and plasma lipoprotein cholesterol distribution in cord blood from 109 term newborn infants and 16 newborn infants have got higher plasma lipid concentrations than term newborn infants (total cholesterol: 76.81 +/- 4.67 mg/dl (mean +/- SEM) vs 66.72 +/- 1.54 mg/dl, p less than 0.02; Phospholipids: 136.00 +/- 5.24 mg/dl vs 113.94 +/- 2.86 mg/dl, p less than 0.005) and a different cholesterol lipoprotein distribution compared to normal full-term infants, standing out in premature babies, that cholesterol is essentially joint with low density lipoproteins (LDLc: 42.40 +/- 3.62 mg/dl vs 28.76 +/- 1.16 mg/dl, p less than 0.01). These results could be the expression of a metabolic-enzymatic fetal mechanism to keep up a good cholesterol and phospholipids biodisponibility to supply the structural tissues needs in this fetal stages of rapid growth and development. PMID: 2285188 [PubMed - indexed for MEDLINE] 6587. Baillieres Clin Obstet Gynaecol. 1990 Sep;4(3):419-39. The right weight: body fat, menarche and ovulation. Frisch RE. Women with moderate weight loss (10-15% of ideal weight), as well as women with the severe weight loss of anorexia nervosa (30% of ideal weight), have secondary or primary amenorrhoea. A high proportion of well-trained dancers and athletes also have amenorrhoea, though weight may be in the normal range, since muscles are heavy (80% water, compared to 5-10% water in adipose tissue). The amenorrhoea is usually reversible with weight gain, decreased exercise or both. The amenorrhoea is due to hypothalamic dysfunction; the pituitary-ovary axis is intact, suggesting that this type of amenorrhoea is adaptive, preventing an unsuccessful pregnancy outcome. Evidence is presented that the high percentage of body fat (26-28%) in mature women is necessary for regular ovulatory cycles. Target weights for height are given for the evaluation and treatment of primary and secondary amenorrhoea due to weight loss. The high percentage of body fat in women may influence reproductive ability directly: (1) as an extragonadal source of oestrogen by aromatization of androgen to oestrogen; (2) by influencing the direction of oestrogen metabolism to more potent or less potent forms; or (3) by changes in the binding properties of sex-hormone-binding globulin. Indirect signals may be of abnormal control of temperature and changes in energy metabolism, which accompany excessive leanness. PMID: 2282736 [PubMed - indexed for MEDLINE] 6588. J Neurosci Methods. 1990 Sep;34(1-3):187-92. Effects of nutrient intake on sympathoadrenal activity and thermogenic mechanisms. Astrup AV(1), Christensen NJ, Simonsen L, Bülow J. Author information: (1)Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark. Ingestion of carbohydrate results in a diphasic activation of the sympathoadrenal system. One component is an insulin-mediated activation of the sympathetic nervous system (SNS). This activation is partly a haemodynamic reflex, but it may cause a weak thermogenic effect via beta 1-adrenoceptors in white adipose tissue, the liver and the heart. The second thermogenic component of carbohydrate occurs later when the blood glucose concentration decreases towards baseline levels. This elicits an increased secretion of adrenaline from the adrenal medulla, and the circulating level exceeds the physiological threshold for thermogenic effect. The target is mainly skeletal muscle where thermogenesis is stimulated via beta 2-adrenoceptors. Also the basal metabolic rate and the thermogenic responses to cold and heat exposure, mental stress and exercise, have facultative components. Inhibition of facultative thermogenesis by beta-blockers such as propranolol, diminishes the daily energy expenditure and promotes weight gain and obesity. Although thermogenesis mediated by the sympathoadrenal system accounts for only a small part of the daily energy expenditure, it is sufficient to explain the positive energy balance and weight gain reported in patients receiving treatment with beta-adrenoceptor blocking agents. PMID: 2259241 [PubMed - indexed for MEDLINE] 6589. FASEB J. 1990 Aug;4(11):2890-8. Brown adipose tissue thermogenesis: interdisciplinary studies. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, University of Ottawa, Ontario, Canada. Energy expenditure for thermogenesis in brown adipose tissue (BAT) serves either to maintain body temperature in the cold or to waste food energy. It has roles in thermal balance and energy balance, and when defective, is usually associated with obesity. BAT can grow or atrophy; it is usually atrophied in obese animals. Control of BAT thermogenesis and growth is by the sympathetic nervous system, with integration of signals in the hypothalamus. Sensory nerves may also be involved. Understanding the control of growth and differentiation of BAT is important for discovering how to reactivate it is obesity. Studies on control of gene expression in BAT are concentrating on thermogenically important components such as the uncoupling protein (which allows BAT mitochondria to operate in a thermogenic uncoupled mode), lipoprotein lipase (which allows BAT to compete with white adipose tissue for dietary lipid), and thyroxine 5'-deiodinase (which allows endogenous triiodothyronine generation, part of the control of differentiation and growth of BAT). Differentiation of BAT cell precursors in culture has recently been achieved. BAT is present in adult humans and some anti-obesity drugs are targeted to stimulation of BAT thermogenesis. However, extrapolation to humans of results of studies of BAT requires the development of novel approaches to the noninvasive assessment of amount and function of human BAT. PMID: 2199286 [PubMed - indexed for MEDLINE] 6590. Am J Clin Nutr. 1990 Aug;52(2):224-7. Do obese individuals gain weight more easily than nonobese individuals? Forbes GB(1). Author information: (1)Department of Pediatrics, University of Rochester School of Medicine and Dentistry, NY 14642. A review of studies done on human subjects who were overfed under controlled conditions for periods ranging from 2 to 12 wk shows that the energy cost of induced weight gain is a function of initial body weight and of lean body mass, body fat, and percent body fat. Therefore, bigger and fatter people need to eat more to gain a given amount of weight than do those who are thin. A likely explanation is that obese individuals tend to put on a large proportion of fat, a high-energy tissue, whereas thin people tend to gain more lean, which is a low-energy tissue. PMID: 2197850 [PubMed - indexed for MEDLINE] 6591. Pediatr Nephrol. 1990 Jul;4(4):421-3. Molecular biology of components of the renin-angiotensin system during development. Gomez RA(1). Author information: (1)Department of Pediatrics, University of Virginia School of Medicine, Charlottesville 22908. Evidence for the expression of genes of the renin-angiotensin system (RAS) in the developing kidney is rapidly accumulating. We have recently demonstrated that the fetal kidney expresses the renin gene and that expression of the gene is developmentally regulated. Kidney renin messenger ribonucleic acid (mRNA) levels decrease markedly with maturation, and as maturation unfolds the intrarenal distribution of renin and its mRNA changes from large intrarenal arteries in the fetus to a restricted juxtaglomerular site in the adult animal. These findings demonstrate that renin is synthesized and stored in the aforementioned vascular segments and that expression of the renin gene follows the centrifugal pattern of nephrovascular development. In addition to storing renin, intact kidney microvessels release renin spontaneously and possess a functionally active adenylate cyclase whose stimulation results in a marked increase in renin release. The increase in renin enzymatic activity appears to be due to a recruitment of renin-releasing cells rather than to an increase in the amount of renin secreted per cell. Expression of the angiotensinogen (Ao) gene is also developmentally regulated. Ao mRNA levels are very low in the fetal liver, markedly increasing after parturition, suggesting that some of the complex neurohumoral changes surrounding extrauterine life may regulate the expression of the Ao gene. As in the adult animal, Ao is expressed in fetal kidney, brain and brown adipose tissue. The contribution of these organs to the fetal plasma pool of Ao remains to be determined. However, unlike the adult, the fetal liver may not be the primary source of circulating Ao in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2206911 [PubMed - indexed for MEDLINE] 6592. Dermatol Clin. 1990 Jul;8(3):385-93. The biochemistry and development of adipose tissue and the pathophysiology of obesity as it relates to liposuction surgery. Skouge JW(1). Author information: (1)Division of Dermatologic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland. It is clear that central obesity is a strong predictor of multiple health risks. It appears likely that much of the influence for the preferential deposition of fat in these various stores is related to sex hormones, although other factors clearly play a role, including genetic, environmental, nutritional, and other factors. Whereas a great deal has been discovered about these relationships in the past 10 years, further study is necessary to clarify them and determine what role dietary and surgical interventions may play in the prevention and reversal of those risk factors. PMID: 2199102 [PubMed - indexed for MEDLINE] 6593. Arteriosclerosis. 1990 Jul-Aug;10(4):497-511. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Després JP(1), Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. Several epidemiological studies have reported that the regional distribution of body fat is a significant and independent risk factor for cardiovascular disease (CVD) and related mortality. Although these associations are well established, the causal mechanisms are not fully understood. Numerous studies have, however, shown that specific topographic features of adipose tissue are associated with metabolic complications that are considered as risk factors for CVD such as insulin resistance, hyperinsulinemia, glucose intolerance and type II diabetes mellitus, hypertension, and changes in the concentration of plasma lipids and lipoproteins. The present article summarizes the evidence on the metabolic correlates of body fat distribution. Potential mechanisms for the association between body fat distribution, metabolic complications, and CVD are reviewed, with an emphasis on plasma lipoprotein levels and plasma lipid transport. From the evidence available, it seems likely that subjects with visceral obesity represent the subgroup of obese individuals with the highest risk for CVD. Although body fat distribution is now considered as a more significant risk factor for CVD and related death rate than obesity per se, further research is clearly needed to identify the determinants of body fat distribution and the causal mechanisms involved in the metabolic alterations. It appears certain, however, that an altered plasma lipid transport is a significant component of the relation between body fat distribution and CVD. PMID: 2196040 [PubMed - indexed for MEDLINE] 6594. J Dermatol Surg Oncol. 1990 Jul;16(7):651-5. Fat transfer for aging skin: technique for rhytids. Scarborough DA(1), Schuen W, Bisaccia E. Author information: (1)Ohio State University, Columbus. Dermatologic surgeons are familiar with many surgical and nonsurgical techniques for the reduction of facial rhytids. Injectable collagen, silicone, and fibril are commonly employed as injectable filler materials. Properly done, fat transfer is another valuable tool for use in facial restoration. Fat transfer is an excellent technique for intervention in the aging process, and is easily managed as an office procedure. We will review the near-century-old history of fat grafting and outline the structural dynamics in the process of facial aging. Our experience from the last 50 fat transfer procedures performed will be reviewed with specific attention to patient selection, extraction and injection technique, complications, and overall results. PMID: 2193960 [PubMed - indexed for MEDLINE] 6595. Biofactors. 1990 Jul;2(3):153-61. Phenylarsine oxide and the mechanism of insulin-stimulated sugar transport. Douen AG(1), Jones MN. Author information: (1)Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada. The actions of phenylarsine oxide (PAO) on hormone receptors and transport processes are reviewed with particular reference to the mechanism of insulin-stimulated sugar transport. It is suggested that as well as reaction with vicinal -SH groups, vicinal -SH/-OH and -SH/-CO2H groups should also be considered as potential reaction sites for PAO. The relatively high levels of these vicinal combinations of groups in many hormone receptors makes them particularly susceptible to reaction with PAO. In the case of insulin-stimulated sugar transport PAO does not inhibit insulin binding to its receptor at low concentrations but may react directly with the glucose transporters in some cells. A hypothesis is proposed suggesting that PAO may react specifically with one transporter isoform (GLUT-4) which is found almost exclusively in rat adipocytes, skeletal muscle and heart tissue (i.e. insulin responsive tissue) whereas in insulin unresponsive cells such as erythrocytes the GLUT-1 isoform is the predominant transporter which is not inhibited by PAO. PMID: 2165780 [PubMed - indexed for MEDLINE] 6596. Scand J Clin Lab Invest. 1990 Jun;50(4):351-61. Development of gangrene during sleep. Jelnes R(1). Author information: (1)Department of Thoracic and Vascular Surgery T, Aalborg, Denmark. A method for continuous measurement of subcutaneous adipose tissue blood flow in the forefoot over 24 h (SBF) is described. The method is based on the radioisotope wash-out principle using 133-Xenon (133Xe). A portable semiconductor detector is placed just above a local depot of 37-74 kBq 133Xe in 0.1 ml isotonic saline, injected into the subcutaneous adipose tissue in the forefoot. The detector is connected to a memory unit allowing for storage of data. Because of the short distance, the recorded elimination rate constant must be corrected for combined convection and diffusion of the radioactive indicator. Characteristic 24-h blood flow patterns were unveiled in patients with normal peripheral circulation and in patients having ischaemic nocturnal rest pain. In normal subjects, SBF doubled from day to night. This is ascribed to the local veno-arteriolar sympathetic axon reflex, which induces vasoconstriction when the transmural pressure of the veins exceeds approximately 25 mmHg. In patients having ischaemic rest pains SBF was reduced by 37% on the average from day to night. This was caused by nocturnal hypotension, which is reflected proportionally in the foot. As the resistance vessels most probably are fully dilatated in feet with rest pain, the blood pressure drop during sleep causes the perfusion pressure and, therefore, blood flow to drop below a certain critical limit. There was a pronounced correlation between the reduction systemic mean arterial blood pressure and SBF. The patients complaining of intermittent claudication, but no rest pains, demonstrated a variety of changes in SBF compatible with the continuous spectrum of peripheral arteriosclerotic disease. The reduced blood flow during sleep in patients having ischaemic rest pains give rise to the concept of the development of gangrene during sleep. PMID: 2203138 [PubMed - indexed for MEDLINE] 6597. Med Sci Sports Exerc. 1990 Jun;22(3):291-7. Body fat distribution in females: metabolic consequences and implications for weight loss. Campaigne BN(1). Author information: (1)Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229-2899. The main function of adipose tissue is to store triglyceride during relative affluence and to break down this fat and release fatty acids and glycerol when needed. Both the deposition and degradation of lipid are under precise hormonal and neural control. Recently, it has become evident that adipose tissue is not homogeneous and that the regional distribution of fat may be important with respect to metabolism and hormonal responsiveness and, thus, of interest from a number of viewpoints. This review will focus on the physiological significance of differences in adipose tissue distribution and implications for the female. Included will be the hormonal and metabolic consequences of child bearing and the metabolic outcome for chronic disease risk. Furthermore, the influence of the distribution of adiposity on weight loss by diet and exercise, as well as changes in fat and lean tissue, will be examined. Possible directions for future research in this area will be discussed. PMID: 2199751 [PubMed - indexed for MEDLINE] 6598. Diabetes Care. 1990 Jun;13(6):548-64. Regulation of glucose-transporter gene expression in vitro and in vivo. Kahn BB(1), Flier JS. Author information: (1)Charles A. Dana Research Institute, Boston, Massachusetts. Understanding of the fundamental mechanisms underlying the complex regulation of glucose homeostasis has been dramatically transformed recently by the realization that glucose transport in mammalian tissues is mediated by a family of structurally related but genetically distinct glucose-transporter proteins. The regulatory factors and intracellular signaling pathways that influence expression of the genes encoding these proteins are just being identified. Factors that regulate glucose-transporter gene expression in vitro include oncogenes, growth factors, insulin, oral hypoglycemic agents, vanadate, glucocorticoids, ambient glucose levels, and the state of cellular differentiation. In vivo, glucose-transporter gene expression in adipose cells, skeletal muscle, and liver is markedly affected by various altered nutritional and metabolic states. Recent studies have demonstrated that two glucose transporters expressed in the same tissue may be regulated differently in response to the same metabolic perturbation. Furthermore, transporter regulation appears to be tissue specific. These observations lay the groundwork for future studies aimed at unraveling the functional roles of the individual transporter species in different tissues, the molecular processes involved in regulating the expression of these genes, and the impact of dysregulated glucose-transporter gene expression in the pathogenesis of insulin-resistant states such as diabetes. PMID: 2192844 [PubMed - indexed for MEDLINE] 6599. J Nutr. 1990 Jun;120(6):649-55. Changes in liver and gastrointestinal tract energy demands in response to physiological workload in ruminants. Johnson DE(1), Johnson KA, Baldwin RL. Author information: (1)Animal Science Department, Colorado State University, Fort Collins 80523. Liver and gastrointestinal tract weights (ingesta- and adipose-free) appear to increase or decrease in direct proportion to dietary intake within and across physiological stages of maintenance, growth, fattening or lactation. Liver and gut mass increase approximately 15 and 30 g per unit of liveweight raised to the 0.75 power (Wt0.75) for each multiple of 500 kJ/Wt0.75 [approximately 1 x maintenance (M)] increase in metabolizable energy (ME) intake, with linearity indicated up to the highest recorded level (4.5 x M). Extrapolation from in vivo arteriovenous O2 measurements across splanchnic tissues and from the previously cited weight information indicates that liver and gut tissue oxidize approximately 3.5 and 1.0 kJ of ME/g of fresh tissue daily, in contrast to whole-animal rates of 0.1 kJ/g. Thus, energy use by the relatively small amount of liver and gut accounts for 45 to 50% of whole-animal heat energy. On a differential basis, increases in energy use by these tissues appear to account for up to 70% of the heat increment of ME use above maintenance. PMID: 2191096 [PubMed - indexed for MEDLINE] 6600. Indian J Biochem Biophys. 1990 Jun;27(3):125-9. What happens after insulin binds to its receptor? Sheorain VS(1). Author information: (1)Nutrition Section, Hindustan Lever Research Centre, Chakala, Andheri (East), Bombay. PMID: 2167289 [PubMed - indexed for MEDLINE] 6601. Diabetes Care. 1990 Jun;13(6):565-75. Insulin-receptor tyrosine kinase and glucose transport. Lane MD(1), Flores-Riveros JR, Hresko RC, Kaestner KH, Liao K, Janicot M, Hoffman RD, McLenithan JC, Kastelic T, Christy RJ. Author information: (1)Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. We identified the earliest events in autophosphorylation of the insulin receptor after insulin addition. Insulin-stimulated autophosphorylation at specific sites in the tyrosine kinase domain of the receptor's beta-subunit is correlated kinetically with activation of kinase-catalyzed phosphorylation of a model substrate (reduced and carboxyamidomethylated lysozyme; RCAM-lysozyme). To identify these sites, the deduced amino acid sequence of the 3T3-L1 adipocyte insulin receptor of the mouse was determined. Insulin-induced activation of substrate phosphorylation was shown to require autophosphorylation of three neighboring tyrosines (Tyr1148, Tyr1152, and Tyr1153) in the mouse receptor. A search for cellular substrates of the receptor kinase revealed that insulin causes accumulation of a 15,000-Mr phosphorylated (on tyrosine) cytosolic protein (pp15) in 3T3-L1 adipocytes treated with oxophenylarsine (PAO). PAO blocks turnover of the phosphoryl group of pp15, causing its accumulation, and thereby appears to interrupt signal transmission from the receptor to the glucose-transport system. Two membrane-bound protein phosphotyrosine phosphatases that are inhibited by PAO and are apparently responsible for the turnover of the pp15 phosphoryl group have been purified from 3T3-L1 adipocytes and characterized. These and other results support the hypothesis that turnover of the phosphoryl group of pp15, a product of insulin-receptor tyrosine kinase action, couples signal transmission to the glucose-transport system. [32P]pp15 was purified to homogeneity from 3T3-L1 adipocytes. Amino acid and radiochemical sequence analysis of the purified tryptic [32P]phosphopeptide revealed that pp15 is the phosphorylation product of 422(aP2) protein, a 15,000-Mr adipocyte protein whose cDNA we previously cloned and sequenced. 422(aP2) protein was found to bind fatty acids. When exposed to a free fatty acid, notably oleic acid, 422(aP2) protein becomes an excellent substrate of the isolated insulin-receptor tyrosine kinase. Compelling evidence indicates that on binding fatty acid, 422(aP2) protein undergoes a conformational change whereby Tyr19 becomes accessible to the receptor tyrosine kinase and undergoes O-phosphorylation. Adipose tissue and skeletal and heart muscle, which exhibit insulin-stimulated glucose uptake, express a specific insulin-responsive glucose transporter. A cDNA (GT2) that encodes this protein was isolated from a mouse 3T3-L1 adipocyte library and sequenced. We also isolated and characterized the corresponding mouse gene GLUT4. DNase I footprinting with nuclear extracts from 3T3-L1 cells revealed that a differentiation-specific nuclear factor binds to the GLUT4 promoter. The purified transcription factor C/EBP binds at the same position.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2162754 [PubMed - indexed for MEDLINE] 6602. Nutr Rev. 1990 May;48(5):225-6. Insulin regulation of lipoprotein lipase in adipocytes is not mediated by gene expression. [No authors listed] PMID: 2196484 [PubMed - indexed for MEDLINE] 6603. Arch Biol Med Exp (Santiago). 1990 May;23(1):1-12. [Adenosine: physiological and pharmacological actions]. [Article in Spanish] Contreras E(1). Author information: (1)Departamento de Ciencias Fisiológicas (Farmacología), Facultad de Ciencias Biológicas y de Recursos Naturales, Universidad de Concepción, Chile. Adenosine exerts numerous effects in the central and autonomic nervous systems, most of which seem to be receptor mediated. Several studies have revealed two distinct receptors, based upon effects of adenosine on adenylate cyclase activity, designed A1 or A2 according to whether the cyclase is inhibited or activated. However, since not all adenosine receptors are linked to adenylate cyclase some authors base their classification on the rank orders of potencies of adenosine analogues in eliciting responses. The purine seems to function as a modulatory substance in the heart, blood, ileum, vas deferens, and adipose tissue. In addition, important responses to exogenously added adenosine are also induced in the bronchi, urinary bladder, taenia coli, parietal cells of the stomach and renin secretion. Adenosine and its analogues elicit anticonvulsant responses, sedation and hypothermia through their actions in the central nervous system. The mechanisms by which adenosine elicits its responses have not been clearly established. The activation of A1 receptors depresses the release of neurotransmitters and inhibit the influx of Ca into nerve terminals. Whether this effect is induced by interaction with Ca channels or by impairment of Ca dependent processes associated with neurotransmitter release is unknown. In the rat heart adenosine inhibits adenylate cyclase and subsequently the phosphorylation of L-type Ca channels, resulting in a decrease of calcium influx in the muscle cell. The responses to activation of A2 receptors in smooth muscle consist in relaxation presumptively by an increase of K current which would hyperpolarize the cell. PMID: 2152291 [PubMed - indexed for MEDLINE] 6604. Biochim Biophys Acta. 1990 Apr 9;1052(1):128-32. Hormone-sensitive lipase--a multipurpose enzyme in lipid metabolism. Yeaman SJ(1). Author information: (1)Department of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, U.K. PMID: 2182129 [PubMed - indexed for MEDLINE] 6605. New Biol. 1990 Apr;2(4):304-12. The function of adipocytes in the bone marrow stroma. Gimble JM(1). Author information: (1)Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Street, Oklahoma City 73104. The fibroblasts and adipocytes of the bone marrow stroma provide the cytokines and extracellular matrix proteins required for the maturation and proliferation of the circulating blood cells. Due to the complexity of the bone marrow as an organ, the normal physiology of these stromal cells is not well understood. In particular, the role of adipocytes in the bone marrow remains controversial. Cloned bone marrow stromal cell lines provide an in vitro model for analysis of the lympho-hematopoietic microenvironment. These cells may be capable of multiple differentiation pathways, assuming the phenotype of adipocytes, chondrocytes, myocytes, and osteocytes in vitro. Characterization of these cell lines and recent in vivo experiments give new insight into the normal physiology of the bone marrow. PMID: 2288904 [PubMed - indexed for MEDLINE] 6606. Infusionstherapie. 1990 Apr;17 Suppl 3:4-8. New approaches to body composition research: a reexamination of two-compartment model assumptions. Heymsfield SB(1), Lichtman S. Author information: (1)Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York. The field of human body composition research by necessity is based upon assumptions related to tissue chemical content. The 2-compartment model, which requires only 1 measurement in addition to body weight, is the cornerstone of current research in this field. Yet the assumptions upon which 2-compartment models are based were developed on a limited scale and their validity under specified conditions is questionable. Recent developments now allow quantification of previously unmeasured somatic constituents. The capacity to extend our models to 4 or more components is now at hand. Not only will this allow us to vastly expand our validation of two 2-compartment approaches, but our ability to explore new and important physiological questions is within reach. PMID: 2205585 [PubMed - indexed for MEDLINE] 6607. Diabetes Care. 1990 Mar;13(3):219-27. Regulation of glucose-transporter function. Kasanicki MA(1), Pilch PF. Author information: (1)Department of Biochemistry, Boston University School of Medicine, MA 02118. Glucose transport in mammals is mediated by a multigene family whose expression can be highly tissue specific. All cells express at least one transporter isoform in a constitutive fashion, because a certain level of glucose uptake is an absolute necessity, regardless of influences by various regulatory factors. The level of the constitutive transporter, usually the erythroid glucose-transporter isoform, can be regulated by environmental factors, e.g., nutrition and transformation. Certain cells express unique transporter isoforms, the quantitatively most important of which is the muscle-adipocyte glucose-transporter isoform that functions in response to insulin to clear most of the blood glucose after a meal. The available data suggest that the major insulin target tissues are uniquely able to produce this transporter isoform, sequester it in a unique organelle, and bring it to the cell surface in response to insulin. This insulin response is dramatically different from that seen in various fibroblastic cells, quantitatively and qualitatively, and suggests the expression in adipose tissue and muscle of a multigene program that defines the insulin-stimulated glucose transport of relevance to organismal glucose homeostasis. PMID: 2407477 [PubMed - indexed for MEDLINE] 6608. Diabetes Care. 1990 Mar;13(3):209-18. Molecular physiology of glucose transporters. Thorens B(1), Charron MJ, Lodish HF. Author information: (1)Whitehead Institute for Biomedical Research, Cambridge, MA 02142. Molecular cloning of cDNA encoding the human erythrocyte facilitated-diffusion glucose transporter (GT) has elucidated its structure and has permitted a careful study of its tissue distribution and of its involvement in processes such as insulin-stimulated glucose uptake by adipose cells or transformation-induced increase in glucose metabolism. An important outcome of these studies was the discovery that additional isoforms of this transporter were expressed in a tissue-specific manner; these comprise a family of structurally and functionally related molecules. Their tissue distribution, differences in kinetic properties, and differential regulation by ambient glucose and insulin levels suggest that they play specific roles in the control of glucose homeostasis. Herein, we will discuss the structure of three members of the GT family: erythroid/brain GT, liver GT, and adipose cell/muscle GT. In the light of their tissue-specific expression, kinetic parameters, and susceptibility to insulin action, we discuss their possible specific functions. PMID: 2407476 [PubMed - indexed for MEDLINE] 6609. Diabetes Care. 1990 Mar;13(3):198-208. Molecular biology of mammalian glucose transporters. Bell GI(1), Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fukumoto H, Seino S. Author information: (1)Howard Hughes Medical Institute, University of Chicago, IL 60637. The oxidation of glucose represents a major source of metabolic energy for mammalian cells. However, because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by membrane-associated carrier proteins that bind and transfer it across the lipid bilayer. Two classes of glucose carriers have been described in mammalian cells: the Na(+)-glucose cotransporter and the facilitative glucose transporter. The Na(+)-glucose cotransporter transports glucose against its concentration gradient by coupling its uptake with the uptake of Na+ that is being transported down its concentration gradient. Facilitative glucose carriers accelerate the transport of glucose down its concentration gradient by facilitative diffusion, a form of passive transport. cDNAs have been isolated from human tissues encoding a Na(+)-glucose-cotransporter protein and five functional facilitative glucose-transporter isoforms. The Na(+)-glucose cotransporter is expressed by absorptive epithelial cells of the small intestine and is involved in the dietary uptake of glucose. The same or a related protein may be responsible for the reabsorption of glucose by the kidney. Facilitative glucose carriers are expressed by most if not all cells. The facilitative glucose-transporter isoforms have distinct tissue distributions and biochemical properties and contribute to the precise disposal of glucose under varying physiological conditions. The GLUT1 (erythrocyte) and GLUT3 (brain) facilitative glucose-transporter isoforms may be responsible for basal or constitutive glucose uptake. The GLUT2 (liver) isoform mediates the bidirectional transport of glucose by the hepatocyte and is responsible, at least in part, for the movement of glucose out of absorptive epithelial cells into the circulation in the small intestine and kidney. This isoform may also comprise part of the glucose-sensing mechanism of the insulin-producing beta-cell. The subcellular localization of the GLUT4 (muscle/fat) isoform changes in response to insulin, and this isoform is responsible for most of the insulin-stimulated uptake of glucose that occurs in muscle and adipose tissue. The GLUT5 (small intestine) facilitative glucose-transporter isoform is expressed at highest levels in the small intestine and may be involved in the transcellular transport of glucose by absorptive epithelial cells. The exon-intron organizations of the human GLUT1, GLUT2, and GLUT4 genes have been determined. In addition, the chromosomal locations of the genes encoding the Na(+)-dependent and facilitative glucose carriers have been determined. Restriction-fragment-length polymorphisms have also been identified at several of these loci.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2407475 [PubMed - indexed for MEDLINE] 6610. Bull N Y Acad Med. 1990 Mar-Apr;66(2):164-80. How much dietary fat in therapeutic nutrition? Simko V(1). Author information: (1)SUNY Health Sciences Center, Brooklyn. Dietary fat has a less prominent role in realimentation than the alternate source of energy, carbohydrate. Presently available therapeutic diets, in typical feeding routines, provide only 3 to 120 g of fat per day. Three major factors contribute to fat underutilization: long-standing belief that fat is to blame for various vague symptoms of indigestion, misconception that daily fecal fat in excess of 7 g represents bowel dysfunction, and fear of fat-induced atherogenesis. None of these apply to refeeding starved and malnourished patients. The small intestine has a vastly underutilized capacity for fat absorption, and at the habitual fat intake of 100 g per day absorption is complete in the proximal one fifth of the gut. In patients requiring vigorous realimentation, the remaining small intestine should also be utilized. Dietary fat is well tolerated, and daily intakes of 500 g of polyunsaturated fat in a complete diet have not been associated with important side effects, while there was a significant improvement in body stores of fat and protein. Compared to diets high in carbohydrate, adequate intake of fat results in better nutrient utilization, less CO2 production and decreased lipogenesis and insulin requirements. Diets higher in fat are also better tolerated because of their lower volume and osmolality. The result is more effective absorption of calories and a faster nutritional recovery. Increased adipose tissue and protein reserve benefits patients who are in stress, immunocompromised, or debilitated. Adequate dietary fat should be considered for malnourished subjects with intact gastrointestinal function, and when intestinal absorptive capacity is reduced by surgery or disease. PMCID: PMC1809743 PMID: 2194611 [PubMed - indexed for MEDLINE] 6611. Electrophoresis. 1990 Mar;11(3):191-200. Application of two-dimensional gel electrophoresis in the study of cytoskeletal protein regulation during growth activation and differentiation. Ben-Ze'ev A(1). Author information: (1)Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel. Two-dimensional gel electrophoresis was used to study the regulation of cytoskeletal protein synthesis during growth activation and development of the differentiated phenotype. We demonstrated a correlation between the state of organization and the expression of the respective cytoskeletal protein by showing that depolymerization of microtubules leads to a rapid decrease in new tubulin synthesis. We found that the synthesis of vimentin in both fibroblasts and epithelial cells correlates with extensive cell spreading on the substrate, while cytokeratin synthesis is maximal when cell to cell contacts are abundant. The analysis of cytoskeletal elements, involved directly in the formation of cell contacts, revealed that the level of vinculin synthesis is dependent on the extent of adherent type of cell contacts formed. Moreover, we found that the transient disappearance of vinculin from adhesion plaques of quiescent fibroblasts in response to serum factors was followed by an induction of vinculin mRNA and protein synthesis. The morphological changes associated with establishment of the differentiated phenotype were also found to include changes in the expression of the cytoskeletal-extracellular matrix complex. This was demonstrated in several differentiating systems: in 3T3 preadipocytes which change their shape from a fibroblastic to a spherical shape when stimulated to differentiate with adipogenic medium, we observed a decrease in mRNA levels and in the synthesis of fibronectin, beta-integrin, and the microfilament proteins, vinculin, alpha-actinin, tropomyosin and actin. The culturing of these cells on a certain extracellular matrix prevented the morphological changes occurring in the presence of adipogenic medium and blocked the shifts in cytoskeletal- and differentiation-related gene expression. Similar changes in the organization and expression of cytoskeletal proteins were identified during maturation of primary ovarian granulosa cell cultures, stimulated with gonadotropic hormones to form highly steroidogenic cells. The cell rounding and aggregation occurring during this process were associated with a decreased synthesis of vinculin, alpha-actinin, actin and the nonmuscle tropomyosins. The physiological relevance of these changes was suggested by the observation that the level of tropomyosin mRNA was lower in follicles of animals at late stages of granulosa cell maturation when compared to earlier stages. The expression of tissue-specific and cytoskeletal proteins was also determined in primary cultures of liver hepatocytes, maintained under conditions either favorable for growth or for expression of liver-specific functions. When DNA synthesis was elevated, cytoskeletal protein synthesis was high and that of liver-specific proteins was low.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2188832 [PubMed - indexed for MEDLINE] 6612. J Nutr. 1990 Mar;120(3):233-42. Absorption, transport and distribution of vitamin E. Bjørneboe A(1), Bjørneboe GE, Drevon CA. Author information: (1)National Institute of Forensic Toxicology, University of Oslo, Norway. Vitamin E is the term used for eight naturally occurring fat-soluble nutrients called tocopherols. alpha-Tocopherol is essential, has the highest biological activity and predominates in many species. In humans vitamin E is the most important lipid soluble antioxidant and deficiency may cause neurological dysfunction, myopathies and diminished erythrocyte life span. alpha-Tocopherol is absorbed via the lymphatic pathway and transported in association with chylomicrons. In plasma, alpha-tocopherol is found in all lipoprotein fractions but mostly is associated with apo B-containing lipoproteins. alpha-Tocopherol is associated with very-low-density lipoprotein when it is secreted from the liver. In the rat, about 90% of total body mass of alpha-tocopherol is recovered in the liver, skeletal muscle and adipose tissue. Most alpha-tocopherol is located in the mitochondrial fractions and in the endoplasmic reticulum, whereas little is found in cytosol and peroxisomes. New clinical evidence from heavy drinkers and from experimental work in rats suggests that alcohol may increase oxidation of alpha-tocopherol. Increased demand for vitamin E has also been observed in premature infants and patients with malabsorption, but there is little evidence that the healthy population requires supplementation of vitamin E to a well-balanced diet. PMID: 2181082 [PubMed - indexed for MEDLINE] 6613. Trends Biochem Sci. 1990 Mar;15(3):108-12. Mechanism and evolution of the uncoupling protein of brown adipose tissue. Klingenberg M(1). Author information: (1)Institut für Physikalische Biochemie, Universität München, FRG. The uncoupling protein found in mitochondria from thermogenic brown adipose tissue is structurally very similar to two other mitochondrial carrier proteins transporting ADP/ATP and phosphate, respectively. Similarities are also seen with the mechanism of these carriers, which are part of a family of H+/OH(-)-substrate anion co-transporters, further strengthening the evidence that the uncoupling protein has evolved from this family of mitochondrial carrier proteins. PMID: 2158156 [PubMed - indexed for MEDLINE] 6614. Nutrition. 1990 Mar-Apr;6(2):131-7. Classification of obese patients and complications related to the distribution of surplus fat. Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgren's Hospital, University of Göteborg, Sweden. The relation between obesity and noninsulin-dependent diabetes mellitus is established. The weak association between obesity and cardiovascular disease or stroke might be attributable to a risk present only in a subgroup of obesity patients. Recent prospective studies have shown such a group to be characterized by abdominal localization of adipose tissue, reviving old empiric observations of such links. The sex-linked adipose tissue distribution is probably dependent on a balance between glucocorticoids and sex steroid hormones. The former are active mainly on intraabdominal adipose tissues through the high density of a specific receptor expressing lipoprotein lipase activity. This effect is counteracted by female sex steroid hormones, mainly progesterone, which promote fat deposition in the gluteal-femoral regions, utilized mainly during pregnancy and lactation. Testosterone stimulates lipid mobilization through transcriptional expression of beta-adrenergic receptors via a specific androgen receptor and also inhibits lipoprotein lipase activity. Intraabdominal adipose tissues, drained by the portal vein, have a very sensitive lipolytic system in men, based on an increased beta-adrenoceptor activity. This is probably a testosterone effect via the mechanisms mentioned. With testosterone deficiency, these mechanisms are less active, permitting accumulation of fat that can be reversed by testosterone substitution. Abdominal distribution of fat in men thus is probably a sign of relative testosterone deficiency.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2134524 [PubMed - indexed for MEDLINE] 6615. FASEB J. 1990 Feb 1;4(2):141-7. Hemodynamic and metabolic correlates in adipose tissue: pathophysiologic considerations. Crandall DL(1), DiGirolamo M. Author information: (1)Cardiovascular Research Department, American Cyanamid Company, Pearl River, New York 10965. Research efforts investigating the pathophysiology of adipose tissue have often focused separately on either the metabolic or cardiovascular components of an expanding fat mass. However, the growth and development of the fat cells and their vasculature are closely interrelated, a fact that has been established through more than a century of diverse studies of adipose tissue. Recently, the prevalence of obesity in the United States has stimulated investigations into the cardiovascular and metabolic correlates occurring with excessive lipid deposition and subsequent adipose tissue expansion. These investigations have resulted in conclusive evidence that, from a cardiovascular perspective, obesity results in an elevated blood volume and cardiac output, accompanied by an expansion of adipose water space, whereas from a metabolic aspect, the disease is characterized by adipocyte enlargement and associated alterations in metabolic pathways and hormonal responsiveness. Because these separate areas of research have independently shown interdepot differences in perfusion requirements and metabolic adaptations during the transition from the lean to obese state, adipocyte expansion may be partially dependent on the pattern of vascularity. This hypothesis is discussed by examining the integral relationship between the cardiovascular system and adipocyte metabolism, hopefully providing new insight into control of the pathophysiological processes of an expanding adipose organ. PMID: 2404816 [PubMed - indexed for MEDLINE] 6616. Infusionstherapie. 1990 Feb;17(1):24-7. Obesity and adipose tissue distribution as risk factors for the development of disease. A review. Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgren's Hospital, University of Göteborg, Sweden. Recent studies have shown the predictive power of abdominal distribution of adipose tissue for the development of cardiovascular disease, stroke, diabetes as well as strong associations to the previously known risk factors for these endpoints. The reason for the accumulation of abdominal fat might be due to an imbalance between cortisol and sex steroid hormones. Cortisol receptor density seems to be particularly high in abdominal adipose tissue, leading to expression of lipoprotein lipase activity primarily here. Progesterone and testosterone seems to counteract this, the former perhaps through competition with the cortisol receptor. Accumulation of intraabdominal fat, particularly in the tissues drained by the portal circulation, probably leads to high free fatty acid concentrations in the portal vein, because of the high lipolytic sensitivity of these tissues. This in turn seems to inhibit hepatic clearance of portal insulin, leading to peripheral hyperinsulinemia, insulin resistance, perhaps hypertension as well as hyperlipidemia via drive by free fatty acids of lipoprotein synthesis in the liver. These are risk factors for diabetes, cardiovascular disease and stroke. It is of interest that subjects with abdominal adipose tissue have several factors leading to increased cortisol and low sex steroid hormone secretion, including stress, high alcohol consumption and smoking. This might provide some of the background to this syndrome. PMID: 2140108 [PubMed - indexed for MEDLINE] 6617. J Clin Pathol. 1990 Feb;43(2):98-101. Aplastic anaemia associated with organochlorine pesticide: case reports and review of evidence. Rugman FP(1), Cosstick R. Author information: (1)Department of Haematology, Royal Liverpool Hospital. Three patients with aplastic anaemia had a history of substantial previous exposure to organochlorine pesticides. The temporal association between chemical exposure and the onset of first symptoms of anaemia was strongly supportive. Organochlorines have the property of lipid affinity and accumulation in adipose tissue. Objective evidence of clinically important concentrations of tissue pesticide residues may be a useful confirmation of previous exposure. In the patients studied the presence of Lindane (gamma hexachlorocyclohexane) was shown using gas chromatography/mass spectrometry with selective ion monitoring of fragments obtained from one heavily exposed patient, with concentrations about five times greater than a matched control. The presence of clinically important tissue concentrations of pentachlorophenol was also confirmed in a second patient exposed to this agent. The long term safety of organochlorine pesticides remains doubtful as they were introduced before adequate toxicological screening tests had been developed. The central registration of possible haematological adverse reactions, however, forms an important epidemiological method in the study of environmental chemical hazards and should be complied with whenever possible. PMCID: PMC502287 PMID: 1690760 [PubMed - indexed for MEDLINE] 6618. Philos Trans R Soc Lond B Biol Sci. 1990 Jan 30;326(1237):669-85, discussion 685-6. Mammalian hibernation. Nedergaard J(1), Cannon B. Author information: (1)Wenner-Gren Institute, Arrhenius Laboratories, University of Stockholm, Sweden. In mammalian hibernation, the body temperature approaches that of the surroundings, allowing large savings in energy costs of basal metabolism and eliminating the need for heat production to compensate for heat loss. During entry into hibernation, heat production ceases while the body temperature set-point gradually decreases during slow-wave sleep. In the hibernating phase, the animal copes with problems concerning the maintenance of ion gradients, possible membrane phase transitions and the risk of ventricular fibrillation. In the arousal phase, the main part of the heat and practically all the necessary substrate comes from brown adipose tissue. The hibernation season is preceded by a preparatory phase. It may be concluded that hibernation is a practical, and perhaps even enviable, solution to a mammalian problem. PMID: 1969651 [PubMed - indexed for MEDLINE] 6619. Adv Cancer Res. 1990;54:235-72. The lymphopoietic microenvironment in bone marrow. Kincade PW(1). Author information: (1)Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City 73104. PMID: 2404379 [PubMed - indexed for MEDLINE] 6620. Horm Metab Res Suppl. 1990;24:41-8. Tracer studies of in vivo insulin action and glucose metabolism in individual peripheral tissues. Kraegen EW(1), Jenkins AB, Storlien LH, Chisholm DJ. Author information: (1)Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia. The ability to study in vivo insulin action in specific muscle types and other individual tissues has been considerably enhanced following adaptation of the euglycemic clamp technique to the rat. The importance of this model derives particularly from its combination with administration of 3H-2-deoxyglucose and 14C-glucose. Analysis of the metabolic fate of these tracers at the conclusion of the clamp enables an assessment to be made of insulin action at both the whole body and the individual tissue level, the latter by estimating a tissue-specific glucose metabolic rate (from 3H-2-deoxyglucose phosphorylation). Information on stored vs utilised glucose can be obtained by simultaneously estimating 14C-glucose incorporation into glycogen and/or lipids. This review briefly considers the basis of the technique and its recent application. It has been used to demonstrate in the rat that in vivo insulin sensitivity differs widely among insulin target tissues, such as adipose tissue, red and white skeletal muscle, and cardiac muscle. The technique has provided a means to study how factors such as diet, exercise, pregnancy, stress hormones and pharmacological agents modify in vivo insulin action in muscle and other tissues, to compare insulin and exercise as stimuli to muscle glucose uptake, and to examine factors which might be important in the aetiology of muscle insulin resistance. These new tracer techniques for in vivo use with the glucose clamp have narrowed the gap that exists between established whole body and cellular in vitro approaches to the study of insulin action and glucose metabolism. PMID: 2272625 [PubMed - indexed for MEDLINE] 6621. Horm Res. 1990;33 Suppl 4:19-24. Growth hormone and body composition. Bengtsson BA(1), Brummer RJ, Bosaeus I. Author information: (1)Department of Internal Medicine II, University of Gothenburg, Göteborg, Sweden. Through its anabolic, lipolytic and antinatriuretic actions, GH has profound effects on body composition. In untreated acromegaly, body weight, body cell mass and extracellular water are increased simultaneously with a decrease of body fat. After successful treatment, extracellular water and body fat normalize, but cell mass remains high. The changes in cell mass, body fat and extracellular water observed in acromegaly suggest different dose-response relationships between GH and these parameters. The relationship between GH concentration and the lipolytic actions of GH is more linear, while the relationship between GH and excess extracellular water is more curvilinear. The sodium-retaining effect of GH seems to be mediated by stimulation of the Na(+)-K+ pump. At higher GH levels, the pump activity is counteracted by an alleged sodium transport inhibitor. In GH-deficient children, GH treatment is followed by rapid loss of adipose tissue and muscular gain. The influence of GH on body composition in GH-deficient adults has recently received attention. Compared to normal subjects, these patients are overweight and have decreased cell mass. Replacement treatment with GH restores body composition towards normal. PMID: 2245966 [PubMed - indexed for MEDLINE] 6622. Acta Paediatr Scand Suppl. 1990;367:132-6. Actions of growth hormone on adipose tissue: possible involvement of autocrine or paracrine factors. Goodman HM(1), Schwartz Y, Tai LR, Gorin E. Author information: (1)Department of Physiology, University of Massachusetts Medical School, Worcester. PMID: 2220378 [PubMed - indexed for MEDLINE] 6623. J Reprod Fertil Suppl. 1990;41:17-23. Developmental regulation and tissue-specific expression of a chimaeric phosphoenolpyruvate carboxykinase/bovine growth hormone gene in transgenic animals. McGrane MM(1), Yun JS, Roesler WJ, Park EA, Wagner TE, Hanson RW. Author information: (1)Pew Center for Molecular Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106. Expression of the bovine growth hormone (bGH) gene, directed by the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter, in transgenic animals was investigated. Different lengths of the 5' PEPCK promoter-regulatory domain were utilized to control bGH expression; these included -2000/+73, -460/+73, -355/+73, and -174/+73. The chimaeric PEPCK/bGH gene containing -460/+73 of PEPCK 5' flanking sequence (PEPCK/bGH(460] is regulated by cAMP, insulin, and dexamethasone in the same manner as the endogenous PEPCK gene. This PEPCK promoter-regulatory domain also controls the tissue-specific expression of the bGH gene to liver, kidney, adipose tissue, jejunum and mammary gland. Furthermore, the correct developmental pattern of expression is observed in the mouse lines which contain PEPCK/bGH(460). The transgene mRNA is not detected during fetal development until Day 19. At Day 1 after birth, due to alterations in the insulin:glucagon ratio, the amounts of transgene mRNA are greatly increased, similar to the endogenous PEPCK gene. PMID: 2213709 [PubMed - indexed for MEDLINE] 6624. Clin Exp Hypertens A. 1990;12(5):817-30. Insulin resistance, energy balance and sympathetic nervous system activity. Landsberg L(1). Author information: (1)Department of Medicine, Harvard Medical School, Boston, MA. Insulin resistance and hyperinsulinemia are commonly associated with hypertension in the obese. The nature of this association is obscure. An hypothesis is developed that attributes obesity-related hypertension to sympathetic stimulation. The relationship between insulin and the sympathetic nervous system (SNS) has its origins in the mediation of dietary thermogenesis. Fasting suppresses while carbohydrate and fat feeding stimulate sympathetic activity. Insulin-mediated glucose metabolism within critical central neurons links dietary intake and central sympathetic outflow. The sympathetic nervous system, in turn, contributes to changes in metabolic rate that accompany alterations in dietary intake. It is hypothesized that insulin resistance is a mechanism recruited in the obese to limit further weight gain and stabilize body mass. Insulin-mediated sympathetic stimulation is one mechanism that may restore energy balance in the obese since the obese are not resistant to the stimulatory effect of insulin on the SNS. Sympathetically mediated stimulation of the heart, vasculature and kidney contributes, in genetically predisposed individuals, to the development of hypertension. Viewed in this light, obesity-related hypertension is the unfortunate by-product of an adaptive mechanism (insulin resistance) recruited to restore energy balance in the obese. Possible implications of this formulation are discussed. PMID: 2208753 [PubMed - indexed for MEDLINE] 6625. Clin Exp Hypertens A. 1990;12(5):783-94. Abdominal obesity and risk. Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgren's Hospital, University of Göteborg, Sweden. PMID: 2208750 [PubMed - indexed for MEDLINE] 6626. Eksp Med Morfol. 1990;29(1):57-64. [The molecular mechanisms of hormonally regulated glucose transport]. [Article in Bulgarian] Mitev V, Sirakov L. PMID: 2204529 [PubMed - indexed for MEDLINE] 6627. Reprod Nutr Dev. 1990;30(3):281-95. [Gene expression regulation of adipocyte differentiation: cell cycle and hormones]. [Article in French] Grimaldi P(1). Author information: (1)CNRS, Centre de biochimie, faculté des sciences, Nice, France. The adipose conversion of cultured preadipose cells involves the activation of numerous genes and is controlled by various adipogenic and mitogenic factors. The differentiation program can be divided into early and late events. Early events are triggered by growth arrest at the G1/S boundary and characterized by the activation of a set of genes (pOb24, lipoprotein lipase, etc.). The expression of the terminal differentiation-related genes takes place after a limited growth resumption of early markers containing cells and requires the presence of permissive hormones (growth hormone and triiodothyronine). Insulin acts solely as a modulator in the expression of the terminal differentiation-related genes. In vivo studies suggest that the acquisition of new adipocytes might result from terminal differentiation of dormant, already committed (pOb24 positive) cells when exposed to appropriate mitogenic or adipogenic stimuli. PMID: 2204347 [PubMed - indexed for MEDLINE] 6628. Horm Metab Res Suppl. 1990;22:11-7. Significance of the Randle-Mechanism in the etiology of diabetes type II. Felber JP(1). Author information: (1)Département de Médecine Interne, Centre Hospitalier, Universitaire Vaudois, Lausanne, Switzerland. In 1963, Randle, Garland, Hales and Newsholme proposed the existence of a glucose fatty-acid cycle in which excess lipid oxidation leads to inhibition of glucose oxidation in muscle tissue. Calorimetric studies confirmed these observations in man. However, as the rate of glucose oxidation is limited in the resting state, a defect in glucose oxidation can only have limited effects on glucose tolerance. The demonstration, by our group, of inhibition of glucose storage following increased lipid oxidation has suggested that excess lipids might induce glucose intolerance through an inhibitory effect on glucose storage. This might be explained by a decrease in glycogen mobilization (a factor that regulates glucose storage) as a consequence of the inhibition of glucose oxidation by excess fatty acids, according to Randle. In obesity, the resistance to glucose storage is present as a constant phenomenon. It is overcome by adaptation of the glycemic response to carbohydrate ingestion. This rise in glycemia, appearing as impaired glucose tolerance, allows glucose to be stored in spite of the resistance to glucose storage. But, simultaneously, this rise in glycemia decreases the possibility for glycogen mobilization, thus further limiting glucose storage. With the duration of obesity and the persistence of the hyperlipacidemia, when the glycemic response to a meal does not return any more to basal levels, the capacity for glucose storage becomes markedly impaired, so that glucose intolerance reaches the stage of diabetes. In type II diabetes of the obese, decrease in insulin response appears a late phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2202623 [PubMed - indexed for MEDLINE] 6629. Annu Rev Nutr. 1990;10:383-95. Appetite regulation by gut peptides. Morley JE(1). Author information: (1)Geriatric Research Education and Clinical Center, St. Louis Veterans Administration Medical Center, Missouri. A number of gastrointestinal hormones that are released from the gut in response to intraluminal food stuffs have been shown to play a role in producing satiety. Some of these hormones apparently activate ascending vagal fibers that send messages to the nucleus tractus solitarius, and perhaps from there messages are sent to the paraventricular nucleus of the hypothalamus. Not only do gastrointestinal hormones play a role in the termination of a meal but they also appear to modulate energy metabolism (at least in rodents) through the activation of brown adipose tissue. PMID: 2200469 [PubMed - indexed for MEDLINE] 6630. Annu Rev Biochem. 1990;59:689-710. Biochemical aspects of obesity. Lardy H(1), Shrago E. Author information: (1)Institute for Enzyme Research, University of Wisconsin, Madison 53705. PMID: 2197988 [PubMed - indexed for MEDLINE] 6631. Journ Annu Diabetol Hotel Dieu. 1990:27-31. [Brown adipose tissue: physiologic effector of thermogenesis]. [Article in French] Ricquier D(1). Author information: (1)Centre de Recherche sur la Nutrition, Centre National de la Recherche Scientifique, Meudon. PMID: 2195211 [PubMed - indexed for MEDLINE] 6632. Ann N Y Acad Sci. 1990;587:339-50. Specificity in metabolic effects of cachectin/TNF and other related cytokines. Kawakami M(1), Watanabe N, Ogawa H, Murase T, Yamada N, Sando H, Shibata S, Oda T, Takaku F. Author information: (1)Clinical Research Institute, National Medical Center Hospital, Tokyo, Japan. PMID: 2193580 [PubMed - indexed for MEDLINE] 6633. Biochem Cell Biol. 1990 Jan;68(1):17-23. Relationship of phospholipid hexagonal phases to biological phenomena. Epand RM(1). Author information: (1)Department of Biochemistry, McMaster University, Hamilton, Ont., Canada. Phospholipid bilayers can undergo morphological rearrangements to other phases. The formation of one of these nonbilayer phases, the hexagonal phase, is preceded by an increase in the hydrophobicity of the bilayer surface and a destabilization of the bilayer structure. Certain membrane additives promote, while others inhibit, the formation of the hexagonal phase. Many of the molecular features that determine this phase preference are understood. Some of the properties of membranes are modulated by agents that affect the relative stability of the bilayer and hexagonal phases. Addition of bilayer stabilizers to a membrane decreases its fusogenic behaviour. One such bilayer stabilizer is cholesterol sulfate, which may function physiologically to inhibit the fusion of sperm cells. Several antiviral agents are also found to be bilayer stabilizers and some have been shown to inhibit membrane fusion phenomena. Another biological property that is modulated in a predictable manner by agents which affect the bilayer-hexagonal phase equilibrium is insulin-promoted glucose uptake in adipocytes. Bilayer stabilizers inhibit this process showing that the effects of insulin can be modulated by the bulk biophysical properties of the membrane. The activity of a number of membrane-bound enzymes is also lowered by bilayer stabilizers. Neutral and zwitterionic bilayer stabilizers are inhibitors of protein kinase C. Thus, the alteration of the bilayer-hexagonal phase transition by drugs may provide a useful parameter for predicting their effects on biological membranes. PMID: 2190616 [PubMed - indexed for MEDLINE] 6634. Neurosci Biobehav Rev. 1990 Summer;14(2):117-23. Does dietary hyperphagia contradict the lipostatic theory? Ramirez I(1). Author information: (1)Monell Chemical Senses Center, Philadelphia, PA 19104-3308. It has frequently been suggested that body weight or fat somehow exerts an inhibitory influence on food intake in a way that acts to maintain a stable body weight or fat. The principal evidence supporting this idea is that animals that have been induced to overeat and become overweight by various means, eat less than control rats when they are permitted to eat freely. If the degree of suppression of appetite by overweight is as large as several experiments suggest, then dietary hyperphagia should be self-limiting. Any overeating induced by dietary treatments should disappear after animals become moderately overweight. Animals fed some kinds of hyperhagia-promoting diets do show this pattern. However, animals fed other kinds of diets do not show this pattern, and with most diets, dietary hyperphagia continues for extended periods. This implies that either 1) overweight does not suppress appetite as much as suggested by various authorities, 2) dietary manipulations can override normal regulatory mechanisms, or 3) certain diets induce irreversible changes in body fat that are not evident from changes in body weight. PMID: 2190112 [PubMed - indexed for MEDLINE] 6635. Adv Second Messenger Phosphoprotein Res. 1990;24:511-6. Insulin resistance in type II diabetes mellitus. Rizza R(1), Butler P. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905. In vivo studies indicate that patients with NIDDM have defects in both insulin secretion and insulin action. The decrease in insulin action is due to both hepatic and extrahepatic insulin resistance. The impairment in glucose uptake is associated with alterations in both oxidative and nonoxidative disposal. Defective glucose transport may limit both of these processes. NIDDM also is associated with increased concentrations and rates of oxidation of plasma free fatty acids. Insulin resistance appears to be familial and in at least some individuals antedates glucose intolerance. In vitro studies indicate that insulin resistance can involve a variety of insulin sensitive tissues including adipocytes, muscle and liver. While most studies note that insulin binding and insulin receptor kinase activity are decreased in insulin sensitive tissues in obese patients with NIDDM, further delineation of the contribution of obesity and diabetes is required. Alterations in glucose transporter number and function likely account at least in part for impaired glucose transport. The cause of the alterations in other insulin responsive pathways and the role of an abnormal metabolic milieu versus intrinsic cellular defects remain to be established. PMID: 2169826 [PubMed - indexed for MEDLINE] 6636. Trends Pharmacol Sci. 1990 Jan;11(1):3-7. Is the adipocyte beta-adrenoceptor a prototype for the recently cloned atypical 'beta 3-adrenoceptor'? Zaagsma J(1), Nahorski SR. Author information: (1)Department of Pharmacology and Therapeutics, University of Groningen, Netherlands. PMID: 2155496 [PubMed - indexed for MEDLINE] 6637. Biochem Soc Symp. 1990;56:137-54. Guanine-nucleotide-binding proteins in diabetes and insulin-resistant states. Bushfield M(1), Griffiths SL, Strassheim D, Tang E, Shakur Y, Lavan B, Houslay MD. Author information: (1)Institute of Biochemistry, University of Glasgow, Scotland, U.K. PMID: 2124120 [PubMed - indexed for MEDLINE] 6638. Przegl Lek. 1990;47(11):760-2. [Hormonal regulation of lipoprotein lipase activity]. [Article in Polish] Piskorska D(1), Kopieczna-Grzebieniak E. Author information: (1)Katedry i Zakładu Biochemii i Chemii Sl. AM w Katowicach. PMID: 2098844 [PubMed - indexed for MEDLINE] 6639. Biotechnol Genet Eng Rev. 1990;8:97-131. Immunological approaches for manipulation of animal growth, body composition and fecundity. Flint DJ(1). Author information: (1)Hannah Research Institute, Ayr, Scotland, UK. The ability to manipulate certain physiological processes by using the immune system, so as to regulate endocrine secretions and/or actions is clearly possible. The dramatic effects of immunocastration and the ability to increase ovulation rates in sheep are probably the best examples. Other approaches along similar lines have produced equivocal results, the effects of immunization against somatostatin being the most notable case. Although anti-idiotypic antibody approaches to producing hormone mimics have also been shown to be attainable and, indeed, possibly involved in certain auto-immune dysfunctions of the endocrine system, to date no successful applications of this approach have been demonstrated in commercial livestock. The ability to enhance hormone action using antibodies is an extremely promising area. Its prospects probably hinge on the ability to synthesize suitable short peptides which will mimic epitopes on the hormone and so permit the development of active immunization techniques to produce polyclonal antibodies of restricted and enhancing specificity. It seems less likely that administration of hormones pre-complexed to monoclonal antibodies has any potential as a practical approach to manipulating animal productivity. All of these approaches involving active immunization suffer the same limitations: the highly variable response of individual animals and the general inability to regulate the duration of the response; a need to find suitable adjuvants to replace the almost universally used and commercially unacceptable Freund's adjuvant; and the problem of trying to generate what, in most cases, is an auto-immune response. A second group of approaches consists of attempts to use antibodies in their classical role, that is by targeting antigens or cells for destruction by the immune system. These include, for example, antibodies directed against adipose tissue or cytotoxic antibodies to specific hormones aimed at destruction of the hormone-secreting cells. Since these are passive immunization techniques, the antibodies can be assessed carefully in vitro and administered in appropriate doses. However, success in these applications is largely dependent on the inability of damaged tissues to regenerate, since retreatment is generally precluded because of the anti-immunoglobulin response induced in treated animals. Toleragenic forms of such antibodies or the use of appropriate immunosuppressants may ultimately remove this limitation. Perhaps the greatest current limitation to the use of all of these techniques in animal production systems, however, is public resistance to the use of such techniques.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2094276 [PubMed - indexed for MEDLINE] 6640. Klin Wochenschr. 1990;68 Suppl 22:7-11. [Postprandial fatty acid metabolism]. [Article in German] Oette K(1). Author information: (1)Institut für Klinische Chemie, Universität Köln. In accordance with metabolic properties in the mucosal and liver cells, the exogenous fatty acids may be classified as short chain (C4 and C6), medium chain (C8 and C10), transitional (C12 and C14) and long chain (C16 upward) fatty acids. The postprandial fatty acid metabolism takes place in two phases. In the first, approximately 8 hour phase, the clearance of chylomicrons and most of the chylomicron remnants as well as the uptake of short and medium chain fatty acids by the liver are completed. Most of the exogenous long chain fatty acids (chylomicron fatty acids) are cleared extrahepatically. However, about 10% of the long chain fatty acids are taken up by the liver, and during the second postprandial phase, lasting about 24 hours, the liver secretes most of these exogenous fatty acids with very low density lipoproteins. The exogenous fatty acids may circulate between the liver and adipose tissue until they are finally metabolized mainly in extrahepatic tissues. PMID: 2087084 [PubMed - indexed for MEDLINE] 6641. Int J Obes. 1990;14 Suppl 3:77-91; discussion 91-2. Obesity--a state of reduced sympathetic activity and normal or high adrenal activity (the autonomic and adrenal hypothesis revisited). Bray GA(1). Author information: (1)Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033. In this paper I have briefly reviewed the effect of nutrition on the sympathetic nervous system. I have also examined the changes in sympathetic activity in experimental models of obesity and leanness. Finally, I have tried to relate these two sets of information to the regulation of energy store by the autonomic nervous system in a nutrient balance model for regulation of food intake. PMID: 2086518 [PubMed - indexed for MEDLINE] 6642. Int J Obes. 1990;14 Suppl 3:69-73; discussion 74-6. A re-assessment of the regulation of adiposity and appetite by the brain insulin system. Woods SC(1), Figlewicz Lattemann DP, Schwartz MW, Porte D Jr. Author information: (1)Department of Psychology, University of Washington, Seattle. We have provided strong support for the hypothesis that the pancreatic hormone, insulin, provides a signal to the brain indicating the level of adiposity. Because insulin is found in the cerebrospinal fluid (CSF) in direct proportion to plasma levels, and because changes of plasma insulin result in subsequent changes of CSF insulin, we previously hypothesized that the blood-borne insulin signal enters the central nervous system by initially entering the CSF and then diffuses into the brain. Such a route explained the time lag for influences of insulin upon food intake and body weight. Recent evidence suggests that insulin may enter the brain directly through brain capillaries, raising the possibility that what is measured in the CSF may not be indicative of insulin on its way into critical brain areas. Implications of this change of route of entry of insulin into the brain for the regulation of food intake and body weight are discussed. PMID: 2086517 [PubMed - indexed for MEDLINE] 6643. Int J Obes. 1990;14 Suppl 3:53-66; discussion 66-7. Body fat and the metabolic control of food intake. Friedman MI(1). Author information: (1)Monell Chemical Senses Center, Philadelphia, PA 19104. The role of body fat in the control of food intake is considered from the point of view that the oxidation of metabolic fuels generates a signal that governs feeding behavior. According to this perspective, the storage and mobilization of fat affect food intake indirectly by altering fuel oxidation. Hyperphagia during the development of obesity is thus treated as an appropriate response to a primary metabolic defect that causes fuels to be stored rather than oxidized. Evidence is presented that changes in insulin level and the activity of carnitine palmitoyltransferase I modulate feeding by altering the partitioning of fatty acids. The possibility that dietary interactions, acting through these mechanisms, may cause overeating of high-fat diets is discussed. It is proposed that the signal for feeding originates in the liver when both fatty acids and glucose are unavailable for oxidation. PMID: 2086516 [PubMed - indexed for MEDLINE] 6644. Int J Obes. 1990;14 Suppl 3:135-52. Perspectives in adipose tissue physiology. Hollenberg CH(1). Author information: (1)Banting and Best Diabetes Centre, Faculty of Medicine, University of Toronto, Canada. PMID: 2086507 [PubMed - indexed for MEDLINE] 6645. J Exp Zool Suppl. 1990;4:98-105. Endocrine-nutrition interactions in birds. Scanes CG(1), Griminger P. Author information: (1)Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick 08903. This review will discuss the uses of avian models, particularly the chicken, to examine nutrition-endocrine interactions. The chicken has been employed extensively to examine nutritional effects. The effects of fasting, protein deficiency and calcium deficiency on endocrine status have been the subject of intense investigation in young chicks and adult female chickens. The ratio of circulating concentrations of triiodothyronine (T3) and thyroxine (T4) is substantially changed by fasting or protein deficiency. Similarly, protein deficiency reduces circulating concentrations of insulin-like growth factor I (IGFI) while protein deficiency increases growth hormone (GH). Moreover, protein deficiency increases the sensitivity and responsiveness of adrenocortical cells. The chicken also as advantages for studying diabetes, endocrine pancreatic functioning due to the splenic lobe of the pancreas being predominantly endocrine in nature, and the cellular mechanism of GH on chicken adipose tissue. The adult female chicken with its high calcium requirement is a unique system for examining nutritional effects on reproduction. PMID: 1974808 [PubMed - indexed for MEDLINE] 6646. J Cardiovasc Pharmacol. 1990;16 Suppl 9:S1-7. Pathophysiology of hyperlipidemia in diabetes mellitus. Abbate SL(1), Brunzell JD. Author information: (1)Department of Medicine, University of Washington, Seattle 98195. Many lipoprotein abnormalities are seen in the untreated, hyperglycemic diabetic patient. The non-insulin-dependent diabetic (NIDDM) patient with mild fasting hyperglycemia commonly has mild hypertriglyceridemia due to overproduction of TG-rich lipoproteins in the liver, associated with decreased high-density lipoprotein (HDL) cholesterol levels. The more hyperglycemic untreated NIDDM and insulin-dependent diabetic (IDDM) patient have mild to moderate hypertriglyceridemia due to decreased adipose tissue and muscle lipoprotein lipase, (LPL) activity. These patients also have decreased HDL cholesterol levels associated with defective LPL catabolism of TG-rich lipoproteins. Treatment of diabetes with oral sulfonylureas or insulin corrects most of the hypertriglyceridemia and some of the decrease in HDL cholesterol. The abnormality in adipose tissue LPL activity corrects slowly over several months of therapy. The treated IDDM patient often has normal lipoprotein levels. The treated NIDDM patient may continue to have mild hypertriglyceridemia, increased intermediate-density lipoprotein levels, small dense low-density lipoproteins (LDL) with increased apoprotein B, and decreased HDL cholesterol levels. The central, abdominal distribution of adipose tissue in IDDM is associated with insulin resistance, hypertension, and the above lipoprotein abnormalities. Improvement in glucose control, in the absence of weight gain, leads to lower triglyceride and higher HDL cholesterol levels. In addition, the diabetic patient is prone to develop other defects that, in themselves, lead to hyperlipidemia, such as proteinuria, hypothyroidism, and hypertension, treated with thiazide diuretics and beta-adrenergic-blocking agents. When a diabetic patient independently inherits a common familial form of hypertriglyceridemia, he might develop the severe hypertriglyceridemia of the chylomicronemia syndrome. PMID: 1710739 [PubMed - indexed for MEDLINE] 6647. Duodecim. 1990;106(6):477-83. [Adipose tissue]. [Article in Finnish] Ohisalo JJ(1). Author information: (1)Helsingin yliopiston lääketieteellisen kemian laitos, Helsinki, Finland. PMID: 1670308 [PubMed - indexed for MEDLINE] 6648. Duodecim. 1990;106(6):457-63. [Who is obese?]. [Article in Finnish] Heliövaara M(1). Author information: (1)Kansaneläkelaitos, Helsinki, Finland. PMID: 1670305 [PubMed - indexed for MEDLINE] 6649. Duodecim. 1990;106(4):360-5. [Chlorinated dioxins and dibenzofurans--threat to the national health?]. [Article in Finnish] Vainio H(1), Hesso A, Jäppinen P. Author information: (1)Työterveyslaitos, Helsinki, Finland. PMID: 1670100 [PubMed - indexed for MEDLINE] 6650. Harefuah. 1989 Dec 15;117(12):437-41. [Regional differences in fat metabolism--diabetogenic and atherogenic obesity]. [Article in Hebrew] Vague J, Vague P, Jubelin J, Barre A. PMID: 2695425 [PubMed - indexed for MEDLINE] 6651. Biochim Biophys Acta. 1989 Dec 14;1014(3):247-58. Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. Cooper GJ(1), Day AJ, Willis AC, Roberts AN, Reid KB, Leighton B. Author information: (1)Department of Biochemistry, University of Oxford, U.K. Amylin, the major peptide component of the islet amyloid commonly found in the pancreases of patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM), is a recently discovered islet polypeptide. This peptide has many structural and functional features suggesting that it is a novel hormone, which may control carbohydrate metabolism in partnership with insulin and other glucoregulatory factors. Amylin is synthesised in, and probably secreted from, the beta-cells of the islets of Langerhans, where it has recently been immunolocalised to secretory granules. DNA cloning studies indicate that in the human and the rat, amylin is generated from a precursor, preproamylin, which displays a typical signal peptide followed by a small prohormone-like sequence containing the amylin sequence. The presence of the signal peptide suggests that amylin is secreted and plays a physiological role. Amylin is probably generated by proteolytic processing similar to that for proinsulin and other islet prohormones. The human amylin gene encodes the complete polypeptide precursor in two exons which are separated by an intron of approx. 5 kb, and is located on chromosome 12. Amylin is a potent modulator of glycogen synthesis and glucose uptake in skeletal muscle, and is capable of inducing an insulin-resistant state in this tissue in vitro, and perhaps also in the liver in vivo. In normal metabolism, amylin could act in concert with insulin as a signal for the body to switch the site of carbohydrate disposal from glycogen to longer-term stores in adipose tissue, by making skeletal muscle relatively insulin-resistant, whilst at the same time leaving rates of insulin-stimulated carbohydrate metabolism in adipose tissue unaltered. Several lines of evidence now implicate elevated amylin levels in the pathogenic mechanisms underlying NIDDM, and suggest to us that the obesity which frequently accompanies this syndrome is a result of, rather than a risk factor for, NIDDM. Following the beta-cell destruction which occurs in type 1 (insulin-dependent) diabetes mellitus (IDDM), it is probable that amylin secretion disappears in addition to that of insulin. As patients with insulin-treated IDDM frequently experience problems with hypoglycaemia, and as amylin acts to modulate the action of insulin in various tissues, it is possible that amylin deficiency may contribute to morbidity in insulin-treated IDDM, perhaps through the loss of a natural damping mechanism which guards against hypoglycaemia under conditions of normal physiology. PMID: 2690958 [PubMed - indexed for MEDLINE] 6652. Curr Opin Cell Biol. 1989 Dec;1(6):1116-21. Adipocyte differentiation and gene expression. Sul HS(1). Author information: (1)Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. PMID: 2699800 [PubMed - indexed for MEDLINE] 6653. Arkh Anat Gistol Embriol. 1989 Dec;97(12):10-4. [The immune system and age]. [Article in Russian] Sapin MR. Basing on numerous facts, obtained during last years at investigation of the immune system organs, a definite idea has been formed on peculiarities of their structure during certain stages of human ontogenesis. The immune organs appear early in embryogenesis and by birth they have reached their morphological maturation. This is evident as formation of diffuse lymphoid tissue in lymphoid noduli, that can have germinative centers, where young cells of the lymphoid line are formed. The immune system organs develop especially quickly after birth during first years of the postnatal ontogenesis. The peak in development of the organs of immunogenesis, amount and size of the lymphoid noduli occurs during the childhood and adolescent age. Each immune organ has its peculiarities that are determined by their place in the organism, value and intensity of antigenic effect. Beginning from the adolescence and youth amount of the lymphoid tissue and lymphoid noduli in the organs decreases, in their place connective and adipose tissue grows out. PMID: 2698610 [PubMed - indexed for MEDLINE] 6654. Diabetologia. 1989 Dec;32(12):831-8. The regulation of glucose transport in insulin-sensitive cells. Joost HG(1), Weber TM. Author information: (1)Institute of Pharmacology and Toxicology, University of Göttingen, FRG. PMID: 2693163 [PubMed - indexed for MEDLINE] 6655. Diabetes Metab Rev. 1989 Dec;5(8):665-89. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Caro JF(1), Dohm LG, Pories WJ, Sinha MK. Author information: (1)Department of Medicine, School of Medicine, East Carolina University, Greenville, North Carolina 27858. PMID: 2693017 [PubMed - indexed for MEDLINE] 6656. J Am Geriatr Soc. 1989 Dec;37(12):1171-87. The aging fat cell. Remacle C(1), Hauser N. Author information: (1)University of Louvain, Laboratory of Cell Biology, Louvain-la-Neuve, Belgium. PMID: 2687352 [PubMed - indexed for MEDLINE] 6657. Infusionstherapie. 1989 Dec;16(6):282-4. Thermogenesis and brown fat: relevance to human obesity. Stock MJ(1). Author information: (1)Department of Physiology, St. George's Hospital Medical School, University of London, UK. Brown adipose tissue (BAT) is a specialized thermogenic tissue, which is highly vascularized and richly innervated with sympathetic nerves. Due to the high thermogenic capacity (500 W/kg) even very small quantities such as those found in adult man can significantly influence het production. As little as 50 g BAT could make a contribution of 10-15% to energy turnover in man. This would be more than sufficient to cause large differences in fat deposition between individuals with active or inactive dietary induced thermogenesis. Recent research has revealed the presence of an atypical beta-adrenoreceptor on BAT, tentatively designated as beta 3-adrenoreceptor. The development of beta 3-agonists offers an opportunity to treat obesity without the cardiovascular and other undesirable side-effects of conventional adrenergic agonists. PMID: 2560467 [PubMed - indexed for MEDLINE] 6658. Biochim Biophys Acta. 1989 Nov 23;977(2):123-41. Slip and leak in mitochondrial oxidative phosphorylation. Murphy MP(1). Author information: (1)Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. During oxidative phosphorylation by mammalian mitochondria part of the free energy stored in reduced substrates is dissipated and energy is released as heat. Here I review the mechanisms and the physiological significance of this phenomenon. PMID: 2553111 [PubMed - indexed for MEDLINE] 6659. Baillieres Clin Endocrinol Metab. 1989 Nov;3(3):869-86. The endocrine control of the onset of thermogenesis at birth. Gunn TR, Gluckman PD. The experimental studies in the fetal sheep demonstrate that the central hypothalamic mechanisms for responding to a cold stress have differentiated well before birth. There are several major determinants of the initiation of maximal thermogenesis at birth. These are cutaneous cooling, oxygenation and separation from the placenta. Firstly the stimulation of cutaneous cold receptors regulates sympathetic nervous system activity, primarily local noradrenaline release from sympathetic nerve termini to the brown adipocyte adrenoreceptors. Circulating catecholamines, the euthyroid state and other hormones also play a role. Secondly an increase in oxygen delivery to brown adipose tissue through increased oxygen content and increased blood flow is required. Finally, our observations suggest that separation from the placenta is necessary for maximal nonshivering thermogenesis. The effects on thermogenesis of interrupting and reestablishing placental flow are rapid and reversible. Umbilical cord occlusion is the signal for a rapid increase in thermogenesis, while the release of cord occlusion is followed by an equally rapid fall in thermogenesis. This strongly suggests the presence of a placental inhibitor of brown adipose tissue thermogenesis. The problem of the regulation of growth and recruitment of brown adipose tissue in the fetus despite the lack of thermal stress in utero may be resolved by this evidence for an inhibitory factor of thermogenesis produced by the placenta. The withdrawal of the inhibitor at birth by separation from the placenta will allow the rapid initiation of thermogenesis in response to sympathetic nervous system stimulation of the brown adipose tissue. PMID: 2698159 [PubMed - indexed for MEDLINE] 6660. Biol Rev Camb Philos Soc. 1989 Nov;64(4):317-40. Wild mice in the cold: some findings on adaptation. Barnett SA, Dickson RG. The house mouse, Mus domesticus, can thrive in natural environments much below its optimum temperature. Thermogenesis is then above that at more usual temperatures. In addition, body weight, and the weights of brown adipose tissue and the kidneys, may be higher than usual. In free populations of house mice cold lowers fertility and may prevent breeding. Other possible limiting factors on breeding are food supply, shelter for nesting and social interactions. In captivity, wild-type house mice exposed to severe cold (around 0 degrees C) at first adapt ontogenetically by shivering and reduced activity. But raised thermogenesis is soon achieved without shivering; nest-building improves; and readiness to explore may be enhanced. Endocrine changes probably include, at least initially, a rise in adrenal cortical activity and in catecholamine secretion. Some females become barren, but many remain fertile. The maturity of fertile females is, however, delayed and intervals between births are lengthened; nestling mortality rises. A limiting factor during lactation may be the capacity of the gut. Similar adaptive changes are observed during winter in some species of small mammals that do not hibernate. But neither the house mouse nor other species present a single, universal pattern of cold-adaptation. Wild-type mice bred for about 10 generations in a warm laboratory environment (20-23 degrees C) change little over generations. In cold they become progressively heavier and fatter at all ages; they mature earlier, and nestling mortality declines. The milk of such 'Eskimo' females is more concentrated than that of controls. If 'Eskimo' mice are returned to a warm environment, they are more fertile, and rear heavier young, than controls that remained in the warm. Despite the heavier young, litter size is not reduced: it may be increased, probably as a result of a higher ovulation rate. Parental effects have been analyzed by cross-fostering and hybridizing. Survival, growth and fertility are all favourably influenced by the intra-uterine and nest environments provided by 'Eskimo' females. 'Eskimo' males are also better fathers. Hence after ten generations the phenotype of cold-adapted house mice shows the combined effects of (a) an ontogenetic response to cold, (b) a superior parental environment and (c) a change genotype. The secular changes in the cold that lead to this phenotype give the appearance of evolution in miniature; but it is equally possible that they represent a genetical versatility that allows rapid, reversible shifts in response to environmental demands.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2696561 [PubMed - indexed for MEDLINE] 6661. Fertil Steril. 1989 Nov;52(5):703-25. Reproductive endocrinologic alterations in female asymptomatic obesity. Azziz R(1). Author information: (1)Department of Obstetrics and Gynecology, University of Alabama, Birmingham. Excess body fat has been clearly associated with an increased risk of oligo-ovulation and endometrial/breast carcinoma. The connection has been assumed to lie within derangements of the metabolic/endocrine compartments, particularly of estrogens and androgens. To differentiate the effect of obesity from its related disease process, an attempt has been made to define the reproductive-endocrinologic alterations encountered in otherwise asymptomatic obese women. Androgen metabolism is accelerated in obesity. It is not clear whether the increased clearance precedes or follows the accelerated production of androgens. A servocontrol mechanism appears to be operative in these asymptomatic individuals, maintaining plasma steroid levels normal. The unbound fraction of T may be somewhat increased in overweight women with predominantly upper body fat deposition. The increased clearance of androgen may arise from an obesity-related depression in SHBG concentration (e.g., for T, E2, delta 5-diol, etc.). Adipose tissue, by virtue of the lipid solubility of most of these steroids, concentrates androgens, estrogens, and progesterone. This steroid sequestration not only contributes to the obesity-related increase in androgen clearance but also leads to an extremely enlarged total body steroid pool. Fat tissue sequestration also increases the concentration of androgens in the vicinity of adipose stromal cells, possibly encouraging their aromatization. Adipose tissue also has a moderate degree of 17-hydroxysteroid dehydrogenase activity, which appears to stimulate the conversion of A to T. Finally, alterations in peripheral and hepatic conjugation and an accelerated urinary excretion may contribute to the elevated clearance of androgens. The accelerated PR of androgens may simply result as compensation for the elevated MCR in obesity. Nonetheless, evidence of alteration(s) in adrenocortical steroidogenesis has been presented suggesting a selective obesity-related enhancement in adrenal androgen secretion. These remain to be confirmed. Nonetheless, adrenocortical abnormalities may arise secondary to the influence of other circulating and intra-adrenal factors, including insulin, prolactin, estrogens, and androgens. It is not known whether the accelerated androgen metabolism or the aberrant adrenal steroidogenesis improve with weight reduction. Excess body fat increases androgen aromatization which, together with an obesity-related decrease in SHBG, is associated with mildly elevated levels of E1 and free E2 in postmenopausal women. Although premenopausal obese individuals have the same tendency, the far greater ovarian estrogen secretion overshadows any differences. The bulk of aromatization activity in fat lies in the stromal comportment. The major substrate for peripheral estrogen production is A. Testosterone also contributes to the estrogen pool via its conversion to E2.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2680625 [PubMed - indexed for MEDLINE] 6662. Biochem J. 1989 Oct 15;263(2):313-23. Fuel selection and carbon flux during the starved-to-fed transition. Sugden MC(1), Holness MJ, Palmer TN. Author information: (1)Department of Biochemistry and Chemical Pathology, London Hospital Medical College, U.K. PMCID: PMC1133432 PMID: 2688629 [PubMed - indexed for MEDLINE] 6663. Clin Dermatol. 1989 Oct-Dec;7(4):93-106. Hypertrophy and atrophy of fat. Ryan TJ(1), Curri SB. Author information: (1)Department of Dermatology, Slade Hospital, Headington, Oxford, United Kingdom. PMID: 2691055 [PubMed - indexed for MEDLINE] 6664. Clin Dermatol. 1989 Oct-Dec;7(4):9-24. Genesis of adipocytes. Ryan TJ(1), Curri SB. Author information: (1)Department of Dermatology, Slade Hospital, Headington, Oxford, United Kingdom. PMID: 2691054 [PubMed - indexed for MEDLINE] 6665. Clin Dermatol. 1989 Oct-Dec;7(4):78-92. Thermoregulatory aspects of adipose tissue. Gregory EL(1). Author information: (1)Department of Dermatology, Slade Hospital, Headington, Oxford, United Kingdom. PMID: 2691053 [PubMed - indexed for MEDLINE] 6666. Clin Dermatol. 1989 Oct-Dec;7(4):62-77. The nervous system and adipose tissue. Dalziel K(1). Author information: (1)Department of Dermatology, Queens Medical Center, University Hospital, Nottingham, United Kingdom. PMID: 2691052 [PubMed - indexed for MEDLINE] 6667. Clin Dermatol. 1989 Oct-Dec;7(4):48-61. Adipose tissue metabolism. Frayn KN(1). Author information: (1)Sheikh Rashid Diabetes Unit, Radcliffe Infirmary, Oxford, United Kingdom. PMID: 2691051 [PubMed - indexed for MEDLINE] 6668. Clin Dermatol. 1989 Oct-Dec;7(4):37-47. The structure of fat. Ryan TJ(1), Curri SB. Author information: (1)Department of Dermatology, Slade Hospital, Headington, Oxford, United Kingdom. PMID: 2691050 [PubMed - indexed for MEDLINE] 6669. Clin Dermatol. 1989 Oct-Dec;7(4):25-36. Blood vessels and lymphatics. Ryan TJ(1), Curri SB. Author information: (1)Department of Dermatology, Slade Hospital, Headington, Oxford, United Kingdom. PMID: 2691049 [PubMed - indexed for MEDLINE] 6670. J Nutr. 1989 Oct;119(10):1483-9. Relationship between dietary fat, adipocyte membrane composition and insulin binding in the rat. Field CJ(1), Toyomizu M, Clandinin MT. Author information: (1)Department of Foods and Nutrition, University of Alberta, Edmonton, Canada. Weanling male Sprague-Dawley rats were fed one of 10 purified, high fat (20% wt/wt) diets for 6 wk to determine if an in vivo relationship exists between dietary fat composition, plasma membrane composition and insulin binding to epididymal adipocytes. The diets fed provided ratios of polyunsaturated to saturated fatty acids (P/S ratios) representative of those consumed by the human population and ranging from 0.14 to 1.80. The dietary P/S ratio fed altered the essential and nonessential fatty acid composition of plasma membrane phospholipids. Diet-induced alterations in membrane phosphatidylcholine and phosphatidylethanolamine composition were found to be related in a dose-dependent manner to insulin binding at both physiological and supraphysiological insulin concentrations. This observation further supports in vivo a dietary mechanism for modulating insulin action. The present study establishes that the effect of diet on the relationship between membrane composition and insulin binding reaches a plateau within the physiological range of dietary P/S ratios. PMID: 2685203 [PubMed - indexed for MEDLINE] 6671. J Nutr. 1989 Oct;119(10):1369-75. Evidence of enhanced storage capacity in adipose tissue of genetically fat chickens. Hermier D(1), Quignard-Boulangé A, Dugail I, Guy G, Salichon MR, Brigant L, Ardouin B, Leclercq B. Author information: (1)INRA, Station de Recherches Avicoles, Nouzilly, France. The storage capacity for plasma triglyceride in abdominal adipose tissue has been investigated in two lines of chickens selected for either high or low adiposity (fat line and lean line, respectively). Adipose tissue cellularity and lipoprotein lipase (LPL) activity were estimated in 2- and 5-wk-old birds. In 2-wk-old birds, cellularity and LPL and glycerophosphate dehydrogenase (GPDH) activity were evaluated in the stromavascular fraction. At both ages studied, the fat line exhibited a twofold increase in mature fat cell number and a marked hypertrophy. LPL activity per cell did not differ with genotype, regardless of the nutritional state; however, LPL activity per whole fat pad was higher in fat birds. In 2-wk-old fat chickens, the stromavascular fraction was characterized by an increase in cell number and a decrease in LPL activity, while GPDH was unchanged. Finally, adipocyte hyperplasia in the fat line appeared to reflect an excessive proliferation of precursor cells. The higher LPL activity in fat birds resulted mainly from cell hyperplasia, rather than from a greater intrinsic activity of adipocytes. Consequently, enhanced fatty acid uptake by adipose tissue represents a major factor in determination of adiposity in the chicken. PMID: 2685199 [PubMed - indexed for MEDLINE] 6672. J Nutr. 1989 Oct;119(10):1361-8. Influence of the sex-linked dwarfing gene (dw) on the lipid composition of plasma, egg yolk and abdominal fat pad in White Leghorn laying hens: effect of dietary fat. Burghelle-Mayeur C(1), Demarne Y, Mérat P. Author information: (1)Station de Recherches de Nutrition, INRA-CRJ, Jouy-en-Josas, France. The levels and fatty acid composition of lipids were determined in very low density lipoproteins (VLDL, d less than 1.006), yolk and abdominal adipose tissue of normal (Dw) and sex-linked dwarf (dw) White Leghorn laying hens. Effects of adding 4% tallow to the diet were also examined. In 40-wk-old hens, neither plasma lipids (triglycerides, phospholipids and cholesterol), VLDL levels, nor the chemical composition of VLDL was altered by the dw gene or dietary fat. Dwarfism reduced egg and yolk weights. Though the yolk lipid content was similar in normal and dwarf hens, yolk from dwarfs had slightly more phospholipids and less triglycerides than yolk from normal hens. Higher linoleic acid [18:2(n-6)] and lower oleic acid [18:1(n-9)] levels were observed in triglycerides of VLDL, yolk and adipose tissue from dwarf hens. In addition, the dietary fatty acid pattern had a greater influence on the fatty acid composition of the yolk lipid major precursors (VLDL triglycerides) in dwarf laying hens than in normal hens. These results suggest that the dwarfing gene might reduce the hepatic de novo fatty acid synthesis and/or dwarf hens might incorporate more dietary lipids into yolk than do normal hens. PMID: 2685198 [PubMed - indexed for MEDLINE] 6673. Am J Kidney Dis. 1989 Oct;14(4):272-6. Insulin resistance of uremia. Hager SR(1). Author information: (1)Department of Medicine, Medical College of Wisconsin, Milwaukee. Glucose intolerance is a nearly universal finding in patients with chronic renal failure and in animal models of uremia. The glucose intolerance results from impaired insulin-mediated glucose disposal by muscle, adipose, and liver tissue. Insulin binding by these tissues is not reduced. Rather, several defects exist in the postreceptor cascade of insulin action. Although impaired insulin-mediated glucose uptake and metabolism occur, the primary defect and causative agent are not established. The purpose of the present article is to review recent literature on the potential mechanisms underlying the insulin resistance of chronic renal failure. PMID: 2679057 [PubMed - indexed for MEDLINE] 6674. Diabete Metab. 1989 Sep-Oct;15(5):211-23. [Recent data on the regulation of glucose transport and glucose transporters in insulin-sensitive tissues]. [Article in French] Guerre-Millo M(1), Hainault I, Lavau M. Author information: (1)U 177 INSERM, Institut biomédical des Cordeliers, Paris. This review concerns the acute and long-term regulation of glucose transport. In insulin-sensitive tissues, the acute effect of insulin on this process occurs mainly through the translocation of glucose transport proteins (glucose transporters) from an intracellular pool to the plasma membrane. Some other factors are also able to modify acutely glucose transport by the translocation mechanism. However, recent data are reported which indicate that in addition, modifications of the glucose transporters activity are involved. The long-term regulation of the glucose transport capacity has been less studied. In different types of cultured cells, a role of two factors, glucose and insulin, has been clearly shown. The availability of cDNA probes encoding for glucose transporters, has given the opportunity to study the molecular regulation of glucose transport. However, it appears that different sub-types of glucose transport proteins exist which might be regulated in a specific manner depending on the cell-type and the regulatory factor. The existence of an insulin-sensitive glucose transporter is strongly suggested. The regulation of this protein, which could be specifically involved in insulin resistant physiopathological situations, remains to be studied. PMID: 2698363 [PubMed - indexed for MEDLINE] 6675. JPEN J Parenter Enteral Nutr. 1989 Sep-Oct;13(5):529-34. Ultrasonography as a method of nutritional assessment. Chiba T(1), Lloyd DA, Bowen A, Condon-Meyers A. Author information: (1)Nutritional Support Service, Children's Hospital of Pittsburgh, Pennsylvania. The composition of the upper arms of five healthy individuals was measured by anthropometry (AN), ultrasonography (US), and computerized tomography (CT). Measurements of midarm fat area (MAFA) and midarm muscle area (MAMA) by CT correlated well with AN and US, but both AN and US overestimated MAMA by 22.8 +/- 17% and 10 +/- 12%, respectively, (mean +/- SD). The overestimate was largest with AN because with this method bone area cannot be excluded. To evaluate the usefulness of US measurements, 10 patients with advanced liver disease were studied. Measurement of MAFA by US, using triceps skinfold thickness as the standard, was found to be an accurate index of fat stores. MAMA measured by US correlated well with lean muscle mass, using creatinine height index as the standard. Ultrasonography is a reliable method of measuring body fat and lean muscle status. PMID: 2691712 [PubMed - indexed for MEDLINE] 6676. J Anim Sci. 1989 Sep;67(9):2263-72. Regulation of gene expression during adipocyte differentiation: a review. Gaskins HR(1), Hausman GJ, Martin RJ. Author information: (1)University of Georgia, Athens 30602. The differentiation of adipose precursor cells is accompanied by the acquisition of adipocyte-specific messenger (m) RNAs allowing characteristic changes in protein composition. The development of methods for cloning and characterizing individual genes has provided the opportunity to study selective gene expression by adipocytes at the molecular level. In this review, the information obtained to date regarding transcriptional and post-transcriptional regulatory mechanisms utilized by adipocytes is summarized. Included are descriptions of conserved DNA sequences found in noncoding regions of adipose genes and of how protein-DNA interactions at these regions are thought to regulate the initiation of transcription. Among the transcription factors implemented in regulation of adipocyte-specific gene expression are the protein product of the proto-oncogene c-fos, the triiodothyronine receptor and steroid hormone receptors. Data also are discussed that indicate that RNA editing and determinants of mRNA stability contribute to the adipocyte phenotype. It is hoped that a review of the regulatory aspects of gene expression during adipocyte differentiation will identify areas deserving further study by researchers interested in understanding adipose development. PMID: 2689417 [PubMed - indexed for MEDLINE] 6677. Can J Physiol Pharmacol. 1989 Aug;67(8):811-9. A commentary on the interpretation of in vitro biochemical measures of brown adipose tissue thermogenesis. Trayhurn P(1), Milner RE. Author information: (1)Department of Medicine, University of Alberta, Edmonton, Canada. In this article we comment on the various in vitro biochemical measurements employed to assess the thermogenic activity and capacity of brown adipose tissue. The meaning and significance of changes in tissue weight, protein content, cell number, and mitochondrial mass are each summarized. In addition, various indices of the proton conductance pathway-mitochondrial swelling, proton conductance, uncoupling protein concentration, and GDP binding studies--are discussed. The issue of unmasking and masking of GDP binding sites is reviewed; recent reports have clearly demonstrated unmasking and masking, and it is concluded that GDP binding studies are an index of the activity of uncoupling protein, rather than a measure of its concentration. It is suggested that tissue mass, mitochondrial content, mitochondrial GDP binding, and uncoupling protein concentration represent core measurements for the biochemical assessment of the thermogenic activity and capacity of brown adipose tissue. Auxiliary measurements include Scatchard analysis of GDP binding data to distinguish changes in the number of binding sites from potential changes in Kd, and mitochondrial swelling studies, as an additional index of proton permeability. The distinction between thermogenic activity (GDP binding, proton permeability) and capacity (uncoupling protein content), both on a per unit of mitochondrial protein and per tissue basis, is emphasized. PMID: 2688850 [PubMed - indexed for MEDLINE] 6678. Hinyokika Kiyo. 1989 Aug;35(8):1373-7. [A case of adrenal myelolipoma]. [Article in Japanese] Miyake O(1), Hosomi M, Matsumiya K, Oka T, Takaha M, Kurata A, Aga Y, Uema K. Author information: (1)Department of Urology, Osaka National Hospital. A case of adrenal myelolipoma is presented. The patient was a 61-year-old woman who complained of lumbago this time. A tumor of the left adrenal gland, however, had been found by computed tomography 4 years earlier. Judging from the CT, the size of this tumor had not changed at all, although the density of the mass on admission had reduced, compared with that of 4 years earlier. Laboratory examinations of adrenal function was normal. Left adrenalectomy was performed. Histologically, this tumor consisted of adipose and some hematopoietic tissue. We reviewed 43 cases of adrenal myelolipoma resected surgically in Japan. PMID: 2683650 [PubMed - indexed for MEDLINE] 6679. J Pediatr Gastroenterol Nutr. 1989 Aug;9(2):219-24. Determinants of arm muscle and fat accretion during the first postnatal month in preterm newborn infants. Georgieff MK(1), Amarnath UM, Mills MM. Author information: (1)Department of Pediatrics, University of Minnesota School of Medicine, Children's Hospital of St. Paul, Minneapolis. We measured arm muscle and fat areas in 22 preterm appropriate for gestational age infants at birth (mean +/- 1 SD birth weight: 1,640 +/- 484 g; gestational age: 31 +/- 2 weeks). Birth arm muscle and fat areas correlated significantly with gestational age (arm muscle: r = 0.86; p less than 0.001; arm fat: r = 0.75; p less than 0.001) and with birth weight. Deviations of birth weights from gestational age means (birth weight z-scores) were related more to variations in arm muscle area (r = 0.69; p less than 0.001) rather than arm fat area (r = 0.44; p = 0.04). Sixteen infants were followed over 4 weeks. They were most physiologically unstable (mean Physiologic Stability Index score = 5.3 +/- 3.5) during the first postnatal week when they also all lost weight. Their mean arm muscle area decreased significantly during the first week by greater than 10%, whereas the mean arm fat area remained unchanged. First week arm muscle losses were directly correlated with the lack of protein intake (r = 0.52; p less than 0.05). The regression equation predicted a protein intake of 4.06 g/kg/day (95% confidence interval: 2.3-6.4) to prevent first week muscle loss. Enteral intake and weight gain were established after week 1, accompanied by a significant reduction in physiologic instability (PSI score = 1.9 +/- 1.9; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2681648 [PubMed - indexed for MEDLINE] 6680. Pediatr Rev. 1989 Aug;11(2):43-55. Obesity in childhood. Rosenbaum M, Leibel RL. PMID: 2668911 [PubMed - indexed for MEDLINE] 6681. J Invest Dermatol. 1989 Aug;93(2 Suppl):18S-24S. Structure and function of lymphatics. Ryan TJ(1). Author information: (1)Department of Dermatology, Slade Hospital, Oxford, England. Lymphatics are large vessels with a lumen potentially ten times wider than blood vessels and have a mean mesh diameter in the upper dermis of approximately 504 +/- 88 microns. The plexus lies just deep to the subpapillary venous plexus and when functioning well it is difficult to identify because of the attenuated endothelium and collapsed lumen. The role of the lymphatic as a pathway for the Langerhans cell and as an exit for macromolecules such as lipid and protein make it an essential organ for normal skin biology. When this system fails, impaired immunity, fibrosis, and recurrent infections are inevitable. Even vasculitis may be a consequence of failure of clearance of immune complexes from the interstitium. The adipose tissue and deep dermis are especially vulnerable in this respect. Elastin fibers support cutaneous lymphatics and may be low resistance pathways through the connective tissues into the lymphatic. Identification of lymphatics by special markers is a concept that currently fails to take into account that changing roles in disease may be associated with a change in the specificity of markers. The anatomy of lymphatic vessels in the skin is described and the role of the lymphatic is emphasized. PMID: 2666518 [PubMed - indexed for MEDLINE] 6682. Diabetes Metab Rev. 1989 Aug;5(5):431-41. Insulin receptor kinase defects in insulin-resistant tissues and their role in the pathogenesis of NIDDM. Häring H(1), Obermaier-Kusser B. Author information: (1)Institut für Diabetesforschung, München, Federal Republic of Germany. PMID: 2547553 [PubMed - indexed for MEDLINE] 6683. Biochem Soc Trans. 1989 Aug;17(4):627-9. Guanine nucleotide regulatory proteins in insulin's action and in diabetes. Houslay MD(1), Pyne NJ, O'Brien RM, Siddle K, Strassheim D, Palmer T, Spence S, Woods M, Wilson A, Lavan B, et al. Author information: (1)Department of Biochemistry, University of Glasgow, Scotland, U.K. PMID: 2504628 [PubMed - indexed for MEDLINE] 6684. Proc Nutr Soc. 1989 Jul;48(2):243-56. Brown adipose tissue in humans. Lean ME(1). Author information: (1)Diabetic Clinic, Aberdeen Royal Infirmary, Woolmanhill Hospital. PMID: 2678120 [PubMed - indexed for MEDLINE] 6685. Proc Nutr Soc. 1989 Jul;48(2):237-41. Comparative physiology of brown adipose tissue. Andrews JF(1). Author information: (1)Department of Physiology, Trinity College, Dublin, Republic of Ireland. PMID: 2678119 [PubMed - indexed for MEDLINE] 6686. Proc Nutr Soc. 1989 Jul;48(2):231-5. Corticosteroid inhibition of thermogenesis in obese animals. York DA(1). Author information: (1)Department of Human Nutrition, School of Biochemical and Physiological Sciences, University of Southampton. PMID: 2678118 [PubMed - indexed for MEDLINE] 6687. Proc Nutr Soc. 1989 Jul;48(2):225-30. Reactivation of brown adipose tissue. Holloway BR(1). Author information: (1)ICI Pharmaceuticals Division, Mereside, Macclesfield, Cheshire. PMID: 2678117 [PubMed - indexed for MEDLINE] 6688. Proc Nutr Soc. 1989 Jul;48(2):207-14. Does brown adipose tissue have a role to play in glucose homeostasis? Cawthorne MA(1). Author information: (1)Beecham Pharmaceuticals Research Division, Great Burgh, Epsom, Surrey. PMID: 2678116 [PubMed - indexed for MEDLINE] 6689. Proc Nutr Soc. 1989 Jul;48(2):197-206. Central control of brown adipose tissue. Rothwell NJ(1). Author information: (1)Department of Physiological Sciences, University of Manchester. PMID: 2678115 [PubMed - indexed for MEDLINE] 6690. Proc Nutr Soc. 1989 Jul;48(2):189-96. The role of brown adipose tissue in diet-induced thermogenesis. Stock MJ(1). Author information: (1)Department of Physiology, St George's Hospital Medical School, University of London, Tooting. PMID: 2678114 [PubMed - indexed for MEDLINE] 6691. Proc Nutr Soc. 1989 Jul;48(2):183-7. Molecular biology of brown adipose tissue. Ricquier D(1). Author information: (1)Centre de Recherche sur la Nutrition, Centre National de la Recherche Scientifique, Meudon-Bellevue, France. PMID: 2678113 [PubMed - indexed for MEDLINE] 6692. Proc Nutr Soc. 1989 Jul;48(2):177-82. Brown adipose tissue: structure and function. Arbuthnott E(1). Author information: (1)Physiology Department, Trinity College, Dublin, Irish Republic. PMID: 2678112 [PubMed - indexed for MEDLINE] 6693. Proc Nutr Soc. 1989 Jul;48(2):165-75. Brown adipose tissue and nutritional energetics--where are we now? Trayhurn P(1). Author information: (1)Department of Medicine, University of Alberta, Edmonton, Canada. PMID: 2678111 [PubMed - indexed for MEDLINE] 6694. Poult Sci. 1989 Jul;68(7):948-57. Role of the basomedial hypothalamus in regulation of adiposity, food intake, and reproductive traits in the domestic fowl. Snapir N(1), Robinzon B. Author information: (1)Department of Animal Science, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel. Bilateral basomedial hypothalamic (BMH) electrolytic lesions in White Leghorn cockerels produced six main physiological categories characterized by typical sets of symptoms: 1) functional castration (FC); hyperphagia, obesity, occasional diabetes insipidus, involuted adenohypophysis, dwarfism, atrophied comb and testes, reduced hematocrit, reduced plasma testosterone and thyroid activity, involuted thymus and adrenal cortex and elevated liver fat and plasma triglycerides and free fatty acids. The FC birds demonstrated defective immune response for the first 12 to 16 wk post-surgery. 2) functional castration with large comb (FCLC); hyperphagia, obesity, transient diabetes insipidus, slight diminution of adenohypophy-seal weight with marked reduction in basophilic cell population, fully atrophied testes but only slight reduction in comb size and hematocrit, plasma testosterone levels between those found in the first category and the control. 3) obese with normal testes (ONT); hyperphagia, obesity, high level of plasma lipids, normal histological organization of the adenohypophysis, normal testes, semen production and comb size. The next three categories exhibited physiological syndromes identical to the former three categories except for food intake, which operationally could be defined as normal. A marked difference among the BMH-lesioned birds was found in sexual behavior when the FC birds completely lost their libido. None of the replacement therapy regimens caused complete rehabilitation from adiposity or restoration of reproductive traits. Lipoprotein lipase activity increased at an early stage postlesioning and preceeded the development of hyperphagia. Placement of BMH lesions in newly hatched chicks resulted in marked dwarfism and obesity without hyperphagia. The BMH-lesioned heavy breed White Rock cockerels exhibited a lesser degree of adiposity than the light White Leghorn birds. Removal of the olfactory bulbs and destruction of the septal area resulted in increased thyroid activity, with secondary hyperphagia without obesity. In a short-term study, administration of sodium pentobarbital to the BMH area resulted in increased feeding. Conversely, glucose administration to the same area suppressed feeding in satiated but not in food-deprived chickens. PMID: 2674924 [PubMed - indexed for MEDLINE] 6695. Arch Intern Med. 1989 Jul;149(7):1514-20. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Kaplan NM(1). Author information: (1)Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9030. The contribution of obesity to cardiovascular risk has not been adequately appreciated because of a failure to recognize the involvement of upper-body predominance of body weight with hypertension, diabetes, and hypertriglyceridemia even in the absence of significant overall obesity. This article examines the evidence that upper-body obesity, as usually induced by caloric excess in the presence of androgens, mediates these problems by way of hyperinsulinemia. Because of these interrelationships, there is a need to identify and prevent upper-body obesity or, failing that, to provide therapies that will control the associated problems without aggravating hyperinsulinemia. PMID: 2662932 [PubMed - indexed for MEDLINE] 6696. Proc Nutr Soc. 1989 Jul;48(2):215-23. The brown adipocyte beta-adrenoceptor. Arch JR(1). Author information: (1)Beecham Pharmaceuticals Research Division, Great Burgh, Epsom, Surrey. PMID: 2552450 [PubMed - indexed for MEDLINE] 6697. Mol Cell Biochem. 1989 Jun 27-Jul 24;88(1-2):129-37. Hormones and triacylglycerol metabolism under normoxic and ischemic conditions. Schoonderwoerd K(1), van der Kraaij T, Hülsmann WC, Stam H. Author information: (1)Department of Biochemistry I, Medical Faculty, Erasmus University Rotterdam, The Netherlands. Fatty acids, the preferred substrate in normoxic myocardium, are derived from either exogenous or endogenous triacylglycerols. The supply of exogenous fatty acids is dependent of the rate of lipolysis in adipose tissue and of the lipoprotein lipase activity at the coronary vascular endothelium. A large part of the liberated fatty acids is reesterified with glycerol-3-phosphate and converted to triacylglycerols. Endogenous lipolysis and lipogenesis are intracellular compartmentalized multienzyme processes of which individual hormone-sensitive steps have been demonstrated in adipose tissue. The triacylglycerol lipase is the rate-limiting enzyme of lipolysis and glycerol-3-phosphate acyltransferase and possibly phosphatidate phosphohydrolase are the rate-limiting enzymes of lipogenesis. The hormonal regulation of both processes in heart is still a matter of dispute. Triacylglycerol lipase activity in myocardial tissue has two intracellular sources: 1. the endoplasmic reticular and soluble neutral lipase, and 2. the lysosomal acid lipase. Studies in our laboratory have indicated that whereas lipolysis is enhanced during global ischemia and anoxia, overall lipolytic enzyme activities in heart homogenates were not altered. In addition we were unable to demonstrate alterations in tissue triacylglycerol content and glycerol-3-phosphate acyltransferase activity under these conditions. Lipolysis, is subject to feedback inhibition by product fatty acids. Therefore all processes leading to an increased removal of fatty acids from the catalytic site of the lipase will stimulate lipolysis. These studies will be reviewed. In addition, studies from our department have demonstrated the capacity of myocardial lysosomes to take up and degrade added triacylglycerol-particles in vitro. Such a process, stimulated by Ca2+ and stimulated by acidosis, offers another physiological target for hormone actions. PMID: 2674663 [PubMed - indexed for MEDLINE] 6698. Pol Tyg Lek. 1989 May 22-29;44(21-22):514-8. [Pathogenesis of hyperglycemia in diabetes mellitus type II (insulin-independent)]. [Article in Polish] Brozyński K, Loba J, Torzecka W. The most important causes of hyperglycaemia in the course of diabetes mellitus type 2 are discussed. Those include: insulin secretion disorders, resistance to the insulin and overproduction of glucose in the liver. Affected secretory function of B cells in the pancreatic islets results, first of all, from the primary genetic error and secondary regulatory disorders, chiefly hyperglycaemia. Resistance to the insulin caused by decreased insulin activity in the muscle tissue and adipose tissue includes so-called receptor and postreceptor defects. Mechanism of these disorders is partially explained. Overproduction of glucose in the liver is probably secondary to the above metabolic disturbances and decides on the basic hyperglycaemia. Pathogenetic aspects of the insulin independent diabetes mellitus therapy with particular reference to the role of sulfonylurea derivatives are also discussed. PMID: 2702344 [PubMed - indexed for MEDLINE] 6699. Endocr Rev. 1989 May;10(2):136-48. Regulation of estrogen biosynthesis by human adipose cells. Simpson ER(1), Merrill JC, Hollub AJ, Graham-Lorence S, Mendelson CR. Author information: (1)Cecil H. & Ida Green Center for Reproductive Biology Sciences, Departments Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas 75235. PMID: 2666116 [PubMed - indexed for MEDLINE] 6700. J Mol Endocrinol. 1989 May;2(3):169-74. Gastric inhibitory polypeptide: a gut hormone with anabolic functions. Beck B(1). Author information: (1)INSERM U 308, Unité de Recherches sur les Mécanismes de Régulation du Comportement Alimentaire, Nancy, France. The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), has been isolated and characterized because of its enterogastrone-type effects. It is also named glucose-dependent insulinotropic polypeptide and is actually considered to be the main incretin factor of the entero-insular axis. Besides these well-described effects on gastric secretion and pancreatic beta cells, it also has direct metabolic effects on other tissues and organs, such as adipose tissue, liver, muscle, gastrointestinal tract and brain. In adipose tissue it is involved in the activation and regulation of lipoprotein lipase (LPL); it also inhibits glucagon-induced lipolysis and potentiates the effect of insulin on incorporation of fatty acids into triglycerides. It may play a role in the development of obesity because of the hypersensitivity of adipose tissue of obese animals to some of these actions. In the liver it does not modify insulin extraction, and its incretin effects are due only to the stimulation of insulin secretion and synthesis. It reduces hepatic glucose output and inhibits glucagon-stimulated glycogenolysis. It might increase glucose utilization in peripheral tissues such as muscle. GIP also has an effect on the volume and/or electrolyte composition of intestinal secretion and saliva. The functional importance of its effect on the hormones of the anterior pituitary lobe remains to be established, as it has never been detected in the brain. Its links with insulin are very close and the presence of insulin is sometimes necessary for the greater efficiency of both hormones. GIP can be considered as a true metabolic hormone, with most of its functions tending to increase anabolism. PMID: 2665779 [PubMed - indexed for MEDLINE] 6701. J Pediatr Gastroenterol Nutr. 1989 May;8(4):426-9. Regulation of milk fat synthesis. Neville MC(1). Author information: (1)Department of Physiology, University of Colorado School of Medicine, Denver. PMID: 2656963 [PubMed - indexed for MEDLINE] 6702. Can J Physiol Pharmacol. 1989 Apr;67(4):394-401. Role of thermogenesis in the regulation of energy balance in relation to obesity. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, University of Ottawa, Ont., Canada. Obligatory thermogenesis is a necessary accompaniment of all metabolic processes involved in maintenance of the body in the living state, and occurs in all organs. It includes energy expenditure involved in ingesting, digesting, and processing food (thermic effect of food (TEF]. At certain life stages extra energy expenditure for growth, pregnancy, or lactation would also be obligatory. Facultative thermogenesis is superimposed on obligatory thermogenesis and can be rapidly switched on and rapidly suppressed by the nervous system. Facultative thermogenesis is important in both thermal balance, in which control of thermoregulatory thermogenesis (shivering in muscle, nonshivering in brown adipose tissue (BAT] balances neural control of heat loss mechanisms, and in energy balance, in which control of facultative thermogenesis (exercise-induced in muscle, diet-induced thermogenesis (DIT) in BAT) balances control of energy intake. Thermal balance (i.e., body temperature) is much more stringently controlled than energy balance (i.e., body energy stores). Reduced energy expenditure for thermogenesis is important in two types of obesity in laboratory animals. In the first type, deficient DIT in BAT is a prominent feature of altered energy balance. It may or may not be associated with hyperphagia. In a second type, reduced cold-induced thermogenesis in BAT as well as in other organs is a prominent feature of altered thermal balance. This in turn results in altered energy balance and obesity, exacerbated in some examples by hyperphagia. In some of the hyperphagic obese animals it is likely that the exaggerated obligatory thermic effect of food so alters thermal balance that BAT thermogenesis is suppressed. In all obese animals, deficient hypothalamic control of facultative thermogenesis and (or) food intake is implicated. PMID: 2667732 [PubMed - indexed for MEDLINE] 6703. Can J Physiol Pharmacol. 1989 Apr;67(4):370-5. Thermogenesis and the energetics of pregnancy and lactation. Trayhurn P(1). Author information: (1)Department of Medicine, University of Alberta, Edmonton, Canada. Energy balance studies suggest that the overall efficiency of energy utilization does not increase during pregnancy in rodents, other than as a consequence of "hyperphagia". Diet-induced thermogenesis is not stimulated in response to the increased energy intake of the pregnant animal, the extra intake being retained at the maximum efficiency. Biochemical studies on brown adipose tissue, the main site of adaptive thermogenesis in rodents, are consistent with the energy balance data, at least in rats and mice. However, in hamsters (golden and Djungarian) some atrophy of the tissue is evident during pregnancy. In contrast to pregnancy, the thermogenic activity (mitochondrial GDP binding) and capacity (uncoupling protein content) of brown adipose tissue are substantially reduced during lactation in rats and mice. These changes result from a fall in sympathetic activity in the tissue in lactation. Sympathetic activity and thermogenic capacity are, however, fully restored following weaning of the pups. The functional atrophy of brown adipose tissue during lactation is linked to a substantial saving in maternal energy expenditure, reducing the energy requirements for milk production. The lactating-post-lactating animal provides an excellent example of a physiologically programmed reversible atrophy of brown adipose tissue. PMID: 2667730 [PubMed - indexed for MEDLINE] 6704. Eur J Clin Nutr. 1989 Apr;43(4):231-6. Body mass index as a measure of body fatness in the elderly. Deurenberg P(1), van der Kooy K, Hulshof T, Evers P. Author information: (1)Department of Human Nutrition, Agricultural University, Wageningen, The Netherlands. Body composition was assessed in a group of 35 apparently health elderly males and 37 elderly females, aged 60-83 years, by means of anthropometry and densitometry. Mean body mass index (BMI) of the males was 25.0 +/- 2.2 kg/m2 and of the females 25.9 +/- 3.2 kg/m2, which indicates normal weight to only minor overweight. Body fat as assessed by densitometry was 31 per cent in men and 44 per cent in women, a rather high value, especially when compared to the rather low BMI. Body fat percentage as calculated from the sum of four skinfolds (bicipitalis, tricipitalis, subscapularis and supra-iliacalis) using regression equations from the literature was 27.9 +/- 2.5 per cent and 38.7 +/- 3.2 per cent for men and women respectively. These values are probably an underestimation of the body fat, due to a higher proportion of internal fat in elderly subjects, which is not measured by skinfolds. Body fat percentage as determined by the BMI has an estimation error of about 4 per cent when derived from sex- and age-specific regression equations. The body fat percentage as predicted from skinfold thicknesses had a comparable error of estimate. These prediction errors in the body fat percentage in the elderly are comparable with the prediction errors found in young and middle-aged subjects as reported in the literature. PMID: 2661215 [PubMed - indexed for MEDLINE] 6705. Clin Plast Surg. 1989 Apr;16(2):235-44. Anatomy and physiology of adipose tissue. Markman B(1). Author information: (1)University of Nevada School of Medicine, Las Vegas. In summary, the increasing frequency with which we perform lipectomy prompts us to investigate the risks and benefits to which we may be subjecting our patients. It is hoped that this article has shed some light on the biology and anatomy of adipose tissue so that we can make educated guesses as to the effects of its removal. PMID: 2661105 [PubMed - indexed for MEDLINE] 6706. Clin Podiatr Med Surg. 1989 Apr;6(2):229-46. Functional anatomy of the skin. Bressler RS(1), Bressler CH. Author information: (1)Department of Anatomy, New York College of Podiatric Medicine, New York. The skin is one of the best examples in the body for illustrating the correlation of form with function. Instead of looking at it from the viewpoint of its organization, this article takes each function and matches it with the cells meeting that need: keratinocytes for durability and cohesion for mechanical protection; epidermal intercellular substances to form an inpermeable barrier; melanocytes for ultraviolet protection; Langerhans cells for immune response; Merkle cells for sensation; hair follicles, sweat glands, extensive vascular supply, and adipose tissue for thermoregulation; and free and encapsulated nerve endings for sensation. PMID: 2650838 [PubMed - indexed for MEDLINE] 6707. Vrach Delo. 1989 Apr;(4):33-7. [Effect of corticotropin and glucocorticoids on lipid metabolism (a review of the literature)]. [Article in Russian] Korkach VI. PMID: 2547269 [PubMed - indexed for MEDLINE] 6708. Acta Physiol Pol. 1989 Mar-Apr;40(2):156-63. Regulation of new fat cell formation. Sypniewska G(1). Author information: (1)Department of Clinical Nutrition, National Institute of Food and Nutrition, Warsaw. The formation of new adipocytes occurs either at the stage of multiplication or differentiation or both. It seems possible that the formation of new fat cells is dependent on the average cell weight in a given adipose tissue depot, but there may also be other regional, local regulatory factors. Multiplication of fat cells has been suggested to be stimulated by 17-beta-oestradiol while the differentiation of adipocytes is stimulated by growth hormone, glucocorticoids, insulin, insulin-like growth factor and female sex hormones. There are, probably, other factors acting in circulation or locally. The factors promoting growth of new fat cells with overfeeding are at present unknown. Some hypothetical possibilities are discussed. PMID: 2701495 [PubMed - indexed for MEDLINE] 6709. Environ Health Perspect. 1989 Mar;80:17-23. Coupling growth arrest and adipocyte differentiation. Ailhaud G(1), Dani C, Amri EZ, Djian P, Vannier C, Doglio A, Forest C, Gaillard D, Négrel R, Grimaldi P. Author information: (1)Centre de Biochimie du CNRS, Université de Nice, France. The complete differentiation program of preadipose cells can be divided into early and late events. The expression of early markers takes place at growth arrest (G1/S boundary), whereas that of late markers, leading to terminal differentiation, takes place after a limited number of mitoses of early marker-containing cells. Only terminal differentiation requires the presence of growth hormone and triiodothyronine and results in the formation of triacylglycerol-filled, nondividing cells. The events of adipose cell differentiation which take place in vitro allow a better understanding of the development of adipose tissue in vivo. PMCID: PMC1567619 PMID: 2647477 [PubMed - indexed for MEDLINE] 6710. Diabetes Metab Rev. 1989 Mar;5(2):83-109. Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Kissebah AH(1), Peiris AN. Author information: (1)Department of Medicine, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee 53005. Our studies support the view that body fat distribution and the accompanying metabolic abnormalities could be exacerabated by variability in the androgenic/estrogenic balance. Sensitivity to the androgenic milieu might be initiated by an early developmental aberration in sexual dimorphism. The possible direct and indirect sites of interaction between androgenic activity and the abnormal metabolic pathways in upper body obesity are summarized in Figure 19. PMID: 2647436 [PubMed - indexed for MEDLINE] 6711. Am J Hypertens. 1989 Mar;2(3 Pt 2):125S-132S. Obesity, metabolism, and the sympathetic nervous system. Landsberg L(1), Krieger DR. Author information: (1)Department of Medicine, Harvard Medical School, Boston, Massachusetts. The association of hypertension and obesity is poorly understood. Studies conducted in our laboratory over the last decade, in conjunction with recent clinical and epidemiological observations, suggest that hypertension in the obese is derived from a fundamental relationship between dietary intake and sympathetic nervous system (SNS) activity. The application of kinetic techniques to the measurement of norepinephrine (NE) turnover rate in sympathetically innervated tissues of laboratory rodents has defined a relationship between the SNS and dietary intake. Fasting or caloric restriction suppresses sympathetic activity in a variety of organs of the rat, including heart and interscapular brown adipose tissue. Overfeeding a mixed, palatable, "cafeteria" diet stimulates sympathetic activity in these same tissues. The stimulatory effect of mixed diets is due to the carbohydrate and fat content, because these two latter nutrients stimulate sympathetic activity even when total caloric intake is not increased. Insulin-mediated glucose metabolism within central neurons associated with the ventromedial hypothalamus (VMH) plays an important role in the relationship between dietary intake and SNS activity as indicated by the following observations: (1) Hypoglycemia (noninsulin-mediated) is associated with suppression of the SNS (despite concomitant adrenal medullary stimulation); (2) 2-deoxyglucose, an intracellular inhibitor of glucose metabolism, decreases sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2647103 [PubMed - indexed for MEDLINE] 6712. Nutr Rev. 1989 Feb;47(2):58-9. Insulin activation of adipocyte lipoprotein lipase. [No authors listed] PMID: 2654772 [PubMed - indexed for MEDLINE] 6713. Eur J Clin Nutr. 1989 Feb;43(2):107-15. Effect of acetate infusion on energy expenditure and substrate oxidation rates in non-diabetic and diabetic subjects. Akanji AO(1), Bruce MA, Frayn KN. Author information: (1)Sheikh Rashid Diabetes Unit, Radcliffe Infirmary, Oxford, UK. Sodium acetate was infused intravenously at 2.5 mmoles/min for 60 min into 6 normal subjects and 6 non-insulin dependent diabetic patients. In control experiments the same subjects received equimolar sodium bicarbonate infusions. Plasma non-esterified fatty acid and blood glycerol levels fell during acetate infusion in both groups, suggesting impairment of lipolysis. The respiratory quotient fell on acetate infusion as expected, although total energy expenditure was unaffected. If acetate oxidation was assumed to be 90 per cent of the infusion rate, then it accounted for about 40 per cent of total oxygen consumption; fat oxidation was reduced, whilst carbohydrate oxidation was unchanged. These results suggest that resting energy expenditure is maintained during acetate infusion since acetate replaces fat as an oxidative fuel, without affecting glucose oxidation. The reduction in fat oxidation appears to be due to reduced fat mobilization from adipose tissue. The metabolic effects of acetate infusion are similar in normal and in non-insulin dependent diabetic subjects. PMID: 2651106 [PubMed - indexed for MEDLINE] 6714. An Med Interna. 1989 Feb;6(2):94-9. [Physiopathology of obesity]. [Article in Spanish] de Portugal Alvarez J. PMID: 2491081 [PubMed - indexed for MEDLINE] 6715. Am J Ind Med. 1989;16(2):135-46. Levels of polychlorinated dibenzo-p-dioxins and dibenzofurans in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Patterson DG Jr(1), Fingerhut MA, Roberts DW, Needham LL, Sweeney MH, Marlow DA, Andrews JS Jr, Halperin WE. Author information: (1)Center for Environmental health and Injury Control, U.S. Department of Health and Human Services, Atlanta, GA 30333. Review of employment and chemical production records at a Missouri chemical plant and of questionnaires with self-reported occupational exposure to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2,3,7,8-TCDD) for 16 Missouri workers has explained the wide diversity of 2,3,7,8-TCDD levels previously reported in the workers' adipose tissue (3.5-750 ppt on whole-weight basis). We show that the highest exposures reported to date in the United States occurred in a group of nine production workers who made products contaminated with 2,3,7,8-TCDD. The nine workers had adipose tissue levels with a mean of 246 ppt and a range of 42 to 750 ppt. Seven persons who worked at the same chemical company, but not in the 2,3,7,8-TCDD-contaminated process, had a mean of 8.7 ppt and a range of 3.5 to 25.8 ppt. We also report serum levels of 2,3,7,8-TCDD in these individuals. The adipose tissue from a subset of four production workers with elevated levels of 2,3,7,8-TCDD and seven Missouri residents with normal 2,3,7,8-TCDD levels was also analyzed for other isomers of the PCDDs and PCDFs. The mean adipose tissue level of 2,3,7,8-TCDD in the subset of production workers was 45 times higher than the mean level in the unexposed Missouri residents, but similar levels of the other PCDDs and PCDFs were found in both groups. PMID: 2773945 [PubMed - indexed for MEDLINE] 6716. Ann N Y Acad Sci. 1989;573:285-96. Studies into the mechanism whereby insulin activates pyruvate dehydrogenase complex in adipose tissue. Denton RM(1), Midgley PJ, Rutter GA, Thomas AP, McCormack JG. Author information: (1)Department of Biochemistry, School of Medical Sciences, University of Bristol, United Kingdom. PMID: 2699402 [PubMed - indexed for MEDLINE] 6717. Ann N Y Acad Sci. 1989;575:236-43. The regulation of food intake by peptides. Woods SC(1), Gibbs J. Author information: (1)Department of Psychology, University of Washington, Seattle 98195. Historically, nutrients and related metabolic signals were considered to control the onset and offset of meals. Recent research has focused upon the roles of peptides found in the gastrointestinal tract and brain as alternate controllers of these processes. During a meal, the gut secretes a variety of peptides as part of the digestive process. Some of these substances, acting as hormonal or as local signals, may also provide information which is relayed to the central nervous system, causing eating to stop and producing the sense of satiety. When administered to animals or people before a meal, exogenous cholecystokinin (CCK), the most studied of the putative satiety peptides, reduces food intake in a dose-dependent manner. Recent findings support the concept that endogenous CCK acts during meals to limit meal size, and evidence is reviewed suggesting a possible pathophysiological role for CCK in bulimia. Adiposity is also regulated via peptide hormones, especially insulin. Insulin is secreted in direct proportion to adiposity, and blood-borne insulin gains access to brain areas important in the regulation of feeding. The administration of insulin into the brain causes reduced eating and weight loss. PMID: 2699189 [PubMed - indexed for MEDLINE] 6718. Ann N Y Acad Sci. 1989;570:46-60. Products in vivo peroxidation are present in tissues of vitamin E-deficient rats and dogs. Dratz EA(1), Farnsworth CC, Loew EC, Stephens RJ, Thomas DW, Van Kuijk FJ. Author information: (1)Department of Chemistry, Montana State University, Bozeman 59717. PMID: 2698110 [PubMed - indexed for MEDLINE] 6719. Ann N Y Acad Sci. 1989;569:211-8. Studies of cachexia in parasitic infection. Tracey KJ(1), Cerami A. Author information: (1)Division of Neurosurgery, New York Hospital-Cornell University Medical Center, New York 10021. Cachexia and septic shock, syndromes associated with chronic and acute infection, respectively, are mediated by endogenous factors. The search for humoral mediators of cachexia led to the isolation of the cytokine known as cachectin/TNF. A biologic role for cachectin/TNF in cachexia has been identified: it induces a catabolic state in adipose and skeletal muscle cells in vitro, and animals persistently exposed to it in vivo become cachectic. Cachectin/TNF was also discovered to be a primary, essential mediator of septic shock. The acute administration of the recombinant protein causes shock, tissue injury, and derangements of metabolic homeostasis that mimic endotoxemia and septic shock syndrome. Anti-cachectin antibodies protect against the lethal effects of septic shock and cachexia, suggesting that this mediator has a central role as a trigger to the inflammatory and deleterious host responses to infection. Future investigations will undoubtedly be directed towards the effects of inhibiting cachectin/TNF in the treatment of the complications of infectious disease. PMID: 2698089 [PubMed - indexed for MEDLINE] 6720. Prog Lipid Res. 1989;28(2):67-115. Brown adipose tissue thermogenesis and obesity. Himms-Hagen J(1). Author information: (1)Department of Biochemistry, University of Ottawa, Ontario, Canada. PMID: 2692032 [PubMed - indexed for MEDLINE] 6721. Vitam Horm. 1989;45:1-125. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Bray GA, York DA, Fisler JS. The basic hypothesis of this review is that studies on models of experimental obesity can provide insight into the control systems regulating body nutrient stores in humans. In this homeostatic or feedback approach to analysis of the nutrient control system, we have examined the afferent feedback signals, the central controller, and the efferent control elements regulating the controlled system of nutrient intake, storage, and oxidation. The mechanisms involved in the beginning and ending of single meals must clearly be related to the long-term changes in fat stores, although this relationship is far from clear. Changes in total nutrient storage in adipose tissue can arise as a consequence of changes in the quantity of nutrients ingested in one form or another or a decrease in the utilization of the ingested nutrients. A change in energy intake can be effected by increased size of individual meals, increased number of meals in a 24-hour period, or a combination of these events. Similarly, a decrease in utilization of these nutrients can develop through changes in resting metabolic energy expenditure which are associated with one of more of the biological cycles such as protein metabolism, triglyceride for glycogen synthesis and breakdown, or maintenance of ionic gradients for Na+ + K+ across cell walls. In addition, differences in energy expenditure related to the thermogenesis of eating or to the level of physical activity may account for differences in nutrient utilization. PMID: 2688303 [PubMed - indexed for MEDLINE] 6722. Ann Nutr Metab. 1989;33(2):79-87. Interrelationships between body weight, body fat distribution and insulin in obese women before and after hypocaloric feeding and weight loss. Casimirri F(1), Pasquali R, Cesari MP, Melchionda N, Barbara L. Author information: (1)Institute of Clinical Medicine and Gastroenterology, S. Orsola Hospital, Alma Mater Studiorum University of Bologna, Italy. The effects were investigated of weight loss on the relationship between hyperinsulinemia, body weight and body fat distribution in two groups of women with central-type obesity (CTO) (waist-to-hip ratio WHR greater than 0.85) or peripheral-type obesity (PTO) (WHR less than 0.85). An oral glucose tolerance test was carried out before and after a hypocaloric nutritional treatment lasting 4 months. Both groups were matched for age, body mass index and amount of body fat. At the basal condition, group CTO had fasting and glucose-stimulated insulin levels significantly higher than group PTO; fasting (but not stimulated) C peptide levels were also higher in CTO compared with PTO. Weight and fat loss were significantly higher in CTO than in PTO women. Moreover, unlike PTO, CTO subjects significantly reduced their WHR values. In both groups weight loss led to a significant drop in fasting and glucose-stimulated insulin and C peptide levels. However, PTO women reduced their C peptide levels significantly less than CTO. In conclusion, weight loss only modified body fat distribution in women with CTO, who appeared to be prone to a greater weight loss than the PTO women. Compared to PTO, CTO women were characterized by higher insulin levels and peripheral insulin resistance, which improved during hypocaloric feeding probably due to the combined effect of weight loss and the change in body fat distribution. PMID: 2683982 [PubMed - indexed for MEDLINE] 6723. Prog Lipid Res. 1989;28(1):53-66. The obese Zucker rat: a choice for fat metabolism 1968-1988: twenty years of research on the insights of the Zucker mutation. Argilés JM(1). Author information: (1)Departament de Bioquímica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Spain. PMID: 2682670 [PubMed - indexed for MEDLINE] 6724. Lymphokine Res. 1989 Winter;8(4):459-69. The effect of tumor necrosis factor alpha on the activity of lipoprotein lipase in adipose tissue. Porat O(1). Author information: (1)Department of Immunology, McMaster University, Hamilton, Ontario, Canada. TNF alpha may play a critical role in many physiologic and pathophysiologic responses. It shows a bifunctional regulatory nature of both inhibiting tumor cell proliferation and enhancing growth and differentiation of other cells. TNF alpha acts as a mediator, binding to specific high affinity receptors to elicit biological responses. TNF alpha may be an essential local and systemic mediator in the pathogenesis of cachexia. By inhibiting the activity of lipogenic enzymes, it affects lipid mobilization from adipose tissue and adipocyte differentiation. The ability of TNF alpha to inhibit anabolic processes in adipocytes and preadipocytes is not unique and has been displayed, though to a lesser degree, by other cytokines such as LT, IFN-gamma, and IL-1. In infected animals, the effect of TNF alpha on LPL of inhibiting anabolic processes and enhancing secretion of FFA by adipocytes, may be important in providing additional energy needed by the immune system to combat invasion. However, the relationship between the suppression of the anabolic processes and the cytotoxicity is uncertain and prolonged action may lead to wasting. The evidence suggests that in the adipocyte, TNF alpha is the unique molecule that suppresses LPL through the selective inhibition of mRNA production. As a consequence of the decrease in the enzyme amounts, there is a reduction in TG-uptake and lipid deposition contributing to cachexia. Neutralizing the action of TNF alpha may reverse the cachectic processes and potentially improve the condition. Further research into the induction, synthesis and regulation of TNF alpha production is necessary. Modern molecular biology techniques should serve as useful models in understanding the regulation of TNF alpha functions in response to stimuli. Development of faster and more sensitive detection methods would improve the measurement of the low concentrations of cytokines. PMID: 2682038 [PubMed - indexed for MEDLINE] 6725. Prog Neurobiol. 1989;33(2):135-47. Nervous regulation of metabolism. Niijima A(1). Author information: (1)Department of Physiology, Niigata University, School of Medicine, Japan. As described previously, the regulatory roles played by the autonomic nervous system on blood glucose homeostasis is well documented in comparison with those on fat and protein metabolism. It can be summarized as follows: It was shown that an increase in blood glucose concentration produced an increase in the activity of the pancreatic branch of the vagus nerve whereas it induced a decrease in the activity of the pancreatic branch of the splanchnic nerve and adrenal nerve. It was also shown that a decrease in blood glucose concentration activated the sympatho-adrenal system and suppressed vago-pancreatic system. It seems rational that these responses are involved in the maintenance of blood glucose level. Studies on the innervation of the liver led us to a conclusion that sympathetic innervation of the liver plays a role in eliciting a prompt hyperglycemic response through liberation of norepinephrine from the nerve terminals, and that the vagal innervation synergically worked with the humoral factor (insulin) for glycogen synthesis in the hyperglycemic condition. The glucose-sensitive afferents from the liver seem to initiate a reflex control of blood glucose level. The gustatory information on early insulin response (EIR), reported by Steffens (1976), is supported by the electrophysiological observations. Mei's reports (1981) also indicated the importance of information from the intestinal glucoreceptors in the reflex control of insulin secretion via the vagus, which has been proved electrophysiologically. The role of integrative function of the hypothalamus and brainstem through neuronal networks on neural control of blood glucose homeostasis is evident. On the neural control of fat metabolism, it is evident that the sympathetic outflows to the brown adipose tissue as well as white adipose tissue predominantly play important roles. However, there is still little information on the central mechanism played by the hypothalamus on the fat metabolism and the neural pathways from the hypothalamus to the sympathetic motoneurons innervating adipose tissues. The reports on the neural control of protein metabolism are very few. Only several studies were reported on the liver function in relation to the protein metabolism. Further extensive studies should be expected. PMID: 2678269 [PubMed - indexed for MEDLINE] 6726. Int J Obes. 1989;13(4):455-64. Studies in the distribution of body fat. II. Longitudinal effects of change in weight. Shimokata H(1), Andres R, Coon PJ, Elahi D, Muller DC, Tobin JD. Author information: (1)Laboratory of Clinical Physiology, National Institute on Aging, Baltimore, MD 21224. Information on the effects of age, sex, obesity and weight change on the fat distribution pattern has not been systematically reported. As an index of body fat distribution, the waist hip circumference ratio (WHR) was computed in 370 men and 177 women aged 22-86 years, participants of the Baltimore Longitudinal Study of Aging. For cross-sectional analysis, initial data on the participants were analyzed; for longitudinal study, the changes in the measurements related to weight change during a 5-year follow-up were analyzed. From cross-sectional analysis: (1) waist circumference is larger in men than in women and increases progressively with age; (2) hip circumference shows no consistent age or sex differences; (3) thus, the well known sex differences in WHR are totally attributable to differences in waist circumference; (4) increases in WHR with age occur in both men and women. From longitudinal analysis of weight change: (1) changes in waist and hip circumferences are correlated directly with changes in weight in both sexes, but there are large differential sex effects; (2) in men, waist changes dominate; (3) in women, waist and hip changes are nearly the same; (4) thus, weight changes in men have large effects on the WHR, while in women changes in WHR are very small. Men, as a group, have a more dangerous fat distribution pattern than women, but men as a group will show a more beneficial pattern of change in WHR with weight control than women. PMID: 2676875 [PubMed - indexed for MEDLINE] 6727. Annu Rev Nutr. 1989;9:417-43. Physiologic basis for the control of body fat distribution in humans. Leibel RL(1), Edens NK, Fried SK. Author information: (1)Rockefeller University New York, NY 10021. PMID: 2669880 [PubMed - indexed for MEDLINE] 6728. Acta Clin Belg. 1989;44(1):37-51. Amyloid proteins and amyloidoses: complexity updated. Goffin YA. Amyloid is a beta-pleated fibrillar protein principally constituted of light chains of immunoglobulins (kappa or lambda) in primary or myeloma-associated amyloidosis, of AA proteins in secondary amyloidosis and familial. Mediterranean fever, and of variants of prealbumin - now called transthyretin - in senile amyloidosis and in familial polyneuropathies. Other identified amyloidogenic proteins involve APUD protein derivatives (calcitonin), beta 2 microglobulin in chronic hemodialysis-related amyloidosis and beta protein in Alzheimer disease. After a short review of experimental findings and theories concerning the pathogenesis of amyloid deposition, the clinical aspects of amyloidosis are discussed stressing their great diversity. The diagnostic approach is also examined, with particular emphasis on rectal and kidney biopsy and subcutaneous adipose tissue aspirates. Finally, some comments on the treatment of amyloidosis (role of colchicine and DMSO) are made. PMID: 2669433 [PubMed - indexed for MEDLINE] 6729. Crit Rev Biomed Eng. 1989;17(1):25-104. Dielectric properties of tissues and biological materials: a critical review. Foster KR(1), Schwan HP. Author information: (1)Department of Bioengineering, University of Pennsylvania, Philadelphia. We critically review bulk electrical properties of tissues and other biological materials, from DC to 20 GHz, with emphasis on the underlying mechanisms responsible for the properties. We summarize the classical principles behind dielectric relaxation and critically review recent developments in this field. Special topics include a summary of the significant recent advances in theories of counterion polarization effects, dielectric properties of cancer vs. normal tissues, properties of low-water-content tissues, and macroscopic field-coupling considerations. Finally, the dielectric properties of tissues are summarized as empirical correlations with tissue water content in other compositional variables; in addition, a comprehensive table is presented of dielectric properties. The bulk electrical properties of tissues are needed for many bioengineering applications of electric fields or currents, and they provide insight into the basic mechanisms that govern the interaction of electric fields with tissue. PMID: 2651001 [PubMed - indexed for MEDLINE] 6730. Cardiovasc Clin. 1989;19(3):147-58. Pathophysiology of coronary artery atherosclerosis: animal studies of gender differences. Clarkson TB, Adams MR, Kaplan JR, Shively CA. PMID: 2644028 [PubMed - indexed for MEDLINE] 6731. J Nutr. 1989 Jan;119(1):101-4. Carotenoids in human blood and tissues. Parker RS(1). Author information: (1)Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853. The occurrence of carotenoid pigments in human blood and tissues has recently become an area of renewed interest due to the observed inverse relationship between consumption of carotenoid-rich fruits and vegetables and risk of certain cancers. This article reviews current knowledge of the kinds and concentrations of carotenoids in human plasma (or serum) and solid tissues. Most reports have focused on the hydrocarbon carotenoids (lycopene, alpha-carotene, and beta-carotene) with fewer dealing with the more polar xanthophyll pigments. The available literature indicates substantial interindividual heterogeneity with respect to blood levels of both total and individual carotenoids. Reports of solid tissue levels are few, but also indicate large variation, with adipose tissue and liver seemingly the major sites of deposition. The relationship between the types and concentrations of circulating carotenoids and those in solid tissues of the same individuals is not known, but preliminary investigations in our laboratory show considerable qualitative homology between the carotenoids in fasting serum and those in fatty tissue. PMID: 2643690 [PubMed - indexed for MEDLINE] 6732. Med Clin North Am. 1989 Jan;73(1):83-96. The fat cell. Hirsch J(1), Fried SK, Edens NK, Leibel RL. Author information: (1)Rockefeller University Laboratory of Human Behavior and Metabolism, New York, New York. Investigations of how fat cells develop, store, and release energy, and what role they play in energy metabolism are presented. The importance of adipose tissue in the pathogenesis of obesity is considered. PMID: 2643010 [PubMed - indexed for MEDLINE] 6733. Med Clin North Am. 1989 Jan;73(1):67-81. Genetic factors in obesity. Bouchard C(1). Author information: (1)Physical Activity Sciences Laboratory, PEPS, Laval University, Sainte-Foy, Québec, Canada. Several points should be emphasized in summarizing the role of biological inheritance in human body-fat variation. First, at least two kinds of genetic effects must be considered: the additive genetic effect and the genotype-environment interaction effect. Second, from the data reviewed here, we conclude that the additive genetic effect in amount of subcutaneous fat is quite low but that it is higher (around 25 to 30 per cent) for fat mass and regional fat distribution. These results suggest that visceral fat, perhaps, is more influenced by the genotype than subcutaneous fat. Third, it appears that a genotype-overfeeding interaction component exists for body fat, which suggests that sensitivity of individuals to changes in body fat following overfeeding are genotype-dependent. Fourth, the limited data available suggest that the genotype accounts for a significant fraction (equal to or greater than 40 per cent) of the individual differences in RMR, TEM, and TEE. Fifth, one finds a slight genetic effect for the proportion of protein, fat, and carbohydrate in the diet. Sixth, there is some indication that individual differences in habitual physical activity level are characterized by a significant genetic component. The search for genetic markers of the various obesity phenotypes has not been initiated to any extent at this time. However, one can anticipate considerable development in this area in the coming decade. PMID: 2643009 [PubMed - indexed for MEDLINE] 6734. Med Clin North Am. 1989 Jan;73(1):111-38. Health risks of obesity. Kissebah AH(1), Freedman DS, Peiris AN. Author information: (1)Division of Endocrinology, Medical College of Wisconsin, Milwaukee. Evidence implicating obesity as a risk-factor disease is critically reviewed. Possible reasons for the many conflicting findings are addressed. The classification of obesity, based upon the site of body fat distribution, and possible biologic mechanisms associating regional adiposity with morbidity, are discussed. PMID: 2643000 [PubMed - indexed for MEDLINE] 6735. Bibl Nutr Dieta. 1989;(44):32-7. New approaches to the control of obesity in animals and their clinical potential. Stock MJ(1). Author information: (1)Department of Physiology, St George's Hospital Medical School, University of London, UK. PMID: 2571330 [PubMed - indexed for MEDLINE] 6736. Int J Obes. 1989;13(2):137-46. Antilipolytic effects of insulin and adenylate cyclase inhibitors on isolated human fat cells. Lönnqvist F(1), Wennlund A, Arner P. Author information: (1)Karolinska Institute, Department of Medicine, Stockholm, Sweden. Antilipolysis induced by insulin by adenylate cyclase inhibitors was compared in isolated human fat cells when lipolysis was activated at well-defined steps in the cyclic AMP system. The latter was achieved with isoprenaline (beta-adrenoreceptor agonist), cholera toxin and pertussis toxin (acting on the GTP-sensitive coupling proteins), forskolin (stimulating the catalytic component of adenylate cyclase), enprofylline (selective phosphodiesterase inhibitor) and N6-monobutyryl-cyclic-AMP or 8-bromo cyclic-AMP (cyclic AMP analogues which are resistant or sensitive to phosphodiesterase, respectively). Clonidine (alpha 2-adrenoreceptor agonist), prostaglandin E2 and N6-(phenylisopropyl) adenosine (adenosine analogue) failed to inhibit lipolysis stimulated by cholera toxin or pertussis toxin, but were effective under all other conditions. Insulin failed to inhibit lipolysis stimulated by enprofylline or N6-monobutyryl cyclic AMP, but was effective under all other circumstances. In conclusion, insulin and adenylate cyclase inhibitors are antilipolytic in human fat cells through different mechanisms. Adenylate cyclase inhibitors act predominantly on the GTP-sensitive coupling proteins and, to a minor extent, at some yet unidentified distal step in the lipolytic machinery. As regards insulin, the major site of the antilipolytic action is phosphodiesterase. PMID: 2545639 [PubMed - indexed for MEDLINE] 6737. Curr Top Cell Regul. 1989;30:105-42. The intracellular site of action of insulin: the mitochondrial Krebs cycle. Mohan C(1), Geiger PJ, Bessman SP. Author information: (1)Department of Pharmacology and Nutrition, University of Southern California School of Medicine, Los Angeles 90033. PMID: 2515941 [PubMed - indexed for MEDLINE] 6738. Med Sci Sports Exerc. 1988 Dec;20(6):531-8. Cyclic AMP regulation of fuel metabolism during exercise: regulation of adipose tissue lipolysis during exercise. Shepherd RE(1), Bah MD. Author information: (1)Department of Physiology, Louisiana State University, New Orleans 70112. Adipocytes from trained rats release more free fatty acids in response to hormonal challenge compared to fat cells from sedentary rats. Lipolysis results from increased triglyceride hydrolysis that is catalyzed by a hormone-sensitive lipase, which, in turn, is activated by a phosphorylation mechanism involving cyclic AMP-dependent protein kinase. Cyclic AMP levels within the fat cell are regulated by beta-adrenergic receptor/adenylate cyclase interactions and cyclic AMP phosphodiesterase activity. This review focuses on cyclic AMP regulation of lipolysis in adipocytes from trained and sedentary animals. Although lipolysis is elevated in fat cells from trained rats, no differences are found in beta-adrenergic receptor number or affinity, adenylate cyclase activity, protein kinase activity, or partially purified hormone-sensitive lipase activity when compared to sedentary rats. The major lipolytic alteration induced by exercise training appears to occur at a site distal to hormonal regulation of the beta-adrenergic receptor. PMID: 2853268 [PubMed - indexed for MEDLINE] 6739. Am J Med. 1988 Nov 28;85(5A):44-58. Intracellular calcium, insulin secretion, and action. Draznin B(1). Author information: (1)Medical Research Service, Veterans Administration Medical Center, Denver, Colorado 80220. Changes in cytosolic free calcium concentration [( Ca2+]i) constitute an important element of signal transduction in various cells. These changes either reflect alterations in calcium (Ca2+) fluxes or result from mobilization of intracellular Ca2+ stores. In pancreatic islet cells, an increase in [Ca2+]i is critical for secretagogue-induced insulin release. Thus, glucose evokes a rapid increase in [Ca2+]i, primarily by stimulating Ca2+ influx. Under physiologic conditions, glucose may also promote mobilization of intracellular Ca2+ stores by virtue of stimulating membrane phospholipid hydrolysis and formation of inositol triphosphate, a potent stimulus for Ca2+ mobilization. This action of glucose requires the presence of extracellular Ca2+. The magnitude of change in [Ca2+]i may not parallel the level of insulin release, suggesting that the role of [Ca2+]i in the process of insulin release must be considered in concert with other cellular mechanisms. The role of [Ca2+]i in promoting insulin action is a subject of continuous controversy. Recent observations that chelation of intracellular Ca2+ with quin-2 diminishes insulin action (and that of insulin mimetics) support the role of Ca2+ in mediating the insulin-generated signal. Insulin has also been demonstrated to increase [Ca2+]i in adipocytes in close association with its effect on 2-deoxyglucose uptake. Finally, in both pancreatic islet cells and adipocytes, high concentrations of either extracellular or intracellular Ca2+ inhibit cellular responsiveness. The optimal concentrations of cytosolic Ca2+ appear to be within the 140 to 350 nM range. When Ca2+ concentrations are too low or too high, the ability of pancreatic islets and insulin target cells to respond appropriately to physiologic stimuli is significantly diminished. Impaired cellular Ca2+ homeostasis (either primary or secondary to other cellular lesions) may represent a crucial and identical link in the pathogenesis of impaired insulin secretion and in the pathogenesis of impaired insulin action. PMID: 3057895 [PubMed - indexed for MEDLINE] 6740. Vopr Med Khim. 1988 Nov-Dec;34(6):11-6. [Organ-specific characteristics of metabolism of ketone bodies in tissues (review of the literature)]. [Article in Russian] Anikeeva SP. PMID: 3070931 [PubMed - indexed for MEDLINE] 6741. JPEN J Parenter Enteral Nutr. 1988 Nov-Dec;12(6 Suppl):53S-58S. Alterations in lipid and carbohydrate metabolism in sepsis. Spitzer JJ(1), Bagby GJ, Mészáros K, Lang CH. Author information: (1)Louisiana State University Medical Center, Department of Physiology, New Orleans 70112. The effects of sepsis on lipid metabolism may be summarized as follows: The increased plasma catecholamine concentration stimulates adipose tissue FFA release. The increased FFA mobilization and plasma concentration results in an enhanced FFA uptake by the liver which promotes TGFA synthesis and output. Thus, triglyceride appearance rate also can be increased during hypermetabolic sepsis. In severe sepsis, the regulatory signals to increase FFA release from adipose tissue may be counterbalanced by blood flow limitations that inhibit FFA release, possibly due to the inadequate availability of the plasma carrier, albumin. Under such conditions, the arterial FFA concentration may be unchanged or decreased along with similar changes in the rate of peripheral FFA utilization. Triglyceride metabolism can also be altered during septic conditions in which plasma levels of cytokines are very high. Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance. Thus, hypertriglyceridemia can develop in the absence of elevated plasma FFA levels. The plasma concentration of cytokines necessary to inhibit LPL and how often this form of hypertriglyceridemia occurs in human sepsis are unknown at present. The sequence of events describing the influence of sepsis on carbohydrate metabolism is postulated to be the following: The presence of bacteria, or their products (eg, endotoxin) either directly or indirectly (via stimulating mononuclear phagocytes to release cytokines) activate the immune tissues. Glucose utilization by these tissues, which are predominantly glycolytic, is thereby stimulated resulting in increased lactate production. At the same time, glucose uptake by skeletal muscle and lactate release are also elevated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3063839 [PubMed - indexed for MEDLINE] 6742. JPEN J Parenter Enteral Nutr. 1988 Nov-Dec;12(6 Suppl):127S-132S. Novel triglycerides for special medical purposes. Mascioli EA(1), Babayan VK, Bistrian BR, Blackburn GL. Author information: (1)Department of Medicine, Harvard Medical School, Boston, Massachusetts. The clinical use of intravenous lipid emulsions have been routine for over 25 years. For most of that time period the use of the vegetable oils, soybean and safflower, were the exclusive lipid source for these emulsions. Recently intravenous medium-chain triglycerides have been commercially available. This review will discuss several important new research developments coming from the laboratory which should prove to enhance the nutritional effectiveness as well as minimize the adverse effects of lipid emulsions. The use of medium-chain triglycerides either enterally or parenterally has shown them to be superior energy sources when compared to long-chain triglycerides. Under experimental conditions of burn injury, their support of certain aspects of protein metabolism is superior to that of the current emulsions. This may be due to their rapid and preferential oxidation and poor storage into adipose tissue, and increased thermogenesis which has been observed from either enteral or parenteral administration in humans. This increased metabolic rate is not accompanied by an increase in temperature. Lipid emulsions have been described as having many different effects on variable aspects of the immunologic system. Some of these could be considered to be beneficial or without harm, and others are considered potentially deleterious. We have focused on the effects of parenteral lipid emulsions, in animals as well as in humans, on the function of the reticuloendothelial system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3063836 [PubMed - indexed for MEDLINE] 6743. Biochim Biophys Acta. 1988 Oct 11;947(3):571-90. The biology and biochemistry of the glucose transporter. Baly DL(1), Horuk R. Author information: (1)Department of Nutrition, Rutgers University, New Brunswick, NJ 08903. PMID: 3048404 [PubMed - indexed for MEDLINE] 6744. Br Med Bull. 1988 Oct;44(4):971-83. Thermal control in very immature infants. Hull D. PMID: 3076839 [PubMed - indexed for MEDLINE] 6745. Pathology. 1988 Oct;20(4):377-80. Functioning lipoadenoma of the parathyroid gland. de Leacy EA(1), Axelsen RA, Kleinman DS, Kunze HE. Author information: (1)Department of Pathology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. A lipoadenoma of the parathyroid gland was discovered at autopsy as the result of a search for the cause of terminally detected hyperparathyroidism in an elderly man who had suffered cerebral infarction. It is the only case known to the authors in which this uncommon cause of hyperparathyroidism was found at post-mortem examination after hypercalcemia and raised levels of serum immunoreactive parathormone were documented during life. PMID: 3071774 [PubMed - indexed for MEDLINE] 6746. J Dairy Sci. 1988 Oct;71(10):2855-74. Organization and growth of mammary epithelia in the mammary gland fat pad. Sheffield LG(1). Author information: (1)Dairy Science Department, University of Wisconsin, Madison 53706. Mammary gland development consists of a series of very highly ordered events involving interactions among a number of distinct cell types. An important aspect of mammary gland development is that the mammary gland consists of a fat pad of mesodermal origin into which epithelial cells of ectodermal origin proliferate. This proliferation of epithelial cells into the mammary fat pad is the subject of this review. The nature of the stroma into which epithelial cells proliferate is of considerable importance in determining the structure of the resulting gland. In mice, white adipose tissue appears to be required for normal mammary development. Transplantation of mammary epithelia to other types of stroma does not support epithelial growth or result in abnormal growth. To date, a synthetic substratum capable of mimicking white adipose tissue has not been developed. Although collagen gel cultures are generally considered superior to glass or plastic substratum in supporting near normal epithelial growth, the technique has not advanced to the point that the in vivo growth pattern is duplicated. Recent research on the generation of chimeric mammary tissue (by transplanting mammary epithelia from rats, cows, and women to the mammary fat pads of athymic nude mice) suggests that there are important species differences in the stromal requirements for mammary gland development. In particular, extensive and expansive growth of rat mammary tissue is observed in mouse mammary fat pads. However, the mouse mammary fat pad appears incapable of supporting expansive growth of bovine or human mammary epithelia. The reason for this difference is not clear. However, human and bovine mammary epithelia may require the presence of more fibrous (collagenous) tissue than rodent mammary epithelia for normal proliferation. PMID: 3060494 [PubMed - indexed for MEDLINE] 6747. Med Sci Sports Exerc. 1988 Oct;20(5 Suppl):S193-6. Factors affecting cold acclimation and thermogenesis in man. Leblanc J(1). Author information: (1)Department of Physiology, School of Medicine, Laval University, Quebec City, Canada. Three types of cold exposure are observed in man: systemic moderate cold (SM), systemic severe cold (SS), and local severe cold (LS). Contrary to rat, prolonged exposure to SM cold does not produce non-shivering thermogenesis, as it does in the rat, possibly because of lack of active brown adipose tissue. Instead there is a reduction in heat production, in shivering, and in discomfort through a process known as habituation. No adaptation was found with exposure to SS cold, since shivering and discomfort always prevail and there is indirect evidence of enhanced sympathetic response after repeated exposure to SS cold. Exposure to LS cold leads to adaptive responses in which discomfort and autonomic activity are reduced. It is suggested that LS adaptation is also related to habituation. PMID: 3057321 [PubMed - indexed for MEDLINE] 6748. J Cell Biol. 1988 Sep;107(3):829-32. fos protooncogene and the regulation of gene expression in adipocyte differentiation. Spiegelman BM(1), Distel RJ, Ro HS, Rosen BS, Satterberg B. Author information: (1)Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. PMCID: PMC2115271 PMID: 3138249 [PubMed - indexed for MEDLINE] 6749. Proc Nutr Soc. 1988 Sep;47(3):277-85. Lipid metabolism in man. Gurr MI(1). Author information: (1)Milk Marketing Board, Thames Ditton, Surrey. PMID: 3076008 [PubMed - indexed for MEDLINE] 6750. Diabetes Metab Rev. 1988 Sep;4(6):595-601. Brown adipose tissue: does it play a role in the development of obesity? Rothwell NJ(1), Stock MJ. Author information: (1)Department of Physiological Sciences, University of Manchester, United Kingdom. PMID: 3065012 [PubMed - indexed for MEDLINE] 6751. Clin Pharmacokinet. 1988 Sep;15(3):165-79. Digitalis. An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Mooradian AD(1). Author information: (1)Geriatric Research, Education and Clinical Center, Sepulveda Veterans Administration Medical Center, Los Angeles, California. The intestinal absorption of digoxin is essentially a passive non-saturable diffusion process, although a saturable carrier-mediated component also plays an important role. The bioavailability varies between 40 and 100%: the presence of food may reduce the peak serum concentration, but does not reduce the amount of digoxin absorbed. Recent development of a capsule containing a hydroalcoholic vehicle may reduce interindividual variations in absorption. Pharmacokinetic analysis of the distribution of digoxin suggests 3 compartments, the slow distribution phase accounting for the lag time between the inotropic effects and the plasma concentration profile. Digoxin is extensively bound to tissues such as myocardium, renal, skeletal muscle as well as red blood cells, but not to adipose tissue. Plasma protein binding varies between 20 and 30%: displacement of digoxin from protein binding sites does not cause significant clinical effects. As expected, haemodialysis or exchange transfusions do not significantly alter the body load of digoxin. The apparent volume of distribution of digoxin varies between 5 and 7.3 L/kg; this may be reduced by, for example, electrolyte abnormalities which reduce digoxin binding to the myocardium. The elimination half-life of digoxin is 36 hours, with 60 to 80% being excreted unchanged, by passive glomerular filtration and active tubular secretion. The remainder is excreted non-renally. Clearance is therefore dependent on renal function and declines in renal disease and in elderly patients. Digoxin interacts with other drugs at any stage of absorption (e.g. cholestyramine), distribution (e.g. quinidine), metabolism (e.g. phenytoin) or elimination (e.g. diltiazem). Patients should, therefore, be carefully monitored when changing a therapeutic regimen which includes any drugs known to interact with digoxin. Clinical monitoring is more important than therapeutic drug monitoring which should be reserved for suspected toxicity, doubts about efficacy, or in cases of poor compliance. With the advent of newer treatment modalities, digoxin is no longer the treatment of first choice in supraventricular arrhythmias and congestive heart failure. However, with careful monitoring, digoxin remains an important therapeutic option. PMID: 3052985 [PubMed - indexed for MEDLINE] 6752. Endocr Rev. 1988 Aug;9(3):319-45. Insulin degradation: mechanisms, products, and significance. Duckworth WC(1). Author information: (1)Veterans Administration Medical Center, Omaha, Nebraska. Although much remains to be learned, our understanding of the mechanisms and processes by which insulin is degraded has advanced considerably over the past few years. The roles of receptor binding and internalization in mediating insulin degradation have been clarified, and the endosomal pathway for intracellular insulin degradation has been established and partially characterized. The importance of IP (IDE) in cellular insulin degradation has been established and the importance of lysosomal degradation questioned. Studies on IP have identified the degradation products resulting from insulin metabolism by this enzyme and shown that the degradation products by IP are identical with those produced by isolated hepatocytes. A major remaining question for future investigation is the potential role of insulin degradation and intracellular processing in insulin action. PMID: 3061785 [PubMed - indexed for MEDLINE] 6753. Diabetes Metab Rev. 1988 Aug;4(5):507-15. Control of lipolysis and its relevance to development of obesity in man. Arner P(1). Author information: (1)Karolinska Institute, Huddinge Hospital, Stockholm, Sweden. PMID: 3061758 [PubMed - indexed for MEDLINE] 6754. Dan Med Bull. 1988 Aug;35(4):303-15. The regulation of subcutaneous adipose tissue blood flow in the ischaemic forefoot during 24 hours. Studies using the 133-xenon wash-out technique continuously over 24 hours. Jelnes R(1). Author information: (1)Department of Clinical Physiology/Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark. A method for continuous measurement of subcutaneous adipose tissue blood flow in the forefoot during 24 hours (SBF) is described. The method is based on the radioisotope wash-out principle using 133-Xenon. A portable semiconductor detector is placed just above a local depot of 1-2 microCi 133-Xenon in 0.1 ml isotonic saline injected into the subcutaneous adipose tissue in the forefoot. The detector is connected to a memory unit allowing for storage of data. Due to the short distance, the recorded elimination rate constant must be corrected for combined convection and diffusion of the radioactive indicator. Characteristic 24-hour blood flow patterns were unveiled in patients with normal peripheral circulation and in patients having ischaemic nocturnal rest pain. In normals SBF doubled from day to night. This is ascribed to the local veno-arteriolar sympathetic axon reflex, which induces arteriolar vasoconstriction when the transmural pressure of the veins exceeds approximately 25 mmHg. In patients having ischaemic rest pains SBF was reduced by 37% on the average from day to night. This was caused by nocturnal hypotension, which is reflected proportionally in the foot. As the resistance vessels most probably are fully dilatated in feet with rest pain, the blood pressure drop during sleep causes the perfusion pressure and thus blood flow to come below a certain critical limit. There was a pronounced correlation between the reduction of systemic mean arterial blood pressure and SBF. The patients complaining of intermittent claudication, but no rest pains showed a variety of changes in SBF compatible with the continuous spectrum of the peripheral arteriosclerotic disease. After reconstructive vascular surgery, the 24-hour blood flow pattern normalized although the ankle/arm systolic blood pressure index did not come within normal range. SBF during day-time activities decreased by up to 50% postoperatively. This is caused by the reappearance of the local, sympathetic, veno-arteriolar vasoconstrictor response. During sleep SBF increased by 71%. The term postreconstructive hyperaemia seems improper, at least in a long-term context, normalization of preoperative ischaemia is a more correct notation. The coefficient of variation of nocturnal SBF was calculated to 10%. The method thus seems apt as a monitor in medical therapy for occlusive arterial disease. Changes of lambda has, however, to be considered in each study. PMID: 3048919 [PubMed - indexed for MEDLINE] 6755. J Pediatr. 1988 Jul;113(1 Pt 1):1-9. Growth and development of adipose tissue. Poissonnet CM(1), LaVelle M, Burdi AR. Author information: (1)Department of Anatomy and Cell Biology, University of Michigan, Ann Arbor 48109. PMID: 3290412 [PubMed - indexed for MEDLINE] 6756. Trends Genet. 1988 Jul;4(7):203-7. Regulation of gene expression in the adipocyte: implications for obesity and proto-oncogene function. Spiegelman BM. PMID: 3070869 [PubMed - indexed for MEDLINE] 6757. Arch Environ Contam Toxicol. 1988 Jul;17(4):473-8. Relationship between dietary intake of organic chemicals and their concentrations in human adipose tissue and breast milk. Travis CC, Hattemer-Frey HA, Arms AD. PMID: 3044283 [PubMed - indexed for MEDLINE] 6758. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 2):1575-83. Role of lipoprotein lipase activity on lipoprotein metabolism and the fate of circulating triglycerides in pregnancy. Herrera E(1), Lasunción MA, Gomez-Coronado D, Aranda P, López-Luna P, Maier I. Author information: (1)Departamento de Bioquimica, Hospital Ramon y Cajal, Madrid, Spain. The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3287929 [PubMed - indexed for MEDLINE] 6759. Lab Invest. 1988 Jun;58(6):613-29. Receptor-mediated endocytosis and intracellular processing of insulin: ultrastructural and biochemical evidence for cell-specific heterogeneity and distinction from nonhormonal ligands. Smith RM(1), Jarett L. Author information: (1)Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia. This review has presented some of the data which indicate that there are substantial differences in the mechanisms of receptor-mediated uptake and intracellular processing of ligands. Data from various laboratories indicate that receptor-mediated endocytosis is not necessarily synonymous with the concentrative, coated-pit-mediated internalization of ligand-receptor complexes. That differences exist both between the internalization of different types of ligands on the same cell type and between different types of cells for same ligand has clearly been documented. The differences in mechanisms or structures involved in receptor-mediated endocytosis have been demonstrated both biochemically and ultrastructurally. The reasons for these two diverse internalization pathways utilizing coated and non-coated membrane domains are not known and require further investigation to substantiate or disprove hypotheses presented here and elsewhere. Similarly, while differences in intracellular routing of hormonal and non-hormonal ligands and their receptors certainly exist, the factors controlling the itinerary of the ligand or its receptor need to be identified. The differences in ligand-receptor processing already demonstrated should indicate that interpretation of the results of future studies must be made with a great deal of caution and conservatism particularly when attempting to apply knowledge of one ligand and cell system to pharmacologically, ultrastructurally, or physiologically dissimilar systems. PMID: 2454347 [PubMed - indexed for MEDLINE] 6760. Hinyokika Kiyo. 1988 May;34(5):855-61. [Adrenal myelolipoma: two case reports]. [Article in Japanese] Sumi S(1), Kokuho M, Ishibashi Y, Yamauchi T, Washizuka M, Kawai T. Author information: (1)Department of Urology, Cancer Institute Hospital. We report 2 cases of adrenal myelolipoma which were suspected preoperatively and confirmed by surgical resection. As with most cases previously reported, the lesions were found in obese, middle-aged persons. Laboratory tests of adrenal function revealed values within the normal level. Excretory urography showed radiolucent masses in the suprarenal area displacing the kidney inferiorly. Computerized tomography revealed well-defined masses consisting of fat density areas and higher density areas. Ultrasonography demonstrated hyperechoic, heterogeneous tumors. The tumors were shown to be hypovascular and adrenal in origin on the angiogram. An operation was performed because of complaint of flank pain in the first case and hypertension associated with elevated plasma renin activity in the second case. The pathological study disclosed typical adrenal myelolipoma with a mixture of hematopoietic and adipose tissue. Adrenal myelolipoma is clinically unusual and only 41 cases with premortem diagnosis have been reported in English literature. We herein report the 14th and 15th cases in Japan. As computerized tomography and ultrasonography become more widely used, we believe that the number of cases difficult to differentiate from a malignancy will increase. PMID: 3051940 [PubMed - indexed for MEDLINE] 6761. Semin Perinatol. 1988 Apr;12(2):151-6. Thyroid hormone effects on neonatal thermogenesis. Polk DH(1). Author information: (1)Perinatal Research Laboratories, King-Drew Medical Center, Los Angeles, CA 90059. It is clear that thyroid hormones modulate non-shivering heat production of the newborn mammal. While some obvious thyroid hormone effects on thermogenesis can be demonstrated in adult, cold-acclimated or hibernating animals, these findings cannot be directly applied to the newborn, in which changes in amount and composition of brown adipose tissue, as well as sympathetic and thyroid system maturational events, are occurring. Thyroid hormones do influence the prenatal development and subsequent responses of brown adipose tissue in neonates through primary actions on brown adipose tissue iodothyronine 5'monodeiodinase and mitochondrial uncoupling protein. Secondary effects involving brown adipocyte growth, lipid composition, oxidation proteins, and sympathoadrenal activity are of lesser importance in thyroid hormone modulation of newborn thermogenesis. The acute surge in thyroid hormones that occurs at birth seems of limited significance with regard to neonatal thermogenesis. The stimulation of sympathoadrenal activity at the time of birth, as well as continued in situ conversion of T4 to T3 in the brown adipocyte, are of critical importance in stimulating and modulating heat production in the newborn. PMID: 3293226 [PubMed - indexed for MEDLINE] 6762. Am J Clin Nutr. 1988 Apr;47(4):591-607. Theory and validity of indirect calorimetry during net lipid synthesis. Elia M(1), Livesey G. Author information: (1)Dunn Clinical Nutrition Center, Cambridge, UK. A critical examination is made of the validity of indirect calorimetry when the nonprotein respiratory quotient is greater than 1. The different published stoichiometries for lipogenesis from glucose are excluded as a source of uncertainty in the interpretation of gaseous exchange measurements. The validity of indirect calorimetry is proved independently by an algebraic approach which, in contrast to previous attempts, makes minimal assumptions about stoichiometries. Although equations relating the respiratory quotient to the heat equivalent of oxygen are found valid, there is uncertainty in using these equations to predict accurately carbohydrate utilization and fat oxidized or synthesized. Reference tables interrelating respiratory data, the heat equivalent of oxygen, and net fuel utilization or synthesis for specified fuels are provided. A suggested framework for calculating energy expenditure in terms of ATP gain is given as an appendix. PMID: 3281433 [PubMed - indexed for MEDLINE] 6763. Sports Med. 1988 Apr;5(4):209-25. Beta-adrenoceptor blockade and exercise. An update. Van Baak MA(1). Author information: (1)Department of Pharmacology, University of Limburg. Blockade of beta-adrenoceptors interferes with haemodynamic and metabolic adaptations and ion balance during dynamic exercise. After administration of a beta-blocker exercise heart rate is reduced. Exercise cardiac output and blood pressure are reduced also, but to a lesser extent than heart rate. At submaximal exercise intensities blood flow to the active skeletal muscle is also reduced. The availability of non-esterified fatty acids for energy production is decreased, due to inhibition of beta-adrenoceptor-mediated adipose tissue lipolysis, and possibly also of intramuscular triglyceride breakdown. During submaximal exercise muscle glycogenolysis is unaffected, but there are indications that the maximal glycogenolytic rate at high exercise intensities is decreased. In normally fed subjects plasma glucose concentration is maintained at a normal level during submaximal endurance exercise after beta-blocker administration, although lower glucose concentrations are found in fasting subjects and during high intensity exercise after beta-blocker administration. Plasma lactate concentrations tend to be somewhat lower after beta-blocker administration while plasma potassium concentration during exercise is increased. beta-Blocker administration may also interfere with thermoregulation during prolonged exercise. Maximal aerobic exercise capacity is reduced in normotensive and probably also in hypertensive subjects after beta-blocker administration. Submaximal endurance performance is impaired to a much more important extent in both groups of subjects. In patients with coronary artery disease, on the other hand, symptom-limited exercise capacity is improved during beta-blocker treatment. Studies on trainability during beta-blocker treatment show inconsistent results in healthy subjects, although the majority of studies suggest a similar training-induced increase in VO2max during placebo and beta-blocker treatment. In patients with coronary artery disease the training effects are also similar in patients treated with beta-blockers and those without. The negative effects of beta-blockers on maximal and especially submaximal exercise capacity should be considered when prescribing beta-blockers to physically active hypertensive patients. The negative influence is shared by all types of beta-blockers, although the impairment of submaximal exercise capacity is more pronounced with non-selective than with beta 1-selective beta-blockers. beta-Blockers with intrinsic sympathomimetic activity have similar effects during exercise to those without intrinsic sympathomimetic activity. PMID: 2897710 [PubMed - indexed for MEDLINE] 6764. Ann Hum Biol. 1988 Mar-Apr;15(2):131-42. Relations between anthropometric characteristics and androgen hormone levels in healthy young men. Knussmann R(1), Sperwien A. Author information: (1)Institut für Humanbiologie, Universität Hamburg. Inter-individual correlations between androgen hormone levels and anthropometric features were computed using data from a sample of 110 healthy young men. Radioimmunoassays were used to determine the total testosterone and dihydrotestosterone in the serum and the free testosterone in the saliva. The 58 body measures encompassed the head, trunk and extremities in terms of their length, breadth and circumference. In addition, skin-fold thicknesses were also measured. This set of features was also subjected to factor analysis; the correlations of the resulting individual factor scores with the body measurements were also determined. The total testosterone and dihydrotestosterone were found to have a number of significant correlations with the various body measures and factors, while the free testosterone did not yield any significant findings. These correlations indicate in particular that there is a relation between the serum androgens and leptomorphism (especially negative correlations to indicators of the fat development), whereas a connection between the serum androgens and masculinity is only hinted at. PMID: 3281575 [PubMed - indexed for MEDLINE] 6765. Sci Am. 1988 Mar;258(3):88-95. Fatness and fertility. Frisch RE. PIP: The relationship between fatness and fecundity in women is explored. The author presents evidence that a woman must store a threshold or minimum amount of body fat in order to be able to reproduce. The possible mechanisms by which the amount of body fat might affect fecundity are examined. Consideration is also given to the effects of dieting and exercise on fecundity. PMID: 3051352 [PubMed - indexed for MEDLINE] 6766. Curr Top Cell Regul. 1988;29:217-63. The glycogen storage disease (gsd/gsd) rat. Clark D(1), Haynes D. Author information: (1)CSIRO Australia, Division of Human Nutrition, Adelaide. PMID: 3293925 [PubMed - indexed for MEDLINE] 6767. Acta Med Scand Suppl. 1988;723:91-4. Potential role of adipose tissue for the development of insulin resistance in obesity. Lönnroth P(1). Author information: (1)Department of Medicine II, Sahlgrenska Hospital, Göteborg, Sweden. PMID: 3293361 [PubMed - indexed for MEDLINE] 6768. Acta Med Scand Suppl. 1988;723:79-89. Mechanisms associating body fat distribution to glucose intolerance and diabetes mellitus: window with a view. Kissebah AH(1), Peiris AN, Evans DJ. Author information: (1)Department of Medicine, Medical College of Wisconsin, Milwaukee. PMID: 3293360 [PubMed - indexed for MEDLINE] 6769. Acta Med Scand Suppl. 1988;723:135-41. Genetic factors in the regulation of adipose tissue distribution. Bouchard C(1). Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Quebec, Canada. This paper reviews current data concerning the role of the genotype in human variation in fat distribution and its contribution in regulating fat deposition in various regions of the body, primarily the lower trunk area. After statistical control over age, gender and total amount of subcutaneous fat, one finds an additive genetic effect of about 20-25% of remaining human variance in amount of lower trunk fat and in the relative proportion of lower trunk versus extremity fat. In spite of such a moderate genetic effect in fat distribution, the preferential site of fat deposition when exposed to chronic overfeeding is largely determined by one's genotype. Characteristics of regional adipose tissue metabolism and morphology are probably involved in mediating some of these genetic effects but other regulatory mechanisms are undoubtedly implicated. PMID: 3293357 [PubMed - indexed for MEDLINE] 6770. Acta Med Scand Suppl. 1988;723:121-34. The associations between obesity, adipose tissue distribution and disease. Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgrenska Hospital, University of Göteborg, Sweden. Recent research has shown the marked differences in association with disease between obesity localized to the abdominal respectively to the gluteal-femoral regions. In this review systematic analyses were performed of the associations between obesity (body mass index, BMI) or abdominal obesity (increased waist-over-hip circumference ratio, WHR) on the one hand, and a number of disease end points, and their risk factors, as well as other factors on the other, WHR was associated with cardiovascular disease, premature death, stroke, non-insulin-dependent diabetes mellitus and female carcinomas. In contrast, BMI tended to be negatively correlated to cardiovascular disease, premature death, and stroke, but positively to diabetes. The established risk factors for these end points were found to correlate to WHR, while this was often not the case with BMI. BMI was positively correlated only to insulin, triglycerides and blood pressure. Together with diabetes mellitus, this seems to constitute a metabolic group of conditions which are thus associated with BMI. Androgens (in women), and perhaps cortisol, seem to be positively, and progesterone negatively correlated to WHR. The WHR was also positively associated with sick leave, several psychological maladjustments, psychosomatic and psychiatric disease. Attempts were made to interpret these findings. In a first alternative an elevation of FFA concentration, produced from abdominal adipose tissue, was considered to be the trigger factor for the pathologic aberrations associated with abdominal distribution of body fat. When obesity is added, the metabolic aberrations may be exaggerated. In a second alternative adrenal cortex hyperactivity was tested as the cause. When combined with the FFA hypothesis, this might explain many but not all of the findings. It seems possible to produce an almost identical syndrome in primates by defined experimental stress. Women with high WHR were found to have a number of symptoms of poor coping to stress. It was therefore suggested that part of the background to this syndrome might be a hypothalamic arousal syndrome developing with stress. It was concluded that obesity and abdominal distribution of adipose tissue constitute two separate entities with different pathogenesis, clinical consequences and probably treatment. PMID: 3293356 [PubMed - indexed for MEDLINE] 6771. Life Sci. 1988;43(2):93-110. Obesity: thermodynamic principles in perspective. Rampone AJ(1), Reynolds PJ. Author information: (1)Department of Physiology, School of Medicine, Oregon Health Sciences University, Portland 97201. The energy balance equation applicable to all living organisms was used as a framework on which to construct a critical review of some of the more controversial aspects of the obesity problem. The equation matches energy intake against all the known forms of work that the body does in utilizing that energy, including external and internal work and the work of adipose tissue synthesis (stored energy). Equations representing everyday living conditions, resting, fasting and basal conditions were constructed. The equation applicable to everyday living (working, non-fasting) was used to develop a set of model paradigms to illustrate some of the devices that can be invoked to decrease expenditure and conserve energy. These served as models of how obesity can arise in the absence of calorie overconsumption. The same equation was then used to create a set of opposite paradigms showing how obesity can be prevented by increasing expenditure to waste energy and stabilize body weight when challenged by hyperphagia. In order to see caloric intake and the various work terms in their proper quantitative relationships it was necessary to assign numerical values to the equation. These were selected from published reports of caloric values representative of a non-obese adult of average size engaged in a typical white collar occupation. It was then easy to adjust these assigned values commensurate with the objectives described in the preceding paragraph. Since obesity research is hampered by a confusing array of metabolic interactions it was essential to alter only one of the energy terms at a time, excluding all metabolic interactions except for those unavoidable ones dictated by the laws of thermodynamics. Only in this way could we see the body's multiple energy forms in clear perspective with regard to their real quantitative significance in the energy balance sheet and their potential impact on body weight. Creating these models gave us the added advantage of enabling us better to evaluate the scientific literature because the data we generated, although theoretical, served as excellent standards against which to compare the real data that have emanated from research laboratories.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3292870 [PubMed - indexed for MEDLINE] 6772. Life Sci. 1988;43(1):1-5. Growth hormone receptors. Mendelsohn LG(1). Author information: (1)Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285. The receptor for rabbit liver growth hormone (GH) has recently been purified and cloned. Sequencing data demonstrates that this site represents a new class of transmembrane receptor proteins containing covalently linked ubiquitin and N-linked oligosaccharides. Homology with the human GH liver receptor is estimated to be 84%. GH receptors are also present on non-liver cells, however, their function is poorly understood, and it is not yet known if there is homology with the liver site. Direct stimulation of differentiation of preadipocytes to adipocytes by GH has been demonstrated. In bone, binding of GH to the resting cell zone, but not the proliferative layers has been reported. Taken together, these data support the hypothesis of Green and colleagues that GH has a dual mechanism of action which includes direct stimulation of differentiation of precursor cells and a secondary effect of enhancing the clonal proliferative response. PMID: 3290607 [PubMed - indexed for MEDLINE] 6773. Int J Obes. 1988;12(2):93-102. Insulin and thermogenesis. Rothwell NJ(1), Stock MJ. Author information: (1)Department of Physiological Sciences, University of Manchester, UK. The evidence reviewed here indicates that insulin can increase sympathetically-mediated thermogenesis, probably via its central actions. However, since hypoglycaemia appears to inhibit thermogenesis, the interpretation of data and design of the experiments to study this phenomenon are highly problematic and further confounded by marked changes in insulin sensitivity. This review has purposely concentrated on work performed on experimental animals without directly referring to man. This is because of the very limited number of studies carried out in man, and the fact that difficulties of interpretation discussed above are multiplied many-fold by the limitations of human studies. The evidence to support a role for DIT in energy balance regulation and the importance of brown fat in man has been reviewed elsewhere. A limited number of studies have reported increases in metabolic rate in human subjects infused with glucose and insulin. This response is partially inhibited by the beta-adrenergic antagonist propranolol, and the effects diminished in some grossly obese subjects (e.g. Pima Indians). Landsberg has recently presented and discussed data which indicate that insulin can stimulate thermogenesis in man, and concluded that 'insulin is a major signal that relates dietary intake to sympathetic activity'. PMID: 3290134 [PubMed - indexed for MEDLINE] 6774. Reprod Nutr Dev. 1988;28(1):39-59. [Roles and mechanisms of action of somatotropin (growth hormone) in lactating ruminants]. [Article in French] Chilliard Y(1). Author information: (1)Laboratoire de la Lactation, I.N.R.A., Ceyrat, France. In 18 short-term trials from the literature using dairy cows, somatotropin resulted in increased milk yield (+4.0 kg/d), increased fat, lactose and protein secretions, decreased dry matter intake (-0.5 kg/d) and decreased calculated energy balance (-4.2 Mcal/d). Milk composition was also changed (fat, + 1.9 g/kg; protein, - 1.4 g/kg, and lactose, + 0.6 g/kg), due to the fact that treated cows were often in negative energy balance. In 15 long term trials, somatotropin resulted in increased milk yield (+ 5.7 kg/d) and increased dry matter intake (+ 1.2 kg/d), whereas calculated energy balance decreased (- 2.2 Mcal/d). In 4 trials, digestive efficiency did not seem to be altered by somatotropin. In two long-term trials, body lipids (as estimated by deuterium marked water space) were about 40 kg lower in treated cows, probably reflecting a lower lipid deposition, owing to their lowered energy balance. Current hypothesis on mechanisms of action of somatotropin or somatomedins are discussed, concerning mammary tissue (secretory cell number or metabolic activity), as well as teleophoretic adaptations that alter nutrient partitioning between mammary, liver, muscle and adipose tissues, by way of modifications of tissue responsiveness to homeostatic insulin or adrenergic regulations. Somatotropin could indirectly stimulate metabolic activity in mammary cells. Simultaneously, it could decrease adipose tissue lipogenesis and increase fatty acid mobilization and oxidation in other tissues, thus allowing decreased glucose and amino acid oxidations that insure adequate nutrient supply to the mammary gland. PMID: 3281197 [PubMed - indexed for MEDLINE] 6775. Sports Med. 1988 Jan;5(1):11-40. Techniques of measurement of body composition. Part I. Brodie DA(1). Author information: (1)School of Physical Education and Recreation, University of Liverpool. The measurement of lean body and fat mass has developed with the increase in sports participation and the prescription of exercise. Quantification of body fat is also related to the treatment of obesity and to assess nutritional status. Different levels of evaluation have been proposed depending on expertise and need. Body density estimation from skinfold measurements has the advantage of simplicity, low cost and reasonable validity with predictions to within 3 to 4% for 70% of the population. The choice of prediction equation will depend on whether a generalised equation or a population-specific equation is appropriate. In all cases tester reliability and standard error of estimation should be established. There is strong evidence that a quadratic equation should be applied and that measures of the lower limb should be included with circumference and diameter measures to strengthen the prediction. Methodological errors need to be reduced by careful training of experimenters. Crossvalidation of regression equation will strengthen their validity, particularly when fat loss is to be quantified. The popularity of skinfold assessment of body fat is enhanced by the use of nomograms to predict body fat, although some accuracy will be lost. Skinfold estimation of body fat will continue to be a useful guide to adiposity for epidemiological studies and for popular usage. The hydrostatic weighing procedure to estimate body density is considered by many to be the criterion method. Under carefully controlled conditions with maximum subject compliance, it is highly reliable, particularly if residual volume can be determined accurately. The conversion of body density to percentage body fat is based on a number of assumptions which need to be considered with respect to the population being studied. Simple methods for adiposity include various weight for height indices, for example, the body mass index of weight (kg) divided by height2 (m) which is often used to define obesity, frame size for the prediction of ideal weight and visual estimation for predicting body fat. Differences in the literature concerning fat cell size and number have their origins in variations of methodology. The choice of site for removal of tissue will influence the size of adipocytes, those obtained from deep sites are generally smaller than subcutaneous fat cells. If total cell number is determined from cell size, there will also be variability of cell number. The correlation between different methods of sizing cells is high for most techniques, but as the validity of the criterion method is not based on statistical evidence, the validity of the other methods cannot be readily accepted.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3278354 [PubMed - indexed for MEDLINE] 6776. J Pediatr Gastroenterol Nutr. 1988 Jan-Feb;7(1):10-6. Does infant nutrition affect adiposity and cholesterol levels in the adult? Hamosh M(1). Author information: (1)Department of Pediatrics, Georgetown University Medical Center, Washington, D.C. PMID: 3275768 [PubMed - indexed for MEDLINE] 6777. Braz J Med Biol Res. 1988;21(1):27-30. Does PEPCK play a key role in amino acid oxidation? Curi R(1). Author information: (1)Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Brasil. The major role of phosphoenolpyruvate carboxykinase (PEPCK) in gluconeogenesis is well known. However, studies on amino acid metabolism indicate that this enzyme may also play an important role in complete oxidation of amino acids by several tissues. Here we review evidence to support this proposition, focussing on experiment performed on glutamine metabolism in immune tissues and white adipose tissue. PMID: 3179574 [PubMed - indexed for MEDLINE] 6778. Prog Clin Biol Res. 1988;284:187-209. Involvement of fos as a trans-acting factor in adipogenic gene expression. Distel RJ(1), Spiegelman BM. Author information: (1)Dana-Farber Cancer Institute, Boston, MA. PMID: 3146066 [PubMed - indexed for MEDLINE] 6779. J Inherit Metab Dis. 1988;11 Suppl 1:4-17. The biochemistry of lipoproteins. Salter AM(1), Brindley DN. Author information: (1)Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, UK. Lipids are transported in the blood in four major classes of lipoproteins. The triacylglycerol-rich lipoproteins are chylomicrons and very-low-density lipoproteins (VLDL) which are produced by the small intestine and liver, respectively. These lipoproteins mainly carry fatty acids to adipose tissue and muscle where the triacylglycerol is hydrolysed by lipoprotein lipase. The resulting particles that remain in the blood are chylomicron remnants and low-density lipoprotein (LDL), respectively. The remnant is taken up by the liver via endocytosis which is mediated by a specific receptor for apolipoprotein E (apoE). LDL, which are rich in cholesterol, can also be taken up by the liver or extrahepatic tissues by a receptor-mediated endocytosis that specifically recognises apoB or apoE. 'Nascent' high-density lipoprotein (HDL) particles are secreted by the liver and intestine and then undergo modification to become HDL3 and then HDL2 as they acquire cholesterol ester. They facilitate the reverse transport of cholesterol back to the liver. Little is known of the hormonal regulation of lipoprotein uptake by the liver. Recently, we have shown that insulin and tri-iodothyronine (T3) increase the specific binding of LDL to cultured hepatocytes whereas dexamethasone (a synthetic glucocorticoid) has the opposite effect. The changes in binding produced by insulin and dexamethasone are paralleled by alterations in the rate of degradation of apoB. These findings may in part explain the hypercholesterolaemia and increased risk of premature atherosclerosis that can be associated with poorly controlled diabetes or hypothyroidism. PMID: 3141685 [PubMed - indexed for MEDLINE] 6780. Adv Second Messenger Phosphoprotein Res. 1988;21:157-64. The role of Ca2+ in the hormonal control of intramitochondrial metabolism in heart, liver, and adipose tissue. Denton RM(1), McCormack JG, Midgley PJ, Rutter GA, Thomas AP. Author information: (1)Department of Biochemistry, University of Bristol Medical School, England. PMID: 3137956 [PubMed - indexed for MEDLINE] 6781. Arch Anat Histol Embryol. 1988;71:9-41. [Extra-osseous and intra-osseous microvascularization of the sternum of the child]. [Article in French] Simeoni U(1), Sick H, Koritke JG. Author information: (1)Institut d'Anatomie Normale de la Faculté de Médecine de Strasbourg. The microvascularization of the sternum of the child has been studied by a method of India ink injection and by histology. Extra-osseous vasculature includes vascular pedicles and sternal vascular networks. Vascular anterior and posterior pedicles issue from internal mammary vessels. Sternal anterior and posterior networks are disposed on the faces of the sternum and are divided in a superficial one and a deep one; both are included in the perichondrium. In newborns and in young infants, vascular structures looking like baskets are affixed to the deep sternal network. It is unlikely that they intervene in the constitution of the adult pattern of the sternal vasculature. The early complete development of sternal networks contrasts with the existence of evolutive characteristics of the intra-osseous vasculature. Intra-osseous vasculature includes the cartilage canal vessels and the vessels of the ossification centers. Cartilage canals are provided with an axial artery, issued from the deep sternal network, which produces short capillaries which continue in peripheral sinuses. Cartilage canals permit the penetration of perichondral tissue deep in the cartilage of the developing sternum, allowing the formation of the ossification center. The ossification center is vascularized by centrifugal arteries, issued from the cartilage canal artery, and disposed in a radiant pattern. They continue, through a conical progressive dilatation, into a sinusoid network, which presents a convergent disposition towards the center of the ossification point. Vascular events precede ossification. Hematopoietic development is consecutive to the vascular events too. The slenderness of vascular pedicles contrasts in neonates with the wide development of the sinusoid network. Adipose tissue is rare in the bone marrow sternum of the child. Secondary evolution of the ossification center vasculature permits its connections with the deep sternal vascular network, with adjacent cartilage canals, and with adjacent ossification centers. Progressively, the number and the importance of the peripheral pedicles of the ossification centers increase. Thus, a multiple and centripetal vascular provision takes the place of the initial, unique, centrifugal one. These modifications correspond to the transition from the vascular pattern of an expanding structure (the ossification center) to the one which is adapted to the full expression of its hematopoietic function. PMID: 3078484 [PubMed - indexed for MEDLINE] 6782. Przegl Lek. 1988;45(8):641-4. [The role of metabolic disorders in the pathogenesis of obesity]. [Article in Polish] Zahorska-Markiewicz B, Waluga M, Kucio C. PMID: 3070643 [PubMed - indexed for MEDLINE] 6783. Horm Metab Res Suppl. 1988;19:53-7. Lipoprotein lipase. Taskinen MR(1). Author information: (1)Department of Medicine II, University of Helsinki, Finland. PMID: 3069696 [PubMed - indexed for MEDLINE] 6784. Horm Metab Res Suppl. 1988;19:50-2. Effects of insulin on glucose transport and lipolysis. Smith U(1). Author information: (1)Department of Medicine II, University of Gothenburg, Sweden. PMID: 3069695 [PubMed - indexed for MEDLINE] 6785. Horm Metab Res Suppl. 1988;19:26-9. Lipolysis in human adipocytes, effects of cell size, age and of regional differences. Engfeldt P(1), Arner P. Author information: (1)Department of Medicine, Huddinge Hospital, Karolinska Institute, Sweden. In man only catecholamines and insulin have pronounced and acute effects on lipolysis in fat cells. In obesity the effects of these hormones seem to be normal or even increased. When the rate of lipolysis is expressed per cell there is a strong association between hormonal effect and cell size. Indicating that catecholamines and insulin may be involved in the regulation of adipocyte volume. There are, however, site variations in the effects of the regulatory hormones, which may be of importance for the development of various regional forms of obesity. The lipolytic effect of catecholamines is more pronounced in the abdominal than in the femoral/gluteal subcutaneous fat depots, partly owing to an increased alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines in the latter region. This alteration in lipolysis favour accumulation of fat in the femoral/gluteal region and may be of importance for the development of the female type of obesity. Furthermore, in omental fat cells the lipolytic activity is higher than in subcutaneous fat cells owing in part to less marked insulin action and lower alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines. These alterations may cause elevation of the free fatty acid levels in the portal blood so that the handling of glucose and insulin is impaired in the liver which may be one mechanism behind the increased risk to develop cardiovascular complications in the male type of obesity. Age also influences hormone-induced lipolysis. Catecholamine resistance is observed at birth and at the latest stages of life. Insulin resistance is observed in old as compared to middle-aged subjects. PMID: 3069692 [PubMed - indexed for MEDLINE] 6786. Horm Metab Res Suppl. 1988;19:23-5. Are regional metabolic differences of adipose tissue responsible for different risks of obesity? Björntorp P(1). Author information: (1)Department of Medicine I, Sahlgren's Hospital, University of Götenborg, Sweden. Recent research has shown that statistical correlation of disease is usually stronger to abdominal distribution of adipose tissue than to obesity. Abdominal distribution of adipose tissue in women is associated to other male characteristics of muscle tissue mass and morphology, as well as signs of androgenicity in circulating hormones. Abdominal adipose tissue is sensitive to lipolytic stimuli. It might be considered that the endocrine aberrations in combination with elevated concentrations of circulating free fatty acids might cause the complications associated with abdominal obesity. PMID: 3069691 [PubMed - indexed for MEDLINE] 6787. Braz J Med Biol Res. 1988;21(2):171-6. Thermogenic mechanisms in cold-acclimated animals. Griggio MA(1). Author information: (1)Departamento de Fisiologia, Escola Paulista de Medicina, São Paulo, Brasil. 1. This paper reviews the mechanisms of thermogenesis after cold-acclimation. 2. Upon exposure to cold, the oxygen consumption of animals increases by means of shivering and non-shivering thermogenesis. As cold exposure progresses, shivering decreases while non-shivering thermogenesis increases, so that the cold-acclimated animal produces heat mostly by non-shivering thermogenesis. 3. Brown adipose tissue in several species, including man, is an essentially thermogenic organ that produces heat by uncoupling mechanisms in mitochondria. 4. The activity of brown adipose tissue can be assessed by physiological and biochemical methods. 5. After cold acclimation, the activity and mass of brown adipose tissue are higher than in control animals. Brown adipose tissue is considered the main factor responsible for non-shivering thermogenesis. PMID: 3060204 [PubMed - indexed for MEDLINE] 6788. Annu Rev Nutr. 1988;8:259-77. Heredity and body fat. Bouchard C(1), Pérusse L. Author information: (1)Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. The genetics of human obesity was reviewed here in terms of studies dealing with body fat and fat distribution. The role of heredity was examined by reviewing genetic disorders in which obesity is a clinical feature. Two kinds of genetic effects were discussed: the additive genetic effect and the genotype-environment interaction effect. Several indicators of body fat exist, including body mass index, amount of subcutaneous fat, percentage body fat, fat mass, regional fat distribution, and subcutaneous fat pattern. A low additive genetic effect of less than 10% of human phenotypic variation is found in body mass index and amount of subcutaneous fat, while percentage body fat, fat mass, fat distribution, and fat patterning are characterized by heritability estimates of about 25%. On the other hand, a recent study demonstrates that there is an important genotype-environment interaction effect in human body fat variation induced by overfeeding. Limitations of current approaches to the study of the genetics of human body fat and obesity are considered and comments are offered concerning promising areas of future research. PMID: 3060167 [PubMed - indexed for MEDLINE] 6789. Adv Pediatr. 1988;35:73-137. Pathophysiology of childhood obesity. Rosenbaum M(1), Leibel RL. Author information: (1)Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, New York. PMID: 3055868 [PubMed - indexed for MEDLINE] 6790. Biomater Artif Cells Artif Organs. 1988;16(1-3):473-83. Discussion and considerations for the excretion mechanism of perfluorochemical emulsion. Tsuda Y(1), Yamanouchi K, Yokoyama K, Suyama T, Watanabe M, Ohyanagi H, Saitoh Y. Author information: (1)Research Division, Green Cross Corporation, Hirakata, Japan. It has been assumed that a mononuclear phagocyte system is related to the excretion of PFC emulsions: PFC particles are phagocytized by blood monocytes to be expelled through the lung alveoli. This monocyte-related mechanism may well explain excretion at an early stage when PFC particles are abundant in the blood stream. It does not, however, fully explain the manner by which PFC cells are released from the RES cells into the blood stream and into the adipose tissue. To explain this, the following mechanism has been proposed and discussed based on some experimental results. PFC emulsion particles taken up by the RES organs, are stripped at their surfactant layers in the cells and move across the cell membranes to the blood vessels and into other tissues such as adipose, at a rate that depends on the lipophilicity of the PFC's. In the blood stream, PFCs are delivered by lipoproteins to the lung and excreted into the expired air. Pharmacokinetical analysis with a compartmental model for the excretion also supported this proposed mechanism. PMID: 3052648 [PubMed - indexed for MEDLINE] 6791. Prog Clin Biol Res. 1988;265:69-85. The role of brown adipose tissue in the development of the obese-hyperglycemic syndrome in mice. Trayhurn P(1). Author information: (1)Department of Medicine, University of Alberta, Edmonton, Canada. PMID: 3043447 [PubMed - indexed for MEDLINE] 6792. J Sports Sci. 1988 Spring;6(1):49-57. Echocardiographic dimensions in trained and untrained 12-year-old boys and girls. Telford RD(1), McDonald IG, Ellis LB, Chennells MH, Sandstrom ER, Fuller PJ. Author information: (1)Sport Science Department, Australian Institute of Sport, Canberra, A.C.T. The purpose of this study was to compare echocardiographically measured left ventricular (LV) dimensions of 85 trained 11-12-year-old athletes with 106 untrained children matched for skeletal age and fat-free mass. Training status for each group applied to the 3 years prior to the measurements. It was found that 12 min and 100 m runs demonstrated the superior athletic ability of the trained children, but there were no significant differences in LV internal diameters at diastole and systole, in LV posterior wall thickness, or in LV end-diastolic volume and LV mass. These data indicate that little difference occurs in LV size between moderately trained and untrained 11-12-year olds or between boys and girls matched for fat-free mass and skeletal age. It is also evident that consistent but moderate training during late pre-adolescence has little effect on LV development. PMID: 3043014 [PubMed - indexed for MEDLINE] 6793. Reprod Nutr Dev. 1988;28(1):61-84. [Beta adrenergic agonists. Mechanisms of action: lipid mobilization and anabolism]. [Article in French] Lafontan M(1), Berlan M, Prud'Hon M. Author information: (1)Institut de Physiologie, UA 644 C.N.R.S., Université Paul Sabatier, Toulouse, France. In this review, the results obtained in commercial livestock with certain beta-adrenergic agonists (clenbuterol and cimaterol) having an anabolic potential associated with lipid mobilizing properties are considered. The first chapter summarizes major data concerning the effects of beta-agonists on growth and carcass composition in cattle, sheep and pigs. The effect of clenbuterol and cimaterol on carcass quality is to increase the deposition of protein while reducing fat accretion. Then, we briefly consider the physiology and pharmacology of the sympathoadrenal system with a special attention to the distribution and properties of beta-adrenoceptors of various tissues which are putative targets for the beta-adrenergic agonists. Several mechanisms liable to be responsible for the anabolic action of these compounds are also discussed. This chapter includes the evaluation of the effects of beta-agonist on central nervous system and pancreas. A special attention is devoted to their metabolic impact on adipose tissue and muscle. In isolated fat cells, beta-agonists promote stimulation of lipolysis associated with reduction of lipogenesis and of insulin action. The in vitro effects on adipocytes are consistent with the in vivo effects of the compounds. Beta-agonist impact on protein synthesis and muscle accretion is also discussed with reference: 1) to the vascular effects of the compounds that should modify the nutrient flow into the muscle, 2) to a reduction of proteolysis mainly observed for the moment in in vitro studies, 3) to the possible beta-adrenergic-dependent enhancement of insulin action on the muscle. However, more direct experimental evidence is still needed to clearly assess the nature of the action(s) of such anabolic agents on muscle. PMID: 2895488 [PubMed - indexed for MEDLINE] 6794. Exp Pathol. 1988;35(1):1-23. Isolated cells in suspension for biological research--Part III. Structure and functional properties of enterocytes and adipocytes. Remke H(1), Repin VS, Sviridov DD. Author information: (1)Institute of Pathological Biochemistry, Karl Marx University, Leipzig, GDR. PMID: 2852602 [PubMed - indexed for MEDLINE] 6795. Adv Exp Med Biol. 1988;243:271-7. HDL receptor and reverse cholesterol transport in adipose cells. Barbaras R(1), Puchois P, Grimaldi P, Barkia A, Fruchart JC, Ailhaud G. Author information: (1)Centre de Biochimie (CNRS), Parc Valrose, Nice, France. PMID: 2851928 [PubMed - indexed for MEDLINE] 6796. Pharmacol Ther. 1988;38(2):129-68. Role of adenine compounds in autonomic neurotransmission. White TD(1). Author information: (1)Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. Clearly adenine compounds exert numerous effects throughout the autonomic nervous system. The responses of various peripheral tissues to purines are summarized in Table 2. The evidence supporting a possible excitatory neurotransmitter function for ATP is very good in the vas deferens and good in both the bladder detrusor and certain blood vessels. ATP may also be an excitatory neurotransmitter in the colon, hepatocytes and frog atrium. These responses appear to be mediated by P2x-purinoceptors. There is good evidence supporting a role for ATP as an inhibitory neurotransmitter in the taenia coli and duodenum, and some support in the anal sphincter and possibly the rabbit portal vein; these responses appear to be mediated by P2y-purinoceptors. There is good evidence against ATP being an inhibitory neurotransmitter in the stomach fundic muscle and ileum. ATP (or more likely its metabolite adenosine) may act as an inhibitory neurotransmitter by interacting with postsynaptic P1-purinoceptors in cultured sympathetic neurones and also in the parasympathetic vesicle ganglion of the cat. It seems likely that ATP released from heart, platelets or vascular endothelium could be an endogenous relaxant of blood vessels through its actions on the endothelium. Although the addition of exogenous adenosine affects many tissues, evidence supporting modulatory functions for endogenous extracellular adenosine has only been clearly demonstrated in the ileum, gallbladder, vas deferens, fallopian tubes, kidney, blood vessels, carotid sinus, heart and adipose tissue. Both ATP and adenosine, released during periods of hypoxia or ischemia, could exert negative inotropic, chronotropic and dromotropic actions in the heart. In many cases, the potential sources of extracellular purines have not been established. This is particularly important when attempting to establish a neurotransmitter function for ATP in a tissue. For instance, the one outstanding piece of evidence required to confirm that ATP is an excitatory neurotransmitter released from sympathetic nerves in blood vessels is the unequivocal demonstration that it is, in fact, released from the sympathetic nerves when they are stimulated. To date, only the release of radiolabeled metabolites of ATP, possibly from post- rather than presynaptic sites, has been detected. Studies of the release of ATP are complicated by its rapid degradation extracellularly by ecto-ATPase. Unfortunately, there are no specific inhibitors of ecto-ATPase available at present, but one hopes that a suitable inhibitor will be developed shortly.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2847203 [PubMed - indexed for MEDLINE] 6797. Curr Top Cell Regul. 1988;29:77-128. Regulation of fatty acid uptake and synthesis in mammary and adipose tissues: contrasting roles for cyclic AMP. Clegg RA(1). Author information: (1)Hannah Research Institute, Ayr, Scotland. PMID: 2840244 [PubMed - indexed for MEDLINE] 6798. Acta Med Scand Suppl. 1988;723:147-52. Role of antilipolytic mechanisms in adipose tissue distribution and function in man. Arner P(1). Author information: (1)Karolinska Institute, Huddinge Hospital, Stockholm, Sweden. Regional differences have been found in the hormone regulation of adipose tissue lipolysis. Lipolytic activity is greater in omental than in subcutaneous adipocytes owing, in part, to a less marked insulin action and lower alpha 2-adrenoceptor antilipolytic activity in the omental region. In the subcutaneous region catecholamines are less lipolytic in gluteal/femoral than in subcutaneous abdominal adipocytes, which is partly due to enhanced alpha 2-adrenoceptor responsiveness in the gluteal/femoral cells. Insulin action also differs in the two subcutaneous adipose regions in a complex way that is influenced by the degree of obesity and nutritional factors. The regional differences in the antilipolytic effects of hormones seem to be caused by site variations in the receptors as well as in the signals from the receptors. The site variations may be involved in the development of regional forms of obesity, such as android or gynoid obesity and may raise the free fatty acid levels in the portal system and therefore impair metabolism of glucose and insulin by the liver. PMID: 2839956 [PubMed - indexed for MEDLINE] 6799. Acta Med Scand Suppl. 1988;723:143-6. Steroid hormones and distribution of adipose tissue. Rebuffé-Scrive M(1). Author information: (1)Department of Medicine I, Sahlgrenska Hospital, Göteborg, Sweden. Several descriptive studies, performed in women before and after menopause, in young and older men and in women with Cushing's disease, have suggested that steroid hormones have a role in the regulation of regional fat metabolism. Femoral lipoprotein lipase (LPL) activity seems to be increased by progesterone, while it might be inhibited by testosterone. Estradiol and testosterone might be lipolytic in the abdominal region. Long-term exposure to corticosteroid might increase femoral LPL activity and decrease abdominal lipolysis. These conclusions, however, are only tentative. Corticosteroid hormones bind to the cytosolic fraction of human adipose tissue, while no binding was observed with estradiol or progesterone. The relationship between steroid hormone receptors and biological effects in unknown. Further work should be performed to investigate the mechanisms by which steroid hormones might influence human adipose tissue metabolism and distribution. PMID: 2839955 [PubMed - indexed for MEDLINE] 6800. Ann Biol Clin (Paris). 1988;46(1):16-23. [Receptors and molecular heterogeneity of lipoprotein particles containing apolipoprotein A-I]. [Article in French] Broutin H(1), Puchois P, Ailhaud G, Barbaras R, Torpier G, Fruchart JC. Author information: (1)Institut Pasteur-SERLIA, Lille. High density lipoproteins (HDL) are heterogeneous, with respect to their hydrated density (HDL2, HDL3), and to their apolipoprotein composition (Lp A-I : A-II contains both apolipoprotein A-I and A-II, Lp A-I contains apolipoprotein A-I but not apolipoprotein A-II). Lp A-I and Lp A-I and Lp A-I : A-II particles have different metabolic functions. Only Lp A-I particles seem to be involved in the antiatherogenic role of HDL. Alcohol consumption raises Lp A-I : A-II level but not Lp A-I. Different tissue possess specific binding sites for HDL: steroidogenic tissue, hepatocytes peripheral cells. Apolipoprotein A-I and/or A-II are possible ligands. HLD, after binding to the receptor, can provide the cells with cholesterol, or promote an efflux of cholesterol from the cells and the "reverse cholesterol transport" from the peripheral cells to the liver. The HDL subfractions possess different metabolic roles: binding of Lp A-I to mouse adipose cell receptors promotes cholesterol efflux. Apo A-II are antagonists for this effect. PMID: 2839056 [PubMed - indexed for MEDLINE] 6801. Clin Orthop Relat Res. 1987 Dec;(225):279-87. Pathogenesis of membranous lipodystrophy. Case report and review of the literature. Pazzaglia UE(1), Benazzo F, Byers PD, Riboni L, Ceciliani L. Author information: (1)Clinica Ortopedica e Traumatologica dell'Università di Pavia ed I.R.C.C.S. Policlinico San Matteo, Italy. Membranous lipodystrophy occurred in a 35-year-old woman and membrane-like material was found in her epiphyses and short bones. Electron microscopy allowed a study of the relationship between the pathologic tissue and normal fat, suggesting that the membrane-like material is derived from degenerated cells. Nucleation of hydroxyapatite crystals was also observed in the membranous material. Because basal ganglia calcifications were demonstrated with the use of computed tomography, brain and bone lesions may be assumed to share the same pathogenesis. Lipid and mucopolysaccharide metabolism was found to be normal. PMID: 3677514 [PubMed - indexed for MEDLINE] 6802. J Anim Sci. 1987 Dec;65(6):1712-26. Biochemical and physiological indicators of selenium status in animals. Ullrey DE(1). Author information: (1)Anim. Sci. Dept., Michigan State University, East Lansing 48824-1225. Selenium (Se) concentrations in animal tissues vary with the tissue and with the amount and chemical form of Se in the diet. In cattle, sheep and swine, Se concentrations rank in kidney greater than liver greater than heart greater than skeletal muscle greater than adipose tissue. Selenium concentrations (wet basis) in skeletal muscle of swine (.03 to .52 ppm) reflect natural dietary Se concentrations ranging from .03 to .49 ppm. Inorganic Se additions to diets low in natural Se (.05 ppm) increase skeletal muscle Se concentrations until dietary Se levels are adequate. After a period of Se repletion, skeletal muscle Se concentrations should be at least .08 ppm on a wet basis. Selenium concentrations in plasma, serum or whole blood are also related to inorganic Se intake and rise in direct relation to each other in the deficient to adequate range. Plasma or serum Se concentrations of .08 to .12 ppm are consistent with dietary adequacy. Selenium-dependent glutathione peroxidase (GSH-Px) activity of plasma or whole blood may also be used to assess Se status in some animals since plasma or whole blood Se concentrations are positively correlated with GSH-Px activity in animals that are low to adequate in dietary inorganic Se. However, inter-laboratory variation in GSH-Px values is large, and it is doubtful that limits of normalcy developed in one laboratory are applicable in others. In certain tissues it is important to distinguish between GSH-Px and glutathione (GSH) S-transferases, which can reduce organic hydroperoxides but which are not Se-dependent. It is also important that the instability of GSH-Px be considered so that losses in activity during handling and storage may be minimized. Urinary Se excretion and Se retention as percentages of Se intake may be helpful in assessing Se status when facilities for metabolism studies are available. PMID: 3327849 [PubMed - indexed for MEDLINE] 6803. Gig Sanit. 1987 Dec;(12):59-63. [Current hygienic aspects of the accumulation of persistent organochlorine pesticides in human biosubstrates]. [Article in Russian] Borisenko NF, Voloshchenko ZL, Demchenko VF, Klisenko MA, Kuchak IuA. PMID: 3327759 [PubMed - indexed for MEDLINE] 6804. Med Sci Sports Exerc. 1987 Dec;19(6):546-56. Weight regulation practices in athletes: analysis of metabolic and health effects. Brownell KD(1), Steen SN, Wilmore JH. Author information: (1)Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia 19104-3246. Athletes engage in a number of dietary and weight control practices which may influence metabolism, health, and performance. This paper reviews the literature on these factors with special emphasis on athletes who show large, frequent, and rapid fluctuations in weight (wrestlers) and athletes who maintain low weight and low percent body fat (e.g., distance runners, gymnasts, and figure skaters). A theory is presented which relates these weight patterns and the accompanying dietary habits to changes in body composition, metabolism, metabolic activity of adipose tissue, and the distribution of body fat. Changes in these physiological variables may be manifested in enhanced food efficiency (weight as a function of caloric intake) as the body seeks to protect and replenish its energy stores. This may explain the surprisingly low caloric intakes of some athletes. The health status of the athlete is a concern in this regard because there may be changes in fat distribution, risk factors for cardiovascular disease, and hormonal factors associated with reproductive functioning in both females and males. Amenorrhea in female athletes may be mediated at least in part by regional fat distribution; depletion of femoral fat depots (lactational energy reserves) may be the stimulus for cessation or disruption of menses. PMID: 3323766 [PubMed - indexed for MEDLINE] 6805. J Nutr. 1987 Dec;117(12):2147-53. Effect of high fat diets on energy balance and thermogenesis in brown adipose tissue of lean and genetically obese ob/ob mice. Mercer SW(1), Trayhurn P. Author information: (1)Dunn Nutrition Laboratory, Medical Research Council, Cambridge, United Kingdom. The effects on energy balance and brown adipose tissue thermogenesis of feeding high fat diets of differing fatty acid composition have been investigated in lean and genetically obese (ob/ob) mice. Groups of mice were fed either a low fat diet or a high fat diet based on corn oil or beef tallow for 2 wk. Energy intake and body weight gain were higher in both lean and obese animals fed the high fat diets than in respective mice fed the low fat diets. Carcass energy gain was greater for the obese than for the lean consuming each of the diets. Both lean and obese mice had a higher energy gain when fed the beef tallow diet than when fed the corn oil, despite isoenergetic intakes of the two diets. The thermogenic activity of brown adipose tissue, assessed from measurements of cytochrome oxidase activity and mitochondrial guanosine 5'-diphosphate (GDP) binding, were greater in both lean and obese mice fed the corn oil diet than in those fed the low fat diet. However, GDP binding and cytochrome oxidase activities in lean or obese mice fed the beef tallow diet were not different from those of mice of the same genotype fed the low fat diet. These results indicate that in both lean and obese (ob/ob) mice energy deposition and the stimulation of brown adipose tissue thermogenesis during the voluntary hyperphagia induced by feeding high fat diets are influenced by the fatty acid composition of the diet. A diet rich in polyunsaturated fatty acids appears to result in preferential stimulation of the thermogenic activity of brown adipose tissue, particularly in the ob/ob mouse. PMID: 3320290 [PubMed - indexed for MEDLINE] 6806. Z Gesamte Inn Med. 1987 Nov 15;42(22):629-33. [Metabolism of free fatty acids in fatty tissue]. [Article in German] Kuhfahl E(1). Author information: (1)Abteilung Klinische Laboratorien, Bezirkskrankenhauses Dresden-Neustadt. Hyperlipacidaemias play a role as etiological partial factor in the pathogenesis of various acute and chronic functional disturbances and are essentially the sequel of a disturbed metabolism of the free fatty acids of the fatty tissue. With regard to its clinical relevance a survey is given of the free fatty acid metabolism of the fatty tissue and its free fatty acid net balance as resultants from lipolysis and triglyceride synthesis is described. The author deals with the regulation of the lipolysis by cyclic mononucleotides, adenosine triphosphate, adenosine, fatty acids, ions, beta-hydroxybutyrate, lactate as well as hormones and finally with the control of the triglyceride synthesis. PMID: 3327256 [PubMed - indexed for MEDLINE] 6807. Nutr Rev. 1987 Nov;45(11):335-6. Coronary heart disease and linoleic acid content of adipose tissue. [No authors listed] PMID: 3332709 [PubMed - indexed for MEDLINE] 6808. Baillieres Clin Endocrinol Metab. 1987 Nov;1(4):797-816. The use of isotopic tracers in studying lipid metabolism in human subjects. Klein S, Wolfe RR. We have attempted to evaluate some of the tracer methodologies involved in studying lipid metabolism in humans. The magnitude of this subject prohibits a comprehensive review of all areas. Since the major function of adipose tissue appears to be to supply the body with energy, we have particularly emphasized the approaches used to study the mobilization and oxidation of fat. The importance of these issues, as well as the increasing availability of non-radioactive tracers, suggest an optimistic future for this area of research. PMID: 3330430 [PubMed - indexed for MEDLINE] 6809. Baillieres Clin Endocrinol Metab. 1987 Nov;1(4):1023-35. Use of adipose tissue for metabolic studies. Taylor R. Open biopsy of adipose tissue from volunteer subjects has led to a greater understanding of the mechanisms of adipose-tissue insulin resistance in various clinical states. Studies of adipose tissue obtained during surgical operations have allowed development of techniques and exploration of adipocyte physiology. This has been particularly valuable in examining the relationship between cellular insulin binding and action. Examination of the lipid stores and of enzyme activities has been possible by using the more convenient technique of needle biopsy. Regional differences in adipose tissue metabolism have been identified and must be considered in experimental design. It is now clear that the insulin sensitivity of any one metabolic pathway does not necessarily reflect that of others, and care must be taken to avoid inappropriate extrapolation of data both between metabolic pathways in the adipocyte itself and from the adipocyte to the whole body. PMID: 3330427 [PubMed - indexed for MEDLINE] 6810. J Nutr. 1987 Oct;117(10):1655-62. Lipoprotein metabolism in a rat model of diet-induced adiposity. Mela DJ(1), Cohen RS, Kris-Etherton PM. Author information: (1)Nutrition Program, Pennsylvania State University, University Park 16802. Obesity in humans is associated with decreased plasma levels of high density lipoprotein (HDL), but the mechanisms effecting this relationship have not been established. Four treatment groups were used to develop a range of moderate adiposity: rat pups were raised in litters of 4 or 14 and fed from weaning diets of 6 or 24% fat (wt/wt) for 15-17 wk. Lipoproteins from plasma and from a recirculating in situ liver perfusion system were then separated and analyzed, lipoprotein lipase (LPL) activity was assayed in samples of adipose tissue and skeletal muscle and body composition and cholesterol concentrations of various tissues were determined. There was little effect of the diet or litter size treatments on plasma lipids or lipoprotein profiles. Compared to the marked changes in lipid and lipoprotein metabolism that have been observed in severely obese animal models, there was generally little effect of the treatments used to produce this model of moderate diet-induced adiposity. Adiposity was unrelated to plasma total cholesterol and triglycerides. While fatness was positively, although weakly, correlated with plasma levels of several HDL components, including HDL cholesterol, there were no consistent treatment effects on these measures. Plasma HDL levels and adiposity were unrelated to hepatic HDL production or tissue LPL activities. A review of the literature suggests that differences in plasma HDL responses to adiposity in humans and in experimental animals may be due to inherent species differences in lipoprotein metabolism. PMID: 3668678 [PubMed - indexed for MEDLINE] 6811. Steroids. 1987 Oct-Dec;50(4-6):523-36. Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation. Killinger DW(1), Perel E, Daniilescu D, Kharlip L, Blackstein ME. Author information: (1)Department of Medicine, University of Toronto, Ontario, Canada. Studies using [3H]androstenedione (A) demonstrated that this substrate can be aromatized to estrone (E1) in homogenates of breast carcinoma tissue and breast adipose tissue, in breast carcinoma and breast adipose stromal cells in culture, and in cultured adipose stromal cells from sites remote from the tumor. Using cultured breast carcinoma cells, it was shown that estrogen formation was stimulated by cortisol (10(-6) M) and inhibited by endogenous 5 alpha-reduced androgens: 5 alpha-androstene-dione greater than androsterone greater than dihydrotestosterone greater than epiandrosterone greater than 3 alpha- and 3 beta- androstanediol. It was also shown that 19-nortestosterone and 19-norandrostenedione (10(-6) M) inhibited E1 formation by 80%. Progesterone (10(-6) M) had no effect on aromatase activity, while the progestational agent R5020 (10(-6) M) caused a 70% inhibition. These studies emphasize that a variety of compounds can influence aromatase activity and that drugs which are used as aromatase inhibitors in patients with breast carcinoma may have multiple sites of action. PMID: 3332939 [PubMed - indexed for MEDLINE] 6812. Med Sci Sports Exerc. 1987 Oct;19(5 Suppl):S150-6. Amino acid and protein metabolism during exercise and recovery. Brooks GA(1). Author information: (1)Department of Physical Education, University of California, Berkeley 94720. The integrated use of several energy sources allows high muscular power outputs to be sustained. Muscle glycogen provides the major fuel source for muscular exercise, but other fuels can provide alternative energy sources which allow for muscle glycogen-sparing and an increased potential for prolonged high metabolic rates. Blood-borne glucose, derived from liver glycogenolysis and glyconeogenesis, as well as intra-muscular lipids and plasma free fatty acids derived from adipose tissue provide the main energy alternatives to muscle glycogen. Several amino acids, including the essential amino acid leucine, are also used directly as oxidizable fuels during exercise. Depending on the duration and intensity of exercise and other factors such as glycogen stores and energy intake, amino acids can provide from a few to approximately 10% of the total energy for sustained exercise. Additionally, many amino acids can be converted to glutamate (via glutamate dehydrogenase) and then to alanine (via glutamate-pyruvate transaminase). Alanine, along with lactate and pyruvate, are recognized as the major gluconeogenic precursors. Via this mechanism, several amino acids play crucial roles in providing the carbon sources for maintaining blood glucose homeostasis during exercise and glycogen restitution during recovery. And finally, during exercise and recovery, amino acids likely play important anaplerotic functions sustaining the whole metabolic apparatus. PMID: 3316914 [PubMed - indexed for MEDLINE] 6813. J Mol Cell Cardiol. 1987 Oct;19(10):1037-40. Subcellular localization and biological function of specific cyclic nucleotide phosphodiesterases. Manganiello VC(1). Author information: (1)Laboratory of Cellular Metabolism, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892. PMID: 2830403 [PubMed - indexed for MEDLINE] 6814. Clin Pharm. 1987 Sep;6(9):706-14. Influence of obesity on drug disposition. Blouin RA(1), Kolpek JH, Mann HJ. Author information: (1)College of Pharmacy, University of Kentucky, Lexington 40536-0082. Physiologic changes associated with obesity and their effects on the distribution, protein binding, metabolism, and renal excretion of drugs are described. Changes in the volume of distribution correlate with drug lipophilicity. Drugs that have a high affinity for adipose tissue have an increased volume of distribution, whereas the distribution of drugs that have low partition coefficients is not altered substantially. Albumin and total protein concentrations are comparable in lean and obese subjects, but concentrations of alpha 1-acid glycoprotein are increased. Consequently, protein binding of acidic drugs is unchanged, but the free fraction of basic drugs may be decreased. Changes in hepatic drug clearance are complex. Phase 1 reactions and acetylation, a Phase 2 reaction, appear to be unaffected by obesity, but activity of Phase 2 glucuronidation and sulfation pathways is enhanced. Available physiologic and pharmacokinetic data on the effect of obesity on systemic clearance of highly extracted drugs are conflicting. Both glomerular filtration and tubular secretion appear to be increased in obese individuals, and tubular secretion may be disproportionately increased compared with filtration. Clearance of drugs that depend on glomerular filtration for elimination is consistently higher in obese subjects. Differences among patient populations, other conditions associated with obesity, and the small study populations described to date may account for some discrepancies in reported results. Awareness of the physiologic effects of obesity is essential for ensuring appropriate drug therapy in obese patients. PMID: 3315402 [PubMed - indexed for MEDLINE] 6815. Klin Wochenschr. 1987 Sep 1;65(17):812-7. Adipose tissue development: the role of precursor cells and adipogenic factors. Part II: The regulation of the adipogenic conversion by hormones and serum factors. Löffler G(1), Hauner H. Author information: (1)Institut für Biochemie, Mikrobiologie und Genetik der Universität Regensburg. Cell culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells. Two separate steps may be distinguished in adipocyte development. First, the determination of a mesenchymal stem cell into a preadipocyte, second, its conversion into a mature fat cell. In cloned cell lines adipose conversion depends on at least one postconfluent mitosis possibly induced by insulin-like growth factors or by as yet unknown mitogens. In addition growth hormone, glucocorticoids, and insulin are needed for conversion to take place. The adipose conversion of preadipocytes originating from the stromal vascular fraction of adipose tissue does not depend on postconfluent mitoses and needs only insulin and glucocorticoid hormones in physiological concentrations. However, the ability to undergo adipose conversion is not stable in these cells, but gets lost after repeated subcultures or seeding at low densities. In addition to stimulating hormones an increasing number of factors inhibiting the conversion process have also been detected, the physiological function of which remains unclear at the moment. PMID: 3309457 [PubMed - indexed for MEDLINE] 6816. Baillieres Clin Endocrinol Metab. 1987 Aug;1(3):495-514. Lipid transport through the plasma: the metabolic basis of hyperlipidaemia. Shepherd J, Packard CJ. Plasma lipid abnormalities derive their importance from their association with coronary artery disease. Elevated cholesterol levels accentuate risk, and clinical trials have shown that reductions lead to a decline in coronary events. The major plasma lipids, cholesterol and triglyceride, circulate in association with specific proteins as lipid-protein or lipoprotein complexes. The proteins direct and regulate the metabolism of these complexes by interacting with tissue enzymes and receptors. The metabolic fate of circulating triglyceride is governed by the activity of the enzyme lipoprotein lipase, situated in adipose tissue and skeletal muscle. Cellular demand for cholesterol, on the other hand, is met by activation of a specific receptor which mediates the delivery of sterol-rich lipoproteins to lysosomal degradation in liver and peripheral tissues. In order to prevent excess cholesterol accumulation at the periphery, there is a system of reverse cholesterol transport which involves assimilation and trapping of the sterol in the plasma lipoproteins through the action of the enzyme lecithin:cholesterol acyltransferase. Thereafter, the cholesterol is delivered to the liver, the only organ capable of excreting it in significant amounts. Disturbances in these processes may produce gross changes in the plasma lipid profile, clearly recognizable as hyperlipidaemia. However, it is becoming increasingly clear that a number of inherited traits can subtly perturb the lipoprotein spectrum and increase coronary risk even in subjects whose plasma lipoprotein profile would be considered normal. PMID: 3330420 [PubMed - indexed for MEDLINE] 6817. Mol Cell Endocrinol. 1987 Aug;52(3):169-76. Regulation of estrogen biosynthesis by human adipose cells in vitro. Mendelson CR(1), Simpson ER. Author information: (1)Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Biochemistry, University of Texas Health Science Center, Dallas 75235-9051. PMID: 3308575 [PubMed - indexed for MEDLINE] 6818. Hum Reprod. 1987 Aug;2(6):521-33. Body fat, menarche, fitness and fertility. Frisch RE(1). Author information: (1)Harvard Center for Population Studies, Cambridge, MA 02138. Many well-trained athletes, ballet dancers and women who diet excessively have secondary or primary amenorrhoea. Less extensive training or weight loss may result in anovulatory menstrual cycles, or a shortened luteal phase. These disruptions of reproductive ability are due to hypothalamic dysfunction, which is correlated with weight loss or excessive leanness. It is proposed that these associations are causal and that the high percentage of body fat (26-28%) in the mature human female may influence reproduction directly. Four mechanisms are known: (i) adipose tissue converts androgens to oestrogen by aromatization. Body fat is thus a significant extragonadal source of oestrogen; (ii) body weight, hence fatness, influences the direction of oestrogen metabolism to more potent or less potent forms; leaner women make more catechol oestrogens, the less potent form; (iii) obese women and young, fat girls have a diminished capacity for oestrogen to bind sex-hormone-binding-globulin; (iv) adipose tissue can store steroid hormones. An indirect mechanism may be signals of abnormal control of temperature and changes in energy metabolism, which accompany excessive leanness. The hypothalamic reproductive dysfunction results in abnormal gonadotrophin secretion: there is an age inappropriate secretory pattern of luteinizing hormone (LH) and follicle stimulating hormone (FSH), resembling that of prepubertal children. The secretion of LH and the responses to LHRH are reduced in direct correlation with the amount of weight loss. Other evidence from non-athletic and athletic women and mammals is presented in support of the hypothesis that a particular, minimum ratio of fat to lean mass is normally necessary for menarche (approximately 17% fat/body wt) and the maintenance of female reproductive ability (approximately 22% fat/body wt). Nomograms are given for the prediction of these critical weights for height from a fatness index; these weights are useful clinically in the evaluation of nutritional amenorrhoea and the restoration of fertility in underweight women. Evidence is presented that undernutrition and hard physical work can affect the natural fertility of populations, by the delay of menarche, a longer period of adolescent subfecundity, a longer birth interval and an earlier age of menopause. Data from a study of the long-term reproductive health of 2622 former college athletes compared with 2766 non-athletes show that the former college athletes had a significantly lower lifetime occurrence of breast cancer and cancers of the reproductive system, and a lower lifetime occurrence of benign tumours of these tissues, compared with the non-athletes.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3117838 [PubMed - indexed for MEDLINE] 6819. Prev Med. 1987 Jul;16(4):481-4. Dietary fats and lipids of adipose tissue and cell membranes in carcinogenesis. Insull W Jr. PMID: 3306652 [PubMed - indexed for MEDLINE] 6820. Nutr Rev. 1987 Jul;45(7):203-5. Dietary medium-chain fatty acids in adipose tissue of infants. [No authors listed] PMID: 3302783 [PubMed - indexed for MEDLINE] 6821. Clin Cardiol. 1987 Jul;10(7 Suppl 1):I10-6. Practical follow-up guidelines for patients treated with amiodarone. Podrid PJ(1). Author information: (1)Harvard School of Public Health, Boston, Massachusetts. Amiodarone is a new antiarrhythmic drug approved for therapy of life-threatening ventricular tachycardia and ventricular fibrillation refractory to previous antiarrhythmic therapy. The drug is poorly absorbed and avidly binds to all adipose tissue within the body. As a result of its unique pharmacologic properties, a 1-2 month period of loading with a high dose is required before therapeutic and steady state tissue concentrations are achieved. Therefore, there is a delay in the onset of antiarrhythmic effects of the drug and evaluation of efficacy using either noninvasive or invasive techniques should be performed 1-2 months after the initiation of therapy. It has been reported that suppression of runs of ventricular tachycardia (VT) documented on ambulatory monitor correlates with long-term efficacy. When invasive electrophysiologic (EP) studies are used, continued inducibility does not predict recurrence. Other important factors from the EP test include the rate of the induced VT and prolongation of the refractory period. Another problem related to amiodarone's pharmacologic properties is the occurrence of side effects which generally develop after weeks to months of drug therapy. Moreover, the incidence of toxicity increases over time. Although most side effects are unrelated to dose or blood level, it is possible that they correlate with the cumulative dose administered or total period of drug exposure. Amiodarone causes side effects which involve many organ systems. Most side effects are minor and cause no or only minor symptoms. Serious side effects, primarily cardiac, pulmonary, neurologic and thyroid, occur in about 18% of patients and often requires drug discontinuation. Therefore, use of amiodarone requires careful and continuous follow-up and monitoring for efficacy and toxicity. PMID: 3078154 [PubMed - indexed for MEDLINE] 6822. Am J Physiol. 1987 Jul;253(1 Pt 1):E1-5. Lipid transport function of lipoproteins in blood plasma. Havel RJ. Fatty acid and cholesterol transport in plasma lipoproteins evolved in the context of an open circulatory system in which lipoprotein particles are secreted directly into the blood and have ready access to cells in various tissues. In higher vertebrates with closed capillary beds, hydrolysis of triglycerides at capillary surfaces is required for efficient uptake of their component fatty acids into cells. Likewise, hydrolysis of cellular triglycerides in cells of adipose tissue precedes mobilization of the fatty acids and permits large amounts to be transported in the blood. However, in all Metazoa lipoproteins are secreted primarily from cells adjacent to an open microvascular bed. Uptake of lipoprotein particles as such into cells occurs in invertebrates and vertebrates alike, facilitated by binding to high-affinity receptors on cell surfaces. In vertebrates, a concentration gradient created between cholesterol in cells and lipoproteins by a cholesterol-esterifying enzyme that acts on lipoproteins promotes movement of cholesterol into the plasma compartment. Thus the strategies to transport poorly soluble lipids include enzymatic reactions at cell surfaces and in blood plasma as well as the processes of exocytosis and endocytosis. PMID: 3037916 [PubMed - indexed for MEDLINE] 6823. Gastroenterol Clin North Am. 1987 Jun;16(2):207-13. Adipose tissue of morbidly obese patients: clinical implications of distribution, morphology, and metabolism. Fried SK(1), Kral JG. Author information: (1)Department of Surgery, College of Physicians and Surgeons of Columbia University, St. Luke's-Roosevelt Hospital Center, New York, New York. As a consequence of their increased total adipose tissue mass, morbidly obese patients have many more fat cells than individuals of normal weight and the cells are enlarged compared to normal. Contrary to earlier beliefs, fat cell numbers can increase throughout adult life. Once formed, fat cells do not undergo involution. Thus, it seems that an individual who has reached the morbidly obese state maintains an increased amount of body fat that limits his/her ability to achieve and maintain commonly accepted levels of "ideal" body weight. Recently the distribution of adipose tissue has been shown to be an important predictor of obesity-associated morbidity and mortality in large population studies. A "male" or central distribution of fat is a significant risk factor for the development of diabetes, hyperlipidemia, hypertension, and coronary heart disease. Sex- and site-specific variations in the distribution of adipose tissue cell size and metabolic activity have been demonstrated that may be of etiologic importance for the development of serious comorbid conditions in obesity. PMID: 3319901 [PubMed - indexed for MEDLINE] 6824. Prostaglandins. 1987 Jun;33(6):831-6. Role of "local" hormones in regulation of lipolysis. Kather H(1). Author information: (1)Klinishces Institut für Herzinfarktforschung, Medizinische Universitätsklinik, Heidelberg, F.R.G. Lipid mobilization from adipose tissue can be activated by two distinct mechanisms, i.e. relief of inhibitory influences or reversal of a preexisting inhibition by lipolytic hormones. Adenosine and prostaglandins which are produced within adipose tissue may serve to maintain a functional state that is susceptible for stimulation and adjust non-stimulated lipolysis to the energetic demands of the organism. PMID: 3313524 [PubMed - indexed for MEDLINE] 6825. J Am Diet Assoc. 1987 Jun;87(6):761-4. Brown adipose tissue: regulation of thermogenesis and implications for obesity. Schulz LO. The role of brown adipose tissue in the development and maintenance of obesity has been a recent focus of research efforts. Brown fat serves as a heat-producing tissue, via nonshivering and diet-induced thermogenesis, because of a unique mechanism that uncouples oxidative phosphorylation. The importance of these forms of thermogenesis to energy balance has been characterized in animal models of obesity; increased metabolic efficiency has been attributed to impaired heat production and compositional and functional alterations in brown fat. Although the possibility exists that human obesity may partly result from inadequate thermogenesis, evidence that the defect is related to brown fat is tenuous. Currently, the contribution of brown fat to metabolic rate in human beings has been estimated as minor. However, even if it is found that differences in brown fat cannot explain differences in corpulence, interest in the tissue will likely continue. Because of its ability to waste calories, the potential for manipulating body weight by stimulation of brown fat remains a promising field of investigation. PMID: 3294979 [PubMed - indexed for MEDLINE] 6826. J Am Coll Nutr. 1987 Jun;6(3):231-53. Caloric requirements in total parenteral nutrition. Foster GD, Knox LS, Dempsey DT, Mullen JL. Resting energy expenditure (REE) was measured in 100 consecutive total parenteral nutrition (TPN) patients. Only forty-eight percent of the measured REEs were within 90-110% of the predicted Harris-Benedict values. A literature review revealed 191 published guidelines for non-protein caloric requirements of hospitalized TPN patients. These guidelines were appropriately matched and applied to the 100 individual TPN patients. The relationship between the recommended caloric supply and measured caloric expenditure was minimal. The recommendations exceeded measured REE by an average of 1076 +/- 660 kcal/day. These published guidelines were substantially above and below caloric requirements based on measured REE for both fat maintained (130% REE) and fat depleted (150% REE) patients. Following published guidelines rather than standards based on measured REE results in the administration of 6947 excess liters of TPN per year. Improvement in the precision of TPN caloric prescription can be accomplished by using measured REE as a reference base. When published guidelines were compared to prescriptions based on measured REE it was found that published guidelines were inaccurate both overall and individually and a substantial cost savings justifies actual measurement of energy needs. PMID: 3110244 [PubMed - indexed for MEDLINE] 6827. Pol Tyg Lek. 1987 May 18;42(20):603-6. [Theories on the development of obesity]. [Article in Polish] Daniel K, Szurkowski M, Grzeszczak W. PMID: 3313308 [PubMed - indexed for MEDLINE] 6828. Rev Clin Esp. 1987 May;180(8):444-50. [Physiologic effects of somatostatin in various organs and tissues. Mechanisms of action]. [Article in Spanish] Calle García C, Simón Arauzo MA, Santos Montes A. PMID: 2887012 [PubMed - indexed for MEDLINE] 6829. Diabetes Metab Rev. 1987 Apr;3(2):551-70. Lipoprotein lipase in diabetes. Taskinen MR. Lipoprotein lipase has a central role in the metabolism of both triglyceride-rich particles and high density lipoproteins, and it is one determinant of both serum triglyceride and HDL concentrations. In man the enzyme activity in both adipose tissue and skeletal muscle is insulin dependent, and therefore it varies in diabetes according to ambient insulin level and insulin sensitivity. In insulin deficiency (untreated Type 1 diabetes) the enzyme activity in both adipose tissue and muscle tissue is low but increases upon insulin therapy. In chronically insulin-treated patients with good control, the enzyme activity in postheparin plasma is increased. In untreated Type 2 diabetic patients, the average enzyme activity in adipose tissue and postheparin plasma is normal or subnormal. Therapy with oral agents or insulin, resulting in good glycemic control, is followed by an increase of LPL activity in both adipose tissue and postheparin plasma. In both Types 1 and 2 diabetes, changes of LPL activity are associated with relevant alterations in lipoprotein pattern. In insulin deficiency with low LPL, serum total and VLDL triglyceride levels are elevated, and HDL concentration is reduced. In chronically insulin-treated patients with high LPL activity, VLDL triglyceride concentrations are normal or subnormal, and HDL level is increased. In untreated Type 2 diabetic patients subnormal LPL activity may contribute to the elevation of serum triglycerides and to the reduction of HDL level. PMID: 3552532 [PubMed - indexed for MEDLINE] 6830. Scand J Work Environ Health. 1987 Apr;13(2):81-93. Pharmacokinetics of organic solvent vapors in relation to their toxicity. Sato A, Nakajima T. The volatility and lipophilicity by which organic solvents are distinct from other chemicals constitute a characteristic pharmacokinetic feature. They enter a living body by inhalation, preferentially distribute in the adipose tissue, and are eliminated by both expiration and metabolic degradation. This review article is centered on experimental studies conducted by the authors and their co-workers, and it deals with pharmacokinetic principles, partition coefficients in relation to toxicity, significance of metabolism in the development of organic solvent toxicity, and environmental factors that alter the metabolism and toxicity of solvents. PMID: 3299685 [PubMed - indexed for MEDLINE] 6831. Clin Perinatol. 1987 Mar;14(1):51-70. The significance of drugs in breast milk. Pharmacokinetic considerations. Rivera-Calimlim L. This article discusses the importance of the pharmacokinetic properties of various drugs in adults and in infants in the interpretation of the significance of the excretion of drugs in breast milk to the neonates. PMID: 3549115 [PubMed - indexed for MEDLINE] 6832. Presse Med. 1987 Feb 7;16(4):167-70. [Influence of the distribution of body fat on vascular risk]. [Article in French] Basdevant A, Raison J, Guy-Grand B. The metabolic and cardiovascular complications of obesity are dependent upon the distribution of body fat excess: predominantly abdominal or "android" obesity is more pathogenic than "gynoid" obesity which predominates in the lower part of the body. Adipose tissue overloads localized to the abdomen are associated with hypermortality from vascular diseases, even in patients who are not overweight. The metabolic characteristics of abdominal adipocytes, which have increased lipolytic capacity, might account for this situation, as they would facilitate hyperinsulinism, insulin resistance and such-metabolic disturbances as arterial hypertension, diabetes mellitus and dyslipidemia. Androgens seem to play a key role in the development of obesity morphotypes. These notions have important practical applications: an excess of body fat is not necessarily pathogenic; as regards vascular and metabolic risks, body fat distribution seems to be more important than overweight. PMID: 2950448 [PubMed - indexed for MEDLINE] 6833. Proc Nutr Soc. 1987 Feb;46(1):135-42. Control of white and brown adipose tissues by the autonomic nervous system. Trayhurn P, Ashwell M. PMID: 3554253 [PubMed - indexed for MEDLINE] 6834. Am Heart J. 1987 Feb;113(2 Pt 2):458-64. Alcohol-induced changes in serum lipoproteins and in their metabolism. Taskinen MR, Nikkilä EA, Välimäki M, Sane T, Kuusi T, Kesäniemi A, Ylikahri R. The effects of alcohol intake on serum lipids and lipoproteins depend on the dose and mode of alcohol intake, individual susceptibility, genetic variables, and dietary factors. Therefore the changes of lipoprotein pattern are different among moderate and heavy drinkers. Moderate intake of alcohol increases the concentrations of apolipoproteins (apo) AI, apo AII, and high-density lipoprotein subfraction (HDL3) in plasma without any effects on other lipoproteins. If alcohol intake exceeds 60 to 80 gm per day, the synthesis of very low-density lipoprotein (VLDL) particles is stimulated. Even short-term use of alcohol stimulates lipoprotein lipase (LPL) activity in adipose tissue, and consequently the concentration of VLDL in plasma stays normal or is even subnormal. If alcohol intake continues in excessive amounts, the increased transport rate of VLDL particles as a result of high LPL activity results in the up regulation of HDL2. This is clearly evident in chronic alcoholics. Low or subnormal low-density lipoprotein (LDL) levels are another characteristic of the lipoprotein pattern in chronic alcoholics. The increase of HDL (HDL2) and reduction of LDL levels could well explain the reduced risk of coronary heart disease in chronic alcoholics, whereas the causal factors remain open among moderate drinkers. PMID: 3544760 [PubMed - indexed for MEDLINE] 6835. Biol Neonate. 1987;51(2):70-7. Lipid metabolism in pregnancy. Herrera E, Gómez-Coronado D, Lasunción MA. On the basis of bibliographic references and new own data, major adaptations of lipid metabolism occurring at late gestation are reviewed. Maternal hypertriglyceridemia at late gestation results from the juxtaposition of several factors: enhanced adipose tissue lipolysis facilitating the availability to the liver of substrates for triglyceride synthesis and contributing to augmented flux of very low density lipoproteins (VLDL) into the circulation; maternal hyperphagia and unmodified gut lipid absorption increasing chylomicron formation from dietary lipid; reduced lipoprotein lipase (LPL) activity in extrahepatic tissues (especially adipose tissue) which does not allow a triglyceride removal proportional to their enhanced production. It is proposed that these changes are also responsible for the altered composition of VLDL in late pregnancy. In conditions of food deprivation the use of glycerol released from adipose tissue as preferential gluconeogenic substrate, and the enhanced maternal ketogenesis warrants the availability of fuels for the fetus. Just prior to parturition the increase in mammary gland LPL activity is responsible for the reduction in circulating triglycerides and prepares the mother for lactation. PMID: 3552060 [PubMed - indexed for MEDLINE] 6836. Biol Neonate. 1987;51(2):64-9. Glucose metabolism in pregnancy. Leturque A, Hauguel S, Ferré P, Girard J. Pregnancy is characterized by a number of maternal metabolic modifications in order to meet the energy requirements of the growing fetus. A progressive alteration of maternal glucose homeostasis develops throughout gestation and becomes maximal during the last trimester. A relative hypoglycemia is observed during the postabsorptive period despite an elevated plasma insulin concentration and an enhanced hepatic glucose production. In addition, the glucose utilization rate by peripheral maternal tissues is lowered in late gestation indicating that the mother supplies glucose to the fetus at the expense of her own tissues. Concomitantly, an insulin-resistant state develops in the mother to help sparing glucose for the pregnant uterus. It involves both glucose-producing (liver) and glucose-utilizing tissues. So far, the factor(s) responsible for the development of pregnancy-induced insulin resistance has not been identified although a number of circulating hormones are known to counteract insulin effects. PMID: 3552059 [PubMed - indexed for MEDLINE] 6837. Sports Med. 1987 Jan-Feb;4(1):34-45. Body composition and menstrual function in athletes. Sinning WE, Little KD. The problem of menstrual dysfunction in athletes was recognised at about the same time as a theory was developed that a critical fat level was necessary for the onset and maintenance of menstrual function (17% and 22% of bodyweight, respectively). This theory was acceptable because of the frequency of leanness in athletes experiencing menstrual dysfunction and because of the role of adipose tissue in the intraconversion of hormones which could affect hypothalamic and pituitary regulatory centres. Research on this topic has been hampered by the extensive use of surveys, confining sampling to specific sports, use of inaccurate methods of body composition assessment, and lack of data on hormonal changes. Studies using appropriate body composition measures do not support the critical fat theory, but they do not exclude a role for body composition changes in the regulation of menstrual function. The probability of finding menstrual dysfunction in very lean athletes is high, but not absolute, and there is no assurance that dysfunction will improve merely by increasing bodyweight. Perhaps of more concern, however, is recent research on very lean, long term amenorrhoeic athletes who train intensely and show a loss of bone mineral, apparently related to low oestrogen levels. This mineral deficiency is apparently a factor in stress fractures. The bone mineral content of these athletes is similar to that of post-menopausal women susceptible to osteoporosis. Although the loss of bone due to short term amenorrhoea may be reversible, the prognosis for a long term deficiency is not presently known. PMID: 3547537 [PubMed - indexed for MEDLINE] 6838. Am J Clin Nutr. 1987 Jan;45(1 Suppl):277-82. Adipose tissue as a source of hormones. Siiteri PK. Obesity is known to increase the risk for cancer of the reproductive tract in women. The mechanism underlying this association can be explained by increased estrogenic stimulus to estrogen-target tissues as the result of three factors. First, increased adrenal secretory activity makes more androgen precursors available for conversion to estrogen in peripheral tissues. Second, the efficiency of conversion of androstenedione (A) to estrone (E1), is elevated in obese subjects because adipose tissue is the major tissue site of conversion. Third, plasma levels of SHBG, which binds estradiol (E2), are depressed in obese subjects and greater than normal amounts of serum estradiol are therefore available to target tissues from the circulation. Recent studies have shown that the levels of estrogens and other steroid hormones in breast fluids are much higher than in serum, which may be the result of local synthesis or increased uptake from the circulation. No differences in estrogen levels of breast fluid have been found between normal women and those with breast disease. A possible explanation may be differences in the levels of estrogen antagonists, such as progesterone. PMID: 3541569 [PubMed - indexed for MEDLINE] 6839. Verh Dtsch Ges Inn Med. 1987;93:448-62. [Forms of obesity and metabolic disorders]. [Article in German] Vague J, Vague P, Jubelin J, Barré A. PMID: 3327296 [PubMed - indexed for MEDLINE] 6840. Verh Dtsch Ges Inn Med. 1987;93:443-8. Obesity, atherosclerosis and diabetes mellitus. Björntorp P. PMID: 3327295 [PubMed - indexed for MEDLINE] 6841. World Rev Nutr Diet. 1987;53:171-217. The biochemical mechanism of brown fat thermogenesis. Shrago E, Strieleman PJ. PMID: 3327236 [PubMed - indexed for MEDLINE] 6842. Med Biol. 1987;65(4):181-91. Regulatory functions of adenosine. Ohisalo JJ(1). Author information: (1)Department of Medical Chemistry, University of Helsinki, Finland. Adenosine has emerged as an important regulator of many physiological processes. This review briefly describes the formation and inactivation of the nucleoside, its effects in different tissues and the mechanism by which these effects are executed. PMID: 3325699 [PubMed - indexed for MEDLINE] 6843. Ann Endocrinol (Paris). 1987;48(5):400-6. [Interactions between the central nervous system, the endocrine pancreas and metabolism]. [Article in French] Rohner-Jeanrenaud F(1), Jeanrenaud B. Author information: (1)Laboratoires de Recherches Métaboliques, Faculté de Médecine, Genève, Suisse. 1. The importance of nervous circuits including neural afferences, their integration by the central nervous system and the resulting efferents is illustrated by comparing glucose tolerance following the spontaneous ingestion or the intragastric administration of a glucose load. When these circuits are by-passed (intragastric glucose administration), glucose tolerance is impaired and accompanied by an increased insulin output compared to the situation of normal glucose ingestion. This is due to a decreased glucose utilization in the absence of the numerous reflexes that are elicited by the presence of glucose in the oropharynx. 2. In normal animals, insulin secretion by the B cell of the endocrine pancreas is under an inhibitory tonus by the sympathetic nervous system while the parasympathetic system has no stimulatory tonus. After acute bilateral destruction of the ventromedial hypothalamic nuclei (VMH), such a situation is reversed and there is an activation of the parasympathetic outflow leading to hyperinsulinemia. This hyperinsulinemia is partly responsible for the development of the obesity of VMH-lesioned animals and is accompanied by a decreased activity of some sympathetic efferents amongst which those innervating brown adipose tissue. Analogous data have been obtained when studying genetically obese fa/fa rats. 3. A peptide of around 1'000 daltons extracted from the rat hypothalamus and having insulin secretion promoting activity could possibly be an insulin-releasing factor since it is present not only in the hypothalamus but also in the plasma. PMID: 3324925 [PubMed - indexed for MEDLINE] 6844. Revis Biol Celular. 1987;11:75-104. The uncoupling protein from brown adipose tissue mitochondria. Rial E(1), Nicholls DG. Author information: (1)Department of Biochemistry, University of Dundee, Scotland, UK. PMID: 3324211 [PubMed - indexed for MEDLINE] 6845. Nauchnye Doki Vyss Shkoly Biol Nauki. 1987;(10):28-36. [Energy dissipation in the brown fatty tissue of warm-blooded animals]. [Article in Russian] Kolesova GM. The uncoupling mechanism of respiration and phosphorylation in brown adipose tissue as well as factors affecting this process are discussed. An assumption has been suggested and substantiated experimentally that the uncoupling of respiration and phosphorylation in liver mitochondria caused by vitamin K alimentary deficit may have mechanism similar to the unique uncoupling mechanism of brown fat mitochondria. PMID: 3322412 [PubMed - indexed for MEDLINE] 6846. Ann Genet. 1987;30(4):221-7. [A rare polydysmorphic syndrome: leprechaunism. Review of 49 cases reported in the literature]. [Article in French] Cantani A(1), Ziruolo MG, Tacconi ML. Author information: (1)Département de Pédiatrie, Université de Rome La Sapienza, Italie. Leprechaunism is a very rare condition of obscure etiology. Since the first report (Donohue, 1948) 48 patients have been described. The typical stigmata are a "gnome" facies with a saddle nose, broad mouth, large and low-set ears, hirsutism, cutis laxa with atrophy of adipose tissue, dwarfism, extreme wasting, and dysphagia requiring parenteral feeding. After reviewing the literature and discussing the morphological, biological, and etiopathogenetic aspects, the authors conclude that the diagnosis of leprechaunism is essentially a clinic one, as there are no specific laboratory tests. PMID: 3322162 [PubMed - indexed for MEDLINE] 6847. Aesthetic Plast Surg. 1987;11(3):131-56. Controversies in plastic surgery: suction-assisted lipectomy (SAL) and the hCG (human chorionic gonadotropin) protocol for obesity treatment. Vogt T, Belluscio D. The advent of SAL (suction-assisted lipectomy) has dramatically increased the number of obese patients coming to our consultation offices. Despite several articles suggesting a conservative approach to fat suction, some reports insinuate that SAL might be a useful tool for obesity treatment. This hypothesis is refuted by a vast body of evidence that concludes that the adipose tissue may regenerate in adult humans. Therefore, surgical procedures are not advised as the method of choice to manage the disease. On the other hand, the terms obesity and being overweight may not be interchangeable. Obesity may be a disease whereas being overweight is a sign of the disease. Consequently, proper preoperative selection of candidates for SAL becomes mandatory. The hCG (human chorionic gonadotropin) method for obesity treatment appears to be a complete program for the management of obesity. It contains pharmacologic, dietetic, and behavior modification aspects in a 40-day course of treatment. Some data suggest hCG to be lipolytic, thus explaining former clinical observations regarding body fat redistribution in treated patients. hCG commercial preparations contain beta-endorphin, an opioid peptide linked to mood behavior. This article speculates on the possible actions of the complex hCG beta-endorphin in the neuromodulation of mood and energy metabolism. The method comprises a behavior modification that helps in handling the patient better. There are some correlations between a current behavior modification program and the basic guidelines contained in the hCG protocol. Thus, the hCG method appears to be a reasonable alternative in the management of a long-standing, unsolved problem of human metabolism. PMID: 3314409 [PubMed - indexed for MEDLINE] 6848. Vestn Akad Med Nauk SSSR. 1987;(7):48-53. [Enzymological research on hyperlipidemic states]. [Article in Russian] Tutel'ian VA, Vasel'ev AV. PMID: 3314224 [PubMed - indexed for MEDLINE] 6849. Ann N Y Acad Sci. 1987;499:66-72. Fat cell distribution and metabolism. Björntorp P. PMID: 3300494 [PubMed - indexed for MEDLINE] 6850. Ann N Y Acad Sci. 1987;499:104-23. The difference in the storage capacities for carbohydrate and for fat, and its implications in the regulation of body weight. Flatt JP. The two-compartment model presented here suggests that weight maintenance can be achieved by a regulation of food intake geared primarily toward the maintenance of stable glycogen levels, rather than toward the preservation of the overall energy balance. This concept is reminiscent of the glucostatic theory of food intake regulation proposed by Mayer. It is viewed here as being linked to changes in the body's carbohydrate stores, which represent an integration of carbohydrate and lipid fluxes, rather than to changes in blood glucose levels, whose substantial variations during the day are dependent on various circumstantial events. The model illustrates that the fat to carbohydrate ratio of the diet may have considerable potential influence on steady state body composition, even though carbohydrates and fats are both able to meet the body's energy substrate requirements. It appears that failure of appropriately reducing the range within which glycogen levels are maintained when the diet's fat content rises will require an expansion of the adipose tissue mass to raise FFA levels and fat oxidation to a rate commensurate with the proportion of fat in the diet. Maintenance of glycogen reserves below their level of saturation is made less likely by the high palatability and ubiquitous availability of foods in affluent societies. Thus, one can understand the high incidence of obesity among populations consuming mixed diets with a relatively high fat content, without having to attribute this to some defect(s) in the mechanism(s) controlling food intake. PMID: 3300476 [PubMed - indexed for MEDLINE] 6851. Ann N Y Acad Sci. 1987;496:3-26. Brown adipose tissue. Its in vivo immunology and involvement in neuroimmunomodulation. Janković BD. The material presented here summarizes the bulk of the presently available immunologic data bearing upon the in vivo relationship between brown adipose tissue and the immune system. The experiments were carried out in rats adipectomized (by surgical excision of the interscapular brown adipose tissue at birth), thymectomized (by neonatal removal of the thymus), adipectomized and thymectomized, and corresponding sham-operated controls. The following immune phenomena were studied: antibody production to soluble and corpuscular antigens; Arthus and delayed hypersensitivity skin reactions to bovine serum albumin; rejection of allogeneic skin and thyroid grafts; lymph node enlargement in a host-versus-graft reaction; experimental allergic encephalomyelitis and thyroiditis; immune response in normal animals treated with extracts from brown adipose tissue; allergic encephalomyelitis in thymoadipectomized animals; plaque-forming cell response and hemagglutinating antibody titers in animals injected with met-enkephalin and leu-enkephalin; and survival rate of adipectomized mice inoculated with Sarcoma-I cells. The results indicated that the cell-mediated immune reactions were potentiated in adipectomized rats. Antibody production was not significantly changed by neonatal adipectomy. Adipectomized mice, inoculated with Sa-I tumor cells, survived longer than controls, thus indicating that adipectomy made possible the recognition of discrete histocompatible differences between Sa-I cells and A/JAX mice. Adipectomy increased the ability of rats to develop autoimmune diseases. Saline extracts from brown adipose tissue of newborn rats suppressed hypersensitivity skin reactions in normal adult rats. Thymoadipectomized rats showed an almost normal ability to develop allergic encephalomyelitis, a finding that suggested that the potentiating influence of adipectomy on encephalomyelitis was neutralized by thymectomy. It appears that brown adipose tissue functions as a natural antagonist of the thymus. Enkephalins were found to be more effective immunosuppressors in adipectomized than in normal animals. The last finding establishes a functional link between brown adipose tissue and neuropeptides. It seems that the potentiation of immune response in adipectomized animals is effected by altered release of yet unidentified mediators and modulators. The evidence indicates that brown adipose tissue, in which neurohumoral activity occurs, may be an important component of an integrated immunoneuroendocrine system. PMID: 3300471 [PubMed - indexed for MEDLINE] 6852. Reprod Nutr Dev. 1987;27(2A):327-98. [Bibliographic review: quantitative variations and metabolism of lipids in adipose tissue and liver during the gestation-lactation cycle. 2: In the ewe and the cow]. [Article in French] Chilliard Y. This comprehensive review describes changes in body lipids, energy balance and metabolic pathways and endocrine regulations in the adipose tissues and liver of ewes and cows during pregnancy and lactation. These profiles are discussed in relation to litter size, food intake and diet composition. The interactions between teleophoretic mechanisms (that direct nutrients to the gravid uterus or to the mammary gland) and homeostatic mechanisms (that ensure maintenance of the mother organism) have been emphasized. PMID: 3296059 [PubMed - indexed for MEDLINE] 6853. J Inherit Metab Dis. 1987;10 Suppl 1:11-22. The role of peroxisomes in mammalian cellular metabolism. Lazarow PB(1). Author information: (1)Rockefeller University, New York, NY 10021. Peroxisomes, which are widely distributed in mammalian tissues, carry out several important functions in cellular metabolism. Production of alkylglycerol-3-phosphate, a key intermediate in the synthesis of plasmalogens and other ether lipids, occurs in the peroxisome. A fatty acid beta-oxidation system with significant differences from mitochondrial beta-oxidation is also found in the peroxisomes; the acetyl-CoA produced is used for synthetic reactions. This pathway has a particularly important physiological role in the oxidation of very long chain fatty acids and the side chain of cholesterol. Peroxisomes also possess a number of oxidases that produce H2O2 which is decomposed by peroxisomal catalase. The function of this peroxisomal respiratory pathway is disposal of excess reducing equivalents, protection of the cell against H2O2 and possibly a role in thermogenesis in brown adipose tissue. Other peroxisomal functions include a role in gluconeogenesis and in purine and polyamine catabolism. Some enzymes of peroxisomes can be induced by dietary, hormonal and other physiological changes. The entire organelle proliferates under certain of these conditions. PMID: 3119935 [PubMed - indexed for MEDLINE] 6854. Ann N Y Acad Sci. 1987;499:167-78. The place of animal models and animal experimentation in the study of food intake regulation and obesity in humans. Fuller RW, Yen TT. PMID: 2886100 [PubMed - indexed for MEDLINE] 6855. Diabete Metab. 1986 Dec;12(6):329-36. Carbohydrate metabolism of female rat adipocytes: effects and mechanisms of action of progesterone. Sutter-Dub MT. This short review describes the role of progesterone in the insulin-resistance of pregnancy and the present knowledge of the intracellular mechanisms of action of the steroid in carbohydrate metabolism of female rat adipocytes. Observations concerning steroid effects on the binding of insulin to its specific receptors are often contradictory, and depend on cells used to study it. It is now generally accepted that, in isolated adipocytes, the decreased responsiveness to insulin produced by progesterone is due to a post-receptor effect. Furthermore, basal glucose metabolism (in the absence of insulin) is decreased by progesterone treatment and by the acute effect of progesterone when added directly into the incubation medium. Progesterone induces an intrinsic post-receptor effect which is related to decreased phosphorylation of glucose by hexokinase but has no effect on glucose transport. The effect on hexokinase activity is an indirect one taking place either before or after activation of the enzyme. During the last decade, a large body of evidence (Xenopus oocytes and other cells) indicates that steroids interact with the cell surface rather than penetrating the cell and interacting exclusively with a nuclear receptor. The second messengers, such as cyclic AMP and calcium, play a major role in this non-genomic mechanism. The direct and rapid effect (20 min.) of progesterone in adipocytes supports the non-genomic mechanism of action; there is neither any lag period prior to the appearance of the physiological response nor any inhibition of protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3817256 [PubMed - indexed for MEDLINE] 6856. Acta Pathol Jpn. 1986 Nov;36(11):1693-705. Idiopathic right ventricular dilation. Special reference to "arrhythmogenic right ventricular dysplasia" and analogous lesions. Kawamura O, Ohaki Y, Nakatani Y, Misugi K, Yoshimura H, Kobayashi H, Haraguchi S, Niimura I. Two autopsy cases which showed marked depletion of the right ventricular musculature of the heart accompanied with marked infiltration of the adipose tissue were reported. The first cases was an 18-year-old female who died of right sided congestive heart failure after about 4-years clinical course. The autopsy disclosed marked dilation of the right atrium and ventricle. The entire free wall of the right ventricle was markedly thin. Microscopically, most of the myocardial fibers of the right ventricle were replaced by fat and fibrous tissue. The second case, a 15-year-old boy, whose identical twin was previously diagnosed as arrhythmogenic right ventricular dysplasia designated by Fontaine et al., died suddenly during exercise. He showed no cardiac symptoms but electrocardiogram was abnormal. Autopsy revealed majority of the myocardial fibers of the right ventricular free wall were replaced by fatty tissue. In both cases, fatty infiltration was mainly noticed at the epicardial side and some myocardial fibers remained in the fatty tissue showed hypertrophic and/or degenerative changes. Review of the literature on similar cases showing depletion of the right ventricular musculature including so-called adult's Uhl anomaly, ARVD and dilated right ventricular myocardiopathy was conducted and the relationship of the present cases with these lesions was discussed. PMID: 2949485 [PubMed - indexed for MEDLINE] 6857. Cell Biochem Funct. 1986 Oct;4(4):241-7. Physiological functions of the pentose phosphate pathway. Wood T. PMID: 3539386 [PubMed - indexed for MEDLINE] 6858. Clin Chem. 1986 Oct;32(10 Suppl):B19-27. Cellular mechanisms of insulin action: implications for insulin resistance and type II diabetes mellitus. Pershadsingh HA, Christensen RL, McDonald JM. PMID: 3530537 [PubMed - indexed for MEDLINE] 6859. Proc Soc Exp Biol Med. 1986 Oct;183(1):1-10. Evidence for a central mechanism of obesity in the Zucker fatty rat (fa/fa). Martin RJ, Harris RB, Jones DD. PMID: 2875461 [PubMed - indexed for MEDLINE] 6860. Med Clin (Barc). 1986 Sep 20;87(8):337-41. [New perspectives on the origin of obesity. II. Factors and theories implicated in its etiology]. [Article in Spanish] Castro Fornieles J, Toro Trallero J. PMID: 3534479 [PubMed - indexed for MEDLINE] 6861. Arerugi. 1986 Sep;35(9):927-35. [Arachidonic acid cascade--with special reference to SRS-A]. [Article in Japanese] Kawano S. PMID: 3541857 [PubMed - indexed for MEDLINE] 6862. Clin Physiol. 1986 Aug;6(4):311-7. Insulin resistance, insulin deficiency and the pathogenesis of diabetes mellitus. Ferrannini E. PMID: 3527530 [PubMed - indexed for MEDLINE] 6863. Clin Pharmacokinet. 1986 Jul-Aug;11(4):299-315. Clinical pharmacokinetics of dapsone. Zuidema J, Hilbers-Modderman ES, Merkus FW. Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly haematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. Alcoholic liver disease decreases the protein binding of dapsone; coeliac disease and dermatitis herpetiformis may delay its oral absorption and severe leprosy has been reported to affect the extent of absorption.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3530584 [PubMed - indexed for MEDLINE] 6864. Maturitas. 1986 Jul;8(2):141-58. Progestogens and lipid metabolism. Crona N, Enk L, Mattsson LA, Samsioe G, Silfverstolpe G. PMID: 3528760 [PubMed - indexed for MEDLINE] 6865. Sports Med. 1986 Jul-Aug;3(4):275-88. Diabetes, insulin and exercise. Richter EA, Galbo H. The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so-called counter-regulatory hormones tend to increase plasma glucose by increasing hepatic glucose production and adipose tissue lipolysis. If the pre-exercise plasma insulin level is high, hypoglycaemia may develop during exercise whereas hyperglycaemia and ketosis may develop if pre-exercise plasma insulin levels are low. Physical activity is often difficult to carry out on a precise schedule and the exercise-induced changes in demand for insulin and calories vary according to the intensity and duration of exercise, time of day, and differ within and between individuals. Thus, physical training can not be recommended as a means of improving metabolic control in insulin-dependent diabetes. However, our present knowledge and technology allows the well-informed and cooperative patient to exercise and even to reach the elite level. To achieve this, pre-exercise metabolic control should be optimal and knowledge of the patient's reaction to exercise is desirable, which necessitates frequent self-monitoring of plasma glucose. It may often be necessary to diminish the insulin dose before exercise, and/or to ingest additional carbohydrate during or after exercise. In non-insulin-dependent (type II) diabetes, exercise is associated with less risk of metabolic derangement, and in genetically disposed individuals physical training may prevent development of overt diabetes possibly by diminishing the strain on the pancreatic beta cell. The latter, however, is only achieved if exercise is not accompanied by increased caloric intake. Whether physical training in diabetes can reduce cardiovascular morbidity and mortality is at present unknown, but training has in diabetic patients been shown to lessen some risk factors for development of arteriosclerosis. However, training of diabetics (especially in the less well-regulated patient) may not lessen coronary risk factors to the same extent as in healthy subjects. PMID: 3526507 [PubMed - indexed for MEDLINE] 6866. Kardiologiia. 1986 Jul;26(7):116-21. [Beta-adrenoblockaders and lipid metabolism]. [Article in Russian] Tokar' AV, Persidskiĭ IV. PMID: 2876123 [PubMed - indexed for MEDLINE] 6867. Am J Cardiol. 1986 May 30;57(14):27G-30G. Hypertriglyceridemia and carbohydrate intolerance: interrelations and therapeutic implications. Steiner G. Atherosclerosis, the most frequent complication of diabetes, could be the result of hyperlipidemia, among other factors. Mounting evidence suggests that reducing the concentration of triglyceride-rich lipoprotein, which influences the production of the possibly atherogenic intermediate density lipoprotein (IDL), might diminish the circulating level of potentially atherogenic lipoproteins. Hypertriglyceridemia, even in the absence of obesity, is associated with insulin resistance. To compensate, pancreatic B cells respond to glucose challenge by producing hyperinsulinemia. If the B cells cannot respond adequately, carbohydrate intolerance ensues. Insulin-treated diabetics may also become hyperinsulinemic because routine insulin injection may not reflect physiologic need and because the insulin is administered peripherally rather than portally. Hyperinsulinemia increases the production of circulating triglyceride. It appears to do this in rats by causing the production of more triglyceride-rich lipoprotein particles rather than by increasing the triglyceride content of each particle. Further, at least in rats, the insulin-induced increase in triglyceride production requires the presence of supplementary dietary fructose. Hyperinsulinemia also increases the activity of adipose tissue lipoprotein lipase and the degradation of very low density lipoprotein (VLDL). The concentration of VLDL depends on balance of production and degradation. Accelerated VLDL degradation leads to an increase in IDL production. Because there is mounting evidence that IDL may be atherogenic, this cycle could accelerate atherogenesis. As such, it is reasonable to postulate that reducing the concentration of triglyceride-rich lipoproteins would break this cycle and would diminish the circulating level of potentially atherogenic lipoproteins. PMID: 3521248 [PubMed - indexed for MEDLINE] 6868. Ann Plast Surg. 1986 May;16(5):444-53. Adipose tissue in plastic surgery. Smahel J(1). Author information: (1)Reconstructive Surgery Clinic, Research Section, University Hospital, Zurich, Switzerland. In this article I review the present state of knowledge about adipose tissue as it is relevant to the practical purposes of plastic surgery. Fat cells are normal constituents of loose connective tissue. Large numbers of fat cells organized into lobules are classified as adipose tissue. Adipose tissue is a special form of reticular connective tissue. The lobules are both morphologically and angiologically independent units. They are seen as well-vascularized structures supplied with blood through a pedicle. Severance of the lobule normally results in necrosis. The subcutaneous fat layer derives from the "primitive organs" identifiable in the hypodermis from the fourth fetal month onward. The primitive organs are the basis for individual fat lobules. The development of adipose tissue continues until physical growth is complete. The disposition of the subcutis to develop adipose tissue shows great variation in different regions of the body. The in-situ mechanical resistance of adipose tissue is provided by the supporting structures. The development, structural characteristics, and physiology of adipose tissue can provide an explanation for many of the observations plastic surgeons have made on this tissue. The processes involved in healing, grafting, and reduction of adipose tissue are analyzed and considered in relation to the clinical picture. PMID: 3078615 [PubMed - indexed for MEDLINE] 6869. Br Med J (Clin Res Ed). 1986 Apr 5;292(6525):919-22. Insulin receptors and the clinician. Taylor R. PMCID: PMC1339851 PMID: 3083940 [PubMed - indexed for MEDLINE] 6870. Arteriosclerosis. 1986 Mar-Apr;6(2):123-30. Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Stern MP, Haffner SM. Differences in body fat distribution between diabetics and nondiabetics have been recognized for several decades; diabetics have a more centralized or upper body fat pattern than nondiabetics. Recently, attention has focused on fat patterning and also on hyperinsulinemia as possible risk factors for cardiovascular disease, as well. The case for insulin as a cardiovascular risk factor is bolstered by theoretical considerations related to its possibly atherogenic effects on serum and arterial wall lipids. Empirical evidence for fat patterning and hyperinsulinemia as cardiovascular risk factors rests on six prospective epidemiologic studies, three on fat patterning and three on insulin. Although provocative, none of these studies can be regarded as definitive. In none was a dose-response effect demonstrated, and there are various inconsistencies within and across the studies. Moreover, in none of the studies were hyperinsulinemia and fat patterning evaluated simultaneously. This is of particular importance in view of the well-documented interrelationships between these two variables. For example, insulin resistance and hyperinsulinemia have been found to be greater in women with upper body obesity compared to women with lower body obesity of equivalent degree. Considerable progress has been made recently in understanding the mechanisms of the differential metabolic effects of these two types of obesity. The extent to which fat patterning and hyperinsulinemia are genetic or acquired has received relatively little attention. Further research on this question is warranted since elucidation of any environmental influences on these variables might suggest new clinical and public health control measures. PMID: 3513749 [PubMed - indexed for MEDLINE] 6871. Am J Med. 1986 Feb 14;80(2A):71-81. Adrenergic effects on plasma lipoprotein metabolism. Speculation on mechanisms of action. Sacks FM, Dzau VJ. Recently, the effects of alpha-adrenergic and beta-adrenergic antagonists on plasma lipoprotein concentrations have been reported. Evidence from diverse lines of research has been brought together that suggests three potential mechanisms by which these antihypertensive agents affect lipoprotein metabolism. First, the known alterations in plasma triglyceride levels caused by adrenergic antagonists may be mediated through the activity of lipoprotein lipase. This enzyme, located on the capillary endothelium of adipose tissue and skeletal muscle, catabolizes chylomicrons and very-low-density lipoproteins. Catecholamine-induced changes in precapillary sphincter tone could affect the delivery of triglyceride-rich lipoproteins to endothelial lipase, cause changes in capillary endothelial surface area for lipase-binding sites, and/or modulate the synthesis of lipoprotein lipase by adipocytes and myocytes. Since high-density lipoprotein levels increase by taking up components of chylomicrons released by lipoprotein lipase, these pathways might explain the adrenergic-induced changes in high-density lipoprotein that are reciprocal to those in plasma triglycerides. Second, hepatic production of very-low-density lipoproteins might be affected by adrenergic-induced changes in insulin release. Decreased insulin release may direct glucose metabolites from adipocytes to hepatocytes for lipogenesis. Catecholamines and other glucoregulatory hormones are known to alter hepatic cholesterol synthesis and secretion of very-low-density lipoproteins. These observations also suggest that dietary carbohydrate and fat might modulate adrenergic influences on lipoprotein metabolism by other than classic means. Third, as suggested by studies of cultured fibroblasts, alpha-adrenergic antagonists may increase receptor-mediated catabolism of low-density lipoprotein. PMID: 3080883 [PubMed - indexed for MEDLINE] 6872. S Afr Med J. 1986 Feb 1;69(3):185-90. Obesity in perspective. Macfarlane CM. Attitudes to obesity are changing. It is currently regarded as a common, multifactorial disorder with serious medical and psychological consequences. It is also resistant to treatment. Recent research with experimental animals has given new insights into the molecular pathology of this condition and gives some hope of novel therapeutic intervention. PMID: 3003937 [PubMed - indexed for MEDLINE] 6873. Contemp Issues Clin Biochem. 1986;4:123-39. Biochemistry of hospital nutrition. Nutritional assessment. Bastow M. PMID: 3556002 [PubMed - indexed for MEDLINE] 6874. Ann N Y Acad Sci. 1986;488:406-18. The role of calcium and calmodulin in insulin receptor function in the adipocyte. McDonald JM, Pershadsingh HA, Colca J. PMID: 3555257 [PubMed - indexed for MEDLINE] 6875. Ann N Y Acad Sci. 1986;488:356-69. Cell biology of insulin's stimulatory action on glucose transport and its perturbation in altered metabolic states. Kahn BB, Cushman SW. PMID: 3555256 [PubMed - indexed for MEDLINE] 6876. Prog Clin Biol Res. 1986;226:445-54. Regulation of gene expression during the differentiation of 3T3-adipocytes. Spiegelman BM, Cook KS, Hunt CR. PMID: 3543967 [PubMed - indexed for MEDLINE] 6877. Prog Clin Biol Res. 1986;226:433-43. Hormonal control of developmentally regulated adipose genes. Knight DM, Chapman AB, Torti FM, Ringold GM. PMID: 3543966 [PubMed - indexed for MEDLINE] 6878. Prog Clin Biol Res. 1986;226:191-204. Endocrine and autocrine control of growth and differentiation of teratoma-derived cell lines. Serrero G. PMID: 3543955 [PubMed - indexed for MEDLINE] 6879. Biol Neonate. 1986;50(6):297-317. Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H, Van Allen MI. The objective of this paper is to review the extent and mechanisms of lipoprotein alterations in pregnancy, present new data relating to placental lipid transport in normal humans and diabetic animals and consider possible effects on fetal growth and development in normal and diabetic pregnancy. The concentration of all lipoprotein fractions increases during pregnancy. VLDL cholesterol and triglyceride increase 2.5-fold over prepregnancy levels and LDL cholesterol increases 1.6-fold, all with peak levels at term. HDL cholesterol is maximally increased in midgestation by 1.45-fold and subsequently declines to 1.15-fold at term. The mechanisms of these lipoprotein changes have not been studied in humans but the hypertriglyceridemia in animal models is related to enhanced VLDL entry into the circulation. In addition, diminished adipose tissue lipoprotein lipase (LPL) activity in late gestation may cause a rerouting of triglyceride fatty acids to other tissues such as muscle and uterus for oxidation, rather than storage, since triglyceride transport is not reduced in pregnancy. All of these changes appear to be sex hormone mediated. In diabetic pregnancies, the available data indicate that triglyceride concentrations are increased and HDL cholesterol concentrations are decreased with reference to lipoproteins in nondiabetic pregnant women. Previously unpublished data show that a transplacental FFA gradient exists across the umbilical circulation in the direction of the fetus and is proportional to the maternal FFA concentration. No gradient is seen for triglyceride or total plasma cholesterol. However, transport of unmeasured amounts of triglyceride fatty acids may still occur via placental LPL and be exaggerated in diabetes where LPL declines in adipose tissue but not in placenta. The mechanism of transplacental cholesterol transport remains to be defined. Preliminary studies suggest that it depends on HDL as well as LDL since both can provide cholesterol for placental progesterone synthesis. In addition, fetal weight and length are associated with maternal apoproteins A-I and A-II, both major apoproteins of HDL. By lowering HDL in pregnancy, diabetes mellitus could negatively affect these relationships. In conclusion, sex hormone mediated modifications of lipoprotein physiology are described in pregnancy which may enhance triglyceride fatty acid transport to muscle for oxidation and LDL and HDL cholesterol delivery to growing maternal and fetal tissues, a process that diabetes could globally disrupt. PMID: 3542067 [PubMed - indexed for MEDLINE] 6880. Ann N Y Acad Sci. 1986;478:77-92. Regulation and structure of murine malic enzyme mRNA. Bagchi S, Wise LS, Brown ML, Sul HS, Bregman D, Rubin CS. PMID: 3541755 [PubMed - indexed for MEDLINE] 6881. Ann N Y Acad Sci. 1986;478:109-19. Hormonal control of adipogenesis. Ringold GM, Chapman AB, Knight DM, Torti FM. The concept that hormonal substances can alter the expression of entire developmental programs is in itself not particularly new. The ability to define conditions under which a specific hormone can precociously activate the differentiation of a well-defined population of cells and under which another hormone can both block and reverse such a developmental progression, however, provides a major step forward toward unraveling the biochemical events that define the transition from a committed precursor to a fully differentiated cell. Further analysis of the molecular events initiated by glucocorticoids and TNF should provide insights into the control of adipogenesis and may generate a foundation for understanding the mechanisms by which other cells enter a particular differentiative lineage. In a more applied sense, such knowledge may also provide a rational approach to controlling metabolic disease syndromes related to adipogenesis gone awry such as obesity-associated diabetes and cachexia. PMID: 3541748 [PubMed - indexed for MEDLINE] 6882. Adv Exp Med Biol. 1986;201:67-81. Clinical, nutritional and biochemical consequences of apolipoprotein B deficiency. Kayden HJ, Traber MG. PMID: 3541524 [PubMed - indexed for MEDLINE] 6883. Adv Exp Med Biol. 1986;201:61-6. HDL binding to human adipocyte plasma membranes: regional variation in omental and subcutaneous depots. Fong B, Salter A, Jimenez J, Despres JP, Angel A. PMID: 3541523 [PubMed - indexed for MEDLINE] 6884. Adv Exp Med Biol. 1986;201:37-49. Modifications and degradation of high density lipoproteins. Angel A, Fong B. It is evident that lipoprotein modifications, degradation and clearance from plasma and interstitial compartments involves both cellular and extracellular processing. Cellular uptake of the intact particle as a whole and/or selective removal of constituent apoproteins and lipids by various parenchymal cells goes on continuously. Regulation of these processes undoubtedly varies tissue to tissue and much remains to be clarified in human tissues in vivo. The metabolic effects of chemical, proteolytic, and lipolytic modification of lipoproteins secondary to transient cellular encounters (e.g. during transit through endothelial barriers, or reversible binding to cells) on apolipoprotein clearance remains to be defined. It is likely that multiple post-secretory modifications occur and together represent subtle regulatory events that modulate lipid shuttle functions and cellular targetting properties of HDL particles. PMID: 3541522 [PubMed - indexed for MEDLINE] 6885. Adv Exp Med Biol. 1986;201:227-39. Primary lipoprotein lipase deficiency. Brunzell JD, Iverius PH, Scheibel MS, Fujimoto WY, Hayden MR, McLeod R, Frolich J. The enzyme lipoprotein lipase plays a central role in the processing of energy in the form of calorically dense triglyceride. Classical LPL deficiency usually presents in childhood with the multiple manifestations related to chylomicronemia. Many patients with genetic variations have been noted who differ in one of many ways from the classical patients. With the development of techniques to measure enzyme mass and to study gene expression, the molecular defects in each of these families should become evident. PMID: 3541517 [PubMed - indexed for MEDLINE] 6886. Reprod Nutr Dev. 1986;26(5A):1057-103. [Bibliographic review: Quantitative variations and metabolism of lipids in adipose tissue and the liver during the gestation-lactation cycle. 1. In the rat]. [Article in French] Chilliard Y. This comprehensive review describes changes in body lipids, energy balance, and metabolic pathways and endocrine regulations in the adipose tissues and liver of rats during pregnancy and lactation. These profiles are discussed in relation to litter size, food intake and diet composition; the interactions between mechanisms that are teleophoretic (direct nutrients to the gravid uterus or to the mammary gland) and homeostatic (insure the maintenance of the mother organism) have been emphasized. PMID: 3541089 [PubMed - indexed for MEDLINE] 6887. Prog Clin Biol Res. 1986;220:45-60. Uptake and distribution of common industrial solvents. Cohr KH. PMID: 3540985 [PubMed - indexed for MEDLINE] 6888. Physiol Behav. 1986;38(3):407-14. Body fat: what is regulated? Mrosovsky N. This paper assumes that body fat is regulated and then reviews our ignorance about how this is accomplished. It concentrates on the challenge posed by site differences between different depots, and discusses a variety of experimental approaches that may be helpful. PMID: 3538074 [PubMed - indexed for MEDLINE] 6889. Prog Clin Biol Res. 1986;222:531-53. Metabolic adaptations to dietary fats. Clarke SD. PMID: 3538046 [PubMed - indexed for MEDLINE] 6890. Acta Endocrinol Suppl (Copenh). 1986;277:11-8. Some aspects of the metabolic and hormonal adaptation to pregnancy. Baird JD. Metabolic adaptations to pregnancy are directed towards ensuring fetal growth and development, provision of a fetal store of energy, and the establishment of a maternal bank of energy. At any one time the demands of these objectives are competing for the available dietary energy, yet to ensure successful reproduction all three must be met. Current concepts suggest that the metabolic adaptation to pregnancy is designed primarily to safeguard against variable and restricted energy intake and that this is achieved by 1) a reduction in energy expenditure, resulting from decreased activity combined with increased metabolic efficiency, 2) phased metabolic activity affecting carbohydrate, fat and protein. Conservation of energy in maternal adipose tissue dominates the first half of pregnancy, while in late pregnancy the available energy is redirected to the fetus. This biphasic metabolism is programmed by the placental steroids whose secretion is independent of maternal diet. Internal redistribution of substrate under hormonal control is the main characteristic of the metabolic adaptation to pregnancy. The precise mechanisms underlying these adjustments have still to be defined. PMID: 3532660 [PubMed - indexed for MEDLINE] 6891. Hum Nutr Appl Nutr. 1986;40 Suppl 1:1-10. Maternal nutrition and breast feeding. Whitehead RG, Lawrence M, Prentice AM. In this short review we will first summarize current theories relating to maternal nutritional needs during human lactation, then deal with dietary situations where theory and experimental findings differ. In fact such a divergence occurs most of the time, both in affluent countries and especially in the Third World. We will then consider the various hypotheses which are currently being tested in an attempt to rationalize this complex but crucially important enigma. These hypotheses suggest that the mother can 'adapt' both physiologically and behaviourally in order to protect the adequate nutrition of her baby. Finally we will discuss the health significance of what happens when the mother's ability to accommodate the nutritional stresses of pregnancy and lactation fails. Although we have been asked to deal just with lactation, from time to time it will also become necessary to consider events occurring during pregnancy in order to place the nutritional stresses of lactation within a rational biological perspective. Whilst in the medical world, parturition tends to be a watershed event which divides one clinical specialty from another, in nutritional terms its main significance is merely that the mother switches feeding her baby from one part of her anatomy to another. In so far as her nutritional requirements are concerned pregnancy and lactation are part of the same continuum. PMID: 3528069 [PubMed - indexed for MEDLINE] 6892. Annu Rev Biochem. 1986;55:1059-89. Hormonal regulation of mammalian glucose transport. Simpson IA, Cushman SW. PMID: 3527041 [PubMed - indexed for MEDLINE] 6893. Prog Neurobiol. 1986;27(1):13-62. Neurobiology of an anorectic drug: fenfluramine. Rowland NE, Carlton J. PMID: 3526413 [PubMed - indexed for MEDLINE] 6894. Reprod Nutr Dev. 1986;26(2B):619-31. Changes in energy metabolism during the suckling and weaning period in the newborn. Ferré P, Decaux JF, Issad T, Girard J. In most of the mammals, birth and weaning are two periods of nutritional transitions. Whereas the fetus oxidizes mainly glucose, lactate and aminoacids, the newborn is fed with milk, a high fat, low carbohydrate diet. At weaning, milk is replaced progressively by the adult diet which contains less fat and more carbohydrate. In the hours and days following birth, the newborn adapts itself to the new nutritional environment by increasing its capacity to produce glucose de novo (gluconeogenesis) in order to satisfy its high glucose needs. Oxidation of fatty acids is enhanced in the liver and at the peripheral level. Ketone bodies synthetized from fatty acids in the liver in large amounts are utilized by other tissues and specially the brain where they can met energetic and synthetic needs. In the rat, during the suckling period, lipogenesis is decreased in the liver and in white adipose tissue and triglyceride accretion is minimized. At weaning, these adaptations are reversed: decreased gluconeogenic and oxidative capacity of the liver, decrease of the role of ketone bodies, increase of the lipogenic rate in the liver and the adipose tissue, storage of triglycerides. The nutritional and hormonal factors involved in these metabolic adaptations are numerous but insulin and glucagon might play a major role. PMID: 3523657 [PubMed - indexed for MEDLINE] 6895. Reprod Nutr Dev. 1986;26(2B):597-603. Regulation of metabolism during lactation in the rat. Williamson DH. The physiological, endocrine and biochemical alterations which occur in the lactating rat to allow direction of the nutrients (glucose, amino acids, non-esterified fatty acids, triacylglycerols) to the lactating gland are described. In addition, the short-term changes in the rate of synthesis of milk constituents and the mechanisms whereby they occur are discussed. PMID: 3523656 [PubMed - indexed for MEDLINE] 6896. Prog Biochem Pharmacol. 1986;21:59-73. Effects of dietary sucrose or fructose on carbohydrate and lipid metabolism. Animal studies. Vrána A, Kazdová L. PMID: 3523503 [PubMed - indexed for MEDLINE] 6897. J Gynecol Obstet Biol Reprod (Paris). 1986;15(2):147-52. [Metabolism of sex hormones and adipose tissue]. [Article in French] Basdevant A, Raison J, De Lignières B, Guy-Grand B. Adipose tissue is a catchment area for storing, converting and releasing the sex hormones. The role of adipose tissue in the general metabolism of endogenous and exogenous steroids deserves to be considered seeing how big the volume of fat is in the human body. The fatty pool of sex steroids seems to be greater than the plasma pool. Hormones which have been stored can be released by adipocytes into the general circulation even if they have been converted while in the adipocytes. Similarly, androgens are changed by adipose tissue into oestrogens by aromatisation and are liberated. This extraglandular production of oestrogens can have clinical and pathological consequences. PMID: 3522721 [PubMed - indexed for MEDLINE] 6898. Diabetes Metab Rev. 1986;2(1-2):53-68. Therapy and better quality of life: the dichotomous role of exercise in diabetes mellitus. Kemmer FW, Berger M. PMID: 3522144 [PubMed - indexed for MEDLINE] 6899. Diabetes Metab Rev. 1986;2(1-2):19-34. Exercise, resting metabolic rate, and thermogenesis. Segal KR, Pi-Sunyer FX. PMID: 3522143 [PubMed - indexed for MEDLINE] 6900. Diabetes Metab Rev. 1986;2(1-2):1-17. Exercise and physical training: effects on insulin sensitivity and glucose metabolism. Horton ES. PMID: 3522142 [PubMed - indexed for MEDLINE] 6901. Metabolism. 1986 Jan;35(1):78-87. Nutrition, somatomedins, and the brain. Phillips LS. Conditions of decreased nutrient supply (malnutrition) and/or decreased nutrient utilization (diabetes) are attended by impairment of growth despite an increase in circulating levels of growth hormone (GH). Growth involves the actions of somatomedins, circulating insulinlike polypeptides with anabolic effects on cartilage, fat, and muscle. In malnutrition and diabetes, mechanisms of growth impairment appear to include a decrease in GH-induced generation of somatomedins, together with an increase in somatomedin inhibitors, factors which antagonize somatomedin action. Brain mediation of these alterations involves a rise in GH secretion due to decreased negative feedback from somatomedins, perhaps accentuated by blunting of feedback via actions of somatomedin inhibitors. In combination these processes lead to shunting of metabolic fuels toward vital processes and away from growth (via decreased somatomedin action) and to protein-sparing and increase in alternate metabolic fuels (via direct GH actions on muscle and fat). Further study of involved hypothalamic and pituitary mechanisms should yield additional insights into the role of the brain in metabolic homeostasis. PMID: 3510365 [PubMed - indexed for MEDLINE] 6902. Prog Lipid Res. 1986;25(1-4):437-50. Serum fatty acids and coronary heart disease in Finnish populations. Nikkari T(1). Author information: (1)Department of Biomedical Sciences, University of Tampere, Finland. Finland has one of the highest coronary heart disease (CHD) rates in the whole world, and within the country, the rates are higher in men and eastern Finland than in women and western Finland, respectively. The differences are not wholly explained by the 3 classical risk factors. Several cross-sectional and longitudinal studies suggest that the intake of dietary linoleate (18:2), as reflected in the composition of serum and tissue fatty acids, has an inverse association with CHD, although there are also studies with negative results. Our own retrospective study failed to show any differences in the fatty acid composition of serum CE, TG or PL between men who had died of CHD and age- and risk factor-matched controls, but the negative finding may be due to changes in the fatty acids during storage. Among Finnish populations, most serum CE fatty acids had highly significant correlations with those in other serum lipid fractions, adipose tissue and platelets, and they had good "tracking" for up to 4 yr. Serum CE and TG 18:2, and total omega 6 polyunsaturated fatty acids (PUFA) had strong correlations with dietary 18:2 and PUFA, and can thus be used in the evaluation of population differences in the intake of PUFA. CE fatty acids were analyzed in a total of 2820 free-living 1- to 85-yr-old males and females. The percentages of serum fatty acids were age-dependent. West-Finnish populations had higher contents of 18:2 than those in eastern Finland, and middle-aged women had higher proportions of 18:2 than men. The content of 18:2 in adipose tissue and/or serum CE of middle-aged men was comparable to that in Scotland and lower than those in Italy and Sweden. These findings are compatible with the idea that 18:2 is a negative risk factor of CHD, but the evidence is only circumstantial. Possible mechanisms whereby 18:2 could affect CHD have been discussed. The contents of omega 3 fatty acids in CE were opposite to those of omega 6 fatty acids in that eastern Finnish and male populations had higher contents of 18:3 omega 3 and 20:5 omega 3 than western Finns and females, respectively. This finding is apparently due to substitution of vegetable fat for milk fat in the diet, resulting in a relative deficiency of the omega 3 fatty acids at the expense of 18:2. Experimental evidence for such a mechanism was obtained in an intervention study.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3321090 [PubMed - indexed for MEDLINE] 6903. Int J Vitam Nutr Res Suppl. 1986;29:41-8. Neuro-endocrine disorders in obesity. Jeanrenaud B. PMID: 3084675 [PubMed - indexed for MEDLINE] 6904. Ann N Y Acad Sci. 1986;488:385-405. Characterization of mediators of insulin action. Gottschalk WK, Macaulay SL, Macaulay JO, Kelly K, Smith JA, Jarett L. PMID: 3034120 [PubMed - indexed for MEDLINE] 6905. Biosci Rep. 1986 Jan;6(1):3-18. Whither brown fat? Rothwell NJ, Stock MJ. PMID: 3008874 [PubMed - indexed for MEDLINE] 6906. Usp Fiziol Nauk. 1986 Jan-Mar;17(1):36-54. [Role of insulin in regulating carbohydrate metabolism]. [Article in Russian] Kendysh IN. PMID: 3006377 [PubMed - indexed for MEDLINE] 6907. Ann N Y Acad Sci. 1986;464:58-65. Breast development in puberty. Drife JO. PMID: 2942075 [PubMed - indexed for MEDLINE] 6908. Prog Clin Biol Res. 1986;205:115-36. Growth hormone in birds: a comparative perspective. Scanes CG, Campbell R, Harvey S, King D, Malamed S, Perez F. PMID: 2869500 [PubMed - indexed for MEDLINE] 6909. J Cyclic Nucleotide Protein Phosphor Res. 1986-1987;11(7):497-511. Hormonal regulation of adipocyte particulate "low Km" cAMP phosphodiesterase. Manganiello VC(1), Smith CJ, Newman AH, Rice K, Degerman E, Belfrage P. Author information: (1)Laboratory of Cellular Metabolism, NHLBI, Bethesda, Maryland. PMID: 2450112 [PubMed - indexed for MEDLINE] 6910. Annu Rev Nutr. 1986;6:563-97. Metabolism and function of myo-inositol and inositol phospholipids. Holub BJ. Alterations in the level of dietary inositol can significantly influence the concentration of free inositol and inositol-containing phospholipid in the circulation and in selected mammalian tissues and cells. The 1-stearoyl 2-arachidonyl molecular species that commonly predominates in cellular phosphoinositides may be of considerable importance for the functioning of these phospholipids in biological membranes. Retailoring reactions subsequent to the de novo biosynthesis of PI involving the acylation of lyso(1-acyl) PI allow for the preferential enrichment of this phospholipid in arachidonic acid. The impaired release of plasma lipoprotein, increased fatty acid mobilization from adipose tissue, and enhanced fatty acid synthesis in liver have all been implicated as causative factors in the hepatic triacylglycerol accumulation occurring with experimental inositol deficiency. The severe intestinal lipodystrophy that develops in female gerbils consuming inositol-deficient diets is likely mediated by a reduced synthesis of PI and the associated impairment of chylomicron assembly and secretion. Membrane PI can potentially regulate enzyme activities and transport processes as well as providing a source of free arachidonic acid for production of the eicosanoids. There has been mounting evidence recently to indicate that an accelerated turnover of the phosphoinositides may play a key role in mediating cellular responses to external stimuli. The transient rise of phosphoinositide-derived 1,2-diacylglycerol in stimulated cells may serve as a signal for the transmembrane control of protein phosphorylation by activating protein kinase C. Receptor occupancy also elicits the phosphodiesterase-catalyzed release of the second messenger inositol 1,4,5-trisphosphate, which appears to provide for the mobilization of calcium from internal stores. Subnormal levels of free inositol and inositol phospholipid, as found in the nerves of animals with experimental diabetes and in sciatic nerves removed postmortem from diabetic patients, have been implicated in the impaired nerve conduction of human diabetics. Patients with renal failure exhibit a dramatic hyperinositolemia that may have clinical significance. Nutritional intervention may offer an approach for counteracting abnormalities in inositol and inositol phospholipid profiles and associated physiological responses in certain disease states. PMID: 2425833 [PubMed - indexed for MEDLINE] 6911. Adv Clin Chem. 1986;25:49-115. The somatomedins: insulin-like growth factors. Baxter RC. PMID: 2424282 [PubMed - indexed for MEDLINE] 6912. Life Sci. 1985 Nov 25;37(21):1949-61. Antihyperlipidemic properties of beta-pyridylcarbinol. A review of preclinical studies. Cohen M. The available preclinical literature on the antihyperlipidemic properties of beta-pyridylcarbinol is reviewed. Similarities between the pharmacological profiles for beta-pyridylcarbinol and nicotinic acid, and evidence for the metabolic conversion of beta-pyridylcarbinol to nicotinic acid are discussed. Several reviews discussing the antihyperlipidemic effects of beta-pyridylcarbinol (beta-PC, nicotinyl alcohol, Roniacol) and nicotinic acid (NA) have appeared during the last 15 years (1-6). However, continuing clinical interest in the ability of nicotinic acid analogs to reduce plasma lipids indicated that an update and critical evaluation of the preclinical literature on this subject would be of value in order to permit a more complete assessment of the relevance of several animal models to effects in human subjects. The literature reviewed included (a) preclinical studies of beta-PC where it was the sole compound examined; (b) comparative studies of beta-PC and NA; and (c) studies relating to the metabolism of beta-PC. The literature chosen included experiments involving fasted animals, satiated animals, and effects of Triton-induced hyperlipidemia. Data on other pharmacological properties of beta-PC and/or NA that might contribute to antihyperlipidemic efficacy (e.g., fibrinolysis, inhibition of platelet aggregation, erythrocyte membrane changes) were also included where available. PMID: 3906330 [PubMed - indexed for MEDLINE] 6913. Am J Clin Nutr. 1985 Nov;42(5 Suppl):1063-71. Insulin: its relationship to the central nervous system and to the control of food intake and body weight. Woods SC, Porte D Jr, Bobbioni E, Ionescu E, Sauter JF, Rohner-Jeanrenaud F, Jeanrenaud B. This article describes the close relationship among the hormone insulin, the central nervous system, and the regulation of food intake and body adiposity. The initial section documents the control of insulin output from the pancreas by the central nervous system, and a later section describes the relationship of insulin levels in the blood to the degree of adiposity. Another section documents the ability of insulin to gain access to the brain and to elicit responses there. Finally, the behavioral effects of insulin added to the brain, and especially its ability to reduce food intake and body weight, is discussed. The implications to obesity are stressed throughout. PMID: 3904396 [PubMed - indexed for MEDLINE] 6914. Probl Endokrinol (Mosk). 1985 Nov-Dec;31(6):75-80. [Effect of somatotropin on carbohydrate metabolism and the interaction of somatotropin with insulin]. [Article in Russian] Keda IuM. PMID: 3003737 [PubMed - indexed for MEDLINE] 6915. Clin Endocrinol Metab. 1985 Nov;14(4):997-1020. The adrenal cortex and virilization. McKenna TJ, Cunningham SK, Loughlin T. The physiological control of adrenal androgen secretion has not been definitively established. However, there is evidence to suggest that a dexamethasone-suppressible factor other than ACTH may have a specific role to play. The majority of patients with idiopathic hirsutism (hirsutism associated with regular menstruation) have findings suggestive of adrenal androgen excess, including enhanced androgen responsiveness following administration of metyrapone, and respond to treatment with dexamethasone, 0.5 mg given each night. Patients with idiopathic hirsutism have elevated androgens but normal oestrogen and gonadotrophin levels. In contrast, while patients with polycystic ovary syndrome (PCOS) also demonstrate evidence of adrenal androgen excess, these patients have elevated oestrone levels and gonadotrophin secretion is abnormal. Approximately 50% of patients with PCOS treated with dexamethasone resume regular menstruation. Oestrone excess appears to be primary to the abnormal gonadotrophin secretion and to the development of PCOS. In non-obese patients with PCOS elevated oestrone appears to occur as a consequence of the availability of the excessive amounts of its immediate precursor, androstenedione, an androgen mainly of adrenal origin. Androstenedione is converted to oestrone in fat. Obese amenorrhoeic subjects have normal androstenedione values but elevated oestrone levels with abnormal gonadotrophin secretion as seen in PCOS. These findings indicate that abnormal gonadotrophin secretion is associated with elevated oestrone levels whether these occur as a consequence of excessive adrenal androgen secretion, or the excessive conversion of normal amounts of available androstenedione. Patients with idiopathic hirsutism and elevated androstenedione levels but normal oestrone values appeared to be protected against the development of PCOS by relatively poor conversion of androstenedione to oestrone. It is likely, therefore, that if patients with idiopathic hirsutism gain additional adipose tissue, elevated oestrone levels will result and PCOS will develop. These observations explain the frequent association of PCOS and obesity. There is a close clinical association between elevated androgen levels and hirsutism and between elevated oestrone levels and menstrual disturbances. However, some patients with amenorrhoea but without hirsutism may demonstrate marked elevations of androgens and oestrone, the correction of which leads to the resumption of regular ovulation. This presentation, 'amenorrhoea with cryptic hyperandrogenaemia', is probably explained by diminished sensitivity of androgen receptors.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3002682 [PubMed - indexed for MEDLINE] 6916. Postgrad Med J. 1985 Oct;61(720):915-23. Marasmus--1985. Barltrop D, Sandhu BK. PMCID: PMC2418296 PMID: 3932990 [PubMed - indexed for MEDLINE] 6917. Clin Gastroenterol. 1985 Oct;14(4):811-27. Aspects of nutrition in the elderly. Beaumont DM, James OF. Malnutrition in the elderly is inseparably linked to disease, immobility and social isolation. Although in percentage terms the numbers of malnourished elderly may be small, in hospital practice clinically important malnutrition is more widespread. Prevention of malnutrition is not simply a matter of distributing vitamin supplements to the elderly in the community-consideration must be given to alleviation of many of the adverse environmental conditions affecting older people. The role of dietary manipulations in the prevention and treatment of chronic degenerative disorders of later life needs further studies before satisfactory conclusions may be drawn. PMID: 3910309 [PubMed - indexed for MEDLINE] 6918. Biochimie. 1985 Oct-Nov;67(10-11):1147-53. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Gammeltoft S, Fehlmann M, Van Obberghen E. Insulin receptors in rat and human central nervous system have been identified by binding of 125I-insulin on purified synaptic plasma membranes; affinity labelling of receptors by chemical cross-linking 125I-insulin; or phosphorylation of receptors with [gamma-32P]ATP. Brain insulin receptors showed significant differences in their binding characteristics and subunit structure when compared with receptors in other tissues like adipose and liver cells: absence of negatively cooperative interactions; a distinct binding specificity i.e. porcine proinsulin, coypu insulin and insulin-like growth factor I and II showed 2-5 times higher binding affinity in brain than in other cell types; a smaller molecular size of the brain receptor alpha-subunit than in other tissues (Mr approximately 115,000 instead of 130,000). In contrast, the size (Mr approximately 94,000) and function of the insulin receptor beta-subunit kinase was identical with that described in other cells. We conclude, that insulin receptors in mammalian brain represent a receptor subtype which may mediate growth rather than metabolic activity of insulin. PMID: 3907719 [PubMed - indexed for MEDLINE] 6919. Biochimie. 1985 Oct-Nov;67(10-11):1111-7. Biological action and fate of photoaffinity-labelled insulin-receptor complexes. Brandenburg D, Diaconescu C, Klotz G, Mucke P, Neffe J, Saunders D, Schüttler A. Covalent linking of two photoactivatable insulin derivatives, B2-(2-nitro,4-azidophenylacetyl)-des-PheB1-insulin and B29-(2-nitro,4-azidophenylacetyl)-insulin to viable rat adipocytes gives a system, which contains a fixed stoichiometry between hormone and receptor. The biological signal of prolonged lipogenesis has been used to study several aspects of insulin binding and action: the role of the site of the crosslink between insulin and receptor, recognition of bound photoinsulin by anti-insulin antibodies, the half-life of the biologically active complex, the pH-dependence of the biological signal, and the possible role of internalization. Furthermore, the effect of trypsin on the insulin receptor, as well as the insulin-receptor complex, has been investigated and a refined model of the receptor is presented. PMID: 3907715 [PubMed - indexed for MEDLINE] 6920. Klin Padiatr. 1985 Sep-Oct;197(5):378-85. [Somatomedins and their significance in pediatrics]. [Article in German] Vetter U, Teller WM. Somatomedins are polypeptide hormones (MW: 7500 Daltons) whose plasma concentrations are largely governed by growth hormone secretion. Somatomedins stimulate cartilage growth and mitosis and growth of several extraskeletal cell types. Somatomedins also display insulin-like activity in adipose tissue. Presently four different human somatomedins are known. Somatomedin C (SmC) and insulin like growth factor I (IGF I) turned out to be identical peptides. TO a large extent they are regulated by growth hormone. Thus they mediate growth hormone action at the tissue level. Insulin-like growth factor II (IGF II) is only minimally dependent on growth hormone secretion. Its definite biological role for growth remains to be established. The somatomedins are bound to larger carrier proteins in the circulation. Somatomedins are synthesized in mesenchymal cells of multiple organs, especially in the liver and kidneys. Somatomedins are of clinical relevance for the diagnosis of growth disturbances due to pituitary disorders. In pituitary dwarfism radioimmunological SmC/IGF plasma levels are decreased whereas in acromegaly they are increased. In a small percentage of patients both with pituitary dwarfism and acromegaly normal SmC/IGF I concentrations are encountered. These facts demonstrate that SmC/IGF I determinations cannot replace common diagnostic procedures in the analysis of growth disorders. The reliability of low SmC/IGF I concentrations is limited in conditions like low-calorie malnutrition, malabsorption, various storage diseases, hypothyroidism, chronic liver and kidney diseases, because in these disorders low SmC/IGF I plasma concentrations occur despite high growth hormone levels. PMID: 3906254 [PubMed - indexed for MEDLINE] 6921. Hypertension. 1985 Sep-Oct;7(5):657-67. The role of calcium in genetic hypertension. Lau K, Eby B. PMID: 3897042 [PubMed - indexed for MEDLINE] 6922. Environ Health Perspect. 1985 Sep;61:11-20. The role of structure in the disposition of halogenated aromatic xenobiotics. Birnbaum LS. Halogenated aromatic xenobiotics such as the chlorinated and brominated biphenyls, naphthalenes, dibenzodioxins, and dibenzofurans are widespread environmental contaminants. The number, position, and nature of the halogen atoms as well as the structure of the aromatic rings influence the disposition of these chemicals in living systems. Absorption is governed primarily by the physical properties of lipophilicity and solubility. Distribution through the blood occurs by nonspecific binding to plasma proteins and cellular components. Liver and adipose tissue are the major depots. Metabolism is a prerequisite for excretion. The highly substituted isomers tend to be resistant to metabolism. The route of excretion shifts from urine to feces with increasing size and number of halogen atoms. Although pharmacokinetic modeling has allowed some predictions to be made from one compound to another or across species, more information on metabolism is required in order to improve the ability to predict the disposition in humans of this class of toxic environmental pollutants. PMCID: PMC1568747 PMID: 2998745 [PubMed - indexed for MEDLINE] 6923. Postepy Hig Med Dosw. 1985 Sep-Oct;39(5):518-39. [Current theories on hibernation]. [Article in Polish] Kandefer-Szerszeń M. PMID: 2425345 [PubMed - indexed for MEDLINE] 6924. Am J Med. 1985 Aug 23;79(2B):13-22. Insulin resistance: receptor and post-binding defects in human obesity and non-insulin-dependent diabetes mellitus. Truglia JA, Livingston JN, Lockwood DH. Insulin resistance is a prominent feature of three clinical conditions: obesity, impaired glucose tolerance, and non-insulin-dependent (type II) diabetes mellitus. Numerous studies over the past 15 years have provided a better understanding, from both a clinical and cellular standpoint, of the pathophysiology of these insulin-resistant states as well as of insulin action. In addition, it has recently been recognized that correction of glucose intolerance leads to an improvement in insulin secretion and a reduction in insulin resistance. Examination of the most recent data suggests that the basis for insulin resistance in these common clinical disorders is often multifactorial. In uncomplicated obesity, the cellular alterations responsible for insulin resistance appear to be at the level of the hepatic insulin receptor and in post-binding processes in peripheral target tissues. In type II diabetes, a post-binding defect(s) in peripheral tissues appears to be the primary lesion. In humans, many of the factors that mediate the changes leading to insulin resistance are still unknown and are the object of current investigations. PMID: 3898828 [PubMed - indexed for MEDLINE] 6925. Diabetologia. 1985 Aug;28(8):502-13. An hypothesis on the aetiology of obesity: dysfunction of the central nervous system as a primary cause. Jeanrenaud B. PMID: 3902541 [PubMed - indexed for MEDLINE] 6926. Vet Parasitol. 1985 Aug;18(2):103-10. Interaction of host physiology and efficacy of antiparasitic drugs. Prichard RK. Antiparasitic drugs must be conducted to the parasite by the host and are therefore subject to physiological and biochemical processes in the host. Usually the efficacy of an antiparasitic drug will depend on a toxic concentration being presented to the parasite for sufficient time to lead to irreversible damage. Because many drugs are, in part, absorbed and transported to the site of the parasite by the circulatory system the area under the plasma concentration curve (AUC) may reflect availability of drug to the parasite and likely efficacy. A number of host physiological factors affect the AUC. Many anthelmintics are given orally as solids. Some absorption occurs in the rumen of ruminants, but many heterocyclic compounds such as the benzimidazoles require the low pH of the abomasum or gastric stomach to render them soluble. Certain disease states, including gastrointestinal parasitism, can cause the gastric pH to rise. This may in turn reduce solubility and absorption with resultant faster rate of excretion, particularly when accompanied by diarrhoea, and a reduced AUC. Once the anthelmintic has been absorbed, after oral or systemic administration, it is usually rapidly transported to the liver. The liver and adipose tissue may store the drug, releasing it over a period to produce a sustained effect as occurs with ivermectin, or it may rapidly metabolise it. A few anthelmintics, such as febantel, probably need to be metabolised in order to become active. However, more frequently the liver is involved in oxidation or reduction, followed by conjugation with sulfate, glucuronide or glutathione to render the drug more polar, to increase its molecular weight, inactivate it and facilitate its excretion. The rate of metabolism has been found to vary considerably between species and thus different dose rates and treatment are often required to achieve adequate antiparasite activity, with species such as deer, cattle and probably goats metabolising some anthelmintics faster than sheep. Some interesting possibilities for altering the absorption and metabolism of anthelmintics by the host may allow improved efficacy and reliability of antiparasite activity without necessarily increasing the dose rate of anthelmintic. PMID: 3898541 [PubMed - indexed for MEDLINE] 6927. Mol Cell Endocrinol. 1985 Aug;42(1):1-20. Post-binding events in insulin action. Horuk R, Olefsky JM. PMID: 3896892 [PubMed - indexed for MEDLINE] 6928. Transplant Proc. 1985 Aug;17(4 Suppl 1):27-32. Pharmacologic aspects of cyclosporine therapy: pharmacokinetics. Wood AJ, Lemaire M. PMID: 3895666 [PubMed - indexed for MEDLINE] 6929. Transplant Proc. 1985 Aug;17(4 Suppl 1):19-26. Metabolism of cyclosporine. Maurer G. PMID: 3895660 [PubMed - indexed for MEDLINE] 6930. Biochim Biophys Acta. 1985 Aug 1;811(3):233-64. Transplasma-membrane redox systems in growth and development. Crane FL, Sun IL, Clark MG, Grebing C, Löw H. PMID: 3893544 [PubMed - indexed for MEDLINE] 6931. Br Med Bull. 1985 Jul;41(3):218-25. Neuroendocrine mobilization of body fuels after injury. Barton RN. PMID: 3896377 [PubMed - indexed for MEDLINE] 6932. Proc Nutr Soc. 1985 Jul;44(2):211-20. Membranes and the response to insulin. Tepperman HM, Tepperman J. PMID: 2931725 [PubMed - indexed for MEDLINE] 6933. Ukr Biokhim Zh (1978). 1985 Jul-Aug;57(4):86-98. [Age aspects of receptor-effector reactions and the regulation of adenylate cyclase activity]. [Article in Russian] Burchinskiĭ SG, Kul'chitskiĭ OK. The present-day notions on the trends and mechanisms of changes in the activity of the cyclic nucleotide system are considered in the age aspect. Their role in disturbances of the neurohumoral regulation processes at the molecular level is discussed. Biochemical mechanisms of changes in the receptor-effector reactions are analyzed. An analysis of these changes is very important for elucidating general regularities of the cyclase system functioning with disturbances of biochemical regulation at the membrane and cell levels. PMID: 2863885 [PubMed - indexed for MEDLINE] 6934. Hum Pathol. 1985 Jun;16(6):580-9. Adrenal pheochromocytoma: a clinicopathologic review of 60 cases. Medeiros LJ, Wolf BC, Balogh K, Federman M. The clinical and pathologic features of 60 adrenal pheochromocytomas were reviewed in an attempt to evaluate the utility of histopathologic evaluation in predicting the prognosis for these tumors. Fifty-five tumors were benign, and five were malignant, characterized either by histologically proved metastases or by extensive local invasion. The prevalence of all parameters studied was compared between the benign and malignant groups. Three differences were observed between the benign and malignant tumors. The malignant tumors were usually larger, had extensive areas of necrosis, and were composed of small cells. In agreement with the results of previous investigations, the morphologic criteria generally used to predict the behavior of tumors, i.e., nuclear atypia, capsular and vascular invasion, and mitotic activity, were of little value in predicting the behavior of adrenal pheochromocytomas. Fifteen tumors, all of which had membrane-bound, cytoplasmic granules, were examined electron microscopically. A minority of these tumors fit the classic descriptions of "norepinephrine" and "epinephrine" granules reported in the literature, while the majority of the granules had features of both types, precluding definitive classification. As a result of these observations, the currently accepted criteria of norepinephrine and epinephrine granules were questioned. A review of the literature cast further doubt on the existence of a correlation between granule content and morphology. Both of the patients with locally invasive malignant tumors were alive and well eight and 28 years following diagnosis and radical surgery. In contrast, the patients with histologically proved distant metastases died within one year of diagnosis. These observations suggest that locally invasive tumors may not have the same dismal prognosis as adrenal pheochromocytomas that have metastasized. PMID: 3997135 [PubMed - indexed for MEDLINE] 6935. Fed Proc. 1985 Jun;44(9):2573-8. Selenium inhibition of chemical carcinogenesis. Ip C. In this article I review the work of our laboratory concerning the relationship between dietary Se intake and susceptibility to mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in female rats. The effect of graded levels of Se in the diet was investigated, ranging from deficiency to excessive supplementation that produced marginal toxicity in the animals. In addition, the interdependence between Se status and fat intake was also explored. Further experiments were aimed at defining the role of Se in the initiation and promotion phases of chemical carcinogenesis. In view of the biochemical function of Se as an antioxidant, the chemopreventive efficacy of Se was compared to that of vitamin E in conjunction with their ability to inhibit lipid peroxidation. Results of this study indicated that the antitumorigenic activity of Se could not be accounted for by suppression of tissue peroxidation, although an environment with a lower oxidant stress might enhance the potency of Se in protecting against cancer. The possible mechanisms of action of Se based on the observations and characteristics of several tumor models are briefly discussed. PMID: 3922798 [PubMed - indexed for MEDLINE] 6936. J Anim Sci. 1985 Jun;60(6):1518-29. Energy intake, body composition and reproductive performance of the gilt. Kirkwood RN, Aherne FX. The relationship between age, live weight, body composition and energy status on the onset and maintenance of reproductive activity in females is reviewed. When possible, swine studies have been employed, although, of necessity, much data are drawn from other species. The relationship between age, weight and puberty is controversial. However, from the available data we conclude that neither age nor weight are reliable indices of reproductive development, but that minimum threshold values for these characteristics must be achieved before puberty can occur. Human data provides a strong indication that a minimum adipose to lean tissue ratio is a prerequisite for puberty onset. Limited data from swine support this contention and indeed it may be a superior measure of reproductive development than either age or weight. However, the value of this ratio remains to be defined in pigs, and again it is minimum threshold level, the attainment of which is necessary, but not in itself sufficient, for puberty onset. A positive energy balance seems to be necessary for puberty onset and the maintenance of estrous cycles in some species, but this has not been investigated in swine. The mechanisms whereby adiposity and energy status influences reproduction are discussed. Human studies demonstrate a negative correlation between energy status, body fatness and plasma gonadotrophin levels. Also, adipose tissue has the ability to metabolize sex steroids, aromatizing androgens to estrogens and changing the direction of estrogen metabolism to produce more or less biologically potent estrogens. PMID: 3894311 [PubMed - indexed for MEDLINE] 6937. Brain Res Bull. 1985 Jun;14(6):537-49. Ventromedial and dorsomedial hypothalamic syndromes in the weanling rat: is the "center" concept really outmoded? Bernardis LL. This report juxtaposes findings from weanling rats with precise lesions in the ventromedial (VMNL rats) to data of weanling rats with lesions in the dorsomedial (DMNL) hypothalamic nuclei. Despite the proximity of the two nuclei their destruction produces opposite effects in most cases but similar responses in other parameters. Absolute and relative food intake are normal in VMNL rats yet they become obese in the face of normal body weight gains. DMNL rats show both reduced absolute food intake and body weight but normal relative food intake and body composition. Both VMNL and DMNL cause reduced linear growth and running wheel activity. DMNL rats defend their lower body weight set point against various challenges and maintain normal body composition. Organ growth in both absolute and relative terms is reduced in VMNL rats. In DMNL rats relative organ growth is normal. Pancreatic growth, protein/pancreas and content and concentrations of several pancreatic enzymes are normal in DMNL but reduced in VMNL rats. Mean 24-hour plasma growth hormone (GH) and corticosterone (B) levels are reduced and insulin levels are greatly elevated in VMNL rats; prolactin (PRL) levels are normal. In DMNL rats, GH, B, insulin and somatomedin activity are normal but PRL is elevated. Circadian rhythms of GH, insulin and triiodothyronine are normal in DMNL rats but B levels are disrupted, as they are in VMNL rats. Glucose incorporation and oxidation in adipose tissue of VMNL rats are enhanced in VMNL rats but normal in DMNL rats. Gluconeogenesis in VMNL rats is enhanced as early as 4 hours post-operatively; in DMNL rats it is normal at this time and several weeks thereafter. Basal lipolysis in epididymal fat pads is elevated in both VMNL and DMNL rats but epinephrine-stimulated lipolysis is elevated in VMNL and decreased in DMNL rats. Both VMNL and DMNL rats show normal basal and epinephrine-stimulated lipolysis in interscapular brown adipose tissue. Several hepatic enzymes are normal in DMNL and depressed in VMNL rats. The above data suggest that the DMN and its circuitry are part of an "organismic" set point system with a "true" body weight and no fat set point, as seems to be the case in the VMNL rat. PMID: 2862969 [PubMed - indexed for MEDLINE] 6938. Can J Physiol Pharmacol. 1985 May;63(5):571-6. Role of carnitine during development. Borum PR. Fatty acids are an important fuel source for neonates. The utilization of long chain fatty acids as a fuel source is dependent upon adequate concentrations of carnitine. Carnitine also has functions in other physiological processes critical to the survival of the neonate such as lipolysis, thermogenesis, ketogenesis, and possibly regulation of certain aspects of nitrogen metabolism. Plasma and tissue carnitine concentrations in neonates are depressed compared with those of older individuals. The capability for carnitine biosynthesis is much less in the neonate than in the adult. Human milk contains carnitine and appears to be the major source of carnitine to meet the neonate's metabolic needs. However, total parenteral nutrition solutions and soy-based infant formulas contain no carnitine. Evidence is accumulating that all infant diets may need to supply carnitine to meet the neonate's metabolic needs. PMID: 3899343 [PubMed - indexed for MEDLINE] 6939. Seikagaku. 1985 May;57(5):388-92. [New physiological function of the growth hormone]. [Article in Japanese] Morikawa M. PMID: 3897407 [PubMed - indexed for MEDLINE] 6940. Sports Med. 1985 May-Jun;2(3):223-33. The effects of exercise-training on energy balance and adipose tissue morphology and metabolism. Tremblay A, Després JP, Bouchard C. The effects of exercise training on energy expenditure, energy intake, fat cell size and adipose tissue lipolysis have been reviewed. Individuals engaged in regular and intense training programmes, e.g. long distance runners, seem to exhibit an elevated resting metabolic rate but moderate training is not accompanied by any important change. Diet-induced thermogenesis is a significant component of daily energy expenditure. It is still unclear whether or not exercise or training causes significant alteration in the thermic response to food intake. Energy expenditure associated with physical activity can play a meaningful role in body composition and adipose tissue metabolism. Largest weight losses have been achieved with programmes of long duration, presumably without marked compensation in food intake. However, it has been shown repeatedly that an increase in energy expenditure with exercise training tends to be associated with an elevation in food intake in free-living individuals. Weight loss is concomitant with a reduction in fat cell diameter and, when caused by an exercise training programme, it is generally accompanied by an increase in fat cell lipolytic activities. There are clear indications that weight loss induced by exercise training has a much higher fat content than weight loss caused by dieting. In addition, data suggest that exercise training may result in a greater depletion of fat stores than a low calorie diet, thus delaying the advent of the resistance phase to fat loss. Data on human subjects derived from well controlled energy balance and metabolic experiments are needed to further advance our understanding about the effects of exercise training on the adipose tissue. PMID: 3892629 [PubMed - indexed for MEDLINE] 6941. Environ Health Perspect. 1985 May;60:127-31. Utilization of adipose tissue biopsy in characterizing human halogenated hydrocarbon exposure. Anderson HA. Halogenated hydrocarbons have been successfully utilized for pest control in agriculture and public health. In industry, the polychlorinated biphenyls (PCBs) have been particularly useful. Unfortunately, residues have proven persistent and have been found widely dispersed in the environment. Because they have chemical properties that favor bioaccumulation, it is not surprising that many have been identified in animals and man. Such findings prompted public health concern and initiated review of potential adverse health impacts. In many instances this process has led to total prohibition of use or strict limitations. Highly lipophilic, the primary accumulation site in humans is adipose tissue. Analysis of adipose samples remains the preferred biologic index for estimating exposure. Improved instrumentation has lowered the limit of detection and improved the accuracy of quantification. Accumulated population experience has helped develop understanding of the dynamics of tissue partitioning in humans. Once such relationships have been adequately described, other less invasive procedures may be more confidently used for general surveillance purposes. Whenever adipose tissue is obtained, the blood compartment should also be sampled and the relationship reported. We have only begun to investigate the resulting partition ratio as an investigative tool. PMCID: PMC1568547 PMID: 2992921 [PubMed - indexed for MEDLINE] 6942. Hautarzt. 1985 May;36(5):259-64. [The importance of adrenergic receptors for dermatology]. [Article in German] Raff M, Neumann R. Receptor research is a rather new but most promising field of research. This review summarizes the data available on the adrenergic receptors. in addition, information is provided about the important function of these membrane receptors as control or modulator of dermatophysiology and dermatopathy. PMID: 2989219 [PubMed - indexed for MEDLINE] 6943. Can J Physiol Pharmacol. 1985 May;63(5):546-56. Role of diet fat in subcellular structure and function. Clandinin MT, Field CJ, Hargreaves K, Morson L, Zsigmond E. Current concepts of the biomembrane will be extrapolated to membranes of homeotherms to illustrate the influence of the nature of dietary lipid in nutritionally complete diets on membrane polar head group content and fatty acid composition. Utilizing animal models, the controlling influence of dietary long chain fatty acids on major lipid constituents of the mitochondrial membrane in cardiac tissue, the plasma membrane of liver, and the synaptosomal membrane in brain can be demonstrated. Diet-induced alterations in membrane composition are associated with demonstrable changes in the function of specific membrane proteins. To illustrate this relationship, the effect of diet on mitochondrial ATPase activity and on a hormone receptor-stimulated function in the plasma membrane of the liver will be discussed. These observations suggest that the diet fat modulates enzyme functions in vivo by changing the surrounding lipid environment in the membrane. PMID: 2931167 [PubMed - indexed for MEDLINE] 6944. Am J Cardiol. 1985 Apr 26;55(10):95D-100D. Effect of beta-adrenergic blockade on biochemical and metabolic response to exercise. Opie LH. During normal exercise the myocardium, skeletal muscle, liver and adipose tissue all participate in the metabolic response to exercise. Beta-blockade, by impairing this biochemical-metabolic response at several levels, limits the capacity for maximal exercise. The relevant effects of beta blockade may include hypoglycemia, impaired mobilization of free fatty acids and decreased breakdown of glycogen in skeletal muscle. The organs responsible for these metabolic changes are the liver (blood sugar), adipose tissue (blood free fatty acids) and skeletal muscle. Most of the metabolic beta-adrenergic receptors are thought to be beta 2 in nature. Two populations of receptors (mixed beta 1 and beta 2) may explain some controversial findings. Overall, the data suggest that cardioselective agents may have less effect than nonselective agents in producing metabolic impairment during sustained exercise. PMID: 2859797 [PubMed - indexed for MEDLINE] 6945. Am J Cardiol. 1985 Apr 26;55(10):48D-58D. Metabolic adaptations to exercise: a review of potential beta-adrenoceptor antagonist effects. Karlsson J. Human skeletal muscle contains 2 muscle fiber types: slow twitch (type I) and fast twitch (type II). They have different profiles including their biochemical, metabolic, O2 diffusion, microcirculatory and neuromotor characteristics. The slow twitch fiber represents endurance, high combustive potential and recruitment during moderate activity; in contrast, the fast twitch represents explosiveness, force, high capacity for phosphate splitting and lactate formation, but is more fatiguable. A muscle rich in slow twitch fibers is confined to low peripheral resistance at rest and during exercise, higher exercise leg blood flow and higher maximal oxygen uptake (VO2 max). During graded exercise lactate has been shown to be a good marker for the metabolic and circulatory characteristics of the contracting muscle and the exercise intensity (W) eliciting a blood lactate concentration of 4 mmol/liter-1 [(WOBLA) from onset of blood lactate accumulation] integrated for peripheral metabolic, neuromotor and central circulatory potentials both in health and disease. It is well known that a blood lactate level greater than 4 mmol/liter-1 represents a major increase in sympathetic tone and is incompatible with endurance or prolonged exercise. With prolonged exercise and sympathetic regulation both circulation and metabolism adapt. Adipose tissue is stimulated and fatty acids are released. Muscle tissue lipoprotein lipase activity is enhanced; that is, there is increased utilization of blood triglycerides for local lipolysis in the capillary bed of the contracting muscle. Both mechanisms will increase fatty acid availability and induce a "glycogen-sparing effect" resulting in a reduced respiratory exchange ratio. Studies have shown that both the magnitude of the initial glycogen stores and these adaptive responses will determine performance time. With age, changes take place in heart rate regulation, neuromotor control and muscle fibers. Thus VO2 max is decreased, but partly compensated for by a fast motor unit and fiber loss leading to a muscle more rich in slow twitch fibers--an "endurance training-like effect." Relative endurance is also increased with age; however, lactate metabolism is still a critical feature. The OBLA concept describes capacity for both occupational and leisure-time physical activity. PMID: 2859796 [PubMed - indexed for MEDLINE] 6946. Fed Proc. 1985 Apr;44(7):2369-73. How important are carnitine and ketones for the newborn infant? Hahn P, Novak M. The newborn oxidizes a large amount of fat. This is reflected in the slow rise of plasma levels of ketones and of total carnitines and acylcarnitines. Feeding a diet devoid of carnitine (soy-based formulas, total parenteral nutrition [TPN] ) rapidly results in a fall in plasma total carnitine levels, whereas in the adult such a fall is observed only after a prolonged time of TPN. This suggests that carnitine synthesis in the newborn is less efficient than in the adult. Gluteal adipocytes in the newborn show a rise in carnitine content and in the activity of carnitine transferases soon after birth, when values are higher than in the adult. Their respiration, lipolysis, and triglyceride formation are enhanced by L-carnitine and inhibited by D-carnitine. This is not so in the adult. Addition of L-carnitine to soybean-based formulas decreases plasma triglyceride and free fatty acid levels in premature infants, who have lower carnitine levels at birth than full-term babies. In pregnant women plasma total carnitine levels are significantly depressed. maternal urinary excretion of total carnitine decreases as gestational age increases, and less is also found in amniotic fluid. Plasma levels of total carnitines and acylcarnitine are the same (or higher) in fetal as in maternal plasma. It is concluded that carnitine may be of particular importance to the neonate and that adding it to foods lacking this substance may be advantageous. PMID: 3884394 [PubMed - indexed for MEDLINE] 6947. Fed Proc. 1985 Apr;44(7):2347-51. Ketone body metabolism in the mother and fetus. Shambaugh GE 3rd. Pregnancy is characterized by a rapid accumulation of lipid stores during the first half of gestation and a utilization of these stores during the latter half of gestation. Lipogenesis results from dietary intake, an exaggerated insulin response, and an intensified inhibition of glucagon release. Increasing levels of placental lactogen and a heightened response of adipose tissue to additional lipolytic hormones balance lipogenesis in the fed state. Maternal starvation in late gestation lowers insulin, and lipolysis supervenes. The continued glucose drain by the conceptus aids in converting the maternal liver to a ketogenic organ, and ketone bodies produced from incoming fatty acids are not only utilized by the mother but cross the placenta where they are utilized in several ways by the fetus: as a fuel in lieu of glucose; as an inhibitor of glucose and lactate oxidation with sparing of glucose for biosynthetic disposition; and for inhibition of branched-chain ketoacid oxidation, thereby maximizing formation of their parent amino acids. Ketone bodies are widely incorporated into several classes of lipids including structural lipids as well as lipids for energy stores in fetal tissues, and may inhibit protein catabolism. Finally, it has recently been shown that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal rat brain slices. Thus during maternal starvation ketone bodies may maximize chances for survival both in utero and during neonatal life by restraining cell replication and sustaining protein and lipid stores in fetal tissues. PMID: 3884390 [PubMed - indexed for MEDLINE] 6948. Diagn Cytopathol. 1985 Apr-Jun;1(2):91-104. Cytopathology of mesenchymal repair. James LP. Tissue repair is a common biologic process closely associated with the inflammatory response. The cytologic features of regeneration and repair of epithelial surfaces have been intensely studied and documented. Regeneration and repair occur in mesenchymal tissues and their radiographic and cytologic findings may closely simulate malignancy. This paper reviews the cytologic features of mesenchymal repair as seen in 44 aspiration biopsy specimens of bone, skeletal muscle, fibroadipose tissue, and fibrous connective tissue. In general, cytologic specimens from such lesions display variable but often scanty cellularity, prominent cellular heterogeneity with a spectrum of atypical features, an admixture of reactive fibroblasts, and evidence of a coexisting inflammatory reaction. Careful attention to cytologic detail and review of clinical and radiographic findings are mandatory in the evaluation of these specimens. PMID: 3836082 [PubMed - indexed for MEDLINE] 6949. Usp Fiziol Nauk. 1985 Apr-Jun;16(2):33-60. [Metabolic effect of neurohypophyseal hormones]. [Article in Russian] Abel'son IuO. PMID: 2990118 [PubMed - indexed for MEDLINE] 6950. Curr Probl Pediatr. 1985 Feb;15(2):1-47. Continuities and changes in fatness from infancy through adulthood. Garn SM. PMID: 3888537 [PubMed - indexed for MEDLINE] 6951. J Endocrinol Invest. 1985 Feb;8(1):77-87. Insulin receptor- and nonreceptor-controlled cellular substrate processing. A review of clinical studies in the isolated human adipocyte model. Pedersen O. PMID: 3886773 [PubMed - indexed for MEDLINE] 6952. Fed Proc. 1985 Feb;44(2):358-63. Metabolism of substrates: diet, lipoprotein metabolism, and exercise. Wood PD, Terry RB, Haskell WL. The major classes of serum lipoproteins have been shown to be differentially affected not only by dietary factors but also by levels of physical activity. Individuals engaging in relatively higher amounts of physical activity tend to have lower levels of low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein cholesterol (VLDL-C) and higher levels of high-density lipoprotein cholesterol (HDL-C) than their sedentary counterparts. However, higher levels of physical activity are also associated with lower adiposity and elevated caloric intake, two factors that themselves have independent roles in the regulation of lipoprotein levels. Changes in adiposity appear to be responsible for some, but not all, of the lipoprotein change associated with exercise. A study in which 14 sedentary, middle-aged men engaged in a progressive running program over 2 years showed increased HDL-C and decreased LDL-C, both considered antiatherogenic. Adiposity, expressed as percent body fat, decreased during the study whereas caloric intake, notably in the form of carbohydrates, increased. Elevated physical activity levels alter the relationships among adiposity, dietary intake, and lipoproteins that prevail in the sedentary state. PMID: 3881291 [PubMed - indexed for MEDLINE] 6953. Environ Health Perspect. 1985 Feb;59:121-8. Mechanism of action of toxic halogenated aromatics. Vickers AE, Sloop TC, Lucier GW. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons are a highly toxic class of environmental contaminants, as evidenced by numerous cases of accidental poisonings of human and animal populations and their extreme toxic potency in laboratory animals. The proposed model for the mechanism of action of TCDD and related compounds is analogous to that of the steroid hormones, which modulate gene expression through a receptor mechanism. In the steroid receptor model, the compound enters the cell cytoplasm where it acts as a specific ligand, binding selectively to a high affinity receptor protein. Bound to the appropriate ligand, the receptor concentrates in the nucleus where its increased association with chromatin leads to altered gene expression. This model has been useful in characterizing the Ah receptor; however, it does not provide a unifying hypothesis for all biochemical and toxic effects associated with exposure to halogenated aromatic hydrocarbons. Several findings suggest that a primary factor in determining TCDD toxicity might be tissue and species specific factors that control the actions of Ah receptor(s) in target tissues. Furthermore, numerous mechanisms might be involved. Clarifying the mechanism(s) for TCDD toxicity would enhance our ability to predict human health consequences to toxic halogenated aromatic hydrocarbons and would provide a more rational basis for risk analysis. PMCID: PMC1568090 PMID: 2985378 [PubMed - indexed for MEDLINE] 6954. Comp Biochem Physiol A Comp Physiol. 1985;82(4):745-51. Biological distribution and significance of brown adipose tissue. Rothwell NJ(1), Stock MJ. Author information: (1)Department of Physiology, St. George's Hospital Medical School, Tooting, London. 1. The structure, location, identification and thermogenic function of brown adipose tissue is discussed before describing its distribution in animals. 2. With a few interesting exceptions, brown fat occurs almost exclusively in mammals. 3. This tissue has been positively identified in thirteen orders, but more thorough investigations are required before its absence can be confirmed in the remaining eight mammalian orders. 4. Factors influencing the amount and activity of brown fat seen between and within species are numerous, but some of the most important are body size, diet, environmental temperature, age and reproductive state. 5. The role brown fat, and the effects of impairments in its function, are described in relation to thermoregulation and the control of energy balance and body composition. PMID: 14570080 [PubMed - indexed for MEDLINE] 6955. Essays Biochem. 1985;20:110-64. The biochemistry of an inefficient tissue: brown adipose tissue. Cannon B, Nedergaard J. PMID: 3928372 [PubMed - indexed for MEDLINE] 6956. Annu Rev Nutr. 1985;5:411-33. Regulation of energy balance. Woo R, Daniels-Kush R, Horton ES. PMID: 3927949 [PubMed - indexed for MEDLINE] 6957. Acta Chir Scand Suppl. 1985;522:195-209. Parenteral nutrition in trauma: glucose and lipids. Nordenström J. PMID: 3925668 [PubMed - indexed for MEDLINE] 6958. Neth J Med. 1985;28(2):59-62. Diabetes mellitus and insulin receptors. Krans HM. PMID: 3919324 [PubMed - indexed for MEDLINE] 6959. Prog Lipid Res. 1985;24(4):325-46. Autoradiographic studies with fatty acids and some other lipids: a review. Becker W, Bruce A. In this review, we have mainly included studies in which whole-body autoradiography was used. In lipid research, most studies have been done with fatty acids. These studies showed some common characteristics in the pattern of tissue distribution. A major uptake was seen in the brown fat, liver and adrenal cortex but also to some extent in other tissues with a high metabolic activity or high cell turn-over, e.g. the gastric and intestinal mucosa, diaphragm, kidney cortex and bone marrow. Low levels of radioactivity were generally found in the brain, testes, thymus, white fat, skeletal muscles, lungs and spleen. Most fatty acids showed some specific features, e.g the strong uptake of erucic, arachidonic and docosahexaenoic acid in myocardium and of eicosapentaenoic acid in the adrenal cortex. Studies with PGE1 and LTC3 showed that the liver and kidney and to a lesser degree the lungs were the major sites of metabolism. The distribution of free cholesterol and triolein emulsion labelled in the fatty acid moieties did show some similarities with respect to the general pattern found with most fatty acids. Specific for cholesterol was a very strong uptake in the adrenal cortex. There was also a significant uptake in the spleen whereas the uptake in the brown fat was not as marked as for most fatty acids. Specific for triolein was a marked uptake in the spleen and myocardium, in fed animals also in the white adipose tissue. These studies show that whole-body autoradiography can give much valuable information of the uptake and distribution of lipids that would be rather difficult to obtain with conventional methods. Combined with electron-microscopy, autoradiography can be used to study cellular and even subcellular distribution, and thus given further data on the metabolism of lipids in the body. PMID: 3916594 [PubMed - indexed for MEDLINE] 6960. Prog Lipid Res. 1985;24(3):197-241. Why fatty acids flow in cell membranes. Scow RO, Blanchette-Mackie EJ. PMID: 3916240 [PubMed - indexed for MEDLINE] 6961. Biochem Soc Symp. 1985;50:127-49. Integral membrane protein translocations in the mechanism of insulin action. Cushman SW, Simpson IA. The subcellular distributions of insulin and insulin-like growth factor type II (IGF-II) receptors, and glucose transporters, have been examined in basal and insulin-stimulated rat adipose cells. Plasma membranes (PM), high-density microsomes (HDM) and low-density microsomes (LDM) were prepared by differential ultracentrifugation. Insulin receptors were quantified by 125I-insulin binding or lactoperoxidase 125I-iodination and immunoprecipitation, IGF-II receptors by 125I-IGF-II binding, and glucose transporters by specific D-glucose-inhibitable [3H]cytochalasin B binding. In the basal state, more than 90% of the cells' insulin receptors are localized to PM, and approximately 90% of the cells' glucose transporters and IGF-II receptors are associated with LDM. In the maximally insulin-stimulated state, the number of insulin receptors in PM is decreased by approximately 30%, of which approximately half are recovered in LDM and the remainder in HDM in an inverted configuration. Concomitantly, the numbers of glucose transporters and IGF-II receptors in LDM are decreased by approximately 60% and approximately 22%, respectively, with stoichiometric numbers appearing in PM. All three redistribution processes are rapid (t1(2) = 2-3 min), achieving new steady states in 5-10 min. The redistributions of glucose transporters and IGF-II receptors are half-maximal at approximately 0.1 nM-insulin, whereas insulin receptor redistribution correlates with receptor occupancy (1/2max approximately equal to 3 nM). Thus, insulin stimulates the rapid and simultaneous subcellular translocations of its own receptors and, in the opposite direction, IGF-II receptors and glucose transporters. PMID: 3915867 [PubMed - indexed for MEDLINE] 6962. Diabetes Metab Rev. 1985;1(3):261-91. Neuro-endocrine disorders seen as triggers of the triad: obesity--insulin resistance--abnormal glucose tolerance. Jeanrenaud B, Halimi S, van de Werve G. PMID: 3915255 [PubMed - indexed for MEDLINE] 6963. Diabetes Metab Rev. 1985;1(3):203-27. Subcellular translocation of glucose transporters: role in insulin action and its perturbation in altered metabolic states. Kahn BB, Cushman SW. In this article we have described the hypothesis that insulin stimulates glucose transport through glucose transporter translocation from an intracellular pool to the plasma membrane. In addition, we have shown that changes in the numbers and subcellular distributions of glucose transporters correlate with alterations in insulin-stimulated glucose transport activity in several experimental models of insulin resistance and hyperresponsiveness. However, in experiments with counterregulatory hormones and with hyperresponsive states induced by nutritional repletion following deprivation, changes in insulin responsiveness cannot be fully explained by such alterations in the numbers and/or subcellular distribution of glucose transporters. Thus, evidence has been presented for changes in glucose transporter intrinsic activity that both inhibit and augment insulin-stimulated glucose transport rates. Finally, we have discussed data suggesting that the translocation process is applicable to human tissue and that significant changes in adipose cell glucose transport activity have been correlated with total glucose disposal in various metabolic states in humans. Determining the physiologic factors involved in modulating these events at the cellular level is an important area for further investigation. PMID: 3915254 [PubMed - indexed for MEDLINE] 6964. Diabetes Metab Rev. 1985;1(1-2):99-117. Insulin action at the cellular level: anatomical considerations. Gorden P, Carpentier JL, Orci L. PMID: 3915253 [PubMed - indexed for MEDLINE] 6965. Diabetes Metab Rev. 1985;1(1-2):59-97. Post binding events in insulin action. Horuk R, Olefsky JM. PMID: 3915252 [PubMed - indexed for MEDLINE] 6966. Spec Top Endocrinol Metab. 1985;7:237-66. Hypothalamic hypogonadism. Bhasin S, Swerdloff RS. The reproductive system consists of a series of feedback loops involving the higher centers, the hypothalamus, the pituitary, and the gonads. The factors involved in physiologic restraint of the hypothalamic pituitary gonadal axis until the time of puberty are complex. The pattern (frequency and amplitude) of GnRH signal is important in regulating pituitary LH and FSH secretion. This signal can be amplified and modulated at the pituitary level at least in part by the sex steroids. Hypothalamic hypogonadism can be considered a disorder of the hypothalamic GnRH pulse generator that results in deficient or dysrhythmic GnRH release. The mechanisms underlying the abnormal GnRH release in acquired, functional disorders such as anorexia nervosa and amenorrhea of joggers remain controversial. Evaluation of patients with hypothalamic hypogonadism involves exclusion of hyperprolactinemia, space-occupying lesions, and other systemic disorders. The pulsatile administration of GnRH for induction of fertility represents a major advance in the treatment of these patients. PMID: 3914097 [PubMed - indexed for MEDLINE] 6967. Nihon Seirigaku Zasshi. 1985;47(12):735-45. [Nervous regulation of the metabolism]. [Article in Japanese] Niijima A. PMID: 3913764 [PubMed - indexed for MEDLINE] 6968. Rev Epidemiol Sante Publique. 1985;33(4-5):312-23. [Markers of the dietary supply of fatty acids. Their use in epidemiologic surveys]. [Article in French] Avons P. The use of tissular markers of dietary fatty acids is based on the potential usefulness of a cellular or membrane witness of usual food intake. Prevalence studies among populations and prospective trials on a change of dietary habits allow a definition of the relationship between dietary fatty acids and adipose ones, according to time, sampling site and the stability of fatty acid pool. The physiological parameters of that relationship are weight changes, age, energy balance, tobacco and probably alcohol consumptions and race. The relationship between dietary fatty acids and fatty acids within serum lipids, erythrocytes, certain epithelial cells and platelets are described and validity of these relationships pointed out. A few examples illustrate potential use of fatty acid markers in investigating risk factors of chronic diseases and in checking adherence to regimen in dietary trials. PMID: 3912865 [PubMed - indexed for MEDLINE] 6969. Neurosci Biobehav Rev. 1985 Winter;9(4):599-612. Photoperiodic control of seasonal body weight cycles in hamsters. Bartness TJ, Wade GN. Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus sungorus) hamsters exhibit seasonal changes in body weight mainly by altering their carcass lipid stores. These seasonal changes are triggered largely by the photoperiod. Although both species exhibit gonadal regression when exposed to short photoperiods ("winterlike") daylength), they show opposite body weight changes. Syrian hamsters gain weight, but Siberian hamsters lose weight following short photoperiod exposure. Syrian hamsters prepare for overwintering by increasing energy stored as carcass lipid. In contrast, Siberian hamsters decrease their metabolic mass and therefore require lower energy intake for energy maintenance. In Syrian, and perhaps Siberian hamsters the short day-induced weight changes are exaggerated by high fat diets. Both species show photoperiod-induced changes in body weight without changing their food intake, suggesting a metabolic basis for these effects. In Syrian hamsters, the obesity is not secondary to gonadal regression, whereas in Siberian hamsters, the decrease in body weight is independent of the gonads for males but may be dependent upon the gonads in females. The pineal gland and its hormone, melatonin, are important transducers of photoperiodic signals in hamsters. This is certainly true for Siberian hamsters, in which pinealectomy blocks the short day-induced body weight loss. In contrast, pinealectomy has little effect on short day-induced weight gain in Syrian hamsters. Nevertheless, in both species, the body weight and gonadal changes induced by short day exposure are mimicked by systemic administration of melatonin in long day-housed animals. Thus, for these two hamster species, the same hormone, melatonin, produces opposite effects on body weight but does so by affecting the same carcass component. The target sites of action for the effects of melatonin on body weight change, energy metabolism, and reproductive status are not known. However, the suprachiasmatic and paraventricular nuclei of the hypothalamus are potentially important sites of action. The target site(s) and mechanism(s) of action for the pineal/melatonin-independent effect of photoperiod on body weight in Syrian hamsters are also unknown. This photoperiodic response is highly unusual among mammals in that it is not pineal-dependent. Studies of the mechanisms underlying these body weight changes in Syrian and Siberian hamsters may provide fundamental knowledge about how environmental influences affect obesity and they may also provide insight into the various strategies for overwintering shaped by natural selection.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3909016 [PubMed - indexed for MEDLINE] 6970. Differentiation. 1985;29(3):195-8. A dual effector theory of growth-hormone action. Green H, Morikawa M, Nixon T. Growth hormone increases tissue formation by acting both directly and indirectly on target cells. The direct action promotes the differentiation of precursor cells; this has been demonstrated for two mesenchymal cell types. Insulin-like growth factor I (IGF-I) is not able to substitute for growth hormone in promoting this differentiation, but it is proposed that its mitogenic action selectively promotes cell multiplication in young differentiated clones. As tissue growth results from both the creation of new differentiated cells and their subsequent clonal expansion, both effectors increase tissue growth, but by different means. PMID: 3908201 [PubMed - indexed for MEDLINE] 6971. Endocr Rev. 1985 Fall;6(4):590-607. Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states. Heimberg M, Olubadewo JO, Wilcox HG. This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease. PMID: 3908084 [PubMed - indexed for MEDLINE] 6972. Int J Obes. 1985;9 Suppl 2:9-15. Factors influencing brown fat and the capacity for diet-induced thermogenesis. Stock MJ, Rothwell NJ. The experimental evidence for the existence and importance of diet-induced thermogenesis in laboratory rodents is reviewed, and the influence of various factors (e.g. age, genetic background, diet composition and early environment) discussed. The physiological, pharmacological and biochemical data implicating sympathetic activation of brown fat as the principal source of diet-induced thermogenesis are described, and followed by a review of the neurohumoral influences (e.g. dopamine, histamine, insulin, thyroid and adrenal steroids) on thermogenesis and brown fat activity. The possible relevance of these animal studies to human metabolism is discussed briefly. PMID: 3905656 [PubMed - indexed for MEDLINE] 6973. Int J Obes. 1985;9 Suppl 1:145-8. Regional differences in adipocyte metabolism and possible consequences in vivo. Smith U. Recent studies have shown that adipose tissue metabolism varies in different regions. Thus, hormonal responsiveness and sensitivity to both lipolytic and anti-lipolytic agent is increased in abdominal as compared to femoral cells. Abdominal obesity is also associated with greater aberrations in metabolism than peripheral obesity. The increased lipolytic response in abdominal fat cells may lead to higher FFA concentrations, which may attenuate both glucose uptake and insulin clearance by the liver. PMID: 3905644 [PubMed - indexed for MEDLINE] 6974. Biol Neonate. 1985;48(4):237-44. The role of lactate as an energy substrate for the brain during the early neonatal period. Medina JM. The role played by lactate as an energy substrate for the newborn rat during the early neonatal period was studied. Plasma lactate is mostly removed within the first 2 h after delivery, i.e. during the presuckling period. Lactate removal was enhanced by hyperoxia but strongly inhibited by hypoxia, showing a direct correlation with blood oxygen concentrations. Lactate was not converted into glucose during the presuckling period, gluconeogenesis being insignificant in these circumstances; instead it was rapidly oxidized through the tricarboxylic acid cycle. Likewise, lactate was significantly oxidized by brain slices from newborns at birth. At physiological concentrations, lactate oxidation by brain slices was 10- and 3-fold higher than that of glucose and 3-hydroxybutyrate, respectively. In the same circumstances, lipogenesis de novo from lactate was 2- and 5-fold higher than from glucose and 3-hydroxybutyrate, respectively. The results suggest that lactate is the main metabolic fuel for the brain during the early neonatal period. PMID: 3904842 [PubMed - indexed for MEDLINE] 6975. J Perinat Med. 1985;13(3):107-16. Carnitine in human perinatal fat metabolism. Schmidt-Sommerfeld E, Penn D, Novak M, Wolf H. PMID: 3897503 [PubMed - indexed for MEDLINE] 6976. Ann Clin Res. 1985;17(1):3-9. Obesity and the risk of cardiovascular disease. Björntorp P. The original notion that obesity is associated with disease and premature death was obtained from insurance statistics, which have been rightfully criticized for representing selected populations. In prospective, epidemiological studies a long period of observation on a large number of subjects is needed before obesity can be recognized as a risk factor for cardiovascular disease in spite of the fact that well-known risk factors for such disease are prevalent in obesity populations. This apparent paradox may be explained by the possibility that the risk of getting cardiovascular disease is present mainly in a subgroup of the total obese population. Such a subgroup might be characterized by the distribution of adipose tissue. Indeed abdominal obesity has been demonstrated consistently to be strongly associated with risk factors for cardiovascular disease in cross-sectional investigations of older and more recent dates. Several prospective longitudinal, epidemiological studies in both men and women have shown that abdominal obesity is associated with an increased risk of getting ischemic heart disease, stroke and death, independent of the total degree of obesity. The findings from these recent prospective studies, supported by previous unanimous cross-sectional studies as well as the fact that reasonable potential explanations for the statistical associations have been suggested, now seem to allow the conclusion that abdominal obesity should even be treated when present to a very limited extent. In such subjects, exclusion of conditions complicating obesity should also be performed vigorously. Abdominal obesity can be diagnosed by very simple means: measuring the abdominal circumference in relation to hip circumference.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3893310 [PubMed - indexed for MEDLINE] 6977. Seikagaku. 1985 Jan;57(1):36-47. [Mechanisms involved in metabolic responses to cold exposure]. [Article in Japanese] Shiota M, Sugano T. PMID: 3889179 [PubMed - indexed for MEDLINE] 6978. Annu Rev Physiol. 1985;47:503-17. The glucose transporter of mammalian cells. Wheeler TJ, Hinkle PC. The glucose transporter is now identified but may have modifications or other subunits that control its activity. The kinetics and inhibitor binding studies are consistent with the carrier model with different degrees of asymmetry and a single binding site that varies in specificity depending on the conformation of the protein. The physical structure could actually be quite different from the usual diagrams (rocking bananas), however, and could function as a monomer or higher oligomer. The binding site, or filter, that gives specificity could be in the middle as usually depicted; alternatively it could be entirely on the cytoplasmic side, where the protein is trypsin sensitive, and hydrophobic helices could span the membrane forming a simple channel. Possible restrictions on structures in the membrane from the hydrophobic nature of transmembrane segments of membrane proteins (62) may favor a globular domain outside the membrane as the binding site. Such speculations will have to await more structural information about the transporter. PMID: 3888079 [PubMed - indexed for MEDLINE] 6979. Annu Rev Physiol. 1985;47:483-99. Mode of action of pituitary growth hormone on target cells. Isaksson OG, Edén S, Jansson JO. Normal postnatal somatic growth becomes progressively dependent on GH with time. In contrast to other hormones, GH is the only hormone known to produce a dose-dependent stimulation of postnatal growth. Most of the effects attributed to GH action appear to be the result of a direct effect of GH on cells in different peripheral tissues, including cartilage. In addition to the growth-stimulating effect, GH has the intrinsic properties of being able to exert both insulin-like and insulin-antagonistic effects in adipose tissue and skeletal muscle. These two apparently antagonistic effects seem to be explained by the stage of responsiveness of the target cells to GH, which is determined by the previous influence of endogenous GH. An inhibition of adenylate cyclase with a concomitant decrease in intracellular cAMP might be an important early cellular event in the course of GH action, but it is not known whether or how this change in nucleotide metabolism relates to the various expressed effects of the hormone. The recognition that GH directly interacts with chondrocytes in cartilage suggests that alterations in the concentration of circulating somatomedins cannot be the only factor regulating skeletal growth. The recent discovery by Green and coworkers (42) demonstrating that GH specifically stimulates the differentiation of cloned preadipose cells and myoblasts in tissue culture may be a major breakthrough in the understanding of the mechanism of action of the growth-promoting effect of GH. Green (42) has proposed that GH directly stimulates terminal differentiation of cells in many different tissues including epiphyseal plate cartilage. The finding that GH binds specifically to cells in the resting cell zone but not to differentiated chondrocytes in the growth plate suggests that prechondrocytes in the growth plate are the target cells for GH action. If it is correct that GH directly stimulates the differentiation of prechondrocytes, we suggest that, during the process of chondrocyte differentiation in the growth plate, the genes that code for growth factors of the somatomedin class, such as IGF-I, are expressed. As a consequence, the clonal expansion of the chondrocytes in the proliferative zone of the growth plate that occurs in vivo during the process of normal growth is the result of this local production of growth factors. PMID: 3888078 [PubMed - indexed for MEDLINE] 6980. Reprod Nutr Dev. 1985;25(1B):159-64. Cell surface changes during adipocyte differentiation in vitro. Cryer A. PMID: 3887523 [PubMed - indexed for MEDLINE] 6981. Reprod Nutr Dev. 1985;25(1B):153-8. [Lipoprotein lipase and adipocyte differentiation]. [Article in French] Ailhaud G, Amri E, Czerucka D, Forest C, Gaillard D, Grimaldi P, Négrel R, Vannier C. Some hormonal factors, possibly involved in the proliferation and differentiation of adipose precursor cells in vivo, have been characterized in vitro using different preadipocyte cell lines established from rodent adipose tissue. The process of adipose conversion has also been studied using these cell lines; in this process, stem cells (adipoblasts) were committed at any cell division during the growth phase. At confluence, committed cells (preadipocytes) underwent a limited number of mitoses and differentiated into adipose cells, whereas the uncommitted cells remained as stem cells in the cell population. This stochastic model could be extended to the development of rat adipose tissue in vivo. The study of adipose conversion showed the early emergence of lipoprotein lipase (LPL) and monoglyceride lipase (MGL). LPL activity appeared in the cells before any triglyceride accumulation. In contrast, this accumulation seemed dependent upon the emergence of glycerol-3-phosphate dehydrogenase. In vitro experiments clearly established that LPL-containing (differentiating) cells underwent postconfluent mitoses. This limited proliferation was in agreement with previous data obtained in vivo and indicates that only triglyceride-containing (mature) cells could not divide. PMID: 3887522 [PubMed - indexed for MEDLINE] 6982. No To Shinkei. 1985 Jan;37(1):19-29. [Physiology of the autonomic nervous system--nervous control of metabolic function]. [Article in Japanese] Niijima A. PMID: 3884024 [PubMed - indexed for MEDLINE] 6983. Sports Med. 1985 Jan-Feb;2(1):59-71. Adaptation to exercise in the cold. Shephard RJ. The winter athlete has several potential tactics for sustaining body temperature in the face of severe cold. An increase in the intensity of physical activity may be counter-productive because of increased respiratory heat loss, increased air or water movement over the body surface, and a pumping of air or water beneath the clothing. Shivering can generate heat at a rate of 10 to 15 kJ/min, but it impairs skilled performance, while the resultant glycogen usage hastens the onset of fatigue and mental confusion. Non-shivering thermogenesis could arise in either brown adipose tissue or white fat. Brown adipose tissue generates heat by the action of free fatty acids in uncoupling mitochondrial electron transport, and by noradrenaline-induced membrane depolarisation and sodium pumping. The existence of brown adipose tissue in human adults is controversial, and although there are theoretical mechanisms of heat production in white fat, their contribution to the maintenance of body temperature is small. Acclimatisation to cold develops over the course of about 10 days, and in humans the primary change is an insulative, hypothermic type of response; this reflects the intermittent nature of most occupational and athletic exposures to cold. Nevertheless, with more sustained exposure to cold air or water, humans can apparently develop the humoral type of acclimatisation described in small mammals, with an increased output of noradrenaline and/or thyroxine. The associated mobilisation of free fatty acids suggests the possibility of using winter sport as a pleasant method of treating obesity. In men, a combination of moderate exercise and facial cooling induces a substantial fat loss over a 1- to 2-week period, with an associated ketonuria, proteinuria, and increase of body mass. Possible factors contributing to this fat loss include: (a) a small energy deficit; (b) the energy cost of synthesising new lean tissue; (c) energy loss through the storage and excretion of ketone bodies; (d) catecholamine-induced 'futile' metabolic cycles with increased resting metabolism; and (e) a specific reaction to cold dehydration. Current limitations for the clinical application of such treatment include uncertainty regarding optimal environmental conditions, concern over possible pathological reactions to cold, and suggestions of a less satisfactory fat mobilisation in female patients. Possible interactions between physical fitness and metabolic reactions to cold remain controversial.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3883460 [PubMed - indexed for MEDLINE] 6984. Adv Nutr Res. 1985;7:187-201. Direct and indirect thermogenic effects of anorectic drugs. Levitsky DA, Strupp BJ. PMID: 3006454 [PubMed - indexed for MEDLINE] 6985. Ann N Y Acad Sci. 1985;456:279-88. Principles of carrier catalysis elucidated by comparing two similar membrane translocators from mitochondria, the ADP/ATP carrier and the uncoupling protein. Klingenberg M. PMID: 3004292 [PubMed - indexed for MEDLINE] 6986. Int J Obes. 1985;9 Suppl 1:117-27. Fat cell adrenoceptors: inter- and intraspecific differences and hormone regulation. Lafontan M, Berlan M, Carpene C. The present review summarizes recent data on fat cell adrenoceptors with the aim of clarifying the role played by catecholamines in the regulation of adipocyte metabolism. Part of the review is focused on the possible interest of animal models for the study of catecholamine-mediated effects in human fat cells. It is now clearly demonstrated that human, hamster, dog and rabbit fat cells possess three basic types of adrenoceptor: the beta 1-, alpha 2- and alpha 1-adrenoceptors identified in biological assays or binding studies with selected radioligands. The rat is an exception in the species commonly studied as catecholamines exert an exclusive lipolytic effect through beta-adrenoceptor stimulation, there are no alpha 2-adrenoceptors in rat white fat cells although an alpha 1-adrenoceptor does exist. In human fat cells, physiological amines are lipolytic or antilipolytic. Binding studies have revealed that alpha 2-adrenoceptors are three to four times more numerous than beta 1-adrenoceptors. Moreover physiological amines, in particular epinephrine, have a higher affinity for alpha 2-sites than for beta 1-sites. Dose-response studies of the effect of epinephrine on adenosine-deaminase or isoproterenol-stimulated fat-cells demonstrate an inhibitory effect of epinephrine on lipolysis promoted by stimulation of alpha 2-adrenoceptors which occurs before the commonly described beta 1-adrenergic effect which promotes stimulation of lipolysis. This aspect and its putative physiological interest is described and discussed. Intraspecific variations in adrenergic responses of adipocytes have been briefly analysed. The appearance and disappearance of alpha 2-adrenoceptors according to the extent of adipose tissue and increment of fat cell size are discussed. Variations of adrenergic responsiveness during fasting, calorie restriction or chronic stimulation of the adipocytes by physiological amines are also discussed. PMID: 2999011 [PubMed - indexed for MEDLINE] 6987. Biol Neonate. 1985;48(4):245-9. Contribution of brown fat to the neonatal thermogenesis. Benito M. Homeothermic animals must maintain their body temperatures within a very narrow range. Large homeotherms face problems with dissipation of metabolic heat: for small homeothermic animals heat losses at most environmental temperatures are far in excess of normal metabolic heat production. Accordingly, brown adipocytes exhibit in mammalians a very rapid process of morphological functional maturation perinatally. This thermogenesis occurred without electrical activity in the skeletal muscle and it is therefore termed 'nonshivering thermogenesis'. The anatomical site of nonshivering thermogenesis is mainly the brown adipose tissue in the small newborn mammals. In animals reared under thermoneutral conditions the tissue subsequently involutes and nonshivering thermogenic capacity is largely lost. Cold- and diet-induced adaptation may slow or prevent this involution. The decline in the extent of nonshivering thermogenesis during development at thermoneutral temperatures is reflected by an alteration in the bioenergetic properties of the isolated brown fat mitochondria. PMID: 2998493 [PubMed - indexed for MEDLINE] 6988. Annu Rev Nutr. 1985;5:69-94. Brown adipose tissue metabolism and thermogenesis. Himms-Hagen J. PMID: 2992550 [PubMed - indexed for MEDLINE] 6989. Annu Rev Physiol. 1985;47:469-82. The nature and regulation of the receptors for pituitary growth hormone. Hughes JP, Friesen HG. Recent developments have contributed greatly to our understanding of GH receptor structure and function; however, much remains to be done. One of the first priorities should be to elucidate the early events that follow activation of the GH receptor. The in vitro systems outlined in this review show promise in this regard; however, all three systems require further characterization. Future studies of the GH receptor in these and other systems will undoubtedly be facilitated by the monoclonal antibody generated against the GH receptor and by recently described cross-linking methodologies. Despite these recent advances, however, it is likely that detailed characterization of receptor structure and function awaits cloning of the GH-receptor gene(s). PMID: 2986539 [PubMed - indexed for MEDLINE] 6990. Annu Rev Physiol. 1985;47:425-42. The nature and regulation of the receptors for insulin-like growth factors. Rechler MM, Nissley SP. Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. The alpha subunit binds hormone; the beta subunit appears to have intrinsic tyrosine kinase activity and to be autophosphorylated. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. They have similar subunit structure. Both receptors bind IGFs and insulin. They have similar (but not identical) antigenic determinants. Both receptors are downregulated by IGFs and insulin. Both receptors are affected in certain patients with genetically determined insulin resistance. Type II IGF receptors do not appear to be homologous to type I receptors. They differ in structure, peptide binding specificity, and antigenic determinants. Type II receptors do not appear to be downregulated. Although type II receptors appear to be phosphorylated in intact cells, they do not possess intrinsic tyrosine protein-kinase activity. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways. PMID: 2986537 [PubMed - indexed for MEDLINE] 6991. Reprod Nutr Dev. 1985;25(1B):255-70. Lipoprotein lipase and the uptake of lipids by adipose cells during development. Cryer A. PMID: 2986250 [PubMed - indexed for MEDLINE] 6992. Diabetes Metab Rev. 1985;1(3):229-59. Intracellular mediators of insulin action. Gottschalk WK, Jarett L. PMID: 2873004 [PubMed - indexed for MEDLINE] 6993. Pharmacol Ther. 1985;27(2):143-66. Effects of interferon on differentiation of normal and tumor cells. Fisher PB, Grant S. As described in this review, both partially purified and recombinant interferons are potent modulators of differentiation in diverse cell culture systems (Table 2). Depending on the target cell, interferon exerts either an inhibitory or an inductive effect on cell differentiation. In certain myeloid leukemic cells, such as HL-60, interferon by itself is growth suppressive but does not induce cell maturation, whereas in combination with inducers of differentiation, such as DMSO, TPA or retinoic acid, interferon potentiates their ability to stimulate differentiation in both sensitive and resistant cell populations (Grant et al., 1982, 1983; Tomida et al., 1982). Interferon also interacts synergistically with phorbol ester tumor promoters in inhibiting melanogenesis in murine B-16 cells (Fisher et al., 1981a, 1984a) and adipocyte formation in 3T3 cells (Cioe et al., 1980), whereas the combination is synergistic in inducing differentiation in human melanoma cells (Fisher et al., 1984b,c). In contrast, interferon and TPA display antagonistic effects on differentiation in human skeletal muscle cultures, i.e. interferon induces and TPA inhibits myogenesis (Fisher et al., 1982, 1983). Recent studies have demonstrated the presence of high affinity saturable cell membrane receptors for mouse and human interferons (Aguet, 1980; Branca and Baglioni, 1981, 1982; Mogensen et al., 1981; Branca et al., 1982; Anderson et al., 1982; Joshi et al., 1982; Faltynek et al., 1983; Yonehara et al., 1983; Langer and Pestka, in preparation). Similarly, specific membrane receptors have been identified for phorbol esters and mezerein (Driedger and Blumberg, 1980; Shoyab and Todaro, 1980; Horowitz et al., 1981; Fisher et al., 1981b). These findings suggest that the plasma membrane may be a primary target for mediating the biochemical effects induced by both interferon and phorbol esters. Although the mechanism by which interferon and phorbol esters transmit the necessary membrane signal(s) required for altering differentiation are not known, a possible component of this transmembrane signaling process may involve changes in the physical dynamics of the plasma membrane. It is therefore of interest that both interferon and TPA induce early changes in the fluidity of the plasma membrane (Fisher et al., 1979, 1981b, 1984d; Castagna et al., 1979; Kuhry et al., 1983).(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 2412243 [PubMed - indexed for MEDLINE] 6994. J Cardiovasc Pharmacol. 1985;7 Suppl 2:S110-4. Effects of beta-blockers on plasma lipids during antihypertensive therapy. Lehtonen A. Several drugs used for antihypertensive therapy may interact with lipoprotein metabolism and may increase associated coronary risk levels. beta-Blocker monotherapy with selective or nonselective beta-blockers without intrinsic sympathomimetic activity (ISA) usually increases serum triglyceride and decreases high-density lipoprotein (HDL), especially HDL2 cholesterol concentration. With the exception of the nonselective beta-blocker sotalol, beta-blocker therapy has little influence on the serum total cholesterol or low-density lipoprotein (LDL) cholesterol concentrations. The magnitude of these changes in serum lipids did not distinctly differ between selective and nonselective beta-blockers. Two beta-blockers possessing ISA, acebutolol, and pindolol did not show the increase in serum triglycerides and in serum total cholesterol or LDL cholesterol. Acebutolol showed the nonsignificant decrease in HDL cholesterol level. Pindolol with marked ISA exhibited the most favorable lipid profile, increasing serum HDL cholesterol and the ratio of HDL cholesterol to total cholesterol. The concentration of apolipoprotein A-I increased slightly during pindolol therapy. beta-Blockers with the exception of pindolol decrease the concentration of serum free fatty acids. beta-blocker therapy has little influence on the adipose tissue lipoprotein lipase activity, but lecithin cholesterol acyltransferase activity may increase during pindolol therapy. PMID: 2409357 [PubMed - indexed for MEDLINE] 6995. N Engl J Med. 1984 Dec 13;311(24):1549-58. Thermogenesis in brown adipose tissue as an energy buffer. Implications for obesity. Himms-Hagen J. PMID: 6390200 [PubMed - indexed for MEDLINE] 6996. Psychiatr Clin North Am. 1984 Dec;7(4):845-61. Implications of dosing tricyclic antidepressants and benzodiazepines in geriatrics. Cutler NR, Narang PK. It is important to understand both the kinetic and the dynamic implications of dosing TCAs and BZs in the elderly, for whom these drugs are frequently prescribed. The TCAs are used to treat responsive signs and symptoms including such somatic complaints as chest pain, dizziness, and arthralgias, as well as the endogenous signs such as loss of appetite with associated weight loss, psychomotor retardation, loss of libido, and insomnia. The pharmacokinetic studies of TCAs such as desipramine and nortriptyline have shown few, if any, age-related changes. The dose required for responsivity is significantly reduced for both TCAs (desipramine and nortriptyline) in the elderly, which may suggest increased end-organ responsiveness. The major recommendations for treatment of depression with nortriptyline in the elderly are (1) to administer small doses in order to avoid side effects, and (2) to expect a longer response time for the antidepressant effect than in young and middle-aged depressed patients. Although the BZs are extensively prescribed in the elderly, primarily for insomnia and anxiety, the physiologic and biochemical changes of aging alter the kinetics and dynamics of these extensively metabolized and slowly eliminated drugs. Based on the kinetic data and information in Tables 1 and 2, the relatively sensitive elderly population should receive a reduced dosage. Careful evaluation of the patient and the kinetic profile of the agent employed will ensure safe use of these drugs. A clear understanding of anxiety and respect for the alterations in the pharmacokinetics and pharmacodynamics of these agents in the elderly will allow the physician to prescribe the BZs wisely. As with the TCAs, remember to administer doses of BZs that are reduced by 50 to 75 per cent of the usual recommended doses for young and middle-aged individuals and to increase dosage in small increments. Ultimately, sound, scientifically based, clinical judgment that considers the needs of the patient is the best guide for the selection of an appropriate BZ. PMID: 6441158 [PubMed - indexed for MEDLINE] 6997. Tanpakushitsu Kakusan Koso. 1984 Dec;29(14):1589-99. [The hypothalamus and metabolic regulation, especially hypothalamic regulation of lipid metabolism and its disorder]. [Article in Japanese] Shimazu T. PMID: 6398458 [PubMed - indexed for MEDLINE] 6998. J Anim Sci. 1984 Dec;59(6):1610-20. The influence of photoperiod on body weight gain, body composition, nutrient intake and hormone secretion. Tucker HA, Petitclerc D, Zinn SA. Increasing daily light exposure from 8 to 16 h increases average daily body weight gains of sheep and Holstein cattle but reduces gains of white-tailed doe fawns. Some of these effects on average daily gain in sheep are the result of increased gut fill and pelt weight. Increasing daily exposure to light increases feed intake when sheep or cattle are fed ad libitum. However, increased feed intake is not a prerequisite for the anabolic effects of long duration exposures to light because increased growth occurs in the animals given 16 h light:8 h dark (16L:8D) even when feed intake is restricted. The anabolic effects of increased duration photoperiods in sheep are independent of the gonads, whereas in cattle they are dependent on the gonads. Consistent increases in average daily gains of cattle in response to longer duration photoperiods have not always been achieved. The lack of consistency may be associated with sexual maturity or rate of fattening of the animal. For example, the stimulatory effects of 16L:8D photoperiods on live weight gain are not readily manifested in immature prepubertal heifers, but occur primarily during the peripubertal period. Short days are conducive to deposition of fat, which may account for the stimulatory effects of short days on live weight gain of white-tailed doe fawns and excessively fattened Holsteins. In contrast, long duration photoperiods stimulate protein accretion in cattle. The hormonal signals that mediate the anabolic effects of increasing exposure to light are not associated with change in insulin, thyroxine or growth hormone concentrations in the blood. Glucocorticoid concentrations in serum decrease with longer duration photoperiods which is consistent with an anabolic effect. Increasing daily light exposure to 16 h/d hastens the increase in concentrations of progesterone and testosterone in sera of peripubertal heifers and prepubertal bulls, respectively. Thus, change in secretion of reproductive hormones in the peripubertal period of cattle may be associated with the anabolic effects previously described and is consistent with gonad dependency. Prolactin concentrations in serum increase in sheep and cattle as duration of light exposure increases. But, there is no irrefutable proof that prolactin is responsible for the increased rates of gain or change in carcass composition associated with longer exposures to light. Thus, the hormonal mechanisms involved in photoperiod-induced alterations in growth remain to be established. PMID: 6396293 [PubMed - indexed for MEDLINE] 6999. Biol Psychol. 1984 Dec;19(3-4):305-26. Slow wave sleep, shallow torpor and hibernation: homologous states of diminished metabolism and body temperature. Berger RJ. Until recently, sleep and hibernation were not usually considered to be closely related states (e.g. Dement, 1967). However, two current lines of research point toward a system of relations between caloric intake, thermogenesis, metabolic rate and adiposity in the regulation of the energy balance of warm-blooded animals (endotherms). One line indicates that sleep, shallow torpor and hibernation are homologous energy conserving processes, lying on a continuum of decreasing metabolism and body temperature (Tb). The other line indicates that the metabolic reductions brought about by sleep, shallow torpor and hibernation are regulated in accordance with periodic ecological factors affecting energy intake and energy balance. PMID: 6395910 [PubMed - indexed for MEDLINE] 7000. Med Sci Sports Exerc. 1984 Dec;16(6):596-605. Research progress in validation of laboratory methods of assessing body composition. Lohman TG. This paper presents various laboratory methods designed to estimate body composition and documents some of the progress in their validation. In addition to the well-known methods of densitometry, hydrometry, and spectrometry (40K), many other methods will be reviewed briefly for their relation to body composition. Emphasis is given to validation principles which need to be followed if new methods are to be developed. The reliance of past research on the two-component model and reference man is reviewed, and the need for multicomponent approaches to the study of body composition is emphasized. Past research using the two-component approach has until recently led to lack of research in developing new methodologies, has limited the potential usefulness of various laboratory methods in estimating body composition in different populations, and has made the relation of body composition to health, performance, and exercise an inexact science. The application of several multicomponent approaches to the characterization of both fat-free body composition and body composition of various populations will lead to the development of reference bodies so essential for the advancement of the field. The estimation of body composition changes with exercise, growth, development, and aging and the relation of body composition to health and physical performance are important areas for future research using various multicomponent approaches. PMID: 6392814 [PubMed - indexed for MEDLINE] 7001. J Exp Zool. 1984 Dec;232(3):443-52. Growth hormone: its physiology and control. Scanes CG, Lauterio TJ. Growth hormone (GH) is a protein hormone produced by the somatotrophs of the anterior pituitary gland of birds and other vertebrates. The secretion of GH in birds is under hypothalamic control; it involves three peptidergic releasing factors: growth hormone-releasing factor (GRF) (stimulatory); thyrotropin-releasing hormone (TRH) (stimulatory); and somatostatin (SRIF) (inhibitory). In addition, there is evidence for effects of biogenic amines (including serotonin and norepinephrine) and prostaglandins at the level of the hypothalamus and possibly also the pituitary gland. In all avian species examined, plasma concentrations of GH are high in young posthatching chicks but low in the adult and embryo. The difference in plasma concentrations of GH between young and adult birds is due to both greater GH secretion and reduced clearance. The lower secretion of GH in adult birds reflects fewer somatotrophs in the pituitary, changes in somatotroph structure, and reduced GH responses to TRH or GRF administration. There is only limited data on the role of GH in birds. GH appears to be required for normal growth; acting at least in part by increasing somatomedin production. However, plasma concentrations of GH do not necessarily correlate with growth rate. For instance, in chicks with reduced growth rate owing to either goitrogen or protein deficiency in the diet, plasma concentrations of GH are elevated. GH also can influence lipid metabolism by increasing lipolysis, decreasing lipogenesis, and stimulating the uptake of glucose by adipose tissue. The physiological significance of these actions is, however, not established. In addition, GH affects the secretion of other hormones, the immune system, and perhaps also the reproductive system. PMID: 6151579 [PubMed - indexed for MEDLINE] 7002. Can J Biochem Cell Biol. 1984 Nov;62(11):1228-36. Is intracellular Ca2+ involved in insulin stimulation of sugar transport? Fact and prejudice. Klip A. Insulin stimulates the rate of glucose transport in muscle and fat tissue by incorporation of transporters from internal membranes into the plasma membrane. It is conceivable that cell Ca2+ ions could play a role in transporter translocation. Indeed Ca2+ has been thought to mediate insulin action, but the evidence remains highly controversial. Experiments to this effect include (i) determinations of a requirement for extracellular Ca2+ in the hormonal response, (ii) stimulation of glucose transport by agents thought to elevate cytosolic Ca2+, [Ca2+]i, and (iii) determinations of Ca2+ efflux. Actual measurements of the effect of insulin on [Ca2+]i were missing until recently. Current methods to measure [Ca2+]i include Ca2+-selective intracellular electrodes, metallochromic dyes, and photoproteins. Main drawbacks of these procedures have been the requirement of microinjection for their incorporation, which restricts their use to large cells, and their interaction with cytoplasmic Mg2+ and H+. Recently, a fluorescent Ca2+ chelator, quin-2, has been devised, which circumvents these difficulties. A permeable, nonchelating precursor of quin-2 penetrates cells and once in the cytosol becomes an impermeant, fluorescent Ca2+ chelator. With this technique it was shown that insulin does not change [Ca2+]i while stimulating glucose transport in L6 muscle cells. PMID: 6395946 [PubMed - indexed for MEDLINE] 7003. Klin Padiatr. 1984 Nov-Dec;196(6):327-35. [The development of obesity in childhood]. [Article in German] Zwiauer KF, Widhalm KM. Multiple factors appear to influence and promote the development of obesity: The importance of genetic factors has been demonstrated in some studies, however, it is very difficult to distinguish between environmental and genetic influences. Independently, increased birthweight, massive weight gain in the first months after birth and overweight of the mother or of both parents seem to be risk factors, which are able to promote the development of childhood obesity. In the past few years more attention has been paid to psychological factors and their influence on appetite, physical activity and energy balance. Whether metabolic changes on cellular and microcellular basis can cause obesity is not sufficiently known until now. Nutrition in early childhood and fat cell hyperplasia and hypertrophia induced by nutritional factors probably do not imply persistence of obesity but may promote obesity and worsen the prognosis of therapy. Due to the fact that a high percentage of obese adolescents remain obese in adulthood, and due to the poor results in the treatment of obesity as well as the association of overweight with an increased risk for morbidity and mortality an effective therapy and prevention of obesity even during childhood seem to be of great importance. PMID: 6392719 [PubMed - indexed for MEDLINE] 7004. Clin Endocrinol Metab. 1984 Nov;13(3):635-59. Treatment of obesity: the constraints on success. James WP. PMID: 6391759 [PubMed - indexed for MEDLINE] 7005. Clin Endocrinol Metab. 1984 Nov;13(3):581-95. The role of thyroid hormones in the control of energy expenditure. Danforth E Jr, Burger A. Thyroid hormones have a direct effect on the basal or resting metabolic rate in man and a permissive effect on the adaptive thermogenesis of small animals, while altering the energy expended in exercise to the extent that patients with thyroid disorders exercise to a greater or lesser degree. The physiological concepts of energy expenditure need to be seen in the context of a new method for measuring 'thyroid thermogenesis'. Thyroid hormones seem, in evolutionary terms, to have developed a thermogenic role during the transition from poikilothermy to homeothermy; they are responsible for the increased heat production required for homeotherms to maintain body temperature above that of the environment. The potential mechanisms responsible for thyroid hormone-controlled energy expenditure are complex. Uncoupled oxidative phosphorylation is probably not responsible for thyroid hormone-controlled thermogenesis except in the special case of brown adipose tissue thermogenesis, where thyroid hormones act permissively. The concept that increased ATP generation must be coupled to ATP utilization needs to be linked with the idea that thyroid hormone-controlled thermogenesis must be through inefficient pathways of metabolism. Several of these potentially important pathways of intermediary metabolism in thyroid hormone-controlled thermogenesis can now be defined and measured, but their role in the regulation of nutritionally induced alterations in thyroid status and thermogenesis remains to be explored. PMID: 6391756 [PubMed - indexed for MEDLINE] 7006. Clin Endocrinol Metab. 1984 Nov;13(3):521-46. Integration of energy intake and expenditure in animals and man: the autonomic and adrenal hypothesis. Bray GA. PMID: 6391753 [PubMed - indexed for MEDLINE] 7007. Clin Endocrinol Metab. 1984 Nov;13(3):501-20. Factors affecting brown adipose tissue activity in animals and man. Ricquier D, Mory G. PMID: 6391752 [PubMed - indexed for MEDLINE] 7008. Clin Endocrinol Metab. 1984 Nov;13(3):451-74. The development of obesity in animals: the role of genetic susceptibility. Trayhurn P. There are a number of animals in which obesity is genetically determined. In some the inheritance is polygenic while in others it is by a single-gene mutation. In the most widely studied single-gene mutants--the obese (ob/ob) mouse, the diabetic-obese (db/db) mouse and the Zucker (fa/fa) rat-obesity is very substantial and is initiated before the animals are weaned. Although hyperphagia is a feature of all the major obese mutants, it is not a prerequisite for the development of obesity. The initiation of the disorder during the suckling period takes place on a normal energy intake, and excess rates of energy deposition will still continue after weaning if the obese mutants are pair-fed to the ad libitum energy intake of lean siblings. The ability to become obese without hyperphagia indicates that one or more components of energy expenditure must be reduced in the obese mutants. Studies on the ob/ob mouse have demonstrated that a reduction in thermogenesis in BAT is the main way by which this is achieved. The reduction in energy expenditure in BAT is due primarily to a low activity of the sympathetic innervation to the tissue. Once hyperphagia is established, apparently as a secondary feature of the obese syndrome, the development of obesity is accelerated, the obese mutants having an impairment in the dietary stimulation of BAT thermogenesis. Studies on different types of obese animal suggest that an inability to respond to dietary stimuli is a general feature of obesity. The final syndrome presented by genetically obese animals is of considerable metabolic and endocrinological complexity. However, it is now possible to begin to integrate some of the endocrinological abnormalities within the energy balance framework, centred on BAT, that has been developed over the past few years. This is particularly evident in the case of adrenal function in the Zucker rat; adrenalectomy of this mutant has important effects on energy balance and in the normalization of the thermogenic activity of BAT. The sensitivity of BAT to insulin is also emerging as a possible factor of importance in the modulation of thermogenesis in obese animals.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6391750 [PubMed - indexed for MEDLINE] 7009. J Anim Sci. 1984 Nov;59(5):1362-8. Control of feed intake in sheep. Della-Fera MA, Baile CA. The control of feed intake is highly complex, involving many peripheral, as well as central nervous system (CNS) factors. The various signals involved in the control of feeding behavior are integrated in the hypothalamus and appropriate responses, i.e., feeding or cessation of feeding, are generated. The actual neurochemical events subserving this function are not well understood, although specific roles for each of the neurotransmitter systems have been proposed. More recently, certain neuropeptides have been shown to affect feeding behavior in sheep, as well as many other species. Most of the evidence points to the involvement of two families of neuropeptides in the control of feed intake in sheep: the opioid peptides, which include enkephalins, endorphins and dynorphins, and cholecystokinin (CCK) peptides, of which CCK-8 is the primary brain form. Certain opioid peptides, such as met-enkephalins, beta-endorphin and dynorphin A peptides, have been shown to stimulate feeding after CNS administration in sheep, while CCK peptides suppress feeding. Thus it has been proposed that opioid peptides are involved in the initiation of feeding, or hunger, and CCK peptides, in the inhibition of feeding, or satiety. Although much more is known about the effects of CCK peptides than opioid peptides on feeding behavior of sheep, evidence is accumulating for direct interaction between CCK- and opioid-containing neurons that could lead to better understanding of hunger and satiety in sheep. PMID: 6150929 [PubMed - indexed for MEDLINE] 7010. Physiol Rev. 1984 Oct;64(4):1321-78. Insulin receptors: binding kinetics and structure-function relationship of insulin. Gammeltoft S. During the last decade, earlier suggestions that insulin acts at the plasma membrane level via combination with receptors have been amply confirmed in studies of 125I-labeled insulin binding kinetics. Efforts have been devoted to the development of homogeneous, stable, and bioactive tracers, and a preparation of monoiodo[TyrA14]insulin showed 100-125% biological activity. The initially simple model of reversible, bimolecular, and noncooperative interaction between receptor and insulin has been revised to include the existence of at least three affinity states that may be linked to modulation of the biological response induced by the insulin-receptor complex. Thus negative cooperativity seems important in reducing oscillations of insulin action with variations in plasma insulin concentration, and formation of a high-affinity state or positive cooperativity may lead to desensitization of receptors. The kinetic phenomena suggest that receptor-binding affinity and function are actively regulated by insulin itself. At present the receptor model is purely functional and does not imply molecular mechanisms. However, recent advances in the analysis of receptor structure and biochemistry promise that the molecular equivalents of the kinetic phenomena may be elucidated in the near future. Furthermore the reaction between receptor and insulin is irreversible because of degradation of receptor-bound insulin, which may result in termination of the metabolic activation. Morphological and biochemical work suggests that internalization of the receptor-insulin complex from the plasma membrane transfers insulin to intracellular organelles like the lysosomes, the Golgi apparatus, or nucleus, where degradation by insulin protease takes place, whereas the receptor is recycled back to the membrane. Recent advances in the studies of biosynthesis and cellular dynamics of receptors indicate that intracellular processing and redistribution of binding sites may play a role in the mechanism of insulin action. Insulin receptors are widely distributed in all cell types, but evidence has accumulated that receptors show tissue and species variations in their functional properties regarding binding affinity, insulin specificity, cooperativity, and insulin degradation and in structural properties such as antigenic determinants and glycosidic composition. Perhaps these differences reflect cellular adaptations and variations in the physiological role of insulin.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6387730 [PubMed - indexed for MEDLINE] 7011. Poult Sci. 1984 Oct;63(10):2044-54. Adipose tissue metabolism and its control in birds. Leclercq B. At any age, with increases in body weight, the elevation in total lipid or abdominal fat is more than proportional to body weight. This observation explains why selection of broilers for rapid growth rate leads to excessive fat accumulation. Although adipocyte hyperplasia continues until 12 or 14 weeks of age, hypertrophia becomes increasingly important with age and the degree of fattening. The number of adipocytes appears to be correlated with body size, and the size of the adipocyte is closely related to the fat content of the live bird. The hormonal control of lipolysis involves a number of hormones and appears to be very complex. The increase in fat in adipose tissue is mainly due to hepatic lipogenesis. This review discusses the relative role of hormones in fat metabolism, some pecularities of insulin activity in birds, and the important functions of plasma lipoprotein and adipose lipoprotein lipase. A comparison of a fat line of chickens and mammalian models of obesity is also made. PMID: 6387692 [PubMed - indexed for MEDLINE] 7012. Clin Endocrinol (Oxf). 1984 Oct;21(4):415-33. Fetal growth control: the role of insulin and related peptides. Milner RD, Hill DJ. Both insulin and the related peptides, the insulin-like growth factors/somatomedins, may function as anabolic factors in the regulation of fetal body size. Infants born to women suffering from diabetes mellitus may show increased deposition of subcutaneous fat and enhanced lean body mass, findings reproduced in experimental animal fetuses with induced hyperinsulinaemia. Fetal adiposity may be associated with a life-time tendency to obesity and its associated diseases. Insulin-like growth factors I (IGFI) and II are present in the circulation of the newborn infant and animal fetus and correlate positively with birth size. The fetal tissues are biologically responsive to IGFs in vitro and are rich in specific cell membrane receptors, those predominantly recognizing IGFI being structurally and functionally similar to the insulin receptor. Insulin could theoretically influence fetal tissues by an interaction with either the insulin or IGF receptor. IGF release is a property of multiple fetal tissues in vitro, but, in contrast to postnatal life, is not dependent on growth hormone. Fetal IGF production may be influenced by placental lactogen, especially IGFII which rapidly declines in the circulation following parturition in the rat and sheep. A positive association also exists between circulating levels of insulin and IGFs when the former is experimentally manipulated in the animal fetus. Similarly the infant born with transient diabetes mellitus has low cord blood levels of insulin and IGFI. Insulin has a dual role in prenatal life. In the last trimester insulin functions as a glucoregulatory hormone, but from much earlier in gestation creates an anabolic environment in the fetus supplied with optimal nutrients. This latter mechanism of action is unclear and probably heterogeneous, but in overview is permissive rather than obligatory. In contrast the growth-promoting role of the IGFs is direct but their interaction with fetal tissues, and thus the overall emphasis of fetal growth, may be paracrine. PMID: 6096045 [PubMed - indexed for MEDLINE] 7013. Diabet Med. 1984 Sep;1(3):181-8. Insulin receptor assays--clinical application and limitations (2). Taylor R. PMID: 6242796 [PubMed - indexed for MEDLINE] 7014. J Anim Sci. 1984 Aug;59(2):511-28. Endocrine regulation of fetal and postnatal meat animal growth. Etherton TD, Kensinger RS. Evidence is discussed which indicates that nutrient partitioning between muscle and adipose tissue can be altered by growth hormone administration in meat animals. In the limited number of studies conducted with meat animals, growth rate, feed efficiency and carcass composition were improved by growth hormone administration. When insulin was administered to normally growing swine no improvement in growth performance was observed. The mechanisms by which growth hormone affects growth performance are not clear but considerable data from rodent studies exist to indicate that many of the growth promoting effects of this hormone are due to somatomedins. However, few data are available for meat animals to indicate whether the growth promoting effects of growth hormone are mediated by somatomedins. Knowledge about the mechanisms that regulate growth hormone synthesis, secretion and biological action is accumulating. It is apparent that growth hormone administration induces an insulin-resistant state in rodents and meat animals. It is not clear whether chronic growth hormone administration in meat animals induces a growth hormone resistant state. Based on the available information, manipulation of systemic hormone concentrations and(or) tissue sensitivity to hormones involved in growth and differentiation may result in means to manipulate fetal and postnatal growth and development. PMID: 6384172 [PubMed - indexed for MEDLINE] 7015. Am J Physiol. 1984 Aug;247(2 Pt 1):E181-9. Sympathoadrenal system and regulation of thermogenesis. Landsberg L, Saville ME, Young JB. The sympathetic nervous system (SNS) plays a critical role in the regulation of mammalian thermogenic responses to cold exposure and dietary intake. Catecholamine-stimulated thermogenesis is mediated by the beta-adrenergic receptor. In the rat brown adipose tissue is the major site of metabolic heat production in response to both cold (nonshivering thermogenesis) and diet (diet-induced thermogenesis). Measurements of norepinephrine turnover rate in interscapular brown adipose tissue of the rat demonstrate increased sympathetic activity in response to both cold exposure and overfeeding. In adult humans, a physiologically significant role for brown adipose tissue has not been established but cannot be excluded. It appears likely that dietary changes in SNS activity are related, at least in part, to the changes in metabolic rate that occur in association with changes in dietary intake. PMID: 6380306 [PubMed - indexed for MEDLINE] 7016. J Anim Sci. 1984 Aug;59(2):498-510. A review of endocrine regulation of metabolism during lactation. Collier RJ, McNamara JP, Wallace CR, Dehoff MH. Lactogenesis signals the shift from uterine nutrient transfer to the fetus to neonatal nourishment at the mammary gland. Metabolic adaptations involved in this process are under endocrine regulation. Key events include an increase in blood flow to mammary tissue, a decrease in nutrient utilization by peripheral tissues and an increase in nutrient utilization by mammary tissue for milk synthesis. Deficits of certain substrates during early lactation require mobilization of those substrates from depot stores. Changes in metabolism of various tissues are related to changes in hormone receptor populations of those tissues and hormone concentrations in blood. Hormone receptors are therefore the primary mechanism by which information from the endocrine systems is linked to cellular metabolism. Endocrine changes at parturition result in dramatic changes in receptor populations of key tissues such as adipose and mammary tissues. Knowledge in this area, however, is incomplete. Relationship between hormone receptors and specific cellular metabolic pathways remains unresolved. PMID: 6090379 [PubMed - indexed for MEDLINE] 7017. Med Phys. 1984 Jul-Aug;11(4):425-48. A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from 1-100 MHz: dependence on tissue type, NMR frequency, temperature, species, excision, and age. Bottomley PA, Foster TH, Argersinger RE, Pfeifer LM. The longitudinal (T1) and transverse (T2) hydrogen (1H) nuclear magnetic resonance (NMR) relaxation times of normal human and animal tissue in the frequency range 1-100 MHz are compiled and reviewed as a function of tissue type, NMR frequency, temperature, species, in vivo versus in vitro status, time after excision, and age. The dominant observed factors affecting T1 are tissue type and NMR frequency (V). All tissue frequency dispersions can be fitted to the simple expression T1 = AVB in the range 1-100 MHz, with A and B tissue-dependent constants. This equation provides as good or better fit to the data as previous more complex formulas. T2 is found to be multicomponent, essentially independent of NMR frequency, and dependent mainly on tissue type. Mean and raw values of T1 and T2 for each tissue are tabulated and/or plotted versus frequency and the fitting parameters A, B and the standard deviations determined to establish the normal range of relaxation times applicable to NMR imaging. The mechanisms for tissue NMR relaxation are reviewed with reference to the fast exchange two state (FETS) model of water in biological systems, and an overview of the dynamic state of water and macromolecular hydrogen compatible with the frequency, temperature, and multicomponent data is postulated. This suggests that 1H tissue T1 is determined predominantly by intermolecular (possibly rotational) interactions between macromolecules and a single bound hydration layer, and the T2 is governed mainly by exchange diffusion of water between the bound layer and a free water phase. Deficiencies in measurement techniques are identified as major sources of data irreproducibility. PMID: 6482839 [PubMed - indexed for MEDLINE] 7018. Srp Arh Celok Lek. 1984 Jul-Aug;112(7-8):845-60. [The molecular basis and cellular dynamics of the mechanism of action of insulin]. [Article in Serbian] Japundzić I, Japundzić M. PMID: 6395365 [PubMed - indexed for MEDLINE] 7019. Spine (Phila Pa 1976). 1984 Jul-Aug;9(5):454-60. The menisci of the lumbar zygapophyseal joints. A review of their anatomy and clinical significance. Bogduk N, Engel R. The literature describing menisci in the lumbar zygapophyseal joints is reviewed. The only true menisci in these joints are rudimentary fibrous invaginations of the dorsal and ventral capsule. So-called menisci at the superior and inferior poles of the joint are basically fat-filled synovial reflections, some of which contain dense fibrous tissue, which probably arises as a result of mechanical stress. The theory of meniscus entrapment is appraised, but is considered to have been an overstated cause of those forms of "acute locked back" that responds to manipulation. PMID: 6387951 [PubMed - indexed for MEDLINE] 7020. Can J Biochem Cell Biol. 1984 Jul;62(7):618-22. Quantitative contribution of brown adipose tissue thermogenesis to overall metabolism. Foster DO. Measurement of brown adipose tissue (BAT) blood flow coupled, when feasible, with measurement of the arteriovenous difference in oxygen across the tissue has been used to estimate the contribution of BAT thermogenesis to the metabolism of several species of laboratory, domestic, or wild mammals under various conditions: warm or cold exposure; arousal from hibernation; stimulation of metabolism by exogenous noradrenaline in warm- or cold-acclimated animals, in lean or obese animals, and in animals exhibiting high- or low-diet-induced thermogenesis. These studies have shown that in some species and under certain conditions BAT thermogenesis may account for as much as about one-third of the overall metabolic rate. PMID: 6383576 [PubMed - indexed for MEDLINE] 7021. Can J Biochem Cell Biol. 1984 Jul;62(7):610-7. Brown adipose tissue thermogenesis, energy balance, and obesity. Himms-Hagen J. The concept that thermogenesis in brown adipose tissue can play a role as an energy buffer has developed during the last 5 years. The history of this development is reviewed. Control of brown adipose tissue thermogenesis resides in regions of the brain, located primarily but not exclusively in the hypothalamus, that control the activity of the sympathetic nervous system in response to diet and to environmental temperature. Brown adipose tissue mitochondria are uniquely specialized for thermogenesis, possessing a specific proton leakage mechanism that is regulated by the concentration of fatty acids in the cells of the brown adipose tissue. The level of fatty acids is in turn controlled by the lipolytic action of noradrenaline on the tissue. Sympathetic stimulation also exerts a trophic influence on brown adipose tissue. Effective thermogenesis in brown adipose tissue is associated with leanness and decreased metabolic efficiency, as in the rat rendered hyperphagic and hypermetabolic, by either cold acclimation or cafeteria feeding. Conversely, food restriction is associated with suppressed thermogenesis in brown adipose tissue and increased metabolic efficiency. Defective brown adipose tissue thermogenesis is associated with obesity in a number of different types of obese animals. In three of these (the genetically obese fa/fa Zucker rat, the mouse with hypothalamic damage induced by gold thioglucose, the rat with a surgically induced hypothalamic lesion), diet-induced thermogenesis is defective in brown adipose tissue, but cold-induced thermogenesis is normal. In another type of obese animal, the genetically obese (ob/ob) mouse, control of brown adipose tissue is defective. Studies of this control are complicated by the frequency of torpor in the fed state.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 6383575 [PubMed - indexed for MEDLINE] 7022. Clin Orthop Relat Res. 1984 Jul-Aug;(187):3-17. Fat embolism. An appraisal of the problem. Peltier LF. PMID: 6378481 [PubMed - indexed for MEDLINE] 7023. Can J Biochem Cell Biol. 1984 Jul;62(7):637-47. Mechanisms of hormonal regulations in brown adipose tissue of developing rats. Skala JP. The need for nonshivering heat production, a principal function of brown adipose tissue, is accentuated in neonates. Accordingly, brown fat in the rat exhibits a very pronounced process of morphological and functional maturation perinatally, reaches a peak in its differentiation and heat-generating capacity within 1-2 weeks after birth, and undergoes involutive changes later in life. The later process of dedifferentiation can be either prevented or reversed by exposing the animals to cold ambient temperature for a prolonged period of time (cold acclimatization). The regulation of both the tissue maturation processes and the superimposed acute heat production are hormone mediated. Thus, the hormone receptor system within the adipocyte membrane and the sequence of molecular events interconnecting the initial hormonal stimulus with its final intracellular effect(s) are of considerable importance. The brown adipocytes of developing rats possess adrenoreceptors that can be pharmacologically classified as beta 1 (linked to adenylate cyclase) and alpha 2 (possibly linked to guanylate cyclase), multiple forms of cyclic nucleotide dependent and independent protein kinases, a protein kinase inhibitor, and at least two distinct phosphoprotein phosphatases associated with three phosphoprotein phosphatase modulators. The characteristics and developmental alterations of these regulatory components were studied in considerable detail by our group during the past decade. The results uncovered several target systems for ontogenic modifications of hormonal responses. Strong support was obtained for the hypothesis that protein phosphorylation and dephosphorylation is a major molecular mechanism involved in the regulation of both the brown adipocyte function and its proliferative activity during ontogenic development. PMID: 6148137 [PubMed - indexed for MEDLINE] 7024. Metabolism. 1984 Jul;33(7):672-9. Insulin secretion and action. Fain JN. Recent advances in insulin secretion indicate that pertussis toxin abolishes the inhibition by alpha 2 adrenoceptor activation of insulin release by the pancreas. Pertussis toxin adenosine diphosphate (ADP) ribosylates an inhibitory guanine nucleotide-binding protein (Ni) involved in inhibition of adenylate cyclase. The decrease in cyclic adenosine monophosphate (AMP) by epinephrine may account for its inhibition of insulin release. Insulin interaction with its receptor results in an increase in the tyrosine protein kinase activity of the receptor. Second messengers for insulin are generated, hexose transport is accelerated, and a cyclic AMP-independent protein kinase is activated that phosphorylates at serinethreonine residues. The activity of membrane-bound enzymes such as adenylate cyclase and Ca2+-Mg2+-ATPase is affected. The relative importance of these effects of insulin in its regulation of cellular metabolism remains to be established. PMID: 6146090 [PubMed - indexed for MEDLINE] 7025. Biochimie. 1984 Jul-Aug;66(7-8):IX-XIV. [The adipose cell: a convenient experimental model for analysing the functional interactions of 2 adrenergic receptors as effected by antagonists, the alpha 2- and beta receptor]. [Article in French] Berlan M, Lafontan M. PMID: 6099147 [PubMed - indexed for MEDLINE] 7026. Can J Biochem Cell Biol. 1984 Jul;62(7):631-6. Control mechanisms in brown adipose tissue plasma membrane. Bégin-Heick N, Heick HM. It is generally agreed that the site of heat production during nonshivering thermogenesis is the brown adipose tissue (BAT) and that the triggering event for heat production is the interaction of noradrenaline (NA) with its receptor on the plasma membrane. Following this initial event, several changes occur which result in increased rates of cAMP synthesis, redistribution of ions across the membrane, enhanced rates of lipolysis, and increased mitochondrial oxidation of substrates. BAT is also a target for the anabolic effect of insulin. Available evidence shows that insulin receptors are present on the BAT plasma membrane and that insulin can oppose the metabolic effects of catecholamine on BAT. We have studied more particularly the response of BAT adenylate cyclase to catecholamines in an animal model (the ob/ob mouse) which has a defective thermogenic response. The capacity of adenylate cyclase to be stimulated by catecholamines was significantly less in the tissue of obese mice than in lean controls. To produce a response equal to the half-maximal response in the lean mouse, a 10-fold increase in the NA concentration was required in the BAT of the obese mouse. These results are in harmony with those of others showing that the lipolytic response to catecholamines is abnormal in the BAT of the obese mouse. The adenylate cyclase activity can be altered by changes in the lipid composition of the diet and by manipulation of hormone levels. It is likely that the alteration in adenylate cyclase responsiveness is one of the contributing factors in the impaired thermogenesis and obesity in this animal. PMID: 6089980 [PubMed - indexed for MEDLINE] 7027. Can J Biochem Cell Biol. 1984 Jul;62(7):623-30. Mechanisms of stimulus-calorigenesis coupling in brown adipose tissue. Bukowiecki LJ. The sequence of metabolic events leading to increased calorigenesis in brown adipose tissue has been reviewed. The first step of this sequence consists in the binding of norepinephrine to adrenergic receptors of the beta1 subtype. This results in the stimulation of adenylate cyclase and activation of lipolysis via the system of protein kinases. Hormone-sensitive lipases represent the "flux-generating" step regulating mitochondrial respiration. Fatty acids released from intracellular triglyceride droplets in consequence of lipase activation play a messenger role between lipolysis and mitochondrial respiration. They stimulate respiration by serving as substrates for beta oxidation (via carnitine-dependent pathways) and (or) by simultaneously increasing mitochondrial permeability to protons (physiological "loose coupling"). The control of brown adipose tissue respiration by lipolysis represents a self-regulatory process, as excessive concentrations of fatty acids retroinhibit lipolysis. At the mitochondrial level, fatty acids appear to interact with an "uncoupling" protein (thermogenin or 32 000 relative mass protein) localized in the inner membrane that confers upon brown adipose mitochondria a unique sensitivity for fatty acid uncoupling. This explains that, contrary to other tissues, respiration is principally controlled in brown adipose tissue by substrate supply (mainly long-chain fatty acids), rather than by the phosphorylation state ratio. PMID: 6089979 [PubMed - indexed for MEDLINE] 7028. Recenti Prog Med. 1984 Jun;75(6):603-21. [Weber-Christian syndrome]. [Article in Italian] Marra N, Abrami F, Chiavacci G, Appicciafuoco A. PMID: 6385167 [PubMed - indexed for MEDLINE] 7029. J Anim Sci. 1984 Jun;58(6):1528-39. Biochemical studies on the fate of monensin in animals and in the environment. Donoho AL. Extensive studies have been conducted with monensin in target animals and laboratory animals to determine monensin concentrations in tissues, route of elimination, metabolism and pharmacokinetics of monensin. These studies indicate that monensin administered orally is absorbed, extensively metabolized, excreted in the bile and eliminated in the feces by the several species examined. Monensin did not accumulate in the tissues of orally dosed animals. When fed to cattle and chickens according to recommended practices, monensin was not detected (less than .05 ppm) in edible tissues. Environmental studies indicate that monensin is biodegradable in manure and soil. PMID: 6378868 [PubMed - indexed for MEDLINE] 7030. Sports Med. 1984 May-Jun;1(3):240-51. Response of skeletal muscle to training. Matoba H, Gollnick PD. Physical training induces adaptive changes in skeletal muscle. These changes are localised to the active muscle with their magnitude depending upon the nature, i.e. time and intensity, of the training regimen. The most notable changes are increased concentrations of mitochondria and glycogen. With endurance training there are major changes in metabolism in that there is a greater contribution of fat to the total metabolism during submaximal exercise. This results in a conservation of the stores of glycogen with the net result of increasing total exercise capacity. This increased use of fat during submaximal exercise appears to be more closely related to the elevations in the concentration of mitochondria in muscle than to changes in total body maximal oxygen uptake. The combination of a greater contribution of fat to the metabolism and the elevated concentration of stored glycogen are prime factors contributing to the enhanced endurance capacity after endurance training. The mechanism for the greater use of fat after endurance training is discussed. Evidence now supports the hypothesis that this is due to a tighter control over the Embden-Meyerhof pathway as a result of the greater concentration of mitochondria. The effect of heavy resistance exercise on the size and strength of skeletal muscle is discussed. Some attention is focused on the recently revived controversy concerning whether muscle enlargement is the result of a hypertrophy of pre-existing fibres or of hyperplasia. It is concluded that although there is considerable evidence to support the development of hypertrophy in response to heavy resistance exercise, the contention that a splitting of fibres occurs to produce a greater fibre number is presently poorly supported. PMID: 6390603 [PubMed - indexed for MEDLINE] 7031. Diabetes Care. 1984 May-Jun;7 Suppl 1:81-8. The impact of sulfonylurea treatment upon the mechanisms responsible for the insulin resistance in type II diabetes. Kolterman OG, Olefsky JM. Insulin resistance is a characteristic feature of patients with type II diabetes mellitus as well as patients with impaired glucose tolerance (IGT). The cause of the insulin resistance in patients with IGT appears to be solely related to a decrease in the number of cellular insulin receptors, causing a decrease in insulin sensitivity. On the other hand, the mechanisms of the insulin resistance in patients with type II diabetes mellitus are heterogeneous; in these subjects a combination of receptor and postreceptor defects exists, and the relative contribution of these two abnormalities to the overall insulin-resistant state differs depending on the severity of the diabetes. In those patients with the greatest degree of fasting hyperglycemia, the postreceptor defect is clearly the predominant abnormality. In addition to resistance to insulin's effects to promote glucose disposal, type II diabetic patients also exhibit a marked increase in the rate of entry of glucose into the circulation from the liver, as manifested by accelerated rates of hepatic glucose production. Sulfonylureas exert potent extrapancreatic effects that partially correct all of the abnormalities present in the type II diabetic state. Thus, after 3 mo of glyburide treatment, glycemic control is markedly improved and this is accompanied by an increase in insulin secretion, no change in cellular insulin receptors, decreased hepatic glucose production rates, and an increase in overall insulin-mediated glucose disposal. After 18 mo of glyburide treatment, an increase in insulin secretion can no longer be demonstrated, whereas insulin binding to receptors is now significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 6376033 [PubMed - indexed for MEDLINE] 7032. Diabetes Care. 1984 May-Jun;7 Suppl 1:8-16. Cellular signaling by the insulin receptor. Czech MP, Yu KT, Seals JR. Cellular signaling by insulin is initiated by specific membrane receptors that have been characterized as large multimeric disulfide-linked protein complexes with a minimal subunit structure of (beta-S-S-alpha)-S-S-(alpha-S-S-beta), where the alpha- and beta-subunits are about 125,000 and 90,000 daltons, respectively. The disulfides in this structure are of two classes based on their differential sensitivity to reductants (Massague, J., and Czech, M. P., J. Biol. Chem. 1982; 257:6729-35). An important recent discovery is that the insulin receptor, either in crude detergent extracts or after purification by affinity chromatography, is associated with insulin-activatable tyrosine phosphokinase activity and is itself autophosphorylated (Kasuga, M., et al., Proc. Natl. Acad. Sci. USA 1983; 80:2137-41). We demonstrate here that insulin receptor kinase activity is readily monitored while the receptor is absorbed onto insulin-agarose, using [gamma-32]ATP and histone as substrate. Phosphorylation of histone and the receptor beta-subunit on tyrosine residues is dependent on time, temperature, and Mn2+ in this system. The immobilized insulin receptor kinase is activated by prior phosphorylation with ATP, indicating that the autophosphorylation plays an important role in regulating receptor kinase activity. That the insulin receptor tyrosine kinase activity may be involved in initiating the mechanism of insulin action is currently an attractive hypothesis. A second working model of insulin action proposes that one or more soluble factors are released into the cell in response to insulin as suggested by studies using muscle and fat cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 6376032 [PubMed - indexed for MEDLINE] 7033. Pol Tyg Lek. 1984 Apr 9;39(15):513-7. [Hypertension in obesity]. [Article in Polish] Skórka B, Chlebus H. PMID: 6384963 [PubMed - indexed for MEDLINE] 7034. Minerva Endocrinol. 1984 Apr-Jun;9(2):221-8. [Insulin resistance in type 2 diabetes. Receptor and post-receptor aspects]. [Article in Italian] Purrello F, Trischitta V, Vigneri R. PMID: 6390135 [PubMed - indexed for MEDLINE] 7035. Br Med Bull. 1984 Apr;40(2):160-4. Metabolic applications of high-resolution 13C nuclear magnetic resonance spectroscopy. Alger JR, Shulman RG. PMID: 6378314 [PubMed - indexed for MEDLINE] 7036. Cell Calcium. 1984 Apr;5(2):111-30. Hormone-receptor coupling and the molecular mechanism of insulin action in the adipocyte: a paradigm for Ca2+ homeostasis in the initiation of the insulin-induced metabolic cascade. Pershadsingh HA, McDonald JM. PMID: 6145523 [PubMed - indexed for MEDLINE] 7037. Clin Pharmacokinet. 1984 Mar-Apr;9(2):136-56. Clinical pharmacokinetics of amiodarone. Latini R, Tognoni G, Kates RE. Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug. Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethyl-amiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity. Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro protein binding of amiodarone has been reported to be 96.3 +/- 0.6%. The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg. Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug's kinetics have not been studied. Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide. The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6370540 [PubMed - indexed for MEDLINE] 7038. J Pediatr. 1984 Mar;104(3):327-36. The insulin receptor. Kaplan SA. Cells are endowed with specific cognitive molecules that function as receptors for hormones, neurotransmitters, and other intercellular messengers. The receptor molecules may be present in the plasma membrane, cytoplasm, or nucleus. When occupied by the messenger, the receptor is coupled to the cellular machinery that responds to the message-bearing molecules. For some hormones the events following attachment of the messenger to the receptor are well known. An example is the generation of cAMP after combination of glucagon with its receptor and the series of steps culminating in activation of phosphorylase. In the case of many other messengers, including insulin, the nature of these coupling steps is not known. Receptors are subject to the regulatory processes of synthesis, degradation, and conformational change; alterations in receptor properties may have significant effects on the qualitative and quantitative responses of the cell to the extracellular messenger. The insulin receptor is located in the plasma membrane, is composed of two pairs of subunits, and has a molecular weight of about 350,000. It is located in cells such as adipocytes, hepatocytes, and skeletal muscle cells as well as in cells not considered to be typical target organ cells. Insulin receptors in nonfetal cells are downregulated by exposure of the cells to high concentrations of insulin. Other factors that regulate insulin binding include muscular exercise, diet, thyroid hormones, glucocorticoids, androgens, estrogens, and cyclic nucleotides. The fetus has high concentrations of insulin receptors in several tissues. These begin to appear early in fetal life and may outnumber those found in adult tissues. Fetal insulin receptors are unusual in that they may not undergo downregulation but may experience the opposite when exposed to insulin in high concentrations. Thus the offspring of a mother with poorly controlled diabetes may be placed in double jeopardy by fetal hyperinsulinemia and augmented insulin binding by the receptors. Many disorders in children and adults are associated with changes in the properties of the insulin receptor. In general, the alterations have been measured in receptor-bearing cells that are readily accessible, such as circulating monocytes and erythrocytes. The receptors on these cells generally reflect the status of receptors on the major target organs of insulin, although exceptions are known, and conclusions drawn from studies of receptors on circulating cells must be made with caution.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6368773 [PubMed - indexed for MEDLINE] 7039. J Am Geriatr Soc. 1984 Mar;32(3):219-28. Adipocyte hormone responsiveness and aging in the rat: problems in the interpretation of aging research. Kirkland JL, Dax EM. Fat is a metabolically dynamic tissue. Its metabolism is under the control of several well-characterized hormonal systems. There appear to be changes in the hormonal sensitivity of rat fat with age. No single mechanism has been proved to explain all the changes observed in adipocyte hormonal responsiveness with aging, although it does seem likely that age does have an independent effect on fat metabolism from studies to date. PMID: 6321584 [PubMed - indexed for MEDLINE] 7040. Clin Endocrinol Metab. 1984 Mar;13(1):3-30. Biological and immunological properties of insulin-like growth factors (IGF) I and II. Zapf J, Schmid C, Froesch ER. PMID: 6202445 [PubMed - indexed for MEDLINE] 7041. J Lipid Res. 1984 Feb;25(2):97-110. Adipose tissue and cholesterol metabolism. Krause BR, Hartman AD. Adipose tissue in man is a major site for cholesterol storage. In obesity over half of total body cholesterol may reside within this tissue; however, relatively little attention has been directed toward understanding the cholesterol metabolism and its relationship to whole body cholesterol homeostasis in this tissue. In this review the factors which influence cholesterol storage are discussed, with particular emphasis on the effects of diet and drug treatment in both animals and man. The uptake, synthesis, and mobilization of adipose tissue cholesterol appears to be mediated and/or regulated, as in other tissues, by the plasma lipoproteins, and these processes are examined with regard to both normal and pathologic states. PMID: 6368715 [PubMed - indexed for MEDLINE] 7042. Dan Med Bull. 1984 Feb;31(1):1-32. Studies of insulin receptor binding and insulin action in humans. Pedersen O. PMID: 6365475 [PubMed - indexed for MEDLINE] 7043. Gac Med Mex. 1984 Feb;120(2):35-47. [Recent major research on the physiopathology of adipose tissue]. [Article in Spanish] Llamas R. PMID: 6329873 [PubMed - indexed for MEDLINE] 7044. Exp Hematol. 1984 Feb;12(2):139-46. Marrow adipose cells and hemopoiesis: an interpretative review. Tavassoli M. PMID: 6199224 [PubMed - indexed for MEDLINE] 7045. Pol Tyg Lek. 1984 Jan 23;39(4):129-33. [Somatomedins. General characteristics]. [Article in Polish] Grzywa M. PMID: 6377279 [PubMed - indexed for MEDLINE] 7046. Soc Sci Med. 1984;19(2):177-82. Nutritional thriftiness and human reproduction: beyond the critical body composition hypothesis. Quandt SA. The 'critical body composition hypothesis' (CBCH) is frequently used to explain variations in the duration of postpartum amenorrhea. The hypothesis predicts that ovulation will not occur it fat reserves fall below a critical threshold. This paper attempts to analytically separate the CBCH from the broader concept of nutritional thriftiness on which it is based. A review of previous research on fat cell metabolism and ovulation finds no direct link between fatness and fecundity. Rather they are each regulated by the lactation and mother-infant interactions associated with breast feeding. As a system which delivers available fat into breast milk and prevents ovulation only during the time when the infant is dependent on the mother, the pathways outlined here represent a nutritionally thrifty method of fertility regulation, one which maximizes reproductive success while minimizing energy investment. The cultural patterning both of infant feeding behaviors and the wider range of maternal activities which affect breast feeding suggest specific testable hypotheses to explain interpopulation variations in fertility and infant nutritional status. PMID: 6474234 [PubMed - indexed for MEDLINE] 7047. Acta Physiol Pol. 1984;35 Suppl 27:82-102. [Insulin level in the blood and insulin receptors in the tissues and their metabolism during the growth period]. [Article in Polish] Ostaszewski P. PMID: 6443746 [PubMed - indexed for MEDLINE] 7048. Prog Drug Res. 1984;28:273-303. The role of adipose tissue in the distribution and storage of drugs. Bickel MH. PMID: 6435172 [PubMed - indexed for MEDLINE] 7049. Annu Rev Pharmacol Toxicol. 1984;24:85-103. Pharmacokinetics of PCBs. Matthews HB, Dedrick RL. The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners may be cleared at different rates by different species. With the exception of special situations in which PCBs may be passively eliminated in lipid sinks, e.g. milk or eggs, clearance is minimal prior to metabolism to more polar compounds. Rates of PBC metabolism vary greatly with species and with the degree and positions of chlorination. Mammals metabolize these compounds most rapidly, but even among mammalian species rates of metabolism vary greatly. In all species studied, the more readily metabolized chlorinated biphenyls have adjacent unsubstituted carbon atoms in the 3-4 positions. Congeners that do not have adjacent unsubstituted carbon atoms may be metabolized very slowly and are therefore cleared very slowly. These PCBs not readily cleared concentrate in adipose tissue. A physiologic pharmacokinetic model best illustrates how the concentrations of PCBs in all tissues approach equilibrium with the blood and with one another. Thus, the model illustrates how a depot of PCBs in any tissue, e.g. adipose tissue, will result in exposure of all tissues in proportion to the respective tissue/blood ratios and the body burden. The disposition of a number of PCBs in the rate has been accurately described by a physiologic model, and the model has been extrapolated to predict the disposition of these same PCBs in the mouse (58). Therefore, the physiologic pharmacokinetic model is believed to offer the best opportunity to extrapolate data obtained with laboratory animals to predict the disposition of PCBs in other species, including man. Most of the parameters of a model of PCB disposition in man are available or could be estimated. The major limitation to the construction of such a model is the absence of accurate estimates of metabolic clearance of individual PCBs by man. Accurate estimates of metabolic clearance depend on development of suitable in vitro methods to accurately predict clearance in vivo. PMID: 6428301 [PubMed - indexed for MEDLINE] 7050. Prog Clin Biol Res. 1984;137:31-44. Polychlorinated biphenyls and dibenzofurans in patients with yusho and their toxicological significance: a review. Masuda Y, Yoshimura H. The rice oil ingested by the patients with yusho and their blood, liver, and adipose tissue were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans ( PCDFs ). The individual congeners identified were examined for accumulation in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase, and DT-diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the six PCB congeners detected in yusho patients, 2,3,4,5,3',4'-hexa-CB seems to be the compound most related to yusho judging from its strong enzyme-inducing activities in the liver and the thymus atrophy and liver hypertrophy caused by feeding it to rats. PCDF congeners identified in the patients' tissues showed a stronger toxicity in rats than these PCBs, exhibiting stronger enzyme induction activities and gravimetric changes of the tissues. These PCDF congeners, especially 2,3,4,7,8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for the current symptoms and signs of yusho patients. PMID: 6425852 [PubMed - indexed for MEDLINE] 7051. Am J Ind Med. 1984;5(1-2):31-44. Polychlorinated biphenyls and dibenzofurans in patients with yusho and their toxicological significance: a review. Masuda Y, Yoshimura H. The rice oil ingested by the patients with yusho and their blood, liver, and adipose tissue were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs). The individual congeners identified were examined for accumulation in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase, and DT-diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the six PCB congeners detected in yusho patients, 2,3,4,5,3',4'-hexa-CB seems to be the compound most related to yusho judging from its strong enzyme-inducing activities in the liver and the thymus atrophy and liver hypertrophy caused by feeding it to rats. PCDF congeners identified in the patients' tissues showed a stronger toxicity in rats than these PCBs, exhibiting stronger enzyme induction activities and gravimetric changes of the tissues. These PCDF congeners, especially 2,3,4,7,8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for the current symptoms and signs of yusho patients. PMID: 6422748 [PubMed - indexed for MEDLINE] 7052. Int J Biochem. 1984;16(3):257-61. Adipose tissue glycogen synthesis. Eichner RD. PMID: 6421634 [PubMed - indexed for MEDLINE] 7053. Br J Surg. 1984 Jan;71(1):1-9. Energy and protein requirements of general surgical patients requiring intravenous nutrition. Hill GL, Church J. General surgical patients require intravenous nutrition either because their gastrointestinal tract is blocked, too short or inflamed or because it cannot cope. Such patients can be grouped into four nutritional/metabolic categories: normal and unstressed; normal and stressed; depleted and unstressed; depleted and stressed. The energy requirements of patients in each of these groups vary according to their energy expenditure. Normally nourished and stressed patients have the highest energy expenditure and therefore require the highest energy input (45-55 kcal.kg-1day-1). Other groups of patients rarely require more than 40 kcal.kg-1day-1. Energy can be given mainly as dextrose although calories needed above 40 kcal kg-1day-1 should be given as fat (unless lipogenesis is desirable). In very stressed patients high rates of glucose infusion can themselves constitute a metabolic stress and fat may play a bigger role as a calorie source. For long term feeding, 1 litre of 10 per cent fat emulsion should be given weekly to avoid essential fatty acid deficiency. The level of nitrogen intake required to maintain a positive nitrogen balance is a lot higher in surgical patients than the suggested recommended dietary allowances for normal subjects. It is dependent not only on the nutritional and clinical state of the patient but also on the levels of energy and nitrogen intake given. When energy intake is below energy needs, normally nourished patients cannot retain nitrogen, although depleted patients can. When energy intake exceeds energy needs, both normally nourished and depleted patients retain nitrogen at levels of nitrogen intake ranging from 250 mg kg-1day-1 (depleted and unstressed) to over 400 mg kg-1day-1 (stressed). Depleted patients can maintain a positive nitrogen balance at lower levels of calorie and nitrogen intake than normally nourished patients and in this respect are analogous to a growing child. In all surgical patients, energy and nitrogen intakes can be manipulated to provide for a controlled maintenance or restoration of either wet lean tissue and/or fat. There is little place for protein sparing therapy or the use of insulin and anabolic steroids to promote nitrogen retention in surgical patients requiring intravenous feeding. PMID: 6418265 [PubMed - indexed for MEDLINE] 7054. Acta Physiol Pol. 1984;35 Suppl 27:124-41. [Role of somatomedins in the growth processes in animals]. [Article in Polish] Barowicz T, Bubak K. PMID: 6400440 [PubMed - indexed for MEDLINE] 7055. Journ Annu Diabetol Hotel Dieu. 1984:45-9. [Obesity and the adipose tissue]. [Article in French] Björntorp P, Krotkiewski M, Rebuffé-Scrive M, Sjöström L, Smith U, Strömblad G. PMID: 6399539 [PubMed - indexed for MEDLINE] 7056. Journ Annu Diabetol Hotel Dieu. 1984:361-6. [Metformin, lipids and atherosclerosis]. [Article in French] Joffroy-Lavieuville M, Triadou N, Noel M. PMID: 6399538 [PubMed - indexed for MEDLINE] 7057. Journ Annu Diabetol Hotel Dieu. 1984:137-49. [Insulin resistance in diabetes in the obese subject]. [Article in French] Denard Y, Darnaud J, Barousse C, Navez I. PMID: 6399530 [PubMed - indexed for MEDLINE] 7058. Journ Annu Diabetol Hotel Dieu. 1984:125-36. [Anomalies of glycoregulation in alcoholic cirrhosis of the liver]. [Article in French] Charbonnel B, Murat A, Du Rostu H, Schneebeli S, Guillon J. PMID: 6399528 [PubMed - indexed for MEDLINE] 7059. Nebr Symp Motiv. 1984;32:267-307. Women and weight: a normative discontent. Rodin J, Silberstein L, Striegel-Moore R. PMID: 6398857 [PubMed - indexed for MEDLINE] 7060. Int J Obes. 1984;8 Suppl 1:119-37. Hypothalamic and genetic obesity: an appraisal of the autonomic hypothesis and the endocrine hypothesis. Bray GA. Several lines of evidence support the hypothesis that derangements in the function of the autonomic nervous system play an important role in the development of hypothalamic obesity. Vagotomy below the diaphragm reverses the syndrome. In diabetic rats cured of their diabetes with transplants of fetal pancreatic tissue beneath the renal capsule, ventromedial hypothalamic (VMH) lesions do not produce the characteristic rise in food intake nor do they significantly increase serum insulin. These observations indicate that the hyperinsulinaemia following VMH lesions is the result of neural connections rather than from a circulating humoral factor released following VMH injury. The smaller salivary glands, reduced level of glucagon and impaired mobilization of fatty acids during stress in VMH lesioned rats point to reduced activity of the sympathetic nervous system. The impaired mobilization of fat from retroperitoneal depots in VMH lesioned rats during fasting is similar to the effect of sympathetic denervation of the retroperitoneal fat pad. The turnover of norepinephrine in tissues innervated by the sympathetic nervous system is either reduced or less responsive to nutritional influences after VMH lesions. The thermogenic activity of brown adipose tissue is also impaired after VMH lesions, presumably as a result of reduced sympathetic firing rate of nerves innervating the BAT. In contrast to the reduced activity of the sympathetic nervous system after Vmh lesions there is increased activity after electrolytic lesions of the lateral hypothalamus. Collectively these data indicate that the autonomic nervous system plays a central role in the regulation of metabolic functions following disturbances of hypothalamic function. The concept of the thrifty gene as a mechanism for the development of obesity has been explored in several models. The efficiency with which food is stored as fat appears to be increased in all forms of experimental obesity. Studies in the genetically obese mouse have documented this phenomenon most elegantly. In one experiment animals carrying a double dose of the gene for obesity received exactly the same quality of food on exactly the same schedule throughout a 24 hour period of time as their lean littermates yet gained more body weight and more fat. In a second experiment the importance of a thrifty gene was documented by comparing the rates of weight loss and survival time in homozygous and heterozygous lean animals. Heterozygosity improved survival compared to the homozygous lean animal indicating the value of the genetic trait for survival in the wild.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6398803 [PubMed - indexed for MEDLINE] 7061. Vitam Horm. 1984;41:51-78. Intracellular mediators of insulin action. Jarett L, Kiechle FL. PMID: 6397911 [PubMed - indexed for MEDLINE] 7062. Kroc Found Ser. 1984;18:57-96. Long-term marrow culture: an overview of techniques and experience. Dexter TM, Spooncer E, Simmons P, Allen TD. PMID: 6397576 [PubMed - indexed for MEDLINE] 7063. Kroc Found Ser. 1984;18:3-29. The relationship of stromal cells to hemopoietic cells in marrow. Lichtman MA. PMID: 6397574 [PubMed - indexed for MEDLINE] 7064. Drug Metab Rev. 1984;15(5-6):1033-70. Effects of biosolubility on pulmonary uptake and disposition of gases and vapors of lipophilic chemicals. Fiserova-Bergerova V, Tichy M, Di Carlo FJ. Since statistical analysis proved the intercorrelation of tissue-gas partition coefficients of chemicals with similar chemical structures, bioavailability is controlled by one parameter dependent on the physicochemical properties of the chemicals and two constants distinguishing the tissues. Oil-gas partition coefficients are suggested to describe the biosolubility of volatile halogenated aliphatic chemicals. Tissue-gas partition coefficients derived from oil-gas partition coefficients were substituted in a pharmacokinetic model in order to study the effect of biosolubility on uptake, distribution, and elimination of inhaled chemicals. The simulation was focused on occupational exposures (8 h/day, 5 days/wk). Desaturation curves for all tissues show three exponential decays. The analysis of the simulation data indicates three patterns in behavior of inhaled vapors and gases in the body. Tissue uptake of poorly soluble chemicals (oil-gas partition coefficient less than 10) is flow limited at the beginning of exposure, but the partial pressures of such chemicals in the body equilibrate very rapidly with ambient air. Increased pulmonary uptake compensates for metabolic clearance. The rapid response of tissue concentrations to changes in exposure concentrations indicates that the toxic effect can easily be induced by short-term increase of exposure concentration, and that emergence from the reversible effect is rapid when exposure ceases. Tissue uptake of chemicals with oil-gas partition coefficients between 10 and 10(4) is flow limited during the entire 8-h exposure. Tissue concentrations increase slowly. Pulmonary uptake, being restricted by alveolar ventilation, compensates at steady state only for the amount of chemical removed by metabolic clearance. Therefore, tissue concentrations at steady state are lower than biosolubility. Accumulation during occupational exposure is obvious. Dumping of inhaled chemicals in adipose tissue protects the target organ from the occasional short-term increases in the exposure concentration. Tissue uptake of highly soluble chemicals (oil-gas partition coefficients greater than 10(4)) is limited by alveolar ventilation and exposure concentration. The rising and declining of tissue concentrations is very slow, half-times being in the magnitude of months and years. Metabolism reduces the half-time significantly. A lagging acute toxic effect can develop as the chemical accumulates in the body; the effect is most likely to persist long after the termination of the exposure.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6396052 [PubMed - indexed for MEDLINE] 7065. Vutr Boles. 1984;23(5):12-7. [Diet in diabetes and obesity]. [Article in Bulgarian] Tsanev A. The interrelations between obesity and diabetes mellitus are discussed. Age type diabetes was established in 80-90 per cent of all diabetics. 80-90 per cent of them being with overweight. On the other hand, the incidence of latent and manifested diabetes among the patients with obesity is 10 times higher as compared wth the rest of the population. The role of increased insulin secretion is stressed upon as well as the reduced concentration of insulin receptors in the pathogenesis of the reduced glucose tolerance in diabetes. The purpose of dietetic treatment of diabetes, second type, combined with obesity, is to reach the normal body weight. A diet of 20 kcal/kg is recommended for that purpose. The calories of carbohydrates are increased to 55 per cent with the present diet and at the same time, the calories from lipids are reduced to 25-35 per cent. The carbohydrates are taken in the form of polysaccharides, with increased content of fibres. The ratio between unsaturated and saturated fatty acids should be I. PMID: 6395490 [PubMed - indexed for MEDLINE] 7066. Int J Obes. 1984;8(5):591-7. New techniques: cell culture analysis. Johnson PR, Goldstein AL. PMID: 6394528 [PubMed - indexed for MEDLINE] 7067. Int J Obes. 1984;8(5):561-9. Enzymatic alterations in the obese: long or short-term regulatory errors? Greenwood MR. PMID: 6394525 [PubMed - indexed for MEDLINE] 7068. Int J Obes. 1984;8(5):525-33. Morphological classifications of obesity: what they tell us, what they don't. Björntorp P. PMID: 6394523 [PubMed - indexed for MEDLINE] 7069. Int J Obes. 1984;8(5):509-23. Anthropometric methods: new and old, what they tell us. Roche AF. PMID: 6394522 [PubMed - indexed for MEDLINE] 7070. Reprod Nutr Dev. 1984;24(5B):671-92. [Mechanisms of regulation of energy balance]. [Article in French] Le Magnen J. To establish energy balance, the three distinct terms of the balance must be precisely defined and measured. These terms are: the energy input by food intake, energy expenditure as heat and the body energy content in the form of lean and fat masses. The constancy of this fat store, generally associated with that of body weight, is an indication of the balance between energy intake and the sum of expenditure and non-lipidic energy retention. This balance is only carried out at medium or long-term. It results from the initiation of mechanisms regulating strongly positive or negative short-term balances between gains and losses. Four possible models of this regulation are presented and discussed using experimental data. A number of works is reported, demonstrating the role played by two complementary mechanisms of regulation. The first one is neuroendocrine mechanism controlling food intake and adjusting it to the input and output of glucose in the blood compartment. The second one is an autonomous mechanism regulating the body fat mass. It corrects, at medium and long-term, the filling and depletion of the adipose compartment which result from imbalances in the overall energy balance. This mechanism indirectly affects food intake in a regulatory sense. It is neurally controlled by the sympathetic and parasympathetic nervous system and governed by the medioventral nuclei of the hypothalamus. PMID: 6393248 [PubMed - indexed for MEDLINE] 7071. Neurosci Biobehav Rev. 1984 Winter;8(4):515-22. Is regulation of body weight elucidated. Le Magnen J. A new perspective on mechanisms involved in the regulation of a constant fat body mass and its relation to body energy balance is presented on the basis of a series of experiments. A study of the neuroendocrine conditions underlying the daily weight gain-weight loss cycle in rat and man and experimentally induced over and underweight, leads to the notion that lipogenesis and lipolysis above and below a range of physiological fluctuations of body fat develop a counter-regulatory tendency to correcting lipolysis and lipogenesis respectively. This development is attributed to a chronic central action of plasma insulin concentration on hypothalamic insulin receptors. This liporegulatory system which controls and regulates the filling and emptying of fat stores modulates the feeding system which controls and regulates the filling of a gastrointestinal store by eating and its emptying by metabolic food utilization. PMID: 6392951 [PubMed - indexed for MEDLINE] 7072. Lab Res Methods Biol Med. 1984;10:241-86. Measurement of heparin-releasable triacylglycerol lipases. Gibson JC, Paterniti JR Jr, Goldberg IJ. PMID: 6390053 [PubMed - indexed for MEDLINE] 7073. Lab Res Methods Biol Med. 1984;10:231-40. Quantitation of the rate of fatty acid synthesis. Casazza JP, Veech RL. PMID: 6390052 [PubMed - indexed for MEDLINE] 7074. Tierarztl Prax. 1984;12(3):403-21. [Winter feeding or autumn feeding of game animals?]. [Article in German] Hofmann RR. A literature review of seasonal changes in metabolism and food intake and the accumulation of energy deposits (fat) during the natural mast period in autumn is linked to the results of feeding trials with roe deer (Capreolus capreolus) and red deer (Cervus elaphus) using supplementary feeding and/or planted crops to simulate the mast which is missing in conifer forests planted mainly for timber production. The results indicate that autumn mast simulation is more physiological and effective in reducing forest damage and increasing game quality than the traditional "emergency" winter feeding as practiced in Central Europe over hundred years. PMID: 6388030 [PubMed - indexed for MEDLINE] 7075. Aesthetic Plast Surg. 1984;8(1):13-7. Site differences in human subcutaneous adipose tissue metabolism in obesity. Arner P. The results of several recent studies indicate that there are regional differences in the metabolism of subcutaneous fatty depots in obesity. Fat cells are larger in the femoral than in the abdominal region. Lipids are mobilized at a slower rate but synthesized at a higher rate in the former than the latter region. Fasting is accompanied by an increased rate of fat mobilization and a decreased rate of fat synthesis in all fat depots. These changes are, however, more pronounced in abdominal than in femoral fat. There are also regional differences in the hormonal regulation of fat metabolism in obesity. The action of insulin is most pronounced in the femoral region whereas that of catecholamines is most marked in the abdominal area. The regional differences in hormone action are further enhanced during therapeutic fasting. These differences may partly explain why adiposity is more catching in some fatty regions than in others and also why some obese areas are resistant to slimming. PMID: 6375305 [PubMed - indexed for MEDLINE] 7076. Am J Physiol. 1984 Jan;246(1 Pt 2):R1-12. Viewing the ventromedial hypothalamus from the adrenal gland. Dallman MF. The relationships among food intake, insulin secretion, and adrenocortical function are reviewed. It is hypothesized that a major role of structures in, or passing through, the ventromedial hypothalamus is to inhibit food intake, insulin secretion, and adrenocortical function during the day (in the nocturnally active rat) and that this activity is normally driven by elements within the suprachiasmatic nuclei. Lesions of the ventromedial hypothalamus of rats result in nonrhythmic food intake, hyperinsulinemia, nonrhythmic adrenocortical function, and obesity. Adrenalectomy prevents or reverses the effects of lesions of the ventromedial hypothalamus on food intake, insulin secretion, and obesity, and corticosteroid replacement restores them. Because the actions of corticosteroids are both time- and dose-dependent, it is proposed that the effects of the tonic levels of corticosteroids observed after lesions of the ventromedial hypothalamus are to augment the hyperphagia, hyperinsulinemia, and substrate flow into fat to a greater extent than would occur if there were a normal circadian rhythm in adrenocortical function. PMID: 6320667 [PubMed - indexed for MEDLINE] 7077. Physiol Rev. 1984 Jan;64(1):1-64. Thermogenic mechanisms in brown fat. Nicholls DG, Locke RM. PMID: 6320232 [PubMed - indexed for MEDLINE] 7078. Gynecol Oncol. 1984 Jan;17(1):1-21. Peripheral aromatization as a risk factor for breast and endometrial cancer in postmenopausal women: a review. Enriori CL, Reforzo-Membrives J. In menopause, estrogens are produced almost exclusively through peripheral aromatization of androgens, especially androstenedione. Obesity increases the production rate of estrogens by means of the same mechanism. In postmenopause, plasma levels of SHBG diminish significantly. Obesity even further decreases the levels of SHBG, thus increasing "free" E2 available to target tissues. The increase in circulating estrogenic activity in menopause, whether as a result of obesity or of ingestion of estrogens, implies a risk factor for endometrial and breast cancer not only because of the permissive and stimulating effects of estrogens but also due to the special circumstance that they may act on target tissues in the almost absolute absence of the "protecting effect" of progesterone. The modifications performed by obesity on the values of SHBG and circulating estrogens are reversible, since they tend to normalize with weight loss. PMID: 6319245 [PubMed - indexed for MEDLINE] 7079. Recent Prog Horm Res. 1984;40:347-77. New perspectives on the mechanism of insulin action. Czech MP. PMID: 6207566 [PubMed - indexed for MEDLINE] 7080. Nutr Rev. 1984 Jan;42(1):1-7. Infant nutrition and later achievement. Dobbing J. PMID: 6199699 [PubMed - indexed for MEDLINE] 7081. Int J Obes. 1984;8 Suppl 1:201-13. Application of agents active at the alpha 2-adrenoceptor of fat cells to the treatment of obesity--a critical appraisal. Curtis-Prior PB, Tan S. The extent of cyclic AMP (cAMP) mediated lipolysis in adipose tissue cells of man and several other animal species is regulated by the interplay of alpha- and beta-adrenoceptors modulating adenyl cyclase activity. Although the naturally-occurring catecholamines, and isoprenaline, are thought to act at the same pro-lipolytic beta-adrenoceptor antilipolytic agents, working through the alpha 2-adrenoceptor moiety of adenyl cyclase, appear to act at separate sites for: true alpha 2-agonists such as clonidine, for adenosine and for prostaglandins. Further, such antilipolytic agents are conspicuously more potent against lipolysis stimulated by methyl-isobutylxanthine (MIX) than against that stimulated by catecholamines. The nature of the dual character of adenyl cyclase remains to be elucidated. alpha 2 Adrenoceptor antagonists which promote lipolysis, and may possibly serve a therapeutic role in the treatment of obesity, may also provoke inappropriate insulin release which is contraindicated. Thus a problem in chemotherapy exists which may be resolved by new agents with differential tissue specificities. An example of this chemotherapeutic dilemma is possibly provided by the body weight accruing actions of tricyclic antidepressant compounds whose mechanism of action involves also (central) alpha 2-adrenoceptors. PMID: 6152556 [PubMed - indexed for MEDLINE] 7082. Adv Exp Med Biol. 1984;175:31-45. Role of hormone-sensitive GTPases in adenylate cylase regulation. Aktories K, Schultz G, Jakobs KH. PMID: 6149675 [PubMed - indexed for MEDLINE] 7083. Int J Obes. 1984;8 Suppl 1:159-80. Regulation of thermogenesis in obesity. Levin BE, Sullivan AC. Obesity results when the intake of energy exceeds that which is expended with the resultant storage of the excess energy as fat. Thermogenesis, the metabolic expenditure of energy as heat, is the primary way in which mammals loss dietarily-derived energy and some evidence suggests that certain obese humans may have defective diet-induced thermogenesis. The sympathetic nervous system is the primary effector of thermogenesis through the release of norepinephrine at its nerve terminals. During the early stages of over-eating, there is an increase in sympathetic activity in several organs, including brown adipose tissue (BAT), a major thermogenic organ in many mammals. This increased neural activity is associated with increased thermogenic capacity of the entire animal as well as in BAT and, together, these events are sufficient to prevent the development of obesity in certain young animals such as rats. However, in older rats, obesity eventually develops over several months' of exposure to high energy diets and the early increases in thermogenic capacity and sympathetic activity return to or below baseline levels. Also, genetically obese rodents generally have defective total body and BAT thermogenic capacity, especially to a dietary challenge, as well as abnormal sympathetic function in their BAT. These observations suggest that there are certain types of obesity that are associated with a diminished ability to expend dietarily-derived energy as heat and that chronic obesity in general represents an altered homeostatic state associated with increased metabolic efficiency in some humans and other mammals. PMID: 6100111 [PubMed - indexed for MEDLINE] 7084. Drugs. 1984;28 Suppl 2:1-15. Alpha- and beta-adrenergic receptor subtypes properties, distribution and regulation. Molinoff PB. The effects of catecholamines in the central and peripheral nervous systems appear to be mediated through interactions with 2 major classes of receptor: alpha-adrenoceptors and beta-adrenoceptors. Subtypes of both alpha- and beta-adrenoceptors exist. In the periphery, alpha 1-receptors are located postsynaptically, mediating the excitatory effects of catecholamines at alpha-receptors. alpha 2-Adrenoceptors, on the other hand, are autoreceptors involved in the regulation of noradrenaline (norepinephrine) release. In the central nervous system, both alpha 1- and alpha 2-receptors exist on postsynaptic cells; there are also 2 principal subtypes of beta-adrenoceptors. beta 1-Receptors have a high affinity for both noradrenaline and adrenaline (epinephrine) and are found in the heart, brain, and adipose tissue. beta 2-Receptors have a low affinity for noradrenaline and are involved in mediation of relaxation of vascular and other smooth muscles and in many of the metabolic effects of catecholamines. A variety of effector systems have been implicated in the actions of catecholamines. Most, though not all, of the effects of catecholamines at beta-receptors are mediated through activation of adenyl cyclase and increases in cyclic AMP accumulation. The effects of catecholamines at alpha-receptors generally involve other second messenger systems. Thus, in at least some systems, stimulation of alpha 1-adrenoceptors mediates increases in phosphoinositide breakdown, while alpha 2-adrenoceptors appear to act through inhibition of adenyl cyclase activity. The pharmacological effects of alpha- and beta-adrenoceptors were initially characterised by measuring responses observed in intact preparations. The advent of the use of radioligand binding techniques has allowed direct approaches to the characterisation of receptor properties. The use of radioligands makes it possible to determine the affinities of receptors for specific ligands, and it is possible to determine the density of receptors in a tissue. Finally, in vitro assays serve as a means through which receptors can be followed during solubilisation, isolation, and reconstitution. Several ligands are now available for the study of alpha- and beta-adrenoceptors. In general, relatively selective radioligands are available for the study of alpha-receptors. Thus, 3H-WB 4101 and 3H-prazosin are selective ligands for alpha 1-receptors; the ligand 125I-IBE 2254 also shows high selectivity for alpha 1-receptors. 3H-Yohimbine and 3H-rauwolscine are selective antagonists for the labelling of alpha 2-receptors and 3H-clonidine is a selective agonist used for studying alpha 2-receptors.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6098436 [PubMed - indexed for MEDLINE] 7085. Vutr Boles. 1984;23(4):1-5. [Insulin resistance and anti-insula hormones]. [Article in Bulgarian] Vakov L. PMID: 6095535 [PubMed - indexed for MEDLINE] 7086. Int Rev Cytol. 1984;89:35-64. Histochemistry of adenylate cyclase. Poeggel G, Luppa H, Bernstein HG, Weiss J. PMID: 6088418 [PubMed - indexed for MEDLINE] 7087. Kroc Found Ser. 1984;18:31-54. Hemopoiesis in ectopically implanted bone marrow. Tavassoli M. Ectopically implanted bits of marrow undergo a regenerative process that recapitulates the marrow ontogeny. This process is possible only because marrow tissue has considerable angiogenic potential. The regenerative process originates from marrow stroma, leading to the formation of primitive mesenchyme, osteoid bone, reconstitution of marrow organization including its distinctive sinusoidal system, and repopulation with circulating hemopoietic stem cells. Expansion of hemopoiesis is then associated with bone resorption. Also, few adipose cells develop and they are interspersed with hemopoiesis. The final product is a hemopoietic nodule surrounded by a shell of bone. A similar process occurs within the marrow cavity after ablation of the marrow tissue. In yellow marrow implants, the subsequent development of adipose tissue replaces entirely the hemopoietic tissue. Splenic implants can also regenerate in an analogous fashion despite their lack of significant angiogenic potential. As a model system, ectopic implantation of marrow has been the forerunner of long-term marrow culture and has provided important information on the relationship between hemopoietic cells and their supporting stroma. It has also led us to further understanding of the relationship between the marrow and its surrounding bone. Moreover, it has been an excellent system to study the relationship between red and yellow marrow and their interconversion. The full potential of this model system has not yet been fully realized. In application, for example, the conversion of yellow to red marrow can be exploited to reactivate the areas of hemopoietically inactive marrow in the limbs. Such exploitation may permit more liberal use of ablative radiotherapy in malignant diseases, particularly those of the lymphoreticular system. In basic research, in conjunction with long-term bone marrow culture, ectopic marrow implantation can yet provide considerable information on the role of stroma and bone in hemopoiesis. PMID: 6085113 [PubMed - indexed for MEDLINE] 7088. Prog Clin Biol Res. 1984;158:331-54. Gastrointestinal and metabolic effects of methylxanthines. Fredholm BB. This chapter has covered a wide range of different actions of methylxanthines. They are able to slightly reduce the tone of the lower esophageal sphincter. This is of little concern in the normal individual, but in patients with a reduced initial tone it might lead to heartburn. Coffee intake has been associated with gastritis, but the role of methylxanthines in this effect is obscure. High doses of methylxanthines are also known to be emetic. Practically every function in the intestine can be influenced by high doses of methylxanthines, but the mechanisms involved and the biological significance remain largely obscure. Although in vitro studies with high doses of methylxanthines have demonstrated effects on secretion from salivary glands and exocrine pancreas, there is little evidence that this is clinically important in man. There is also small effects on insulin, glucagon, and TSH secretion. There is a consistent effect on fatty acid mobilization from adipose tissue, which may be of importance, eg, by improving physical performance and by increasing the overall metabolic rate. There is also some evidence for long-term effects on fat depots. By contrast, the effects on carbohydrate metabolism are much less prominent and reproducible, and may to some extent be secondary to altered lipid metabolism. Despite more than a century of effort to elucidate the actions of methylxanthines in man, one of the major conclusions to be drawn is that there is a need for further studies. In view of the newer ideas about the mechanism of action of caffeine and other methylxanthines, careful studies, especially of long-term effects of methylxanthines on several aspects of gastrointestinal function, on calcium homeostasis, on body composition, and on physical performance, would be desirable. PMID: 6084844 [PubMed - indexed for MEDLINE] 7089. Nutr Rev. 1983 Dec;41(12):361-73. Modern concepts of obesity. Vasselli JR, Cleary MP, Van Itallie TB. PMID: 6322060 [PubMed - indexed for MEDLINE] 7090. Nutr Rev. 1983 Sep;41(9):261-7. Brown adipose tissue thermogenesis in obese animals. Himms-Hagen J. PMID: 6358959 [PubMed - indexed for MEDLINE] 7091. Rev Clin Esp. 1983 Aug 15-31;170(3-4):83-7. [Lipoprotein lipase: review]. [Article in Spanish] Nuño J, de Oya M. PMID: 6227953 [PubMed - indexed for MEDLINE] 7092. Am J Obstet Gynecol. 1983 Aug 1;146(7):840-55. Fetal catecholamines. Phillippe M. Experimental data from fetal human and animal research suggest that the fetal sympathoadrenal system, composed of the adrenal medulla, sympathetic neurons, and extra-adrenal chromaffin tissue functions from early fetal life to maintain fetal homeostasis. The extra-adrenal chromaffin tissue undergoes maturation at 9 to 11 weeks of gestation, whereas the adrenal medulla and sympathetic nervous system mature later in fetal life. The fetal catecholamine response to hypoxia, mediated predominantly by norepinephrine, is an important component of the fetal cardiovascular response to hypoxia, i.e., through alpha-receptor stimulation, fetal cardiac output redistribution occurs. Fetal catecholamine secretion in response to substrate availability, through alpha- and beta-receptor stimulation, provide a mechanism by which the fetus can utilize its own substrate stores. Pulmonary beta-receptor stimulation by catecholamines has been demonstrated to increase lecithin synthesis, increase surfactant secretion, and decrease lung fluid production near term. beta-Receptor stimulation has also been demonstrated to have trophic effects on the development of thermogenic brown adipose tissue. Although the exact stimulus for the initiation of parturition in the primate is unknown, fetal catecholamines, through direct myometrial alpha-adrenergic or dopaminergic receptor stimulation and/or through the stimulation of prostaglandin production, have the potential of facilitating the onset of parturition. PMID: 6346884 [PubMed - indexed for MEDLINE] 7093. Philos Trans R Soc Lond B Biol Sci. 1983 Jul 5;302(1108):33-45. The role of phosphorylation in the regulation of fatty acid synthesis by insulin and other hormones. Denton RM, Brownsey RW. Insulin stimulates fatty acid synthesis in white and brown fat cells as well as in liver and mammary tissue. Hormones that increase cellular cyclic AMP concentrations inhibit fatty acid synthesis, at least in white adipose tissue and liver. These changes in fatty acid synthesis occur within minutes. In white fat cells, they are brought about not only by changes in glucose transport but also changes in the activities of pyruvate kinase, pyruvate dehydrogenase and acetyl-CoA carboxylase. The basis of the alterations in pyruvate kinase activity in fat cells is not understood. Unlike the liver isoenzyme, the isoenzyme present in fat cells does not appear to be phosphorylated either in the absence or presence of hormones. The changes in pyruvate dehydrogenase activity in fat cells are undoubtedly due to changes in phosphorylation of the alpha subunits. Insulin appears to act by causing the parallel dephosphorylation of all three sites. The persistence of the effect of insulin during the preparation and subsequent incubation of mitochondria has allowed the demonstration that insulin acts mainly by stimulating pyruvate dehydrogenase phosphatase rather than inhibiting the kinase. Acetyl-CoA carboxylase within fat cells is phosphorylated on a number of different sites. The exposure of cells to insulin leads to activation of the enzyme and this is associated with increased phosphorylation of a specific site on the enzyme. Exposure to adrenalin, which results in a marked diminution in activity, also causes a small increase in the overall level of phosphorylation, but this increase is due to an enhanced phosphorylation of different sites; probably those phosphorylated by cyclic-AMP-dependent protein kinase. Acetyl-CoA carboxylase is one of a number of proteins in fat cells that exhibit increased phosphorylation with insulin. Others include ATP-citrate lyase, the ribosomal protein S6, the beta subunit of the insulin receptor and a heat and acid stable protein of Mr 22000. Changes in phosphorylation of ATP-citrate lyase do not appear to result in any appreciable changes in catalytic activity. A central aspect of insulin action may be the activation and perhaps release of a membrane-associated protein kinase. Plasma membranes from fat cells have been shown to contain a cyclic-nucleotide-independent kinase able to phosphorylate and activate acetyl-CoA carboxylase. Furthermore, high-speed supernatant fractions from cells previously exposed to insulin contain elevated levels of the same or similar kinase activity capable of phosphorylating both ATP-citrate lyase and acetyl-CoA carboxylase. PMID: 6137007 [PubMed - indexed for MEDLINE] 7094. Tanpakushitsu Kakusan Koso. 1983 Jul;28(8):974-84. [Hypothetical theory on hormone-sensitive substrate]. [Article in Japanese] Okuda H, Saito Y. PMID: 6353483 [PubMed - indexed for MEDLINE] 7095. J Anim Sci. 1983 Jul;57 Suppl 2:273-83. Growth and development of meat animals. Trenkle A, Marple DN. During the past 25 yr, animal scientists have learned much about the effects of environmental factors, nutritional treatments, the use of anabolic agents and genetic selection on growth of animals. Progress has been made in terms of body and carcass composition as well as a more fundamental understanding of growth at the cellular level. Current emphasis is directed towards action of hormones on tissue metabolism, factors regulating hormone secretion, mechanisms of synthesis and degradation of proteins and the energetic efficiency of protein and fat synthesis. The overall objectives are to control growth of animals with respect to rate and composition of gain and to improve the efficiency of growth. PMID: 6352586 [PubMed - indexed for MEDLINE] 7096. J Anim Sci. 1983 Jul;57(1):239-46. Application of radioimmunoassay (RIA) for the determination of residues of anabolic sex hormones. Hoffmann B, Blietz C. Based on the basic principles of radioimmunoassay (RIA), it can be expected that by using this method, residues of anabolic sex hormones in animal tissues can be quantitated in the ng/g to pg/g range with adequate reliability. This was demonstrated for various endogenous and exogenous steroids as well as for stilbene-estrogens. Using the RIA for DES as a regulatory method allowed the successful control of the misuse of this compound in animal production, especially by examination of excreta. Also, for muscular tissue, an interlaboratory validation study yielded acceptable results. The need for confirmatory methods is stressed. PMID: 6350253 [PubMed - indexed for MEDLINE] 7097. Schweiz Med Wochenschr. 1983 Jun 18;113(24):870-5. [Physiopathology and treatment of obesity]. [Article in French] Jéquier E. Obesity results from an energy imbalance affecting both energy intake and output to various degrees. In some individuals hyperphagia may be the obvious cause of the imbalance, whereas in other obese patients a defective thermogenic capacity unable to adapt energy expenditure to a variable intake plays an important role. The mechanisms of this thermogenic defect are not well understood: decreased sensitivity to the thermogenic effects of the sympathetic nervous system and insulin resistance may be implicated. The thermogenic defect favours weight gain; it is likely that body weight reaches a plateau (th obese state) when the body weight gain is accompanied by a rise in basal metabolic rate which compensates the thermogenic defect. The excess in body weight becomes a compensated state which allows the whole energy intake to be expended. The principles of the protein sparing modified fast (low carbohydrate and lipid, but high protein intake) are outlined. After the end of the hypocaloric diet period the recommendations for maintaining the new body weight should stress the need to maintain a low lipid intake but allow carbohydrate intake (mainly starch). It is important to realize that the energy needs of the patient are lowered after weight loss. PMID: 6348939 [PubMed - indexed for MEDLINE] 7098. J R Soc Med. 1983 Jun;76(6):514-7. Thermogenesis in stress-susceptible pigs: a review. Lucke J, Hall G. PMCID: PMC1439205 PMID: 6864722 [PubMed - indexed for MEDLINE] 7099. Int J Cell Cloning. 1983 Jun;1(2):79-84. Adipocyte stem cell: a brief review. Soda R, Tavassoli M. PMID: 6366080 [PubMed - indexed for MEDLINE] 7100. Proc Nutr Soc. 1983 Jun;42(2):351-9. Fat supplementation in animal production--monogastric animals. Freeman CP. PMID: 6351090 [PubMed - indexed for MEDLINE] 7101. Proc Nutr Soc. 1983 Jun;42(2):315-31. Control of fatty acid synthesis in lactation. Vernon RG, Flint DJ. Lactation results not only in an increased rate of fatty acid synthesis in the mammary gland but also in a decreased rate of fatty acid synthesis in adipose tissue and, in the rat at least, an increased rate of hepatic fatty acid synthesis. Progesterone (during pregnancy), prolactin and (in ruminants) GH are implicated in the regulation of the reciprocal changes in fatty acid synthesis in mammary gland and adipose tissue. Progesterone and prolactin, at least, appear to influence the rate of fatty acid synthesis by modulating the insulin-binding capacities of the tissues, but it is clear that steps in the mechanism of action of insulin subsequent to its binding to the receptor are also changed in adipose tissue during lactation. PMID: 6351088 [PubMed - indexed for MEDLINE] 7102. Proc Nutr Soc. 1983 Jun;42(2):303-13. Changes in fatty acid synthesis associated with growth and fattening. Hood RL. PMID: 6351087 [PubMed - indexed for MEDLINE] 7103. Proc Nutr Soc. 1983 Jun;42(2):263-71. Fatty acid synthesis in liver and adipose tissue. Pearce J. PMID: 6351084 [PubMed - indexed for MEDLINE] 7104. Dan Med Bull. 1983 Jun;30(4):229-41. Sympathetic reflex control of blood flow in human subcutaneous tissue during orthostatic maneuvres. Skagen K. PMID: 6347540 [PubMed - indexed for MEDLINE] 7105. Proc Nutr Soc. 1983 Jun;42(2):129-36. The hormonal control of fat metabolism in animals. Weekes TE. PMID: 6310618 [PubMed - indexed for MEDLINE] 7106. Proc Nutr Soc. 1983 Jun;42(2):113-27. Hormones and feed intake. Baile CA, Della-Fera MA, McLaughlin CL. During the several decades that hormones have been considered for roles in the control of feeding, certain ones have gained special attention, although the role assigned to any one hormone has varied from time to time. Three classes of hormones have been considered in this review: gastrointestinal, brain, and pancreatic. Of these classes, two have obtained the most compelling evidence for a physiological role in the control of feeding. CCK, an intestinal and brain hormone, appears to be involved in satiety. Glucagon of pancreatic origin appears also to play an important role in satiety. These hormones, when sequestered by a specific antibody, cause a delay in satiety and thus increase food intake. Insulin, another pancreatic hormone, has been considered for several roles in the control of feeding. Recently, attention has been given to the possibility that insulin of the CSF provides an integrated link between the metabolic state of the adipose tissue and the brain structures concerned with the control of feeding. Thus, insulin may be a primary hormone involved in the maintenance of energy balance or of body-weight. Finally, brain opiate peptides, e.g. dynorphin, are very likely involved in the transmission of information concerned with the interaction of feeding and maintenance of energy balance. Clearly, hormones play primary roles in the control of feeding behaviour and the regulation of energy balance, but much remains to be done to establish their specific actions or components of the associated physiological systems. PMID: 6136974 [PubMed - indexed for MEDLINE] 7107. Metabolism. 1983 Jun;32(6):628-41. The phosphatidate-phosphoinositide cycle: an intracellular messenger system in the action of hormones and neurotransmitters. Farese RV. Many hormones and neurotransmitters provoke rapid and striking changes in the metabolism of phospholipids in the phosphatidate-inositide cycle. These changes appear to occur before and after the generation of other accepted "second messengers" (e.g., Ca++ and cAMP), and seem to be important intracellular effector substances for the elicitation of biological effects. The two major mechanisms for perturbing the phosphatidate-inositide cycle are phosphatidylinositol hydrolysis and de novo phosphatidate-inositide synthesis. Phosphatidylinositol hydrolysis occurs in the action of all agents which operate via Ca++ and appears to be provoked both by Ca++-dependent and Ca++-independent mechanisms. Ca++-independent phosphatidylinositol hydrolysis may be triggered directly by receptor activation and may control Ca++ release or entry into the cytosol. Ca++-dependent phosphatidylinositol hydrolysis may be important for further changes in cellular Ca++ distribution and membrane fusion during exocytosis. The de novo phosphatidate-inositide synthesis effect has been observed in the action of most steroidogenic agents (ACTH, luteinizing hormone, angiotensin II, K+, serotonin), parathyroid hormone and insulin. The de novo effect is inhibited by cycloheximide, requires Ca++, and appears to serve as a post-second messenger mechanism to alter membrane structure and the function of membrane associated substances. Considerable evidence suggests that the de novo effect is important in the control of steroidogenesis by the above-mentioned agents; it may also be important in the action of insulin in adipose tissue. PMID: 6133206 [PubMed - indexed for MEDLINE] 7108. Br Med J (Clin Res Ed). 1983 May 28;286(6379):1684-6. Luxuskonsumption, brown fat, and human obesity. Garrow JS. PMCID: PMC1548238 PMID: 6405934 [PubMed - indexed for MEDLINE] 7109. Biosci Rep. 1983 May;3(5):431-41. The thermogenic mechanism of brown adipose tissue. Review. Nicholls DG. PMID: 6882887 [PubMed - indexed for MEDLINE] 7110. Diabete Metab. 1983 May-Jun;9(2):141-7. Recent evidence for the involvement of brown adipose tissue in body weight regulation. Seydoux J. This short review first describes the energy requirements in homeotherms and the components of their energy balance. It emphasizes the role of brown adipose tissue as an effector of both non shivering and adaptive diet-induced thermogenesis. This tissue has in fact been recently found to be a common effector of both thermic and weight regulation in small mammals. This finding is based on experiments performed in genetically or experimentally obese rodents. The possible role of brown adipose tissue in adaptive diet-induced thermogenesis in man is discussed. PMID: 6352351 [PubMed - indexed for MEDLINE] 7111. J R Soc Med. 1983 Mar;76(3):213-6. Brown adipose tissue in man: a review. Blaza S. PMCID: PMC1438720 PMID: 6834374 [PubMed - indexed for MEDLINE] 7112. Internist (Berl). 1983 Mar;24(3):167-81. [The effect of age, weight, sex and smoking habits on drug dosage]. [Article in German] Ochs HR, Verburg-Ochs B. PMID: 6347943 [PubMed - indexed for MEDLINE] 7113. Dan Med Bull. 1983 Mar;30(2):85-100. Adipose tissue blood flow during exercise. Bülow J. PMID: 6342986 [PubMed - indexed for MEDLINE] 7114. Clin Endocrinol Metab. 1983 Mar;12(1):1-13. Regulation of alpha and beta adrenergic receptors in man. Hoffman BB. PMID: 6342875 [PubMed - indexed for MEDLINE] 7115. Drug Intell Clin Pharm. 1983 Feb;17(2):100-4. Amiodarone for tachyarrhythmias: pharmacology, kinetics, and efficacy. Canada AT, Lesko LJ, Haffajee CI, Johnson B, Asdourian GK. Amiodarone, although widely studied in Europe, is a recent addition to the investigational antiarrhythmics being used in the U.S. Pharmacologically, its primary cardiac effects are to increase coronary artery blood flow, increase the effective refractory period, and produce an atropine-resistant bradycardia. Amiodarone is incompletely (approximately 50 percent) and slowly (peak serum concentration approximately 6 h) absorbed. With chronic administration, it deposits both in adipose tissue and in organs with high blood perfusion. It has an apparent elimination half-life of 15-45 days, which presents unique dosing problems. The apparent therapeutic range is 0.6-3 microgram/ml. Amiodarone is 85-95 percent effective in the treatment of atrial tachyarrhythmias and 70-80 percent effective in ventricular tachyarrhythmias. It appears to be of particular value in chronic atrial fibrillation/flutter because it may be able to maintain sinus rhythm after cardioversion. Side effects, although uncommon, may prevent the drug from becoming a standard of therapy. Drug interactions, particularly with warfarin and digoxin, as well as pulmonary fibrosis are of concern. PMID: 6337802 [PubMed - indexed for MEDLINE] 7116. Am J Med. 1983 Jan 17;74(1A):31-7. The chemical mediators of insulin action: possible targets for postreceptor defects. Jarett L, Kiechle FL, Parker JC, Macaulay SL. An insulin-sensitive subcellular system was developed from rat adipocytes consisting of plasma membranes and mitochondria. Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. This was similar to the mechanism by which insulin causes activation of the enzyme in the intact cell. The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. Our laboratory has shown that the mediator that activates pyruvate dehydrogenase was present in intact adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin altered the amount or activity of the mediator consistent with the effect of the hormone on the cell. Other laboratories have shown similar effects on skeletal muscle and liver. We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. Other laboratories have shown the mediator to activate glycogen synthase. A body of direct and indirect evidence exists that demonstrates that more than one mediator exists. The chemical nature of the mediator is unknown but probably represents a new family of intracellular mediators of hormone action. These mediators may have clinical relevance in postreceptor defects of obesity and type II diabetes (noninsulin-dependent diabetes mellitus). PMID: 6337485 [PubMed - indexed for MEDLINE] 7117. Biochem Soc Symp. 1983;48:117-32. A new era of exploitation of microbial metabolites. Demain AL. In the past history of the pharmaceutical industry, secondary metabolites have been screened almost exclusively for antimicrobial activities. This biased and narrow view has severely limited the potential application of microbial metabolites. Fortunately, this situation is changing and we are now entering into a new era in which microbial metabolites are being applied to diseases heretofore only subjected to synthetic compounds. This new approach is the application of microbial secondary metabolites to diseases that are not caused by other bacteria or fungi. For years, major drugs such as hypotensive and anti-inflammatory agents that are used for non-infectious diseases have been strictly synthetic products. Similarly, major therapeutics for parasitic diseases in animals (for example, coccidiostats and anthelminthics) resulted strictly from screens of chemically synthesized compounds followed by molecular modification. However, today fermentation products such as monensin and lasalocid dominate the coccidiostat market. The avermectins, another group of streptomycete products, have high activity against helminths and arthropods. Indeed, their activity appears to be an order of magnitude greater than previously discovered anthelminthic agents, the vast majority of which are synthetic compounds. Umezawa's group in Japan has isolated many microbial products with important pharmacological activities by screening with simple enzymic assays. There is much interest in a natural inhibitor of intestinal glucosidase, which is produced by an actinomycete of the genus Actinoplanes. The aim is to decrease hyperglycaemia and triacylglycerol synthesis in adipose tissue, liver and the intestinal wall of patients with diabetes, obesity and type IV hyperlipidaemia. Another natural compound of interest is mevinolin, a fungal product which acts as a cholesterol-lowering agent in animals. Mevinolin is produced by Aspergillus terreus. In its hydroxyacid form (mevinolinic acid), mevinolin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from liver. It is clear that, although the microbe has contributed greatly to the benefit of mankind, we have merely scratched the surface of the potential of microbial activity. PMID: 6400479 [PubMed - indexed for MEDLINE] 7118. Ann Endocrinol (Paris). 1983;44(5):291-4. [Adrenergic control of adipocyte metabolism]. [Article in French] Lafontan M, Berlan M. PMID: 6372637 [PubMed - indexed for MEDLINE] 7119. Adv Pediatr. 1983;30:473-515. Nutritional physiology in pregnancy and lactation. Nichols BL, Nichols VN. PMID: 6369942 [PubMed - indexed for MEDLINE] 7120. Adv Metab Disord. 1983;10:457-68. The role of insulin as a satiety factor in the central nervous system. Woods SC, Porte D Jr. PMID: 6364721 [PubMed - indexed for MEDLINE] 7121. Ciba Found Symp. 1983;101:70-91. Tocopherol content of adipose tissue from vitamin E-deficient humans. Kayden HJ. The high performance liquid chromatographic isolation of tocopherol with fluorometric quantitation, which we have previously described, has been extended to the analysis of needle aspiration biopsies of adipose tissue. Results are expressed relative to triglyceride content (ng tocopherol per mg triglyceride). In normal subjects adipose tissue content was 262 +/- 33; this value was increased two- to three-fold in normal persons ingesting additional vitamin E. Abetalipoproteinaemic patients have very low adipose tissue tocopherol values--about 10-20% of normal subjects; with massive supplementation of vitamin E (grams per day) a number of such patients have achieved normal tissue tocopherol concentrations. Patients with cholestatic liver disease and low plasma content of tocopherol also had low adipose tissue values; these could be increased by parenteral administration of vitamin E. Neuromuscular improvement noted in response to treatment with supplementary vitamin E has not as yet been correlated to the adipose tissue increment of tocopherol. While extensive observations on the intestinal absorption of tocopherol in humans have been reported, the mode of transfer from plasma lipoproteins to tissues has been less studied. Our results from patients with lipoprotein lipase deficiency and other abnormalities of lipid metabolism suggest that considerable transfer occurs during the initial catabolism of the chylomicrons. PMID: 6360590 [PubMed - indexed for MEDLINE] 7122. Bibl Nutr Dieta. 1983;(33):16-30. Body composition and energy expenditure in elderly people. Durnin JV. PMID: 6360150 [PubMed - indexed for MEDLINE] 7123. Experientia Suppl. 1983;44:77-88. Nutrient intake and energy regulation in physical exercise. Howald H, Decombaz J. Rates of energy expenditure as well as total daily energy cost can be considerable during periods of exercise. In trained athletes, expenditure can be as high as 380 kJ/min during short-term maximal exercise. Training programmes of several hours' duration lead to a daily nutrient intake of 25-35 MJ in most Olympic sports. The mobilization of the energetic fuels of the body is modulated by the nature of the exercise. ATP and creatine phosphate stores in muscle cells are depleted within seconds during maximal work. Glycogen is the main fuel for heavy exercise of a few minutes' duration where performance capacity is limited by the degree of lactate accumulation and intracellular acidosis. Oxidation of both glucose and free fatty acids supplies the energy needed for exercise lasting more than two minutes, the relative contribution of lipids increasing with a longer duration or a lower intensity of the muscular work. Intramuscular stores of glycogen and triglycerides may be almost completely depleted in long-lasting exercise, e.g. a 100 km run. Under these conditions, glycogen stores in the liver and triglycerides in adipose tissue contribute approximately 70% of the energy need whereas 5-10% of the supply comes from oxidation of amino acids. Although adequate nutrition for exercise could be achieved through the intake of a well-balanced diet, the regulation of energy utilization can be influenced by the sources of food energy, by dietary modifications before exercise or by nutrient supplements during exercise. Intake before exercise of fructose or medium-chain triglycerides, both only weakly insulinogenic compared to glucose, leads to changes in blood substrates and metabolites. However, neither glycogen depletion in the working muscles nor performance capacity was influenced by a single meal containing this particular carbohydrate or lipid. Mobilization of free fatty acids in adipose tissue can be enhanced by caffeine or depressed by nicotinic acid. Since the rate of free fatty acid oxidation in skeletal muscle depends on the blood concentration of this substrate, energy regulation during exercise and work output are considerably influenced by the ingestion of such substances. PMID: 6357850 [PubMed - indexed for MEDLINE] 7124. Experientia Suppl. 1983;44:57-76. Energy fuel and hormonal profile in experimental obesities. Jeanrenaud B. Several types of experimental obesities are characterized by the occurrence of an early hypersecretion of insulin that produces an increase in both triglyceride secretion by the liver and fat deposition in adipose tissue. This hypersecretion of insulin, together with other ill-defined factors, is subsequently responsible for a state of insulin resistance. The early oversecretion of insulin in hypothalamic and genetic (e.g. fa/fa rats) obesities can be experimentally demonstrated. Thus, within 20 min of acute lesion of the ventromedial hypothalamus (VMH), glucose-induced insulin secretion is greater in lesioned than in non-lesioned control rats; this increase can be blocked by superimposed, acute vagotomy. Moreover, an infusion of glucose to 17-day-old, pre-weaned control and genetically pre-obese rats (i.e. animals genetically-determined to become obese but with a normal body weight at this age) elicits much greater insulinaemia in the pre-obese than in the controls, despite similar basal, pre-infusion values in both. This increased insulin secretion in the pre-obese rats can be restored to normal by pre-treating them acutely with the cholinergic inhibitor, atropine. Thus, in these two types of obesity, an increased vagal tone appears to be of importance for the early occurrence of insulin over-secretion. Hyperinsulinaemia produced by increased tone of the vagus nerve appears to be reinforced by the decreased activity of the sympathetic system observed in obese rodents. In many obese rodents, plasma growth hormone levels are abnormally low. The inadequate secretion of this hyperglycaemic hormone may explain why, in some types of obesity syndrome, hyperglycaemia is not necessarily present, despite insulin resistance. Insulin resistance in experimental obesities has been shown to occur at the level of the adipose tissue, the muscles and more recently, the liver. The latter has been demonstrated using the in vivo euglycaemic clamp technique; thus, glycogenolysis of genetically obese (fa/fa) rats could not be shut off, as in controls, by either basal or increased plasma insulin levels. This particular pathway is therefore insulin resistant. The precise etiology of the early over-secretion of insulin in VMH-lesioned rats is, however, unknown: with VMH lesions, the origin is clearly the central nervous system (CNS), but the pathways actually interrupted by the lesions and those responsible for the hyperactivity of the vagus, remain to be determined.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6357849 [PubMed - indexed for MEDLINE] 7125. Experientia Suppl. 1983;44:26-44. Thermogenic responses induced by nutrients in man: their importance in energy balance regulation. Jequier E. The regulation of body weight depends upon the control of food intake and the regulation of energy expenditure. In man, the control system for food intake may be overwhelmed by psychological or social influences and the thermogenic response to a variable energy input may play an important role in the energy regulatory system. Energy expenditure can be divided into 3 components: basal metabolic rate, thermogenesis and physical activity. Of these 3 components, thermogenesis, (i.e. the energy expended above the metabolic rate in the resting state) is the expenditure. The two main factors which contribute to thermogenesis, i.e food intake and cold exposure, elicit diet-induced thermogenesis (DIT) and non-shivering thermogenesis (NST), respectively. It is of interest to study thermogenesis in individuals who present a tendency to gain weight, in order to assess whether the thermogenic responses may be lower in these subjects than in lean controls. It has recently been shown that DIT consists of two separate components which can be described as "obligatory" and "regulatory" thermogenesis. The former is due to the energy costs of digesting, absorbing and converting the nutrients to their respective storage forms. The latter is an energy dissipative mechanism, mainly studied in animals. There is good experimental evidence showing that brown adipose tissue (BAT) is involved in the adaptive thermogenesis observed in rats fed a varied and palatable "cafeteria" diet. In addition, a thermogenic defect in BAT has been demonstrated in adult as well as young genetically obese animals, and this defect is present not only in adult, but also in young (12 day old) ob/ob mice, i.e. before the development of obesity. Thus, a defective thermogenesis seems to be a cause, rather than a consequence, of obesity in these animals. In man, the role of thermogenesis in energy balance regulation is not yet understood. Some conflicting results may have arisen from inadequate techniques to measure energy expenditure. In our laboratory, we have developed three different techniques to measure energy expenditure in man, namely direct calorimetry, indirect calorimetry using an open-circuit ventilated hood system, and a respiratory chamber. Data from recent studies on DIT in man support the concept that a defect in thermogenesis may contribute to energy imbalance and weight gain in obese individuals.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6357848 [PubMed - indexed for MEDLINE] 7126. Vestn Akad Med Nauk SSSR. 1983;(7):74-85. [Linking of the insulin-receptor complex with the membrane transport system through ATP generation by plasma membranes]. [Article in Russian] Karelin AA. PMID: 6353801 [PubMed - indexed for MEDLINE] 7127. Acta Paediatr Scand Suppl. 1983;305:7-11. Water distribution in the foetus and newborn infant. Friis-Hansen B. A short survey is given over changes in water metabolism from early foetal life to infancy. The close connection between water metabolism and body composition is described as well as the changes taking place after birth. The impact of intrauterine malnutrition, delivery and postnatal nutrition is discussed. PMID: 6351536 [PubMed - indexed for MEDLINE] 7128. Exerc Sport Sci Rev. 1983;11:159-80. Physiological and clinical aspects of exercise in obese persons. Björntorp P. PMID: 6350017 [PubMed - indexed for MEDLINE] 7129. Ann Endocrinol (Paris). 1983 Jan-Mar;44(1):77-81. [Insulin and the metabolism of lipoproteins]. [Article in French] Romon M, Thomas-Desrousseaux P, Beuscart R, Fossati P, Sezille G, Jaillard J. In normal individuals, insulin regulates lipoprotein metabolism. It increases hepatic triglycerides (TG) secretion and makes VLDL and chylomicrons post prandial removal easy by stimulating adipose tissue lipoprotein lipase (LPL). Insulin activity and cholesterol rich lipoprotein is more complicated: by its action on VLDL and chylomicrons turn-over, it influences LDL and HDL formation. It regulates cellular cholesterol pool at different levels: stimulation of LDL receptor, but also of HMG CoA reductase. Controlling LCAT, in participates in cholesterol removal by HDL. In insulin dependent diabetes, lack of adipose tissue LPL stimulation augments triglycerid-rich lipoproteins, by slowing their catabolism, resulting in a weak increase of LDL and a lowering of HDL. In non insulin dependent diabetes with hyperinsulinism, VLDL are elevated because of insulin stimulation of triglycerid hepatic production. LDL are increasing. HDL status remains discussed: HDL cholesterol is low but HDL triglycerid is high, there is no known disturbance of apo A level. In the two types of diabetes, although mechanism is different, perturbation of lipoprotein metabolism may account for the atherogenicity of this disorders. PMID: 6347030 [PubMed - indexed for MEDLINE] 7130. Adv Nutr Res. 1983;5:201-20. Diet-induced thermogenesis. Rothwell NJ, Stock MJ. PMID: 6342342 [PubMed - indexed for MEDLINE] 7131. Med Sci Sports Exerc. 1983;15(1):32-40. The energetics of obesity. Bray GA. PMID: 6341751 [PubMed - indexed for MEDLINE] 7132. Rev Physiol Biochem Pharmacol. 1983;96:123-70. The mammalian pyruvate dehydrogenase complex: structure and regulation. Wieland OH. PMID: 6338572 [PubMed - indexed for MEDLINE] 7133. J R Soc Med. 1983 Jan;76(1):71-3. Role of brown adipose tissue thermogenesis in overfeeding: a review. Stock MJ, Rothwell NJ. PMCID: PMC1438540 PMID: 6338229 [PubMed - indexed for MEDLINE] 7134. Biochem Soc Trans. 1983 Jan;11(1):52-6. The role of substrate cycles in metabolic regulation. Newsholme EA, Arch JR, Brooks B, Surholt B. PMID: 6337886 [PubMed - indexed for MEDLINE] 7135. Clin Sci (Lond). 1983 Jan;64(1):7-18. Luxuskonsumption, diet-induced thermogenesis and brown fat: a critical review. Hervey GR, Tobin G. PMID: 6337008 [PubMed - indexed for MEDLINE] 7136. Clin Sci (Lond). 1983 Jan;64(1):19-23. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Rothwell NJ, Stock MJ. PMID: 6337007 [PubMed - indexed for MEDLINE] 7137. Adv Lipid Res. 1983;20:195-217. Nicotinic acid and its derivatives: a short survey. Hotz W. Nicotinic acid is used widely in the treatment of hyperlipoproteinemias and reduces both the cholesterol and the triglyceride concentrations in the plasma. However, very high doses are needed to achieve these therapeutic effects, which is why side effects are common and are particularly known to hinder the compliance of patients. Nicotinic acid derivatives have been developed to overcome this problem. As a result of chemical and galenic retardation, these derivatives lessen the side effects and the necessary doses are considerably reduced in comparison with pure nicotinic acid. However, most of these derivatives are not pure prodrugs, and exert their own synergistic pharmacokinetic and pharmacodynamic effects. In general, when nicotinic acid and its derivatives are used in therapy a desirable modification of the composition of the plasma lipids in the sense of an antiatherosclerotic activity can be expected (reductions of VLDL and LDL and an increase of HDL). Good possibilities for using nicotinic acid in the prevention and remission of atherosclerotic processes arise in connection with the activation of fibrinolysis and the reduction of the tendency toward platelet aggregation. In the light of recent studies on the mechanisms of action of nicotinic acid, an influence on the prostaglandin system has been found, as a result of which an interconnection between its various effects and side effects appears to be possible. PMID: 6322545 [PubMed - indexed for MEDLINE] 7138. Int Rev Neurobiol. 1983;24:343-431. Characterization of alpha 1- and alpha 2-adrenergic receptors. Bylund DB, U'Prichard DC. Within the short period of 5 years, the availability of a variety of specific radioligands has allowed the resolution of alpha 1- and alpha 2-adrenergic receptor populations in many different tissues and enabled researchers to begin investigations of the mechanisms of regulation and coupling of alpha 1 and alpha 2 receptors to their different cellular effector systems. Binding data have demonstrated that the pharmacological properties of each type of alpha receptor are, in general, similar across tissues and species, although there are some differences in the relative affinities of antagonist drugs. Further attempts to subclassify alpha 1 and alpha 2 receptors may be expected in the future. The historical development of the interpretation of [3H]clonidine binding is of interest in this regard. [3H]Clonidine was proposed to label the "agonist state" of the alpha receptor, and then to label alpha 2 receptors. It is now thought that it labels the agonist state of alpha 2 receptors. Might it actually label a subpopulation of alpha 2 receptors or just the agonist state of that subpopulation? Alpha-1 receptors by and large appear to occur in a single-affinity state with respect to both agonists and antagonists. By comparison, alpha 2 receptors may exist in multiple-affinity states reflecting the ability of the alpha 2 binding site protein to complex to additional membrane proteins which themselves are receptors for the physiological substrates GTP, Na+, Mg2+, and possibly Ca2+-calmodulin. Binding studies have also strongly indicated that alpha 2 receptors in most, if not all, tissues are probably coupled in an inhibitory manner to adenylate cyclase, as has been demonstrated in platelets, adipocytes, and NG 108-15 cells. Clearly the present status of alpha-receptor research has left many questions unresolved. We still have no idea what membrane effector system and associated second messenger is coupled to the alpha 1 receptor. The prevailing belief is that Ca2+ and the membrane Ca2+ channel fulfill these roles. However, others have suggested that phosphoinositide turnover represents the proximal receptor response, and indeed a membrane-bound phospholipase C may play an analogous role to adenylate cyclase for other adrenergic receptors (Putney et al., 1980). There is, however, some evidence that in some situations alpha 1 receptors may directly stimulate adenylate cyclase, and guanine nucleotide modulation of agonist affinities at alpha 1-receptor sites has been reported. The significance of these data and reported modulatory effects of Na+ at alpha 1 receptors (Glossmann and Presek, 1979; Glossmann et al., 1981) is still to be resolved.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6317599 [PubMed - indexed for MEDLINE] 7139. Endocr Rev. 1983 Fall;4(4):378-88. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Bilezikian JP, Loeb JN. A detailed review has been conducted of studies addressing dressing the subject of the influence of thyroid hormone on alpha- and beta-adrenergic receptors and adrenergic responsiveness in a wide range of experimental animals and tissues. The studies summarized in the present article have been restricted to those in which explicit measurements of receptor number were made by the use of appropriate radioligands. Particular emphasis is given to an examination of the relationship between thyroid hormone-induced changes in alpha- and beta-adrenergic receptor number and accompanying changes in adenylate cyclase activity and more distal adrenergic responses. Although in many instances thyroid hormone-induced changes in receptor number are reflected in coordinate changes in adrenergic sensitivity, this is shown to be by no means uniformly the case. In contrasting instances, modifications at other more distal sites in the sequence of events mediating catecholamine hormone action are responsible for biochemical and physiological changes in catecholamine responsiveness induced by thyroid hormone. PMID: 6317368 [PubMed - indexed for MEDLINE] 7140. Journ Annu Diabetol Hotel Dieu. 1983:211-21. [Progesterone and glucose-lipid metabolism of adipose cells]. [Article in French] Sutter-Dub MT, Latrille F, Sfaxi A. PMID: 6316017 [PubMed - indexed for MEDLINE] 7141. Recent Prog Horm Res. 1983;39:519-57. Actions of insulin on glucose transport and cAMP phosphodiesterase in fat cells: involvement of two distinct molecular mechanisms. Kono T. PMID: 6314449 [PubMed - indexed for MEDLINE] 7142. Exerc Sport Sci Rev. 1983;11:1-23. Cellular control of triacylglycerol metabolism. Oscai LB, Palmer WK. PMID: 6309530 [PubMed - indexed for MEDLINE] 7143. Mol Cell Biochem. 1983;53-54(1-2):221-32. 3T3-L1 preadipocyte differentiation and poly(ADP-ribose) synthetase. Pekala PH, Moss J. Differentiation of 3T3-L1 preadipocytes, induced by methyl-isobutylxanthine (MIX), dexamethasone (DEX), and insulin, results in cells with the morphological and biochemical characteristics of adipocytes. Following incubation of 3T3-L1 cells with MIX, DEX, and insulin, poly(ADP-ribose) synthetase activity decreased abruptly, remained low for several hours and then increased; this rise was delayed by readdition of MIX, DEX, and insulin. The transient reduction in poly(ADP-ribose) synthetase activity in 3T3-L1 cells occurred prior to the appearance of the adipocyte phenotype induced by the above agents. It was not observed when preparations were assayed in the presence of DNase I, indicating that poly(ADP-ribose) synthetase activity was masked following treatment with MIX, DEX, and insulin. The change in synthetase activity represents the earliest alteration of a specific enzyme yet detected during the differentiation of 3T3-L1 cells. It appears to be differentiation specific since nondifferentiating 3T3-C2 control cells did not exhibit changes in poly(ADP-ribose) synthetase activity when treated with MIX, DEX, and insulin. The transient reduction in activity may be an early event in differentiation which reflects changes in chromatin structure. PMID: 6194420 [PubMed - indexed for MEDLINE] 7144. J Histochem Cytochem. 1983 Jan;31(1A Suppl):159-63. What is known of the production of basement membrane components. Laurie GW, Leblond CP. Immunohistochemistry was used to identify basement membrane components and examine their production by associated cells. Four substances were identified in a series of basement membranes in rats aged 20 days to 34 months, namely, type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin. They were then all localized to the basal lamina part of basement membranes and, presumably, are integrated within this layer. The production of type IV collagen was first examined in the embryonic endodermal cells associated with Reichert's membrane in the rat parietal yolk sac. The rough endoplasmic reticulum (rER), Golgi apparatus, and putative secretory granules of endodermal cells were immunostained, suggesting that these organelles participated in the biogenesis of type IV collagen. However, in rats aged 20 days or more, the cells associated with basement membranes were usually unstained. An exception was noted in the continually growing incisor tooth where the endothelial cells at the proliferating end usually showed immunostaining of rER and Golgi apparatus. It is, therefore, proposed that the formation of type IV collagen for basement membrane occurs at an early stage of development in the life of producer cells. Little is known of the formation of other basement membrane components during development, but there is immunohistochemical evidence that laminin and fibronectin are produced along the same secretory pathway as type IV collagen. PMID: 6186721 [PubMed - indexed for MEDLINE] 7145. Acta Med Scand Suppl. 1983;672:49-54. beta-Adrenoceptor blockade and exercise: effects on endurance and physical training. Juhlin-Dannfelt A. beta-adrenoceptor antagonists influence almost all haemodynamic and metabolic actions in the body. High levels of sympathetic stimulation accompany aerobic exercise and it is known that beta-blockade results in a decreased working capacity. Furthermore it has also been questioned whether beta-blockade inhibits the normal response to physical training. Although adrenergic mechanisms are involved in muscle and liver glycogen breakdown, beta-blockade does not seem to reduce glycogen utilisation during exercise. Both selective and non-selective beta-blockade inhibit lipolysis and result in less free fatty acids being available for muscle utilisation. Surgical and chemical sympathectomy in animals has been shown to inhibit the responses to physical training but results are now available showing that beta-adrenergic blockade does not prevent the effect of physical conditioning in patients treated with propranolol. It is concluded that beta-blockade during prolonged exercise a) does not reduce oxygen uptake by the working muscles b) decreases fat metabolism, which secondarily increases the use of carbohydrates, resulting in earlier hypoglycaemia and/or depletion of muscle glycogen with reduction in working capacity c) does not inhibit central and peripheral adaptation to physical conditioning. PMID: 6138934 [PubMed - indexed for MEDLINE] 7146. J Pharmacol. 1983;14 Suppl 2:209-15. The effects of beta-adrenoceptor blocking drugs on non-esterified fatty acid release from adipocytes. Harms HH. A review is presented of the effects of beta-adrenoceptor blocking agents on lipolysis in adipose tissue. Considerable species differences appear to exist between the pharmacological characteristics of beta-adrenoceptors in adipocytes of rat, guinea pig, dog, cat, swine and man. Human adipocyte beta-adrenoceptors probably consist of two subtypes; insufficient data are available to ascertain whether they represent "classical" beta 1- and beta 2-adrenoceptors or atypical receptors similar but not identical to those in the rat. In vivo studies in man suggest that non-cardioselective beta-adrenoceptor blocking agents are more effective antilipolytic agents than cardioselective beta-adrenoceptor antagonists. No clinical evidence could be found to suggest that the quantitative differences in antilipolytic potency between cardioselective and non-cardioselective agents have more than speculative significance. PMID: 6138469 [PubMed - indexed for MEDLINE] 7147. Annu Rev Biochem. 1983;52:537-79. Fatty acid synthesis and its regulation. Wakil SJ, Stoops JK, Joshi VC. PMID: 6137188 [PubMed - indexed for MEDLINE] 7148. Adv Nutr Res. 1983;5:221-53. The influence of dietary fatty acid composition on lipogenesis. Herzberg GR. PMID: 6133419 [PubMed - indexed for MEDLINE] 7149. Endocr Rev. 1983 Winter;4(1):78-95. Phosphoinositide metabolism and hormone action. Farese RV. PMID: 6131819 [PubMed - indexed for MEDLINE] 7150. J Anim Sci. 1982 Dec;55(6):1515-27. Role of peptides from gastrointestinal cells in food intake regulation. McLaughlin CL. Many peptides are contained in specific cells distributed throughout the gastrointestinal tract. Some are known to be released by the presence of specific components of food and to affect specific gastrointestinal functions related to digestion and absorption of nutrients. For many of the more recently identified peptides, however, stimuli for release and physiological functions are unknown. Improved radioimmunoassay techniques have allowed measurement of serum concentration changes of peptides that act via endocrine but not neurocrine or paracrine modes of action. Peptides that may play a role in the control of food intake include cholecystokinin (CCK), bombesin (BBS) and pancreatic polypeptide (PP) as possible satiety components and opiates as possible hunger components. All four have been found in the brain as well as in the gastrointestinal tract. Systemic administration of each has been shown to affect food intake, but whether doses used produced changes that normally occur during a meal awaits further development of radioimmunological assays. In the obese, the decreased sensitivities to, or decreased concentrations of the satiety components CCK, BBS and PP and the increased concentrations of the hunger component, B-endorphin, may contribute to the imbalance of food intake and energy expenditure, which leads to the accumulation of adipose tissue. PMID: 6761331 [PubMed - indexed for MEDLINE] 7151. J Med Chem. 1982 Dec;25(12):1389-401. alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs. Timmermans PB, van Zwieten PA. PMID: 6296387 [PubMed - indexed for MEDLINE] 7152. Usp Sovrem Biol. 1982 Nov-Dec;94(3):376-92. [Internalization and the intracellular transformations of biologically active polypeptides and their receptors]. [Article in Russian] Kusen' SI. PMID: 6186099 [PubMed - indexed for MEDLINE] 7153. Pol Arch Med Wewn. 1982 Oct;68(4):251-7. [Effect of thyroid hormones on lipid metabolism]. [Article in Polish] Lewczuk J. PMID: 6763689 [PubMed - indexed for MEDLINE] 7154. J Anim Sci. 1982 Oct;55(4):804-17. The role of lipoproteins in lipid metabolism of meat animals. Kris-Etherton PM, Etherton TD. The biological mechanisms that regulate the synthesis and degradation of lipids and lipid transport in plasma are of great significance to animal agriculture. Regulation of lipid synthesis and degradation in meat animals has been studied to some extent. However, the role of plasma lipoproteins in transporting lipid to extrahepatic tissues in meat animals is not well defined. In addition, the knowledge that certain constituents of plasma lipoproteins influence pathways of triglyceride and cholesterol metabolism in adipose tissue, liver and skeletal muscle of humans and rodents has not been widely applied by animal scientists studying the mechanisms that regulate adipose tissue growth in meat animals. Therefore, this review will discuss lipoprotein metabolism and the mechanisms by which constituents of lipoproteins influence lipid metabolism in humans and rodents with application to meat animals. PMID: 6754676 [PubMed - indexed for MEDLINE] 7155. Q Rev Biol. 1982 Sep;57(3):247-74. Hormonal and genetic regulation of vitellogenesis in Drosophila. Bownes M. Morphological, genetic, and hormonal studies of the process of vitellogenesis, whereby yolk is accumulated in the developing oocytes, have been going on for many years in Drosophila. Recently there has been a resurgence of interest in vitellogenesis, for it provides a model system for investigating how eukaryotic genes are regulated. The proteins found in the yolk are regulated in a tissue-specific, stage-specific and sex-limited fashion. Molecular studies have identified the major proteins concerned and their genes have been cloned. This has facilitated a new approach to how this fascinating process is controlled. In this review current understanding of the factors required for normal vitellogenesis in Drosophila is analyzed. The nature of the proteins themselves, their sites of synthesis, and the organization and characterization of the genes and transcripts that code for them are emphasized. The manner in which the expression of these genes is regulated by the insect hormones, ecdysone and juvenile hormone, is described and, finally, an analysis is made of how various mutants that disrupt vitellogenesis can contribute further to our understanding of vitellogenesis regulation in Drosophila. PMID: 6815707 [PubMed - indexed for MEDLINE] 7156. Curr Probl Pediatr. 1982 Sep;12(11):1-58. Obesity. Merritt RJ. PMID: 6754266 [PubMed - indexed for MEDLINE] 7157. J Endocrinol Invest. 1982 Sep-Oct;5(5):335-45. Factors influencing estrogen production and metabolism in postmenopausal women with endocrine cancer. James VH, Folkerd EJ, Bonney RC, Beranek PA, Reed MJ. PMID: 6218194 [PubMed - indexed for MEDLINE] 7158. J Toxicol Sci. 1982 Aug;7(3):161-75. Chemical analysis and toxicity of polychlorinated biphenyls and dibenzofurans in relation to yusho. Masuda Y, Yoshimura H. A typical lot of Kanemi rice oil ingested by patients with yusho (PCB poisoning) and the blood, liver and adipose tissue of the patients were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) by gas chromatography and gas chromatography-mass spectrometry. The individual congeners identified were assayed for biological properties such as accumulation ability in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase and DT diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the seven PCB congeners detected in yusho patients, 2, 3, 4, 5, 3', 4'-hexa-CB seems to be the most related compound to yusho by its strong effects on induction of the liver enzymes, and on atrophy of the thymus and hypertrophy of the liver in rats. PCDF congeners identified in the patients showed severe toxicity in rats than this PCB, exhibiting stronger enzyme induction and gravimetric changes of the tissues even at very low doses of 1-10 micrograms/kg. These PCDFs, especially 2, 3, 4, 7, 8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for current symptoms of yusho. PMID: 6818356 [PubMed - indexed for MEDLINE] 7159. Klin Wochenschr. 1982 Jul 15;60(14):717-9. Alterations in carbohydrate and lipid metabolism following administration of endotoxin. Spitzer JJ, Spitzer JA. Endotoxin-induced alterations in blood flow, carbohydrate and lipid metabolism in various organs of the body are outlined. Peripheral utilization of carbohydrates and lipids does not appear to be adversely affected by the administration of mild to moderate doses of endotoxin (in fact, glucose turnover is even elevated). On the other hand, the supply of free fatty acids from adipose tissue is diminished, at least in part, due to severe hemodynamic changes that occur in this tissue following endotoxin. Hepatic gluconeogenesis is elevated, but does not match the increased demand for glucose by the periphery. The experimental conditions discussed in this brief review elicit changes that are reversible. However, during more severe endotoxemia, the metabolic alterations lead to irreversibility. PMID: 6750224 [PubMed - indexed for MEDLINE] 7160. Metabolism. 1982 Jul;31(7):670-90. Internalization and intracellular processing of insulin and insulin receptors in adipocytes. Olefsky JM, Marshall S, Berhanu P, Saekow M, Heidenreich K, Green A. PMID: 7045573 [PubMed - indexed for MEDLINE] 7161. Fed Proc. 1982 Jul;41(9):2555-61. Relationships among growth, adipose cell size, and lipid metabolism in ruminant adipose tissue. Hood RL. In early postnatal development, growth of adipose tissue is due to both cellular hypertrophy and hyperplasia. Adipose cell (adipocyte) hypertrophy is the major mechanism in fattening of ruminants grown to market weight, although evidence is accumulating that preadipose cells can proliferate postnatally, even in mature animals. In interfasicular adipose tissue (marbling), however, small adipose cells are present and their number makes a positive contribution to the size of this fat depot in ruminants of market weight. Present information does not indicate whether these small cells are newly synthesized cells or are cells that differentiated early in postnatal development and fill with lipid at some later time. Limitations on detecting small adipose cells in cell-counting techniques are partly responsible for conflicting conclusions on the cellular basis for adiposity. Nutritional modification of adipose cell number has been reported in rodents. However, the extreme nutritional modifications required to alter cell number have little practical application in the growth of ruminants for meat production. Adipose cells of various sizes respond differently in the esterification and synthesis of fatty acids. The greater rates of lipid synthesis from acetate in large adipose cells may be related to increased uptake of substrate in cells with a large surface area. PMID: 7044834 [PubMed - indexed for MEDLINE] 7162. N Engl J Med. 1982 Jul 1;307(1):18-29. Adrenergic receptors in man: direct identification, physiologic regulation, and clinical alterations. Motulsky HJ, Insel PA. PMID: 6123082 [PubMed - indexed for MEDLINE] 7163. Proc Nutr Soc. 1982 Jun;41(2):183-91. The interrelationship between metabolic regulation, weight control and obesity. Newsholme EA. PMID: 7051016 [PubMed - indexed for MEDLINE] 7164. Proc Nutr Soc. 1982 Jun;41(2):175-81. Energy stores in man, their composition and measurement. Garrow JS. PMID: 7051015 [PubMed - indexed for MEDLINE] 7165. Proc Nutr Soc. 1982 Jun;41(2):167-73. The regulation of adipose cell metabolism. Galton DJ, Wallis S. PMID: 7051014 [PubMed - indexed for MEDLINE] 7166. Proc Nutr Soc. 1982 Jun;41(2):127-31. A role for brown adipose tissue in the genesis of obesity? Studies on experimental animals. Trayhurn P, Goodbody AE, James WP. PMID: 7051011 [PubMed - indexed for MEDLINE] 7167. J Adolesc Health Care. 1982 Jun;2(4):249-60. Critical fat, menarche, and the maintenance of menstrual cycles: a critical review. Scott EC, Johnston FE. The critical weight (fat) hypothesis has generated interest as a mechanism for the onset and maintenance of normal reproductive cycles in human females. It postulates that menarche is triggered by the attainment of a critical percentage fat and that the maintenance of menstrual cycles requires the persistence of a minimal level; each level is argued to be universal for a particular population or race and, by implication, for the species as a whole. However, an examination of the evidence reveals the hypothesis to have a number of serious methodological and empirical shortcomings which may be grouped under three headings. First, there are no acceptable measures of body fatness, and workers rely instead on estimates from height and weight which have been shown to be intolerably erroneous for individuals. Second, using either these estimates, or more reliable ones using appropriate methods, it may be shown that critical levels do not apply: numerous exceptions involving fat levels above and below the suggested threshold may be shown. Finally, where specific conditions involving reduced fatness and menstrual delay or dysfunction are used to support the hypothesis, it may be shown that other confounding factors are equally plausible. Consequently, based on available evidence, the critical weight (fat) hypothesis cannot be accepted. Hypotheses based on normal maturational processes, especially of the central nervous system, currently provide better explanations. PMID: 6749778 [PubMed - indexed for MEDLINE] 7168. S Afr Med J. 1982 Apr 10;61(15):544-6. Drug therapy considerations in the elderly. Herman RA. The growing elderly population receives an increasing proportion of the prescriptions dispensed each year. There are a number of problems associated with drug therapy in the elderly. This article reviews some of the pharmacological factors, which may change with increasing age, including absorption, transportation, tissue localization, receptor sites, homeostasis, excretion and metabolism, and which in turn may alter the action of a drug. Suggestions are made regarding the treatment of elderly patients. PMID: 7038926 [PubMed - indexed for MEDLINE] 7169. Nutr Rev. 1982 Mar;40(3):89-90. Dietary protein and body fat distribution. [No authors listed] PMID: 7050777 [PubMed - indexed for MEDLINE] 7170. Physiol Behav. 1982 Mar;28(3):545-63. Gender and energy balance: sex differences in adaptations for feast and famine. Hoyenga KB, Hoyenga KT. According to this theory/review, the cross-culturally common finding of more women than men among the obese is at least in part a consequence of sex differences in evolutionary selection pressure. James and Trayhurn claim that the propensity to obesity is linked to th ability to survive a fast and both may involve reduced heat production. The present theory extends this relationship to sex differences in energy balance. According to the theory proposed here, mammalian females were subjected to more severe selection pressures during times of short food supply than males were and hence females were under more pressure to evolve mechanisms to facilitate survival during famine, which led to sex differences in obesity. The data relevant to sex differences in starvation survival, obesity and heat production, and the possible evolutionary roles and implications of sex differences in chromosomes and in organizational and activational sex hormones are reviewed. The conclusion is that evolution has created a linkage between sex chromosomes, hormones and energy balance, and this linkage is at least in part responsible for the greater resistance of the female to famine and for her greater tendency to become obese in times of feast. PMID: 7043508 [PubMed - indexed for MEDLINE] 7171. FEBS Lett. 1982 Feb 22;138(2):157-63. Bimodal regulation of adenylate cyclase. Cooper DM. PMID: 6121719 [PubMed - indexed for MEDLINE] 7172. Mol Cell Biochem. 1982 Feb 5;42(2):109-16. Hormone-sensitive cAMP phosphodiesterase in liver and fat cells. Francis SH, Kono T. PMID: 6278284 [PubMed - indexed for MEDLINE] 7173. Biomed Mass Spectrom. 1982 Feb;9(2):45-60. The mass spectrometry of chlorinated dibenzo-p-dioxins. Mahle NH, Shadoff LA. All aspects of the use of mass spectrometry for the identification and quantitation of chlorodibenzo-p-dioxins are critically reviewed. The mass spectra obtained by various ionization methods are discussed. Numerous mass spectral techniques and cleanup procedures are covered, with emphasis on their interrelationships. These techniques have been applied to the determination of chlorodibenzo-p-dioxins in many different matrices, including product materials, such as chlorophenols and phenoxy acid herbicides, and toxicological and environmental materials such as cattle, fish, rodent and human tissues. Formation and degradation studies, which include thermal chemistry, photochemistry and chemical stability and degradation, are presented. Numerous considerations in the handling and quantitation of chlorodibenzo-p-dioxins, such as interferences, detection limits and recovery studies, are evaluated. PMID: 7037063 [PubMed - indexed for MEDLINE] 7174. Prog Clin Biol Res. 1982;92:217-31. Thermogenesis in the avian body and the role of the pineal in thermoregulation. George JC. In the absence of the brown adipose tissue, maintenance of body temperature (Tb) in birds is generally believed to be by shivering thermogenesis (ST), though evidence for nonshivering thermogenesis (NST) is becoming available. In ST, glycogen utilization by the anaerobic white muscle fibers forms the main energy process, while the aerobic red fibers appear to be largely involved in NST. Winter pigeons maintained on a 12 h photophase (PP) and 12 h scotophase (SP) had higher Tb during PP in both warm (25 degrees C) and cold (3 degrees C) acclimated birds. In pinealectomized (Px) pigeons Tb was higher than in controls during PP and SP without affecting the circadian thermal rhythm. This hyperthermic effect (HE) of pinealectomy was nullified with subcutaneous implantation of melatonin. These warm acclimated winter Px pigeons when examined for Tb next winter, did not show HE. Summer Px pigeons did not show HE as did the winter Px pigeons, indicating seasonal difference. No significant difference in circulating levels of T3 and T4 was seen in the summer as well as winter warm acclimated Px pigeons. These results suggest that the HE observed in warm acclimated Px winter pigeons was not mediated by the thyroid and that the pineal has no influence on the thyroid in the warm acclimated birds. The slightly higher HE seen in cold (3 degree C) acclimated Px pigeons may well be due to the influence of the thyroid. PMID: 7051038 [PubMed - indexed for MEDLINE] 7175. Ric Clin Lab. 1982 Jan-Mar;12(1):35-40. Apolipoprotein C-II and lipoprotein lipase activity. Catapano AL. PMID: 7046021 [PubMed - indexed for MEDLINE] 7176. J Anim Sci. 1982 Jan;54(1):58-67. The role of insulin-receptor interactions in regulation of nutrient utilization by skeletal muscle and adipose tissue: a review. Etherton TD. Animal growth is a direct function of tissue growth. Tissue growth in turn is dependent upon the rate and extent of hypertrophy and hyperplasia of cells comprising the respective tissues. Cellular enlargement occurs as the result of nutrient uptake by the cell and the balance between anabolic and catabolic processes that regulate accretion of component and structural material of the cell. It is quite clear that the availability, uptake and intracellular metabolism of nutrients are markedly affected by the endocrine system. This review discusses the role of insulin-receptor interactions in the regulation of nutrient uptake and utilization by myofibers and adipocytes. Binding of insulin to specific receptors on the plasma membrane of target cells is important because of its role in mediation of hormone action. Although insulin binding is essential for hormone action, binding may not represent the rate-limiting step on the action of insulin. Recent evidence suggests that insulin is internalized by target cells. However, the physiological role of insulin internalization has not been elucidated. A better understanding of the basic mechanisms by which insulin and other hormones regulate nutrient utilization by skeletal muscle and adipose tissue during growth may lead to improvements in growth rates and the efficiency with which dietary components are used for tissue growth. PMID: 7045063 [PubMed - indexed for MEDLINE] 7177. Int J Obes. 1982;6(1):69-81. Facts and fictions about infantile obesity. Edelman B, Maller O. This review assesses the present state of knowledge on the etiology of infantile obesity. Current controversies such as bottle vs. breast feeding, the importance of differences in early feeding and activity patterns, and the role of early adipose cell development are discussed. There is continuing debate on the relationship of early obesity to later body weight. The major limitation of current research is the lack of adequate consideration of social and environmental factors particularly how eating and activity behaviors develop and are maintained. The emphasis of this paper is on highlighting the opportunities for different learning experiences inherent in different feeding environments during early life. Implications for research particularly the need for longitudinal studies on the establishment of characteristic eating and activity patterns are discussed. PMID: 7040268 [PubMed - indexed for MEDLINE] 7178. Adv Nutr Res. 1982;4:287-337. Fatty acid metabolism in the neonatal ruminant. Noble RC, Shand JH. PMID: 7039262 [PubMed - indexed for MEDLINE] 7179. Spec Top Endocrinol Metab. 1982;4:1-27. Metabolic and clinical significance of ketosis. Schade DS, Eaton RP. PMID: 6820732 [PubMed - indexed for MEDLINE] 7180. Recent Prog Horm Res. 1982;38:511-56. Insulin mediators and their control of metabolism through protein phosphorylation. Larner J, Cheng K, Schwartz C, Kikuchi K, Tamura S, Creacy S, Dubler R, Galasko G, Pullin C, Katz M. PMID: 6812180 [PubMed - indexed for MEDLINE] 7181. Ciba Found Symp. 1982;87:1-19. The hydrogen ion in normal metabolism: a review. Alberti KG, Cuthbert C. The production of hydrogen ions (H+) by metabolic processes is described, with particular emphasis on glycolysis and ketogenesis. Total metabolic production of H+ is approximately 150 g day-1 but utilization closely balances production, so that intracellular and extracellular H+ production is maintained within narrow limits. H+ is generated at several sites in glycolysis but no net H+ production occurs unless the ATP formed is hydrolysed. The other main source of metabolic H+ production is ketogenesis. Here H+ accumulation depends on both the relative dominance of ketone body production over utilization and the loss of base in urine. The H+ is produced during the synthesis of 3-hydroxy-3-methylglutaryl-CoA and not because of dissociation of acetoacetic acid. Lipolysis and re-esterification of fats are additional major producers of H+, while net H+ production also occurs with pathological accumulation and incomplete combustion of other organic acids. Many metabolic systems are sensitive to the changes in pH. These effects have been examined in vivo using an ammonium chloride acidaemia model in the rat. Severe insulin resistance and impaired glucose metabolism in liver and muscle were found. One mechanism involved inhibition, by H+, of the binding of insulin to its receptors. Further mechanisms include inhibition of key glycolytic enzymes including phosphofructokinase. It is concluded that too little attention is paid to metabolic production of hydrogen ions and to their effects, in turn, on metabolism. PMID: 6804190 [PubMed - indexed for MEDLINE] 7182. Annu Rev Nutr. 1982;2:91-111. Development of lipid metabolism. Hahn P. PMID: 6764738 [PubMed - indexed for MEDLINE] 7183. Postepy Biochem. 1982;28(3):279-300. [Regulation of the pyruvate dehydrogenase complex in animal tissue]. [Article in Polish] Wałajtys-Rode EI. PMID: 6764662 [PubMed - indexed for MEDLINE] 7184. Am J Nephrol. 1982;2(6):330-41. Glucocorticoids in renal disease. Theoretical basis, consequences and efficacy of use in the pediatric patient. Friedman AL, Chesney RW. Glucocorticoids have been used extensively in the management of patients with renal disease. The beneficial effect of glucocorticoids on renal disease is probably mediated via the suppression of immune function, although some evidence exists for a direct influence of corticosteroids on glomerular function. A myriad of glucocorticoid complications have been reported, including: skin, eye, bone, blood and adipose tissue changes, as well as growth retardation, hypertension and an increased susceptibility to infection. A review of the efficacy of glucocorticoid use demonstrates benefit in a small number of glomerulonephritides (minimal change nephrotic syndrome, systemic lupus erythematosus, polyarteritis nodosa and renal transplantation). Since being introduced in the early 1950s, glucocorticoids have proven to be of limited usefulness in the treatment of glomerulonephritis. PMID: 6762095 [PubMed - indexed for MEDLINE] 7185. Bibl Nutr Dieta. 1982;(31):61-74. Overnutrition and obesity in childhood as a potential risk for chronic degenerative diseases in later life. Spahn U, Plenert W, Hesse V, Knöll G, Petrich E, Kauf E. PMID: 6760851 [PubMed - indexed for MEDLINE] 7186. Pharmacol Ther. 1982;17(2):251-68. Diet-induced thermogenesis. Rothwell NJ, Stock MJ, Stribling D. PMID: 6757981 [PubMed - indexed for MEDLINE] 7187. Int Rev Cytol. 1982;74:187-286. The brown fat cell. Nedergaard J, Lindberg O. PMID: 6749742 [PubMed - indexed for MEDLINE] 7188. Horiz Biochem Biophys. 1982;6:309-33. GTP-dependent stimulation and inhibition of adenylate cyclase. Cooper DM, Londos C. PMID: 6311719 [PubMed - indexed for MEDLINE] 7189. Horiz Biochem Biophys. 1982;6:237-76. Involvement of phosphatidylinositol breakdown in elevation of cytosol Ca2+ by hormones and relationship to prostaglandin formation. Fain JN. PMID: 6311717 [PubMed - indexed for MEDLINE] 7190. Prog Lipid Res. 1982;21(1):1-45. Dietary requirements and functions of alpha-linolenic acid in animals. Tinoco J. PMID: 6287500 [PubMed - indexed for MEDLINE] 7191. Monogr Endocrinol. 1982;24:III-XI, 1-88. Gastric inhibitory polypeptide. Brown JC. PMID: 6214707 [PubMed - indexed for MEDLINE] 7192. Crit Rev Food Sci Nutr. 1982;16(2):149-63. Protein synthesis and degradation during development. Mayer RJ, Russell SM, Wilde CJ, Burgess R, Sinnett-Smith PA. PMID: 6175484 [PubMed - indexed for MEDLINE] 7193. Prog Lipid Res. 1982;21(3):195-223. The regulation of fatty acid synthesis in brown adipose tissue by insulin. McCormack JG. PMID: 6128738 [PubMed - indexed for MEDLINE] 7194. Crit Rev Clin Lab Sci. 1982;17(3):247-97. The biochemistry of Reye's syndrome. Brown RE, Forman DT. PMID: 6127187 [PubMed - indexed for MEDLINE] 7195. Br J Clin Pharmacol. 1982;13(Suppl 2):181S-186S. Beta-adrenoceptor blocking agents and lipolysis. Harms HH, De Vente J, Zaagsma J. PMCID: PMC1402182 PMID: 6125168 [PubMed - indexed for MEDLINE] 7196. Ciba Found Symp. 1982;87:120-31. The regulation of ketogenesis. Foster DW, McGarry JD. Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC 6.4.1.2). The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC 2.3.1.21) such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process. PMID: 6122545 [PubMed - indexed for MEDLINE] 7197. Tijdschr Kindergeneeskd. 1981 Dec;49(6):208-13. [Obesity in children. II. Possible relationship of obesity in childhood to obesity at an older age]. [Article in Dutch] de Wijn JF. A review is presented of factors predisposing for obesity in childhood and of the probability to maintain early obesity in later years. From literature about retrospective studies it appears that total weight gain in the first year of life is the highest correlated factor with obesity at age 15. The risk of persisting therapy-resistant obesity at that age is not related to a specific critical period during infancy. The risk for metabolic disturbances at later age seems to be greatest when obesity develops earlier and lasts longer. Analysis of the findings among 8-year old Dutch children suggest that various environmental conditions of family-life are at the age determining the prevalence of obesity. Both material and emotional factors as well as aspects of parental education are involved. Some prospective studies demonstrate that for respectively female and male young adults ca 20 and 30 pct of the degree of fatness correlates with skinfold measurements in childhood. Once obesity among Dutch male adolescents at the age of 18 was established, for two-thirds this obesity was maintained at the age of 33. On the other hand for most of the 33 year old obese, obesity had developed after the age of 18. PMID: 7330841 [PubMed - indexed for MEDLINE] 7198. Fertil Steril. 1981 Dec;36(6):691-6. Menstrual dysfunction and hormonal status in athletic women: a review. Baker ER. Since women have become more involved in physical fitness and competitive endurance sports, the incidence of menstrual dysfunction has increased. Long-distance running and other sports may lead to alterations in gonadotropins, androgens, estrogens, progesterone, or prolactin, which in some women may directly or indirectly result in amenorrhea or infertility. The effects of running and strenuous exercise on the menstrual cycle and reproductive hormones remain controversial. Reported incidences of menstrual dysfunction vary widely, and many factors have been implicated in the onset of this problem. Exercise associated menstrual dysfunction seems to occur more frequently in nulliparous athletes, in athletes with delayed menarche, and in athletes with low body fat. It is important to realize that disruption of the menstrual cycle, ranging from mild changes in flow to amenorrhea, is a relatively common problem for the female athlete engaged in strenuous endurance sports. Yet no evidence exists at present to indicate conclusively that this menstrual dysfunction is harmful to the female athlete's reproductive system. PMID: 7030795 [PubMed - indexed for MEDLINE] 7199. Am J Clin Nutr. 1981 Nov;34(11):2560-90. A simplified approach to lipoprotein kinetics and factors affecting serum cholesterol and triglyceride concentrations. Hopkins PN, Williams RR. Serum lipoproteins have received considerable notoriety as risk factors for atherosclerotic disease, yet the kinetic factors that determine serum concentrations are often unappreciated. Simple compartmental models for lipoprotein kinetics are herein presented which integrate key features of lipoprotein metabolism and allow prediction of very low-density lipoprotein and low-density lipoprotein levels in a wide variety of clinical circumstances. Possible changes in kinetic parameters responsible for hyperlipidemia in obesity, insulin resistance, diabetes, carbohydrate (sugar)-induced hypertriglyceridemia, alcoholic type V hyperlipemia, polyunsaturated fat diets, and several pharmacological interventions are discussed. Key features of lipoprotein metabolism are briefly reviewed. PMID: 7030050 [PubMed - indexed for MEDLINE] 7200. Nutr Rev. 1981 Nov;39(11):385-90. Possible carnitine requirement of the newborn and the effect of genetic disease on the carnitine requirement. Borum PR. PMID: 6796913 [PubMed - indexed for MEDLINE] 7201. Fertil Steril. 1981 Nov;36(5):543-50. Toward an understanding of reproductive function in anorexia nervosa. Eisenberg E. PMID: 6118303 [PubMed - indexed for MEDLINE] 7202. Sem Hop. 1981 Oct 8-15;57(37-38):1467-76. [Aromatization of androgens (author's transl)]. [Article in French] Vague J, Sardo J. Aromatization of androgens into estrogens is an early phenomenon during phylogenesis and ontogenesis which occurs in most tissues. The mechanism which is responsible for this activity and for it's competition with 5 alpha reduction includes hypothalamo-pituitary receptors, genetic induction of sexual differentiation, binding proteins, and sulfo and glyco-conjugation. Aromatization is determinant before, during, and after ovulation, as well as in developing pregnancy. In the testis, in spite of it's importance, it's role is unknown. It's action is essential in the sexual differentiation of the brain. Aromatization in the muscle and the adipose tissue is not negligible under normal and pathological conditions. PMID: 6270810 [PubMed - indexed for MEDLINE] 7203. Metabolism. 1981 Oct;30(10):1024-39. The metabolic effects of dichloroacetate. Crabb DW, Yount EA, Harris RA. PMID: 7024720 [PubMed - indexed for MEDLINE] 7204. Fertil Steril. 1981 Sep;36(3):417-8. Endometriosis and tuboperitoneal fistulas after tubal ligation. Massey JB. PIP: I read with interest the report on endometriosis and the development of tubal peritoneal fistulas after tubal ligation. The authors stated that they had not seen recanalization of the oviducts. I call your attention to observations in the past. A review of these papers will provide evidence that recanalization does in fact occur. I have personally seen 2 such cases after Pomeroy procedures. Your observation that the changes which you describe as endometriosis occur only in the proximal stump may be critical. If this is true, it appears that you may be correct in saying that this is endometriosis and that the past assumption that the process was invasion of tissue by tubal epithelium was incorrect. On the other hand, you did not spell out exactly how many of your cases revealed epithelium-lined spaces which could be strictly classified as endometriosis. Certainly, at least some of them have stroma and epithelium which appeared to be that of endometriosis. Sampson stated that the misplaced tubal mucosa may assume the structure and function of uterine mucosa and he goes on to describe a patient, aged 37, whose tubes and ovaries were severed from the uterus. The uterus was then drawn through the abdominal incision and pulled into the subcutaneous part of the abdomen. Later, a firm mass was detected adherent to the cornua of the uterus. Endosalpingosis was present in both nodules which had invaded the adipose tissue of the abdominal wall. Microscopically, the tubal mucosa appeared to be invading the adipose tissue. Sampson regards the behavior of tubal epithelium in repair of salpingectomy wounds as a striking exception to the rule which covers the healing of operative wounds of hollow viscera. In the stumps of tubes, sprouts of its epithelium often invade the wall and grow beyond it. It may continue after healing is complete. This phenomenon was designated by Sampson as endosalpingosis, and he reported seeing it in 3 similar cases. In reviewing Sampson's observations, it does appear that this anatomical change does not occur in the distal stump, as he speaks only about the described. Why does tubal ligation incite this change? The question is whether it is really endometriosis or some type of transformation of the tubal mucosa? Why should there be more of a tendency for endometrium to implant on this tissue after ligation compared to prior ligation? Sampson seemed to be convinced that this was tubal epithelium. Only careful study of this by experienced pathologists may reveal the answers. Perhaps in some cases, this is tubal epithelium. The other possibilities include metaplasia into endometrial mucosa, as well as true dennovo implants of ectopic endometrium. author's modified author's modified PMID: 7286264 [PubMed - indexed for MEDLINE] 7205. Br Med Bull. 1981 Sep;37(3):281-5. Endocrinological control of growth at puberty. Brook CG. PMID: 7034853 [PubMed - indexed for MEDLINE] 7206. Am J Clin Nutr. 1981 Aug;34(8):1617-21. The "metabolically-obese," normal-weight individual. Ruderman NB, Schneider SH, Berchtold P. A great many disorders including maturity-onset (type II) diabetes, hypertension, and hypertriglyceridemia are frequently associated with adult-onset obesity and improve with caloric restriction. It is the premise of this brief review that there are patients with these disorders who are not obese according to standard weight tables or other readily-available criteria; but who would also respond favorably to caloric restriction. It is proposed that such individuals might be characterized by hyperinsulinism and possibly an increase in fat cell size compared to patients of similar age, height, and weight and/or to themselves at an earlier time. The possibility is also discussed that inactivity is a contributing factor in some of these individuals and that for them, the appropriate therapy might be exercise. PMID: 7270486 [PubMed - indexed for MEDLINE] 7207. Metabolism. 1981 Aug;30(8):825-35. Insulin degradation by insulin target cells. Goldstein BJ, Livingston JN. Recent findings illustrate the complexities associated with the interaction between insulin and its target cells. These results suggest that the processes involved in insulin action and those involved in insulin degradation may have certain steps in common. Both apparently begin when insulin binds to the insulin receptor. The next step is unknown but it ultimately leads to the internalization of the hormone before insulin dissociates from the cell surface. Furthermore, internalization appears to be a requirement for efficient degradation of insulin since the vast majority (perhaps all in certain cells) of the degrading activity is intracellular. Internalization may not be required to produce certain actions of the hormone, however, and the two processes may diverge at the point. It is not clear how insulin enters the target cell other than the process appears to be receptor-mediated. Also, further work is needed to more fully characterize the vesicles that contain internalized insulin. Finally, the actual location of insulin degradation and the enzyme(s) involved need further study, especially to clarify the relative contributions of lysosomes, cytosolic protease, and GIT to physiological insulin destruction. An understanding of the overall process of insulin degradation is required for a complete description of the physiologic disposition of the hormone at the target cell. Moreover, this system has subtle control mechanisms that may have important implications for the management of diabetes and other endocrine and metabolic disorders. PMID: 7022108 [PubMed - indexed for MEDLINE] 7208. Fed Proc. 1981 Aug;40(10):2536-41. Endocrine regulation of energy metabolism in ruminants. Trenkle A. Partitioning of nutrients among tissues of the body is one role of the endocrine system. Skeletal muscle, adipose tissue, and lactating mammary gland are tissues that utilize most of the energy consumed in excess of maintenance. The energy metabolism of ruminants is complicated by the lack of absorption of glucose because of the fermentation of carbohydrates in the rumen. Increased secretion of glucagon after feeding promotes hepatic gluconeogenesis from absorbed amino acids. During fasting, gluconeogenesis is maintained by increased secretion of glucocorticoids. Based on observation form a number of diverse experiments with cattle and sheep, it seems that growth hormone increases the flow of energy to skeletal muscle and the mammary gland, whereas insulin increases the utilization of energy by the adipose tissue. Nutritional and genetic factors associated with secretion of these hormones are discussed. PMID: 7021187 [PubMed - indexed for MEDLINE] 7209. Fed Proc. 1981 Aug;40(10):2524-9. Efficiency of energy retention in genetically obese animals and in dietary-induced thermogenesis. Romsos DR. Genetically obese rodents (ob/ob mice and fa/fa rats) and animals with dietary-induced thermogenesis represent two extremes in efficiency of energy retention: the former deposit dietary energy with high efficiency, whereas the later deposit dietary energy with low efficiency. These differences in efficiency of energy retention must, at the cellular level, be associated with changes in efficiency and/or rate of formation and/or utilization of ATP (and other high energy intermediates). Brown adipose tissue possesses a unique proton-conductance pathway that reduces the efficiency of ATP synthesis. It has been speculated that this pathway is suppressed in obese (ob/ob) mice and accelerated in rats with dietary-induced thermogenesis. Metabolic reactions that alter the rate of ATP utilization in animals include Na+, K+-ATPase and protein turnover. The concentration of Na+, K+-ATPase enzyme unites in skeletal muscle and liver of young adult obese (ob/ob) mice is lower than in tissues of young adult lean mice. There also appear to be alterations in protein turnover in certain tissues of obese (ob/ob) mice, but additional studies are required to determine if whole-body protein turnover is altered in these animals. Data are unavailable on either Na+, K+-ATPase or protein turnover in tissue of animals with dietary-induced thermogenesis. Continuation of studies in these areas should provide a metabolic basis for understanding individual variability in efficiency of energy retention. PMID: 6266881 [PubMed - indexed for MEDLINE] 7210. Am J Cardiol. 1981 Aug;48(2):361-5. Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Vik-Mo H, Mjøs OD. Myocardial oxygen consumption (MVO2) is influenced by the substrate supply to the heart. Utilization of free fatty acids increases MVO2, and catecholamines sensitize the heart to the oxygen-wasting effect of free fatty acids. Alteration of myocardial metabolism from mainly free fatty acid to carbohydrate oxidation reduces the extent of myocardial ischemic injury. Within the ischemic myocardium, lipolysis is stimulated with breakdown of endogenous triglycerides to fatty free acids and glycerol. Antilipolytic agents seem to have a combined effect on myocardial metabolism partly through inhibition of lipolysis in adipose tissue with reduction of free fatty acid mobilization to plasma, and partly through a local inhibition of lipolysis in the ischemic myocardium. In patients with high sympathoadrenal activity, for example, patients with acute myocardial ischemia in unstable ischemic heart disease, elevation of free fatty acids might effect a critical increase in both myocardial oxygen requirement and infarct size. PMID: 6115579 [PubMed - indexed for MEDLINE] 7211. Usp Sovrem Biol. 1981 Jul-Aug;92(1):35-48. [Regulation of insulin receptor expression and its place in the mechanism of insulin action]. [Article in Russian] Bezdrobnyĭ IuV. PMID: 7027664 [PubMed - indexed for MEDLINE] 7212. Kardiologiia. 1981 Jul;21(7):112-20. [Basic lipolysis stages and regulation pathways. Characteristics detectable in hypertension]. [Article in Russian] Reznikova MB. PMID: 6268888 [PubMed - indexed for MEDLINE] 7213. Mol Cell Endocrinol. 1981 Jun;22(3):277-93. Autoantibodies to insulin receptors. Van Obberghen E, Kahn CR. In summary, these studies using antibodies to the insulin receptor have provided some new insights into the structure of the insulin receptor and the action of insulin itself. They suggest that most of insulin's actions are mediated through a common pathway and these can be initiated by interaction of ligands other than insulin with the insulin receptor. These include the entire spectrum of metabolic effects (both acute and chronic). Receptor occupancy alone is not sufficient for signal generation. Both insulin and anti-receptor antibody induce receptor aggregation which appears to be required for activity. And finally, although both insulin and anti-receptor antibody are internalized, there is no evidence to suggest that this is important in their action. The growth effect of insulin appears to be mediated via a different pathway. PMID: 7018954 [PubMed - indexed for MEDLINE] 7214. Hum Biol. 1981 May;53(2):181-225. Skinfolds and body density and their relation to body fatness: a review. Lohman TG. PMID: 7239496 [PubMed - indexed for MEDLINE] 7215. Diabetologia. 1981 Mar;20 Suppl:362-5. Is there a sympathetic regulation of the efficiency of energy utilization? Girardier L, Seydoux J. Brown adipose tissue, a well known effector of regulatory thermogenesis found in mammals, is unique in its ability to steadily increase its heat production several fold for very long periods of time. It constitutes a shunt of energy flow between food intake and heat dissipation, it is activated through its sympathetic nerve supply. There are evidence in the rat, that brown adipose tissue is activated following overfeeding, thus decreasing food efficiency and determining resistance to obesity. Genetically obese (ob/ob) mice fed and kept at 22 degrees C lack the possibility of activating their brown fat energy shunt; they are known to be poorly resistant to cold stress despite their large insulation. This is taken as a further circumstantial evidence of an overlap in thermal and food efficiency regulatory systems in rodents through sympathetically controlled brown fast as a common effector. PMID: 7014332 [PubMed - indexed for MEDLINE] 7216. Diabetologia. 1981 Mar;20 Suppl:357-61. Effects of ventromedial hypothalamic lesions on adipose tissue of weanling male rats. Goldman JK, Bernardis LL, MacKenzie RG, Kodis M, Luboshitzky R. In weanling male rats, destruction of the ventromedial hypothalamus causes increased carcass lipid deposition and decreased linear growth without changes in food intake or blood glucose levels. These changes are not dependent on altered pituitary function. Lipogenesis and glucose utilization are increased in vivo and in vitro, while gluconeogenesis is accelerated in vivo. The enhanced lipogenesis occurs before increased gluconeogenesis. PMID: 7014331 [PubMed - indexed for MEDLINE] 7217. Diabetologia. 1981 Mar;20 Suppl:343-56. Central nervous system regulation of liver and adipose tissue metabolism. Shimazu T. Hypothalamic and autonomic nervous regulation of carbohydrate and amino acid metabolism in the liver and of lipid metabolism in adipose tissues is described. The direct neural mechanism underlying this regulation has been evaluated. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH)-splanchnic nerve system causes glycogenolysis in the liver by rapid activation of glycogen phosphorylase, whereas electrical stimulation of the lateral hypothalamic nucleus (LH)-vagus nerve system promotes glycogenesis in the liver by activation of glycogen synthetase, through direct neural and neural-hormonal mechanisms. Studies on chemical coding of the hypothalamic neurones have revealed that norepinephrine-sensitive neurones in the VMH and acetylcholine-sensitive neurones in the LH are specifically involved in the regulation of liver phosphorylase and glycogen synthetase, respectively. Acetylcholine-sensitive neurones of the LH were also found to be concerned in regulation of hepatic tyrosine and aminotransferase activity, through intermediation of the cholinergic system in the LH-vagal pathway. Finally, it has been shown that the VMH acts as a regulatory centre for lipolysis in adipose tissues by modulating activation of the sympathetic nervous system. In addition, stimulation of the VMH enhanced lipogenesis in brown adipose tissue preferentially, probably through a mechanism mediated by sympathetic innervation of this tissue. The latter finding suggests that both the breakdown and resynthesis of triglycerides in brown adipose tissue, but not in white adipose tissue, are accelerated by stimulation of the VMH. PMID: 7014330 [PubMed - indexed for MEDLINE] 7218. Clin Endocrinol Metab. 1981 Mar;10(1):179-94. Diabetes mellitus. Williams TF. PMID: 7014046 [PubMed - indexed for MEDLINE] 7219. Clin Obstet Gynecol. 1981 Mar;24(1):21-49. Metabolic adjustments in normal and diabetic pregnancy. Knopp RH, Montes A, Childs M, Li JR, Mabuchi H. PMID: 7011634 [PubMed - indexed for MEDLINE] 7220. Diabetes. 1981 Feb;30(2):148-62. LIlly lecture 1980. Insulin resistance and insulin action. An in vitro and in vivo perspective. Olefsky JM. PMID: 7009267 [PubMed - indexed for MEDLINE] 7221. Br J Anaesth. 1981 Feb;53(2):161-7. The scientific basis of nutritional assessment. Goode AW. PMID: 7008817 [PubMed - indexed for MEDLINE] 7222. World Rev Nutr Diet. 1981;37:55-83. Body composition and nutrient reserves in evolutionary perspective. Stini WA. PMID: 7051581 [PubMed - indexed for MEDLINE] 7223. Curr Top Cell Regul. 1981;19:103-58. Kinetic models of metabolism in intact cells, tissues, and organisms. Wright BE, Kelly PJ. PMID: 7037313 [PubMed - indexed for MEDLINE] 7224. Sci Prog. 1981 Autumn;67(267):357-76. The biochemical basis of obesity. Rath EA. PMID: 7036339 [PubMed - indexed for MEDLINE] 7225. Prog Clin Biol Res. 1981;61:55-72. Body composition in adolescence. Forbes GB. PMID: 7033976 [PubMed - indexed for MEDLINE] 7226. Prog Clin Biol Res. 1981;61:25-53. Overgrowth: energetic significance in relation to obesity. James WP, Sahakian BJ. PMID: 7033975 [PubMed - indexed for MEDLINE] 7227. Endocr Rev. 1981 Spring;2(2):210-33. Insulin metabolism and degradation. Duckworth WC, Kitabchi AE. PMID: 7028472 [PubMed - indexed for MEDLINE] 7228. Vopr Med Khim. 1981;27(4):435-41. [Nonesterified fatty acid metabolism in humans during physical loading]. [Article in Russian] Anikeeva SP, Shternberg IuM. PMID: 7027614 [PubMed - indexed for MEDLINE] 7229. Eur J Drug Metab Pharmacokinet. 1981;6(2):85-90. Pharmacokinetics, pharmacodynamics and aspects of neurotoxic effects of four inhaled aliphatic chlorohydrocarbon solvents as relevant in man. Savolainen H. Intermittent inhalation exposure of adult male rats to dichloromethane, trichloroethylene, 1,1,1-trichloroethane, perchloroethylene or to a combination of trichloroethylene and 1,1,1-trichloroethane for 5 days, for 6 h daily, induced significantly different accumulations of solvent molecules in the body. Adipose tissue served as a storage site for these solvents. The fat-stored molecules were not totally mobilized during the intermissions in exposure. Co-exposure of trichloroethylene and 1,1,1-trichloroethane induced higher accumulations than those induced by exposure to a single solvent in both the body and the brain. This increase in the accumulation of trichloroethylene might be due to competition with 1,1,1-trichloroethane for a binding site in the oxidative enzyme complex. Behavioural and neurochemical effects on trichloroethylene and dichloromethane exposure may be due to the formation of reactive metabolites. Experiments with 1,1,1-trichloroethane singly or in combination with trichloroethylene showed no observable behavioural effects. Perchloroethylene-induced effects were similarly small although, it caused the highest body concentration detected in these experiments. The metabolic activation of solvent molecules appears to also be a significant factor in neurotoxicity. Therefore biochemical interactions of agents occurring simultaneously in the environment, merit further consideration. PMID: 7023950 [PubMed - indexed for MEDLINE] 7230. Acta Paediatr Acad Sci Hung. 1981;22(1-2):49-69. Neonatal anthropometry: its value in the assessment of nutritional status and neonatal blood glucose homeostasis. Mestyán J, Járai I. The use and application of neonatal anthropometry in newborns with different body measurements and nutritional evaluation status is reviewed. The neonatal blood glucose level has been used as a model in testing the predictive value of various indices of body size for the capacity of neonatal blood glucose homeostasis. For example, combining weight and length deficit from the expected means for gestational age and relative body measurements such as weight for length and ponderal index not only convey information about the type and magnitude of growth impairment, but are also good predictors of the risk of hypoglycaemia within the different anthropometric groups of growth retarded infants. Efforts have been made to delineate the diagnostic criteria by somatic measurements for identification of the different degrees and types of intrauterine growth deviation. The anthropometric approach to the heterogeneity of the intrauterine growth pattern seems to be a simple and very useful tool in somatic classification and evaluation of the newborn infant. In addition to the assessment of body proportions and nutritional status, the anthropometric approach can be of great help in exploring the relationship of body size and the physiological adaptation to the extrauterine environment. PMID: 7023181 [PubMed - indexed for MEDLINE] 7231. Br Med Bull. 1981 Jan;37(1):43-8. Thermogenesis and obesity. James WP, Trayhurn P. PMID: 7020865 [PubMed - indexed for MEDLINE] 7232. Int J Biochem. 1981;13(5):525-41. Tissue lipoprotein lipase activity and its action in lipoprotein metabolism. Cryer A. PMID: 7016622 [PubMed - indexed for MEDLINE] 7233. Crit Rev Food Sci Nutr. 1981;14(2):135-51. Nutrition and current concepts of obesity. Khan MA. Obesity is and has been one of the foremost health problems in the U.S. and in many other countries. It is so interrelated with different factors that it is very difficult to single out the effect of one particular aspect. However, an effort is made in this review to focus on obesity only from a nutritional point of view. Childhood nutrition and its impact on obesity is particularly emphasised since weight gain during early infancy has been associated with obesity in later stages of life. There is considerable evidence that links obesity with certain diseases of the cardiovascular system and diabetes. A review of this relationship is also outlined based on recent developments. The causes, classification and consequences of obesity are discussed in detail followed by critical evaluation of the possible and prevalent treatment methods. PMID: 7011685 [PubMed - indexed for MEDLINE] 7234. Proc Nutr Soc. 1981 Jan;40(1):93-8. Mechanisms for the regulation of ketogenesis. Williamson DH. PMID: 7010360 [PubMed - indexed for MEDLINE] 7235. Annu Rev Nutr. 1981;1:235-56. Regulation of energy balance. Rothwell NJ, Stock MJ. The past 10-15 years have produced a significant increase in knowledge and theories concerning the regulation of energy balance, but the precision of this regulation is still uncertain. However, the fact that investigators have had to resort to a variety of techniques and ploys (some of them bizarre) to produce marked pertubations in body weight is in itself an indication that the regulatory system can be very robust. Although control of food intake obviously plays a major role in this system, control of energy expenditure (i.e. DIT) also has to be considered as an important factor in the maintenance of energy balance. In this review most of the evidence for DIT and its biochemical origins has been derived from studies on experimental animals. Many of the overfeeding studies carried out on man are consistent with the animal work, but because of differences in interpretation and some equivocal results, the role of DIT in human metabolism is still a contentious issue. This problem may not be fully resolved to everyone's satisfaction until complete, continuous, and very precise energy balance measurements are made on chronically overfed lean subjects. Before this expensive and arduous experiment is undertaken, evidence for thermogenesis in man will continue to depend on acute measurements of the metabolic response to various stimuli. An increasing number of studies (e.g. 35, 80) have demonstrated the existence of NST in man, and the possibility that this could originate from BAT is supported by histological (62, 148) and thermographic data (130). Conversely, reductions in cold tolerance (2, 18) and thermogenic responses to noradrenaline (82) with increasing adiposity are similar to the blunted responses seen in genetically obese animals, which suggests that human obesity may also involve an impairment in thermogenesis. At the present time these ideas concerning the important of DIT in man and its role in obesity remain somewhat speculative, but no doubt this area will now be the subject of further research. Similarly, the impact of early nutritional influences on subsequent energy balance regulation and resistance to obesity will receive more attention following the report (144) that hyperphagia in rats during early life results in a reduced body fat content and leanness in adulthood. The relative contributions and interactions between intake and output in energy balance need clarifying, and in terms of central organization, the mechanisms of appetite control should now be considered for their relevance to the control of thermogenesis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6764716 [PubMed - indexed for MEDLINE] 7236. J Endocrinol. 1981;89 Suppl:119P-129P. Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. Siiteri PK. PMID: 6453915 [PubMed - indexed for MEDLINE] 7237. Acta Diabetol Lat. 1981;18(1):1-17. The relationship between the hyperplastic pancreatic islet and insulin insensitivity in obesity. Mahler RJ. In summary, the present review provides evidence in support of the proposition that pancreatic islet cell hyperplasia precedes the development of insulin insensitivity in the obese mouse and, it is likely, that similar events occur in obese humans. Moreover, the hyperplastic pancreatic islet appears to be responsible for the development of insulin insensitivity, since suppression of the hyperplastic islet, by either alloxan or streptozotocin administration to the obese mouse, results in amelioration of insulin insensitivity in vivo. Since no change occurred in the degree of obesity or in adipocyte cell size or number, it is evident that insulin sensitivity is independent of obesity per se. Hence, although obesity and insulin insensitivity frequently co-exist, insulin insensitivity is independent of obesity and is due rather to the presence of pancreatic islet cell hyperplasia. Light and electron microscopy of the hyperplastic pancreatic islets of the obese mouse reveal increased numbers of A- B- and D-cells. Islet suppression with alloxan or streptozotocin results in the selective reduction of B-cells with preservation of A- and D-cells. Therefore, restoration of insulin sensitivity in the obese mouse following pancreatic islet cell suppression appears to be directly related to suppression of B-cell hypersecretion. Biochemical studies of muscle and adipose tissues from the obese mouse reveal profound insulin unresponsiveness without clear cut improvement in vitro following pancreatic islet cell suppression and restoration of insulin sensitivity in vivo. These data are consistent with a relatively modest reduction in the number of available insulin receptors upon these tissues in relation to the marked insulin resistance and imply an impairment of insulin action beyond the insulin receptor interaction [either transport or intracellular action(s)] as the major site(s) of insulin resistance in the muscle and adipose tissues of obese mice. Conversely a reduction of insulin receptors upon hepatocytes of obese mice and their improvement following a reduction of B-cell hypersecretion support the proposition that the number of available insulin receptors may be the major site for the regulation of insulin action upon that tissue. Finally, evidence is presented which suggests that an inability of insulin to limit hepatic gluconeogenesis may be the predominant cause of insulin insensitivity in the obese mouse. PMID: 6452013 [PubMed - indexed for MEDLINE] 7238. Int J Obes. 1981;5(6):643-9. Adenosine and lipolysis. Fredholm BB. The present review briefly summarizes work from the author's laboratory aiming at the clarification of the role played by adenosine in the regulation of adipose tissue circulation and metabolism. Studies on isolated fat cells demonstrate that adenosine, in mumolar concentrations, can inhibit lipolysis induced by eg noradrenaline. The effect appears to be due to inhibition of cyclic AMP formation. Studies of subcutaneous adipose tissue in situ also demonstrate the effect of exogenous adenosine on lipolysis. Furthermore, adenosine causes vasodilation and inhibition of noradrenaline release from sympathetic nerve endings. The actions of adenosine are antagonized by theophylline and other methylxanthines in concentrations lower than those required to inhibit cyclic AMP breakdown. It is shown that adenosine is normally present in adipose tissue in approximately 0.3 microM concentration and that the level is increased by sympathetic nerve stimulation. From a quantitative comparison of adenosine levels and dose-effect relationships as well as from pharmacological studies it is concluded that adenosine is a physiological regulator of adipose tissue circulation and lipolysis, while the physiological role of adenosine as a transsynaptic modulator of noradrenaline release remains to be established. PMID: 6274819 [PubMed - indexed for MEDLINE] 7239. Biosci Rep. 1981 Jan;1(1):19-34. Membrane phosphorylation: a crucial role in the action of insulin, EGF, and pp60src? Houslay MD. PMID: 6269672 [PubMed - indexed for MEDLINE] 7240. Rev Pure Appl Pharmacol Sci. 1981 Jan-Mar;2(1):1-112. The mechanisms of hormone and drug actions on fatty acid release from adipose tissue. Davies JI, Souness JE. PMID: 6269156 [PubMed - indexed for MEDLINE] 7241. Fed Proc. 1980 Dec;39(14):3178-82. Nutritional probe of the aging process. Masoro EJ, Yu BP, Bertrand HA, Lynd FT. It has long been known that food restriction markedly increases the length of life of rats and other laboratory rodents. It has been further shown that life-prolonging food restriction delays the occurrence or slows the progression of those diseases believed to limit the life span of the animal. However, the mechanisms responsible for this increase in longevity and for the delay in occurrence of age-associated disease are not known. Surprisingly little work hs been done on the effect of these life-prolonging dietary regimens on the many changes in physiological processes and biochemical characteristics that occur with age. Since biochemical and physiological explorations might well provide the information needed to investigate the basic mechanisms underlying these actions of food restriction, such a study was initiated in our laboratory. It was found that in most of the age-related functions studied changes were delayed or partially prevented by food restriction. Our studies provide a start in analyzing the mechanisms by which food restriction prolongs life and delays disease and it is to be anticipated that future research along this line will not only further define these mechanisms but in addition should greatly contribute to our knowledge of the aging process. PMID: 7002620 [PubMed - indexed for MEDLINE] 7242. Ann Endocrinol (Paris). 1980 Nov-Dec;41(6):502-11. [Growth factors with identical insulino-situations : IGF I and II, NSILA and somatomedins (author's transl)]. [Article in French] Froesch ER, Zapf J. NSILA consists of two polypeptides of known structure. IGF I and II are close relatives of insulin. 50% of all amino acid residues in the A-and B-region of IGF I and II are situated in identical positions as in the A-and B-chain of insulin. A C-region of 12 and 8 residues respectively connects the A-and B-region in IG FI and II. A D-region of 8 and 6 residues extends the A-region of IGF I and II. 17 of all invariable 19 amino acid residues in the insulin molecules of all known species are also present in IGF. IGF is attached to a carrier protein in serum. The latter inhibits its action on adipose tissue and muscle. Therefore, IGF cannot be measured in serum but, rather, must be dissociated from the binding protein before quantitation. Most tissues appear to have IGF binding sites for which insulin does not compete with the exception of fibroblasts. IGF probably acts via interaction with the IGF receptor, with the exception of adipose tissue where the IGF effect is mediated by the insulin receptor. The concentration of IGF I in serum is under growth hormone control. It is elevated in acromegalics and decreased in pituitary dwarfs and Laron dwarfs. IGF I and II are potent stimulators of cell growth in culture. Their growth stimulating effect in vivo has not yet been unequivocally proven. PMID: 7018376 [PubMed - indexed for MEDLINE] 7243. Clin Endocrinol (Oxf). 1980 Nov;13(5):489-506. Metabolic aspects of the calorigenic effect of thyroid hormone in mammals. Sestoft L. The increased BMR in hyperthyroidism may be accounted for by the use of chemical energy for metabolic processes and work. Major contributors are the heart work and futile cycling of FFA into triglyceride in adipose tissue, whereas gluconeogenesis in liver and the maintenance of sodium and potassium concentration gradients across the plasma membranes are unlikely to play any significant role. Information on the use of energy for protein turnover and urea production is lacking. The rate of oxygen uptake is not increased in the brain, spleen and testis. The main metabolic fuel seems to be free fatty acid. The mechanism which enables the hyperthyroid tissue to maintain normal concentrations of ATP, ADP and inorganic phosphate, (Pi) despite an increased turnover of energy-rich phosphates, is not fully elucidated. However, ultimately the increased rate of oxygen uptake in hyperthyroidism seems to rely upon an increased capacity for the transport of cytosolic ADP and Pi into mitochondria. The transport capacity is increased by an increased area of the mitochondrial membrane per g tissue and by a change in the kinetics of translocation of substrates for oxidative phosphorylation. Other transport processes across the mitochondrial membrane are also changed by hyperthyroidism, e.g. long chain fatty acid transport via carnitine acyl transferase, and oxaloacetate transport via substrate shuttles. PMID: 7014041 [PubMed - indexed for MEDLINE] 7244. Physiologist. 1980 Oct;23(5):34-43. Adipocytes, aging and cholesterol metabolism. Hartman AD, Krause BR. PMID: 7003615 [PubMed - indexed for MEDLINE] 7245. Physiol Rev. 1980 Oct;60(4):1049-106. Multiple hormone interactions in the developmental biology of the mammary gland. Topper YJ, Freeman CS. PMID: 7001510 [PubMed - indexed for MEDLINE] 7246. J Neurol Sci. 1980 Oct;48(1):81-92. Myopathy with multiple minicore--report of two siblings. Ricoy JR, Cabello A, Goizueta G. Two cases of non-progressive congenital hypotonia are described in siblings, male and female, aged 5 and 9 years, respectively, which morphologically correspond to myopathy with multicore or minicore. The study of these 2 cases is compared with those described in the literature, with special emphasis on the analysis of the histochemical picture. The disease in all the cases is defined by the presence of multiple small foci of loss of cross striation with loss of activity of myofibrillar ATPase and oxidative enzymes. Furthermore, a predominance and hypotrophy of type I fibers and in some cases hypertrophy of type II is constantly recorded, which is interpreted as an alteration in muscle maturation. We review other myopathies described with focal loss of cross-striation which associate central nuclei with the myofibrillar lesion, considering them to be myopathy with multicore or minicore. PMID: 6448277 [PubMed - indexed for MEDLINE] 7247. FEBS Lett. 1980 Sep 22;119(1):1-8. On the role of the calcium transport cycle in heart and other mammalian mitochondria. Denton RM, McCormack JG. PMID: 7000543 [PubMed - indexed for MEDLINE] 7248. Cancer Treat Rev. 1980 Sep;7(3):115-39. Anorexia and cancer in animals and man. Garattini S, Bizzi A, Donelli MG, Guaitani A, Samanin R, Spreafico F. PMID: 7004637 [PubMed - indexed for MEDLINE] 7249. Proc Nutr Soc. 1980 Sep;39(3):219-25. Animal models for the study of energy balance. Gurr MI. PMID: 7001483 [PubMed - indexed for MEDLINE] 7250. Probl Endokrinol (Mosk). 1980 Sep-Oct;26(5):81-9. [Tissue insulin sensitivity and its role in the pathogenesis of diabetes mellitus]. [Article in Russian] Iaroshevskiĭ IuA. PMID: 7001441 [PubMed - indexed for MEDLINE] 7251. J Dairy Sci. 1980 Sep;63(9):1514-29. Partitioning of nutrients during pregnancy and lactation: a review of mechanisms involving homeostasis and homeorhesis. Bauman DE, Currie WB. Control of metabolism during pregnancy and lactation involves two types of regulation-homeostasis and homeorhesis. Homeostasis control involves maintenance of physiological equilibrium or constancy of environmental conditions within the animal. Homeorhesis is the orchestrated or coordinated control in metabolism of body tissues necessary to support a physiological state. Regulation of nutrient partitioning during pregnancy involves homeorhetic controls arising from the conceptus. This assures growth of the conceptus (fetus and fetal membranes) and gravid uterus as well as development of the mammary gland. With the onset of lactation many--perhaps even most--maternal tissues undergo further adaptations to support rates of lipogenesis and lipolysis in adipose tissue are examples of important homeorhetic controls of nutrient partitioning that are necessary to supply mammary needs for milk synthesis. The interactions between homeorhesis and homeostasis during pregnancy and lactation and possible endocrine control are discussed. While not definitively established, roles for placental lactogen and prolactin are attractive possibilities in homeorhetic regulation of maternal tissues to support pregnancy and the initiation of lactaion, respectively. PMID: 7000867 [PubMed - indexed for MEDLINE] 7252. Can J Physiol Pharmacol. 1980 Sep;58(9):1023-30. Histamine receptors and cyclic AMP. McNeill JH. The identification and characterization of histamine receptors in the organ systems of various species has been made possible in recent years by the introduction of relatively selective agonists and antagonists of H1 and H2 receptors. H2 receptors have now been clearly demonstrated in gastric mucosa, heart, rat uterus, brain, and adipose tissue. Less well-defined H2 receptor systems have also been described in the vasculature, bronchioles, and other smooth muscles as well as in the thyroid gland and lymphocytes. In tissues where it has been examined a close correlation between H2 receptors and the adenylate cyclase--cyclic AMP system has been found. With the exception of the central nervous system stimulation of H1 receptors does not seem to be involved with cyclic AMP. In the case of the brain the H1 receptor stimulation of adenylate cyclase can be differentiated from H2 receptor stimulation of the enzyme by the use of blocking agents and by the fact that the H1 receptor response is enhanced in the presence of adenosine. Studies of the involvement of histamine with the adenylate cyclase--cyclic AMP system have been concentrated on such tissues as gastric mucosa, heart, rat uterus, brain, and adipose tissue. The present review will concentrate on the literature concerning those tissues. PMID: 6257356 [PubMed - indexed for MEDLINE] 7253. Acta Cytol. 1980 Sep-Oct;24(5):373-83. The paradox of sarcomas. Hajdu SI. PMID: 6254295 [PubMed - indexed for MEDLINE] 7254. FEBS Lett. 1980 Aug 25;117 Suppl:K93-105. Integration of metabolism in tissues of the lactating rat. Williamson DH. PMID: 6998730 [PubMed - indexed for MEDLINE] 7255. J Lipid Res. 1980 Aug;21(6):657-70. Search for the adipocyte precursor cell and factors that promote its differentiation. Hausman GJ, Campion DR, Martin RJ. PMID: 6999105 [PubMed - indexed for MEDLINE] 7256. Exp Aging Res. 1980 Jun;6(3):261-70. Rats as models for the study of obesity. Masoro EJ. Gerontologists are concerned about obesity for two reasons. First, adiposity increases in humans with increasing age. Secondly, there is a strong possibility that the interaction between obesity and aging is deleterious. Since rats are a widely used animal model for the study of aging, it is likely that rats will be utilized in experiments designed to study in interactions between adiposity and aging. The object of this review is to provide the basic information needed for utilizing rat in such studies. To this end, changes in adipose tissue mass that occur during the life span of normal rats are described as are the types of rat models that have been used in the study of obesity. In addition, the characteristics of each of these obesity models are detailed. PMID: 7398712 [PubMed - indexed for MEDLINE] 7257. J Hand Surg Am. 1980 May;5(3):211-3. Lipofibromatous hamartoma of the radial nerve: a case report. Herrick RT, Godsil RD Jr, Widener JH. Lipofibromatous hamartomas of the radial nerve are exceedingly rare. What is believed to be only the second such reported case is described, and a review of the pertinent histological findings necessary to make the diagnosis is given. PMID: 7400556 [PubMed - indexed for MEDLINE] 7258. Ann Endocrinol (Paris). 1980 May-Jun;41(3):157-92. [Recent data on somatomedins (insulin-like growth factors) (author's transl)]. [Article in French] Binoux M. Data on somatomedins have resulted from the convergence of two initially distinct lines of research relating to the two major aspects of their biological activities, their effects on cartilage growth and their insulin-like action. Human serum has yielded three factors, SM-A, SM-C and NSILA-S. The latter comprises two very similar polypeptides, IGF I and IGF II which structurally closely resemble proinsulin. A fourth factor, MSA, has been isolated from calf serum and from conditioned medium of a rat liver cell strain. All these chemically and biologically closely related factors have a molecular weight of approximately 7 500 but circulate in a form with much higher molecular weight owing to their binding to specific carrier proteins. Over the past five years, the use of purified somatomedins has led to rapid progress in the elucidation of the physiology of these hormones. In this review, present knowledge of somatomedins is analysed in the following terms: physiochemical properties, circulating forms, action on growth, insulin-like activity, interaction with receptors, immunological characteristics, biosynthesis and hormonal regulation of their blood level. Results obtained in our laboratory from rat liver organ culture are discussed: the action of culture media on cartilage sulphation, the detection of a protein which specifically binds NSILA-S and SM-A and its use in a competitive protein binding assay for somatomedins in biological fluids. PMID: 6998350 [PubMed - indexed for MEDLINE] 7259. Diabetes. 1980 May;29(5):399-409. Insulin action and the regulation of hexose transport. Czech MP. PMID: 6991331 [PubMed - indexed for MEDLINE] 7260. Diabete Metab. 1980 Mar;6(1):59-69. [Physical exercise in the diabetic. The importance of understanding endocrine and metabolic responses (author's transl)]. [Article in French] Berger M, Assal JP, Jorgens V. During physical activity in normals, metabolic control is well regulated despite major changes in metabolic fuels, glucose and non esterified fatty acids (NEFA). Release of NEFA from adipose tissue is stimulated by a decrease of insulin and blood glucose as well as by an increase of growth hormone, catecholamines and adrenergic stimulation. The increase in glucose utilisation by muscle during physical activity is balanced by an increase in glucose production by the liver. This hepatic glucose production is due to glycogenolysis (beginning of exercise) and by gluconeogenesis (later in time). The metabolic pathways are favoured by decreased insulin and blood glucose levels induced by physical activity and by increased levels of epinephrine, cortisol and glucagon. On the other hand in insulin-dependent diabetics, these compensatory mechanisms might be seriously unbalanced because of non physiologic insulin levels. In well controlled diabetics, moderate physical activity induces the same changes in energetic fuels as in normal controls. When a diabetic exercises after insulin injection, the levels of circulating insulin are always higher than in non-diabetics where blood insulin levels decrease. In diabetics on insulin this supra-normal level of insulin during physical activity decreases hepatic glucose production and increases peripheral glucose uptake with a resultant tendency to hypoglycemia. On the other hand, in poorly controlled diabetics, physical activity can induce a rise in blood glucose. Increased hepatic glucose output, decreased peripheral utilisation of glucose and increased growth hormone, glucagon, epinephrine and cortisol levels might even lead to development of ketosis. Physical activity can disturb the stability of diabetes when insulin levels are either too low or too high leading to high and low blood glucose responses respectively. The benefit of physical activity in the diabetic will therefore depend upon the degree of diabetes control; ideal control is not always easy to obtain or to maintain. Thus, to derive maximum benefit to health both the diabetic and the physician should clearly understand how to adapt treatment to physical activity (prevention of hypoglycemia, change in insulin doses, etc.). PMID: 6768605 [PubMed - indexed for MEDLINE] 7261. Ann Occup Hyg. 1980;23(4):405-10. Solvents--the relationship between biological monitoring strategies and metabolic handling. A review. Gompertz D. PMID: 7258932 [PubMed - indexed for MEDLINE] 7262. Prog Med Chem. 1980;17:105-49. Adipose tissue, obesity and insulin. Garratt CJ, Hubbard RE, Ponnudurai TB. PMID: 7031767 [PubMed - indexed for MEDLINE] 7263. Prog Food Nutr Sci. 1980;4(5):75-80. Estimation of essential fatty acid requirements in pregnancy and lactation. Crawford MA. PMID: 7005963 [PubMed - indexed for MEDLINE] 7264. Adv Enzyme Regul. 1980;18:97-117. Expression of insulin receptors during preadipocyte differentiation. Reed BC, Lane MD. PMID: 7004132 [PubMed - indexed for MEDLINE] 7265. Ann Nutr Aliment. 1980;34(2):377-87. [Recent research on the physiological effects of various types of compounds present in heated fats]. [Article in French] Grandgirard A. Combe, Constantin and Entressangles's work on the intestinal absorption of various new compounds formed during the heating of fats revealed that most of these compounds may pass through the intestinal mucosa, but that the absorption rate varies from a type of compound to another one. Among all the compounds present in the heated fats, the fraction of cyclic monomers was the most studied; previous works revealed that this fraction was toxic. However recent result of Iwaoka and Perkins seem to indicate that cyclic monomers are well tolerated by rats and induce only a slight effect on lipid metabolism; these surprising results may be due to the fact that the cyclic monomers are well tolerated by rats and induce only a slight effect on lipid metabolism; these surprising results may be due to the fact that the cyclic monomers used by Iwaoka and Perkins included only cyclohexadienic and aromatic compounds; Saito and Kaneda indeed obtained marked toxic effects with cyclic monomers including in particular compounds with cyclohexanic, cyclohexenic and cyclohexyl 1,2 diylidene structures; on the other hand, Potteau, Dubois and Rigaud identified after hydrogenation not only cyclohexanic compounds but also compounds with disubstituted cyclopentanic and hexahydroindane structure, in thermopolymerizated or thermally oxidized oils, which proved to be toxic to experimental animals, in particular in breeding experiments. Some experimental facts suggest a system of detoxification consisting in particular in the urinary glucuronide excretion. The apolar thermic polymers (cyclic or not) are little absorbed and produce few or no physiological effect; however they can be found again in appreciable amounts in adipose tissue (Billek and Rost) or in liver (Perkins and Taubold). Very little is known on the other fractions present in the heated fats, except that the fraction of oxidized acids can globally prove to be toxic. Alexander's work does not seem quite convincing to us: the statement according which oils rich in monoenic fatty acids would be more toxic after heating than the oils rich in polyunsaturated fatty acids is not based on reliable experimental results. PMID: 7001996 [PubMed - indexed for MEDLINE] 7266. Annu Rev Physiol. 1980;42:511-28. Insect endocrinology: action of hormones at the cellular level. Riddiford LM. PMID: 6996595 [PubMed - indexed for MEDLINE] 7267. Contrib Nephrol. 1980;20:118-28. Does parathyroid hormone play a role in lipid metabolism? Heuck CC, Ritz E. PTH activates hormone-sensitive lipolysis in adipose tissue by an adenylate cyclase mechanism. Effects on lipoprotein synthesis and catabolism are conceivable, but have not been studied in detail so far. Information on serum lipids in primary and secondary hyperparathyroidism is conflicting. Some authors find an increase of serum lipids upon administration of PTH and in patients with primary hyperparathyroidism, while others find a decrease of serum cholesterol and serum triglycerides which reverts to normal upon parathyroidectomy in patients with primary hyperparathyroidism. In experimental models of uremia, PTH clearly plays a permissive role for the development of uremic hyperlipemia. In PTX uremic animals, hyperlipoproteinemia is less marked than in PT-intact uremic animals, but serum lipids are still higher in PTX uremic animals than in nonuremic PT-intact animals. This would indicate that hyperlipemia is caused by PTH-independent mechanisms but is intensified by the presence of secondary hyperparathyroidism. The role of PTH in the hyperlipoproteinemia of uremic patients has not been clarified so far. PMID: 6995009 [PubMed - indexed for MEDLINE] 7268. Physiol Rev. 1980 Jan;60(1):143-87. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Robinson AM, Williamson DH. PMID: 6986618 [PubMed - indexed for MEDLINE] 7269. CRC Crit Rev Diagn Imaging. 1980 Jan;12(3):245-308. Radiological assessment of maturity and size of the newborn infant. Kuhns LR, Poznanski AK. PMID: 6985581 [PubMed - indexed for MEDLINE] 7270. Angew Chem Int Ed Engl. 1980;19(9):659-75. Structure and function of the energy-converting system of mitochondria. von Jagow G, Engel WD. PMID: 6778262 [PubMed - indexed for MEDLINE] 7271. Reprod Nutr Dev. 1980;20(5B):1545-62. Neuroendocrinology of hyperphagias and obesities. Louis-Sylvestre J. PMID: 6760283 [PubMed - indexed for MEDLINE] 7272. Endocr Rev. 1980 Spring;1(2):180-99. Corticosteroid-induced changes in phospholipid membranes as mediators of their action. Nelson DH. PMID: 6263603 [PubMed - indexed for MEDLINE] 7273. CRC Crit Rev Biochem. 1980;9(3):171-206. The chemistry and biology of cholera toxin. Lai CY. PMID: 6256124 [PubMed - indexed for MEDLINE] 7274. Annu Rev Biochem. 1980;49:459-87. Enzymes of glycerolipid synthesis in eukaryotes. Bell RM, Coleman RA. PMID: 6250446 [PubMed - indexed for MEDLINE] 7275. Annu Rev Physiol. 1980;42:359-71. Neuronal control of microvessels. Rosell S. PMID: 6157355 [PubMed - indexed for MEDLINE] 7276. Annu Rev Biochem. 1980;49:395-420. Regulation of hepatic fatty acid oxidation and ketone body production. McGarry JD, Foster DW. PMID: 6157353 [PubMed - indexed for MEDLINE] 7277. J Physiol (Paris). 1980;76(1):5-24. [The endocrine pancreas of birds]. [Article in French] Sitbon G, Mialhe P. The endocrine pancreas of birds contains 3 islet types and releases glucagon, insulin, somatostatin and avian pancreatic polypeptide (APP). Interactions between these hormones, and pancreatic hormone-plasma metabolite feedback mechanisms, are the main regulators of these secretions. In birds, total pancreatectomy induces a fatal hypoglycaemia associated with the disappearance of circulating glucagon, and an impaired glucose tolerance ascribed to the lack of insulin. Normoglycaemia can be restored in depancreatized birds by infusion of glucagon and insulin, provided that the G/I ratio is close to normal. Subtotal pancreatectomy provokes a diabetes characterized by a basal hyperglycaemia and an impaired glucose tolerance. However, while a transient diabetes is observed in most species, in the goose a permanent diabetes is obtained. These results point out the importance of the pancreas and especially of glucagon, in birds. This importance can also be detected in the protein metabolism, since total or subtotal pancreatectomy markedly increases the concentration of plasma aminoacids. As for lipid metabolism, in vivo and/or in vitro experiments have shown the sensitivity of the adipose tissue and liver cells to glucagon. Finally, contrary to the general opinion, insulin seems to be antilipolytic, as in mammals. PMID: 6106057 [PubMed - indexed for MEDLINE] 7278. Mol Cell Biochem. 1979 Dec 14;28(1-3):27-43. Control of acetyl-CoA carboxylase by covalent modification. Kim KH. In this review, various experiments which establish the occurrence of covalent modification mechanisms, both in vivo and in vitro, in the control of acetyl-CoA carboxylase have been presented. It is interesting to note that phosphorylation of the carboxylase results in disaggregation of the active species. These studies indicate that aggregation and disaggregation of the enzyme are involved in the control of carboxylase activity. Our covalent modification mechanism and the allosteric control mechanism share a common ground in that both mechanisms affect the equilibrium between protomers and polymers of the enzyme. However, it is clear that the allosteric control mechanism cannot function alone under normal physiological conditions. Covalent modification of the carboxylase is prerequisite for efficient functioning of the allosteric mechanism. There are many aspects of the regulation of acetyl-CoA carboxylase which require further clarification. However, it is now established that short-term control of acetyl-CoA carboxylase involves the covalent modification mechanism. PMID: 43470 [PubMed - indexed for MEDLINE] 7279. Can Med Assoc J. 1979 Nov 17;121(10):1361-4. Obesity may be due to a malfunctioning of brown fat. Himms-Hagen J. Recent basic research on the functioning of brown fat, a heat-producing tissue, has been fitted together with research on obesity to provide an exciting and challenging new approach to the study of the cause of obesity and could serve as a starting point for the development of new modes of treatment. Recent studies on brown adipose tissue have shown that a defect in this tissue is one probable cause of obesity. PMCID: PMC1704532 PMID: 391377 [PubMed - indexed for MEDLINE] 7280. J Endocrinol Invest. 1979 Oct-Dec;2(4):445-60. Recent advances in studies on estrogen biosynthesis. Brodie AM. PIP: Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. The production of estrogens by the testis is not clear, but it may modify testosterone secretion. Estrogen produced locally in the brain may play an important role in male and female sex differentiation and sex behavior. Extraovarian estrogen has been known to maintain growth of estrogen-dependent tumors. Recently developed inhibitors have been used to identify aromatization reaction and to elucidate roles of estrogen in various tissues. They also have the potential of controlling estrogen production in estrogen-dependent diseases. PMID: 395188 [PubMed - indexed for MEDLINE] 7281. Physiol Rev. 1979 Oct;59(4):1078-1104. Blood circulation in adipose tissue. Rosell S, Belfrage E. PMID: 386395 [PubMed - indexed for MEDLINE] 7282. Dis Mon. 1979 Oct;26(1):1-85. Obesity. Bray GA. PMID: 385262 [PubMed - indexed for MEDLINE] 7283. Eur J Clin Invest. 1979 Oct;9(5):317-8. The anatomical biochemistry of obesity. Butterfield WJ. PMID: 118023 [PubMed - indexed for MEDLINE] 7284. Can J Physiol Pharmacol. 1979 Sep;57(9):923-37. Regulation of lipid metabolism in adipose tissue and heart. Severson DL. PMID: 391374 [PubMed - indexed for MEDLINE] 7285. J Lab Clin Med. 1979 Sep;94(3):381-6. Avenues of adrenergic research. Malbon CC. PMID: 224119 [PubMed - indexed for MEDLINE] 7286. Biochim Biophys Acta. 1979 Jul 3;549(1):1-29. Brown adipose tissue mitochondria. Nicholls DG. PMID: 383147 [PubMed - indexed for MEDLINE] 7287. Physiol Rev. 1979 Jul;59(3):719-809. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Bray GA, York DA. PMID: 379887 [PubMed - indexed for MEDLINE] 7288. Clin Ter. 1979 Jun 30;89(6):555-76. [Endocrine rehabilitation of the pancreatectomized patient]. [Article in Italian] Adezati L, Prando R, De Micheli A. PMID: 44492 [PubMed - indexed for MEDLINE] 7289. Mol Cell Biochem. 1979 Jun 15;25(3):143-69. Regulation of adenylate cyclase by adenosine. Fain JN, Malbon CC. PMID: 225658 [PubMed - indexed for MEDLINE] 7290. Horumon To Rinsho. 1979 Jun;27(6):595-600. [Obesity and ovarian hormones (author's transl)]. [Article in Japanese] Mori N. PMID: 380846 [PubMed - indexed for MEDLINE] 7291. Life Sci. 1979 May 28;24(22):2011-22. The oxoglutarate reductive carboxylation pathway: a review. D'Adamo AF Jr, Tobin KD. PMID: 379485 [PubMed - indexed for MEDLINE] 7292. Yale J Biol Med. 1979 May-Jun;52(3):307-29. The pig as a model for the study of obesity and of control of food intake: a review. Houpt KA, Houpt TR, Pond WG. The use of the pig for studies of food intake and obesity is reviewed. Effects of ambient temperature and taste on food intake as well as satiety factors impicating both neural and hormonal mechanisms originating in the gastrointestinal tract are considered; the integration of information in the central nervous system for both internal and external sources is hypothesized. Special concerns of food intake controls in the neonate are discussed, including effects of neonate sweet preference on food intake, gastrointestinal satiety factors, and hypoglycemia as a stimulus for food ingestion.For obesity studies, pigs offer several advantages, including their general physiological similarity to humans, similar fat cell size, and body fat distribution. Lipogenesis, lipolysis, and lipid mobilization are under intensive study in swine and the information obtained may have important application in studies of human obesity. The voluminous literature on metabolic differences between genetically lean versus obese populations of pigs suggests possibilities for application in humans. Greater characterization of differences and similarities between pigs and humans in important metabolic parameters related to regulation of food intake and obesity should facilitate better understanding and control of human obesity. PMCID: PMC2595462 PMID: 380187 [PubMed - indexed for MEDLINE] 7293. Am J Med. 1979 May;66(5):843-52. Lipid metabolism in diabetes mellitus. Saudek CD, Eder HA. PMID: 375725 [PubMed - indexed for MEDLINE] 7294. Am J Clin Nutr. 1979 May;32(5):1082-96. Nutritional regulation of somatomedin. Phillips LS, Vassilopoulou-Sellin R. PMID: 373416 [PubMed - indexed for MEDLINE] 7295. Usp Sovrem Biol. 1979 May-Jun;87(3):359-72. [Role of glucagon in regulating metabolism]. [Article in Russian] Kendysh IN. PMID: 227189 [PubMed - indexed for MEDLINE] 7296. Physiol Rev. 1979 Apr;59(2):285-304. Temperature regulation in newborn polar homeotherms. Blix AS, Steen JB. PMID: 375256 [PubMed - indexed for MEDLINE] 7297. Lipids. 1979 Apr;14(4):417-27. The effect of exercise on plasma high density lipoproteins. Wood PD, Haskell WL. The influence of vigorous activity in man on plasma lipids and lipoproteins is reviewed, with particular emphasis on high density lipoproteins. Both cross sectional and longitudinal (or training) studies have been reported, many of them of less than ideal design. Nonetheless, a consistent pattern emerges in which increased exercise levels lead to lower plasma concentrations of triglycerides and very low density lipoproteins, and of low density lipoproteins. High density lipoprotein levels increase. Sometimes, but not uniformly, plasma total cholesterol level falls as the result of these changes. The increase in plasma high density lipoprotein appears to be the result largely of an increase in the less dense HDL2 subfraction. Plasma apolipoprotein A-I levels (but not apo-A-II levels) seem to increase concomitantly. The precise biochemical mechanism responsible for these changes has not been elucidated; but the recent finding of increased lipoprotein lipase activity in adipose tissue and muscle of endurance runners suggests that increased lipolytic rate of triglyceride-rich lipoproteins may be an initial step in a sequence of events leading to higher plasma levels of HDL-2. PMID: 220492 [PubMed - indexed for MEDLINE] 7298. Cell Tissue Res. 1979 Mar 19;197(2):295-312. The relation between solid cell nests and C cells of the thyroid gland: an immunohistochemical and morphometric investigation. Janzer RC, Weber E, Hedinger C. Thyroid tissue of 300 routine autopsies was processed in a standardized manner. So-called solid cell nests (SCN) were found in 21 patients (7%). These cases were investigated carefully by serial step sectioning. In order to explore the correlation of SCN to the C-cell system, the sections were stained by silver impregnation and the immunoperoxidase method. Morphometric analyses revealed a significant increase in the density of C cells in the proximity of the SCN. With progressive distance from the SCN, the C-cell density decreased and reached normal values. In 30% of the cases argyrophilic and calcitonin-positive cells were found lying within the SCN. Occasionally, mixed follicles could be discerned: These were lined on the one side by a multilayered squamous epithelium, on the other side by normal monolayered cubic follicular epithelium, and contained a peculiar granular material. In one case, SCN were associated with intrathyroid portions of the parathyroids and adult adipose tissue, in a second case with adipose tissue only. Most probably SCN are vestiges of the ultimobranchial body and should be interpreted as such, despite the fact that other authors have expressed different views. The lack of disturbances in the calcium metabolism of the patients and the absence of medullary carcinoma in their family histories led us to interpret locally confined C-cell hyperplasia not as reactive nor premalignant, but rather as normal. PMID: 373883 [PubMed - indexed for MEDLINE] 7299. Physiol Behav. 1979 Mar;22(3):583-93. Gonadal effects on food intake and adiposity: a metabolic hypothesis. Wade GN, Gray JM. PMID: 379889 [PubMed - indexed for MEDLINE] 7300. J Lipid Res. 1979 Mar;20(3):289-315. Effects of ethanol on lipid metabolism. Baraona E, Lieber CS. Alcohol promotes accumulation of fat in the liver mainly by substitution of ethanol for fatty acids as the major hepatic fuel. The degree of lipid accumulation depends on the supply of dietary fat. Progressive alteration of the mitochondria, which occurs during chronic alcohol consumption, decreases fatty acid oxidation by interfering with citric acid cycle activity. This block is partially compensated for by increased ketone body production, which results in ketonemia. Thus, mitochondrial damage perpetuates fatty acid accumulation even in the absence of ethanol oxidation. Alcohol facilitates esterification of the accumulated fatty acids to triglycerides, phospholipids, and cholesterol esters, all of which accumulate in the liver. The accumulated lipids are disposed of in part as serum lipoprotein, resulting in moderate hyperlipemia. In some individuals with pre-existing alterations of lipid metabolism, small ethanol dose may provoke marked hyperlipemia which responds to alcohol withdrawal. Inhibition of the catabolism of cholesterol to bile salt may contribute to the hepatic accumulation and hypercholesterolemia. The capacity of lipoprotein production and hyperlipemia development increases during chronic alcohol consumption, probably as a result of the concomitant hypertrophy of the endoplasmic reticulum and Golgi apparatus. However, this compensation is relatively inefficient in ridding the liver of fat. This inefficiency may be linked to alterations of hepatic microtubules induced by ethanol or its metabolites, which interfere with the export of protein from liver to serum, promoting hepatic accumulation of proteins as well as fat. As liver injury aggravates, hyperlipemia wanes and liver steatosis is exaggerated. Derangements of serum lipids similar to those found in other types of liver disease also become apparent. The changes in serum lipids may be a sensitive indicator of the progression of liver damage in the alcoholic. PMID: 87483 [PubMed - indexed for MEDLINE] 7301. Biol Rev Camb Philos Soc. 1979 Feb;54(1):41-72. The pineal complex and thermoregulation. Ralph CL, Firth BT, Gern WA, Owens DW. PMID: 375995 [PubMed - indexed for MEDLINE] 7302. Int J Obes. 1979;3(1):15-55. Adipose tissue cellularity: a review. 2. The relationship between cellularity and obesity. Kirtland J, Gurr MI. PMID: 528118 [PubMed - indexed for MEDLINE] 7303. G Ital Chemioter. 1979 Jan-Dec;26(1-2):407-12. The use of pharmacokinetics in the design of fixed-ratio antibiotic combinations. Brumfitt W, Hamilton-Miller JM. PMID: 400152 [PubMed - indexed for MEDLINE] 7304. Prog Lipid Res. 1979;18(4):179-216. Lipid metabolism in the neonatal ruminant. Noble RC. PMID: 399523 [PubMed - indexed for MEDLINE] 7305. Int J Obes. 1979;3(4):301-23. Insulin resistance in obesity: a critical analysis at enzyme level. A review. Belfiore F, Iannello S, Rabuazzo AM. Based on the consideration that insulin does not act directly on metabolic processes but affects membrane carriers and key-enzymes that regulate metabolic pathways, determination of insulin responsiveness of the various key-enzymes is suggested as a very appropriate method for studying insulin resistance. Insulin resistance, as it occurs in obese or obese-diabetic humans and animals, is most often associated with hyperinsulinemia, and is characterized not only by increased activity of key-enzymes of pathways known to be stimulated by insulin (glycolysis, lipogenesis), with the possible exception of glycogen synthesis, but also by a trend towards increased activity of key-enzymes of 'catabolic pathways', normally depressed by insulin. In the adipose tissue there is a normal-to-enhanced basal lipolysis, which in man would result from the prevalence of the active over the inactive form of triacylglycerol lipase. In muscle, the increased amino-acid release that can be inferred from the elevated blood level of both alanine and branched-chain amino acids suggests an enhanced proteolysis. In liver, there is an elevation in the activity of the key gluconeogenic enzymes, which forms the basis of the augmented gluconeogenesis. In both muscle and liver, phosphorylase is also elevated with no change in glycogen synthase. Therefore, insulin resistance seems to consist of the failure of insulin to depress the key-enzymes of catabolic pathways. Possible resistance of glycogen synthetase, which might account for decreased glucose utilization in muscle, may be due to the opposing effects of the phosphorylation process on glycogen synthetase and phosphorylase, implying that activation of phosphorylase (which occurs in obesity) entails inhibition of the synthetase. The fact that insulin insensitivity concerns only the 'catabolic' but not most 'anabolic' pathways makes it unlikely that the unresponsiveness is due to a reduction in insulin receptors or increase in insulin degradation. Since resistance to insulin is shown by enzymes regulated by such different mechanisms as induction-repression (gluconeogenic enzymes), covalent modifications (lipase, phosphorylase), and changes in lysosome stability (lysosomal proteases responsible for proteolysis, a single basic mechanism for explaining insulin insensitivity cannot be envisaged at present. PMID: 393647 [PubMed - indexed for MEDLINE] 7306. Curr Concepts Nutr. 1979;8:143-70. Genetic obesity in man and rodents. Greenwood MR, Cleary MP, Hirsch J. PMID: 393467 [PubMed - indexed for MEDLINE] 7307. Curr Concepts Nutr. 1979;8:119-39. Dietary management of the pregnant diabetic. Knopp RH, Childs MT, Warth MR. The tendency of the pregnant diabetic to fasting ketosis limits the extent to which calorie restriction (particularly negative calorie balance) can be used in the treatment of the obese, adult-onset, pregnant diabetic. In addition, the vagaries of measuring excess weight gain and detecting extraneous sources of weight gain in diabetic pregnancy, and the difficulty of accurately enforcing a caloric prescription without forcing the subject to weigh her food, make the determination of an accurate degree of caloric limitation difficult at best. A greater reliance on the mother's appetite center may be more accurate and rewarding in most instances than any devices available to the clinician. Important considerations in the diet of the pregnant diabetic are adequate protein, minerals, and vitamins, an amount of carbohydrate that is constant from day to day but not necessarily restricted, carbohydrate intake in an unrefined form that maximizes the intake of associated fiber, and a reproducible meal and snack schedule which complements in insulin regimen. Insulin must remain the primary therapeutic tool if the effects of maternal diabetes on fetal morbidity and mortality are to be minimized. PMID: 393466 [PubMed - indexed for MEDLINE] 7308. J Hyg Epidemiol Microbiol Immunol. 1979;23(1):1-10. Radiocarbon (14C) migration and metabolism kinetics (a review). Vasilenko IY, Bugryshev PF, Semenov AI, Istomina AG, Novoseltseva VI. Radiocarbon (14C) introduced into the biosphere as a result of nuclear explosions and operation of nuclear power stations has upset the equilibrium existing in nature. The increase in 14C concentration in the biosphere is a problem of considerable hygienic and social importance, since 14C affects all living organism in the world. This paper presents data on 14C migration and metabolism kinetics. Radiocarbon metabolism kinetics depends on the form of the chemical compound metabolized. Inorganic 14C compounds are metabolized relatively fast. Organic 14C compounds (carbohydrates, fats and proteins) are retained longer in the body. Differences in the metabolism kinetics of differents 14C compounds lead to the formation of unequal irradiation doses in various organs and tissues. In establishing standards for admissible 14C intake, one should take into consideration the kind of chemical compound in which the element is incorporated. PMID: 392004 [PubMed - indexed for MEDLINE] 7309. Essays Biochem. 1979;15:37-77. Regulation of pyruvate metabolism in mammalian tissues. Denton RM, Halestrap AP. PMID: 391551 [PubMed - indexed for MEDLINE] 7310. Przegl Lek. 1979;36(7):506-15. [Molecular basis of insulin action on cells (author's transl)]. [Article in Polish] Tatoń J. PMID: 388532 [PubMed - indexed for MEDLINE] 7311. Int Rev Physiol. 1979;20:43-155. Cold thermogenesis. Alexander G. PMID: 387638 [PubMed - indexed for MEDLINE] 7312. Monogr Endocrinol. 1979;12:535-46. Regulation of gluconeogenesis by glucocorticoids. Exton JH. 1. Regulation of gluconeogenic substrate supply and modulation of the gluconeogenic pathway in the liver are both important in the control of gluconeogenesis by glucocorticoids. 2. Adrenal deficiency decreases the release of gluconeogenic and other amino acids from skeletal muscle during starvation. The effect is reversed by glucocorticoid replacement. The changes in amino acid release are accompanied by similar alterations in tissue amino acid levels and are not explained by alterations in net protein breakdown. Glucocorticoids do not alter protein catabolism and cause a small inhibition of protein synthesis. The biochemical alterations underlying the changes in amino acid metabolism induced by these steroids remain to be elucidated. Glucocorticoids may also regulate the supply of gluconeogenic substrates through permissive effects on the lipolytic action of catecholamines and other hormones in adipose tissue and on the glycogenolytic action of catecholamines on skeletal muscle. 3. Glucocorticoids are required for the increases in gluconeogenesis in starvation and diabetes. Part of their action is exerted directly on the liver and appears to involve modulation of P-enlopyruvate carboxykinase levels. Glucocorticoids increase the synthesis of this enzyme apparently through effects at the level of transcription. 4. Glucocorticoids exert permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine. The steroids are not required for cAMP generation or protein kinase activation by these hormones, but appear to act by maintaining the responsiveness of certain enzymes to the effects of the cAMP and alpha-adrenergic systems. It is proposed that this involves the maintenance of a normal intracellular ionic environment. PMID: 386091 [PubMed - indexed for MEDLINE] 7313. Fortschr Tierphysiol Tierernahr. 1979;10:1-136. [Mammalian pheromones with special reference to the boar taint steroid and its relationship to other testicular steroids (author's transl)]. [Article in German] Claus R. PMID: 383590 [PubMed - indexed for MEDLINE] 7314. Ann Nutr Aliment. 1979;33(1):27-38. Animal obesities. Jeanrenaud B. Genetically or experimentally-produced (e.g. via lesions of the hypothalamus) obese animals have several common features such as increased hepatic lipogenesis (resulting in fat infiltration) and increased hepatic lipoprotein secretion, together, with increased adipose tissue lipogenesis. These abnormalities appear to be related primarily to hyperinsulinemia as they are reversed to or toward normal when hyperinsulinemia is corrected or, conversely, as they develop concomitantly with hyperinsulinemia. In the liver (ob/ob mice), another defect can be demonstrated, i.e. a decreased hepatic insulin clearance. This defect is also related to hyperinsulinemia and is markedly reduced upon normalizing hyperinsulinemia of obese mice. Hyperinsulinemia may thus be a key feature of the obesity syndromes, and bring about most of the abnormalities noted, including the subsequent state of insulin resistance known to exist in obese animals. The etiology of hyperinsulinemia of genetically obese animals is still unknown. Among the possible mechanisms one should cite possible primary dysfunction of the pancreas, possible primary dysregulation, by the hypothalamus, of overall endocrine pancreas activity. PMID: 382957 [PubMed - indexed for MEDLINE] 7315. Usp Sovrem Biol. 1979 Jan-Feb;87(1):16-33. [Metabolic interrelationships of lipids]. [Article in Russian] Gribanov GA. PMID: 373285 [PubMed - indexed for MEDLINE] 7316. Bibl Nutr Dieta. 1979;(27):1-10. Energy balance in man with particular reference to low intakes. Durnin JV. PMID: 371608 [PubMed - indexed for MEDLINE] 7317. Adv Exp Med Biol. 1979;111:79-96. Hormonal control of ketogenesis. McGarry JD, Foster DW. PMID: 371356 [PubMed - indexed for MEDLINE] 7318. Adv Exp Med Biol. 1979;111:169-88. Energy metabolism in feasting and fasting. Owen OE, Reichard GA Jr, Patel MS, Boden G. During feasting on a balanced carbohydrate, fat, and protein meal resting metabolic rate, body temperature and respiratory quotient all increase. The dietary components are utilized to replenish and augment glycogen and fat stores in the body. Excessive carbohydrate is also converted to lipid in the liver and stored along with the excessive lipids of dietary origin as triglycerides in adipose tissue, the major fuel storage depot. Amino acids in excess of those needed for protein synthesis are preferentially catabolized over glucose and fat for energy production. This occurs because there are no significant storage sites for amino acids or proteins, and the accumulation of nitrogenous compounds is ill tolerated. During fasting, adipose tissue, muscle, liver, and kidneys work in concert to supply, to convert, and to conserve fuels for the body. During the brief postabsorptive period, blood fuel homeostasis is maintained primarily by hepatic glycogenolysis and adipose tissue lipolysis. As fasting progresses, muscle proteolysis supplies glycogenic amino acids for heightened hepatic gluconeogenesis for a short period of time. After about three days of starvation, the metabolic profile is set to conserve protein and to supply greater quantities of alternate fuels. In particular, free fatty acids and ketone bodies are utilized to maintain energy needs. The ability of the kidney to conserve ketone bodies prevents the loss of large quantities of these valuable fuels in the urine. This delicate interplay among liver, muscle, kidney, and adipose tissue maintains blood fuel homeostasis and allows humans to survive caloric deprivation for extended periods. PMID: 371355 [PubMed - indexed for MEDLINE] 7319. Prog Lipid Res. 1979;17(3):245-77. The effects of diet and other factors on the lipid composition of ruminant tissues and milk. Christie WW. PMID: 370841 [PubMed - indexed for MEDLINE] 7320. Lek Pr. 1979;16(1):3-145. Development of thyroid and adrenal function during ontogenesis. Macho L. PMID: 232440 [PubMed - indexed for MEDLINE] 7321. Monogr Endocrinol. 1979;12:547-60. Inhibition of glucose transport in fat cells and activation of lipolysis by glucocorticoids. Fain JN. The major effects of glucocorticoids on white fat are shown in Fig. 1. The glucocorticoid diffuses into the cytosol of fat cells where it binds to a soluble receptor. The steroid-receptor complex then enters the nucleus where RNA synthesis is increased. The next step may be a selective increase in synthesis of protein(s). In any event, there is an inhibition of the membrane-bound glucose transport system and an increase in the ability of lipolytic agents to activate triglyceride lipolysis. There is also a decrease in phosphoenolpyruvate carboxykinase, lipoprotein lipase, and fatty acid synthetase that occurs after a somewhat longer lag period than is required for inhibition of glucose transport or lipolysis activation. Whether these effects are independent or secondary to the glucose transport inhibition and lipolysis activation remains to be established. PMID: 226873 [PubMed - indexed for MEDLINE] 7322. Tanpakushitsu Kakusan Koso. 1979 Jan 1;24(1):14-21. [Actions of insulin in fat cells (author's transl)]. [Article in Japanese] Kono T. PMID: 219439 [PubMed - indexed for MEDLINE] 7323. Adv Exp Med Biol. 1979;111:43-77. Hormonal regulation of lipolysis: role of cyclic nucleotides, adenosine, and free fatty acids. Fain JN, Shepherd RE. PMID: 218431 [PubMed - indexed for MEDLINE] 7324. Ann Nutr Aliment. 1979;33(1):39-56. Pituitary lipolytic peptides. Schwandt P. PMID: 112903 [PubMed - indexed for MEDLINE] 7325. Ann Nutr Aliment. 1979;33(1):17-25. Human obesity and some of its experimental counterparts. Bray GA. Human obesity is a manifestation of a positive energy balance. A variety of different factors influence this balance. The varieties of human obesity may be classified as follows: 1. Childhood onset with or without an increased number of adipocytes; 2. The syndromes of neuroendocrine dysfunction including hypothalamic obesity, Cushing's disease, and hyperinsulinism; 3. Dietary obesity; 4. Obesity due to physical inactivity; and 5. Genetic forms of obesity. Among the genetic form of obesity are the Laurence-Moon-Bardet-Biedl syndrome. Alstrom's syndrome, and possibly the Prader-Willi syndrome. Studies in experimental animals have increased our understanding of two of these forms of human obesity. These are: 1. Hypothalamic obesity associated with decreased sympathetic activity, hyperphagia and an increased secretion of insulin. Subdiaphragmatic vagotomy can reverse this syndrome; 2. Genetic forms of obesity inherited as recessive or dominant traits. PMID: 112902 [PubMed - indexed for MEDLINE] 7326. Recent Prog Horm Res. 1979;35:477-99. Recent studies of the 3T3-L1 adipocyte-like cell line. Rosen OM, Smith CJ, Hirsch A, Lai E, Rubin CS. PMID: 92801 [PubMed - indexed for MEDLINE] 7327. Z Gesamte Inn Med. 1978 Dec 1;33(23):845-51. [Significance of prostaglandins for fat and carbohydrate metabolism with special reference to pathogenesis of diabetes mellitus ]. [Article in German] Förster W. A survey is given of the literature on the influence of prostaglandins on the lipid- and carbohydrate metabolism. Some common pathobiochemical features in the development of diabetes mellitus and the ischaemic heart disease are outlined, which became apparent by examinations of the fatty acid pattern in patients. Thus a biochemical basis for that epidemiologically well known fact is given, that diabetes represents a risk factor for the ischaemic heart disease. Some of the latest results from the experimental research suggest that the vascular complications occurring in chronic diabetes are caused by a decrease in the formation of prostacyclin and possibly by an increase in the thromboxane A2 production. Similar changes in the prostaglandin metabolism occur in the ischaemic heart disease and myocardial infarction, too, as experimental results have shown. PMID: 369161 [PubMed - indexed for MEDLINE] 7328. Metabolism. 1978 Dec;27(12):1803-28. Nonsuppressible insulin-like activity (NSILA) from human serum: recent accomplishments and their physiologic implications. Zapf J, Rinderknecht E, Humbel RE, Froesch ER. PMID: 364249 [PubMed - indexed for MEDLINE] 7329. Am J Clin Nutr. 1978 Nov;31(11):2005-16. Diet and breast cancer: a review. Hankin JH, Rawlings V. Diet may promote or inhibit human breast cancer through its effects on hormonal systems. In this paper, risk factors with potential dietary components, geographic variations related to diet, experimental studies on diet and mammary tumors, and hormonal hypotheses are reviewed. The associations of early menarche with higher risk, and of early first pregnancy with lower risk suggest that events during teenage years may be determinants of breast cancer. Although data on the association between obesity and mammary cancer are not entirely consistent, it does seem clear that body fatness at menarche and during postmenopausal years may influence hormonal synthesis and metabolism. Published reports based on the Food and Agricultural Organization's food availability data or frequencies of individual foods are inadequate for associating diet with breast cancer incidence or mortality. Also, diets and susceptibility to breast cancer vary among species, and therefore results from rodent experiments should not be extrapolated to humans. Circumstantial evidence suggests that patterns of hormone metabolism in early years of life may be determinants of breast cancer risk. Research concerning the relationship of androgens, prolactin, estrogens, and possibly other hormones to risk factors should be continued. Further, there is a need for data relating dietary factors to hormone synthesis and metabolism. Epidemiological studies among young women in low- and high-risk countries are recommended. Comparisons of diet, body fatness, and hormonal levels could provide further insight about the relationship of diet to breast cancer risk. These same factors should be measured in case-controls studies, along with qualitative estimates of previous diet and possibly weight and height during adolescence. Dietary indices associated with early menarche may be the same as those related to breast cancer. Results of these investigations may provide valuable leads for preventive health programs. PIP: Diet and nutrition may be an indirect cause of human breast cancer. This review of the literature identifies high risk groups, geographic variables, experimental animal studies, and endocrinal research that link diet and obesity to aberant hormonal activity that can cause breast cancer. Studies of high risk groups indicate that some women are predisposed to breast cancer because of similar dietary habit that often cause obesity. Geographical factors influence the kinds of food available to a given population. As a result, people who live in areas that supply a rich diet of sugar, starches, and fats have a higher incidence of obesity and breast cancer than those people who have simple diets. Experimental studies on laboratory animals show that diets with reduced calories, fat, and proteins inhibit tumor development. The results of these studies, although intesting, are impractical for application to human subjects. Studies that address the relationship between breast cancer and specific hormones include investigations of androgens, estrogens and prolactin. At present, these studies are inconclusive and often conflicting. Many dietary factors appear to be causal of breast cancer, especially as they interact with each other. An individual's metabolism, synthesis of hormones, and amount of fat tissue can be predisposing factors for breast cancer. Future research should focus on these interacting factors so that workable, preventative health programs can be developed. PMID: 362882 [PubMed - indexed for MEDLINE] 7330. Semin Perinatol. 1978 Oct;2(4):329-46. Infant of a diabetic mother: energy imbalance between adipose tissue and liver. Adam PA. PMID: 384527 [PubMed - indexed for MEDLINE] 7331. Kidney Int. 1978 Oct;14(4):306-12. Metabolic and nutritional factors in children with renal insufficiency. Holliday MA, Chantler C. Uremia is associated with a decrease in muscle and adipose tissue mass and a low weight-for-height ratio. These findings are related to dietary deficiencies in uremia--particularly energy deficiency and to metabolic disorders characteristic of uremia. These latter have features of an exaggerated catabolic state which may be modified by other stresses, e.g. short starvation or high-protein diets. Recommendations for diet therapy for children with uremia are of limited value because of the lack of definitive studies. At present, diet should be adequate in energy to improve nitrogen balance and weight gain commensurate with age. There may be advantages to using a protein:energy ratio in the diet that is lower than the ratio used in conventional diets. PMID: 366224 [PubMed - indexed for MEDLINE] 7332. Med Biol. 1978 Oct;56(5):249-61. Local regulation of lipolysis in adipose tissue by fatty acids, prostaglandins and adenosine. Fredholm BB. From this review of the literature the following tentative conclusions may be drawn: 1) The relationship between cyclic AMP and lipolysis is not linear. In particular, only very small elevations of cyclic AMP appear to be necessary for essentially maximal lipolysis. One consequence of this is that some of the studies concerning feed-back regulation of cyclic AMP may not be relevant to our understanding of the regulation of lipolysis. 2) The only substances for which a firm role as feed-back regulators has been documented are free fatty acids. Their importance under in vivo conditions are, however, not settled. 3) The bulk of the present evidence fails to suggest a role for endogenous prostaglandins (and related compounds) as feed-back regulators of lipolysis. 4) There is considerable evidence that endogenous adenosine modulates lipolysis in vivo and in vitro. Adenosine does not appear to act as a feed-back regulator in the strict sense but the formation of adenosine may be enhanced under conditions of lipolysis because of simultaneously occurring breakdown of ATP. PMID: 213661 [PubMed - indexed for MEDLINE] 7333. Leber Magen Darm. 1978 Oct;8(5):255-64. [Ethanol and lipid metabolism (author's transl)]. [Article in German] Schneider J, Kaffarnik H. Fatty liver and hyperlipoproteinemia are the main clinical manifestations of interrelationships between ethanol and fat metabolism. Elevation of VLDL is observed more, hyperchylomicronemia less frequently. In metabolic healthy volunteers reversible hypertriglyceridemia can be provoked as well. The pathogenesis of ethanol-induced hyperlipoproteinemia is based on metabolic alterations directly dependent on the oxidation of ethanol in the liver as well as on indirect effects: Besides decreased oxidation and increased de-novo-synthesis by the liver, the sources of fatty acids for the enhanced production of VLDL are the adipose tissue and alimentary fat. VLDL concentrations have been shown to correlate with risk of atherogenesis in the middle-aged. Enhancement of alpha/beta (HDL/LDL)-cholesterol which would indicate an antiatherogenetic effect have been observed in relation to ethanol intake. At the moment it is premature to conclude that ethanol-induced changes in plasma lipoproteins may favour or delay atherogenesis. PMID: 212655 [PubMed - indexed for MEDLINE] 7334. Semin Perinatol. 1978 Oct;2(4):291-307. Carbohydrate and lipid metabolism during normal pregnancy: relationship to gestational hormone action. Kalkhoff RK, Kissebah AH, Kim HJ. PMID: 113884 [PubMed - indexed for MEDLINE] 7335. IARC Monogr Eval Carcinog Risk Chem Hum. 1978 Oct;18:41-103. Polychlorinated biphenyls. [No authors listed] PMID: 103802 [PubMed - indexed for MEDLINE] 7336. Sem Hop. 1978 Sep 8-15;54(21-24):764-70. [Glucocorticoids and gluco-lipidic metabolism]. [Article in French] Hautecouverture M, Luton JP. Glucocorticoids increase the stocks of carbohydrate and the supra-hepatic flow of glucose. Their excess produces a centripetal redistribtution of adipose stocks and potentialises adipocyte lipolysis. Although their role of glucose and lipid metabolism is evident, the mechanisms and sites of action of glucocorticoids are multiple and not entirely clear. The actions of glucocorticoids become clear in cases of insulin deficiency, especially when the deficiency is marked, which is of great interest in current medical practice. PMID: 213847 [PubMed - indexed for MEDLINE] 7337. J Agric Food Chem. 1978 Sep-Oct;26(5):1051-5. Accumulation of organochlorine pesticides in poultry: a review. Kan CA. PMID: 701621 [PubMed - indexed for MEDLINE] 7338. Am J Clin Nutr. 1978 Aug;31(8):1437-52. Triglycerides in clinical medicine. A review. Tzagournis M. There have been many relevant advances in our knowledge of triglycerides as they apply to clinical medicine. Some of the basic concepts of triglyceride metabolism are reviewed in a context of clinical applicability. Hypertriglyceridemia may be associated with dramatic symptoms and signs such as acute abdominal pain, hepatosplenomegaly, and neuromuscular abnormalities, or it may be asymptomatic until an atherosclerotic complication occurs. There is an increased risk of atherosclerosis with elevated endogenous triglycerides, but it is not clear if this is due to triglycerides per se, or the cholesterol content of the common lipoprotein that transports both lipids. Serum triglycerides are affected by diverse underlying disorders. Several factors play a role in the pathogenesis of hypertriglyceridemia including diet, body weight, genetic influences, glucose metabolism, and insulin concentrations. Treatment by diet and/or drugs is quite effective in relieving many of the clinical manifestations of hypertriglyceridemia. Whether a beneficial effect also occurs in atherosclerosis is still unknown. PMID: 677084 [PubMed - indexed for MEDLINE] 7339. J Oral Pathol. 1978 Aug;7(4):175-207. Prostaglandins: physiology, biochemistry, pharmacology and clinical applications. Elattar TM. PMID: 99501 [PubMed - indexed for MEDLINE] 7340. Vopr Okhr Materin Det. 1978 Jul;23(7):33-7. [Metabolic effects of glucagon in obesity in children (a review of the literature)]. [Article in Russian] Smirnova GI. PMID: 210592 [PubMed - indexed for MEDLINE] 7341. Pharmacol Rev. 1978 Jun;30(2):209-45. Stimulus-permeability coupling: role of calcium in the receptor regulation of membrane permeability. Putney JW Jr. PMID: 224401 [PubMed - indexed for MEDLINE] 7342. Biochem Pharmacol. 1978 May 15;27(10):1409-12. Interactions of anti-inflammatory steroids with PG system in adipose tissue. Lewis GP, Piper PJ. PMID: 358988 [PubMed - indexed for MEDLINE] 7343. Nutr Rev. 1978 May;36(5):140-1. Human obesity and adipocyte function. [No authors listed] PMID: 355944 [PubMed - indexed for MEDLINE] 7344. Postgrad Med J. 1978 Apr;54(630):270-7. Physical exercise and the prevention of atherosclerosis and cholesterol gall stones. Simko V. PMCID: PMC2425241 PMID: 351590 [PubMed - indexed for MEDLINE] 7345. Pol Arch Med Wewn. 1978 Apr;59(4):447-53. [Lipid metabolism and acute pancreatitis]. [Article in Polish] Kinalska I. PMID: 351584 [PubMed - indexed for MEDLINE] 7346. Can Med Assoc J. 1978 Mar 18;118(6):675-80. The lipoprotein lipase system: new understandings. Tan MH. Hypertriglyceridemia, a risk factor for premature atherosclerosis, may result from decreased use of plasma triglycerides by tissues. The removal of triglycerides is mediated by the enzyme lipoprotein lipase (LPL). Heparin releases LPL from tissues and post-heparin plasma lipolytic activity (PHLA) has been extensively used to elucidate the mechanism of hypertriglyceridemia in various diseases. There is evidence to show that postheparin plasma contains enzymes other than LPL. Hence data on total PHLA are difficult to interpret. Availability of assays for the LPL component of PHLA has clarified equivocal findings in certain hypertriglyceridemic states. However, the LPL component is also heterogeneous. The LPL "isoenzymes" from various extrahepatic tissues behave differently under various metabolic conditions. Therefore, to understand properly the LPL system it is necessary to study the specific tissue LPL. Furthermore, the serum activator for LPL is now characterized. Its importance is evidenced by the recent discovery of a hypertriglyceridemic patient deficient in this apoprotein. PMCID: PMC1818029 PMID: 207404 [PubMed - indexed for MEDLINE] 7347. Int J Obes. 1978;2(4):401-27. Adipose tissue cellularity: a review. I. Techniques for studying cellularity. Gurr MI, Kirtland J. PMID: 744680 [PubMed - indexed for MEDLINE] 7348. Clin Invest Med. 1978;1(2):71-9. Adipose tissue cellularity and obesity: new perspectives. Roncari DA, Van RL. PMID: 391452 [PubMed - indexed for MEDLINE] 7349. Prog Lipid Res. 1978;17(2):111-205. The composition, structure and function of lipids in the tissues of ruminant animals. Christie WW. PMID: 390540 [PubMed - indexed for MEDLINE] 7350. Biochem Soc Symp. 1978;(43):47-67. Regulation of pyruvate oxidation and the conservation of glucose. Randle PJ, Sugden PH, Kerbey AL, Radcliffe PM, Hutson NJ. In animals the pyruvate dehydrogenase reaction is mainly responsible for the irreversible loss of glucose carbon by oxidation. Regulation of this reaction is shown to be a major determinant of glucose conservation in starvation and diabetes. Estimates of conservation in man in starvation and diabetes are reviewed. The pyruvate dehydrogenase complex is inhibited by products of its reactions; it is also regulated by a phosphorylation-dephosphorylation cycle catalysed by a kinase intrinsic to the complex and by a more loosely associated phosphatase. Inactivation is largely accomplished by phosphorylation of the tetrameric decarboxylase component (alpha2beta2) to alpha2Pbeta2. Complete phosphorylation produces the (alpha2P3)beta2 form. Both forms are completely reactivated by phosphatase action but the initial rate of reactivation of a complex containing alpha2Pbeta2 is approximately three times that of (alpha2P3)beta2. The proportion of active (dephosphorylated) complex is decreased in rat tissues by starvation and diabetes and in perfused rat heart by oxidation of fatty acids and ketone bodies. In adipose tissue in vitro, insulin increases the proportion of active complex and lipolytic hormones may decrease this proportion. It is suggested that rates of oxidation of lipid fuels may be a major determinant of the activity of pyruvate dehydrogenase in tissues in relation to the actions of insulin and lipolytic hormones and the effects of diabetes and starvation. Phosphorylation and inactivation of the complex are enhanced by high mitochondrial ratios of [acetyl-CoA]/[CoA], [ATP]/[ADP], [NADH]/[NAD+] and low concentrations of pyruvate, Mg2+ and Ca2+, and vice versa. PMID: 373769 [PubMed - indexed for MEDLINE] 7351. Adv Exp Med Biol. 1978;109:225-38. Nicotinic acid and inhibition of fat mobilizing lipolysis. Present status of effects on lipid metabolism. Carlson LA. PMID: 364948 [PubMed - indexed for MEDLINE] 7352. Adv Exp Med Biol. 1978;109:209-23. Mechanisms of lipomobilization. Fassina G. PMID: 364947 [PubMed - indexed for MEDLINE] 7353. World Rev Nutr Diet. 1978;30:148-88. Chlorinated hydrocarbon insecticides and nutrition. Varela G, Andujar MM, Navarro MP. PMID: 364846 [PubMed - indexed for MEDLINE] 7354. Sci Prog. 1978 Autumn;65(259):365-93. On the physiology and biochemistry of obesity. Bailey CJ. PMID: 364644 [PubMed - indexed for MEDLINE] 7355. Ann Endocrinol (Paris). 1978;39(2):117-26. Transcriptional and translational effects of hormones. Pimentel E. At present it is not possible to describe the precise sequence of post-transductional phenomena corresponding to the action of any hormone in a given target cell. It seems probable that different events at the levels of DNA replication, DNA transcription, RNA translation, and post-translational phenomena are regulated in each case in a specific sequential way. However, the possibility cannot be discarded of simultaneous and/or independent hormone actions in two or more of these type of phenomena. PMID: 356722 [PubMed - indexed for MEDLINE] 7356. Experientia Suppl. 1978;32:89-93. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Nicholls DG, Bernson VS, Heaton GM. The proton conductance of the inner membrane of hamster brown adipose tissue mitochondria can be regulated in vitro by exogenous purine nucleotides, which bind to a component on the outer face of the inner membrane. This unique mechanism has been proposed to represent the molecular site of non-shivering thermogenesis in this tissue. Using a photo-affinity analogue of ATP, we have identified the nucleotide binding component as a protein of 32,000 daltons. PMID: 348493 [PubMed - indexed for MEDLINE] 7357. Experientia Suppl. 1978;32:75-87. Energy dissipation in brown adipose tissue mitochondria. Rafael J. PMID: 348492 [PubMed - indexed for MEDLINE] 7358. Experientia Suppl. 1978;32:169-75. Hormonal thermogenesis of "non-norepinephrine" type. Jansky L. Physiological significance and mechanisms controlling thermogenesis due to substances other than norepinephrine (NE) are considered. Epinephrine (E) induces a strong calorigenic effect, which is potentiated by cold adaptation to the level observed after application of NE. Thermogenesis due to E is located to a great extent in visceral organs. Cold acclimation increases the component of epinephrine thermogenesis located in the brown adipose tissue and non-visceral organs, predominantly. Although E and NE act on the same thermogenic effector, their effect is realized via different regulatory sites. Steroid hormones are not necessary for inducing cold resistance and thermogenesis due to NE. The permissive role of steroids and other substances in inducing changes in enzyme activity and synthesis during various cold stress is discussed. PMID: 348486 [PubMed - indexed for MEDLINE] 7359. Experientia Suppl. 1978;32:119-34. Thermogenic mechanisms and their control. Himms-Hagen J, Cerf J, Desautels M, Zaror-Behrens G. The alterations in properties of mitochondria and of plasma membrane of brown adipose tissue and skeletal muscle of cold-acclimated rats are reviewed in order to bring out any adaptive changes which are related to the mechanism of nonshivering thermogenesis, and thus to the enhanced calorigenic action of catecholamines known to exist in these animals. Since prevention of the morphological changes in the mitochondria by treatment of the animals with oxytetracycline during acclimation to cold also prevents the development of the enhanced calorigenic response to the catecholamines it is concluded that the changes noted are either a cause of the development of the increased capacity for nonshivering thermogenesis during acclimation to cold or are secondary to the operation of nonshivering thermogenesis. PMID: 348485 [PubMed - indexed for MEDLINE] 7360. Clin Pharmacokinet. 1978 Jan-Feb;3(1):72-91. Clinical pharmacokinetics of diazepam. Mandelli M, Tognoni G, Garattini S. Diazepam is still one of the most used of the benzodiazepine group of drugs. Extensive studies over 10 years have defined a fairly complete profile of its kinetics. Minor aspects relating to patterns of its metabolism and excretion in certain age groups and in some disease states remain to be described quantitatively. However, there is more than sufficient kinetic information available for the requirements of good clinical practice. For optimum clinical benefit with minimum side-effects the following kinetic properties should be borne in mind: (a) there is a large interindividual variation (up to 30-fold) in dose/blood level ratios, especially when treatment is short-term; (b) the elimination half-life is prolonged in the elderly and the newborn and in some cases of liver disease; (c) there is accumulation of the active N-desmethylated metabolite during long-term treatment; and (d) administration of diazepam to pregnant women leads to rapid distribution from the maternal to fetal compartment: accumulation of both diazepam and desmethyldiazepam could cause prolonged sedation in the newborn. As there does not appear to be any clear relationship between the concentration of diazepam in the plasma and clinical effect, measurement of blood levels, other than for research purposes, is unnecessary. Based on kinetic data, a single administration of diazepam at night should be adequate for hypnotic and anxiolytic effects in most patients. PMID: 346285 [PubMed - indexed for MEDLINE] 7361. Birth Defects Orig Artic Ser. 1978;14(1):365-84. Hormonal receptor and responsiveness changes during aging: genetic modulation. Roth GS. PMID: 343829 [PubMed - indexed for MEDLINE] 7362. Arch Maragliano Patol Clin. 1978;34(2):91-108. [Effects of chronic inhibition of adipocyte phosphodiesterase on lipolysis induced with noradrenaline in normal and obese subjects]. [Article in Italian] Chiodini G, Elicio N, Bertolini S, Valice S, Reggiani E, Innocenti-Ducci L. PMID: 233626 [PubMed - indexed for MEDLINE] 7363. Int J Biochem. 1978;9(8):545-52. Pyruvate dehydrogenase and the hormonal regulation of fat synthesis in mammalian tissues. Denton RM, Hughes WA. PMID: 213324 [PubMed - indexed for MEDLINE] 7364. Experientia Suppl. 1978;32:229-45. Role of various sites in thermoregulatory thermogenesis. Donhoffer S. PMID: 206458 [PubMed - indexed for MEDLINE] 7365. Experientia Suppl. 1978;32:69-74. The "second messenger" system in brown adipose tissue of developing rats. Its molecular composition and mechanism of function. Skala JP, Hahn P, Knight BL. Our studies of the hormonal receptor system and of the sequence of enzymatic events interconnecting the initial hormonal stimulus to the brown adipocyte with its final subcellular effect are summarized here. The hormone-mediated regulatory pathway consists of the adenyl cyclase and the protein kinase systems; the former is composed of the receptor and catalytic sites, the latter of regulatory and catalytic subunits. Emphasis is given currently to the diversity and characteristics of the individual components of the protein kinase system, since it seems to carry out the ultimate unifying mechanism involved in a variety of hormone-mediated functions, i.e. the phosphorylation of a protein molecule. PMID: 25784 [PubMed - indexed for MEDLINE] 7366. Fed Proc. 1977 Dec;36(13):2732-4. Inhibition of rat fat cell triglyceride lipase by sulfonylureas. Shepherd RE, Fain JN. PMID: 200495 [PubMed - indexed for MEDLINE] 7367. Clin Endocrinol Metab. 1977 Nov;6(3):599-631. Catecholamines and intermediary metabolism. Young JB, Landsberg L. PMID: 338215 [PubMed - indexed for MEDLINE] 7368. Pediatr Res. 1977 Oct;11(10 Pt 2):1081-3. Fat. McCance RA, Widdowson EM. Fat has been a menace to longevity since biblical times, but detailed studies of its deposition and function in the perinatal period only began comparatively recently. The function of brown fat in thermogenesis as distinct from that of white fat as a reserve of energy is now clear, but not why the guinea pig and the human baby should be two of the very few land mammals to lay down white fat in their bodies before birth. How much of this fat crosses the placenta and how much is synthesized by the fetus? There is evidence that the amounts and timing of the two events may not be the same in the two species but the reasons behind the differences are not at all clear. Genetic obesity in many forms is well known in rodents. None of them have contributed much to paediatrics as yet, but the Egyptian sand rat has promising similarities to persons who develop obesity and diabetes in adult life and a comparison of their metabolism in early life might be a profitable exercise. PMID: 333359 [PubMed - indexed for MEDLINE] 7369. J Invest Dermatol. 1977 Sep;69(3):333-8. Measurement of the thermal properties of human skin. A review. Cohen ML. The effective use of techniques to detect and interpret surface and subsurface temperature patterns depends upon the thermal and electromagnetic properties of the tissues under examination. A review is made of the existent data concerned with the thermal characteristics of skin. The thermal conductivity, k, and thermal inertia, kpc, as measured as a function of local temperature are presented. The radiation properties of the skin are presented as a function of wavelength. It is concluded that the information currently available about the thermal properties and their normal variation with body site, skin color, and age is quite limited. PMID: 894075 [PubMed - indexed for MEDLINE] 7370. Probl Endokrinol (Mosk). 1977 Sep-Oct;23(5):104-10. [Somatomedin; biological characteristics and various clinical data on its content in humans under normal and pathological conditions]. [Article in Russian] Vasil'eva IA. PMID: 337283 [PubMed - indexed for MEDLINE] 7371. Am J Hosp Pharm. 1977 Sep;34(9):965-8. Intramuscular injections and bioavailability. Tuttle CB. Bioavailability of drugs following intramuscular injection is reviewed, with particular emphasis on diazepam, chlordiazepoxide, phenytoin, digoxin and lidocaine. Clinical experience with these drugs has shown that i.m. absorption may be slow, erratic or incomplete. Factors which play a role in the bioavailability of i.m. medications include the water solubility of the drug, dispersion of the injected solution and blood flow at the muscle site. For many drugs, intravenous injection is the parenteral route of choice, and oral administration may be more efficacious than i.m. injection. PMID: 333911 [PubMed - indexed for MEDLINE] 7372. Usp Fiziol Nauk. 1977 Jul-Sep;8(3):97-127. [Fat metabolism in starving mammals]. [Article in Russian] Vasil'eva ED. PMID: 331721 [PubMed - indexed for MEDLINE] 7373. Clin Plast Surg. 1977 Jul;4(3):409-24. The healing of skin grafts. Smahel J. PMID: 328215 [PubMed - indexed for MEDLINE] 7374. Compr Ther. 1977 Jun;3(6):32-7. Potassium depletion and aging. Kromhout D, Broberg U, Carlmark B, Karlsson S, Nisell O, Reizenstein P. PMID: 326466 [PubMed - indexed for MEDLINE] 7375. Diabetologia. 1977 May;13(3):177-86. Studies on the mechanism of insulin action: basic concepts and clinical implications. Hepp KD. PMID: 194810 [PubMed - indexed for MEDLINE] 7376. Arch Pathol Lab Med. 1977 May;101(5):225-9. Lipoprotein lipase. Fielding CJ, Havel RJ. The activity of lipoprotein lipase in the vascular bed represents the major pathway by which triglyceride fatty acid is cleared from the plasma and made available to the epripheral tissues. Recent studies on the properties of the enzyme, both solubilized and membrane-bound have provided new information on the regulation of its activity with the major triglyceride-rich lipoprotein substrates. A key role for this enzyme in the regulation of plasma triglyceride levels is indicated from studies of lipase levels in human adipose tissue and in blood plasma obtained after injection of heparin. PMID: 192170 [PubMed - indexed for MEDLINE] 7377. Nutr Rev. 1977 Apr;35(4):72-3. Insecticides in breast milk. [No authors listed] PMID: 67584 [PubMed - indexed for MEDLINE] 7378. Diabetes. 1977 Apr;26(4):341-5. New forms of insulin and their use in the treatment of diabetes. Yue DK, Turtle JR. PMID: 66165 [PubMed - indexed for MEDLINE] 7379. Geburtshilfe Frauenheilkd. 1977 Mar;37(3):242-51. [Endometrial cancer and extraglandular oestrogen biosynthesis (author's transl)]. [Article in German] Schindler AE. An increasing incidence of endometrial cancer caused by a higher life expectancy and a number of other facters (i.e. obesity, diabetes, hypertension, lower pregnancy rate) as well as the unfavorable location for early detection when compared with cervical cancer has initiated this review in order to single out women with increased risk. Clinical characteristics of patients with endometrial cancer represented by age, menstrual disorders, reduced fertility, obesity, diabetes, hypertension, hirsutism, hyperplasia of the ovarian stroma or hilus cells in connection with an increased oestrogen effect in the vaginal smear and proliferative changes of the endometrium can be explained by extraglandular respectively peripheral aromatization of androgens to oestrogens, particular by the conversion of androstenedione to oestrone. This is supported by an increased plasma oestrone/oestradiol-ratio and increased conversion rate with age and overweight. In vivo- and in vitro-investigations have demonstrated the participation of adipose tissue in peripheral oestrogene production. The compiled data point towards the importance of the extraglandular oestrone production for the etiology of endometrial cancer by effecting the endometrium over a long period of time. The counter action of the normally cyclic changes of oestradiol and progesterone is lacking. Therefore, a dysoestrogenic effect of oestrone upon the endometrium can be fully effective, depending on the hormone receptor content of the respective endometrium. Based upon these data including recent publications, pre- and postmenopausal oestrogen therapy has to be critically reevaluated. PMID: 323098 [PubMed - indexed for MEDLINE] 7380. Fed Proc. 1977 Feb;36(2):148-53. The Zucker-fatty rat: a review. Bray GA. The Zucker (fatty) rat is one of a group of animals that inherit obesity as an autosomal Mendelian recessive trait. These rats are obese, hyperphagic, and hyperinsulinemic, but blood glucose remains at normal levels. Although these rats eat more than normal rats, their response to the addition of adulterants to the food or after exposure to the cold is more like that of normal rats than rats with hypothalamic obesity. The hypertriglyceridemia which characterized these animals is due to the increased hepatic production of a very low density lipoproteins. Adipocytes are increased in size and in number with the subcutaneous fat depot showing the largest increase in the number of fat cells. Lipogenesis from glucose is brisk in the young animals but declines with age. Enzymatic patterns of glycolysis and gluconeogenesis appear to reflect the altered internal milieu rather than specific defects. Endocrine changes in the fatty rat include hyperinsulinemia, reduced levels of glucagon, hypothyroidis, and impaired reproductive function. A model is presented in which the features of the genetically obese (Zucker) fatty rat are compared with those of animals with hypothalamic obesity. PMID: 320051 [PubMed - indexed for MEDLINE] 7381. Int J Obes. 1977;1(1):3-13. The triglyceride storage diseases--a review. Galton DJ. PMID: 361585 [PubMed - indexed for MEDLINE] 7382. Ann N Y Acad Sci. 1977;301:64-71. Free fatty acid turnover and the availability of substrates as a limiting factor in prolonged exercise. Gollnick PD. A continual hydrolysis and release of FFA from the triglycerides stores of adipose tissue occurs during prolonged moderately severe exercise. The uptake and oxidation of plasma FFA by the working skeletal muscles represents a major source of energy during such exercise. During light and moderately intense prolonged exercise, lipolysis and the release of FFA from the adipose tissue exceeds uptake by peripheral tissue and the net result is an increase in plasma FFA levels. FFA uptake appears to be related to plasma concentrations and uses no membrane transport system. As work intensity increases the release of FFA from adipose tissue declines and the relative contribution of the plasma FFA to the work metabolism declines until at high work rates there is an almost complete reliance on the intramuscular glycogen reserves. At work loads above about 65% of the individual's aerobic capacity the limiting factor for prolonged exercise appears to be the glycogen stores of the working muscle. When these stores are depleted the work either must stop or its intensity be reduced. Trained individuals have a greater capacity to oxidize fats at high work loads than do untrained subjects. This, however, is not matched by an increased capacity for lipolysis. Why intramuscular glycogen stores are required for prolonged relatively severe exercise when the amount of FFA and glucose that perfuses the skeletal muscles under such conditions is theoretically capable of supporting the exercise metabolism is unknown. PMID: 337876 [PubMed - indexed for MEDLINE] 7383. Adv Exp Med Biol. 1977;80:153-71. Prolactin, the liporegulatory hormone. Meier AH. PMID: 331896 [PubMed - indexed for MEDLINE] 7384. Expos Annu Biochim Med. 1977;33:143-64. Role of lipoprotein lipase and capillary endothelium in the clearance of chylomicrons from blood: a model for lipid transport by lateral diffusion in cell membranes. Scow RO, Blanchette-Mackie EJ, Smith LC. PMID: 330213 [PubMed - indexed for MEDLINE] 7385. Int Rev Physiol. 1977;15:29-69. Physiological effects of cold exposure. Thompson GE. PMID: 328438 [PubMed - indexed for MEDLINE] 7386. Int Rev Physiol. 1977;15:189-215. Role of the adrenal medulla in thermoregulation. Robertshaw D. PMID: 328436 [PubMed - indexed for MEDLINE] 7387. Ann Endocrinol (Paris). 1977;38(1):13-25. [Metabolism of o,p'-DDD (mitotane) in human and animals. Actual notions and practical deductions (author's transl)]. [Article in French] Touitou Y, Bogdan A, Legrand JC, Desgrez P. The metabolism of o,p'-DDD (mitotane), a well-known inhibitor of adrenal steroidogenesis in man and animal, is reviewed. Following oral administration, about 65% of the ingested drug were found to pass in the stool. The drug appeared in the urine in metabolized forms: o,p'-DDA and mono-and dihydroxylated derivatives of o.p'-DDA. These latters were found as well in the stools. An unsaturated metabolite, o,p'-DDE was described in plasma and tissues in man. Serum specimens of treated patients were analyzed for o,p'-DDD during various phases of therapy: the levels and the rate of rise during treatment were very variable (5 to 90 microng/ml). Tissue levels were obtained from animals (rats, dogs) or men (biopsy as well as autopsy): o,p'-DDD was primarily found stored in adipose tissue and fat-containing tissues, essentially adrenals. Practical conclusions can be drawn from these results: there is no correlation between the dose of o,p'-DDD administered and its blood level; there is no correlation between blood levels and the patient's responsiveness to the drug; there is a possibility that the molecule transformed in an active metabolite through its metabolism. PMID: 324349 [PubMed - indexed for MEDLINE] 7388. World Rev Nutr Diet. 1977;(26):144-207. Foods of ruminant origin with elevated content of polyunsaturated fatty acids. McDonald IW, Scott TW. PMID: 324141 [PubMed - indexed for MEDLINE] 7389. Curr Concepts Nutr. 1977;5:119-35. Adipose tissue cellularity and its relationship to the development of obesity in females. Greenwood MR, Johnson PR. PMID: 322947 [PubMed - indexed for MEDLINE] 7390. Prog Food Nutr Sci. 1977;2(7):307-21. Lipogenesis and obesity in energy storage. Rath R. PMID: 322213 [PubMed - indexed for MEDLINE] 7391. Am J Obstet Gynecol. 1977 Jan 1;127(1):92-103. Fetal carbohydrate metabolism: its clinical importance. Gabbe SG, Quilligan EJ. A basic understanding of fetal nutrition and metabolism is essential in the clinical management of the obstetric patient. The fetus depends upon a constant infusion of glucose for energy production and growth. Maternal glucose is the prime source of this nutrient. Alterations in maternal carbohydrate homeostasis will lead to changes in fetal metabolism. In diabetes mellitus, hyperglycemia may produce hyperinsulinemia and macrosomia. The growth-retarded fetus may have a decreased supply of maternal glucose and reduced amounts of hepatic glycogen and adipose tissue. The fetus must depend upon these stores for survival during periods of intrauterine hypoxia. In the newborn period, hypothermia and hypoxia may rapidly deplete energy reserves. With this information, the clinician may more knowledgeably manage dietary demands in the antepartum patient, fetal distress during labor, and the immediate newborn period. PMID: 318803 [PubMed - indexed for MEDLINE] 7392. Comp Biochem Physiol B. 1977;56(1):87-99. Morphology and biochemical properties of perirenal adipose tissue from lamb (Ovis aries). A comparison with brown adipose tissue. Cannon B, Romert L, Sundin U, Barnard T. PMID: 318610 [PubMed - indexed for MEDLINE] 7393. Front Horm Res. 1977;4:18-25. On the molecular mechanism of alpha-MSH receptor interactions. Schwyzer R, Eberle A. PMID: 207595 [PubMed - indexed for MEDLINE] 7394. Horiz Biochem Biophys. 1977;4:91-129. Regulation of lipolysis in adipose tissue. Meisner H, Carter JR Jr. The normal human or animal has a series of finely coordinated and overlapping control mechanisms that regulate the storage or release of fat according to the overall energy requirements of the body. We have examined only one side of this system, the part responsible for the release of fatty acids from adipose tissue. Considerable information is available on the extracellular factors that control lipolysis on a minute-to-minute or day-to-day basis, but less is known about long-term regulation or about the precise role of intracellular factors that almost surely condition the response of the fat cell to external stimuli. When one poses the question of what determines the overall fat mass or adiposity of an individual, even less is known. Psychogenic factors regulating food intake, circulating hormonal signals, and local regulators of metabolism in the adipose tissue may all play a role. This remains an intriguing but elusive problem to be answered by future research. PMID: 202557 [PubMed - indexed for MEDLINE] 7395. Annu Rev Biochem. 1977;46:359-84. Molecular basis of insulin action. Czech MP. PMID: 197878 [PubMed - indexed for MEDLINE] 7396. Annu Rev Physiol. 1977;39:301-21. Lipids and lipid metabolism. Masoro EJ. PMID: 192136 [PubMed - indexed for MEDLINE] 7397. Prog Food Nutr Sci. 1977;2(9):405-55. Biotin. Murthy PN, Mistry SP. PMID: 18764 [PubMed - indexed for MEDLINE] 7398. Arch Sci Med (Torino). 1977 Jan-Mar;134(1):1-24. [Carbohydrate-dependent lipidogenesis. Review of the literature and experimental study]. [Article in Italian] Trovati M. The literature on glycide-induced lipidogenesis is reviewed. This is an important question also because of its relation to the pathogenesis of pathological conditions such as ketoacidosis, obesity and hypertriglyceridaemia. Doubt is expressed concerning the interpretation of some experimental procedures used in determining the extent of lipidogenesis in man. The questions raised are fully discussed. Their solution is sought via an experiment on the rat involving the comparison of tissue and plasma lipid metabolites values following infusion of a labelled glucose bolus. Little correlation was noted, low plasma levels being found with high tissue radioactivity. It is emphasized that it is very difficult to ideate a valid experimental approach in order to investigate the extent of lipidogenesis in man in vivo: in this respect, the long term risk arising from the use of tracers with a very long half-life (e.g. 14C) in man must be carefully valuated. PMID: 16579 [PubMed - indexed for MEDLINE] 7399. Rev Rhum Mal Osteoartic. 1976 Dec;43(12):693-700. [A special form of lupus disease. Deep cutaneous lupus. Apropos of 2 cases]. [Article in French] Rouaud JP, Bloch-Michel H, Kahn MF, Delfraissy JF, Nissant G, Lallart X. Deep cutaneous lupus is a clinical form of lupus disease for which a very old description has recently been brought up to date. Two new cases are reported here and a review of the literature makes it possible to analyse the clinical, biochemical, histological, and immunological features of this panniculitis. Different from the Weber-Christian syndrome, it is characterized by repeated eruptions of nodules and/or subcutaneous plaques, and histologically by vasculitis, lymphocyte infiltration, and sometimes te presence of immunoglobulins on the basal dermal membrane and around the vessels. PMID: 1006125 [PubMed - indexed for MEDLINE] 7400. Proc Nutr Soc. 1976 Dec;35(3):383-91. A study of growth responses to nutrient inputs by modelling. Whittemore CT. PMID: 800661 [PubMed - indexed for MEDLINE] 7401. Proc Nutr Soc. 1976 Dec;35(3):357-62. Cellular growth and function. Widdowson EM. PMID: 800659 [PubMed - indexed for MEDLINE] 7402. Proc Nutr Soc. 1976 Dec;35(3):351-6. Effects of nutrition and genetics on the composition of the body. Lister D. PMID: 800658 [PubMed - indexed for MEDLINE] 7403. Q Rev Biol. 1976 Dec;51(4):477-514. Hibernation and circannual rhythms of food consumption in marmots and ground squirrels. Davis DE. In order to understand better the evolution and adaptive value of hibernation, ecological aspects and experimental studies of closely related hibernators, the Marmotini, are examined. The central hypothesis is that annual changes in the environment integrate three or, perhaps, four physiological processes: torpor, reporduction, consumption of food, and metabolism. Reproduction occurs promptly after emergence from hibernation. For most species, the breeding season is very short. Although the experimental data are rather meager, no variation in external factors has consistently altered the season of reproduction. Consumption of food and change in weight increases until July or September and then decreases. The large members of the Marmotini store their energy as fat, but small species store their energy as seeds and nuts. Experiments to test the hypothesis that some aspect of the supply, such as fat content, might vary seasonally have produced negative results. Complex experiments on the length of the photoperiod on woodchucks and several species of ground squirrels failed to alter the annual cycle of consumption of food. Animals kept in constant conditions showed a cycle of about 11 months, but woodchucks sent tto Australia changed their cycle in two years to match the seasons of the southern hemisphere. Experiments with temperature and torpor and castration did not alter the annual did not alter the rhythm... PMID: 799318 [PubMed - indexed for MEDLINE] 7404. Diabetes. 1976 Dec;25(12):1154-62. The insulin receptor: its role in insulin resistance of obesity and diabetes. Olefsky JM. PMID: 791735 [PubMed - indexed for MEDLINE] 7405. Akush Ginekol (Mosk). 1976 Nov;(11):4-6. [Thermo-adaptation of newborn infants under physiologic conditions and hypoxic conditions]. [Article in Russian] Lur'e GA. PMID: 797266 [PubMed - indexed for MEDLINE] 7406. Clin Endocrinol Metab. 1976 Nov;5(3):543-78. Carbohydrate metabolism in vivo: regulation of the blood glucose level. Newsholme EA. PMID: 189956 [PubMed - indexed for MEDLINE] 7407. Life Sci. 1976 Oct 15;19(8):1103-16. Possible roles of dietary fats in carcinogenesis. Hopkins GJ, West CE. PMID: 792608 [PubMed - indexed for MEDLINE] 7408. Environ Health Perspect. 1976 Oct;17:183-7. Evidence for existence in human tissues of monomers for plastics and rubber manufacture. Wolff MS. Although exposure to many industrially important monomers is controlled by law, few of these reactive chemicals have been determined in human tissues. Analogy with other fat-soluble organic substances strongly implies that these monomers may be retained in tissue, subject to the usual physiological constraints of metabolism, solubility and volatility. The storage of DDT and PCBs is discussed, as well as tetrachloro-ethylene (PCE) and trichloroethylene (TCE), which are chemically similar to many industrially used monomers. Styrene in blood and breath and its metabolites in urine have been studied in humans. Styrene and vinyl chloride have been measured in fat tissue of polymerization workers. PMCID: PMC1475257 PMID: 829070 [PubMed - indexed for MEDLINE] 7409. Rev Prat. 1976 Sep 11;26(39):2655-67. [Why do certain types of obesity "resist" diet?]. [Article in French] Apfelbaum M. PMID: 788131 [PubMed - indexed for MEDLINE] 7410. Acta Diabetol Lat. 1976 Sep-Dec;13(5-6):177-85. Diabetogenic activity of the anterior pituitary (a progress report). Tutwiler GF. The exact nature of the diabetogenic activity of the anterior pituitary gland remains a mystery. While growth hormone (GH) fractions clearly can produce a diabetogenic effect, there is increasing evidence that GH itself does not exert this effect. Several new theories that purport to explain the nature of diabetogenic activity are discussed. The current evidence supports the view that the activity is the result of a GH fragment or some other closely related protein such as the one ("diabetogenic protein") first described by LOUIS and CONN. A progress report of the research on this new "diabetogenic protein" is given. PMID: 800921 [PubMed - indexed for MEDLINE] 7411. Probl Endokrinol (Mosk). 1976 Sep-Oct;22(5):94-100. [Gluconeogenesis and diabetes]. [Article in Russian] Kendysh IN. PMID: 799299 [PubMed - indexed for MEDLINE] 7412. Probl Endokrinol (Mosk). 1976 Sep-Oct;22(5):100-9. [Diabetes mellitus and coronary arteriosclerosis]. [Article in Russian] Slavina LS. PMID: 799297 [PubMed - indexed for MEDLINE] 7413. Isr J Med Sci. 1976 Sep;12(9):924-33. Temperature regulation and catecholamines. Brück K. PMID: 794028 [PubMed - indexed for MEDLINE] 7414. Fed Proc. 1976 Sep;35(11):2314-8. Theoretical model of ruminant adipose tissue metabolism in relation to the whole animal. Baldwin RL, Yang YT, Crist K, Grichting G. Based on theoretical considerations and experimental data, estimates of contributions of adipose tissue to energy expenditures in a lactating cow and a growing steer were developed. The estimates indicate that adipose energy expenditures range between 5 and 10% of total animal heat production dependent on productive function and diet. These energy expenditures can be partitioned among maintenance (3%), lipogenesis (1-5%) and lipolysis and triglyceride resynthesis (less thatn 1.0%). Specific sites at which acute and chronic effectors can act to produce changes in adipose function, and changes in adipose function produced by diet and during pregnancy, lactation and aging were discussed with emphasis being placed on the need for additional, definitive studies of specific interactions among pregnancy, diet, age, lactation and growth in producing ruminants. PMID: 782926 [PubMed - indexed for MEDLINE] 7415. Fed Proc. 1976 Sep;35(11):2302-7. Cellularity of adipose tissue in meat animals. Allen CE. Present information indicates that for meat animals adipocyte number is achieved most rapidly in the perirenal depot and least rapidly in the interfascicular of intramuscular depot. Adipocyte volume appears to be largest in the perirenal depot and smallest in the interfascicular and intermuscular depots. The best estimates available suggest that adipocyte hyperplasia is completed by 14 months of age in bovine animals and 5 months of age in porcine animals. However, because of certain technique limitations and the presence of many small adipocytes in very obese animals, these estimates must be considered very tentative. Studies in ovine and porcine animals indicate that early under-nutrition is not effective in reducing the number of subcutaneous and perirenal adipocytes later in life. However, the number of interfascicular adipocytes may be reduced. Several studies have demonstrated that the interfascicular adipocytes are very late developing and that adipocyte number is very important to the total quantity of intramuscular lipid. PMID: 782925 [PubMed - indexed for MEDLINE] 7416. Klin Wochenschr. 1976 Aug 15;54(16):747-54. [Human ethanol-induced hyperlipoproteinemia (author's transl)]. [Article in German] Kaffarnik H, Schneider J. Reversible hyperlipoproteinemia may be observed after ethanol loads in healthy man before any ethanol-induced disease is being established. Different pathogenetic ways to this acute ethanol-induced hyperlipoproteinemia have been investigated or postulated in recent years. Two main sites have appeared: changes in the metabolism of lipids and their precursors which depend from acutal oxidation of ethanol in the liver, and ethanol-induced activation of lipolysis in adipose tissue, transmitted by the sympathico-adrenal system. The changes in liver metabolism during ethanol oxidation have been well confirmed in many experiments, they nevertheless do not seem to lead to hyperlipoproteinemia in many experimental designs in animals and after drinkable amounts of ethanol in healthy man when lipolysis of adipose tissue is blocked and no food is ingested. After the intake of a fatty meal these triglycerides are becoming importance as a source of fatty acids. A possible increased de novo synthesis of palmitic acid may to a minor degree contribute to hypertriglyceridemia. PMID: 785087 [PubMed - indexed for MEDLINE] 7417. Circ Res. 1976 Aug;39(2):149-62. Role of capillary endothelium in the clearance of chylomicrons. A model for lipid transport from blood by lateral diffusion in cell membranes. Scow RO, Blanchette-Mackie EJ, Smith LC. PMID: 779999 [PubMed - indexed for MEDLINE] 7418. Clin Endocrinol Metab. 1976 Jul;5(2):417-30. The effects of very restrictive high protein diets. Apfelbaum M. PMID: 782746 [PubMed - indexed for MEDLINE] 7419. Clin Endocrinol Metab. 1976 Jul;5(2):377-95. Experimental obesity, dietary-induced thermogenesis, and their clinical implications. Sims EA. PMID: 782745 [PubMed - indexed for MEDLINE] 7420. Clin Endocrinol Metab. 1976 Jul;5(2):397-415. Starvation in man. Cahill GF Jr. Starvation entails a progressive selection of fat as body fuel. Soon after a meal glucose utilisation by muscle ceases and fatty acids are used instead. Ketoacid levels in blood become elevated over the first week, and the brain preferentially uses these instead of glucose. The net effect is to spare protein even further, as glucose utilisation by brain is diminished. Nevertheless, there is still net negative nitrogen balance, but this can be nullified by amino acid or protein supplementation. Insulin appears to be the principal regulatory hormone. Recent data suggest that decreased levels of active T3 may play a role by sparing otherwise obligated calories by decreasing metabolic needs. PMID: 182420 [PubMed - indexed for MEDLINE] 7421. Clin Endocrinol Metab. 1976 Jul;5(2):337-65. The hormonal and metabolic basis of experimental obesity. Assimacopoulos-Jeannet F, Jeanrenaud B. PMID: 182419 [PubMed - indexed for MEDLINE] 7422. Clin Endocrinol Metab. 1976 Jul;5(2):313-35. Obesity: changes in lipid metabolism and the role of insulin. Nestel P, Goldrick B. PMID: 182418 [PubMed - indexed for MEDLINE] 7423. Nutr Rev. 1976 Jun;34(6):174-6. Protein sparing produced by proteins and amino acids. [No authors listed] PMID: 821023 [PubMed - indexed for MEDLINE] 7424. Biomedicine. 1976 Jun;24(3):159-62. Calcitonin 1975. Milhaud G. PMID: 791386 [PubMed - indexed for MEDLINE] 7425. J Physiol (Paris). 1976 Jun;72(3):345-58. [Hormonal control of the adenyl cyclase activity of adipose cell membranes prepared from badger, rabbit, fox and rat adipose tissues]. [Article in French] Péjoan C, Desbals B. 1. We have shown differences in hormonal regulation of adenylate cyclase activity in fat cell ghosts prepared from rat, rabbit, fox and badger adipose tissue, under the influence of catecholamines, ACTH and insulin. a) In the rat, catecholamines induced a large stimulation (+315%) of adenylate cyclase. b) In the rabbit, ACTH was the most effective hormone. c) In the fox and the badger, only catecholamines could stimulate adenylate cyclase. d) In both rat and rabbit, insulin did not reduce spontaneous enzymatic activity. Moreover, the activation of adenylate cyclase by ACTH in the rabbit was not altered by insulin, while in the rat, this hormone slightly decreased epinephrine stimulation. 2. Hormonal regulation of adenylate cyclase correlated with the lipolytic response. PMID: 182972 [PubMed - indexed for MEDLINE] 7426. Nutr Rev. 1976 Jun;34(6):185-7. Effects of dexamethasone on glucose metabolism. [No authors listed] PMID: 181698 [PubMed - indexed for MEDLINE] 7427. Vopr Pitan. 1976 May-Jun;(1):64-72. [Role of alimentary and metabolic factors in regulating the growth of adipose tissue (review of the literature)]. [Article in Russian] Konyshev VA. PMID: 184595 [PubMed - indexed for MEDLINE] 7428. Diabetologia. 1976 May;12(2):83-100. Interactions polypeptide hormones with cell membrane specific receptors: studies with insulin and glucagon. Freychet P. PMID: 178558 [PubMed - indexed for MEDLINE] 7429. Med Klin. 1976 Apr 30;71(18):739-44. [Adipose-tissue adenylcyclase]. [Article in German] Kather H, Simon B. PMID: 775277 [PubMed - indexed for MEDLINE] 7430. J Anim Sci. 1976 Apr;42(4):1024-35. Growth patterns in swine. Robison OW. PMID: 770410 [PubMed - indexed for MEDLINE] 7431. Physiol Rev. 1976 Apr;56(2):339-417. Mechanisms and regulation of biosynthesis of saturated fatty acids. Volpe JJ, Vagelos PR. PMID: 6981 [PubMed - indexed for MEDLINE] 7432. Clin Endocrinol Metab. 1976 Mar;5(1):39-54. Temperature regulation and disturbance in the newborn infant. Hull D. PMID: 776461 [PubMed - indexed for MEDLINE] 7433. Nutr Rev. 1976 Feb;34(2):38-40. Weight gain during hyperalimentation. [No authors listed] PMID: 815852 [PubMed - indexed for MEDLINE] 7434. J Clin Pathol. 1976 Feb;29(2):144-9. Weber-Christian panniculitis and auto-immune disease: a case report. Allen-Mersh TG. A case is described of Weber-Christian panniculitis accompanied by a gammaglobulin disturbance which preceded by five years the diagnosis of an autoimmune hepatitis and pancytopenia. Also associated was the onset of diabetes mellitus, found at necropsy to be related to pancreatic islet amyloid deposition. This case reinforces the view that Weber-Christian panniculitis may be an adipose response to a variety of immunological stimuli. PMCID: PMC475992 PMID: 777034 [PubMed - indexed for MEDLINE] 7435. FEBS Lett. 1976 Jan 15;61(2):103-110. The bioenergetics of brown adipose tissue mitochondria. Nicholls DG. PMID: 765149 [PubMed - indexed for MEDLINE] 7436. Pharmacol Ther B. 1976;2(3):605-69. Glucocorticoid hormone action. Baxter JD. PMID: 790403 [PubMed - indexed for MEDLINE] 7437. Immunol Commun. 1976;5(5):361-73. The immunology of the insulin receptor. Flier JS, Kahn CR, Jarrett DB, Roth J. We have detected and characterized anti-insulin-receptor autoantibodies which circulate in several patients with insulin resistance diabetes. These antibodies are predominantly IgG and are polyclonal. They inhibit insulin binding to its receptor on a variety of tissues from widely separated species. Antibodies obtained from different patients appear to bind to different determinants on the receptor and alter receptor function in several ways. Some anti-receptor antibodies are capable of stimulating insulin-like effects on target tissues, while others block insulin-stimulated effects. Direct labeling of anti-receptor antibody with 125I permits use of these antibodies as an assay and probe of insulin receptors. PMID: 786863 [PubMed - indexed for MEDLINE] 7438. Environ Qual Saf Suppl. 1976;(5):159-70. Endogenous anabolic agents in farm animals. Velle W. This presentation is limited to the three groups of steroid sex hormones which alone or in combination have been shown to be anabolic when used in farm animals. It seems essential for realistic evaluation of public health aspects of use of these hormones that the discussions include naturally occurring levels of the hormones. The following topics will be dealt with for each group of hormones: 1. Types and sources; 2. Production rates; 3. Plasma levels; 4. Tissue concentrations; 5. Metabolism and excretion. Gestagens. Progesterone and 20-dihydroprogesterones are mainly produced in ovaries and placenta. Production rates are estimated to 10 and 14 mg/24 hrs in pregnant goats and sheep, respectively. Plasma levels during the luteal phase are of the order of 2--10 ng/ml, during pregnancy somewhat higher. Muscular tissue from calves contain 0.25 mg/g. In dairy cows progesterone is excreted with the milk which contains up to 30 ng/ml; butterfat up to 300 mg/g. In ruminants progesterone is metabolized mainly to androgens excreted with faeces. In pigs large parts are metabolized to pregnanediols excreted with urine. Androgens. Testosterone is mainly secreted by testes. Boar testes also produce large amounts of dehydroepiandrosterone and its sulphate. Production rates have been estimated to be 10 mg and 40--50 mg/24 hrs. in boars and bulls respectively. Plasma levels in bulls and rams are generally 2--10 ng/ml, in boars 2--25 ng/ml. Adipose tissue levels up to 22 ng/g are reported for bulls. In ruminants epitestosterone seems to be a major metabolite excreted mainly with faeces. In boars, urinary 11-deoxy-17-ketosteroids are major metabolites of testicular dehydroepiandrosterone. Castration shows elimination to be rapid. Estrogens. 17beta-Estradiol and estrone are produced in ovaries and placenta and, in large amounts, in boar and stallion testes. Production rates in late pregnancy are estimated to 10 mg oestrone/24 hrs. in goats, 2 mg estrone and up to 28 mg 17beta-estradiol/24 hrs. in sheep. In cows much higher values are found. Boars and stallions produce huge amounts daily. Plasma levels in non-pregnant animals are at the pg/ml level. In late pregnancy levels of 2--4 thousand pg/ml are encountered in sows and cows, in sheep and goats lower levels. Calf muscular tissue contains up to 410 and 610 pg/g of estrone and 17beta-estradiol respectively. In muscle from pregnant heifers corresponding values were 120 and 860 pg/g in the 4th month and 2100 and 370 pg/g in the 9th month of pregnancy. Ruminants in large measure metabolize 17 beta-estradiol and estrone to 17alpha-estradiol which possesses low estrogenic activity. In pigs estrone dominates in blood and urine. Major routes of elimination arre with faeces in ruminants, with urine in pigs and horses. Elimination rates are high. Results obtained during the last few years clearly show that all three groups of steroid sex hormones occur in considerable concentrations in plasma and tissue... PMID: 782866 [PubMed - indexed for MEDLINE] 7439. Drugs. 1976;11(5):378-93. Anorectic drugs: use in general practice. Craddock D. The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively. Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent. Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs. The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs. PMID: 782835 [PubMed - indexed for MEDLINE] 7440. Major Probl Intern Med. 1976;9:1-450. The obese patient. Bray GA. PMID: 778504 [PubMed - indexed for MEDLINE] 7441. Adv Intern Med. 1976;21:267-308. The overweight patient. Bray GA. PMID: 766587 [PubMed - indexed for MEDLINE] 7442. Adv Cyclic Nucleotide Res. 1976;7:157-98. Interconvertible enzymes in adipose tissue regulated by cyclic AMP-dependent protein kinase. Steinberg D. PMID: 188314 [PubMed - indexed for MEDLINE] 7443. Przegl Lek. 1976;30(10):851-6. [Some aspects of carbohydrate-lipids metabolism abnormalities in state of hunger (author's transl)]. [Article in Polish] Adamczyk A. PMID: 188078 [PubMed - indexed for MEDLINE] 7444. Major Probl Clin Pediatr. 1976;3:3-28. The metabolism of carbohydrate. Schwartz AL. The purpose of this review has been to establish a background in carbohydrate biochemistry as it relates to the human neonate. The emphasis has therefore been placed on the developing human, although many concepts are derived from studies in animal models. Further discussions of the physiology of carbohydrate metabolism are included in the chapters that follow. PMID: 185470 [PubMed - indexed for MEDLINE] 7445. Biochem Soc Symp. 1976;(41):61-109. Substrate cycles in metabolic regulation and in heat generation. Newsholme EA, Crabtree B. 1. The presence of substrate cycles in tissues has been demonstrated by direct isotope methods in recent years. This demonstration has provided the impetus for a reappraisal of the roles of substrate cycling in metabolic regulation and in heat production. These aspects of substrate cycling are discussed in this paper. The relationship between near-equilibrium reactions and substrate cycles is emphasized, since this provides a basis for the derivation of a function describing in precise quantitative terms the factors governing the amplification provided by substrate cycles in metabolic regulation. Some examples of the roles of substrate cycles in providing sensitivity in metabolic regulation are described. The importance of substrate cycling in heat generation in the flight muscle of the bumble-bee and in brown adipose tissue is discussed in detail. 2. We point out that the two possible roles of cycling, heat production and amplification, are intimately linked so that they must be discussed together. It is proposed that variable rates of substrate cycling may be possible so that, for short periods of time. sensitivity can be maximal without excessive heat generation. Variable rates over the long term may be involved in weight control, and the control of such variability in cycling rates may be impaired in obese subjects. Finally, the possibilities that substrate cycles provide explanations for the specific dynamic action of food and for alcoholic and accidental hypothermia are raised. PMID: 184791 [PubMed - indexed for MEDLINE] 7446. Annu Rev Physiol. 1976;38:315-51. Cellular thermogenesis. Himms-Hagen J. The principal conclusion presented in this review is that no single mechanism underlies any of the examples of basal or altered cellular thermogenesis. Both increased Na+ pump operation and uncoupling may occur to a greater or lesser extent, as may other heat-producing mechanisms. There are areas in which further information is needed in order to explain fully the composite nature of the mechanisms involved in cellular thermogenesis. The control of mitochondrial oxidations in their natural habitat (i.e. inside cells) by regulatory proteins, fatty acids, ions (Ca2+, Na+, K+), cyclic AMP, protein kinases, prostaglandins, purine nucleotides, and other factors must be elucidated. There is evidence for the participation of all of these substances in the control of cellular thermogenesis, but no scheme has been developed that takes them all into account. Further emphasis on the tissue-specific differences in the regulation of mitochondrial function is desirable. The regulation of the biogenesis of mammalian mitochondria is another area currently under intense study for which no clear hypothesis has as yet emerged. Information in this area is needed in order to understand the mechanism and role of mitochondrial adaptations associated with altered thermogenesis in hyperthyroidism, in acclimation to cold, and in exercise training, as well as the nature of altered mitochondrial biogenesis, such as appears to underlie the Luft hypermetabolic syndrome. PMID: 130826 [PubMed - indexed for MEDLINE] 7447. Nihon Rinsho. 1976;34(3):534-9. [Hydroxybenzylpindolol--activation mechanism of adenylate cyclase and beta-adrenergic receptor]. [Article in Japanese] Yamamura H. PMID: 6811 [PubMed - indexed for MEDLINE] 7448. Cesk Fysiol. 1976;25(2):129-38. [Regulation of fatty acid synthesis]. [Article in Czech] Vrána A, Fábry P, Kazdová L. PMID: 4230 [PubMed - indexed for MEDLINE] 7449. Proc R Soc Med. 1975 Dec;68(12):785-91. Is insulin's second messenger calcium? Fraser TR. PMCID: PMC1864380 PMID: 176665 [PubMed - indexed for MEDLINE] 7450. Proc Nutr Soc. 1975 Dec;34(3):249-55. Lipid metabolism in genetic models of obesity. York DA. PMID: 174122 [PubMed - indexed for MEDLINE] 7451. Proc Nutr Soc. 1975 Dec;34(3):233-9. Hormonal control of adipose tissue lipolysis. Siddle K, Hales CN. PMID: 174121 [PubMed - indexed for MEDLINE] 7452. Proc Nutr Soc. 1975 Dec;34(3):211-5. The role of clearing-factor lipase (lipoprotein lipase) in the transport of plasma triglycerides. Robinson DS, Cryer A, Davies P. PMID: 174120 [PubMed - indexed for MEDLINE] 7453. Proc Nutr Soc. 1975 Dec;34(3):257-64. Effects of diet on fatty acid metabolism. Garton GA, Wahle KW. PMID: 1765 [PubMed - indexed for MEDLINE] 7454. Proc Nutr Soc. 1975 Dec;34(3):217-24. Hormonal regulation of fatty acid synthesis in adipose tissue through changes in the activities of pyruvate dehydrogenase (EC 1.2.4.1) and acetyl-CoA carboxylase (EC 6.4.1.2). Denton RM. PMID: 1764 [PubMed - indexed for MEDLINE] 7455. Nihon Rinsho. 1975 Nov 10;33(11):3236-43. [Hyperlipemia in diabetes mellitus]. [Article in Japanese] Ohira S, Goto Y. PMID: 173904 [PubMed - indexed for MEDLINE] 7456. Cancer. 1975 Nov;36(5):1785-93. On the ultrastructure of hibernoma. Seemayer TA, Knaack J, Wang NS, Ahmed MN. An electron-microscopic study of hibernoma and a review of the histogenesis, development, and post-natal structural composition of brown and white adipose tissue are presented. The ultrastructural features of hibernoma include multivacuolated and univacuolated cells containing variable numbers of lipid vacuoles, abundant moderately pleomorphic mitochondria with transverse cristae, lysosomes, lipofuscin granules, pinocytotic vesicles, well-formed basal lamina, and prominent subplasmalemmal condensations. The latter have not been previously reported in hibernoma, brown adipose tissue or white adipose tissue, although gap junctions have been observed in brown adipose tissue of newborn mice. It is concluded that the ultrastructural observations support the concept proposed decades ago that hibernoma represents the neoplastic counterpart of brown adipose tissue. PMID: 1192364 [PubMed - indexed for MEDLINE] 7457. Nutr Rev. 1975 Nov;33(11):341-3. The effect of prolactin on lipoprotein lipase activity. [No authors listed] PMID: 1105256 [PubMed - indexed for MEDLINE] 7458. Usp Fiziol Nauk. 1975 Oct-Dec;6(4):78-99. [Modern concepts of the regulation of the processes of tissue, organ and body growth as dependent on the nutritional conditions]. [Article in Russian] Konyshev VA. PMID: 1108488 [PubMed - indexed for MEDLINE] 7459. Postgrad Med. 1975 Oct;58(4):107-13. Commonly overlooked pain syndromes responsive to simple therapy. Pace JB. PMID: 1099564 [PubMed - indexed for MEDLINE] 7460. Med Clin North Am. 1975 Sep;59(5):1123-31. Thyroid-catecholamine interactions. Spaulding SW, Noth RH. PMID: 1099359 [PubMed - indexed for MEDLINE] 7461. Nutr Rev. 1975 Aug;33(8):236-8. The influence of dietary fat on the composition of the body fat of infants. [No authors listed] PMID: 1095973 [PubMed - indexed for MEDLINE] 7462. Biochem Pharmacol. 1975 Jul 15;24(13-14):1261-6. Glucagon and adipose tissue. Lefebvre P. PMID: 167786 [PubMed - indexed for MEDLINE] 7463. Pharmazie. 1975 Jul;30(7):422-33. [The fundamentals of the pharmacology of antidiabetic substances]. [Article in German] Losert W. PMID: 1101277 [PubMed - indexed for MEDLINE] 7464. Poult Sci. 1975 Jul;54(4):1075-93. Lipid biosynthesis in the chick. A consideration of site of synthesis, influence of diet and possible regulatory mechanisms. Leveille GA, Romsos DR, Yeh Y, O'Hea EK. Studies in vitro and with intact chicks support the view that liver is the major site of lipid biosynthesis in the chicken. Adipose tissue is relatively unimportant as a site of fatty acid biosynthesis in this species although it does have the ability to esterify fatty acids to triglycerides. The available evidence, therefore, suggests that in the chicken, and presumably other avian species, fatty acids are synthesized in liver and are transported as triglycerides in the plasma low-density lipoproteins to the adipose tissue for storage. Fasting, even for short periods of time, markedly depresses the capacity for hepatic lipogenesis in the chick. Food restriction for 2 hr. depresses hepatic lipogenesis by about 90% and refeeding for 1 hr./or/the intravenous administration of glucose or fructose restores the lipogenic capacity. Feeding diets high in fat or protein cannot be adequately explained on the basis of the reduction of dietary carbohydrate which accompanies increased dietary protein or fat levels. Dietary fat and protein appear to exert their effects on hepatic lipid synthesis by different mechanisms. The depression in hepatic fatty acid synthesis brought about by fasting or fat-feeding is accompanied, and probably preceded, by an increased plasma free fatty acid level. Under these conditions hepatic fatty-acyl CoA levels increase while free CoA levels are reduced. Long-chain acyl CoA derivatives are capable of inhibiting acetyl CoA carboxylase activity as well as citrate transport. The reduced availability of free CoA may limit the citrate cleavage reaction. Dietary alterations influence the hepatic lactate-pyruvate ratio of chicks, however the changes observed are not always consistent with the changes observed in rat liver. Chicks fed high-protein diets have a decreased hepatic lactate/pyruvate ratio indicative of a more oxidized cytoplasmic environment. This change in redox state may be associated with control of fatty acid synthesis in chicks fed high-protein diets. Thyroxine and glucagon affect hepatic fatty acid synthesis in the chick, however insulin appears to play a lesser role. PMID: 240159 [PubMed - indexed for MEDLINE] 7465. Science. 1975 Jun 20;188(4194):1177-84. Membrane transport: its relation to cellular metabolic rates. Elbrink J, Bihler I. PMID: 1096301 [PubMed - indexed for MEDLINE] 7466. Masui. 1975 Jun;24(6):525-37. [Etiology of malignant hyperthermia]. [Article in Japanese] Okumura F, Kuro M. PMID: 169408 [PubMed - indexed for MEDLINE] 7467. Pol Tyg Lek. 1975 May 26;30(21):917-9. [Perinatal hypoxia]. [Article in Polish] Nyka W. PMID: 1094439 [PubMed - indexed for MEDLINE] 7468. Clin Orthop Relat Res. 1975 May;(108):228-40. Somatomedin. Bomboy JD Jr, Salmon WD Jr. Somatomedin is a peptide component of serum which has been postulated to mediate the action of growth hormone on skeletal tissue. Direct effects on cartilage include stimulation of the synthesis of mucopolysacharide, protein, and nucleic acids. Insulin-like effects on non-skeletal tissues and cells have been described, and a relationship to NSILA-S and MSA has been suggested. The liver may be an important source. Non-specificity of bioassays is a problem. Growth hormone deficiency, malnutrition, therapy with corticosteroids or estrogens, and a type of dwarfism characterized by high serum growth hormone are associated with decreased somatomedin. An unexplained phenomenon is the normal somatomedin with low or undetectable growth hormone in certain cases of craniopharyngioma or other tumors involving the hypothalamus. Somatomedin is increased in acromegaly. PMID: 1095277 [PubMed - indexed for MEDLINE] 7469. Med Clin North Am. 1975 May;59(3):751-61. Renal gluconeogenesis and amino-acid metabolism in man. Cahill GF Jr, Aoki TT. PMID: 1092934 [PubMed - indexed for MEDLINE] 7470. Acta Ginecol (Madr). 1975 Apr 1;26(7):379-402. [Extragenital actions of sex hormones in the woman]. [Article in Spanish] Vague J. PMID: 1096519 [PubMed - indexed for MEDLINE] 7471. J Dairy Sci. 1975 Apr;58(4):602-10. Efficiency of conversion of digested energy to milk. Moe PW, Tyrrell HF. PMID: 1092740 [PubMed - indexed for MEDLINE] 7472. Kinderarztl Prax. 1975 Apr;43(4):166-80. [Adiposity in children]. [Article in German] Spahn U, Knöll G, Plenert W. PMID: 772270 [PubMed - indexed for MEDLINE] 7473. Biochim Biophys Acta. 1975 Mar 31;416(1):53-103. Brown adipose tissue mitochondria. Flatmark T, Pedersen JI. PMID: 235330 [PubMed - indexed for MEDLINE] 7474. Am J Med. 1975 Mar;58(3):417-23. Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis. Case report and review of literature. Potts DE, Mass MF, Iseman MD. Immunologic evaluation of a patient with pancreatitis, subcutaneous fat necrosis, pleuritis, pericarditis and synovitis is presented. The previously recognized syndrome of pancreatic disease, subcutaneous fat necrosis and arthritis is reviewed. Based on analysis of all the cases described in the English language literature it is suggested that this syndrome be expanded to include polyserositis rather than arthritis alone. Although experimental and clinical evidence tends to implicate physiocochemical tissue injury by pancreatic lipase as the primary pathogenic mechanism in this syndrome, studies in our patient suggest the possible contribution of immune-mediated injury. Supporting data include eosinophilia, biopsy demonstration of vasculitis antedating the subcutaneous fat necrosis, immunofluorescent identification of immunoglobulin G (IgG) and C3 in the pleura, and reduced levels of total hemolytic complement in the serum, and pleural and pericardial effusions. PMID: 1090161 [PubMed - indexed for MEDLINE] 7475. Diabete Metab. 1975 Mar;1:57-68. [Insulin receptors-a review (author's transl)]. [Article in French] Freychet P. The first step in insulin action is interaction of the hormone with specific receptors on the plasma membrane of target cells. The receptor site is defined by its functional properties: it binds insulin with a high degree of specificity and affinity; the specific binding sites are finite in number; hormone binding is rapid and reversible; the binding sites are, or predominate, on the plasma membrane; hormone binding can be related to biological effects. The use of biologically active monoiodoinsulin permits direct study of the binding of 125I-insulin to receptor in isolated cells or in cell membranes. The binding of 125I-insulin is highly specific and strictly dependent on the biologically active structure of the insulin molecule. Both the rate and the amount of binding are time and temperature-dependent. The insulin--receptor interaction is a complex reaction, whose quantitative analysis requires consideration of, in addition to hormone binding to receptor, degradation of the hormone and of the receptor. By measuring binding at steady state, one can determine both the apparent insulin--binding capacity and the apparent dissociation constant of the insulin--receptor complex. Scatchard analyses of these data reveals heterogeneity of the binding sites with respect to equilibrium constant, a result which is also compatible with negative cooperativity between the receptor sites. Studies of insulin--receptor interactions have led to a variety of applications, two of which are of special interest from pharmacological, pathophysiological and clinical viewpoints. One is concerned with the use of insulin--receptor binding systems to study hormone structure--activity relationships and to analyze endogenous forms of insulin. These studies have shown that, in every instance, the binding affinity of an insulin or insulin analogue is in direct proportion to its biological potency. No antagonist of native insulin has been found thus far, including data obtained with proinsulin, proinsulin intermediates and Non-Suppressible Insulin-Like Activity (NSILA) or somatomedin (s). These studies have also revealed that proinsulin reacts only with insulin receptors in contrast to NSILA which, inaddition to reacting with insulin receptors, also possesses its own specific receptor sites. The other application deals with studies of receptor alteration in pathological states. This investigation has been well documented in the obese hyperglycemic (ob/ob) mouse which exhibits a receptor defect in the liver, fat, thymic lymphocyte and myocardium. The defect essentially involves a decrease in the number of binding sites and selectively affects the insulin receptor. A variety of data, both in vivo and in vitro, indicate an inverse relationship between the concentration of insulin and the number of insulin receptors, and suggest a negative feedback effect of the hormone on its own receptor... PMID: 791721 [PubMed - indexed for MEDLINE] 7476. Thromb Diath Haemorrh. 1975 Feb 28;33(1):73-6. Antilipemic action of heparin. Markwardt F. PMID: 1091020 [PubMed - indexed for MEDLINE] 7477. Nihon Naika Gakkai Zasshi. 1975 Feb 10;64(2):99-113. [Recent development in the study of somatomedin (author's transl)]. [Article in Japanese] Shizume K, Takano K. PMID: 1100738 [PubMed - indexed for MEDLINE] 7478. Z Kinderheilkd. 1975;118(4):271-81. Permanent neonatal diabetes mellitus: a case report with plasma insulin studies. Dorchy H, Ooms H, Loeb H. The 11th case of permanent neonatal diabetes mellitus appearing during the first month of life is reported. A critical review of the literature is also presented. The permanence of diabetes is demonstrated by the duration of insulin therapy still necessary after 30 months. Insulin-stimulation tests have been performed some for the first time in such a young diabetic. They have shown a nearly total failure in beta-cell response, only very high doses of glucagon provoking a moderate insulin secretion. The absence of acetonuria is discussed. It can perhaps be explained by the hyperglycemia which, by a mass effect, brings about cellular glucose penetration and this stops liberation of Nefa's from adipose tissue. PMID: 1130120 [PubMed - indexed for MEDLINE] 7479. Adv Metab Disord. 1975;8:211-35. Biological properties of NSILA-S. Froesch ER, Zapf J, Meuli C, Mäder M, Waldvogel M, Kaufmann U, Morell B. PMID: 1106155 [PubMed - indexed for MEDLINE] 7480. Adv Food Res. 1975;21:1-69. Regulation of food intake. Lepkovsky S. PMID: 1098416 [PubMed - indexed for MEDLINE] 7481. Obstet Gynecol Annu. 1975;4:39-70. Fetal lipid metabolism. Biezenski JJ. PMID: 1095993 [PubMed - indexed for MEDLINE] 7482. Curr Concepts Nutr. 1975;3:47-57. Modification of adipose tissue fatty acid composition. Hashim SA. PMID: 1093813 [PubMed - indexed for MEDLINE] 7483. Curr Concepts Nutr. 1975;3:15-21. Cell number and size as a determinant of subsequent obesity. Hirsch J. PMID: 1093809 [PubMed - indexed for MEDLINE] 7484. Cesk Fysiol. 1975;24(1):21-50. [Utilization of fructose and metabolic consequences of fructose supply]. [Article in Czech] Vrána A, Fábry P, Kazdová L. PMID: 1090388 [PubMed - indexed for MEDLINE] 7485. Annu Rev Biochem. 1975;44:669-95. Prostaglandins. Samuelsson B, Granström E, Green K, Hamberg M, Hammarström S. PIP: Since the literature on PGs (prostaglandins) is increasing so rapidly, this literature review covers only the following PG-related topics: 1) PG biosynthesis; 2) PG metabolism; 3) analysis of PGs; 4) PG receptors; 5) PGs and cyclic nucleotides; and 6) the effect of PGs on platelet function. PG biosynthesis has been monitored by labeled precursor acids and chromatographic identification, gas-liquid chromatography, radioimmunoassay and multiple ion analysis, and measurement of urinary metabolites. These methods have shown that many mammalian tissues produce PGs. Various conditions and agents have been found to alter the rate of PG synthesis; aspirin is 1 agent which inhibits PG biosynthesis. The metabolic pathways of PGs are diagrammed chemically. The highly sensitive methods for performing quantitative analysis of PGs which have been developed in recent years are explained. These include gas chromatography with electron capture detectors, gas chromatography/mass spectrometry, and radio-immunoassay. PGs are known to react with adenyl cyclase in many different tissues. This may explain their wide variety of pharmacological effects. Platelet aggregation is stimulated in its 2nd stage by PGE2 and inhibited by PGE1. PMID: 806254 [PubMed - indexed for MEDLINE] 7486. Adv Exp Med Biol. 1975;52:269-79. Lipoprotein lipase. Olivecrona T, Hernell O, Egelrud T. PMID: 804806 [PubMed - indexed for MEDLINE] 7487. Postgrad Med J. 1975;51 Suppl 1:13-7. Peripheral and metabolic effects of fenfluramine, 780SE, norfenfluramine and hydroxyethylnorfenfluramine--a review. Macrae SM. PMID: 768953 [PubMed - indexed for MEDLINE] 7488. Adv Exp Med Biol. 1975;60:1-12. Some aspects of the control of lipid biosynthesis. Bloch K. PMID: 238370 [PubMed - indexed for MEDLINE] 7489. Adv Cyclic Nucleotide Res. 1975;5:3-29. Role of adenine and guanine nucleotides in the activity and response of adenylate cyclase systems to hormones: evidence for multisite transition states. Rodbell M, Lin MC, Salomon Y, Londos C, Harwood JP, Martin BR, Rendell M, Berman M. PMID: 236641 [PubMed - indexed for MEDLINE] 7490. Annu Rev Physiol. 1975;37:245-72. Peripheral actions of glucocorticoids. Leung K, Munck A. PMID: 235876 [PubMed - indexed for MEDLINE] 7491. Curr Top Cell Regul. 1975;9:157-81. Regulation and physiological functions of malic enzymes. Frenkel R. PMID: 235406 [PubMed - indexed for MEDLINE] 7492. Cardiology. 1975;60(5):280-303. Insulin: fundamental mechanism of action and the heart. Kones RJ, Phillips JH. Insulin accelerates the entry of glucose and amino acids into muscle cells by acting upon the 'carrier-facilitated' transport mechanism. For glucose this process is passive and leads to equilibration of intracellular and extracellular concentrations. In heart muscle, glucose transport is a rate-limiting step for glucose uptake. During hypoxia and ischemia the heart turns to anaerobic glycolysis for energy production and therefore, maximal glucose transport becomes important. Insulin is necessary to insure proper protein synthesis, probably at the level of membrane-bound polyribosomes. However, during myocardial hypoxia, insulin alone cannot restore the associated depression in protein synthesis. Although insulin hyperpolarizes the cell, a change in the ratio of intracellular to extracellular activities of potassium is not its primary mode of action. An insulin-induced configurational change in the plasma membrane could simultaneously account for the effects of insulin on sodium and potassium permeability and the action on facilitated transport. Intracellular levels of cyclic adenylate may be reduced by insulin in adipose tissue because of inhibition of adenyl cyclase or stimulation of phosphodiesterase. However, at this time there is little evidence that insulin alters cyclic AMP levels in the heart. Insulin secretion is depressed in patients with heart disease in proportion to the reduction of cardiac index sustained. Since the ischemic heart is dependent upon glucose as the major fuel, insulin lack may deprive the heart of adequate substrate. PMID: 182367 [PubMed - indexed for MEDLINE] 7493. Ter Arkh. 1975;47(7):15-24. [Problems of the pathogenesis of arteriosclerosis]. [Article in Russian] Gerasimova EN. PMID: 178063 [PubMed - indexed for MEDLINE] 7494. Adv Metab Disord. 1975;8:7-16. Regulation of cellular growth. Pastan I. PMID: 173164 [PubMed - indexed for MEDLINE] 7495. Adv Metab Disord. 1975;8:19-46. Somatomedins. Hall K, Takano K, Fryklund L, Sievertsson H. PMID: 173159 [PubMed - indexed for MEDLINE] 7496. Adv Metab Disord. 1975;8:127-50. Explorations of the insulinlike and growth-promoting properties of somatomedin by membrane receptor assays. van Wyk JJ, Underwood LE, Baseman JB, Hintz RL, Clemmons DR, Marshall RN. PMID: 173158 [PubMed - indexed for MEDLINE] 7497. Recent Prog Horm Res. 1975;31:37-94. Hormone receptor complexes and their modulation of membrane function. Cuatrecasas P, Hollenberg MD, Chang KJ, Bennett V. PMID: 172994 [PubMed - indexed for MEDLINE] 7498. Adv Exp Med Biol. 1975;61:195-208. Changes in hormone binding and responsiveness in target cells and tissues during aging. Roth GS. PMID: 170808 [PubMed - indexed for MEDLINE] 7499. Adv Cyclic Nucleotide Res. 1975;5:79-104. Hormone receptors - their function in cell membranes and some problems related to methodology. Cuatrecasas P. PMID: 165699 [PubMed - indexed for MEDLINE] 7500. Surg Annu. 1975;7:115-36. Principles of diagnosis and management of soft tissue sarcomas. Das Gupta TK, Ghosh BC. PMID: 126496 [PubMed - indexed for MEDLINE] 7501. Vutr Boles. 1975;14(3):16-23. [Disorders of carbohydrate and fat metabolism in diabetes mellitus]. [Article in Bulgarian] Bozadzhieva E. PMID: 5808 [PubMed - indexed for MEDLINE] 7502. Pol Tyg Lek. 1974 Dec 23;29(51):2229-31. [Variation in blood lipid contents during the acute phase of heart infarct]. [Article in Polish] Rymar B. PMID: 4374691 [PubMed - indexed for MEDLINE] 7503. Z Gesamte Inn Med. 1974 Dec 1;29(23):953-9. [Possibilities for the determination of fat portion in body weight]. [Article in German] Lantzsch W, Seige K. PMID: 4618949 [PubMed - indexed for MEDLINE] 7504. Nihon Rinsho. 1974 Nov 10;32(11):3309-16. [Metabolism of corticoids]. [Article in Japanese] Takeda R. PMID: 4217392 [PubMed - indexed for MEDLINE] 7505. Nutr Rev. 1974 Nov;32(11):340-2. The role of sugars in hyperlipidemia. [No authors listed] PMID: 4614129 [PubMed - indexed for MEDLINE] 7506. Metabolism. 1974 Nov;23(11):1091-102. Effects of age, sex, and clinical conditions on adipose tissue cellularity in man. Björntorp P. PMID: 4607783 [PubMed - indexed for MEDLINE] 7507. Arch Fr Pediatr. 1974 Nov;31(9):837-41. [Vitamin d: recent acquisitions]. [Article in French] Balsan S. PMID: 4376939 [PubMed - indexed for MEDLINE] 7508. Pediatr Clin North Am. 1974 Nov;21(4):871-84. Diabetes mellitus in childhood. Ehrlich RM. PMID: 4215063 [PubMed - indexed for MEDLINE] 7509. Fiziol Zh. 1974 Nov-Dec;20(6):831-40. [The role of the adrenoreceptors in several organs in regulating carbohydrate and lipid metabolism]. [Article in Ukrainian] Henes SH, Poltorak VV. PMID: 4156967 [PubMed - indexed for MEDLINE] 7510. Isr J Med Sci. 1974 Oct;10(10):1222-9. Role of insulin in obesity. Sims EA, Danforth E Jr. PMID: 4611963 [PubMed - indexed for MEDLINE] 7511. Nutr Rev. 1974 Oct;32(10):312-3. Lipolysis, aging, and hormones. [No authors listed] PMID: 4370166 [PubMed - indexed for MEDLINE] 7512. J Lipid Res. 1974 Sep;15(5):439-56. Transport of lipids in insects. Gilbert LI, Chino H. Many insect species are almost completely dependent on lipids for their metabolic needs, although this is usually a function of developmental stage. The primary storage organ is the fat body, which can constitute 50% of the fresh weight of the insect and also acts as the major metabolic center (analogous to the vertebrate adipose tissue and liver). Bathing the fat body (and all other tissues and organs) is the hemolymph, the main functions of which are to transport nutrient substrates to utilization sites and to deliver metabolic wastes to the excretory system. Although neutral lipids are stored as triglycerides, in times of need they appear to be endergonically released into the hemolymph as diglycerides in the majority of insects thus far studied (particularly silkmoths and locusts). Indeed, diglycerides constitute the largest neutral lipid fraction in the hemolymph of silkmoths, locusts, cockroaches, bugs, etc. In the hemolymph the diglyceride is found as a constituent of specific lipoproteins, and one specific lipoprotein class (lipoprotein I; high density lipoprotein) appears to be necessary for the transport of diglyceride from the fat body cell into the hemolymph. This particular lipoprotein is also involved in the transport of cholesterol from the gut into the hemolymph. Thus, lipoprotein I appears to be the major neutral lipid and sterol transport agent in the insects studied and, in addition, plays a regulatory role in the release of both diglycerides and sterols. Hemolymph lipoprotein II (very high density lipoprotein) may be important in providing protein and lipid to the insect ovary during oogenesis. Ecdysone, the polyhydroxy steroidal insect molting hormone, is probably carried "free" in the hemolymph, although reports exist of specific hemolymph-binding proteins in some species. The other major insect growth hormone, juvenile hormone, is transported by hemolymph lipoproteins in silkmoths and locusts and by a lower molecular weight hemolymph protein in the tobacco hornworm. PMID: 4370522 [PubMed - indexed for MEDLINE] 7513. Vopr Med Khim. 1974 Sep-Oct;20(5):451-62. [Regulation of biosynthesis and oxidation of fatty acids and glycerides at the cellular level in mammalian tissues]. [Article in Russian] Alimova EK, Astvatsatur'ian AT, Zharov LV. PMID: 4156442 [PubMed - indexed for MEDLINE] 7514. Circ Res. 1974 Sep;35 Suppl 3:129-37. Effect of catecholamines on cardiac metabolism. Mayer SE. PMID: 4153325 [PubMed - indexed for MEDLINE] 7515. N Engl J Med. 1974 Aug 1;291(5):226-32. The influence of obesity on health (second of two parts). Mann GV. PMID: 4599983 [PubMed - indexed for MEDLINE] 7516. Fed Proc. 1974 Aug;33(8):1952-5. A review of development of adipose cellularity in man and animals. Stern JS, Greenwood MR. PMID: 4135740 [PubMed - indexed for MEDLINE] 7517. N Engl J Med. 1974 Jul 25;291(4):178-85. The influence of obesity on health (first of two parts). Mann GV. PMID: 4599657 [PubMed - indexed for MEDLINE] 7518. Usp Sovrem Biol. 1974 Jul-Aug;78(1):139-56. [Thermogenesis and lipid metabolism in mammals exposed to cold]. [Article in Russian] Vasil'eva ED. PMID: 4613044 [PubMed - indexed for MEDLINE] 7519. Medicina (B Aires). 1974 Jul-Aug;34(4):393-410. [Studies and comments on human impregnation with organochloride insecticides in the Argentine republic]. [Article in Spanish] Garcia Fernandez JC. PMID: 4607834 [PubMed - indexed for MEDLINE] 7520. Klin Med (Mosk). 1974 Jul;52(7):25-32. [Obesity and the functions of beta-cells of the insular apparatus of the pancreas]. [Article in Russian] Genes CG. PMID: 4603717 [PubMed - indexed for MEDLINE] 7521. Z Gesamte Inn Med. 1974 Jun 15;29(12):469-76. [Pathogenesis of hyperlipoproteinemias]. [Article in German] Müller G. PMID: 4368206 [PubMed - indexed for MEDLINE] 7522. Nutr Rev. 1974 Jun;32(6):173-5. Heat production by malnourished babies. [No authors listed] PMID: 4600162 [PubMed - indexed for MEDLINE] 7523. J Anim Sci. 1974 May;38(5):1079-91. Protein synthesis in animal models. Bergen WG. PMID: 4601493 [PubMed - indexed for MEDLINE] 7524. Pediatr Clin North Am. 1974 May;21(2):353-9. A developmental approach to adolescence. Faigel HC. PMID: 4599896 [PubMed - indexed for MEDLINE] 7525. J Anim Sci. 1974 May;38(5):1022-30. Metabolic patterns in the neonatal swine. Mersmann HJ. PMID: 4596886 [PubMed - indexed for MEDLINE] 7526. J Steroid Biochem. 1974 May;5(3):279-85. The role of cyclic AMP in the regulation of steroid biosynthesis in testis tissue. Rommerts FF, Cooke BA, van der Molen HJ. PMID: 4369354 [PubMed - indexed for MEDLINE] 7527. Vnitr Lek. 1974 May;20(5):504-6. [New knowledge on the pathogenesis, physiopathology and economic treatment of obesity]. [Article in Czech] Masek O, Hamplová B. PMID: 4210805 [PubMed - indexed for MEDLINE] 7528. Life Sci. 1974 Mar 16;14(6):993-1005. Protein and polypeptide hormones as inhibitors. Ramachandran J. PMID: 4362779 [PubMed - indexed for MEDLINE] 7529. Am J Clin Nutr. 1974 Mar;27(3):226-8. Letter: A brief review of scientific opinion on the etiology of obesity. Blumenfield A. PMID: 4814876 [PubMed - indexed for MEDLINE] 7530. Pharmazie. 1974 Mar;29(3):153-9. [Current problems in hormone research. 2. The role of receptors in some insulin effects at the cellular level]. [Article in German] Heder G. PMID: 4368099 [PubMed - indexed for MEDLINE] 7531. Klin Wochenschr. 1974 Feb 15;52(4):153-65. [The lipotropins (author's transl)]. [Article in German] Schwandt P. PMID: 4365500 [PubMed - indexed for MEDLINE] 7532. Nutr Rev. 1974 Feb;32(2):33-8. Energy needs and energy utilization. Hegsted DM. PMID: 4594020 [PubMed - indexed for MEDLINE] 7533. Nutr Rev. 1974 Feb;32(2):53-5. New roles for ascorbic acid. [No authors listed] PMID: 4361670 [PubMed - indexed for MEDLINE] 7534. J Perinat Med. 1974;2(2):75-87. Recent investigations on neonatal fat metabolism. Wolf H, Stave U, Novak M, Monkus EF. PMID: 4619634 [PubMed - indexed for MEDLINE] 7535. Adv Exp Med Biol. 1974;49(0):47-72. Overnutrition, overgrowth and hormones (with special reference to the infant born of the diabetic mother). Cheek DB, Brayton JB, Scott RE. PMID: 4611169 [PubMed - indexed for MEDLINE] 7536. Adv Exp Med Biol. 1974;49(0):119-49. Interrelationships between body size, body composition and function. Parízková J. PMID: 4611166 [PubMed - indexed for MEDLINE] 7537. Horm Metab Res. 1974;Suppl 4:63-9. Genetic and regulatory aspects in obesity of animals and man. Bray GA. PMID: 4609196 [PubMed - indexed for MEDLINE] 7538. Horm Metab Res. 1974;Suppl 4:56-62. Interrelationship between fatty acid metabolism and hepatic gluconeogenesis. Söling HD. PMID: 4609066 [PubMed - indexed for MEDLINE] 7539. Obstet Gynecol Annu. 1974;3(0):203-33. Maternal lipid metabolism. Biezenski JJ. PMID: 4609037 [PubMed - indexed for MEDLINE] 7540. Pathol Annu. 1974;9(0):157-207. Lesions of the conduction system and their functional significance. Lev M, Bharati S. PMID: 4608803 [PubMed - indexed for MEDLINE] 7541. Horm Metab Res. 1974;Suppl 4:37-44. Current views on cholesterol metabolism. Miettinen TA. PMID: 4608004 [PubMed - indexed for MEDLINE] 7542. Adv Lipid Res. 1974;12(0):311-77. Inhibition of fatty acid oxidation by biguanides: implications for metabolic physiopathology. Muntoni S. PMID: 4607669 [PubMed - indexed for MEDLINE] 7543. Horm Metab Res. 1974;Suppl 4:77-83. Size, number and function of adipose tissue cells in human obesity. Björntorp P. PMID: 4607511 [PubMed - indexed for MEDLINE] 7544. Adv Metab Disord. 1974;7(0):243-55. Obesity and diabetes mellitus. Pfeiffer EF, Laube H. PMID: 4606857 [PubMed - indexed for MEDLINE] 7545. Adv Metab Disord. 1974;7(0):1-36. Growth hormone and somatomedin. Hall K, Luft R. PMID: 4606597 [PubMed - indexed for MEDLINE] 7546. Nahrung. 1974;18(1):59-72. [Dietary induction of obesity in the rat and mouse. A survey]. [Article in German] Voss C, Hartmann N. PMID: 4603267 [PubMed - indexed for MEDLINE] 7547. Int Anesthesiol Clin. 1974 Summer;12(2):157-77. Biotransformation and disposition of ketamine. Chang T, Glazko AJ. PMID: 4603048 [PubMed - indexed for MEDLINE] 7548. Anat Anz. 1974;136(1-2):172-90. [Abdominal adipose tissue in man. Review of literature and electron microscopy study on morphological adipose tissue research. I. History of adipose tissue research]. [Article in German] Hegewald G, Bärenwald G. PMID: 4451280 [PubMed - indexed for MEDLINE] 7549. Biochem Soc Symp. 1974;(39):75-88. Calcium ions and the regulation of pyruvate dehydrogenase. Randle PJ, Denton RM, Pask HT, Severson DL. PMID: 4377912 [PubMed - indexed for MEDLINE] 7550. Cesk Fysiol. 1974;23(1):1-35. [Progress in the research on cyclic nucleotides. I. Cyclic 3',5' adenosine monophosphate: chemical properties, metabolism and biological role]. [Article in Czech] Hynie S, Kenerová V. PMID: 4375544 [PubMed - indexed for MEDLINE] 7551. Acta Endocrinol Suppl (Copenh). 1974;191:93-129. Molecular events in the action of insulin on cell metabolism. The significance of cyclic AMP dependent protein kinases. Walaas O, Walaas E, Gronnerod O. PMID: 4375385 [PubMed - indexed for MEDLINE] 7552. Acta Endocrinol Suppl (Copenh). 1974;191:191-8. Androgen transport mechanisms in the testis and epididymis. Hansson V, Ritzén EM, French FS. PMID: 4375380 [PubMed - indexed for MEDLINE] 7553. Acta Endocrinol Suppl (Copenh). 1974;191:131-6. The significance of insulin receptors in fat cells. Gliemann J, Gammeltoft S, Vinten J. PMID: 4375376 [PubMed - indexed for MEDLINE] 7554. Acta Endocrinol Suppl (Copenh). 1974;191:11-37. The role of adenine and guanine nucleotides in the activity and response of adenylate cyclase systems to hormones: evidence for multi-site transition states. Rodbell M, Lin MC, Salomon Y, Londos C, Harwood JP, Martin BR, Rendell M, Berman M. PMID: 4375375 [PubMed - indexed for MEDLINE] 7555. Triangle. 1974;13(2):63-71. Obesity and pituitary lipolytic hormones. Chrétien M. PMID: 4372752 [PubMed - indexed for MEDLINE] 7556. Horm Metab Res. 1974;Suppl 4:51-3. Lipid transport and the availability of insulin. Havel RJ. PMID: 4370825 [PubMed - indexed for MEDLINE] 7557. Adv Biochem Psychopharmacol. 1974;10:263-71. Availability of tryptophan to the brain and some hormonal and drug influences on it. Curzon G. PMID: 4367771 [PubMed - indexed for MEDLINE] 7558. Recent Prog Horm Res. 1974;30(0):259-318. The somatomedins: a family of insulinlike hormones under growth hormone control. Van Wyk JJ, Underwood LE, Hintz RL, Clemmons DR, Voina SJ, Weaver RP. PMID: 4366786 [PubMed - indexed for MEDLINE] 7559. Surg Annu. 1974;6:1-16. Metabolic aspects of shock. Schumer W. PMID: 4139771 [PubMed - indexed for MEDLINE] 7560. Proc Nutr Soc. 1973 Dec;32(3):181-6. Body composition and lipid metabolism. Parízková J. PMID: 4604172 [PubMed - indexed for MEDLINE] 7561. Proc Nutr Soc. 1973 Dec;32(3):175-9. Aetiological factors in obesity. Goth E. PMID: 4604068 [PubMed - indexed for MEDLINE] 7562. Recenti Prog Med. 1973 Dec;55(6):487-502. [Insulin metabolism]. [Article in Italian] Stimmler L. PMID: 4592314 [PubMed - indexed for MEDLINE] 7563. Ann N Y Acad Sci. 1973 Nov 26;226:172-94. Influence of binding on drug metabolism and distribution. Dayton PG, Israili ZH, Perel JM. PMID: 4588440 [PubMed - indexed for MEDLINE] 7564. Pediatr Clin North Am. 1973 Nov;20(4):807-17. Teenage obesity. Heald FP, Khan MA. PMID: 4584743 [PubMed - indexed for MEDLINE] 7565. Health Phys. 1973 Oct;25(4):387-404. Uncertainties in the evaluation of the biological effects of microwave and radiofrequency radiation. Cleary SF. PMID: 4594409 [PubMed - indexed for MEDLINE] 7566. Biochim Biophys Acta. 1973 Sep 10;300(2):129-58. Hormone-sensitive adenylyl cyclases. Useful models for studying hormone receptor functions in cell-free systems. Birnbaumer L. PMID: 4356127 [PubMed - indexed for MEDLINE] 7567. J Dairy Sci. 1973 Sep;56(9):1187-95. Biosynthesis of milk fat. Emery RS. PMID: 4593734 [PubMed - indexed for MEDLINE] 7568. Clin Obstet Gynecol. 1973 Sep;16(3):130-47. Endocrine regulation of metabolic homeostasis during pregnancy. Yen SS. PMID: 4590319 [PubMed - indexed for MEDLINE] 7569. Med Ann Dist Columbia. 1973 Sep;42(9):423-8. Obesity--a form of malnutrition. Martin MM, Martin AL. PMID: 4590136 [PubMed - indexed for MEDLINE] 7570. Nutr Rev. 1973 Sep;31(9):287-9. Glucose ingestion and the control of lipogenesis. [No authors listed] PMID: 4586896 [PubMed - indexed for MEDLINE] 7571. Nutr Rev. 1973 Aug;31(8):257-9. Metabolism of developing adipose tissue in the pig. [No authors listed] PMID: 4586204 [PubMed - indexed for MEDLINE] 7572. Dtsch Med Wochenschr. 1973 Aug;98(32):1509-10. [Significance of lipophilia of drugs for their distribution in the body]. [Article in German] Krieglstein J. PMID: 4579809 [PubMed - indexed for MEDLINE] 7573. Biol Rev Camb Philos Soc. 1973 Aug;48(3):333-75. Protein and nucleic acid metabolism in insect fat body. Price GM. PMID: 4201066 [PubMed - indexed for MEDLINE] 7574. Zh Obshch Biol. 1973 Jul-Aug;34(4):581-93. [Ultraweak luminescence and free-radical oxidation in animal tissue metabolism]. [Article in Russian] Zhuravlev AI. PMID: 4356805 [PubMed - indexed for MEDLINE] 7575. JAMA. 1973 Jun 4;224(10):1415-9. A critique of low-carbohydrate ketogenic weight reduction regimens. A review of Dr. Atkins' diet revolution. [No authors listed] PMID: 4739993 [PubMed - indexed for MEDLINE] 7576. Z Ernahrungswiss. 1973 Jun;12(2):109-20. [The effect of caffeine on the metabolism of lipids and carbohydrates]. [Article in German] Studlar M. PMID: 4588738 [PubMed - indexed for MEDLINE] 7577. Md State Med J. 1973 May;22(5):48-53. Reye's syndrome in Baltimore. A review of 16 cases. Walker SH, Schleupner CJ. PMID: 4707360 [PubMed - indexed for MEDLINE] 7578. Br Med Bull. 1973 May;29(2):148-51. Prostaglandins at adrenergic nerve-endings. Horton EW. PMID: 4356550 [PubMed - indexed for MEDLINE] 7579. Res Commun Chem Pathol Pharmacol. 1973 May;5(3):789-96. Actions of lithium on cerebral carbohydrate metabolism. DeFeudis FV. PMID: 4349610 [PubMed - indexed for MEDLINE] 7580. Nutr Rev. 1973 May;31(5):157-8. Genetic factors in fat mobilization. [No authors listed] PMID: 4126028 [PubMed - indexed for MEDLINE] 7581. Nutr Rev. 1973 Apr;31(4):119-20. Plasticizers and intravenous therapy. [No authors listed] PMID: 4578893 [PubMed - indexed for MEDLINE] 7582. Ital J Biochem. 1973 Mar-Jun;22(2):74-91. Biogenesis of saturated, mono- and poly-unsaturated fatty acids. Ghirardi P, Marzo A, Zambotti V. PMID: 4589175 [PubMed - indexed for MEDLINE] 7583. Anesth Analg. 1973 Mar;52(2):303-9. Nonfulminant fat embolism: review of concepts on its genesis and physiopathology. Weisz GM, Barzilai A. PMID: 4576884 [PubMed - indexed for MEDLINE] 7584. Nutr Rev. 1973 Mar;31(3):79-80. Fat-controlled diet and mortality from coronary heart disease. [No authors listed] PMID: 4574831 [PubMed - indexed for MEDLINE] 7585. Am J Clin Nutr. 1973 Mar;26(3):271-84. Newer concepts in the regulation of food intake. Lepkovsky S. PMID: 4570226 [PubMed - indexed for MEDLINE] 7586. Pharmacol Rev. 1973 Mar;25(1):67-118. Biochemical aspects of drug and hormone action on adipose tissue. Fain JN. PMID: 4144270 [PubMed - indexed for MEDLINE] 7587. Dtsch Tierarztl Wochenschr. 1973 Feb 15;80(4):82-5. [Effect of polychlorinated hydrocarbons on the metabolism of warm-blooded animals. II. Metabolism of DDT and related compounds]. [Article in German] Krampitz G, Hardebeck H. PMID: 4573333 [PubMed - indexed for MEDLINE] 7588. Biol Rev Camb Philos Soc. 1973 Feb;48(1):85-132. Non-shivering thermogenesis and its thermoregulatory significance. Janský L. PMID: 4578360 [PubMed - indexed for MEDLINE] 7589. Probl Actuels Endocrinol Nutr. 1973;SERIE 17:209-26. [Liporegulation in the third life-period]. [Article in French] Bour H. PMID: 4620400 [PubMed - indexed for MEDLINE] 7590. Prog Biochem Pharmacol. 1973;8:271-99. Triglyceride metabolism in diabetes mellitus. Nikkilä EA. PMID: 4597901 [PubMed - indexed for MEDLINE] 7591. Symp Soc Exp Biol. 1973;27:283-98. Tissue-specific direction of blood metabolites. Williamson DH. PMID: 4588145 [PubMed - indexed for MEDLINE] 7592. Adv Exp Med Biol. 1973;38:133-42. Hyperlipoproteinemias and diabetes mellitus. Pozza G. PMID: 4588023 [PubMed - indexed for MEDLINE] 7593. Gerontologia. 1973;19(2):79-125. Enzyme changes in ageing mammals. Wilson PD. PMID: 4583683 [PubMed - indexed for MEDLINE] 7594. Bibl Nutr Dieta. 1973;(18):123-52. Overfeeding and obesity in infants and children. Dwyer JT, Mayer J. PMID: 4573741 [PubMed - indexed for MEDLINE] 7595. Symp Soc Exp Biol. 1973;27:401-28. Rate control by insulin and its mechanism. Randle PJ, Denton RM. PMID: 4358369 [PubMed - indexed for MEDLINE] 7596. Annu Rev Med. 1973;24:233-40. Insulin receptors. Desbuquois B, Cuatrecasas P. PMID: 4354664 [PubMed - indexed for MEDLINE] 7597. Arch Dis Child. 1973 Jan;48(1):2-7. Vitamin D metabolism. Recent advances. Stamp TC. PMCID: PMC1647813 PMID: 4346640 [PubMed - indexed for MEDLINE] 7598. Am J Clin Nutr. 1973 Jan;26(1):55-63. Phosphoenolpyruvate carboxykinase. II. Hormonal controls. Hanson RW, Garber AJ, Reshef L, Ballard FJ. PMID: 4345515 [PubMed - indexed for MEDLINE] 7599. Symp Soc Exp Biol. 1973;27:371-400. Regulation of the mammalian pyruvate dehydrogenase complex by covalent modification. Wieland OH, Siess EA, Weiss L, Löffler G, Patzelt C, Portenhauser R, Hartmann U, Schirmann A. PMID: 4271940 [PubMed - indexed for MEDLINE] 7600. Ann N Y Acad Sci. 1972 Dec 18;203:192-8. The role of polyunsaturated fatty acids in determining vitamin E requirement. Witting LA. PMID: 4572178 [PubMed - indexed for MEDLINE] 7601. N Engl J Med. 1972 Dec 7;287(23):1186-92. Caloric homeostasis and disorders of fuel transport. Havel RJ. PMID: 4563084 [PubMed - indexed for MEDLINE] 7602. Proc Nutr Soc. 1972 Dec;31(3):355-62. Modification of the diet in primary prevention trials. Karvonen MJ. 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Lipid metabolism during infectious illness. Beisel WR, Fiser RH Jr. PMID: 4994183 [PubMed - indexed for MEDLINE] 7729. Nutr Rev. 1970 Aug;28(8):214-5. Lipogenesis from carbohydrate--an energy-yielding process for the adipose cell. [No authors listed] PMID: 4920164 [PubMed - indexed for MEDLINE] 7730. N Engl J Med. 1970 Jul 30;283(5):237-46. Carbohydrate homeostasis. Levine R, Haft DE. PMID: 4912791 [PubMed - indexed for MEDLINE] 7731. Circ Res. 1970 Jul;27(1 Suppl 1):147-61. Sympathin E, sympathin I, and the intracellular level of cyclic AMP. Robison GA, Sutherland EW. PMID: 4393715 [PubMed - indexed for MEDLINE] 7732. Pathol Biol (Paris). 1970 May;18(9):551-8. [Biochemical study of Refsum's disease]. [Article in French] Sezille G, Biserte G. PMID: 4192793 [PubMed - indexed for MEDLINE] 7733. N Y State J Med. 1970 Mar 1;70(5):668-70. Significance of meal frequency in man. Fábry P. PMID: 4905747 [PubMed - indexed for MEDLINE] 7734. Annee Biol. 1970 Mar-Apr;9(3):157-88. [Brown fat]. [Article in French] Boulouard R. PMID: 4316351 [PubMed - indexed for MEDLINE] 7735. Curr Probl Surg. 1970 Mar:1-60. Tumors and tumor-like conditions of the adipose tissue. Das Gupta TK. PMID: 4190913 [PubMed - indexed for MEDLINE] 7736. Vestn Khir Im I I Grek. 1970 Feb;104(2):139-42. [Fat embolism (review of Soviet and foreign literature)]. [Article in Russian] Egurnov NI, Tsybuliak GN, Pron'ko VM. PMID: 4914174 [PubMed - indexed for MEDLINE] 7737. Pediatrics. 1970 Feb;45(2):315-34. Cellular growth, nutrition and development. Cheek DB, Graystone JE, Read MS. PMID: 4905111 [PubMed - indexed for MEDLINE] 7738. Tidsskr Nor Laegeforen. 1970 Jan 25;90(2):197-202. [Enzymatic views on obesity]. [Article in Swedish] Pedersen JI. PMID: 4914232 [PubMed - indexed for MEDLINE] 7739. Vestn Akad Med Nauk SSSR. 1970;25(10):20-31. [Chronic infection and antiviral cellular immunity]. [Article in Russian] Solov'ev VD, Khesin IaE. PMID: 5499585 [PubMed - indexed for MEDLINE] 7740. Folia Med Neerl. 1970;13(5):171-6. Proinsulin. Touber JL. PMID: 4992534 [PubMed - indexed for MEDLINE] 7741. J Clin Pathol Suppl (R Coll Pathol). 1970;4:65-72. Tissue fuel and weight loss after injury. Kinney JM, Duke JH Jr, Long CL, Gump FE. PMCID: PMC1519990 PMID: 4950033 [PubMed - indexed for MEDLINE] 7742. Horm Metab Res. 1970;2:Suppl 2:143-51. Pathways of lipid synthesis and their regulation in rat epididymal fat cells. Dneton RM, Martin BR. PMID: 4949429 [PubMed - indexed for MEDLINE] 7743. Horm Metab Res. 1970;2:Suppl 2:136-42. The physiological function and regulation of lycerogenesis in adipose tissue. Reshef L, Shapiro B. PMID: 4949428 [PubMed - indexed for MEDLINE] 7744. Horm Metab Res. 1970;2:Suppl 2:93-101. Energy metabolism and the control of lipogenesis in adipose tissue. Flatt JP. PMID: 4949051 [PubMed - indexed for MEDLINE] 7745. Horm Metab Res. 1970;2:Suppl 2:63-5. The role of ions in the hormonal control of adipose tissue. Hales CN, Perry MC. PMID: 4949050 [PubMed - indexed for MEDLINE] 7746. Horm Metab Res. 1970;2:Suppl 2:41-6. Regulation of adipose tissue clearing factor lipase activity. Robinson DS, Wing DR. PMID: 4949049 [PubMed - indexed for MEDLINE] 7747. Horm Metab Res. 1970;2:Suppl 2:196-20. Interrelationship between adipose tissue and liver: gluconeogenesis and ketogenesis. Weiss L, Löffler G. PMID: 4949047 [PubMed - indexed for MEDLINE] 7748. Horm Metab Res. 1970;2:Suppl 2:181-5. Fat and nitrogen metabolism in fasting man. Cahill GF Jr, Marliss EB, Aoki TT. PMID: 4949046 [PubMed - indexed for MEDLINE] 7749. Horm Metab Res. 1970;2:Suppl 2:130-5. Regulatory aspects in carbohydrate metabolism of adipose tissue: glycolysis, glycogen synthesis, and glyceroneogenesis. Shafrir E, Gutman A, Gorin E, Orevi M. PMID: 4949045 [PubMed - indexed for MEDLINE] 7750. Horm Metab Res. 1970;2:Suppl 2:125-9. Nutritional and hormonal regulation of DNA synthesis in rat adipose tissue. Hollenberg CH, Vost A. PMID: 4949044 [PubMed - indexed for MEDLINE] 7751. Vitam Horm. 1970;28:345-63. Tricarboxylic acid activator-induced changes at the active site of acetyl-CoA carboxylase. Lane MD, Edwards J, Stoll E, Moss J. PMID: 4946806 [PubMed - indexed for MEDLINE] 7752. Adv Enzyme Regul. 1970;9:237-51. The activation of acetyl CoA carboxylase by tricarboxylic acids. Lane MD, Moss J, Ryder E, Stoll E. PMID: 4938678 [PubMed - indexed for MEDLINE] 7753. Ann Nutr Aliment. 1970;24(5):75-144. [Fats with short and medium chains. Physiological, biochemical, nutritional, and therapeutic aspects]. [Article in French] Bach A, Métais P. PMID: 4926121 [PubMed - indexed for MEDLINE] 7754. World Rev Nutr Diet. 1970;12:1-42. Nutritional and epidemiologic factors related to heart disease. Brown J, Bourke GJ, Gearty GF, Finnegan A, Hill M, Heffernan-Fox FC, Fitzgerald DE, Kennedy J, Childers RW, Jessop WJ, Trulson MF, Latham MC, Cronin S, McCann MB, Clancy RE, Gore I, Stoudt HW, Hegsted DM, Stare FJ. PMID: 4924054 [PubMed - indexed for MEDLINE] 7755. Annee Endocrinol. 1970;22:193-212. [Recent studies on obesity]. [Article in French] Albeaux-Fernet M, Bellot L, Canet L, Deribreux J, Gelinet M. PMID: 4922077 [PubMed - indexed for MEDLINE] 7756. Adv Enzyme Regul. 1970;8:131-51. Regulation of metabolic processes in brown adipose tissue in relation to nonshivering thermogenesis. Himms-Hagen J. PMID: 4920377 [PubMed - indexed for MEDLINE] 7757. Adv Pediatr. 1970;17:99-123. Human growth hormone: current knowledge regarding its role in normal and abnormal metabolic states. Raiti S, Blizzard RM. PMID: 4919953 [PubMed - indexed for MEDLINE] 7758. Recent Prog Horm Res. 1970;26:287-308. Multiple hormone interactions in the development of mammary gland in vitro. Topper YJ. PMID: 4919093 [PubMed - indexed for MEDLINE] 7759. Ann Biol Clin (Paris). 1970;28(2):115-9. [The metabolism of adipose tissue in normal man and in various metabolic disorders. I. Metabolism of normal human adipose tissue]. [Article in French] Sezille G, Jaillard J, Biserte G. PMID: 4915931 [PubMed - indexed for MEDLINE] 7760. Annu Rev Pharmacol. 1970;10:353-78. Persistent pesticides. Robinson J. PMID: 4914354 [PubMed - indexed for MEDLINE] 7761. Rev Iber Endocrinol. 1970 Jan-Feb;17(97):31-46. [Current hypothesis concerning the physiological role of glucagon]. [Article in Spanish] Fernández-Cruz Pérez. PMID: 4912258 [PubMed - indexed for MEDLINE] 7762. Naika. 1970;25(5):858-64. [Weber-Christian disease, with special reference to its concept and histological factors]. [Article in Japanese] Nishiyama S. PMID: 4912156 [PubMed - indexed for MEDLINE] 7763. Annu Rev Physiol. 1970;32:313-44. Systemic circulation: local control. Mellander S. PMID: 4906123 [PubMed - indexed for MEDLINE] 7764. Horm Metab Res. 1970;2:Suppl 2:5-10. The role of cyclic AMP in the actions of some lipolytic and anti-lipolytic agents. Butcher RW. PMID: 4403191 [PubMed - indexed for MEDLINE] 7765. Horm Metab Res. 1970;2:Suppl 2:55-62. Adrenotropic drugs in lipid mobilization. Wenke M. PMID: 4403190 [PubMed - indexed for MEDLINE] 7766. Horm Metab Res. 1970;2:Suppl 2:47-54. Inhibitors of lipolysis: potency and mode of action of - and -adrenolytics, methoxamine derivatives, prostaglandin E 1 and phenylisopropyl adenosine. Westermann E, Stock K. PMID: 4403189 [PubMed - indexed for MEDLINE] 7767. Horm Metab Res. 1970;2:Suppl 2:71-5. Cations and lipolytic activity in rat adipose tissue. Mosinger B. PMID: 4340428 [PubMed - indexed for MEDLINE] 7768. Horm Metab Res. 1970;2:Suppl 2:66-70. Electrolytes and the hormonal control of organic metabolism in adipocytes. Clausen T. PMID: 4340427 [PubMed - indexed for MEDLINE] 7769. Horm Metab Res. 1970;2:Suppl 2:32-6. Lipase activities in adipose tissue. Löffler G, Weiss L. PMID: 4340426 [PubMed - indexed for MEDLINE] 7770. Horm Metab Res. 1970;2:Suppl 2:20-7. The involvement of RNA synthesis and cyclic AMP in the activation of fat cell lipolysis by growth hormone and glucocorticoids. Fain JN, Saperstein R. PMID: 4340424 [PubMed - indexed for MEDLINE] 7771. Horm Metab Res. 1970;2:Suppl 2:1-4. The fat cell in mid-term: its past and future. Rodbell M. PMID: 4340423 [PubMed - indexed for MEDLINE] 7772. Horm Metab Res. 1970;2:Suppl 2:167-71. Hormonal control of human adipose tissue metabolism in vitro. Gries FA. PMID: 4340421 [PubMed - indexed for MEDLINE] 7773. Horm Metab Res. 1970;2:Suppl 2:11-9. Comparative study of hormonal regulation of adenyl cyclase activity in rat and rabbit fat cell membranes. Braun T, Hechter O. PMID: 4340418 [PubMed - indexed for MEDLINE] 7774. Horm Metab Res. 1970;2:Suppl 2:112-5. Effects of insulin and substances having insulin-like activity on adipose cells: sugar utilization, lipolysis, adenyl cyclase-cyclic AMP system and cyclic AMP-dependent protein kinase. Kuo JF. PMID: 4340417 [PubMed - indexed for MEDLINE] 7775. Horm Metab Res. 1970;2:Suppl 2:102-7. Some considerations of the multiplicity of insulin action on adipose tissue. Ball EG. PMID: 4340415 [PubMed - indexed for MEDLINE] 7776. Adv Biochem Psychopharmacol. 1970;3:209-16. Cyclic 3',5' -adenosine monophosphate and the effects of hormones on hormone sensitive lipase from adipose tissue. Appleman MM, Sevilla CL. PMID: 4331456 [PubMed - indexed for MEDLINE] 7777. Adv Biochem Psychopharmacol. 1970;3:173-83. Prostaglandins and cyclic AMP. Butcher RW. PMID: 4331455 [PubMed - indexed for MEDLINE] 7778. Adv Enzyme Regul. 1970;8:219-38. Insulin-receptor interaction in isolated fat cells. Crofford OB, Minemura T, Kono T. PMID: 4320026 [PubMed - indexed for MEDLINE] 7779. Recent Prog Horm Res. 1970;26:463-503. Regulation of adipose mass: control of fat cell development and lipid content. Hollenberg CH, Vost A, Patten RL. PMID: 4319351 [PubMed - indexed for MEDLINE] 7780. Recent Prog Horm Res. 1970;26:139-87. Biological significance of the prostaglandins. Ramwell PW, Shaw JE. PMID: 4319349 [PubMed - indexed for MEDLINE] 7781. Adv Metab Disord. 1970;4:229-96. Metabolic aspects of obesity. Gordon ES. PMID: 4247986 [PubMed - indexed for MEDLINE] 7782. Postgrad Med J. 1969 Dec:Suppl:812+. The development of ideas about the mode of action of insulin. Young FG. PMID: 4313996 [PubMed - indexed for MEDLINE] 7783. Tanpakushitsu Kakusan Koso. 1969 Dec;14(14):1432-41. [Thyroid hormone and catecholamines]. [Article in Japanese] Tomita K. PMID: 4313682 [PubMed - indexed for MEDLINE] 7784. Diabetologia. 1969 Dec;5(6):361-5. Antilipolysis as a tool in the study of clinical and experimental diabetes. Lecture for the 1968 Minkowski Award. Carlson LA. PMID: 4313598 [PubMed - indexed for MEDLINE] 7785. Dan Med Bull. 1969 Sep:Suppl 7:1-64. Insulin in serum. Gjedde F. PMID: 4988523 [PubMed - indexed for MEDLINE] 7786. Food Cosmet Toxicol. 1969 Sep;7(5):501-14. Estimation of the exposure of the general population to dieldrin (HEOD). Robinson J, Roberts M. PMID: 4902881 [PubMed - indexed for MEDLINE] 7787. Mo Med. 1969 Sep;66(9):719-23 passim. The management of obesity: some recent concepts. Weinhaus RS. PMID: 4897933 [PubMed - indexed for MEDLINE] 7788. Turk J Pediatr. 1969 Jul;11(3):132-9. Encephalopathy and fatty degeneration of the viscera (Reye's syndrome): report of a case and brief review of the literature. Tinaztepe K, Baykara E, Yalaz K. PMID: 5371155 [PubMed - indexed for MEDLINE] 7789. Ala J Med Sci. 1969 Jul;6(3):275-84. Factors affecting obesity. Foster ME. PMID: 4897054 [PubMed - indexed for MEDLINE] 7790. Seikagaku. 1969 Jul;41(7):309-24. [ATP citrate lyase]. [Article in Japanese] Takeda Y. PMID: 4311922 [PubMed - indexed for MEDLINE] 7791. Union Med Can. 1969 May;98(5):781-96. [Obesity: general review]. [Article in French] Vinay P, Pesant P, Beauregard HF, Bernier J, Dufault C. PMID: 4919193 [PubMed - indexed for MEDLINE] 7792. Dan Med Bull. 1969 May;16:Suppl 4:1-42. Action of insulin on isolated fat cells. Gliemann J. PMID: 4913074 [PubMed - indexed for MEDLINE] 7793. Nutr Rev. 1969 May;27(5):146-9. Cellularity of rat adipose tissue in relation to growth, starvation, and obesity. [No authors listed] PMID: 4893713 [PubMed - indexed for MEDLINE] 7794. Physiol Rev. 1969 Apr;49(2):330-425. Brown fat and thermogenesis. Smith RE, Horwitz BA. PMID: 4888392 [PubMed - indexed for MEDLINE] 7795. Sem Hop. 1969 Mar 14;45(13):827-39. [Subacute and chronic pancreatitis, massive ascites and subcutaneous fatty necrosis: 2 cases; review of the literature]. [Article in French] Debray C, Hardouin JP, Leymarios J, Gouin B, Modigliani R, Marche C. PMID: 4327256 [PubMed - indexed for MEDLINE] 7796. Food Cosmet Toxicol. 1969 Mar;7(2):175-81. Pesticides turning the corner? [No authors listed] PMID: 4917479 [PubMed - indexed for MEDLINE] 7797. Nutr Rev. 1969 Mar;27(3):82-5. Absorption and utilization of glucose by rats fed once daily or ad libitum. [No authors listed] PMID: 4891094 [PubMed - indexed for MEDLINE] 7798. Saishin Igaku. 1969 Mar;24(3):534-43. [Spontaneous diabetes mellitus in animals]. [Article in Japanese] Nakamura M, Yamada K. PMID: 4890888 [PubMed - indexed for MEDLINE] 7799. Arch Intern Med. 1969 Mar;123(3):314-22. Appraisal of the extrapancreatic actions of sulfonylureas. Feldman JM, Lebovitz HE. PMID: 4885677 [PubMed - indexed for MEDLINE] 7800. Arch Intern Med. 1969 Mar;123(3):299-313. Role of free fatty acids in glucose homeostasis. Ruderman NB, Toews CJ, Shafrir E. PMID: 4303992 [PubMed - indexed for MEDLINE] 7801. Postgrad Med J. 1969 Feb;45(520):107-15. Protein deficiency disorders. Vis HL. PMCID: PMC2466554 PMID: 4891572 [PubMed - indexed for MEDLINE] 7802. Australas Ann Med. 1969 Feb;18(1):1-3. Obesity and diabetes. [No authors listed] PMID: 4887675 [PubMed - indexed for MEDLINE] 7803. Nutr Rev. 1969 Feb;27(2):59-61. Lipogenesis in fat cells from genetically obese rats. [No authors listed] PMID: 4886512 [PubMed - indexed for MEDLINE] 7804. Adv Biochem Psychopharmacol. 1969;1:219-38. On mechanisms of norepinephrine release by amphetamine and tyramine and tolerance to their effects. Brodie BB, Cho AK, Stefano FJ, Gessa GL. PMID: 4947255 [PubMed - indexed for MEDLINE] 7805. Arkh Patol. 1969;31(9):3-12. [Evolution of concepts on the pathogenesis of diabetes mellitus]. [Article in Russian] Genes SG. PMID: 4908635 [PubMed - indexed for MEDLINE] 7806. Residue Rev. 1969;29:51-60. Accelerated removal of pesticides from domestic animals. Liska BJ, Stadelman WJ. PMID: 4900807 [PubMed - indexed for MEDLINE] 7807. Residue Rev. 1969;27:43-79. On the problem of the harmful effect of DDT and its mechanism of action. Kagan YS, Fudel-Ossipova SI, Khaikina BJ, Kuzminskaya UA, Kouton SD. PMID: 4898339 [PubMed - indexed for MEDLINE] 7808. Ann N Y Acad Sci. 1969;160(1):274-90. VI. Biochemical and pathological effects. Organochlorine insecticides and the stimulation of liver microsome enzymes. Street JC. PMID: 4897063 [PubMed - indexed for MEDLINE] 7809. Ann N Y Acad Sci. 1969;160(1):183-95. Body burden of pesticides in man. Durham WF. PMID: 4896087 [PubMed - indexed for MEDLINE] 7810. Nutr Rev. 1969 Jan;27(1):23-4. Factors affecting the cellularity of adipose tissue. [No authors listed] PMID: 4888670 [PubMed - indexed for MEDLINE] 7811. Fed Proc. 1969 Jan-Feb;28(1):218-31. Gluconeogenesis and lipogenesis in tissue from ruminant and nonruminant animals. Ballard FJ, Hanson RW, Kronfeld DS. PMID: 4884664 [PubMed - indexed for MEDLINE] 7812. Am J Clin Nutr. 1968 Dec;21(12):1455-70. Endocrine and metabolic adaptation to obesity and starvation. Sims EA, Horton ES. PMID: 4881681 [PubMed - indexed for MEDLINE] 7813. Horumon To Rinsho. 1968 Nov;16(11):855-62. [Progesterone]. [Article in Japanese] Tokuda G, Okada K. PMID: 4886772 [PubMed - indexed for MEDLINE] 7814. Acta Hepatosplenol. 1968 Nov-Dec;15(6):361-76. [Problems of metabolism regulation in the liver. IV. On the mechanism of action of various hormones]. [Article in German] Holldorf AW, Förster E, Falk H. PMID: 4885533 [PubMed - indexed for MEDLINE] 7815. Proc R Soc Med. 1968 Nov;61(11 Pt 2):1231-6. Metabolic fuels in the foetus. Schwartz R. PMCID: PMC1902671 PMID: 4882058 [PubMed - indexed for MEDLINE] 7816. Naturwissenschaften. 1968 Oct;55(10):470-7. [On the dissemination of pesticides]. [Article in German] Maier-Bode H. PMID: 4883028 [PubMed - indexed for MEDLINE] 7817. Bordens Rev Nutr Res. 1968 Sep-Dec;29:41-54. Nutrition, body fat and physical fitness. Parízková J. PMID: 4892519 [PubMed - indexed for MEDLINE] 7818. ANL Rep. 1968 Jul:73-90. Body composition estimates derived from potassium measurements. ANL-7461. Remenchik AP, Miller CE, Kessler WV. PMID: 4896533 [PubMed - indexed for MEDLINE] 7819. Z Gesamte Inn Med. 1968 Jul 1;23(13):207-8 contd. [On various recent viewpoints on the etiology and pathogenesis of diabetes mellitus]. [Article in German] Schöffling K. PMID: 4879352 [PubMed - indexed for MEDLINE] 7820. Anesthesiology. 1968 Jul-Aug;29(4):702-13. The autonomic nervous system and intermediary carbohydrate and fat metabolism. Havel RJ. PMID: 4874155 [PubMed - indexed for MEDLINE] 7821. Lakartidningen. 1968 Jun 19;65(25):2586-95. [The possibilities to study the function of the human cells in clinical cell research]. [Article in Swedish] Björkerud S, Björntorp P, Scherstén T. PMID: 4305287 [PubMed - indexed for MEDLINE] 7822. Dtsch Med J. 1968 Jun 5;19(11):421-5. [Clinical picture and treatment of obesity]. [Article in German] Henning H. PMID: 4894531 [PubMed - indexed for MEDLINE] 7823. Act Nerv Super (Praha). 1968 May;10(2):232-40. [Some metabolic correlates of emotional stress]. [Article in Czech] Hrubes V. PMID: 4883401 [PubMed - indexed for MEDLINE] 7824. Nihon Rinsho. 1968 Apr;26(4):841-9. [Significance of nutrition in cardiovascular diseases]. [Article in Japanese] Kimura N, Kodama S, Nakayama Y, Nambu S. PMID: 4879390 [PubMed - indexed for MEDLINE] 7825. Rev Fr Etud Clin Biol. 1968 Apr;13(4):329-40. [Recent data on the phenomena of lipolysis in adipose tissue]. [Article in French] Combret Y, Laudat P. PMID: 4300788 [PubMed - indexed for MEDLINE] 7826. J Atheroscler Res. 1968 Mar-Apr;8(2):197-9. The origin and significance of the changes in the lipids of vascular tissue with age. Mith EB. PMID: 4874488 [PubMed - indexed for MEDLINE] 7827. Nutr Rev. 1968 Feb;26(2):49-51. Utilization of glucose and palmitic acid in adipose tissue of rats deficient in essential fatty acids. [No authors listed] PMID: 4867316 [PubMed - indexed for MEDLINE] 7828. Essays Biochem. 1968;4:155-212. The catabolism of long chain fatty acids in mammalian tissues. Greville GD, Tubbs PK. PMID: 4895802 [PubMed - indexed for MEDLINE] 7829. Residue Rev. 1968;24:19-39. Pesticides in blood. Schafer ML. PMID: 4880907 [PubMed - indexed for MEDLINE] 7830. Bordens Rev Nutr Res. 1968;29:1-13. Obesity in childhood. Goldbloom RG. PMID: 4880875 [PubMed - indexed for MEDLINE] 7831. Ann Nutr Aliment. 1968;22(3):Suppl:93-128. [The fate of antioxidants in the organism and the biologic role of selenium]. [Article in French] Loriette C, Raulin J. PMID: 4877495 [PubMed - indexed for MEDLINE] 7832. Annu Rev Physiol. 1968;30:147-70. Systemic circulation: local control. Sonnenschein RR, White FN. PMID: 4873160 [PubMed - indexed for MEDLINE] 7833. Ann Endocrinol (Paris). 1968 Jan-Feb;29(1):21-8. [Physiological effects of cortisol]. [Article in French] Leboeuf B, Durocher JG. PMID: 4872636 [PubMed - indexed for MEDLINE] 7834. Adv Enzyme Regul. 1968;6:357-89. The role of cyclic AMP in hormone actions. Butcher RW, Robison GA, Hardman JG, Sutherland EW. PMID: 4306736 [PubMed - indexed for MEDLINE] 7835. Recent Prog Horm Res. 1968;24:215-54. The actions of insulin and catabolic hormones on the plasma membrane of the fat cells. Rodbell M, Jones AB, Chiappe de Cingolani GE, Birnbaumer L. PMID: 4302429 [PubMed - indexed for MEDLINE] 7836. Ergeb Physiol. 1968;60:57-140. Adipose tissue dynamics and regulation, revisited. Jeanrenaud B. PMID: 4298672 [PubMed - indexed for MEDLINE] 7837. Presse Med. 1967 Dec 2;75(51):2605-10. [Review of the metabolic and endocrine examination of a case of lipoatrophic diabetes]. [Article in French] de Gennes JL, Saltiel H, Tremolieres J, Appelbaum M, Laudat P. PMID: 6075022 [PubMed - indexed for MEDLINE] 7838. Cesk Fysiol. 1967 Nov;16(6):526-40. [Significance of the sympathetic nervous system for the mobilization of fatty acids from adipose tissue]. [Article in Czech] Wenke M. PMID: 4876735 [PubMed - indexed for MEDLINE] 7839. Cesk Fysiol. 1967 Nov;16(6):584-92. [Effect of movement activity on the metabolism of adipose tissue]. [Article in Czech] Parízková J, Rath R, Stanková L, Koutecký Z, Kohout M. PMID: 4875163 [PubMed - indexed for MEDLINE] 7840. Cesk Fysiol. 1967 Nov;16(6):578-83. [Nutritional state and metabolism of adipose tissue]. [Article in Czech] Braun T, Kazdová L, Fábry P, Vrána A. PMID: 4875162 [PubMed - indexed for MEDLINE] 7841. Cesk Fysiol. 1967 Nov;16(6):541-64. [Enzymes of adipose tissue participating in the mobilization of nonesterified fatty acids]. [Article in Czech] Hynie S. PMID: 4875161 [PubMed - indexed for MEDLINE] 7842. Nutr Rev. 1967 Oct;25(10):313-5. Effects of feeding frequency on fat and protein deposition in pigs. [No authors listed] PMID: 4861853 [PubMed - indexed for MEDLINE] 7843. Klin Wochenschr. 1967 Sep 15;45(18):905-17. [The physiological role of adipose tissue]. [Article in German] Brech WJ, Gordon ES. PMID: 4297570 [PubMed - indexed for MEDLINE] 7844. Saishin Igaku. 1967 Aug;22(8):1755-66. [Pediatric nutrition and lipids]. [Article in Japanese] Usui T, Sudo M. PMID: 4868631 [PubMed - indexed for MEDLINE] 7845. Saishin Igaku. 1967 Aug;22(8):1655-65. [Insulin reaction in the fatty tissue--problems in the cell permeability of glucose]. [Article in Japanese] Tarui S, Saito Y. PMID: 4866154 [PubMed - indexed for MEDLINE] 7846. Nutr Rev. 1967 Aug;25(8):252-4. Thyroid status and adipose tissue lipolysis. [No authors listed] PMID: 4864216 [PubMed - indexed for MEDLINE] 7847. Saishin Igaku. 1967 Aug;22(8):1666-77. [Enzyme system in fatty acid mobilization]. [Article in Japanese] Fujii S, Okuda H. PMID: 4295247 [PubMed - indexed for MEDLINE] 7848. Science. 1967 Jul 28;157(3787):382-91. Prostaglandins: members of a new hormonal system. These physiologically very potent compounds of ubiquitous occurrence are formed from essential fatty acids. Bergström S. PMID: 4291104 [PubMed - indexed for MEDLINE] 7849. Usp Sovrem Biol. 1967 Jul-Aug;64(1):136-50. [Physiologic importance of brown fat]. [Article in Russian] Berkovich EM. PMID: 4911730 [PubMed - indexed for MEDLINE] 7850. Farmaco Sci. 1967 Jul;22(7):543-71. The regulation of lipid synthesis in adipose tissue. Porcellati G. PMID: 4864082 [PubMed - indexed for MEDLINE] 7851. Cesk Pediatr. 1967 May;22(5):477-8. [Brown adipose tissue and its significance in thermoregulation]. [Article in Czech] Straková M. PMID: 4866456 [PubMed - indexed for MEDLINE] 7852. Science. 1967 Apr 21;156(3773):328-37. Regulation of food intake and obesity. Mayer J, Thomas DW. This is not the place to consider the medical significance of obesity in terms of conditions such as heart disease and hypertension, diabetes, and arthritis. These very complex interrelationships have been dealt with elsewhere (69). We hope that enough evidence has been presented to demonstrate that energy balance is normally maintained by a precise and reliable physiologic mechanism, and that the energy surplus represented by obesity may reflect direct failure of this mechanism or some combination from a variety of neurological, endocrine, enzymatic, and psychological disorders. Environmental conditions as well as genetic and traumatic factors may contribute to the development of obesity. If increasing mechanization brings tus below the level of energy expenditure at which food intake is properly regulated, appropriate habits of exercise will have to be established and maintained. PMID: 4886532 [PubMed - indexed for MEDLINE] 7853. Naturwissenschaften. 1967 Apr;54(7):156-62. [Importance of brown adipose tissue for temperature regulation in the newborn and cold-adapted mammal]. [Article in German] Brück K. PMID: 4385280 [PubMed - indexed for MEDLINE] 7854. Diabetologia. 1967 Apr;3(2):65-73. The colony of Chinese hamsters of the C.H. Best Institute. A review of experimental work. Sirek OV, Sirek A. PMID: 4244685 [PubMed - indexed for MEDLINE] 7855. Nutr Rev. 1967 Mar;25(3):68-71. Dietary intake and fat storage of pesticides. [No authors listed] PMID: 5343316 [PubMed - indexed for MEDLINE] 7856. Toxicol Appl Pharmacol. 1967 Mar;10(3):613-75. Toxicology and no-effect levels of aldrin and dieldrin. Hodge HC, Boyce AM, Deichmann WB, Kraybill HF. PMID: 4964063 [PubMed - indexed for MEDLINE] 7857. Nutr Rev. 1967 Jan;25(1):28-9. Acetate metabolism in ruminant tissues. [No authors listed] PMID: 5341518 [PubMed - indexed for MEDLINE] 7858. Recent Prog Horm Res. 1967;23:565-616. Nonsuppressible insulinlike activity of human serum: purification, physiochemical and biological properties and its relation to total serum ILA. Froesch ER, Bürgi H, Müller WA, Humbel RE, Jakob A, Labhart A. PMID: 4876486 [PubMed - indexed for MEDLINE] 7859. Annee Endocrinol. 1967;19:111-5. 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